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8. Nicotinamide as a repair inhibitor in vivo: single and fractionated X-ray dose studies in mouse skin and kidneys

Author

Rojas, Ana Maria, Denekamp, J, Johns, H, Kjellen, E, Tsang, R, Nilsson, P, Stratford, M R L, Dennis, M F, Joiner, M C, Rojas, Ana Maria, Denekamp, J, Johns, H, Kjellen, E, Tsang, R, Nilsson, P, Stratford, M R L, Dennis, M F, and Joiner, M C

Abstract

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced

Published
1996

16. Pharmacokinetics and biochemistry studies on nicotinamide in the mouse.

Author

Stratford, Michael, Dennis, Madeleine, Stratford, M R, and Dennis, M F

Subjects
ANIMAL experimentation, BIOAVAILABILITY, BIOTRANSFORMATION (Metabolism), COMPARATIVE studies, DOSE-effect relationship in pharmacology, HIGH performance liquid chromatography, INJECTIONS, RESEARCH methodology, MEDICAL cooperation, MICE, RESEARCH, SEROTONIN, TIME, TUMORS, VITAMIN B complex, EVALUATION research
Abstract

Nicotinamide sensitizes murine tumours to the effect of radiation, but the pharmacokinetics are not well characterized at doses that are achievable in humans. In the mouse, nicotinamide given i.p. at doses of 100-500 mg/kg showed biphasic elimination with dose-dependent changes in half-life. The initial half-life increased significantly (P < 0.05) from 0.8 to 2 h and the terminal half-life increased from 3.4 to 5.6 h over the dose range studied. Clearance, however, decreased significantly from 0.3 to 0.24 l kg-1 h-1 only at the highest dose. Peak concentrations increased in a dose-dependent manner from 1,000 to 4,800 nmol/ml. The main plasma metabolite in the mouse is nicotinamide N-oxide, the peak concentration of which increased only from 80 to 160 nmol/ml. The N-oxide, which is also a weak radiosensitizer, is subject to reduction to the parent nicotinamide following administration at a dose of 276 mg/kg; peak concentrations of the N-oxide of 1900 nmol/ml were reached in 10 min, whereas concentrations of nicotinamide produced by reduction reached a maximum of 144 nmol/ml at 1 h. Elimination of the N-oxide was also biphasic, with initial and terminal half-lives being 0.39 and 1.8 h, respectively. The bioavailability of both drugs given via the i.p. as compared with the i.v. route was close to 100%. Tumour concentrations of nicotinamide paralleled those in the plasma after a short lag. Tumour nicotinamide adenine dinucleotide (NAD) concentrations were elevated by factors of 1.5 and 1.8 following doses of 100 and 500 mg/kg nicotinamide, respectively. Maximal concentrations were seen after 3-6 h, but levels remained elevated for 16 h. No change in tumour energy charge or in plasma 5-hydroxytryptamine was detected following a dose of 500 mg/kg nicotinamide. [ABSTRACT FROM AUTHOR]

Published
1994
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17. Localisation of receptors that initiate reflex vascular responses to vasoactive substances

Author

Dennis M. F. Li and Geoffrey A. Bentley

Subjects
Male, Epinephrine, Sensory Receptor Cells, Physiology, Dopamine, Vasodilator Agents, Clinical Biochemistry, Subclavian Artery, Aorta, Thoracic, Blood Pressure, Hindlimb, Kidney, Veratrine, chemistry.chemical_compound, Physiology (medical), medicine.artery, Reflex, medicine, Animals, Vasoconstrictor Agents, Thoracic aorta, Receptor, Aorta, business.industry, Angiotensin II, Carotid sinus, Vagus Nerve, Anatomy, Perfusion, Vasomotor System, Carotid Sinus, medicine.anatomical_structure, Injections, Intra-Arterial, chemistry, Injections, Intravenous, Cats, Female, medicine.symptom, business, Vasoconstriction, Histamine
Abstract

1. An attempt was made to localise the receptor mechanism that elicits hindlimb vascular reflexes in response to intravenously injected vasoactive substances. Cats were used, anaesthetised with pentobarbitone and with hindquarters autoperfused through a delay circuit. Various modifications of this preparation were made, including those with additional delay circuits in other vascular beds. 2. It was confirmed that neither the carotid sinus mechanism nor receptors innervated by the vagus were important in governing these reflex responses. 3. When vasoactive drugs were given by close intra-arterial injection into selected vascular beds, it was shown that receptors in the central nervous system, along the great arteries of the head and neck, and in the visceral and renal circulations were not essential to the hindquarter reflexes. 4. When preparations were used in which the descending thoracic aorta was autoperfused retrogradely through the coeliac artery, it was found that intravenous injections of adrenaline or histamine produced reflex hindlimb responses before they reached this part of the aorta. This suggested that the most proximal part of the aorta from its junction with the heart to the origin of the left subclavian artery is an important site of receptors. It was also shown, however, that when the pressure in the descending thoracic aorte between the left subclavian and the coeliac artery was lowered mechanically, hindlimb vasoconstriction occurred. It would thus appear that the whole length of the thoracic aorta contains receptors for these reflexes. 5. By using another preparation with a delay circuit supplying the renal beds, reflex vascular responses have been demonstrated in the kidneys in response to intravenously injected vasoactive drugs.

Published
1971

21. Cellular Uptake of Misonidazole and Analogues with Acidic or Basic Functions

Author

Dennis, M. F., Stratford, M. R. L., Wardman, P., and Watts, M. E.

