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1. Assessment: dermatomal somatosensory evoked potentials. Report of the American Academy of Neurology's Therapeutics and Technology Assessments Subcommittee.

Author

Ferguson, JH, Brin, M, Goldstein, ML, Gorelich, PB, Hanley, DF, Lange, DJ, Nuwer, MR, Roach, ES, Goldman, R, Goodin, D, and Marini, AM

Subjects
Brain, Humans, Therapeutics, Electric Stimulation, Technology, Medical, Neurology, Evoked Potentials, Somatosensory, Societies, Medical, United States, Evaluation Studies as Topic, Skin Physiological Phenomena, Medical Laboratory Science, Technology, Medical, Evoked Potentials, Somatosensory, Societies, Neurology & Neurosurgery, Clinical Sciences, Neurosciences, Cognitive Sciences
Abstract

The different conclusions reached by studies investigating the utility of DSEPs prevent a confident conclusion regarding utility. Some investigators are strong believers in the diagnostic usefulness of this technique. Others are mere skeptical. One possible cause is variable study design. Most studies provide evidence no higher than level III (case reports, expert opinions). Controlled studies, especially with blinded interpreters of the tests, would provide needed evidence of efficacy in view of the existing confusion in the literature. It is our consensus that the current evidence supporting the diagnostic use of DSEPs is Type D and that DSEPs should be regarded as Investigational, meaning that current evidence is insufficient to determine appropriateness. This group does encourage further study.

