Datasets:

SotiriosKastanas

/

trygroto

like 0

[ [ 76, 47, 84, 34 ], [ 172, 47, 233, 34 ], [ 417, 47, 139, 34 ], [ 76, 118, 70, 20 ], [ 151, 118, 46, 20 ], [ 76, 143, 101, 23 ], [ 182, 143, 38, 23 ], [ 226, 143, 131, 23 ], [ 363, 143, 20, 23 ], [ 389, 143, 113, 23 ], [ 507, 143, 183, 23 ], [ 76, 168, 96, 23 ], [ 178, 168, 65, 23 ], [ 249, 168, 130, 23 ], [ 385, 168, 72, 23 ], [ 464, 168, 20, 23 ], [ 490, 168, 35, 23 ], [ 530, 168, 111, 23 ], [ 76, 193, 183, 23 ], [ 265, 193, 96, 23 ], [ 366, 193, 50, 23 ], [ 422, 193, 53, 23 ], [ 76, 218, 96, 21 ], [ 177, 218, 64, 22 ], [ 246, 218, 49, 21 ], [ 300, 218, 12, 21 ], [ 316, 218, 100, 22 ], [ 421, 218, 65, 21 ], [ 491, 218, 80, 22 ], [ 576, 218, 35, 21 ], [ 76, 243, 74, 21 ], [ 155, 243, 112, 22 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 293, 41, 12 ], [ 119, 293, 45, 12 ], [ 166, 293, 10, 12 ], [ 179, 293, 49, 12 ], [ 230, 293, 19, 12 ], [ 251, 293, 20, 12 ], [ 274, 293, 40, 12 ], [ 316, 293, 39, 12 ], [ 357, 293, 39, 12 ], [ 399, 293, 14, 12 ], [ 415, 293, 39, 12 ], [ 456, 293, 56, 12 ], [ 515, 293, 19, 12 ], [ 536, 293, 50, 12 ], [ 589, 293, 43, 12 ], [ 634, 293, 40, 12 ], [ 677, 293, 48, 12 ], [ 731, 293, 19, 12 ], [ 76, 306, 50, 12 ], [ 128, 306, 42, 11 ], [ 173, 306, 40, 11 ], [ 215, 306, 9, 11 ], [ 227, 306, 38, 11 ], [ 268, 306, 36, 11 ], [ 306, 306, 35, 11 ], [ 343, 306, 59, 11 ], [ 404, 306, 34, 11 ], [ 441, 306, 21, 11 ], [ 76, 326, 31, 12 ], [ 110, 326, 51, 12 ], [ 164, 326, 27, 12 ], [ 193, 326, 4, 12 ], [ 200, 326, 136, 12 ], [ 338, 326, 26, 12 ], [ 366, 326, 6, 12 ], [ 375, 326, 46, 12 ], [ 424, 326, 4, 12 ], [ 430, 326, 165, 12 ], [ 76, 339, 35, 11 ], [ 113, 339, 38, 11 ], [ 154, 339, 4, 11 ], [ 160, 339, 150, 11 ], [ 313, 339, 40, 11 ], [ 355, 339, 56, 11 ], [ 413, 339, 4, 11 ], [ 419, 339, 131, 11 ], [ 76, 355, 7, 12 ], [ 85, 355, 73, 12 ], [ 160, 355, 33, 12 ], [ 76, 414, 45, 12 ], [ 124, 414, 12, 12 ], [ 138, 414, 29, 12 ], [ 170, 414, 23, 12 ], [ 76, 434, 21, 11 ], [ 100, 434, 51, 11 ], [ 153, 434, 29, 11 ], [ 185, 434, 25, 11 ], [ 213, 434, 20, 12 ], [ 245, 434, 128, 11 ], [ 76, 454, 20, 11 ], [ 98, 454, 28, 11 ], [ 129, 454, 7, 11 ], [ 139, 454, 38, 11 ], [ 179, 454, 25, 11 ], [ 207, 454, 215, 11 ], [ 430, 414, 43, 12 ], [ 476, 414, 12, 12 ], [ 490, 414, 33, 12 ], [ 525, 414, 23, 12 ], [ 430, 427, 46, 11 ], [ 478, 427, 11, 11 ], [ 492, 427, 29, 11 ], [ 523, 427, 23, 11 ], [ 76, 473, 9, 12 ], [ 87, 473, 23, 12 ], [ 113, 473, 27, 12 ], [ 143, 473, 10, 12 ], [ 155, 473, 10, 12 ], [ 167, 473, 36, 12 ], [ 206, 473, 35, 12 ], [ 244, 473, 34, 12 ], [ 281, 473, 18, 12 ], [ 76, 487, 20, 12 ], [ 98, 487, 7, 12 ], [ 108, 487, 11, 12 ], [ 121, 487, 26, 12 ], [ 150, 487, 32, 12 ], [ 184, 487, 28, 12 ], [ 215, 487, 49, 12 ], [ 267, 487, 27, 12 ], [ 296, 487, 15, 12 ], [ 314, 487, 27, 12 ], [ 343, 487, 10, 12 ], [ 355, 487, 15, 12 ], [ 373, 487, 39, 12 ], [ 415, 487, 48, 12 ], [ 465, 487, 51, 12 ], [ 519, 487, 34, 12 ], [ 555, 487, 202, 12 ], [ 76, 500, 27, 12 ], [ 106, 500, 35, 12 ], [ 143, 500, 56, 12 ], [ 201, 500, 18, 12 ], [ 222, 500, 55, 12 ], [ 279, 500, 16, 12 ], [ 298, 500, 60, 12 ], [ 361, 500, 8, 12 ], [ 372, 500, 16, 12 ], [ 390, 500, 39, 12 ], [ 432, 500, 40, 12 ], [ 475, 500, 15, 12 ], [ 493, 500, 34, 12 ], [ 529, 500, 24, 12 ], [ 556, 500, 7, 12 ], [ 565, 500, 39, 12 ], [ 607, 500, 25, 12 ], [ 115, 560, 61, 15 ], [ 115, 581, 80, 14 ], [ 204, 581, 22, 14 ], [ 235, 581, 62, 14 ], [ 306, 581, 97, 14 ], [ 411, 581, 59, 14 ], [ 480, 581, 64, 14 ], [ 552, 581, 20, 14 ], [ 581, 581, 48, 14 ], [ 638, 581, 18, 14 ], [ 665, 581, 46, 14 ], [ 720, 581, 10, 14 ], [ 115, 597, 86, 14 ], [ 205, 597, 20, 14 ], [ 229, 597, 40, 14 ], [ 272, 597, 42, 14 ], [ 318, 597, 38, 14 ], [ 360, 597, 64, 14 ], [ 427, 597, 68, 14 ], [ 499, 597, 16, 14 ], [ 518, 597, 32, 14 ], [ 554, 597, 63, 14 ], [ 621, 597, 41, 14 ], [ 665, 597, 11, 14 ], [ 680, 597, 25, 14 ], [ 709, 597, 21, 14 ], [ 115, 614, 49, 14 ], [ 170, 614, 25, 14 ], [ 202, 614, 11, 14 ], [ 220, 614, 64, 14 ], [ 290, 614, 20, 14 ], [ 316, 614, 48, 14 ], [ 370, 614, 46, 14 ], [ 423, 614, 39, 14 ], [ 468, 614, 63, 14 ], [ 537, 614, 40, 14 ], [ 584, 614, 6, 14 ], [ 597, 614, 31, 14 ], [ 633, 614, 97, 14 ], [ 115, 630, 51, 14 ], [ 169, 630, 31, 14 ], [ 203, 630, 55, 14 ], [ 261, 630, 22, 14 ], [ 285, 630, 64, 14 ], [ 351, 630, 49, 14 ], [ 402, 630, 10, 14 ], [ 415, 630, 87, 14 ], [ 504, 630, 63, 14 ], [ 570, 630, 9, 14 ], [ 581, 630, 55, 14 ], [ 639, 630, 20, 14 ], [ 661, 630, 18, 14 ], [ 682, 630, 48, 14 ], [ 115, 646, 49, 14 ], [ 168, 646, 9, 14 ], [ 180, 646, 58, 14 ], [ 241, 646, 10, 14 ], [ 255, 646, 78, 14 ], [ 336, 646, 56, 14 ], [ 396, 646, 58, 14 ], [ 457, 646, 20, 14 ], [ 481, 646, 92, 14 ], [ 576, 646, 10, 14 ], [ 590, 646, 56, 14 ], [ 649, 646, 20, 14 ], [ 673, 646, 44, 14 ], [ 720, 646, 10, 14 ], [ 115, 663, 55, 14 ], [ 174, 663, 34, 14 ], [ 210, 663, 22, 14 ], [ 235, 663, 31, 14 ], [ 269, 663, 50, 14 ], [ 322, 663, 64, 14 ], [ 388, 663, 20, 14 ], [ 411, 663, 48, 14 ], [ 463, 663, 31, 14 ], [ 497, 663, 18, 14 ], [ 518, 663, 37, 14 ], [ 559, 663, 33, 14 ], [ 595, 663, 10, 14 ], [ 608, 663, 18, 14 ], [ 629, 663, 37, 14 ], [ 669, 663, 20, 14 ], [ 692, 663, 38, 14 ], [ 115, 679, 49, 14 ], [ 167, 679, 10, 14 ], [ 180, 679, 6, 14 ], [ 189, 679, 54, 14 ], [ 246, 679, 65, 14 ], [ 313, 679, 11, 14 ], [ 326, 679, 49, 14 ], [ 378, 679, 27, 14 ], [ 407, 679, 51, 14 ], [ 461, 679, 54, 14 ], [ 518, 679, 57, 14 ], [ 578, 679, 20, 14 ], [ 600, 679, 48, 14 ], [ 651, 679, 18, 14 ], [ 672, 679, 40, 14 ], [ 715, 679, 15, 14 ], [ 115, 695, 18, 14 ], [ 140, 695, 28, 14 ], [ 174, 695, 35, 14 ], [ 215, 695, 11, 14 ], [ 232, 695, 30, 14 ], [ 268, 695, 24, 14 ], [ 299, 695, 44, 14 ], [ 348, 695, 26, 14 ], [ 380, 695, 40, 14 ], [ 427, 695, 52, 14 ], [ 484, 695, 11, 14 ], [ 502, 695, 52, 14 ], [ 560, 695, 26, 14 ], [ 592, 695, 54, 14 ], [ 652, 695, 13, 14 ], [ 671, 695, 19, 14 ], [ 696, 695, 34, 14 ], [ 115, 712, 56, 14 ], [ 175, 712, 22, 14 ], [ 201, 712, 20, 14 ], [ 225, 712, 29, 14 ], [ 257, 712, 18, 14 ], [ 280, 712, 68, 14 ], [ 351, 712, 87, 14 ], [ 442, 712, 10, 14 ], [ 456, 712, 33, 14 ], [ 493, 712, 62, 14 ], [ 559, 712, 13, 14 ], [ 576, 712, 55, 14 ], [ 635, 712, 19, 14 ], [ 658, 712, 41, 14 ], [ 703, 712, 13, 14 ], [ 720, 712, 10, 14 ], [ 115, 728, 26, 14 ], [ 145, 728, 46, 14 ], [ 194, 728, 22, 14 ], [ 219, 728, 64, 14 ], [ 287, 728, 39, 14 ], [ 329, 728, 6, 14 ], [ 339, 728, 37, 14 ], [ 379, 728, 69, 14 ], [ 452, 728, 45, 14 ], [ 500, 728, 29, 14 ], [ 532, 728, 12, 14 ], [ 548, 728, 18, 14 ], [ 569, 728, 60, 14 ], [ 632, 728, 11, 14 ], [ 647, 728, 18, 14 ], [ 668, 728, 62, 14 ], [ 115, 744, 20, 14 ], [ 139, 744, 55, 14 ], [ 197, 744, 19, 14 ], [ 219, 744, 46, 14 ], [ 115, 767, 49, 14 ], [ 176, 768, 21, 14 ], [ 208, 768, 25, 14 ], [ 245, 768, 58, 14 ], [ 314, 768, 6, 14 ], [ 331, 768, 59, 14 ], [ 401, 768, 52, 14 ], [ 465, 768, 70, 14 ], [ 546, 768, 27, 14 ], [ 584, 768, 30, 14 ], [ 625, 768, 76, 14 ], [ 712, 768, 18, 14 ], [ 115, 784, 96, 14 ], [ 216, 784, 51, 14 ], [ 271, 784, 31, 14 ], [ 305, 784, 20, 14 ], [ 329, 784, 65, 14 ], [ 398, 784, 18, 14 ], [ 420, 784, 69, 14 ], [ 492, 784, 39, 14 ], [ 535, 784, 11, 14 ], [ 550, 784, 18, 14 ], [ 572, 784, 58, 14 ], [ 633, 784, 97, 14 ], [ 115, 800, 51, 14 ], [ 174, 800, 26, 14 ], [ 207, 800, 29, 14 ], [ 243, 800, 34, 14 ], [ 284, 800, 6, 14 ], [ 298, 800, 68, 14 ], [ 373, 800, 51, 14 ], [ 431, 800, 64, 14 ], [ 502, 800, 22, 14 ], [ 531, 800, 59, 14 ], [ 598, 800, 46, 14 ], [ 650, 800, 52, 14 ], [ 710, 800, 20, 14 ], [ 115, 816, 58, 14 ], [ 177, 816, 31, 14 ], [ 211, 816, 19, 14 ], [ 234, 816, 87, 14 ], [ 325, 816, 56, 14 ], [ 385, 816, 22, 14 ], [ 410, 816, 59, 14 ], [ 473, 816, 31, 14 ], [ 507, 816, 18, 14 ], [ 529, 816, 42, 14 ], [ 575, 816, 15, 14 ], [ 593, 816, 18, 14 ], [ 615, 816, 28, 14 ], [ 647, 816, 35, 14 ], [ 685, 816, 11, 14 ], [ 700, 816, 30, 14 ], [ 115, 833, 24, 14 ], [ 146, 833, 15, 14 ], [ 167, 833, 61, 14 ], [ 235, 833, 34, 14 ], [ 275, 833, 24, 14 ], [ 306, 833, 18, 14 ], [ 331, 833, 52, 14 ], [ 390, 833, 26, 14 ], [ 422, 833, 40, 14 ], [ 469, 833, 52, 14 ], [ 527, 833, 11, 14 ], [ 545, 833, 18, 14 ], [ 569, 833, 58, 14 ], [ 633, 833, 29, 14 ], [ 669, 833, 61, 14 ], [ 115, 849, 56, 14 ], [ 175, 849, 11, 14 ], [ 189, 849, 18, 14 ], [ 210, 849, 39, 14 ], [ 252, 849, 33, 14 ], [ 288, 849, 11, 14 ], [ 302, 849, 18, 14 ], [ 324, 849, 22, 14 ], [ 349, 849, 31, 14 ], [ 383, 849, 18, 14 ], [ 404, 849, 33, 14 ], [ 439, 849, 47, 14 ], [ 489, 849, 49, 14 ], [ 541, 849, 45, 14 ], [ 589, 849, 6, 14 ], [ 599, 849, 57, 14 ], [ 658, 849, 48, 14 ], [ 709, 849, 21, 14 ], [ 115, 865, 25, 14 ], [ 144, 865, 22, 14 ], [ 170, 865, 47, 14 ], [ 220, 865, 18, 14 ], [ 241, 865, 96, 14 ], [ 341, 865, 51, 14 ], [ 396, 865, 26, 14 ], [ 425, 865, 29, 14 ], [ 457, 865, 10, 14 ], [ 471, 865, 18, 14 ], [ 493, 865, 49, 14 ], [ 545, 865, 11, 14 ], [ 560, 865, 53, 14 ], [ 616, 865, 42, 14 ], [ 661, 865, 20, 14 ], [ 685, 865, 46, 14 ], [ 115, 882, 48, 14 ], [ 169, 882, 22, 14 ], [ 195, 882, 50, 14 ], [ 250, 882, 46, 14 ], [ 301, 882, 22, 14 ], [ 328, 882, 41, 14 ], [ 374, 882, 35, 14 ], [ 415, 882, 11, 14 ], [ 431, 882, 64, 14 ], [ 499, 882, 20, 14 ], [ 524, 882, 58, 14 ], [ 587, 882, 34, 14 ], [ 626, 882, 22, 14 ], [ 653, 882, 52, 14 ], [ 710, 882, 20, 14 ], [ 115, 898, 58, 14 ], [ 176, 898, 31, 14 ], [ 210, 898, 10, 14 ], [ 223, 898, 42, 14 ], [ 268, 898, 20, 14 ], [ 291, 898, 49, 14 ], [ 342, 898, 20, 14 ], [ 365, 898, 18, 14 ], [ 386, 898, 64, 14 ], [ 453, 898, 20, 14 ], [ 475, 898, 58, 14 ], [ 536, 898, 31, 14 ], [ 570, 898, 10, 14 ], [ 583, 898, 50, 14 ], [ 636, 898, 18, 14 ], [ 657, 898, 33, 14 ], [ 693, 898, 37, 14 ], [ 115, 914, 26, 14 ], [ 145, 914, 36, 14 ], [ 184, 914, 12, 14 ], [ 200, 914, 27, 14 ], [ 230, 914, 53, 14 ], [ 287, 914, 10, 14 ], [ 300, 914, 59, 14 ], [ 362, 914, 20, 14 ], [ 385, 914, 33, 14 ], [ 422, 914, 26, 14 ], [ 451, 914, 54, 14 ], [ 509, 914, 10, 14 ], [ 522, 914, 37, 14 ], [ 562, 914, 20, 14 ], [ 586, 914, 46, 14 ], [ 115, 938, 74, 14 ], [ 193, 938, 24, 14 ], [ 220, 938, 37, 14 ], [ 260, 938, 43, 14 ], [ 306, 938, 22, 14 ], [ 332, 938, 18, 14 ], [ 353, 938, 96, 14 ], [ 453, 938, 51, 14 ], [ 508, 938, 26, 14 ], [ 537, 938, 29, 14 ], [ 569, 938, 18, 14 ], [ 591, 938, 68, 14 ], [ 662, 938, 68, 14 ], [ 115, 954, 87, 14 ], [ 205, 954, 10, 14 ], [ 218, 954, 26, 14 ], [ 247, 954, 48, 14 ], [ 299, 954, 51, 14 ], [ 353, 954, 20, 14 ], [ 376, 954, 38, 14 ], [ 417, 954, 33, 14 ], [ 454, 954, 22, 14 ], [ 479, 954, 59, 14 ], [ 540, 954, 44, 14 ], [ 587, 954, 43, 14 ], [ 633, 954, 12, 14 ], [ 648, 954, 14, 14 ], [ 665, 954, 30, 14 ], [ 698, 954, 32, 14 ], [ 115, 970, 24, 14 ], [ 143, 970, 62, 14 ], [ 208, 970, 20, 14 ], [ 231, 970, 38, 14 ], [ 272, 970, 19, 14 ], [ 294, 970, 52, 14 ], [ 350, 970, 15, 14 ], [ 367, 970, 28, 14 ], [ 399, 970, 8, 14 ], [ 410, 970, 35, 14 ], [ 448, 970, 11, 14 ], [ 463, 970, 6, 14 ], [ 472, 970, 44, 14 ], [ 519, 970, 51, 14 ], [ 574, 970, 17, 14 ], [ 594, 970, 45, 14 ], [ 642, 970, 18, 14 ], [ 664, 970, 52, 14 ], [ 719, 970, 11, 14 ], [ 115, 987, 62, 14 ], [ 180, 987, 20, 14 ], [ 204, 987, 38, 14 ], [ 245, 987, 19, 14 ], [ 267, 987, 52, 14 ], [ 698, 1052, 30, 13 ], [ 731, 1052, 7, 13 ], [ 741, 1052, 11, 13 ], [ 755, 1052, 14, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "BMC", "Evolutionary", "Biology", "Research", "article", "Sequence", "and", "organization", "of", "coelacanth", "neurohypophysial", "hormone", "genes:", "evolutionary", "history", "of", "the", "vertebrate", "neurohypophysial", "hormone", "gene", "locus", "Pai-Chung", "Gwee1,", "Chris", "T", "Amemiya2,", "Sydney", "Brenner1", "and", "Byrappa", "Venkatesh*1", "BioMed", "Central", "Open", "Access", "Address:", "1Institute", "of", "Molecular", "and", "Cell", "Biology,", "A*STAR", "(Agency", "for", "Science,", "Technology", "and", "Research),", "Biopolis,", "138673,", "Singapore", "and", "2Benaroya", "Research", "Institute", "at", "Virginia", "Mason,", "Seattle,", "Washington", "98101,", "USA", "Email:", "Pai-Chung", "Gwee", "-", "pcgwee@imcb.a-star.edu.sg;", "Chris", "T", "Amemiya", "-", "camemiya@benaroyaresearch.org;", "Sydney", "Brenner", "-", "sydney_brenner@a-star.edu.sg;", "Byrappa", "Venkatesh*", "-", "mcbbv@imcb.a-star.edu.sg", "*", "Corresponding", "author", "Published:", "26", "March", "2008", "BMC", "Evolutionary", "Biology", "2008,", "8:93", "doi:10.1186/1471-2148-8-93", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2148/8/93", "Received:", "11", "January", "2008", "Accepted:", "26", "March", "2008", "©", "2008", "Gwee", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "mammalian", "neurohypophysial", "hormones,", "vasopressin", "and", "oxytocin", "are", "involved", "in", "osmoregulation", "and", "uterine", "smooth", "muscle", "contraction", "respectively.", "All", "jawed", "vertebrates", "contain", "at", "least", "one", "homolog", "each", "of", "vasopressin", "and", "oxytocin", "whereas", "jawless", "vertebrates", "contain", "a", "single", "neurohypophysial", "hormone", "called", "vasotocin.", "The", "vasopressin", "homolog", "in", "non-mammalian", "vertebrates", "is", "vasotocin;", "and", "the", "oxytocin", "homolog", "is", "mesotocin", "in", "non-eutherian", "tetrapods,", "mesotocin", "and", "[Phe2]mesotocin", "in", "lungfishes,", "and", "isotocin", "in", "ray-finned", "fishes.", "The", "genes", "encoding", "vasopressin", "and", "oxytocin", "genes", "are", "closely", "linked", "in", "the", "human", "and", "rodent", "genomes", "in", "a", "tail-to-tail", "orientation.", "In", "contrast,", "their", "pufferfish", "homologs", "(vasotocin", "and", "isotocin)", "are", "located", "on", "the", "same", "strand", "of", "DNA", "with", "isotocin", "gene", "located", "upstream", "of", "vasotocin", "gene", "separated", "by", "five", "genes,", "suggesting", "that", "this", "locus", "has", "experienced", "rearrangements", "in", "either", "mammalian", "or", "ray-finned", "fish", "lineage,", "or", "in", "both", "lineages.", "The", "coelacanths", "occupy", "a", "unique", "phylogenetic", "position", "close", "to", "the", "divergence", "of", "the", "mammalian", "and", "ray-finned", "fish", "lineages.", "Results:", "We", "have", "sequenced", "a", "coelacanth", "(Latimeria", "menadoensis)", "BAC", "clone", "encompassing", "the", "neurohypophysial", "hormone", "genes", "and", "investigated", "the", "evolutionary", "history", "of", "the", "vertebrate", "neurohypophysial", "hormone", "gene", "locus", "within", "a", "comparative", "genomics", "framework.", "The", "coelacanth", "contains", "vasotocin", "and", "mesotocin", "genes", "like", "non-mammalian", "tetrapods.", "The", "coelacanth", "genes", "are", "present", "on", "the", "same", "strand", "of", "DNA", "with", "no", "intervening", "genes,", "with", "the", "vasotocin", "gene", "located", "upstream", "of", "the", "mesotocin", "gene.", "Nucleotide", "sequences", "of", "the", "second", "exons", "of", "the", "two", "genes", "are", "under", "purifying", "selection", "implying", "a", "regulatory", "function.", "We", "have", "also", "analyzed", "the", "neurohypophysial", "hormone", "gene", "locus", "in", "the", "genomes", "of", "opossum,", "chicken", "and", "Xenopus", "tropicalis.", "The", "opossum", "contains", "two", "tandem", "copies", "of", "vasopressin", "and", "mesotocin", "genes.", "The", "vasotocin", "and", "mesotocin", "genes", "in", "chicken", "and", "Xenopus,", "and", "the", "vasopressin", "and", "mesotocin", "genes", "in", "opossum", "are", "linked", "tail-to-", "head", "similar", "to", "their", "orthologs", "in", "coelacanth", "and", "unlike", "their", "homologs", "in", "human", "and", "rodents.", "Conclusion:", "Our", "results", "indicate", "that", "the", "neurohypophysial", "hormone", "gene", "locus", "has", "experienced", "independent", "rearrangements", "in", "both", "placental", "mammals", "and", "teleost", "fishes.", "The", "coelacanth", "genome", "appears", "to", "be", "more", "stable", "than", "mammalian", "and", "teleost", "fish", "genomes.", "As", "such,", "it", "serves", "as", "a", "valuable", "outgroup", "for", "studying", "the", "evolution", "of", "mammalian", "and", "teleost", "fish", "genomes.", "Page", "1", "of", "12", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 78, 47, 19, 12 ], [ 100, 47, 9, 12 ], [ 113, 47, 11, 12 ], [ 127, 47, 21, 12 ], [ 150, 47, 30, 12 ], [ 184, 47, 35, 12 ], [ 222, 47, 40, 12 ], [ 265, 47, 25, 12 ], [ 293, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 10, 18 ], [ 95, 128, 10, 18 ], [ 106, 128, 13, 18 ], [ 121, 128, 13, 18 ], [ 135, 128, 11, 18 ], [ 154, 128, 11, 18 ], [ 166, 128, 11, 18 ], [ 178, 128, 13, 18 ], [ 193, 128, 10, 18 ], [ 205, 128, 13, 18 ], [ 220, 128, 11, 18 ], [ 232, 128, 13, 18 ], [ 247, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 87, 34 ], [ 175, 169, 27, 34 ], [ 212, 169, 158, 34 ], [ 380, 169, 143, 34 ], [ 533, 169, 33, 34 ], [ 576, 169, 159, 34 ], [ 78, 216, 45, 16 ], [ 128, 216, 8, 16 ], [ 140, 213, 36, 19 ], [ 180, 216, 39, 16 ], [ 224, 216, 9, 16 ], [ 237, 213, 53, 19 ], [ 295, 216, 34, 16 ], [ 333, 216, 8, 16 ], [ 345, 213, 67, 19 ], [ 416, 216, 28, 16 ], [ 449, 216, 10, 16 ], [ 463, 213, 36, 19 ], [ 503, 216, 30, 16 ], [ 538, 216, 9, 16 ], [ 551, 213, 38, 19 ], [ 87, 270, 54, 15 ], [ 87, 295, 76, 14 ], [ 167, 295, 49, 14 ], [ 220, 295, 60, 14 ], [ 284, 295, 66, 14 ], [ 355, 295, 19, 14 ], [ 378, 295, 50, 14 ], [ 432, 295, 12, 14 ], [ 448, 295, 51, 14 ], [ 503, 295, 19, 14 ], [ 526, 295, 56, 14 ], [ 587, 295, 67, 14 ], [ 658, 295, 15, 14 ], [ 87, 312, 85, 14 ], [ 177, 312, 21, 14 ], [ 202, 312, 35, 14 ], [ 242, 312, 40, 14 ], [ 286, 312, 53, 14 ], [ 342, 312, 36, 14 ], [ 382, 312, 21, 14 ], [ 408, 312, 37, 14 ], [ 449, 312, 11, 14 ], [ 465, 312, 26, 14 ], [ 495, 312, 42, 14 ], [ 541, 312, 19, 14 ], [ 564, 312, 47, 14 ], [ 615, 312, 45, 14 ], [ 664, 312, 11, 14 ], [ 87, 328, 66, 14 ], [ 157, 328, 22, 14 ], [ 184, 328, 27, 14 ], [ 215, 328, 31, 14 ], [ 250, 328, 66, 14 ], [ 320, 328, 26, 14 ], [ 351, 328, 55, 14 ], [ 410, 328, 29, 14 ], [ 444, 328, 17, 14 ], [ 465, 328, 21, 14 ], [ 490, 328, 46, 14 ], [ 540, 328, 63, 14 ], [ 607, 328, 11, 14 ], [ 622, 328, 30, 14 ], [ 657, 328, 33, 14 ], [ 87, 345, 49, 14 ], [ 140, 345, 22, 14 ], [ 167, 345, 30, 14 ], [ 201, 345, 19, 14 ], [ 225, 345, 47, 14 ], [ 276, 345, 7, 14 ], [ 287, 345, 42, 14 ], [ 333, 345, 27, 14 ], [ 365, 345, 33, 14 ], [ 402, 345, 42, 14 ], [ 448, 345, 11, 14 ], [ 463, 345, 34, 14 ], [ 501, 345, 54, 14 ], [ 558, 345, 25, 14 ], [ 587, 345, 42, 14 ], [ 633, 345, 22, 14 ], [ 660, 345, 44, 14 ], [ 87, 362, 66, 14 ], [ 158, 362, 12, 14 ], [ 174, 362, 81, 14 ], [ 259, 362, 32, 14 ], [ 295, 362, 21, 14 ], [ 321, 362, 35, 14 ], [ 360, 362, 73, 14 ], [ 438, 362, 18, 14 ], [ 460, 362, 67, 14 ], [ 531, 362, 20, 14 ], [ 556, 362, 33, 14 ], [ 593, 362, 53, 14 ], [ 650, 362, 27, 14 ], [ 681, 362, 54, 14 ], [ 87, 378, 21, 14 ], [ 113, 378, 27, 14 ], [ 144, 378, 30, 14 ], [ 179, 378, 53, 14 ], [ 235, 378, 40, 14 ], [ 279, 378, 59, 14 ], [ 342, 378, 12, 14 ], [ 358, 378, 65, 14 ], [ 428, 378, 21, 14 ], [ 453, 378, 46, 14 ], [ 504, 378, 25, 14 ], [ 533, 378, 58, 14 ], [ 595, 378, 47, 14 ], [ 647, 378, 22, 14 ], [ 87, 399, 102, 14 ], [ 194, 399, 18, 14 ], [ 216, 399, 19, 14 ], [ 239, 399, 30, 14 ], [ 274, 399, 7, 14 ], [ 285, 399, 98, 14 ], [ 387, 399, 37, 14 ], [ 428, 399, 11, 14 ], [ 444, 399, 79, 14 ], [ 527, 399, 7, 14 ], [ 538, 399, 38, 14 ], [ 580, 399, 15, 14 ], [ 600, 399, 50, 14 ], [ 654, 399, 27, 14 ], [ 685, 399, 27, 14 ], [ 87, 416, 45, 14 ], [ 137, 416, 29, 14 ], [ 170, 416, 18, 14 ], [ 193, 416, 19, 14 ], [ 216, 416, 19, 14 ], [ 240, 416, 25, 14 ], [ 268, 416, 27, 14 ], [ 299, 416, 15, 14 ], [ 319, 416, 62, 14 ], [ 385, 416, 15, 14 ], [ 404, 416, 12, 14 ], [ 421, 416, 11, 14 ], [ 436, 416, 19, 14 ], [ 459, 416, 71, 14 ], [ 535, 416, 50, 14 ], [ 589, 416, 14, 14 ], [ 607, 416, 20, 14 ], [ 631, 416, 37, 14 ], [ 672, 416, 37, 14 ], [ 713, 416, 19, 14 ], [ 87, 432, 30, 14 ], [ 122, 432, 39, 14 ], [ 165, 432, 21, 14 ], [ 190, 432, 19, 14 ], [ 214, 432, 8, 14 ], [ 226, 432, 12, 14 ], [ 242, 432, 78, 14 ], [ 324, 432, 40, 14 ], [ 368, 432, 27, 14 ], [ 399, 432, 57, 14 ], [ 460, 432, 21, 14 ], [ 485, 432, 44, 14 ], [ 533, 432, 61, 14 ], [ 599, 432, 32, 14 ], [ 635, 432, 63, 14 ], [ 702, 432, 25, 14 ], [ 87, 449, 31, 14 ], [ 122, 449, 45, 14 ], [ 171, 449, 17, 14 ], [ 192, 449, 19, 14 ], [ 215, 449, 30, 14 ], [ 250, 449, 67, 14 ], [ 321, 449, 47, 14 ], [ 372, 449, 11, 14 ], [ 386, 449, 27, 14 ], [ 417, 449, 54, 14 ], [ 476, 449, 21, 14 ], [ 501, 449, 30, 14 ], [ 536, 449, 63, 14 ], [ 603, 449, 61, 14 ], [ 668, 449, 21, 14 ], [ 694, 449, 32, 14 ], [ 87, 465, 26, 14 ], [ 118, 465, 35, 14 ], [ 157, 465, 23, 14 ], [ 185, 465, 22, 14 ], [ 211, 465, 43, 14 ], [ 257, 465, 30, 14 ], [ 292, 465, 63, 14 ], [ 359, 465, 59, 14 ], [ 423, 465, 17, 14 ], [ 444, 465, 19, 14 ], [ 467, 465, 47, 14 ], [ 519, 465, 19, 14 ], [ 541, 465, 37, 14 ], [ 583, 465, 11, 14 ], [ 598, 465, 19, 14 ], [ 620, 465, 48, 14 ], [ 672, 465, 57, 14 ], [ 87, 482, 42, 14 ], [ 133, 482, 21, 14 ], [ 159, 482, 66, 14 ], [ 229, 482, 31, 14 ], [ 264, 482, 22, 14 ], [ 290, 482, 17, 14 ], [ 312, 482, 58, 14 ], [ 374, 482, 25, 14 ], [ 403, 482, 66, 14 ], [ 473, 482, 65, 14 ], [ 542, 482, 22, 14 ], [ 568, 482, 52, 14 ], [ 87, 503, 67, 14 ], [ 158, 503, 11, 14 ], [ 173, 503, 7, 14 ], [ 184, 503, 35, 14 ], [ 224, 503, 36, 14 ], [ 263, 503, 11, 14 ], [ 279, 503, 52, 14 ], [ 335, 503, 75, 14 ], [ 414, 503, 31, 14 ], [ 449, 503, 69, 14 ], [ 523, 503, 38, 14 ], [ 565, 503, 19, 14 ], [ 588, 503, 27, 14 ], [ 619, 503, 11, 14 ], [ 635, 503, 62, 14 ], [ 87, 519, 53, 14 ], [ 144, 519, 12, 14 ], [ 160, 519, 22, 14 ], [ 186, 519, 11, 14 ], [ 202, 519, 25, 14 ], [ 231, 519, 28, 14 ], [ 264, 519, 46, 14 ], [ 315, 519, 33, 14 ], [ 352, 519, 56, 14 ], [ 412, 519, 17, 14 ], [ 433, 519, 37, 14 ], [ 474, 519, 19, 14 ], [ 497, 519, 35, 14 ], [ 536, 519, 11, 14 ], [ 552, 519, 19, 14 ], [ 575, 519, 33, 14 ], [ 612, 519, 25, 14 ], [ 641, 519, 19, 14 ], [ 665, 519, 15, 14 ], [ 683, 519, 55, 14 ], [ 87, 536, 15, 14 ], [ 107, 536, 75, 14 ], [ 186, 536, 12, 14 ], [ 201, 536, 19, 14 ], [ 225, 536, 25, 14 ], [ 253, 536, 19, 14 ], [ 277, 536, 30, 14 ], [ 311, 536, 33, 14 ], [ 349, 536, 51, 14 ], [ 404, 536, 68, 14 ], [ 476, 536, 61, 14 ], [ 542, 536, 62, 14 ], [ 608, 536, 30, 14 ], [ 642, 536, 90, 14 ], [ 78, 582, 77, 15 ], [ 78, 600, 44, 13 ], [ 78, 616, 42, 14 ], [ 125, 616, 12, 14 ], [ 143, 616, 49, 14 ], [ 197, 616, 26, 14 ], [ 228, 616, 10, 14 ], [ 243, 616, 15, 14 ], [ 263, 616, 62, 14 ], [ 331, 616, 50, 14 ], [ 386, 616, 18, 14 ], [ 78, 632, 50, 14 ], [ 135, 632, 12, 14 ], [ 154, 632, 41, 14 ], [ 202, 632, 33, 14 ], [ 242, 632, 72, 14 ], [ 320, 632, 63, 14 ], [ 390, 632, 13, 14 ], [ 78, 649, 46, 14 ], [ 128, 649, 35, 14 ], [ 168, 649, 7, 14 ], [ 179, 649, 41, 14 ], [ 225, 649, 62, 14 ], [ 291, 649, 36, 14 ], [ 331, 649, 20, 14 ], [ 355, 649, 38, 14 ], [ 397, 649, 7, 14 ], [ 78, 665, 40, 14 ], [ 123, 665, 53, 14 ], [ 180, 665, 21, 14 ], [ 205, 665, 25, 14 ], [ 234, 665, 7, 14 ], [ 245, 665, 40, 14 ], [ 290, 665, 35, 14 ], [ 329, 665, 59, 14 ], [ 392, 665, 11, 14 ], [ 78, 682, 54, 14 ], [ 136, 682, 42, 14 ], [ 183, 682, 13, 14 ], [ 200, 682, 47, 14 ], [ 251, 682, 24, 14 ], [ 279, 682, 19, 14 ], [ 303, 682, 20, 14 ], [ 327, 682, 11, 14 ], [ 342, 682, 26, 14 ], [ 373, 682, 31, 14 ], [ 78, 699, 12, 14 ], [ 94, 699, 30, 14 ], [ 129, 699, 66, 14 ], [ 199, 699, 21, 14 ], [ 225, 699, 17, 14 ], [ 246, 699, 40, 14 ], [ 290, 699, 71, 14 ], [ 366, 699, 12, 14 ], [ 382, 699, 22, 14 ], [ 78, 715, 30, 14 ], [ 114, 715, 38, 14 ], [ 157, 715, 29, 14 ], [ 190, 715, 86, 14 ], [ 281, 715, 38, 14 ], [ 324, 715, 79, 14 ], [ 78, 732, 25, 14 ], [ 107, 732, 55, 14 ], [ 167, 732, 71, 14 ], [ 243, 732, 71, 14 ], [ 319, 732, 35, 14 ], [ 358, 732, 10, 14 ], [ 373, 732, 31, 14 ], [ 78, 749, 48, 14 ], [ 130, 749, 49, 14 ], [ 184, 749, 15, 14 ], [ 203, 749, 18, 14 ], [ 225, 749, 50, 14 ], [ 280, 749, 11, 14 ], [ 295, 749, 55, 14 ], [ 355, 749, 49, 14 ], [ 78, 765, 26, 14 ], [ 110, 765, 12, 14 ], [ 126, 765, 47, 14 ], [ 178, 765, 25, 14 ], [ 208, 765, 20, 14 ], [ 233, 765, 24, 14 ], [ 262, 765, 59, 14 ], [ 325, 765, 22, 14 ], [ 352, 765, 52, 14 ], [ 78, 782, 61, 14 ], [ 143, 782, 11, 14 ], [ 159, 782, 30, 14 ], [ 193, 782, 69, 14 ], [ 267, 782, 35, 14 ], [ 306, 782, 12, 14 ], [ 322, 782, 7, 14 ], [ 333, 782, 71, 14 ], [ 78, 798, 45, 14 ], [ 127, 798, 12, 14 ], [ 143, 798, 54, 14 ], [ 201, 798, 64, 14 ], [ 269, 798, 40, 14 ], [ 314, 798, 54, 14 ], [ 372, 798, 31, 14 ], [ 78, 815, 65, 14 ], [ 148, 815, 19, 14 ], [ 172, 815, 34, 14 ], [ 212, 815, 12, 14 ], [ 229, 815, 59, 14 ], [ 294, 815, 49, 14 ], [ 348, 815, 25, 14 ], [ 378, 815, 14, 14 ], [ 397, 815, 6, 14 ], [ 78, 832, 76, 14 ], [ 159, 832, 22, 14 ], [ 186, 832, 12, 14 ], [ 202, 832, 48, 14 ], [ 255, 832, 40, 14 ], [ 299, 832, 36, 14 ], [ 340, 832, 22, 14 ], [ 366, 832, 38, 14 ], [ 78, 848, 26, 14 ], [ 109, 848, 12, 14 ], [ 125, 848, 61, 14 ], [ 190, 848, 21, 14 ], [ 216, 848, 12, 14 ], [ 232, 848, 39, 14 ], [ 275, 848, 18, 14 ], [ 298, 848, 41, 14 ], [ 343, 848, 41, 14 ], [ 388, 848, 15, 14 ], [ 78, 865, 45, 14 ], [ 127, 865, 24, 14 ], [ 155, 865, 61, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 81, 11 ], [ 78, 923, 32, 13 ], [ 113, 925, 12, 11 ], [ 128, 925, 27, 11 ], [ 158, 925, 33, 11 ], [ 194, 925, 16, 11 ], [ 214, 925, 25, 11 ], [ 241, 925, 39, 11 ], [ 283, 925, 28, 11 ], [ 315, 925, 9, 11 ], [ 326, 925, 45, 11 ], [ 375, 925, 16, 11 ], [ 78, 937, 25, 11 ], [ 107, 937, 29, 11 ], [ 139, 937, 16, 11 ], [ 158, 937, 41, 11 ], [ 202, 937, 9, 11 ], [ 213, 937, 25, 11 ], [ 242, 937, 42, 11 ], [ 287, 937, 38, 11 ], [ 328, 937, 17, 11 ], [ 348, 937, 19, 11 ], [ 78, 950, 46, 11 ], [ 127, 950, 13, 11 ], [ 143, 950, 15, 11 ], [ 162, 950, 18, 11 ], [ 182, 950, 31, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 16, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 434, 583, 46, 14 ], [ 484, 583, 24, 14 ], [ 513, 583, 12, 14 ], [ 529, 583, 61, 14 ], [ 595, 583, 16, 14 ], [ 615, 583, 22, 14 ], [ 642, 583, 13, 14 ], [ 659, 583, 31, 14 ], [ 695, 583, 53, 14 ], [ 423, 599, 31, 14 ], [ 459, 599, 28, 14 ], [ 492, 599, 29, 14 ], [ 527, 599, 23, 14 ], [ 555, 599, 11, 14 ], [ 572, 599, 28, 14 ], [ 606, 599, 23, 14 ], [ 635, 599, 12, 14 ], [ 652, 599, 32, 14 ], [ 690, 599, 59, 14 ], [ 423, 616, 44, 14 ], [ 471, 616, 69, 14 ], [ 544, 616, 27, 14 ], [ 575, 616, 12, 14 ], [ 591, 616, 44, 14 ], [ 640, 616, 82, 14 ], [ 727, 616, 21, 14 ], [ 423, 632, 39, 14 ], [ 466, 632, 29, 14 ], [ 499, 632, 55, 14 ], [ 558, 632, 28, 14 ], [ 590, 632, 12, 14 ], [ 606, 632, 64, 14 ], [ 675, 632, 19, 14 ], [ 698, 632, 12, 14 ], [ 714, 632, 34, 14 ], [ 423, 649, 29, 14 ], [ 456, 649, 17, 14 ], [ 478, 649, 44, 14 ], [ 526, 649, 61, 14 ], [ 591, 649, 18, 14 ], [ 613, 649, 30, 14 ], [ 648, 649, 69, 14 ], [ 722, 649, 26, 14 ], [ 423, 665, 20, 14 ], [ 447, 665, 25, 14 ], [ 477, 665, 69, 14 ], [ 550, 665, 41, 14 ], [ 595, 665, 40, 14 ], [ 639, 665, 12, 14 ], [ 655, 665, 81, 14 ], [ 741, 665, 7, 14 ], [ 423, 682, 45, 14 ], [ 473, 682, 12, 14 ], [ 489, 682, 30, 14 ], [ 524, 682, 57, 14 ], [ 586, 682, 31, 14 ], [ 622, 682, 15, 14 ], [ 642, 682, 12, 14 ], [ 659, 682, 7, 14 ], [ 671, 682, 34, 14 ], [ 710, 682, 8, 14 ], [ 723, 682, 25, 14 ], [ 423, 699, 19, 14 ], [ 446, 699, 62, 14 ], [ 513, 699, 37, 14 ], [ 556, 699, 12, 14 ], [ 573, 699, 48, 14 ], [ 626, 699, 25, 14 ], [ 656, 699, 45, 14 ], [ 706, 699, 17, 14 ], [ 729, 699, 19, 14 ], [ 423, 715, 49, 14 ], [ 477, 715, 12, 14 ], [ 494, 715, 75, 14 ], [ 574, 715, 48, 14 ], [ 627, 715, 25, 14 ], [ 658, 715, 14, 14 ], [ 677, 715, 7, 14 ], [ 689, 715, 42, 14 ], [ 736, 715, 12, 14 ], [ 423, 732, 70, 14 ], [ 498, 732, 63, 14 ], [ 567, 732, 13, 14 ], [ 585, 732, 62, 14 ], [ 653, 732, 29, 14 ], [ 687, 732, 61, 14 ], [ 423, 749, 34, 14 ], [ 461, 749, 50, 14 ], [ 516, 749, 72, 14 ], [ 592, 749, 67, 14 ], [ 664, 749, 55, 14 ], [ 723, 749, 25, 14 ], [ 423, 765, 51, 14 ], [ 479, 765, 67, 14 ], [ 553, 765, 39, 14 ], [ 597, 765, 13, 14 ], [ 615, 765, 79, 14 ], [ 700, 765, 49, 14 ], [ 423, 782, 70, 14 ], [ 497, 782, 18, 14 ], [ 519, 782, 36, 14 ], [ 559, 782, 41, 14 ], [ 605, 782, 12, 14 ], [ 620, 782, 44, 14 ], [ 669, 782, 40, 14 ], [ 713, 782, 12, 14 ], [ 729, 782, 19, 14 ], [ 423, 798, 41, 14 ], [ 468, 798, 73, 14 ], [ 546, 798, 22, 14 ], [ 572, 798, 68, 14 ], [ 645, 798, 20, 14 ], [ 669, 798, 12, 14 ], [ 686, 798, 62, 14 ], [ 423, 815, 28, 14 ], [ 455, 815, 52, 14 ], [ 511, 815, 10, 14 ], [ 525, 815, 42, 14 ], [ 572, 815, 34, 14 ], [ 610, 815, 30, 14 ], [ 645, 815, 12, 14 ], [ 661, 815, 7, 14 ], [ 672, 815, 50, 14 ], [ 726, 815, 22, 14 ], [ 423, 832, 29, 14 ], [ 456, 832, 35, 14 ], [ 495, 832, 24, 14 ], [ 523, 832, 48, 14 ], [ 575, 832, 11, 14 ], [ 590, 832, 65, 14 ], [ 659, 832, 46, 14 ], [ 434, 848, 54, 14 ], [ 492, 848, 60, 14 ], [ 556, 848, 56, 14 ], [ 616, 848, 57, 14 ], [ 678, 848, 27, 14 ], [ 710, 848, 39, 14 ], [ 423, 865, 43, 14 ], [ 470, 865, 54, 14 ], [ 528, 865, 50, 14 ], [ 582, 865, 12, 14 ], [ 598, 865, 41, 14 ], [ 643, 865, 18, 14 ], [ 665, 865, 32, 14 ], [ 701, 865, 11, 14 ], [ 717, 865, 31, 14 ], [ 423, 881, 32, 14 ], [ 462, 881, 53, 14 ], [ 522, 881, 24, 14 ], [ 553, 881, 25, 14 ], [ 585, 881, 54, 14 ], [ 646, 881, 13, 14 ], [ 666, 881, 33, 14 ], [ 706, 881, 12, 14 ], [ 725, 881, 23, 14 ], [ 423, 898, 51, 14 ], [ 478, 898, 21, 14 ], [ 504, 898, 46, 14 ], [ 554, 898, 35, 14 ], [ 593, 898, 75, 14 ], [ 672, 898, 7, 14 ], [ 683, 898, 49, 14 ], [ 736, 898, 12, 14 ], [ 423, 915, 29, 14 ], [ 456, 915, 24, 14 ], [ 484, 915, 37, 14 ], [ 525, 915, 71, 14 ], [ 601, 915, 12, 14 ], [ 618, 915, 54, 14 ], [ 677, 915, 71, 14 ], [ 423, 931, 22, 14 ], [ 450, 931, 34, 14 ], [ 489, 931, 48, 14 ], [ 543, 931, 81, 14 ], [ 629, 931, 21, 14 ], [ 655, 931, 26, 14 ], [ 686, 931, 25, 14 ], [ 717, 931, 31, 14 ], [ 423, 948, 84, 14 ], [ 511, 948, 12, 14 ], [ 528, 948, 70, 14 ], [ 602, 948, 12, 14 ], [ 619, 948, 19, 14 ], [ 642, 948, 51, 14 ], [ 698, 948, 50, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 15, 10 ], [ 296, 987, 8, 10 ], [ 306, 987, 8, 10 ], [ 317, 987, 30, 10 ], [ 350, 987, 29, 10 ], [ 381, 987, 27, 10 ], [ 410, 987, 14, 10 ], [ 427, 987, 15, 10 ], [ 445, 987, 6, 10 ], [ 453, 987, 10, 10 ], [ 465, 987, 21, 10 ], [ 489, 987, 25, 10 ], [ 517, 987, 23, 10 ], [ 542, 987, 41, 10 ], [ 586, 987, 23, 10 ], [ 611, 987, 13, 10 ], [ 626, 987, 22, 10 ], [ 650, 987, 8, 10 ], [ 660, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Law", "et", "al.", "BMC", "Health", "Services", "Research", "2010,", "10:313", "http://www.biomedcentral.com/1472-6963/10/313", "S", "T", "U", "D", "Y", "P", "R", "O", "T", "O", "C", "O", "L", "Open", "Access", "Effects", "of", "prescription", "adaptation", "by", "pharmacists", "Michael", "R", "Law1*,", "Steven", "G", "Morgan2,", "Sumit", "R", "Majumdar3,", "Larry", "D", "Lynd4,", "Carlo", "A", "Marra4", "Abstract", "Background:", "Granting", "dispensing", "pharmacists", "the", "authority", "to", "prescribe", "has", "significant", "implications", "for", "pharmaceutical", "and", "health", "human", "resources", "policy,", "and", "quality", "of", "care.", "Despite", "the", "growing", "number", "of", "jurisdictions", "that", "have", "given", "pharmacists", "such", "privileges,", "there", "are", "few", "rigorous", "evaluations", "of", "these", "policy", "changes.", "This", "study", "will", "examine", "a", "January", "2009", "policy", "change", "in", "British", "Columbia", "(BC),", "Canada", "that", "allowed", "pharmacists", "to", "independently", "adapt", "and", "renew", "prescriptions.", "We", "hypothesize", "this", "policy", "increased", "drug", "utilization", "and", "drug", "costs,", "increased", "patient", "adherence", "to", "medication,", "and", "reduced", "total", "healthcare", "resource", "use.", "Methods/Design:", "We", "will", "study", "a", "population-based", "cohort", "of", "approximately", "4", "million", "BC", "residents", "from", "2004", "through", "2010.", "We", "will", "use", "data", "from", "BC", "PharmaNet", "on", "all", "of", "the", "prescriptions", "obtained", "by", "this", "cohort", "during", "the", "study", "period,", "and", "link", "it", "to", "administrative", "billings", "from", "physicians", "and", "hospital", "discharges.", "Using", "interrupted", "time", "series", "analysis,", "we", "will", "study", "longitudinal", "changes", "in", "drug", "utilization", "and", "costs,", "medication", "adherence,", "and", "short-", "term", "health", "care", "use.", "Further,", "using", "hierarchical", "modelling,", "we", "will", "examine", "the", "factors", "at", "the", "regional,", "pharmacy,", "patient,", "and", "prescription", "levels", "that", "are", "associated", "with", "prescription", "adaptations", "and", "renewals.", "Discussion:", "In", "a", "recent", "survey", "of", "Canadian", "policymakers,", "many", "respondents", "ranked", "the", "issue", "of", "prescribing", "privileges", "as", "one", "of", "their", "most", "pressing", "policy", "questions.", "No", "matter", "the", "results", "of", "our", "study,", "they", "will", "be", "important", "for", "policymakers,", "as", "our", "data", "will", "make", "policy", "decisions", "surrounding", "pharmacist", "prescribing", "more", "evidence-based.", "Background", "Context", "Access", "to", "primary", "care", "is", "an", "important", "concern", "for", "patients", "in", "almost", "every", "jurisdiction", "examined.", "In", "Canada,", "nearly", "4", "million", "individuals", "report", "not", "having", "a", "regular", "physician", "and", "over", "2", "million", "report", "difficulties", "in", "accessing", "routine", "or", "ongoing", "care", "[1].", "For", "at", "least", "some", "of", "these", "individuals,", "and", "for", "certain", "components", "of", "pri-", "mary", "health", "care,", "non-physician", "health", "professionals", "may", "represent", "high-quality", "alternatives.", "There", "is", "some", "research", "evidence", "on", "the", "potential", "of", "deploying", "pharma-", "cists", "in", "primary", "care", "[2];", "that", "literature,", "and", "practical", "experience", "in", "other", "jurisdictions", "points", "to", "a", "considerable", "amount", "of", "untapped", "pharmacist", "human", "resources", "[3-7].", "Expanding", "the", "scope", "of", "pharmacy", "practice", "may", "be", "a", "cost-effective", "way", "to", "enhance", "patient", "access", "and", "adher-", "ence", "to", "medicines,", "and", "to", "reduce", "the", "clinical", "burden", "on", "primary", "care", "physicians.", "*", "Correspondence:", "mlaw@chspr.ubc.ca", "1Centre", "for", "Health", "Services", "and", "Policy", "Research,", "School", "of", "Population", "and", "Public", "Health,", "The", "University", "of", "British", "Columbia.", "201-2206", "East", "Mall,", "Vancouver,", "BC,", "V6T", "1Z3,", "Canada", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "Around", "53%", "of", "Canadians", "fill", "one", "or", "more", "prescrip-", "tions", "each", "year,", "and", "at", "least", "half", "of", "these", "represent", "chronic", "medications", "used", "to", "manage", "cardiovascular", "risk", "factors", "[8,9].", "However,", "rates", "of", "continuous", "use", "of", "medi-", "cines", "for", "chronic", "conditions", "are", "often", "sub-optimal", "[10].", "But", "with", "prescription", "lengths", "limited", "to", "approximately", "3", "months", "in", "most", "provinces", "(with", "up", "to", "4", "refills", "if", "they", "are", "provided),", "access", "to", "primary", "care", "doctors", "for", "the", "purpose", "of", "prescription", "renewal", "may", "be", "a", "barrier", "to", "continuous", "adherence", "to", "long-term", "drug", "therapies.", "Thus,", "granting", "pharmacists", "prescribing", "authority", "may", "increase", "Canadians’", "access", "to", "medications.", "Though", "pharmacists", "are", "highly", "trained", "in", "matters", "related", "to", "the", "effects,", "interactions,", "and", "appropriate", "use", "of", "medicines,", "their", "expertise", "is", "seldom", "called", "upon", "as", "a", "first-line", "pri-", "mary", "health", "care", "provider", "in", "community", "settings.", "Recently,", "numerous", "Canadian", "provinces", "have", "imple-", "mented", "programs", "designed", "to", "expand", "the", "scope", "of", "phar-", "macy", "practice.", "The", "first", "province", "to", "move", "in", "this", "direction", "was", "Alberta,", "which", "implemented", "a", "program", "in", "2007", "that", "allows", "pharmacists", "to", "prescribe", "medications", "and", "adapt", "existing", "prescriptions", "[3].", "One", "year", "later,", "three-quarters", "of", "pharmacists", "in", "the", "province", "reported", "©", "2010", "Law", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 76, 47, 215, 34 ], [ 76, 118, 70, 20 ], [ 76, 143, 63, 23 ], [ 145, 143, 20, 23 ], [ 171, 143, 67, 23 ], [ 243, 143, 19, 23 ], [ 268, 143, 35, 23 ], [ 308, 143, 95, 23 ], [ 408, 143, 20, 23 ], [ 434, 143, 39, 23 ], [ 479, 143, 60, 23 ], [ 544, 143, 101, 23 ], [ 650, 143, 56, 23 ], [ 712, 143, 52, 23 ], [ 76, 168, 12, 23 ], [ 94, 168, 80, 23 ], [ 180, 168, 70, 23 ], [ 255, 168, 79, 23 ], [ 340, 168, 68, 23 ], [ 414, 168, 19, 23 ], [ 439, 168, 51, 23 ], [ 76, 193, 59, 21 ], [ 140, 193, 77, 22 ], [ 222, 193, 38, 21 ], [ 266, 193, 17, 21 ], [ 287, 193, 71, 22 ], [ 363, 193, 68, 21 ], [ 436, 193, 15, 21 ], [ 456, 193, 74, 22 ], [ 535, 193, 35, 21 ], [ 575, 193, 24, 21 ], [ 603, 193, 76, 22 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 243, 41, 12 ], [ 119, 243, 28, 12 ], [ 150, 243, 10, 12 ], [ 162, 243, 52, 12 ], [ 216, 243, 20, 12 ], [ 239, 243, 48, 12 ], [ 288, 243, 35, 12 ], [ 325, 243, 13, 12 ], [ 340, 243, 10, 12 ], [ 352, 243, 10, 12 ], [ 364, 243, 28, 12 ], [ 394, 243, 27, 12 ], [ 424, 243, 44, 12 ], [ 470, 243, 40, 12 ], [ 513, 243, 26, 12 ], [ 540, 243, 19, 12 ], [ 561, 243, 42, 12 ], [ 606, 243, 27, 12 ], [ 634, 243, 63, 12 ], [ 699, 243, 68, 12 ], [ 76, 256, 8, 11 ], [ 87, 256, 38, 11 ], [ 127, 256, 27, 11 ], [ 156, 256, 22, 11 ], [ 181, 256, 41, 11 ], [ 224, 256, 47, 11 ], [ 274, 256, 32, 11 ], [ 308, 256, 14, 11 ], [ 325, 256, 52, 11 ], [ 380, 256, 43, 11 ], [ 424, 256, 8, 11 ], [ 435, 256, 49, 11 ], [ 487, 256, 10, 11 ], [ 500, 256, 31, 11 ], [ 533, 256, 54, 11 ], [ 589, 256, 21, 11 ], [ 612, 256, 48, 11 ], [ 662, 256, 35, 11 ], [ 700, 256, 40, 11 ], [ 742, 256, 23, 11 ], [ 76, 269, 45, 12 ], [ 123, 269, 26, 12 ], [ 76, 289, 31, 11 ], [ 110, 289, 32, 11 ], [ 144, 289, 34, 11 ], [ 181, 289, 4, 11 ], [ 187, 289, 124, 11 ], [ 313, 289, 21, 11 ], [ 336, 289, 9, 11 ], [ 348, 289, 31, 11 ], [ 381, 289, 4, 11 ], [ 387, 289, 102, 11 ], [ 492, 289, 37, 11 ], [ 531, 289, 8, 11 ], [ 541, 289, 35, 11 ], [ 579, 289, 4, 11 ], [ 585, 289, 113, 11 ], [ 76, 302, 13, 12 ], [ 91, 302, 36, 12 ], [ 130, 302, 4, 12 ], [ 136, 302, 117, 12 ], [ 76, 319, 7, 11 ], [ 85, 319, 73, 11 ], [ 160, 319, 33, 11 ], [ 76, 377, 45, 11 ], [ 124, 377, 12, 11 ], [ 138, 377, 40, 11 ], [ 180, 377, 23, 11 ], [ 76, 397, 48, 12 ], [ 126, 397, 25, 12 ], [ 154, 397, 20, 12 ], [ 186, 397, 128, 12 ], [ 76, 417, 20, 12 ], [ 98, 417, 28, 12 ], [ 129, 417, 7, 12 ], [ 139, 417, 38, 12 ], [ 179, 417, 25, 12 ], [ 207, 417, 196, 12 ], [ 430, 377, 43, 11 ], [ 475, 377, 6, 11 ], [ 484, 377, 32, 11 ], [ 519, 377, 23, 11 ], [ 430, 390, 46, 12 ], [ 478, 390, 12, 12 ], [ 492, 390, 40, 12 ], [ 534, 390, 23, 12 ], [ 76, 437, 9, 12 ], [ 87, 437, 23, 12 ], [ 113, 437, 26, 12 ], [ 141, 437, 10, 12 ], [ 153, 437, 10, 12 ], [ 166, 437, 36, 12 ], [ 205, 437, 35, 12 ], [ 242, 437, 34, 12 ], [ 279, 437, 18, 12 ], [ 76, 450, 20, 12 ], [ 98, 450, 7, 12 ], [ 108, 450, 11, 12 ], [ 121, 450, 26, 12 ], [ 150, 450, 32, 12 ], [ 184, 450, 28, 12 ], [ 215, 450, 49, 12 ], [ 267, 450, 27, 12 ], [ 296, 450, 15, 12 ], [ 314, 450, 27, 12 ], [ 343, 450, 10, 12 ], [ 355, 450, 15, 12 ], [ 373, 450, 39, 12 ], [ 415, 450, 48, 12 ], [ 465, 450, 51, 12 ], [ 519, 450, 34, 12 ], [ 555, 450, 202, 12 ], [ 76, 463, 27, 12 ], [ 106, 463, 35, 12 ], [ 143, 463, 56, 12 ], [ 201, 463, 18, 12 ], [ 222, 463, 55, 12 ], [ 279, 463, 16, 12 ], [ 298, 463, 60, 12 ], [ 361, 463, 8, 12 ], [ 372, 463, 16, 12 ], [ 390, 463, 39, 12 ], [ 432, 463, 40, 12 ], [ 475, 463, 15, 12 ], [ 493, 463, 34, 12 ], [ 529, 463, 24, 12 ], [ 556, 463, 7, 12 ], [ 565, 463, 39, 12 ], [ 607, 463, 25, 12 ], [ 155, 523, 62, 15 ], [ 155, 544, 80, 14 ], [ 239, 544, 23, 14 ], [ 266, 544, 36, 14 ], [ 307, 544, 54, 14 ], [ 365, 544, 46, 14 ], [ 415, 544, 45, 14 ], [ 464, 544, 32, 14 ], [ 501, 544, 21, 14 ], [ 526, 544, 11, 14 ], [ 541, 544, 18, 14 ], [ 564, 544, 22, 14 ], [ 590, 544, 55, 14 ], [ 648, 544, 28, 14 ], [ 681, 544, 10, 14 ], [ 155, 560, 18, 14 ], [ 175, 560, 56, 14 ], [ 234, 560, 11, 14 ], [ 247, 560, 43, 14 ], [ 293, 560, 14, 14 ], [ 309, 560, 23, 14 ], [ 334, 560, 10, 14 ], [ 347, 560, 57, 14 ], [ 406, 560, 21, 14 ], [ 429, 560, 32, 14 ], [ 463, 560, 40, 14 ], [ 506, 560, 32, 14 ], [ 540, 560, 18, 14 ], [ 560, 560, 27, 14 ], [ 590, 560, 27, 14 ], [ 619, 560, 72, 14 ], [ 155, 577, 12, 14 ], [ 170, 577, 23, 14 ], [ 196, 577, 11, 14 ], [ 210, 577, 47, 14 ], [ 261, 577, 42, 14 ], [ 307, 577, 30, 14 ], [ 340, 577, 21, 14 ], [ 364, 577, 33, 14 ], [ 401, 577, 11, 14 ], [ 415, 577, 54, 14 ], [ 472, 577, 13, 14 ], [ 489, 577, 32, 14 ], [ 525, 577, 10, 14 ], [ 538, 577, 57, 14 ], [ 598, 577, 21, 14 ], [ 623, 577, 29, 14 ], [ 655, 577, 11, 14 ], [ 670, 577, 21, 14 ], [ 155, 593, 32, 14 ], [ 190, 593, 43, 14 ], [ 155, 616, 59, 14 ], [ 216, 616, 74, 14 ], [ 292, 616, 20, 14 ], [ 314, 616, 20, 14 ], [ 337, 616, 31, 14 ], [ 370, 616, 41, 14 ], [ 414, 616, 21, 14 ], [ 437, 616, 46, 14 ], [ 485, 616, 10, 14 ], [ 498, 616, 12, 14 ], [ 513, 616, 18, 14 ], [ 533, 616, 32, 14 ], [ 568, 616, 123, 14 ], [ 155, 633, 32, 14 ], [ 190, 633, 21, 14 ], [ 214, 633, 59, 14 ], [ 277, 633, 10, 14 ], [ 290, 633, 14, 14 ], [ 307, 633, 32, 14 ], [ 343, 633, 96, 14 ], [ 442, 633, 35, 14 ], [ 480, 633, 29, 14 ], [ 512, 633, 46, 14 ], [ 561, 633, 10, 14 ], [ 575, 633, 21, 14 ], [ 599, 633, 32, 14 ], [ 155, 656, 49, 14 ], [ 210, 656, 23, 14 ], [ 239, 656, 29, 14 ], [ 273, 656, 29, 14 ], [ 308, 656, 46, 14 ], [ 360, 656, 17, 14 ], [ 382, 656, 6, 14 ], [ 394, 656, 43, 14 ], [ 443, 656, 52, 14 ], [ 501, 656, 29, 14 ], [ 536, 656, 33, 14 ], [ 574, 656, 9, 14 ], [ 589, 656, 33, 14 ], [ 628, 656, 29, 14 ], [ 662, 656, 29, 14 ], [ 155, 672, 52, 14 ], [ 209, 672, 17, 14 ], [ 228, 672, 53, 14 ], [ 284, 672, 20, 14 ], [ 306, 672, 56, 14 ], [ 365, 672, 41, 14 ], [ 408, 672, 69, 14 ], [ 479, 672, 63, 14 ], [ 544, 672, 29, 14 ], [ 575, 672, 18, 14 ], [ 595, 672, 65, 14 ], [ 663, 672, 28, 14 ], [ 155, 689, 18, 14 ], [ 177, 689, 39, 14 ], [ 219, 689, 21, 14 ], [ 243, 689, 29, 14 ], [ 275, 689, 42, 14 ], [ 320, 689, 29, 14 ], [ 352, 689, 39, 14 ], [ 394, 689, 11, 14 ], [ 409, 689, 55, 14 ], [ 468, 689, 46, 14 ], [ 517, 689, 14, 14 ], [ 535, 689, 29, 14 ], [ 567, 689, 35, 14 ], [ 605, 689, 29, 14 ], [ 637, 689, 39, 14 ], [ 680, 689, 11, 14 ], [ 155, 705, 39, 14 ], [ 199, 705, 22, 14 ], [ 227, 705, 54, 14 ], [ 286, 705, 14, 14 ], [ 306, 705, 29, 14 ], [ 341, 705, 32, 14 ], [ 378, 705, 28, 14 ], [ 412, 705, 19, 14 ], [ 437, 705, 64, 14 ], [ 507, 705, 20, 14 ], [ 532, 705, 29, 14 ], [ 566, 705, 39, 14 ], [ 611, 705, 11, 14 ], [ 628, 705, 63, 14 ], [ 155, 721, 53, 14 ], [ 212, 721, 96, 14 ], [ 312, 721, 70, 14 ], [ 386, 721, 10, 14 ], [ 400, 721, 21, 14 ], [ 425, 721, 32, 14 ], [ 461, 721, 24, 14 ], [ 490, 721, 6, 14 ], [ 500, 721, 55, 14 ], [ 559, 721, 48, 14 ], [ 610, 721, 11, 14 ], [ 626, 721, 26, 14 ], [ 656, 721, 24, 14 ], [ 685, 721, 6, 14 ], [ 155, 738, 43, 14 ], [ 200, 738, 55, 14 ], [ 258, 738, 28, 14 ], [ 289, 738, 11, 14 ], [ 303, 738, 23, 14 ], [ 328, 738, 10, 14 ], [ 341, 738, 52, 14 ], [ 396, 738, 29, 14 ], [ 428, 738, 20, 14 ], [ 450, 738, 6, 14 ], [ 459, 738, 45, 14 ], [ 507, 738, 55, 14 ], [ 564, 738, 28, 14 ], [ 595, 738, 11, 14 ], [ 609, 738, 30, 14 ], [ 642, 738, 10, 14 ], [ 655, 738, 36, 14 ], [ 155, 754, 32, 14 ], [ 191, 754, 26, 14 ], [ 220, 754, 29, 14 ], [ 253, 754, 29, 14 ], [ 286, 754, 24, 14 ], [ 314, 754, 46, 14 ], [ 364, 754, 40, 14 ], [ 407, 754, 18, 14 ], [ 429, 754, 40, 14 ], [ 473, 754, 58, 14 ], [ 535, 754, 59, 14 ], [ 598, 754, 14, 14 ], [ 616, 754, 29, 14 ], [ 649, 754, 42, 14 ], [ 155, 770, 29, 14 ], [ 189, 770, 11, 14 ], [ 207, 770, 38, 14 ], [ 251, 770, 19, 14 ], [ 276, 770, 27, 14 ], [ 309, 770, 48, 14 ], [ 362, 770, 13, 14 ], [ 382, 770, 14, 14 ], [ 402, 770, 42, 14 ], [ 449, 770, 11, 14 ], [ 466, 770, 34, 14 ], [ 506, 770, 19, 14 ], [ 531, 770, 24, 14 ], [ 561, 770, 20, 14 ], [ 587, 770, 14, 14 ], [ 607, 770, 29, 14 ], [ 642, 770, 32, 14 ], [ 679, 770, 11, 14 ], [ 155, 787, 61, 14 ], [ 220, 787, 27, 14 ], [ 251, 787, 35, 14 ], [ 290, 787, 14, 14 ], [ 308, 787, 29, 14 ], [ 341, 787, 35, 14 ], [ 380, 787, 29, 14 ], [ 413, 787, 11, 14 ], [ 429, 787, 70, 14 ], [ 503, 787, 27, 14 ], [ 534, 787, 7, 14 ], [ 545, 787, 35, 14 ], [ 584, 787, 29, 14 ], [ 618, 787, 11, 14 ], [ 633, 787, 58, 14 ], [ 155, 803, 24, 14 ], [ 182, 803, 20, 14 ], [ 205, 803, 54, 14 ], [ 262, 803, 7, 14 ], [ 272, 803, 29, 14 ], [ 305, 803, 28, 14 ], [ 336, 803, 11, 14 ], [ 351, 803, 41, 14 ], [ 395, 803, 27, 14 ], [ 425, 803, 15, 14 ], [ 444, 803, 18, 14 ], [ 465, 803, 34, 14 ], [ 502, 803, 22, 14 ], [ 527, 803, 70, 14 ], [ 600, 803, 20, 14 ], [ 623, 803, 41, 14 ], [ 667, 803, 24, 14 ], [ 155, 819, 11, 14 ], [ 171, 819, 40, 14 ], [ 215, 819, 29, 14 ], [ 248, 819, 55, 14 ], [ 307, 819, 46, 14 ], [ 358, 819, 33, 14 ], [ 395, 819, 29, 14 ], [ 428, 819, 11, 14 ], [ 444, 819, 39, 14 ], [ 487, 819, 19, 14 ], [ 510, 819, 24, 14 ], [ 539, 819, 29, 14 ], [ 571, 819, 39, 14 ], [ 615, 819, 11, 14 ], [ 630, 819, 60, 14 ], [ 155, 836, 30, 14 ], [ 189, 836, 58, 14 ], [ 251, 836, 19, 14 ], [ 274, 836, 33, 14 ], [ 311, 836, 21, 14 ], [ 335, 836, 40, 14 ], [ 379, 836, 10, 14 ], [ 393, 836, 14, 14 ], [ 411, 836, 32, 14 ], [ 447, 836, 24, 14 ], [ 475, 836, 109, 14 ], [ 588, 836, 34, 14 ], [ 626, 836, 11, 14 ], [ 641, 836, 18, 14 ], [ 663, 836, 28, 14 ], [ 155, 852, 56, 14 ], [ 215, 852, 19, 14 ], [ 239, 852, 31, 14 ], [ 275, 852, 38, 14 ], [ 318, 852, 22, 14 ], [ 344, 852, 22, 14 ], [ 371, 852, 24, 14 ], [ 400, 852, 43, 14 ], [ 448, 852, 52, 14 ], [ 504, 852, 29, 14 ], [ 538, 852, 29, 14 ], [ 571, 852, 11, 14 ], [ 587, 852, 68, 14 ], [ 660, 852, 20, 14 ], [ 685, 852, 6, 14 ], [ 155, 868, 58, 14 ], [ 220, 868, 74, 14 ], [ 302, 868, 15, 14 ], [ 324, 868, 39, 14 ], [ 370, 868, 23, 14 ], [ 401, 868, 11, 14 ], [ 420, 868, 14, 14 ], [ 442, 868, 57, 14 ], [ 506, 868, 40, 14 ], [ 554, 868, 33, 14 ], [ 595, 868, 33, 14 ], [ 636, 868, 29, 14 ], [ 673, 868, 18, 14 ], [ 155, 885, 65, 14 ], [ 227, 885, 20, 14 ], [ 254, 885, 17, 14 ], [ 278, 885, 60, 14 ], [ 345, 885, 24, 14 ], [ 376, 885, 58, 14 ], [ 441, 885, 40, 14 ], [ 488, 885, 22, 14 ], [ 518, 885, 40, 14 ], [ 565, 885, 39, 14 ], [ 611, 885, 61, 14 ], [ 680, 885, 11, 14 ], [ 155, 901, 57, 14 ], [ 215, 901, 32, 14 ], [ 155, 924, 74, 14 ], [ 234, 924, 36, 14 ], [ 274, 924, 9, 14 ], [ 288, 924, 27, 14 ], [ 319, 924, 40, 14 ], [ 364, 924, 20, 14 ], [ 389, 924, 47, 14 ], [ 440, 924, 10, 14 ], [ 455, 924, 23, 14 ], [ 483, 924, 53, 14 ], [ 541, 924, 17, 14 ], [ 562, 924, 46, 14 ], [ 613, 924, 53, 14 ], [ 671, 924, 20, 14 ], [ 155, 940, 57, 14 ], [ 215, 940, 40, 14 ], [ 260, 940, 22, 14 ], [ 285, 940, 58, 14 ], [ 347, 940, 32, 14 ], [ 383, 940, 52, 14 ], [ 439, 940, 34, 14 ], [ 476, 940, 19, 14 ], [ 499, 940, 20, 14 ], [ 522, 940, 70, 14 ], [ 596, 940, 55, 14 ], [ 654, 940, 19, 14 ], [ 677, 940, 14, 14 ], [ 155, 957, 38, 14 ], [ 196, 957, 54, 14 ], [ 253, 957, 104, 14 ], [ 361, 957, 62, 14 ], [ 426, 957, 24, 14 ], [ 453, 957, 23, 14 ], [ 479, 957, 11, 14 ], [ 494, 957, 13, 14 ], [ 510, 957, 43, 14 ], [ 556, 957, 18, 14 ], [ 578, 957, 44, 14 ], [ 625, 957, 10, 14 ], [ 638, 957, 30, 14 ], [ 672, 957, 19, 14 ], [ 155, 973, 36, 14 ], [ 698, 1052, 30, 13 ], [ 731, 1052, 7, 13 ], [ 741, 1052, 11, 13 ], [ 755, 1052, 14, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "CytoJournal", "Research", "Scope", "of", "FNAC", "in", "the", "diagnosis", "of", "soft", "tissue", "tumors-A", "study", "from", "a", "tertiary", "cancer", "referral", "center", "in", "India", "Bharat", "Rekhi*1,", "Biru", "D", "Gorad1,", "Anagha", "C", "Kakade2", "and", "RF", "Chinoy1", "BioMed", "Central", "Open", "Access", "Address:", "1Dept", "of", "Pathology,", "Tata", "Memorial", "Centre,", "Dr", "E.", "B.", "Road,", "Parel,", "Mumbai,", "400012,", "India", "and", "2Clinical", "Trials", "Coordinator,", "Epidemiology", "&", "Clinical", "Trials", "Unit", "(ECTU),", "Advanced", "Centre", "for", "Treatment,", "Research", "&", "Education", "in", "cancer", "(ACTREC),", "Tata", "Memorial", "Centre,", "Khargar,", "Navi", "Mumbai,", "India", "Email:", "Bharat", "Rekhi*", "-", "rekhi.bharat@gmail.com;", "Biru", "D", "Gorad", "-", "drbdev@yahoo.com;", "Anagha", "C", "Kakade", "-", "akakade@actrec.gov.in;", "RF", "Chinoy", "-", "roshchinoy@gmail.com", "*", "Corresponding", "author", "Published:", "31", "October", "2007", "CytoJournal", "2007,", "4:20", "doi:10.1186/1742-6413-4-20", "This", "article", "is", "available", "from:", "http://www.cytojournal.com/content/4/1/20", "Received:", "7", "August", "2007", "Accepted:", "31", "October", "2007", "©", "2007", "Rekhi", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Fine", "needle", "aspiration", "cytology", "(FNAC)", "forms", "one", "of", "the", "first", "diagnostic", "tools", "in", "the", "evaluation", "of", "tumors.", "Its", "role", "in", "diagnosing", "soft", "tissue", "tumors", "(STT)", "has", "been", "fairly", "documented,", "as", "well", "as", "debated.", "Present", "study", "was", "aimed", "at", "evaluating", "its", "scope", "in", "diagnosing", "127", "cases", "of", "soft", "tissue", "tumors.", "Methods:", "Conventional", "Pap", "and", "MGG", "staining", "was", "available", "in", "all", "the", "cases.", "Immunocytochemistry", "(ICC)", "was", "performed", "in", "15", "cases.", "Histopathological", "details", "were", "available", "in", "115", "cases.", "Results:", "50%", "cases", "were", "referred", "for", "a", "primary", "diagnosis,", "while", "26.8%", "&", "22.8%", "cases", "were", "evaluated", "for", "recurrent", "and", "metastatic", "lesions,", "respectively.", "Extremities", "were", "the", "commonest", "sites.", "On", "FNAC,", "101", "cases", "(79.5%)", "were", "labeled", "as", "malignant,", "whereas", "10", "cases", "(7.9%)", "were", "labeled", "as", "benign.", "The", "remaining", "16", "cases", "(11%)", "were", "not", "categorized", "and", "were", "labeled", "as", "'unsure/not", "specified'.", "Histopathological", "confirmation", "in", "115", "cases,", "gave", "a", "diagnostic", "accuracy", "of", "98%,", "with", "a", "positive", "predictive", "value", "of", "98%", "in", "malignant", "cases", "and", "a", "negative", "predictive", "value", "of", "100%", "in", "benign", "cases.", "Two", "cases", "were", "false", "positive.", "Among", "the", "various", "cytological", "categories,", "60", "cases", "(47.2%)", "were", "of", "spindle", "cell", "type,", "followed", "by", "32", "(25.2%)", "of", "round", "cell", "type", "and", "14", "cases", "(11%)", "of", "lipomatous", "type.", "Other", "12", "cases", "(9.4%)", "were", "of", "pleomorphic", "type;", "7", "(5.5%)", "cases", "of", "epithelioid", "type", "and", "remaining", "2", "cases", "were", "of", "myxoid", "type.", "All", "the", "round", "cell,", "pleomorphic", "and", "myxoid", "type", "of", "tumors", "were", "sarcomas,", "whereas", "73.3%", "cases", "of", "spindle", "cell", "type", "were", "labeled", "as", "'malignant'.", "Exact", "cytological", "sub", "typing", "was", "offered", "in", "58", "cases,", "with", "rhabdomyosarcoma", "(RMS)", "as", "the", "most", "frequently", "sub", "typed", "tumor.", "The", "two", "false", "positive", "malignant", "cases", "were", "of", "fibromatosis", "and", "a", "pigmented", "schwannoma,", "on", "biopsy.", "Out", "of", "28", "metastatic", "lesions,", "lymph", "nodes", "were", "the", "commonest", "site", "for", "metastasis,", "with", "epithelioid", "tumors", "that", "formed", "highest", "percentage", "of", "metastatic", "cases.", "Conclusion:", "FNAC", "is", "fairly", "specific", "and", "sensitive", "in", "STT", "diagnoses", "for", "primary,", "recurrent", "and", "metastatic", "lesions.", "The", "cytological", "types,", "especially", "round", "cell", "and", "pleomorphic", "sarcomas,", "can", "be", "quickly", "identified.", "Clinicopathological", "correlation", "with", "ICC", "as", "an", "adjunct,", "are", "valuable", "in", "exact", "sub", "typing.", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 78, 47, 28, 12 ], [ 110, 47, 9, 12 ], [ 122, 47, 11, 12 ], [ 136, 47, 47, 12 ], [ 186, 47, 40, 12 ], [ 229, 47, 30, 12 ], [ 261, 47, 25, 12 ], [ 290, 47, 26, 12 ], [ 78, 61, 231, 12 ], [ 83, 128, 13, 18 ], [ 98, 128, 12, 18 ], [ 111, 128, 13, 18 ], [ 125, 128, 13, 18 ], [ 146, 128, 10, 18 ], [ 158, 128, 11, 18 ], [ 170, 128, 11, 18 ], [ 183, 128, 11, 18 ], [ 195, 128, 10, 18 ], [ 207, 128, 10, 18 ], [ 218, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 204, 34 ], [ 292, 169, 37, 34 ], [ 340, 169, 184, 34 ], [ 534, 169, 51, 34 ], [ 595, 169, 104, 34 ], [ 709, 169, 27, 34 ], [ 78, 205, 44, 34 ], [ 132, 205, 118, 34 ], [ 261, 205, 153, 34 ], [ 424, 205, 92, 34 ], [ 526, 205, 212, 34 ], [ 78, 241, 540, 34 ], [ 78, 288, 23, 16 ], [ 106, 288, 7, 16 ], [ 117, 285, 54, 19 ], [ 176, 288, 51, 16 ], [ 231, 288, 18, 16 ], [ 254, 285, 75, 19 ], [ 333, 288, 63, 16 ], [ 400, 288, 15, 16 ], [ 419, 285, 53, 19 ], [ 477, 288, 31, 16 ], [ 512, 288, 18, 16 ], [ 535, 285, 51, 19 ], [ 590, 288, 23, 16 ], [ 617, 288, 9, 16 ], [ 630, 285, 59, 19 ], [ 694, 288, 22, 16 ], [ 78, 307, 46, 16 ], [ 129, 305, 36, 19 ], [ 87, 361, 54, 15 ], [ 87, 382, 9, 14 ], [ 100, 382, 50, 14 ], [ 154, 382, 64, 14 ], [ 222, 382, 61, 14 ], [ 288, 382, 35, 14 ], [ 327, 382, 56, 14 ], [ 388, 382, 39, 14 ], [ 431, 382, 251, 14 ], [ 87, 399, 66, 14 ], [ 157, 399, 22, 14 ], [ 183, 399, 54, 14 ], [ 241, 399, 15, 14 ], [ 261, 399, 19, 14 ], [ 284, 399, 10, 14 ], [ 298, 399, 24, 14 ], [ 326, 399, 19, 14 ], [ 349, 399, 41, 14 ], [ 394, 399, 53, 14 ], [ 452, 399, 15, 14 ], [ 471, 399, 29, 14 ], [ 505, 399, 40, 14 ], [ 549, 399, 35, 14 ], [ 587, 399, 19, 14 ], [ 610, 399, 27, 14 ], [ 642, 399, 36, 14 ], [ 682, 399, 38, 14 ], [ 87, 416, 99, 14 ], [ 190, 416, 47, 14 ], [ 241, 416, 69, 14 ], [ 315, 416, 21, 14 ], [ 340, 416, 53, 14 ], [ 397, 416, 59, 14 ], [ 460, 416, 19, 14 ], [ 483, 416, 25, 14 ], [ 513, 416, 43, 14 ], [ 560, 416, 25, 14 ], [ 589, 416, 7, 14 ], [ 600, 416, 63, 14 ], [ 666, 416, 51, 14 ], [ 721, 416, 11, 14 ], [ 87, 432, 14, 14 ], [ 105, 432, 10, 14 ], [ 119, 432, 56, 14 ], [ 179, 432, 23, 14 ], [ 206, 432, 21, 14 ], [ 231, 432, 22, 15 ], [ 257, 432, 35, 14 ], [ 296, 432, 15, 14 ], [ 315, 432, 12, 14 ], [ 332, 432, 19, 14 ], [ 354, 432, 19, 14 ], [ 377, 432, 25, 14 ], [ 407, 432, 35, 14 ], [ 445, 432, 26, 14 ], [ 476, 432, 12, 14 ], [ 492, 432, 23, 14 ], [ 519, 432, 24, 15 ], [ 547, 432, 22, 14 ], [ 573, 432, 62, 14 ], [ 639, 432, 22, 14 ], [ 665, 432, 74, 14 ], [ 87, 449, 11, 14 ], [ 102, 449, 47, 14 ], [ 153, 449, 56, 14 ], [ 214, 449, 51, 14 ], [ 269, 449, 72, 14 ], [ 346, 449, 60, 14 ], [ 410, 449, 22, 14 ], [ 436, 449, 41, 14 ], [ 481, 449, 50, 14 ], [ 535, 449, 62, 14 ], [ 601, 449, 113, 14 ], [ 87, 465, 40, 14 ], [ 132, 465, 62, 14 ], [ 198, 465, 116, 14 ], [ 318, 465, 41, 14 ], [ 364, 465, 33, 14 ], [ 401, 465, 63, 14 ], [ 468, 465, 66, 14 ], [ 539, 465, 62, 14 ], [ 605, 465, 21, 14 ], [ 630, 465, 57, 14 ], [ 87, 482, 49, 14 ], [ 141, 482, 25, 14 ], [ 170, 482, 55, 14 ], [ 229, 482, 82, 14 ], [ 315, 482, 44, 14 ], [ 364, 482, 22, 14 ], [ 390, 482, 85, 14 ], [ 479, 482, 25, 14 ], [ 508, 482, 19, 14 ], [ 531, 482, 74, 14 ], [ 609, 482, 62, 14 ], [ 675, 482, 17, 14 ], [ 87, 499, 51, 14 ], [ 142, 499, 79, 14 ], [ 225, 499, 21, 14 ], [ 251, 499, 25, 14 ], [ 280, 499, 80, 14 ], [ 365, 499, 55, 14 ], [ 424, 499, 31, 14 ], [ 459, 499, 25, 14 ], [ 489, 499, 20, 14 ], [ 513, 499, 21, 14 ], [ 539, 499, 30, 14 ], [ 573, 499, 42, 14 ], [ 620, 499, 21, 14 ], [ 645, 499, 23, 14 ], [ 673, 499, 50, 14 ], [ 87, 515, 35, 14 ], [ 126, 515, 31, 14 ], [ 162, 515, 26, 14 ], [ 191, 515, 18, 14 ], [ 213, 515, 21, 14 ], [ 238, 515, 41, 14 ], [ 283, 515, 69, 14 ], [ 356, 515, 44, 14 ], [ 404, 515, 12, 14 ], [ 420, 515, 45, 14 ], [ 469, 515, 62, 14 ], [ 535, 515, 48, 14 ], [ 588, 515, 45, 14 ], [ 637, 515, 19, 14 ], [ 660, 515, 24, 14 ], [ 87, 532, 64, 14 ], [ 155, 532, 27, 14 ], [ 186, 532, 67, 14 ], [ 257, 532, 34, 14 ], [ 296, 532, 56, 14 ], [ 356, 532, 12, 14 ], [ 372, 532, 72, 14 ], [ 449, 532, 95, 14 ], [ 549, 532, 49, 14 ], [ 601, 532, 59, 14 ], [ 78, 578, 80, 15 ], [ 78, 595, 61, 14 ], [ 143, 595, 31, 14 ], [ 178, 595, 18, 14 ], [ 199, 595, 38, 14 ], [ 240, 595, 36, 14 ], [ 278, 595, 12, 14 ], [ 293, 595, 18, 14 ], [ 315, 595, 34, 14 ], [ 352, 595, 52, 14 ], [ 78, 612, 12, 14 ], [ 94, 612, 26, 14 ], [ 124, 612, 40, 14 ], [ 168, 612, 72, 14 ], [ 243, 612, 76, 14 ], [ 323, 612, 43, 14 ], [ 369, 612, 6, 14 ], [ 380, 612, 24, 14 ], [ 78, 628, 21, 14 ], [ 103, 628, 47, 14 ], [ 154, 628, 12, 14 ], [ 170, 628, 34, 14 ], [ 208, 628, 37, 14 ], [ 249, 628, 65, 14 ], [ 318, 628, 43, 14 ], [ 365, 628, 39, 14 ], [ 78, 645, 49, 14 ], [ 130, 645, 41, 14 ], [ 175, 645, 21, 14 ], [ 199, 645, 18, 14 ], [ 220, 645, 56, 14 ], [ 278, 645, 12, 14 ], [ 293, 645, 49, 14 ], [ 345, 645, 37, 14 ], [ 385, 645, 18, 14 ], [ 78, 661, 27, 14 ], [ 109, 661, 86, 14 ], [ 198, 661, 18, 14 ], [ 219, 661, 21, 14 ], [ 243, 661, 11, 14 ], [ 258, 661, 18, 14 ], [ 279, 661, 23, 14 ], [ 305, 661, 26, 14 ], [ 335, 661, 44, 14 ], [ 382, 661, 22, 14 ], [ 78, 678, 29, 14 ], [ 111, 678, 18, 14 ], [ 133, 678, 21, 14 ], [ 159, 678, 60, 14 ], [ 223, 678, 40, 14 ], [ 268, 678, 37, 14 ], [ 309, 678, 48, 14 ], [ 362, 678, 42, 14 ], [ 78, 695, 51, 14 ], [ 133, 695, 50, 14 ], [ 187, 695, 21, 14 ], [ 212, 695, 41, 14 ], [ 257, 695, 32, 14 ], [ 293, 695, 89, 14 ], [ 386, 695, 18, 14 ], [ 78, 711, 24, 14 ], [ 106, 711, 12, 14 ], [ 122, 711, 49, 14 ], [ 175, 711, 19, 14 ], [ 198, 711, 75, 14 ], [ 276, 711, 12, 14 ], [ 292, 711, 52, 14 ], [ 348, 711, 38, 14 ], [ 390, 711, 14, 14 ], [ 78, 728, 57, 14 ], [ 139, 728, 26, 14 ], [ 168, 728, 79, 14 ], [ 250, 728, 12, 14 ], [ 265, 728, 26, 14 ], [ 293, 728, 21, 14 ], [ 317, 728, 12, 14 ], [ 332, 728, 22, 14 ], [ 358, 728, 46, 14 ], [ 78, 744, 12, 14 ], [ 95, 744, 24, 14 ], [ 123, 744, 12, 14 ], [ 139, 744, 64, 14 ], [ 207, 744, 28, 14 ], [ 240, 744, 59, 14 ], [ 302, 744, 71, 14 ], [ 377, 744, 26, 14 ], [ 78, 761, 30, 14 ], [ 112, 761, 56, 14 ], [ 172, 761, 31, 14 ], [ 206, 761, 9, 14 ], [ 219, 761, 9, 14 ], [ 231, 761, 46, 14 ], [ 281, 761, 22, 14 ], [ 307, 761, 18, 14 ], [ 328, 761, 45, 14 ], [ 377, 761, 27, 14 ], [ 78, 778, 36, 14 ], [ 118, 778, 42, 14 ], [ 164, 778, 20, 14 ], [ 188, 778, 14, 14 ], [ 206, 778, 57, 14 ], [ 267, 778, 12, 14 ], [ 283, 778, 19, 14 ], [ 305, 778, 49, 14 ], [ 358, 778, 46, 14 ], [ 78, 794, 21, 14 ], [ 103, 794, 18, 14 ], [ 125, 794, 66, 14 ], [ 195, 794, 78, 14 ], [ 276, 794, 12, 14 ], [ 292, 794, 19, 14 ], [ 314, 794, 52, 14 ], [ 370, 794, 34, 14 ], [ 78, 811, 38, 14 ], [ 120, 811, 11, 14 ], [ 135, 811, 18, 14 ], [ 157, 811, 36, 14 ], [ 196, 811, 32, 14 ], [ 232, 811, 16, 14 ], [ 252, 811, 18, 14 ], [ 274, 811, 55, 14 ], [ 333, 811, 71, 14 ], [ 78, 827, 21, 14 ], [ 102, 827, 51, 14 ], [ 156, 827, 30, 14 ], [ 190, 827, 30, 14 ], [ 89, 844, 88, 14 ], [ 181, 844, 24, 14 ], [ 209, 844, 46, 14 ], [ 259, 844, 11, 14 ], [ 275, 844, 47, 14 ], [ 326, 844, 12, 14 ], [ 342, 844, 61, 14 ], [ 78, 861, 27, 14 ], [ 110, 861, 31, 14 ], [ 146, 861, 58, 14 ], [ 208, 861, 27, 14 ], [ 240, 861, 12, 14 ], [ 256, 861, 64, 14 ], [ 324, 861, 26, 14 ], [ 355, 861, 35, 14 ], [ 394, 861, 10, 14 ], [ 78, 877, 14, 14 ], [ 97, 877, 60, 14 ], [ 162, 877, 67, 14 ], [ 234, 877, 12, 14 ], [ 250, 877, 29, 14 ], [ 284, 877, 42, 14 ], [ 331, 877, 72, 14 ], [ 78, 925, 5, 11 ], [ 86, 925, 70, 11 ], [ 159, 925, 120, 11 ], [ 78, 936, 32, 13 ], [ 113, 937, 9, 11 ], [ 125, 937, 30, 11 ], [ 158, 937, 33, 11 ], [ 193, 937, 41, 11 ], [ 237, 937, 9, 11 ], [ 249, 937, 29, 11 ], [ 281, 937, 34, 11 ], [ 318, 937, 11, 11 ], [ 332, 937, 32, 11 ], [ 367, 937, 23, 11 ], [ 78, 950, 15, 11 ], [ 97, 950, 25, 11 ], [ 125, 950, 35, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 578, 23, 14 ], [ 450, 578, 78, 14 ], [ 532, 578, 12, 14 ], [ 547, 578, 17, 14 ], [ 569, 578, 20, 14 ], [ 593, 578, 46, 14 ], [ 643, 578, 44, 14 ], [ 692, 578, 14, 14 ], [ 710, 578, 39, 14 ], [ 423, 595, 32, 14 ], [ 459, 595, 18, 14 ], [ 481, 595, 40, 14 ], [ 525, 595, 11, 14 ], [ 541, 595, 18, 14 ], [ 563, 595, 25, 14 ], [ 593, 595, 38, 14 ], [ 635, 595, 60, 14 ], [ 699, 595, 49, 14 ], [ 423, 611, 37, 14 ], [ 465, 611, 12, 14 ], [ 482, 611, 19, 14 ], [ 506, 611, 79, 14 ], [ 590, 611, 24, 14 ], [ 619, 611, 39, 14 ], [ 663, 611, 22, 14 ], [ 690, 611, 58, 14 ], [ 423, 628, 31, 14 ], [ 458, 628, 57, 14 ], [ 519, 628, 12, 14 ], [ 535, 628, 27, 14 ], [ 566, 628, 64, 14 ], [ 634, 628, 43, 14 ], [ 681, 628, 51, 14 ], [ 737, 628, 11, 14 ], [ 423, 645, 53, 14 ], [ 480, 645, 49, 14 ], [ 533, 645, 34, 14 ], [ 571, 645, 23, 14 ], [ 599, 645, 41, 14 ], [ 645, 645, 74, 14 ], [ 722, 645, 26, 14 ], [ 423, 661, 75, 14 ], [ 503, 661, 35, 14 ], [ 543, 661, 39, 14 ], [ 587, 661, 36, 14 ], [ 627, 661, 10, 14 ], [ 642, 661, 29, 14 ], [ 675, 661, 12, 14 ], [ 692, 661, 19, 14 ], [ 716, 661, 32, 14 ], [ 423, 678, 51, 14 ], [ 478, 678, 44, 14 ], [ 526, 678, 18, 14 ], [ 549, 678, 53, 14 ], [ 606, 678, 11, 14 ], [ 622, 678, 52, 14 ], [ 678, 678, 14, 14 ], [ 696, 678, 26, 14 ], [ 727, 678, 21, 14 ], [ 423, 695, 52, 14 ], [ 479, 695, 35, 14 ], [ 519, 695, 36, 14 ], [ 559, 695, 61, 14 ], [ 625, 695, 18, 14 ], [ 647, 695, 11, 14 ], [ 662, 695, 18, 14 ], [ 685, 695, 27, 14 ], [ 716, 695, 32, 14 ], [ 423, 711, 18, 14 ], [ 444, 711, 39, 14 ], [ 487, 711, 11, 14 ], [ 503, 711, 18, 14 ], [ 525, 711, 32, 14 ], [ 562, 711, 19, 14 ], [ 585, 711, 54, 14 ], [ 643, 711, 55, 14 ], [ 702, 711, 46, 14 ], [ 423, 728, 31, 14 ], [ 462, 728, 20, 14 ], [ 491, 728, 40, 14 ], [ 539, 728, 31, 14 ], [ 578, 728, 63, 14 ], [ 650, 728, 67, 14 ], [ 725, 728, 23, 14 ], [ 423, 744, 63, 14 ], [ 490, 744, 44, 14 ], [ 539, 744, 12, 14 ], [ 555, 744, 35, 14 ], [ 595, 744, 38, 14 ], [ 638, 744, 58, 14 ], [ 700, 744, 20, 14 ], [ 725, 744, 23, 14 ], [ 423, 761, 19, 14 ], [ 446, 761, 38, 14 ], [ 488, 761, 12, 14 ], [ 504, 761, 86, 14 ], [ 594, 761, 9, 14 ], [ 607, 761, 23, 14 ], [ 634, 761, 14, 14 ], [ 653, 761, 58, 14 ], [ 714, 761, 33, 14 ], [ 423, 778, 22, 14 ], [ 450, 778, 55, 14 ], [ 511, 778, 45, 14 ], [ 561, 778, 22, 14 ], [ 589, 778, 44, 14 ], [ 638, 778, 61, 14 ], [ 704, 778, 44, 14 ], [ 423, 794, 37, 14 ], [ 464, 794, 26, 14 ], [ 495, 794, 46, 14 ], [ 546, 794, 58, 14 ], [ 608, 794, 12, 14 ], [ 625, 794, 19, 14 ], [ 648, 794, 33, 14 ], [ 685, 794, 63, 14 ], [ 423, 811, 26, 14 ], [ 453, 811, 66, 14 ], [ 523, 811, 50, 14 ], [ 577, 811, 29, 14 ], [ 434, 827, 13, 14 ], [ 451, 827, 19, 14 ], [ 475, 827, 45, 14 ], [ 524, 827, 36, 14 ], [ 564, 827, 19, 14 ], [ 588, 827, 72, 14 ], [ 664, 827, 44, 14 ], [ 712, 827, 12, 14 ], [ 729, 827, 19, 14 ], [ 423, 844, 65, 14 ], [ 491, 844, 37, 14 ], [ 532, 844, 57, 14 ], [ 592, 844, 11, 14 ], [ 607, 844, 40, 14 ], [ 651, 844, 97, 14 ], [ 423, 860, 235, 14 ], [ 662, 860, 41, 14 ], [ 706, 860, 15, 14 ], [ 724, 860, 24, 14 ], [ 423, 877, 40, 14 ], [ 467, 877, 66, 14 ], [ 536, 877, 14, 14 ], [ 554, 877, 13, 14 ], [ 570, 877, 26, 14 ], [ 600, 877, 22, 14 ], [ 625, 877, 34, 14 ], [ 664, 877, 17, 14 ], [ 684, 877, 19, 14 ], [ 706, 877, 12, 14 ], [ 721, 877, 27, 14 ], [ 423, 894, 42, 14 ], [ 469, 894, 12, 14 ], [ 486, 894, 31, 14 ], [ 521, 894, 42, 14 ], [ 567, 894, 37, 14 ], [ 608, 894, 21, 14 ], [ 633, 894, 31, 14 ], [ 669, 894, 50, 14 ], [ 723, 894, 25, 14 ], [ 423, 910, 21, 14 ], [ 448, 910, 26, 15 ], [ 478, 910, 40, 14 ], [ 521, 910, 72, 14 ], [ 597, 910, 14, 14 ], [ 615, 910, 60, 14 ], [ 679, 910, 35, 14 ], [ 718, 910, 12, 14 ], [ 734, 910, 14, 14 ], [ 423, 927, 69, 14 ], [ 495, 927, 30, 14 ], [ 529, 927, 63, 14 ], [ 596, 927, 8, 14 ], [ 607, 927, 22, 14 ], [ 633, 927, 75, 14 ], [ 712, 927, 12, 14 ], [ 727, 927, 21, 14 ], [ 423, 944, 34, 14 ], [ 460, 944, 80, 14 ], [ 543, 944, 72, 14 ], [ 618, 944, 21, 14 ], [ 643, 944, 18, 14 ], [ 665, 944, 31, 14 ], [ 699, 944, 24, 14 ], [ 727, 944, 21, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 277, 987, 23, 10 ], [ 302, 987, 8, 10 ], [ 312, 987, 8, 10 ], [ 322, 987, 30, 10 ], [ 354, 987, 33, 10 ], [ 390, 987, 15, 10 ], [ 407, 987, 6, 10 ], [ 415, 987, 10, 10 ], [ 427, 987, 21, 10 ], [ 450, 987, 25, 10 ], [ 477, 987, 23, 10 ], [ 502, 987, 41, 10 ], [ 545, 987, 23, 10 ], [ 570, 987, 13, 10 ], [ 585, 987, 22, 10 ], [ 608, 987, 8, 10 ], [ 618, 987, 13, 10 ], [ 633, 987, 31, 10 ], [ 666, 987, 39, 10 ], [ 707, 987, 41, 10 ], [ 248, 998, 28, 10 ], [ 278, 998, 171, 10 ], [ 451, 998, 23, 10 ], [ 477, 998, 29, 10 ], [ 508, 998, 45, 10 ], [ 555, 998, 15, 10 ], [ 573, 998, 45, 10 ], [ 620, 998, 15, 10 ], [ 637, 998, 49, 10 ], [ 689, 998, 7, 10 ], [ 698, 998, 14, 10 ], [ 714, 998, 34, 10 ], [ 248, 1009, 34, 10 ], [ 284, 1009, 13, 10 ], [ 300, 1009, 28, 10 ], [ 331, 1009, 19, 10 ], [ 352, 1009, 6, 10 ], [ 361, 1009, 32, 10 ], [ 395, 1009, 21, 10 ] ]

[ "Abreu", "et", "al.", "Nanoscale", "Research", "Letters", "2011,", "6:482", "http://www.nanoscalereslett.com/content/6/1/482", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Open", "Access", "Nanoliposomes", "for", "encapsulation", "and", "delivery", "of", "the", "potential", "antitumoral", "methyl", "6-methoxy-3-(4-", "methoxyphenyl)-1H-indole-2-carboxylate", "Ana", "S", "Abreu1,2*,", "Elisabete", "MS", "Castanheira1,", "Maria-João", "RP", "Queiroz2,", "Paula", "MT", "Ferreira2,", "Luís", "A", "Vale-Silva3", "and", "Eugénia", "Pinto3", "Abstract", "A", "potential", "antitumoral", "fluorescent", "indole", "derivative,", "methyl", "6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-", "carboxylate,", "was", "evaluated", "for", "the", "in", "vitro", "cell", "growth", "inhibition", "on", "three", "human", "tumor", "cell", "lines,", "MCF-7", "(breast", "adenocarcinoma),", "A375-C5", "(melanoma),", "and", "NCI-H460", "(non-small", "cell", "lung", "cancer),", "after", "a", "continuous", "exposure", "of", "48", "h,", "exhibiting", "very", "low", "GI50", "values", "for", "all", "the", "cell", "lines", "tested", "(0.25", "to", "0.33", "μM).", "This", "compound", "was", "encapsulated", "in", "different", "nanosized", "liposome", "formulations,", "containing", "egg", "lecithin", "(Egg-PC),", "dipalmitoyl", "phosphatidylcholine", "(DPPC),", "dipalmitoyl", "phosphatidylglycerol", "(DPPG),", "DSPC,", "cholesterol,", "dihexadecyl", "phosphate,", "and", "DSPE-PEG.", "Dynamic", "light", "scattering", "measurements", "showed", "that", "nanoliposomes", "with", "the", "encapsulated", "compound", "are", "generally", "monodisperse", "and", "with", "hydrodynamic", "diameters", "lower", "than", "120", "nm,", "good", "stability", "and", "zeta", "potential", "values", "lower", "than", "-18", "mV.", "Dialysis", "experiments", "allowed", "to", "monitor", "compound", "diffusion", "through", "the", "lipid", "membrane,", "from", "DPPC/DPPG", "donor", "liposomes", "to", "NBD-labelled", "lipid/DPPC/DPPG", "acceptor", "liposomes.", "Introduction", "Anticancer", "drugs", "are", "crucial", "agents", "in", "the", "global", "approach", "to", "fight", "cancer.", "Drug-loaded", "nanoparticles", "provide", "a", "per-", "fect", "solution", "to", "afford", "higher", "therapeutic", "efficacy", "and/or", "reducing", "toxicity", "and", "the", "possibility", "of", "targeting", "cancer", "tis-", "sues.", "Nanoliposomes", "are", "one", "of", "the", "best", "drug", "delivery", "sys-", "tems", "for", "low", "molecular", "weight", "drugs,", "imaging", "agents,", "peptides,", "proteins,", "and", "nucleic", "acids.", "Nanoliposomes", "are", "able", "to", "enhance", "the", "performance", "of", "bioactive", "agents", "by", "improving", "their", "bioavailability,", "in", "vitro", "and", "in", "vivo", "stability,", "as", "well", "as", "preventing", "their", "unwanted", "interactions", "with", "other", "molecules", "[1-3].", "It", "is", "believed", "that", "the", "efficient", "anti-", "tumor", "activity", "can", "be", "attributed", "to", "the", "selective", "delivery", "and", "the", "preferential", "accumulation", "of", "the", "liposome", "nano-", "carrier", "in", "the", "tumor", "tissue", "via", "the", "enhanced", "permeability", "and", "retention", "effect", "[4-6].", "Nanoliposomes", "may", "contain,", "in", "addition", "to", "phospholi-", "pids,", "other", "molecules", "such", "as", "cholesterol", "(Ch)", "which", "is", "an", "important", "component", "of", "most", "natural", "membranes.", "*", "Correspondence:", "anabreu@quimica.uminho.pt", "1Centre", "of", "Physics", "(CFUM),", "University", "of", "Minho,", "Campus", "de", "Gualtar,", "4710-", "057", "Braga,", "Portugal", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "The", "incorporation", "of", "Ch", "can", "increase", "stability", "by", "modu-", "lating", "the", "fluidity", "of", "the", "lipid", "bilayer", "preventing", "crystalli-", "zation", "of", "the", "phospholipid", "acyl", "chains", "and", "providing", "steric", "hindrance", "to", "their", "movement.", "Further", "advances", "in", "liposome", "research", "found", "that", "surface", "modification", "with", "polyethylene", "glycol", "(PEG),", "which", "is", "inert", "in", "the", "body,", "generally", "reduces", "the", "clearance", "of", "liposome", "by", "RES,", "and", "therefore", "allows", "longer", "circulatory", "life", "of", "the", "drug", "deliv-", "ery", "system", "in", "the", "blood", "[3].", "Pegylated", "liposomal", "doxoru-", "bicin", "has", "shown", "great", "prolonged", "circulation", "and", "substantial", "efficacy", "in", "breast", "cancer", "treatment", "[7].", "The", "net", "charge", "of", "nanoliposomes", "is", "also", "an", "important", "factor", "and", "generally", "anionic", "and", "neutral", "liposomes", "survive", "longer", "than", "cationic", "liposomes", "in", "the", "blood", "circulation", "after", "intravenous", "injection", "[8,9].", "In", "the", "present", "study,", "the", "antitumoral", "activity", "of", "the", "fluorescent", "indole", "derivative", "1,", "methyl", "6-methoxy-3-(4-", "methoxyphenyl)-1H-indole-2-carboxylate", "(Figure", "1),", "pre-", "viously", "synthesized", "by", "us", "[10],", "was", "tested", "for", "the", "in", "vitro", "growth", "of", "three", "human", "tumor", "cell", "lines,", "showing", "very", "low", "GI50", "values.", "Considering", "its", "promising", "utility", "as", "an", "antitumoral", "drug,", "compound", "1", "was", "encapsulated", "in", "dif-", "ferent", "nanoliposome", "formulations", "and", "the", "mean", "size,", "size", "©", "2011", "Abreu", "et", "al;", "licensee", "Springer.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 26, 11 ], [ 98, 75, 40, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 11, 12 ], [ 230, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 41, 25 ], [ 116, 220, 71, 25 ], [ 191, 220, 22, 25 ], [ 218, 220, 205, 25 ], [ 427, 220, 28, 25 ], [ 459, 220, 106, 25 ], [ 570, 220, 155, 25 ], [ 70, 248, 40, 25 ], [ 115, 248, 155, 25 ], [ 274, 248, 22, 25 ], [ 301, 248, 140, 25 ], [ 445, 248, 87, 25 ], [ 120, 316, 34, 17 ], [ 157, 316, 55, 17 ], [ 120, 348, 41, 13 ], [ 164, 348, 9, 13 ], [ 176, 348, 47, 13 ], [ 225, 348, 40, 13 ], [ 268, 348, 19, 13 ], [ 289, 348, 41, 13 ], [ 333, 348, 9, 13 ], [ 345, 348, 45, 13 ], [ 392, 348, 59, 13 ], [ 454, 348, 9, 13 ], [ 466, 348, 48, 13 ], [ 516, 348, 40, 13 ], [ 558, 348, 50, 13 ], [ 611, 348, 37, 13 ], [ 650, 348, 44, 13 ], [ 120, 362, 30, 13 ], [ 153, 362, 28, 13 ], [ 183, 362, 43, 13 ], [ 228, 362, 38, 13 ], [ 120, 390, 83, 13 ], [ 205, 390, 34, 13 ], [ 242, 390, 12, 13 ], [ 256, 390, 49, 13 ], [ 308, 390, 11, 13 ], [ 321, 390, 23, 13 ], [ 346, 390, 42, 13 ], [ 391, 390, 99, 13 ], [ 120, 417, 44, 13 ], [ 166, 417, 12, 13 ], [ 181, 417, 33, 13 ], [ 216, 417, 27, 13 ], [ 246, 417, 46, 13 ], [ 294, 417, 12, 13 ], [ 309, 417, 35, 13 ], [ 347, 417, 24, 13 ], [ 120, 443, 75, 13 ], [ 198, 443, 12, 13 ], [ 213, 443, 52, 13 ], [ 267, 443, 38, 13 ], [ 120, 468, 34, 13 ], [ 159, 468, 29, 13 ], [ 193, 468, 67, 13 ], [ 264, 468, 38, 13 ], [ 307, 468, 105, 13 ], [ 416, 468, 50, 13 ], [ 471, 468, 71, 13 ], [ 546, 468, 37, 13 ], [ 588, 468, 59, 13 ], [ 651, 468, 24, 13 ], [ 679, 468, 11, 13 ], [ 694, 468, 69, 13 ], [ 120, 483, 39, 13 ], [ 161, 483, 29, 13 ], [ 191, 483, 35, 13 ], [ 228, 483, 19, 13 ], [ 249, 483, 35, 13 ], [ 286, 483, 52, 13 ], [ 340, 483, 96, 13 ], [ 438, 483, 15, 13 ], [ 455, 483, 92, 13 ], [ 549, 483, 59, 13 ], [ 610, 483, 32, 13 ], [ 644, 483, 53, 13 ], [ 699, 483, 13, 13 ], [ 714, 483, 49, 13 ], [ 120, 497, 20, 13 ], [ 144, 497, 27, 13 ], [ 174, 497, 10, 13 ], [ 188, 497, 28, 13 ], [ 220, 497, 40, 13 ], [ 264, 497, 92, 13 ], [ 360, 497, 23, 13 ], [ 386, 497, 68, 13 ], [ 457, 497, 60, 13 ], [ 521, 497, 17, 13 ], [ 542, 497, 49, 13 ], [ 594, 497, 59, 13 ], [ 656, 497, 19, 13 ], [ 679, 497, 44, 13 ], [ 726, 497, 37, 13 ], [ 120, 512, 11, 13 ], [ 136, 512, 47, 13 ], [ 189, 512, 40, 13 ], [ 235, 512, 23, 13 ], [ 264, 512, 37, 13 ], [ 307, 512, 30, 13 ], [ 343, 512, 11, 13 ], [ 359, 512, 72, 13 ], [ 437, 512, 30, 13 ], [ 472, 512, 22, 13 ], [ 500, 512, 23, 13 ], [ 528, 512, 15, 13 ], [ 550, 512, 11, 13 ], [ 566, 512, 12, 13 ], [ 584, 512, 36, 13 ], [ 626, 512, 25, 13 ], [ 657, 512, 11, 13 ], [ 674, 512, 42, 13 ], [ 722, 512, 41, 13 ], [ 120, 526, 92, 13 ], [ 216, 526, 28, 13 ], [ 248, 526, 12, 13 ], [ 263, 526, 30, 13 ], [ 297, 526, 11, 13 ], [ 311, 526, 16, 13 ], [ 330, 526, 50, 13 ], [ 383, 526, 11, 13 ], [ 397, 526, 95, 13 ], [ 495, 526, 50, 13 ], [ 549, 526, 74, 13 ], [ 626, 526, 20, 13 ], [ 649, 526, 33, 13 ], [ 685, 526, 10, 13 ], [ 699, 526, 26, 13 ], [ 728, 526, 35, 13 ], [ 120, 541, 40, 13 ], [ 164, 541, 22, 13 ], [ 190, 541, 40, 13 ], [ 234, 541, 8, 13 ], [ 246, 541, 20, 13 ], [ 270, 541, 27, 13 ], [ 301, 541, 14, 13 ], [ 319, 541, 62, 13 ], [ 385, 541, 23, 13 ], [ 412, 541, 45, 13 ], [ 461, 541, 19, 13 ], [ 484, 541, 11, 13 ], [ 498, 541, 42, 13 ], [ 544, 541, 41, 13 ], [ 589, 541, 43, 13 ], [ 636, 541, 16, 13 ], [ 657, 541, 48, 13 ], [ 709, 541, 30, 13 ], [ 743, 541, 20, 13 ], [ 120, 555, 35, 13 ], [ 158, 555, 30, 13 ], [ 191, 555, 12, 13 ], [ 206, 555, 27, 13 ], [ 235, 555, 54, 13 ], [ 292, 555, 10, 13 ], [ 306, 555, 40, 13 ], [ 349, 555, 18, 13 ], [ 369, 555, 32, 13 ], [ 403, 555, 52, 13 ], [ 458, 555, 46, 13 ], [ 507, 555, 38, 13 ], [ 548, 555, 16, 13 ], [ 567, 555, 25, 13 ], [ 594, 555, 27, 13 ], [ 624, 555, 14, 13 ], [ 640, 555, 61, 13 ], [ 704, 555, 59, 13 ], [ 120, 570, 39, 13 ], [ 163, 570, 49, 13 ], [ 216, 570, 35, 13 ], [ 255, 570, 53, 13 ], [ 312, 570, 47, 13 ], [ 364, 570, 48, 13 ], [ 415, 570, 64, 13 ], [ 484, 570, 41, 13 ], [ 529, 570, 41, 13 ], [ 574, 570, 31, 13 ], [ 610, 570, 14, 13 ], [ 628, 570, 30, 13 ], [ 662, 570, 31, 13 ], [ 697, 570, 40, 13 ], [ 741, 570, 22, 13 ], [ 120, 584, 14, 13 ], [ 137, 584, 18, 13 ], [ 158, 584, 39, 13 ], [ 200, 584, 44, 13 ], [ 247, 584, 15, 13 ], [ 266, 584, 16, 13 ], [ 285, 584, 17, 13 ], [ 306, 584, 11, 13 ], [ 320, 584, 92, 13 ], [ 415, 584, 11, 13 ], [ 429, 584, 16, 13 ], [ 449, 584, 50, 13 ], [ 502, 584, 10, 13 ], [ 516, 584, 95, 13 ], [ 614, 584, 61, 13 ], [ 679, 584, 17, 13 ], [ 699, 584, 50, 13 ], [ 752, 584, 11, 13 ], [ 120, 599, 113, 13 ], [ 237, 599, 41, 13 ], [ 281, 599, 21, 13 ], [ 305, 599, 12, 13 ], [ 321, 599, 55, 13 ], [ 378, 599, 20, 13 ], [ 401, 599, 20, 13 ], [ 424, 599, 11, 13 ], [ 438, 599, 92, 13 ], [ 533, 599, 15, 13 ], [ 552, 599, 27, 13 ], [ 582, 599, 59, 13 ], [ 644, 599, 23, 13 ], [ 671, 599, 10, 13 ], [ 684, 599, 79, 13 ], [ 120, 613, 35, 13 ], [ 157, 613, 12, 13 ], [ 171, 613, 37, 13 ], [ 211, 613, 11, 13 ], [ 224, 613, 26, 13 ], [ 252, 613, 43, 13 ], [ 120, 640, 52, 13 ], [ 174, 640, 9, 13 ], [ 186, 640, 24, 13 ], [ 213, 640, 23, 13 ], [ 239, 640, 42, 13 ], [ 282, 640, 22, 13 ], [ 307, 640, 8, 13 ], [ 317, 640, 13, 13 ], [ 332, 640, 26, 13 ], [ 359, 640, 30, 13 ], [ 391, 640, 31, 13 ], [ 425, 640, 55, 13 ], [ 482, 640, 30, 13 ], [ 514, 640, 16, 13 ], [ 532, 640, 41, 13 ], [ 576, 640, 53, 13 ], [ 631, 640, 58, 13 ], [ 690, 640, 40, 13 ], [ 732, 640, 31, 13 ], [ 120, 654, 39, 13 ], [ 161, 654, 61, 13 ], [ 225, 654, 20, 13 ], [ 247, 654, 63, 13 ], [ 312, 654, 19, 13 ], [ 334, 654, 66, 13 ], [ 403, 654, 11, 13 ], [ 416, 654, 18, 13 ], [ 436, 654, 46, 13 ], [ 484, 654, 45, 13 ], [ 532, 654, 16, 13 ], [ 551, 654, 39, 13 ], [ 592, 654, 26, 13 ], [ 621, 654, 8, 13 ], [ 631, 654, 43, 13 ], [ 677, 654, 28, 13 ], [ 70, 715, 13, 17 ], [ 86, 715, 92, 17 ], [ 70, 751, 22, 14 ], [ 100, 751, 54, 14 ], [ 161, 751, 12, 14 ], [ 181, 751, 79, 14 ], [ 267, 751, 19, 14 ], [ 293, 751, 57, 14 ], [ 357, 751, 47, 14 ], [ 70, 767, 26, 14 ], [ 99, 767, 18, 14 ], [ 120, 767, 71, 14 ], [ 195, 767, 12, 14 ], [ 209, 767, 72, 14 ], [ 284, 767, 74, 14 ], [ 362, 767, 42, 14 ], [ 70, 783, 17, 14 ], [ 92, 783, 29, 14 ], [ 126, 783, 44, 14 ], [ 175, 783, 12, 14 ], [ 191, 783, 11, 14 ], [ 207, 783, 35, 14 ], [ 246, 783, 32, 14 ], [ 283, 783, 74, 14 ], [ 362, 783, 42, 14 ], [ 70, 798, 59, 14 ], [ 134, 798, 30, 14 ], [ 168, 798, 18, 14 ], [ 191, 798, 63, 14 ], [ 258, 798, 12, 14 ], [ 275, 798, 18, 14 ], [ 297, 798, 28, 14 ], [ 330, 798, 9, 14 ], [ 344, 798, 60, 14 ], [ 70, 814, 25, 14 ], [ 98, 814, 41, 14 ], [ 141, 814, 56, 14 ], [ 200, 814, 17, 14 ], [ 219, 814, 21, 14 ], [ 243, 814, 28, 14 ], [ 273, 814, 46, 14 ], [ 321, 814, 55, 14 ], [ 379, 814, 25, 14 ], [ 70, 830, 45, 14 ], [ 118, 830, 20, 14 ], [ 140, 830, 13, 14 ], [ 156, 830, 46, 14 ], [ 204, 830, 31, 14 ], [ 238, 830, 56, 14 ], [ 296, 830, 12, 14 ], [ 311, 830, 63, 14 ], [ 376, 830, 28, 14 ], [ 70, 846, 20, 14 ], [ 94, 846, 21, 14 ], [ 119, 846, 44, 14 ], [ 168, 846, 27, 14 ], [ 199, 846, 12, 14 ], [ 215, 846, 49, 14 ], [ 268, 846, 43, 14 ], [ 315, 846, 89, 14 ], [ 70, 861, 21, 14 ], [ 94, 861, 74, 14 ], [ 91, 877, 46, 14 ], [ 141, 877, 50, 14 ], [ 196, 877, 12, 14 ], [ 213, 877, 45, 14 ], [ 263, 877, 24, 14 ], [ 292, 877, 44, 14 ], [ 341, 877, 11, 14 ], [ 357, 877, 7, 14 ], [ 368, 877, 36, 14 ], [ 70, 893, 28, 14 ], [ 103, 893, 21, 14 ], [ 130, 893, 17, 14 ], [ 153, 893, 57, 14 ], [ 215, 893, 55, 14 ], [ 276, 893, 41, 14 ], [ 323, 893, 35, 14 ], [ 363, 893, 41, 14 ], [ 70, 909, 18, 14 ], [ 94, 909, 80, 14 ], [ 180, 909, 39, 14 ], [ 225, 909, 57, 14 ], [ 289, 909, 88, 14 ], [ 383, 909, 21, 14 ], [ 70, 925, 52, 14 ], [ 127, 925, 80, 14 ], [ 212, 925, 57, 14 ], [ 274, 925, 15, 14 ], [ 294, 925, 16, 14 ], [ 315, 925, 22, 14 ], [ 342, 925, 28, 14 ], [ 375, 925, 29, 14 ], [ 70, 940, 50, 14 ], [ 123, 940, 64, 14 ], [ 191, 940, 12, 14 ], [ 205, 940, 106, 14 ], [ 314, 940, 77, 14 ], [ 395, 940, 9, 14 ], [ 70, 956, 18, 14 ], [ 90, 956, 21, 14 ], [ 114, 956, 12, 14 ], [ 128, 956, 76, 14 ], [ 207, 956, 43, 14 ], [ 253, 956, 32, 14 ], [ 287, 956, 17, 14 ], [ 307, 956, 34, 14 ], [ 344, 956, 19, 14 ], [ 365, 956, 39, 14 ], [ 70, 972, 12, 14 ], [ 85, 972, 13, 14 ], [ 101, 972, 24, 14 ], [ 127, 972, 44, 15 ], [ 174, 972, 12, 14 ], [ 188, 972, 26, 14 ], [ 217, 972, 41, 14 ], [ 260, 972, 16, 14 ], [ 91, 988, 106, 14 ], [ 202, 988, 66, 14 ], [ 272, 988, 17, 14 ], [ 294, 988, 22, 14 ], [ 320, 988, 84, 14 ], [ 70, 1004, 24, 14 ], [ 100, 1004, 66, 14 ], [ 172, 1004, 39, 14 ], [ 216, 1004, 14, 14 ], [ 237, 1004, 14, 14 ], [ 257, 1004, 54, 14 ], [ 317, 1004, 22, 14 ], [ 345, 1004, 34, 15 ], [ 385, 1004, 19, 14 ], [ 70, 1019, 42, 14 ], [ 118, 1019, 45, 14 ], [ 170, 1019, 76, 14 ], [ 253, 1019, 15, 14 ], [ 275, 1019, 28, 14 ], [ 309, 1019, 12, 14 ], [ 328, 1019, 44, 14 ], [ 379, 1019, 25, 14 ], [ 428, 717, 25, 14 ], [ 459, 717, 7, 14 ], [ 472, 717, 45, 14 ], [ 523, 717, 34, 14 ], [ 564, 717, 72, 14 ], [ 641, 717, 12, 14 ], [ 659, 717, 52, 14 ], [ 718, 717, 45, 14 ], [ 428, 733, 44, 14 ], [ 478, 733, 25, 14 ], [ 508, 733, 41, 14 ], [ 555, 733, 33, 14 ], [ 593, 733, 12, 14 ], [ 610, 733, 80, 14 ], [ 695, 733, 67, 14 ], [ 428, 749, 19, 14 ], [ 450, 749, 54, 14 ], [ 507, 749, 55, 14 ], [ 565, 749, 41, 14 ], [ 609, 749, 21, 14 ], [ 633, 749, 76, 14 ], [ 713, 749, 50, 14 ], [ 428, 764, 21, 14 ], [ 453, 764, 27, 14 ], [ 485, 764, 33, 14 ], [ 522, 764, 102, 14 ], [ 628, 764, 21, 14 ], [ 654, 764, 69, 14 ], [ 727, 764, 35, 15 ], [ 428, 780, 12, 14 ], [ 445, 780, 55, 14 ], [ 506, 780, 26, 14 ], [ 537, 780, 23, 14 ], [ 565, 780, 12, 14 ], [ 582, 780, 38, 14 ], [ 625, 780, 40, 14 ], [ 670, 780, 28, 14 ], [ 703, 780, 59, 14 ], [ 428, 796, 46, 14 ], [ 479, 796, 29, 14 ], [ 512, 796, 32, 14 ], [ 548, 796, 31, 14 ], [ 584, 796, 39, 14 ], [ 628, 796, 65, 14 ], [ 698, 796, 21, 14 ], [ 724, 796, 39, 14 ], [ 428, 812, 54, 14 ], [ 485, 812, 12, 14 ], [ 499, 812, 44, 14 ], [ 546, 812, 25, 14 ], [ 574, 812, 106, 14 ], [ 683, 812, 80, 14 ], [ 449, 827, 22, 14 ], [ 478, 827, 44, 14 ], [ 530, 827, 37, 14 ], [ 574, 827, 9, 14 ], [ 590, 827, 43, 14 ], [ 641, 827, 15, 14 ], [ 663, 827, 74, 14 ], [ 744, 827, 18, 14 ], [ 428, 843, 51, 14 ], [ 484, 843, 48, 14 ], [ 536, 843, 40, 14 ], [ 581, 843, 24, 14 ], [ 609, 843, 15, 14 ], [ 629, 843, 18, 14 ], [ 651, 843, 19, 14 ], [ 675, 843, 12, 14 ], [ 691, 843, 55, 14 ], [ 751, 843, 12, 14 ], [ 428, 859, 44, 14 ], [ 475, 859, 25, 14 ], [ 503, 859, 106, 14 ], [ 612, 859, 77, 14 ], [ 428, 895, 13, 17 ], [ 444, 895, 136, 17 ], [ 428, 925, 106, 14 ], [ 543, 925, 17, 14 ], [ 567, 925, 50, 14 ], [ 625, 925, 40, 14 ], [ 673, 925, 17, 14 ], [ 698, 925, 65, 14 ], [ 428, 940, 118, 14 ], [ 550, 940, 46, 14 ], [ 600, 940, 42, 14 ], [ 645, 940, 53, 15 ], [ 701, 940, 39, 15 ], [ 743, 940, 9, 14 ], [ 756, 940, 7, 14 ], [ 428, 956, 41, 14 ], [ 475, 956, 46, 14 ], [ 526, 956, 34, 14 ], [ 564, 956, 30, 14 ], [ 599, 956, 59, 14 ], [ 663, 956, 12, 14 ], [ 679, 956, 47, 14 ], [ 731, 956, 31, 14 ], [ 428, 972, 53, 14 ], [ 488, 972, 30, 14 ], [ 525, 972, 56, 14 ], [ 588, 972, 26, 14 ], [ 620, 972, 21, 14 ], [ 649, 972, 41, 14 ], [ 697, 972, 66, 14 ], [ 428, 988, 27, 14 ], [ 461, 988, 39, 15 ], [ 506, 988, 9, 14 ], [ 520, 988, 54, 14 ], [ 580, 988, 39, 14 ], [ 624, 988, 12, 14 ], [ 641, 988, 43, 14 ], [ 689, 988, 32, 14 ], [ 726, 988, 21, 14 ], [ 753, 988, 9, 14 ], [ 428, 1004, 22, 14 ], [ 456, 1004, 34, 14 ], [ 495, 1004, 12, 14 ], [ 512, 1004, 58, 14 ], [ 575, 1004, 24, 14 ], [ 604, 1004, 27, 14 ], [ 636, 1004, 46, 14 ], [ 687, 1004, 75, 14 ], [ 428, 1019, 21, 14 ], [ 452, 1019, 77, 14 ], [ 531, 1019, 21, 14 ], [ 555, 1019, 12, 14 ], [ 570, 1019, 20, 14 ], [ 593, 1019, 55, 14 ], [ 650, 1019, 12, 14 ], [ 665, 1019, 30, 14 ], [ 697, 1019, 37, 14 ], [ 736, 1019, 26, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "PPAR", "Research", "Volume", "2009,", "Article", "ID", "373524,", "15", "pages", "doi:10.1155/2009/373524", "Review", "Article", "The", "Effects", "of", "Thiazolidinediones", "on", "Metabolic", "Complications", "and", "Lipodystrophy", "in", "HIV-Infected", "Patients", "Jussi", "Sutinen", "Division", "of", "Infectious", "Diseases", "and", "Division", "of", "Diabetes,", "Department", "of", "Medicine,", "Helsinki", "University", "Central", "Hospital,", "00029", "HUS,", "Helsinki,", "Finland", "Correspondence", "should", "be", "addressed", "to", "Jussi", "Sutinen,", "jussi.sutinen@hus.fi", "Received", "18", "March", "2008;", "Accepted", "25", "August", "2008", "Recommended", "by", "Jacqueline", "Capeau", "Highly", "active", "antiretroviral", "therapy", "(HAART)-associated", "metabolic", "complications", "include", "lipoatrophy", "(loss", "of", "subcutaneous", "adipose", "tissue", "(SAT))", "and", "insulin", "resistance.", "Thiazolidinediones", "are", "insulin-sensitizing", "antidiabetic", "agents", "which—as", "an", "untoward", "side", "effect", "in", "obese", "diabetic", "patients—increase", "SAT.", "Furthermore,", "troglitazone", "has", "improved", "lipoatrophy", "and", "glycemic", "control", "in", "non-HIV", "patients", "with", "various", "forms", "of", "lipodystrophy.", "These", "data", "have", "led", "to", "14", "clinical", "trials", "to", "examine", "whether", "thiazolidinediones", "could", "be", "useful", "in", "the", "treatment", "of", "HAART-associated", "metabolic", "complications.", "The", "results", "of", "these", "studies", "indicate", "very", "modest,", "if", "any,", "effect", "on", "lipoatrophic", "SAT,", "probably", "due", "to", "ongoing", "HAART", "negating", "the", "beneficial", "effect.", "The", "benefit", "might", "be", "more", "prominent", "in", "patients", "not", "taking", "thymidine", "analoges.", "Despite", "the", "poor", "effect", "on", "lipoatrophy,", "thiazolidin-", "ediones", "improved", "insulin", "sensitivity.", "However,", "especially", "rosiglitazone", "induced", "harmful", "effects", "on", "blood", "lipids.", "Current", "data", "do", "not", "provide", "evidence", "for", "the", "use", "of", "thiazolidinediones", "in", "the", "treatment", "of", "HAART-associated", "lipoatrophy,", "but", "treatment", "of", "lipoatrophy-associated", "diabetes", "may", "be", "warranted.", "The", "role", "of", "thiazolidinediones", "for", "novel", "indications,", "such", "as", "hepatosteatosis,", "should", "be", "studied", "in", "these", "patients.", "Copyright", "©", "2009", "Jussi", "Sutinen.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "1.", "Introduction", "The", "prognosis", "of", "HIV-infection", "has", "drastically", "changed", "after", "the", "introduction", "of", "combination", "antiretroviral", "therapy", "[1]", "often", "referred", "to", "as", "highly", "active", "antiretroviral", "therapy", "(HAART).", "Since", "the", "eradication", "of", "the", "virus", "is", "impossible", "with", "current", "medicines", "[2]", "and", "since", "periodic", "treatment", "with", "HAART", "can", "be", "harmful", "when", "compared", "to", "continuous", "ther-", "apy", "[3],", "patients", "need", "to", "continue", "therapy", "uninterruptedly", "and", "permanently.", "Lifelong", "exposure", "to", "HAART", "puts", "patients", "at", "a", "signif-", "icant", "risk", "for", "long-term", "metabolic", "adverse", "effects", "includ-", "ing", "lipodystrophy,", "insulin", "resistance,", "hyperlipidemia,", "and", "increased", "cardiovascular", "morbidity", "[4,", "5].", "The", "most", "char-", "acteristic", "component", "of", "HAART-associated", "lipodystrophy", "is", "the", "loss", "of", "subcutaneous", "adipose", "tissue", "[6]", "which", "has", "proven", "to", "be", "very", "difficult", "to", "treat", "(Figure", "1).", "Thiazolidinediones", "(glitazones)", "are", "oral", "insulin-sensiti-", "zing", "antidiabetic", "agents.", "As", "an", "untoward", "side", "effect,", "gli-", "tazones", "increase", "subcutaneous", "fat", "mass", "in", "patients", "with", "type", "2", "diabetes", "[7–9].", "Additionally,", "in", "non-HIV", "infected", "patients", "with", "various", "forms", "of", "lipodystrophy,", "troglitazone", "has", "improved", "metabolic", "control", "and", "subcutaneous", "lipoatro-", "phy", "[10].", "These", "insulin-sensitizing", "and", "fat-inducing", "effects", "of", "glitazones", "have", "lead", "to", "several", "clinical", "trials", "examining", "whether", "these", "drugs", "could", "reverse", "lipoatrophy", "and", "insulin", "resistance", "in", "patients", "with", "HAART-associated", "lipodystrophy.", "The", "ensuing", "review", "is", "focused", "on", "summarizing", "the", "currently", "available", "clinical", "data", "on", "the", "use", "of", "glitazones", "in", "patients", "with", "HAART-associated", "lipodystrophy", "2.", "Thiazolidinediones", "Thiazolidinediones", "are", "synthetic", "ligands", "for", "peroxisome", "proliferator-activated", "receptor", "gamma", "(PPARγ).", "PPARγ", "is", "a", "nuclear", "receptor", "which", "alters", "expression", "of", "multiple", "genes", "including", "those", "regulating", "lipid", "and", "glucose", "metabolism", "[11].", "PPARγ", "is", "expressed", "mainly", "in", "adipose", "tissue", "and", "is", "also", "found", "in", "pancreatic", "beta", "cells,", "vascular", "endothelium,", "and", "macrophages,", "and", "in", "low", "quantities", "in", "other", "tissues", "such" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 78, 47, 60, 12 ], [ 141, 47, 9, 12 ], [ 153, 47, 11, 12 ], [ 168, 47, 21, 12 ], [ 191, 47, 35, 12 ], [ 230, 47, 50, 12 ], [ 283, 47, 18, 12 ], [ 304, 47, 38, 12 ], [ 345, 47, 34, 12 ], [ 382, 47, 25, 12 ], [ 410, 47, 42, 12 ], [ 455, 47, 22, 12 ], [ 78, 61, 242, 12 ], [ 83, 128, 11, 18 ], [ 95, 128, 11, 18 ], [ 108, 128, 13, 18 ], [ 123, 128, 11, 18 ], [ 135, 128, 10, 18 ], [ 147, 128, 10, 18 ], [ 158, 128, 13, 18 ], [ 173, 128, 6, 18 ], [ 180, 128, 13, 18 ], [ 194, 128, 13, 18 ], [ 208, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 96, 34 ], [ 185, 169, 16, 34 ], [ 210, 169, 51, 34 ], [ 271, 169, 182, 34 ], [ 463, 169, 157, 34 ], [ 631, 169, 37, 34 ], [ 78, 205, 106, 34 ], [ 195, 205, 86, 34 ], [ 290, 205, 51, 34 ], [ 351, 205, 104, 34 ], [ 465, 205, 107, 34 ], [ 583, 205, 27, 34 ], [ 620, 205, 90, 34 ], [ 78, 241, 63, 34 ], [ 78, 288, 41, 16 ], [ 124, 285, 80, 19 ], [ 209, 288, 49, 16 ], [ 262, 288, 21, 16 ], [ 288, 288, 40, 16 ], [ 332, 288, 63, 16 ], [ 78, 317, 31, 16 ], [ 114, 317, 30, 16 ], [ 148, 317, 27, 16 ], [ 180, 317, 77, 16 ], [ 261, 317, 62, 16 ], [ 327, 317, 17, 16 ], [ 349, 317, 29, 16 ], [ 382, 317, 24, 16 ], [ 410, 317, 26, 16 ], [ 440, 317, 43, 16 ], [ 488, 317, 12, 16 ], [ 504, 317, 67, 16 ], [ 576, 317, 67, 16 ], [ 648, 317, 52, 16 ], [ 704, 317, 34, 16 ], [ 78, 335, 55, 16 ], [ 138, 335, 20, 16 ], [ 163, 335, 15, 16 ], [ 182, 335, 50, 16 ], [ 237, 335, 30, 16 ], [ 87, 389, 54, 15 ], [ 87, 410, 39, 14 ], [ 131, 410, 26, 14 ], [ 161, 410, 17, 14 ], [ 182, 410, 61, 14 ], [ 247, 410, 52, 14 ], [ 304, 410, 58, 14 ], [ 366, 410, 44, 14 ], [ 414, 410, 46, 14 ], [ 464, 410, 15, 14 ], [ 484, 410, 45, 14 ], [ 533, 410, 22, 14 ], [ 558, 410, 40, 14 ], [ 603, 410, 19, 14 ], [ 626, 410, 28, 14 ], [ 658, 410, 46, 14 ], [ 87, 427, 42, 14 ], [ 133, 427, 11, 14 ], [ 149, 427, 44, 14 ], [ 197, 427, 44, 14 ], [ 245, 427, 53, 14 ], [ 302, 427, 55, 14 ], [ 361, 427, 16, 14 ], [ 381, 427, 26, 14 ], [ 411, 427, 45, 14 ], [ 459, 427, 12, 14 ], [ 476, 427, 31, 14 ], [ 510, 427, 32, 14 ], [ 547, 427, 8, 14 ], [ 559, 427, 51, 14 ], [ 614, 427, 22, 14 ], [ 640, 427, 12, 14 ], [ 656, 427, 19, 14 ], [ 679, 427, 51, 14 ], [ 87, 443, 45, 14 ], [ 136, 443, 11, 14 ], [ 151, 443, 43, 14 ], [ 199, 443, 55, 14 ], [ 257, 443, 31, 14 ], [ 292, 443, 27, 14 ], [ 323, 443, 38, 14 ], [ 365, 443, 39, 14 ], [ 409, 443, 24, 14 ], [ 437, 443, 26, 14 ], [ 467, 443, 46, 14 ], [ 517, 443, 63, 14 ], [ 584, 443, 45, 14 ], [ 633, 443, 50, 14 ], [ 687, 443, 40, 14 ], [ 87, 460, 34, 14 ], [ 125, 460, 34, 14 ], [ 163, 460, 15, 14 ], [ 182, 460, 94, 14 ], [ 280, 460, 53, 14 ], [ 338, 460, 15, 14 ], [ 357, 460, 24, 14 ], [ 386, 460, 65, 14 ], [ 455, 460, 11, 14 ], [ 469, 460, 20, 14 ], [ 494, 460, 32, 14 ], [ 530, 460, 17, 14 ], [ 551, 460, 42, 14 ], [ 597, 460, 38, 14 ], [ 640, 460, 14, 14 ], [ 658, 460, 44, 14 ], [ 87, 476, 36, 14 ], [ 127, 476, 62, 14 ], [ 193, 476, 64, 14 ], [ 261, 476, 15, 14 ], [ 280, 476, 38, 14 ], [ 322, 476, 28, 14 ], [ 355, 477, 36, 14 ], [ 395, 476, 24, 14 ], [ 423, 476, 21, 14 ], [ 449, 476, 40, 14 ], [ 493, 476, 21, 14 ], [ 519, 476, 25, 14 ], [ 547, 476, 40, 14 ], [ 591, 476, 50, 14 ], [ 645, 476, 12, 14 ], [ 661, 476, 35, 14 ], [ 700, 476, 38, 14 ], [ 87, 493, 26, 14 ], [ 117, 493, 25, 14 ], [ 146, 493, 55, 14 ], [ 205, 493, 22, 14 ], [ 232, 493, 11, 14 ], [ 247, 493, 23, 14 ], [ 274, 493, 29, 14 ], [ 308, 493, 12, 14 ], [ 323, 493, 47, 14 ], [ 375, 493, 27, 14 ], [ 406, 493, 12, 14 ], [ 422, 493, 40, 14 ], [ 466, 493, 33, 14 ], [ 503, 493, 38, 14 ], [ 545, 493, 11, 14 ], [ 560, 493, 49, 14 ], [ 613, 493, 36, 14 ], [ 653, 493, 55, 14 ], [ 712, 493, 7, 14 ], [ 87, 510, 65, 14 ], [ 157, 510, 15, 14 ], [ 177, 510, 86, 14 ], [ 267, 510, 50, 14 ], [ 321, 510, 37, 14 ], [ 363, 510, 33, 14 ], [ 400, 510, 15, 14 ], [ 419, 510, 7, 14 ], [ 430, 510, 16, 14 ], [ 451, 510, 11, 14 ], [ 466, 510, 46, 14 ], [ 517, 510, 55, 14 ], [ 78, 556, 80, 15 ], [ 78, 573, 47, 14 ], [ 131, 573, 31, 14 ], [ 168, 573, 19, 14 ], [ 192, 573, 86, 14 ], [ 283, 573, 52, 14 ], [ 340, 573, 43, 14 ], [ 388, 573, 16, 14 ], [ 78, 590, 50, 14 ], [ 133, 590, 10, 14 ], [ 147, 590, 66, 14 ], [ 218, 590, 12, 14 ], [ 235, 590, 7, 14 ], [ 246, 590, 42, 14 ], [ 292, 590, 24, 14 ], [ 321, 590, 42, 14 ], [ 368, 590, 7, 14 ], [ 379, 590, 25, 14 ], [ 78, 606, 42, 14 ], [ 125, 606, 48, 14 ], [ 177, 606, 21, 14 ], [ 202, 606, 48, 14 ], [ 254, 606, 41, 14 ], [ 299, 606, 67, 14 ], [ 371, 606, 32, 14 ], [ 78, 623, 19, 14 ], [ 102, 623, 35, 14 ], [ 141, 623, 14, 14 ], [ 160, 623, 27, 14 ], [ 192, 623, 19, 14 ], [ 215, 623, 57, 14 ], [ 276, 623, 35, 14 ], [ 316, 623, 64, 14 ], [ 385, 623, 19, 14 ], [ 78, 639, 36, 14 ], [ 118, 639, 18, 14 ], [ 140, 639, 81, 14 ], [ 225, 639, 12, 14 ], [ 241, 639, 45, 14 ], [ 290, 639, 23, 14 ], [ 316, 639, 20, 14 ], [ 340, 639, 63, 14 ], [ 78, 656, 40, 14 ], [ 124, 656, 35, 14 ], [ 164, 656, 20, 14 ], [ 189, 656, 71, 14 ], [ 265, 656, 25, 14 ], [ 295, 656, 84, 14 ], [ 384, 656, 20, 14 ], [ 78, 672, 35, 14 ], [ 118, 672, 21, 14 ], [ 144, 672, 46, 14 ], [ 194, 672, 30, 14 ], [ 229, 672, 18, 14 ], [ 252, 672, 40, 14 ], [ 297, 672, 19, 14 ], [ 321, 672, 29, 14 ], [ 355, 672, 49, 14 ], [ 78, 689, 43, 14 ], [ 125, 689, 17, 14 ], [ 146, 689, 43, 14 ], [ 193, 689, 86, 14 ], [ 284, 689, 44, 14 ], [ 333, 689, 45, 14 ], [ 382, 689, 21, 14 ], [ 78, 706, 59, 14 ], [ 143, 706, 25, 14 ], [ 173, 706, 35, 14 ], [ 214, 706, 58, 14 ], [ 278, 706, 20, 14 ], [ 303, 706, 24, 14 ], [ 333, 706, 22, 14 ], [ 360, 706, 43, 14 ], [ 78, 722, 48, 14 ], [ 131, 722, 46, 14 ], [ 181, 722, 12, 14 ], [ 198, 722, 46, 14 ], [ 248, 722, 30, 14 ], [ 282, 722, 44, 14 ], [ 331, 722, 19, 14 ], [ 355, 722, 49, 14 ], [ 78, 739, 20, 14 ], [ 104, 739, 12, 14 ], [ 123, 739, 23, 14 ], [ 151, 739, 78, 14 ], [ 235, 739, 67, 14 ], [ 308, 739, 34, 14 ], [ 348, 739, 20, 14 ], [ 374, 739, 29, 14 ], [ 78, 755, 45, 14 ], [ 127, 755, 12, 14 ], [ 143, 755, 46, 14 ], [ 193, 755, 36, 14 ], [ 234, 755, 68, 14 ], [ 306, 755, 17, 14 ], [ 327, 755, 40, 14 ], [ 372, 755, 31, 14 ], [ 78, 772, 39, 14 ], [ 122, 772, 14, 14 ], [ 140, 772, 42, 14 ], [ 187, 772, 56, 14 ], [ 247, 772, 19, 14 ], [ 271, 772, 19, 14 ], [ 294, 772, 20, 14 ], [ 318, 772, 46, 14 ], [ 369, 772, 35, 14 ], [ 78, 789, 50, 14 ], [ 133, 789, 162, 14 ], [ 299, 789, 24, 14 ], [ 328, 789, 75, 14 ], [ 78, 805, 55, 14 ], [ 138, 805, 72, 14 ], [ 215, 805, 63, 14 ], [ 283, 805, 35, 14 ], [ 323, 805, 80, 14 ], [ 78, 822, 24, 14 ], [ 106, 822, 21, 14 ], [ 131, 822, 158, 14 ], [ 293, 822, 54, 14 ], [ 352, 822, 29, 14 ], [ 384, 822, 19, 14 ], [ 78, 838, 63, 14 ], [ 147, 838, 13, 14 ], [ 165, 838, 39, 14 ], [ 210, 838, 20, 14 ], [ 236, 838, 24, 14 ], [ 265, 838, 24, 14 ], [ 295, 838, 76, 14 ], [ 376, 838, 27, 14 ], [ 78, 855, 62, 14 ], [ 145, 855, 54, 14 ], [ 204, 855, 24, 14 ], [ 233, 855, 12, 14 ], [ 250, 855, 45, 14 ], [ 300, 855, 38, 14 ], [ 342, 855, 26, 14 ], [ 374, 855, 30, 14 ], [ 78, 872, 80, 14 ], [ 162, 872, 41, 14 ], [ 207, 872, 41, 14 ], [ 251, 872, 17, 14 ], [ 272, 872, 64, 14 ], [ 340, 872, 39, 14 ], [ 89, 888, 25, 14 ], [ 117, 888, 11, 14 ], [ 132, 888, 18, 14 ], [ 154, 888, 28, 14 ], [ 185, 888, 43, 14 ], [ 232, 888, 28, 14 ], [ 264, 888, 11, 14 ], [ 278, 888, 45, 14 ], [ 327, 888, 7, 14 ], [ 337, 888, 24, 14 ], [ 364, 888, 40, 14 ], [ 78, 905, 23, 14 ], [ 105, 905, 9, 14 ], [ 118, 905, 35, 14 ], [ 156, 905, 18, 14 ], [ 178, 905, 52, 14 ], [ 234, 905, 44, 14 ], [ 281, 905, 16, 14 ], [ 300, 905, 18, 14 ], [ 322, 905, 81, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 162, 11 ], [ 78, 950, 35, 11 ], [ 116, 950, 28, 11 ], [ 147, 950, 12, 11 ], [ 162, 950, 18, 11 ], [ 183, 950, 30, 11 ], [ 215, 950, 6, 11 ], [ 224, 950, 29, 11 ], [ 256, 950, 9, 11 ], [ 267, 950, 42, 11 ], [ 313, 950, 34, 11 ], [ 350, 950, 16, 11 ], [ 78, 962, 41, 11 ], [ 122, 962, 9, 11 ], [ 134, 962, 50, 11 ], [ 187, 962, 50, 11 ], [ 240, 962, 14, 11 ], [ 257, 962, 20, 11 ], [ 280, 962, 12, 11 ], [ 423, 556, 12, 14 ], [ 438, 556, 72, 14 ], [ 515, 556, 15, 14 ], [ 533, 556, 19, 14 ], [ 556, 556, 30, 14 ], [ 590, 556, 30, 14 ], [ 623, 556, 54, 14 ], [ 681, 556, 42, 14 ], [ 727, 556, 20, 14 ], [ 423, 573, 44, 14 ], [ 470, 573, 32, 14 ], [ 506, 573, 19, 14 ], [ 529, 573, 40, 14 ], [ 572, 573, 12, 14 ], [ 588, 573, 19, 14 ], [ 610, 573, 66, 14 ], [ 680, 573, 22, 14 ], [ 705, 573, 14, 14 ], [ 723, 573, 25, 14 ], [ 423, 589, 35, 14 ], [ 461, 589, 55, 14 ], [ 520, 589, 17, 14 ], [ 541, 589, 70, 14 ], [ 615, 589, 66, 14 ], [ 685, 589, 63, 14 ], [ 423, 606, 19, 14 ], [ 445, 606, 53, 14 ], [ 502, 606, 41, 14 ], [ 547, 606, 12, 14 ], [ 562, 606, 7, 14 ], [ 573, 606, 24, 14 ], [ 600, 606, 34, 14 ], [ 638, 606, 14, 14 ], [ 656, 606, 92, 14 ], [ 423, 623, 17, 14 ], [ 444, 623, 83, 14 ], [ 531, 623, 27, 14 ], [ 563, 623, 9, 14 ], [ 575, 623, 36, 14 ], [ 616, 623, 14, 14 ], [ 634, 623, 100, 14 ], [ 738, 623, 10, 14 ], [ 423, 639, 36, 14 ], [ 463, 639, 33, 14 ], [ 500, 639, 56, 14 ], [ 561, 639, 17, 14 ], [ 582, 639, 47, 14 ], [ 634, 639, 30, 14 ], [ 667, 639, 22, 14 ], [ 693, 639, 55, 14 ], [ 423, 656, 21, 14 ], [ 447, 656, 25, 14 ], [ 475, 656, 59, 14 ], [ 537, 656, 32, 14 ], [ 434, 672, 13, 14 ], [ 450, 672, 21, 14 ], [ 475, 672, 33, 14 ], [ 511, 672, 16, 14 ], [ 531, 672, 43, 14 ], [ 578, 672, 44, 14 ], [ 625, 672, 54, 14 ], [ 683, 672, 39, 14 ], [ 725, 672, 23, 14 ], [ 423, 689, 51, 14 ], [ 478, 689, 14, 14 ], [ 496, 689, 43, 14 ], [ 543, 689, 43, 14 ], [ 590, 689, 14, 14 ], [ 608, 689, 48, 14 ], [ 659, 689, 38, 14 ], [ 701, 689, 47, 14 ], [ 423, 706, 23, 14 ], [ 450, 706, 65, 14 ], [ 518, 706, 12, 14 ], [ 533, 706, 41, 14 ], [ 578, 706, 29, 14 ], [ 610, 706, 23, 14 ], [ 637, 706, 27, 14 ], [ 667, 706, 12, 14 ], [ 683, 706, 43, 14 ], [ 730, 706, 19, 14 ], [ 423, 722, 69, 14 ], [ 496, 722, 50, 14 ], [ 550, 722, 49, 14 ], [ 602, 722, 22, 14 ], [ 628, 722, 12, 14 ], [ 643, 722, 31, 14 ], [ 678, 722, 19, 14 ], [ 700, 722, 48, 14 ], [ 423, 739, 12, 14 ], [ 438, 739, 24, 14 ], [ 466, 739, 59, 14 ], [ 529, 739, 45, 14 ], [ 578, 739, 49, 14 ], [ 631, 739, 90, 14 ], [ 725, 739, 23, 14 ], [ 423, 755, 40, 14 ], [ 466, 755, 74, 14 ], [ 544, 755, 56, 14 ], [ 603, 755, 21, 14 ], [ 628, 755, 27, 14 ], [ 659, 755, 57, 14 ], [ 719, 755, 29, 14 ], [ 423, 772, 40, 14 ], [ 467, 772, 45, 14 ], [ 516, 772, 16, 14 ], [ 537, 772, 30, 14 ], [ 571, 772, 44, 14 ], [ 620, 772, 25, 14 ], [ 650, 772, 70, 14 ], [ 724, 772, 10, 14 ], [ 738, 772, 10, 14 ], [ 423, 789, 49, 14 ], [ 475, 789, 14, 14 ], [ 492, 789, 223, 14 ], [ 434, 805, 13, 14 ], [ 452, 805, 32, 14 ], [ 489, 805, 37, 14 ], [ 531, 805, 39, 14 ], [ 575, 805, 39, 14 ], [ 619, 805, 27, 14 ], [ 651, 805, 7, 14 ], [ 663, 805, 42, 14 ], [ 710, 805, 38, 14 ], [ 423, 822, 33, 14 ], [ 460, 822, 8, 14 ], [ 473, 822, 20, 14 ], [ 497, 822, 14, 14 ], [ 514, 822, 54, 14 ], [ 572, 822, 32, 14 ], [ 608, 822, 12, 14 ], [ 624, 822, 7, 14 ], [ 634, 822, 55, 14 ], [ 694, 822, 11, 14 ], [ 710, 822, 30, 14 ], [ 444, 855, 5, 14 ], [ 453, 855, 14, 14 ], [ 472, 855, 51, 14 ], [ 528, 855, 36, 14 ], [ 568, 855, 17, 14 ], [ 590, 855, 59, 14 ], [ 654, 855, 23, 14 ], [ 682, 855, 66, 14 ], [ 444, 872, 12, 14 ], [ 459, 872, 30, 14 ], [ 494, 872, 30, 14 ], [ 528, 872, 11, 14 ], [ 543, 872, 18, 14 ], [ 565, 872, 40, 14 ], [ 610, 872, 23, 14 ], [ 637, 872, 56, 14 ], [ 444, 888, 5, 14 ], [ 453, 888, 14, 14 ], [ 472, 888, 51, 14 ], [ 527, 888, 21, 14 ], [ 553, 888, 12, 14 ], [ 569, 888, 19, 14 ], [ 592, 888, 78, 14 ], [ 675, 888, 47, 14 ], [ 726, 888, 22, 14 ], [ 444, 905, 44, 14 ], [ 491, 905, 43, 14 ], [ 539, 905, 11, 14 ], [ 554, 905, 40, 14 ], [ 598, 905, 23, 14 ], [ 626, 905, 56, 14 ], [ 444, 921, 5, 14 ], [ 454, 921, 14, 14 ], [ 472, 921, 51, 14 ], [ 528, 921, 6, 14 ], [ 539, 921, 38, 14 ], [ 582, 921, 13, 14 ], [ 599, 921, 58, 14 ], [ 662, 921, 18, 14 ], [ 685, 921, 46, 14 ], [ 736, 921, 12, 14 ], [ 444, 938, 33, 14 ], [ 481, 938, 12, 14 ], [ 498, 938, 19, 14 ], [ 521, 938, 59, 14 ], [ 585, 938, 13, 14 ], [ 602, 938, 60, 14 ], [ 667, 938, 55, 14 ], [ 727, 938, 21, 14 ], [ 444, 955, 26, 14 ], [ 473, 955, 11, 14 ], [ 489, 955, 18, 14 ], [ 511, 955, 40, 14 ], [ 555, 955, 23, 14 ], [ 582, 955, 56, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 48, 10 ], [ 329, 987, 8, 10 ], [ 339, 987, 10, 10 ], [ 352, 987, 30, 10 ], [ 385, 987, 29, 10 ], [ 416, 987, 27, 10 ], [ 446, 987, 14, 10 ], [ 463, 987, 15, 10 ], [ 481, 987, 6, 10 ], [ 489, 987, 10, 10 ], [ 502, 987, 20, 10 ], [ 524, 987, 24, 10 ], [ 551, 987, 23, 10 ], [ 577, 987, 41, 10 ], [ 620, 987, 23, 10 ], [ 646, 987, 13, 10 ], [ 661, 987, 22, 10 ], [ 685, 987, 8, 10 ], [ 696, 987, 13, 10 ], [ 711, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 50, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Korkontzelos", "et", "al.", "BMC", "Medical", "Informatics", "and", "Decision", "Making", "2012,", "12(Suppl", "1):S3", "http://www.biomedcentral.com/1472-6947/12/S1/S3", "P", "R", "O", "C", "E", "E", "D", "I", "N", "G", "S", "Open", "Access", "ASCOT:", "a", "text", "mining-based", "web-service", "for", "efficient", "search", "and", "assisted", "creation", "of", "clinical", "trials", "Ioannis", "Korkontzelos*,", "Tingting", "Mu,", "Sophia", "Ananiadou", "From", "ACM", "Fifth", "International", "Workshop", "on", "Data", "and", "Text", "Mining", "in", "Biomedical", "Informatics", "(DTMBio", "2011)", "Glasgow,", "UK.", "24", "October", "2011", "Abstract", "Clinical", "trials", "are", "mandatory", "protocols", "describing", "medical", "research", "on", "humans", "and", "among", "the", "most", "valuable", "sources", "of", "medical", "practice", "evidence.", "Searching", "for", "trials", "relevant", "to", "some", "query", "is", "laborious", "due", "to", "the", "immense", "number", "of", "existing", "protocols.", "Apart", "from", "search,", "writing", "new", "trials", "includes", "composing", "detailed", "eligibility", "criteria,", "which", "might", "be", "time-consuming,", "especially", "for", "new", "researchers.", "In", "this", "paper", "we", "present", "ASCOT,", "an", "efficient", "search", "application", "customised", "for", "clinical", "trials.", "ASCOT", "uses", "text", "mining", "and", "data", "mining", "methods", "to", "enrich", "clinical", "trials", "with", "metadata,", "that", "in", "turn", "serve", "as", "effective", "tools", "to", "narrow", "down", "search.", "In", "addition,", "ASCOT", "integrates", "a", "component", "for", "recommending", "eligibility", "criteria", "based", "on", "a", "set", "of", "selected", "protocols.", "Introduction", "Clinical", "trials", "are", "health-related", "research", "studies", "on", "humans.", "A", "description", "of", "a", "clinical", "trial", "follows", "a", "pre-", "defined", "protocol", "and", "contains", "various", "information", "about", "the", "study:", "its", "title,", "the", "condition", "under", "inspection,", "the", "target,", "the", "characteristics", "of", "patients", "that", "can", "participate,", "details", "about", "the", "institutions", "that", "accomplished", "the", "study,", "etc.", "Clinical", "trials", "are", "among", "the", "most", "valuable", "sources", "for", "guiding", "evidence-based", "medical", "practice", "and", "designing", "new", "trials.", "However,", "the", "vast", "and", "rapidly", "growing", "number", "of", "existing", "trails", "hinders", "the", "effective", "use", "of", "this", "information.", "Significant", "effort", "has", "been", "devoted", "to", "efficient", "search", "applications", "for", "clinical", "trials,", "mainly", "by", "various", "registries,", "e.g.", "the", "UK", "Clinical", "Trials", "Gateway", "http://www.ukctg.nihr.ac.uk,", "Free", "International", "Standard", "Randomised", "Controlled", "Trials", "(http://isrctn.", "org)", "and", "http://controlled-trials.com.", "However,", "none", "has", "attempted", "to", "enrich", "the", "free", "text", "descriptions", "with", "structured", "metadata", "able", "to", "provide", "search", "with", "extra", "discriminative", "powers", "needed", "for", "customised", "search.", "One", "of", "the", "most", "difficult", "parts", "of", "creating", "a", "new", "clinical", "trial", "is", "listing", "the", "eligibility", "criteria,", "i.e.", "the", "characteristics", "*", "Correspondence:", "Ioannis.Korkontzelos@manchester.ac.uk", "National", "Centre", "for", "Text", "Mining", "&", "School", "of", "Computer", "Science,", "The", "University", "of", "Manchester,", "Manchester,", "M1", "7DN,", "UK", "of", "participants.", "At", "the", "same", "time,", "eligibility", "criteria", "can", "directly", "affect", "the", "quality", "of", "the", "experiment", "and", "its", "out-", "come.", "Although", "for", "experienced", "researchers", "composing", "the", "eligibility", "section", "of", "a", "trial", "might", "be", "straightforward,", "for", "inexperienced", "ones", "it", "would", "be", "time-consuming.", "It", "would", "imply", "searching", "for", "relevant", "trials", "and", "literature", "and", "then", "processing", "them.", "In", "this", "paper", "we", "present", "ASCOT", "(Assisting", "Search", "and", "Creation", "Of", "clinical", "Trials),", "an", "efficient", "search", "applica-", "tion", "customised", "to", "clinical", "trials", "that", "aims", "to", "address", "the", "information", "overload", "problem", "and", "to", "assist", "the", "creation", "of", "new", "protocols.", "ASCOT", "employs", "state-of-the-art", "text", "mining", "technologies,", "clustering", "and", "term", "extraction", "algo-", "rithms", "applied", "on", "large", "clinical", "trial", "collections.", "It", "is", "available", "at:", "http://www.nactem.ac.uk/clinical_trials.", "In", "more", "detail,", "search", "begins", "with", "a", "textual", "query.", "Then,", "it", "can", "be", "narrowed", "down", "in", "a", "multitude", "of", "ways:", "-", "by", "selecting", "values", "for", "properties", "that", "correspond", "to", "XML", "fields", "of", "the", "clinical", "trial", "protocols.", "-", "by", "selecting", "one", "of", "the", "automatically", "induced", "and", "labelled", "clusters", "of", "clinical", "trial", "protocols.", "-", "by", "selecting", "a", "UMLS", "or", "SNOMED", "CT", "concept", "to", "occur", "in", "the", "(inclusion", "or", "exclusion)", "eligibility", "cri-", "teria", "of", "the", "clinical", "trial", "protocols.", "©", "2012", "Korkontzelos", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 699, 35, 84, 25 ], [ 66, 88, 38, 20 ], [ 109, 88, 126, 20 ], [ 240, 88, 35, 20 ], [ 280, 88, 83, 20 ], [ 368, 88, 103, 20 ], [ 476, 88, 18, 20 ], [ 498, 88, 31, 20 ], [ 534, 88, 52, 20 ], [ 591, 88, 53, 20 ], [ 650, 88, 51, 20 ], [ 66, 116, 47, 14 ], [ 115, 116, 33, 14 ], [ 151, 116, 39, 14 ], [ 193, 116, 71, 14 ], [ 267, 116, 38, 14 ], [ 308, 116, 14, 14 ], [ 325, 116, 65, 14 ], [ 393, 116, 24, 14 ], [ 420, 116, 21, 14 ], [ 444, 116, 36, 14 ], [ 483, 116, 36, 14 ], [ 523, 116, 36, 14 ], [ 562, 116, 26, 14 ], [ 591, 116, 75, 14 ], [ 66, 139, 43, 12 ], [ 112, 139, 11, 12 ], [ 125, 139, 33, 12 ], [ 161, 139, 38, 12 ], [ 201, 139, 55, 12 ], [ 258, 139, 63, 12 ], [ 324, 139, 11, 12 ], [ 337, 139, 34, 12 ], [ 374, 139, 20, 12 ], [ 397, 139, 36, 12 ], [ 435, 139, 48, 12 ], [ 486, 139, 49, 12 ], [ 538, 139, 58, 12 ], [ 598, 139, 25, 12 ], [ 72, 193, 26, 12 ], [ 101, 193, 21, 12 ], [ 125, 193, 12, 12 ], [ 141, 193, 34, 12 ], [ 178, 193, 28, 12 ], [ 209, 193, 16, 12 ], [ 229, 193, 10, 12 ], [ 241, 193, 15, 12 ], [ 260, 193, 24, 12 ], [ 286, 193, 21, 12 ], [ 310, 193, 26, 12 ], [ 339, 193, 46, 12 ], [ 388, 193, 15, 12 ], [ 406, 193, 27, 12 ], [ 436, 193, 29, 12 ], [ 468, 193, 40, 12 ], [ 512, 193, 22, 12 ], [ 72, 207, 24, 12 ], [ 99, 207, 18, 12 ], [ 120, 207, 22, 12 ], [ 145, 207, 27, 12 ], [ 176, 207, 5, 12 ], [ 184, 207, 84, 12 ], [ 271, 207, 83, 12 ], [ 357, 207, 46, 12 ], [ 406, 207, 30, 12 ], [ 439, 207, 10, 12 ], [ 452, 207, 28, 12 ], [ 483, 207, 37, 12 ], [ 523, 207, 10, 12 ], [ 72, 222, 27, 12 ], [ 101, 222, 26, 12 ], [ 131, 222, 23, 12 ], [ 157, 222, 26, 12 ], [ 186, 222, 18, 12 ], [ 206, 222, 48, 12 ], [ 257, 222, 10, 12 ], [ 270, 222, 26, 12 ], [ 300, 222, 61, 12 ], [ 364, 222, 10, 12 ], [ 377, 222, 54, 12 ], [ 434, 222, 18, 12 ], [ 455, 222, 59, 12 ], [ 516, 222, 17, 12 ], [ 72, 236, 18, 12 ], [ 92, 236, 46, 12 ], [ 141, 236, 10, 12 ], [ 153, 236, 53, 12 ], [ 209, 236, 61, 12 ], [ 273, 236, 45, 12 ], [ 321, 236, 14, 12 ], [ 337, 236, 16, 12 ], [ 356, 236, 20, 12 ], [ 378, 236, 16, 12 ], [ 397, 236, 15, 12 ], [ 415, 236, 23, 12 ], [ 440, 236, 10, 12 ], [ 452, 236, 15, 12 ], [ 470, 236, 42, 12 ], [ 515, 236, 18, 12 ], [ 72, 251, 16, 12 ], [ 91, 251, 23, 12 ], [ 117, 251, 66, 12 ], [ 187, 251, 23, 12 ], [ 213, 251, 10, 12 ], [ 226, 251, 15, 12 ], [ 244, 251, 28, 12 ], [ 276, 251, 26, 12 ], [ 305, 251, 10, 12 ], [ 319, 251, 24, 12 ], [ 346, 251, 26, 12 ], [ 375, 251, 40, 12 ], [ 419, 251, 17, 12 ], [ 439, 251, 10, 12 ], [ 452, 251, 22, 12 ], [ 478, 251, 25, 12 ], [ 506, 251, 27, 12 ], [ 72, 265, 35, 12 ], [ 109, 265, 15, 12 ], [ 127, 265, 45, 12 ], [ 175, 265, 15, 12 ], [ 193, 265, 34, 12 ], [ 230, 265, 32, 12 ], [ 264, 265, 47, 12 ], [ 314, 265, 17, 12 ], [ 334, 265, 31, 12 ], [ 368, 265, 23, 12 ], [ 394, 265, 15, 12 ], [ 411, 265, 27, 12 ], [ 441, 265, 29, 12 ], [ 473, 265, 19, 12 ], [ 495, 265, 39, 12 ], [ 72, 280, 16, 12 ], [ 90, 280, 10, 12 ], [ 103, 280, 41, 12 ], [ 147, 280, 20, 12 ], [ 170, 280, 18, 12 ], [ 190, 280, 47, 12 ], [ 240, 280, 59, 12 ], [ 302, 280, 17, 12 ], [ 321, 280, 27, 12 ], [ 351, 280, 17, 12 ], [ 371, 280, 26, 12 ], [ 399, 280, 34, 12 ], [ 436, 280, 28, 12 ], [ 467, 280, 46, 12 ], [ 516, 280, 18, 12 ], [ 72, 295, 18, 12 ], [ 93, 295, 34, 12 ], [ 130, 295, 32, 12 ], [ 166, 295, 25, 12 ], [ 194, 295, 20, 12 ], [ 218, 295, 23, 12 ], [ 244, 295, 10, 12 ], [ 257, 295, 50, 12 ], [ 311, 295, 30, 12 ], [ 345, 295, 18, 12 ], [ 366, 295, 49, 12 ], [ 418, 295, 33, 12 ], [ 455, 295, 65, 12 ], [ 524, 295, 10, 12 ], [ 72, 309, 16, 12 ], [ 91, 309, 24, 12 ], [ 118, 309, 17, 12 ], [ 138, 309, 18, 12 ], [ 159, 309, 34, 12 ], [ 196, 309, 32, 12 ], [ 231, 309, 41, 12 ], [ 275, 309, 10, 12 ], [ 288, 309, 45, 12 ], [ 336, 309, 30, 12 ], [ 369, 309, 18, 12 ], [ 390, 309, 25, 12 ], [ 418, 309, 33, 12 ], [ 454, 309, 35, 12 ], [ 492, 309, 41, 12 ], [ 72, 324, 21, 12 ], [ 96, 324, 18, 12 ], [ 117, 324, 25, 12 ], [ 145, 324, 16, 12 ], [ 165, 324, 20, 12 ], [ 188, 324, 47, 12 ], [ 239, 324, 10, 12 ], [ 252, 324, 62, 12 ], [ 318, 324, 46, 12 ], [ 367, 324, 29, 12 ], [ 400, 324, 12, 12 ], [ 415, 324, 32, 12 ], [ 450, 324, 18, 12 ], [ 472, 324, 19, 12 ], [ 494, 324, 18, 12 ], [ 516, 324, 18, 12 ], [ 72, 338, 30, 12 ], [ 105, 338, 32, 12 ], [ 141, 338, 35, 12 ], [ 179, 338, 30, 12 ], [ 213, 338, 18, 12 ], [ 234, 338, 25, 12 ], [ 263, 338, 42, 12 ], [ 308, 338, 33, 12 ], [ 344, 338, 46, 12 ], [ 394, 338, 23, 12 ], [ 420, 338, 10, 12 ], [ 433, 338, 25, 12 ], [ 462, 338, 20, 12 ], [ 485, 338, 48, 12 ], [ 72, 353, 16, 12 ], [ 91, 353, 59, 12 ], [ 154, 353, 17, 12 ], [ 174, 353, 25, 12 ], [ 202, 353, 5, 12 ], [ 211, 353, 32, 12 ], [ 246, 353, 11, 12 ], [ 260, 353, 25, 12 ], [ 288, 353, 15, 12 ], [ 307, 353, 45, 12 ], [ 355, 353, 40, 12 ], [ 398, 353, 28, 12 ], [ 430, 353, 28, 12 ], [ 462, 353, 11, 12 ], [ 476, 353, 24, 12 ], [ 504, 353, 30, 12 ], [ 72, 368, 22, 12 ], [ 96, 368, 27, 12 ], [ 126, 368, 10, 12 ], [ 139, 368, 15, 12 ], [ 156, 368, 48, 12 ], [ 207, 368, 41, 12 ], [ 251, 368, 23, 12 ], [ 277, 368, 17, 12 ], [ 297, 368, 30, 12 ], [ 329, 368, 37, 12 ], [ 369, 368, 19, 12 ], [ 390, 368, 41, 12 ], [ 434, 368, 10, 12 ], [ 447, 368, 45, 12 ], [ 495, 368, 39, 12 ], [ 72, 382, 29, 12 ], [ 104, 382, 28, 12 ], [ 135, 382, 10, 12 ], [ 148, 382, 16, 12 ], [ 167, 382, 17, 12 ], [ 187, 382, 8, 12 ], [ 198, 382, 25, 12 ], [ 227, 382, 34, 12 ], [ 264, 382, 10, 12 ], [ 277, 382, 5, 12 ], [ 285, 382, 42, 12 ], [ 331, 382, 25, 12 ], [ 359, 382, 67, 12 ], [ 429, 382, 10, 12 ], [ 442, 382, 20, 12 ], [ 465, 382, 44, 12 ], [ 512, 382, 21, 12 ], [ 72, 397, 37, 12 ], [ 112, 397, 35, 12 ], [ 151, 397, 19, 12 ], [ 173, 397, 53, 12 ], [ 229, 397, 16, 12 ], [ 248, 397, 30, 12 ], [ 282, 397, 30, 12 ], [ 316, 397, 55, 12 ], [ 374, 397, 10, 12 ], [ 388, 397, 47, 12 ], [ 438, 397, 14, 12 ], [ 456, 397, 56, 12 ], [ 515, 397, 18, 12 ], [ 72, 411, 36, 12 ], [ 110, 411, 12, 12 ], [ 124, 411, 45, 12 ], [ 172, 411, 15, 12 ], [ 190, 411, 34, 12 ], [ 226, 411, 28, 12 ], [ 257, 411, 26, 12 ], [ 286, 411, 10, 12 ], [ 299, 411, 24, 12 ], [ 325, 411, 26, 12 ], [ 353, 411, 41, 12 ], [ 397, 411, 24, 12 ], [ 424, 411, 22, 12 ], [ 448, 411, 19, 12 ], [ 469, 411, 17, 12 ], [ 489, 411, 27, 12 ], [ 518, 411, 15, 12 ], [ 72, 426, 20, 12 ], [ 96, 426, 18, 12 ], [ 118, 426, 21, 12 ], [ 142, 426, 12, 12 ], [ 157, 426, 10, 12 ], [ 171, 426, 18, 12 ], [ 193, 426, 10, 12 ], [ 206, 426, 48, 12 ], [ 258, 426, 16, 12 ], [ 277, 426, 45, 12 ], [ 326, 426, 26, 12 ], [ 356, 426, 15, 12 ], [ 374, 426, 78, 12 ], [ 456, 426, 77, 12 ], [ 72, 440, 49, 12 ], [ 124, 440, 18, 12 ], [ 146, 440, 25, 12 ], [ 175, 440, 77, 12 ], [ 255, 440, 68, 12 ], [ 327, 441, 18, 12 ], [ 348, 441, 31, 12 ], [ 382, 440, 43, 12 ], [ 428, 440, 50, 12 ], [ 482, 440, 21, 12 ], [ 506, 440, 27, 12 ], [ 72, 455, 29, 12 ], [ 104, 455, 24, 12 ], [ 131, 455, 20, 12 ], [ 153, 455, 38, 12 ], [ 194, 455, 32, 12 ], [ 228, 455, 37, 12 ], [ 268, 455, 75, 12 ], [ 346, 455, 35, 12 ], [ 386, 455, 105, 12 ], [ 493, 455, 40, 12 ], [ 72, 470, 14, 12 ], [ 88, 470, 76, 12 ], [ 167, 470, 37, 12 ], [ 206, 470, 12, 12 ], [ 221, 470, 22, 12 ], [ 245, 470, 28, 12 ], [ 66, 512, 70, 14 ], [ 140, 512, 48, 14 ], [ 191, 512, 15, 14 ], [ 209, 512, 63, 14 ], [ 275, 512, 18, 14 ], [ 66, 527, 24, 14 ], [ 94, 527, 21, 14 ], [ 118, 527, 31, 14 ], [ 153, 527, 13, 14 ], [ 170, 527, 30, 14 ], [ 203, 527, 29, 14 ], [ 236, 527, 26, 14 ], [ 265, 527, 28, 14 ], [ 66, 542, 33, 14 ], [ 102, 542, 16, 14 ], [ 121, 542, 33, 14 ], [ 157, 542, 29, 14 ], [ 190, 542, 47, 14 ], [ 240, 542, 23, 14 ], [ 266, 542, 27, 14 ], [ 66, 556, 13, 14 ], [ 83, 556, 40, 14 ], [ 126, 556, 24, 14 ], [ 153, 556, 66, 14 ], [ 222, 556, 10, 14 ], [ 236, 556, 16, 14 ], [ 255, 556, 38, 14 ], [ 66, 571, 46, 14 ], [ 116, 571, 60, 14 ], [ 179, 571, 22, 14 ], [ 206, 571, 20, 14 ], [ 230, 571, 48, 14 ], [ 282, 571, 11, 14 ], [ 66, 585, 55, 14 ], [ 125, 585, 32, 14 ], [ 160, 585, 19, 14 ], [ 182, 585, 14, 14 ], [ 199, 585, 18, 14 ], [ 221, 585, 28, 14 ], [ 252, 585, 41, 14 ], [ 66, 600, 28, 14 ], [ 98, 600, 21, 14 ], [ 122, 600, 27, 14 ], [ 153, 600, 56, 14 ], [ 212, 600, 24, 14 ], [ 239, 600, 54, 14 ], [ 66, 615, 20, 14 ], [ 89, 615, 6, 14 ], [ 98, 615, 32, 14 ], [ 133, 615, 10, 14 ], [ 146, 615, 26, 14 ], [ 175, 615, 46, 14 ], [ 224, 615, 70, 14 ], [ 66, 629, 75, 14 ], [ 145, 629, 50, 14 ], [ 198, 629, 29, 14 ], [ 231, 629, 62, 14 ], [ 66, 644, 29, 14 ], [ 99, 644, 58, 14 ], [ 161, 644, 30, 14 ], [ 195, 644, 99, 14 ], [ 66, 658, 80, 14 ], [ 149, 658, 19, 14 ], [ 171, 658, 77, 14 ], [ 251, 658, 42, 14 ], [ 66, 673, 34, 14 ], [ 103, 673, 19, 14 ], [ 126, 673, 31, 14 ], [ 160, 673, 24, 14 ], [ 188, 673, 20, 14 ], [ 212, 673, 21, 14 ], [ 237, 673, 16, 14 ], [ 256, 673, 37, 14 ], [ 66, 687, 23, 14 ], [ 93, 687, 28, 14 ], [ 124, 687, 19, 14 ], [ 146, 687, 30, 14 ], [ 180, 687, 22, 14 ], [ 206, 687, 6, 14 ], [ 215, 687, 19, 14 ], [ 237, 687, 11, 14 ], [ 251, 687, 42, 14 ], [ 66, 702, 53, 14 ], [ 122, 702, 10, 14 ], [ 136, 702, 27, 14 ], [ 166, 702, 48, 14 ], [ 217, 702, 21, 14 ], [ 242, 702, 52, 14 ], [ 66, 717, 30, 14 ], [ 99, 717, 60, 14 ], [ 163, 717, 33, 14 ], [ 198, 717, 22, 14 ], [ 223, 717, 70, 14 ], [ 66, 731, 40, 14 ], [ 109, 731, 10, 14 ], [ 123, 731, 13, 14 ], [ 139, 731, 26, 14 ], [ 169, 731, 23, 14 ], [ 195, 731, 65, 14 ], [ 263, 731, 31, 14 ], [ 66, 746, 24, 14 ], [ 93, 746, 15, 14 ], [ 112, 746, 24, 14 ], [ 139, 746, 65, 14 ], [ 208, 746, 50, 14 ], [ 261, 746, 21, 14 ], [ 285, 746, 8, 14 ], [ 66, 760, 33, 14 ], [ 101, 760, 19, 14 ], [ 122, 760, 17, 14 ], [ 141, 760, 52, 14 ], [ 85, 775, 21, 14 ], [ 109, 775, 31, 14 ], [ 143, 775, 76, 14 ], [ 223, 775, 45, 14 ], [ 271, 775, 22, 14 ], [ 66, 789, 39, 14 ], [ 108, 789, 25, 14 ], [ 136, 789, 16, 14 ], [ 156, 789, 43, 14 ], [ 203, 789, 11, 14 ], [ 217, 789, 16, 14 ], [ 237, 789, 43, 14 ], [ 66, 804, 44, 14 ], [ 113, 804, 26, 14 ], [ 143, 804, 11, 14 ], [ 157, 804, 32, 14 ], [ 192, 804, 23, 14 ], [ 219, 804, 46, 14 ], [ 269, 804, 25, 14 ], [ 66, 819, 28, 14 ], [ 98, 819, 19, 14 ], [ 121, 819, 34, 14 ], [ 158, 819, 41, 14 ], [ 204, 819, 11, 14 ], [ 218, 819, 28, 14 ], [ 249, 819, 16, 14 ], [ 269, 819, 24, 14 ], [ 66, 833, 15, 14 ], [ 85, 833, 6, 14 ], [ 95, 833, 60, 14 ], [ 158, 833, 19, 14 ], [ 181, 833, 46, 14 ], [ 231, 833, 12, 14 ], [ 246, 833, 27, 14 ], [ 277, 833, 16, 14 ], [ 66, 848, 23, 14 ], [ 92, 848, 74, 14 ], [ 169, 848, 52, 14 ], [ 223, 848, 36, 14 ], [ 263, 848, 31, 14 ], [ 66, 862, 19, 14 ], [ 89, 862, 16, 14 ], [ 108, 862, 23, 14 ], [ 135, 862, 26, 14 ], [ 165, 862, 19, 14 ], [ 187, 862, 27, 14 ], [ 218, 862, 76, 14 ], [ 66, 877, 34, 14 ], [ 104, 877, 33, 14 ], [ 140, 877, 30, 14 ], [ 174, 877, 66, 14 ], [ 244, 877, 31, 14 ], [ 279, 877, 15, 14 ], [ 66, 892, 58, 14 ], [ 128, 892, 18, 14 ], [ 150, 892, 20, 14 ], [ 173, 892, 18, 14 ], [ 195, 892, 45, 14 ], [ 243, 892, 11, 14 ], [ 258, 892, 36, 14 ], [ 66, 906, 38, 14 ], [ 108, 906, 11, 14 ], [ 122, 906, 64, 14 ], [ 190, 906, 17, 14 ], [ 211, 906, 19, 14 ], [ 234, 906, 32, 14 ], [ 270, 906, 24, 14 ], [ 66, 921, 23, 14 ], [ 92, 921, 34, 14 ], [ 128, 921, 16, 14 ], [ 147, 921, 100, 14 ], [ 250, 921, 31, 14 ], [ 283, 921, 10, 14 ], [ 66, 935, 80, 14 ], [ 150, 935, 9, 14 ], [ 163, 935, 38, 14 ], [ 205, 935, 45, 14 ], [ 253, 935, 11, 14 ], [ 267, 935, 26, 14 ], [ 66, 950, 30, 14 ], [ 100, 950, 22, 14 ], [ 127, 950, 28, 14 ], [ 159, 950, 20, 14 ], [ 183, 950, 6, 14 ], [ 193, 950, 26, 14 ], [ 223, 950, 16, 14 ], [ 243, 950, 6, 14 ], [ 253, 950, 41, 14 ], [ 66, 965, 81, 14 ], [ 151, 965, 20, 14 ], [ 175, 965, 70, 14 ], [ 249, 965, 44, 14 ], [ 66, 979, 21, 14 ], [ 91, 979, 52, 14 ], [ 147, 979, 33, 14 ], [ 184, 979, 40, 14 ], [ 227, 979, 66, 14 ], [ 66, 994, 18, 14 ], [ 88, 994, 19, 14 ], [ 111, 994, 59, 14 ], [ 174, 994, 21, 14 ], [ 199, 994, 17, 14 ], [ 219, 994, 25, 14 ], [ 247, 994, 19, 14 ], [ 270, 994, 23, 14 ], [ 66, 1008, 66, 14 ], [ 136, 1008, 19, 14 ], [ 160, 1008, 51, 14 ], [ 215, 1008, 35, 14 ], [ 253, 1008, 40, 14 ], [ 311, 512, 53, 14 ], [ 368, 512, 27, 14 ], [ 399, 512, 64, 14 ], [ 467, 512, 24, 14 ], [ 495, 512, 44, 14 ], [ 311, 527, 50, 14 ], [ 365, 527, 15, 14 ], [ 384, 527, 46, 14 ], [ 434, 527, 11, 14 ], [ 449, 527, 26, 14 ], [ 479, 527, 36, 14 ], [ 519, 527, 20, 14 ], [ 311, 542, 52, 14 ], [ 366, 542, 10, 14 ], [ 380, 542, 57, 14 ], [ 441, 542, 18, 14 ], [ 462, 542, 10, 14 ], [ 475, 542, 42, 14 ], [ 521, 542, 18, 14 ], [ 311, 556, 19, 14 ], [ 334, 556, 11, 14 ], [ 349, 556, 47, 14 ], [ 401, 556, 73, 14 ], [ 478, 556, 10, 14 ], [ 492, 556, 22, 14 ], [ 518, 556, 11, 14 ], [ 533, 556, 6, 14 ], [ 311, 571, 39, 14 ], [ 353, 571, 43, 14 ], [ 399, 571, 22, 14 ], [ 330, 585, 12, 14 ], [ 345, 585, 26, 14 ], [ 374, 585, 12, 14 ], [ 390, 585, 47, 14 ], [ 441, 585, 23, 14 ], [ 467, 585, 36, 14 ], [ 507, 585, 31, 14 ], [ 311, 600, 23, 14 ], [ 338, 600, 52, 14 ], [ 393, 600, 38, 14 ], [ 435, 600, 11, 14 ], [ 449, 600, 19, 14 ], [ 472, 600, 14, 14 ], [ 489, 600, 16, 14 ], [ 509, 600, 29, 14 ], [ 311, 615, 28, 14 ], [ 341, 615, 26, 14 ], [ 371, 615, 60, 14 ], [ 434, 615, 10, 14 ], [ 447, 615, 16, 14 ], [ 465, 615, 38, 14 ], [ 506, 615, 33, 14 ], [ 311, 629, 49, 14 ], [ 363, 629, 19, 14 ], [ 386, 629, 30, 14 ], [ 420, 629, 36, 14 ], [ 460, 629, 13, 14 ], [ 476, 629, 34, 14 ], [ 514, 629, 25, 14 ], [ 311, 644, 36, 14 ], [ 350, 644, 25, 14 ], [ 379, 644, 23, 14 ], [ 405, 644, 36, 14 ], [ 445, 644, 11, 14 ], [ 459, 644, 30, 14 ], [ 492, 644, 17, 14 ], [ 513, 644, 26, 14 ], [ 311, 658, 34, 14 ], [ 348, 658, 48, 14 ], [ 400, 658, 11, 14 ], [ 414, 658, 12, 14 ], [ 429, 658, 6, 14 ], [ 438, 658, 39, 14 ], [ 481, 658, 58, 14 ], [ 311, 673, 36, 14 ], [ 350, 673, 15, 14 ], [ 369, 673, 28, 14 ], [ 400, 673, 41, 14 ], [ 445, 673, 45, 14 ], [ 493, 673, 45, 14 ], [ 311, 687, 11, 14 ], [ 326, 687, 19, 14 ], [ 348, 687, 26, 14 ], [ 378, 687, 26, 14 ], [ 408, 687, 25, 14 ], [ 437, 687, 17, 14 ], [ 458, 687, 25, 14 ], [ 487, 687, 52, 14 ], [ 311, 702, 22, 14 ], [ 336, 702, 31, 14 ], [ 370, 702, 25, 14 ], [ 397, 702, 39, 14 ], [ 439, 702, 10, 14 ], [ 452, 702, 31, 14 ], [ 485, 702, 32, 14 ], [ 520, 702, 19, 14 ], [ 311, 717, 29, 14 ], [ 344, 717, 194, 14 ], [ 311, 731, 58, 14 ], [ 373, 731, 10, 14 ], [ 387, 731, 13, 14 ], [ 405, 731, 32, 14 ], [ 441, 731, 29, 14 ], [ 474, 731, 10, 14 ], [ 489, 731, 13, 14 ], [ 506, 731, 32, 14 ], [ 311, 746, 61, 14 ], [ 379, 746, 33, 14 ], [ 417, 746, 51, 14 ], [ 474, 746, 6, 14 ], [ 486, 746, 14, 14 ], [ 506, 746, 33, 14 ], [ 311, 760, 50, 14 ], [ 365, 760, 10, 14 ], [ 379, 760, 13, 14 ], [ 396, 760, 31, 14 ], [ 431, 760, 36, 14 ], [ 472, 760, 10, 14 ], [ 485, 760, 13, 14 ], [ 503, 760, 36, 14 ], [ 311, 775, 30, 14 ], [ 345, 775, 48, 14 ], [ 396, 775, 68, 14 ], [ 468, 775, 57, 14 ], [ 528, 775, 11, 14 ], [ 311, 789, 16, 14 ], [ 331, 789, 25, 14 ], [ 360, 789, 22, 14 ], [ 385, 789, 23, 14 ], [ 411, 789, 19, 14 ], [ 434, 789, 40, 14 ], [ 477, 789, 16, 14 ], [ 497, 789, 18, 14 ], [ 519, 789, 10, 14 ], [ 533, 789, 6, 14 ], [ 311, 804, 33, 14 ], [ 347, 804, 10, 14 ], [ 360, 804, 30, 14 ], [ 394, 804, 45, 14 ], [ 442, 804, 22, 14 ], [ 468, 804, 10, 14 ], [ 481, 804, 21, 14 ], [ 505, 804, 33, 14 ], [ 311, 819, 18, 14 ], [ 332, 819, 9, 14 ], [ 344, 819, 12, 14 ], [ 358, 819, 33, 14 ], [ 393, 819, 61, 14 ], [ 457, 819, 24, 14 ], [ 483, 819, 9, 14 ], [ 495, 819, 12, 14 ], [ 510, 819, 29, 14 ], [ 311, 833, 53, 14 ], [ 367, 833, 10, 14 ], [ 380, 833, 12, 14 ], [ 396, 833, 31, 14 ], [ 430, 833, 19, 14 ], [ 453, 833, 54, 14 ], [ 510, 833, 28, 14 ], [ 311, 848, 24, 14 ], [ 339, 848, 39, 14 ], [ 381, 848, 20, 14 ], [ 405, 848, 39, 14 ], [ 447, 848, 35, 14 ], [ 486, 848, 52, 14 ], [ 311, 862, 41, 14 ], [ 355, 862, 51, 14 ], [ 411, 862, 10, 14 ], [ 424, 862, 13, 14 ], [ 440, 862, 31, 14 ], [ 475, 862, 34, 14 ], [ 512, 862, 10, 14 ], [ 526, 862, 13, 14 ], [ 311, 877, 35, 14 ], [ 350, 877, 20, 14 ], [ 373, 877, 76, 14 ], [ 452, 877, 31, 14 ], [ 487, 877, 51, 14 ], [ 311, 892, 10, 14 ], [ 324, 892, 12, 14 ], [ 339, 892, 29, 14 ], [ 372, 892, 45, 14 ], [ 420, 892, 10, 14 ], [ 433, 892, 12, 14 ], [ 448, 892, 29, 14 ], [ 480, 892, 58, 14 ], [ 311, 906, 19, 14 ], [ 334, 906, 46, 14 ], [ 384, 906, 30, 14 ], [ 417, 906, 59, 14 ], [ 480, 906, 10, 14 ], [ 493, 906, 12, 14 ], [ 509, 906, 30, 14 ], [ 311, 921, 34, 14 ], [ 349, 921, 20, 14 ], [ 372, 921, 54, 14 ], [ 430, 921, 35, 14 ], [ 469, 921, 33, 14 ], [ 505, 921, 33, 14 ], [ 311, 935, 20, 14 ], [ 335, 935, 29, 14 ], [ 368, 935, 24, 14 ], [ 396, 935, 25, 14 ], [ 425, 935, 48, 14 ], [ 477, 935, 10, 14 ], [ 491, 935, 47, 14 ], [ 311, 950, 38, 14 ], [ 353, 950, 63, 14 ], [ 420, 950, 13, 14 ], [ 437, 950, 17, 14 ], [ 458, 950, 24, 14 ], [ 487, 950, 28, 14 ], [ 518, 950, 20, 14 ], [ 311, 965, 53, 14 ], [ 368, 965, 72, 14 ], [ 444, 965, 18, 14 ], [ 465, 965, 43, 14 ], [ 513, 965, 26, 14 ], [ 311, 979, 48, 14 ], [ 362, 979, 22, 14 ], [ 388, 979, 12, 14 ], [ 403, 979, 45, 14 ], [ 451, 979, 18, 14 ], [ 472, 979, 10, 14 ], [ 485, 979, 29, 14 ], [ 517, 979, 21, 14 ], [ 311, 994, 16, 14 ], [ 331, 994, 37, 14 ], [ 372, 994, 37, 14 ], [ 413, 994, 82, 14 ], [ 499, 994, 39, 14 ], [ 311, 1008, 47, 14 ], [ 361, 1008, 9, 14 ], [ 372, 1008, 12, 14 ], [ 386, 1008, 33, 14 ], [ 66, 1049, 68, 13 ], [ 137, 1049, 32, 13 ], [ 172, 1049, 60, 13 ], [ 238, 1051, 6, 10 ], [ 250, 1053, 30, 9 ], [ 283, 1050, 16, 12 ], [ 301, 1050, 3, 12 ], [ 306, 1053, 30, 9 ], [ 338, 1050, 11, 12 ], [ 351, 1050, 3, 12 ], [ 356, 1050, 36, 12 ], [ 394, 1050, 21, 12 ], [ 575, 177, 42, 14 ], [ 621, 177, 45, 14 ], [ 670, 177, 11, 14 ], [ 685, 177, 78, 14 ], [ 766, 177, 17, 14 ], [ 556, 192, 25, 14 ], [ 585, 192, 52, 14 ], [ 641, 192, 24, 14 ], [ 669, 192, 31, 14 ], [ 704, 192, 43, 14 ], [ 751, 192, 32, 14 ], [ 556, 206, 19, 14 ], [ 579, 206, 29, 14 ], [ 611, 206, 40, 14 ], [ 655, 206, 39, 14 ], [ 698, 206, 57, 14 ], [ 758, 206, 10, 14 ], [ 771, 206, 12, 14 ], [ 556, 221, 30, 14 ], [ 589, 221, 46, 14 ], [ 639, 221, 10, 14 ], [ 652, 221, 12, 14 ], [ 668, 221, 34, 14 ], [ 705, 221, 78, 14 ], [ 556, 235, 44, 14 ], [ 604, 235, 34, 14 ], [ 641, 235, 52, 14 ], [ 696, 235, 16, 14 ], [ 716, 235, 40, 14 ], [ 760, 235, 24, 14 ], [ 556, 250, 31, 14 ], [ 590, 250, 11, 14 ], [ 603, 250, 32, 14 ], [ 638, 250, 23, 14 ], [ 664, 250, 10, 14 ], [ 677, 250, 70, 14 ], [ 750, 250, 34, 14 ], [ 556, 265, 20, 14 ], [ 580, 265, 29, 14 ], [ 614, 265, 61, 14 ], [ 679, 265, 55, 14 ], [ 737, 265, 46, 14 ], [ 556, 279, 10, 14 ], [ 568, 279, 12, 14 ], [ 583, 279, 29, 14 ], [ 615, 279, 40, 14 ], [ 657, 279, 10, 14 ], [ 669, 279, 12, 14 ], [ 684, 279, 33, 14 ], [ 575, 294, 27, 14 ], [ 605, 294, 16, 14 ], [ 624, 294, 23, 14 ], [ 651, 294, 30, 14 ], [ 684, 294, 46, 14 ], [ 734, 294, 49, 14 ], [ 556, 308, 21, 14 ], [ 580, 308, 48, 14 ], [ 632, 308, 23, 14 ], [ 658, 308, 50, 14 ], [ 712, 308, 71, 14 ], [ 556, 323, 12, 14 ], [ 572, 323, 22, 14 ], [ 597, 323, 25, 14 ], [ 625, 323, 66, 14 ], [ 695, 323, 10, 14 ], [ 709, 323, 25, 14 ], [ 736, 323, 47, 14 ], [ 556, 337, 21, 14 ], [ 580, 337, 23, 14 ], [ 606, 337, 23, 14 ], [ 633, 337, 27, 14 ], [ 664, 337, 13, 14 ], [ 681, 337, 30, 14 ], [ 714, 337, 70, 14 ], [ 556, 352, 11, 14 ], [ 571, 352, 23, 14 ], [ 598, 352, 11, 14 ], [ 613, 352, 44, 14 ], [ 661, 352, 25, 14 ], [ 691, 352, 17, 14 ], [ 712, 352, 11, 14 ], [ 728, 352, 56, 14 ], [ 556, 367, 37, 14 ], [ 597, 367, 60, 14 ], [ 660, 367, 26, 14 ], [ 689, 367, 26, 14 ], [ 719, 367, 44, 14 ], [ 765, 367, 18, 14 ], [ 556, 381, 31, 14 ], [ 591, 381, 34, 14 ], [ 629, 381, 16, 14 ], [ 648, 381, 17, 14 ], [ 669, 381, 30, 14 ], [ 703, 381, 35, 14 ], [ 742, 381, 27, 14 ], [ 772, 381, 11, 14 ], [ 556, 396, 30, 14 ], [ 589, 396, 23, 14 ], [ 615, 396, 43, 14 ], [ 660, 396, 18, 14 ], [ 681, 396, 48, 14 ], [ 732, 396, 14, 14 ], [ 750, 396, 34, 14 ], [ 556, 410, 19, 14 ], [ 578, 410, 21, 14 ], [ 602, 410, 23, 14 ], [ 628, 410, 39, 14 ], [ 670, 410, 53, 14 ], [ 726, 410, 10, 14 ], [ 740, 410, 16, 14 ], [ 759, 410, 25, 14 ], [ 556, 425, 30, 14 ], [ 589, 425, 12, 14 ], [ 604, 425, 16, 14 ], [ 622, 425, 44, 14 ], [ 669, 425, 10, 14 ], [ 681, 425, 16, 14 ], [ 700, 425, 40, 14 ], [ 742, 425, 10, 14 ], [ 755, 425, 28, 14 ], [ 556, 440, 29, 14 ], [ 589, 440, 58, 14 ], [ 651, 440, 17, 14 ], [ 671, 440, 28, 14 ], [ 704, 440, 21, 14 ], [ 728, 440, 35, 14 ], [ 767, 440, 17, 14 ], [ 556, 454, 31, 14 ], [ 591, 454, 31, 14 ], [ 626, 454, 48, 14 ], [ 677, 454, 46, 14 ], [ 727, 454, 56, 14 ], [ 556, 469, 59, 14 ], [ 618, 469, 25, 14 ], [ 647, 469, 28, 14 ], [ 679, 469, 31, 14 ], [ 713, 469, 70, 14 ], [ 556, 483, 20, 14 ], [ 580, 483, 60, 14 ], [ 643, 483, 53, 14 ], [ 700, 483, 6, 14 ], [ 710, 483, 45, 14 ], [ 758, 483, 16, 14 ], [ 778, 483, 6, 14 ], [ 556, 498, 43, 14 ], [ 602, 498, 28, 14 ], [ 632, 498, 27, 14 ], [ 662, 498, 27, 14 ], [ 692, 498, 21, 14 ], [ 715, 498, 68, 14 ], [ 556, 512, 45, 14 ], [ 605, 512, 53, 14 ], [ 661, 512, 10, 14 ], [ 675, 512, 12, 14 ], [ 690, 512, 34, 14 ], [ 728, 512, 25, 14 ], [ 757, 512, 27, 14 ], [ 556, 527, 40, 14 ], [ 600, 527, 41, 14 ], [ 644, 527, 41, 14 ], [ 689, 527, 59, 14 ], [ 751, 527, 13, 14 ], [ 767, 527, 16, 14 ], [ 556, 542, 30, 14 ], [ 589, 542, 37, 14 ], [ 630, 542, 10, 14 ], [ 643, 542, 21, 14 ], [ 667, 542, 35, 14 ], [ 706, 542, 30, 14 ], [ 739, 542, 10, 14 ], [ 752, 542, 31, 14 ], [ 556, 556, 45, 14 ], [ 604, 556, 73, 14 ], [ 680, 556, 46, 14 ], [ 730, 556, 53, 14 ], [ 556, 571, 19, 14 ], [ 579, 571, 26, 14 ], [ 608, 571, 11, 14 ], [ 623, 571, 18, 14 ], [ 644, 571, 11, 14 ], [ 659, 571, 48, 14 ], [ 710, 571, 73, 14 ], [ 556, 585, 33, 14 ], [ 591, 585, 46, 14 ], [ 640, 585, 19, 14 ], [ 661, 585, 55, 14 ], [ 719, 585, 42, 14 ], [ 764, 585, 20, 14 ], [ 556, 600, 17, 14 ], [ 576, 600, 12, 14 ], [ 591, 600, 22, 14 ], [ 617, 600, 10, 14 ], [ 631, 600, 32, 14 ], [ 666, 600, 43, 14 ], [ 712, 600, 11, 14 ], [ 726, 600, 58, 14 ], [ 556, 615, 27, 14 ], [ 587, 615, 69, 14 ], [ 660, 615, 23, 14 ], [ 686, 615, 10, 14 ], [ 700, 615, 29, 14 ], [ 732, 615, 19, 14 ], [ 755, 615, 28, 14 ], [ 556, 629, 51, 14 ], [ 609, 629, 9, 14 ], [ 620, 629, 12, 14 ], [ 634, 629, 32, 14 ], [ 575, 644, 12, 14 ], [ 592, 644, 29, 14 ], [ 626, 644, 18, 14 ], [ 649, 644, 32, 14 ], [ 686, 644, 31, 14 ], [ 723, 644, 31, 14 ], [ 759, 644, 24, 14 ], [ 556, 658, 60, 14 ], [ 618, 658, 10, 14 ], [ 631, 658, 30, 14 ], [ 664, 658, 60, 14 ], [ 726, 658, 10, 14 ], [ 739, 658, 13, 14 ], [ 755, 658, 10, 14 ], [ 767, 658, 16, 14 ], [ 556, 673, 26, 14 ], [ 585, 673, 17, 14 ], [ 606, 673, 28, 14 ], [ 637, 673, 53, 14 ], [ 694, 673, 19, 14 ], [ 717, 673, 66, 14 ], [ 556, 687, 23, 14 ], [ 582, 687, 17, 14 ], [ 602, 687, 45, 14 ], [ 650, 687, 10, 14 ], [ 664, 687, 16, 14 ], [ 683, 687, 37, 14 ], [ 724, 687, 60, 14 ], [ 556, 702, 18, 14 ], [ 578, 702, 36, 14 ], [ 617, 702, 19, 14 ], [ 639, 702, 40, 14 ], [ 683, 702, 58, 14 ], [ 744, 702, 39, 14 ], [ 556, 717, 26, 14 ], [ 586, 717, 17, 14 ], [ 606, 717, 39, 14 ], [ 649, 717, 15, 14 ], [ 668, 717, 31, 14 ], [ 703, 717, 57, 14 ], [ 764, 717, 20, 14 ], [ 556, 731, 37, 14 ], [ 597, 731, 50, 14 ], [ 650, 731, 11, 14 ], [ 665, 731, 58, 14 ], [ 727, 731, 16, 14 ], [ 746, 731, 37, 14 ], [ 556, 746, 24, 14 ], [ 583, 746, 51, 14 ], [ 637, 746, 6, 14 ], [ 646, 746, 86, 14 ], [ 736, 746, 48, 14 ], [ 556, 760, 31, 14 ], [ 590, 760, 10, 14 ], [ 602, 760, 29, 14 ], [ 634, 760, 43, 14 ], [ 679, 760, 10, 14 ], [ 692, 760, 16, 14 ], [ 710, 760, 25, 14 ], [ 737, 760, 17, 14 ], [ 757, 760, 26, 14 ], [ 556, 775, 11, 14 ], [ 570, 775, 41, 14 ], [ 615, 775, 24, 14 ], [ 643, 775, 23, 14 ], [ 670, 775, 18, 14 ], [ 691, 775, 19, 14 ], [ 714, 775, 17, 14 ], [ 735, 775, 48, 14 ], [ 556, 789, 65, 14 ], [ 625, 789, 33, 14 ], [ 660, 789, 30, 14 ], [ 694, 789, 31, 14 ], [ 728, 789, 55, 14 ], [ 556, 804, 27, 14 ], [ 586, 804, 19, 14 ], [ 607, 804, 27, 14 ], [ 636, 804, 16, 14 ], [ 654, 804, 59, 14 ], [ 716, 804, 10, 14 ], [ 728, 804, 55, 14 ], [ 556, 819, 71, 14 ], [ 631, 819, 56, 14 ], [ 691, 819, 64, 14 ], [ 759, 819, 25, 14 ], [ 556, 833, 39, 14 ], [ 598, 833, 13, 14 ], [ 614, 833, 6, 14 ], [ 623, 833, 68, 14 ], [ 695, 833, 89, 14 ], [ 556, 848, 41, 14 ], [ 601, 848, 20, 14 ], [ 626, 848, 13, 14 ], [ 643, 848, 29, 14 ], [ 676, 848, 20, 14 ], [ 700, 848, 25, 14 ], [ 730, 848, 54, 14 ], [ 555, 885, 34, 12 ], [ 593, 885, 68, 12 ], [ 664, 885, 9, 12 ], [ 677, 885, 10, 12 ], [ 689, 885, 25, 12 ], [ 717, 885, 54, 12 ], [ 774, 885, 9, 12 ], [ 555, 897, 33, 12 ], [ 591, 897, 17, 12 ], [ 612, 897, 32, 12 ], [ 648, 897, 40, 12 ], [ 692, 897, 6, 12 ], [ 702, 897, 24, 12 ], [ 730, 897, 34, 12 ], [ 767, 897, 16, 12 ], [ 555, 910, 28, 12 ], [ 586, 910, 20, 12 ], [ 610, 910, 42, 12 ], [ 655, 910, 15, 12 ], [ 673, 910, 29, 12 ], [ 705, 910, 24, 12 ], [ 733, 910, 50, 12 ], [ 555, 922, 27, 12 ], [ 585, 922, 50, 12 ], [ 639, 922, 20, 12 ], [ 663, 922, 27, 12 ], [ 694, 922, 50, 12 ], [ 748, 922, 36, 12 ], [ 555, 935, 106, 12 ], [ 563, 947, 22, 12 ], [ 589, 947, 24, 12 ], [ 617, 947, 17, 12 ], [ 637, 947, 34, 12 ], [ 675, 947, 11, 12 ], [ 690, 947, 21, 12 ], [ 716, 947, 31, 12 ], [ 750, 947, 33, 12 ], [ 555, 960, 32, 12 ], [ 590, 960, 33, 12 ], [ 627, 960, 13, 12 ], [ 643, 960, 26, 12 ], [ 673, 960, 49, 12 ], [ 725, 960, 17, 12 ], [ 746, 960, 38, 12 ], [ 555, 972, 35, 12 ], [ 593, 972, 23, 12 ], [ 618, 972, 89, 12 ], [ 563, 985, 18, 12 ], [ 584, 985, 32, 12 ], [ 619, 985, 30, 12 ], [ 651, 985, 19, 12 ], [ 672, 985, 20, 12 ], [ 695, 985, 12, 12 ], [ 709, 985, 46, 12 ], [ 757, 985, 26, 12 ], [ 555, 997, 15, 12 ], [ 572, 997, 38, 12 ], [ 563, 1010, 39, 12 ], [ 604, 1010, 12, 12 ], [ 618, 1010, 33, 12 ], [ 654, 1010, 25, 12 ], [ 682, 1010, 37, 12 ], [ 721, 1010, 12, 12 ], [ 735, 1010, 20, 12 ], [ 758, 1010, 25, 12 ], [ 750, 1048, 33, 14 ] ]

[ "Research", "Fish", "Consumption", "and", "Advisory", "Awareness", "in", "the", "Great", "Lakes", "Basin", "Pamela", "Imm,", "Lynda", "Knobeloch,", "Henry", "A.", "Anderson,", "and", "the", "Great", "Lakes", "Sport", "Fish", "Consortium", "Division", "of", "Public", "Health,", "Wisconsin", "Department", "of", "Health", "and", "Family", "Services,", "Madison,", "Wisconsin,", "USA", "More", "than", "61", "million", "adults", "live", "in", "the", "eight", "U.S.", "states", "bordering", "the", "Great", "Lakes.", "Between", "June", "2001", "and", "June", "2002,", "a", "population-based,", "random-digit-dial", "telephone", "survey", "of", "adults", "residing", "in", "Great", "Lakes", "(GL)", "states", "was", "conducted", "to", "assess", "consumption", "of", "commercial", "and", "sport-caught", "fish", "and", "awareness", "of", "state-issued", "consumption", "advisories", "for", "GL", "fish.", "On", "the", "basis", "of", "the", "weighted", "sur-", "vey", "data,", "approximately", "84%", "of", "the", "adults", "living", "in", "these", "states", "included", "fish", "in", "their", "diets.", "Seven", "percent", "(an", "estimated", "4.2", "million", "adults)", "consumed", "fish", "caught", "from", "the", "Great", "Lakes.", "The", "percent-", "age", "of", "residents", "who", "had", "consumed", "sport-caught", "fish", "(from", "any", "water", "source)", "varied", "regionally", "and", "was", "highest", "among", "those", "who", "lived", "in", "Minnesota", "(44%)", "and", "Wisconsin", "(39%).", "Consumption", "of", "GL", "sport", "fish", "was", "highest", "among", "residents", "of", "Michigan", "(16%)", "and", "Ohio", "(12%).", "Among", "residents", "who", "had", "eaten", "GL", "fish,", "awareness", "of", "consumption", "advisories", "varied", "by", "gender", "and", "race", "and", "was", "lowest", "among", "women", "(30%)", "and", "black", "residents", "(15%).", "However,", "70%", "of", "those", "who", "consumed", "GL", "sport-caught", "fish", "twice", "a", "month", "or", "more", "(an", "estimated", "509,000", "adults", "across", "all", "eight", "states)", "were", "aware", "of", "the", "advisories.", "Findings", "from", "this", "survey", "indicate", "that", "exposure", "to", "persistent", "contam-", "inants", "found", "in", "GL", "fish", "is", "likely", "limited", "to", "a", "relatively", "small", "subpopulation", "of", "avid", "sport-fish", "con-", "sumers.", "Results", "also", "underscore", "the", "public", "health", "importance", "of", "advisories", "for", "commercial", "fish", "because", "an", "estimated", "2.9", "million", "adults", "living", "in", "these", "states", "consume", "more", "than", "104", "fish", "meals", "per", "year", "and", "may", "be", "at", "risk", "of", "exceeding", "the", "reference", "doses", "for", "methylmercury,", "polychlorinated", "biphenyls,", "and", "other", "bioaccumulative", "contaminants.", "Key", "words:", "advisory,", "awareness,", "fish,", "Great", "Lakes,", "sport", "fish.", "Environ", "Health", "Perspect", "113:1325–1329", "(2005).", "doi:10.1289/ehp.7980", "available", "via", "http://dx.doi.org/", "[Online", "13", "June", "2005]", "Consumption", "advisories", "for", "sport-caught", "fish", "were", "first", "issued", "by", "Great", "Lakes", "(GL)", "states", "during", "the", "1970s.", "These", "advisories", "were", "based", "on", "findings", "from", "investigations", "of", "the", "methyl-", "mercury", "poisonings", "that", "had", "occurred", "in", "Minamata,", "Japan,", "and", "on", "fish", "tissue", "analysis.", "Since", "that", "time,", "researchers", "have", "discovered", "that", "a", "variety", "of", "other", "persistent", "environmental", "contaminants,", "including", "PCBs", "(polychlori-", "nated", "biphenyls),", "DDT", "(dichlorodiphenyl-", "trichloroethane),", "and", "polybrominated", "diphenyl", "ethers,", "had", "found", "their", "way", "into", "the", "aquatic", "food", "chain", "and", "might", "pose", "a", "risk", "to", "frequent", "consumers", "of", "large,", "predatory", "fish.", "Currently,", "health", "departments", "and/or", "state", "environmental", "agencies", "in", "48", "states", "issue", "consumption", "guide-", "lines", "for", "local", "sport-caught", "fish—fish", "that", "is", "caught", "and", "not", "purchased.", "The", "recent", "methylmercury", "reference", "dose", "revision", "from", "0.5", "gµ/kg/day", "to", "0.1", "gµ/kg/day", "triggered", "states", "to", "review", "their", "sport-fish", "advi-", "sories", "and", "federal", "agencies", "to", "assess", "the", "need", "for", "a", "commercial", "fish", "advisory.", "In", "2004", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA)", "and", "the", "U.S.", "Food", "and", "Drug", "Administration", "(FDA)", "jointly", "issued", "consumption", "advice", "for", "commercial", "fish", "that", "was", "intended", "to", "protect", "women", "of", "childbearing", "age", "and", "young", "chil-", "dren", "against", "the", "neurodevelopmental", "effects", "of", "methylmercury.", "It", "became", "apparent", "to", "some", "states", "that", "there", "was", "a", "need", "for", "a", "holistic", "methylmercury", "fish", "consumption", "advisory", "that", "combined", "advice", "forlocal", "sport-caught", "fish", "and", "commercial", "fish.", "Up", "until", "this", "time", "sport-caught", "fish", "advisories", "largely", "ignored", "exposures", "from", "commercial", "fish.", "Current", "advisories", "are", "intended", "to", "assist", "anglers", "and", "consumers", "of", "commercial", "fish", "in", "selecting", "fish", "low", "in", "chemical", "contaminants", "as", "part", "of", "a", "healthy,", "balanced", "diet.", "In", "2001", "an", "estimated", "1.85", "million", "fisher-", "men", "purchased", "licenses", "to", "fish", "on", "the", "Great", "Lakes", "(U.S.", "Department", "of", "the", "Interior", "2002).", "Although", "this", "figure", "reflects", "an", "almost", "30%", "decline", "from", "2.55", "million", "in", "1991,", "GL", "sport", "fishing", "continues", "to", "be", "a", "popular", "recreational", "activity", "for", "many", "families.", "Frequent", "ingestion", "of", "fish", "from", "these", "lakes", "has", "been", "associated", "with", "higher", "body", "burdens", "of", "PCBs,", "DDT,", "and", "DDE", "(dichlorodiphenyldichloroethylene)", "(Anderson", "et", "al.", "1998;", "Fiore", "et", "al.", "1989;", "Humphrey", "1983;", "Schwartz", "e", "al.", "1983;", "Sonzogni", "et", "al.", "1991;", "Tilden", "et", "al.", "1997).", "These", "persistent", "contaminants", "accumulate", "in", "the", "body", "over", "time", "and", "increase", "the", "risk", "of", "a", "variety", "of", "health", "problems", "such", "as", "liver", "disease", "(Yu", "et", "al.", "1997),", "reproductive", "(Dar", "et", "al.", "1992;", "Weisskopf", "et", "al.", "2003)", "and", "neurologic", "prob-", "lems", "(Rogan", "and", "Gladen", "1992),", "endocrine", "changes", "(Braathen", "et", "al.", "2004;", "Persky", "et", "al.", "2001),", "and", "developmental", "delays", "(Jacobson", "et", "al.", "1990;", "Jacobson", "et", "al.", "1986;", "Kimbrough", "and", "Krouskas", "2003;", "Longnecker", "et", "al.", "1997;", "Tilson", "and", "Kodavanti", "1998).", "PCBs,", "DDT,", "and", "DDE", "have", "been", "classified", "as", "probable", "human", "carcinogens", "by", "the", "U.S.", "EPA,", "and", "sport-fish", "consumption", "has", "recently", "been", "associated", "with", "an", "increased", "risk", "of", "breast", "can-", "cer", "among", "young,", "premenopausal", "women", "(McElroy", "et", "al.", "2004).", "Environmental", "Health", "Perspectives", "•", "VOLUME", "113", "|", "NUMBER", "10", "|", "October", "2005", "Prenatal", "exposure", "to", "methylmercury", "has", "been", "associated", "with", "subtle", "learning", "delays", "and", "blood", "pressure", "changes", "(Grandjean", "et", "al.", "1998;", "Sorenson", "et", "al.", "1999).", "Methylmercury", "exposure", "during", "adulthood", "has", "recently", "been", "linked", "to", "higher", "rates", "of", "cardiovascular", "disease", "and", "acute", "myocardial", "infarction", "(Guallar", "et", "al.", "2002;", "Salonen", "et", "al.", "1995).", "Until", "the", "early", "1990s", "sport-fish", "consump-", "tion", "advisories", "were", "developed", "independently", "by", "each", "state.", "Development", "of", "these", "advisories", "may", "have", "been", "based", "on", "policy", "considerations", "as", "well", "as", "science.", "This", "led", "to", "confusion", "because", "neighboring", "states", "often", "provided", "dif-", "ferent", "advice", "for", "the", "same,", "shared", "body", "of", "water.", "This", "situation", "was", "confusing", "for", "anglers", "and", "may", "have", "reduced", "confidence", "in", "the", "advi-", "sories.", "At", "the", "direction", "of", "the", "Council", "of", "Great", "Lakes", "Governors,", "the", "states", "that", "border", "the", "Great", "Lakes", "(Illinois,", "Indiana,", "Michigan,", "Minnesota,", "New", "York,", "Ohio,", "Pennsylvania,", "and", "Wisconsin)", "developed", "a", "protocol", "for", "a", "Uniform", "Great", "Lakes", "Sport", "Fish", "Consumption", "Advisory", "(Anderson", "et", "al.", "1993).", "That", "1993", "advisory", "protocol", "provides", "information", "on", "the", "health", "benefits", "of", "fish;", "adverse", "effects", "of", "conta-", "minants;", "recommended", "quantity,", "frequency,", "and", "types", "of", "fish", "to", "consume;", "recommended", "fishing", "locations;", "and", "preparation", "methods", "that", "can", "be", "used", "to", "reduce", "exposure", "to", "bioaccumu-", "lative", "contaminants", "such", "as", "PCBs", "and", "DDE", "(Anderson", "et", "al.", "1993).", "In", "1991", "the", "Great", "Lakes", "Sport", "Fish", "Consortium", "of", "health", "departments", "in", "six", "of", "the", "eight", "GL", "states", "(Michigan", "and", "Pennsylvania", "were", "not", "members", "of", "the", "original", "consortium)", "was", "formed", "and", "received", "competitive", "funding", "from", "the", "Agency", "for", "Toxic", "Substances", "and", "Disease", "Registries.", "In", "1993–1994", "the", "consor-", "tium", "conducted", "a", "random-digit-dial", "telephone", "survey", "of", "8,306", "residents", "of", "the", "eight", "GL", "states", "to", "evaluate", "their", "total", "fish", "and", "GL", "sport-fish", "consumption", "habits,", "define", "at-risk", "subpopula-", "tions,", "and", "assess", "the", "effectiveness", "of", "state-issued", "consumption", "advisories.", "Households", "were", "selected", "by", "a", "computerized", "random-digit-dial", "system,", "and", "an", "adult", "was", "then", "randomly", "Address", "correspondence", "to", "P.", "Imm,", "Department", "of", "Health", "and", "Family", "Services,", "1", "West", "Wilson", "St.,", "Room", "150,", "Madison,", "WI", "53703", "USA.", "Telephone:", "(608)", "267-3565.", "Fax:", "(608)", "267-4853.", "E-mail:", "immpb@dhfs.state.wi.us", "This", "work", "was", "funded", "by", "U.S.", "Public", "Health", "Service", "Agency", "for", "Toxic", "Substances", "and", "Diseases", "Registry", "grant", "75/ATH598322-03.", "The", "authors", "declare", "they", "have", "no", "competing", "finan-", "cial", "interests.", "Received", "31", "January", "2005;", "accepted", "13", "June", "2005.", "1325" ]

[ 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 4 ]

[ [ 78, 47, 36, 12 ], [ 117, 47, 9, 12 ], [ 129, 47, 11, 12 ], [ 143, 47, 21, 12 ], [ 167, 47, 44, 12 ], [ 214, 47, 25, 12 ], [ 243, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 121, 34 ], [ 209, 169, 129, 34 ], [ 348, 169, 83, 34 ], [ 441, 169, 20, 34 ], [ 472, 169, 138, 34 ], [ 620, 169, 58, 34 ], [ 688, 169, 16, 34 ], [ 78, 205, 85, 34 ], [ 174, 205, 141, 34 ], [ 325, 205, 44, 34 ], [ 379, 205, 79, 34 ], [ 468, 205, 93, 34 ], [ 571, 205, 51, 34 ], [ 632, 205, 94, 34 ], [ 78, 241, 35, 34 ], [ 123, 241, 100, 34 ], [ 233, 241, 174, 34 ], [ 418, 241, 33, 34 ], [ 78, 288, 24, 16 ], [ 107, 285, 56, 19 ], [ 167, 288, 33, 16 ], [ 205, 285, 46, 19 ], [ 255, 288, 50, 16 ], [ 309, 285, 38, 19 ], [ 351, 288, 41, 16 ], [ 396, 285, 35, 19 ], [ 436, 288, 46, 16 ], [ 487, 285, 69, 19 ], [ 560, 288, 49, 16 ], [ 614, 285, 34, 19 ], [ 87, 342, 54, 15 ], [ 87, 367, 76, 14 ], [ 167, 367, 27, 14 ], [ 198, 367, 48, 14 ], [ 250, 367, 8, 14 ], [ 263, 367, 14, 14 ], [ 281, 367, 56, 14 ], [ 342, 367, 48, 14 ], [ 394, 367, 11, 14 ], [ 409, 367, 12, 14 ], [ 425, 367, 51, 14 ], [ 481, 367, 40, 14 ], [ 525, 367, 52, 14 ], [ 582, 367, 28, 14 ], [ 613, 367, 65, 14 ], [ 683, 367, 21, 14 ], [ 87, 384, 72, 14 ], [ 164, 384, 11, 14 ], [ 180, 384, 34, 14 ], [ 217, 384, 48, 14 ], [ 269, 384, 11, 14 ], [ 284, 384, 40, 14 ], [ 328, 384, 43, 14 ], [ 375, 384, 28, 14 ], [ 407, 384, 48, 14 ], [ 459, 384, 42, 14 ], [ 506, 384, 46, 14 ], [ 556, 384, 65, 14 ], [ 625, 384, 11, 14 ], [ 641, 384, 41, 14 ], [ 686, 384, 36, 14 ], [ 727, 384, 11, 14 ], [ 87, 400, 35, 14 ], [ 126, 400, 77, 14 ], [ 208, 400, 40, 14 ], [ 252, 400, 76, 14 ], [ 332, 400, 11, 14 ], [ 348, 400, 19, 14 ], [ 371, 400, 35, 14 ], [ 410, 400, 28, 14 ], [ 442, 400, 21, 14 ], [ 468, 400, 75, 14 ], [ 547, 400, 11, 14 ], [ 562, 400, 19, 14 ], [ 585, 400, 54, 14 ], [ 644, 400, 17, 14 ], [ 665, 400, 47, 14 ], [ 716, 400, 15, 14 ], [ 87, 417, 31, 14 ], [ 123, 417, 37, 14 ], [ 164, 417, 11, 14 ], [ 179, 417, 19, 14 ], [ 202, 417, 40, 14 ], [ 246, 417, 50, 14 ], [ 300, 417, 18, 14 ], [ 323, 417, 61, 14 ], [ 388, 417, 7, 14 ], [ 399, 417, 50, 14 ], [ 453, 417, 54, 14 ], [ 512, 417, 35, 14 ], [ 551, 417, 31, 14 ], [ 587, 417, 19, 14 ], [ 610, 417, 29, 14 ], [ 643, 417, 48, 14 ], [ 695, 417, 34, 14 ], [ 87, 434, 43, 14 ], [ 135, 434, 12, 14 ], [ 151, 434, 15, 14 ], [ 170, 434, 11, 14 ], [ 186, 434, 42, 14 ], [ 231, 434, 35, 14 ], [ 270, 434, 11, 14 ], [ 285, 434, 47, 14 ], [ 337, 434, 39, 14 ], [ 380, 434, 17, 14 ], [ 401, 434, 27, 14 ], [ 432, 434, 38, 14 ], [ 474, 434, 22, 14 ], [ 501, 434, 7, 14 ], [ 511, 434, 28, 14 ], [ 543, 434, 45, 14 ], [ 592, 434, 11, 14 ], [ 608, 434, 45, 14 ], [ 657, 434, 72, 14 ], [ 87, 450, 27, 14 ], [ 118, 450, 7, 14 ], [ 129, 450, 31, 14 ], [ 164, 450, 45, 14 ], [ 214, 450, 43, 14 ], [ 261, 450, 12, 14 ], [ 277, 450, 19, 14 ], [ 300, 450, 32, 14 ], [ 337, 450, 22, 14 ], [ 363, 450, 11, 14 ], [ 379, 450, 19, 14 ], [ 402, 450, 57, 14 ], [ 87, 471, 46, 14 ], [ 137, 471, 90, 14 ], [ 231, 471, 11, 14 ], [ 247, 471, 19, 14 ], [ 269, 471, 50, 14 ], [ 324, 471, 54, 14 ], [ 382, 471, 45, 14 ], [ 431, 471, 35, 14 ], [ 471, 471, 47, 14 ], [ 522, 471, 22, 14 ], [ 549, 471, 27, 14 ], [ 580, 471, 19, 14 ], [ 602, 471, 57, 14 ], [ 663, 471, 47, 14 ], [ 715, 471, 21, 14 ], [ 87, 488, 57, 14 ], [ 149, 488, 17, 14 ], [ 170, 488, 47, 14 ], [ 222, 488, 22, 14 ], [ 248, 488, 25, 14 ], [ 277, 488, 11, 14 ], [ 292, 488, 24, 14 ], [ 321, 488, 43, 14 ], [ 369, 488, 12, 14 ], [ 385, 488, 15, 14 ], [ 404, 488, 7, 14 ], [ 414, 488, 56, 14 ], [ 475, 488, 53, 14 ], [ 532, 488, 21, 14 ], [ 558, 488, 39, 14 ], [ 600, 488, 27, 14 ], [ 631, 488, 11, 14 ], [ 647, 488, 19, 14 ], [ 670, 488, 37, 14 ], [ 711, 488, 9, 14 ], [ 87, 504, 47, 14 ], [ 139, 504, 27, 14 ], [ 170, 504, 25, 14 ], [ 200, 504, 25, 14 ], [ 229, 504, 77, 14 ], [ 310, 504, 66, 14 ], [ 380, 504, 53, 14 ], [ 437, 504, 42, 14 ], [ 484, 504, 19, 14 ], [ 507, 504, 24, 14 ], [ 535, 504, 58, 14 ], [ 597, 504, 36, 14 ], [ 638, 504, 35, 14 ], [ 677, 504, 16, 14 ], [ 697, 504, 26, 14 ], [ 87, 521, 15, 14 ], [ 107, 521, 42, 14 ], [ 153, 521, 74, 14 ], [ 231, 521, 16, 14 ], [ 252, 521, 24, 14 ], [ 280, 521, 36, 14 ], [ 320, 521, 39, 14 ], [ 363, 521, 21, 14 ], [ 389, 521, 42, 14 ], [ 435, 521, 41, 14 ], [ 480, 521, 35, 14 ], [ 520, 521, 20, 14 ], [ 544, 521, 36, 14 ], [ 584, 521, 28, 14 ], [ 616, 521, 64, 14 ], [ 684, 521, 21, 14 ], [ 87, 537, 59, 14 ], [ 150, 537, 11, 14 ], [ 166, 537, 30, 14 ], [ 200, 537, 34, 14 ], [ 238, 537, 53, 14 ], [ 295, 537, 66, 14 ], [ 365, 537, 11, 14 ], [ 380, 537, 64, 14 ], [ 448, 537, 22, 14 ], [ 474, 537, 40, 14 ], [ 518, 537, 33, 14 ], [ 555, 537, 21, 14 ], [ 580, 537, 38, 14 ], [ 622, 537, 47, 14 ], [ 673, 537, 11, 14 ], [ 689, 537, 41, 14 ], [ 87, 554, 11, 14 ], [ 102, 554, 55, 14 ], [ 161, 554, 75, 14 ], [ 240, 554, 65, 14 ], [ 308, 554, 20, 14 ], [ 332, 554, 29, 14 ], [ 365, 554, 12, 14 ], [ 381, 554, 7, 14 ], [ 392, 554, 30, 14 ], [ 426, 554, 55, 14 ], [ 485, 554, 63, 14 ], [ 553, 554, 15, 14 ], [ 573, 554, 19, 14 ], [ 595, 554, 27, 14 ], [ 626, 554, 24, 14 ], [ 87, 571, 93, 14 ], [ 184, 571, 23, 14 ], [ 211, 571, 22, 14 ], [ 237, 571, 53, 14 ], [ 293, 571, 35, 14 ], [ 333, 571, 19, 14 ], [ 355, 571, 40, 14 ], [ 399, 571, 31, 14 ], [ 434, 571, 52, 14 ], [ 491, 571, 12, 14 ], [ 507, 571, 20, 14 ], [ 531, 571, 51, 14 ], [ 586, 571, 22, 14 ], [ 612, 571, 33, 14 ], [ 650, 571, 11, 14 ], [ 665, 571, 72, 14 ], [ 87, 587, 27, 14 ], [ 118, 587, 11, 14 ], [ 133, 587, 59, 14 ], [ 196, 587, 25, 14 ], [ 225, 587, 40, 14 ], [ 269, 587, 37, 14 ], [ 310, 587, 20, 14 ], [ 335, 587, 8, 14 ], [ 347, 587, 19, 14 ], [ 371, 587, 28, 14 ], [ 402, 587, 12, 14 ], [ 419, 587, 15, 14 ], [ 437, 587, 19, 14 ], [ 460, 587, 34, 14 ], [ 498, 587, 53, 14 ], [ 87, 608, 75, 14 ], [ 167, 608, 11, 14 ], [ 182, 608, 20, 14 ], [ 206, 608, 30, 14 ], [ 240, 608, 17, 14 ], [ 262, 608, 53, 14 ], [ 318, 608, 22, 14 ], [ 345, 608, 55, 14 ], [ 404, 608, 34, 14 ], [ 442, 608, 15, 14 ], [ 461, 608, 7, 14 ], [ 472, 608, 36, 14 ], [ 512, 608, 35, 14 ], [ 551, 608, 49, 14 ], [ 604, 608, 27, 14 ], [ 635, 608, 19, 14 ], [ 658, 608, 35, 14 ], [ 87, 625, 54, 14 ], [ 146, 625, 21, 14 ], [ 172, 625, 57, 14 ], [ 233, 625, 22, 14 ], [ 260, 625, 37, 14 ], [ 300, 625, 50, 14 ], [ 355, 625, 24, 14 ], [ 383, 625, 11, 14 ], [ 398, 625, 30, 14 ], [ 433, 625, 36, 14 ], [ 473, 625, 42, 14 ], [ 519, 625, 28, 14 ], [ 551, 625, 14, 14 ], [ 570, 625, 55, 14 ], [ 629, 625, 21, 14 ], [ 655, 625, 11, 14 ], [ 87, 641, 80, 14 ], [ 172, 641, 7, 14 ], [ 183, 641, 66, 14 ], [ 253, 641, 15, 14 ], [ 272, 641, 57, 14 ], [ 334, 641, 67, 14 ], [ 405, 641, 21, 14 ], [ 431, 641, 54, 14 ], [ 490, 641, 57, 14 ], [ 551, 641, 68, 14 ], [ 623, 641, 19, 14 ], [ 646, 641, 70, 14 ], [ 720, 641, 11, 14 ], [ 87, 658, 20, 14 ], [ 111, 658, 29, 14 ], [ 144, 658, 11, 14 ], [ 159, 658, 19, 14 ], [ 182, 658, 50, 14 ], [ 236, 658, 54, 14 ], [ 295, 658, 35, 14 ], [ 334, 658, 22, 14 ], [ 360, 658, 27, 14 ], [ 391, 658, 50, 14 ], [ 78, 704, 77, 15 ], [ 78, 721, 29, 14 ], [ 111, 721, 52, 14 ], [ 168, 721, 9, 14 ], [ 181, 721, 56, 14 ], [ 241, 721, 68, 14 ], [ 313, 721, 53, 14 ], [ 370, 721, 33, 14 ], [ 78, 737, 22, 14 ], [ 107, 737, 13, 14 ], [ 126, 737, 91, 14 ], [ 223, 737, 46, 14 ], [ 275, 737, 20, 14 ], [ 302, 737, 34, 14 ], [ 342, 737, 44, 14 ], [ 391, 737, 12, 14 ], [ 78, 754, 35, 14 ], [ 118, 754, 73, 14 ], [ 195, 754, 26, 14 ], [ 225, 754, 28, 14 ], [ 257, 754, 6, 14 ], [ 267, 754, 40, 14 ], [ 312, 754, 34, 14 ], [ 350, 754, 53, 14 ], [ 78, 771, 11, 14 ], [ 94, 771, 18, 14 ], [ 116, 771, 63, 14 ], [ 183, 771, 21, 14 ], [ 209, 771, 63, 14 ], [ 276, 771, 11, 14 ], [ 291, 771, 35, 14 ], [ 331, 771, 18, 14 ], [ 353, 771, 18, 14 ], [ 375, 771, 28, 14 ], [ 78, 787, 54, 14 ], [ 138, 787, 40, 14 ], [ 184, 787, 12, 14 ], [ 202, 787, 30, 14 ], [ 238, 787, 59, 14 ], [ 303, 787, 55, 14 ], [ 364, 787, 12, 14 ], [ 382, 787, 22, 14 ], [ 78, 804, 37, 14 ], [ 120, 804, 56, 14 ], [ 182, 804, 98, 14 ], [ 285, 804, 58, 14 ], [ 348, 804, 37, 14 ], [ 390, 804, 13, 14 ], [ 78, 820, 21, 14 ], [ 104, 820, 37, 14 ], [ 146, 820, 47, 14 ], [ 197, 820, 33, 14 ], [ 235, 820, 45, 14 ], [ 284, 820, 38, 14 ], [ 327, 820, 12, 14 ], [ 345, 820, 35, 14 ], [ 385, 820, 19, 14 ], [ 78, 837, 33, 14 ], [ 117, 837, 22, 14 ], [ 143, 837, 28, 14 ], [ 177, 837, 56, 14 ], [ 238, 837, 12, 14 ], [ 255, 837, 102, 14 ], [ 361, 837, 28, 14 ], [ 394, 837, 10, 14 ], [ 78, 854, 40, 14 ], [ 123, 854, 34, 14 ], [ 161, 854, 19, 14 ], [ 185, 854, 64, 14 ], [ 253, 854, 38, 14 ], [ 296, 854, 12, 14 ], [ 312, 854, 28, 14 ], [ 345, 854, 58, 14 ], [ 78, 870, 62, 14 ], [ 145, 870, 19, 14 ], [ 169, 870, 68, 14 ], [ 241, 870, 22, 14 ], [ 268, 870, 79, 14 ], [ 351, 870, 12, 14 ], [ 368, 870, 36, 14 ], [ 78, 887, 31, 14 ], [ 115, 887, 69, 14 ], [ 189, 887, 54, 14 ], [ 249, 887, 103, 14 ], [ 357, 887, 47, 14 ], [ 78, 925, 5, 11 ], [ 86, 925, 70, 11 ], [ 159, 925, 77, 11 ], [ 78, 936, 40, 13 ], [ 122, 937, 37, 11 ], [ 162, 937, 33, 11 ], [ 197, 937, 20, 11 ], [ 220, 937, 60, 11 ], [ 284, 937, 16, 11 ], [ 303, 937, 22, 11 ], [ 328, 937, 39, 11 ], [ 78, 950, 43, 11 ], [ 125, 950, 35, 11 ], [ 163, 950, 41, 11 ], [ 208, 950, 31, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 704, 61, 14 ], [ 489, 704, 72, 14 ], [ 565, 704, 17, 14 ], [ 587, 704, 76, 14 ], [ 669, 704, 19, 14 ], [ 693, 704, 39, 14 ], [ 736, 704, 12, 14 ], [ 423, 721, 27, 14 ], [ 454, 721, 55, 14 ], [ 434, 737, 73, 14 ], [ 511, 737, 100, 14 ], [ 617, 737, 10, 14 ], [ 631, 737, 7, 14 ], [ 643, 737, 52, 14 ], [ 699, 737, 49, 14 ], [ 423, 754, 35, 14 ], [ 461, 754, 40, 14 ], [ 504, 754, 84, 14 ], [ 591, 754, 44, 14 ], [ 638, 754, 23, 14 ], [ 665, 754, 45, 14 ], [ 713, 754, 35, 14 ], [ 423, 771, 61, 14 ], [ 488, 771, 75, 14 ], [ 567, 771, 95, 14 ], [ 666, 771, 47, 14 ], [ 716, 771, 31, 14 ], [ 423, 787, 80, 14 ], [ 506, 787, 56, 14 ], [ 566, 787, 23, 14 ], [ 594, 787, 18, 14 ], [ 616, 787, 60, 14 ], [ 680, 787, 14, 14 ], [ 698, 787, 50, 14 ], [ 423, 804, 57, 14 ], [ 483, 804, 70, 14 ], [ 556, 804, 28, 14 ], [ 588, 804, 40, 14 ], [ 631, 804, 88, 14 ], [ 722, 804, 26, 14 ], [ 423, 820, 22, 14 ], [ 448, 820, 35, 14 ], [ 486, 820, 62, 14 ], [ 551, 820, 47, 14 ], [ 602, 820, 50, 14 ], [ 655, 820, 68, 14 ], [ 727, 820, 21, 14 ], [ 423, 837, 84, 14 ], [ 511, 837, 46, 14 ], [ 561, 837, 23, 14 ], [ 588, 837, 18, 14 ], [ 610, 837, 54, 14 ], [ 667, 837, 14, 14 ], [ 685, 837, 63, 14 ], [ 423, 854, 27, 14 ], [ 454, 854, 62, 14 ], [ 519, 854, 22, 14 ], [ 545, 854, 69, 14 ], [ 618, 854, 48, 14 ], [ 670, 854, 42, 14 ], [ 716, 854, 32, 14 ], [ 423, 870, 22, 14 ], [ 449, 870, 29, 14 ], [ 482, 870, 44, 14 ], [ 530, 870, 53, 14 ], [ 588, 870, 20, 14 ], [ 613, 870, 81, 14 ], [ 698, 870, 12, 14 ], [ 714, 870, 34, 14 ], [ 423, 887, 47, 14 ], [ 473, 887, 11, 14 ], [ 488, 887, 35, 14 ], [ 527, 887, 72, 14 ], [ 602, 887, 9, 14 ], [ 615, 887, 7, 14 ], [ 625, 887, 67, 14 ], [ 695, 887, 12, 14 ], [ 710, 887, 38, 14 ], [ 423, 904, 48, 14 ], [ 473, 904, 18, 14 ], [ 495, 904, 55, 14 ], [ 553, 904, 69, 14 ], [ 625, 904, 12, 14 ], [ 640, 904, 94, 14 ], [ 434, 920, 38, 14 ], [ 476, 920, 75, 14 ], [ 556, 920, 10, 14 ], [ 570, 920, 40, 14 ], [ 614, 920, 12, 14 ], [ 631, 920, 14, 14 ], [ 649, 920, 55, 14 ], [ 709, 920, 39, 14 ], [ 423, 937, 88, 14 ], [ 515, 937, 12, 14 ], [ 531, 937, 40, 14 ], [ 575, 937, 59, 14 ], [ 639, 937, 43, 14 ], [ 687, 937, 20, 14 ], [ 711, 937, 37, 14 ], [ 423, 953, 71, 14 ], [ 500, 953, 12, 14 ], [ 517, 953, 52, 14 ], [ 575, 953, 37, 14 ], [ 618, 953, 79, 14 ], [ 703, 953, 25, 14 ], [ 733, 953, 15, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 276, 987, 29, 10 ], [ 307, 987, 8, 10 ], [ 317, 987, 8, 10 ], [ 327, 987, 30, 10 ], [ 359, 987, 29, 10 ], [ 390, 987, 27, 10 ], [ 419, 987, 14, 10 ], [ 435, 987, 15, 10 ], [ 452, 987, 6, 10 ], [ 460, 987, 10, 10 ], [ 471, 987, 21, 10 ], [ 494, 987, 25, 10 ], [ 522, 987, 23, 10 ], [ 546, 987, 41, 10 ], [ 589, 987, 23, 10 ], [ 614, 987, 13, 10 ], [ 628, 987, 22, 10 ], [ 652, 987, 8, 10 ], [ 662, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Sironen", "et", "al.", "BMC", "Genomics", "2010,", "11:699", "http://www.biomedcentral.com/1471-2164/11/699", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Knobbed", "acrosome", "defect", "is", "associated", "with", "a", "region", "containing", "the", "genes", "STK17b", "and", "HECW2", "on", "porcine", "chromosome", "15", "Anu", "Sironen1*,", "Pekka", "Uimari1,", "Szabolcs", "Nagy2,", "Sándor", "Paku3,", "Magnus", "Andersson4,", "Johanna", "Vilkki1", "Abstract", "Background:", "Male", "infertility", "is", "an", "increasing", "problem", "in", "all", "domestic", "species", "including", "man.", "Localization", "and", "identification", "of", "genes", "involved", "in", "defects", "causing", "male", "infertility", "provide", "valuable", "information", "of", "specific", "events", "in", "sperm", "development.", "Correct", "condensation", "of", "the", "sperm", "head", "and", "development", "of", "the", "acrosome", "are", "required", "for", "fertile", "sperm.", "In", "the", "Finnish", "Yorkshire", "pig", "population", "a", "knobbed", "acrosome", "defect", "(KAD)", "has", "been", "reported", "which", "appears", "to", "be", "of", "genetic", "origin.", "In", "previous", "studies", "we", "have", "shown", "that", "a", "large", "number", "of", "affected", "spermatozoa", "have", "a", "cystic", "swelling", "anterior", "to", "the", "apical", "part", "of", "the", "acrosome.", "Results:", "Characterization", "of", "the", "knobbed", "acrosome", "affected", "sperm", "revealed", "that", "both", "the", "acrosomal", "granules", "and", "chromatin", "are", "affected.", "This", "type", "of", "KAD", "appears", "to", "be", "a", "previously", "unknown", "and", "serious", "form", "of", "the", "defect.", "A", "genome", "wide", "scan", "with", "PorcineSNP60", "Genotyping", "BeadChip", "defined", "the", "KAD", "associated", "region", "within", "0.7", "Mbp", "on", "porcine", "chromosome", "15.", "Two", "genes,", "STK17b", "and", "HECW2,", "located", "within", "this", "region", "were", "sequenced.", "The", "expression", "of", "these", "genes", "appeared", "comparable", "in", "KA-affected", "and", "control", "boars.", "The", "known", "function", "of", "HECW2", "in", "acrosome", "development", "highlighted", "this", "gene", "as", "a", "good", "candidate", "responsible", "for", "the", "KAD.", "One", "nonsynonymous", "SNP", "was", "identified", "within", "the", "HECW2", "gene.", "However,", "as", "this", "mutation", "was", "found", "in", "homozygous", "state", "in", "individuals", "with", "normal", "sperm,", "this", "is", "not", "likely", "to", "be", "the", "causal", "mutation.", "Conclusions:", "In", "this", "study", "we", "identified", "two", "candidate", "genes", "for", "a", "severe", "defect", "affecting", "both", "the", "sperm", "acrosome", "and", "chromatin", "that", "causes", "infertility.", "One", "of", "these", "genes,", "HECW2,", "plays", "an", "important", "role", "in", "ubiquitination,", "a", "prerequisite", "for", "chromatin", "remodelling", "and", "acrosome", "formation,", "highlighting", "the", "involvement", "of", "this", "gene", "in", "the", "knobbed", "acrosome", "defect", "and", "male", "infertility.", "Background", "Male", "infertility", "is", "becoming", "increasingly", "prevalent", "partly", "due", "to", "environmental", "factors,", "but", "many", "defects", "in", "sperm", "development", "arise", "from", "a", "genetic", "cause.", "Problems", "in", "the", "production", "and", "maturation", "of", "sperm", "are", "the", "most", "common", "causes", "of", "male", "infertility", "resulting", "in", "low", "sperm", "numbers,", "morphologically", "abnormal", "sperm", "or", "low", "sperm", "motility", "[1-3].", "Despite", "efforts", "to", "reveal", "the", "genes", "and", "their", "functions", "in", "spermatogenesis,", "little", "is", "known", "about", "the", "underlying", "causes", "of", "male", "infertility.", "Therefore,", "the", "localization", "and", "identification", "of", "muta-", "tions", "specifically", "affecting", "spermatogenesis", "provide", "*", "Correspondence:", "anu.sironen@mtt.fi", "1Agrifood", "Research", "Finland,", "MTT,", "Biotechnology", "and", "Food", "Research,", "Genomics,", "FI-36100", "Jokioinen,", "Finland", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "invaluable", "information", "for", "investigating", "the", "causes", "of", "male", "infertility.", "Mammalian", "spermatogenesis", "is", "a", "complex", "process,", "where", "diploid", "spermatogonia", "develop", "into", "haploid,", "highly", "specialized", "spermatozoa.", "Spermatogenesis", "includes", "many", "testis-specific", "processes", "that", "are", "controlled", "by", "complex", "regulatory", "mechanisms", "[4,5].", "During", "spermiogenesis,", "hap-", "loid", "round", "spermatids", "undergo", "dramatic", "biochemical", "and", "morphological", "changes", "that", "are", "governed", "by", "specialized", "gene", "expression", "and", "interactions", "between", "various", "genes", "and", "their", "protein", "products", "[6].", "Identification", "of", "genes", "involved", "in", "sperm", "development", "is", "a", "prerequisite", "to", "under-", "standing", "the", "molecular", "mechanisms", "of", "spermatogenesis.", "Sperm", "development", "is", "known", "to", "be", "disrupted", "during", "spermiogenesis", "in", "several", "acrosomal", "defects;", "e.g.", "globo-", "zoospermia", "in", "humans,", "where", "spermatozoa", "lack", "an", "©", "2010", "Sironen", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 70, 45, 20, 12 ], [ 93, 45, 29, 12 ], [ 124, 45, 48, 12 ], [ 175, 45, 32, 12 ], [ 209, 45, 63, 12 ], [ 70, 61, 21, 12 ], [ 95, 61, 135, 12 ], [ 78, 90, 10, 14 ], [ 89, 90, 9, 14 ], [ 99, 90, 5, 14 ], [ 105, 90, 10, 14 ], [ 116, 90, 5, 14 ], [ 122, 90, 10, 14 ], [ 132, 90, 10, 14 ], [ 143, 90, 9, 14 ], [ 157, 90, 8, 14 ], [ 166, 90, 10, 14 ], [ 177, 90, 8, 14 ], [ 185, 90, 9, 14 ], [ 195, 90, 9, 14 ], [ 70, 146, 130, 23 ], [ 206, 146, 82, 23 ], [ 293, 146, 29, 23 ], [ 327, 146, 73, 23 ], [ 405, 146, 19, 23 ], [ 429, 146, 167, 23 ], [ 70, 171, 104, 23 ], [ 180, 171, 19, 23 ], [ 204, 171, 50, 23 ], [ 259, 171, 46, 23 ], [ 310, 171, 153, 23 ], [ 468, 171, 46, 23 ], [ 70, 219, 56, 14 ], [ 130, 219, 86, 14 ], [ 219, 219, 4, 14 ], [ 225, 219, 33, 14 ], [ 261, 219, 58, 14 ], [ 323, 219, 4, 14 ], [ 330, 219, 20, 16 ], [ 353, 219, 39, 14 ], [ 70, 338, 48, 12 ], [ 121, 338, 6, 12 ], [ 130, 338, 20, 12 ], [ 152, 338, 24, 12 ], [ 179, 338, 4, 12 ], [ 185, 338, 48, 12 ], [ 236, 338, 12, 12 ], [ 250, 338, 35, 12 ], [ 288, 338, 24, 12 ], [ 314, 338, 4, 12 ], [ 320, 338, 47, 12 ], [ 370, 338, 33, 12 ], [ 406, 338, 6, 12 ], [ 415, 338, 51, 12 ], [ 468, 338, 24, 12 ], [ 70, 353, 0, 12 ], [ 84, 352, 77, 12 ], [ 164, 352, 24, 12 ], [ 70, 391, 52, 14 ], [ 136, 391, 29, 14 ], [ 168, 391, 50, 14 ], [ 220, 391, 17, 14 ], [ 240, 391, 7, 14 ], [ 250, 391, 41, 14 ], [ 294, 391, 33, 14 ], [ 329, 391, 12, 14 ], [ 344, 391, 28, 14 ], [ 375, 391, 27, 14 ], [ 70, 409, 59, 14 ], [ 135, 409, 92, 14 ], [ 233, 409, 75, 14 ], [ 313, 409, 14, 14 ], [ 333, 409, 40, 14 ], [ 378, 409, 24, 14 ], [ 70, 423, 24, 17 ], [ 99, 426, 48, 14 ], [ 152, 426, 20, 14 ], [ 177, 426, 12, 14 ], [ 193, 426, 34, 14 ], [ 232, 426, 10, 14 ], [ 246, 426, 7, 14 ], [ 257, 426, 58, 14 ], [ 320, 426, 12, 14 ], [ 336, 426, 17, 14 ], [ 358, 426, 44, 14 ], [ 70, 443, 36, 14 ], [ 115, 443, 22, 14 ], [ 145, 443, 21, 14 ], [ 174, 443, 92, 14 ], [ 274, 443, 27, 14 ], [ 309, 443, 42, 14 ], [ 360, 443, 42, 14 ], [ 70, 461, 34, 14 ], [ 109, 461, 38, 14 ], [ 152, 461, 17, 14 ], [ 173, 461, 51, 14 ], [ 228, 461, 21, 14 ], [ 253, 461, 35, 14 ], [ 292, 461, 38, 14 ], [ 335, 461, 17, 14 ], [ 356, 461, 46, 14 ], [ 70, 478, 24, 14 ], [ 99, 478, 49, 14 ], [ 153, 478, 49, 14 ], [ 207, 478, 89, 14 ], [ 301, 478, 12, 14 ], [ 318, 478, 29, 14 ], [ 352, 478, 50, 14 ], [ 70, 495, 27, 14 ], [ 102, 495, 40, 14 ], [ 146, 495, 28, 14 ], [ 179, 495, 41, 14 ], [ 224, 495, 47, 14 ], [ 276, 495, 21, 14 ], [ 302, 495, 22, 14 ], [ 328, 495, 12, 14 ], [ 345, 495, 26, 14 ], [ 375, 495, 27, 14 ], [ 70, 513, 37, 14 ], [ 110, 513, 29, 14 ], [ 143, 513, 18, 14 ], [ 163, 513, 36, 14 ], [ 203, 513, 47, 14 ], [ 253, 513, 34, 14 ], [ 290, 513, 20, 14 ], [ 314, 513, 38, 14 ], [ 355, 513, 47, 14 ], [ 70, 530, 20, 14 ], [ 96, 530, 75, 14 ], [ 176, 530, 28, 14 ], [ 209, 530, 43, 14 ], [ 257, 530, 12, 14 ], [ 275, 530, 20, 14 ], [ 300, 530, 33, 14 ], [ 338, 530, 17, 14 ], [ 360, 530, 42, 14 ], [ 70, 548, 31, 14 ], [ 104, 548, 7, 14 ], [ 115, 548, 60, 14 ], [ 178, 548, 21, 14 ], [ 203, 548, 21, 14 ], [ 227, 548, 36, 14 ], [ 266, 548, 57, 14 ], [ 326, 548, 14, 14 ], [ 343, 548, 34, 14 ], [ 380, 548, 21, 14 ], [ 70, 565, 10, 14 ], [ 84, 565, 40, 14 ], [ 128, 565, 18, 14 ], [ 150, 565, 27, 14 ], [ 181, 565, 22, 14 ], [ 207, 565, 12, 14 ], [ 223, 565, 18, 14 ], [ 244, 565, 29, 14 ], [ 277, 565, 58, 14 ], [ 339, 565, 12, 14 ], [ 355, 565, 7, 14 ], [ 366, 565, 36, 14 ], [ 70, 582, 17, 14 ], [ 91, 582, 64, 14 ], [ 159, 582, 60, 14 ], [ 223, 582, 12, 14 ], [ 239, 582, 85, 14 ], [ 328, 582, 45, 14 ], [ 377, 582, 25, 14 ], [ 70, 600, 30, 14 ], [ 105, 600, 47, 14 ], [ 157, 600, 14, 14 ], [ 176, 600, 17, 14 ], [ 199, 600, 51, 14 ], [ 255, 600, 75, 14 ], [ 335, 600, 39, 14 ], [ 380, 600, 22, 14 ], [ 70, 617, 68, 14 ], [ 144, 617, 49, 14 ], [ 198, 617, 45, 14 ], [ 248, 617, 12, 14 ], [ 265, 617, 71, 14 ], [ 340, 617, 44, 14 ], [ 390, 617, 12, 14 ], [ 70, 632, 70, 17 ], [ 145, 634, 29, 14 ], [ 178, 634, 65, 14 ], [ 247, 634, 11, 14 ], [ 263, 634, 7, 14 ], [ 274, 634, 35, 14 ], [ 313, 634, 28, 14 ], [ 346, 634, 56, 14 ], [ 70, 652, 58, 14 ], [ 136, 652, 20, 14 ], [ 164, 652, 69, 14 ], [ 241, 652, 12, 14 ], [ 260, 652, 58, 14 ], [ 326, 652, 47, 14 ], [ 380, 652, 21, 14 ], [ 70, 669, 35, 14 ], [ 109, 669, 20, 14 ], [ 132, 669, 29, 14 ], [ 164, 669, 34, 14 ], [ 201, 669, 55, 14 ], [ 260, 669, 36, 14 ], [ 299, 669, 7, 14 ], [ 309, 669, 38, 14 ], [ 350, 669, 51, 14 ], [ 70, 686, 12, 14 ], [ 88, 686, 49, 14 ], [ 142, 686, 45, 14 ], [ 192, 686, 30, 14 ], [ 228, 686, 27, 14 ], [ 260, 686, 73, 14 ], [ 339, 686, 63, 14 ], [ 70, 704, 39, 14 ], [ 113, 704, 21, 14 ], [ 138, 704, 17, 14 ], [ 159, 704, 36, 14 ], [ 198, 704, 47, 14 ], [ 249, 704, 35, 14 ], [ 287, 704, 20, 14 ], [ 310, 704, 35, 14 ], [ 349, 704, 10, 14 ], [ 362, 704, 40, 14 ], [ 70, 721, 27, 14 ], [ 102, 721, 29, 14 ], [ 135, 721, 58, 14 ], [ 197, 721, 21, 14 ], [ 221, 721, 43, 14 ], [ 268, 721, 21, 14 ], [ 293, 721, 21, 14 ], [ 317, 721, 42, 14 ], [ 363, 721, 10, 14 ], [ 376, 721, 25, 14 ], [ 70, 775, 73, 12 ], [ 145, 775, 12, 12 ], [ 160, 775, 29, 12 ], [ 192, 775, 66, 12 ], [ 70, 804, 52, 12 ], [ 125, 804, 76, 12 ], [ 203, 804, 43, 12 ], [ 258, 804, 19, 12 ], [ 279, 804, 30, 12 ], [ 312, 804, 35, 12 ], [ 350, 804, 10, 12 ], [ 362, 804, 17, 12 ], [ 70, 818, 30, 12 ], [ 103, 818, 162, 12 ], [ 267, 818, 40, 12 ], [ 309, 818, 70, 12 ], [ 70, 832, 42, 12 ], [ 115, 832, 29, 12 ], [ 147, 832, 8, 12 ], [ 158, 832, 43, 12 ], [ 203, 832, 10, 12 ], [ 215, 832, 50, 12 ], [ 268, 832, 28, 12 ], [ 70, 860, 12, 12 ], [ 85, 860, 68, 12 ], [ 155, 860, 3, 12 ], [ 161, 860, 10, 12 ], [ 174, 860, 46, 12 ], [ 223, 860, 3, 12 ], [ 229, 860, 8, 12 ], [ 239, 860, 31, 12 ], [ 273, 860, 22, 13 ], [ 70, 874, 39, 12 ], [ 112, 874, 10, 12 ], [ 125, 874, 25, 12 ], [ 152, 874, 49, 12 ], [ 204, 874, 42, 12 ], [ 70, 888, 39, 12 ], [ 112, 888, 32, 12 ], [ 146, 888, 34, 12 ], [ 183, 888, 59, 13 ], [ 244, 888, 15, 12 ], [ 70, 902, 30, 12 ], [ 103, 902, 30, 13 ], [ 135, 902, 57, 12 ], [ 195, 902, 30, 12 ], [ 227, 902, 43, 12 ], [ 70, 916, 34, 12 ], [ 107, 916, 97, 12 ], [ 70, 930, 27, 12 ], [ 100, 930, 155, 12 ], [ 70, 957, 12, 12 ], [ 85, 957, 68, 12 ], [ 70, 971, 36, 12 ], [ 109, 971, 10, 12 ], [ 122, 971, 40, 12 ], [ 164, 971, 50, 12 ], [ 217, 971, 10, 12 ], [ 230, 971, 28, 12 ], [ 260, 971, 46, 12 ], [ 70, 985, 30, 13 ], [ 103, 985, 57, 12 ], [ 163, 985, 30, 12 ], [ 195, 985, 43, 12 ], [ 425, 391, 40, 14 ], [ 468, 391, 50, 14 ], [ 522, 391, 20, 14 ], [ 546, 391, 11, 14 ], [ 561, 391, 30, 14 ], [ 595, 391, 33, 14 ], [ 631, 391, 42, 14 ], [ 677, 391, 25, 14 ], [ 706, 391, 10, 14 ], [ 720, 391, 20, 14 ], [ 744, 391, 12, 14 ], [ 425, 409, 25, 14 ], [ 453, 409, 21, 14 ], [ 478, 409, 38, 14 ], [ 519, 409, 30, 14 ], [ 552, 409, 12, 14 ], [ 567, 409, 40, 14 ], [ 610, 409, 27, 14 ], [ 640, 409, 92, 14 ], [ 735, 409, 21, 14 ], [ 425, 426, 18, 14 ], [ 447, 426, 25, 14 ], [ 477, 426, 20, 14 ], [ 502, 426, 34, 14 ], [ 541, 426, 44, 14 ], [ 590, 426, 26, 14 ], [ 620, 426, 18, 14 ], [ 643, 426, 42, 14 ], [ 690, 426, 28, 14 ], [ 722, 426, 12, 14 ], [ 739, 426, 17, 14 ], [ 425, 443, 55, 14 ], [ 484, 443, 38, 14 ], [ 527, 443, 60, 14 ], [ 591, 443, 24, 14 ], [ 620, 443, 62, 14 ], [ 686, 443, 34, 14 ], [ 725, 443, 31, 14 ], [ 425, 461, 18, 14 ], [ 446, 461, 33, 14 ], [ 482, 461, 11, 14 ], [ 496, 461, 28, 14 ], [ 527, 461, 42, 14 ], [ 572, 461, 36, 14 ], [ 425, 495, 61, 14 ], [ 499, 495, 81, 14 ], [ 583, 495, 4, 14 ], [ 590, 495, 75, 14 ], [ 668, 495, 4, 14 ], [ 675, 495, 47, 14 ], [ 725, 495, 4, 14 ], [ 425, 513, 56, 14 ], [ 484, 513, 58, 14 ], [ 545, 513, 4, 14 ], [ 552, 513, 35, 14 ], [ 590, 513, 44, 14 ], [ 425, 566, 76, 14 ], [ 425, 601, 30, 14 ], [ 461, 601, 46, 14 ], [ 513, 601, 34, 14 ], [ 553, 601, 36, 14 ], [ 595, 601, 91, 14 ], [ 692, 601, 51, 14 ], [ 750, 601, 7, 14 ], [ 425, 618, 33, 14 ], [ 460, 618, 12, 14 ], [ 475, 618, 39, 14 ], [ 516, 618, 40, 14 ], [ 559, 618, 50, 14 ], [ 611, 618, 74, 14 ], [ 687, 618, 14, 14 ], [ 704, 618, 7, 14 ], [ 714, 618, 42, 14 ], [ 425, 636, 21, 14 ], [ 450, 636, 94, 14 ], [ 547, 636, 31, 14 ], [ 582, 636, 12, 14 ], [ 598, 636, 71, 14 ], [ 673, 636, 53, 14 ], [ 730, 636, 26, 14 ], [ 425, 653, 48, 14 ], [ 476, 653, 12, 14 ], [ 491, 653, 17, 14 ], [ 511, 653, 45, 14 ], [ 558, 653, 48, 14 ], [ 608, 653, 40, 14 ], [ 651, 653, 70, 14 ], [ 724, 653, 12, 14 ], [ 739, 653, 17, 14 ], [ 425, 670, 49, 14 ], [ 478, 670, 30, 14 ], [ 512, 670, 22, 14 ], [ 539, 670, 34, 14 ], [ 577, 670, 20, 14 ], [ 602, 670, 62, 14 ], [ 668, 670, 60, 14 ], [ 733, 670, 12, 14 ], [ 750, 670, 7, 14 ], [ 425, 688, 24, 14 ], [ 454, 688, 44, 14 ], [ 504, 688, 22, 14 ], [ 531, 688, 17, 14 ], [ 554, 688, 47, 14 ], [ 607, 688, 22, 14 ], [ 635, 688, 35, 14 ], [ 675, 688, 34, 14 ], [ 715, 688, 41, 14 ], [ 425, 705, 57, 14 ], [ 488, 705, 56, 14 ], [ 551, 705, 16, 14 ], [ 575, 705, 73, 14 ], [ 655, 703, 28, 17 ], [ 690, 705, 17, 14 ], [ 714, 705, 42, 14 ], [ 425, 723, 36, 14 ], [ 464, 723, 52, 14 ], [ 521, 723, 51, 14 ], [ 575, 723, 45, 14 ], [ 624, 723, 25, 14 ], [ 653, 723, 52, 14 ], [ 709, 723, 12, 14 ], [ 725, 723, 31, 14 ], [ 425, 740, 31, 14 ], [ 459, 740, 55, 14 ], [ 517, 740, 22, 14 ], [ 542, 740, 21, 14 ], [ 566, 740, 26, 14 ], [ 595, 740, 32, 14 ], [ 630, 740, 17, 14 ], [ 650, 740, 45, 14 ], [ 697, 740, 39, 14 ], [ 739, 740, 17, 14 ], [ 425, 757, 14, 14 ], [ 441, 757, 51, 14 ], [ 495, 757, 12, 14 ], [ 510, 757, 53, 14 ], [ 566, 757, 47, 14 ], [ 616, 757, 20, 14 ], [ 639, 757, 29, 14 ], [ 671, 757, 60, 14 ], [ 734, 757, 22, 14 ], [ 425, 775, 18, 14 ], [ 446, 775, 26, 14 ], [ 476, 775, 45, 14 ], [ 524, 775, 49, 14 ], [ 575, 775, 46, 14 ], [ 625, 775, 32, 14 ], [ 660, 775, 40, 14 ], [ 703, 775, 53, 14 ], [ 425, 792, 72, 14 ], [ 499, 792, 50, 14 ], [ 552, 792, 20, 14 ], [ 575, 792, 50, 14 ], [ 628, 792, 36, 14 ], [ 666, 792, 41, 14 ], [ 710, 792, 20, 14 ], [ 732, 792, 24, 14 ], [ 425, 809, 42, 14 ], [ 470, 809, 17, 14 ], [ 491, 809, 85, 14 ], [ 580, 809, 30, 14 ], [ 613, 809, 22, 14 ], [ 638, 809, 30, 14 ], [ 672, 809, 20, 14 ], [ 696, 809, 49, 14 ], [ 748, 809, 8, 14 ], [ 425, 827, 22, 14 ], [ 452, 827, 17, 14 ], [ 475, 827, 47, 14 ], [ 528, 827, 70, 14 ], [ 604, 827, 63, 14 ], [ 672, 827, 12, 14 ], [ 690, 827, 17, 14 ], [ 713, 827, 43, 14 ], [ 425, 844, 36, 14 ], [ 464, 844, 10, 14 ], [ 476, 844, 45, 14 ], [ 525, 844, 27, 14 ], [ 555, 844, 7, 14 ], [ 565, 844, 33, 14 ], [ 601, 844, 20, 14 ], [ 624, 844, 14, 14 ], [ 642, 844, 58, 14 ], [ 703, 844, 30, 14 ], [ 736, 844, 20, 14 ], [ 425, 861, 56, 14 ], [ 485, 861, 56, 14 ], [ 544, 861, 45, 14 ], [ 593, 861, 17, 14 ], [ 613, 861, 46, 14 ], [ 663, 861, 27, 14 ], [ 694, 861, 7, 14 ], [ 704, 861, 52, 14 ], [ 425, 879, 64, 14 ], [ 491, 879, 15, 14 ], [ 508, 879, 17, 14 ], [ 528, 879, 34, 14 ], [ 565, 879, 12, 14 ], [ 580, 879, 46, 14 ], [ 629, 879, 43, 14 ], [ 675, 879, 20, 14 ], [ 698, 879, 58, 14 ], [ 425, 896, 32, 14 ], [ 460, 896, 53, 14 ], [ 515, 896, 10, 14 ], [ 529, 896, 14, 14 ], [ 545, 896, 36, 14 ], [ 440, 914, 34, 14 ], [ 478, 914, 18, 14 ], [ 499, 914, 44, 14 ], [ 546, 914, 32, 14 ], [ 582, 914, 17, 14 ], [ 603, 914, 49, 14 ], [ 655, 914, 11, 14 ], [ 670, 914, 15, 14 ], [ 688, 914, 68, 14 ], [ 425, 931, 27, 14 ], [ 455, 931, 96, 14 ], [ 554, 931, 28, 14 ], [ 586, 931, 17, 14 ], [ 607, 928, 61, 17 ], [ 671, 931, 11, 14 ], [ 686, 931, 17, 14 ], [ 707, 931, 49, 14 ], [ 425, 948, 12, 14 ], [ 443, 948, 26, 14 ], [ 475, 948, 38, 14 ], [ 519, 948, 45, 14 ], [ 569, 948, 35, 14 ], [ 609, 948, 17, 14 ], [ 633, 948, 49, 14 ], [ 688, 948, 11, 14 ], [ 705, 948, 34, 14 ], [ 744, 948, 12, 14 ], [ 425, 966, 47, 14 ], [ 477, 966, 71, 14 ], [ 555, 966, 12, 14 ], [ 572, 966, 51, 14 ], [ 629, 966, 42, 14 ], [ 677, 966, 42, 14 ], [ 725, 966, 31, 14 ], [ 425, 983, 18, 14 ], [ 450, 983, 53, 14 ], [ 512, 983, 45, 14 ], [ 565, 983, 47, 14 ], [ 620, 983, 11, 14 ], [ 639, 983, 17, 14 ], [ 665, 983, 21, 14 ], [ 695, 983, 36, 14 ], [ 739, 983, 17, 14 ], [ 699, 1017, 56, 21 ] ]