Abstract

Average intracellular concentrations of five radiosensitizers in hamster fibroblast-like V79-379A cells in vitro were measured by high performance liquid chromatography, varying the extracellular pH (pHe) and estimating the apparent intracellular pH from the distribution of 5,5-dimethyloxazolidine-2,4-dione. The intracellular: extracellular concentration ratio for the 2-nitroimidazole, misonidazole was constant at about 0·7 for pHe = 6·6-7·6, whereas the weak base, Ro 03-8799 (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propanol) was concentrated intracellularly at pHe = 7·3-7·4 by a factor of 3·3, the factor increasing from about 0·8 at pHe = 6·0, to 7·5 at pHe = 7·85. The weak acid, azomycin (2-nitroimidazole) showed approximately constant uptake (factor 1·1) between pHe = 6·0-7·0, decreasing to 0·8 at pHe = 7·3 and 0·4 at pHe = 7·8. Measurements of intracellular uptake of Ro 31-0052 (the more hydrophilic and less basic 3'-hydroxypiperidino analogue of Ro 03-8799) and of Ro 31-0258 (3-(2-nitro-1-imidazolyl)propionic acid, a stronger acid than azomycin) were made for comparison. The results were compared with theoretical calculations of pH-induced concentration gradients; the time dependence of the uptake of the bases is not at present clearly understood. These measurements of uptake are broadly consistent with the distribution of misonidazole and Ro 03-8799 in human and animal tissues and provide a useful insight into the likely intracellular concentrations in the clinical use of Ro 03-8799 or other basic radiosensitizers. The measurements also resolve the apparent discrepancy in radiosensitizer efficiency for weak bases in vitro and in vivo which has been previously noted.

Published
1985
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22. Indolequinone Antitumor Agents:  Reductive Activation and Elimination from (5-Methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl Derivatives and Hypoxia-Selective Cytotoxicity in Vitro

Author

Naylor, M. A., Swann, E., Everett, S. A., Jaffar, M., Nolan, J., Robertson, N., Lockyer, S. D., Patel, K. B., Dennis, M. F., Stratford, M. R. L., Wardman, P., Adams, G. E., Moody, C. J., and Stratford, I. J.

Abstract

A series of indolequinones bearing a variety of leaving groups at the (indol-3-yl)methyl position was synthesized by functionalization of the corresponding 3-(hydroxymethyl)indolequinone, and the resulting compounds were evaluated in vitro as bioreductively activated cytotoxins. The elimination of a range of functional groups&sbd;carboxylate, phenol, and thiol&sbd;was demonstrated upon reductive activation under both chemical and quantitative radiolytic conditions. Only those compounds which eliminated such groups under both sets of conditions exhibited significant hypoxia selectivity, with anoxic:oxic toxicity ratios in the range 10−200. With the exception of the 3-hydroxymethyl derivative, radiolytic generation of semiquinone radicals and HPLC analysis indicated that efficient elimination of the leaving group occurred following one-electron reduction of the parent compound. The active species in leaving group elimination was predominantly the hydroquinone rather than the semiquinone radical. The resulting iminium derivative acted as an alkylating agent and was efficiently trapped by added thiol following chemical reduction and by either water or 2-propanol following radiolytic reduction. A chain reaction in the radical-initiated reduction of these indolequinones (not seen in a simpler benzoquinone) in the presence of a hydrogen donor (2-propanol) was observed. Compounds that were unsubstituted at C-2 were found to be up to 300 times more potent as cytotoxins than their 2-alkyl-substituted analogues in V79-379A cells, but with lower hypoxic cytotoxicity ratios.

Published
1998

26. Scavenging of nitrogen dioxide, thiyl, and sulfonyl free radicals by the nutritional antioxidant beta-carotene.

Author

Everett, S A, Dennis, M F, Patel, K B, Maddix, S, Kundu, S C, and Willson, R L

Abstract

Mechanisms of free radical scavenging by the nutritional antioxidant beta-carotene have been investigated by pulse radiolysis. Free radicals, which can initiate the chain of lipid peroxidation, including nitrogen dioxide (NO2.), thiyl (RS.), and sulfonyl (RSO2.) radicals, are rapidly scavenged by beta-carotene. Absolute rate constant k[NO2. + beta-carotene] = (1.1 +/- 0.1) x 10(8) m-1 s-1 and for the glutathione thiyl radical k[GS. + beta-carotene] = (2.2 +/- 0.1) x 10(8) m-1 s-1 have been determined. The mechanisms however are mutually exclusive, the former involving electron transfer to generate the radical-cation [ beta-carotene]+. and the latter by radical-addition to generate an adduct-radical [RS... beta-carotene].. Rate constants for thiyl radical-addition reactions vary from 10(6) to 10(9) m-1 s-1 and correlate with the lipophilicity of the thiyl radical under study. Sulfonyl radicals undergo both electron abstraction, [ beta-carotene]+. and radical-addition, [RSO2... beta-carotene]. in an approximate 3:1 ratio. The beta-carotene radical-cation and adduct-radicals are highly resonance stabilized and undergo slow bimolecular decay to non-radical products. These carotenoid-derived radicals react differently with oxygen, a factor which is expected to influence the antioxidant activity of beta-carotene within tissues of varying oxygen tension in vivo.

Published
1996

32. Uptake and additivity of the radiosensitising effects of Ro 03–8799 and SR-2508 in mammalian cells in vitro

Author

Watts, M. E., Dennis, M. F., and Woodcock, M.

Abstract

There is currently considerable interest in combining the two 2- nitroimidazole radiosensitisers, Ro 03–8799 and SR-2508. The weak, lipophilic base Ro 03–8799 and the neutral, hydrophilic compound SR-2508 are both efficient radiosensitisers, but the dose-limiting toxic effects of these two agents are clinically somewhat different. The dose-limiting effect for Ro 03–8799 is predominantly central neuropathy (Roberts et al, 1984; Saunders et al, 1984) and that for SR-2508 is predominantly peripheral neuropathy (Coleman et al, 1986). Thus, by combining these two radiosensitisers it should be possible to increase the effective sensitising concentration without increasing toxicity.The effect of combining these two radiosensitisers should be additive, providing the intracellular distributions of the compounds do not differ greatly. Combinations of two rather similar nitro-containing radiosensitisers have been studied previously (McNally et al, 1978), but the hydrophilic and prototropic characteristics of SR-2508 and Ro 03–8799 differ considerably; hence the subcellular distribution may be different for these two compounds.