Published
1997

3. Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment

Author

Abu-Shawareb, H, Acree, R, Adams, P, Adams, J, Addis, B, Aden, R, Adrian, P, Afeyan, BB, Aggleton, M, Aghaian, L, Aguirre, A, Aikens, D, Akre, J, Albert, F, Albrecht, M, Albright, BJ, Albritton, J, Alcala, J, Alday, C, Alessi, DA, Alexander, N, Alfonso, J, Alfonso, N, Alger, E, Ali, SJ, Ali, ZA, Alley, WE, Amala, P, Amendt, PA, Amick, P, Ammula, S, Amorin, C, Ampleford, DJ, Anderson, RW, Anklam, T, Antipa, N, Appelbe, B, Aracne-Ruddle, C, Araya, E, Arend, M, Arnold, P, Arnold, T, Asay, J, Atherton, LJ, Atkinson, D, Atkinson, R, Auerbach, JM, Austin, B, Auyang, L, Awwal, AS, Ayers, J, Ayers, S, Ayers, T, Azevedo, S, Bachmann, B, Back, CA, Bae, J, Bailey, DS, Bailey, J, Baisden, T, Baker, KL, Baldis, H, Barber, D, Barberis, M, Barker, D, Barnes, A, Barnes, CW, Barrios, MA, Barty, C, Bass, I, Batha, SH, Baxamusa, SH, Bazan, G, Beagle, JK, Beale, R, Beck, BR, Beck, JB, Bedzyk, M, Beeler, RG, Behrendt, W, Belk, L, Bell, P, Belyaev, M, Benage, JF, Bennett, G, Benedetti, LR, Benedict, LX, Berger, R, Bernat, T, Bernstein, LA, Berry, B, Bertolini, L, Besenbruch, G, Betcher, J, Bettenhausen, R, Betti, R, Bezzerides, B, Bhandarkar, SD, Bickel, R, Biener, J, Biesiada, T, Bigelow, K, Bigelow-Granillo, J, Bigman, V, Bionta, RM, Birge, NW, Bitter, M, Black, AC, Bleile, R, Bleuel, DL, Bliss, E, Blue, B, Boehly, T, Boehm, K, Boley, CD, Bonanno, R, Bond, EJ, Bond, T, Bonino, MJ, Borden, M, Bourgade, J-L, Bousquet, J, Bowers, J, Bowers, M, Boyd, R, Bozek, A, Bradley, DK, Bradley, KS, Bradley, PA, Bradley, L, Brannon, L, Brantley, PS, Braun, D, Braun, T, Brienza-Larsen, K, Briggs, TM, Britten, J, Brooks, ED, Browning, D, Bruhn, MW, Brunner, TA, Bruns, H, Brunton, G, Bryant, B, Buczek, T, Bude, J, Buitano, L, Burkhart, S, Burmark, J, Burnham, A, Burr, R, Busby, LE, Butlin, B, Cabeltis, R, Cable, M, Cabot, WH, Cagadas, B, Caggiano, J, Cahayag, R, Caldwell, SE, Calkins, S, Callahan, DA, Calleja-Aguirre, J, Camara, L, Camp, D, Campbell, EM, Campbell, JH, Carey, B, Carey, R, Carlisle, K, Carlson, L, Carman, L, Carmichael, J, Carpenter, A, Carr, C, Carrera, JA, Casavant, D, Casey, A, Casey, DT, Castillo, A, Castillo, E, Castor, JI, Castro, C, Caughey, W, Cavitt, R, Celeste, J, Celliers, PM, Cerjan, C, Chandler, G, Chang, B, Chang, C, Chang, J, Chang, L, Chapman, R, Chapman, T, Chase, L, Chen, H, Chen, K, Chen, L-Y, Cheng, B, Chittenden, J, Choate, C, Chou, J, Chrien, RE, Chrisp, M, Christensen, K, Christensen, M, Christopherson, AR, Chung, M, Church, JA, Clark, A, Clark, DS, Clark, K, Clark, R, Claus, L, Cline, B, Cline, JA, Cobble, JA, Cochrane, K, Cohen, B, Cohen, S, Collette, MR, Collins, G, Collins, LA, Collins, TJB, Conder, A, Conrad, B, Conyers, M, Cook, AW, Cook, D, Cook, R, Cooley, JC, Cooper, G, Cope, T, Copeland, SR, Coppari, F, Cortez, J, Cox, J, Crandall, DH, Crane, J, Craxton, RS, Cray, M, Crilly, A, Crippen, JW, Cross, D, Cuneo, M, Cuotts, G, Czajka, CE, Czechowicz, D, Daly, T, Danforth, P, Darbee, R, Darlington, B, Datte, P, Dauffy, L, Davalos, G, Davidovits, S, Davis, P, Davis, J, Dawson, S, Day, RD, Day, TH, Dayton, M, Deck, C, Decker, C, Deeney, C, DeFriend, KA, Deis, G, Delamater, ND, Delettrez, JA, Demaret, R, Demos, S, Dempsey, SM, Desjardin, R, Desjardins, T, Desjarlais, MP, Dewald, EL, DeYoreo, J, Diaz, S, Dimonte, G, Dittrich, TR, Divol, L, Dixit, SN, Dixon, J, Dodd, ES, Dolan, D, Donovan, A, Donovan, M, Döppner, T, Dorrer, C, Dorsano, N, Douglas, MR, Dow, D, Downie, J, Downing, E, Dozieres, M, Draggoo, V, Drake, D, Drake, RP, Drake, T, Dreifuerst, G, DuBois, DF, DuBois, PF, Dunham, G, Dylla-Spears, R, Dymoke-Bradshaw, AKL, Dzenitis, B, Ebbers, C, Eckart, M, Eddinger, S, Eder, D, Edgell, D, Edwards, MJ, Efthimion, P, Eggert, JH, Ehrlich, B, Ehrmann, P, Elhadj, S, Ellerbee, C, Elliott, NS, Ellison, CL, Elsner, F, Emerich, M, Engelhorn, K, England, T, English, E, Epperson, P, Epstein, R, Erbert, G, Erickson, MA, Erskine, DJ, Erlandson, A, Espinosa, RJ, Estes, C, Estabrook, KG, Evans, S, Fabyan, A, Fair, J, Fallejo, R, Farmer, N, Farmer, WA, Farrell, M, Fatherley, VE, Fedorov, M, Feigenbaum, E, Feit, M, Ferguson, W, Fernandez, JC, Fernandez-Panella, A, Fess, S, Field, JE, Filip, CV, Fincke, JR, Finn, T, Finnegan, SM, Finucane, RG, Fischer, M, Fisher, A, Fisher, J, Fishler, B, Fittinghoff, D, Fitzsimmons, P, Flegel, M, Flippo, KA, Florio, J, Folta, J, Folta, P, Foreman, LR, Forrest, C, Forsman, A, Fooks, J, Foord, M, Fortner, R, Fournier, K, Fratanduono, DE, Frazier, N, Frazier, T, Frederick, C, Freeman, MS, Frenje, J, Frey, D, Frieders, G, Friedrich, S, Froula, DH, Fry, J, Fuller, T, Gaffney, J, Gales, S, Le Galloudec, B, Le Galloudec, KK, Gambhir, A, Gao, L, Garbett, WJ, Garcia, A, Gates, C, Gaut, E, Gauthier, P, Gavin, Z, Gaylord, J, Geissel, M, Génin, F, Georgeson, J, Geppert-Kleinrath, H, Geppert-Kleinrath, V, Gharibyan, N, Gibson, J, Gibson, C, Giraldez, E, Glebov, V, Glendinning, SG, Glenn, S, Glenzer, SH, Goade, S, Gobby, PL, Goldman, SR, Golick, B, Gomez, M, Goncharov, V, Goodin, D, Grabowski, P, Grafil, E, Graham, P, Grandy, J, Grasz, E, Graziani, F, Greenman, G, Greenough, JA, Greenwood, A, Gregori, G, Green, T, Griego, JR, Grim, GP, Grondalski, J, Gross, S, Guckian, J, Guler, N, Gunney, B, Guss, G, Haan, S, Hackbarth, J, Hackel, L, Hackel, R, Haefner, C, Hagmann, C, Hahn, KD, Hahn, S, Haid, BJ, Haines, BM, Hall, BM, Hall, C, Hall, GN, Hamamoto, M, Hamel, S, Hamilton, CE, Hammel, BA, Hammer, JH, Hampton, G, Hamza, A, Handler, A, Hansen, S, Hanson, D, Haque, R, Harding, D, Harding, E, Hares, JD, Harris, DB, Harte, JA, Hartouni, EP, Hatarik, R, Hatchett, S, Hauer, AA, Havre, M, Hawley, R, Hayes, J, Hayes, S, Hayes-Sterbenz, A, Haynam, CA, Haynes, DA, Headley, D, Heal, A, Heebner, JE, Heerey, S, Heestand, GM, Heeter, R, Hein, N, Heinbockel, C, Hendricks, C, Henesian, M, Heninger, J, Henrikson, J, Henry, EA, Herbold, EB, Hermann, MR, Hermes, G, Hernandez, JE, Hernandez, VJ, Herrmann, MC, Herrmann, HW, Herrera, OD, Hewett, D, Hibbard, R, Hicks, DG, Hill, D, Hill, K, Hilsabeck, T, Hinkel, DE, Ho, DD, Ho, VK, Hoffer, JK, Hoffman, NM, Hohenberger, M, Hohensee, M, Hoke, W, Holdener, D, Holdener, F, Holder, JP, Holko, B, Holunga, D, Holzrichter, JF, Honig, J, Hoover, D, Hopkins, D, Berzak Hopkins, L, Hoppe, M, Hoppe, ML, Horner, J, Hornung, R, Horsfield, CJ, Horvath, J, Hotaling, D, House, R, Howell, L, Hsing, WW, Hu, SX, Huang, H, Huckins, J, Hui, H, Humbird, KD, Hund, J, Hunt, J, Hurricane, OA, Hutton, M, Huynh, KH-K, Inandan, L, Iglesias, C, Igumenshchev, IV, Izumi, N, Jackson, M, Jackson, J, Jacobs, SD, James, G, Jancaitis, K, Jarboe, J, Jarrott, LC, Jasion, D, Jaquez, J, Jeet, J, Jenei, AE, Jensen, J, Jimenez, J, Jimenez, R, Jobe, D, Johal, Z, Johns, HM, Johnson, D, Johnson, MA, Gatu Johnson, M, Johnson, RJ, Johnson, S, Johnson, SA, Johnson, T, Jones, K, Jones, O, Jones, M, Jorge, R, Jorgenson, HJ, Julian, M, Jun, BI, Jungquist, R, Kaae, J, Kabadi, N, Kaczala, D, Kalantar, D, Kangas, K, Karasiev, VV, Karasik, M, Karpenko, V, Kasarky, A, Kasper, K, Kauffman, R, Kaufman, MI, Keane, C, Keaty, L, Kegelmeyer, L, Keiter, PA, Kellett, PA, Kellogg, J, Kelly, JH, Kemic, S, Kemp, AJ, Kemp, GE, Kerbel, GD, Kershaw, D, Kerr, SM, Kessler, TJ, Key, MH, Khan, SF, Khater, H, Kiikka, C, Kilkenny, J, Kim, Y, Kim, Y-J, Kimko, J, Kimmel, M, Kindel, JM, King, J, Kirkwood, RK, Klaus, L, Klem, D, Kline, JL, Klingmann, J, Kluth, G, Knapp, P, Knauer, J, Knipping, J, Knudson, M, Kobs, D, Koch, J, Kohut, T, Kong, C, Koning, JM, Koning, P, Konior, S, Kornblum, H, Kot, LB, Kozioziemski, B, Kozlowski, M, Kozlowski, PM, Krammen, J, Krasheninnikova, NS, Kraus, B, Krauser, W, Kress, JD, Kritcher, AL, Krieger, E, Kroll, JJ, Kruer, WL, Kruse, MKG, Kucheyev, S, Kumbera, M, Kumpan, S, Kunimune, J, Kustowski, B, Kwan, TJT, Kyrala, GA, Laffite, S, Lafon, M, LaFortune, K, Lahmann, B, Lairson, B, Landen, OL, Langenbrunner, J, Lagin, L, Land, T, Lane, M, Laney, D, Langdon, AB, Langer, SH, Langro, A, Lanier, NE, Lanier, TE, Larson, D, Lasinski, BF, Lassle, D, LaTray, D, Lau, G, Lau, N, Laumann, C, Laurence, A, Laurence, TA, Lawson, J, Le, HP, Leach, RR, Leal, L, Leatherland, A, LeChien, K, Lechleiter, B, Lee, A, Lee, M, Lee, T, Leeper, RJ, Lefebvre, E, Leidinger, J-P, LeMire, B, Lemke, RW, Lemos, NC, Le