[ "Mol", "Genet", "Genomics", "(2008)", "280:427–436", "DOI", "10.1007/s00438-008-0376-8", "O", "R", "I", "G", "I", "N", "A", "L", "P", "A", "P", "E", "R", "Experimental", "evidence", "for", "splicing", "of", "intron-containing", "transcripts", "of", "plant", "LTR", "retrotransposon", "Ogre", "Veronika", "Steinbauerová", "·", "Pavel", "Neumann", "·", "Jilí", "Macas", "Received:", "8", "July", "2008", "/", "Accepted:", "19", "August", "2008", "/", "Published", "online:", "2", "September", "2008", "©", "Springer-Verlag", "2008", "Abstract", "Ogre", "elements", "are", "a", "distinct", "group", "of", "plant", "Ty3/", "gypsy-like", "retrotransposons", "characterized", "by", "several", "spe-", "ciWc", "features,", "one", "of", "which", "is", "a", "separation", "of", "the", "gag-pol", "region", "into", "two", "non-overlapping", "open", "reading", "frames:", "ORF2", "coding", "for", "Gag-Pro,", "and", "ORF3", "coding", "for", "RT/RH-", "INT", "proteins.", "Previous", "characterization", "of", "Ogre", "elements", "from", "several", "plant", "species", "revealed", "that", "part", "of", "their", "tran-", "scripts", "lacks", "the", "region", "between", "ORF2", "and", "ORF3,", "carrying", "one", "uninterrupted", "ORF", "instead.", "In", "this", "work,", "we", "investi-", "gated", "a", "hypothesis", "that", "this", "region", "represents", "an", "intron", "that", "is", "spliced", "out", "from", "part", "of", "the", "Ogre", "transcripts", "as", "a", "means", "for", "preferential", "production", "of", "ORF2-encoded", "proteins", "over", "those", "encoded", "by", "the", "complete", "ORF2–ORF3", "region.", "The", "experiments", "involved", "analysis", "of", "transcription", "patterns", "of", "well-deWned", "Ogre", "populations", "in", "a", "model", "plant", "Medicago", "truncatula", "and", "examination", "of", "transcripts", "carrying", "dis-", "sected", "pea", "Ogre", "intron", "expressed", "within", "a", "coding", "sequence", "of", "chimeric", "reporter", "gene.", "Both", "experimental", "approaches", "proved", "that", "the", "region", "between", "ORF2", "and", "ORF3", "is", "spliced", "from", "Ogre", "transcripts", "and", "showed", "that", "this", "process", "is", "only", "Communicated", "by", "M.-A.", "Grandbastien.", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s00438-008-0376-8)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "V.", "Steinbauerová", "·", "P.", "Neumann", "·", "J.", "Macas", "(&)", "Institute", "of", "Plant", "Molecular", "Biology,", "Biology", "Centre", "ASCR,", "Braninovská", "31,", "37005", "Beské", "Bud5jovice,", "Czech", "Republic", "e-mail:", "macas@umbr.cas.cz", "URL:", "http://w3lamc.umbr.cas.cz/lamc/", "V.", "Steinbauerová", "Faculty", "of", "Science,", "University", "of", "South", "Bohemia,", "Beské", "Bud5jovice,", "Czech", "Republic", "partial,", "probably", "due", "to", "weak", "splice", "signals.", "This", "is", "one", "of", "very", "few", "known", "cases", "of", "spliced", "LTR", "retrotransposons", "and", "the", "only", "one", "where", "splicing", "does", "not", "involve", "parts", "of", "the", "element’s", "coding", "sequences,", "thus", "resembling", "intron", "splic-", "ing", "found", "in", "most", "cellular", "genes.", "Keywords", "Retroelements", "·", "Transcription", "·", "Splicing", "·", "Medicago", "truncatula", "·", "Pisum", "sativum", "Introduction", "Long", "terminal", "repeat", "(LTR)", "retrotransposons", "represent", "a", "group", "of", "mobile", "genetic", "elements", "characterized", "by", "a", "replica-", "tive", "(copy-and-paste)", "mode", "of", "transposition", "involving", "tran-", "scription", "of", "the", "parental", "element,", "reverse", "transcription", "of", "the", "resulting", "RNA", "into", "DNA,", "and", "subsequent", "integration", "of", "a", "new", "element", "into", "the", "genome.", "The", "LTRs,", "which", "contain", "regulatory", "sequences", "for", "transcription,", "Xank", "the", "internal", "region", "(gag-pol)", "encoding", "proteins", "with", "structural", "or", "enzy-", "matic", "functions.", "The", "gag", "gene", "codes", "for", "proteins", "needed", "for", "an", "assembly", "of", "virus-like", "particles", "and", "RNA", "packaging.", "The", "pol", "gene", "encodes", "enzymes", "protease", "(Pro),", "reverse", "transcrip-", "tase/RNaseH", "(RT/RH)", "and", "integrase", "(INT).", "RT/RH", "and", "INT", "convert", "the", "retrotransposon", "RNA", "into", "DNA", "and", "integrate", "it", "into", "the", "genome,", "respectively.", "Translation", "of", "the", "gag-pol", "region", "is", "initiated", "from", "a", "single", "site", "on", "full-length", "RNA", "and", "individual", "functional", "proteins", "are", "released", "from", "a", "precursor", "polyprotein", "by", "the", "action", "of", "protease", "(Kumar", "and", "Bennetzen", "1999;", "Havecker", "et", "al.", "2004).", "While", "the", "gag-pol", "genes", "are", "common", "to", "all", "autonomous", "LTR", "retrotransposons,", "there", "are", "diVerences", "in", "the", "structure", "of", "their", "coding", "regions,", "which", "are", "arranged", "in", "single", "or", "multiple", "(overlapping", "or", "adjacent)", "reading", "frames.", "Since", "the", "structural", "proteins", "encoded", "in", "the", "gag", "region", "are", "123" ]

[ 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 11, 11, 11, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4 ]

[ [ 90, 71, 75, 19 ], [ 171, 71, 38, 19 ], [ 90, 93, 190, 34 ], [ 291, 93, 54, 34 ], [ 356, 93, 132, 34 ], [ 498, 93, 124, 34 ], [ 633, 93, 92, 34 ], [ 90, 129, 183, 34 ], [ 284, 129, 134, 34 ], [ 429, 129, 28, 34 ], [ 468, 129, 99, 34 ], [ 90, 165, 190, 34 ], [ 90, 221, 31, 20 ], [ 127, 218, 72, 23 ], [ 205, 221, 47, 20 ], [ 257, 218, 48, 23 ], [ 311, 221, 55, 20 ], [ 373, 218, 76, 23 ], [ 455, 221, 60, 20 ], [ 520, 221, 30, 20 ], [ 557, 221, 40, 20 ], [ 596, 218, 7, 13 ], [ 602, 221, 6, 20 ], [ 614, 220, 34, 21 ], [ 653, 221, 50, 20 ], [ 90, 240, 70, 23 ], [ 166, 244, 64, 20 ], [ 237, 244, 48, 20 ], [ 284, 240, 7, 13 ], [ 290, 244, 6, 20 ], [ 302, 244, 50, 20 ], [ 359, 240, 84, 23 ], [ 90, 277, 74, 17 ], [ 168, 280, 12, 14 ], [ 184, 280, 80, 14 ], [ 269, 280, 23, 14 ], [ 296, 280, 84, 14 ], [ 383, 280, 23, 14 ], [ 410, 277, 75, 17 ], [ 490, 280, 12, 14 ], [ 506, 280, 85, 14 ], [ 595, 280, 23, 14 ], [ 621, 280, 44, 14 ], [ 669, 280, 77, 14 ], [ 90, 296, 42, 15 ], [ 137, 296, 5, 14 ], [ 145, 296, 121, 15 ], [ 271, 296, 39, 14 ], [ 314, 296, 53, 14 ], [ 90, 340, 23, 14 ], [ 119, 340, 23, 14 ], [ 147, 340, 12, 14 ], [ 165, 340, 30, 14 ], [ 200, 340, 67, 14 ], [ 273, 340, 10, 14 ], [ 288, 340, 8, 14 ], [ 302, 340, 54, 14 ], [ 362, 340, 47, 14 ], [ 415, 340, 11, 14 ], [ 431, 340, 38, 14 ], [ 475, 340, 26, 14 ], [ 506, 340, 51, 14 ], [ 563, 340, 20, 14 ], [ 589, 340, 39, 14 ], [ 633, 340, 83, 14 ], [ 722, 340, 24, 14 ], [ 90, 357, 60, 14 ], [ 155, 357, 59, 14 ], [ 219, 357, 22, 14 ], [ 246, 357, 12, 14 ], [ 263, 357, 20, 14 ], [ 288, 357, 30, 14 ], [ 323, 357, 62, 14 ], [ 390, 357, 31, 14 ], [ 426, 357, 67, 14 ], [ 499, 357, 25, 14 ], [ 529, 357, 27, 14 ], [ 561, 357, 49, 14 ], [ 615, 357, 24, 14 ], [ 644, 357, 21, 14 ], [ 670, 357, 47, 14 ], [ 723, 357, 23, 14 ], [ 90, 374, 52, 14 ], [ 145, 374, 12, 14 ], [ 160, 374, 22, 14 ], [ 185, 374, 34, 14 ], [ 223, 374, 25, 14 ], [ 251, 374, 12, 14 ], [ 266, 374, 53, 14 ], [ 321, 374, 20, 14 ], [ 344, 374, 42, 14 ], [ 389, 374, 12, 14 ], [ 404, 374, 28, 14 ], [ 435, 374, 67, 14 ], [ 506, 374, 16, 14 ], [ 525, 374, 20, 14 ], [ 547, 374, 76, 14 ], [ 626, 374, 80, 14 ], [ 708, 374, 38, 14 ], [ 90, 390, 58, 14 ], [ 157, 390, 12, 14 ], [ 178, 390, 43, 14 ], [ 230, 390, 89, 14 ], [ 327, 390, 88, 14 ], [ 424, 390, 31, 14 ], [ 463, 390, 49, 14 ], [ 521, 390, 28, 14 ], [ 558, 390, 52, 14 ], [ 619, 390, 43, 14 ], [ 670, 390, 30, 14 ], [ 710, 390, 37, 14 ], [ 90, 407, 69, 14 ], [ 163, 407, 11, 14 ], [ 178, 407, 50, 14 ], [ 231, 407, 44, 14 ], [ 279, 407, 24, 14 ], [ 307, 407, 63, 14 ], [ 373, 407, 17, 14 ], [ 394, 407, 16, 14 ], [ 413, 407, 24, 14 ], [ 442, 407, 16, 14 ], [ 461, 407, 49, 14 ], [ 514, 407, 25, 14 ], [ 543, 407, 83, 14 ], [ 630, 407, 53, 14 ], [ 687, 407, 60, 14 ], [ 90, 424, 55, 14 ], [ 153, 424, 34, 14 ], [ 194, 424, 13, 14 ], [ 214, 424, 124, 14 ], [ 345, 424, 36, 14 ], [ 389, 424, 36, 14 ], [ 433, 424, 17, 14 ], [ 457, 424, 46, 14 ], [ 511, 424, 82, 14 ], [ 601, 424, 38, 14 ], [ 646, 424, 67, 14 ], [ 721, 424, 25, 14 ], [ 90, 440, 62, 14 ], [ 157, 440, 48, 14 ], [ 209, 440, 27, 14 ], [ 241, 440, 76, 14 ], [ 322, 440, 50, 14 ], [ 377, 440, 12, 14 ], [ 394, 440, 39, 14 ], [ 437, 440, 27, 14 ], [ 469, 440, 53, 14 ], [ 526, 440, 24, 14 ], [ 555, 440, 48, 14 ], [ 608, 440, 24, 14 ], [ 637, 440, 74, 14 ], [ 716, 440, 30, 14 ], [ 90, 457, 56, 14 ], [ 152, 457, 16, 14 ], [ 174, 457, 70, 14 ], [ 250, 457, 54, 14 ], [ 310, 457, 87, 14 ], [ 404, 457, 49, 14 ], [ 458, 457, 8, 14 ], [ 473, 457, 67, 14 ], [ 546, 457, 51, 14 ], [ 603, 457, 12, 14 ], [ 621, 457, 27, 14 ], [ 654, 457, 58, 14 ], [ 718, 457, 28, 14 ], [ 90, 473, 60, 14 ], [ 156, 473, 59, 14 ], [ 220, 473, 41, 14 ], [ 267, 473, 31, 14 ], [ 303, 473, 12, 14 ], [ 321, 473, 50, 14 ], [ 377, 473, 12, 14 ], [ 394, 473, 27, 14 ], [ 427, 473, 43, 14 ], [ 475, 473, 20, 14 ], [ 500, 473, 22, 14 ], [ 528, 473, 48, 14 ], [ 581, 473, 21, 14 ], [ 608, 473, 28, 14 ], [ 641, 473, 27, 14 ], [ 674, 473, 20, 14 ], [ 699, 473, 20, 14 ], [ 725, 473, 22, 14 ], [ 90, 490, 74, 14 ], [ 168, 490, 48, 14 ], [ 220, 490, 53, 14 ], [ 277, 490, 20, 14 ], [ 301, 490, 48, 14 ], [ 353, 490, 83, 14 ], [ 440, 490, 23, 14 ], [ 466, 490, 32, 14 ], [ 502, 490, 30, 14 ], [ 536, 490, 54, 14 ], [ 593, 490, 27, 14 ], [ 624, 490, 60, 14 ], [ 687, 490, 59, 14 ], [ 90, 507, 40, 14 ], [ 134, 507, 16, 14 ], [ 153, 507, 20, 14 ], [ 175, 507, 24, 14 ], [ 202, 507, 24, 14 ], [ 229, 507, 20, 14 ], [ 252, 507, 22, 14 ], [ 277, 507, 48, 14 ], [ 328, 507, 24, 14 ], [ 355, 507, 74, 14 ], [ 433, 507, 25, 14 ], [ 461, 507, 20, 14 ], [ 484, 507, 44, 14 ], [ 530, 507, 16, 14 ], [ 549, 507, 20, 14 ], [ 572, 507, 72, 14 ], [ 647, 507, 12, 14 ], [ 662, 507, 20, 14 ], [ 685, 507, 61, 14 ], [ 90, 523, 96, 14 ], [ 190, 523, 20, 14 ], [ 214, 523, 34, 14 ], [ 252, 523, 51, 14 ], [ 307, 523, 12, 14 ], [ 324, 523, 39, 14 ], [ 367, 523, 27, 14 ], [ 398, 523, 49, 14 ], [ 451, 523, 12, 14 ], [ 468, 523, 44, 14 ], [ 516, 523, 85, 14 ], [ 606, 523, 57, 14 ], [ 667, 523, 8, 14 ], [ 679, 523, 67, 14 ], [ 90, 540, 107, 14 ], [ 201, 540, 38, 14 ], [ 244, 540, 58, 14 ], [ 306, 540, 16, 14 ], [ 326, 540, 83, 14 ], [ 414, 540, 32, 14 ], [ 450, 540, 27, 14 ], [ 481, 540, 16, 14 ], [ 501, 540, 60, 14 ], [ 565, 540, 55, 14 ], [ 624, 540, 24, 14 ], [ 653, 540, 47, 14 ], [ 90, 567, 50, 10 ], [ 142, 567, 50, 10 ], [ 195, 567, 32, 10 ], [ 230, 567, 61, 10 ], [ 293, 567, 42, 10 ], [ 338, 567, 40, 10 ], [ 381, 567, 61, 10 ], [ 445, 567, 62, 10 ], [ 90, 611, 81, 16 ], [ 90, 631, 54, 14 ], [ 148, 631, 40, 14 ], [ 191, 631, 45, 14 ], [ 239, 631, 24, 14 ], [ 267, 631, 51, 14 ], [ 321, 631, 23, 14 ], [ 347, 631, 28, 14 ], [ 378, 631, 28, 14 ], [ 90, 649, 57, 14 ], [ 154, 649, 31, 14 ], [ 192, 649, 33, 14 ], [ 232, 649, 29, 14 ], [ 269, 649, 69, 14 ], [ 344, 649, 26, 14 ], [ 378, 649, 28, 14 ], [ 90, 667, 75, 14 ], [ 169, 667, 93, 14 ], [ 266, 667, 14, 14 ], [ 284, 667, 63, 14 ], [ 351, 667, 25, 14 ], [ 380, 667, 26, 14 ], [ 90, 685, 29, 14 ], [ 122, 685, 13, 14 ], [ 138, 685, 20, 14 ], [ 160, 685, 28, 14 ], [ 191, 685, 57, 14 ], [ 251, 685, 35, 14 ], [ 289, 685, 19, 14 ], [ 311, 685, 35, 14 ], [ 348, 685, 58, 14 ], [ 90, 703, 18, 14 ], [ 111, 703, 60, 14 ], [ 174, 703, 13, 14 ], [ 190, 703, 66, 14 ], [ 259, 700, 64, 17 ], [ 325, 703, 13, 14 ], [ 341, 703, 50, 14 ], [ 393, 703, 13, 14 ], [ 90, 721, 74, 14 ], [ 168, 721, 13, 14 ], [ 185, 721, 29, 14 ], [ 219, 721, 77, 14 ], [ 300, 721, 19, 14 ], [ 323, 721, 66, 14 ], [ 393, 721, 13, 14 ], [ 90, 739, 28, 14 ], [ 128, 739, 60, 14 ], [ 199, 739, 9, 14 ], [ 218, 739, 7, 14 ], [ 236, 739, 51, 14 ], [ 297, 739, 59, 14 ], [ 366, 739, 12, 14 ], [ 388, 739, 18, 14 ], [ 90, 757, 57, 14 ], [ 155, 757, 13, 14 ], [ 175, 757, 28, 14 ], [ 210, 757, 61, 14 ], [ 278, 757, 23, 14 ], [ 309, 757, 29, 14 ], [ 346, 757, 60, 14 ], [ 90, 775, 27, 14 ], [ 120, 775, 62, 14 ], [ 184, 775, 13, 14 ], [ 199, 775, 28, 14 ], [ 230, 775, 28, 14 ], [ 260, 775, 23, 14 ], [ 285, 775, 41, 14 ], [ 328, 775, 57, 14 ], [ 387, 775, 19, 14 ], [ 90, 793, 82, 14 ], [ 176, 793, 23, 14 ], [ 204, 793, 56, 14 ], [ 264, 793, 55, 14 ], [ 323, 793, 13, 14 ], [ 341, 793, 48, 14 ], [ 393, 793, 13, 14 ], [ 90, 811, 55, 14 ], [ 155, 811, 65, 14 ], [ 229, 811, 25, 14 ], [ 263, 811, 15, 14 ], [ 288, 811, 20, 14 ], [ 318, 811, 31, 14 ], [ 359, 811, 47, 14 ], [ 90, 829, 71, 14 ], [ 170, 829, 22, 14 ], [ 202, 829, 69, 14 ], [ 280, 829, 28, 14 ], [ 318, 829, 60, 14 ], [ 388, 829, 18, 14 ], [ 90, 847, 32, 14 ], [ 132, 847, 43, 14 ], [ 184, 847, 13, 14 ], [ 206, 847, 55, 14 ], [ 270, 847, 61, 14 ], [ 341, 847, 20, 14 ], [ 370, 847, 12, 14 ], [ 392, 847, 14, 14 ], [ 90, 865, 65, 14 ], [ 165, 865, 18, 14 ], [ 192, 865, 31, 14 ], [ 232, 865, 32, 14 ], [ 274, 865, 43, 14 ], [ 326, 865, 24, 14 ], [ 360, 865, 46, 14 ], [ 90, 883, 35, 14 ], [ 130, 883, 10, 14 ], [ 145, 883, 15, 14 ], [ 166, 883, 48, 14 ], [ 220, 883, 60, 14 ], [ 285, 883, 48, 14 ], [ 339, 883, 67, 14 ], [ 90, 901, 13, 14 ], [ 110, 901, 47, 14 ], [ 164, 901, 23, 14 ], [ 193, 901, 44, 14 ], [ 245, 901, 42, 14 ], [ 294, 899, 95, 17 ], [ 395, 901, 10, 14 ], [ 90, 919, 41, 14 ], [ 137, 919, 14, 14 ], [ 158, 919, 51, 14 ], [ 216, 919, 25, 14 ], [ 248, 919, 19, 14 ], [ 273, 919, 27, 14 ], [ 306, 919, 13, 14 ], [ 326, 919, 80, 14 ], [ 90, 958, 72, 10 ], [ 167, 958, 11, 10 ], [ 183, 958, 17, 10 ], [ 205, 958, 35, 10 ], [ 244, 958, 29, 10 ], [ 279, 958, 12, 10 ], [ 295, 958, 69, 10 ], [ 369, 958, 37, 10 ], [ 90, 969, 53, 10 ], [ 146, 969, 54, 10 ], [ 203, 969, 31, 10 ], [ 237, 969, 43, 10 ], [ 283, 969, 38, 10 ], [ 323, 969, 28, 10 ], [ 354, 969, 52, 10 ], [ 90, 980, 9, 10 ], [ 101, 980, 27, 10 ], [ 131, 980, 28, 10 ], [ 162, 980, 43, 10 ], [ 208, 980, 27, 10 ], [ 238, 980, 104, 10 ], [ 430, 615, 44, 14 ], [ 480, 615, 27, 14 ], [ 512, 615, 29, 14 ], [ 545, 615, 63, 14 ], [ 613, 615, 40, 14 ], [ 659, 615, 14, 14 ], [ 678, 615, 49, 14 ], [ 732, 615, 14, 14 ], [ 430, 633, 23, 14 ], [ 465, 633, 14, 14 ], [ 483, 633, 46, 14 ], [ 542, 633, 13, 14 ], [ 567, 633, 54, 14 ], [ 633, 633, 29, 14 ], [ 674, 633, 48, 14 ], [ 734, 633, 13, 14 ], [ 430, 651, 48, 14 ], [ 485, 651, 23, 14 ], [ 514, 651, 43, 14 ], [ 563, 651, 13, 14 ], [ 582, 651, 28, 14 ], [ 616, 651, 75, 14 ], [ 697, 651, 49, 14 ], [ 430, 670, 24, 14 ], [ 460, 670, 30, 14 ], [ 496, 670, 50, 14 ], [ 553, 670, 52, 14 ], [ 612, 670, 36, 14 ], [ 654, 670, 19, 14 ], [ 679, 670, 67, 14 ], [ 430, 688, 18, 14 ], [ 455, 688, 41, 14 ], [ 503, 688, 23, 14 ], [ 532, 688, 28, 14 ], [ 567, 688, 62, 14 ], [ 636, 688, 19, 14 ], [ 661, 688, 85, 14 ], [ 430, 706, 76, 14 ], [ 514, 706, 23, 14 ], [ 545, 706, 90, 14 ], [ 642, 703, 76, 17 ], [ 726, 706, 20, 14 ], [ 430, 724, 29, 14 ], [ 464, 724, 52, 14 ], [ 521, 724, 20, 14 ], [ 547, 724, 37, 14 ], [ 589, 724, 57, 14 ], [ 652, 724, 64, 14 ], [ 720, 724, 26, 14 ], [ 430, 742, 27, 14 ], [ 463, 742, 19, 14 ], [ 487, 742, 99, 14 ], [ 591, 742, 54, 14 ], [ 650, 742, 13, 14 ], [ 668, 742, 78, 14 ], [ 430, 760, 12, 14 ], [ 451, 760, 80, 14 ], [ 540, 760, 23, 14 ], [ 571, 760, 45, 14 ], [ 625, 760, 34, 14 ], [ 667, 760, 19, 14 ], [ 695, 760, 51, 14 ], [ 430, 778, 37, 14 ], [ 478, 778, 23, 14 ], [ 512, 778, 71, 14 ], [ 594, 778, 64, 14 ], [ 669, 778, 48, 14 ], [ 728, 778, 19, 14 ], [ 430, 796, 80, 14 ], [ 516, 796, 23, 14 ], [ 544, 796, 74, 14 ], [ 624, 796, 40, 14 ], [ 669, 796, 31, 14 ], [ 706, 796, 15, 14 ], [ 726, 796, 20, 14 ], [ 430, 814, 45, 14 ], [ 486, 814, 23, 14 ], [ 520, 814, 18, 14 ], [ 549, 814, 19, 14 ], [ 579, 814, 60, 14 ], [ 650, 814, 13, 14 ], [ 673, 814, 73, 14 ], [ 430, 832, 77, 14 ], [ 515, 832, 36, 14 ], [ 560, 832, 10, 14 ], [ 578, 832, 61, 14 ], [ 647, 832, 18, 14 ], [ 673, 832, 19, 14 ], [ 700, 832, 46, 14 ], [ 430, 850, 39, 14 ], [ 478, 850, 19, 14 ], [ 505, 850, 80, 14 ], [ 594, 850, 23, 14 ], [ 625, 850, 19, 14 ], [ 652, 850, 73, 14 ], [ 734, 850, 13, 14 ], [ 430, 868, 74, 14 ], [ 510, 866, 88, 17 ], [ 603, 868, 86, 14 ], [ 694, 868, 15, 14 ], [ 714, 868, 33, 14 ], [ 430, 886, 45, 14 ], [ 480, 886, 13, 14 ], [ 496, 886, 78, 14 ], [ 579, 886, 54, 14 ], [ 636, 886, 39, 14 ], [ 679, 886, 12, 14 ], [ 695, 886, 51, 14 ], [ 430, 905, 47, 14 ], [ 482, 905, 27, 14 ], [ 513, 905, 19, 14 ], [ 536, 905, 23, 14 ], [ 563, 905, 13, 14 ], [ 581, 902, 102, 17 ], [ 444, 923, 27, 14 ], [ 479, 923, 13, 14 ], [ 499, 923, 19, 14 ], [ 524, 923, 30, 14 ], [ 561, 923, 63, 14 ], [ 631, 923, 27, 14 ], [ 665, 923, 62, 14 ], [ 735, 923, 12, 14 ], [ 430, 941, 34, 14 ], [ 470, 941, 28, 14 ], [ 503, 941, 44, 14 ], [ 553, 941, 19, 14 ], [ 577, 941, 79, 14 ], [ 662, 941, 23, 14 ], [ 690, 941, 56, 14 ], [ 430, 959, 55, 14 ], [ 493, 959, 60, 14 ], [ 559, 959, 44, 14 ], [ 610, 959, 31, 14 ], [ 648, 959, 65, 14 ], [ 720, 959, 27, 14 ], [ 430, 977, 35, 14 ], [ 471, 977, 19, 14 ], [ 495, 977, 38, 14 ], [ 538, 977, 13, 14 ], [ 556, 977, 62, 14 ], [ 624, 977, 16, 14 ], [ 645, 977, 42, 14 ], [ 692, 977, 55, 14 ], [ 100, 1020, 18, 9 ], [ 121, 1020, 34, 9 ], [ 158, 1020, 30, 9 ], [ 190, 1020, 11, 9 ], [ 205, 1020, 66, 9 ], [ 90, 1030, 23, 9 ], [ 116, 1030, 48, 9 ], [ 167, 1030, 30, 9 ], [ 200, 1030, 13, 9 ], [ 216, 1030, 20, 9 ], [ 238, 1030, 27, 9 ], [ 268, 1030, 15, 9 ], [ 285, 1030, 45, 9 ], [ 333, 1030, 23, 9 ], [ 359, 1030, 13, 9 ], [ 375, 1030, 23, 9 ], [ 400, 1030, 8, 9 ], [ 411, 1030, 13, 9 ], [ 427, 1030, 33, 9 ], [ 463, 1030, 39, 9 ], [ 505, 1030, 44, 9 ], [ 551, 1030, 30, 9 ], [ 584, 1030, 13, 9 ], [ 90, 1040, 15, 9 ], [ 107, 1040, 150, 9 ], [ 489, 1039, 33, 10 ], [ 526, 1039, 9, 10 ], [ 538, 1039, 77, 10 ], [ 635, 1039, 24, 10 ], [ 678, 1041, 16, 8 ], [ 696, 1039, 12, 10 ], [ 727, 1041, 12, 8 ], [ 741, 1039, 6, 10 ], [ 775, 1038, 13, 11 ] ]

[ "Technical", "Note", "Polyhexanide", "and", "hydrogen", "peroxide", "inhibit", "proteoglycan", "synthesis", "of", "human", "chondrocytes", "Eric", "Ro¨hner1,", "Paula", "Hoff2,", "Tobias", "Winkler1,", "Philipp", "von", "Roth", "1", ",", "Jo¨rn", "Bengt", "Seeger1,", "Carsten", "Perka", "1", ",", "Georg", "Matziolis1", "1Department", "of", "Traumatology", "and", "Orthopaedics,", "and", "2Department", "of", "Rheumatology", "and", "Clinical", "Immunology,", "Charite´", "-", "Universita¨tsmedizin,", "Berlin,", "Germany", "The", "use", "of", "local", "antiseptics", "is", "a", "common", "method", "in", "septic", "joint", "surgery.", "We", "tested", "polyhexanide", "and", "hydrogen", "peroxide,", "two", "of", "the", "most", "frequently", "used", "antiseptics", "with", "high", "efficacy", "and", "low", "toxicity.", "The", "purpose", "of", "this", "study", "was", "to", "evaluate", "the", "effects", "of", "both", "antiseptics", "on", "the", "extracellular", "cartilaginous", "matrix", "synthesis", "of", "human", "chondrocytes.", "Chondrocytes", "were", "isolated", "from", "donated", "human", "knee", "joints,", "embedded", "in", "alginate", "beads,", "and", "incubated", "for", "10", "and", "30", "minutes", "with", "polyhexanide", "(0.04%),", "hydrogen", "peroxide", "(3%),", "or", "phosphate-buffered", "saline", "(PBS)", "for", "control.", "Cartilaginous", "matrix", "production", "was", "quantified", "through", "light", "microscopic", "analysis", "of", "Alcian", "blue", "staining.", "Cell", "number", "and", "morphology", "were", "detected", "by", "histological", "analysis.", "Chondrocytes", "showed", "a", "decreased", "intensity", "of", "blue", "colouring", "after", "antiseptic", "treatment", "versus", "PBS.", "In", "contrast", "to", "that,", "neither", "the", "cell", "number", "per", "view", "field", "nor", "the", "cell", "morphology", "differed", "between", "the", "groups.", "Polyhexanide", "has", "more", "toxic", "potential", "than", "hydrogen", "peroxide.", "Based", "on", "the", "fact", "that", "the", "cell", "number", "and", "morphology", "was", "not", "altered", "by", "the", "substances", "at", "the", "examined", "concentrations,", "the", "lower", "intensity", "of", "Alcian", "blue", "staining", "of", "treated", "chondrocytes", "indicates", "a", "decreased", "cartilage-specific", "matrix", "synthesis", "by", "polyhexanide", "more", "than", "by", "hydrogen", "peroxide", "and", "control.", "Keywords:", "Antiseptics,", "Human", "chondrocytes,", "Hydrogen", "peroxide,", "Polyhexanide,", "Proteoglycans", "Introduction", "Different", "studies", "showed", "that", "shoulder", "and", "knee", "joint", "infections", "often", "result", "from", "infiltrations", "with", "local", "anaesthetics,", "glucocorticoids,", "or", "hyaluronic", "acid", "con-", "trary", "to", "hip", "joint", "infections", "which", "are", "rarely", "infiltrated", "for", "diagnostic", "or", "therapeutic", "reasons.1–3", "In", "addition", "to", "arthroscopic", "or", "open", "debridement,", "the", "application", "of", "local", "antiseptics", "is", "a", "standard", "procedure", "in", "the", "treatment", "of", "joint", "infections.", "The", "most", "frequently", "used", "antiseptics", "of", "local", "joint", "and", "wound", "infections", "are", "polyhexanide,", "and", "hydrogen", "peroxide.", "In", "contrast", "to", "antibiotic", "substances,", "they", "do", "not", "differ", "between", "procariontic", "and", "eukaryontic", "cells.", "Therefore,", "the", "tissue", "toxicity", "of", "antiseptic", "substances", "has", "to", "be", "determined", "for", "every", "tissue", "coming", "into", "contact.", "There", "is", "an", "ongoing", "discussion", "between", "elimination", "of", "bacteria", "and", "toxicity", "against", "chondrocytes.4,5", "It", "should", "be", "assumed", "that", "the", "time", "of", "chondrocytes", "Correspondence", "to:", "Eric", "Ro¨hner,", "Center", "for", "Musculoskeletal", "Surgery,", "Orthopaedic", "Department,", "Charite´", "University", "Hospital,", "Berlin,", "Charite´platz", "1,", "10117", "Berlin,", "Germany.", "Email:", "eric.roehner@charite.de", "contact", "with", "local", "antiseptics", "should", "be", "between", "10", "and", "30", "minutes", "to", "eliminate", "most", "colonies", "of", "bacteria", "and", "though", "to", "limit", "chondrocyte", "toxicity.", "The", "most", "frequent", "bacteria,", "which", "are", "responsible", "for", "wound", "and", "joint", "infections,", "are", "staphylococci,", "streptococci,", "and", "Gram-negative", "bacteria.1,6–8", "Be-", "sides", "inducing", "cell", "death,", "antiseptic", "substances", "may", "alter", "the", "cartilage-specific", "synthesis", "of", "proteoglycan", "in", "chondrocytes", "and", "thereby", "affect", "the", "cartilage", "tissue.", "The", "undisturbed", "interaction", "between", "the", "chondrocytes", "and", "extracellular", "matrix", "plays", "an", "im-", "portant", "role", "for", "the", "regulation", "of", "chondrocyte", "homeostasis,", "which", "is", "important", "for", "the", "mainte-", "nance,", "the", "development,", "and", "the", "stabilisation", "of", "chondrocyte", "phenotype.9–12", "Consequently,", "an", "inter-", "ruption", "of", "proteoglycan", "synthesis", "results", "in", "cartilage", "damage", "with", "the", "loss", "of", "chondrocytes.9,13", "Two", "of", "the", "most", "commonly", "used", "antiseptics", "in", "septic", "joint", "surgery", "are", "polyhexanide", "and", "hydrogen", "peroxide.", "Literature", "reviews", "show", "insufficient", "data", "about", "the", "effects", "of", "antiseptics", "on", "human", "cartilage.", "2011", "National", "Society", "for", "Histotechnology", "MORE", "OpenChoice", "articles", "are", "open", "access", "and", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "3.0", "DOI", "10.1179/014788811X12949268296121", "Journal", "of", "Histotechnology", "2011", "VOL", "34", "NO", "1", "35" ]

[ 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 0, 0, 0, 0, 4 ]

[ [ 462, 57, 50, 12 ], [ 514, 57, 34, 12 ], [ 550, 57, 221, 12 ], [ 78, 115, 85, 21 ], [ 168, 115, 54, 21 ], [ 78, 118, 13, 3 ], [ 78, 139, 90, 23 ], [ 174, 139, 22, 23 ], [ 202, 139, 45, 23 ], [ 252, 139, 38, 23 ], [ 295, 139, 45, 23 ], [ 346, 139, 40, 23 ], [ 391, 139, 49, 23 ], [ 446, 138, 83, 23 ], [ 535, 138, 90, 23 ], [ 630, 139, 54, 23 ], [ 690, 139, 40, 23 ], [ 78, 164, 69, 23 ], [ 151, 164, 63, 23 ], [ 219, 164, 85, 23 ], [ 309, 164, 20, 23 ], [ 333, 164, 111, 23 ], [ 448, 164, 93, 23 ], [ 546, 164, 59, 23 ], [ 609, 164, 158, 23 ], [ 78, 189, 87, 23 ], [ 171, 189, 96, 23 ], [ 273, 189, 27, 23 ], [ 305, 189, 61, 23 ], [ 372, 189, 22, 23 ], [ 400, 189, 35, 23 ], [ 440, 189, 105, 23 ], [ 551, 188, 77, 23 ], [ 634, 189, 43, 23 ], [ 682, 189, 40, 23 ], [ 78, 214, 68, 23 ], [ 152, 214, 36, 23 ], [ 194, 214, 111, 23 ], [ 310, 214, 28, 23 ], [ 344, 214, 82, 23 ], [ 432, 214, 141, 23 ], [ 662, 116, 44, 16 ], [ 709, 116, 61, 16 ], [ 78, 240, 60, 17 ], [ 142, 240, 60, 17 ], [ 206, 240, 51, 17 ], [ 261, 240, 11, 17 ], [ 277, 240, 88, 17 ], [ 369, 240, 54, 17 ], [ 426, 240, 59, 17 ], [ 489, 240, 27, 17 ], [ 520, 240, 54, 17 ], [ 578, 240, 82, 17 ], [ 78, 286, 61, 12 ], [ 141, 286, 10, 11 ], [ 154, 286, 71, 11 ], [ 227, 286, 24, 11 ], [ 253, 286, 46, 11 ], [ 302, 286, 42, 11 ], [ 346, 286, 27, 11 ], [ 375, 286, 40, 11 ], [ 78, 299, 61, 12 ], [ 142, 299, 9, 12 ], [ 154, 299, 51, 12 ], [ 207, 299, 46, 12 ], [ 255, 299, 37, 12 ], [ 295, 299, 10, 12 ], [ 307, 299, 64, 12 ], [ 373, 299, 57, 12 ], [ 433, 299, 18, 12 ], [ 453, 299, 65, 12 ], [ 521, 299, 24, 12 ], [ 547, 299, 49, 12 ], [ 598, 299, 27, 12 ], [ 628, 299, 40, 12 ], [ 78, 324, 72, 12 ], [ 152, 324, 33, 12 ], [ 188, 324, 36, 12 ], [ 227, 324, 53, 12 ], [ 282, 324, 133, 12 ], [ 78, 349, 47, 12 ], [ 128, 349, 13, 12 ], [ 144, 349, 20, 12 ], [ 167, 349, 26, 12 ], [ 199, 349, 46, 12 ], [ 247, 349, 51, 12 ], [ 301, 349, 13, 12 ], [ 316, 349, 16, 12 ], [ 335, 349, 26, 12 ], [ 367, 349, 45, 12 ], [ 415, 349, 43, 12 ], [ 461, 349, 13, 12 ], [ 477, 349, 16, 12 ], [ 496, 349, 26, 12 ], [ 528, 349, 50, 12 ], [ 580, 349, 13, 12 ], [ 596, 349, 13, 12 ], [ 611, 349, 26, 12 ], [ 643, 349, 50, 12 ], [ 696, 349, 13, 12 ], [ 712, 349, 20, 12 ], [ 734, 349, 26, 12 ], [ 78, 375, 37, 12 ], [ 118, 375, 19, 12 ], [ 140, 375, 22, 12 ], [ 165, 375, 29, 12 ], [ 196, 375, 67, 12 ], [ 265, 375, 23, 12 ], [ 291, 375, 139, 12 ], [ 78, 389, 10, 12 ], [ 91, 389, 26, 12 ], [ 120, 389, 33, 12 ], [ 156, 389, 9, 12 ], [ 168, 389, 14, 12 ], [ 184, 389, 39, 12 ], [ 226, 389, 37, 12 ], [ 266, 389, 35, 12 ], [ 304, 389, 18, 12 ], [ 78, 403, 20, 11 ], [ 101, 403, 8, 11 ], [ 112, 403, 12, 11 ], [ 126, 403, 27, 11 ], [ 156, 403, 36, 11 ], [ 194, 403, 29, 11 ], [ 225, 403, 51, 11 ], [ 279, 403, 28, 11 ], [ 309, 403, 15, 11 ], [ 326, 403, 27, 11 ], [ 356, 403, 10, 11 ], [ 368, 403, 15, 11 ], [ 386, 403, 40, 11 ], [ 428, 403, 49, 11 ], [ 480, 403, 49, 11 ], [ 531, 403, 37, 11 ], [ 571, 403, 195, 11 ], [ 78, 417, 22, 12 ], [ 103, 417, 28, 12 ], [ 134, 417, 35, 12 ], [ 172, 417, 57, 12 ], [ 231, 417, 20, 12 ], [ 253, 417, 55, 12 ], [ 311, 417, 18, 12 ], [ 332, 417, 61, 12 ], [ 395, 417, 9, 12 ], [ 406, 417, 17, 12 ], [ 425, 417, 40, 12 ], [ 468, 417, 42, 12 ], [ 512, 417, 15, 12 ], [ 530, 417, 34, 12 ], [ 567, 417, 23, 12 ], [ 593, 417, 8, 12 ], [ 603, 417, 26, 12 ], [ 78, 700, 53, 12 ], [ 134, 700, 17, 12 ], [ 154, 700, 43, 12 ], [ 199, 700, 24, 12 ], [ 225, 700, 58, 12 ], [ 286, 700, 40, 12 ], [ 329, 700, 52, 12 ], [ 384, 700, 76, 12 ], [ 462, 700, 28, 12 ], [ 492, 700, 42, 12 ], [ 537, 700, 26, 12 ], [ 565, 700, 69, 12 ], [ 78, 458, 60, 15 ], [ 78, 495, 63, 13 ], [ 149, 495, 10, 13 ], [ 166, 495, 38, 13 ], [ 211, 495, 27, 13 ], [ 246, 495, 11, 13 ], [ 264, 495, 42, 13 ], [ 313, 495, 46, 13 ], [ 367, 495, 26, 13 ], [ 400, 495, 13, 13 ], [ 78, 510, 42, 13 ], [ 136, 510, 52, 13 ], [ 204, 510, 42, 13 ], [ 262, 510, 44, 13 ], [ 322, 510, 55, 13 ], [ 393, 510, 20, 13 ], [ 78, 524, 70, 13 ], [ 151, 524, 19, 13 ], [ 174, 524, 13, 13 ], [ 190, 524, 36, 13 ], [ 229, 524, 14, 13 ], [ 246, 524, 72, 13 ], [ 321, 524, 10, 13 ], [ 334, 524, 47, 13 ], [ 384, 524, 29, 13 ], [ 78, 539, 78, 13 ], [ 161, 539, 33, 13 ], [ 200, 539, 20, 13 ], [ 225, 539, 71, 13 ], [ 300, 539, 21, 13 ], [ 326, 539, 71, 13 ], [ 402, 539, 11, 13 ], [ 78, 554, 46, 13 ], [ 128, 554, 41, 13 ], [ 173, 554, 11, 13 ], [ 188, 554, 33, 13 ], [ 224, 554, 43, 13 ], [ 272, 554, 10, 13 ], [ 285, 554, 30, 13 ], [ 318, 554, 42, 13 ], [ 364, 554, 49, 13 ], [ 78, 568, 17, 13 ], [ 98, 568, 58, 13 ], [ 159, 568, 22, 13 ], [ 184, 568, 69, 13 ], [ 256, 568, 11, 13 ], [ 270, 568, 26, 13 ], [ 298, 568, 20, 13 ], [ 321, 568, 48, 13 ], [ 372, 568, 41, 13 ], [ 78, 583, 26, 13 ], [ 108, 583, 50, 13 ], [ 162, 583, 24, 13 ], [ 189, 583, 28, 13 ], [ 220, 583, 24, 13 ], [ 248, 583, 30, 13 ], [ 281, 583, 45, 13 ], [ 330, 582, 19, 13 ], [ 352, 583, 45, 13 ], [ 400, 583, 12, 13 ], [ 78, 597, 47, 13 ], [ 128, 597, 50, 13 ], [ 181, 597, 24, 13 ], [ 208, 597, 19, 13 ], [ 230, 597, 45, 13 ], [ 278, 597, 15, 13 ], [ 296, 597, 50, 13 ], [ 349, 597, 50, 13 ], [ 401, 597, 11, 13 ], [ 78, 612, 10, 13 ], [ 95, 612, 85, 13 ], [ 187, 612, 29, 13 ], [ 223, 612, 33, 13 ], [ 263, 612, 50, 13 ], [ 320, 612, 54, 13 ], [ 380, 612, 7, 13 ], [ 394, 612, 19, 13 ], [ 78, 626, 33, 13 ], [ 119, 626, 73, 13 ], [ 200, 626, 11, 13 ], [ 219, 626, 26, 13 ], [ 253, 626, 58, 13 ], [ 320, 626, 20, 13 ], [ 348, 626, 65, 13 ], [ 78, 641, 45, 13 ], [ 131, 641, 56, 13 ], [ 194, 641, 43, 13 ], [ 245, 641, 50, 13 ], [ 302, 641, 22, 13 ], [ 332, 641, 81, 13 ], [ 78, 656, 27, 13 ], [ 110, 656, 47, 13 ], [ 161, 656, 10, 13 ], [ 176, 656, 22, 13 ], [ 203, 656, 57, 13 ], [ 264, 656, 43, 13 ], [ 311, 656, 22, 13 ], [ 338, 656, 23, 13 ], [ 366, 656, 20, 13 ], [ 391, 656, 22, 13 ], [ 78, 670, 38, 13 ], [ 120, 670, 46, 13 ], [ 169, 670, 24, 13 ], [ 197, 670, 25, 13 ], [ 225, 670, 10, 13 ], [ 238, 670, 23, 13 ], [ 264, 670, 43, 13 ], [ 310, 670, 22, 13 ], [ 335, 670, 10, 13 ], [ 348, 670, 26, 13 ], [ 378, 670, 21, 13 ], [ 402, 670, 11, 13 ], [ 78, 732, 90, 16 ], [ 78, 749, 22, 14 ], [ 103, 749, 43, 14 ], [ 150, 749, 69, 14 ], [ 221, 749, 12, 14 ], [ 236, 749, 19, 14 ], [ 258, 749, 52, 14 ], [ 313, 749, 11, 14 ], [ 328, 749, 50, 14 ], [ 381, 749, 31, 14 ], [ 78, 765, 84, 14 ], [ 169, 765, 33, 14 ], [ 208, 765, 10, 14 ], [ 224, 765, 28, 14 ], [ 258, 765, 14, 14 ], [ 278, 765, 10, 14 ], [ 294, 765, 53, 14 ], [ 353, 765, 14, 14 ], [ 374, 765, 39, 14 ], [ 78, 781, 69, 14 ], [ 150, 781, 22, 14 ], [ 175, 781, 7, 14 ], [ 185, 781, 36, 14 ], [ 223, 781, 76, 14 ], [ 302, 781, 22, 14 ], [ 327, 781, 10, 14 ], [ 340, 781, 73, 14 ], [ 78, 798, 25, 14 ], [ 107, 798, 51, 14 ], [ 162, 798, 31, 14 ], [ 196, 798, 20, 14 ], [ 219, 798, 22, 14 ], [ 245, 798, 32, 14 ], [ 280, 798, 100, 14 ], [ 384, 798, 29, 14 ], [ 78, 814, 23, 14 ], [ 106, 814, 40, 14 ], [ 150, 814, 56, 14 ], [ 210, 814, 26, 14 ], [ 240, 814, 109, 14 ], [ 353, 814, 10, 14 ], [ 367, 814, 46, 14 ], [ 78, 830, 63, 14 ], [ 148, 830, 24, 14 ], [ 179, 830, 25, 14 ], [ 211, 830, 10, 14 ], [ 228, 830, 68, 14 ], [ 302, 830, 31, 14 ], [ 340, 830, 22, 14 ], [ 369, 830, 22, 14 ], [ 398, 830, 15, 14 ], [ 78, 847, 55, 14 ], [ 139, 847, 40, 14 ], [ 184, 847, 12, 14 ], [ 201, 847, 15, 14 ], [ 221, 847, 55, 14 ], [ 280, 847, 10, 14 ], [ 295, 847, 18, 14 ], [ 319, 847, 78, 14 ], [ 401, 847, 12, 14 ], [ 78, 863, 28, 14 ], [ 110, 863, 14, 14 ], [ 127, 863, 46, 14 ], [ 175, 863, 52, 14 ], [ 231, 863, 14, 14 ], [ 248, 863, 44, 14 ], [ 295, 863, 22, 14 ], [ 320, 863, 38, 14 ], [ 362, 863, 20, 14 ], [ 385, 863, 28, 14 ], [ 78, 879, 19, 14 ], [ 100, 879, 32, 14 ], [ 136, 879, 38, 14 ], [ 178, 879, 11, 14 ], [ 193, 879, 10, 14 ], [ 206, 879, 54, 14 ], [ 264, 879, 42, 14 ], [ 309, 879, 11, 14 ], [ 324, 879, 10, 14 ], [ 338, 879, 56, 14 ], [ 398, 879, 15, 14 ], [ 78, 896, 35, 14 ], [ 120, 896, 25, 14 ], [ 150, 896, 46, 14 ], [ 202, 896, 27, 14 ], [ 236, 896, 19, 14 ], [ 261, 896, 33, 14 ], [ 300, 896, 11, 14 ], [ 318, 895, 20, 14 ], [ 344, 896, 49, 14 ], [ 399, 896, 13, 14 ], [ 78, 911, 51, 15 ], [ 132, 912, 12, 14 ], [ 147, 912, 25, 14 ], [ 176, 912, 28, 16 ], [ 205, 912, 10, 14 ], [ 218, 912, 62, 14 ], [ 283, 912, 20, 14 ], [ 306, 912, 51, 14 ], [ 361, 912, 14, 14 ], [ 378, 912, 35, 14 ], [ 78, 928, 25, 14 ], [ 106, 928, 67, 14 ], [ 176, 928, 10, 14 ], [ 190, 928, 46, 14 ], [ 239, 928, 24, 14 ], [ 266, 928, 83, 14 ], [ 351, 928, 16, 14 ], [ 371, 928, 42, 14 ], [ 78, 945, 11, 14 ], [ 93, 945, 33, 14 ], [ 130, 945, 21, 14 ], [ 154, 945, 10, 14 ], [ 168, 945, 19, 14 ], [ 190, 944, 20, 14 ], [ 214, 945, 49, 14 ], [ 266, 945, 17, 14 ], [ 286, 944, 54, 14 ], [ 344, 945, 47, 14 ], [ 394, 945, 19, 14 ], [ 437, 495, 17, 13 ], [ 461, 495, 52, 13 ], [ 521, 495, 24, 13 ], [ 552, 495, 103, 13 ], [ 662, 495, 32, 13 ], [ 701, 495, 22, 13 ], [ 730, 495, 42, 13 ], [ 437, 510, 58, 13 ], [ 500, 510, 22, 13 ], [ 527, 510, 23, 13 ], [ 554, 510, 31, 13 ], [ 590, 510, 24, 13 ], [ 618, 510, 27, 13 ], [ 649, 510, 21, 13 ], [ 674, 510, 26, 13 ], [ 705, 510, 13, 13 ], [ 722, 510, 50, 13 ], [ 437, 524, 44, 13 ], [ 487, 524, 11, 13 ], [ 504, 524, 71, 13 ], [ 581, 524, 11, 13 ], [ 597, 524, 27, 13 ], [ 630, 524, 41, 13 ], [ 677, 524, 45, 13 ], [ 728, 524, 21, 13 ], [ 755, 524, 17, 13 ], [ 437, 539, 34, 13 ], [ 481, 539, 60, 13 ], [ 550, 539, 22, 13 ], [ 582, 539, 23, 13 ], [ 614, 539, 15, 13 ], [ 638, 539, 24, 13 ], [ 671, 539, 101, 13 ], [ 437, 554, 49, 13 ], [ 490, 554, 24, 13 ], [ 518, 554, 65, 13 ], [ 586, 554, 22, 13 ], [ 612, 553, 39, 13 ], [ 654, 554, 24, 13 ], [ 682, 553, 42, 13 ], [ 727, 554, 21, 13 ], [ 752, 554, 20, 13 ], [ 437, 568, 48, 13 ], [ 489, 568, 45, 13 ], [ 537, 568, 68, 13 ], [ 609, 568, 17, 13 ], [ 629, 568, 65, 13 ], [ 698, 568, 11, 13 ], [ 712, 568, 17, 13 ], [ 733, 568, 39, 13 ], [ 437, 583, 21, 13 ], [ 461, 583, 20, 13 ], [ 484, 583, 35, 13 ], [ 523, 583, 19, 13 ], [ 544, 583, 56, 13 ], [ 603, 583, 38, 13 ], [ 644, 583, 7, 13 ], [ 653, 583, 34, 13 ], [ 690, 583, 56, 13 ], [ 750, 583, 22, 13 ], [ 437, 597, 23, 13 ], [ 463, 597, 23, 13 ], [ 488, 597, 28, 13 ], [ 518, 597, 26, 13 ], [ 547, 597, 13, 13 ], [ 562, 597, 57, 13 ], [ 620, 597, 22, 13 ], [ 645, 597, 29, 13 ], [ 676, 597, 73, 13 ], [ 751, 597, 21, 13 ], [ 437, 612, 36, 13 ], [ 487, 612, 71, 13 ], [ 572, 612, 11, 13 ], [ 596, 612, 27, 13 ], [ 637, 612, 41, 13 ], [ 691, 612, 22, 13 ], [ 727, 612, 45, 13 ], [ 437, 626, 69, 13 ], [ 514, 626, 11, 13 ], [ 533, 626, 26, 13 ], [ 566, 626, 59, 13 ], [ 633, 626, 19, 13 ], [ 660, 626, 51, 13 ], [ 719, 626, 15, 13 ], [ 741, 626, 31, 13 ], [ 437, 641, 42, 13 ], [ 481, 641, 7, 13 ], [ 491, 641, 22, 13 ], [ 515, 641, 46, 13 ], [ 564, 641, 33, 13 ], [ 599, 641, 42, 13 ], [ 643, 641, 51, 13 ], [ 697, 641, 17, 13 ], [ 717, 641, 24, 13 ], [ 743, 641, 29, 13 ], [ 437, 656, 73, 13 ], [ 513, 656, 55, 13 ], [ 437, 732, 35, 17 ], [ 475, 732, 35, 17 ], [ 512, 732, 22, 14 ], [ 537, 732, 74, 17 ], [ 614, 732, 48, 14 ], [ 665, 732, 11, 14 ], [ 679, 732, 19, 14 ], [ 700, 732, 49, 14 ], [ 752, 732, 20, 14 ], [ 437, 749, 35, 14 ], [ 481, 749, 45, 14 ], [ 535, 749, 21, 14 ], [ 564, 749, 32, 14 ], [ 605, 749, 10, 14 ], [ 624, 749, 63, 14 ], [ 696, 749, 56, 14 ], [ 760, 749, 11, 14 ], [ 437, 765, 45, 14 ], [ 487, 765, 62, 14 ], [ 552, 765, 26, 14 ], [ 582, 765, 19, 14 ], [ 605, 765, 62, 14 ], [ 671, 765, 34, 14 ], [ 710, 765, 32, 14 ], [ 746, 765, 26, 14 ], [ 437, 781, 37, 14 ], [ 479, 781, 12, 14 ], [ 496, 781, 19, 14 ], [ 519, 781, 78, 14 ], [ 602, 781, 11, 14 ], [ 618, 781, 154, 14 ], [ 437, 798, 83, 14 ], [ 524, 798, 20, 14 ], [ 437, 818, 93, 14 ], [ 534, 818, 31, 14 ], [ 569, 818, 36, 14 ], [ 609, 818, 10, 14 ], [ 623, 818, 63, 14 ], [ 690, 818, 37, 14 ], [ 730, 818, 12, 14 ], [ 746, 818, 26, 14 ], [ 437, 834, 22, 14 ], [ 465, 834, 21, 14 ], [ 491, 834, 18, 14 ], [ 515, 834, 33, 14 ], [ 554, 834, 12, 14 ], [ 572, 834, 45, 14 ], [ 622, 834, 18, 14 ], [ 646, 834, 71, 14 ], [ 723, 834, 49, 14 ], [ 437, 851, 45, 14 ], [ 485, 851, 19, 14 ], [ 505, 851, 31, 14 ], [ 539, 851, 51, 14 ], [ 593, 851, 30, 14 ], [ 625, 851, 56, 14 ], [ 684, 851, 18, 14 ], [ 705, 851, 33, 14 ], [ 740, 851, 10, 14 ], [ 753, 851, 19, 14 ], [ 437, 867, 54, 14 ], [ 496, 867, 29, 14 ], [ 531, 867, 22, 14 ], [ 558, 867, 33, 14 ], [ 596, 867, 19, 14 ], [ 619, 867, 28, 14 ], [ 652, 867, 36, 14 ], [ 693, 867, 79, 14 ], [ 437, 883, 22, 14 ], [ 462, 883, 19, 14 ], [ 483, 883, 44, 14 ], [ 529, 883, 11, 14 ], [ 543, 883, 28, 14 ], [ 574, 883, 48, 14 ], [ 625, 883, 54, 14 ], [ 681, 883, 48, 14 ], [ 732, 883, 16, 14 ], [ 750, 883, 22, 14 ], [ 437, 900, 28, 14 ], [ 470, 900, 71, 14 ], [ 546, 900, 55, 14 ], [ 606, 900, 20, 14 ], [ 630, 900, 11, 14 ], [ 645, 900, 18, 14 ], [ 669, 900, 53, 14 ], [ 726, 900, 46, 14 ], [ 437, 916, 30, 14 ], [ 470, 916, 18, 14 ], [ 492, 916, 22, 14 ], [ 516, 916, 87, 14 ], [ 606, 916, 22, 14 ], [ 631, 916, 52, 14 ], [ 686, 916, 36, 14 ], [ 725, 916, 47, 14 ], [ 437, 932, 40, 14 ], [ 484, 932, 24, 14 ], [ 515, 932, 16, 14 ], [ 537, 932, 59, 14 ], [ 602, 932, 19, 14 ], [ 627, 932, 38, 14 ], [ 672, 932, 28, 14 ], [ 706, 932, 29, 14 ], [ 742, 932, 16, 14 ], [ 765, 932, 7, 14 ], [ 437, 949, 46, 14 ], [ 486, 949, 29, 14 ], [ 519, 949, 22, 14 ], [ 544, 949, 19, 14 ], [ 566, 949, 19, 14 ], [ 587, 949, 43, 14 ], [ 633, 949, 40, 14 ], [ 676, 949, 28, 14 ], [ 707, 949, 38, 14 ], [ 748, 949, 24, 14 ], [ 78, 978, 23, 12 ], [ 104, 978, 8, 12 ], [ 115, 978, 45, 12 ], [ 162, 978, 37, 12 ], [ 202, 978, 10, 12 ], [ 214, 978, 71, 12 ], [ 288, 978, 6, 12 ], [ 297, 978, 8, 12 ], [ 307, 978, 67, 12 ], [ 377, 978, 35, 12 ], [ 414, 978, 8, 12 ], [ 425, 978, 17, 12 ], [ 444, 978, 40, 12 ], [ 487, 978, 14, 12 ], [ 504, 978, 37, 12 ], [ 544, 978, 8, 12 ], [ 554, 978, 17, 12 ], [ 573, 978, 40, 12 ], [ 616, 978, 17, 12 ], [ 635, 978, 9, 12 ], [ 647, 978, 8, 12 ], [ 657, 978, 43, 12 ], [ 702, 978, 31, 12 ], [ 736, 978, 8, 12 ], [ 747, 978, 24, 12 ], [ 78, 991, 37, 11 ], [ 118, 991, 40, 11 ], [ 160, 991, 52, 11 ], [ 215, 991, 23, 11 ], [ 240, 991, 8, 11 ], [ 250, 991, 76, 11 ], [ 327, 991, 29, 11 ], [ 358, 991, 135, 11 ], [ 495, 991, 8, 11 ], [ 505, 991, 23, 11 ], [ 530, 991, 44, 11 ], [ 577, 991, 48, 11 ], [ 627, 991, 6, 11 ], [ 635, 991, 102, 11 ], [ 740, 991, 30, 11 ], [ 78, 1004, 65, 12 ], [ 146, 1004, 9, 12 ], [ 158, 1004, 26, 12 ], [ 186, 1004, 26, 12 ], [ 215, 1004, 8, 12 ], [ 225, 1004, 26, 12 ], [ 254, 1004, 82, 12 ], [ 339, 1004, 43, 12 ], [ 384, 1004, 17, 12 ], [ 404, 1004, 8, 12 ], [ 414, 1004, 24, 12 ], [ 441, 1004, 24, 12 ], [ 468, 1004, 23, 12 ], [ 493, 1004, 8, 12 ], [ 504, 1004, 54, 12 ], [ 561, 1004, 26, 12 ], [ 589, 1004, 41, 12 ], [ 633, 1004, 8, 12 ], [ 643, 1004, 8, 12 ], [ 654, 1004, 41, 12 ], [ 697, 1004, 25, 12 ], [ 724, 1004, 8, 12 ], [ 734, 1004, 34, 12 ], [ 78, 1018, 33, 12 ], [ 114, 1018, 17, 12 ], [ 133, 1018, 18, 12 ], [ 154, 1018, 10, 12 ], [ 166, 1018, 53, 12 ], [ 221, 1018, 20, 12 ], [ 244, 1018, 8, 12 ], [ 255, 1018, 42, 12 ], [ 299, 1018, 26, 12 ], [ 327, 1018, 72, 12 ], [ 402, 1018, 7, 12 ], [ 412, 1018, 8, 12 ], [ 422, 1018, 30, 12 ], [ 790, 1019, 26, 12 ] ]

[ "Available", "online", "http://arthritis-research.com/content/6/6/R557", "Research", "article", "Vol6No6", "Analysis", "of", "HLA", "DR,", "HLA", "DQ,", "C4A,", "FcγRIIa,", "FcγRIIIa,", "MBL,", "and", "IL-1Ra", "allelic", "variants", "in", "Caucasian", "systemic", "lupus", "erythematosus", "patients", "suggests", "an", "effect", "of", "the", "combined", "FcγRIIa", "R/R", "and", "IL-1Ra", "2/2", "genotypes", "on", "disease", "susceptibility", "Open", "Access", "Andreas", "Jönsen1,", "Anders", "A", "Bengtsson1,", "Gunnar", "Sturfelt1", "and", "Lennart", "Truedsson2", "1Department", "of", "Rheumatology,", "Lund", "University", "Hospital,", "Lund,", "Sweden", "2Department", "of", "Laboratory", "Medicine,", "Section", "of", "Microbiology,", "Immunology", "and", "Glycobiology,", "Lund", "University,", "Lund,", "Sweden", "Corresponding", "author:", "Lennart", "Truedsson,", "lennart.truedsson@skane.se", "Received:", "22", "Dec", "2003", "Revisions", "requested:", "12", "Jan", "2004", "Revisions", "received:", "16", "Jun", "2004", "Accepted:", "16", "Jul", "2004", "Published:", "23", "Sep", "2004", "Arthritis", "Res", "Ther", "2004,", "6:R557-R562", "(DOI", "10.1186/ar1224)htp:/arthrits-research.com/content/6/6/R557", "©", "2004", "Jönsen", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/", "2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "cited.", "Keywords:", "Fcγ", "receptor,", "HLA,", "interleukin-1", "receptor", "antagonist,", "mannan-binding", "lectin,", "systemic", "lupus", "erythematosus", "Abstract", "Dysfunction", "in", "various", "parts", "of", "immune", "defence,", "such", "as", "immune", "response,", "immune", "complex", "clearance,", "and", "inflammation,", "has", "an", "impact", "on", "pathogenesis", "in", "systemic", "lupus", "erythematosus", "(SLE).", "We", "hypothesised", "that", "combinations", "of", "common", "variants", "of", "genes", "involved", "in", "these", "immune", "functions", "are", "associated", "with", "susceptibility", "to", "SLE.", "The", "following", "variants", "were", "analysed:", "HLA", "DR3,", "HLA", "DQ2,", "C4AQ0,", "Fcγ", "receptor", "IIa", "(FcγRIIa)", "genotype", "R/R,", "Fcγ", "receptor", "IIIa", "(FcRγIIIa)", "genotype", "F/", "F,", "mannan-binding", "lectin", "(MBL)", "genotype", "conferring", "a", "low", "serum", "concentration", "of", "MBL", "(MBL-low),", "and", "interleukin-1", "receptor", "antagonist", "(IL-1Ra)", "genotype", "2/2.", "Polymorphisms", "were", "analysed", "in", "143", "Caucasian", "patients", "with", "SLE", "and", "200", "healthy", "controls.", "HLA", "DR3", "in", "SLE", "patients", "was", "in", "90%", "part", "of", "Introduction", "The", "genetic", "contribution", "to", "the", "aetiology", "of", "systemic", "lupus", "erythematosus", "(SLE)", "is", "high,", "as", "is", "indicated", "by", "familial", "aggregation", "and", "a", "higher", "concordance", "rate", "in", "monozygotic", "than", "dizygotic", "twins", "[1].", "The", "major", "histocompatibility", "com-", "plex", "(MHC)", "haplotype", "HLA", "DR3-DQ2-C4AQ0", "is", "strongly", "associated", "with", "SLE", "in", "Caucasians", "[2,3].", "The", "IgG", "Fc", "receptors", "appear", "to", "be", "important", "in", "the", "pathogenesis", "of", "SLE,", "as", "recently", "reviewed", "by", "Salmon", "and", "Pricop", "[4].", "With", "the", "allelic", "variant", "of", "R", "(arginine)", "instead", "of", "H", "(histidine)", "on", "amino", "acid", "position", "131,", "the", "ability", "of", "Fcγ", "receptor", "IIa", "(FcγRIIa)", "to", "bind", "IgG2", "is", "diminished", "[5].", "Similarly,", "an", "amino", "acid", "substitution", "in", "position", "158", "(phenylalanine", "[F]", "instead", "of", "valine", "[V])", "in", "the", "Fcγ", "receptor", "IIIa", "(FcγRIIIa)", "reduces", "the", "the", "haplotype", "HLA", "DR3-DQ2-C4AQ0,", "which", "was", "strongly", "associated", "with", "SLE", "(odds", "ratio", "[OR]", "2.8,", "95%", "CI", "1.7–4.5).", "Analysis", "of", "combinations", "of", "gene", "variants", "revealed", "that", "the", "strong", "association", "with", "SLE", "for", "HLA", "DR3-DQ2-C4AQ0", "remained", "after", "combination", "with", "FcγRIIa", "R/R,", "FcγRIIIa", "F/F,", "and", "MBL-low", "(OR>2).", "Furthermore,", "the", "combination", "of", "the", "FcγRIIa", "R/R", "and", "IL-1Ra", "2/2", "genotypes", "yielded", "a", "strong", "correlation", "with", "SLE", "(OR", "11.8,", "95%", "CI", "1.5–95.4).", "This", "study", "demonstrates", "that", "certain", "combinations", "of", "gene", "variants", "may", "increase", "susceptibility", "to", "SLE,", "suggesting", "this", "approach", "for", "future", "studies.", "It", "also", "confirms", "earlier", "findings", "regarding", "the", "HLA", "DR3-", "DQ2-C4AQ0", "haplotype.", "IgG1-,", "IgG3-,", "and", "IgG4-binding", "capacity", "of", "the", "receptor", "[6].", "These", "variants", "can", "result", "in", "suboptimal", "clearance", "of", "immune", "complexes", "from", "the", "circulation,", "which", "might", "con-", "tribute", "to", "the", "pathogenesis", "of", "immune-complex-mediated", "manifestations", "[7].", "Mannan-binding", "lectin", "(MBL)", "is", "structurally", "similar", "to", "C1q", "and", "has", "the", "ability", "to", "activate", "the", "complement", "cascade", "through", "the", "lectin", "pathway.", "Point", "mutations", "are", "found", "in", "the", "structural", "gene", "that", "affect", "the", "MBL", "serum", "concentration", "and", "the", "stability", "of", "MBL", "complex", "formation", "required", "for", "effi-", "cient", "complement", "activation", "[8].", "In", "the", "promoter", "regions,", "there", "are", "two", "polymorphisms", "that", "influence", "serum", "concen-", "tration,", "with", "LX", "conferring", "the", "lowest", "MBL", "level,", "LY", "a", "medium", "level,", "and", "HY", "the", "highest", "[8-11].", "MBL", "variant", "alle-", "ACR", "=", "American", "College", "of", "Rheumatology;", "F", "=", "phenylalanine;", "FcγRIIa", "=", "Fcγ", "receptor", "IIa;", "FcγRIIIa", "=", "Fcγ", "receptor", "IIIa;", "H", "=", "histidine;", "IL-1Ra", "=", "inter-", "leukin-1", "receptor", "antagonist;", "MBL", "=", "mannan-binding", "lectin;", "MBL-low/-intermediate/-high", "=", "MBL", "genotype", "conferring", "a", "low/intermediate/high", "serum", "concentration", "of", "MBL;", "MHC", "=", "major", "histocompatibility", "complex;", "OR", "=", "odds", "ratio;", "PCR", "=", "polymerase", "chain", "reaction;", "R", "=", "arginine;", "RERI", "=", "relative", "excess", "risk", "due", "to", "interaction;", "SLE", "=", "systemic", "lupus", "erythematosus;", "V", "=", "valine.", "R557" ]

[ 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 9, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0 ]

[ [ 76, 47, 84, 34 ], [ 172, 47, 182, 34 ], [ 366, 47, 158, 34 ], [ 76, 118, 70, 20 ], [ 151, 118, 46, 20 ], [ 76, 143, 74, 23 ], [ 155, 143, 20, 23 ], [ 180, 143, 82, 23 ], [ 267, 143, 144, 23 ], [ 416, 143, 88, 23 ], [ 509, 143, 27, 23 ], [ 540, 143, 109, 23 ], [ 654, 143, 19, 23 ], [ 679, 143, 86, 23 ], [ 76, 168, 46, 23 ], [ 128, 168, 110, 23 ], [ 244, 168, 35, 23 ], [ 284, 168, 38, 23 ], [ 328, 168, 93, 23 ], [ 427, 168, 122, 23 ], [ 554, 168, 128, 23 ], [ 688, 168, 18, 23 ], [ 76, 193, 76, 23 ], [ 158, 193, 60, 23 ], [ 76, 218, 44, 21 ], [ 125, 218, 14, 21 ], [ 144, 218, 80, 22 ], [ 228, 218, 55, 21 ], [ 288, 218, 11, 21 ], [ 304, 218, 104, 22 ], [ 413, 218, 61, 21 ], [ 479, 218, 13, 21 ], [ 497, 218, 58, 22 ], [ 559, 218, 61, 21 ], [ 625, 218, 15, 21 ], [ 645, 218, 103, 22 ], [ 76, 243, 31, 21 ], [ 112, 243, 12, 21 ], [ 130, 243, 80, 22 ], [ 215, 243, 25, 21 ], [ 244, 243, 17, 21 ], [ 265, 243, 127, 22 ], [ 398, 243, 35, 21 ], [ 438, 243, 79, 21 ], [ 522, 243, 17, 21 ], [ 543, 243, 64, 22 ], [ 706, 60, 54, 14 ], [ 761, 60, 38, 14 ], [ 697, 118, 44, 17 ], [ 745, 118, 62, 17 ], [ 76, 293, 41, 12 ], [ 119, 293, 63, 12 ], [ 184, 293, 10, 12 ], [ 197, 293, 68, 12 ], [ 266, 293, 19, 12 ], [ 287, 293, 50, 12 ], [ 340, 293, 48, 12 ], [ 390, 293, 50, 12 ], [ 441, 293, 10, 12 ], [ 454, 293, 47, 12 ], [ 503, 293, 33, 12 ], [ 538, 293, 10, 12 ], [ 551, 293, 48, 12 ], [ 601, 293, 51, 12 ], [ 653, 293, 22, 12 ], [ 677, 293, 24, 12 ], [ 704, 293, 63, 12 ], [ 76, 306, 10, 11 ], [ 89, 306, 48, 11 ], [ 139, 306, 32, 11 ], [ 174, 306, 54, 11 ], [ 230, 306, 62, 11 ], [ 295, 306, 39, 11 ], [ 336, 306, 19, 11 ], [ 358, 306, 50, 11 ], [ 410, 306, 10, 11 ], [ 422, 306, 49, 11 ], [ 474, 306, 49, 11 ], [ 525, 306, 60, 11 ], [ 587, 306, 41, 12 ], [ 630, 306, 10, 11 ], [ 643, 306, 51, 11 ], [ 696, 306, 37, 11 ], [ 735, 306, 24, 11 ], [ 76, 319, 53, 12 ], [ 131, 319, 45, 12 ], [ 179, 319, 19, 12 ], [ 200, 319, 21, 12 ], [ 224, 319, 19, 12 ], [ 245, 319, 40, 12 ], [ 288, 319, 31, 12 ], [ 322, 319, 47, 12 ], [ 371, 319, 33, 12 ], [ 406, 319, 22, 12 ], [ 431, 319, 37, 12 ], [ 470, 319, 51, 12 ], [ 524, 319, 22, 12 ], [ 548, 319, 21, 12 ], [ 76, 339, 31, 11 ], [ 110, 339, 24, 11 ], [ 136, 339, 7, 11 ], [ 146, 339, 35, 11 ], [ 184, 339, 4, 11 ], [ 190, 339, 171, 11 ], [ 364, 339, 30, 11 ], [ 396, 339, 6, 11 ], [ 404, 339, 48, 11 ], [ 455, 339, 4, 11 ], [ 461, 339, 153, 11 ], [ 76, 352, 33, 12 ], [ 112, 352, 7, 12 ], [ 121, 352, 24, 12 ], [ 147, 352, 4, 12 ], [ 153, 352, 124, 12 ], [ 280, 352, 33, 12 ], [ 315, 352, 8, 12 ], [ 326, 352, 48, 12 ], [ 376, 352, 4, 12 ], [ 382, 352, 103, 12 ], [ 487, 352, 17, 12 ], [ 507, 352, 7, 12 ], [ 516, 352, 36, 12 ], [ 554, 352, 4, 12 ], [ 560, 352, 142, 12 ], [ 76, 366, 13, 12 ], [ 92, 366, 9, 12 ], [ 103, 366, 57, 12 ], [ 163, 366, 4, 12 ], [ 170, 366, 148, 12 ], [ 320, 366, 42, 12 ], [ 364, 366, 9, 12 ], [ 376, 366, 30, 12 ], [ 408, 366, 4, 12 ], [ 415, 366, 135, 12 ], [ 76, 382, 7, 12 ], [ 85, 382, 73, 12 ], [ 160, 382, 33, 12 ], [ 76, 440, 45, 12 ], [ 124, 440, 12, 12 ], [ 138, 440, 49, 12 ], [ 190, 440, 23, 12 ], [ 76, 460, 21, 12 ], [ 100, 460, 40, 12 ], [ 143, 460, 37, 12 ], [ 182, 460, 25, 12 ], [ 209, 460, 26, 12 ], [ 247, 460, 134, 12 ], [ 76, 480, 20, 12 ], [ 98, 480, 28, 12 ], [ 129, 480, 7, 12 ], [ 139, 480, 38, 12 ], [ 179, 480, 25, 12 ], [ 207, 480, 220, 12 ], [ 430, 440, 43, 12 ], [ 476, 440, 12, 12 ], [ 490, 440, 41, 12 ], [ 533, 440, 23, 12 ], [ 430, 454, 46, 12 ], [ 478, 454, 11, 12 ], [ 492, 454, 49, 12 ], [ 544, 454, 23, 12 ], [ 76, 500, 9, 12 ], [ 87, 500, 23, 12 ], [ 113, 500, 27, 12 ], [ 143, 500, 10, 12 ], [ 155, 500, 10, 12 ], [ 168, 500, 36, 12 ], [ 206, 500, 35, 12 ], [ 244, 500, 35, 12 ], [ 281, 500, 18, 12 ], [ 76, 513, 20, 12 ], [ 98, 513, 7, 12 ], [ 108, 513, 11, 12 ], [ 121, 513, 26, 12 ], [ 150, 513, 32, 12 ], [ 184, 513, 28, 12 ], [ 215, 513, 49, 12 ], [ 267, 513, 27, 12 ], [ 296, 513, 15, 12 ], [ 314, 513, 27, 12 ], [ 343, 513, 10, 12 ], [ 355, 513, 15, 12 ], [ 373, 513, 39, 12 ], [ 415, 513, 48, 12 ], [ 465, 513, 51, 12 ], [ 519, 513, 34, 12 ], [ 555, 513, 202, 12 ], [ 76, 526, 27, 12 ], [ 106, 526, 35, 12 ], [ 143, 526, 56, 12 ], [ 201, 526, 18, 12 ], [ 222, 526, 55, 12 ], [ 279, 526, 16, 12 ], [ 298, 526, 60, 12 ], [ 361, 526, 8, 12 ], [ 372, 526, 16, 12 ], [ 390, 526, 39, 12 ], [ 432, 526, 40, 12 ], [ 475, 526, 15, 12 ], [ 493, 526, 34, 12 ], [ 529, 526, 24, 12 ], [ 556, 526, 7, 12 ], [ 565, 526, 39, 12 ], [ 607, 526, 25, 12 ], [ 96, 587, 61, 15 ], [ 96, 607, 80, 14 ], [ 181, 607, 8, 14 ], [ 195, 607, 9, 14 ], [ 208, 607, 40, 14 ], [ 254, 607, 47, 14 ], [ 306, 607, 65, 14 ], [ 375, 607, 41, 14 ], [ 422, 607, 71, 14 ], [ 498, 607, 42, 14 ], [ 545, 607, 51, 14 ], [ 602, 607, 55, 14 ], [ 661, 607, 10, 14 ], [ 677, 607, 43, 14 ], [ 725, 607, 25, 14 ], [ 96, 624, 61, 14 ], [ 160, 624, 21, 14 ], [ 184, 624, 13, 14 ], [ 200, 624, 57, 14 ], [ 260, 624, 17, 14 ], [ 280, 624, 13, 14 ], [ 297, 624, 50, 14 ], [ 350, 624, 22, 14 ], [ 376, 624, 50, 14 ], [ 429, 624, 11, 14 ], [ 444, 624, 20, 14 ], [ 467, 624, 30, 14 ], [ 500, 624, 9, 14 ], [ 512, 624, 12, 14 ], [ 527, 624, 34, 14 ], [ 564, 624, 18, 14 ], [ 586, 624, 37, 14 ], [ 626, 624, 11, 14 ], [ 641, 624, 64, 14 ], [ 708, 624, 41, 14 ], [ 96, 640, 71, 14 ], [ 170, 640, 42, 14 ], [ 214, 640, 15, 14 ], [ 232, 640, 57, 14 ], [ 291, 640, 50, 14 ], [ 344, 640, 20, 14 ], [ 367, 640, 76, 14 ], [ 446, 640, 34, 14 ], [ 482, 640, 11, 14 ], [ 496, 640, 22, 14 ], [ 521, 640, 10, 14 ], [ 534, 640, 44, 14 ], [ 580, 640, 24, 14 ], [ 607, 640, 57, 14 ], [ 667, 640, 17, 14 ], [ 686, 640, 13, 14 ], [ 702, 640, 48, 14 ], [ 96, 656, 61, 14 ], [ 160, 656, 29, 14 ], [ 193, 656, 48, 14 ], [ 244, 656, 17, 14 ], [ 264, 656, 55, 14 ], [ 322, 656, 67, 14 ], [ 393, 656, 51, 14 ], [ 96, 680, 59, 14 ], [ 159, 680, 21, 14 ], [ 185, 680, 59, 14 ], [ 249, 680, 6, 14 ], [ 259, 680, 74, 14 ], [ 338, 680, 38, 14 ], [ 380, 680, 30, 14 ], [ 415, 680, 11, 14 ], [ 431, 680, 27, 14 ], [ 463, 680, 43, 14 ], [ 511, 680, 24, 14 ], [ 540, 680, 6, 14 ], [ 551, 680, 43, 14 ], [ 599, 680, 32, 14 ], [ 635, 680, 39, 14 ], [ 679, 680, 17, 14 ], [ 700, 680, 10, 14 ], [ 715, 680, 17, 14 ], [ 736, 680, 13, 14 ], [ 96, 696, 48, 14 ], [ 146, 696, 48, 14 ], [ 197, 696, 40, 14 ], [ 241, 696, 10, 14 ], [ 254, 696, 28, 14 ], [ 285, 696, 20, 14 ], [ 308, 696, 24, 14 ], [ 335, 696, 10, 14 ], [ 348, 696, 28, 14 ], [ 379, 696, 20, 14 ], [ 402, 696, 55, 14 ], [ 461, 696, 57, 14 ], [ 521, 696, 50, 14 ], [ 574, 696, 20, 14 ], [ 597, 696, 76, 14 ], [ 676, 696, 34, 14 ], [ 713, 696, 11, 14 ], [ 728, 696, 22, 14 ], [ 96, 712, 48, 14 ], [ 149, 712, 44, 14 ], [ 199, 712, 24, 14 ], [ 230, 712, 47, 14 ], [ 282, 712, 64, 14 ], [ 353, 712, 20, 14 ], [ 378, 712, 74, 14 ], [ 458, 712, 41, 14 ], [ 505, 712, 71, 14 ], [ 582, 712, 45, 14 ], [ 633, 712, 42, 14 ], [ 681, 712, 42, 14 ], [ 729, 712, 21, 14 ], [ 96, 729, 40, 14 ], [ 139, 729, 11, 14 ], [ 154, 729, 18, 14 ], [ 175, 729, 39, 14 ], [ 217, 729, 11, 14 ], [ 232, 729, 13, 14 ], [ 248, 729, 71, 14 ], [ 322, 729, 30, 14 ], [ 355, 729, 48, 14 ], [ 406, 729, 7, 14 ], [ 417, 729, 32, 14 ], [ 452, 729, 36, 14 ], [ 491, 729, 20, 14 ], [ 515, 729, 14, 14 ], [ 532, 729, 32, 14 ], [ 567, 729, 26, 14 ], [ 596, 729, 18, 14 ], [ 618, 729, 30, 14 ], [ 651, 729, 32, 14 ], [ 686, 729, 39, 14 ], [ 729, 729, 21, 14 ], [ 96, 745, 35, 14 ], [ 137, 745, 20, 14 ], [ 162, 745, 21, 14 ], [ 190, 745, 61, 14 ], [ 256, 745, 64, 14 ], [ 327, 745, 7, 14 ], [ 339, 745, 8, 14 ], [ 353, 745, 46, 14 ], [ 405, 745, 76, 14 ], [ 487, 745, 12, 14 ], [ 506, 745, 33, 14 ], [ 544, 745, 18, 14 ], [ 569, 745, 40, 14 ], [ 614, 745, 36, 14 ], [ 656, 745, 50, 14 ], [ 712, 745, 9, 14 ], [ 728, 745, 22, 14 ], [ 96, 761, 73, 14 ], [ 174, 761, 27, 14 ], [ 205, 761, 29, 14 ], [ 239, 761, 50, 14 ], [ 294, 761, 73, 14 ], [ 371, 761, 20, 14 ], [ 396, 761, 44, 14 ], [ 445, 761, 29, 14 ], [ 478, 761, 40, 14 ], [ 523, 761, 42, 14 ], [ 570, 761, 41, 14 ], [ 616, 761, 21, 14 ], [ 642, 761, 26, 14 ], [ 673, 761, 13, 14 ], [ 690, 761, 60, 14 ], [ 96, 778, 34, 14 ], [ 133, 778, 18, 14 ], [ 156, 778, 60, 14 ], [ 220, 778, 48, 14 ], [ 272, 778, 41, 14 ], [ 318, 778, 71, 14 ], [ 393, 778, 42, 14 ], [ 439, 778, 20, 14 ], [ 463, 778, 50, 14 ], [ 517, 778, 55, 14 ], [ 575, 778, 13, 14 ], [ 593, 778, 34, 14 ], [ 631, 778, 11, 14 ], [ 646, 778, 29, 14 ], [ 680, 778, 70, 14 ], [ 96, 794, 24, 14 ], [ 123, 794, 70, 14 ], [ 197, 794, 42, 14 ], [ 242, 794, 40, 14 ], [ 285, 794, 28, 14 ], [ 317, 794, 26, 14 ], [ 346, 794, 12, 14 ], [ 362, 794, 48, 14 ], [ 412, 794, 37, 14 ], [ 452, 794, 32, 14 ], [ 487, 794, 27, 14 ], [ 518, 794, 20, 14 ], [ 541, 794, 23, 14 ], [ 568, 794, 60, 14 ], [ 630, 794, 46, 14 ], [ 680, 794, 25, 14 ], [ 96, 817, 49, 14 ], [ 149, 817, 40, 14 ], [ 192, 817, 21, 14 ], [ 216, 817, 48, 14 ], [ 268, 817, 11, 14 ], [ 283, 817, 64, 14 ], [ 350, 817, 21, 14 ], [ 375, 817, 42, 14 ], [ 420, 817, 44, 14 ], [ 467, 817, 47, 14 ], [ 517, 817, 64, 14 ], [ 585, 817, 41, 14 ], [ 630, 817, 71, 14 ], [ 705, 817, 45, 14 ], [ 96, 834, 68, 14 ], [ 167, 834, 32, 14 ], [ 201, 834, 43, 14 ], [ 248, 834, 24, 14 ], [ 274, 834, 36, 14 ], [ 314, 834, 52, 14 ], [ 368, 834, 27, 14 ], [ 398, 834, 18, 14 ], [ 419, 834, 46, 14 ], [ 468, 834, 22, 14 ], [ 493, 834, 39, 14 ], [ 535, 834, 11, 14 ], [ 549, 834, 65, 14 ], [ 617, 834, 71, 14 ], [ 691, 834, 35, 14 ], [ 729, 834, 21, 14 ], [ 96, 850, 30, 14 ], [ 129, 850, 49, 14 ], [ 181, 850, 10, 14 ], [ 194, 850, 43, 14 ], [ 240, 850, 51, 14 ], [ 294, 850, 24, 14 ], [ 321, 850, 10, 14 ], [ 334, 850, 31, 14 ], [ 368, 850, 24, 14 ], [ 395, 850, 24, 14 ], [ 422, 850, 12, 14 ], [ 436, 850, 8, 14 ], [ 448, 850, 31, 14 ], [ 482, 850, 29, 14 ], [ 514, 850, 59, 14 ], [ 576, 850, 17, 14 ], [ 596, 850, 67, 14 ], [ 666, 850, 51, 14 ], [ 720, 850, 30, 14 ], [ 96, 866, 21, 14 ], [ 120, 866, 15, 14 ], [ 137, 866, 60, 14 ], [ 201, 866, 48, 14 ], [ 251, 866, 18, 14 ], [ 272, 866, 39, 14 ], [ 314, 866, 11, 14 ], [ 328, 866, 64, 14 ], [ 395, 866, 41, 14 ], [ 440, 866, 71, 14 ], [ 514, 866, 42, 14 ], [ 559, 866, 20, 14 ], [ 581, 866, 57, 14 ], [ 641, 866, 50, 14 ], [ 694, 866, 26, 14 ], [ 723, 866, 27, 14 ], [ 96, 882, 23, 14 ], [ 123, 882, 16, 14 ], [ 144, 882, 24, 14 ], [ 172, 882, 12, 14 ], [ 189, 882, 31, 14 ], [ 225, 882, 22, 14 ], [ 251, 882, 40, 14 ], [ 295, 882, 76, 14 ], [ 375, 882, 34, 14 ], [ 414, 882, 11, 14 ], [ 429, 882, 22, 14 ], [ 456, 882, 21, 14 ], [ 481, 882, 7, 14 ], [ 493, 882, 27, 14 ], [ 525, 882, 22, 14 ], [ 551, 882, 39, 14 ], [ 594, 882, 11, 14 ], [ 610, 882, 64, 14 ], [ 679, 882, 71, 14 ], [ 96, 899, 35, 14 ], [ 134, 899, 21, 14 ], [ 158, 899, 19, 14 ], [ 180, 899, 57, 14 ], [ 240, 899, 24, 14 ], [ 267, 899, 56, 14 ], [ 326, 899, 76, 14 ], [ 405, 899, 34, 14 ], [ 442, 899, 11, 14 ], [ 456, 899, 25, 14 ], [ 484, 899, 26, 14 ], [ 513, 899, 26, 14 ], [ 542, 899, 59, 14 ], [ 604, 899, 17, 14 ], [ 624, 899, 67, 14 ], [ 694, 899, 26, 14 ], [ 723, 899, 27, 14 ], [ 96, 915, 23, 14 ], [ 122, 915, 14, 14 ], [ 139, 915, 24, 14 ], [ 166, 915, 12, 14 ], [ 182, 915, 31, 14 ], [ 96, 938, 74, 14 ], [ 173, 938, 68, 14 ], [ 244, 938, 41, 14 ], [ 288, 938, 71, 14 ], [ 362, 938, 42, 14 ], [ 407, 938, 17, 14 ], [ 426, 938, 10, 14 ], [ 440, 938, 17, 14 ], [ 459, 938, 20, 14 ], [ 482, 938, 48, 14 ], [ 533, 938, 61, 14 ], [ 596, 938, 9, 14 ], [ 608, 938, 19, 14 ], [ 630, 938, 57, 14 ], [ 690, 938, 24, 14 ], [ 717, 938, 32, 14 ], [ 96, 955, 57, 14 ], [ 157, 955, 50, 14 ], [ 211, 955, 13, 14 ], [ 229, 955, 56, 14 ], [ 289, 955, 76, 14 ], [ 369, 955, 34, 14 ], [ 407, 955, 11, 14 ], [ 423, 955, 25, 14 ], [ 452, 955, 24, 14 ], [ 479, 955, 45, 14 ], [ 529, 955, 22, 14 ], [ 555, 955, 18, 14 ], [ 578, 955, 36, 14 ], [ 618, 955, 11, 14 ], [ 633, 955, 41, 14 ], [ 679, 955, 71, 14 ], [ 96, 971, 35, 14 ], [ 134, 971, 23, 14 ], [ 160, 971, 19, 14 ], [ 182, 971, 46, 14 ], [ 232, 971, 55, 14 ], [ 290, 971, 20, 14 ], [ 313, 971, 22, 14 ], [ 338, 971, 48, 14 ], [ 389, 971, 24, 14 ], [ 416, 971, 12, 14 ], [ 432, 971, 43, 14 ], [ 478, 971, 6, 14 ], [ 488, 971, 65, 14 ], [ 556, 971, 22, 14 ], [ 582, 971, 12, 14 ], [ 598, 971, 21, 14 ], [ 622, 971, 18, 14 ], [ 644, 971, 59, 14 ], [ 705, 971, 22, 14 ], [ 731, 971, 19, 14 ], [ 96, 987, 24, 14 ], [ 123, 987, 49, 14 ], [ 175, 987, 11, 14 ], [ 190, 987, 88, 14 ], [ 281, 987, 56, 14 ], [ 341, 987, 28, 14 ], [ 373, 987, 12, 14 ], [ 388, 987, 18, 14 ], [ 410, 987, 56, 14 ], [ 469, 987, 11, 14 ], [ 484, 987, 39, 14 ], [ 526, 987, 37, 14 ], [ 566, 987, 9, 14 ], [ 578, 987, 19, 14 ], [ 601, 987, 60, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "BMC", "Infectious", "Diseases", "Research", "article", "Impact", "of", "Empiric", "Antimicrobial", "Therapy", "on", "Outcomes", "in", "Patients", "with", "Escherichia", "coli", "and", "Klebsiella", "pneumoniae", "Bacteremia:", "A", "Cohort", "Study", "Kerri", "A", "Thom*1,", "Marin", "L", "Schweizer1,", "Regina", "B", "Osih2,", "Jessina", "C", "McGregor3,", "Jon", "P", "Furuno1,", "Eli", "N", "Perencevich4,1", "and", "Anthony", "D", "Harris1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "Epidemiology", "and", "Preventive", "Medicine,", "University", "of", "Maryland", "School", "of", "Medicine,", "Baltimore,", "MD,", "USA,", "2Department", "of", "Medicine,", "Centre", "Hospitalier", "Universitaire", "Vaudois", "and", "University", "of", "Lausanne,", "Lausanne,", "Switzerland,", "3College", "of", "Pharmacy,", "Oregon", "State", "University,", "Portland,", "OR,", "USA", "and", "4Vetrans", "Affairs", "Maryland", "Health", "Care", "System,", "Baltimore,", "MD,", "USA", "Email:", "Kerri", "A", "Thom*", "-", "kthoms@medicine.umaryland.edu;", "Marin", "L", "Schweizer", "-", "mschweiz@epi.umaryland.edu;", "Regina", "B", "Osih", "-", "regina_osih@yahoo.com;", "Jessina", "C", "McGregor", "-", "mcgregoj@ohsu.edu;", "Jon", "P", "Furuno", "-", "jfuruno@epi.umaryland.edu;", "Eli", "N", "Perencevich", "-", "eperence@epi.umaryland.edu;", "Anthony", "D", "Harris", "-", "aharris@epi.umaryland.edu", "*", "Corresponding", "author", "Published:", "15", "September", "2008", "BMC", "Infectious", "Diseases", "2008,", "8:116", "doi:10.1186/1471-2334-8-116", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2334/8/116", "Received:", "12", "February", "2008", "Accepted:", "15", "September", "2008", "©", "2008", "Thom", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "It", "is", "unclear", "whether", "appropriate", "empiric", "antimicrobial", "therapy", "improves", "outcomes", "in", "patients", "with", "bacteremia", "due", "to", "Escherichia", "coli", "or", "Klebsiella.", "The", "objective", "of", "this", "study", "is", "to", "assess", "the", "impact", "of", "appropriate", "empiric", "antimicrobial", "therapy", "on", "in-hospital", "mortality", "and", "post-infection", "length", "of", "stay", "in", "patients", "with", "Escherichia", "coli", "or", "Klebsiella", "bacteremia", "while", "adjusting", "for", "important", "confounding", "variables.", "Methods:", "We", "performed", "a", "retrospective", "cohort", "study", "of", "adult", "patients", "with", "a", "positive", "blood", "culture", "for", "E.", "coli", "or", "Klebsiella", "between", "January", "1,", "2001", "and", "June", "8,", "2005", "and", "compared", "in-hospital", "mortality", "and", "post-infection", "length", "of", "stay", "between", "subjects", "who", "received", "appropriate", "and", "inappropriate", "empiric", "antimicrobial", "therapy.", "Empiric", "therapy", "was", "defined", "as", "the", "receipt", "of", "an", "antimicrobial", "agent", "between", "8", "hours", "before", "and", "24", "hours", "after", "the", "index", "blood", "culture", "was", "drawn", "and", "was", "considered", "appropriate", "if", "it", "included", "antimicrobials", "to", "which", "the", "specific", "isolate", "displayed", "in", "vitro", "susceptibility.", "Data", "were", "collected", "electronically", "and", "through", "chart", "review.", "Survival", "analysis", "was", "used", "to", "statistically", "assess", "the", "association", "between", "empiric", "antimicrobial", "therapy", "and", "outcome", "(mortality", "or", "length", "of", "stay).", "Multivariable", "Cox", "proportional", "hazards", "models", "were", "used", "to", "calculate", "hazard", "ratios", "(HR)", "and", "95%", "confidence", "intervals", "(CI).", "Results:", "Among", "416", "episodes", "of", "bacteremia,", "305", "(73.3%)", "patients", "received", "appropriate", "empiric", "antimicrobial", "therapy.", "Seventy-one", "(17%)", "patients", "died", "before", "discharge", "from", "the", "hospital.", "The", "receipt", "of", "appropriate", "antimicrobial", "agents", "was", "more", "common", "in", "hospital", "survivors", "than", "in", "those", "who", "died", "(p", "=", "0.04).", "After", "controlling", "for", "confounding", "variables,", "there", "was", "no", "association", "between", "the", "receipt", "of", "appropriate", "empiric", "antimicrobial", "therapy", "and", "in-hospital", "mortality", "(HR,", "1.03;", "95%", "CI,", "0.60", "to", "1.78).", "The", "median", "post-infection", "length", "of", "stay", "was", "7", "days.", "The", "receipt", "of", "appropriate", "antimicrobial", "agents", "was", "not", "associated", "with", "shortened", "post-infection", "length", "of", "stay,", "even", "after", "controlling", "for", "confounding", "(HR,", "1.11;", "95%", "CI", "0.86", "to", "1.44).", "Conclusion:", "Appropriate", "empiric", "antimicrobial", "therapy", "for", "E.", "coli", "and", "Klebsiella", "bacteremia", "is", "not", "associated", "with", "lower", "in-hospital", "mortality", "or", "shortened", "post-infection", "length", "of", "stay.", "This", "suggests", "that", "the", "choice", "of", "empiric", "antimicrobial", "agents", "may", "not", "improve", "outcomes", "and", "also", "provides", "data", "to", "support", "a", "randomized", "trial", "to", "test", "the", "hypothesis", "that", "use", "(and", "overuse)", "of", "broad-spectrum", "antibiotics", "prior", "to", "the", "availability", "of", "culture", "results", "is", "not", "warranted.", "Page", "1", "of", "9", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 72, 61, 39, 12 ], [ 113, 61, 48, 12 ], [ 163, 61, 56, 12 ], [ 72, 75, 60, 11 ], [ 134, 75, 39, 11 ], [ 175, 75, 40, 11 ], [ 72, 88, 35, 12 ], [ 109, 88, 24, 12 ], [ 135, 88, 30, 12 ], [ 168, 88, 12, 12 ], [ 182, 88, 35, 12 ], [ 219, 88, 6, 12 ], [ 227, 88, 25, 12 ], [ 72, 101, 112, 12 ], [ 72, 177, 134, 25 ], [ 210, 177, 67, 25 ], [ 72, 210, 128, 25 ], [ 204, 210, 51, 25 ], [ 260, 210, 48, 25 ], [ 313, 210, 31, 25 ], [ 349, 210, 74, 25 ], [ 427, 210, 110, 25 ], [ 542, 210, 53, 25 ], [ 600, 210, 122, 25 ], [ 72, 238, 43, 25 ], [ 120, 238, 92, 25 ], [ 216, 238, 102, 25 ], [ 323, 238, 91, 25 ], [ 418, 238, 33, 25 ], [ 455, 238, 37, 25 ], [ 497, 238, 47, 25 ], [ 549, 238, 42, 25 ], [ 595, 238, 99, 25 ], [ 120, 313, 51, 14 ], [ 173, 311, 62, 16 ], [ 238, 313, 69, 14 ], [ 310, 311, 64, 16 ], [ 377, 313, 52, 14 ], [ 431, 313, 13, 14 ], [ 447, 311, 50, 16 ], [ 500, 313, 48, 14 ], [ 550, 311, 35, 16 ], [ 588, 313, 43, 14 ], [ 634, 311, 70, 16 ], [ 120, 330, 39, 14 ], [ 161, 328, 64, 16 ], [ 228, 330, 30, 14 ], [ 261, 330, 12, 14 ], [ 275, 328, 53, 16 ], [ 332, 330, 24, 14 ], [ 358, 330, 22, 14 ], [ 382, 328, 51, 16 ], [ 434, 328, 6, 10 ], [ 121, 355, 5, 9 ], [ 126, 356, 40, 13 ], [ 169, 356, 28, 13 ], [ 199, 356, 33, 13 ], [ 235, 356, 14, 13 ], [ 251, 356, 51, 13 ], [ 304, 356, 45, 13 ], [ 351, 356, 50, 13 ], [ 404, 356, 9, 13 ], [ 416, 356, 47, 13 ], [ 465, 356, 30, 13 ], [ 498, 356, 24, 13 ], [ 524, 356, 33, 13 ], [ 559, 356, 31, 13 ], [ 593, 356, 28, 13 ], [ 623, 356, 37, 13 ], [ 663, 356, 18, 13 ], [ 683, 356, 33, 13 ], [ 718, 356, 23, 13 ], [ 121, 370, 5, 9 ], [ 126, 371, 64, 13 ], [ 193, 371, 19, 13 ], [ 214, 371, 79, 13 ], [ 296, 371, 9, 13 ], [ 308, 371, 15, 13 ], [ 325, 371, 42, 13 ], [ 369, 371, 19, 13 ], [ 391, 371, 46, 13 ], [ 439, 371, 61, 13 ], [ 502, 371, 23, 13 ], [ 527, 371, 21, 13 ], [ 550, 371, 6, 13 ], [ 559, 371, 34, 13 ], [ 596, 371, 40, 13 ], [ 638, 371, 52, 13 ], [ 693, 371, 33, 13 ], [ 728, 371, 33, 13 ], [ 121, 384, 5, 9 ], [ 126, 385, 32, 13 ], [ 161, 385, 42, 13 ], [ 206, 385, 44, 13 ], [ 252, 385, 59, 13 ], [ 314, 385, 9, 13 ], [ 325, 385, 25, 13 ], [ 352, 385, 19, 13 ], [ 374, 385, 19, 13 ], [ 395, 385, 62, 13 ], [ 460, 385, 44, 13 ], [ 506, 385, 49, 13 ], [ 557, 385, 32, 13 ], [ 591, 385, 24, 13 ], [ 618, 385, 31, 13 ], [ 651, 385, 37, 13 ], [ 126, 400, 51, 13 ], [ 180, 400, 19, 13 ], [ 202, 400, 33, 13 ], [ 237, 400, 23, 13 ], [ 120, 425, 83, 13 ], [ 205, 425, 35, 13 ], [ 242, 425, 12, 13 ], [ 256, 425, 49, 13 ], [ 308, 425, 11, 13 ], [ 321, 425, 17, 13 ], [ 340, 425, 36, 13 ], [ 378, 425, 84, 13 ], [ 121, 451, 44, 13 ], [ 167, 451, 12, 13 ], [ 182, 451, 53, 13 ], [ 237, 451, 27, 13 ], [ 267, 451, 46, 13 ], [ 315, 451, 6, 13 ], [ 324, 451, 20, 13 ], [ 346, 451, 24, 13 ], [ 121, 476, 75, 13 ], [ 199, 476, 12, 13 ], [ 213, 476, 16, 13 ], [ 232, 476, 44, 13 ], [ 121, 502, 49, 13 ], [ 172, 502, 16, 13 ], [ 191, 502, 22, 13 ], [ 216, 502, 42, 13 ], [ 260, 502, 16, 13 ], [ 280, 502, 65, 13 ], [ 348, 502, 10, 13 ], [ 361, 502, 6, 13 ], [ 370, 502, 28, 13 ], [ 400, 502, 43, 13 ], [ 447, 502, 32, 13 ], [ 482, 502, 43, 13 ], [ 528, 502, 45, 13 ], [ 576, 502, 56, 13 ], [ 635, 502, 22, 13 ], [ 660, 502, 23, 13 ], [ 686, 502, 31, 13 ], [ 720, 502, 17, 13 ], [ 739, 502, 24, 13 ], [ 121, 516, 36, 13 ], [ 162, 516, 15, 13 ], [ 181, 516, 16, 13 ], [ 202, 516, 52, 13 ], [ 258, 516, 20, 13 ], [ 283, 516, 19, 13 ], [ 306, 516, 52, 13 ], [ 363, 516, 74, 13 ], [ 441, 516, 38, 13 ], [ 483, 516, 58, 13 ], [ 545, 516, 61, 13 ], [ 611, 516, 42, 13 ], [ 658, 516, 33, 13 ], [ 695, 516, 19, 13 ], [ 719, 516, 45, 13 ], [ 121, 531, 16, 13 ], [ 142, 531, 23, 13 ], [ 170, 531, 51, 13 ], [ 226, 531, 56, 13 ], [ 287, 531, 22, 13 ], [ 315, 531, 20, 13 ], [ 340, 531, 10, 13 ], [ 355, 531, 6, 13 ], [ 366, 531, 41, 13 ], [ 412, 531, 58, 13 ], [ 475, 531, 10, 13 ], [ 491, 531, 16, 13 ], [ 512, 531, 56, 13 ], [ 573, 531, 46, 13 ], [ 624, 531, 49, 13 ], [ 679, 531, 6, 13 ], [ 690, 531, 74, 13 ], [ 121, 545, 22, 13 ], [ 148, 545, 51, 13 ], [ 205, 545, 11, 13 ], [ 221, 545, 44, 13 ], [ 271, 545, 19, 13 ], [ 296, 545, 65, 13 ], [ 366, 545, 40, 13 ], [ 411, 545, 55, 13 ], [ 472, 545, 23, 13 ], [ 500, 545, 16, 13 ], [ 522, 545, 86, 13 ], [ 613, 545, 56, 13 ], [ 675, 545, 46, 13 ], [ 727, 545, 37, 13 ], [ 121, 560, 56, 13 ], [ 182, 560, 22, 13 ], [ 210, 560, 20, 13 ], [ 235, 560, 31, 13 ], [ 272, 560, 16, 13 ], [ 293, 560, 29, 13 ], [ 328, 560, 11, 13 ], [ 343, 560, 43, 13 ], [ 391, 560, 50, 13 ], [ 446, 560, 19, 13 ], [ 470, 560, 63, 13 ], [ 539, 560, 28, 13 ], [ 572, 560, 48, 13 ], [ 625, 560, 40, 13 ], [ 670, 560, 11, 13 ], [ 685, 560, 6, 13 ], [ 696, 560, 67, 13 ], [ 121, 574, 37, 13 ], [ 162, 574, 89, 13 ], [ 255, 574, 44, 13 ], [ 303, 574, 19, 13 ], [ 326, 574, 8, 13 ], [ 338, 574, 38, 13 ], [ 380, 574, 11, 13 ], [ 394, 574, 42, 13 ], [ 440, 574, 59, 13 ], [ 503, 574, 33, 13 ], [ 539, 574, 25, 13 ], [ 568, 574, 67, 13 ], [ 640, 574, 39, 13 ], [ 682, 574, 11, 13 ], [ 697, 574, 23, 13 ], [ 724, 574, 40, 13 ], [ 121, 589, 94, 13 ], [ 218, 589, 53, 13 ], [ 274, 589, 54, 13 ], [ 331, 589, 23, 13 ], [ 357, 589, 16, 13 ], [ 376, 589, 80, 13 ], [ 459, 589, 120, 13 ], [ 583, 589, 39, 13 ], [ 624, 589, 45, 13 ], [ 673, 589, 12, 13 ], [ 688, 589, 16, 13 ], [ 708, 589, 56, 13 ], [ 121, 603, 46, 13 ], [ 169, 603, 16, 13 ], [ 187, 603, 21, 13 ], [ 211, 603, 8, 13 ], [ 221, 603, 21, 13 ], [ 244, 603, 11, 13 ], [ 256, 603, 31, 13 ], [ 289, 603, 33, 13 ], [ 324, 603, 53, 13 ], [ 379, 603, 55, 13 ], [ 436, 603, 11, 13 ], [ 449, 603, 28, 13 ], [ 479, 603, 23, 13 ], [ 504, 603, 20, 13 ], [ 525, 603, 11, 13 ], [ 538, 603, 6, 13 ], [ 546, 603, 45, 13 ], [ 593, 603, 24, 13 ], [ 619, 603, 37, 13 ], [ 658, 603, 33, 13 ], [ 693, 603, 16, 13 ], [ 712, 603, 52, 13 ], [ 121, 618, 53, 13 ], [ 176, 618, 30, 13 ], [ 209, 618, 16, 13 ], [ 227, 618, 39, 13 ], [ 268, 618, 34, 13 ], [ 305, 618, 75, 13 ], [ 382, 618, 21, 13 ], [ 405, 618, 35, 13 ], [ 442, 618, 11, 13 ], [ 455, 618, 47, 13 ], [ 504, 618, 11, 13 ], [ 517, 618, 20, 13 ], [ 540, 618, 17, 13 ], [ 559, 618, 38, 13 ], [ 599, 618, 19, 13 ], [ 620, 618, 65, 13 ], [ 688, 618, 11, 13 ], [ 701, 618, 16, 13 ], [ 720, 618, 44, 13 ], [ 121, 632, 20, 13 ], [ 145, 632, 39, 13 ], [ 187, 632, 27, 13 ], [ 219, 632, 35, 13 ], [ 257, 632, 21, 13 ], [ 281, 632, 20, 13 ], [ 306, 632, 40, 13 ], [ 349, 632, 61, 13 ], [ 414, 632, 20, 13 ], [ 438, 632, 65, 13 ], [ 506, 632, 10, 13 ], [ 520, 632, 13, 13 ], [ 537, 632, 52, 13 ], [ 593, 632, 72, 13 ], [ 668, 632, 61, 13 ], [ 733, 632, 10, 13 ], [ 747, 632, 16, 13 ], [ 121, 647, 71, 13 ], [ 195, 647, 23, 13 ], [ 220, 647, 23, 13 ], [ 246, 647, 26, 13 ], [ 274, 647, 22, 13 ], [ 298, 647, 11, 13 ], [ 311, 647, 38, 13 ], [ 351, 647, 11, 13 ], [ 364, 647, 16, 13 ], [ 383, 647, 21, 13 ], [ 406, 647, 44, 13 ], [ 452, 647, 35, 13 ], [ 489, 647, 27, 13 ], [ 519, 647, 44, 13 ], [ 565, 647, 15, 13 ], [ 583, 647, 89, 13 ], [ 674, 647, 45, 13 ], [ 722, 647, 42, 13 ], [ 121, 661, 51, 13 ], [ 175, 661, 40, 13 ], [ 217, 661, 11, 13 ], [ 230, 661, 6, 13 ], [ 238, 661, 27, 13 ], [ 267, 661, 40, 13 ], [ 310, 661, 46, 13 ], [ 358, 661, 18, 13 ], [ 378, 661, 44, 13 ], [ 424, 661, 51, 13 ], [ 121, 688, 52, 13 ], [ 175, 688, 9, 13 ], [ 187, 688, 24, 13 ], [ 214, 688, 41, 13 ], [ 257, 688, 44, 13 ], [ 304, 688, 10, 13 ], [ 316, 688, 12, 13 ], [ 332, 688, 22, 13 ], [ 359, 688, 8, 13 ], [ 371, 688, 13, 13 ], [ 388, 688, 26, 13 ], [ 418, 688, 30, 13 ], [ 452, 688, 31, 13 ], [ 488, 688, 55, 13 ], [ 548, 688, 30, 13 ], [ 582, 688, 16, 13 ], [ 603, 688, 41, 13 ], [ 649, 688, 53, 13 ], [ 706, 688, 58, 13 ], [ 121, 702, 40, 13 ], [ 164, 702, 31, 13 ], [ 198, 702, 39, 13 ], [ 240, 702, 61, 13 ], [ 304, 702, 20, 13 ], [ 327, 702, 63, 13 ], [ 394, 702, 19, 13 ], [ 416, 702, 66, 13 ], [ 486, 702, 11, 13 ], [ 499, 702, 18, 13 ], [ 521, 702, 46, 13 ], [ 570, 702, 45, 13 ], [ 618, 702, 16, 13 ], [ 637, 702, 39, 13 ], [ 680, 702, 26, 13 ], [ 709, 702, 8, 13 ], [ 721, 702, 43, 13 ], [ 121, 717, 28, 13 ], [ 72, 766, 12, 14 ], [ 97, 766, 98, 14 ], [ 72, 798, 56, 14 ], [ 132, 798, 9, 14 ], [ 144, 798, 41, 14 ], [ 188, 798, 7, 14 ], [ 198, 798, 46, 14 ], [ 247, 798, 22, 14 ], [ 272, 798, 12, 14 ], [ 287, 798, 38, 14 ], [ 328, 798, 20, 14 ], [ 351, 798, 55, 14 ], [ 72, 814, 96, 14 ], [ 176, 814, 33, 14 ], [ 216, 814, 15, 14 ], [ 239, 814, 51, 14 ], [ 298, 814, 48, 14 ], [ 354, 814, 52, 14 ], [ 72, 830, 19, 14 ], [ 96, 830, 59, 14 ], [ 160, 830, 29, 14 ], [ 194, 830, 73, 14 ], [ 272, 830, 14, 14 ], [ 292, 830, 65, 14 ], [ 362, 830, 9, 14 ], [ 376, 830, 30, 14 ], [ 72, 846, 38, 14 ], [ 113, 846, 68, 14 ], [ 184, 846, 48, 14 ], [ 235, 846, 12, 14 ], [ 250, 846, 83, 14 ], [ 336, 846, 44, 14 ], [ 383, 846, 22, 14 ], [ 72, 861, 48, 14 ], [ 127, 861, 17, 14 ], [ 151, 861, 31, 14 ], [ 189, 861, 49, 14 ], [ 245, 861, 17, 14 ], [ 269, 861, 26, 14 ], [ 302, 861, 75, 14 ], [ 384, 861, 21, 14 ], [ 72, 877, 59, 14 ], [ 134, 877, 53, 14 ], [ 190, 877, 58, 14 ], [ 251, 877, 24, 14 ], [ 278, 877, 41, 14 ], [ 322, 877, 28, 14 ], [ 353, 877, 53, 14 ], [ 72, 893, 44, 14 ], [ 122, 893, 9, 14 ], [ 137, 893, 76, 14 ], [ 219, 893, 21, 14 ], [ 246, 893, 12, 14 ], [ 264, 893, 7, 14 ], [ 276, 893, 27, 14 ], [ 309, 893, 34, 14 ], [ 350, 893, 9, 14 ], [ 365, 893, 41, 14 ], [ 72, 909, 18, 14 ], [ 95, 909, 50, 14 ], [ 150, 909, 12, 14 ], [ 167, 909, 18, 14 ], [ 191, 909, 57, 14 ], [ 253, 909, 77, 14 ], [ 335, 909, 22, 14 ], [ 363, 909, 43, 14 ], [ 72, 925, 46, 14 ], [ 121, 925, 12, 14 ], [ 137, 925, 53, 14 ], [ 193, 925, 24, 14 ], [ 221, 925, 43, 14 ], [ 268, 925, 32, 14 ], [ 303, 925, 28, 14 ], [ 334, 925, 71, 14 ], [ 72, 940, 33, 14 ], [ 107, 940, 47, 14 ], [ 156, 940, 11, 14 ], [ 170, 940, 26, 14 ], [ 198, 940, 62, 14 ], [ 263, 940, 66, 14 ], [ 332, 940, 20, 14 ], [ 354, 940, 30, 14 ], [ 386, 940, 19, 14 ], [ 72, 956, 64, 14 ], [ 141, 956, 45, 14 ], [ 191, 956, 68, 14 ], [ 264, 956, 19, 14 ], [ 289, 956, 61, 14 ], [ 355, 956, 28, 14 ], [ 388, 956, 18, 14 ], [ 72, 972, 57, 14 ], [ 133, 972, 44, 14 ], [ 181, 972, 34, 14 ], [ 220, 972, 52, 14 ], [ 276, 972, 26, 14 ], [ 307, 972, 99, 14 ], [ 72, 988, 50, 14 ], [ 128, 988, 9, 14 ], [ 142, 988, 29, 14 ], [ 177, 988, 42, 14 ], [ 225, 988, 43, 14 ], [ 273, 988, 11, 14 ], [ 290, 988, 57, 14 ], [ 353, 988, 53, 14 ], [ 72, 1004, 69, 14 ], [ 145, 1004, 17, 14 ], [ 167, 1004, 60, 14 ], [ 232, 1004, 12, 14 ], [ 248, 1004, 48, 15 ], [ 301, 1004, 70, 14 ], [ 375, 1004, 30, 14 ], [ 72, 1019, 55, 14 ], [ 133, 1019, 86, 14 ], [ 224, 1019, 28, 14 ], [ 258, 1019, 29, 14 ], [ 293, 1019, 24, 14 ], [ 323, 1019, 38, 14 ], [ 367, 1019, 20, 14 ], [ 392, 1019, 13, 14 ], [ 430, 767, 52, 14 ], [ 492, 767, 21, 14 ], [ 522, 767, 48, 14 ], [ 579, 767, 80, 14 ], [ 668, 767, 12, 14 ], [ 689, 767, 18, 14 ], [ 716, 767, 48, 14 ], [ 430, 782, 47, 14 ], [ 482, 782, 24, 14 ], [ 512, 782, 43, 14 ], [ 560, 782, 54, 14 ], [ 619, 782, 60, 14 ], [ 684, 782, 29, 14 ], [ 719, 782, 46, 14 ], [ 430, 798, 43, 14 ], [ 476, 798, 12, 14 ], [ 490, 798, 103, 14 ], [ 596, 798, 36, 14 ], [ 635, 798, 35, 14 ], [ 673, 798, 50, 14 ], [ 726, 798, 19, 14 ], [ 747, 798, 17, 14 ], [ 430, 814, 57, 14 ], [ 490, 814, 24, 14 ], [ 518, 814, 43, 14 ], [ 564, 814, 12, 14 ], [ 579, 814, 73, 14 ], [ 655, 814, 24, 14 ], [ 682, 814, 21, 14 ], [ 707, 814, 25, 14 ], [ 735, 814, 30, 14 ], [ 430, 830, 17, 14 ], [ 452, 830, 132, 14 ], [ 589, 830, 37, 14 ], [ 631, 830, 18, 14 ], [ 654, 830, 49, 14 ], [ 708, 830, 26, 14 ], [ 739, 830, 25, 14 ], [ 430, 846, 25, 14 ], [ 459, 846, 9, 14 ], [ 472, 846, 45, 14 ], [ 521, 846, 45, 14 ], [ 571, 846, 53, 14 ], [ 628, 846, 43, 14 ], [ 675, 846, 54, 14 ], [ 734, 846, 30, 14 ], [ 430, 861, 46, 14 ], [ 478, 861, 26, 14 ], [ 506, 861, 17, 14 ], [ 525, 861, 39, 14 ], [ 566, 861, 53, 14 ], [ 620, 861, 18, 14 ], [ 640, 861, 41, 14 ], [ 684, 861, 9, 14 ], [ 695, 861, 54, 14 ], [ 750, 861, 14, 14 ], [ 430, 877, 18, 14 ], [ 451, 877, 21, 14 ], [ 475, 877, 22, 14 ], [ 500, 877, 18, 14 ], [ 521, 877, 43, 14 ], [ 568, 877, 12, 14 ], [ 583, 877, 6, 14 ], [ 592, 877, 45, 14 ], [ 640, 877, 39, 14 ], [ 682, 877, 17, 14 ], [ 702, 877, 62, 14 ], [ 430, 893, 50, 14 ], [ 485, 893, 45, 14 ], [ 535, 893, 18, 14 ], [ 557, 893, 75, 14 ], [ 636, 893, 12, 14 ], [ 653, 893, 18, 14 ], [ 675, 893, 50, 14 ], [ 730, 893, 12, 14 ], [ 746, 893, 18, 14 ], [ 430, 909, 27, 14 ], [ 461, 909, 43, 14 ], [ 507, 909, 83, 14 ], [ 593, 909, 21, 14 ], [ 618, 909, 38, 14 ], [ 659, 909, 12, 14 ], [ 674, 909, 57, 14 ], [ 735, 909, 29, 14 ], [ 430, 925, 25, 14 ], [ 458, 925, 25, 14 ], [ 486, 925, 22, 14 ], [ 512, 925, 21, 14 ], [ 537, 925, 54, 14 ], [ 594, 925, 48, 14 ], [ 645, 925, 21, 14 ], [ 670, 925, 53, 14 ], [ 727, 925, 7, 14 ], [ 737, 925, 27, 14 ], [ 430, 940, 43, 14 ], [ 476, 940, 17, 14 ], [ 495, 940, 18, 14 ], [ 515, 940, 55, 14 ], [ 572, 940, 42, 14 ], [ 616, 940, 48, 14 ], [ 667, 940, 14, 14 ], [ 682, 940, 36, 14 ], [ 721, 940, 43, 14 ], [ 430, 956, 13, 14 ], [ 446, 956, 48, 14 ], [ 498, 956, 21, 14 ], [ 522, 956, 9, 14 ], [ 535, 956, 26, 14 ], [ 564, 956, 66, 14 ], [ 633, 956, 21, 14 ], [ 658, 956, 19, 14 ], [ 681, 956, 83, 14 ], [ 430, 972, 17, 14 ], [ 450, 972, 28, 14 ], [ 481, 972, 57, 14 ], [ 451, 988, 12, 14 ], [ 470, 988, 18, 14 ], [ 495, 988, 23, 14 ], [ 524, 988, 21, 14 ], [ 552, 988, 23, 14 ], [ 581, 988, 82, 14 ], [ 670, 988, 42, 14 ], [ 718, 988, 46, 14 ], [ 430, 1003, 33, 14 ], [ 466, 1003, 7, 14 ], [ 476, 1003, 73, 14 ], [ 551, 1003, 46, 14 ], [ 600, 1003, 15, 14 ], [ 619, 1003, 12, 14 ], [ 634, 1003, 35, 14 ], [ 672, 1003, 53, 14 ], [ 728, 1003, 24, 14 ], [ 755, 1003, 9, 14 ], [ 430, 1019, 55, 14 ], [ 489, 1019, 52, 14 ], [ 543, 1019, 28, 14 ], [ 575, 1019, 33, 14 ], [ 611, 1019, 52, 14 ], [ 666, 1019, 12, 14 ], [ 681, 1019, 26, 14 ], [ 711, 1019, 53, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Experimental", "Diabetes", "Research", "Volume", "2008,", "Article", "ID", "312060,", "9", "pages", "doi:10.1155/2008/312060", "Methodology", "Report", "GeneSpeed", "Beta", "Cell:", "An", "Online", "Genomics", "Data", "Repository", "and", "Analysis", "Resource", "Tailored", "for", "the", "Islet", "Cell", "Biologist", "Nayeem", "Quayum,1", "Alecksandr", "Kutchma,1", "Suparna", "A.", "Sarkar,1", "Kirstine", "Juhl,1", "Gerard", "Gradwohl,2", "Georg", "Mellitzer,2", "John", "C.", "Hutton,1", "and", "Jan", "Jensen1,", "3", "1", "Barbara", "Davis", "Center", "for", "Childhood", "Diabetes,", "University", "of", "Colorado,", "HSC.,", "1775", "Ursula", "Street,", "B140,", "Aurora,", "CO", "80045,", "USA", "2", "Development", "and", "Physiopathology", "of", "the", "Intestine", "and", "Pancreas,", "Inserm-ULP", "Unit", "682,", "3", "avenue", "Moli`ere,", "Strasbourg", "67200,", "France", "3", "Lerner", "Research", "Institute,", "Department", "of", "Stem", "Cell", "and", "Regenerative", "medicine", "Cleveland", "Clinic,", "9500", "Euclid", "avenue,", "Cleveland,", "OH", "44195,", "USA", "Correspondence", "should", "be", "addressed", "to", "Jan", "Jensen,", "jensenj2@ccf.org", "Received", "29", "November", "2007;", "Accepted", "9", "July", "2008", "Recommended", "by", "Ulf", "Eriksson", "Objective.", "We", "here", "describe", "the", "development", "of", "a", "freely", "available", "online", "database", "resource,", "GeneSpeed", "Beta", "Cell,", "which", "has", "been", "created", "for", "the", "pancreatic", "islet", "and", "pancreatic", "developmental", "biology", "investigator", "community.", "Research", "Design", "and", "Methods.", "We", "have", "developed", "GeneSpeed", "Beta", "Cell", "as", "a", "separate", "component", "of", "the", "GeneSpeed", "database,", "providing", "a", "genomics-type", "data", "repository", "of", "pancreas", "and", "islet-relevant", "datasets", "interlinked", "with", "the", "domain-oriented", "GeneSpeed", "database.", "Results.", "GeneSpeed", "Beta", "Cell", "allows", "the", "query", "of", "multiple", "published", "and", "unpublished", "select", "genomics", "datasets", "in", "a", "simultaneous", "fashion", "(multiexperiment", "viewing)", "and", "is", "capable", "of", "defining", "intersection", "results", "from", "precomputed", "analysis", "of", "such", "datasets", "(multidimensional", "querying).", "Combined", "with", "the", "protein-domain", "categorization/assembly", "toolbox", "provided", "by", "the", "GeneSpeed", "database,", "the", "user", "is", "able", "to", "define", "spatial", "expression", "constraints", "of", "select", "gene", "lists", "in", "a", "relatively", "rigid", "fashion", "within", "the", "pancreatic", "expression", "space.", "We", "provide", "several", "demonstration", "case", "studies", "of", "relevance", "to", "islet", "cell", "biology", "and", "development", "of", "the", "pancreas", "that", "provide", "novel", "insight", "into", "islet", "biology.", "Conclusions.", "The", "combination", "of", "an", "exhaustive", "domain-based", "compilation", "of", "the", "transcriptome", "with", "gene", "array", "data", "of", "interest", "to", "the", "islet", "biologist", "affords", "novel", "methods", "for", "multidimensional", "querying", "between", "individual", "datasets", "in", "a", "rapid", "fashion,", "presently", "not", "available", "elsewhere.", "Copyright", "©", "2008", "Nayeem", "Quayum", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "1.", "INTRODUCTION", "Genomics", "is", "playing", "a", "growing", "role", "in", "almost", "any", "biological", "experimentation.", "Based", "on", "presently", "available", "commer-", "cial", "expression", "array", "technologies,", "an", "investigator", "is", "given", "almost", "full-genome", "coverage", "of", "transcriptional", "changes", "that", "provides", "for", "novel", "methods", "for", "gene", "identification", "and", "validation.", "However,", "exhaustive", "data", "mining", "from", "genomics", "datasets", "is", "cumbersome,", "and", "to", "a", "large", "extent", "is", "outside", "the", "expertise", "of", "the", "individual", "experimenter.", "The", "greatest", "strength", "in", "genomics", "data", "analysis", "stems", "from", "multidimen-", "sional", "analysis,", "as", "such", "orthogonal", "comparison", "can", "bring", "out", "biologically", "relevant", "information", "not", "extractable", "from", "the", "individual", "datasets", "alone.", "However,", "such", "multidimensional", "querying", "is", "often", "advised", "against,", "as", "individual", "genomics", "experiments", "are", "performed", "in", "different", "laboratories,", "using", "dissimilar", "methodologies.", "Such", "array", "data", "should", "not", "be", "uploaded", "and", "analyzed", "concomitantly", "in", "the", "available", "software", "data", "analysis", "programs", "commonly", "used.", "Prudent", "analysis", "of", "multiexperimental", "results", "would", "therefore", "call", "for", "individual", "data", "analysis", "of", "experimental", "sets,", "and", "only", "parse", "for", "intersections/exclusions", "within", "the", "resulting", "gene", "lists.", "This", "is", "possible", "through", "genomics", "analysis", "platforms", "using", "separate", "gene", "list", "saving.", "However,", "the", "process", "is", "burdened", "by", "the", "fact", "that", "the", "analysis", "of", "a", "relevant", "dataset", "for", "orthogonal", "querying", "requires", "the", "identification", "of", "the", "existence", "of", "the", "data,", "upload,", "normalization,", "and", "scaling", "of", "individual", "DNA", "chip", "scan", "files", "and", "thereafter", "selecting", "and", "executing", "a", "valid", "analysis", "for", "the", "particular", "dataset,", "followed", "by", "results", "storage.", "In", "practice,", "this", "is", "time", "consuming,", "and", "too", "overwhelming,", "for", "most", "biologists.", "In", "the", "islet", "and", "islet", "developmental", "biology", "research", "fields,", "a", "continuously", "growing", "set", "of", "public", "genomics", "data", "is", "becoming", "available.", "Also,", "initial", "problems", "in", "both", "genomics" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 11, 11, 11, 11, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 78, 47, 24, 12 ], [ 105, 47, 9, 12 ], [ 117, 47, 11, 12 ], [ 131, 47, 48, 12 ], [ 182, 47, 46, 12 ], [ 231, 47, 25, 12 ], [ 259, 47, 20, 12 ], [ 78, 61, 241, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 109, 34 ], [ 198, 169, 152, 34 ], [ 360, 169, 27, 34 ], [ 397, 169, 155, 34 ], [ 562, 169, 25, 34 ], [ 597, 169, 139, 34 ], [ 78, 205, 82, 34 ], [ 170, 205, 106, 34 ], [ 287, 205, 27, 34 ], [ 323, 205, 71, 34 ], [ 405, 205, 70, 34 ], [ 485, 205, 72, 34 ], [ 567, 205, 69, 34 ], [ 78, 241, 167, 34 ], [ 255, 241, 25, 34 ], [ 290, 241, 16, 34 ], [ 316, 241, 78, 34 ], [ 404, 241, 134, 34 ], [ 78, 288, 47, 16 ], [ 129, 288, 32, 16 ], [ 166, 288, 53, 16 ], [ 223, 288, 40, 16 ], [ 267, 288, 42, 16 ], [ 313, 288, 18, 16 ], [ 335, 288, 21, 16 ], [ 361, 288, 32, 16 ], [ 398, 288, 31, 16 ], [ 433, 288, 18, 16 ], [ 456, 288, 40, 16 ], [ 500, 288, 37, 16 ], [ 542, 288, 72, 16 ], [ 618, 288, 13, 16 ], [ 635, 288, 31, 16 ], [ 671, 288, 26, 16 ], [ 78, 307, 58, 16 ], [ 140, 307, 37, 16 ], [ 182, 307, 27, 16 ], [ 213, 307, 41, 16 ], [ 259, 307, 18, 16 ], [ 281, 307, 19, 16 ], [ 305, 307, 22, 16 ], [ 331, 307, 52, 16 ], [ 388, 305, 22, 19 ], [ 87, 361, 54, 15 ], [ 87, 386, 76, 14 ], [ 167, 387, 21, 14 ], [ 192, 387, 45, 14 ], [ 241, 387, 64, 14 ], [ 309, 387, 11, 14 ], [ 324, 387, 53, 14 ], [ 382, 387, 60, 14 ], [ 446, 387, 11, 14 ], [ 461, 387, 59, 14 ], [ 524, 387, 32, 14 ], [ 560, 387, 22, 14 ], [ 586, 387, 49, 14 ], [ 639, 387, 55, 14 ], [ 698, 387, 12, 14 ], [ 87, 403, 30, 14 ], [ 121, 403, 76, 14 ], [ 202, 403, 22, 14 ], [ 228, 403, 31, 14 ], [ 263, 403, 26, 14 ], [ 293, 403, 12, 14 ], [ 309, 403, 41, 14 ], [ 354, 403, 45, 14 ], [ 403, 403, 64, 14 ], [ 471, 403, 11, 14 ], [ 486, 403, 65, 14 ], [ 556, 403, 11, 14 ], [ 571, 403, 58, 14 ], [ 633, 403, 34, 14 ], [ 87, 424, 56, 14 ], [ 148, 424, 57, 14 ], [ 208, 424, 60, 14 ], [ 272, 424, 59, 14 ], [ 335, 424, 35, 14 ], [ 374, 424, 7, 14 ], [ 386, 424, 28, 14 ], [ 418, 424, 11, 14 ], [ 433, 424, 7, 14 ], [ 444, 424, 33, 14 ], [ 481, 424, 56, 14 ], [ 541, 424, 11, 14 ], [ 556, 424, 59, 14 ], [ 619, 424, 32, 14 ], [ 655, 424, 28, 14 ], [ 687, 424, 49, 14 ], [ 87, 441, 55, 14 ], [ 147, 441, 12, 14 ], [ 163, 441, 19, 14 ], [ 186, 441, 30, 14 ], [ 220, 441, 71, 14 ], [ 87, 461, 46, 14 ], [ 137, 461, 30, 14 ], [ 171, 461, 42, 14 ], [ 218, 461, 27, 14 ], [ 249, 461, 12, 14 ], [ 265, 461, 58, 14 ], [ 327, 461, 29, 14 ], [ 361, 461, 7, 14 ], [ 372, 461, 25, 14 ], [ 401, 461, 45, 14 ], [ 450, 461, 11, 14 ], [ 465, 461, 29, 14 ], [ 499, 461, 45, 14 ], [ 548, 461, 25, 14 ], [ 576, 461, 60, 14 ], [ 641, 461, 28, 14 ], [ 673, 461, 65, 14 ], [ 87, 478, 11, 14 ], [ 103, 478, 34, 14 ], [ 141, 478, 40, 14 ], [ 185, 478, 30, 14 ], [ 219, 478, 60, 14 ], [ 283, 478, 59, 14 ], [ 347, 478, 15, 14 ], [ 366, 478, 26, 14 ], [ 397, 478, 40, 14 ], [ 441, 478, 11, 14 ], [ 456, 478, 21, 14 ], [ 481, 478, 38, 14 ], [ 524, 478, 60, 14 ], [ 588, 478, 52, 14 ], [ 644, 478, 26, 14 ], [ 674, 478, 21, 14 ], [ 87, 495, 52, 14 ], [ 144, 495, 53, 14 ], [ 201, 495, 60, 14 ], [ 265, 495, 22, 14 ], [ 291, 495, 47, 14 ], [ 343, 495, 65, 14 ], [ 412, 495, 28, 14 ], [ 444, 495, 17, 14 ], [ 465, 495, 21, 14 ], [ 491, 495, 26, 14 ], [ 522, 495, 68, 14 ], [ 593, 495, 34, 14 ], [ 632, 495, 52, 14 ], [ 688, 495, 31, 14 ], [ 87, 511, 22, 14 ], [ 113, 511, 19, 14 ], [ 136, 511, 32, 14 ], [ 172, 511, 45, 14 ], [ 221, 511, 11, 14 ], [ 237, 511, 44, 14 ], [ 285, 511, 47, 14 ], [ 336, 511, 63, 14 ], [ 403, 511, 21, 14 ], [ 429, 511, 19, 14 ], [ 452, 511, 46, 14 ], [ 502, 511, 21, 14 ], [ 527, 511, 63, 14 ], [ 595, 511, 22, 14 ], [ 620, 511, 19, 14 ], [ 644, 511, 54, 14 ], [ 702, 511, 21, 14 ], [ 87, 528, 19, 14 ], [ 111, 528, 14, 14 ], [ 129, 528, 50, 14 ], [ 183, 528, 11, 14 ], [ 199, 528, 74, 14 ], [ 277, 528, 60, 14 ], [ 341, 528, 28, 14 ], [ 373, 528, 12, 14 ], [ 389, 528, 42, 14 ], [ 435, 528, 37, 14 ], [ 476, 528, 28, 14 ], [ 508, 528, 30, 14 ], [ 542, 528, 63, 14 ], [ 609, 528, 59, 14 ], [ 672, 528, 50, 14 ], [ 87, 544, 63, 14 ], [ 154, 544, 28, 14 ], [ 186, 544, 27, 14 ], [ 218, 544, 59, 14 ], [ 281, 544, 49, 14 ], [ 334, 544, 27, 14 ], [ 365, 544, 60, 14 ], [ 430, 544, 11, 14 ], [ 445, 544, 44, 14 ], [ 493, 544, 58, 14 ], [ 555, 544, 53, 14 ], [ 612, 544, 34, 14 ], [ 650, 544, 46, 14 ], [ 87, 561, 63, 14 ], [ 154, 561, 52, 14 ], [ 211, 561, 53, 14 ], [ 268, 561, 62, 14 ], [ 335, 561, 21, 14 ], [ 360, 561, 42, 14 ], [ 406, 561, 68, 14 ], [ 478, 561, 83, 14 ], [ 565, 561, 68, 14 ], [ 638, 561, 63, 14 ], [ 87, 578, 58, 14 ], [ 150, 578, 65, 14 ], [ 220, 578, 59, 14 ], [ 282, 578, 33, 14 ], [ 320, 578, 21, 14 ], [ 344, 578, 11, 14 ], [ 360, 578, 12, 14 ], [ 376, 578, 32, 14 ], [ 412, 578, 21, 14 ], [ 438, 578, 28, 14 ], [ 470, 578, 57, 14 ], [ 531, 578, 47, 14 ], [ 583, 577, 59, 15 ], [ 646, 578, 25, 14 ], [ 87, 594, 84, 14 ], [ 176, 594, 28, 14 ], [ 208, 594, 51, 14 ], [ 263, 594, 36, 14 ], [ 303, 594, 21, 14 ], [ 329, 594, 24, 14 ], [ 87, 615, 75, 14 ], [ 167, 615, 21, 14 ], [ 192, 615, 53, 14 ], [ 249, 615, 60, 14 ], [ 313, 615, 11, 14 ], [ 329, 615, 59, 14 ], [ 392, 615, 32, 14 ], [ 428, 615, 53, 14 ], [ 485, 615, 31, 14 ], [ 520, 615, 80, 14 ], [ 604, 615, 44, 14 ], [ 652, 615, 36, 14 ], [ 692, 615, 12, 14 ], [ 708, 615, 31, 14 ], [ 87, 632, 48, 14 ], [ 140, 632, 11, 14 ], [ 155, 632, 49, 14 ], [ 208, 632, 27, 14 ], [ 239, 632, 44, 14 ], [ 288, 632, 22, 14 ], [ 313, 632, 30, 14 ], [ 348, 632, 54, 14 ], [ 405, 632, 12, 14 ], [ 421, 632, 23, 14 ], [ 448, 632, 12, 14 ], [ 464, 632, 30, 14 ], [ 498, 632, 41, 14 ], [ 544, 632, 11, 14 ], [ 559, 632, 34, 14 ], [ 598, 632, 46, 14 ], [ 648, 632, 31, 14 ], [ 683, 632, 50, 14 ], [ 87, 648, 44, 14 ], [ 136, 648, 41, 14 ], [ 180, 648, 46, 14 ], [ 231, 648, 21, 14 ], [ 256, 648, 25, 14 ], [ 286, 648, 56, 14 ], [ 346, 648, 11, 14 ], [ 361, 648, 40, 14 ], [ 405, 648, 27, 14 ], [ 437, 648, 19, 14 ], [ 460, 648, 60, 14 ], [ 524, 648, 21, 14 ], [ 549, 648, 59, 14 ], [ 612, 648, 68, 14 ], [ 684, 648, 53, 14 ], [ 87, 665, 15, 14 ], [ 107, 665, 59, 14 ], [ 170, 665, 50, 14 ], [ 224, 665, 63, 14 ], [ 290, 665, 28, 14 ], [ 323, 665, 27, 14 ], [ 354, 665, 8, 14 ], [ 367, 665, 19, 14 ], [ 390, 665, 28, 14 ], [ 422, 665, 67, 14 ], [ 494, 665, 72, 14 ], [ 570, 665, 11, 14 ], [ 586, 665, 20, 14 ], [ 610, 665, 33, 14 ], [ 87, 688, 62, 14 ], [ 154, 688, 67, 14 ], [ 225, 688, 66, 14 ], [ 295, 688, 48, 14 ], [ 348, 688, 30, 14 ], [ 381, 688, 69, 14 ], [ 78, 734, 77, 15 ], [ 78, 751, 59, 14 ], [ 141, 751, 60, 14 ], [ 206, 751, 18, 14 ], [ 228, 751, 6, 14 ], [ 239, 751, 41, 14 ], [ 284, 751, 34, 14 ], [ 322, 751, 12, 14 ], [ 338, 751, 66, 14 ], [ 78, 768, 23, 14 ], [ 106, 768, 51, 14 ], [ 161, 768, 28, 14 ], [ 194, 768, 34, 14 ], [ 232, 768, 12, 14 ], [ 248, 768, 10, 14 ], [ 262, 768, 13, 14 ], [ 279, 768, 20, 14 ], [ 304, 768, 23, 14 ], [ 331, 768, 72, 14 ], [ 78, 785, 32, 14 ], [ 115, 785, 17, 14 ], [ 136, 785, 11, 14 ], [ 151, 785, 18, 14 ], [ 174, 785, 24, 14 ], [ 202, 785, 29, 14 ], [ 235, 785, 11, 14 ], [ 251, 785, 37, 14 ], [ 292, 785, 57, 14 ], [ 354, 785, 12, 14 ], [ 369, 785, 34, 14 ], [ 78, 801, 26, 14 ], [ 109, 801, 27, 14 ], [ 140, 801, 42, 14 ], [ 186, 801, 30, 14 ], [ 220, 801, 18, 14 ], [ 243, 801, 31, 14 ], [ 278, 801, 29, 14 ], [ 311, 801, 51, 14 ], [ 366, 801, 38, 14 ], [ 78, 818, 21, 14 ], [ 103, 818, 18, 14 ], [ 126, 818, 30, 14 ], [ 160, 818, 41, 14 ], [ 205, 818, 31, 14 ], [ 240, 818, 11, 14 ], [ 255, 818, 37, 14 ], [ 297, 818, 31, 14 ], [ 332, 818, 19, 14 ], [ 355, 818, 49, 14 ], [ 78, 834, 85, 14 ], [ 168, 834, 42, 14 ], [ 216, 834, 28, 14 ], [ 248, 834, 39, 14 ], [ 292, 834, 68, 14 ], [ 365, 834, 38, 14 ], [ 78, 851, 32, 14 ], [ 114, 851, 12, 14 ], [ 130, 851, 18, 14 ], [ 152, 851, 66, 14 ], [ 223, 851, 11, 14 ], [ 238, 851, 60, 14 ], [ 303, 851, 49, 14 ], [ 356, 851, 47, 14 ], [ 78, 868, 33, 14 ], [ 115, 868, 21, 14 ], [ 141, 868, 45, 14 ], [ 190, 868, 67, 14 ], [ 262, 868, 31, 14 ], [ 297, 868, 54, 14 ], [ 356, 868, 18, 14 ], [ 378, 868, 25, 14 ], [ 78, 884, 27, 14 ], [ 109, 884, 44, 14 ], [ 158, 884, 12, 14 ], [ 174, 884, 64, 14 ], [ 242, 884, 63, 14 ], [ 310, 884, 12, 14 ], [ 326, 884, 19, 14 ], [ 349, 884, 55, 14 ], [ 78, 901, 12, 14 ], [ 96, 901, 65, 14 ], [ 167, 901, 43, 14 ], [ 216, 901, 61, 14 ], [ 282, 901, 42, 14 ], [ 330, 901, 48, 14 ], [ 384, 901, 20, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 122, 11 ], [ 78, 950, 51, 11 ], [ 132, 950, 9, 11 ], [ 144, 950, 44, 11 ], [ 191, 950, 21, 11 ], [ 215, 950, 24, 11 ], [ 242, 950, 34, 11 ], [ 279, 950, 9, 11 ], [ 290, 950, 33, 11 ], [ 326, 950, 43, 11 ], [ 78, 962, 41, 11 ], [ 122, 962, 24, 11 ], [ 423, 735, 46, 14 ], [ 473, 735, 12, 14 ], [ 490, 735, 62, 14 ], [ 556, 735, 10, 14 ], [ 570, 735, 38, 14 ], [ 613, 735, 58, 14 ], [ 675, 735, 27, 14 ], [ 707, 735, 41, 14 ], [ 423, 751, 32, 14 ], [ 462, 751, 23, 14 ], [ 491, 751, 42, 14 ], [ 540, 751, 28, 14 ], [ 575, 751, 29, 14 ], [ 611, 751, 77, 14 ], [ 695, 751, 54, 14 ], [ 423, 768, 53, 14 ], [ 480, 768, 41, 14 ], [ 525, 768, 41, 14 ], [ 570, 768, 68, 14 ], [ 643, 768, 11, 14 ], [ 658, 768, 59, 14 ], [ 721, 768, 27, 14 ], [ 423, 785, 37, 14 ], [ 464, 785, 92, 14 ], [ 561, 785, 55, 14 ], [ 621, 785, 87, 14 ], [ 714, 785, 34, 14 ], [ 423, 801, 34, 14 ], [ 462, 801, 12, 14 ], [ 479, 801, 24, 14 ], [ 507, 801, 12, 14 ], [ 524, 801, 43, 14 ], [ 572, 801, 32, 14 ], [ 609, 801, 12, 14 ], [ 626, 801, 58, 14 ], [ 689, 801, 40, 14 ], [ 734, 801, 14, 14 ], [ 423, 818, 48, 14 ], [ 475, 818, 42, 14 ], [ 521, 818, 70, 14 ], [ 595, 818, 21, 14 ], [ 620, 818, 58, 14 ], [ 682, 818, 19, 14 ], [ 434, 834, 36, 14 ], [ 475, 834, 70, 14 ], [ 550, 834, 20, 14 ], [ 575, 834, 28, 14 ], [ 608, 834, 32, 14 ], [ 645, 834, 12, 14 ], [ 662, 834, 86, 14 ], [ 423, 851, 19, 14 ], [ 446, 851, 77, 14 ], [ 527, 851, 12, 14 ], [ 544, 851, 31, 14 ], [ 579, 851, 47, 14 ], [ 631, 851, 12, 14 ], [ 647, 851, 19, 14 ], [ 671, 851, 21, 14 ], [ 696, 851, 22, 14 ], [ 722, 851, 26, 14 ], [ 423, 868, 29, 14 ], [ 456, 868, 42, 14 ], [ 503, 868, 12, 14 ], [ 520, 868, 19, 14 ], [ 543, 868, 75, 14 ], [ 623, 868, 12, 14 ], [ 639, 868, 19, 14 ], [ 663, 868, 85, 14 ], [ 423, 884, 46, 14 ], [ 473, 884, 35, 14 ], [ 512, 884, 72, 14 ], [ 589, 884, 39, 14 ], [ 632, 884, 21, 14 ], [ 657, 884, 14, 14 ], [ 675, 884, 46, 14 ], [ 725, 884, 23, 14 ], [ 423, 901, 25, 14 ], [ 453, 901, 31, 14 ], [ 488, 901, 32, 14 ], [ 525, 901, 27, 14 ], [ 557, 901, 19, 14 ], [ 580, 901, 33, 14 ], [ 618, 901, 42, 14 ], [ 665, 901, 15, 14 ], [ 685, 901, 63, 14 ], [ 423, 917, 58, 14 ], [ 486, 917, 50, 14 ], [ 541, 917, 13, 14 ], [ 559, 917, 78, 14 ], [ 642, 917, 29, 14 ], [ 676, 917, 52, 14 ], [ 733, 917, 15, 14 ], [ 423, 934, 26, 14 ], [ 454, 934, 19, 14 ], [ 478, 934, 38, 14 ], [ 521, 934, 57, 14 ], [ 583, 934, 51, 14 ], [ 639, 934, 15, 14 ], [ 660, 934, 71, 14 ], [ 736, 934, 12, 14 ], [ 423, 950, 61, 14 ], [ 489, 950, 12, 14 ], [ 505, 950, 55, 14 ], [ 564, 950, 35, 14 ], [ 604, 950, 21, 14 ], [ 629, 950, 21, 14 ], [ 655, 950, 44, 14 ], [ 704, 950, 22, 14 ], [ 730, 950, 19, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 277, 987, 19, 10 ], [ 299, 987, 8, 10 ], [ 309, 987, 8, 10 ], [ 320, 987, 30, 10 ], [ 352, 987, 29, 10 ], [ 384, 987, 27, 10 ], [ 413, 987, 14, 10 ], [ 429, 987, 15, 10 ], [ 447, 987, 6, 10 ], [ 455, 987, 10, 10 ], [ 467, 987, 21, 10 ], [ 490, 987, 26, 10 ], [ 518, 987, 23, 10 ], [ 543, 987, 41, 10 ], [ 587, 987, 23, 10 ], [ 612, 987, 13, 10 ], [ 627, 987, 21, 10 ], [ 650, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Yang", "et", "al.", "Diagnostic", "Pathology", "2011,", "6:77", "http://www.diagnosticpathology.org/content/6/1/77", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Subtype", "distribution", "of", "lymphomas", "in", "Southwest", "China:", "Analysis", "of", "6,382", "cases", "using", "WHO", "classification", "in", "a", "single", "institution", "Qun-Pei", "Yang,", "Wen-Yan", "Zhang,", "Jian-Bo", "Yu,", "Sha", "Zhao,", "Huan", "Xu,", "Wei-Ya", "Wang,", "Cheng-Feng", "Bi,", "Zhuo", "Zuo,", "Xiao-Qing", "Wang,", "Juan", "Huang,", "Lin", "Dai", "and", "Wei-Ping", "Liu*", "Abstract", "Background:", "The", "subtype", "distribution", "of", "lymphoid", "neoplasms", "in", "Southwest", "China", "was", "analyzed", "according", "to", "WHO", "classifications.", "This", "study", "aims", "to", "analyze", "subtype", "distribution", "of", "lymphomas", "in", "southwest", "China.", "Methods:", "Lymphoid", "neoplasms", "diagnosed", "within", "9", "years", "in", "a", "single", "institution", "in", "Southwest", "China", "were", "analyzed", "according", "to", "the", "WHO", "classification.", "Results:", "From", "January", "2000", "to", "December", "2008,", "a", "total", "number", "of", "6,382", "patients", "with", "lymphoma", "were", "established,", "of", "which", "mature", "B-cell", "neoplasms", "accounted", "for", "56%,", "mature", "T-", "and", "NK-cell", "neoplasms", "occupied", "26%,", "and", "precursor", "lymphoid", "neoplasms", "and", "Hodgkin", "lymphomas", "were", "5%", "and", "13%,", "respectively.", "Mixed", "cellularity", "(76%)", "was", "the", "major", "subtype", "of", "classical", "Hodgkin", "lymphoma;", "and", "the", "bimodal", "age", "distribution", "was", "not", "observed.", "The", "top", "six", "subtypes", "of", "non-Hodgkin", "lymphoma", "were", "as", "follows:", "diffuse", "large", "B-cell", "lymphoma,", "extranodal", "NK/T-cell", "lymphoma,", "nasal", "type,", "extranodal", "marginal", "zone", "lymphoma", "of", "mucosa", "associated", "lymphoid", "tissue,", "follicular", "lymphoma,", "precursor", "lymphoid", "neoplasms,", "and", "chronic", "lymphocytic", "leukemia/small", "lymphocytic", "lymphoma.", "Extranodal", "lymphomas", "comprised", "about", "half", "of", "all", "cases,", "and", "most", "frequently", "involved", "Waldeyer’s", "ring,", "gastrointestinal", "tract,", "sinonasal", "region", "and", "skin.", "Conclusions:", "The", "lymphoid", "neoplasms", "of", "Southwest", "China", "displayed", "some", "epidemiologic", "features", "similar", "to", "those", "reported", "in", "literature", "from", "western", "and", "Asian", "countries,", "as", "well", "as", "other", "regions", "of", "China,", "whereas", "some", "subtypes", "showed", "distinct", "features.", "The", "high", "frequency", "of", "mature", "T/NK", "cell", "neoplasms", "and", "extranodal", "lymphomas,", "especially", "for", "extranodal", "NK/T-cell", "lymphoma,", "nasal", "type,", "is", "the", "most", "outstanding", "characteristic", "of", "this", "series.", "Keywords:", "Distribution,", "Lymphoma,", "Subtype,", "WHO", "classification", "Background", "Lymphoid", "neoplasms", "are", "a", "diverse", "group", "of", "malignancy", "that", "originate", "from", "either", "B,", "T", "or", "NK", "cell,", "representing", "about", "4%", "of", "the", "new", "cases", "of", "cancer", "diagnosed", "in", "China", "each", "year,", "making", "them", "the", "ninth", "most", "common", "cancer", "and", "the", "tenth", "leading", "cause", "of", "cancer", "death", "[1].", "Previous", "epidemiologic", "studies", "have", "shown", "remarkable", "differ-", "ences", "in", "the", "distribution", "of", "lymphoma", "subtypes", "between", "Asian", "and", "western", "populations", "[2-4].", "However,", "the", "pos-", "sible", "reasons", "of", "geographic", "differences", "in", "the", "spectrum", "of", "lymphoma", "remain", "unknown,", "mainly", "because", "the", "*", "Correspondence:", "liuweiping2001@vip.sina.com", "Department", "of", "Pathology,", "West", "China", "Hospital", "of", "Sichuan", "University,", "Chengdu,", "China", "etiology", "of", "lymphoma", "is", "largely", "unknown,", "even", "though", "some", "risk", "factors", "have", "been", "documented", "recently,", "including", "genetic", "factors,", "abnormality", "of", "immunity,", "indi-", "vidual", "susceptibilities,", "lifestyles,", "environmental", "expo-", "sures,", "as", "well", "as", "various", "kinds", "of", "infections", "caused", "by", "bacteria,", "viruses,", "mycoplasma", "and", "chlamydia", "[5].", "Major", "progression", "has", "been", "made", "in", "understanding", "the", "pathobiology", "of", "these", "diseases", "in", "the", "last", "two", "dec-", "ades,", "leading", "to", "the", "development", "of", "the", "internationally", "adopted", "WHO", "classification", "system", "and", "its", "updated", "ver-", "sion", "[5,6].", "From", "then", "on,", "many", "studies", "on", "lymphoma", "incidence", "patterns", "or", "distributions", "were", "reported", "all", "over", "the", "world.", "However,", "research", "on", "distribution", "of", "lymphoma", "in", "Mainland", "China", "was", "still", "limited,", "and", "the", "©", "2011", "Yang", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 80, 78, 106, 28 ], [ 195, 78, 119, 28 ], [ 322, 78, 115, 28 ], [ 446, 78, 142, 28 ], [ 597, 78, 76, 28 ], [ 80, 109, 107, 28 ], [ 194, 109, 84, 28 ], [ 285, 109, 81, 28 ], [ 373, 109, 128, 28 ], [ 507, 109, 47, 28 ], [ 561, 109, 93, 28 ], [ 661, 109, 109, 28 ], [ 80, 139, 157, 28 ], [ 246, 139, 25, 28 ], [ 279, 139, 62, 28 ], [ 350, 139, 76, 28 ], [ 80, 183, 60, 14 ], [ 145, 183, 35, 14 ], [ 179, 180, 7, 10 ], [ 185, 183, 4, 14 ], [ 194, 183, 31, 14 ], [ 229, 183, 10, 14 ], [ 243, 180, 68, 17 ], [ 316, 183, 52, 14 ], [ 372, 183, 15, 14 ], [ 391, 183, 57, 14 ], [ 448, 180, 7, 10 ], [ 454, 183, 4, 14 ], [ 462, 183, 32, 14 ], [ 498, 183, 10, 14 ], [ 513, 180, 71, 17 ], [ 588, 183, 11, 14 ], [ 603, 183, 13, 14 ], [ 620, 180, 36, 17 ], [ 80, 205, 6, 10 ], [ 88, 205, 50, 10 ], [ 140, 205, 9, 10 ], [ 151, 205, 40, 10 ], [ 193, 205, 61, 10 ], [ 256, 205, 25, 10 ], [ 284, 205, 32, 10 ], [ 319, 205, 31, 10 ], [ 352, 205, 9, 10 ], [ 363, 205, 40, 10 ], [ 405, 205, 26, 10 ], [ 433, 205, 19, 10 ], [ 454, 205, 21, 10 ], [ 477, 205, 28, 10 ], [ 508, 205, 25, 10 ], [ 535, 205, 9, 10 ], [ 546, 205, 36, 10 ], [ 584, 205, 6, 10 ], [ 591, 205, 50, 10 ], [ 643, 205, 9, 10 ], [ 654, 205, 37, 10 ], [ 694, 205, 16, 10 ], [ 712, 205, 57, 10 ], [ 80, 219, 25, 10 ], [ 108, 219, 32, 10 ], [ 143, 219, 31, 10 ], [ 176, 219, 9, 10 ], [ 187, 219, 40, 10 ], [ 229, 219, 26, 10 ], [ 258, 219, 19, 10 ], [ 279, 219, 21, 10 ], [ 302, 219, 28, 10 ], [ 333, 219, 25, 10 ], [ 360, 219, 9, 10 ], [ 371, 219, 36, 10 ], [ 409, 219, 6, 10 ], [ 417, 219, 50, 10 ], [ 469, 219, 9, 10 ], [ 480, 219, 42, 10 ], [ 524, 219, 16, 10 ], [ 543, 219, 15, 10 ], [ 560, 219, 33, 10 ], [ 596, 219, 40, 10 ], [ 638, 219, 43, 10 ], [ 683, 219, 19, 10 ], [ 705, 219, 21, 10 ], [ 728, 219, 19, 10 ], [ 749, 219, 21, 10 ], [ 80, 233, 28, 10 ], [ 111, 233, 25, 10 ], [ 139, 233, 9, 10 ], [ 150, 233, 34, 10 ], [ 102, 272, 57, 14 ], [ 102, 294, 51, 13 ], [ 161, 294, 47, 13 ], [ 216, 294, 59, 13 ], [ 282, 294, 33, 13 ], [ 323, 294, 8, 13 ], [ 339, 294, 6, 13 ], [ 353, 294, 18, 13 ], [ 379, 294, 48, 13 ], [ 435, 294, 11, 13 ], [ 454, 294, 50, 13 ], [ 512, 294, 97, 13 ], [ 616, 294, 20, 13 ], [ 645, 294, 6, 13 ], [ 659, 294, 31, 13 ], [ 697, 294, 32, 13 ], [ 737, 294, 11, 13 ], [ 102, 307, 85, 13 ], [ 192, 307, 87, 13 ], [ 284, 307, 25, 13 ], [ 313, 307, 11, 13 ], [ 330, 307, 54, 13 ], [ 389, 307, 50, 13 ], [ 444, 307, 47, 13 ], [ 495, 307, 50, 13 ], [ 550, 307, 37, 13 ], [ 592, 307, 22, 13 ], [ 618, 307, 29, 13 ], [ 652, 307, 26, 13 ], [ 682, 307, 44, 13 ], [ 731, 307, 17, 13 ], [ 102, 321, 36, 13 ], [ 142, 321, 12, 13 ], [ 158, 321, 30, 13 ], [ 192, 321, 25, 13 ], [ 221, 321, 32, 13 ], [ 257, 321, 20, 13 ], [ 282, 321, 27, 13 ], [ 313, 321, 39, 13 ], [ 357, 321, 28, 13 ], [ 389, 321, 16, 13 ], [ 409, 321, 41, 13 ], [ 454, 321, 39, 13 ], [ 497, 321, 47, 13 ], [ 549, 321, 22, 13 ], [ 575, 321, 25, 13 ], [ 604, 321, 32, 13 ], [ 640, 321, 20, 13 ], [ 665, 321, 62, 13 ], [ 731, 321, 17, 13 ], [ 102, 335, 51, 13 ], [ 155, 335, 13, 13 ], [ 171, 335, 51, 13 ], [ 225, 335, 65, 13 ], [ 293, 335, 11, 13 ], [ 307, 335, 26, 13 ], [ 335, 335, 47, 13 ], [ 384, 335, 75, 13 ], [ 462, 335, 25, 13 ], [ 490, 335, 17, 13 ], [ 509, 335, 19, 13 ], [ 531, 335, 35, 13 ], [ 569, 335, 25, 13 ], [ 597, 335, 37, 13 ], [ 637, 335, 21, 13 ], [ 661, 335, 20, 13 ], [ 684, 335, 24, 13 ], [ 710, 335, 14, 13 ], [ 727, 335, 21, 13 ], [ 102, 349, 43, 13 ], [ 149, 349, 20, 13 ], [ 173, 349, 43, 13 ], [ 221, 349, 25, 13 ], [ 250, 349, 32, 13 ], [ 287, 349, 20, 13 ], [ 312, 349, 71, 13 ], [ 387, 349, 24, 13 ], [ 415, 349, 49, 13 ], [ 468, 349, 45, 13 ], [ 517, 349, 38, 13 ], [ 559, 349, 30, 13 ], [ 594, 349, 32, 13 ], [ 631, 349, 40, 13 ], [ 675, 349, 43, 13 ], [ 723, 349, 25, 13 ], [ 102, 363, 35, 13 ], [ 141, 363, 75, 13 ], [ 219, 363, 25, 13 ], [ 248, 363, 50, 13 ], [ 301, 363, 41, 13 ], [ 346, 363, 59, 13 ], [ 408, 363, 20, 13 ], [ 432, 363, 35, 13 ], [ 470, 363, 55, 13 ], [ 529, 363, 20, 13 ], [ 553, 363, 69, 13 ], [ 626, 363, 56, 13 ], [ 685, 363, 39, 13 ], [ 728, 363, 20, 13 ], [ 102, 376, 39, 13 ], [ 145, 376, 48, 13 ], [ 197, 376, 38, 13 ], [ 239, 376, 24, 13 ], [ 268, 376, 11, 13 ], [ 283, 376, 47, 13 ], [ 334, 376, 42, 13 ], [ 380, 376, 22, 13 ], [ 406, 376, 18, 13 ], [ 428, 376, 53, 13 ], [ 484, 376, 38, 13 ], [ 526, 376, 11, 13 ], [ 541, 376, 75, 13 ], [ 620, 376, 25, 13 ], [ 650, 376, 17, 13 ], [ 670, 376, 62, 13 ], [ 736, 376, 12, 13 ], [ 102, 390, 43, 13 ], [ 150, 390, 90, 13 ], [ 245, 390, 10, 13 ], [ 260, 390, 54, 13 ], [ 319, 390, 38, 13 ], [ 362, 390, 25, 13 ], [ 392, 390, 75, 13 ], [ 471, 390, 25, 13 ], [ 502, 390, 50, 13 ], [ 556, 390, 45, 13 ], [ 606, 390, 60, 13 ], [ 671, 390, 20, 13 ], [ 696, 390, 51, 13 ], [ 102, 404, 56, 13 ], [ 162, 404, 42, 13 ], [ 207, 404, 64, 13 ], [ 274, 404, 44, 13 ], [ 322, 404, 45, 13 ], [ 370, 404, 71, 13 ], [ 444, 404, 45, 13 ], [ 492, 404, 20, 13 ], [ 516, 404, 38, 13 ], [ 557, 404, 20, 13 ], [ 581, 404, 58, 13 ], [ 643, 404, 81, 13 ], [ 727, 404, 21, 13 ], [ 102, 418, 52, 13 ], [ 156, 418, 10, 13 ], [ 169, 418, 18, 13 ], [ 190, 418, 22, 13 ], [ 215, 418, 11, 13 ], [ 229, 418, 75, 13 ], [ 306, 418, 28, 13 ], [ 337, 418, 75, 13 ], [ 415, 418, 25, 13 ], [ 443, 418, 50, 13 ], [ 495, 418, 54, 13 ], [ 552, 418, 38, 13 ], [ 592, 418, 20, 13 ], [ 615, 418, 90, 13 ], [ 708, 418, 25, 13 ], [ 736, 418, 12, 13 ], [ 102, 432, 18, 13 ], [ 125, 432, 70, 13 ], [ 200, 432, 11, 13 ], [ 217, 432, 41, 13 ], [ 263, 432, 30, 13 ], [ 298, 432, 56, 13 ], [ 359, 432, 21, 13 ], [ 385, 432, 48, 13 ], [ 438, 432, 13, 13 ], [ 456, 432, 28, 13 ], [ 489, 432, 53, 13 ], [ 547, 432, 50, 13 ], [ 603, 432, 41, 13 ], [ 649, 432, 49, 13 ], [ 703, 432, 10, 13 ], [ 719, 432, 29, 13 ], [ 102, 446, 46, 13 ], [ 152, 446, 28, 13 ], [ 184, 446, 31, 13 ], [ 219, 446, 43, 13 ], [ 266, 446, 26, 13 ], [ 295, 446, 48, 13 ], [ 347, 446, 64, 13 ], [ 415, 446, 15, 13 ], [ 434, 446, 52, 13 ], [ 490, 446, 45, 13 ], [ 540, 446, 26, 13 ], [ 570, 446, 30, 13 ], [ 604, 446, 15, 13 ], [ 623, 446, 37, 13 ], [ 664, 446, 38, 13 ], [ 706, 446, 20, 13 ], [ 730, 446, 18, 13 ], [ 102, 460, 53, 13 ], [ 158, 460, 11, 13 ], [ 173, 460, 52, 13 ], [ 229, 460, 60, 13 ], [ 92, 495, 40, 10 ], [ 135, 495, 22, 10 ], [ 159, 495, 8, 10 ], [ 169, 495, 35, 10 ], [ 207, 495, 11, 10 ], [ 220, 495, 35, 10 ], [ 257, 495, 17, 10 ], [ 277, 495, 37, 10 ], [ 316, 495, 12, 10 ], [ 331, 495, 14, 10 ], [ 348, 495, 9, 10 ], [ 359, 495, 26, 10 ], [ 388, 495, 36, 10 ], [ 426, 495, 40, 10 ], [ 468, 495, 39, 10 ], [ 510, 495, 48, 10 ], [ 560, 495, 25, 10 ], [ 588, 495, 36, 10 ], [ 626, 495, 29, 10 ], [ 657, 495, 27, 10 ], [ 687, 495, 43, 10 ], [ 732, 495, 16, 10 ], [ 92, 506, 32, 10 ], [ 126, 506, 36, 10 ], [ 166, 506, 53, 10 ], [ 221, 506, 9, 10 ], [ 233, 506, 21, 10 ], [ 257, 506, 27, 10 ], [ 287, 506, 20, 10 ], [ 310, 506, 18, 10 ], [ 331, 506, 18, 10 ], [ 352, 506, 32, 10 ], [ 387, 506, 139, 10 ], [ 92, 523, 31, 10 ], [ 126, 523, 30, 10 ], [ 160, 523, 21, 10 ], [ 184, 523, 41, 10 ], [ 227, 523, 61, 10 ], [ 291, 523, 8, 10 ], [ 302, 523, 43, 10 ], [ 348, 523, 17, 10 ], [ 92, 540, 42, 10 ], [ 137, 540, 45, 10 ], [ 185, 540, 12, 10 ], [ 200, 540, 22, 10 ], [ 225, 540, 44, 10 ], [ 272, 540, 32, 10 ], [ 307, 540, 12, 10 ], [ 322, 540, 22, 10 ], [ 347, 540, 47, 10 ], [ 397, 540, 26, 10 ], [ 425, 540, 7, 10 ], [ 435, 540, 20, 10 ], [ 92, 558, 50, 10 ], [ 158, 558, 20, 10 ], [ 183, 558, 22, 10 ], [ 208, 558, 9, 10 ], [ 221, 558, 9, 10 ], [ 235, 558, 17, 10 ], [ 255, 558, 7, 10 ], [ 266, 558, 10, 10 ], [ 280, 558, 50, 10 ], [ 335, 558, 25, 10 ], [ 364, 558, 45, 10 ], [ 413, 558, 25, 10 ], [ 442, 558, 14, 10 ], [ 460, 558, 24, 10 ], [ 487, 558, 9, 10 ], [ 500, 558, 14, 10 ], [ 518, 558, 34, 10 ], [ 556, 558, 42, 10 ], [ 602, 558, 45, 10 ], [ 651, 558, 33, 10 ], [ 688, 558, 25, 10 ], [ 717, 558, 31, 10 ], [ 92, 569, 49, 10 ], [ 144, 569, 17, 10 ], [ 163, 569, 50, 10 ], [ 216, 569, 16, 10 ], [ 235, 569, 54, 10 ], [ 291, 569, 8, 10 ], [ 302, 569, 15, 10 ], [ 320, 569, 37, 10 ], [ 359, 569, 37, 10 ], [ 399, 569, 14, 10 ], [ 416, 569, 31, 10 ], [ 450, 569, 27, 10 ], [ 480, 569, 16, 10 ], [ 498, 569, 27, 10 ], [ 529, 569, 13, 10 ], [ 545, 569, 36, 10 ], [ 92, 586, 42, 10 ], [ 136, 586, 17, 10 ], [ 155, 586, 21, 10 ], [ 179, 586, 16, 10 ], [ 197, 586, 43, 10 ], [ 242, 586, 11, 10 ], [ 255, 586, 26, 10 ], [ 284, 586, 20, 10 ], [ 306, 586, 14, 10 ], [ 322, 586, 35, 10 ], [ 359, 586, 38, 10 ], [ 399, 586, 9, 10 ], [ 410, 586, 27, 10 ], [ 440, 586, 66, 10 ], [ 508, 586, 16, 10 ], [ 526, 586, 12, 10 ], [ 540, 586, 30, 10 ], [ 573, 586, 12, 10 ], [ 588, 586, 52, 10 ], [ 642, 586, 15, 10 ], [ 660, 586, 27, 10 ], [ 690, 586, 16, 10 ], [ 708, 586, 11, 10 ], [ 722, 586, 16, 10 ], [ 740, 586, 8, 10 ], [ 92, 597, 23, 10 ], [ 118, 597, 30, 10 ], [ 150, 597, 19, 10 ], [ 171, 597, 40, 10 ], [ 214, 597, 16, 10 ], [ 233, 597, 34, 10 ], [ 269, 597, 34, 10 ], [ 306, 597, 9, 10 ], [ 318, 597, 32, 10 ], [ 353, 597, 9, 10 ], [ 365, 597, 48, 10 ], [ 416, 597, 9, 10 ], [ 427, 597, 14, 10 ], [ 444, 597, 48, 10 ], [ 92, 614, 52, 10 ], [ 147, 614, 44, 10 ], [ 193, 614, 16, 10 ], [ 212, 614, 31, 10 ], [ 246, 614, 20, 10 ], [ 268, 614, 35, 10 ], [ 307, 614, 17, 10 ], [ 326, 614, 11, 10 ], [ 340, 614, 45, 10 ], [ 388, 614, 35, 10 ], [ 426, 614, 21, 10 ], [ 92, 632, 5, 10 ], [ 99, 632, 27, 10 ], [ 129, 632, 106, 10 ], [ 80, 672, 84, 14 ], [ 93, 696, 66, 13 ], [ 163, 696, 10, 13 ], [ 178, 696, 37, 13 ], [ 219, 696, 60, 13 ], [ 284, 696, 35, 13 ], [ 324, 696, 54, 13 ], [ 383, 696, 30, 13 ], [ 80, 711, 33, 13 ], [ 116, 711, 24, 13 ], [ 144, 711, 25, 13 ], [ 172, 711, 63, 13 ], [ 238, 711, 55, 13 ], [ 295, 711, 28, 13 ], [ 326, 711, 21, 13 ], [ 351, 711, 62, 13 ], [ 80, 726, 15, 13 ], [ 101, 726, 18, 13 ], [ 125, 726, 61, 13 ], [ 192, 726, 16, 13 ], [ 214, 726, 46, 13 ], [ 266, 726, 50, 13 ], [ 322, 726, 20, 13 ], [ 348, 726, 16, 13 ], [ 370, 726, 26, 13 ], [ 402, 726, 10, 13 ], [ 80, 741, 36, 13 ], [ 123, 741, 35, 13 ], [ 165, 741, 39, 13 ], [ 210, 741, 53, 13 ], [ 270, 741, 19, 13 ], [ 296, 741, 73, 13 ], [ 376, 741, 37, 13 ], [ 80, 755, 54, 13 ], [ 138, 755, 54, 13 ], [ 195, 755, 16, 13 ], [ 215, 755, 51, 13 ], [ 270, 755, 10, 13 ], [ 283, 755, 50, 13 ], [ 336, 755, 60, 13 ], [ 400, 755, 13, 13 ], [ 80, 770, 28, 13 ], [ 113, 770, 53, 13 ], [ 170, 770, 10, 13 ], [ 184, 770, 75, 13 ], [ 264, 770, 46, 13 ], [ 314, 770, 22, 13 ], [ 340, 770, 30, 13 ], [ 375, 770, 38, 13 ], [ 80, 785, 20, 13 ], [ 104, 785, 16, 13 ], [ 123, 785, 82, 13 ], [ 209, 785, 10, 13 ], [ 223, 785, 23, 13 ], [ 250, 785, 35, 13 ], [ 288, 785, 19, 13 ], [ 311, 785, 49, 13 ], [ 364, 785, 49, 13 ], [ 80, 800, 21, 13 ], [ 106, 800, 47, 13 ], [ 158, 800, 44, 13 ], [ 206, 800, 56, 13 ], [ 267, 800, 39, 13 ], [ 310, 800, 8, 13 ], [ 323, 800, 6, 13 ], [ 334, 800, 30, 13 ], [ 369, 800, 29, 13 ], [ 403, 800, 10, 13 ], [ 80, 814, 80, 13 ], [ 163, 814, 44, 13 ], [ 209, 814, 47, 13 ], [ 259, 814, 44, 13 ], [ 306, 814, 48, 13 ], [ 356, 814, 38, 13 ], [ 396, 814, 16, 13 ], [ 80, 829, 41, 13 ], [ 131, 829, 10, 13 ], [ 150, 829, 25, 13 ], [ 185, 829, 72, 13 ], [ 266, 829, 31, 13 ], [ 306, 829, 13, 13 ], [ 328, 829, 43, 13 ], [ 380, 829, 33, 13 ], [ 80, 844, 44, 13 ], [ 133, 844, 47, 13 ], [ 188, 844, 35, 13 ], [ 232, 844, 25, 13 ], [ 265, 844, 62, 13 ], [ 335, 844, 31, 13 ], [ 374, 844, 38, 13 ], [ 80, 858, 52, 13 ], [ 137, 858, 29, 13 ], [ 171, 858, 45, 13 ], [ 220, 858, 18, 13 ], [ 243, 858, 12, 13 ], [ 260, 858, 18, 13 ], [ 282, 858, 30, 13 ], [ 317, 858, 14, 13 ], [ 336, 858, 38, 13 ], [ 379, 858, 13, 13 ], [ 396, 858, 16, 13 ], [ 80, 873, 35, 13 ], [ 120, 873, 10, 13 ], [ 135, 873, 58, 13 ], [ 198, 873, 33, 13 ], [ 236, 873, 51, 13 ], [ 291, 873, 13, 13 ], [ 310, 873, 34, 13 ], [ 349, 873, 39, 13 ], [ 393, 873, 19, 13 ], [ 80, 888, 37, 13 ], [ 121, 888, 60, 13 ], [ 184, 888, 10, 13 ], [ 198, 888, 28, 13 ], [ 93, 903, 84, 13 ], [ 180, 903, 34, 13 ], [ 216, 903, 24, 13 ], [ 243, 903, 22, 13 ], [ 268, 903, 53, 13 ], [ 323, 903, 29, 13 ], [ 355, 903, 10, 13 ], [ 368, 903, 44, 13 ], [ 80, 918, 23, 13 ], [ 106, 918, 31, 13 ], [ 141, 918, 19, 13 ], [ 164, 918, 25, 13 ], [ 193, 918, 34, 13 ], [ 230, 918, 37, 13 ], [ 270, 918, 58, 13 ], [ 332, 918, 36, 13 ], [ 372, 918, 41, 13 ], [ 80, 932, 10, 13 ], [ 99, 932, 38, 13 ], [ 146, 932, 69, 13 ], [ 223, 932, 20, 13 ], [ 252, 932, 69, 13 ], [ 330, 932, 29, 13 ], [ 368, 932, 45, 13 ], [ 80, 947, 40, 13 ], [ 125, 947, 23, 13 ], [ 152, 947, 34, 13 ], [ 190, 947, 18, 13 ], [ 213, 947, 46, 13 ], [ 263, 947, 16, 13 ], [ 283, 947, 29, 13 ], [ 317, 947, 42, 13 ], [ 363, 947, 50, 13 ], [ 80, 962, 8, 13 ], [ 92, 962, 31, 13 ], [ 127, 962, 49, 13 ], [ 180, 962, 10, 13 ], [ 194, 962, 16, 13 ], [ 214, 962, 71, 13 ], [ 289, 962, 19, 13 ], [ 313, 962, 50, 13 ], [ 366, 962, 46, 13 ], [ 80, 977, 24, 13 ], [ 108, 977, 39, 13 ], [ 150, 977, 66, 13 ], [ 220, 977, 35, 13 ], [ 259, 977, 19, 13 ], [ 281, 977, 34, 13 ], [ 318, 977, 49, 13 ], [ 370, 977, 28, 13 ], [ 401, 977, 12, 13 ], [ 80, 991, 45, 13 ], [ 129, 991, 16, 13 ], [ 150, 991, 29, 13 ], [ 183, 991, 42, 13 ], [ 229, 991, 52, 13 ], [ 286, 991, 52, 13 ], [ 342, 991, 16, 13 ], [ 362, 991, 36, 13 ], [ 403, 991, 10, 13 ], [ 80, 1006, 67, 13 ], [ 151, 1006, 41, 13 ], [ 195, 1006, 10, 13 ], [ 209, 1006, 46, 13 ], [ 259, 1006, 23, 13 ], [ 285, 1006, 31, 13 ], [ 320, 1006, 18, 13 ], [ 450, 671, 14, 13 ], [ 468, 671, 44, 13 ], [ 516, 671, 16, 13 ], [ 537, 671, 35, 13 ], [ 576, 671, 10, 13 ], [ 591, 671, 32, 13 ], [ 627, 671, 13, 13 ], [ 645, 671, 58, 13 ], [ 708, 671, 8, 13 ], [ 720, 671, 17, 13 ], [ 742, 671, 28, 13 ], [ 437, 685, 71, 13 ], [ 513, 685, 10, 13 ], [ 527, 685, 36, 13 ], [ 567, 685, 25, 13 ], [ 596, 685, 43, 13 ], [ 644, 685, 51, 13 ], [ 699, 685, 34, 13 ], [ 737, 685, 18, 13 ], [ 760, 685, 10, 13 ], [ 437, 700, 39, 13 ], [ 481, 700, 36, 13 ], [ 521, 700, 22, 13 ], [ 548, 700, 50, 13 ], [ 603, 700, 40, 13 ], [ 648, 700, 21, 13 ], [ 674, 700, 27, 13 ], [ 705, 700, 10, 13 ], [ 720, 700, 32, 13 ], [ 756, 700, 13, 13 ], [ 437, 715, 34, 13 ], [ 477, 715, 18, 13 ], [ 501, 715, 11, 13 ], [ 518, 715, 46, 13 ], [ 570, 715, 26, 13 ], [ 601, 715, 27, 13 ], [ 635, 715, 19, 13 ], [ 660, 715, 55, 13 ], [ 721, 715, 32, 13 ], [ 759, 715, 11, 13 ], [ 437, 729, 41, 13 ], [ 483, 729, 37, 13 ], [ 524, 729, 35, 13 ], [ 564, 729, 50, 13 ], [ 619, 729, 32, 13 ], [ 655, 729, 53, 13 ], [ 713, 729, 40, 13 ], [ 758, 729, 11, 13 ], [ 437, 744, 26, 13 ], [ 468, 744, 28, 13 ], [ 500, 744, 27, 13 ], [ 532, 744, 53, 13 ], [ 590, 744, 36, 13 ], [ 630, 744, 73, 13 ], [ 708, 744, 19, 13 ], [ 732, 744, 6, 13 ], [ 742, 744, 27, 13 ], [ 437, 758, 40, 13 ], [ 480, 758, 41, 13 ], [ 525, 758, 56, 13 ], [ 584, 758, 70, 13 ], [ 658, 758, 44, 13 ], [ 706, 758, 40, 13 ], [ 750, 758, 20, 13 ], [ 437, 773, 16, 13 ], [ 457, 773, 31, 13 ], [ 492, 773, 10, 13 ], [ 506, 773, 32, 13 ], [ 542, 773, 13, 13 ], [ 559, 773, 63, 13 ], [ 625, 773, 16, 13 ], [ 645, 773, 17, 13 ], [ 666, 773, 35, 13 ], [ 705, 773, 51, 13 ], [ 759, 773, 10, 13 ], [ 437, 787, 68, 13 ], [ 507, 787, 10, 13 ], [ 520, 787, 42, 13 ], [ 565, 787, 30, 13 ], [ 598, 787, 17, 13 ], [ 618, 787, 20, 13 ], [ 640, 787, 29, 13 ], [ 672, 787, 22, 13 ], [ 697, 787, 15, 13 ], [ 715, 787, 10, 13 ], [ 727, 787, 23, 13 ], [ 754, 787, 16, 13 ], [ 437, 802, 27, 13 ], [ 479, 802, 20, 13 ], [ 513, 802, 52, 13 ], [ 580, 802, 31, 13 ], [ 626, 802, 10, 13 ], [ 651, 802, 46, 13 ], [ 711, 802, 58, 13 ], [ 437, 816, 71, 13 ], [ 515, 816, 49, 13 ], [ 571, 816, 16, 13 ], [ 594, 816, 35, 13 ], [ 635, 816, 10, 13 ], [ 651, 816, 33, 13 ], [ 691, 816, 59, 13 ], [ 756, 816, 13, 13 ], [ 437, 831, 37, 13 ], [ 478, 831, 60, 13 ], [ 542, 831, 19, 13 ], [ 566, 831, 34, 13 ], [ 603, 831, 45, 13 ], [ 652, 831, 17, 13 ], [ 673, 831, 17, 13 ], [ 694, 831, 25, 13 ], [ 723, 831, 47, 13 ], [ 437, 845, 26, 13 ], [ 467, 845, 45, 13 ], [ 516, 845, 10, 13 ], [ 530, 845, 25, 13 ], [ 450, 861, 21, 13 ], [ 476, 861, 40, 13 ], [ 522, 861, 10, 13 ], [ 538, 861, 18, 13 ], [ 561, 861, 27, 13 ], [ 594, 861, 19, 13 ], [ 618, 861, 10, 13 ], [ 634, 861, 17, 13 ], [ 657, 861, 41, 13 ], [ 704, 861, 24, 13 ], [ 734, 861, 36, 13 ], [ 437, 875, 33, 13 ], [ 475, 875, 24, 13 ], [ 505, 875, 31, 13 ], [ 541, 875, 42, 13 ], [ 589, 874, 66, 14 ], [ 660, 875, 35, 13 ], [ 701, 875, 41, 13 ], [ 747, 875, 23, 13 ], [ 437, 890, 34, 13 ], [ 475, 890, 38, 13 ], [ 518, 890, 51, 13 ], [ 573, 890, 26, 13 ], [ 603, 890, 35, 13 ], [ 643, 890, 35, 13 ], [ 683, 890, 19, 13 ], [ 706, 890, 44, 13 ], [ 754, 890, 15, 13 ], [ 437, 904, 57, 13 ], [ 502, 904, 45, 13 ], [ 555, 904, 69, 13 ], [ 633, 904, 10, 13 ], [ 651, 904, 64, 13 ], [ 724, 904, 46, 13 ], [ 437, 919, 29, 13 ], [ 473, 919, 10, 13 ], [ 489, 919, 41, 13 ], [ 535, 919, 14, 13 ], [ 556, 919, 38, 13 ], [ 599, 919, 13, 13 ], [ 619, 919, 25, 13 ], [ 649, 919, 27, 13 ], [ 683, 919, 13, 13 ], [ 702, 919, 48, 13 ], [ 755, 919, 14, 13 ], [ 437, 933, 30, 13 ], [ 475, 933, 60, 14 ], [ 542, 933, 24, 13 ], [ 575, 933, 15, 13 ], [ 598, 933, 20, 13 ], [ 626, 933, 49, 13 ], [ 683, 933, 43, 13 ], [ 734, 933, 10, 13 ], [ 752, 933, 18, 13 ], [ 437, 948, 65, 13 ], [ 507, 948, 33, 13 ], [ 544, 948, 43, 13 ], [ 592, 948, 24, 13 ], [ 621, 948, 47, 13 ], [ 672, 948, 37, 13 ], [ 713, 948, 56, 13 ], [ 437, 962, 19, 13 ], [ 462, 962, 34, 13 ], [ 501, 962, 52, 13 ], [ 558, 962, 19, 13 ], [ 583, 962, 65, 13 ], [ 653, 962, 51, 13 ], [ 710, 962, 35, 13 ], [ 750, 962, 19, 13 ], [ 437, 977, 22, 13 ], [ 464, 977, 44, 13 ], [ 512, 977, 18, 13 ], [ 534, 977, 30, 13 ], [ 568, 977, 20, 13 ], [ 593, 976, 60, 14 ], [ 657, 977, 24, 13 ], [ 686, 977, 24, 13 ], [ 715, 977, 55, 13 ], [ 437, 992, 34, 13 ], [ 475, 992, 73, 13 ], [ 552, 992, 19, 13 ], [ 575, 992, 86, 13 ], [ 665, 992, 25, 13 ], [ 695, 992, 10, 13 ], [ 709, 992, 50, 13 ], [ 763, 992, 6, 13 ], [ 437, 1006, 58, 13 ], [ 498, 1006, 41, 13 ], [ 541, 1006, 10, 13 ], [ 554, 1006, 25, 13 ], [ 582, 1006, 13, 13 ], [ 598, 1006, 41, 13 ], [ 642, 1006, 18, 13 ], [ 662, 1006, 47, 13 ], [ 712, 1006, 20, 13 ], [ 735, 1006, 35, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 21, 12 ], [ 165, 1047, 3, 12 ], [ 174, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 559, 1047, 29, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "Reduced", "Serotonin", "Reuptake", "Transporter", "(SERT)", "Function", "Causes", "Insulin", "Resistance", "and", "Hepatic", "Steatosis", "Independent", "of", "Food", "Intake", "Xiaoning", "Chen", "1", ",", "Kara", "J.", "Margolis3,", "Michael", "D.", "Gershon", "3", ",", "Gary", "J.", "Schwartz2,", "Ji", "Y.", "Sze1*", "1", "Department", "of", "Molecular", "Pharmacology,", "Albert", "Einstein", "College", "of", "Medicine,", "Bronx,", "New", "York,", "United", "States", "of", "America,", "2", "Department", "of", "Medicine", "and", "Neuroscience,", "Albert", "Einstein", "College", "of", "Medicine,", "Bronx,", "New", "York,", "United", "States", "of", "America,", "3", "Department", "of", "Pathology", "and", "Cell", "Biology,", "Columbia", "University,", "New", "York,", "New", "York,", "United", "States", "of", "America", "Abstract", "Serotonin", "reuptake", "transporter", "(SERT)", "is", "a", "key", "regulator", "of", "serotonin", "neurotransmission", "and", "a", "major", "target", "of", "antidepressants.", "Antidepressants,", "such", "as", "selectively", "serotonin", "reuptake", "inhibitors", "(SSRIs),", "that", "block", "SERT", "function", "are", "known", "to", "affect", "food", "intake", "and", "body", "weight.", "Here,", "we", "provide", "genetic", "evidence", "that", "food", "intake", "and", "metabolism", "are", "regulated", "by", "separable", "mechanisms", "of", "SERT", "function.", "SERT-deficient", "mice", "ate", "less", "during", "both", "normal", "diet", "and", "high", "fat", "diet", "feeding.", "The", "reduced", "food", "intake", "was", "accompanied", "with", "markedly", "elevated", "plasma", "leptin", "levels.", "Despite", "reduced", "food", "intake,", "SERT-deficient", "mice", "exhibited", "glucose", "intolerance", "and", "insulin", "resistance,", "and", "progressively", "developed", "obesity", "and", "hepatic", "steatosis.", "Several", "lines", "of", "evidence", "indicate", "that", "the", "metabolic", "deficits", "of", "SERT-deficient", "mice", "are", "attributable", "to", "reduced", "insulin-sensitivity", "in", "peripheral", "tissues.", "First,", "SERT-deficient", "mice", "exhibited", "beta-cell", "hyperplasia", "and", "islet-mass", "expansion.", "Second,", "biochemical", "analyses", "revealed", "constitutively", "elevated", "JNK", "activity", "and", "diminished", "insulin-induced", "AKT", "activation", "in", "the", "liver", "of", "SERT-deficient", "mice.", "SERT-deficient", "mice", "exhibited", "hyper-JNK", "activity", "and", "hyperinsulinemia", "prior", "to", "the", "development", "of", "obesity.", "Third,", "enhancing", "AKT", "signaling", "by", "PTEN", "deficiency", "corrected", "glucose", "tolerance", "in", "SERT-", "deficient", "mice.", "These", "findings", "have", "potential", "implications", "for", "designing", "selective", "SERT", "drugs", "for", "weight", "control", "and", "the", "treatment", "of", "metabolic", "syndromes.", "Citation:", "Chen", "X,", "Margolis", "KJ,", "Gershon", "MD,", "Schwartz", "GJ,", "Sze", "JY", "(2012)", "Reduced", "Serotonin", "Reuptake", "Transporter", "(SERT)", "Function", "Causes", "Insulin", "Resistance", "and", "Hepatic", "Steatosis", "Independent", "of", "Food", "Intake.", "PLoS", "ONE", "7(3):", "e32511.", "doi:10.1371/journal.pone.0032511", "Editor:", "Giorgio", "Sesti,", "Universita", "Magna-Graecia", "di", "Catanzaro,", "Italy", "Received", "September", "13,", "2011;", "Accepted", "January", "27,", "2012;", "Published", "March", "8,", "2012", "Copyright:", "2012", "Chen", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "grants", "from", "the", "National", "Institutes", "of", "Health", "(MH083982)(JS),", "NIH", "DK", "020541", "DK", "026687(GJS).", "The", "funder", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "jiying.sze@einstein.yu.edu", "Introduction", "Disturbances", "in", "glucose", "homeostasis", "among", "psychiatric", "popu-", "lations", "have", "been", "documented", "extensively", "[1,2].", "The", "mechanisms", "for", "this", "comorbidity", "are", "currently", "unknown,", "and", "are", "likely", "to", "involve", "diverse", "genetic,", "behavioral", "and", "environmental", "factors.", "Therefore,", "identifying", "the", "regulation", "of", "metabolic", "homeostasis", "by", "genes", "implicated", "in", "anxiety-related", "disorders", "may", "reveal", "insights", "into", "the", "pathophysiology", "of", "both", "mental", "and", "metabolic", "disorders.", "The", "serotonin", "reuptake", "transporter", "(SERT)", "is", "a", "major", "target", "of", "antidepressants.", "Selective", "serotonin", "reuptake", "inhibitors", "(SSRIs)", "are", "believed", "to", "exert", "antidepressant", "effects", "by", "blocking", "SERT", "uptaking", "serotonin", "(5-HT)", "from", "extracellular", "space,", "thereby", "enhancing", "5-HT", "signaling", "[3].", "In", "this", "study,", "we", "focused", "on", "the", "impact", "of", "constitutive", "SERT", "deficiency", "on", "energy", "balance", "and", "glucose", "homeostasis", "in", "mice.", "Pharmacological", "studies", "have", "long", "implicated", "5-HT", "in", "reducing", "food", "intake", "and", "body", "weight", "[4,5,6].", "Subsequent", "genetic", "analyses", "in", "rodents", "demonstrated", "that", "hypothalamic", "5-HT", "signaling", "controls", "food", "intake.", "For", "example,", "the", "5-HT", "receptor", "5HTR2C", "is", "highly", "expressed", "in", "the", "hypothalamus", "and", "5HTR2C", "knockout", "mice", "develop", "hyperphagia,", "obesity", "and", "insulin", "resistance", "[7,8].", "In", "addition,", "the", "5-HT", "receptor", "5-HTR1B", "modulates", "the", "activity", "of", "melanocortin", "neurons", "to", "influence", "food", "intake", "[9].", "By", "contrast,", "the", "impact", "of", "SSRIs", "on", "metabolism", "is", "less", "clear.", "Meta-analyses", "of", "clinical", "trials", "reported", "significant", "weight", "loss", "in", "subjects", "treated", "with", "fluoxetine", "[10,11].", "The", "effect", "of", "SSRIs", "on", "weight", "loss", "is,", "however,", "short", "term,", "and", "individuals", "regain", "or", "increase", "weight,", "despite", "continued", "SSRIs", "treatments", "[12,13].", "In", "some", "cases,", "SSRI", "treatments", "yielded", "hyperglycemia", "and", "a", "trend", "towards", "diabetes", "[13,14,15].", "Accumulating", "evidence", "suggests", "that", "the", "effects", "of", "SSRIs", "on", "metabolisms", "are", "not", "merely", "secondary", "to", "improvement", "in", "affective", "states,", "but", "that", "5-HT", "may", "act", "at", "both", "the", "brain", "and", "peripheral", "tissues", "to", "influence", "metabolism", "[16,17,18,19].", "However,", "the", "impact", "of", "SERT", "inactivation", "on", "glucose", "homeostasis", "and", "insulin", "signaling", "has", "not", "been", "systemat-", "ically", "analyzed", "to", "date.", "The", "purpose", "of", "this", "study", "was", "to", "test", "whether", "mice", "lacking", "SERT", "gene", "Slc6a4", "function", "(SERT2/2)", "exhibit", "reduced", "food", "intake,", "thereby", "protecting", "them", "against", "obesity", "and", "diabetes.", "To", "circumvent", "potential", "complications", "of", "reproductive", "hormone", "cycles", "in", "females,", "we", "focused", "on", "male", "mice.", "As", "expected,", "we", "found", "SERT2/2", "mice", "ate", "less.", "However,", "contrary", "to", "our", "expectations,", "SERT", "deficient", "mice", "exhibited", "glucose", "intolerance", "and", "insulin", "resistance,", "and", "progressively", "developed", "obesity", "and", "liver", "steatosis.", "We", "found", "that", "SERT2/2", "mice", "were", "hyperlepti-", "nemic,", "hyperglycemic", "and", "hyperinsulinemic", "prior", "to", "exhibiting", "a", "measurable", "increase", "in", "body", "fat", "content.", "We", "identified", "that", "C-Jun-", "PLoS", "ONE", "|", "www.plosone.org", "1", "March", "2012", "|", "Volume", "7", "|", "Issue", "3", "|", "e32511" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 699, 28, 78, 26 ], [ 60, 82, 15, 20 ], [ 79, 82, 109, 20 ], [ 193, 82, 56, 20 ], [ 253, 82, 19, 20 ], [ 277, 82, 154, 20 ], [ 436, 82, 18, 20 ], [ 459, 82, 76, 20 ], [ 540, 82, 60, 20 ], [ 605, 82, 35, 20 ], [ 645, 82, 39, 20 ], [ 60, 103, 19, 20 ], [ 84, 103, 117, 20 ], [ 206, 103, 105, 20 ], [ 60, 131, 36, 14 ], [ 99, 131, 53, 14 ], [ 155, 130, 59, 15 ], [ 218, 131, 38, 14 ], [ 259, 130, 69, 15 ], [ 331, 131, 24, 14 ], [ 358, 130, 71, 15 ], [ 432, 131, 33, 14 ], [ 468, 130, 59, 15 ], [ 530, 131, 45, 14 ], [ 579, 131, 46, 14 ], [ 628, 130, 56, 15 ], [ 60, 146, 33, 14 ], [ 97, 144, 80, 15 ], [ 180, 146, 25, 14 ], [ 208, 144, 62, 15 ], [ 274, 146, 24, 14 ], [ 301, 146, 22, 14 ], [ 326, 144, 118, 15 ], [ 60, 167, 48, 13 ], [ 110, 168, 11, 12 ], [ 124, 168, 37, 12 ], [ 163, 168, 76, 12 ], [ 242, 168, 37, 12 ], [ 282, 168, 37, 12 ], [ 321, 168, 42, 12 ], [ 366, 168, 70, 12 ], [ 439, 168, 51, 12 ], [ 493, 167, 40, 13 ], [ 535, 168, 14, 12 ], [ 551, 168, 59, 12 ], [ 612, 168, 14, 12 ], [ 629, 168, 44, 12 ], [ 675, 168, 37, 12 ], [ 715, 168, 45, 12 ], [ 60, 180, 13, 12 ], [ 76, 180, 31, 12 ], [ 109, 180, 47, 12 ], [ 159, 180, 14, 12 ], [ 175, 180, 44, 12 ], [ 222, 180, 41, 12 ], [ 265, 180, 24, 12 ], [ 291, 180, 44, 12 ], [ 338, 180, 43, 12 ], [ 384, 179, 67, 13 ], [ 453, 180, 11, 12 ], [ 467, 180, 76, 12 ], [ 546, 180, 37, 12 ], [ 585, 180, 11, 12 ], [ 599, 180, 33, 12 ], [ 634, 180, 38, 12 ], [ 674, 180, 38, 12 ], [ 715, 180, 57, 12 ], [ 60, 193, 41, 12 ], [ 104, 193, 48, 12 ], [ 65, 242, 11, 12 ], [ 134, 242, 4, 12 ], [ 141, 241, 46, 12 ], [ 191, 241, 10, 12 ], [ 205, 241, 79, 12 ], [ 288, 241, 16, 12 ], [ 308, 241, 23, 12 ], [ 335, 241, 47, 12 ], [ 386, 241, 10, 12 ], [ 400, 241, 5, 12 ], [ 409, 241, 45, 12 ], [ 458, 241, 18, 12 ], [ 480, 241, 29, 12 ], [ 513, 241, 15, 12 ], [ 65, 255, 64, 12 ], [ 132, 255, 50, 12 ], [ 186, 255, 36, 12 ], [ 225, 255, 22, 12 ], [ 249, 255, 56, 12 ], [ 308, 255, 30, 12 ], [ 341, 255, 19, 12 ], [ 363, 255, 20, 12 ], [ 386, 255, 11, 12 ], [ 400, 255, 32, 12 ], [ 434, 255, 10, 12 ], [ 447, 255, 34, 12 ], [ 484, 255, 43, 12 ], [ 65, 268, 29, 12 ], [ 97, 268, 10, 12 ], [ 110, 268, 10, 12 ], [ 122, 268, 45, 12 ], [ 169, 268, 41, 12 ], [ 212, 268, 70, 12 ], [ 65, 285, 0, 12 ], [ 75, 288, 7, 9 ], [ 116, 285, 4, 12 ], [ 123, 285, 20, 12 ], [ 147, 285, 38, 12 ], [ 188, 285, 18, 12 ], [ 209, 285, 10, 12 ], [ 223, 285, 40, 12 ], [ 266, 285, 56, 12 ], [ 325, 285, 40, 12 ], [ 368, 285, 72, 12 ], [ 444, 285, 70, 12 ], [ 517, 285, 10, 12 ], [ 65, 298, 62, 12 ], [ 130, 298, 35, 12 ], [ 168, 298, 26, 12 ], [ 196, 298, 37, 12 ], [ 235, 298, 18, 12 ], [ 255, 298, 15, 12 ], [ 272, 298, 17, 12 ], [ 292, 298, 10, 12 ], [ 304, 298, 29, 12 ], [ 65, 316, 11, 12 ], [ 113, 316, 4, 12 ], [ 119, 316, 17, 12 ], [ 138, 316, 49, 12 ], [ 189, 316, 5, 12 ], [ 197, 316, 55, 12 ], [ 255, 316, 26, 12 ], [ 283, 316, 25, 12 ], [ 311, 316, 5, 12 ], [ 319, 316, 53, 12 ], [ 374, 316, 34, 12 ], [ 410, 316, 31, 12 ], [ 444, 316, 10, 12 ], [ 456, 316, 33, 12 ], [ 492, 316, 35, 12 ], [ 65, 329, 39, 12 ], [ 108, 329, 40, 12 ], [ 151, 329, 25, 12 ], [ 180, 329, 18, 12 ], [ 201, 329, 28, 12 ], [ 233, 329, 35, 12 ], [ 271, 329, 15, 12 ], [ 290, 329, 31, 12 ], [ 325, 329, 14, 12 ], [ 342, 329, 46, 12 ], [ 392, 329, 19, 12 ], [ 414, 329, 36, 12 ], [ 454, 329, 48, 12 ], [ 506, 329, 22, 12 ], [ 65, 342, 26, 12 ], [ 94, 342, 10, 12 ], [ 107, 342, 15, 12 ], [ 125, 342, 81, 12 ], [ 208, 342, 52, 12 ], [ 263, 342, 34, 12 ], [ 300, 342, 33, 12 ], [ 336, 342, 39, 12 ], [ 378, 342, 18, 12 ], [ 398, 342, 45, 12 ], [ 446, 342, 36, 12 ], [ 485, 342, 18, 12 ], [ 507, 342, 20, 12 ], [ 65, 355, 31, 12 ], [ 98, 355, 38, 12 ], [ 139, 355, 17, 12 ], [ 158, 355, 45, 12 ], [ 205, 355, 68, 12 ], [ 276, 355, 10, 12 ], [ 288, 355, 6, 12 ], [ 296, 355, 45, 12 ], [ 344, 355, 18, 12 ], [ 364, 355, 12, 12 ], [ 378, 355, 73, 12 ], [ 453, 355, 41, 12 ], [ 497, 355, 30, 12 ], [ 65, 369, 46, 12 ], [ 114, 369, 10, 12 ], [ 127, 369, 35, 12 ], [ 164, 369, 26, 12 ], [ 193, 369, 41, 12 ], [ 236, 369, 25, 12 ], [ 263, 369, 55, 12 ], [ 320, 369, 57, 12 ], [ 379, 369, 39, 12 ], [ 420, 369, 15, 12 ], [ 438, 369, 13, 12 ], [ 453, 369, 74, 12 ], [ 65, 382, 18, 12 ], [ 85, 382, 26, 12 ], [ 114, 382, 22, 12 ], [ 138, 382, 40, 12 ], [ 180, 382, 10, 12 ], [ 193, 382, 20, 12 ], [ 214, 382, 47, 12 ], [ 263, 382, 36, 12 ], [ 302, 382, 43, 12 ], [ 347, 382, 14, 12 ], [ 364, 382, 24, 12 ], [ 389, 382, 23, 12 ], [ 415, 382, 29, 12 ], [ 65, 399, 0, 12 ], [ 73, 401, 1, 9 ], [ 106, 399, 4, 12 ], [ 113, 399, 46, 12 ], [ 162, 399, 18, 12 ], [ 184, 399, 27, 12 ], [ 214, 399, 18, 12 ], [ 235, 399, 51, 12 ], [ 290, 399, 40, 12 ], [ 334, 399, 25, 12 ], [ 362, 399, 14, 12 ], [ 380, 399, 59, 12 ], [ 442, 399, 26, 12 ], [ 472, 399, 42, 12 ], [ 517, 399, 10, 12 ], [ 65, 412, 70, 12 ], [ 139, 412, 10, 12 ], [ 153, 412, 148, 12 ], [ 305, 412, 38, 12 ], [ 346, 412, 67, 13 ], [ 416, 412, 18, 12 ], [ 437, 412, 64, 12 ], [ 505, 412, 23, 12 ], [ 65, 425, 21, 12 ], [ 89, 425, 26, 12 ], [ 118, 425, 16, 12 ], [ 136, 425, 24, 12 ], [ 163, 425, 28, 12 ], [ 194, 425, 21, 12 ], [ 218, 425, 26, 12 ], [ 246, 425, 16, 12 ], [ 265, 425, 24, 12 ], [ 291, 425, 28, 12 ], [ 322, 425, 18, 12 ], [ 342, 425, 21, 12 ], [ 366, 425, 26, 12 ], [ 395, 425, 16, 12 ], [ 413, 425, 24, 12 ], [ 440, 425, 28, 12 ], [ 470, 425, 57, 12 ], [ 65, 439, 21, 12 ], [ 90, 439, 51, 12 ], [ 143, 439, 67, 12 ], [ 212, 439, 29, 12 ], [ 244, 439, 14, 12 ], [ 260, 439, 27, 12 ], [ 290, 439, 18, 12 ], [ 310, 439, 62, 13 ], [ 374, 439, 26, 12 ], [ 403, 439, 12, 12 ], [ 418, 439, 50, 12 ], [ 470, 439, 36, 12 ], [ 509, 439, 20, 12 ], [ 65, 452, 34, 12 ], [ 103, 452, 18, 12 ], [ 124, 452, 43, 12 ], [ 171, 452, 22, 12 ], [ 196, 452, 30, 12 ], [ 230, 452, 14, 12 ], [ 247, 452, 21, 12 ], [ 272, 452, 22, 12 ], [ 296, 452, 14, 12 ], [ 314, 452, 38, 12 ], [ 355, 452, 11, 12 ], [ 369, 452, 41, 12 ], [ 414, 452, 13, 12 ], [ 429, 452, 22, 12 ], [ 455, 452, 51, 12 ], [ 510, 452, 18, 12 ], [ 65, 465, 28, 12 ], [ 96, 465, 39, 12 ], [ 137, 465, 26, 12 ], [ 165, 465, 18, 12 ], [ 185, 465, 30, 12 ], [ 65, 483, 0, 12 ], [ 74, 485, 1, 9 ], [ 128, 483, 4, 12 ], [ 135, 482, 17, 12 ], [ 155, 482, 28, 12 ], [ 187, 482, 6, 12 ], [ 195, 482, 31, 12 ], [ 229, 482, 18, 12 ], [ 250, 482, 10, 12 ], [ 263, 482, 26, 12 ], [ 293, 482, 10, 12 ], [ 306, 482, 52, 12 ], [ 361, 482, 22, 12 ], [ 386, 482, 30, 12 ], [ 420, 482, 36, 12 ], [ 459, 482, 27, 12 ], [ 489, 482, 25, 12 ], [ 517, 482, 10, 12 ], [ 65, 496, 30, 12 ], [ 99, 496, 66, 13 ], [ 169, 496, 18, 12 ], [ 190, 496, 67, 12 ], [ 260, 496, 16, 12 ], [ 280, 496, 13, 12 ], [ 296, 496, 52, 12 ], [ 352, 496, 22, 12 ], [ 377, 496, 30, 12 ], [ 411, 496, 22, 12 ], [ 437, 496, 8, 12 ], [ 448, 496, 15, 12 ], [ 467, 496, 20, 12 ], [ 490, 496, 26, 12 ], [ 519, 496, 10, 12 ], [ 65, 509, 74, 12 ], [ 141, 509, 18, 12 ], [ 161, 509, 26, 12 ], [ 189, 509, 25, 12 ], [ 217, 509, 62, 12 ], [ 281, 509, 35, 12 ], [ 318, 509, 26, 12 ], [ 346, 509, 36, 12 ], [ 385, 509, 10, 12 ], [ 397, 509, 15, 12 ], [ 414, 509, 41, 12 ], [ 457, 509, 50, 12 ], [ 510, 509, 18, 12 ], [ 65, 522, 39, 12 ], [ 107, 522, 19, 12 ], [ 128, 522, 67, 12 ], [ 197, 522, 29, 12 ], [ 228, 522, 40, 12 ], [ 270, 522, 19, 12 ], [ 291, 522, 24, 12 ], [ 317, 522, 74, 12 ], [ 393, 522, 48, 12 ], [ 443, 522, 10, 12 ], [ 455, 522, 26, 12 ], [ 483, 522, 20, 12 ], [ 65, 540, 0, 12 ], [ 74, 542, 0, 9 ], [ 87, 542, 0, 9 ], [ 120, 540, 4, 12 ], [ 126, 539, 35, 12 ], [ 163, 539, 29, 12 ], [ 194, 539, 58, 12 ], [ 254, 539, 64, 12 ], [ 321, 539, 53, 12 ], [ 376, 539, 77, 12 ], [ 456, 540, 38, 12 ], [ 495, 540, 32, 12 ], [ 65, 553, 37, 12 ], [ 105, 553, 63, 12 ], [ 170, 553, 35, 12 ], [ 210, 553, 187, 12 ], [ 399, 553, 37, 12 ], [ 438, 553, 12, 12 ], [ 453, 553, 33, 12 ], [ 489, 553, 28, 12 ], [ 60, 594, 72, 14 ], [ 135, 594, 58, 14 ], [ 196, 594, 40, 14 ], [ 240, 594, 15, 14 ], [ 258, 594, 6, 14 ], [ 267, 594, 20, 14 ], [ 60, 609, 55, 14 ], [ 118, 609, 30, 14 ], [ 151, 609, 10, 14 ], [ 165, 609, 12, 14 ], [ 181, 609, 19, 14 ], [ 204, 609, 29, 14 ], [ 236, 609, 51, 14 ], [ 60, 623, 32, 14 ], [ 94, 623, 45, 14 ], [ 141, 623, 10, 14 ], [ 154, 623, 16, 14 ], [ 172, 623, 32, 14 ], [ 207, 623, 31, 14 ], [ 240, 623, 47, 14 ], [ 60, 638, 22, 14 ], [ 85, 638, 22, 14 ], [ 110, 638, 30, 14 ], [ 143, 638, 40, 14 ], [ 186, 638, 10, 14 ], [ 199, 638, 41, 14 ], [ 243, 638, 44, 14 ], [ 60, 652, 25, 14 ], [ 89, 652, 16, 14 ], [ 108, 652, 34, 14 ], [ 146, 652, 45, 14 ], [ 194, 652, 14, 14 ], [ 211, 652, 35, 14 ], [ 250, 652, 17, 14 ], [ 271, 652, 16, 14 ], [ 60, 667, 24, 14 ], [ 88, 667, 44, 14 ], [ 136, 667, 25, 14 ], [ 165, 667, 16, 14 ], [ 185, 667, 55, 14 ], [ 244, 667, 44, 14 ], [ 60, 682, 19, 14 ], [ 83, 682, 44, 14 ], [ 130, 682, 34, 14 ], [ 169, 682, 58, 14 ], [ 231, 682, 19, 14 ], [ 253, 682, 34, 14 ], [ 60, 696, 36, 14 ], [ 99, 696, 34, 14 ], [ 137, 696, 63, 14 ], [ 203, 696, 19, 14 ], [ 225, 696, 41, 14 ], [ 269, 696, 18, 14 ], [ 60, 711, 20, 14 ], [ 84, 711, 10, 14 ], [ 98, 711, 50, 14 ], [ 151, 711, 33, 14 ], [ 188, 711, 34, 14 ], [ 226, 711, 10, 14 ], [ 239, 711, 12, 14 ], [ 254, 711, 33, 14 ], [ 60, 725, 77, 14 ], [ 140, 725, 53, 14 ], [ 197, 725, 15, 14 ], [ 216, 725, 19, 14 ], [ 239, 725, 34, 14 ], [ 277, 725, 11, 14 ], [ 60, 740, 18, 14 ], [ 82, 740, 30, 14 ], [ 115, 740, 10, 14 ], [ 128, 740, 39, 14 ], [ 171, 740, 10, 14 ], [ 184, 740, 49, 14 ], [ 236, 740, 12, 14 ], [ 252, 740, 6, 14 ], [ 261, 740, 26, 14 ], [ 60, 755, 23, 14 ], [ 87, 755, 44, 14 ], [ 134, 755, 46, 14 ], [ 184, 755, 18, 14 ], [ 207, 755, 11, 14 ], [ 221, 755, 28, 14 ], [ 253, 755, 35, 14 ], [ 60, 769, 28, 14 ], [ 91, 769, 49, 14 ], [ 144, 769, 47, 14 ], [ 194, 769, 43, 14 ], [ 240, 769, 47, 14 ], [ 60, 784, 56, 14 ], [ 120, 784, 38, 14 ], [ 161, 784, 35, 14 ], [ 200, 784, 19, 14 ], [ 222, 784, 31, 14 ], [ 257, 784, 30, 14 ], [ 60, 798, 19, 14 ], [ 81, 798, 12, 14 ], [ 95, 798, 44, 14 ], [ 141, 798, 46, 14 ], [ 189, 798, 34, 14 ], [ 225, 798, 38, 14 ], [ 265, 798, 22, 14 ], [ 60, 813, 40, 14 ], [ 103, 813, 93, 14 ], [ 200, 813, 19, 14 ], [ 223, 813, 65, 14 ], [ 60, 827, 38, 14 ], [ 102, 827, 36, 14 ], [ 142, 827, 10, 14 ], [ 155, 827, 12, 14 ], [ 171, 827, 34, 14 ], [ 209, 827, 49, 14 ], [ 262, 827, 26, 14 ], [ 60, 842, 36, 14 ], [ 99, 842, 11, 14 ], [ 113, 842, 63, 14 ], [ 180, 842, 23, 14 ], [ 206, 842, 31, 14 ], [ 241, 842, 16, 14 ], [ 260, 842, 27, 14 ], [ 60, 857, 20, 14 ], [ 84, 857, 41, 14 ], [ 129, 857, 11, 14 ], [ 144, 857, 53, 14 ], [ 201, 857, 46, 14 ], [ 251, 857, 36, 14 ], [ 60, 871, 36, 14 ], [ 99, 871, 12, 14 ], [ 115, 871, 27, 14 ], [ 145, 871, 19, 14 ], [ 167, 871, 28, 14 ], [ 199, 871, 53, 14 ], [ 256, 871, 32, 14 ], [ 60, 886, 17, 14 ], [ 81, 886, 20, 14 ], [ 104, 886, 16, 14 ], [ 123, 886, 39, 14 ], [ 165, 886, 8, 14 ], [ 176, 886, 29, 14 ], [ 208, 886, 19, 14 ], [ 230, 886, 10, 14 ], [ 244, 886, 43, 14 ], [ 60, 900, 11, 14 ], [ 75, 900, 75, 14 ], [ 154, 900, 36, 14 ], [ 194, 900, 49, 14 ], [ 247, 900, 40, 14 ], [ 60, 915, 43, 14 ], [ 106, 915, 41, 14 ], [ 149, 915, 19, 14 ], [ 170, 915, 38, 14 ], [ 210, 915, 32, 14 ], [ 79, 930, 166, 14 ], [ 249, 930, 38, 14 ], [ 60, 944, 20, 14 ], [ 84, 944, 28, 14 ], [ 115, 944, 83, 14 ], [ 202, 944, 16, 14 ], [ 222, 944, 65, 14 ], [ 60, 959, 11, 14 ], [ 74, 959, 38, 14 ], [ 115, 959, 68, 14 ], [ 186, 959, 36, 14 ], [ 226, 959, 15, 14 ], [ 244, 959, 44, 14 ], [ 60, 973, 14, 14 ], [ 78, 973, 37, 14 ], [ 120, 973, 35, 14 ], [ 159, 973, 20, 14 ], [ 183, 973, 17, 14 ], [ 204, 973, 59, 14 ], [ 268, 973, 20, 14 ], [ 60, 988, 77, 14 ], [ 141, 988, 35, 14 ], [ 180, 988, 11, 14 ], [ 195, 988, 27, 14 ], [ 226, 988, 62, 14 ], [ 60, 1002, 23, 14 ], [ 86, 1002, 56, 14 ], [ 146, 1002, 84, 14 ], [ 233, 1002, 54, 14 ], [ 305, 594, 38, 14 ], [ 349, 594, 18, 14 ], [ 373, 594, 43, 14 ], [ 423, 594, 26, 14 ], [ 456, 594, 29, 14 ], [ 491, 594, 41, 14 ], [ 305, 609, 52, 14 ], [ 361, 609, 45, 14 ], [ 410, 609, 35, 14 ], [ 449, 609, 55, 14 ], [ 508, 609, 24, 14 ], [ 305, 623, 49, 14 ], [ 356, 623, 47, 14 ], [ 406, 623, 23, 14 ], [ 431, 623, 15, 14 ], [ 448, 623, 28, 14 ], [ 478, 623, 10, 14 ], [ 491, 623, 42, 14 ], [ 305, 638, 61, 14 ], [ 369, 638, 82, 14 ], [ 453, 638, 15, 14 ], [ 470, 638, 62, 14 ], [ 305, 652, 38, 14 ], [ 346, 652, 10, 14 ], [ 360, 652, 6, 14 ], [ 370, 652, 40, 14 ], [ 415, 652, 11, 14 ], [ 430, 652, 38, 14 ], [ 472, 652, 60, 14 ], [ 305, 667, 19, 14 ], [ 328, 667, 58, 14 ], [ 390, 667, 11, 14 ], [ 404, 667, 16, 14 ], [ 425, 667, 65, 14 ], [ 494, 667, 19, 14 ], [ 517, 667, 15, 14 ], [ 305, 682, 64, 14 ], [ 372, 682, 13, 14 ], [ 387, 682, 22, 14 ], [ 413, 682, 23, 14 ], [ 439, 682, 49, 14 ], [ 490, 682, 42, 14 ], [ 305, 696, 35, 14 ], [ 343, 696, 57, 14 ], [ 404, 696, 84, 14 ], [ 491, 696, 41, 14 ], [ 305, 711, 15, 14 ], [ 325, 711, 31, 14 ], [ 360, 711, 57, 14 ], [ 421, 711, 20, 14 ], [ 445, 711, 40, 14 ], [ 489, 711, 43, 14 ], [ 305, 725, 33, 14 ], [ 341, 725, 19, 14 ], [ 362, 725, 22, 14 ], [ 387, 725, 47, 14 ], [ 437, 725, 44, 14 ], [ 484, 725, 10, 14 ], [ 497, 725, 35, 14 ], [ 305, 740, 27, 14 ], [ 335, 740, 33, 14 ], [ 372, 740, 10, 14 ], [ 384, 740, 12, 14 ], [ 399, 740, 33, 14 ], [ 435, 740, 35, 14 ], [ 473, 740, 34, 14 ], [ 510, 740, 23, 14 ], [ 305, 755, 46, 14 ], [ 355, 755, 80, 14 ], [ 438, 755, 10, 14 ], [ 452, 755, 38, 14 ], [ 493, 755, 39, 14 ], [ 305, 769, 46, 14 ], [ 354, 769, 56, 14 ], [ 414, 769, 10, 14 ], [ 428, 769, 12, 14 ], [ 444, 769, 30, 14 ], [ 477, 769, 26, 14 ], [ 507, 769, 10, 14 ], [ 520, 769, 12, 14 ], [ 305, 784, 29, 14 ], [ 336, 784, 54, 14 ], [ 393, 784, 9, 14 ], [ 404, 784, 12, 14 ], [ 419, 784, 33, 14 ], [ 324, 798, 21, 14 ], [ 348, 798, 44, 14 ], [ 396, 798, 39, 14 ], [ 438, 798, 79, 14 ], [ 521, 798, 11, 14 ], [ 305, 813, 29, 14 ], [ 338, 813, 19, 14 ], [ 361, 813, 17, 14 ], [ 383, 813, 25, 14 ], [ 412, 813, 46, 14 ], [ 463, 813, 45, 14 ], [ 512, 813, 20, 14 ], [ 305, 827, 44, 14 ], [ 353, 827, 31, 14 ], [ 388, 827, 19, 14 ], [ 411, 827, 17, 14 ], [ 432, 827, 56, 14 ], [ 492, 827, 41, 14 ], [ 305, 842, 40, 14 ], [ 349, 842, 23, 14 ], [ 375, 842, 26, 14 ], [ 405, 842, 34, 14 ], [ 444, 842, 47, 14 ], [ 494, 842, 38, 14 ], [ 305, 857, 26, 14 ], [ 335, 857, 20, 14 ], [ 359, 857, 32, 14 ], [ 395, 857, 38, 14 ], [ 437, 857, 30, 14 ], [ 471, 857, 42, 14 ], [ 517, 857, 15, 14 ], [ 305, 871, 27, 14 ], [ 336, 871, 69, 14 ], [ 409, 871, 22, 14 ], [ 435, 871, 39, 14 ], [ 478, 871, 19, 14 ], [ 501, 871, 31, 14 ], [ 305, 886, 22, 14 ], [ 331, 886, 32, 14 ], [ 367, 886, 11, 14 ], [ 382, 886, 49, 14 ], [ 436, 886, 46, 14 ], [ 485, 886, 47, 14 ], [ 305, 900, 34, 14 ], [ 343, 900, 23, 14 ], [ 370, 900, 10, 14 ], [ 384, 900, 47, 14 ], [ 434, 900, 46, 14 ], [ 484, 900, 49, 14 ], [ 305, 915, 59, 14 ], [ 368, 915, 11, 14 ], [ 384, 915, 67, 14 ], [ 455, 915, 77, 14 ], [ 305, 930, 43, 14 ], [ 352, 930, 23, 14 ], [ 378, 930, 49, 14 ], [ 431, 930, 28, 14 ], [ 463, 930, 31, 14 ], [ 498, 930, 35, 14 ], [ 305, 944, 23, 14 ], [ 332, 944, 48, 14 ], [ 384, 944, 50, 14 ], [ 437, 944, 45, 14 ], [ 486, 944, 46, 14 ], [ 305, 959, 31, 14 ], [ 340, 959, 19, 14 ], [ 364, 959, 24, 14 ], [ 392, 959, 27, 14 ], [ 423, 959, 61, 14 ], [ 488, 959, 44, 14 ], [ 305, 973, 60, 14 ], [ 369, 973, 43, 14 ], [ 416, 973, 29, 14 ], [ 449, 973, 19, 14 ], [ 472, 973, 20, 14 ], [ 495, 973, 37, 14 ], [ 305, 988, 74, 14 ], [ 383, 988, 47, 14 ], [ 433, 988, 19, 14 ], [ 455, 988, 77, 14 ], [ 305, 1002, 46, 14 ], [ 355, 1002, 34, 14 ], [ 394, 1002, 52, 14 ], [ 450, 1002, 51, 14 ], [ 505, 1002, 10, 14 ], [ 520, 1002, 13, 14 ], [ 60, 1043, 66, 13 ], [ 129, 1043, 30, 13 ], [ 162, 1043, 57, 13 ], [ 225, 1044, 4, 12 ], [ 235, 1046, 0, 9 ], [ 267, 1044, 16, 12 ], [ 286, 1044, 2, 9 ], [ 290, 1046, 0, 9 ], [ 322, 1044, 6, 12 ], [ 330, 1044, 2, 9 ], [ 334, 1044, 35, 12 ], [ 371, 1044, 22, 12 ], [ 550, 230, 29, 14 ], [ 581, 230, 35, 14 ], [ 619, 230, 9, 14 ], [ 631, 230, 12, 14 ], [ 645, 230, 29, 14 ], [ 676, 230, 15, 14 ], [ 694, 230, 25, 14 ], [ 722, 230, 10, 14 ], [ 734, 230, 12, 14 ], [ 748, 230, 29, 14 ], [ 550, 244, 28, 14 ], [ 581, 244, 9, 14 ], [ 592, 244, 12, 14 ], [ 607, 244, 29, 14 ], [ 638, 244, 31, 14 ], [ 672, 244, 9, 14 ], [ 683, 244, 12, 14 ], [ 698, 244, 29, 14 ], [ 729, 244, 48, 14 ], [ 550, 259, 9, 14 ], [ 562, 259, 12, 14 ], [ 576, 259, 29, 14 ], [ 608, 259, 37, 14 ], [ 648, 259, 10, 14 ], [ 660, 259, 12, 14 ], [ 675, 259, 33, 14 ], [ 710, 259, 48, 14 ], [ 761, 259, 16, 14 ], [ 550, 273, 37, 14 ], [ 591, 273, 59, 14 ], [ 654, 273, 49, 14 ], [ 706, 273, 24, 14 ], [ 734, 273, 18, 14 ], [ 755, 273, 22, 14 ], [ 550, 288, 32, 14 ], [ 586, 288, 35, 14 ], [ 625, 288, 16, 14 ], [ 645, 288, 38, 14 ], [ 686, 288, 19, 14 ], [ 709, 288, 44, 14 ], [ 757, 288, 20, 14 ], [ 550, 302, 32, 14 ], [ 585, 302, 30, 14 ], [ 618, 302, 23, 14 ], [ 645, 302, 26, 14 ], [ 673, 302, 50, 14 ], [ 727, 302, 50, 14 ], [ 550, 317, 11, 14 ], [ 564, 317, 16, 14 ], [ 584, 317, 20, 14 ], [ 608, 317, 71, 14 ], [ 682, 317, 10, 14 ], [ 697, 317, 49, 14 ], [ 749, 317, 28, 14 ], [ 550, 332, 21, 14 ], [ 575, 332, 24, 14 ], [ 602, 332, 25, 14 ], [ 631, 332, 30, 14 ], [ 665, 332, 48, 14 ], [ 717, 332, 10, 14 ], [ 731, 332, 12, 14 ], [ 747, 332, 30, 14 ], [ 550, 346, 57, 14 ], [ 611, 346, 10, 14 ], [ 625, 346, 13, 14 ], [ 641, 346, 35, 14 ], [ 681, 346, 20, 14 ], [ 705, 346, 39, 14 ], [ 748, 346, 29, 14 ], [ 550, 361, 38, 14 ], [ 591, 361, 23, 14 ], [ 616, 361, 24, 14 ], [ 642, 361, 43, 14 ], [ 687, 361, 12, 14 ], [ 702, 361, 35, 14 ], [ 740, 361, 37, 14 ], [ 550, 375, 34, 14 ], [ 587, 375, 19, 14 ], [ 609, 375, 36, 14 ], [ 648, 375, 29, 14 ], [ 680, 375, 38, 14 ], [ 720, 375, 10, 14 ], [ 733, 375, 12, 14 ], [ 748, 375, 29, 14 ], [ 550, 390, 48, 14 ], [ 601, 390, 9, 14 ], [ 614, 390, 12, 14 ], [ 629, 390, 30, 14 ], [ 662, 390, 10, 14 ], [ 675, 390, 16, 14 ], [ 695, 390, 45, 14 ], [ 743, 390, 34, 14 ], [ 550, 405, 15, 14 ], [ 567, 405, 10, 14 ], [ 580, 405, 35, 14 ], [ 617, 405, 43, 14 ], [ 663, 405, 38, 14 ], [ 703, 405, 74, 14 ], [ 550, 419, 26, 14 ], [ 579, 419, 15, 14 ], [ 597, 419, 35, 14 ], [ 634, 419, 11, 14 ], [ 647, 419, 12, 14 ], [ 662, 419, 32, 14 ], [ 697, 419, 10, 14 ], [ 710, 419, 37, 14 ], [ 750, 419, 27, 14 ], [ 550, 434, 20, 14 ], [ 574, 434, 27, 14 ], [ 605, 434, 73, 14 ], [ 683, 434, 11, 14 ], [ 698, 434, 17, 14 ], [ 719, 434, 58, 14 ], [ 550, 448, 39, 14 ], [ 592, 448, 47, 14 ], [ 642, 448, 48, 14 ], [ 695, 448, 22, 14 ], [ 720, 448, 19, 14 ], [ 743, 448, 34, 14 ], [ 550, 463, 23, 14 ], [ 576, 463, 51, 14 ], [ 631, 463, 48, 14 ], [ 683, 463, 80, 14 ], [ 766, 463, 11, 14 ], [ 550, 477, 37, 14 ], [ 591, 477, 27, 14 ], [ 622, 477, 42, 14 ], [ 667, 477, 10, 14 ], [ 680, 477, 12, 14 ], [ 696, 477, 29, 14 ], [ 729, 477, 48, 14 ], [ 550, 492, 10, 14 ], [ 563, 492, 12, 14 ], [ 579, 492, 34, 14 ], [ 616, 492, 19, 14 ], [ 639, 492, 10, 14 ], [ 654, 492, 24, 14 ], [ 681, 492, 35, 14 ], [ 719, 492, 16, 14 ], [ 739, 492, 38, 14 ], [ 550, 507, 27, 14 ], [ 580, 507, 18, 14 ], [ 601, 507, 41, 14 ], [ 645, 507, 22, 14 ], [ 671, 507, 16, 14 ], [ 690, 507, 48, 14 ], [ 741, 507, 36, 14 ], [ 550, 521, 16, 14 ], [ 570, 521, 32, 14 ], [ 605, 521, 40, 14 ], [ 648, 521, 11, 14 ], [ 662, 521, 43, 14 ], [ 709, 521, 38, 14 ], [ 750, 521, 27, 14 ], [ 550, 536, 27, 14 ], [ 581, 536, 22, 14 ], [ 606, 536, 28, 14 ], [ 639, 536, 57, 14 ], [ 700, 536, 77, 14 ], [ 550, 550, 72, 14 ], [ 624, 550, 52, 14 ], [ 679, 550, 10, 14 ], [ 691, 550, 12, 14 ], [ 705, 550, 29, 14 ], [ 737, 550, 40, 14 ], [ 550, 565, 19, 14 ], [ 571, 565, 27, 14 ], [ 600, 565, 33, 14 ], [ 569, 580, 12, 14 ], [ 584, 580, 16, 14 ], [ 604, 580, 37, 14 ], [ 645, 580, 31, 14 ], [ 679, 580, 14, 14 ], [ 697, 580, 60, 14 ], [ 761, 580, 16, 14 ], [ 550, 594, 52, 14 ], [ 605, 594, 20, 14 ], [ 629, 594, 79, 14 ], [ 711, 594, 15, 14 ], [ 730, 594, 34, 14 ], [ 766, 594, 11, 14 ], [ 550, 609, 12, 14 ], [ 565, 609, 46, 14 ], [ 614, 609, 28, 14 ], [ 644, 609, 22, 14 ], [ 669, 609, 19, 14 ], [ 690, 609, 14, 14 ], [ 707, 609, 15, 14 ], [ 725, 609, 16, 14 ], [ 744, 609, 20, 14 ], [ 767, 609, 11, 14 ], [ 550, 623, 17, 14 ], [ 570, 623, 39, 14 ], [ 613, 623, 29, 14 ], [ 646, 623, 42, 14 ], [ 692, 623, 32, 14 ], [ 728, 623, 16, 14 ], [ 749, 623, 29, 14 ], [ 550, 638, 47, 14 ], [ 600, 638, 11, 14 ], [ 615, 638, 28, 14 ], [ 647, 638, 77, 14 ], [ 728, 638, 49, 14 ], [ 550, 652, 10, 14 ], [ 563, 652, 6, 14 ], [ 571, 652, 86, 14 ], [ 660, 652, 36, 14 ], [ 550, 675, 68, 16 ], [ 622, 675, 28, 16 ], [ 653, 675, 65, 16 ], [ 550, 696, 45, 14 ], [ 600, 696, 55, 14 ], [ 660, 696, 28, 14 ], [ 692, 696, 20, 14 ], [ 717, 696, 24, 14 ], [ 746, 696, 31, 14 ], [ 550, 711, 45, 14 ], [ 599, 711, 40, 14 ], [ 644, 711, 34, 14 ], [ 683, 711, 26, 14 ], [ 715, 711, 11, 14 ], [ 730, 711, 17, 14 ], [ 752, 711, 25, 14 ], [ 550, 725, 35, 14 ], [ 588, 725, 11, 14 ], [ 602, 725, 52, 14 ], [ 658, 725, 10, 14 ], [ 672, 725, 16, 14 ], [ 692, 725, 56, 14 ], [ 751, 725, 26, 14 ], [ 550, 740, 35, 14 ], [ 587, 740, 19, 14 ], [ 609, 740, 34, 14 ], [ 645, 740, 30, 14 ], [ 677, 740, 20, 14 ], [ 700, 740, 57, 14 ], [ 760, 740, 19, 14 ], [ 550, 755, 11, 14 ], [ 564, 755, 12, 14 ], [ 580, 755, 24, 14 ], [ 608, 755, 11, 14 ], [ 622, 755, 52, 14 ], [ 678, 755, 18, 14 ], [ 699, 755, 11, 14 ], [ 713, 755, 64, 14 ], [ 549, 780, 36, 12 ], [ 589, 780, 71, 12 ], [ 663, 780, 10, 12 ], [ 677, 780, 12, 12 ], [ 693, 780, 85, 12 ], [ 549, 792, 39, 12 ], [ 591, 792, 9, 12 ], [ 604, 792, 32, 12 ], [ 640, 792, 66, 12 ], [ 709, 792, 33, 12 ], [ 745, 792, 32, 12 ], [ 549, 805, 35, 12 ], [ 588, 805, 57, 12 ], [ 648, 805, 26, 12 ], [ 678, 805, 46, 12 ], [ 727, 805, 51, 12 ], [ 549, 817, 12, 12 ], [ 565, 817, 50, 12 ], [ 618, 817, 19, 12 ], [ 641, 817, 23, 12 ], [ 668, 817, 50, 12 ], [ 722, 817, 56, 12 ], [ 549, 830, 42, 12 ], [ 558, 842, 61, 12 ], [ 621, 842, 37, 12 ], [ 662, 842, 7, 12 ], [ 672, 842, 38, 12 ], [ 714, 842, 28, 12 ], [ 745, 842, 33, 12 ], [ 549, 855, 152, 12 ], [ 558, 867, 32, 12 ], [ 594, 867, 17, 12 ], [ 615, 867, 47, 12 ], [ 666, 867, 11, 12 ], [ 682, 867, 15, 12 ], [ 701, 867, 34, 12 ], [ 739, 867, 38, 12 ], [ 549, 880, 38, 12 ], [ 591, 880, 38, 12 ], [ 632, 880, 32, 12 ], [ 667, 880, 31, 12 ], [ 701, 880, 34, 12 ], [ 738, 880, 20, 12 ], [ 761, 880, 16, 12 ], [ 549, 892, 25, 12 ], [ 578, 892, 53, 12 ], [ 636, 892, 23, 12 ], [ 662, 892, 44, 12 ], [ 710, 892, 15, 12 ], [ 729, 892, 25, 12 ], [ 757, 892, 20, 12 ], [ 549, 905, 33, 12 ], [ 585, 905, 14, 12 ], [ 603, 905, 46, 12 ], [ 652, 905, 40, 12 ], [ 696, 905, 14, 12 ], [ 713, 905, 52, 12 ], [ 768, 905, 9, 12 ], [ 549, 917, 25, 12 ], [ 578, 917, 35, 12 ], [ 616, 917, 38, 12 ], [ 657, 917, 16, 12 ], [ 676, 917, 28, 12 ], [ 707, 917, 27, 12 ], [ 737, 917, 41, 12 ], [ 549, 930, 41, 12 ], [ 594, 930, 31, 12 ], [ 629, 930, 55, 12 ], [ 688, 930, 17, 12 ], [ 708, 930, 29, 12 ], [ 741, 930, 36, 12 ], [ 549, 942, 56, 12 ], [ 608, 942, 21, 12 ], [ 632, 942, 39, 12 ], [ 673, 942, 26, 12 ], [ 701, 942, 11, 12 ], [ 714, 942, 45, 12 ], [ 761, 942, 16, 12 ], [ 549, 955, 29, 12 ], [ 580, 955, 25, 12 ], [ 558, 967, 18, 12 ], [ 578, 967, 32, 12 ], [ 612, 967, 30, 12 ], [ 644, 967, 19, 12 ], [ 665, 967, 20, 12 ], [ 687, 967, 12, 12 ], [ 701, 967, 25, 12 ], [ 729, 967, 10, 12 ], [ 740, 967, 38, 12 ], [ 549, 980, 46, 12 ], [ 597, 980, 37, 12 ], [ 636, 980, 38, 12 ], [ 558, 992, 40, 12 ], [ 601, 992, 12, 12 ], [ 616, 992, 40, 12 ], [ 659, 992, 26, 12 ], [ 689, 992, 38, 12 ], [ 731, 992, 12, 12 ], [ 746, 992, 31, 12 ], [ 549, 1005, 25, 12 ], [ 753, 1042, 24, 14 ] ]