Published
1987
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33. Registration of Slow Darkening Pinto Bean Germplasm Line SDIP-1.

Author

Singh, S. P., Teran, H., Lema, M., Dennis, M. F., and Hayes, R.

Subjects
RECORDING & registration, COMMON bean varieties, BREEDING, PLANT germplasm, PLANT materials centers, CULTIVARS, AGRICULTURE, AGRICULTURAL industries
Abstract

The article presents the registration of slow darkening pinto bean germplasm line SDIP-1. The pinto bean was developed by the dry bean breeding program at the University of Idaho, Kimbersly Research and Extension Center in 2003. Pinto SDIP-1 breeding line was derived from the double-cross Kodiak made in 1999-2000. Pinto Kodiak and great northern matterhorn were released by the Michigan Agricultural Experiment Station in 1998-1999. Both cultivars have an indeterminate upright erect Type II growth habit with small to medium vine in Southern Idaho.

Published
2006
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39. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., O'Connell, Kevin S., Coombes, Brandon, Qiao, Zhen, Als, Thomas D., Børte, Sigrid, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Gizer, Ian R., Gordon-Smith, Katherine, Greenwood, Tiffany A., Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lundberg, Martin, Magnusson, Sigurdur H., Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, McGregor, Nathaniel W., McKay, James D., Medeiros, Helena, Millischer, Vincent, Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Quested, Digby, Raj, Towfique, Rapaport, Mark H., Regeer, Eline J., Rivas, Fabio, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Xi, Simon, Xu, Wei, Kay Yang, Jessica Mei, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dikeos, Dimitris, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Mitchell, Philip B., Morken, Gunnar, Mowry, Bryan, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Oedegaard, Ketil J., Olsson, Tomas, Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Stordal, Eystein, Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Adan, Roger A. H., Ando, Tetsuya, Aschauer, Harald, Baker, Jessica H., Bencko, Vladimir, Bergen, Andrew W., Birgegård, Andreas, Boden, Joseph M., Boehm, Ilka, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Buehren, Katharina, Bulik, Cynthia M., Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S. P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dina, Christian, Dmitrzak-Weglarz, Monika, Martinez, Elisa Docampo, Duncan, Laramie E., Egberts, Karin, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Munn-Chernoff, Melissa A., Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, Olsen, Catherine M., O'Toole, Julie K., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Parker, Richard, Pearson, John F., Ehrlich, Stefan, Escaramís, Geòrgia, Espeseth, Thomas, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Floyd, James A. B., Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Giuranna, Johanna, Giusti-Rodríquez, Paola, Gonidakis, Fragiskos, Gordon, Scott, Gorwood, Philip, Mayora, Monica Gratacos, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hanscombe, Ken B., Hatzikotoulas, Konstantinos, Hebebrand, Johannes, Helder, Sietske G., Henders, Anjali K., Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Horwood, L. John, Hübel, Christopher, Petersen, Liselotte V., Pinto, Dalila, Purves, Kirstin L., Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op 't Landt, Margarita C. T., Slopien, Agnieszka, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar W., Strober, Michael, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jennifer, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaplan, Allan S., Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J. H., Kaye, Walter H., Kennedy, Martin A., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Kirk, Katherine M., Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., Larsen, Janne T., Le Hellard, Stephanie, Leppä, Virpi M., Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lin, Bochao Danae, Lundervold, Astri, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Stuber, Garret D., Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Thornton, Laura M., Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wade, Tracey D., Wagner, Gudrun, Walton, Esther, Watson, Hunna J., Whiteman, David C., Wichmann, H. Erich, Widen, Elisabeth, Woodside, D. Blake, Yao, Shuyang, Yilmaz, Zeynep, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Jungkunz, Martin, Mullins, N., Kang, J., Campos, A. I., Coleman, J. R. I., Edwards, A. C., Galfalvy, H., Levey, D. F., Lori, A., Shabalin, A., Starnawska, A., Su, M. -H., Watson, H. J., Adams, M., Awasthi, S., Gandal, M., Hafferty, J. D., Hishimoto, A., Kim, M., Okazaki, S., Otsuka, I., Ripke, S., Ware, E. B., Bergen, A. W., Berrettini, W. H., Bohus, M., Brandt, H., Chang, X., Chen, W. J., Chen, H. -C., Crawford, S., Crow, S., Diblasi, E., Duriez, P., Fernandez-Aranda, F., Fichter, M. M., Gallinger, S., Glatt, S. J., Gorwood, P., Guo, Y., Hakonarson, H., Halmi, K. A., Hwu, H. -G., Jain, S., Jamain, S., Jimenez-Murcia, S., Johnson, C., Kaplan, A. S., Kaye, W. H., Keel, P. K., Kennedy, J. L., Klump, K. L., Li, D., Liao, S. -C., Lieb, K., Lilenfeld, L., Liu, C. -M., Magistretti, P. J., Marshall, C. R., Mitchell, J. E., Monson, E. T., Myers, R. M., Pinto, D., Powers, A., Ramoz, N., Roepke, S., Rozanov, V., Scherer, S. W., Schmahl, C., Sokolowski, M., Strober, M., Thornton, L. M., Treasure, J., Tsuang, M. T., Witt, S. H., Woodside, D. B., Yilmaz, Z., Zillich, L., Adolfsson, R., Agartz, I., Air, T. M., Alda, M., Alfredsson, L., Andreassen, O. A., Anjorin, A., Appadurai, V., Soler