Pape, S, Lerche, R, Lerner, S, Letts, S, Levedahl, K, Lewis, T, Li, CK, Li, H, Li, J, Liao, W, Liao, ZM, Liedahl, D, Liebman, J, Lindford, G, Lindman, EL, Lindl, JD, Loey, H, London, RA, Long, F, Loomis, EN, Lopez, FE, Lopez, H, Losbanos, E, Loucks, S, Lowe-Webb, R, Lundgren, E, Ludwigsen, AP, Luo, R, Lusk, J, Lyons, R, Ma, T, Macallop, Y, MacDonald, MJ, MacGowan, BJ, Mack, JM, Mackinnon, AJ, MacLaren, SA, MacPhee, AG, Magelssen, GR, Magoon, J, Malone, RM, Malsbury, T, Managan, R, Mancini, R, Manes, K, Maney, D, Manha, D, Mannion, OM, Manuel, AM, Mapoles, E, Mara, G, Marcotte, T, Marin, E, Marinak, MM, Mariscal, C, Mariscal, DA, Mariscal, EF, Marley, EV, Marozas, JA, Marquez, R, Marshall, CD, Marshall, FJ, Marshall, M, Marshall, S, Marticorena, J, Martinez, D, Maslennikov, I, Mason, D, Mason, RJ, Masse, L, Massey, W, Masson-Laborde, P-E, Masters, ND, Mathisen, D, Mathison, E, Matone, J, Matthews, MJ, Mattoon, C, Mattsson, TR, Matzen, K, Mauche, CW, Mauldin, M, McAbee, T, McBurney, M, Mccarville, T, McCrory, RL, McEvoy, AM, McGuffey, C, Mcinnis, M, McKenty, P, McKinley, MS, McLeod, JB, McPherson, A, Mcquillan, B, Meamber, M, Meaney, KD, Meezan, NB, Meissner, R, Mehlhorn, TA, Mehta, NC, Menapace, J, Merrill, FE, Merritt, BT, Merritt, EC, Meyerhofer, DD, Mezyk, S, Mich, RJ, Michel, PA, Milam, D, Miller, C, Miller, D, Miller, DS, Miller, E, Miller, EK, Miller, J, Miller, M, Miller, PE, Miller, T, Miller, W, Miller-Kamm, V, Millot, M, Milovich, JL, Minner, P, Miquel, J-L, Mitchell, S, Molvig, K, Montesanti, RC, Montgomery, DS, Monticelli, M, Montoya, A, Moody, JD, Moore, AS, Moore, E, Moran, M, Moreno, JC, Moreno, K, Morgan, BE, Morrow, T, Morton, JW, Moses, E, Moy, K, Muir, R, Murillo, MS, Murray, JE, Murray, JR, Munro, DH, Murphy, TJ, Munteanu, FM, Nafziger, J, Nagayama, T, Nagel, SR, Nast, R, Negres, RA, Nelson, A, Nelson, D, Nelson, J, Nelson, S, Nemethy, S, Neumayer, P, Newman, K, Newton, M, Nguyen, H, Di Nicola, J-MG, Di Nicola, P, Niemann, C, Nikroo, A, Nilson, PM, Nobile, A, Noorai, V, Nora, R, Norton, M, Nostrand, M, Note, V, Novell, S, Nowak, PF, Nunez, A, Nyholm, RA, O'Brien, M, Oceguera, A, Oertel, JA, Okui, J, Olejniczak, B, Oliveira, J, Olsen, P, Olson, B, Olson, K, Olson, RE, Opachich, YP, Orsi, N, Orth, CD, Owen, M, Padalino, S, Padilla, E, Paguio, R, Paguio, S, Paisner, J, Pajoom, S, Pak, A, Palaniyappan, S, Palma, K, Pannell, T, Papp, F, Paras, D, Parham, T, Park, H-S, Pasternak, A, Patankar, S, Patel, MV, Patel, PK, Patterson, R, Patterson, S, Paul, B, Paul, M, Pauli, E, Pearce, OT, Pearcy, J, Pedrotti, B, Peer, A, Pelz, LJ, Penetrante, B, Penner, J, Perez, A, Perkins, LJ, Pernice, E, Perry, TS, Person, S, Petersen, D, Petersen, T, Peterson, DL, Peterson, EB, Peterson, JE, Peterson, JL, Peterson, K, Peterson, RR, Petrasso, RD, Philippe, F, Phipps, TJ, Piceno, E, Ping, Y, Pickworth, L, Pino, J, Plummer, R, Pollack, GD, Pollaine, SM, Pollock, BB, Ponce, D, Ponce, J, Pontelandolfo, J, Porter, JL, Post, J, Poujade, O, Powell, C, Powell, H, Power, G, Pozulp, M, Prantil, M, Prasad, M, Pratuch, S, Price, S, Primdahl, K, Prisbrey, S, Procassini, R, Pruyne, A, Pudliner, B, Qiu, SR, Quan, K, Quinn, M, Quintenz, J, Radha, PB, Rainer, F, Ralph, JE, Raman, KS, Raman, R, Rambo, P, Rana, S, Randewich, A, Rardin, D, Ratledge, M, Ravelo, N, Ravizza, F, Rayce, M, Raymond, A, Raymond, B, Reed, B, Reed, C, Regan, S, Reichelt, B, Reis, V, Reisdorf, S, Rekow, V, Remington, BA, Rendon, A, Requieron, W, Rever, M, Reynolds, H, Reynolds, J, Rhodes, J, Rhodes, M, Richardson, MC, Rice, B, Rice, NG, Rieben, R, Rigatti, A, Riggs, S, Rinderknecht, HG, Ring, K, Riordan, B, Riquier, R, Rivers, C, Roberts, D, Roberts, V, Robertson, G, Robey, HF, Robles, J, Rocha, P, Rochau, G, Rodriguez, J, Rodriguez, S, Rosen, M, Rosenberg, M, Ross, G, Ross, JS, Ross, P, Rouse, J, Rovang, D, Rubenchik, AM, Rubery, MS, Ruiz, CL, Rushford, M, Russ, B, Rygg, JR, Ryujin, BS, Sacks, RA, Sacks, RF, Saito, K, Salmon, T, Salmonson, JD, Sanchez, J, Samuelson, S, Sanchez, M, Sangster, C, Saroyan, A, Sater, J, Satsangi, A, Sauers, S, Saunders, R, Sauppe, JP, Sawicki, R, Sayre, D, Scanlan, M, Schaffers, K, Schappert, GT, Schiaffino, S, Schlossberg, DJ, Schmidt, DW, Schmitt, MJ, Schneider, DHG, Schneider, MB, Schneider, R, Schoff, M, Schollmeier, M, Schölmerich, M, Schroeder, CR, Schrauth, SE, Scott, HA, Scott, I, Scott, JM, Scott, RHH, Scullard, CR, Sedillo, T, Seguin, FH, Seka, W, Senecal, J, Sepke, SM, Seppala, L, Sequoia, K, Severyn, J, Sevier, JM, Sewell, N, Seznec, S, Shah, RC, Shamlian, J, Shaughnessy, D, Shaw, M, Shaw, R, Shearer, C, Shelton, R, Shen, N, Sherlock, MW, Shestakov, AI, Shi, EL, Shin, SJ, Shingleton, N, Shmayda, W, Shor, M, Shoup, M, Shuldberg, C, Siegel, L, Silva, FJ, Simakov, AN, Sims, BT, Sinars, D, Singh, P, Sio, H, Skulina, K, Skupsky, S, Slutz, S, Sluyter, M, Smalyuk, VA, Smauley, D, Smeltser, RM, Smith, C, Smith, I, Smith, J, Smith, L, Smith, R, Sohn, R, Sommer, S, Sorce, C, Sorem, M, Soures, JM, Spaeth, ML, Spears, BK, Speas, S, Speck, D, Speck, R, Spears, J, Spinka, T, Springer, PT, Stadermann, M, Stahl, B, Stahoviak, J, Stanton, LG, Steele, R, Steele, W, Steinman, D, Stemke, R, Stephens, R, Sterbenz, S, Sterne, P, Stevens, D, Stevers, J, Still, CB, Stoeckl, C, Stoeffl, W, Stolken, JS, Stolz, C, Storm, E, Stone, G, Stoupin, S, Stout, E, Stowers, I, Strauser, R, Streckart, H, Streit, J, Strozzi, DJ, Suratwala, T, Sutcliffe, G, Suter, LJ, Sutton, SB, Svidzinski, V, Swadling, G, Sweet, W, Szoke, A, Tabak, M, Takagi, M, Tambazidis, A, Tang, V, Taranowski, M, Taylor, LA, Telford, S, Theobald, W, Thi, M, Thomas, A, Thomas, CA, Thomas, I, Thomas, R, Thompson, IJ, Thongstisubskul, A, Thorsness, CB, Tietbohl, G, Tipton, RE, Tobin, M, Tomlin, N, Tommasini, R, Toreja, AJ, Torres, J, Town, RPJ, Townsend, S, Trenholme, J, Trivelpiece, A, Trosseille, C, Truax, H, Trummer, D, Trummer, S, Truong, T, Tubbs, D, Tubman, ER, Tunnell, T, Turnbull, D, Turner, RE, Ulitsky, M, Upadhye, R, Vaher, JL, VanArsdall, P, VanBlarcom, D, Vandenboomgaerde, M, VanQuinlan, R, Van Wonterghem, BM, Varnum, WS, Velikovich, AL, Vella, A, Verdon, CP, Vermillion, B, Vernon, S, Vesey, R, Vickers, J, Vignes, RM, Visosky, M, Vocke, J, Volegov, PL, Vonhof, S, Von Rotz, R, Vu, HX, Vu, M, Wall, D, Wall, J, Wallace, R, Wallin, B, Walmer, D, Walsh, CA, Walters, CF, Waltz, C, Wan, A, Wang, A, Wang, Y, Wark, JS, Warner, BE, Watson, J, Watt, RG, Watts, P, Weaver, J, Weaver, RP, Weaver, S, Weber, CR, Weber, P, Weber, SV, Wegner, P, Welday, B, Welser-Sherrill, L, Weiss, K, Widmann, K, Wheeler, GF, Whistler, W, White, RK, Whitley, HD, Whitman, P, Wickett, ME, Widmayer, C, Wiedwald, J, Wilcox, R, Wilcox, S, Wild, C, Wilde, BH, Wilde, CH, Wilhelmsen, K, Wilke, MD, Wilkens, H, Wilkins, P, Wilks, SC, Williams, EA, Williams, GJ, Williams, W, Williams, WH, Wilson, DC, Wilson, B, Wilson, E, Wilson, R, Winters, S, Wisoff, J, Wittman, M, Wolfe, J, Wong, A, Wong, KW, Wong, L, Wong, N, Wood, R, Woodhouse, D, Woodruff, J, Woods, DT, Woods, S, Woodworth, BN, Wooten, E, Wootton, A, Work, K, Workman, JB, Wright, J, Wu, M, Wuest, C, Wysocki, FJ, Xu, H, Yamaguchi, M, Yang, B, Yang, ST, Yatabe, J, Yeamans, CB, Yee, BC, Yi, SA, Yin, L, Young, B, Young, CS, Young, CV, Young, P, Youngblood, K, Zacharias, R, Zagaris, G, Zaitseva, N, Zaka, F, Ze, F, Zeiger, B, Zika, M, Zimmerman, GB, Zobrist, T, Zuegel, JD, Zylstra, AB, Indirect Drive ICF Collaboration, Collaboration, Indirect Drive ICF, AWE Plc, Lawrence Livermore National Laboratory, and U.S Department of Energy