[ "Research", "A", "Prospective", "Study", "of", "Organochlorines", "in", "Adipose", "Tissue", "and", "Risk", "of", "Non‑Hodgkin", "Lymphoma", "Elvira", "Vaclavik", "Bräuner,1", "Mette", "Sørensen,1", "Eric", "Gaudreau,2", "Alain", "LeBlanc,2", "Kirsten", "Thorup", "Eriksen,1", "Anne", "Tjønneland,1", "Kim", "Overvad,3", "and", "Ole", "Raaschou-Nielsen1", "1Institute", "of", "Cancer", "Epidemiology,", "Danish", "Cancer", "Society,", "Copenhagen,", "Denmark;", "2Centre", "de", "toxicologie", "du", "Québec,", "Institut", "National", "de", "Santé", "Publique", "du", "Québec,", "Quebec", "City,", "Quebec,", "Canada;", "3Department", "of", "Epidemiology,", "School", "of", "Public", "Health,", "Aarhus", "University,", "Aarhus,", "Denmark", "Background", ":", "Exposure", "to", "organochlorines", "has", "been", "examined", "as", "a", "potential", "risk", "factor", "for", "non-Hodgkin", "lymphoma", "(NHL),", "with", "inconsistent", "results", "that", "may", "be", "related", "to", "limited", "statistical", "power", "or", "to", "imprecise", "exposure", "measurements.", "o", "Bjectiv", ":", "Our", "purpose", "was", "to", "examine", "associations", "between", "organochlorine", "concentrations", "in", "prediagnostic", "adipose", "tissue", "samples", "and", "the", "risk", "of", "NHL.", "Methods", ":", "We", "conducted", "a", "case–cohort", "study", "using", "a", "prospective", "Danish", "cohort", "of", "57,053", "persons", "enrolled", "between", "1993", "and", "1997.", "Within", "the", "cohort", "we", "identified", "256", "persons", "diagnosed", "with", "NHL", "in", "the", "population-based", "nationwide", "Danish", "Cancer", "Registry", "and", "randomly", "selected", "256", "sub-", "cohort", "persons.", "We", "measured", "concentrations", "of", "8", "pesticides", "and", "10", "polychlorinated", "biphenyl", "(PCB)", "congeners", "in", "adipose", "tissue", "collected", "upon", "enrollment.", "Associations", "between", "the", "18", "organochlorines", "and", "NHL", "were", "analyzed", "in", "Cox", "regression", "models,", "adjusting", "for", "body", "mass", "index.", "r", "esult", ":", "Incidence", "rate", "ratios", "and", "confidence", "intervals", "(CIs)", "for", "interquartile", "range", "increases", "in", "concentrations", "of", "dichlorodiphenyltrichlorethane", "(DDT),", "cis-nonachlor,", "and", "oxychlordane", "were", "1.35", "(95%", "CI:", "1.10,", "1.66),", "1.13", "(95%", "CI:", "0.94,", "1.36),", "and", "1.11", "(95%", "CI:", "0.89,", "1.38),", "respectively,", "with", "monotonic", "dose–response", "trends", "for", "DDT", "and", "cis-nonachlor", "based", "on", "categorical", "models.", "The", "relative", "risk", "estimates", "were", "higher", "for", "men", "than", "for", "women.", "In", "contrast,", "no", "clear", "association", "was", "found", "between", "NHL", "and", "PCBs.", "c", "onclusi", ":", "We", "found", "a", "higher", "risk", "of", "NHL", "in", "association", "with", "higher", "adipose", "tissue", "levels", "of", "DDT,", "cis-nonachlor,", "and", "oxychlordane,", "but", "no", "association", "with", "PCBs.", "This", "is", "the", "first", "study", "of", "organochlorines", "and", "NHL", "using", "prediagnostic", "adipose", "tissue", "samples", "in", "the", "exposure", "assessment", "and", "provides", "new", "environmental", "health", "evidence", "that", "these", "organochlorines", "contribute", "to", "NHL", "risk.", "k", "ey", "words", ":", "adipose", "tissue,", "case–cohort,", "non-Hodgkin", "lymphoma,", "organochlorines.", "Environ", "Health", "Perspect", "120:105–111", "(2012).", "http://dx.doi.org/10.1289/ehp.1103573", "[Online", "26", "August", "2011]", "Non-Hodgkin", "lymphomas", "(NHLs)", "are", "a", "het-", "erogeneous", "group", "of", "B-", "and", "T-cell", "neoplasms", "arising", "primarily", "in", "the", "lymph", "nodes.", "Incidence", "rates", "have", "nearly", "doubled", "in", "Western", "countries", "since", "the", "1970s,", "although", "no", "further", "rise", "has", "been", "observed", "since", "the", "mid-1990s", "(Dreiher", "and", "Kordysh", "2006).", "Established", "risk", "factors", "include", "genetic", "susceptibility", "and", "previous", "his-", "tory", "of", "malignant", "disease", "(Wang", "et", "al.", "2007).", "Immunological", "conditions", "are", "also", "related", "to", "this", "group", "of", "cancers,", "as", "evidenced", "by", "a", "more", "than", "100-fold", "increased", "risk", "of", "NHL", "among", "organ", "transplant", "recipients", "receiving", "immuno-", "suppressive", "therapy", "(Fisher", "and", "Fisher", "2004)", "and", "an", "increased", "incidence", "among", "subjects", "with", "primary", "immunodeficiency", "and", "autoimmune", "diseases", "(Vineis", "et", "al.", "2000).", "However,", "these", "factors,", "in", "combination", "with", "longer", "life", "spans", "and", "changes", "in", "diagnostic", "patterns,", "cannot", "explain", "all", "cases,", "and", "many", "researchers", "specu-", "late", "that", "the", "increase", "is", "partly", "due", "to", "exposure", "to", "environmental", "agents,", "including", "organo-", "chlorines", "(Hardell", "and", "Axelson", "1998).", "Dichlorodiphenyltrichlorethane", "(DDT)", "and", "other", "organochlorines", "are", "carcinogenic", "in", "animals", "(International", "Agency", "for", "Research", "on", "Cancer", "1987),", "and", "the", "production", "and", "environmental", "release", "of", "these", "compounds", "with", "subsequent", "bioaccumulation", "accelerated", "during", "the", "decades", "after", "1945", "(World", "Resources", "Institute", "1990),", "coinciding", "with", "increasing", "incidence", "rates", "for", "NHL", "in", "Western", "populations.", "Organochlorines", "are", "ubiquitously", "present", "as", "a", "mixture", "of", "mother", "compounds", "and", "metabolites", "in", "the", "environment", "and", "are", "characterized", "by", "high", "lipid", "solubility,", "environ-", "mental", "persistence,", "bioaccumulation", "(Agency", "for", "Toxic", "Substances", "and", "Disease", "Registry", "1993),", "and", "long", "biological", "half-lives", "in", "human", "tissue", "(Wolff", "et", "al.", "2000).", "Several", "studies", "have", "described", "immunotoxicity", "of", "selected", "organo-", "chlorines", "(Heilmann", "et", "al.", "2006;", "Reed", "et", "al.", "2004;", "Tryphonas", "et", "al.", "2003).", "The", "evidence", "relating", "organochlorines", "to", "NHL", "risk", "has", "been", "reviewed", "(Dreiher", "and", "Kordysh", "2006)", "and", "the", "association", "remains", "unclear,", "with", "some", "studies", "reporting", "associa-", "tions", "and", "others", "finding", "none.", "Reasons", "for", "these", "discrepancies", "may", "include", "low", "statis-", "tical", "power", "or", "imprecise", "exposure", "measure-", "ments,", "such", "as", "surrogate", "measures", "including", "occupation", "or", "self-reported", "questionnaires", "gathered", "after", "diagnosis.", "More", "recent", "studies", "have", "evaluated", "biological", "exposure", "measure-", "ments", "and", "have", "more", "consistently", "reported", "associations", "between", "NHL", "risk", "and", "various", "organochlorine", "pesticides", "and", "polychlorinated", "biphenyl", "(PCB)", "congeners", "(Bertrand", "et", "al.", "Environmental", "Health", "Perspectives", "•", "volume", "120", "|", "number", "1", "|", "January", "2012", "2010;", "Cantor", "et", "al.", "2003;", "De", "Roos", "et", "al.", "2005;", "Engel", "et", "al.", "2007;", "Laden", "et", "al.", "2010;", "Quintana", "et", "al.", "2004;", "Spinelli", "et", "al.", "2007).", "However,", "the", "specific", "compounds", "identified", "were", "not", "con-", "sistent", "among", "the", "studies,", "and", "different", "bio-", "logical", "media", "were", "used.", "Questions", "pertaining", "to", "the", "best", "quantification", "of", "biological", "expo-", "sure", "have", "been", "raised", "(Aronson", "et", "al.", "2000;", "Whitcomb", "et", "al.", "2005),", "and", "adipose", "tissue", "samples", "have", "been", "regarded", "by", "various", "authors", "(Allam", "and", "Lucena", "2001;", "Hardell", "et", "al.", "1996;", "Quintana", "et", "al.", "2004)", "as", "the", "preferred", "indica-", "tor", "of", "human", "exposure", "because", "organochlorine", "levels", "are", "known", "to", "be", "higher", "in", "adipose", "tissue", "and", "more", "representative", "of", "the", "cumulative", "internal", "exposure.", "However,", "only", "two", "studies", "have", "previously", "measured", "organochlorines", "in", "adipose", "tissue", "(Hardell", "et", "al.", "1996;", "Quintana", "et", "al.", "2004),", "and", "in", "both", "studies", "the", "adipose", "tissue", "was", "sampled", "after", "the", "diagnosis,", "render-", "ing", "results", "difficult", "to", "interpret", "because", "treat-", "ment", "may", "affect", "subsequent", "organochlorine", "concentrations", "(Gammon", "et", "al.", "1996;", "Morgan", "and", "Roan", "1971).", "In", "the", "present", "study,", "we", "investigated", "the", "hypothesis", "that", "organochlorines", "are", "related", "to", "an", "increased", "NHL", "risk,", "and", "we", "are", "the", "first", "to", "use", "adipose", "tissue", "sampled", "before", "the", "NHL", "diagnosis", "to", "assess", "organochlorine", "exposures", "in", "a", "population-based", "setting.", "Materials", "and", "Methods", "Between", "December", "1993", "and", "May", "1997,", "160,725", "persons", "50–64", "years", "of", "age", "were", "invited", "to", "participate", "in", "the", "prospective", "Diet,", "Cancer", "and", "Health", "study.", "The", "participants", "had", "to", "be", "born", "in", "Denmark,", "live", "in", "Copenhagen", "Address", "correspondence", "to", "O.", "Raaschou-Nielsen,", "Institute", "of", "Cancer", "Epidemiology,", "Danish", "Cancer", "Society,", "Copenhagen", "2100,", "Denmark.", "Telephone:", "45", "35257617.", "Fax:", "0045", "35257731.", "E-mail:ole@", "cancer.dk", "Supplemental", "Material", "is", "available", "online", "(http://", "dx.doi.org/10.1289/ehp.1103573).", "E.V.B.", "was", "supported", "by", "the", "Danish", "Medical", "Research", "Council,", "Danish", "Cancer", "Society,", "Aase", "and", "Ejnar", "Danielsens,", "King", "Christian", "the", "10th,", "A.P.", "Møller,", "the", "Hartmann", "Brothers,", "the", "Foundation", "of", "1870,", "Snedker", "Jacobsen", "and", "hustru", "Astrid", "Jacobsen,", "Architect", "Holger", "Hjortenberg", "and", "hustru", "Dagmar", "Hjortenberg,", "Civil", "Engineer", "Frode", "V.", "Nyegaard,", "and", "Simon", "Spies.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "competing", "financial", "interests.", "Received", "14", "February", "2011;", "accepted", "26", "August", "2011.", "105" ]

[ 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 4 ]

[ [ 469, 62, 46, 12 ], [ 517, 62, 31, 12 ], [ 551, 62, 221, 12 ], [ 79, 120, 150, 21 ], [ 79, 144, 25, 23 ], [ 109, 144, 52, 23 ], [ 167, 144, 35, 23 ], [ 207, 144, 57, 23 ], [ 269, 144, 13, 23 ], [ 288, 144, 43, 23 ], [ 336, 144, 19, 23 ], [ 360, 144, 35, 23 ], [ 400, 144, 100, 23 ], [ 506, 144, 13, 23 ], [ 525, 144, 94, 23 ], [ 624, 144, 84, 23 ], [ 714, 144, 22, 23 ], [ 79, 169, 35, 23 ], [ 119, 169, 35, 23 ], [ 159, 169, 75, 23 ], [ 240, 169, 76, 23 ], [ 322, 169, 106, 23 ], [ 434, 169, 115, 23 ], [ 79, 195, 39, 17 ], [ 122, 195, 11, 17 ], [ 137, 195, 66, 17 ], [ 79, 233, 56, 12 ], [ 137, 233, 10, 12 ], [ 149, 233, 71, 12 ], [ 222, 233, 24, 12 ], [ 249, 233, 46, 12 ], [ 298, 233, 42, 12 ], [ 342, 233, 27, 12 ], [ 371, 233, 40, 12 ], [ 79, 258, 71, 12 ], [ 153, 258, 33, 12 ], [ 189, 258, 26, 12 ], [ 218, 258, 8, 12 ], [ 228, 258, 45, 12 ], [ 275, 258, 35, 12 ], [ 312, 258, 135, 12 ], [ 79, 283, 47, 12 ], [ 129, 283, 7, 12 ], [ 138, 283, 18, 12 ], [ 158, 283, 26, 12 ], [ 196, 283, 50, 12 ], [ 248, 283, 7, 12 ], [ 258, 283, 18, 12 ], [ 278, 283, 26, 12 ], [ 316, 283, 50, 12 ], [ 369, 283, 14, 12 ], [ 385, 283, 18, 12 ], [ 405, 283, 26, 12 ], [ 79, 308, 37, 12 ], [ 119, 308, 19, 12 ], [ 140, 308, 29, 12 ], [ 172, 308, 36, 12 ], [ 79, 321, 10, 12 ], [ 91, 321, 26, 12 ], [ 120, 321, 38, 12 ], [ 160, 321, 35, 12 ], [ 197, 321, 16, 12 ], [ 216, 321, 24, 12 ], [ 242, 321, 24, 11 ], [ 267, 321, 57, 12 ], [ 327, 321, 29, 11 ], [ 358, 321, 24, 11 ], [ 384, 321, 58, 12 ], [ 157, 381, 60, 15 ], [ 157, 409, 20, 13 ], [ 182, 408, 15, 14 ], [ 202, 409, 36, 13 ], [ 242, 409, 39, 13 ], [ 286, 409, 55, 13 ], [ 345, 409, 23, 13 ], [ 373, 409, 10, 13 ], [ 386, 409, 56, 13 ], [ 447, 409, 14, 13 ], [ 465, 409, 37, 13 ], [ 506, 409, 25, 13 ], [ 535, 409, 32, 13 ], [ 571, 409, 20, 13 ], [ 596, 409, 7, 13 ], [ 607, 409, 38, 13 ], [ 649, 409, 11, 13 ], [ 664, 409, 29, 13 ], [ 157, 423, 55, 13 ], [ 216, 423, 35, 13 ], [ 255, 423, 44, 13 ], [ 303, 423, 11, 13 ], [ 318, 423, 19, 13 ], [ 341, 423, 31, 13 ], [ 376, 423, 35, 13 ], [ 415, 423, 59, 13 ], [ 478, 423, 24, 13 ], [ 506, 423, 10, 13 ], [ 519, 423, 41, 13 ], [ 564, 423, 20, 13 ], [ 589, 423, 32, 13 ], [ 624, 423, 22, 13 ], [ 650, 423, 29, 13 ], [ 682, 423, 11, 13 ], [ 157, 438, 28, 13 ], [ 190, 438, 44, 13 ], [ 238, 438, 32, 13 ], [ 275, 438, 32, 13 ], [ 312, 438, 15, 13 ], [ 331, 438, 34, 13 ], [ 370, 438, 46, 13 ], [ 421, 438, 10, 13 ], [ 435, 438, 17, 13 ], [ 457, 438, 50, 13 ], [ 511, 438, 21, 13 ], [ 536, 438, 20, 13 ], [ 561, 438, 43, 13 ], [ 608, 438, 34, 13 ], [ 647, 438, 46, 13 ], [ 157, 453, 26, 13 ], [ 187, 453, 21, 13 ], [ 211, 453, 50, 13 ], [ 263, 453, 25, 13 ], [ 292, 453, 14, 13 ], [ 308, 453, 17, 13 ], [ 328, 453, 19, 13 ], [ 350, 453, 19, 13 ], [ 372, 453, 10, 13 ], [ 385, 453, 17, 13 ], [ 405, 453, 55, 13 ], [ 463, 453, 20, 13 ], [ 486, 453, 52, 13 ], [ 541, 453, 34, 13 ], [ 579, 453, 48, 13 ], [ 630, 453, 64, 13 ], [ 157, 467, 17, 13 ], [ 181, 467, 38, 13 ], [ 226, 467, 25, 13 ], [ 257, 467, 43, 13 ], [ 307, 467, 17, 13 ], [ 330, 467, 39, 13 ], [ 376, 467, 11, 13 ], [ 393, 467, 46, 13 ], [ 446, 467, 77, 13 ], [ 529, 467, 40, 13 ], [ 575, 467, 49, 13 ], [ 631, 467, 20, 13 ], [ 657, 467, 19, 13 ], [ 683, 467, 11, 13 ], [ 157, 482, 50, 13 ], [ 211, 482, 17, 13 ], [ 232, 482, 32, 13 ], [ 269, 482, 47, 13 ], [ 319, 482, 57, 13 ], [ 381, 482, 22, 13 ], [ 406, 482, 29, 13 ], [ 439, 482, 50, 13 ], [ 494, 482, 18, 13 ], [ 515, 482, 49, 13 ], [ 568, 482, 55, 13 ], [ 627, 482, 66, 13 ], [ 157, 496, 14, 13 ], [ 174, 496, 42, 13 ], [ 219, 496, 65, 13 ], [ 286, 496, 33, 13 ], [ 322, 496, 45, 13 ], [ 370, 496, 52, 13 ], [ 425, 496, 20, 13 ], [ 448, 496, 64, 13 ], [ 515, 496, 22, 13 ], [ 539, 496, 7, 13 ], [ 549, 496, 17, 13 ], [ 569, 496, 68, 13 ], [ 640, 496, 54, 13 ], [ 157, 511, 11, 13 ], [ 171, 511, 20, 13 ], [ 195, 511, 10, 13 ], [ 209, 511, 17, 13 ], [ 229, 511, 20, 13 ], [ 252, 511, 45, 13 ], [ 300, 511, 64, 13 ], [ 368, 511, 74, 13 ], [ 445, 511, 29, 13 ], [ 478, 511, 49, 13 ], [ 530, 511, 26, 13 ], [ 560, 511, 55, 13 ], [ 618, 511, 13, 13 ], [ 635, 511, 45, 13 ], [ 683, 511, 11, 13 ], [ 157, 525, 29, 13 ], [ 189, 525, 45, 13 ], [ 237, 525, 10, 13 ], [ 249, 525, 7, 13 ], [ 259, 525, 33, 13 ], [ 295, 525, 34, 13 ], [ 332, 525, 11, 13 ], [ 345, 525, 50, 13 ], [ 398, 525, 52, 13 ], [ 452, 525, 20, 13 ], [ 475, 525, 40, 13 ], [ 518, 525, 50, 13 ], [ 571, 525, 23, 13 ], [ 597, 525, 28, 13 ], [ 627, 525, 43, 13 ], [ 673, 525, 20, 13 ], [ 157, 540, 19, 13 ], [ 180, 540, 50, 13 ], [ 234, 540, 26, 13 ], [ 264, 540, 21, 13 ], [ 289, 540, 50, 13 ], [ 343, 540, 26, 13 ], [ 372, 540, 42, 13 ], [ 417, 540, 48, 13 ], [ 469, 540, 11, 13 ], [ 483, 540, 22, 13 ], [ 509, 540, 50, 13 ], [ 563, 540, 24, 13 ], [ 591, 540, 10, 13 ], [ 604, 540, 40, 13 ], [ 647, 540, 46, 13 ], [ 157, 555, 20, 13 ], [ 184, 555, 10, 13 ], [ 200, 555, 17, 13 ], [ 224, 555, 58, 13 ], [ 288, 555, 22, 13 ], [ 316, 555, 21, 13 ], [ 343, 555, 85, 13 ], [ 435, 555, 20, 13 ], [ 461, 555, 37, 13 ], [ 504, 555, 39, 13 ], [ 549, 555, 52, 13 ], [ 608, 555, 67, 13 ], [ 681, 555, 13, 13 ], [ 157, 569, 42, 13 ], [ 203, 569, 13, 13 ], [ 219, 569, 20, 13 ], [ 243, 569, 11, 13 ], [ 257, 569, 17, 13 ], [ 278, 569, 20, 13 ], [ 302, 569, 26, 13 ], [ 332, 569, 50, 13 ], [ 385, 569, 35, 13 ], [ 424, 569, 61, 13 ], [ 489, 569, 11, 13 ], [ 503, 569, 74, 13 ], [ 581, 569, 18, 13 ], [ 602, 569, 39, 13 ], [ 645, 569, 48, 13 ], [ 157, 584, 20, 13 ], [ 180, 584, 61, 13 ], [ 244, 584, 42, 13 ], [ 289, 584, 17, 13 ], [ 308, 584, 18, 13 ], [ 329, 584, 18, 13 ], [ 349, 584, 49, 13 ], [ 401, 584, 10, 13 ], [ 413, 584, 39, 13 ], [ 455, 584, 11, 13 ], [ 468, 584, 44, 13 ], [ 157, 614, 53, 12 ], [ 213, 614, 26, 12 ], [ 242, 614, 38, 12 ], [ 282, 614, 31, 12 ], [ 315, 614, 44, 12 ], [ 362, 614, 64, 12 ], [ 428, 614, 47, 12 ], [ 478, 614, 36, 12 ], [ 517, 614, 45, 12 ], [ 79, 690, 90, 16 ], [ 79, 708, 9, 14 ], [ 93, 708, 25, 14 ], [ 122, 708, 22, 14 ], [ 149, 708, 4, 14 ], [ 158, 708, 33, 14 ], [ 195, 708, 7, 14 ], [ 208, 708, 50, 14 ], [ 262, 708, 43, 14 ], [ 310, 708, 12, 14 ], [ 327, 708, 19, 14 ], [ 350, 708, 19, 15 ], [ 374, 708, 40, 14 ], [ 79, 725, 43, 14 ], [ 125, 725, 57, 14 ], [ 185, 725, 10, 14 ], [ 199, 725, 42, 14 ], [ 244, 725, 16, 14 ], [ 263, 725, 21, 14 ], [ 287, 725, 39, 14 ], [ 329, 725, 20, 14 ], [ 352, 725, 24, 14 ], [ 379, 725, 28, 14 ], [ 410, 725, 4, 14 ], [ 79, 741, 24, 14 ], [ 105, 741, 35, 14 ], [ 143, 741, 16, 14 ], [ 162, 741, 7, 14 ], [ 173, 741, 37, 14 ], [ 213, 741, 35, 14 ], [ 251, 741, 15, 14 ], [ 269, 741, 19, 14 ], [ 291, 740, 17, 15 ], [ 311, 741, 43, 14 ], [ 357, 741, 57, 14 ], [ 79, 757, 10, 14 ], [ 92, 757, 65, 14 ], [ 160, 757, 22, 14 ], [ 185, 757, 50, 14 ], [ 238, 757, 41, 14 ], [ 282, 757, 7, 14 ], [ 293, 757, 30, 14 ], [ 325, 757, 23, 14 ], [ 351, 757, 10, 14 ], [ 365, 757, 19, 14 ], [ 386, 757, 27, 14 ], [ 79, 774, 59, 14 ], [ 141, 774, 60, 14 ], [ 205, 774, 4, 14 ], [ 212, 774, 18, 14 ], [ 234, 774, 53, 14 ], [ 290, 774, 44, 14 ], [ 337, 774, 12, 14 ], [ 352, 774, 40, 14 ], [ 395, 774, 19, 14 ], [ 79, 790, 59, 14 ], [ 142, 790, 24, 14 ], [ 171, 790, 19, 14 ], [ 194, 790, 19, 14 ], [ 218, 790, 15, 14 ], [ 237, 790, 7, 14 ], [ 249, 790, 39, 14 ], [ 293, 790, 46, 14 ], [ 344, 790, 39, 14 ], [ 387, 790, 4, 14 ], [ 395, 790, 19, 14 ], [ 79, 806, 19, 14 ], [ 101, 806, 28, 14 ], [ 133, 806, 44, 14 ], [ 180, 806, 12, 14 ], [ 196, 806, 61, 14 ], [ 261, 806, 19, 14 ], [ 284, 806, 51, 14 ], [ 338, 806, 22, 14 ], [ 364, 806, 50, 14 ], [ 79, 822, 4, 14 ], [ 87, 822, 24, 14 ], [ 116, 822, 43, 14 ], [ 165, 822, 12, 14 ], [ 182, 822, 45, 14 ], [ 232, 822, 12, 14 ], [ 248, 822, 40, 14 ], [ 294, 822, 52, 14 ], [ 351, 822, 22, 14 ], [ 378, 822, 21, 14 ], [ 404, 822, 10, 14 ], [ 79, 839, 19, 14 ], [ 104, 839, 29, 14 ], [ 140, 839, 55, 14 ], [ 202, 839, 82, 14 ], [ 291, 839, 46, 14 ], [ 345, 839, 43, 14 ], [ 395, 839, 19, 14 ], [ 79, 855, 31, 14 ], [ 113, 855, 4, 14 ], [ 120, 855, 19, 14 ], [ 142, 855, 44, 14 ], [ 190, 855, 12, 14 ], [ 205, 855, 41, 14 ], [ 250, 855, 45, 14 ], [ 298, 855, 22, 14 ], [ 323, 855, 49, 14 ], [ 375, 855, 39, 14 ], [ 79, 871, 38, 14 ], [ 121, 871, 23, 14 ], [ 148, 871, 35, 14 ], [ 188, 871, 11, 14 ], [ 204, 871, 19, 14 ], [ 226, 871, 64, 14 ], [ 295, 871, 33, 14 ], [ 332, 871, 34, 14 ], [ 371, 871, 43, 14 ], [ 79, 888, 37, 14 ], [ 121, 888, 12, 14 ], [ 137, 888, 44, 14 ], [ 186, 888, 7, 14 ], [ 198, 888, 44, 14 ], [ 246, 888, 11, 14 ], [ 263, 888, 35, 14 ], [ 302, 888, 48, 14 ], [ 354, 888, 60, 14 ], [ 79, 904, 70, 14 ], [ 152, 904, 51, 14 ], [ 207, 904, 22, 14 ], [ 233, 904, 37, 14 ], [ 273, 904, 15, 14 ], [ 292, 904, 19, 14 ], [ 314, 904, 55, 14 ], [ 372, 904, 19, 14 ], [ 395, 904, 19, 14 ], [ 79, 920, 28, 14 ], [ 110, 920, 12, 14 ], [ 125, 920, 44, 14 ], [ 172, 920, 88, 14 ], [ 79, 952, 11, 16 ], [ 94, 952, 59, 16 ], [ 156, 952, 60, 16 ], [ 79, 969, 22, 14 ], [ 105, 969, 44, 14 ], [ 154, 969, 11, 14 ], [ 170, 969, 57, 14 ], [ 231, 969, 59, 14 ], [ 295, 969, 39, 14 ], [ 339, 969, 9, 14 ], [ 352, 969, 38, 14 ], [ 395, 969, 19, 14 ], [ 79, 986, 31, 14 ], [ 116, 986, 44, 14 ], [ 166, 986, 22, 14 ], [ 194, 986, 52, 14 ], [ 252, 986, 19, 14 ], [ 276, 986, 57, 14 ], [ 339, 986, 10, 14 ], [ 356, 986, 42, 14 ], [ 403, 986, 10, 14 ], [ 437, 692, 36, 14 ], [ 478, 692, 24, 14 ], [ 507, 692, 15, 14 ], [ 527, 692, 36, 14 ], [ 568, 692, 16, 14 ], [ 588, 692, 19, 14 ], [ 612, 692, 43, 14 ], [ 660, 692, 54, 14 ], [ 719, 692, 53, 14 ], [ 437, 708, 25, 14 ], [ 466, 708, 10, 14 ], [ 482, 708, 45, 14 ], [ 532, 708, 22, 14 ], [ 559, 708, 14, 14 ], [ 577, 708, 27, 14 ], [ 609, 708, 41, 14 ], [ 656, 708, 10, 14 ], [ 671, 708, 65, 14 ], [ 740, 708, 32, 14 ], [ 437, 725, 36, 14 ], [ 479, 725, 29, 14 ], [ 514, 725, 33, 14 ], [ 553, 725, 16, 14 ], [ 575, 725, 13, 14 ], [ 593, 725, 19, 14 ], [ 618, 725, 60, 14 ], [ 684, 725, 50, 14 ], [ 740, 725, 32, 14 ], [ 437, 741, 42, 14 ], [ 484, 741, 43, 14 ], [ 531, 741, 49, 14 ], [ 585, 741, 70, 14 ], [ 660, 741, 22, 14 ], [ 687, 741, 12, 14 ], [ 704, 741, 40, 14 ], [ 749, 741, 23, 14 ], [ 437, 757, 25, 14 ], [ 470, 757, 36, 14 ], [ 515, 757, 96, 14 ], [ 619, 757, 32, 14 ], [ 659, 757, 51, 14 ], [ 718, 757, 54, 14 ], [ 437, 773, 52, 14 ], [ 492, 773, 16, 14 ], [ 511, 773, 32, 14 ], [ 546, 773, 30, 14 ], [ 579, 773, 19, 14 ], [ 601, 773, 38, 14 ], [ 642, 773, 52, 14 ], [ 698, 773, 22, 14 ], [ 723, 773, 7, 14 ], [ 733, 773, 39, 14 ], [ 437, 790, 22, 14 ], [ 464, 790, 41, 14 ], [ 510, 790, 26, 14 ], [ 541, 790, 29, 14 ], [ 575, 790, 12, 14 ], [ 591, 790, 54, 14 ], [ 650, 790, 40, 14 ], [ 695, 790, 22, 14 ], [ 722, 790, 19, 14 ], [ 746, 790, 26, 14 ], [ 437, 806, 25, 14 ], [ 465, 806, 57, 14 ], [ 525, 806, 29, 14 ], [ 557, 806, 51, 14 ], [ 611, 806, 24, 14 ], [ 639, 806, 7, 14 ], [ 650, 806, 28, 14 ], [ 681, 806, 16, 14 ], [ 700, 806, 36, 14 ], [ 739, 806, 33, 14 ], [ 437, 822, 27, 14 ], [ 467, 822, 34, 14 ], [ 505, 822, 25, 14 ], [ 535, 822, 29, 14 ], [ 567, 822, 12, 14 ], [ 583, 822, 19, 14 ], [ 605, 822, 39, 14 ], [ 648, 822, 39, 14 ], [ 691, 822, 10, 14 ], [ 705, 822, 16, 14 ], [ 724, 822, 49, 14 ], [ 437, 839, 22, 14 ], [ 463, 839, 35, 14 ], [ 503, 839, 24, 14 ], [ 531, 839, 54, 14 ], [ 589, 839, 19, 14 ], [ 613, 839, 28, 14 ], [ 645, 839, 19, 14 ], [ 668, 839, 19, 14 ], [ 691, 839, 39, 14 ], [ 735, 839, 37, 14 ], [ 437, 855, 22, 14 ], [ 462, 855, 20, 14 ], [ 485, 855, 34, 14 ], [ 523, 855, 43, 14 ], [ 569, 855, 51, 14 ], [ 624, 855, 58, 14 ], [ 686, 855, 46, 14 ], [ 735, 855, 37, 14 ], [ 437, 871, 28, 14 ], [ 469, 871, 22, 14 ], [ 494, 871, 51, 14 ], [ 549, 871, 47, 14 ], [ 600, 871, 8, 14 ], [ 611, 871, 24, 14 ], [ 638, 871, 27, 14 ], [ 669, 871, 12, 14 ], [ 684, 871, 19, 14 ], [ 707, 871, 48, 14 ], [ 758, 871, 14, 14 ], [ 437, 888, 44, 14 ], [ 487, 888, 19, 14 ], [ 512, 888, 49, 14 ], [ 567, 888, 32, 14 ], [ 605, 888, 34, 14 ], [ 646, 888, 79, 14 ], [ 731, 888, 16, 14 ], [ 754, 888, 19, 14 ], [ 437, 904, 38, 14 ], [ 484, 904, 54, 14 ], [ 546, 904, 50, 14 ], [ 604, 904, 11, 14 ], [ 624, 904, 34, 14 ], [ 667, 904, 26, 14 ], [ 701, 904, 35, 14 ], [ 745, 904, 27, 14 ], [ 437, 920, 41, 14 ], [ 483, 920, 16, 14 ], [ 503, 920, 31, 14 ], [ 538, 920, 11, 14 ], [ 553, 920, 19, 14 ], [ 576, 920, 46, 14 ], [ 627, 920, 30, 14 ], [ 661, 920, 60, 14 ], [ 726, 920, 11, 14 ], [ 741, 920, 31, 14 ], [ 437, 937, 56, 14 ], [ 496, 937, 34, 14 ], [ 534, 937, 44, 14 ], [ 581, 937, 24, 14 ], [ 608, 937, 10, 14 ], [ 621, 937, 55, 14 ], [ 437, 969, 8, 14 ], [ 449, 969, 23, 14 ], [ 477, 969, 24, 14 ], [ 505, 969, 12, 14 ], [ 521, 969, 58, 14 ], [ 583, 969, 7, 14 ], [ 595, 969, 29, 14 ], [ 628, 969, 44, 14 ], [ 676, 969, 11, 14 ], [ 692, 969, 80, 14 ], [ 437, 986, 60, 14 ], [ 501, 986, 50, 14 ], [ 554, 986, 32, 14 ], [ 589, 986, 37, 14 ], [ 630, 986, 24, 14 ], [ 658, 986, 22, 14 ], [ 684, 986, 20, 14 ], [ 708, 986, 32, 14 ], [ 744, 986, 28, 14 ], [ 79, 1020, 23, 12 ], [ 104, 1020, 8, 12 ], [ 115, 1020, 45, 12 ], [ 162, 1020, 37, 12 ], [ 202, 1020, 10, 12 ], [ 214, 1020, 71, 12 ], [ 288, 1020, 35, 12 ], [ 326, 1020, 8, 12 ], [ 336, 1020, 46, 12 ], [ 384, 1020, 35, 12 ], [ 422, 1020, 36, 12 ], [ 461, 1020, 62, 12 ], [ 525, 1020, 17, 12 ], [ 545, 1020, 8, 12 ], [ 555, 1020, 19, 12 ], [ 577, 1020, 45, 12 ], [ 625, 1020, 36, 12 ] ]

[ "Available", "online", "http://arthritis-research.com/content/4/5/E007", "Correspondence", "To", "keep", "the", "catch", "–", "that", "is", "the", "question:", "a", "personal", "account", "of", "the", "3rd", "Annual", "EULAR", "Congress,", "Stockholm", "Frank", "A", "Wollheim", "Department", "of", "Rheumatology,", "Lund", "University", "Hospital,", "Lund,", "Sweden", "Corresponding", "author:", "Frank", "A", "Wollheim", "(e-mail:", "Frank.Wollheim@reum.lu.se)", "Received:", "8", "July", "2002", "Accepted:", "9", "July", "2002", "Published:", "18", "July", "2002", "Arthritis", "Res", "2002,", "4:E007", "©", "2002", "BioMed", "Central", "Ltd", "(Print", "ISSN", "1465-9905;", "Online", "ISSN", "1465-9913)", "Abstract", "The", "3rd", "Annual", "EULAR", "Congress,", "held", "in", "Stockholm", "on", "12–15", "June", "2002,", "had", "a", "turnout", "of", "8300", "delegates,", "almost", "identical", "to", "last", "year’s", "record", "attendance", "level", "in", "Prague.", "The", "venue", "was", "close", "to", "ideal,", "allowing", "ample", "space", "for", "poster", "sessions", "in", "the", "exhibition", "hall.", "The", "manned", "poster", "sessions", "were", "well", "attended,", "even", "on", "the", "last", "day", "of", "the", "Congress.", "The", "numerous", "invited", "speakers", "represented", "the", "world’s", "elite,", "allowing", "the", "staging", "of", "excellent", "state-of-the-art", "podium", "sessions.", "The", "aim", "of", "attracting", "the", "young", "scientific", "community", "was", "partly", "achieved,", "but", "individual", "delegates’", "dependence", "on", "industry", "sponsorship", "poses", "potential", "problems.", "The", "organization", "was", "a", "big", "improvement", "compared", "to", "that", "of", "the", "two", "previous", "congresses.", "Approximately", "1800", "abstracts", "were", "submitted,", "an", "increase", "of", "50%,", "resulting", "in", "a", "higher", "quality", "of", "accepted", "abstracts.", "The", "satellite", "symposia", "held", "every", "morning", "and", "late", "afternoon", "were", "well", "attended;", "thus,", "industry", "exposure", "of", "new", "products,", "both", "in", "podium", "sessions", "and", "at", "the", "exhibitions,", "was", "well", "accommodated.", "The", "Annual", "EULAR", "Congress", "consolidates", "its", "position", "as", "one", "of", "the", "two", "most", "important", "annual", "congresses", "of", "rheumatology,", "but", "EULAR", "economy", "and", "commercial", "aspects", "are", "still", "too", "dominant", "in", "relation", "to", "science.", "Keywords:", "ACR,", "EULAR,", "poster", "sessions,", "rheumatology", "congress,", "satellite", "symposia", "Introduction", "A", "year", "ago", "I", "wrote", "a", "personal", "critique", "of", "the", "2nd", "Annual", "EULAR", "Congress", "in", "Prague", "for", "this", "journal", "[1].", "This", "year,", "I", "was", "asked", "for", "a", "similar", "article", "on", "the", "3rd", "EULAR", "Congress", "in", "Stockholm,", "and", "although", "playing", "a", "small", "part", "in", "the", "local", "organizing", "committee", "I", "felt", "unbiased", "enough", "to", "accept", "the", "challenge.", "This", "will", "not", "be", "a", "normal", "meeting", "report;", "I", "will", "not", "even", "attempt", "to", "summarize", "the", "sessions", "and", "activities", "I", "was", "obliged", "or", "allowed", "to", "attend.", "Realizing", "that", "this", "is", "the", "most", "important", "rheumatologic", "meeting", "outside", "the", "USA,", "I", "will", "attempt", "to", "convey", "positive", "and", "negative", "experi-", "ences,", "fully", "aware", "of", "the", "constraints", "under", "which", "EULAR", "strives", "to", "achieve", "a", "number", "of", "goals,", "political,", "economic,", "educational,", "scientific", "and", "social.", "All", "are", "important", "but", "dif-", "ficult", "to", "achieve", "simultaneously.", "A", "gigantic", "meeting", "The", "number", "of", "delegates", "registered", "(8,300", "—", "almost", "the", "same", "number", "that", "attended", "the", "Congress", "in", "Prague", "in", "2001)", "was", "no", "match", "for", "the", "EULAR", "congress", "organizer", "CMI", "in", "Geneva", "and", "its", "local", "partner", "in", "Stockholm.", "Hotel", "rooms", "were", "found", "for", "all", "the", "delegates,", "although", "those", "arriving", "without", "previous", "reservations", "had", "to", "accept", "less", "than", "classy", "accommodation.", "Volvo", "provided", "limousine", "transport", "for", "some", "VIPs,", "the", "invited", "speakers", "had", "a", "shuttle", "bus", "service", "from", "hotel", "to", "congress", "center,", "and", "the", "ordi-", "nary", "delegates", "were", "provided", "with", "a", "pass", "for", "public", "trans-", "port,", "which", "took", "them", "to", "the", "central", "station", "in", "11", "minutes.", "The", "venue", "was", "excellent,", "not", "least", "the", "big", "central", "exhibi-", "tion", "hall", "which", "housed", "nonprofit", "exhibitors,", "industry", "exhibi-", "tions", "and", "scientific", "posters.", "It", "was", "easy", "to", "get", "oriented", "by", "reading", "the", "program", "book,", "which", "compensated", "for", "the", "almost", "complete", "absence", "of", "signs.", "One", "would", "have", "wished", "for", "signs", "at", "the", "meeting", "room", "entrances,", "at", "least,", "indicating", "which", "session", "was", "in", "progress.", "It", "was", "nice", "to", "encounter", "a", "large", "number", "of", "non-European", "attendees,", "although", "some", "voices", "said", "that", "this", "made", "ACR", "ACR", "=", "American", "College", "of", "Rheumatology;", "EULAR", "=", "European", "League", "Against", "Rheumatism;", "VIP", "=", "very", "important", "person." ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 70, 46, 50, 12 ], [ 123, 46, 18, 12 ], [ 145, 46, 20, 12 ], [ 168, 46, 32, 12 ], [ 203, 46, 51, 12 ], [ 70, 62, 21, 12 ], [ 95, 62, 135, 12 ], [ 78, 91, 10, 14 ], [ 89, 91, 10, 14 ], [ 100, 91, 10, 14 ], [ 111, 91, 10, 14 ], [ 126, 91, 9, 14 ], [ 135, 91, 10, 14 ], [ 146, 91, 8, 14 ], [ 155, 91, 9, 14 ], [ 165, 91, 9, 14 ], [ 175, 91, 8, 14 ], [ 183, 91, 8, 14 ], [ 70, 147, 88, 23 ], [ 165, 147, 19, 23 ], [ 191, 147, 86, 23 ], [ 284, 147, 24, 23 ], [ 315, 147, 116, 23 ], [ 437, 147, 85, 23 ], [ 529, 147, 116, 23 ], [ 70, 172, 36, 23 ], [ 113, 172, 83, 23 ], [ 203, 172, 99, 23 ], [ 309, 172, 19, 23 ], [ 335, 172, 106, 23 ], [ 70, 220, 42, 14 ], [ 116, 220, 35, 14 ], [ 156, 220, 4, 14 ], [ 164, 220, 50, 14 ], [ 217, 220, 92, 14 ], [ 313, 220, 4, 14 ], [ 70, 237, 26, 14 ], [ 100, 237, 15, 14 ], [ 119, 237, 64, 14 ], [ 70, 339, 48, 12 ], [ 122, 339, 6, 12 ], [ 131, 339, 38, 12 ], [ 173, 339, 24, 12 ], [ 199, 339, 4, 12 ], [ 204, 339, 48, 12 ], [ 256, 339, 12, 12 ], [ 272, 339, 37, 12 ], [ 312, 339, 24, 12 ], [ 338, 339, 4, 12 ], [ 343, 339, 47, 12 ], [ 393, 339, 33, 12 ], [ 430, 339, 12, 12 ], [ 446, 339, 43, 12 ], [ 492, 339, 24, 12 ], [ 84, 353, 10, 12 ], [ 97, 353, 15, 12 ], [ 115, 353, 35, 12 ], [ 154, 353, 24, 12 ], [ 70, 392, 52, 14 ], [ 136, 392, 22, 14 ], [ 162, 392, 12, 14 ], [ 179, 392, 33, 14 ], [ 216, 392, 64, 14 ], [ 285, 392, 50, 14 ], [ 339, 392, 11, 14 ], [ 355, 392, 47, 14 ], [ 70, 409, 41, 14 ], [ 115, 409, 56, 14 ], [ 174, 409, 12, 14 ], [ 189, 409, 34, 14 ], [ 226, 409, 60, 14 ], [ 289, 409, 22, 14 ], [ 314, 409, 68, 14 ], [ 385, 409, 17, 14 ], [ 70, 427, 18, 14 ], [ 93, 427, 22, 14 ], [ 120, 427, 29, 14 ], [ 153, 427, 42, 14 ], [ 200, 427, 37, 14 ], [ 242, 427, 29, 14 ], [ 276, 427, 21, 14 ], [ 301, 427, 40, 14 ], [ 347, 427, 55, 14 ], [ 70, 444, 37, 14 ], [ 111, 444, 36, 14 ], [ 151, 444, 50, 14 ], [ 205, 444, 27, 14 ], [ 237, 444, 49, 14 ], [ 290, 444, 14, 14 ], [ 308, 444, 93, 14 ], [ 70, 461, 12, 14 ], [ 90, 461, 17, 14 ], [ 115, 461, 57, 14 ], [ 180, 461, 37, 14 ], [ 224, 461, 43, 14 ], [ 275, 461, 34, 14 ], [ 317, 461, 50, 14 ], [ 374, 461, 27, 14 ], [ 70, 479, 75, 14 ], [ 152, 479, 14, 14 ], [ 174, 479, 48, 14 ], [ 229, 479, 26, 14 ], [ 262, 479, 58, 14 ], [ 327, 479, 38, 14 ], [ 373, 479, 29, 14 ], [ 70, 496, 65, 14 ], [ 144, 496, 43, 14 ], [ 196, 496, 40, 14 ], [ 245, 496, 51, 14 ], [ 305, 496, 67, 14 ], [ 381, 496, 21, 14 ], [ 70, 513, 48, 14 ], [ 124, 513, 64, 14 ], [ 194, 513, 48, 14 ], [ 246, 513, 84, 14 ], [ 335, 513, 66, 14 ], [ 70, 530, 12, 14 ], [ 85, 530, 18, 14 ], [ 106, 530, 20, 14 ], [ 129, 530, 37, 14 ], [ 169, 530, 10, 14 ], [ 182, 530, 41, 14 ], [ 226, 530, 31, 14 ], [ 260, 530, 22, 14 ], [ 285, 530, 39, 14 ], [ 327, 530, 22, 14 ], [ 352, 530, 50, 14 ], [ 70, 548, 12, 14 ], [ 88, 548, 20, 14 ], [ 113, 548, 23, 14 ], [ 141, 548, 39, 14 ], [ 185, 548, 54, 14 ], [ 244, 548, 17, 14 ], [ 267, 548, 31, 14 ], [ 304, 548, 45, 14 ], [ 354, 548, 12, 14 ], [ 371, 548, 30, 14 ], [ 70, 565, 46, 14 ], [ 119, 565, 49, 14 ], [ 171, 565, 12, 14 ], [ 186, 565, 27, 14 ], [ 216, 565, 50, 14 ], [ 269, 565, 45, 14 ], [ 316, 565, 39, 14 ], [ 359, 565, 43, 14 ], [ 70, 582, 45, 14 ], [ 119, 582, 11, 14 ], [ 134, 582, 23, 14 ], [ 161, 582, 20, 14 ], [ 184, 582, 51, 14 ], [ 239, 582, 46, 14 ], [ 289, 582, 12, 14 ], [ 304, 582, 14, 14 ], [ 323, 582, 19, 14 ], [ 345, 582, 12, 14 ], [ 361, 582, 20, 14 ], [ 384, 582, 17, 14 ], [ 70, 600, 53, 14 ], [ 126, 600, 18, 14 ], [ 147, 600, 57, 14 ], [ 207, 600, 37, 14 ], [ 247, 600, 31, 14 ], [ 282, 600, 31, 14 ], [ 315, 600, 12, 14 ], [ 331, 600, 24, 14 ], [ 357, 600, 27, 14 ], [ 387, 600, 14, 14 ], [ 70, 617, 29, 14 ], [ 106, 617, 24, 14 ], [ 138, 617, 29, 14 ], [ 174, 617, 61, 14 ], [ 242, 617, 46, 14 ], [ 295, 617, 11, 14 ], [ 313, 617, 28, 14 ], [ 349, 617, 53, 14 ], [ 70, 634, 67, 14 ], [ 143, 634, 12, 14 ], [ 161, 634, 17, 14 ], [ 184, 634, 17, 14 ], [ 207, 634, 29, 14 ], [ 241, 634, 44, 14 ], [ 291, 634, 22, 14 ], [ 319, 634, 23, 14 ], [ 348, 634, 54, 14 ], [ 70, 652, 70, 14 ], [ 144, 652, 12, 14 ], [ 159, 652, 29, 14 ], [ 191, 652, 17, 14 ], [ 212, 652, 29, 14 ], [ 245, 652, 60, 14 ], [ 308, 652, 22, 14 ], [ 333, 652, 41, 14 ], [ 377, 652, 14, 14 ], [ 395, 652, 7, 14 ], [ 70, 669, 70, 14 ], [ 146, 669, 12, 14 ], [ 165, 669, 38, 14 ], [ 209, 669, 57, 14 ], [ 272, 669, 33, 14 ], [ 311, 669, 53, 14 ], [ 369, 669, 32, 14 ], [ 70, 686, 44, 14 ], [ 126, 686, 45, 14 ], [ 183, 686, 69, 14 ], [ 264, 686, 21, 14 ], [ 296, 686, 30, 14 ], [ 338, 686, 63, 14 ], [ 70, 704, 60, 14 ], [ 139, 704, 27, 14 ], [ 173, 704, 58, 14 ], [ 239, 704, 79, 14 ], [ 325, 704, 40, 14 ], [ 374, 704, 27, 14 ], [ 70, 721, 26, 14 ], [ 101, 721, 11, 14 ], [ 117, 721, 61, 14 ], [ 183, 721, 17, 14 ], [ 205, 721, 79, 14 ], [ 288, 721, 64, 14 ], [ 356, 721, 12, 14 ], [ 373, 721, 29, 14 ], [ 70, 738, 53, 14 ], [ 70, 772, 61, 14 ], [ 144, 773, 53, 14 ], [ 70, 790, 66, 14 ], [ 140, 790, 56, 14 ], [ 210, 773, 62, 14 ], [ 285, 773, 26, 14 ], [ 209, 790, 48, 14 ], [ 260, 790, 56, 14 ], [ 70, 886, 53, 12 ], [ 126, 886, 76, 12 ], [ 206, 886, 43, 12 ], [ 261, 886, 19, 12 ], [ 283, 886, 30, 12 ], [ 317, 886, 35, 12 ], [ 356, 886, 10, 12 ], [ 370, 886, 18, 12 ], [ 70, 899, 30, 12 ], [ 104, 899, 162, 12 ], [ 270, 899, 40, 12 ], [ 313, 899, 70, 12 ], [ 70, 912, 43, 12 ], [ 116, 912, 30, 12 ], [ 149, 912, 8, 12 ], [ 161, 912, 44, 12 ], [ 208, 912, 10, 12 ], [ 221, 912, 51, 12 ], [ 275, 912, 28, 12 ], [ 70, 940, 10, 12 ], [ 84, 940, 27, 12 ], [ 121, 940, 10, 12 ], [ 134, 940, 72, 12 ], [ 217, 940, 12, 12 ], [ 232, 940, 12, 12 ], [ 247, 940, 52, 12 ], [ 303, 940, 22, 12 ], [ 70, 954, 35, 12 ], [ 109, 954, 57, 12 ], [ 169, 954, 35, 12 ], [ 208, 954, 31, 12 ], [ 242, 954, 39, 12 ], [ 284, 954, 10, 12 ], [ 298, 954, 60, 12 ], [ 70, 968, 51, 12 ], [ 125, 968, 39, 12 ], [ 167, 968, 25, 12 ], [ 70, 982, 34, 12 ], [ 108, 982, 122, 12 ], [ 72, 1017, 56, 21 ], [ 425, 392, 76, 14 ], [ 425, 427, 37, 14 ], [ 464, 427, 55, 14 ], [ 523, 427, 56, 14 ], [ 582, 427, 60, 14 ], [ 645, 427, 27, 14 ], [ 675, 427, 57, 14 ], [ 735, 427, 21, 14 ], [ 425, 444, 47, 14 ], [ 476, 444, 20, 14 ], [ 500, 444, 49, 14 ], [ 553, 444, 12, 14 ], [ 569, 444, 30, 14 ], [ 603, 444, 11, 14 ], [ 619, 444, 55, 14 ], [ 678, 444, 29, 14 ], [ 711, 444, 44, 14 ], [ 425, 461, 60, 14 ], [ 491, 461, 21, 14 ], [ 518, 461, 11, 14 ], [ 536, 461, 41, 14 ], [ 583, 461, 26, 14 ], [ 615, 461, 68, 14 ], [ 690, 461, 11, 14 ], [ 707, 461, 48, 14 ], [ 425, 479, 34, 14 ], [ 462, 479, 59, 14 ], [ 525, 479, 36, 14 ], [ 564, 479, 26, 14 ], [ 593, 479, 12, 14 ], [ 608, 479, 38, 14 ], [ 650, 479, 34, 14 ], [ 687, 479, 33, 14 ], [ 724, 479, 32, 14 ], [ 425, 496, 45, 14 ], [ 474, 496, 63, 14 ], [ 541, 496, 38, 14 ], [ 584, 496, 60, 14 ], [ 649, 496, 27, 14 ], [ 680, 496, 29, 14 ], [ 714, 496, 20, 14 ], [ 738, 496, 17, 14 ], [ 425, 513, 29, 14 ], [ 458, 513, 34, 14 ], [ 495, 513, 11, 14 ], [ 510, 513, 50, 14 ], [ 565, 513, 60, 14 ], [ 629, 513, 32, 14 ], [ 665, 513, 41, 14 ], [ 709, 513, 47, 14 ], [ 425, 530, 21, 14 ], [ 449, 530, 64, 14 ], [ 517, 530, 56, 14 ], [ 576, 530, 12, 14 ], [ 592, 530, 52, 14 ], [ 648, 530, 11, 14 ], [ 663, 530, 31, 14 ], [ 698, 530, 32, 14 ], [ 734, 530, 22, 14 ], [ 425, 548, 12, 14 ], [ 441, 548, 38, 14 ], [ 483, 548, 30, 14 ], [ 518, 548, 17, 14 ], [ 539, 548, 58, 14 ], [ 601, 548, 79, 14 ], [ 684, 548, 56, 14 ], [ 744, 548, 12, 14 ], [ 425, 565, 14, 14 ], [ 445, 565, 55, 14 ], [ 506, 565, 19, 14 ], [ 532, 565, 27, 14 ], [ 565, 565, 41, 14 ], [ 612, 565, 64, 14 ], [ 683, 565, 11, 14 ], [ 701, 565, 55, 14 ], [ 425, 582, 78, 14 ], [ 506, 582, 15, 14 ], [ 526, 582, 15, 14 ], [ 546, 582, 51, 14 ], [ 601, 582, 18, 14 ], [ 623, 582, 51, 14 ], [ 678, 582, 36, 14 ], [ 718, 582, 38, 14 ], [ 425, 600, 30, 14 ], [ 460, 600, 48, 14 ], [ 514, 600, 17, 14 ], [ 537, 600, 23, 14 ], [ 566, 600, 62, 14 ], [ 633, 600, 56, 14 ], [ 695, 600, 20, 14 ], [ 721, 600, 12, 14 ], [ 738, 600, 17, 14 ], [ 425, 617, 20, 14 ], [ 448, 617, 43, 14 ], [ 494, 617, 8, 14 ], [ 506, 617, 19, 14 ], [ 528, 617, 27, 14 ], [ 558, 617, 37, 14 ], [ 598, 617, 21, 14 ], [ 623, 617, 49, 14 ], [ 676, 617, 80, 14 ], [ 425, 634, 11, 14 ], [ 443, 634, 64, 14 ], [ 513, 634, 20, 14 ], [ 540, 634, 29, 14 ], [ 576, 634, 56, 14 ], [ 639, 634, 20, 14 ], [ 665, 634, 14, 14 ], [ 685, 634, 50, 14 ], [ 742, 634, 14, 14 ], [ 425, 652, 75, 14 ], [ 505, 652, 12, 14 ], [ 521, 652, 7, 14 ], [ 533, 652, 21, 14 ], [ 558, 652, 38, 14 ], [ 601, 652, 66, 14 ], [ 672, 652, 35, 14 ], [ 712, 652, 12, 14 ], [ 728, 652, 27, 14 ], [ 425, 669, 31, 14 ], [ 459, 669, 56, 14 ], [ 518, 669, 24, 14 ], [ 545, 669, 48, 14 ], [ 597, 669, 57, 14 ], [ 657, 669, 12, 14 ], [ 673, 669, 38, 14 ], [ 714, 669, 41, 14 ], [ 425, 686, 45, 14 ], [ 478, 686, 11, 14 ], [ 497, 686, 47, 14 ], [ 552, 686, 48, 14 ], [ 608, 686, 41, 14 ], [ 656, 686, 34, 14 ], [ 698, 686, 18, 14 ], [ 724, 686, 32, 14 ], [ 425, 704, 38, 14 ], [ 467, 704, 12, 14 ], [ 483, 704, 47, 14 ], [ 534, 704, 93, 14 ], [ 631, 704, 42, 14 ], [ 677, 704, 79, 14 ], [ 425, 721, 11, 14 ], [ 442, 721, 41, 14 ], [ 489, 721, 56, 14 ], [ 550, 721, 27, 14 ], [ 583, 721, 23, 14 ], [ 611, 721, 27, 14 ], [ 644, 721, 47, 14 ], [ 696, 721, 25, 14 ], [ 727, 721, 29, 14 ], [ 425, 738, 30, 14 ], [ 458, 738, 12, 14 ], [ 474, 738, 59, 14 ], [ 537, 738, 20, 14 ], [ 562, 738, 67, 14 ], [ 633, 738, 38, 14 ], [ 675, 738, 57, 14 ], [ 735, 738, 21, 14 ], [ 425, 755, 41, 14 ], [ 470, 755, 38, 14 ], [ 513, 755, 62, 14 ], [ 579, 755, 22, 14 ], [ 606, 755, 22, 14 ], [ 440, 773, 53, 14 ], [ 497, 773, 18, 14 ], [ 519, 773, 39, 14 ], [ 562, 773, 65, 14 ], [ 630, 773, 12, 14 ], [ 646, 773, 30, 14 ], [ 680, 773, 19, 14 ], [ 702, 773, 12, 14 ], [ 718, 773, 23, 14 ], [ 745, 773, 11, 14 ], [ 425, 790, 47, 14 ], [ 475, 790, 41, 14 ], [ 520, 790, 47, 14 ], [ 571, 790, 56, 14 ], [ 630, 790, 12, 14 ], [ 646, 790, 63, 14 ], [ 713, 790, 25, 14 ], [ 742, 790, 14, 14 ], [ 425, 807, 34, 14 ], [ 461, 807, 57, 14 ], [ 521, 807, 12, 14 ], [ 536, 807, 46, 14 ], [ 585, 807, 81, 14 ], [ 669, 807, 20, 14 ], [ 692, 807, 14, 14 ], [ 709, 807, 33, 14 ], [ 745, 807, 11, 14 ], [ 425, 825, 18, 14 ], [ 445, 825, 57, 14 ], [ 506, 825, 51, 14 ], [ 560, 825, 48, 14 ], [ 611, 825, 57, 14 ], [ 671, 825, 11, 14 ], [ 685, 825, 14, 14 ], [ 702, 825, 24, 14 ], [ 729, 825, 27, 14 ], [ 425, 842, 47, 14 ], [ 479, 842, 17, 14 ], [ 503, 842, 32, 14 ], [ 542, 842, 12, 14 ], [ 561, 842, 18, 14 ], [ 586, 842, 14, 14 ], [ 607, 842, 31, 14 ], [ 645, 842, 45, 14 ], [ 698, 842, 12, 14 ], [ 717, 842, 39, 14 ], [ 425, 859, 40, 14 ], [ 469, 859, 12, 14 ], [ 486, 859, 27, 14 ], [ 518, 859, 12, 14 ], [ 534, 859, 18, 14 ], [ 556, 859, 34, 14 ], [ 594, 859, 32, 14 ], [ 631, 859, 18, 14 ], [ 653, 859, 41, 14 ], [ 699, 859, 27, 14 ], [ 730, 859, 26, 14 ], [ 425, 876, 58, 14 ], [ 489, 876, 64, 14 ], [ 559, 876, 12, 14 ], [ 578, 876, 55, 14 ], [ 639, 876, 46, 14 ], [ 691, 876, 26, 14 ], [ 724, 876, 32, 14 ], [ 425, 894, 28, 14 ], [ 464, 894, 19, 14 ], [ 494, 894, 35, 14 ], [ 540, 894, 65, 14 ], [ 617, 894, 29, 14 ], [ 658, 894, 25, 14 ], [ 694, 894, 62, 14 ], [ 425, 911, 64, 14 ], [ 493, 911, 50, 14 ], [ 547, 911, 20, 14 ], [ 571, 911, 84, 14 ], [ 659, 911, 19, 14 ], [ 683, 911, 48, 14 ], [ 735, 911, 21, 14 ], [ 425, 928, 46, 14 ], [ 474, 928, 12, 14 ], [ 490, 928, 29, 14 ], [ 523, 928, 23, 14 ], [ 549, 928, 29, 14 ], [ 582, 928, 11, 14 ], [ 597, 928, 7, 14 ], [ 607, 928, 71, 14 ], [ 681, 928, 75, 14 ], [ 425, 946, 11, 14 ], [ 444, 946, 81, 14 ], [ 533, 946, 67, 14 ], [ 608, 946, 21, 14 ], [ 636, 946, 49, 14 ], [ 692, 946, 64, 14 ], [ 425, 963, 56, 14 ], [ 485, 963, 12, 14 ], [ 501, 963, 34, 14 ], [ 539, 963, 39, 14 ], [ 583, 963, 37, 14 ], [ 624, 963, 29, 14 ], [ 657, 963, 21, 14 ], [ 682, 963, 41, 14 ], [ 727, 963, 29, 14 ], [ 425, 980, 31, 14 ], [ 466, 980, 37, 14 ], [ 514, 980, 36, 14 ], [ 560, 980, 48, 14 ], [ 619, 980, 74, 14 ], [ 704, 980, 12, 14 ], [ 727, 980, 29, 14 ] ]

[ "Nanoscale", "Res", "Lett", "(2009)", "4:420–430", "DOI", "10.1007/s11671-009-9262-5", "N", "A", "N", "O", "E", "X", "P", "R", "E", "S", "S", "Influence", "of", "Nanogels", "on", "Mechanical,", "Dynamic", "Mechanical,", "and", "Thermal", "Properties", "of", "Elastomers", "Suman", "Mitra", "Æ", "Santanu", "Chattopadhyay", "Æ", "Anil", "K.", "Bhowmick", "Received:", "6", "October", "2008", "/", "Accepted:", "27", "January", "2009", "/", "Published", "online:", "13", "February", "2009", "to", "the", "authors", "2009", "Abstract", "Use", "of", "sulfur", "crosslinked", "nanogels", "to", "improve", "various", "properties", "of", "virgin", "elastomers", "was", "investigated", "for", "the", "first", "time.", "Natural", "rubber", "(NR)", "and", "styrene", "butadiene", "rubber", "(SBR)", "nanogels", "were", "prepared", "by", "prevulcanization", "of", "the", "respective", "rubber", "lattices.", "These", "nanogels", "were", "characterized", "by", "dynamic", "light", "scattering,", "atomic", "force", "microscopy", "(AFM),", "solvent", "swelling,", "mechanical,", "and", "dynamic", "mechanical", "property", "measurements.", "Intermixing", "of", "gel", "and", "matrix", "at", "various", "ratios", "was", "carried", "out.", "Addition", "of", "NR", "gels", "greatly", "improved", "the", "green", "strength", "of", "SBR,", "whereas", "presence", "of", "SBR", "nanogels", "induced", "greater", "thermal", "stability", "in", "NR.", "For", "example,", "addition", "of", "16", "phr", "of", "NR", "gel", "increased", "the", "maximum", "tensile", "stress", "value", "of", "neat", "SBR", "by", "more", "than", "48%.", "Noticeable", "increase", "in", "glass", "transition", "temperature", "of", "the", "gel", "filled", "systems", "was", "also", "observed.", "Morphology", "of", "these", "gel", "filled", "elastomers", "was", "studied", "by", "a", "combination", "of", "energy", "dispersive", "X-ray", "mapping,", "trans-", "mission", "electron", "microscopy,", "and", "AFM", "techniques.", "Particulate", "filler", "composite", "reinforcement", "models", "were", "used", "to", "understand", "the", "reinforcement", "mechanism", "of", "these", "nanogels.", "Keywords", "Nanogels", "Mechanical", "properties", "Elastomers", "Gels", "Thermal", "properties", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s11671-009-9262-5)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "S.", "Mitra", "S.", "Chattopadhyay", "A.", "K.", "Bhowmick", "(&)", "Rubber", "Technology", "Centre,", "Indian", "Institute", "of", "Technology,", "Kharagpur", "721302,", "India", "e-mail:", "anilkb@rtc.iitkgp.ernet.in", "123", "Introduction", "Virgin", "polymers,", "especially", "elastomers", "have", "inherently", "low", "stiffness", "and", "strength.", "In", "order", "to", "overcome", "these", "obvious", "limitations", "and", "to", "expand", "their", "applications", "in", "different", "fields,", "particulate", "fillers,", "such", "as", "carbon", "black,", "silica,", "glass,", "calcium", "carbonates,", "carbon", "nanotubes,", "nano", "clays", "etc.", "are", "often", "added", "to", "polymer.", "Particulate", "fillers", "modify", "physical", "and", "mechanical", "properties", "of", "polymers", "in", "many", "ways.", "Use", "of", "carbon", "black", "for", "improving", "reinforcement", "properties", "of", "an", "elastomer", "has", "been", "studied", "extensively", "in", "numerous", "investigations", "[1,", "2].", "Amongst", "the", "nonblack", "fillers,", "mostly", "silica", "provides", "the", "best", "reinforcing", "properties", "[3].", "In", "the", "last", "decade,", "it", "has", "been", "shown", "that", "dramatic", "improvements", "in", "mechanical", "and", "other", "properties", "can", "be", "achieved", "by", "incorporation", "of", "a", "few", "weight", "percentages", "(wt%)", "of", "inor-", "ganic", "exfoliated", "clay", "minerals", "consisting", "of", "mostly", "layered", "silicates", "in", "polymer", "matrices", "[4–10].", "These", "are", "better", "known", "as", "polymer", "nanocomposites.", "Similar", "enhancements", "in", "various", "properties", "have", "also", "been", "reported", "with", "other", "types", "of", "nanofillers", "e.g.", "multiwalled", "carbon", "nanotubes", "and", "layered", "double", "hydroxides", "[11,", "12].", "Although", "not", "strictly", "categorized", "as", "filler,", "use", "of", "gels", "to", "improve", "various", "physical", "properties", "of", "elastomers,", "with", "an", "added", "advantage", "of", "superior", "processability,", "can", "be", "found", "in", "the", "prevailing", "literature", "[13–15].", "Kawahara", "et", "al.", "[16]", "have", "reported", "the", "effect", "of", "gel", "on", "green", "strength", "of", "natural", "rubber.", "In", "most", "of", "the", "above", "work,", "the", "authors", "have", "used", "physically", "crosslinked", "or", "entangled", "network", "gels.", "How-", "ever,", "our", "recent", "preliminary", "work", "with", "chemically", "crosslinked", "nanogels", "and", "quasi-nanogels", "has", "revealed", "that", "addition", "of", "these", "gels", "leads", "to", "a", "considerable", "improvement", "in", "processability,", "mechanical,", "and", "dynamic", "mechanical", "properties", "of", "virgin", "natural", "rubber", "(NR)", "and", "styrene", "buta-", "diene", "rubber", "(SBR)", "[17–19].", "Optimization", "of", "these" ]

[ 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 683, 52, 12, 17 ], [ 698, 52, 11, 17 ], [ 711, 52, 10, 17 ], [ 723, 52, 5, 17 ], [ 730, 52, 12, 17 ], [ 745, 52, 9, 17 ], [ 756, 52, 11, 17 ], [ 75, 98, 183, 22 ], [ 263, 98, 54, 22 ], [ 322, 98, 20, 22 ], [ 348, 98, 28, 22 ], [ 381, 98, 90, 22 ], [ 476, 98, 24, 22 ], [ 506, 98, 24, 22 ], [ 535, 98, 115, 22 ], [ 75, 123, 111, 22 ], [ 191, 123, 113, 22 ], [ 116, 168, 61, 16 ], [ 181, 168, 19, 16 ], [ 203, 168, 54, 16 ], [ 260, 168, 26, 16 ], [ 290, 168, 52, 16 ], [ 346, 168, 18, 16 ], [ 368, 168, 49, 16 ], [ 116, 195, 61, 12 ], [ 180, 195, 11, 12 ], [ 193, 195, 50, 12 ], [ 245, 195, 19, 12 ], [ 267, 195, 38, 12 ], [ 308, 195, 56, 12 ], [ 367, 195, 43, 12 ], [ 413, 195, 52, 12 ], [ 467, 195, 46, 12 ], [ 516, 195, 16, 12 ], [ 535, 195, 31, 12 ], [ 116, 210, 38, 12 ], [ 156, 210, 11, 12 ], [ 170, 210, 72, 12 ], [ 244, 210, 49, 12 ], [ 295, 210, 11, 12 ], [ 309, 210, 28, 12 ], [ 339, 210, 10, 12 ], [ 352, 210, 35, 12 ], [ 390, 210, 35, 12 ], [ 427, 210, 14, 12 ], [ 444, 210, 31, 12 ], [ 116, 249, 72, 14 ], [ 191, 249, 53, 14 ], [ 246, 249, 13, 14 ], [ 262, 249, 63, 14 ], [ 329, 249, 67, 14 ], [ 399, 249, 31, 14 ], [ 433, 249, 58, 14 ], [ 494, 249, 12, 14 ], [ 509, 249, 32, 14 ], [ 543, 249, 58, 14 ], [ 604, 249, 52, 14 ], [ 659, 249, 9, 14 ], [ 671, 249, 27, 14 ], [ 700, 249, 67, 14 ], [ 116, 264, 35, 14 ], [ 155, 264, 19, 14 ], [ 177, 264, 73, 14 ], [ 253, 264, 17, 14 ], [ 273, 264, 47, 14 ], [ 323, 264, 49, 14 ], [ 374, 264, 9, 14 ], [ 386, 264, 59, 14 ], [ 448, 264, 14, 14 ], [ 464, 264, 7, 14 ], [ 474, 264, 92, 14 ], [ 570, 264, 67, 14 ], [ 640, 264, 12, 14 ], [ 655, 264, 32, 14 ], [ 689, 264, 12, 14 ], [ 704, 264, 19, 14 ], [ 727, 264, 40, 14 ], [ 116, 278, 36, 14 ], [ 155, 278, 42, 14 ], [ 200, 278, 51, 14 ], [ 254, 278, 21, 14 ], [ 278, 278, 9, 14 ], [ 290, 278, 19, 14 ], [ 312, 278, 24, 14 ], [ 339, 278, 17, 14 ], [ 359, 278, 31, 14 ], [ 393, 278, 22, 14 ], [ 418, 278, 95, 14 ], [ 516, 278, 58, 14 ], [ 577, 278, 29, 14 ], [ 609, 278, 55, 14 ], [ 667, 278, 50, 14 ], [ 720, 278, 46, 14 ], [ 116, 293, 46, 14 ], [ 167, 293, 49, 14 ], [ 220, 293, 29, 14 ], [ 253, 293, 22, 14 ], [ 279, 293, 18, 14 ], [ 302, 293, 22, 14 ], [ 329, 293, 27, 14 ], [ 360, 293, 47, 14 ], [ 412, 293, 31, 14 ], [ 448, 293, 8, 14 ], [ 460, 293, 25, 14 ], [ 490, 293, 40, 14 ], [ 534, 293, 64, 14 ], [ 603, 293, 59, 14 ], [ 666, 293, 55, 14 ], [ 726, 293, 7, 14 ], [ 737, 293, 30, 14 ], [ 116, 307, 67, 14 ], [ 186, 307, 50, 14 ], [ 239, 307, 41, 14 ], [ 283, 307, 20, 14 ], [ 306, 307, 19, 14 ], [ 328, 307, 30, 14 ], [ 362, 307, 19, 14 ], [ 384, 307, 57, 14 ], [ 444, 307, 12, 14 ], [ 460, 307, 104, 14 ], [ 567, 307, 35, 14 ], [ 605, 307, 33, 14 ], [ 642, 307, 15, 14 ], [ 660, 307, 35, 14 ], [ 699, 307, 18, 14 ], [ 720, 307, 47, 14 ], [ 116, 322, 52, 14 ], [ 172, 322, 13, 14 ], [ 190, 322, 7, 14 ], [ 200, 322, 32, 14 ], [ 235, 322, 20, 14 ], [ 259, 322, 59, 14 ], [ 322, 322, 45, 14 ], [ 370, 322, 20, 14 ], [ 394, 322, 26, 14 ], [ 424, 322, 67, 14 ], [ 495, 322, 39, 14 ], [ 537, 322, 19, 14 ], [ 560, 322, 57, 14 ], [ 621, 322, 12, 14 ], [ 637, 322, 96, 14 ], [ 737, 322, 30, 14 ], [ 116, 337, 46, 14 ], [ 164, 337, 35, 14 ], [ 201, 337, 73, 14 ], [ 276, 337, 19, 14 ], [ 297, 337, 51, 14 ], [ 350, 337, 40, 14 ], [ 393, 337, 70, 14 ], [ 465, 337, 12, 14 ], [ 479, 337, 31, 14 ], [ 513, 337, 32, 14 ], [ 547, 337, 14, 14 ], [ 563, 337, 52, 14 ], [ 618, 337, 12, 14 ], [ 632, 337, 42, 14 ], [ 676, 337, 90, 14 ], [ 116, 351, 35, 14 ], [ 155, 351, 18, 14 ], [ 176, 351, 27, 14 ], [ 206, 351, 27, 14 ], [ 237, 351, 65, 14 ], [ 305, 351, 22, 14 ], [ 331, 351, 40, 14 ], [ 374, 351, 84, 14 ], [ 461, 351, 12, 14 ], [ 476, 351, 41, 14 ], [ 521, 351, 52, 14 ], [ 577, 351, 12, 14 ], [ 592, 351, 33, 14 ], [ 628, 351, 12, 14 ], [ 643, 351, 72, 14 ], [ 718, 351, 48, 14 ], [ 116, 366, 30, 14 ], [ 148, 366, 20, 14 ], [ 170, 366, 67, 14 ], [ 240, 366, 40, 14 ], [ 282, 366, 19, 14 ], [ 303, 366, 20, 14 ], [ 324, 366, 67, 14 ], [ 393, 366, 24, 14 ], [ 419, 366, 68, 14 ], [ 490, 366, 43, 14 ], [ 535, 366, 11, 14 ], [ 547, 366, 55, 14 ], [ 605, 366, 47, 14 ], [ 654, 366, 31, 14 ], [ 687, 366, 22, 14 ], [ 711, 366, 32, 14 ], [ 745, 366, 22, 14 ], [ 116, 380, 61, 14 ], [ 182, 380, 23, 14 ], [ 209, 380, 52, 14 ], [ 266, 380, 21, 14 ], [ 291, 380, 29, 14 ], [ 325, 380, 69, 14 ], [ 399, 380, 13, 14 ], [ 417, 380, 38, 14 ], [ 460, 380, 45, 14 ], [ 510, 380, 18, 14 ], [ 533, 380, 42, 14 ], [ 579, 380, 24, 14 ], [ 608, 380, 16, 14 ], [ 628, 380, 51, 14 ], [ 684, 380, 23, 14 ], [ 712, 380, 41, 14 ], [ 758, 380, 9, 14 ], [ 116, 395, 45, 14 ], [ 163, 395, 34, 14 ], [ 200, 395, 17, 14 ], [ 220, 395, 50, 14 ], [ 273, 395, 26, 14 ], [ 302, 395, 43, 14 ], [ 347, 395, 82, 14 ], [ 431, 395, 12, 14 ], [ 446, 395, 35, 14 ], [ 483, 395, 26, 14 ], [ 511, 395, 54, 14 ], [ 568, 395, 31, 14 ], [ 601, 395, 11, 14 ], [ 615, 395, 25, 14 ], [ 642, 395, 20, 14 ], [ 665, 395, 47, 14 ], [ 715, 395, 7, 14 ], [ 724, 395, 42, 14 ], [ 116, 410, 42, 14 ], [ 161, 410, 12, 14 ], [ 176, 410, 52, 14 ], [ 231, 410, 40, 14 ], [ 274, 410, 17, 14 ], [ 295, 410, 7, 14 ], [ 304, 410, 40, 14 ], [ 347, 410, 42, 14 ], [ 392, 410, 12, 14 ], [ 407, 410, 16, 15 ], [ 426, 410, 12, 14 ], [ 441, 410, 44, 14 ], [ 488, 410, 47, 14 ], [ 537, 410, 12, 14 ], [ 552, 410, 19, 14 ], [ 574, 410, 40, 14 ], [ 617, 410, 42, 14 ], [ 662, 410, 56, 14 ], [ 721, 410, 13, 14 ], [ 737, 410, 30, 14 ], [ 116, 424, 63, 14 ], [ 182, 424, 35, 14 ], [ 220, 424, 41, 14 ], [ 264, 424, 19, 14 ], [ 286, 424, 67, 14 ], [ 355, 424, 12, 14 ], [ 370, 424, 7, 14 ], [ 380, 424, 29, 14 ], [ 412, 424, 40, 14 ], [ 454, 424, 67, 14 ], [ 524, 424, 12, 14 ], [ 538, 424, 41, 14 ], [ 582, 424, 53, 14 ], [ 637, 424, 11, 14 ], [ 651, 424, 27, 14 ], [ 680, 424, 86, 14 ], [ 116, 439, 9, 14 ], [ 128, 439, 76, 14 ], [ 207, 439, 25, 14 ], [ 235, 439, 93, 14 ], [ 330, 439, 35, 14 ], [ 368, 439, 24, 14 ], [ 395, 439, 37, 14 ], [ 436, 439, 42, 14 ], [ 481, 439, 23, 14 ], [ 507, 439, 35, 14 ], [ 545, 439, 12, 14 ], [ 560, 439, 71, 14 ], [ 633, 439, 41, 14 ], [ 677, 439, 12, 14 ], [ 692, 439, 19, 14 ], [ 714, 439, 18, 14 ], [ 735, 439, 32, 14 ], [ 116, 453, 19, 14 ], [ 137, 453, 32, 14 ], [ 172, 453, 9, 14 ], [ 184, 453, 20, 14 ], [ 206, 453, 38, 14 ], [ 247, 453, 32, 14 ], [ 281, 453, 13, 14 ], [ 297, 453, 47, 14 ], [ 347, 453, 49, 14 ], [ 398, 453, 22, 14 ], [ 423, 453, 44, 14 ], [ 470, 453, 22, 14 ], [ 495, 453, 32, 14 ], [ 530, 453, 23, 14 ], [ 556, 453, 19, 14 ], [ 578, 453, 68, 14 ], [ 648, 453, 25, 14 ], [ 675, 453, 17, 14 ], [ 695, 453, 18, 14 ], [ 715, 453, 52, 14 ], [ 116, 468, 24, 14 ], [ 143, 468, 20, 14 ], [ 166, 468, 15, 14 ], [ 183, 468, 73, 14 ], [ 42, 403, 10, 0 ], [ 42, 414, 12, 0 ], [ 42, 425, 12, 0 ], [ 42, 430, 5, 0 ], [ 42, 441, 12, 0 ], [ 42, 445, 5, 0 ], [ 42, 454, 9, 0 ], [ 42, 463, 10, 0 ], [ 42, 473, 11, 0 ], [ 42, 484, 12, 0 ], [ 42, 494, 5, 0 ], [ 42, 504, 10, 0 ], [ 42, 511, 8, 0 ], [ 42, 521, 11, 0 ], [ 42, 532, 11, 0 ], [ 42, 542, 11, 0 ], [ 42, 556, 15, 0 ], [ 42, 568, 7, 0 ], [ 42, 579, 12, 0 ], [ 42, 589, 5, 0 ], [ 42, 599, 10, 0 ], [ 42, 609, 11, 0 ], [ 42, 616, 8, 0 ], [ 42, 626, 11, 0 ], [ 42, 637, 12, 0 ], [ 42, 646, 10, 0 ], [ 42, 662, 11, 0 ], [ 42, 672, 11, 0 ], [ 42, 683, 11, 0 ], [ 75, 511, 4, 13 ], [ 80, 511, 10, 13 ], [ 93, 511, 8, 13 ], [ 103, 511, 8, 13 ], [ 113, 511, 11, 13 ], [ 126, 511, 10, 13 ], [ 138, 511, 10, 13 ], [ 150, 511, 9, 13 ], [ 161, 511, 8, 13 ], [ 170, 511, 4, 13 ], [ 176, 511, 11, 13 ], [ 189, 511, 10, 13 ], [ 75, 535, 25, 14 ], [ 103, 535, 70, 14 ], [ 177, 535, 13, 14 ], [ 193, 535, 21, 14 ], [ 217, 535, 49, 14 ], [ 270, 535, 51, 14 ], [ 325, 535, 24, 14 ], [ 352, 535, 43, 14 ], [ 399, 535, 9, 14 ], [ 75, 552, 38, 14 ], [ 116, 552, 49, 14 ], [ 169, 552, 13, 14 ], [ 185, 552, 13, 14 ], [ 202, 552, 34, 14 ], [ 240, 552, 13, 14 ], [ 256, 552, 7, 14 ], [ 267, 552, 26, 14 ], [ 296, 552, 24, 14 ], [ 325, 552, 46, 14 ], [ 375, 552, 14, 14 ], [ 392, 552, 16, 14 ], [ 75, 568, 35, 14 ], [ 114, 568, 37, 14 ], [ 155, 568, 13, 14 ], [ 173, 568, 20, 14 ], [ 197, 568, 34, 14 ], [ 235, 568, 29, 14 ], [ 269, 568, 17, 14 ], [ 290, 568, 7, 14 ], [ 301, 568, 59, 14 ], [ 365, 568, 44, 14 ], [ 75, 585, 54, 14 ], [ 132, 585, 48, 14 ], [ 184, 585, 35, 14 ], [ 223, 585, 56, 14 ], [ 283, 585, 20, 14 ], [ 307, 585, 30, 14 ], [ 341, 585, 47, 14 ], [ 392, 585, 17, 14 ], [ 75, 602, 49, 14 ], [ 128, 602, 20, 14 ], [ 152, 602, 26, 14 ], [ 182, 602, 13, 14 ], [ 199, 601, 17, 15 ], [ 220, 602, 58, 14 ], [ 282, 602, 12, 14 ], [ 298, 602, 7, 14 ], [ 310, 602, 24, 14 ], [ 337, 602, 25, 14 ], [ 366, 602, 42, 14 ], [ 75, 618, 89, 14 ], [ 167, 618, 20, 14 ], [ 190, 618, 94, 14 ], [ 288, 618, 49, 14 ], [ 340, 618, 24, 14 ], [ 368, 618, 40, 14 ], [ 75, 635, 15, 14 ], [ 94, 635, 20, 14 ], [ 118, 635, 38, 14 ], [ 160, 635, 49, 14 ], [ 213, 635, 26, 14 ], [ 243, 635, 74, 14 ], [ 321, 635, 62, 14 ], [ 388, 635, 20, 14 ], [ 75, 652, 13, 14 ], [ 93, 652, 75, 14 ], [ 173, 652, 46, 14 ], [ 225, 652, 51, 14 ], [ 282, 652, 24, 14 ], [ 312, 652, 35, 14 ], [ 352, 652, 34, 14 ], [ 391, 651, 17, 15 ], [ 75, 668, 54, 14 ], [ 133, 668, 26, 14 ], [ 162, 668, 33, 14 ], [ 199, 668, 26, 14 ], [ 229, 668, 29, 14 ], [ 261, 668, 32, 14 ], [ 296, 668, 75, 14 ], [ 375, 668, 33, 14 ], [ 75, 685, 33, 14 ], [ 112, 685, 35, 14 ], [ 152, 685, 59, 14 ], [ 216, 685, 20, 14 ], [ 240, 685, 24, 14 ], [ 269, 685, 39, 14 ], [ 312, 685, 54, 14 ], [ 370, 685, 18, 14 ], [ 393, 685, 15, 14 ], [ 75, 702, 75, 14 ], [ 151, 702, 59, 14 ], [ 212, 702, 29, 14 ], [ 244, 702, 25, 14 ], [ 271, 702, 38, 14 ], [ 311, 702, 49, 14 ], [ 362, 702, 13, 14 ], [ 377, 702, 31, 14 ], [ 75, 718, 67, 14 ], [ 145, 718, 38, 14 ], [ 187, 718, 55, 14 ], [ 247, 718, 34, 14 ], [ 284, 718, 47, 14 ], [ 335, 718, 13, 14 ], [ 352, 718, 22, 14 ], [ 378, 718, 30, 14 ], [ 75, 735, 74, 14 ], [ 152, 735, 35, 14 ], [ 190, 735, 45, 14 ], [ 238, 735, 19, 14 ], [ 260, 735, 96, 14 ], [ 360, 735, 33, 14 ], [ 396, 735, 13, 14 ], [ 75, 752, 76, 14 ], [ 155, 752, 49, 14 ], [ 209, 752, 37, 14 ], [ 251, 752, 68, 14 ], [ 324, 752, 34, 14 ], [ 362, 752, 46, 14 ], [ 75, 768, 72, 14 ], [ 152, 768, 26, 14 ], [ 184, 768, 29, 14 ], [ 218, 768, 32, 14 ], [ 256, 768, 66, 14 ], [ 327, 768, 9, 14 ], [ 342, 768, 66, 14 ], [ 75, 785, 32, 14 ], [ 109, 785, 21, 14 ], [ 133, 785, 7, 14 ], [ 143, 785, 30, 14 ], [ 176, 785, 13, 14 ], [ 192, 785, 20, 14 ], [ 215, 785, 35, 14 ], [ 253, 785, 34, 14 ], [ 290, 785, 13, 14 ], [ 306, 785, 46, 14 ], [ 355, 785, 17, 14 ], [ 375, 785, 34, 14 ], [ 75, 802, 20, 14 ], [ 98, 802, 47, 14 ], [ 148, 802, 37, 14 ], [ 189, 802, 58, 14 ], [ 251, 802, 40, 14 ], [ 296, 802, 67, 14 ], [ 366, 802, 42, 14 ], [ 75, 818, 33, 14 ], [ 111, 818, 33, 14 ], [ 147, 818, 25, 14 ], [ 176, 818, 13, 14 ], [ 192, 818, 7, 14 ], [ 202, 818, 56, 14 ], [ 262, 818, 22, 14 ], [ 288, 818, 29, 14 ], [ 320, 818, 37, 14 ], [ 360, 818, 13, 14 ], [ 376, 818, 32, 14 ], [ 75, 835, 44, 14 ], [ 123, 835, 13, 14 ], [ 141, 835, 20, 14 ], [ 166, 835, 59, 14 ], [ 229, 835, 29, 14 ], [ 263, 835, 24, 14 ], [ 291, 835, 19, 14 ], [ 315, 835, 64, 14 ], [ 384, 835, 13, 14 ], [ 401, 835, 7, 14 ], [ 75, 852, 46, 14 ], [ 124, 852, 56, 14 ], [ 184, 852, 37, 14 ], [ 224, 852, 20, 14 ], [ 247, 852, 49, 14 ], [ 300, 852, 29, 14 ], [ 332, 852, 29, 14 ], [ 364, 852, 44, 14 ], [ 75, 868, 13, 14 ], [ 91, 868, 20, 14 ], [ 115, 868, 59, 14 ], [ 178, 868, 29, 14 ], [ 211, 868, 37, 14 ], [ 252, 868, 76, 14 ], [ 332, 868, 49, 14 ], [ 384, 868, 24, 14 ], [ 75, 885, 39, 14 ], [ 122, 885, 24, 14 ], [ 155, 885, 75, 14 ], [ 238, 885, 51, 14 ], [ 297, 885, 53, 14 ], [ 359, 885, 49, 14 ], [ 75, 902, 51, 14 ], [ 129, 902, 13, 14 ], [ 145, 902, 34, 14 ], [ 182, 902, 13, 14 ], [ 198, 902, 37, 14 ], [ 238, 902, 30, 14 ], [ 271, 902, 29, 14 ], [ 303, 902, 20, 14 ], [ 326, 902, 32, 14 ], [ 362, 902, 24, 14 ], [ 389, 902, 20, 14 ], [ 75, 918, 31, 14 ], [ 110, 918, 24, 14 ], [ 138, 918, 20, 14 ], [ 163, 918, 38, 14 ], [ 205, 918, 55, 14 ], [ 264, 918, 63, 14 ], [ 330, 918, 37, 14 ], [ 371, 918, 13, 14 ], [ 388, 918, 20, 14 ], [ 75, 935, 46, 14 ], [ 123, 935, 13, 14 ], [ 139, 935, 20, 14 ], [ 162, 935, 29, 14 ], [ 193, 935, 30, 14 ], [ 226, 935, 15, 14 ], [ 244, 935, 45, 14 ], [ 291, 935, 17, 14 ], [ 311, 935, 20, 14 ], [ 334, 935, 75, 14 ], [ 75, 974, 81, 12 ], [ 158, 974, 10, 12 ], [ 171, 974, 39, 12 ], [ 212, 974, 13, 12 ], [ 227, 974, 40, 12 ], [ 270, 974, 124, 12 ], [ 75, 1020, 8, 11 ], [ 85, 1020, 23, 11 ], [ 110, 1020, 35, 11 ], [ 148, 1020, 9, 11 ], [ 159, 1020, 18, 11 ], [ 179, 1020, 52, 11 ], [ 233, 1020, 45, 11 ], [ 280, 1020, 24, 11 ], [ 315, 1020, 25, 11 ], [ 75, 1032, 38, 12 ], [ 115, 1032, 18, 12 ], [ 143, 1032, 41, 12 ], [ 187, 1032, 6, 12 ], [ 204, 1032, 56, 12 ], [ 262, 1032, 24, 12 ], [ 296, 1032, 41, 12 ], [ 75, 1046, 250, 12 ], [ 433, 535, 25, 14 ], [ 461, 535, 13, 14 ], [ 476, 535, 20, 14 ], [ 500, 535, 53, 14 ], [ 556, 535, 64, 14 ], [ 623, 535, 63, 14 ], [ 689, 535, 42, 14 ], [ 734, 535, 13, 14 ], [ 750, 535, 17, 15 ], [ 433, 552, 54, 14 ], [ 491, 552, 72, 14 ], [ 566, 552, 24, 14 ], [ 593, 552, 34, 14 ], [ 631, 552, 33, 14 ], [ 668, 552, 72, 14 ], [ 743, 552, 24, 14 ], [ 433, 569, 39, 14 ], [ 476, 569, 33, 14 ], [ 512, 569, 72, 14 ], [ 587, 569, 24, 14 ], [ 615, 569, 40, 14 ], [ 659, 569, 33, 14 ], [ 695, 569, 72, 14 ], [ 433, 585, 12, 14 ], [ 447, 585, 18, 14 ], [ 467, 585, 33, 14 ], [ 503, 585, 37, 14 ], [ 542, 585, 12, 14 ], [ 556, 585, 18, 14 ], [ 576, 585, 33, 14 ], [ 612, 585, 85, 14 ], [ 699, 585, 12, 14 ], [ 713, 585, 18, 14 ], [ 734, 585, 33, 14 ], [ 433, 602, 21, 14 ], [ 457, 602, 12, 14 ], [ 472, 602, 18, 14 ], [ 494, 602, 33, 14 ], [ 530, 602, 28, 14 ], [ 561, 602, 12, 14 ], [ 576, 602, 18, 14 ], [ 598, 602, 35, 14 ], [ 636, 602, 24, 14 ], [ 663, 602, 59, 14 ], [ 725, 602, 42, 14 ], [ 433, 619, 13, 14 ], [ 449, 619, 53, 14 ], [ 505, 619, 41, 14 ], [ 549, 619, 12, 14 ], [ 564, 619, 18, 14 ], [ 585, 619, 33, 14 ], [ 622, 619, 31, 14 ], [ 656, 619, 12, 14 ], [ 671, 619, 18, 14 ], [ 693, 619, 40, 14 ], [ 735, 619, 31, 14 ], [ 433, 635, 12, 14 ], [ 450, 635, 18, 14 ], [ 473, 635, 33, 14 ], [ 511, 635, 26, 14 ], [ 541, 635, 12, 14 ], [ 558, 635, 18, 14 ], [ 582, 635, 35, 14 ], [ 622, 635, 24, 14 ], [ 651, 635, 72, 14 ], [ 728, 635, 39, 14 ], [ 433, 652, 12, 14 ], [ 449, 652, 18, 14 ], [ 472, 652, 35, 14 ], [ 512, 651, 17, 15 ], [ 533, 652, 54, 14 ], [ 592, 652, 28, 14 ], [ 624, 652, 64, 14 ], [ 693, 652, 74, 14 ], [ 433, 669, 48, 14 ], [ 484, 669, 68, 14 ], [ 445, 685, 25, 14 ], [ 477, 685, 55, 14 ], [ 538, 685, 13, 14 ], [ 557, 685, 20, 14 ], [ 584, 685, 72, 14 ], [ 663, 685, 80, 14 ], [ 750, 685, 17, 15 ], [ 433, 702, 49, 14 ], [ 486, 702, 15, 14 ], [ 506, 702, 19, 14 ], [ 529, 702, 39, 14 ], [ 571, 702, 12, 14 ], [ 588, 702, 18, 14 ], [ 610, 702, 35, 14 ], [ 650, 702, 70, 14 ], [ 723, 702, 20, 14 ], [ 748, 702, 19, 14 ], [ 433, 719, 34, 14 ], [ 472, 719, 77, 14 ], [ 553, 719, 13, 14 ], [ 571, 719, 15, 14 ], [ 591, 719, 63, 14 ], [ 659, 718, 17, 15 ], [ 680, 719, 49, 14 ], [ 734, 719, 32, 14 ], [ 433, 735, 25, 14 ], [ 462, 735, 15, 14 ], [ 481, 735, 24, 14 ], [ 509, 735, 15, 14 ], [ 529, 735, 97, 14 ], [ 630, 735, 52, 14 ], [ 686, 735, 30, 14 ], [ 721, 735, 29, 14 ], [ 754, 735, 13, 14 ], [ 433, 752, 26, 14 ], [ 465, 752, 51, 14 ], [ 522, 752, 39, 14 ], [ 567, 752, 20, 14 ], [ 594, 752, 43, 14 ], [ 642, 752, 32, 14 ], [ 681, 752, 7, 14 ], [ 694, 752, 31, 14 ], [ 731, 752, 36, 14 ], [ 433, 769, 32, 14 ], [ 468, 769, 34, 14 ], [ 506, 769, 72, 14 ], [ 581, 769, 12, 14 ], [ 597, 769, 20, 14 ], [ 621, 769, 77, 14 ], [ 701, 769, 24, 14 ], [ 729, 769, 14, 14 ], [ 746, 769, 20, 14 ], [ 433, 785, 43, 14 ], [ 480, 785, 58, 14 ], [ 542, 785, 32, 14 ], [ 578, 785, 24, 14 ], [ 606, 785, 12, 14 ], [ 622, 785, 20, 14 ], [ 646, 785, 75, 14 ], [ 725, 785, 24, 14 ], [ 753, 785, 14, 14 ], [ 433, 802, 20, 14 ], [ 457, 802, 49, 14 ], [ 510, 802, 59, 14 ], [ 573, 802, 37, 14 ], [ 615, 802, 20, 14 ], [ 639, 802, 15, 14 ], [ 658, 802, 42, 14 ], [ 704, 802, 34, 14 ], [ 742, 802, 25, 14 ], [ 433, 819, 30, 14 ], [ 467, 819, 68, 14 ], [ 539, 819, 21, 14 ], [ 565, 819, 20, 14 ], [ 589, 819, 50, 14 ], [ 643, 819, 13, 14 ], [ 660, 818, 17, 15 ], [ 681, 819, 58, 14 ], [ 743, 819, 24, 14 ], [ 433, 835, 50, 14 ], [ 487, 835, 13, 14 ], [ 503, 835, 17, 15 ], [ 523, 835, 25, 14 ], [ 552, 835, 47, 14 ], [ 603, 835, 13, 14 ], [ 619, 835, 15, 14 ], [ 637, 835, 57, 14 ], [ 698, 835, 14, 14 ], [ 715, 835, 52, 14 ], [ 433, 852, 25, 14 ], [ 461, 852, 24, 14 ], [ 488, 852, 78, 14 ], [ 569, 852, 13, 14 ], [ 585, 852, 20, 14 ], [ 608, 852, 15, 14 ], [ 627, 852, 56, 14 ], [ 686, 852, 20, 14 ], [ 710, 852, 20, 14 ], [ 733, 852, 34, 14 ], [ 433, 869, 35, 14 ], [ 472, 869, 9, 14 ], [ 484, 869, 9, 14 ], [ 497, 869, 30, 14 ], [ 530, 869, 24, 14 ], [ 558, 869, 32, 14 ], [ 594, 869, 43, 14 ], [ 640, 869, 20, 14 ], [ 664, 869, 54, 14 ], [ 722, 869, 45, 14 ], [ 433, 885, 7, 14 ], [ 449, 885, 54, 14 ], [ 510, 885, 38, 14 ], [ 557, 885, 74, 14 ], [ 639, 885, 25, 14 ], [ 673, 885, 25, 14 ], [ 707, 885, 18, 14 ], [ 733, 885, 33, 14 ], [ 433, 919, 67, 12 ], [ 507, 919, 23, 12 ], [ 537, 919, 10, 12 ], [ 554, 919, 18, 12 ], [ 579, 919, 32, 12 ], [ 617, 919, 38, 12 ], [ 662, 919, 105, 12 ], [ 433, 932, 124, 12 ], [ 559, 932, 45, 12 ], [ 607, 932, 18, 12 ], [ 627, 932, 90, 12 ], [ 719, 932, 26, 12 ], [ 748, 932, 19, 12 ], [ 433, 946, 83, 12 ], [ 521, 946, 54, 12 ], [ 581, 946, 23, 12 ], [ 610, 946, 123, 12 ], [ 739, 946, 28, 12 ], [ 433, 960, 27, 12 ], [ 463, 960, 84, 12 ], [ 550, 960, 14, 13 ], [ 567, 960, 25, 12 ], [ 595, 960, 56, 12 ], [ 654, 960, 20, 12 ], [ 676, 960, 53, 12 ], [ 733, 960, 34, 12 ], [ 433, 974, 29, 12 ], [ 464, 974, 25, 12 ], [ 492, 974, 106, 12 ], [ 748, 1019, 19, 12 ] ]

[ "A", "R", "T", "I", "C", "L", "E", "State-independent", "Block", "of", "BK", "Channels", "by", "an", "Intracellular", "Quaternary", "Ammonium", "Christina", "M.", "Wilkens", "and", "Richard", "W.", "Aldrich", "Department", "of", "Molecular", "and", "Cellular", "Physiology,", "Stanford", "University,", "Stanford,", "CA", "94305", "Section", "of", "Neurobiology,", "University", "of", "Texas", "at", "Austin,", "Austin,", "TX", "78705", "Intracellular", "blockade", "by", "quaternary", "ammonium", "(QA)", "molecules", "of", "many", "potassium", "channels", "is", "state", "dependent,", "where", "the", "requirement", "for", "channel", "opening", "is", "evidenced", "by", "a", "time-dependent", "component", "of", "block", "in", "the", "macro-", "scopic", "record.", "Whether", "this", "is", "the", "case", "for", "Ca2+-", "and", "voltage-activated", "potassium", "(BK)", "channels,", "however,", "remains", "unclear.", "Previous", "work", "(Li,", "W.,", "and", "R.W.", "Aldrich.", "2004.", "J.", "Gen.", "Physiol.", "124:43–57)", "tentatively", "proposed", "a", "state-", "dependent,", "trapping", "model,", "but", "left", "open", "the", "possibility", "of", "state-independent", "block.", "Here,", "we", "found", "BK", "channel", "blockade", "by", "a", "novel", "QA", "derivative,", "bbTBA,", "was", "time", "dependent,", "raising", "the", "possibility", "of", "state-dependent,", "open", "channel", "block.", "Alternatively,", "the", "observed", "voltage", "dependence", "of", "block", "could", "be", "sufficient", "to", "explain", "time-dependent", "block.", "We", "have", "used", "steady-state", "and", "kinetic", "measurements", "of", "bbTBA", "blockade", "in", "order", "to", "discriminate", "between", "these", "two", "possibilities.", "bbTBA", "did", "not", "significantly", "slow", "deactivation", "kinetics", "at", "potentials", "between", "−200", "and", "−100", "mV,", "suggesting", "that", "channels", "can", "close", "unhindered", "by", "bound", "bbTBA.", "We", "further", "find", "no", "evidence", "that", "bbTBA", "is", "trapped", "inside", "BK", "channels", "after", "closing.", "Measurements", "of", "steady", "state", "fractional", "block", "at", "+40", "mV", "revealed", "a", "1.3-fold", "change", "in", "apparent", "affinity", "for", "a", "33-fold", "change", "in", "Po,", "in", "striking", "contrast", "to", "the", "31-fold", "change", "predicted", "by", "state-", "dependent", "block.", "Finally,", "the", "appearance", "of", "a", "third", "kinetic", "component", "of", "bbTBA", "blockade", "at", "high", "concentrations", "is", "incompatible", "with", "state-dependent", "block.", "Our", "results", "suggest", "that", "access", "of", "intracellular", "bbTBA", "to", "the", "BK", "chan-", "nel", "cavity", "is", "not", "strictly", "gated", "by", "channel", "opening", "and", "closing,", "and", "imply", "that", "the", "permeation", "gate", "for", "BK", "channels", "may", "not", "be", "intracellular.", "y", "g", "o", "l", "o", "i", "s", "y", "h", "P", "l", "a", "r", "e", "n", "e", "G", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "I", "N", "T", "R", "O", "D", "U", "C", "T", "I", "O", "N", "The", "mechanism", "of", "ion", "channel", "opening", "and", "closing", "is", "widely", "thought", "of", "in", "terms", "of", "a", "gate", "that", "permits", "or", "re-", "stricts", "access", "to", "the", "inner", "pore", "via", "a", "reversible", "confor-", "mational", "change.", "Much", "attention", "has", "been", "focused", "on", "locating", "the", "gate", "of", "K+", "channels,", "as", "a", "first", "step", "toward", "understanding", "the", "conformational", "changes", "that", "under-", "lie", "the", "gating", "process.", "Clay", "Armstrong’s", "innovative", "use", "of", "intracellular", "organic", "blockers", "that", "could", "block", "K+", "channels", "only", "when", "they", "were", "open", "(Armstrong,", "1966,", "1969,", "1971)", "produced", "the", "first", "strong", "evidence", "for", "an", "intracellular", "activation", "gate.", "The", "classic", "features", "of", "state-", "dependent", "(open", "channel)", "block", "defined", "in", "this", "work", "(Armstrong,", "1971)", "include", "(a)", "time-dependent", "block", "of", "macroscopic", "current,", "where", "steady-state", "block", "reaches", "equilibrium", "only", "after", "open", "probability", "is", "sufficiently", "high,", "(b)", "a", "“foot", "in", "the", "door”", "effect", "of", "blocker", "on", "chan-", "nel", "closing,", "where", "internally", "bound", "quaternary", "ammo-", "nium", "(QA)", "ions", "of", "a", "sufficient", "size", "were", "found", "to", "delay", "closure", "of", "the", "activation", "gate,", "and", "(c)", "“trapping”", "of", "a", "blocker", "molecule", "inside", "the", "channel", "pore", "after", "closure", "of", "the", "activation", "gate.", "These", "observations", "strongly", "sug-", "gested", "that", "intracellular", "blockers", "required", "channel", "opening", "in", "order", "to", "access", "(and", "exit)", "the", "pore,", "and", "im-", "plied", "that", "the", "gating", "structure", "regulating", "access", "of", "the", "blocker", "to", "the", "pore", "must", "be", "located", "on", "the", "intracellular", "Correspondence", "to", "Richard", "W.", "Aldrich:", "raldrich@mail.utexas.edu", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "$8.00", "Volume", "128", "Number", "3", "September", "2006", "347–364", "http://www.jgp.org/cgi/doi/10.1085/jgp.200609579", "face", "of", "the", "channel.", "Numerous", "functional", "studies", "of", "K+", "channels", "(Armstrong", "and", "Hille,", "1972;", "MacKinnon", "and", "Miller,", "1989;", "MacKinnon", "and", "Yellen,", "1990;", "MacKinnon", "et", "al.,", "1990;", "Yellen", "et", "al.,", "1991;", "Heginbotham", "et", "al.,", "1992;", "Liu", "et", "al.,", "1997;", "Shin", "et", "al.,", "2001)", "and", "structural", "studies", "of", "bacterial", "(Doyle", "et", "al.,", "1998;", "Jiang", "et", "al.,", "2002a;", "Jiang", "et", "al.,", "2003;", "Kuo", "et", "al.,", "2003)", "and", "mammalian", "(Long", "et", "al.,", "2005)", "K+", "channels", "have", "confirmed", "Armstrong’s", "original", "hypothesis.", "The", "structure", "of", "the", "mammalian", "voltage-gated", "K+", "channel", "Kv", "1.2", "(Long", "et", "al.,", "2005)", "exemplifies", "the", "de-", "tailed", "organization", "of", "an", "archetypal", "K+", "channel", "pore.", "The", "S5", "and", "S6", "transmembrane", "domains", "from", "each", "of", "four", "subunits", "define", "the", "central", "pore,", "a", "large", "water-", "filled", "cavity", "constrained", "at", "the", "extracellular", "end", "by", "the", "narrow", "selectivity", "filter,", "and", "at", "the", "intracellular", "end", "by", "the", "“bundle", "crossing,”", "where", "the", "S6", "helices", "come", "into", "close", "apposition.", "For", "the", "majority", "of", "K+", "channels,", "per-", "meation", "of", "K+", "ions", "appears", "to", "be", "governed", "by", "constric-", "tion", "and", "enlargement", "of", "the", "S6", "aperture.", "On", "the", "other", "hand,", "it", "is", "clear", "that", "some", "related", "ion", "channels", "employ", "a", "different", "gating", "mechanism.", "The", "case", "for", "cyclic", "Abbreviations", "used", "in", "this", "paper:", "bbTBA,", "N-(4-[benzoyl]benyl)-", "N,N,N-tributylammonium", "bromide;", "BK,", "large-conductance", "Ca2+-", "and", "voltage-activated", "potassium;", "C10,", "decyltriethylammonium;", "CNG,", "cyclic", "nucleotide-gated;", "Po,", "open", "probability;", "QA,", "quaternary", "ammo-", "nium;", "TBA,", "tetrabutylammonium.", "347" ]

[ 16, 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4 ]

[ [ 496, 57, 50, 12 ], [ 548, 57, 34, 12 ], [ 584, 57, 187, 12 ], [ 78, 115, 85, 21 ], [ 78, 118, 15, 3 ], [ 78, 139, 142, 23 ], [ 226, 139, 74, 23 ], [ 305, 139, 97, 23 ], [ 408, 139, 77, 23 ], [ 490, 139, 16, 23 ], [ 511, 139, 127, 23 ], [ 644, 139, 51, 23 ], [ 78, 164, 136, 23 ], [ 220, 164, 47, 23 ], [ 273, 164, 60, 23 ], [ 338, 164, 20, 23 ], [ 364, 164, 70, 23 ], [ 440, 164, 65, 23 ], [ 78, 190, 53, 17 ], [ 136, 190, 85, 17 ], [ 225, 190, 49, 17 ], [ 278, 190, 11, 17 ], [ 293, 190, 56, 17 ], [ 353, 190, 65, 17 ], [ 422, 190, 11, 17 ], [ 437, 190, 71, 17 ], [ 512, 190, 57, 17 ], [ 572, 190, 12, 17 ], [ 589, 190, 50, 17 ], [ 642, 190, 27, 17 ], [ 78, 212, 31, 17 ], [ 113, 212, 7, 17 ], [ 124, 212, 75, 17 ], [ 662, 116, 44, 16 ], [ 709, 116, 61, 16 ], [ 78, 258, 60, 12 ], [ 141, 258, 10, 12 ], [ 154, 258, 75, 12 ], [ 231, 258, 38, 12 ], [ 271, 258, 10, 12 ], [ 283, 258, 35, 12 ], [ 321, 258, 46, 12 ], [ 370, 258, 34, 12 ], [ 406, 258, 10, 12 ], [ 418, 258, 46, 12 ], [ 467, 258, 46, 12 ], [ 515, 258, 10, 12 ], [ 527, 258, 39, 12 ], [ 568, 258, 26, 12 ], [ 597, 258, 38, 12 ], [ 638, 258, 36, 12 ], [ 78, 271, 60, 12 ], [ 141, 272, 10, 11 ], [ 153, 272, 75, 11 ], [ 231, 272, 42, 11 ], [ 275, 272, 26, 11 ], [ 304, 272, 37, 11 ], [ 344, 272, 49, 11 ], [ 395, 272, 36, 11 ], [ 434, 272, 34, 11 ], [ 470, 272, 16, 11 ], [ 489, 272, 39, 11 ], [ 530, 272, 61, 11 ], [ 594, 272, 38, 11 ], [ 634, 272, 51, 11 ], [ 78, 297, 72, 11 ], [ 152, 297, 33, 11 ], [ 188, 297, 21, 11 ], [ 212, 297, 5, 11 ], [ 219, 297, 48, 11 ], [ 269, 297, 137, 11 ], [ 78, 322, 47, 11 ], [ 128, 322, 7, 11 ], [ 138, 322, 19, 11 ], [ 159, 322, 26, 11 ], [ 191, 322, 46, 11 ], [ 239, 322, 51, 11 ], [ 293, 322, 13, 11 ], [ 309, 322, 19, 11 ], [ 330, 322, 26, 11 ], [ 362, 322, 46, 11 ], [ 410, 322, 44, 11 ], [ 456, 322, 7, 11 ], [ 465, 322, 19, 11 ], [ 487, 322, 26, 11 ], [ 519, 322, 50, 11 ], [ 571, 322, 13, 11 ], [ 587, 322, 19, 11 ], [ 609, 322, 26, 11 ], [ 640, 322, 50, 11 ], [ 693, 322, 13, 11 ], [ 709, 322, 19, 11 ], [ 731, 322, 26, 11 ], [ 78, 347, 34, 12 ], [ 115, 347, 24, 12 ], [ 142, 347, 29, 12 ], [ 173, 347, 43, 12 ], [ 219, 347, 107, 12 ], [ 78, 361, 20, 12 ], [ 101, 361, 29, 12 ], [ 132, 361, 8, 12 ], [ 143, 361, 29, 12 ], [ 174, 361, 12, 12 ], [ 189, 361, 187, 12 ], [ 78, 375, 10, 12 ], [ 91, 375, 26, 12 ], [ 120, 375, 50, 12 ], [ 172, 375, 9, 12 ], [ 184, 375, 14, 12 ], [ 201, 375, 39, 12 ], [ 243, 375, 38, 12 ], [ 283, 375, 35, 12 ], [ 320, 375, 18, 12 ], [ 78, 389, 20, 12 ], [ 100, 389, 8, 12 ], [ 110, 389, 12, 12 ], [ 123, 389, 24, 12 ], [ 150, 389, 34, 12 ], [ 185, 389, 29, 12 ], [ 216, 389, 51, 12 ], [ 268, 389, 28, 12 ], [ 298, 389, 15, 12 ], [ 315, 389, 27, 12 ], [ 343, 389, 10, 12 ], [ 354, 389, 15, 12 ], [ 371, 389, 40, 12 ], [ 413, 389, 49, 12 ], [ 464, 389, 49, 12 ], [ 515, 389, 37, 12 ], [ 554, 389, 216, 12 ], [ 78, 403, 28, 11 ], [ 109, 403, 35, 11 ], [ 147, 403, 57, 11 ], [ 206, 403, 20, 11 ], [ 229, 403, 55, 11 ], [ 287, 403, 18, 11 ], [ 307, 403, 61, 11 ], [ 370, 403, 9, 11 ], [ 382, 403, 17, 11 ], [ 401, 403, 40, 11 ], [ 444, 403, 42, 11 ], [ 488, 403, 15, 11 ], [ 506, 403, 35, 11 ], [ 543, 403, 23, 11 ], [ 568, 403, 8, 11 ], [ 579, 403, 39, 11 ], [ 620, 403, 26, 11 ], [ 78, 444, 60, 15 ], [ 78, 472, 69, 13 ], [ 150, 472, 32, 13 ], [ 185, 472, 23, 13 ], [ 211, 472, 28, 13 ], [ 242, 472, 26, 13 ], [ 271, 472, 22, 13 ], [ 295, 472, 26, 13 ], [ 324, 472, 25, 13 ], [ 351, 472, 24, 13 ], [ 378, 472, 35, 13 ], [ 78, 487, 20, 13 ], [ 102, 487, 56, 13 ], [ 161, 487, 67, 13 ], [ 231, 487, 55, 13 ], [ 289, 487, 20, 13 ], [ 313, 487, 9, 13 ], [ 325, 487, 27, 13 ], [ 355, 487, 58, 13 ], [ 78, 501, 22, 13 ], [ 103, 501, 17, 13 ], [ 123, 501, 39, 13 ], [ 164, 501, 11, 13 ], [ 177, 501, 23, 13 ], [ 202, 501, 32, 13 ], [ 236, 501, 48, 13 ], [ 287, 501, 25, 13 ], [ 314, 501, 23, 13 ], [ 340, 501, 29, 13 ], [ 371, 501, 42, 13 ], [ 78, 516, 11, 13 ], [ 92, 516, 19, 13 ], [ 113, 516, 19, 13 ], [ 135, 516, 27, 13 ], [ 165, 516, 26, 13 ], [ 194, 516, 57, 13 ], [ 254, 516, 11, 13 ], [ 268, 516, 31, 13 ], [ 302, 516, 21, 13 ], [ 325, 516, 38, 13 ], [ 366, 516, 46, 13 ], [ 78, 531, 19, 13 ], [ 107, 531, 45, 13 ], [ 161, 531, 20, 13 ], [ 191, 531, 69, 13 ], [ 269, 531, 69, 13 ], [ 346, 531, 66, 13 ], [ 78, 545, 36, 13 ], [ 119, 545, 48, 13 ], [ 171, 545, 37, 13 ], [ 213, 545, 10, 13 ], [ 227, 545, 44, 13 ], [ 275, 545, 9, 13 ], [ 288, 545, 23, 13 ], [ 315, 545, 11, 13 ], [ 331, 545, 57, 13 ], [ 392, 545, 21, 13 ], [ 78, 560, 21, 13 ], [ 103, 560, 19, 13 ], [ 125, 560, 22, 13 ], [ 150, 560, 11, 13 ], [ 165, 560, 20, 13 ], [ 188, 560, 17, 13 ], [ 209, 560, 43, 13 ], [ 256, 560, 36, 13 ], [ 295, 560, 49, 13 ], [ 348, 560, 65, 13 ], [ 78, 574, 18, 13 ], [ 99, 574, 10, 13 ], [ 112, 574, 36, 13 ], [ 78, 604, 50, 13 ], [ 133, 604, 59, 13 ], [ 195, 604, 39, 13 ], [ 239, 604, 31, 13 ], [ 275, 604, 54, 13 ], [ 333, 604, 80, 13 ], [ 78, 618, 25, 13 ], [ 106, 618, 7, 13 ], [ 115, 618, 24, 13 ], [ 142, 618, 10, 13 ], [ 154, 618, 46, 13 ], [ 203, 618, 38, 13 ], [ 244, 618, 25, 13 ], [ 271, 618, 46, 13 ], [ 320, 618, 46, 13 ], [ 368, 618, 11, 13 ], [ 381, 618, 19, 13 ], [ 403, 618, 10, 13 ], [ 78, 633, 26, 13 ], [ 108, 633, 39, 13 ], [ 150, 633, 14, 13 ], [ 167, 633, 13, 13 ], [ 183, 633, 60, 13 ], [ 246, 633, 30, 13 ], [ 279, 633, 10, 13 ], [ 293, 633, 8, 13 ], [ 305, 633, 11, 13 ], [ 319, 633, 46, 13 ], [ 368, 633, 18, 13 ], [ 389, 633, 24, 13 ], [ 78, 647, 32, 13 ], [ 115, 647, 37, 13 ], [ 156, 647, 22, 13 ], [ 183, 647, 16, 13 ], [ 203, 647, 35, 13 ], [ 243, 647, 10, 13 ], [ 257, 647, 14, 13 ], [ 276, 647, 40, 13 ], [ 320, 647, 9, 13 ], [ 334, 647, 36, 13 ], [ 375, 647, 21, 13 ], [ 400, 647, 13, 13 ], [ 78, 662, 58, 13 ], [ 140, 662, 39, 13 ], [ 182, 662, 10, 13 ], [ 196, 662, 35, 13 ], [ 233, 662, 14, 13 ], [ 251, 662, 32, 13 ], [ 287, 662, 17, 13 ], [ 307, 662, 23, 13 ], [ 333, 662, 22, 13 ], [ 358, 662, 16, 13 ], [ 378, 662, 35, 13 ], [ 78, 676, 10, 13 ], [ 91, 676, 8, 13 ], [ 101, 676, 31, 13 ], [ 135, 676, 15, 13 ], [ 152, 676, 13, 13 ], [ 167, 676, 18, 13 ], [ 187, 676, 30, 13 ], [ 220, 676, 10, 13 ], [ 233, 676, 8, 13 ], [ 244, 676, 11, 13 ], [ 258, 676, 46, 13 ], [ 306, 676, 18, 13 ], [ 326, 676, 12, 13 ], [ 341, 676, 34, 13 ], [ 377, 676, 11, 13 ], [ 390, 676, 14, 13 ], [ 406, 676, 6, 13 ], [ 78, 691, 76, 13 ], [ 157, 691, 30, 13 ], [ 189, 691, 10, 13 ], [ 202, 691, 8, 13 ], [ 213, 691, 14, 13 ], [ 229, 691, 25, 13 ], [ 256, 691, 7, 13 ], [ 266, 691, 31, 13 ], [ 300, 691, 31, 13 ], [ 333, 691, 25, 13 ], [ 361, 691, 52, 13 ], [ 78, 706, 78, 13 ], [ 159, 706, 21, 13 ], [ 183, 706, 48, 13 ], [ 233, 706, 12, 13 ], [ 248, 706, 47, 13 ], [ 299, 706, 9, 13 ], [ 310, 706, 16, 13 ], [ 329, 706, 52, 13 ], [ 384, 706, 29, 13 ], [ 78, 720, 19, 13 ], [ 103, 720, 16, 13 ], [ 124, 720, 29, 13 ], [ 157, 720, 19, 13 ], [ 182, 720, 66, 13 ], [ 252, 720, 22, 13 ], [ 279, 720, 28, 13 ], [ 312, 720, 27, 13 ], [ 344, 720, 43, 13 ], [ 392, 720, 21, 13 ], [ 78, 789, 90, 16 ], [ 78, 805, 47, 13 ], [ 131, 805, 25, 13 ], [ 161, 805, 31, 13 ], [ 197, 805, 24, 13 ], [ 227, 805, 29, 13 ], [ 261, 805, 27, 13 ], [ 293, 805, 18, 13 ], [ 317, 805, 43, 13 ], [ 365, 805, 48, 13 ], [ 78, 822, 27, 13 ], [ 111, 822, 21, 13 ], [ 136, 822, 27, 13 ], [ 169, 822, 19, 13 ], [ 193, 822, 45, 13 ], [ 242, 822, 23, 13 ], [ 270, 822, 31, 13 ], [ 306, 822, 58, 13 ], [ 370, 822, 43, 13 ], [ 78, 838, 54, 13 ], [ 136, 838, 46, 13 ], [ 185, 838, 18, 13 ], [ 206, 838, 27, 13 ], [ 237, 838, 36, 13 ], [ 277, 838, 25, 13 ], [ 305, 838, 11, 13 ], [ 320, 838, 21, 13 ], [ 345, 838, 42, 13 ], [ 390, 838, 23, 13 ], [ 78, 854, 46, 13 ], [ 129, 854, 39, 13 ], [ 173, 854, 81, 13 ], [ 258, 854, 11, 13 ], [ 274, 854, 26, 13 ], [ 304, 854, 24, 13 ], [ 332, 854, 30, 13 ], [ 367, 854, 33, 13 ], [ 404, 854, 9, 13 ], [ 78, 871, 21, 13 ], [ 104, 871, 11, 13 ], [ 120, 871, 18, 13 ], [ 143, 871, 27, 13 ], [ 175, 871, 60, 13 ], [ 240, 871, 52, 13 ], [ 298, 871, 23, 13 ], [ 326, 871, 30, 13 ], [ 361, 871, 10, 13 ], [ 376, 871, 37, 13 ], [ 78, 887, 39, 13 ], [ 121, 887, 19, 13 ], [ 143, 887, 21, 13 ], [ 167, 887, 57, 13 ], [ 228, 887, 11, 13 ], [ 242, 887, 19, 13 ], [ 264, 887, 53, 13 ], [ 320, 887, 10, 13 ], [ 333, 887, 18, 13 ], [ 354, 887, 59, 13 ], [ 78, 903, 33, 13 ], [ 115, 903, 35, 13 ], [ 154, 903, 23, 13 ], [ 180, 903, 11, 13 ], [ 194, 903, 44, 13 ], [ 241, 903, 23, 13 ], [ 268, 903, 60, 13 ], [ 331, 903, 21, 13 ], [ 356, 903, 35, 13 ], [ 394, 903, 19, 13 ], [ 78, 920, 10, 13 ], [ 92, 920, 67, 13 ], [ 163, 920, 23, 13 ], [ 190, 920, 38, 13 ], [ 232, 920, 14, 13 ], [ 249, 920, 54, 13 ], [ 307, 920, 39, 13 ], [ 350, 920, 25, 13 ], [ 379, 920, 11, 13 ], [ 394, 920, 19, 13 ], [ 437, 472, 57, 13 ], [ 507, 472, 21, 13 ], [ 540, 472, 16, 13 ], [ 569, 472, 30, 13 ], [ 611, 472, 77, 13 ], [ 700, 472, 72, 13 ], [ 437, 487, 53, 13 ], [ 498, 487, 22, 13 ], [ 527, 487, 49, 13 ], [ 583, 487, 21, 13 ], [ 612, 487, 49, 13 ], [ 668, 487, 10, 13 ], [ 685, 487, 42, 13 ], [ 735, 487, 19, 13 ], [ 762, 487, 10, 13 ], [ 437, 501, 49, 13 ], [ 491, 501, 10, 13 ], [ 506, 501, 16, 13 ], [ 528, 501, 58, 13 ], [ 591, 501, 24, 13 ], [ 620, 501, 25, 13 ], [ 650, 501, 44, 13 ], [ 699, 501, 12, 13 ], [ 717, 501, 40, 13 ], [ 762, 501, 10, 13 ], [ 437, 516, 45, 13 ], [ 486, 516, 6, 13 ], [ 496, 516, 8, 13 ], [ 508, 516, 26, 13 ], [ 537, 516, 10, 13 ], [ 551, 516, 20, 13 ], [ 575, 516, 22, 13 ], [ 600, 516, 24, 13 ], [ 628, 516, 21, 13 ], [ 652, 516, 46, 13 ], [ 701, 516, 12, 13 ], [ 717, 516, 55, 13 ], [ 437, 531, 54, 13 ], [ 437, 567, 43, 13 ], [ 483, 567, 19, 13 ], [ 505, 567, 43, 13 ], [ 551, 567, 48, 13 ], [ 602, 567, 59, 13 ], [ 664, 567, 52, 13 ], [ 719, 567, 24, 13 ], [ 746, 567, 26, 13 ], [ 437, 582, 20, 13 ], [ 465, 582, 55, 13 ], [ 526, 582, 30, 13 ], [ 563, 582, 53, 13 ], [ 623, 582, 20, 13 ], [ 650, 582, 38, 13 ], [ 694, 582, 50, 13 ], [ 752, 582, 20, 13 ], [ 437, 596, 57, 13 ], [ 497, 596, 40, 13 ], [ 540, 596, 31, 13 ], [ 574, 596, 36, 13 ], [ 613, 596, 71, 13 ], [ 687, 596, 17, 13 ], [ 707, 596, 65, 13 ], [ 437, 611, 46, 13 ], [ 488, 611, 10, 13 ], [ 503, 611, 38, 13 ], [ 545, 611, 20, 13 ], [ 571, 611, 36, 13 ], [ 612, 611, 63, 13 ], [ 680, 611, 20, 13 ], [ 705, 611, 44, 13 ], [ 755, 611, 17, 13 ], [ 437, 625, 65, 13 ], [ 509, 625, 59, 13 ], [ 574, 625, 10, 13 ], [ 590, 625, 24, 13 ], [ 621, 625, 26, 13 ], [ 653, 625, 20, 13 ], [ 680, 625, 55, 13 ], [ 742, 625, 30, 13 ], [ 437, 640, 56, 13 ], [ 437, 676, 70, 13 ], [ 511, 676, 10, 13 ], [ 524, 676, 28, 13 ], [ 555, 676, 65, 13 ], [ 623, 676, 23, 13 ], [ 649, 676, 31, 13 ], [ 683, 676, 36, 13 ], [ 722, 676, 50, 13 ], [ 437, 691, 17, 13 ], [ 458, 691, 45, 13 ], [ 507, 691, 10, 13 ], [ 521, 691, 55, 13 ], [ 580, 691, 30, 13 ], [ 613, 691, 47, 13 ], [ 664, 691, 20, 13 ], [ 688, 691, 63, 13 ], [ 755, 691, 17, 13 ], [ 437, 706, 69, 13 ], [ 511, 706, 11, 13 ], [ 527, 706, 23, 13 ], [ 555, 706, 36, 13 ], [ 597, 706, 20, 13 ], [ 622, 706, 17, 13 ], [ 645, 706, 70, 13 ], [ 720, 706, 11, 13 ], [ 736, 706, 36, 13 ], [ 437, 720, 66, 13 ], [ 437, 789, 28, 13 ], [ 468, 789, 11, 13 ], [ 482, 789, 18, 13 ], [ 502, 789, 19, 13 ], [ 524, 789, 11, 13 ], [ 538, 789, 62, 13 ], [ 602, 789, 35, 13 ], [ 640, 789, 19, 13 ], [ 662, 789, 52, 13 ], [ 717, 789, 55, 13 ], [ 437, 805, 18, 13 ], [ 458, 805, 11, 13 ], [ 471, 805, 44, 13 ], [ 519, 805, 7, 13 ], [ 528, 805, 24, 13 ], [ 555, 805, 39, 13 ], [ 597, 805, 75, 13 ], [ 675, 805, 11, 13 ], [ 688, 805, 19, 13 ], [ 710, 805, 62, 13 ], [ 437, 822, 11, 13 ], [ 451, 822, 35, 13 ], [ 489, 822, 11, 13 ], [ 503, 822, 21, 13 ], [ 526, 822, 43, 13 ], [ 571, 822, 11, 13 ], [ 585, 822, 19, 13 ], [ 606, 822, 20, 13 ], [ 629, 822, 28, 13 ], [ 659, 822, 35, 13 ], [ 696, 822, 27, 13 ], [ 726, 822, 11, 13 ], [ 740, 822, 32, 13 ], [ 437, 838, 58, 13 ], [ 497, 838, 24, 13 ], [ 523, 838, 29, 13 ], [ 554, 838, 10, 13 ], [ 566, 838, 69, 13 ], [ 637, 838, 46, 13 ], [ 686, 838, 72, 13 ], [ 761, 838, 11, 13 ], [ 437, 854, 44, 13 ], [ 485, 854, 19, 13 ], [ 508, 854, 53, 13 ], [ 565, 854, 57, 13 ], [ 625, 854, 45, 13 ], [ 674, 854, 48, 13 ], [ 725, 854, 21, 13 ], [ 750, 854, 22, 13 ], [ 437, 871, 51, 13 ], [ 491, 871, 47, 13 ], [ 540, 871, 10, 13 ], [ 552, 871, 18, 13 ], [ 572, 871, 71, 13 ], [ 645, 871, 11, 13 ], [ 658, 871, 24, 13 ], [ 684, 871, 37, 13 ], [ 724, 871, 21, 13 ], [ 747, 871, 25, 13 ], [ 437, 887, 16, 13 ], [ 457, 887, 58, 13 ], [ 517, 887, 21, 13 ], [ 542, 887, 18, 13 ], [ 562, 887, 35, 13 ], [ 601, 887, 15, 13 ], [ 619, 887, 20, 13 ], [ 641, 887, 51, 13 ], [ 695, 887, 19, 13 ], [ 78, 952, 37, 14 ], [ 118, 952, 71, 11 ], [ 191, 952, 34, 11 ], [ 227, 952, 35, 11 ], [ 265, 952, 50, 11 ], [ 317, 952, 19, 11 ], [ 339, 952, 27, 11 ], [ 368, 952, 21, 11 ], [ 391, 952, 28, 11 ], [ 421, 952, 26, 11 ], [ 450, 952, 43, 11 ], [ 495, 952, 33, 11 ], [ 531, 952, 12, 11 ], [ 545, 952, 33, 11 ], [ 581, 952, 27, 11 ], [ 610, 952, 50, 11 ], [ 663, 952, 37, 11 ], [ 703, 952, 50, 11 ], [ 755, 952, 14, 11 ], [ 78, 965, 35, 12 ], [ 116, 965, 28, 12 ], [ 147, 965, 37, 12 ], [ 186, 965, 61, 12 ], [ 250, 965, 21, 12 ], [ 273, 965, 27, 12 ], [ 302, 965, 28, 12 ], [ 333, 965, 19, 12 ], [ 354, 965, 24, 12 ], [ 381, 965, 21, 12 ], [ 405, 965, 12, 12 ], [ 419, 965, 51, 12 ], [ 473, 965, 30, 12 ], [ 506, 965, 43, 12 ], [ 551, 965, 51, 12 ], [ 605, 965, 45, 12 ], [ 653, 965, 37, 12 ], [ 693, 965, 15, 12 ], [ 710, 965, 49, 12 ], [ 78, 978, 29, 12 ], [ 110, 978, 23, 12 ], [ 136, 978, 28, 12 ], [ 166, 978, 27, 12 ], [ 195, 978, 26, 12 ], [ 224, 978, 42, 12 ], [ 268, 978, 32, 12 ], [ 302, 978, 45, 12 ], [ 350, 978, 20, 12 ], [ 372, 978, 23, 12 ], [ 397, 978, 23, 12 ], [ 422, 978, 30, 14 ], [ 455, 978, 29, 12 ], [ 486, 978, 35, 12 ], [ 523, 978, 10, 12 ], [ 535, 978, 33, 12 ], [ 571, 978, 9, 12 ], [ 582, 978, 32, 12 ], [ 617, 978, 30, 12 ], [ 650, 978, 34, 12 ], [ 685, 978, 49, 12 ], [ 737, 978, 32, 12 ], [ 78, 991, 46, 11 ], [ 126, 991, 45, 11 ], [ 172, 991, 25, 11 ], [ 198, 991, 49, 11 ], [ 249, 991, 32, 11 ], [ 283, 991, 45, 11 ], [ 330, 991, 25, 11 ], [ 356, 991, 49, 11 ], [ 407, 991, 39, 11 ], [ 447, 991, 75, 11 ], [ 524, 991, 45, 11 ], [ 571, 991, 27, 11 ], [ 599, 991, 49, 11 ], [ 650, 991, 39, 11 ], [ 691, 991, 49, 11 ], [ 742, 991, 28, 11 ], [ 78, 1004, 34, 12 ], [ 115, 1004, 34, 12 ], [ 151, 1004, 49, 12 ], [ 203, 1004, 25, 12 ], [ 230, 1004, 21, 12 ], [ 254, 1004, 23, 12 ], [ 280, 1004, 45, 12 ], [ 327, 1004, 35, 12 ], [ 365, 1004, 59, 12 ], [ 426, 1004, 32, 12 ], [ 461, 1004, 43, 12 ], [ 506, 1004, 33, 12 ], [ 542, 1004, 12, 12 ], [ 556, 1004, 39, 12 ], [ 598, 1004, 21, 12 ], [ 622, 1004, 49, 12 ], [ 673, 1004, 30, 12 ], [ 705, 1004, 23, 12 ], [ 731, 1004, 28, 12 ], [ 78, 1018, 30, 14 ], [ 111, 1018, 32, 12 ], [ 146, 1018, 33, 12 ], [ 182, 1018, 50, 12 ], [ 234, 1018, 28, 12 ], [ 264, 1018, 42, 12 ], [ 308, 1018, 39, 12 ], [ 350, 1018, 49, 12 ], [ 401, 1018, 28, 12 ], [ 714, 1052, 25, 12 ], [ 741, 1052, 7, 12 ], [ 750, 1052, 10, 12 ], [ 763, 1052, 7, 12 ], [ 603, 1067, 25, 10 ], [ 630, 1067, 32, 10 ], [ 664, 1067, 14, 10 ], [ 680, 1067, 11, 10 ], [ 694, 1067, 30, 10 ], [ 727, 1067, 43, 10 ] ]

[ "Available", "online", "http://ccforum.com/content/12/6/R146", "Research", "Vol12No6", "Recombinant", "human", "activated", "protein", "C", "ameliorates", "oleic", "acid-induced", "lung", "injury", "in", "awake", "sheep", "Kristine", "Waerhaug1,", "Mikhail", "Y", "Kirov1,2,", "Vsevolod", "V", "Kuzkov1,2,", "Vladimir", "N", "Kuklin1", "and", "Lars", "J", "Bjertnaes1", "Open", "Access", "1Department", "of", "Anesthesiology,", "Institute", "of", "Clinical", "Medicine,", "Faculty", "of", "Medicine,", "University", "of", "Tromsø,", "9037", "Tromsø,", "Norway", "2Department", "of", "Anesthesiology,", "Northern", "State", "Medical", "University,", "Troitzky", "avenue", "51,", "163000", "Arkhangelsk,", "Russian", "Federation", "Corresponding", "author:", "Lars", "J", "Bjertnaes,", "lars.bjertnaes@fagmed.uit.no", "Received:", "7", "Oct", "2008", "Revisions", "requested:", "25", "Oct", "2008", "Revisions", "received:", "7", "Nov", "2008", "Accepted:", "20", "Nov", "2008", "Published:", "20", "Nov", "2008", "Critical", "Care", "2008,", "12:R146", "(doi:10.1186/cc7128)", "This", "article", "is", "online", "at:", "http://ccforum.com/content/12/6/R146", "©", "2008", "Waerhaug", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Introduction", "Acute", "lung", "injury", "(ALI)", "may", "arise", "both", "after", "sepsis", "and", "non-septic", "inflammatory", "conditions", "and", "is", "often", "associated", "with", "the", "release", "of", "fatty", "acids,", "including", "oleic", "acid", "(OA).", "Infusion", "of", "OA", "has", "been", "used", "extensively", "to", "mimic", "ALI.", "Recent", "research", "has", "revealed", "that", "intravenously", "administered", "recombinant", "human", "activated", "protein", "C", "(rhAPC)", "is", "able", "to", "counteract", "ALI.", "Our", "aim", "was", "to", "find", "out", "whether", "rhAPC", "dampens", "OA-induced", "ALI", "in", "sheep.", "Methods", "Twenty-two", "yearling", "sheep", "underwent", "instrumentation.", "After", "2", "days", "of", "recovery,", "animals", "were", "randomly", "assigned", "to", "one", "of", "three", "groups:", "(a)", "an", "OA+rhAPC", "group", "(n", "=", "8)", "receiving", "OA", "0.06", "mL/kg", "infused", "over", "the", "course", "of", "30", "minutes", "in", "parallel", "with", "an", "intravenous", "infusion", "of", "rhAPC", "24", "mg/kg", "per", "hour", "over", "the", "course", "of", "2", "hours,", "(b)", "an", "OA", "group", "(n", "=", "8)", "receiving", "OA", "as", "above,", "or", "(c)", "a", "sham-operated", "group", "(n", "=", "6).", "After", "2", "hours,", "sheep", "were", "sacrificed.", "Hemodynamics", "was", "assessed", "by", "catheters", "in", "the", "pulmonary", "artery", "and", "the", "aorta,", "and", "extravascular", "lung", "water", "index", "(EVLWI)", "was", "Introduction", "Mortality", "from", "acute", "lung", "injury", "(ALI)", "still", "remains", "between", "30%", "and", "40%", "[1].", "Patients", "with", "acute", "respiratory", "distress", "syndrome", "(ARDS),", "the", "most", "severe", "form", "of", "ALI,", "present", "with", "elevated", "plasma", "concentrations", "of", "oleic", "acid", "(OA),", "which", "is", "one", "of", "the", "most", "abundantly", "occurring", "fatty", "acids", "in", "human", "plasma", "[2].", "The", "proportion", "of", "OA", "increases", "in", "the", "bronchoal-", "veolar", "lavage", "fluid", "of", "patients", "with", "pneumonia", "and", "ARDS", "[3].", "In", "combination", "with", "sepsis,", "an", "enhanced", "plasma", "level", "of", "OA", "determined", "with", "the", "single", "transpulmonary", "thermodilution", "technique.", "Gas", "exchange", "was", "evaluated", "at", "baseline", "and", "at", "cessation", "of", "the", "experiment.", "Data", "were", "analyzed", "by", "analysis", "of", "variance;", "a", "P", "value", "of", "less", "than", "0.05", "was", "regarded", "as", "statistically", "significant.", "Results", "OA", "induced", "profound", "hypoxemia,", "increased", "right", "atrial", "and", "pulmonary", "artery", "pressures", "and", "EVLWI", "markedly,", "and", "decreased", "cardiac", "index.", "rhAPC", "counteracted", "the", "OA-induced", "changes", "in", "EVLWI", "and", "arterial", "oxygenation", "and", "reduced", "the", "OA-induced", "increments", "in", "right", "atrial", "and", "pulmonary", "artery", "pressures.", "Conclusions", "In", "ovine", "OA-induced", "lung", "injury,", "rhAPC", "dampens", "the", "increase", "in", "pulmonary", "artery", "pressure", "and", "counteracts", "the", "development", "of", "lung", "edema", "and", "the", "derangement", "of", "arterial", "oxygenation.", "adds", "to", "the", "risk", "of", "contracting", "ARDS", "[4].", "However,", "independ-", "ent", "of", "whether", "a", "high", "plasma", "concentration", "of", "OA", "contributes", "to", "ARDS", "or", "not,", "infusion", "of", "OA", "has", "been", "widely", "used", "to", "mimic", "non-septic", "lung", "injury", "in", "experimental", "settings.", "Administered", "to", "animals,", "OA", "increases", "pulmonary", "vascular", "pressure", "and", "per-", "meability,", "resulting", "in", "the", "development", "of", "lung", "edema", "and", "arte-", "rial", "hypoxemia", "that", "are", "typical", "for", "this", "condition", "[5].", "AaPO2:", "alveolar-arterial", "oxygen", "tension", "difference;", "ALI:", "acute", "lung", "injury;", "APC:", "activated", "protein", "C;", "ARDS:", "acute", "respiratory", "distress", "syndrome;", "CI:", "cardiac", "index;", "EVLWI:", "extravascular", "lung", "water", "index;", "HR:", "heart", "rate;", "IL:", "interleukin;", "iNOS:", "inducible", "nitric-oxide", "synthase;", "LVSWI:", "left", "ventricular", "stroke", "work", "index;", "MAP:", "mean", "systemic", "arterial", "pressure;", "OA:", "oleic", "acid;", "PaO2:", "partial", "tension", "of", "oxygen", "in", "arterial", "blood;", "PAOP:", "pulmonary", "arterial", "occlusion", "pressure;", "PAP:", "pulmonary", "arterial", "pressure;", "Pmo:", "pulmonary", "capillary", "micro-occlusion", "pressure;", "PVRI:", "pulmonary", "vascular", "resistance", "index;", "Qs/Qt:", "venous", "admixture;", "RAP:", "right", "atrial", "pressure;", "rhAPC:", "recombinant", "human", "activated", "protein", "C;", "RVSWI:", "right", "ventricular", "stroke", "work", "index;", "SaO2:", "arterial", "oxygen", "saturation;", "SVRI:", "systemic", "vascular", "resistance", "index.", "Page", "1", "of", "8", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 76, 47, 183, 34 ], [ 271, 47, 123, 34 ], [ 76, 118, 70, 20 ], [ 76, 143, 96, 23 ], [ 177, 143, 20, 23 ], [ 203, 143, 68, 23 ], [ 277, 143, 90, 23 ], [ 373, 143, 53, 23 ], [ 431, 143, 23, 23 ], [ 460, 143, 114, 23 ], [ 580, 143, 68, 23 ], [ 653, 143, 19, 23 ], [ 76, 168, 149, 23 ], [ 231, 168, 110, 23 ], [ 346, 168, 45, 23 ], [ 76, 193, 36, 21 ], [ 117, 193, 49, 22 ], [ 171, 193, 71, 21 ], [ 247, 193, 74, 22 ], [ 326, 193, 53, 21 ], [ 384, 193, 82, 22 ], [ 471, 193, 35, 21 ], [ 510, 193, 67, 21 ], [ 583, 193, 14, 21 ], [ 601, 193, 31, 22 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 243, 41, 12 ], [ 119, 243, 31, 12 ], [ 153, 243, 24, 12 ], [ 179, 243, 35, 12 ], [ 217, 243, 59, 12 ], [ 278, 243, 10, 12 ], [ 291, 243, 39, 12 ], [ 332, 243, 42, 12 ], [ 376, 243, 50, 12 ], [ 428, 243, 33, 12 ], [ 464, 243, 10, 12 ], [ 476, 243, 48, 12 ], [ 527, 243, 45, 12 ], [ 574, 243, 15, 12 ], [ 591, 243, 34, 12 ], [ 628, 243, 21, 12 ], [ 651, 243, 19, 12 ], [ 673, 243, 63, 12 ], [ 76, 256, 53, 11 ], [ 132, 256, 25, 11 ], [ 159, 256, 42, 11 ], [ 204, 256, 25, 11 ], [ 231, 256, 44, 11 ], [ 278, 256, 17, 11 ], [ 297, 256, 34, 11 ], [ 333, 256, 21, 11 ], [ 76, 276, 31, 12 ], [ 110, 276, 19, 12 ], [ 131, 276, 19, 12 ], [ 153, 276, 4, 12 ], [ 159, 276, 121, 12 ], [ 283, 276, 38, 12 ], [ 323, 276, 33, 12 ], [ 358, 276, 4, 12 ], [ 364, 276, 108, 12 ], [ 475, 276, 29, 12 ], [ 506, 276, 40, 12 ], [ 548, 276, 4, 12 ], [ 554, 276, 128, 12 ], [ 76, 289, 36, 11 ], [ 115, 289, 8, 11 ], [ 124, 289, 12, 11 ], [ 139, 289, 4, 11 ], [ 146, 289, 103, 11 ], [ 76, 305, 7, 12 ], [ 85, 305, 73, 12 ], [ 160, 305, 33, 12 ], [ 76, 364, 45, 12 ], [ 124, 364, 12, 12 ], [ 138, 364, 49, 12 ], [ 190, 364, 23, 12 ], [ 76, 384, 42, 11 ], [ 120, 384, 30, 11 ], [ 153, 384, 25, 11 ], [ 180, 384, 20, 12 ], [ 212, 384, 128, 11 ], [ 76, 404, 20, 11 ], [ 98, 404, 28, 11 ], [ 129, 404, 7, 11 ], [ 139, 404, 38, 11 ], [ 179, 404, 25, 11 ], [ 207, 404, 224, 11 ], [ 430, 364, 43, 12 ], [ 475, 364, 6, 12 ], [ 484, 364, 32, 12 ], [ 519, 364, 23, 12 ], [ 430, 377, 46, 11 ], [ 478, 377, 11, 11 ], [ 492, 377, 49, 11 ], [ 544, 377, 23, 11 ], [ 76, 423, 9, 12 ], [ 87, 423, 23, 12 ], [ 113, 423, 20, 12 ], [ 135, 423, 9, 12 ], [ 147, 423, 10, 12 ], [ 160, 423, 36, 12 ], [ 198, 423, 35, 12 ], [ 236, 423, 35, 12 ], [ 273, 423, 18, 12 ], [ 76, 437, 20, 12 ], [ 98, 437, 7, 12 ], [ 108, 437, 11, 12 ], [ 121, 437, 26, 12 ], [ 150, 437, 32, 12 ], [ 184, 437, 28, 12 ], [ 215, 437, 49, 12 ], [ 267, 437, 27, 12 ], [ 296, 437, 15, 12 ], [ 314, 437, 27, 12 ], [ 343, 437, 10, 12 ], [ 355, 437, 15, 12 ], [ 373, 437, 39, 12 ], [ 415, 437, 48, 12 ], [ 465, 437, 51, 12 ], [ 519, 437, 34, 12 ], [ 555, 437, 202, 12 ], [ 76, 450, 27, 12 ], [ 106, 450, 35, 12 ], [ 143, 450, 56, 12 ], [ 201, 450, 18, 12 ], [ 222, 450, 55, 12 ], [ 279, 450, 16, 12 ], [ 298, 450, 60, 12 ], [ 361, 450, 8, 12 ], [ 372, 450, 16, 12 ], [ 390, 450, 39, 12 ], [ 432, 450, 40, 12 ], [ 475, 450, 15, 12 ], [ 493, 450, 34, 12 ], [ 529, 450, 24, 12 ], [ 556, 450, 7, 12 ], [ 565, 450, 39, 12 ], [ 607, 450, 25, 12 ], [ 155, 510, 62, 15 ], [ 155, 531, 80, 14 ], [ 239, 531, 80, 14 ], [ 324, 531, 57, 14 ], [ 385, 531, 38, 14 ], [ 428, 531, 9, 14 ], [ 441, 531, 13, 14 ], [ 458, 531, 55, 14 ], [ 518, 531, 40, 14 ], [ 562, 531, 20, 14 ], [ 586, 531, 9, 14 ], [ 599, 531, 18, 14 ], [ 621, 531, 27, 14 ], [ 653, 531, 38, 14 ], [ 155, 547, 31, 14 ], [ 188, 547, 11, 14 ], [ 202, 547, 37, 14 ], [ 241, 547, 31, 14 ], [ 275, 547, 62, 14 ], [ 340, 547, 49, 14 ], [ 391, 547, 42, 14 ], [ 435, 547, 9, 14 ], [ 447, 547, 56, 14 ], [ 505, 547, 32, 14 ], [ 540, 547, 44, 14 ], [ 586, 547, 30, 14 ], [ 618, 547, 9, 14 ], [ 629, 547, 61, 14 ], [ 155, 564, 47, 14 ], [ 205, 564, 12, 14 ], [ 221, 564, 70, 14 ], [ 294, 564, 82, 14 ], [ 379, 564, 14, 14 ], [ 396, 564, 27, 14 ], [ 427, 564, 54, 14 ], [ 483, 564, 20, 14 ], [ 506, 564, 38, 14 ], [ 547, 564, 55, 14 ], [ 605, 564, 42, 14 ], [ 650, 564, 30, 14 ], [ 683, 564, 8, 14 ], [ 155, 580, 37, 14 ], [ 195, 580, 12, 14 ], [ 210, 580, 43, 14 ], [ 257, 580, 30, 14 ], [ 290, 580, 20, 14 ], [ 313, 580, 47, 14 ], [ 364, 580, 100, 14 ], [ 467, 580, 38, 14 ], [ 508, 580, 29, 14 ], [ 540, 580, 18, 14 ], [ 561, 580, 80, 15 ], [ 645, 580, 46, 14 ], [ 155, 596, 9, 14 ], [ 169, 596, 47, 14 ], [ 220, 596, 10, 14 ], [ 236, 596, 29, 14 ], [ 270, 596, 83, 14 ], [ 358, 596, 17, 14 ], [ 380, 596, 40, 14 ], [ 425, 596, 18, 14 ], [ 448, 596, 51, 14 ], [ 505, 596, 11, 14 ], [ 521, 596, 92, 14 ], [ 618, 596, 45, 14 ], [ 668, 596, 11, 14 ], [ 685, 596, 6, 14 ], [ 155, 613, 49, 14 ], [ 207, 613, 55, 14 ], [ 265, 613, 33, 14 ], [ 301, 613, 10, 14 ], [ 314, 613, 32, 14 ], [ 155, 636, 49, 14 ], [ 209, 636, 21, 14 ], [ 234, 636, 77, 14 ], [ 316, 636, 22, 14 ], [ 342, 636, 37, 14 ], [ 384, 636, 9, 14 ], [ 397, 636, 32, 14 ], [ 433, 636, 56, 14 ], [ 493, 636, 10, 14 ], [ 507, 636, 37, 14 ], [ 549, 636, 55, 14 ], [ 608, 636, 19, 14 ], [ 631, 636, 25, 14 ], [ 660, 636, 20, 14 ], [ 685, 636, 6, 14 ], [ 155, 652, 51, 14 ], [ 210, 652, 11, 14 ], [ 225, 652, 37, 14 ], [ 266, 652, 29, 14 ], [ 299, 652, 37, 14 ], [ 339, 652, 55, 14 ], [ 398, 652, 12, 14 ], [ 415, 652, 35, 14 ], [ 453, 652, 46, 14 ], [ 502, 652, 60, 14 ], [ 566, 652, 40, 14 ], [ 610, 652, 16, 14 ], [ 630, 652, 61, 14 ], [ 155, 669, 48, 14 ], [ 207, 669, 98, 14 ], [ 310, 669, 56, 14 ], [ 370, 669, 41, 14 ], [ 416, 669, 20, 14 ], [ 441, 669, 69, 14 ], [ 514, 669, 11, 14 ], [ 530, 669, 31, 14 ], [ 566, 669, 20, 14 ], [ 590, 669, 37, 14 ], [ 632, 669, 24, 14 ], [ 661, 669, 30, 14 ], [ 155, 685, 58, 14 ], [ 217, 685, 37, 14 ], [ 258, 685, 20, 14 ], [ 282, 685, 54, 14 ], [ 339, 685, 23, 14 ], [ 366, 685, 24, 14 ], [ 394, 684, 54, 15 ], [ 452, 685, 19, 14 ], [ 475, 685, 17, 14 ], [ 496, 685, 19, 14 ], [ 519, 685, 30, 14 ], [ 553, 685, 39, 14 ], [ 596, 685, 66, 14 ], [ 666, 685, 25, 14 ], [ 155, 701, 71, 14 ], [ 231, 701, 37, 14 ], [ 274, 701, 63, 14 ], [ 342, 701, 56, 14 ], [ 404, 701, 21, 14 ], [ 431, 701, 22, 14 ], [ 458, 701, 51, 14 ], [ 515, 701, 10, 14 ], [ 531, 701, 31, 14 ], [ 567, 701, 20, 14 ], [ 593, 701, 37, 14 ], [ 635, 701, 24, 14 ], [ 665, 701, 26, 14 ], [ 155, 718, 55, 14 ], [ 213, 718, 24, 14 ], [ 241, 718, 61, 14 ], [ 305, 718, 50, 14 ], [ 359, 718, 11, 14 ], [ 372, 718, 30, 14 ], [ 405, 718, 22, 14 ], [ 430, 718, 19, 14 ], [ 452, 718, 28, 14 ], [ 483, 718, 18, 14 ], [ 505, 718, 61, 14 ], [ 569, 718, 47, 14 ], [ 620, 718, 56, 14 ], [ 679, 717, 12, 15 ], [ 155, 734, 68, 14 ], [ 231, 734, 80, 14 ], [ 319, 734, 51, 14 ], [ 378, 734, 33, 14 ], [ 419, 734, 29, 14 ], [ 456, 734, 57, 14 ], [ 521, 734, 24, 14 ], [ 554, 734, 90, 14 ], [ 653, 734, 11, 14 ], [ 673, 734, 18, 14 ], [ 155, 750, 67, 14 ], [ 225, 750, 79, 14 ], [ 309, 750, 33, 14 ], [ 346, 750, 31, 14 ], [ 381, 750, 36, 14 ], [ 422, 750, 31, 14 ], [ 457, 750, 20, 14 ], [ 481, 750, 20, 14 ], [ 505, 750, 45, 14 ], [ 554, 750, 70, 14 ], [ 628, 750, 47, 14 ], [ 679, 750, 11, 14 ], [ 155, 766, 61, 14 ], [ 220, 766, 47, 14 ], [ 271, 766, 61, 14 ], [ 336, 766, 9, 14 ], [ 349, 766, 19, 14 ], [ 371, 766, 35, 14 ], [ 410, 766, 40, 14 ], [ 453, 766, 10, 14 ], [ 467, 766, 6, 14 ], [ 477, 766, 31, 14 ], [ 511, 766, 53, 14 ], [ 567, 766, 38, 14 ], [ 608, 766, 33, 14 ], [ 644, 766, 21, 14 ], [ 669, 766, 22, 14 ], [ 155, 783, 57, 14 ], [ 215, 783, 24, 14 ], [ 242, 783, 53, 14 ], [ 298, 783, 20, 14 ], [ 321, 783, 45, 14 ], [ 370, 783, 36, 14 ], [ 410, 783, 31, 14 ], [ 444, 783, 20, 14 ], [ 467, 783, 20, 14 ], [ 490, 783, 42, 14 ], [ 536, 783, 68, 14 ], [ 155, 806, 74, 14 ], [ 234, 806, 24, 14 ], [ 263, 806, 37, 14 ], [ 305, 806, 40, 14 ], [ 351, 806, 22, 14 ], [ 379, 806, 37, 14 ], [ 421, 806, 9, 14 ], [ 435, 806, 6, 14 ], [ 446, 806, 41, 14 ], [ 493, 806, 33, 14 ], [ 531, 806, 17, 14 ], [ 553, 806, 30, 14 ], [ 588, 806, 27, 14 ], [ 620, 806, 20, 14 ], [ 645, 806, 22, 14 ], [ 673, 806, 18, 14 ], [ 155, 822, 49, 14 ], [ 208, 822, 11, 14 ], [ 223, 822, 92, 14 ], [ 319, 822, 45, 14 ], [ 368, 822, 23, 14 ], [ 394, 822, 26, 14 ], [ 424, 822, 6, 14 ], [ 434, 822, 49, 14 ], [ 487, 822, 90, 14 ], [ 580, 822, 63, 14 ], [ 647, 822, 44, 14 ], [ 155, 839, 17, 14 ], [ 175, 839, 18, 14 ], [ 196, 839, 55, 14 ], [ 255, 839, 11, 14 ], [ 270, 839, 6, 14 ], [ 279, 839, 51, 14 ], [ 334, 839, 11, 14 ], [ 348, 839, 30, 14 ], [ 381, 839, 22, 14 ], [ 406, 839, 84, 14 ], [ 493, 839, 40, 14 ], [ 76, 907, 84, 15 ], [ 76, 924, 87, 14 ], [ 167, 924, 61, 14 ], [ 233, 924, 41, 14 ], [ 278, 924, 10, 14 ], [ 291, 924, 19, 14 ], [ 315, 924, 47, 14 ], [ 365, 924, 29, 14 ], [ 399, 924, 12, 14 ], [ 76, 940, 43, 14 ], [ 121, 940, 31, 14 ], [ 154, 940, 26, 14 ], [ 182, 940, 41, 14 ], [ 226, 940, 9, 14 ], [ 237, 940, 10, 14 ], [ 249, 940, 19, 14 ], [ 271, 940, 25, 14 ], [ 298, 940, 30, 14 ], [ 330, 940, 54, 14 ], [ 386, 940, 25, 14 ], [ 76, 956, 17, 14 ], [ 98, 956, 66, 14 ], [ 170, 956, 27, 14 ], [ 201, 956, 35, 14 ], [ 241, 956, 22, 14 ], [ 268, 956, 44, 14 ], [ 318, 956, 25, 14 ], [ 347, 956, 30, 14 ], [ 382, 956, 30, 14 ], [ 76, 973, 36, 14 ], [ 114, 973, 55, 14 ], [ 172, 973, 23, 14 ], [ 197, 973, 40, 14 ], [ 240, 973, 15, 14 ], [ 258, 973, 33, 14 ], [ 293, 973, 47, 14 ], [ 342, 973, 12, 14 ], [ 357, 973, 42, 14 ], [ 402, 973, 9, 14 ], [ 76, 989, 10, 14 ], [ 90, 989, 78, 14 ], [ 172, 989, 12, 14 ], [ 188, 989, 40, 14 ], [ 232, 989, 30, 14 ], [ 266, 989, 29, 14 ], [ 299, 989, 12, 14 ], [ 316, 989, 35, 14 ], [ 355, 989, 24, 14 ], [ 383, 989, 28, 14 ], [ 76, 1005, 23, 14 ], [ 102, 1005, 35, 14 ], [ 140, 1005, 38, 14 ], [ 181, 1005, 36, 14 ], [ 220, 1005, 51, 14 ], [ 274, 1005, 9, 14 ], [ 285, 1005, 29, 14 ], [ 317, 1005, 39, 14 ], [ 358, 1005, 53, 14 ], [ 434, 907, 10, 14 ], [ 452, 907, 51, 14 ], [ 511, 907, 21, 14 ], [ 540, 907, 22, 14 ], [ 570, 907, 20, 14 ], [ 598, 907, 41, 14 ], [ 647, 907, 20, 14 ], [ 675, 907, 26, 14 ], [ 710, 907, 16, 14 ], [ 734, 907, 35, 14 ], [ 434, 924, 53, 14 ], [ 493, 924, 12, 14 ], [ 512, 924, 19, 14 ], [ 536, 924, 57, 14 ], [ 599, 924, 13, 14 ], [ 618, 924, 33, 14 ], [ 657, 924, 87, 14 ], [ 750, 924, 20, 14 ], [ 434, 940, 27, 14 ], [ 465, 940, 12, 14 ], [ 480, 940, 30, 14 ], [ 513, 940, 47, 14 ], [ 562, 940, 18, 14 ], [ 583, 940, 63, 14 ], [ 649, 940, 17, 14 ], [ 669, 940, 45, 14 ], [ 717, 940, 53, 14 ], [ 434, 956, 23, 14 ], [ 462, 956, 26, 14 ], [ 494, 956, 94, 14 ], [ 593, 956, 19, 14 ], [ 617, 956, 50, 14 ], [ 672, 956, 12, 14 ], [ 690, 956, 47, 14 ], [ 742, 956, 28, 14 ], [ 434, 973, 43, 14 ], [ 484, 973, 57, 14 ], [ 547, 973, 45, 14 ], [ 599, 973, 22, 14 ], [ 628, 973, 13, 14 ], [ 646, 973, 19, 14 ], [ 672, 973, 24, 14 ], [ 702, 973, 13, 14 ], [ 721, 973, 48, 14 ], [ 434, 989, 84, 14 ], [ 521, 989, 42, 14 ], [ 565, 989, 22, 14 ], [ 590, 989, 70, 14 ], [ 661, 989, 49, 14 ], [ 713, 989, 37, 14 ], [ 752, 989, 17, 14 ], [ 434, 1005, 16, 14 ], [ 457, 1005, 27, 14 ], [ 490, 1005, 98, 14 ], [ 594, 1005, 78, 14 ], [ 678, 1005, 24, 14 ], [ 708, 1005, 28, 14 ], [ 742, 1005, 28, 14 ], [ 698, 1052, 30, 13 ], [ 731, 1052, 7, 13 ], [ 741, 1052, 11, 13 ], [ 755, 1052, 14, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "Molecular", "Cancer", "Research", "Blockade", "of", "Wnt-1", "signaling", "leads", "to", "anti-tumor", "effects", "in", "hepatocellular", "carcinoma", "cells", "Wei", "Wei1,", "Mei-Sze", "Chua*1,", "Susan", "Grepper2", "and", "Samuel", "K", "So1", "BioMed", "Central", "Open", "Access", "Address:", "1Asian", "Liver", "Center,", "Department", "of", "Surgery,", "Stanford", "University", "School", "of", "Medicine,", "Stanford,", "CA", "94305,", "USA", "and", "2CellzDirect/", "Invitrogen,", "4301", "Emperor", "Blvd,", "Durham,", "NC", "27703,", "USA", "Email:", "Wei", "Wei", "-", "weiwei25@stanford.edu;", "Mei-Sze", "Chua*", "-", "mchua@stanford.edu;", "Susan", "Grepper", "-", "sue.grepper@lifetech.com;", "Samuel", "K", "So", "-", "samso@stanford.edu", "*", "Corresponding", "author", "Published:", "24", "September", "2009", "Molecular", "Cancer", "2009,", "8:76", "doi:10.1186/1476-4598-8-76", "This", "article", "is", "available", "from:", "http://www.molecular-cancer.com/content/8/1/76", "Received:", "6", "August", "2009", "Accepted:", "24", "September", "2009", "©", "2009", "Wei", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Hepatocellular", "carcinoma", "(HCC)", "is", "an", "aggressive", "cancer,", "and", "is", "the", "third", "leading", "cause", "of", "cancer", "death", "worldwide.", "Standard", "therapy", "is", "ineffective", "partly", "because", "HCC", "is", "intrinsically", "resistant", "to", "conventional", "chemotherapy.", "Its", "poor", "prognosis", "and", "limited", "treatment", "options", "make", "it", "critical", "to", "develop", "novel", "and", "selective", "chemotherapeutic", "agents.", "Since", "the", "Wnt/β-catenin", "pathway", "is", "essential", "in", "HCC", "carcinogenesis,", "we", "studied", "the", "inhibition", "of", "Wnt-1-mediated", "signaling", "as", "a", "potential", "molecular", "target", "in", "HCC.", "Results:", "We", "demonstrated", "that", "Wnt-1", "is", "highly", "expressed", "in", "human", "hepatoma", "cell", "lines", "and", "a", "subgroup", "of", "human", "HCC", "tissues", "compared", "to", "paired", "adjacent", "non-tumor", "tissues.", "An", "anti-Wnt-1", "antibody", "dose-dependently", "decreased", "viability", "and", "proliferation", "of", "Huh7", "and", "Hep40", "cells", "over-", "expressing", "Wnt-1", "and", "harboring", "wild", "type", "β-catenin,", "but", "did", "not", "affect", "normal", "hepatocytes", "with", "undetectable", "Wnt-1", "expression.", "Apoptosis", "was", "also", "observed", "in", "Huh7", "and", "Hep40", "cells", "after", "treatment", "with", "anti-Wnt-1", "antibody.", "In", "these", "two", "cell", "lines,", "the", "anti-Wnt-1", "antibody", "decreased", "β-", "catenin/Tcf4", "transcriptional", "activities,", "which", "were", "associated", "with", "down-regulation", "of", "the", "endogenous", "β-catenin/Tcf4", "target", "genes", "c-Myc,", "cyclin", "D1,", "and", "survivin.", "Intratumoral", "injection", "of", "anti-Wnt-1", "antibody", "suppressed", "in", "vivo", "tumor", "growth", "in", "a", "Huh7", "xenograft", "model,", "which", "was", "also", "associated", "with", "apoptosis", "and", "reduced", "c-Myc,", "cyclin", "D1,", "and", "survivin", "expressions.", "Conclusion:", "Our", "results", "suggest", "that", "Wnt-1", "is", "a", "survival", "factor", "for", "HCC", "cells,", "and", "that", "the", "blockade", "of", "Wnt-1-mediated", "signaling", "may", "offer", "a", "potential", "pathway-specific", "therapeutic", "strategy", "for", "the", "treatment", "of", "a", "subgroup", "of", "HCC", "that", "over-expresses", "Wnt-1.", "Background", "Hepatocellular", "carcinoma", "(HCC)", "is", "the", "primary", "form", "of", "human", "adult", "liver", "cancer.", "It", "is", "the", "fifth", "most", "common", "can-", "cer", "worldwide,", "with", "about", "one", "million", "new", "cases", "diag-", "nosed", "annually,", "and", "almost", "an", "equal", "number", "of", "deaths.", "It", "is", "predominant", "in", "China,", "most", "parts", "of", "South", "East", "Asia,", "and", "South", "Africa,", "where", "hepatitis", "B", "virus", "(HBV)", "infection", "is", "endemic", "[1].", "The", "last", "decade", "has", "seen", "no", "major", "advances", "in", "the", "treatment", "of", "HCC.", "Approximately", "10-", "25%", "of", "HCC", "patients", "are", "candidates", "for", "surgical", "resection", "and", "liver", "transplantation;", "the", "majority", "of", "patients", "have", "limited", "treatment", "options", "due", "to", "the", "lack", "of", "effective", "chemotherapy", "against", "this", "intrinsically", "resistant", "tumor", "[2-", "4].", "New", "pharmacological", "interventions", "that", "offer", "even", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 80, 78, 143, 28 ], [ 231, 78, 155, 28 ], [ 394, 78, 118, 28 ], [ 521, 78, 99, 28 ], [ 628, 78, 25, 28 ], [ 661, 78, 41, 28 ], [ 708, 78, 60, 28 ], [ 80, 109, 69, 28 ], [ 80, 146, 57, 12 ], [ 140, 146, 10, 12 ], [ 153, 144, 37, 14 ], [ 194, 146, 40, 12 ], [ 236, 146, 12, 12 ], [ 252, 144, 43, 14 ], [ 298, 146, 30, 12 ], [ 331, 144, 44, 14 ], [ 377, 146, 40, 12 ], [ 420, 146, 9, 12 ], [ 432, 144, 43, 14 ], [ 80, 171, 6, 12 ], [ 88, 171, 57, 12 ], [ 149, 171, 10, 12 ], [ 163, 171, 43, 12 ], [ 210, 171, 40, 12 ], [ 255, 171, 49, 12 ], [ 308, 171, 42, 12 ], [ 355, 171, 46, 12 ], [ 406, 171, 32, 12 ], [ 442, 171, 29, 12 ], [ 475, 171, 10, 12 ], [ 489, 171, 41, 12 ], [ 535, 171, 6, 12 ], [ 542, 171, 57, 12 ], [ 604, 171, 10, 12 ], [ 618, 171, 40, 12 ], [ 662, 171, 42, 12 ], [ 709, 171, 46, 12 ], [ 760, 171, 10, 12 ], [ 80, 184, 59, 12 ], [ 142, 184, 35, 12 ], [ 180, 184, 59, 12 ], [ 242, 184, 32, 12 ], [ 277, 184, 28, 12 ], [ 309, 184, 10, 12 ], [ 323, 184, 41, 12 ], [ 367, 184, 6, 12 ], [ 375, 184, 57, 12 ], [ 435, 184, 10, 12 ], [ 448, 184, 50, 12 ], [ 501, 184, 40, 12 ], [ 545, 184, 49, 12 ], [ 597, 184, 42, 12 ], [ 643, 184, 46, 12 ], [ 693, 184, 32, 12 ], [ 728, 184, 29, 12 ], [ 760, 184, 10, 12 ], [ 80, 197, 41, 11 ], [ 124, 197, 6, 11 ], [ 132, 197, 57, 11 ], [ 192, 197, 10, 11 ], [ 205, 197, 47, 11 ], [ 255, 197, 40, 11 ], [ 298, 197, 49, 11 ], [ 350, 197, 42, 11 ], [ 396, 197, 46, 11 ], [ 445, 197, 32, 11 ], [ 480, 197, 29, 11 ], [ 512, 197, 10, 11 ], [ 525, 197, 38, 11 ], [ 79, 236, 80, 13 ], [ 164, 236, 40, 13 ], [ 211, 236, 46, 13 ], [ 261, 236, 7, 13 ], [ 273, 236, 75, 13 ], [ 353, 236, 23, 13 ], [ 381, 236, 57, 13 ], [ 443, 236, 26, 13 ], [ 474, 236, 37, 13 ], [ 515, 236, 27, 13 ], [ 549, 236, 59, 13 ], [ 613, 236, 11, 13 ], [ 629, 236, 19, 13 ], [ 652, 236, 29, 13 ], [ 686, 236, 9, 13 ], [ 700, 236, 52, 13 ], [ 758, 236, 12, 13 ], [ 80, 252, 45, 13 ], [ 130, 252, 11, 13 ], [ 145, 252, 18, 13 ], [ 168, 252, 41, 13 ], [ 214, 252, 42, 13 ], [ 260, 252, 11, 13 ], [ 276, 252, 18, 13 ], [ 299, 252, 78, 13 ], [ 382, 252, 21, 13 ], [ 408, 252, 9, 13 ], [ 421, 252, 48, 13 ], [ 473, 252, 14, 13 ], [ 492, 252, 33, 13 ], [ 529, 252, 11, 13 ], [ 545, 252, 48, 13 ], [ 597, 252, 38, 13 ], [ 640, 252, 46, 13 ], [ 690, 252, 20, 13 ], [ 715, 252, 54, 13 ], [ 80, 267, 68, 13 ], [ 151, 267, 60, 13 ], [ 212, 267, 27, 13 ], [ 243, 267, 60, 13 ], [ 306, 267, 51, 13 ], [ 359, 267, 39, 13 ], [ 401, 267, 36, 13 ], [ 439, 267, 45, 13 ], [ 487, 267, 31, 13 ], [ 521, 267, 7, 13 ], [ 531, 267, 69, 13 ], [ 603, 267, 12, 13 ], [ 617, 267, 58, 13 ], [ 677, 267, 21, 13 ], [ 701, 267, 68, 13 ], [ 80, 282, 52, 13 ], [ 136, 282, 46, 13 ], [ 186, 282, 16, 13 ], [ 206, 282, 27, 13 ], [ 236, 282, 57, 13 ], [ 297, 282, 53, 13 ], [ 354, 282, 7, 13 ], [ 365, 282, 20, 13 ], [ 389, 282, 15, 13 ], [ 407, 282, 56, 13 ], [ 467, 282, 36, 13 ], [ 507, 282, 52, 13 ], [ 563, 282, 11, 13 ], [ 577, 282, 27, 13 ], [ 609, 282, 33, 13 ], [ 645, 282, 46, 13 ], [ 695, 282, 28, 13 ], [ 727, 282, 43, 13 ], [ 80, 297, 50, 13 ], [ 134, 297, 23, 13 ], [ 160, 297, 60, 13 ], [ 222, 297, 11, 13 ], [ 235, 297, 27, 13 ], [ 267, 297, 80, 13 ], [ 350, 297, 60, 13 ], [ 413, 297, 11, 13 ], [ 427, 297, 21, 13 ], [ 450, 297, 34, 13 ], [ 487, 297, 16, 13 ], [ 507, 297, 44, 13 ], [ 554, 297, 12, 13 ], [ 569, 297, 46, 13 ], [ 618, 297, 19, 13 ], [ 640, 297, 55, 13 ], [ 698, 297, 16, 13 ], [ 717, 297, 53, 13 ], [ 80, 313, 56, 13 ], [ 142, 313, 50, 13 ], [ 199, 313, 11, 13 ], [ 215, 313, 20, 13 ], [ 241, 313, 36, 13 ], [ 283, 313, 14, 13 ], [ 303, 313, 59, 13 ], [ 368, 313, 48, 13 ], [ 421, 313, 57, 13 ], [ 484, 313, 26, 13 ], [ 516, 313, 14, 13 ], [ 536, 313, 65, 13 ], [ 606, 313, 43, 13 ], [ 655, 313, 21, 13 ], [ 682, 313, 43, 13 ], [ 731, 313, 39, 13 ], [ 80, 328, 7, 13 ], [ 92, 328, 67, 13 ], [ 164, 328, 69, 13 ], [ 239, 328, 11, 13 ], [ 256, 328, 56, 13 ], [ 317, 328, 57, 13 ], [ 380, 328, 52, 13 ], [ 437, 328, 11, 13 ], [ 453, 328, 31, 13 ], [ 489, 328, 33, 13 ], [ 528, 328, 37, 13 ], [ 570, 328, 22, 13 ], [ 597, 328, 21, 13 ], [ 624, 328, 46, 13 ], [ 675, 328, 36, 13 ], [ 716, 328, 53, 13 ], [ 80, 343, 58, 13 ], [ 142, 343, 57, 13 ], [ 202, 343, 35, 13 ], [ 241, 343, 30, 13 ], [ 274, 343, 50, 13 ], [ 328, 343, 43, 13 ], [ 374, 343, 7, 13 ], [ 385, 343, 22, 13 ], [ 409, 343, 16, 13 ], [ 429, 343, 80, 13 ], [ 512, 343, 46, 13 ], [ 561, 343, 11, 13 ], [ 575, 343, 18, 13 ], [ 597, 343, 57, 13 ], [ 657, 343, 11, 13 ], [ 671, 343, 27, 13 ], [ 703, 343, 21, 13 ], [ 727, 343, 42, 13 ], [ 80, 358, 56, 13 ], [ 140, 358, 39, 13 ], [ 182, 358, 16, 13 ], [ 202, 358, 56, 13 ], [ 261, 358, 61, 13 ], [ 80, 381, 39, 12 ], [ 124, 381, 28, 12 ], [ 157, 381, 15, 12 ], [ 176, 381, 35, 12 ], [ 214, 381, 19, 12 ], [ 237, 381, 29, 12 ], [ 270, 381, 10, 12 ], [ 283, 381, 26, 12 ], [ 313, 381, 13, 12 ], [ 330, 381, 29, 12 ], [ 363, 381, 55, 12 ], [ 421, 381, 60, 12 ], [ 485, 381, 46, 12 ], [ 535, 381, 38, 12 ], [ 576, 381, 10, 12 ], [ 590, 381, 16, 12 ], [ 610, 381, 22, 12 ], [ 635, 381, 30, 12 ], [ 669, 381, 23, 12 ], [ 696, 381, 21, 12 ], [ 720, 381, 20, 12 ], [ 745, 381, 25, 12 ], [ 80, 394, 158, 12 ], [ 80, 434, 109, 16 ], [ 80, 452, 34, 13 ], [ 117, 452, 8, 13 ], [ 128, 452, 13, 13 ], [ 143, 452, 54, 13 ], [ 200, 452, 67, 13 ], [ 271, 452, 37, 13 ], [ 310, 452, 31, 13 ], [ 344, 452, 19, 13 ], [ 366, 452, 10, 13 ], [ 379, 452, 33, 13 ], [ 80, 467, 59, 13 ], [ 145, 467, 17, 13 ], [ 167, 467, 24, 13 ], [ 197, 467, 50, 13 ], [ 252, 467, 33, 13 ], [ 291, 467, 50, 13 ], [ 347, 467, 49, 13 ], [ 401, 467, 11, 13 ], [ 80, 481, 6, 13 ], [ 90, 481, 24, 13 ], [ 117, 481, 28, 13 ], [ 149, 481, 10, 13 ], [ 162, 481, 37, 13 ], [ 203, 481, 46, 13 ], [ 252, 481, 49, 13 ], [ 304, 481, 27, 13 ], [ 335, 481, 25, 13 ], [ 363, 481, 27, 13 ], [ 394, 481, 19, 13 ], [ 80, 496, 17, 13 ], [ 100, 496, 18, 13 ], [ 120, 496, 44, 13 ], [ 166, 496, 20, 13 ], [ 188, 496, 51, 13 ], [ 242, 496, 8, 13 ], [ 251, 496, 46, 13 ], [ 299, 496, 10, 13 ], [ 311, 496, 6, 13 ], [ 320, 496, 38, 13 ], [ 359, 496, 54, 13 ], [ 80, 510, 10, 13 ], [ 94, 510, 40, 13 ], [ 138, 510, 20, 13 ], [ 161, 510, 26, 13 ], [ 191, 510, 16, 13 ], [ 211, 510, 27, 13 ], [ 241, 510, 10, 13 ], [ 255, 510, 51, 13 ], [ 310, 510, 33, 13 ], [ 347, 510, 31, 13 ], [ 382, 510, 19, 13 ], [ 405, 510, 8, 13 ], [ 80, 525, 61, 13 ], [ 145, 525, 41, 13 ], [ 188, 525, 13, 13 ], [ 204, 525, 34, 13 ], [ 241, 525, 10, 13 ], [ 255, 525, 33, 13 ], [ 291, 525, 41, 13 ], [ 93, 540, 35, 13 ], [ 130, 540, 40, 13 ], [ 174, 540, 38, 13 ], [ 214, 540, 35, 13 ], [ 253, 540, 60, 13 ], [ 315, 540, 29, 13 ], [ 347, 540, 34, 13 ], [ 384, 540, 29, 13 ], [ 80, 555, 25, 13 ], [ 108, 555, 32, 13 ], [ 142, 555, 13, 13 ], [ 158, 555, 90, 13 ], [ 251, 555, 46, 13 ], [ 300, 555, 20, 13 ], [ 323, 555, 47, 13 ], [ 373, 555, 10, 13 ], [ 386, 555, 27, 13 ], [ 80, 569, 63, 13 ], [ 149, 569, 10, 13 ], [ 164, 569, 13, 13 ], [ 182, 569, 28, 13 ], [ 215, 569, 59, 13 ], [ 279, 569, 27, 13 ], [ 311, 569, 10, 13 ], [ 326, 569, 53, 13 ], [ 384, 569, 29, 13 ], [ 80, 584, 56, 13 ], [ 142, 584, 10, 13 ], [ 157, 584, 47, 13 ], [ 209, 584, 21, 13 ], [ 235, 584, 37, 13 ], [ 277, 584, 27, 13 ], [ 309, 584, 18, 13 ], [ 332, 584, 33, 13 ], [ 371, 584, 42, 13 ], [ 80, 598, 54, 13 ], [ 139, 598, 13, 13 ], [ 157, 598, 35, 13 ], [ 197, 598, 41, 13 ], [ 242, 598, 32, 13 ], [ 279, 598, 10, 13 ], [ 295, 598, 16, 13 ], [ 316, 598, 82, 13 ], [ 403, 598, 10, 13 ], [ 80, 613, 19, 13 ], [ 102, 613, 64, 13 ], [ 169, 613, 37, 13 ], [ 208, 613, 36, 13 ], [ 247, 613, 15, 13 ], [ 265, 613, 19, 13 ], [ 287, 613, 39, 13 ], [ 329, 613, 18, 13 ], [ 350, 613, 44, 13 ], [ 397, 613, 16, 13 ], [ 80, 627, 59, 13 ], [ 143, 627, 58, 13 ], [ 204, 627, 10, 13 ], [ 218, 627, 36, 13 ], [ 257, 627, 19, 13 ], [ 280, 627, 16, 13 ], [ 300, 627, 38, 13 ], [ 341, 627, 58, 13 ], [ 403, 627, 10, 13 ], [ 80, 642, 42, 13 ], [ 125, 642, 9, 13 ], [ 137, 642, 31, 13 ], [ 171, 642, 27, 13 ], [ 201, 642, 13, 13 ], [ 216, 642, 50, 13 ], [ 268, 642, 19, 13 ], [ 290, 642, 51, 13 ], [ 344, 642, 15, 13 ], [ 362, 642, 50, 13 ], [ 80, 656, 6, 13 ], [ 93, 656, 32, 13 ], [ 131, 656, 50, 13 ], [ 187, 656, 20, 13 ], [ 213, 656, 15, 13 ], [ 233, 656, 23, 13 ], [ 263, 656, 39, 13 ], [ 308, 656, 20, 13 ], [ 334, 656, 36, 13 ], [ 376, 656, 10, 13 ], [ 392, 656, 21, 13 ], [ 80, 671, 54, 13 ], [ 140, 671, 31, 13 ], [ 176, 671, 39, 13 ], [ 220, 671, 45, 13 ], [ 271, 671, 20, 13 ], [ 295, 671, 36, 13 ], [ 337, 671, 50, 13 ], [ 392, 671, 21, 13 ], [ 80, 685, 67, 13 ], [ 151, 685, 49, 13 ], [ 203, 685, 50, 13 ], [ 257, 685, 33, 13 ], [ 293, 685, 39, 13 ], [ 335, 685, 21, 13 ], [ 359, 685, 10, 13 ], [ 373, 685, 16, 13 ], [ 392, 685, 21, 13 ], [ 80, 700, 47, 13 ], [ 130, 700, 32, 13 ], [ 165, 700, 13, 13 ], [ 181, 700, 17, 13 ], [ 201, 700, 42, 13 ], [ 246, 700, 10, 13 ], [ 259, 700, 33, 13 ], [ 295, 700, 46, 13 ], [ 343, 700, 44, 13 ], [ 390, 700, 23, 13 ], [ 80, 714, 71, 13 ], [ 155, 714, 16, 13 ], [ 174, 714, 43, 13 ], [ 220, 714, 15, 13 ], [ 239, 714, 33, 13 ], [ 275, 714, 40, 13 ], [ 319, 714, 56, 13 ], [ 378, 714, 10, 13 ], [ 392, 714, 21, 13 ], [ 80, 729, 64, 13 ], [ 152, 729, 18, 13 ], [ 179, 729, 51, 13 ], [ 238, 729, 6, 13 ], [ 252, 729, 27, 13 ], [ 286, 729, 43, 13 ], [ 337, 729, 57, 13 ], [ 403, 729, 10, 13 ], [ 80, 744, 51, 13 ], [ 135, 744, 46, 13 ], [ 185, 744, 51, 13 ], [ 240, 744, 48, 13 ], [ 93, 759, 41, 13 ], [ 137, 759, 15, 13 ], [ 154, 759, 18, 13 ], [ 175, 759, 20, 13 ], [ 198, 759, 28, 13 ], [ 229, 759, 25, 13 ], [ 257, 759, 16, 13 ], [ 276, 759, 59, 13 ], [ 338, 759, 20, 13 ], [ 361, 759, 52, 13 ], [ 80, 773, 34, 13 ], [ 121, 773, 33, 13 ], [ 160, 773, 27, 13 ], [ 194, 773, 23, 13 ], [ 223, 773, 29, 13 ], [ 258, 773, 41, 13 ], [ 305, 773, 21, 13 ], [ 333, 773, 56, 13 ], [ 395, 773, 18, 13 ], [ 80, 788, 46, 13 ], [ 129, 788, 35, 13 ], [ 166, 788, 41, 13 ], [ 210, 788, 38, 13 ], [ 251, 788, 40, 13 ], [ 294, 788, 16, 13 ], [ 313, 788, 52, 13 ], [ 368, 788, 31, 13 ], [ 403, 788, 10, 13 ], [ 80, 802, 75, 13 ], [ 158, 802, 37, 13 ], [ 198, 802, 19, 13 ], [ 220, 802, 36, 13 ], [ 258, 802, 25, 13 ], [ 285, 802, 38, 13 ], [ 327, 802, 73, 13 ], [ 403, 802, 10, 13 ], [ 80, 817, 29, 13 ], [ 114, 817, 39, 13 ], [ 158, 817, 21, 13 ], [ 183, 817, 37, 13 ], [ 225, 817, 27, 13 ], [ 257, 817, 40, 13 ], [ 301, 817, 19, 13 ], [ 325, 817, 29, 13 ], [ 359, 817, 54, 13 ], [ 80, 831, 22, 13 ], [ 107, 831, 45, 13 ], [ 158, 831, 8, 13 ], [ 171, 831, 43, 13 ], [ 220, 831, 15, 13 ], [ 240, 831, 33, 13 ], [ 279, 831, 40, 13 ], [ 325, 831, 45, 13 ], [ 376, 831, 10, 13 ], [ 392, 831, 21, 13 ], [ 80, 846, 53, 13 ], [ 136, 846, 25, 13 ], [ 165, 846, 39, 13 ], [ 207, 846, 39, 13 ], [ 250, 846, 18, 13 ], [ 271, 846, 36, 13 ], [ 311, 846, 8, 13 ], [ 322, 846, 6, 13 ], [ 332, 846, 34, 13 ], [ 370, 846, 29, 13 ], [ 403, 846, 10, 13 ], [ 80, 860, 71, 13 ], [ 155, 860, 11, 13 ], [ 170, 860, 36, 13 ], [ 209, 860, 48, 13 ], [ 93, 875, 64, 13 ], [ 162, 875, 61, 13 ], [ 229, 875, 45, 13 ], [ 279, 875, 38, 13 ], [ 322, 875, 17, 13 ], [ 344, 875, 47, 13 ], [ 397, 875, 16, 13 ], [ 80, 890, 45, 13 ], [ 130, 890, 10, 13 ], [ 145, 890, 49, 13 ], [ 198, 890, 43, 13 ], [ 246, 890, 20, 13 ], [ 270, 890, 52, 13 ], [ 327, 890, 10, 13 ], [ 342, 890, 70, 13 ], [ 80, 904, 50, 13 ], [ 135, 904, 24, 13 ], [ 163, 904, 53, 13 ], [ 221, 904, 14, 13 ], [ 240, 904, 46, 13 ], [ 291, 904, 32, 13 ], [ 328, 904, 25, 13 ], [ 358, 904, 30, 13 ], [ 393, 904, 20, 13 ], [ 80, 919, 57, 13 ], [ 143, 919, 20, 13 ], [ 169, 919, 51, 13 ], [ 225, 919, 10, 13 ], [ 241, 919, 50, 13 ], [ 297, 919, 24, 13 ], [ 326, 919, 19, 13 ], [ 351, 919, 20, 13 ], [ 376, 919, 37, 13 ], [ 80, 933, 35, 13 ], [ 119, 933, 10, 13 ], [ 132, 933, 22, 13 ], [ 158, 933, 45, 13 ], [ 206, 933, 62, 13 ], [ 272, 933, 41, 13 ], [ 316, 933, 32, 13 ], [ 352, 933, 19, 13 ], [ 375, 933, 38, 13 ], [ 80, 948, 45, 13 ], [ 128, 948, 6, 13 ], [ 136, 948, 19, 13 ], [ 158, 948, 13, 13 ], [ 174, 948, 31, 13 ], [ 207, 948, 35, 13 ], [ 244, 948, 60, 13 ], [ 307, 948, 46, 13 ], [ 355, 948, 10, 13 ], [ 366, 948, 20, 13 ], [ 389, 948, 24, 13 ], [ 80, 962, 30, 13 ], [ 114, 962, 14, 13 ], [ 132, 962, 27, 13 ], [ 164, 962, 37, 13 ], [ 205, 962, 48, 13 ], [ 257, 962, 38, 13 ], [ 299, 962, 43, 13 ], [ 345, 962, 10, 13 ], [ 360, 962, 17, 13 ], [ 381, 962, 31, 13 ], [ 80, 977, 28, 13 ], [ 111, 977, 13, 13 ], [ 127, 977, 47, 13 ], [ 177, 977, 45, 13 ], [ 225, 977, 18, 13 ], [ 246, 977, 16, 13 ], [ 265, 977, 22, 13 ], [ 290, 977, 10, 13 ], [ 303, 977, 48, 13 ], [ 354, 977, 44, 13 ], [ 400, 977, 13, 13 ], [ 80, 992, 73, 13 ], [ 158, 992, 45, 13 ], [ 207, 992, 57, 13 ], [ 269, 992, 16, 13 ], [ 290, 992, 17, 13 ], [ 311, 992, 33, 13 ], [ 348, 992, 11, 13 ], [ 364, 992, 10, 13 ], [ 378, 992, 35, 13 ], [ 80, 1006, 40, 13 ], [ 123, 1006, 38, 13 ], [ 163, 1006, 43, 13 ], [ 209, 1006, 28, 13 ], [ 241, 1006, 27, 13 ], [ 271, 1006, 13, 13 ], [ 287, 1006, 45, 13 ], [ 335, 1006, 65, 13 ], [ 450, 433, 21, 13 ], [ 477, 433, 45, 13 ], [ 528, 433, 10, 13 ], [ 544, 433, 50, 13 ], [ 600, 433, 25, 13 ], [ 631, 433, 45, 13 ], [ 682, 433, 47, 13 ], [ 735, 433, 35, 13 ], [ 437, 448, 37, 13 ], [ 477, 448, 6, 13 ], [ 486, 448, 54, 13 ], [ 543, 448, 38, 13 ], [ 583, 448, 53, 13 ], [ 639, 448, 46, 13 ], [ 688, 448, 16, 13 ], [ 707, 448, 50, 13 ], [ 760, 448, 10, 13 ], [ 437, 462, 63, 13 ], [ 506, 462, 46, 13 ], [ 559, 462, 42, 13 ], [ 608, 462, 21, 13 ], [ 635, 462, 50, 13 ], [ 693, 462, 33, 13 ], [ 732, 462, 10, 13 ], [ 749, 462, 21, 13 ], [ 437, 477, 53, 13 ], [ 495, 477, 10, 13 ], [ 510, 477, 55, 13 ], [ 570, 477, 40, 13 ], [ 615, 477, 20, 13 ], [ 641, 477, 46, 13 ], [ 692, 477, 63, 13 ], [ 760, 477, 10, 13 ], [ 437, 492, 46, 13 ], [ 488, 492, 51, 13 ], [ 543, 492, 35, 13 ], [ 583, 492, 38, 13 ], [ 626, 492, 13, 13 ], [ 643, 492, 59, 13 ], [ 707, 492, 63, 13 ], [ 437, 507, 28, 13 ], [ 472, 507, 15, 13 ], [ 493, 507, 54, 13 ], [ 553, 507, 21, 13 ], [ 581, 507, 52, 13 ], [ 639, 507, 47, 13 ], [ 693, 507, 49, 13 ], [ 749, 507, 21, 13 ], [ 437, 522, 43, 13 ], [ 484, 522, 50, 13 ], [ 538, 522, 25, 13 ], [ 567, 522, 43, 13 ], [ 613, 522, 35, 13 ], [ 652, 522, 51, 13 ], [ 707, 522, 35, 13 ], [ 746, 522, 24, 13 ], [ 437, 536, 44, 13 ], [ 487, 536, 10, 13 ], [ 503, 536, 16, 13 ], [ 525, 536, 31, 13 ], [ 562, 536, 20, 13 ], [ 588, 536, 41, 13 ], [ 635, 536, 64, 13 ], [ 705, 536, 8, 13 ], [ 718, 536, 13, 13 ], [ 738, 536, 32, 13 ], [ 437, 551, 51, 13 ], [ 491, 551, 27, 13 ], [ 520, 551, 52, 13 ], [ 575, 551, 50, 13 ], [ 628, 551, 73, 13 ], [ 703, 551, 18, 13 ], [ 724, 551, 29, 13 ], [ 755, 551, 14, 13 ], [ 437, 566, 41, 13 ], [ 485, 566, 6, 13 ], [ 498, 566, 63, 13 ], [ 566, 566, 46, 13 ], [ 619, 566, 39, 13 ], [ 664, 566, 10, 13 ], [ 680, 566, 13, 13 ], [ 700, 566, 21, 13 ], [ 727, 566, 43, 13 ], [ 437, 581, 32, 13 ], [ 473, 581, 25, 13 ], [ 500, 581, 16, 13 ], [ 520, 581, 61, 13 ], [ 583, 581, 38, 13 ], [ 624, 581, 62, 13 ], [ 690, 581, 35, 13 ], [ 727, 581, 42, 13 ], [ 437, 596, 32, 13 ], [ 472, 596, 19, 13 ], [ 495, 596, 12, 13 ], [ 511, 596, 26, 13 ], [ 540, 596, 50, 13 ], [ 594, 596, 10, 13 ], [ 607, 596, 57, 13 ], [ 668, 596, 22, 13 ], [ 693, 596, 39, 13 ], [ 735, 596, 35, 13 ], [ 437, 610, 6, 13 ], [ 448, 610, 61, 13 ], [ 514, 610, 63, 13 ], [ 583, 610, 10, 13 ], [ 598, 610, 50, 13 ], [ 653, 610, 50, 13 ], [ 708, 610, 47, 13 ], [ 760, 610, 10, 13 ], [ 437, 625, 24, 13 ], [ 465, 625, 31, 13 ], [ 499, 625, 33, 13 ], [ 536, 625, 20, 13 ], [ 559, 625, 19, 13 ], [ 582, 625, 41, 13 ], [ 627, 625, 32, 13 ], [ 662, 625, 44, 13 ], [ 710, 625, 35, 13 ], [ 749, 625, 21, 13 ], [ 437, 640, 49, 13 ], [ 495, 640, 10, 13 ], [ 514, 640, 16, 13 ], [ 539, 640, 44, 13 ], [ 592, 640, 10, 13 ], [ 611, 640, 21, 13 ], [ 641, 640, 20, 13 ], [ 670, 640, 16, 13 ], [ 695, 640, 32, 13 ], [ 735, 640, 35, 13 ], [ 437, 655, 63, 13 ], [ 505, 655, 64, 13 ], [ 574, 655, 10, 13 ], [ 589, 655, 24, 13 ], [ 618, 655, 37, 13 ], [ 659, 655, 55, 13 ], [ 720, 655, 50, 13 ], [ 437, 670, 10, 13 ], [ 450, 670, 12, 13 ], [ 465, 670, 16, 13 ], [ 484, 670, 61, 13 ], [ 548, 670, 35, 13 ], [ 585, 670, 19, 13 ], [ 607, 670, 10, 13 ], [ 620, 670, 43, 13 ], [ 666, 670, 36, 13 ], [ 704, 670, 6, 13 ], [ 713, 670, 20, 13 ], [ 736, 670, 10, 13 ], [ 749, 670, 21, 13 ], [ 437, 685, 54, 13 ], [ 496, 685, 12, 13 ], [ 512, 685, 45, 13 ], [ 561, 685, 16, 13 ], [ 582, 685, 50, 13 ], [ 636, 685, 10, 13 ], [ 650, 685, 16, 13 ], [ 671, 685, 50, 13 ], [ 726, 685, 44, 13 ], [ 437, 699, 45, 13 ], [ 486, 699, 13, 13 ], [ 503, 699, 18, 13 ], [ 525, 699, 48, 13 ], [ 577, 699, 31, 13 ], [ 613, 699, 37, 13 ], [ 654, 699, 56, 13 ], [ 714, 699, 56, 13 ], [ 437, 714, 41, 13 ], [ 482, 714, 80, 13 ], [ 566, 714, 37, 13 ], [ 437, 745, 71, 16 ], [ 437, 767, 41, 15 ], [ 483, 767, 81, 15 ], [ 568, 767, 13, 15 ], [ 584, 767, 32, 15 ], [ 621, 767, 55, 15 ], [ 681, 767, 48, 15 ], [ 437, 784, 47, 13 ], [ 486, 784, 46, 13 ], [ 535, 784, 62, 13 ], [ 599, 784, 16, 13 ], [ 617, 784, 21, 13 ], [ 641, 784, 26, 13 ], [ 669, 784, 15, 13 ], [ 686, 784, 61, 13 ], [ 749, 784, 21, 13 ], [ 437, 799, 50, 13 ], [ 491, 799, 36, 13 ], [ 530, 799, 30, 13 ], [ 564, 799, 37, 13 ], [ 604, 799, 19, 13 ], [ 627, 799, 28, 13 ], [ 659, 799, 47, 13 ], [ 710, 799, 33, 13 ], [ 746, 799, 24, 13 ], [ 437, 842, 42, 10 ], [ 482, 842, 28, 10 ], [ 513, 842, 16, 10 ], [ 532, 842, 50, 10 ], [ 585, 842, 41, 10 ], [ 628, 842, 9, 10 ], [ 640, 842, 28, 10 ], [ 670, 842, 23, 10 ], [ 437, 864, 39, 10 ], [ 479, 864, 17, 10 ], [ 499, 864, 7, 10 ], [ 509, 864, 22, 10 ], [ 534, 864, 40, 10 ], [ 577, 864, 20, 10 ], [ 599, 864, 12, 10 ], [ 615, 864, 22, 10 ], [ 640, 864, 42, 10 ], [ 685, 864, 30, 10 ], [ 717, 864, 7, 10 ], [ 728, 864, 20, 10 ], [ 437, 886, 45, 10 ], [ 499, 886, 20, 10 ], [ 522, 886, 25, 10 ], [ 550, 886, 9, 10 ], [ 562, 886, 9, 10 ], [ 574, 886, 17, 10 ], [ 593, 886, 6, 10 ], [ 603, 886, 10, 10 ], [ 616, 886, 50, 10 ], [ 669, 886, 25, 10 ], [ 697, 886, 45, 10 ], [ 745, 886, 25, 10 ], [ 437, 897, 14, 10 ], [ 458, 897, 24, 10 ], [ 489, 897, 9, 10 ], [ 504, 897, 14, 10 ], [ 525, 897, 34, 10 ], [ 566, 897, 42, 10 ], [ 615, 897, 45, 10 ], [ 667, 897, 33, 10 ], [ 706, 897, 25, 10 ], [ 738, 897, 31, 10 ], [ 437, 909, 50, 10 ], [ 491, 909, 17, 10 ], [ 511, 909, 50, 10 ], [ 565, 909, 16, 10 ], [ 585, 909, 54, 10 ], [ 643, 909, 8, 10 ], [ 655, 909, 15, 10 ], [ 674, 909, 37, 10 ], [ 715, 909, 37, 10 ], [ 756, 909, 14, 10 ], [ 437, 920, 31, 10 ], [ 471, 920, 27, 10 ], [ 501, 920, 16, 10 ], [ 520, 920, 27, 10 ], [ 550, 920, 13, 10 ], [ 566, 920, 36, 10 ], [ 437, 942, 38, 10 ], [ 478, 942, 17, 10 ], [ 497, 942, 53, 10 ], [ 552, 942, 16, 10 ], [ 570, 942, 43, 10 ], [ 615, 942, 11, 10 ], [ 628, 942, 26, 10 ], [ 657, 942, 20, 10 ], [ 679, 942, 14, 10 ], [ 695, 942, 35, 10 ], [ 732, 942, 38, 10 ], [ 437, 953, 9, 10 ], [ 449, 953, 27, 10 ], [ 479, 953, 9, 10 ], [ 490, 953, 17, 10 ], [ 510, 953, 47, 10 ], [ 437, 975, 48, 10 ], [ 489, 975, 39, 10 ], [ 532, 975, 15, 10 ], [ 551, 975, 31, 10 ], [ 587, 975, 20, 10 ], [ 610, 975, 35, 10 ], [ 650, 975, 17, 10 ], [ 671, 975, 11, 10 ], [ 686, 975, 45, 10 ], [ 735, 975, 35, 10 ], [ 437, 986, 21, 10 ], [ 437, 1008, 5, 10 ], [ 445, 1008, 11, 10 ], [ 458, 1008, 27, 10 ], [ 487, 1008, 69, 10 ], [ 559, 1008, 29, 10 ], [ 590, 1008, 11, 10 ], [ 604, 1008, 46, 10 ], [ 653, 1008, 27, 10 ], [ 683, 1008, 87, 10 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 21, 12 ], [ 165, 1047, 3, 12 ], [ 174, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 626, 1047, 34, 12 ], [ 663, 1047, 23, 12 ], [ 691, 1047, 3, 12 ], [ 699, 1047, 24, 12 ], [ 728, 1047, 6, 12 ], [ 739, 1047, 3, 12 ], [ 747, 1047, 23, 12 ] ]

[ "Mammalian", "Comparative", "Sequence", "Analysis", "of", "the", "Agrp", "Locus", "Christopher", "B.", "Kaelin1,", "Gregory", "M.", "Cooper2,", "Arend", "Sidow1,3,", "Gregory", "S.", "Barsh1,4*", "1", "Department", "of", "Genetics,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America,", "2", "Department", "of", "Genome", "Sciences,", "University", "of", "Washington,", "Seattle,", "Washington,", "United", "States", "of", "America,", "3", "Department", "of", "Pathology,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America,", "4", "Department", "of", "Pediatrics,", "Stanford", "University,", "Stanford,", "California,", "United", "States", "of", "America", "Agouti-related", "protein", "encodes", "a", "neuropeptide", "that", "stimulates", "food", "intake.", "Agrp", "expression", "in", "the", "brain", "is", "restricted", "to", "neurons", "in", "the", "arcuate", "nucleus", "of", "the", "hypothalamus", "and", "is", "elevated", "by", "states", "of", "negative", "energy", "balance.", "The", "molecular", "mechanisms", "underlying", "Agrp", "regulation,", "however,", "remain", "poorly", "defined.", "Using", "a", "combination", "of", "transgenic", "and", "comparative", "sequence", "analysis,", "we", "have", "previously", "identified", "a", "760", "bp", "conserved", "region", "upstream", "of", "Agrp", "which", "contains", "STAT", "binding", "elements", "that", "participate", "in", "Agrp", "transcriptional", "regulation.", "In", "this", "study,", "we", "attempt", "to", "improve", "the", "specificity", "for", "detecting", "conserved", "elements", "in", "this", "region", "by", "comparing", "genomic", "sequences", "from", "10", "mammalian", "species.", "Our", "analysis", "reveals", "a", "symmetrical", "organization", "of", "conserved", "sequences", "upstream", "of", "Agrp,", "which", "cluster", "into", "two", "inverted", "repeat", "elements.", "Conserved", "sequences", "within", "these", "elements", "suggest", "a", "role", "for", "homeodomain", "proteins", "in", "the", "regulation", "of", "Agrp", "and", "provide", "additional", "targets", "for", "functional", "evaluation.", "Citation:", "Kaelin", "CB,", "Cooper", "GM,", "Sidow", "A,", "Barsh", "GS", "(2007)", "Mammalian", "Comparative", "Sequence", "Analysis", "of", "the", "Agrp", "Locus.", "PLoS", "ONE", "2(8):", "e702.", "doi:10.1371/journal.pone.0000702", "INTRODUCTION", "AGRP", "is", "an", "orexigenic,", "hypothalamic", "peptide", "whose", "role", "in", "energy", "homeostasis", "has", "been", "conserved", "during", "vertebrate", "evolution.", "In", "a", "wide", "range", "of", "species,", "including", "mammals", "[1,2],", "birds", "[3,4],", "and", "fish", "[5],", "neuronal", "Agrp", "expression", "is", "restricted", "to", "a", "discrete", "population", "of", "neurons", "that", "sense", "the", "levels", "of", "peripheral", "energy", "stores,", "and", "is", "dramatically", "elevated", "by", "deficits", "in", "energy", "balance.", "AGRP", "neurons", "directly", "receive", "information", "about", "energy", "stores", "from", "leptin,", "an", "adipocyte-derived", "hormone", "that", "circulates", "at", "levels", "proportional", "to", "fat", "mass.", "Diminished", "levels", "of", "circulating", "leptin", "correspond", "to", "increased", "Agrp", "mRNA", "levels", "[6].", "Leptin", "receptor", "occupancy", "on", "AGRP", "neurons", "results", "in", "the", "phosphorylation", "of", "two", "transcription", "factors,", "FoxO1", "[7]", "and", "STAT3", "[8],", "inducing", "the", "cytoplasmic", "localization", "of", "FoxO1", "and", "the", "nuclear", "localization", "of", "STAT3.", "A", "recent", "study", "by", "Kitamura", "and", "colleagues", "[7]", "implicates", "a", "direct,", "reciprocal", "role", "for", "both", "STAT3", "and", "FoxO1", "in", "Agrp", "regulation,", "where", "STAT3", "represses", "and", "FoxO1", "stimulates", "Agrp", "transcription.", "However,", "conserved", "STAT", "binding", "sites", "in", "the", "Agrp", "promoter", "region", "do", "not", "function", "as", "simple", "repressor", "elements", "and,", "paradoxically,", "are", "required", "for", "fasting", "induced", "stimulation", "of", "Agrp", "transcription", "[9],", "suggesting", "a", "more", "complex", "mechanism", "of", "regulation", "involving", "additional", "cofactors.", "Support", "for", "this", "also", "stems", "from", "the", "observation", "that", "peripheral", "energy", "signals", "other", "than", "leptin", "regulate", "Agrp", "expression.", "For", "example,", "AGRP", "neurons", "directly", "mediate", "the", "orexigenic", "effects", "of", "glucocorticoids", "[10,11]", "and", "ghrelin", "[12].", "Central", "administration", "of", "either", "elevates", "Agrp", "mRNA", "levels", "[13,14],", "and", "intact", "glucocorti-", "coid", "signaling", "is", "required", "for", "fasting", "induced", "increases", "in", "Agrp", "expression", "[14].", "Neither", "STAT3", "nor", "FoxO1", "is", "a", "known", "target", "of", "glucocorticoid", "or", "ghrelin", "signaling.", "Cross-species", "comparative", "sequence", "analysis", "has", "facilitated", "the", "detection", "of", "functional", "elements", "that", "participate", "in", "transcriptional", "regulation", "[15].", "Previously,", "we", "identified", "mouse", "BAC", "clones", "that", "recapitulate", "Agrp", "expression", "in", "transgenic", "mice", "and", "that", "contain", "regions", "of", "high", "sequence", "conservation", "between", "mouse", "and", "human,", "including", "a", "760", "bp", "region", "located", "immediately", "upstream", "of", "Agrp", "[16].", "While", "we", "could", "identify", "candidate", "binding", "elements", "in", "this", "region", "based", "on", "biological", "inference", "[9],", "the", "level", "of", "resolution", "provided", "by", "mouse/human", "sequence", "comparison", "did", "not", "permit", "us", "to", "predict", "putative", "binding", "elements", "based", "solely", "on", "sequence", "conservation.", "The", "inclusion", "of", "sequences", "from", "multiple,", "divergent", "species", "sharing", "a", "commonly", "derived", "phenotype", "improves", "the", "resolution", "of", "comparative", "sequence", "analysis.", "The", "conserved", "nature", "of", "Agrp", "expression", "in", "vertebrates", "suggests", "that", "sequence", "comparisons", "of", "disparate", "vertebrate", "species", "provide", "an", "appropriate", "evolutionary", "scope", "for", "identifying", "Agrp", "regulatory", "elements.", "However,", "Agrp", "genomic", "sequences", "from", "distantly", "related", "vertebrate", "species", "have", "diverged", "to", "the", "extent", "that", "regional", "conservation", "is", "no", "longer", "detectable", "using", "traditional", "alignment", "methodologies", "[9].", "Here,", "we", "describe", "a", "comparative", "sequence", "analysis", "of", "an", "Agrp", "genomic", "region", "from", "ten", "mammalian", "species,", "representing", "several", "different", "orders", "and", "all", "three", "subclasses", "of", "mammalia.", "Our", "analysis", "reveals", "a", "symmetrical", "organization", "of", "conserved", "sequences", "upstream", "of", "Agrp,", "which", "cluster", "into", "two", "inverted", "repeat", "elements", "(IREs).", "The", "proximity", "of", "the", "elements", "to", "Agrp", "and", "the", "nearly", "perfect", "evolutionary", "conservation", "of", "their", "specific", "constituent", "sequences", "in", "all", "ten", "mammalian", "species", "and", "in", "chickens", "suggest", "a", "role", "in", "Agrp", "regulation.", "In", "addition,", "the", "resolution", "of", "the", "conserved", "elements", "provided", "by", "this", "approach", "allows", "general", "predictions", "concerning", "putative", "trans-regulatory", "factors.", "METHODS", "Matrix", "comparisons", "of", "Agrp", "genomic", "regions", "Genomic", "sequence", "surrounding", "the", "Agrp", "locus", "for", "chimpanzee", "(Pan", "troglodytes),", "human", "(Homo", "sapiens),", "dog", "(Canis", "familiaris),", "mouse", "(Mus", "Academic", "Editor:", "Luis", "Corrochano,", "University", "of", "Sevilla,", "Spain", "Received", "May", "3,", "2007;", "Accepted", "June", "29,", "2007;", "Published", "August", "8,", "2007", "Copyright:", "2007", "Kaelin", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "investigation", "was", "supported", "by", "grants", "from", "the", "National", "Institutes", "of", "Health", "to", "GSB", "(DK-48506).", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "gbarsh@stanford.edu", "PLoS", "ONE", "|", "www.plosone.org", "1", "August", "2007", "|", "Issue", "8", "|", "e702" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 13, 13, 13, 13, 13, 13, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 9, 12 ], [ 90, 47, 9, 12 ], [ 102, 47, 11, 12 ], [ 116, 47, 21, 12 ], [ 140, 47, 31, 12 ], [ 175, 47, 25, 12 ], [ 203, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 129, 34 ], [ 217, 169, 119, 34 ], [ 347, 169, 28, 34 ], [ 385, 169, 158, 34 ], [ 552, 169, 167, 34 ], [ 78, 205, 192, 34 ], [ 281, 205, 63, 34 ], [ 354, 205, 45, 34 ], [ 410, 205, 63, 34 ], [ 483, 205, 70, 34 ], [ 563, 205, 90, 34 ], [ 78, 241, 118, 34 ], [ 206, 241, 25, 34 ], [ 242, 241, 106, 34 ], [ 358, 241, 58, 34 ], [ 427, 241, 137, 34 ], [ 574, 241, 82, 34 ], [ 78, 277, 87, 34 ], [ 175, 277, 58, 34 ], [ 244, 277, 192, 34 ], [ 446, 277, 144, 34 ], [ 78, 324, 37, 16 ], [ 120, 324, 31, 16 ], [ 155, 321, 18, 19 ], [ 178, 324, 16, 16 ], [ 198, 324, 28, 16 ], [ 230, 321, 36, 19 ], [ 270, 324, 9, 16 ], [ 283, 324, 22, 16 ], [ 310, 321, 37, 19 ], [ 351, 324, 17, 16 ], [ 373, 324, 46, 16 ], [ 424, 321, 29, 19 ], [ 457, 324, 29, 16 ], [ 491, 324, 33, 16 ], [ 528, 321, 16, 19 ], [ 548, 324, 31, 16 ], [ 583, 324, 28, 16 ], [ 616, 321, 28, 19 ], [ 649, 324, 45, 16 ], [ 698, 324, 16, 16 ], [ 718, 321, 30, 19 ], [ 78, 343, 41, 16 ], [ 124, 343, 23, 16 ], [ 151, 340, 46, 19 ], [ 202, 343, 22, 16 ], [ 228, 343, 19, 16 ], [ 252, 340, 32, 19 ], [ 288, 343, 22, 16 ], [ 315, 343, 31, 16 ], [ 350, 340, 32, 19 ], [ 386, 343, 31, 16 ], [ 421, 343, 13, 16 ], [ 439, 340, 35, 19 ], [ 478, 343, 30, 16 ], [ 512, 343, 23, 16 ], [ 540, 340, 32, 19 ], [ 576, 343, 78, 16 ], [ 658, 340, 20, 19 ], [ 87, 397, 54, 15 ], [ 87, 423, 76, 14 ], [ 167, 423, 18, 14 ], [ 190, 423, 49, 14 ], [ 243, 423, 19, 14 ], [ 266, 423, 55, 14 ], [ 325, 423, 12, 14 ], [ 341, 423, 20, 14 ], [ 365, 423, 20, 14 ], [ 390, 423, 55, 14 ], [ 449, 423, 21, 14 ], [ 475, 423, 38, 14 ], [ 517, 423, 56, 14 ], [ 576, 423, 11, 14 ], [ 592, 423, 57, 14 ], [ 654, 423, 34, 14 ], [ 692, 423, 37, 14 ], [ 87, 439, 45, 14 ], [ 136, 439, 40, 14 ], [ 180, 439, 25, 14 ], [ 209, 439, 49, 14 ], [ 262, 439, 176, 14 ], [ 443, 439, 24, 14 ], [ 470, 439, 55, 14 ], [ 530, 439, 12, 14 ], [ 546, 439, 55, 14 ], [ 605, 439, 37, 14 ], [ 646, 439, 47, 14 ], [ 87, 460, 56, 14 ], [ 147, 460, 9, 14 ], [ 160, 460, 72, 14 ], [ 236, 460, 42, 14 ], [ 282, 460, 22, 14 ], [ 308, 460, 59, 14 ], [ 371, 460, 15, 14 ], [ 391, 460, 20, 14 ], [ 415, 460, 57, 14 ], [ 477, 460, 34, 14 ], [ 515, 460, 37, 14 ], [ 556, 460, 45, 14 ], [ 604, 460, 46, 14 ], [ 654, 460, 15, 14 ], [ 674, 460, 19, 14 ], [ 696, 460, 27, 14 ], [ 728, 460, 11, 14 ], [ 87, 476, 49, 14 ], [ 140, 476, 16, 14 ], [ 161, 476, 55, 14 ], [ 220, 476, 21, 14 ], [ 246, 476, 19, 14 ], [ 269, 476, 58, 14 ], [ 330, 476, 11, 14 ], [ 346, 476, 124, 14 ], [ 474, 476, 25, 14 ], [ 503, 476, 16, 14 ], [ 523, 476, 49, 14 ], [ 576, 476, 47, 14 ], [ 627, 476, 23, 14 ], [ 655, 476, 75, 14 ], [ 87, 493, 47, 14 ], [ 138, 493, 24, 14 ], [ 166, 493, 22, 14 ], [ 192, 493, 40, 14 ], [ 236, 493, 56, 14 ], [ 296, 493, 41, 14 ], [ 341, 493, 32, 14 ], [ 377, 493, 58, 14 ], [ 439, 493, 66, 14 ], [ 510, 493, 35, 14 ], [ 87, 514, 46, 14 ], [ 137, 514, 13, 14 ], [ 155, 514, 19, 14 ], [ 178, 514, 20, 14 ], [ 202, 514, 45, 14 ], [ 251, 514, 51, 14 ], [ 306, 514, 14, 14 ], [ 324, 514, 40, 14 ], [ 368, 514, 28, 14 ], [ 400, 514, 52, 14 ], [ 456, 514, 47, 14 ], [ 507, 514, 43, 14 ], [ 555, 514, 34, 14 ], [ 593, 514, 14, 14 ], [ 611, 514, 40, 14 ], [ 655, 514, 28, 14 ], [ 687, 514, 40, 14 ], [ 87, 530, 21, 14 ], [ 113, 530, 14, 14 ], [ 131, 530, 40, 14 ], [ 175, 530, 28, 14 ], [ 207, 530, 29, 14 ], [ 240, 530, 48, 14 ], [ 292, 530, 25, 14 ], [ 321, 530, 32, 14 ], [ 357, 530, 28, 14 ], [ 389, 530, 15, 14 ], [ 408, 530, 61, 14 ], [ 473, 530, 11, 14 ], [ 488, 530, 23, 14 ], [ 515, 530, 30, 14 ], [ 549, 530, 11, 14 ], [ 564, 530, 55, 14 ], [ 623, 530, 25, 14 ], [ 652, 530, 45, 14 ], [ 701, 530, 11, 14 ], [ 87, 547, 33, 14 ], [ 125, 547, 11, 14 ], [ 140, 547, 49, 14 ], [ 193, 547, 83, 14 ], [ 281, 547, 54, 14 ], [ 339, 547, 11, 14 ], [ 355, 547, 40, 14 ], [ 399, 547, 60, 14 ], [ 463, 547, 22, 14 ], [ 489, 547, 57, 14 ], [ 550, 547, 24, 14 ], [ 579, 547, 25, 14 ], [ 608, 547, 19, 14 ], [ 630, 547, 55, 14 ], [ 690, 547, 11, 14 ], [ 705, 547, 23, 14 ], [ 87, 564, 40, 14 ], [ 132, 564, 34, 14 ], [ 170, 564, 37, 14 ], [ 211, 564, 52, 14 ], [ 267, 564, 21, 14 ], [ 292, 564, 37, 14 ], [ 333, 564, 50, 14 ], [ 387, 564, 27, 14 ], [ 418, 564, 12, 14 ], [ 434, 564, 16, 14 ], [ 455, 564, 28, 14 ], [ 486, 564, 33, 14 ], [ 523, 564, 15, 14 ], [ 543, 564, 19, 14 ], [ 566, 564, 24, 14 ], [ 594, 564, 56, 14 ], [ 655, 564, 33, 14 ], [ 692, 564, 15, 14 ], [ 711, 564, 19, 14 ], [ 87, 580, 37, 14 ], [ 129, 580, 56, 14 ], [ 189, 580, 21, 14 ], [ 215, 580, 33, 14 ], [ 252, 580, 15, 14 ], [ 271, 580, 19, 14 ], [ 294, 580, 16, 14 ], [ 314, 580, 56, 14 ], [ 374, 580, 21, 14 ], [ 399, 580, 90, 14 ], [ 494, 580, 41, 14 ], [ 539, 580, 27, 14 ], [ 570, 580, 11, 14 ], [ 585, 580, 45, 14 ], [ 634, 580, 25, 14 ], [ 663, 580, 37, 14 ], [ 705, 580, 21, 14 ], [ 87, 597, 15, 14 ], [ 107, 597, 28, 14 ], [ 139, 597, 65, 14 ], [ 209, 597, 39, 14 ], [ 252, 597, 25, 14 ], [ 282, 597, 11, 14 ], [ 296, 597, 19, 14 ], [ 319, 597, 24, 14 ], [ 348, 597, 46, 14 ], [ 398, 597, 23, 14 ], [ 424, 597, 16, 14 ], [ 444, 597, 11, 14 ], [ 460, 597, 16, 14 ], [ 480, 597, 11, 14 ], [ 495, 597, 23, 14 ], [ 522, 597, 45, 14 ], [ 571, 597, 68, 14 ], [ 643, 597, 8, 14 ], [ 655, 597, 9, 14 ], [ 668, 597, 42, 14 ], [ 714, 597, 21, 14 ], [ 87, 614, 37, 14 ], [ 128, 614, 41, 14 ], [ 173, 614, 23, 14 ], [ 201, 614, 22, 14 ], [ 226, 614, 23, 14 ], [ 253, 614, 43, 14 ], [ 300, 614, 11, 14 ], [ 315, 614, 19, 14 ], [ 338, 614, 16, 14 ], [ 358, 614, 54, 14 ], [ 416, 614, 22, 14 ], [ 441, 614, 23, 14 ], [ 468, 614, 43, 14 ], [ 515, 614, 11, 14 ], [ 530, 614, 37, 14 ], [ 572, 614, 56, 14 ], [ 632, 614, 21, 14 ], [ 657, 614, 42, 14 ], [ 703, 614, 16, 14 ], [ 724, 614, 16, 14 ], [ 87, 630, 30, 14 ], [ 122, 630, 22, 14 ], [ 148, 630, 39, 14 ], [ 191, 630, 22, 14 ], [ 217, 630, 65, 14 ], [ 287, 630, 39, 14 ], [ 330, 630, 26, 14 ], [ 360, 630, 15, 14 ], [ 379, 630, 44, 14 ], [ 428, 630, 11, 14 ], [ 443, 630, 19, 14 ], [ 466, 630, 24, 14 ], [ 494, 630, 54, 14 ], [ 552, 630, 48, 14 ], [ 605, 630, 23, 14 ], [ 631, 630, 45, 14 ], [ 681, 630, 24, 14 ], [ 709, 630, 13, 14 ], [ 87, 647, 49, 14 ], [ 140, 647, 45, 14 ], [ 190, 647, 8, 14 ], [ 202, 647, 9, 14 ], [ 215, 647, 42, 14 ], [ 87, 667, 75, 14 ], [ 167, 668, 21, 14 ], [ 192, 668, 50, 14 ], [ 246, 668, 12, 14 ], [ 262, 668, 49, 14 ], [ 315, 668, 16, 14 ], [ 336, 668, 81, 14 ], [ 421, 668, 18, 14 ], [ 444, 668, 19, 14 ], [ 467, 668, 29, 14 ], [ 500, 668, 40, 14 ], [ 545, 668, 34, 14 ], [ 583, 668, 37, 14 ], [ 624, 668, 52, 14 ], [ 680, 668, 42, 14 ], [ 87, 684, 92, 14 ], [ 184, 684, 15, 14 ], [ 204, 684, 49, 14 ], [ 257, 684, 19, 14 ], [ 280, 684, 19, 14 ], [ 302, 684, 16, 14 ], [ 322, 684, 45, 14 ], [ 371, 684, 19, 14 ], [ 394, 684, 7, 14 ], [ 405, 684, 39, 14 ], [ 448, 684, 37, 14 ], [ 489, 684, 41, 14 ], [ 535, 684, 26, 14 ], [ 564, 684, 42, 14 ], [ 610, 684, 52, 14 ], [ 666, 684, 58, 14 ], [ 87, 701, 55, 14 ], [ 147, 701, 53, 14 ], [ 204, 701, 38, 14 ], [ 246, 701, 15, 14 ], [ 264, 701, 59, 14 ], [ 328, 701, 12, 14 ], [ 344, 701, 26, 14 ], [ 374, 701, 19, 14 ], [ 397, 701, 37, 14 ], [ 438, 701, 11, 14 ], [ 453, 701, 43, 14 ], [ 78, 747, 77, 15 ], [ 78, 764, 37, 14 ], [ 121, 764, 40, 14 ], [ 165, 764, 78, 14 ], [ 248, 764, 7, 14 ], [ 259, 764, 87, 14 ], [ 351, 764, 35, 14 ], [ 392, 764, 12, 14 ], [ 78, 780, 47, 14 ], [ 129, 780, 11, 14 ], [ 145, 780, 19, 14 ], [ 168, 780, 58, 14 ], [ 231, 780, 27, 14 ], [ 262, 780, 32, 14 ], [ 298, 780, 22, 14 ], [ 324, 780, 20, 14 ], [ 349, 780, 14, 14 ], [ 367, 780, 36, 14 ], [ 78, 797, 22, 14 ], [ 105, 797, 24, 14 ], [ 133, 797, 11, 14 ], [ 149, 797, 27, 14 ], [ 180, 797, 21, 14 ], [ 206, 797, 44, 14 ], [ 255, 797, 51, 14 ], [ 310, 797, 14, 14 ], [ 328, 797, 27, 14 ], [ 360, 797, 43, 14 ], [ 78, 814, 24, 14 ], [ 107, 814, 53, 14 ], [ 164, 814, 44, 14 ], [ 212, 814, 13, 14 ], [ 230, 814, 44, 14 ], [ 278, 814, 12, 14 ], [ 294, 814, 42, 14 ], [ 340, 814, 64, 14 ], [ 78, 830, 42, 14 ], [ 125, 830, 21, 14 ], [ 150, 830, 28, 14 ], [ 183, 830, 20, 14 ], [ 207, 830, 38, 14 ], [ 249, 830, 30, 14 ], [ 283, 830, 45, 14 ], [ 332, 830, 41, 14 ], [ 377, 830, 26, 14 ], [ 78, 847, 26, 14 ], [ 109, 847, 30, 14 ], [ 144, 847, 21, 14 ], [ 169, 847, 13, 14 ], [ 187, 847, 15, 14 ], [ 206, 847, 62, 14 ], [ 273, 847, 12, 14 ], [ 289, 847, 34, 14 ], [ 328, 847, 22, 14 ], [ 354, 847, 50, 14 ], [ 78, 863, 48, 14 ], [ 131, 863, 28, 14 ], [ 163, 863, 21, 14 ], [ 189, 863, 25, 14 ], [ 219, 863, 61, 14 ], [ 284, 863, 12, 14 ], [ 300, 863, 32, 14 ], [ 336, 863, 67, 14 ], [ 78, 880, 15, 14 ], [ 99, 880, 12, 14 ], [ 116, 880, 30, 14 ], [ 151, 880, 56, 14 ], [ 213, 880, 27, 14 ], [ 245, 880, 69, 14 ], [ 319, 880, 36, 14 ], [ 360, 880, 43, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 56, 11 ], [ 78, 923, 37, 13 ], [ 118, 925, 9, 11 ], [ 130, 925, 97, 11 ], [ 229, 925, 51, 11 ], [ 283, 925, 9, 11 ], [ 295, 925, 40, 11 ], [ 338, 925, 39, 11 ], [ 78, 937, 33, 11 ], [ 114, 937, 30, 11 ], [ 146, 937, 64, 11 ], [ 213, 937, 41, 11 ], [ 257, 937, 28, 11 ], [ 289, 937, 9, 11 ], [ 300, 937, 40, 11 ], [ 343, 937, 10, 11 ], [ 357, 937, 27, 11 ], [ 78, 950, 23, 11 ], [ 104, 950, 57, 11 ], [ 164, 950, 23, 11 ], [ 190, 950, 33, 11 ], [ 227, 950, 24, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 16, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 747, 25, 14 ], [ 452, 747, 32, 14 ], [ 490, 747, 43, 14 ], [ 538, 747, 22, 14 ], [ 565, 747, 48, 14 ], [ 618, 747, 61, 14 ], [ 684, 747, 27, 14 ], [ 715, 747, 33, 14 ], [ 423, 764, 47, 14 ], [ 474, 764, 35, 14 ], [ 514, 764, 43, 14 ], [ 561, 764, 51, 14 ], [ 617, 764, 23, 14 ], [ 644, 764, 23, 14 ], [ 671, 764, 61, 14 ], [ 736, 764, 12, 14 ], [ 423, 780, 20, 14 ], [ 447, 780, 75, 14 ], [ 526, 780, 48, 14 ], [ 578, 780, 32, 14 ], [ 614, 780, 21, 14 ], [ 640, 780, 34, 14 ], [ 678, 780, 31, 14 ], [ 714, 780, 34, 14 ], [ 423, 797, 9, 14 ], [ 436, 797, 58, 14 ], [ 499, 797, 50, 14 ], [ 553, 797, 23, 14 ], [ 580, 797, 35, 14 ], [ 619, 797, 38, 14 ], [ 661, 797, 57, 14 ], [ 723, 797, 25, 14 ], [ 423, 814, 32, 14 ], [ 459, 814, 33, 14 ], [ 498, 814, 12, 14 ], [ 515, 814, 29, 14 ], [ 549, 814, 59, 14 ], [ 614, 814, 12, 14 ], [ 631, 814, 70, 14 ], [ 706, 814, 42, 14 ], [ 423, 830, 38, 14 ], [ 465, 830, 10, 14 ], [ 479, 830, 64, 14 ], [ 548, 830, 7, 14 ], [ 559, 830, 53, 14 ], [ 617, 830, 45, 14 ], [ 667, 830, 46, 14 ], [ 717, 830, 12, 14 ], [ 734, 830, 14, 14 ], [ 423, 847, 52, 14 ], [ 481, 847, 50, 14 ], [ 538, 847, 44, 14 ], [ 588, 847, 24, 14 ], [ 618, 847, 40, 14 ], [ 664, 847, 84, 14 ], [ 423, 863, 36, 14 ], [ 463, 863, 85, 14 ], [ 552, 863, 21, 14 ], [ 577, 863, 57, 14 ], [ 639, 863, 44, 14 ], [ 687, 863, 12, 14 ], [ 703, 863, 45, 14 ], [ 423, 880, 26, 14 ], [ 456, 880, 32, 14 ], [ 495, 880, 15, 14 ], [ 518, 880, 21, 14 ], [ 546, 880, 43, 14 ], [ 596, 880, 30, 14 ], [ 633, 880, 51, 14 ], [ 691, 880, 57, 14 ], [ 423, 897, 46, 14 ], [ 474, 897, 47, 14 ], [ 525, 897, 31, 14 ], [ 561, 897, 9, 14 ], [ 575, 897, 66, 14 ], [ 646, 897, 25, 14 ], [ 676, 897, 15, 14 ], [ 696, 897, 35, 14 ], [ 736, 897, 12, 14 ], [ 423, 913, 25, 14 ], [ 452, 913, 56, 14 ], [ 513, 913, 54, 14 ], [ 571, 913, 15, 14 ], [ 591, 913, 43, 14 ], [ 638, 913, 49, 14 ], [ 691, 913, 56, 14 ], [ 423, 930, 45, 14 ], [ 472, 930, 9, 14 ], [ 486, 930, 53, 14 ], [ 543, 930, 83, 14 ], [ 631, 930, 17, 14 ], [ 652, 930, 18, 14 ], [ 675, 930, 57, 14 ], [ 736, 930, 12, 14 ], [ 423, 946, 40, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 7, 10 ], [ 288, 987, 8, 10 ], [ 298, 987, 8, 10 ], [ 309, 987, 30, 10 ], [ 342, 987, 29, 10 ], [ 374, 987, 27, 10 ], [ 403, 987, 14, 10 ], [ 420, 987, 15, 10 ], [ 438, 987, 6, 10 ], [ 447, 987, 10, 10 ], [ 459, 987, 21, 10 ], [ 483, 987, 25, 10 ], [ 511, 987, 23, 10 ], [ 536, 987, 41, 10 ], [ 580, 987, 23, 10 ], [ 605, 987, 13, 10 ], [ 621, 987, 21, 10 ], [ 645, 987, 8, 10 ], [ 656, 987, 13, 10 ], [ 671, 987, 31, 10 ], [ 705, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Yi", "et", "al.", "BMC", "Cancer", "2010,", "10:527", "http://www.biomedcentral.com/1471-2407/10/527", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Favorable", "response", "to", "doxorubicin", "combination", "chemotherapy", "does", "not", "yield", "good", "clinical", "outcome", "in", "patients", "with", "metastatic", "breast", "cancer", "with", "triple-negative", "phenotype", "Seong", "Yoon", "Yi1,", "Jin", "Seok", "Ahn1*,", "Ji", "Eun", "Uhm1,", "Do", "Hyoung", "Lim1,", "Sang", "Hoon", "Ji1,", "Hyun", "Jung", "Jun1,", "Kyoung", "Ha", "Kim1,", "Myung", "Hee", "Chang1,", "Min", "Jae", "Park1,", "Eun", "Yoon", "Cho2,", "Yoon", "La", "Choi2,", "Yeon", "Hee", "Park1,", "Young-Hyuck", "Im1", "Abstract", "Background:", "We", "analyzed", "the", "responses", "to", "first", "line", "treatment", "and", "clinical", "outcomes", "of", "metastatic", "breast", "cancer", "patients", "treated", "with", "palliative", "doxorubicin/cyclophosphamide", "(AC)", "according", "to", "molecular", "cancer", "subtype.", "Methods:", "A", "retrospective", "analysis", "was", "performed", "for", "110", "metastatic", "breast", "cancer", "patients", "selected", "on", "the", "basis", "of", "palliative", "AC", "treatment", "and", "the", "availability", "of", "immunohistochemical", "data", "for", "estrogen", "receptor", "(ER),", "progesterone", "receptor", "(PR),", "and", "human", "epidermal", "growth", "factor", "receptor-2", "(HER-2/neu)", "status.", "Results:", "Of", "the", "110", "patients", "analyzed,", "71", "(64.5%)", "were", "hormone", "receptor", "positive", "(HR+),", "14", "(12.7%)", "were", "HER2+,", "and", "25", "(22.7%)", "were", "triple", "negative", "(TN).", "There", "were", "no", "differences", "in", "age,", "stage", "at", "diagnosis,", "total", "number", "of", "cycles", "of", "palliative", "chemotherapy,", "incidence", "of", "visceral", "metastasis,", "and", "metastatic", "sites", "with", "the", "exception", "of", "liver", "among", "breast", "cancer", "subtypes.", "The", "overall", "response", "rates", "to", "AC", "were", "55.9%", "for", "the", "HR+", "subgroup,", "42.9%", "for", "the", "HER2+", "subgroup,", "and", "56.5%", "for", "the", "TN", "subgroup.", "The", "progression-free", "survival", "(PFS)", "in", "patients", "with", "HER2+", "and", "TN", "were", "significantly", "shorter", "than", "in", "the", "HR+", "(median", "PFS,", "9.1", "vs", "8.1", "vs", "11.5", "months,", "respectively;", "p", "=", "0.0002).", "The", "overall", "survival", "(OS)", "was", "25.4", "months", "in", "the", "TN", "subgroup", "and", "27.3", "months", "in", "HER2+", "subgroup.", "The", "median", "OS", "for", "these", "two", "groups", "was", "significantly", "shorter", "than", "for", "patients", "in", "the", "HR+", "subgroup", "(median,", "38.5", "months;", "95%", "CI,", "30.1-46.9", "months;", "p", "<", "0.0001).", "Conclusions:", "The", "response", "to", "palliative", "AC", "chemotherapy", "did", "not", "differ", "among", "breast", "cancer", "subtypes.", "Despite", "chemosensitivity", "for", "palliative", "AC,", "the", "TN", "subtype", "has", "a", "shorter", "overall", "survival", "than", "non-TN", "subtypes.", "Innovative", "treatment", "strategies", "should", "be", "developed", "to", "slow", "the", "course", "of", "disease.", "Background", "Breast", "cancer", "encompasses", "a", "heterogeneous", "group", "of", "diseases", "at", "the", "molecular", "level", "[1-4],", "and", "can", "be", "classi-", "fied", "into", "at", "least", "five", "distinct", "subtypes", "by", "gene", "expres-", "sion", "profiling:", "luminal", "A,", "luminal", "B,", "normal", "breast-like,", "ERBB2,", "and", "basal", "like", "[5-10].", "Basal", "cell-like", "tumors", "typi-", "cally", "show", "low", "or", "no", "expression", "of", "HER2", "and", "estrogen", "receptor", "(ER),", "and", "high", "expression", "of", "genes", "characteris-", "tic", "of", "basal", "epithelial", "cells", "[1,4,11-13].", "These", "tumors", "*", "Correspondence:", "ajis@skku.edu", "1Division", "of", "Hematology-Oncology,", "Department", "of", "Medicine,", "Samsung", "Medical", "Center,", "Sungkyunkwan", "University", "School", "of", "Medicine,", "50", "Irwon-", "dong", "Gangnam-gu,", "Seoul", "135-710", "Korea", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "may", "share", "clinical", "and", "biologic", "properties", "with", "triple", "negative", "breast", "cancers", "(TNBCs)", "that", "lack", "expression", "of", "ER,", "progesterone", "receptor", "(PgR)", "and", "HER2", "[5-8].", "There", "is", "increasing", "evidence", "that", "breast", "cancer", "molecular", "sub-", "types", "differ", "in", "their", "responses", "to", "therapeutic", "agents.", "TNBC", "is", "considered", "a", "high-risk", "subtype", "because", "of", "its", "typically", "younger", "patient", "age,", "poorly", "differentiated", "tumor", "characteristics,", "and", "shortened", "survival", "of", "patients", "who", "often", "do", "not", "benefit", "from", "targeted", "therapies", "[11-19].", "Because", "there", "is", "insufficient", "data", "on", "which", "to", "base", "treatment", "selection,", "no", "specific", "systemic", "treatment", "strategy", "is", "currently", "recommended", "for", "the", "treatment", "of", "TNBC.", "©", "2010", "Yi", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 76, 47, 84, 34 ], [ 172, 47, 139, 34 ], [ 76, 118, 70, 20 ], [ 151, 118, 46, 20 ], [ 76, 143, 18, 23 ], [ 100, 143, 97, 23 ], [ 202, 143, 19, 23 ], [ 227, 143, 35, 23 ], [ 268, 143, 208, 23 ], [ 481, 143, 77, 23 ], [ 564, 143, 75, 23 ], [ 644, 143, 67, 23 ], [ 76, 168, 89, 23 ], [ 171, 168, 101, 23 ], [ 278, 168, 30, 23 ], [ 313, 168, 99, 23 ], [ 418, 168, 138, 23 ], [ 562, 168, 39, 23 ], [ 607, 168, 20, 23 ], [ 76, 193, 163, 23 ], [ 245, 193, 102, 23 ], [ 76, 218, 40, 21 ], [ 121, 218, 71, 21 ], [ 196, 218, 35, 21 ], [ 236, 218, 71, 21 ], [ 312, 218, 11, 21 ], [ 327, 218, 91, 21 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 268, 41, 12 ], [ 119, 268, 27, 12 ], [ 149, 268, 10, 12 ], [ 162, 268, 63, 12 ], [ 227, 268, 8, 12 ], [ 238, 268, 55, 12 ], [ 295, 268, 50, 12 ], [ 347, 268, 10, 12 ], [ 360, 268, 52, 12 ], [ 414, 268, 18, 12 ], [ 434, 268, 48, 12 ], [ 485, 268, 19, 12 ], [ 506, 268, 23, 12 ], [ 532, 268, 15, 12 ], [ 549, 268, 18, 12 ], [ 570, 268, 48, 12 ], [ 620, 268, 52, 12 ], [ 675, 268, 28, 12 ], [ 705, 268, 21, 12 ], [ 76, 288, 31, 12 ], [ 110, 288, 22, 12 ], [ 134, 288, 38, 12 ], [ 174, 288, 4, 12 ], [ 180, 288, 95, 12 ], [ 278, 288, 38, 12 ], [ 319, 288, 6, 12 ], [ 327, 288, 49, 12 ], [ 378, 288, 4, 12 ], [ 384, 288, 147, 12 ], [ 76, 304, 7, 11 ], [ 85, 304, 73, 11 ], [ 160, 304, 33, 11 ], [ 76, 363, 45, 11 ], [ 124, 363, 12, 11 ], [ 138, 363, 19, 11 ], [ 160, 363, 23, 11 ], [ 76, 382, 21, 12 ], [ 100, 382, 29, 12 ], [ 132, 382, 25, 12 ], [ 160, 382, 20, 12 ], [ 192, 382, 128, 12 ], [ 76, 402, 20, 12 ], [ 98, 402, 28, 12 ], [ 129, 402, 7, 12 ], [ 139, 402, 38, 12 ], [ 179, 402, 25, 12 ], [ 207, 402, 215, 12 ], [ 430, 363, 43, 11 ], [ 476, 363, 11, 11 ], [ 490, 363, 23, 11 ], [ 515, 363, 23, 11 ], [ 430, 376, 46, 12 ], [ 478, 376, 12, 12 ], [ 492, 376, 19, 12 ], [ 513, 376, 23, 12 ], [ 76, 422, 9, 12 ], [ 87, 422, 23, 12 ], [ 113, 422, 36, 12 ], [ 151, 422, 16, 12 ], [ 170, 422, 40, 12 ], [ 213, 422, 36, 12 ], [ 252, 422, 35, 12 ], [ 289, 422, 35, 12 ], [ 327, 422, 18, 12 ], [ 76, 435, 20, 12 ], [ 98, 435, 7, 12 ], [ 108, 435, 11, 12 ], [ 121, 435, 26, 12 ], [ 150, 435, 32, 12 ], [ 184, 435, 28, 12 ], [ 215, 435, 49, 12 ], [ 267, 435, 27, 12 ], [ 296, 435, 15, 12 ], [ 314, 435, 27, 12 ], [ 343, 435, 10, 12 ], [ 355, 435, 15, 12 ], [ 373, 435, 39, 12 ], [ 415, 435, 48, 12 ], [ 465, 435, 51, 12 ], [ 519, 435, 34, 12 ], [ 555, 435, 202, 12 ], [ 76, 448, 27, 12 ], [ 106, 448, 35, 12 ], [ 143, 448, 56, 12 ], [ 201, 448, 18, 12 ], [ 222, 448, 55, 12 ], [ 279, 448, 16, 12 ], [ 298, 448, 60, 12 ], [ 361, 448, 8, 12 ], [ 372, 448, 16, 12 ], [ 390, 448, 39, 12 ], [ 432, 448, 40, 12 ], [ 475, 448, 15, 12 ], [ 493, 448, 34, 12 ], [ 529, 448, 24, 12 ], [ 556, 448, 7, 12 ], [ 565, 448, 39, 12 ], [ 607, 448, 25, 12 ], [ 155, 509, 62, 15 ], [ 155, 530, 80, 14 ], [ 238, 530, 22, 14 ], [ 262, 530, 23, 14 ], [ 288, 530, 11, 14 ], [ 302, 530, 55, 14 ], [ 360, 530, 10, 14 ], [ 373, 530, 39, 14 ], [ 415, 530, 38, 14 ], [ 456, 530, 45, 14 ], [ 504, 530, 44, 14 ], [ 550, 530, 43, 14 ], [ 597, 530, 25, 14 ], [ 625, 530, 51, 14 ], [ 678, 530, 12, 14 ], [ 155, 546, 58, 14 ], [ 216, 546, 39, 14 ], [ 259, 546, 50, 14 ], [ 313, 546, 45, 14 ], [ 362, 546, 9, 14 ], [ 374, 546, 12, 14 ], [ 390, 546, 18, 14 ], [ 412, 546, 46, 14 ], [ 462, 546, 50, 14 ], [ 516, 546, 11, 14 ], [ 531, 546, 110, 14 ], [ 645, 546, 46, 14 ], [ 155, 562, 19, 14 ], [ 177, 562, 30, 14 ], [ 211, 562, 46, 14 ], [ 260, 562, 55, 14 ], [ 155, 585, 49, 14 ], [ 208, 585, 21, 14 ], [ 233, 585, 56, 14 ], [ 293, 585, 18, 14 ], [ 315, 585, 23, 14 ], [ 342, 585, 11, 14 ], [ 358, 585, 18, 14 ], [ 380, 585, 110, 14 ], [ 494, 585, 44, 14 ], [ 542, 585, 41, 14 ], [ 587, 585, 39, 14 ], [ 630, 585, 10, 14 ], [ 645, 585, 46, 14 ], [ 155, 602, 42, 14 ], [ 199, 602, 28, 14 ], [ 230, 602, 6, 14 ], [ 238, 602, 84, 14 ], [ 325, 602, 52, 14 ], [ 379, 602, 39, 14 ], [ 421, 602, 39, 14 ], [ 462, 602, 22, 14 ], [ 487, 602, 32, 14 ], [ 521, 602, 60, 14 ], [ 584, 602, 38, 14 ], [ 625, 602, 44, 14 ], [ 671, 602, 20, 14 ], [ 155, 618, 27, 14 ], [ 186, 618, 18, 14 ], [ 209, 618, 75, 14 ], [ 288, 618, 54, 14 ], [ 346, 618, 57, 14 ], [ 407, 618, 22, 14 ], [ 433, 618, 21, 14 ], [ 458, 618, 55, 14 ], [ 517, 618, 12, 14 ], [ 534, 618, 18, 14 ], [ 557, 618, 44, 14 ], [ 606, 618, 31, 14 ], [ 641, 618, 6, 14 ], [ 651, 618, 39, 14 ], [ 155, 635, 28, 14 ], [ 188, 635, 17, 14 ], [ 210, 635, 21, 14 ], [ 236, 635, 11, 14 ], [ 252, 635, 84, 14 ], [ 341, 635, 17, 14 ], [ 363, 635, 32, 14 ], [ 399, 635, 22, 14 ], [ 426, 635, 20, 14 ], [ 451, 635, 39, 14 ], [ 495, 635, 39, 14 ], [ 539, 635, 43, 14 ], [ 587, 635, 52, 14 ], [ 645, 635, 46, 14 ], [ 155, 651, 52, 14 ], [ 210, 651, 55, 14 ], [ 269, 651, 12, 14 ], [ 285, 651, 51, 14 ], [ 339, 651, 27, 14 ], [ 369, 651, 20, 14 ], [ 393, 651, 17, 14 ], [ 413, 651, 64, 14 ], [ 480, 651, 22, 14 ], [ 505, 651, 18, 14 ], [ 527, 651, 45, 14 ], [ 576, 651, 10, 14 ], [ 590, 651, 46, 14 ], [ 639, 651, 52, 14 ], [ 155, 667, 21, 14 ], [ 179, 667, 21, 14 ], [ 203, 667, 12, 14 ], [ 219, 667, 6, 14 ], [ 228, 667, 46, 14 ], [ 277, 667, 45, 14 ], [ 326, 667, 10, 14 ], [ 339, 667, 73, 14 ], [ 416, 667, 21, 14 ], [ 440, 667, 28, 14 ], [ 471, 667, 56, 14 ], [ 530, 667, 12, 14 ], [ 546, 667, 23, 14 ], [ 572, 667, 27, 14 ], [ 602, 667, 22, 14 ], [ 628, 667, 19, 14 ], [ 650, 667, 41, 14 ], [ 155, 683, 39, 14 ], [ 197, 683, 13, 14 ], [ 213, 683, 52, 14 ], [ 268, 683, 23, 14 ], [ 294, 683, 10, 14 ], [ 307, 683, 19, 14 ], [ 329, 683, 31, 14 ], [ 363, 683, 35, 14 ], [ 401, 683, 17, 14 ], [ 421, 683, 10, 14 ], [ 435, 683, 40, 14 ], [ 478, 683, 24, 14 ], [ 505, 683, 22, 14 ], [ 530, 683, 9, 14 ], [ 542, 683, 56, 14 ], [ 601, 683, 25, 14 ], [ 629, 683, 13, 14 ], [ 645, 683, 46, 14 ], [ 155, 700, 23, 14 ], [ 181, 700, 11, 14 ], [ 195, 700, 73, 14 ], [ 272, 700, 24, 14 ], [ 299, 700, 20, 14 ], [ 323, 700, 41, 14 ], [ 367, 700, 11, 14 ], [ 382, 700, 19, 14 ], [ 404, 700, 31, 14 ], [ 438, 700, 35, 14 ], [ 476, 700, 49, 14 ], [ 529, 700, 26, 14 ], [ 559, 700, 43, 14 ], [ 605, 700, 36, 14 ], [ 644, 700, 37, 14 ], [ 685, 700, 6, 14 ], [ 155, 716, 23, 14 ], [ 181, 716, 17, 14 ], [ 201, 716, 56, 14 ], [ 261, 716, 44, 14 ], [ 308, 716, 10, 14 ], [ 321, 716, 20, 14 ], [ 344, 716, 46, 14 ], [ 155, 739, 74, 14 ], [ 234, 739, 22, 14 ], [ 262, 739, 52, 14 ], [ 319, 739, 73, 14 ], [ 398, 739, 21, 14 ], [ 425, 739, 28, 14 ], [ 458, 739, 51, 14 ], [ 515, 739, 10, 14 ], [ 530, 739, 6, 14 ], [ 542, 739, 39, 14 ], [ 586, 739, 39, 14 ], [ 631, 739, 22, 14 ], [ 658, 739, 32, 14 ], [ 155, 756, 60, 14 ], [ 218, 756, 44, 14 ], [ 265, 756, 45, 14 ], [ 314, 756, 6, 14 ], [ 323, 756, 23, 14 ], [ 349, 756, 17, 14 ], [ 369, 756, 39, 14 ], [ 412, 756, 44, 14 ], [ 459, 756, 20, 14 ], [ 482, 756, 44, 14 ], [ 529, 756, 57, 14 ], [ 590, 756, 10, 14 ], [ 603, 756, 39, 14 ], [ 645, 756, 40, 14 ], [ 76, 824, 84, 15 ], [ 76, 841, 60, 14 ], [ 143, 841, 18, 14 ], [ 167, 841, 62, 14 ], [ 235, 841, 57, 14 ], [ 298, 841, 43, 14 ], [ 347, 841, 39, 14 ], [ 392, 841, 19, 14 ], [ 76, 857, 25, 14 ], [ 104, 857, 12, 14 ], [ 120, 857, 19, 14 ], [ 142, 857, 72, 14 ], [ 218, 857, 55, 14 ], [ 276, 857, 19, 14 ], [ 298, 857, 69, 14 ], [ 371, 857, 13, 14 ], [ 386, 857, 25, 14 ], [ 76, 873, 37, 14 ], [ 117, 873, 39, 14 ], [ 160, 873, 19, 14 ], [ 183, 873, 69, 14 ], [ 255, 873, 49, 14 ], [ 308, 873, 27, 14 ], [ 339, 873, 28, 14 ], [ 371, 873, 41, 14 ], [ 76, 890, 68, 14 ], [ 146, 890, 30, 14 ], [ 178, 890, 12, 14 ], [ 193, 890, 43, 14 ], [ 238, 890, 20, 14 ], [ 260, 890, 56, 14 ], [ 319, 890, 7, 14 ], [ 328, 890, 23, 14 ], [ 354, 890, 13, 14 ], [ 368, 890, 43, 14 ], [ 76, 906, 44, 14 ], [ 123, 906, 54, 14 ], [ 180, 906, 13, 14 ], [ 196, 906, 54, 14 ], [ 253, 906, 19, 14 ], [ 275, 906, 35, 14 ], [ 313, 906, 23, 14 ], [ 339, 906, 13, 14 ], [ 355, 906, 57, 14 ], [ 76, 922, 13, 14 ], [ 93, 922, 20, 14 ], [ 118, 922, 48, 14 ], [ 171, 922, 47, 14 ], [ 222, 922, 44, 14 ], [ 270, 922, 23, 14 ], [ 298, 922, 80, 14 ], [ 382, 922, 29, 14 ], [ 76, 939, 29, 14 ], [ 110, 939, 36, 14 ], [ 151, 939, 57, 14 ], [ 213, 939, 23, 14 ], [ 241, 939, 74, 14 ], [ 319, 939, 18, 14 ], [ 342, 939, 44, 14 ], [ 390, 939, 21, 14 ], [ 76, 955, 22, 14 ], [ 101, 955, 29, 14 ], [ 134, 955, 43, 14 ], [ 181, 955, 49, 14 ], [ 233, 955, 18, 14 ], [ 254, 955, 7, 14 ], [ 264, 955, 147, 14 ], [ 76, 971, 99, 14 ], [ 181, 971, 47, 14 ], [ 234, 971, 20, 14 ], [ 261, 971, 19, 14 ], [ 286, 971, 73, 14 ], [ 365, 971, 13, 14 ], [ 384, 971, 27, 14 ], [ 76, 988, 49, 14 ], [ 131, 988, 13, 14 ], [ 150, 988, 33, 14 ], [ 189, 988, 12, 14 ], [ 208, 988, 78, 14 ], [ 292, 988, 67, 14 ], [ 364, 988, 20, 14 ], [ 391, 988, 21, 14 ], [ 76, 1004, 29, 14 ], [ 108, 1004, 50, 14 ], [ 161, 1004, 60, 14 ], [ 225, 1004, 34, 14 ], [ 262, 1004, 16, 14 ], [ 281, 1004, 19, 14 ], [ 303, 1004, 83, 14 ], [ 390, 1004, 21, 14 ], [ 434, 825, 35, 14 ], [ 473, 825, 24, 14 ], [ 500, 825, 37, 14 ], [ 540, 825, 26, 14 ], [ 570, 825, 36, 14 ], [ 610, 825, 42, 14 ], [ 656, 825, 51, 14 ], [ 710, 825, 59, 14 ], [ 434, 841, 24, 14 ], [ 462, 841, 60, 14 ], [ 526, 841, 32, 14 ], [ 561, 841, 66, 14 ], [ 631, 841, 12, 14 ], [ 647, 841, 52, 14 ], [ 702, 841, 51, 14 ], [ 756, 841, 13, 14 ], [ 434, 857, 28, 14 ], [ 467, 857, 47, 14 ], [ 518, 857, 32, 14 ], [ 555, 857, 9, 14 ], [ 568, 857, 20, 14 ], [ 592, 857, 29, 14 ], [ 625, 857, 55, 14 ], [ 685, 857, 24, 14 ], [ 713, 857, 57, 14 ], [ 434, 873, 25, 14 ], [ 464, 873, 62, 14 ], [ 530, 873, 12, 14 ], [ 546, 873, 19, 14 ], [ 568, 873, 76, 14 ], [ 648, 873, 12, 14 ], [ 664, 873, 51, 14 ], [ 719, 873, 50, 14 ], [ 434, 890, 9, 14 ], [ 447, 890, 57, 14 ], [ 507, 890, 25, 14 ], [ 535, 890, 7, 14 ], [ 546, 890, 23, 14 ], [ 572, 890, 13, 14 ], [ 588, 890, 78, 14 ], [ 669, 890, 70, 14 ], [ 742, 890, 27, 14 ], [ 434, 906, 60, 14 ], [ 497, 906, 13, 14 ], [ 512, 906, 33, 14 ], [ 547, 906, 55, 14 ], [ 605, 906, 57, 14 ], [ 664, 906, 49, 14 ], [ 715, 906, 38, 14 ], [ 755, 906, 15, 14 ], [ 434, 922, 51, 14 ], [ 488, 922, 13, 14 ], [ 504, 922, 33, 14 ], [ 540, 922, 12, 14 ], [ 555, 922, 51, 14 ], [ 609, 922, 63, 14 ], [ 434, 955, 22, 14 ], [ 460, 955, 49, 14 ], [ 513, 955, 43, 14 ], [ 560, 955, 42, 14 ], [ 606, 955, 17, 14 ], [ 627, 955, 10, 14 ], [ 640, 955, 22, 14 ], [ 667, 955, 12, 14 ], [ 683, 955, 19, 14 ], [ 706, 955, 21, 14 ], [ 730, 955, 39, 14 ], [ 434, 971, 23, 14 ], [ 460, 971, 57, 14 ], [ 518, 971, 52, 14 ], [ 573, 971, 45, 14 ], [ 620, 971, 10, 14 ], [ 632, 971, 36, 14 ], [ 671, 971, 12, 14 ], [ 686, 971, 15, 14 ], [ 703, 971, 66, 14 ], [ 434, 988, 23, 14 ], [ 461, 988, 10, 14 ], [ 474, 988, 53, 14 ], [ 530, 988, 13, 14 ], [ 547, 988, 57, 14 ], [ 607, 988, 12, 14 ], [ 623, 988, 58, 14 ], [ 685, 988, 26, 14 ], [ 714, 988, 21, 14 ], [ 739, 988, 31, 14 ], [ 434, 1004, 39, 14 ], [ 477, 1004, 13, 14 ], [ 493, 1004, 32, 14 ], [ 528, 1004, 30, 14 ], [ 561, 1004, 21, 14 ], [ 586, 1004, 23, 14 ], [ 611, 1004, 44, 14 ], [ 658, 1004, 26, 14 ], [ 688, 1004, 39, 14 ], [ 730, 1004, 39, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1069, 25, 10 ], [ 627, 1069, 33, 10 ], [ 662, 1069, 14, 10 ], [ 678, 1069, 12, 10 ], [ 692, 1069, 31, 10 ], [ 726, 1069, 44, 10 ] ]