Artigas, M., Van der Auwera, S., Azevedo, M. H., Bass, N., Bau, C. H. D., Baune, B. T., Bellivier, F., Berger, K., Biernacka, J. M., Bigdeli, T. B., Binder, E. B., Boehnke, M., Boks, M. P., Bosch, R., Braff, D. L., Bryant, R., Budde, M., Byrne, E. M., Cahn, W., Casas, M., Castelao, E., Cervilla, J. A., Chaumette, B., Cichon, S., Corvin, A., Craddock, N., Craig, D., Degenhardt, F., Djurovic, S., Edenberg, H. J., Fanous, A. H., Foo, J. C., Forstner, A. J., Frye, M., Fullerton, J. M., Gatt, J. M., Gejman, P. V., Giegling, I., Grabe, H. J., Green, M. J., Grevet, E. H., Grigoroiu-Serbanescu, M., Gutierrez, B., Guzman-Parra, J., Hamilton, S. P., Hamshere, M. L., Hartmann, A., Hauser, J., Heilmann-Heimbach, S., Hoffmann, P., Ising, M., Jones, I., Jones, L. A., Jonsson, L., Kahn, R. S., Kelsoe, J. R., Kendler, K. S., Kloiber, S., Koenen, K. C., Kogevinas, M., Konte, B., Krebs, M. -O., Landen, M., Lawrence, J., Leboyer, M., Lee, P. H., Levinson, D. F., Liao, C., Lissowska, J., Lucae, S., Mayoral, F., Mcelroy, S. L., Mcgrath, P., Mcguffin, P., Mcquillin, A., Medland, S. E., Mehta, D., Melle, I., Milaneschi, Y., Mitchell, P. B., Molina, E., Morken, G., Mortensen, P. B., Muller-Myhsok, B., Nievergelt, C., Nimgaonkar, V., Nothen, M. M., O'Donovan, M. C., Ophoff, R. A., Owen, M. J., Pato, C., Pato, M. T., Penninx, B. W. J. H., Pimm, J., Pistis, G., Potash, J. B., Power, R. A., Preisig, M., Quested, D., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Richarte, V., Rietschel, M., Rivera, M., Roberts, A., Roberts, G., Rouleau, G. A., Rovaris, D. L., Rujescu, D., Sanchez-Mora, C., Sanders, A. R., Schofield, P. R., Schulze, T. G., Scott, L. J., Serretti, A., Shi, J., Shyn, S. I., Sirignano, L., Sklar, P., Smeland, O. B., Smoller, J. W., Sonuga-Barke, E. J. S., Spalletta, G., Strauss, J. 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A., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Kirk, K. M., Klareskog, L., Knudsen, G. P. S., Larsen, J. T., Le Hellard, S., Leppa, V. M., Lichtenstein, P., Lin, B. D., Lundervold, A., Luykx, J., Maj, M., Mannik, K., Marsal, S., Stuber, G. D., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wade, T. D., Wagner, G., Walton, E., Whiteman, D. C., Wichmann, H. E., Widen, E., Yao, S., Zeggini, E., Zerwas, S., Zipfel, S., Jungkunz, M., Dietl, L., Schwarze, C. E., Dahmen, N., Schott, B. H., Mobascher, A., Crivelli, S., Dennis, M. F., Harvey, P. D., Carter, B. W., Huffman, J. E., Jacobson, D., Madduri, R., Olsen, M. K., Pestian, J., Gaziano, J. M., Muralidhar, S., Ramoni, R., Beckham, J., Chang, K. -M., O'Donnell, C. J., Tsao, P. S., Breeling, J., Huang, G., Romero, J. P. C., Moser, J., Whitbourne, S. B., Brewer, J. V., Aslan, M., Connor, T., Argyres, D. P., Stephens, B., Brophy, M. T., Humphries, D. E., Selva, L. E., Do, N., Shayan, S., Cho, K., Pyarajan, S., Hauser, E., Sun, Y., Zhao, H., Wilson, P., Mcardle, R., Dellitalia, L., Mattocks, K., Harley, J., Zablocki, C. J., Whittle, J., Jacono, F., Gutierrez, S., Gibson, G., Hammer, K., Kaminsky, L., Villareal, G., Kinlay, S., Xu, J., Hamner, M., Mathew, R., Bhushan, S., Iruvanti, P., Godschalk, M., Ballas, Z., Ivins, D., Mastorides, S., Moorman, J., Gappy, S., Klein, J., Ratcliffe, N., Florez, H., Okusaga, O., Murdoch, M., Sriram, P., Yeh, S. S., Tandon, N., Jhala, D., Aguayo, S., Cohen, D., Sharma, S., Liangpunsakul, S., Oursler, K. A., Whooley, M., Ahuja, S., Constans, J., Meyer, P., Greco, J., Rauchman, M., Servatius, R., Gaddy, M., Wallbom, A., Morgan, T., Stapley, T., Sherman, S., Ross, G., Tsao, P., Strollo, P., Boyko, E., Meyer, L., Gupta, S., Huq, M., Fayad, J., Hung, A., Lichy, J., Hurley, R., Robey, B., Striker, R., Erlangsen, A., Kessler, R. C., Porteous, D., Ursano, R. J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards A.C., Galfalvy H., Levey D.F., Lori A., Shabalin A., Starnawska A., Su M.-H., Watson H.J., Adams M., Awasthi S., Gandal M., Hafferty J.D., Hishimoto A., Kim M., Okazaki S., Otsuka I., Ripke S., Ware E.B., Bergen A.W., Berrettini W.H., Bohus M., Brandt H., Chang X., Chen W.J., Chen H.-C., Crawford S., Crow S., DiBlasi E., Duriez P., Fernandez-Aranda F., Fichter M.M., Gallinger S., Glatt S.J., Gorwood P., Guo Y., Hakonarson H., Halmi K.A., Hwu H.-G., Jain S., Jamain S., Jimenez-Murcia S., Johnson C., Kaplan A.S., Kaye W.H., Keel P.K., Kennedy J.L., Klump K.L., Li D., Liao S.-C., Lieb K., Lilenfeld L., Liu C.-M., Magistretti P.J., Marshall C.R., Mitchell J.E., Monson E.T., Myers R.M., Pinto D., Powers A., Ramoz N., Roepke S., Rozanov V., Scherer S.W., Schmahl C., Sokolowski M., Strober M., Thornton L.M., Treasure J., Tsuang M.T., Witt S.H., Woodside D.B., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Air T.M., Alda M., Alfredsson L., Andreassen O.A., Anjorin A., Appadurai V., Soler 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Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