Subjects
General Physics, 02 Physical Sciences, General Physics and Astronomy, Indirect Drive ICF Collaboration, 01 Mathematical Sciences, 09 Engineering
Abstract

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Published
2022

6. Additional file 1 of Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions

Author

Goodin, D. S., Khankhanian, P., Gourraud, P. A., and Vince, N.

Subjects
animal structures, embryonic structures
Abstract

Additional file 1: This Supplemental File describes composition of the CEHs found in the WTCCC dataset as well as their individual relationships to MS susceptibility, the impact on susceptibility of various combinations either of CEHs at the MHC or of the non-MHC loci and, finally, how this CEH composition differs between populations around the world. Furthermore, this file considers the theoretical underpinnings for the commonly used additive and multiplicative Models for the accumulation of disease “risk” with increasing number of “risk haplotypes” being present in an individual’s genotype.

Published
2021
Full Text
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11. Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures

Author

Okuda, D. T., Srinivasan, R., Oksenberg, J. R., Goodin, D. S., Baranzini, S. E., Beheshtian, A., Waubant, E., Zamvil, S. S., Leppert, D., Qualley, P., Lincoln, R., Gomez, R., Caillier, S., George, M., Wang, J., Nelson, S. J., Cree, B. A. C., Hauser, S. L., Pelletier, D., Okuda, D. T., Srinivasan, R., Oksenberg, J. R., Goodin, D. S., Baranzini, S. E., Beheshtian, A., Waubant, E., Zamvil, S. S., Leppert, D., Qualley, P., Lincoln, R., Gomez, R., Caillier, S., George, M., Wang, J., Nelson, S. J., Cree, B. A. C., Hauser, S. L., and Pelletier, D.

Abstract

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via 1HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm3; P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention

Published
2017

12. 250 mu g or 500 mu g interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study

Author

O'Connor, P., Filippi, M., Arnason, B., Comi, G., Cook, S., Goodin, D., Hartung, H., Jeffery, D., Kappos, L., Boateng, F., Filippov, V., Groth, M., Knappertz, V., Kraus, C., Sandbrink, R., Pohl, C., BogumilAbramsky O, T., Achiron, A, Agius, M, Aichner, F, Altenkirch, H, Amato, Mp, Anten, B, Arbizu, T, Ash, P, Ballario, C, Bashir, K, Baum, K, Baumhackl, U, Beaver, G, Belova, A, Berger, J, Berger, T, Berlit, P, Beuche, W, Bhan, V, Bigley, K, Bissay, V, Blake, C, Bö, L, Boyko, A, Brochet, B, Brown, M, Callegaro, D, Carra, A, Carroll, W, Cascione, M, Christie, S, Clanet, M, Clavelou, P, Clementino, Vi, Confavreux, C, Cooper, J, Cross, A, Csanyi, A, Czlonkowska, A, D'Hooghe, M, Damier, P, Debouverie, M, Defer, G, Demina, T, Deri, N, Diem, R, Dressel, A, Dubois, B, Dunne, P, Duquette, P, Durelli, L, Edan, G, Elias, S, Elovaara, I, Esfahani, F, Evtushenko, S, Fabijan, Th, Fernández, O, Ferreira, Ml, Fink, A, Flechter, S, Ford, C, Francesconi, C, Freedman, M, Fryze, W, Gabbai, A, Gács, G, Gallo, Paolo, Gazda, S, Gerloff, C, Glyman, S, Goodman, A, Gottesman, M, Grand'Maison, F, Guarnaccia, J, Gutierrez, A, Haas, J, Hansen, Hj, Hardiman, O, Heard, R, Heidenreich, F, Herbert, J, Herminia Scola, R, Hodgkinson, S, Hoffmann, F, Holub, R, Huddlestone, J, Hughes, B, Hughes, M, Hunter, S, Hurwitz, B, Izquierdo, G, Jacobasch, E, Jacques, F, Jakab, G, Jongen, P, Karageorgiou, C, Karni, A, Kasper, L, Kaufman, M, Keidel, M, Khatri, B, Kiefer, R, Kirzinger, S, Kita, M, Komoly, S, Kotov, S, Kozubski, W, Kumlien, E, Kwiecinski, H, Labouge, P, Laganke, C, Lapierre, Y, Lebrun Frenay, C, Leist, T, Leon, Sa, Luetic, G, Lynch, S, Lynch, T, Malkova, N, Maltezou, M, Markowitz, C, Martin, C, Mattle, H, Mattson, D, Metra, M, Meyding Lamadé, U, Milo, R, Milonas, I, Miller, A, Miller, T, Minagar, A, Mitchell, G, Moreau, T, Mosberg, R, Murphy, R, Nehrych, T, Nikl, J, Odinak, M, Oschmann, P, Owen King, J, Pagani, L, Pereira Damasceno, B, Podemski, R, Pöhlau, D, Pozzilli, C, Rammohan, K, Reunanen, M, Rice, G, Richardson, P, Rivera, V, Rizvi, S, Rogozhyn, V, Rolak, L, Rosenkranz, T, Rotta, R, Sanders, E, Sater, R, Satgur Gupta, A, Schwartz, R, Sedal, L, Sega Jazbec, S, Selchen, D, Selmaj, K, Sheremata, W, Shvets, T, Silver, D, Simsarian, J, Skoromets, A, Smiroldo, J, Sokolova, L, Solovyova, Y, Sommer, N, Spirin, N, Stangel, M, Stark, E, Steinbrecher, A, Stemper, B, Stolyarov, I, Strasser Fuchs, S, Sweeney, B, Tettenborn, B, Thrower, B, Tilbery, Cp, Traboulsee, A, Trojano, M, Tubridy, N, Tyor, W, Valikovics, A, Vermersch, P, Vollmer, T, Voloshyna, N, Vrech, C, Wajgt, A, Weller, B, Wendt, J, Yakhno, N, Yeung, M, Zavalishin, I., O'Connor, P, Filippi, Massimo, Arnason, B, Comi, G, Cook, S, Goodin, D, Hartung, Hp, Jeffery, D, Kappos, L, Boateng, F, Filippov, V, Groth, M, Knappertz, V, Kraus, C, Sandbrink, R, Pohl, C, Bogumil, T., and Dubois, Bénédicte

Subjects
Adult, Male, medicine.medical_specialty, interferon beta-1b, Adolescent, Pharmacology, relapsing-remitting multiple sclerosis, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Humans, Immunologic Factors, Glatiramer acetate, Adverse effect, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Interferon beta-1b, Brain, Glatiramer Acetate, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Tolerability, glatiramer acetate, Female, Neurology (clinical), business, Peptides, medicine.drug
Abstract

BACKGROUND: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. METHODS: Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. FINDINGS: We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p

Published
2009

13. Incidence and course of depression in multiple sclerosis in the multinational BEYOND trial

Author

Schippling, S, O'Connor, P, Knappertz, V, Pohl, C, Bogumil, T, Suarez, G, Cook, S, Filippi, M, Hartung, H P, Comi, G, Jeffery, D R, Kappos, L, Goodin, D S, Arnason, B, Schippling, S, O'Connor, P, Knappertz, V, Pohl, C, Bogumil, T, Suarez, G, Cook, S, Filippi, M, Hartung, H P, Comi, G, Jeffery, D R, Kappos, L, Goodin, D S, and Arnason, B

Abstract

Early experience in MS generated concerns that interferon beta treatment might provoke onset or worsening of depression. The objective of the study was to compare depression incidence in relapsing-remitting MS patients receiving interferon beta-1b (IFNB-1b) or glatiramer acetate (GA) in the BEYOND trial. 891/897 (99 %) of English, French, Spanish and Italian speakers among 2244 patients randomized (2:2:1) to receive either IFNB-1b 500 µg, 250 µg, or GA 20 mg QD for 2-3.5 years submitted Beck Depression Inventory Second Edition (BDI-II) scores at screening and serially thereafter, in which scores ≥14 indicated depression. Baseline BDI-II scores ≥14 were reported in 232/891 patients (26.3 %), with no meaningful difference among the three treatment arms noted at this or at any other time during the study including trial end. Percentages of patients depressed by BDI-II scores deviated little in any arm at any time (IFNB-1b 500 µg: 24.7 %, IFNB-1b 250 µg: 24.4 %, GA: 32.4 %). Antidepressant usage was likewise similar among the three treatment arms (IFNB-1b 500 µg: 33.7 %, IFNB-1b 250 µg: 31.8 %, GA: 28.8 %) as was depression severity and the frequency with which non-blinded treating physicians recorded depression as an adverse event (IFNB-1b 500 µg: 17.2 %, IFNB-1b 250 µg: 17.0 %, GA: 14.4 %). Treating physicians attributed depression to IFNB-1b 250 µg therapy in 53.6 % and to GA in 21.9 % of instances. This large, prospective, randomized-controlled MS dataset showed no increased risk of depression above baseline values with standard or double-dose IFNB-1b or GA QD treatment.

Published
2016

15. The good and the bad of neuroinflammation in multiple sclerosis

Author

Goodin, Douglas, Goodin, D ( Douglas ), Naegele, Matthias, Martin, Roland, Goodin, Douglas, Goodin, D ( Douglas ), Naegele, Matthias, and Martin, Roland

Abstract

Multiple sclerosis (MS) is the most common inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS). It is widely considered a T-cell mediated autoimmune disease that develops in genetically susceptible individuals, possibly under the influence of certain environmental trigger factors. The invasion of autoreactive CD4+ T-cells into the CNS is thought to be a central step that initiates the disease. Several other cell types, including CD8+ T-cells, B-cells and phagocytes appear to be involved in causing inflammation and eventually neurodegeneration. But inflammation is not entirely deleterious in MS. Evidence has accumulated in the recent years that show the importance of regulatory immune mechanisms which restrain tissue damage and initiate regeneration. More insight into the beneficial aspects of neuroinflammation might allow us to develop new treatment strategies for this enigmatic disease.