[ "BMC", "Biology", "Research", "article", "A", "mutation", "in", "the", "centriole-associated", "protein", "centrin", "causes", "genomic", "instability", "via", "increased", "chromosome", "loss", "in", "Chlamydomonas", "reinhardtii", "Ivan", "Zamora", "and", "Wallace", "F", "Marshall*", "BioMed", "Central", "Open", "Access", "Address:", "Dept.", "of", "Biochemistry", "&", "Biophysics,", "University", "of", "California,", "San", "Francisco,", "600", "16th", "St.,", "San", "Francisco,", "California,", "9414,", "USA", "Email:", "Ivan", "Zamora", "-", "dsjiz@itsa.ucsf.edu;", "Wallace", "F", "Marshall*", "-", "wmarshall@biochem.ucsf.edu", "*", "Corresponding", "author", "Published:", "31", "May", "2005", "BMC", "Biology", "2005,", "3:15", "doi:10.1186/1741-7007-3-15", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1741-7007/3/15", "Received:", "15", "April", "2005", "Accepted:", "31", "May", "2005", "©", "2005", "Zamora", "and", "Marshall;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "role", "of", "centrioles", "in", "mitotic", "spindle", "function", "remains", "unclear.", "One", "approach", "to", "investigate", "mitotic", "centriole", "function", "is", "to", "ask", "whether", "mutation", "of", "centriole-associated", "proteins", "can", "cause", "genomic", "instability.", "Results:", "We", "addressed", "the", "role", "of", "the", "centriole-associated", "EF-hand", "protein", "centrin", "in", "genomic", "stability", "using", "a", "Chlamydomonas", "reinhardtii", "centrin", "mutant", "that", "forms", "acentriolar", "bipolar", "spindles", "and", "lacks", "the", "centrin-based", "rhizoplast", "structures", "that", "join", "centrioles", "to", "the", "nucleus.", "Using", "a", "genetic", "assay", "for", "loss", "of", "heterozygosity,", "we", "found", "that", "this", "centrin", "mutant", "showed", "increased", "genomic", "instability", "compared", "to", "wild-type", "cells,", "and", "we", "determined", "that", "the", "increase", "in", "genomic", "instability", "was", "due", "to", "a", "100-fold", "increase", "in", "chromosome", "loss", "rates", "compared", "to", "wild", "type.", "Live", "cell", "imaging", "reveals", "an", "increased", "rate", "in", "cell", "death", "during", "G1", "in", "haploid", "cells", "that", "is", "consistent", "with", "an", "elevated", "rate", "of", "chromosome", "loss,", "and", "analysis", "of", "cell", "death", "versus", "centriole", "copy", "number", "argues", "against", "a", "role", "for", "multipolar", "spindles", "in", "this", "process.", "Conclusion:", "The", "increased", "chromosome", "loss", "rates", "observed", "in", "a", "centrin", "mutant", "that", "forms", "acentriolar", "spindles", "suggests", "a", "role", "for", "centrin", "protein,", "and", "possibly", "centrioles,", "in", "mitotic", "fidelity.", "Background", "Centrioles", "are", "cylindrical", "structures", "located", "within", "the", "core", "of", "the", "centrosome.", "Although", "the", "localization", "of", "cen-", "trioles", "within", "the", "centrosome", "together", "with", "their", "precise", "duplication", "prior", "to", "mitosis", "has", "suggested", "a", "role", "in", "bipolar", "spindle", "assembly", "or", "function,", "the", "actual", "role", "of", "centrioles", "in", "cell", "division", "remains", "unclear", "and", "controversial.", "Cells", "from", "which", "centrioles", "and", "centrosomes", "are", "ablated", "can", "still", "form", "bipolar", "spindles", "via", "a", "centrosome-independent", "self-organization", "process,", "but", "the", "effectiveness", "of", "such", "spindles", "in", "terms", "of", "chromosome", "segregation", "has", "not", "been", "carefully", "measured.", "Based", "on", "the", "circumstantial", "evi-", "dence", "that", "tumor", "cells", "which", "display", "genomic", "instability", "also", "frequently", "show", "aberrations", "in", "centriole", "structure", "or", "copy", "number", "[1,2],", "it", "has", "been", "proposed", "that", "centrioles", "may", "participate", "in", "the", "maintenance", "of", "genomic", "stability.", "If", "centrioles", "play", "a", "role", "in", "chromosome", "segregation,", "then", "mutations", "in", "genes", "encoding", "centriolar", "proteins", "would", "be", "expected", "to", "result", "in", "genomic", "instability.", "The", "EF-hand", "protein", "centrin", "[3]", "is", "one", "of", "the", "few", "identi-", "fied", "centriolar", "proteins.", "Centrin", "is", "found", "in", "all", "eukaryotes,", "and", "is", "localized", "to", "centrioles", "in", "vertebrate", "cells", "[4],", "basal", "bodies", "in", "green", "algae", "[5],", "and", "spindle", "pole", "bodies", "(SPBs)", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 467, 62, 46, 12 ], [ 516, 62, 31, 12 ], [ 549, 62, 223, 12 ], [ 79, 120, 65, 21 ], [ 79, 144, 103, 23 ], [ 187, 144, 110, 23 ], [ 303, 144, 22, 23 ], [ 330, 144, 105, 23 ], [ 441, 144, 70, 23 ], [ 516, 144, 149, 23 ], [ 670, 144, 42, 23 ], [ 718, 144, 22, 23 ], [ 79, 169, 70, 23 ], [ 154, 169, 81, 23 ], [ 241, 169, 76, 23 ], [ 79, 195, 29, 17 ], [ 112, 195, 49, 17 ], [ 164, 195, 27, 17 ], [ 195, 195, 30, 17 ], [ 229, 195, 12, 17 ], [ 245, 195, 55, 17 ], [ 79, 240, 55, 12 ], [ 136, 240, 9, 12 ], [ 147, 240, 69, 12 ], [ 218, 240, 40, 12 ], [ 261, 240, 45, 12 ], [ 308, 240, 37, 12 ], [ 347, 240, 35, 12 ], [ 384, 240, 51, 12 ], [ 438, 240, 18, 12 ], [ 458, 240, 56, 12 ], [ 79, 281, 85, 12 ], [ 166, 281, 20, 12 ], [ 188, 281, 8, 12 ], [ 198, 281, 39, 12 ], [ 239, 281, 29, 12 ], [ 270, 281, 23, 12 ], [ 296, 281, 79, 12 ], [ 377, 281, 18, 12 ], [ 397, 281, 46, 12 ], [ 445, 281, 35, 12 ], [ 482, 281, 52, 12 ], [ 537, 281, 37, 12 ], [ 576, 281, 9, 12 ], [ 587, 281, 69, 12 ], [ 658, 281, 40, 12 ], [ 701, 281, 45, 12 ], [ 79, 294, 37, 12 ], [ 118, 294, 35, 12 ], [ 155, 294, 12, 12 ], [ 169, 294, 70, 12 ], [ 241, 294, 16, 12 ], [ 259, 294, 26, 12 ], [ 288, 294, 16, 12 ], [ 306, 294, 51, 12 ], [ 360, 294, 18, 12 ], [ 380, 294, 59, 12 ], [ 441, 294, 17, 12 ], [ 460, 294, 21, 12 ], [ 483, 294, 13, 12 ], [ 499, 294, 48, 12 ], [ 549, 294, 16, 12 ], [ 567, 294, 21, 12 ], [ 590, 294, 13, 12 ], [ 606, 294, 20, 12 ], [ 628, 294, 29, 12 ], [ 79, 307, 30, 12 ], [ 111, 307, 114, 12 ], [ 79, 347, 47, 12 ], [ 129, 347, 13, 12 ], [ 145, 347, 30, 12 ], [ 177, 347, 26, 12 ], [ 79, 364, 46, 12 ], [ 127, 364, 51, 12 ], [ 180, 364, 7, 12 ], [ 190, 364, 20, 12 ], [ 212, 364, 26, 12 ], [ 79, 381, 46, 12 ], [ 127, 381, 44, 12 ], [ 173, 381, 13, 12 ], [ 189, 381, 40, 12 ], [ 231, 381, 26, 12 ], [ 79, 397, 50, 12 ], [ 131, 397, 13, 12 ], [ 147, 397, 40, 12 ], [ 189, 397, 26, 12 ], [ 79, 414, 50, 12 ], [ 131, 414, 13, 12 ], [ 147, 414, 49, 12 ], [ 199, 414, 26, 12 ], [ 437, 347, 31, 12 ], [ 471, 347, 19, 12 ], [ 492, 347, 29, 12 ], [ 524, 347, 23, 12 ], [ 437, 367, 20, 12 ], [ 459, 367, 29, 12 ], [ 491, 367, 19, 12 ], [ 513, 367, 35, 12 ], [ 550, 367, 69, 12 ], [ 622, 367, 21, 12 ], [ 646, 367, 28, 12 ], [ 677, 367, 18, 12 ], [ 697, 367, 19, 12 ], [ 719, 367, 13, 12 ], [ 734, 367, 27, 12 ], [ 437, 380, 29, 12 ], [ 468, 380, 9, 12 ], [ 480, 380, 206, 12 ], [ 437, 400, 10, 12 ], [ 449, 400, 26, 12 ], [ 478, 400, 37, 12 ], [ 518, 400, 35, 12 ], [ 556, 400, 16, 12 ], [ 437, 414, 24, 12 ], [ 462, 414, 24, 12 ], [ 488, 414, 56, 12 ], [ 546, 414, 30, 12 ], [ 579, 414, 25, 12 ], [ 606, 414, 57, 12 ], [ 157, 462, 60, 15 ], [ 157, 487, 42, 13 ], [ 206, 487, 34, 13 ], [ 246, 487, 66, 13 ], [ 318, 487, 9, 13 ], [ 334, 487, 20, 13 ], [ 360, 487, 11, 13 ], [ 377, 487, 17, 13 ], [ 400, 487, 25, 13 ], [ 432, 487, 43, 13 ], [ 481, 487, 10, 13 ], [ 497, 487, 41, 13 ], [ 545, 487, 43, 13 ], [ 594, 487, 10, 13 ], [ 611, 487, 52, 13 ], [ 669, 487, 24, 13 ], [ 157, 501, 51, 13 ], [ 215, 501, 66, 13 ], [ 287, 501, 24, 13 ], [ 318, 501, 10, 13 ], [ 334, 501, 17, 13 ], [ 357, 501, 34, 13 ], [ 397, 501, 42, 13 ], [ 445, 501, 19, 13 ], [ 470, 501, 27, 13 ], [ 504, 501, 51, 13 ], [ 561, 501, 11, 13 ], [ 578, 501, 53, 13 ], [ 638, 501, 38, 13 ], [ 682, 501, 11, 13 ], [ 157, 516, 47, 13 ], [ 209, 516, 11, 13 ], [ 225, 516, 45, 13 ], [ 275, 516, 10, 13 ], [ 289, 516, 34, 13 ], [ 327, 516, 47, 13 ], [ 379, 516, 20, 13 ], [ 404, 516, 45, 13 ], [ 454, 516, 20, 13 ], [ 479, 516, 34, 13 ], [ 517, 516, 39, 13 ], [ 561, 516, 41, 13 ], [ 607, 516, 31, 13 ], [ 643, 516, 19, 13 ], [ 666, 516, 27, 13 ], [ 157, 530, 48, 13 ], [ 214, 530, 13, 13 ], [ 236, 530, 7, 13 ], [ 251, 530, 55, 13 ], [ 315, 530, 60, 13 ], [ 384, 530, 11, 13 ], [ 403, 530, 17, 13 ], [ 429, 530, 40, 13 ], [ 478, 530, 60, 13 ], [ 546, 530, 11, 13 ], [ 566, 530, 38, 13 ], [ 612, 530, 52, 13 ], [ 673, 530, 20, 13 ], [ 157, 545, 95, 13 ], [ 258, 545, 19, 13 ], [ 284, 545, 42, 13 ], [ 331, 545, 27, 13 ], [ 365, 545, 59, 13 ], [ 430, 545, 13, 13 ], [ 449, 545, 7, 13 ], [ 462, 545, 20, 13 ], [ 488, 545, 36, 13 ], [ 530, 545, 11, 13 ], [ 547, 545, 87, 13 ], [ 641, 545, 52, 13 ], [ 157, 560, 63, 13 ], [ 223, 560, 20, 13 ], [ 246, 560, 37, 13 ], [ 285, 560, 39, 13 ], [ 327, 560, 10, 13 ], [ 340, 560, 19, 13 ], [ 361, 560, 37, 13 ], [ 401, 560, 16, 13 ], [ 420, 560, 41, 13 ], [ 463, 560, 17, 13 ], [ 483, 560, 20, 13 ], [ 505, 560, 10, 13 ], [ 518, 560, 34, 13 ], [ 555, 560, 40, 13 ], [ 597, 560, 38, 13 ], [ 637, 560, 24, 13 ], [ 664, 560, 10, 13 ], [ 676, 560, 17, 13 ], [ 157, 574, 52, 13 ], [ 212, 574, 20, 13 ], [ 235, 574, 67, 13 ], [ 305, 574, 11, 13 ], [ 318, 574, 34, 13 ], [ 354, 574, 66, 13 ], [ 423, 574, 20, 13 ], [ 446, 574, 53, 13 ], [ 503, 574, 11, 13 ], [ 516, 574, 17, 13 ], [ 536, 574, 71, 13 ], [ 610, 574, 11, 13 ], [ 623, 574, 41, 13 ], [ 157, 605, 53, 12 ], [ 213, 605, 30, 12 ], [ 246, 605, 35, 12 ], [ 284, 605, 37, 12 ], [ 323, 605, 54, 12 ], [ 380, 605, 42, 12 ], [ 424, 605, 33, 12 ], [ 460, 605, 30, 12 ], [ 493, 605, 60, 12 ], [ 79, 690, 90, 16 ], [ 79, 708, 73, 14 ], [ 154, 708, 11, 14 ], [ 169, 708, 19, 14 ], [ 190, 708, 37, 14 ], [ 230, 708, 23, 14 ], [ 256, 708, 10, 14 ], [ 269, 708, 7, 14 ], [ 279, 708, 39, 14 ], [ 321, 708, 78, 14 ], [ 402, 708, 11, 14 ], [ 79, 725, 42, 14 ], [ 125, 725, 20, 14 ], [ 148, 725, 50, 14 ], [ 202, 725, 52, 14 ], [ 258, 725, 30, 14 ], [ 292, 725, 25, 14 ], [ 320, 725, 12, 14 ], [ 336, 725, 14, 14 ], [ 354, 725, 60, 14 ], [ 79, 741, 22, 14 ], [ 110, 741, 11, 14 ], [ 131, 741, 69, 14 ], [ 209, 741, 72, 14 ], [ 291, 741, 85, 14 ], [ 386, 741, 28, 14 ], [ 79, 757, 32, 14 ], [ 115, 757, 28, 14 ], [ 147, 757, 27, 14 ], [ 178, 757, 22, 14 ], [ 204, 757, 82, 14 ], [ 290, 757, 50, 14 ], [ 343, 757, 10, 14 ], [ 357, 757, 14, 14 ], [ 376, 757, 38, 14 ], [ 79, 774, 39, 14 ], [ 123, 774, 47, 14 ], [ 176, 774, 10, 14 ], [ 192, 774, 19, 14 ], [ 216, 774, 49, 14 ], [ 271, 774, 60, 14 ], [ 336, 774, 50, 14 ], [ 392, 774, 21, 14 ], [ 79, 790, 49, 14 ], [ 131, 790, 37, 14 ], [ 172, 790, 14, 14 ], [ 190, 790, 77, 14 ], [ 270, 790, 22, 14 ], [ 296, 790, 42, 14 ], [ 341, 790, 11, 14 ], [ 357, 790, 57, 14 ], [ 79, 806, 26, 14 ], [ 109, 806, 32, 14 ], [ 145, 806, 73, 14 ], [ 222, 806, 27, 14 ], [ 253, 806, 21, 14 ], [ 278, 806, 29, 14 ], [ 312, 806, 56, 14 ], [ 372, 806, 12, 14 ], [ 388, 806, 26, 14 ], [ 79, 822, 37, 14 ], [ 120, 822, 42, 14 ], [ 166, 822, 12, 14 ], [ 182, 822, 52, 14 ], [ 238, 822, 12, 14 ], [ 253, 822, 50, 14 ], [ 307, 822, 10, 14 ], [ 321, 822, 37, 14 ], [ 362, 822, 52, 14 ], [ 79, 839, 22, 14 ], [ 104, 839, 50, 14 ], [ 79, 871, 55, 14 ], [ 139, 871, 54, 14 ], [ 198, 871, 50, 14 ], [ 253, 871, 12, 14 ], [ 269, 871, 49, 14 ], [ 323, 871, 43, 14 ], [ 372, 871, 42, 14 ], [ 79, 888, 51, 14 ], [ 135, 888, 20, 14 ], [ 161, 888, 57, 14 ], [ 223, 888, 57, 14 ], [ 285, 888, 61, 14 ], [ 351, 888, 62, 14 ], [ 79, 904, 37, 14 ], [ 124, 904, 20, 14 ], [ 152, 904, 66, 14 ], [ 226, 904, 53, 14 ], [ 288, 904, 10, 14 ], [ 307, 904, 20, 14 ], [ 335, 904, 48, 14 ], [ 392, 904, 22, 14 ], [ 79, 920, 68, 14 ], [ 151, 920, 53, 14 ], [ 209, 920, 10, 14 ], [ 224, 920, 20, 14 ], [ 248, 920, 30, 14 ], [ 283, 920, 14, 14 ], [ 301, 920, 23, 14 ], [ 328, 920, 14, 14 ], [ 346, 920, 14, 14 ], [ 365, 920, 49, 14 ], [ 79, 937, 10, 14 ], [ 93, 937, 37, 14 ], [ 134, 937, 43, 14 ], [ 181, 937, 41, 14 ], [ 227, 937, 38, 14 ], [ 269, 937, 44, 14 ], [ 317, 937, 20, 14 ], [ 341, 937, 35, 14 ], [ 380, 937, 33, 14 ], [ 437, 692, 25, 14 ], [ 470, 692, 50, 14 ], [ 528, 692, 77, 14 ], [ 612, 692, 26, 14 ], [ 646, 692, 19, 14 ], [ 673, 692, 31, 14 ], [ 712, 692, 16, 14 ], [ 735, 692, 37, 14 ], [ 437, 708, 70, 14 ], [ 514, 708, 7, 14 ], [ 529, 708, 76, 14 ], [ 611, 708, 48, 14 ], [ 667, 708, 12, 14 ], [ 685, 708, 27, 14 ], [ 720, 708, 52, 14 ], [ 437, 725, 85, 14 ], [ 527, 725, 16, 14 ], [ 547, 725, 37, 14 ], [ 589, 725, 46, 14 ], [ 640, 725, 20, 14 ], [ 665, 725, 55, 14 ], [ 724, 725, 48, 14 ], [ 437, 741, 70, 14 ], [ 511, 741, 24, 14 ], [ 539, 741, 14, 14 ], [ 557, 741, 49, 14 ], [ 610, 741, 10, 14 ], [ 624, 741, 23, 14 ], [ 650, 741, 22, 14 ], [ 676, 741, 44, 14 ], [ 724, 741, 12, 14 ], [ 739, 741, 33, 14 ], [ 437, 757, 43, 14 ], [ 486, 757, 14, 14 ], [ 505, 757, 23, 14 ], [ 534, 757, 14, 14 ], [ 554, 757, 48, 14 ], [ 608, 757, 66, 14 ], [ 680, 757, 27, 14 ], [ 713, 757, 29, 14 ], [ 748, 757, 24, 14 ], [ 437, 773, 37, 14 ], [ 477, 773, 14, 14 ], [ 494, 773, 69, 14 ], [ 567, 773, 40, 14 ], [ 610, 773, 10, 14 ], [ 624, 773, 37, 14 ], [ 665, 773, 23, 14 ], [ 691, 773, 67, 14 ], [ 762, 773, 10, 14 ], [ 437, 790, 46, 14 ], [ 486, 790, 24, 14 ], [ 514, 790, 43, 14 ], [ 560, 790, 45, 14 ], [ 437, 822, 22, 14 ], [ 465, 822, 29, 14 ], [ 501, 822, 20, 14 ], [ 528, 822, 29, 14 ], [ 564, 822, 45, 14 ], [ 615, 822, 57, 14 ], [ 679, 822, 14, 14 ], [ 699, 822, 7, 14 ], [ 713, 822, 59, 14 ], [ 437, 839, 37, 14 ], [ 484, 839, 64, 14 ], [ 558, 839, 12, 14 ], [ 580, 839, 94, 14 ], [ 684, 839, 56, 14 ], [ 750, 839, 22, 14 ], [ 437, 855, 98, 14 ], [ 547, 855, 14, 14 ], [ 573, 855, 67, 14 ], [ 651, 855, 22, 14 ], [ 685, 855, 64, 14 ], [ 760, 855, 12, 14 ], [ 437, 871, 88, 14 ], [ 528, 871, 14, 14 ], [ 544, 871, 46, 14 ], [ 593, 871, 7, 14 ], [ 604, 871, 20, 14 ], [ 627, 871, 45, 14 ], [ 674, 871, 29, 14 ], [ 706, 871, 66, 14 ], [ 437, 888, 51, 14 ], [ 493, 888, 22, 14 ], [ 519, 888, 18, 14 ], [ 542, 888, 51, 14 ], [ 598, 888, 45, 14 ], [ 648, 888, 11, 14 ], [ 664, 888, 29, 14 ], [ 698, 888, 26, 14 ], [ 729, 888, 23, 14 ], [ 757, 888, 15, 14 ], [ 437, 904, 39, 14 ], [ 483, 904, 12, 14 ], [ 502, 904, 18, 14 ], [ 527, 904, 71, 14 ], [ 606, 904, 22, 14 ], [ 635, 904, 46, 14 ], [ 688, 904, 11, 14 ], [ 706, 904, 36, 14 ], [ 750, 904, 22, 14 ], [ 437, 920, 74, 14 ], [ 515, 920, 9, 14 ], [ 528, 920, 43, 14 ], [ 576, 920, 11, 14 ], [ 591, 920, 36, 14 ], [ 632, 920, 41, 14 ], [ 677, 920, 27, 14 ], [ 708, 920, 38, 14 ], [ 750, 920, 22, 14 ], [ 437, 937, 29, 14 ], [ 473, 937, 26, 14 ], [ 506, 937, 18, 14 ], [ 531, 937, 24, 14 ], [ 562, 937, 7, 14 ], [ 576, 937, 21, 14 ], [ 605, 937, 39, 14 ], [ 651, 937, 11, 14 ], [ 669, 937, 62, 14 ], [ 739, 937, 33, 14 ], [ 79, 967, 24, 12 ], [ 105, 967, 8, 12 ], [ 116, 967, 30, 12 ], [ 149, 967, 35, 12 ], [ 187, 967, 37, 12 ], [ 226, 967, 21, 12 ], [ 250, 967, 8, 12 ], [ 261, 967, 75, 12 ], [ 339, 967, 34, 12 ], [ 375, 967, 25, 12 ], [ 403, 967, 8, 12 ], [ 413, 967, 78, 12 ], [ 494, 967, 25, 12 ], [ 521, 967, 8, 12 ], [ 531, 967, 56, 12 ], [ 590, 967, 31, 12 ], [ 624, 967, 22, 12 ], [ 648, 967, 8, 12 ], [ 659, 967, 44, 12 ], [ 705, 967, 33, 12 ], [ 741, 967, 31, 12 ], [ 79, 980, 44, 12 ], [ 125, 980, 8, 12 ], [ 137, 980, 152, 12 ], [ 292, 980, 51, 12 ], [ 346, 980, 31, 12 ], [ 380, 980, 17, 12 ], [ 400, 980, 8, 12 ], [ 411, 980, 48, 12 ], [ 463, 980, 18, 12 ], [ 484, 980, 8, 12 ], [ 495, 980, 49, 12 ], [ 547, 980, 33, 12 ], [ 584, 980, 30, 12 ], [ 618, 980, 9, 12 ], [ 630, 980, 8, 12 ], [ 641, 980, 51, 12 ], [ 696, 980, 15, 12 ], [ 714, 980, 8, 12 ], [ 725, 980, 47, 12 ], [ 79, 993, 43, 12 ], [ 124, 993, 30, 12 ], [ 158, 993, 25, 12 ], [ 186, 993, 8, 12 ], [ 196, 993, 74, 12 ], [ 273, 993, 12, 12 ], [ 288, 993, 8, 12 ], [ 299, 993, 55, 12 ], [ 357, 993, 25, 12 ], [ 384, 993, 8, 12 ], [ 395, 993, 47, 12 ], [ 444, 993, 58, 12 ], [ 505, 993, 36, 12 ], [ 545, 993, 26, 12 ], [ 574, 993, 8, 12 ], [ 584, 993, 26, 12 ], [ 613, 993, 82, 12 ], [ 699, 993, 43, 12 ], [ 744, 993, 17, 12 ], [ 764, 993, 8, 12 ], [ 79, 1007, 23, 12 ], [ 105, 1007, 28, 12 ], [ 135, 1007, 30, 12 ], [ 168, 1007, 8, 12 ], [ 179, 1007, 73, 12 ], [ 254, 1007, 33, 12 ], [ 290, 1007, 31, 12 ], [ 323, 1007, 16, 12 ], [ 342, 1007, 8, 12 ], [ 353, 1007, 68, 12 ], [ 423, 1007, 43, 12 ], [ 469, 1007, 8, 12 ], [ 479, 1007, 45, 12 ], [ 527, 1007, 12, 12 ], [ 542, 1007, 48, 12 ], [ 592, 1007, 32, 12 ], [ 627, 1007, 7, 12 ], [ 636, 1007, 17, 12 ], [ 655, 1007, 49, 12 ], [ 706, 1007, 18, 12 ], [ 727, 1007, 45, 12 ], [ 79, 1020, 21, 12 ], [ 103, 1020, 8, 12 ], [ 113, 1020, 59, 12 ], [ 175, 1020, 33, 12 ], [ 211, 1020, 31, 12 ], [ 244, 1020, 12, 12 ], [ 259, 1020, 8, 12 ], [ 269, 1020, 6, 12 ], [ 278, 1020, 30, 12 ], [ 311, 1020, 25, 12 ], [ 338, 1020, 31, 12 ], [ 371, 1020, 8, 12 ], [ 382, 1020, 33, 12 ], [ 418, 1020, 40, 12 ], [ 460, 1020, 41, 12 ], [ 504, 1020, 14, 12 ], [ 520, 1020, 8, 12 ], [ 530, 1020, 64, 12 ], [ 708, 1048, 25, 12 ], [ 736, 1048, 7, 12 ], [ 745, 1048, 10, 12 ], [ 757, 1048, 14, 12 ], [ 583, 1062, 28, 12 ], [ 613, 1062, 36, 12 ], [ 652, 1062, 16, 12 ], [ 670, 1062, 13, 12 ], [ 685, 1062, 35, 12 ], [ 722, 1062, 48, 12 ] ]

[ "Available", "online", "http://respiratory-research.com/content/3/1/11", "Review", "Autocrine", "regulation", "of", "asthmatic", "airway", "inflammation:", "role", "of", "airway", "smooth", "muscle", "Sue", "McKay", "and", "Hari", "S", "Sharma", "Department", "of", "Pharmacology,", "Erasmus", "University", "Medical", "Centre,", "Rotterdam,", "The", "Netherlands", "Correspondence:", "Hari", "S", "Sharma,", "MPhil,", "PhD,", "Cardiopulmonary", "and", "Molecular", "Biology", "Laboratory,", "Institute", "of", "Pharmacology,", "Erasmus", "University", "Medical", "Center,", "Dr", "Molewaterplein", "50,", "3015", "GE", "Rotterdam,", "The", "Netherlands.", "Tel:", "+31", "10", "4087963;", "fax:", "+31", "10", "408", "9458;", "e-mail:", "sharma@farma.fgg.eur.nl", "Received:", "26", "March", "2001", "Revisions", "requested:", "3", "May", "2001", "Revisions", "received:", "18", "October", "2001", "Accepted:", "23", "October", "2001", "Published:", "28", "November", "2001", "Respir", "Res", "2002,", "3:11", "This", "article", "may", "contain", "supplementary", "data", "which", "can", "only", "be", "found", "online", "at", "http://respiratory-research.com/content/2/X", "©", "2002", "BioMed", "Central", "Ltd", "(Print", "ISSN", "1465-9921;", "Online", "ISSN", "1465-993X)", "Abstract", "Chronic", "airway", "inflammation", "is", "one", "of", "the", "main", "features", "of", "asthma.", "Release", "of", "mediators", "from", "infiltrating", "inflammatory", "cells", "in", "the", "airway", "mucosa", "has", "been", "proposed", "to", "contribute", "directly", "or", "indirectly", "to", "changes", "in", "airway", "structure", "and", "function.", "The", "airway", "smooth", "muscle,", "which", "has", "been", "regarded", "as", "a", "contractile", "component", "of", "the", "airways", "responding", "to", "various", "mediators", "and", "neurotransmitters,", "has", "recently", "been", "recognised", "as", "a", "rich", "source", "of", "pro-inflammatory", "cytokines,", "chemokines", "and", "growth", "factors.", "In", "this", "review,", "we", "discuss", "the", "role", "of", "airway", "smooth", "muscle", "cells", "in", "the", "regulation", "and", "perpetuation", "of", "airway", "inflammation", "that", "contribute", "to", "the", "pathogenesis", "of", "asthma.", "Keywords:", "airway", "smooth", "muscle,", "chemokine,", "cytokine,", "growth", "factor,", "inflammation", "Introduction", "Inflammation", "of", "the", "airway", "wall", "is", "a", "central", "characteristic", "of", "asthma", "[1].", "Airborne", "allergens", "often", "lead", "to", "an", "accumula-", "tion", "of", "eosinophils,", "lymphocytes", "(predominantly", "CD4", "type),", "mast", "cells", "and", "macrophages,", "resulting", "in", "an", "inflam-", "matory", "reaction", "in", "the", "mucosa.", "Neutrophil", "numbers", "can", "increase", "during", "an", "exacerbation.", "The", "release", "of", "mediators", "from", "these", "inflammatory", "cells", "has", "been", "proposed", "to", "con-", "tribute", "directly", "or", "indirectly", "to", "changes", "in", "airway", "structure", "and", "function.", "Important", "structural", "changes", "of", "inflamed", "airways", "include", "epithelial", "cell", "shedding,", "basement", "membrane", "thickening,", "goblet", "cell", "hyperplasia", "(increase", "in", "cell", "number)", "and", "hypertrophy", "(increase", "in", "cell", "size),", "as", "well", "as", "an", "increase", "in", "airway", "smooth", "muscle", "(ASM)", "content", "[2].", "These", "struc-", "tural", "changes", "consequently", "form", "the", "basis", "for", "airway", "remodelling,", "a", "phenomenon", "believed", "to", "have", "profound", "consequences", "for", "airway", "function", "[3].", "Bronchial", "vascular", "remodelling,", "with", "an", "increase", "in", "size", "and", "number", "of", "blood", "vessels", "as", "well", "as", "vascular", "hyperaemia", "have", "been", "pro-", "posed", "as", "contributing", "factors", "in", "airway", "wall", "remodelling", "in", "patients", "with", "chronic", "asthma.", "The", "ASM", "has", "been", "typically", "described", "as", "a", "contractile", "tissue,", "responding", "to", "pro-inflammatory", "mediators", "and", "neurotransmitters", "by", "contracting,", "and", "responding", "to", "bronchodilators", "by", "relaxing.", "It", "has", "recently", "been", "recognised,", "however,", "that", "the", "synthetic", "function", "of", "ASM", "cells", "may", "be", "related", "to", "the", "perpetuation", "and", "intensity", "of", "airway", "wall", "inflammation.", "A", "number", "of", "recent", "studies", "have", "shown", "that", "ASM", "cells", "are", "also", "a", "rich", "source", "of", "biologically", "active", "ASM", "=", "airway", "smooth", "muscle;", "BAL", "=", "bronchoalveolar", "lavage;", "COX", "=", "cyclooxygenase;", "ECM", "=", "extracellular", "matrix;", "FGF", "=", "fibroblast", "growth", "factor;", "GM-CSF", "=", "granulocyte/macrophage-colony", "stimulating", "factor;", "IFN", "=", "interferon;", "IGF", "=", "insulin-like", "growth", "factor;", "IL", "=", "interleukin;", "LIF", "=", "leukaemia", "inhibitory", "factor;", "5-LO", "=", "5-lipoxygenase;", "LT", "=", "leukotriene;", "MCP", "=", "monocyte", "chemotactic", "protein;", "MHC", "=", "major", "histocompatibility", "complex;", "NO", "=", "nitric", "oxide;", "PDGF", "=", "platelet-derived", "growth", "factor;", "PG", "=", "prostaglandin;", "RANTES", "=", "regulated", "on", "activation,", "normal", "T", "cell", "expressed", "and", "secreted;", "TGF", "=", "transforming", "growth", "factor;", "Th", "=", "T", "helper", "cells;", "TNF-α", "=", "tumour", "necrosis", "factor-α;", "TX", "=", "thromboxane.", "Page", "1", "of", "13", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 29, 381, 10, 0 ], [ 29, 393, 12, 0 ], [ 29, 399, 6, 0 ], [ 29, 409, 11, 0 ], [ 29, 415, 6, 0 ], [ 29, 427, 12, 0 ], [ 29, 437, 10, 0 ], [ 29, 456, 20, 0 ], [ 29, 469, 6, 0 ], [ 29, 479, 10, 0 ], [ 29, 486, 8, 0 ], [ 29, 498, 12, 0 ], [ 29, 508, 10, 0 ], [ 29, 527, 20, 0 ], [ 29, 534, 6, 0 ], [ 29, 542, 9, 0 ], [ 29, 552, 10, 0 ], [ 29, 564, 12, 0 ], [ 29, 575, 11, 0 ], [ 29, 588, 14, 0 ], [ 29, 602, 7, 0 ], [ 29, 614, 12, 0 ], [ 29, 626, 6, 0 ], [ 29, 636, 10, 0 ], [ 29, 648, 12, 0 ], [ 29, 657, 9, 0 ], [ 29, 669, 12, 0 ], [ 29, 680, 12, 0 ], [ 29, 688, 8, 0 ], [ 29, 705, 10, 0 ], [ 29, 716, 12, 0 ], [ 29, 731, 16, 0 ], [ 75, 793, 77, 11 ], [ 75, 805, 31, 11 ], [ 107, 805, 43, 11 ], [ 75, 818, 124, 11 ], [ 75, 843, 58, 11 ], [ 135, 843, 22, 11 ], [ 159, 843, 17, 11 ], [ 178, 843, 26, 11 ], [ 75, 855, 58, 11 ], [ 135, 855, 24, 11 ], [ 161, 855, 32, 11 ], [ 75, 868, 44, 11 ], [ 120, 868, 25, 11 ], [ 148, 868, 8, 11 ], [ 159, 868, 41, 11 ], [ 75, 880, 108, 11 ], [ 184, 880, 20, 11 ], [ 75, 893, 24, 11 ], [ 101, 893, 34, 11 ], [ 138, 893, 25, 11 ], [ 165, 893, 19, 11 ], [ 186, 893, 23, 11 ], [ 75, 905, 29, 11 ], [ 106, 905, 34, 11 ], [ 143, 905, 20, 11 ], [ 165, 905, 31, 11 ], [ 75, 918, 61, 11 ], [ 138, 918, 24, 11 ], [ 165, 918, 37, 11 ], [ 75, 930, 37, 11 ], [ 679, 48, 12, 17 ], [ 693, 48, 14, 17 ], [ 708, 48, 12, 17 ], [ 721, 48, 6, 17 ], [ 728, 48, 13, 17 ], [ 742, 48, 10, 17 ], [ 754, 48, 10, 17 ], [ 233, 113, 20, 28 ], [ 262, 113, 45, 28 ], [ 316, 113, 34, 28 ], [ 359, 113, 73, 28 ], [ 458, 113, 98, 28 ], [ 564, 113, 43, 28 ], [ 615, 113, 55, 28 ], [ 233, 146, 97, 28 ], [ 338, 146, 104, 28 ], [ 451, 146, 23, 28 ], [ 483, 146, 37, 28 ], [ 529, 146, 111, 28 ], [ 649, 146, 24, 28 ], [ 233, 178, 147, 28 ], [ 389, 178, 57, 28 ], [ 447, 178, 34, 28 ], [ 489, 178, 23, 28 ], [ 520, 178, 125, 28 ], [ 233, 211, 126, 28 ], [ 368, 211, 56, 28 ], [ 233, 264, 63, 17 ], [ 298, 264, 90, 18 ], [ 392, 264, 52, 17 ], [ 449, 264, 90, 18 ], [ 545, 264, 55, 17 ], [ 605, 264, 81, 18 ], [ 233, 283, 54, 17 ], [ 292, 283, 17, 17 ], [ 312, 283, 58, 18 ], [ 373, 283, 71, 17 ], [ 447, 283, 62, 18 ], [ 512, 283, 55, 17 ], [ 572, 283, 77, 18 ], [ 655, 283, 33, 17 ], [ 693, 283, 56, 18 ], [ 233, 302, 50, 17 ], [ 286, 301, 60, 18 ], [ 349, 302, 53, 17 ], [ 407, 301, 69, 18 ], [ 482, 302, 42, 17 ], [ 528, 301, 44, 18 ], [ 577, 302, 53, 17 ], [ 635, 301, 65, 18 ], [ 233, 321, 48, 17 ], [ 285, 320, 49, 18 ], [ 335, 321, 53, 17 ], [ 393, 320, 84, 18 ], [ 482, 321, 26, 17 ], [ 513, 321, 54, 17 ], [ 572, 320, 94, 18 ], [ 233, 360, 54, 12 ], [ 289, 360, 9, 12 ], [ 301, 360, 55, 12 ], [ 359, 360, 44, 12 ], [ 405, 360, 36, 12 ], [ 443, 360, 13, 12 ], [ 458, 360, 34, 12 ], [ 494, 360, 33, 12 ], [ 530, 360, 38, 12 ], [ 570, 360, 25, 12 ], [ 597, 360, 43, 12 ], [ 642, 360, 16, 12 ], [ 661, 360, 54, 12 ], [ 717, 360, 9, 12 ], [ 236, 373, 47, 12 ], [ 286, 373, 34, 12 ], [ 322, 373, 25, 12 ], [ 350, 373, 43, 12 ], [ 394, 373, 40, 12 ], [ 436, 373, 29, 12 ], [ 467, 373, 9, 12 ], [ 479, 373, 41, 12 ], [ 522, 373, 25, 12 ], [ 549, 373, 44, 12 ], [ 595, 373, 25, 12 ], [ 233, 386, 49, 12 ], [ 284, 387, 13, 12 ], [ 299, 387, 80, 12 ], [ 382, 387, 39, 12 ], [ 422, 387, 28, 12 ], [ 453, 387, 13, 12 ], [ 468, 387, 30, 12 ], [ 500, 387, 16, 12 ], [ 518, 387, 55, 12 ], [ 576, 387, 36, 12 ], [ 614, 387, 9, 12 ], [ 626, 387, 35, 12 ], [ 662, 387, 16, 12 ], [ 681, 387, 39, 12 ], [ 722, 387, 40, 12 ], [ 236, 400, 44, 12 ], [ 283, 400, 44, 12 ], [ 329, 400, 25, 12 ], [ 233, 413, 54, 12 ], [ 289, 414, 9, 12 ], [ 301, 414, 31, 12 ], [ 334, 414, 66, 12 ], [ 402, 414, 39, 12 ], [ 443, 414, 30, 12 ], [ 475, 414, 28, 12 ], [ 505, 414, 29, 12 ], [ 536, 414, 18, 12 ], [ 556, 414, 38, 12 ], [ 597, 414, 42, 12 ], [ 641, 414, 25, 12 ], [ 233, 427, 40, 12 ], [ 275, 427, 9, 12 ], [ 286, 427, 42, 12 ], [ 331, 427, 32, 12 ], [ 365, 427, 16, 12 ], [ 383, 427, 42, 12 ], [ 428, 427, 41, 12 ], [ 471, 427, 43, 12 ], [ 516, 427, 9, 12 ], [ 528, 427, 21, 12 ], [ 551, 427, 25, 12 ], [ 578, 427, 21, 12 ], [ 602, 427, 23, 12 ], [ 627, 427, 24, 12 ], [ 653, 427, 26, 12 ], [ 681, 427, 25, 12 ], [ 233, 440, 15, 12 ], [ 250, 441, 32, 12 ], [ 285, 441, 24, 12 ], [ 310, 441, 29, 12 ], [ 341, 441, 9, 12 ], [ 353, 441, 44, 12 ], [ 399, 441, 43, 12 ], [ 444, 441, 9, 12 ], [ 456, 441, 31, 12 ], [ 489, 441, 29, 12 ], [ 520, 441, 18, 12 ], [ 540, 441, 19, 12 ], [ 561, 441, 37, 12 ], [ 600, 441, 13, 12 ], [ 233, 454, 54, 12 ], [ 289, 454, 9, 12 ], [ 301, 454, 20, 12 ], [ 323, 454, 36, 12 ], [ 362, 454, 39, 12 ], [ 402, 454, 36, 12 ], [ 441, 454, 13, 12 ], [ 456, 454, 40, 12 ], [ 498, 454, 38, 12 ], [ 538, 454, 25, 12 ], [ 565, 454, 44, 12 ], [ 612, 454, 25, 12 ], [ 639, 454, 43, 12 ], [ 685, 454, 25, 12 ], [ 233, 467, 23, 12 ], [ 258, 468, 39, 12 ], [ 299, 468, 13, 12 ], [ 314, 468, 48, 12 ], [ 364, 468, 32, 12 ], [ 398, 468, 16, 12 ], [ 417, 468, 50, 12 ], [ 469, 468, 32, 12 ], [ 503, 468, 16, 12 ], [ 522, 468, 48, 12 ], [ 572, 468, 31, 12 ], [ 605, 468, 9, 12 ], [ 617, 468, 27, 12 ], [ 646, 468, 46, 12 ], [ 695, 468, 44, 12 ], [ 741, 468, 25, 12 ], [ 233, 501, 9, 14 ], [ 245, 501, 72, 14 ], [ 321, 501, 13, 14 ], [ 338, 501, 43, 14 ], [ 384, 501, 21, 14 ], [ 409, 501, 83, 14 ], [ 496, 501, 41, 14 ], [ 540, 501, 21, 14 ], [ 565, 501, 32, 14 ], [ 601, 501, 73, 14 ], [ 677, 501, 41, 14 ], [ 722, 501, 11, 14 ], [ 233, 518, 48, 14 ], [ 284, 518, 24, 14 ], [ 312, 518, 31, 14 ], [ 347, 518, 35, 14 ], [ 385, 518, 19, 14 ], [ 407, 518, 63, 14 ], [ 474, 518, 33, 14 ], [ 510, 518, 13, 14 ], [ 527, 518, 44, 14 ], [ 575, 518, 73, 14 ], [ 651, 518, 50, 14 ], [ 705, 518, 20, 14 ], [ 728, 518, 13, 14 ], [ 233, 534, 44, 14 ], [ 281, 534, 20, 14 ], [ 304, 534, 41, 14 ], [ 349, 534, 33, 14 ], [ 386, 534, 7, 14 ], [ 397, 534, 64, 14 ], [ 464, 534, 31, 14 ], [ 499, 534, 58, 14 ], [ 560, 534, 41, 14 ], [ 605, 534, 35, 14 ], [ 644, 534, 40, 14 ], [ 687, 534, 63, 14 ], [ 233, 551, 13, 14 ], [ 249, 551, 76, 14 ], [ 329, 551, 73, 14 ], [ 405, 551, 7, 14 ], [ 416, 551, 26, 14 ], [ 445, 551, 21, 14 ], [ 470, 551, 28, 14 ], [ 502, 551, 65, 14 ], [ 570, 551, 11, 14 ], [ 585, 551, 20, 14 ], [ 608, 551, 58, 14 ], [ 669, 551, 53, 14 ], [ 726, 551, 11, 14 ], [ 741, 551, 19, 14 ], [ 233, 568, 31, 14 ], [ 267, 568, 76, 14 ], [ 347, 568, 7, 14 ], [ 358, 568, 34, 14 ], [ 395, 568, 87, 14 ], [ 486, 568, 51, 14 ], [ 540, 568, 13, 14 ], [ 556, 568, 52, 14 ], [ 612, 568, 7, 14 ], [ 623, 568, 32, 14 ], [ 659, 568, 38, 14 ], [ 709, 568, 48, 14 ], [ 233, 584, 12, 14 ], [ 249, 584, 45, 14 ], [ 307, 584, 50, 14 ], [ 361, 584, 26, 14 ], [ 391, 584, 12, 14 ], [ 407, 584, 44, 14 ], [ 454, 584, 21, 14 ], [ 479, 584, 55, 14 ], [ 538, 584, 21, 14 ], [ 562, 584, 40, 14 ], [ 605, 584, 36, 14 ], [ 645, 584, 43, 14 ], [ 692, 584, 47, 14 ], [ 743, 584, 11, 14 ], [ 233, 601, 24, 14 ], [ 260, 601, 30, 14 ], [ 293, 601, 20, 14 ], [ 316, 601, 24, 14 ], [ 343, 601, 52, 14 ], [ 398, 601, 46, 14 ], [ 447, 601, 11, 14 ], [ 461, 601, 40, 14 ], [ 504, 601, 30, 14 ], [ 537, 601, 51, 14 ], [ 592, 601, 13, 14 ], [ 607, 601, 54, 14 ], [ 665, 601, 7, 14 ], [ 675, 601, 33, 14 ], [ 719, 601, 45, 14 ], [ 233, 618, 52, 14 ], [ 288, 618, 21, 14 ], [ 312, 618, 44, 14 ], [ 359, 618, 24, 14 ], [ 386, 618, 47, 14 ], [ 436, 618, 53, 14 ], [ 492, 618, 14, 14 ], [ 518, 618, 54, 14 ], [ 574, 618, 34, 14 ], [ 612, 618, 47, 14 ], [ 662, 618, 47, 14 ], [ 711, 618, 52, 14 ], [ 233, 634, 26, 14 ], [ 263, 634, 11, 14 ], [ 278, 634, 28, 14 ], [ 310, 634, 12, 14 ], [ 325, 634, 7, 14 ], [ 337, 634, 122, 14 ], [ 463, 634, 20, 14 ], [ 487, 634, 49, 14 ], [ 540, 634, 129, 14 ], [ 673, 634, 48, 14 ], [ 233, 651, 76, 14 ], [ 312, 651, 56, 14 ], [ 372, 651, 59, 14 ], [ 434, 651, 42, 14 ], [ 480, 651, 31, 14 ], [ 514, 651, 21, 14 ], [ 539, 651, 44, 14 ], [ 586, 651, 24, 14 ], [ 614, 651, 47, 14 ], [ 665, 651, 11, 14 ], [ 680, 651, 15, 14 ], [ 698, 651, 54, 14 ], [ 233, 668, 33, 14 ], [ 270, 668, 54, 14 ], [ 327, 668, 76, 14 ], [ 407, 668, 49, 14 ], [ 460, 668, 56, 14 ], [ 520, 668, 13, 14 ], [ 536, 668, 146, 14 ], [ 686, 668, 24, 14 ], [ 714, 668, 45, 14 ], [ 233, 684, 50, 14 ], [ 287, 684, 26, 14 ], [ 317, 684, 23, 14 ], [ 343, 684, 29, 14 ], [ 376, 684, 25, 14 ], [ 405, 684, 47, 14 ], [ 456, 684, 11, 14 ], [ 471, 684, 24, 14 ], [ 499, 684, 31, 14 ], [ 534, 684, 30, 14 ], [ 567, 684, 44, 14 ], [ 615, 684, 55, 14 ], [ 673, 684, 53, 14 ], [ 730, 684, 31, 14 ], [ 233, 701, 21, 14 ], [ 258, 701, 43, 14 ], [ 304, 701, 24, 14 ], [ 332, 701, 33, 14 ], [ 369, 701, 73, 14 ], [ 445, 701, 47, 14 ], [ 496, 701, 26, 14 ], [ 526, 701, 12, 14 ], [ 542, 701, 67, 14 ], [ 613, 701, 47, 14 ], [ 663, 701, 14, 14 ], [ 681, 701, 66, 14 ], [ 233, 718, 37, 14 ], [ 274, 718, 55, 14 ], [ 332, 718, 11, 14 ], [ 347, 718, 62, 14 ], [ 412, 718, 24, 14 ], [ 440, 718, 38, 14 ], [ 482, 718, 62, 14 ], [ 549, 718, 76, 14 ], [ 628, 718, 73, 14 ], [ 704, 718, 7, 14 ], [ 715, 718, 26, 14 ], [ 233, 734, 12, 14 ], [ 249, 734, 7, 14 ], [ 260, 734, 33, 14 ], [ 297, 734, 13, 14 ], [ 313, 734, 43, 14 ], [ 359, 734, 58, 14 ], [ 421, 734, 12, 14 ], [ 437, 734, 60, 14 ], [ 233, 787, 28, 14 ], [ 266, 787, 40, 14 ], [ 312, 787, 20, 14 ], [ 338, 787, 80, 14 ], [ 423, 787, 36, 14 ], [ 464, 787, 26, 14 ], [ 233, 803, 37, 14 ], [ 276, 803, 12, 14 ], [ 295, 803, 18, 14 ], [ 319, 803, 71, 14 ], [ 397, 803, 11, 14 ], [ 415, 803, 50, 14 ], [ 472, 803, 19, 14 ], [ 233, 820, 57, 14 ], [ 294, 820, 44, 14 ], [ 341, 820, 25, 14 ], [ 369, 820, 10, 14 ], [ 382, 820, 63, 14 ], [ 449, 820, 41, 14 ], [ 233, 836, 29, 14 ], [ 267, 836, 20, 14 ], [ 292, 836, 24, 14 ], [ 321, 836, 7, 14 ], [ 333, 836, 44, 14 ], [ 382, 836, 15, 14 ], [ 401, 836, 15, 14 ], [ 421, 836, 56, 14 ], [ 482, 836, 8, 14 ], [ 233, 852, 43, 14 ], [ 281, 852, 43, 14 ], [ 330, 852, 25, 14 ], [ 361, 852, 25, 14 ], [ 392, 852, 32, 14 ], [ 429, 852, 8, 14 ], [ 443, 852, 48, 14 ], [ 233, 868, 23, 14 ], [ 259, 868, 6, 14 ], [ 269, 868, 32, 14 ], [ 305, 868, 30, 14 ], [ 339, 868, 11, 14 ], [ 354, 868, 73, 14 ], [ 431, 868, 34, 14 ], [ 469, 868, 21, 14 ], [ 233, 909, 12, 11 ], [ 247, 909, 45, 11 ], [ 294, 909, 15, 11 ], [ 312, 909, 12, 11 ], [ 327, 909, 43, 11 ], [ 372, 909, 49, 11 ], [ 424, 909, 30, 11 ], [ 456, 909, 9, 11 ], [ 233, 922, 15, 11 ], [ 250, 922, 25, 11 ], [ 233, 935, 10, 11 ], [ 245, 935, 38, 11 ], [ 285, 935, 30, 11 ], [ 317, 935, 29, 11 ], [ 349, 935, 6, 11 ], [ 358, 935, 46, 11 ], [ 406, 935, 19, 11 ], [ 427, 935, 19, 11 ], [ 449, 935, 39, 11 ], [ 233, 948, 43, 11 ], [ 278, 948, 25, 11 ], [ 233, 962, 10, 11 ], [ 245, 962, 45, 11 ], [ 293, 962, 30, 11 ], [ 325, 962, 29, 11 ], [ 357, 962, 6, 11 ], [ 365, 962, 45, 11 ], [ 413, 962, 12, 11 ], [ 428, 962, 32, 11 ], [ 463, 962, 22, 11 ], [ 233, 974, 16, 11 ], [ 250, 974, 15, 11 ], [ 267, 974, 42, 11 ], [ 311, 974, 38, 11 ], [ 352, 974, 29, 11 ], [ 382, 974, 12, 11 ], [ 396, 974, 41, 11 ], [ 440, 974, 32, 11 ], [ 473, 974, 15, 11 ], [ 233, 987, 53, 11 ], [ 288, 987, 44, 11 ], [ 334, 987, 9, 11 ], [ 345, 987, 31, 11 ], [ 379, 987, 28, 11 ], [ 410, 987, 43, 11 ], [ 455, 987, 25, 11 ], [ 233, 1001, 17, 11 ], [ 252, 1001, 26, 11 ], [ 280, 1001, 30, 11 ], [ 311, 1001, 9, 11 ], [ 322, 1001, 15, 11 ], [ 338, 1001, 25, 11 ], [ 365, 1001, 33, 11 ], [ 400, 1001, 53, 11 ], [ 456, 1001, 35, 11 ], [ 509, 787, 10, 14 ], [ 525, 787, 23, 14 ], [ 554, 787, 17, 14 ], [ 577, 787, 18, 14 ], [ 601, 787, 28, 14 ], [ 634, 787, 54, 14 ], [ 694, 787, 12, 14 ], [ 711, 787, 31, 14 ], [ 748, 787, 19, 14 ], [ 509, 803, 58, 14 ], [ 573, 803, 45, 14 ], [ 623, 803, 21, 14 ], [ 650, 803, 11, 14 ], [ 666, 803, 18, 14 ], [ 690, 803, 20, 14 ], [ 715, 803, 30, 14 ], [ 751, 803, 16, 14 ], [ 509, 820, 64, 14 ], [ 579, 820, 19, 14 ], [ 604, 820, 65, 14 ], [ 675, 820, 12, 14 ], [ 693, 820, 74, 14 ], [ 509, 836, 37, 14 ], [ 552, 836, 35, 14 ], [ 593, 836, 14, 14 ], [ 612, 836, 12, 14 ], [ 630, 836, 61, 14 ], [ 696, 836, 25, 14 ], [ 727, 836, 40, 14 ], [ 509, 852, 20, 14 ], [ 533, 852, 80, 14 ], [ 617, 852, 36, 14 ], [ 657, 852, 30, 14 ], [ 690, 852, 18, 14 ], [ 711, 852, 40, 14 ], [ 755, 852, 11, 14 ], [ 509, 868, 18, 14 ], [ 534, 868, 62, 14 ], [ 603, 868, 57, 14 ], [ 667, 868, 20, 14 ], [ 693, 868, 55, 14 ], [ 755, 868, 11, 14 ], [ 509, 885, 61, 14 ], [ 573, 885, 66, 14 ], [ 643, 885, 10, 14 ], [ 656, 885, 27, 14 ], [ 529, 901, 21, 14 ], [ 554, 901, 8, 14 ], [ 565, 901, 6, 14 ], [ 574, 901, 42, 14 ], [ 620, 901, 46, 14 ], [ 669, 901, 74, 14 ], [ 746, 901, 21, 14 ], [ 509, 917, 22, 14 ], [ 537, 917, 21, 14 ], [ 564, 917, 50, 14 ], [ 620, 917, 34, 14 ], [ 659, 917, 18, 14 ], [ 682, 917, 45, 14 ], [ 733, 917, 34, 14 ], [ 509, 933, 35, 14 ], [ 548, 933, 11, 14 ], [ 564, 933, 46, 14 ], [ 614, 933, 30, 14 ], [ 648, 933, 19, 14 ], [ 671, 933, 28, 14 ], [ 703, 933, 40, 14 ], [ 747, 933, 20, 14 ], [ 509, 950, 84, 14 ], [ 601, 950, 38, 14 ], [ 646, 950, 17, 14 ], [ 671, 950, 50, 14 ], [ 729, 950, 12, 14 ], [ 748, 950, 18, 14 ], [ 509, 966, 69, 14 ], [ 582, 966, 15, 14 ], [ 600, 966, 11, 14 ], [ 615, 966, 15, 14 ], [ 633, 966, 20, 14 ], [ 656, 966, 50, 14 ], [ 709, 966, 34, 14 ], [ 747, 966, 20, 14 ], [ 509, 982, 63, 14 ], [ 576, 982, 31, 14 ], [ 611, 982, 23, 14 ], [ 639, 982, 58, 14 ], [ 701, 982, 27, 14 ], [ 732, 982, 11, 14 ], [ 747, 982, 19, 14 ], [ 509, 998, 56, 14 ], [ 572, 998, 18, 14 ], [ 598, 998, 41, 14 ], [ 646, 998, 73, 14 ], [ 726, 998, 12, 14 ], [ 745, 998, 21, 14 ], [ 75, 1040, 15, 10 ], [ 93, 1040, 5, 10 ], [ 100, 1040, 13, 10 ], [ 115, 1040, 41, 10 ], [ 158, 1040, 38, 10 ], [ 197, 1040, 20, 10 ], [ 226, 1040, 21, 10 ], [ 75, 1052, 14, 10 ], [ 90, 1052, 16, 10 ], [ 109, 1052, 13, 10 ], [ 123, 1052, 7, 10 ], [ 135, 1052, 24, 10 ], [ 160, 1052, 12, 10 ], [ 174, 1052, 19, 10 ], [ 198, 1052, 33, 10 ], [ 240, 1052, 165, 10 ], [ 750, 1040, 17, 10 ] ]

[ "e", "n", "i", "c", "i", "d", "e", "M", "l", "a", "t", "n", "e", "m", "i", "r", "e", "p", "x", "E", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "CORRESPONDENCE", "Shimon", "Sakaguchi:", "shimon@frontier.kyoto-u.ac.jp", "Abbreviations", "used:", "CP,", "cyclo-", "phosphamide;", "ITS1,", "internal", "transcriber", "spacer", "1;", "poly(I:C),", "polyinosinic-polycytidylic", "acid;", "PTX,", "pertussis", "toxin;", "RA,", "rheu-", "matoid", "arthritis;", "SPF,", "specific", "pathogen-free;", "TLR,", "Toll-like", "receptor.", "A", "R", "T", "I", "C", "L", "E", "A", "role", "for", "fungal", "-glucans", "and", "their", "receptor", "Dectin-1", "in", "the", "induction", "of", "autoimmune", "arthr", "itis", "in", "genetically", "susceptible", "mice", "Hiroyuki", "Yoshitomi,1,2", "Noriko", "Sakaguchi,1,3", "Katsuya", "Kobayashi,4", "Gordon", "D.", "Brown,5", "Tomoyuki", "Tagami,1", "Toshiko", "Sakihama,1", "Keiji", "Hirota,1", "Satoshi", "Tanaka,1", "Takashi", "Nomura,1", "Ichiro", "Miki,4", "Siamon", "Gordon,6", "Shizuo", "Akira,7", "Takashi", "Nakamura,2", "and", "Shimon", "Sakaguchi1,3,8", "1Department", "of", "Experimental", "Pathology,", "Institute", "for", "Frontier", "Medical", "Sciences,", "Kyoto", "University", "and", "2Department", "of", "Orthopedic", "Surgery,", "Kyoto", "University", "Graduate", "School", "of", "Medicine,", "Kyoto", "606-8507,", "Japan", "3Laboratory", "for", "Immunopathology,", "Research", "Center", "for", "Allergy", "and", "Immunology,", "Institute", "of", "Physical", "and", "Chemical", "Research,", "Yokohama", "230-0045,", "Japan", "4Department", "of", "Allergy,", "Pharmaceutical", "Research", "Center,", "Kyowa", "Hakko,", "Ltd.,", "Shizuoka", "411-8731,", "Japan", "5Institute", "of", "Infectious", "Disease", "and", "Molecular", "Medicine,", "University", "of", "Cape", "Town,", "Cape", "Town", "7925,", "South", "Africa", "6Sir", "William", "Dunn", "School", "of", "Pathology,", "University", "of", "Oxford,", "Oxford", "OX1", "3RE,", "England,", "UK", "7Department", "of", "Host", "Defense,", "Research", "Institute", "for", "Microbial", "Diseases,", "Osaka", "University,", "Osaka", "565-0871,", "Japan", "8Core", "Research", "for", "Evolutional", "Science", "and", "Technology,", "Science", "and", "Technology", "Agency", "of", "Japan,", "Kawaguchi", "332-0012,", "Japan", "A", "combination", "of", "genetic", "and", "environmental", "factors", "can", "cause", "autoimmune", "disease", "in", "animals.", "SKG", "mice,", "which", "are", "genetically", "prone", "to", "develop", "autoimmune", "arthritis,", "fail", "to", "develop", "the", "disease", "under", "a", "microbially", "clean", "condition,", "despite", "active", "thymic", "production", "of", "arthritogenic", "autoimmune", "T", "cells", "and", "their", "persistence", "in", "the", "periphery.", "However,", "in", "the", "clean", "environment,", "a", "single", "intraperitoneal", "injection", "of", "zymosan,", "a", "crude", "fungal", "-glucan,", "or", "purified", "-glucans", "such", "as", "curdlan", "and", "laminarin", "can", "trigger", "severe", "chronic", "arthritis", "in", "SKG", "mice,", "but", "only", "transient", "arthritis", "in", "normal", "mice.", "Blockade", "of", "Dectin-1,", "a", "major", "-glucan", "receptor,", "can", "prevent", "SKG", "arthritis", "triggered", "by", "-glucans,", "which", "strongly", "activate", "dendritic", "cells", "in", "vitro", "in", "a", "Dectin-1–dependent", "but", "Toll-like", "receptor-independent", "manner.", "Furthermore,", "antibiotic", "treatment", "against", "fungi", "can", "prevent", "SKG", "arthritis", "in", "an", "arthritis-", "prone", "microbial", "environment.", "Multiple", "injections", "of", "polyinosinic-polycytidylic", "acid", "double-", "stranded", "RNA", "also", "elicit", "mild", "arthritis", "in", "SKG", "mice.", "Thus,", "specific", "microbes,", "including", "fungi", "and", "viruses,", "may", "evoke", "autoimmune", "arthritis", "such", "as", "rheumatoid", "arthritis", "by", "stimulating", "innate", "immunity", "in", "individuals", "who", "harbor", "potentially", "arthritogenic", "autoimmune", "T", "cells", "as", "a", "result", "of", "genetic", "anomalies", "or", "variations.", "Both", "genetic", "and", "environmental", "factors", "con-", "tribute", "to", "the", "development", "of", "common", "au-", "toimmune", "diseases,", "such", "as", "rheumatoid", "arthritis", "(RA)", "and", "type", "1", "diabetes", "(1,", "2).", "However,", "it", "remains", "obscure", "how", "each", "factor", "is", "arranged", "into", "a", "causal", "chain", "of", "pathogenesis.", "Given", "that", "H.", "Yoshitomi", "and", "N.", "Sakaguchi", "contributed", "equally", "to", "this", "work.", "T.", "Tagami’s", "present", "address", "is", "Ajinomoto", "Co.,", "Inc.,", "Kawasaki", "210-8681,", "Japan.", "T.", "Sakihama’s", "present", "address", "is", "Laboratory", "for", "Systems", "Biol-", "ogy", "and", "Medicine,", "Research", "Center", "for", "Advanced", "Science", "and", "Technology,", "University", "of", "Tokyo,", "Tokyo", "153-8904,", "Japan.", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "T", "cells", "are", "the", "main", "mediators", "of", "many", "au-", "toimmune", "diseases,", "one", "of", "the", "key", "issues", "for", "elucidating", "the", "mechanism", "of", "autoimmune", "disease", "would", "be", "to", "understand", "how", "genetic", "and", "environmental", "factors", "affect", "the", "control", "of", "the", "generation,", "activation,", "and", "expansion", "of", "pathogenic", "self-reactive", "T", "cells.", "RA", "is", "a", "chronic", "systemic", "inflammatory", "dis-", "ease", "that", "primarily", "affects", "the", "synovial", "mem-", "branes", "of", "multiple", "joints", "(1).", "Both", "genetic", "and", "environmental", "factors", "are", "involved", "in", "the", "pathogenesis", "(1,", "3,", "4).", "For", "example,", "MHC", "and", "non-MHC", "genes", "play", "significant", "roles", "in", "de-", "termining", "the", "genetic", "susceptibility", "to", "RA", "JEM", "©", "The", "Rockefeller", "University", "Press", "$8.00", "Vol.", "201,", "No.", "6,", "March", "21,", "2005", "949–960", "www.jem.org/cgi/doi/10.1084/jem.20041758", "949" ]

[ 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 16, 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4 ]

[ [ 233, 114, 77, 20 ], [ 316, 114, 21, 20 ], [ 343, 114, 91, 20 ], [ 440, 114, 14, 20 ], [ 460, 114, 15, 20 ], [ 481, 114, 74, 20 ], [ 561, 114, 87, 20 ], [ 654, 114, 18, 20 ], [ 233, 137, 107, 20 ], [ 346, 137, 59, 20 ], [ 410, 137, 108, 20 ], [ 524, 137, 26, 20 ], [ 556, 137, 81, 20 ], [ 233, 160, 18, 20 ], [ 255, 160, 130, 20 ], [ 233, 188, 19, 17 ], [ 256, 188, 33, 17 ], [ 293, 187, 121, 18 ], [ 417, 188, 40, 17 ], [ 460, 187, 70, 18 ], [ 534, 188, 55, 17 ], [ 594, 187, 59, 18 ], [ 233, 206, 27, 17 ], [ 264, 206, 34, 17 ], [ 301, 206, 54, 18 ], [ 359, 206, 24, 17 ], [ 385, 206, 50, 17 ], [ 440, 206, 58, 18 ], [ 233, 254, 25, 13 ], [ 261, 254, 14, 13 ], [ 278, 254, 60, 13 ], [ 341, 254, 9, 13 ], [ 353, 254, 62, 13 ], [ 416, 254, 14, 13 ], [ 434, 254, 60, 14 ], [ 496, 254, 9, 13 ], [ 509, 254, 45, 13 ], [ 556, 254, 14, 13 ], [ 573, 254, 59, 14 ], [ 635, 254, 8, 13 ], [ 647, 254, 20, 13 ], [ 233, 270, 35, 13 ], [ 271, 270, 17, 13 ], [ 290, 270, 45, 13 ], [ 337, 270, 17, 13 ], [ 358, 270, 14, 13 ], [ 375, 270, 46, 13 ], [ 425, 270, 38, 13 ], [ 466, 270, 10, 13 ], [ 479, 270, 60, 13 ], [ 540, 270, 25, 13 ], [ 569, 270, 40, 13 ], [ 612, 270, 48, 13 ], [ 233, 286, 30, 13 ], [ 266, 286, 9, 13 ], [ 278, 286, 45, 13 ], [ 325, 286, 48, 13 ], [ 374, 286, 46, 13 ], [ 423, 286, 33, 13 ], [ 233, 330, 67, 16 ], [ 233, 350, 50, 15 ], [ 287, 350, 72, 15 ], [ 363, 350, 42, 15 ], [ 410, 350, 17, 15 ], [ 431, 350, 6, 15 ], [ 441, 350, 60, 15 ], [ 505, 350, 53, 15 ], [ 562, 350, 82, 15 ], [ 648, 350, 34, 15 ], [ 686, 350, 12, 15 ], [ 702, 350, 50, 15 ], [ 756, 350, 12, 15 ], [ 233, 366, 36, 15 ], [ 273, 366, 18, 15 ], [ 295, 366, 48, 15 ], [ 347, 366, 37, 15 ], [ 388, 366, 36, 15 ], [ 429, 366, 6, 15 ], [ 439, 366, 40, 15 ], [ 483, 366, 19, 15 ], [ 506, 366, 36, 15 ], [ 546, 366, 42, 15 ], [ 591, 366, 34, 15 ], [ 630, 366, 12, 15 ], [ 645, 366, 66, 15 ], [ 716, 366, 52, 15 ], [ 233, 382, 29, 15 ], [ 265, 382, 24, 15 ], [ 292, 382, 56, 15 ], [ 352, 382, 45, 15 ], [ 400, 382, 17, 15 ], [ 421, 382, 19, 15 ], [ 444, 382, 40, 15 ], [ 487, 382, 14, 15 ], [ 505, 382, 51, 15 ], [ 559, 382, 53, 15 ], [ 616, 382, 52, 15 ], [ 671, 382, 13, 15 ], [ 687, 382, 65, 15 ], [ 756, 382, 12, 15 ], [ 233, 398, 41, 15 ], [ 277, 398, 24, 15 ], [ 305, 398, 19, 15 ], [ 328, 398, 45, 15 ], [ 376, 398, 50, 15 ], [ 430, 398, 21, 15 ], [ 454, 398, 73, 15 ], [ 530, 398, 12, 15 ], [ 546, 398, 39, 15 ], [ 588, 398, 29, 15 ], [ 620, 398, 32, 15 ], [ 656, 398, 24, 15 ], [ 683, 398, 48, 15 ], [ 734, 398, 33, 15 ], [ 233, 414, 28, 15 ], [ 265, 414, 21, 15 ], [ 290, 414, 30, 15 ], [ 325, 414, 25, 15 ], [ 354, 414, 22, 15 ], [ 380, 414, 18, 15 ], [ 403, 414, 48, 15 ], [ 455, 414, 12, 15 ], [ 471, 414, 71, 15 ], [ 546, 414, 45, 15 ], [ 596, 414, 33, 15 ], [ 633, 414, 18, 15 ], [ 656, 414, 52, 15 ], [ 712, 414, 12, 15 ], [ 728, 414, 40, 15 ], [ 233, 430, 47, 15 ], [ 284, 430, 73, 15 ], [ 360, 430, 42, 15 ], [ 407, 430, 17, 15 ], [ 428, 430, 56, 15 ], [ 488, 430, 42, 15 ], [ 534, 430, 14, 15 ], [ 552, 430, 55, 15 ], [ 611, 430, 10, 15 ], [ 624, 430, 12, 15 ], [ 640, 430, 27, 15 ], [ 671, 430, 21, 15 ], [ 696, 430, 37, 15 ], [ 737, 430, 30, 15 ], [ 233, 446, 29, 15 ], [ 267, 446, 67, 15 ], [ 339, 446, 94, 15 ], [ 439, 446, 35, 15 ], [ 479, 446, 59, 15 ], [ 544, 446, 40, 15 ], [ 589, 446, 55, 15 ], [ 649, 446, 19, 15 ], [ 674, 446, 50, 15 ], [ 730, 446, 38, 15 ], [ 233, 462, 20, 15 ], [ 257, 462, 30, 15 ], [ 291, 462, 28, 15 ], [ 323, 462, 12, 15 ], [ 339, 462, 55, 15 ], [ 398, 462, 34, 15 ], [ 436, 462, 56, 15 ], [ 496, 462, 17, 15 ], [ 517, 462, 20, 15 ], [ 540, 462, 42, 15 ], [ 586, 462, 14, 15 ], [ 605, 462, 56, 15 ], [ 664, 462, 50, 15 ], [ 718, 462, 20, 15 ], [ 742, 462, 25, 15 ], [ 233, 478, 27, 15 ], [ 264, 478, 18, 15 ], [ 286, 478, 6, 15 ], [ 297, 478, 25, 15 ], [ 326, 478, 37, 15 ], [ 367, 478, 56, 15 ], [ 428, 478, 12, 15 ], [ 444, 478, 55, 15 ], [ 503, 478, 13, 15 ], [ 520, 478, 24, 15 ], [ 548, 478, 55, 15 ], [ 608, 478, 10, 15 ], [ 621, 478, 47, 15 ], [ 673, 478, 23, 15 ], [ 700, 478, 12, 15 ], [ 716, 478, 52, 15 ], [ 233, 494, 25, 15 ], [ 262, 494, 42, 15 ], [ 309, 494, 36, 15 ], [ 349, 494, 27, 15 ], [ 380, 494, 12, 15 ], [ 396, 494, 18, 15 ], [ 419, 494, 13, 17 ], [ 436, 494, 21, 15 ], [ 461, 494, 13, 17 ], [ 478, 494, 50, 15 ], [ 532, 494, 22, 15 ], [ 558, 494, 17, 15 ], [ 580, 494, 51, 15 ], [ 635, 494, 14, 15 ], [ 654, 494, 55, 15 ], [ 713, 494, 10, 15 ], [ 727, 494, 19, 15 ], [ 750, 494, 17, 15 ], [ 233, 510, 20, 15 ], [ 256, 510, 50, 15 ], [ 310, 510, 14, 15 ], [ 328, 510, 56, 15 ], [ 388, 510, 13, 15 ], [ 405, 510, 44, 15 ], [ 453, 510, 12, 15 ], [ 469, 510, 74, 15 ], [ 547, 510, 93, 15 ], [ 644, 510, 17, 15 ], [ 665, 510, 33, 15 ], [ 702, 510, 19, 15 ], [ 725, 510, 42, 15 ], [ 233, 526, 14, 15 ], [ 250, 526, 55, 15 ], [ 309, 526, 10, 15 ], [ 321, 526, 13, 15 ], [ 337, 526, 17, 15 ], [ 358, 526, 42, 15 ], [ 403, 526, 12, 15 ], [ 418, 526, 48, 15 ], [ 470, 526, 55, 15 ], [ 528, 526, 48, 15 ], [ 579, 526, 12, 15 ], [ 594, 526, 30, 15 ], [ 627, 526, 41, 15 ], [ 672, 526, 12, 15 ], [ 687, 526, 30, 15 ], [ 720, 526, 32, 15 ], [ 756, 526, 12, 15 ], [ 233, 542, 55, 15 ], [ 292, 542, 24, 15 ], [ 320, 542, 42, 15 ], [ 366, 542, 35, 15 ], [ 405, 542, 12, 15 ], [ 420, 542, 55, 15 ], [ 479, 542, 10, 15 ], [ 493, 542, 12, 15 ], [ 509, 542, 48, 15 ], [ 560, 542, 40, 15 ], [ 604, 542, 55, 15 ], [ 663, 542, 9, 15 ], [ 675, 542, 51, 15 ], [ 731, 542, 14, 15 ], [ 748, 542, 19, 15 ], [ 233, 558, 38, 15 ], [ 275, 558, 49, 15 ], [ 327, 558, 12, 15 ], [ 342, 558, 71, 15 ], [ 416, 558, 21, 15 ], [ 440, 558, 37, 15 ], [ 481, 558, 18, 15 ], [ 502, 558, 48, 15 ], [ 554, 558, 12, 15 ], [ 569, 558, 56, 15 ], [ 628, 558, 45, 15 ], [ 677, 558, 12, 15 ], [ 692, 558, 20, 15 ], [ 716, 558, 52, 15 ], [ 233, 574, 12, 15 ], [ 247, 574, 45, 15 ], [ 295, 574, 34, 15 ], [ 332, 574, 34, 15 ], [ 369, 574, 29, 15 ], [ 401, 574, 50, 15 ], [ 453, 574, 15, 15 ], [ 471, 574, 18, 15 ], [ 492, 574, 22, 15 ], [ 517, 574, 12, 15 ], [ 531, 574, 18, 15 ], [ 552, 574, 52, 15 ], [ 607, 574, 66, 15 ], [ 675, 574, 92, 15 ], [ 233, 590, 31, 15 ], [ 267, 590, 48, 15 ], [ 319, 590, 12, 15 ], [ 334, 590, 18, 15 ], [ 355, 590, 51, 15 ], [ 410, 590, 21, 15 ], [ 435, 590, 67, 15 ], [ 505, 590, 12, 15 ], [ 521, 590, 47, 15 ], [ 571, 590, 85, 15 ], [ 233, 614, 23, 15 ], [ 259, 614, 37, 15 ], [ 310, 614, 52, 15 ], [ 365, 614, 5, 15 ], [ 374, 614, 52, 15 ], [ 428, 614, 10, 15 ], [ 442, 614, 67, 15 ], [ 512, 614, 5, 15 ], [ 521, 614, 46, 15 ], [ 570, 614, 5, 15 ], [ 579, 614, 40, 15 ], [ 75, 658, 99, 41 ], [ 181, 679, 42, 15 ], [ 230, 679, 51, 15 ], [ 287, 679, 44, 15 ], [ 338, 679, 18, 15 ], [ 363, 679, 46, 15 ], [ 101, 663, 14, 15 ], [ 121, 663, 36, 15 ], [ 163, 663, 42, 15 ], [ 210, 663, 74, 15 ], [ 290, 663, 48, 15 ], [ 344, 663, 12, 15 ], [ 362, 663, 47, 15 ], [ 75, 695, 60, 15 ], [ 138, 695, 12, 15 ], [ 154, 695, 18, 15 ], [ 176, 695, 42, 15 ], [ 221, 695, 42, 15 ], [ 267, 695, 82, 15 ], [ 353, 695, 56, 15 ], [ 75, 711, 26, 15 ], [ 104, 711, 33, 15 ], [ 141, 711, 15, 15 ], [ 161, 711, 15, 15 ], [ 180, 711, 54, 15 ], [ 238, 711, 56, 15 ], [ 298, 711, 45, 15 ], [ 347, 711, 14, 15 ], [ 366, 711, 18, 15 ], [ 388, 711, 21, 15 ], [ 75, 727, 33, 15 ], [ 112, 727, 37, 15 ], [ 154, 727, 12, 15 ], [ 171, 727, 29, 15 ], [ 204, 727, 42, 15 ], [ 251, 727, 17, 15 ], [ 273, 727, 75, 15 ], [ 353, 727, 40, 15 ], [ 397, 727, 12, 15 ], [ 75, 743, 31, 15 ], [ 110, 743, 12, 15 ], [ 126, 743, 53, 15 ], [ 183, 743, 52, 15 ], [ 239, 743, 21, 15 ], [ 264, 743, 60, 15 ], [ 328, 743, 66, 15 ], [ 397, 743, 12, 15 ], [ 75, 759, 41, 15 ], [ 121, 759, 28, 15 ], [ 154, 759, 25, 15 ], [ 183, 759, 17, 15 ], [ 205, 759, 52, 15 ], [ 263, 759, 71, 15 ], [ 339, 759, 12, 15 ], [ 356, 759, 53, 15 ], [ 75, 775, 28, 15 ], [ 106, 775, 56, 15 ], [ 166, 775, 50, 15 ], [ 221, 775, 21, 15 ], [ 245, 775, 73, 15 ], [ 322, 775, 12, 15 ], [ 338, 775, 23, 15 ], [ 365, 775, 44, 15 ], [ 75, 791, 27, 15 ], [ 106, 791, 12, 15 ], [ 121, 791, 39, 15 ], [ 164, 791, 54, 15 ], [ 222, 791, 15, 15 ], [ 241, 791, 18, 15 ], [ 263, 791, 32, 15 ], [ 299, 791, 20, 15 ], [ 323, 791, 20, 15 ], [ 346, 791, 9, 15 ], [ 360, 791, 18, 15 ], [ 381, 791, 27, 15 ], [ 75, 807, 52, 15 ], [ 131, 807, 22, 15 ], [ 157, 807, 47, 15 ], [ 208, 807, 12, 15 ], [ 224, 807, 45, 15 ], [ 274, 807, 34, 15 ], [ 312, 807, 23, 15 ], [ 340, 807, 6, 15 ], [ 350, 807, 22, 15 ], [ 376, 807, 12, 15 ], [ 392, 807, 17, 15 ], [ 75, 823, 38, 15 ], [ 120, 823, 56, 15 ], [ 184, 823, 10, 15 ], [ 202, 823, 74, 15 ], [ 284, 823, 43, 15 ], [ 334, 823, 14, 15 ], [ 356, 823, 53, 15 ], [ 75, 839, 46, 15 ], [ 124, 839, 56, 15 ], [ 183, 839, 12, 15 ], [ 199, 839, 39, 15 ], [ 241, 839, 47, 15 ], [ 292, 839, 15, 15 ], [ 311, 839, 15, 15 ], [ 330, 839, 13, 15 ], [ 346, 839, 20, 15 ], [ 369, 839, 39, 15 ], [ 75, 855, 38, 15 ], [ 117, 855, 12, 15 ], [ 134, 855, 18, 15 ], [ 157, 855, 50, 15 ], [ 212, 855, 46, 15 ], [ 264, 855, 17, 15 ], [ 285, 855, 53, 15 ], [ 343, 855, 16, 15 ], [ 365, 855, 44, 15 ], [ 75, 871, 38, 15 ], [ 118, 871, 55, 15 ], [ 178, 871, 34, 15 ], [ 218, 871, 42, 15 ], [ 265, 871, 25, 15 ], [ 296, 871, 77, 15 ], [ 378, 871, 31, 15 ], [ 75, 887, 39, 15 ], [ 117, 887, 54, 15 ], [ 174, 887, 60, 15 ], [ 238, 887, 18, 15 ], [ 260, 887, 46, 15 ], [ 309, 887, 42, 15 ], [ 354, 887, 12, 15 ], [ 370, 887, 38, 15 ], [ 75, 933, 60, 12 ], [ 138, 933, 18, 12 ], [ 160, 933, 9, 12 ], [ 173, 933, 15, 12 ], [ 192, 933, 25, 12 ], [ 222, 933, 34, 12 ], [ 260, 933, 52, 12 ], [ 316, 933, 36, 12 ], [ 357, 933, 32, 12 ], [ 393, 933, 15, 12 ], [ 75, 946, 30, 12 ], [ 108, 946, 39, 12 ], [ 151, 946, 39, 12 ], [ 194, 946, 9, 12 ], [ 206, 946, 28, 12 ], [ 238, 946, 64, 12 ], [ 305, 946, 20, 12 ], [ 330, 946, 34, 12 ], [ 367, 946, 41, 12 ], [ 75, 959, 28, 12 ], [ 105, 959, 94, 12 ], [ 202, 959, 23, 12 ], [ 227, 959, 69, 12 ], [ 300, 959, 37, 12 ], [ 339, 959, 33, 12 ], [ 376, 959, 33, 12 ], [ 75, 972, 42, 12 ], [ 119, 972, 36, 12 ], [ 158, 972, 31, 12 ], [ 192, 972, 43, 12 ], [ 238, 972, 43, 12 ], [ 283, 972, 33, 12 ], [ 318, 972, 33, 12 ], [ 354, 972, 20, 12 ], [ 377, 972, 31, 12 ], [ 75, 986, 31, 12 ], [ 108, 986, 54, 12 ], [ 165, 986, 25, 12 ], [ 192, 986, 26, 12 ], [ 221, 986, 53, 12 ], [ 276, 986, 36, 12 ], [ 433, 664, 60, 15 ], [ 496, 664, 41, 15 ], [ 541, 664, 35, 15 ], [ 580, 664, 75, 16 ], [ 659, 664, 18, 15 ], [ 681, 664, 41, 15 ], [ 726, 664, 41, 15 ], [ 433, 680, 52, 15 ], [ 494, 680, 41, 15 ], [ 544, 680, 55, 15 ], [ 607, 680, 54, 15 ], [ 669, 680, 53, 15 ], [ 730, 680, 37, 15 ], [ 433, 695, 67, 15 ], [ 503, 695, 38, 15 ], [ 545, 695, 80, 15 ], [ 628, 695, 9, 15 ], [ 640, 695, 32, 15 ], [ 675, 695, 65, 15 ], [ 743, 695, 24, 15 ], [ 433, 711, 24, 15 ], [ 460, 711, 59, 15 ], [ 523, 711, 21, 15 ], [ 547, 711, 32, 15 ], [ 583, 711, 10, 15 ], [ 596, 711, 41, 15 ], [ 640, 711, 57, 15 ], [ 701, 711, 18, 15 ], [ 723, 711, 44, 15 ], [ 433, 727, 29, 15 ], [ 467, 727, 55, 15 ], [ 527, 727, 54, 15 ], [ 587, 727, 14, 15 ], [ 607, 727, 44, 15 ], [ 656, 727, 38, 15 ], [ 699, 727, 13, 15 ], [ 718, 727, 32, 15 ], [ 755, 727, 12, 15 ], [ 433, 743, 53, 15 ], [ 490, 743, 31, 15 ], [ 524, 743, 53, 15 ], [ 581, 743, 12, 15 ], [ 596, 743, 24, 15 ], [ 623, 743, 58, 15 ], [ 684, 743, 60, 15 ], [ 748, 743, 19, 15 ], [ 433, 759, 45, 15 ], [ 484, 759, 18, 15 ], [ 508, 759, 14, 15 ], [ 527, 759, 54, 15 ], [ 588, 759, 44, 15 ], [ 637, 759, 9, 15 ], [ 652, 759, 33, 15 ], [ 691, 759, 23, 15 ], [ 720, 759, 47, 15 ], [ 433, 775, 43, 15 ], [ 481, 775, 55, 15 ], [ 541, 775, 27, 15 ], [ 573, 775, 58, 15 ], [ 637, 775, 27, 15 ], [ 669, 775, 55, 15 ], [ 730, 775, 38, 15 ], [ 433, 791, 52, 15 ], [ 489, 791, 21, 15 ], [ 514, 791, 49, 15 ], [ 568, 791, 48, 15 ], [ 621, 791, 21, 15 ], [ 646, 791, 67, 15 ], [ 718, 791, 22, 15 ], [ 745, 791, 22, 15 ], [ 433, 807, 76, 15 ], [ 518, 807, 29, 15 ], [ 556, 807, 17, 15 ], [ 581, 807, 38, 15 ], [ 628, 807, 71, 15 ], [ 707, 807, 60, 15 ], [ 433, 823, 65, 15 ], [ 503, 823, 41, 15 ], [ 549, 823, 66, 15 ], [ 620, 823, 22, 15 ], [ 646, 823, 23, 15 ], [ 674, 823, 21, 15 ], [ 700, 823, 18, 15 ], [ 723, 823, 22, 15 ], [ 750, 823, 17, 15 ], [ 433, 839, 20, 15 ], [ 459, 839, 42, 15 ], [ 507, 839, 14, 15 ], [ 527, 839, 44, 15 ], [ 578, 839, 38, 15 ], [ 621, 839, 55, 15 ], [ 683, 839, 56, 15 ], [ 745, 839, 22, 15 ], [ 433, 855, 73, 15 ], [ 509, 855, 12, 15 ], [ 524, 855, 47, 15 ], [ 575, 855, 14, 15 ], [ 593, 855, 44, 15 ], [ 640, 855, 9, 15 ], [ 652, 855, 20, 15 ], [ 675, 855, 6, 15 ], [ 684, 855, 41, 15 ], [ 729, 855, 39, 15 ], [ 433, 871, 12, 15 ], [ 448, 871, 71, 15 ], [ 522, 871, 21, 15 ], [ 546, 871, 39, 15 ], [ 589, 871, 17, 15 ], [ 609, 871, 52, 15 ], [ 665, 871, 22, 15 ], [ 447, 887, 59, 15 ], [ 509, 887, 10, 15 ], [ 521, 887, 8, 15 ], [ 533, 887, 6, 15 ], [ 542, 887, 33, 15 ], [ 578, 887, 46, 15 ], [ 628, 887, 34, 15 ], [ 665, 887, 12, 15 ], [ 680, 887, 18, 15 ], [ 701, 887, 66, 15 ], [ 433, 903, 46, 15 ], [ 483, 903, 12, 15 ], [ 498, 903, 33, 15 ], [ 534, 903, 21, 15 ], [ 559, 903, 22, 15 ], [ 584, 903, 24, 15 ], [ 611, 903, 22, 15 ], [ 637, 903, 28, 15 ], [ 668, 903, 14, 15 ], [ 685, 903, 56, 15 ], [ 745, 903, 22, 15 ], [ 433, 919, 12, 15 ], [ 448, 919, 50, 15 ], [ 501, 919, 53, 15 ], [ 558, 919, 44, 15 ], [ 606, 919, 12, 15 ], [ 621, 919, 32, 15 ], [ 657, 919, 24, 15 ], [ 684, 919, 38, 15 ], [ 725, 919, 42, 15 ], [ 433, 935, 110, 15 ], [ 548, 935, 68, 15 ], [ 621, 935, 48, 15 ], [ 675, 935, 25, 15 ], [ 705, 935, 48, 15 ], [ 759, 935, 9, 15 ], [ 433, 951, 50, 15 ], [ 486, 951, 32, 15 ], [ 522, 951, 14, 15 ], [ 540, 951, 56, 15 ], [ 599, 951, 18, 15 ], [ 621, 951, 47, 15 ], [ 672, 951, 21, 15 ], [ 697, 951, 55, 15 ], [ 755, 951, 12, 15 ], [ 433, 967, 38, 15 ], [ 478, 967, 48, 15 ], [ 533, 967, 10, 15 ], [ 550, 967, 24, 15 ], [ 581, 967, 10, 15 ], [ 599, 967, 46, 15 ], [ 652, 967, 116, 15 ], [ 433, 983, 52, 15 ], [ 491, 983, 48, 15 ], [ 546, 983, 21, 15 ], [ 573, 983, 45, 15 ], [ 625, 983, 76, 15 ], [ 708, 983, 22, 15 ], [ 737, 983, 31, 15 ], [ 233, 1012, 21, 14 ], [ 278, 1013, 8, 13 ], [ 289, 1013, 24, 13 ], [ 315, 1013, 27, 13 ], [ 359, 1013, 21, 13 ], [ 382, 1013, 59, 13 ], [ 444, 1013, 52, 13 ], [ 499, 1013, 25, 13 ], [ 527, 1013, 5, 13 ], [ 535, 1013, 132, 13 ], [ 670, 1013, 28, 13 ], [ 278, 1027, 40, 13 ], [ 322, 1027, 22, 13 ], [ 347, 1027, 43, 13 ], [ 393, 1027, 10, 13 ], [ 408, 1027, 53, 13 ], [ 465, 1027, 16, 13 ], [ 484, 1027, 25, 13 ], [ 514, 1027, 44, 13 ], [ 278, 1042, 105, 13 ] ]

[ "Cleavage", "by", "Granzyme", "B", "Is", "Strongly", "Predictive", "of", "Autoantigen", "Status:", "Implications", "for", "Initiation", "of", "Autoimmunity", "By", "Livia", "Casciola-Rosen,*§", "Felipe", "Andrade,‡i", "Danielle", "Ulanet,‡i", "Wes", "Bang", "Wong,‡i", "and", "Antony", "Rosen‡§i", "From", "the", "*Department", "of", "Dermatology,", "the", "‡Department", "of", "Medicine,", "the", "§Department", "of", "Cell", "Biology", "and", "Anatomy,", "and", "the", "iGraduate", "Program", "in", "Immunology,", "Johns", "Hopkins", "University", "School", "of", "Medicine,", "Baltimore,", "Maryland", "21205", "Summary", "Systemic", "autoimmune", "diseases", "are", "a", "genetically", "complex,", "heterogeneous", "group", "of", "disorders", "in", "which", "the", "immune", "system", "targets", "a", "diverse", "but", "highly", "specific", "group", "of", "intracellular", "autoanti-", "gens.", "The", "molecules", "targeted", "are", "not", "unified", "by", "common", "structure,", "function,", "or", "distribution", "in", "control", "cells", "but", "become", "clustered", "and", "concentrated", "in", "surface", "blebs", "when", "cells", "undergo", "apop-", "tosis.", "We", "show", "here", "that", "the", "majority", "of", "autoantigens", "targeted", "across", "the", "spectrum", "of", "human", "systemic", "autoimmune", "diseases", "are", "efficiently", "cleaved", "by", "granzyme", "B", "in", "vitro", "and", "during", "cyto-", "toxic", "lymphocyte", "granule–induced", "death,", "generating", "unique", "fragments", "not", "observed", "during", "any", "other", "form", "of", "apoptosis.", "These", "molecules", "are", "not", "cleaved", "by", "caspase-8,", "although", "this", "pro-", "tease", "has", "a", "very", "similar", "specificity", "to", "granzyme", "B.", "The", "granzyme", "B", "cleavage", "sites", "in", "autoanti-", "gens", "contain", "amino", "acids", "in", "the", "P2", "and", "P3", "positions", "that", "are", "preferred", "by", "granzyme", "B", "but", "are", "not", "tolerated", "by", "caspase-8.", "In", "contrast", "to", "autoantigens,", "nonautoantigens", "are", "either", "not", "cleaved", "by", "granzyme", "B", "or", "are", "cleaved", "to", "generate", "fragments", "identical", "to", "those", "formed", "in", "other", "forms", "of", "apoptosis.", "The", "striking", "ability", "of", "granzyme", "B", "to", "generate", "unique", "fragments", "is", "therefore", "an", "ex-", "clusive", "property", "of", "autoantigens", "and", "unifies", "the", "majority", "of", "molecules", "targeted", "in", "this", "spectrum", "of", "diseases.", "These", "results", "focus", "attention", "on", "the", "role", "of", "the", "cytotoxic", "lymphocyte", "granule–induced", "death", "pathway", "in", "the", "initiation", "and", "propagation", "of", "systemic", "autoimmunity.", "Key", "words:", "apoptosis", "•", "cytotoxic", "T", "lymphocyte", "•", "protease", "•", "caspase", "Tautoimmune", "diseases", "generally", "predicts", "the", "biologic", "he", "highly", "specific", "autoantibody", "response", "in", "systemic", "phenotype", "of", "the", "disease,", "making", "autoantibodies", "diagnosti-", "cally", "useful", "(1,", "2).", "Although", "molecules", "targeted", "by", "the", "im-", "mune", "system", "in", "these", "diseases", "are", "exceptionally", "diverse", "in", "terms", "of", "structure,", "function,", "and", "subcellular", "distribution", "in", "healthy", "cells,", "they", "are", "strikingly", "redistributed", "in", "apoptotic", "cells,", "becoming", "clustered", "and", "concentrated", "in", "two", "popula-", "tions", "of", "surface", "structures", "on", "the", "dying", "cell", "(3).", "It", "has", "been", "proposed", "that", "cleavage", "of", "proteins", "might", "play", "a", "role", "in", "se-", "lecting", "molecules", "as", "autoantigens,", "perhaps", "by", "cleavage-", "induced", "revelation", "of", "cryptic", "epitopes", "(4,", "5).", "In", "this", "regard,", "several", "of", "the", "clustered", "antigens", "are", "substrates", "for", "caspases", "during", "apoptosis.", "These", "include", "poly", "(ADP-ribose)", "poly-", "merase", "(PARP),1", "U1-70kD,", "the", "catalytic", "subunit", "of", "DNA-", "1Abbreviations", "used", "in", "this", "paper:", "CENP,", "centromere", "protein;", "CrmA,", "cy-", "tokine", "response", "modifier", "1;", "DTT,", "dithiothreitol;", "GC,", "granule", "contents;", "FMK,", "fluoromethylketone;", "IAA,", "iodoacetamide;", "NuMA,", "nuclear", "mitotic", "apparatus", "protein;", "NOR,", "nucleolus", "organizer", "region;", "PARP,", "poly", "(ADP-", "ribose)", "polymerase;", "SRP,", "signal", "recognition", "particle.", "dependent", "protein", "kinase", "(DNA-PKcs),", "the", "nuclear", "mitotic", "apparatus", "protein", "(NuMA),", "nucleolus", "organizer", "region", "(NOR)-90,", "fodrin,", "topoisomerase", "I,", "signal", "recognition", "par-", "ticle", "(SRP)-72,", "and", "lamin", "B", "(6–10).", "However,", "the", "autoan-", "tigen", "fragments", "produced", "by", "caspases", "during", "all", "forms", "of", "apoptotic", "death", "described", "to", "date", "(including", "thymocyte", "ap-", "optosis)", "are", "all", "identical,", "making", "it", "likely", "that", "caspase-", "derived", "fragments", "have", "previously", "been", "generated", "during", "apoptosis", "and", "tolerized", "centrally", "and", "peripherally", "(11,", "12).", "Furthermore,", "there", "are", "several", "autoantigens", "(fibrillarin,", "centromere", "protein", "(CENP)-B,", "Ku,", "Ro,", "and", "La)", "that", "are", "not", "cleaved", "by", "caspases", "during", "apoptosis,", "indicating", "that", "susceptibility", "to", "cleavage", "by", "caspases", "is", "not", "a", "general", "feature", "of", "autoantigens", "(for", "review", "see", "reference", "13).", "Granzyme", "B", "is", "a", "serine", "protease", "found", "in", "the", "cytoplasmic", "granules", "of", "CTLs", "and", "NK", "cells", "that", "plays", "an", "important", "role", "in", "inducing", "apoptotic", "changes", "in", "target", "cells", "during", "granule", "exocytosis–induced", "cytotoxicity", "(14–16).", "This", "function", "is", "achieved", "partly", "by", "catalyzing", "the", "cleavage", "and", "activation", "of", "several", "caspases,", "as", "well", "as", "through", "caspase-independent", "pathways", "(17–20).", "We", "recently", "demonstrated", "that", "gran-", "815", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/99/09/815/14", "$5.00", "Volume", "190,", "Number", "6,", "September", "20,", "1999", "815–825", "http://www.jem.org" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 419, 52, 37, 13 ], [ 460, 52, 11, 13 ], [ 473, 52, 45, 13 ], [ 521, 52, 57, 13 ], [ 580, 52, 34, 13 ], [ 617, 52, 10, 13 ], [ 630, 51, 32, 14 ], [ 419, 65, 32, 14 ], [ 454, 66, 22, 13 ], [ 479, 66, 16, 13 ], [ 498, 66, 29, 13 ], [ 529, 66, 46, 13 ], [ 578, 66, 89, 13 ], [ 70, 100, 63, 17 ], [ 137, 100, 52, 17 ], [ 70, 134, 71, 21 ], [ 146, 134, 120, 21 ], [ 270, 134, 18, 21 ], [ 292, 134, 88, 21 ], [ 385, 134, 14, 21 ], [ 404, 134, 88, 21 ], [ 496, 134, 27, 21 ], [ 527, 134, 60, 21 ], [ 592, 134, 94, 21 ], [ 70, 159, 82, 21 ], [ 157, 159, 18, 21 ], [ 179, 159, 70, 21 ], [ 254, 159, 39, 21 ], [ 297, 159, 47, 21 ], [ 349, 159, 100, 21 ], [ 453, 159, 94, 21 ], [ 551, 159, 70, 21 ], [ 625, 159, 18, 21 ], [ 647, 159, 42, 21 ], [ 694, 159, 45, 21 ], [ 648, 103, 4, 7 ], [ 655, 100, 39, 17 ], [ 697, 100, 47, 17 ], [ 747, 103, 4, 7 ], [ 70, 204, 70, 17 ], [ 143, 204, 40, 17 ], [ 187, 204, 67, 17 ], [ 257, 204, 38, 17 ], [ 299, 204, 59, 17 ], [ 361, 204, 19, 17 ], [ 383, 204, 67, 17 ], [ 453, 204, 29, 17 ], [ 70, 228, 35, 11 ], [ 108, 228, 9, 11 ], [ 119, 228, 40, 11 ], [ 161, 228, 52, 11 ], [ 215, 228, 35, 11 ], [ 253, 228, 20, 11 ], [ 275, 228, 36, 11 ], [ 312, 228, 40, 11 ], [ 355, 228, 32, 11 ], [ 388, 228, 36, 11 ], [ 426, 228, 27, 11 ], [ 70, 263, 46, 13 ], [ 94, 288, 65, 13 ], [ 171, 288, 20, 13 ], [ 196, 288, 35, 13 ], [ 237, 288, 27, 13 ], [ 269, 288, 59, 13 ], [ 333, 288, 15, 13 ], [ 353, 288, 52, 13 ], [ 410, 288, 27, 13 ], [ 443, 288, 11, 13 ], [ 458, 288, 39, 13 ], [ 503, 288, 67, 13 ], [ 575, 288, 9, 13 ], [ 590, 288, 50, 13 ], [ 645, 288, 15, 13 ], [ 665, 288, 34, 13 ], [ 704, 288, 52, 13 ], [ 70, 304, 45, 13 ], [ 118, 304, 10, 13 ], [ 131, 304, 38, 13 ], [ 172, 304, 22, 13 ], [ 198, 304, 26, 13 ], [ 227, 304, 55, 13 ], [ 285, 304, 48, 13 ], [ 335, 304, 35, 13 ], [ 374, 304, 46, 13 ], [ 431, 304, 10, 13 ], [ 443, 304, 22, 13 ], [ 469, 304, 11, 13 ], [ 482, 304, 25, 13 ], [ 510, 304, 38, 13 ], [ 551, 304, 22, 13 ], [ 576, 304, 25, 13 ], [ 604, 304, 24, 13 ], [ 631, 304, 43, 13 ], [ 677, 304, 10, 13 ], [ 690, 304, 40, 13 ], [ 733, 304, 24, 13 ], [ 70, 321, 39, 13 ], [ 115, 321, 42, 13 ], [ 161, 321, 41, 13 ], [ 207, 321, 38, 13 ], [ 251, 321, 10, 13 ], [ 265, 321, 25, 13 ], [ 296, 321, 18, 13 ], [ 319, 321, 51, 13 ], [ 375, 321, 16, 13 ], [ 395, 321, 28, 13 ], [ 428, 321, 40, 13 ], [ 474, 321, 67, 13 ], [ 546, 321, 46, 13 ], [ 597, 321, 66, 13 ], [ 669, 321, 40, 13 ], [ 714, 321, 42, 13 ], [ 70, 338, 42, 13 ], [ 116, 338, 55, 13 ], [ 174, 338, 50, 13 ], [ 228, 338, 40, 13 ], [ 271, 338, 25, 13 ], [ 299, 338, 38, 13 ], [ 340, 338, 37, 13 ], [ 380, 338, 54, 13 ], [ 438, 338, 53, 13 ], [ 494, 338, 35, 13 ], [ 533, 338, 44, 13 ], [ 580, 338, 25, 13 ], [ 608, 338, 67, 13 ], [ 678, 338, 42, 13 ], [ 723, 338, 33, 13 ], [ 70, 354, 25, 13 ], [ 101, 354, 52, 13 ], [ 158, 354, 18, 13 ], [ 180, 354, 39, 13 ], [ 224, 354, 24, 13 ], [ 253, 354, 47, 13 ], [ 304, 354, 9, 13 ], [ 319, 354, 53, 13 ], [ 376, 354, 20, 13 ], [ 400, 354, 38, 13 ], [ 443, 354, 24, 13 ], [ 473, 354, 37, 13 ], [ 514, 354, 20, 13 ], [ 538, 354, 7, 13 ], [ 550, 354, 34, 13 ], [ 588, 354, 28, 13 ], [ 621, 354, 13, 13 ], [ 639, 354, 15, 13 ], [ 659, 354, 38, 13 ], [ 702, 354, 11, 13 ], [ 717, 354, 39, 13 ], [ 70, 371, 67, 13 ], [ 140, 371, 9, 13 ], [ 152, 371, 50, 13 ], [ 205, 371, 14, 13 ], [ 221, 371, 10, 13 ], [ 233, 371, 10, 13 ], [ 245, 371, 18, 13 ], [ 266, 370, 13, 13 ], [ 282, 371, 14, 13 ], [ 298, 371, 21, 13 ], [ 322, 371, 50, 13 ], [ 375, 371, 39, 13 ], [ 417, 371, 20, 13 ], [ 439, 371, 23, 13 ], [ 464, 371, 10, 13 ], [ 477, 371, 43, 13 ], [ 523, 371, 37, 13 ], [ 562, 371, 19, 13 ], [ 584, 371, 25, 13 ], [ 611, 371, 18, 13 ], [ 632, 371, 23, 13 ], [ 658, 371, 54, 13 ], [ 714, 371, 42, 13 ], [ 70, 388, 24, 13 ], [ 99, 388, 22, 13 ], [ 126, 388, 54, 13 ], [ 184, 388, 15, 13 ], [ 203, 388, 21, 13 ], [ 228, 388, 20, 13 ], [ 253, 388, 25, 13 ], [ 282, 388, 32, 13 ], [ 319, 388, 18, 13 ], [ 342, 388, 64, 13 ], [ 411, 388, 44, 13 ], [ 459, 388, 59, 13 ], [ 522, 388, 31, 13 ], [ 558, 388, 38, 13 ], [ 607, 388, 20, 13 ], [ 632, 388, 27, 13 ], [ 663, 388, 17, 13 ], [ 685, 388, 11, 13 ], [ 701, 388, 15, 13 ], [ 721, 388, 36, 13 ], [ 70, 404, 52, 13 ], [ 126, 404, 20, 13 ], [ 149, 404, 22, 13 ], [ 174, 404, 7, 13 ], [ 185, 404, 22, 13 ], [ 210, 404, 29, 13 ], [ 242, 404, 18, 13 ], [ 264, 404, 32, 13 ], [ 299, 404, 11, 13 ], [ 313, 404, 15, 13 ], [ 332, 404, 38, 13 ], [ 374, 404, 24, 13 ], [ 401, 404, 27, 13 ], [ 432, 404, 11, 13 ], [ 446, 404, 32, 13 ], [ 481, 404, 11, 13 ], [ 495, 404, 15, 13 ], [ 514, 404, 38, 13 ], [ 555, 404, 9, 13 ], [ 568, 404, 23, 13 ], [ 594, 404, 18, 13 ], [ 616, 404, 60, 13 ], [ 679, 404, 24, 13 ], [ 706, 404, 50, 13 ], [ 70, 421, 66, 13 ], [ 141, 421, 43, 13 ], [ 188, 421, 40, 13 ], [ 233, 421, 40, 13 ], [ 277, 421, 40, 13 ], [ 322, 421, 18, 13 ], [ 344, 421, 42, 13 ], [ 391, 421, 55, 13 ], [ 451, 421, 47, 13 ], [ 503, 421, 31, 13 ], [ 538, 421, 24, 13 ], [ 567, 421, 15, 13 ], [ 587, 421, 36, 13 ], [ 627, 421, 43, 13 ], [ 675, 421, 67, 13 ], [ 747, 421, 9, 13 ], [ 70, 438, 53, 13 ], [ 126, 438, 20, 13 ], [ 148, 438, 34, 13 ], [ 184, 438, 52, 13 ], [ 239, 438, 45, 13 ], [ 286, 438, 10, 13 ], [ 299, 438, 38, 13 ], [ 340, 438, 22, 13 ], [ 364, 438, 10, 13 ], [ 376, 438, 10, 13 ], [ 388, 438, 10, 13 ], [ 401, 438, 18, 13 ], [ 421, 437, 13, 13 ], [ 436, 438, 7, 13 ], [ 446, 438, 67, 13 ], [ 515, 438, 9, 13 ], [ 527, 438, 50, 13 ], [ 579, 438, 34, 13 ], [ 616, 438, 20, 13 ], [ 638, 438, 29, 13 ], [ 669, 438, 29, 13 ], [ 701, 438, 35, 13 ], [ 738, 438, 18, 13 ], [ 70, 454, 35, 13 ], [ 110, 454, 62, 13 ], [ 177, 454, 20, 13 ], [ 201, 454, 43, 13 ], [ 249, 454, 11, 13 ], [ 264, 454, 7, 13 ], [ 275, 454, 11, 13 ], [ 291, 454, 26, 13 ], [ 321, 454, 67, 13 ], [ 393, 454, 20, 13 ], [ 417, 454, 50, 13 ], [ 472, 454, 22, 13 ], [ 499, 454, 32, 13 ], [ 535, 454, 34, 13 ], [ 575, 454, 52, 13 ], [ 631, 454, 45, 13 ], [ 681, 454, 49, 13 ], [ 734, 454, 22, 13 ], [ 70, 471, 38, 13 ], [ 114, 471, 38, 13 ], [ 156, 471, 60, 13 ], [ 221, 471, 24, 13 ], [ 251, 471, 25, 13 ], [ 280, 471, 23, 13 ], [ 309, 471, 16, 13 ], [ 330, 471, 50, 13 ], [ 385, 471, 8, 13 ], [ 398, 471, 8, 13 ], [ 410, 471, 31, 13 ], [ 446, 471, 18, 13 ], [ 469, 471, 20, 13 ], [ 495, 471, 25, 13 ], [ 524, 471, 23, 13 ], [ 553, 471, 16, 13 ], [ 574, 471, 50, 13 ], [ 629, 471, 8, 13 ], [ 642, 471, 7, 13 ], [ 654, 471, 31, 13 ], [ 690, 471, 66, 13 ], [ 70, 488, 63, 13 ], [ 145, 488, 40, 13 ], [ 190, 488, 67, 13 ], [ 262, 488, 24, 13 ], [ 290, 488, 50, 13 ], [ 345, 488, 29, 13 ], [ 378, 488, 10, 13 ], [ 392, 488, 38, 13 ], [ 435, 488, 22, 13 ], [ 461, 488, 27, 13 ], [ 493, 488, 24, 13 ], [ 522, 488, 38, 13 ], [ 564, 488, 22, 13 ], [ 591, 488, 26, 13 ], [ 621, 488, 67, 13 ], [ 692, 488, 18, 13 ], [ 714, 488, 6, 13 ], [ 725, 488, 32, 13 ], [ 70, 504, 34, 13 ], [ 107, 504, 52, 13 ], [ 162, 504, 45, 13 ], [ 210, 504, 29, 13 ], [ 241, 504, 12, 13 ], [ 256, 504, 49, 13 ], [ 307, 504, 11, 13 ], [ 320, 504, 25, 13 ], [ 348, 504, 23, 13 ], [ 373, 504, 43, 13 ], [ 418, 504, 10, 13 ], [ 430, 504, 38, 13 ], [ 471, 504, 22, 13 ], [ 495, 504, 27, 13 ], [ 70, 529, 6, 13 ], [ 79, 529, 37, 13 ], [ 118, 529, 38, 13 ], [ 159, 529, 28, 13 ], [ 190, 529, 10, 13 ], [ 202, 529, 35, 14 ], [ 239, 529, 20, 13 ], [ 261, 529, 153, 13 ], [ 70, 555, 58, 13 ], [ 130, 555, 26, 13 ], [ 159, 555, 55, 13 ], [ 217, 555, 51, 13 ], [ 270, 555, 64, 13 ], [ 336, 555, 45, 13 ], [ 70, 618, 9, 17 ], [ 95, 614, 92, 21 ], [ 86, 649, 12, 14 ], [ 106, 649, 17, 14 ], [ 131, 649, 22, 14 ], [ 161, 649, 21, 14 ], [ 191, 649, 47, 14 ], [ 245, 649, 17, 14 ], [ 270, 649, 26, 14 ], [ 304, 649, 54, 14 ], [ 366, 649, 32, 14 ], [ 70, 667, 78, 15 ], [ 156, 667, 11, 15 ], [ 176, 667, 17, 15 ], [ 201, 667, 70, 15 ], [ 279, 667, 12, 15 ], [ 299, 667, 29, 15 ], [ 336, 667, 61, 15 ], [ 70, 685, 53, 14 ], [ 127, 683, 49, 17 ], [ 179, 685, 54, 14 ], [ 236, 685, 27, 14 ], [ 267, 685, 44, 14 ], [ 314, 685, 7, 14 ], [ 324, 685, 40, 14 ], [ 367, 685, 31, 14 ], [ 70, 703, 12, 14 ], [ 85, 703, 30, 14 ], [ 119, 703, 62, 14 ], [ 184, 703, 20, 14 ], [ 207, 703, 17, 14 ], [ 227, 703, 50, 14 ], [ 280, 703, 21, 14 ], [ 304, 703, 27, 14 ], [ 334, 703, 27, 14 ], [ 365, 703, 10, 14 ], [ 377, 703, 20, 14 ], [ 70, 721, 72, 15 ], [ 147, 719, 44, 17 ], [ 196, 721, 32, 15 ], [ 234, 721, 58, 15 ], [ 296, 721, 38, 15 ], [ 339, 721, 11, 15 ], [ 355, 721, 17, 15 ], [ 377, 721, 21, 15 ], [ 70, 739, 69, 14 ], [ 142, 739, 20, 14 ], [ 165, 739, 70, 14 ], [ 237, 739, 12, 14 ], [ 252, 739, 43, 14 ], [ 297, 739, 25, 14 ], [ 325, 739, 30, 14 ], [ 358, 739, 25, 14 ], [ 386, 739, 12, 14 ], [ 70, 757, 42, 14 ], [ 118, 757, 21, 14 ], [ 145, 757, 68, 14 ], [ 220, 757, 12, 14 ], [ 237, 757, 46, 14 ], [ 289, 757, 25, 14 ], [ 320, 757, 78, 14 ], [ 70, 775, 78, 15 ], [ 159, 775, 24, 15 ], [ 194, 775, 31, 15 ], [ 235, 775, 46, 15 ], [ 291, 775, 40, 15 ], [ 342, 775, 56, 15 ], [ 70, 793, 50, 14 ], [ 124, 793, 52, 14 ], [ 180, 793, 37, 14 ], [ 220, 793, 12, 14 ], [ 236, 793, 21, 14 ], [ 260, 793, 20, 14 ], [ 284, 791, 35, 17 ], [ 322, 793, 76, 14 ], [ 70, 811, 11, 14 ], [ 86, 811, 43, 14 ], [ 133, 811, 25, 14 ], [ 162, 811, 30, 14 ], [ 196, 811, 25, 14 ], [ 226, 811, 12, 14 ], [ 243, 811, 27, 14 ], [ 274, 811, 74, 14 ], [ 353, 811, 45, 14 ], [ 70, 829, 44, 15 ], [ 120, 829, 20, 15 ], [ 146, 829, 37, 15 ], [ 188, 829, 24, 15 ], [ 217, 829, 37, 15 ], [ 259, 829, 17, 15 ], [ 282, 829, 47, 15 ], [ 334, 829, 64, 15 ], [ 70, 848, 40, 14 ], [ 115, 848, 20, 14 ], [ 140, 848, 41, 14 ], [ 186, 848, 45, 14 ], [ 236, 848, 17, 14 ], [ 258, 848, 21, 14 ], [ 284, 848, 12, 14 ], [ 300, 848, 42, 14 ], [ 347, 848, 50, 14 ], [ 70, 866, 54, 14 ], [ 130, 866, 17, 14 ], [ 152, 866, 61, 14 ], [ 219, 866, 12, 14 ], [ 236, 866, 67, 14 ], [ 308, 866, 10, 14 ], [ 323, 866, 53, 14 ], [ 381, 866, 16, 14 ], [ 70, 908, 75, 12 ], [ 148, 908, 13, 12 ], [ 163, 908, 43, 11 ], [ 208, 908, 25, 11 ], [ 235, 908, 21, 11 ], [ 258, 908, 35, 11 ], [ 295, 908, 9, 11 ], [ 307, 908, 38, 11 ], [ 348, 908, 50, 11 ], [ 70, 925, 35, 11 ], [ 109, 925, 21, 11 ], [ 133, 925, 35, 11 ], [ 172, 925, 40, 11 ], [ 215, 925, 31, 11 ], [ 250, 925, 23, 11 ], [ 276, 925, 14, 11 ], [ 294, 925, 32, 11 ], [ 330, 925, 35, 11 ], [ 369, 925, 29, 11 ], [ 70, 941, 33, 11 ], [ 105, 941, 110, 11 ], [ 70, 958, 51, 12 ], [ 123, 958, 79, 11 ], [ 244, 958, 22, 12 ], [ 268, 958, 79, 11 ], [ 70, 975, 45, 12 ], [ 118, 975, 46, 11 ], [ 166, 975, 9, 11 ], [ 177, 975, 22, 11 ], [ 244, 975, 40, 12 ], [ 286, 975, 29, 11 ], [ 317, 975, 14, 11 ], [ 333, 975, 22, 11 ], [ 70, 991, 46, 12 ], [ 119, 991, 29, 11 ], [ 150, 991, 14, 11 ], [ 165, 991, 22, 11 ], [ 245, 991, 46, 12 ], [ 293, 991, 32, 12 ], [ 327, 991, 29, 11 ], [ 358, 991, 14, 11 ], [ 374, 991, 22, 11 ], [ 429, 613, 21, 15 ], [ 456, 613, 68, 15 ], [ 532, 613, 12, 15 ], [ 550, 613, 30, 15 ], [ 587, 613, 16, 15 ], [ 610, 613, 26, 15 ], [ 643, 613, 25, 15 ], [ 675, 613, 64, 15 ], [ 747, 613, 10, 15 ], [ 429, 631, 49, 14 ], [ 485, 631, 14, 14 ], [ 505, 631, 17, 14 ], [ 529, 631, 37, 14 ], [ 572, 631, 12, 14 ], [ 591, 631, 47, 14 ], [ 645, 631, 67, 14 ], [ 718, 631, 14, 14 ], [ 739, 631, 17, 14 ], [ 429, 649, 47, 14 ], [ 482, 649, 12, 14 ], [ 500, 649, 43, 14 ], [ 548, 649, 25, 14 ], [ 578, 649, 30, 14 ], [ 615, 649, 12, 14 ], [ 632, 649, 17, 14 ], [ 655, 649, 40, 14 ], [ 701, 649, 33, 14 ], [ 739, 649, 17, 14 ], [ 429, 667, 66, 15 ], [ 501, 667, 44, 15 ], [ 552, 667, 43, 15 ], [ 602, 667, 75, 15 ], [ 684, 667, 10, 15 ], [ 701, 667, 55, 15 ], [ 429, 685, 32, 14 ], [ 465, 685, 14, 14 ], [ 483, 685, 55, 14 ], [ 542, 685, 16, 14 ], [ 563, 685, 17, 14 ], [ 585, 685, 38, 14 ], [ 627, 685, 58, 14 ], [ 690, 685, 50, 14 ], [ 744, 685, 12, 14 ], [ 429, 703, 43, 14 ], [ 474, 703, 25, 14 ], [ 501, 703, 27, 14 ], [ 531, 703, 66, 14 ], [ 600, 703, 11, 14 ], [ 614, 703, 7, 14 ], [ 623, 703, 33, 14 ], [ 659, 703, 43, 14 ], [ 705, 703, 37, 14 ], [ 429, 745, 9, 17 ], [ 429, 771, 18, 14 ], [ 453, 745, 62, 17 ], [ 459, 771, 29, 14 ], [ 491, 771, 44, 14 ], [ 444, 796, 31, 15 ], [ 479, 796, 28, 15 ], [ 511, 796, 7, 15 ], [ 522, 796, 74, 15 ], [ 600, 796, 43, 15 ], [ 647, 796, 35, 15 ], [ 686, 796, 47, 15 ], [ 737, 796, 19, 15 ], [ 429, 815, 26, 14 ], [ 458, 815, 60, 14 ], [ 522, 815, 11, 14 ], [ 536, 815, 17, 14 ], [ 556, 815, 44, 14 ], [ 603, 815, 26, 14 ], [ 632, 815, 43, 14 ], [ 679, 815, 50, 14 ], [ 731, 815, 25, 14 ], [ 429, 833, 17, 14 ], [ 452, 833, 57, 14 ], [ 515, 833, 32, 14 ], [ 553, 833, 32, 14 ], [ 591, 833, 14, 14 ], [ 612, 833, 17, 14 ], [ 635, 833, 29, 14 ], [ 670, 833, 45, 14 ], [ 721, 833, 12, 14 ], [ 739, 833, 17, 14 ], [ 429, 852, 70, 15 ], [ 504, 852, 75, 15 ], [ 585, 852, 12, 15 ], [ 603, 852, 48, 15 ], [ 657, 852, 56, 15 ], [ 719, 852, 14, 15 ], [ 739, 852, 17, 15 ], [ 429, 871, 35, 14 ], [ 467, 871, 37, 14 ], [ 507, 871, 74, 14 ], [ 585, 871, 59, 14 ], [ 646, 871, 43, 14 ], [ 693, 871, 11, 14 ], [ 707, 871, 12, 14 ], [ 722, 871, 34, 14 ], [ 429, 890, 22, 14 ], [ 453, 890, 43, 14 ], [ 499, 890, 40, 14 ], [ 542, 890, 12, 14 ], [ 557, 890, 17, 14 ], [ 577, 890, 42, 14 ], [ 622, 890, 25, 14 ], [ 649, 890, 7, 14 ], [ 658, 890, 43, 14 ], [ 704, 890, 52, 14 ], [ 429, 909, 12, 15 ], [ 445, 909, 27, 15 ], [ 477, 909, 24, 15 ], [ 506, 909, 27, 15 ], [ 538, 909, 48, 15 ], [ 590, 909, 46, 15 ], [ 640, 909, 43, 15 ], [ 688, 909, 11, 15 ], [ 703, 909, 28, 15 ], [ 736, 909, 20, 15 ], [ 429, 928, 58, 14 ], [ 494, 928, 18, 14 ], [ 519, 928, 29, 14 ], [ 554, 928, 28, 14 ], [ 589, 928, 55, 14 ], [ 650, 928, 44, 14 ], [ 701, 928, 55, 14 ], [ 429, 947, 52, 14 ], [ 484, 947, 12, 14 ], [ 500, 947, 31, 14 ], [ 535, 947, 26, 14 ], [ 565, 947, 24, 14 ], [ 593, 947, 10, 14 ], [ 607, 947, 24, 14 ], [ 635, 947, 12, 14 ], [ 651, 947, 28, 14 ], [ 683, 947, 43, 14 ], [ 729, 947, 27, 14 ], [ 429, 966, 55, 15 ], [ 489, 966, 20, 15 ], [ 515, 966, 17, 15 ], [ 537, 966, 43, 15 ], [ 585, 966, 40, 15 ], [ 631, 966, 12, 15 ], [ 648, 966, 28, 15 ], [ 681, 966, 43, 15 ], [ 729, 966, 27, 15 ], [ 429, 985, 25, 14 ], [ 460, 985, 55, 14 ], [ 521, 985, 25, 14 ], [ 553, 985, 52, 14 ], [ 612, 985, 15, 14 ], [ 633, 985, 23, 14 ], [ 663, 985, 42, 14 ], [ 712, 985, 45, 14 ], [ 70, 1018, 115, 12 ], [ 188, 1018, 117, 12 ], [ 308, 1018, 4, 11 ], [ 314, 1018, 40, 11 ], [ 357, 1018, 11, 11 ], [ 371, 1018, 46, 11 ], [ 419, 1018, 58, 11 ] ]

[ "Journal", "of", "Geriatric", "Cardiology", "(2011)", "8:", "3134", "©2011", "IGC", "All", "rights", "reserved;", "www.jgc301.com", "Research", "Articles", "Medical", "comorbidities", "at", "admission", "is", "predictive", "for", "30-day", "in-hospital", "mortality", "in", "patients", "with", "acute", "myocardial", "infarction:", "analysis", "of", "5161", "cases", "", "Open", "Access", "", "Xue-Dong", "Yang,", "Yu-Sheng", "Zhao,", "Yu-Feng", "Li,", "Xin-Hong", "Guo", "Institute", "of", "Geriatric", "Cardiology,", "Chinese", "PLA", "General", "Hospital,", "Beijing", "100853,", "China", "Abstract", "Background", "The", "present", "study", "investigated", "the", "prognostic", "value", "of", "medical", "comorbidities", "at", "admission", "for", "30-day", "in-hospital", "mortality", "in", "patients", "with", "acute", "myocardial", "infarction", "(AMI).", "Methods", "A", "total", "of", "5161", "patients", "with", "AMI", "were", "admitted", "in", "Chinese", "PLA", "General", "Hospital", "between", "January", "1,", "1993", "and", "December", "31,", "2007.", "Medical", "comorbidities", "including", "hypertension,", "diabetes", "mellitus,", "previous", "myocardial", "infarction,", "valvular", "heart", "disease,", "chronic", "obstructive", "pulmonary", "disease", "(COPD),", "renal", "insufficiency,", "previous", "stroke,", "atrial", "fibrillation", "and", "anemia,", "were", "identified", "at", "admission.", "The", "patients", "were", "divided", "into", "4", "groups", "based", "on", "the", "number", "of", "medical", "comorbidities", "at", "admission", "(0,", "1,", "2,", "and", "≥", "3).", "Cox", "regression", "analysis", "was", "used", "to", "calculate", "relative", "risk", "(RR)", "and", "95%", "confidence", "intervals", "(CI),", "with", "adjustment", "for", "age,", "sex,", "heart", "failure", "and", "percutaneous", "coronary", "intervention", "(PCI).", "Results", "The", "mean", "age", "of", "the", "studied", "population", "was", "63.9", "±", "13.6", "years,", "and", "80.1%", "of", "the", "patients", "were", "male.", "In", "74.6%", "of", "the", "patients", "at", "least", "one", "comorbidity", "were", "identified.", "Hypertension", "(50.7%),", "diabetes", "mellitus", "(24.0%)", "and", "previous", "myocardial", "infarction", "(12%)", "were", "the", "leading", "common", "comorbidities", "at", "admission.", "The", "30-day", "in-hospital", "mortality", "in", "patients", "with", "0,", "1,", "2,", "and", "≥", "3", "comorbidities", "at", "admission", "(7.2%)", "was", "4.9%,", "7.2%,", "11.1%,", "and", "20.3%,", "respectively.", "The", "presence", "of", "2", "or", "more", "comorbidities", "was", "associated", "with", "higher", "30-day", "in-hospital", "mortality", "compared", "with", "patients", "without", "comorbidity", "(RR:", "1.41,", "95%", "CI:", "1.13-1.77,", "P", "=", "0.003,", "and", "RR:", "1.95,", "95%", "CI:", "1.59-2.39,", "P", "=", "0.000,", "respectively).", "Conclusions", "Medical", "comorbidities", "were", "frequently", "found", "in", "patients", "with", "AMI.", "AMI", "patients", "with", "more", "comorbidities", "had", "a", "higher", "30-day", "in-hospital", "mortality", "might", "be", "predictive", "of", "early", "poor", "outcome", "in", "patients", "with", "AMI.", "J", "Geriatr", "Cardiol", "2011;", "8:", "3134.", "doi:", "10.3724/SP.J.1263.2011.00031", "Keywords:", "acute", "myocardial", "infarction;", "comorbidity;", "mortality", "1", "Introduction", "In", "the", "past", "five", "decades,", "we", "have", "witnessed", "major", "breakthroughs", "in", "the", "management", "of", "acute", "myocardial", "infarction", "(AMI).[1]", "However,", "AMI", "remains", "a", "leading", "cause", "of", "death", "worldwide,", "and", "the", "mortality", "rate", "from", "AMI", "is", "still", "unacceptably", "high.[2,3]", "Many", "challenges", "remain", "in", "the", "risk", "stratification", "and", "management", "of", "patients", "with", "AMI,", "such", "as", "optimal", "risk", "stratification", "of", "patients,", "with", "comorbidities.", "Comorbidities", "may", "affect", "multiple", "clinical", "outcomes,", "including", "mortality,", "quality", "of", "life,", "and", "cost.[4]", "Comorbidities", "in", "patients", "with", "AMI,", "such", "as", "renal", "insufficiency,", "diabetes", "mellitus", "and", "stroke,", "may", "reduce", "the", "patient’s", "physiologic", "reserve", "and", "thereby", "increase", "the", "risk", "of", "adverse", "outcome.", "Therefore", "the", "assessment", "of", "comorbidity", "is", "important", "for", "Correspondence", "to:", "Yu-Sheng", "Zhao,", "MD,", "Institute", "of", "Geriatric", "Cardiology,", "Chinese", "PLA", "General", "Hospital,", "Fuxing", "Road", "28,", "Beijing", "100853,", "China.", "E-mail:", "zys3012002@yahoo.com", "Telephone:", "+86-10-55499139", "Fax:", "+86-10-68188906", "Received:", "September", "5,", "2010", "Revised:", "March", "17,", "2011", "Accepted:", "March", "24,", "2011", "Published", "online:", "March", "28,", "2011", "risk", "stratification", "of", "AMI.", "To", "date,", "little", "information", "is", "available", "on", "the", "effects", "of", "patients’", "comorbidity", "on", "the", "outcome", "of", "patients", "with", "AMI.", "In", "the", "present", "study,", "we", "investigated", "whether", "medical", "comorbidities", "at", "admission", "might", "be", "predictive", "for", "the", "30-day", "in-hospital", "mortality", "of", "patients", "with", "AMI", "hospitalized", "in", "a", "single", "medical", "center.", "2", "2.1", "Methods", "Data", "sources", "Since", "1992", "a", "computerized", "medical", "record", "database", "has", "been", "established", "in", "the", "Chinese", "PLA", "General", "Hospital,", "with", "the", "diagnostic", "codes", "based", "on", "the", "ninth", "revision", "of", "the", "International", "Classification", "of", "Diseases", "developed", "by", "the", "World", "Health", "Organization,", "commonly", "referred", "to", "as", "ICD9.", "The", "medical", "records", "of", "the", "patients", "with", "a", "primary", "diagnosis", "of", "AMI", "who", "were", "admitted", "between", "January", "1,", "1993", "and", "December", "31,", "2007", "were", "identified", "through", "discharge", "diagnosis", "of", "ICD9", "code", "410.", "A", "total", "of", "5161", "patients", "were", "identified,", "and", "the", "medical", "records", "of", "these", "patients", "were", "then", "reviewed,", "with", "emphasis", "on", "age,", "gender,", "medical", "http://www.jgc301.com;", "jgc@mail.sciencep.com", "|", "Journal", "of", "Geriatric", "Cardiology" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 9, 9, 9, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 17, 17, 17, 17, 17, 17, 11, 11, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 34, 11 ], [ 105, 75, 9, 11 ], [ 117, 75, 43, 11 ], [ 162, 75, 17, 11 ], [ 181, 75, 53, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 114, 25 ], [ 189, 220, 82, 25 ], [ 275, 220, 40, 25 ], [ 320, 220, 125, 25 ], [ 449, 220, 57, 25 ], [ 510, 220, 68, 25 ], [ 120, 289, 40, 17 ], [ 163, 289, 53, 17 ], [ 218, 289, 27, 17 ], [ 248, 289, 48, 17 ], [ 299, 289, 14, 17 ], [ 316, 289, 57, 17 ], [ 120, 320, 41, 13 ], [ 164, 320, 9, 13 ], [ 176, 320, 55, 13 ], [ 234, 320, 48, 13 ], [ 284, 320, 19, 13 ], [ 305, 320, 41, 13 ], [ 349, 320, 17, 13 ], [ 368, 320, 20, 13 ], [ 390, 320, 46, 13 ], [ 439, 320, 18, 13 ], [ 459, 320, 50, 13 ], [ 512, 320, 39, 13 ], [ 553, 320, 41, 13 ], [ 596, 320, 22, 13 ], [ 620, 320, 39, 13 ], [ 661, 320, 26, 13 ], [ 689, 320, 20, 13 ], [ 120, 347, 83, 13 ], [ 205, 347, 35, 13 ], [ 241, 347, 12, 13 ], [ 256, 347, 49, 13 ], [ 308, 347, 11, 13 ], [ 321, 347, 28, 13 ], [ 351, 347, 40, 13 ], [ 394, 347, 127, 13 ], [ 120, 374, 44, 13 ], [ 166, 374, 12, 13 ], [ 181, 374, 22, 13 ], [ 206, 374, 27, 13 ], [ 235, 374, 45, 13 ], [ 283, 374, 12, 13 ], [ 298, 374, 20, 13 ], [ 320, 374, 25, 13 ], [ 120, 399, 49, 13 ], [ 172, 399, 35, 13 ], [ 209, 399, 58, 13 ], [ 270, 399, 35, 13 ], [ 120, 425, 51, 13 ], [ 174, 425, 9, 13 ], [ 186, 425, 24, 13 ], [ 213, 425, 8, 13 ], [ 223, 425, 37, 13 ], [ 263, 425, 19, 13 ], [ 285, 425, 7, 13 ], [ 294, 425, 10, 13 ], [ 307, 425, 43, 13 ], [ 352, 425, 22, 13 ], [ 377, 425, 8, 13 ], [ 388, 425, 13, 13 ], [ 403, 425, 26, 13 ], [ 431, 425, 30, 13 ], [ 463, 425, 31, 13 ], [ 497, 425, 55, 13 ], [ 555, 425, 30, 13 ], [ 588, 425, 16, 13 ], [ 606, 425, 41, 13 ], [ 650, 425, 53, 13 ], [ 705, 425, 57, 13 ], [ 120, 439, 40, 13 ], [ 163, 439, 31, 13 ], [ 197, 439, 39, 13 ], [ 239, 439, 61, 13 ], [ 303, 439, 20, 13 ], [ 326, 439, 63, 13 ], [ 393, 439, 19, 13 ], [ 415, 439, 66, 13 ], [ 485, 439, 11, 13 ], [ 499, 439, 18, 13 ], [ 520, 439, 46, 13 ], [ 569, 439, 45, 13 ], [ 617, 439, 16, 13 ], [ 637, 439, 39, 13 ], [ 680, 439, 26, 13 ], [ 709, 439, 8, 13 ], [ 720, 439, 43, 13 ], [ 120, 454, 27, 13 ], [ 120, 480, 20, 13 ], [ 145, 480, 31, 13 ], [ 181, 480, 46, 13 ], [ 233, 480, 10, 13 ], [ 248, 480, 51, 13 ], [ 305, 480, 19, 13 ], [ 329, 480, 53, 13 ], [ 387, 480, 36, 13 ], [ 428, 480, 19, 13 ], [ 452, 480, 12, 13 ], [ 470, 480, 54, 13 ], [ 529, 480, 10, 13 ], [ 544, 480, 20, 13 ], [ 570, 480, 10, 13 ], [ 585, 480, 51, 13 ], [ 641, 480, 68, 13 ], [ 714, 480, 15, 13 ], [ 735, 480, 28, 13 ], [ 120, 495, 56, 13 ], [ 178, 495, 19, 13 ], [ 199, 495, 35, 13 ], [ 236, 495, 10, 13 ], [ 248, 495, 6, 13 ], [ 256, 495, 30, 13 ], [ 288, 495, 35, 13 ], [ 325, 495, 12, 13 ], [ 339, 495, 84, 13 ], [ 425, 495, 39, 13 ], [ 466, 495, 11, 13 ], [ 478, 495, 51, 13 ], [ 531, 495, 19, 13 ], [ 553, 495, 59, 13 ], [ 614, 495, 8, 13 ], [ 624, 495, 51, 13 ], [ 676, 495, 23, 13 ], [ 701, 495, 13, 13 ], [ 716, 495, 47, 13 ], [ 120, 509, 19, 13 ], [ 144, 509, 11, 13 ], [ 159, 509, 26, 13 ], [ 189, 509, 36, 13 ], [ 229, 509, 19, 13 ], [ 253, 509, 45, 13 ], [ 302, 509, 52, 13 ], [ 358, 509, 68, 13 ], [ 431, 509, 43, 13 ], [ 479, 509, 16, 13 ], [ 499, 509, 72, 13 ], [ 576, 509, 19, 13 ], [ 600, 509, 50, 13 ], [ 654, 509, 42, 13 ], [ 700, 509, 63, 13 ], [ 120, 524, 36, 13 ], [ 159, 524, 8, 13 ], [ 171, 524, 60, 13 ], [ 234, 524, 61, 13 ], [ 299, 524, 12, 13 ], [ 314, 524, 56, 13 ], [ 374, 524, 25, 13 ], [ 402, 524, 30, 13 ], [ 435, 524, 36, 13 ], [ 474, 524, 49, 13 ], [ 527, 524, 11, 13 ], [ 540, 524, 14, 13 ], [ 558, 524, 11, 13 ], [ 571, 524, 23, 13 ], [ 598, 524, 11, 13 ], [ 611, 524, 28, 13 ], [ 643, 524, 45, 13 ], [ 691, 524, 27, 13 ], [ 721, 524, 31, 13 ], [ 755, 524, 8, 13 ], [ 120, 538, 51, 13 ], [ 174, 538, 27, 13 ], [ 203, 538, 16, 13 ], [ 222, 538, 22, 13 ], [ 247, 538, 44, 13 ], [ 293, 538, 83, 13 ], [ 378, 538, 34, 13 ], [ 415, 538, 8, 13 ], [ 425, 538, 66, 13 ], [ 494, 538, 12, 13 ], [ 509, 538, 42, 13 ], [ 553, 538, 47, 13 ], [ 602, 538, 33, 13 ], [ 638, 538, 63, 13 ], [ 703, 538, 11, 13 ], [ 717, 538, 46, 13 ], [ 120, 553, 43, 13 ], [ 168, 553, 59, 13 ], [ 230, 553, 11, 13 ], [ 245, 553, 16, 13 ], [ 265, 553, 30, 13 ], [ 299, 553, 35, 13 ], [ 339, 553, 24, 13 ], [ 366, 553, 8, 13 ], [ 379, 553, 51, 13 ], [ 434, 553, 51, 13 ], [ 489, 553, 23, 13 ], [ 516, 553, 61, 13 ], [ 581, 553, 78, 13 ], [ 663, 553, 71, 13 ], [ 738, 553, 25, 13 ], [ 120, 567, 56, 13 ], [ 178, 567, 19, 13 ], [ 200, 567, 25, 13 ], [ 227, 567, 75, 13 ], [ 305, 567, 30, 13 ], [ 336, 567, 8, 13 ], [ 347, 567, 47, 13 ], [ 396, 567, 22, 13 ], [ 420, 567, 20, 13 ], [ 443, 567, 24, 13 ], [ 469, 567, 8, 13 ], [ 479, 567, 51, 13 ], [ 532, 567, 23, 13 ], [ 557, 567, 72, 13 ], [ 631, 567, 37, 13 ], [ 670, 567, 48, 13 ], [ 720, 567, 43, 13 ], [ 120, 582, 69, 13 ], [ 191, 582, 40, 13 ], [ 233, 582, 11, 13 ], [ 246, 582, 55, 13 ], [ 303, 582, 46, 13 ], [ 351, 582, 19, 13 ], [ 372, 582, 46, 13 ], [ 421, 582, 36, 13 ], [ 459, 582, 43, 13 ], [ 505, 582, 19, 13 ], [ 526, 582, 50, 13 ], [ 578, 582, 58, 13 ], [ 638, 582, 29, 13 ], [ 669, 582, 24, 13 ], [ 695, 582, 11, 13 ], [ 707, 582, 16, 13 ], [ 726, 582, 37, 13 ], [ 120, 596, 11, 13 ], [ 132, 596, 36, 13 ], [ 170, 596, 22, 13 ], [ 193, 596, 72, 13 ], [ 267, 596, 12, 13 ], [ 280, 596, 70, 13 ], [ 352, 596, 41, 13 ], [ 395, 596, 16, 13 ], [ 413, 596, 55, 13 ], [ 470, 596, 72, 13 ], [ 544, 596, 19, 13 ], [ 565, 596, 50, 13 ], [ 617, 596, 40, 13 ], [ 658, 596, 22, 13 ], [ 682, 596, 8, 13 ], [ 692, 596, 11, 13 ], [ 705, 596, 58, 13 ], [ 120, 611, 10, 13 ], [ 132, 611, 25, 13 ], [ 159, 611, 58, 13 ], [ 219, 611, 19, 13 ], [ 240, 611, 50, 13 ], [ 292, 611, 11, 13 ], [ 304, 611, 24, 13 ], [ 330, 611, 10, 13 ], [ 343, 611, 28, 13 ], [ 373, 611, 42, 13 ], [ 417, 611, 16, 13 ], [ 434, 611, 27, 13 ], [ 463, 611, 11, 13 ], [ 476, 611, 28, 13 ], [ 506, 611, 11, 13 ], [ 519, 611, 16, 13 ], [ 537, 611, 49, 13 ], [ 588, 611, 11, 13 ], [ 600, 611, 81, 13 ], [ 684, 611, 37, 13 ], [ 722, 611, 11, 13 ], [ 735, 611, 28, 13 ], [ 120, 625, 45, 13 ], [ 168, 625, 22, 13 ], [ 194, 625, 29, 13 ], [ 226, 625, 60, 13 ], [ 290, 625, 16, 13 ], [ 310, 625, 37, 13 ], [ 350, 625, 23, 13 ], [ 377, 625, 11, 13 ], [ 391, 625, 73, 13 ], [ 468, 625, 11, 13 ], [ 482, 625, 74, 13 ], [ 559, 625, 27, 13 ], [ 589, 625, 58, 13 ], [ 651, 625, 19, 13 ], [ 673, 625, 29, 13 ], [ 705, 625, 19, 13 ], [ 727, 625, 35, 13 ], [ 120, 640, 71, 13 ], [ 193, 640, 85, 13 ], [ 281, 640, 81, 13 ], [ 364, 640, 40, 13 ], [ 406, 640, 19, 13 ], [ 428, 640, 65, 13 ], [ 496, 640, 11, 13 ], [ 509, 640, 28, 13 ], [ 539, 640, 42, 13 ], [ 583, 640, 19, 13 ], [ 605, 640, 57, 13 ], [ 664, 640, 23, 13 ], [ 690, 640, 27, 13 ], [ 70, 685, 13, 17 ], [ 86, 685, 92, 17 ], [ 70, 715, 22, 14 ], [ 94, 715, 51, 14 ], [ 148, 715, 12, 14 ], [ 162, 715, 50, 14 ], [ 214, 715, 40, 14 ], [ 256, 715, 19, 14 ], [ 277, 715, 38, 14 ], [ 317, 715, 40, 14 ], [ 359, 715, 45, 14 ], [ 70, 731, 14, 14 ], [ 86, 731, 25, 14 ], [ 114, 731, 18, 14 ], [ 135, 731, 33, 14 ], [ 170, 731, 11, 14 ], [ 184, 731, 18, 14 ], [ 205, 731, 59, 14 ], [ 267, 731, 19, 14 ], [ 289, 731, 52, 14 ], [ 344, 731, 60, 14 ], [ 70, 747, 25, 14 ], [ 101, 747, 29, 14 ], [ 137, 747, 20, 14 ], [ 164, 747, 25, 14 ], [ 195, 747, 12, 14 ], [ 214, 747, 57, 14 ], [ 278, 747, 52, 14 ], [ 337, 747, 19, 14 ], [ 363, 747, 22, 14 ], [ 392, 747, 12, 14 ], [ 70, 762, 61, 14 ], [ 134, 762, 52, 14 ], [ 189, 762, 15, 14 ], [ 207, 762, 16, 14 ], [ 226, 762, 75, 14 ], [ 304, 762, 29, 14 ], [ 335, 762, 9, 14 ], [ 347, 762, 57, 14 ], [ 70, 778, 64, 14 ], [ 139, 778, 22, 14 ], [ 165, 778, 57, 14 ], [ 226, 778, 40, 14 ], [ 270, 778, 9, 14 ], [ 283, 778, 55, 14 ], [ 342, 778, 11, 14 ], [ 357, 778, 47, 14 ], [ 70, 794, 31, 14 ], [ 103, 794, 46, 14 ], [ 151, 794, 24, 14 ], [ 177, 794, 21, 14 ], [ 200, 794, 38, 14 ], [ 241, 794, 69, 14 ], [ 312, 794, 26, 14 ], [ 340, 794, 64, 14 ], [ 70, 810, 18, 14 ], [ 91, 810, 52, 14 ], [ 145, 810, 12, 14 ], [ 160, 810, 46, 14 ], [ 209, 810, 57, 14 ], [ 269, 810, 40, 14 ], [ 311, 810, 12, 14 ], [ 326, 810, 6, 14 ], [ 335, 810, 44, 14 ], [ 382, 810, 22, 14 ], [ 70, 825, 9, 14 ], [ 82, 825, 26, 14 ], [ 111, 825, 49, 14 ], [ 163, 825, 32, 14 ], [ 197, 825, 11, 14 ], [ 211, 825, 23, 14 ], [ 237, 825, 11, 14 ], [ 251, 825, 57, 14 ], [ 311, 825, 56, 14 ], [ 370, 825, 34, 14 ], [ 70, 841, 48, 15 ], [ 120, 841, 42, 14 ], [ 166, 841, 21, 14 ], [ 189, 841, 13, 14 ], [ 205, 841, 44, 14 ], [ 252, 841, 7, 14 ], [ 261, 841, 52, 14 ], [ 316, 841, 55, 14 ], [ 374, 841, 30, 14 ], [ 70, 857, 26, 14 ], [ 100, 857, 17, 14 ], [ 121, 857, 19, 14 ], [ 144, 857, 9, 14 ], [ 157, 857, 26, 14 ], [ 187, 857, 45, 14 ], [ 236, 857, 34, 15 ], [ 274, 857, 55, 14 ], [ 333, 857, 9, 14 ], [ 347, 857, 42, 14 ], [ 393, 857, 11, 14 ], [ 70, 873, 62, 14 ], [ 135, 873, 21, 14 ], [ 160, 873, 34, 15 ], [ 198, 873, 55, 14 ], [ 256, 873, 11, 14 ], [ 271, 873, 40, 14 ], [ 315, 873, 21, 14 ], [ 339, 873, 13, 14 ], [ 355, 873, 49, 14 ], [ 70, 889, 18, 14 ], [ 93, 889, 34, 14 ], [ 132, 889, 40, 14 ], [ 177, 889, 40, 14 ], [ 222, 889, 11, 14 ], [ 238, 889, 26, 14 ], [ 269, 889, 17, 14 ], [ 291, 889, 19, 14 ], [ 314, 889, 43, 15 ], [ 362, 889, 15, 15 ], [ 383, 889, 21, 14 ], [ 70, 905, 62, 14 ], [ 136, 905, 11, 14 ], [ 152, 905, 43, 15 ], [ 200, 905, 19, 15 ], [ 223, 905, 9, 14 ], [ 237, 905, 58, 14 ], [ 300, 905, 69, 14 ], [ 374, 905, 30, 14 ], [ 70, 920, 56, 14 ], [ 129, 920, 26, 14 ], [ 157, 920, 12, 14 ], [ 171, 920, 46, 14 ], [ 220, 920, 21, 14 ], [ 244, 920, 63, 14 ], [ 310, 920, 21, 14 ], [ 335, 920, 70, 14 ], [ 70, 937, 18, 14 ], [ 93, 937, 38, 15 ], [ 136, 937, 35, 14 ], [ 175, 937, 17, 14 ], [ 197, 937, 29, 14 ], [ 231, 937, 40, 14 ], [ 276, 937, 31, 14 ], [ 311, 937, 9, 14 ], [ 325, 937, 19, 14 ], [ 349, 937, 21, 14 ], [ 375, 937, 29, 14 ], [ 70, 953, 37, 14 ], [ 110, 953, 31, 14 ], [ 143, 954, 9, 14 ], [ 154, 953, 22, 14 ], [ 178, 953, 12, 14 ], [ 193, 953, 18, 14 ], [ 213, 953, 81, 14 ], [ 296, 953, 35, 14 ], [ 333, 953, 12, 14 ], [ 347, 953, 57, 14 ], [ 70, 970, 21, 14 ], [ 96, 970, 69, 14 ], [ 170, 970, 33, 14 ], [ 207, 970, 15, 14 ], [ 227, 970, 24, 14 ], [ 255, 970, 24, 14 ], [ 284, 970, 26, 14 ], [ 315, 970, 23, 14 ], [ 343, 970, 12, 14 ], [ 359, 970, 45, 14 ], [ 70, 986, 24, 14 ], [ 96, 986, 21, 14 ], [ 121, 986, 84, 14 ], [ 207, 986, 38, 15 ], [ 248, 986, 34, 14 ], [ 285, 986, 17, 14 ], [ 305, 986, 46, 14 ], [ 354, 986, 21, 14 ], [ 378, 986, 26, 14 ], [ 70, 1003, 43, 14 ], [ 116, 1003, 21, 14 ], [ 141, 1003, 13, 14 ], [ 158, 1003, 18, 14 ], [ 179, 1003, 41, 14 ], [ 224, 1003, 29, 14 ], [ 257, 1003, 29, 14 ], [ 289, 1003, 79, 14 ], [ 372, 1003, 9, 14 ], [ 385, 1003, 19, 14 ], [ 70, 1019, 26, 14 ], [ 99, 1019, 51, 14 ], [ 152, 1019, 12, 14 ], [ 167, 1019, 35, 14 ], [ 204, 1019, 40, 14 ], [ 246, 1019, 12, 14 ], [ 261, 1019, 46, 14 ], [ 310, 1019, 21, 14 ], [ 334, 1019, 67, 14 ], [ 449, 687, 22, 14 ], [ 473, 687, 25, 14 ], [ 501, 687, 59, 14 ], [ 562, 687, 12, 14 ], [ 576, 687, 40, 14 ], [ 618, 687, 9, 14 ], [ 629, 687, 46, 14 ], [ 677, 687, 12, 14 ], [ 690, 687, 14, 14 ], [ 706, 687, 7, 14 ], [ 715, 687, 48, 14 ], [ 428, 703, 50, 14 ], [ 485, 703, 12, 14 ], [ 503, 703, 43, 14 ], [ 553, 703, 82, 14 ], [ 642, 703, 61, 14 ], [ 710, 703, 53, 14 ], [ 428, 719, 39, 14 ], [ 471, 719, 47, 14 ], [ 521, 719, 21, 14 ], [ 545, 719, 75, 14 ], [ 623, 719, 38, 14 ], [ 664, 719, 34, 14 ], [ 701, 719, 17, 14 ], [ 721, 719, 41, 14 ], [ 428, 735, 18, 14 ], [ 451, 735, 31, 14 ], [ 487, 735, 12, 14 ], [ 503, 735, 21, 14 ], [ 529, 735, 35, 14 ], [ 568, 735, 53, 14 ], [ 625, 735, 69, 14 ], [ 699, 735, 18, 14 ], [ 721, 735, 41, 14 ], [ 428, 750, 12, 14 ], [ 444, 750, 12, 14 ], [ 459, 750, 30, 14 ], [ 493, 750, 40, 14 ], [ 537, 750, 24, 14 ], [ 565, 750, 49, 14 ], [ 618, 750, 18, 14 ], [ 639, 750, 41, 14 ], [ 684, 750, 12, 14 ], [ 700, 750, 63, 14 ], [ 428, 766, 28, 14 ], [ 462, 766, 15, 14 ], [ 482, 766, 59, 14 ], [ 547, 766, 21, 14 ], [ 574, 766, 89, 14 ], [ 668, 766, 66, 14 ], [ 740, 766, 22, 14 ], [ 428, 782, 48, 14 ], [ 481, 782, 34, 14 ], [ 520, 782, 52, 14 ], [ 577, 782, 65, 14 ], [ 646, 782, 29, 14 ], [ 680, 782, 9, 14 ], [ 693, 782, 14, 14 ], [ 712, 782, 50, 14 ], [ 428, 798, 45, 14 ], [ 478, 798, 12, 14 ], [ 494, 798, 57, 14 ], [ 556, 798, 40, 14 ], [ 600, 798, 25, 14 ], [ 631, 798, 57, 14 ], [ 692, 798, 28, 14 ], [ 725, 798, 37, 14 ], [ 428, 814, 21, 14 ], [ 452, 814, 105, 14 ], [ 560, 814, 39, 14 ], [ 601, 814, 25, 14 ], [ 630, 814, 20, 14 ], [ 653, 814, 28, 14 ], [ 684, 814, 37, 14 ], [ 724, 814, 21, 14 ], [ 748, 814, 14, 14 ], [ 428, 830, 27, 14 ], [ 459, 830, 51, 14 ], [ 513, 830, 48, 14 ], [ 565, 830, 17, 14 ], [ 585, 830, 22, 14 ], [ 610, 830, 67, 14 ], [ 681, 830, 12, 14 ], [ 696, 830, 36, 14 ], [ 736, 830, 27, 14 ], [ 428, 845, 12, 14 ], [ 443, 845, 40, 14 ], [ 485, 845, 12, 14 ], [ 500, 845, 25, 14 ], [ 527, 845, 57, 14 ], [ 587, 845, 21, 14 ], [ 449, 861, 33, 14 ], [ 484, 861, 17, 14 ], [ 503, 861, 38, 14 ], [ 543, 861, 97, 14 ], [ 643, 861, 41, 14 ], [ 687, 861, 76, 14 ], [ 428, 877, 12, 14 ], [ 445, 877, 57, 14 ], [ 508, 877, 42, 14 ], [ 556, 877, 43, 14 ], [ 605, 877, 65, 14 ], [ 675, 877, 56, 14 ], [ 737, 877, 25, 14 ], [ 428, 893, 40, 14 ], [ 471, 893, 41, 14 ], [ 516, 893, 77, 14 ], [ 596, 893, 18, 14 ], [ 618, 893, 61, 14 ], [ 682, 893, 80, 14 ], [ 428, 908, 39, 14 ], [ 473, 908, 57, 14 ], [ 535, 908, 25, 14 ], [ 565, 908, 7, 14 ], [ 578, 908, 49, 14 ], [ 632, 908, 74, 14 ], [ 712, 908, 50, 14 ], [ 428, 924, 28, 14 ], [ 462, 924, 26, 14 ], [ 494, 924, 24, 14 ], [ 524, 924, 42, 14 ], [ 573, 924, 21, 14 ], [ 600, 924, 62, 14 ], [ 668, 924, 28, 14 ], [ 702, 924, 33, 14 ], [ 742, 924, 21, 14 ], [ 428, 940, 45, 14 ], [ 477, 940, 12, 14 ], [ 491, 940, 31, 14 ], [ 526, 940, 65, 14 ], [ 594, 940, 18, 14 ], [ 615, 940, 55, 14 ], [ 673, 940, 12, 14 ], [ 688, 940, 74, 14 ], [ 428, 956, 77, 14 ], [ 509, 956, 21, 14 ], [ 534, 956, 51, 14 ], [ 589, 956, 41, 14 ], [ 635, 956, 94, 14 ], [ 733, 956, 30, 14 ], [ 428, 972, 30, 14 ], [ 460, 972, 9, 14 ], [ 471, 972, 44, 14 ], [ 518, 972, 12, 14 ], [ 532, 972, 11, 14 ], [ 546, 972, 18, 14 ], [ 566, 972, 56, 14 ], [ 624, 972, 57, 14 ], [ 683, 972, 43, 14 ], [ 728, 972, 34, 14 ], [ 428, 987, 40, 14 ], [ 470, 987, 50, 14 ], [ 522, 987, 18, 14 ], [ 542, 987, 21, 14 ], [ 565, 987, 12, 14 ], [ 579, 987, 82, 14 ], [ 663, 987, 29, 14 ], [ 694, 987, 39, 14 ], [ 735, 987, 27, 14 ], [ 428, 1003, 12, 14 ], [ 446, 1003, 7, 14 ], [ 457, 1003, 50, 14 ], [ 512, 1003, 12, 14 ], [ 528, 1003, 25, 14 ], [ 558, 1003, 44, 14 ], [ 606, 1003, 62, 14 ], [ 673, 1003, 67, 14 ], [ 744, 1003, 18, 14 ], [ 428, 1019, 40, 14 ], [ 471, 1019, 21, 14 ], [ 495, 1019, 12, 14 ], [ 510, 1019, 31, 14 ], [ 544, 1019, 21, 14 ], [ 567, 1019, 12, 14 ], [ 582, 1019, 55, 14 ], [ 639, 1019, 29, 14 ], [ 671, 1019, 39, 14 ], [ 713, 1019, 17, 14 ], [ 732, 1019, 30, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Journal", "of", "Nutrition", "and", "Metabolism", "Volume", "2012,", "Article", "ID", "134202,", "8", "pages", "doi:10.1155/2012/134202", "Review", "Article", "Childhood", "Obesity", "and", "Obstructive", "Sleep", "Apnea", "Indra", "Narang", "and", "Joseph", "L.", "Mathew", "Division", "of", "Respiratory", "Medicine,", "The", "Hospital", "For", "Sick", "Children,", "555", "University", "Avenue,", "Toronto,", "ON,", "Canada", "M5G", "1X8", "Correspondence", "should", "be", "addressed", "to", "Indra", "Narang,", "indra.narang@sickkids.ca", "Received", "29", "May", "2012;", "Accepted", "31", "July", "2012", "Academic", "Editor:", "Dominique", "Bougle´", "Copyright", "©", "2012", "I.", "Narang", "and", "J.", "L.", "Mathew.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "The", "global", "epidemic", "of", "childhood", "and", "adolescent", "obesity", "and", "its", "immediate", "as", "well", "as", "long-term", "consequences", "for", "obese", "individuals", "and", "society", "as", "a", "whole", "cannot", "be", "overemphasized.", "Obesity", "in", "childhood", "and", "adolescence", "is", "associated", "with", "an", "increased", "risk", "of", "adult", "obesity", "and", "clinically", "significant", "consequences", "affecting", "the", "cardiovascular", "and", "metabolic", "systems.", "Importantly,", "obesity", "is", "additionally", "complicated", "by", "obstructive", "sleep", "apnea", "(OSA),", "occurring", "in", "up", "to", "60%", "of", "obese", "children.", "OSA,", "which", "is", "diagnosed", "using", "the", "gold", "standard", "polysomnogram", "(PSG),", "is", "characterised", "by", "snoring,", "recurrent", "partial", "(hypopneas)", "or", "complete", "(apneas)", "obstruction", "of", "the", "upper", "airway.", "OSA", "is", "frequently", "associated", "with", "intermittent", "oxyhemoglobin", "desaturations,", "sleep", "disruption,", "and", "sleep", "fragmentation.", "There", "is", "emerging", "data", "that", "OSA", "is", "associated", "with", "cardiovascular", "burden", "including", "systemic", "hypertension,", "changes", "in", "ventricular", "structure", "and", "function,", "arterial", "stiffness,", "and", "metabolic", "syndromes.", "Thus,", "OSA", "in", "the", "context", "of", "obesity", "may", "independently", "or", "synergistically", "magnify", "the", "underlying", "cardiovascular", "and", "metabolic", "burden.", "This", "is", "of", "importance", "as", "early", "recognition", "and", "treatment", "of", "OSA", "in", "obese", "children", "are", "likely", "to", "result", "in", "the", "reduction", "of", "cardiometabolic", "burden", "in", "obese", "children.", "This", "paper", "summarizes", "the", "current", "state", "of", "understanding", "of", "obesity-related", "OSA.", "Specifically,", "this", "paper", "will", "discuss", "epidemiology,", "pathophysiology,", "cardiometabolic", "burden,", "and", "management", "of", "obese", "children", "and", "adolescents", "with", "OSA.", "1.", "Introduction", "The", "epidemic", "of", "pediatric", "obesity", "has", "caused", "serious", "concern", "all", "over", "the", "world", "as", "the", "prevalence", "has", "increased", "alarmingly", "over", "time,", "not", "only", "in", "developed", "countries", "but", "also", "in", "developing", "countries", "[1,", "2].", "Furthermore,", "there", "is", "increasing", "recognition", "that", "childhood", "obesity", "is", "occurring", "at", "progres-", "sively", "younger", "ages", "[3].", "Recent", "publications", "have", "highlighted", "the", "challenge", "of", "defining", "childhood", "obesity", "in", "a", "manner", "that", "is", "both", "evidence", "based", "as", "well", "as", "uniformly", "applicable", "across", "different", "settings", "[4].", "In", "general,", "a", "statistical", "definition", "using", "BMI", "for", "age", "is", "used", "wherein", ">85th", "percentile", "is", "defined", "as", "overweight", "and", ">95th", "percentile", "as", "obesity", "[5].", "In", "contrast,", "the", "WHO", "defines", "obesity", "as", "BMI", "for", "age", "Z-score", ">3", "and", "overweight", "as", "Z-score", ">2.", "A", "large-scale", "multicentric", "study", "calculated", "BMI", "in", "children", "and", "adolescents", "and", "extrapolated", "the", "cut-off", "values", "for", "adult", "obesity", "(BMI", ">", "30)", "and", "over-", "weight", "(BMI", ">", "25),", "to", "the", "corresponding", "values", "in", "childhood", "and", "adolescence.", "Based", "on", "this,", "they", "were", "able", "to", "tabulate", "age-", "and", "gender-specific", "cut-off", "values", "for", "children", "and", "ado-", "lescents", "[6].", "At", "the", "present", "time,", "waist", "circumference", "is", "not", "used", "routinely", "to", "define", "obesity", "in", "children", "and", "adolescents.", "The", "high", "prevalence", "of", "obesity", "is", "believed", "to", "be", "a", "complex", "interplay", "of", "genetic,", "environmental", "(life-style),", "socioeco-", "nomic,", "cultural,", "and", "psychological", "factors", "which", "are", "beyond", "the", "scope", "of", "this", "paper.", "However,", "interestingly", "the", "pattern", "of", "in", "utero", "growth", "may", "program", "the", "pattern", "of", "subsequent", "body", "fat", "deposition", "and", "neuroendocrine", "interactions", "that", "promote", "eating", "behavior.", "Specifically,", "there", "is", "an", "observed", "increase", "in", "childhood", "obesity", "with", "increasing", "birth", "weight", "[7].", "Counterintuitively,", "infants", "with", "low", "birth", "weight", "and", "an", "early", "adiposity", "rebound", "are", "also", "predisposed", "to", "higher", "rates", "of", "obesity", "in", "later", "childhood", "[8].", "There", "are", "several", "well-documented", "adverse", "consequences", "of", "childhood", "obesity.", "Specific", "morbidities", "associated", "with", "obesity", "include", "hypertension,", "left", "ventricular", "abnormalities,", "insulin", "resistance,", "type", "2", "diabetes,", "dyslipidemia,", "nonalco-", "holic", "fatty", "liver", "disease,", "and", "obstructive", "sleep", "apnea", "[9].", "Further,", "in", "obese", "individuals,", "the", "clustering", "of", "dyslipidemia,", "hypertension,", "and", "impaired", "glucose", "tolerance/insulin", "resis-", "tance", "is", "referred", "to", "as", "the", "Metabolic", "Syndrome", "(MetS),", "which", "further", "increases", "the", "risk", "of", "atherosclerotic", "heart", "disease", "[10].", "In", "a", "followup", "of", "over", "200,000", "Norwegian", "adolescents,", "the", "relative", "risk", "of", "death", "due", "to", "ischaemic", "heart", "disease", "for", "those" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 59, 53, 32, 10 ], [ 93, 53, 6, 10 ], [ 101, 53, 23, 10 ], [ 125, 53, 17, 10 ], [ 144, 53, 31, 10 ], [ 177, 53, 27, 10 ], [ 206, 53, 7, 10 ], [ 215, 53, 18, 10 ], [ 235, 53, 25, 10 ], [ 269, 53, 87, 10 ], [ 746, 52, 19, 13 ], [ 59, 91, 82, 23 ], [ 145, 91, 94, 23 ], [ 245, 91, 55, 23 ], [ 305, 91, 78, 23 ], [ 388, 91, 30, 23 ], [ 423, 91, 130, 23 ], [ 558, 91, 102, 23 ], [ 666, 91, 68, 23 ], [ 59, 119, 18, 23 ], [ 82, 119, 30, 23 ], [ 117, 119, 146, 23 ], [ 269, 119, 83, 23 ], [ 357, 119, 18, 23 ], [ 379, 119, 132, 23 ], [ 517, 119, 89, 23 ], [ 614, 119, 35, 23 ], [ 654, 119, 30, 23 ], [ 59, 146, 99, 23 ], [ 163, 146, 117, 23 ], [ 286, 146, 107, 23 ], [ 398, 146, 18, 23 ], [ 421, 146, 50, 23 ], [ 476, 146, 105, 23 ], [ 59, 183, 40, 14 ], [ 102, 183, 64, 14 ], [ 169, 183, 46, 14 ], [ 217, 183, 11, 14 ], [ 231, 183, 50, 20 ], [ 285, 183, 20, 14 ], [ 308, 183, 54, 14 ], [ 365, 182, 31, 21 ], [ 59, 203, 19, 11 ], [ 80, 203, 26, 11 ], [ 107, 203, 35, 11 ], [ 144, 203, 28, 11 ], [ 173, 203, 8, 11 ], [ 183, 203, 45, 11 ], [ 230, 203, 37, 11 ], [ 270, 203, 20, 11 ], [ 292, 203, 41, 11 ], [ 335, 203, 28, 11 ], [ 364, 203, 23, 11 ], [ 389, 203, 35, 11 ], [ 426, 203, 23, 11 ], [ 450, 203, 41, 11 ], [ 493, 203, 26, 11 ], [ 521, 203, 50, 16 ], [ 573, 203, 8, 11 ], [ 583, 203, 51, 11 ], [ 636, 203, 15, 11 ], [ 653, 203, 39, 11 ], [ 694, 203, 32, 11 ], [ 728, 203, 27, 11 ], [ 757, 203, 8, 11 ], [ 59, 217, 15, 12 ], [ 75, 217, 37, 12 ], [ 115, 217, 39, 12 ], [ 156, 217, 8, 12 ], [ 166, 217, 31, 12 ], [ 198, 217, 29, 12 ], [ 229, 217, 36, 12 ], [ 267, 217, 17, 12 ], [ 286, 217, 20, 12 ], [ 308, 217, 20, 12 ], [ 330, 217, 15, 12 ], [ 346, 217, 65, 16 ], [ 413, 217, 35, 12 ], [ 450, 217, 27, 12 ], [ 480, 217, 28, 12 ], [ 510, 217, 8, 12 ], [ 520, 217, 45, 12 ], [ 567, 217, 20, 12 ], [ 589, 217, 41, 12 ], [ 632, 217, 27, 12 ], [ 662, 217, 23, 12 ], [ 686, 217, 35, 12 ], [ 723, 217, 23, 12 ], [ 59, 231, 41, 11 ], [ 102, 231, 23, 11 ], [ 59, 304, 75, 14 ], [ 140, 304, 50, 14 ], [ 197, 304, 20, 14 ], [ 222, 304, 30, 14 ], [ 259, 304, 59, 14 ], [ 324, 304, 17, 14 ], [ 347, 304, 36, 14 ], [ 389, 304, 11, 14 ], [ 59, 318, 43, 14 ], [ 110, 318, 55, 14 ], [ 174, 318, 22, 14 ], [ 205, 318, 35, 14 ], [ 249, 318, 17, 14 ], [ 274, 318, 35, 14 ], [ 318, 318, 11, 14 ], [ 338, 318, 25, 14 ], [ 371, 318, 28, 14 ], [ 59, 333, 71, 14 ], [ 137, 333, 17, 14 ], [ 161, 333, 23, 14 ], [ 191, 333, 18, 14 ], [ 217, 333, 45, 14 ], [ 269, 333, 54, 14 ], [ 331, 333, 69, 14 ], [ 59, 347, 16, 14 ], [ 83, 347, 83, 14 ], [ 174, 347, 52, 14 ], [ 234, 347, 24, 14 ], [ 266, 347, 46, 14 ], [ 320, 347, 80, 14 ], [ 59, 362, 14, 14 ], [ 82, 362, 36, 14 ], [ 128, 362, 35, 14 ], [ 172, 362, 17, 14 ], [ 197, 362, 53, 14 ], [ 260, 362, 27, 14 ], [ 296, 362, 11, 14 ], [ 317, 362, 83, 14 ], [ 59, 376, 76, 14 ], [ 139, 376, 11, 14 ], [ 154, 376, 35, 14 ], [ 193, 376, 11, 14 ], [ 208, 376, 17, 14 ], [ 229, 376, 38, 14 ], [ 271, 376, 29, 14 ], [ 304, 376, 16, 14 ], [ 324, 376, 25, 14 ], [ 353, 376, 46, 14 ], [ 59, 391, 16, 14 ], [ 78, 391, 32, 14 ], [ 112, 391, 52, 14 ], [ 166, 391, 20, 14 ], [ 189, 391, 56, 14 ], [ 248, 391, 42, 14 ], [ 292, 391, 11, 14 ], [ 306, 391, 17, 14 ], [ 325, 391, 74, 14 ], [ 59, 405, 57, 14 ], [ 120, 405, 64, 14 ], [ 189, 405, 11, 14 ], [ 203, 405, 10, 14 ], [ 218, 405, 50, 14 ], [ 273, 405, 20, 14 ], [ 296, 405, 12, 14 ], [ 312, 405, 62, 14 ], [ 379, 405, 21, 14 ], [ 59, 420, 65, 14 ], [ 129, 420, 43, 14 ], [ 177, 420, 29, 14 ], [ 211, 420, 25, 14 ], [ 242, 420, 32, 14 ], [ 280, 420, 33, 14 ], [ 318, 420, 52, 14 ], [ 376, 420, 24, 14 ], [ 59, 434, 26, 14 ], [ 91, 434, 17, 14 ], [ 115, 434, 36, 14 ], [ 157, 434, 137, 14 ], [ 301, 434, 44, 14 ], [ 351, 434, 24, 14 ], [ 381, 434, 18, 14 ], [ 59, 449, 45, 14 ], [ 109, 449, 20, 14 ], [ 134, 449, 16, 14 ], [ 156, 449, 63, 14 ], [ 225, 449, 11, 14 ], [ 242, 449, 17, 14 ], [ 264, 449, 57, 14 ], [ 327, 449, 56, 14 ], [ 389, 449, 11, 14 ], [ 59, 463, 24, 14 ], [ 85, 463, 32, 14 ], [ 120, 463, 26, 14 ], [ 149, 463, 47, 14 ], [ 199, 463, 40, 14 ], [ 242, 463, 17, 14 ], [ 262, 463, 20, 14 ], [ 285, 463, 37, 14 ], [ 325, 463, 74, 14 ], [ 59, 478, 64, 14 ], [ 132, 478, 48, 14 ], [ 188, 478, 11, 14 ], [ 208, 478, 13, 14 ], [ 230, 478, 56, 14 ], [ 294, 478, 52, 14 ], [ 355, 478, 11, 14 ], [ 375, 478, 25, 14 ], [ 59, 492, 66, 14 ], [ 130, 492, 39, 14 ], [ 175, 492, 45, 14 ], [ 225, 492, 46, 14 ], [ 276, 492, 9, 14 ], [ 290, 492, 11, 14 ], [ 307, 492, 10, 14 ], [ 323, 492, 50, 14 ], [ 379, 492, 21, 14 ], [ 424, 303, 44, 14 ], [ 475, 303, 11, 14 ], [ 493, 303, 6, 14 ], [ 505, 303, 20, 14 ], [ 528, 303, 22, 14 ], [ 557, 303, 44, 14 ], [ 607, 303, 57, 14 ], [ 670, 303, 13, 14 ], [ 690, 303, 57, 14 ], [ 753, 303, 11, 14 ], [ 424, 318, 81, 14 ], [ 511, 318, 46, 14 ], [ 563, 318, 11, 14 ], [ 579, 318, 26, 14 ], [ 610, 318, 55, 14 ], [ 670, 318, 17, 14 ], [ 692, 318, 56, 14 ], [ 753, 318, 11, 14 ], [ 424, 333, 13, 14 ], [ 440, 333, 43, 14 ], [ 486, 333, 54, 14 ], [ 544, 333, 79, 14 ], [ 627, 333, 21, 14 ], [ 651, 333, 31, 14 ], [ 686, 333, 11, 14 ], [ 700, 333, 13, 14 ], [ 717, 333, 34, 14 ], [ 754, 333, 11, 14 ], [ 424, 347, 12, 14 ], [ 438, 347, 59, 14 ], [ 499, 347, 23, 14 ], [ 525, 347, 11, 14 ], [ 538, 347, 10, 14 ], [ 551, 347, 54, 14 ], [ 607, 347, 44, 14 ], [ 653, 347, 13, 14 ], [ 668, 347, 41, 14 ], [ 711, 347, 54, 14 ], [ 424, 362, 79, 14 ], [ 507, 362, 21, 14 ], [ 531, 362, 52, 14 ], [ 587, 362, 10, 14 ], [ 601, 362, 6, 14 ], [ 611, 362, 37, 14 ], [ 652, 362, 25, 14 ], [ 681, 362, 11, 14 ], [ 695, 362, 24, 14 ], [ 723, 362, 42, 14 ], [ 424, 376, 59, 14 ], [ 486, 376, 41, 14 ], [ 530, 376, 21, 14 ], [ 554, 376, 44, 14 ], [ 602, 376, 11, 14 ], [ 616, 376, 56, 14 ], [ 675, 376, 37, 14 ], [ 715, 376, 20, 14 ], [ 739, 376, 26, 14 ], [ 424, 391, 52, 14 ], [ 479, 391, 14, 14 ], [ 496, 391, 17, 14 ], [ 516, 391, 21, 14 ], [ 541, 391, 55, 14 ], [ 600, 391, 24, 14 ], [ 627, 391, 6, 14 ], [ 637, 391, 25, 14 ], [ 666, 391, 10, 14 ], [ 679, 391, 37, 14 ], [ 720, 391, 20, 14 ], [ 742, 391, 22, 14 ], [ 424, 405, 11, 14 ], [ 437, 405, 24, 14 ], [ 463, 405, 42, 14 ], [ 507, 405, 21, 14 ], [ 530, 405, 63, 14 ], [ 596, 405, 20, 14 ], [ 618, 405, 60, 14 ], [ 680, 405, 11, 14 ], [ 694, 405, 28, 14 ], [ 724, 405, 22, 14 ], [ 748, 405, 17, 14 ], [ 424, 420, 51, 14 ], [ 478, 420, 11, 14 ], [ 491, 420, 30, 14 ], [ 524, 420, 11, 14 ], [ 538, 420, 91, 14 ], [ 631, 420, 11, 14 ], [ 645, 420, 35, 14 ], [ 424, 463, 22, 14 ], [ 453, 463, 36, 14 ], [ 497, 463, 55, 14 ], [ 560, 463, 41, 14 ], [ 608, 463, 40, 14 ], [ 656, 463, 25, 14 ], [ 689, 463, 32, 14 ], [ 728, 463, 36, 14 ], [ 424, 477, 74, 14 ], [ 505, 477, 57, 14 ], [ 570, 477, 32, 14 ], [ 610, 477, 66, 14 ], [ 683, 477, 35, 14 ], [ 725, 477, 23, 14 ], [ 756, 477, 9, 14 ], [ 424, 492, 54, 14 ], [ 481, 492, 83, 14 ], [ 59, 558, 80, 13 ], [ 59, 586, 78, 14 ], [ 139, 586, 76, 14 ], [ 218, 586, 54, 14 ], [ 275, 586, 24, 14 ], [ 301, 586, 28, 14 ], [ 332, 586, 68, 14 ], [ 59, 600, 18, 14 ], [ 89, 600, 25, 14 ], [ 126, 600, 23, 14 ], [ 161, 600, 65, 14 ], [ 238, 600, 11, 14 ], [ 261, 600, 32, 14 ], [ 305, 600, 26, 14 ], [ 343, 600, 6, 14 ], [ 362, 600, 38, 14 ], [ 59, 615, 30, 14 ], [ 95, 615, 11, 14 ], [ 114, 615, 46, 14 ], [ 167, 615, 50, 14 ], [ 224, 615, 17, 14 ], [ 248, 615, 100, 14 ], [ 355, 615, 44, 14 ], [ 59, 630, 19, 14 ], [ 84, 630, 81, 14 ], [ 172, 630, 85, 14 ], [ 264, 630, 16, 14 ], [ 286, 630, 20, 14 ], [ 312, 630, 87, 14 ], [ 59, 644, 65, 14 ], [ 130, 644, 19, 14 ], [ 155, 644, 28, 14 ], [ 190, 644, 66, 14 ], [ 262, 644, 48, 14 ], [ 316, 644, 11, 14 ], [ 334, 644, 27, 14 ], [ 368, 644, 32, 14 ], [ 59, 659, 19, 14 ], [ 85, 659, 13, 14 ], [ 105, 659, 61, 14 ], [ 173, 659, 21, 14 ], [ 201, 659, 20, 14 ], [ 228, 659, 31, 14 ], [ 267, 659, 11, 14 ], [ 285, 659, 60, 14 ], [ 352, 659, 24, 14 ], [ 383, 659, 17, 14 ], [ 59, 673, 50, 14 ], [ 115, 673, 42, 14 ], [ 163, 673, 11, 14 ], [ 181, 673, 25, 14 ], [ 212, 673, 30, 14 ], [ 249, 673, 66, 14 ], [ 321, 673, 50, 14 ], [ 377, 673, 22, 14 ], [ 59, 688, 57, 14 ], [ 121, 688, 18, 14 ], [ 145, 688, 25, 14 ], [ 175, 688, 48, 14 ], [ 228, 688, 11, 14 ], [ 244, 688, 17, 14 ], [ 266, 688, 45, 14 ], [ 317, 688, 11, 14 ], [ 333, 688, 66, 14 ], [ 59, 702, 32, 14 ], [ 95, 702, 50, 14 ], [ 149, 702, 33, 14 ], [ 185, 702, 16, 14 ], [ 206, 702, 63, 14 ], [ 273, 702, 11, 14 ], [ 289, 702, 6, 14 ], [ 299, 702, 66, 14 ], [ 369, 702, 30, 14 ], [ 59, 717, 25, 14 ], [ 90, 717, 84, 14 ], [ 181, 717, 24, 14 ], [ 211, 717, 19, 14 ], [ 238, 717, 11, 14 ], [ 256, 717, 20, 14 ], [ 283, 717, 37, 14 ], [ 327, 717, 24, 14 ], [ 358, 717, 23, 14 ], [ 388, 717, 11, 14 ], [ 59, 731, 76, 14 ], [ 138, 731, 18, 14 ], [ 159, 731, 25, 14 ], [ 187, 731, 23, 14 ], [ 213, 731, 39, 14 ], [ 254, 731, 11, 14 ], [ 267, 731, 30, 14 ], [ 300, 731, 39, 14 ], [ 341, 731, 27, 14 ], [ 371, 731, 28, 14 ], [ 59, 746, 44, 14 ], [ 107, 746, 47, 14 ], [ 158, 746, 21, 14 ], [ 184, 746, 65, 14 ], [ 253, 746, 17, 14 ], [ 274, 746, 66, 14 ], [ 344, 746, 40, 14 ], [ 388, 746, 11, 14 ], [ 59, 760, 32, 14 ], [ 96, 760, 11, 14 ], [ 112, 760, 17, 14 ], [ 135, 760, 51, 14 ], [ 191, 760, 28, 14 ], [ 224, 760, 18, 14 ], [ 247, 760, 19, 14 ], [ 272, 760, 19, 14 ], [ 296, 760, 47, 14 ], [ 349, 760, 8, 14 ], [ 362, 760, 9, 14 ], [ 377, 760, 23, 14 ], [ 59, 775, 36, 14 ], [ 98, 775, 36, 14 ], [ 137, 775, 20, 14 ], [ 160, 775, 59, 14 ], [ 222, 775, 11, 14 ], [ 236, 775, 30, 14 ], [ 269, 775, 59, 14 ], [ 331, 775, 19, 14 ], [ 353, 775, 13, 14 ], [ 368, 775, 31, 14 ], [ 59, 789, 23, 14 ], [ 85, 789, 14, 14 ], [ 100, 789, 15, 14 ], [ 117, 789, 10, 14 ], [ 130, 789, 16, 14 ], [ 150, 789, 25, 14 ], [ 178, 789, 11, 14 ], [ 192, 789, 25, 14 ], [ 220, 789, 46, 14 ], [ 268, 789, 80, 14 ], [ 351, 789, 29, 14 ], [ 383, 789, 17, 14 ], [ 59, 804, 43, 14 ], [ 106, 804, 63, 14 ], [ 175, 804, 9, 14 ], [ 189, 804, 44, 14 ], [ 238, 804, 27, 14 ], [ 266, 804, 15, 14 ], [ 285, 804, 39, 14 ], [ 329, 804, 17, 14 ], [ 351, 804, 16, 14 ], [ 372, 804, 28, 14 ], [ 59, 818, 29, 14 ], [ 94, 818, 83, 14 ], [ 182, 818, 22, 14 ], [ 210, 818, 57, 14 ], [ 273, 818, 18, 14 ], [ 297, 818, 22, 14 ], [ 324, 818, 25, 14 ], [ 355, 818, 44, 14 ], [ 59, 833, 11, 14 ], [ 74, 833, 6, 14 ], [ 85, 833, 38, 14 ], [ 127, 833, 41, 14 ], [ 172, 833, 11, 14 ], [ 187, 833, 42, 14 ], [ 234, 833, 25, 14 ], [ 263, 833, 11, 14 ], [ 278, 833, 34, 14 ], [ 317, 833, 26, 14 ], [ 347, 833, 52, 14 ], [ 59, 847, 48, 14 ], [ 113, 847, 19, 14 ], [ 139, 847, 32, 14 ], [ 177, 847, 44, 14 ], [ 226, 847, 79, 14 ], [ 312, 847, 43, 14 ], [ 361, 847, 39, 14 ], [ 59, 862, 11, 14 ], [ 76, 862, 28, 14 ], [ 109, 862, 35, 14 ], [ 150, 862, 17, 14 ], [ 172, 862, 66, 14 ], [ 244, 862, 30, 14 ], [ 280, 862, 42, 14 ], [ 328, 862, 10, 14 ], [ 343, 862, 6, 14 ], [ 355, 862, 44, 14 ], [ 59, 876, 63, 14 ], [ 129, 876, 16, 14 ], [ 151, 876, 37, 14 ], [ 195, 876, 25, 14 ], [ 226, 876, 24, 14 ], [ 256, 876, 60, 14 ], [ 322, 876, 52, 14 ], [ 381, 876, 19, 14 ], [ 59, 891, 48, 14 ], [ 108, 891, 17, 14 ], [ 127, 891, 45, 14 ], [ 173, 891, 11, 14 ], [ 186, 891, 10, 14 ], [ 198, 891, 50, 14 ], [ 250, 891, 17, 14 ], [ 269, 891, 44, 14 ], [ 314, 891, 11, 14 ], [ 327, 891, 47, 14 ], [ 375, 891, 25, 14 ], [ 59, 905, 30, 14 ], [ 92, 905, 63, 14 ], [ 158, 905, 10, 14 ], [ 171, 905, 6, 14 ], [ 180, 905, 50, 14 ], [ 233, 905, 31, 14 ], [ 267, 905, 14, 14 ], [ 282, 909, 11, 14 ], [ 295, 905, 17, 14 ], [ 313, 905, 18, 14 ], [ 334, 905, 47, 14 ], [ 383, 905, 17, 14 ], [ 282, 914, 11, 14 ], [ 59, 920, 43, 14 ], [ 105, 920, 63, 14 ], [ 172, 920, 32, 14 ], [ 208, 920, 23, 14 ], [ 235, 920, 6, 14 ], [ 245, 920, 26, 14 ], [ 275, 920, 30, 14 ], [ 309, 920, 19, 14 ], [ 332, 920, 68, 14 ], [ 59, 935, 20, 14 ], [ 80, 935, 27, 14 ], [ 108, 935, 19, 14 ], [ 128, 935, 43, 14 ], [ 173, 935, 22, 14 ], [ 197, 935, 20, 14 ], [ 218, 935, 9, 14 ], [ 229, 935, 49, 14 ], [ 280, 935, 11, 14 ], [ 292, 935, 24, 14 ], [ 317, 935, 17, 14 ], [ 335, 935, 64, 14 ], [ 59, 949, 28, 14 ], [ 89, 949, 11, 14 ], [ 103, 949, 13, 14 ], [ 119, 949, 37, 14 ], [ 158, 949, 66, 14 ], [ 228, 949, 26, 14 ], [ 436, 556, 21, 14 ], [ 461, 556, 53, 14 ], [ 517, 556, 27, 14 ], [ 547, 556, 11, 14 ], [ 562, 556, 76, 14 ], [ 642, 556, 11, 14 ], [ 656, 556, 32, 14 ], [ 691, 556, 18, 14 ], [ 712, 556, 24, 14 ], [ 739, 556, 25, 14 ], [ 424, 571, 55, 14 ], [ 484, 571, 24, 14 ], [ 513, 571, 17, 14 ], [ 535, 571, 57, 14 ], [ 597, 571, 11, 14 ], [ 613, 571, 89, 14 ], [ 708, 571, 57, 14 ], [ 424, 585, 19, 14 ], [ 451, 585, 27, 14 ], [ 486, 585, 57, 14 ], [ 551, 585, 9, 14 ], [ 568, 585, 51, 14 ], [ 627, 585, 11, 14 ], [ 645, 585, 17, 14 ], [ 670, 585, 40, 14 ], [ 718, 585, 11, 14 ], [ 737, 585, 28, 14 ], [ 424, 600, 60, 14 ], [ 488, 600, 48, 14 ], [ 540, 600, 33, 14 ], [ 577, 600, 9, 14 ], [ 591, 600, 38, 14 ], [ 633, 600, 14, 14 ], [ 651, 600, 17, 14 ], [ 672, 600, 35, 14 ], [ 711, 600, 38, 14 ], [ 753, 600, 11, 14 ], [ 424, 615, 17, 14 ], [ 445, 615, 27, 14 ], [ 477, 615, 74, 14 ], [ 556, 615, 56, 14 ], [ 617, 615, 20, 14 ], [ 641, 615, 48, 14 ], [ 694, 615, 16, 14 ], [ 715, 615, 50, 14 ], [ 424, 629, 11, 14 ], [ 441, 629, 51, 14 ], [ 497, 629, 20, 14 ], [ 522, 629, 17, 14 ], [ 544, 629, 50, 14 ], [ 599, 629, 11, 14 ], [ 616, 629, 53, 14 ], [ 675, 629, 39, 14 ], [ 719, 629, 11, 14 ], [ 735, 629, 30, 14 ], [ 424, 644, 26, 14 ], [ 455, 644, 28, 14 ], [ 488, 644, 9, 14 ], [ 502, 644, 13, 14 ], [ 521, 644, 96, 14 ], [ 622, 644, 45, 14 ], [ 672, 644, 27, 14 ], [ 705, 644, 8, 14 ], [ 718, 644, 25, 14 ], [ 748, 644, 17, 14 ], [ 424, 658, 54, 14 ], [ 481, 658, 11, 14 ], [ 495, 658, 16, 14 ], [ 515, 658, 52, 14 ], [ 571, 658, 11, 14 ], [ 586, 658, 6, 14 ], [ 596, 658, 35, 14 ], [ 634, 658, 84, 14 ], [ 721, 658, 44, 14 ], [ 424, 673, 33, 14 ], [ 464, 673, 17, 14 ], [ 488, 673, 27, 14 ], [ 522, 673, 56, 14 ], [ 585, 673, 23, 14 ], [ 614, 673, 11, 14 ], [ 633, 673, 6, 14 ], [ 646, 673, 71, 14 ], [ 723, 673, 11, 14 ], [ 741, 673, 24, 14 ], [ 424, 687, 52, 14 ], [ 478, 687, 21, 14 ], [ 500, 687, 36, 14 ], [ 538, 687, 38, 14 ], [ 577, 687, 11, 14 ], [ 589, 687, 21, 14 ], [ 612, 687, 36, 14 ], [ 650, 687, 33, 14 ], [ 684, 687, 9, 14 ], [ 695, 687, 70, 14 ], [ 424, 702, 14, 14 ], [ 443, 702, 17, 14 ], [ 465, 702, 43, 14 ], [ 513, 702, 49, 14 ], [ 568, 702, 14, 14 ], [ 587, 702, 28, 14 ], [ 620, 702, 9, 14 ], [ 634, 702, 45, 14 ], [ 684, 702, 11, 14 ], [ 700, 702, 13, 14 ], [ 718, 702, 46, 14 ], [ 424, 716, 11, 14 ], [ 440, 716, 22, 14 ], [ 466, 716, 11, 14 ], [ 481, 716, 66, 14 ], [ 552, 716, 35, 14 ], [ 591, 716, 11, 14 ], [ 607, 716, 23, 14 ], [ 634, 716, 6, 14 ], [ 645, 716, 26, 14 ], [ 675, 716, 89, 14 ], [ 424, 731, 57, 14 ], [ 486, 731, 44, 14 ], [ 537, 731, 18, 14 ], [ 560, 731, 25, 14 ], [ 592, 731, 48, 14 ], [ 645, 731, 11, 14 ], [ 662, 731, 13, 14 ], [ 681, 731, 55, 14 ], [ 741, 731, 24, 14 ], [ 424, 745, 76, 14 ], [ 506, 745, 11, 14 ], [ 523, 745, 35, 14 ], [ 564, 745, 54, 14 ], [ 624, 745, 11, 14 ], [ 641, 745, 43, 14 ], [ 690, 745, 8, 14 ], [ 704, 745, 9, 14 ], [ 719, 745, 46, 14 ], [ 424, 760, 11, 14 ], [ 440, 760, 83, 14 ], [ 528, 760, 42, 14 ], [ 575, 760, 50, 14 ], [ 630, 760, 6, 14 ], [ 641, 760, 27, 14 ], [ 672, 760, 44, 14 ], [ 721, 760, 11, 14 ], [ 737, 760, 28, 14 ], [ 424, 774, 38, 14 ], [ 464, 774, 18, 14 ], [ 485, 774, 25, 14 ], [ 513, 774, 35, 14 ], [ 550, 774, 11, 14 ], [ 564, 774, 60, 14 ], [ 627, 774, 11, 14 ], [ 640, 774, 71, 14 ], [ 714, 774, 51, 14 ], [ 424, 789, 17, 14 ], [ 443, 789, 28, 14 ], [ 474, 789, 11, 14 ], [ 487, 789, 76, 14 ], [ 566, 789, 11, 14 ], [ 579, 789, 28, 14 ], [ 610, 789, 38, 14 ], [ 651, 789, 42, 14 ], [ 695, 789, 20, 14 ], [ 717, 789, 9, 14 ], [ 729, 789, 17, 14 ], [ 748, 789, 17, 14 ], [ 424, 803, 63, 14 ], [ 495, 803, 16, 14 ], [ 520, 803, 6, 14 ], [ 535, 803, 67, 14 ], [ 610, 803, 89, 14 ], [ 708, 803, 57, 14 ], [ 424, 818, 44, 14 ], [ 471, 818, 11, 14 ], [ 485, 818, 56, 14 ], [ 544, 818, 71, 14 ], [ 618, 818, 11, 14 ], [ 631, 818, 12, 14 ], [ 646, 818, 59, 14 ], [ 708, 818, 26, 14 ], [ 436, 833, 56, 14 ], [ 495, 833, 30, 14 ], [ 528, 833, 32, 14 ], [ 563, 833, 37, 14 ], [ 604, 833, 18, 14 ], [ 625, 833, 41, 14 ], [ 670, 833, 6, 14 ], [ 679, 833, 31, 14 ], [ 713, 833, 52, 14 ], [ 424, 847, 11, 14 ], [ 441, 847, 17, 14 ], [ 464, 847, 43, 14 ], [ 513, 847, 11, 14 ], [ 531, 847, 65, 14 ], [ 603, 847, 60, 14 ], [ 669, 847, 61, 14 ], [ 737, 847, 28, 14 ], [ 424, 862, 48, 14 ], [ 475, 862, 11, 14 ], [ 489, 862, 61, 14 ], [ 553, 862, 26, 14 ], [ 581, 862, 24, 14 ], [ 608, 862, 40, 14 ], [ 651, 862, 9, 14 ], [ 663, 862, 53, 14 ], [ 719, 862, 46, 14 ], [ 424, 876, 29, 14 ], [ 456, 876, 52, 14 ], [ 511, 876, 24, 14 ], [ 537, 876, 16, 14 ], [ 556, 876, 97, 14 ], [ 656, 876, 61, 14 ], [ 720, 876, 20, 14 ], [ 742, 876, 23, 14 ], [ 424, 891, 11, 14 ], [ 441, 891, 8, 14 ], [ 455, 891, 9, 14 ], [ 470, 891, 23, 14 ], [ 500, 891, 44, 14 ], [ 549, 891, 11, 14 ], [ 566, 891, 41, 14 ], [ 613, 891, 17, 14 ], [ 636, 891, 61, 14 ], [ 703, 891, 44, 14 ], [ 753, 891, 11, 14 ], [ 424, 905, 6, 14 ], [ 436, 905, 49, 14 ], [ 490, 905, 17, 14 ], [ 514, 905, 11, 14 ], [ 531, 905, 16, 14 ], [ 553, 905, 36, 14 ], [ 595, 905, 27, 14 ], [ 627, 905, 74, 14 ], [ 707, 905, 57, 14 ], [ 424, 920, 56, 14 ], [ 483, 920, 25, 14 ], [ 511, 920, 25, 14 ], [ 540, 920, 70, 14 ], [ 613, 920, 29, 14 ], [ 645, 920, 19, 14 ], [ 668, 920, 52, 14 ], [ 723, 920, 42, 14 ], [ 424, 934, 17, 14 ], [ 444, 934, 31, 14 ], [ 479, 934, 43, 14 ], [ 525, 934, 11, 14 ], [ 540, 934, 33, 14 ], [ 576, 934, 25, 14 ], [ 604, 934, 45, 14 ], [ 652, 934, 20, 14 ], [ 675, 934, 27, 14 ], [ 706, 934, 17, 14 ], [ 726, 934, 39, 14 ], [ 424, 949, 59, 14 ], [ 488, 949, 44, 14 ], [ 537, 949, 27, 14 ], [ 569, 949, 20, 14 ], [ 594, 949, 63, 14 ], [ 661, 949, 74, 14 ], [ 740, 949, 25, 14 ], [ 70, 986, 64, 11 ], [ 136, 986, 26, 11 ], [ 165, 986, 17, 11 ], [ 184, 986, 80, 11 ], [ 266, 986, 17, 11 ], [ 285, 986, 79, 11 ], [ 366, 986, 25, 11 ], [ 393, 986, 49, 11 ], [ 444, 986, 40, 11 ], [ 486, 986, 25, 11 ], [ 513, 986, 62, 11 ], [ 577, 986, 24, 11 ], [ 603, 986, 48, 11 ], [ 653, 986, 21, 11 ], [ 677, 986, 28, 11 ], [ 707, 986, 30, 11 ], [ 739, 986, 25, 11 ], [ 59, 999, 55, 11 ], [ 116, 999, 6, 11 ], [ 125, 999, 40, 11 ], [ 168, 999, 15, 11 ], [ 186, 999, 57, 11 ], [ 246, 999, 36, 11 ], [ 284, 999, 36, 11 ], [ 323, 999, 18, 11 ], [ 343, 999, 31, 11 ], [ 377, 999, 25, 11 ], [ 404, 999, 59, 11 ], [ 466, 999, 9, 11 ], [ 478, 999, 28, 11 ], [ 508, 999, 26, 11 ], [ 537, 999, 15, 11 ], [ 555, 999, 35, 11 ], [ 592, 999, 61, 11 ], [ 656, 999, 24, 11 ], [ 682, 999, 57, 11 ], [ 741, 999, 24, 11 ], [ 59, 1011, 24, 11 ], [ 85, 1011, 58, 11 ], [ 145, 1011, 33, 11 ], [ 70, 1022, 4, 7 ], [ 80, 1023, 11, 11 ], [ 93, 1023, 28, 11 ], [ 123, 1023, 77, 11 ], [ 203, 1023, 32, 11 ], [ 237, 1023, 13, 11 ], [ 252, 1023, 50, 11 ], [ 305, 1023, 29, 11 ], [ 336, 1023, 104, 11 ], [ 58, 1053, 7, 8 ], [ 66, 1053, 19, 8 ], [ 87, 1053, 15, 8 ], [ 104, 1053, 35, 8 ], [ 543, 1054, 6, 10 ], [ 552, 1055, 13, 10 ], [ 567, 1055, 27, 10 ], [ 595, 1055, 26, 10 ], [ 623, 1055, 40, 10 ], [ 667, 1054, 6, 10 ], [ 677, 1055, 18, 10 ], [ 696, 1055, 42, 10 ], [ 740, 1055, 25, 10 ], [ 58, 1066, 15, 8 ], [ 75, 1066, 34, 8 ], [ 110, 1066, 14, 8 ], [ 126, 1066, 16, 8 ], [ 144, 1066, 10, 8 ], [ 156, 1066, 13, 8 ], [ 171, 1066, 23, 8 ], [ 196, 1066, 7, 8 ], [ 205, 1066, 10, 8 ], [ 217, 1066, 21, 8 ], [ 239, 1066, 33, 8 ], [ 275, 1066, 22, 8 ], [ 298, 1066, 12, 8 ], [ 312, 1066, 21, 8 ], [ 335, 1066, 7, 8 ], [ 345, 1066, 12, 8 ], [ 358, 1066, 32, 8 ], [ 392, 1066, 39, 8 ], [ 432, 1066, 38, 8 ], [ 472, 1066, 63, 8 ], [ 537, 1066, 29, 8 ], [ 568, 1066, 178, 8 ], [ 58, 1074, 22, 8 ], [ 81, 1074, 28, 8 ], [ 111, 1074, 44, 8 ], [ 157, 1074, 60, 8 ], [ 219, 1074, 16, 8 ], [ 237, 1074, 41, 8 ], [ 279, 1074, 14, 8 ], [ 295, 1074, 47, 8 ], [ 344, 1074, 7, 8 ], [ 353, 1074, 14, 8 ], [ 369, 1074, 33, 8 ], [ 403, 1074, 32, 8 ], [ 437, 1074, 12, 8 ], [ 451, 1074, 27, 8 ], [ 480, 1074, 18, 8 ], [ 500, 1074, 7, 8 ], [ 508, 1074, 31, 8 ], [ 541, 1074, 20, 8 ], [ 813, 227, 10, 0 ], [ 813, 237, 10, 0 ], [ 813, 363, 10, 0 ], [ 813, 395, 10, 0 ], [ 813, 530, 10, 0 ], [ 813, 670, 10, 0 ], [ 813, 721, 10, 0 ], [ 813, 847, 10, 0 ] ]

[ "Biochem.", "J.", "(2012)", "445,", "237–246", "(Printed", "in", "Great", "Britain)", "doi:10.1042/BJ20111978", "237", "Different", "molecular", "bases", "underlie", "the", "mitochondrial", "respiratory", "activity", "in", "the", "homoeothermic", "spadices", "of", "Symplocarpus", "renifolius", "and", "the", "transiently", "thermogenic", "appendices", "of", "Arum", "maculatum", "Yusuke", "KAKIZAKI*,", "Anthony", "L.", "MOORE†", "and", "Kikukatsu", "ITO‡1", "*The", "United", "Graduate", "School", "of", "Agricultural", "Sciences,", "Iwate", "University,", "3-18-8", "Ueda,", "Morioka,", "Iwate,", "020-8550,", "Japan,", "†Department", "of", "Biochemistry", "and", "Molecular", "Biology,", "School", "of", "Life", "Sciences,", "University", "of", "Sussex,", "Falmer,", "Brighton,", "BN1", "9QG,", "U.K.,", "and", "‡Cryobiofrontier", "Research", "Center,", "Faculty", "of", "Agriculture,", "Iwate", "University,", "3-18-8", "Ueda,", "Morioka,", "Iwate,", "020-8550,", "Japan", "Symplocarpus", "renifolius", "and", "Arum", "maculatum", "are", "known", "to", "produce", "significant", "heat", "during", "the", "course", "of", "their", "floral", "development,", "but", "they", "use", "different", "regulatory", "mechanisms,", "i.e.", "homoeothermic", "compared", "with", "transient", "thermogenesis.", "To", "further", "clarify", "the", "molecular", "basis", "of", "species-specific", "thermogenesis", "in", "plants,", "in", "the", "present", "study", "we", "have", "analysed", "the", "native", "structures", "and", "expression", "patterns", "of", "the", "mitochondrial", "respiratory", "components", "in", "S.", "renifolius", "and", "A.", "maculatum.", "Our", "comparative", "analysis", "using", "Blue", "native", "PAGE", "combined", "with", "nano", "LC", "(liquid", "chromatography)-MS/MS", "(tandem", "MS)", "has", "revealed", "that", "the", "constituents", "of", "the", "respiratory", "complexes", "in", "both", "plants", "were", "basically", "similar,", "but", "that", "several", "mitochondrial", "components", "appeared", "to", "be", "differently", "expressed", "in", "their", "thermogenic", "organs.", "Namely,", "complex", "II", "in", "S.", "renifolius", "was", "detected", "as", "a", "340", "kDa", "product,", "suggesting", "an", "oligomeric", "or", "supramolecular", "structure", "in", "vivo.", "Moreover,", "the", "expression", "of", "an", "external", "NAD(P)H", "dehydrogenase", "was", "found", "to", "be", "higher", "in", "A.", "maculatum", "than", "in", "S.", "renifolius,", "whereas", "an", "internal", "NAD(P)H", "dehydrogenase", "was", "expressed", "at", "a", "similar", "level", "in", "both", "species.", "Alternative", "oxidase", "was", "detected", "as", "smear-like", "signals", "that", "were", "elongated", "on", "the", "first", "dimension", "with", "a", "peak", "at", "around", "200", "kDa", "in", "both", "species.", "The", "significance", "and", "implication", "of", "these", "data", "are", "discussed", "in", "terms", "of", "thermoregulation", "in", "plants.", "Key", "words:", "alternative", "oxidase", "(AOX),", "Blue", "native", "PAGE,", "mitochondrial", "respiratory", "chain,", "thermogenic", "plants,", "type", "II", "NAD(P)H", "dehydrogenase.", "INTRODUCTION", "Organ-specific", "thermogenesis", "associated", "with", "floral", "development", "has", "been", "well", "documented", "in", "plants", "from", "a", "diverse", "range", "of", "families,", "including", "the", "monocotyledonous", "Araceae", "[1],", "dicotyledonous", "Nelumbonaceae", "[2]", "and", "gymnospermous", "Cycadaceae", "[3].", "Most", "thermogenic", "activities", "in", "these", "plants", "can", "be", "categorized", "into", "two", "types,", "in", "accordance", "with", "the", "transition", "patterns", "of", "their", "tissue", "temperature.", "Transient", "heat", "production", "has", "been", "observed", "in", "the", "majority", "of", "thermogenic", "plants", "analysed,", "where", "the", "temperature", "of", "a", "thermogenic", "organ", "rises", "discontinuously", "over", "one", "or", "two", "events.", "This", "type", "of", "thermogenesis", "has", "been", "well", "studied", "in", "Arum", "species", "since", "Jean-", "Baptiste", "Lamarck", "first", "documented", "the", "thermogenic", "activity", "of", "plants", "in", "the", "European", "arum", "lily", "[4].", "For", "instance,", "it", "is", "now", "widely", "known", "that", "appendices", "of", "Arum", "maculatum", "can", "be", "hotter", "than", "30", "◦C", "at", "the", "peak", "of", "their", "transient", "thermogenesis,", "when", "the", "ambient", "temperature", "is", "between", "7–22", "◦C", "[5,6,7].", "On", "the", "other", "hand,", "homoeothermic", "heat", "production", "has", "also", "been", "reported", "in", "a", "limited", "number", "of", "species,", "such", "as", "sacred", "lotus", "(Nelumbo", "nucifera)", "and", "skunk", "cabbage", "(Symplocarpus", "species)", "[2,8,9].", "In", "these", "plants,", "the", "thermogenic", "organ", "remains", "at", "a", "constant", "temperature", "for", "several", "days", "with", "remarkable", "precision.", "For", "example,", "the", "spadices", "of", "S.", "renifolius", "are", "reported", "to", "maintain", "their", "tissue", "temperature", "at", "a", "relatively", "stable", "21", "+", "2.4", "◦C,", "although", "the", "−", "ambient", "temperature", "varies", "over", "a", "wide", "range", "[8].", "Surprisingly,", "this", "plant", "can", "produce", "heat", "that", "is", "sufficient", "to", "melt", "the", "surrounding", "snow", "in", "its", "natural", "environment", "[10].", "The", "molecular", "basis", "of", "thermogenesis", "in", "plants", "has", "long", "been", "associated", "with", "the", "expression", "of", "cyanide-resistant", "respiration", "[4].", "Such", "respiration", "is", "attributed", "to", "the", "activity", "of", "AOX", "(alternative", "oxidase),", "which", "is", "located", "on", "the", "matrix", "surface", "of", "the", "inner", "mitochondrial", "membrane", "and", "catalyses", "the", "oxidation", "of", "ubiquinol", "and", "the", "reduction", "of", "molecular", "oxygen", "to", "water", "[11].", "AOX", "is", "an", "energy-dissipative", "enzyme,", "since", "it", "does", "not", "contribute", "to", "the", "formation", "of", "a", "proton", "electrochemical", "gradient", "across", "the", "inner", "membrane", "and,", "as", "a", "consequence,", "to", "ATP", "synthesis.", "The", "drastic", "change", "in", "free", "energy", "which", "is", "accompanied", "by", "the", "reaction", "catalysed", "by", "AOX", "is", "believed", "to", "be", "liberated", "as", "heat", "in", "thermogenic", "plants.", "In", "fact,", "a", "large", "cyanide-resistant", "respiration", "capacity", "has", "been", "observed", "to", "be", "associated", "with", "thermogenesis", "in", "plants,", "regardless", "of", "whether", "it", "is", "transient", "or", "homoeothermic", "[12,13].", "Although", "a", "large", "quantity", "of", "AOX", "protein", "has", "been", "shown", "to", "accumulate", "in", "mitochondria", "following", "the", "onset", "of", "thermogenesis", "in", "some", "species", "[13,14],", "this", "is", "not", "the", "prerequisite", "for", "a", "considerable", "cyanide-resistant", "respiration", "capacity", "as", "previously", "demonstrated", "in", "A.", "maculatum", "[12].", "BN-PAGE", "(Blue", "native", "PAGE)", "has", "become", "a", "major", "technique", "in", "the", "analysis", "of", "multiprotein", "complexes,", "particularly", "those", "localized", "to", "membranes", "[15].", "This", "method", "is", "especially", "effective", "when", "combined", "with", "2D", "(two-dimensional)", "SDS/PAGE", "and", "MS,", "as", "it", "is", "then", "possible", "to", "identify", "the", "constitutive", "subunits", "of", "a", "complex.", "All", "of", "the", "typical", "plant", "mitochondrial", "respiratory", "complexes", "have", "been", "characterized", "using", "this", "technique", "[16,17],", "the", "major", "findings", "of", "which", "have", "revealed", "that", "there", "are", "distinct", "differences", "between", "plant", "and", "mammalian", "mitochondria,", "such", "Abbreviations", "used:", "1D,", "one-dimensional;", "2D,", "two-dimensional;", "AOX,", "alternative", "oxidase;", "BCA,", "bicinchoninic", "acid;", "BN-PAGE,", "Blue", "native", "PAGE;", "COX,", "cytochrome", "c", "oxidase;", "Fp,", "flavoprotein;", "MS/MS,", "tandem", "MS;", "RACE,", "rapid", "amplification", "of", "cDNA", "ends;", "RT,", "reverse", "transcription;", "TCA,", "tricarboxylic", "acid;", "UTR,", "untranslated", "region.", "1", "To", "whom", "correspondence", "should", "be", "addressed", "(email", "kikuito@iwate-u.ac.jp).", "©", "2012", "The", "Author(s)", "c", "The", "Authors", "Journal", "compilation", "c", "2012", "Biochemical", "Society", "The", "author(s)", "has", "paid", "for", "this", "article", "to", "be", "freely", "available", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "Licence", "(http://creativecommons.org/licenses/by-nc/2.5/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", ".", "j", "i", ".", "l", "l", "i", "i" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 11, 11, 11, 11, 11, 11, 11, 11 ]

[ [ 70, 46, 42, 12 ], [ 116, 46, 32, 12 ], [ 151, 46, 57, 12 ], [ 70, 62, 21, 12 ], [ 95, 62, 135, 12 ], [ 78, 91, 10, 14 ], [ 89, 91, 9, 14 ], [ 99, 91, 5, 14 ], [ 105, 91, 10, 14 ], [ 116, 91, 5, 14 ], [ 122, 91, 10, 14 ], [ 132, 91, 10, 14 ], [ 143, 91, 9, 14 ], [ 157, 91, 10, 14 ], [ 168, 91, 9, 14 ], [ 178, 91, 9, 14 ], [ 187, 91, 5, 14 ], [ 193, 91, 9, 14 ], [ 203, 91, 9, 14 ], [ 213, 91, 9, 14 ], [ 70, 147, 106, 23 ], [ 183, 147, 79, 23 ], [ 269, 147, 19, 23 ], [ 295, 147, 68, 23 ], [ 370, 147, 106, 23 ], [ 483, 147, 86, 23 ], [ 70, 172, 12, 23 ], [ 89, 172, 115, 23 ], [ 210, 172, 75, 23 ], [ 70, 220, 45, 14 ], [ 119, 220, 38, 14 ], [ 161, 222, 4, 9 ], [ 169, 220, 40, 14 ], [ 214, 220, 50, 14 ], [ 268, 222, 3, 9 ], [ 276, 220, 39, 14 ], [ 319, 220, 31, 14 ], [ 355, 222, 3, 9 ], [ 70, 237, 50, 14 ], [ 124, 237, 41, 14 ], [ 70, 339, 48, 12 ], [ 122, 339, 12, 12 ], [ 137, 339, 50, 12 ], [ 191, 339, 24, 12 ], [ 216, 339, 4, 12 ], [ 222, 339, 48, 12 ], [ 274, 339, 6, 12 ], [ 283, 339, 22, 12 ], [ 309, 339, 24, 12 ], [ 334, 339, 4, 12 ], [ 340, 339, 47, 12 ], [ 390, 339, 33, 12 ], [ 427, 339, 12, 12 ], [ 442, 339, 22, 12 ], [ 468, 339, 24, 12 ], [ 84, 353, 27, 12 ], [ 114, 353, 40, 12 ], [ 157, 353, 32, 12 ], [ 193, 353, 18, 12 ], [ 214, 353, 41, 12 ], [ 258, 353, 24, 12 ], [ 70, 392, 52, 14 ], [ 136, 392, 20, 14 ], [ 162, 392, 52, 14 ], [ 221, 392, 12, 14 ], [ 239, 392, 17, 14 ], [ 263, 392, 31, 14 ], [ 301, 392, 29, 14 ], [ 336, 392, 65, 14 ], [ 70, 409, 59, 14 ], [ 133, 409, 34, 14 ], [ 171, 409, 37, 14 ], [ 211, 409, 11, 14 ], [ 226, 409, 62, 14 ], [ 292, 409, 10, 14 ], [ 305, 409, 7, 14 ], [ 315, 409, 66, 14 ], [ 385, 409, 17, 14 ], [ 70, 427, 75, 14 ], [ 150, 427, 22, 14 ], [ 176, 427, 61, 14 ], [ 242, 427, 12, 14 ], [ 258, 427, 62, 14 ], [ 324, 427, 10, 14 ], [ 338, 427, 45, 14 ], [ 387, 427, 14, 14 ], [ 70, 444, 41, 14 ], [ 121, 444, 75, 14 ], [ 205, 444, 20, 14 ], [ 235, 444, 33, 14 ], [ 277, 444, 42, 14 ], [ 328, 444, 17, 14 ], [ 354, 444, 48, 14 ], [ 70, 461, 71, 14 ], [ 145, 461, 26, 14 ], [ 174, 461, 12, 14 ], [ 190, 461, 28, 14 ], [ 221, 461, 20, 14 ], [ 245, 461, 38, 14 ], [ 287, 461, 20, 14 ], [ 311, 461, 63, 14 ], [ 378, 461, 24, 14 ], [ 70, 479, 30, 14 ], [ 104, 479, 12, 14 ], [ 120, 479, 20, 14 ], [ 144, 479, 35, 14 ], [ 183, 479, 17, 14 ], [ 203, 479, 41, 14 ], [ 248, 479, 66, 14 ], [ 318, 479, 20, 14 ], [ 342, 479, 59, 14 ], [ 70, 496, 24, 14 ], [ 98, 496, 14, 14 ], [ 117, 496, 45, 14 ], [ 165, 496, 12, 14 ], [ 181, 496, 36, 14 ], [ 221, 496, 56, 14 ], [ 282, 496, 11, 14 ], [ 297, 496, 7, 14 ], [ 308, 496, 41, 14 ], [ 353, 496, 33, 14 ], [ 390, 496, 12, 14 ], [ 70, 513, 61, 14 ], [ 136, 513, 47, 14 ], [ 188, 513, 38, 15 ], [ 232, 513, 70, 15 ], [ 307, 513, 7, 14 ], [ 319, 513, 41, 14 ], [ 365, 513, 25, 14 ], [ 395, 513, 7, 14 ], [ 70, 530, 132, 14 ], [ 206, 530, 39, 14 ], [ 249, 530, 42, 14 ], [ 295, 530, 20, 14 ], [ 318, 530, 50, 14 ], [ 372, 530, 29, 14 ], [ 70, 548, 24, 14 ], [ 100, 548, 21, 14 ], [ 126, 548, 65, 14 ], [ 195, 548, 20, 14 ], [ 221, 548, 49, 14 ], [ 275, 548, 38, 14 ], [ 318, 548, 21, 14 ], [ 345, 548, 20, 14 ], [ 369, 548, 32, 14 ], [ 70, 565, 18, 14 ], [ 91, 565, 62, 14 ], [ 155, 565, 12, 14 ], [ 170, 565, 65, 14 ], [ 238, 565, 59, 14 ], [ 300, 565, 41, 14 ], [ 344, 565, 57, 14 ], [ 70, 582, 45, 14 ], [ 121, 582, 20, 14 ], [ 147, 582, 50, 14 ], [ 203, 582, 66, 14 ], [ 274, 582, 48, 14 ], [ 327, 582, 33, 14 ], [ 366, 582, 35, 14 ], [ 70, 600, 50, 14 ], [ 125, 600, 61, 14 ], [ 192, 600, 48, 14 ], [ 245, 600, 21, 14 ], [ 271, 600, 17, 14 ], [ 294, 600, 61, 14 ], [ 361, 600, 12, 14 ], [ 378, 600, 24, 14 ], [ 70, 617, 39, 14 ], [ 115, 617, 59, 14 ], [ 179, 617, 53, 14 ], [ 237, 617, 12, 14 ], [ 255, 617, 18, 14 ], [ 277, 617, 22, 14 ], [ 305, 617, 12, 14 ], [ 322, 617, 39, 14 ], [ 366, 617, 36, 14 ], [ 70, 634, 53, 14 ], [ 131, 634, 56, 14 ], [ 195, 634, 56, 14 ], [ 259, 634, 53, 14 ], [ 320, 634, 61, 14 ], [ 390, 634, 12, 14 ], [ 70, 652, 57, 14 ], [ 130, 652, 21, 14 ], [ 155, 652, 12, 14 ], [ 170, 652, 18, 14 ], [ 192, 652, 43, 14 ], [ 238, 652, 12, 14 ], [ 254, 652, 44, 14 ], [ 301, 652, 18, 14 ], [ 323, 652, 52, 14 ], [ 379, 652, 22, 14 ], [ 70, 669, 42, 14 ], [ 122, 669, 59, 14 ], [ 191, 669, 12, 14 ], [ 212, 669, 48, 14 ], [ 270, 669, 61, 14 ], [ 341, 669, 12, 14 ], [ 363, 669, 38, 14 ], [ 70, 761, 10, 12 ], [ 84, 761, 31, 12 ], [ 125, 761, 10, 12 ], [ 139, 761, 41, 12 ], [ 191, 761, 12, 12 ], [ 206, 761, 32, 12 ], [ 241, 760, 22, 13 ], [ 70, 775, 47, 12 ], [ 121, 775, 44, 12 ], [ 168, 775, 56, 12 ], [ 227, 775, 38, 12 ], [ 269, 775, 37, 12 ], [ 310, 775, 35, 12 ], [ 70, 788, 55, 12 ], [ 129, 788, 9, 12 ], [ 142, 788, 30, 12 ], [ 175, 788, 50, 13 ], [ 229, 788, 44, 12 ], [ 70, 802, 34, 12 ], [ 108, 802, 87, 12 ], [ 70, 830, 10, 12 ], [ 84, 830, 31, 12 ], [ 70, 844, 56, 12 ], [ 130, 844, 10, 12 ], [ 144, 844, 36, 12 ], [ 183, 844, 53, 12 ], [ 239, 844, 50, 12 ], [ 293, 844, 10, 12 ], [ 306, 844, 47, 12 ], [ 70, 858, 47, 12 ], [ 121, 858, 44, 12 ], [ 70, 885, 12, 12 ], [ 86, 885, 25, 12 ], [ 70, 899, 56, 12 ], [ 130, 899, 10, 12 ], [ 144, 899, 61, 12 ], [ 208, 899, 32, 12 ], [ 244, 899, 37, 12 ], [ 285, 899, 40, 12 ], [ 70, 913, 39, 12 ], [ 113, 913, 10, 12 ], [ 127, 913, 53, 12 ], [ 183, 913, 40, 12 ], [ 227, 913, 17, 12 ], [ 70, 940, 36, 12 ], [ 110, 940, 42, 12 ], [ 70, 954, 10, 12 ], [ 84, 954, 41, 12 ], [ 70, 968, 56, 12 ], [ 130, 968, 10, 12 ], [ 144, 968, 66, 12 ], [ 214, 968, 61, 12 ], [ 70, 982, 50, 12 ], [ 124, 982, 10, 12 ], [ 138, 982, 44, 12 ], [ 185, 982, 44, 12 ], [ 233, 982, 44, 12 ], [ 425, 392, 59, 14 ], [ 489, 392, 29, 14 ], [ 524, 392, 19, 14 ], [ 549, 392, 12, 14 ], [ 566, 392, 17, 14 ], [ 589, 392, 59, 14 ], [ 654, 392, 48, 14 ], [ 707, 392, 21, 14 ], [ 733, 392, 23, 14 ], [ 425, 409, 30, 14 ], [ 461, 409, 28, 14 ], [ 494, 409, 60, 14 ], [ 559, 409, 39, 14 ], [ 604, 409, 44, 14 ], [ 653, 409, 18, 14 ], [ 677, 409, 18, 14 ], [ 701, 409, 32, 14 ], [ 738, 409, 17, 14 ], [ 425, 427, 62, 14 ], [ 489, 427, 12, 14 ], [ 505, 427, 65, 14 ], [ 573, 427, 61, 14 ], [ 637, 427, 12, 14 ], [ 652, 427, 40, 14 ], [ 695, 427, 35, 14 ], [ 733, 427, 23, 14 ], [ 425, 444, 21, 14 ], [ 449, 444, 14, 14 ], [ 467, 444, 32, 14 ], [ 502, 444, 32, 14 ], [ 538, 444, 32, 14 ], [ 574, 444, 44, 14 ], [ 622, 444, 17, 14 ], [ 643, 444, 40, 14 ], [ 686, 444, 22, 14 ], [ 712, 444, 22, 14 ], [ 738, 444, 18, 14 ], [ 425, 461, 39, 14 ], [ 469, 461, 20, 14 ], [ 495, 461, 23, 14 ], [ 524, 461, 51, 14 ], [ 580, 461, 14, 14 ], [ 600, 461, 65, 14 ], [ 671, 461, 65, 14 ], [ 742, 461, 14, 14 ], [ 425, 479, 21, 14 ], [ 456, 479, 54, 14 ], [ 519, 479, 36, 14 ], [ 565, 479, 22, 14 ], [ 597, 479, 37, 14 ], [ 643, 479, 45, 14 ], [ 697, 479, 21, 14 ], [ 728, 479, 28, 14 ], [ 425, 496, 61, 14 ], [ 492, 496, 47, 14 ], [ 545, 496, 55, 14 ], [ 606, 496, 29, 14 ], [ 642, 496, 68, 14 ], [ 717, 496, 39, 14 ], [ 425, 513, 18, 14 ], [ 447, 513, 25, 14 ], [ 477, 513, 12, 14 ], [ 493, 513, 53, 14 ], [ 551, 513, 20, 14 ], [ 576, 513, 21, 14 ], [ 602, 513, 33, 14 ], [ 639, 513, 11, 14 ], [ 655, 513, 28, 14 ], [ 688, 513, 38, 14 ], [ 731, 513, 25, 14 ], [ 425, 530, 31, 14 ], [ 461, 530, 44, 14 ], [ 509, 530, 24, 14 ], [ 538, 530, 14, 14 ], [ 556, 530, 61, 14 ], [ 622, 530, 14, 14 ], [ 641, 530, 25, 14 ], [ 671, 530, 12, 14 ], [ 687, 530, 68, 14 ], [ 425, 548, 35, 14 ], [ 463, 548, 56, 14 ], [ 425, 582, 61, 14 ], [ 499, 582, 38, 14 ], [ 541, 582, 56, 14 ], [ 610, 582, 62, 14 ], [ 676, 582, 39, 14 ], [ 425, 599, 34, 14 ], [ 463, 599, 62, 14 ], [ 537, 600, 50, 14 ], [ 592, 600, 67, 14 ], [ 663, 600, 51, 14 ], [ 425, 651, 76, 14 ], [ 425, 686, 51, 14 ], [ 480, 686, 59, 14 ], [ 544, 686, 21, 14 ], [ 569, 686, 29, 14 ], [ 602, 686, 11, 14 ], [ 617, 686, 62, 14 ], [ 683, 686, 10, 14 ], [ 697, 686, 39, 14 ], [ 739, 686, 17, 14 ], [ 425, 704, 58, 14 ], [ 488, 704, 71, 14 ], [ 565, 704, 21, 14 ], [ 591, 704, 33, 14 ], [ 629, 704, 17, 14 ], [ 651, 704, 39, 14 ], [ 696, 704, 60, 14 ], [ 425, 721, 59, 14 ], [ 488, 721, 10, 14 ], [ 501, 721, 45, 14 ], [ 551, 721, 14, 14 ], [ 569, 721, 7, 14 ], [ 579, 721, 43, 14 ], [ 626, 721, 12, 14 ], [ 642, 721, 42, 14 ], [ 688, 721, 17, 14 ], [ 708, 721, 48, 14 ], [ 425, 738, 18, 14 ], [ 447, 738, 39, 14 ], [ 491, 738, 20, 14 ], [ 516, 738, 46, 14 ], [ 567, 738, 12, 14 ], [ 584, 738, 34, 14 ], [ 624, 738, 56, 14 ], [ 684, 738, 20, 14 ], [ 710, 738, 46, 14 ], [ 425, 755, 32, 14 ], [ 463, 755, 37, 14 ], [ 507, 755, 33, 14 ], [ 546, 755, 20, 14 ], [ 574, 755, 37, 14 ], [ 617, 755, 11, 14 ], [ 635, 755, 43, 14 ], [ 685, 755, 11, 14 ], [ 703, 755, 53, 14 ], [ 425, 773, 34, 14 ], [ 462, 773, 20, 14 ], [ 487, 773, 45, 14 ], [ 536, 773, 32, 14 ], [ 572, 773, 40, 14 ], [ 616, 773, 36, 14 ], [ 657, 773, 12, 14 ], [ 673, 773, 52, 14 ], [ 729, 773, 12, 14 ], [ 745, 773, 11, 14 ], [ 425, 790, 29, 14 ], [ 465, 790, 58, 14 ], [ 533, 790, 59, 14 ], [ 603, 790, 57, 14 ], [ 671, 790, 54, 14 ], [ 735, 790, 21, 14 ], [ 425, 807, 73, 14 ], [ 505, 807, 11, 14 ], [ 523, 807, 26, 14 ], [ 557, 807, 45, 14 ], [ 609, 807, 36, 14 ], [ 653, 807, 12, 14 ], [ 672, 807, 20, 14 ], [ 700, 807, 28, 14 ], [ 735, 807, 21, 14 ], [ 425, 825, 46, 14 ], [ 476, 825, 66, 14 ], [ 547, 825, 17, 14 ], [ 569, 825, 59, 14 ], [ 634, 825, 11, 14 ], [ 650, 825, 14, 14 ], [ 669, 825, 49, 14 ], [ 723, 825, 10, 14 ], [ 738, 825, 17, 14 ], [ 425, 842, 62, 14 ], [ 490, 842, 12, 14 ], [ 506, 842, 65, 14 ], [ 575, 842, 22, 14 ], [ 600, 842, 36, 14 ], [ 640, 842, 12, 14 ], [ 656, 842, 7, 14 ], [ 667, 842, 28, 14 ], [ 698, 842, 11, 14 ], [ 713, 842, 43, 14 ], [ 425, 859, 34, 14 ], [ 464, 859, 37, 14 ], [ 506, 859, 59, 14 ], [ 570, 859, 46, 14 ], [ 621, 859, 25, 14 ], [ 651, 859, 14, 14 ], [ 670, 859, 17, 14 ], [ 692, 859, 24, 14 ], [ 721, 859, 34, 14 ], [ 425, 876, 41, 14 ], [ 470, 876, 62, 14 ], [ 536, 876, 20, 14 ], [ 561, 876, 56, 14 ], [ 621, 876, 20, 14 ], [ 645, 876, 14, 14 ], [ 664, 876, 18, 14 ], [ 685, 876, 71, 14 ], [ 425, 894, 32, 14 ], [ 462, 894, 20, 14 ], [ 487, 894, 56, 14 ], [ 548, 894, 12, 14 ], [ 565, 894, 17, 14 ], [ 587, 894, 39, 14 ], [ 631, 894, 43, 14 ], [ 679, 894, 29, 14 ], [ 713, 894, 43, 14 ], [ 425, 911, 33, 14 ], [ 463, 911, 20, 14 ], [ 488, 911, 25, 14 ], [ 519, 911, 48, 14 ], [ 572, 911, 31, 14 ], [ 608, 911, 44, 14 ], [ 657, 911, 55, 14 ], [ 717, 911, 39, 14 ], [ 425, 928, 32, 14 ], [ 463, 928, 61, 14 ], [ 530, 928, 36, 14 ], [ 572, 928, 62, 14 ], [ 640, 928, 42, 14 ], [ 688, 928, 20, 14 ], [ 714, 928, 23, 14 ], [ 742, 928, 14, 14 ], [ 425, 946, 45, 14 ], [ 473, 946, 14, 14 ], [ 491, 946, 17, 14 ], [ 512, 946, 56, 14 ], [ 571, 946, 25, 14 ], [ 600, 946, 34, 14 ], [ 637, 946, 33, 14 ], [ 674, 946, 48, 14 ], [ 725, 946, 31, 14 ], [ 425, 963, 21, 14 ], [ 453, 963, 34, 14 ], [ 495, 963, 20, 14 ], [ 521, 963, 14, 14 ], [ 542, 963, 7, 14 ], [ 555, 963, 40, 14 ], [ 603, 963, 47, 14 ], [ 657, 963, 11, 14 ], [ 675, 963, 30, 14 ], [ 712, 963, 44, 14 ], [ 425, 980, 44, 14 ], [ 472, 980, 12, 14 ], [ 487, 980, 51, 14 ], [ 541, 980, 14, 14 ], [ 559, 980, 33, 14 ], [ 595, 980, 41, 14 ], [ 639, 980, 28, 14 ], [ 670, 980, 7, 14 ], [ 680, 980, 48, 14 ], [ 731, 980, 24, 14 ], [ 700, 1017, 56, 21 ] ]

[ "Primates", "(2011)", "52:373–383", "DOI", "10.1007/s10329-011-0258-2", "O", "R", "I", "G", "I", "N", "A", "L", "A", "R", "T", "I", "C", "L", "E", "Copulation", "patterns", "in", "captive", "hamadryas", "baboons:", "a", "quantitative", "analysis", "Florian", "Nitsch", "•", "Sabine", "Stueckle", "•", "Daniel", "Stahl", "•", "Dietmar", "Zinner", "Received:", "22", "November", "2010", "/", "Accepted:", "6", "June", "2011", "/", "Published", "online:", "28", "June", "2011", "Japan", "Monkey", "Centre", "and", "Springer", "2011", "Abstract", "For", "primates,", "as", "for", "many", "other", "vertebrates,", "copulation", "which", "results", "in", "ejaculation", "is", "a", "prerequisite", "for", "reproduction.", "The", "probability", "of", "ejaculation", "is", "affected", "by", "various", "physiological", "and", "social", "factors,", "for", "example", "reproductive", "state", "of", "male", "and", "female", "and", "operational", "sex-", "ratio.", "In", "this", "paper,", "we", "present", "quantitative", "and", "qualitative", "data", "on", "patterns", "of", "sexual", "behaviour", "in", "a", "captive", "group", "of", "hamadryas", "baboons", "(Papio", "hamadryas),", "a", "species", "with", "a", "polygynous–monandric", "mating", "system.", "We", "observed", "more", "than", "700", "copulations", "and", "analysed", "factors", "that", "can", "affect", "the", "probability", "of", "ejaculation.", "Multilevel", "logistic", "regression", "analysis", "and", "Akaike’s", "information", "criterion", "(AIC)", "model", "selection", "procedures", "revealed", "that", "the", "probability", "of", "suc-", "cessful", "copulation", "increased", "as", "the", "size", "of", "female", "sexual", "swellings", "increased,", "indicating", "increased", "probability", "of", "ovulation,", "and", "as", "the", "number", "of", "females", "per", "one-male", "unit", "(OMU)", "decreased.", "In", "contrast,", "occurrence", "of", "female", "F.", "Nitsch", "S.", "Stueckle", "D.", "Zinner", "(&)", "Cognitive", "Ethology", "Laboratory,", "German", "Primate", "Center,", "Kellnerweg", "4,", "37077", "Go¨ttingen,", "Germany", "e-mail:", "dzinner@gwdg.de", "F.", "Nitsch", "Department", "of", "Animal", "Behaviour,", "University", "of", "Bielefeld,", "Bielefeld,", "Germany", "D.", "Stahl", "Department", "of", "Biostatistics,", "King’s", "College", "London,", "Institute", "of", "Psychiatry,", "London,", "UK", "Present", "Address:", "S.", "Stueckle", "Department", "of", "Microsystems", "Engineering,", "University", "of", "Freiburg,", "Freiburg,", "Germany", "copulation", "calls,", "sex", "of", "the", "copulation", "initiator,", "and", "pre-", "vious", "male", "aggression", "toward", "females", "did", "not", "affect", "the", "probability", "of", "ejaculation.", "Synchrony", "of", "oestrus", "cycles", "also", "had", "no", "effect", "(most", "likely", "because", "the", "sample", "size", "was", "too", "small).", "We", "also", "observed", "29", "extra-group", "copulations", "by", "two", "non-adult", "males.", "Our", "results", "indicate", "that", "male", "hamadryas", "baboons", "copulated", "more", "successfully", "around", "the", "time", "of", "ovulation", "and", "that", "males", "in", "large", "OMUs", "with", "many", "females", "may", "be", "confronted", "by", "time", "or", "energy-allo-", "cation", "problems.", "Keywords", "Sexual", "behaviour", "Copulation", "pattern", "Papio", "hamadryas", "Akaike’s", "Information", "Criterion", "Introduction", "Effective", "copulation", "that", "leads", "to", "conception", "is", "crucial", "for", "successful", "reproduction", "and", "hence", "for", "fitness.", "Successful", "copulation", "is", "affected", "by", "a", "number", "of", "factors,", "for", "example", "the", "quality", "and", "quantity", "of", "sperm", "(Birkhead", "and", "Fletcher", "1995;", "Parker", "1998)", "and", "timing", "in", "relation", "to", "ovulation", "(Hrdy", "and", "Whitten", "1987;", "Dixson", "1998).", "In", "primates,", "as", "in", "other", "mammals,", "copulation", "comprises", "mounting", "and", "intromission,", "at", "least", "(Dixson", "1998).", "In", "any", "case,", "one", "decisive", "prerequisite", "for", "copulation", "to", "be", "effective", "is", "the", "occurrence", "of", "ejaculation.", "The", "ability", "of", "a", "male", "to", "provide", "sperm", "during", "copulation", "depends", "both", "on", "his", "own", "repro-", "ductive", "physiology", "and", "behaviour", "and", "on", "the", "reproductive", "status", "and", "behaviour", "of", "his", "mating", "partner.", "Most", "primate", "males", "can", "only", "copulate", "when", "females", "cooperate", "(Strum", "1982;", "Bercovitch", "1995).", "Copulation", "success", "can", "also", "be", "affected", "by", "the", "frequency", "with", "which", "males", "copulate", "given", "that", "sperm", "can", "be", "a", "limited", "resource", "in", "some", "circum-", "stances,", "as", "proposed", "by", "Small", "(1988).", "Such", "a", "situation", "may", "123" ]

[ 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4 ]