40. Smoking in help-seeking veterans with PTSD returning from Afghanistan and Iraq.

Author

Kirby AC, Hertzberg BP, Collie CF, Yeatts B, Dennis MF, McDonald SD, Calhoun PS, and Beckham JC

Subjects
Adult, Afghan Campaign 2001-, Humans, Iraq War, 2003-2011, Male, Smoking epidemiology, Smoking Prevention, Stress Disorders, Post-Traumatic complications, Stress Disorders, Post-Traumatic epidemiology, Surveys and Questionnaires, Patient Acceptance of Health Care psychology, Smoking psychology, Smoking Cessation psychology, Stress Disorders, Post-Traumatic psychology, Veterans psychology
Abstract

Past research has shown that veterans and individuals with posttraumatic stress disorder (PTSD) have increased rates of smoking. However, the rates of smoking in younger help-seeking veterans returning from Afghanistan and Iraq, and possible correlates of smoking among this population are unknown. In this study, we evaluated the rate of lifetime and current smoking among a sample of 90 returning male veterans diagnosed with PTSD. Fifty-nine percent reported a lifetime history of smoking including 32% that were current smokers. Current smokers were significantly younger than non-smokers. Current smokers (mean age=31) reported a mean age of smoking onset as 15.86 with a pack year history of 8.89. These smokers reported on average five previous quit attempts. According to a stages of change model, one-half of the smokers were in the contemplation phase of stopping smoking (50%), 29% were in the pre-contemplation phase and 21% were in the preparation phase. The results are placed in the context of non-psychiatric and psychiatric smokers.

Published
2008
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41. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues.

Author

Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MR, Dennis MF, and Chaplin DJ

Subjects
Animals, Blood Pressure drug effects, Male, NG-Nitroarginine Methyl Ester pharmacology, Neoplasms, Experimental blood supply, Phosphorylation, Rats, Regional Blood Flow drug effects, Stilbenes metabolism, Vascular Resistance drug effects, Antineoplastic Agents, Phytogenic pharmacology, Neoplasms, Experimental drug therapy, Stilbenes pharmacology
Abstract

The potential for tumor vascular-targeting by using the tubulin destabilizing agent disodium combretastatin A-4 3-0-phosphate (CA-4-P) was assessed in a rat system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The early vascular effects of CA-4-P were assessed in the s.c. implanted P22 carcinosarcoma and in a range of normal tissues. Blood flow was measured by the uptake of radiolabeled iodoantipyrine, and quantitative autoradiography was used to measure spatial heterogeneity of blood flow in tumor sections. CA-4-P (100 mg/kg i.p.) caused a significant increase in mean arterial blood pressure at 1 and 6 h after treatment and a very large decrease in tumor blood flow, which-by 6 h-was reduced approximately 100-fold. The spleen was the most affected normal tissue with a 7-fold reduction in blood flow at 6 h. Calculations of vascular resistance revealed some vascular changes in the heart and kidney for which there were no significant changes in blood flow. Quantitative autoradiography showed that CA-4-P increased the spatial heterogeneity in tumor blood flow. The drug affected peripheral tumor regions less than central regions. Administration of CA-4-P (30 mg/kg) in the presence of the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester, potentiated the effect of CA-4-P in tumor tissue. The combination increased tumor vascular resistance 300-fold compared with less than 7-fold for any of the normal tissues. This shows that tissue production of nitric oxide protects against the damaging vascular effects of CA-4-P. Significant changes in tumor vascular resistance could also be obtained in isolated tumor perfusions using a cell-free perfusate, although the changes were much less than those observed in vivo. This shows that the action of CA-4-P includes mechanisms other than those involving red cell viscosity, intravascular coagulation, and neutrophil adhesion. The uptake of CA-4-P and combretastatin A-4 (CA-4) was more efficient in tumor than in skeletal muscle tissue and dephosphorylation of CA-4-P to CA-4 was faster in the former. These results are promising for the use of CA-4-P as a tumor vascular-targeting agent.

Published
1999

42. Determination of combretastatin A-4 and its phosphate ester pro-drug in plasma by high-performance liquid chromatography.

Author

Stratford MR and Dennis MF

Subjects
Animals, Antineoplastic Agents, Phytogenic chemistry, Calibration, Esters, Humans, Isomerism, Mice, Reproducibility of Results, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Stilbenes chemistry, Antineoplastic Agents, Phytogenic blood, Chromatography, High Pressure Liquid methods, Prodrugs analysis, Stilbenes blood
Abstract

High-performance liquid chromatography with both absorbance and fluorescence detection has been applied to the determination of the potential anti-tumour agent combretastatin A-4 and its phosphate ester in murine and human plasma. The presence of different interfering peaks in the two species makes absorbance detection at 295 nm the method of choice for the mouse, and fluorescence detection (295 nm/390 nm) for human plasma. The calibration was linear over the range studied (0.01-50 microM for combretastatin A-4, 0.02-200 microM for combretastatin A-4 phosphate), with quantitation limits of 0.05 microM for both drugs in the mouse, and 0.05 microM and 0.0125 microM for the phosphate ester and free drug, respectively, in human plasma. The method should be useful for pharmacokinetic studies in the forthcoming Phase I clinical trial of combretastatin A-4 phosphate.