Published
2014

16. Interferons in relapsing remitting multiple sclerosis [1] (multiple letters)

Author

Goodin, D. S., Kappos, L., Kesselring, J., Paty, D., Arnason, B., Li, D., Traboulsee, A., Freedman, M., King, J., Oger, J., Sharief, M., Hartung, H. -P., Filippini, G., Munari, L., Ebers, G. C., D'Amico, R., Rice, G. P. A., Rudick, R. A., Cookfair, D. L., Griffin, J., Hauser, S., Piantadosi, S., Kolar, O. J., Bauerle, J. A., and Lee, H.

Published
2003

17. Patient preferences for attributes of disease modifying Therapies: Results of a choice based conjoint analysis

Author

Wilson, L.S., primary, Loucks, A., additional, Bui, C.T., additional, Gipson, G., additional, Zhong, L., additional, Tang, J., additional, Goodin, D., additional, Owen, M., additional, Waubaunt, E., additional, Cree, B., additional, Schwartzburg, A., additional, Miller, E., additional, Macedo, A., additional, Scott, D., additional, and McCulloch, C.E., additional

Published
2013
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18. Assessment: Dermatomal somatosensory evoked potentials

Author

Ferguson, JH, Brin, M, Goldstein, ML, Gorelich, PB, Hanley, DF, Lange, DJ, Nuwer, MR, Roach, ES, Goldman, R, Goodin, D, and Marini, AM

Abstract

The different conclusions reached by studies investigating the utility of DSEPs prevent a confident conclusion regarding utility. Some investigators are strong believers in the diagnostic usefulness of this technique. Others are mere skeptical. One possible cause is variable study design. Most studies provide evidence no higher than level III (case reports, expert opinions). Controlled studies, especially with blinded interpreters of the tests, would provide needed evidence of efficacy in view of the existing confusion in the literature. It is our consensus that the current evidence supporting the diagnostic use of DSEPs is Type D and that DSEPs should be regarded as Investigational, meaning that current evidence is insufficient to determine appropriateness. This group does encourage further study.

Published
1997
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19. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: Experience during the first three years

Author

Duquette, P, Girard, M, Dubois, R, Kobler, RL, Lublin, F, Kelley, L, Francis, GS, Freedman, M, Greenstein, JI, Mishra, B, DeLillio, N, Whitaker, J, Layton, B, Sibley, WA, Laguna, J, Krikawa, J, Paty, DW, Oger, JJ, Kastrukoff, LF, Morrison, W, Nelson, J, Goodin, D, Massa, SM, Gutteridge, E, Arnason, BGW, Noronha, A, Reder, AT, Martia, R, Ebers, GC, Rice, GPA, Lesaux, J, Johnson, KP, Panitch, HS, Bever, CT, Conway, K, Li, DKB, Tanton, EL, Zhao, GJ, Flak, B, Riddebough, A, Cover, K, Rhodes, B, Cook, A, Smith, K, Costley, L, Renneberg, S, Shaw, T, Genton, M, vandenNoort, S, Weinshenker, B, Weiss, W, Reingold, S, Taylor, W, Wallenberg, JC, Bedell, L, and Lublin, FD

Subjects
medicine.medical_specialty, Neurology, Expanded Disability Status Scale, Exacerbation, business.industry, Multiple sclerosis, Interferon beta-1b, medicine.disease, Placebo, Regimen, Internal medicine, Multicenter trial, medicine, Neurology (clinical), business
Abstract

Evidence of diminution of therapeutic efficacy in 35% of interferon beta-1b (IFNB)-treated multiple sclerosis (MS) patients who developed neutralizing antibodies (NABs) led to extensive study of the effects of NABs on therapeutic benefits, side effects, and magnetic resonance imaging (MRI) data. First, we validated the IFNB NAB assay used in the multicenter trial by having representative stored serum samples reanalyzed by an independent laboratory. When NABs developed (as defined), usually in the first year, the exacerbation rates after 18 months resembled placebo rates, the numbers of enlarging MRI lesions significantly increased compared with those in NAB-negative patients, and there was increased new lesion formation in the MRI (p = 0.067). However, worsening of the mean Expanded Disability Status Scale score in the 8-MIU treatment arm was higher in patients who remained NAB-negative in the third year (p = 0.083). NAB-positive patients were not overrepresented among the noncompleters, or in five patients having at least one episode of skin-site necrosis. After 18 months, flu-like symptoms were about twice as common in NAB-negative as in NAB-positive patients, although the frequency did not exceed 21% in any semester. Decisions to discontinue IFNB therapy should be made individually based on clinical response and a positive titer of NABs in the serum with the use of a reliable assay. ELISA and Western blot techniques measure binding antibodies, not NABs specifically, and are unsuitable for use. Possible, but as yet unproven, means of dealing with NAB positivity should be studied in properly designed trials. IFNB-1b remains an effective therapy for a majority (65%) of MS patients having relapses. The annual exacerbation rates in NAB-negative patients receiving the 8-MIU dosage regimen are about 50% of those seen in untreated patients, a greater reduction than the one-third reduction earlier reported for the entire high-dose arm, and a meaningful treatment benefit. NEUROLOGY 1996;47: 889-894

Published
1996

20. The Science and Technologies for Fusion Energy With Lasers and Direct-Drive Targets

Author

Sethian, J. D., primary, Colombant, D. G., additional, Giuliani, J. L., additional, Lehmberg, R. H., additional, Myers, M. C., additional, Obenschain, S. P., additional, Schmitt, A. J., additional, Weaver, J., additional, Wolford, M. F., additional, Hegeler, F., additional, Friedman, M., additional, Robson, A. E., additional, Bayramian, A., additional, Caird, J., additional, Ebbers, C., additional, Latkowski, J., additional, Hogan, W., additional, Meier, W. R., additional, Perkins, L. J., additional, Schaffers, K., additional, Abdel Kahlik, S., additional, Schoonover, K., additional, Sadowski, D., additional, Boehm, K., additional, Carlson, L., additional, Pulsifer, J., additional, Najmabadi, F., additional, Raffray, A. R., additional, Tillack, M. S., additional, Kulcinski, G., additional, Blanchard, J. P., additional, Heltemes, T., additional, Ibrahim, A., additional, Marriott, E., additional, Moses, G., additional, Radell, R., additional, Sawan, M., additional, Santarius, J., additional, Sviatoslavsky, G., additional, Zenobia, S., additional, Ghoniem, N. M., additional, Sharafat, S., additional, El-Awady, J., additional, Hu, Q., additional, Duty, C., additional, Leonard, K., additional, Romanoski, G., additional, Snead, L. L., additional, Zinkle, S. J., additional, Gentile, C., additional, Parsells, W., additional, Prinksi, C., additional, Kozub, T., additional, Dodson, T., additional, Rose, D. V., additional, Renk, T., additional, Olson, C., additional, Alexander, N., additional, Bozek, A., additional, Flint, G., additional, Goodin, D. T., additional, Hund, J., additional, Paguio, R., additional, Petzoldt, R. W., additional, Schroen, D. G., additional, Sheliak, J., additional, Bernat, T., additional, Bittner, D., additional, Karnes, J., additional, Petta, N., additional, Streit, J., additional, Geller, D., additional, Hoffer, J. K., additional, McGeoch, M. W., additional, Glidden, S. C., additional, Sanders, H., additional, Weidenheimer, D., additional, Morton, D., additional, Smith, I. D., additional, Bobecia, M., additional, Harding, D., additional, Lehecka, T., additional, Gilliam, S. B., additional, Gidcumb, S. M., additional, Forsythe, D., additional, Parikh, N. R., additional, O'Dell, S., additional, and Gorensek, M., additional

Published
2010
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23. Energetics of Cation Radical Formation at the Proximal Active Site Tryptophan of Cytochrome-c-Peroxidase and Ascorbate Peroxidase.

Author

ARMY RESEARCH LAB ABERDEEN PROVING GROUND MD, Jensen, G. M., Bunte, S. W., Warshel, A., Goodin, D. B., ARMY RESEARCH LAB ABERDEEN PROVING GROUND MD, Jensen, G. M., Bunte, S. W., Warshel, A., and Goodin, D. B.