[ [ 62, 98, 30, 10 ], [ 94, 98, 8, 10 ], [ 62, 112, 75, 14 ], [ 62, 128, 58, 14 ], [ 62, 151, 20, 10 ], [ 85, 151, 46, 10 ], [ 62, 192, 38, 10 ], [ 103, 192, 6, 10 ], [ 111, 192, 29, 10 ], [ 143, 192, 22, 10 ], [ 62, 206, 39, 10 ], [ 104, 206, 6, 10 ], [ 112, 206, 36, 10 ], [ 151, 206, 22, 10 ], [ 629, 49, 83, 23 ], [ 719, 49, 64, 23 ], [ 286, 97, 130, 23 ], [ 423, 97, 20, 23 ], [ 450, 97, 12, 23 ], [ 468, 97, 45, 23 ], [ 520, 97, 52, 23 ], [ 579, 97, 52, 23 ], [ 637, 97, 36, 23 ], [ 680, 97, 29, 23 ], [ 716, 97, 52, 23 ], [ 286, 122, 69, 23 ], [ 362, 122, 107, 23 ], [ 475, 122, 127, 23 ], [ 609, 122, 36, 23 ], [ 652, 122, 93, 23 ], [ 286, 147, 125, 23 ], [ 417, 147, 118, 23 ], [ 542, 147, 19, 23 ], [ 568, 147, 52, 23 ], [ 627, 147, 125, 23 ], [ 286, 172, 46, 23 ], [ 339, 172, 73, 23 ], [ 286, 224, 58, 14 ], [ 348, 221, 63, 17 ], [ 416, 224, 57, 14 ], [ 477, 221, 43, 17 ], [ 525, 224, 34, 14 ], [ 563, 221, 126, 17 ], [ 693, 224, 33, 14 ], [ 730, 221, 44, 17 ], [ 286, 242, 27, 14 ], [ 317, 239, 58, 17 ], [ 379, 242, 53, 14 ], [ 436, 239, 61, 17 ], [ 501, 242, 66, 14 ], [ 571, 239, 39, 17 ], [ 614, 242, 51, 14 ], [ 669, 239, 46, 17 ], [ 720, 242, 23, 14 ], [ 286, 260, 51, 14 ], [ 341, 257, 48, 18 ], [ 286, 296, 58, 13 ], [ 347, 298, 129, 11 ], [ 479, 298, 15, 11 ], [ 497, 298, 51, 11 ], [ 551, 298, 50, 11 ], [ 604, 298, 57, 11 ], [ 664, 298, 36, 11 ], [ 286, 313, 59, 11 ], [ 348, 313, 16, 11 ], [ 368, 313, 43, 11 ], [ 414, 313, 48, 11 ], [ 465, 313, 48, 11 ], [ 516, 311, 49, 13 ], [ 568, 313, 57, 11 ], [ 629, 313, 45, 11 ], [ 677, 313, 38, 11 ], [ 286, 328, 7, 12 ], [ 296, 328, 15, 12 ], [ 315, 328, 22, 12 ], [ 340, 328, 48, 12 ], [ 391, 328, 13, 12 ], [ 408, 328, 22, 12 ], [ 433, 328, 31, 12 ], [ 467, 328, 45, 12 ], [ 515, 328, 30, 12 ], [ 549, 328, 16, 12 ], [ 568, 328, 35, 12 ], [ 606, 328, 18, 12 ], [ 628, 326, 30, 14 ], [ 661, 328, 41, 12 ], [ 286, 343, 54, 12 ], [ 343, 343, 54, 12 ], [ 400, 343, 25, 12 ], [ 428, 343, 24, 12 ], [ 455, 343, 18, 12 ], [ 476, 343, 28, 12 ], [ 508, 343, 31, 12 ], [ 542, 343, 25, 12 ], [ 569, 343, 15, 12 ], [ 588, 343, 35, 12 ], [ 625, 343, 25, 12 ], [ 286, 359, 34, 12 ], [ 323, 359, 125, 12 ], [ 286, 394, 11, 14 ], [ 302, 394, 26, 14 ], [ 333, 394, 33, 14 ], [ 370, 394, 31, 14 ], [ 405, 394, 21, 14 ], [ 431, 394, 44, 14 ], [ 479, 394, 12, 14 ], [ 496, 394, 46, 14 ], [ 546, 394, 21, 14 ], [ 572, 394, 48, 14 ], [ 625, 394, 33, 14 ], [ 662, 394, 33, 14 ], [ 700, 394, 35, 14 ], [ 286, 410, 19, 14 ], [ 312, 410, 28, 14 ], [ 346, 410, 59, 14 ], [ 412, 410, 25, 14 ], [ 443, 410, 18, 14 ], [ 468, 410, 21, 14 ], [ 496, 410, 12, 14 ], [ 515, 410, 64, 14 ], [ 585, 410, 33, 14 ], [ 625, 410, 41, 14 ], [ 672, 410, 63, 14 ], [ 286, 427, 73, 14 ], [ 363, 427, 45, 14 ], [ 412, 427, 21, 14 ], [ 438, 427, 33, 14 ], [ 475, 427, 73, 14 ], [ 551, 427, 70, 14 ], [ 625, 427, 11, 14 ], [ 640, 427, 27, 14 ], [ 671, 427, 33, 14 ], [ 708, 427, 27, 14 ], [ 286, 444, 47, 14 ], [ 336, 444, 27, 14 ], [ 366, 444, 45, 14 ], [ 415, 444, 22, 14 ], [ 440, 444, 72, 14 ], [ 516, 444, 12, 14 ], [ 532, 444, 19, 14 ], [ 554, 444, 36, 14 ], [ 594, 444, 21, 14 ], [ 618, 444, 34, 14 ], [ 656, 444, 25, 14 ], [ 684, 444, 23, 14 ], [ 710, 444, 24, 14 ], [ 286, 460, 68, 14 ], [ 358, 460, 55, 14 ], [ 416, 460, 29, 14 ], [ 449, 460, 36, 14 ], [ 489, 460, 15, 14 ], [ 507, 460, 12, 14 ], [ 523, 460, 23, 14 ], [ 549, 460, 13, 14 ], [ 565, 460, 27, 14 ], [ 596, 460, 28, 14 ], [ 627, 460, 81, 14 ], [ 712, 460, 22, 14 ], [ 286, 477, 55, 14 ], [ 345, 477, 12, 14 ], [ 362, 477, 18, 14 ], [ 385, 477, 36, 14 ], [ 425, 477, 17, 14 ], [ 447, 477, 64, 14 ], [ 515, 477, 35, 14 ], [ 554, 477, 39, 14 ], [ 598, 477, 21, 14 ], [ 623, 477, 34, 14 ], [ 662, 477, 14, 14 ], [ 680, 477, 55, 14 ], [ 286, 493, 30, 14 ], [ 322, 493, 42, 14 ], [ 370, 493, 49, 14 ], [ 425, 493, 22, 14 ], [ 454, 493, 50, 14 ], [ 510, 493, 42, 14 ], [ 558, 493, 46, 14 ], [ 610, 493, 12, 14 ], [ 628, 493, 26, 14 ], [ 660, 493, 50, 14 ], [ 716, 493, 19, 14 ], [ 286, 510, 58, 14 ], [ 347, 510, 12, 14 ], [ 363, 510, 64, 14 ], [ 430, 510, 52, 14 ], [ 486, 510, 35, 14 ], [ 525, 510, 39, 14 ], [ 568, 510, 25, 14 ], [ 596, 510, 19, 14 ], [ 618, 510, 31, 14 ], [ 653, 510, 24, 14 ], [ 286, 551, 58, 13 ], [ 347, 551, 29, 13 ], [ 380, 551, 25, 13 ], [ 409, 551, 34, 13 ], [ 446, 551, 74, 13 ], [ 524, 551, 29, 13 ], [ 557, 551, 36, 13 ], [ 62, 612, 13, 15 ], [ 79, 612, 80, 15 ], [ 62, 646, 45, 14 ], [ 111, 646, 38, 14 ], [ 153, 646, 15, 14 ], [ 172, 646, 25, 14 ], [ 201, 646, 33, 14 ], [ 238, 646, 43, 14 ], [ 285, 646, 28, 14 ], [ 317, 646, 78, 14 ], [ 399, 646, 12, 14 ], [ 62, 662, 73, 14 ], [ 137, 662, 9, 14 ], [ 148, 662, 21, 14 ], [ 172, 662, 12, 14 ], [ 187, 662, 18, 14 ], [ 208, 662, 21, 14 ], [ 231, 662, 55, 14 ], [ 288, 662, 42, 14 ], [ 332, 662, 14, 14 ], [ 348, 662, 33, 14 ], [ 384, 662, 27, 14 ], [ 62, 679, 47, 14 ], [ 112, 679, 32, 14 ], [ 147, 679, 51, 14 ], [ 201, 679, 53, 14 ], [ 258, 679, 10, 14 ], [ 271, 679, 17, 15 ], [ 291, 679, 30, 14 ], [ 323, 679, 55, 14 ], [ 381, 679, 10, 14 ], [ 394, 679, 17, 15 ], [ 62, 696, 30, 14 ], [ 95, 696, 50, 14 ], [ 149, 695, 10, 14 ], [ 162, 695, 16, 14 ], [ 182, 696, 35, 14 ], [ 220, 696, 34, 14 ], [ 258, 696, 23, 14 ], [ 285, 696, 33, 14 ], [ 321, 696, 42, 14 ], [ 367, 696, 44, 14 ], [ 62, 712, 61, 14 ], [ 129, 712, 21, 14 ], [ 156, 712, 50, 14 ], [ 213, 712, 35, 14 ], [ 255, 712, 23, 14 ], [ 284, 712, 29, 14 ], [ 320, 712, 30, 14 ], [ 356, 712, 26, 14 ], [ 388, 710, 23, 16 ], [ 62, 729, 46, 14 ], [ 115, 729, 19, 14 ], [ 142, 729, 33, 14 ], [ 183, 729, 34, 14 ], [ 225, 729, 28, 14 ], [ 260, 729, 19, 14 ], [ 286, 729, 57, 14 ], [ 350, 729, 25, 14 ], [ 383, 729, 28, 14 ], [ 62, 745, 58, 14 ], [ 124, 745, 21, 14 ], [ 149, 745, 61, 14 ], [ 214, 745, 19, 14 ], [ 236, 745, 28, 14 ], [ 268, 745, 60, 14 ], [ 332, 745, 41, 14 ], [ 376, 745, 12, 14 ], [ 392, 745, 18, 14 ], [ 62, 762, 36, 14 ], [ 102, 762, 53, 14 ], [ 158, 762, 9, 14 ], [ 171, 762, 27, 14 ], [ 202, 762, 26, 14 ], [ 231, 762, 54, 14 ], [ 288, 762, 22, 14 ], [ 314, 762, 57, 14 ], [ 375, 762, 36, 14 ], [ 62, 779, 21, 14 ], [ 90, 779, 39, 14 ], [ 137, 779, 44, 14 ], [ 183, 779, 39, 14 ], [ 230, 779, 35, 14 ], [ 272, 779, 55, 14 ], [ 335, 779, 14, 14 ], [ 356, 779, 20, 14 ], [ 379, 779, 13, 14 ], [ 400, 779, 11, 14 ], [ 62, 795, 35, 14 ], [ 100, 795, 32, 14 ], [ 135, 795, 45, 14 ], [ 183, 795, 25, 14 ], [ 211, 795, 7, 14 ], [ 221, 795, 56, 14 ], [ 280, 795, 23, 14 ], [ 306, 795, 12, 14 ], [ 321, 795, 14, 14 ], [ 338, 795, 17, 14 ], [ 358, 795, 53, 14 ], [ 62, 812, 10, 14 ], [ 76, 812, 17, 15 ], [ 98, 812, 35, 14 ], [ 138, 812, 22, 14 ], [ 165, 812, 32, 14 ], [ 202, 812, 54, 14 ], [ 261, 812, 31, 14 ], [ 297, 812, 40, 14 ], [ 341, 812, 44, 14 ], [ 390, 812, 21, 14 ], [ 62, 828, 44, 14 ], [ 111, 828, 44, 14 ], [ 158, 828, 10, 14 ], [ 173, 828, 35, 14 ], [ 214, 828, 11, 14 ], [ 231, 828, 7, 14 ], [ 243, 828, 56, 14 ], [ 305, 828, 23, 14 ], [ 333, 828, 15, 14 ], [ 354, 828, 12, 14 ], [ 371, 828, 20, 14 ], [ 394, 828, 17, 14 ], [ 62, 845, 43, 14 ], [ 108, 845, 10, 14 ], [ 122, 845, 17, 15 ], [ 142, 845, 35, 14 ], [ 76, 862, 28, 14 ], [ 108, 862, 64, 14 ], [ 176, 862, 12, 14 ], [ 193, 862, 18, 14 ], [ 216, 862, 23, 14 ], [ 243, 862, 26, 14 ], [ 274, 862, 42, 14 ], [ 320, 862, 20, 14 ], [ 345, 862, 38, 14 ], [ 388, 862, 23, 14 ], [ 62, 878, 30, 14 ], [ 101, 878, 12, 14 ], [ 123, 878, 70, 14 ], [ 202, 878, 52, 14 ], [ 263, 878, 19, 14 ], [ 291, 878, 44, 14 ], [ 345, 878, 25, 14 ], [ 379, 878, 32, 14 ], [ 62, 895, 61, 14 ], [ 126, 895, 42, 14 ], [ 170, 895, 30, 14 ], [ 203, 895, 55, 14 ], [ 261, 895, 18, 14 ], [ 283, 895, 46, 14 ], [ 331, 895, 25, 14 ], [ 360, 895, 51, 14 ], [ 62, 911, 12, 14 ], [ 76, 911, 19, 14 ], [ 97, 911, 53, 14 ], [ 153, 911, 21, 14 ], [ 177, 911, 19, 14 ], [ 198, 911, 36, 14 ], [ 237, 911, 28, 14 ], [ 267, 911, 48, 14 ], [ 318, 911, 33, 14 ], [ 353, 911, 21, 14 ], [ 377, 911, 34, 14 ], [ 62, 928, 36, 14 ], [ 104, 928, 28, 14 ], [ 137, 928, 12, 14 ], [ 155, 928, 14, 14 ], [ 175, 928, 57, 14 ], [ 237, 928, 12, 14 ], [ 255, 928, 26, 14 ], [ 286, 928, 35, 14 ], [ 326, 928, 18, 14 ], [ 350, 928, 60, 14 ], [ 62, 945, 30, 14 ], [ 96, 945, 52, 14 ], [ 153, 945, 20, 14 ], [ 177, 945, 50, 14 ], [ 231, 945, 11, 14 ], [ 246, 945, 33, 14 ], [ 284, 945, 72, 14 ], [ 360, 945, 34, 14 ], [ 398, 945, 13, 14 ], [ 62, 961, 33, 14 ], [ 100, 961, 41, 14 ], [ 145, 961, 63, 14 ], [ 213, 961, 73, 14 ], [ 291, 961, 45, 14 ], [ 341, 961, 70, 14 ], [ 62, 978, 43, 14 ], [ 107, 978, 10, 14 ], [ 120, 978, 17, 15 ], [ 139, 978, 30, 14 ], [ 171, 978, 23, 15 ], [ 194, 978, 18, 14 ], [ 214, 978, 11, 14 ], [ 228, 978, 52, 14 ], [ 283, 978, 31, 14 ], [ 317, 978, 18, 14 ], [ 338, 978, 45, 14 ], [ 385, 978, 25, 14 ], [ 62, 994, 28, 14 ], [ 96, 994, 23, 14 ], [ 126, 994, 20, 14 ], [ 153, 994, 14, 14 ], [ 173, 994, 55, 14 ], [ 235, 994, 9, 14 ], [ 251, 994, 16, 14 ], [ 274, 994, 14, 14 ], [ 295, 994, 18, 14 ], [ 320, 994, 54, 14 ], [ 381, 994, 30, 14 ], [ 62, 1011, 42, 14 ], [ 111, 1011, 21, 14 ], [ 140, 1011, 18, 14 ], [ 166, 1011, 30, 14 ], [ 203, 1011, 49, 14 ], [ 259, 1011, 12, 14 ], [ 278, 1011, 19, 14 ], [ 304, 1011, 40, 14 ], [ 351, 1011, 60, 14 ], [ 62, 1028, 60, 14 ], [ 125, 1028, 19, 14 ], [ 147, 1028, 46, 14 ], [ 197, 1028, 25, 14 ], [ 226, 1028, 51, 14 ], [ 281, 1028, 12, 14 ], [ 296, 1028, 18, 14 ], [ 319, 1028, 36, 14 ], [ 359, 1028, 37, 14 ], [ 400, 1028, 11, 14 ], [ 62, 1062, 7, 12 ], [ 72, 1062, 58, 12 ], [ 133, 1062, 22, 12 ], [ 158, 1062, 34, 12 ], [ 196, 1062, 16, 12 ], [ 215, 1062, 44, 12 ], [ 435, 612, 35, 14 ], [ 474, 612, 13, 14 ], [ 490, 612, 33, 14 ], [ 527, 612, 72, 14 ], [ 602, 612, 33, 14 ], [ 639, 612, 70, 14 ], [ 712, 612, 20, 14 ], [ 736, 612, 26, 14 ], [ 766, 612, 19, 14 ], [ 435, 629, 35, 14 ], [ 477, 629, 12, 14 ], [ 495, 629, 26, 14 ], [ 526, 629, 33, 14 ], [ 565, 629, 41, 14 ], [ 612, 629, 26, 14 ], [ 644, 629, 20, 14 ], [ 667, 629, 13, 14 ], [ 686, 629, 11, 14 ], [ 703, 629, 19, 14 ], [ 728, 629, 57, 14 ], [ 435, 645, 36, 14 ], [ 475, 645, 13, 14 ], [ 492, 645, 17, 14 ], [ 512, 645, 16, 14 ], [ 531, 645, 11, 14 ], [ 546, 645, 37, 14 ], [ 449, 662, 54, 14 ], [ 509, 662, 19, 14 ], [ 533, 662, 25, 14 ], [ 564, 662, 51, 14 ], [ 621, 662, 12, 14 ], [ 639, 662, 19, 14 ], [ 663, 662, 36, 14 ], [ 705, 662, 37, 14 ], [ 748, 662, 12, 14 ], [ 766, 662, 19, 14 ], [ 435, 679, 33, 14 ], [ 472, 679, 12, 14 ], [ 487, 679, 19, 14 ], [ 509, 679, 90, 14 ], [ 603, 679, 70, 14 ], [ 676, 679, 20, 14 ], [ 699, 679, 14, 14 ], [ 717, 679, 50, 14 ], [ 770, 679, 14, 14 ], [ 435, 695, 24, 14 ], [ 465, 695, 30, 14 ], [ 499, 695, 21, 14 ], [ 526, 695, 31, 14 ], [ 561, 695, 61, 14 ], [ 627, 695, 21, 15 ], [ 653, 695, 32, 14 ], [ 690, 695, 12, 14 ], [ 707, 695, 7, 14 ], [ 719, 695, 31, 14 ], [ 755, 695, 30, 14 ], [ 435, 712, 60, 14 ], [ 499, 712, 18, 14 ], [ 522, 712, 35, 14 ], [ 562, 712, 51, 14 ], [ 617, 712, 14, 14 ], [ 635, 712, 7, 14 ], [ 647, 712, 31, 14 ], [ 682, 712, 21, 14 ], [ 708, 712, 21, 15 ], [ 733, 712, 18, 14 ], [ 756, 712, 28, 14 ], [ 435, 728, 30, 14 ], [ 468, 728, 21, 14 ], [ 492, 728, 13, 14 ], [ 508, 728, 44, 14 ], [ 555, 728, 44, 14 ], [ 601, 728, 51, 14 ], [ 655, 728, 28, 14 ], [ 685, 728, 19, 14 ], [ 706, 728, 29, 14 ], [ 738, 728, 47, 14 ], [ 435, 745, 35, 14 ], [ 474, 745, 21, 14 ], [ 499, 745, 24, 14 ], [ 527, 745, 24, 14 ], [ 554, 745, 14, 14 ], [ 571, 745, 46, 14 ], [ 621, 745, 90, 14 ], [ 714, 745, 12, 14 ], [ 730, 745, 18, 14 ], [ 752, 745, 33, 14 ], [ 435, 761, 40, 14 ], [ 480, 761, 76, 14 ], [ 560, 761, 19, 14 ], [ 582, 761, 25, 14 ], [ 612, 761, 57, 14 ], [ 673, 761, 12, 14 ], [ 689, 761, 19, 14 ], [ 712, 761, 72, 14 ], [ 435, 778, 65, 14 ], [ 503, 778, 9, 14 ], [ 516, 778, 65, 14 ], [ 584, 778, 19, 14 ], [ 607, 778, 14, 14 ], [ 624, 778, 7, 14 ], [ 634, 778, 47, 14 ], [ 685, 778, 19, 14 ], [ 707, 778, 19, 14 ], [ 729, 778, 31, 14 ], [ 763, 778, 21, 14 ], [ 435, 795, 31, 14 ], [ 472, 795, 13, 14 ], [ 490, 795, 52, 14 ], [ 548, 795, 35, 14 ], [ 589, 795, 70, 14 ], [ 665, 794, 28, 15 ], [ 693, 795, 18, 14 ], [ 716, 795, 10, 14 ], [ 732, 795, 17, 15 ], [ 755, 795, 30, 14 ], [ 435, 811, 27, 14 ], [ 466, 811, 10, 14 ], [ 480, 811, 17, 15 ], [ 500, 811, 32, 14 ], [ 535, 811, 8, 14 ], [ 548, 811, 49, 14 ], [ 600, 811, 14, 14 ], [ 618, 811, 46, 14 ], [ 668, 811, 79, 14 ], [ 750, 811, 12, 14 ], [ 766, 811, 19, 14 ], [ 435, 828, 55, 14 ], [ 494, 828, 42, 14 ], [ 539, 828, 41, 14 ], [ 584, 828, 49, 14 ], [ 636, 828, 13, 14 ], [ 652, 828, 21, 14 ], [ 675, 828, 27, 14 ], [ 705, 828, 21, 14 ], [ 729, 828, 55, 14 ], [ 435, 845, 35, 14 ], [ 478, 845, 65, 14 ], [ 550, 844, 24, 15 ], [ 582, 845, 40, 14 ], [ 630, 845, 12, 14 ], [ 650, 845, 49, 14 ], [ 706, 845, 13, 14 ], [ 726, 845, 58, 14 ], [ 435, 861, 58, 14 ], [ 498, 861, 12, 14 ], [ 514, 861, 40, 14 ], [ 558, 861, 41, 14 ], [ 604, 861, 28, 14 ], [ 636, 861, 18, 14 ], [ 659, 861, 36, 14 ], [ 699, 861, 37, 14 ], [ 741, 861, 20, 14 ], [ 765, 861, 19, 14 ], [ 435, 878, 32, 14 ], [ 472, 878, 19, 14 ], [ 495, 878, 68, 14 ], [ 567, 878, 13, 14 ], [ 584, 878, 50, 14 ], [ 639, 878, 18, 14 ], [ 661, 878, 19, 14 ], [ 685, 878, 12, 14 ], [ 701, 878, 7, 14 ], [ 713, 878, 31, 14 ], [ 748, 878, 21, 14 ], [ 773, 878, 11, 14 ], [ 435, 894, 35, 14 ], [ 475, 894, 24, 14 ], [ 505, 894, 21, 14 ], [ 530, 894, 51, 14 ], [ 586, 894, 15, 14 ], [ 606, 894, 18, 14 ], [ 630, 894, 47, 14 ], [ 682, 894, 75, 14 ], [ 762, 894, 22, 14 ], [ 435, 911, 26, 14 ], [ 464, 911, 57, 14 ], [ 524, 911, 12, 14 ], [ 538, 911, 18, 14 ], [ 559, 911, 47, 14 ], [ 609, 911, 26, 14 ], [ 638, 911, 11, 14 ], [ 652, 911, 18, 14 ], [ 673, 911, 65, 14 ], [ 740, 911, 28, 14 ], [ 770, 911, 14, 14 ], [ 435, 928, 25, 14 ], [ 466, 928, 35, 14 ], [ 507, 928, 26, 14 ], [ 539, 928, 19, 14 ], [ 564, 928, 54, 14 ], [ 624, 928, 30, 14 ], [ 660, 928, 42, 14 ], [ 709, 928, 12, 14 ], [ 727, 928, 19, 14 ], [ 752, 928, 33, 14 ], [ 435, 944, 40, 14 ], [ 449, 961, 46, 14 ], [ 502, 961, 31, 14 ], [ 540, 961, 26, 14 ], [ 573, 961, 44, 14 ], [ 624, 961, 11, 14 ], [ 641, 961, 19, 14 ], [ 667, 961, 45, 14 ], [ 718, 961, 32, 14 ], [ 757, 961, 28, 14 ], [ 435, 977, 37, 14 ], [ 475, 977, 52, 14 ], [ 529, 977, 12, 14 ], [ 543, 977, 21, 14 ], [ 567, 977, 38, 14 ], [ 608, 977, 50, 14 ], [ 661, 977, 10, 14 ], [ 673, 977, 17, 14 ], [ 693, 977, 30, 14 ], [ 725, 977, 60, 14 ], [ 435, 994, 10, 14 ], [ 450, 994, 17, 14 ], [ 473, 994, 35, 14 ], [ 513, 994, 62, 14 ], [ 580, 994, 42, 14 ], [ 627, 994, 17, 14 ], [ 649, 994, 27, 14 ], [ 681, 994, 38, 14 ], [ 724, 994, 27, 14 ], [ 757, 994, 28, 14 ], [ 435, 1010, 53, 14 ], [ 493, 1010, 17, 14 ], [ 514, 1010, 31, 14 ], [ 550, 1010, 30, 14 ], [ 585, 1010, 21, 14 ], [ 610, 1010, 40, 14 ], [ 655, 1010, 31, 14 ], [ 690, 1010, 62, 14 ], [ 757, 1010, 27, 14 ], [ 435, 1027, 28, 14 ], [ 470, 1027, 53, 14 ], [ 530, 1027, 53, 14 ], [ 590, 1027, 10, 14 ], [ 607, 1027, 17, 15 ], [ 631, 1027, 30, 14 ], [ 667, 1027, 40, 14 ], [ 714, 1027, 10, 14 ], [ 731, 1027, 17, 15 ], [ 755, 1027, 30, 14 ], [ 575, 1062, 165, 12 ], [ 756, 1058, 28, 17 ] ]

[ "Journal", "of", "Synchrotron", "Radiation", "ISSN", "0909-0495", "Received", "9", "August", "2010", "Accepted", "7", "February", "2011", "research", "papers", "Development", "of", "a", "hard", "X-ray", "delay", "line", "for", "X-ray", "photon", "correlation", "spectroscopy", "and", "jitter-free", "pump–probe", "experiments", "at", "X-ray", "free-electron", "laser", "sources", "Wojciech", "Roseker,a*", "Hermann", "Franz,a", "Horst", "Schulte-Schrepping,a", "Anita", "Ehnes,a", "Olaf", "Leupold,a", "Federico", "Zontone,b", "Sooheyong", "Lee,a,c", "Aymeric", "Robertc", "and", "Gerhard", "Gru¨bela", "aHamburger", "Synchrotronstrahlungslabor", "am", "Deutschen", "Elektronen", "Synchrotron", "(DESY),", "Notkestrasse", "85,", "D-22603", "Hamburg,", "Germany,", "bEuropean", "Synchrotron", "Radiation", "Facility,", "6", "rue", "Jules", "Horowitz,", "BP", "220,", "38043", "Grenoble", "Cedex", "09,", "France,", "and", "cSLAC", "National", "Accelerator", "Laboratory,", "2575", "Sand", "Hill", "Road,", "Menlo", "Park,", "CA", "94025,", "USA.", "E-mail:", "wojciech.roseker@desy.de", "A", "hard", "X-ray", "delay", "line", "capable", "of", "splitting", "and", "delaying", "single", "X-ray", "pulses", "has", "been", "developed", "with", "the", "aim", "of", "performing", "X-ray", "photon", "correlation", "spectroscopy", "(XPCS)", "and", "X-ray", "pump–probe", "experiments", "at", "hard", "X-ray", "free-", "electron", "laser", "sources.", "The", "performance", "of", "the", "device", "was", "tested", "with", "8.39", "keV", "synchrotron", "radiation.", "Time", "delays", "up", "to", "2.95", "ns", "have", "been", "demonstrated.", "The", "feasibility", "of", "the", "device", "for", "performing", "XPCS", "studies", "was", "tested", "by", "recording", "static", "speckle", "patterns.", "The", "achieved", "speckle", "contrast", "of", "56%", "indicates", "the", "possibility", "of", "performing", "ultra-fast", "XPCS", "studies", "with", "the", "delay", "line.", "Keywords:", "delay", "line;", "XPCS;", "pump–probe;", "X-ray", "optics.", "1.", "Introduction", "Probing", "matter", "on", "time", "scales", "ranging", "from", "femtoseconds", "to", "nanoseconds", "is", "one", "of", "the", "key", "attributes", "offered", "by", "X-ray", "free-", "electron", "lasers", "(XFELs)", "(Altarelli", "et", "al.,", "2006;", "Patterson", "et", "al.,", "2010;", "Shintake", "et", "al.,", "2008).", "These", "new", "X-ray", "sources", "provide", "ultra-short", "and", "coherent", "pulses", "that", "carry", "more", "than", "1012", "photons", "per", "pulse.", "Apart", "from", "the", "extremely", "high", "peak", "brightness", "and", "coherence,", "the", "most", "prominent", "feature", "of", "the", "XFEL", "machines", "is", "their", "time", "structure.", "The", "European", "XFEL", "will", "deliver", "sub-100", "fs-long", "pulses", "separated", "by", "200", "ns", "in", "bunch", "trains", "arriving", "with", "a", "repetition", "rate", "of", "10", "Hz", "(Altarelli", "et", "al.,", "2006).", "The", "Linac", "Coherent", "Light", "Source", "(LCLS)", "will", "provide", "sub-100", "fs", "pulses", "at", "a", "repetition", "rate", "up", "to", "120", "Hz", "(Emma", "et", "al.,", "2010).", "Such", "capabilities", "of", "the", "new", "light", "sources", "will", "enable", "new", "types", "of", "experiments", "currently", "not", "feasible", "with", "third-", "generation", "storage", "rings.", "However,", "the", "intrinsic", "time", "structure", "of", "the", "machines", "and", "the", "timing", "jitter", "between", "pump", "and", "probe", "beams", "need", "to", "be", "addressed", "to", "fully", "utilize", "the", "ultra-short", "pulse", "duration.", "For", "instance,", "in", "X-ray", "pump–X-ray", "probe", "or", "X-ray", "photon", "correlation", "spectroscopy", "(XPCS)", "experiments", "(Sutton", "et", "al.,", "1991;", "Gru¨", "bel", "&", "Zontone,", "2004)", "the", "shortest", "time", "scale", "that", "can", "be", "measured", "is", "set", "by", "the", "minimum", "pulse", "spacing", "and", "the", "pulse", "duration", "of", "the", "source.", "Therefore,", "employing", "the", "intrinsic", "time", "structure", "of", "the", "XFEL", "source", "in", "J.", "Synchrotron", "Rad.", "(2011).", "18,", "481–491", "XPCS", "or", "X-ray", "pump–X-ray", "pump", "experiments", "will", "limit", "the", "access", "to", "time", "scales", "shorter", "than", "200", "ns", "at", "the", "European", "XFEL", "or", "8.3", "ms", "at", "LCLS.", "Adapting", "the", "time", "structure", "of", "the", "XFEL", "source", "to", "the", "needs", "of", "the", "aforementioned", "experiments", "can", "be", "achieved", "by", "split", "pulse", "and", "delay", "techniques", "(i.e.", "usage", "of", "a", "delay", "line).", "Moreover,", "the", "pulses", "provided", "by", "a", "delay", "line", "(i.e.", "the", "main", "pulse", "and", "its", "delayed", "replica)", "originate", "from", "the", "same", "electron", "bunch", "and", "thus", "give", "an", "intrinsic", "synchronization", "to", "the", "X-ray", "source.", "Furthermore,", "the", "time", "resolution", "of", "the", "pump–probe", "experiment", "is", "determined", "not", "by", "a", "detector", "but", "the", "delay", "line", "itself.", "In", "ultra-fast", "XPCS", "experiments", "(Gru¨", "bel", "et", "al.,", "2007;", "Gutt", "et", "al.,", "2007)", "it", "provides", "an", "intrinsic", "normalization", "of", "the", "measured", "speckle", "pattern", "contrast.", "In", "this", "case,", "any", "bunch-to-", "bunch", "instabilities", "(e.g.", "change", "of", "intensity", "or", "coherence", "properties", "of", "pulses)", "coming", "from", "the", "XFEL", "source", "will", "not", "affect", "the", "experiment.", "In", "addition,", "the", "use", "of", "a", "delay", "line", "in", "XPCS", "puts", "less", "demands", "on", "the", "detector", "performance.", "The", "time", "resolution", "of", "the", "detector", "used", "in", "the", "experiment", "must", "be", "only", "better", "than", "the", "minimum", "pulse", "spacing", "of", "the", "X-ray", "source.", "Existing", "delay", "lines", "operate", "in", "the", "spectral", "range", "from", "visible", "radiation", "to", "soft", "X-rays", "(Mitzner", "et", "al.,", "2005;", "Sorgenfrei", "et", "al.,", "2010).", "Equivalent", "devices", "for", "hard", "X-rays", "have", "been", "discussed", "for", "many", "years", "and", "several", "beam", "geometries", "have", "been", "proposed", "(Altarelli", "et", "al.,", "2006;", "Arthur", "et", "al.,", "2002;", "doi:10.1107/S0909049511004511", "481" ]

[ 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 4 ]

[ [ 71, 47, 5, 12 ], [ 80, 47, 57, 12 ], [ 140, 47, 23, 12 ], [ 165, 47, 32, 12 ], [ 200, 47, 68, 12 ], [ 71, 63, 21, 12 ], [ 96, 63, 134, 12 ], [ 79, 90, 16, 15 ], [ 99, 90, 48, 15 ], [ 71, 149, 87, 25 ], [ 165, 149, 80, 25 ], [ 253, 149, 145, 25 ], [ 71, 199, 26, 14 ], [ 102, 199, 46, 14 ], [ 150, 201, 4, 12 ], [ 158, 199, 59, 14 ], [ 221, 199, 29, 14 ], [ 253, 201, 4, 12 ], [ 260, 199, 51, 14 ], [ 315, 199, 38, 14 ], [ 357, 201, 4, 12 ], [ 71, 216, 46, 14 ], [ 122, 216, 53, 14 ], [ 178, 218, 4, 12 ], [ 185, 216, 39, 14 ], [ 228, 216, 66, 14 ], [ 298, 218, 4, 12 ], [ 305, 216, 41, 14 ], [ 350, 216, 22, 14 ], [ 375, 218, 4, 12 ], [ 71, 233, 48, 14 ], [ 123, 233, 37, 14 ], [ 163, 236, 4, 12 ], [ 170, 233, 33, 14 ], [ 207, 233, 35, 14 ], [ 245, 236, 5, 12 ], [ 252, 233, 48, 14 ], [ 304, 233, 12, 14 ], [ 320, 233, 32, 14 ], [ 71, 338, 47, 12 ], [ 122, 338, 12, 12 ], [ 137, 338, 50, 12 ], [ 191, 338, 24, 12 ], [ 217, 338, 4, 12 ], [ 222, 338, 48, 12 ], [ 273, 338, 12, 12 ], [ 289, 338, 43, 12 ], [ 335, 338, 24, 12 ], [ 361, 338, 4, 12 ], [ 365, 338, 47, 12 ], [ 415, 338, 33, 12 ], [ 451, 338, 12, 12 ], [ 467, 338, 31, 12 ], [ 501, 338, 24, 12 ], [ 71, 352, 12, 12 ], [ 87, 352, 24, 12 ], [ 114, 352, 19, 12 ], [ 136, 352, 49, 12 ], [ 192, 352, 21, 12 ], [ 217, 352, 29, 12 ], [ 250, 352, 8, 12 ], [ 261, 352, 46, 12 ], [ 310, 352, 21, 12 ], [ 335, 352, 23, 12 ], [ 362, 352, 30, 12 ], [ 395, 352, 9, 12 ], [ 408, 352, 82, 12 ], [ 71, 407, 60, 14 ], [ 137, 407, 78, 14 ], [ 217, 404, 4, 14 ], [ 223, 407, 43, 14 ], [ 268, 407, 53, 14 ], [ 324, 404, 4, 14 ], [ 71, 425, 43, 14 ], [ 116, 425, 65, 14 ], [ 71, 476, 71, 14 ], [ 150, 476, 75, 14 ], [ 231, 476, 35, 14 ], [ 274, 476, 10, 14 ], [ 290, 476, 6, 14 ], [ 304, 476, 21, 14 ], [ 333, 476, 34, 14 ], [ 374, 476, 29, 14 ], [ 71, 494, 38, 14 ], [ 114, 494, 29, 14 ], [ 147, 494, 26, 14 ], [ 178, 494, 26, 14 ], [ 209, 494, 53, 14 ], [ 265, 494, 11, 14 ], [ 281, 494, 17, 14 ], [ 303, 494, 21, 14 ], [ 328, 494, 37, 14 ], [ 369, 494, 12, 14 ], [ 385, 494, 17, 14 ], [ 71, 509, 34, 17 ], [ 111, 511, 44, 14 ], [ 160, 511, 40, 14 ], [ 205, 511, 75, 14 ], [ 285, 511, 10, 14 ], [ 300, 511, 55, 14 ], [ 360, 511, 42, 14 ], [ 71, 528, 25, 14 ], [ 99, 528, 25, 14 ], [ 127, 528, 25, 14 ], [ 155, 528, 31, 14 ], [ 190, 528, 29, 14 ], [ 222, 528, 46, 14 ], [ 271, 528, 11, 14 ], [ 285, 528, 17, 14 ], [ 306, 528, 41, 14 ], [ 350, 528, 52, 14 ], [ 71, 545, 15, 14 ], [ 90, 545, 28, 14 ], [ 122, 545, 33, 14 ], [ 158, 545, 14, 14 ], [ 175, 545, 37, 14 ], [ 216, 545, 47, 14 ], [ 267, 545, 28, 14 ], [ 299, 545, 24, 14 ], [ 327, 545, 7, 14 ], [ 338, 545, 35, 14 ], [ 376, 545, 27, 14 ], [ 71, 563, 17, 14 ], [ 93, 563, 25, 14 ], [ 123, 563, 12, 14 ], [ 139, 563, 55, 14 ], [ 199, 563, 18, 14 ], [ 223, 563, 46, 14 ], [ 273, 563, 7, 14 ], [ 285, 563, 35, 14 ], [ 324, 563, 37, 14 ], [ 366, 563, 25, 14 ], [ 396, 563, 7, 14 ], [ 71, 580, 71, 14 ], [ 148, 580, 43, 14 ], [ 198, 580, 40, 14 ], [ 244, 580, 75, 14 ], [ 324, 580, 21, 14 ], [ 351, 580, 22, 14 ], [ 379, 580, 23, 14 ], [ 71, 597, 49, 14 ], [ 124, 597, 37, 14 ], [ 165, 597, 14, 14 ], [ 184, 597, 43, 14 ], [ 231, 597, 50, 14 ], [ 285, 597, 20, 14 ], [ 310, 597, 47, 14 ], [ 361, 597, 41, 14 ], [ 71, 615, 44, 14 ], [ 119, 615, 21, 14 ], [ 144, 615, 10, 14 ], [ 158, 615, 27, 14 ], [ 188, 615, 20, 14 ], [ 213, 615, 33, 14 ], [ 250, 615, 21, 14 ], [ 275, 615, 7, 14 ], [ 286, 615, 29, 14 ], [ 320, 615, 25, 14 ], [ 349, 615, 44, 14 ], [ 71, 667, 29, 14 ], [ 104, 667, 42, 14 ], [ 71, 701, 10, 14 ], [ 88, 701, 43, 14 ], [ 137, 701, 41, 14 ], [ 183, 701, 64, 14 ], [ 253, 701, 42, 14 ], [ 301, 701, 54, 14 ], [ 361, 701, 41, 14 ], [ 71, 719, 53, 14 ], [ 130, 719, 16, 14 ], [ 152, 719, 7, 14 ], [ 164, 719, 44, 14 ], [ 213, 719, 58, 14 ], [ 277, 719, 12, 14 ], [ 294, 719, 6, 14 ], [ 306, 719, 34, 14 ], [ 346, 719, 56, 14 ], [ 71, 736, 40, 14 ], [ 114, 736, 31, 14 ], [ 148, 736, 22, 14 ], [ 173, 736, 38, 14 ], [ 213, 736, 46, 14 ], [ 262, 736, 80, 14 ], [ 344, 736, 14, 14 ], [ 361, 736, 41, 14 ], [ 71, 753, 12, 14 ], [ 92, 753, 61, 14 ], [ 162, 753, 21, 14 ], [ 191, 753, 67, 14 ], [ 267, 753, 50, 14 ], [ 326, 753, 12, 14 ], [ 346, 753, 56, 14 ], [ 71, 770, 63, 14 ], [ 138, 770, 52, 14 ], [ 193, 770, 19, 14 ], [ 215, 770, 20, 14 ], [ 239, 770, 57, 14 ], [ 299, 770, 57, 14 ], [ 360, 770, 12, 14 ], [ 375, 770, 28, 14 ], [ 71, 788, 36, 14 ], [ 114, 788, 20, 14 ], [ 141, 788, 51, 14 ], [ 199, 788, 17, 14 ], [ 223, 788, 46, 14 ], [ 276, 788, 34, 14 ], [ 316, 788, 19, 14 ], [ 342, 788, 20, 14 ], [ 369, 788, 33, 14 ], [ 71, 805, 38, 14 ], [ 116, 805, 32, 14 ], [ 154, 805, 58, 14 ], [ 218, 805, 58, 14 ], [ 283, 805, 20, 14 ], [ 309, 805, 7, 14 ], [ 322, 805, 27, 14 ], [ 355, 805, 47, 14 ], [ 71, 822, 28, 14 ], [ 103, 822, 11, 14 ], [ 118, 822, 17, 14 ], [ 139, 822, 18, 14 ], [ 161, 822, 32, 14 ], [ 196, 822, 49, 14 ], [ 248, 822, 55, 14 ], [ 307, 822, 11, 14 ], [ 322, 822, 17, 14 ], [ 343, 822, 46, 14 ], [ 392, 822, 10, 14 ], [ 71, 839, 47, 14 ], [ 123, 839, 18, 14 ], [ 147, 839, 32, 14 ], [ 183, 839, 49, 14 ], [ 236, 839, 28, 14 ], [ 269, 839, 22, 14 ], [ 295, 839, 25, 14 ], [ 325, 839, 14, 14 ], [ 344, 839, 59, 14 ], [ 71, 857, 32, 14 ], [ 109, 857, 30, 14 ], [ 145, 857, 36, 14 ], [ 187, 857, 14, 14 ], [ 206, 857, 61, 14 ], [ 273, 857, 29, 14 ], [ 308, 857, 27, 14 ], [ 341, 857, 61, 14 ], [ 71, 893, 12, 12 ], [ 87, 893, 37, 12 ], [ 125, 887, 5, 17 ], [ 132, 893, 10, 12 ], [ 145, 893, 23, 12 ], [ 169, 887, 5, 17 ], [ 176, 893, 12, 12 ], [ 191, 893, 32, 12 ], [ 225, 887, 5, 17 ], [ 232, 893, 11, 12 ], [ 247, 893, 41, 12 ], [ 290, 887, 5, 17 ], [ 296, 893, 10, 12 ], [ 310, 893, 53, 12 ], [ 364, 887, 5, 17 ], [ 71, 907, 8, 12 ], [ 83, 907, 18, 12 ], [ 102, 901, 5, 17 ], [ 109, 907, 10, 12 ], [ 122, 907, 29, 12 ], [ 153, 901, 5, 17 ], [ 160, 907, 12, 12 ], [ 175, 907, 28, 12 ], [ 205, 901, 5, 17 ], [ 212, 907, 12, 12 ], [ 228, 907, 10, 12 ], [ 241, 907, 26, 12 ], [ 269, 907, 21, 12 ], [ 71, 921, 55, 12 ], [ 130, 921, 10, 12 ], [ 144, 921, 39, 12 ], [ 186, 921, 60, 12 ], [ 250, 921, 39, 12 ], [ 292, 921, 34, 12 ], [ 71, 935, 24, 12 ], [ 99, 935, 14, 12 ], [ 115, 935, 16, 12 ], [ 135, 935, 30, 12 ], [ 169, 935, 18, 12 ], [ 190, 935, 26, 12 ], [ 71, 949, 18, 12 ], [ 93, 949, 42, 12 ], [ 138, 949, 17, 12 ], [ 158, 949, 33, 12 ], [ 194, 949, 24, 12 ], [ 71, 962, 33, 12 ], [ 108, 962, 83, 12 ], [ 426, 407, 58, 14 ], [ 492, 407, 22, 14 ], [ 523, 407, 63, 14 ], [ 594, 407, 17, 14 ], [ 619, 407, 52, 14 ], [ 680, 407, 57, 14 ], [ 745, 407, 12, 14 ], [ 426, 425, 44, 14 ], [ 474, 425, 68, 14 ], [ 545, 425, 20, 14 ], [ 570, 425, 30, 14 ], [ 604, 425, 64, 14 ], [ 441, 442, 15, 14 ], [ 462, 442, 37, 14 ], [ 505, 442, 46, 14 ], [ 558, 442, 17, 14 ], [ 581, 442, 31, 14 ], [ 618, 442, 7, 14 ], [ 630, 442, 18, 14 ], [ 653, 442, 25, 14 ], [ 684, 442, 12, 14 ], [ 702, 442, 17, 14 ], [ 725, 442, 32, 14 ], [ 426, 459, 55, 14 ], [ 483, 459, 20, 14 ], [ 507, 459, 33, 14 ], [ 543, 459, 22, 14 ], [ 568, 459, 57, 14 ], [ 629, 459, 27, 14 ], [ 658, 459, 15, 14 ], [ 677, 459, 34, 14 ], [ 714, 459, 43, 14 ], [ 426, 476, 6, 14 ], [ 437, 476, 28, 14 ], [ 469, 476, 80, 14 ], [ 554, 476, 28, 14 ], [ 586, 476, 58, 14 ], [ 649, 476, 17, 14 ], [ 671, 476, 18, 14 ], [ 694, 476, 24, 14 ], [ 723, 476, 12, 14 ], [ 739, 476, 17, 14 ], [ 426, 494, 25, 14 ], [ 454, 494, 25, 14 ], [ 483, 494, 7, 14 ], [ 492, 494, 29, 14 ], [ 524, 494, 23, 14 ], [ 551, 494, 12, 14 ], [ 566, 494, 68, 14 ], [ 637, 494, 11, 14 ], [ 652, 494, 17, 14 ], [ 672, 494, 43, 14 ], [ 719, 494, 38, 14 ], [ 426, 511, 26, 14 ], [ 455, 511, 74, 14 ], [ 533, 511, 7, 14 ], [ 542, 511, 33, 14 ], [ 579, 511, 91, 14 ], [ 672, 511, 57, 14 ], [ 732, 511, 23, 14 ], [ 426, 528, 14, 14 ], [ 441, 528, 34, 14 ], [ 479, 528, 17, 14 ], [ 500, 528, 52, 14 ], [ 557, 528, 28, 14 ], [ 589, 528, 63, 14 ], [ 656, 528, 27, 14 ], [ 688, 528, 17, 14 ], [ 710, 528, 18, 14 ], [ 733, 528, 24, 14 ], [ 426, 546, 12, 14 ], [ 441, 546, 17, 14 ], [ 462, 546, 25, 14 ], [ 491, 546, 27, 14 ], [ 522, 546, 15, 14 ], [ 541, 546, 22, 14 ], [ 567, 546, 19, 14 ], [ 589, 546, 32, 14 ], [ 625, 546, 24, 14 ], [ 653, 546, 22, 14 ], [ 679, 546, 18, 14 ], [ 701, 546, 56, 14 ], [ 426, 563, 20, 14 ], [ 451, 563, 28, 14 ], [ 485, 563, 22, 14 ], [ 512, 563, 14, 14 ], [ 532, 563, 36, 14 ], [ 573, 563, 56, 14 ], [ 635, 563, 20, 14 ], [ 660, 563, 20, 14 ], [ 686, 563, 71, 14 ], [ 426, 580, 56, 14 ], [ 490, 580, 43, 14 ], [ 540, 580, 7, 14 ], [ 554, 580, 29, 14 ], [ 590, 580, 23, 14 ], [ 621, 580, 12, 14 ], [ 640, 580, 33, 14 ], [ 681, 580, 75, 14 ], [ 426, 598, 25, 14 ], [ 460, 598, 47, 14 ], [ 516, 598, 69, 14 ], [ 593, 598, 85, 14 ], [ 686, 598, 32, 14 ], [ 728, 598, 29, 14 ], [ 426, 615, 61, 14 ], [ 491, 615, 17, 14 ], [ 513, 615, 28, 14 ], [ 546, 615, 55, 14 ], [ 606, 615, 25, 14 ], [ 636, 615, 28, 14 ], [ 669, 615, 12, 14 ], [ 685, 615, 71, 14 ], [ 426, 632, 10, 14 ], [ 441, 632, 30, 14 ], [ 477, 632, 42, 14 ], [ 524, 632, 12, 14 ], [ 542, 632, 80, 14 ], [ 627, 632, 21, 14 ], [ 654, 632, 26, 14 ], [ 686, 632, 22, 14 ], [ 713, 632, 44, 14 ], [ 426, 649, 43, 14 ], [ 473, 649, 29, 14 ], [ 506, 649, 20, 14 ], [ 532, 649, 29, 14 ], [ 565, 649, 18, 14 ], [ 588, 649, 74, 14 ], [ 667, 649, 14, 14 ], [ 686, 649, 49, 14 ], [ 740, 649, 16, 14 ], [ 426, 667, 56, 14 ], [ 487, 667, 43, 14 ], [ 537, 667, 37, 14 ], [ 580, 667, 28, 14 ], [ 614, 667, 43, 14 ], [ 663, 667, 30, 14 ], [ 699, 667, 27, 14 ], [ 732, 667, 25, 14 ], [ 426, 684, 74, 14 ], [ 507, 684, 14, 14 ], [ 528, 684, 49, 14 ], [ 584, 684, 12, 14 ], [ 602, 684, 42, 14 ], [ 651, 684, 56, 14 ], [ 713, 684, 44, 14 ], [ 426, 701, 22, 14 ], [ 456, 701, 56, 14 ], [ 521, 701, 61, 14 ], [ 591, 701, 53, 14 ], [ 652, 701, 47, 14 ], [ 707, 701, 50, 14 ], [ 426, 719, 52, 14 ], [ 482, 719, 56, 14 ], [ 542, 719, 78, 14 ], [ 625, 719, 20, 14 ], [ 650, 719, 72, 14 ], [ 726, 719, 31, 14 ], [ 426, 736, 52, 14 ], [ 482, 736, 61, 14 ], [ 441, 753, 14, 14 ], [ 461, 753, 56, 14 ], [ 523, 753, 6, 14 ], [ 536, 753, 31, 14 ], [ 573, 753, 40, 14 ], [ 619, 753, 33, 14 ], [ 658, 753, 51, 14 ], [ 715, 753, 17, 14 ], [ 738, 753, 19, 14 ], [ 426, 770, 42, 14 ], [ 476, 770, 25, 14 ], [ 510, 770, 22, 14 ], [ 542, 770, 72, 14 ], [ 622, 770, 60, 14 ], [ 691, 770, 22, 14 ], [ 722, 770, 35, 14 ], [ 426, 788, 50, 14 ], [ 481, 788, 35, 14 ], [ 521, 788, 17, 14 ], [ 544, 788, 51, 14 ], [ 600, 788, 48, 14 ], [ 654, 788, 22, 14 ], [ 681, 788, 46, 14 ], [ 732, 788, 7, 14 ], [ 745, 788, 12, 14 ], [ 426, 805, 17, 14 ], [ 448, 805, 28, 14 ], [ 482, 805, 9, 14 ], [ 496, 805, 22, 14 ], [ 523, 805, 22, 14 ], [ 551, 805, 48, 14 ], [ 604, 805, 15, 14 ], [ 624, 805, 18, 14 ], [ 647, 805, 18, 14 ], [ 670, 805, 18, 14 ], [ 694, 805, 41, 14 ], [ 739, 805, 17, 14 ], [ 426, 822, 50, 14 ], [ 483, 822, 22, 14 ], [ 513, 822, 58, 14 ], [ 580, 822, 34, 14 ], [ 622, 822, 22, 14 ], [ 652, 822, 54, 14 ], [ 714, 822, 20, 14 ], [ 742, 822, 14, 14 ], [ 426, 840, 56, 14 ], [ 486, 840, 45, 14 ], [ 535, 840, 27, 14 ], [ 567, 840, 35, 14 ], [ 605, 840, 22, 14 ], [ 632, 840, 26, 14 ], [ 662, 840, 40, 14 ], [ 707, 840, 24, 14 ], [ 735, 840, 22, 14 ], [ 426, 857, 54, 14 ], [ 488, 857, 25, 14 ], [ 521, 857, 25, 14 ], [ 554, 857, 51, 14 ], [ 614, 857, 20, 14 ], [ 642, 857, 76, 14 ], [ 727, 857, 30, 14 ], [ 426, 874, 37, 14 ], [ 466, 874, 20, 14 ], [ 490, 874, 22, 14 ], [ 515, 874, 22, 14 ], [ 540, 874, 12, 14 ], [ 555, 874, 36, 14 ], [ 594, 874, 10, 14 ], [ 608, 874, 19, 14 ], [ 630, 874, 40, 14 ], [ 673, 874, 59, 14 ], [ 735, 874, 22, 14 ], [ 426, 892, 57, 14 ], [ 487, 892, 25, 14 ], [ 516, 892, 42, 14 ], [ 562, 892, 93, 14 ], [ 659, 892, 30, 14 ], [ 694, 892, 7, 14 ], [ 705, 892, 52, 14 ], [ 426, 909, 22, 14 ], [ 452, 909, 12, 14 ], [ 469, 909, 78, 14 ], [ 552, 909, 20, 14 ], [ 577, 909, 46, 14 ], [ 628, 909, 59, 14 ], [ 691, 909, 22, 14 ], [ 718, 909, 38, 14 ], [ 426, 926, 40, 14 ], [ 470, 926, 24, 14 ], [ 498, 926, 22, 14 ], [ 524, 926, 18, 14 ], [ 546, 926, 49, 14 ], [ 599, 926, 11, 14 ], [ 615, 926, 17, 14 ], [ 636, 926, 28, 14 ], [ 668, 926, 20, 14 ], [ 692, 926, 22, 14 ], [ 718, 926, 19, 14 ], [ 741, 926, 15, 14 ], [ 426, 943, 24, 14 ], [ 454, 943, 21, 14 ], [ 479, 943, 79, 14 ], [ 563, 943, 48, 14 ], [ 616, 943, 22, 14 ], [ 642, 943, 63, 14 ], [ 709, 943, 21, 14 ], [ 735, 943, 22, 14 ], [ 426, 961, 60, 14 ], [ 490, 961, 14, 14 ], [ 508, 961, 17, 14 ], [ 529, 961, 24, 14 ], [ 557, 961, 79, 14 ], [ 640, 961, 23, 14 ] ]

[ "J", "Gastrointest", "Surg", "(2009)", "13:1550–1553", "DOI", "10.1007/s11605-009-0852-4", "GI", "IMAGE", "Primary", "Hepatic", "Osteosarcoma", "Atta", "Nawabi", "&", "Sidhartha", "Rath", "&", "Nicholas", "Nissen", "&", "Charles", "Forscher", "&", "Steven", "Colquhoun", "&", "Joseph", "Lee", "&", "Stephen", "Geller", "&", "Anna", "Wong", "&", "Andrew", "S.", "Klein", "Received:", "30", "September", "2008", "/", "Accepted:", "26", "February", "2009", "/", "Published", "online:", "18", "March", "2009", "#", "2009", "The", "Author(s).", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Keywords", "Osteosarcoma", ".", "Hepatic", "neoplasm", ".", "Hepatic", "malignancy", "Extraskeletal", "osteosarcoma", "(EOS)", "is", "a", "rare", "entity.", "Most", "human", "cases", "have", "been", "described", "in", "the", "soft", "tissues", "of", "the", "limb.1", "Primary", "hepatic", "osteosarcoma", "is", "extremely", "uncom-", "mon", "with", "only", "seven", "cases", "reported", "in", "the", "world’s", "literature.", "Of", "these", "cases,", "no", "patient", "survived", "more", "than", "8", "weeks", "from", "the", "time", "of", "diagnosis.", "We", "describe", "a", "young", "patient", "with", "a", "symptomatic", "primary", "hepatic", "osteosarcoma", "that", "was", "suc-", "cessfully", "treated", "by", "surgical", "resection", "and", "adjuvant", "chemo-", "therapy.", "She", "is", "alive", "and", "tumor", "free", "3", "years", "after", "surgery.", "Case", "Report", "A", "healthy,", "athletic", "19-year-old", "African", "American", "woman", "presented", "for", "a", "surgical", "evaluation", "of", "a", "newly", "diagnosed", "hepatic", "mass.", "The", "patient", "reported", "approximately", "18", "months", "of", "occasional", "and", "intermittent", "episodes", "of", "epigastric", "discomfort.", "Recently,", "she", "had", "developed", "symptoms", "of", "early", "satiety", "and", "anorexia.", "On", "physical", "exam,", "she", "had", "vague", "diffuse", "upper", "abdominal", "tenderness", "and", "a", "firm,", "palpable", "mass", "in", "the", "left", "upper", "quadrant", "extending", "to", "the", "midline.", "A", "calcified", "left", "upper", "quadrant", "mass", "was", "seen", "on", "abdominal", "X-ray", "taken", "during", "an", "emergency", "room", "visit.", "Laboratory", "A.", "Nawabi", ":", "S.", "Rath", ":", "N.", "Nissen", ":", "C.", "Forscher", ":", "S.", "Colquhoun", ":", "J.", "Lee", ":", "S.", "Geller", ":", "A.", "Wong", ":", "A.", "S.", "Klein", "(*)", "Department", "of", "Surgery,", "Cedars-Sinai", "Medical", "Center,", "8635", "W.", "3rd", "Street,", "590", "West,", "Los", "Angeles,", "CA", "90048,", "USA", "e-mail:", "kleinas@cshs.org", "evaluation", "was", "remarkable", "for", "moderate", "elevations", "of", "alkaline", "phosphatase", "and", "alpha", "fetoprotein.", "To", "further", "evaluate", "the", "mass,", "a", "CT", "scan", "of", "the", "chest,", "abdomen,", "and", "pelvis", "was", "performed", "(Fig.", "1),", "which", "showed", "a", "large", "heterogeneous", "mass", "occupying", "the", "left", "lobe", "of", "the", "liver", "with", "a", "5-cm", "area", "of", "calcification", "in", "the", "anterior", "aspect.", "MRI", "demonstrated", "a", "single", "heterogeneously", "enhancing", "15×", "10", "×13.8", "cm", "lobulated", "mass", "inseparable", "from", "the", "left", "lobe", "of", "the", "liver", "(Fig.", "2).", "The", "left", "portal", "vein", "was", "not", "visualized", "and", "there", "was", "no", "biliary", "dilatation.", "T1-", "and", "T2-weighted", "sequences", "showed", "a", "5-cm", "area", "of", "signal", "hypointensity", "with", "multiple", "hypointense", "non-enhancing", "linear", "areas", "throughout", "the", "mass", "consistent", "with", "areas", "of", "calcification.", "A", "small", "amount", "of", "intraperitoneal", "free", "fluid", "was", "present.", "Staging", "chest", "and", "brain", "CT", "demonstrated", "no", "evidence", "for", "metastatic", "disease.", "Whole", "body", "Tc-99m", "MDP", "bone", "scan", "demonstrated", "no", "evidence", "of", "skeletal", "metastatic", "disease.", "The", "radiologic", "differential", "diagnosis", "includes", "sarcoma,", "including", "metastatic", "osteosarcoma,", "and", "fibrolamellar", "hepa-", "tocellular", "carcinoma.", "At", "operation,", "a", "large,", "scarred", "lesion", "replacing", "the", "left", "hepatic", "lobe", "was", "immediately", "identified.", "The", "lesion", "extended", "across", "the", "falciform", "ligament", "into", "segment", "4", "of", "the", "liver.", "It", "was", "also", "adherent", "to,", "but", "did", "not", "invade,", "the", "stomach.", "The", "abdominal", "cavity", "was", "examined", "and", "no", "metastatic", "deposits", "were", "noted.", "The", "right", "hepatic", "lobe", "was", "examined", "with", "both", "palpation", "and", "intraoperative", "ultra-", "sound,", "and", "was", "free", "of", "tumor.", "A", "left", "hepatic", "lobectomy", "was", "performed", "with", "en-bloc", "cholecystectomy", "using", "a", "combina-", "tion", "of", "electrocautery", "and", "hydrojet", "dissection.", "The", "middle", "hepatic", "vein", "was", "not", "involved", "in", "the", "mass", "and", "was", "left", "in-", "situ.", "Her", "post-operative", "recovery", "was", "uneventful.", "She", "was", "discharged", "on", "the", "fifth", "post-operative", "day." ]

[ 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 62, 49, 73, 23 ], [ 141, 49, 112, 23 ], [ 62, 98, 19, 10 ], [ 84, 98, 72, 10 ], [ 158, 98, 31, 10 ], [ 192, 98, 5, 10 ], [ 62, 112, 57, 14 ], [ 122, 112, 46, 14 ], [ 62, 128, 42, 14 ], [ 62, 151, 20, 10 ], [ 85, 151, 46, 10 ], [ 62, 188, 260, 20 ], [ 328, 188, 81, 20 ], [ 62, 210, 93, 20 ], [ 160, 210, 59, 20 ], [ 62, 250, 26, 14 ], [ 92, 250, 42, 14 ], [ 138, 250, 54, 15 ], [ 196, 250, 23, 14 ], [ 223, 250, 25, 14 ], [ 252, 250, 30, 14 ], [ 286, 250, 66, 14 ], [ 62, 280, 49, 10 ], [ 113, 280, 8, 10 ], [ 124, 280, 45, 10 ], [ 171, 280, 42, 10 ], [ 216, 280, 8, 10 ], [ 227, 280, 23, 10 ], [ 253, 280, 14, 10 ], [ 269, 280, 16, 10 ], [ 288, 280, 22, 10 ], [ 312, 280, 39, 10 ], [ 353, 280, 32, 10 ], [ 388, 280, 23, 10 ], [ 62, 294, 33, 10 ], [ 62, 308, 68, 10 ], [ 133, 308, 29, 10 ], [ 165, 308, 106, 10 ], [ 62, 334, 38, 10 ], [ 103, 334, 6, 10 ], [ 111, 334, 43, 10 ], [ 157, 334, 25, 10 ], [ 185, 334, 38, 10 ], [ 225, 334, 6, 10 ], [ 234, 334, 31, 10 ], [ 268, 334, 22, 10 ], [ 62, 361, 16, 10 ], [ 80, 361, 44, 10 ], [ 127, 361, 54, 10 ], [ 184, 361, 22, 10 ], [ 209, 361, 25, 10 ], [ 237, 361, 6, 10 ], [ 245, 361, 6, 10 ], [ 254, 361, 17, 10 ], [ 273, 361, 9, 10 ], [ 285, 361, 23, 10 ], [ 316, 361, 24, 10 ], [ 343, 361, 6, 10 ], [ 352, 361, 25, 10 ], [ 379, 359, 10, 12 ], [ 62, 375, 6, 10 ], [ 71, 375, 24, 10 ], [ 97, 375, 6, 10 ], [ 106, 375, 28, 10 ], [ 137, 375, 14, 10 ], [ 154, 375, 24, 10 ], [ 180, 375, 6, 10 ], [ 190, 375, 28, 10 ], [ 220, 375, 73, 10 ], [ 297, 375, 19, 10 ], [ 318, 375, 6, 10 ], [ 327, 375, 17, 10 ], [ 62, 416, 22, 14 ], [ 86, 416, 51, 14 ], [ 140, 416, 12, 14 ], [ 154, 416, 18, 14 ], [ 175, 416, 23, 14 ], [ 200, 416, 60, 14 ], [ 263, 416, 63, 14 ], [ 329, 416, 35, 14 ], [ 365, 416, 46, 14 ], [ 62, 433, 349, 15 ], [ 62, 450, 32, 14 ], [ 104, 450, 112, 14 ], [ 227, 450, 48, 14 ], [ 285, 450, 70, 15 ], [ 358, 450, 53, 15 ], [ 62, 466, 48, 14 ], [ 117, 466, 101, 14 ], [ 226, 466, 30, 14 ], [ 263, 466, 38, 14 ], [ 309, 466, 17, 14 ], [ 334, 466, 77, 14 ], [ 62, 483, 31, 14 ], [ 100, 483, 22, 14 ], [ 129, 483, 51, 14 ], [ 187, 483, 9, 14 ], [ 203, 483, 54, 14 ], [ 264, 483, 14, 14 ], [ 285, 483, 36, 14 ], [ 327, 483, 84, 14 ], [ 62, 499, 67, 14 ], [ 133, 499, 12, 14 ], [ 148, 499, 19, 14 ], [ 170, 499, 30, 14 ], [ 204, 499, 35, 14 ], [ 254, 499, 11, 14 ], [ 269, 499, 21, 14 ], [ 294, 499, 34, 14 ], [ 344, 499, 11, 14 ], [ 358, 499, 53, 14 ], [ 62, 516, 19, 14 ], [ 90, 516, 54, 14 ], [ 153, 516, 21, 14 ], [ 184, 516, 19, 14 ], [ 212, 516, 41, 14 ], [ 262, 516, 59, 14 ], [ 331, 516, 22, 14 ], [ 363, 516, 48, 14 ], [ 62, 533, 76, 14 ], [ 141, 533, 21, 14 ], [ 166, 533, 39, 14 ], [ 209, 533, 28, 14 ], [ 240, 533, 19, 14 ], [ 263, 533, 43, 14 ], [ 310, 533, 55, 14 ], [ 62, 574, 48, 15 ], [ 114, 574, 59, 15 ], [ 62, 596, 20, 14 ], [ 87, 596, 40, 14 ], [ 132, 596, 59, 14 ], [ 195, 596, 22, 14 ], [ 222, 596, 38, 14 ], [ 265, 596, 10, 14 ], [ 280, 596, 14, 14 ], [ 299, 596, 40, 14 ], [ 343, 596, 34, 14 ], [ 382, 596, 10, 14 ], [ 397, 596, 14, 14 ], [ 62, 613, 40, 14 ], [ 105, 613, 42, 14 ], [ 150, 613, 10, 14 ], [ 164, 613, 14, 14 ], [ 181, 613, 40, 14 ], [ 224, 613, 20, 14 ], [ 247, 613, 11, 14 ], [ 261, 613, 33, 14 ], [ 298, 613, 40, 14 ], [ 341, 613, 36, 14 ], [ 381, 613, 10, 14 ], [ 394, 613, 17, 15 ], [ 62, 629, 40, 14 ], [ 107, 629, 24, 14 ], [ 137, 629, 11, 14 ], [ 154, 629, 48, 14 ], [ 208, 629, 40, 14 ], [ 254, 629, 18, 15 ], [ 271, 629, 26, 14 ], [ 304, 629, 40, 14 ], [ 350, 629, 18, 15 ], [ 367, 629, 26, 14 ], [ 400, 629, 11, 14 ], [ 62, 646, 63, 14 ], [ 132, 646, 40, 14 ], [ 179, 646, 43, 14 ], [ 230, 646, 54, 14 ], [ 291, 646, 18, 15 ], [ 309, 646, 26, 14 ], [ 343, 646, 11, 14 ], [ 361, 646, 49, 14 ], [ 62, 663, 40, 14 ], [ 105, 663, 63, 14 ], [ 172, 663, 57, 14 ], [ 232, 663, 57, 14 ], [ 293, 663, 32, 14 ], [ 329, 663, 40, 14 ], [ 62, 883, 83, 15 ], [ 62, 906, 36, 13 ], [ 101, 906, 22, 13 ], [ 62, 926, 55, 12 ], [ 120, 926, 40, 12 ], [ 62, 938, 13, 12 ], [ 78, 938, 7, 12 ], [ 87, 938, 29, 12 ], [ 62, 951, 54, 12 ], [ 118, 950, 16, 13 ], [ 62, 963, 6, 11 ], [ 70, 963, 7, 11 ], [ 80, 963, 29, 11 ], [ 112, 963, 14, 11 ], [ 128, 960, 9, 14 ], [ 62, 975, 6, 12 ], [ 71, 975, 7, 12 ], [ 80, 975, 34, 12 ], [ 117, 975, 14, 12 ], [ 134, 973, 9, 14 ], [ 62, 988, 5, 12 ], [ 70, 988, 7, 11 ], [ 79, 988, 34, 11 ], [ 116, 988, 14, 11 ], [ 133, 985, 9, 14 ], [ 71, 1000, 7, 12 ], [ 81, 1000, 29, 12 ], [ 113, 1000, 14, 12 ], [ 249, 926, 8, 12 ], [ 259, 926, 7, 12 ], [ 269, 926, 34, 12 ], [ 306, 926, 14, 12 ], [ 322, 923, 9, 15 ], [ 331, 924, 4, 8 ], [ 249, 938, 8, 11 ], [ 259, 938, 7, 12 ], [ 269, 938, 6, 12 ], [ 249, 951, 16, 12 ], [ 267, 950, 9, 12 ], [ 285, 951, 41, 12 ], [ 259, 963, 7, 11 ], [ 269, 963, 19, 11 ], [ 290, 963, 17, 11 ], [ 313, 961, 4, 8 ], [ 249, 975, 7, 12 ], [ 259, 975, 7, 12 ], [ 268, 975, 16, 12 ], [ 287, 975, 14, 12 ], [ 304, 975, 9, 12 ], [ 249, 988, 19, 11 ], [ 282, 988, 19, 11 ], [ 315, 988, 19, 11 ], [ 337, 988, 18, 11 ], [ 435, 106, 25, 13 ], [ 464, 106, 48, 13 ], [ 435, 126, 38, 11 ], [ 476, 126, 39, 11 ], [ 518, 126, 24, 11 ], [ 446, 138, 65, 12 ], [ 435, 150, 52, 12 ], [ 490, 150, 49, 12 ], [ 542, 150, 47, 12 ], [ 446, 163, 50, 12 ], [ 500, 163, 46, 12 ], [ 548, 163, 25, 12 ], [ 446, 175, 20, 12 ], [ 469, 175, 7, 11 ], [ 479, 175, 26, 11 ], [ 508, 175, 21, 12 ], [ 531, 175, 7, 11 ], [ 541, 175, 24, 11 ], [ 435, 202, 57, 13 ], [ 435, 221, 18, 12 ], [ 454, 220, 4, 8 ], [ 461, 221, 7, 11 ], [ 470, 221, 6, 11 ], [ 482, 221, 11, 12 ], [ 494, 220, 12, 13 ], [ 508, 221, 7, 11 ], [ 518, 221, 24, 11 ], [ 435, 234, 26, 12 ], [ 462, 232, 8, 13 ], [ 473, 234, 7, 12 ], [ 482, 234, 24, 12 ], [ 435, 246, 6, 12 ], [ 444, 246, 7, 12 ], [ 454, 246, 19, 12 ], [ 435, 259, 21, 12 ], [ 459, 259, 47, 12 ], [ 435, 271, 16, 11 ], [ 454, 271, 51, 11 ], [ 435, 284, 6, 12 ], [ 444, 284, 39, 12 ], [ 435, 315, 30, 13 ], [ 469, 315, 7, 13 ], [ 435, 329, 77, 12 ], [ 515, 329, 46, 12 ], [ 564, 326, 14, 15 ], [ 578, 329, 3, 12 ], [ 588, 329, 7, 12 ], [ 435, 352, 26, 11 ], [ 473, 352, 8, 11 ], [ 435, 375, 35, 11 ], [ 435, 387, 35, 11 ], [ 435, 399, 35, 11 ], [ 435, 411, 36, 11 ], [ 482, 374, 15, 12 ], [ 482, 386, 17, 12 ], [ 482, 397, 19, 12 ], [ 483, 411, 21, 11 ], [ 537, 352, 26, 11 ], [ 537, 375, 17, 11 ], [ 557, 375, 13, 11 ], [ 537, 387, 17, 11 ], [ 557, 387, 13, 11 ], [ 537, 399, 17, 11 ], [ 557, 399, 13, 11 ], [ 537, 411, 17, 11 ], [ 557, 411, 13, 11 ], [ 622, 126, 21, 11 ], [ 646, 126, 44, 11 ], [ 693, 126, 47, 11 ], [ 622, 138, 21, 12 ], [ 646, 138, 57, 12 ], [ 706, 138, 47, 12 ], [ 622, 150, 21, 12 ], [ 646, 150, 47, 12 ], [ 696, 150, 20, 12 ], [ 719, 150, 5, 12 ], [ 726, 150, 7, 12 ], [ 736, 150, 6, 12 ], [ 747, 150, 12, 12 ], [ 622, 163, 17, 13 ], [ 642, 163, 7, 12 ], [ 651, 163, 24, 12 ], [ 622, 221, 9, 11 ], [ 634, 221, 27, 11 ], [ 664, 221, 33, 11 ], [ 700, 221, 11, 11 ], [ 714, 221, 6, 11 ], [ 723, 221, 35, 11 ], [ 761, 221, 10, 11 ], [ 633, 234, 57, 12 ], [ 693, 234, 17, 12 ], [ 713, 234, 53, 12 ], [ 633, 246, 49, 12 ], [ 637, 264, 14, 8 ], [ 654, 259, 7, 12 ], [ 663, 259, 19, 12 ], [ 685, 259, 6, 12 ], [ 693, 256, 9, 14 ], [ 708, 257, 4, 8 ], [ 637, 276, 13, 8 ], [ 653, 271, 7, 11 ], [ 671, 271, 19, 11 ], [ 692, 271, 6, 11 ], [ 700, 268, 9, 14 ], [ 715, 270, 4, 8 ], [ 603, 352, 8, 11 ], [ 622, 352, 8, 11 ], [ 603, 375, 17, 11 ], [ 623, 375, 13, 11 ], [ 603, 387, 17, 11 ], [ 623, 387, 13, 11 ], [ 603, 399, 17, 11 ], [ 623, 399, 13, 11 ], [ 603, 411, 17, 11 ], [ 623, 411, 13, 11 ], [ 668, 352, 8, 11 ], [ 688, 352, 8, 11 ], [ 668, 375, 22, 11 ], [ 693, 375, 13, 11 ], [ 668, 387, 22, 11 ], [ 693, 387, 13, 11 ], [ 668, 399, 22, 11 ], [ 693, 399, 13, 11 ], [ 668, 411, 22, 11 ], [ 693, 411, 13, 11 ], [ 739, 352, 26, 11 ], [ 776, 352, 8, 11 ], [ 739, 375, 15, 11 ], [ 757, 375, 13, 11 ], [ 739, 387, 15, 11 ], [ 757, 387, 13, 11 ], [ 739, 399, 15, 11 ], [ 757, 399, 13, 11 ], [ 739, 411, 15, 11 ], [ 757, 411, 13, 11 ], [ 435, 430, 41, 10 ], [ 479, 430, 25, 10 ], [ 506, 430, 10, 10 ], [ 518, 430, 5, 10 ], [ 525, 433, 8, 10 ], [ 535, 430, 8, 10 ], [ 544, 430, 8, 10 ], [ 553, 430, 7, 10 ], [ 563, 430, 13, 10 ], [ 578, 430, 5, 10 ], [ 594, 430, 8, 10 ], [ 604, 430, 8, 10 ], [ 613, 430, 7, 10 ], [ 623, 430, 15, 10 ], [ 648, 430, 8, 10 ], [ 657, 430, 5, 10 ], [ 664, 433, 8, 10 ], [ 673, 429, 7, 13 ], [ 689, 430, 5, 10 ], [ 695, 433, 8, 10 ], [ 705, 430, 7, 10 ], [ 449, 459, 26, 13 ], [ 478, 459, 52, 13 ], [ 534, 459, 43, 13 ], [ 580, 459, 44, 13 ], [ 627, 459, 31, 13 ], [ 661, 459, 18, 13 ], [ 682, 459, 58, 13 ], [ 743, 459, 41, 13 ], [ 435, 475, 23, 13 ], [ 460, 475, 44, 13 ], [ 506, 475, 31, 13 ], [ 540, 475, 22, 13 ], [ 565, 475, 52, 13 ], [ 619, 475, 66, 13 ], [ 688, 475, 57, 13 ], [ 748, 475, 24, 13 ], [ 774, 475, 11, 13 ], [ 435, 490, 26, 13 ], [ 467, 490, 49, 13 ], [ 520, 490, 60, 13 ], [ 586, 490, 56, 13 ], [ 646, 490, 31, 13 ], [ 683, 490, 57, 13 ], [ 745, 490, 24, 13 ], [ 774, 490, 11, 13 ], [ 435, 505, 30, 13 ], [ 472, 505, 49, 13 ], [ 527, 505, 58, 13 ], [ 593, 505, 44, 13 ], [ 643, 505, 31, 13 ], [ 681, 505, 51, 13 ], [ 739, 505, 45, 13 ], [ 435, 520, 61, 13 ], [ 504, 520, 44, 13 ], [ 555, 520, 24, 13 ], [ 586, 520, 11, 13 ], [ 604, 520, 40, 13 ], [ 652, 520, 42, 13 ], [ 701, 520, 15, 13 ], [ 724, 520, 60, 13 ], [ 435, 535, 61, 13 ], [ 449, 567, 22, 14 ], [ 479, 567, 51, 14 ], [ 537, 567, 12, 14 ], [ 556, 567, 18, 14 ], [ 582, 567, 82, 14 ], [ 671, 567, 21, 14 ], [ 700, 567, 31, 14 ], [ 739, 567, 46, 14 ], [ 435, 584, 45, 14 ], [ 489, 584, 44, 14 ], [ 541, 584, 28, 14 ], [ 578, 584, 18, 14 ], [ 605, 584, 53, 14 ], [ 666, 584, 44, 14 ], [ 719, 584, 12, 14 ], [ 739, 584, 45, 14 ], [ 435, 600, 42, 14 ], [ 435, 637, 73, 12 ], [ 513, 637, 21, 12 ], [ 539, 637, 18, 12 ], [ 562, 637, 32, 12 ], [ 599, 637, 15, 12 ], [ 618, 637, 18, 12 ], [ 640, 637, 28, 12 ], [ 672, 637, 16, 12 ], [ 693, 637, 43, 12 ], [ 741, 637, 24, 12 ], [ 769, 637, 16, 12 ], [ 435, 650, 26, 12 ], [ 464, 650, 48, 12 ], [ 515, 650, 40, 12 ], [ 558, 650, 57, 12 ], [ 618, 650, 45, 12 ], [ 435, 688, 70, 15 ], [ 435, 709, 28, 12 ], [ 466, 709, 8, 12 ], [ 478, 709, 11, 12 ], [ 492, 709, 32, 12 ], [ 526, 709, 21, 12 ], [ 550, 709, 27, 12 ], [ 580, 709, 21, 12 ], [ 603, 709, 39, 12 ], [ 435, 721, 33, 12 ], [ 470, 721, 32, 12 ], [ 503, 721, 41, 12 ], [ 546, 721, 35, 12 ], [ 583, 721, 26, 12 ], [ 611, 721, 33, 12 ], [ 646, 721, 23, 12 ], [ 670, 721, 20, 12 ], [ 692, 721, 42, 12 ], [ 736, 721, 49, 12 ], [ 446, 734, 26, 12 ], [ 435, 746, 33, 12 ], [ 475, 746, 32, 12 ], [ 514, 746, 54, 12 ], [ 575, 746, 35, 12 ], [ 618, 746, 21, 12 ], [ 646, 746, 33, 12 ], [ 686, 746, 23, 12 ], [ 716, 746, 20, 12 ], [ 743, 746, 42, 12 ], [ 446, 759, 49, 12 ], [ 498, 759, 26, 12 ], [ 435, 771, 33, 11 ], [ 475, 771, 32, 11 ], [ 513, 771, 59, 12 ], [ 578, 771, 35, 11 ], [ 620, 771, 21, 11 ], [ 648, 771, 33, 11 ], [ 687, 771, 23, 11 ], [ 716, 771, 20, 11 ], [ 743, 771, 42, 11 ], [ 446, 784, 49, 12 ], [ 498, 784, 26, 12 ], [ 435, 796, 15, 12 ], [ 450, 796, 24, 12 ], [ 476, 796, 10, 12 ], [ 489, 796, 11, 12 ], [ 504, 796, 32, 12 ], [ 538, 796, 21, 12 ], [ 562, 796, 29, 12 ], [ 594, 796, 30, 12 ], [ 627, 796, 10, 12 ], [ 640, 796, 13, 12 ], [ 656, 796, 29, 12 ], [ 435, 808, 15, 12 ], [ 450, 809, 24, 12 ], [ 476, 809, 10, 12 ], [ 489, 809, 11, 12 ], [ 504, 809, 9, 12 ], [ 515, 809, 53, 12 ], [ 571, 809, 10, 12 ], [ 584, 809, 13, 12 ], [ 599, 809, 32, 12 ], [ 634, 809, 21, 12 ], [ 658, 809, 26, 12 ], [ 687, 809, 21, 12 ], [ 711, 809, 61, 12 ], [ 435, 821, 15, 12 ], [ 450, 821, 24, 12 ], [ 476, 821, 10, 12 ], [ 489, 821, 11, 12 ], [ 504, 821, 9, 12 ], [ 515, 821, 42, 12 ], [ 560, 821, 22, 12 ], [ 585, 821, 32, 12 ], [ 620, 821, 21, 12 ], [ 644, 821, 27, 12 ], [ 673, 821, 21, 12 ], [ 697, 821, 50, 12 ], [ 435, 834, 30, 12 ], [ 468, 834, 11, 12 ], [ 481, 834, 13, 12 ], [ 497, 834, 26, 12 ], [ 526, 834, 12, 12 ], [ 540, 834, 13, 12 ], [ 556, 834, 29, 12 ], [ 587, 834, 8, 12 ], [ 598, 834, 9, 12 ], [ 610, 834, 26, 12 ], [ 638, 834, 12, 12 ], [ 652, 834, 13, 12 ], [ 668, 834, 9, 12 ], [ 679, 834, 37, 12 ], [ 719, 834, 7, 12 ], [ 728, 834, 12, 12 ], [ 743, 834, 32, 12 ], [ 777, 833, 8, 12 ], [ 446, 846, 29, 11 ], [ 479, 846, 52, 11 ], [ 534, 846, 13, 11 ], [ 550, 846, 39, 11 ], [ 435, 858, 19, 12 ], [ 457, 858, 21, 12 ], [ 481, 858, 9, 12 ], [ 493, 858, 29, 12 ], [ 524, 858, 10, 12 ], [ 537, 858, 10, 12 ], [ 550, 858, 32, 12 ], [ 585, 858, 8, 12 ], [ 595, 858, 20, 12 ], [ 618, 858, 29, 12 ], [ 650, 858, 19, 12 ], [ 672, 858, 13, 12 ], [ 688, 858, 50, 12 ], [ 435, 871, 21, 11 ], [ 459, 871, 19, 11 ], [ 481, 871, 13, 11 ], [ 496, 871, 9, 11 ], [ 508, 871, 40, 11 ], [ 551, 871, 11, 11 ], [ 565, 871, 9, 11 ], [ 577, 871, 11, 11 ], [ 591, 871, 32, 11 ], [ 625, 871, 26, 11 ], [ 655, 871, 35, 11 ], [ 692, 871, 20, 11 ], [ 715, 871, 8, 12 ], [ 726, 871, 39, 11 ], [ 435, 883, 33, 12 ], [ 471, 883, 12, 12 ], [ 485, 883, 9, 12 ], [ 497, 883, 37, 12 ], [ 537, 883, 12, 12 ], [ 551, 883, 7, 12 ], [ 561, 883, 9, 12 ], [ 573, 883, 46, 12 ], [ 621, 883, 10, 12 ], [ 633, 883, 32, 12 ], [ 668, 883, 27, 12 ], [ 697, 883, 29, 12 ], [ 729, 883, 45, 12 ], [ 776, 883, 8, 12 ], [ 446, 896, 39, 12 ], [ 435, 908, 32, 12 ], [ 470, 908, 7, 12 ], [ 481, 908, 14, 12 ], [ 498, 908, 48, 12 ], [ 549, 908, 38, 12 ], [ 590, 908, 19, 12 ], [ 613, 908, 11, 12 ], [ 627, 908, 21, 12 ], [ 651, 908, 28, 12 ], [ 682, 908, 27, 12 ], [ 713, 908, 24, 12 ], [ 740, 908, 32, 12 ], [ 775, 908, 9, 12 ], [ 446, 921, 30, 11 ], [ 480, 921, 25, 11 ], [ 507, 921, 9, 11 ], [ 519, 921, 22, 11 ], [ 544, 921, 25, 11 ], [ 571, 921, 32, 11 ], [ 605, 921, 21, 11 ], [ 630, 921, 26, 11 ], [ 659, 921, 21, 11 ], [ 682, 921, 50, 11 ], [ 435, 933, 46, 12 ], [ 484, 933, 11, 12 ], [ 497, 933, 13, 12 ], [ 513, 933, 32, 12 ], [ 547, 933, 46, 12 ], [ 597, 933, 47, 12 ], [ 647, 933, 10, 12 ], [ 660, 933, 15, 12 ], [ 674, 933, 35, 12 ], [ 711, 933, 45, 12 ], [ 435, 946, 46, 11 ], [ 484, 946, 11, 11 ], [ 497, 946, 13, 11 ], [ 513, 946, 32, 11 ], [ 547, 945, 21, 11 ], [ 571, 945, 27, 11 ], [ 601, 946, 22, 12 ], [ 626, 946, 39, 11 ], [ 435, 958, 36, 12 ], [ 475, 958, 14, 12 ], [ 492, 958, 59, 12 ], [ 554, 958, 8, 12 ], [ 566, 958, 9, 12 ], [ 578, 958, 35, 12 ], [ 617, 958, 11, 12 ], [ 631, 958, 11, 12 ], [ 645, 958, 32, 12 ], [ 680, 958, 21, 12 ], [ 705, 958, 26, 12 ], [ 734, 958, 21, 12 ], [ 758, 958, 26, 12 ], [ 446, 970, 24, 12 ], [ 62, 1058, 37, 17 ], [ 115, 1062, 9, 12 ], [ 124, 1062, 28, 13 ], [ 154, 1062, 18, 12 ], [ 176, 1062, 51, 12 ], [ 351, 1062, 165, 12 ], [ 641, 1062, 22, 12 ], [ 666, 1062, 28, 12 ], [ 697, 1062, 34, 12 ], [ 735, 1062, 22, 12 ], [ 760, 1062, 25, 12 ] ]

[ "organic", "compounds", "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "Cyclo(L-tyrosyl-L-tryptophanyl)", "dimethyl-", "formamide", "solvate", "Carl", "Henrik", "Go¨rbitz*", "and", "Lars", "Male", "Hartviksen", "Department", "of", "Chemistry,", "University", "of", "Oslo,", "PO", "Box", "1033", "Blindern,", "N-0315", "Oslo,", "Norway", "Correspondence", "e-mail:", "c.h.gorbitz@kjemi.uio.no", "Received", "3", "December", "2007;", "accepted", "8", "January", "2008", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "105", "K;", "mean", "(C–C)", "=", "0.004", "A˚;", "R", "factor", "=", "0.046;", "wR", "factor", "=", "0.123;", "data-to-parameter", "ratio", "=", "9.4.", "The", "structure", "of", "the", "title", "compound", "[systematic", "name:", "(3S,6S)-", "3-(4-hydroxybenzyl)-6-(1H-indol-3-ylmethyl)piperazine-2,5-", "dione", "dimethylformamide", "solvate],", "C20H19N3O3", "C3H7NO,", "contains", "hydrogen-bonded", "tapes", "typical", "for", "diketopipera-", "zines.", "The", "structure", "is", "stabilized", "by", "strong", "intermolecular", "interactions", "of", "the", "types", "O—H", "O", "and", "N—H", "O", "involving", "the", "dipeptide", "and", "the", "solvent", "molecules.", "The", "absolute", "configuration", "was", "known", "from", "the", "starting", "materials.", "Related", "literature", "For", "related", "structures,", "see:", "Morris", "et", "al.", "(1974);", "Grant", "et", "al.", "(1999);", "Suguna", "et", "al.", "(1984);", "Lin", "&", "Webb", "(1973);", "Razak", "et", "al.,", "(2000);", "Luo", "&", "Palmore", "(2002);", "Go¨", "rbitz", "(1987);", "Go¨", "rbitz", "&", "Hartviksen", "(2006).", "Solvent", "inclusion:", "Go¨", "rbitz", "&", "Hersleth", "(2000).", "Cambridge", "Structural", "Database:", "Allen", "(2002).", "Experimental", "Crystal", "data", "C20H19N3O3", "C3H7NO", "Mr", "=", "422.48", "Monoclinic,", "P21", "a", "=", "6.1923", "(2)", "A˚", "b", "=", "15.3873", "(5)", "A˚", "c", "=", "11.3780", "(3)", "A˚", "=", "96.661", "(1)", "V", "=", "1076.81", "(6)", "A˚", "3", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.09", "mm", "1", "T", "=", "105", "(2)", "K", "0.80", "0.65", "0.20", "mm", "Data", "collection", "Siemens", "SMART", "CCD", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Sheldrick,", "1996)", "Tmin", "=", "0.800,", "Tmax", "=", "0.982", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.045", "wR(F", "2)", "=", "0.122", "S", "=", "1.15", "2786", "reflections", "297", "parameters", "1", "restraint", "Table", "1", "Hydrogen-bond", "geometry", "(A˚", ",", ").", "D—H", "A", "N1—H1", "N2—H2", "N3—H3", "O2—H4", "O1i", "O3ii", "O1iii", "O1D", "D—H", "0.96", "(3)", "0.87", "(3)", "0.81", "(4)", "1.04", "(5)", "9514", "measured", "reflections", "2786", "independent", "reflections", "2454", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.038", "H", "atoms", "treated", "by", "a", "mixture", "of", "independent", "and", "constrained", "refinement", "max", "=", "0.23", "e", "A˚", "3", "min", "=", "0.27", "e", "A˚", "3", "H", "A", "1.94", "(3)", "2.01", "(3)", "2.16", "(4)", "1.59", "(5)", "D", "A", "2.902", "(3)", "2.884", "(3)", "2.851", "(3)", "2.606", "(3)", "D—H", "A", "174", "(3)", "178", "(3)", "144", "(3)", "163", "(4)", "Symmetry", "codes:", "(i)", "x", "þ", "1;", "y;", "z;", "(ii)", "x", "1;", "y;", "z;", "(iii)", "x;", "y", "þ", "12;", "z", "þ", "1.", "Data", "collection:", "SMART", "(Bruker,", "1998);", "cell", "refinement:", "SAINT-", "Plus", "(Bruker,", "2001);", "data", "reduction:", "SAINT-Plus;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXTL", "(Bruker,", "2000);", "molecular", "graphics:", "SHELXTL;", "software", "used", "to", "prepare", "material", "for", "publication:", "SHELXTL.", "The", "purchase", "of", "the", "diffractometer", "was", "made", "possible", "through", "support", "from", "the", "Research", "Council", "of", "Norway", "(NFR).", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "PV2058).", "References", "Allen,", "F.", "H.", "(2002).", "Acta", "Cryst.", "B58,", "380–388.", "Bruker", "(1998).", "SMART.", "Version", "5.054.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Bruker", "(2000).", "SHELXTL.", "Version", "6.10.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Bruker", "(2001).", "SAINT-Plus.", "Version", "6.22.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Go¨", "rbitz,", "C.", "H.", "(1987).", "Acta", "Chem.", "Scand.", "B,", "41,", "83–86.", "Go¨", "rbitz,", "C.", "H.", "&", "Hartviksen,", "L.", "M.", "(2006).", "Acta", "Cryst.", "E62,", "o2358–o2360.", "Go¨", "rbitz,", "C.", "H.", "&", "Hersleth,", "H.-P.", "(2000).", "Acta", "Cryst.", "B56,", "1094–1102.", "Grant,", "G.", "D.,", "Hunt,", "A.", "L.,", "Milne,", "P.", "J.,", "Roos,", "H.", "M.", "&", "Joubert,", "J.", "A.", "(1999).", "J.", "Chem.", "Crystallogr.", "29,", "435–447.", "Lin,", "C.-F.", "&", "Webb,", "L.", "E.", "(1973).", "J.", "Am.", "Chem.", "Soc.", "95,", "6803–6811.", "Luo,", "T.-J.", "M.", "&", "Palmore,", "G.", "T.", "R.", "(2002).", "Cryst.", "Growth", "Des.", "2,", "337–350.", "Morris,", "A.", "J.,", "Geddes,", "A.", "J.", "&", "Sheldrick,", "B.", "(1974).", "Cryst.", "Struct.", "Commun.", "3,", "345–349.", "Razak,", "I.", "A.,", "Shanmuga", "Sundara", "Raj,", "S.,", "Fun,", "H.-K.,", "Chen,", "Z.-F.,", "Zhang,", "J.,", "Xiong,", "R.-G.", "&", "You,", "X.-Z.", "(2000).", "Acta", "Cryst.", "C56,", "e341–e342.", "Sheldrick,", "G.", "M.", "(1996).", "SADABS.", "University", "of", "Go¨", "ttingen,", "Germany.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Suguna,", "K.,", "Ramakumar,", "S.", "&", "Kopple,", "K.", "D.", "(1984).", "Acta", "Cryst.", "C40,", "2053–", "2056.", "o436", "G", "o¨rbitz", "and", "Hartviksen", "doi:10.1107/S1600536808000640", "Acta", "Cryst.", "(2008).", "E64,", "o436" ]

[ 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 11, 11, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 4, 9, 9, 9, 9, 0, 7, 7, 7, 7, 7 ]

[ [ 78, 45, 49, 12 ], [ 129, 45, 9, 12 ], [ 139, 45, 11, 12 ], [ 152, 45, 21, 12 ], [ 175, 45, 27, 12 ], [ 204, 45, 30, 12 ], [ 236, 45, 26, 12 ], [ 264, 45, 26, 12 ], [ 78, 59, 231, 12 ], [ 82, 127, 13, 18 ], [ 97, 127, 10, 18 ], [ 108, 127, 11, 18 ], [ 121, 127, 12, 18 ], [ 134, 127, 10, 18 ], [ 146, 127, 10, 18 ], [ 645, 126, 44, 19 ], [ 692, 126, 54, 19 ], [ 78, 160, 148, 34 ], [ 232, 160, 84, 34 ], [ 322, 160, 99, 34 ], [ 427, 160, 16, 34 ], [ 449, 160, 84, 34 ], [ 539, 160, 126, 34 ], [ 78, 213, 40, 16 ], [ 121, 213, 69, 16 ], [ 193, 213, 27, 16 ], [ 223, 213, 30, 16 ], [ 255, 213, 23, 16 ], [ 281, 213, 32, 16 ], [ 316, 213, 46, 16 ], [ 86, 286, 55, 15 ], [ 86, 306, 76, 14 ], [ 165, 306, 41, 14 ], [ 209, 306, 22, 14 ], [ 233, 306, 58, 14 ], [ 294, 306, 35, 14 ], [ 331, 306, 51, 14 ], [ 385, 306, 14, 14 ], [ 402, 306, 85, 14 ], [ 490, 306, 76, 14 ], [ 568, 306, 40, 14 ], [ 610, 306, 15, 14 ], [ 628, 306, 38, 14 ], [ 668, 306, 38, 14 ], [ 86, 323, 56, 14 ], [ 145, 323, 50, 14 ], [ 198, 323, 28, 14 ], [ 228, 323, 22, 14 ], [ 252, 323, 30, 14 ], [ 285, 323, 22, 14 ], [ 310, 323, 37, 14 ], [ 350, 323, 50, 14 ], [ 402, 323, 23, 14 ], [ 427, 323, 32, 14 ], [ 462, 323, 36, 14 ], [ 500, 323, 41, 14 ], [ 544, 323, 57, 14 ], [ 604, 323, 66, 14 ], [ 672, 323, 50, 14 ], [ 86, 340, 28, 14 ], [ 117, 340, 22, 14 ], [ 141, 340, 30, 14 ], [ 174, 340, 16, 14 ], [ 192, 340, 54, 14 ], [ 248, 340, 76, 14 ], [ 326, 340, 25, 14 ], [ 354, 340, 21, 14 ], [ 378, 340, 40, 14 ], [ 420, 340, 58, 14 ], [ 480, 340, 7, 14 ], [ 489, 340, 41, 14 ], [ 533, 340, 11, 14 ], [ 546, 340, 36, 14 ], [ 585, 340, 41, 14 ], [ 628, 340, 15, 14 ], [ 646, 340, 19, 14 ], [ 667, 340, 37, 14 ], [ 707, 340, 27, 14 ], [ 86, 356, 28, 14 ], [ 117, 356, 12, 14 ], [ 131, 356, 28, 14 ], [ 162, 356, 37, 14 ], [ 201, 356, 21, 14 ], [ 225, 356, 19, 14 ], [ 247, 356, 50, 14 ], [ 299, 356, 11, 14 ], [ 313, 356, 19, 14 ], [ 335, 356, 79, 14 ], [ 416, 356, 9, 14 ], [ 428, 356, 23, 14 ], [ 453, 356, 36, 14 ], [ 491, 356, 38, 14 ], [ 532, 356, 27, 14 ], [ 562, 356, 57, 14 ], [ 622, 356, 44, 14 ], [ 669, 356, 14, 14 ], [ 685, 356, 33, 14 ], [ 86, 373, 24, 14 ], [ 113, 373, 25, 14 ], [ 141, 373, 19, 14 ], [ 162, 373, 24, 14 ], [ 189, 373, 49, 14 ], [ 240, 373, 22, 14 ], [ 265, 373, 64, 14 ], [ 332, 373, 19, 14 ], [ 354, 373, 29, 14 ], [ 385, 373, 66, 14 ], [ 86, 394, 68, 14 ], [ 156, 394, 9, 14 ], [ 167, 394, 33, 14 ], [ 202, 394, 89, 14 ], [ 293, 394, 48, 14 ], [ 344, 394, 11, 14 ], [ 358, 394, 19, 14 ], [ 379, 394, 76, 14 ], [ 457, 394, 9, 14 ], [ 468, 394, 19, 14 ], [ 489, 394, 20, 14 ], [ 511, 394, 11, 14 ], [ 525, 394, 25, 14 ], [ 553, 394, 51, 14 ], [ 606, 394, 11, 14 ], [ 620, 394, 47, 14 ], [ 669, 394, 54, 14 ], [ 726, 394, 11, 14 ], [ 86, 410, 47, 14 ], [ 136, 410, 33, 14 ], [ 172, 410, 15, 14 ], [ 190, 410, 47, 14 ], [ 239, 410, 67, 14 ], [ 309, 410, 22, 14 ], [ 333, 410, 25, 14 ], [ 361, 410, 47, 14 ], [ 411, 410, 50, 14 ], [ 464, 410, 12, 14 ], [ 478, 410, 38, 14 ], [ 518, 410, 45, 14 ], [ 566, 410, 73, 14 ], [ 641, 410, 19, 14 ], [ 662, 410, 36, 14 ], [ 701, 410, 11, 14 ], [ 86, 427, 40, 14 ], [ 129, 427, 64, 14 ], [ 195, 427, 38, 14 ], [ 236, 427, 43, 14 ], [ 281, 427, 17, 14 ], [ 301, 427, 57, 14 ], [ 361, 427, 37, 14 ], [ 400, 427, 19, 14 ], [ 422, 427, 14, 14 ], [ 439, 427, 50, 14 ], [ 492, 427, 38, 14 ], [ 533, 427, 11, 14 ], [ 547, 427, 61, 14 ], [ 610, 427, 11, 14 ], [ 624, 427, 29, 14 ], [ 655, 427, 40, 14 ], [ 697, 427, 15, 14 ], [ 86, 444, 40, 14 ], [ 129, 444, 38, 14 ], [ 170, 444, 79, 14 ], [ 251, 444, 19, 14 ], [ 272, 444, 67, 14 ], [ 342, 444, 34, 14 ], [ 378, 444, 31, 14 ], [ 411, 444, 17, 14 ], [ 431, 444, 70, 14 ], [ 504, 444, 43, 14 ], [ 550, 444, 22, 14 ], [ 574, 444, 19, 14 ], [ 595, 444, 31, 14 ], [ 629, 444, 66, 14 ], [ 697, 444, 17, 14 ], [ 717, 444, 20, 14 ], [ 86, 460, 7, 14 ], [ 96, 460, 80, 14 ], [ 178, 460, 62, 14 ], [ 242, 460, 43, 14 ], [ 287, 460, 21, 14 ], [ 310, 460, 55, 14 ], [ 367, 460, 11, 14 ], [ 381, 460, 51, 14 ], [ 434, 460, 38, 14 ], [ 474, 460, 19, 14 ], [ 495, 460, 53, 14 ], [ 551, 460, 11, 14 ], [ 564, 460, 56, 14 ], [ 623, 460, 26, 14 ], [ 651, 460, 62, 14 ], [ 716, 460, 21, 14 ], [ 86, 477, 72, 14 ], [ 161, 477, 11, 14 ], [ 175, 477, 52, 14 ], [ 229, 477, 19, 14 ], [ 250, 477, 38, 14 ], [ 291, 477, 15, 14 ], [ 309, 477, 28, 14 ], [ 339, 477, 71, 14 ], [ 413, 477, 51, 14 ], [ 466, 477, 45, 14 ], [ 514, 477, 23, 14 ], [ 540, 477, 52, 14 ], [ 594, 477, 90, 14 ], [ 686, 477, 40, 14 ], [ 86, 494, 22, 14 ], [ 111, 494, 19, 14 ], [ 132, 494, 55, 14 ], [ 190, 494, 11, 14 ], [ 204, 494, 55, 14 ], [ 261, 494, 27, 14 ], [ 86, 515, 62, 14 ], [ 151, 515, 40, 14 ], [ 193, 515, 79, 14 ], [ 275, 515, 12, 14 ], [ 290, 515, 36, 14 ], [ 328, 515, 33, 14 ], [ 363, 515, 25, 14 ], [ 391, 515, 30, 14 ], [ 424, 515, 7, 14 ], [ 433, 515, 35, 14 ], [ 471, 515, 60, 14 ], [ 534, 515, 33, 14 ], [ 569, 515, 22, 14 ], [ 594, 515, 61, 14 ], [ 658, 515, 38, 14 ], [ 699, 515, 15, 14 ], [ 86, 531, 63, 14 ], [ 152, 531, 25, 14 ], [ 180, 531, 45, 14 ], [ 227, 531, 21, 14 ], [ 250, 531, 49, 14 ], [ 302, 531, 40, 14 ], [ 345, 531, 17, 14 ], [ 364, 531, 12, 14 ], [ 379, 531, 29, 14 ], [ 410, 531, 79, 14 ], [ 492, 531, 22, 14 ], [ 516, 531, 12, 14 ], [ 531, 531, 73, 14 ], [ 607, 531, 38, 14 ], [ 648, 531, 45, 14 ], [ 86, 548, 51, 14 ], [ 140, 548, 47, 14 ], [ 190, 548, 31, 14 ], [ 223, 548, 43, 14 ], [ 269, 548, 22, 14 ], [ 293, 548, 47, 14 ], [ 343, 548, 89, 14 ], [ 434, 548, 56, 14 ], [ 493, 548, 98, 14 ], [ 594, 548, 65, 14 ], [ 662, 548, 40, 14 ], [ 704, 548, 17, 14 ], [ 86, 565, 43, 14 ], [ 132, 565, 12, 14 ], [ 147, 565, 61, 14 ], [ 210, 565, 39, 14 ], [ 252, 565, 36, 14 ], [ 290, 565, 11, 14 ], [ 304, 565, 28, 14 ], [ 334, 565, 71, 14 ], [ 408, 565, 53, 14 ], [ 78, 600, 78, 15 ], [ 78, 619, 51, 14 ], [ 132, 619, 12, 14 ], [ 147, 619, 36, 14 ], [ 186, 619, 33, 14 ], [ 222, 619, 25, 14 ], [ 250, 619, 42, 14 ], [ 295, 619, 7, 14 ], [ 305, 619, 35, 14 ], [ 343, 619, 61, 14 ], [ 78, 635, 31, 14 ], [ 115, 635, 20, 14 ], [ 141, 635, 19, 14 ], [ 166, 635, 38, 14 ], [ 210, 635, 18, 14 ], [ 234, 635, 74, 14 ], [ 315, 635, 18, 14 ], [ 338, 635, 47, 14 ], [ 392, 635, 12, 14 ], [ 78, 652, 28, 14 ], [ 109, 652, 73, 14 ], [ 186, 652, 53, 14 ], [ 242, 652, 21, 14 ], [ 266, 652, 88, 14 ], [ 357, 652, 22, 14 ], [ 382, 652, 22, 14 ], [ 78, 669, 37, 14 ], [ 119, 669, 38, 14 ], [ 160, 669, 27, 14 ], [ 191, 669, 19, 14 ], [ 213, 669, 50, 14 ], [ 266, 669, 12, 14 ], [ 281, 669, 51, 14 ], [ 336, 669, 21, 14 ], [ 361, 669, 43, 14 ], [ 78, 685, 27, 14 ], [ 112, 685, 15, 14 ], [ 133, 685, 53, 14 ], [ 192, 685, 38, 14 ], [ 236, 685, 36, 14 ], [ 279, 685, 18, 14 ], [ 303, 685, 40, 14 ], [ 349, 685, 33, 14 ], [ 388, 685, 15, 14 ], [ 78, 702, 100, 14 ], [ 185, 702, 38, 14 ], [ 230, 702, 53, 14 ], [ 290, 702, 26, 14 ], [ 323, 702, 29, 14 ], [ 359, 702, 44, 14 ], [ 78, 719, 23, 14 ], [ 105, 719, 83, 14 ], [ 192, 719, 25, 14 ], [ 220, 719, 28, 14 ], [ 252, 719, 42, 14 ], [ 298, 719, 40, 14 ], [ 342, 719, 28, 14 ], [ 374, 719, 29, 14 ], [ 78, 735, 16, 14 ], [ 96, 735, 78, 14 ], [ 177, 735, 12, 14 ], [ 191, 735, 33, 14 ], [ 227, 735, 12, 14 ], [ 242, 735, 50, 14 ], [ 295, 735, 22, 14 ], [ 319, 735, 42, 14 ], [ 89, 752, 44, 14 ], [ 139, 752, 11, 14 ], [ 156, 752, 13, 14 ], [ 175, 752, 16, 14 ], [ 197, 752, 52, 14 ], [ 254, 752, 40, 14 ], [ 300, 752, 15, 14 ], [ 321, 752, 40, 14 ], [ 367, 752, 36, 14 ], [ 78, 769, 42, 14 ], [ 124, 769, 70, 14 ], [ 198, 769, 28, 14 ], [ 229, 769, 51, 14 ], [ 284, 769, 8, 14 ], [ 296, 769, 25, 14 ], [ 324, 769, 50, 14 ], [ 378, 769, 26, 14 ], [ 78, 785, 28, 14 ], [ 113, 785, 45, 14 ], [ 165, 785, 43, 14 ], [ 215, 785, 13, 14 ], [ 235, 785, 31, 14 ], [ 273, 785, 46, 14 ], [ 326, 785, 17, 14 ], [ 350, 785, 54, 14 ], [ 78, 802, 46, 14 ], [ 128, 802, 13, 14 ], [ 144, 802, 30, 14 ], [ 179, 802, 39, 14 ], [ 221, 802, 72, 14 ], [ 296, 802, 76, 14 ], [ 376, 802, 27, 14 ], [ 78, 819, 48, 14 ], [ 130, 819, 28, 14 ], [ 161, 819, 51, 14 ], [ 215, 819, 8, 14 ], [ 226, 819, 25, 14 ], [ 255, 819, 50, 14 ], [ 308, 819, 26, 14 ], [ 337, 819, 46, 14 ], [ 387, 819, 17, 14 ], [ 78, 835, 34, 14 ], [ 115, 835, 26, 14 ], [ 145, 835, 13, 14 ], [ 161, 835, 21, 14 ], [ 185, 835, 36, 14 ], [ 225, 835, 33, 14 ], [ 261, 835, 21, 14 ], [ 286, 835, 8, 14 ], [ 298, 835, 51, 14 ], [ 352, 835, 12, 14 ], [ 367, 835, 36, 14 ], [ 78, 852, 25, 14 ], [ 107, 852, 21, 14 ], [ 133, 852, 28, 14 ], [ 166, 852, 61, 14 ], [ 231, 852, 26, 14 ], [ 261, 852, 70, 14 ], [ 335, 852, 54, 14 ], [ 393, 852, 10, 14 ], [ 78, 869, 26, 14 ], [ 111, 869, 12, 14 ], [ 128, 869, 14, 14 ], [ 148, 869, 40, 14 ], [ 195, 869, 20, 14 ], [ 220, 869, 28, 14 ], [ 254, 869, 50, 14 ], [ 310, 869, 49, 14 ], [ 365, 869, 38, 14 ], [ 78, 885, 56, 14 ], [ 137, 885, 48, 14 ], [ 188, 885, 28, 14 ], [ 219, 885, 22, 14 ], [ 243, 885, 28, 14 ], [ 274, 885, 45, 14 ], [ 322, 885, 20, 14 ], [ 345, 885, 58, 14 ], [ 78, 902, 20, 14 ], [ 102, 902, 63, 14 ], [ 169, 902, 23, 14 ], [ 195, 902, 25, 14 ], [ 224, 902, 28, 14 ], [ 255, 902, 50, 14 ], [ 309, 902, 14, 14 ], [ 326, 902, 33, 14 ], [ 363, 902, 40, 14 ], [ 78, 934, 4, 10 ], [ 84, 934, 67, 10 ], [ 153, 934, 123, 10 ], [ 78, 948, 38, 11 ], [ 118, 948, 9, 11 ], [ 129, 948, 33, 11 ], [ 164, 948, 50, 11 ], [ 216, 948, 58, 11 ], [ 276, 948, 16, 11 ], [ 294, 948, 48, 11 ], [ 344, 948, 41, 11 ], [ 78, 965, 33, 11 ], [ 113, 965, 28, 11 ], [ 143, 965, 9, 11 ], [ 154, 965, 14, 11 ], [ 170, 965, 40, 11 ], [ 212, 965, 46, 11 ], [ 259, 965, 43, 11 ], [ 304, 965, 25, 11 ], [ 423, 610, 24, 14 ], [ 450, 610, 12, 14 ], [ 465, 610, 35, 14 ], [ 503, 610, 19, 14 ], [ 524, 610, 38, 14 ], [ 566, 610, 12, 14 ], [ 580, 610, 27, 14 ], [ 610, 610, 31, 14 ], [ 644, 610, 22, 14 ], [ 669, 610, 61, 14 ], [ 733, 610, 15, 14 ], [ 423, 626, 19, 14 ], [ 445, 626, 45, 14 ], [ 494, 626, 12, 14 ], [ 510, 626, 26, 14 ], [ 539, 626, 50, 14 ], [ 593, 626, 12, 14 ], [ 608, 626, 19, 14 ], [ 631, 626, 34, 14 ], [ 668, 626, 23, 14 ], [ 695, 626, 38, 14 ], [ 736, 626, 12, 14 ], [ 423, 643, 21, 14 ], [ 452, 643, 78, 14 ], [ 538, 643, 46, 14 ], [ 592, 643, 23, 14 ], [ 623, 643, 32, 14 ], [ 663, 643, 36, 14 ], [ 707, 643, 41, 14 ], [ 423, 660, 57, 14 ], [ 484, 660, 28, 14 ], [ 517, 660, 21, 14 ], [ 542, 660, 9, 14 ], [ 555, 659, 39, 15 ], [ 598, 660, 12, 14 ], [ 614, 660, 28, 14 ], [ 646, 660, 12, 14 ], [ 662, 660, 14, 14 ], [ 680, 660, 9, 14 ], [ 693, 659, 39, 15 ], [ 736, 660, 12, 14 ], [ 423, 677, 31, 14 ], [ 456, 677, 22, 14 ], [ 481, 677, 45, 14 ], [ 528, 677, 42, 14 ], [ 573, 677, 57, 14 ], [ 633, 677, 28, 14 ], [ 664, 677, 24, 14 ], [ 691, 677, 15, 14 ], [ 709, 677, 12, 14 ], [ 724, 677, 24, 14 ], [ 423, 694, 15, 14 ], [ 442, 694, 38, 14 ], [ 483, 694, 19, 14 ], [ 505, 694, 30, 14 ], [ 539, 694, 41, 14 ], [ 583, 694, 35, 14 ], [ 621, 694, 38, 14 ], [ 663, 694, 39, 14 ], [ 706, 694, 42, 14 ], [ 423, 710, 35, 14 ], [ 462, 710, 55, 14 ], [ 521, 710, 31, 14 ], [ 556, 710, 11, 14 ], [ 571, 710, 13, 14 ], [ 589, 710, 16, 14 ], [ 609, 710, 51, 14 ], [ 664, 710, 28, 14 ], [ 697, 710, 51, 14 ], [ 423, 727, 78, 14 ], [ 508, 727, 30, 14 ], [ 546, 727, 125, 14 ], [ 679, 727, 40, 14 ], [ 726, 727, 22, 14 ], [ 423, 744, 22, 14 ], [ 449, 744, 40, 14 ], [ 492, 744, 23, 14 ], [ 519, 744, 50, 14 ], [ 573, 744, 26, 14 ], [ 603, 744, 25, 14 ], [ 631, 744, 57, 14 ], [ 692, 744, 25, 14 ], [ 721, 744, 27, 14 ], [ 423, 760, 14, 14 ], [ 440, 760, 53, 14 ], [ 496, 760, 29, 14 ], [ 528, 760, 18, 14 ], [ 549, 760, 13, 14 ], [ 565, 760, 30, 14 ], [ 597, 760, 14, 14 ], [ 614, 760, 40, 14 ], [ 657, 760, 28, 14 ], [ 687, 760, 61, 14 ], [ 423, 777, 49, 14 ], [ 476, 777, 38, 14 ], [ 519, 777, 56, 14 ], [ 579, 777, 48, 14 ], [ 632, 777, 28, 14 ], [ 664, 777, 22, 14 ], [ 690, 777, 31, 14 ], [ 725, 777, 23, 14 ], [ 423, 794, 52, 14 ], [ 478, 794, 50, 14 ], [ 531, 794, 12, 14 ], [ 546, 794, 36, 14 ], [ 585, 794, 39, 14 ], [ 627, 794, 22, 14 ], [ 652, 794, 63, 14 ], [ 718, 794, 13, 14 ], [ 734, 794, 14, 14 ], [ 423, 810, 52, 14 ], [ 478, 810, 45, 14 ], [ 525, 810, 16, 14 ], [ 544, 810, 40, 14 ], [ 586, 810, 56, 14 ], [ 645, 810, 48, 14 ], [ 696, 810, 28, 14 ], [ 726, 810, 22, 14 ], [ 423, 827, 28, 14 ], [ 455, 827, 28, 14 ], [ 487, 827, 63, 14 ], [ 554, 827, 35, 14 ], [ 593, 827, 29, 14 ], [ 626, 827, 19, 14 ], [ 649, 827, 53, 14 ], [ 706, 827, 42, 14 ], [ 423, 844, 12, 14 ], [ 438, 844, 44, 14 ], [ 486, 844, 11, 14 ], [ 502, 844, 13, 14 ], [ 519, 844, 19, 14 ], [ 542, 844, 13, 14 ], [ 559, 844, 26, 14 ], [ 589, 844, 14, 14 ], [ 607, 844, 24, 14 ], [ 635, 844, 40, 14 ], [ 679, 844, 28, 14 ], [ 711, 844, 37, 14 ], [ 423, 860, 77, 14 ], [ 503, 860, 19, 14 ], [ 525, 860, 44, 14 ], [ 572, 860, 60, 14 ], [ 636, 860, 7, 14 ], [ 646, 860, 41, 14 ], [ 691, 860, 37, 14 ], [ 731, 860, 17, 14 ], [ 423, 877, 19, 14 ], [ 444, 877, 43, 14 ], [ 490, 877, 38, 14 ], [ 530, 877, 60, 14 ], [ 592, 877, 22, 14 ], [ 617, 877, 55, 14 ], [ 674, 877, 14, 14 ], [ 690, 877, 58, 14 ], [ 423, 894, 41, 14 ], [ 469, 894, 44, 14 ], [ 518, 894, 25, 14 ], [ 548, 894, 40, 14 ], [ 594, 894, 26, 14 ], [ 625, 894, 21, 14 ], [ 651, 894, 26, 14 ], [ 682, 894, 14, 14 ], [ 702, 894, 46, 14 ], [ 423, 910, 28, 14 ], [ 454, 910, 51, 14 ], [ 508, 910, 28, 14 ], [ 539, 910, 19, 14 ], [ 561, 910, 44, 14 ], [ 609, 910, 44, 14 ], [ 656, 910, 44, 14 ], [ 703, 910, 13, 14 ], [ 719, 910, 30, 14 ], [ 423, 927, 21, 14 ], [ 448, 927, 40, 14 ], [ 492, 927, 27, 14 ], [ 524, 927, 52, 14 ], [ 581, 927, 59, 14 ], [ 645, 927, 12, 14 ], [ 661, 927, 31, 14 ], [ 696, 927, 11, 14 ], [ 712, 927, 13, 14 ], [ 730, 927, 19, 14 ], [ 423, 944, 52, 14 ], [ 482, 944, 78, 14 ], [ 566, 944, 59, 14 ], [ 632, 944, 7, 14 ], [ 645, 944, 41, 14 ], [ 693, 944, 12, 14 ], [ 712, 944, 36, 14 ], [ 423, 960, 41, 14 ], [ 468, 960, 17, 14 ], [ 488, 960, 19, 14 ], [ 510, 960, 38, 14 ], [ 552, 960, 28, 14 ], [ 584, 960, 28, 14 ], [ 615, 960, 12, 14 ], [ 631, 960, 28, 14 ], [ 662, 960, 19, 14 ], [ 685, 960, 23, 14 ], [ 712, 960, 36, 14 ], [ 236, 988, 7, 10 ], [ 244, 988, 19, 10 ], [ 265, 988, 41, 10 ], [ 308, 988, 8, 10 ], [ 318, 988, 9, 10 ], [ 329, 988, 32, 10 ], [ 362, 988, 30, 10 ], [ 394, 988, 28, 10 ], [ 424, 988, 15, 10 ], [ 440, 988, 16, 10 ], [ 458, 988, 6, 10 ], [ 466, 988, 10, 10 ], [ 478, 988, 22, 10 ], [ 502, 988, 26, 10 ], [ 530, 988, 24, 10 ], [ 556, 988, 43, 10 ], [ 601, 988, 24, 10 ], [ 626, 988, 13, 10 ], [ 641, 988, 23, 10 ], [ 665, 988, 8, 10 ], [ 675, 988, 13, 10 ], [ 690, 988, 32, 10 ], [ 725, 988, 21, 10 ], [ 236, 999, 22, 10 ], [ 260, 999, 43, 10 ], [ 305, 999, 29, 10 ], [ 336, 999, 177, 10 ], [ 515, 999, 24, 10 ], [ 541, 999, 30, 10 ], [ 573, 999, 47, 10 ], [ 623, 999, 16, 10 ], [ 640, 999, 47, 10 ], [ 690, 999, 15, 10 ], [ 707, 999, 39, 10 ], [ 236, 1010, 16, 10 ], [ 253, 1010, 8, 10 ], [ 262, 1010, 15, 10 ], [ 278, 1010, 35, 10 ], [ 314, 1010, 35, 10 ], [ 351, 1010, 13, 10 ], [ 366, 1010, 30, 10 ], [ 397, 1010, 20, 10 ], [ 418, 1010, 6, 10 ], [ 426, 1010, 33, 10 ], [ 461, 1010, 21, 10 ] ]

[ "Merzenich", "et", "al:", "BMC", "Public", "Health", "2010,", "10:24", "http://www.biomedcentral.com/1471-2458/10/24", "D", "E", "B", "A", "T", "E", "Open", "Access", "DDebeatcereasing", "sperm", "quality:", "a", "global", "problem?", "Hiltrud", "Merzenich*,", "Hajo", "Zeeb", "and", "Maria", "Blettner", "Abstract", "Background:", "Carlsen", "and", "coworkers", "(1992)", "reviewed", "61", "heterogeneous", "observational", "studies", "on", "semen", "quality", "published", "between", "1938", "and", "1990.", "This", "review", "indicates", "that", "mean", "sperm", "density", "decreased", "significantly", "between", "1940", "and", "1990.", "An", "extended", "meta-analysis", "with", "101", "studies", "confirmed", "a", "decline", "in", "sperm", "density", "for", "the", "period", "from", "1934", "to", "1996", "(2000).", "The", "key", "message", "of", "the", "meta-analyses", "is", "that", "sperm", "counts", "have", "decreased", "globally", "by", "about", "50%", "over", "the", "past", "decades.", "This", "assessment", "has", "been", "questioned.", "Discussion:", "A", "major", "methodological", "problem", "of", "the", "meta-analysis", "is", "the", "use", "of", "data", "collected", "in", "different", "countries,", "at", "different", "times,", "on", "different", "populations", "and", "with", "different", "methods", "of", "semen", "analysis.", "Furthermore,", "the", "results", "of", "studies", "concerning", "semen", "analysis", "are", "frequently", "biased", "e.g.", "by", "selection", "criteria", "of", "volunteers.", "In", "most", "studies", "on", "human", "semen", "characteristics", "the", "populations", "under", "study", "are", "insufficiently", "defined", "and", "the", "study", "participants", "are", "not", "a", "representative", "population", "sample.", "The", "incidence", "of", "testicular", "cancer", "has", "increased", "in", "Caucasian", "men", "worldwide.", "The", "investigation", "of", "common", "risk", "factors", "for", "male", "reproductive", "disorders", "requires", "well", "designed", "epidemiological", "studies", "and", "the", "collection", "of", "individual", "data.", "Summary:", "Former", "meta-analyses", "of", "sperm", "count", "data", "show", "a", "global", "downward", "trend.", "This", "conclusion", "should", "be", "interpreted", "with", "caution.", "The", "included", "studies", "are", "of", "great", "heterogeneity", "due", "to", "geographical", "and/or", "ethnical", "variation,", "different", "study", "designs", "and", "different", "methodological", "standards.", "Population-based", "prospective", "studies", "are", "needed", "to", "investigate", "secular", "trends", "in", "male", "reproductive", "disorders.", "Background", "Analyses", "of", "sperm", "count", "data", "suggest", "a", "global", "downward", "trend", "but", "the", "results", "are", "inconclusive.", "An", "increase", "in", "male", "reproductive", "disorders", "like", "cryptorchidism", "and", "tes-", "ticular", "cancer", "raise", "the", "question", "of", "common", "risk", "factors.", "Data", "on", "testicular", "cancer", "trends", "are", "usually", "based", "on", "population-based", "cancer", "registries", "with", "good", "validity.", "The", "corresponding", "data", "from", "fertility", "studies", "need", "care-", "ful", "consideration", "in", "terms", "of", "methods", "and", "results.", "Carlsen", "et", "al.", "[1]", "reviewed", "studies", "on", "human", "sperm", "quality.", "Publications", "were", "excluded", "if", "they", "included", "men", "from", "infertile", "couples", "or", "those", "referred", "for", "oligozoo-", "spermia", "or", "some", "genital", "abnormality.", "Furthermore,", "pub-", "lications", "were", "excluded", "if", "they", "included", "men", "selected", "for", "either", "high", "or", "low", "sperm", "count", "and", "if", "counting", "of", "sperm", "cells", "had", "been", "performed", "with", "non-manual", "methods.", "A", "total", "of", "61", "studies", "has", "been", "included", "covering", "results", "published", "between", "1938", "and", "1990", "without", "any", "geograph-", "ical", "restriction.", "The", "data", "were", "analyzed", "by", "linear", "regres-", "*", "Correspondence:", "merzenich@imbei.uni-mainz.de", "1Institute", "of", "Medical", "Biostatistics,", "Epidemiology", "and", "Informatics,", "University", "Medical", "Center", "of", "the", "Johannes", "Gutenberg", "University,", "Mainz", "sion", "in", "which", "the", "weight", "of", "each", "study", "was", "dependent", "on", "the", "number", "of", "men", "included", "in", "the", "study.", "The", "results", "of", "this", "meta-analysis", "indicate", "that", "mean", "sperm", "density", "decreased", "from", "113", "×", "106/ml", "in", "1940", "to", "66", "×", "106/ml", "in", "1990,", "and", "seminal", "volume", "decreased", "from", "3.40", "ml", "to", "2.75", "ml", "during", "the", "same", "period.", "These", "results", "caused", "consid-", "erable", "attention.", "Swan", "et", "al.", "[2]", "excluded", "from", "Carlsens'", "meta-analysis", "three", "non-English-language", "studies", "and", "two", "studies", "that", "included", "men", "who", "conceived", "only", "after", "an", "infertility", "work", "up.", "In", "total,", "56", "studies", "were", "reanalysed", "covering", "results", "published", "between", "1938", "and", "1990.", "The", "observed", "decrease", "in", "sperm", "quality", "was", "confirmed.", "In", "an", "extended", "analysis", "[3]", "studies", "published", "between", "1934", "and", "1996", "were", "considered", "which", "meet", "the", "eligibility", "criteria", "of", "Carlsen", "et", "al.", "[1].", "In", "total", "19", "new", "studies", "were", "found.", "Furthermore,", "the", "authors", "conducted", "a", "further", "search", "for", "the", "60-year", "period", "1930-1990", "and", "identified", "28", "additional", "eligible", "studies.", "Two", "studies", "with", "less", "than", "10", "subjects", "were", "excluded", "from", "the", "original", "Carlsen", "studies.", "In", "total,", "101", "studies", "were", "analysed.", "According", "to", "Swan", "et", "al.", "the", "extended", "meta-analysis", "supported", "a", "decline", "in", "sperm", "density", "for", "the", "period", "from", "1934", "to", "1996", "[3].", "The", "sperm", "©", "2010", "Merzenich", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Com-", "mons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduc-", "tion", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 575, 45, 82, 21 ], [ 662, 45, 102, 21 ], [ 534, 88, 23, 12 ], [ 559, 88, 55, 12 ], [ 616, 88, 52, 12 ], [ 670, 88, 12, 12 ], [ 685, 88, 18, 12 ], [ 705, 88, 33, 12 ], [ 740, 88, 24, 12 ], [ 655, 101, 109, 12 ], [ 100, 148, 204, 14 ], [ 307, 148, 82, 14 ], [ 72, 206, 86, 19 ], [ 162, 206, 56, 19 ], [ 222, 206, 16, 19 ], [ 243, 206, 39, 19 ], [ 286, 206, 20, 19 ], [ 310, 206, 25, 19 ], [ 340, 206, 106, 19 ], [ 450, 206, 16, 19 ], [ 470, 206, 259, 19 ], [ 72, 228, 140, 19 ], [ 216, 228, 86, 19 ], [ 306, 228, 64, 19 ], [ 375, 228, 16, 19 ], [ 395, 228, 37, 19 ], [ 134, 270, 43, 16 ], [ 179, 270, 39, 17 ], [ 222, 270, 47, 16 ], [ 272, 270, 51, 17 ], [ 327, 270, 37, 16 ], [ 367, 270, 41, 17 ], [ 412, 270, 26, 16 ], [ 441, 270, 45, 16 ], [ 490, 270, 45, 17 ], [ 134, 297, 60, 14 ], [ 196, 299, 10, 12 ], [ 209, 299, 30, 12 ], [ 241, 299, 44, 12 ], [ 288, 299, 10, 12 ], [ 300, 299, 33, 12 ], [ 335, 299, 52, 12 ], [ 390, 299, 33, 12 ], [ 425, 299, 10, 12 ], [ 437, 299, 31, 12 ], [ 471, 299, 35, 12 ], [ 509, 299, 33, 12 ], [ 544, 299, 53, 12 ], [ 599, 299, 38, 12 ], [ 639, 299, 39, 12 ], [ 681, 299, 29, 12 ], [ 712, 299, 18, 12 ], [ 134, 312, 60, 14 ], [ 196, 313, 10, 12 ], [ 209, 313, 35, 12 ], [ 246, 313, 52, 12 ], [ 301, 313, 50, 12 ], [ 353, 313, 10, 12 ], [ 365, 313, 53, 12 ], [ 420, 313, 80, 12 ], [ 503, 313, 46, 12 ], [ 551, 313, 33, 12 ], [ 586, 313, 10, 12 ], [ 598, 313, 44, 12 ], [ 645, 313, 18, 12 ], [ 666, 313, 62, 12 ], [ 134, 328, 53, 12 ], [ 189, 328, 51, 12 ], [ 242, 328, 29, 12 ], [ 100, 367, 14, 14 ], [ 134, 367, 44, 12 ], [ 180, 367, 43, 12 ], [ 226, 367, 15, 12 ], [ 244, 367, 27, 12 ], [ 274, 367, 42, 12 ], [ 318, 367, 31, 12 ], [ 351, 367, 15, 12 ], [ 369, 367, 27, 12 ], [ 399, 367, 46, 12 ], [ 448, 367, 30, 12 ], [ 480, 367, 22, 12 ], [ 505, 367, 15, 12 ], [ 523, 367, 24, 12 ], [ 100, 420, 57, 15 ], [ 159, 420, 44, 15 ], [ 205, 420, 30, 15 ], [ 241, 420, 34, 14 ], [ 284, 420, 12, 14 ], [ 305, 420, 25, 14 ], [ 339, 420, 16, 14 ], [ 364, 420, 20, 14 ], [ 393, 420, 80, 14 ], [ 482, 420, 12, 14 ], [ 503, 420, 200, 14 ], [ 134, 437, 103, 14 ], [ 244, 437, 62, 14 ], [ 313, 437, 47, 14 ], [ 367, 437, 16, 14 ], [ 390, 437, 42, 14 ], [ 439, 437, 103, 14 ], [ 549, 437, 24, 14 ], [ 580, 437, 44, 14 ], [ 631, 437, 25, 14 ], [ 663, 437, 41, 14 ], [ 134, 454, 30, 14 ], [ 170, 454, 45, 14 ], [ 219, 454, 23, 14 ], [ 248, 454, 8, 14 ], [ 261, 454, 43, 14 ], [ 310, 454, 24, 14 ], [ 339, 454, 34, 14 ], [ 378, 454, 8, 14 ], [ 392, 454, 12, 14 ], [ 409, 454, 8, 14 ], [ 423, 454, 23, 14 ], [ 451, 454, 55, 14 ], [ 512, 454, 17, 14 ], [ 534, 454, 16, 14 ], [ 555, 454, 40, 14 ], [ 601, 454, 15, 14 ], [ 621, 454, 28, 14 ], [ 654, 454, 49, 14 ], [ 134, 470, 37, 14 ], [ 174, 470, 29, 14 ], [ 206, 470, 47, 14 ], [ 257, 470, 41, 14 ], [ 302, 470, 48, 14 ], [ 354, 470, 13, 14 ], [ 370, 470, 20, 14 ], [ 394, 470, 38, 14 ], [ 435, 470, 24, 14 ], [ 463, 470, 25, 14 ], [ 492, 470, 36, 14 ], [ 532, 470, 48, 14 ], [ 584, 470, 8, 14 ], [ 595, 470, 72, 14 ], [ 671, 470, 32, 14 ], [ 134, 487, 59, 14 ], [ 197, 487, 37, 14 ], [ 238, 487, 11, 14 ], [ 253, 487, 36, 14 ], [ 293, 487, 80, 14 ], [ 377, 487, 62, 14 ], [ 443, 487, 25, 14 ], [ 472, 487, 20, 14 ], [ 496, 487, 35, 14 ], [ 534, 487, 36, 14 ], [ 574, 487, 37, 14 ], [ 615, 487, 24, 14 ], [ 643, 487, 25, 14 ], [ 672, 487, 31, 14 ], [ 134, 504, 47, 14 ], [ 185, 504, 12, 14 ], [ 203, 504, 20, 14 ], [ 228, 504, 47, 14 ], [ 280, 504, 41, 14 ], [ 326, 504, 36, 14 ], [ 367, 504, 41, 14 ], [ 414, 504, 35, 14 ], [ 454, 504, 36, 14 ], [ 495, 504, 47, 14 ], [ 548, 504, 20, 14 ], [ 574, 504, 17, 14 ], [ 596, 504, 11, 14 ], [ 612, 504, 20, 14 ], [ 637, 504, 25, 14 ], [ 667, 504, 36, 14 ], [ 134, 520, 25, 14 ], [ 163, 520, 72, 14 ], [ 240, 520, 39, 14 ], [ 283, 520, 28, 14 ], [ 315, 520, 24, 14 ], [ 343, 520, 11, 14 ], [ 358, 520, 20, 14 ], [ 383, 520, 34, 14 ], [ 421, 520, 36, 14 ], [ 462, 520, 64, 15 ], [ 530, 520, 21, 14 ], [ 555, 520, 58, 14 ], [ 617, 520, 20, 14 ], [ 641, 520, 62, 14 ], [ 134, 537, 43, 14 ], [ 182, 537, 23, 14 ], [ 211, 537, 32, 14 ], [ 248, 537, 69, 14 ], [ 323, 537, 38, 14 ], [ 366, 537, 65, 14 ], [ 437, 537, 64, 14 ], [ 506, 537, 89, 14 ], [ 601, 537, 24, 14 ], [ 630, 537, 73, 14 ], [ 134, 554, 39, 14 ], [ 178, 554, 55, 14 ], [ 239, 554, 20, 14 ], [ 265, 554, 47, 14 ], [ 317, 554, 12, 14 ], [ 335, 554, 65, 14 ], [ 405, 554, 60, 14 ], [ 471, 554, 24, 14 ], [ 500, 554, 85, 14 ], [ 591, 554, 25, 14 ], [ 622, 554, 41, 14 ], [ 669, 554, 34, 14 ], [ 134, 570, 43, 14 ], [ 182, 570, 20, 14 ], [ 207, 570, 32, 14 ], [ 245, 570, 47, 14 ], [ 297, 570, 61, 14 ], [ 363, 570, 36, 14 ], [ 405, 570, 25, 14 ], [ 435, 570, 35, 14 ], [ 476, 570, 26, 14 ], [ 508, 570, 11, 14 ], [ 525, 570, 20, 14 ], [ 550, 570, 25, 14 ], [ 580, 570, 24, 14 ], [ 610, 570, 47, 14 ], [ 662, 570, 41, 14 ], [ 134, 587, 47, 14 ], [ 186, 587, 12, 14 ], [ 205, 587, 70, 14 ], [ 281, 587, 21, 14 ], [ 308, 587, 41, 14 ], [ 355, 587, 48, 14 ], [ 410, 587, 24, 14 ], [ 440, 587, 25, 14 ], [ 471, 587, 15, 14 ], [ 492, 587, 24, 14 ], [ 523, 587, 15, 14 ], [ 544, 587, 47, 14 ], [ 597, 587, 41, 14 ], [ 645, 587, 58, 14 ], [ 134, 604, 20, 14 ], [ 159, 604, 80, 14 ], [ 244, 604, 12, 14 ], [ 262, 604, 94, 14 ], [ 361, 604, 62, 14 ], [ 429, 604, 43, 14 ], [ 477, 604, 11, 14 ], [ 494, 604, 17, 14 ], [ 516, 604, 24, 14 ], [ 545, 604, 34, 14 ], [ 585, 604, 16, 14 ], [ 606, 604, 67, 14 ], [ 678, 604, 25, 14 ], [ 134, 620, 20, 14 ], [ 158, 620, 69, 14 ], [ 231, 620, 12, 14 ], [ 248, 620, 107, 14 ], [ 134, 652, 25, 14 ], [ 161, 652, 44, 14 ], [ 210, 652, 59, 14 ], [ 272, 652, 38, 14 ], [ 313, 652, 28, 14 ], [ 344, 652, 44, 14 ], [ 391, 652, 42, 14 ], [ 436, 652, 32, 14 ], [ 471, 652, 69, 14 ], [ 544, 652, 20, 14 ], [ 567, 652, 44, 14 ], [ 614, 652, 47, 14 ], [ 210, 668, 52, 14 ], [ 265, 668, 49, 14 ], [ 72, 731, 11, 16 ], [ 99, 731, 87, 16 ], [ 100, 757, 36, 14 ], [ 138, 757, 37, 14 ], [ 177, 757, 10, 14 ], [ 190, 757, 17, 14 ], [ 209, 757, 28, 14 ], [ 239, 757, 49, 14 ], [ 291, 757, 56, 14 ], [ 349, 757, 57, 14 ], [ 72, 774, 21, 14 ], [ 99, 774, 10, 14 ], [ 115, 774, 17, 14 ], [ 138, 774, 43, 14 ], [ 187, 774, 21, 14 ], [ 213, 774, 31, 14 ], [ 250, 774, 12, 14 ], [ 268, 774, 79, 14 ], [ 353, 774, 36, 14 ], [ 395, 774, 11, 14 ], [ 72, 790, 69, 14 ], [ 145, 790, 41, 14 ], [ 189, 790, 20, 14 ], [ 213, 790, 22, 14 ], [ 238, 790, 54, 14 ], [ 295, 790, 12, 14 ], [ 310, 790, 34, 14 ], [ 347, 790, 37, 14 ], [ 387, 790, 19, 14 ], [ 72, 806, 27, 14 ], [ 102, 806, 58, 14 ], [ 163, 806, 11, 14 ], [ 177, 806, 25, 14 ], [ 205, 806, 58, 14 ], [ 266, 806, 20, 14 ], [ 290, 806, 62, 14 ], [ 355, 806, 51, 14 ], [ 72, 823, 20, 14 ], [ 97, 823, 53, 14 ], [ 154, 823, 90, 14 ], [ 248, 823, 39, 14 ], [ 291, 823, 27, 14 ], [ 322, 823, 54, 14 ], [ 380, 823, 27, 14 ], [ 72, 839, 20, 14 ], [ 96, 839, 21, 14 ], [ 121, 839, 42, 14 ], [ 167, 839, 53, 14 ], [ 223, 839, 44, 14 ], [ 271, 839, 55, 14 ], [ 330, 839, 10, 14 ], [ 344, 839, 35, 14 ], [ 383, 839, 23, 14 ], [ 72, 855, 21, 14 ], [ 98, 855, 21, 14 ], [ 123, 855, 66, 14 ], [ 194, 855, 29, 14 ], [ 227, 855, 38, 14 ], [ 270, 855, 21, 14 ], [ 296, 855, 38, 14 ], [ 339, 855, 29, 14 ], [ 373, 855, 11, 14 ], [ 389, 855, 17, 14 ], [ 72, 872, 31, 14 ], [ 109, 872, 17, 14 ], [ 130, 872, 25, 14 ], [ 160, 872, 7, 14 ], [ 171, 872, 27, 14 ], [ 203, 872, 12, 14 ], [ 220, 872, 17, 14 ], [ 242, 872, 34, 14 ], [ 280, 872, 37, 14 ], [ 322, 872, 30, 14 ], [ 356, 872, 22, 14 ], [ 384, 872, 22, 14 ], [ 72, 888, 53, 14 ], [ 130, 888, 14, 14 ], [ 148, 888, 90, 14 ], [ 242, 888, 45, 14 ], [ 291, 888, 47, 14 ], [ 343, 888, 21, 14 ], [ 369, 888, 17, 14 ], [ 390, 888, 16, 14 ], [ 72, 904, 43, 14 ], [ 119, 904, 12, 14 ], [ 134, 904, 34, 14 ], [ 171, 904, 37, 14 ], [ 211, 904, 11, 14 ], [ 225, 904, 14, 14 ], [ 243, 904, 51, 14 ], [ 298, 904, 10, 14 ], [ 311, 904, 36, 14 ], [ 350, 904, 56, 14 ], [ 72, 920, 46, 15 ], [ 123, 920, 25, 14 ], [ 153, 920, 17, 14 ], [ 175, 920, 72, 14 ], [ 252, 920, 12, 14 ], [ 269, 920, 26, 14 ], [ 299, 920, 20, 14 ], [ 324, 920, 29, 14 ], [ 358, 920, 48, 14 ], [ 72, 955, 77, 12 ], [ 153, 955, 13, 12 ], [ 169, 955, 35, 12 ], [ 207, 955, 32, 12 ], [ 243, 955, 56, 12 ], [ 303, 955, 10, 12 ], [ 316, 955, 35, 12 ], [ 355, 955, 51, 12 ], [ 72, 970, 50, 12 ], [ 124, 970, 10, 12 ], [ 135, 970, 54, 12 ], [ 190, 970, 79, 12 ], [ 270, 970, 44, 12 ], [ 315, 970, 33, 12 ], [ 350, 970, 10, 12 ], [ 361, 970, 45, 12 ], [ 72, 984, 18, 12 ], [ 92, 984, 61, 12 ], [ 155, 984, 24, 12 ], [ 181, 984, 55, 12 ], [ 237, 984, 29, 12 ], [ 268, 984, 54, 12 ], [ 323, 984, 51, 12 ], [ 376, 984, 30, 12 ], [ 72, 999, 36, 12 ], [ 111, 999, 118, 12 ], [ 72, 1013, 34, 12 ], [ 110, 1013, 32, 12 ], [ 146, 1013, 56, 12 ], [ 207, 1013, 10, 12 ], [ 221, 1013, 30, 12 ], [ 256, 1013, 45, 12 ], [ 305, 1013, 10, 12 ], [ 319, 1013, 32, 12 ], [ 355, 1013, 51, 12 ], [ 72, 1028, 33, 12 ], [ 109, 1028, 10, 12 ], [ 123, 1028, 31, 12 ], [ 158, 1028, 35, 12 ], [ 196, 1028, 33, 12 ], [ 233, 1028, 53, 12 ], [ 290, 1028, 38, 12 ], [ 332, 1028, 39, 12 ], [ 375, 1028, 32, 12 ], [ 72, 1043, 36, 12 ], [ 111, 1043, 105, 12 ], [ 431, 725, 27, 14 ], [ 461, 725, 22, 14 ], [ 487, 725, 44, 14 ], [ 534, 725, 62, 14 ], [ 600, 725, 47, 14 ], [ 650, 725, 26, 14 ], [ 679, 725, 21, 14 ], [ 703, 725, 34, 14 ], [ 740, 725, 24, 14 ], [ 431, 741, 17, 14 ], [ 451, 741, 19, 14 ], [ 472, 741, 27, 14 ], [ 502, 741, 39, 14 ], [ 543, 741, 15, 14 ], [ 560, 741, 30, 14 ], [ 593, 741, 68, 14 ], [ 664, 741, 39, 14 ], [ 705, 741, 21, 14 ], [ 729, 741, 36, 14 ], [ 431, 757, 39, 14 ], [ 473, 757, 22, 14 ], [ 498, 757, 22, 14 ], [ 459, 774, 53, 14 ], [ 518, 774, 21, 14 ], [ 545, 771, 11, 14 ], [ 562, 771, 15, 14 ], [ 582, 774, 47, 14 ], [ 635, 774, 21, 14 ], [ 662, 774, 40, 14 ], [ 709, 774, 26, 14 ], [ 741, 774, 24, 14 ], [ 431, 790, 35, 14 ], [ 470, 790, 17, 14 ], [ 492, 790, 72, 14 ], [ 568, 790, 12, 14 ], [ 584, 790, 180, 14 ], [ 431, 806, 100, 14 ], [ 535, 806, 57, 14 ], [ 597, 806, 39, 14 ], [ 641, 806, 11, 14 ], [ 657, 806, 20, 14 ], [ 683, 806, 27, 14 ], [ 715, 806, 20, 14 ], [ 740, 806, 24, 14 ], [ 431, 823, 18, 14 ], [ 454, 823, 18, 14 ], [ 477, 823, 61, 14 ], [ 544, 823, 44, 14 ], [ 592, 823, 26, 14 ], [ 623, 823, 39, 14 ], [ 667, 823, 39, 14 ], [ 711, 823, 20, 14 ], [ 737, 823, 28, 14 ], [ 431, 839, 50, 14 ], [ 485, 839, 12, 14 ], [ 501, 839, 45, 14 ], [ 551, 839, 69, 14 ], [ 625, 839, 74, 14 ], [ 704, 839, 17, 14 ], [ 725, 839, 40, 14 ], [ 431, 855, 38, 14 ], [ 473, 855, 39, 14 ], [ 516, 855, 11, 14 ], [ 531, 855, 35, 14 ], [ 569, 855, 17, 14 ], [ 591, 855, 37, 14 ], [ 632, 855, 12, 14 ], [ 648, 855, 26, 14 ], [ 678, 855, 14, 14 ], [ 696, 855, 68, 14 ], [ 431, 872, 20, 14 ], [ 455, 872, 56, 14 ], [ 516, 872, 12, 14 ], [ 532, 872, 43, 14 ], [ 579, 872, 9, 14 ], [ 592, 872, 10, 14 ], [ 606, 872, 46, 14 ], [ 656, 872, 11, 14 ], [ 672, 872, 47, 14 ], [ 722, 872, 42, 14 ], [ 431, 888, 30, 14 ], [ 466, 888, 49, 14 ], [ 520, 888, 14, 14 ], [ 540, 888, 47, 14 ], [ 592, 888, 42, 14 ], [ 640, 888, 18, 14 ], [ 663, 888, 17, 14 ], [ 685, 888, 22, 14 ], [ 712, 888, 35, 14 ], [ 752, 888, 12, 14 ], [ 431, 904, 47, 14 ], [ 486, 904, 39, 14 ], [ 534, 904, 20, 14 ], [ 560, 904, 14, 14 ], [ 580, 904, 63, 14 ], [ 650, 904, 25, 14 ], [ 682, 904, 44, 14 ], [ 732, 904, 32, 14 ], [ 431, 920, 38, 14 ], [ 475, 920, 69, 14 ], [ 551, 920, 27, 14 ], [ 584, 920, 59, 14 ], [ 649, 920, 17, 14 ], [ 673, 920, 74, 14 ], [ 753, 920, 12, 14 ], [ 431, 937, 39, 14 ], [ 475, 937, 10, 14 ], [ 490, 937, 25, 14 ], [ 520, 937, 35, 14 ], [ 560, 937, 17, 14 ], [ 582, 937, 17, 14 ], [ 605, 937, 38, 14 ], [ 648, 937, 75, 14 ], [ 729, 937, 12, 14 ], [ 746, 937, 18, 14 ], [ 431, 953, 60, 14 ], [ 496, 953, 24, 14 ], [ 525, 953, 27, 14 ], [ 558, 953, 12, 14 ], [ 575, 953, 17, 14 ], [ 598, 953, 41, 14 ], [ 644, 953, 34, 14 ], [ 684, 953, 17, 14 ], [ 706, 953, 58, 14 ], [ 431, 970, 110, 14 ], [ 544, 970, 44, 14 ], [ 592, 970, 28, 14 ], [ 623, 970, 20, 14 ], [ 647, 970, 50, 14 ], [ 700, 970, 64, 14 ], [ 431, 986, 14, 14 ], [ 450, 986, 69, 14 ], [ 524, 986, 74, 14 ], [ 603, 986, 17, 14 ], [ 624, 986, 14, 14 ], [ 644, 986, 73, 14 ], [ 722, 986, 42, 14 ], [ 431, 1002, 31, 14 ], [ 469, 1002, 18, 14 ], [ 494, 1002, 49, 14 ], [ 551, 1002, 12, 14 ], [ 570, 1002, 77, 14 ], [ 654, 1002, 26, 14 ], [ 688, 1002, 10, 14 ], [ 705, 1002, 60, 14 ], [ 431, 1018, 49, 14 ], [ 483, 1018, 12, 14 ], [ 499, 1018, 17, 14 ], [ 520, 1018, 50, 14 ], [ 573, 1018, 12, 14 ], [ 588, 1018, 53, 14 ], [ 645, 1018, 17, 14 ], [ 665, 1018, 38, 14 ], [ 706, 1018, 39, 14 ], [ 749, 1018, 15, 14 ], [ 431, 1035, 19, 14 ], [ 454, 1035, 21, 14 ], [ 478, 1035, 70, 14 ], [ 552, 1035, 20, 14 ], [ 576, 1035, 41, 14 ], [ 622, 1035, 41, 14 ], [ 667, 1035, 47, 14 ], [ 718, 1035, 10, 14 ], [ 731, 1035, 33, 14 ], [ 459, 1067, 10, 12 ], [ 471, 1067, 24, 12 ], [ 497, 1067, 19, 12 ], [ 519, 1067, 27, 12 ], [ 549, 1067, 36, 12 ], [ 587, 1067, 10, 12 ], [ 600, 1067, 73, 12 ], [ 675, 1067, 18, 12 ], [ 695, 1067, 70, 12 ] ]

[ "Advance", "Publication", "Acta", "Histochem.", "Cytochem.", "40", "(2):", "61–67,", "2007", "doi:10.1267/ahc.07008", "J01TRAa03oecHp.4kgt1aaC47yu2n-0olH65aS7,7r98io0Js/90Aatc0o10phi8recacttihn.yc0el7meo0fi0cH8aisetoCchyetomcihsetrmyiacnad", "Cytochemistry", "Promoting", "Effects", "of", "Milk", "on", "the", "Development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "Mammary", "Tumors", "in", "Rats", "De-Fu", "Ma1,2,", "Ryohei", "Katoh2,", "Hong", "Zhou1", "and", "Pei-Yu", "Wang1", "1Department", "of", "Social", "Medicine", "&", "Health", "Education,", "School", "of", "Public", "Health,", "Peking", "University,", "Beijing,", "100083,", "China", "and", "2Department", "of", "Human", "Pathology,", "University", "of", "Yamanashi", "Interdisciplinary", "Graduate", "School", "of", "Medicine", "and", "Engineering,", "Yamanashi", "409–3898,", "Japan", "00", "Received", "February", "19,", "2007;", "accepted", "March", "20,", "2007;", "published", "online", "May", "10,", "2007", "CopyrTigoht", "a©ss2e00s7s", "AtHheC", "effect", "of", "milk", "on", "the", "development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "mammary", "tumors,", "48", "female", "Sprague-Dawley", "rats", "treated", "with", "DMBA", "were", "divided", "into", "3", "groups", "and", "given", "1", "of", "3", "test", "solutions", "for", "20", "weeks", "as", "their", "drinking", "liquid:", "milk,", "estrone", "sulfate", "solution", "or", "tap", "water.", "The", "milk", "group", "showed", "a", "significantly", "great", "incidence", "(75%)", "in", "tumor", "development", "compared", "with", "the", "water", "group", "(38%)", "and", "was", "com-", "parable", "to", "the", "estrone", "sulfate", "group", "(69%).", "Mean", "tumor", "number", "per", "rat", "in", "the", "milk", "group", "was", "significantly", "higher", "than", "that", "in", "the", "water", "group", "(p=0.009).", "We", "classified", "the", "mammary", "tumors", "into", "three", "histological", "types:", "intraductal", "papilloma,", "fibroadenoma,", "and", "adenocarci-", "noma.", "Although", "the", "percent", "of", "intraductal", "papilloma", "and", "fibroadenoma", "was", "almost", "same", "among", "the", "three", "groups,", "malignant", "tumor", "was", "found", "only", "in", "the", "milk", "and", "estrone", "sulfate", "groups.", "In", "conclusion,", "our", "results", "indicate", "that", "milk", "as", "well", "as", "estrone", "sulfate", "promotes", "the", "development", "of", "DMBA-induced", "mammary", "tumors", "in", "rat", "and", "could", "be", "associated", "with", "the", "occurrence", "of", "adenocarcinoma.", "Key", "words:", "mammary", "tumor,", "milk,", "smooth", "muscle", "actin,", "proliferating", "cell", "nuclear", "antigen,", "estrogen", "receptor", "I.", "Introduction", "Breast", "cancer", "is", "the", "most", "common", "malignant", "neoplasm,", "and", "is", "the", "number", "one", "cause", "of", "cancer-related", "deaths", "in", "nonsmoking", "women", "[3].", "The", "incidence", "of", "breast", "cancer", "has", "been", "increasing", "in", "both", "developed", "and", "developing", "countries", "[4].", "Although", "epidemiological", "studies", "have", "identified", "vari-", "ous", "risk", "factors,", "including", "obesity,", "menarche", "at", "young", "age,", "and", "late", "menopause,", "these", "known", "risk", "factors", "seem", "to", "ac-", "count", "for", "only", "a", "third", "of", "the", "breast", "cancer", "cases", "[10,", "23].", "Recently,", "an", "epidemiological", "analysis", "revealed", "that", "the", "in-", "cidence", "of", "breast", "cancer", "in", "42", "countries", "is", "highly", "correlated", "(r=0.79)", "with", "the", "consumption", "of", "milk", "and", "dairy", "products", "Correspondence", "to:", "Ryohei", "Katoh,", "Department", "of", "Human", "Pathology,", "University", "of", "Yamanashi", "Interdisciplinary", "Graduate", "School", "of", "Medicine", "and", "Engineering,", "1110", "Shimokato,", "Chuo,", "Yamanashi", "409–3898,", "Japan.", "E-mail:", "rkatoh@yamanashi.ac.jp", "Pei-Yu", "Wang,", "Department", "of", "Social", "Medicine", "&", "Health", "Education,", "School", "of", "Public", "Health,", "Peking", "University,", "Beijing,", "100083,", "China.", "E-mail:", "wpeiyu@bjmu.edu.cn", "[22].", "The", "positive", "association", "between", "milk", "and", "breast", "can-", "cer", "has", "been", "proved", "by", "some", "case-control", "studies", "and", "cohort", "studies", "[18,", "26].", "Recently,", "Qin", "et", "al.", "reported", "that", "low-fat", "milk", "pro-", "moted", "the", "development", "of", "7,12-dimethylbenz(a)anthracene", "(DMBA)-induced", "mammary", "tumors", "in", "rats", "[17].", "But", "they", "did", "not", "thoroughly", "observe", "their", "natural", "history", "and", "mor-", "phology,", "or", "perform", "pathological", "classification", "for", "experi-", "mental", "tumors", "to", "assess", "the", "effects", "of", "milk", "on", "morphology", "and", "pathology", "of", "tumors.", "It", "is", "possible", "to", "evaluate", "tumori-", "genic", "response", "by", "palpable", "tumors,", "but", "the", "true", "nature", "of", "palpable", "lesions", "can", "be", "determined", "only", "through", "histo-", "logical", "examination", "[21].", "Moreover,", "the", "classification", "of", "tumors", "is", "very", "useful", "for", "the", "further", "interpretation", "of", "ex-", "perimental", "data", "[21].", "In", "the", "present", "study,", "we", "performed", "haematoxylin-eosin", "staining", "(HE)", "and", "carefully", "implement-", "ed", "pathological", "classification", "for", "all", "experimental", "tumors.", "Since", "the", "presence", "of", "myoepithelial", "cells", "is", "commonly", "regarded", "as", "the", "hallmark", "of", "benignity", "for", "human", "tumors", "[2,", "14]", "and", "proliferating", "cell", "nuclear", "antigen", "(PCNA)", "is", "sensi-", "©", "2007", "The", "Japan", "Society", "of", "Histochemistry", "and", "Cytochemistry" ]

[ 11, 11, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 11, 11, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 76, 47, 84, 34 ], [ 172, 47, 167, 34 ], [ 350, 47, 107, 34 ], [ 76, 118, 42, 20 ], [ 123, 118, 54, 20 ], [ 76, 143, 166, 23 ], [ 246, 143, 54, 23 ], [ 305, 143, 85, 23 ], [ 395, 143, 70, 23 ], [ 469, 143, 19, 23 ], [ 493, 143, 112, 23 ], [ 609, 143, 85, 23 ], [ 699, 143, 39, 23 ], [ 742, 143, 23, 23 ], [ 76, 168, 87, 23 ], [ 169, 168, 85, 23 ], [ 259, 168, 74, 23 ], [ 76, 193, 51, 21 ], [ 132, 193, 77, 22 ], [ 215, 193, 65, 21 ], [ 285, 193, 78, 22 ], [ 367, 193, 35, 21 ], [ 407, 193, 73, 21 ], [ 485, 193, 87, 22 ], [ 706, 60, 54, 14 ], [ 761, 60, 38, 14 ], [ 697, 118, 44, 17 ], [ 745, 118, 62, 17 ], [ 76, 243, 41, 12 ], [ 119, 243, 75, 12 ], [ 196, 243, 12, 12 ], [ 210, 243, 43, 12 ], [ 255, 243, 15, 12 ], [ 273, 243, 51, 12 ], [ 327, 243, 6, 12 ], [ 335, 243, 47, 12 ], [ 384, 243, 52, 12 ], [ 438, 243, 42, 12 ], [ 482, 243, 12, 12 ], [ 496, 243, 70, 12 ], [ 569, 243, 59, 12 ], [ 630, 243, 44, 12 ], [ 676, 243, 52, 12 ], [ 730, 243, 12, 12 ], [ 76, 256, 38, 11 ], [ 116, 256, 59, 11 ], [ 178, 256, 43, 11 ], [ 223, 256, 35, 11 ], [ 260, 256, 19, 11 ], [ 281, 256, 23, 12 ], [ 306, 256, 37, 11 ], [ 346, 256, 56, 11 ], [ 404, 256, 16, 11 ], [ 423, 256, 38, 11 ], [ 463, 256, 17, 11 ], [ 482, 256, 34, 11 ], [ 519, 256, 21, 11 ], [ 76, 276, 31, 12 ], [ 110, 276, 28, 12 ], [ 140, 276, 34, 12 ], [ 176, 276, 4, 12 ], [ 183, 276, 101, 12 ], [ 287, 276, 35, 12 ], [ 324, 276, 37, 12 ], [ 364, 276, 4, 12 ], [ 370, 276, 117, 12 ], [ 489, 276, 39, 12 ], [ 530, 276, 42, 12 ], [ 575, 276, 4, 12 ], [ 581, 276, 99, 12 ], [ 76, 292, 7, 12 ], [ 85, 292, 73, 12 ], [ 160, 292, 33, 12 ], [ 76, 351, 45, 12 ], [ 124, 351, 6, 12 ], [ 133, 351, 40, 12 ], [ 176, 351, 23, 12 ], [ 76, 371, 21, 12 ], [ 100, 371, 38, 12 ], [ 141, 371, 25, 12 ], [ 169, 371, 25, 12 ], [ 196, 371, 20, 12 ], [ 228, 371, 128, 12 ], [ 76, 390, 20, 12 ], [ 98, 390, 28, 12 ], [ 129, 390, 7, 12 ], [ 139, 390, 38, 12 ], [ 179, 390, 25, 12 ], [ 207, 390, 215, 12 ], [ 430, 351, 43, 12 ], [ 476, 351, 6, 12 ], [ 484, 351, 48, 12 ], [ 535, 351, 23, 12 ], [ 430, 364, 46, 12 ], [ 478, 364, 6, 12 ], [ 486, 364, 41, 12 ], [ 530, 364, 23, 12 ], [ 76, 410, 9, 12 ], [ 87, 410, 23, 12 ], [ 113, 410, 34, 12 ], [ 149, 410, 10, 12 ], [ 161, 410, 10, 12 ], [ 174, 410, 36, 12 ], [ 213, 410, 35, 12 ], [ 250, 410, 35, 12 ], [ 287, 410, 18, 12 ], [ 76, 423, 20, 12 ], [ 98, 423, 7, 12 ], [ 108, 423, 11, 12 ], [ 121, 423, 26, 12 ], [ 150, 423, 32, 12 ], [ 184, 423, 28, 12 ], [ 215, 423, 49, 12 ], [ 267, 423, 27, 12 ], [ 296, 423, 15, 12 ], [ 314, 423, 27, 12 ], [ 343, 423, 10, 12 ], [ 355, 423, 15, 12 ], [ 373, 423, 39, 12 ], [ 415, 423, 48, 12 ], [ 465, 423, 51, 12 ], [ 519, 423, 34, 12 ], [ 555, 423, 202, 12 ], [ 76, 437, 27, 12 ], [ 106, 437, 35, 12 ], [ 143, 437, 56, 12 ], [ 201, 437, 18, 12 ], [ 222, 437, 55, 12 ], [ 279, 437, 16, 12 ], [ 298, 437, 60, 12 ], [ 361, 437, 8, 12 ], [ 372, 437, 16, 12 ], [ 390, 437, 39, 12 ], [ 432, 437, 40, 12 ], [ 475, 437, 15, 12 ], [ 493, 437, 34, 12 ], [ 529, 437, 24, 12 ], [ 556, 437, 7, 12 ], [ 565, 437, 39, 12 ], [ 607, 437, 25, 12 ], [ 155, 497, 62, 15 ], [ 155, 518, 80, 14 ], [ 239, 518, 52, 14 ], [ 294, 518, 11, 14 ], [ 309, 518, 18, 14 ], [ 331, 518, 25, 14 ], [ 360, 518, 26, 14 ], [ 390, 518, 35, 14 ], [ 429, 518, 33, 14 ], [ 465, 518, 40, 14 ], [ 510, 518, 22, 14 ], [ 535, 518, 31, 14 ], [ 570, 518, 46, 14 ], [ 620, 518, 22, 14 ], [ 646, 518, 45, 14 ], [ 155, 534, 12, 14 ], [ 171, 534, 80, 14 ], [ 255, 534, 62, 14 ], [ 321, 534, 22, 14 ], [ 348, 534, 47, 14 ], [ 399, 534, 28, 14 ], [ 431, 534, 35, 14 ], [ 471, 534, 59, 14 ], [ 534, 534, 72, 14 ], [ 610, 534, 10, 14 ], [ 625, 534, 66, 14 ], [ 155, 550, 37, 14 ], [ 195, 550, 48, 14 ], [ 246, 550, 25, 14 ], [ 273, 550, 61, 14 ], [ 337, 550, 45, 14 ], [ 385, 550, 11, 14 ], [ 399, 550, 18, 14 ], [ 420, 550, 32, 14 ], [ 455, 550, 38, 14 ], [ 495, 550, 26, 14 ], [ 524, 550, 10, 14 ], [ 537, 550, 18, 14 ], [ 558, 550, 45, 14 ], [ 606, 550, 18, 14 ], [ 628, 550, 19, 14 ], [ 650, 550, 10, 14 ], [ 663, 550, 28, 14 ], [ 155, 567, 87, 14 ], [ 246, 567, 67, 14 ], [ 316, 567, 38, 14 ], [ 357, 567, 39, 14 ], [ 400, 567, 10, 14 ], [ 414, 567, 48, 14 ], [ 465, 567, 61, 14 ], [ 529, 567, 67, 14 ], [ 600, 567, 20, 14 ], [ 624, 567, 53, 14 ], [ 680, 567, 11, 14 ], [ 155, 583, 59, 14 ], [ 217, 583, 24, 14 ], [ 245, 583, 44, 14 ], [ 292, 583, 18, 14 ], [ 313, 583, 52, 14 ], [ 368, 583, 49, 14 ], [ 420, 583, 37, 14 ], [ 461, 583, 29, 14 ], [ 493, 583, 17, 14 ], [ 513, 583, 46, 14 ], [ 562, 583, 61, 14 ], [ 626, 583, 39, 14 ], [ 669, 583, 22, 14 ], [ 155, 599, 32, 14 ], [ 190, 599, 10, 14 ], [ 203, 599, 31, 14 ], [ 238, 599, 11, 14 ], [ 252, 599, 18, 14 ], [ 274, 599, 39, 14 ], [ 316, 599, 48, 14 ], [ 367, 599, 13, 14 ], [ 384, 599, 17, 14 ], [ 404, 599, 24, 14 ], [ 432, 599, 11, 14 ], [ 446, 599, 53, 14 ], [ 155, 623, 56, 14 ], [ 214, 623, 61, 14 ], [ 277, 623, 24, 14 ], [ 303, 623, 73, 14 ], [ 379, 623, 10, 14 ], [ 392, 623, 86, 14 ], [ 480, 623, 80, 14 ], [ 562, 623, 51, 14 ], [ 615, 623, 19, 14 ], [ 636, 623, 55, 14 ], [ 155, 639, 11, 14 ], [ 173, 639, 13, 14 ], [ 192, 639, 84, 14 ], [ 283, 639, 44, 14 ], [ 333, 639, 47, 14 ], [ 387, 639, 21, 14 ], [ 415, 639, 55, 14 ], [ 476, 639, 16, 14 ], [ 499, 639, 57, 14 ], [ 562, 639, 46, 14 ], [ 615, 639, 18, 14 ], [ 640, 639, 51, 14 ], [ 155, 655, 44, 14 ], [ 202, 655, 39, 14 ], [ 245, 655, 29, 14 ], [ 277, 655, 58, 14 ], [ 339, 655, 15, 14 ], [ 357, 655, 56, 14 ], [ 417, 655, 11, 14 ], [ 431, 655, 32, 14 ], [ 467, 655, 27, 14 ], [ 497, 655, 17, 14 ], [ 517, 655, 47, 14 ], [ 568, 655, 44, 14 ], [ 615, 655, 62, 14 ], [ 681, 655, 10, 14 ], [ 155, 672, 46, 14 ], [ 204, 672, 45, 14 ], [ 251, 672, 46, 14 ], [ 300, 672, 27, 14 ], [ 330, 672, 18, 14 ], [ 350, 672, 39, 14 ], [ 392, 672, 51, 14 ], [ 446, 672, 37, 14 ], [ 486, 672, 44, 14 ], [ 533, 672, 39, 14 ], [ 575, 672, 29, 14 ], [ 606, 672, 51, 14 ], [ 660, 672, 10, 14 ], [ 673, 672, 18, 14 ], [ 155, 688, 39, 14 ], [ 197, 688, 45, 14 ], [ 245, 688, 49, 14 ], [ 155, 711, 74, 14 ], [ 232, 711, 34, 14 ], [ 269, 711, 39, 14 ], [ 311, 711, 70, 14 ], [ 384, 711, 22, 14 ], [ 410, 711, 43, 14 ], [ 456, 711, 10, 14 ], [ 470, 711, 18, 14 ], [ 491, 711, 94, 14 ], [ 588, 711, 39, 14 ], [ 631, 711, 48, 14 ], [ 682, 711, 9, 14 ], [ 155, 728, 38, 14 ], [ 196, 728, 13, 14 ], [ 212, 728, 44, 14 ], [ 260, 728, 39, 14 ], [ 302, 728, 10, 14 ], [ 316, 728, 18, 14 ], [ 337, 728, 79, 14 ], [ 419, 728, 41, 14 ], [ 76, 796, 84, 15 ], [ 76, 813, 13, 14 ], [ 95, 813, 62, 14 ], [ 163, 813, 30, 14 ], [ 199, 813, 18, 14 ], [ 222, 813, 30, 14 ], [ 258, 813, 30, 14 ], [ 294, 813, 38, 14 ], [ 337, 813, 36, 14 ], [ 379, 813, 32, 14 ], [ 76, 829, 56, 14 ], [ 143, 829, 38, 14 ], [ 191, 829, 32, 14 ], [ 235, 829, 56, 14 ], [ 302, 829, 33, 14 ], [ 346, 829, 23, 14 ], [ 379, 829, 32, 14 ], [ 76, 845, 58, 14 ], [ 137, 845, 12, 14 ], [ 153, 845, 38, 14 ], [ 194, 845, 19, 14 ], [ 217, 845, 28, 14 ], [ 248, 845, 40, 14 ], [ 291, 845, 24, 14 ], [ 318, 845, 40, 14 ], [ 360, 845, 51, 14 ], [ 76, 862, 76, 14 ], [ 155, 862, 17, 14 ], [ 175, 862, 7, 14 ], [ 185, 862, 32, 14 ], [ 221, 862, 24, 14 ], [ 248, 862, 55, 14 ], [ 306, 861, 47, 14 ], [ 355, 862, 56, 14 ], [ 76, 878, 41, 14 ], [ 122, 878, 40, 14 ], [ 168, 878, 12, 14 ], [ 186, 878, 63, 14 ], [ 253, 878, 60, 14 ], [ 319, 878, 23, 14 ], [ 346, 878, 19, 14 ], [ 370, 878, 41, 14 ], [ 76, 894, 27, 14 ], [ 105, 894, 63, 14 ], [ 171, 894, 21, 14 ], [ 194, 894, 19, 14 ], [ 216, 894, 19, 14 ], [ 237, 894, 21, 14 ], [ 260, 894, 32, 14 ], [ 295, 894, 22, 14 ], [ 320, 894, 12, 14 ], [ 335, 894, 40, 14 ], [ 377, 894, 12, 14 ], [ 392, 894, 19, 14 ], [ 76, 910, 91, 14 ], [ 171, 910, 73, 14 ], [ 247, 910, 13, 14 ], [ 264, 910, 50, 14 ], [ 318, 910, 40, 14 ], [ 360, 910, 51, 14 ], [ 76, 927, 70, 14 ], [ 149, 927, 52, 14 ], [ 203, 927, 56, 14 ], [ 262, 927, 27, 14 ], [ 291, 927, 49, 14 ], [ 342, 927, 13, 14 ], [ 357, 927, 19, 14 ], [ 379, 927, 32, 14 ], [ 76, 943, 28, 14 ], [ 108, 943, 65, 14 ], [ 177, 943, 12, 14 ], [ 194, 943, 19, 14 ], [ 217, 943, 46, 14 ], [ 268, 943, 27, 14 ], [ 299, 943, 19, 14 ], [ 322, 943, 45, 14 ], [ 372, 943, 40, 14 ], [ 76, 960, 25, 14 ], [ 106, 960, 91, 14 ], [ 202, 960, 68, 14 ], [ 274, 960, 42, 14 ], [ 320, 960, 24, 14 ], [ 349, 960, 19, 14 ], [ 373, 960, 39, 14 ], [ 76, 976, 13, 14 ], [ 92, 976, 48, 14 ], [ 144, 976, 11, 14 ], [ 159, 976, 30, 14 ], [ 192, 976, 34, 14 ], [ 229, 976, 51, 14 ], [ 283, 976, 41, 14 ], [ 328, 976, 40, 14 ], [ 372, 976, 13, 14 ], [ 388, 976, 24, 14 ], [ 76, 992, 28, 14 ], [ 107, 992, 65, 14 ], [ 175, 992, 74, 14 ], [ 252, 992, 23, 14 ], [ 278, 992, 46, 14 ], [ 327, 992, 69, 14 ], [ 399, 992, 12, 14 ], [ 76, 1008, 63, 14 ], [ 141, 1008, 26, 14 ], [ 170, 1008, 47, 14 ], [ 220, 1008, 19, 14 ], [ 241, 1008, 53, 14 ], [ 297, 1008, 54, 14 ], [ 353, 1008, 35, 14 ], [ 390, 1008, 21, 14 ], [ 434, 796, 28, 14 ], [ 472, 796, 17, 14 ], [ 499, 796, 48, 14 ], [ 557, 796, 67, 14 ], [ 633, 796, 40, 14 ], [ 683, 796, 13, 14 ], [ 705, 796, 65, 14 ], [ 434, 812, 53, 14 ], [ 491, 813, 57, 14 ], [ 554, 813, 63, 14 ], [ 623, 813, 60, 14 ], [ 689, 813, 51, 14 ], [ 746, 813, 24, 14 ], [ 434, 829, 33, 14 ], [ 471, 829, 12, 14 ], [ 487, 829, 33, 14 ], [ 525, 829, 13, 14 ], [ 541, 829, 19, 14 ], [ 564, 829, 43, 14 ], [ 611, 829, 51, 14 ], [ 666, 829, 15, 14 ], [ 685, 829, 85, 14 ], [ 434, 845, 46, 14 ], [ 434, 878, 61, 15 ], [ 434, 894, 29, 14 ], [ 434, 910, 22, 14 ], [ 462, 910, 47, 14 ], [ 515, 910, 24, 14 ], [ 545, 910, 31, 14 ], [ 583, 910, 12, 14 ], [ 601, 910, 19, 14 ], [ 626, 911, 32, 14 ], [ 665, 910, 28, 14 ], [ 698, 910, 17, 14 ], [ 722, 910, 23, 14 ], [ 750, 910, 19, 14 ], [ 434, 927, 46, 14 ], [ 488, 927, 68, 14 ], [ 566, 927, 31, 14 ], [ 607, 927, 18, 14 ], [ 634, 927, 28, 14 ], [ 671, 927, 29, 14 ], [ 710, 927, 60, 14 ], [ 434, 943, 67, 14 ], [ 509, 943, 28, 14 ], [ 548, 943, 28, 14 ], [ 586, 943, 68, 14 ], [ 664, 943, 12, 14 ], [ 687, 943, 82, 14 ], [ 434, 960, 61, 14 ], [ 498, 960, 28, 14 ], [ 529, 960, 18, 14 ], [ 549, 960, 28, 14 ], [ 579, 960, 53, 14 ], [ 635, 960, 29, 14 ], [ 666, 960, 19, 14 ], [ 688, 960, 45, 14 ], [ 736, 960, 34, 14 ], [ 434, 976, 38, 14 ], [ 475, 976, 20, 14 ], [ 498, 976, 19, 14 ], [ 519, 976, 72, 14 ], [ 593, 976, 56, 14 ], [ 652, 976, 29, 14 ], [ 683, 976, 29, 14 ], [ 715, 976, 29, 14 ], [ 746, 976, 23, 14 ], [ 434, 992, 59, 14 ], [ 496, 992, 17, 14 ], [ 515, 992, 28, 14 ], [ 546, 992, 19, 14 ], [ 567, 992, 61, 14 ], [ 630, 992, 31, 14 ], [ 664, 992, 23, 14 ], [ 689, 992, 19, 14 ], [ 710, 992, 32, 14 ], [ 745, 992, 24, 14 ], [ 434, 1008, 31, 14 ], [ 470, 1008, 55, 14 ], [ 530, 1008, 28, 14 ], [ 562, 1008, 43, 14 ], [ 610, 1008, 13, 14 ], [ 627, 1008, 63, 14 ], [ 694, 1008, 49, 14 ], [ 747, 1008, 23, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "BMC", "Research", "Notes", "Short", "Report", "Epiblast-specific", "Snai1", "deletion", "results", "in", "embryonic", "lethality", "due", "to", "multiple", "vascular", "defects", "Hilda", "Lomelí1,", "Christa", "Starling2", "and", "Thomas", "Gridley*2", "BioMed", "Central", "Open", "Access", "Address:", "1Departamento", "de", "Genética", "del", "Desarrollo", "y", "Fisiología", "Molecular,", "Instituto", "de", "Biotecnología,", "Universidad", "Nacional", "Autónoma", "de", "México,", "Cuernavaca,", "Morelos,", "México", "and", "2The", "Jackson", "Laboratory,", "Bar", "Harbor,", "ME", "04609,", "USA", "Email:", "Hilda", "Lomelí", "-", "hilda@ibt.unam.mx;", "Christa", "Starling", "-", "christa.starling@jax.org;", "Thomas", "Gridley*", "-", "tom.gridley@jax.org", "*", "Corresponding", "author", "Published:", "6", "February", "2009", "BMC", "Research", "Notes", "2009,", "2:22", "doi:10.1186/1756-0500-2-22", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1756-0500/2/22", "Received:", "6", "December", "2008", "Accepted:", "6", "February", "2009", "©", "2009", "Gridley", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Members", "of", "the", "Snail", "gene", "family,", "which", "encode", "zinc", "finger", "proteins", "that", "function", "as", "transcriptional", "repressors,", "play", "essential", "roles", "during", "embryonic", "development", "in", "vertebrates.", "Mouse", "embryos", "with", "conditional", "deletion", "of", "the", "Snail1", "(Snai1)", "gene", "in", "the", "epiblast,", "but", "not", "in", "most", "extraembryonic", "membranes,", "exhibit", "defects", "in", "left-right", "asymmetry", "specification", "and", "migration", "of", "mesoderm", "cells", "through", "the", "posterior", "primitive", "streak.", "Here", "we", "describe", "phenotypic", "defects", "that", "result", "in", "death", "of", "the", "mutant", "embryos", "by", "9.5", "days", "of", "gestation.", "Findings:", "Endothelial", "cells", "differentiated", "in", "epiblast-specific", "Snai1-deficient", "embryos,", "but", "formation", "of", "an", "interconnected", "vascular", "network", "was", "abnormal.", "To", "determine", "whether", "the", "observed", "vascular", "defects", "were", "dependent", "on", "disruption", "of", "blood", "flow,", "we", "analyzed", "vascular", "remodeling", "in", "cultured", "allantois", "explants", "from", "the", "mutant", "embryos.", "Similar", "vascular", "defects", "were", "observed", "in", "the", "mutant", "allantois", "explants.", "Conclusion:", "These", "studies", "demonstrate", "that", "lethality", "in", "the", "Snai1-conditional", "mutant", "embryos", "is", "caused", "by", "multiple", "defects", "in", "the", "cardiovascular", "system.", "Background", "In", "mammals,", "there", "are", "three", "Snail", "family", "genes:", "Snai1", "(formerly", "Snail),", "Snai2", "(formerly", "Slug),", "and", "Snai3", "(reviewed", "in", "[1,2]).", "We", "have", "shown", "that", "mouse", "embryos", "homozygous", "for", "a", "Snai1", "null", "mutation", "(Snai1-/-", "embryos)", "exhibit", "defects", "in", "mesoderm", "formation", "and", "die", "shortly", "after", "embryonic", "day", "(E)", "7.5", "[3],", "likely", "due", "to", "defects", "in", "the", "extraembryonic", "membranes.", "In", "contrast,", "mouse", "embryos", "(Meox2-Cre;", "Snai1flox/-", "embryos)", "with", "deletion", "of", "the", "Snai1", "gene", "specifically", "in", "the", "epiblast", "(i.e.,", "the", "embryo", "proper", "plus", "extraembryonic", "mesoderm)", "survive", "past", "the", "period", "of", "lethality", "at", "E7.5.", "These", "embryos", "exhibit", "defects", "in", "left-", "right", "asymmetry", "specification", "and", "delayed", "progression", "of", "mesoderm", "cells", "through", "the", "posterior", "primitive", "streak", "[4].", "Here", "we", "describe", "phenotypic", "defects", "in", "Meox2-Cre;", "Snai1flox/-", "(hereafter", "designated", "Snai1-cko)", "embryos", "that", "result", "in", "death", "of", "the", "mutant", "embryos", "by", "approximately", "E9-E10.", "Methods", "Mice", "The", "targeted", "null", "allele", "of", "the", "Snai1", "gene", "[3]", "and", "the", "Snai1flox", "conditional", "allele", "[5]", "have", "been", "described.", "Snail1flox/flox", "mice", "were", "maintained", "as", "homozygotes.", "Meox2-Cre", "mice", "[6]", "were", "obtained", "from", "the", "Jackson", "Labo-", "ratory.", "For", "the", "experiments", "described", "here,", "male", "mice", "het-", "erozygous", "for", "both", "the", "Meox2-Cre", "allele", "and", "the", "Snai1", "null", "allele", "(Snai1+/-)", "were", "crossed", "to", "Snai1flox/flox", "females,", "and", "Page", "1", "of", "6", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 35, 11 ], [ 107, 75, 17, 11 ], [ 126, 75, 68, 11 ], [ 196, 75, 59, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 41, 25 ], [ 116, 220, 120, 25 ], [ 240, 220, 22, 25 ], [ 266, 220, 125, 25 ], [ 395, 220, 87, 25 ], [ 70, 248, 145, 25 ], [ 219, 248, 40, 25 ], [ 264, 248, 72, 25 ], [ 341, 248, 138, 25 ], [ 120, 318, 47, 17 ], [ 169, 318, 29, 17 ], [ 201, 317, 89, 18 ], [ 293, 318, 49, 17 ], [ 345, 317, 99, 18 ], [ 448, 318, 57, 17 ], [ 508, 318, 17, 17 ], [ 528, 317, 71, 18 ], [ 602, 318, 51, 17 ], [ 657, 317, 60, 18 ], [ 120, 337, 41, 17 ], [ 164, 337, 14, 17 ], [ 181, 336, 50, 18 ], [ 234, 337, 87, 17 ], [ 324, 337, 15, 17 ], [ 342, 336, 55, 18 ], [ 400, 337, 27, 17 ], [ 430, 337, 51, 17 ], [ 484, 337, 16, 17 ], [ 503, 336, 56, 18 ], [ 120, 367, 4, 9 ], [ 126, 368, 20, 13 ], [ 148, 368, 40, 13 ], [ 191, 368, 46, 13 ], [ 239, 368, 65, 13 ], [ 306, 368, 42, 13 ], [ 351, 368, 61, 13 ], [ 414, 368, 51, 13 ], [ 468, 368, 16, 13 ], [ 486, 368, 33, 13 ], [ 521, 368, 23, 13 ], [ 120, 382, 4, 9 ], [ 126, 383, 59, 13 ], [ 188, 383, 9, 13 ], [ 200, 383, 49, 13 ], [ 251, 383, 46, 13 ], [ 299, 383, 19, 13 ], [ 320, 383, 52, 13 ], [ 375, 383, 40, 13 ], [ 417, 383, 50, 13 ], [ 469, 383, 9, 13 ], [ 481, 383, 27, 13 ], [ 511, 383, 65, 13 ], [ 578, 383, 39, 13 ], [ 620, 383, 35, 13 ], [ 126, 397, 34, 13 ], [ 163, 397, 16, 13 ], [ 181, 397, 33, 13 ], [ 216, 397, 23, 13 ], [ 120, 411, 4, 9 ], [ 126, 412, 59, 13 ], [ 188, 412, 9, 13 ], [ 200, 412, 49, 13 ], [ 251, 412, 48, 13 ], [ 301, 412, 30, 13 ], [ 334, 412, 32, 13 ], [ 368, 412, 31, 13 ], [ 402, 412, 9, 13 ], [ 414, 412, 45, 13 ], [ 461, 412, 10, 13 ], [ 473, 412, 35, 13 ], [ 510, 412, 16, 13 ], [ 529, 412, 39, 13 ], [ 571, 412, 16, 13 ], [ 590, 412, 33, 13 ], [ 625, 412, 23, 13 ], [ 120, 425, 4, 9 ], [ 126, 426, 59, 13 ], [ 188, 426, 9, 13 ], [ 200, 426, 49, 13 ], [ 251, 426, 48, 13 ], [ 301, 426, 34, 13 ], [ 337, 426, 68, 13 ], [ 407, 426, 37, 13 ], [ 447, 426, 13, 13 ], [ 463, 426, 33, 13 ], [ 498, 426, 23, 13 ], [ 120, 440, 4, 9 ], [ 126, 440, 41, 13 ], [ 170, 440, 9, 13 ], [ 181, 440, 49, 13 ], [ 232, 440, 39, 13 ], [ 273, 440, 40, 13 ], [ 315, 440, 51, 13 ], [ 368, 440, 44, 13 ], [ 415, 440, 28, 13 ], [ 445, 440, 24, 13 ], [ 471, 440, 15, 13 ], [ 489, 440, 33, 13 ], [ 524, 440, 23, 13 ], [ 120, 466, 82, 13 ], [ 205, 466, 34, 13 ], [ 241, 466, 12, 13 ], [ 256, 466, 50, 13 ], [ 308, 466, 11, 13 ], [ 321, 466, 33, 13 ], [ 356, 466, 21, 13 ], [ 379, 466, 58, 13 ], [ 439, 466, 90, 13 ], [ 120, 491, 44, 13 ], [ 166, 491, 12, 13 ], [ 181, 491, 36, 13 ], [ 219, 491, 27, 13 ], [ 249, 491, 46, 13 ], [ 297, 491, 6, 13 ], [ 305, 491, 54, 13 ], [ 362, 491, 24, 13 ], [ 120, 517, 49, 13 ], [ 172, 517, 35, 13 ], [ 209, 517, 24, 13 ], [ 236, 517, 49, 13 ], [ 120, 542, 52, 13 ], [ 174, 542, 9, 13 ], [ 186, 542, 24, 13 ], [ 213, 542, 33, 13 ], [ 249, 542, 21, 13 ], [ 271, 542, 55, 13 ], [ 329, 542, 10, 13 ], [ 340, 542, 12, 13 ], [ 355, 542, 22, 13 ], [ 379, 542, 8, 13 ], [ 390, 542, 13, 13 ], [ 405, 542, 26, 13 ], [ 432, 542, 30, 13 ], [ 465, 542, 31, 13 ], [ 498, 542, 55, 13 ], [ 556, 542, 30, 13 ], [ 588, 542, 16, 13 ], [ 606, 542, 41, 13 ], [ 650, 542, 53, 13 ], [ 705, 542, 58, 13 ], [ 120, 557, 40, 13 ], [ 163, 557, 31, 13 ], [ 197, 557, 39, 13 ], [ 239, 557, 61, 13 ], [ 303, 557, 20, 13 ], [ 326, 557, 63, 13 ], [ 393, 557, 19, 13 ], [ 415, 557, 66, 13 ], [ 485, 557, 11, 13 ], [ 499, 557, 18, 13 ], [ 520, 557, 46, 13 ], [ 569, 557, 45, 13 ], [ 617, 557, 16, 13 ], [ 637, 557, 39, 13 ], [ 680, 557, 26, 13 ], [ 709, 557, 8, 13 ], [ 720, 557, 43, 13 ], [ 120, 571, 28, 13 ], [ 120, 598, 58, 13 ], [ 181, 598, 46, 13 ], [ 231, 598, 57, 13 ], [ 290, 598, 16, 13 ], [ 309, 598, 38, 13 ], [ 350, 598, 27, 13 ], [ 379, 598, 53, 13 ], [ 435, 598, 15, 13 ], [ 453, 598, 16, 13 ], [ 472, 598, 50, 13 ], [ 525, 598, 11, 13 ], [ 539, 598, 59, 13 ], [ 600, 598, 10, 13 ], [ 613, 598, 20, 13 ], [ 637, 598, 10, 13 ], [ 650, 598, 60, 13 ], [ 713, 598, 37, 13 ], [ 752, 598, 10, 13 ], [ 120, 612, 34, 13 ], [ 157, 612, 23, 13 ], [ 184, 612, 10, 13 ], [ 198, 612, 16, 13 ], [ 217, 612, 22, 13 ], [ 243, 612, 19, 13 ], [ 266, 612, 26, 13 ], [ 295, 612, 60, 13 ], [ 358, 612, 31, 13 ], [ 393, 612, 23, 13 ], [ 419, 612, 40, 13 ], [ 463, 612, 8, 13 ], [ 474, 612, 37, 13 ], [ 514, 612, 16, 13 ], [ 534, 612, 27, 13 ], [ 564, 612, 46, 13 ], [ 614, 612, 11, 13 ], [ 628, 612, 57, 13 ], [ 688, 612, 25, 13 ], [ 717, 612, 46, 13 ], [ 120, 627, 38, 13 ], [ 161, 627, 41, 13 ], [ 204, 627, 20, 13 ], [ 227, 627, 35, 13 ], [ 264, 627, 10, 13 ], [ 277, 627, 57, 13 ], [ 337, 627, 39, 13 ], [ 378, 627, 65, 13 ], [ 445, 627, 42, 13 ], [ 489, 627, 11, 13 ], [ 502, 627, 16, 13 ], [ 521, 627, 27, 13 ], [ 551, 627, 19, 13 ], [ 573, 627, 11, 13 ], [ 586, 627, 45, 13 ], [ 633, 627, 11, 13 ], [ 646, 627, 35, 13 ], [ 684, 627, 57, 13 ], [ 744, 627, 19, 13 ], [ 120, 641, 48, 13 ], [ 171, 641, 48, 13 ], [ 222, 641, 73, 13 ], [ 297, 641, 11, 13 ], [ 311, 641, 32, 13 ], [ 346, 641, 37, 13 ], [ 386, 641, 23, 13 ], [ 412, 641, 24, 13 ], [ 439, 641, 73, 13 ], [ 515, 641, 45, 13 ], [ 562, 641, 18, 13 ], [ 583, 641, 54, 13 ], [ 640, 641, 11, 13 ], [ 654, 641, 37, 13 ], [ 694, 641, 28, 13 ], [ 725, 641, 38, 13 ], [ 120, 656, 44, 13 ], [ 166, 656, 62, 13 ], [ 231, 656, 11, 13 ], [ 244, 656, 25, 13 ], [ 270, 656, 40, 13 ], [ 313, 656, 23, 13 ], [ 338, 656, 8, 13 ], [ 348, 656, 39, 13 ], [ 390, 656, 38, 13 ], [ 430, 656, 14, 13 ], [ 446, 656, 19, 13 ], [ 467, 656, 36, 13 ], [ 504, 656, 22, 13 ], [ 528, 656, 30, 13 ], [ 560, 656, 18, 13 ], [ 580, 656, 34, 13 ], [ 617, 656, 37, 13 ], [ 656, 656, 53, 13 ], [ 711, 656, 11, 13 ], [ 724, 656, 29, 13 ], [ 755, 656, 8, 13 ], [ 120, 670, 45, 13 ], [ 168, 670, 53, 13 ], [ 224, 670, 70, 13 ], [ 297, 670, 53, 13 ], [ 353, 670, 22, 13 ], [ 377, 670, 29, 13 ], [ 409, 670, 44, 13 ], [ 456, 670, 69, 13 ], [ 528, 670, 53, 13 ], [ 584, 670, 103, 13 ], [ 690, 670, 50, 13 ], [ 744, 670, 19, 13 ], [ 120, 685, 28, 13 ], [ 151, 685, 46, 13 ], [ 199, 685, 11, 13 ], [ 212, 685, 42, 13 ], [ 256, 685, 52, 13 ], [ 310, 685, 43, 13 ], [ 356, 685, 51, 13 ], [ 70, 734, 13, 17 ], [ 86, 734, 92, 17 ], [ 70, 767, 65, 14 ], [ 138, 767, 71, 14 ], [ 212, 767, 33, 14 ], [ 247, 767, 21, 14 ], [ 271, 767, 53, 14 ], [ 328, 767, 57, 14 ], [ 387, 767, 17, 14 ], [ 70, 783, 18, 14 ], [ 92, 783, 55, 14 ], [ 150, 783, 12, 14 ], [ 166, 783, 65, 14 ], [ 235, 783, 41, 14 ], [ 279, 783, 21, 14 ], [ 304, 783, 19, 14 ], [ 327, 783, 77, 14 ], [ 70, 798, 40, 14 ], [ 117, 798, 69, 15 ], [ 192, 798, 12, 14 ], [ 210, 798, 43, 14 ], [ 261, 798, 7, 14 ], [ 274, 798, 38, 14 ], [ 319, 798, 12, 14 ], [ 337, 798, 39, 14 ], [ 383, 798, 21, 14 ], [ 70, 814, 57, 14 ], [ 129, 814, 63, 14 ], [ 194, 814, 14, 14 ], [ 210, 814, 66, 14 ], [ 278, 814, 70, 14 ], [ 350, 814, 54, 14 ], [ 70, 830, 14, 14 ], [ 86, 830, 28, 14 ], [ 117, 830, 51, 14 ], [ 170, 830, 43, 14 ], [ 215, 830, 45, 14 ], [ 262, 830, 22, 14 ], [ 286, 830, 39, 14 ], [ 327, 830, 11, 14 ], [ 341, 830, 63, 14 ], [ 70, 846, 43, 14 ], [ 120, 846, 72, 14 ], [ 199, 846, 46, 14 ], [ 253, 846, 19, 14 ], [ 279, 846, 30, 14 ], [ 316, 846, 44, 14 ], [ 367, 846, 37, 14 ], [ 70, 861, 41, 15 ], [ 119, 861, 17, 14 ], [ 142, 861, 18, 14 ], [ 167, 861, 55, 14 ], [ 230, 861, 12, 14 ], [ 248, 861, 41, 14 ], [ 296, 861, 12, 14 ], [ 315, 861, 38, 14 ], [ 360, 861, 26, 14 ], [ 393, 861, 11, 14 ], [ 70, 877, 18, 14 ], [ 93, 877, 25, 14 ], [ 123, 877, 21, 14 ], [ 149, 877, 29, 14 ], [ 183, 877, 22, 14 ], [ 210, 877, 50, 14 ], [ 265, 877, 17, 14 ], [ 287, 877, 30, 14 ], [ 322, 877, 33, 14 ], [ 360, 877, 9, 14 ], [ 374, 877, 30, 14 ], [ 70, 893, 39, 14 ], [ 114, 893, 26, 14 ], [ 145, 893, 17, 14 ], [ 167, 893, 22, 14 ], [ 194, 893, 30, 14 ], [ 230, 893, 18, 14 ], [ 253, 893, 32, 14 ], [ 290, 893, 42, 14 ], [ 337, 893, 12, 14 ], [ 354, 893, 50, 14 ], [ 70, 909, 62, 14 ], [ 136, 909, 41, 14 ], [ 180, 909, 18, 14 ], [ 202, 909, 39, 14 ], [ 244, 909, 45, 14 ], [ 293, 909, 41, 14 ], [ 337, 909, 67, 14 ], [ 70, 925, 34, 14 ], [ 108, 925, 26, 14 ], [ 138, 925, 44, 14 ], [ 186, 925, 9, 14 ], [ 200, 925, 41, 14 ], [ 244, 925, 18, 14 ], [ 266, 925, 30, 14 ], [ 300, 925, 51, 14 ], [ 355, 925, 12, 14 ], [ 371, 925, 33, 14 ], [ 70, 940, 12, 14 ], [ 85, 940, 18, 14 ], [ 107, 940, 30, 14 ], [ 141, 940, 21, 14 ], [ 165, 940, 12, 14 ], [ 181, 940, 50, 14 ], [ 234, 940, 12, 14 ], [ 249, 940, 39, 14 ], [ 292, 940, 67, 14 ], [ 362, 940, 42, 14 ], [ 70, 956, 44, 14 ], [ 118, 956, 59, 14 ], [ 182, 956, 21, 14 ], [ 208, 956, 39, 14 ], [ 251, 956, 50, 14 ], [ 305, 956, 25, 14 ], [ 335, 956, 34, 14 ], [ 374, 956, 30, 14 ], [ 70, 972, 29, 14 ], [ 103, 972, 53, 14 ], [ 161, 972, 80, 14 ], [ 246, 972, 12, 14 ], [ 262, 972, 36, 14 ], [ 302, 972, 41, 14 ], [ 347, 972, 26, 14 ], [ 377, 972, 27, 14 ], [ 70, 988, 77, 14 ], [ 152, 988, 12, 14 ], [ 169, 988, 38, 14 ], [ 212, 988, 39, 14 ], [ 256, 988, 21, 14 ], [ 282, 988, 12, 14 ], [ 298, 988, 18, 14 ], [ 321, 988, 83, 14 ], [ 70, 1004, 22, 14 ], [ 100, 1004, 24, 14 ], [ 132, 1004, 37, 14 ], [ 177, 1004, 26, 14 ], [ 211, 1004, 20, 14 ], [ 238, 1004, 13, 14 ], [ 260, 1004, 50, 14 ], [ 318, 1004, 14, 14 ], [ 340, 1004, 19, 14 ], [ 366, 1004, 12, 14 ], [ 386, 1004, 18, 14 ], [ 70, 1019, 61, 14 ], [ 135, 1019, 64, 14 ], [ 203, 1019, 52, 14 ], [ 259, 1019, 20, 14 ], [ 283, 1019, 60, 14 ], [ 347, 1019, 12, 14 ], [ 363, 1019, 41, 14 ], [ 428, 736, 31, 14 ], [ 463, 736, 42, 14 ], [ 508, 736, 49, 14 ], [ 560, 736, 69, 14 ], [ 632, 736, 12, 14 ], [ 647, 736, 27, 14 ], [ 677, 736, 44, 14 ], [ 725, 736, 25, 14 ], [ 753, 736, 9, 14 ], [ 428, 752, 50, 14 ], [ 481, 752, 40, 14 ], [ 524, 752, 56, 14 ], [ 583, 752, 12, 14 ], [ 597, 752, 72, 14 ], [ 672, 752, 76, 14 ], [ 428, 784, 13, 17 ], [ 444, 784, 99, 17 ], [ 546, 784, 108, 17 ], [ 428, 814, 9, 14 ], [ 442, 814, 71, 14 ], [ 518, 814, 27, 14 ], [ 550, 814, 12, 14 ], [ 566, 814, 33, 14 ], [ 604, 814, 9, 14 ], [ 617, 814, 46, 14 ], [ 668, 814, 45, 14 ], [ 717, 814, 46, 14 ], [ 428, 830, 34, 14 ], [ 468, 830, 53, 14 ], [ 527, 830, 25, 14 ], [ 559, 830, 18, 14 ], [ 582, 830, 90, 14 ], [ 678, 830, 28, 14 ], [ 712, 830, 36, 14 ], [ 753, 830, 9, 14 ], [ 428, 846, 6, 14 ], [ 440, 846, 27, 14 ], [ 473, 846, 44, 14 ], [ 522, 846, 12, 14 ], [ 539, 846, 32, 14 ], [ 577, 846, 18, 14 ], [ 600, 846, 64, 14 ], [ 670, 846, 46, 14 ], [ 720, 846, 26, 14 ], [ 751, 846, 11, 14 ], [ 428, 861, 18, 14 ], [ 451, 861, 25, 14 ], [ 481, 861, 30, 14 ], [ 516, 861, 47, 14 ], [ 568, 861, 70, 14 ], [ 643, 861, 12, 14 ], [ 659, 861, 73, 14 ], [ 737, 861, 25, 14 ], [ 428, 877, 30, 14 ], [ 464, 877, 21, 14 ], [ 490, 877, 44, 14 ], [ 540, 877, 12, 14 ], [ 557, 877, 73, 14 ], [ 636, 877, 37, 14 ], [ 678, 877, 12, 14 ], [ 695, 877, 50, 14 ], [ 750, 877, 12, 14 ], [ 428, 893, 51, 14 ], [ 485, 893, 51, 14 ], [ 542, 893, 16, 14 ], [ 563, 893, 15, 14 ], [ 583, 893, 34, 14 ], [ 623, 893, 45, 14 ], [ 673, 893, 39, 14 ], [ 717, 893, 22, 14 ], [ 745, 893, 18, 14 ], [ 428, 909, 58, 14 ], [ 488, 909, 21, 14 ], [ 512, 909, 65, 14 ], [ 579, 909, 34, 14 ], [ 615, 909, 64, 14 ], [ 682, 909, 21, 14 ], [ 706, 909, 57, 14 ], [ 428, 925, 53, 14 ], [ 485, 925, 8, 14 ], [ 497, 925, 21, 14 ], [ 521, 925, 80, 14 ], [ 604, 925, 53, 14 ], [ 660, 925, 54, 14 ], [ 718, 925, 9, 14 ], [ 731, 925, 32, 14 ], [ 428, 940, 15, 14 ], [ 447, 940, 18, 14 ], [ 469, 940, 60, 14 ], [ 532, 940, 12, 14 ], [ 548, 940, 18, 14 ], [ 569, 940, 18, 14 ], [ 591, 940, 36, 14 ], [ 630, 940, 12, 14 ], [ 646, 940, 40, 14 ], [ 689, 940, 73, 14 ], [ 428, 956, 21, 14 ], [ 453, 956, 52, 14 ], [ 508, 956, 35, 15 ], [ 546, 956, 12, 14 ], [ 562, 956, 73, 14 ], [ 638, 956, 40, 14 ], [ 682, 956, 11, 14 ], [ 697, 956, 26, 14 ], [ 726, 956, 21, 14 ], [ 751, 956, 11, 14 ], [ 428, 972, 23, 14 ], [ 455, 972, 11, 14 ], [ 471, 972, 31, 14 ], [ 506, 972, 15, 14 ], [ 525, 972, 12, 14 ], [ 542, 972, 14, 14 ], [ 557, 972, 19, 14 ], [ 580, 972, 25, 14 ], [ 610, 972, 61, 14 ], [ 675, 972, 9, 14 ], [ 689, 972, 32, 14 ], [ 725, 972, 15, 14 ], [ 744, 972, 18, 14 ], [ 428, 988, 44, 14 ], [ 477, 988, 22, 14 ], [ 503, 988, 19, 14 ], [ 526, 988, 36, 14 ], [ 566, 988, 9, 14 ], [ 579, 988, 18, 14 ], [ 601, 988, 55, 14 ], [ 660, 988, 41, 14 ], [ 706, 988, 56, 14 ], [ 428, 1004, 18, 14 ], [ 450, 1004, 93, 14 ], [ 546, 1004, 49, 14 ], [ 598, 1004, 17, 14 ], [ 619, 1004, 26, 14 ], [ 648, 1004, 27, 14 ], [ 679, 1004, 21, 14 ], [ 704, 1004, 20, 14 ], [ 727, 1004, 35, 15 ], [ 428, 1019, 53, 14 ], [ 484, 1019, 46, 14 ], [ 532, 1019, 38, 15 ], [ 573, 1019, 45, 14 ], [ 620, 1019, 39, 14 ], [ 662, 1019, 26, 14 ], [ 690, 1019, 12, 14 ], [ 704, 1019, 27, 14 ], [ 734, 1019, 29, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Clinical", "and", "Developmental", "Immunology", "Volume", "2011,", "Article", "ID", "439752,", "7", "pages", "doi:10.1155/2011/439752", "Review", "Article", "The", "Confluence", "of", "Stereotactic", "Ablative", "Radiotherapy", "and", "Tumor", "Immunology", "Steven", "Eric", "Finkelstein,1", "Robert", "Timmerman,2", "William", "H.", "McBride,3", "Do¨rthe", "Schaue,3", "Sarah", "E.", "Hoffe,4", "Constantine", "A.", "Mantz,1", "and", "George", "D.", "Wilson5", "1", "21st", "Century", "Oncology", "Translational", "Research", "Consortium,", "Scottsdale,", "AZ", "85251,", "USA", "2", "Department", "of", "Radiation", "Oncology", "and", "Neurologic", "Surgery,", "University", "of", "Texas", "Southwestern", "Medical", "Center,", "Dallas,", "TX", "75391,", "USA", "3", "Department", "of", "Radiation", "Oncology,", "David", "Geffen", "School", "of", "Medicine", "at", "UCLA,", "Los", "Angeles,", "CA", "90095,", "USA", "4", "Department", "of", "Radiation", "Oncology,", "Moffitt", "International,", "Tampa,", "FL", "33612,", "USA", "5", "Division", "of", "Radiation", "Biology,", "William", "Beaumont", "Hospital,", "Royal", "Oak,", "MI", "48073,", "USA", "Correspondence", "should", "be", "addressed", "to", "Steven", "Eric", "Finkelstein,", "sfinkels@rtsx.com", "Received", "25", "August", "2011;", "Accepted", "5", "September", "2011", "Academic", "Editor:", "Luca", "Gattinoni", "Copyright", "©", "2011", "Steven", "Eric", "Finkelstein", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Stereotactic", "radiation", "approaches", "are", "gaining", "more", "popularity", "for", "the", "treatment", "of", "intracranial", "as", "well", "as", "extracranial", "tumors", "in", "organs", "such", "as", "the", "liver", "and", "lung.", "Technology,", "rather", "than", "biology,", "is", "driving", "the", "rapid", "adoption", "of", "stereotactic", "body", "radiation", "therapy", "(SBRT),", "also", "known", "as", "stereotactic", "ablative", "radiotherapy", "(SABR),", "in", "the", "clinic", "due", "to", "advances", "in", "precise", "positioning", "and", "targeting.", "Dramatic", "improvements", "in", "tumor", "control", "have", "been", "demonstrated;", "however,", "our", "knowledge", "of", "normal", "tissue", "biology", "response", "mechanisms", "to", "large", "fraction", "sizes", "is", "lacking.", "Herein,", "we", "will", "discuss", "how", "SABR", "can", "induce", "cellular", "expression", "of", "MHC", "I,", "adhesion", "molecules,", "costimulatory", "molecules,", "heat", "shock", "proteins,", "inflammatory", "mediators,", "immunomodulatory", "cytokines,", "and", "death", "receptors", "to", "enhance", "antitumor", "immune", "responses.", "1.", "Introduction", "Stereotactic", "radiosurgery", "(SRS)", "was", "originally", "developed", "for", "the", "treatment", "of", "intracranial", "tumors", "and", "has", "demonstrated", "clinical", "effectiveness", "in", "treating", "a", "variety", "of", "benign", "and", "malignant", "conditions.", "Its", "extracranial", "counterpart,", "stereotac-", "tic", "body", "radiation", "therapy", "(SBRT),", "also", "known", "as", "stereotactic", "ablative", "radiotherapy", "(SABR),", "has", "more", "recently", "shown", "efficacy", "for", "the", "treatment", "of", "tumors", "in", "organs", "such", "as", "the", "liver", "and", "lung.", "The", "potential", "for", "using", "SABR", "is", "likely", "greater", "than", "for", "SRS", "given", "the", "larger", "volume", "of", "potential", "indications", "outside", "the", "central", "nervous", "system.", "Technology,", "rather", "than", "biology,", "is", "driving", "the", "rapid", "adoption", "of", "SABR", "in", "the", "clinic", "due", "to", "advances", "in", "precise", "positioning,", "motion", "control,", "dosimetry,", "and", "precise", "targeting", "with", "image", "guid-", "ance.", "Dramatic", "improvements", "in", "tumor", "control", "have", "been", "demonstrated", "in", "several", "studies", "due", "to", "the", "demonstration", "that", "very", "potent", "dose", "can", "be", "delivered", "by", "use", "of", "the", "mentioned", "technology.", "However,", "our", "knowledge", "of", "normal", "tissue", "biology", "response", "mechanisms", "to", "large", "fraction", "sizes", "is", "relatively", "lacking", "compared", "to", "conventional", "fractionation.", "2.", "Radiobiologic", "Considerations", "A", "fundamental", "issue", "in", "SABR", "is", "whether", "classical", "radiobi-", "ologic", "modeling", "with", "the", "linear-quadratic", "(LQ)", "model", "is", "a", "valid", "method", "to", "assess", "the", "biologically", "effective", "dose", "at", "the", "high", "doses", "typically", "encountered", "in", "radiosurgery.", "This", "point", "was", "debated", "in", "back-to-back", "papers", "in", "seminars", "in", "radiation", "oncology", "[1,", "2],", "where", "Brenner", "argued", "that", "LQ", "formalism", "was", "appropriate", "whilst", "Kirkpatrick", "and", "colleagues", "suggested", "it", "was", "inappropriate.", "Brenner’s", "argument", "is", "based", "on", "the", "robustness", "of", "the", "LQ", "model", "to", "predict", "fractionation", "and", "dose-rate", "effects", "in", "experimental", "models", "in", "vitro", "and", "in", "vivo", "at", "doses", "up", "to", "10", "Gy.", "This", "conclusion", "is", "based", "on", "the", "premise", "that", "cell", "killing", "is", "the", "dominant", "process", "mediating", "the", "radiotherapeutic", "response", "for", "both", "early", "and", "late", "effects", "including", "vascular", "effects.", "Brenner", "argued", "that,", "to", "date,", "there" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 9, 9, 9, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 56, 61, 63, 14 ], [ 133, 61, 43, 14 ], [ 180, 61, 31, 14 ], [ 215, 61, 55, 14 ], [ 275, 61, 32, 14 ], [ 311, 61, 23, 14 ], [ 338, 61, 18, 14 ], [ 360, 61, 20, 14 ], [ 384, 61, 14, 14 ], [ 56, 77, 133, 14 ], [ 570, 61, 56, 14 ], [ 630, 61, 35, 14 ], [ 669, 61, 7, 14 ], [ 681, 61, 57, 14 ], [ 743, 61, 28, 14 ], [ 56, 112, 61, 28 ], [ 125, 112, 27, 28 ], [ 159, 112, 73, 28 ], [ 240, 112, 58, 28 ], [ 305, 112, 25, 28 ], [ 338, 112, 117, 28 ], [ 463, 112, 33, 28 ], [ 503, 112, 47, 28 ], [ 56, 142, 123, 28 ], [ 187, 142, 117, 28 ], [ 312, 142, 75, 28 ], [ 395, 142, 16, 28 ], [ 418, 142, 156, 28 ], [ 582, 142, 59, 28 ], [ 56, 173, 184, 28 ], [ 248, 173, 77, 28 ], [ 56, 214, 45, 17 ], [ 105, 214, 15, 17 ], [ 125, 214, 71, 17 ], [ 201, 214, 30, 17 ], [ 236, 214, 66, 17 ], [ 306, 214, 17, 17 ], [ 328, 214, 83, 17 ], [ 56, 250, 73, 14 ], [ 133, 250, 12, 14 ], [ 148, 250, 81, 14 ], [ 233, 250, 61, 14 ], [ 298, 250, 12, 14 ], [ 313, 250, 82, 14 ], [ 399, 250, 43, 14 ], [ 446, 250, 12, 14 ], [ 461, 250, 59, 14 ], [ 525, 250, 31, 14 ], [ 559, 250, 55, 14 ], [ 618, 250, 31, 14 ], [ 652, 250, 79, 14 ], [ 56, 266, 18, 14 ], [ 78, 266, 78, 14 ], [ 159, 266, 29, 14 ], [ 56, 301, 46, 12 ], [ 105, 301, 20, 12 ], [ 128, 301, 16, 12 ], [ 147, 301, 28, 12 ], [ 178, 301, 40, 12 ], [ 221, 301, 54, 12 ], [ 278, 301, 16, 12 ], [ 296, 301, 28, 12 ], [ 327, 301, 46, 12 ], [ 376, 301, 40, 12 ], [ 419, 301, 10, 12 ], [ 431, 301, 25, 12 ], [ 56, 349, 76, 14 ], [ 56, 373, 43, 14 ], [ 103, 373, 36, 14 ], [ 144, 373, 29, 14 ], [ 177, 373, 32, 14 ], [ 213, 373, 33, 14 ], [ 249, 373, 64, 14 ], [ 317, 373, 14, 14 ], [ 335, 373, 17, 14 ], [ 355, 373, 46, 14 ], [ 56, 390, 14, 14 ], [ 74, 390, 21, 14 ], [ 100, 390, 56, 14 ], [ 160, 390, 84, 14 ], [ 249, 390, 14, 14 ], [ 267, 390, 43, 14 ], [ 315, 390, 10, 14 ], [ 330, 390, 71, 14 ], [ 56, 406, 57, 14 ], [ 116, 406, 94, 14 ], [ 212, 406, 54, 14 ], [ 269, 406, 55, 14 ], [ 326, 406, 76, 14 ], [ 56, 423, 60, 14 ], [ 121, 423, 70, 14 ], [ 194, 423, 25, 14 ], [ 224, 423, 37, 14 ], [ 264, 423, 35, 14 ], [ 303, 423, 63, 14 ], [ 370, 423, 31, 14 ], [ 56, 439, 19, 14 ], [ 80, 439, 50, 14 ], [ 136, 439, 8, 14 ], [ 149, 439, 60, 14 ], [ 214, 439, 39, 14 ], [ 258, 439, 19, 14 ], [ 282, 439, 30, 14 ], [ 317, 439, 84, 14 ], [ 56, 456, 41, 14 ], [ 105, 456, 13, 14 ], [ 126, 456, 40, 14 ], [ 173, 456, 59, 14 ], [ 240, 456, 17, 14 ], [ 264, 456, 46, 14 ], [ 317, 456, 84, 14 ], [ 56, 473, 44, 14 ], [ 106, 473, 67, 14 ], [ 178, 473, 8, 14 ], [ 192, 473, 45, 14 ], [ 243, 473, 62, 14 ], [ 311, 473, 24, 14 ], [ 340, 473, 61, 14 ], [ 56, 489, 25, 14 ], [ 85, 489, 30, 14 ], [ 120, 489, 50, 14 ], [ 176, 489, 97, 14 ], [ 277, 489, 63, 14 ], [ 345, 489, 56, 14 ], [ 56, 506, 62, 14 ], [ 121, 506, 38, 14 ], [ 161, 506, 78, 14 ], [ 241, 506, 30, 14 ], [ 273, 506, 51, 14 ], [ 327, 506, 21, 14 ], [ 351, 506, 50, 14 ], [ 56, 522, 60, 14 ], [ 119, 522, 75, 14 ], [ 196, 522, 26, 14 ], [ 224, 522, 21, 14 ], [ 248, 522, 34, 14 ], [ 285, 522, 40, 14 ], [ 328, 522, 57, 14 ], [ 388, 522, 14, 14 ], [ 56, 539, 21, 14 ], [ 85, 539, 14, 14 ], [ 106, 539, 40, 14 ], [ 153, 539, 24, 14 ], [ 184, 539, 55, 14 ], [ 247, 539, 53, 14 ], [ 307, 539, 37, 14 ], [ 350, 539, 51, 14 ], [ 56, 555, 38, 14 ], [ 101, 555, 36, 14 ], [ 145, 555, 49, 14 ], [ 202, 555, 13, 14 ], [ 222, 555, 25, 14 ], [ 255, 555, 54, 14 ], [ 317, 555, 21, 14 ], [ 345, 555, 56, 14 ], [ 56, 572, 40, 14 ], [ 105, 572, 57, 14 ], [ 171, 572, 32, 14 ], [ 211, 572, 32, 14 ], [ 252, 572, 75, 14 ], [ 336, 572, 28, 14 ], [ 373, 572, 28, 14 ], [ 56, 589, 45, 14 ], [ 105, 586, 35, 17 ], [ 144, 589, 37, 14 ], [ 185, 589, 42, 14 ], [ 231, 589, 14, 14 ], [ 249, 589, 21, 14 ], [ 274, 589, 39, 14 ], [ 317, 589, 41, 14 ], [ 362, 589, 14, 14 ], [ 380, 589, 21, 14 ], [ 56, 605, 56, 14 ], [ 115, 605, 61, 14 ], [ 180, 605, 22, 14 ], [ 205, 603, 35, 17 ], [ 243, 605, 33, 14 ], [ 279, 605, 26, 14 ], [ 309, 605, 21, 14 ], [ 333, 605, 39, 14 ], [ 375, 605, 26, 14 ], [ 56, 619, 39, 17 ], [ 100, 622, 22, 14 ], [ 126, 622, 22, 14 ], [ 153, 619, 39, 17 ], [ 196, 622, 37, 14 ], [ 238, 622, 45, 14 ], [ 288, 622, 59, 14 ], [ 351, 622, 14, 14 ], [ 369, 622, 32, 14 ], [ 56, 639, 135, 14 ], [ 195, 639, 55, 14 ], [ 253, 639, 64, 14 ], [ 320, 639, 60, 14 ], [ 382, 639, 19, 14 ], [ 56, 655, 79, 14 ], [ 143, 655, 64, 14 ], [ 215, 655, 37, 14 ], [ 260, 655, 51, 14 ], [ 319, 655, 17, 14 ], [ 343, 655, 16, 14 ], [ 367, 655, 34, 14 ], [ 56, 672, 61, 14 ], [ 123, 672, 21, 14 ], [ 150, 672, 28, 14 ], [ 184, 672, 33, 14 ], [ 222, 672, 21, 14 ], [ 249, 672, 88, 14 ], [ 343, 672, 39, 14 ], [ 388, 672, 14, 14 ], [ 56, 688, 36, 14 ], [ 95, 688, 26, 14 ], [ 123, 688, 36, 14 ], [ 162, 688, 14, 14 ], [ 179, 688, 38, 14 ], [ 219, 688, 34, 14 ], [ 256, 688, 22, 14 ], [ 281, 688, 120, 14 ], [ 56, 705, 62, 14 ], [ 123, 705, 62, 14 ], [ 189, 705, 30, 14 ], [ 224, 705, 11, 14 ], [ 240, 705, 58, 14 ], [ 302, 705, 48, 14 ], [ 354, 705, 16, 14 ], [ 375, 705, 27, 14 ], [ 56, 722, 16, 14 ], [ 75, 722, 11, 14 ], [ 89, 722, 66, 14 ], [ 157, 722, 16, 14 ], [ 176, 722, 89, 14 ], [ 268, 722, 44, 14 ], [ 315, 722, 19, 14 ], [ 337, 722, 36, 14 ], [ 375, 722, 26, 14 ], [ 56, 735, 35, 17 ], [ 99, 738, 17, 14 ], [ 123, 738, 33, 14 ], [ 163, 738, 25, 14 ], [ 195, 738, 50, 14 ], [ 252, 738, 56, 14 ], [ 315, 738, 24, 14 ], [ 347, 738, 54, 14 ], [ 56, 755, 64, 14 ], [ 125, 755, 14, 14 ], [ 143, 755, 8, 14 ], [ 156, 755, 24, 14 ], [ 184, 755, 31, 14 ], [ 220, 755, 14, 14 ], [ 238, 755, 107, 14 ], [ 349, 755, 52, 14 ], [ 56, 771, 39, 14 ], [ 101, 771, 53, 14 ], [ 160, 771, 75, 14 ], [ 241, 771, 56, 14 ], [ 303, 771, 17, 14 ], [ 325, 771, 14, 14 ], [ 345, 771, 56, 14 ], [ 56, 788, 21, 14 ], [ 82, 788, 26, 14 ], [ 111, 788, 90, 14 ], [ 205, 788, 25, 14 ], [ 235, 788, 14, 14 ], [ 252, 788, 21, 14 ], [ 278, 788, 66, 14 ], [ 348, 788, 54, 14 ], [ 56, 805, 16, 14 ], [ 76, 805, 13, 14 ], [ 92, 805, 32, 14 ], [ 128, 805, 16, 14 ], [ 147, 805, 79, 14 ], [ 56, 844, 107, 14 ], [ 56, 866, 48, 14 ], [ 113, 866, 31, 14 ], [ 153, 866, 24, 14 ], [ 185, 866, 17, 14 ], [ 210, 866, 47, 14 ], [ 266, 866, 17, 14 ], [ 290, 866, 48, 14 ], [ 347, 866, 14, 14 ], [ 370, 866, 31, 14 ], [ 56, 881, 49, 14 ], [ 109, 881, 21, 14 ], [ 134, 881, 29, 14 ], [ 166, 881, 18, 14 ], [ 188, 881, 41, 14 ], [ 232, 881, 24, 14 ], [ 260, 881, 110, 14 ], [ 373, 881, 28, 14 ], [ 56, 896, 31, 14 ], [ 91, 896, 9, 14 ], [ 105, 896, 19, 14 ], [ 128, 896, 27, 14 ], [ 159, 896, 51, 14 ], [ 214, 896, 17, 14 ], [ 235, 896, 31, 14 ], [ 271, 896, 26, 14 ], [ 301, 896, 49, 14 ], [ 354, 896, 21, 14 ], [ 380, 896, 21, 14 ], [ 56, 912, 74, 14 ], [ 134, 912, 10, 14 ], [ 147, 912, 38, 14 ], [ 188, 912, 21, 14 ], [ 212, 912, 11, 14 ], [ 227, 912, 79, 14 ], [ 309, 912, 24, 14 ], [ 336, 912, 65, 14 ], [ 56, 927, 11, 14 ], [ 72, 927, 17, 14 ], [ 94, 927, 53, 14 ], [ 151, 927, 29, 14 ], [ 185, 927, 21, 14 ], [ 210, 927, 17, 14 ], [ 232, 927, 22, 14 ], [ 259, 927, 12, 14 ], [ 275, 927, 17, 14 ], [ 297, 927, 40, 14 ], [ 342, 927, 45, 14 ], [ 392, 927, 10, 14 ], [ 56, 942, 39, 14 ], [ 102, 942, 11, 14 ], [ 119, 942, 25, 14 ], [ 150, 942, 20, 14 ], [ 177, 942, 45, 14 ], [ 228, 942, 18, 14 ], [ 252, 942, 31, 14 ], [ 290, 942, 24, 14 ], [ 319, 942, 20, 14 ], [ 346, 942, 55, 14 ], [ 426, 348, 31, 14 ], [ 459, 348, 25, 14 ], [ 488, 348, 24, 14 ], [ 515, 348, 42, 14 ], [ 560, 348, 17, 14 ], [ 580, 348, 36, 14 ], [ 620, 348, 12, 14 ], [ 635, 348, 55, 14 ], [ 693, 348, 31, 14 ], [ 728, 348, 43, 14 ], [ 426, 364, 40, 14 ], [ 469, 364, 21, 14 ], [ 493, 364, 30, 14 ], [ 526, 364, 49, 14 ], [ 578, 364, 11, 14 ], [ 593, 364, 29, 14 ], [ 625, 364, 18, 14 ], [ 646, 364, 38, 14 ], [ 688, 364, 51, 14 ], [ 742, 364, 28, 14 ], [ 426, 379, 28, 14 ], [ 457, 379, 34, 14 ], [ 440, 394, 22, 14 ], [ 466, 394, 22, 14 ], [ 492, 394, 12, 14 ], [ 508, 394, 35, 14 ], [ 547, 394, 37, 14 ], [ 588, 394, 19, 14 ], [ 611, 394, 27, 14 ], [ 642, 394, 41, 14 ], [ 686, 394, 64, 14 ], [ 754, 394, 17, 14 ], [ 426, 409, 51, 14 ], [ 485, 409, 12, 14 ], [ 505, 409, 18, 14 ], [ 531, 409, 71, 14 ], [ 610, 409, 10, 14 ], [ 628, 409, 42, 14 ], [ 678, 409, 40, 14 ], [ 727, 409, 44, 14 ], [ 426, 424, 70, 14 ], [ 502, 424, 34, 14 ], [ 542, 424, 47, 14 ], [ 595, 424, 33, 14 ], [ 634, 424, 56, 14 ], [ 696, 424, 49, 14 ], [ 750, 424, 21, 14 ], [ 426, 440, 52, 14 ], [ 485, 440, 37, 14 ], [ 530, 440, 19, 14 ], [ 557, 440, 49, 14 ], [ 613, 440, 70, 14 ], [ 690, 440, 20, 14 ], [ 718, 440, 52, 14 ], [ 426, 455, 60, 14 ], [ 489, 455, 14, 14 ], [ 507, 455, 12, 14 ], [ 523, 455, 34, 14 ], [ 561, 455, 29, 14 ], [ 594, 455, 18, 14 ], [ 616, 455, 83, 14 ], [ 703, 455, 67, 14 ], [ 426, 470, 61, 14 ], [ 490, 470, 54, 14 ], [ 549, 470, 34, 14 ], [ 586, 470, 49, 14 ], [ 640, 470, 27, 14 ], [ 671, 470, 39, 14 ], [ 714, 470, 57, 14 ], [ 426, 485, 55, 14 ], [ 486, 485, 36, 14 ], [ 527, 485, 26, 14 ], [ 559, 485, 48, 14 ], [ 613, 485, 51, 14 ], [ 669, 485, 22, 14 ], [ 697, 485, 40, 14 ], [ 743, 485, 28, 14 ], [ 426, 500, 30, 14 ], [ 461, 500, 46, 14 ], [ 513, 500, 28, 14 ], [ 548, 500, 12, 14 ], [ 566, 500, 24, 14 ], [ 595, 500, 57, 14 ], [ 658, 500, 34, 14 ], [ 697, 500, 46, 14 ], [ 749, 500, 21, 14 ], [ 426, 516, 17, 14 ], [ 451, 516, 43, 14 ], [ 502, 516, 11, 14 ], [ 521, 516, 14, 14 ], [ 543, 516, 49, 14 ], [ 600, 516, 11, 14 ], [ 619, 516, 31, 14 ], [ 658, 516, 71, 14 ], [ 737, 516, 34, 14 ], [ 426, 531, 34, 14 ], [ 465, 531, 49, 14 ], [ 519, 531, 20, 14 ], [ 544, 531, 35, 14 ], [ 584, 528, 31, 17 ], [ 620, 531, 36, 14 ], [ 661, 528, 31, 17 ], [ 697, 531, 17, 14 ], [ 719, 531, 52, 14 ], [ 426, 546, 39, 14 ], [ 471, 546, 29, 14 ], [ 507, 546, 31, 14 ], [ 546, 546, 24, 14 ], [ 576, 546, 20, 14 ], [ 602, 546, 25, 14 ], [ 634, 546, 20, 14 ], [ 662, 546, 17, 14 ], [ 685, 546, 30, 14 ], [ 722, 546, 49, 14 ], [ 426, 561, 42, 14 ], [ 472, 561, 36, 14 ], [ 512, 561, 47, 14 ], [ 563, 561, 41, 14 ], [ 440, 577, 33, 14 ], [ 481, 577, 62, 14 ], [ 551, 577, 17, 14 ], [ 576, 577, 31, 14 ], [ 615, 577, 43, 14 ], [ 667, 577, 14, 14 ], [ 689, 577, 37, 14 ], [ 735, 577, 36, 14 ], [ 426, 592, 49, 14 ], [ 483, 592, 27, 14 ], [ 517, 592, 27, 14 ], [ 551, 592, 55, 14 ], [ 614, 592, 42, 14 ], [ 664, 592, 37, 14 ], [ 709, 592, 10, 14 ], [ 727, 592, 44, 14 ], [ 426, 607, 55, 14 ], [ 487, 607, 63, 14 ], [ 557, 607, 14, 14 ], [ 578, 607, 33, 14 ], [ 617, 607, 87, 14 ], [ 710, 607, 27, 14 ], [ 744, 607, 27, 14 ], [ 426, 622, 37, 14 ], [ 467, 622, 11, 14 ], [ 484, 622, 42, 14 ], [ 531, 622, 21, 14 ], [ 557, 622, 31, 14 ], [ 594, 622, 34, 14 ], [ 633, 622, 35, 14 ], [ 673, 622, 10, 14 ], [ 689, 622, 17, 14 ], [ 712, 622, 34, 14 ], [ 751, 622, 20, 14 ], [ 426, 637, 48, 14 ], [ 478, 637, 18, 14 ], [ 500, 637, 18, 14 ], [ 523, 637, 48, 14 ], [ 575, 637, 12, 14 ], [ 591, 637, 55, 14 ], [ 650, 637, 27, 14 ], [ 681, 637, 25, 14 ], [ 711, 637, 20, 14 ], [ 736, 637, 35, 14 ], [ 426, 653, 31, 14 ], [ 462, 653, 58, 14 ], [ 525, 653, 22, 14 ], [ 552, 653, 29, 14 ], [ 587, 653, 65, 14 ], [ 657, 653, 47, 14 ], [ 709, 653, 17, 14 ], [ 732, 653, 39, 14 ], [ 426, 668, 60, 14 ], [ 494, 668, 21, 14 ], [ 524, 668, 25, 14 ], [ 557, 668, 20, 14 ], [ 586, 668, 31, 14 ], [ 626, 668, 10, 14 ], [ 644, 668, 49, 14 ], [ 702, 668, 69, 14 ], [ 426, 683, 62, 14 ], [ 494, 683, 55, 14 ], [ 555, 683, 65, 14 ], [ 626, 683, 12, 14 ], [ 645, 683, 7, 14 ], [ 658, 683, 34, 14 ], [ 698, 683, 35, 14 ], [ 739, 683, 31, 14 ], [ 426, 698, 11, 14 ], [ 441, 698, 17, 14 ], [ 463, 698, 44, 14 ], [ 511, 698, 12, 14 ], [ 528, 698, 50, 14 ], [ 582, 698, 31, 14 ], [ 617, 698, 35, 14 ], [ 657, 698, 17, 14 ], [ 678, 698, 27, 14 ], [ 709, 698, 17, 14 ], [ 730, 698, 41, 14 ], [ 426, 714, 24, 14 ], [ 453, 714, 50, 14 ], [ 506, 714, 43, 14 ], [ 552, 714, 11, 14 ], [ 566, 714, 47, 14 ], [ 616, 714, 31, 14 ], [ 651, 714, 43, 14 ], [ 697, 714, 10, 14 ], [ 711, 714, 17, 14 ], [ 732, 714, 39, 14 ], [ 426, 729, 23, 14 ], [ 453, 729, 16, 14 ], [ 472, 729, 7, 14 ], [ 482, 729, 27, 14 ], [ 513, 729, 62, 14 ], [ 578, 729, 8, 14 ], [ 590, 729, 19, 14 ], [ 613, 729, 23, 14 ], [ 639, 729, 27, 14 ], [ 670, 729, 51, 14 ], [ 724, 729, 21, 14 ], [ 749, 729, 21, 14 ], [ 426, 744, 37, 14 ], [ 466, 744, 29, 14 ], [ 499, 744, 25, 14 ], [ 528, 744, 18, 14 ], [ 549, 744, 22, 14 ], [ 575, 744, 55, 14 ], [ 634, 744, 48, 14 ], [ 686, 744, 20, 14 ], [ 710, 744, 18, 14 ], [ 732, 744, 39, 14 ], [ 426, 759, 55, 14 ], [ 485, 759, 27, 14 ], [ 440, 775, 22, 14 ], [ 466, 775, 38, 14 ], [ 510, 775, 104, 14 ], [ 619, 775, 28, 14 ], [ 652, 775, 34, 14 ], [ 691, 775, 51, 14 ], [ 746, 775, 24, 14 ], [ 426, 790, 10, 14 ], [ 440, 790, 7, 14 ], [ 451, 790, 46, 14 ], [ 502, 790, 12, 14 ], [ 519, 790, 18, 14 ], [ 541, 790, 37, 14 ], [ 583, 790, 36, 14 ], [ 624, 790, 67, 14 ], [ 695, 790, 20, 14 ], [ 720, 790, 19, 14 ], [ 744, 790, 27, 14 ], [ 426, 805, 64, 14 ], [ 494, 805, 40, 14 ], [ 540, 805, 17, 14 ], [ 561, 805, 31, 14 ], [ 597, 805, 43, 14 ], [ 645, 805, 11, 14 ], [ 660, 805, 17, 14 ], [ 683, 805, 53, 16 ], [ 740, 805, 31, 14 ], [ 426, 820, 61, 14 ], [ 491, 820, 12, 14 ], [ 507, 820, 28, 14 ], [ 538, 820, 31, 14 ], [ 573, 820, 20, 14 ], [ 598, 820, 38, 14 ], [ 640, 820, 42, 14 ], [ 686, 820, 53, 14 ], [ 743, 820, 28, 14 ], [ 426, 835, 16, 14 ], [ 447, 835, 12, 14 ], [ 464, 835, 52, 14 ], [ 522, 835, 20, 14 ], [ 547, 835, 11, 14 ], [ 564, 835, 17, 14 ], [ 586, 835, 45, 14 ], [ 636, 835, 12, 14 ], [ 653, 835, 30, 14 ], [ 689, 835, 50, 14 ], [ 744, 835, 27, 14 ], [ 426, 850, 47, 14 ], [ 476, 850, 43, 14 ], [ 522, 850, 12, 14 ], [ 538, 850, 7, 14 ], [ 548, 850, 34, 14 ], [ 585, 848, 31, 17 ], [ 619, 850, 18, 14 ], [ 640, 850, 47, 14 ], [ 691, 850, 18, 14 ], [ 712, 850, 21, 14 ], [ 736, 850, 34, 14 ], [ 426, 866, 21, 14 ], [ 450, 866, 46, 14 ], [ 499, 866, 55, 14 ], [ 557, 866, 18, 14 ], [ 579, 866, 27, 14 ], [ 610, 866, 27, 14 ], [ 640, 866, 36, 14 ], [ 680, 863, 31, 17 ], [ 714, 866, 43, 14 ], [ 760, 866, 10, 14 ], [ 426, 881, 18, 14 ], [ 450, 881, 39, 14 ], [ 496, 881, 20, 14 ], [ 523, 881, 47, 14 ], [ 577, 881, 46, 14 ], [ 630, 881, 24, 14 ], [ 662, 881, 20, 14 ], [ 690, 881, 33, 14 ], [ 730, 881, 41, 14 ], [ 426, 896, 55, 14 ], [ 485, 896, 12, 14 ], [ 501, 896, 17, 14 ], [ 524, 896, 31, 14 ], [ 559, 896, 47, 14 ], [ 610, 896, 28, 14 ], [ 643, 896, 37, 14 ], [ 685, 896, 15, 14 ], [ 705, 896, 11, 14 ], [ 720, 896, 18, 14 ], [ 743, 896, 28, 14 ], [ 426, 911, 26, 14 ], [ 456, 911, 12, 14 ], [ 472, 909, 28, 17 ], [ 504, 911, 12, 14 ], [ 521, 909, 27, 17 ], [ 552, 911, 24, 14 ], [ 580, 911, 48, 14 ], [ 632, 911, 21, 14 ], [ 658, 911, 35, 14 ], [ 697, 911, 37, 14 ], [ 738, 911, 10, 14 ], [ 753, 911, 17, 14 ], [ 426, 927, 48, 14 ], [ 478, 927, 26, 14 ], [ 509, 927, 20, 14 ], [ 534, 927, 55, 14 ], [ 594, 927, 29, 14 ], [ 628, 927, 60, 14 ], [ 692, 927, 18, 14 ], [ 715, 927, 18, 14 ], [ 738, 927, 32, 14 ], [ 426, 942, 40, 14 ], [ 470, 942, 48, 14 ], [ 522, 942, 46, 14 ], [ 572, 942, 73, 14 ], [ 649, 942, 79, 14 ], [ 56, 975, 18, 12 ], [ 78, 975, 28, 12 ], [ 109, 975, 70, 12 ], [ 182, 975, 30, 12 ], [ 215, 975, 11, 12 ], [ 229, 975, 47, 12 ], [ 279, 975, 19, 12 ], [ 301, 975, 12, 12 ], [ 316, 975, 17, 12 ], [ 336, 975, 17, 12 ], [ 356, 975, 26, 12 ], [ 385, 975, 20, 12 ], [ 409, 975, 12, 12 ], [ 424, 975, 17, 12 ], [ 444, 975, 17, 12 ], [ 464, 975, 26, 12 ], [ 493, 975, 30, 12 ], [ 526, 975, 141, 12 ], [ 69, 1000, 23, 12 ], [ 94, 1000, 18, 12 ], [ 115, 1000, 46, 12 ], [ 56, 1013, 20, 12 ], [ 79, 1013, 8, 12 ], [ 89, 1013, 11, 12 ], [ 102, 1013, 24, 12 ], [ 129, 1013, 32, 12 ], [ 163, 1013, 28, 12 ], [ 194, 1013, 48, 12 ], [ 244, 1013, 26, 12 ], [ 272, 1013, 14, 12 ], [ 289, 1013, 25, 12 ], [ 316, 1013, 10, 12 ], [ 328, 1013, 14, 12 ], [ 345, 1013, 38, 12 ], [ 385, 1013, 46, 12 ], [ 433, 1013, 50, 12 ], [ 485, 1013, 78, 12 ], [ 566, 1013, 35, 12 ], [ 603, 1013, 168, 12 ], [ 56, 1025, 64, 11 ], [ 123, 1025, 28, 11 ], [ 154, 1025, 34, 11 ], [ 190, 1025, 53, 11 ], [ 246, 1025, 73, 11 ], [ 323, 1025, 18, 11 ], [ 344, 1025, 54, 11 ], [ 401, 1025, 16, 11 ], [ 421, 1025, 57, 11 ], [ 481, 1025, 9, 11 ], [ 493, 1025, 17, 11 ], [ 513, 1025, 40, 11 ], [ 556, 1025, 40, 11 ], [ 599, 1025, 14, 11 ], [ 616, 1025, 35, 11 ], [ 654, 1025, 23, 11 ], [ 680, 1025, 8, 11 ], [ 691, 1025, 38, 11 ], [ 733, 1025, 25, 11 ] ]

[ "6116–6125", "Nucleic", "Acids", "Research,", "2006,", "Vol.", "34,", "No.", "21", "doi:10.1093/nar/gkl862", "Published", "online", "3", "November", "2006", "Role", "of", "metal", "ions", "in", "catalysis", "by", "HIV", "integrase", "analyzed", "using", "a", "quantitative", "PCR", "disintegration", "assay", "Tracy", "L.", "Diamond", "and", "Frederic", "D.", "Bushman*", "Department", "of", "Microbiology,", "University", "of", "Pennsylvania", "School", "of", "Medicine,", "3610", "Hamilton", "Walk", "Philadelphia,", "PA", "19104-6076,", "USA", "Received", "July", "27,", "2006;", "Revised", "September", "29,", "2006;", "Accepted", "October", "3,", "2006", "ABSTRACT", "Paired", "metal", "ions", "have", "been", "proposed", "to", "be", "central", "to", "the", "catalytic", "mechanisms", "of", "RNase", "H", "nucleases,", "bacterial", "transposases,", "Holliday", "junction", "resolvases,", "retroviral", "integrases", "and", "many", "other", "enzymes.", "Here", "we", "present", "a", "sensitive", "assay", "for", "DNA", "transesterifi-", "cation", "in", "which", "catalysis", "by", "human", "immunodefi-", "ciency", "virus-type", "1", "(HIV-1)", "integrase", "(IN)", "connects", "two", "DNA", "strands", "(disintegration", "reaction),", "allowing", "detection", "using", "quantitative", "PCR", "(qPCR).", "We", "present", "evidence", "suggesting", "that", "the", "three", "acidic", "residues", "of", "the", "IN", "active", "site", "function", "through", "metal", "binding", "using", "metal", "rescue.", "In", "this", "method,", "the", "catalytic", "acidic", "residues", "were", "each", "substituted", "with", "cys-", "teines.", "Mn21", "binds", "tightly", "to", "the", "sulfur", "atoms", "of", "the", "cysteine", "residues,", "but", "Mg21", "does", "not.", "We", "found", "that", "Mn21,", "but", "not", "Mg21,", "could", "rescue", "catalysis", "of", "each", "cysteine-substituted", "enzyme,", "providing", "evidence", "for", "functionally", "important", "metal", "binding", "by", "all", "three", "residues.", "We", "also", "used", "the", "PCR-boosted", "assay", "to", "show", "that", "HIV-1", "IN", "could", "carry", "out", "transesterification", "reactions", "involving", "DNA", "50", "hydroxyl", "groups", "as", "well", "as", "30", "hydroxyls", "as", "nucleophiles.", "Lastly,", "we", "show", "that", "Mn21", "by", "itself", "(i.e.", "without", "enzyme)", "can", "catalyze", "formation", "of", "a", "low", "level", "of", "PCR-amplifiable", "product", "under", "extreme", "conditions,", "allowing", "us", "to", "estimate", "the", "rate", "enhancement", "due", "to", "the", "IN-protein", "scaffold", "as", "at", "least", "60", "million-fold.", "INTRODUCTION", "Divalent", "metal", "ions", "are", "required", "for", "catalysis", "by", "many", "enzymes", "that", "carry", "out", "nucleic", "acid", "phosphoryl-transfer", "reac-", "tions.", "It", "has", "been", "proposed", "for", "many", "such", "enzymes", "that", "rate", "enhancement", "is", "mostly", "due", "to", "metal–nucleic", "acid", "interactions", "in", "the", "transition", "state,", "and", "the", "role", "of", "the", "protein", "scaffold", "is", "mainly", "to", "bind", "and", "position", "the", "metal", "ions", "and", "substrates", "(1,2).", "This", "may", "explain", "the", "ability", "of", "dissimilar", "metal", "binding", "protein", "and", "RNA", "enzymes", "to", "carry", "out", "related", "chemical", "reac-", "tions", "(3–5).", "The", "role", "of", "bound", "metals", "has", "been", "studied", "extensively", "for", "members", "of", "the", "ribonuclease", "H", "(RNase", "H)-like", "enzyme", "superfamily,", "which", "includes", "RuvC", "resolvase,", "bacterial", "and", "retroviral", "RNase", "Hs,", "bacterial", "transposases", "and", "retroviral", "integrases,", "all", "of", "which", "carry", "out", "polynucleotide", "phosphoryl-", "transferase", "reactions.", "These", "enzymes", "have", "similar", "secondary", "structures", "within", "their", "catalytic", "domains.", "The", "protein", "folds", "bring", "together", "three", "or", "four", "conserved", "acidic", "residues", "that", "are", "thought", "to", "be", "involved", "in", "metal", "coordination", "(4–7).", "These", "enzymes", "can", "utilize", "Mn2+", "and/or", "Mg2+", "for", "catalysis,", "though", "other", "metal", "ions", "can", "bind", "and", "for", "some", "enzymes", "support", "partial", "function", "(8–12).", "Three", "hypotheses", "for", "metal", "binding", "by", "RNase", "H-like", "enzymes", "have", "been", "proposed.", "Several", "RNase", "H", "enzyme", "structures", "determined", "by", "X-ray", "crystallography", "have", "been", "shown", "to", "contain", "two", "metal", "atoms", "bound", "at", "the", "active", "site", "(12–14),", "but", "the", "majority", "of", "structures", "have", "only", "one", "bound", "metal", "(9,15–19).", "The", "latter", "observation", "supports", "the", "second", "hypothesis", "that", "only", "one", "metal", "is", "involved", "catalytically", "(16,20,21).", "However,", "observation", "of", "a", "single", "bound", "metal", "in", "the", "absence", "of", "substrate", "could", "reflect", "the", "need", "for", "nucleic", "acid", "substrate", "binding", "to", "stabilize", "metal", "binding", "at", "the", "second", "site.", "As", "a", "third", "possibility,", "it", "has", "also", "been", "proposed", "that", "two", "metals", "bind,", "with", "the", "first", "activating", "catalysis", "and", "the", "second", "inhibiting", "(22).", "The", "human", "immunodeficiency", "virus", "(HIV)", "integrase", "(IN)", "is", "a", "member", "of", "the", "RNase", "H-like", "superfamily", "and", "has", "been", "extensively", "studied", "for", "metal", "binding", "at", "the", "D,DX35E", "motif", "(composed", "of", "D64,", "D116", "and", "E152).", "Several", "structural", "stud-", "ies", "of", "retroviral", "INs", "in", "the", "absence", "of", "DNA", "substrate", "have", "reported", "binding", "of", "a", "single", "Mg2+", "ion", "between", "the", "two", "aspar-", "tate", "residues", "(8,17,18),", "but", "none", "have", "shown", "Mg2+", "binding", "at", "the", "second", "site", "between", "residues", "D64", "and", "E152.", "Crystal", "structures", "of", "the", "avian", "sarcoma", "virus", "(ASV)", "IN", "in", "the", "pres-", "ence", "of", "Cd2+", "or", "Zn2+", "ions", "revealed", "two", "bound", "metals", "at", "the", "catalytic", "triad", "(8).", "However,", "these", "complexes", "did", "not", "retain", "normal", "catalytic", "activity,", "complicating", "interpretation.", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "215", "573", "8732;", "Fax:", "+1", "215", "573", "4856;", "Email:", "bushman@mail.med.upenn.edu", "2006", "The", "Author(s).", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 233, 114, 104, 20 ], [ 343, 114, 44, 20 ], [ 393, 114, 8, 20 ], [ 407, 114, 52, 20 ], [ 465, 114, 164, 20 ], [ 634, 114, 80, 20 ], [ 233, 137, 63, 20 ], [ 302, 137, 77, 20 ], [ 383, 137, 31, 20 ], [ 421, 137, 79, 20 ], [ 506, 137, 18, 20 ], [ 530, 137, 53, 20 ], [ 589, 137, 109, 20 ], [ 233, 160, 76, 20 ], [ 315, 160, 21, 20 ], [ 342, 160, 27, 20 ], [ 375, 160, 66, 20 ], [ 447, 160, 148, 20 ], [ 601, 160, 77, 20 ], [ 233, 183, 45, 20 ], [ 284, 183, 77, 20 ], [ 368, 183, 36, 20 ], [ 410, 183, 32, 20 ], [ 448, 183, 46, 20 ], [ 233, 211, 19, 17 ], [ 256, 211, 45, 17 ], [ 305, 211, 9, 17 ], [ 316, 211, 54, 17 ], [ 374, 211, 71, 17 ], [ 447, 211, 75, 17 ], [ 527, 211, 28, 17 ], [ 559, 210, 64, 18 ], [ 233, 229, 42, 17 ], [ 279, 229, 45, 17 ], [ 328, 229, 24, 17 ], [ 356, 229, 42, 17 ], [ 402, 229, 14, 17 ], [ 418, 229, 53, 17 ], [ 233, 277, 25, 13 ], [ 261, 277, 14, 13 ], [ 278, 277, 60, 13 ], [ 341, 277, 9, 13 ], [ 353, 277, 47, 13 ], [ 402, 277, 38, 13 ], [ 443, 277, 36, 13 ], [ 482, 277, 34, 13 ], [ 518, 277, 35, 13 ], [ 555, 277, 64, 13 ], [ 623, 277, 37, 13 ], [ 661, 277, 17, 13 ], [ 682, 277, 14, 13 ], [ 233, 293, 76, 14 ], [ 312, 293, 35, 13 ], [ 350, 293, 40, 13 ], [ 393, 293, 34, 13 ], [ 429, 293, 64, 13 ], [ 496, 293, 37, 13 ], [ 536, 293, 43, 13 ], [ 581, 293, 36, 13 ], [ 233, 309, 64, 13 ], [ 300, 309, 33, 13 ], [ 233, 365, 63, 15 ], [ 233, 385, 33, 15 ], [ 271, 385, 21, 15 ], [ 296, 385, 26, 15 ], [ 327, 385, 41, 15 ], [ 373, 385, 27, 15 ], [ 405, 385, 49, 15 ], [ 459, 385, 54, 15 ], [ 518, 385, 27, 15 ], [ 550, 385, 12, 15 ], [ 566, 385, 18, 15 ], [ 590, 385, 58, 15 ], [ 653, 385, 29, 15 ], [ 687, 385, 12, 15 ], [ 704, 385, 40, 15 ], [ 749, 385, 19, 15 ], [ 233, 401, 80, 15 ], [ 315, 401, 57, 15 ], [ 376, 401, 36, 15 ], [ 415, 401, 30, 15 ], [ 448, 401, 61, 15 ], [ 512, 401, 12, 15 ], [ 527, 401, 40, 15 ], [ 570, 401, 21, 15 ], [ 593, 401, 41, 15 ], [ 638, 401, 33, 15 ], [ 674, 401, 92, 15 ], [ 233, 417, 15, 15 ], [ 251, 417, 49, 15 ], [ 304, 417, 44, 15 ], [ 351, 417, 24, 15 ], [ 379, 417, 5, 15 ], [ 388, 417, 56, 15 ], [ 448, 417, 28, 15 ], [ 479, 417, 18, 15 ], [ 501, 417, 36, 15 ], [ 541, 417, 12, 15 ], [ 556, 417, 18, 15 ], [ 578, 417, 70, 15 ], [ 652, 417, 55, 15 ], [ 710, 417, 12, 15 ], [ 726, 417, 18, 15 ], [ 748, 417, 19, 15 ], [ 233, 433, 31, 15 ], [ 267, 433, 36, 15 ], [ 306, 433, 18, 15 ], [ 328, 433, 24, 15 ], [ 355, 433, 5, 15 ], [ 364, 433, 33, 15 ], [ 400, 433, 35, 15 ], [ 439, 433, 17, 15 ], [ 459, 433, 39, 15 ], [ 501, 433, 55, 15 ], [ 560, 433, 43, 15 ], [ 606, 433, 101, 15 ], [ 711, 433, 55, 15 ], [ 233, 449, 46, 15 ], [ 282, 449, 54, 15 ], [ 340, 449, 21, 15 ], [ 364, 449, 45, 15 ], [ 412, 449, 17, 15 ], [ 433, 449, 50, 15 ], [ 486, 449, 45, 15 ], [ 535, 449, 12, 15 ], [ 550, 449, 18, 15 ], [ 572, 449, 35, 15 ], [ 611, 449, 12, 15 ], [ 626, 449, 27, 15 ], [ 656, 449, 33, 15 ], [ 692, 449, 21, 15 ], [ 716, 449, 26, 15 ], [ 745, 449, 12, 15 ], [ 760, 449, 6, 15 ], [ 233, 465, 40, 15 ], [ 276, 465, 63, 15 ], [ 342, 465, 20, 15 ], [ 365, 465, 21, 15 ], [ 390, 465, 10, 15 ], [ 403, 465, 24, 15 ], [ 431, 465, 11, 15 ], [ 444, 465, 12, 15 ], [ 459, 465, 43, 15 ], [ 506, 465, 63, 15 ], [ 571, 465, 24, 15 ], [ 599, 465, 32, 15 ], [ 634, 465, 60, 15 ], [ 697, 465, 26, 15 ], [ 727, 465, 40, 15 ], [ 233, 481, 24, 15 ], [ 262, 481, 5, 15 ], [ 271, 481, 35, 15 ], [ 311, 481, 65, 15 ], [ 380, 481, 21, 15 ], [ 405, 481, 66, 15 ], [ 476, 481, 12, 15 ], [ 493, 481, 35, 15 ], [ 532, 481, 24, 15 ], [ 561, 481, 5, 15 ], [ 571, 481, 33, 15 ], [ 609, 481, 35, 15 ], [ 648, 481, 15, 15 ], [ 668, 481, 20, 15 ], [ 692, 481, 37, 15 ], [ 734, 481, 12, 15 ], [ 750, 481, 17, 15 ], [ 233, 497, 31, 15 ], [ 267, 497, 20, 15 ], [ 290, 497, 73, 15 ], [ 366, 497, 40, 15 ], [ 409, 497, 10, 15 ], [ 423, 497, 33, 15 ], [ 458, 497, 21, 15 ], [ 482, 497, 26, 15 ], [ 511, 497, 17, 15 ], [ 531, 497, 25, 15 ], [ 560, 497, 33, 15 ], [ 596, 497, 12, 15 ], [ 610, 497, 20, 15 ], [ 634, 497, 65, 15 ], [ 701, 497, 40, 15 ], [ 744, 497, 22, 15 ], [ 233, 513, 55, 15 ], [ 292, 513, 68, 15 ], [ 364, 513, 46, 15 ], [ 414, 513, 21, 15 ], [ 439, 513, 45, 15 ], [ 489, 513, 38, 15 ], [ 531, 513, 40, 15 ], [ 575, 513, 77, 15 ], [ 657, 513, 22, 15 ], [ 683, 513, 31, 15 ], [ 719, 513, 27, 15 ], [ 750, 513, 17, 15 ], [ 233, 529, 25, 15 ], [ 263, 529, 28, 15 ], [ 296, 529, 105, 15 ], [ 406, 529, 35, 15 ], [ 447, 529, 24, 15 ], [ 476, 529, 5, 15 ], [ 486, 529, 70, 15 ], [ 561, 529, 69, 15 ], [ 635, 529, 24, 15 ], [ 664, 529, 5, 15 ], [ 674, 529, 56, 15 ], [ 736, 529, 32, 15 ], [ 233, 545, 28, 15 ], [ 264, 545, 19, 15 ], [ 286, 545, 25, 15 ], [ 314, 545, 12, 15 ], [ 329, 545, 31, 15 ], [ 362, 545, 63, 15 ], [ 429, 545, 14, 15 ], [ 446, 545, 38, 15 ], [ 486, 545, 28, 15 ], [ 517, 545, 27, 15 ], [ 547, 545, 19, 15 ], [ 569, 545, 20, 15 ], [ 592, 545, 12, 15 ], [ 607, 545, 31, 15 ], [ 641, 545, 71, 15 ], [ 715, 545, 52, 15 ], [ 233, 561, 21, 15 ], [ 257, 561, 45, 15 ], [ 305, 561, 104, 15 ], [ 412, 561, 53, 15 ], [ 469, 561, 86, 15 ], [ 558, 561, 12, 15 ], [ 574, 561, 27, 15 ], [ 604, 561, 40, 15 ], [ 233, 585, 23, 15 ], [ 259, 585, 37, 15 ], [ 310, 585, 63, 15 ], [ 376, 585, 5, 15 ], [ 385, 585, 92, 15 ], [ 480, 585, 5, 15 ], [ 490, 585, 40, 15 ], [ 533, 585, 5, 15 ], [ 541, 585, 35, 15 ], [ 580, 585, 24, 15 ], [ 608, 585, 5, 15 ], [ 616, 585, 6, 15 ], [ 625, 585, 45, 15 ], [ 75, 641, 107, 41 ], [ 183, 646, 67, 31 ], [ 254, 646, 55, 31 ], [ 310, 646, 99, 31 ], [ 75, 678, 28, 15 ], [ 107, 678, 20, 15 ], [ 132, 678, 31, 15 ], [ 169, 678, 32, 15 ], [ 206, 678, 18, 15 ], [ 229, 678, 44, 15 ], [ 278, 678, 12, 15 ], [ 295, 678, 92, 15 ], [ 392, 678, 17, 15 ], [ 75, 694, 39, 15 ], [ 118, 694, 12, 15 ], [ 134, 694, 18, 15 ], [ 157, 694, 61, 15 ], [ 222, 694, 63, 15 ], [ 290, 694, 21, 15 ], [ 315, 694, 55, 15 ], [ 374, 694, 12, 15 ], [ 391, 694, 18, 15 ], [ 75, 710, 23, 15 ], [ 103, 710, 12, 15 ], [ 120, 710, 24, 15 ], [ 150, 710, 5, 15 ], [ 160, 710, 35, 15 ], [ 201, 710, 59, 15 ], [ 266, 710, 15, 15 ], [ 287, 710, 29, 15 ], [ 321, 710, 28, 15 ], [ 354, 710, 9, 15 ], [ 369, 710, 9, 15 ], [ 383, 710, 26, 15 ], [ 75, 726, 27, 15 ], [ 106, 726, 22, 15 ], [ 133, 726, 63, 15 ], [ 201, 726, 24, 15 ], [ 230, 726, 40, 15 ], [ 276, 726, 27, 15 ], [ 307, 726, 43, 15 ], [ 356, 726, 53, 15 ], [ 75, 742, 57, 15 ], [ 136, 742, 26, 15 ], [ 167, 742, 21, 15 ], [ 193, 742, 65, 15 ], [ 263, 742, 53, 15 ], [ 321, 742, 57, 15 ], [ 383, 742, 26, 15 ], [ 75, 758, 24, 15 ], [ 104, 758, 5, 15 ], [ 114, 758, 53, 15 ], [ 171, 758, 18, 15 ], [ 194, 758, 27, 15 ], [ 226, 758, 18, 15 ], [ 249, 758, 48, 15 ], [ 302, 758, 12, 15 ], [ 319, 758, 29, 15 ], [ 353, 758, 56, 15 ], [ 75, 774, 21, 15 ], [ 104, 774, 27, 15 ], [ 139, 774, 71, 15 ], [ 218, 774, 12, 15 ], [ 238, 774, 45, 15 ], [ 292, 774, 14, 15 ], [ 313, 774, 95, 15 ], [ 75, 790, 56, 15 ], [ 136, 790, 19, 15 ], [ 160, 790, 10, 15 ], [ 175, 790, 18, 15 ], [ 199, 790, 80, 15 ], [ 283, 790, 49, 15 ], [ 337, 790, 44, 15 ], [ 386, 790, 23, 15 ], [ 75, 806, 25, 15 ], [ 106, 806, 54, 15 ], [ 167, 806, 52, 15 ], [ 226, 806, 12, 15 ], [ 244, 806, 45, 15 ], [ 296, 806, 12, 15 ], [ 315, 806, 45, 15 ], [ 366, 806, 21, 15 ], [ 394, 806, 15, 15 ], [ 75, 822, 56, 15 ], [ 134, 822, 45, 15 ], [ 182, 822, 22, 15 ], [ 207, 822, 45, 15 ], [ 256, 822, 16, 15 ], [ 275, 822, 24, 15 ], [ 302, 822, 48, 15 ], [ 353, 822, 12, 15 ], [ 368, 822, 6, 15 ], [ 378, 822, 30, 15 ], [ 75, 838, 19, 15 ], [ 100, 838, 56, 15 ], [ 163, 838, 12, 15 ], [ 182, 838, 13, 15 ], [ 202, 838, 43, 15 ], [ 252, 838, 74, 15 ], [ 332, 838, 45, 15 ], [ 385, 838, 24, 15 ], [ 75, 854, 27, 15 ], [ 104, 854, 6, 15 ], [ 114, 854, 22, 15 ], [ 139, 854, 12, 15 ], [ 154, 854, 42, 15 ], [ 199, 854, 69, 15 ], [ 271, 854, 44, 15 ], [ 319, 854, 39, 15 ], [ 361, 854, 12, 15 ], [ 376, 854, 32, 15 ], [ 75, 870, 18, 15 ], [ 96, 870, 22, 15 ], [ 122, 870, 78, 15 ], [ 203, 870, 23, 15 ], [ 230, 870, 22, 15 ], [ 255, 870, 22, 15 ], [ 281, 870, 50, 15 ], [ 335, 870, 18, 15 ], [ 356, 870, 52, 15 ], [ 75, 886, 12, 15 ], [ 91, 886, 104, 15 ], [ 200, 886, 10, 15 ], [ 215, 886, 24, 15 ], [ 244, 886, 12, 15 ], [ 261, 886, 25, 15 ], [ 291, 886, 44, 15 ], [ 340, 886, 12, 15 ], [ 357, 886, 14, 15 ], [ 375, 886, 34, 15 ], [ 75, 902, 36, 15 ], [ 116, 902, 69, 15 ], [ 191, 902, 45, 15 ], [ 242, 902, 29, 15 ], [ 277, 902, 49, 15 ], [ 331, 902, 34, 15 ], [ 370, 902, 27, 15 ], [ 403, 902, 6, 15 ], [ 75, 918, 88, 15 ], [ 171, 918, 13, 15 ], [ 192, 918, 67, 15 ], [ 268, 918, 49, 15 ], [ 325, 918, 57, 15 ], [ 391, 918, 18, 15 ], [ 75, 934, 40, 15 ], [ 119, 934, 21, 15 ], [ 144, 934, 40, 15 ], [ 188, 934, 64, 15 ], [ 257, 934, 12, 15 ], [ 273, 934, 45, 15 ], [ 323, 934, 48, 15 ], [ 375, 934, 13, 15 ], [ 392, 934, 17, 15 ], [ 75, 950, 41, 15 ], [ 122, 950, 82, 15 ], [ 211, 950, 48, 15 ], [ 265, 950, 21, 15 ], [ 292, 950, 18, 15 ], [ 317, 950, 41, 15 ], [ 363, 950, 45, 15 ], [ 75, 966, 39, 15 ], [ 118, 966, 43, 15 ], [ 166, 966, 12, 15 ], [ 182, 966, 45, 15 ], [ 232, 966, 29, 15 ], [ 266, 966, 49, 15 ], [ 320, 966, 44, 15 ], [ 369, 966, 40, 15 ], [ 75, 982, 22, 15 ], [ 100, 982, 40, 15 ], [ 142, 982, 63, 15 ], [ 209, 982, 35, 15 ], [ 247, 982, 24, 15 ], [ 275, 982, 5, 15 ], [ 283, 982, 56, 15 ], [ 342, 982, 24, 15 ], [ 370, 982, 38, 15 ], [ 433, 646, 52, 15 ], [ 488, 646, 22, 15 ], [ 514, 646, 31, 15 ], [ 548, 646, 6, 15 ], [ 557, 646, 40, 15 ], [ 600, 646, 48, 15 ], [ 652, 646, 10, 15 ], [ 665, 646, 18, 15 ], [ 687, 646, 79, 15 ], [ 433, 662, 52, 15 ], [ 447, 678, 43, 15 ], [ 494, 678, 92, 15 ], [ 589, 678, 58, 15 ], [ 651, 678, 8, 15 ], [ 663, 678, 6, 15 ], [ 672, 678, 51, 15 ], [ 727, 678, 40, 15 ], [ 433, 694, 52, 15 ], [ 489, 694, 22, 15 ], [ 514, 694, 47, 15 ], [ 564, 694, 34, 15 ], [ 602, 694, 56, 15 ], [ 662, 694, 25, 15 ], [ 690, 694, 12, 15 ], [ 705, 694, 18, 15 ], [ 727, 694, 40, 15 ], [ 433, 710, 92, 15 ], [ 533, 710, 24, 15 ], [ 565, 710, 13, 15 ], [ 586, 710, 32, 15 ], [ 626, 710, 50, 15 ], [ 685, 710, 37, 15 ], [ 730, 710, 38, 15 ], [ 433, 726, 62, 15 ], [ 500, 726, 45, 15 ], [ 549, 726, 36, 15 ], [ 590, 726, 63, 15 ], [ 658, 726, 27, 15 ], [ 690, 726, 8, 15 ], [ 703, 726, 8, 15 ], [ 716, 726, 6, 15 ], [ 727, 726, 40, 15 ], [ 433, 742, 57, 15 ], [ 498, 742, 21, 15 ], [ 526, 742, 45, 15 ], [ 579, 742, 50, 15 ], [ 637, 742, 38, 15 ], [ 683, 742, 58, 15 ], [ 749, 742, 18, 15 ], [ 433, 758, 27, 15 ], [ 463, 758, 35, 15 ], [ 501, 758, 12, 15 ], [ 517, 758, 68, 15 ], [ 588, 758, 57, 15 ], [ 648, 758, 20, 15 ], [ 671, 758, 22, 15 ], [ 697, 758, 22, 15 ], [ 722, 758, 45, 15 ], [ 433, 774, 18, 15 ], [ 455, 774, 40, 15 ], [ 499, 774, 59, 15 ], [ 562, 774, 28, 15 ], [ 593, 774, 14, 15 ], [ 611, 774, 76, 15 ], [ 691, 774, 61, 15 ], [ 756, 774, 10, 15 ], [ 433, 790, 18, 15 ], [ 454, 790, 27, 15 ], [ 485, 790, 18, 15 ], [ 506, 790, 58, 15 ], [ 567, 790, 6, 15 ], [ 577, 790, 45, 15 ], [ 625, 790, 12, 15 ], [ 640, 790, 50, 15 ], [ 693, 790, 22, 15 ], [ 718, 790, 36, 15 ], [ 758, 790, 8, 15 ], [ 433, 806, 12, 15 ], [ 448, 806, 33, 15 ], [ 484, 806, 48, 15 ], [ 535, 806, 53, 15 ], [ 591, 806, 22, 15 ], [ 617, 806, 22, 15 ], [ 642, 806, 16, 15 ], [ 662, 806, 41, 15 ], [ 706, 806, 16, 15 ], [ 726, 806, 20, 15 ], [ 749, 806, 17, 15 ], [ 433, 822, 28, 15 ], [ 466, 822, 95, 15 ], [ 567, 822, 24, 15 ], [ 596, 822, 57, 15 ], [ 658, 822, 23, 15 ], [ 686, 822, 27, 15 ], [ 718, 822, 49, 15 ], [ 433, 838, 27, 15 ], [ 468, 838, 12, 15 ], [ 487, 838, 18, 15 ], [ 513, 838, 45, 15 ], [ 566, 838, 55, 15 ], [ 629, 838, 33, 15 ], [ 669, 838, 26, 15 ], [ 702, 838, 21, 15 ], [ 731, 838, 36, 15 ], [ 433, 854, 36, 15 ], [ 475, 854, 30, 15 ], [ 511, 854, 18, 15 ], [ 535, 854, 61, 15 ], [ 603, 854, 12, 15 ], [ 621, 854, 35, 15 ], [ 662, 854, 64, 15 ], [ 732, 854, 24, 15 ], [ 762, 854, 5, 15 ], [ 433, 870, 33, 15 ], [ 471, 870, 31, 15 ], [ 507, 870, 28, 15 ], [ 540, 870, 18, 15 ], [ 563, 870, 70, 15 ], [ 638, 870, 55, 15 ], [ 698, 870, 29, 15 ], [ 732, 870, 12, 15 ], [ 749, 870, 18, 15 ], [ 433, 886, 44, 15 ], [ 480, 886, 54, 15 ], [ 537, 886, 24, 15 ], [ 564, 886, 5, 15 ], [ 573, 886, 33, 15 ], [ 609, 886, 35, 15 ], [ 647, 886, 17, 15 ], [ 667, 886, 81, 15 ], [ 752, 886, 14, 15 ], [ 433, 957, 60, 12 ], [ 495, 957, 18, 12 ], [ 516, 957, 9, 12 ], [ 528, 957, 15, 12 ], [ 545, 957, 25, 12 ], [ 574, 957, 22, 12 ], [ 599, 957, 42, 12 ], [ 644, 957, 41, 12 ], [ 688, 957, 19, 12 ], [ 710, 957, 56, 12 ], [ 433, 970, 47, 12 ], [ 483, 970, 39, 12 ], [ 526, 970, 32, 12 ], [ 561, 970, 77, 12 ], [ 641, 970, 27, 12 ], [ 671, 970, 53, 12 ], [ 727, 970, 10, 12 ], [ 740, 970, 27, 12 ], [ 433, 984, 22, 12 ], [ 233, 1012, 21, 14 ], [ 278, 1013, 7, 13 ], [ 289, 1013, 24, 13 ], [ 315, 1013, 27, 13 ], [ 358, 1013, 21, 13 ], [ 382, 1013, 58, 13 ], [ 443, 1013, 52, 13 ], [ 498, 1013, 25, 13 ], [ 525, 1013, 5, 13 ], [ 533, 1013, 132, 13 ], [ 668, 1013, 28, 13 ], [ 278, 1027, 40, 13 ], [ 322, 1027, 22, 13 ], [ 347, 1027, 43, 13 ], [ 392, 1027, 10, 13 ], [ 408, 1027, 35, 13 ], [ 446, 1027, 10, 13 ], [ 459, 1027, 25, 13 ], [ 489, 1027, 43, 13 ], [ 278, 1042, 104, 13 ] ]