Published
1999
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43. Involvement of oxygen free radicals in ischaemia-reperfusion injury to murine tumours: role of nitric oxide.

Author

Parkins CS, Holder AL, Dennis MF, Stratford MR, and Chaplin DJ

Subjects
Adenocarcinoma blood supply, Animals, Catalase pharmacology, Deferoxamine pharmacology, Endothelium, Vascular enzymology, Endothelium, Vascular physiology, Female, Free Radical Scavengers pharmacology, Hydroxylation, L-Lactate Dehydrogenase blood, Mammary Neoplasms, Experimental blood supply, Mice, Mice, Inbred CBA, Nitric Oxide Synthase antagonists & inhibitors, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Oxidative Stress, Salicylates pharmacology, Salicylic Acid, Sarcoma, Small Cell blood supply, Adenocarcinoma metabolism, Hydroxyl Radical metabolism, Mammary Neoplasms, Experimental metabolism, Nitric Oxide physiology, Reperfusion Injury metabolism, Sarcoma, Small Cell metabolism
Abstract

Ischaemia-reperfusion (I/R) injury is a model system of oxidative stress and a potential anti-cancer therapy. Tumour cytotoxicity follows oxygen radical damage to the vasculature which is modulated by tumour production of the vasoactive agent, nitric oxide (NO.). In vivo hydroxylation of salicylate, to 2,3- and 2,5-dihydroxybenzoate (DHBs), was used to measure the generation of hydroxyl radicals (OH.) following temporary vascular occlusion in two murine tumours (with widely differing capacity to produce NO.) and normal skin. Significantly greater OH. generation followed I/R of murine adenocarcinoma CaNT tumours (low NO. production) compared to round cell sarcoma SaS tumours (high NO. production) and normal skin. These data suggest that tumour production of NO. confers resistance to I/R injury, in part by reducing production of oxygen radicals and oxidative stress to the vasculature. Inhibition of NO synthase (NOS), during vascular reperfusion, significantly increased OH. generation in both tumour types, but not skin. This increase in cytotoxicity suggests oxidative injury may be attenuation by tumour production of NO.. Hydroxyl radical generation following I/R injury correlated with vascular damage and response of tumours in vivo, but not skin, which indicates a potential therapeutic benefit from this approach.

Published
1998
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44. Metabolic and clonogenic consequences of ischaemia reperfusion insult in solid tumours.

Author

Parkins CS, Hill SA, Stratford MR, Dennis MF, and Chaplin DJ

Subjects
Animals, Humans, Neoplasms, Experimental blood supply, Neoplasms, Experimental metabolism, Regional Blood Flow physiology, Ischemia metabolism, Ischemia physiopathology, Neoplasms blood supply, Neoplasms metabolism, Reperfusion Injury metabolism, Reperfusion Injury physiopathology, Tumor Stem Cell Assay
Abstract

Tumour cell survival is intimately related to blood vessel function and so the tumour vasculature represents a novel target for cancer therapy. We have investigated a murine tumour model in which a metal clamp was used to occlude the vascular supply temporarily and then removed to allow reperfusion. This allows the study of ischaemia-reperfusion as a model system for investigating tumour response to metabolic and oxidative stress. Recent studies have shown that prolonged reduction of tumour blood flow results in a deterioration of the hypoxic and acidic microenvironment found within tumours which leads to cytotoxicity. This cytotoxicity is dramatically enhanced if these cells are subsequently reperfused. It was the aim of the present study to determine the relative contribution of cytotoxicity occurring during the ischaemic period and that occurring during reperfusion. Although significant reductions in tumour energy status were induced during the clamping period itself, these were poorly correlated with the degree of tumour cytotoxicity. Relative vascular perfusion, measured using a radiolabelled tracer, remained significantly depressed below the control value following clamp removal. The degree of recovery of perfusion was also dependent upon the clamp duration. Relative tumour perfusion at 1 h after clamp removal was 70.1 +/- 14.6 and 50.5 +/- 6.3% of control values after a 1 or 3 h clamp, respectively, and showed no significant further increase when measured at 24 h after clamp removal. Tumour cytotoxicity following ischaemia reperfusion insult was modulated by administering the anti-oxidant enzymes superoxide dismutase or catalase intravenously just before clamp removal. These enzymes are restricted to the vascular compartment, where it is proposed that they modulate the concentration of oxygen free radicals released during reperfusion and by neutrophil oxidative burst. Reperfusion injury to the tumour was enhanced by administration of an inhibitor of nitric oxide synthase, nitro-L-arginine, probably owing to enhanced neutrophil adhesion and oxidative burst. Conversely, reperfusion injury to the tumour was reduced by administration of a nitric oxide donor, diethylamine nitric oxide. The murine model reported in this paper shows that ischaemia-reperfusion damage mediated by oxygen free radical formation provides a model system for investigating tumour response to oxidative stress at the level of the vascular endothelium.

Published
1997
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45. Nitric oxide involvement in the toxicity of hydroxyguanidine in leukaemia HL60 cells.