Abstract

Despite very similar protein structures, ascorbate peroxidase (APX) and yeast cytochrome-c-peroxidase (CCP) stabilize different radical species during enzyme turnover. Both enzymes contain similar active site residues, including the tryptophan that is oxidized to a stable cation radical in CCP. However, the analogous trytophan is not oxidized in APX, and the second oxidizing equivalent is retained as a porphyrin pi-cation radical. In this study, we provide an improved computational approach to estimate the contribution of solvent and protein electrostatics to the energetics of tryptophan cation radical formation in the two enzyme environments. The Protein Dipoles Langevin Dipoles (PDLD) model is combined with molecular dynamics to estimate the role of discrete solvation, atomic polarizabilitis, and dynamic motional averaging on the electrostatic potentials. The PDLD model shows that the protein environment of CCP stabilizes the tryptophan cation radical by 330 mV relative to that in APX. Analysis of the components contributing to this difference supports proposals that the cation binding site contributes to, but is not the sole cause of, the different sites of radical stabilization. The enzymes have thus evolved this distinction using several contributing interactions including the cation binding site, solvent access, and subtle differences in protein structure and dynamics., Prepared in cooperation with The Scripps Research Institute, LaJolla, Ca. and University of Southern California, Ca.

Published
1998

25. Density Functional and MP2 Calculations of Spin Densities of Oxidized 3-Methyl Indole. Models for Tryptophan Radicals.

Author

ARMY RESEARCH LAB ABERDEEN PROVING GROUND MD, Jensen, G. M., Goodin, D. B., Bunte, S. W., ARMY RESEARCH LAB ABERDEEN PROVING GROUND MD, Jensen, G. M., Goodin, D. B., and Bunte, S. W.

Abstract

Ab initio calculations have been carried out on 3-methyl indole, and the cation and neutral radicals of 3-methyl indole, using Density Functional Theory (DFT), the Becke3-Lee-Yang-Parr functional, and the 6-31G*, 6-31+G*, 3-21G*, and TZ2P basis sets. Optimized geometries, vibrational frequencies and, for the radicals, atomic spin densities are calculated. The latter are compared to experimental spin densities recently determined for the tryptophan-191 radical of compound ES of the enzyme cytochrome-c-peroxidase. The DFT spin densities for the cation radical of 3-methyl indole are in excellent agreement with the data for the tryptophan-l91 radical, which supports the conclusion that the tryptophan radical is a cation radical. The results are compared to calculations using second-order Moller-Plesset theory (MP2) and the 6-31G** basis set. The MP2 spin densities are in significantly worse agreement with the experiment spin densities. jg p3, Prepared in collaboration with Scripps Research Inst., La Jolla, CA.

Published
1996

32. Magnitude and sources of variation in albedo within an alpine tundra.

Author

Goodin, D. and Isard, S.

Abstract

Copyright of Theoretical & Applied Climatology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
1989
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33. Unusual oxidative chemistry of N(omega)-hydroxyarginine and N-hydroxyguanidine catalyzed at an engineered cavity in a heme peroxidase.

Author

Hirst, J and Goodin, D B

Abstract

Heme enzymes are capable of catalyzing a range of oxidative chemistry with high specificity, depending on the surrounding protein environment. We describe here a reaction catalyzed by a mutant of cytochrome c peroxidase, which is similar but distinct from those catalyzed by nitric-oxide synthase. In the R48A mutant, an expanded water-filled cavity was created above the distal heme face. N-hydroxyguanidine (NHG) but not guanidine was shown to bind in the cavity with K(d) = 8.5 mM, and coordinate to the heme to give a low spin state. Reaction of R48A with peroxide produced a Fe(IV)=O/Trp(.+) center capable of oxidizing either NHG or N(omega)-hydroxyarginine (NHA), but not arginine or guanidine, by a multi-turnover catalytic process. Oxidation of either NHG or NHA by R48A did not result in the accumulation of NO, NO(2)(-), NO(3)(-), urea, or citrulline, but instead afforded a yellow product with absorption maxima of 257 and 400 nm. Mass spectrometry of the derivatized NHA products identified the yellow species as N-nitrosoarginine. We suggest that a nitrosylating agent, possibly derived from HNO, is produced by the oxidation of one molecule of substrate. This then reacts with a second substrate molecule to form the observed N-nitroso products. This complex chemistry illustrates how the active sites of enzymes such as nitric-oxide synthase may serve to prevent alternative reactions from occurring, in addition to enabling those desired.

Published
2000

34. Studies of the radical species in compound ES of cytochrome c peroxidase altered by site-directed mutagenesis.

Author

Goodin, D B, Mauk, A G, and Smith, M

Abstract

Yeast cytochrome c peroxidase reacts with hydrogen peroxide to form an intermediate, compound ES, in which the heme iron atom is converted to a ferryl function (Fe4+ = O) and a radical center is generated on a reversibly oxidizable amino acid residue of uncertain identity. As methionine-172 is a possible site of this radical, we have constructed specific variants of cytochrome c peroxidase in which methionine-172 is replaced by serine or cysteine. These mutants and the wild-type enzyme have been expressed in Saccharomyces cerevisiae, purified, and crystallized. Both mutant enzymes are fully active. A stable, reversible, peroxide-induced intermediate with optical properties characteristic of compound ES is observed for the three forms of the enzyme. The electron paramagnetic resonance spectrum of this intermediate at 93 K for the serine mutant exhibits the narrow free-radical signal and hyperfine structure observed for the wild-type enzyme. However, a broader component of the signal that is observed for the wild-type enzyme at this temperature is absent from the spectrum observed with the serine mutant. These results demonstrate that the narrow component of the free-radical signal observed at 93 K cannot reside at methionine-172. The absence of the broader component of the signal for the serine mutant may reflect the loss of spin density on methionine or, alternatively, could arise from conformationally induced changes in the properties of the radical. The results are consistent with a heterogeneity of radical species in the ES complex.

Published
1986
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35. Horseradish peroxidase Phe172-->Tyr mutant. Sequential formation of compound I with a porphyrin radical cation and a protein radical.

Author

Miller, V P, Goodin, D B, Friedman, A E, Hartmann, C, and Ortiz de Montellano, P R

Abstract

A gene coding for the F172Y mutant of horseradish peroxidase isozyme C (HRP) has been constructed and expressed in both Spodoptera frugiperda (SF-9) and Trichoplusia ni egg cell homogenate (HighFive) cells. Homology modeling with respect to three peroxidases for which crystal structures are available places Phe172 on the proximal side of the heme in the vicinity of porphyrin pyrrole ring C. The pH optimum and spectroscopic properties of the F172Y mutant are essentially identical to those of wild type HRP. Vmax values show that the mutant protein retains most of the guaiacol oxidizing activity. Stopped flow studies indicate that Compound I is formed with H2O2 at the same rate (kappa 1 = 1.6 x 10(7) M-1 s-1) at both pH 6.0 and 8.0 as it is with the wild type enzyme. This Compound I species decays rapidly at a rate kappa 2 = 1.01 s-1, pH 7.0, to a second two-electron oxidized species that retains the ferryl (FeIV = O) absorption. EPR studies establish that a ferryl porphyrin radical cation is present in the initial Compound I, but electron transfer from the protein results in formation of a second Compound I species with an unpaired electron on the protein (presumably on Tyr172). The presence or absence of oxidizable amino acids adjacent to the heme is thus a key determinant of whether the second oxidation equivalent in Compound I is found as a porphyrin or protein radical cation.

Published
1995

36. The peroxide complex of yeast cytochrome c peroxidase contains two distinct radical species, neither of which resides at methionine 172 or tryptophan 51.

Author

Goodin, D B, Mauk, A G, and Smith, M

Abstract

The nature of the free radical species observed in the peroxide complex of yeast cytochrome c peroxidase is described for protein variants containing amino acid substitutions at Met-172 and Trp-51. As was the case with Met-172 mutations (Goodin, D.B., Mauk, A.G., and Smith, M. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 1295-1299), Trp-51 can be substituted to give active enzyme. Phe-51-containing enzyme has a higher turnover rate than the original enzyme and exhibits an altered pH dependence. The properties of the isotropic and axial components (Hoffman, B.M., Roberts, J.E., Kang, C.H., and Margoliash, E. (1981) J. Biol. Chem. 256, 6556-6564; Hori, H., and Yonetani, T. (1985) J. Biol. Chem. 260, 349-355) of the EPR signal of the wild-type enzyme-peroxide complex, studied as a function of H2O2 stoichiometry, support proposals (Goodin et al. (1985) and Hori and Yonetani (1985), see above) that two distinct radical species are formed, and spin quantification shows that the isotropic radical is always formed in substoichiometric amounts. The peroxide complexes for proteins containing amino acid substitutions at either Met-172 or Trp-51 exhibit somewhat larger than normal levels of the isotropic radical signal. In addition, these mutants are unlike wild-type enzyme in that the axial EPR signal associated with the peroxide complex is seen only at 10 K and not at 90 K. Thus, neither amino acid can be considered to be the molecular species responsible for either radical signal, but both mutations appear to affect the physical properties of the axial signal representing the major radical species.