[ "Trophoblast", "Class", "I", "Major", "Histocompatibility", "Complex", "(MHC)", "Products", "Are", "Resistant", "to", "Rapid", "Degradation", "Imposed", "by", "the", "Human", "Cytomegalovirus", "(HCMV)", "Gene", "Products", "US2", "and", "US11", "By", "Danny", "J.", "Schust,*", "Domenico", "Tortorella,*", "Jörg", "Seebach,‡", "Cindy", "Phan,*", "and", "Hidde", "L.", "Ploegh*", "From", "the", "*Department", "of", "Pathology,", "Harvard", "Medical", "School,", "Boston,", "Massachusetts", "02115;", "and", "the", "‡Transplantation", "Biology", "Research", "Center,", "Massachusetts", "General", "Hospital,", "Boston,", "Massachusetts", "02119", "Summary", "US11", "and", "US2", "encode", "gene", "products", "expressed", "early", "in", "the", "replicative", "cycle", "of", "human", "cy-", "tomegalovirus", "(HCMV),", "which", "cause", "dislocation", "of", "human", "and", "murine", "major", "histocompatibil-", "ity", "complex", "(MHC)", "class", "I", "molecules", "from", "the", "lumen", "of", "the", "endoplasmic", "reticulum", "to", "the", "cy-", "tosol,", "where", "the", "class", "I", "heavy", "chains", "are", "rapidly", "degraded.", "Human", "histocompatibility", "leukocyte", "antigens", "(HLA)-C", "and", "HLA-G", "are", "uniquely", "resistant", "to", "the", "effects", "of", "both", "US11", "and", "US2", "in", "a", "human", "trophoblast", "cell", "line", "as", "well", "as", "in", "porcine", "endothelial", "cells", "stably", "transfected", "with", "human", "class", "I", "genes.", "Dislocation", "and", "degradation", "of", "MHC", "class", "I", "heavy", "chains", "do", "not", "appear", "to", "in-", "volve", "cell", "type–specific", "factors,", "as", "US11", "and", "US2", "are", "fully", "active", "in", "this", "xenogeneic", "model.", "Im-", "portantly,", "trophoblasts", "HLA-G", "and", "HLA-C", "possess", "unique", "characteristics", "that", "allow", "their", "es-", "cape", "from", "HCMV-associated", "MHC", "class", "I", "degradation.", "Trophoblast", "class", "I", "molecules", "could", "serve", "not", "only", "to", "block", "recognition", "by", "natural", "killer", "cells,", "but", "also", "to", "guide", "virus-specific", "HLA-C–", "and", "possibly", "HLA-G–restricted", "cytotoxic", "T-lymphocytes", "to", "their", "targets.", "Key", "words:", "trophoblast", "•", "cytomegalovirus", "•", "human", "•", "MHC", "class", "I", "•", "HLA-G", "Daurreingexhpuomsedan", "dpirreecgtnlyantcoy,", "malalotegrennailc", "imtrompuhnoeblaesftfeccetollrs", "cells.", "For", "many", "years,", "the", "absence", "of", "MHC-restricted", "re-", "jection", "of", "the", "implanting", "trophoblast", "was", "attributed", "to", "the", "lack", "of", "class", "I", "MHC", "expression", "on", "these", "cells.", "It", "is", "now", "clear", "that", "trophoblast", "cells", "express", "both", "classical", "(HLA-C;", "references", "1–4)", "and", "nonclassical", "(HLA-G;", "references", "5–9)", "class", "I", "products.", "To", "date,", "the", "function", "of", "these", "molecules", "and", "their", "involvement", "in", "creating", "an", "immunologically", "privileged", "site", "at", "the", "maternal–fetal", "interface", "remains", "elu-", "sive.", "Sequence", "similarity", "of", "HLA-G", "to", "HLA-A", "and", "-B", "molecules", "suggests", "that", "HLA-G", "(7)", "may", "function", "in", "a", "man-", "ner", "analogous", "to", "its", "classical", "counterparts:", "HLA-G", "may", "have", "a", "role", "in", "antigen", "presentation", "(10–12)", "and/or", "in", "evad-", "ing", "NK", "cell–mediated", "lysis", "(13,", "14),", "although", "the", "existence", "of", "HLA-G–restricted", "T", "cells", "in", "vivo", "remains", "to", "be", "estab-", "lished.", "Trophoblast", "HLA-C", "locus", "products", "might", "have", "a", "complementary", "or", "overlapping", "purpose.", "However,", "the", "unique", "and", "limited", "localization", "of", "HLA-G", "(15–18),", "its", "re-", "stricted", "polymorphism", "(19–23),", "and", "the", "known", "reduced", "surface", "stability", "of", "HLA-C", "locus", "products", "(24–27)", "suggest", "that", "human", "trophoblast", "MHC", "class", "I", "molecules", "may", "possess", "attributes", "that", "allow", "a", "unique", "function", "at", "the", "maternal–fetal", "interface.", "Human", "cytomegalovirus", "(HCMV)1", "is", "a", "common", "human", "pathogen", "that", "typically", "causes", "morbidity", "only", "in", "the", "immu-", "nocompromised", "host", "or", "when", "infection", "occurs", "during", "pregnancy.", "HCMV", "infects", "trophoblast", "(28),", "it", "is", "a", "known", "teratogen,", "and", "HCMV", "infection", "during", "pregnancy", "has", "been", "linked", "to", "spontaneous", "pregnancy", "loss", "(29,", "30).", "HCMV", "has", "proven", "interesting", "from", "an", "immunologic", "viewpoint,", "as", "the", "virus", "has", "developed", "a", "number", "of", "strategies", "that", "enable", "it", "to", "evade", "immune", "detection", "(31,", "32).", "Of", "interest", "for", "this", "re-", "port,", "HCMV-infected", "cells", "synthesize", "two", "gene", "products", "early", "in", "the", "HCMV", "infectious", "cycle,", "US2", "and", "US11,", "which", "cause", "the", "dislocation", "of", "newly", "synthesized", "class", "I", "heavy", "chain", "from", "the", "endoplasmic", "reticulum", "(ER)", "to", "the", "cytosol.", "Cytosolic", "class", "I", "heavy", "chains", "are", "deglycosylated", "by", "1Abbreviations", "used", "in", "this", "paper:", "CM,", "complete", "medium;", "ER,", "endoplasmic", "reticulum;", "HCMV,", "human", "cytomegalovirus;", "MOI,", "multiplicity", "of", "infec-", "tion.", "497", "J.", "Exp.", "Med.", "The", "Rockefeller", "University", "Press", "•", "0022-1007/98/08/497/07", "$2.00", "Volume", "188,", "Number", "3,", "August", "3,", "1998", "497–503", "http://www.jem.org" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 328, 53, 18, 12 ], [ 348, 53, 25, 12 ], [ 376, 53, 67, 12 ], [ 446, 53, 40, 12 ], [ 487, 53, 26, 12 ], [ 515, 53, 9, 12 ], [ 526, 53, 27, 12 ], [ 785, 53, 12, 12 ], [ 695, 80, 43, 17 ], [ 742, 80, 59, 17 ], [ 89, 107, 89, 22 ], [ 187, 107, 90, 22 ], [ 286, 107, 114, 22 ], [ 409, 107, 36, 22 ], [ 454, 107, 122, 22 ], [ 586, 107, 19, 22 ], [ 613, 107, 109, 22 ], [ 731, 107, 70, 22 ], [ 89, 130, 47, 23 ], [ 141, 130, 30, 23 ], [ 176, 130, 132, 23 ], [ 314, 130, 68, 23 ], [ 387, 130, 56, 23 ], [ 89, 171, 38, 17 ], [ 131, 171, 79, 17 ], [ 213, 171, 33, 17 ], [ 250, 171, 62, 17 ], [ 315, 171, 31, 17 ], [ 350, 171, 56, 17 ], [ 409, 171, 17, 17 ], [ 430, 171, 37, 17 ], [ 471, 171, 43, 17 ], [ 517, 171, 27, 17 ], [ 548, 171, 50, 17 ], [ 602, 171, 14, 17 ], [ 619, 171, 68, 17 ], [ 692, 171, 16, 17 ], [ 711, 171, 50, 17 ], [ 89, 190, 25, 17 ], [ 117, 190, 34, 17 ], [ 155, 187, 70, 20 ], [ 89, 243, 30, 14 ], [ 121, 243, 52, 14 ], [ 176, 243, 42, 14 ], [ 221, 243, 59, 14 ], [ 282, 243, 11, 14 ], [ 296, 243, 77, 14 ], [ 376, 243, 74, 14 ], [ 454, 243, 46, 14 ], [ 502, 243, 52, 14 ], [ 557, 243, 74, 14 ], [ 634, 243, 31, 14 ], [ 668, 243, 29, 14 ], [ 700, 243, 20, 14 ], [ 148, 276, 51, 13 ], [ 201, 276, 18, 13 ], [ 223, 276, 34, 13 ], [ 260, 276, 15, 13 ], [ 278, 276, 54, 13 ], [ 335, 276, 42, 13 ], [ 380, 276, 25, 13 ], [ 409, 276, 63, 13 ], [ 475, 276, 19, 13 ], [ 497, 276, 25, 13 ], [ 525, 276, 41, 13 ], [ 569, 276, 10, 13 ], [ 583, 276, 70, 13 ], [ 656, 276, 11, 13 ], [ 670, 276, 25, 13 ], [ 698, 276, 38, 13 ], [ 739, 276, 23, 13 ], [ 148, 291, 19, 13 ], [ 170, 291, 37, 13 ], [ 211, 291, 18, 13 ], [ 233, 291, 25, 13 ], [ 262, 291, 39, 13 ], [ 305, 291, 36, 13 ], [ 345, 291, 37, 13 ], [ 386, 291, 34, 13 ], [ 425, 291, 19, 13 ], [ 448, 291, 22, 13 ], [ 474, 291, 18, 13 ], [ 496, 291, 19, 13 ], [ 520, 291, 37, 13 ], [ 561, 291, 15, 13 ], [ 579, 291, 32, 13 ], [ 615, 291, 24, 13 ], [ 643, 291, 37, 13 ], [ 684, 291, 25, 13 ], [ 713, 291, 49, 13 ], [ 148, 306, 59, 13 ], [ 211, 306, 52, 13 ], [ 267, 306, 6, 13 ], [ 276, 306, 31, 13 ], [ 311, 306, 71, 13 ], [ 385, 306, 18, 13 ], [ 407, 306, 25, 13 ], [ 436, 306, 66, 13 ], [ 505, 306, 36, 13 ], [ 544, 306, 11, 13 ], [ 559, 306, 16, 13 ], [ 578, 306, 36, 13 ], [ 618, 306, 27, 13 ], [ 648, 306, 18, 13 ], [ 670, 306, 39, 13 ], [ 713, 306, 24, 13 ], [ 741, 306, 21, 13 ], [ 148, 321, 40, 13 ], [ 148, 344, 18, 13 ], [ 169, 344, 30, 13 ], [ 203, 344, 13, 13 ], [ 220, 344, 64, 13 ], [ 287, 344, 42, 13 ], [ 333, 344, 44, 13 ], [ 380, 344, 18, 13 ], [ 403, 344, 37, 13 ], [ 444, 344, 68, 13 ], [ 516, 344, 42, 13 ], [ 562, 344, 38, 13 ], [ 603, 344, 18, 13 ], [ 626, 344, 29, 13 ], [ 658, 344, 28, 13 ], [ 691, 344, 11, 13 ], [ 705, 344, 29, 13 ], [ 738, 344, 24, 13 ], [ 148, 359, 55, 13 ], [ 206, 359, 15, 13 ], [ 225, 359, 21, 13 ], [ 249, 359, 26, 13 ], [ 278, 359, 25, 13 ], [ 306, 359, 31, 13 ], [ 341, 359, 35, 13 ], [ 380, 359, 43, 13 ], [ 426, 359, 30, 13 ], [ 459, 359, 28, 13 ], [ 490, 359, 25, 13 ], [ 519, 359, 17, 13 ], [ 540, 359, 18, 13 ], [ 561, 359, 27, 13 ], [ 592, 359, 26, 13 ], [ 621, 359, 60, 13 ], [ 684, 359, 50, 13 ], [ 737, 359, 25, 13 ], [ 148, 375, 36, 13 ], [ 186, 375, 42, 13 ], [ 231, 375, 10, 13 ], [ 244, 375, 16, 13 ], [ 263, 375, 33, 13 ], [ 299, 375, 24, 13 ], [ 325, 375, 11, 13 ], [ 339, 375, 24, 13 ], [ 366, 375, 35, 13 ], [ 404, 375, 18, 13 ], [ 425, 375, 29, 13 ], [ 457, 375, 39, 13 ], [ 499, 375, 24, 13 ], [ 526, 375, 29, 13 ], [ 558, 375, 22, 13 ], [ 583, 375, 17, 13 ], [ 602, 375, 11, 13 ], [ 615, 375, 28, 13 ], [ 647, 375, 42, 13 ], [ 692, 375, 24, 13 ], [ 720, 375, 16, 13 ], [ 738, 375, 24, 13 ], [ 148, 390, 14, 13 ], [ 165, 390, 24, 13 ], [ 192, 390, 35, 13 ], [ 230, 390, 24, 13 ], [ 257, 390, 11, 13 ], [ 271, 390, 28, 13 ], [ 302, 390, 15, 13 ], [ 320, 390, 54, 13 ], [ 377, 390, 23, 13 ], [ 404, 390, 7, 13 ], [ 415, 390, 30, 13 ], [ 447, 390, 38, 13 ], [ 488, 390, 31, 13 ], [ 522, 390, 25, 13 ], [ 550, 390, 23, 13 ], [ 576, 390, 22, 13 ], [ 602, 390, 39, 13 ], [ 645, 390, 24, 13 ], [ 672, 390, 28, 13 ], [ 704, 390, 18, 13 ], [ 725, 390, 36, 13 ], [ 148, 405, 27, 13 ], [ 177, 405, 31, 13 ], [ 148, 427, 57, 13 ], [ 208, 427, 11, 13 ], [ 222, 427, 29, 13 ], [ 255, 427, 24, 13 ], [ 282, 427, 35, 13 ], [ 321, 427, 22, 13 ], [ 346, 427, 13, 13 ], [ 362, 427, 58, 13 ], [ 424, 427, 53, 13 ], [ 481, 427, 10, 13 ], [ 495, 427, 16, 13 ], [ 514, 427, 34, 13 ], [ 551, 427, 11, 13 ], [ 566, 427, 25, 13 ], [ 594, 427, 40, 13 ], [ 638, 427, 35, 13 ], [ 677, 427, 23, 13 ], [ 704, 427, 11, 13 ], [ 718, 427, 44, 13 ], [ 148, 443, 46, 13 ], [ 89, 477, 111, 14 ], [ 108, 501, 92, 14 ], [ 205, 501, 39, 14 ], [ 250, 501, 27, 14 ], [ 282, 501, 37, 14 ], [ 324, 501, 21, 14 ], [ 351, 501, 62, 14 ], [ 418, 501, 12, 14 ], [ 89, 516, 21, 14 ], [ 114, 516, 64, 14 ], [ 183, 516, 24, 14 ], [ 212, 516, 14, 14 ], [ 230, 516, 11, 14 ], [ 245, 516, 53, 14 ], [ 302, 516, 21, 14 ], [ 328, 516, 12, 14 ], [ 345, 516, 70, 14 ], [ 419, 516, 11, 14 ], [ 89, 532, 28, 14 ], [ 123, 532, 19, 14 ], [ 149, 532, 32, 14 ], [ 187, 532, 50, 14 ], [ 243, 532, 38, 14 ], [ 288, 532, 11, 14 ], [ 306, 532, 55, 14 ], [ 369, 532, 23, 14 ], [ 398, 532, 32, 14 ], [ 89, 547, 28, 14 ], [ 124, 547, 43, 14 ], [ 175, 547, 41, 14 ], [ 225, 547, 40, 14 ], [ 274, 547, 20, 14 ], [ 303, 547, 28, 14 ], [ 338, 547, 43, 14 ], [ 389, 547, 41, 14 ], [ 89, 562, 41, 14 ], [ 135, 562, 49, 14 ], [ 189, 562, 18, 14 ], [ 212, 562, 34, 14 ], [ 251, 562, 12, 14 ], [ 269, 562, 20, 14 ], [ 295, 562, 52, 14 ], [ 352, 562, 24, 14 ], [ 382, 562, 25, 14 ], [ 412, 562, 18, 14 ], [ 89, 577, 33, 14 ], [ 127, 577, 66, 14 ], [ 198, 577, 48, 14 ], [ 251, 577, 39, 14 ], [ 295, 577, 27, 14 ], [ 326, 577, 55, 14 ], [ 387, 577, 21, 14 ], [ 413, 577, 18, 14 ], [ 89, 593, 28, 14 ], [ 121, 593, 71, 14 ], [ 195, 593, 24, 14 ], [ 224, 593, 42, 14 ], [ 270, 593, 25, 14 ], [ 300, 593, 28, 14 ], [ 332, 593, 45, 14 ], [ 382, 593, 11, 14 ], [ 397, 593, 33, 14 ], [ 89, 608, 28, 14 ], [ 121, 608, 21, 14 ], [ 147, 608, 39, 14 ], [ 190, 608, 17, 14 ], [ 211, 608, 49, 14 ], [ 265, 608, 49, 14 ], [ 319, 608, 12, 14 ], [ 335, 608, 20, 14 ], [ 361, 608, 34, 14 ], [ 400, 608, 31, 14 ], [ 89, 623, 14, 14 ], [ 107, 623, 53, 14 ], [ 164, 623, 10, 14 ], [ 178, 623, 15, 14 ], [ 197, 623, 62, 14 ], [ 262, 623, 12, 14 ], [ 279, 623, 21, 14 ], [ 304, 623, 26, 14 ], [ 334, 623, 38, 14 ], [ 376, 623, 28, 14 ], [ 407, 623, 23, 14 ], [ 89, 638, 46, 14 ], [ 140, 638, 62, 14 ], [ 206, 638, 11, 14 ], [ 222, 638, 17, 14 ], [ 244, 638, 32, 14 ], [ 280, 638, 12, 14 ], [ 297, 638, 25, 14 ], [ 327, 638, 39, 14 ], [ 370, 638, 15, 14 ], [ 390, 638, 40, 14 ], [ 89, 654, 30, 14 ], [ 123, 654, 32, 14 ], [ 160, 654, 61, 14 ], [ 225, 654, 33, 14 ], [ 262, 654, 28, 14 ], [ 294, 654, 53, 14 ], [ 351, 654, 20, 14 ], [ 376, 654, 16, 14 ], [ 396, 654, 34, 14 ], [ 89, 669, 31, 14 ], [ 125, 669, 45, 14 ], [ 176, 669, 7, 14 ], [ 188, 669, 39, 14 ], [ 233, 669, 60, 14 ], [ 298, 669, 33, 14 ], [ 336, 669, 42, 14 ], [ 383, 669, 47, 14 ], [ 89, 684, 25, 14 ], [ 119, 684, 45, 14 ], [ 169, 684, 39, 14 ], [ 212, 684, 20, 14 ], [ 238, 684, 40, 14 ], [ 283, 684, 11, 14 ], [ 300, 684, 28, 14 ], [ 334, 684, 19, 14 ], [ 357, 684, 11, 14 ], [ 374, 684, 56, 14 ], [ 89, 700, 17, 14 ], [ 109, 700, 21, 14 ], [ 134, 700, 12, 14 ], [ 150, 700, 28, 14 ], [ 182, 700, 74, 14 ], [ 259, 700, 17, 14 ], [ 280, 700, 54, 14 ], [ 338, 700, 17, 14 ], [ 359, 700, 72, 14 ], [ 89, 715, 46, 14 ], [ 140, 715, 27, 14 ], [ 172, 715, 42, 14 ], [ 219, 715, 45, 14 ], [ 270, 715, 38, 14 ], [ 313, 715, 20, 14 ], [ 339, 715, 28, 14 ], [ 372, 715, 32, 14 ], [ 410, 715, 21, 14 ], [ 89, 730, 31, 14 ], [ 125, 730, 11, 14 ], [ 142, 730, 7, 14 ], [ 155, 730, 36, 14 ], [ 196, 730, 12, 14 ], [ 214, 730, 24, 14 ], [ 244, 730, 20, 14 ], [ 271, 730, 41, 14 ], [ 318, 730, 28, 14 ], [ 351, 730, 79, 14 ], [ 89, 745, 24, 14 ], [ 89, 769, 84, 14 ], [ 176, 769, 30, 14 ], [ 209, 769, 71, 14 ], [ 108, 793, 27, 14 ], [ 139, 793, 46, 14 ], [ 188, 793, 20, 14 ], [ 212, 793, 35, 14 ], [ 251, 793, 28, 14 ], [ 282, 793, 24, 14 ], [ 310, 793, 20, 14 ], [ 334, 793, 21, 14 ], [ 359, 793, 41, 14 ], [ 404, 793, 26, 14 ], [ 89, 808, 33, 14 ], [ 125, 808, 30, 14 ], [ 158, 808, 28, 14 ], [ 188, 808, 50, 14 ], [ 242, 808, 11, 14 ], [ 256, 808, 20, 14 ], [ 280, 808, 34, 14 ], [ 317, 808, 34, 14 ], [ 355, 808, 22, 14 ], [ 380, 808, 50, 14 ], [ 89, 823, 11, 14 ], [ 104, 823, 48, 14 ], [ 157, 823, 18, 14 ], [ 179, 823, 66, 14 ], [ 250, 823, 47, 14 ], [ 301, 823, 40, 14 ], [ 347, 823, 11, 14 ], [ 363, 823, 42, 14 ], [ 410, 823, 21, 14 ], [ 89, 838, 17, 14 ], [ 110, 838, 62, 14 ], [ 175, 838, 21, 14 ], [ 201, 838, 12, 14 ], [ 217, 838, 74, 14 ], [ 294, 838, 22, 14 ], [ 320, 838, 50, 14 ], [ 374, 838, 56, 14 ], [ 89, 854, 17, 14 ], [ 108, 854, 29, 14 ], [ 140, 854, 62, 14 ], [ 205, 854, 22, 14 ], [ 230, 854, 12, 14 ], [ 245, 854, 46, 14 ], [ 295, 854, 11, 14 ], [ 309, 854, 30, 14 ], [ 342, 854, 25, 14 ], [ 370, 854, 17, 14 ], [ 391, 854, 24, 14 ], [ 418, 854, 12, 14 ], [ 89, 869, 17, 14 ], [ 111, 869, 48, 14 ], [ 165, 869, 37, 14 ], [ 208, 869, 42, 14 ], [ 256, 869, 41, 14 ], [ 303, 869, 47, 14 ], [ 356, 869, 10, 14 ], [ 371, 869, 59, 14 ], [ 89, 884, 20, 14 ], [ 116, 884, 75, 14 ], [ 197, 884, 40, 14 ], [ 244, 884, 37, 14 ], [ 289, 884, 42, 14 ], [ 337, 884, 70, 14 ], [ 414, 884, 17, 14 ], [ 89, 900, 34, 14 ], [ 128, 900, 24, 14 ], [ 158, 900, 20, 14 ], [ 184, 900, 41, 14 ], [ 230, 900, 24, 14 ], [ 260, 900, 27, 14 ], [ 293, 900, 26, 14 ], [ 325, 900, 37, 14 ], [ 367, 900, 47, 14 ], [ 419, 900, 11, 14 ], [ 89, 915, 79, 14 ], [ 172, 915, 20, 14 ], [ 198, 915, 22, 14 ], [ 225, 915, 28, 14 ], [ 258, 915, 28, 14 ], [ 291, 915, 37, 14 ], [ 334, 915, 17, 14 ], [ 356, 915, 36, 14 ], [ 397, 915, 33, 14 ], [ 89, 960, 43, 11 ], [ 135, 960, 70, 11 ], [ 208, 960, 9, 11 ], [ 220, 960, 16, 11 ], [ 240, 960, 29, 11 ], [ 271, 960, 9, 11 ], [ 283, 960, 14, 11 ], [ 300, 960, 25, 11 ], [ 329, 960, 42, 11 ], [ 374, 960, 33, 11 ], [ 410, 960, 21, 11 ], [ 89, 973, 31, 11 ], [ 122, 973, 10, 11 ], [ 134, 973, 63, 11 ], [ 199, 973, 59, 11 ], [ 261, 973, 36, 11 ], [ 299, 973, 41, 11 ], [ 343, 973, 60, 11 ], [ 405, 973, 25, 11 ], [ 89, 986, 25, 11 ], [ 115, 986, 20, 11 ], [ 138, 986, 18, 11 ], [ 158, 986, 18, 11 ], [ 178, 986, 25, 11 ], [ 205, 986, 23, 11 ], [ 230, 986, 26, 11 ], [ 259, 986, 20, 11 ], [ 281, 986, 18, 11 ], [ 301, 986, 25, 11 ], [ 328, 986, 23, 11 ], [ 353, 986, 26, 11 ], [ 89, 999, 34, 11 ], [ 124, 999, 101, 11 ], [ 459, 477, 32, 14 ], [ 494, 477, 30, 14 ], [ 527, 477, 53, 14 ], [ 583, 477, 40, 14 ], [ 626, 477, 61, 14 ], [ 691, 477, 28, 14 ], [ 722, 477, 26, 14 ], [ 751, 477, 50, 14 ], [ 459, 493, 44, 14 ], [ 507, 493, 69, 14 ], [ 579, 493, 17, 14 ], [ 599, 493, 64, 14 ], [ 666, 493, 26, 14 ], [ 695, 493, 38, 14 ], [ 736, 493, 14, 14 ], [ 754, 493, 32, 14 ], [ 789, 493, 11, 14 ], [ 459, 508, 19, 14 ], [ 482, 508, 28, 14 ], [ 514, 508, 9, 14 ], [ 527, 508, 24, 14 ], [ 555, 508, 35, 14 ], [ 594, 508, 14, 14 ], [ 612, 508, 40, 14 ], [ 656, 508, 11, 14 ], [ 671, 508, 14, 14 ], [ 689, 508, 53, 14 ], [ 746, 508, 14, 14 ], [ 764, 508, 21, 14 ], [ 789, 508, 12, 14 ], [ 459, 523, 19, 14 ], [ 485, 523, 46, 14 ], [ 537, 523, 40, 14 ], [ 583, 523, 10, 14 ], [ 599, 523, 24, 14 ], [ 629, 523, 41, 14 ], [ 676, 523, 7, 14 ], [ 689, 523, 46, 14 ], [ 741, 523, 31, 14 ], [ 778, 523, 23, 14 ], [ 459, 538, 40, 14 ], [ 505, 538, 7, 14 ], [ 516, 538, 31, 14 ], [ 553, 538, 28, 14 ], [ 586, 538, 35, 14 ], [ 626, 538, 24, 14 ], [ 656, 538, 72, 14 ], [ 733, 538, 7, 14 ], [ 745, 538, 56, 14 ], [ 459, 554, 79, 14 ], [ 543, 554, 25, 14 ], [ 573, 554, 48, 14 ], [ 626, 554, 66, 14 ], [ 698, 554, 14, 14 ], [ 717, 554, 84, 14 ], [ 459, 569, 35, 14 ], [ 498, 569, 45, 14 ], [ 546, 569, 43, 14 ], [ 593, 569, 48, 14 ], [ 645, 569, 52, 14 ], [ 701, 569, 41, 14 ], [ 746, 569, 55, 14 ], [ 459, 584, 22, 14 ], [ 487, 584, 20, 14 ], [ 514, 584, 39, 14 ], [ 559, 584, 44, 14 ], [ 610, 584, 38, 14 ], [ 654, 584, 48, 14 ], [ 708, 584, 42, 14 ], [ 756, 584, 22, 14 ], [ 784, 584, 17, 14 ], [ 459, 600, 36, 14 ], [ 499, 600, 14, 14 ], [ 518, 600, 7, 14 ], [ 529, 600, 59, 14 ], [ 591, 600, 51, 14 ], [ 647, 600, 75, 14 ], [ 726, 600, 20, 14 ], [ 751, 600, 22, 14 ], [ 777, 600, 24, 14 ], [ 459, 615, 20, 14 ], [ 483, 615, 22, 14 ], [ 508, 615, 24, 14 ], [ 535, 615, 39, 14 ], [ 577, 615, 11, 14 ], [ 591, 615, 34, 14 ], [ 629, 615, 7, 14 ], [ 639, 615, 27, 14 ], [ 669, 615, 35, 14 ], [ 479, 637, 38, 14 ], [ 521, 637, 22, 14 ], [ 548, 637, 54, 14 ], [ 606, 637, 11, 14 ], [ 623, 637, 17, 14 ], [ 644, 637, 40, 14 ], [ 689, 637, 35, 14 ], [ 728, 637, 31, 14 ], [ 763, 637, 7, 14 ], [ 775, 637, 26, 14 ], [ 459, 652, 40, 14 ], [ 506, 652, 37, 14 ], [ 550, 652, 65, 14 ], [ 621, 652, 61, 14 ], [ 689, 652, 27, 14 ], [ 722, 652, 47, 14 ], [ 775, 652, 25, 14 ], [ 459, 668, 20, 14 ], [ 486, 668, 38, 14 ], [ 532, 668, 11, 14 ], [ 550, 668, 17, 14 ], [ 575, 668, 40, 14 ], [ 621, 668, 32, 14 ], [ 660, 668, 14, 14 ], [ 681, 668, 7, 14 ], [ 695, 668, 36, 14 ], [ 738, 668, 28, 14 ], [ 773, 668, 28, 14 ], [ 459, 683, 60, 14 ], [ 524, 683, 27, 14 ], [ 554, 683, 47, 14 ], [ 605, 683, 29, 14 ], [ 638, 683, 30, 14 ], [ 672, 683, 28, 14 ], [ 704, 683, 31, 14 ], [ 739, 683, 36, 14 ], [ 779, 683, 22, 14 ], [ 459, 698, 56, 14 ], [ 519, 698, 12, 14 ], [ 534, 698, 39, 14 ], [ 575, 698, 42, 14 ], [ 620, 698, 14, 14 ], [ 638, 698, 35, 14 ], [ 675, 698, 7, 14 ], [ 686, 696, 46, 17 ], [ 479, 720, 30, 14 ], [ 515, 720, 43, 14 ], [ 565, 720, 41, 14 ], [ 613, 720, 20, 14 ], [ 640, 720, 28, 14 ], [ 675, 720, 43, 14 ], [ 725, 720, 41, 14 ], [ 773, 720, 28, 14 ], [ 459, 736, 53, 14 ], [ 516, 736, 11, 14 ], [ 530, 736, 26, 14 ], [ 559, 736, 43, 14 ], [ 605, 736, 14, 14 ], [ 623, 736, 24, 14 ], [ 650, 736, 38, 14 ], [ 691, 736, 33, 14 ], [ 727, 736, 74, 14 ], [ 459, 751, 16, 14 ], [ 480, 751, 10, 14 ], [ 494, 751, 18, 14 ], [ 516, 751, 39, 14 ], [ 560, 751, 30, 14 ], [ 595, 751, 20, 14 ], [ 620, 751, 51, 14 ], [ 675, 751, 33, 14 ], [ 713, 751, 35, 14 ], [ 752, 751, 29, 14 ], [ 785, 751, 16, 14 ], [ 459, 766, 81, 14 ], [ 545, 766, 20, 14 ], [ 570, 766, 66, 14 ], [ 641, 766, 45, 14 ], [ 690, 766, 37, 14 ], [ 732, 766, 47, 14 ], [ 783, 766, 18, 14 ], [ 459, 782, 18, 14 ], [ 480, 782, 7, 14 ], [ 490, 782, 45, 14 ], [ 539, 782, 30, 14 ], [ 572, 782, 28, 14 ], [ 604, 782, 63, 14 ], [ 670, 782, 76, 14 ], [ 749, 782, 52, 14 ], [ 459, 797, 31, 14 ], [ 496, 797, 55, 14 ], [ 556, 797, 12, 14 ], [ 574, 797, 60, 14 ], [ 639, 797, 12, 14 ], [ 656, 797, 53, 14 ], [ 715, 797, 22, 14 ], [ 742, 797, 36, 14 ], [ 784, 797, 17, 14 ], [ 459, 812, 39, 14 ], [ 505, 812, 30, 14 ], [ 540, 812, 35, 14 ], [ 581, 812, 36, 14 ], [ 623, 812, 17, 14 ], [ 646, 812, 25, 14 ], [ 676, 812, 34, 14 ], [ 716, 812, 20, 14 ], [ 742, 812, 36, 14 ], [ 784, 812, 17, 14 ], [ 459, 827, 44, 14 ], [ 506, 827, 27, 14 ], [ 536, 827, 32, 14 ], [ 571, 827, 17, 14 ], [ 592, 827, 17, 14 ], [ 612, 827, 45, 14 ], [ 661, 827, 30, 14 ], [ 694, 827, 32, 14 ], [ 730, 827, 29, 14 ], [ 761, 827, 40, 14 ], [ 459, 843, 27, 14 ], [ 491, 843, 48, 14 ], [ 544, 843, 14, 14 ], [ 563, 843, 38, 14 ], [ 605, 843, 22, 14 ], [ 632, 843, 58, 14 ], [ 695, 843, 24, 14 ], [ 724, 843, 28, 14 ], [ 756, 843, 18, 14 ], [ 779, 843, 22, 14 ], [ 459, 858, 12, 14 ], [ 476, 858, 17, 14 ], [ 497, 858, 31, 14 ], [ 532, 858, 64, 14 ], [ 600, 858, 21, 14 ], [ 625, 858, 30, 14 ], [ 660, 858, 14, 14 ], [ 679, 858, 18, 14 ], [ 700, 858, 29, 14 ], [ 733, 858, 24, 14 ], [ 762, 858, 39, 14 ], [ 459, 873, 14, 14 ], [ 478, 873, 20, 14 ], [ 502, 873, 17, 14 ], [ 524, 873, 17, 14 ], [ 545, 873, 27, 14 ], [ 576, 873, 47, 14 ], [ 628, 873, 78, 14 ], [ 710, 873, 60, 14 ], [ 775, 873, 26, 14 ], [ 459, 888, 40, 14 ], [ 504, 888, 51, 14 ], [ 560, 888, 27, 14 ], [ 591, 888, 17, 14 ], [ 613, 888, 17, 14 ], [ 634, 888, 30, 14 ], [ 668, 888, 28, 14 ], [ 701, 888, 22, 14 ], [ 728, 888, 21, 14 ], [ 753, 888, 24, 14 ], [ 781, 888, 19, 14 ], [ 459, 904, 17, 14 ], [ 484, 904, 25, 14 ], [ 516, 904, 25, 14 ], [ 549, 904, 85, 14 ], [ 641, 904, 47, 14 ], [ 695, 904, 63, 14 ], [ 766, 904, 35, 14 ], [ 459, 919, 31, 14 ], [ 495, 919, 38, 14 ], [ 537, 919, 11, 14 ], [ 552, 919, 25, 14 ], [ 581, 919, 28, 14 ], [ 613, 919, 65, 14 ], [ 682, 919, 31, 14 ], [ 716, 919, 12, 14 ], [ 732, 919, 69, 14 ], [ 459, 934, 33, 14 ], [ 498, 934, 28, 14 ], [ 531, 934, 50, 14 ], [ 586, 934, 28, 14 ], [ 619, 934, 20, 14 ], [ 645, 934, 22, 14 ], [ 672, 934, 12, 14 ], [ 690, 934, 17, 14 ], [ 712, 934, 34, 14 ], [ 752, 934, 49, 14 ], [ 459, 950, 41, 14 ], [ 507, 950, 35, 14 ], [ 549, 950, 50, 14 ], [ 605, 950, 69, 14 ], [ 680, 950, 42, 14 ], [ 729, 950, 38, 14 ], [ 773, 950, 28, 14 ], [ 459, 965, 44, 14 ], [ 509, 965, 11, 14 ], [ 525, 965, 63, 14 ], [ 592, 965, 20, 14 ], [ 617, 965, 11, 14 ], [ 634, 965, 17, 14 ], [ 656, 965, 28, 14 ], [ 689, 965, 48, 14 ], [ 742, 965, 12, 14 ], [ 759, 965, 42, 14 ], [ 459, 980, 35, 14 ], [ 500, 980, 20, 14 ], [ 527, 980, 62, 14 ], [ 596, 980, 29, 14 ], [ 632, 980, 64, 14 ], [ 701, 980, 62, 14 ], [ 769, 980, 11, 14 ], [ 787, 980, 14, 14 ], [ 459, 995, 55, 14 ], [ 519, 995, 33, 14 ], [ 555, 995, 28, 14 ], [ 586, 995, 14, 14 ], [ 605, 995, 29, 14 ], [ 638, 995, 53, 14 ], [ 695, 995, 40, 14 ], [ 739, 995, 11, 14 ], [ 754, 995, 20, 14 ], [ 779, 995, 22, 14 ], [ 366, 1031, 63, 11 ], [ 458, 1031, 23, 11 ], [ 483, 1031, 43, 11 ], [ 529, 1031, 27, 11 ] ]

[ "The", "Open", "Rheumatology", "Journal,", "2008,", "2,", "33-37", "33", "Open", "Access", "Cigarette", "Smoking,", "Birthweight", "and", "Osteoporosis", "in", "Adulthood:", "Results", "from", "the", "Hertfordshire", "Cohort", "Study", "M.M.", "Moinuddin,", "K.A.", "Jameson,", "H.E.", "Syddall,", "A.", "Aihie", "Sayer,", "H.J.", "Martin,", "S.", "Robinson,", "C.", "Cooper", "and", "E.M.", "Dennison*", "MRC", "Resource", "Centre,", "University", "of", "Southampton,", "Southampton", "General", "Hospital,", "Southampton", "SO16", "6YD,", "UK", "Abstract:", "We", "looked", "for", "interaction", "between", "early", "environment", "and", "adult", "lifestyle", "in", "determination", "of", "bone", "mineral", "con-", "tent", "(BMC)", "and", "bone", "mineral", "density", "(BMD)", "among", "498", "men", "and", "468", "women", "for", "whom", "birth", "records", "were", "available.", "Participants", "completed", "a", "health", "questionnaire,", "and", "bone", "densitometry", "(DXA)", "of", "the", "lumbar", "spine", "and", "femoral", "neck", "per-", "formed.", "We", "found", "no", "relationships", "between", "cigarette", "and", "alcohol", "consumption,", "physical", "activity", "and", "either", "BMC", "or", "BMD", "after", "adjustment", "for", "age,", "body", "mass", "index,", "dietary", "calcium,", "social", "class,", "HRT", "use", "and", "years", "since", "menopause.", "However,", "male", "current", "smokers", "in", "the", "lowest", "third", "of", "birth", "weight", "had", "lower", "femoral", "neck", "BMD", "than", "ex-", "or", "never", "smokers", "from", "the", "low-", "est", "birth", "weight", "third", "(p", "value", "for", "interaction", "term", "=", "0.04).", "Similar", "trends", "were", "seen", "with", "femoral", "neck", "BMC", "and", "lumber", "spine", "BMC.", "Individuals", "of", "lower", "birth", "weight", "may", "be", "particularly", "vulnerable", "to", "the", "effects", "of", "bone", "noxious", "stimuli", "such", "as", "cigarette", "smoking.", "INTRODUCTION", "Epidemiological", "studies", "have", "shown", "that", "individuals", "of", "low", "birthweight", "may", "be", "at", "increased", "risk", "of", "osteoporosis", "in", "adult", "life", "[1-6].", "Lifestyle", "factors", "in", "adulthood", "also", "affect", "bone", "mineral", "content", "(BMC)", "and", "bone", "mineral", "density", "(BMD)", "although", "the", "extent", "of", "this", "influence", "may", "vary", "be-", "tween", "individuals;", "previous", "studies", "have", "suggested", "that", "the", "early", "environment", "may", "interact", "with", "adult", "lifestyle", "to", "deter-", "mine", "risk", "factors", "for", "common", "diseases.", "In", "one", "recent", "study", "by", "Robinson", "et", "al.", "individuals", "of", "low", "birth", "weight", "were", "par-", "ticularly", "susceptible", "to", "the", "effect", "of", "high", "dietary", "fat", "intakes", "when", "blood", "cholesterol", "levels", "were", "measured", "[7].", "To", "inves-", "tigate", "whether", "a", "similar", "interaction", "might", "operate", "between", "later", "lifestyle", "factors", "and", "growth", "in", "early", "life", "to", "determine", "the", "risk", "of", "adult", "osteoporosis,", "we", "examined", "the", "relationships", "between", "birth", "weight,", "lifestyle", "factors", "and", "adult", "BMD", "and", "BMC", "in", "a", "cohort", "of", "men", "and", "women", "from", "Hertfordshire,", "UK.", "MATERIALS", "AND", "METHODS", "Four", "hundred", "and", "ninety", "eight", "men", "and", "468", "women", "aged", "59-71", "years", "were", "recruited", "to", "this", "study,", "which", "was", "designed", "to", "examine", "the", "relationship", "between", "growth", "in", "infancy", "and", "the", "subsequent", "risk", "of", "osteoporosis.", "The", "selection", "procedure", "for", "these", "individuals", "was", "as", "follows:", "in", "brief,", "with", "the", "help", "of", "the", "National", "Health", "Service", "Central", "Registry", "at", "Southport,", "and", "Hertfordshire", "Family", "Health", "Service", "Association,", "we", "traced", "men", "and", "women", "who", "were", "born", "during", "1931-39", "in", "Hertfordshire,", "and", "still", "lived", "there", "during", "the", "period", "1998-", "*Address", "correspondence", "to", "this", "author", "at", "the", "MRC", "Resource", "Centre,", "Uni-", "versity", "of", "Southampton,", "Southampton", "General", "Hospital,", "Southampton", "SO16", "6YD,", "UK;", "Tel:", "+44", "(0)23", "8077", "7624;", "Fax:", "+44", "(0)23", "8070", "4021;", "E-mail:", "emd@mrc.soton.ac.uk", "2003.", "After", "obtaining", "written", "permission", "from", "each", "subject’s", "General", "Practitioner,", "we", "approached", "each", "person", "by", "letter,", "to", "ask", "them", "if", "they", "would", "be", "willing", "to", "be", "contacted", "by", "one", "of", "our", "research", "nurses.", "If", "they", "agreed,", "a", "research", "nurse", "per-", "formed", "a", "home", "visit,", "where", "they", "administered", "a", "structured", "questionnaire.", "This", "included", "information", "on", "socioeconomic", "status,", "medical", "history,", "cigarette", "smoking,", "alcohol", "consump-", "tion", "and", "dietary", "calcium", "intake.", "Physical", "activity", "was", "as-", "sessed", "by", "a", "previously", "validated", "questionnaire", "[8].", "The", "sub-", "ject", "was", "then", "invited", "to", "attend", "a", "local", "clinic.", "Height", "was", "measured", "to", "the", "nearest", "0.1cm", "using", "a", "Har-", "penden", "pocket", "stadiometer", "(Chasmors", "Ltd.,", "London,", "UK)", "and", "weight", "to", "the", "nearest", "0.1kg", "on", "a", "SECA", "floor", "scale", "(Chasmors", "Ltd.,", "London,", "UK).", "Body", "mass", "index", "(BMI)", "was", "calculated", "as", "weight", "divided", "by", "height", "2", "(kg/m2).", "Bone", "mineral", "density", "and", "bone", "mineral", "content", "were", "measured", "in", "each", "subject,", "by", "dual", "energy", "X-ray", "absorptiome-", "try", "at", "the", "lumbar", "spine", "and", "proximal", "femur", "(neck,", "total,", "in-", "tertrochanteric", "and", "trochanteric", "regions,", "Wards", "triangle)", "us-", "ing", "a", "Hologic", "QDR", "4500", "instrument.", "Measurement", "precision", "error,", "expressed", "as", "coefficient", "of", "variation,", "was", "1.55%", "for", "lumbar", "spine", "BMD,", "1.45%", "for", "total", "femur", "and", "1.83%", "for", "femoral", "neck", "BMD", "for", "the", "Hologic", "QDR", "4500;", "these", "figures", "were", "obtained", "by", "twenty", "five", "volunteers", "who", "were", "not", "part", "of", "the", "study", "undergoing", "two", "scans", "on", "the", "same", "day,", "getting", "on", "and", "off", "the", "table", "between", "examinations.", "Short-term", "(two", "month)", "precision", "error", "for", "the", "QDR", "4500", "was", "less", "than", "1%", "for", "both", "sites", "(manufacturers", "figures).", "Individuals", "taking", "drugs", "known", "to", "alter", "bone", "metabolism", "(such", "as", "bisphospho-", "nates)", "were", "excluded", "from", "this", "part", "of", "the", "study,", "although", "women", "taking", "hormone", "replacement", "therapy", "(HRT)", "were", "allowed", "to", "participate,", "due", "to", "the", "large", "numbers", "of", "women", "taking", "this", "medication", "(with", "appropriate", "adjustment", "in", "all", "analyses).", "There", "were", "no", "other", "exclusion", "criteria", "to", "this", "part", "1874-3129/08", "2008", "Bentham", "Open" ]

[ 0, 0, 0, 0, 0, 0, 0, 4, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 46, 11 ], [ 118, 75, 17, 11 ], [ 137, 75, 53, 11 ], [ 192, 75, 59, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 81, 25 ], [ 155, 220, 99, 25 ], [ 259, 220, 58, 25 ], [ 321, 220, 102, 25 ], [ 428, 220, 22, 25 ], [ 454, 220, 64, 25 ], [ 120, 289, 39, 17 ], [ 162, 289, 13, 17 ], [ 178, 289, 66, 17 ], [ 120, 320, 41, 13 ], [ 164, 320, 9, 13 ], [ 176, 320, 35, 13 ], [ 213, 320, 28, 13 ], [ 244, 320, 45, 13 ], [ 291, 320, 19, 13 ], [ 313, 320, 70, 13 ], [ 385, 320, 40, 13 ], [ 427, 320, 59, 13 ], [ 489, 320, 9, 13 ], [ 500, 320, 49, 13 ], [ 551, 320, 10, 13 ], [ 564, 320, 55, 13 ], [ 621, 320, 19, 13 ], [ 643, 320, 43, 13 ], [ 688, 320, 36, 13 ], [ 120, 335, 30, 13 ], [ 153, 335, 40, 13 ], [ 195, 335, 35, 13 ], [ 232, 335, 9, 13 ], [ 244, 335, 101, 13 ], [ 347, 335, 39, 13 ], [ 389, 335, 35, 13 ], [ 426, 335, 33, 13 ], [ 461, 335, 17, 13 ], [ 480, 335, 33, 13 ], [ 516, 335, 23, 13 ], [ 120, 363, 83, 13 ], [ 205, 363, 34, 13 ], [ 242, 363, 12, 13 ], [ 256, 363, 49, 13 ], [ 308, 363, 11, 13 ], [ 321, 363, 27, 13 ], [ 350, 363, 10, 13 ], [ 363, 363, 50, 13 ], [ 415, 363, 135, 13 ], [ 120, 390, 44, 13 ], [ 166, 390, 6, 13 ], [ 175, 390, 23, 13 ], [ 200, 390, 27, 13 ], [ 230, 390, 39, 13 ], [ 271, 390, 12, 13 ], [ 286, 390, 35, 13 ], [ 324, 390, 27, 13 ], [ 354, 390, 46, 13 ], [ 402, 390, 12, 13 ], [ 417, 390, 35, 13 ], [ 454, 390, 24, 13 ], [ 120, 415, 49, 13 ], [ 172, 415, 35, 13 ], [ 209, 415, 26, 13 ], [ 238, 415, 26, 13 ], [ 266, 415, 27, 13 ], [ 120, 440, 52, 13 ], [ 174, 440, 9, 13 ], [ 186, 440, 24, 13 ], [ 213, 440, 27, 13 ], [ 243, 440, 10, 13 ], [ 255, 440, 50, 13 ], [ 308, 440, 22, 13 ], [ 333, 440, 8, 13 ], [ 343, 440, 13, 13 ], [ 359, 440, 25, 13 ], [ 387, 440, 30, 13 ], [ 419, 440, 31, 13 ], [ 453, 440, 55, 13 ], [ 511, 440, 30, 13 ], [ 544, 440, 16, 13 ], [ 563, 440, 41, 13 ], [ 607, 440, 53, 13 ], [ 663, 440, 58, 13 ], [ 723, 440, 40, 13 ], [ 120, 455, 31, 13 ], [ 153, 455, 39, 13 ], [ 194, 455, 61, 13 ], [ 258, 455, 20, 13 ], [ 280, 455, 63, 13 ], [ 345, 455, 19, 13 ], [ 367, 455, 66, 13 ], [ 436, 455, 11, 13 ], [ 449, 455, 18, 13 ], [ 469, 455, 46, 13 ], [ 517, 455, 45, 13 ], [ 565, 455, 16, 13 ], [ 584, 455, 39, 13 ], [ 625, 455, 26, 13 ], [ 654, 455, 8, 13 ], [ 664, 455, 43, 13 ], [ 710, 455, 28, 13 ], [ 120, 481, 38, 13 ], [ 161, 481, 43, 13 ], [ 207, 481, 8, 13 ], [ 218, 481, 6, 13 ], [ 226, 481, 49, 13 ], [ 278, 481, 20, 13 ], [ 301, 481, 17, 13 ], [ 321, 481, 27, 13 ], [ 351, 481, 39, 13 ], [ 393, 481, 38, 13 ], [ 433, 481, 15, 13 ], [ 451, 481, 12, 13 ], [ 466, 481, 11, 13 ], [ 479, 481, 23, 13 ], [ 505, 481, 10, 13 ], [ 518, 481, 8, 13 ], [ 529, 481, 8, 13 ], [ 540, 481, 63, 13 ], [ 606, 481, 11, 13 ], [ 619, 481, 16, 13 ], [ 638, 481, 30, 13 ], [ 671, 481, 40, 13 ], [ 714, 481, 49, 13 ], [ 120, 496, 13, 13 ], [ 136, 496, 38, 13 ], [ 177, 496, 10, 13 ], [ 189, 496, 16, 13 ], [ 207, 496, 51, 13 ], [ 261, 496, 48, 13 ], [ 311, 496, 11, 13 ], [ 324, 496, 12, 13 ], [ 338, 496, 44, 13 ], [ 385, 496, 35, 13 ], [ 423, 496, 14, 13 ], [ 440, 496, 16, 13 ], [ 458, 496, 21, 13 ], [ 481, 496, 11, 13 ], [ 494, 496, 52, 13 ], [ 548, 496, 16, 13 ], [ 567, 496, 48, 13 ], [ 617, 496, 11, 13 ], [ 630, 496, 74, 13 ], [ 706, 496, 19, 13 ], [ 728, 496, 11, 13 ], [ 741, 496, 22, 13 ], [ 120, 510, 56, 13 ], [ 178, 510, 14, 13 ], [ 194, 510, 16, 13 ], [ 213, 510, 51, 13 ], [ 266, 510, 26, 13 ], [ 295, 510, 12, 13 ], [ 309, 510, 35, 13 ], [ 346, 510, 34, 13 ], [ 382, 510, 30, 13 ], [ 414, 510, 46, 13 ], [ 462, 510, 19, 13 ], [ 484, 510, 71, 13 ], [ 557, 510, 45, 13 ], [ 604, 510, 10, 13 ], [ 616, 510, 24, 13 ], [ 643, 510, 44, 13 ], [ 689, 510, 11, 13 ], [ 701, 510, 23, 13 ], [ 727, 510, 36, 13 ], [ 120, 525, 19, 13 ], [ 142, 525, 36, 13 ], [ 180, 525, 25, 13 ], [ 208, 525, 46, 13 ], [ 385, 566, 22, 14 ], [ 409, 566, 23, 14 ], [ 435, 566, 37, 14 ], [ 474, 566, 35, 14 ], [ 512, 566, 14, 14 ], [ 529, 566, 42, 14 ], [ 574, 566, 11, 14 ], [ 587, 566, 39, 14 ], [ 629, 566, 10, 14 ], [ 642, 566, 11, 14 ], [ 656, 566, 24, 14 ], [ 683, 566, 27, 14 ], [ 712, 566, 50, 14 ], [ 425, 582, 28, 14 ], [ 456, 582, 10, 14 ], [ 469, 582, 28, 14 ], [ 499, 582, 20, 14 ], [ 522, 582, 36, 14 ], [ 562, 582, 29, 14 ], [ 594, 582, 11, 14 ], [ 608, 582, 17, 14 ], [ 627, 582, 47, 14 ], [ 677, 582, 10, 14 ], [ 690, 582, 73, 14 ], [ 578, 598, 44, 14 ], [ 625, 598, 63, 14 ], [ 690, 598, 12, 14 ], [ 705, 598, 58, 14 ], [ 70, 654, 13, 17 ], [ 86, 654, 92, 17 ], [ 70, 684, 25, 14 ], [ 98, 684, 38, 14 ], [ 138, 684, 27, 14 ], [ 168, 684, 48, 14 ], [ 219, 684, 94, 14 ], [ 316, 684, 25, 14 ], [ 344, 684, 18, 14 ], [ 365, 684, 39, 14 ], [ 70, 700, 34, 14 ], [ 107, 700, 12, 14 ], [ 121, 700, 41, 14 ], [ 165, 700, 35, 14 ], [ 202, 700, 50, 14 ], [ 254, 700, 23, 14 ], [ 279, 700, 26, 14 ], [ 307, 700, 21, 14 ], [ 331, 700, 21, 14 ], [ 355, 700, 49, 14 ], [ 70, 715, 12, 14 ], [ 86, 715, 36, 14 ], [ 126, 715, 20, 14 ], [ 151, 715, 68, 14 ], [ 222, 715, 48, 14 ], [ 274, 715, 88, 14 ], [ 367, 715, 8, 14 ], [ 379, 715, 25, 14 ], [ 70, 731, 29, 14 ], [ 103, 731, 13, 14 ], [ 120, 731, 25, 14 ], [ 150, 731, 18, 14 ], [ 172, 731, 68, 14 ], [ 245, 731, 12, 14 ], [ 261, 731, 25, 14 ], [ 290, 731, 26, 14 ], [ 321, 731, 21, 14 ], [ 347, 731, 57, 14 ], [ 70, 747, 18, 14 ], [ 91, 747, 54, 14 ], [ 149, 747, 53, 14 ], [ 205, 747, 22, 14 ], [ 230, 747, 26, 14 ], [ 259, 747, 17, 14 ], [ 279, 747, 13, 14 ], [ 295, 747, 12, 14 ], [ 310, 747, 20, 14 ], [ 334, 747, 41, 14 ], [ 378, 747, 26, 14 ], [ 70, 763, 12, 14 ], [ 86, 763, 37, 15 ], [ 128, 763, 9, 14 ], [ 142, 763, 9, 14 ], [ 155, 763, 26, 14 ], [ 185, 763, 21, 14 ], [ 211, 763, 33, 14 ], [ 248, 763, 45, 14 ], [ 298, 763, 12, 14 ], [ 314, 763, 48, 14 ], [ 367, 763, 37, 14 ], [ 70, 779, 22, 14 ], [ 96, 779, 21, 14 ], [ 121, 779, 32, 14 ], [ 157, 779, 21, 14 ], [ 182, 779, 30, 14 ], [ 216, 779, 13, 14 ], [ 234, 779, 51, 14 ], [ 289, 779, 15, 14 ], [ 308, 779, 6, 14 ], [ 318, 779, 26, 14 ], [ 349, 779, 39, 14 ], [ 392, 779, 12, 14 ], [ 70, 794, 18, 14 ], [ 91, 794, 72, 14 ], [ 166, 794, 12, 14 ], [ 180, 794, 40, 14 ], [ 223, 794, 51, 14 ], [ 70, 832, 13, 17 ], [ 86, 832, 68, 17 ], [ 157, 832, 15, 17 ], [ 174, 832, 23, 17 ], [ 200, 832, 66, 17 ], [ 270, 832, 25, 17 ], [ 70, 861, 43, 14 ], [ 117, 861, 47, 14 ], [ 169, 861, 9, 14 ], [ 183, 861, 14, 14 ], [ 202, 861, 43, 14 ], [ 249, 861, 22, 14 ], [ 277, 861, 19, 14 ], [ 300, 861, 56, 14 ], [ 361, 861, 44, 15 ], [ 70, 877, 42, 14 ], [ 118, 877, 17, 14 ], [ 142, 877, 14, 14 ], [ 162, 877, 12, 14 ], [ 181, 877, 29, 14 ], [ 216, 877, 13, 14 ], [ 236, 877, 24, 14 ], [ 266, 877, 18, 14 ], [ 291, 877, 48, 14 ], [ 345, 877, 12, 14 ], [ 364, 877, 40, 14 ], [ 70, 893, 47, 14 ], [ 120, 893, 21, 14 ], [ 144, 893, 13, 14 ], [ 159, 893, 50, 14 ], [ 211, 893, 55, 14 ], [ 269, 893, 9, 14 ], [ 280, 893, 53, 14 ], [ 336, 893, 12, 14 ], [ 350, 893, 18, 14 ], [ 371, 893, 33, 14 ], [ 70, 909, 70, 14 ], [ 142, 909, 44, 14 ], [ 189, 909, 55, 14 ], [ 245, 909, 18, 14 ], [ 265, 909, 50, 14 ], [ 318, 909, 40, 14 ], [ 360, 909, 34, 14 ], [ 396, 909, 8, 14 ], [ 70, 925, 9, 14 ], [ 81, 925, 44, 14 ], [ 127, 925, 17, 14 ], [ 147, 925, 6, 14 ], [ 155, 925, 42, 14 ], [ 199, 925, 35, 14 ], [ 237, 925, 53, 14 ], [ 292, 925, 29, 14 ], [ 324, 925, 21, 14 ], [ 347, 925, 57, 14 ], [ 70, 940, 12, 14 ], [ 86, 940, 19, 14 ], [ 110, 940, 35, 14 ], [ 149, 940, 17, 14 ], [ 170, 940, 43, 14 ], [ 218, 940, 17, 14 ], [ 240, 940, 27, 14 ], [ 271, 940, 11, 14 ], [ 287, 940, 12, 14 ], [ 304, 940, 12, 14 ], [ 320, 940, 8, 14 ], [ 333, 940, 9, 14 ], [ 346, 940, 18, 14 ], [ 369, 940, 35, 14 ], [ 70, 956, 12, 14 ], [ 87, 956, 18, 14 ], [ 110, 956, 43, 14 ], [ 159, 956, 43, 14 ], [ 207, 956, 45, 14 ], [ 257, 956, 16, 14 ], [ 278, 956, 27, 14 ], [ 310, 956, 40, 14 ], [ 356, 956, 21, 14 ], [ 382, 956, 22, 14 ], [ 70, 972, 31, 14 ], [ 104, 972, 45, 14 ], [ 151, 972, 25, 14 ], [ 179, 972, 15, 14 ], [ 196, 972, 12, 14 ], [ 211, 972, 67, 14 ], [ 281, 972, 18, 14 ], [ 301, 972, 39, 14 ], [ 343, 972, 7, 14 ], [ 352, 972, 52, 14 ], [ 70, 988, 39, 14 ], [ 113, 988, 25, 14 ], [ 142, 988, 15, 14 ], [ 160, 988, 12, 14 ], [ 176, 988, 29, 14 ], [ 209, 988, 68, 14 ], [ 281, 988, 25, 14 ], [ 311, 988, 36, 14 ], [ 350, 988, 54, 14 ], [ 70, 1004, 21, 14 ], [ 95, 1004, 38, 14 ], [ 137, 1004, 20, 14 ], [ 160, 1004, 18, 14 ], [ 182, 1004, 28, 14 ], [ 213, 1004, 12, 14 ], [ 228, 1004, 18, 14 ], [ 250, 1004, 47, 14 ], [ 300, 1004, 36, 14 ], [ 340, 1004, 45, 14 ], [ 388, 1004, 16, 14 ], [ 70, 1019, 27, 14 ], [ 100, 1019, 40, 14 ], [ 143, 1019, 21, 14 ], [ 449, 656, 28, 14 ], [ 481, 656, 21, 14 ], [ 506, 656, 52, 14 ], [ 562, 656, 28, 14 ], [ 595, 656, 28, 14 ], [ 626, 656, 38, 14 ], [ 668, 656, 18, 14 ], [ 690, 656, 26, 14 ], [ 720, 656, 12, 14 ], [ 735, 656, 27, 14 ], [ 428, 672, 47, 14 ], [ 478, 672, 15, 14 ], [ 495, 672, 47, 14 ], [ 545, 672, 40, 14 ], [ 588, 672, 21, 14 ], [ 612, 672, 18, 14 ], [ 632, 672, 63, 14 ], [ 698, 672, 65, 14 ], [ 428, 688, 22, 14 ], [ 454, 688, 14, 14 ], [ 472, 688, 62, 14 ], [ 538, 688, 18, 14 ], [ 560, 688, 56, 14 ], [ 619, 688, 44, 14 ], [ 667, 688, 45, 14 ], [ 715, 688, 21, 14 ], [ 740, 688, 22, 14 ], [ 428, 704, 18, 14 ], [ 451, 704, 35, 14 ], [ 490, 704, 30, 14 ], [ 525, 704, 11, 14 ], [ 540, 704, 14, 14 ], [ 559, 704, 39, 14 ], [ 602, 704, 27, 14 ], [ 633, 704, 30, 14 ], [ 668, 704, 25, 14 ], [ 697, 704, 44, 14 ], [ 745, 704, 17, 14 ], [ 428, 719, 12, 14 ], [ 444, 719, 60, 14 ], [ 508, 719, 26, 14 ], [ 538, 719, 11, 14 ], [ 554, 719, 65, 14 ], [ 624, 719, 12, 14 ], [ 640, 719, 34, 14 ], [ 678, 719, 46, 14 ], [ 728, 719, 34, 14 ], [ 428, 735, 35, 14 ], [ 470, 735, 13, 14 ], [ 490, 735, 36, 14 ], [ 532, 735, 11, 14 ], [ 549, 735, 6, 14 ], [ 562, 735, 49, 14 ], [ 617, 735, 27, 14 ], [ 651, 735, 21, 14 ], [ 679, 735, 20, 14 ], [ 705, 735, 26, 14 ], [ 737, 735, 25, 14 ], [ 428, 751, 19, 14 ], [ 453, 751, 55, 14 ], [ 513, 751, 38, 14 ], [ 557, 751, 12, 14 ], [ 575, 751, 31, 14 ], [ 611, 751, 12, 14 ], [ 628, 751, 52, 14 ], [ 686, 751, 18, 14 ], [ 709, 751, 35, 14 ], [ 750, 751, 12, 14 ], [ 428, 767, 40, 14 ], [ 471, 767, 47, 14 ], [ 520, 767, 6, 14 ], [ 529, 767, 30, 14 ], [ 561, 767, 12, 14 ], [ 575, 767, 68, 14 ], [ 646, 767, 26, 14 ], [ 675, 767, 16, 14 ], [ 694, 767, 68, 14 ], [ 428, 782, 32, 14 ], [ 465, 782, 12, 14 ], [ 481, 782, 16, 14 ], [ 502, 782, 32, 14 ], [ 539, 782, 21, 14 ], [ 564, 782, 24, 14 ], [ 593, 782, 47, 14 ], [ 644, 782, 12, 14 ], [ 660, 782, 52, 14 ], [ 716, 782, 12, 14 ], [ 732, 782, 30, 14 ], [ 428, 798, 51, 14 ], [ 481, 798, 17, 14 ], [ 501, 798, 40, 14 ], [ 543, 798, 47, 14 ], [ 593, 798, 53, 14 ], [ 649, 798, 18, 14 ], [ 669, 798, 63, 14 ], [ 734, 798, 12, 14 ], [ 748, 798, 14, 14 ], [ 428, 814, 56, 14 ], [ 488, 814, 12, 14 ], [ 504, 814, 18, 14 ], [ 525, 814, 35, 14 ], [ 564, 814, 48, 14 ], [ 616, 814, 14, 14 ], [ 634, 814, 58, 14 ], [ 695, 814, 12, 14 ], [ 711, 814, 6, 14 ], [ 721, 814, 42, 14 ], [ 428, 830, 38, 14 ], [ 472, 830, 43, 14 ], [ 520, 830, 13, 14 ], [ 538, 830, 36, 14 ], [ 580, 830, 77, 14 ], [ 662, 830, 9, 14 ], [ 677, 830, 29, 14 ], [ 711, 830, 52, 14 ], [ 428, 846, 34, 14 ], [ 465, 846, 42, 14 ], [ 510, 846, 26, 14 ], [ 539, 846, 53, 14 ], [ 595, 846, 12, 14 ], [ 609, 846, 91, 14 ], [ 703, 846, 44, 14 ], [ 751, 846, 12, 14 ], [ 428, 861, 29, 14 ], [ 462, 861, 6, 14 ], [ 474, 861, 42, 14 ], [ 521, 861, 37, 14 ], [ 563, 861, 32, 14 ], [ 600, 861, 14, 14 ], [ 619, 861, 19, 14 ], [ 643, 861, 20, 14 ], [ 668, 861, 12, 14 ], [ 685, 861, 7, 14 ], [ 697, 861, 27, 14 ], [ 729, 861, 33, 14 ], [ 428, 877, 21, 14 ], [ 452, 877, 53, 14 ], [ 508, 877, 19, 14 ], [ 529, 877, 57, 14 ], [ 589, 877, 27, 14 ], [ 618, 877, 19, 14 ], [ 640, 877, 47, 14 ], [ 690, 877, 45, 14 ], [ 737, 877, 25, 14 ], [ 428, 893, 40, 14 ], [ 474, 893, 19, 14 ], [ 499, 893, 21, 14 ], [ 526, 893, 37, 14 ], [ 569, 893, 17, 14 ], [ 592, 893, 29, 14 ], [ 626, 893, 25, 14 ], [ 657, 893, 25, 14 ], [ 689, 893, 19, 14 ], [ 714, 893, 21, 14 ], [ 741, 893, 22, 14 ], [ 428, 909, 46, 14 ], [ 477, 909, 21, 14 ], [ 449, 925, 52, 14 ], [ 507, 925, 6, 14 ], [ 518, 925, 42, 14 ], [ 566, 925, 25, 14 ], [ 596, 925, 12, 14 ], [ 613, 925, 44, 14 ], [ 662, 925, 45, 14 ], [ 712, 925, 33, 14 ], [ 750, 925, 12, 14 ], [ 428, 940, 32, 14 ], [ 462, 940, 39, 14 ], [ 503, 940, 18, 14 ], [ 524, 940, 21, 14 ], [ 547, 940, 12, 14 ], [ 561, 940, 18, 14 ], [ 581, 940, 67, 14 ], [ 650, 940, 21, 14 ], [ 673, 940, 52, 14 ], [ 727, 940, 35, 14 ], [ 428, 956, 33, 14 ], [ 467, 956, 12, 14 ], [ 484, 956, 21, 14 ], [ 511, 956, 27, 14 ], [ 543, 956, 28, 14 ], [ 576, 956, 18, 14 ], [ 599, 956, 52, 14 ], [ 656, 956, 12, 14 ], [ 673, 956, 46, 14 ], [ 724, 956, 15, 14 ], [ 744, 956, 18, 14 ], [ 428, 972, 22, 14 ], [ 454, 972, 43, 14 ], [ 500, 972, 24, 14 ], [ 528, 972, 49, 14 ], [ 580, 972, 18, 14 ], [ 601, 972, 28, 14 ], [ 633, 972, 42, 14 ], [ 678, 972, 69, 14 ], [ 751, 972, 12, 14 ], [ 428, 988, 53, 14 ], [ 484, 988, 35, 14 ], [ 521, 988, 38, 14 ], [ 562, 988, 18, 14 ], [ 582, 988, 67, 14 ], [ 652, 988, 63, 14 ], [ 717, 988, 12, 14 ], [ 731, 988, 31, 14 ], [ 428, 1003, 18, 14 ], [ 449, 1003, 40, 14 ], [ 492, 1003, 51, 14 ], [ 546, 1003, 17, 14 ], [ 565, 1003, 60, 14 ], [ 629, 1003, 62, 14 ], [ 694, 1003, 68, 14 ], [ 428, 1019, 49, 14 ], [ 481, 1019, 18, 14 ], [ 503, 1019, 19, 14 ], [ 526, 1019, 12, 14 ], [ 541, 1019, 78, 14 ], [ 624, 1019, 11, 14 ], [ 639, 1019, 50, 14 ], [ 693, 1019, 21, 14 ], [ 718, 1019, 44, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Obstetrics", "and", "Gynecology", "International", "Volume", "2012,", "Article", "ID", "649459,", "9", "pages", "doi:10.1155/2012/649459", "Review", "Article", "Uterine", "Prolapse:", "From", "Antiquity", "to", "Today", "Keith", "T.", "Downing", "Division", "of", "Female", "Pelvic", "Medicine", "and", "Reconstructive", "Surgery,", "Department", "of", "Obstetrics", "&", "Gynecology", "and", "Women’s", "Health,", "Albert", "Einstein", "College", "of", "Medicine/Montefiore", "Medical", "Center,", "Bronx,", "NY", "10461,", "USA", "Correspondence", "should", "be", "addressed", "to", "Keith", "T.", "Downing,", "kdowning@montefiore.org", "Received", "2", "June", "2011;", "Revised", "26", "August", "2011;", "Accepted", "26", "August", "2011", "Academic", "Editor:", "Hans", "Peter", "Dietz", "Copyright", "©", "2012", "Keith", "T.", "Downing.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Uterine", "prolapse", "is", "a", "condition", "that", "has", "likely", "affected", "women", "for", "all", "of", "time", "as", "it", "is", "documented", "in", "the", "oldest", "medical", "literature.", "By", "looking", "at", "the", "watershed", "moments", "in", "its", "recorded", "history", "we", "are", "able", "to", "appreciate", "the", "evolution", "of", "urogynecology", "and", "to", "gain", "perspective", "on", "the", "challenges", "faced", "by", "today’s", "female", "pelvic", "medicine", "and", "reconstructive", "surgeons", "in", "their", "attempts", "to", "treat", "uterine", "and", "vaginal", "vault", "prolapse.", "“He", "who", "cannot", "render", "an", "account", "to", "himself", "of", "at", "least", "three", "thousand", "years", "of", "time,", "will", "always", "grope", "in", "the", "darkness", "of", "inexperience”", "Goethe,", "Translation", "of", "Panebaker", "1.", "Introduction", "This", "special", "issue", "provides", "urogynecologists", "with", "the", "oppor-", "tunity", "to", "explore", "recent", "advances", "that", "have", "and", "will", "continue", "to", "propel", "our", "subspecialty", "forward.", "Simultaneously,", "it", "pro-", "vides", "us", "with", "the", "opportunity", "to", "look", "back", "and", "appreciate", "the", "landmark", "moments", "that", "have", "led", "us", "to", "our", "current", "state", "of", "affairs.", "It", "is", "with", "this", "spirit,", "mindful", "of", "Goethe’s", "words,", "that", "this", "paper", "will", "focus", "its", "attention", "on", "a", "brief", "history", "of", "the", "management", "of", "uterine", "prolapse.", "2.", "Antiquity", "to", "the", "Common", "Era", "Uterine", "prolapse", "is", "an", "ailment", "that", "has", "seemingly", "affected", "women", "for", "all", "of", "time.", "In", "fact,", "the", "problem", "of", "uterine", "prolapse", "and", "its", "potential", "treatment", "is", "described", "in", "the", "oldest", "documented", "medical", "literature,", "the", "Egyptian", "Papyri,", "where", "it", "is", "written,", "“of", "a", "woman", "whose", "posterior,", "belly,", "and", "branching", "of", "her", "thighs", "are", "painful,", "say", "thou", "as", "to", "it,", "it", "is", "the", "falling", "of", "the", "womb,”", "(Kahun", "papyrus", "ca.", "1835", "B.C.E.)", "[1].", "The", "Ebers", "papyrus", "goes", "on", "to", "recommend", "“to", "correct", "a", "displaced", "womb:", "with", "oil", "of", "earth", "(petroleum)", "with", "fedder", "(manure)", "and", "honey;", "rub", "the", "body", "of", "the", "patient,”", "(Ebers", "papyrus", "ca.", "1550", "B.C.E.)", "[2].", "Over", "one", "thousand", "years", "later,", "during", "the", "time", "of", "Hip-", "pocrates", "(c.", "460–377", "B.C.E.)", "and", "the", "subsequent", "generations", "that", "he", "influenced,", "the", "prevailing", "medical", "thought", "was", "that", "the", "uterus", "acted", "as", "an", "animal", "unto", "itself.", "This", "concept", "led", "to", "treatments", "such", "as", "fumigation,", "in", "which", "pleasant", "fumes", "would", "be", "placed", "at", "a", "woman’s", "head", "and", "vile", "ones", "near", "her", "prolapsed", "womb,", "in", "order", "to", "stimulate", "the", "uterus", "to", "retreat.", "Polybus,", "a", "pupil", "of", "Hippocrates", "(and", "his", "son-in-law),", "wrote", "in", "his", "noted", "text", "“On", "Diseases", "of", "Women,”", "of", "other", "therapies", "for", "uterine", "prolapse", "including", "the", "application", "of", "an", "astringent", "to", "the", "womb", "followed", "by", "placement", "of", "a", "vinegar", "soaked", "sponge,", "or", "halved", "pomegranate.", "If", "these", "measures", "failed,", "women", "were", "subjected", "to", "succussion—the", "practice", "of", "tying", "a", "woman", "upside", "down", "by", "her", "feet", "to", "a", "fixed", "frame", "and", "bouncing", "her", "repeatedly", "until", "her", "prolapse", "reduced", "then", "leaving", "her", "bed", "bound", "for", "three", "days", "with", "her", "legs", "tied", "together", "[3].", "However,", "a", "gradual", "shift", "in", "medical", "thought", "began", "to", "occur", "toward", "the", "end", "of", "the", "Hippocratic", "era.", "Medicine", "slowly", "began", "to", "free", "itself", "from", "the", "influence", "of", "theurgy.", "By", "the", "first", "century", "C.E.", "Soranus,", "the", "most", "notable", "gynecologist", "of", "antiquity,", "would", "rebuke", "the", "Hippocratic", "approaches", "to", "treat-", "ing", "uterine", "prolapse.", "He", "considered", "fumigation", "nonsensical,", "regarded", "the", "use", "of", "pomegranates", "as", "bruising,", "and", "deemed" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 98, 61, 60, 17 ], [ 161, 61, 17, 17 ], [ 181, 61, 142, 17 ], [ 327, 61, 91, 17 ], [ 113, 115, 20, 9 ], [ 134, 115, 24, 9 ], [ 160, 115, 12, 9 ], [ 173, 115, 15, 9 ], [ 189, 115, 24, 9 ], [ 98, 137, 61, 34 ], [ 168, 137, 74, 34 ], [ 251, 137, 49, 34 ], [ 309, 137, 61, 34 ], [ 378, 137, 144, 34 ], [ 531, 137, 27, 34 ], [ 567, 137, 106, 34 ], [ 98, 176, 98, 34 ], [ 204, 176, 96, 34 ], [ 309, 176, 129, 34 ], [ 689, 61, 86, 17 ], [ 588, 84, 21, 9 ], [ 610, 84, 26, 9 ], [ 638, 84, 9, 9 ], [ 649, 84, 35, 9 ], [ 685, 84, 16, 9 ], [ 702, 84, 33, 9 ], [ 737, 84, 36, 9 ], [ 657, 115, 8, 14 ], [ 667, 115, 7, 14 ], [ 676, 115, 9, 14 ], [ 688, 115, 7, 14 ], [ 697, 115, 8, 14 ], [ 707, 115, 7, 14 ], [ 717, 115, 10, 14 ], [ 730, 115, 9, 14 ], [ 741, 115, 4, 14 ], [ 747, 115, 7, 14 ], [ 756, 115, 7, 14 ], [ 766, 115, 7, 14 ], [ 98, 344, 42, 16 ], [ 143, 344, 11, 16 ], [ 159, 344, 91, 16 ], [ 98, 364, 35, 16 ], [ 135, 364, 10, 16 ], [ 150, 364, 38, 16 ], [ 98, 383, 52, 16 ], [ 154, 383, 10, 16 ], [ 169, 383, 57, 16 ], [ 98, 409, 43, 12 ], [ 144, 409, 38, 12 ], [ 186, 409, 47, 12 ], [ 235, 409, 42, 12 ], [ 98, 423, 96, 12 ], [ 197, 423, 45, 12 ], [ 98, 436, 50, 12 ], [ 152, 436, 10, 12 ], [ 165, 436, 47, 12 ], [ 215, 436, 37, 12 ], [ 98, 449, 37, 12 ], [ 137, 449, 38, 12 ], [ 177, 449, 18, 12 ], [ 198, 449, 22, 12 ], [ 98, 900, 79, 12 ], [ 178, 900, 28, 12 ], [ 208, 900, 8, 12 ], [ 218, 900, 53, 12 ], [ 98, 914, 35, 12 ], [ 135, 914, 90, 12 ], [ 98, 927, 46, 12 ], [ 146, 927, 9, 12 ], [ 159, 927, 44, 12 ], [ 205, 927, 35, 12 ], [ 242, 927, 34, 12 ], [ 98, 940, 34, 12 ], [ 134, 940, 44, 12 ], [ 180, 940, 35, 12 ], [ 218, 940, 34, 12 ], [ 98, 953, 36, 12 ], [ 135, 953, 15, 12 ], [ 152, 953, 56, 12 ], [ 210, 953, 21, 12 ], [ 98, 966, 13, 12 ], [ 114, 966, 12, 12 ], [ 129, 966, 17, 12 ], [ 148, 966, 17, 12 ], [ 168, 966, 23, 12 ], [ 98, 980, 16, 12 ], [ 116, 980, 12, 12 ], [ 131, 980, 17, 12 ], [ 151, 980, 17, 12 ], [ 171, 980, 23, 12 ], [ 98, 993, 24, 12 ], [ 125, 993, 88, 12 ], [ 98, 1045, 23, 7 ], [ 122, 1045, 15, 7 ], [ 139, 1045, 37, 7 ], [ 177, 1045, 2, 7 ], [ 181, 1045, 59, 7 ], [ 98, 1058, 43, 9 ], [ 98, 1073, 127, 7 ], [ 307, 347, 55, 13 ], [ 364, 346, 34, 13 ], [ 400, 346, 21, 13 ], [ 423, 346, 66, 13 ], [ 492, 346, 10, 13 ], [ 504, 346, 13, 13 ], [ 519, 346, 54, 13 ], [ 575, 346, 22, 13 ], [ 599, 346, 21, 13 ], [ 623, 346, 15, 13 ], [ 640, 346, 30, 13 ], [ 673, 346, 23, 13 ], [ 698, 346, 16, 13 ], [ 716, 346, 59, 13 ], [ 307, 364, 10, 13 ], [ 319, 364, 41, 13 ], [ 362, 364, 16, 13 ], [ 379, 364, 31, 13 ], [ 412, 364, 11, 13 ], [ 424, 364, 16, 13 ], [ 442, 364, 22, 13 ], [ 465, 364, 56, 13 ], [ 522, 364, 20, 13 ], [ 544, 364, 54, 13 ], [ 600, 364, 11, 13 ], [ 612, 364, 55, 13 ], [ 669, 364, 18, 13 ], [ 689, 364, 36, 13 ], [ 727, 364, 48, 13 ], [ 307, 382, 10, 13 ], [ 319, 382, 19, 13 ], [ 340, 382, 10, 13 ], [ 352, 382, 41, 13 ], [ 396, 382, 19, 13 ], [ 417, 382, 30, 13 ], [ 449, 382, 35, 13 ], [ 487, 382, 16, 13 ], [ 505, 382, 32, 13 ], [ 538, 382, 14, 13 ], [ 555, 382, 47, 13 ], [ 604, 382, 32, 13 ], [ 638, 382, 15, 13 ], [ 656, 382, 33, 13 ], [ 691, 382, 17, 13 ], [ 711, 382, 40, 13 ], [ 753, 382, 22, 13 ], [ 307, 400, 9, 13 ], [ 317, 400, 10, 13 ], [ 330, 400, 38, 13 ], [ 369, 400, 16, 13 ], [ 387, 400, 31, 13 ], [ 420, 400, 29, 13 ], [ 451, 400, 11, 13 ], [ 464, 400, 17, 13 ], [ 483, 400, 42, 13 ], [ 527, 400, 47, 13 ], [ 577, 400, 7, 13 ], [ 586, 400, 9, 13 ], [ 597, 400, 49, 13 ], [ 648, 400, 10, 13 ], [ 660, 400, 49, 13 ], [ 711, 400, 19, 13 ], [ 732, 400, 43, 13 ], [ 307, 418, 16, 13 ], [ 325, 418, 17, 13 ], [ 344, 418, 39, 13 ], [ 386, 418, 22, 13 ], [ 410, 418, 23, 13 ], [ 435, 418, 41, 13 ], [ 479, 418, 18, 13 ], [ 498, 418, 21, 13 ], [ 522, 418, 25, 13 ], [ 549, 418, 10, 13 ], [ 561, 418, 28, 13 ], [ 592, 418, 32, 13 ], [ 625, 418, 49, 13 ], [ 676, 418, 19, 13 ], [ 697, 418, 20, 13 ], [ 719, 418, 12, 13 ], [ 734, 418, 41, 13 ], [ 307, 436, 13, 13 ], [ 323, 436, 23, 13 ], [ 351, 436, 41, 13 ], [ 396, 436, 23, 13 ], [ 423, 436, 46, 13 ], [ 473, 436, 41, 13 ], [ 518, 436, 16, 13 ], [ 538, 436, 34, 13 ], [ 576, 436, 29, 13 ], [ 609, 436, 18, 13 ], [ 632, 436, 34, 13 ], [ 669, 436, 31, 13 ], [ 705, 436, 24, 13 ], [ 733, 436, 15, 13 ], [ 752, 436, 23, 13 ], [ 307, 454, 49, 13 ], [ 358, 454, 65, 13 ], [ 427, 454, 28, 13 ], [ 459, 454, 39, 13 ], [ 502, 454, 16, 13 ], [ 521, 454, 26, 13 ], [ 550, 454, 50, 13 ], [ 604, 454, 10, 13 ], [ 618, 454, 28, 13 ], [ 649, 454, 44, 13 ], [ 697, 454, 41, 13 ], [ 741, 454, 15, 13 ], [ 760, 454, 16, 13 ], [ 307, 472, 23, 13 ], [ 332, 472, 11, 13 ], [ 346, 472, 23, 13 ], [ 372, 472, 41, 13 ], [ 416, 472, 22, 13 ], [ 441, 472, 15, 13 ], [ 459, 472, 23, 13 ], [ 485, 472, 21, 13 ], [ 509, 472, 34, 13 ], [ 545, 472, 16, 13 ], [ 564, 472, 11, 13 ], [ 578, 472, 33, 13 ], [ 613, 472, 58, 13 ], [ 675, 472, 41, 13 ], [ 719, 472, 22, 13 ], [ 743, 472, 12, 13 ], [ 758, 472, 17, 13 ], [ 307, 490, 25, 13 ], [ 336, 490, 39, 13 ], [ 380, 490, 10, 13 ], [ 394, 490, 13, 13 ], [ 411, 490, 27, 13 ], [ 441, 490, 7, 13 ], [ 452, 490, 50, 13 ], [ 506, 490, 8, 13 ], [ 518, 490, 22, 13 ], [ 544, 490, 23, 13 ], [ 571, 490, 37, 13 ], [ 613, 490, 51, 13 ], [ 668, 490, 72, 13 ], [ 744, 490, 31, 13 ], [ 307, 509, 50, 13 ], [ 359, 509, 47, 13 ], [ 410, 509, 15, 13 ], [ 428, 509, 13, 13 ], [ 444, 509, 10, 13 ], [ 457, 509, 38, 13 ], [ 498, 509, 50, 13 ], [ 552, 509, 37, 13 ], [ 592, 509, 9, 13 ], [ 604, 509, 12, 13 ], [ 619, 509, 55, 13 ], [ 677, 509, 10, 13 ], [ 691, 509, 16, 13 ], [ 710, 509, 31, 13 ], [ 744, 509, 11, 13 ], [ 758, 509, 17, 13 ], [ 307, 527, 34, 13 ], [ 344, 527, 35, 13 ], [ 383, 527, 23, 13 ], [ 409, 527, 22, 13 ], [ 433, 527, 19, 13 ], [ 455, 527, 10, 13 ], [ 468, 527, 16, 13 ], [ 487, 527, 33, 13 ], [ 523, 527, 31, 13 ], [ 557, 527, 55, 13 ], [ 615, 527, 21, 13 ], [ 639, 527, 19, 13 ], [ 662, 527, 27, 13 ], [ 692, 527, 10, 13 ], [ 704, 527, 31, 13 ], [ 738, 527, 25, 13 ], [ 766, 527, 9, 13 ], [ 307, 545, 32, 13 ], [ 340, 545, 45, 13 ], [ 386, 545, 15, 13 ], [ 403, 545, 16, 13 ], [ 421, 545, 31, 13 ], [ 454, 545, 11, 13 ], [ 466, 545, 55, 13 ], [ 523, 545, 10, 13 ], [ 535, 545, 29, 13 ], [ 565, 545, 34, 13 ], [ 602, 545, 46, 13 ], [ 650, 545, 57, 13 ], [ 709, 545, 25, 13 ], [ 736, 545, 39, 13 ], [ 307, 563, 29, 13 ], [ 340, 563, 38, 13 ], [ 383, 563, 50, 13 ], [ 439, 563, 21, 13 ], [ 464, 563, 36, 13 ], [ 505, 563, 17, 13 ], [ 526, 563, 23, 13 ], [ 554, 563, 18, 13 ], [ 576, 563, 41, 13 ], [ 622, 563, 29, 13 ], [ 655, 563, 17, 13 ], [ 677, 563, 18, 13 ], [ 699, 563, 41, 13 ], [ 745, 563, 10, 13 ], [ 760, 563, 16, 13 ], [ 307, 581, 30, 13 ], [ 340, 581, 11, 13 ], [ 353, 581, 25, 13 ], [ 307, 599, 60, 13 ], [ 369, 599, 39, 13 ], [ 411, 599, 58, 13 ], [ 471, 599, 45, 13 ], [ 519, 599, 41, 13 ], [ 562, 599, 39, 13 ], [ 604, 599, 41, 13 ], [ 647, 599, 51, 13 ], [ 701, 599, 63, 13 ], [ 307, 637, 114, 20 ], [ 307, 660, 17, 14 ], [ 327, 660, 50, 14 ], [ 381, 660, 11, 14 ], [ 395, 660, 32, 14 ], [ 429, 660, 50, 14 ], [ 482, 660, 44, 14 ], [ 529, 660, 17, 14 ], [ 550, 660, 26, 14 ], [ 579, 660, 29, 14 ], [ 611, 660, 12, 14 ], [ 626, 660, 18, 14 ], [ 646, 660, 38, 14 ], [ 687, 660, 37, 14 ], [ 728, 660, 47, 14 ], [ 307, 679, 21, 14 ], [ 331, 679, 14, 14 ], [ 348, 679, 56, 14 ], [ 407, 679, 43, 14 ], [ 452, 679, 22, 14 ], [ 477, 679, 26, 14 ], [ 507, 679, 35, 14 ], [ 545, 679, 58, 14 ], [ 606, 679, 10, 14 ], [ 619, 679, 14, 14 ], [ 635, 679, 55, 14 ], [ 693, 679, 45, 14 ], [ 742, 679, 34, 14 ], [ 307, 698, 21, 14 ], [ 330, 698, 11, 14 ], [ 345, 698, 52, 14 ], [ 400, 698, 56, 14 ], [ 459, 698, 40, 14 ], [ 502, 698, 36, 14 ], [ 541, 698, 7, 14 ], [ 551, 698, 63, 14 ], [ 326, 718, 34, 14 ], [ 362, 718, 55, 14 ], [ 420, 718, 40, 14 ], [ 462, 718, 24, 14 ], [ 488, 718, 29, 14 ], [ 519, 718, 21, 14 ], [ 542, 718, 7, 14 ], [ 550, 718, 65, 14 ], [ 618, 718, 12, 14 ], [ 632, 718, 44, 14 ], [ 678, 718, 23, 14 ], [ 703, 718, 72, 14 ], [ 307, 737, 57, 14 ], [ 368, 737, 8, 14 ], [ 380, 737, 13, 14 ], [ 396, 737, 11, 14 ], [ 411, 737, 25, 14 ], [ 440, 737, 7, 14 ], [ 451, 737, 35, 14 ], [ 489, 737, 34, 14 ], [ 527, 737, 46, 14 ], [ 578, 737, 21, 14 ], [ 603, 737, 52, 14 ], [ 659, 737, 35, 14 ], [ 698, 737, 17, 14 ], [ 718, 737, 34, 14 ], [ 755, 737, 20, 14 ], [ 307, 757, 34, 14 ], [ 343, 757, 11, 14 ], [ 357, 757, 26, 14 ], [ 385, 757, 38, 14 ], [ 426, 757, 61, 14 ], [ 489, 757, 12, 14 ], [ 503, 757, 31, 14 ], [ 537, 757, 12, 14 ], [ 552, 757, 25, 14 ], [ 579, 757, 39, 14 ], [ 621, 757, 18, 14 ], [ 642, 757, 75, 14 ], [ 719, 757, 56, 14 ], [ 307, 776, 18, 14 ], [ 329, 776, 18, 14 ], [ 351, 776, 64, 14 ], [ 419, 776, 12, 14 ], [ 436, 776, 34, 14 ], [ 475, 776, 24, 14 ], [ 503, 776, 52, 14 ], [ 559, 776, 45, 14 ], [ 608, 776, 26, 14 ], [ 638, 776, 42, 14 ], [ 685, 776, 11, 14 ], [ 701, 776, 21, 14 ], [ 726, 776, 49, 14 ], [ 307, 796, 30, 14 ], [ 340, 796, 8, 14 ], [ 351, 796, 33, 14 ], [ 387, 796, 21, 14 ], [ 411, 796, 30, 14 ], [ 444, 796, 36, 14 ], [ 326, 815, 22, 14 ], [ 351, 815, 48, 14 ], [ 403, 815, 18, 14 ], [ 423, 815, 48, 14 ], [ 475, 815, 25, 14 ], [ 503, 815, 20, 14 ], [ 527, 815, 11, 14 ], [ 541, 815, 28, 14 ], [ 572, 815, 34, 14 ], [ 609, 815, 20, 14 ], [ 633, 815, 22, 14 ], [ 658, 815, 12, 14 ], [ 673, 815, 46, 14 ], [ 722, 815, 11, 14 ], [ 736, 815, 17, 14 ], [ 757, 815, 18, 14 ], [ 307, 835, 31, 14 ], [ 341, 835, 62, 14 ], [ 405, 835, 12, 14 ], [ 420, 835, 36, 14 ], [ 458, 835, 14, 14 ], [ 475, 835, 36, 14 ], [ 514, 835, 17, 14 ], [ 534, 835, 35, 14 ], [ 571, 835, 24, 14 ], [ 597, 835, 58, 14 ], [ 658, 835, 16, 14 ], [ 676, 835, 26, 14 ], [ 705, 835, 19, 14 ], [ 727, 835, 29, 14 ], [ 758, 835, 18, 14 ], [ 307, 854, 18, 14 ], [ 328, 854, 17, 14 ], [ 347, 854, 26, 14 ], [ 377, 854, 12, 14 ], [ 392, 854, 18, 14 ], [ 412, 854, 22, 14 ], [ 437, 854, 14, 14 ], [ 454, 854, 11, 14 ], [ 468, 854, 26, 14 ], [ 497, 854, 12, 14 ], [ 512, 854, 32, 14 ], [ 547, 854, 7, 14 ], [ 557, 854, 24, 14 ], [ 584, 854, 24, 14 ], [ 611, 854, 21, 14 ], [ 634, 854, 26, 14 ], [ 663, 854, 12, 14 ], [ 678, 854, 32, 14 ], [ 713, 854, 35, 14 ], [ 751, 854, 24, 14 ], [ 307, 873, 24, 14 ], [ 333, 873, 24, 14 ], [ 360, 873, 26, 14 ], [ 389, 873, 14, 14 ], [ 405, 873, 32, 14 ], [ 440, 873, 35, 14 ], [ 478, 873, 22, 14 ], [ 503, 873, 44, 14 ], [ 549, 873, 32, 14 ], [ 584, 873, 35, 14 ], [ 622, 873, 45, 14 ], [ 670, 873, 19, 14 ], [ 691, 873, 35, 14 ], [ 729, 873, 46, 14 ], [ 307, 893, 25, 14 ], [ 334, 893, 14, 14 ], [ 350, 893, 32, 14 ], [ 385, 893, 39, 14 ], [ 426, 893, 17, 14 ], [ 446, 893, 21, 14 ], [ 470, 893, 12, 14 ], [ 484, 893, 31, 14 ], [ 518, 893, 32, 14 ], [ 553, 893, 12, 14 ], [ 567, 893, 14, 14 ], [ 583, 893, 28, 14 ], [ 614, 893, 10, 14 ], [ 626, 893, 53, 14 ], [ 681, 893, 54, 14 ], [ 738, 893, 10, 14 ], [ 750, 893, 25, 14 ], [ 307, 912, 43, 14 ], [ 355, 912, 18, 14 ], [ 379, 912, 37, 14 ], [ 421, 912, 7, 14 ], [ 433, 912, 39, 14 ], [ 477, 912, 22, 14 ], [ 505, 912, 12, 14 ], [ 523, 912, 43, 14 ], [ 571, 912, 12, 14 ], [ 588, 912, 59, 14 ], [ 653, 912, 10, 14 ], [ 668, 912, 56, 14 ], [ 730, 912, 46, 14 ], [ 307, 932, 77, 14 ], [ 389, 932, 41, 14 ], [ 434, 932, 21, 14 ], [ 460, 932, 37, 14 ], [ 501, 932, 58, 14 ], [ 565, 932, 38, 14 ], [ 608, 932, 25, 14 ], [ 637, 932, 18, 14 ], [ 659, 932, 23, 14 ], [ 687, 932, 58, 14 ], [ 750, 932, 25, 14 ], [ 307, 951, 56, 14 ], [ 366, 951, 41, 14 ], [ 411, 951, 20, 14 ], [ 435, 951, 41, 14 ], [ 479, 951, 25, 14 ], [ 508, 951, 11, 14 ], [ 523, 951, 31, 14 ], [ 557, 951, 59, 14 ], [ 620, 951, 41, 14 ], [ 665, 951, 10, 14 ], [ 678, 951, 14, 14 ], [ 695, 951, 55, 14 ], [ 754, 951, 21, 14 ], [ 307, 971, 33, 14 ], [ 343, 971, 17, 14 ], [ 362, 971, 59, 14 ], [ 424, 971, 28, 14 ], [ 455, 971, 55, 14 ], [ 514, 971, 21, 14 ], [ 537, 971, 57, 14 ], [ 597, 971, 54, 14 ], [ 654, 971, 21, 14 ], [ 677, 971, 17, 14 ], [ 698, 971, 63, 14 ], [ 764, 971, 12, 14 ], [ 307, 990, 60, 14 ], [ 369, 990, 8, 14 ], [ 381, 990, 37, 14 ], [ 421, 990, 14, 14 ], [ 438, 990, 109, 14 ], [ 307, 1044, 32, 12 ], [ 341, 1044, 9, 12 ], [ 353, 1044, 73, 12 ], [ 429, 1044, 50, 12 ], [ 481, 1044, 31, 12 ], [ 514, 1044, 39, 12 ], [ 752, 1044, 24, 14 ], [ 307, 1059, 9, 12 ], [ 318, 1059, 23, 12 ], [ 343, 1059, 53, 12 ], [ 399, 1059, 10, 12 ], [ 411, 1059, 10, 12 ], [ 423, 1059, 41, 12 ], [ 467, 1059, 16, 12 ], [ 486, 1059, 36, 12 ], [ 525, 1059, 25, 12 ], [ 552, 1059, 35, 12 ], [ 589, 1059, 24, 12 ], [ 616, 1059, 18, 12 ], [ 636, 1059, 19, 12 ], [ 658, 1059, 7, 12 ], [ 668, 1059, 11, 12 ], [ 681, 1059, 26, 12 ], [ 709, 1059, 31, 12 ], [ 743, 1059, 29, 12 ], [ 307, 1072, 27, 12 ], [ 336, 1072, 35, 12 ], [ 374, 1072, 55, 12 ], [ 432, 1072, 70, 12 ], [ 504, 1072, 18, 12 ], [ 524, 1072, 40, 12 ], [ 566, 1072, 15, 12 ], [ 584, 1072, 33, 12 ], [ 620, 1072, 24, 12 ], [ 647, 1072, 7, 12 ], [ 657, 1072, 39, 12 ], [ 698, 1072, 25, 12 ] ]

[ "Journal", "of", "Multidisciplinary", "Healthcare", "Open", "Access", "Full", "Text", "Article", "Let’s", "move", "our", "next", "generation", "of", "patients", "toward", "healthy", "behaviors", "Dovepress", "open", "access", "to", "scientific", "and", "medical", "research", "P", "E", "R", "S", "P", "E", "C", "T", "I", "v", "E", "S", "Phyllis", "A", "Nsiah-Kumi1,2", "Lydia", "Y", "Kang1", "Jennifer", "R", "Parker1,2", "1General", "Internal", "Medicine,", "2Internal", "Medicine-Pediatrics", "Program,", "University", "of", "Nebraska", "Medical", "Center,", "Omaha,", "NE,", "USA", "Correspondence:", "Phyllis", "A", "Nsiah-Kumi", "Internal", "Medicine-Pediatrics,", "University", "of", "Nebraska", "Medical", "Center,", "984085", "Nebraska", "Medical", "Center,", "Omaha,", "NE", "68198-4085,", "USA", "Tel", "+1", "402", "559", "6946", "Fax", "+1", "402", "559", "6113", "Email", "pnkumi@unmc.edu", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "http://dx.doi.org/10.2147/JMDH.S23578", "Abstract:", "Health", "care", "professionals", "in", "all", "disciplines", "who", "care", "for", "adults", "have", "the", "opportunity", "to", "improve", "the", "health", "of", "the", "next", "generation.", "The", "prevalence", "of", "overweight", "and", "obesity", "continues", "to", "rise", "in", "children", "and", "adults", "around", "the", "world.", "As", "providers", "caring", "for", "adults,", "our", "primary", "goal", "is", "to", "address", "the", "health", "needs", "of", "our", "patients.", "However,", "it", "is", "important", "to", "recognize", "that", "counsel-", "ing", "our", "patients", "who", "have", "children", "can", "lead", "them", "to", "adopt", "model", "behaviors", "that", "will", "be", "imitated", "by", "their", "children", "(and", "therefore", "improve", "the", "weight", "status", "and", "reduce", "health", "risks", "for", "their", "children).", "Additionally,", "many", "patients", "are", "more", "motivated", "to", "adopt", "behavior", "changes", "for", "the", "sake", "of", "their", "children", "than", "for", "their", "own", "health.", "All", "of", "2012’s", "11-year-old", "children", "may", "be", "our", "adult", "patients", "in", "10", "years", "–", "especially", "if", "they", "have", "already", "developed", "weight-related", "health", "problems.", "Anything", "we", "do", "to", "address", "childhood", "obesity", "is", "an", "investment", "in", "the", "health", "of", "our", "patient", "panels,", "both", "now", "and", "in", "the", "future.", "While", "counseling", "may", "feel", "futile", "at", "times,", "there", "is", "strong", "evidence", "for", "the", "power", "of", "counseling", "to", "shape", "patient", "behavior.", "Counseling", "adult", "patients", "about", "healthy", "behaviors", "will", "benefit", "not", "only", "our", "patients", "today", "but", "our", "patients", "in", "the", "future", "as", "well.", "Keywords:", "obesity,", "counseling,", "provider,", "lifestyle", "change,", "parental", "modeling,", "self-efficacy", "Introduction", "On", "February", "9,", "2010,", "Michelle", "Obama,", "the", "First", "Lady", "of", "the", "United", "States,", "declared", "war", "on", "childhood", "obesity.", "The", "Let’s", "Move!", "Campaign", "is", "an", "ambitious", "national", "initia-", "tive", "to", "eliminate", "childhood", "obesity", "within", "a", "generation.", "While", "childhood", "obesity", "may", "seem", "like", "a", "pediatrician", "or", "primary", "care", "practitioner’s", "challenge,", "it", "is,", "in", "fact,", "a", "public", "health", "problem", "that", "providers", "caring", "for", "adults", "can", "tackle", "in", "their", "patient", "encounters", "as", "well.1", "In", "fact,", "several", "US", "organizations", "represent-", "ing", "the", "community", "of", "health", "care", "providers", "pledged", "their", "support", "to", "this", "initiative", "when", "it", "began", "two", "years", "ago.2–7", "The", "statistics", "are", "sobering", "with", "one", "in", "three", "adults", "and", "half", "of", "children", "in", "the", "US", "being", "overweight", "or", "obese,", "no", "matter", "the", "health", "care", "discipline,", "we", "have", "our", "work", "cut", "out", "for", "us.8,9", "In", "the", "US,", "up", "to", "50%", "of", "obese", "6", "year", "olds", "and", "80%", "of", "obese", "10–14", "year", "olds", "who", "have", "an", "obese", "parent", "will", "become", "obese", "young", "adults.10", "For", "young", "children", "with", "an", "obese", "parent,", "the", "risk", "of", "being", "obese", "as", "an", "adult", "is", "increased", "threefold.", "If", "both", "parents", "are", "obese,", "a", "child’s", "risk", "of", "obesity", "in", "adulthood", "is", "increased", "tenfold.", "Prepregnancy", "obesity", "and", "excess", "pregnancy", "weight", "gain", "are", "also", "associated", "with", "childhood", "obesity", "and", "obesity", "later", "in", "life.11", "Childhood", "obesity", "is", "an", "important", "risk", "factor", "for", "significant", "adult", "morbidity", "and", "premature", "mortality,", "and", "the", "importance", "of", "addressing", "it", "cannot", "be", "underestimated.12–14", "Journal", "of", "Multidisciplinary", "Healthcare", "2012:5", "115–119", "115", "©", "2012", "Nsiah-Kumi", "et", "al,", "publisher", "and", "licensee", "Dove", "Medical", "Press", "Ltd.", "This", "is", "an", "Open", "Access", "article", "which", "permits", "unrestricted", "noncommercial", "use,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 9, 9, 9, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 335, 117, 34, 13 ], [ 372, 117, 28, 13 ], [ 404, 117, 109, 13 ], [ 321, 200, 37, 12 ], [ 360, 200, 28, 12 ], [ 391, 200, 28, 12 ], [ 422, 200, 88, 12 ], [ 84, 186, 68, 17 ], [ 78, 249, 61, 21 ], [ 143, 249, 83, 21 ], [ 231, 249, 12, 21 ], [ 247, 249, 85, 21 ], [ 337, 249, 20, 21 ], [ 361, 249, 72, 21 ], [ 437, 249, 125, 21 ], [ 566, 249, 82, 21 ], [ 652, 249, 116, 21 ], [ 78, 274, 19, 21 ], [ 102, 274, 64, 21 ], [ 169, 274, 36, 21 ], [ 209, 274, 84, 21 ], [ 78, 306, 49, 17 ], [ 130, 306, 74, 17 ], [ 207, 306, 8, 17 ], [ 218, 306, 92, 17 ], [ 313, 306, 61, 17 ], [ 376, 306, 10, 17 ], [ 389, 306, 52, 17 ], [ 444, 306, 81, 17 ], [ 528, 306, 8, 12 ], [ 78, 333, 3, 9 ], [ 82, 337, 34, 10 ], [ 118, 337, 40, 10 ], [ 159, 337, 56, 10 ], [ 216, 337, 33, 10 ], [ 250, 337, 38, 10 ], [ 290, 337, 9, 10 ], [ 301, 337, 21, 10 ], [ 323, 337, 33, 10 ], [ 357, 337, 9, 10 ], [ 368, 337, 19, 10 ], [ 78, 349, 5, 9 ], [ 84, 352, 32, 10 ], [ 118, 352, 31, 10 ], [ 150, 352, 13, 10 ], [ 165, 352, 36, 10 ], [ 202, 352, 35, 10 ], [ 239, 352, 20, 10 ], [ 261, 352, 44, 10 ], [ 307, 352, 39, 10 ], [ 347, 352, 33, 10 ], [ 381, 352, 9, 10 ], [ 392, 352, 19, 10 ], [ 80, 382, 7, 12 ], [ 91, 382, 8, 12 ], [ 103, 382, 7, 12 ], [ 113, 382, 5, 12 ], [ 122, 382, 7, 12 ], [ 133, 382, 6, 12 ], [ 143, 382, 6, 12 ], [ 160, 382, 5, 12 ], [ 169, 382, 8, 12 ], [ 181, 382, 6, 12 ], [ 191, 382, 9, 12 ], [ 80, 405, 30, 12 ], [ 112, 405, 24, 12 ], [ 80, 419, 30, 12 ], [ 111, 419, 11, 12 ], [ 123, 419, 31, 12 ], [ 78, 451, 30, 12 ], [ 110, 451, 35, 12 ], [ 78, 465, 47, 12 ], [ 127, 465, 10, 12 ], [ 139, 465, 18, 12 ], [ 158, 465, 23, 12 ], [ 78, 479, 41, 12 ], [ 121, 479, 10, 12 ], [ 133, 479, 18, 12 ], [ 152, 479, 23, 12 ], [ 78, 493, 48, 12 ], [ 128, 493, 10, 12 ], [ 140, 493, 19, 12 ], [ 160, 493, 23, 12 ], [ 78, 523, 48, 12 ], [ 78, 537, 33, 12 ], [ 113, 537, 46, 12 ], [ 160, 537, 7, 12 ], [ 169, 537, 46, 12 ], [ 78, 550, 68, 12 ], [ 78, 610, 34, 17 ], [ 115, 610, 45, 17 ], [ 90, 639, 17, 13 ], [ 111, 639, 40, 13 ], [ 155, 639, 45, 13 ], [ 203, 639, 44, 13 ], [ 251, 639, 19, 13 ], [ 274, 639, 51, 13 ], [ 329, 639, 37, 13 ], [ 370, 639, 14, 13 ], [ 388, 639, 24, 13 ], [ 78, 655, 34, 13 ], [ 118, 655, 22, 13 ], [ 146, 655, 59, 13 ], [ 211, 655, 15, 13 ], [ 232, 655, 35, 13 ], [ 273, 655, 50, 13 ], [ 329, 655, 8, 13 ], [ 342, 655, 51, 13 ], [ 399, 655, 12, 13 ], [ 78, 670, 44, 13 ], [ 126, 670, 75, 13 ], [ 205, 670, 27, 13 ], [ 237, 670, 46, 13 ], [ 287, 670, 16, 13 ], [ 308, 670, 13, 13 ], [ 325, 670, 54, 13 ], [ 384, 670, 10, 13 ], [ 398, 670, 13, 13 ], [ 78, 686, 63, 13 ], [ 147, 686, 12, 13 ], [ 165, 686, 28, 13 ], [ 199, 686, 39, 13 ], [ 244, 686, 20, 13 ], [ 270, 686, 41, 13 ], [ 316, 686, 27, 13 ], [ 349, 686, 38, 13 ], [ 393, 686, 19, 13 ], [ 78, 702, 61, 13 ], [ 142, 702, 12, 13 ], [ 157, 702, 35, 13 ], [ 195, 702, 50, 13 ], [ 248, 702, 8, 13 ], [ 258, 702, 29, 13 ], [ 289, 702, 33, 13 ], [ 325, 702, 51, 13 ], [ 378, 702, 12, 13 ], [ 393, 702, 18, 13 ], [ 78, 718, 49, 13 ], [ 130, 718, 23, 13 ], [ 155, 718, 12, 13 ], [ 170, 718, 19, 13 ], [ 192, 718, 59, 13 ], [ 254, 718, 74, 13 ], [ 330, 718, 12, 13 ], [ 345, 718, 26, 13 ], [ 373, 718, 18, 13 ], [ 394, 718, 17, 13 ], [ 78, 734, 33, 13 ], [ 114, 734, 18, 13 ], [ 136, 734, 11, 13 ], [ 151, 734, 27, 13 ], [ 181, 734, 21, 13 ], [ 206, 734, 12, 13 ], [ 222, 734, 55, 13 ], [ 280, 734, 22, 13 ], [ 306, 734, 28, 13 ], [ 338, 734, 45, 13 ], [ 386, 734, 25, 13 ], [ 78, 750, 28, 13 ], [ 112, 750, 49, 13 ], [ 168, 750, 33, 13 ], [ 207, 750, 71, 13 ], [ 283, 750, 22, 13 ], [ 311, 750, 49, 13 ], [ 366, 750, 45, 13 ], [ 78, 766, 64, 13 ], [ 145, 766, 24, 13 ], [ 171, 766, 65, 13 ], [ 238, 766, 50, 13 ], [ 291, 766, 18, 13 ], [ 312, 766, 21, 13 ], [ 335, 766, 61, 13 ], [ 399, 766, 12, 13 ], [ 78, 782, 35, 13 ], [ 117, 782, 24, 13 ], [ 145, 782, 51, 13 ], [ 199, 782, 12, 13 ], [ 215, 782, 30, 13 ], [ 249, 782, 46, 13 ], [ 299, 782, 10, 13 ], [ 312, 782, 48, 13 ], [ 364, 782, 8, 13 ], [ 375, 782, 12, 13 ], [ 391, 782, 20, 13 ], [ 78, 798, 27, 13 ], [ 107, 798, 21, 13 ], [ 130, 798, 50, 13 ], [ 181, 798, 66, 13 ], [ 249, 798, 12, 13 ], [ 263, 798, 35, 13 ], [ 300, 798, 24, 13 ], [ 326, 798, 51, 13 ], [ 379, 798, 12, 13 ], [ 393, 798, 18, 13 ], [ 78, 814, 46, 13 ], [ 128, 814, 25, 13 ], [ 156, 814, 14, 13 ], [ 174, 814, 22, 13 ], [ 199, 814, 12, 13 ], [ 214, 814, 51, 13 ], [ 269, 814, 12, 13 ], [ 285, 814, 19, 13 ], [ 307, 814, 61, 13 ], [ 372, 814, 12, 13 ], [ 387, 814, 24, 13 ], [ 78, 830, 51, 13 ], [ 135, 830, 40, 13 ], [ 180, 830, 57, 13 ], [ 241, 830, 58, 13 ], [ 304, 830, 12, 13 ], [ 321, 830, 58, 13 ], [ 384, 830, 28, 13 ], [ 78, 846, 41, 13 ], [ 124, 846, 22, 13 ], [ 150, 846, 19, 13 ], [ 173, 846, 22, 13 ], [ 199, 846, 22, 13 ], [ 226, 846, 60, 13 ], [ 290, 846, 46, 13 ], [ 340, 846, 12, 13 ], [ 357, 846, 19, 13 ], [ 380, 846, 31, 13 ], [ 78, 862, 43, 13 ], [ 124, 862, 12, 13 ], [ 139, 862, 21, 13 ], [ 163, 862, 33, 13 ], [ 199, 862, 16, 13 ], [ 218, 862, 67, 13 ], [ 287, 862, 19, 13 ], [ 309, 862, 23, 13 ], [ 335, 862, 12, 13 ], [ 350, 862, 35, 13 ], [ 387, 862, 24, 13 ], [ 78, 878, 51, 13 ], [ 134, 878, 12, 13 ], [ 150, 878, 41, 13 ], [ 196, 878, 18, 13 ], [ 219, 878, 46, 13 ], [ 270, 878, 26, 13 ], [ 300, 878, 45, 13 ], [ 349, 878, 50, 13 ], [ 404, 878, 8, 13 ], [ 78, 894, 25, 13 ], [ 105, 894, 51, 13 ], [ 158, 894, 57, 13 ], [ 217, 894, 19, 13 ], [ 238, 894, 13, 13 ], [ 254, 894, 20, 13 ], [ 277, 894, 46, 13 ], [ 325, 894, 48, 13 ], [ 375, 894, 12, 13 ], [ 390, 894, 22, 13 ], [ 78, 910, 33, 13 ], [ 113, 910, 11, 13 ], [ 126, 910, 46, 13 ], [ 174, 910, 22, 13 ], [ 197, 910, 45, 13 ], [ 244, 910, 48, 13 ], [ 294, 910, 22, 13 ], [ 317, 910, 52, 13 ], [ 371, 910, 22, 13 ], [ 394, 910, 17, 13 ], [ 78, 926, 35, 13 ], [ 116, 926, 12, 13 ], [ 131, 926, 22, 13 ], [ 155, 926, 11, 13 ], [ 170, 926, 46, 13 ], [ 218, 926, 25, 13 ], [ 246, 926, 22, 13 ], [ 270, 926, 45, 13 ], [ 318, 926, 51, 13 ], [ 371, 926, 40, 13 ], [ 78, 942, 52, 13 ], [ 132, 942, 25, 13 ], [ 159, 942, 22, 13 ], [ 183, 942, 21, 13 ], [ 205, 942, 27, 13 ], [ 234, 942, 15, 13 ], [ 251, 942, 32, 13 ], [ 284, 942, 12, 13 ], [ 298, 942, 26, 13 ], [ 326, 942, 44, 13 ], [ 372, 942, 22, 13 ], [ 396, 942, 15, 13 ], [ 78, 958, 63, 13 ], [ 144, 958, 44, 13 ], [ 190, 958, 24, 13 ], [ 217, 958, 35, 13 ], [ 255, 958, 24, 13 ], [ 282, 958, 51, 13 ], [ 336, 958, 22, 13 ], [ 360, 958, 51, 13 ], [ 78, 974, 12, 13 ], [ 93, 974, 18, 13 ], [ 114, 974, 46, 13 ], [ 163, 974, 26, 13 ], [ 191, 974, 45, 13 ], [ 239, 974, 48, 13 ], [ 290, 974, 58, 13 ], [ 350, 974, 11, 13 ], [ 365, 974, 23, 13 ], [ 390, 974, 21, 13 ], [ 78, 990, 104, 13 ], [ 186, 990, 35, 13 ], [ 224, 990, 13, 13 ], [ 241, 990, 37, 13 ], [ 282, 990, 12, 13 ], [ 297, 990, 27, 13 ], [ 328, 990, 15, 13 ], [ 346, 990, 42, 13 ], [ 392, 990, 19, 13 ], [ 78, 1006, 22, 13 ], [ 103, 1006, 25, 13 ], [ 131, 1006, 10, 13 ], [ 144, 1006, 12, 13 ], [ 158, 1006, 61, 13 ], [ 223, 1006, 26, 13 ], [ 252, 1006, 19, 13 ], [ 273, 1006, 38, 13 ], [ 315, 1006, 12, 13 ], [ 330, 1006, 53, 13 ], [ 385, 1006, 10, 13 ], [ 398, 1006, 13, 13 ], [ 83, 1044, 5, 10 ], [ 89, 1044, 58, 10 ], [ 148, 1044, 27, 10 ], [ 176, 1044, 11, 10 ], [ 188, 1044, 29, 10 ], [ 219, 1044, 48, 10 ], [ 268, 1044, 32, 10 ], [ 301, 1044, 38, 10 ], [ 340, 1044, 53, 10 ], [ 395, 1044, 16, 10 ], [ 79, 1057, 18, 10 ], [ 98, 1057, 36, 10 ], [ 135, 1057, 9, 10 ], [ 146, 1057, 20, 10 ], [ 167, 1057, 13, 10 ], [ 181, 1057, 13, 10 ], [ 196, 1057, 32, 10 ], [ 229, 1057, 19, 10 ], [ 249, 1057, 31, 10 ], [ 281, 1057, 9, 10 ], [ 292, 1057, 20, 10 ], [ 313, 1057, 14, 10 ], [ 328, 1057, 65, 10 ], [ 395, 1057, 16, 10 ], [ 79, 1069, 65, 10 ], [ 84, 1082, 25, 10 ], [ 110, 1082, 33, 10 ], [ 144, 1082, 110, 10 ], [ 255, 1082, 116, 10 ], [ 80, 1103, 4, 7 ], [ 86, 1102, 18, 10 ], [ 106, 1102, 31, 10 ], [ 138, 1102, 30, 10 ], [ 169, 1102, 12, 10 ], [ 183, 1102, 27, 10 ], [ 211, 1102, 40, 10 ], [ 444, 509, 30, 12 ], [ 475, 509, 17, 12 ], [ 494, 509, 18, 12 ], [ 513, 509, 28, 12 ], [ 543, 509, 14, 12 ], [ 435, 525, 50, 12 ], [ 486, 525, 10, 12 ], [ 497, 525, 40, 12 ], [ 539, 525, 13, 12 ], [ 553, 525, 54, 12 ], [ 609, 525, 10, 12 ], [ 620, 525, 33, 12 ], [ 655, 525, 45, 12 ], [ 701, 525, 7, 12 ], [ 710, 525, 46, 12 ], [ 757, 525, 11, 12 ], [ 435, 540, 39, 12 ], [ 475, 540, 67, 12 ], [ 543, 540, 44, 12 ], [ 588, 540, 62, 12 ], [ 651, 540, 10, 12 ], [ 664, 540, 34, 12 ], [ 699, 540, 20, 12 ], [ 720, 540, 47, 12 ], [ 435, 555, 29, 12 ], [ 465, 555, 24, 12 ], [ 491, 555, 83, 12 ], [ 570, 583, 4, 7 ], [ 577, 580, 20, 12 ], [ 599, 580, 35, 12 ], [ 635, 580, 34, 12 ], [ 671, 580, 14, 12 ], [ 687, 580, 30, 12 ], [ 719, 580, 45, 12 ], [ 435, 614, 13, 13 ], [ 451, 614, 22, 13 ], [ 477, 614, 49, 13 ], [ 529, 614, 7, 13 ], [ 539, 614, 52, 13 ], [ 595, 614, 27, 13 ], [ 625, 614, 61, 13 ], [ 690, 614, 12, 13 ], [ 705, 614, 35, 13 ], [ 744, 614, 24, 13 ], [ 435, 630, 51, 13 ], [ 489, 630, 12, 13 ], [ 505, 630, 75, 13 ], [ 583, 630, 49, 13 ], [ 636, 630, 22, 13 ], [ 662, 630, 32, 13 ], [ 697, 630, 44, 13 ], [ 744, 630, 24, 13 ], [ 435, 645, 54, 13 ], [ 493, 645, 12, 13 ], [ 510, 645, 45, 13 ], [ 559, 645, 48, 13 ], [ 612, 645, 32, 13 ], [ 649, 645, 36, 13 ], [ 690, 645, 78, 13 ], [ 435, 660, 35, 13 ], [ 472, 660, 24, 13 ], [ 497, 660, 51, 13 ], [ 550, 660, 12, 13 ], [ 564, 660, 18, 13 ], [ 585, 660, 46, 13 ], [ 633, 660, 35, 13 ], [ 670, 660, 10, 13 ], [ 681, 660, 12, 13 ], [ 695, 660, 73, 13 ], [ 435, 675, 26, 13 ], [ 463, 675, 19, 13 ], [ 483, 675, 67, 13 ], [ 553, 675, 12, 13 ], [ 567, 675, 54, 13 ], [ 623, 675, 10, 13 ], [ 635, 675, 13, 13 ], [ 650, 675, 21, 13 ], [ 673, 675, 49, 13 ], [ 723, 675, 11, 13 ], [ 737, 675, 30, 13 ], [ 435, 690, 57, 13 ], [ 493, 690, 28, 13 ], [ 523, 690, 59, 13 ], [ 584, 690, 26, 13 ], [ 612, 690, 21, 13 ], [ 635, 690, 26, 13 ], [ 663, 690, 30, 13 ], [ 695, 690, 19, 13 ], [ 716, 690, 12, 13 ], [ 731, 690, 37, 13 ], [ 435, 705, 12, 13 ], [ 449, 705, 33, 13 ], [ 484, 705, 16, 13 ], [ 503, 705, 67, 13 ], [ 572, 705, 19, 13 ], [ 593, 705, 53, 13 ], [ 648, 705, 22, 13 ], [ 672, 705, 41, 13 ], [ 715, 705, 28, 13 ], [ 745, 705, 23, 13 ], [ 435, 720, 40, 13 ], [ 477, 720, 12, 13 ], [ 492, 720, 24, 13 ], [ 518, 720, 12, 13 ], [ 533, 720, 18, 13 ], [ 554, 720, 46, 13 ], [ 603, 720, 26, 13 ], [ 631, 720, 35, 13 ], [ 669, 720, 24, 13 ], [ 696, 720, 54, 13 ], [ 752, 720, 15, 13 ], [ 435, 735, 24, 13 ], [ 462, 735, 43, 13 ], [ 508, 735, 53, 13 ], [ 565, 735, 12, 13 ], [ 581, 735, 53, 13 ], [ 637, 735, 12, 13 ], [ 652, 735, 21, 13 ], [ 676, 735, 29, 13 ], [ 709, 735, 59, 13 ], [ 435, 750, 59, 13 ], [ 496, 750, 28, 13 ], [ 526, 750, 19, 13 ], [ 547, 750, 52, 13 ], [ 601, 750, 12, 13 ], [ 616, 750, 7, 13 ], [ 625, 750, 34, 13 ], [ 662, 750, 64, 13 ], [ 727, 750, 40, 13 ], [ 435, 765, 24, 13 ], [ 462, 765, 25, 13 ], [ 490, 765, 41, 13 ], [ 533, 765, 11, 13 ], [ 548, 765, 34, 13 ], [ 584, 765, 22, 13 ], [ 609, 765, 31, 13 ], [ 643, 765, 22, 13 ], [ 668, 765, 35, 13 ], [ 706, 765, 62, 13 ], [ 435, 780, 17, 13 ], [ 455, 780, 17, 13 ], [ 475, 780, 72, 13 ], [ 550, 780, 59, 13 ], [ 612, 780, 28, 13 ], [ 643, 780, 37, 13 ], [ 684, 780, 22, 13 ], [ 709, 780, 32, 13 ], [ 744, 780, 24, 13 ], [ 435, 795, 37, 13 ], [ 474, 795, 24, 13 ], [ 500, 795, 17, 13 ], [ 519, 795, 96, 13 ], [ 618, 795, 15, 13 ], [ 635, 795, 20, 13 ], [ 658, 795, 24, 13 ], [ 685, 795, 7, 13 ], [ 694, 795, 34, 13 ], [ 730, 795, 23, 13 ], [ 756, 795, 12, 13 ], [ 435, 810, 36, 13 ], [ 475, 810, 54, 13 ], [ 532, 810, 18, 13 ], [ 553, 810, 24, 13 ], [ 580, 810, 37, 13 ], [ 621, 810, 49, 13 ], [ 674, 810, 59, 13 ], [ 736, 810, 31, 13 ], [ 435, 825, 42, 13 ], [ 480, 825, 33, 13 ], [ 517, 825, 19, 13 ], [ 540, 825, 43, 13 ], [ 587, 825, 50, 13 ], [ 641, 825, 22, 13 ], [ 667, 825, 46, 13 ], [ 717, 825, 12, 13 ], [ 733, 825, 35, 13 ], [ 435, 840, 24, 13 ], [ 460, 840, 51, 13 ], [ 513, 840, 12, 13 ], [ 527, 840, 44, 13 ], [ 573, 840, 18, 13 ], [ 593, 840, 49, 13 ], [ 644, 840, 22, 13 ], [ 667, 840, 32, 13 ], [ 701, 840, 10, 13 ], [ 712, 840, 42, 13 ], [ 756, 840, 12, 13 ], [ 435, 855, 24, 13 ], [ 461, 855, 16, 13 ], [ 480, 855, 36, 13 ], [ 519, 855, 15, 13 ], [ 538, 855, 25, 13 ], [ 566, 855, 15, 13 ], [ 584, 855, 25, 13 ], [ 612, 855, 86, 13 ], [ 702, 855, 13, 13 ], [ 717, 855, 50, 13 ], [ 435, 870, 87, 13 ], [ 524, 870, 30, 13 ], [ 556, 870, 39, 13 ], [ 598, 870, 14, 13 ], [ 614, 870, 69, 13 ], [ 685, 870, 12, 13 ], [ 699, 870, 19, 13 ], [ 720, 870, 39, 13 ], [ 435, 899, 80, 16 ], [ 462, 928, 6, 10 ], [ 474, 928, 42, 10 ], [ 517, 928, 13, 10 ], [ 531, 928, 52, 10 ], [ 585, 928, 7, 10 ], [ 593, 928, 59, 10 ], [ 652, 928, 8, 10 ], [ 662, 928, 33, 10 ], [ 696, 928, 15, 10 ], [ 712, 928, 29, 10 ], [ 742, 928, 25, 10 ], [ 474, 940, 18, 10 ], [ 493, 940, 6, 10 ], [ 501, 940, 40, 10 ], [ 542, 940, 10, 10 ], [ 553, 940, 35, 10 ], [ 590, 940, 60, 10 ], [ 651, 940, 38, 10 ], [ 691, 940, 35, 10 ], [ 727, 940, 41, 10 ], [ 474, 953, 17, 10 ], [ 493, 953, 38, 10 ], [ 532, 953, 25, 10 ], [ 558, 953, 21, 10 ], [ 581, 953, 23, 10 ], [ 605, 953, 59, 10 ], [ 458, 965, 8, 10 ], [ 474, 965, 41, 10 ], [ 517, 965, 8, 10 ], [ 527, 965, 36, 10 ], [ 564, 965, 9, 10 ], [ 574, 965, 44, 10 ], [ 619, 965, 8, 10 ], [ 629, 965, 35, 10 ], [ 665, 965, 7, 10 ], [ 674, 965, 37, 10 ], [ 712, 965, 7, 10 ], [ 720, 965, 39, 10 ], [ 760, 965, 7, 10 ], [ 474, 978, 9, 10 ], [ 484, 978, 10, 10 ], [ 496, 978, 40, 10 ], [ 537, 978, 7, 10 ], [ 545, 978, 22, 10 ], [ 569, 978, 40, 10 ], [ 610, 978, 10, 10 ], [ 621, 978, 33, 10 ], [ 655, 978, 22, 10 ], [ 678, 978, 18, 10 ], [ 697, 978, 25, 10 ], [ 723, 978, 20, 10 ], [ 744, 978, 24, 10 ], [ 474, 990, 47, 10 ], [ 458, 1003, 7, 10 ], [ 474, 1003, 29, 10 ], [ 504, 1003, 14, 10 ], [ 519, 1003, 17, 10 ], [ 537, 1003, 14, 10 ], [ 552, 1003, 47, 10 ], [ 600, 1003, 9, 10 ], [ 610, 1003, 28, 10 ], [ 639, 1003, 11, 10 ], [ 651, 1003, 38, 10 ], [ 691, 1003, 9, 10 ], [ 700, 1003, 39, 10 ], [ 740, 1003, 6, 10 ], [ 747, 1003, 9, 10 ], [ 757, 1003, 10, 10 ], [ 474, 1015, 29, 10 ], [ 504, 1015, 39, 10 ], [ 544, 1015, 6, 10 ], [ 552, 1015, 22, 10 ], [ 575, 1015, 40, 10 ], [ 617, 1015, 10, 10 ], [ 627, 1015, 5, 10 ], [ 634, 1015, 26, 10 ], [ 662, 1015, 43, 10 ], [ 706, 1015, 24, 10 ], [ 731, 1015, 37, 10 ], [ 474, 1028, 24, 10 ], [ 500, 1028, 32, 10 ], [ 533, 1028, 52, 10 ], [ 586, 1028, 49, 10 ], [ 637, 1028, 25, 10 ], [ 664, 1028, 54, 10 ], [ 458, 1040, 8, 10 ], [ 474, 1040, 43, 10 ], [ 519, 1040, 11, 10 ], [ 533, 1040, 46, 10 ], [ 582, 1040, 6, 10 ], [ 590, 1040, 42, 10 ], [ 635, 1040, 9, 10 ], [ 646, 1040, 25, 10 ], [ 673, 1040, 9, 10 ], [ 685, 1040, 36, 10 ], [ 723, 1040, 7, 10 ], [ 733, 1040, 35, 10 ], [ 474, 1053, 12, 10 ], [ 488, 1053, 35, 10 ], [ 525, 1053, 9, 10 ], [ 537, 1053, 39, 10 ], [ 578, 1053, 6, 10 ], [ 586, 1053, 22, 10 ], [ 610, 1053, 20, 10 ], [ 632, 1053, 10, 10 ], [ 644, 1053, 28, 10 ], [ 674, 1053, 17, 10 ], [ 693, 1053, 47, 10 ], [ 742, 1053, 26, 10 ], [ 474, 1065, 60, 10 ], [ 536, 1065, 20, 10 ], [ 558, 1065, 22, 10 ], [ 583, 1065, 39, 10 ], [ 624, 1065, 6, 10 ], [ 632, 1065, 32, 10 ], [ 667, 1065, 74, 10 ], [ 743, 1065, 25, 10 ], [ 474, 1078, 49, 10 ], [ 525, 1078, 26, 10 ], [ 552, 1078, 49, 10 ], [ 458, 1090, 8, 10 ], [ 474, 1090, 30, 10 ], [ 506, 1090, 7, 10 ], [ 515, 1090, 27, 10 ], [ 544, 1090, 14, 10 ], [ 560, 1090, 31, 10 ], [ 594, 1090, 9, 10 ], [ 605, 1090, 32, 10 ], [ 639, 1090, 7, 10 ], [ 648, 1090, 34, 10 ], [ 685, 1090, 7, 10 ], [ 694, 1090, 42, 10 ], [ 737, 1090, 7, 10 ], [ 746, 1090, 9, 10 ], [ 757, 1090, 11, 10 ] ]

[ "Hepat", "Mon.", "2011;11(2):128-129", "Journal", "home", "page:", "www.HepatMon.ir", "KOWSAR", "Occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "patients:", "Comparison", "of", "results", "and", "concepts", "Amitis", "Ramezani", "1,", "Mohammad", "Banifazl", "2,", "Arezoo", "Aghakhani", "1*", "1", "Clinical", "Research", "Department,", "Pasteur", "Institute", "of", "Iran,", "Tehran,", "IR", "Iran", "2", "Iranian", "Society", "for", "Support", "Patients", "with", "Infectious", "Diseases,", "Tehran,", "IR", "Iran", "A", "R", "T", "I", "C", "L", "E", "I", "N", "F", "O", "Article", "Type:", "Letter", "to", "Editor", "Article", "history:", "Received:", "14", "Sep", "2010", "Revised:", "19", "Sep", "2010", "Accepted:", "21", "Dec", "2010", "Keywords:", "Occult", "hepatitia", "B", "infection", "Hemodialysis", "Dear", "Editor,", "We", "greatly", "enjoyed", "reading", "the", "excellent", "review", "by", "Hol-", "linger", "and", "colleagues", "on", "occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "(HD)", "patients", "(1).", "As", "Hollinger", "et", "al.", "mentioned", "in", "their", "review,", "few", "studies", "have", "shown", "the", "prevalence", "of", "occult", "hepatitis", "B", "virus", "(HBV)", "infection", "in", "HD", "patients.", "Due", "to", "the", "parenteral", "transmission", "of", "HBV,", "HD", "pa-", "tients", "are", "at", "high", "risk", "of", "acquiring", "this", "virus", "because", "they", "need", "frequent", "blood", "transfusions", "and", "undergo", "medical", "procedures", "that", "accompany", "bleeding", "(2).", "The", "prevalence", "of", "occult", "HBV", "infection", "in", "these", "patients", "is", "between", "0", "to", "58%", "(3-5).", "The", "different", "frequencies", "of", "occult", "HBV", "infection", "in", "HD", "patients", "may", "be", "due", "to", "variation", "in", "the", "prevalence", "of", "HBV", "infection", "among", "countries,", "sensitivity", "of", "molecular", "tech-", "niques,", "and", "the", "size", "and", "virological", "features", "of", "the", "study", "groups.", "In", "one", "study,", "we", "determined", "the", "rate", "of", "occult", "HBV", "infection", "in", "Iranian", "HD", "patients", "with", "isolated", "hepatitis", "B", "core", "antibody", "(anti-HBc)", "(6).", "Of", "289", "patients", "enrolled", "in", "this", "study,", "18", "subjects", "had", "isolated", "anti-HBc", "and", "HBV-DNA", "was", "de-", "tected", "in", "50%", "of", "patients", "who", "had", "isolated", "anti-HBc.", "Plasma", "HBV-DNA", "load", "was", "less", "than", "50", "IU/ml", "in", "each", "patient.", "Our", "in-", "vestigation", "showed", "that", "occult", "HBV", "infection", "was", "common", "in", "HD", "patients", "with", "isolated", "anti-HBc", "regardless", "of", "age,", "sex,", "aminotransferases", "levels,", "or", "length", "of", "time", "on", "dialysis", "(6).", "Our", "data", "is", "in", "agreement", "with", "the", "results", "of", "hollinger", "et", "al.", "*", "Corresponding", "author", "at:", "Arezoo", "Aghakhani,", "Clinical", "Research", "Department,", "Pas-", "teur", "Institute", "of", "Iran,", "No", "69,", "Pasteur", "Ave.,", "Tehran,", "IR", "Iran.", "Tel:", "+98-2166465147,", "Fax:", "+98-2166465147.", "E-mail", "address:", "aaghakhani@pasteur.ac.ir,", "araghakhani@hotmail.com", "c", "2011", "Kowsar", "M.P.Co.", "All", "rights", "reserved.", "Please", "cite", "this", "paper", "as:", "Ramezani", "A,", "Banifazl", "M,", "Aghakhani", "A.", "Occult", "hepatitis", "B", "infection", "in", "chronic", "hemodialysis", "patients:", "Comparison", "of", "results", "and", "concepts.", "Hepat", "Mon.", "2011;11(2):128-129.", "c", "2011", "Kowsar", "M.P.Co.", "All", "rights", "reserved.", "(1)", "and", "suggests", "a", "relatively", "high", "prevalence", "of", "occult", "HBV", "infection", "in", "hemodialysis", "patients.", "Our", "study", "showed", "that", "detection", "of", "isolated", "anti-HBc", "could", "reflect", "unrecognized", "occult", "HBV", "infection", "in", "HD", "patients", "which", "is", "in", "concordance", "with", "the", "conclusions", "of", "Hollinger", "et", "al.", "The", "majority", "of", "these", "infections", "were", "associated", "with", "low", "viral", "loads", "(6).", "In", "anoth-", "er", "study,", "we", "determined", "the", "genotype", "and", "surface", "gene", "mu-", "tations", "of", "HBV", "in", "HD", "patients", "with", "occult", "HBV", "infection.", "All", "HBV", "isolates", "belonged", "to", "genotype", "D.", "The", "most", "important", "mutations", "were", "the", "insertion", "of", "a", "single", "nucleotide,", "prema-", "ture", "stop", "codons", "at", "Leu15,", "and", "Gly10", "and", "S207N", "mutations.", "No", "“a”", "determinant", "mutations", "were", "found.", "Our", "study", "sug-", "gested", "that", "“a”", "regionmutations", "do", "not", "play", "a", "major", "role", "in", "HBsAg", "detection", "(7).", "This", "review", "provides", "important", "infor-", "mation", "about", "the", "current", "concepts", "and", "strategy", "in", "occult", "HBV", "infection", "in", "chronic", "HD", "patients.", "Our", "study", "is", "limited", "in", "that", "we", "report", "no", "data", "on", "liver", "histopathology", "or", "outcome", "measurements;", "these", "should", "be", "investigated", "in", "the", "future.", "References", "1.", "Hollinger", "FB,", "Habibollahi", "P,", "Daneshmand", "A,", "Alavian", "SM.", "Occult", "Hepa-", "titis", "B", "Infection", "in", "Chronic", "Hemodialysis", "Patients:", "Current", "Concepts", "and", "Strategy.", "Hepat", "Mon.", "2010;", "10(3):199-204.", "2.", "Eslamifar", "A,", "Hamkar", "R,", "Ramezani", "A,", "Ahmadi", "F,", "Gachkar", "L,", "Jalilvand", "S,", "et", "al.", "Hepatitis", "G", "virus", "exposure", "in", "dialysis", "staff.", "Ther", "Apher", "Dial.", "2007;", "11(5):370-4.", "3.", "Minuk", "GY,", "Sun", "DF,", "Greenberg", "R,", "Zhang", "M,", "Hawkins", "K,", "Uhanova", "J,", "et", "al.", "Occult", "hepatitis", "B", "virus", "infection", "in", "a", "North", "American", "adult", "hemodi-", "alysis", "patient", "population.", "Hepatology.", "2004;", "40(5):1072-7.", "4.", "Cabrerizo", "M,", "Bartolome", "J,", "Caramelo", "C,", "Barril", "G,", "Carreno", "V.", "Molecu-", "lar", "analysis", "of", "hepatitis", "B", "virus", "DNA", "in", "serum", "and", "peripheral", "blood", "mononuclear", "cells", "from", "hepatitis", "B", "surface", "antigen-negative", "cases.", "Hepatology.", "2000;", "32(1):116-23.", "5.", "Fabrizi", "F,", "Messa", "PG,", "Lunghi", "G,", "Aucella", "F,", "Bisegna", "S,", "Mangano", "S,", "et", "al." ]

[ 14, 14, 14, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 16, 16, 16, 16, 16, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2 ]

[ [ 78, 47, 27, 12 ], [ 108, 47, 9, 12 ], [ 120, 47, 11, 12 ], [ 134, 47, 33, 12 ], [ 171, 47, 9, 12 ], [ 183, 47, 35, 12 ], [ 221, 47, 21, 12 ], [ 246, 47, 34, 12 ], [ 283, 47, 25, 12 ], [ 311, 47, 26, 12 ], [ 78, 61, 249, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 12, 18 ], [ 109, 128, 10, 18 ], [ 121, 128, 10, 18 ], [ 139, 128, 11, 18 ], [ 151, 128, 10, 18 ], [ 163, 128, 11, 18 ], [ 175, 128, 13, 18 ], [ 190, 128, 11, 18 ], [ 202, 128, 10, 18 ], [ 601, 60, 62, 14 ], [ 666, 60, 18, 14 ], [ 688, 60, 60, 14 ], [ 601, 70, 52, 22 ], [ 659, 70, 89, 22 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 77, 34 ], [ 165, 169, 84, 34 ], [ 259, 169, 159, 34 ], [ 428, 169, 145, 34 ], [ 583, 168, 108, 35 ], [ 78, 205, 141, 34 ], [ 229, 205, 25, 34 ], [ 265, 205, 16, 34 ], [ 290, 205, 70, 34 ], [ 371, 205, 138, 34 ], [ 519, 205, 58, 34 ], [ 587, 205, 16, 34 ], [ 613, 205, 115, 34 ], [ 78, 241, 122, 34 ], [ 211, 241, 15, 34 ], [ 236, 241, 58, 34 ], [ 304, 241, 81, 34 ], [ 78, 288, 64, 16 ], [ 147, 285, 44, 19 ], [ 195, 288, 41, 16 ], [ 241, 285, 51, 19 ], [ 297, 288, 49, 16 ], [ 350, 285, 61, 19 ], [ 416, 288, 54, 16 ], [ 474, 285, 41, 19 ], [ 519, 288, 52, 16 ], [ 576, 288, 8, 16 ], [ 588, 285, 45, 19 ], [ 638, 288, 52, 16 ], [ 694, 285, 53, 19 ], [ 78, 307, 54, 16 ], [ 137, 305, 85, 19 ], [ 226, 307, 41, 16 ], [ 272, 307, 10, 16 ], [ 286, 305, 55, 19 ], [ 87, 361, 54, 15 ], [ 87, 386, 78, 14 ], [ 170, 386, 42, 15 ], [ 215, 387, 56, 14 ], [ 275, 387, 74, 14 ], [ 353, 387, 14, 14 ], [ 372, 387, 30, 14 ], [ 406, 387, 33, 14 ], [ 443, 387, 67, 14 ], [ 514, 387, 21, 14 ], [ 540, 387, 74, 14 ], [ 618, 387, 22, 14 ], [ 643, 387, 40, 14 ], [ 688, 387, 8, 14 ], [ 700, 387, 30, 14 ], [ 87, 403, 58, 14 ], [ 150, 403, 11, 14 ], [ 165, 403, 48, 14 ], [ 216, 403, 8, 14 ], [ 228, 403, 47, 14 ], [ 279, 403, 11, 14 ], [ 294, 403, 29, 14 ], [ 328, 403, 38, 14 ], [ 369, 403, 46, 14 ], [ 419, 403, 44, 14 ], [ 467, 403, 42, 15 ], [ 513, 403, 58, 14 ], [ 575, 403, 38, 14 ], [ 617, 403, 25, 14 ], [ 647, 403, 7, 14 ], [ 658, 403, 59, 14 ], [ 87, 420, 25, 14 ], [ 116, 420, 51, 14 ], [ 172, 420, 128, 14 ], [ 304, 420, 57, 14 ], [ 365, 420, 38, 14 ], [ 407, 420, 12, 14 ], [ 424, 420, 31, 14 ], [ 459, 420, 82, 14 ], [ 545, 420, 52, 14 ], [ 602, 420, 21, 14 ], [ 627, 420, 78, 14 ], [ 710, 420, 18, 14 ], [ 87, 436, 44, 14 ], [ 136, 436, 12, 14 ], [ 152, 436, 19, 14 ], [ 175, 436, 24, 14 ], [ 203, 436, 11, 14 ], [ 218, 436, 19, 14 ], [ 241, 436, 64, 14 ], [ 310, 436, 19, 14 ], [ 333, 436, 20, 14 ], [ 357, 436, 24, 14 ], [ 386, 436, 11, 14 ], [ 401, 436, 7, 14 ], [ 412, 436, 48, 14 ], [ 464, 436, 95, 14 ], [ 563, 436, 42, 15 ], [ 609, 436, 58, 14 ], [ 87, 457, 28, 14 ], [ 120, 457, 80, 14 ], [ 204, 457, 16, 14 ], [ 224, 457, 77, 14 ], [ 305, 457, 21, 14 ], [ 331, 457, 11, 14 ], [ 346, 457, 44, 14 ], [ 395, 457, 32, 14 ], [ 432, 457, 22, 14 ], [ 457, 457, 44, 14 ], [ 505, 457, 12, 14 ], [ 521, 457, 13, 14 ], [ 538, 457, 25, 14 ], [ 567, 457, 48, 14 ], [ 619, 457, 30, 14 ], [ 653, 457, 69, 14 ], [ 87, 474, 36, 14 ], [ 128, 474, 21, 14 ], [ 153, 474, 40, 14 ], [ 198, 474, 73, 14 ], [ 275, 474, 18, 14 ], [ 297, 474, 41, 14 ], [ 343, 474, 21, 14 ], [ 369, 474, 81, 14 ], [ 454, 474, 72, 14 ], [ 530, 474, 9, 14 ], [ 542, 474, 22, 14 ], [ 568, 474, 37, 14 ], [ 609, 474, 57, 14 ], [ 670, 474, 19, 14 ], [ 87, 490, 55, 14 ], [ 146, 490, 55, 14 ], [ 205, 490, 54, 14 ], [ 263, 490, 18, 14 ], [ 286, 490, 19, 14 ], [ 309, 490, 33, 14 ], [ 347, 490, 20, 14 ], [ 371, 490, 60, 14 ], [ 435, 490, 48, 14 ], [ 487, 490, 35, 14 ], [ 527, 490, 37, 14 ], [ 568, 490, 15, 14 ], [ 588, 490, 19, 14 ], [ 611, 490, 71, 14 ], [ 686, 490, 11, 14 ], [ 701, 490, 14, 14 ], [ 87, 507, 29, 14 ], [ 120, 507, 48, 14 ], [ 172, 507, 51, 14 ], [ 227, 507, 21, 14 ], [ 252, 507, 56, 14 ], [ 312, 507, 60, 14 ], [ 377, 507, 51, 14 ], [ 432, 507, 30, 14 ], [ 466, 507, 76, 14 ], [ 546, 507, 82, 14 ], [ 633, 507, 15, 14 ], [ 652, 507, 59, 14 ], [ 715, 507, 22, 14 ], [ 87, 524, 54, 14 ], [ 87, 544, 70, 14 ], [ 161, 544, 41, 14 ], [ 206, 544, 58, 14 ], [ 268, 544, 19, 14 ], [ 291, 544, 63, 14 ], [ 358, 544, 11, 14 ], [ 374, 544, 42, 15 ], [ 420, 544, 56, 14 ], [ 480, 544, 12, 14 ], [ 496, 544, 7, 14 ], [ 506, 544, 48, 14 ], [ 558, 544, 51, 14 ], [ 614, 544, 20, 14 ], [ 638, 544, 24, 14 ], [ 666, 544, 34, 14 ], [ 705, 544, 8, 14 ], [ 717, 544, 22, 14 ], [ 87, 561, 7, 14 ], [ 98, 561, 51, 14 ], [ 153, 561, 22, 14 ], [ 179, 561, 11, 14 ], [ 194, 561, 7, 14 ], [ 205, 561, 27, 14 ], [ 236, 561, 60, 14 ], [ 300, 561, 25, 14 ], [ 329, 561, 7, 14 ], [ 340, 561, 35, 14 ], [ 378, 561, 86, 14 ], [ 468, 561, 23, 14 ], [ 496, 561, 25, 14 ], [ 525, 561, 67, 14 ], [ 596, 560, 42, 15 ], [ 641, 561, 56, 14 ], [ 701, 561, 38, 14 ], [ 87, 578, 15, 14 ], [ 106, 578, 48, 14 ], [ 159, 578, 11, 14 ], [ 174, 578, 19, 14 ], [ 196, 578, 61, 14 ], [ 78, 624, 80, 15 ], [ 78, 641, 41, 14 ], [ 124, 641, 56, 14 ], [ 184, 641, 35, 14 ], [ 223, 641, 36, 14 ], [ 264, 641, 69, 14 ], [ 337, 641, 66, 14 ], [ 78, 657, 9, 14 ], [ 92, 657, 78, 14 ], [ 174, 657, 14, 14 ], [ 192, 657, 7, 14 ], [ 203, 657, 74, 14 ], [ 282, 657, 12, 14 ], [ 298, 657, 41, 14 ], [ 344, 657, 60, 14 ], [ 78, 674, 22, 14 ], [ 105, 674, 48, 14 ], [ 159, 674, 51, 14 ], [ 215, 674, 36, 14 ], [ 256, 674, 44, 14 ], [ 305, 674, 33, 14 ], [ 343, 674, 34, 14 ], [ 381, 674, 22, 14 ], [ 78, 690, 34, 14 ], [ 116, 690, 75, 14 ], [ 196, 690, 42, 14 ], [ 243, 690, 12, 14 ], [ 260, 690, 19, 14 ], [ 283, 690, 76, 14 ], [ 363, 690, 12, 14 ], [ 379, 690, 24, 14 ], [ 78, 707, 23, 14 ], [ 106, 707, 81, 14 ], [ 191, 707, 80, 14 ], [ 276, 707, 25, 14 ], [ 305, 707, 40, 14 ], [ 350, 707, 53, 14 ], [ 78, 724, 49, 14 ], [ 132, 724, 53, 14 ], [ 190, 724, 111, 14 ], [ 306, 724, 79, 14 ], [ 390, 724, 14, 14 ], [ 78, 740, 18, 14 ], [ 101, 740, 50, 14 ], [ 155, 740, 11, 14 ], [ 171, 740, 54, 14 ], [ 229, 740, 41, 14 ], [ 274, 740, 65, 14 ], [ 343, 740, 19, 14 ], [ 366, 740, 9, 14 ], [ 380, 740, 24, 14 ], [ 78, 757, 30, 14 ], [ 114, 757, 12, 14 ], [ 130, 757, 31, 14 ], [ 167, 757, 43, 14 ], [ 215, 757, 50, 14 ], [ 269, 757, 55, 14 ], [ 330, 757, 74, 14 ], [ 78, 773, 36, 14 ], [ 118, 773, 42, 14 ], [ 164, 773, 60, 14 ], [ 228, 773, 71, 14 ], [ 304, 773, 6, 14 ], [ 314, 773, 89, 14 ], [ 78, 790, 51, 14 ], [ 134, 790, 61, 14 ], [ 200, 790, 59, 14 ], [ 264, 790, 139, 14 ], [ 78, 807, 102, 14 ], [ 185, 807, 42, 14 ], [ 231, 807, 56, 14 ], [ 291, 807, 16, 14 ], [ 312, 807, 47, 14 ], [ 363, 807, 40, 14 ], [ 78, 823, 60, 14 ], [ 142, 823, 26, 14 ], [ 173, 823, 31, 14 ], [ 209, 823, 77, 14 ], [ 290, 823, 61, 14 ], [ 356, 823, 22, 14 ], [ 382, 823, 21, 14 ], [ 78, 840, 62, 14 ], [ 145, 840, 12, 14 ], [ 162, 840, 15, 14 ], [ 182, 840, 45, 14 ], [ 232, 840, 28, 14 ], [ 265, 840, 53, 14 ], [ 322, 840, 64, 14 ], [ 392, 840, 12, 14 ], [ 78, 856, 69, 14 ], [ 153, 856, 27, 14 ], [ 186, 856, 43, 14 ], [ 236, 856, 67, 14 ], [ 308, 856, 50, 14 ], [ 364, 856, 39, 14 ], [ 78, 873, 46, 14 ], [ 129, 873, 42, 14 ], [ 175, 873, 61, 14 ], [ 240, 873, 19, 14 ], [ 264, 873, 67, 14 ], [ 335, 873, 12, 14 ], [ 351, 873, 14, 14 ], [ 369, 873, 35, 14 ], [ 78, 890, 45, 14 ], [ 131, 890, 23, 14 ], [ 161, 890, 64, 14 ], [ 232, 890, 31, 14 ], [ 271, 890, 12, 14 ], [ 290, 890, 45, 14 ], [ 343, 890, 61, 14 ], [ 78, 925, 5, 11 ], [ 86, 925, 70, 11 ], [ 159, 925, 70, 11 ], [ 78, 936, 25, 13 ], [ 107, 937, 27, 11 ], [ 137, 937, 52, 11 ], [ 193, 937, 41, 11 ], [ 236, 937, 9, 11 ], [ 248, 937, 36, 11 ], [ 287, 937, 33, 11 ], [ 323, 937, 30, 11 ], [ 356, 937, 16, 11 ], [ 375, 937, 16, 11 ], [ 78, 950, 22, 11 ], [ 103, 950, 40, 11 ], [ 146, 950, 38, 11 ], [ 187, 950, 29, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 16, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 624, 48, 14 ], [ 475, 624, 55, 14 ], [ 534, 624, 12, 14 ], [ 551, 624, 50, 14 ], [ 606, 624, 91, 14 ], [ 702, 624, 46, 14 ], [ 423, 641, 34, 14 ], [ 461, 641, 57, 14 ], [ 522, 641, 9, 14 ], [ 536, 641, 49, 14 ], [ 589, 641, 50, 14 ], [ 643, 641, 7, 14 ], [ 654, 641, 55, 14 ], [ 713, 641, 35, 14 ], [ 423, 657, 24, 14 ], [ 450, 657, 37, 14 ], [ 492, 657, 25, 14 ], [ 521, 657, 43, 14 ], [ 568, 657, 9, 14 ], [ 581, 657, 18, 14 ], [ 604, 657, 23, 14 ], [ 630, 657, 19, 14 ], [ 434, 674, 43, 14 ], [ 481, 674, 58, 14 ], [ 543, 674, 10, 14 ], [ 557, 674, 34, 14 ], [ 595, 674, 59, 14 ], [ 659, 674, 12, 14 ], [ 675, 674, 48, 14 ], [ 728, 674, 20, 14 ], [ 423, 690, 33, 14 ], [ 460, 690, 15, 14 ], [ 480, 690, 19, 14 ], [ 504, 690, 52, 14 ], [ 561, 690, 12, 14 ], [ 577, 690, 7, 14 ], [ 589, 690, 30, 14 ], [ 623, 690, 26, 14 ], [ 655, 690, 52, 14 ], [ 711, 690, 37, 14 ], [ 423, 707, 65, 14 ], [ 493, 707, 44, 14 ], [ 542, 707, 59, 14 ], [ 607, 707, 16, 14 ], [ 628, 707, 48, 14 ], [ 682, 707, 12, 14 ], [ 699, 707, 19, 14 ], [ 723, 707, 25, 14 ], [ 423, 724, 12, 14 ], [ 440, 724, 21, 14 ], [ 466, 724, 65, 14 ], [ 536, 724, 18, 14 ], [ 559, 724, 19, 14 ], [ 584, 724, 25, 14 ], [ 614, 724, 27, 14 ], [ 646, 724, 12, 14 ], [ 663, 724, 19, 14 ], [ 688, 724, 60, 14 ], [ 423, 740, 59, 14 ], [ 487, 740, 19, 14 ], [ 511, 740, 66, 14 ], [ 582, 740, 12, 14 ], [ 599, 740, 22, 14 ], [ 626, 740, 59, 14 ], [ 690, 740, 12, 14 ], [ 707, 740, 7, 14 ], [ 718, 740, 30, 14 ], [ 423, 757, 30, 14 ], [ 457, 757, 57, 14 ], [ 519, 757, 24, 14 ], [ 548, 757, 45, 14 ], [ 597, 757, 37, 14 ], [ 640, 757, 49, 14 ], [ 694, 757, 54, 14 ], [ 423, 773, 12, 14 ], [ 440, 773, 19, 14 ], [ 463, 773, 18, 14 ], [ 486, 773, 12, 14 ], [ 503, 773, 58, 14 ], [ 566, 773, 38, 14 ], [ 609, 773, 61, 14 ], [ 674, 773, 26, 14 ], [ 705, 773, 43, 14 ], [ 423, 790, 60, 14 ], [ 488, 790, 25, 14 ], [ 518, 790, 60, 14 ], [ 582, 790, 19, 14 ], [ 605, 790, 54, 14 ], [ 664, 790, 59, 14 ], [ 727, 790, 21, 14 ], [ 423, 807, 26, 14 ], [ 454, 807, 20, 14 ], [ 423, 839, 30, 15 ], [ 457, 839, 82, 15 ], [ 423, 856, 18, 14 ], [ 446, 856, 84, 14 ], [ 535, 856, 22, 14 ], [ 562, 856, 12, 14 ], [ 579, 856, 50, 14 ], [ 634, 856, 36, 14 ], [ 675, 856, 22, 14 ], [ 702, 856, 46, 14 ], [ 423, 873, 55, 14 ], [ 483, 873, 13, 14 ], [ 501, 873, 48, 14 ], [ 554, 873, 49, 14 ], [ 608, 873, 48, 14 ], [ 662, 873, 12, 14 ], [ 679, 873, 30, 14 ], [ 714, 873, 16, 14 ], [ 735, 873, 13, 14 ], [ 423, 890, 39, 14 ], [ 466, 890, 40, 14 ], [ 511, 890, 17, 14 ], [ 533, 890, 21, 14 ], [ 559, 890, 30, 14 ], [ 594, 890, 6, 14 ], [ 605, 890, 27, 14 ], [ 637, 890, 40, 14 ], [ 682, 890, 22, 14 ], [ 709, 890, 12, 14 ], [ 726, 890, 22, 14 ], [ 423, 906, 38, 14 ], [ 465, 906, 21, 14 ], [ 491, 906, 21, 14 ], [ 516, 906, 12, 14 ], [ 532, 906, 30, 14 ], [ 566, 906, 53, 14 ], [ 623, 906, 52, 14 ], [ 679, 906, 19, 14 ], [ 702, 906, 23, 14 ], [ 729, 906, 19, 14 ], [ 423, 923, 73, 14 ], [ 500, 923, 29, 14 ], [ 533, 923, 28, 14 ], [ 565, 923, 28, 14 ], [ 597, 923, 45, 14 ], [ 646, 923, 15, 14 ], [ 665, 923, 30, 14 ], [ 700, 923, 48, 14 ], [ 423, 940, 29, 14 ], [ 459, 940, 50, 14 ], [ 516, 940, 29, 14 ], [ 552, 940, 50, 14 ], [ 609, 940, 68, 14 ], [ 684, 940, 64, 14 ], [ 423, 956, 49, 14 ], [ 476, 956, 72, 14 ], [ 552, 956, 65, 14 ], [ 621, 956, 26, 14 ], [ 652, 956, 24, 14 ], [ 681, 956, 67, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 19, 10 ], [ 277, 987, 21, 10 ], [ 300, 987, 8, 10 ], [ 310, 987, 8, 10 ], [ 321, 987, 30, 10 ], [ 354, 987, 29, 10 ], [ 385, 987, 27, 10 ], [ 414, 987, 14, 10 ], [ 430, 987, 15, 10 ], [ 448, 987, 6, 10 ], [ 456, 987, 10, 10 ], [ 468, 987, 21, 10 ], [ 491, 987, 26, 10 ], [ 519, 987, 23, 10 ], [ 544, 987, 41, 10 ], [ 587, 987, 23, 10 ], [ 612, 987, 13, 10 ], [ 627, 987, 21, 10 ], [ 651, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Makis", "et", "al.", "Journal", "of", "Medical", "Case", "Reports", "2010,", "4:281", "http://www.jmedicalcasereports.com/content/4/1/281", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "JOURNAL", "OF", "MEDICAL", "CASE", "REPORTS", "Open", "Access", "Acute", "febrile", "neutrophilic", "dermatosis", "(Sweet’s", "syndrome)", "in", "a", "child,", "associated", "with", "a", "rotavirus", "infection:", "a", "case", "report", "Alexandros", "Makis1*,", "Stavros", "Stavrou1,", "Nikolaos", "Chaliasos1,", "Aikaterini", "Zioga2,", "Antonios", "P", "Vlahos1,", "Georgios", "Gaitanis3,", "Antigone", "Siamopoulou1,", "Ioannis", "D", "Bassukas3", "Abstract", "Introduction:", "Sweet’s", "syndrome", "characterized", "by", "fever,", "blood", "neutrophilia", "and", "inflammatory", "skin", "lesions,", "is", "rarely", "diagnosed", "in", "children.", "It", "presents", "in", "three", "clinical", "settings:", "classical", "Sweet’s", "syndrome,", "usually", "after", "a", "respiratory", "tract", "infection;", "malignancy-associated,", "frequently", "related", "to", "acute", "myelogeneous", "leukemia;", "and", "drug-induced.", "We", "present,", "to", "the", "best", "of", "our", "knowledge,", "the", "first", "case", "of", "a", "rotavirus", "-infection-related", "Sweet’s", "syndrome.", "Case", "presentation:", "An", "18-month-old", "boy", "of", "Hellenic", "origin", "was", "referred", "to", "us", "with", "diarrhea,", "fever,", "neutrophilia,", "typical", "skin", "lesions,", "asymmetrical", "hip", "arthritis", "and", "oropharyngeal", "involvement.", "A", "skin", "biopsy", "confirmed", "the", "diagnosis.", "Thorough", "screening", "did", "not", "reveal", "any", "underlying", "systemic", "illness,", "except", "for", "the", "confirmation", "of", "an", "overt", "rotavirus", "infection.", "The", "syndrome", "responded", "promptly", "upon", "corticosteroid", "administration;", "no", "recurrence", "was", "observed.", "Conclusion:", "Besides", "describing", "the", "connection", "of", "Sweet’s", "syndrome", "to", "a", "rotavirus", "infection,", "this", "case", "report", "is", "also", "a", "reminder", "that", "in", "a", "child", "presenting", "with", "a", "febrile", "papulo-nodular", "rash", "with", "neutrophilia", "Sweet’s", "syndrome", "should", "be", "included", "in", "the", "differential.", "Introduction", "Sweet’s", "syndrome", "(acute", "febrile", "neutrophilic", "dermatosis)", "is", "characterized", "by", "a", "constellation", "of", "clinical", "symptoms", "and", "physical", "findings,", "which", "include", "fever,", "blood", "and", "tissue", "neutrophilia,", "leading", "to", "the", "development", "of", "ten-", "der,", "erythematous", "inflammatory", "skin", "lesions", "(papules,", "nodules,", "plaques),", "histopathologically", "characterized", "by", "the", "presence", "of", "abundant", "mature", "neutrophils", "[1].", "It", "pre-", "sents", "in", "three", "clinical", "settings:", "‘classical’", "(’para-infec-", "tious’)", "Sweet’s", "syndrome,", "representing", "a", "hypersensitivity", "reaction", "preceding", "infection;", "malignancy-associated", "(’para-neoplastic’)", "Sweet’s", "syndrome", "(in", "children", "usually", "associated", "with", "acute", "myelogenous", "leukemia);", "and", "less", "frequently", "as", "an", "adverse", "drug", "reaction,", "sometimes", "in", "connection", "with", "certain", "underlying", "diseases", "(drug-", "induced", "Sweet’s", "syndrome)", "[2].", "Irrespective", "of", "its", "cause,", "clinical", "and", "laboratory", "signs", "in", "Sweet’s", "syndrome", "*", "Correspondence:", "amakis@cc.uoi.gr", "1Child", "Health", "Department,", "University", "of", "Ioannina", "Medical", "School,", "P.O.", "Box", "1187,", "GR-45110", "Ioannina,", "Greece", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "respond", "promptly", "to", "systemic", "corticosteroids.", "Sponta-", "neous", "resolution", "is", "possible,", "although", "a", "persisting", "recur-", "rent", "course", "over", "months", "is", "the", "rule", "[3].", "Sweet’s", "syndrome", "is", "rarely", "diagnosed", "in", "children", "[4].", "Here,", "on", "the", "occasion", "of", "a", "child", "with", "classical,", "“para-", "infectious”", "Sweet’s", "syndrome", "we", "present,", "to", "the", "best", "of", "our", "knowledge", "for", "the", "first", "time", "in", "the", "accessible", "literature,", "the", "association", "of", "this", "syndrome", "to", "a", "rota-", "virus", "infection.", "The", "current", "report", "appends", "rotavirus", "to", "the", "list", "of", "infectious", "agents", "associated", "with", "Sweet’s", "syndrome,", "thus", "expanding", "the", "pertinent", "diagnostic", "cri-", "teria", "[5].", "Case", "presentation", "An", "18-month-old", "boy", "of", "Hellenic", "origin", "was", "initially", "admitted", "to", "another", "hospital", "because", "of", "fever", "up", "to", "39.9°C", "lasting", "for", "five", "days,", "a", "mild", "cough,", "one", "to", "two", "vomits", "and", "two", "to", "three", "yellowish", "diarrheas", "per", "day.", "On", "examination,", "apart", "from", "fever", "(38.8°C)", "no", "other", "patholo-", "gical", "findings", "were", "present.", "Laboratory", "evaluation", "revealed", "leukocytosis", "(26,500/μl)", "with", "47%", "neutrophils", "©", "2010", "Makis", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 76, 25, 90, 25 ], [ 175, 25, 134, 25 ], [ 318, 25, 179, 25 ], [ 76, 50, 205, 25 ], [ 290, 50, 114, 25 ], [ 412, 50, 25, 25 ], [ 446, 50, 159, 25 ], [ 76, 118, 38, 20 ], [ 119, 118, 49, 20 ], [ 76, 143, 70, 23 ], [ 151, 143, 81, 23 ], [ 238, 143, 80, 23 ], [ 325, 143, 20, 23 ], [ 351, 143, 35, 23 ], [ 391, 143, 95, 23 ], [ 492, 143, 74, 23 ], [ 572, 143, 19, 23 ], [ 597, 143, 12, 23 ], [ 615, 143, 125, 23 ], [ 76, 168, 68, 23 ], [ 149, 168, 71, 23 ], [ 226, 168, 12, 23 ], [ 244, 168, 45, 23 ], [ 295, 168, 68, 23 ], [ 76, 193, 36, 21 ], [ 117, 193, 53, 21 ], [ 174, 193, 83, 21 ], [ 262, 193, 35, 21 ], [ 301, 193, 74, 21 ], [ 380, 193, 113, 21 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 243, 41, 12 ], [ 119, 243, 59, 12 ], [ 179, 243, 10, 12 ], [ 191, 243, 33, 12 ], [ 226, 243, 43, 12 ], [ 271, 243, 22, 12 ], [ 296, 243, 10, 12 ], [ 308, 243, 30, 12 ], [ 340, 243, 70, 12 ], [ 413, 243, 31, 12 ], [ 446, 243, 9, 12 ], [ 457, 243, 12, 12 ], [ 471, 243, 25, 12 ], [ 498, 243, 10, 12 ], [ 509, 243, 50, 12 ], [ 561, 243, 10, 12 ], [ 573, 243, 29, 12 ], [ 604, 243, 28, 12 ], [ 633, 243, 39, 12 ], [ 674, 243, 39, 12 ], [ 714, 243, 32, 12 ], [ 748, 243, 22, 12 ], [ 76, 263, 31, 12 ], [ 110, 263, 19, 12 ], [ 131, 263, 28, 12 ], [ 162, 263, 44, 12 ], [ 209, 263, 4, 12 ], [ 215, 263, 109, 12 ], [ 326, 263, 40, 12 ], [ 368, 263, 60, 12 ], [ 431, 263, 4, 12 ], [ 438, 263, 71, 12 ], [ 76, 279, 7, 11 ], [ 85, 279, 73, 11 ], [ 160, 279, 33, 11 ], [ 76, 338, 45, 11 ], [ 124, 338, 12, 11 ], [ 138, 338, 16, 11 ], [ 157, 338, 23, 11 ], [ 76, 357, 27, 12 ], [ 105, 357, 40, 12 ], [ 148, 357, 51, 12 ], [ 202, 357, 59, 12 ], [ 263, 357, 35, 12 ], [ 300, 357, 8, 12 ], [ 311, 357, 47, 12 ], [ 360, 357, 25, 12 ], [ 387, 357, 20, 12 ], [ 419, 357, 128, 12 ], [ 76, 377, 20, 12 ], [ 98, 377, 28, 12 ], [ 129, 377, 7, 12 ], [ 139, 377, 38, 12 ], [ 179, 377, 25, 12 ], [ 207, 377, 206, 12 ], [ 571, 338, 43, 11 ], [ 618, 338, 12, 11 ], [ 632, 338, 19, 11 ], [ 653, 338, 23, 11 ], [ 571, 351, 46, 12 ], [ 620, 351, 12, 12 ], [ 634, 351, 16, 12 ], [ 653, 351, 23, 12 ], [ 76, 397, 9, 12 ], [ 87, 397, 23, 12 ], [ 113, 397, 33, 12 ], [ 149, 397, 16, 12 ], [ 168, 397, 57, 12 ], [ 228, 397, 36, 12 ], [ 266, 397, 35, 12 ], [ 304, 397, 35, 12 ], [ 341, 397, 18, 12 ], [ 76, 410, 20, 12 ], [ 98, 410, 7, 12 ], [ 108, 410, 11, 12 ], [ 121, 410, 26, 12 ], [ 150, 410, 32, 12 ], [ 184, 410, 28, 12 ], [ 215, 410, 49, 12 ], [ 267, 410, 27, 12 ], [ 296, 410, 15, 12 ], [ 314, 410, 27, 12 ], [ 343, 410, 10, 12 ], [ 355, 410, 15, 12 ], [ 373, 410, 39, 12 ], [ 415, 410, 48, 12 ], [ 465, 410, 51, 12 ], [ 519, 410, 34, 12 ], [ 555, 410, 202, 12 ], [ 76, 423, 27, 12 ], [ 106, 423, 35, 12 ], [ 143, 423, 56, 12 ], [ 201, 423, 18, 12 ], [ 222, 423, 55, 12 ], [ 279, 423, 16, 12 ], [ 298, 423, 60, 12 ], [ 361, 423, 8, 12 ], [ 372, 423, 16, 12 ], [ 390, 423, 39, 12 ], [ 432, 423, 40, 12 ], [ 475, 423, 15, 12 ], [ 493, 423, 34, 12 ], [ 529, 423, 24, 12 ], [ 556, 423, 7, 12 ], [ 565, 423, 39, 12 ], [ 607, 423, 25, 12 ], [ 155, 484, 62, 15 ], [ 155, 505, 22, 14 ], [ 180, 505, 51, 14 ], [ 234, 505, 43, 14 ], [ 280, 505, 42, 14 ], [ 325, 505, 11, 14 ], [ 340, 505, 18, 14 ], [ 361, 505, 50, 14 ], [ 414, 505, 39, 14 ], [ 456, 505, 18, 14 ], [ 477, 505, 27, 14 ], [ 507, 505, 53, 14 ], [ 564, 505, 11, 14 ], [ 578, 505, 6, 14 ], [ 587, 505, 23, 14 ], [ 614, 505, 31, 14 ], [ 648, 505, 20, 14 ], [ 671, 505, 20, 14 ], [ 155, 521, 36, 14 ], [ 196, 521, 52, 14 ], [ 252, 521, 18, 14 ], [ 274, 521, 24, 14 ], [ 303, 521, 11, 14 ], [ 318, 521, 6, 14 ], [ 329, 521, 64, 14 ], [ 397, 521, 37, 14 ], [ 438, 521, 34, 14 ], [ 476, 521, 25, 14 ], [ 505, 521, 51, 14 ], [ 560, 521, 6, 14 ], [ 571, 521, 35, 14 ], [ 610, 521, 42, 14 ], [ 657, 521, 11, 14 ], [ 673, 521, 18, 14 ], [ 155, 537, 50, 14 ], [ 208, 537, 39, 14 ], [ 251, 537, 35, 14 ], [ 289, 537, 6, 14 ], [ 298, 537, 32, 14 ], [ 333, 537, 22, 14 ], [ 358, 537, 31, 14 ], [ 393, 537, 21, 14 ], [ 417, 537, 55, 14 ], [ 475, 537, 46, 14 ], [ 524, 537, 20, 14 ], [ 547, 537, 11, 14 ], [ 561, 537, 23, 14 ], [ 586, 537, 19, 14 ], [ 608, 537, 56, 14 ], [ 667, 537, 24, 14 ], [ 155, 554, 13, 14 ], [ 173, 554, 18, 14 ], [ 195, 554, 70, 14 ], [ 270, 554, 70, 14 ], [ 345, 554, 22, 14 ], [ 371, 554, 55, 14 ], [ 431, 554, 52, 14 ], [ 487, 554, 10, 14 ], [ 502, 554, 28, 14 ], [ 535, 554, 64, 14 ], [ 603, 554, 25, 14 ], [ 632, 554, 15, 14 ], [ 652, 554, 39, 14 ], [ 155, 570, 33, 14 ], [ 192, 570, 13, 14 ], [ 209, 570, 77, 14 ], [ 289, 570, 32, 14 ], [ 325, 570, 35, 14 ], [ 364, 570, 82, 14 ], [ 449, 570, 18, 14 ], [ 471, 570, 38, 14 ], [ 513, 570, 21, 14 ], [ 537, 570, 77, 14 ], [ 618, 570, 20, 14 ], [ 642, 570, 49, 14 ], [ 155, 586, 12, 14 ], [ 170, 586, 65, 14 ], [ 237, 586, 66, 14 ], [ 305, 586, 37, 14 ], [ 345, 586, 11, 14 ], [ 358, 586, 18, 14 ], [ 378, 586, 28, 14 ], [ 409, 586, 50, 14 ], [ 461, 586, 28, 14 ], [ 492, 586, 22, 14 ], [ 516, 586, 37, 14 ], [ 555, 586, 20, 14 ], [ 577, 586, 70, 14 ], [ 650, 586, 41, 14 ], [ 155, 603, 11, 14 ], [ 170, 603, 18, 14 ], [ 191, 603, 24, 14 ], [ 218, 603, 50, 14 ], [ 271, 603, 40, 14 ], [ 315, 603, 6, 14 ], [ 324, 603, 44, 14 ], [ 372, 603, 44, 14 ], [ 419, 603, 40, 14 ], [ 462, 603, 25, 14 ], [ 490, 603, 70, 14 ], [ 563, 603, 63, 14 ], [ 76, 671, 88, 15 ], [ 76, 688, 22, 14 ], [ 104, 688, 55, 14 ], [ 166, 688, 42, 14 ], [ 214, 688, 56, 14 ], [ 276, 688, 12, 14 ], [ 294, 688, 7, 14 ], [ 308, 688, 51, 14 ], [ 365, 688, 46, 14 ], [ 76, 704, 41, 14 ], [ 121, 704, 13, 14 ], [ 137, 704, 19, 14 ], [ 160, 704, 30, 14 ], [ 195, 704, 20, 14 ], [ 219, 704, 22, 14 ], [ 245, 704, 39, 14 ], [ 288, 704, 44, 14 ], [ 336, 704, 13, 14 ], [ 352, 704, 19, 14 ], [ 375, 704, 36, 14 ], [ 76, 720, 24, 14 ], [ 105, 720, 41, 14 ], [ 152, 720, 10, 14 ], [ 167, 720, 42, 14 ], [ 215, 720, 60, 14 ], [ 280, 720, 27, 14 ], [ 312, 720, 31, 14 ], [ 348, 720, 13, 14 ], [ 367, 720, 45, 14 ], [ 76, 737, 81, 14 ], [ 160, 737, 59, 14 ], [ 222, 737, 12, 14 ], [ 237, 737, 19, 14 ], [ 259, 737, 31, 14 ], [ 293, 737, 22, 14 ], [ 318, 737, 46, 14 ], [ 367, 737, 44, 14 ], [ 76, 753, 13, 14 ], [ 91, 753, 19, 14 ], [ 112, 753, 55, 14 ], [ 169, 753, 43, 14 ], [ 214, 753, 10, 14 ], [ 226, 753, 7, 14 ], [ 235, 753, 25, 14 ], [ 262, 753, 23, 14 ], [ 287, 753, 35, 14 ], [ 324, 753, 23, 14 ], [ 349, 753, 9, 14 ], [ 360, 753, 20, 14 ], [ 383, 753, 29, 14 ], [ 76, 769, 33, 14 ], [ 113, 769, 50, 14 ], [ 166, 769, 12, 14 ], [ 182, 769, 19, 14 ], [ 204, 769, 53, 14 ], [ 261, 769, 12, 14 ], [ 276, 769, 7, 14 ], [ 286, 769, 32, 14 ], [ 322, 769, 12, 14 ], [ 338, 769, 28, 14 ], [ 369, 769, 42, 14 ], [ 76, 785, 40, 14 ], [ 123, 785, 23, 14 ], [ 152, 785, 61, 14 ], [ 220, 785, 67, 14 ], [ 294, 785, 35, 14 ], [ 336, 785, 30, 14 ], [ 373, 785, 13, 14 ], [ 392, 785, 19, 14 ], [ 76, 802, 50, 14 ], [ 130, 802, 30, 14 ], [ 164, 802, 25, 14 ], [ 192, 802, 27, 14 ], [ 223, 802, 43, 14 ], [ 270, 802, 55, 14 ], [ 329, 802, 29, 14 ], [ 362, 802, 13, 14 ], [ 379, 802, 32, 14 ], [ 76, 818, 57, 14 ], [ 138, 818, 49, 14 ], [ 192, 818, 32, 14 ], [ 229, 818, 38, 14 ], [ 272, 818, 44, 14 ], [ 320, 818, 20, 14 ], [ 345, 818, 32, 14 ], [ 382, 818, 29, 14 ], [ 76, 835, 50, 14 ], [ 129, 835, 65, 14 ], [ 196, 835, 22, 14 ], [ 220, 835, 48, 14 ], [ 270, 835, 13, 14 ], [ 285, 835, 22, 14 ], [ 310, 835, 36, 14 ], [ 348, 835, 10, 14 ], [ 360, 835, 13, 14 ], [ 375, 835, 36, 14 ], [ 76, 851, 23, 14 ], [ 103, 851, 24, 14 ], [ 132, 851, 13, 14 ], [ 149, 851, 38, 14 ], [ 192, 851, 44, 14 ], [ 240, 851, 12, 14 ], [ 257, 851, 19, 14 ], [ 280, 851, 55, 14 ], [ 340, 851, 43, 14 ], [ 387, 851, 12, 14 ], [ 404, 851, 7, 14 ], [ 76, 867, 72, 14 ], [ 153, 867, 36, 14 ], [ 193, 867, 36, 14 ], [ 234, 867, 41, 14 ], [ 279, 867, 15, 14 ], [ 298, 867, 69, 14 ], [ 372, 867, 23, 14 ], [ 399, 867, 13, 14 ], [ 76, 883, 42, 14 ], [ 121, 883, 19, 14 ], [ 143, 883, 73, 14 ], [ 220, 883, 48, 14 ], [ 271, 883, 13, 14 ], [ 287, 883, 22, 14 ], [ 312, 883, 36, 14 ], [ 351, 883, 24, 14 ], [ 378, 883, 34, 14 ], [ 76, 900, 42, 14 ], [ 121, 900, 15, 14 ], [ 139, 900, 45, 14 ], [ 188, 900, 42, 14 ], [ 232, 900, 13, 14 ], [ 248, 900, 19, 14 ], [ 270, 900, 43, 14 ], [ 315, 900, 13, 14 ], [ 331, 900, 7, 14 ], [ 341, 900, 44, 14 ], [ 76, 932, 35, 15 ], [ 114, 932, 89, 15 ], [ 76, 949, 9, 14 ], [ 95, 949, 68, 14 ], [ 174, 949, 72, 14 ], [ 256, 949, 23, 14 ], [ 290, 949, 48, 14 ], [ 348, 949, 64, 14 ], [ 76, 965, 43, 14 ], [ 123, 965, 18, 14 ], [ 144, 965, 28, 14 ], [ 176, 965, 28, 14 ], [ 208, 965, 40, 14 ], [ 251, 965, 19, 14 ], [ 274, 965, 43, 14 ], [ 321, 965, 27, 14 ], [ 352, 965, 19, 14 ], [ 375, 965, 37, 14 ], [ 434, 671, 24, 14 ], [ 463, 671, 12, 14 ], [ 479, 671, 19, 14 ], [ 503, 671, 28, 14 ], [ 535, 671, 26, 14 ], [ 566, 671, 45, 14 ], [ 615, 671, 7, 14 ], [ 627, 671, 25, 14 ], [ 656, 671, 39, 14 ], [ 700, 671, 7, 14 ], [ 711, 671, 35, 14 ], [ 751, 671, 19, 14 ], [ 434, 688, 50, 14 ], [ 491, 688, 41, 14 ], [ 538, 688, 44, 14 ], [ 588, 688, 28, 14 ], [ 622, 688, 56, 14 ], [ 684, 688, 15, 14 ], [ 705, 688, 19, 14 ], [ 730, 688, 40, 14 ], [ 434, 704, 33, 14 ], [ 471, 704, 15, 14 ], [ 489, 704, 38, 14 ], [ 530, 704, 25, 14 ], [ 559, 704, 13, 14 ], [ 575, 704, 45, 14 ], [ 624, 704, 19, 14 ], [ 647, 704, 30, 14 ], [ 680, 704, 51, 14 ], [ 734, 704, 12, 14 ], [ 750, 704, 19, 14 ], [ 434, 720, 46, 14 ], [ 485, 720, 18, 14 ], [ 507, 720, 45, 14 ], [ 557, 720, 74, 14 ], [ 635, 720, 27, 14 ], [ 667, 720, 51, 14 ], [ 722, 720, 47, 14 ], [ 434, 737, 21, 14 ], [ 460, 737, 23, 14 ], [ 487, 737, 16, 14 ], [ 508, 737, 52, 14 ], [ 564, 737, 48, 14 ], [ 617, 737, 23, 14 ], [ 644, 737, 15, 14 ], [ 663, 737, 60, 14 ], [ 727, 737, 12, 14 ], [ 744, 737, 25, 14 ], [ 434, 753, 20, 14 ], [ 457, 753, 29, 14 ], [ 488, 753, 8, 14 ], [ 498, 753, 39, 14 ], [ 539, 753, 19, 14 ], [ 561, 753, 64, 14 ], [ 627, 753, 63, 14 ], [ 693, 753, 42, 14 ], [ 737, 753, 32, 14 ], [ 434, 769, 60, 14 ], [ 496, 769, 17, 14 ], [ 516, 769, 71, 14 ], [ 589, 769, 42, 14 ], [ 633, 769, 22, 14 ], [ 658, 769, 33, 14 ], [ 693, 769, 17, 14 ], [ 713, 769, 57, 14 ], [ 434, 785, 27, 14 ], [ 465, 785, 43, 14 ], [ 511, 785, 11, 14 ], [ 526, 785, 28, 14 ], [ 558, 785, 37, 14 ], [ 599, 785, 36, 14 ], [ 639, 785, 27, 14 ], [ 669, 785, 39, 14 ], [ 712, 785, 18, 14 ], [ 734, 785, 36, 14 ], [ 434, 802, 46, 14 ], [ 486, 802, 22, 14 ], [ 515, 802, 23, 14 ], [ 544, 802, 71, 14 ], [ 621, 802, 47, 14 ], [ 674, 802, 33, 14 ], [ 714, 802, 7, 14 ], [ 727, 802, 43, 14 ], [ 434, 818, 55, 14 ], [ 493, 818, 12, 14 ], [ 509, 818, 7, 14 ], [ 519, 818, 37, 14 ], [ 559, 818, 52, 14 ], [ 615, 818, 22, 14 ], [ 640, 818, 23, 14 ], [ 666, 818, 57, 14 ], [ 726, 818, 15, 14 ], [ 744, 818, 25, 14 ], [ 434, 835, 74, 14 ], [ 513, 835, 24, 14 ], [ 542, 835, 22, 14 ], [ 569, 835, 40, 14 ], [ 614, 835, 52, 14 ], [ 672, 835, 13, 14 ], [ 690, 835, 24, 14 ], [ 718, 835, 27, 14 ], [ 750, 835, 19, 14 ], [ 434, 851, 41, 14 ], [ 479, 851, 31, 14 ], [ 514, 851, 13, 14 ], [ 530, 851, 21, 14 ], [ 554, 851, 62, 14 ], [ 620, 851, 46, 14 ], [ 670, 851, 21, 14 ], [ 695, 851, 41, 14 ], [ 739, 851, 31, 14 ], [ 434, 867, 31, 14 ], [ 468, 867, 40, 14 ], [ 510, 867, 20, 14 ], [ 532, 867, 46, 14 ], [ 581, 867, 74, 14 ], [ 657, 867, 49, 14 ], [ 708, 867, 46, 14 ], [ 757, 867, 13, 14 ], [ 434, 883, 48, 14 ], [ 490, 883, 23, 14 ], [ 521, 883, 72, 14 ], [ 600, 883, 37, 14 ], [ 644, 883, 55, 14 ], [ 707, 883, 63, 14 ], [ 434, 900, 27, 14 ], [ 466, 900, 20, 14 ], [ 491, 900, 57, 14 ], [ 552, 900, 23, 14 ], [ 580, 900, 45, 14 ], [ 629, 900, 9, 14 ], [ 643, 900, 22, 14 ], [ 670, 900, 49, 14 ], [ 723, 900, 13, 14 ], [ 741, 900, 29, 14 ], [ 434, 916, 33, 14 ], [ 474, 916, 27, 14 ], [ 507, 916, 56, 14 ], [ 569, 916, 19, 14 ], [ 595, 916, 55, 14 ], [ 657, 916, 43, 14 ], [ 706, 916, 11, 14 ], [ 723, 916, 46, 14 ], [ 434, 932, 43, 14 ], [ 481, 932, 22, 14 ], [ 506, 932, 56, 14 ], [ 565, 932, 12, 14 ], [ 580, 932, 32, 14 ], [ 615, 932, 50, 14 ], [ 669, 932, 27, 14 ], [ 699, 932, 12, 14 ], [ 714, 932, 55, 14 ], [ 434, 949, 43, 14 ], [ 482, 949, 54, 14 ], [ 542, 949, 13, 14 ], [ 560, 949, 102, 14 ], [ 667, 949, 42, 14 ], [ 714, 949, 22, 14 ], [ 742, 949, 28, 14 ], [ 434, 965, 31, 14 ], [ 469, 965, 20, 14 ], [ 492, 965, 27, 14 ], [ 522, 965, 19, 14 ], [ 545, 965, 63, 14 ], [ 611, 965, 20, 14 ], [ 635, 965, 23, 14 ], [ 660, 965, 19, 14 ], [ 683, 965, 36, 14 ], [ 722, 965, 21, 14 ], [ 746, 965, 24, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "Sports", "Medicine,", "Arthroscopy,", "Rehabilitation,", "Therapy", "&", "Technology", "Case", "report", "Partial", "isolated", "rupture", "of", "the", "popliteus", "tendon", "in", "a", "professional", "soccer", "player:", "a", "case", "report", "Pier", "Paolo", "Mariani*", "and", "Fabrizio", "Margheritini", "BioMed", "Central", "Open", "Access", "Address:", "Department", "of", "Health", "Sciences,", "Unit", "of", "Sports", "Traumatology,", "Piazza", "L.", "de", "Bosis", "6,", "University", "of", "Rome", "\"Foro", "Italico\",", "I-00135", "Rome,", "Italy", "Email:", "Pier", "Paolo", "Mariani*", "-", "ppmariani@virgilio.it;", "Fabrizio", "Margheritini", "-", "fab.mar@iol.it", "*", "Corresponding", "author", "Published:", "31", "July", "2009", "Sports", "Medicine,", "Arthroscopy,", "Rehabilitation,", "Therapy", "&", "Technology", "2009,", "1:18", "doi:10.1186/1758-2555-1-18", "This", "article", "is", "available", "from:", "http://www.smarttjournal.com/content/1/1/18", "Received:", "29", "May", "2009", "Accepted:", "31", "July", "2009", "©", "2009", "Mariani", "and", "Margheritini;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "The", "complete", "isolated", "rupture", "of", "the", "popliteus", "tendon", "has", "been", "described", "as", "a", "rare", "injury", "and", "this", "report", "describes", "the", "case", "of", "a", "31-year-old", "soccer", "player", "who", "sustained", "a", "partial", "rupture", "of", "the", "popliteus", "tendon", "during", "a", "game.", "The", "injury", "was", "suspected", "clinically", "and", "at", "MRI", "but", "confirmed", "only", "by", "the", "arthroscopic", "examination.", "The", "treatment", "consisted", "in", "open", "debridment", "with", "no", "tendon", "repair", "or", "augmentation.", "Seven", "weeks", "post-operation", "the", "patient", "was", "symptom-free", "and", "returned", "to", "competitive", "professional", "soccer", "at", "the", "same", "preinjury", "level.", "The", "clinical", "and", "arthroscopic", "findings", "of", "the", "case", "reported", "suggest", "a", "possible", "overuse", "disease", "with", "degenerative", "expression.", "Introduction", "The", "popliteus", "muscle", "functions", "as", "a", "dynamic", "internal", "rotator", "of", "the", "tibia.", "For", "this", "reason", "rupture", "of", "the", "popli-", "teus", "muscle", "is", "usually", "associated", "with", "acute", "or", "chronic", "posterolateral", "instability", "of", "the", "knee.", "The", "isolated", "rupture", "of", "the", "popliteus", "tendon", "is", "a", "very", "rare", "injury", "and", "it", "has", "been", "rarely", "reported", "in", "the", "literature", "as", "a", "cause", "of", "knee", "hemar-", "throsis", "and", "functional", "disabilities.", "While", "most", "of", "the", "reported", "cases", "deal", "with", "tendon", "avulsions", "[1-6]", "or", "intra-", "substance", "ruptures", "[7,8],", "partial", "rupture", "has", "never", "been", "reported", "previously.", "The", "purpose", "of", "this", "article", "is", "to", "report", "one", "case", "of", "partial", "rupture", "of", "the", "popliteus", "tendon", "in", "a", "professional", "soccer", "player", "treated", "by", "debridment", "and", "to", "discuss", "the", "pathological", "findings", "of", "this", "lesion", "that", "could", "suggest", "an", "overuse", "disease", "of", "the", "tendon", "in", "a", "athlete.", "Case", "presentation", "A", "31-year-old", "professional", "first", "division", "goalkeeper", "injured", "his", "right", "knee", "hitting", "the", "ground", "with", "the", "lateral", "side", "of", "the", "knee", "after", "making", "a", "save", "during", "a", "game.", "No", "previous", "similar", "injuries", "were", "sustained", "by", "the", "player,", "while", "he", "wasn't", "able", "to", "identify", "the", "exact", "moment", "of", "the", "trauma.", "He", "referred", "immediately", "only", "minimal", "discom-", "fort", "and", "no", "apparent", "effusion", "and", "he", "continued", "to", "play", "on.", "After", "2", "weeks,", "the", "discomfort", "progressed", "despite", "phys-", "iotherapy.", "An", "orthopaedic", "referral", "was", "made", "for", "persistent", "pain", "located", "at", "knee", "lateral", "aspect", "only", "during", "his", "sports", "activity.", "The", "first", "orthopaedic", "surgeon", "made", "a", "clinical", "diagnosis", "of", "a", "lateral", "meniscal", "tear", "and", "requested", "an", "MRI", "examination", "that", "was", "judged", "negative.", "At", "that", "time", "the", "patient", "came", "to", "our", "institution", "without", "any", "further", "treat-", "ment", "carried", "on.", "Clinical", "examination", "revealed", "absence", "of", "effusion", "and", "non-specific", "lateral", "joint-line", "tenderness", "with", "full", "extension", "and", "flexion.", "It", "was", "possible", "to", "elicit", "sharp", "pain", "palpating", "the", "popliteus", "tendon", "at", "femoral", "groove.", "The", "suspicion", "of", "other", "diseases,", "such", "as", "popliteus", "tendon", "snapping", "or", "popliteomeniscal", "fascicle", "tear", "were", "ruled", "out", "with", "the", "figure-four", "test", "and", "the", "Cabot", "test", "that", "Page", "1", "of", "4", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 0, 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 78, 47, 26, 12 ], [ 107, 47, 9, 12 ], [ 119, 47, 11, 12 ], [ 133, 47, 44, 12 ], [ 180, 47, 57, 12 ], [ 240, 47, 25, 12 ], [ 269, 47, 20, 12 ], [ 78, 61, 250, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 167, 34 ], [ 256, 169, 51, 34 ], [ 317, 169, 93, 34 ], [ 419, 169, 179, 34 ], [ 609, 169, 25, 34 ], [ 644, 169, 45, 34 ], [ 78, 205, 61, 34 ], [ 149, 205, 100, 34 ], [ 259, 205, 63, 34 ], [ 332, 205, 113, 34 ], [ 455, 205, 95, 34 ], [ 560, 205, 87, 34 ], [ 78, 241, 130, 34 ], [ 219, 241, 98, 34 ], [ 327, 241, 67, 34 ], [ 404, 241, 138, 34 ], [ 78, 288, 29, 16 ], [ 111, 285, 51, 19 ], [ 167, 288, 29, 16 ], [ 201, 285, 56, 19 ], [ 261, 288, 31, 16 ], [ 296, 285, 36, 19 ], [ 337, 288, 43, 16 ], [ 385, 288, 8, 16 ], [ 397, 285, 33, 19 ], [ 435, 288, 33, 16 ], [ 471, 285, 44, 19 ], [ 520, 288, 22, 16 ], [ 546, 288, 45, 16 ], [ 596, 285, 42, 19 ], [ 87, 342, 54, 15 ], [ 87, 367, 76, 14 ], [ 167, 367, 76, 14 ], [ 247, 367, 40, 14 ], [ 291, 367, 58, 14 ], [ 353, 367, 31, 14 ], [ 388, 367, 7, 14 ], [ 399, 367, 30, 14 ], [ 433, 367, 36, 14 ], [ 473, 367, 12, 14 ], [ 489, 367, 60, 14 ], [ 554, 367, 19, 14 ], [ 577, 367, 45, 14 ], [ 626, 367, 59, 14 ], [ 690, 367, 49, 14 ], [ 87, 384, 41, 14 ], [ 133, 384, 29, 14 ], [ 165, 384, 56, 14 ], [ 226, 384, 21, 14 ], [ 251, 384, 74, 14 ], [ 330, 384, 55, 14 ], [ 389, 384, 46, 14 ], [ 439, 384, 40, 14 ], [ 483, 384, 60, 14 ], [ 547, 384, 17, 14 ], [ 569, 384, 74, 14 ], [ 647, 384, 14, 14 ], [ 665, 384, 47, 14 ], [ 87, 400, 48, 14 ], [ 140, 400, 50, 14 ], [ 194, 400, 42, 14 ], [ 240, 400, 60, 14 ], [ 304, 400, 31, 14 ], [ 339, 400, 11, 14 ], [ 354, 400, 34, 14 ], [ 393, 400, 17, 14 ], [ 414, 400, 58, 14 ], [ 476, 400, 25, 14 ], [ 505, 400, 62, 14 ], [ 571, 400, 22, 14 ], [ 597, 400, 58, 14 ], [ 659, 400, 63, 14 ], [ 87, 421, 46, 14 ], [ 137, 421, 18, 14 ], [ 160, 421, 68, 14 ], [ 232, 421, 19, 14 ], [ 255, 421, 66, 14 ], [ 325, 421, 32, 14 ], [ 362, 421, 21, 14 ], [ 388, 421, 39, 14 ], [ 431, 421, 75, 14 ], [ 510, 421, 11, 14 ], [ 525, 421, 29, 14 ], [ 558, 421, 40, 14 ], [ 603, 421, 103, 14 ], [ 710, 421, 19, 14 ], [ 87, 438, 28, 14 ], [ 119, 438, 27, 14 ], [ 150, 438, 67, 14 ], [ 221, 438, 19, 14 ], [ 243, 438, 44, 14 ], [ 291, 438, 63, 14 ], [ 358, 438, 45, 14 ], [ 407, 438, 29, 14 ], [ 440, 438, 53, 14 ], [ 496, 438, 51, 14 ], [ 552, 438, 14, 14 ], [ 570, 438, 19, 14 ], [ 593, 438, 45, 14 ], [ 642, 438, 42, 14 ], [ 689, 438, 50, 14 ], [ 87, 454, 83, 14 ], [ 174, 454, 11, 14 ], [ 189, 454, 30, 14 ], [ 224, 454, 75, 14 ], [ 303, 454, 21, 14 ], [ 329, 454, 72, 14 ], [ 405, 452, 51, 17 ], [ 460, 454, 51, 14 ], [ 516, 454, 11, 14 ], [ 531, 454, 14, 14 ], [ 549, 454, 21, 14 ], [ 575, 454, 11, 14 ], [ 589, 454, 43, 14 ], [ 637, 454, 67, 14 ], [ 709, 454, 11, 14 ], [ 87, 471, 30, 14 ], [ 122, 471, 24, 14 ], [ 150, 471, 44, 14 ], [ 198, 471, 7, 14 ], [ 209, 471, 59, 14 ], [ 272, 471, 57, 14 ], [ 333, 471, 11, 14 ], [ 348, 471, 9, 14 ], [ 361, 471, 26, 14 ], [ 391, 471, 36, 14 ], [ 432, 471, 56, 14 ], [ 491, 471, 11, 14 ], [ 507, 471, 53, 14 ], [ 564, 471, 39, 14 ], [ 608, 471, 37, 14 ], [ 649, 471, 57, 14 ], [ 711, 471, 12, 14 ], [ 87, 488, 28, 14 ], [ 120, 488, 22, 14 ], [ 145, 488, 14, 14 ], [ 163, 488, 26, 14 ], [ 87, 508, 75, 14 ], [ 167, 508, 21, 14 ], [ 192, 508, 25, 14 ], [ 221, 508, 44, 14 ], [ 269, 508, 22, 14 ], [ 296, 508, 50, 14 ], [ 350, 508, 59, 14 ], [ 413, 508, 39, 14 ], [ 456, 508, 8, 14 ], [ 469, 508, 19, 14 ], [ 492, 508, 39, 14 ], [ 535, 508, 12, 14 ], [ 551, 508, 39, 14 ], [ 595, 508, 74, 14 ], [ 673, 508, 65, 14 ], [ 87, 525, 22, 14 ], [ 113, 525, 85, 14 ], [ 202, 525, 49, 14 ], [ 255, 525, 33, 14 ], [ 293, 525, 15, 14 ], [ 312, 525, 19, 14 ], [ 335, 525, 57, 14 ], [ 395, 525, 55, 14 ], [ 455, 525, 11, 14 ], [ 470, 525, 98, 14 ], [ 572, 525, 11, 14 ], [ 588, 525, 66, 14 ], [ 659, 525, 21, 14 ], [ 684, 525, 40, 14 ], [ 87, 542, 75, 14 ], [ 166, 542, 51, 14 ], [ 222, 542, 50, 14 ], [ 275, 542, 14, 14 ], [ 294, 542, 22, 14 ], [ 319, 542, 41, 14 ], [ 365, 542, 26, 14 ], [ 395, 542, 19, 14 ], [ 418, 542, 113, 14 ], [ 536, 542, 31, 14 ], [ 571, 542, 32, 14 ], [ 607, 542, 11, 14 ], [ 623, 539, 51, 17 ], [ 678, 542, 51, 14 ], [ 87, 558, 35, 14 ], [ 126, 558, 12, 14 ], [ 143, 558, 15, 14 ], [ 161, 558, 19, 14 ], [ 185, 558, 52, 14 ], [ 241, 558, 11, 14 ], [ 256, 558, 41, 14 ], [ 300, 558, 12, 14 ], [ 316, 558, 77, 14 ], [ 397, 558, 53, 14 ], [ 454, 558, 77, 14 ], [ 87, 582, 62, 14 ], [ 154, 582, 40, 14 ], [ 198, 582, 60, 14 ], [ 262, 582, 69, 14 ], [ 335, 582, 39, 14 ], [ 379, 582, 42, 14 ], [ 425, 582, 46, 14 ], [ 475, 582, 27, 14 ], [ 78, 628, 77, 15 ], [ 78, 645, 82, 14 ], [ 164, 645, 56, 14 ], [ 224, 645, 37, 14 ], [ 265, 645, 7, 14 ], [ 276, 645, 41, 14 ], [ 321, 645, 55, 14 ], [ 380, 645, 23, 14 ], [ 78, 661, 57, 14 ], [ 140, 661, 7, 14 ], [ 152, 661, 27, 14 ], [ 184, 661, 24, 14 ], [ 212, 661, 12, 14 ], [ 229, 661, 78, 14 ], [ 313, 661, 91, 14 ], [ 78, 678, 41, 14 ], [ 125, 678, 48, 14 ], [ 178, 678, 10, 14 ], [ 193, 678, 7, 14 ], [ 205, 678, 41, 14 ], [ 251, 678, 43, 14 ], [ 300, 678, 12, 14 ], [ 318, 678, 30, 14 ], [ 353, 678, 50, 14 ], [ 78, 695, 67, 14 ], [ 149, 695, 9, 14 ], [ 163, 695, 7, 14 ], [ 174, 695, 59, 14 ], [ 238, 695, 25, 14 ], [ 266, 695, 12, 14 ], [ 282, 695, 29, 14 ], [ 315, 695, 40, 14 ], [ 360, 695, 43, 14 ], [ 78, 711, 22, 14 ], [ 105, 711, 20, 14 ], [ 130, 711, 29, 14 ], [ 164, 711, 37, 14 ], [ 206, 711, 12, 14 ], [ 224, 711, 27, 14 ], [ 255, 711, 45, 14 ], [ 306, 711, 37, 14 ], [ 347, 711, 56, 14 ], [ 78, 728, 32, 14 ], [ 114, 728, 21, 14 ], [ 139, 728, 27, 14 ], [ 170, 728, 58, 14 ], [ 232, 728, 51, 14 ], [ 287, 728, 14, 14 ], [ 305, 728, 22, 14 ], [ 331, 728, 11, 14 ], [ 346, 728, 57, 14 ], [ 78, 744, 85, 14 ], [ 168, 744, 21, 14 ], [ 193, 744, 18, 14 ], [ 216, 744, 68, 14 ], [ 288, 744, 25, 14 ], [ 317, 744, 24, 14 ], [ 346, 744, 18, 14 ], [ 368, 744, 35, 14 ], [ 78, 761, 28, 14 ], [ 110, 761, 42, 14 ], [ 157, 761, 19, 14 ], [ 180, 761, 10, 14 ], [ 194, 761, 38, 14 ], [ 237, 761, 12, 14 ], [ 253, 761, 60, 14 ], [ 317, 761, 26, 14 ], [ 347, 761, 27, 14 ], [ 379, 761, 25, 14 ], [ 78, 778, 34, 14 ], [ 116, 778, 12, 14 ], [ 132, 778, 31, 14 ], [ 168, 778, 65, 14 ], [ 237, 778, 17, 14 ], [ 258, 778, 28, 14 ], [ 290, 778, 54, 14 ], [ 348, 778, 40, 14 ], [ 392, 778, 11, 14 ], [ 78, 794, 18, 14 ], [ 101, 794, 41, 14 ], [ 147, 794, 66, 14 ], [ 217, 794, 51, 14 ], [ 272, 794, 94, 14 ], [ 371, 794, 32, 14 ], [ 78, 811, 27, 14 ], [ 110, 811, 68, 14 ], [ 182, 811, 55, 14 ], [ 241, 811, 73, 14 ], [ 318, 811, 12, 14 ], [ 334, 811, 42, 14 ], [ 380, 811, 24, 14 ], [ 78, 827, 24, 14 ], [ 106, 827, 11, 14 ], [ 122, 827, 55, 14 ], [ 181, 827, 21, 14 ], [ 206, 827, 66, 14 ], [ 277, 827, 77, 14 ], [ 358, 827, 19, 14 ], [ 381, 827, 23, 14 ], [ 78, 844, 42, 14 ], [ 125, 844, 50, 14 ], [ 179, 844, 22, 14 ], [ 206, 844, 49, 14 ], [ 259, 844, 49, 14 ], [ 313, 844, 12, 14 ], [ 330, 844, 74, 14 ], [ 78, 861, 20, 14 ], [ 103, 861, 14, 14 ], [ 121, 861, 45, 14 ], [ 170, 861, 43, 14 ], [ 217, 861, 14, 14 ], [ 235, 861, 19, 14 ], [ 258, 861, 48, 14 ], [ 310, 861, 51, 14 ], [ 365, 861, 12, 14 ], [ 381, 861, 23, 14 ], [ 78, 877, 24, 14 ], [ 107, 877, 104, 14 ], [ 217, 877, 23, 14 ], [ 245, 877, 119, 14 ], [ 369, 877, 34, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 60, 11 ], [ 78, 925, 5, 11 ], [ 87, 925, 50, 11 ], [ 140, 925, 30, 11 ], [ 78, 936, 59, 13 ], [ 140, 937, 8, 11 ], [ 152, 937, 32, 11 ], [ 186, 937, 5, 11 ], [ 195, 937, 46, 11 ], [ 244, 937, 51, 11 ], [ 298, 937, 41, 11 ], [ 342, 937, 8, 11 ], [ 354, 937, 33, 11 ], [ 78, 950, 27, 11 ], [ 108, 950, 17, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 628, 30, 14 ], [ 457, 628, 13, 14 ], [ 475, 628, 61, 14 ], [ 540, 628, 69, 14 ], [ 613, 628, 77, 14 ], [ 695, 628, 23, 14 ], [ 723, 628, 25, 14 ], [ 423, 645, 32, 14 ], [ 459, 645, 12, 14 ], [ 475, 645, 19, 14 ], [ 498, 645, 20, 14 ], [ 523, 645, 12, 14 ], [ 539, 645, 30, 14 ], [ 574, 645, 26, 14 ], [ 605, 645, 22, 14 ], [ 631, 645, 78, 14 ], [ 713, 645, 35, 14 ], [ 423, 661, 12, 14 ], [ 440, 661, 14, 14 ], [ 458, 661, 14, 14 ], [ 477, 661, 29, 14 ], [ 511, 661, 32, 14 ], [ 547, 661, 12, 14 ], [ 564, 661, 91, 14 ], [ 659, 661, 20, 14 ], [ 684, 661, 22, 14 ], [ 710, 661, 9, 14 ], [ 723, 661, 25, 14 ], [ 423, 678, 32, 14 ], [ 459, 678, 25, 14 ], [ 488, 678, 12, 14 ], [ 504, 678, 50, 14 ], [ 558, 678, 31, 14 ], [ 594, 678, 60, 14 ], [ 658, 678, 15, 14 ], [ 678, 678, 19, 14 ], [ 701, 678, 47, 14 ], [ 423, 695, 12, 14 ], [ 440, 695, 52, 14 ], [ 496, 695, 6, 14 ], [ 507, 695, 42, 14 ], [ 554, 695, 42, 14 ], [ 600, 695, 76, 14 ], [ 681, 695, 67, 14 ], [ 423, 711, 12, 14 ], [ 440, 711, 19, 14 ], [ 464, 711, 53, 14 ], [ 521, 711, 12, 14 ], [ 538, 711, 63, 14 ], [ 606, 711, 52, 14 ], [ 663, 711, 13, 14 ], [ 681, 711, 50, 14 ], [ 736, 711, 12, 14 ], [ 423, 728, 80, 14 ], [ 508, 728, 57, 14 ], [ 570, 728, 22, 14 ], [ 596, 728, 60, 14 ], [ 660, 728, 41, 14 ], [ 706, 728, 12, 14 ], [ 722, 728, 26, 14 ], [ 423, 744, 52, 14 ], [ 479, 744, 24, 14 ], [ 507, 744, 52, 14 ], [ 563, 744, 25, 14 ], [ 591, 744, 19, 14 ], [ 434, 761, 54, 14 ], [ 493, 761, 45, 14 ], [ 542, 761, 64, 14 ], [ 611, 761, 41, 14 ], [ 658, 761, 68, 14 ], [ 730, 761, 18, 14 ], [ 423, 778, 84, 14 ], [ 511, 778, 24, 14 ], [ 540, 778, 12, 14 ], [ 556, 778, 79, 14 ], [ 639, 778, 43, 14 ], [ 687, 778, 61, 14 ], [ 423, 794, 41, 14 ], [ 468, 794, 19, 14 ], [ 491, 794, 7, 14 ], [ 502, 794, 45, 14 ], [ 552, 794, 12, 14 ], [ 567, 794, 45, 14 ], [ 617, 794, 25, 14 ], [ 647, 794, 43, 14 ], [ 694, 794, 54, 14 ], [ 423, 811, 16, 14 ], [ 443, 811, 85, 14 ], [ 533, 811, 23, 14 ], [ 560, 811, 47, 14 ], [ 611, 811, 28, 14 ], [ 643, 811, 12, 14 ], [ 659, 811, 26, 14 ], [ 690, 811, 24, 14 ], [ 718, 811, 30, 14 ], [ 423, 827, 59, 14 ], [ 487, 827, 12, 14 ], [ 504, 827, 19, 14 ], [ 528, 827, 34, 14 ], [ 567, 827, 28, 14 ], [ 600, 827, 13, 14 ], [ 618, 827, 58, 14 ], [ 680, 827, 51, 14 ], [ 736, 827, 12, 14 ], [ 423, 844, 43, 14 ], [ 471, 844, 22, 14 ], [ 497, 844, 43, 14 ], [ 545, 844, 12, 14 ], [ 562, 844, 34, 14 ], [ 600, 844, 69, 14 ], [ 674, 844, 20, 14 ], [ 698, 844, 24, 14 ], [ 726, 844, 22, 14 ], [ 423, 860, 63, 14 ], [ 490, 860, 18, 14 ], [ 514, 860, 42, 14 ], [ 560, 860, 53, 14 ], [ 617, 860, 57, 14 ], [ 679, 860, 13, 14 ], [ 697, 860, 51, 14 ], [ 423, 877, 73, 14 ], [ 500, 877, 20, 14 ], [ 524, 877, 30, 14 ], [ 558, 877, 18, 14 ], [ 580, 877, 60, 14 ], [ 645, 877, 50, 14 ], [ 699, 877, 12, 14 ], [ 715, 877, 33, 14 ], [ 423, 894, 34, 14 ], [ 462, 894, 55, 14 ], [ 522, 894, 13, 14 ], [ 539, 894, 58, 14 ], [ 602, 894, 88, 14 ], [ 695, 894, 20, 14 ], [ 720, 894, 28, 14 ], [ 423, 910, 60, 14 ], [ 487, 910, 20, 14 ], [ 511, 910, 64, 14 ], [ 580, 910, 19, 14 ], [ 603, 910, 62, 14 ], [ 669, 910, 23, 14 ], [ 697, 910, 25, 14 ], [ 726, 910, 22, 14 ], [ 423, 927, 35, 14 ], [ 462, 927, 48, 14 ], [ 516, 927, 19, 14 ], [ 540, 927, 65, 14 ], [ 610, 927, 62, 14 ], [ 677, 927, 42, 14 ], [ 724, 927, 24, 14 ], [ 423, 944, 51, 14 ], [ 479, 944, 12, 14 ], [ 496, 944, 53, 14 ], [ 554, 944, 44, 14 ], [ 603, 944, 63, 14 ], [ 671, 944, 37, 14 ], [ 713, 944, 35, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 277, 987, 21, 10 ], [ 300, 987, 8, 10 ], [ 310, 987, 8, 10 ], [ 320, 987, 31, 10 ], [ 353, 987, 29, 10 ], [ 384, 987, 27, 10 ], [ 414, 987, 14, 10 ], [ 430, 987, 15, 10 ], [ 447, 987, 6, 10 ], [ 456, 987, 10, 10 ], [ 467, 987, 21, 10 ], [ 491, 987, 25, 10 ], [ 519, 987, 23, 10 ], [ 544, 987, 41, 10 ], [ 587, 987, 23, 10 ], [ 612, 987, 13, 10 ], [ 627, 987, 21, 10 ], [ 651, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Maric", "et", "al.", "Molecular", "Cytogenetics", "2011,", "4:26", "http://www.molecularcytogenetics.org/content/4/1/26", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "Centrosomal", "and", "mitotic", "abnormalities", "in", "cell", "lines", "derived", "from", "papillary", "thyroid", "cancer", "harboring", "specific", "gene", "alterations", "Irena", "Maric1,2†,", "Silvia", "Viaggi1,2†,", "Paola", "Caria3,", "Daniela", "V", "Frau3,", "Paolo", "Degan2", "and", "Roberta", "Vanni3*", "Abstract", "Background:", "Differentiated", "thyroid", "carcinoma", "offers", "a", "good", "model", "to", "investigate", "the", "possible", "correlation", "between", "specific", "gene", "mutations", "and", "chromosome", "instability.", "Papillary", "thyroid", "neoplasms", "are", "characterized", "by", "different", "mutually", "exclusive", "genetic", "alterations,", "some", "of", "which", "are", "associated", "with", "aneuploidy", "and", "aggressive", "phenotype.", "Results:", "We", "investigated", "the", "centrosome", "status", "and", "mitotic", "abnormalities", "in", "three", "thyroid", "carcinoma-derived", "cell", "lines,", "each", "maintaining", "the", "specific,", "biologically", "relevant", "gene", "alteration", "harbored", "by", "the", "parental", "tumors:", "RET/PTC1", "rearrangement", "in", "TPC1;", "heterozygous", "and", "homozygous", "BRAFV600E", "mutation", "in", "K1", "and", "in", "B-CPAP,", "respectively.", "B-", "CPAP", "cells", "showed", "a", "statistically", "significant", "(P", "<", "0.01)", "higher", "frequency", "of", "abnormal", "mitotic", "figures", "compared", "to", "TPC1", "and", "K1", "cells.", "Conclusions:", "Our", "data", "indicate", "that", "RET/PTC1", "oncogenic", "activity", "is", "not", "related", "to", "mitotic", "chromosome", "impairment", "and", "missegregation", "whereas,", "based", "on", "the", "consistent", "difference", "in", "types/frequencies", "of", "centrosome", "and", "spindle", "abnormalities", "observed", "between", "K1", "and", "B-CPAP", "cells,", "the", "hetero/homozygous", "allelic", "status", "of", "BRAFV600E", "mutation", "seems", "to", "be", "not", "irrelevant", "in", "respect", "to", "chromosomal", "instability", "development.", "Keywords:", "thyroid", "carcinoma,", "centrosome,", "mitotic", "spindle,", "RET/PTC,", "BRAF", "Background", "Chromosomal", "instability", "(CIN),", "a", "genetic", "condition", "that", "promotes", "a", "high", "rate", "of", "chromosome", "missegregation", "during", "mitosis,", "is", "a", "shared", "feature", "of", "most", "cancers.", "Aneuploidy", "is", "a", "distinctive", "trait", "of", "most", "human", "cancers", "and", "has", "been", "linked", "to", "high", "tumour", "grade,", "advanced", "stage,", "and", "poor", "prognosis;", "however,", "its", "role", "in", "neoplastic", "transformation", "and", "the", "relationship", "with", "CIN", "are", "some-", "what", "unclear", "[1].", "A", "variety", "of", "alterations", "have", "been", "pro-", "posed", "as", "being", "responsible", "for", "CIN,", "including", "defects", "in", "the", "spindle", "checkpoint,", "defective", "sister-chromatid", "cohe-", "sion,", "kinetochore", "assembly,", "upregulation", "of", "cyclins,", "ero-", "sion", "of", "telomeres", "and", "centrosome", "abnormalities", "[2].", "The", "normal", "function", "and", "numeral", "integrity", "of", "centrosomes", "can", "be", "affected", "directly", "by", "the", "mutated", "products", "of", "cer-", "tain", "proto-oncogenes", "and", "tumour-suppressor", "genes", "*", "Correspondence:", "vanni@unica.it", "†", "Contributed", "equally", "3Dipartimento", "di", "Scienze", "e", "Tecnologie", "Biomediche,", "Università", "di", "Cagliari,", "09042,", "Italy", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "[3,4].", "In", "particular,", "centrosome", "amplification", "(the", "pre-", "sence", "in", "the", "cell", "of", "more", "than", "two", "centrosomes)", "seems", "to", "be", "an", "early", "event", "in", "tumourigenesis", "[5],", "and", "it", "may", "affect", "CIN", "in", "different", "ways,", "depending", "on", "the", "capacity", "to", "maintain", "a", "correct", "bipolar", "chromosome", "segregation", "in", "the", "presence", "of", "multipolar", "spindles.", "In", "addition", "to", "amplification,", "structural", "and", "functional", "defects", "of", "cen-", "trosomes", "may", "influence", "CIN", "[4].", "Papillary", "thyroid", "carcinoma", "(PTC),", "accounting", "for", "approximately", "80%", "of", "differentiated", "thyroid", "carcinoma", "(DTC),", "has", "a", "number", "of", "variants", "with", "specific", "histologi-", "cal", "characteristics.", "The", "classical", "form", "of", "PTC", "may", "show", "activation", "of", "the", "BRAF", "gene", "or", "RET/PTC", "variants,", "in", "40-45%", "and", "10-20%", "of", "cases,", "respectively", "[6].", "The", "two", "alterations", "are", "usually", "mutually", "exclusive.", "In", "different", "PTC-derived", "cell", "lines,", "the", "alternative", "presence", "of", "either", "BRAF", "mutation", "or", "RET/PTC", "rearrangement", "has", "been", "confirmed", "[7],", "reinforcing", "the", "hypothesis", "that", "RET", "and", "BRAF", "changes", "are", "alternative", "oncogenic", "events.", "The", "majority", "of", "papillary", "thyroid", "carcinoma", "shows", "stable", "©", "2011", "Maric", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 152, 240, 231, 27 ], [ 398, 242, 173, 24 ], [ 578, 242, 66, 24 ], [ 659, 238, 19, 12 ], [ 680, 238, 13, 12 ], [ 696, 238, 16, 12 ], [ 715, 238, 13, 12 ], [ 731, 238, 28, 12 ], [ 762, 238, 30, 12 ], [ 795, 238, 55, 12 ], [ 679, 252, 171, 12 ], [ 152, 291, 75, 17 ], [ 232, 291, 58, 17 ], [ 152, 321, 148, 23 ], [ 306, 321, 165, 23 ], [ 477, 321, 21, 23 ], [ 505, 321, 13, 23 ], [ 525, 321, 78, 23 ], [ 609, 321, 201, 23 ], [ 152, 350, 85, 23 ], [ 244, 350, 105, 23 ], [ 355, 350, 101, 23 ], [ 462, 350, 19, 23 ], [ 488, 350, 34, 23 ], [ 528, 350, 90, 23 ], [ 625, 350, 91, 23 ], [ 722, 350, 40, 23 ], [ 768, 350, 26, 23 ], [ 152, 380, 152, 23 ], [ 311, 380, 27, 23 ], [ 344, 380, 34, 23 ], [ 385, 380, 87, 23 ], [ 478, 380, 143, 23 ], [ 299, 408, 8, 14 ], [ 432, 408, 8, 14 ], [ 592, 408, 8, 14 ], [ 726, 408, 8, 14 ], [ 152, 410, 45, 19 ], [ 202, 410, 16, 19 ], [ 223, 410, 76, 19 ], [ 307, 410, 5, 19 ], [ 318, 410, 51, 19 ], [ 374, 410, 58, 19 ], [ 440, 410, 5, 19 ], [ 451, 410, 74, 19 ], [ 530, 410, 62, 19 ], [ 600, 410, 6, 19 ], [ 611, 410, 65, 19 ], [ 680, 410, 46, 19 ], [ 735, 410, 5, 19 ], [ 152, 431, 31, 18 ], [ 189, 428, 79, 21 ], [ 273, 431, 30, 18 ], [ 308, 431, 51, 18 ], [ 364, 428, 107, 21 ], [ 152, 453, 47, 17 ], [ 203, 455, 20, 14 ], [ 227, 455, 54, 14 ], [ 285, 455, 64, 14 ], [ 352, 455, 54, 14 ], [ 410, 455, 35, 14 ], [ 449, 455, 65, 14 ], [ 517, 455, 37, 14 ], [ 558, 455, 18, 14 ], [ 580, 455, 41, 14 ], [ 625, 455, 54, 14 ], [ 682, 455, 20, 14 ], [ 706, 455, 39, 14 ], [ 749, 455, 64, 14 ], [ 152, 469, 78, 17 ], [ 234, 472, 12, 14 ], [ 250, 472, 60, 14 ], [ 314, 472, 48, 14 ], [ 365, 472, 23, 14 ], [ 392, 472, 54, 14 ], [ 450, 472, 74, 14 ], [ 527, 472, 58, 14 ], [ 589, 472, 12, 14 ], [ 604, 472, 39, 14 ], [ 647, 472, 51, 14 ], [ 702, 472, 16, 14 ], [ 721, 472, 56, 14 ], [ 781, 472, 14, 14 ], [ 799, 472, 16, 14 ], [ 152, 489, 41, 14 ], [ 197, 489, 7, 14 ], [ 207, 489, 20, 14 ], [ 231, 489, 52, 14 ], [ 287, 489, 35, 14 ], [ 326, 489, 23, 14 ], [ 353, 486, 78, 17 ], [ 434, 489, 12, 14 ], [ 450, 489, 60, 14 ], [ 514, 489, 72, 14 ], [ 589, 489, 23, 14 ], [ 616, 489, 59, 14 ], [ 679, 489, 56, 14 ], [ 738, 489, 66, 14 ], [ 152, 505, 62, 14 ], [ 218, 505, 16, 14 ], [ 238, 505, 64, 14 ], [ 306, 505, 51, 14 ], [ 360, 505, 32, 14 ], [ 396, 505, 35, 14 ], [ 435, 505, 15, 14 ], [ 453, 505, 39, 14 ], [ 496, 505, 56, 14 ], [ 556, 505, 71, 14 ], [ 630, 505, 34, 14 ], [ 152, 525, 47, 12 ], [ 202, 525, 31, 12 ], [ 236, 525, 44, 12 ], [ 284, 525, 23, 12 ], [ 152, 567, 60, 12 ], [ 152, 584, 54, 12 ], [ 220, 584, 16, 12 ], [ 242, 584, 38, 12 ], [ 286, 584, 16, 12 ], [ 308, 584, 19, 12 ], [ 332, 584, 36, 12 ], [ 374, 584, 77, 12 ], [ 457, 584, 10, 12 ], [ 473, 584, 16, 12 ], [ 152, 599, 42, 11 ], [ 200, 599, 94, 11 ], [ 299, 599, 40, 11 ], [ 343, 599, 35, 11 ], [ 383, 599, 16, 11 ], [ 404, 599, 56, 11 ], [ 465, 599, 6, 11 ], [ 476, 599, 13, 11 ], [ 152, 614, 16, 12 ], [ 173, 614, 41, 12 ], [ 218, 614, 33, 12 ], [ 256, 614, 30, 12 ], [ 290, 614, 27, 12 ], [ 322, 614, 19, 12 ], [ 345, 614, 27, 12 ], [ 377, 614, 20, 12 ], [ 400, 614, 16, 12 ], [ 421, 614, 68, 12 ], [ 152, 629, 51, 12 ], [ 207, 629, 9, 12 ], [ 219, 629, 55, 12 ], [ 276, 629, 45, 12 ], [ 325, 629, 16, 12 ], [ 344, 629, 21, 12 ], [ 369, 629, 46, 12 ], [ 418, 629, 20, 12 ], [ 441, 629, 14, 12 ], [ 458, 629, 6, 12 ], [ 468, 629, 21, 12 ], [ 152, 645, 31, 12 ], [ 187, 645, 21, 12 ], [ 212, 645, 48, 12 ], [ 263, 645, 30, 12 ], [ 298, 645, 23, 12 ], [ 324, 645, 56, 12 ], [ 385, 645, 16, 12 ], [ 404, 645, 28, 12 ], [ 436, 645, 43, 12 ], [ 483, 645, 6, 12 ], [ 152, 660, 68, 12 ], [ 223, 660, 52, 12 ], [ 278, 660, 10, 12 ], [ 291, 660, 44, 12 ], [ 337, 660, 62, 12 ], [ 152, 675, 60, 11 ], [ 218, 675, 42, 11 ], [ 264, 675, 8, 11 ], [ 276, 675, 6, 11 ], [ 286, 675, 43, 11 ], [ 332, 675, 25, 11 ], [ 361, 675, 34, 11 ], [ 399, 675, 43, 11 ], [ 445, 675, 44, 11 ], [ 152, 690, 23, 12 ], [ 178, 690, 192, 12 ], [ 152, 705, 46, 11 ], [ 203, 705, 126, 12 ], [ 152, 729, 46, 12 ], [ 201, 729, 13, 12 ], [ 217, 729, 32, 12 ], [ 251, 729, 16, 12 ], [ 269, 729, 28, 12 ], [ 300, 729, 36, 12 ], [ 338, 729, 13, 12 ], [ 354, 729, 22, 12 ], [ 378, 729, 16, 12 ], [ 396, 729, 28, 12 ], [ 427, 729, 47, 12 ], [ 476, 729, 13, 12 ], [ 152, 744, 25, 11 ], [ 180, 744, 10, 11 ], [ 192, 744, 25, 11 ], [ 152, 788, 8, 14 ], [ 174, 788, 108, 14 ], [ 152, 808, 45, 13 ], [ 201, 808, 20, 13 ], [ 224, 808, 16, 13 ], [ 243, 808, 20, 13 ], [ 267, 808, 41, 13 ], [ 312, 808, 45, 13 ], [ 361, 808, 12, 13 ], [ 377, 808, 79, 13 ], [ 459, 808, 11, 13 ], [ 473, 808, 16, 13 ], [ 152, 824, 91, 13 ], [ 245, 824, 58, 13 ], [ 305, 824, 50, 13 ], [ 356, 824, 49, 13 ], [ 407, 824, 19, 13 ], [ 428, 824, 43, 13 ], [ 473, 824, 16, 13 ], [ 152, 839, 30, 13 ], [ 185, 839, 19, 13 ], [ 206, 839, 55, 13 ], [ 263, 839, 33, 13 ], [ 298, 839, 31, 13 ], [ 331, 839, 16, 13 ], [ 350, 839, 17, 13 ], [ 369, 839, 11, 13 ], [ 382, 839, 59, 13 ], [ 444, 839, 9, 13 ], [ 455, 839, 34, 13 ], [ 152, 854, 55, 13 ], [ 212, 854, 11, 13 ], [ 228, 854, 12, 13 ], [ 245, 854, 49, 13 ], [ 299, 854, 65, 13 ], [ 369, 854, 10, 13 ], [ 384, 854, 16, 13 ], [ 404, 854, 23, 13 ], [ 431, 854, 11, 13 ], [ 447, 854, 42, 13 ], [ 152, 869, 46, 13 ], [ 200, 869, 54, 13 ], [ 256, 869, 19, 13 ], [ 276, 869, 67, 13 ], [ 345, 869, 32, 13 ], [ 379, 869, 9, 13 ], [ 390, 869, 6, 13 ], [ 398, 869, 24, 13 ], [ 424, 869, 66, 13 ], [ 152, 885, 29, 13 ], [ 188, 885, 43, 13 ], [ 236, 885, 24, 13 ], [ 267, 885, 47, 13 ], [ 320, 885, 25, 13 ], [ 351, 885, 19, 13 ], [ 376, 885, 42, 13 ], [ 424, 885, 65, 13 ], [ 152, 900, 62, 13 ], [ 217, 900, 10, 13 ], [ 229, 900, 16, 13 ], [ 247, 900, 39, 13 ], [ 287, 900, 11, 13 ], [ 300, 900, 51, 13 ], [ 353, 900, 28, 13 ], [ 383, 900, 53, 13 ], [ 438, 900, 23, 13 ], [ 463, 900, 26, 13 ], [ 152, 915, 24, 13 ], [ 179, 915, 9, 13 ], [ 190, 915, 65, 13 ], [ 257, 915, 23, 13 ], [ 282, 915, 16, 13 ], [ 300, 915, 20, 13 ], [ 322, 915, 11, 13 ], [ 335, 915, 16, 13 ], [ 353, 915, 40, 13 ], [ 395, 915, 28, 13 ], [ 425, 915, 49, 13 ], [ 476, 915, 13, 13 ], [ 152, 930, 22, 13 ], [ 178, 930, 53, 13 ], [ 235, 930, 57, 13 ], [ 295, 930, 66, 13 ], [ 366, 930, 46, 13 ], [ 416, 930, 45, 13 ], [ 465, 930, 24, 13 ], [ 152, 945, 24, 13 ], [ 181, 945, 46, 13 ], [ 232, 945, 21, 13 ], [ 257, 945, 10, 13 ], [ 272, 945, 16, 13 ], [ 293, 945, 30, 13 ], [ 327, 945, 19, 13 ], [ 351, 945, 20, 13 ], [ 375, 945, 13, 13 ], [ 393, 945, 6, 13 ], [ 404, 945, 70, 13 ], [ 478, 945, 11, 13 ], [ 152, 961, 16, 13 ], [ 172, 961, 54, 13 ], [ 231, 961, 16, 13 ], [ 251, 961, 13, 13 ], [ 268, 961, 28, 13 ], [ 300, 961, 19, 13 ], [ 323, 961, 16, 13 ], [ 343, 961, 24, 13 ], [ 371, 961, 42, 13 ], [ 418, 961, 10, 13 ], [ 432, 961, 57, 13 ], [ 152, 976, 52, 13 ], [ 207, 976, 59, 13 ], [ 268, 976, 29, 13 ], [ 300, 976, 49, 13 ], [ 351, 976, 19, 13 ], [ 372, 976, 34, 13 ], [ 409, 976, 25, 13 ], [ 436, 976, 16, 13 ], [ 455, 976, 34, 13 ], [ 152, 991, 45, 13 ], [ 201, 991, 52, 13 ], [ 256, 991, 33, 13 ], [ 291, 991, 13, 13 ], [ 307, 991, 17, 13 ], [ 327, 991, 55, 13 ], [ 385, 991, 19, 13 ], [ 406, 991, 30, 13 ], [ 439, 991, 9, 13 ], [ 451, 991, 16, 13 ], [ 469, 991, 20, 13 ], [ 152, 1006, 18, 13 ], [ 174, 1006, 52, 13 ], [ 230, 1006, 6, 13 ], [ 240, 1006, 72, 13 ], [ 315, 1006, 11, 13 ], [ 329, 1006, 13, 13 ], [ 346, 1006, 25, 13 ], [ 375, 1006, 48, 13 ], [ 426, 1006, 63, 13 ], [ 152, 1021, 29, 13 ], [ 183, 1021, 58, 13 ], [ 243, 1021, 20, 13 ], [ 264, 1021, 21, 13 ], [ 287, 1021, 79, 13 ], [ 368, 1021, 9, 13 ], [ 378, 1021, 45, 13 ], [ 426, 1021, 25, 13 ], [ 452, 1021, 37, 13 ], [ 152, 1037, 22, 13 ], [ 178, 1037, 18, 13 ], [ 200, 1037, 32, 13 ], [ 235, 1037, 11, 13 ], [ 249, 1037, 48, 13 ], [ 300, 1037, 11, 13 ], [ 314, 1037, 43, 13 ], [ 360, 1037, 12, 13 ], [ 376, 1037, 29, 13 ], [ 408, 1037, 9, 13 ], [ 420, 1037, 56, 13 ], [ 479, 1037, 10, 13 ], [ 152, 1052, 16, 13 ], [ 172, 1052, 24, 13 ], [ 201, 1052, 23, 13 ], [ 227, 1052, 16, 13 ], [ 247, 1052, 41, 13 ], [ 293, 1052, 68, 13 ], [ 366, 1052, 19, 13 ], [ 388, 1052, 48, 13 ], [ 440, 1052, 49, 13 ], [ 152, 1067, 10, 13 ], [ 169, 1067, 38, 13 ], [ 212, 1067, 28, 13 ], [ 247, 1067, 49, 13 ], [ 301, 1067, 52, 13 ], [ 360, 1067, 53, 13 ], [ 419, 1067, 16, 13 ], [ 441, 1067, 49, 13 ], [ 152, 1082, 20, 13 ], [ 175, 1082, 50, 13 ], [ 229, 1082, 43, 13 ], [ 275, 1082, 13, 13 ], [ 292, 1082, 33, 13 ], [ 328, 1082, 11, 13 ], [ 342, 1082, 45, 13 ], [ 390, 1082, 15, 13 ], [ 409, 1082, 41, 13 ], [ 453, 1082, 36, 13 ], [ 152, 1098, 59, 13 ], [ 216, 1098, 10, 13 ], [ 230, 1098, 16, 13 ], [ 250, 1098, 30, 13 ], [ 284, 1098, 11, 13 ], [ 300, 1098, 27, 13 ], [ 330, 1098, 32, 13 ], [ 367, 1098, 10, 13 ], [ 380, 1098, 16, 13 ], [ 401, 1098, 30, 13 ], [ 435, 1098, 54, 13 ], [ 152, 1113, 8, 13 ], [ 165, 1113, 22, 13 ], [ 192, 1113, 13, 13 ], [ 210, 1113, 13, 13 ], [ 228, 1113, 16, 13 ], [ 248, 1113, 48, 13 ], [ 301, 1113, 31, 13 ], [ 337, 1113, 16, 13 ], [ 357, 1113, 43, 13 ], [ 405, 1113, 45, 13 ], [ 454, 1113, 18, 13 ], [ 477, 1113, 12, 13 ], [ 152, 1128, 47, 13 ], [ 202, 1128, 19, 13 ], [ 224, 1128, 43, 13 ], [ 269, 1128, 55, 13 ], [ 327, 1128, 51, 13 ], [ 381, 1128, 33, 13 ], [ 417, 1128, 35, 13 ], [ 455, 1128, 25, 13 ], [ 152, 1165, 17, 12 ], [ 172, 1165, 28, 12 ], [ 203, 1165, 70, 12 ], [ 275, 1165, 30, 12 ], [ 308, 1165, 11, 12 ], [ 321, 1165, 47, 12 ], [ 526, 566, 17, 13 ], [ 550, 566, 68, 13 ], [ 625, 566, 18, 13 ], [ 650, 566, 21, 13 ], [ 679, 566, 79, 13 ], [ 765, 566, 13, 13 ], [ 785, 566, 16, 13 ], [ 808, 566, 43, 13 ], [ 514, 581, 34, 13 ], [ 553, 581, 31, 13 ], [ 589, 581, 31, 13 ], [ 625, 581, 10, 13 ], [ 640, 581, 27, 13 ], [ 672, 581, 10, 13 ], [ 687, 581, 42, 13 ], [ 734, 581, 12, 13 ], [ 752, 581, 49, 13 ], [ 806, 581, 19, 13 ], [ 830, 581, 21, 13 ], [ 514, 597, 42, 13 ], [ 560, 597, 16, 13 ], [ 580, 597, 21, 13 ], [ 604, 597, 52, 13 ], [ 660, 597, 23, 13 ], [ 687, 597, 39, 13 ], [ 731, 597, 18, 13 ], [ 753, 597, 22, 13 ], [ 779, 597, 11, 13 ], [ 795, 597, 56, 13 ], [ 514, 612, 13, 13 ], [ 534, 612, 6, 13 ], [ 547, 612, 98, 13 ], [ 653, 612, 31, 13 ], [ 692, 612, 63, 13 ], [ 762, 612, 9, 13 ], [ 778, 612, 49, 13 ], [ 835, 612, 16, 13 ], [ 514, 627, 57, 13 ], [ 576, 627, 23, 13 ], [ 604, 627, 12, 13 ], [ 622, 627, 61, 13 ], [ 689, 627, 39, 13 ], [ 733, 627, 53, 13 ], [ 791, 627, 10, 13 ], [ 807, 627, 43, 13 ], [ 514, 642, 72, 13 ], [ 591, 642, 51, 13 ], [ 648, 642, 8, 13 ], [ 662, 642, 9, 13 ], [ 676, 642, 45, 13 ], [ 728, 642, 50, 13 ], [ 783, 642, 12, 13 ], [ 801, 642, 49, 13 ], [ 514, 657, 43, 13 ], [ 560, 657, 10, 13 ], [ 574, 657, 50, 13 ], [ 628, 657, 16, 13 ], [ 647, 657, 38, 13 ], [ 689, 657, 20, 13 ], [ 713, 657, 11, 13 ], [ 727, 657, 26, 13 ], [ 757, 657, 21, 13 ], [ 782, 657, 68, 13 ], [ 514, 673, 27, 13 ], [ 544, 673, 54, 13 ], [ 601, 673, 25, 13 ], [ 629, 673, 23, 13 ], [ 655, 673, 26, 13 ], [ 684, 673, 52, 13 ], [ 738, 673, 75, 13 ], [ 514, 718, 8, 14 ], [ 535, 718, 62, 14 ], [ 514, 738, 65, 12 ], [ 596, 738, 8, 12 ], [ 622, 738, 45, 12 ], [ 685, 738, 20, 12 ], [ 724, 738, 14, 12 ], [ 756, 738, 17, 12 ], [ 791, 738, 59, 11 ], [ 514, 752, 121, 12 ], [ 641, 752, 28, 12 ], [ 674, 752, 14, 12 ], [ 694, 752, 17, 12 ], [ 718, 752, 25, 12 ], [ 748, 752, 8, 12 ], [ 762, 752, 45, 12 ], [ 814, 752, 12, 12 ], [ 831, 752, 19, 12 ], [ 514, 766, 38, 11 ], [ 556, 766, 46, 11 ], [ 606, 766, 21, 11 ], [ 631, 766, 49, 11 ], [ 684, 766, 5, 11 ], [ 693, 766, 34, 11 ], [ 732, 766, 45, 11 ], [ 780, 766, 21, 11 ], [ 805, 766, 27, 11 ], [ 836, 766, 14, 11 ], [ 514, 780, 46, 12 ], [ 566, 780, 39, 12 ], [ 610, 780, 43, 12 ], [ 659, 780, 22, 12 ], [ 687, 780, 30, 12 ], [ 723, 780, 59, 12 ], [ 788, 780, 26, 12 ], [ 820, 780, 30, 12 ], [ 514, 794, 48, 12 ], [ 564, 794, 21, 12 ], [ 589, 794, 51, 12 ], [ 643, 794, 48, 12 ], [ 694, 794, 65, 12 ], [ 761, 794, 16, 12 ], [ 780, 794, 11, 12 ], [ 794, 794, 40, 12 ], [ 837, 794, 13, 12 ], [ 514, 808, 20, 11 ], [ 536, 808, 74, 11 ], [ 613, 808, 10, 11 ], [ 625, 808, 51, 11 ], [ 679, 808, 20, 11 ], [ 701, 808, 84, 11 ], [ 526, 821, 13, 12 ], [ 541, 821, 41, 12 ], [ 584, 821, 43, 12 ], [ 629, 821, 10, 12 ], [ 640, 821, 40, 12 ], [ 682, 821, 22, 12 ], [ 707, 821, 42, 12 ], [ 751, 821, 29, 12 ], [ 783, 821, 48, 12 ], [ 833, 821, 18, 12 ], [ 514, 835, 30, 12 ], [ 545, 835, 16, 12 ], [ 563, 835, 50, 12 ], [ 615, 835, 41, 12 ], [ 658, 835, 16, 12 ], [ 675, 835, 52, 12 ], [ 729, 835, 33, 12 ], [ 764, 835, 42, 12 ], [ 807, 835, 43, 12 ], [ 514, 849, 14, 12 ], [ 531, 849, 61, 12 ], [ 595, 849, 46, 12 ], [ 645, 849, 20, 12 ], [ 668, 849, 62, 12 ], [ 734, 849, 48, 12 ], [ 785, 849, 46, 12 ], [ 835, 849, 16, 12 ], [ 514, 863, 26, 12 ], [ 543, 863, 11, 12 ], [ 558, 863, 42, 12 ], [ 604, 863, 12, 12 ], [ 619, 863, 35, 12 ], [ 658, 863, 5, 12 ], [ 667, 863, 36, 12 ], [ 707, 863, 32, 12 ], [ 742, 863, 11, 12 ], [ 757, 863, 51, 12 ], [ 812, 863, 39, 12 ], [ 514, 877, 10, 11 ], [ 527, 877, 42, 11 ], [ 573, 877, 12, 11 ], [ 588, 877, 42, 11 ], [ 634, 877, 18, 11 ], [ 655, 877, 24, 11 ], [ 683, 877, 45, 11 ], [ 732, 877, 39, 11 ], [ 775, 877, 52, 11 ], [ 830, 877, 20, 11 ], [ 514, 890, 30, 12 ], [ 549, 890, 36, 12 ], [ 590, 890, 34, 12 ], [ 629, 890, 12, 12 ], [ 646, 890, 14, 12 ], [ 665, 890, 14, 12 ], [ 684, 890, 10, 12 ], [ 699, 890, 19, 12 ], [ 723, 890, 40, 12 ], [ 768, 890, 45, 12 ], [ 818, 890, 16, 12 ], [ 839, 890, 11, 12 ], [ 514, 904, 72, 12 ], [ 590, 904, 40, 12 ], [ 635, 904, 16, 12 ], [ 656, 904, 48, 12 ], [ 709, 904, 5, 12 ], [ 719, 904, 31, 12 ], [ 755, 904, 16, 12 ], [ 775, 904, 27, 12 ], [ 807, 904, 25, 12 ], [ 837, 904, 13, 12 ], [ 514, 918, 67, 11 ], [ 526, 932, 13, 12 ], [ 547, 932, 34, 12 ], [ 588, 932, 59, 12 ], [ 654, 932, 34, 12 ], [ 694, 932, 56, 12 ], [ 757, 932, 38, 12 ], [ 802, 932, 48, 12 ], [ 514, 946, 38, 12 ], [ 554, 946, 13, 12 ], [ 570, 946, 41, 12 ], [ 614, 946, 49, 12 ], [ 666, 946, 25, 12 ], [ 693, 946, 24, 12 ], [ 720, 946, 51, 12 ], [ 773, 946, 36, 12 ], [ 815, 946, 35, 12 ], [ 514, 960, 20, 12 ], [ 539, 960, 10, 12 ], [ 554, 960, 40, 12 ], [ 599, 960, 16, 12 ], [ 620, 960, 15, 12 ], [ 641, 960, 11, 12 ], [ 658, 960, 36, 12 ], [ 699, 960, 41, 12 ], [ 746, 960, 16, 12 ], [ 767, 960, 39, 12 ], [ 812, 960, 38, 12 ], [ 514, 974, 65, 12 ], [ 580, 974, 8, 12 ], [ 590, 974, 40, 12 ], [ 632, 974, 12, 12 ], [ 646, 974, 40, 12 ], [ 689, 974, 14, 12 ], [ 705, 974, 45, 12 ], [ 752, 974, 23, 12 ], [ 777, 974, 18, 12 ], [ 796, 974, 6, 12 ], [ 804, 974, 34, 12 ], [ 841, 974, 10, 12 ], [ 514, 987, 45, 11 ], [ 562, 987, 19, 11 ], [ 585, 987, 25, 11 ], [ 612, 987, 9, 11 ], [ 625, 987, 14, 11 ], [ 642, 987, 34, 11 ], [ 680, 987, 10, 11 ], [ 693, 987, 40, 11 ], [ 737, 987, 50, 11 ], [ 790, 987, 20, 11 ], [ 813, 987, 14, 11 ], [ 831, 987, 20, 11 ], [ 514, 1001, 44, 12 ], [ 561, 1001, 70, 12 ], [ 634, 1001, 16, 12 ], [ 653, 1001, 21, 12 ], [ 677, 1001, 29, 12 ], [ 709, 1001, 34, 12 ], [ 746, 1001, 18, 12 ], [ 767, 1001, 5, 12 ], [ 775, 1001, 27, 12 ], [ 806, 1001, 30, 12 ], [ 839, 1001, 12, 12 ], [ 514, 1015, 14, 12 ], [ 530, 1015, 30, 12 ], [ 563, 1015, 36, 12 ], [ 526, 1029, 13, 11 ], [ 546, 1029, 34, 11 ], [ 587, 1029, 45, 11 ], [ 638, 1029, 18, 11 ], [ 663, 1029, 30, 11 ], [ 700, 1029, 43, 11 ], [ 749, 1029, 34, 11 ], [ 790, 1029, 45, 11 ], [ 841, 1029, 9, 11 ], [ 514, 1043, 44, 12 ], [ 561, 1043, 18, 12 ], [ 583, 1043, 8, 12 ], [ 595, 1043, 15, 12 ], [ 613, 1043, 30, 12 ], [ 647, 1043, 38, 12 ], [ 689, 1043, 59, 12 ], [ 751, 1043, 14, 12 ], [ 769, 1043, 24, 12 ], [ 796, 1043, 13, 12 ], [ 814, 1043, 37, 12 ], [ 514, 1057, 25, 12 ], [ 542, 1057, 33, 12 ], [ 577, 1057, 20, 12 ], [ 600, 1057, 20, 12 ], [ 623, 1057, 42, 12 ], [ 668, 1057, 8, 12 ], [ 679, 1057, 40, 12 ], [ 722, 1057, 12, 12 ], [ 737, 1057, 52, 12 ], [ 792, 1057, 9, 12 ], [ 804, 1057, 18, 12 ], [ 825, 1057, 25, 12 ], [ 514, 1070, 18, 12 ], [ 534, 1070, 10, 12 ], [ 546, 1070, 45, 12 ], [ 594, 1070, 16, 12 ], [ 614, 1070, 58, 12 ], [ 675, 1070, 39, 12 ], [ 716, 1070, 14, 12 ], [ 733, 1070, 32, 12 ], [ 768, 1070, 7, 12 ], [ 778, 1070, 16, 12 ], [ 796, 1070, 40, 12 ], [ 839, 1070, 11, 12 ], [ 514, 1084, 52, 12 ], [ 568, 1084, 25, 12 ], [ 595, 1084, 14, 12 ], [ 612, 1084, 30, 12 ], [ 644, 1084, 56, 12 ], [ 703, 1084, 38, 12 ], [ 526, 1098, 13, 11 ], [ 545, 1098, 52, 12 ], [ 602, 1098, 48, 12 ], [ 655, 1098, 18, 11 ], [ 677, 1098, 51, 11 ], [ 734, 1098, 45, 11 ], [ 784, 1098, 23, 11 ], [ 812, 1098, 38, 11 ], [ 514, 1112, 37, 12 ], [ 555, 1112, 45, 12 ], [ 605, 1112, 13, 12 ], [ 624, 1112, 37, 12 ], [ 666, 1112, 17, 12 ], [ 688, 1112, 12, 12 ], [ 704, 1112, 20, 12 ], [ 729, 1112, 25, 12 ], [ 759, 1112, 44, 12 ], [ 808, 1112, 14, 12 ], [ 826, 1112, 24, 12 ], [ 514, 1126, 41, 12 ], [ 559, 1126, 11, 12 ], [ 574, 1126, 5, 12 ], [ 584, 1126, 29, 12 ], [ 616, 1126, 25, 12 ], [ 645, 1126, 20, 12 ], [ 669, 1126, 10, 12 ], [ 683, 1126, 38, 12 ], [ 725, 1126, 26, 12 ], [ 755, 1126, 22, 12 ], [ 781, 1126, 17, 12 ], [ 802, 1126, 9, 12 ], [ 815, 1126, 15, 12 ], [ 834, 1126, 16, 12 ], [ 514, 1140, 20, 11 ], [ 537, 1140, 39, 11 ], [ 580, 1140, 61, 11 ], [ 644, 1140, 55, 11 ], [ 703, 1140, 16, 11 ], [ 723, 1140, 39, 11 ], [ 766, 1140, 26, 11 ], [ 797, 1140, 9, 11 ], [ 810, 1140, 23, 11 ], [ 836, 1140, 14, 11 ], [ 514, 1153, 17, 12 ], [ 535, 1153, 23, 12 ], [ 561, 1153, 82, 12 ], [ 647, 1153, 46, 12 ], [ 697, 1153, 20, 12 ], [ 721, 1153, 21, 12 ], [ 745, 1153, 25, 12 ], [ 774, 1153, 64, 12 ], [ 842, 1153, 8, 12 ], [ 514, 1167, 40, 12 ], [ 557, 1167, 11, 12 ], [ 571, 1167, 45, 12 ], [ 620, 1167, 48, 12 ], [ 671, 1167, 12, 12 ], [ 685, 1167, 14, 12 ], [ 703, 1167, 55, 12 ], [ 760, 1167, 29, 12 ], [ 793, 1167, 20, 12 ], [ 816, 1167, 34, 12 ], [ 152, 1214, 8, 10 ], [ 163, 1214, 17, 10 ], [ 183, 1214, 39, 10 ], [ 225, 1214, 25, 10 ], [ 253, 1214, 43, 10 ], [ 300, 1214, 11, 10 ], [ 313, 1214, 30, 10 ], [ 346, 1214, 43, 10 ], [ 392, 1214, 27, 10 ], [ 152, 1226, 18, 10 ], [ 173, 1226, 8, 10 ], [ 184, 1226, 11, 10 ], [ 197, 1226, 24, 10 ], [ 224, 1226, 32, 10 ], [ 259, 1226, 27, 10 ], [ 288, 1226, 47, 10 ], [ 337, 1226, 25, 10 ], [ 365, 1226, 14, 10 ], [ 382, 1226, 25, 10 ], [ 410, 1226, 9, 10 ], [ 421, 1226, 14, 10 ], [ 438, 1226, 36, 10 ], [ 476, 1226, 45, 10 ], [ 524, 1226, 46, 10 ], [ 573, 1226, 74, 10 ], [ 649, 1226, 34, 10 ], [ 686, 1226, 165, 10 ], [ 152, 1238, 47, 10 ], [ 203, 1238, 26, 10 ], [ 231, 1238, 33, 10 ], [ 267, 1238, 52, 10 ], [ 322, 1238, 71, 10 ], [ 395, 1238, 19, 10 ], [ 417, 1238, 52, 10 ], [ 471, 1238, 17, 10 ], [ 491, 1238, 56, 10 ], [ 549, 1238, 8, 10 ], [ 560, 1238, 16, 10 ], [ 579, 1238, 38, 10 ], [ 620, 1238, 38, 10 ], [ 661, 1238, 14, 10 ], [ 678, 1238, 32, 10 ], [ 712, 1238, 22, 10 ], [ 737, 1238, 7, 10 ], [ 747, 1238, 36, 10 ], [ 786, 1238, 25, 10 ], [ 78, 1304, 24, 9 ], [ 106, 1304, 37, 9 ], [ 147, 1304, 96, 9 ], [ 813, 1304, 22, 9 ], [ 837, 1304, 19, 9 ], [ 863, 1304, 42, 9 ] ]