Author

Everett SA, Smith KA, Patel KB, Dennis MF, Stratford MR, and Wardman P

Subjects
Cell Cycle drug effects, Cell Hypoxia, DNA Damage, Guanidines metabolism, HL-60 Cells, Humans, Hydroxylamines, Oxidation-Reduction, Antineoplastic Agents pharmacology, Guanidines pharmacology, Nitric Oxide physiology
Abstract

The free-radical intermediates and the stable products formed on one-electron oxidation of hydroxyguanidine (HOG) were investigated in order to suggest a mechanistic basis for HOG-induced cytotoxicity and cytostasis in leukaemia HL60 cells. The azide radical (generated radiolytically) reacted with HOG to produce a carbon-centred radical which in the absence of oxygen decays by a first-order process (k = 3.2 x 10(3) s-1) to yield nitric oxide (NO) and urea. Although the HOG radical reacts rapidly with oxygen (rate constant for O2 addition, k = 4.2 x 10(8) dm3 mol-1 s-1) this neither prevented the elimination of NO. nor generated alternative nitrogen oxides (e.g. peroxynitrite) capable of contributing to cellular oxidative stress. The detection of NO. in HL60 cells corroborated mechanistic studies that oxidative denitrification of HOG does not require catalysis by nitric oxide synthase. Quantitation of NO. by electron paramagnetic resonance (EPR) spectroscopy (utilising a NO. -selective probe) shows higher amounts of NO. under anoxic conditions, reflecting competition for NO. with molecular oxygen in oxic cells. Inhibition of cytochrome P450 and myeloperoxidase activity decreased NO. production thereby identifying these enzyme systems as capable of oxidizing HOG in vitro. A correlation exists between the intracellular levels of NO. with both the cytotoxic and cytostatic effects of HOG within HL60 cells. A higher toxicity was observed with hypoxic than with oxic cells. The lower levels of NO. associated with aerobic conditions caused a G1 --> S block in the cell cycle which under anoxia potentiated NO. -induced apoptotic cell death.

Published
1996

46. Oxidative denitrification of N omega-hydroxy-L-arginine by the superoxide radical anion.

Author

Everett SA, Dennis MF, Patel KB, Stratford MR, and Wardman P

Subjects
Arginine chemistry, Arginine radiation effects, Hydrogen-Ion Concentration, Models, Chemical, Nitric Oxide analysis, Nitrites analysis, Oxidation-Reduction, Arginine analogs & derivatives, Superoxides chemistry
Abstract

The superoxide radical anion (O2-.) produced during the catalytic activity of nitric oxide synthase (NOS) and cytochrome P-450 has been implicated in the oxidative denitrification of hydroxyguanidines ( > C = NOH). The reactivity of the radiolytically generated O2-. radical with N omega-hydroxy-L-arginine (NHA) is pH dependent and appears to parallel the prototropic equilibrium of the hydroxyguanidino group ( > C = NOH reversible > C = NO(-)+H+; pK = 8). The N omega-hydroxyguanidino group is more reactive towards O2-. when deprotonated but exhibits negligible reactivity when protonated. Based on a model, the rate constant for the reaction of the O2-. with NHA was estimated as kappa (O2-.+ > C = NO-) approximately 200-500 M-1.s-1, which is probably too low to compete with O2-. reactions with NO- or superoxide dismutase, which occur many orders of magnitude faster. The oxidative elimination of NO from NHA by O2-. was not accompanied by the formation of L-citrulline. Since only 21% of NHA will exist in the deprotonated > C = NO- form at physiological pH, it is unlikely that oxidative denitrification of NHA by cytochrome P-450 or NOS-derived O2-. radicals will prove a major free-radical pathway to NO. and L-citrulline.

Published
1996
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47. Chemical properties which control selectivity and efficacy of aromatic N-oxide bioreductive drugs.

Author

Wardman P, Priyadarsini KI, Dennis MF, Everett SA, Naylor MA, Patel KB, Stratford IJ, Stratford MR, and Tracy M

Subjects
Free Radicals, Hydrogen-Ion Concentration, Oxidation-Reduction, Oxides chemistry, Pulse Radiolysis, Pyrazines pharmacology, Tirapazamine, Triazines pharmacology, Antineoplastic Agents chemistry, Pyrazines chemistry, Triazines chemistry
Abstract

Pulse radiolysis was used to generate radicals from one electron reduction of 1,2,4-benzotriazine-1,4-dioxides (derivatives of tirapazamine), and of imidazo [1,2-a]quinoxaline-4-oxides (analogues of RB90740), which have selective toxicity towards hypoxic cells. Radicals from the mono N-oxides (from the latter compounds) react with oxygen approximately 10-40 times faster than does the tirapazamine radical. Radicals from the tirapazamine analogues studied react with oxygen up to approximately 10 times slower than tirapazamine radicals. The quinoxaline N-oxide radicals are involved in prototropic equilibria with pK(a) values (5.5 to 7.4) spanning that reported for tirapazamine (6.0). Generation of radicals radiolytically in the presence of H donors (formate, 2-propanol, deoxyribose) indicate a chain reaction ascribed to H abstraction by the drug radical. The protonated drug radical is much more reactive than the radical anion (H abstraction rate constant approximately equal to 10(2) - 10(3) dm3 mol-1 s-1). Chain termination is ascribed to drug radical-radical reactions, i.e. radical stability in anoxia, with rate constants 2k approximately equal to 1 x 10(7) to 2 x 10(8) dm3 mol-1 s-1 at pH approximately 7.4. Estimates of the reduction potentials of the drug-radical couples in water at pH 7 for two of the mono-N-oxides were in the range-0.7 to 0.8 V vs NHE at pH 7.