Published
1987
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39. Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures

Author

Okuda, D. T., Srinivasan, R., Oksenberg, J. R., Goodin, D. S., Baranzini, S. E., Beheshtian, A., Waubant, E., Zamvil, S. S., Leppert, D., Qualley, P., Lincoln, R., Gomez, R., Caillier, S., George, M., Wang, J., Nelson, S. J., Cree, B. A. C., Hauser, S. L., Pelletier, D., Okuda, D. T., Srinivasan, R., Oksenberg, J. R., Goodin, D. S., Baranzini, S. E., Beheshtian, A., Waubant, E., Zamvil, S. S., Leppert, D., Qualley, P., Lincoln, R., Gomez, R., Caillier, S., George, M., Wang, J., Nelson, S. J., Cree, B. A. C., Hauser, S. L., and Pelletier, D.

Abstract

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via 1HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm3; P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention

43. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

Author

Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, Sandbrink R, Pohl C, Edan G, Kappos L, Miller D, Montalbán X, Polman CH, Freedman MS, Hartung HP, Arnason BGW, COMI , GIANCARLO, Cook S, FILIPPI , MASSIMO, Goodin DS, Jeffery D, O'Connor P, Ebers GC, Langdon D, Reder AT, Traboulsee A, Zipp F, Schimrigk J, Hillert J, Bahlo M, Booth DR, BroadleyS, Brown MA, Browning BL, Browning SR, Butzkueven H, Carroll WM, Chapman C, Foote SJ, Griffiths L, Kermode AG, Kilpatrick TJ, Lechner Scott J, Marriott M, Mason D, Moscato P, Heard RN, Pender MP, Perreau VM, Perera D, Rubio JP, Scott RJ, Slee M, Stankovich J, Stewart GJ, Taylor BV, Tubridy N, Willoughby E, Wiley J, Matthews P, Boneschi F, Compston A, Haines J, Hauser SL, McCauley J, Ivinson A, Oksenberg JR, Pericak Vance M, Sawcer SJ, De Jager PL, Hafler DA, de Bakker PIW, the BSP MS Genetics working group, the steering committees of studies evaluating IFNb 1b, a. CCR1 antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium, Neurology, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, Patsopoulos, Na, Esposito, F, Reischl, J, Lehr, S, Bauer, D, Heubach, J, Sandbrink, R, Pohl, C, Edan, G, Kappos, L, Miller, D, Montalbán, X, Polman, Ch, Freedman, M, Hartung, Hp, Arnason, Bgw, Comi, Giancarlo, Cook, S, Filippi, Massimo, Goodin, D, Jeffery, D, O'Connor, P, Ebers, Gc, Langdon, D, Reder, At, Traboulsee, A, Zipp, F, Schimrigk, J, Hillert, J, Bahlo, M, Booth, Dr, Broadleys, Brown, Ma, Browning, Bl, Browning, Sr, Butzkueven, H, Carroll, Wm, Chapman, C, Foote, Sj, Griffiths, L, Kermode, Ag, Kilpatrick, Tj, Lechner Scott, J, Marriott, M, Mason, D, Moscato, P, Heard, Rn, Pender, Mp, Perreau, Vm, Perera, D, Rubio, Jp, Scott, Rj, Slee, M, Stankovich, J, Stewart, Gj, Taylor, Bv, Tubridy, N, Willoughby, E, Wiley, J, Matthews, P, Boneschi, F, Compston, A, Haines, J, Hauser, Sl, Mccauley, J, Ivinson, A, Oksenberg, Jr, Pericak Vance, M, Sawcer, Sj, De Jager, Pl, Hafler, Da, de Bakker, Piw, the BSP MS Genetics working, Group, the steering committees of studies evaluating IFNb, 1b, A., CCR1 antagonist, Anzgene, Consortium, Genemsa, and International Multiple Sclerosis Genetics, Consortium

Subjects
Male, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, Major Histocompatibility Complex, Animals, Humans, Genetic Predisposition to Disease, International HapMap Project, Genetic association, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Genetics, T-Lymphocytes, Helper-Inducer, Genetic architecture, Neurology, Mutation, Expression quantitative trait loci, Female, Disease Susceptibility, Neurology (clinical), Imputation (genetics)
Abstract

OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

Published
2016
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44. Incidence and course of depression in multiple sclerosis in the multinational BEYOND trial

Author

Massimo Filippi, Stuart D. Cook, Paul O'Connor, Douglas Jeffery, Timon Bogumil, Gustavo Suarez, Giancarlo Comi, Sven Schippling, Ludwig Kappos, Douglas S. Goodin, Barry G. W. Arnason, Christoph Pohl, Hans-Peter Hartung, Volker Knappertz, Schippling, S, O’Connor, P, Knappertz, V, Pohl, C, Bogumil, T, Suarez, G, Cook, S, Filippi, Massimo, Hartung, Hp, Comi, Giancarlo, Jeffery, Dr, Kappos, L, Goodin, D, Arnason, B., and University of Zurich

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, International Cooperation, Clinical Neurology, 610 Medicine & health, Young Adult, 03 medical and health sciences, BEYOND study, 0302 clinical medicine, Adjuvants, Immunologic, Internal medicine, medicine, Humans, 030212 general & internal medicine, Glatiramer acetate, Young adult, Adverse effect, Depression (differential diagnoses), Psychiatric Status Rating Scales, Original Communication, Dose-Response Relationship, Drug, Depression, business.industry, Incidence, Incidence (epidemiology), Interferon beta-1a, Beck Depression Inventory, Glatiramer Acetate, Middle Aged, Interferon beta, Antidepressive Agents, 10040 Clinic for Neurology, Clinical trial, Suicide, 2728 Neurology (clinical), Neurology, 2808 Neurology, Disease Progression, Physical therapy, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Early experience in MS generated concerns that interferon beta treatment might provoke onset or worsening of depression. The objective of the study was to compare depression incidence in relapsing–remitting MS patients receiving interferon beta-1b (IFNB-1b) or glatiramer acetate (GA) in the BEYOND trial. 891/897 (99 %) of English, French, Spanish and Italian speakers among 2244 patients randomized (2:2:1) to receive either IFNB-1b 500 µg, 250 µg, or GA 20 mg QD for 2–3.5 years submitted Beck Depression Inventory Second Edition (BDI-II) scores at screening and serially thereafter, in which scores ≥14 indicated depression. Baseline BDI-II scores ≥14 were reported in 232/891 patients (26.3 %), with no meaningful difference among the three treatment arms noted at this or at any other time during the study including trial end. Percentages of patients depressed by BDI-II scores deviated little in any arm at any time (IFNB-1b 500 µg: 24.7 %, IFNB-1b 250 µg: 24.4 %, GA: 32.4 %). Antidepressant usage was likewise similar among the three treatment arms (IFNB-1b 500 µg: 33.7 %, IFNB-1b 250 µg: 31.8 %, GA: 28.8 %) as was depression severity and the frequency with which non-blinded treating physicians recorded depression as an adverse event (IFNB-1b 500 µg: 17.2 %, IFNB-1b 250 µg: 17.0 %, GA: 14.4 %). Treating physicians attributed depression to IFNB-1b 250 µg therapy in 53.6 % and to GA in 21.9 % of instances. This large, prospective, randomized-controlled MS dataset showed no increased risk of depression above baseline values with standard or double-dose IFNB-1b or GA QD treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8146-8) contains supplementary material, which is available to authorized users.

Published
2016

45. Association of vitamin D levels with multiple sclerosis activity and progression in patients receiving interferon beta-1b

Author

Ludwig Kappos, Gustavo Suarez, Paul O'Connor, Alberto Ascherio, Christoph Pohl, Kathryn C. Fitzgerald, Hans-Peter Hartung, Stuart D. Cook, Giancarlo Comi, Massimo Filippi, Douglas Jeffery, Barry G. W. Arnason, Rupert Sandbrink, Kassandra L. Munger, Douglas S. Goodin, Karl Köchert, Fitzgerald, Kc, Munger, Kl, Köchert, K, Arnason, Bg, Comi, Giancarlo, Cook, S, Goodin, D, Filippi, Massimo, Hartung, Hp, Jeffery, Dr, O'Connor, P, Suarez, G, Sandbrink, R, Kappos, L, Pohl, C, and Ascherio, A.

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Time Factors, Genotype, Gastroenterology, vitamin D deficiency, law.invention, Disability Evaluation, Randomized controlled trial, Adjuvants, Immunologic, Double-Blind Method, law, Internal medicine, medicine, Vitamin D and neurology, Humans, Longitudinal Studies, Vitamin D, Prospective cohort study, Retrospective Studies, Cerebral atrophy, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Vitamin D-Binding Protein, Age Factors, Retrospective cohort study, Middle Aged, medicine.disease, Surgery, Disease Progression, Female, Neurology (clinical), business, HLA-DRB1 Chains, Interferon beta-1b
Abstract

Importance Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. Objective To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. Design, Setting, and Participants We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. Exposures Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. Main Outcomes and Measures Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate–enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. Results Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D–binding protein status. Conclusions and Relevance Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

Published
2015

46. Predictors of disease activity in 857 patients with MS treated with interferon beta-1b

Author

Brigitte Stemper, John Petkau, Gustavo Suarez, Hans-Peter Hartung, Richard A. White, Christoph Pohl, Barry G. W. Arnason, Timon Bogumil, K. Beckmann, Douglas S. Goodin, Massimo Filippi, Paul O'Connor, Douglas Jeffery, Ludwig Kappos, Rupert Sandbrink, Stuart D. Cook, Giancarlo Comi, Hartung, Hp, Kappos, L, Goodin, D, O’Connor, P, Filippi, Massimo, Arnason, B, Comi, Giancarlo, Cook, S, Jeffery, D, Petkau, J, White, R, Bogumil, T, Beckmann, K, Stemper, B, Suarez, G, Sandbrink, R, and Pohl, C.