[ "BIOINFORMATICS", "APPLICATIONS", "NOTE", "Vol.", "26", "no.", "15", "2010,", "pages", "1903–1904", "doi:10.1093/bioinformatics/btq304", "Sequence", "analysis", "Cloud-Coffee:", "implementation", "of", "a", "parallel", "consistency-based", "multiple", "alignment", "algorithm", "in", "the", "T-Coffee", "package", "and", "its", "benchmarking", "on", "the", "Amazon", "Elastic-Cloud", "1", "2", "2", "2", "Paolo", "Di", "Tommaso", ",", "Miquel", "Orobitg", ",", "Fernando", "Guirado", ",", "Fernado", "Cores", ",", "Toni", "Espinosa3", "and", "Cedric", "Notredame1,∗", "1Centre", "For", "Genomic", "Regulation", "(Pompeu", "Fabra", "University),", "Carrer", "del", "Doctor", "Aiguader", "88,", "08003", "Barcelona,", "2Department", "of", "Computer", "Science", "and", "Industrial", "Engineering,", "University", "of", "Lleida,", "Campus", "de", "Cappont,", "C.", "de", "Jaume", "II", "69,", "E-25001", "Lleida", "and", "3Department", "of", "Computer", "Architecture", "and", "Operating", "Systems,", "Universitad", "Autonoma", "de", "Barcelona,", "Campus", "UAB,", "Edifici", "Q,", "08193", "Bellaterra", "(Barcelona),", "Spain", "Associate", "Editor:", "Burkhard", "Rost", "ABSTRACT", "Summary:", "We", "present", "the", "first", "parallel", "implementation", "of", "the", "T-Coffee", "consistency-based", "multiple", "aligner.", "We", "benchmark", "it", "on", "the", "Amazon", "Elastic", "Cloud", "(EC2)", "and", "show", "that", "the", "parallelization", "procedure", "is", "reasonably", "effective.", "We", "also", "conclude", "that", "for", "a", "web", "server", "with", "moderate", "usage", "(10K", "hits/month)", "the", "cloud", "provides", "a", "cost-effective", "alternative", "to", "in-house", "deployment.", "Availability:", "T-Coffee", "is", "a", "freeware", "open", "source", "package", "available", "from", "http://www.tcoffee.org/homepage.html", "Contact:", "cedric.notredame@crg.es", "Received", "on", "March", "30,", "2010;", "revised", "on", "May", "18,", "2010;", "accepted", "on", "June", "2,", "2010", "1", "INTRODUCTION", "T-Coffee", "was", "the", "first", "package", "featuring", "an", "implementation", "of", "the", "consistency-based", "progressive", "alignment", "algorithm", "(for", "Reviews", "see", "Edgar", "and", "Batzoglou,", "2006).", "While", "the", "use", "of", "consistency", "is", "widely", "recognized", "as", "an", "important", "development", "in", "the", "field", "of", "multiple", "sequence", "alignment,", "this", "improvement", "comes", "at", "a", "cost.", "Consistency-", "based", "methods", "have", "increased", "CPU", "and", "memory", "consumption", "proportional", "to", "the", "number", "of", "sequences", "being", "processed.", "This", "over-", "head", "is", "incompatible", "with", "the", "size", "of", "the", "datasets", "being", "generated", "by", "next", "generation", "sequencing", "technologies.", "Heuristic", "solutions", "have", "been", "proposed", "(Pei", "et", "al.,", "2003)", "that", "rely", "on", "a", "pre-clustering", "of", "the", "sequences,", "but", "no", "effort", "had", "yet", "been", "reported", "to", "extensively", "parallelize", "consistency", "based", "algorithm", "and", "benefit", "from", "the", "widely", "available", "multi-core", "CPUs.", "To", "our", "knowledge", "this", "report", "is", "the", "first", "one", "describing", "a", "parallelization", "of", "all", "steps", "involving", "consistency-", "based", "alignments.", "The", "new", "implementation", "is", "available", "from", "version", "8.00", "and", "higher", "of", "T-Coffee.", "In", "practice,", "its", "usage", "is", "transparent", "to", "the", "user,", "with", "the", "package", "automatically", "and", "explicitly", "switching", "to", "parallel", "mode", "whenever", "multi-core", "processors", "are", "available.", "The", "procedure", "supports", "all", "modes", "of", "T-Coffee", "for", "aligning", "protein", "(O’Sullivan", "et", "al.,", "2004)", "or", "RNA", "(Wilm", "et", "al.,", "2008)", "sequences.", "It", "runs", "on", "all", "the", "platforms", "where", "the", "standard", "T-Coffee", "can", "be", "compiled", "and", "installed", "(Windows,", "MacOSX,", "Linux,", "UNIX,", "etc.).", "∗To", "whom", "correspondence", "should", "be", "addressed.", "We", "benchmarked", "this", "new", "implementation", "on", "the", "Amazon", "Elastic", "Cloud", "(EC2)", "in", "order", "to", "estimate", "its", "efficiency", "and", "also", "measure", "the", "cost", "associated", "with", "running", "this", "type", "of", "application", "on", "a", "cloud-environment.", "Cloud", "computation", "is", "providing", "the", "community", "with", "an", "increasingly", "popular", "alternative", "to", "in-house", "computational", "resources.", "It", "is", "therefore", "becoming", "an", "important", "question", "to", "determine", "the", "relative", "cost", "of", "these", "new", "environments", "when", "comparing", "them", "with", "more", "traditional", "infrastructures.", "2", "METHOD", "Parallelization", "is", "controlled", "with", "the", "flag", "-multi_core=", "templates_jobs_relax_msa,", "where", "the", "flag", "value", "is", "composed", "by", "four", "different", "keywords,", "each", "controlling", "a", "specific", "alignment", "step.", "These", "are", "templates:", "template", "selection;", "jobs:", "library", "computation;", "relax:", "library", "relaxation;", "msa:", "progressive", "alignment.", "Parallelization", "can", "be", "switched", "off", "(e.g.", "-multi_core=no)", "or", "customized", "(e.g.", "-multi_core=jobs).", "(1)", "Template", "selection.", "In", "T-Coffee", "most", "advanced", "modes", "[R-Coffee,", "3D-", "Coffee", "and", "PSI-Coffee", "(Kemena", "and", "Notredame,", "2009)],", "structural", "templates", "are", "automatically", "associated", "with", "user-provided", "sequences.", "Templates", "can", "either", "be", "identified", "by", "running", "a", "BLAST", "against", "an", "appropriate", "database", "or", "produced", "by", "modeling", "(i.e.", "RNA", "secondary", "structure", "prediction).", "This", "simple", "process,", "iterated", "on", "the", "list", "of", "user", "provided", "sequences", "can", "be", "computationally", "intensive", "and", "constitutes", "a", "natural", "and", "trivial", "target", "for", "parallelization.", "(2)", "Library", "computation.", "Library", "computation", "involves", "computing", "pairwise", "(or", "multiple)", "alignments", "using", "some", "pre-defined", "method.", "Release", "8.00", "of", "T-Coffee", "can", "use", "21", "external", "sequence", "and", "structure", "aligners.", "Parallelization", "is", "achieved", "by", "grouping", "the", "alignment", "tasks", "into", "a", "number", "of", "individual", "jobs", "equal", "to", "the", "number", "of", "available", "processors.", "Jobs", "are", "then", "submitted", "simultaneously,", "and", "their", "output", "merged", "into", "a", "single", "library", "by", "the", "master", "process.", "(3)", "Library", "extension.", "The", "library", "extension", "[named", "relaxation", "in", "ProbCons", "(Do", "et", "al.,", "2005)]", "involves", "re-evaluating", "the", "score", "for", "aligning", "every", "residue", "pair.", "This", "operation", "is", "achieved", "by", "considering", "in", "turn", "every", "pair", "of", "sequences", "and", "subsequently", "updating", "the", "library.", "It", "can", "therefore", "be", "parallelized", "using", "the", "library", "computation", "strategy.", "(4)", "Progressive", "alignment.", "The", "progressive", "alignment", "stage", "involves", "aligning", "sequences", "(or", "profiles)", "two", "by", "two,", "while", "following", "the", "order", "indicated", "by", "a", "binary", "guide", "tree.", "In", "practice,", "going", "from", "leaf", "to", "tip,", "one", "uses", "dynamic", "programming", "(Needleman", "and", "Wunsch,", "1970)", "to", "align", "the", "two", "child", "sequences/profiles", "associated", "with", "each", "node.", "Parallelization", "is", "achieved", "by", "separately", "processing", "all", "the", "independent", "nodes,", "with", "optimal", "©", "The", "Author(s)", "2010.", "Published", "by", "Oxford", "University", "Press.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.5),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "[16:45", "30/6/2010", "Bioinformatics-btq304.tex]", "Page:", "1903", "1903–1904" ]

[ 0, 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 0, 0, 0, 0, 0, 0 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 60, 11 ], [ 132, 75, 39, 11 ], [ 173, 75, 40, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 62, 25 ], [ 136, 220, 86, 25 ], [ 227, 220, 112, 25 ], [ 344, 220, 98, 25 ], [ 446, 220, 24, 25 ], [ 475, 220, 99, 25 ], [ 120, 289, 40, 17 ], [ 162, 287, 91, 18 ], [ 257, 289, 60, 17 ], [ 320, 287, 80, 18 ], [ 404, 289, 27, 17 ], [ 434, 289, 40, 17 ], [ 477, 289, 43, 17 ], [ 522, 287, 56, 18 ], [ 120, 319, 4, 9 ], [ 126, 320, 35, 13 ], [ 163, 320, 9, 13 ], [ 175, 320, 72, 13 ], [ 249, 320, 59, 13 ], [ 311, 320, 9, 13 ], [ 323, 320, 38, 13 ], [ 364, 320, 81, 13 ], [ 447, 320, 38, 13 ], [ 487, 320, 43, 13 ], [ 532, 320, 44, 13 ], [ 126, 334, 50, 13 ], [ 179, 334, 9, 13 ], [ 190, 334, 40, 13 ], [ 233, 334, 19, 13 ], [ 255, 334, 37, 13 ], [ 294, 334, 37, 13 ], [ 333, 334, 30, 13 ], [ 365, 334, 44, 13 ], [ 411, 334, 22, 13 ], [ 120, 348, 4, 9 ], [ 126, 349, 38, 13 ], [ 166, 349, 43, 13 ], [ 212, 349, 44, 13 ], [ 259, 349, 42, 13 ], [ 303, 349, 37, 13 ], [ 342, 349, 30, 13 ], [ 374, 349, 44, 13 ], [ 420, 349, 22, 13 ], [ 120, 374, 83, 13 ], [ 205, 374, 35, 13 ], [ 241, 374, 12, 13 ], [ 256, 374, 49, 13 ], [ 308, 374, 11, 13 ], [ 321, 374, 28, 13 ], [ 351, 374, 30, 13 ], [ 384, 374, 38, 13 ], [ 425, 374, 102, 13 ], [ 120, 400, 44, 13 ], [ 166, 400, 6, 13 ], [ 175, 400, 33, 13 ], [ 210, 400, 27, 13 ], [ 240, 400, 46, 13 ], [ 288, 400, 6, 13 ], [ 297, 400, 22, 13 ], [ 322, 400, 24, 13 ], [ 120, 425, 49, 13 ], [ 172, 425, 35, 13 ], [ 209, 425, 47, 13 ], [ 258, 425, 13, 13 ], [ 274, 425, 44, 13 ], [ 120, 450, 51, 13 ], [ 174, 450, 9, 13 ], [ 186, 450, 24, 13 ], [ 213, 450, 27, 13 ], [ 242, 450, 58, 13 ], [ 302, 450, 10, 13 ], [ 314, 450, 12, 13 ], [ 331, 450, 22, 13 ], [ 358, 450, 8, 13 ], [ 370, 450, 13, 13 ], [ 387, 450, 26, 13 ], [ 417, 450, 30, 13 ], [ 451, 450, 31, 13 ], [ 487, 450, 55, 13 ], [ 547, 450, 30, 13 ], [ 582, 450, 16, 13 ], [ 602, 450, 41, 13 ], [ 648, 450, 53, 13 ], [ 705, 450, 58, 13 ], [ 120, 465, 40, 13 ], [ 163, 465, 31, 13 ], [ 197, 465, 39, 13 ], [ 239, 465, 61, 13 ], [ 303, 465, 20, 13 ], [ 326, 465, 63, 13 ], [ 393, 465, 19, 13 ], [ 415, 465, 66, 13 ], [ 485, 465, 11, 13 ], [ 499, 465, 18, 13 ], [ 520, 465, 46, 13 ], [ 569, 465, 45, 13 ], [ 617, 465, 16, 13 ], [ 637, 465, 39, 13 ], [ 680, 465, 26, 13 ], [ 709, 465, 8, 13 ], [ 720, 465, 43, 13 ], [ 120, 480, 27, 13 ], [ 120, 506, 30, 13 ], [ 153, 506, 72, 13 ], [ 228, 506, 32, 13 ], [ 262, 506, 23, 13 ], [ 288, 506, 10, 13 ], [ 302, 506, 68, 13 ], [ 372, 506, 48, 13 ], [ 424, 506, 42, 13 ], [ 468, 506, 41, 13 ], [ 512, 506, 37, 13 ], [ 552, 506, 21, 13 ], [ 576, 506, 19, 13 ], [ 598, 506, 51, 13 ], [ 652, 506, 58, 13 ], [ 714, 506, 49, 13 ], [ 120, 520, 49, 13 ], [ 172, 520, 23, 13 ], [ 197, 520, 24, 13 ], [ 224, 520, 17, 13 ], [ 244, 520, 56, 13 ], [ 303, 520, 10, 13 ], [ 316, 520, 16, 13 ], [ 335, 520, 83, 13 ], [ 421, 520, 50, 13 ], [ 473, 520, 11, 13 ], [ 486, 520, 22, 13 ], [ 511, 520, 6, 13 ], [ 520, 520, 44, 13 ], [ 567, 520, 11, 13 ], [ 581, 520, 16, 13 ], [ 600, 520, 17, 13 ], [ 620, 520, 18, 13 ], [ 640, 520, 28, 13 ], [ 671, 520, 16, 13 ], [ 690, 520, 38, 13 ], [ 730, 520, 14, 13 ], [ 747, 520, 16, 13 ], [ 120, 535, 60, 13 ], [ 183, 535, 11, 13 ], [ 197, 535, 17, 13 ], [ 217, 535, 51, 13 ], [ 271, 535, 23, 13 ], [ 297, 535, 25, 13 ], [ 326, 535, 59, 13 ], [ 388, 535, 11, 13 ], [ 402, 535, 41, 13 ], [ 446, 535, 17, 13 ], [ 466, 535, 24, 13 ], [ 493, 535, 54, 13 ], [ 550, 535, 20, 13 ], [ 574, 535, 20, 13 ], [ 596, 535, 10, 13 ], [ 610, 535, 37, 13 ], [ 650, 535, 29, 13 ], [ 682, 535, 8, 13 ], [ 693, 535, 11, 13 ], [ 707, 535, 43, 13 ], [ 753, 535, 10, 13 ], [ 120, 549, 23, 13 ], [ 146, 549, 19, 13 ], [ 167, 549, 10, 13 ], [ 180, 549, 20, 13 ], [ 203, 549, 44, 13 ], [ 249, 549, 14, 13 ], [ 265, 549, 16, 13 ], [ 284, 549, 61, 13 ], [ 347, 549, 42, 13 ], [ 391, 549, 40, 13 ], [ 433, 549, 51, 13 ], [ 486, 549, 19, 13 ], [ 508, 549, 25, 13 ], [ 536, 549, 62, 13 ], [ 600, 549, 16, 13 ], [ 619, 549, 20, 13 ], [ 641, 549, 36, 13 ], [ 679, 549, 33, 13 ], [ 714, 549, 11, 13 ], [ 727, 549, 36, 13 ], [ 120, 564, 25, 13 ], [ 150, 564, 19, 13 ], [ 173, 564, 67, 13 ], [ 243, 564, 37, 13 ], [ 285, 564, 16, 13 ], [ 305, 564, 31, 13 ], [ 340, 564, 11, 13 ], [ 355, 564, 39, 13 ], [ 398, 564, 29, 13 ], [ 431, 564, 10, 13 ], [ 445, 564, 23, 13 ], [ 472, 564, 14, 13 ], [ 490, 564, 53, 13 ], [ 547, 564, 22, 13 ], [ 572, 564, 19, 13 ], [ 596, 564, 56, 13 ], [ 656, 564, 19, 13 ], [ 679, 564, 46, 13 ], [ 729, 564, 14, 13 ], [ 747, 564, 16, 13 ], [ 120, 578, 51, 13 ], [ 174, 578, 10, 13 ], [ 186, 578, 43, 13 ], [ 231, 578, 31, 13 ], [ 265, 578, 11, 13 ], [ 278, 578, 33, 13 ], [ 313, 578, 16, 13 ], [ 331, 578, 19, 13 ], [ 352, 578, 37, 13 ], [ 391, 578, 14, 13 ], [ 407, 578, 16, 13 ], [ 425, 578, 19, 13 ], [ 446, 578, 11, 13 ], [ 459, 578, 25, 13 ], [ 487, 578, 44, 13 ], [ 533, 578, 19, 13 ], [ 554, 578, 11, 13 ], [ 567, 578, 44, 13 ], [ 613, 578, 48, 13 ], [ 663, 578, 39, 13 ], [ 704, 578, 59, 13 ], [ 120, 593, 44, 13 ], [ 167, 593, 41, 13 ], [ 211, 593, 6, 13 ], [ 219, 593, 50, 13 ], [ 272, 593, 27, 13 ], [ 302, 593, 14, 13 ], [ 319, 593, 16, 13 ], [ 338, 593, 28, 13 ], [ 369, 593, 10, 13 ], [ 382, 593, 23, 13 ], [ 407, 593, 15, 13 ], [ 425, 593, 40, 13 ], [ 468, 593, 36, 13 ], [ 506, 593, 55, 13 ], [ 564, 593, 51, 13 ], [ 618, 593, 35, 13 ], [ 655, 593, 23, 13 ], [ 681, 593, 68, 13 ], [ 752, 593, 10, 13 ], [ 120, 607, 25, 13 ], [ 148, 607, 44, 13 ], [ 194, 607, 25, 13 ], [ 222, 607, 39, 13 ], [ 263, 607, 19, 13 ], [ 285, 607, 36, 13 ], [ 323, 607, 44, 13 ], [ 369, 607, 24, 13 ], [ 396, 607, 16, 13 ], [ 414, 607, 36, 13 ], [ 452, 607, 11, 13 ], [ 465, 607, 60, 13 ], [ 528, 607, 19, 13 ], [ 549, 607, 40, 13 ], [ 592, 607, 27, 13 ], [ 622, 607, 44, 13 ], [ 70, 674, 13, 17 ], [ 86, 674, 92, 17 ], [ 70, 704, 48, 14 ], [ 126, 704, 44, 14 ], [ 178, 704, 21, 14 ], [ 207, 704, 15, 14 ], [ 229, 704, 21, 14 ], [ 258, 704, 35, 14 ], [ 301, 704, 27, 14 ], [ 336, 704, 51, 14 ], [ 395, 704, 9, 14 ], [ 70, 719, 56, 14 ], [ 131, 719, 25, 14 ], [ 161, 719, 6, 14 ], [ 172, 719, 58, 14 ], [ 234, 719, 55, 14 ], [ 293, 719, 12, 14 ], [ 310, 719, 45, 14 ], [ 360, 719, 12, 14 ], [ 376, 719, 28, 14 ], [ 70, 735, 62, 14 ], [ 136, 735, 56, 14 ], [ 197, 735, 14, 14 ], [ 215, 735, 38, 14 ], [ 258, 735, 45, 14 ], [ 308, 735, 26, 14 ], [ 338, 735, 41, 14 ], [ 383, 735, 21, 14 ], [ 70, 751, 29, 14 ], [ 104, 751, 57, 14 ], [ 166, 751, 9, 14 ], [ 180, 751, 22, 14 ], [ 207, 751, 62, 14 ], [ 274, 751, 19, 14 ], [ 298, 751, 8, 14 ], [ 311, 751, 33, 14 ], [ 350, 751, 12, 14 ], [ 366, 751, 13, 14 ], [ 385, 751, 20, 14 ], [ 70, 767, 59, 14 ], [ 135, 767, 12, 14 ], [ 153, 767, 51, 14 ], [ 211, 767, 26, 14 ], [ 243, 767, 58, 14 ], [ 308, 767, 21, 14 ], [ 335, 767, 69, 14 ], [ 70, 783, 61, 14 ], [ 135, 783, 12, 14 ], [ 150, 783, 28, 14 ], [ 182, 783, 49, 14 ], [ 235, 783, 75, 14 ], [ 314, 783, 23, 14 ], [ 340, 783, 26, 14 ], [ 370, 783, 34, 14 ], [ 70, 798, 9, 14 ], [ 85, 798, 18, 14 ], [ 109, 798, 34, 14 ], [ 149, 798, 30, 14 ], [ 185, 798, 12, 14 ], [ 203, 798, 18, 14 ], [ 226, 798, 45, 14 ], [ 277, 798, 28, 14 ], [ 311, 798, 49, 14 ], [ 366, 798, 38, 14 ], [ 70, 814, 49, 14 ], [ 123, 814, 34, 14 ], [ 162, 814, 9, 14 ], [ 175, 814, 48, 14 ], [ 228, 814, 14, 14 ], [ 246, 814, 6, 14 ], [ 257, 814, 55, 14 ], [ 317, 814, 45, 14 ], [ 366, 814, 21, 14 ], [ 391, 814, 13, 14 ], [ 70, 830, 51, 14 ], [ 123, 830, 18, 14 ], [ 144, 830, 66, 14 ], [ 212, 830, 22, 14 ], [ 237, 830, 57, 14 ], [ 296, 830, 41, 14 ], [ 340, 830, 9, 14 ], [ 352, 830, 38, 14 ], [ 392, 830, 12, 14 ], [ 70, 846, 28, 14 ], [ 102, 846, 28, 14 ], [ 133, 846, 55, 14 ], [ 191, 846, 17, 14 ], [ 212, 846, 45, 14 ], [ 261, 846, 7, 14 ], [ 271, 846, 58, 14 ], [ 332, 846, 22, 14 ], [ 358, 846, 46, 14 ], [ 70, 861, 19, 14 ], [ 94, 861, 21, 14 ], [ 121, 861, 28, 14 ], [ 155, 861, 66, 14 ], [ 227, 861, 45, 14 ], [ 278, 861, 57, 14 ], [ 341, 861, 63, 14 ], [ 70, 877, 12, 14 ], [ 89, 877, 51, 14 ], [ 147, 877, 64, 14 ], [ 218, 877, 26, 14 ], [ 251, 877, 15, 14 ], [ 272, 877, 52, 14 ], [ 331, 877, 22, 14 ], [ 360, 877, 44, 14 ], [ 70, 893, 12, 14 ], [ 87, 893, 49, 14 ], [ 140, 893, 19, 14 ], [ 164, 893, 27, 14 ], [ 196, 893, 62, 14 ], [ 263, 893, 12, 14 ], [ 279, 893, 35, 14 ], [ 319, 893, 85, 14 ], [ 70, 909, 57, 14 ], [ 133, 909, 45, 14 ], [ 184, 909, 26, 14 ], [ 216, 909, 27, 14 ], [ 250, 909, 55, 14 ], [ 310, 909, 34, 14 ], [ 351, 909, 53, 14 ], [ 70, 925, 41, 14 ], [ 115, 925, 71, 14 ], [ 190, 925, 39, 14 ], [ 233, 925, 45, 14 ], [ 283, 925, 26, 14 ], [ 313, 925, 91, 14 ], [ 70, 940, 75, 14 ], [ 148, 940, 12, 14 ], [ 162, 940, 39, 14 ], [ 203, 940, 50, 14 ], [ 256, 940, 21, 14 ], [ 280, 940, 56, 14 ], [ 339, 940, 12, 14 ], [ 353, 940, 51, 14 ], [ 70, 956, 41, 14 ], [ 114, 956, 26, 14 ], [ 144, 956, 11, 14 ], [ 160, 956, 75, 14 ], [ 239, 956, 54, 14 ], [ 296, 956, 50, 14 ], [ 350, 956, 54, 14 ], [ 70, 972, 76, 14 ], [ 155, 972, 40, 14 ], [ 203, 972, 15, 14 ], [ 227, 972, 28, 14 ], [ 264, 972, 41, 14 ], [ 313, 972, 33, 14 ], [ 354, 972, 50, 14 ], [ 70, 988, 75, 14 ], [ 150, 988, 40, 14 ], [ 195, 988, 21, 14 ], [ 221, 988, 62, 14 ], [ 289, 988, 48, 14 ], [ 342, 988, 17, 14 ], [ 364, 988, 40, 14 ], [ 70, 1004, 52, 14 ], [ 127, 1004, 33, 14 ], [ 165, 1004, 32, 14 ], [ 202, 1004, 32, 14 ], [ 239, 1004, 15, 14 ], [ 259, 1004, 18, 14 ], [ 283, 1004, 44, 14 ], [ 332, 1004, 41, 14 ], [ 378, 1004, 26, 14 ], [ 70, 1019, 15, 14 ], [ 90, 1019, 75, 14 ], [ 171, 1019, 54, 14 ], [ 231, 1019, 46, 14 ], [ 283, 1019, 45, 14 ], [ 334, 1019, 41, 14 ], [ 381, 1019, 23, 14 ], [ 428, 676, 21, 14 ], [ 455, 676, 57, 14 ], [ 516, 676, 65, 14 ], [ 586, 676, 55, 14 ], [ 646, 676, 54, 14 ], [ 705, 676, 26, 14 ], [ 735, 676, 27, 14 ], [ 428, 692, 52, 14 ], [ 483, 692, 17, 14 ], [ 501, 692, 18, 14 ], [ 522, 692, 43, 14 ], [ 566, 692, 12, 14 ], [ 580, 692, 25, 14 ], [ 607, 692, 7, 14 ], [ 616, 692, 45, 14 ], [ 664, 692, 21, 14 ], [ 686, 692, 13, 14 ], [ 701, 692, 18, 14 ], [ 721, 692, 19, 14 ], [ 743, 692, 20, 14 ], [ 428, 708, 32, 14 ], [ 463, 708, 18, 14 ], [ 485, 708, 42, 14 ], [ 530, 708, 15, 14 ], [ 548, 708, 18, 14 ], [ 569, 708, 67, 14 ], [ 640, 708, 12, 14 ], [ 655, 708, 19, 14 ], [ 676, 708, 57, 14 ], [ 737, 708, 25, 14 ], [ 428, 723, 28, 14 ], [ 458, 723, 57, 14 ], [ 517, 723, 21, 14 ], [ 541, 723, 49, 14 ], [ 592, 723, 12, 14 ], [ 605, 723, 45, 14 ], [ 653, 723, 19, 14 ], [ 673, 723, 27, 14 ], [ 702, 723, 60, 14 ], [ 428, 739, 25, 14 ], [ 458, 739, 66, 14 ], [ 528, 739, 24, 14 ], [ 557, 739, 58, 14 ], [ 619, 739, 18, 14 ], [ 641, 739, 57, 14 ], [ 703, 739, 12, 14 ], [ 719, 739, 43, 14 ], [ 428, 755, 35, 14 ], [ 466, 755, 12, 14 ], [ 481, 755, 36, 14 ], [ 520, 755, 18, 14 ], [ 542, 755, 21, 14 ], [ 566, 755, 41, 14 ], [ 610, 755, 15, 14 ], [ 628, 755, 28, 14 ], [ 659, 755, 38, 14 ], [ 701, 755, 22, 14 ], [ 726, 755, 22, 14 ], [ 750, 755, 12, 14 ], [ 428, 771, 41, 14 ], [ 474, 771, 32, 14 ], [ 510, 771, 9, 14 ], [ 524, 771, 12, 14 ], [ 540, 771, 47, 14 ], [ 591, 771, 12, 14 ], [ 607, 771, 27, 14 ], [ 639, 771, 21, 14 ], [ 665, 771, 12, 14 ], [ 680, 771, 24, 14 ], [ 709, 771, 54, 14 ], [ 428, 786, 15, 14 ], [ 449, 786, 18, 14 ], [ 472, 786, 68, 14 ], [ 545, 786, 46, 14 ], [ 596, 786, 44, 14 ], [ 645, 786, 57, 14 ], [ 707, 786, 21, 14 ], [ 734, 786, 28, 14 ], [ 428, 802, 69, 14 ], [ 503, 802, 18, 14 ], [ 527, 802, 22, 14 ], [ 555, 802, 40, 14 ], [ 601, 802, 36, 14 ], [ 643, 802, 12, 14 ], [ 661, 802, 40, 14 ], [ 707, 802, 28, 14 ], [ 741, 802, 21, 14 ], [ 428, 818, 79, 14 ], [ 511, 818, 24, 14 ], [ 540, 818, 41, 14 ], [ 585, 818, 70, 14 ], [ 659, 818, 18, 14 ], [ 681, 818, 12, 14 ], [ 696, 818, 27, 14 ], [ 727, 818, 35, 15 ], [ 428, 834, 12, 14 ], [ 446, 834, 44, 14 ], [ 496, 834, 32, 14 ], [ 534, 834, 12, 14 ], [ 552, 834, 27, 14 ], [ 585, 834, 15, 14 ], [ 606, 834, 60, 14 ], [ 672, 834, 21, 14 ], [ 700, 834, 62, 14 ], [ 428, 850, 21, 14 ], [ 454, 850, 51, 14 ], [ 509, 850, 15, 14 ], [ 529, 850, 18, 14 ], [ 551, 850, 24, 14 ], [ 579, 850, 21, 14 ], [ 604, 850, 59, 14 ], [ 667, 850, 18, 14 ], [ 689, 850, 57, 14 ], [ 750, 850, 12, 14 ], [ 428, 865, 48, 15 ], [ 479, 865, 35, 15 ], [ 518, 865, 12, 14 ], [ 533, 865, 36, 14 ], [ 573, 865, 18, 14 ], [ 594, 865, 21, 14 ], [ 619, 865, 41, 14 ], [ 663, 865, 35, 15 ], [ 701, 865, 15, 14 ], [ 720, 865, 18, 14 ], [ 741, 865, 21, 14 ], [ 428, 881, 12, 14 ], [ 443, 881, 28, 14 ], [ 473, 881, 49, 14 ], [ 525, 881, 21, 14 ], [ 549, 881, 12, 14 ], [ 563, 881, 45, 14 ], [ 611, 881, 40, 14 ], [ 654, 881, 42, 14 ], [ 428, 926, 13, 17 ], [ 444, 926, 28, 17 ], [ 474, 926, 115, 17 ], [ 592, 926, 31, 17 ], [ 626, 926, 27, 17 ], [ 656, 926, 62, 17 ], [ 428, 956, 22, 14 ], [ 455, 956, 57, 14 ], [ 517, 956, 12, 14 ], [ 534, 956, 28, 14 ], [ 567, 956, 49, 14 ], [ 620, 956, 12, 14 ], [ 637, 956, 49, 14 ], [ 691, 956, 12, 14 ], [ 707, 956, 41, 14 ], [ 753, 956, 9, 14 ], [ 428, 972, 48, 14 ], [ 481, 972, 25, 14 ], [ 513, 972, 49, 14 ], [ 568, 972, 69, 14 ], [ 642, 972, 12, 14 ], [ 660, 972, 38, 14 ], [ 703, 972, 59, 14 ], [ 428, 988, 22, 14 ], [ 458, 988, 28, 14 ], [ 495, 988, 57, 14 ], [ 560, 988, 56, 14 ], [ 624, 988, 53, 14 ], [ 685, 988, 17, 14 ], [ 711, 988, 52, 14 ], [ 428, 1004, 45, 14 ], [ 478, 1004, 40, 14 ], [ 522, 1004, 108, 14 ], [ 636, 1004, 80, 14 ], [ 720, 1004, 42, 14 ], [ 428, 1019, 13, 14 ], [ 446, 1019, 24, 14 ], [ 475, 1019, 21, 14 ], [ 501, 1019, 42, 14 ], [ 547, 1019, 22, 14 ], [ 574, 1019, 21, 14 ], [ 600, 1019, 58, 14 ], [ 663, 1019, 24, 14 ], [ 691, 1019, 19, 14 ], [ 715, 1019, 47, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Experimental", "Diabetes", "Research", "Volume", "2012,", "Article", "ID", "519784,", "5", "pages", "doi:10.1155/2012/519784", "Review", "Article", "Bone:", "Incretin", "Hormones", "Perceiver", "or", "Receiver?", "Ilaria", "Dicembrini,1", "Edoardo", "Mannucci,2", "and", "Carlo", "Maria", "Rotella1", "1", "Section", "of", "Endocrinology,", "Department", "of", "Clinical", "Pathophysiology,", "Careggi", "Teaching", "Hospital,", "University", "of", "Florence", "and", "Obesity", "Agency,", "50127", "Florence,", "Italy", "2", "Careggi", "Teaching", "Hospital,", "Diabetes", "Agency,", "50127", "Florence,", "Italy", "Correspondence", "should", "be", "addressed", "to", "Carlo", "Maria", "Rotella,", "c.rotella@dfc.unifi.it", "Received", "6", "March", "2012;", "Accepted", "9", "May", "2012", "Academic", "Editor:", "Giovanni", "Di", "Pasquale", "Copyright", "©", "2012", "Ilaria", "Dicembrini", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Novel", "incretin-based", "drugs,", "such", "as", "glucagon-like", "peptide-1", "receptor", "agonists", "(GLP-1", "RA)", "and", "dipeptidyl", "peptidase-4", "inhibitors", "(DPP-4i),", "have", "been", "last", "introduced", "in", "the", "pharmacological", "treatment", "of", "type", "2", "diabetes.", "In", "the", "last", "few", "years,", "the", "interest", "on", "the", "relationship", "of", "gut", "hormones", "with", "bone", "metabolism", "in", "diabetes", "has", "been", "increasing.", "The", "aim", "of", "present", "paper", "is", "to", "examine", "in", "vitro", "and", "in", "vivo", "evidence", "on", "the", "connections", "between", "incretin", "hormones", "and", "bone", "metabolism.", "We", "also", "discuss", "results", "of", "clinical", "trials", "and", "metaanalysis,", "explore", "the", "effects", "of", "incretin", "drugs", "in", "vitro", "on", "osteogenic", "cells", "and", "osteoclasts,", "and", "speculate", "on", "the", "possibility", "of", "different", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "on", "the", "risk", "of", "bone", "fractures", "risk", "in", "humans.", "Although", "existing", "preliminary", "evidence", "suggests", "a", "protective", "effect", "on", "the", "bone,", "at", "least", "for", "DPP-4i,", "further", "controlled,", "long-term", "studies", "with", "measurement", "of", "bone", "markers,", "bone", "density,", "and", "clinical", "fractures", "rates", "are", "needed", "to", "substantiate", "and", "confirm", "those", "findings.", "1.", "Introduction", "Glucose,", "protein,", "and", "fat", "and", "mixed", "meal", "ingestion", "is", "associated", "with", "a", "significant", "reduction", "in", "markers", "of", "bone", "resorption,", "detectable", "by", "twenty", "minutes", "after", "feeding", "[1].", "Bone", "formation", "is", "also", "influenced,", "but", "it", "seems", "to", "be", "less", "responsive", "to", "nutrients", "than", "resorption", "[2].", "Biochemical", "assessment", "of", "bone", "turnover", "demonstrates", "that", "food", "intake", "is", "the", "major", "cause", "of", "the", "reduced", "bone", "turnover", "during", "daytime,", "which", "is", "followed", "by", "a", "nocturnal", "increase", "[3].", "In", "addition,", "the", "observation", "that", "parenteral", "feeding", "is", "related", "to", "bone", "mass", "reduction", "[4]", "suggests", "a", "functional", "link", "between", "gut", "and", "bone", "metabolism", "through", "hormones", "responding", "to", "nutrients", "absorption,", "such", "as,", "incretins.", "The", "concept", "of", "incretins", "has", "been", "introduced", "to", "define", "gastrointestinal", "hormones", "released", "after", "meal", "ingestion,", "which", "modulate", "glucose", "homeostasis,", "mainly", "through", "both", "glucose-induced", "enhancement", "of", "insulin", "secretion", "and", "inhibition", "of", "glucagon", "release,", "such", "as", "glucagon-like", "peptide-1", "(GLP-1).", "Beneficial", "extraglycemic", "actions", "on", "body", "weight,", "blood", "pressure,", "dyslipidemia,", "cardiac", "and", "endothelial", "function", "are", "further", "reported.", "Novel", "drugs", "based", "on", "the", "incretin", "system,", "such", "as,", "glucagon-like", "peptide-1", "receptor", "agonists", "(GLP-1", "RA)", "and", "dipeptidyl", "peptidase-4", "inhibitors", "(DPP-4i),", "have", "been", "approved", "for", "the", "therapy", "of", "type", "2", "diabetes", "[5].", "In", "the", "last", "few", "years,", "the", "interest", "on", "the", "relationship", "of", "gut", "hormones", "with", "bone", "formation", "and", "turnover", "in", "diabetes", "has", "been", "increasing,", "with", "preliminary", "data", "suggesting", "the", "possibility", "of", "positive", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "on", "bone", "health.", "The", "aim", "of", "present", "paper", "is", "to", "examine", "in", "vitro", "and", "in", "vivo", "evidences", "on", "the", "connections", "between", "incretin", "hormones", "and", "bone", "metabolism.", "We", "also", "discuss", "results", "of", "clinical", "trials", "and", "meta-analysis,", "thus", "explore", "investigating", "the", "in", "vitro", "effects", "of", "incretin", "drugs", "in", "vitro", "on", "osteoblasts", "and", "osteoclasts,", "and", "speculate", "on", "the", "cells", "and", "presenting", "the", "possibility", "of", "different", "effects", "of", "GLP-1", "RA", "and", "DPP-4i", "effects", "on", "the", "risk", "of", "bone", "fractures", "risk", "in", "humans", "clinical", "studies.", "2.", "The", "Gut-Brain-Bone", "Axis", "and", "Diabetes", "The", "regulation", "of", "bone", "turnover", "in", "response", "to", "feeding", "is", "complex", "with", "probable", "involvement", "of", "several", "mediators.", "The", "most", "important", "mediators", "identified", "are", "intestinal", "(GLP-1,", "GLP-2,", "Glucose-dependent", "Insulinotropic", "Peptide", "or", "GIP,", "and", "Peptide", "YY)", "and", "pancreatic", "beta", "cell", "(insulin," ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 80, 78, 18, 28 ], [ 107, 78, 70, 28 ], [ 186, 78, 85, 28 ], [ 280, 78, 105, 28 ], [ 394, 78, 213, 28 ], [ 616, 78, 18, 28 ], [ 643, 78, 32, 28 ], [ 80, 109, 116, 28 ], [ 205, 109, 125, 28 ], [ 339, 109, 83, 28 ], [ 431, 109, 45, 28 ], [ 485, 109, 102, 28 ], [ 596, 109, 47, 28 ], [ 80, 139, 163, 28 ], [ 252, 139, 31, 28 ], [ 292, 139, 141, 28 ], [ 441, 139, 150, 28 ], [ 600, 139, 63, 28 ], [ 80, 183, 29, 14 ], [ 114, 183, 26, 14 ], [ 139, 180, 7, 10 ], [ 145, 183, 4, 14 ], [ 153, 183, 31, 14 ], [ 189, 180, 46, 17 ], [ 239, 183, 43, 14 ], [ 286, 180, 57, 17 ], [ 348, 183, 54, 14 ], [ 405, 183, 35, 14 ], [ 440, 180, 7, 10 ], [ 446, 183, 4, 14 ], [ 454, 183, 49, 14 ], [ 508, 180, 60, 17 ], [ 572, 183, 53, 14 ], [ 629, 180, 82, 17 ], [ 80, 202, 56, 14 ], [ 141, 200, 74, 17 ], [ 80, 225, 6, 10 ], [ 88, 225, 40, 10 ], [ 132, 225, 25, 10 ], [ 162, 225, 54, 10 ], [ 220, 225, 47, 10 ], [ 271, 225, 28, 10 ], [ 303, 225, 59, 10 ], [ 367, 225, 35, 10 ], [ 406, 225, 26, 10 ], [ 436, 225, 34, 10 ], [ 474, 225, 9, 10 ], [ 487, 225, 44, 10 ], [ 536, 225, 38, 10 ], [ 578, 225, 26, 10 ], [ 608, 225, 30, 10 ], [ 643, 225, 21, 10 ], [ 669, 225, 22, 10 ], [ 695, 225, 6, 10 ], [ 703, 225, 30, 10 ], [ 737, 225, 32, 10 ], [ 80, 238, 43, 10 ], [ 126, 238, 26, 10 ], [ 155, 238, 34, 10 ], [ 192, 238, 9, 10 ], [ 203, 238, 44, 10 ], [ 250, 238, 38, 10 ], [ 291, 238, 26, 10 ], [ 319, 238, 30, 10 ], [ 352, 238, 21, 10 ], [ 377, 238, 20, 10 ], [ 102, 277, 57, 14 ], [ 101, 305, 69, 13 ], [ 176, 305, 54, 13 ], [ 235, 305, 11, 13 ], [ 250, 305, 32, 13 ], [ 286, 305, 8, 13 ], [ 299, 305, 6, 13 ], [ 310, 305, 46, 13 ], [ 361, 305, 40, 13 ], [ 405, 305, 45, 13 ], [ 455, 305, 42, 13 ], [ 501, 305, 18, 13 ], [ 524, 305, 27, 13 ], [ 556, 305, 32, 13 ], [ 592, 305, 11, 13 ], [ 608, 305, 41, 13 ], [ 654, 305, 69, 13 ], [ 728, 305, 20, 13 ], [ 102, 318, 55, 13 ], [ 160, 318, 10, 13 ], [ 174, 318, 38, 13 ], [ 215, 318, 33, 13 ], [ 250, 318, 41, 13 ], [ 295, 318, 8, 13 ], [ 306, 318, 18, 13 ], [ 327, 318, 21, 13 ], [ 352, 318, 27, 13 ], [ 382, 318, 58, 13 ], [ 444, 318, 13, 13 ], [ 460, 318, 45, 13 ], [ 509, 318, 37, 13 ], [ 549, 318, 15, 13 ], [ 567, 318, 56, 13 ], [ 626, 318, 90, 13 ], [ 720, 318, 28, 13 ], [ 102, 332, 50, 13 ], [ 155, 332, 10, 13 ], [ 168, 332, 26, 13 ], [ 197, 332, 11, 13 ], [ 211, 332, 29, 13 ], [ 243, 332, 37, 13 ], [ 284, 332, 14, 13 ], [ 301, 332, 70, 13 ], [ 374, 332, 25, 13 ], [ 401, 332, 43, 13 ], [ 447, 332, 78, 13 ], [ 529, 332, 60, 13 ], [ 592, 332, 11, 13 ], [ 606, 332, 33, 13 ], [ 642, 332, 50, 13 ], [ 695, 332, 53, 13 ], [ 102, 346, 20, 13 ], [ 125, 346, 38, 13 ], [ 166, 346, 29, 13 ], [ 198, 346, 18, 13 ], [ 220, 346, 35, 13 ], [ 258, 346, 12, 13 ], [ 273, 346, 40, 13 ], [ 316, 346, 18, 13 ], [ 337, 346, 55, 13 ], [ 395, 346, 45, 13 ], [ 443, 346, 10, 13 ], [ 456, 346, 44, 13 ], [ 503, 346, 54, 13 ], [ 560, 346, 13, 13 ], [ 576, 346, 32, 13 ], [ 611, 346, 52, 13 ], [ 666, 346, 11, 13 ], [ 680, 346, 54, 13 ], [ 737, 346, 11, 13 ], [ 102, 360, 39, 13 ], [ 144, 360, 54, 13 ], [ 202, 360, 8, 13 ], [ 214, 360, 64, 13 ], [ 282, 360, 10, 13 ], [ 296, 360, 37, 13 ], [ 337, 360, 39, 13 ], [ 380, 360, 27, 13 ], [ 410, 360, 20, 13 ], [ 434, 360, 44, 13 ], [ 482, 360, 25, 13 ], [ 510, 360, 25, 13 ], [ 101, 386, 48, 13 ], [ 152, 386, 21, 13 ], [ 176, 386, 48, 13 ], [ 227, 386, 50, 13 ], [ 281, 386, 50, 13 ], [ 333, 386, 73, 13 ], [ 410, 386, 11, 13 ], [ 424, 386, 91, 13 ], [ 518, 386, 8, 13 ], [ 529, 386, 42, 13 ], [ 574, 386, 22, 13 ], [ 599, 386, 47, 13 ], [ 649, 386, 35, 13 ], [ 687, 386, 18, 13 ], [ 707, 386, 40, 13 ], [ 102, 400, 20, 13 ], [ 125, 400, 44, 13 ], [ 172, 400, 10, 13 ], [ 185, 400, 37, 13 ], [ 225, 400, 39, 13 ], [ 267, 400, 20, 13 ], [ 290, 400, 40, 13 ], [ 333, 400, 47, 13 ], [ 382, 400, 44, 13 ], [ 429, 400, 13, 13 ], [ 445, 400, 63, 13 ], [ 511, 400, 37, 13 ], [ 551, 400, 38, 13 ], [ 592, 400, 10, 13 ], [ 605, 400, 36, 13 ], [ 644, 400, 66, 13 ], [ 712, 400, 20, 13 ], [ 735, 400, 12, 13 ], [ 102, 414, 56, 13 ], [ 162, 414, 18, 13 ], [ 184, 414, 38, 13 ], [ 225, 414, 12, 13 ], [ 240, 414, 14, 13 ], [ 257, 414, 6, 13 ], [ 267, 414, 31, 13 ], [ 301, 414, 44, 13 ], [ 349, 414, 10, 13 ], [ 363, 414, 94, 13 ], [ 460, 414, 17, 13 ], [ 481, 414, 26, 13 ], [ 510, 414, 56, 13 ], [ 570, 414, 6, 13 ], [ 580, 414, 29, 13 ], [ 613, 414, 60, 13 ], [ 677, 414, 11, 13 ], [ 691, 414, 57, 13 ], [ 102, 428, 43, 13 ], [ 149, 428, 64, 13 ], [ 216, 428, 73, 13 ], [ 293, 428, 52, 13 ], [ 349, 428, 33, 13 ], [ 386, 428, 58, 13 ], [ 447, 428, 27, 13 ], [ 479, 428, 39, 13 ], [ 521, 428, 59, 13 ], [ 584, 428, 10, 13 ], [ 598, 428, 64, 13 ], [ 666, 428, 33, 13 ], [ 703, 428, 20, 13 ], [ 727, 428, 21, 13 ], [ 102, 442, 40, 13 ], [ 149, 442, 6, 13 ], [ 163, 442, 67, 13 ], [ 237, 442, 40, 13 ], [ 284, 442, 51, 13 ], [ 342, 442, 10, 13 ], [ 360, 442, 25, 13 ], [ 392, 442, 20, 13 ], [ 420, 442, 27, 13 ], [ 454, 442, 48, 13 ], [ 509, 442, 13, 13 ], [ 530, 442, 66, 13 ], [ 603, 442, 43, 13 ], [ 654, 442, 69, 13 ], [ 730, 442, 18, 13 ], [ 102, 455, 66, 13 ], [ 171, 455, 34, 13 ], [ 208, 455, 42, 13 ], [ 253, 455, 57, 13 ], [ 313, 455, 43, 13 ], [ 359, 455, 37, 13 ], [ 399, 455, 51, 13 ], [ 453, 455, 21, 13 ], [ 476, 455, 50, 13 ], [ 530, 455, 43, 13 ], [ 576, 455, 48, 13 ], [ 627, 455, 30, 13 ], [ 660, 455, 20, 13 ], [ 683, 455, 51, 13 ], [ 737, 455, 11, 13 ], [ 102, 469, 51, 13 ], [ 156, 469, 14, 13 ], [ 172, 469, 57, 13 ], [ 231, 469, 30, 13 ], [ 264, 469, 18, 13 ], [ 285, 469, 37, 13 ], [ 324, 469, 37, 13 ], [ 364, 469, 53, 13 ], [ 420, 469, 40, 13 ], [ 463, 469, 10, 13 ], [ 476, 469, 44, 13 ], [ 523, 469, 11, 13 ], [ 537, 469, 22, 13 ], [ 561, 469, 18, 13 ], [ 582, 469, 10, 13 ], [ 595, 469, 21, 13 ], [ 619, 469, 35, 13 ], [ 656, 469, 65, 13 ], [ 724, 469, 24, 13 ], [ 102, 483, 42, 13 ], [ 147, 483, 57, 13 ], [ 208, 483, 55, 13 ], [ 266, 483, 97, 13 ], [ 367, 483, 10, 13 ], [ 381, 483, 25, 13 ], [ 410, 483, 58, 13 ], [ 472, 483, 41, 13 ], [ 516, 483, 10, 13 ], [ 530, 483, 36, 13 ], [ 570, 483, 43, 13 ], [ 617, 483, 24, 13 ], [ 645, 483, 31, 13 ], [ 101, 509, 133, 13 ], [ 238, 509, 17, 13 ], [ 258, 509, 19, 13 ], [ 280, 509, 35, 13 ], [ 319, 509, 16, 13 ], [ 337, 509, 32, 13 ], [ 372, 509, 22, 13 ], [ 396, 509, 57, 13 ], [ 456, 509, 60, 13 ], [ 519, 509, 40, 13 ], [ 562, 509, 20, 13 ], [ 585, 509, 44, 13 ], [ 631, 509, 11, 13 ], [ 645, 509, 27, 13 ], [ 675, 509, 20, 13 ], [ 698, 509, 25, 13 ], [ 725, 509, 23, 13 ], [ 102, 523, 10, 13 ], [ 118, 523, 37, 13 ], [ 160, 523, 58, 13 ], [ 224, 523, 43, 13 ], [ 273, 523, 20, 13 ], [ 298, 523, 10, 13 ], [ 313, 523, 23, 13 ], [ 342, 523, 30, 13 ], [ 377, 523, 43, 13 ], [ 425, 523, 46, 13 ], [ 477, 523, 22, 13 ], [ 505, 523, 48, 13 ], [ 558, 523, 30, 13 ], [ 594, 523, 11, 13 ], [ 610, 523, 57, 13 ], [ 673, 523, 52, 13 ], [ 730, 523, 18, 13 ], [ 102, 537, 48, 13 ], [ 153, 537, 11, 13 ], [ 166, 537, 64, 13 ], [ 233, 537, 27, 13 ], [ 262, 537, 22, 13 ], [ 286, 537, 51, 13 ], [ 340, 537, 48, 13 ], [ 391, 537, 37, 13 ], [ 431, 537, 56, 13 ], [ 490, 537, 20, 13 ], [ 512, 537, 40, 13 ], [ 555, 537, 52, 13 ], [ 610, 537, 11, 13 ], [ 623, 537, 48, 13 ], [ 674, 537, 27, 13 ], [ 704, 537, 44, 13 ], [ 102, 551, 37, 13 ], [ 142, 551, 56, 13 ], [ 202, 551, 20, 13 ], [ 225, 551, 44, 13 ], [ 272, 551, 51, 13 ], [ 326, 551, 11, 13 ], [ 340, 551, 27, 13 ], [ 370, 551, 20, 13 ], [ 394, 551, 24, 13 ], [ 422, 551, 25, 13 ], [ 450, 551, 41, 13 ], [ 495, 551, 18, 13 ], [ 516, 551, 42, 13 ], [ 562, 551, 40, 13 ], [ 605, 551, 22, 13 ], [ 630, 551, 57, 13 ], [ 690, 551, 58, 13 ], [ 102, 565, 40, 13 ], [ 147, 565, 70, 13 ], [ 222, 565, 20, 13 ], [ 247, 565, 69, 13 ], [ 320, 565, 56, 13 ], [ 381, 565, 10, 13 ], [ 396, 565, 6, 13 ], [ 407, 565, 25, 13 ], [ 437, 565, 58, 13 ], [ 499, 565, 41, 13 ], [ 545, 565, 32, 13 ], [ 581, 565, 22, 13 ], [ 608, 565, 6, 13 ], [ 619, 565, 18, 13 ], [ 642, 565, 20, 13 ], [ 667, 565, 10, 13 ], [ 682, 565, 51, 13 ], [ 737, 565, 11, 13 ], [ 102, 579, 36, 13 ], [ 141, 579, 69, 13 ], [ 214, 579, 13, 13 ], [ 231, 579, 59, 13 ], [ 92, 614, 40, 10 ], [ 134, 614, 16, 10 ], [ 152, 614, 8, 10 ], [ 162, 614, 22, 10 ], [ 187, 614, 9, 10 ], [ 198, 614, 28, 10 ], [ 228, 614, 8, 10 ], [ 238, 614, 21, 10 ], [ 262, 614, 7, 10 ], [ 271, 614, 31, 10 ], [ 304, 614, 9, 10 ], [ 315, 614, 9, 10 ], [ 326, 614, 9, 10 ], [ 337, 614, 26, 10 ], [ 365, 614, 6, 10 ], [ 374, 614, 24, 10 ], [ 400, 614, 29, 10 ], [ 431, 614, 35, 10 ], [ 469, 614, 71, 10 ], [ 542, 614, 6, 10 ], [ 551, 614, 50, 10 ], [ 603, 614, 42, 10 ], [ 648, 614, 28, 10 ], [ 678, 614, 15, 10 ], [ 696, 614, 34, 10 ], [ 732, 614, 16, 10 ], [ 92, 625, 55, 10 ], [ 150, 625, 10, 10 ], [ 163, 625, 48, 10 ], [ 214, 625, 50, 10 ], [ 266, 625, 23, 10 ], [ 292, 625, 20, 10 ], [ 315, 625, 18, 10 ], [ 336, 625, 18, 10 ], [ 357, 625, 32, 10 ], [ 392, 625, 139, 10 ], [ 92, 642, 31, 10 ], [ 126, 642, 27, 10 ], [ 156, 642, 16, 10 ], [ 175, 642, 38, 10 ], [ 215, 642, 26, 10 ], [ 244, 642, 41, 10 ], [ 288, 642, 28, 10 ], [ 319, 642, 9, 10 ], [ 330, 642, 40, 10 ], [ 372, 642, 28, 10 ], [ 403, 642, 25, 10 ], [ 431, 642, 9, 10 ], [ 442, 642, 34, 10 ], [ 92, 659, 42, 10 ], [ 137, 659, 17, 10 ], [ 157, 659, 12, 10 ], [ 172, 659, 22, 10 ], [ 198, 659, 44, 10 ], [ 244, 659, 30, 10 ], [ 277, 659, 7, 10 ], [ 287, 659, 22, 10 ], [ 312, 659, 47, 10 ], [ 362, 659, 45, 10 ], [ 410, 659, 7, 10 ], [ 420, 659, 20, 10 ], [ 92, 677, 50, 10 ], [ 154, 677, 20, 10 ], [ 176, 677, 16, 10 ], [ 194, 677, 9, 10 ], [ 205, 677, 9, 10 ], [ 216, 677, 17, 10 ], [ 235, 677, 6, 10 ], [ 243, 677, 10, 10 ], [ 256, 677, 50, 10 ], [ 308, 677, 25, 10 ], [ 335, 677, 45, 10 ], [ 382, 677, 25, 10 ], [ 409, 677, 14, 10 ], [ 425, 677, 24, 10 ], [ 450, 677, 9, 10 ], [ 461, 677, 14, 10 ], [ 477, 677, 34, 10 ], [ 512, 677, 42, 10 ], [ 557, 677, 45, 10 ], [ 604, 677, 32, 10 ], [ 638, 677, 25, 10 ], [ 665, 677, 31, 10 ], [ 699, 677, 49, 10 ], [ 92, 688, 16, 10 ], [ 111, 688, 50, 10 ], [ 164, 688, 16, 10 ], [ 182, 688, 54, 10 ], [ 239, 688, 8, 10 ], [ 250, 688, 15, 10 ], [ 268, 688, 36, 10 ], [ 307, 688, 37, 10 ], [ 347, 688, 14, 10 ], [ 363, 688, 31, 10 ], [ 397, 688, 28, 10 ], [ 428, 688, 16, 10 ], [ 446, 688, 27, 10 ], [ 476, 688, 13, 10 ], [ 492, 688, 36, 10 ], [ 92, 705, 42, 10 ], [ 137, 705, 15, 10 ], [ 155, 705, 31, 10 ], [ 189, 705, 20, 10 ], [ 212, 705, 11, 10 ], [ 226, 705, 32, 10 ], [ 261, 705, 9, 10 ], [ 273, 705, 33, 10 ], [ 308, 705, 9, 10 ], [ 320, 705, 28, 10 ], [ 92, 722, 52, 10 ], [ 147, 722, 44, 10 ], [ 193, 722, 16, 10 ], [ 212, 722, 31, 10 ], [ 246, 722, 20, 10 ], [ 268, 722, 35, 10 ], [ 307, 722, 17, 10 ], [ 326, 722, 11, 10 ], [ 340, 722, 45, 10 ], [ 388, 722, 35, 10 ], [ 426, 722, 21, 10 ], [ 92, 739, 5, 10 ], [ 99, 739, 27, 10 ], [ 129, 739, 85, 10 ], [ 80, 782, 84, 14 ], [ 93, 811, 65, 13 ], [ 161, 811, 45, 13 ], [ 210, 811, 47, 13 ], [ 261, 811, 16, 13 ], [ 281, 811, 54, 13 ], [ 339, 811, 10, 13 ], [ 353, 811, 21, 13 ], [ 378, 811, 34, 13 ], [ 80, 826, 20, 13 ], [ 106, 826, 10, 13 ], [ 122, 826, 36, 13 ], [ 165, 826, 57, 13 ], [ 227, 826, 34, 13 ], [ 267, 826, 22, 13 ], [ 295, 826, 50, 13 ], [ 351, 826, 19, 13 ], [ 377, 826, 36, 13 ], [ 80, 841, 33, 13 ], [ 122, 841, 16, 13 ], [ 146, 841, 41, 13 ], [ 195, 841, 19, 13 ], [ 222, 841, 22, 13 ], [ 252, 841, 36, 13 ], [ 296, 841, 16, 13 ], [ 320, 841, 65, 13 ], [ 393, 841, 19, 13 ], [ 80, 856, 71, 13 ], [ 160, 856, 10, 13 ], [ 180, 856, 34, 13 ], [ 222, 856, 10, 13 ], [ 242, 856, 37, 13 ], [ 288, 856, 65, 13 ], [ 362, 856, 51, 13 ], [ 80, 870, 46, 13 ], [ 132, 870, 42, 13 ], [ 179, 870, 68, 13 ], [ 253, 870, 41, 13 ], [ 298, 870, 43, 13 ], [ 347, 870, 30, 13 ], [ 382, 870, 9, 13 ], [ 396, 870, 17, 13 ], [ 80, 885, 42, 13 ], [ 125, 885, 34, 13 ], [ 161, 885, 27, 13 ], [ 191, 885, 36, 13 ], [ 229, 885, 19, 13 ], [ 251, 885, 47, 13 ], [ 301, 885, 18, 13 ], [ 322, 885, 41, 13 ], [ 365, 885, 47, 13 ], [ 80, 900, 43, 13 ], [ 130, 900, 7, 13 ], [ 144, 900, 34, 13 ], [ 185, 900, 8, 13 ], [ 199, 900, 62, 13 ], [ 268, 900, 49, 13 ], [ 324, 900, 19, 13 ], [ 350, 900, 63, 13 ], [ 80, 915, 50, 13 ], [ 137, 915, 69, 13 ], [ 212, 915, 36, 13 ], [ 255, 915, 31, 13 ], [ 293, 915, 53, 13 ], [ 352, 915, 19, 13 ], [ 378, 915, 35, 13 ], [ 80, 930, 51, 13 ], [ 135, 930, 22, 13 ], [ 160, 930, 16, 13 ], [ 180, 930, 21, 13 ], [ 205, 930, 20, 13 ], [ 228, 930, 42, 13 ], [ 274, 930, 47, 13 ], [ 324, 930, 19, 13 ], [ 346, 930, 10, 13 ], [ 360, 930, 53, 13 ], [ 80, 945, 31, 13 ], [ 121, 945, 18, 13 ], [ 149, 945, 29, 13 ], [ 187, 945, 25, 13 ], [ 221, 945, 11, 13 ], [ 242, 945, 61, 13 ], [ 312, 945, 45, 13 ], [ 366, 945, 16, 13 ], [ 392, 945, 21, 13 ], [ 80, 959, 56, 13 ], [ 141, 959, 10, 13 ], [ 155, 959, 62, 13 ], [ 222, 959, 45, 13 ], [ 271, 959, 10, 13 ], [ 285, 959, 43, 13 ], [ 332, 959, 34, 13 ], [ 370, 959, 21, 13 ], [ 396, 959, 17, 13 ], [ 80, 974, 56, 13 ], [ 144, 974, 16, 13 ], [ 168, 974, 57, 13 ], [ 233, 974, 44, 13 ], [ 285, 974, 10, 13 ], [ 303, 974, 28, 13 ], [ 339, 974, 18, 13 ], [ 365, 974, 48, 13 ], [ 80, 989, 59, 13 ], [ 144, 989, 10, 13 ], [ 158, 989, 16, 13 ], [ 179, 989, 24, 13 ], [ 207, 989, 33, 13 ], [ 245, 989, 20, 13 ], [ 269, 989, 61, 13 ], [ 335, 989, 21, 13 ], [ 361, 989, 10, 13 ], [ 376, 989, 37, 13 ], [ 80, 1004, 34, 13 ], [ 119, 1004, 45, 13 ], [ 169, 1004, 10, 13 ], [ 184, 1004, 31, 13 ], [ 220, 1004, 49, 13 ], [ 274, 1004, 16, 13 ], [ 295, 1004, 47, 13 ], [ 347, 1004, 48, 13 ], [ 400, 1004, 13, 13 ], [ 437, 782, 62, 13 ], [ 503, 782, 28, 13 ], [ 535, 782, 49, 13 ], [ 588, 782, 15, 13 ], [ 607, 782, 21, 13 ], [ 632, 782, 35, 13 ], [ 671, 782, 42, 13 ], [ 717, 782, 19, 13 ], [ 740, 782, 30, 13 ], [ 437, 796, 10, 13 ], [ 451, 796, 43, 13 ], [ 498, 796, 17, 13 ], [ 520, 796, 42, 13 ], [ 565, 796, 20, 13 ], [ 589, 796, 69, 13 ], [ 662, 796, 18, 13 ], [ 684, 796, 21, 13 ], [ 709, 796, 61, 13 ], [ 437, 811, 10, 13 ], [ 451, 811, 75, 13 ], [ 530, 811, 43, 13 ], [ 576, 811, 13, 13 ], [ 592, 811, 28, 13 ], [ 624, 811, 17, 13 ], [ 645, 811, 24, 13 ], [ 673, 811, 54, 13 ], [ 730, 811, 13, 13 ], [ 746, 811, 24, 13 ], [ 437, 826, 40, 13 ], [ 481, 826, 20, 13 ], [ 504, 826, 10, 13 ], [ 518, 826, 62, 13 ], [ 584, 826, 31, 13 ], [ 450, 841, 52, 13 ], [ 506, 841, 8, 13 ], [ 518, 841, 6, 13 ], [ 529, 841, 50, 13 ], [ 583, 841, 37, 13 ], [ 624, 841, 46, 13 ], [ 675, 841, 17, 13 ], [ 697, 841, 49, 13 ], [ 750, 841, 19, 13 ], [ 437, 856, 57, 13 ], [ 503, 856, 53, 13 ], [ 565, 856, 10, 13 ], [ 585, 856, 29, 13 ], [ 623, 856, 20, 13 ], [ 652, 856, 45, 13 ], [ 706, 856, 34, 13 ], [ 748, 856, 21, 13 ], [ 437, 871, 52, 13 ], [ 493, 871, 18, 13 ], [ 514, 871, 35, 13 ], [ 552, 871, 93, 13 ], [ 648, 871, 44, 13 ], [ 695, 871, 16, 13 ], [ 714, 871, 56, 13 ], [ 437, 885, 15, 13 ], [ 460, 885, 16, 13 ], [ 485, 885, 60, 13 ], [ 553, 885, 10, 13 ], [ 572, 885, 73, 13 ], [ 653, 885, 42, 13 ], [ 704, 885, 23, 13 ], [ 735, 885, 10, 13 ], [ 754, 885, 16, 13 ], [ 437, 900, 62, 13 ], [ 506, 900, 34, 13 ], [ 547, 900, 19, 13 ], [ 573, 900, 48, 13 ], [ 628, 900, 55, 13 ], [ 690, 900, 28, 13 ], [ 724, 900, 45, 13 ], [ 437, 915, 16, 13 ], [ 462, 915, 31, 13 ], [ 502, 915, 31, 13 ], [ 542, 915, 50, 13 ], [ 601, 915, 41, 13 ], [ 651, 915, 19, 13 ], [ 679, 915, 11, 13 ], [ 699, 915, 16, 13 ], [ 724, 915, 46, 13 ], [ 437, 930, 54, 13 ], [ 497, 930, 10, 13 ], [ 513, 930, 12, 13 ], [ 531, 930, 16, 13 ], [ 553, 930, 58, 13 ], [ 618, 930, 10, 13 ], [ 633, 930, 36, 13 ], [ 676, 930, 35, 13 ], [ 717, 930, 11, 13 ], [ 733, 930, 20, 13 ], [ 759, 930, 11, 13 ], [ 437, 945, 24, 13 ], [ 465, 945, 48, 13 ], [ 516, 945, 10, 13 ], [ 529, 945, 29, 13 ], [ 561, 945, 38, 13 ], [ 602, 945, 18, 13 ], [ 624, 945, 30, 13 ], [ 657, 945, 38, 13 ], [ 698, 945, 16, 13 ], [ 717, 945, 39, 13 ], [ 760, 945, 10, 13 ], [ 437, 960, 41, 13 ], [ 483, 960, 22, 13 ], [ 509, 960, 14, 13 ], [ 527, 960, 48, 13 ], [ 579, 960, 55, 13 ], [ 639, 960, 42, 13 ], [ 685, 960, 44, 13 ], [ 732, 960, 19, 13 ], [ 756, 960, 14, 13 ], [ 437, 974, 19, 13 ], [ 464, 974, 19, 13 ], [ 490, 974, 27, 13 ], [ 524, 974, 15, 13 ], [ 545, 974, 24, 13 ], [ 576, 974, 68, 13 ], [ 651, 974, 59, 13 ], [ 717, 974, 52, 13 ], [ 437, 989, 34, 13 ], [ 478, 989, 25, 13 ], [ 509, 989, 35, 13 ], [ 550, 989, 59, 13 ], [ 616, 989, 24, 13 ], [ 647, 989, 45, 13 ], [ 698, 989, 71, 13 ], [ 437, 1004, 38, 13 ], [ 480, 1004, 15, 13 ], [ 500, 1004, 29, 13 ], [ 534, 1004, 59, 13 ], [ 598, 1004, 42, 13 ], [ 645, 1004, 41, 13 ], [ 690, 1004, 22, 13 ], [ 717, 1004, 53, 13 ], [ 80, 1047, 25, 12 ], [ 108, 1047, 21, 12 ], [ 134, 1047, 3, 12 ], [ 142, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 536, 1047, 52, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "A", "Novel", "MMP-2", "Inhibitor", "3-azidowithaferin", "A", "(3-", "azidoWA)", "Abrogates", "Cancer", "Cell", "Invasion", "and", "Angiogenesis", "by", "Modulating", "Extracellular", "Par-4", "Bilal", "Rah", "1", ",", "Hina", "Amin1,", "Khalid", "Yousuf2,", "Sheema", "Khan", "1", ",", "Gayatri", "Jamwal1,", "Debaraj", "Mukherjee2,", "Anindya", "Goswami1*", "1", "Molecular", "Signal", "Transduction", "Laboratory,", "Cancer", "Pharmacology", "Division,", "Indian", "Institute", "of", "Integrative", "Medicine", "(CSIR),", "Jammu", "Tawi,", "India,", "2", "Nautral", "Product", "Chemistry,", "Indian", "Institute", "of", "Integrative", "Medicine", "(CSIR),", "Jammu", "Tawi,", "India", "Abstract", "Background:", "Withaferin", "A,", "which", "is", "a", "naturally", "derived", "steroidal", "lactone,", "has", "been", "found", "to", "prevent", "angiogenesis", "and", "metastasis", "in", "diverse", "tumor", "models.", "It", "has", "also", "been", "recognized", "by", "different", "groups", "for", "prominent", "anti-carcinogenic", "roles.", "However,", "in", "spite", "of", "these", "studies", "on", "withanolides,", "their", "detailed", "anti-metastatic", "mechanism", "of", "action", "remained", "unknown.", "The", "current", "study", "has", "poised", "to", "address", "the", "machinery", "involved", "in", "invasion", "regulation", "by", "stable", "derivative", "of", "Withaferin", "A,", "3-azido", "Withaferin", "A", "(3-azidoWA)", "in", "human", "cervical", "HeLa", "and", "prostate", "PC-3", "cells.", "Methods", "and", "Principal", "Findings:", "Sub-toxic", "concentration", "of", "3-azidowithaferin", "A", "(3-azido", "WA)", "inhibited", "cancer", "cell", "motility", "and", "invasion", "in", "wound", "healing", "and", "Boyden", "chamber", "invasion", "by", "suppressing", "MMP-2", "activity", "in", "gelatin", "zymography", "and", "its", "expression", "has", "proved", "to", "be", "a", "major", "obstacle", "in", "chemo-sensitivity.", "We", "have", "uncovered", "a", "novel", "mechanism", "of", "3-azidoWA", "induced", "extracellular", "pro-apoptotic", "candidate", "tumor", "suppressor", "Par-4", "protein", "stimulation", "in", "conditioned", "media", "and", "also", "noticed", "a", "concomitant", "marked", "reduction", "in", "pAkt", "and", "pERK", "signaling", "by", "immunoblot", "analysis.", "Furthermore,", "our", "zymography", "results", "suggest", "3-azidoWA", "induced", "MMP-2", "inhibition", "was", "mediated", "through", "secretory", "Par-4.", "The", "inhibition", "of", "apoptosis", "by", "3-azidoWA", "could", "not", "restore", "MMP-2", "gelatinase", "activity.", "In", "addition", "to", "this,", "our", "in", "vivo", "animal", "experiments", "data", "showed", "3-azidoWA", "abrogated", "neovascularisation", "in", "dose", "dependent", "manner", "in", "mouse", "Matrigel", "plug", "assay.", "Conclusion/Significance:", "For", "this", "report,", "we", "found", "that", "3-azidoWA", "suppressed", "motility", "and", "invasion", "of", "HeLa", "and", "PC-3", "cells", "in", "MMP-2", "dependent", "manner.", "Our", "in", "vitro", "result", "strongly", "suggests", "that", "sub-toxic", "doses", "of", "3-azidoWA", "enhanced", "the", "secretion", "of", "extracellular", "Par-4", "that", "abolished", "secretory", "MMP-2", "expression", "and", "activity.", "Depletion", "of", "secretory", "Par-4", "restored", "MMP-2", "expression", "and", "invasion", "capability", "of", "HeLa", "and", "PC-3", "cells.", "Further,", "our", "findings", "implied", "that", "3-azidoWA", "attenuated", "internal", "phospho-ERK", "and", "phospho-Akt", "expression", "in", "a", "dose", "dependent", "manner", "might", "play", "a", "key", "role", "in", "inhibition", "of", "mouse", "angiogenesis", "by", "3-azidoWA.", "Citation:", "Rah", "B,", "Amin", "H,", "Yousuf", "K,", "Khan", "S,", "Jamwal", "G,", "et", "al.", "(2012)", "A", "Novel", "MMP-2", "Inhibitor", "3-azidowithaferin", "A", "(3-azidoWA)", "Abrogates", "Cancer", "Cell", "Invasion", "and", "Angiogenesis", "by", "Modulating", "Extracellular", "Par-4.", "PLoS", "ONE", "7(9):", "e44039.", "doi:10.1371/journal.pone.0044039", "Editor:", "Daotai", "Nie,", "Southern", "Illinois", "University", "School", "of", "Medicine,", "United", "States", "of", "America", "Received", "May", "23,", "2012;", "Accepted", "August", "1,", "2012;", "Published", "September", "4,", "2012", "Copyright:", "2012", "Rah", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "authors", "have", "no", "support", "or", "funding", "to", "report.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "agoswami@iiim.ac.in", "Introduction", "Extracellular", "secretory", "pathways", "are", "considered", "to", "play", "pivotal", "role", "in", "human", "physiology.", "Body’s", "vital", "hormones", "and", "growth", "factors", "are", "secreted", "and", "they", "control", "the", "development", "and", "differentiation", "of", "organs", "in", "normal", "physiological", "condition.", "Likewise,", "systemic", "(extracellular)", "proteins", "attribute", "major", "in", "vivo", "function", "during", "tissue", "growth", "and", "apoptosis", "[1].", "Prostate", "apoptotic", "response", "4", "(Par-4)", "is", "ubiquitously", "expressed", "and", "evolutionary", "conserved", "pro-apoptotic", "protein", "whose", "expression", "was", "mainly", "correlated", "with", "the", "cells", "that", "undergo", "apoptosis", "due", "to", "exogenous", "insults", "[2].", "Apart", "from", "its", "intracellular", "function,", "the", "new", "perspective", "of", "extracellular", "secretion", "in", "different", "cancer", "cells", "has", "augmented", "the", "therapeutic", "potential", "of", "Par-4", "[3].", "Recently,", "Burikhanov", "et", "al.", "have", "shown", "that", "mammalian", "cells", "in", "general", "caused", "secretion", "of", "Par-4.", "However,", "the", "apoptotic", "induction", "by", "extracellular", "Par-4", "occurring", "via", "cell-", "surface", "GRP-78", "was", "found", "to", "promote", "cell", "invasion", "and", "tumorigenesis", "[3].", "The", "stabilization", "of", "pro-angiogenic", "GRP-78", "by", "Par-4", "has", "been", "designated", "an", "anti-", "invasive", "role", "of", "extracellular", "Par-4.", "Metastasis", "is", "a", "multi-step", "process", "involving", "cell", "migration", "and", "pericellular", "proteolysis", "of", "ECM", "that", "mediates", "cancer", "cells", "protrusion", "[4].", "Matrix", "metalloproteinases", "(MMP’s)", "are", "responsible", "for", "the", "degradation", "of", "environmental", "barriers,", "such", "as", "the", "extracellular", "matrix", "and", "basement", "membrane", "[5,6].", "Amongst", "the", "MMP", "family", "members,", "MMP-2", "and", "-9", "are", "generally", "considered", "to", "be", "the", "malignancy", "of", "various", "tumors", "as", "well", "as", "poor", "prognosis", "of", "many", "cancers", "[6].", "Thus,", "MMP’s", "are", "capable", "of", "cleaving", "type", "IV", "basement", "membrane", "collagen", "(MMP-2", "and", "-9)", "and", "add", "value", "for", "drug", "development.", "Compelling", "preclinical", "studies", "from", "diverse", "laboratories", "have", "provided", "overwhelming", "support", "for", "direct", "relationship", "between", "MMP-2", "over", "expression", "PLOS", "ONE", "|", "www.plosone.org", "1", "September", "2012", "|", "Volume", "7", "|", "Issue", "9", "|", "e44039" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 438, 57, 50, 12 ], [ 490, 57, 34, 12 ], [ 527, 57, 245, 12 ], [ 78, 115, 85, 21 ], [ 168, 115, 54, 21 ], [ 78, 118, 13, 3 ], [ 78, 139, 166, 23 ], [ 250, 139, 87, 23 ], [ 342, 139, 22, 23 ], [ 369, 139, 35, 23 ], [ 409, 139, 56, 23 ], [ 469, 139, 77, 23 ], [ 551, 139, 40, 23 ], [ 596, 139, 75, 23 ], [ 676, 139, 65, 23 ], [ 746, 139, 20, 23 ], [ 78, 164, 83, 23 ], [ 167, 164, 22, 23 ], [ 195, 164, 68, 23 ], [ 268, 164, 77, 23 ], [ 351, 164, 155, 23 ], [ 511, 164, 40, 23 ], [ 557, 164, 88, 23 ], [ 651, 164, 13, 23 ], [ 78, 189, 188, 23 ], [ 272, 189, 132, 23 ], [ 410, 189, 40, 23 ], [ 455, 189, 101, 23 ], [ 562, 189, 58, 23 ], [ 662, 116, 44, 16 ], [ 709, 116, 61, 16 ], [ 78, 215, 61, 17 ], [ 144, 215, 92, 17 ], [ 239, 215, 35, 17 ], [ 278, 215, 12, 17 ], [ 294, 215, 89, 17 ], [ 386, 215, 37, 17 ], [ 427, 215, 92, 17 ], [ 522, 215, 47, 17 ], [ 574, 215, 72, 17 ], [ 649, 215, 28, 17 ], [ 680, 215, 88, 17 ], [ 78, 237, 50, 17 ], [ 133, 237, 23, 17 ], [ 160, 237, 14, 17 ], [ 179, 237, 23, 17 ], [ 206, 237, 28, 17 ], [ 238, 237, 12, 17 ], [ 254, 237, 44, 17 ], [ 302, 237, 49, 17 ], [ 355, 237, 10, 17 ], [ 368, 237, 32, 17 ], [ 405, 237, 25, 17 ], [ 433, 237, 38, 17 ], [ 476, 237, 48, 17 ], [ 528, 237, 28, 17 ], [ 560, 237, 27, 17 ], [ 591, 237, 33, 17 ], [ 628, 237, 65, 17 ], [ 78, 283, 60, 12 ], [ 141, 283, 10, 12 ], [ 154, 283, 37, 12 ], [ 193, 283, 64, 12 ], [ 260, 283, 18, 12 ], [ 281, 283, 61, 12 ], [ 344, 283, 49, 12 ], [ 395, 283, 40, 12 ], [ 438, 283, 34, 12 ], [ 475, 283, 17, 12 ], [ 494, 283, 23, 12 ], [ 520, 283, 20, 12 ], [ 542, 283, 13, 12 ], [ 558, 283, 30, 12 ], [ 591, 283, 40, 12 ], [ 78, 296, 55, 12 ], [ 136, 297, 46, 11 ], [ 185, 297, 41, 11 ], [ 229, 297, 38, 11 ], [ 269, 297, 10, 11 ], [ 281, 297, 52, 11 ], [ 336, 297, 13, 11 ], [ 351, 297, 39, 11 ], [ 393, 297, 32, 11 ], [ 427, 297, 41, 11 ], [ 471, 297, 40, 11 ], [ 513, 297, 49, 11 ], [ 565, 297, 39, 11 ], [ 78, 310, 60, 12 ], [ 141, 310, 10, 12 ], [ 154, 310, 63, 12 ], [ 219, 310, 51, 12 ], [ 272, 310, 49, 12 ], [ 324, 310, 67, 12 ], [ 393, 310, 22, 12 ], [ 418, 310, 20, 12 ], [ 440, 310, 13, 12 ], [ 456, 310, 53, 12 ], [ 512, 310, 40, 12 ], [ 78, 323, 57, 12 ], [ 138, 323, 18, 12 ], [ 159, 323, 63, 12 ], [ 225, 323, 47, 12 ], [ 274, 323, 41, 12 ], [ 318, 323, 38, 12 ], [ 359, 323, 9, 12 ], [ 370, 323, 52, 12 ], [ 425, 323, 13, 12 ], [ 441, 323, 39, 12 ], [ 482, 323, 32, 12 ], [ 516, 323, 41, 12 ], [ 560, 323, 40, 12 ], [ 603, 323, 49, 12 ], [ 655, 323, 39, 12 ], [ 78, 336, 37, 12 ], [ 118, 336, 13, 11 ], [ 134, 336, 47, 11 ], [ 183, 336, 66, 11 ], [ 252, 336, 56, 11 ], [ 310, 336, 10, 11 ], [ 323, 336, 56, 11 ], [ 381, 336, 64, 11 ], [ 448, 336, 18, 11 ], [ 469, 336, 30, 11 ], [ 501, 336, 46, 11 ], [ 550, 336, 39, 11 ], [ 591, 336, 46, 11 ], [ 640, 336, 10, 11 ], [ 652, 336, 52, 11 ], [ 706, 336, 13, 11 ], [ 722, 336, 38, 11 ], [ 78, 349, 27, 12 ], [ 108, 349, 49, 12 ], [ 160, 349, 39, 12 ], [ 78, 374, 72, 12 ], [ 152, 374, 33, 12 ], [ 188, 374, 41, 12 ], [ 232, 374, 57, 12 ], [ 291, 374, 128, 12 ], [ 78, 399, 48, 12 ], [ 128, 399, 7, 12 ], [ 138, 399, 18, 12 ], [ 159, 399, 26, 12 ], [ 191, 399, 46, 12 ], [ 239, 399, 51, 12 ], [ 293, 399, 13, 12 ], [ 309, 399, 19, 12 ], [ 330, 399, 26, 12 ], [ 362, 399, 46, 12 ], [ 410, 399, 44, 12 ], [ 456, 399, 13, 12 ], [ 472, 399, 19, 12 ], [ 494, 399, 26, 12 ], [ 526, 399, 50, 12 ], [ 578, 399, 13, 12 ], [ 594, 399, 19, 12 ], [ 616, 399, 26, 12 ], [ 648, 399, 50, 12 ], [ 700, 399, 13, 12 ], [ 716, 399, 19, 12 ], [ 738, 399, 26, 12 ], [ 78, 425, 32, 12 ], [ 113, 425, 36, 12 ], [ 151, 425, 45, 12 ], [ 199, 425, 29, 12 ], [ 230, 425, 30, 12 ], [ 263, 425, 111, 12 ], [ 78, 439, 20, 12 ], [ 101, 439, 29, 12 ], [ 132, 439, 8, 12 ], [ 143, 439, 29, 12 ], [ 174, 439, 12, 12 ], [ 189, 439, 245, 12 ], [ 78, 453, 10, 12 ], [ 91, 453, 26, 12 ], [ 120, 453, 54, 12 ], [ 176, 453, 9, 12 ], [ 189, 453, 14, 12 ], [ 205, 453, 39, 12 ], [ 247, 453, 37, 12 ], [ 287, 453, 35, 12 ], [ 325, 453, 18, 12 ], [ 78, 467, 20, 12 ], [ 100, 467, 8, 12 ], [ 110, 467, 12, 12 ], [ 123, 467, 24, 12 ], [ 150, 467, 34, 12 ], [ 185, 467, 29, 12 ], [ 216, 467, 51, 12 ], [ 268, 467, 28, 12 ], [ 298, 467, 15, 12 ], [ 315, 467, 27, 12 ], [ 343, 467, 10, 12 ], [ 354, 467, 15, 12 ], [ 371, 467, 40, 12 ], [ 413, 467, 49, 12 ], [ 464, 467, 49, 12 ], [ 515, 467, 37, 12 ], [ 554, 467, 216, 12 ], [ 78, 481, 28, 12 ], [ 109, 481, 35, 12 ], [ 147, 481, 57, 12 ], [ 206, 481, 20, 12 ], [ 229, 481, 55, 12 ], [ 287, 481, 18, 12 ], [ 307, 481, 61, 12 ], [ 370, 481, 9, 12 ], [ 382, 481, 17, 12 ], [ 401, 481, 40, 12 ], [ 444, 481, 42, 12 ], [ 488, 481, 15, 12 ], [ 506, 481, 35, 12 ], [ 543, 481, 23, 12 ], [ 568, 481, 8, 12 ], [ 579, 481, 39, 12 ], [ 620, 481, 26, 12 ], [ 78, 522, 60, 15 ], [ 78, 550, 69, 13 ], [ 155, 550, 53, 13 ], [ 214, 550, 10, 13 ], [ 231, 550, 17, 13 ], [ 255, 550, 107, 13 ], [ 369, 550, 44, 13 ], [ 78, 565, 34, 13 ], [ 123, 565, 20, 13 ], [ 154, 565, 59, 13 ], [ 224, 565, 34, 13 ], [ 269, 565, 8, 13 ], [ 287, 565, 50, 13 ], [ 349, 565, 33, 13 ], [ 393, 565, 20, 13 ], [ 78, 579, 67, 13 ], [ 149, 579, 11, 13 ], [ 164, 579, 17, 13 ], [ 185, 579, 45, 13 ], [ 234, 579, 28, 13 ], [ 265, 579, 72, 13 ], [ 341, 579, 47, 13 ], [ 392, 579, 21, 13 ], [ 78, 594, 54, 13 ], [ 136, 594, 46, 13 ], [ 186, 594, 8, 13 ], [ 198, 594, 49, 13 ], [ 251, 594, 27, 13 ], [ 282, 594, 25, 13 ], [ 311, 594, 27, 13 ], [ 342, 594, 57, 13 ], [ 402, 594, 11, 13 ], [ 78, 608, 25, 13 ], [ 109, 608, 13, 13 ], [ 128, 608, 50, 13 ], [ 184, 608, 20, 13 ], [ 209, 608, 10, 13 ], [ 224, 608, 34, 13 ], [ 264, 608, 37, 13 ], [ 306, 608, 51, 13 ], [ 362, 608, 51, 13 ], [ 78, 623, 43, 13 ], [ 127, 623, 46, 13 ], [ 179, 623, 44, 13 ], [ 229, 623, 10, 13 ], [ 244, 623, 30, 13 ], [ 279, 623, 33, 13 ], [ 318, 623, 19, 13 ], [ 342, 623, 7, 13 ], [ 355, 623, 20, 13 ], [ 381, 623, 10, 13 ], [ 396, 623, 17, 13 ], [ 78, 638, 69, 13 ], [ 154, 638, 11, 13 ], [ 171, 638, 34, 13 ], [ 212, 638, 37, 13 ], [ 255, 638, 11, 13 ], [ 273, 638, 34, 13 ], [ 314, 638, 37, 13 ], [ 357, 638, 39, 13 ], [ 403, 638, 10, 13 ], [ 78, 652, 42, 13 ], [ 123, 652, 9, 13 ], [ 135, 652, 18, 13 ], [ 156, 652, 17, 13 ], [ 176, 652, 29, 13 ], [ 78, 681, 50, 13 ], [ 131, 681, 20, 13 ], [ 153, 681, 55, 13 ], [ 211, 681, 7, 13 ], [ 220, 681, 81, 13 ], [ 303, 681, 52, 13 ], [ 358, 681, 42, 13 ], [ 402, 681, 11, 13 ], [ 78, 696, 17, 13 ], [ 99, 696, 29, 13 ], [ 131, 696, 43, 13 ], [ 177, 696, 20, 13 ], [ 200, 696, 42, 13 ], [ 245, 696, 33, 13 ], [ 281, 696, 10, 13 ], [ 294, 696, 7, 13 ], [ 304, 696, 46, 13 ], [ 353, 696, 60, 13 ], [ 78, 710, 33, 13 ], [ 116, 710, 32, 13 ], [ 153, 710, 32, 13 ], [ 189, 710, 46, 13 ], [ 240, 710, 32, 13 ], [ 277, 710, 34, 13 ], [ 315, 710, 37, 13 ], [ 356, 710, 32, 13 ], [ 393, 710, 20, 13 ], [ 78, 725, 32, 13 ], [ 118, 725, 46, 13 ], [ 171, 725, 20, 13 ], [ 198, 725, 45, 13 ], [ 250, 725, 17, 13 ], [ 275, 725, 32, 13 ], [ 314, 725, 15, 13 ], [ 335, 725, 18, 13 ], [ 360, 725, 31, 13 ], [ 399, 725, 14, 13 ], [ 78, 740, 45, 13 ], [ 129, 740, 20, 13 ], [ 154, 740, 47, 13 ], [ 206, 740, 59, 13 ], [ 270, 740, 14, 13 ], [ 289, 740, 17, 13 ], [ 311, 740, 24, 13 ], [ 340, 740, 20, 13 ], [ 365, 740, 32, 13 ], [ 402, 740, 11, 13 ], [ 78, 754, 30, 13 ], [ 111, 754, 34, 13 ], [ 147, 754, 20, 13 ], [ 170, 754, 34, 13 ], [ 207, 754, 24, 13 ], [ 233, 754, 17, 13 ], [ 253, 754, 58, 13 ], [ 313, 754, 46, 13 ], [ 362, 754, 38, 13 ], [ 402, 754, 11, 13 ], [ 78, 769, 31, 13 ], [ 115, 769, 42, 13 ], [ 164, 769, 20, 13 ], [ 190, 769, 46, 13 ], [ 242, 769, 31, 13 ], [ 279, 769, 96, 13 ], [ 381, 769, 31, 13 ], [ 78, 783, 56, 13 ], [ 138, 783, 10, 13 ], [ 151, 783, 17, 13 ], [ 172, 783, 26, 13 ], [ 202, 783, 30, 13 ], [ 236, 783, 14, 13 ], [ 253, 783, 48, 13 ], [ 305, 783, 10, 13 ], [ 319, 783, 17, 13 ], [ 339, 783, 43, 13 ], [ 386, 783, 27, 13 ], [ 437, 550, 20, 13 ], [ 462, 550, 31, 13 ], [ 499, 550, 48, 13 ], [ 552, 550, 10, 13 ], [ 566, 550, 17, 13 ], [ 588, 550, 42, 13 ], [ 635, 550, 27, 13 ], [ 666, 550, 20, 13 ], [ 691, 550, 51, 13 ], [ 747, 550, 24, 13 ], [ 437, 565, 55, 13 ], [ 497, 565, 20, 13 ], [ 521, 565, 32, 13 ], [ 557, 565, 29, 13 ], [ 590, 565, 50, 13 ], [ 645, 565, 10, 13 ], [ 658, 565, 17, 13 ], [ 680, 565, 55, 13 ], [ 739, 565, 33, 13 ], [ 437, 579, 22, 13 ], [ 464, 579, 14, 13 ], [ 481, 579, 34, 13 ], [ 520, 579, 7, 13 ], [ 532, 579, 21, 13 ], [ 557, 579, 33, 13 ], [ 595, 579, 48, 13 ], [ 648, 579, 26, 13 ], [ 679, 579, 57, 13 ], [ 740, 579, 10, 13 ], [ 755, 579, 17, 13 ], [ 437, 594, 50, 13 ], [ 492, 594, 17, 13 ], [ 513, 594, 11, 13 ], [ 528, 594, 32, 13 ], [ 565, 594, 20, 13 ], [ 589, 594, 46, 13 ], [ 640, 594, 20, 13 ], [ 664, 594, 54, 13 ], [ 723, 594, 49, 13 ], [ 437, 608, 52, 13 ], [ 493, 608, 46, 13 ], [ 542, 608, 11, 13 ], [ 556, 608, 17, 13 ], [ 576, 608, 42, 13 ], [ 621, 608, 58, 13 ], [ 683, 608, 20, 13 ], [ 706, 608, 46, 13 ], [ 755, 608, 17, 13 ], [ 437, 623, 46, 13 ], [ 486, 623, 13, 13 ], [ 501, 623, 60, 13 ], [ 564, 623, 47, 13 ], [ 614, 623, 10, 13 ], [ 626, 623, 22, 13 ], [ 650, 623, 64, 13 ], [ 717, 623, 41, 13 ], [ 761, 623, 11, 13 ], [ 437, 638, 38, 13 ], [ 479, 638, 56, 13 ], [ 538, 638, 42, 13 ], [ 437, 667, 43, 13 ], [ 483, 667, 20, 13 ], [ 505, 667, 31, 13 ], [ 538, 667, 14, 13 ], [ 554, 667, 60, 13 ], [ 616, 667, 46, 13 ], [ 665, 667, 19, 13 ], [ 685, 667, 40, 13 ], [ 727, 667, 45, 13 ], [ 437, 681, 10, 13 ], [ 454, 681, 17, 13 ], [ 477, 681, 29, 13 ], [ 513, 681, 43, 13 ], [ 562, 681, 11, 13 ], [ 580, 681, 42, 13 ], [ 629, 681, 33, 13 ], [ 668, 681, 20, 13 ], [ 695, 681, 34, 13 ], [ 735, 681, 37, 13 ], [ 437, 696, 39, 13 ], [ 486, 696, 11, 13 ], [ 507, 696, 17, 13 ], [ 534, 696, 19, 13 ], [ 562, 696, 11, 13 ], [ 582, 696, 59, 13 ], [ 650, 696, 44, 13 ], [ 704, 696, 22, 13 ], [ 735, 696, 36, 13 ], [ 437, 710, 81, 13 ], [ 437, 740, 64, 13 ], [ 506, 740, 21, 13 ], [ 532, 740, 36, 13 ], [ 572, 740, 42, 13 ], [ 619, 740, 20, 13 ], [ 644, 740, 46, 13 ], [ 695, 740, 41, 13 ], [ 740, 740, 10, 13 ], [ 755, 740, 17, 13 ], [ 437, 754, 29, 13 ], [ 470, 754, 43, 13 ], [ 518, 754, 11, 13 ], [ 533, 754, 41, 13 ], [ 579, 754, 33, 13 ], [ 616, 754, 17, 13 ], [ 637, 754, 17, 13 ], [ 659, 754, 43, 13 ], [ 707, 754, 10, 13 ], [ 720, 754, 51, 13 ], [ 437, 769, 34, 13 ], [ 478, 769, 37, 13 ], [ 522, 769, 39, 13 ], [ 569, 769, 11, 13 ], [ 587, 769, 17, 13 ], [ 612, 769, 19, 13 ], [ 638, 769, 11, 13 ], [ 656, 769, 116, 13 ], [ 437, 783, 40, 13 ], [ 480, 783, 34, 13 ], [ 517, 783, 39, 13 ], [ 78, 830, 90, 16 ], [ 78, 847, 26, 13 ], [ 109, 847, 21, 13 ], [ 134, 847, 31, 13 ], [ 170, 847, 40, 13 ], [ 214, 847, 65, 13 ], [ 283, 847, 43, 13 ], [ 331, 847, 21, 13 ], [ 356, 847, 18, 13 ], [ 378, 847, 19, 13 ], [ 402, 847, 11, 13 ], [ 78, 863, 35, 13 ], [ 117, 863, 38, 13 ], [ 158, 863, 9, 13 ], [ 171, 863, 60, 13 ], [ 234, 863, 10, 13 ], [ 247, 863, 25, 13 ], [ 276, 863, 13, 13 ], [ 292, 863, 54, 13 ], [ 350, 863, 41, 13 ], [ 395, 863, 18, 13 ], [ 78, 879, 46, 13 ], [ 131, 879, 53, 13 ], [ 190, 879, 30, 13 ], [ 226, 879, 11, 13 ], [ 243, 879, 44, 13 ], [ 294, 879, 15, 13 ], [ 315, 879, 22, 13 ], [ 343, 879, 35, 13 ], [ 384, 879, 11, 13 ], [ 401, 879, 12, 13 ], [ 78, 896, 35, 13 ], [ 116, 896, 38, 13 ], [ 156, 896, 33, 13 ], [ 191, 896, 10, 13 ], [ 203, 896, 18, 13 ], [ 224, 896, 41, 13 ], [ 267, 896, 58, 13 ], [ 327, 896, 19, 13 ], [ 349, 896, 9, 13 ], [ 360, 896, 53, 13 ], [ 78, 912, 34, 13 ], [ 116, 912, 20, 13 ], [ 139, 912, 28, 13 ], [ 170, 912, 53, 13 ], [ 227, 912, 11, 13 ], [ 241, 912, 44, 13 ], [ 289, 912, 15, 13 ], [ 308, 912, 18, 13 ], [ 329, 912, 43, 13 ], [ 375, 912, 37, 13 ], [ 78, 928, 19, 13 ], [ 102, 928, 19, 13 ], [ 125, 928, 33, 13 ], [ 162, 928, 60, 13 ], [ 226, 928, 28, 13 ], [ 259, 928, 37, 13 ], [ 300, 928, 11, 13 ], [ 316, 928, 39, 13 ], [ 359, 928, 54, 13 ], [ 78, 945, 35, 13 ], [ 116, 945, 41, 13 ], [ 160, 945, 19, 13 ], [ 183, 945, 42, 13 ], [ 228, 945, 10, 13 ], [ 241, 945, 67, 13 ], [ 311, 945, 23, 13 ], [ 337, 945, 76, 13 ], [ 78, 961, 52, 13 ], [ 134, 961, 49, 13 ], [ 185, 961, 14, 13 ], [ 202, 961, 37, 13 ], [ 242, 961, 24, 13 ], [ 269, 961, 25, 13 ], [ 296, 961, 15, 13 ], [ 314, 961, 18, 13 ], [ 334, 961, 31, 13 ], [ 367, 961, 11, 13 ], [ 381, 961, 32, 13 ], [ 437, 830, 19, 13 ], [ 461, 830, 82, 13 ], [ 548, 830, 14, 13 ], [ 567, 830, 39, 13 ], [ 610, 830, 51, 13 ], [ 666, 830, 28, 13 ], [ 699, 830, 9, 13 ], [ 713, 830, 35, 13 ], [ 753, 830, 19, 13 ], [ 437, 847, 35, 13 ], [ 476, 847, 21, 13 ], [ 502, 847, 30, 13 ], [ 537, 847, 65, 13 ], [ 606, 847, 9, 13 ], [ 620, 847, 7, 13 ], [ 631, 847, 56, 13 ], [ 691, 847, 65, 13 ], [ 761, 847, 11, 13 ], [ 437, 863, 18, 13 ], [ 458, 863, 38, 13 ], [ 499, 863, 53, 13 ], [ 555, 863, 11, 13 ], [ 569, 863, 69, 13 ], [ 640, 863, 53, 13 ], [ 696, 863, 63, 13 ], [ 762, 863, 10, 13 ], [ 437, 879, 26, 13 ], [ 467, 879, 30, 13 ], [ 500, 879, 20, 13 ], [ 524, 879, 24, 13 ], [ 551, 879, 17, 13 ], [ 571, 879, 18, 13 ], [ 592, 879, 11, 13 ], [ 606, 879, 30, 13 ], [ 639, 879, 18, 13 ], [ 660, 879, 21, 13 ], [ 684, 879, 11, 13 ], [ 698, 879, 48, 13 ], [ 749, 879, 23, 13 ], [ 437, 896, 27, 13 ], [ 467, 896, 10, 13 ], [ 479, 896, 19, 13 ], [ 500, 896, 35, 13 ], [ 537, 896, 38, 13 ], [ 577, 896, 54, 13 ], [ 633, 896, 34, 13 ], [ 669, 896, 10, 13 ], [ 681, 896, 40, 13 ], [ 724, 896, 11, 13 ], [ 737, 896, 35, 13 ], [ 437, 912, 38, 13 ], [ 478, 912, 52, 13 ], [ 534, 912, 40, 13 ], [ 577, 912, 21, 13 ], [ 601, 912, 39, 13 ], [ 642, 912, 83, 13 ], [ 437, 945, 21, 13 ], [ 468, 945, 110, 13 ], [ 587, 945, 45, 13 ], [ 642, 945, 34, 13 ], [ 686, 945, 24, 13 ], [ 720, 945, 52, 13 ], [ 437, 961, 60, 13 ], [ 504, 961, 35, 13 ], [ 544, 961, 8, 13 ], [ 558, 961, 51, 13 ], [ 614, 961, 24, 13 ], [ 644, 961, 49, 13 ], [ 699, 961, 21, 13 ], [ 725, 961, 46, 13 ], [ 78, 990, 17, 12 ], [ 98, 990, 8, 12 ], [ 108, 990, 98, 12 ], [ 209, 990, 23, 12 ], [ 234, 990, 8, 12 ], [ 245, 990, 95, 12 ], [ 342, 990, 42, 12 ], [ 387, 990, 37, 12 ], [ 426, 990, 8, 12 ], [ 437, 990, 52, 12 ], [ 491, 990, 30, 12 ], [ 524, 990, 10, 12 ], [ 537, 990, 11, 12 ], [ 551, 990, 8, 12 ], [ 561, 990, 53, 12 ], [ 616, 990, 37, 12 ], [ 656, 990, 35, 12 ], [ 693, 990, 8, 12 ], [ 704, 990, 30, 12 ], [ 737, 990, 31, 12 ], [ 78, 1004, 24, 11 ], [ 105, 1004, 67, 11 ], [ 174, 1004, 47, 11 ], [ 223, 1004, 36, 11 ], [ 261, 1004, 8, 11 ], [ 272, 1004, 40, 11 ], [ 314, 1004, 25, 11 ], [ 341, 1004, 64, 11 ], [ 407, 1004, 42, 11 ], [ 450, 1004, 19, 11 ], [ 472, 1004, 48, 11 ], [ 521, 1004, 41, 11 ], [ 565, 1004, 10, 11 ], [ 577, 1004, 27, 11 ], [ 606, 1004, 8, 11 ], [ 616, 1004, 82, 11 ], [ 700, 1004, 55, 11 ], [ 757, 1004, 12, 11 ], [ 78, 1017, 8, 12 ], [ 89, 1017, 42, 12 ], [ 133, 1017, 14, 12 ], [ 150, 1017, 8, 12 ], [ 160, 1017, 34, 12 ], [ 197, 1017, 68, 12 ], [ 268, 1017, 17, 12 ], [ 287, 1017, 8, 12 ], [ 298, 1017, 24, 12 ], [ 324, 1017, 24, 12 ], [ 351, 1017, 23, 12 ], [ 376, 1017, 8, 12 ], [ 387, 1017, 28, 12 ], [ 417, 1017, 50, 12 ], [ 469, 1017, 69, 12 ], [ 541, 1017, 38, 12 ], [ 581, 1017, 8, 12 ], [ 592, 1017, 85, 12 ], [ 680, 1017, 25, 12 ], [ 707, 1052, 25, 12 ], [ 735, 1052, 7, 12 ], [ 744, 1052, 10, 12 ], [ 756, 1052, 13, 12 ], [ 603, 1067, 25, 10 ], [ 630, 1067, 32, 10 ], [ 665, 1067, 14, 10 ], [ 680, 1067, 11, 10 ], [ 694, 1067, 30, 10 ], [ 727, 1067, 43, 10 ] ]

[ "Available", "online", "http://breast-cancer-research.com/content/8/6/R67", "Research", "article", "Vol8No6", "Comprehensive", "analysis", "of", "the", "ATM,", "CHEK2", "and", "ERBB2", "genes", "in", "relation", "to", "breast", "tumour", "characteristics", "and", "survival:", "a", "population-based", "case-control", "and", "follow-up", "study", "Open", "Access", "Kristjana", "Einarsdóttir1,", "Lena", "U", "Rosenberg1,", "Keith", "Humphreys1,", "Carine", "Bonnard2,", "Juni", "Palmgren1,3,", "Yuqing", "Li2,", "Yi", "Li4,", "Kee", "S", "Chia5,", "Edison", "T", "Liu2,", "Per", "Hall1,", "Jianjun", "Liu2", "and", "Sara", "Wedrén1", "1Department", "of", "Medical", "Epidemiology", "and", "Biostatistics,", "Karolinska", "Institute,", "Nobels", "väg", "12A,", "171", "77", "Solna,", "Sweden", "2Population", "Genetics,", "Genome", "Institute", "of", "Singapore,", "60", "Biopolis", "Street,", "Genome", "#02-01,", "Singapore", "138672", "3Department", "of", "Mathematics,", "Stockholm", "University,", "Roslagsvägen", "101,", "106", "91", "Stockholm,", "Sweden", "4Information", "and", "Mathematical", "Sciences,", "Genome", "Institute", "of", "Singapore,", "60", "Biopolis", "Street,", "Genome", "#02-01,", "Singapore", "138672", "5Centre", "for", "Molecular", "Epidemiology,", "Department", "of", "Community,", "Occupational", "and", "Family", "Medicine,", "National", "University", "of", "Singapore,", "16", "Medical", "Drive,", "Singapore", "117597", "Corresponding", "author:", "Kristjana", "Einarsdóttir,", "Kristjana.Einarsdottir@ki.se", "Received:", "3", "Oct", "2006", "Revisions", "requested:", "13", "Nov", "2006", "Revisions", "received:", "16", "Nov", "2006", "Accepted:", "28", "Nov", "2006", "Published:", "28", "Nov", "2006", "Breast", "Cancer", "Research", "2006,", "8:R67", "(doi:10.1186/bcr1623)", "This", "article", "is", "online", "at:", "http://breast-cancer-research.com/content/8/6/R67", "©", "2006", "Einarsdóttir", "et", "al.;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background", "Mutations", "in", "the", "ataxia-telangiectasia", "mutated", "(ATM)", "and", "checkpoint", "kinase", "2", "(CHEK2)", "genes", "and", "amplification", "of", "the", "v-erb-b2", "avian", "erythroblastic", "leukemia", "viral", "oncogene", "homolog", "2", "(ERBB2)", "gene", "have", "been", "suggested", "to", "have", "an", "important", "role", "in", "breast", "cancer", "aetiology.", "However,", "whether", "common", "variation", "in", "these", "genes", "has", "a", "role", "in", "the", "development", "of", "breast", "cancer", "or", "breast", "cancer", "survival", "in", "humans", "is", "still", "not", "clear.", "Methods", "We", "performed", "a", "comprehensive", "haplotype", "analysis", "of", "the", "ATM,", "CHEK2", "and", "ERBB2", "genes", "in", "a", "Swedish", "population-", "based", "study,", "which", "included", "1,579", "breast", "cancer", "cases", "and", "1,516", "controls.", "We", "followed", "the", "cases", "for", "8.5", "years,", "on", "average,", "and", "retrieved", "information", "on", "the", "date", "and", "cause", "of", "death", "during", "that", "period", "from", "the", "nationwide", "Swedish", "causes", "of", "death", "registry.", "We", "selected", "seven", "haplotype-tagging", "SNPs", "(tagSNPs)", "in", "the", "ATM", "gene,", "six", "tagSNPs", "in", "the", "CHEK2", "gene", "and", "seven", "tagSNPs", "in", "the", "ERBB2", "gene", "that", "predicted", "both", "haplotypic", "and", "single", "locus", "variations", "in", "the", "respective", "genes", "with", "R2", "values", "≥", "0.8.", "These", "tagSNPs", "were", "genotyped", "in", "the", "complete", "set", "of", "cases", "and", "controls.", "We", "computed", "expected", "haplotype", "dosages", "of", "the", "tagSNP", "haplotypes", "and", "included", "the", "dosages", "as", "explanatory", "variables", "in", "Cox", "proportional", "hazards", "or", "logistic", "regression", "models.", "Results", "We", "found", "no", "association", "between", "any", "genetic", "variation", "in", "the", "ATM,", "CHEK2", "or", "ERBB2", "genes", "and", "breast", "cancer", "survival", "or", "the", "risk", "of", "developing", "tumours", "with", "certain", "characteristics.", "Conclusion", "Our", "results", "indicate", "that", "common", "variants", "in", "the", "ATM,", "CHEK2", "or", "ERBB2", "genes", "are", "not", "involved", "in", "modifying", "breast", "cancer", "survival", "or", "the", "risk", "of", "tumour-characteristic-", "defined", "breast", "cancer.", "Introduction", "Twin", "and", "family", "studies", "consistently", "indicate", "that", "the", "risk", "of", "breast", "cancer", "is", "influenced,", "in", "part,", "by", "hereditary", "factors,", "but", "high-risk", "mutations", "seem", "to", "account", "for", "only", "1–2%", "of", "all", "breast", "cancer", "cases", "in", "the", "general", "population", "[1].", "A", "polygenic", "model", "has", "been", "proposed", "to", "account", "for", "the", "residual", "familial", "risk", "[2],", "which", "anticipates", "small", "effects", "of", "several", "low-pene-", "trance", "genetic", "risk", "variants", "in", "combination", "with", "environmental", "influence.", "Although", "no", "human", "data", "exist", "for", "the", "affect", "of", "germ-", "line", "polymorphisms", "on", "tumour", "outcome,", "there", "is", "strong", "evi-", "dence", "that", "strain", "background", "is", "a", "significant", "determinant", "of", "the", "clinical", "behaviour", "of", "experimental", "mammary", "carcinomas", "in", "mice", "[3-5].", "We", "thus", "set", "out", "to", "study", "the", "role", "of", "common", "vari-", "ation", "in", "key", "breast", "cancer", "candidate", "genes", "in", "relation", "to", "breast", "cancer", "aetiology,", "survival", "and", "tumour", "characteristics.", "The", "ataxia-telangiectasia", "mutated", "(ATM;", "MIM", "607585),", "checkpoint", "kinase", "2", "(CHEK2;", "MIM", "604373)", "and", "v-erb-b2", "A-T", "=", "ataxia-telangiectasia;", "ATM", "=", "ataxia-telangiectasia", "mutated;", "CHEK2", "=", "checkpoint", "kinase", "2;", "CI", "=", "confidence", "interval;", "dbSNP", "=", "Single", "Nucle-", "otide", "Polymorphism", "database;", "ERBB2", "=", "v-erb-b2", "avian", "erythroblastic", "leukemia", "viral", "oncogene", "homolog", "2;", "HWE", "=", "Hardy–Weinberg", "equilibrium;", "kb", "=", "kilobase;", "LD", "=", "linkage", "disequilibrium;", "OR", "=", "odds", "ratio;", "SNP", "=", "single", "nucleotide", "polymorphism;", "tagSNP", "=", "haplotype-tagging", "SNP.", "Page", "1", "of", "12", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 9, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 80, 78, 32, 28 ], [ 120, 78, 119, 28 ], [ 246, 78, 40, 28 ], [ 294, 78, 214, 28 ], [ 515, 78, 47, 28 ], [ 569, 78, 89, 28 ], [ 665, 78, 105, 28 ], [ 80, 109, 82, 28 ], [ 171, 109, 25, 28 ], [ 205, 109, 56, 28 ], [ 269, 109, 178, 28 ], [ 456, 109, 69, 28 ], [ 533, 109, 78, 28 ], [ 620, 109, 24, 28 ], [ 652, 109, 88, 28 ], [ 80, 139, 97, 28 ], [ 186, 139, 57, 28 ], [ 80, 183, 50, 14 ], [ 134, 180, 59, 17 ], [ 197, 183, 17, 14 ], [ 217, 183, 27, 14 ], [ 248, 183, 28, 14 ], [ 279, 183, 48, 14 ], [ 330, 180, 84, 17 ], [ 417, 183, 61, 14 ], [ 482, 183, 43, 14 ], [ 528, 183, 48, 14 ], [ 579, 183, 50, 14 ], [ 633, 183, 25, 14 ], [ 662, 183, 14, 14 ], [ 679, 183, 91, 14 ], [ 80, 205, 50, 10 ], [ 133, 205, 9, 10 ], [ 144, 205, 55, 10 ], [ 202, 205, 40, 10 ], [ 245, 205, 33, 10 ], [ 281, 205, 16, 10 ], [ 299, 205, 45, 10 ], [ 347, 205, 41, 10 ], [ 391, 205, 9, 10 ], [ 402, 205, 43, 10 ], [ 448, 205, 32, 10 ], [ 483, 205, 30, 10 ], [ 515, 205, 52, 10 ], [ 570, 205, 45, 10 ], [ 618, 205, 28, 10 ], [ 649, 205, 25, 10 ], [ 676, 205, 9, 10 ], [ 688, 205, 34, 10 ], [ 102, 244, 57, 14 ], [ 102, 266, 20, 13 ], [ 126, 266, 31, 13 ], [ 162, 266, 11, 13 ], [ 177, 266, 25, 13 ], [ 207, 266, 74, 13 ], [ 285, 266, 35, 13 ], [ 325, 266, 34, 13 ], [ 363, 266, 8, 13 ], [ 376, 266, 34, 13 ], [ 415, 266, 15, 13 ], [ 435, 266, 18, 13 ], [ 457, 266, 68, 13 ], [ 530, 266, 11, 13 ], [ 545, 266, 46, 13 ], [ 596, 266, 44, 13 ], [ 645, 266, 20, 13 ], [ 670, 266, 41, 13 ], [ 716, 266, 15, 13 ], [ 736, 266, 12, 13 ], [ 102, 280, 57, 13 ], [ 165, 280, 51, 13 ], [ 222, 280, 25, 13 ], [ 253, 280, 42, 13 ], [ 301, 280, 11, 13 ], [ 317, 280, 25, 13 ], [ 348, 280, 21, 13 ], [ 374, 280, 57, 13 ], [ 437, 280, 41, 13 ], [ 485, 280, 26, 13 ], [ 517, 280, 11, 13 ], [ 535, 280, 43, 13 ], [ 584, 280, 25, 13 ], [ 614, 280, 22, 13 ], [ 642, 280, 33, 13 ], [ 681, 280, 67, 13 ], [ 102, 294, 77, 13 ], [ 182, 294, 22, 13 ], [ 208, 294, 20, 13 ], [ 231, 294, 91, 13 ], [ 325, 294, 21, 13 ], [ 349, 294, 37, 13 ], [ 389, 294, 37, 13 ], [ 429, 294, 10, 13 ], [ 442, 294, 62, 13 ], [ 507, 294, 25, 13 ], [ 536, 294, 27, 13 ], [ 566, 294, 27, 13 ], [ 595, 294, 17, 13 ], [ 615, 294, 69, 13 ], [ 687, 294, 44, 13 ], [ 734, 294, 13, 13 ], [ 102, 307, 30, 13 ], [ 138, 307, 36, 13 ], [ 180, 307, 26, 13 ], [ 213, 307, 18, 13 ], [ 237, 307, 74, 13 ], [ 317, 307, 22, 13 ], [ 345, 307, 28, 13 ], [ 379, 307, 41, 13 ], [ 426, 307, 11, 13 ], [ 443, 307, 11, 13 ], [ 460, 307, 25, 13 ], [ 490, 307, 21, 13 ], [ 517, 307, 103, 13 ], [ 626, 307, 26, 13 ], [ 659, 307, 14, 13 ], [ 679, 307, 69, 13 ], [ 102, 321, 58, 13 ], [ 165, 321, 11, 13 ], [ 182, 321, 44, 13 ], [ 230, 321, 28, 13 ], [ 263, 321, 45, 13 ], [ 314, 321, 45, 13 ], [ 365, 321, 20, 13 ], [ 390, 321, 13, 13 ], [ 409, 321, 66, 13 ], [ 480, 321, 28, 13 ], [ 512, 321, 46, 13 ], [ 564, 321, 48, 13 ], [ 617, 321, 32, 13 ], [ 654, 321, 37, 13 ], [ 696, 321, 52, 13 ], [ 102, 335, 137, 13 ], [ 242, 335, 54, 13 ], [ 299, 335, 11, 13 ], [ 312, 335, 31, 13 ], [ 345, 335, 51, 13 ], [ 398, 335, 10, 13 ], [ 411, 335, 18, 13 ], [ 432, 335, 32, 13 ], [ 466, 335, 67, 13 ], [ 536, 335, 92, 13 ], [ 630, 335, 25, 13 ], [ 658, 335, 49, 13 ], [ 710, 335, 38, 13 ], [ 102, 349, 26, 13 ], [ 132, 349, 39, 13 ], [ 174, 349, 12, 13 ], [ 189, 349, 50, 13 ], [ 241, 349, 6, 13 ], [ 251, 349, 30, 13 ], [ 284, 349, 11, 13 ], [ 299, 349, 44, 13 ], [ 346, 349, 37, 13 ], [ 387, 349, 41, 13 ], [ 431, 349, 18, 13 ], [ 453, 349, 24, 13 ], [ 480, 349, 46, 13 ], [ 530, 349, 10, 13 ], [ 543, 349, 18, 13 ], [ 564, 349, 23, 13 ], [ 591, 349, 39, 13 ], [ 633, 349, 36, 13 ], [ 672, 349, 20, 13 ], [ 696, 349, 52, 14 ], [ 102, 363, 22, 13 ], [ 127, 363, 20, 13 ], [ 151, 363, 33, 13 ], [ 187, 363, 20, 13 ], [ 211, 363, 18, 13 ], [ 232, 363, 46, 13 ], [ 281, 363, 18, 13 ], [ 302, 363, 24, 13 ], [ 330, 363, 26, 13 ], [ 359, 363, 70, 13 ], [ 432, 363, 15, 13 ], [ 450, 363, 25, 13 ], [ 478, 363, 32, 13 ], [ 513, 363, 11, 13 ], [ 528, 363, 26, 13 ], [ 557, 363, 18, 13 ], [ 579, 363, 25, 13 ], [ 606, 363, 22, 13 ], [ 631, 363, 33, 13 ], [ 667, 363, 20, 13 ], [ 690, 363, 43, 13 ], [ 737, 363, 11, 13 ], [ 102, 376, 52, 14 ], [ 157, 376, 22, 13 ], [ 182, 376, 11, 13 ], [ 196, 376, 27, 13 ], [ 226, 376, 43, 13 ], [ 272, 376, 10, 13 ], [ 285, 376, 18, 13 ], [ 306, 376, 24, 13 ], [ 333, 376, 22, 13 ], [ 358, 376, 26, 13 ], [ 387, 376, 58, 13 ], [ 448, 376, 47, 13 ], [ 498, 376, 10, 13 ], [ 511, 376, 25, 13 ], [ 538, 376, 22, 13 ], [ 563, 376, 31, 13 ], [ 596, 376, 40, 13 ], [ 640, 376, 75, 13 ], [ 717, 376, 31, 13 ], [ 102, 390, 20, 13 ], [ 127, 390, 23, 13 ], [ 156, 390, 42, 13 ], [ 203, 390, 50, 13 ], [ 258, 390, 30, 13 ], [ 293, 390, 11, 13 ], [ 309, 390, 25, 13 ], [ 340, 390, 22, 13 ], [ 367, 390, 31, 13 ], [ 403, 390, 38, 13 ], [ 446, 390, 22, 13 ], [ 473, 390, 20, 13 ], [ 499, 390, 58, 13 ], [ 563, 390, 13, 13 ], [ 581, 390, 84, 13 ], [ 671, 390, 37, 13 ], [ 713, 390, 35, 13 ], [ 102, 404, 51, 13 ], [ 156, 404, 11, 13 ], [ 171, 404, 42, 13 ], [ 216, 404, 64, 13 ], [ 285, 404, 39, 13 ], [ 327, 404, 25, 13 ], [ 356, 404, 22, 13 ], [ 381, 404, 31, 13 ], [ 415, 404, 38, 13 ], [ 457, 404, 30, 13 ], [ 490, 404, 21, 13 ], [ 515, 404, 14, 13 ], [ 533, 404, 51, 13 ], [ 587, 404, 68, 13 ], [ 659, 404, 10, 13 ], [ 673, 404, 50, 13 ], [ 728, 404, 20, 13 ], [ 102, 418, 73, 14 ], [ 177, 418, 23, 13 ], [ 203, 418, 13, 13 ], [ 219, 418, 70, 13 ], [ 291, 418, 47, 13 ], [ 341, 418, 18, 13 ], [ 361, 418, 25, 13 ], [ 388, 418, 11, 13 ], [ 401, 418, 29, 13 ], [ 433, 418, 31, 13 ], [ 467, 418, 37, 13 ], [ 507, 418, 67, 13 ], [ 576, 418, 22, 13 ], [ 600, 418, 10, 13 ], [ 613, 418, 37, 13 ], [ 653, 418, 23, 13 ], [ 678, 418, 39, 13 ], [ 719, 418, 8, 13 ], [ 730, 418, 18, 13 ], [ 102, 432, 31, 13 ], [ 136, 432, 25, 13 ], [ 164, 432, 22, 13 ], [ 189, 432, 31, 13 ], [ 223, 432, 46, 13 ], [ 272, 432, 20, 13 ], [ 295, 432, 24, 13 ], [ 322, 432, 28, 13 ], [ 354, 432, 22, 13 ], [ 379, 432, 14, 13 ], [ 396, 432, 8, 13 ], [ 407, 432, 18, 13 ], [ 428, 432, 34, 13 ], [ 466, 432, 39, 13 ], [ 508, 432, 31, 13 ], [ 542, 432, 22, 13 ], [ 567, 432, 49, 13 ], [ 619, 432, 25, 13 ], [ 646, 432, 28, 13 ], [ 677, 432, 22, 13 ], [ 702, 432, 45, 13 ], [ 102, 446, 37, 13 ], [ 92, 481, 40, 10 ], [ 135, 481, 26, 10 ], [ 163, 481, 7, 10 ], [ 173, 481, 15, 10 ], [ 190, 481, 14, 10 ], [ 206, 481, 41, 10 ], [ 249, 481, 9, 10 ], [ 260, 481, 24, 10 ], [ 287, 481, 8, 10 ], [ 297, 481, 28, 10 ], [ 327, 481, 9, 10 ], [ 338, 481, 9, 10 ], [ 349, 481, 9, 10 ], [ 361, 481, 26, 10 ], [ 389, 481, 11, 10 ], [ 402, 481, 40, 10 ], [ 445, 481, 14, 10 ], [ 461, 481, 73, 10 ], [ 537, 481, 16, 10 ], [ 555, 481, 30, 10 ], [ 588, 481, 35, 10 ], [ 625, 481, 28, 10 ], [ 656, 481, 9, 10 ], [ 667, 481, 19, 10 ], [ 688, 481, 60, 10 ], [ 92, 492, 23, 10 ], [ 118, 492, 26, 10 ], [ 146, 492, 8, 10 ], [ 157, 492, 30, 10 ], [ 190, 492, 33, 10 ], [ 226, 492, 21, 10 ], [ 250, 492, 20, 10 ], [ 273, 492, 25, 10 ], [ 301, 492, 18, 10 ], [ 322, 492, 42, 10 ], [ 366, 492, 139, 10 ], [ 92, 509, 31, 10 ], [ 126, 509, 48, 10 ], [ 177, 509, 7, 10 ], [ 187, 509, 35, 10 ], [ 225, 509, 16, 10 ], [ 243, 509, 34, 10 ], [ 280, 509, 12, 10 ], [ 294, 509, 16, 10 ], [ 313, 509, 35, 10 ], [ 351, 509, 16, 10 ], [ 369, 509, 41, 10 ], [ 413, 509, 9, 10 ], [ 425, 509, 35, 10 ], [ 462, 509, 31, 10 ], [ 92, 526, 42, 10 ], [ 137, 526, 16, 10 ], [ 156, 526, 12, 10 ], [ 171, 526, 22, 10 ], [ 196, 526, 44, 10 ], [ 243, 526, 32, 10 ], [ 278, 526, 12, 10 ], [ 293, 526, 22, 10 ], [ 318, 526, 47, 10 ], [ 368, 526, 36, 10 ], [ 407, 526, 12, 10 ], [ 422, 526, 20, 10 ], [ 92, 544, 50, 10 ], [ 158, 544, 20, 10 ], [ 182, 544, 26, 10 ], [ 212, 544, 9, 10 ], [ 225, 544, 9, 10 ], [ 238, 544, 17, 10 ], [ 258, 544, 7, 10 ], [ 269, 544, 10, 10 ], [ 283, 544, 50, 10 ], [ 337, 544, 25, 10 ], [ 366, 544, 45, 10 ], [ 415, 544, 25, 10 ], [ 444, 544, 14, 10 ], [ 461, 544, 24, 10 ], [ 489, 544, 9, 10 ], [ 501, 544, 14, 10 ], [ 519, 544, 34, 10 ], [ 557, 544, 42, 10 ], [ 603, 544, 45, 10 ], [ 652, 544, 32, 10 ], [ 688, 544, 25, 10 ], [ 717, 544, 31, 10 ], [ 92, 555, 49, 10 ], [ 144, 555, 17, 10 ], [ 163, 555, 50, 10 ], [ 216, 555, 16, 10 ], [ 235, 555, 54, 10 ], [ 291, 555, 8, 10 ], [ 302, 555, 15, 10 ], [ 320, 555, 37, 10 ], [ 359, 555, 37, 10 ], [ 399, 555, 14, 10 ], [ 416, 555, 31, 10 ], [ 450, 555, 27, 10 ], [ 480, 555, 16, 10 ], [ 498, 555, 27, 10 ], [ 529, 555, 13, 10 ], [ 545, 555, 36, 10 ], [ 92, 572, 42, 10 ], [ 136, 572, 17, 10 ], [ 156, 572, 21, 10 ], [ 179, 572, 16, 10 ], [ 198, 572, 43, 10 ], [ 243, 572, 10, 10 ], [ 256, 572, 14, 10 ], [ 272, 572, 16, 10 ], [ 290, 572, 29, 10 ], [ 322, 572, 44, 10 ], [ 369, 572, 16, 10 ], [ 387, 572, 41, 10 ], [ 431, 572, 9, 10 ], [ 443, 572, 20, 10 ], [ 465, 572, 14, 10 ], [ 481, 572, 26, 10 ], [ 509, 572, 14, 10 ], [ 526, 572, 9, 10 ], [ 538, 572, 55, 10 ], [ 595, 572, 14, 10 ], [ 611, 572, 41, 10 ], [ 655, 572, 9, 10 ], [ 666, 572, 14, 10 ], [ 683, 572, 20, 10 ], [ 705, 572, 43, 10 ], [ 92, 583, 19, 10 ], [ 114, 583, 29, 10 ], [ 145, 583, 9, 10 ], [ 156, 583, 14, 10 ], [ 172, 583, 34, 10 ], [ 209, 583, 28, 10 ], [ 239, 583, 30, 10 ], [ 271, 583, 5, 10 ], [ 279, 583, 63, 10 ], [ 344, 583, 27, 10 ], [ 373, 583, 26, 10 ], [ 402, 583, 46, 10 ], [ 450, 583, 11, 10 ], [ 463, 583, 14, 10 ], [ 480, 583, 35, 10 ], [ 516, 583, 28, 10 ], [ 547, 583, 36, 10 ], [ 586, 583, 43, 10 ], [ 631, 583, 8, 10 ], [ 641, 583, 17, 10 ], [ 661, 583, 11, 10 ], [ 674, 583, 15, 10 ], [ 691, 583, 39, 10 ], [ 733, 583, 16, 10 ], [ 92, 594, 31, 10 ], [ 126, 594, 16, 10 ], [ 145, 594, 11, 10 ], [ 159, 594, 16, 10 ], [ 177, 594, 8, 10 ], [ 188, 594, 23, 10 ], [ 214, 594, 30, 10 ], [ 246, 594, 18, 10 ], [ 268, 594, 40, 10 ], [ 310, 594, 16, 10 ], [ 329, 594, 34, 10 ], [ 365, 594, 34, 10 ], [ 402, 594, 9, 10 ], [ 414, 594, 33, 10 ], [ 450, 594, 9, 10 ], [ 461, 594, 48, 10 ], [ 512, 594, 9, 10 ], [ 524, 594, 14, 10 ], [ 540, 594, 48, 10 ], [ 92, 612, 52, 10 ], [ 147, 612, 44, 10 ], [ 193, 612, 16, 10 ], [ 212, 612, 31, 10 ], [ 246, 612, 20, 10 ], [ 268, 612, 35, 10 ], [ 307, 612, 17, 10 ], [ 326, 612, 11, 10 ], [ 340, 612, 45, 10 ], [ 388, 612, 35, 10 ], [ 426, 612, 21, 10 ], [ 92, 629, 5, 10 ], [ 99, 629, 27, 10 ], [ 129, 629, 83, 10 ], [ 92, 646, 10, 10 ], [ 105, 646, 31, 10 ], [ 140, 646, 34, 10 ], [ 177, 646, 50, 10 ], [ 230, 646, 9, 10 ], [ 242, 646, 61, 10 ], [ 306, 646, 33, 10 ], [ 342, 646, 32, 10 ], [ 377, 646, 32, 10 ], [ 412, 646, 36, 10 ], [ 451, 646, 41, 10 ], [ 495, 646, 9, 10 ], [ 507, 646, 23, 10 ], [ 534, 646, 57, 10 ], [ 594, 646, 32, 10 ], [ 629, 646, 30, 10 ], [ 662, 646, 26, 10 ], [ 692, 646, 25, 10 ], [ 720, 646, 28, 10 ], [ 92, 657, 25, 10 ], [ 120, 657, 9, 10 ], [ 131, 657, 34, 10 ], [ 92, 668, 11, 10 ], [ 106, 668, 31, 10 ], [ 140, 668, 34, 10 ], [ 176, 668, 28, 10 ], [ 207, 668, 9, 10 ], [ 218, 668, 38, 10 ], [ 258, 668, 16, 10 ], [ 277, 668, 25, 10 ], [ 305, 668, 29, 10 ], [ 337, 668, 41, 10 ], [ 381, 668, 9, 10 ], [ 392, 668, 43, 10 ], [ 438, 668, 37, 10 ], [ 478, 668, 43, 10 ], [ 524, 668, 28, 10 ], [ 555, 668, 25, 10 ], [ 582, 668, 9, 10 ], [ 594, 668, 34, 10 ], [ 80, 711, 84, 14 ], [ 93, 740, 23, 13 ], [ 119, 740, 10, 13 ], [ 132, 740, 16, 13 ], [ 151, 740, 25, 13 ], [ 179, 740, 40, 13 ], [ 223, 740, 33, 13 ], [ 259, 740, 6, 13 ], [ 269, 740, 17, 13 ], [ 289, 740, 18, 13 ], [ 310, 740, 51, 13 ], [ 365, 740, 8, 13 ], [ 375, 740, 6, 13 ], [ 385, 740, 28, 13 ], [ 80, 755, 70, 13 ], [ 155, 755, 29, 13 ], [ 189, 755, 33, 13 ], [ 228, 755, 12, 13 ], [ 245, 755, 12, 13 ], [ 262, 755, 54, 13 ], [ 322, 755, 40, 13 ], [ 367, 755, 31, 13 ], [ 403, 755, 10, 13 ], [ 80, 770, 26, 13 ], [ 109, 770, 28, 13 ], [ 140, 770, 8, 13 ], [ 150, 770, 34, 13 ], [ 187, 770, 15, 13 ], [ 204, 770, 16, 13 ], [ 223, 770, 65, 13 ], [ 290, 770, 10, 13 ], [ 303, 770, 43, 13 ], [ 349, 770, 42, 13 ], [ 393, 770, 19, 13 ], [ 80, 784, 40, 13 ], [ 129, 784, 18, 13 ], [ 157, 784, 74, 13 ], [ 240, 784, 29, 13 ], [ 277, 784, 16, 13 ], [ 303, 784, 51, 13 ], [ 363, 784, 50, 13 ], [ 80, 799, 69, 13 ], [ 156, 799, 34, 13 ], [ 196, 799, 37, 13 ], [ 240, 799, 37, 13 ], [ 284, 799, 46, 13 ], [ 338, 799, 23, 13 ], [ 368, 799, 10, 13 ], [ 385, 799, 28, 13 ], [ 80, 814, 57, 13 ], [ 140, 814, 48, 13 ], [ 191, 814, 30, 13 ], [ 223, 814, 11, 13 ], [ 237, 814, 58, 13 ], [ 298, 814, 74, 13 ], [ 374, 814, 19, 13 ], [ 396, 814, 16, 13 ], [ 80, 829, 40, 13 ], [ 126, 829, 61, 13 ], [ 193, 829, 13, 13 ], [ 210, 829, 16, 13 ], [ 232, 829, 45, 13 ], [ 282, 829, 10, 13 ], [ 298, 829, 6, 13 ], [ 309, 829, 34, 13 ], [ 349, 829, 10, 13 ], [ 364, 829, 49, 13 ], [ 80, 843, 32, 13 ], [ 116, 843, 23, 13 ], [ 143, 843, 10, 13 ], [ 157, 843, 40, 13 ], [ 202, 843, 46, 13 ], [ 252, 843, 11, 13 ], [ 267, 843, 95, 13 ], [ 365, 843, 18, 13 ], [ 388, 843, 25, 13 ], [ 80, 858, 24, 13 ], [ 107, 858, 49, 13 ], [ 159, 858, 10, 13 ], [ 172, 858, 25, 13 ], [ 200, 858, 18, 13 ], [ 220, 858, 41, 13 ], [ 265, 858, 13, 13 ], [ 280, 858, 24, 13 ], [ 307, 858, 36, 13 ], [ 346, 858, 42, 13 ], [ 390, 858, 22, 13 ], [ 80, 873, 16, 13 ], [ 101, 873, 47, 13 ], [ 153, 873, 10, 13 ], [ 168, 873, 19, 13 ], [ 192, 873, 77, 13 ], [ 274, 873, 37, 13 ], [ 315, 873, 47, 13 ], [ 367, 873, 10, 13 ], [ 382, 873, 30, 13 ], [ 80, 888, 32, 13 ], [ 115, 888, 61, 13 ], [ 179, 888, 74, 13 ], [ 255, 888, 29, 13 ], [ 287, 888, 30, 13 ], [ 320, 888, 25, 13 ], [ 348, 888, 52, 13 ], [ 403, 888, 10, 13 ], [ 80, 903, 29, 13 ], [ 112, 903, 6, 13 ], [ 122, 903, 61, 13 ], [ 186, 903, 65, 13 ], [ 254, 903, 11, 13 ], [ 268, 903, 6, 13 ], [ 277, 903, 25, 13 ], [ 306, 903, 52, 13 ], [ 361, 903, 10, 13 ], [ 374, 903, 20, 13 ], [ 397, 903, 16, 13 ], [ 80, 917, 35, 13 ], [ 119, 917, 28, 13 ], [ 149, 917, 23, 13 ], [ 175, 917, 15, 13 ], [ 193, 917, 20, 13 ], [ 215, 917, 85, 13 ], [ 303, 917, 19, 13 ], [ 325, 917, 35, 13 ], [ 363, 917, 41, 13 ], [ 406, 917, 6, 13 ], [ 80, 932, 37, 13 ], [ 123, 932, 20, 13 ], [ 149, 932, 38, 13 ], [ 193, 932, 24, 13 ], [ 222, 932, 16, 13 ], [ 244, 932, 24, 13 ], [ 274, 932, 22, 13 ], [ 302, 932, 22, 13 ], [ 330, 932, 11, 13 ], [ 348, 932, 13, 13 ], [ 367, 932, 46, 13 ], [ 80, 947, 50, 13 ], [ 136, 947, 42, 13 ], [ 183, 947, 16, 13 ], [ 204, 947, 35, 13 ], [ 245, 947, 23, 13 ], [ 274, 947, 18, 13 ], [ 297, 947, 11, 13 ], [ 314, 947, 41, 13 ], [ 360, 947, 20, 13 ], [ 385, 947, 28, 13 ], [ 80, 962, 57, 13 ], [ 140, 962, 20, 13 ], [ 162, 962, 52, 13 ], [ 216, 962, 16, 13 ], [ 235, 962, 28, 13 ], [ 265, 962, 24, 13 ], [ 292, 962, 30, 13 ], [ 325, 962, 31, 13 ], [ 359, 962, 41, 13 ], [ 402, 962, 10, 13 ], [ 80, 976, 33, 13 ], [ 120, 976, 57, 13 ], [ 184, 976, 19, 13 ], [ 210, 976, 48, 13 ], [ 266, 976, 10, 13 ], [ 283, 976, 52, 13 ], [ 342, 976, 32, 13 ], [ 382, 976, 8, 13 ], [ 397, 976, 16, 13 ], [ 80, 991, 47, 13 ], [ 130, 991, 43, 13 ], [ 176, 991, 15, 13 ], [ 194, 991, 28, 13 ], [ 224, 991, 24, 13 ], [ 252, 991, 34, 13 ], [ 288, 991, 32, 13 ], [ 323, 991, 38, 13 ], [ 364, 991, 10, 13 ], [ 377, 991, 10, 13 ], [ 390, 991, 23, 13 ], [ 80, 1006, 19, 13 ], [ 102, 1006, 53, 13 ], [ 158, 1006, 19, 13 ], [ 180, 1006, 70, 13 ], [ 252, 1006, 36, 13 ], [ 291, 1006, 71, 13 ], [ 365, 1006, 6, 13 ], [ 374, 1006, 39, 13 ], [ 437, 710, 113, 13 ], [ 555, 710, 43, 13 ], [ 603, 710, 51, 13 ], [ 659, 710, 19, 13 ], [ 683, 710, 19, 13 ], [ 706, 710, 63, 13 ], [ 437, 725, 21, 13 ], [ 462, 725, 40, 13 ], [ 506, 725, 10, 13 ], [ 520, 725, 10, 13 ], [ 534, 725, 130, 13 ], [ 667, 725, 19, 13 ], [ 689, 725, 35, 13 ], [ 728, 725, 42, 13 ], [ 437, 740, 18, 13 ], [ 458, 740, 53, 13 ], [ 514, 740, 32, 13 ], [ 549, 740, 53, 13 ], [ 605, 740, 11, 13 ], [ 619, 740, 37, 13 ], [ 658, 740, 32, 13 ], [ 693, 740, 50, 13 ], [ 745, 740, 25, 13 ], [ 437, 755, 48, 13 ], [ 490, 755, 40, 13 ], [ 535, 755, 10, 13 ], [ 549, 755, 10, 13 ], [ 564, 755, 50, 13 ], [ 619, 755, 48, 13 ], [ 671, 755, 27, 13 ], [ 703, 755, 13, 13 ], [ 720, 755, 13, 13 ], [ 737, 755, 32, 13 ], [ 437, 770, 38, 13 ], [ 478, 770, 32, 13 ], [ 513, 770, 10, 13 ], [ 526, 770, 42, 13 ], [ 571, 770, 28, 13 ], [ 601, 770, 19, 13 ], [ 623, 770, 55, 13 ], [ 682, 770, 41, 13 ], [ 725, 770, 44, 13 ], [ 437, 784, 77, 13 ], [ 522, 784, 32, 13 ], [ 562, 784, 10, 13 ], [ 580, 784, 45, 13 ], [ 633, 784, 17, 13 ], [ 658, 784, 25, 13 ], [ 691, 784, 20, 13 ], [ 720, 784, 16, 13 ], [ 744, 784, 26, 13 ], [ 437, 799, 67, 13 ], [ 510, 799, 13, 13 ], [ 529, 799, 79, 13 ], [ 614, 799, 10, 13 ], [ 630, 799, 16, 13 ], [ 652, 799, 30, 13 ], [ 689, 799, 42, 13 ], [ 736, 799, 34, 13 ], [ 437, 814, 45, 13 ], [ 486, 814, 13, 13 ], [ 502, 814, 34, 13 ], [ 450, 829, 31, 13 ], [ 485, 829, 16, 13 ], [ 505, 829, 10, 13 ], [ 518, 829, 22, 13 ], [ 545, 829, 28, 13 ], [ 576, 829, 41, 13 ], [ 621, 829, 43, 13 ], [ 667, 829, 15, 13 ], [ 686, 829, 48, 13 ], [ 737, 829, 32, 13 ], [ 437, 844, 32, 13 ], [ 472, 844, 16, 13 ], [ 491, 844, 28, 13 ], [ 521, 844, 53, 13 ], [ 577, 844, 36, 13 ], [ 616, 844, 31, 13 ], [ 650, 844, 42, 13 ], [ 695, 844, 37, 13 ], [ 735, 844, 35, 13 ], [ 437, 858, 30, 14 ], [ 470, 858, 43, 13 ], [ 516, 858, 30, 13 ], [ 549, 858, 25, 13 ], [ 577, 858, 78, 13 ], [ 658, 858, 7, 13 ], [ 667, 858, 52, 13 ], [ 723, 858, 47, 13 ], [ 437, 873, 18, 13 ], [ 458, 873, 29, 13 ], [ 490, 873, 31, 13 ], [ 524, 873, 19, 13 ], [ 546, 873, 28, 13 ], [ 577, 873, 28, 13 ], [ 608, 873, 14, 13 ], [ 625, 873, 41, 13 ], [ 669, 873, 51, 13 ], [ 723, 873, 13, 13 ], [ 739, 873, 31, 13 ], [ 437, 888, 21, 13 ], [ 463, 888, 25, 13 ], [ 492, 888, 57, 13 ], [ 554, 888, 10, 13 ], [ 568, 888, 45, 13 ], [ 617, 888, 17, 13 ], [ 638, 888, 25, 13 ], [ 667, 888, 37, 13 ], [ 709, 888, 17, 13 ], [ 730, 888, 10, 13 ], [ 744, 888, 26, 13 ], [ 437, 903, 31, 13 ], [ 472, 903, 29, 13 ], [ 504, 903, 19, 13 ], [ 527, 903, 29, 13 ], [ 559, 903, 25, 13 ], [ 587, 903, 6, 13 ], [ 597, 903, 62, 13 ], [ 662, 903, 23, 13 ], [ 688, 903, 20, 13 ], [ 711, 903, 42, 13 ], [ 757, 903, 13, 13 ], [ 437, 917, 39, 13 ], [ 479, 917, 33, 13 ], [ 514, 917, 31, 13 ], [ 547, 917, 17, 13 ], [ 566, 917, 21, 13 ], [ 589, 917, 10, 13 ], [ 602, 917, 23, 13 ], [ 628, 917, 10, 13 ], [ 640, 917, 20, 13 ], [ 662, 917, 39, 13 ], [ 704, 917, 35, 13 ], [ 742, 917, 28, 13 ], [ 437, 932, 23, 13 ], [ 464, 932, 25, 13 ], [ 493, 932, 20, 13 ], [ 516, 932, 36, 13 ], [ 556, 932, 51, 13 ], [ 611, 932, 28, 13 ], [ 642, 932, 23, 13 ], [ 669, 932, 25, 13 ], [ 698, 932, 72, 13 ], [ 437, 947, 34, 13 ], [ 476, 947, 20, 13 ], [ 502, 947, 38, 13 ], [ 545, 947, 59, 14 ], [ 610, 947, 6, 13 ], [ 622, 947, 110, 13 ], [ 738, 947, 31, 13 ], [ 437, 962, 85, 13 ], [ 525, 962, 36, 13 ], [ 565, 962, 31, 13 ], [ 600, 962, 25, 13 ], [ 628, 962, 50, 13 ], [ 682, 962, 32, 13 ], [ 718, 962, 29, 13 ], [ 750, 962, 19, 13 ], [ 437, 976, 55, 14 ], [ 500, 976, 25, 13 ], [ 531, 976, 16, 13 ], [ 554, 976, 84, 13 ], [ 645, 976, 36, 13 ], [ 689, 976, 31, 13 ], [ 727, 976, 43, 13 ], [ 437, 991, 54, 13 ], [ 495, 991, 19, 13 ], [ 518, 991, 16, 13 ], [ 537, 991, 45, 13 ], [ 586, 991, 10, 13 ], [ 599, 991, 18, 13 ], [ 620, 991, 40, 13 ], [ 664, 991, 43, 13 ], [ 710, 991, 13, 13 ], [ 727, 991, 16, 13 ], [ 746, 991, 23, 13 ], [ 437, 1006, 10, 13 ], [ 453, 1006, 82, 13 ], [ 540, 1006, 28, 13 ], [ 573, 1006, 43, 13 ], [ 622, 1006, 16, 13 ], [ 644, 1006, 31, 13 ], [ 680, 1006, 36, 13 ], [ 722, 1006, 10, 13 ], [ 738, 1006, 32, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 40, 12 ], [ 185, 1047, 3, 12 ], [ 193, 1047, 104, 12 ], [ 422, 1047, 6, 12 ], [ 535, 1047, 41, 12 ], [ 580, 1047, 23, 12 ], [ 608, 1047, 3, 12 ], [ 616, 1047, 36, 12 ], [ 657, 1047, 6, 12 ], [ 668, 1047, 3, 12 ], [ 676, 1047, 24, 12 ], [ 705, 1047, 6, 12 ], [ 716, 1047, 3, 12 ], [ 724, 1047, 45, 12 ] ]

[ "Ku", "Regulates", "the", "Non-Homologous", "End", "Joining", "Pathway", "Choice", "of", "DNA", "Double-Strand", "Break", "Repair", "in", "Human", "Somatic", "Cells", "Farjana", "Fattah¤a,", "Eu", "Han", "Lee,", "Natalie", "Weisensel¤b,", "Yongbao", "Wang,", "Natalie", "Lichter,", "Eric", "A.", "Hendrickson*", "Department", "of", "Biochemistry,", "Molecular", "Biology,", "and", "Biophysics,", "University", "of", "Minnesota", "Medical", "School,", "Minneapolis,", "Minnesota,", "United", "States", "of", "America", "Abstract", "The", "repair", "of", "DNA", "double-strand", "breaks", "(DSBs)", "is", "critical", "for", "the", "maintenance", "of", "genomic", "integrity", "and", "viability", "for", "all", "organisms.", "Mammals", "have", "evolved", "at", "least", "two", "genetically", "discrete", "ways", "to", "mediate", "DNA", "DSB", "repair:", "homologous", "recombination", "(HR)", "and", "non-homologous", "end", "joining", "(NHEJ).", "In", "mammalian", "cells,", "most", "DSBs", "are", "preferentially", "repaired", "by", "NHEJ.", "Recent", "work", "has", "demonstrated", "that", "NHEJ", "consists", "of", "at", "least", "two", "sub-pathways—the", "main", "Ku", "heterodimer-", "dependent", "or", "‘‘classic’’", "NHEJ", "(C-NHEJ)", "pathway", "and", "an", "‘‘alternative’’", "NHEJ", "(A-NHEJ)", "pathway,", "which", "usually", "generates", "microhomology-mediated", "signatures", "at", "repair", "junctions.", "In", "our", "study,", "recombinant", "adeno-associated", "virus", "knockout", "vectors", "were", "utilized", "to", "construct", "a", "series", "of", "isogenic", "human", "somatic", "cell", "lines", "deficient", "in", "the", "core", "C-NHEJ", "factors", "(Ku,", "DNA-PKcs,", "XLF,", "and", "LIGIV),", "and", "the", "resulting", "cell", "lines", "were", "characterized", "for", "their", "ability", "to", "carry", "out", "DNA", "DSB", "repair.", "The", "absence", "of", "DNA-PKcs,", "XLF,", "or", "LIGIV", "resulted", "in", "cell", "lines", "that", "were", "profoundly", "impaired", "in", "DNA", "DSB", "repair", "activity.", "Unexpectedly,", "Ku86-", "null", "cells", "showed", "wild-type", "levels", "of", "DNA", "DSB", "repair", "activity", "that", "was", "dominated", "by", "microhomology", "joining", "events", "indicative", "of", "A-NHEJ.", "Importantly,", "A-NHEJ", "DNA", "DSB", "repair", "activity", "could", "also", "be", "efficiently", "de-repressed", "in", "LIGIV-null", "and", "DNA-PKcs-null", "cells", "by", "subsequently", "reducing", "the", "level", "of", "Ku70.", "These", "studies", "demonstrate", "that", "in", "human", "cells", "C-NHEJ", "is", "the", "major", "DNA", "DSB", "repair", "pathway", "and", "they", "show", "that", "Ku", "is", "the", "critical", "C-NHEJ", "factor", "that", "regulates", "DNA", "NHEJ", "DSB", "pathway", "choice.", "Citation:", "Fattah", "F,", "Lee", "EH,", "Weisensel", "N,", "Wang", "Y,", "Lichter", "N,", "et", "al.", "(2010)", "Ku", "Regulates", "the", "Non-Homologous", "End", "Joining", "Pathway", "Choice", "of", "DNA", "Double-Strand", "Break", "Repair", "in", "Human", "Somatic", "Cells.", "PLoS", "Genet", "6(2):", "e1000855.", "doi:10.1371/journal.pgen.1000855", "Editor:", "Christopher", "E.", "Pearson,", "The", "Hospital", "for", "Sick", "Children", "and", "University", "of", "Toronto,", "Canada", "Received", "July", "31,", "2009;", "Accepted", "January", "23,", "2010;", "Published", "February", "26,", "2010", "Copyright:", "2010", "Fattah", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "the", "NIH", "awards", "GM069576", "and", "HL079559", "to", "EAH.", "We", "would", "like", "to", "acknowledge", "the", "assistance", "of", "the", "Flow", "Cytometry", "Core", "Facility", "of", "the", "Masonic", "Cancer", "Center,", "a", "comprehensive", "cancer", "center", "designated", "by", "the", "National", "Cancer", "Institute,", "supported", "in", "part", "by", "P30", "CA77598.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "hendr064@umn.edu", "¤a", "Current", "address:", "Department", "of", "Pharmacology,", "Howard", "Hughes", "Medical", "Institute,", "University", "of", "Texas", "Southwestern", "Medical", "Center,", "Dallas,", "Texas,", "United", "States", "of", "America", "¤b", "Current", "address:", "School", "of", "Medicine", "and", "Public", "Health,", "University", "of", "Wisconsin,", "Madison,", "Wisconsin,", "United", "States", "of", "America", "Introduction", "One", "of", "the", "most", "harmful", "lesions", "a", "cell", "can", "encounter", "is", "a", "DNA", "double-strand", "break", "(DSB).", "In", "all", "organisms,", "efficient", "repair", "of", "these", "DSBs", "is", "critical", "for", "the", "maintenance", "of", "genomic", "integrity", "and", "viability", "[1].", "Unfortunately,", "DSBs", "are", "frequently", "generated", "endogenously", "during", "normal", "cellular", "processes", "such", "as", "DNA", "replication,", "lymphoid", "V(D)J", "or", "class-switch", "recombination", "and", "are", "induced", "exogenously", "by", "the", "exposure", "to", "a", "variety", "of", "genotoxic", "agents", "such", "as", "ionizing", "radiation", "or", "chemotherapeutics", "[2].", "Cells", "have", "conspired", "to", "meet", "this", "demand", "on", "their", "genetic", "material", "with", "the", "evolution", "of", "two", "mechanistically", "distinct", "pathways", "to", "repair", "DSBs:", "homologous", "recombination", "(HR),", "which", "takes", "advantage", "of", "either", "a", "homologous", "chromosome", "or", "a", "sister", "chromatid", "to", "join", "the", "broken", "DNA", "ends", "[3]", "and", "non-homologous", "end", "joining", "(NHEJ),", "a", "process", "that", "directly", "joins", "the", "DSB", "with", "little", "or", "no", "sequence", "homology", "between", "the", "broken", "ends", "[2].", "In", "bacteria", "and", "lower", "eukaryotes,", "HR", "dominates", "the", "DNA", "DSB", "repair", "events", "whereas", "in", "higher", "eukaryotes,", "and", "especially", "in", "mammals,", "NHEJ", "is", "the", "preferred", "pathway", "for", "DNA", "DSB", "repair.", "NHEJ", "consists", "of", "at", "least", "two", "genetically", "and", "biochemically", "distinct", "sub-pathways:", "a", "main—", "‘‘classic’’—end-joining", "pathway", "(C-NHEJ)", "and", "one", "interchange-", "ably", "referred", "to", "as", "microhomology-mediated", "end", "joining", "(MMEJ)", "[4],", "alternative", "NHEJ", "(A-NHEJ),", "or", "backup", "NHEJ", "(B-NHEJ)", "[5,6]", "(hereafter", "referred", "to", "as", "A-NHEJ).", "C-NHEJ,", "while", "by", "no", "means", "precise,", "results", "in", "minimal", "DNA", "end", "processing,", "whereas", "A-NHEJ", "mechanistically", "results", "in", "deletions", "per", "force", "that", "are", "often", "accompanied", "by", "microhomology", "at", "the", "repair", "junction", "{[7,8];", "reviewed", "by", "[6,9]}.", "There", "are", "at", "least", "seven", "proteins", "required", "for", "C-NHEJ:", "Ku70,", "Ku86,", "the", "DNA", "dependent", "protein", "kinase", "catalytic", "subunit", "(DNA-", "PKcs),", "Artemis,", "X-ray", "cross", "complementing", "4", "(XRCC4),", "XRCC4-", "like", "factor", "(XLF)", "and", "DNA", "ligase", "IV", "(LIGIV)", "{reviewed", "by", "[10]}.", "The", "basic", "mechanism", "of", "C-NHEJ", "has", "been", "worked", "out", "in", "great", "detail.", "Ku70", "and", "Ku86", "form", "a", "heterodimer", "(Ku)", "that", "contains", "an", "internal", "cavity,", "which", "Ku", "uses", "to", "bind", "to", "and", "encircle", "broken", "DNA", "ends", "[11].", "Ku,", "besides", "protecting", "DNA", "ends", "from", "exonucleolytic", "attack,", "also", "recruits", "DNA-PKcs,", "a", "phosphoinositol-3-like", "family", "serine/threonine", "protein", "kinase", "[12].", "Together,", "Ku70,", "Ku86", "and", "DNA-PKcs", "form", "the", "DNA-dependent", "protein", "kinase", "complex", "(DNA-PK)", "and", "the", "assembly", "of", "this", "trimeric", "complex", "on", "the", "ends", "of", "double-stranded", "DNA", "activates", "the", "kinase", "activity", "of", "DNA-", "PLoS", "Genetics", "|", "www.plosgenetics.org", "1", "February", "2010", "|", "Volume", "6", "|", "Issue", "2", "|", "e1000855" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 36, 12 ], [ 118, 47, 9, 12 ], [ 130, 47, 11, 12 ], [ 144, 47, 21, 12 ], [ 168, 47, 70, 12 ], [ 241, 47, 41, 12 ], [ 286, 47, 25, 12 ], [ 314, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 49, 34 ], [ 137, 169, 100, 34 ], [ 247, 169, 27, 34 ], [ 284, 169, 50, 34 ], [ 344, 169, 105, 34 ], [ 460, 169, 25, 34 ], [ 495, 169, 44, 34 ], [ 549, 169, 173, 34 ], [ 78, 205, 27, 34 ], [ 115, 205, 140, 34 ], [ 265, 205, 94, 34 ], [ 369, 205, 165, 34 ], [ 544, 205, 106, 34 ], [ 78, 252, 45, 16 ], [ 128, 249, 57, 18 ], [ 189, 252, 33, 16 ], [ 226, 249, 46, 18 ], [ 277, 252, 26, 16 ], [ 308, 249, 52, 18 ], [ 364, 252, 31, 16 ], [ 399, 249, 66, 18 ], [ 469, 252, 33, 16 ], [ 507, 249, 47, 18 ], [ 559, 252, 39, 16 ], [ 602, 249, 38, 18 ], [ 78, 271, 39, 16 ], [ 121, 269, 85, 19 ], [ 210, 271, 26, 16 ], [ 241, 269, 58, 19 ], [ 303, 271, 53, 16 ], [ 361, 269, 81, 19 ], [ 446, 271, 39, 16 ], [ 490, 269, 43, 19 ], [ 537, 271, 37, 16 ], [ 579, 269, 43, 19 ], [ 626, 271, 22, 16 ], [ 78, 291, 69, 16 ], [ 151, 288, 60, 18 ], [ 87, 345, 54, 15 ], [ 87, 370, 76, 14 ], [ 167, 370, 72, 14 ], [ 243, 370, 25, 14 ], [ 272, 370, 8, 14 ], [ 285, 370, 7, 14 ], [ 295, 370, 84, 14 ], [ 384, 370, 56, 14 ], [ 444, 370, 21, 14 ], [ 470, 370, 13, 14 ], [ 486, 370, 69, 14 ], [ 560, 370, 22, 14 ], [ 586, 370, 59, 14 ], [ 649, 370, 23, 14 ], [ 677, 370, 15, 14 ], [ 696, 370, 37, 14 ], [ 87, 387, 33, 14 ], [ 125, 387, 59, 14 ], [ 188, 387, 18, 14 ], [ 210, 387, 74, 14 ], [ 288, 387, 34, 14 ], [ 326, 387, 26, 14 ], [ 356, 387, 12, 14 ], [ 372, 387, 32, 14 ], [ 409, 387, 55, 14 ], [ 468, 387, 55, 14 ], [ 528, 387, 12, 14 ], [ 544, 387, 47, 14 ], [ 595, 387, 61, 14 ], [ 660, 387, 29, 14 ], [ 693, 387, 11, 14 ], [ 708, 387, 25, 14 ], [ 87, 403, 15, 14 ], [ 106, 403, 76, 14 ], [ 186, 403, 21, 14 ], [ 212, 403, 51, 14 ], [ 267, 403, 73, 14 ], [ 344, 403, 30, 14 ], [ 378, 403, 35, 14 ], [ 416, 403, 40, 14 ], [ 460, 403, 11, 14 ], [ 476, 403, 21, 14 ], [ 501, 403, 8, 14 ], [ 513, 403, 37, 14 ], [ 555, 403, 39, 14 ], [ 597, 403, 12, 14 ], [ 613, 403, 52, 14 ], [ 669, 403, 49, 14 ], [ 722, 403, 17, 14 ], [ 87, 420, 74, 14 ], [ 166, 420, 22, 14 ], [ 193, 420, 21, 14 ], [ 218, 420, 43, 14 ], [ 266, 420, 31, 14 ], [ 301, 420, 15, 14 ], [ 320, 420, 11, 14 ], [ 336, 420, 41, 14 ], [ 381, 420, 11, 14 ], [ 396, 420, 19, 14 ], [ 419, 420, 73, 14 ], [ 496, 420, 11, 14 ], [ 511, 420, 17, 14 ], [ 533, 419, 47, 15 ], [ 584, 420, 61, 14 ], [ 649, 420, 22, 14 ], [ 675, 420, 57, 14 ], [ 87, 436, 30, 14 ], [ 122, 436, 35, 14 ], [ 161, 436, 11, 14 ], [ 176, 436, 77, 14 ], [ 258, 436, 21, 14 ], [ 283, 436, 50, 14 ], [ 338, 436, 11, 14 ], [ 352, 436, 20, 14 ], [ 376, 436, 21, 14 ], [ 402, 436, 72, 14 ], [ 478, 436, 17, 14 ], [ 500, 436, 44, 14 ], [ 548, 436, 55, 14 ], [ 608, 436, 12, 14 ], [ 624, 436, 21, 14 ], [ 649, 436, 43, 14 ], [ 697, 436, 26, 14 ], [ 727, 436, 12, 14 ], [ 87, 453, 31, 14 ], [ 122, 453, 56, 14 ], [ 182, 453, 23, 14 ], [ 209, 453, 31, 14 ], [ 244, 453, 52, 14 ], [ 300, 453, 23, 14 ], [ 327, 453, 21, 14 ], [ 353, 453, 75, 14 ], [ 432, 453, 36, 14 ], [ 472, 453, 30, 14 ], [ 506, 453, 34, 14 ], [ 545, 453, 53, 14 ], [ 601, 453, 40, 14 ], [ 87, 474, 56, 14 ], [ 148, 474, 9, 14 ], [ 160, 474, 66, 14 ], [ 231, 474, 74, 14 ], [ 309, 474, 29, 14 ], [ 343, 474, 21, 14 ], [ 367, 474, 46, 14 ], [ 417, 474, 44, 14 ], [ 466, 474, 25, 14 ], [ 495, 474, 43, 14 ], [ 542, 474, 18, 14 ], [ 563, 474, 26, 14 ], [ 594, 474, 9, 14 ], [ 607, 474, 16, 14 ], [ 627, 474, 12, 14 ], [ 644, 474, 21, 14 ], [ 669, 474, 50, 14 ], [ 87, 490, 45, 14 ], [ 136, 490, 26, 14 ], [ 167, 490, 9, 14 ], [ 180, 490, 16, 14 ], [ 200, 490, 12, 14 ], [ 216, 490, 52, 14 ], [ 273, 490, 82, 14 ], [ 359, 490, 22, 14 ], [ 385, 490, 21, 14 ], [ 410, 490, 46, 14 ], [ 460, 490, 28, 14 ], [ 492, 490, 48, 14 ], [ 545, 490, 15, 14 ], [ 564, 490, 14, 14 ], [ 582, 490, 28, 14 ], [ 615, 490, 9, 14 ], [ 627, 490, 35, 14 ], [ 666, 490, 50, 14 ], [ 87, 507, 42, 14 ], [ 134, 507, 22, 14 ], [ 159, 507, 38, 14 ], [ 201, 507, 21, 14 ], [ 227, 507, 9, 14 ], [ 240, 507, 62, 14 ], [ 306, 507, 33, 14 ], [ 343, 507, 29, 14 ], [ 376, 507, 42, 14 ], [ 422, 507, 31, 14 ], [ 457, 507, 47, 14 ], [ 508, 507, 37, 14 ], [ 549, 507, 22, 14 ], [ 575, 507, 59, 14 ], [ 638, 507, 12, 14 ], [ 654, 507, 14, 14 ], [ 672, 507, 30, 14 ], [ 87, 524, 54, 14 ], [ 146, 524, 11, 14 ], [ 161, 524, 21, 14 ], [ 187, 524, 46, 14 ], [ 237, 524, 28, 14 ], [ 269, 524, 11, 14 ], [ 284, 524, 30, 14 ], [ 318, 524, 12, 14 ], [ 334, 524, 45, 14 ], [ 384, 524, 17, 14 ], [ 405, 524, 45, 14 ], [ 454, 524, 55, 14 ], [ 514, 524, 12, 14 ], [ 530, 524, 75, 14 ], [ 609, 524, 21, 14 ], [ 635, 524, 21, 14 ], [ 660, 524, 48, 14 ], [ 712, 524, 14, 14 ], [ 87, 540, 29, 14 ], [ 121, 540, 60, 14 ], [ 185, 540, 42, 14 ], [ 231, 540, 61, 14 ], [ 296, 540, 44, 14 ], [ 345, 540, 21, 14 ], [ 370, 540, 45, 14 ], [ 419, 540, 28, 14 ], [ 451, 540, 34, 14 ], [ 490, 540, 21, 14 ], [ 516, 540, 65, 14 ], [ 584, 540, 49, 14 ], [ 638, 540, 21, 14 ], [ 663, 540, 48, 14 ], [ 716, 540, 21, 14 ], [ 87, 557, 28, 14 ], [ 120, 557, 55, 14 ], [ 179, 557, 28, 14 ], [ 211, 557, 59, 14 ], [ 274, 557, 35, 14 ], [ 313, 557, 30, 14 ], [ 348, 557, 36, 14 ], [ 389, 557, 45, 14 ], [ 437, 557, 17, 14 ], [ 459, 557, 54, 14 ], [ 517, 557, 59, 14 ], [ 580, 557, 15, 14 ], [ 600, 557, 27, 14 ], [ 631, 557, 21, 14 ], [ 656, 557, 43, 14 ], [ 703, 557, 22, 14 ], [ 87, 574, 38, 14 ], [ 129, 574, 15, 14 ], [ 149, 574, 56, 14 ], [ 210, 574, 60, 14 ], [ 274, 574, 11, 14 ], [ 289, 574, 70, 14 ], [ 364, 574, 71, 14 ], [ 87, 594, 46, 14 ], [ 137, 594, 13, 14 ], [ 155, 594, 22, 14 ], [ 181, 594, 19, 14 ], [ 203, 594, 28, 14 ], [ 236, 594, 79, 14 ], [ 319, 594, 21, 14 ], [ 344, 594, 43, 14 ], [ 391, 594, 28, 14 ], [ 423, 594, 11, 14 ], [ 438, 594, 45, 14 ], [ 487, 594, 21, 14 ], [ 513, 594, 51, 14 ], [ 568, 594, 15, 14 ], [ 587, 594, 16, 14 ], [ 607, 594, 21, 14 ], [ 633, 594, 23, 14 ], [ 660, 594, 28, 14 ], [ 692, 594, 47, 14 ], [ 87, 611, 49, 14 ], [ 141, 611, 44, 14 ], [ 190, 611, 21, 14 ], [ 215, 611, 47, 14 ], [ 266, 611, 31, 14 ], [ 302, 611, 22, 14 ], [ 328, 611, 7, 14 ], [ 339, 611, 83, 14 ], [ 425, 611, 61, 14 ], [ 491, 611, 50, 14 ], [ 544, 611, 15, 14 ], [ 564, 611, 19, 14 ], [ 587, 611, 21, 14 ], [ 613, 611, 44, 14 ], [ 661, 611, 71, 14 ], [ 87, 627, 27, 14 ], [ 118, 627, 63, 14 ], [ 185, 627, 14, 14 ], [ 203, 627, 12, 14 ], [ 219, 627, 9, 14 ], [ 232, 627, 29, 14 ], [ 264, 627, 14, 14 ], [ 282, 627, 22, 14 ], [ 308, 627, 56, 14 ], [ 368, 627, 12, 14 ], [ 385, 627, 19, 14 ], [ 408, 627, 12, 14 ], [ 423, 627, 9, 14 ], [ 436, 627, 26, 14 ], [ 467, 627, 21, 14 ], [ 492, 627, 85, 14 ], [ 581, 627, 12, 14 ], [ 597, 627, 9, 14 ], [ 610, 627, 26, 14 ], [ 640, 627, 30, 14 ], [ 675, 627, 23, 14 ], [ 702, 627, 22, 14 ], [ 87, 644, 56, 14 ], [ 147, 644, 12, 14 ], [ 164, 644, 25, 14 ], [ 192, 644, 12, 14 ], [ 208, 644, 9, 14 ], [ 221, 644, 29, 14 ], [ 254, 644, 21, 14 ], [ 279, 644, 13, 14 ], [ 296, 644, 37, 14 ], [ 337, 644, 52, 14 ], [ 393, 644, 7, 14 ], [ 405, 644, 59, 14 ], [ 468, 644, 25, 14 ], [ 497, 644, 7, 14 ], [ 507, 644, 52, 14 ], [ 563, 644, 22, 14 ], [ 589, 644, 74, 14 ], [ 667, 644, 14, 14 ], [ 685, 644, 40, 14 ], [ 87, 661, 15, 14 ], [ 107, 661, 21, 14 ], [ 132, 661, 27, 14 ], [ 163, 661, 26, 14 ], [ 192, 661, 39, 14 ], [ 236, 661, 22, 14 ], [ 261, 661, 71, 14 ], [ 337, 661, 21, 14 ], [ 362, 661, 14, 14 ], [ 380, 661, 36, 14 ], [ 420, 661, 53, 14 ], [ 477, 661, 7, 14 ], [ 488, 661, 40, 14 ], [ 533, 661, 61, 14 ], [ 599, 661, 19, 14 ], [ 621, 661, 22, 14 ], [ 647, 661, 25, 14 ], [ 676, 661, 7, 14 ], [ 687, 661, 46, 14 ], [ 87, 677, 14, 14 ], [ 105, 677, 22, 14 ], [ 131, 677, 75, 14 ], [ 210, 677, 14, 14 ], [ 228, 677, 25, 14 ], [ 258, 677, 21, 14 ], [ 283, 677, 27, 14 ], [ 314, 677, 39, 14 ], [ 357, 677, 22, 14 ], [ 383, 677, 39, 14 ], [ 426, 677, 47, 14 ], [ 476, 677, 35, 14 ], [ 87, 698, 70, 14 ], [ 161, 698, 22, 14 ], [ 187, 698, 42, 14 ], [ 234, 698, 24, 14 ], [ 262, 698, 42, 14 ], [ 309, 698, 55, 14 ], [ 368, 698, 65, 14 ], [ 438, 698, 11, 14 ], [ 452, 698, 19, 14 ], [ 475, 698, 72, 14 ], [ 552, 698, 11, 14 ], [ 567, 698, 59, 14 ], [ 630, 698, 40, 14 ], [ 87, 715, 69, 14 ], [ 160, 715, 47, 14 ], [ 211, 715, 22, 14 ], [ 238, 715, 42, 14 ], [ 284, 715, 50, 14 ], [ 338, 715, 45, 14 ], [ 387, 715, 65, 14 ], [ 456, 715, 33, 14 ], [ 493, 715, 45, 14 ], [ 542, 715, 22, 14 ], [ 568, 715, 52, 14 ], [ 624, 715, 35, 14 ], [ 662, 715, 22, 14 ], [ 688, 715, 24, 14 ], [ 87, 731, 51, 14 ], [ 142, 731, 40, 14 ], [ 187, 731, 39, 14 ], [ 230, 731, 17, 14 ], [ 252, 731, 43, 14 ], [ 298, 731, 12, 14 ], [ 315, 731, 34, 14 ], [ 352, 731, 64, 14 ], [ 420, 731, 21, 14 ], [ 445, 731, 42, 14 ], [ 492, 731, 67, 14 ], [ 563, 731, 11, 14 ], [ 578, 731, 20, 14 ], [ 78, 777, 77, 15 ], [ 78, 794, 13, 14 ], [ 97, 794, 45, 14 ], [ 147, 794, 31, 14 ], [ 183, 794, 23, 14 ], [ 211, 794, 83, 14 ], [ 300, 794, 52, 14 ], [ 357, 794, 47, 14 ], [ 78, 811, 76, 14 ], [ 160, 811, 31, 14 ], [ 196, 811, 10, 14 ], [ 211, 811, 43, 14 ], [ 259, 811, 61, 14 ], [ 326, 811, 60, 14 ], [ 391, 811, 12, 14 ], [ 78, 827, 56, 14 ], [ 139, 827, 43, 14 ], [ 186, 827, 12, 14 ], [ 202, 827, 83, 14 ], [ 289, 827, 37, 14 ], [ 330, 827, 28, 14 ], [ 362, 827, 41, 14 ], [ 78, 844, 20, 14 ], [ 103, 844, 56, 14 ], [ 164, 844, 47, 14 ], [ 215, 844, 50, 14 ], [ 270, 844, 19, 14 ], [ 294, 844, 28, 14 ], [ 327, 844, 76, 14 ], [ 78, 861, 41, 14 ], [ 124, 861, 17, 14 ], [ 145, 861, 20, 14 ], [ 169, 861, 15, 14 ], [ 189, 861, 20, 14 ], [ 212, 861, 57, 14 ], [ 274, 861, 6, 14 ], [ 285, 861, 80, 14 ], [ 369, 861, 34, 14 ], [ 78, 877, 22, 14 ], [ 105, 877, 19, 14 ], [ 130, 877, 78, 14 ], [ 213, 877, 12, 14 ], [ 230, 877, 20, 14 ], [ 255, 877, 24, 14 ], [ 285, 877, 52, 14 ], [ 341, 877, 62, 14 ], [ 78, 894, 26, 14 ], [ 109, 894, 17, 14 ], [ 130, 894, 72, 14 ], [ 206, 894, 63, 14 ], [ 274, 894, 34, 14 ], [ 313, 894, 11, 14 ], [ 328, 894, 10, 14 ], [ 343, 894, 16, 14 ], [ 364, 894, 39, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 116, 11 ], [ 78, 948, 55, 13 ], [ 136, 950, 37, 11 ], [ 176, 950, 20, 11 ], [ 199, 950, 21, 11 ], [ 223, 950, 36, 11 ], [ 262, 950, 25, 11 ], [ 290, 950, 23, 11 ], [ 316, 950, 28, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 778, 12, 14 ], [ 440, 778, 46, 14 ], [ 492, 778, 52, 14 ], [ 549, 778, 20, 14 ], [ 575, 778, 63, 14 ], [ 643, 778, 14, 14 ], [ 662, 778, 86, 14 ], [ 423, 794, 47, 14 ], [ 474, 794, 20, 14 ], [ 498, 794, 25, 14 ], [ 528, 794, 21, 14 ], [ 553, 794, 44, 14 ], [ 602, 794, 64, 14 ], [ 670, 794, 29, 14 ], [ 703, 794, 11, 14 ], [ 718, 794, 10, 14 ], [ 732, 794, 16, 14 ], [ 423, 811, 45, 14 ], [ 473, 811, 24, 14 ], [ 502, 811, 62, 14 ], [ 570, 811, 58, 14 ], [ 632, 811, 14, 14 ], [ 651, 811, 41, 14 ], [ 698, 811, 50, 14 ], [ 423, 827, 34, 14 ], [ 461, 827, 15, 14 ], [ 481, 827, 19, 14 ], [ 505, 827, 106, 14 ], [ 616, 827, 26, 14 ], [ 647, 827, 58, 14 ], [ 709, 827, 39, 14 ], [ 423, 844, 34, 14 ], [ 461, 844, 14, 14 ], [ 480, 844, 61, 14 ], [ 546, 844, 12, 14 ], [ 564, 844, 20, 14 ], [ 589, 844, 51, 14 ], [ 645, 844, 22, 14 ], [ 673, 844, 75, 14 ], [ 423, 861, 21, 14 ], [ 448, 861, 33, 14 ], [ 485, 861, 15, 14 ], [ 505, 861, 72, 14 ], [ 581, 861, 21, 14 ], [ 607, 861, 52, 14 ], [ 663, 861, 85, 14 ], [ 423, 877, 51, 14 ], [ 478, 877, 11, 14 ], [ 493, 877, 10, 14 ], [ 508, 877, 16, 14 ], [ 528, 877, 43, 14 ], [ 576, 877, 23, 14 ], [ 603, 877, 18, 14 ], [ 625, 877, 72, 14 ], [ 702, 877, 11, 14 ], [ 718, 877, 30, 14 ], [ 423, 894, 22, 14 ], [ 450, 894, 49, 14 ], [ 504, 894, 22, 14 ], [ 531, 894, 26, 14 ], [ 563, 894, 62, 14 ], [ 630, 894, 43, 14 ], [ 678, 894, 25, 14 ], [ 708, 894, 40, 14 ], [ 423, 910, 48, 14 ], [ 476, 910, 64, 14 ], [ 546, 910, 12, 14 ], [ 565, 910, 21, 14 ], [ 591, 910, 53, 14 ], [ 650, 910, 36, 14 ], [ 692, 910, 20, 14 ], [ 718, 910, 30, 14 ], [ 423, 927, 47, 14 ], [ 476, 927, 11, 14 ], [ 494, 927, 11, 14 ], [ 511, 927, 17, 14 ], [ 535, 927, 60, 14 ], [ 600, 927, 32, 14 ], [ 639, 927, 64, 14 ], [ 709, 927, 12, 14 ], [ 727, 927, 21, 14 ], [ 423, 944, 50, 14 ], [ 481, 944, 16, 14 ], [ 506, 944, 20, 14 ], [ 535, 944, 30, 14 ], [ 574, 944, 12, 14 ], [ 595, 944, 45, 14 ], [ 649, 944, 23, 14 ], [ 680, 944, 68, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 276, 987, 29, 10 ], [ 308, 987, 8, 10 ], [ 317, 987, 8, 10 ], [ 327, 987, 31, 10 ], [ 360, 987, 29, 10 ], [ 390, 987, 27, 10 ], [ 419, 987, 14, 10 ], [ 435, 987, 15, 10 ], [ 452, 987, 6, 10 ], [ 460, 987, 10, 10 ], [ 471, 987, 21, 10 ], [ 494, 987, 25, 10 ], [ 522, 987, 23, 10 ], [ 547, 987, 41, 10 ], [ 589, 987, 23, 10 ], [ 614, 987, 13, 10 ], [ 629, 987, 21, 10 ], [ 652, 987, 8, 10 ], [ 662, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Auvinet", "et", "al.", "BMC", "Musculoskeletal", "Disorders", "2011,", "12:258", "http://www.biomedcentral.com/1471-2474/12/258", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "The", "interest", "of", "gait", "markers", "in", "the", "identification", "of", "subgroups", "among", "fibromyalgia", "patients", "Bernard", "Auvinet1*,", "Denis", "Chaleil2,", "Jean", "Cabane3,", "Anne", "Dumolard4,", "Pierre", "Hatron5,", "Robert", "Juvin4,", "Michel", "Lanteri-Minet6,", "Yves", "Mainguy7,", "Laurence", "Negre-Pages8,", "Fabien", "Pillard9,", "Daniel", "Riviere9", "and", "Yves-Michel", "Maugars10", "Abstract", "Background:", "Fibromyalgia", "(FM)", "is", "a", "heterogeneous", "syndrome", "and", "its", "classification", "into", "subgroups", "calls", "for", "broad-", "based", "discussion.", "FM", "subgrouping,", "which", "aims", "to", "adapt", "treatment", "according", "to", "different", "subgroups,", "relies", "in", "part,", "on", "psychological", "and", "cognitive", "dysfunctions.", "Since", "motor", "control", "of", "gait", "is", "closely", "related", "to", "cognitive", "function,", "we", "hypothesized", "that", "gait", "markers", "could", "be", "of", "interest", "in", "the", "identification", "of", "FM", "patients’", "subgroups.", "This", "controlled", "study", "aimed", "at", "characterizing", "gait", "disorders", "in", "FM,", "and", "subgrouping", "FM", "patients", "according", "to", "gait", "markers", "such", "as", "stride", "frequency", "(SF),", "stride", "regularity", "(SR),", "and", "cranio-caudal", "power", "(CCP)", "which", "measures", "kinesia.", "Methods:", "A", "multicentre,", "observational", "open", "trial", "enrolled", "patients", "with", "primary", "FM", "(44.1", "±", "8.1", "y),", "and", "matched", "controls", "(44.1", "±", "7.3", "y).", "Outcome", "measurements", "and", "gait", "analyses", "were", "available", "for", "52", "pairs.", "A", "3-step", "statistical", "analysis", "was", "carried", "out.", "A", "preliminary", "single", "blind", "analysis", "using", "k-means", "cluster", "was", "performed", "as", "an", "initial", "validation", "of", "gait", "markers.", "Then", "in", "order", "to", "quantify", "FM", "patients", "according", "to", "psychometric", "and", "gait", "variables", "an", "open", "descriptive", "analysis", "comparing", "patients", "and", "controls", "were", "made,", "and", "correlations", "between", "gait", "variables", "and", "main", "outcomes", "were", "calculated.", "Finally", "using", "cluster", "analysis,", "we", "described", "subgroups", "for", "each", "gait", "variable", "and", "looked", "for", "significant", "differences", "in", "self-reported", "assessments.", "Results:", "SF", "was", "the", "most", "discriminating", "gait", "variable", "(73%", "of", "patients", "and", "controls).", "SF,", "SR,", "and", "CCP", "were", "different", "between", "patients", "and", "controls.", "There", "was", "a", "non-significant", "association", "between", "SF,", "FIQ", "and", "physical", "components", "from", "Short-Form", "36", "(p", "=", "0.06).", "SR", "was", "correlated", "to", "FIQ", "(p", "=", "0.01)", "and", "catastrophizing", "(p", "=", "0.05)", "while", "CCP", "was", "correlated", "to", "pain", "(p", "=", "0.01).", "The", "SF", "cluster", "identified", "3", "subgroups", "with", "a", "particular", "one", "characterized", "by", "normal", "SF,", "low", "pain,", "high", "activity", "and", "hyperkinesia.", "The", "SR", "cluster", "identified", "2", "distinct", "subgroups:", "the", "one", "with", "a", "reduced", "SR", "was", "distinguished", "by", "high", "FIQ,", "poor", "coping", "and", "altered", "affective", "status.", "Conclusion:", "Gait", "analysis", "may", "provide", "additional", "information", "in", "the", "identification", "of", "subgroups", "among", "fibromyalgia", "patients.", "Gait", "analysis", "provided", "relevant", "information", "about", "physical", "and", "cognitive", "status,", "and", "pain", "behavior.", "Further", "studies", "are", "needed", "to", "better", "understand", "gait", "analysis", "implications", "in", "FM.", "Background", "In", "clinical", "trials", "and", "observational", "research", "studies,", "fibromyalgia", "(FM)", "is", "usually", "diagnosed", "according", "to", "American", "College", "of", "Rheumatology", "(ACR)", "1990", "criteria", "[1].", "However,", "patients", "fulfilling", "the", "ACR", "classification", "criteria", "for", "FM", "do", "not", "constitute", "a", "homogeneous", "group", "and", "the", "classification", "of", "FM", "into", "different", "subgroups", "calls", "for", "broad-based", "discussion.", "Strazt", "et", "al", "[2]", "sought", "*", "Correspondence:", "bernard.auvinet@gmail.com", "1Locomotion", "Research", "Unit,", "Laval", "Hospital,", "53015", "Laval,", "France", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "to", "identify", "different", "FM", "subgroups", "by", "distinguishing", "between", "FM", "with", "and", "without", "depression.", "Turk", "et", "al", "[3]", "showed", "that", "subgroups", "identified", "by", "cluster", "analysis,", "based", "on", "the", "Multidimensional", "Pain", "Inventory", "(MPI),", "could", "be", "applicable", "to", "FM", "patients;", "this", "subgrouping", "was", "based", "on", "psychosocial", "and", "cognitive", "characteristics.", "Giesecke", "et", "al", "[4]", "showed", "that", "the", "combination", "of", "these", "two", "features", "and", "pain", "sensitivity", "indices", "best", "distin-", "guished", "subgroups", "of", "FM", "patients.", "Using", "the", "MPI,", "Thieme", "et", "al", "[5]", "identified", "three", "subgroups", "of", "FM", "patients", "on", "the", "basis", "of", "anxiety", "and", "psychiatric", "©", "2011", "Auvinet", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 78, 47, 49, 12 ], [ 130, 47, 9, 12 ], [ 142, 47, 11, 12 ], [ 156, 47, 21, 12 ], [ 180, 47, 71, 12 ], [ 255, 47, 18, 12 ], [ 276, 47, 48, 12 ], [ 327, 47, 40, 12 ], [ 370, 47, 25, 12 ], [ 399, 47, 26, 12 ], [ 78, 61, 227, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 20, 34 ], [ 108, 169, 208, 34 ], [ 326, 169, 101, 34 ], [ 437, 169, 63, 34 ], [ 510, 169, 146, 34 ], [ 78, 205, 96, 34 ], [ 185, 205, 108, 34 ], [ 302, 205, 91, 34 ], [ 404, 205, 105, 34 ], [ 519, 205, 120, 34 ], [ 649, 205, 94, 34 ], [ 78, 241, 51, 34 ], [ 139, 241, 74, 34 ], [ 222, 241, 130, 34 ], [ 363, 241, 28, 34 ], [ 400, 241, 158, 34 ], [ 568, 241, 25, 34 ], [ 603, 241, 16, 34 ], [ 628, 241, 120, 34 ], [ 78, 277, 45, 34 ], [ 133, 277, 48, 34 ], [ 78, 324, 33, 16 ], [ 116, 324, 12, 16 ], [ 132, 321, 73, 19 ], [ 209, 324, 23, 16 ], [ 236, 324, 40, 16 ], [ 281, 321, 55, 19 ], [ 341, 324, 43, 16 ], [ 388, 324, 42, 16 ], [ 434, 321, 50, 19 ], [ 488, 324, 29, 16 ], [ 521, 324, 32, 16 ], [ 558, 321, 68, 19 ], [ 631, 324, 22, 16 ], [ 78, 343, 40, 16 ], [ 123, 340, 69, 19 ], [ 87, 397, 54, 15 ], [ 87, 423, 76, 14 ], [ 167, 423, 77, 14 ], [ 249, 423, 11, 14 ], [ 264, 423, 35, 14 ], [ 303, 423, 19, 14 ], [ 326, 423, 54, 14 ], [ 384, 423, 24, 14 ], [ 412, 423, 25, 14 ], [ 441, 423, 46, 14 ], [ 492, 423, 7, 14 ], [ 503, 423, 54, 14 ], [ 560, 423, 11, 14 ], [ 575, 423, 27, 14 ], [ 606, 423, 41, 14 ], [ 651, 423, 30, 14 ], [ 87, 439, 72, 14 ], [ 164, 439, 92, 14 ], [ 260, 439, 79, 14 ], [ 343, 439, 8, 14 ], [ 355, 439, 8, 14 ], [ 367, 439, 63, 14 ], [ 434, 439, 12, 14 ], [ 451, 439, 36, 14 ], [ 491, 439, 15, 14 ], [ 510, 439, 53, 14 ], [ 568, 439, 25, 14 ], [ 597, 439, 19, 14 ], [ 620, 439, 50, 14 ], [ 673, 439, 11, 14 ], [ 87, 456, 56, 14 ], [ 148, 456, 102, 14 ], [ 254, 456, 27, 14 ], [ 285, 456, 71, 14 ], [ 360, 456, 21, 14 ], [ 386, 456, 58, 14 ], [ 448, 456, 40, 14 ], [ 491, 456, 37, 14 ], [ 533, 456, 11, 14 ], [ 548, 456, 19, 14 ], [ 571, 456, 40, 14 ], [ 616, 456, 49, 14 ], [ 669, 456, 17, 14 ], [ 691, 456, 7, 14 ], [ 701, 456, 23, 14 ], [ 87, 472, 30, 14 ], [ 122, 472, 37, 14 ], [ 163, 472, 11, 14 ], [ 178, 472, 26, 14 ], [ 209, 472, 55, 14 ], [ 87, 493, 56, 14 ], [ 148, 493, 21, 14 ], [ 173, 493, 54, 14 ], [ 231, 493, 39, 14 ], [ 274, 493, 11, 14 ], [ 290, 493, 7, 14 ], [ 300, 493, 42, 14 ], [ 347, 493, 49, 14 ], [ 400, 493, 11, 14 ], [ 415, 493, 70, 14 ], [ 489, 493, 68, 14 ], [ 562, 493, 32, 14 ], [ 598, 493, 50, 14 ], [ 652, 493, 27, 14 ], [ 87, 510, 61, 14 ], [ 153, 510, 40, 14 ], [ 198, 510, 22, 14 ], [ 223, 510, 54, 14 ], [ 282, 510, 30, 14 ], [ 316, 510, 19, 14 ], [ 339, 510, 81, 14 ], [ 424, 510, 19, 14 ], [ 447, 510, 20, 14 ], [ 472, 510, 29, 14 ], [ 505, 510, 22, 14 ], [ 532, 510, 42, 14 ], [ 578, 510, 22, 14 ], [ 604, 510, 35, 14 ], [ 643, 510, 31, 14 ], [ 678, 510, 12, 14 ], [ 694, 510, 11, 14 ], [ 87, 526, 71, 14 ], [ 162, 526, 25, 14 ], [ 191, 526, 19, 14 ], [ 214, 526, 72, 14 ], [ 291, 526, 102, 14 ], [ 397, 526, 32, 14 ], [ 433, 526, 69, 14 ], [ 506, 526, 58, 14 ], [ 569, 526, 58, 14 ], [ 631, 526, 78, 14 ], [ 712, 526, 22, 14 ], [ 87, 543, 29, 14 ], [ 121, 543, 21, 14 ], [ 146, 543, 62, 14 ], [ 212, 543, 54, 14 ], [ 270, 543, 28, 14 ], [ 302, 543, 78, 14 ], [ 384, 543, 81, 14 ], [ 470, 543, 43, 14 ], [ 517, 543, 7, 14 ], [ 529, 543, 56, 14 ], [ 589, 543, 57, 14 ], [ 650, 543, 76, 14 ], [ 87, 560, 21, 14 ], [ 113, 560, 62, 14 ], [ 179, 560, 41, 14 ], [ 87, 580, 46, 14 ], [ 137, 580, 18, 14 ], [ 160, 580, 34, 14 ], [ 198, 580, 22, 14 ], [ 224, 580, 19, 14 ], [ 247, 580, 25, 14 ], [ 276, 580, 42, 14 ], [ 322, 580, 46, 14 ], [ 372, 580, 78, 14 ], [ 454, 580, 81, 14 ], [ 539, 580, 51, 14 ], [ 594, 580, 43, 14 ], [ 642, 580, 9, 14 ], [ 655, 580, 46, 14 ], [ 87, 597, 57, 14 ], [ 149, 597, 76, 14 ], [ 229, 597, 21, 14 ], [ 254, 597, 57, 14 ], [ 315, 597, 19, 14 ], [ 338, 597, 62, 14 ], [ 404, 597, 46, 14 ], [ 454, 597, 11, 14 ], [ 470, 597, 19, 14 ], [ 492, 597, 27, 14 ], [ 524, 597, 19, 14 ], [ 547, 597, 22, 14 ], [ 574, 597, 33, 14 ], [ 611, 597, 19, 14 ], [ 634, 597, 25, 14 ], [ 662, 597, 42, 14 ], [ 709, 597, 22, 14 ], [ 87, 614, 27, 14 ], [ 118, 614, 11, 14 ], [ 133, 614, 71, 14 ], [ 208, 614, 25, 14 ], [ 237, 614, 102, 14 ], [ 343, 614, 32, 14 ], [ 379, 614, 11, 14 ], [ 394, 614, 55, 14 ], [ 452, 614, 85, 14 ], [ 541, 614, 7, 14 ], [ 552, 614, 44, 14 ], [ 600, 614, 54, 14 ], [ 658, 614, 11, 14 ], [ 672, 614, 66, 14 ], [ 87, 630, 53, 14 ], [ 144, 630, 78, 14 ], [ 226, 630, 14, 14 ], [ 244, 630, 28, 16 ], [ 276, 630, 22, 14 ], [ 302, 630, 26, 14 ], [ 333, 630, 11, 14 ], [ 348, 630, 19, 14 ], [ 370, 630, 27, 14 ], [ 402, 630, 19, 14 ], [ 425, 630, 22, 14 ], [ 451, 630, 22, 14 ], [ 478, 630, 40, 14 ], [ 521, 630, 58, 14 ], [ 583, 630, 22, 14 ], [ 610, 630, 25, 14 ], [ 639, 630, 42, 14 ], [ 685, 630, 39, 14 ], [ 728, 630, 8, 14 ], [ 87, 647, 41, 14 ], [ 133, 647, 15, 14 ], [ 152, 647, 19, 14 ], [ 175, 647, 55, 14 ], [ 234, 647, 33, 14 ], [ 272, 647, 11, 14 ], [ 287, 647, 69, 14 ], [ 87, 667, 75, 14 ], [ 167, 668, 21, 14 ], [ 192, 668, 35, 14 ], [ 232, 668, 44, 14 ], [ 279, 668, 22, 14 ], [ 306, 668, 7, 14 ], [ 317, 668, 38, 14 ], [ 360, 668, 42, 14 ], [ 406, 668, 52, 14 ], [ 462, 668, 27, 14 ], [ 493, 668, 61, 14 ], [ 558, 668, 41, 14 ], [ 603, 668, 11, 14 ], [ 618, 668, 71, 14 ], [ 693, 668, 25, 14 ], [ 87, 684, 72, 14 ], [ 164, 684, 81, 14 ], [ 249, 684, 11, 14 ], [ 264, 684, 71, 14 ], [ 339, 684, 25, 14 ], [ 368, 684, 38, 14 ], [ 411, 684, 49, 14 ], [ 464, 684, 15, 14 ], [ 484, 684, 50, 14 ], [ 538, 684, 24, 14 ], [ 566, 684, 24, 14 ], [ 594, 684, 45, 14 ], [ 644, 684, 63, 14 ], [ 87, 701, 71, 14 ], [ 162, 701, 11, 14 ], [ 177, 701, 42, 14 ], [ 224, 701, 12, 14 ], [ 240, 701, 52, 14 ], [ 87, 724, 62, 14 ], [ 154, 724, 58, 14 ], [ 215, 724, 71, 14 ], [ 290, 724, 53, 14 ], [ 347, 724, 39, 14 ], [ 391, 724, 53, 14 ], [ 78, 770, 77, 15 ], [ 78, 787, 70, 14 ], [ 153, 787, 44, 14 ], [ 201, 787, 10, 14 ], [ 216, 787, 7, 14 ], [ 227, 787, 34, 14 ], [ 265, 787, 62, 14 ], [ 332, 787, 40, 14 ], [ 376, 787, 27, 14 ], [ 78, 804, 25, 14 ], [ 107, 804, 10, 14 ], [ 121, 804, 9, 14 ], [ 135, 804, 82, 14 ], [ 221, 804, 12, 14 ], [ 238, 804, 27, 14 ], [ 269, 804, 77, 14 ], [ 350, 804, 21, 14 ], [ 376, 804, 27, 14 ], [ 78, 820, 47, 14 ], [ 132, 820, 49, 14 ], [ 187, 820, 23, 14 ], [ 217, 820, 10, 14 ], [ 233, 820, 77, 14 ], [ 316, 820, 42, 14 ], [ 364, 820, 18, 14 ], [ 389, 820, 15, 14 ], [ 78, 837, 58, 14 ], [ 140, 837, 41, 14 ], [ 186, 837, 19, 14 ], [ 210, 837, 18, 14 ], [ 232, 837, 43, 14 ], [ 279, 837, 40, 14 ], [ 323, 837, 28, 14 ], [ 356, 837, 18, 14 ], [ 378, 837, 25, 14 ], [ 78, 854, 12, 14 ], [ 96, 854, 59, 14 ], [ 160, 854, 20, 14 ], [ 186, 854, 29, 14 ], [ 221, 854, 43, 14 ], [ 269, 854, 13, 14 ], [ 287, 854, 28, 14 ], [ 320, 854, 83, 14 ], [ 78, 900, 5, 11 ], [ 86, 900, 70, 11 ], [ 159, 900, 144, 11 ], [ 78, 912, 5, 11 ], [ 87, 913, 50, 11 ], [ 140, 913, 30, 11 ], [ 78, 923, 30, 13 ], [ 111, 925, 11, 11 ], [ 125, 925, 66, 11 ], [ 195, 925, 5, 11 ], [ 203, 925, 34, 11 ], [ 239, 925, 30, 11 ], [ 273, 925, 35, 11 ], [ 311, 925, 11, 11 ], [ 325, 925, 36, 11 ], [ 364, 925, 38, 11 ], [ 78, 937, 49, 11 ], [ 130, 937, 40, 11 ], [ 173, 937, 32, 11 ], [ 208, 937, 42, 11 ], [ 253, 937, 30, 11 ], [ 286, 937, 5, 11 ], [ 295, 937, 9, 11 ], [ 306, 937, 23, 11 ], [ 333, 937, 34, 11 ], [ 370, 937, 12, 11 ], [ 78, 950, 25, 11 ], [ 106, 950, 15, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 771, 44, 14 ], [ 471, 771, 42, 14 ], [ 518, 771, 82, 14 ], [ 605, 771, 22, 14 ], [ 632, 771, 85, 14 ], [ 722, 771, 26, 14 ], [ 423, 787, 29, 14 ], [ 456, 787, 51, 14 ], [ 511, 787, 21, 14 ], [ 537, 787, 12, 14 ], [ 553, 787, 19, 14 ], [ 576, 787, 51, 14 ], [ 631, 787, 12, 14 ], [ 647, 787, 72, 14 ], [ 724, 787, 24, 14 ], [ 423, 804, 25, 14 ], [ 452, 804, 12, 14 ], [ 468, 804, 19, 14 ], [ 492, 804, 31, 14 ], [ 527, 804, 20, 14 ], [ 551, 804, 76, 14 ], [ 632, 804, 44, 14 ], [ 680, 804, 18, 14 ], [ 702, 804, 7, 14 ], [ 714, 804, 35, 14 ], [ 423, 820, 11, 14 ], [ 438, 820, 30, 14 ], [ 472, 820, 23, 14 ], [ 500, 820, 33, 14 ], [ 536, 820, 57, 14 ], [ 598, 820, 25, 14 ], [ 627, 820, 40, 14 ], [ 671, 820, 50, 14 ], [ 725, 820, 23, 14 ], [ 423, 837, 30, 14 ], [ 458, 837, 51, 14 ], [ 513, 837, 28, 14 ], [ 546, 837, 38, 14 ], [ 589, 837, 25, 14 ], [ 618, 837, 22, 14 ], [ 645, 837, 57, 14 ], [ 707, 837, 41, 14 ], [ 423, 854, 45, 14 ], [ 472, 854, 36, 14 ], [ 512, 854, 19, 14 ], [ 536, 854, 38, 14 ], [ 578, 854, 40, 14 ], [ 623, 854, 21, 14 ], [ 648, 854, 14, 14 ], [ 667, 854, 41, 14 ], [ 713, 854, 35, 14 ], [ 423, 870, 37, 14 ], [ 464, 870, 14, 14 ], [ 483, 870, 80, 14 ], [ 568, 870, 13, 14 ], [ 586, 870, 56, 14 ], [ 647, 870, 12, 14 ], [ 664, 870, 29, 14 ], [ 698, 870, 50, 14 ], [ 423, 887, 62, 14 ], [ 490, 887, 24, 14 ], [ 518, 887, 72, 14 ], [ 594, 887, 36, 14 ], [ 635, 887, 24, 14 ], [ 663, 887, 38, 14 ], [ 706, 887, 18, 14 ], [ 729, 887, 19, 14 ], [ 423, 904, 49, 14 ], [ 477, 904, 74, 14 ], [ 555, 904, 47, 14 ], [ 607, 904, 28, 14 ], [ 640, 904, 108, 14 ], [ 423, 920, 114, 15 ], [ 541, 920, 75, 14 ], [ 621, 920, 43, 14 ], [ 669, 920, 42, 14 ], [ 715, 920, 10, 14 ], [ 729, 920, 19, 14 ], [ 423, 937, 59, 14 ], [ 487, 937, 22, 14 ], [ 515, 937, 42, 14 ], [ 562, 937, 65, 14 ], [ 632, 937, 12, 14 ], [ 649, 937, 19, 14 ], [ 674, 937, 75, 14 ], [ 423, 953, 51, 14 ], [ 484, 953, 21, 14 ], [ 515, 953, 24, 14 ], [ 549, 953, 55, 14 ], [ 613, 953, 12, 14 ], [ 635, 953, 33, 14 ], [ 678, 953, 12, 14 ], [ 701, 953, 25, 14 ], [ 736, 953, 12, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 39, 10 ], [ 320, 987, 8, 10 ], [ 330, 987, 8, 10 ], [ 341, 987, 30, 10 ], [ 374, 987, 29, 10 ], [ 406, 987, 27, 10 ], [ 435, 987, 14, 10 ], [ 452, 987, 15, 10 ], [ 470, 987, 6, 10 ], [ 479, 987, 10, 10 ], [ 491, 987, 21, 10 ], [ 515, 987, 25, 10 ], [ 543, 987, 23, 10 ], [ 568, 987, 41, 10 ], [ 612, 987, 23, 10 ], [ 637, 987, 13, 10 ], [ 653, 987, 22, 10 ], [ 677, 987, 8, 10 ], [ 688, 987, 13, 10 ], [ 703, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 50, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Castañeda", "et", "al.", "BMC", "Complementary", "and", "Alternative", "Medicine", "2012,", "12:38", "http://www.biomedcentral.com/1472-6882/12/38", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "A", "gallotannin-rich", "fraction", "from", "Caesalpinia", "spinosa", "(Molina)", "Kuntze", "displays", "cytotoxic", "activity", "and", "raises", "sensitivity", "to", "doxorubicin", "in", "a", "leukemia", "cell", "line", "Diana", "M", "Castañeda1†,", "Luis", "Miguel", "Pombo2†,", "Claudia", "Patricia", "Urueña1,", "John", "Fredy", "Hernandez1", "and", "Susana", "Fiorentino1*", "Abstract", "Background:", "Enhancement", "of", "tumor", "cell", "sensitivity", "may", "help", "facilitate", "a", "reduction", "in", "drug", "dosage", "using", "conventional", "chemotherapies.", "Consequently,", "it", "is", "worthwhile", "to", "search", "for", "adjuvants", "with", "the", "potential", "of", "increasing", "chemotherapeutic", "drug", "effectiveness", "and", "improving", "patient", "quality", "of", "life.", "Natural", "products", "are", "a", "very", "good", "source", "of", "such", "adjuvants.", "Methods:", "The", "biological", "activity", "of", "a", "fraction", "enriched", "in", "hydrolysable", "polyphenols", "(P2Et)", "obtained", "from", "Caesalpinia", "spinosa", "was", "evaluated", "using", "the", "hematopoietic", "cell", "line", "K562.", "This", "fraction", "was", "tested", "alone", "or", "in", "combination", "with", "the", "conventional", "chemotherapeutic", "drugs", "doxorubicin,", "vincristine,", "etoposide,", "camptothecin", "and", "taxol.", "The", "parameters", "evaluated", "were", "mitochondrial", "depolarization,", "caspase", "3", "activation,", "chromatin", "condensation", "and", "clonogenic", "activity.", "Results:", "We", "found", "that", "the", "P2Et", "fraction", "induced", "mitochondrial", "depolarization,", "activated", "caspase", "3,", "induced", "chromatin", "condensation", "and", "decreased", "the", "clonogenic", "capacity", "of", "the", "K562", "cell", "line.", "When", "the", "P2Et", "fraction", "was", "used", "in", "combination", "with", "chemotherapeutic", "drugs", "at", "sub-lethal", "concentrations,", "a", "fourfold", "reduction", "in", "doxorubicin", "inhibitory", "concentration", "50", "(IC50)", "was", "seen", "in", "the", "K562", "cell", "line.", "This", "finding", "suggested", "that", "P2Et", "fraction", "activity", "is", "specific", "for", "the", "molecular", "target", "of", "doxorubicin.", "Conclusions:", "Our", "results", "suggest", "that", "a", "natural", "fraction", "extracted", "from", "Caesalpinia", "spinosa", "in", "combination", "with", "conventional", "chemotherapy", "in", "combination", "with", "natural", "products", "on", "leukemia", "cells", "may", "increase", "therapeutic", "effectiveness", "in", "relation", "to", "leukemia.", "Keywords:", "Adjuvants,", "Gallotannins,", "C.spinosa,", "Tumor,", "Leukemia", "Background", "Caesalpinia", "spinosa", "is", "a", "shrub", "commonly", "named", "divi-", "divi.", "It", "is", "acknowledged", "to", "have", "antimicrobial", "and", "anti-", "oxidant", "activity,", "and", "is", "traditionally", "known", "for", "its", "antitumor", "activity", "[1].", "An", "ethanol", "extract", "from", "the", "fruit", "of", "C.spinosa", "has", "been", "proven", "to", "have", "antimicrobial", "*", "Correspondence:", "susana.fiorentino@javeriana.edu.co", "†", "Contributed", "equally", "1Grupo", "de", "Inmunobiología", "y", "Biología", "Celular,", "Facultad", "de", "Ciencias,", "Pontificia", "Universidad", "Javeriana,", "Bogotá,", "Colombia,", "Carrera", "7", "N.", "43-82", "Building", "52,", "Office", "608", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "activity", "against", "gram-positive", "and", "gram-negative", "bac-", "teria,", "probably", "due", "to", "the", "presence", "of", "hydrolysable", "tan-", "nins", "in", "the", "fruits", "[2].", "Hydrolysable", "tannins", "are", "a", "group", "of", "gallic", "acid", "esters", "associated", "with", "polyols", "(glucose,", "glu-", "citol,", "shikimic", "acid,", "quinic", "acid", "and", "quercitol,", "among", "others),", "where", "the", "galloyl", "groups", "can", "be", "further", "cross-", "linked", "by", "etherification", "or", "oxidation", "to", "form", "complex", "structures.", "The", "gallotannins", "(gallic", "acid", "esters)", "are", "the", "simplest", "hydrolysable", "tannins,", "were", "1,2,3,4,6-penta-O-", "galloyl-b-D-glucose", "(pentagalloyl", "glucose", "[PGG])", "is", "the", "prototype", "and", "central", "compound", "of", "the", "biosynthetic", "pathway", "[3].", "The", "presence", "of", "PGG,", "as", "well", "as", "©", "2012", "Castañeda", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 83, 154, 53, 27 ], [ 141, 154, 69, 27 ], [ 325, 155, 207, 21 ], [ 367, 186, 79, 24 ], [ 451, 186, 40, 24 ], [ 647, 154, 120, 27 ], [ 83, 241, 107, 32 ], [ 197, 241, 27, 32 ], [ 231, 241, 147, 32 ], [ 385, 241, 110, 32 ], [ 502, 241, 72, 32 ], [ 582, 241, 51, 32 ], [ 640, 241, 68, 32 ], [ 83, 277, 114, 32 ], [ 204, 277, 27, 32 ], [ 238, 277, 173, 32 ], [ 418, 277, 257, 32 ], [ 682, 277, 67, 32 ], [ 83, 313, 79, 32 ], [ 169, 313, 81, 32 ], [ 257, 313, 124, 32 ], [ 388, 313, 116, 32 ], [ 511, 313, 40, 32 ], [ 83, 372, 47, 19 ], [ 134, 372, 106, 19 ], [ 244, 372, 54, 19 ], [ 302, 372, 77, 19 ], [ 383, 372, 74, 19 ], [ 461, 372, 54, 19 ], [ 83, 415, 47, 11 ], [ 132, 415, 9, 11 ], [ 143, 415, 28, 11 ], [ 173, 415, 41, 11 ], [ 217, 415, 19, 11 ], [ 238, 415, 18, 11 ], [ 257, 415, 19, 11 ], [ 279, 415, 29, 11 ], [ 309, 415, 4, 11 ], [ 316, 415, 35, 11 ], [ 352, 415, 25, 11 ], [ 379, 415, 38, 11 ], [ 419, 415, 25, 11 ], [ 447, 415, 4, 11 ], [ 453, 415, 28, 11 ], [ 483, 415, 128, 11 ], [ 613, 415, 68, 11 ], [ 683, 415, 27, 11 ], [ 83, 451, 39, 11 ], [ 124, 451, 18, 11 ], [ 144, 451, 14, 11 ], [ 160, 451, 24, 11 ], [ 186, 451, 40, 11 ], [ 228, 451, 33, 11 ], [ 263, 451, 14, 11 ], [ 279, 451, 24, 11 ], [ 305, 451, 42, 11 ], [ 349, 451, 20, 11 ], [ 371, 451, 14, 11 ], [ 386, 451, 21, 11 ], [ 83, 487, 43, 11 ], [ 83, 499, 21, 11 ], [ 107, 499, 9, 11 ], [ 119, 499, 46, 11 ], [ 169, 499, 9, 11 ], [ 181, 499, 21, 11 ], [ 206, 499, 52, 11 ], [ 260, 499, 41, 11 ], [ 305, 499, 9, 11 ], [ 317, 499, 23, 11 ], [ 343, 499, 15, 11 ], [ 362, 499, 21, 11 ], [ 387, 499, 35, 11 ], [ 425, 499, 9, 11 ], [ 438, 499, 25, 11 ], [ 466, 499, 32, 11 ], [ 501, 499, 80, 11 ], [ 584, 499, 42, 11 ], [ 629, 499, 9, 11 ], [ 641, 499, 25, 11 ], [ 670, 499, 14, 11 ], [ 687, 499, 37, 11 ], [ 727, 499, 28, 11 ], [ 758, 499, 9, 11 ], [ 83, 511, 46, 11 ], [ 133, 511, 13, 11 ], [ 150, 511, 33, 11 ], [ 187, 511, 43, 11 ], [ 234, 511, 9, 11 ], [ 247, 511, 38, 11 ], [ 289, 511, 16, 11 ], [ 308, 511, 36, 11 ], [ 348, 511, 51, 11 ], [ 403, 511, 24, 11 ], [ 431, 511, 9, 11 ], [ 444, 511, 46, 11 ], [ 494, 511, 13, 11 ], [ 511, 511, 37, 11 ], [ 553, 511, 32, 11 ], [ 588, 511, 53, 11 ], [ 645, 511, 13, 11 ], [ 662, 511, 41, 11 ], [ 708, 511, 21, 11 ], [ 732, 511, 20, 11 ], [ 756, 511, 11, 11 ], [ 83, 523, 43, 11 ], [ 128, 523, 43, 11 ], [ 173, 523, 24, 11 ], [ 199, 523, 11, 11 ], [ 212, 523, 28, 11 ], [ 243, 523, 37, 11 ], [ 282, 523, 9, 11 ], [ 294, 523, 26, 11 ], [ 323, 523, 22, 11 ], [ 347, 523, 57, 11 ], [ 406, 523, 83, 11 ], [ 491, 523, 36, 11 ], [ 529, 523, 31, 11 ], [ 562, 523, 21, 11 ], [ 585, 523, 30, 11 ], [ 617, 523, 11, 11 ], [ 630, 523, 29, 11 ], [ 662, 523, 56, 11 ], [ 720, 523, 16, 11 ], [ 738, 523, 29, 11 ], [ 83, 535, 39, 11 ], [ 124, 535, 11, 11 ], [ 137, 535, 39, 11 ], [ 178, 535, 16, 11 ], [ 196, 535, 45, 11 ], [ 243, 535, 37, 11 ], [ 282, 535, 63, 11 ], [ 347, 535, 17, 11 ], [ 366, 535, 33, 11 ], [ 401, 535, 16, 11 ], [ 419, 535, 30, 11 ], [ 451, 535, 21, 11 ], [ 475, 535, 23, 11 ], [ 500, 535, 15, 11 ], [ 518, 535, 17, 11 ], [ 537, 535, 23, 11 ], [ 563, 535, 46, 11 ], [ 611, 535, 13, 11 ], [ 627, 535, 48, 11 ], [ 677, 535, 44, 11 ], [ 723, 535, 33, 11 ], [ 758, 535, 9, 11 ], [ 83, 547, 13, 11 ], [ 99, 547, 31, 11 ], [ 132, 547, 21, 11 ], [ 156, 547, 45, 11 ], [ 204, 547, 34, 11 ], [ 241, 547, 20, 11 ], [ 264, 547, 13, 11 ], [ 280, 547, 57, 11 ], [ 340, 547, 16, 11 ], [ 359, 547, 18, 11 ], [ 381, 547, 13, 11 ], [ 397, 547, 9, 11 ], [ 408, 547, 13, 11 ], [ 425, 547, 24, 11 ], [ 451, 547, 9, 11 ], [ 463, 547, 13, 11 ], [ 480, 547, 39, 11 ], [ 522, 547, 46, 11 ], [ 570, 547, 34, 11 ], [ 607, 547, 30, 11 ], [ 640, 547, 13, 11 ], [ 657, 547, 53, 11 ], [ 712, 547, 9, 11 ], [ 725, 547, 13, 11 ], [ 740, 547, 26, 11 ], [ 83, 559, 22, 11 ], [ 109, 559, 9, 11 ], [ 122, 559, 40, 11 ], [ 167, 559, 35, 11 ], [ 206, 559, 134, 11 ], [ 345, 559, 25, 11 ], [ 375, 559, 101, 11 ], [ 480, 559, 127, 11 ], [ 612, 559, 126, 11 ], [ 742, 559, 25, 11 ], [ 83, 571, 103, 11 ], [ 189, 571, 16, 11 ], [ 207, 571, 129, 11 ], [ 338, 571, 30, 11 ], [ 371, 571, 27, 11 ], [ 401, 571, 22, 11 ], [ 426, 571, 9, 11 ], [ 438, 571, 23, 11 ], [ 464, 571, 31, 11 ], [ 498, 571, 21, 11 ], [ 522, 571, 18, 11 ], [ 542, 571, 9, 11 ], [ 554, 571, 23, 11 ], [ 580, 571, 53, 11 ], [ 636, 571, 35, 11 ], [ 674, 571, 19, 11 ], [ 696, 571, 42, 11 ], [ 740, 571, 26, 11 ], [ 83, 583, 22, 11 ], [ 107, 583, 9, 11 ], [ 119, 583, 21, 11 ], [ 142, 583, 34, 11 ], [ 179, 583, 55, 11 ], [ 236, 583, 37, 11 ], [ 275, 583, 9, 11 ], [ 287, 583, 13, 11 ], [ 302, 583, 31, 11 ], [ 336, 583, 43, 11 ], [ 381, 583, 31, 11 ], [ 414, 583, 18, 11 ], [ 434, 583, 9, 11 ], [ 445, 583, 13, 11 ], [ 461, 583, 27, 11 ], [ 490, 583, 22, 11 ], [ 515, 583, 37, 11 ], [ 554, 583, 9, 11 ], [ 565, 583, 45, 11 ], [ 613, 583, 21, 11 ], [ 636, 583, 17, 11 ], [ 656, 583, 38, 11 ], [ 696, 583, 14, 11 ], [ 713, 583, 13, 11 ], [ 728, 583, 39, 11 ], [ 83, 595, 21, 11 ], [ 107, 595, 31, 11 ], [ 142, 595, 9, 11 ], [ 155, 595, 35, 11 ], [ 194, 595, 19, 11 ], [ 217, 595, 9, 11 ], [ 229, 595, 29, 11 ], [ 262, 595, 17, 11 ], [ 283, 595, 31, 11 ], [ 318, 595, 23, 11 ], [ 345, 595, 37, 11 ], [ 386, 595, 11, 11 ], [ 401, 595, 59, 11 ], [ 463, 595, 37, 11 ], [ 504, 595, 9, 11 ], [ 518, 595, 44, 11 ], [ 566, 595, 19, 11 ], [ 589, 595, 39, 11 ], [ 632, 595, 36, 11 ], [ 673, 595, 14, 11 ], [ 691, 595, 19, 11 ], [ 714, 595, 35, 11 ], [ 752, 595, 14, 11 ], [ 83, 607, 60, 11 ], [ 145, 607, 9, 11 ], [ 157, 607, 13, 11 ], [ 173, 607, 45, 11 ], [ 220, 607, 48, 11 ], [ 271, 607, 35, 11 ], [ 309, 607, 22, 11 ], [ 334, 607, 35, 11 ], [ 372, 607, 35, 11 ], [ 409, 607, 15, 11 ], [ 428, 607, 34, 11 ], [ 465, 607, 14, 11 ], [ 481, 607, 17, 11 ], [ 501, 607, 28, 11 ], [ 531, 607, 9, 11 ], [ 543, 607, 29, 11 ], [ 574, 607, 23, 11 ], [ 600, 607, 9, 11 ], [ 611, 607, 27, 11 ], [ 641, 607, 24, 11 ], [ 668, 607, 34, 11 ], [ 704, 607, 9, 11 ], [ 716, 607, 15, 11 ], [ 734, 607, 33, 11 ], [ 83, 619, 13, 11 ], [ 97, 619, 13, 11 ], [ 113, 619, 56, 11 ], [ 171, 619, 9, 11 ], [ 182, 619, 13, 11 ], [ 198, 619, 21, 11 ], [ 221, 619, 24, 11 ], [ 83, 655, 49, 11 ], [ 136, 655, 37, 11 ], [ 178, 655, 57, 11 ], [ 239, 655, 83, 11 ], [ 326, 655, 33, 11 ], [ 363, 655, 34, 11 ], [ 402, 655, 45, 11 ], [ 451, 655, 42, 11 ], [ 498, 655, 37, 11 ], [ 539, 655, 40, 11 ], [ 583, 655, 37, 11 ], [ 625, 655, 53, 11 ], [ 683, 655, 37, 11 ], [ 724, 655, 43, 11 ], [ 83, 667, 31, 11 ], [ 115, 667, 21, 11 ], [ 83, 730, 59, 11 ], [ 83, 742, 28, 11 ], [ 116, 742, 40, 11 ], [ 161, 742, 38, 11 ], [ 204, 742, 13, 11 ], [ 223, 742, 7, 11 ], [ 236, 742, 16, 11 ], [ 257, 742, 9, 11 ], [ 272, 742, 13, 11 ], [ 290, 742, 21, 11 ], [ 317, 742, 41, 11 ], [ 363, 742, 25, 11 ], [ 394, 742, 23, 11 ], [ 83, 754, 48, 11 ], [ 134, 754, 19, 11 ], [ 156, 754, 5, 11 ], [ 165, 754, 19, 11 ], [ 188, 754, 46, 11 ], [ 237, 754, 9, 11 ], [ 250, 754, 19, 11 ], [ 272, 754, 16, 11 ], [ 292, 754, 31, 11 ], [ 326, 754, 28, 11 ], [ 358, 754, 39, 11 ], [ 400, 754, 17, 11 ], [ 83, 766, 19, 11 ], [ 105, 766, 32, 11 ], [ 141, 766, 15, 11 ], [ 160, 766, 19, 11 ], [ 182, 766, 29, 11 ], [ 215, 766, 13, 11 ], [ 231, 766, 30, 11 ], [ 264, 766, 21, 11 ], [ 289, 766, 51, 11 ], [ 343, 766, 9, 11 ], [ 356, 766, 28, 11 ], [ 387, 766, 30, 11 ], [ 83, 778, 26, 11 ], [ 112, 778, 37, 11 ], [ 153, 778, 33, 11 ], [ 190, 778, 9, 11 ], [ 203, 778, 25, 11 ], [ 231, 778, 19, 11 ], [ 254, 778, 31, 11 ], [ 289, 778, 7, 11 ], [ 300, 778, 5, 11 ], [ 309, 778, 25, 11 ], [ 338, 778, 50, 11 ], [ 391, 778, 25, 11 ], [ 83, 790, 24, 11 ], [ 109, 790, 27, 11 ], [ 139, 790, 8, 11 ], [ 149, 790, 29, 11 ], [ 180, 790, 9, 11 ], [ 191, 790, 10, 11 ], [ 204, 790, 10, 11 ], [ 217, 790, 41, 11 ], [ 261, 790, 55, 11 ], [ 318, 790, 15, 11 ], [ 336, 790, 13, 11 ], [ 352, 790, 34, 11 ], [ 388, 790, 29, 11 ], [ 83, 802, 28, 11 ], [ 113, 802, 13, 11 ], [ 128, 802, 28, 11 ], [ 158, 802, 29, 11 ], [ 190, 802, 42, 11 ], [ 234, 802, 40, 11 ], [ 276, 802, 51, 11 ], [ 330, 802, 12, 11 ], [ 344, 802, 12, 11 ], [ 358, 802, 7, 11 ], [ 368, 802, 8, 11 ], [ 378, 802, 39, 11 ], [ 83, 814, 37, 11 ], [ 123, 814, 16, 11 ], [ 142, 814, 18, 11 ], [ 163, 814, 37, 11 ], [ 203, 814, 18, 11 ], [ 225, 814, 19, 11 ], [ 247, 814, 5, 11 ], [ 255, 814, 15, 11 ], [ 273, 814, 17, 11 ], [ 293, 814, 9, 11 ], [ 305, 814, 26, 11 ], [ 334, 814, 55, 11 ], [ 392, 814, 25, 11 ], [ 83, 826, 32, 11 ], [ 120, 826, 83, 11 ], [ 208, 826, 26, 11 ], [ 240, 826, 39, 11 ], [ 284, 826, 25, 11 ], [ 315, 826, 42, 11 ], [ 363, 826, 33, 11 ], [ 401, 826, 16, 11 ], [ 83, 838, 25, 11 ], [ 111, 838, 52, 11 ], [ 167, 838, 33, 11 ], [ 203, 838, 15, 11 ], [ 221, 838, 57, 11 ], [ 281, 838, 80, 11 ], [ 365, 838, 42, 11 ], [ 410, 838, 7, 11 ], [ 83, 850, 37, 11 ], [ 123, 850, 9, 11 ], [ 135, 850, 20, 11 ], [ 157, 850, 34, 11 ], [ 194, 850, 33, 11 ], [ 230, 850, 9, 11 ], [ 242, 850, 25, 11 ], [ 270, 850, 55, 11 ], [ 328, 850, 19, 11 ], [ 350, 850, 33, 11 ], [ 386, 850, 23, 11 ], [ 412, 850, 5, 11 ], [ 83, 862, 15, 11 ], [ 101, 862, 17, 11 ], [ 122, 862, 9, 11 ], [ 134, 862, 13, 11 ], [ 151, 862, 48, 11 ], [ 202, 862, 9, 11 ], [ 215, 862, 62, 11 ], [ 280, 862, 42, 11 ], [ 326, 862, 9, 11 ], [ 338, 862, 28, 11 ], [ 369, 862, 28, 11 ], [ 401, 862, 16, 11 ], [ 83, 874, 17, 11 ], [ 104, 874, 46, 11 ], [ 155, 874, 13, 11 ], [ 172, 874, 21, 11 ], [ 198, 874, 9, 11 ], [ 211, 874, 31, 11 ], [ 246, 874, 26, 11 ], [ 276, 874, 9, 11 ], [ 289, 874, 18, 11 ], [ 311, 874, 31, 11 ], [ 347, 874, 18, 11 ], [ 369, 874, 48, 11 ], [ 83, 886, 29, 11 ], [ 115, 886, 19, 11 ], [ 137, 886, 21, 11 ], [ 161, 886, 40, 11 ], [ 203, 886, 7, 11 ], [ 213, 886, 39, 11 ], [ 255, 886, 13, 11 ], [ 270, 886, 17, 11 ], [ 291, 886, 17, 11 ], [ 311, 886, 9, 11 ], [ 323, 886, 25, 11 ], [ 351, 886, 52, 11 ], [ 406, 886, 11, 11 ], [ 83, 898, 44, 11 ], [ 129, 898, 13, 11 ], [ 145, 898, 23, 11 ], [ 170, 898, 44, 11 ], [ 217, 898, 57, 11 ], [ 276, 898, 15, 11 ], [ 294, 898, 40, 11 ], [ 336, 898, 62, 11 ], [ 401, 898, 16, 11 ], [ 83, 910, 21, 11 ], [ 107, 910, 87, 11 ], [ 199, 910, 15, 11 ], [ 218, 910, 23, 11 ], [ 245, 910, 57, 11 ], [ 306, 910, 40, 11 ], [ 350, 910, 9, 11 ], [ 364, 910, 13, 11 ], [ 381, 910, 36, 11 ], [ 83, 922, 25, 11 ], [ 111, 922, 13, 11 ], [ 127, 922, 28, 11 ], [ 159, 922, 39, 11 ], [ 201, 922, 11, 11 ], [ 216, 922, 25, 11 ], [ 245, 922, 39, 11 ], [ 287, 922, 35, 11 ], [ 325, 922, 21, 11 ], [ 350, 922, 27, 11 ], [ 380, 922, 25, 11 ], [ 410, 922, 7, 11 ], [ 83, 934, 71, 11 ], [ 159, 934, 43, 11 ], [ 207, 934, 9, 11 ], [ 221, 934, 16, 11 ], [ 242, 934, 21, 11 ], [ 269, 934, 35, 11 ], [ 309, 934, 38, 11 ], [ 352, 934, 15, 11 ], [ 373, 934, 16, 11 ], [ 394, 934, 23, 11 ], [ 83, 946, 35, 11 ], [ 122, 946, 38, 11 ], [ 164, 946, 35, 11 ], [ 204, 946, 11, 11 ], [ 220, 946, 16, 11 ], [ 240, 946, 31, 11 ], [ 276, 946, 24, 11 ], [ 305, 946, 15, 11 ], [ 324, 946, 21, 11 ], [ 350, 946, 21, 11 ], [ 375, 946, 16, 11 ], [ 395, 946, 21, 11 ], [ 83, 958, 35, 11 ], [ 121, 958, 39, 11 ], [ 165, 958, 13, 11 ], [ 182, 958, 40, 11 ], [ 226, 958, 11, 11 ], [ 242, 958, 53, 11 ], [ 299, 958, 9, 11 ], [ 312, 958, 46, 11 ], [ 362, 958, 35, 11 ], [ 401, 958, 16, 11 ], [ 83, 970, 20, 11 ], [ 106, 970, 35, 11 ], [ 144, 970, 15, 11 ], [ 162, 970, 36, 11 ], [ 201, 970, 21, 11 ], [ 225, 970, 31, 11 ], [ 260, 970, 13, 11 ], [ 276, 970, 37, 11 ], [ 316, 970, 19, 11 ], [ 338, 970, 60, 11 ], [ 402, 970, 15, 11 ], [ 83, 982, 9, 11 ], [ 95, 982, 13, 11 ], [ 112, 982, 31, 11 ], [ 146, 982, 23, 11 ], [ 173, 982, 13, 11 ], [ 189, 982, 13, 11 ], [ 206, 982, 41, 11 ], [ 250, 982, 9, 11 ], [ 263, 982, 13, 11 ], [ 280, 982, 35, 11 ], [ 319, 982, 25, 11 ], [ 347, 982, 16, 11 ], [ 366, 982, 27, 11 ], [ 396, 982, 21, 11 ], [ 83, 994, 25, 11 ], [ 112, 994, 21, 11 ], [ 136, 994, 39, 11 ], [ 179, 994, 11, 11 ], [ 194, 994, 13, 11 ], [ 210, 994, 9, 11 ], [ 223, 994, 23, 11 ], [ 250, 994, 43, 11 ], [ 296, 994, 45, 11 ], [ 345, 994, 23, 11 ], [ 372, 994, 13, 11 ], [ 389, 994, 28, 11 ], [ 432, 730, 37, 11 ], [ 472, 730, 9, 11 ], [ 483, 730, 23, 11 ], [ 509, 730, 31, 11 ], [ 542, 730, 21, 11 ], [ 565, 730, 27, 11 ], [ 594, 730, 22, 11 ], [ 618, 730, 9, 11 ], [ 630, 730, 5, 11 ], [ 637, 730, 39, 11 ], [ 678, 730, 44, 11 ], [ 725, 730, 42, 11 ], [ 432, 742, 34, 11 ], [ 471, 742, 35, 11 ], [ 511, 742, 22, 11 ], [ 538, 742, 35, 11 ], [ 578, 742, 17, 11 ], [ 599, 742, 17, 11 ], [ 621, 742, 44, 11 ], [ 670, 742, 9, 11 ], [ 683, 742, 18, 11 ], [ 706, 742, 13, 11 ], [ 724, 742, 29, 11 ], [ 758, 742, 9, 11 ], [ 432, 754, 48, 11 ], [ 432, 778, 63, 11 ], [ 432, 790, 30, 11 ], [ 465, 790, 22, 11 ], [ 490, 790, 43, 11 ], [ 536, 790, 9, 11 ], [ 548, 790, 21, 11 ], [ 572, 790, 31, 11 ], [ 606, 790, 39, 11 ], [ 649, 790, 15, 11 ], [ 667, 790, 23, 11 ], [ 693, 790, 31, 11 ], [ 728, 790, 39, 11 ], [ 432, 802, 21, 11 ], [ 459, 802, 38, 11 ], [ 503, 802, 21, 11 ], [ 529, 802, 46, 11 ], [ 581, 802, 37, 11 ], [ 623, 802, 15, 11 ], [ 645, 802, 40, 11 ], [ 690, 802, 17, 11 ], [ 713, 802, 37, 11 ], [ 756, 802, 11, 11 ], [ 432, 814, 43, 11 ], [ 481, 814, 34, 11 ], [ 520, 814, 30, 11 ], [ 556, 814, 21, 11 ], [ 582, 814, 39, 11 ], [ 627, 814, 17, 11 ], [ 649, 814, 28, 11 ], [ 683, 814, 37, 11 ], [ 725, 814, 9, 11 ], [ 740, 814, 26, 11 ], [ 432, 826, 35, 11 ], [ 473, 826, 31, 11 ], [ 511, 826, 38, 11 ], [ 555, 826, 8, 11 ], [ 569, 826, 21, 11 ], [ 596, 826, 17, 11 ], [ 619, 826, 20, 11 ], [ 645, 826, 9, 11 ], [ 660, 826, 37, 11 ], [ 703, 826, 13, 11 ], [ 721, 826, 46, 11 ], [ 432, 838, 41, 11 ], [ 476, 838, 42, 11 ], [ 521, 838, 35, 11 ], [ 559, 838, 13, 11 ], [ 575, 838, 27, 11 ], [ 605, 838, 39, 11 ], [ 647, 838, 15, 11 ], [ 665, 838, 37, 11 ], [ 705, 838, 17, 11 ], [ 724, 838, 21, 11 ], [ 748, 838, 19, 11 ], [ 432, 850, 40, 11 ], [ 477, 850, 15, 11 ], [ 496, 850, 45, 11 ], [ 546, 850, 31, 11 ], [ 581, 850, 9, 11 ], [ 594, 850, 21, 11 ], [ 620, 850, 15, 11 ], [ 640, 850, 23, 11 ], [ 667, 850, 35, 11 ], [ 707, 850, 21, 11 ], [ 732, 850, 20, 11 ], [ 756, 850, 11, 11 ], [ 432, 862, 39, 11 ], [ 475, 862, 13, 11 ], [ 492, 862, 31, 11 ], [ 527, 862, 19, 11 ], [ 550, 862, 18, 11 ], [ 571, 862, 26, 11 ], [ 602, 862, 21, 11 ], [ 626, 862, 20, 11 ], [ 650, 862, 31, 11 ], [ 685, 862, 17, 11 ], [ 706, 862, 34, 11 ], [ 744, 862, 23, 11 ], [ 432, 874, 56, 11 ], [ 491, 874, 13, 11 ], [ 506, 874, 16, 11 ], [ 524, 874, 44, 11 ], [ 570, 874, 21, 11 ], [ 593, 874, 34, 11 ], [ 629, 874, 30, 11 ], [ 662, 874, 21, 11 ], [ 685, 874, 40, 11 ], [ 727, 874, 9, 11 ], [ 738, 874, 29, 11 ], [ 432, 886, 56, 11 ], [ 494, 886, 23, 11 ], [ 523, 886, 56, 11 ], [ 584, 886, 55, 11 ], [ 644, 886, 13, 11 ], [ 663, 886, 44, 11 ], [ 712, 886, 29, 11 ], [ 746, 886, 21, 11 ], [ 432, 898, 30, 11 ], [ 465, 898, 9, 11 ], [ 478, 898, 13, 11 ], [ 494, 898, 26, 11 ], [ 523, 898, 41, 11 ], [ 567, 898, 9, 11 ], [ 580, 898, 31, 11 ], [ 614, 898, 15, 11 ], [ 632, 898, 31, 11 ], [ 666, 898, 21, 11 ], [ 689, 898, 40, 11 ], [ 733, 898, 21, 11 ], [ 757, 898, 10, 11 ], [ 432, 910, 37, 11 ], [ 475, 910, 23, 11 ], [ 505, 910, 13, 11 ], [ 524, 910, 59, 11 ], [ 589, 910, 21, 11 ], [ 616, 910, 36, 11 ], [ 659, 910, 9, 11 ], [ 674, 910, 27, 11 ], [ 707, 910, 37, 11 ], [ 750, 910, 17, 11 ], [ 432, 922, 44, 11 ], [ 481, 922, 11, 11 ], [ 497, 922, 52, 11 ], [ 554, 922, 21, 11 ], [ 580, 922, 28, 11 ], [ 613, 922, 37, 11 ], [ 655, 922, 17, 11 ], [ 677, 922, 29, 11 ], [ 711, 922, 40, 11 ], [ 756, 922, 11, 11 ], [ 432, 934, 44, 11 ], [ 480, 934, 20, 11 ], [ 504, 934, 19, 11 ], [ 527, 934, 31, 11 ], [ 561, 934, 37, 11 ], [ 602, 934, 24, 11 ], [ 630, 934, 11, 11 ], [ 644, 934, 30, 11 ], [ 678, 934, 16, 11 ], [ 697, 934, 44, 11 ], [ 744, 934, 23, 11 ], [ 432, 946, 17, 11 ], [ 455, 946, 29, 11 ], [ 491, 946, 13, 11 ], [ 510, 946, 29, 11 ], [ 545, 946, 37, 11 ], [ 588, 946, 42, 11 ], [ 636, 946, 15, 11 ], [ 658, 946, 54, 11 ], [ 718, 946, 49, 11 ], [ 432, 958, 35, 11 ], [ 471, 958, 22, 11 ], [ 496, 958, 35, 11 ], [ 535, 958, 21, 11 ], [ 559, 958, 38, 11 ], [ 600, 958, 11, 11 ], [ 614, 958, 31, 11 ], [ 648, 958, 20, 11 ], [ 672, 958, 32, 11 ], [ 707, 958, 60, 11 ], [ 432, 970, 17, 11 ], [ 453, 970, 41, 11 ], [ 498, 970, 19, 11 ], [ 521, 970, 43, 11 ], [ 569, 970, 26, 11 ], [ 599, 970, 41, 11 ], [ 644, 970, 49, 11 ], [ 696, 970, 21, 11 ], [ 721, 970, 46, 11 ], [ 432, 982, 31, 11 ], [ 469, 982, 18, 11 ], [ 493, 982, 17, 11 ], [ 516, 982, 43, 11 ], [ 565, 982, 11, 11 ], [ 582, 982, 23, 11 ], [ 612, 982, 43, 11 ], [ 661, 982, 51, 11 ], [ 718, 982, 49, 11 ], [ 432, 994, 55, 11 ], [ 490, 994, 9, 11 ], [ 500, 994, 37, 11 ], [ 539, 994, 21, 11 ], [ 81, 1018, 23, 11 ], [ 107, 1018, 46, 11 ], [ 155, 1018, 34, 11 ], [ 190, 1018, 46, 11 ], [ 238, 1018, 27, 11 ], [ 81, 1030, 65, 11 ], [ 149, 1030, 21, 11 ], [ 172, 1030, 35, 11 ], [ 209, 1030, 28, 11 ], [ 83, 1043, 4, 15 ], [ 416, 1030, 16, 11 ], [ 588, 1030, 9, 11 ], [ 599, 1030, 21, 11 ], [ 623, 1030, 49, 11 ], [ 673, 1030, 49, 11 ] ]

[ "open", "access", "www.bioinformation.net", "Volume", "6(4)", "Hypothesis", "Insights", "of", "interaction", "between", "small", "and", "large", "subunits", "of", "ADP-glucose", "pyrophosphorylase", "from", "bread", "wheat", "(Triticum", "aestivum", "L.)", "Mohd", "Danishuddin,", "Ravish", "Chatrath,", "Rajender", "Singh*", "Directorate", "of", "Wheat", "Research,", "Post", "Box", "158,", "Karnal", "-", "132001,", "India;", "Rajender", "Singh", "-", "Email:", "rajenderkhokhar@yahoo.com;", "*Corresponding", "author", "Received", "July", "26,", "2010,", "Accepted", "January", "29,", "2011;", "Published", "May", "07,", "2011", "Abstract:", "Lack", "of", "knowledge", "of", "three", "dimensional", "structures", "of", "small", "and", "large", "subunits", "of", "ADP-", "glucose", "pyrophosphorylase", "(AGPase)", "in", "wheat", "has", "hindered", "efforts", "to", "understand", "the", "binding", "specifities", "of", "substrate", "and", "catalytic", "mechanism.", "Thus,", "to", "understand", "the", "structure", "activity", "relationship,", "3D", "structures", "were", "built", "by", "homology", "modelling", "based", "on", "crystal", "structure", "of", "potato", "tuber", "ADP-glucose", "pyrophosphorylase.", "Selected", "models", "were", "refined", "by", "energy", "minimization", "and", "further", "validated", "by", "Procheck", "and", "Prosa-web", "analysis.", "Ramachandran", "plot", "showed", "that", "overall", "main", "chain", "and", "side", "chain", "parameters", "are", "favourable.", "Moreover,", "Z-score", "of", "the", "models", "from", "Prosa-web", "analysis", "gave", "the", "conformation", "that", "they", "are", "in", "the", "range", "of", "the", "template.", "Interaction", "analysis", "depicts", "the", "involvement", "of", "six", "amino", "acids", "in", "hydrogen", "bonding", "(AGP-SThr422-AGP-LMet138,", "AGP-", "SArg420-AGP-LGly47,", "AGP-SSer259-AGP-LSer306,", "AGP-SGlu241-AGP-LIle311,", "AGP-", "SGln113-AGP-LGlu286", "and", "AGP-SGln70-AGP-LLys291).", "Fifteen", "amino", "acids", "of", "small", "subunit", "were", "able", "to", "make", "hydrophobic", "contacts", "with", "seventeen", "amino", "acids", "of", "large", "subunit.", "Furthermore,", "decrease", "in", "the", "solvent", "accessible", "surface", "area", "in", "the", "amino", "acids", "involved", "in", "interaction", "were", "also", "reported.", "All", "the", "distances", "were", "formed", "in", "between", "2.27", "to", "3.78Å.", "The", "present", "study", "focussed", "on", "heterodimeric", "structure", "of", "(AGPase).", "This", "predicted", "complex", "not", "only", "enhance", "our", "understanding", "of", "the", "interaction", "mechanism", "between", "these", "subunits", "(AGP-L", "and", "AGP-S)", "but", "also", "enable", "to", "further", "study", "to", "obtain", "better", "variants", "of", "this", "enzyme", "for", "the", "improvement", "of", "the", "plant", "yield.", "Keywords:", "AGPase,", "ADP-glucose", "pyrophosphorylase,", "AGP-S,", "AGP-L,", "modelling,", "molecular", "docking,", "hydrogen", "bonding,", "hydrophobic", "contacts,", "accessible", "surface", "area.", "Background:", "Wheat", "(Triticum", "aestivum", "L.)", "is", "one", "of", "the", "most", "important", "staple", "crops", "worldwide,", "with", "a", "total", "production", "of", "over", "600", "million", "tonnes", "annually.", "The", "seed", "number", "and", "seed", "weight", "are", "critical", "yield", "components", "of", "wheat.", "Starch,", "which", "accounts", "65-75%", "of", "wheat", "seed", "weight,", "is", "a", "major", "determinant", "wheat", "yield.", "Starch", "is", "known", "to", "be", "an", "important", "carbohydrate", "and", "the", "primary", "energy", "source", "for", "plants,", "having", "numerous", "industrial", "applications", "[1,", "2].", "It", "is", "generally", "accepted", "that", "four", "enzymes", "may", "play", "a", "key", "role", "in", "starch", "biosynthesis:", "ADP-", "glucose", "pyrophosphorylase,", "starch", "synthase,", "starch", "branching", "enzyme", "and", "starch", "debranching", "enzyme", "[3].", "ADP-glucose", "pyrophosphorylase", "(AGPase)", "is", "regarded", "as", "rate-", "limiting", "enzyme", "in", "starch", "biosynthesis.", "This", "enzyme", "plays", "a", "key", "role", "in", "the", "modulation", "of", "photosynthetic", "efficiency", "in", "source", "tissues", "and", "also", "determines", "the", "level", "of", "storage", "starch", "in", "sink", "tissues,", "thus", "influencing", "overall", "crop", "yield", "potential.", "It", "catalyzes", "the", "first", "step", "of", "starch", "biosynthesis", "by", "generating", "the", "sugar", "nucleotide", "ADP-glucose", "and", "inorganic", "pyrophosphate", "(Pi)", "from", "glucose-1-phosphate", "and", "ATP.", "ADP-glucose", "functions", "as", "the", "glucosyl", "donor", "for", "glucan", "synthesis", "by", "starch", "synthase.", "AGPase", "from", "higher", "plants", "is", "heterotetrameric,", "consisting", "of", "two", "large", "subunits", "(AGP-L)", "and", "two", "small", "subunits", "(AGP-S)", "encoded", "by", "two", "distinct", "genes", "[4].", "Seed", "yield", "and", "plant", "biomass", "increases", "are", "conferred", "by", "deregulation", "of", "endosperm", "AGPase", "and", "thus,", "AGPase", "has", "attracted", "wide", "interest", "for", "potential", "crop", "improvements", "[5].", "In", "the", "present", "study", "the", "3D", "structures", "of", "the", "subunits", "(large", "and", "small)", "from", "wheat", "were", "modelled", "by", "the", "in", "silico", "homology", "techniques", "using", "the", "crystal", "structure", "of", "small", "subunit", "from", "potato", "tuber", "as", "a", "template.", "Moreover,", "molecular", "docking", "between", "these", "subunits", "was", "also", "performed", "to", "gain", "the", "insight", "of", "interaction.", "Methodology:", "Amino", "acids", "sequences", "of", "large", "subunit", "(P12299)", "and", "small", "subunit", "(P30523)", "were", "retrieved", "from", "Swiss-Prot", "database", "[6].", "Template", "was", "searched", "by", "BLAST-P", "analysis", "against", "PDB", "database.", "The", "crystal", "structure", "of", "potato", "AGPase", "(1YP2)", "available", "at", "PDB", "was", "used", "as", "template", "for", "modelling.", "Sequence", "alignment", "between", "the", "model", "sequence", "and", "template", "was", "done", "with", "ClustalW", "[7].", "Homology", "models", "of", "large", "and", "small", "subunits", "were", "built", "by", "Modeller", "[8]", "version", "9v7.", "One", "model", "from", "each", "subunit", "was", "selected", "using", "PROCHECK", "[9]", "and", "Prosa-web", "[10].", "Further,", "models", "were", "subjected", "to", "energy", "minimization", "using", "GROMOS96", "implemented", "via", "Swiss-pdb", "viewer", "[11].", "RMSD", "of", "the", "model", "structures", "of", "AGP-L", "and", "AGP-S", "were", "evaluated", "form", "its", "template", "using", "the", "SUPERPOSE", "[12].", "Docking", "of", "model", "structure", "was", "performed", "by", "GRAMM-X", "[13].", "Model", "structure", "was", "further", "evaluated", "by", "Patchdock", "[14].", "Best", "docked", "structure", "based", "on", "RMSD", "and", "Patchdock", "score", "was", "chosen", "for", "further", "analysis.", "Hydrogen", "and", "hydrophobic", "interactions", "between", "these", "subunits", "were", "analyzed", "by", "Ligplot", "[15].", "Figures", "representation", "was", "generated", "with", "Discovery", "studio", "visualizer", "programme", "[16].", "Accessible", "surface", "area", "was", "calculated", "by", "Mark", "Gerstein’s", "calc-surface", "programme", "implemented", "in", "Chimera", "[17].", "ISSN", "0973-2063", "(online)", "0973-8894", "(print)", "Bioinformation", "6(4):", "144-148", "(2011)", " ", "144", "©", "2011", "Biomedical", "Informatics" ]