Published
1996

48. Nicotinamide pharmacokinetics in normal volunteers and patients undergoing palliative radiotherapy.

Author

Stratford MR, Dennis MF, Hoskin PJ, Saunders MI, Hodgkiss RJ, and Rojas A

Subjects
Administration, Oral, Female, Half-Life, Humans, Incidence, Male, Neoplasms blood, Niacinamide administration & dosage, Reference Values, Time Factors, Neoplasms radiotherapy, Niacinamide adverse effects, Niacinamide pharmacokinetics, Palliative Care
Abstract

The influence of nicotinamide formulation on absorption characteristics and incidence of adverse side-effects has been studied in normal volunteers and in patients undergoing radiotherapy. Escalating single or repeated oral doses of nicotinamide were administered in tablet or liquid form under fasting or non-fasting conditions. Drug absorption was slowed both by the presence of food in the stomach and by the administration of nicotinamide in tablet form compared with when it was dissolved in orange juice. Peak concentrations were generally slightly higher following the liquid preparation, but the incidence of adverse side-effects (chiefly nausea) was increased. A single dose of 9 g (88-97 mg/kg) nicotinamide in tablet form was well tolerated in two fasting normal volunteers, and in patients, doses of up to 133 mg/kg as tablets were tolerated twice/week for three weeks. Daily administration of 80 mg/kg nicotinamide was tolerated when given as tablets, but not in a liquid formulation. Neither the peak concentration nor the area under the concentration/time curve (AUC) of nicotinamide, nor the main metabolites of nicotinamide appeared to correlate with the incidence of toxicity.

Published
1996
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49. Ischemia reperfusion injury in tumors: the role of oxygen radicals and nitric oxide.

Author

Parkins CS, Dennis MF, Stratford MR, Hill SA, and Chaplin DJ

Subjects
Adenocarcinoma blood supply, Animals, Catalase blood, Cell Survival, Female, Mice, Mice, Inbred CBA, Sarcoma, Experimental blood supply, Superoxide Dismutase blood, Neoplasms, Experimental blood supply, Nitric Oxide physiology, Reactive Oxygen Species metabolism, Reperfusion Injury physiopathology
Abstract

Oxidative stress is a key process involved in the action of several therapeutic modalities used in cancer treatment. Ischemia reperfusion insult provides a model system for investigating the processes involved in determining the sensitivity of tumor tissue to oxidative stress. We have investigated the response of the murine CaNT tumor to ischemia reperfusion injury and the role that oxygen radicals and nitric oxide may play in this phenomenon. Our results show that little or no cell kill is detected in tumors exposed to up to 3 h of ischemia if the tumors are excised immediately before reperfusion. However, if reperfusion is permitted, then extensive cell kill is evident 24 h later. i.v. administration of superoxide dismutase or catalase, at the time when vascular reperfusion occurred, resulted in a significant protection against tumor cell kill, suggesting that the damage was mediated by oxygen radicals. Conversely, administration of an inhibitor of nitric oxide synthase, N omega-nitro-L-arginine, resulted in potentiation of tumor cell damage. Administration of a nitric oxide (NO) donor, diethylamine NO, at the time when vascular reperfusion occurred resulted in significant protection against tumor damage. These results suggest that nitric oxide is a potent mediator in determining tumor damage after ischemia reperfusion injury. The role of intrinsic NO production by murine tumors was investigated by measuring the accumulation of nitrate in the medium of tumor explants cultured in vitro in two tumors with differing sensitivity to ischemia reperfusion damage. The clamp-insensitive tumor SaS showed a greater nitrate accumulation than the clamp-sensitive tumor CaNT, which may confer a greater capacity for preventing tumor and endothelial cell damage after oxidative stress.

Published
1995

50. Pharmacokinetics and binding of the bioreductive probe for hypoxia, NITP: effect of route of administration.

Author

Hodgkiss RJ, Stratford MR, Dennis MF, and Hill SA

Subjects
2-Hydroxypropyl-beta-cyclodextrin, Animals, Cell Hypoxia, Chromatography, High Pressure Liquid, Cyclodextrins administration & dosage, Dimethyl Sulfoxide administration & dosage, Drug Administration Routes, Flow Cytometry, Mammary Neoplasms, Experimental metabolism, Mice, Mice, Inbred CBA, Neoplasm Transplantation, Nitroimidazoles administration & dosage, Nitroimidazoles pharmacokinetics, Peanut Oil, Plant Oils administration & dosage, Radiation-Sensitizing Agents administration & dosage, Radiation-Sensitizing Agents pharmacokinetics, Theophylline administration & dosage, Theophylline metabolism, Theophylline pharmacokinetics, Nitroimidazoles metabolism, Radiation-Sensitizing Agents metabolism, Theophylline analogs & derivatives, beta-Cyclodextrins
Abstract

The novel compound 7(-)[4'-(2-nitroimidazol-l-yl)-butyl]-theophylline (NITP) can be used as an immunologically detectable probe for hypoxic cells. Because of the limited water solubility of NITP, it has been administered dissolved in peanut oil with 10% dimethylsulphoxide (DMSO). A new aqueous formulation has been devised, based on a 50% solution of a modified beta-cyclodextrin (Molecusol HPB), which increases the water solubility of NITP 10-fold. The pharmacokinetics of NITP in plasma and tumours have been compared following oral and intraperitoneal (i.p.) administration of the NITP in Molecusol, i.p. administration of NITP dissolved in peanut oil + 10% DMSO and injection of a near-saturated aqueous solution of the drug intravenously via the tail vein or i.p. or directly into the tumours. Binding of the marker to hypoxic cells within tumours was also measured after the different routes of administration. The Molecusol vehicle was unexpectedly toxic when administered i.p., but there was no toxicity from NITP dissolved in Molecusol when administered orally. Binding of the drug within tumours was seen for both the peanut oil + 10% DMSO and Molecusol formulations and for both oral and intraperitoneal routes. Binding of NITP within tumours has also been observed following direct injection of the drug, with minimal whole-body exposure to NITP. However, the bound metabolites of NITP within tumours were localised to the injection site, suggesting that direct injection is unlikely to be a useful method of administering bioreductive hypoxia markers. The data in this paper demonstrate that bound metabolites of the hypoxia marker NITP can be detected in tumours following oral administration of an aqueous formulation of NITP, and suggest that oral administration could be a satisfactory administration route for clinical studies with NITP.

Published
1995
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