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Multivariate analysis, Clinical Neurology, Disease, Multiple sclerosis, Therapeutic approach, Multiple Sclerosis, Relapsing-Remitting, Adjuvants, Immunologic, Recurrence, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, MRI lesion, Relapse, Neuroradiology, Original Communication, medicine.diagnostic_test, business.industry, Interferon beta-1b, Age Factors, Magnetic resonance imaging, Middle Aged, medicine.disease, Prognosis, Magnetic Resonance Imaging, Surgery, Female, Neurology (clinical), business, Follow-Up Studies, Predictor
Abstract

Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the CNS that requires long-term treatment. The identification of patient characteristics that can help predict disease outcomes could improve care for patients with MS. The objective of this study is to identify predictors of disease activity in patients from the BEYOND trial. This regression analysis of patients with relapsing–remitting MS from BEYOND examined the predictive value of patient characteristics at baseline and after 1 year of treatment with interferon beta-1b 250 μg every other day for clinical and MRI outcomes after year 1 of the study. 857 and 765 patients were included in the analyses of clinical and MRI outcomes, respectively. In multivariate analyses of age, a higher number of relapses in the past 2 years, ≥3 new MRI lesions in the first year, and, especially, a higher number of relapses in year 1 predicted the future occurrence of relapses. By contrast, age, MRI activity, and the presence of neutralizing antibodies in the first year were principally predictive of future MRI activity. In patients with continued clinical disease activity or substantial MRI activity on therapy, an alternative therapeutic approach should be strongly considered.

Published
2015

47. Insights from magnetic resonance imaging

Author

FILIPPI , MASSIMO, Charil A, Rovaris M, Absinta M, Rocca MA, Goodin D, Polman C, Filippi, Massimo, Charil, A, Rovaris, M, Absinta, M, and Rocca, Ma

Published
2014

48. Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial

Author

Christoph Pohl, Richard A. White, Paul O'Connor, Rupert Sandbrink, Massimo Filippi, John Petkau, Timon Bogumil, Douglas Jeffery, Barry G. W. Arnason, K. Beckmann, Ludwig Kappos, Douglas S. Goodin, Hans-Peter Hartung, Stuart D. Cook, Giancarlo Comi, Volker Knappertz, Goodin, D, Hartung, Hp, O’Connor, P, Filippi, M, Arnason, R, Comi, G, Cook, S, Jeffery, D, Kappos, L, Bogumil, T, Knappertz, V, Sandbrink, R, Beckmann, K, White, R, Petkau, J, Pohl, C, and BEYOND Study, Group.

Subjects
Adult, medicine.medical_specialty, Adolescent, Radiography, Drug Resistance, Gadolinium, Relapse rate, Gastroenterology, Disability Evaluation, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Adjuvants, Immunologic, Interferon, Recurrence, Internal medicine, medicine, Humans, Glatiramer acetate, biology, business.industry, Multiple sclerosis, Interferon beta-1b, Interferon-beta, Middle Aged, medicine.disease, Antibodies, Neutralizing, Magnetic Resonance Imaging, Titer, Cross-Sectional Studies, Neurology, Immunology, biology.protein, Neurology (clinical), Antibody, business, medicine.drug
Abstract

Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial. Objective: To assess NAb impact in the BEYOND study. Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2–3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. Results: In the IFNβ-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes. Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.

Published
2012

49. Variability in detection and quantification of interferon-beta-1b-induced neutralizing antibodies

Author

Barry G. W. Arnason, Ludwig Kappos, Haruhiko Nakajima, Joachim Reischl, Timon Bogumil, Yukiko Nakada, Christoph Pohl, Rupert Sandbrink, Hans-Peter Hartung, Brigitte Stemper, Bernd C. Kieseier, Stuart D. Cook, Douglas S. Goodin, Giancarlo Comi, Susanne Schwenke, Douglas Jeffery, Stephan Lehr, Jürgen Heubach, Massimo Filippi, Hartung, Hp, Kieseier, B, Goodin, D, Arnason, B, Comi, G, Cook, S, Filippi, M, Jeffery, Dr, Kappos, L, Bogumil, T, Stemper, B, Sandbrink, R, Nakada, Y, Nakajima, H, Schwenke, S, Lehr, S, Heubach, J, Pohl, C, and Reischl, J

Subjects
Immunology, Dose-Response Relationship, Immunologic, Neutralizing antibodies, lcsh:RC346-429, Clinical study, Multiple sclerosis, Cellular and Molecular Neuroscience, Adjuvants, Immunologic, Round robin, Medicine, Humans, lcsh:Neurology. Diseases of the nervous system, Cytopathic effect, Observer Variation, biology, business.industry, Clinical Laboratory Techniques, General Neuroscience, Research, Clinical trials randomized controlled, Interferon-beta, Interferon beta, Virology, Antibodies, Neutralizing, Clinical Practice, Titer, Interferon β 1b, IFNB-1b, Neurology, biology.protein, Antibody, Observer variation, business, Kappa, Interferon beta-1b
Abstract

Background Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. Methods Blood samples from 125 IFNB-1b–treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. Results High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. Conclusions There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.

Published
2012

50. Interferon beta-1b and glatiramer acetate effects on permanent black hole evolution

Author

T.M. DeSimone, Stuart D. Cook, Douglas L. Arnold, H.-P. Hartung, Massimo Filippi, G. Comi, Ludwig Kappos, Volker Knappertz, E. Croze, K. Beckmann, Timon Bogumil, G. Cutter, F. Camesasca, Barry G. W. Arnason, C. Brown, Jerry S. Wolinsky, Douglas Jeffery, Christoph Pohl, M A Rocca, Douglas S. Goodin, Paul O'Connor, Rupert Sandbrink, Filippi, Massimo, Rocca, Ma, Camesasca, F, Cook, S, O’Connor, P, Arnason, Bg, Kappos, L, Goodin, D, Jeffery, D, Hartung, Hp, Comi, Giancarlo, Wolinsky, J, Bogumil, T, Pohl, C, Beckmann, K, Sandbrink, R, Croze, E, Brown, C, Desimone, Tm, Arnold, Dl, Cutter, G, and Knappertz, V.

Subjects
Adult, Male, medicine.medical_specialty, Post hoc, Treatment outcome, Class iii, Gastroenterology, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, medicine, Humans, Prospective Studies, Glatiramer acetate, Interferon beta, business.industry, Interferon beta-1b, Follow up studies, Glatiramer Acetate, Interferon-beta, Articles, Magnetic Resonance Imaging, Surgery, Interferon β 1b, Treatment Outcome, Female, Neurology (clinical), business, Peptides, medicine.drug, Follow-Up Studies
Abstract

Objective: To compare interferon β-1b (IFNβ-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)—a marker of irreversible tissue damage—in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: BEYOND was a large, phase III, clinical trial comparing IFNβ-1b 250 μg, IFNβ-1b 500 μg, and GA (2:2:1). Patient scans were reexamined post hoc for PBH in a rater-blinded manner. Two predefined coprimary endpoints compared IFNβ-1b 250 μg with GA: first, number of PBH per patient at year 2 evolving from year 1 NL, then proportion of year 1 NL evolving into PBH at year 2. IFNβ-1b 500 μg and GA were compared in an exploratory fashion. Results: Approximately 90% (1,957/2,244) of patients had NL at year 1 with follow-up at year 2. Mean numbers of PBH per patient at year 2 evolving from year 1 NL were lower for IFNβ-1b 250 μg than GA (0.30 vs 0.43; p = 0.0451). The proportion of NL evolving into PBH was similar (IFNβ-1b 250 μg vs GA: 21.6% vs 23.5%; p > 0.20). For IFNβ-1b 500 μg, both the mean PBH number per patient at year 2 evolving from year 1 NL (0.26 vs 0.43; p = 0.0037) and proportion of NL evolving into PBH (16.3% vs 23.5%; p = 0.0409) were lower relative to GA. Conclusion: IFNβ-1b affected PBH development to a similar or better extent than GA. IFNβ-1b favorably influences an MRI outcome indicative of permanent tissue destruction in the brains of patients with multiple sclerosis. Classification of evidence: This study provides Class III evidence that IFNβ-1b is associated with a reduction in MRI PBH formation and evolution compared with GA between years 1 and 2 of treatment.

Published
2011

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