[ 9, 9, 11, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4, 9, 9, 9, 9 ]

[ [ 76, 47, 141, 34 ], [ 229, 47, 135, 34 ], [ 76, 118, 70, 20 ], [ 76, 143, 120, 23 ], [ 201, 143, 38, 23 ], [ 245, 143, 64, 23 ], [ 315, 143, 23, 23 ], [ 343, 143, 36, 23 ], [ 385, 143, 30, 23 ], [ 421, 143, 185, 23 ], [ 612, 143, 131, 23 ], [ 76, 168, 81, 23 ], [ 163, 168, 19, 23 ], [ 188, 168, 51, 23 ], [ 245, 168, 95, 23 ], [ 76, 193, 72, 21 ], [ 153, 193, 15, 21 ], [ 172, 193, 65, 22 ], [ 242, 193, 53, 21 ], [ 300, 193, 15, 21 ], [ 320, 193, 102, 22 ], [ 427, 193, 31, 21 ], [ 463, 193, 73, 22 ], [ 541, 193, 45, 21 ], [ 591, 193, 19, 21 ], [ 615, 193, 125, 22 ], [ 76, 218, 35, 21 ], [ 116, 218, 63, 21 ], [ 184, 218, 98, 22 ], [ 706, 60, 54, 14 ], [ 761, 60, 38, 14 ], [ 697, 118, 44, 17 ], [ 745, 118, 62, 17 ], [ 76, 268, 41, 12 ], [ 119, 268, 41, 12 ], [ 163, 268, 42, 12 ], [ 208, 268, 22, 12 ], [ 232, 268, 28, 12 ], [ 263, 268, 42, 12 ], [ 307, 268, 10, 12 ], [ 320, 268, 48, 12 ], [ 370, 268, 44, 12 ], [ 417, 268, 59, 12 ], [ 478, 268, 10, 12 ], [ 490, 268, 48, 12 ], [ 540, 268, 52, 12 ], [ 594, 268, 50, 12 ], [ 646, 268, 45, 12 ], [ 694, 268, 19, 12 ], [ 715, 268, 13, 12 ], [ 76, 281, 55, 11 ], [ 134, 281, 40, 11 ], [ 176, 281, 46, 12 ], [ 224, 281, 10, 11 ], [ 237, 281, 64, 11 ], [ 303, 281, 33, 11 ], [ 338, 281, 46, 11 ], [ 386, 281, 58, 11 ], [ 447, 281, 10, 11 ], [ 459, 281, 31, 11 ], [ 492, 281, 33, 11 ], [ 528, 281, 43, 11 ], [ 573, 281, 52, 11 ], [ 626, 281, 47, 11 ], [ 675, 281, 19, 11 ], [ 697, 281, 13, 11 ], [ 711, 281, 56, 11 ], [ 76, 294, 40, 12 ], [ 119, 294, 63, 12 ], [ 184, 294, 10, 12 ], [ 197, 294, 59, 12 ], [ 258, 294, 19, 12 ], [ 279, 294, 63, 12 ], [ 344, 294, 53, 12 ], [ 399, 294, 50, 12 ], [ 451, 294, 37, 12 ], [ 490, 294, 10, 12 ], [ 503, 294, 33, 12 ], [ 538, 294, 43, 12 ], [ 584, 294, 16, 12 ], [ 602, 294, 19, 12 ], [ 623, 294, 34, 12 ], [ 659, 294, 18, 12 ], [ 680, 294, 10, 12 ], [ 692, 294, 38, 12 ], [ 733, 294, 34, 12 ], [ 76, 307, 43, 12 ], [ 121, 307, 10, 12 ], [ 134, 307, 44, 12 ], [ 181, 307, 19, 12 ], [ 202, 307, 42, 12 ], [ 246, 307, 68, 12 ], [ 316, 307, 25, 12 ], [ 344, 307, 59, 12 ], [ 405, 307, 10, 12 ], [ 418, 307, 48, 12 ], [ 468, 307, 52, 12 ], [ 522, 307, 50, 12 ], [ 574, 307, 45, 12 ], [ 621, 307, 52, 12 ], [ 675, 307, 47, 12 ], [ 724, 307, 19, 12 ], [ 745, 307, 13, 12 ], [ 76, 321, 55, 11 ], [ 134, 321, 37, 11 ], [ 76, 341, 31, 12 ], [ 110, 341, 38, 12 ], [ 150, 341, 8, 12 ], [ 161, 341, 27, 12 ], [ 191, 341, 4, 12 ], [ 197, 341, 118, 12 ], [ 317, 341, 29, 12 ], [ 348, 341, 8, 12 ], [ 359, 341, 48, 12 ], [ 409, 341, 4, 12 ], [ 415, 341, 105, 12 ], [ 523, 341, 17, 12 ], [ 542, 341, 32, 12 ], [ 577, 341, 4, 12 ], [ 583, 341, 108, 12 ], [ 76, 354, 24, 11 ], [ 103, 354, 10, 11 ], [ 115, 354, 63, 11 ], [ 181, 354, 4, 11 ], [ 187, 354, 123, 11 ], [ 313, 354, 34, 11 ], [ 349, 354, 48, 11 ], [ 399, 354, 4, 11 ], [ 406, 354, 156, 11 ], [ 76, 370, 7, 12 ], [ 85, 370, 73, 12 ], [ 160, 370, 33, 12 ], [ 76, 429, 45, 12 ], [ 124, 429, 12, 12 ], [ 138, 429, 40, 12 ], [ 180, 429, 23, 12 ], [ 76, 449, 33, 11 ], [ 111, 449, 29, 11 ], [ 143, 449, 25, 11 ], [ 171, 448, 26, 12 ], [ 209, 449, 134, 11 ], [ 76, 468, 20, 11 ], [ 98, 468, 28, 11 ], [ 129, 468, 7, 11 ], [ 139, 468, 38, 11 ], [ 179, 468, 25, 11 ], [ 207, 468, 215, 11 ], [ 430, 429, 43, 12 ], [ 475, 429, 6, 12 ], [ 484, 429, 23, 12 ], [ 510, 429, 23, 12 ], [ 430, 442, 46, 11 ], [ 478, 442, 12, 11 ], [ 492, 442, 40, 11 ], [ 534, 442, 23, 11 ], [ 76, 488, 9, 12 ], [ 87, 488, 23, 12 ], [ 113, 488, 24, 12 ], [ 140, 488, 10, 12 ], [ 152, 488, 10, 12 ], [ 165, 488, 36, 12 ], [ 203, 488, 35, 12 ], [ 241, 488, 34, 12 ], [ 278, 488, 18, 12 ], [ 76, 501, 20, 12 ], [ 98, 501, 7, 12 ], [ 108, 501, 11, 12 ], [ 121, 501, 26, 12 ], [ 150, 501, 32, 12 ], [ 184, 501, 28, 12 ], [ 215, 501, 49, 12 ], [ 267, 501, 27, 12 ], [ 296, 501, 15, 12 ], [ 314, 501, 27, 12 ], [ 343, 501, 10, 12 ], [ 355, 501, 15, 12 ], [ 373, 501, 39, 12 ], [ 415, 501, 48, 12 ], [ 465, 501, 51, 12 ], [ 519, 501, 34, 12 ], [ 555, 501, 202, 12 ], [ 76, 514, 27, 12 ], [ 106, 514, 35, 12 ], [ 143, 514, 56, 12 ], [ 201, 514, 18, 12 ], [ 222, 514, 55, 12 ], [ 279, 514, 16, 12 ], [ 298, 514, 60, 12 ], [ 361, 514, 8, 12 ], [ 372, 514, 16, 12 ], [ 390, 514, 39, 12 ], [ 432, 514, 40, 12 ], [ 475, 514, 15, 12 ], [ 493, 514, 34, 12 ], [ 529, 514, 24, 12 ], [ 556, 514, 7, 12 ], [ 565, 514, 39, 12 ], [ 607, 514, 25, 12 ], [ 115, 575, 61, 15 ], [ 115, 595, 80, 14 ], [ 199, 596, 22, 14 ], [ 225, 596, 20, 14 ], [ 248, 596, 11, 14 ], [ 263, 596, 20, 14 ], [ 287, 596, 30, 14 ], [ 320, 596, 21, 14 ], [ 345, 596, 12, 14 ], [ 361, 596, 39, 14 ], [ 405, 596, 58, 14 ], [ 466, 596, 12, 14 ], [ 482, 596, 19, 14 ], [ 505, 596, 38, 14 ], [ 547, 596, 20, 14 ], [ 571, 596, 32, 14 ], [ 607, 596, 12, 14 ], [ 623, 596, 19, 14 ], [ 645, 596, 33, 14 ], [ 682, 596, 17, 14 ], [ 703, 596, 27, 14 ], [ 115, 612, 17, 14 ], [ 136, 612, 45, 14 ], [ 185, 612, 34, 14 ], [ 223, 612, 19, 14 ], [ 247, 612, 29, 14 ], [ 280, 612, 11, 14 ], [ 296, 612, 18, 14 ], [ 319, 612, 10, 14 ], [ 333, 612, 6, 14 ], [ 344, 612, 27, 14 ], [ 375, 612, 37, 14 ], [ 415, 612, 10, 14 ], [ 430, 612, 48, 14 ], [ 482, 612, 36, 14 ], [ 523, 612, 18, 14 ], [ 545, 612, 69, 14 ], [ 618, 612, 11, 14 ], [ 634, 612, 96, 14 ], [ 115, 628, 68, 14 ], [ 187, 628, 42, 14 ], [ 232, 628, 36, 14 ], [ 271, 628, 11, 14 ], [ 285, 628, 45, 14 ], [ 334, 628, 55, 14 ], [ 392, 628, 17, 14 ], [ 412, 628, 80, 14 ], [ 495, 628, 43, 14 ], [ 541, 628, 88, 14 ], [ 632, 628, 38, 14 ], [ 674, 628, 57, 14 ], [ 115, 645, 24, 14 ], [ 143, 645, 30, 14 ], [ 176, 645, 20, 14 ], [ 199, 645, 70, 14 ], [ 273, 645, 15, 14 ], [ 290, 645, 64, 14 ], [ 358, 645, 34, 14 ], [ 394, 645, 48, 14 ], [ 446, 645, 30, 14 ], [ 479, 645, 29, 14 ], [ 511, 645, 22, 14 ], [ 536, 645, 53, 14 ], [ 115, 668, 59, 14 ], [ 177, 668, 59, 14 ], [ 240, 668, 57, 14 ], [ 300, 668, 20, 14 ], [ 323, 668, 29, 14 ], [ 355, 668, 33, 14 ], [ 391, 668, 61, 14 ], [ 455, 668, 29, 14 ], [ 487, 668, 24, 14 ], [ 514, 668, 24, 14 ], [ 541, 668, 50, 14 ], [ 594, 668, 57, 14 ], [ 654, 668, 35, 14 ], [ 692, 668, 38, 14 ], [ 115, 684, 24, 14 ], [ 143, 684, 47, 14 ], [ 194, 684, 20, 14 ], [ 218, 684, 33, 14 ], [ 255, 684, 40, 14 ], [ 298, 684, 10, 14 ], [ 313, 684, 35, 14 ], [ 351, 684, 28, 14 ], [ 383, 684, 20, 14 ], [ 407, 684, 39, 14 ], [ 450, 684, 33, 14 ], [ 488, 684, 10, 14 ], [ 502, 684, 61, 14 ], [ 567, 684, 48, 14 ], [ 620, 684, 10, 14 ], [ 634, 684, 30, 14 ], [ 668, 684, 62, 14 ], [ 115, 700, 49, 14 ], [ 168, 700, 43, 14 ], [ 215, 700, 38, 14 ], [ 255, 700, 21, 14 ], [ 280, 700, 26, 14 ], [ 309, 700, 24, 14 ], [ 337, 700, 106, 14 ], [ 446, 700, 11, 14 ], [ 461, 700, 18, 14 ], [ 482, 700, 42, 14 ], [ 528, 700, 46, 14 ], [ 577, 700, 56, 14 ], [ 636, 700, 11, 14 ], [ 651, 700, 30, 14 ], [ 684, 700, 17, 14 ], [ 704, 700, 6, 14 ], [ 714, 700, 17, 14 ], [ 115, 717, 38, 14 ], [ 156, 717, 11, 14 ], [ 171, 717, 27, 14 ], [ 201, 717, 17, 14 ], [ 221, 717, 6, 14 ], [ 230, 717, 26, 14 ], [ 259, 717, 20, 14 ], [ 282, 717, 65, 14 ], [ 350, 717, 66, 14 ], [ 419, 717, 24, 14 ], [ 445, 717, 11, 14 ], [ 460, 717, 27, 14 ], [ 490, 717, 21, 14 ], [ 514, 717, 26, 14 ], [ 543, 717, 12, 14 ], [ 559, 717, 34, 14 ], [ 596, 717, 27, 14 ], [ 626, 717, 22, 14 ], [ 651, 717, 30, 14 ], [ 684, 717, 46, 14 ], [ 115, 733, 60, 14 ], [ 179, 733, 45, 14 ], [ 226, 733, 24, 14 ], [ 254, 733, 65, 14 ], [ 322, 733, 61, 14 ], [ 386, 733, 17, 14 ], [ 406, 733, 49, 14 ], [ 458, 733, 67, 14 ], [ 529, 733, 41, 14 ], [ 115, 756, 49, 14 ], [ 169, 756, 40, 14 ], [ 213, 756, 21, 14 ], [ 238, 756, 47, 14 ], [ 289, 756, 20, 14 ], [ 313, 756, 57, 14 ], [ 374, 756, 35, 14 ], [ 413, 756, 21, 14 ], [ 438, 756, 30, 14 ], [ 473, 756, 13, 14 ], [ 490, 756, 8, 14 ], [ 503, 756, 57, 14 ], [ 564, 756, 29, 14 ], [ 597, 756, 35, 14 ], [ 635, 756, 13, 14 ], [ 652, 756, 19, 14 ], [ 675, 756, 55, 14 ], [ 115, 773, 43, 14 ], [ 162, 773, 30, 14 ], [ 195, 773, 21, 14 ], [ 219, 773, 28, 14 ], [ 250, 773, 28, 14 ], [ 282, 773, 17, 14 ], [ 301, 773, 6, 14 ], [ 311, 773, 34, 14 ], [ 348, 773, 26, 14 ], [ 378, 773, 11, 14 ], [ 392, 773, 30, 14 ], [ 425, 773, 19, 14 ], [ 447, 773, 24, 14 ], [ 474, 773, 23, 14 ], [ 500, 773, 61, 14 ], [ 565, 773, 29, 14 ], [ 597, 773, 35, 14 ], [ 635, 773, 12, 14 ], [ 650, 773, 19, 14 ], [ 672, 773, 30, 14 ], [ 706, 773, 24, 14 ], [ 115, 789, 21, 14 ], [ 141, 789, 24, 14 ], [ 169, 789, 47, 14 ], [ 219, 789, 29, 14 ], [ 252, 789, 30, 14 ], [ 286, 789, 29, 14 ], [ 319, 789, 35, 14 ], [ 358, 789, 12, 14 ], [ 374, 789, 19, 14 ], [ 397, 789, 24, 14 ], [ 425, 789, 26, 14 ], [ 456, 789, 57, 14 ], [ 517, 789, 32, 14 ], [ 552, 789, 50, 14 ], [ 607, 789, 27, 14 ], [ 637, 789, 27, 14 ], [ 668, 789, 8, 14 ], [ 680, 789, 20, 14 ], [ 704, 789, 13, 14 ], [ 722, 789, 8, 14 ], [ 115, 805, 48, 14 ], [ 167, 805, 88, 14 ], [ 258, 805, 33, 14 ], [ 295, 805, 20, 14 ], [ 318, 805, 15, 14 ], [ 337, 805, 54, 14 ], [ 394, 805, 31, 14 ], [ 428, 805, 15, 14 ], [ 446, 805, 33, 14 ], [ 483, 805, 22, 14 ], [ 508, 805, 40, 14 ], [ 551, 805, 35, 14 ], [ 590, 805, 82, 14 ], [ 676, 805, 27, 14 ], [ 706, 805, 24, 14 ], [ 115, 822, 17, 14 ], [ 136, 822, 37, 14 ], [ 176, 822, 40, 14 ], [ 219, 822, 48, 14 ], [ 271, 822, 10, 14 ], [ 285, 822, 13, 14 ], [ 301, 822, 42, 14 ], [ 347, 822, 57, 14 ], [ 408, 822, 21, 14 ], [ 433, 822, 55, 14 ], [ 491, 822, 11, 14 ], [ 506, 822, 24, 14 ], [ 534, 822, 20, 14 ], [ 557, 822, 33, 14 ], [ 593, 822, 34, 14 ], [ 631, 822, 54, 14 ], [ 689, 822, 26, 14 ], [ 719, 822, 11, 14 ], [ 115, 838, 18, 14 ], [ 137, 838, 42, 14 ], [ 183, 838, 26, 14 ], [ 212, 838, 71, 14 ], [ 288, 838, 72, 14 ], [ 363, 838, 11, 14 ], [ 378, 838, 54, 14 ], [ 436, 838, 27, 14 ], [ 466, 838, 35, 14 ], [ 505, 838, 23, 14 ], [ 533, 838, 10, 14 ], [ 547, 838, 30, 14 ], [ 581, 838, 22, 14 ], [ 606, 838, 24, 14 ], [ 634, 838, 11, 14 ], [ 649, 838, 82, 14 ], [ 115, 854, 27, 14 ], [ 146, 854, 67, 14 ], [ 217, 854, 26, 14 ], [ 247, 854, 11, 14 ], [ 262, 854, 50, 14 ], [ 315, 854, 26, 14 ], [ 345, 854, 35, 14 ], [ 384, 854, 67, 14 ], [ 454, 854, 15, 14 ], [ 472, 854, 26, 14 ], [ 502, 854, 20, 14 ], [ 525, 854, 33, 14 ], [ 562, 854, 11, 14 ], [ 577, 854, 26, 14 ], [ 606, 854, 35, 14 ], [ 645, 854, 67, 14 ], [ 715, 854, 15, 14 ], [ 115, 871, 34, 14 ], [ 152, 871, 27, 14 ], [ 115, 894, 36, 14 ], [ 155, 894, 38, 14 ], [ 196, 894, 20, 14 ], [ 219, 894, 43, 14 ], [ 265, 894, 35, 14 ], [ 304, 894, 20, 14 ], [ 327, 894, 74, 14 ], [ 404, 894, 29, 14 ], [ 435, 894, 18, 14 ], [ 457, 894, 28, 14 ], [ 488, 894, 41, 14 ], [ 532, 894, 44, 14 ], [ 580, 894, 11, 14 ], [ 594, 894, 13, 14 ], [ 611, 894, 67, 14 ], [ 681, 894, 28, 14 ], [ 115, 917, 74, 14 ], [ 193, 917, 30, 14 ], [ 225, 917, 17, 14 ], [ 245, 917, 27, 14 ], [ 275, 917, 10, 14 ], [ 289, 917, 20, 14 ], [ 312, 917, 30, 14 ], [ 345, 917, 21, 14 ], [ 369, 917, 20, 14 ], [ 392, 917, 24, 14 ], [ 420, 917, 13, 14 ], [ 436, 917, 21, 14 ], [ 460, 917, 24, 14 ], [ 487, 917, 20, 14 ], [ 510, 917, 6, 14 ], [ 519, 917, 40, 14 ], [ 562, 917, 12, 14 ], [ 577, 917, 56, 14 ], [ 635, 917, 40, 14 ], [ 679, 917, 12, 14 ], [ 695, 917, 36, 14 ], [ 115, 934, 13, 14 ], [ 131, 934, 50, 14 ], [ 184, 934, 68, 14 ], [ 255, 934, 22, 14 ], [ 280, 934, 45, 14 ], [ 328, 934, 30, 14 ], [ 361, 934, 10, 14 ], [ 374, 934, 48, 14 ], [ 425, 934, 12, 14 ], [ 441, 934, 49, 14 ], [ 493, 933, 57, 14 ], [ 552, 934, 22, 14 ], [ 578, 934, 11, 14 ], [ 591, 934, 75, 14 ], [ 669, 934, 34, 14 ], [ 706, 934, 24, 14 ], [ 115, 950, 44, 14 ], [ 164, 950, 20, 14 ], [ 190, 950, 11, 14 ], [ 206, 950, 6, 14 ], [ 217, 950, 55, 14 ], [ 277, 950, 28, 14 ], [ 311, 950, 11, 14 ], [ 327, 950, 21, 14 ], [ 354, 950, 48, 14 ], [ 407, 950, 28, 14 ], [ 441, 950, 58, 14 ], [ 504, 950, 11, 14 ], [ 520, 950, 36, 14 ], [ 562, 950, 58, 14 ], [ 626, 950, 32, 14 ], [ 663, 950, 44, 14 ], [ 712, 950, 18, 14 ], [ 115, 966, 64, 14 ], [ 183, 966, 11, 14 ], [ 198, 966, 61, 14 ], [ 262, 966, 28, 14 ], [ 294, 966, 59, 14 ], [ 356, 966, 42, 14 ], [ 402, 966, 55, 14 ], [ 460, 966, 43, 14 ], [ 506, 966, 12, 14 ], [ 521, 966, 14, 14 ], [ 538, 966, 23, 14 ], [ 564, 966, 48, 14 ], [ 698, 1052, 30, 13 ], [ 731, 1052, 7, 13 ], [ 741, 1052, 11, 13 ], [ 755, 1052, 14, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "Malaria", "Journal", "Research", "Willingness", "and", "ability", "to", "pay", "for", "artemisinin-based", "combination", "therapy", "in", "rural", "Tanzania", "Eleonor", "C", "Saulo1,", "Birger", "C", "Forsberg*2,", "Zul", "Premji3,", "Scott", "M", "Montgomery4", "and", "Anders", "Björkman1", "BioMed", "Central", "Open", "Access", "Address:", "1Malaria", "Research", "Unit", "(M9),", "Division", "of", "Infectious", "Diseases,", "Department", "of", "Medicine,", "Karolinska", "University", "Hospital,", "171", "76", "Stockholm,", "Sweden,", "2Division", "of", "International", "Health", "(IHCAR),", "Department", "of", "Public", "Health", "Sciences,", "Karolinska", "Institutet,", "171", "77", "Stockholm,", "Sweden,", "3Department", "of", "Parasitology", "and", "Entomology,", "Muhimbili", "University", "College", "of", "Health", "Sciences,", "PO", "Box", "65001,", "Dar", "es", "Salaam,", "United", "Republic", "of", "Tanzania", "and", "4Clinical", "Epidemiology", "Unit,", "Department", "of", "Medicine,", "Karolinska", "University", "Hospital,", "Karolinska", "Institutet,", "171", "76", "Stockholm,", "Sweden", "Email:", "Eleonor", "C", "Saulo", "-", "eleonor76@yahoo.com;", "Birger", "C", "Forsberg*", "-", "birger.forsberg@ki.se;", "Zul", "Premji", "-", "zpremji@muchs.ac.tz;", "Scott", "M", "Montgomery", "-", "scott.montgomery@ki.se;", "Anders", "Björkman", "-", "anders.bjorkman@karolinska.se", "*", "Corresponding", "author", "Published:", "31", "October", "2008", "Malaria", "Journal", "2008,", "7:227", "doi:10.1186/1475-2875-7-227", "This", "article", "is", "available", "from:", "http://www.malariajournal.com/content/7/1/227", "Received:", "3", "April", "2008", "Accepted:", "31", "October", "2008", "©", "2008", "Saulo", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "aim", "of", "this", "study", "was", "to", "analyse", "willingness", "to", "pay", "(WTP)", "and", "ability", "to", "pay", "(ATP)", "for", "ACT", "for", "children", "below", "five", "years", "of", "age", "in", "a", "rural", "setting", "in", "Tanzania", "before", "the", "introduction", "of", "artemisinin-based", "combination", "therapy", "(ACT)", "as", "first-line", "treatment", "for", "uncomplicated", "malaria.", "Socio-economic", "factors", "associated", "with", "WTP", "and", "expectations", "on", "anti-malaria", "drugs,", "including", "ACT,", "were", "also", "explored.", "Methods:", "Structured", "interviews", "and", "focus", "group", "discussions", "were", "held", "with", "mothers,", "household", "heads,", "health-", "care", "workers", "and", "village", "leaders", "in", "Ishozi,", "Gera", "and", "Ishunju", "wards", "in", "north-west", "Tanzania", "in", "2004.", "Contingent", "valuation", "method", "(CVM)", "was", "used", "with", "\"take-it-or-leave-it\"", "as", "the", "eliciting", "method,", "expressed", "as", "WTP", "for", "a", "full", "course", "of", "ACT", "for", "a", "child", "and", "households'", "opportunity", "cost", "of", "ACT", "was", "used", "to", "assess", "ATP.", "The", "study", "included", "descriptive", "analyses", "with", "multivariate", "adjustment", "for", "potential", "confounding", "factors.", "Results:", "Among", "265", "mothers", "and", "household", "heads,", "244", "(92%,", "CI", "=", "88%–95%)", "were", "willing", "to", "pay", "Tanzanian", "Shillings", "(TSh)", "500", "(US$", "0.46)", "for", "a", "child's", "dose", "of", "ACT,", "but", "only", "55%", "(49%–61%)", "were", "willing", "to", "pay", "more", "than", "TSh", "500.", "Mothers", "were", "more", "often", "willing", "to", "pay", "than", "male", "household", "heads", "(adjusted", "odds", "ratio", "=", "2.1,", "CI", "=", "1.2–3.6).", "Socio-economic", "status", "had", "no", "significant", "effect", "on", "WTP.", "The", "median", "annual", "non-subsidized", "ACT", "cost", "for", "clinical", "malaria", "episodes", "in", "an", "average", "household", "was", "calculated", "as", "US$", "6.0,", "which", "would", "represent", "0.9%", "of", "the", "average", "total", "consumption", "expenditures", "as", "estimated", "from", "official", "data", "in", "2001.", "The", "cost", "of", "non-subsidized", "ACT", "represented", "7.0%", "of", "reported", "total", "annual", "expenditure", "on", "food", "and", "33.0%", "of", "total", "annual", "expenditure", "on", "health", "care.", "\"Rapid", "effect,\"", "\"no", "adverse", "effect\"", "and", "\"inexpensive\"", "were", "the", "most", "desired", "features", "of", "an", "anti-malarial", "drug.", "Conclusion:", "WTP", "for", "ACT", "in", "this", "study", "was", "less", "than", "its", "real", "cost", "and", "a", "subsidy", "is,", "therefore,", "needed", "to", "enable", "its", "equitable", "affordability.", "The", "decision", "taken", "in", "Tanzania", "to", "subsidize", "Coartem®", "fully", "at", "governmental", "health", "care", "facilities", "and", "at", "a", "consumer", "price", "of", "TSh", "300–500", "(US$", "0.28–0.46)", "at", "special", "designated", "shops", "through", "the", "programme", "of", "Accredited", "Drug", "Dispensing", "Outlets", "(ADDOs)", "appears", "to", "be", "well", "founded.", "Page", "1", "of", "10", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 60, 30, 72, 23 ], [ 137, 27, 2, 25 ], [ 145, 30, 91, 23 ], [ 242, 30, 61, 23 ], [ 60, 82, 168, 20 ], [ 233, 82, 84, 20 ], [ 321, 82, 87, 20 ], [ 413, 82, 35, 20 ], [ 453, 82, 89, 20 ], [ 547, 82, 18, 20 ], [ 570, 82, 61, 20 ], [ 60, 103, 173, 20 ], [ 238, 103, 84, 20 ], [ 327, 103, 35, 20 ], [ 367, 103, 115, 20 ], [ 487, 103, 55, 20 ], [ 60, 131, 30, 14 ], [ 93, 131, 13, 14 ], [ 109, 130, 48, 15 ], [ 161, 131, 25, 14 ], [ 189, 130, 50, 15 ], [ 242, 131, 24, 14 ], [ 269, 130, 67, 15 ], [ 339, 131, 61, 14 ], [ 404, 130, 48, 15 ], [ 455, 131, 33, 14 ], [ 490, 131, 33, 14 ], [ 526, 130, 36, 15 ], [ 565, 131, 53, 14 ], [ 621, 130, 64, 15 ], [ 60, 146, 44, 14 ], [ 107, 144, 66, 15 ], [ 176, 146, 24, 14 ], [ 203, 146, 45, 14 ], [ 251, 146, 55, 14 ], [ 308, 144, 6, 10 ], [ 60, 167, 40, 13 ], [ 102, 168, 15, 12 ], [ 120, 168, 54, 12 ], [ 176, 168, 78, 12 ], [ 256, 168, 34, 12 ], [ 294, 168, 52, 12 ], [ 348, 168, 37, 12 ], [ 387, 168, 11, 12 ], [ 401, 168, 33, 12 ], [ 436, 168, 37, 12 ], [ 476, 168, 54, 12 ], [ 533, 168, 11, 12 ], [ 547, 168, 54, 12 ], [ 603, 168, 49, 12 ], [ 655, 168, 49, 12 ], [ 706, 168, 54, 12 ], [ 60, 180, 28, 12 ], [ 90, 179, 40, 13 ], [ 132, 180, 57, 12 ], [ 192, 180, 36, 12 ], [ 231, 180, 37, 12 ], [ 271, 180, 11, 12 ], [ 284, 180, 33, 12 ], [ 319, 180, 38, 12 ], [ 360, 180, 41, 12 ], [ 403, 180, 46, 12 ], [ 452, 180, 28, 12 ], [ 482, 179, 40, 13 ], [ 524, 180, 15, 12 ], [ 542, 180, 17, 12 ], [ 562, 180, 35, 12 ], [ 599, 180, 64, 12 ], [ 665, 180, 11, 12 ], [ 679, 180, 44, 12 ], [ 726, 180, 20, 12 ], [ 60, 193, 45, 12 ], [ 107, 193, 11, 12 ], [ 121, 193, 42, 12 ], [ 165, 193, 36, 12 ], [ 204, 193, 13, 12 ], [ 220, 193, 31, 12 ], [ 253, 193, 16, 12 ], [ 272, 193, 26, 12 ], [ 301, 193, 13, 12 ], [ 317, 193, 42, 12 ], [ 362, 193, 42, 12 ], [ 406, 193, 54, 12 ], [ 463, 193, 25, 12 ], [ 65, 242, 8, 12 ], [ 130, 242, 4, 12 ], [ 137, 242, 43, 12 ], [ 182, 242, 10, 12 ], [ 195, 242, 80, 12 ], [ 278, 242, 24, 12 ], [ 305, 242, 48, 12 ], [ 355, 242, 51, 12 ], [ 409, 242, 72, 12 ], [ 483, 242, 16, 12 ], [ 501, 242, 22, 12 ], [ 65, 255, 46, 12 ], [ 114, 255, 21, 12 ], [ 138, 255, 75, 12 ], [ 215, 255, 33, 12 ], [ 251, 255, 10, 12 ], [ 263, 255, 41, 12 ], [ 65, 273, 0, 12 ], [ 75, 275, 8, 9 ], [ 122, 273, 4, 12 ], [ 129, 273, 17, 12 ], [ 149, 273, 58, 12 ], [ 211, 273, 39, 12 ], [ 254, 273, 17, 12 ], [ 274, 273, 46, 12 ], [ 324, 273, 10, 12 ], [ 337, 273, 46, 12 ], [ 386, 273, 12, 12 ], [ 402, 273, 35, 12 ], [ 441, 273, 33, 12 ], [ 477, 273, 50, 12 ], [ 65, 286, 32, 12 ], [ 101, 286, 55, 12 ], [ 159, 286, 10, 12 ], [ 172, 286, 43, 12 ], [ 219, 286, 35, 12 ], [ 257, 286, 18, 12 ], [ 278, 286, 23, 12 ], [ 305, 286, 42, 12 ], [ 350, 286, 18, 12 ], [ 371, 286, 47, 12 ], [ 422, 286, 22, 12 ], [ 448, 286, 76, 12 ], [ 65, 299, 45, 12 ], [ 112, 299, 32, 12 ], [ 147, 299, 85, 12 ], [ 234, 299, 38, 12 ], [ 275, 299, 26, 12 ], [ 303, 299, 10, 12 ], [ 315, 299, 12, 12 ], [ 329, 299, 54, 12 ], [ 385, 299, 30, 12 ], [ 417, 299, 10, 12 ], [ 430, 299, 50, 12 ], [ 65, 317, 11, 12 ], [ 113, 317, 4, 12 ], [ 119, 316, 42, 12 ], [ 164, 316, 22, 12 ], [ 189, 316, 37, 12 ], [ 229, 316, 9, 12 ], [ 240, 316, 20, 12 ], [ 263, 316, 15, 12 ], [ 281, 316, 24, 12 ], [ 307, 316, 10, 13 ], [ 320, 316, 6, 12 ], [ 330, 316, 22, 12 ], [ 354, 316, 18, 12 ], [ 375, 316, 7, 12 ], [ 384, 316, 24, 12 ], [ 410, 316, 10, 13 ], [ 423, 316, 7, 12 ], [ 433, 316, 25, 12 ], [ 460, 316, 40, 12 ], [ 503, 316, 20, 12 ], [ 65, 330, 29, 12 ], [ 97, 330, 15, 12 ], [ 115, 330, 27, 12 ], [ 145, 330, 42, 12 ], [ 189, 330, 44, 12 ], [ 236, 330, 41, 12 ], [ 280, 330, 17, 12 ], [ 299, 330, 61, 12 ], [ 363, 330, 15, 12 ], [ 381, 330, 44, 12 ], [ 428, 330, 27, 12 ], [ 457, 330, 43, 12 ], [ 503, 330, 17, 12 ], [ 523, 330, 0, 12 ], [ 65, 343, 17, 12 ], [ 85, 343, 10, 12 ], [ 97, 343, 38, 12 ], [ 138, 343, 9, 12 ], [ 149, 343, 15, 12 ], [ 167, 343, 24, 12 ], [ 193, 343, 18, 12 ], [ 213, 343, 43, 12 ], [ 258, 343, 31, 12 ], [ 292, 343, 56, 12 ], [ 350, 343, 59, 12 ], [ 412, 343, 21, 12 ], [ 435, 343, 39, 12 ], [ 476, 343, 9, 12 ], [ 488, 343, 6, 12 ], [ 497, 343, 27, 12 ], [ 65, 356, 20, 12 ], [ 89, 356, 9, 12 ], [ 99, 356, 24, 12 ], [ 126, 356, 34, 12 ], [ 164, 356, 5, 12 ], [ 173, 356, 60, 12 ], [ 237, 356, 44, 12 ], [ 284, 356, 96, 12 ], [ 383, 356, 39, 12 ], [ 425, 356, 44, 12 ], [ 473, 356, 55, 12 ], [ 65, 369, 27, 12 ], [ 95, 369, 27, 12 ], [ 125, 369, 81, 12 ], [ 210, 369, 30, 12 ], [ 243, 369, 40, 12 ], [ 287, 369, 10, 12 ], [ 300, 369, 15, 12 ], [ 318, 369, 44, 12 ], [ 373, 369, 32, 12 ], [ 408, 369, 32, 12 ], [ 443, 369, 25, 12 ], [ 471, 369, 15, 12 ], [ 490, 369, 37, 12 ], [ 65, 382, 42, 12 ], [ 109, 382, 32, 12 ], [ 143, 382, 27, 12 ], [ 65, 400, 0, 12 ], [ 74, 402, 1, 9 ], [ 107, 400, 4, 12 ], [ 114, 400, 41, 12 ], [ 158, 400, 29, 12 ], [ 190, 400, 56, 12 ], [ 250, 400, 16, 12 ], [ 270, 400, 24, 12 ], [ 297, 400, 23, 12 ], [ 324, 400, 79, 12 ], [ 406, 400, 49, 12 ], [ 458, 400, 22, 12 ], [ 484, 400, 43, 12 ], [ 65, 413, 29, 12 ], [ 97, 413, 10, 12 ], [ 109, 413, 43, 12 ], [ 154, 413, 43, 12 ], [ 199, 413, 18, 12 ], [ 219, 413, 36, 12 ], [ 257, 413, 9, 12 ], [ 269, 413, 16, 12 ], [ 287, 413, 15, 12 ], [ 304, 413, 24, 12 ], [ 330, 413, 16, 12 ], [ 349, 413, 22, 12 ], [ 373, 413, 57, 12 ], [ 432, 413, 32, 12 ], [ 466, 413, 9, 12 ], [ 477, 413, 16, 12 ], [ 495, 413, 6, 12 ], [ 504, 413, 24, 12 ], [ 65, 426, 34, 12 ], [ 102, 426, 43, 12 ], [ 147, 426, 46, 12 ], [ 196, 426, 7, 12 ], [ 206, 426, 6, 12 ], [ 215, 426, 15, 12 ], [ 232, 426, 32, 12 ], [ 267, 426, 23, 12 ], [ 292, 426, 50, 12 ], [ 345, 426, 35, 12 ], [ 383, 426, 23, 12 ], [ 408, 426, 39, 12 ], [ 450, 426, 39, 12 ], [ 490, 426, 7, 12 ], [ 500, 426, 7, 12 ], [ 509, 426, 18, 12 ], [ 65, 439, 23, 12 ], [ 91, 439, 16, 12 ], [ 110, 439, 43, 12 ], [ 157, 439, 39, 12 ], [ 199, 439, 28, 12 ], [ 230, 439, 22, 12 ], [ 256, 439, 47, 12 ], [ 306, 439, 21, 12 ], [ 330, 439, 28, 12 ], [ 361, 439, 13, 12 ], [ 377, 439, 15, 12 ], [ 396, 439, 32, 12 ], [ 430, 439, 36, 12 ], [ 470, 439, 54, 12 ], [ 65, 453, 27, 12 ], [ 95, 453, 7, 12 ], [ 105, 453, 22, 12 ], [ 130, 453, 46, 12 ], [ 179, 453, 26, 12 ], [ 208, 453, 22, 12 ], [ 234, 453, 25, 12 ], [ 262, 453, 6, 12 ], [ 271, 453, 18, 12 ], [ 293, 453, 23, 12 ], [ 319, 453, 16, 12 ], [ 337, 453, 46, 12 ], [ 386, 453, 18, 12 ], [ 407, 453, 21, 12 ], [ 432, 453, 5, 12 ], [ 440, 453, 48, 12 ], [ 491, 453, 36, 12 ], [ 65, 466, 42, 12 ], [ 110, 466, 10, 12 ], [ 122, 466, 15, 12 ], [ 139, 466, 34, 12 ], [ 175, 466, 43, 12 ], [ 220, 466, 21, 12 ], [ 243, 466, 7, 12 ], [ 252, 466, 18, 12 ], [ 272, 466, 23, 12 ], [ 297, 466, 16, 12 ], [ 315, 466, 49, 12 ], [ 366, 466, 26, 12 ], [ 395, 466, 45, 12 ], [ 442, 466, 43, 12 ], [ 487, 466, 40, 12 ], [ 65, 479, 10, 12 ], [ 78, 479, 25, 12 ], [ 106, 479, 60, 12 ], [ 169, 479, 12, 12 ], [ 184, 479, 17, 12 ], [ 204, 479, 21, 12 ], [ 228, 479, 55, 12 ], [ 286, 479, 28, 12 ], [ 317, 479, 21, 12 ], [ 340, 479, 32, 12 ], [ 375, 479, 25, 12 ], [ 403, 479, 28, 12 ], [ 434, 479, 17, 12 ], [ 454, 479, 18, 12 ], [ 475, 479, 34, 12 ], [ 512, 479, 10, 12 ], [ 522, 479, 4, 12 ], [ 65, 492, 27, 12 ], [ 95, 492, 10, 12 ], [ 107, 492, 55, 12 ], [ 164, 492, 39, 12 ], [ 205, 492, 23, 12 ], [ 231, 492, 28, 12 ], [ 261, 492, 18, 12 ], [ 281, 492, 46, 12 ], [ 65, 510, 0, 12 ], [ 74, 512, 0, 9 ], [ 131, 510, 4, 12 ], [ 137, 510, 11, 12 ], [ 150, 510, 24, 12 ], [ 176, 510, 28, 12 ], [ 207, 510, 21, 12 ], [ 230, 510, 10, 12 ], [ 242, 510, 5, 12 ], [ 250, 510, 25, 12 ], [ 278, 510, 32, 12 ], [ 312, 510, 43, 12 ], [ 357, 510, 28, 12 ], [ 387, 510, 22, 12 ], [ 412, 510, 46, 12 ], [ 461, 510, 42, 12 ], [ 506, 510, 21, 12 ], [ 65, 523, 43, 12 ], [ 111, 523, 9, 12 ], [ 123, 523, 37, 12 ], [ 163, 523, 12, 12 ], [ 177, 523, 41, 12 ], [ 221, 523, 32, 12 ], [ 256, 523, 76, 12 ], [ 335, 523, 57, 12 ], [ 394, 523, 18, 12 ], [ 415, 523, 27, 12 ], [ 444, 523, 53, 12 ], [ 500, 523, 28, 12 ], [ 65, 536, 55, 12 ], [ 123, 536, 22, 12 ], [ 147, 536, 47, 12 ], [ 196, 536, 39, 12 ], [ 237, 536, 9, 12 ], [ 249, 536, 6, 12 ], [ 258, 536, 24, 12 ], [ 283, 536, 22, 12 ], [ 307, 536, 9, 12 ], [ 319, 536, 15, 12 ], [ 336, 536, 24, 12 ], [ 362, 536, 18, 12 ], [ 382, 536, 22, 12 ], [ 407, 536, 39, 12 ], [ 448, 536, 10, 12 ], [ 460, 536, 25, 12 ], [ 65, 553, 0, 12 ], [ 75, 556, 1, 9 ], [ 91, 556, 3, 9 ], [ 126, 553, 4, 12 ], [ 135, 553, 41, 12 ], [ 180, 553, 51, 12 ], [ 236, 553, 29, 12 ], [ 270, 553, 46, 12 ], [ 320, 553, 52, 12 ], [ 377, 553, 33, 12 ], [ 415, 553, 64, 12 ], [ 483, 553, 44, 12 ], [ 65, 566, 52, 12 ], [ 121, 566, 70, 12 ], [ 194, 566, 87, 12 ], [ 285, 566, 48, 12 ], [ 336, 567, 38, 12 ], [ 377, 567, 32, 12 ], [ 412, 567, 37, 12 ], [ 452, 566, 75, 12 ], [ 65, 580, 35, 12 ], [ 106, 580, 123, 12 ], [ 230, 580, 37, 12 ], [ 270, 580, 13, 12 ], [ 285, 580, 33, 12 ], [ 320, 580, 28, 12 ], [ 550, 230, 44, 14 ], [ 597, 230, 31, 14 ], [ 632, 230, 10, 14 ], [ 646, 230, 51, 14 ], [ 701, 230, 50, 14 ], [ 754, 230, 23, 14 ], [ 550, 244, 47, 14 ], [ 601, 244, 75, 14 ], [ 680, 244, 42, 14 ], [ 726, 244, 37, 14 ], [ 767, 244, 10, 14 ], [ 550, 259, 20, 14 ], [ 573, 259, 10, 14 ], [ 585, 259, 10, 14 ], [ 598, 259, 45, 14 ], [ 646, 259, 99, 14 ], [ 748, 259, 29, 14 ], [ 550, 273, 16, 14 ], [ 569, 273, 47, 14 ], [ 620, 273, 11, 14 ], [ 634, 273, 45, 14 ], [ 682, 273, 50, 14 ], [ 735, 273, 9, 14 ], [ 746, 273, 31, 14 ], [ 550, 288, 71, 14 ], [ 623, 288, 27, 14 ], [ 653, 288, 19, 14 ], [ 675, 288, 42, 14 ], [ 719, 288, 58, 14 ], [ 550, 302, 42, 14 ], [ 595, 302, 25, 14 ], [ 624, 302, 18, 14 ], [ 646, 302, 53, 14 ], [ 703, 302, 74, 14 ], [ 550, 317, 19, 14 ], [ 572, 317, 39, 14 ], [ 615, 317, 10, 14 ], [ 629, 317, 11, 14 ], [ 643, 317, 11, 14 ], [ 657, 317, 61, 14 ], [ 722, 317, 55, 14 ], [ 550, 332, 19, 14 ], [ 572, 332, 11, 14 ], [ 587, 332, 16, 14 ], [ 607, 332, 23, 14 ], [ 634, 332, 56, 14 ], [ 694, 332, 54, 14 ], [ 751, 332, 10, 14 ], [ 765, 332, 12, 14 ], [ 550, 346, 34, 14 ], [ 587, 346, 47, 14 ], [ 638, 346, 14, 14 ], [ 656, 346, 51, 14 ], [ 711, 346, 43, 14 ], [ 757, 346, 20, 14 ], [ 550, 361, 41, 14 ], [ 595, 361, 18, 14 ], [ 617, 361, 54, 14 ], [ 675, 361, 75, 14 ], [ 753, 361, 24, 14 ], [ 550, 375, 55, 14 ], [ 610, 375, 25, 14 ], [ 640, 375, 48, 14 ], [ 693, 375, 34, 14 ], [ 732, 375, 11, 14 ], [ 748, 375, 29, 14 ], [ 550, 390, 53, 14 ], [ 607, 390, 11, 14 ], [ 622, 390, 58, 14 ], [ 684, 390, 30, 14 ], [ 718, 390, 11, 14 ], [ 732, 390, 17, 14 ], [ 753, 390, 24, 14 ], [ 550, 405, 39, 14 ], [ 593, 405, 35, 14 ], [ 632, 405, 32, 14 ], [ 668, 405, 10, 14 ], [ 683, 405, 55, 14 ], [ 742, 405, 14, 14 ], [ 760, 405, 17, 14 ], [ 550, 419, 18, 14 ], [ 571, 419, 21, 14 ], [ 596, 419, 13, 14 ], [ 613, 419, 55, 14 ], [ 672, 419, 42, 14 ], [ 717, 419, 45, 14 ], [ 766, 419, 11, 14 ], [ 550, 434, 26, 14 ], [ 580, 434, 35, 14 ], [ 619, 434, 57, 14 ], [ 680, 434, 39, 14 ], [ 724, 434, 19, 14 ], [ 747, 434, 30, 14 ], [ 550, 448, 21, 14 ], [ 575, 448, 11, 14 ], [ 589, 448, 47, 14 ], [ 640, 448, 10, 14 ], [ 653, 448, 7, 14 ], [ 664, 448, 25, 14 ], [ 693, 448, 11, 14 ], [ 708, 448, 17, 14 ], [ 729, 448, 49, 14 ], [ 550, 463, 10, 14 ], [ 564, 463, 13, 14 ], [ 581, 463, 35, 14 ], [ 620, 463, 51, 14 ], [ 675, 463, 17, 14 ], [ 696, 463, 43, 14 ], [ 744, 463, 11, 14 ], [ 759, 463, 18, 14 ], [ 550, 477, 28, 14 ], [ 582, 477, 24, 14 ], [ 610, 477, 110, 14 ], [ 724, 477, 17, 14 ], [ 745, 477, 32, 14 ], [ 550, 492, 10, 14 ], [ 563, 492, 7, 14 ], [ 574, 492, 25, 14 ], [ 603, 492, 11, 14 ], [ 617, 492, 17, 14 ], [ 637, 492, 11, 14 ], [ 652, 492, 43, 14 ], [ 699, 492, 46, 14 ], [ 749, 492, 28, 14 ], [ 550, 507, 23, 14 ], [ 576, 507, 11, 14 ], [ 590, 507, 15, 14 ], [ 607, 507, 41, 14 ], [ 651, 507, 11, 14 ], [ 665, 507, 30, 14 ], [ 698, 507, 29, 14 ], [ 730, 507, 47, 14 ], [ 550, 521, 42, 14 ], [ 596, 521, 65, 14 ], [ 664, 521, 13, 14 ], [ 680, 521, 59, 14 ], [ 743, 521, 34, 14 ], [ 550, 536, 31, 14 ], [ 585, 536, 35, 14 ], [ 625, 536, 72, 14 ], [ 701, 536, 8, 14 ], [ 714, 536, 63, 14 ], [ 550, 550, 50, 14 ], [ 602, 550, 10, 14 ], [ 615, 550, 41, 14 ], [ 659, 550, 10, 14 ], [ 671, 550, 31, 14 ], [ 705, 550, 10, 14 ], [ 717, 550, 7, 14 ], [ 726, 550, 11, 14 ], [ 740, 550, 7, 14 ], [ 749, 550, 28, 14 ], [ 550, 565, 8, 14 ], [ 560, 565, 8, 14 ], [ 571, 565, 26, 14 ], [ 599, 565, 44, 14 ], [ 646, 565, 23, 14 ], [ 671, 565, 41, 14 ], [ 715, 565, 28, 14 ], [ 745, 565, 32, 14 ], [ 550, 580, 19, 14 ], [ 572, 580, 8, 14 ], [ 583, 580, 26, 14 ], [ 612, 580, 54, 14 ], [ 669, 580, 42, 14 ], [ 714, 580, 11, 14 ], [ 728, 580, 23, 14 ], [ 754, 580, 23, 14 ], [ 549, 616, 35, 12 ], [ 587, 616, 69, 12 ], [ 659, 616, 10, 12 ], [ 672, 616, 10, 12 ], [ 685, 616, 41, 12 ], [ 730, 616, 31, 12 ], [ 764, 616, 13, 12 ], [ 549, 629, 46, 12 ], [ 598, 629, 66, 12 ], [ 668, 629, 31, 12 ], [ 702, 629, 42, 12 ], [ 747, 629, 30, 12 ], [ 549, 641, 10, 12 ], [ 562, 641, 30, 12 ], [ 595, 641, 35, 12 ], [ 634, 641, 17, 12 ], [ 655, 641, 43, 12 ], [ 701, 641, 24, 12 ], [ 729, 641, 48, 12 ], [ 549, 654, 25, 12 ], [ 580, 654, 26, 12 ], [ 611, 654, 22, 12 ], [ 640, 654, 47, 12 ], [ 692, 654, 16, 12 ], [ 713, 654, 32, 12 ], [ 751, 654, 26, 12 ], [ 549, 666, 50, 12 ], [ 602, 666, 25, 12 ], [ 630, 666, 47, 12 ], [ 680, 666, 19, 12 ], [ 703, 666, 25, 12 ], [ 731, 666, 47, 12 ], [ 549, 679, 32, 12 ], [ 583, 679, 98, 12 ], [ 557, 691, 69, 12 ], [ 632, 691, 43, 12 ], [ 681, 691, 8, 12 ], [ 695, 691, 44, 12 ], [ 745, 691, 32, 12 ], [ 549, 704, 118, 12 ], [ 669, 704, 13, 12 ], [ 684, 704, 83, 12 ], [ 557, 716, 15, 12 ], [ 575, 716, 55, 12 ], [ 633, 716, 14, 12 ], [ 649, 716, 63, 12 ], [ 715, 716, 21, 12 ], [ 739, 716, 39, 12 ], [ 549, 729, 51, 12 ], [ 603, 729, 39, 12 ], [ 645, 729, 17, 12 ], [ 665, 729, 52, 12 ], [ 720, 729, 17, 12 ], [ 740, 729, 37, 12 ], [ 549, 741, 34, 12 ], [ 586, 741, 28, 12 ], [ 616, 741, 16, 12 ], [ 635, 741, 24, 12 ], [ 661, 741, 27, 12 ], [ 691, 741, 15, 12 ], [ 709, 741, 10, 12 ], [ 722, 741, 37, 12 ], [ 761, 741, 16, 12 ], [ 549, 754, 28, 12 ], [ 580, 754, 49, 12 ], [ 633, 754, 16, 12 ], [ 652, 754, 10, 12 ], [ 665, 754, 26, 12 ], [ 695, 754, 14, 12 ], [ 713, 754, 65, 12 ], [ 549, 766, 22, 12 ], [ 574, 766, 27, 12 ], [ 604, 766, 18, 12 ], [ 625, 766, 9, 12 ], [ 637, 766, 18, 12 ], [ 657, 766, 9, 12 ], [ 669, 766, 12, 12 ], [ 684, 766, 36, 12 ], [ 723, 766, 13, 12 ], [ 739, 766, 14, 12 ], [ 756, 766, 21, 12 ], [ 549, 779, 24, 12 ], [ 577, 779, 10, 12 ], [ 590, 779, 43, 12 ], [ 637, 779, 59, 12 ], [ 699, 779, 17, 12 ], [ 720, 779, 11, 12 ], [ 735, 779, 25, 12 ], [ 764, 779, 13, 12 ], [ 549, 791, 27, 12 ], [ 578, 791, 12, 12 ], [ 592, 791, 40, 12 ], [ 634, 791, 64, 12 ], [ 557, 804, 21, 12 ], [ 582, 804, 52, 12 ], [ 637, 804, 16, 12 ], [ 657, 804, 25, 12 ], [ 686, 804, 36, 12 ], [ 725, 804, 11, 12 ], [ 740, 804, 37, 12 ], [ 549, 816, 49, 12 ], [ 603, 816, 12, 12 ], [ 620, 816, 30, 12 ], [ 655, 816, 17, 12 ], [ 678, 816, 50, 12 ], [ 733, 816, 24, 12 ], [ 762, 816, 15, 12 ], [ 549, 829, 21, 12 ], [ 575, 829, 72, 12 ], [ 651, 829, 50, 12 ], [ 705, 829, 35, 12 ], [ 745, 829, 33, 12 ], [ 549, 841, 22, 12 ], [ 575, 841, 49, 12 ], [ 629, 841, 23, 12 ], [ 656, 841, 15, 12 ], [ 676, 841, 42, 12 ], [ 722, 841, 41, 12 ], [ 767, 841, 10, 12 ], [ 549, 854, 72, 12 ], [ 625, 854, 33, 12 ], [ 663, 854, 40, 12 ], [ 707, 854, 48, 12 ], [ 759, 854, 18, 12 ], [ 549, 866, 23, 12 ], [ 575, 866, 54, 12 ], [ 632, 866, 22, 12 ], [ 659, 866, 15, 12 ], [ 677, 866, 40, 12 ], [ 721, 866, 39, 12 ], [ 764, 866, 13, 12 ], [ 549, 879, 59, 12 ], [ 610, 879, 26, 12 ], [ 638, 879, 16, 12 ], [ 657, 879, 30, 12 ], [ 690, 879, 46, 12 ], [ 557, 891, 18, 12 ], [ 579, 891, 39, 12 ], [ 621, 891, 14, 12 ], [ 638, 891, 25, 12 ], [ 667, 891, 15, 12 ], [ 685, 891, 61, 12 ], [ 750, 891, 9, 12 ], [ 763, 891, 15, 12 ], [ 549, 904, 33, 12 ], [ 585, 904, 16, 12 ], [ 605, 904, 12, 12 ], [ 620, 904, 15, 12 ], [ 638, 904, 46, 12 ], [ 687, 904, 40, 12 ], [ 730, 904, 14, 12 ], [ 748, 904, 30, 12 ], [ 549, 916, 23, 12 ], [ 575, 916, 9, 12 ], [ 587, 916, 14, 12 ], [ 603, 916, 37, 12 ], [ 642, 916, 39, 12 ], [ 684, 916, 38, 12 ], [ 725, 916, 41, 12 ], [ 768, 916, 9, 12 ], [ 549, 929, 33, 12 ], [ 584, 929, 10, 12 ], [ 596, 929, 20, 12 ], [ 618, 929, 23, 12 ], [ 557, 941, 24, 12 ], [ 585, 941, 17, 12 ], [ 605, 941, 25, 12 ], [ 634, 941, 16, 12 ], [ 654, 941, 36, 12 ], [ 693, 941, 20, 12 ], [ 717, 941, 33, 12 ], [ 754, 941, 9, 12 ], [ 766, 941, 11, 12 ], [ 549, 954, 28, 12 ], [ 581, 954, 33, 12 ], [ 618, 954, 10, 12 ], [ 631, 954, 5, 12 ], [ 640, 954, 40, 12 ], [ 684, 954, 45, 12 ], [ 733, 954, 21, 12 ], [ 758, 954, 19, 12 ], [ 549, 966, 32, 12 ], [ 584, 966, 30, 12 ], [ 616, 966, 19, 12 ], [ 637, 966, 20, 12 ], [ 660, 966, 12, 12 ], [ 674, 966, 25, 12 ], [ 702, 966, 10, 12 ], [ 714, 966, 38, 12 ], [ 755, 966, 22, 12 ], [ 549, 979, 27, 12 ], [ 578, 979, 37, 12 ], [ 617, 979, 38, 12 ], [ 557, 991, 40, 12 ], [ 601, 991, 12, 12 ], [ 616, 991, 40, 12 ], [ 660, 991, 26, 12 ], [ 690, 991, 39, 12 ], [ 732, 991, 12, 12 ], [ 747, 991, 30, 12 ], [ 549, 1004, 25, 12 ], [ 428, 1047, 0, 9 ], [ 460, 1045, 16, 12 ], [ 479, 1045, 2, 9 ], [ 483, 1047, 0, 9 ], [ 515, 1045, 11, 12 ], [ 528, 1045, 2, 9 ], [ 532, 1045, 45, 12 ], [ 580, 1045, 21, 12 ], [ 606, 1045, 4, 12 ], [ 617, 1044, 66, 13 ], [ 686, 1044, 30, 13 ], [ 719, 1044, 57, 13 ], [ 60, 623, 90, 14 ], [ 154, 623, 26, 14 ], [ 184, 623, 48, 14 ], [ 235, 623, 15, 14 ], [ 254, 623, 33, 14 ], [ 60, 638, 46, 14 ], [ 110, 638, 21, 14 ], [ 135, 638, 30, 14 ], [ 169, 638, 16, 14 ], [ 189, 638, 40, 14 ], [ 234, 638, 39, 14 ], [ 276, 638, 11, 14 ], [ 60, 652, 33, 14 ], [ 95, 652, 19, 14 ], [ 117, 652, 27, 14 ], [ 146, 652, 24, 14 ], [ 173, 652, 53, 14 ], [ 229, 652, 33, 14 ], [ 265, 652, 22, 14 ], [ 60, 667, 38, 14 ], [ 102, 667, 48, 14 ], [ 154, 667, 42, 14 ], [ 200, 667, 17, 14 ], [ 220, 667, 52, 14 ], [ 277, 667, 11, 14 ], [ 60, 682, 99, 14 ], [ 163, 682, 12, 14 ], [ 179, 682, 38, 14 ], [ 220, 682, 20, 14 ], [ 244, 682, 43, 14 ], [ 60, 696, 16, 14 ], [ 80, 696, 86, 14 ], [ 170, 696, 70, 14 ], [ 243, 696, 44, 14 ], [ 60, 711, 11, 14 ], [ 74, 711, 6, 14 ], [ 83, 711, 40, 14 ], [ 127, 711, 11, 14 ], [ 141, 711, 65, 14 ], [ 209, 711, 11, 14 ], [ 223, 711, 16, 14 ], [ 243, 711, 45, 14 ], [ 60, 725, 46, 14 ], [ 111, 725, 66, 14 ], [ 181, 725, 20, 14 ], [ 206, 725, 41, 14 ], [ 251, 725, 36, 14 ], [ 60, 740, 49, 14 ], [ 113, 740, 56, 14 ], [ 173, 740, 51, 14 ], [ 228, 740, 22, 14 ], [ 254, 740, 18, 14 ], [ 275, 740, 12, 14 ], [ 60, 755, 16, 14 ], [ 80, 755, 20, 14 ], [ 104, 755, 58, 14 ], [ 165, 755, 11, 14 ], [ 180, 755, 31, 14 ], [ 215, 755, 58, 14 ], [ 277, 755, 11, 14 ], [ 60, 769, 24, 14 ], [ 88, 769, 10, 14 ], [ 102, 769, 45, 14 ], [ 150, 769, 44, 14 ], [ 198, 769, 33, 14 ], [ 234, 769, 30, 14 ], [ 267, 769, 20, 14 ], [ 60, 784, 19, 14 ], [ 83, 784, 45, 14 ], [ 132, 784, 30, 14 ], [ 165, 784, 54, 14 ], [ 224, 784, 10, 14 ], [ 237, 784, 12, 14 ], [ 253, 784, 34, 14 ], [ 60, 798, 47, 14 ], [ 111, 798, 44, 14 ], [ 158, 798, 10, 14 ], [ 172, 798, 36, 14 ], [ 211, 798, 49, 14 ], [ 264, 798, 23, 14 ], [ 60, 813, 27, 14 ], [ 91, 813, 61, 14 ], [ 157, 813, 24, 14 ], [ 185, 813, 45, 14 ], [ 234, 813, 54, 14 ], [ 60, 827, 23, 14 ], [ 86, 827, 10, 14 ], [ 99, 827, 45, 14 ], [ 146, 827, 72, 14 ], [ 221, 827, 34, 14 ], [ 259, 827, 29, 14 ], [ 60, 842, 36, 14 ], [ 100, 842, 52, 14 ], [ 155, 842, 19, 14 ], [ 177, 842, 31, 14 ], [ 212, 842, 46, 14 ], [ 262, 842, 25, 14 ], [ 60, 857, 19, 14 ], [ 83, 857, 55, 14 ], [ 143, 857, 44, 14 ], [ 191, 857, 39, 14 ], [ 234, 857, 20, 14 ], [ 258, 857, 29, 14 ], [ 60, 871, 64, 14 ], [ 129, 871, 20, 14 ], [ 153, 871, 40, 14 ], [ 197, 871, 31, 14 ], [ 233, 871, 30, 14 ], [ 267, 871, 20, 14 ], [ 60, 886, 55, 14 ], [ 119, 886, 35, 14 ], [ 158, 886, 18, 14 ], [ 180, 886, 36, 14 ], [ 220, 886, 24, 14 ], [ 249, 886, 39, 14 ], [ 60, 900, 28, 14 ], [ 92, 900, 17, 14 ], [ 113, 900, 33, 14 ], [ 150, 900, 33, 14 ], [ 188, 900, 11, 14 ], [ 203, 900, 41, 14 ], [ 249, 900, 11, 14 ], [ 264, 900, 23, 14 ], [ 60, 915, 23, 14 ], [ 86, 915, 38, 14 ], [ 128, 915, 44, 14 ], [ 176, 915, 11, 14 ], [ 191, 915, 18, 14 ], [ 213, 915, 51, 14 ], [ 268, 915, 21, 14 ], [ 60, 930, 46, 14 ], [ 110, 930, 32, 14 ], [ 146, 930, 11, 14 ], [ 161, 930, 24, 14 ], [ 188, 930, 46, 14 ], [ 238, 930, 49, 14 ], [ 60, 944, 14, 14 ], [ 77, 944, 82, 14 ], [ 164, 944, 60, 14 ], [ 227, 944, 15, 14 ], [ 247, 944, 40, 14 ], [ 60, 959, 22, 14 ], [ 86, 959, 40, 14 ], [ 129, 959, 15, 14 ], [ 147, 959, 33, 14 ], [ 184, 959, 19, 14 ], [ 207, 959, 32, 14 ], [ 243, 959, 45, 14 ], [ 60, 973, 22, 14 ], [ 86, 973, 22, 14 ], [ 112, 973, 12, 14 ], [ 128, 973, 49, 14 ], [ 181, 973, 53, 14 ], [ 238, 973, 11, 14 ], [ 253, 973, 34, 14 ], [ 60, 988, 45, 14 ], [ 109, 988, 39, 14 ], [ 152, 988, 10, 14 ], [ 166, 988, 24, 14 ], [ 194, 988, 50, 14 ], [ 248, 988, 40, 14 ], [ 60, 1002, 41, 14 ], [ 104, 1002, 24, 14 ], [ 132, 1002, 26, 14 ], [ 162, 1002, 19, 14 ], [ 184, 1002, 11, 14 ], [ 199, 1002, 26, 14 ], [ 229, 1002, 36, 14 ], [ 268, 1002, 19, 14 ], [ 60, 1043, 32, 14 ], [ 305, 623, 65, 14 ], [ 373, 623, 10, 14 ], [ 387, 623, 25, 14 ], [ 415, 623, 19, 14 ], [ 438, 623, 34, 14 ], [ 475, 623, 24, 14 ], [ 503, 623, 29, 14 ], [ 305, 638, 31, 14 ], [ 340, 638, 20, 14 ], [ 365, 638, 25, 14 ], [ 394, 638, 19, 14 ], [ 418, 638, 29, 14 ], [ 451, 638, 11, 14 ], [ 466, 638, 17, 14 ], [ 488, 638, 45, 14 ], [ 305, 652, 44, 14 ], [ 353, 652, 11, 14 ], [ 368, 652, 17, 14 ], [ 389, 652, 60, 14 ], [ 454, 652, 20, 14 ], [ 477, 652, 55, 14 ], [ 305, 667, 21, 14 ], [ 330, 667, 11, 14 ], [ 345, 667, 18, 14 ], [ 366, 667, 49, 14 ], [ 419, 667, 49, 14 ], [ 472, 667, 10, 14 ], [ 486, 667, 12, 14 ], [ 502, 667, 30, 14 ], [ 305, 682, 29, 14 ], [ 337, 682, 10, 14 ], [ 349, 682, 12, 14 ], [ 364, 682, 33, 14 ], [ 400, 682, 37, 14 ], [ 440, 682, 34, 14 ], [ 476, 682, 23, 14 ], [ 502, 682, 30, 14 ], [ 305, 696, 36, 14 ], [ 344, 696, 31, 14 ], [ 377, 696, 10, 14 ], [ 390, 696, 18, 14 ], [ 411, 696, 44, 14 ], [ 457, 696, 34, 14 ], [ 493, 696, 16, 14 ], [ 512, 696, 20, 14 ], [ 305, 711, 25, 14 ], [ 332, 711, 19, 14 ], [ 354, 711, 24, 14 ], [ 380, 711, 45, 14 ], [ 428, 711, 36, 14 ], [ 467, 711, 33, 14 ], [ 503, 711, 29, 14 ], [ 305, 725, 43, 14 ], [ 351, 725, 10, 14 ], [ 363, 725, 12, 14 ], [ 378, 725, 33, 14 ], [ 324, 740, 47, 14 ], [ 374, 740, 40, 14 ], [ 418, 740, 8, 14 ], [ 429, 740, 39, 14 ], [ 471, 740, 6, 14 ], [ 480, 740, 18, 14 ], [ 502, 740, 31, 14 ], [ 305, 755, 76, 14 ], [ 385, 755, 37, 14 ], [ 427, 755, 24, 14 ], [ 456, 755, 46, 14 ], [ 506, 755, 26, 14 ], [ 305, 769, 40, 14 ], [ 349, 769, 43, 14 ], [ 396, 769, 11, 14 ], [ 411, 769, 25, 14 ], [ 441, 769, 18, 14 ], [ 463, 769, 46, 14 ], [ 513, 769, 20, 14 ], [ 305, 784, 40, 14 ], [ 349, 784, 34, 14 ], [ 388, 784, 14, 14 ], [ 407, 784, 88, 14 ], [ 500, 784, 33, 14 ], [ 305, 798, 41, 14 ], [ 350, 798, 35, 14 ], [ 389, 798, 10, 14 ], [ 403, 798, 13, 14 ], [ 420, 798, 31, 14 ], [ 455, 798, 46, 14 ], [ 505, 798, 10, 14 ], [ 520, 798, 13, 14 ], [ 305, 813, 30, 14 ], [ 338, 813, 27, 14 ], [ 369, 813, 10, 14 ], [ 383, 813, 12, 14 ], [ 399, 813, 30, 14 ], [ 432, 813, 33, 14 ], [ 469, 813, 10, 14 ], [ 482, 813, 12, 14 ], [ 498, 813, 34, 14 ], [ 305, 827, 32, 14 ], [ 341, 827, 37, 14 ], [ 382, 827, 24, 14 ], [ 410, 827, 32, 14 ], [ 447, 827, 21, 14 ], [ 473, 827, 59, 14 ], [ 305, 842, 11, 14 ], [ 319, 842, 41, 14 ], [ 365, 842, 18, 14 ], [ 387, 842, 45, 14 ], [ 435, 842, 15, 14 ], [ 455, 842, 51, 14 ], [ 509, 842, 23, 14 ], [ 305, 857, 13, 14 ], [ 322, 857, 48, 14 ], [ 374, 857, 41, 14 ], [ 419, 857, 11, 14 ], [ 434, 857, 50, 14 ], [ 487, 857, 45, 14 ], [ 305, 871, 40, 14 ], [ 349, 871, 10, 14 ], [ 362, 871, 48, 14 ], [ 414, 871, 13, 14 ], [ 430, 871, 16, 14 ], [ 450, 871, 48, 14 ], [ 502, 871, 30, 14 ], [ 305, 886, 10, 14 ], [ 319, 886, 46, 14 ], [ 368, 886, 68, 14 ], [ 439, 886, 33, 14 ], [ 475, 886, 10, 14 ], [ 488, 886, 12, 14 ], [ 503, 886, 29, 14 ], [ 305, 900, 33, 14 ], [ 341, 900, 10, 14 ], [ 354, 900, 12, 14 ], [ 369, 900, 33, 14 ], [ 406, 900, 19, 14 ], [ 428, 900, 33, 14 ], [ 464, 900, 35, 14 ], [ 502, 900, 30, 14 ], [ 305, 915, 40, 14 ], [ 349, 915, 11, 14 ], [ 364, 915, 25, 14 ], [ 392, 915, 56, 14 ], [ 452, 915, 10, 14 ], [ 466, 915, 49, 14 ], [ 518, 915, 14, 14 ], [ 305, 930, 17, 14 ], [ 327, 930, 36, 14 ], [ 367, 930, 32, 14 ], [ 404, 930, 11, 14 ], [ 420, 930, 34, 14 ], [ 459, 930, 73, 14 ], [ 305, 944, 52, 14 ], [ 361, 944, 10, 14 ], [ 376, 944, 13, 14 ], [ 394, 944, 31, 14 ], [ 430, 944, 29, 14 ], [ 463, 944, 10, 14 ], [ 478, 944, 13, 14 ], [ 496, 944, 36, 14 ], [ 305, 959, 27, 14 ], [ 336, 959, 10, 14 ], [ 349, 959, 12, 14 ], [ 365, 959, 35, 14 ], [ 404, 959, 19, 14 ], [ 427, 959, 30, 14 ], [ 461, 959, 11, 14 ], [ 475, 959, 6, 14 ], [ 485, 959, 33, 14 ], [ 522, 959, 11, 14 ], [ 305, 973, 55, 14 ], [ 363, 973, 28, 14 ], [ 394, 973, 11, 14 ], [ 407, 973, 24, 14 ], [ 434, 973, 25, 14 ], [ 461, 973, 22, 14 ], [ 487, 973, 20, 14 ], [ 510, 973, 23, 14 ], [ 305, 988, 57, 14 ], [ 365, 988, 11, 14 ], [ 380, 988, 16, 14 ], [ 400, 988, 18, 14 ], [ 422, 988, 45, 14 ], [ 471, 988, 61, 14 ], [ 305, 1002, 11, 14 ], [ 320, 1002, 45, 14 ], [ 369, 1002, 31, 14 ], [ 405, 1002, 24, 14 ], [ 433, 1002, 51, 14 ], [ 488, 1002, 23, 14 ], [ 515, 1002, 17, 14 ] ]

[ "Research", "|", "Children’s", "Health", "Organophosphate", "Pesticide", "Exposure", "and", "Attention", "in", "Young", "Mexican-American", "Children:", "The", "CHAMACOS", "Study", "Amy", "R.", "Marks,1", "Kim", "Harley,1", "Asa", "Bradman,1", "Katherine", "Kogut,1", "Dana", "Boyd", "Barr,2", "Caroline", "Johnson,1", "Norma", "Calderon,3", "and", "Brenda", "Eskenazi", "1", "1Center", "for", "Children’s", "Environmental", "Health", "Research,", "School", "of", "Public", "Health,", "University", "of", "California,", "Berkeley,", "Berkeley,", "California,", "USA;", "2Emory", "University,", "Rollins", "School", "of", "Public", "Health,", "Atlanta,", "Georgia,", "USA;", "3Center", "for", "the", "Health", "Assessment", "of", "Mothers", "and", "Children", "of", "Salinas,", "Clinica", "de", "Salud", "del", "Valle", "de", "Salinas,", "Salinas,", "California,", "USA", "Background", ":", "Exposure", "to", "organophosphate", "(OP)", "pesticides,", "wellk‑nown", "neurotoxicants,", "has", "been", "associated", "with", "neurobehavioral", "deficits", "in", "children.", "o", "Bjectivs", ":", "We", "investigated", "whether", "OP", "exposure,", "as", "measured", "by", "urinary", "dialkyl", "phosphate", "(DAP)", "metabolites", "in", "pregnant", "women", "and", "their", "children,", "was", "associated", "with", "attention‑related", "outcomes", "among", "MexicanA‑merican", "children", "living", "in", "an", "agricultural", "region", "of", "California.", "Methods", ":", "Children", "were", "assessed", "at", "ages", "3.5", "years", "(n", "=", "331)", "and", "5", "years", "(n", "=", "323).", "Mothers", "com‑", "pleted", "the", "Child", "Behavior", "Checklist", "(CBCL).", "We", "administered", "the", "NEPSYI‑I", "visual", "attention", "sub", "‑", "test", "to", "children", "at", "3.5", "years", "and", "Conners’", "Kiddie", "Continuous", "Performance", "Test", "(KC‑PT)", "at", "5", "years.", "The", "K‑", "CPT", "yielded", "a", "standardized", "attention", "deficit/hyperactivity", "disorder", "(ADHD)", "Confidence", "Index", "score.", "Psychometricians", "scored", "behavior", "of", "the", "5y‑earo‑lds", "during", "testing", "using", "the", "Hillside", "Behavior", "Rating", "Scale.", "r", "esult", ":", "Prenatal", "DAPs", "(nanomoles", "per", "liter)", "were", "nonsignificantly", "associated", "with", "maternal", "report", "of", "attention", "problems", "and", "ADHD", "at", "age", "3.5", "years", "but", "were", "significantly", "related", "at", "age", "5", "years", "[CBCL", "attention", "problems:", "β", "=", "0.7", "points;", "95%", "confidence", "interval", "(CI),", "0.2–1.2;", "ADHD:", "β", "=", "1.3;", "95%", "CI,", "0.4–2.1].", "Prenatal", "DAPs", "were", "associated", "with", "scores", "on", "the", "KC‑PT", "ADHD", "Confidence", "Index", ">", "70th", "percentile", "[odds", "ratio", "(OR)", "=", "5.1;", "95%", "CI,", "1.7–15.7]", "and", "with", "a", "composite", "ADHD", "indicator", "of", "the", "various", "measures", "(OR", "=", "3.5;", "95%", "CI,", "1.1–10.7).", "Some", "outcomes", "exhibited", "evidence", "of", "effect", "modification", "by", "sex,", "with", "associations", "found", "only", "among", "boys.", "There", "was", "also", "limited", "ev", "i‑", "dence", "of", "associations", "between", "child", "DAPs", "and", "attention.", "c", "onclusi", ":", "In", "utero", "DAPs", "and,", "to", "a", "lesser", "extent,", "postnatal", "DAPs", "were", "associated", "adversely", "with", "attention", "as", "assessed", "by", "maternal", "report,", "psychometrician", "observation,", "and", "direct", "assessment.", "These", "associations", "were", "somewhat", "stronger", "at", "5", "years", "than", "at", "3.5", "years", "and", "were", "stronger", "in", "boys.", "k", "ey", "words", ":", "ADHD,", "attention,", "Child", "Behavior", "Checklist,", "DAPs,", "farmworker,", "Mexican", "Americans,", "neurobehavior,", "organophosphates,", "pesticides.", "Environ", "Health", "Perspect", "118:1768–1774", "(2010).", "doi:10.1289/ehp.1002056", "[Online", "19", "August", "2010]", "mothers’", "report", "of", "symptoms", "consistent", "with", "pervasive", "developmental", "disorder", "(PDD)", "as", "well", "as", "of", "attention", "deficit/hyperactivity", "disor-", "der", "(ADHD)", "or", "attention", "problems.", "A", "recent", "cross-sectional", "study", "also", "reported", "associations", "between", "child", "OP", "metabolite", "concentrations", "and", "ADHD", "in", "8-", "to", "15-year-olds", "representa-", "tive", "of", "the", "U.S.", "population", "(Bouchard", "et", "al.", "2010).", "Although", "we", "previously", "reported", "that", "prenatal", "OP", "metabolite", "concentrations", "were", "associated", "with", "mothers’", "report", "of", "PDD", "symptoms", "in", "2-year-olds", "living", "in", "the", "agri-", "cultural", "Salinas", "Valley", "of", "California,", "we", "did", "not", "find", "an", "association", "between", "maternal", "or", "child", "dialkyl", "phosphates", "(DAPs)", "and", "meas-", "ures", "of", "attention", "at", "2", "years", "of", "age", "(Eskenazi", "et", "al.", "2007).", "However,", "the", "children", "in", "our", "study", "were", "younger—potentially", "too", "young", "at", "2", "years", "of", "age", "to", "manifest", "attention", "prob-", "lems", "or", "for", "mothers", "to", "detect", "them.", "Although", "ADHD,", "characterized", "by", "inattention,", "impul-", "sivity,", "and/or", "hyperactivity,", "is", "occasionally", "diagnosed", "in", "children", "as", "young", "as", "2", "or", "3", "years,", "it", "is", "more", "apparent", "after", "children", "begin", "school", "and", "is", "more", "commonly", "reported", "in", "boys", "than", "Address", "correspondence", "to", "B.", "Eskenazi,", "Center", "for", "Children’s", "Environmental", "Health", "Research,", "School", "of", "Public", "Health,", "UC", "Berkeley,", "1995", "University", "Ave.,", "Suite", "265,", "Berkeley,", "CA", "94720", "USA.", "Telephone:", "(510)", "643-1337.", "Fax:", "(510)", "642-9083.", "E-mail:", "eskenazi@berkeley.edu", "Supplemental", "Material", "is", "available", "online", "(doi:10.1289/ehp.1002056", "via", "http://dx.doi.org/).", "We", "acknowledge", "the", "CHAMACOS", "staff,", "students,", "community", "partners,", "and", "participants", "and", "families,", "without", "whom", "this", "study", "would", "not", "be", "possible.", "We", "would", "specifically", "like", "to", "thank", "the", "CHAMACOS", "Field", "Office", "staff", "as", "well", "as", "N.", "Holland", "for", "her", "assis-", "tance", "in", "specimen", "management", "and", "R.", "Klein", "for", "advice", "on", "attention", "measurements.", "This", "publication", "was", "made", "possible", "by", "research", "supported", "by", "grants", "RD", "83171001", "from", "the", "U.S.", "Environmental", "Protection", "Agency", "(EPA),", "PO1", "ES009605", "from", "the", "National", "Institute", "of", "Environmental", "Health", "Sciences", "(NIEHS),", "and", "RO1", "OH007400", "from", "the", "National", "Institute", "for", "Occupational", "Safety", "and", "Health", "(NIOSH).", "The", "contents", "are", "solely", "the", "responsibility", "of", "the", "authors", "and", "do", "not", "necessarily", "represent", "the", "official", "views", "of", "the", "NIEHS,", "NIOSH,", "National", "Institutes", "of", "Health,", "or", "U.S.", "EPA.", "Since", "this", "paper", "was", "written,", "B.E.", "worked", "as", "an", "expert", "witness", "in", "a", "pesticide", "poisoning", "case.", "The", "authors", "declare", "they", "have", "no", "actual", "or", "potential", "com-", "peting", "financial", "interests.", "Received", "12", "February", "2010;", "accepted", "29", "March", "2010.", "ovlume", "118", "|", "number", "12", "|", "December", "2010", "•", "Environmental", "Health", "Perspectives", "Organophosphate", "(OP)", "pesticides", "are", "potent", "toxicants", "that", "target", "the", "nervous", "systems", "of", "insects", "and", "other", "pests", "(Jokanovic", "2009).", "OPs", "operate", "primarily", "through", "the", "inhibition", "of", "acetylcholinesterase,", "an", "enzyme", "that", "degrades", "the", "neurotransmitter", "acetylcholine,", "resulting", "in", "a", "buildup", "of", "acetylcholine", "in", "the", "neuronal", "junction", "(Jeyaratnam", "and", "Maroni", "1994).", "However,", "cholinergic", "inhibition", "may", "not", "be", "the", "sole", "mechanism", "of", "effect,", "particularly", "in", "cases", "of", "low-level", "exposure", "(Costa", "2006;", "Ray", "and", "Richards", "2001;", "Timofeeva", "et", "al.", "2008).", "Although", "accounts", "of", "human", "poisoning", "with", "these", "compounds", "have", "reported", "symptoms", "such", "as", "impaired", "concentration,", "slowed", "infor-", "mation", "processing", "and", "motor", "function,", "anxi-", "ety,", "confusion,", "tremors,", "seizure,", "and", "death", "(Jeyaratnam", "and", "Maroni", "1994;", "Levin", "and", "Rodnitzky", "1976),", "few", "studies", "have", "investi-", "gated", "the", "health", "effects", "in", "humans", "of", "low-", "level", "chronic", "exposure", "to", "OP", "pesticides.", "The", "potential", "effects", "of", "such", "low-level", "exposures", "on", "neurobehavioral", "functioning", "are", "particu-", "larly", "relevant", "for", "fetuses", "and", "young", "children,", "who", "may", "be", "especially", "vulnerable", "to", "neuro-", "toxicants", "because", "of", "their", "immature", "nervous", "systems,", "their", "rapid", "rate", "of", "brain", "growth", "and", "1768", "development", "in", "utero", "and", "during", "early", "child-", "hood,", "and", "their", "low", "levels", "of", "the", "enzymes", "involved", "in", "the", "metabolism", "and", "detoxifica-", "tion", "of", "OP", "pesticides", "(Eskenazi", "et", "al.", "1999;", "Huen", "et", "al.", "2009).", "Animal", "studies", "have", "found", "adverse", "effects", "of", "OP", "exposure", "during", "the", "pre-", "natal", "and", "early", "postnatal", "periods", "(Costa", "2006;", "Eskenazi", "et", "al.", "1999).", "Although", "research", "is", "limited,", "a", "few", "recent", "epidemiologic", "studies", "have", "reported", "asso-", "ciations", "between", "in", "utero", "OP", "exposure", "and", "adverse", "effects", "on", "neurobehavioral", "devel-", "opment", "(Engel", "et", "al.", "2007;", "Eskenazi", "et", "al.", "2007;", "Rauh", "et", "al.", "2006;", "Young", "et", "al.", "2005).", "These", "studies", "have", "found", "that", "biomarkers", "of", "prenatal", "OP", "exposure", "are", "associated", "with", "an", "increased", "number", "of", "abnormal", "neonatal", "reflexes,", "as", "measured", "by", "the", "Brazelton", "Scales", "of", "Neonatal", "Development", "(Engel", "et", "al.", "2007;", "Young", "et", "al.", "2005),", "and", "poorer", "mental", "devel-", "opment", "in", "early", "childhood,", "as", "measured", "on", "the", "Bayley", "Scales", "of", "Infant", "Development", "(Eskenazi", "et", "al.", "2007;", "Rauh", "et", "al.", "2006).", "Rauh", "et", "al.", "(2006)", "also", "found", "in", "a", "cohort", "of", "3-year-olds", "living", "in", "New", "York", "City", "that", "con-", "centrations", "of", "the", "OP", "pesticide", "chlorpyrifos", "in", "maternal", "serum", "were", "associated", "with", "the" ]

[ 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 15, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 14, 14, 14, 14, 14, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 68, 75, 52, 17 ], [ 124, 75, 38, 17 ], [ 166, 75, 21, 17 ], [ 191, 75, 77, 17 ], [ 272, 75, 167, 17 ], [ 655, 101, 39, 14 ], [ 696, 101, 55, 14 ], [ 622, 107, 137, 45 ], [ 644, 162, 38, 17 ], [ 686, 162, 73, 17 ], [ 545, 182, 213, 17 ], [ 68, 222, 46, 17 ], [ 68, 260, 18, 25 ], [ 93, 260, 117, 25 ], [ 216, 260, 41, 25 ], [ 263, 260, 148, 25 ], [ 416, 260, 284, 25 ], [ 68, 290, 150, 25 ], [ 225, 290, 64, 25 ], [ 295, 290, 27, 25 ], [ 327, 290, 101, 25 ], [ 434, 290, 275, 27 ], [ 68, 319, 167, 25 ], [ 242, 319, 267, 26 ], [ 68, 368, 35, 17 ], [ 107, 368, 31, 17 ], [ 141, 368, 13, 17 ], [ 158, 368, 57, 17 ], [ 219, 368, 35, 17 ], [ 258, 368, 42, 17 ], [ 304, 368, 27, 17 ], [ 334, 368, 50, 17 ], [ 388, 368, 33, 17 ], [ 425, 368, 61, 17 ], [ 489, 368, 20, 17 ], [ 514, 368, 60, 17 ], [ 577, 368, 31, 17 ], [ 612, 368, 27, 17 ], [ 643, 368, 27, 17 ], [ 674, 368, 43, 17 ], [ 68, 408, 26, 17 ], [ 98, 408, 34, 17 ], [ 136, 408, 24, 17 ], [ 164, 408, 74, 17 ], [ 241, 408, 14, 17 ], [ 259, 408, 41, 17 ], [ 304, 408, 72, 17 ], [ 379, 408, 63, 17 ], [ 446, 408, 24, 17 ], [ 474, 408, 77, 17 ], [ 555, 408, 56, 17 ], [ 615, 408, 50, 17 ], [ 668, 408, 14, 17 ], [ 686, 408, 57, 17 ], [ 68, 432, 52, 17 ], [ 124, 432, 24, 17 ], [ 152, 432, 64, 17 ], [ 220, 432, 86, 17 ], [ 310, 432, 50, 17 ], [ 364, 432, 75, 17 ], [ 442, 432, 50, 17 ], [ 496, 432, 55, 17 ], [ 554, 432, 45, 17 ], [ 68, 455, 59, 17 ], [ 131, 455, 163, 17 ], [ 297, 455, 43, 17 ], [ 344, 455, 140, 17 ], [ 488, 455, 46, 17 ], [ 537, 455, 164, 17 ], [ 704, 455, 48, 17 ], [ 68, 479, 147, 17 ], [ 219, 479, 44, 17 ], [ 267, 479, 167, 17 ], [ 438, 479, 42, 17 ], [ 68, 520, 9, 17 ], [ 88, 520, 48, 17 ], [ 139, 520, 13, 17 ], [ 156, 520, 42, 17 ], [ 202, 520, 105, 17 ], [ 311, 520, 45, 17 ], [ 359, 520, 16, 17 ], [ 379, 520, 71, 17 ], [ 454, 520, 199, 17 ], [ 88, 543, 27, 17 ], [ 119, 543, 139, 17 ], [ 261, 543, 30, 17 ], [ 295, 543, 139, 17 ], [ 68, 583, 66, 17 ], [ 138, 583, 17, 17 ], [ 159, 583, 32, 17 ], [ 194, 583, 39, 17 ], [ 237, 583, 14, 17 ], [ 254, 583, 48, 17 ], [ 306, 583, 38, 17 ], [ 348, 583, 17, 17 ], [ 369, 583, 28, 17 ], [ 400, 583, 34, 17 ], [ 438, 583, 5, 17 ], [ 447, 583, 67, 17 ], [ 517, 583, 17, 17 ], [ 538, 583, 28, 17 ], [ 570, 583, 34, 17 ], [ 607, 583, 5, 17 ], [ 68, 607, 73, 17 ], [ 145, 607, 9, 17 ], [ 157, 607, 47, 17 ], [ 208, 607, 34, 17 ], [ 108, 673, 68, 17 ], [ 196, 674, 21, 17 ], [ 237, 674, 89, 17 ], [ 346, 674, 25, 17 ], [ 391, 674, 69, 17 ], [ 480, 674, 177, 17 ], [ 676, 674, 43, 17 ], [ 108, 697, 99, 17 ], [ 212, 697, 26, 17 ], [ 244, 697, 69, 17 ], [ 319, 697, 20, 17 ], [ 345, 697, 21, 17 ], [ 371, 697, 61, 17 ], [ 439, 697, 14, 17 ], [ 459, 697, 40, 17 ], [ 505, 697, 54, 17 ], [ 565, 697, 17, 17 ], [ 587, 697, 72, 17 ], [ 665, 697, 8, 17 ], [ 678, 697, 41, 17 ], [ 108, 721, 60, 17 ], [ 175, 721, 33, 17 ], [ 216, 721, 21, 17 ], [ 245, 721, 24, 17 ], [ 278, 721, 128, 17 ], [ 414, 721, 61, 17 ], [ 483, 721, 57, 17 ], [ 548, 721, 67, 17 ], [ 623, 721, 26, 17 ], [ 658, 721, 33, 17 ], [ 698, 721, 21, 17 ], [ 108, 745, 186, 18 ], [ 298, 745, 26, 17 ], [ 329, 745, 59, 17 ], [ 392, 745, 17, 17 ], [ 413, 745, 50, 17 ], [ 467, 741, 180, 21 ], [ 652, 745, 68, 17 ], [ 108, 768, 69, 17 ], [ 183, 768, 75, 17 ], [ 264, 768, 17, 17 ], [ 287, 768, 77, 18 ], [ 370, 768, 81, 17 ], [ 458, 768, 38, 18 ], [ 502, 768, 41, 17 ], [ 549, 768, 21, 17 ], [ 576, 768, 118, 18 ], [ 700, 768, 19, 17 ], [ 108, 792, 59, 17 ], [ 171, 792, 21, 17 ], [ 197, 792, 103, 17 ], [ 305, 792, 52, 17 ], [ 361, 792, 33, 17 ], [ 399, 792, 42, 17 ], [ 446, 792, 30, 17 ], [ 482, 792, 80, 17 ], [ 567, 792, 31, 17 ], [ 603, 792, 53, 17 ], [ 661, 792, 59, 17 ], [ 108, 815, 91, 17 ], [ 213, 815, 35, 17 ], [ 262, 815, 25, 17 ], [ 301, 815, 178, 17 ], [ 493, 815, 76, 17 ], [ 583, 815, 29, 17 ], [ 626, 815, 21, 17 ], [ 660, 815, 59, 17 ], [ 108, 839, 330, 17 ], [ 505, 839, 53, 17 ], [ 626, 839, 93, 17 ], [ 108, 863, 127, 17 ], [ 239, 863, 33, 17 ], [ 275, 863, 60, 17 ], [ 340, 863, 17, 17 ], [ 361, 863, 43, 17 ], [ 408, 863, 48, 17 ], [ 459, 863, 46, 17 ], [ 509, 863, 61, 17 ], [ 574, 863, 52, 17 ], [ 630, 863, 20, 17 ], [ 653, 863, 66, 17 ], [ 108, 886, 26, 17 ], [ 138, 886, 128, 17 ], [ 270, 886, 24, 17 ], [ 298, 886, 16, 17 ], [ 318, 886, 39, 17 ], [ 361, 886, 50, 17 ], [ 415, 886, 36, 17 ], [ 455, 886, 33, 17 ], [ 491, 886, 21, 17 ], [ 516, 886, 48, 17 ], [ 569, 886, 14, 17 ], [ 588, 886, 21, 17 ], [ 613, 886, 40, 17 ], [ 657, 886, 37, 17 ], [ 698, 886, 21, 17 ], [ 108, 910, 61, 17 ], [ 179, 910, 31, 17 ], [ 220, 910, 26, 17 ], [ 256, 910, 63, 17 ], [ 329, 910, 41, 17 ], [ 380, 910, 37, 17 ], [ 426, 910, 21, 17 ], [ 456, 910, 99, 17 ], [ 565, 910, 60, 17 ], [ 635, 910, 26, 17 ], [ 670, 910, 49, 17 ], [ 108, 934, 99, 17 ], [ 211, 934, 51, 17 ], [ 266, 934, 8, 17 ], [ 279, 934, 33, 17 ], [ 316, 934, 38, 17 ], [ 358, 934, 37, 17 ], [ 400, 934, 14, 17 ], [ 419, 934, 63, 17 ], [ 486, 934, 17, 17 ], [ 508, 930, 35, 21 ], [ 547, 934, 20, 17 ], [ 571, 934, 61, 17 ], [ 637, 934, 35, 17 ], [ 676, 934, 30, 17 ], [ 711, 934, 8, 17 ], [ 108, 958, 25, 17 ], [ 138, 958, 61, 17 ], [ 204, 958, 32, 17 ], [ 241, 958, 14, 17 ], [ 260, 958, 30, 17 ], [ 294, 958, 17, 17 ], [ 316, 954, 35, 21 ], [ 355, 958, 56, 17 ], [ 416, 958, 14, 17 ], [ 436, 958, 27, 17 ], [ 467, 958, 10, 17 ], [ 482, 958, 19, 17 ], [ 505, 958, 26, 17 ], [ 537, 958, 50, 17 ], [ 592, 958, 35, 17 ], [ 632, 958, 68, 17 ], [ 705, 958, 14, 17 ], [ 108, 981, 34, 17 ], [ 149, 981, 67, 17 ], [ 224, 981, 14, 17 ], [ 247, 981, 21, 17 ], [ 275, 981, 103, 17 ], [ 386, 981, 44, 17 ], [ 438, 981, 21, 17 ], [ 467, 981, 175, 18 ], [ 650, 981, 69, 17 ], [ 108, 1005, 63, 17 ], [ 178, 1005, 29, 17 ], [ 214, 1005, 89, 17 ], [ 310, 1005, 35, 17 ], [ 352, 1005, 32, 18 ], [ 391, 1005, 37, 17 ], [ 435, 1005, 29, 17 ], [ 472, 1005, 34, 17 ], [ 512, 1005, 50, 17 ], [ 570, 1005, 14, 17 ], [ 591, 1005, 53, 17 ], [ 651, 1005, 68, 17 ], [ 108, 1029, 41, 17 ], [ 154, 1029, 20, 17 ], [ 178, 1029, 40, 17 ], [ 224, 1029, 93, 17 ], [ 322, 1029, 34, 17 ], [ 361, 1029, 57, 17 ], [ 423, 1029, 37, 17 ], [ 465, 1029, 51, 17 ], [ 521, 1029, 8, 17 ], [ 534, 1029, 34, 17 ], [ 573, 1029, 40, 17 ], [ 618, 1029, 48, 17 ], [ 671, 1029, 14, 17 ], [ 690, 1029, 29, 17 ], [ 108, 1052, 35, 17 ], [ 148, 1052, 53, 17 ], [ 206, 1052, 68, 17 ], [ 279, 1052, 79, 17 ], [ 363, 1052, 87, 17 ], [ 455, 1052, 52, 17 ], [ 513, 1052, 21, 17 ], [ 539, 1052, 32, 17 ], [ 576, 1052, 59, 17 ], [ 640, 1052, 14, 17 ], [ 659, 1052, 30, 17 ], [ 695, 1052, 25, 17 ], [ 108, 1076, 99, 17 ], [ 212, 1076, 47, 17 ], [ 264, 1076, 8, 17 ], [ 277, 1076, 42, 17 ], [ 324, 1076, 32, 17 ], [ 360, 1076, 40, 17 ], [ 406, 1076, 26, 17 ], [ 437, 1076, 58, 17 ], [ 500, 1076, 25, 17 ], [ 530, 1076, 16, 17 ], [ 551, 1076, 89, 17 ], [ 646, 1076, 54, 17 ], [ 705, 1076, 14, 17 ] ]

[ "Sensors", "2011,", "11,", "7749-7762;", "doi:10.3390/s110807749", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "A", "Renewable", "and", "Ultrasensitive", "Electrochemiluminescence", "Immunosenor", "Based", "on", "Magnetic", "RuL@SiO2-Au~RuL-Ab2", "Sandwich-Type", "Nano-Immunocomplexes", "Ning", "Gan", "*,", "Jianguo", "Hou,", "Futao", "Hu,", "Yuting", "Cao,", "Tianhua", "Li,", "Zhiyong", "Guo", "and", "Jun", "Wang", "The", "State", "key", "Laboratory", "of", "Novel", "Functional", "Materials", "and", "Preparation", "Science,", "Faculty", "of", "Material", "Science", "and", "Chemical", "Engineering,", "Ningbo", "University,", "Ningbo", "315211,", "China;", "E-Mails:", "aaaguolong@gmail.com", "(J.H.);", "hufutao@nbu.edu.cn", "(F.H.);", "caoyuting001@126.com", "(Y.C.);", "litianhua@nbu.edu.cn", "(T.L.);", "guozhiyong@nbu.edu.cn", "(Z.G.)", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:ganning@nbu.edu.cn;", "Tel:", "+86-574-8760-9933.", "Fax:", "+86-574-8760-0734.", "Received:", "23", "June", "2011;", "in", "revised", "form:", "20", "July", "2011", "/", "Accepted:", "21", "July", "2011", "/", "Published:", "5", "August", "2011", "Abstract:", "An", "ultrasensitive", "and", "renewable", "electrochemiluminescence", "(ECL)", "immunosensor", "was", "developed", "for", "the", "detection", "of", "tumor", "markers", "by", "combining", "a", "newly", "designed", "trace", "tag", "and", "streptavidin-coated", "magnetic", "particles", "(SCMPs).", "The", "trace", "tag", "(RuL@SiO2-Au~RuL-Ab2)", "was", "prepared", "by", "loading", "Ru(bpy)32+(RuL)-conjuged", "secondary", "antibodies", "(RuL-Ab2)", "on", "RuL@SiO2", "(RuL-doped", "SiO2)", "doped", "Au", "(RuL@SiO2-Au).", "To", "fabricate", "the", "immunosensor,", "SCMPs", "were", "mixed", "with", "biotinylated", "AFP", "primary", "antibody", "(Biotin-Ab1),", "AFP,", "and", "RuL@SiO2-Au~RuL-Ab2", "complexes,", "then", "the", "resulting", "SCMP/Biotin-Ab1/AFP/RuL@SiO2-Au~RuL-Ab2", "(SBAR)", "sandwich-type", "immunocomplexes", "were", "absorbed", "on", "screen", "printed", "carbon", "electrode", "(SPCE)", "for", "detection.", "The", "immunocomplexes", "can", "be", "easily", "washed", "away", "from", "the", "surface", "of", "the", "SPCE", "when", "the", "magnetic", "field", "was", "removed,", "which", "made", "the", "immunosensor", "reusable.", "The", "present", "immunosensor", "showed", "a", "wide", "linear", "range", "of", "0.05–100", "ng", "mL–1", "for", "detecting", "AFP,", "with", "a", "low", "detection", "limit", "of", "0.02", "ng", "mL–1", "(defined", "as", "S/N", "=", "3).", "The", "method", "takes", "advantage", "of", "three", "properties", "of", "the", "immunosensor:", "firstly,", "the", "RuL@SiO2-Au~RuL-Ab2", "composite", "exhibited", "dual", "amplification", "since", "SiO2", "could", "load", "large", "amount", "of", "reporter", "molecules", "(RuL)", "for", "signal", "amplification.", "Gold", "particles", "could", "provide", "a", "large", "active", "surface", "to", "load", "more", "reporter", "molecules", "(RuL-Ab2).", "Accordingly,", "through", "the", "ECL", "response", "of", "RuL", "and", "tripropylamine", "(TPA),", "a", "strong", "ECL", "signal", "was", "obtained", "and", "an", "amplification", "analysis", "of" ]

[ 0, 0, 0, 0, 0, 9, 9, 9, 0, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5 ]

[ [ 90, 49, 53, 12 ], [ 145, 49, 9, 12 ], [ 155, 49, 11, 12 ], [ 168, 49, 32, 12 ], [ 201, 49, 21, 12 ], [ 224, 49, 25, 12 ], [ 251, 49, 32, 12 ], [ 90, 63, 176, 12 ], [ 96, 128, 11, 19 ], [ 108, 128, 14, 19 ], [ 123, 128, 16, 19 ], [ 141, 128, 16, 19 ], [ 158, 128, 10, 19 ], [ 170, 128, 13, 19 ], [ 185, 128, 23, 19 ], [ 209, 128, 11, 19 ], [ 222, 128, 11, 19 ], [ 90, 170, 174, 34 ], [ 271, 170, 61, 34 ], [ 338, 170, 75, 34 ], [ 419, 170, 25, 34 ], [ 451, 170, 73, 34 ], [ 530, 170, 144, 34 ], [ 90, 206, 100, 34 ], [ 196, 206, 140, 34 ], [ 342, 206, 120, 34 ], [ 468, 206, 91, 34 ], [ 566, 206, 78, 34 ], [ 90, 242, 168, 34 ], [ 264, 242, 51, 34 ], [ 322, 242, 140, 34 ], [ 90, 290, 28, 16 ], [ 121, 290, 72, 16 ], [ 195, 290, 28, 16 ], [ 227, 290, 17, 16 ], [ 246, 290, 28, 16 ], [ 276, 290, 23, 16 ], [ 302, 290, 43, 16 ], [ 347, 290, 31, 16 ], [ 90, 318, 18, 13 ], [ 110, 318, 33, 13 ], [ 145, 318, 40, 13 ], [ 188, 318, 12, 13 ], [ 202, 318, 28, 13 ], [ 232, 318, 9, 13 ], [ 243, 318, 13, 13 ], [ 258, 318, 174, 13 ], [ 99, 385, 55, 15 ], [ 99, 406, 72, 14 ], [ 174, 406, 26, 14 ], [ 202, 406, 32, 14 ], [ 237, 406, 19, 14 ], [ 259, 406, 29, 14 ], [ 290, 406, 54, 14 ], [ 347, 406, 12, 14 ], [ 361, 406, 7, 14 ], [ 99, 422, 39, 14 ], [ 141, 422, 11, 14 ], [ 155, 422, 41, 14 ], [ 199, 422, 45, 14 ], [ 246, 422, 51, 14 ], [ 299, 422, 12, 14 ], [ 314, 422, 56, 14 ], [ 373, 422, 22, 14 ], [ 99, 439, 51, 14 ], [ 152, 439, 11, 14 ], [ 166, 439, 45, 14 ], [ 214, 439, 25, 14 ], [ 241, 439, 31, 14 ], [ 275, 439, 60, 14 ], [ 337, 439, 41, 14 ], [ 99, 456, 59, 14 ], [ 160, 456, 29, 14 ], [ 192, 456, 17, 14 ], [ 211, 456, 40, 14 ], [ 254, 456, 13, 14 ], [ 269, 456, 50, 14 ], [ 322, 456, 30, 14 ], [ 355, 456, 22, 14 ], [ 99, 472, 58, 14 ], [ 160, 472, 11, 14 ], [ 173, 472, 38, 14 ], [ 214, 472, 47, 14 ], [ 90, 524, 34, 14 ], [ 130, 524, 63, 14 ], [ 198, 524, 43, 14 ], [ 246, 524, 57, 14 ], [ 308, 524, 45, 14 ], [ 358, 524, 9, 14 ], [ 373, 524, 43, 14 ], [ 90, 541, 39, 14 ], [ 134, 541, 14, 14 ], [ 153, 541, 39, 14 ], [ 196, 541, 45, 14 ], [ 246, 541, 44, 14 ], [ 295, 541, 22, 14 ], [ 322, 541, 55, 14 ], [ 381, 541, 34, 14 ], [ 90, 557, 47, 14 ], [ 142, 557, 26, 14 ], [ 171, 557, 32, 14 ], [ 208, 557, 51, 14 ], [ 263, 557, 51, 14 ], [ 318, 557, 56, 14 ], [ 379, 557, 14, 14 ], [ 397, 557, 19, 14 ], [ 90, 574, 94, 14 ], [ 187, 574, 86, 14 ], [ 277, 574, 89, 14 ], [ 369, 574, 46, 14 ], [ 90, 591, 54, 14 ], [ 149, 591, 20, 14 ], [ 174, 591, 24, 14 ], [ 203, 591, 12, 14 ], [ 220, 591, 19, 14 ], [ 244, 591, 59, 14 ], [ 308, 591, 41, 14 ], [ 354, 591, 17, 14 ], [ 376, 591, 39, 14 ], [ 90, 607, 55, 14 ], [ 148, 607, 38, 14 ], [ 190, 607, 10, 14 ], [ 203, 607, 40, 14 ], [ 246, 607, 12, 14 ], [ 262, 607, 19, 14 ], [ 284, 607, 94, 14 ], [ 381, 607, 12, 14 ], [ 397, 607, 19, 14 ], [ 90, 624, 57, 14 ], [ 151, 624, 22, 14 ], [ 176, 624, 56, 14 ], [ 235, 624, 26, 14 ], [ 264, 624, 19, 14 ], [ 286, 624, 45, 14 ], [ 334, 624, 12, 14 ], [ 350, 624, 25, 14 ], [ 379, 624, 37, 14 ], [ 90, 641, 51, 14 ], [ 144, 641, 12, 14 ], [ 160, 641, 57, 14 ], [ 220, 641, 22, 14 ], [ 245, 641, 41, 14 ], [ 290, 641, 53, 14 ], [ 346, 641, 13, 14 ], [ 362, 641, 21, 14 ], [ 387, 641, 28, 14 ], [ 90, 657, 12, 14 ], [ 107, 657, 44, 14 ], [ 155, 657, 31, 14 ], [ 191, 657, 33, 14 ], [ 229, 657, 22, 14 ], [ 256, 657, 59, 14 ], [ 319, 657, 19, 14 ], [ 344, 657, 12, 14 ], [ 360, 657, 14, 14 ], [ 379, 657, 36, 14 ], [ 90, 674, 46, 14 ], [ 140, 674, 31, 14 ], [ 175, 674, 53, 14 ], [ 231, 674, 14, 14 ], [ 250, 674, 84, 14 ], [ 337, 674, 62, 14 ], [ 404, 674, 12, 14 ], [ 90, 691, 46, 14 ], [ 142, 691, 26, 14 ], [ 175, 691, 37, 14 ], [ 218, 691, 36, 14 ], [ 261, 691, 19, 14 ], [ 286, 691, 23, 14 ], [ 315, 691, 12, 14 ], [ 334, 691, 38, 14 ], [ 379, 691, 12, 14 ], [ 397, 691, 19, 14 ], [ 90, 707, 43, 14 ], [ 140, 707, 12, 14 ], [ 160, 707, 22, 14 ], [ 189, 707, 45, 14 ], [ 241, 707, 14, 14 ], [ 263, 707, 35, 14 ], [ 306, 707, 12, 14 ], [ 326, 707, 41, 14 ], [ 374, 707, 41, 14 ], [ 90, 724, 45, 14 ], [ 138, 724, 22, 14 ], [ 163, 724, 50, 14 ], [ 217, 724, 22, 14 ], [ 241, 724, 14, 14 ], [ 259, 724, 35, 14 ], [ 297, 724, 30, 14 ], [ 331, 724, 12, 14 ], [ 346, 724, 7, 14 ], [ 357, 724, 59, 14 ], [ 90, 741, 50, 14 ], [ 143, 741, 12, 14 ], [ 157, 741, 39, 14 ], [ 101, 757, 19, 14 ], [ 123, 757, 19, 14 ], [ 144, 757, 23, 14 ], [ 170, 757, 39, 14 ], [ 212, 757, 34, 14 ], [ 248, 757, 22, 14 ], [ 273, 757, 59, 14 ], [ 334, 757, 16, 14 ], [ 353, 757, 36, 14 ], [ 392, 757, 23, 14 ], [ 90, 774, 46, 14 ], [ 140, 774, 26, 14 ], [ 170, 774, 37, 14 ], [ 211, 774, 38, 14 ], [ 254, 774, 40, 14 ], [ 298, 774, 57, 14 ], [ 359, 774, 22, 14 ], [ 385, 774, 30, 14 ], [ 90, 791, 36, 14 ], [ 130, 791, 41, 14 ], [ 175, 791, 26, 14 ], [ 205, 791, 40, 14 ], [ 250, 791, 30, 14 ], [ 283, 791, 35, 14 ], [ 323, 791, 35, 14 ], [ 362, 791, 22, 14 ], [ 388, 791, 28, 14 ], [ 90, 807, 21, 14 ], [ 114, 807, 30, 14 ], [ 148, 807, 12, 14 ], [ 163, 807, 41, 14 ], [ 207, 807, 25, 14 ], [ 235, 807, 19, 14 ], [ 258, 807, 34, 14 ], [ 294, 807, 46, 14 ], [ 344, 807, 18, 14 ], [ 365, 807, 12, 14 ], [ 380, 807, 36, 14 ], [ 90, 824, 34, 14 ], [ 128, 824, 26, 14 ], [ 159, 824, 19, 14 ], [ 182, 824, 49, 14 ], [ 235, 824, 53, 14 ], [ 293, 824, 31, 14 ], [ 328, 824, 35, 14 ], [ 368, 824, 48, 14 ], [ 90, 841, 23, 14 ], [ 116, 841, 38, 14 ], [ 158, 841, 9, 14 ], [ 170, 841, 7, 14 ], [ 180, 841, 29, 14 ], [ 213, 841, 53, 14 ], [ 269, 841, 12, 14 ], [ 284, 841, 53, 14 ], [ 341, 841, 26, 14 ], [ 370, 841, 14, 14 ], [ 388, 841, 28, 14 ], [ 90, 857, 27, 14 ], [ 121, 857, 12, 14 ], [ 136, 857, 17, 14 ], [ 157, 857, 19, 14 ], [ 180, 857, 54, 14 ], [ 238, 857, 30, 14 ], [ 272, 857, 9, 14 ], [ 285, 857, 21, 14 ], [ 310, 857, 15, 14 ], [ 328, 857, 25, 14 ], [ 357, 857, 58, 14 ], [ 90, 874, 15, 14 ], [ 112, 874, 14, 14 ], [ 133, 874, 32, 14 ], [ 172, 874, 12, 14 ], [ 190, 874, 42, 14 ], [ 239, 874, 36, 14 ], [ 281, 874, 22, 14 ], [ 310, 874, 19, 14 ], [ 335, 874, 24, 14 ], [ 366, 874, 50, 14 ], [ 90, 891, 59, 14 ], [ 153, 891, 21, 14 ], [ 177, 891, 51, 14 ], [ 232, 891, 35, 14 ], [ 270, 891, 13, 14 ], [ 286, 891, 55, 14 ], [ 345, 891, 29, 14 ], [ 377, 891, 38, 14 ], [ 90, 935, 72, 11 ], [ 164, 935, 112, 11 ], [ 90, 948, 49, 11 ], [ 141, 948, 8, 11 ], [ 151, 948, 22, 11 ], [ 175, 948, 27, 11 ], [ 204, 948, 18, 11 ], [ 224, 948, 3, 11 ], [ 229, 948, 21, 11 ], [ 252, 948, 16, 11 ], [ 269, 948, 8, 11 ], [ 279, 948, 33, 11 ], [ 313, 948, 18, 11 ], [ 332, 948, 46, 11 ], [ 379, 948, 21, 11 ], [ 90, 960, 8, 11 ], [ 100, 960, 33, 11 ], [ 134, 960, 34, 11 ], [ 170, 960, 12, 11 ], [ 184, 960, 20, 11 ], [ 206, 960, 16, 11 ], [ 223, 960, 23, 11 ], [ 248, 960, 36, 11 ], [ 286, 960, 25, 11 ], [ 313, 960, 22, 11 ], [ 337, 960, 33, 11 ], [ 371, 960, 15, 11 ], [ 388, 960, 18, 11 ], [ 90, 973, 27, 11 ], [ 119, 973, 37, 11 ], [ 90, 1009, 7, 10 ], [ 98, 1009, 18, 10 ], [ 118, 1009, 28, 10 ], [ 147, 1009, 26, 10 ], [ 175, 1009, 12, 10 ], [ 262, 1009, 7, 10 ], [ 270, 1009, 18, 10 ], [ 290, 1009, 28, 10 ], [ 320, 1009, 26, 10 ], [ 347, 1009, 12, 10 ], [ 435, 374, 13, 14 ], [ 457, 374, 63, 14 ], [ 529, 374, 33, 14 ], [ 571, 374, 47, 14 ], [ 628, 374, 40, 14 ], [ 677, 374, 35, 14 ], [ 722, 374, 38, 14 ], [ 435, 391, 39, 14 ], [ 479, 391, 14, 14 ], [ 499, 391, 68, 14 ], [ 572, 391, 33, 14 ], [ 612, 391, 22, 14 ], [ 639, 391, 59, 14 ], [ 704, 391, 16, 14 ], [ 726, 391, 34, 14 ], [ 435, 407, 23, 14 ], [ 461, 407, 38, 14 ], [ 502, 407, 45, 14 ], [ 550, 407, 12, 14 ], [ 565, 407, 48, 14 ], [ 616, 407, 29, 14 ], [ 648, 407, 38, 14 ], [ 689, 407, 46, 14 ], [ 738, 407, 12, 14 ], [ 753, 407, 7, 14 ], [ 435, 424, 48, 14 ], [ 490, 424, 64, 14 ], [ 560, 424, 26, 14 ], [ 593, 424, 53, 14 ], [ 653, 424, 25, 14 ], [ 684, 424, 33, 14 ], [ 724, 424, 36, 14 ], [ 435, 441, 28, 14 ], [ 472, 441, 49, 14 ], [ 531, 441, 41, 14 ], [ 582, 441, 40, 14 ], [ 632, 441, 48, 14 ], [ 689, 441, 23, 14 ], [ 722, 441, 38, 14 ], [ 435, 457, 45, 14 ], [ 485, 457, 12, 14 ], [ 502, 457, 55, 14 ], [ 562, 457, 29, 14 ], [ 596, 457, 38, 14 ], [ 640, 457, 40, 14 ], [ 685, 457, 10, 14 ], [ 700, 457, 7, 14 ], [ 712, 457, 48, 14 ], [ 435, 474, 53, 14 ], [ 493, 474, 12, 14 ], [ 509, 474, 53, 14 ], [ 567, 474, 19, 14 ], [ 591, 474, 12, 14 ], [ 607, 474, 62, 14 ], [ 674, 474, 48, 14 ], [ 727, 474, 33, 14 ], [ 435, 491, 37, 14 ], [ 477, 491, 16, 14 ], [ 499, 491, 22, 14 ], [ 526, 491, 17, 14 ], [ 549, 491, 19, 14 ], [ 573, 491, 53, 14 ], [ 632, 491, 12, 14 ], [ 650, 491, 36, 14 ], [ 691, 491, 41, 14 ], [ 738, 491, 22, 14 ], [ 435, 507, 65, 14 ], [ 504, 507, 51, 14 ], [ 559, 507, 17, 14 ], [ 580, 507, 31, 14 ], [ 615, 507, 55, 14 ], [ 674, 507, 29, 14 ], [ 708, 507, 38, 14 ], [ 750, 507, 9, 14 ], [ 435, 524, 23, 14 ], [ 464, 524, 25, 14 ], [ 495, 524, 22, 14 ], [ 523, 524, 22, 14 ], [ 550, 524, 26, 14 ], [ 582, 524, 38, 14 ], [ 626, 524, 43, 14 ], [ 675, 524, 15, 14 ], [ 696, 524, 36, 14 ], [ 738, 524, 22, 14 ], [ 435, 541, 40, 14 ], [ 478, 541, 5, 14 ], [ 488, 541, 22, 14 ], [ 513, 541, 52, 14 ], [ 570, 541, 55, 14 ], [ 628, 541, 29, 14 ], [ 661, 541, 38, 14 ], [ 703, 541, 5, 14 ], [ 713, 541, 47, 14 ], [ 435, 557, 52, 14 ], [ 492, 557, 38, 14 ], [ 536, 557, 17, 14 ], [ 558, 557, 48, 14 ], [ 611, 557, 29, 14 ], [ 645, 557, 38, 14 ], [ 689, 557, 24, 14 ], [ 719, 557, 24, 14 ], [ 748, 557, 12, 14 ], [ 435, 574, 58, 14 ], [ 496, 574, 66, 14 ], [ 566, 574, 12, 14 ], [ 581, 574, 38, 14 ], [ 623, 574, 12, 14 ], [ 638, 574, 33, 14 ], [ 674, 574, 49, 14 ], [ 727, 574, 33, 14 ], [ 435, 591, 27, 14 ], [ 464, 591, 41, 14 ], [ 508, 591, 24, 14 ], [ 535, 591, 14, 14 ], [ 551, 591, 14, 14 ], [ 568, 591, 67, 14 ], [ 638, 591, 45, 14 ], [ 686, 591, 35, 14 ], [ 724, 591, 26, 14 ], [ 753, 591, 7, 14 ], [ 435, 607, 73, 14 ], [ 510, 607, 25, 14 ], [ 538, 607, 45, 14 ], [ 585, 607, 24, 14 ], [ 612, 607, 43, 14 ], [ 659, 607, 32, 14 ], [ 693, 607, 38, 14 ], [ 735, 607, 5, 14 ], [ 743, 607, 17, 14 ], [ 435, 624, 51, 14 ], [ 490, 624, 14, 14 ], [ 508, 624, 61, 14 ], [ 573, 624, 19, 14 ], [ 596, 624, 79, 14 ], [ 680, 624, 33, 14 ], [ 717, 624, 43, 14 ], [ 435, 641, 41, 14 ], [ 482, 641, 13, 14 ], [ 502, 641, 19, 14 ], [ 527, 641, 57, 14 ], [ 590, 641, 54, 14 ], [ 651, 641, 12, 14 ], [ 669, 641, 38, 14 ], [ 714, 641, 46, 14 ], [ 435, 657, 55, 14 ], [ 498, 657, 93, 14 ], [ 599, 657, 22, 14 ], [ 630, 657, 40, 14 ], [ 678, 657, 57, 14 ], [ 744, 657, 16, 14 ], [ 435, 674, 38, 14 ], [ 477, 674, 9, 14 ], [ 490, 674, 58, 14 ], [ 552, 674, 12, 14 ], [ 569, 674, 19, 14 ], [ 591, 674, 57, 14 ], [ 652, 674, 48, 14 ], [ 705, 674, 19, 14 ], [ 727, 674, 33, 14 ], [ 435, 691, 47, 14 ], [ 490, 691, 45, 14 ], [ 545, 691, 42, 14 ], [ 596, 691, 22, 14 ], [ 627, 691, 33, 14 ], [ 669, 691, 20, 14 ], [ 699, 691, 41, 14 ], [ 748, 691, 12, 14 ], [ 435, 707, 63, 14 ], [ 500, 707, 55, 14 ], [ 558, 707, 22, 14 ], [ 582, 707, 32, 14 ], [ 617, 707, 21, 14 ], [ 640, 707, 32, 14 ], [ 675, 707, 40, 14 ], [ 446, 724, 13, 14 ], [ 461, 724, 50, 14 ], [ 514, 724, 18, 14 ], [ 535, 724, 67, 14 ], [ 605, 724, 48, 14 ], [ 655, 724, 38, 14 ], [ 695, 724, 21, 14 ], [ 720, 724, 40, 14 ], [ 435, 741, 47, 14 ], [ 489, 741, 22, 14 ], [ 518, 741, 38, 14 ], [ 564, 741, 22, 14 ], [ 593, 741, 53, 14 ], [ 654, 741, 24, 14 ], [ 686, 741, 36, 14 ], [ 730, 741, 30, 14 ], [ 435, 757, 72, 14 ], [ 509, 757, 20, 14 ], [ 532, 757, 64, 14 ], [ 598, 757, 71, 14 ], [ 446, 774, 30, 14 ], [ 477, 774, 43, 14 ], [ 523, 774, 24, 14 ], [ 549, 774, 49, 14 ], [ 600, 774, 19, 14 ], [ 621, 774, 45, 14 ], [ 668, 774, 12, 14 ], [ 682, 774, 78, 14 ], [ 435, 791, 45, 14 ], [ 485, 791, 30, 14 ], [ 520, 791, 80, 14 ], [ 605, 791, 22, 14 ], [ 632, 791, 27, 14 ], [ 664, 791, 12, 14 ], [ 681, 791, 38, 14 ], [ 724, 791, 12, 14 ], [ 741, 791, 19, 14 ], [ 435, 807, 63, 14 ], [ 503, 807, 33, 14 ], [ 541, 807, 43, 14 ], [ 589, 807, 20, 14 ], [ 613, 807, 28, 14 ], [ 646, 807, 27, 14 ], [ 678, 807, 12, 14 ], [ 696, 807, 14, 14 ], [ 715, 807, 45, 14 ], [ 435, 824, 32, 14 ], [ 470, 824, 12, 14 ], [ 486, 824, 63, 14 ], [ 553, 824, 47, 14 ], [ 604, 824, 72, 14 ], [ 680, 824, 12, 14 ], [ 695, 824, 50, 14 ], [ 749, 824, 11, 14 ], [ 435, 841, 46, 14 ], [ 484, 841, 29, 14 ], [ 516, 841, 13, 14 ], [ 533, 841, 11, 14 ], [ 547, 841, 22, 14 ], [ 572, 841, 15, 14 ], [ 591, 841, 36, 14 ], [ 630, 841, 19, 14 ], [ 653, 841, 26, 14 ], [ 682, 841, 42, 14 ], [ 727, 841, 32, 14 ], [ 435, 857, 43, 14 ], [ 484, 857, 12, 14 ], [ 503, 857, 44, 14 ], [ 553, 857, 26, 14 ], [ 585, 857, 63, 14 ], [ 655, 857, 72, 14 ], [ 734, 857, 26, 14 ], [ 435, 874, 33, 14 ], [ 474, 874, 22, 14 ], [ 501, 874, 59, 14 ], [ 566, 874, 16, 14 ], [ 588, 874, 30, 14 ], [ 624, 874, 23, 14 ], [ 652, 874, 21, 14 ], [ 679, 874, 27, 14 ], [ 712, 874, 35, 14 ], [ 753, 874, 7, 14 ], [ 435, 891, 34, 14 ], [ 473, 891, 41, 14 ], [ 518, 891, 12, 14 ], [ 533, 891, 41, 14 ], [ 578, 891, 45, 14 ], [ 626, 891, 12, 14 ], [ 641, 891, 46, 14 ], [ 690, 891, 26, 14 ], [ 720, 891, 7, 14 ], [ 730, 891, 30, 14 ], [ 435, 907, 35, 14 ], [ 475, 907, 32, 14 ], [ 513, 907, 28, 14 ], [ 547, 907, 45, 14 ], [ 598, 907, 50, 14 ], [ 654, 907, 23, 14 ], [ 683, 907, 46, 14 ], [ 734, 907, 26, 14 ], [ 435, 924, 36, 14 ], [ 475, 924, 36, 14 ], [ 515, 924, 26, 14 ], [ 545, 924, 40, 14 ], [ 590, 924, 25, 14 ], [ 619, 924, 49, 14 ], [ 672, 924, 46, 14 ], [ 722, 924, 21, 14 ], [ 748, 924, 12, 14 ], [ 435, 941, 40, 14 ], [ 481, 941, 63, 14 ], [ 550, 941, 75, 14 ], [ 630, 941, 22, 14 ], [ 658, 941, 40, 14 ], [ 704, 941, 56, 14 ], [ 435, 957, 61, 14 ], [ 502, 957, 70, 14 ], [ 577, 957, 40, 14 ], [ 623, 957, 12, 14 ], [ 641, 957, 46, 14 ], [ 692, 957, 26, 14 ], [ 724, 957, 36, 14 ], [ 435, 974, 27, 14 ], [ 468, 974, 56, 14 ], [ 531, 974, 23, 14 ], [ 561, 974, 46, 14 ], [ 614, 974, 26, 14 ], [ 647, 974, 36, 14 ], [ 690, 974, 36, 14 ], [ 733, 974, 26, 14 ], [ 435, 991, 40, 14 ], [ 479, 991, 78, 14 ], [ 560, 991, 45, 14 ], [ 609, 991, 22, 14 ], [ 634, 991, 26, 14 ], [ 664, 991, 42, 14 ], [ 709, 991, 7, 14 ], [ 719, 991, 41, 14 ], [ 435, 1007, 51, 14 ], [ 496, 1007, 12, 14 ], [ 519, 1007, 25, 14 ], [ 555, 1007, 69, 14 ], [ 635, 1007, 22, 14 ], [ 667, 1007, 37, 14 ], [ 715, 1007, 45, 14 ] ]

[ "Camporota", "et", "al.", "Critical", "Care", "2012,", "16:114", "http://ccforum.com/content/16/1/114", "C", "O", "M", "M", "E", "N", "TA", "R", "Y", "Extravascular", "lung", "water", "in", "acute", "respiratory", "distress", "syndrome:", "potential", "clinical", "value,", "assumptions", "and", "limitations", "Luigi", "Camporota*,", "Mark", "De", "Neef", "and", "Richard", "Beale", "See", "related", "research", "by", "Chew", "et", "al.,", "http://ccforum.com/content/16/1/R1", "Abstract", "Extravascular", "lung", "water", "has", "been", "proposed", "as", "a", "marker", "of", "disease", "severity,", "response", "to", "treatment", "and", "mortality", "in", "patients", "with", "acute", "respiratory", "distress", "syndrome.", "Here,", "we", "discuss", "its", "potential", "value", "and", "limitations", "in", "clinical", "practice.", "Acute", "respiratory", "distress", "syndrome", "(ARDS)", "is", "charac-", "terised", "by", "diffuse", "alveolar", "damage", "and", "increased", "extra-", "vascular", "lung", "water", "(EVLW),", "clinically", "measured", "by", "the", "trans-pulmonary", "single-indicator", "thermo-dilution", "method.", "Although", "not", "part", "of", "the", "diagnostic", "criteria", "for", "ARDS,", "increased", "EVLW", "is", "central", "to", "the", "pathophysiology", "of", "the", "syndrome", "and", "correlates", "with", "the", "severity", "of", "lung", "injury,", "response", "to", "treatment", "and", "clinical", "outcome.", "In", "this", "issue", "of", "Critical", "Care,", "Chew", "and", "colleagues", "[1],", "in", "an", "obser-", "vational", "study", "involving", "an", "heterogeneous", "population", "of", "patients", "with", "shock,", "report", "the", "role", "of", "EVLW", "in", "the", "context", "of", "two", "themes:", "its", "ability", "to", "predict", "disease", "severity", "and", "outcome", "and", "its", "added", "value", "as", "a", "diagnostic", "criterion", "of", "ARDS.", "On", "the", "first", "theme,", "Chew", "and", "colleagues", "[1]", "report", "that", "patients", "with", "higher", "EVLW", "indices", "(EVLWIs)", "had", "more", "severe", "disease", "with", "greater", "Lung", "Injury", "Score,", "and", "were", "less", "likely", "to", "survive", "ICU", "[1].", "These", "findings", "are", "in", "accor-", "dance", "with", "the", "available", "literature", "[2-4],", "which", "suggests", "that", "EVLW", "is", "a", "good", "predictor", "of", "mortality", "with", "an", "odds", "ratio", "of", "8.8", "[5].", "However,", "there", "is", "still", "no", "firm", "consensus", "on", "its", "range", "of", "normal", "values", "and", "the", "best", "indexing", "parameter", "(for", "example,", "actual", "or", "predicted", "body", "weight", "*Correspondence:", "luigi.camporota@gstt.nhs.uk", "Department", "of", "Adult", "Critical", "Care", "-", "Guy’s", "and", "St", "Thomas’", "NHS", "Foundation", "Trust,", "St", "Thomas’", "Hospital,", "1st", "Floor", "East", "Wing,", "Lambeth", "Palace", "Road,", "London,", "SE1", "7EH,", "United", "Kingdom", "©", "2010", "BioMed", "Central", "Ltd", "©", "2012", "BioMed", "Central", "Ltd", "or", "pulmonary", "blood", "volume)", "against", "which", "EVLW", "should", "be", "normalised.", "Chew", "and", "colleagues", "[1]", "found", "that", "EVLW", "indexed", "to", "absolute", "body", "weight", "resulted", "in", "a", "stronger", "association", "with", "outcome.", "This", "result", "differs", "from", "previous", "clinical", "studies", "showing", "that", "EVLW", "indexed", "to", "predicted", "body", "weight", "(PBW)", "is", "a", "superior", "predictor", "of", "mortality", "[6],", "of", "developing", "multiple", "organ", "failure", "[2]", "and", "for", "the", "diagnosis", "of", "ARDS", "[4,6-8].", "The", "physiologic", "rationale", "for", "using", "predicted", "body", "weight", "is", "that", "lung", "size", "and", "lung", "weight", "depend", "on", "height", "and", "gender", "-", "and", "therefore", "predicted", "body", "weight", "-", "whereas", "adjusting", "EVLW", "for", "absolute", "body", "weight", "may", "lead", "to", "erroneous", "estimations", "of", "EVLW", "in", "obese", "patients.", "How-", "ever,", "obesity", "may", "be", "an", "explanatory", "variable", "rather", "than", "a", "confounding", "one.", "Obesity", "may", "directly", "affect", "EVLW", "-", "for", "example,", "by", "decreasing", "the", "intra-thoracic", "blood", "volume", "(ITBV)", "or", "the", "lymphatic", "clearance", "of", "EVLW", "through", "increased", "intra-abdominal", "and", "pleural", "pressures.", "As", "EVLW", "is", "calculated", "as", "the", "difference", "between", "the", "intra-", "thoracic", "thermal", "volume", "and", "ITBV,", "any", "change", "in", "pulmonary", "perfusion", "and", "ITBV", "will", "affect", "EVLW.", "In", "addition,", "the", "relationship", "between", "EVLW", "and", "disease", "severity,", "and", "EVLW", "and", "outcome,", "may", "reflect", "three", "independent", "but", "concurrent", "possibilities.", "First,", "EVLWI", "may", "measure", "the", "amount", "of", "inflammatory", "oedema", "(high", "permeability).", "The", "ratio", "of", "EVLW", "to", "the", "pulmonary", "blood", "volume", "has", "been", "used", "as", "an", "indirect", "index", "of", "pulmonary", "vascular", "permeability", "in", "critically", "ill", "patients", "with,", "or", "at", "risk", "of,", "ARDS", "[9],", "with", "normal", "ratios", "helping", "to", "exclude", "high", "pulmonary", "permeability", "[10].", "Chew", "and", "colleagues", "[1]", "show", "that", "this", "ratio", "seems", "a", "better", "marker", "of", "disease", "severity", "in", "patients", "with", "a", "Lung", "Injury", "Score", ">2.5,", "perhaps", "implying", "that", "patients", "with", "severe", "ARDS", "have", "greater", "lung", "oedema,", "possibly", "due", "to", "greater", "pulmonary", "permeability,", "and", "greater", "mortality.", "Computed", "tomography", "studies", "of", "patients", "with", "ARDS", "have", "suggested", "that", "patients", "with", "severe", "ARDS", "have", "greater", "inflammatory", "oedema", "and", "lung", "weight,", "a", "greater", "response", "to", "lung", "recruitment", "and", "higher", "positive" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 56, 35, 77, 45 ], [ 81, 59, 58, 20 ], [ 69, 113, 103, 30 ], [ 195, 113, 17, 30 ], [ 219, 113, 20, 30 ], [ 246, 113, 90, 30 ], [ 343, 113, 37, 30 ], [ 388, 113, 115, 30 ], [ 510, 113, 46, 30 ], [ 563, 113, 190, 30 ], [ 69, 147, 62, 30 ], [ 139, 147, 158, 30 ], [ 305, 147, 48, 30 ], [ 360, 147, 161, 30 ], [ 69, 182, 25, 30 ], [ 101, 182, 41, 30 ], [ 150, 182, 131, 30 ], [ 289, 182, 71, 30 ], [ 69, 243, 45, 16 ], [ 117, 243, 34, 16 ], [ 155, 243, 24, 16 ], [ 182, 243, 43, 16 ], [ 228, 243, 65, 16 ], [ 69, 273, 60, 14 ], [ 132, 273, 11, 14 ], [ 146, 273, 75, 14 ], [ 223, 273, 21, 14 ], [ 247, 273, 50, 14 ], [ 300, 273, 22, 14 ], [ 325, 273, 60, 14 ], [ 388, 273, 58, 14 ], [ 449, 273, 26, 14 ], [ 478, 273, 29, 14 ], [ 509, 273, 19, 14 ], [ 531, 273, 35, 14 ], [ 30, 436, 12, 0 ], [ 30, 447, 12, 0 ], [ 30, 459, 13, 0 ], [ 30, 465, 7, 0 ], [ 30, 478, 13, 0 ], [ 30, 484, 7, 0 ], [ 30, 498, 14, 0 ], [ 30, 510, 7, 0 ], [ 30, 516, 7, 0 ], [ 30, 527, 12, 0 ], [ 30, 542, 15, 0 ], [ 30, 554, 7, 0 ], [ 30, 567, 13, 0 ], [ 30, 579, 7, 0 ], [ 30, 590, 12, 0 ], [ 30, 603, 13, 0 ], [ 30, 610, 8, 0 ], [ 30, 622, 13, 0 ], [ 30, 635, 13, 0 ], [ 30, 641, 7, 0 ], [ 30, 658, 12, 0 ], [ 30, 670, 13, 0 ], [ 30, 683, 13, 0 ], [ 65, 337, 50, 58 ], [ 122, 356, 45, 14 ], [ 175, 356, 21, 14 ], [ 203, 356, 45, 14 ], [ 255, 356, 22, 14 ], [ 285, 356, 50, 14 ], [ 342, 356, 61, 14 ], [ 93, 340, 45, 14 ], [ 141, 340, 18, 14 ], [ 162, 340, 80, 14 ], [ 245, 340, 70, 14 ], [ 318, 340, 36, 14 ], [ 357, 340, 46, 14 ], [ 93, 372, 61, 14 ], [ 158, 372, 12, 14 ], [ 182, 372, 12, 14 ], [ 207, 372, 12, 14 ], [ 223, 372, 22, 14 ], [ 257, 372, 8, 14 ], [ 269, 372, 42, 14 ], [ 316, 372, 10, 14 ], [ 329, 372, 7, 14 ], [ 341, 372, 35, 14 ], [ 380, 372, 23, 14 ], [ 69, 388, 20, 14 ], [ 93, 388, 67, 14 ], [ 165, 388, 12, 14 ], [ 181, 388, 19, 14 ], [ 205, 388, 60, 14 ], [ 270, 388, 46, 14 ], [ 321, 388, 40, 14 ], [ 366, 388, 37, 14 ], [ 69, 404, 14, 14 ], [ 88, 404, 63, 14 ], [ 157, 404, 19, 14 ], [ 180, 404, 23, 14 ], [ 209, 404, 12, 14 ], [ 226, 404, 45, 14 ], [ 277, 404, 12, 14 ], [ 294, 404, 19, 14 ], [ 318, 404, 29, 14 ], [ 352, 404, 18, 14 ], [ 375, 404, 28, 14 ], [ 69, 420, 19, 14 ], [ 95, 420, 52, 14 ], [ 153, 420, 39, 14 ], [ 198, 420, 11, 14 ], [ 216, 420, 39, 14 ], [ 261, 420, 18, 14 ], [ 286, 420, 44, 14 ], [ 343, 420, 8, 14 ], [ 357, 420, 28, 14 ], [ 391, 420, 11, 14 ], [ 69, 436, 52, 14 ], [ 125, 436, 30, 14 ], [ 158, 436, 33, 14 ], [ 195, 436, 28, 14 ], [ 228, 436, 27, 14 ], [ 259, 436, 71, 14 ], [ 334, 436, 47, 14 ], [ 385, 436, 18, 14 ], [ 69, 452, 47, 14 ], [ 120, 452, 11, 14 ], [ 135, 452, 45, 14 ], [ 191, 452, 8, 14 ], [ 202, 452, 12, 14 ], [ 218, 452, 53, 14 ], [ 275, 452, 31, 14 ], [ 310, 452, 36, 14 ], [ 350, 452, 38, 14 ], [ 391, 452, 12, 14 ], [ 69, 468, 7, 14 ], [ 82, 468, 40, 14 ], [ 128, 468, 55, 14 ], [ 188, 468, 11, 14 ], [ 205, 468, 44, 14 ], [ 263, 468, 8, 14 ], [ 276, 468, 22, 14 ], [ 311, 468, 8, 14 ], [ 325, 468, 41, 14 ], [ 370, 468, 33, 14 ], [ 69, 484, 28, 14 ], [ 100, 484, 39, 14 ], [ 143, 484, 34, 14 ], [ 180, 484, 40, 14 ], [ 223, 484, 35, 14 ], [ 261, 484, 25, 14 ], [ 289, 484, 11, 14 ], [ 304, 484, 26, 14 ], [ 333, 484, 17, 14 ], [ 354, 484, 49, 14 ], [ 69, 556, 100, 19 ], [ 69, 579, 69, 15 ], [ 141, 579, 12, 15 ], [ 156, 579, 35, 15 ], [ 195, 579, 9, 15 ], [ 207, 579, 46, 15 ], [ 257, 579, 16, 15 ], [ 277, 579, 37, 15 ], [ 318, 579, 48, 15 ], [ 369, 579, 12, 15 ], [ 385, 579, 18, 15 ], [ 69, 595, 43, 15 ], [ 115, 595, 40, 15 ], [ 158, 595, 81, 15 ], [ 242, 595, 14, 15 ], [ 258, 595, 47, 15 ], [ 308, 595, 29, 15 ], [ 340, 595, 63, 15 ], [ 69, 611, 42, 15 ], [ 114, 611, 11, 15 ], [ 129, 611, 34, 15 ], [ 166, 611, 56, 15 ], [ 225, 611, 13, 15 ], [ 241, 611, 18, 15 ], [ 262, 611, 55, 15 ], [ 320, 611, 43, 15 ], [ 366, 611, 37, 15 ], [ 69, 627, 39, 15 ], [ 114, 627, 44, 15 ], [ 163, 627, 11, 15 ], [ 180, 627, 32, 15 ], [ 217, 627, 17, 15 ], [ 239, 627, 56, 15 ], [ 300, 627, 37, 15 ], [ 343, 627, 60, 15 ], [ 69, 643, 77, 15 ], [ 153, 643, 29, 15 ], [ 188, 643, 32, 15 ], [ 227, 643, 86, 15 ], [ 320, 643, 52, 15 ], [ 378, 643, 24, 15 ], [ 69, 659, 44, 15 ], [ 118, 659, 28, 15 ], [ 151, 659, 44, 15 ], [ 200, 659, 14, 15 ], [ 219, 659, 55, 15 ], [ 278, 659, 50, 15 ], [ 334, 659, 46, 15 ], [ 385, 659, 18, 15 ], [ 69, 675, 35, 15 ], [ 108, 675, 68, 15 ], [ 180, 675, 51, 15 ], [ 235, 675, 24, 15 ], [ 263, 675, 47, 15 ], [ 314, 675, 6, 15 ], [ 325, 675, 18, 15 ], [ 347, 675, 26, 15 ], [ 377, 675, 25, 15 ], [ 69, 690, 34, 15 ], [ 106, 690, 21, 15 ], [ 130, 690, 42, 15 ], [ 175, 690, 29, 15 ], [ 207, 690, 11, 15 ], [ 221, 690, 6, 15 ], [ 231, 690, 38, 15 ], [ 271, 690, 38, 15 ], [ 313, 690, 90, 15 ], [ 69, 706, 51, 15 ], [ 125, 706, 24, 15 ], [ 153, 706, 37, 15 ], [ 195, 706, 66, 15 ], [ 265, 706, 50, 15 ], [ 320, 706, 46, 15 ], [ 371, 706, 32, 15 ], [ 69, 722, 21, 15 ], [ 93, 722, 44, 15 ], [ 140, 722, 33, 15 ], [ 176, 722, 19, 15 ], [ 198, 722, 15, 15 ], [ 216, 722, 19, 15 ], [ 238, 722, 28, 15 ], [ 269, 722, 6, 15 ], [ 278, 722, 38, 15 ], [ 320, 722, 36, 15 ], [ 358, 722, 44, 15 ], [ 69, 738, 21, 15 ], [ 93, 738, 37, 15 ], [ 133, 738, 37, 15 ], [ 81, 754, 23, 15 ], [ 111, 754, 32, 15 ], [ 150, 754, 18, 15 ], [ 175, 754, 27, 15 ], [ 208, 754, 60, 15 ], [ 274, 754, 12, 15 ], [ 292, 754, 68, 15 ], [ 366, 754, 12, 15 ], [ 384, 754, 18, 15 ], [ 69, 770, 27, 15 ], [ 101, 770, 18, 15 ], [ 125, 770, 40, 15 ], [ 170, 770, 38, 15 ], [ 213, 770, 21, 15 ], [ 240, 770, 49, 15 ], [ 294, 770, 17, 15 ], [ 316, 770, 69, 15 ], [ 391, 770, 12, 15 ], [ 69, 786, 18, 15 ], [ 90, 786, 32, 15 ], [ 126, 786, 23, 15 ], [ 152, 786, 37, 15 ], [ 193, 786, 12, 15 ], [ 209, 786, 13, 15 ], [ 225, 786, 53, 15 ], [ 282, 786, 61, 15 ], [ 346, 786, 41, 15 ], [ 391, 786, 12, 15 ], [ 69, 802, 19, 15 ], [ 92, 802, 40, 15 ], [ 135, 802, 26, 15 ], [ 165, 802, 54, 15 ], [ 222, 802, 23, 15 ], [ 249, 802, 44, 15 ], [ 296, 802, 28, 15 ], [ 329, 802, 6, 15 ], [ 339, 802, 38, 15 ], [ 381, 802, 22, 15 ], [ 69, 818, 12, 15 ], [ 85, 818, 68, 15 ], [ 157, 818, 37, 15 ], [ 199, 818, 11, 15 ], [ 214, 818, 17, 15 ], [ 236, 818, 33, 15 ], [ 274, 818, 92, 15 ], [ 370, 818, 11, 15 ], [ 385, 818, 17, 15 ], [ 69, 834, 33, 15 ], [ 107, 834, 92, 15 ], [ 205, 834, 11, 15 ], [ 221, 834, 17, 15 ], [ 243, 834, 33, 15 ], [ 282, 834, 43, 15 ], [ 331, 834, 11, 15 ], [ 347, 834, 17, 15 ], [ 369, 834, 33, 15 ], [ 69, 850, 37, 15 ], [ 112, 850, 21, 15 ], [ 139, 850, 65, 15 ], [ 210, 850, 38, 15 ], [ 254, 850, 13, 15 ], [ 273, 850, 24, 15 ], [ 303, 850, 39, 15 ], [ 348, 850, 26, 15 ], [ 380, 850, 22, 15 ], [ 69, 866, 52, 15 ], [ 123, 866, 22, 15 ], [ 148, 866, 43, 15 ], [ 193, 866, 9, 15 ], [ 205, 866, 59, 15 ], [ 266, 866, 57, 15 ], [ 326, 866, 12, 15 ], [ 340, 866, 18, 15 ], [ 361, 866, 42, 15 ], [ 78, 882, 8, 15 ], [ 88, 882, 26, 15 ], [ 117, 882, 12, 15 ], [ 132, 882, 27, 15 ], [ 162, 882, 33, 15 ], [ 198, 882, 21, 15 ], [ 222, 881, 47, 17 ], [ 272, 882, 17, 15 ], [ 292, 882, 10, 15 ], [ 305, 882, 17, 15 ], [ 325, 882, 33, 15 ], [ 361, 882, 41, 15 ], [ 69, 929, 36, 12 ], [ 108, 929, 71, 12 ], [ 182, 929, 10, 12 ], [ 195, 929, 30, 12 ], [ 227, 929, 48, 12 ], [ 278, 929, 49, 12 ], [ 329, 929, 10, 12 ], [ 341, 929, 62, 12 ], [ 69, 943, 17, 12 ], [ 90, 943, 43, 12 ], [ 137, 943, 19, 12 ], [ 160, 943, 51, 12 ], [ 215, 943, 51, 12 ], [ 269, 943, 24, 12 ], [ 297, 943, 23, 12 ], [ 323, 943, 24, 12 ], [ 351, 943, 22, 12 ], [ 377, 943, 25, 12 ], [ 69, 958, 16, 12 ], [ 88, 958, 33, 12 ], [ 123, 958, 22, 12 ], [ 148, 958, 26, 12 ], [ 176, 958, 49, 12 ], [ 227, 958, 20, 12 ], [ 249, 958, 26, 12 ], [ 277, 958, 49, 12 ], [ 69, 972, 28, 12 ], [ 100, 972, 121, 12 ], [ 69, 990, 18, 12 ], [ 90, 990, 31, 12 ], [ 123, 990, 42, 12 ], [ 167, 990, 22, 12 ], [ 192, 990, 35, 12 ], [ 229, 990, 44, 12 ], [ 276, 990, 55, 12 ], [ 334, 990, 30, 12 ], [ 69, 1025, 9, 12 ], [ 80, 1026, 18, 12 ], [ 101, 1026, 48, 12 ], [ 151, 1026, 45, 12 ], [ 198, 1026, 24, 12 ], [ 225, 1026, 124, 12 ], [ 351, 1026, 25, 12 ], [ 69, 1037, 18, 12 ], [ 89, 1037, 32, 12 ], [ 123, 1037, 9, 12 ], [ 135, 1037, 18, 12 ], [ 155, 1037, 36, 12 ], [ 193, 1037, 34, 12 ], [ 230, 1037, 20, 12 ], [ 252, 1037, 37, 12 ], [ 291, 1037, 9, 12 ], [ 302, 1037, 46, 12 ], [ 350, 1037, 14, 12 ], [ 367, 1037, 23, 12 ], [ 392, 1037, 39, 12 ], [ 69, 1049, 224, 12 ], [ 427, 340, 22, 14 ], [ 453, 340, 40, 14 ], [ 498, 340, 40, 14 ], [ 542, 340, 78, 14 ], [ 625, 340, 52, 14 ], [ 681, 340, 26, 14 ], [ 711, 340, 22, 14 ], [ 737, 340, 24, 14 ], [ 427, 356, 44, 14 ], [ 482, 356, 8, 14 ], [ 494, 356, 29, 14 ], [ 527, 356, 42, 14 ], [ 574, 356, 12, 14 ], [ 590, 356, 59, 14 ], [ 653, 356, 41, 14 ], [ 699, 356, 22, 14 ], [ 725, 356, 36, 14 ], [ 427, 372, 36, 14 ], [ 469, 372, 22, 14 ], [ 496, 372, 62, 14 ], [ 563, 372, 54, 14 ], [ 622, 372, 39, 14 ], [ 666, 372, 11, 14 ], [ 683, 372, 41, 14 ], [ 729, 372, 32, 14 ], [ 427, 388, 55, 14 ], [ 486, 388, 25, 14 ], [ 514, 388, 28, 14 ], [ 547, 388, 39, 14 ], [ 590, 388, 12, 14 ], [ 605, 388, 68, 14 ], [ 677, 388, 22, 14 ], [ 702, 388, 59, 14 ], [ 427, 404, 39, 14 ], [ 469, 404, 50, 14 ], [ 522, 404, 22, 14 ], [ 546, 404, 51, 14 ], [ 600, 404, 39, 14 ], [ 643, 404, 12, 14 ], [ 657, 404, 21, 14 ], [ 681, 404, 22, 14 ], [ 706, 404, 55, 14 ], [ 427, 420, 37, 14 ], [ 468, 420, 11, 14 ], [ 483, 420, 40, 14 ], [ 527, 420, 32, 14 ], [ 563, 420, 25, 14 ], [ 592, 420, 36, 14 ], [ 632, 420, 32, 14 ], [ 667, 420, 35, 14 ], [ 706, 420, 18, 14 ], [ 728, 420, 34, 14 ], [ 427, 436, 44, 14 ], [ 475, 436, 51, 14 ], [ 530, 436, 75, 14 ], [ 607, 436, 33, 14 ], [ 644, 436, 69, 14 ], [ 717, 436, 45, 14 ], [ 427, 452, 30, 14 ], [ 461, 452, 22, 14 ], [ 487, 452, 44, 14 ], [ 535, 452, 9, 14 ], [ 548, 452, 15, 14 ], [ 566, 452, 49, 14 ], [ 619, 452, 65, 14 ], [ 687, 452, 16, 14 ], [ 707, 452, 28, 14 ], [ 739, 452, 22, 14 ], [ 427, 468, 50, 14 ], [ 481, 468, 22, 14 ], [ 506, 468, 71, 14 ], [ 580, 468, 12, 14 ], [ 595, 468, 18, 14 ], [ 616, 468, 28, 14 ], [ 427, 579, 11, 15 ], [ 444, 579, 17, 15 ], [ 468, 579, 34, 15 ], [ 508, 579, 12, 15 ], [ 527, 579, 45, 15 ], [ 578, 579, 41, 15 ], [ 626, 579, 94, 15 ], [ 727, 579, 11, 15 ], [ 744, 579, 17, 15 ], [ 427, 595, 34, 15 ], [ 465, 595, 31, 15 ], [ 500, 595, 12, 15 ], [ 515, 595, 51, 15 ], [ 570, 595, 56, 15 ], [ 630, 595, 21, 15 ], [ 655, 595, 6, 15 ], [ 665, 595, 35, 15 ], [ 704, 595, 57, 15 ], [ 427, 611, 68, 15 ], [ 498, 611, 34, 15 ], [ 536, 611, 48, 15 ], [ 587, 611, 21, 15 ], [ 611, 611, 53, 15 ], [ 667, 611, 33, 15 ], [ 704, 611, 43, 15 ], [ 750, 611, 11, 15 ], [ 427, 627, 17, 15 ], [ 450, 627, 33, 15 ], [ 488, 627, 42, 15 ], [ 536, 627, 11, 15 ], [ 552, 627, 17, 15 ], [ 575, 627, 38, 15 ], [ 618, 627, 13, 15 ], [ 636, 627, 21, 15 ], [ 663, 627, 26, 15 ], [ 694, 627, 43, 15 ], [ 743, 627, 18, 15 ], [ 427, 643, 57, 15 ], [ 488, 643, 22, 15 ], [ 513, 643, 31, 15 ], [ 547, 643, 18, 15 ], [ 568, 643, 43, 15 ], [ 614, 643, 18, 15 ], [ 636, 643, 60, 15 ], [ 699, 643, 9, 15 ], [ 711, 643, 6, 15 ], [ 720, 643, 40, 15 ], [ 427, 659, 37, 15 ], [ 467, 659, 12, 15 ], [ 483, 659, 35, 15 ], [ 521, 659, 15, 15 ], [ 540, 659, 18, 15 ], [ 561, 659, 30, 15 ], [ 595, 659, 21, 15 ], [ 620, 659, 18, 15 ], [ 641, 659, 39, 15 ], [ 684, 659, 42, 15 ], [ 730, 659, 11, 15 ], [ 744, 659, 17, 15 ], [ 427, 675, 37, 15 ], [ 468, 675, 34, 15 ], [ 505, 675, 48, 15 ], [ 556, 675, 57, 15 ], [ 617, 675, 6, 15 ], [ 626, 675, 44, 15 ], [ 673, 675, 21, 15 ], [ 698, 675, 16, 15 ], [ 717, 675, 44, 15 ], [ 427, 690, 12, 15 ], [ 442, 690, 68, 15 ], [ 513, 690, 31, 15 ], [ 547, 690, 28, 15 ], [ 578, 690, 18, 15 ], [ 599, 690, 65, 15 ], [ 667, 690, 23, 15 ], [ 702, 690, 8, 15 ], [ 713, 690, 48, 15 ], [ 427, 706, 6, 15 ], [ 439, 706, 64, 15 ], [ 509, 706, 12, 15 ], [ 526, 706, 32, 15 ], [ 563, 706, 44, 15 ], [ 613, 706, 55, 15 ], [ 673, 706, 9, 15 ], [ 687, 706, 52, 15 ], [ 744, 706, 16, 15 ], [ 427, 722, 38, 15 ], [ 468, 722, 68, 15 ], [ 538, 722, 12, 15 ], [ 553, 722, 57, 15 ], [ 613, 722, 35, 15 ], [ 651, 722, 35, 15 ], [ 689, 722, 11, 15 ], [ 703, 722, 17, 15 ], [ 723, 722, 38, 15 ], [ 440, 738, 33, 15 ], [ 477, 738, 34, 15 ], [ 515, 738, 39, 15 ], [ 558, 738, 22, 15 ], [ 585, 738, 42, 15 ], [ 631, 738, 33, 15 ], [ 668, 738, 13, 15 ], [ 686, 738, 55, 15 ], [ 745, 738, 16, 15 ], [ 427, 754, 67, 15 ], [ 500, 754, 12, 15 ], [ 518, 754, 56, 15 ], [ 580, 754, 38, 15 ], [ 625, 754, 19, 15 ], [ 651, 754, 18, 15 ], [ 675, 754, 63, 15 ], [ 745, 754, 16, 15 ], [ 427, 770, 42, 15 ], [ 473, 770, 34, 15 ], [ 511, 770, 11, 15 ], [ 526, 770, 23, 15 ], [ 553, 770, 18, 15 ], [ 575, 770, 19, 15 ], [ 598, 770, 26, 15 ], [ 628, 770, 58, 15 ], [ 690, 770, 51, 15 ], [ 745, 770, 16, 15 ], [ 427, 786, 77, 15 ], [ 507, 786, 44, 15 ], [ 554, 786, 55, 15 ], [ 612, 786, 11, 15 ], [ 627, 786, 14, 15 ], [ 653, 786, 4, 15 ], [ 668, 786, 4, 15 ], [ 676, 786, 21, 15 ], [ 711, 786, 33, 15 ], [ 748, 786, 14, 15 ], [ 427, 802, 43, 15 ], [ 473, 802, 20, 15 ], [ 508, 802, 38, 15 ], [ 549, 802, 28, 15 ], [ 592, 802, 38, 15 ], [ 633, 802, 21, 15 ], [ 657, 802, 28, 15 ], [ 699, 802, 34, 15 ], [ 736, 802, 25, 15 ], [ 427, 818, 26, 15 ], [ 456, 818, 55, 15 ], [ 513, 818, 21, 15 ], [ 537, 818, 11, 15 ], [ 551, 818, 17, 15 ], [ 571, 818, 43, 15 ], [ 616, 818, 15, 15 ], [ 633, 818, 48, 15 ], [ 684, 818, 43, 15 ], [ 729, 818, 32, 15 ], [ 427, 834, 27, 15 ], [ 457, 834, 22, 15 ], [ 482, 834, 30, 15 ], [ 516, 834, 13, 15 ], [ 532, 834, 52, 15 ], [ 587, 834, 27, 15 ], [ 618, 834, 27, 15 ], [ 648, 834, 38, 15 ], [ 689, 834, 15, 15 ], [ 707, 834, 25, 15 ], [ 735, 834, 26, 15 ], [ 427, 850, 47, 15 ], [ 480, 850, 62, 15 ], [ 548, 850, 21, 15 ], [ 575, 850, 62, 15 ], [ 642, 850, 32, 15 ], [ 680, 850, 43, 15 ], [ 728, 850, 10, 15 ], [ 745, 850, 16, 15 ], [ 427, 866, 36, 15 ], [ 467, 866, 47, 15 ], [ 525, 866, 8, 15 ], [ 536, 866, 30, 15 ], [ 569, 866, 9, 15 ], [ 581, 866, 20, 15 ], [ 605, 866, 11, 15 ], [ 620, 866, 18, 15 ], [ 641, 866, 27, 15 ], [ 671, 866, 52, 15 ], [ 727, 866, 34, 15 ], [ 427, 882, 21, 15 ], [ 451, 882, 9, 15 ], [ 462, 882, 39, 15 ], [ 505, 882, 11, 15 ], [ 519, 882, 13, 15 ], [ 535, 882, 38, 15 ], [ 576, 882, 42, 15 ], [ 621, 882, 46, 15 ], [ 670, 882, 35, 15 ], [ 707, 882, 54, 15 ], [ 427, 898, 21, 15 ], [ 453, 898, 47, 15 ], [ 504, 898, 36, 15 ], [ 544, 898, 47, 15 ], [ 596, 898, 10, 15 ], [ 611, 898, 16, 15 ], [ 632, 898, 36, 15 ], [ 673, 898, 46, 15 ], [ 724, 898, 37, 15 ], [ 427, 914, 25, 15 ], [ 455, 914, 36, 15 ], [ 494, 914, 22, 15 ], [ 519, 914, 33, 15 ], [ 555, 914, 56, 15 ], [ 614, 914, 11, 15 ], [ 628, 914, 42, 15 ], [ 681, 914, 8, 15 ], [ 692, 914, 25, 15 ], [ 720, 914, 27, 15 ], [ 750, 914, 12, 15 ], [ 427, 930, 26, 15 ], [ 456, 930, 35, 15 ], [ 493, 930, 58, 15 ], [ 554, 930, 44, 15 ], [ 600, 930, 40, 15 ], [ 644, 930, 10, 15 ], [ 657, 930, 16, 15 ], [ 676, 930, 36, 15 ], [ 427, 963, 64, 12 ], [ 494, 963, 21, 12 ], [ 517, 963, 10, 12 ], [ 530, 963, 17, 12 ], [ 549, 963, 29, 12 ], [ 581, 963, 40, 12 ], [ 628, 963, 4, 12 ], [ 634, 963, 126, 12 ], [ 427, 976, 21, 12 ], [ 451, 976, 34, 12 ], [ 488, 976, 29, 12 ], [ 519, 976, 8, 12 ], [ 538, 976, 4, 12 ], [ 544, 976, 28, 12 ], [ 575, 976, 32, 12 ], [ 609, 976, 23, 12 ], [ 635, 976, 37, 12 ], [ 675, 975, 22, 14 ], [ 700, 976, 45, 12 ], [ 748, 976, 13, 12 ], [ 427, 989, 38, 12 ], [ 468, 989, 25, 12 ], [ 495, 989, 46, 12 ], [ 544, 989, 36, 12 ], [ 583, 989, 34, 12 ], [ 742, 1049, 17, 12 ] ]

[ "JCB", "Article", "Laminin", "1", "is", "critical", "for", "Schwann", "cell", "differentiation,", "axon", "myelination,", "and", "regeneration", "in", "the", "peripheral", "nerve", "Zu-Lin", "Chen", "and", "Sidney", "Strickland", "Laboratory", "of", "Neurobiology", "and", "Genetics,", "The", "Rockefeller", "University,", "New", "York,", "NY", "10021", "y", "g", "o", "l", "o", "i", "B", "l", "l", "e", "C", "f", "o", "l", "a", "n", "r", "u", "o", "J", "e", "h", "T", "Lthat", "regulate", "cell", "viability", "and", "function.", "Laminin-2,", "aminins", "are", "heterotrimeric", "extracellular", "matrix", "proteins", "composed", "of", "2,", "1,", "and", "1", "chains,", "is", "a", "major", "ma-", "trix", "component", "of", "the", "peripheral", "nervous", "system", "(PNS).", "To", "investigate", "the", "role", "of", "laminin", "in", "the", "PNS,", "we", "used", "the", "Cre–loxP", "system", "to", "disrupt", "the", "laminin", "1", "gene", "in", "Schwann", "cells.", "These", "mice", "have", "dramatically", "reduced", "ex-", "pression", "of", "laminin", "1", "in", "Schwann", "cells,", "which", "results", "in", "a", "similar", "reduction", "in", "laminin", "2", "and", "1", "chains.", "These", "mice", "exhibit", "motor", "defects", "which", "lead", "to", "hind", "leg", "paralysis", "Introduction", "Myelination", "of", "nerves", "is", "essential", "for", "proper", "function", "of", "the", "nervous", "system,", "predominantly", "by", "allowing", "faster", "conduction", "velocity", "of", "action", "potentials.", "In", "the", "peripheral", "nervous", "system", "(PNS),", "bundles", "of", "axons", "are", "assembled", "during", "embryonic", "development.", "After", "birth,", "premyelinating", "Schwann", "cells", "separate", "these", "bundles", "by", "extending", "processes", "between", "the", "axons.", "Myelinating", "Schwann", "cells", "establish", "a", "1:1", "ratio", "with", "axons,", "and", "envelop", "them", "in", "a", "myelin", "sheath.", "Nonmyelinating", "Schwann", "cells", "extend", "cytoplasmic", "processes", "between", "axons", "and", "separate", "them,", "but", "do", "not", "form", "a", "myelin", "sheath", "(Mirsky", "and", "Jessen,", "1999).", "The", "ECM", "has", "been", "implicated", "in", "myelination", "in", "the", "PNS", "(R.", "Bunge,", "1993),", "and", "laminins", "are", "components", "of", "the", "ECM", "that", "appear", "to", "be", "especially", "important.", "Studies", "in", "cell", "culture", "have", "suggested", "that", "laminin", "plays", "a", "critical", "role", "in", "myelination", "(Doyu", "et", "al.,", "1993;", "Fernandez-Valle", "et", "al.,", "1993;", "Fernandez-Valle", "et", "al.,", "1994;", "Podratz", "et", "al.,", "2001;", "Tsiper", "and", "Yurchenco,", "2002).", "In", "vivo", "studies", "have", "also", "suggested", "that", "laminin", "is", "important.", "Mutations", "in", "the", "laminin", "2", "gene", "in", "mice", "(dy/dy", "and", "dy2J/dy2J;", "Xu", "et", "al.,", "1994;", "Sunada", "Address", "correspondence", "to", "Sidney", "Strickland,", "Laboratory", "of", "Neurobiology", "and", "Genetics,", "The", "Rockefeller", "University,", "1230", "York", "Ave.,", "New", "York,", "NY", "10021.", "Tel.:", "(212)", "327-8705.", "Fax:", "(212)", "327-8774.", "email:", "strickland@rockefeller.edu", "Key", "words:", "paralysis;", "axon", "sorting;", "Cre-loxP;", "extracellular", "matrix", "", "The", "Rockefeller", "University", "Press,", "0021-9525/2003/11/889/11", "$8.00", "The", "Journal", "of", "Cell", "Biology,", "Volume", "163,", "Number", "4,", "November", "24,", "2003", "889–899", "http://www.jcb.org/cgi/doi/10.1083/jcb.200307068", "and", "tremor.", "During", "development,", "Schwann", "cells", "that", "lack", "laminin", "1", "were", "present", "in", "peripheral", "nerves,", "and", "prolif-", "erated", "and", "underwent", "apoptosis", "similar", "to", "control", "mice.", "However,", "they", "were", "unable", "to", "differentiate", "and", "synthesize", "myelin", "proteins,", "and", "therefore", "unable", "to", "sort", "and", "myelinate", "axons.", "In", "mutant", "mice,", "after", "sciatic", "nerve", "crush,", "the", "axons", "showed", "impaired", "regeneration.", "These", "experiments", "demon-", "strate", "that", "laminin", "is", "an", "essential", "component", "for", "axon", "my-", "elination", "and", "regeneration", "in", "the", "PNS.", "et", "al.,", "1995)", "or", "humans", "(CMD;", "Helbling-Leclerc", "et", "al.,", "1995)", "result", "in", "muscular", "dystrophy", "and", "a", "minor", "peripheral", "myelination", "defect", "(Bradley", "and", "Jenkison,", "1973;", "Madrid", "et", "al.,", "1975;", "Perkins", "et", "al.,", "1981).", "In", "this", "case,", "because", "the", "mutations", "also", "affect", "the", "muscle,", "the", "phenotype", "is", "a", "combi-", "nation", "of", "effects", "on", "the", "nerve", "and", "the", "muscle", "(Kuang", "et", "al.,", "1998).", "Other", "evidence", "suggesting", "a", "possible", "role", "for", "laminin", "in", "myelination", "stems", "from", "the", "observation", "that", "1", "integrin,", "a", "component", "of", "many", "laminin", "receptors,", "is", "necessary", "for", "proper", "myelination", "of", "peripheral", "nerves", "(Feltri", "et", "al.,", "2002).", "These", "results", "suggest", "that", "laminin", "might", "be", "important", "for", "myelination", "of", "peripheral", "nerves,", "but", "the", "mechanism", "for", "laminin", "action", "in", "vivo", "has", "not", "been", "elucidated.", "Laminins", "are", "heterotrimeric", "proteins", "composed", "of", "an", ",", ",", "and", "chain.", "At", "present,", "five", "chains,", "three", "chains,", "and", "three", "chains", "have", "been", "identified,", "and", "of", "the", "possible", "45", "potential", "trimeric", "mole-", "cules", "that", "could", "be", "generated", "from", "these", "chains,", "15", "have", "been", "observed", "(Colognato", "and", "Yurchenco,", "2000;", "Grimpe", "et", "al.,", "2002).", "Laminin", "1", "chain", "is", "one", "of", "the", "most", "abundant", "chains", "and", "is", "present", "in", "all", "known", "laminin", "isoforms", "except", "laminin-5", "and", "laminins", "12–15", "(Grimpe", "et", "al.,", "2002).", "Previous", "studies", "have", "shown", "that", "global", "disruption", "of", "laminin", "1", "gene", "leads", "to", "early", "(E5.5)", "embryonic", "lethality", "(Smyth", "et", "al.,", "1999).", "Abbreviations", "used", "in", "this", "paper:", "CaMKII", ",", "calcium/calmodulin-depen-", "dent", "protein", "kinase", "II", ";", "MBP,", "myelin", "basic", "protein;", "neoR,", "neomycin", "re-", "sistance;", "PNS,", "peripheral", "nervous", "system.", "889" ]

[ 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 17, 17, 17, 17, 17, 17, 17, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4 ]

[ [ 80, 78, 56, 28 ], [ 143, 78, 108, 28 ], [ 257, 78, 134, 28 ], [ 397, 78, 41, 28 ], [ 443, 78, 93, 28 ], [ 543, 78, 84, 28 ], [ 633, 78, 24, 28 ], [ 662, 78, 15, 28 ], [ 683, 78, 86, 28 ], [ 80, 109, 76, 28 ], [ 165, 109, 25, 28 ], [ 199, 109, 101, 28 ], [ 309, 109, 105, 28 ], [ 80, 152, 41, 14 ], [ 125, 150, 51, 17 ], [ 180, 152, 52, 14 ], [ 236, 150, 55, 17 ], [ 294, 152, 14, 14 ], [ 312, 152, 35, 14 ], [ 346, 150, 7, 10 ], [ 352, 152, 4, 14 ], [ 360, 152, 36, 14 ], [ 400, 152, 13, 14 ], [ 417, 150, 57, 17 ], [ 477, 152, 39, 14 ], [ 520, 152, 17, 14 ], [ 541, 150, 73, 17 ], [ 618, 152, 13, 14 ], [ 635, 152, 35, 14 ], [ 673, 150, 47, 17 ], [ 724, 152, 45, 14 ], [ 80, 169, 77, 17 ], [ 162, 172, 41, 14 ], [ 207, 172, 10, 14 ], [ 221, 169, 63, 17 ], [ 80, 194, 6, 10 ], [ 88, 194, 50, 10 ], [ 140, 194, 9, 10 ], [ 151, 194, 45, 10 ], [ 198, 194, 23, 10 ], [ 223, 194, 25, 10 ], [ 250, 194, 43, 10 ], [ 295, 194, 45, 10 ], [ 342, 194, 28, 10 ], [ 372, 194, 25, 10 ], [ 400, 194, 9, 10 ], [ 410, 194, 36, 10 ], [ 449, 194, 6, 10 ], [ 456, 194, 33, 10 ], [ 491, 194, 9, 10 ], [ 502, 194, 40, 10 ], [ 544, 194, 37, 10 ], [ 584, 194, 41, 10 ], [ 627, 194, 40, 10 ], [ 670, 194, 34, 10 ], [ 706, 194, 32, 10 ], [ 740, 194, 30, 10 ], [ 80, 208, 43, 10 ], [ 125, 208, 22, 10 ], [ 149, 208, 28, 10 ], [ 179, 208, 25, 10 ], [ 206, 208, 9, 10 ], [ 216, 208, 36, 10 ], [ 254, 208, 6, 10 ], [ 261, 208, 50, 10 ], [ 313, 208, 9, 10 ], [ 323, 208, 43, 10 ], [ 368, 208, 16, 10 ], [ 386, 208, 55, 10 ], [ 442, 208, 23, 10 ], [ 467, 208, 25, 10 ], [ 494, 208, 43, 10 ], [ 538, 208, 45, 10 ], [ 585, 208, 28, 10 ], [ 615, 208, 25, 10 ], [ 642, 208, 9, 10 ], [ 652, 208, 36, 10 ], [ 690, 208, 6, 10 ], [ 697, 208, 34, 10 ], [ 733, 208, 37, 10 ], [ 80, 222, 30, 10 ], [ 112, 222, 41, 10 ], [ 156, 222, 40, 10 ], [ 199, 222, 34, 10 ], [ 235, 222, 32, 10 ], [ 269, 222, 30, 10 ], [ 301, 222, 43, 10 ], [ 346, 222, 22, 10 ], [ 371, 222, 28, 10 ], [ 401, 222, 25, 10 ], [ 429, 222, 9, 10 ], [ 440, 222, 36, 10 ], [ 478, 222, 6, 10 ], [ 485, 222, 50, 10 ], [ 537, 222, 9, 10 ], [ 548, 222, 43, 10 ], [ 594, 222, 16, 10 ], [ 612, 222, 29, 10 ], [ 643, 222, 59, 10 ], [ 705, 222, 33, 10 ], [ 740, 222, 30, 10 ], [ 80, 236, 41, 10 ], [ 124, 236, 9, 10 ], [ 135, 236, 31, 10 ], [ 169, 236, 31, 10 ], [ 203, 236, 19, 10 ], [ 224, 236, 21, 10 ], [ 248, 236, 28, 10 ], [ 278, 236, 25, 10 ], [ 306, 236, 9, 10 ], [ 318, 236, 34, 10 ], [ 102, 275, 57, 14 ], [ 102, 296, 36, 13 ], [ 141, 296, 47, 13 ], [ 191, 296, 10, 13 ], [ 204, 296, 44, 13 ], [ 250, 296, 44, 13 ], [ 296, 296, 24, 13 ], [ 322, 296, 46, 13 ], [ 371, 296, 22, 13 ], [ 395, 296, 31, 13 ], [ 429, 296, 25, 13 ], [ 456, 296, 46, 13 ], [ 505, 296, 23, 13 ], [ 531, 296, 30, 13 ], [ 563, 296, 10, 13 ], [ 575, 296, 28, 13 ], [ 606, 296, 37, 13 ], [ 646, 296, 36, 13 ], [ 684, 296, 41, 13 ], [ 728, 296, 20, 13 ], [ 102, 310, 23, 13 ], [ 130, 310, 11, 13 ], [ 146, 310, 19, 13 ], [ 170, 310, 24, 13 ], [ 199, 310, 29, 13 ], [ 233, 310, 20, 13 ], [ 258, 310, 11, 13 ], [ 274, 310, 55, 13 ], [ 333, 310, 44, 13 ], [ 382, 310, 57, 13 ], [ 444, 310, 38, 13 ], [ 486, 310, 25, 13 ], [ 515, 310, 42, 13 ], [ 562, 310, 46, 13 ], [ 613, 310, 35, 13 ], [ 652, 310, 18, 13 ], [ 675, 310, 35, 13 ], [ 714, 310, 11, 13 ], [ 730, 310, 18, 13 ], [ 102, 324, 43, 13 ], [ 150, 324, 38, 13 ], [ 191, 324, 63, 13 ], [ 259, 324, 25, 13 ], [ 288, 324, 37, 13 ], [ 329, 324, 43, 13 ], [ 376, 324, 38, 13 ], [ 418, 324, 34, 13 ], [ 456, 324, 11, 13 ], [ 471, 324, 19, 13 ], [ 495, 324, 8, 13 ], [ 507, 324, 32, 13 ], [ 544, 324, 11, 13 ], [ 559, 324, 28, 13 ], [ 591, 324, 76, 13 ], [ 671, 324, 25, 13 ], [ 701, 324, 26, 13 ], [ 731, 324, 17, 13 ], [ 102, 338, 43, 13 ], [ 148, 338, 24, 13 ], [ 175, 338, 35, 13 ], [ 213, 338, 11, 13 ], [ 227, 338, 7, 13 ], [ 237, 338, 33, 13 ], [ 274, 338, 25, 13 ], [ 302, 338, 12, 13 ], [ 317, 338, 30, 13 ], [ 350, 338, 46, 13 ], [ 400, 338, 29, 13 ], [ 432, 338, 6, 13 ], [ 442, 338, 38, 13 ], [ 483, 338, 32, 13 ], [ 519, 338, 11, 13 ], [ 533, 338, 76, 13 ], [ 612, 338, 25, 13 ], [ 641, 338, 45, 13 ], [ 689, 338, 35, 13 ], [ 727, 338, 21, 13 ], [ 102, 352, 33, 13 ], [ 138, 352, 24, 13 ], [ 165, 352, 32, 13 ], [ 200, 352, 17, 13 ], [ 220, 352, 21, 13 ], [ 245, 352, 25, 13 ], [ 273, 352, 7, 13 ], [ 283, 352, 38, 13 ], [ 324, 352, 40, 13 ], [ 367, 352, 33, 13 ], [ 403, 352, 11, 13 ], [ 416, 352, 18, 13 ], [ 437, 352, 33, 13 ], [ 473, 352, 24, 13 ], [ 500, 352, 33, 13 ], [ 536, 352, 35, 13 ], [ 574, 352, 21, 13 ], [ 598, 352, 45, 13 ], [ 646, 352, 24, 13 ], [ 673, 352, 23, 13 ], [ 699, 352, 49, 13 ], [ 102, 365, 50, 13 ], [ 156, 365, 46, 13 ], [ 205, 365, 14, 13 ], [ 222, 365, 44, 13 ], [ 270, 365, 59, 13 ], [ 333, 365, 11, 13 ], [ 348, 365, 47, 13 ], [ 398, 365, 15, 13 ], [ 417, 365, 39, 13 ], [ 460, 365, 15, 13 ], [ 478, 365, 7, 13 ], [ 489, 365, 43, 13 ], [ 535, 365, 14, 13 ], [ 553, 365, 10, 13 ], [ 567, 365, 22, 13 ], [ 592, 365, 20, 13 ], [ 616, 365, 15, 13 ], [ 635, 365, 27, 13 ], [ 665, 365, 41, 13 ], [ 710, 365, 37, 13 ], [ 102, 379, 20, 13 ], [ 125, 379, 14, 13 ], [ 141, 379, 28, 13 ], [ 172, 379, 41, 13 ], [ 215, 379, 11, 13 ], [ 229, 379, 27, 13 ], [ 259, 379, 55, 13 ], [ 316, 379, 67, 13 ], [ 386, 379, 11, 13 ], [ 399, 379, 7, 13 ], [ 408, 379, 41, 13 ], [ 452, 379, 24, 13 ], [ 478, 379, 30, 13 ], [ 510, 379, 49, 13 ], [ 562, 379, 64, 13 ], [ 629, 379, 24, 13 ], [ 655, 379, 35, 13 ], [ 692, 379, 55, 13 ], [ 102, 393, 18, 13 ], [ 124, 393, 39, 13 ], [ 168, 393, 35, 13 ], [ 207, 393, 10, 13 ], [ 222, 393, 25, 13 ], [ 252, 393, 43, 13 ], [ 300, 393, 25, 13 ], [ 330, 393, 12, 13 ], [ 346, 393, 30, 13 ], [ 381, 393, 49, 13 ], [ 435, 393, 10, 13 ], [ 449, 393, 19, 13 ], [ 473, 393, 35, 13 ], [ 513, 393, 39, 13 ], [ 557, 393, 56, 13 ], [ 618, 393, 33, 13 ], [ 655, 393, 67, 13 ], [ 727, 393, 21, 13 ], [ 102, 407, 63, 13 ], [ 168, 407, 51, 13 ], [ 221, 407, 40, 13 ], [ 265, 407, 7, 13 ], [ 274, 407, 40, 13 ], [ 318, 407, 73, 13 ], [ 394, 407, 20, 13 ], [ 417, 407, 40, 13 ], [ 460, 407, 56, 13 ], [ 519, 407, 10, 13 ], [ 532, 407, 47, 13 ], [ 581, 407, 25, 13 ], [ 609, 407, 27, 13 ], [ 639, 407, 41, 13 ], [ 683, 407, 21, 13 ], [ 707, 407, 27, 13 ], [ 736, 407, 12, 13 ], [ 102, 421, 23, 13 ], [ 128, 421, 43, 13 ], [ 175, 421, 11, 13 ], [ 189, 421, 7, 13 ], [ 199, 421, 43, 13 ], [ 246, 421, 19, 13 ], [ 268, 421, 19, 13 ], [ 290, 421, 20, 13 ], [ 315, 421, 23, 13 ], [ 341, 421, 40, 13 ], [ 384, 421, 11, 13 ], [ 399, 421, 6, 13 ], [ 409, 421, 29, 13 ], [ 441, 421, 21, 13 ], [ 465, 421, 12, 13 ], [ 480, 421, 20, 13 ], [ 502, 421, 34, 13 ], [ 540, 421, 11, 13 ], [ 552, 421, 8, 13 ], [ 562, 421, 28, 13 ], [ 593, 421, 8, 13 ], [ 605, 421, 54, 13 ], [ 662, 421, 51, 13 ], [ 717, 421, 10, 13 ], [ 730, 421, 18, 13 ], [ 102, 435, 57, 13 ], [ 162, 435, 11, 13 ], [ 176, 435, 27, 13 ], [ 206, 435, 55, 13 ], [ 263, 434, 29, 13 ], [ 295, 435, 23, 13 ], [ 321, 435, 21, 13 ], [ 344, 435, 47, 13 ], [ 394, 435, 10, 13 ], [ 407, 435, 19, 13 ], [ 429, 435, 32, 13 ], [ 464, 435, 11, 13 ], [ 476, 435, 8, 13 ], [ 486, 435, 35, 13 ], [ 523, 435, 29, 13 ], [ 555, 435, 18, 13 ], [ 575, 435, 57, 13 ], [ 635, 435, 11, 13 ], [ 649, 434, 36, 13 ], [ 687, 434, 35, 13 ], [ 725, 435, 23, 13 ], [ 102, 449, 63, 13 ], [ 168, 449, 50, 13 ], [ 220, 449, 11, 13 ], [ 233, 449, 8, 13 ], [ 243, 449, 35, 13 ], [ 280, 449, 30, 13 ], [ 313, 449, 21, 13 ], [ 336, 449, 21, 13 ], [ 360, 449, 6, 13 ], [ 370, 449, 34, 13 ], [ 407, 449, 29, 13 ], [ 438, 449, 15, 13 ], [ 456, 449, 6, 13 ], [ 465, 449, 43, 13 ], [ 512, 449, 57, 13 ], [ 572, 449, 11, 13 ], [ 586, 448, 29, 13 ], [ 618, 449, 23, 13 ], [ 644, 449, 11, 13 ], [ 656, 449, 8, 13 ], [ 666, 449, 26, 13 ], [ 694, 449, 29, 13 ], [ 725, 449, 22, 13 ], [ 102, 462, 20, 13 ], [ 126, 462, 33, 13 ], [ 162, 462, 18, 13 ], [ 183, 462, 57, 13 ], [ 244, 462, 17, 13 ], [ 264, 462, 18, 13 ], [ 286, 462, 42, 13 ], [ 330, 462, 31, 13 ], [ 365, 462, 42, 13 ], [ 410, 462, 41, 13 ], [ 455, 462, 13, 13 ], [ 472, 462, 106, 13 ], [ 580, 462, 30, 13 ], [ 614, 462, 11, 13 ], [ 628, 462, 35, 13 ], [ 666, 462, 46, 13 ], [ 715, 462, 10, 13 ], [ 729, 462, 19, 13 ], [ 102, 476, 17, 13 ], [ 121, 476, 36, 13 ], [ 160, 476, 35, 13 ], [ 198, 476, 37, 13 ], [ 238, 476, 10, 13 ], [ 251, 476, 19, 13 ], [ 273, 476, 63, 13 ], [ 338, 476, 34, 13 ], [ 374, 476, 18, 13 ], [ 395, 476, 41, 13 ], [ 438, 476, 36, 13 ], [ 477, 476, 21, 13 ], [ 501, 476, 65, 13 ], [ 569, 476, 32, 13 ], [ 604, 476, 51, 13 ], [ 657, 476, 18, 13 ], [ 677, 476, 70, 13 ], [ 102, 490, 11, 13 ], [ 117, 490, 75, 13 ], [ 196, 490, 20, 13 ], [ 220, 490, 23, 13 ], [ 246, 490, 14, 13 ], [ 264, 490, 39, 13 ], [ 306, 490, 15, 13 ], [ 325, 490, 18, 13 ], [ 346, 490, 70, 13 ], [ 420, 490, 11, 13 ], [ 435, 490, 29, 13 ], [ 468, 490, 60, 13 ], [ 532, 490, 53, 13 ], [ 92, 525, 40, 10 ], [ 136, 525, 21, 10 ], [ 161, 525, 5, 10 ], [ 170, 525, 27, 10 ], [ 201, 525, 8, 10 ], [ 213, 525, 22, 10 ], [ 238, 525, 8, 10 ], [ 250, 525, 28, 10 ], [ 282, 525, 14, 10 ], [ 300, 525, 38, 10 ], [ 342, 525, 17, 10 ], [ 363, 525, 9, 10 ], [ 376, 525, 9, 10 ], [ 389, 525, 26, 10 ], [ 419, 525, 19, 10 ], [ 442, 525, 36, 10 ], [ 482, 525, 45, 10 ], [ 531, 525, 14, 10 ], [ 549, 525, 31, 10 ], [ 585, 525, 29, 10 ], [ 617, 525, 8, 10 ], [ 629, 525, 5, 10 ], [ 638, 525, 29, 10 ], [ 672, 525, 26, 10 ], [ 702, 525, 9, 10 ], [ 714, 525, 34, 10 ], [ 92, 536, 37, 10 ], [ 132, 536, 20, 10 ], [ 155, 536, 18, 10 ], [ 176, 536, 18, 10 ], [ 196, 536, 32, 10 ], [ 231, 536, 139, 10 ], [ 92, 553, 31, 10 ], [ 126, 553, 28, 10 ], [ 157, 553, 40, 10 ], [ 200, 553, 35, 10 ], [ 238, 553, 38, 10 ], [ 279, 553, 9, 10 ], [ 290, 553, 29, 10 ], [ 322, 553, 28, 10 ], [ 352, 553, 25, 10 ], [ 380, 553, 9, 10 ], [ 392, 553, 34, 10 ], [ 92, 571, 42, 10 ], [ 137, 571, 45, 10 ], [ 185, 571, 12, 10 ], [ 200, 571, 22, 10 ], [ 225, 571, 44, 10 ], [ 272, 571, 32, 10 ], [ 307, 571, 12, 10 ], [ 322, 571, 22, 10 ], [ 347, 571, 47, 10 ], [ 397, 571, 36, 10 ], [ 436, 571, 12, 10 ], [ 451, 571, 20, 10 ], [ 92, 588, 50, 10 ], [ 158, 588, 20, 10 ], [ 183, 588, 21, 10 ], [ 208, 588, 9, 10 ], [ 220, 588, 9, 10 ], [ 234, 588, 17, 10 ], [ 255, 588, 7, 10 ], [ 265, 588, 10, 10 ], [ 280, 588, 50, 10 ], [ 334, 588, 25, 10 ], [ 364, 588, 45, 10 ], [ 413, 588, 25, 10 ], [ 441, 588, 14, 10 ], [ 459, 588, 24, 10 ], [ 487, 588, 9, 10 ], [ 500, 588, 14, 10 ], [ 518, 588, 34, 10 ], [ 555, 588, 42, 10 ], [ 602, 588, 45, 10 ], [ 651, 588, 33, 10 ], [ 688, 588, 25, 10 ], [ 717, 588, 31, 10 ], [ 92, 599, 49, 10 ], [ 144, 599, 17, 10 ], [ 163, 599, 50, 10 ], [ 216, 599, 16, 10 ], [ 235, 599, 54, 10 ], [ 291, 599, 8, 10 ], [ 302, 599, 15, 10 ], [ 320, 599, 37, 10 ], [ 359, 599, 37, 10 ], [ 399, 599, 14, 10 ], [ 416, 599, 31, 10 ], [ 450, 599, 27, 10 ], [ 480, 599, 16, 10 ], [ 498, 599, 27, 10 ], [ 529, 599, 13, 10 ], [ 545, 599, 36, 10 ], [ 92, 616, 42, 10 ], [ 136, 616, 17, 10 ], [ 154, 616, 23, 10 ], [ 179, 616, 16, 10 ], [ 197, 616, 30, 10 ], [ 229, 616, 10, 10 ], [ 241, 616, 14, 10 ], [ 257, 616, 35, 10 ], [ 293, 616, 13, 10 ], [ 308, 616, 32, 10 ], [ 342, 616, 10, 10 ], [ 354, 616, 42, 10 ], [ 398, 616, 23, 10 ], [ 423, 616, 8, 10 ], [ 434, 616, 14, 10 ], [ 449, 616, 41, 10 ], [ 492, 616, 9, 10 ], [ 502, 616, 47, 10 ], [ 551, 616, 34, 10 ], [ 587, 616, 27, 10 ], [ 616, 616, 12, 10 ], [ 630, 616, 34, 10 ], [ 665, 616, 37, 10 ], [ 704, 616, 16, 10 ], [ 722, 616, 11, 10 ], [ 734, 616, 14, 10 ], [ 92, 627, 34, 10 ], [ 129, 627, 38, 10 ], [ 169, 627, 9, 10 ], [ 180, 627, 27, 10 ], [ 210, 627, 29, 10 ], [ 241, 627, 16, 10 ], [ 259, 627, 46, 10 ], [ 308, 627, 15, 10 ], [ 326, 627, 31, 10 ], [ 359, 627, 16, 10 ], [ 378, 627, 11, 10 ], [ 391, 627, 16, 10 ], [ 410, 627, 8, 10 ], [ 420, 627, 23, 10 ], [ 445, 627, 30, 10 ], [ 477, 627, 18, 10 ], [ 498, 627, 40, 10 ], [ 540, 627, 16, 10 ], [ 559, 627, 34, 10 ], [ 595, 627, 34, 10 ], [ 631, 627, 9, 10 ], [ 643, 627, 32, 10 ], [ 678, 627, 9, 10 ], [ 689, 627, 48, 10 ], [ 740, 627, 9, 10 ], [ 92, 638, 14, 10 ], [ 109, 638, 48, 10 ], [ 92, 656, 52, 10 ], [ 147, 656, 44, 10 ], [ 193, 656, 16, 10 ], [ 212, 656, 31, 10 ], [ 246, 656, 20, 10 ], [ 268, 656, 35, 10 ], [ 307, 656, 17, 10 ], [ 326, 656, 11, 10 ], [ 340, 656, 45, 10 ], [ 388, 656, 35, 10 ], [ 426, 656, 21, 10 ], [ 92, 673, 5, 10 ], [ 99, 673, 27, 10 ], [ 129, 673, 68, 10 ], [ 80, 716, 84, 14 ], [ 93, 741, 43, 13 ], [ 143, 741, 41, 13 ], [ 191, 741, 25, 13 ], [ 223, 741, 8, 13 ], [ 237, 741, 16, 13 ], [ 261, 741, 25, 13 ], [ 292, 741, 45, 13 ], [ 344, 741, 68, 13 ], [ 80, 755, 71, 13 ], [ 155, 755, 35, 13 ], [ 193, 755, 10, 13 ], [ 207, 755, 16, 13 ], [ 226, 755, 35, 13 ], [ 265, 755, 40, 13 ], [ 308, 755, 34, 13 ], [ 345, 755, 35, 13 ], [ 383, 755, 19, 13 ], [ 405, 755, 8, 13 ], [ 80, 770, 16, 13 ], [ 100, 770, 37, 13 ], [ 140, 770, 28, 13 ], [ 171, 770, 10, 13 ], [ 185, 770, 72, 13 ], [ 261, 770, 45, 13 ], [ 309, 770, 35, 13 ], [ 348, 770, 31, 13 ], [ 383, 770, 30, 13 ], [ 80, 785, 10, 13 ], [ 93, 785, 24, 13 ], [ 119, 785, 25, 13 ], [ 146, 785, 54, 13 ], [ 203, 785, 26, 13 ], [ 232, 785, 18, 13 ], [ 253, 785, 47, 13 ], [ 303, 785, 16, 13 ], [ 322, 785, 27, 13 ], [ 351, 785, 28, 13 ], [ 381, 785, 10, 13 ], [ 394, 785, 19, 13 ], [ 80, 800, 40, 13 ], [ 124, 800, 37, 13 ], [ 165, 800, 7, 13 ], [ 175, 800, 8, 13 ], [ 187, 800, 33, 13 ], [ 223, 800, 44, 13 ], [ 271, 800, 20, 13 ], [ 295, 800, 16, 13 ], [ 315, 800, 50, 13 ], [ 369, 800, 10, 13 ], [ 383, 800, 19, 13 ], [ 405, 800, 8, 13 ], [ 80, 814, 47, 13 ], [ 132, 814, 13, 13 ], [ 149, 814, 16, 13 ], [ 170, 814, 42, 13 ], [ 217, 814, 34, 13 ], [ 255, 814, 10, 13 ], [ 270, 814, 53, 13 ], [ 329, 814, 54, 13 ], [ 387, 814, 25, 13 ], [ 80, 829, 18, 13 ], [ 105, 829, 11, 13 ], [ 124, 829, 42, 13 ], [ 173, 829, 10, 13 ], [ 190, 829, 36, 13 ], [ 233, 829, 18, 13 ], [ 258, 829, 37, 13 ], [ 301, 829, 31, 13 ], [ 339, 829, 51, 13 ], [ 397, 829, 16, 13 ], [ 80, 844, 64, 13 ], [ 150, 844, 19, 13 ], [ 174, 844, 22, 13 ], [ 202, 844, 46, 13 ], [ 253, 844, 35, 13 ], [ 293, 844, 41, 13 ], [ 340, 844, 73, 13 ], [ 80, 859, 33, 13 ], [ 117, 859, 16, 13 ], [ 137, 859, 20, 13 ], [ 160, 859, 48, 13 ], [ 211, 859, 10, 13 ], [ 225, 859, 52, 13 ], [ 280, 859, 10, 13 ], [ 294, 859, 35, 13 ], [ 333, 859, 45, 13 ], [ 381, 859, 31, 13 ], [ 80, 873, 18, 13 ], [ 107, 873, 52, 13 ], [ 168, 873, 48, 13 ], [ 224, 873, 10, 13 ], [ 243, 873, 23, 13 ], [ 274, 873, 43, 13 ], [ 325, 873, 24, 13 ], [ 358, 873, 22, 13 ], [ 388, 873, 24, 13 ], [ 80, 888, 48, 13 ], [ 134, 888, 10, 13 ], [ 150, 888, 73, 13 ], [ 229, 888, 34, 13 ], [ 269, 888, 20, 13 ], [ 295, 888, 22, 13 ], [ 323, 888, 52, 13 ], [ 380, 888, 10, 13 ], [ 397, 888, 16, 13 ], [ 80, 903, 65, 13 ], [ 153, 903, 10, 13 ], [ 172, 903, 19, 13 ], [ 199, 903, 10, 13 ], [ 218, 903, 42, 13 ], [ 268, 903, 10, 13 ], [ 286, 903, 73, 13 ], [ 368, 903, 45, 13 ], [ 80, 918, 47, 13 ], [ 134, 918, 52, 13 ], [ 192, 918, 50, 13 ], [ 249, 918, 18, 13 ], [ 274, 918, 37, 13 ], [ 317, 918, 34, 13 ], [ 358, 918, 24, 13 ], [ 388, 918, 24, 13 ], [ 80, 932, 48, 13 ], [ 132, 932, 10, 13 ], [ 147, 932, 19, 13 ], [ 169, 932, 41, 13 ], [ 214, 932, 52, 13 ], [ 270, 932, 16, 13 ], [ 290, 932, 25, 13 ], [ 319, 932, 54, 13 ], [ 376, 932, 36, 13 ], [ 80, 947, 24, 13 ], [ 110, 947, 31, 13 ], [ 147, 947, 39, 13 ], [ 192, 947, 10, 13 ], [ 208, 947, 12, 13 ], [ 226, 947, 51, 13 ], [ 283, 947, 22, 13 ], [ 310, 947, 19, 13 ], [ 335, 947, 8, 13 ], [ 349, 947, 64, 13 ], [ 80, 962, 28, 13 ], [ 115, 962, 34, 13 ], [ 156, 962, 6, 13 ], [ 169, 962, 42, 13 ], [ 219, 962, 10, 13 ], [ 236, 962, 16, 13 ], [ 259, 962, 58, 13 ], [ 324, 962, 31, 13 ], [ 362, 962, 18, 13 ], [ 388, 962, 25, 13 ], [ 80, 977, 52, 13 ], [ 137, 977, 6, 13 ], [ 148, 977, 48, 13 ], [ 200, 977, 44, 13 ], [ 249, 977, 10, 13 ], [ 264, 977, 8, 13 ], [ 276, 977, 25, 13 ], [ 305, 977, 66, 13 ], [ 375, 977, 25, 13 ], [ 405, 977, 8, 13 ], [ 80, 991, 20, 13 ], [ 104, 991, 48, 13 ], [ 155, 991, 10, 13 ], [ 169, 991, 21, 13 ], [ 195, 991, 6, 13 ], [ 205, 991, 20, 13 ], [ 228, 991, 10, 13 ], [ 242, 991, 16, 13 ], [ 262, 991, 64, 13 ], [ 329, 991, 10, 13 ], [ 343, 991, 35, 13 ], [ 381, 991, 31, 13 ], [ 80, 1006, 64, 13 ], [ 148, 1006, 42, 13 ], [ 194, 1006, 47, 13 ], [ 245, 1006, 65, 13 ], [ 313, 1006, 26, 13 ], [ 342, 1006, 70, 13 ], [ 437, 715, 23, 13 ], [ 466, 715, 45, 13 ], [ 516, 715, 53, 13 ], [ 575, 715, 59, 13 ], [ 640, 715, 43, 13 ], [ 689, 715, 55, 13 ], [ 750, 715, 20, 13 ], [ 437, 730, 27, 13 ], [ 469, 730, 26, 13 ], [ 499, 730, 17, 13 ], [ 521, 730, 43, 13 ], [ 568, 730, 53, 13 ], [ 626, 730, 79, 13 ], [ 710, 730, 19, 13 ], [ 734, 730, 36, 13 ], [ 437, 744, 28, 13 ], [ 469, 744, 36, 13 ], [ 508, 744, 18, 13 ], [ 530, 744, 9, 13 ], [ 543, 744, 35, 13 ], [ 581, 744, 33, 13 ], [ 617, 744, 28, 13 ], [ 649, 744, 36, 13 ], [ 688, 744, 82, 13 ], [ 437, 759, 49, 13 ], [ 491, 759, 17, 13 ], [ 512, 759, 20, 13 ], [ 536, 759, 25, 13 ], [ 565, 759, 46, 13 ], [ 616, 759, 10, 13 ], [ 631, 759, 6, 13 ], [ 642, 759, 44, 13 ], [ 690, 759, 19, 13 ], [ 714, 759, 33, 13 ], [ 751, 759, 18, 13 ], [ 437, 773, 49, 13 ], [ 491, 773, 27, 13 ], [ 522, 773, 31, 13 ], [ 558, 773, 34, 13 ], [ 596, 773, 22, 13 ], [ 623, 773, 46, 13 ], [ 673, 773, 21, 13 ], [ 699, 773, 71, 13 ], [ 437, 788, 28, 13 ], [ 470, 788, 10, 13 ], [ 486, 788, 62, 13 ], [ 554, 788, 23, 13 ], [ 582, 788, 13, 13 ], [ 601, 788, 55, 13 ], [ 661, 788, 18, 13 ], [ 685, 788, 38, 13 ], [ 728, 788, 42, 13 ], [ 437, 802, 64, 13 ], [ 504, 802, 55, 13 ], [ 561, 802, 41, 13 ], [ 605, 802, 40, 13 ], [ 648, 802, 20, 13 ], [ 670, 802, 25, 13 ], [ 698, 802, 24, 13 ], [ 725, 802, 45, 13 ], [ 437, 817, 22, 13 ], [ 463, 817, 10, 13 ], [ 477, 817, 16, 13 ], [ 497, 817, 21, 13 ], [ 521, 817, 10, 13 ], [ 535, 817, 22, 13 ], [ 561, 817, 39, 13 ], [ 604, 817, 18, 13 ], [ 450, 832, 11, 13 ], [ 465, 832, 6, 13 ], [ 475, 832, 31, 13 ], [ 510, 832, 27, 13 ], [ 540, 832, 48, 13 ], [ 592, 832, 16, 13 ], [ 612, 832, 20, 13 ], [ 635, 832, 10, 13 ], [ 649, 832, 30, 13 ], [ 682, 832, 40, 13 ], [ 726, 832, 44, 13 ], [ 437, 846, 10, 13 ], [ 452, 846, 19, 13 ], [ 476, 846, 28, 13 ], [ 509, 846, 42, 13 ], [ 555, 846, 41, 13 ], [ 601, 846, 69, 13 ], [ 675, 846, 6, 13 ], [ 686, 846, 25, 13 ], [ 715, 846, 55, 13 ], [ 437, 861, 42, 13 ], [ 482, 861, 45, 13 ], [ 529, 861, 45, 13 ], [ 577, 861, 35, 13 ], [ 615, 861, 40, 13 ], [ 658, 861, 20, 13 ], [ 680, 861, 30, 13 ], [ 712, 861, 36, 13 ], [ 750, 861, 19, 13 ], [ 437, 875, 25, 13 ], [ 466, 875, 48, 13 ], [ 517, 875, 18, 13 ], [ 538, 875, 31, 13 ], [ 572, 875, 41, 13 ], [ 616, 875, 46, 13 ], [ 666, 875, 20, 13 ], [ 689, 875, 39, 13 ], [ 731, 875, 38, 13 ], [ 437, 890, 15, 13 ], [ 454, 890, 51, 13 ], [ 508, 890, 35, 13 ], [ 546, 890, 40, 13 ], [ 589, 890, 19, 13 ], [ 611, 890, 60, 13 ], [ 673, 890, 26, 13 ], [ 702, 890, 18, 13 ], [ 722, 890, 10, 13 ], [ 735, 890, 35, 13 ], [ 437, 904, 30, 13 ], [ 474, 904, 28, 13 ], [ 510, 904, 37, 13 ], [ 555, 904, 35, 13 ], [ 598, 904, 23, 13 ], [ 629, 904, 33, 13 ], [ 669, 904, 27, 13 ], [ 704, 904, 66, 13 ], [ 437, 919, 39, 13 ], [ 481, 919, 41, 13 ], [ 526, 919, 54, 13 ], [ 585, 919, 29, 13 ], [ 618, 919, 51, 13 ], [ 674, 919, 17, 13 ], [ 695, 919, 27, 13 ], [ 727, 919, 43, 13 ], [ 437, 933, 82, 13 ], [ 522, 933, 39, 13 ], [ 565, 933, 22, 13 ], [ 590, 933, 19, 13 ], [ 613, 933, 33, 13 ], [ 649, 933, 45, 13 ], [ 697, 933, 21, 13 ], [ 721, 933, 49, 13 ], [ 437, 948, 22, 13 ], [ 463, 948, 28, 13 ], [ 495, 948, 15, 13 ], [ 513, 948, 45, 13 ], [ 562, 948, 29, 13 ], [ 595, 948, 22, 13 ], [ 620, 948, 19, 13 ], [ 643, 948, 33, 13 ], [ 680, 948, 22, 13 ], [ 705, 948, 51, 13 ], [ 759, 948, 10, 13 ], [ 437, 962, 39, 13 ], [ 482, 962, 22, 13 ], [ 510, 962, 28, 13 ], [ 543, 962, 30, 13 ], [ 579, 962, 14, 13 ], [ 598, 962, 26, 13 ], [ 629, 962, 18, 13 ], [ 653, 962, 36, 13 ], [ 694, 962, 28, 13 ], [ 728, 962, 20, 13 ], [ 754, 962, 16, 13 ], [ 437, 977, 45, 13 ], [ 489, 977, 23, 13 ], [ 519, 977, 31, 13 ], [ 556, 977, 12, 13 ], [ 575, 977, 56, 13 ], [ 638, 977, 15, 13 ], [ 660, 977, 16, 13 ], [ 683, 977, 50, 13 ], [ 739, 977, 30, 13 ], [ 437, 992, 39, 13 ], [ 484, 992, 7, 13 ], [ 498, 992, 36, 13 ], [ 542, 992, 20, 13 ], [ 569, 992, 31, 13 ], [ 609, 992, 30, 13 ], [ 646, 992, 44, 13 ], [ 697, 992, 34, 13 ], [ 739, 992, 17, 13 ], [ 763, 992, 6, 13 ], [ 437, 1006, 50, 13 ], [ 491, 1006, 23, 13 ], [ 517, 1006, 15, 13 ], [ 535, 1006, 6, 13 ], [ 545, 1006, 58, 13 ], [ 606, 1006, 20, 13 ], [ 630, 1006, 25, 13 ], [ 658, 1006, 12, 13 ], [ 674, 1006, 38, 13 ], [ 715, 1006, 41, 13 ], [ 760, 1006, 10, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 21, 12 ], [ 165, 1047, 3, 12 ], [ 174, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 546, 1047, 41, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "CMV", "Infection", "Attenuates", "the", "Disease", "Course", "in", "a", "Murine", "Model", "of", "Multiple", "Sclerosis", "Istvan", "Pirko1*,", "Rhonda", "Cardin2,", "Yi", "Chen", "3", ",", "Anne", "K.", "Lohrey3,", "Diana", "M.", "Lindquist4,", "R.", "Scott", "Dunn4,", "Robert", "Zivadinov5,", "Aaron", "J.", "Johnson3", "1", "Department", "of", "Neurology,", "Mayo", "Clinic,", "Rochester,", "Minnesota,", "United", "States", "of", "America,", "2", "Division", "of", "Infectious", "Diseases,", "Cincinnati", "Children’s", "Hospital", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America,", "3", "Department", "of", "Neurology", "and", "Immunology,", "Mayo", "Clinic,", "Rochester,", "Minnesota,", "United", "States", "of", "America,", "4", "Imaging", "Research", "Center,", "Cincinnati", "Children’s", "Hospital", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America,", "5", "Department", "of", "Neurology", "and", "Buffalo", "Neuroimaging", "Analysis", "Center,", "University", "of", "Buffalo,", "Buffalo,", "New", "York,", "United", "States", "of", "America", "Abstract", "Recent", "evidence", "in", "multiple", "sclerosis", "(MS)", "suggests", "that", "active", "CMV", "infection", "may", "result", "in", "more", "benign", "clinical", "disease.", "The", "goal", "of", "this", "pilot", "study", "was", "to", "determine", "whether", "underlying", "murine", "CMV", "(MCMV)", "infection", "affects", "the", "course", "of", "the", "Theiler’s", "murine", "encephalitis", "virus", "(TMEV)", "induced", "murine", "model", "of", "MS.", "A", "group", "of", "eight", "TMEV-infected", "mice", "were", "co-", "infected", "with", "MCMV", "at", "2", "weeks", "prior", "to", "TMEV", "infection", "while", "a", "second", "group", "of", "TMEV-infected", "mice", "received", "MCMV", "two", "weeks", "post", "TMEV.", "We", "also", "used", "2", "control", "groups,", "where", "at", "the", "above", "time", "points", "MCMV", "was", "replaced", "with", "PBS.", "Outcome", "measures", "included", "(1)", "monthly", "monitoring", "of", "disability", "via", "rotarod", "for", "8", "months;", "(2)", "in", "vivo", "MRI", "for", "brain", "atrophy", "studies", "and", "(3)", "FACS", "analysis", "of", "brain", "infiltrating", "lymphocytes", "at", "8", "months", "post", "TMEV", "infection.", "Co-infection", "with", "MCMV", "influenced", "the", "disease", "course", "in", "mice", "infected", "prior", "to", "TMEV", "infection.", "In", "this", "group,", "rotarod", "detectable", "motor", "performance", "was", "significantly", "improved", "starting", "3", "months", "post-infection", "and", "beyond", "(p#0.024).", "In", "addition,", "their", "brain", "atrophy", "was", "close", "to", "30%", "reduced", "at", "8", "months,", "but", "this", "was", "only", "present", "as", "a", "trend", "due", "to", "low", "power", "(p", "=", "0.19).", "A", "significant", "reduction", "in", "the", "proportion", "of", "brain", "infiltrating", "CD3+", "cells", "was", "detected", "in", "this", "group", "(p", "=", "0.026),", "while", "the", "proportion", "of", "CD45+", "Mac1+", "cells", "significantly", "increased", "(p", "=", "0.003).", "There", "was", "also", "a", "strong", "trend", "for", "a", "reduced", "proportion", "of", "CD4+", "cells", "(p", "=", "0.17)", "while", "CD8", "and", "B220+", "cell", "proportion", "did", "not", "change.", "These", "findings", "support", "an", "immunomodulatory", "effect", "of", "MCMV", "infection", "in", "this", "MS", "model.", "Future", "studies", "in", "this", "co-infection", "model", "will", "provide", "insight", "into", "mechanisms", "which", "modulate", "the", "development", "of", "demyelination", "and", "may", "be", "utilized", "for", "the", "development", "of", "novel", "therapeutic", "strategies.", "Citation:", "Pirko", "I,", "Cardin", "R,", "Chen", "Y,", "Lohrey", "AK,", "Lindquist", "DM,", "et", "al.", "(2012)", "CMV", "Infection", "Attenuates", "the", "Disease", "Course", "in", "a", "Murine", "Model", "of", "Multiple", "Sclerosis.", "PLoS", "ONE", "7(2):", "e32767.", "doi:10.1371/journal.pone.0032767", "Editor:", "Steven", "Jacobson,", "National", "Institutes", "of", "Health,", "United", "States", "of", "America", "Received", "September", "19,", "2011;", "Accepted", "January", "30,", "2012;", "Published", "February", "29,", "2012", "Copyright:", "2012", "Pirko", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "study", "was", "funded", "by", "the", "National", "MS", "Society,", "by", "intramural", "funds", "at", "the", "University", "of", "Cincinnati’s", "Waddell", "Center", "for", "Multiple", "Sclerosis,", "and", "by", "the", "National", "Institutes", "of", "Heatlh", "(NINDS", "R01", "NS058698).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "Pirko@mayo.edu", "Introduction", "Multiple", "sclerosis", "(MS)", "is", "the", "most", "common", "inflammatory", "demyelinating", "disease", "of", "the", "central", "nervous", "system", "(CNS).", "MS", "is", "the", "leading", "cause", "of", "non-traumatic", "disability", "among", "young", "adults", "in", "their", "most", "productive", "years", "[1].", "Although", "the", "exact", "cause", "of", "MS", "remains", "elusive,", "it", "is", "widely", "accepted", "that", "the", "pathology", "of", "MS", "is", "mediated", "by", "the", "immune", "system", "in", "genetically", "susceptible", "hosts", "[2].", "In", "addition", "to", "genetic", "risk", "factors,", "which", "determine", "the", "susceptibility", "and", "may", "influence", "disease", "severity,", "environmental", "factors", "are", "also", "suspected", "to", "contribute", "as", "disease", "initiating", "events", "[3].", "Infections,", "especially", "of", "viral", "etiology,", "have", "long", "been", "suspected", "as", "environmental", "factors", "that", "may", "contribute", "to", "the", "development", "of", "MS", "in", "addition", "to", "environmental", "variables", "including", "vitamin-D", "deficiency", "[4].", "Several", "viruses", "have", "been", "suspected", "as", "MS", "triggers.", "Currently,", "the", "most", "commonly", "studied", "virus", "which", "appears", "to", "be", "associated", "with", "MS", "is", "Epstein-Barr", "Virus", "(EBV),", "a", "member", "of", "the", "Herpesviridae", "family", "[5].", "EBV", "establishes", "a", "persistent", "infection", "in", "B", "cells.", "Interestingly,", "EBV", "is", "also", "suspected", "to", "play", "a", "role", "in", "the", "pathogenesis", "of", "several", "classic", "autoimmune", "diseases,", "including", "polymyositis,", "SLE,", "anti-phospho-", "lipid", "antibody", "syndrome,", "rheumatoid", "arthritis,", "pemphigus", "vul-", "garis,", "giant", "cell", "arthritis,", "Wegener’s", "granulomatosis,", "and", "polyar-", "teritis", "nodosa", "[6].", "A", "second", "herpes", "virus,", "human", "cytomegalovirus", "(HCMV),", "has", "also", "been", "proposed", "as", "a", "potential", "MS", "trigger", "[7].", "However,", "more", "recent", "studies", "with", "extensive", "case", "ascertainment", "failed", "to", "demonstrate", "such", "an", "association", "[5].", "Among", "systemic", "autoimmune", "conditions,", "elevated", "HCMV", "IgG", "titers", "were", "observed", "only", "in", "the", "sera", "of", "SLE", "patients", "[6].", "In", "a", "recent", "study", "analyzing", "the", "role", "of", "active", "HCMV", "infection", "in", "MS", "cases,", "multiple", "analyses", "demonstrated", "a", "clear", "association", "between", "antibody", "positivity", "against", "HCMV", "and", "better", "clinical", "and", "MRI", "outcomes", "[8].", "These", "analyses", "indicated", "that", "patients", "positive", "for", "antibodies", "against", "HCMV", "had", "significantly", "older", "age", "of", "disease", "onset,", "lower", "lifetime", "relapse", "rate,", "higher", "brain", "parenchymal", "fraction", "(BPF)on", "volumetric", "MRI,", "suggesting", "less", "brain", "atrophy.", "HCMV-positive", "patients", "who", "had", "higher", "antibody", "titer", "presented", "with", "lower", "T2", "weighted", "lesion", "load", "and", "higher", "BPF", "compared", "to", "patients", "with", "lower", "levels.", "Of", "note,", "this", "doesn’t", "mean", "that", "the", "antibody", "itself", "would", "be", "responsible", "for", "the", "protective", "effect;", "instead,", "it", "implies", "that", "recent", "active", "infection", "overall", "has", "a", "protective", "role,", "via", "a", "mechanism", "that", "can’t", "be", "directly", "clarified", "in", "PLoS", "ONE", "|", "www.plosone.org", "1", "February", "2012", "|", "Volume", "7", "|", "Issue", "2", "|", "e32767" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 76, 47, 84, 34 ], [ 172, 47, 144, 34 ], [ 76, 118, 38, 20 ], [ 119, 118, 49, 20 ], [ 76, 143, 136, 23 ], [ 218, 143, 38, 23 ], [ 262, 143, 94, 23 ], [ 361, 143, 111, 23 ], [ 479, 143, 58, 23 ], [ 542, 143, 20, 23 ], [ 567, 143, 12, 23 ], [ 585, 143, 62, 23 ], [ 653, 143, 37, 23 ], [ 76, 168, 90, 23 ], [ 172, 168, 75, 23 ], [ 252, 168, 46, 23 ], [ 303, 168, 139, 23 ], [ 448, 168, 63, 23 ], [ 517, 168, 43, 23 ], [ 566, 168, 120, 23 ], [ 76, 193, 71, 21 ], [ 152, 193, 66, 21 ], [ 223, 193, 82, 22 ], [ 310, 193, 50, 21 ], [ 366, 193, 42, 22 ], [ 413, 193, 70, 21 ], [ 488, 193, 79, 22 ], [ 572, 193, 46, 21 ], [ 623, 193, 75, 22 ], [ 76, 218, 55, 21 ], [ 135, 218, 60, 22 ], [ 200, 218, 35, 21 ], [ 240, 218, 61, 21 ], [ 306, 218, 49, 21 ], [ 360, 218, 147, 22 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 268, 41, 12 ], [ 119, 268, 63, 12 ], [ 183, 268, 10, 12 ], [ 195, 268, 18, 12 ], [ 215, 268, 39, 12 ], [ 256, 268, 14, 12 ], [ 271, 268, 26, 12 ], [ 299, 268, 40, 12 ], [ 341, 268, 10, 12 ], [ 353, 268, 39, 12 ], [ 393, 268, 43, 12 ], [ 438, 268, 22, 12 ], [ 462, 268, 30, 12 ], [ 494, 268, 40, 12 ], [ 537, 268, 26, 12 ], [ 564, 268, 19, 12 ], [ 585, 268, 63, 12 ], [ 649, 268, 10, 12 ], [ 661, 268, 63, 12 ], [ 726, 268, 14, 12 ], [ 742, 268, 26, 12 ], [ 76, 281, 40, 11 ], [ 119, 281, 10, 11 ], [ 132, 281, 39, 11 ], [ 173, 281, 43, 11 ], [ 218, 281, 22, 11 ], [ 243, 281, 30, 11 ], [ 275, 281, 40, 11 ], [ 318, 281, 26, 11 ], [ 76, 301, 31, 12 ], [ 110, 301, 38, 12 ], [ 150, 301, 35, 12 ], [ 188, 301, 37, 12 ], [ 227, 301, 4, 12 ], [ 234, 301, 106, 12 ], [ 343, 301, 27, 12 ], [ 372, 301, 15, 12 ], [ 390, 301, 4, 12 ], [ 396, 301, 117, 12 ], [ 516, 301, 38, 12 ], [ 556, 301, 35, 12 ], [ 594, 301, 4, 12 ], [ 600, 301, 117, 12 ], [ 76, 314, 25, 11 ], [ 103, 314, 33, 11 ], [ 139, 314, 4, 11 ], [ 145, 314, 129, 11 ], [ 276, 314, 29, 11 ], [ 308, 314, 28, 11 ], [ 338, 314, 4, 11 ], [ 345, 314, 137, 11 ], [ 484, 314, 33, 11 ], [ 519, 314, 26, 11 ], [ 548, 314, 74, 11 ], [ 624, 314, 4, 11 ], [ 631, 314, 100, 11 ], [ 76, 330, 7, 12 ], [ 85, 330, 73, 12 ], [ 160, 330, 33, 12 ], [ 76, 389, 45, 12 ], [ 124, 389, 12, 12 ], [ 138, 389, 19, 12 ], [ 160, 389, 23, 12 ], [ 76, 409, 21, 11 ], [ 100, 409, 31, 11 ], [ 134, 409, 25, 11 ], [ 162, 409, 15, 12 ], [ 188, 409, 122, 11 ], [ 76, 429, 20, 11 ], [ 98, 429, 28, 11 ], [ 129, 429, 7, 11 ], [ 139, 429, 38, 11 ], [ 179, 429, 25, 11 ], [ 207, 429, 209, 11 ], [ 430, 389, 43, 12 ], [ 476, 389, 11, 12 ], [ 490, 389, 49, 12 ], [ 542, 389, 23, 12 ], [ 430, 402, 46, 11 ], [ 478, 402, 12, 11 ], [ 492, 402, 19, 11 ], [ 513, 402, 23, 11 ], [ 76, 448, 9, 12 ], [ 87, 448, 23, 12 ], [ 113, 448, 28, 12 ], [ 144, 448, 10, 12 ], [ 156, 448, 10, 12 ], [ 168, 448, 36, 12 ], [ 207, 448, 35, 12 ], [ 245, 448, 34, 12 ], [ 282, 448, 18, 12 ], [ 76, 462, 20, 12 ], [ 98, 462, 7, 12 ], [ 108, 462, 11, 12 ], [ 121, 462, 26, 12 ], [ 150, 462, 32, 12 ], [ 184, 462, 28, 12 ], [ 215, 462, 49, 12 ], [ 267, 462, 27, 12 ], [ 296, 462, 15, 12 ], [ 314, 462, 27, 12 ], [ 343, 462, 10, 12 ], [ 355, 462, 15, 12 ], [ 373, 462, 39, 12 ], [ 415, 462, 48, 12 ], [ 465, 462, 51, 12 ], [ 519, 462, 34, 12 ], [ 555, 462, 202, 12 ], [ 76, 475, 27, 12 ], [ 106, 475, 35, 12 ], [ 143, 475, 56, 12 ], [ 201, 475, 18, 12 ], [ 222, 475, 55, 12 ], [ 279, 475, 16, 12 ], [ 298, 475, 60, 12 ], [ 361, 475, 8, 12 ], [ 372, 475, 16, 12 ], [ 390, 475, 39, 12 ], [ 432, 475, 40, 12 ], [ 475, 475, 15, 12 ], [ 493, 475, 34, 12 ], [ 529, 475, 24, 12 ], [ 556, 475, 7, 12 ], [ 565, 475, 39, 12 ], [ 607, 475, 25, 12 ], [ 155, 535, 62, 15 ], [ 155, 556, 80, 14 ], [ 238, 556, 22, 14 ], [ 264, 556, 80, 14 ], [ 347, 556, 60, 14 ], [ 411, 556, 20, 14 ], [ 434, 556, 54, 14 ], [ 492, 556, 70, 14 ], [ 565, 556, 11, 14 ], [ 579, 556, 6, 14 ], [ 589, 556, 23, 14 ], [ 616, 556, 24, 14 ], [ 643, 556, 11, 14 ], [ 658, 556, 33, 14 ], [ 155, 572, 19, 14 ], [ 179, 572, 17, 14 ], [ 202, 572, 54, 14 ], [ 261, 572, 24, 14 ], [ 291, 572, 33, 14 ], [ 330, 572, 72, 14 ], [ 407, 572, 20, 14 ], [ 432, 572, 79, 14 ], [ 516, 572, 21, 14 ], [ 541, 572, 12, 14 ], [ 559, 572, 54, 14 ], [ 618, 572, 73, 14 ], [ 155, 589, 33, 14 ], [ 191, 589, 39, 14 ], [ 234, 589, 64, 14 ], [ 301, 589, 9, 14 ], [ 313, 589, 58, 14 ], [ 155, 612, 31, 14 ], [ 189, 612, 84, 14 ], [ 276, 612, 10, 14 ], [ 288, 612, 42, 14 ], [ 332, 612, 18, 14 ], [ 353, 612, 21, 14 ], [ 376, 612, 20, 14 ], [ 399, 612, 98, 14 ], [ 499, 612, 42, 14 ], [ 544, 612, 49, 14 ], [ 595, 612, 73, 14 ], [ 671, 612, 20, 14 ], [ 155, 628, 82, 14 ], [ 242, 628, 38, 14 ], [ 285, 628, 71, 14 ], [ 361, 628, 43, 14 ], [ 409, 628, 56, 14 ], [ 471, 628, 71, 14 ], [ 547, 628, 25, 14 ], [ 577, 628, 20, 14 ], [ 602, 628, 49, 14 ], [ 656, 628, 35, 14 ], [ 155, 645, 84, 14 ], [ 242, 645, 25, 14 ], [ 270, 645, 28, 14 ], [ 302, 645, 52, 14 ], [ 357, 645, 33, 14 ], [ 392, 645, 15, 14 ], [ 410, 645, 39, 14 ], [ 453, 645, 56, 14 ], [ 511, 645, 37, 14 ], [ 552, 645, 19, 14 ], [ 574, 645, 12, 14 ], [ 590, 645, 14, 14 ], [ 607, 645, 21, 14 ], [ 630, 645, 12, 14 ], [ 646, 645, 33, 14 ], [ 682, 645, 9, 14 ], [ 155, 661, 57, 14 ], [ 220, 661, 49, 14 ], [ 278, 661, 59, 14 ], [ 345, 661, 30, 14 ], [ 384, 661, 20, 14 ], [ 412, 661, 69, 14 ], [ 490, 661, 29, 14 ], [ 527, 661, 63, 14 ], [ 599, 661, 59, 14 ], [ 666, 661, 24, 14 ], [ 155, 677, 61, 14 ], [ 218, 677, 11, 14 ], [ 232, 677, 28, 14 ], [ 263, 677, 36, 14 ], [ 301, 677, 37, 14 ], [ 341, 677, 35, 14 ], [ 379, 677, 20, 14 ], [ 401, 677, 26, 14 ], [ 430, 677, 18, 14 ], [ 451, 677, 41, 14 ], [ 495, 677, 61, 14 ], [ 559, 677, 14, 14 ], [ 575, 677, 41, 14 ], [ 619, 677, 30, 14 ], [ 652, 677, 21, 14 ], [ 676, 677, 15, 14 ], [ 155, 694, 52, 14 ], [ 209, 694, 48, 14 ], [ 260, 694, 22, 14 ], [ 285, 694, 74, 14 ], [ 361, 694, 38, 14 ], [ 402, 694, 21, 14 ], [ 425, 694, 57, 14 ], [ 485, 694, 20, 14 ], [ 508, 694, 18, 14 ], [ 529, 694, 38, 14 ], [ 570, 694, 9, 14 ], [ 581, 694, 30, 14 ], [ 614, 694, 23, 14 ], [ 639, 694, 15, 14 ], [ 656, 694, 34, 14 ], [ 155, 710, 17, 14 ], [ 155, 733, 74, 14 ], [ 232, 733, 42, 14 ], [ 277, 733, 33, 14 ], [ 313, 733, 82, 14 ], [ 398, 733, 63, 14 ], [ 464, 733, 19, 14 ], [ 485, 733, 14, 14 ], [ 502, 733, 30, 14 ], [ 535, 733, 63, 14 ], [ 601, 733, 10, 14 ], [ 614, 733, 41, 14 ], [ 658, 733, 33, 14 ], [ 155, 749, 47, 14 ], [ 209, 749, 43, 14 ], [ 260, 749, 24, 14 ], [ 292, 749, 33, 14 ], [ 332, 749, 72, 14 ], [ 411, 749, 7, 14 ], [ 425, 749, 60, 14 ], [ 493, 749, 41, 14 ], [ 541, 749, 60, 14 ], [ 609, 749, 9, 14 ], [ 625, 749, 48, 14 ], [ 680, 749, 11, 14 ], [ 155, 766, 54, 14 ], [ 212, 766, 20, 14 ], [ 235, 766, 18, 14 ], [ 257, 766, 47, 14 ], [ 307, 766, 33, 14 ], [ 343, 766, 9, 14 ], [ 355, 766, 59, 14 ], [ 417, 766, 47, 14 ], [ 467, 766, 10, 14 ], [ 481, 766, 18, 14 ], [ 502, 766, 74, 14 ], [ 579, 766, 39, 14 ], [ 76, 834, 84, 15 ], [ 76, 851, 65, 14 ], [ 146, 851, 59, 14 ], [ 210, 851, 13, 14 ], [ 227, 851, 34, 14 ], [ 266, 851, 9, 14 ], [ 280, 851, 105, 14 ], [ 390, 851, 10, 14 ], [ 404, 851, 7, 14 ], [ 76, 867, 23, 14 ], [ 104, 867, 54, 14 ], [ 162, 867, 49, 14 ], [ 216, 867, 12, 14 ], [ 233, 867, 69, 14 ], [ 308, 867, 36, 14 ], [ 349, 867, 45, 14 ], [ 399, 867, 12, 14 ], [ 76, 883, 38, 14 ], [ 118, 883, 15, 14 ], [ 136, 883, 62, 14 ], [ 202, 883, 51, 14 ], [ 257, 883, 13, 14 ], [ 273, 883, 49, 14 ], [ 326, 883, 59, 14 ], [ 388, 883, 23, 14 ], [ 76, 900, 24, 14 ], [ 104, 900, 33, 14 ], [ 141, 900, 55, 14 ], [ 201, 900, 19, 14 ], [ 224, 900, 42, 14 ], [ 271, 900, 46, 14 ], [ 321, 900, 18, 14 ], [ 344, 900, 35, 14 ], [ 383, 900, 28, 14 ], [ 76, 916, 59, 14 ], [ 145, 916, 27, 14 ], [ 182, 916, 72, 14 ], [ 265, 916, 22, 14 ], [ 297, 916, 45, 14 ], [ 352, 916, 59, 14 ], [ 76, 932, 67, 14 ], [ 150, 932, 47, 14 ], [ 204, 932, 72, 14 ], [ 283, 932, 45, 14 ], [ 335, 932, 10, 14 ], [ 352, 932, 60, 14 ], [ 76, 949, 72, 14 ], [ 152, 949, 15, 14 ], [ 170, 949, 52, 14 ], [ 226, 949, 71, 14 ], [ 301, 949, 43, 14 ], [ 347, 949, 14, 14 ], [ 365, 949, 34, 14 ], [ 403, 949, 9, 14 ], [ 76, 965, 68, 14 ], [ 148, 965, 10, 14 ], [ 161, 965, 21, 14 ], [ 185, 965, 56, 14 ], [ 245, 965, 29, 14 ], [ 278, 965, 38, 14 ], [ 319, 965, 43, 14 ], [ 365, 965, 33, 14 ], [ 401, 965, 10, 14 ], [ 76, 981, 19, 14 ], [ 99, 981, 27, 14 ], [ 130, 981, 52, 14 ], [ 186, 981, 38, 14 ], [ 228, 981, 12, 14 ], [ 245, 981, 34, 14 ], [ 283, 981, 9, 14 ], [ 295, 981, 11, 14 ], [ 311, 981, 19, 14 ], [ 334, 981, 43, 14 ], [ 381, 981, 31, 14 ], [ 76, 998, 19, 14 ], [ 98, 998, 36, 14 ], [ 137, 998, 7, 14 ], [ 147, 998, 23, 14 ], [ 172, 998, 27, 14 ], [ 202, 998, 75, 14 ], [ 280, 998, 35, 14 ], [ 318, 998, 42, 14 ], [ 363, 998, 48, 14 ], [ 434, 835, 25, 14 ], [ 464, 835, 60, 14 ], [ 529, 835, 35, 14 ], [ 569, 835, 77, 14 ], [ 651, 835, 23, 14 ], [ 678, 835, 35, 14 ], [ 718, 835, 52, 14 ], [ 434, 851, 43, 14 ], [ 487, 851, 36, 14 ], [ 533, 851, 71, 14 ], [ 615, 851, 26, 14 ], [ 651, 851, 24, 14 ], [ 685, 851, 23, 14 ], [ 717, 851, 34, 14 ], [ 761, 851, 9, 14 ], [ 434, 867, 63, 14 ], [ 500, 867, 55, 14 ], [ 560, 867, 34, 14 ], [ 597, 867, 61, 14 ], [ 662, 867, 61, 14 ], [ 726, 867, 27, 14 ], [ 757, 867, 12, 14 ], [ 434, 883, 25, 14 ], [ 463, 883, 39, 14 ], [ 506, 883, 41, 14 ], [ 551, 883, 69, 14 ], [ 624, 883, 31, 14 ], [ 658, 883, 43, 14 ], [ 705, 883, 65, 14 ], [ 434, 900, 30, 14 ], [ 467, 900, 35, 14 ], [ 504, 900, 39, 14 ], [ 545, 900, 63, 14 ], [ 611, 900, 35, 14 ], [ 648, 900, 39, 14 ], [ 689, 900, 66, 14 ], [ 757, 900, 13, 14 ], [ 434, 916, 34, 14 ], [ 472, 916, 68, 14 ], [ 545, 916, 12, 14 ], [ 561, 916, 19, 14 ], [ 585, 916, 80, 14 ], [ 668, 916, 57, 14 ], [ 730, 916, 40, 14 ], [ 434, 932, 28, 14 ], [ 466, 932, 29, 14 ], [ 498, 932, 60, 14 ], [ 561, 932, 27, 14 ], [ 592, 932, 62, 14 ], [ 657, 932, 59, 14 ], [ 720, 932, 12, 14 ], [ 736, 932, 34, 14 ], [ 434, 949, 9, 14 ], [ 445, 949, 33, 14 ], [ 480, 949, 19, 14 ], [ 502, 949, 79, 14 ], [ 583, 949, 63, 14 ], [ 649, 949, 12, 14 ], [ 663, 949, 34, 14 ], [ 699, 949, 9, 14 ], [ 710, 949, 59, 14 ], [ 434, 965, 27, 14 ], [ 464, 965, 46, 14 ], [ 513, 965, 20, 14 ], [ 536, 965, 20, 14 ], [ 559, 965, 29, 14 ], [ 591, 965, 56, 14 ], [ 650, 965, 17, 14 ], [ 670, 965, 29, 14 ], [ 701, 965, 46, 14 ], [ 750, 965, 10, 14 ], [ 763, 965, 7, 14 ], [ 434, 981, 53, 14 ], [ 491, 981, 54, 14 ], [ 548, 981, 32, 14 ], [ 584, 981, 13, 14 ], [ 599, 981, 35, 14 ], [ 638, 981, 77, 14 ], [ 719, 981, 12, 14 ], [ 735, 981, 35, 14 ], [ 434, 998, 57, 14 ], [ 496, 998, 12, 14 ], [ 513, 998, 19, 14 ], [ 537, 998, 48, 14 ], [ 590, 998, 20, 14 ], [ 614, 998, 35, 14 ], [ 654, 998, 32, 14 ], [ 690, 998, 34, 14 ], [ 729, 998, 41, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1069, 25, 10 ], [ 627, 1069, 33, 10 ], [ 662, 1069, 14, 10 ], [ 678, 1069, 12, 10 ], [ 692, 1069, 31, 10 ], [ 726, 1069, 44, 10 ] ]

[ "BMC", "Surgery", "Case", "report", "Splenectomy", "and", "proximal", "lieno-renal", "shunt", "in", "a", "factor", "five", "deficient", "patient", "with", "extra-hepatic", "portal", "vein", "obstruction", "Srinivas", "Prabhu", "Chava*1,", "Sujoy", "Pal1,", "Supriyo", "Ghatak1,", "Rajat", "Kumar2,", "Peush", "Sahni1", "and", "Tushar", "Kanti", "Chattopadhyay1", "BioMed", "Central", "Open", "Access", "Address:", "1Department", "of", "G.I.", "Surgery,", "All", "India", "Institute", "of", "Medical", "Sciences,", "New", "Delhi,", "110029,", "India", "and", "2Department", "of", "Hematology,", "All", "India", "Institute", "of", "Medical", "Sciences,", "New", "Delhi,", "110029,", "India", "Email:", "Srinivas", "Prabhu", "Chava*", "-", "spchava@yahoo.com;", "Sujoy", "Pal", "-", "sujoypal@hotmail.com;", "Supriyo", "Ghatak", "-", "drsupriyo@yahoo.co.in;", "Rajat", "Kumar", "-", "rajatkumar@hotmail.com;", "Peush", "Sahni", "-", "peush_sahni@hotmail.com;", "Tushar", "Kanti", "Chattopadhyay", "-", "tkc46@hotmail.com", "*", "Corresponding", "author", "Published:", "19", "May", "2006", "BMC", "Surgery", "2006,", "6:7", "doi:10.1186/1471-2482-6-7", "This", "article", "is", "available", "from:", "http://www.biomedcentral.com/1471-2482/6/7", "Received:", "20", "September", "2005", "Accepted:", "19", "May", "2006", "©", "2006", "Chava", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "The", "clinico-surgical", "implication", "and", "successful", "management", "of", "a", "rare", "case", "of", "factor", "five", "(V)", "deficiency", "with", "portal", "hypertension", "and", "hypersplenism", "due", "to", "idiopathic", "extra-hepatic", "portal", "venous", "obstruction", "is", "presented.", "Case", "presentation:", "A", "16-year", "old", "boy", "had", "gastro-esophageal", "variceal", "bleeding,", "splenomegaly", "and", "hypersplenism.", "During", "preoperative", "workup", "prolonged", "prothrombin", "time", "and", "activated", "partial", "thromboplastin", "time", "were", "detected,", "which", "on", "further", "evaluation", "turned", "out", "to", "be", "due", "to", "factor", "V", "deficiency.", "Proximal", "lieno-renal", "shunt", "and", "splenectomy", "were", "successfully", "performed", "with", "transfusion", "of", "fresh", "frozen", "plasma", "during", "and", "after", "the", "surgical", "procedure.", "At", "surgery", "there", "was", "no", "excessive", "bleeding.", "The", "perioperative", "course", "was", "uneventful", "and", "the", "patient", "is", "doing", "well", "on", "follow", "up.", "Conclusion:", "Surgical", "portal", "decompressive", "procedures", "can", "be", "safely", "undertaken", "in", "clotting", "factor", "deficient", "patients", "with", "portal", "hypertension", "if", "meticulous", "surgical", "hemostasis", "is", "achieved", "at", "operation", "and", "the", "deficient", "factor", "is", "adequately", "replaced", "in", "the", "perioperative", "period.", "Background", "Congenital", "deficiency", "of", "factor", "V", "(parahemophilia)", "is", "a", "rare", "inherited", "disorder", "of", "coagulation", "which", "appears", "to", "follow", "an", "autosomal", "recessive", "or", "partially", "dominant", "pat-", "tern", "[1-4].", "Although", "the", "clinical", "features", "are", "rather", "mild", "compared", "with", "hemophilia,", "any", "surgical", "procedure", "undertaken", "without", "replacement", "therapy", "is", "uniformly", "complicated", "by", "excessive", "hemorrhage", "[1,2,5].", "As", "factor", "V", "concentrate", "is", "not", "available,", "fresh", "frozen", "plasma", "(FFP)", "is", "the", "only", "available", "source", "of", "factor", "V", "at", "the", "present", "time.", "We", "report", "a", "boy", "with", "extra-hepatic", "portal", "venous", "obstruc-", "tion", "(EHPVO),", "portal", "hypertension", "and", "upper", "gastroin-", "testinal", "(UGI)", "hemorrhage", "who", "also", "had", "factor", "V", "deficiency.", "Although", "many", "congenital", "anomalies", "such", "as", "cleft", "palate,", "mental", "retardation,", "short", "stature,", "syndactyly,", "atrial", "septal", "defect,", "ventricular", "septal", "defect,", "coarctation", "of", "aorta,", "duplication", "of", "the", "genitourinary", "collecting", "system", "have", "been", "associated", "with", "congenital", "deficiency", "of", "factor", "V", "[1-4],", "the", "simultaneous", "occurrence", "of", "factor", "V", "deficiency", "with", "EHPVO", "has", "not", "been", "described", "till", "date.", "EHPVO", "is", "a", "relatively", "common", "cause", "of", "portal", "hypertension", "in", "India,", "especially", "in", "the", "younger", "age", "group", "[6,7].", "Many", "causes,", "Page", "1", "of", "5", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 608, 33, 47, 12 ], [ 658, 33, 52, 12 ], [ 604, 45, 41, 10 ], [ 647, 45, 10, 10 ], [ 660, 45, 29, 10 ], [ 691, 45, 19, 10 ], [ 587, 56, 15, 10 ], [ 604, 56, 106, 10 ], [ 62, 83, 95, 26 ], [ 164, 83, 131, 26 ], [ 301, 83, 59, 26 ], [ 366, 83, 41, 26 ], [ 414, 83, 90, 26 ], [ 510, 83, 187, 26 ], [ 704, 83, 27, 26 ], [ 62, 112, 88, 25 ], [ 157, 112, 34, 25 ], [ 197, 112, 85, 25 ], [ 289, 112, 142, 25 ], [ 62, 154, 48, 14 ], [ 114, 154, 59, 14 ], [ 174, 153, 17, 15 ], [ 194, 154, 59, 14 ], [ 257, 154, 12, 14 ], [ 272, 154, 69, 14 ], [ 342, 153, 10, 15 ], [ 355, 154, 43, 14 ], [ 402, 154, 14, 14 ], [ 420, 154, 17, 14 ], [ 441, 154, 38, 14 ], [ 480, 153, 10, 15 ], [ 493, 154, 47, 14 ], [ 543, 154, 14, 14 ], [ 560, 154, 51, 14 ], [ 613, 153, 5, 9 ], [ 622, 154, 25, 14 ], [ 62, 170, 27, 14 ], [ 93, 170, 15, 14 ], [ 111, 170, 49, 14 ], [ 161, 169, 5, 9 ], [ 62, 194, 4, 6 ], [ 69, 195, 53, 10 ], [ 124, 195, 9, 10 ], [ 135, 195, 30, 10 ], [ 168, 195, 16, 10 ], [ 186, 195, 58, 10 ], [ 246, 195, 48, 10 ], [ 296, 195, 24, 10 ], [ 322, 195, 29, 10 ], [ 354, 195, 40, 10 ], [ 396, 195, 32, 10 ], [ 430, 195, 43, 10 ], [ 475, 195, 35, 10 ], [ 512, 195, 32, 10 ], [ 546, 195, 44, 10 ], [ 592, 195, 9, 10 ], [ 603, 195, 54, 10 ], [ 659, 195, 54, 10 ], [ 69, 208, 53, 10 ], [ 62, 221, 4, 6 ], [ 69, 221, 53, 10 ], [ 124, 221, 9, 10 ], [ 135, 221, 39, 10 ], [ 176, 221, 16, 10 ], [ 195, 221, 54, 10 ], [ 251, 221, 30, 10 ], [ 283, 221, 44, 10 ], [ 328, 221, 35, 10 ], [ 365, 221, 32, 10 ], [ 399, 221, 33, 10 ], [ 433, 221, 53, 10 ], [ 62, 234, 4, 6 ], [ 69, 234, 53, 10 ], [ 124, 234, 9, 10 ], [ 135, 234, 41, 10 ], [ 178, 234, 54, 10 ], [ 234, 234, 16, 10 ], [ 253, 234, 49, 10 ], [ 304, 234, 24, 10 ], [ 330, 234, 29, 10 ], [ 361, 234, 41, 10 ], [ 404, 234, 32, 10 ], [ 438, 234, 43, 10 ], [ 483, 234, 35, 10 ], [ 520, 234, 32, 10 ], [ 553, 234, 44, 10 ], [ 599, 234, 9, 10 ], [ 611, 234, 54, 10 ], [ 667, 234, 54, 10 ], [ 69, 247, 53, 10 ], [ 62, 288, 30, 10 ], [ 95, 288, 14, 10 ], [ 62, 301, 23, 10 ], [ 87, 301, 18, 10 ], [ 107, 301, 38, 10 ], [ 147, 301, 44, 10 ], [ 193, 301, 9, 10 ], [ 62, 314, 54, 10 ], [ 118, 314, 53, 10 ], [ 62, 331, 46, 10 ], [ 110, 331, 15, 10 ], [ 62, 344, 21, 10 ], [ 86, 344, 7, 10 ], [ 94, 344, 13, 10 ], [ 110, 344, 23, 10 ], [ 135, 344, 44, 10 ], [ 181, 344, 35, 10 ], [ 62, 357, 30, 10 ], [ 94, 357, 35, 10 ], [ 132, 357, 53, 10 ], [ 62, 370, 34, 10 ], [ 98, 370, 23, 10 ], [ 123, 370, 29, 10 ], [ 154, 370, 29, 10 ], [ 62, 388, 84, 10 ], [ 62, 401, 32, 10 ], [ 96, 401, 42, 10 ], [ 140, 401, 53, 10 ], [ 195, 401, 9, 10 ], [ 62, 414, 31, 10 ], [ 95, 414, 16, 10 ], [ 114, 414, 58, 10 ], [ 62, 427, 48, 10 ], [ 112, 427, 24, 10 ], [ 139, 427, 29, 10 ], [ 170, 427, 40, 10 ], [ 62, 440, 32, 10 ], [ 96, 440, 43, 10 ], [ 141, 440, 35, 10 ], [ 178, 440, 32, 10 ], [ 62, 454, 44, 10 ], [ 108, 454, 9, 10 ], [ 120, 454, 54, 10 ], [ 62, 467, 23, 10 ], [ 88, 467, 32, 10 ], [ 122, 467, 60, 10 ], [ 183, 467, 14, 10 ], [ 62, 480, 14, 10 ], [ 78, 480, 17, 10 ], [ 98, 480, 31, 10 ], [ 130, 480, 21, 10 ], [ 153, 480, 14, 10 ], [ 62, 493, 54, 10 ], [ 119, 493, 56, 10 ], [ 62, 506, 29, 10 ], [ 94, 506, 103, 10 ], [ 242, 285, 44, 14 ], [ 290, 285, 69, 14 ], [ 364, 285, 19, 14 ], [ 388, 285, 7, 14 ], [ 400, 285, 33, 14 ], [ 438, 285, 35, 14 ], [ 478, 285, 12, 14 ], [ 496, 285, 55, 14 ], [ 556, 285, 22, 14 ], [ 583, 285, 55, 14 ], [ 643, 285, 11, 14 ], [ 659, 285, 48, 14 ], [ 712, 285, 51, 14 ], [ 242, 301, 19, 14 ], [ 267, 301, 48, 14 ], [ 321, 301, 12, 14 ], [ 340, 301, 44, 14 ], [ 390, 301, 41, 14 ], [ 438, 301, 40, 14 ], [ 484, 301, 28, 14 ], [ 518, 301, 14, 14 ], [ 539, 301, 61, 14 ], [ 607, 301, 62, 14 ], [ 675, 301, 43, 14 ], [ 725, 301, 39, 14 ], [ 242, 318, 29, 14 ], [ 276, 318, 19, 14 ], [ 301, 318, 21, 14 ], [ 327, 318, 14, 14 ], [ 347, 318, 35, 14 ], [ 388, 318, 60, 14 ], [ 454, 318, 51, 14 ], [ 511, 318, 21, 14 ], [ 538, 318, 30, 14 ], [ 573, 318, 34, 14 ], [ 612, 318, 11, 14 ], [ 629, 318, 61, 14 ], [ 695, 318, 19, 14 ], [ 721, 318, 43, 14 ], [ 242, 335, 39, 14 ], [ 284, 335, 69, 14 ], [ 357, 335, 22, 14 ], [ 382, 335, 11, 14 ], [ 396, 335, 50, 14 ], [ 450, 335, 19, 14 ], [ 472, 335, 30, 14 ], [ 506, 335, 41, 14 ], [ 551, 335, 22, 14 ], [ 576, 335, 44, 14 ], [ 623, 335, 74, 14 ], [ 701, 335, 62, 14 ], [ 242, 351, 26, 14 ], [ 274, 351, 20, 14 ], [ 300, 351, 45, 14 ], [ 351, 351, 62, 14 ], [ 420, 351, 73, 14 ], [ 499, 351, 62, 14 ], [ 568, 351, 69, 14 ], [ 644, 351, 74, 14 ], [ 725, 351, 12, 14 ], [ 744, 351, 19, 14 ], [ 242, 368, 114, 14 ], [ 363, 368, 85, 14 ], [ 455, 368, 12, 14 ], [ 474, 368, 15, 14 ], [ 495, 368, 18, 14 ], [ 519, 368, 45, 14 ], [ 571, 368, 53, 14 ], [ 630, 368, 10, 14 ], [ 647, 368, 37, 14 ], [ 690, 368, 30, 14 ], [ 727, 368, 11, 14 ], [ 744, 368, 19, 14 ], [ 242, 384, 35, 14 ], [ 282, 384, 85, 14 ], [ 373, 384, 29, 14 ], [ 408, 384, 77, 14 ], [ 491, 384, 55, 14 ], [ 552, 384, 20, 14 ], [ 577, 384, 47, 14 ], [ 630, 384, 12, 14 ], [ 647, 384, 28, 14 ], [ 680, 384, 42, 14 ], [ 728, 384, 15, 14 ], [ 748, 384, 16, 14 ], [ 242, 401, 28, 14 ], [ 274, 401, 32, 14 ], [ 311, 401, 15, 14 ], [ 331, 401, 77, 14 ], [ 413, 401, 64, 14 ], [ 482, 401, 50, 14 ], [ 536, 401, 11, 14 ], [ 552, 401, 35, 14 ], [ 591, 401, 35, 14 ], [ 631, 401, 18, 14 ], [ 654, 401, 45, 14 ], [ 704, 401, 36, 14 ], [ 745, 401, 19, 14 ], [ 242, 417, 61, 14 ], [ 309, 417, 11, 14 ], [ 325, 417, 67, 14 ], [ 398, 417, 30, 14 ], [ 435, 417, 12, 14 ], [ 453, 417, 33, 14 ], [ 492, 417, 38, 14 ], [ 536, 417, 61, 14 ], [ 603, 417, 41, 14 ], [ 650, 417, 44, 14 ], [ 700, 417, 28, 14 ], [ 734, 417, 30, 14 ], [ 242, 434, 63, 14 ], [ 311, 434, 19, 14 ], [ 337, 434, 33, 14 ], [ 376, 434, 24, 14 ], [ 407, 434, 28, 14 ], [ 440, 434, 60, 14 ], [ 507, 434, 84, 14 ], [ 597, 434, 50, 14 ], [ 653, 434, 41, 14 ], [ 700, 434, 12, 14 ], [ 718, 434, 45, 14 ], [ 242, 451, 69, 14 ], [ 316, 451, 22, 14 ], [ 343, 451, 56, 14 ], [ 404, 451, 23, 14 ], [ 432, 451, 47, 14 ], [ 484, 451, 27, 14 ], [ 516, 451, 21, 14 ], [ 542, 451, 15, 14 ], [ 562, 451, 87, 14 ], [ 655, 451, 12, 14 ], [ 672, 451, 72, 14 ], [ 750, 451, 14, 14 ], [ 242, 467, 46, 14 ], [ 293, 467, 63, 14 ], [ 361, 467, 30, 14 ], [ 396, 467, 27, 14 ], [ 427, 467, 36, 14 ], [ 467, 467, 21, 14 ], [ 493, 467, 59, 14 ], [ 557, 467, 33, 14 ], [ 595, 467, 45, 14 ], [ 645, 467, 31, 14 ], [ 680, 467, 8, 14 ], [ 693, 467, 51, 14 ], [ 749, 467, 14, 14 ], [ 242, 484, 67, 14 ], [ 314, 484, 12, 14 ], [ 331, 484, 52, 14 ], [ 389, 484, 44, 14 ], [ 438, 484, 22, 14 ], [ 465, 484, 93, 14 ], [ 564, 484, 20, 14 ], [ 589, 484, 27, 14 ], [ 622, 484, 28, 14 ], [ 656, 484, 35, 14 ], [ 696, 484, 41, 14 ], [ 742, 484, 22, 14 ], [ 242, 500, 52, 14 ], [ 298, 500, 41, 14 ], [ 343, 500, 28, 14 ], [ 375, 500, 21, 14 ], [ 400, 500, 15, 14 ], [ 419, 500, 51, 14 ], [ 474, 500, 36, 14 ], [ 514, 500, 62, 14 ], [ 581, 500, 42, 14 ], [ 627, 500, 41, 14 ], [ 672, 500, 37, 14 ], [ 713, 500, 50, 14 ], [ 242, 517, 21, 14 ], [ 265, 517, 15, 14 ], [ 283, 517, 43, 14 ], [ 329, 517, 11, 14 ], [ 342, 517, 26, 14 ], [ 371, 517, 22, 14 ], [ 395, 517, 29, 14 ], [ 427, 517, 12, 14 ], [ 441, 517, 51, 14 ], [ 495, 517, 74, 14 ], [ 572, 517, 12, 14 ], [ 587, 517, 45, 14 ], [ 635, 517, 22, 14 ], [ 659, 517, 43, 14 ], [ 705, 517, 58, 14 ], [ 242, 534, 22, 14 ], [ 266, 534, 51, 14 ], [ 321, 534, 16, 14 ], [ 340, 534, 26, 14 ], [ 369, 534, 58, 14 ], [ 430, 534, 33, 14 ], [ 466, 534, 18, 14 ], [ 487, 534, 39, 14 ], [ 530, 534, 20, 14 ], [ 552, 534, 45, 14 ], [ 600, 534, 30, 14 ], [ 634, 534, 12, 14 ], [ 649, 534, 20, 14 ], [ 671, 534, 16, 14 ], [ 690, 534, 26, 14 ], [ 719, 534, 44, 14 ], [ 242, 550, 12, 14 ], [ 257, 550, 41, 14 ], [ 301, 550, 45, 14 ], [ 350, 550, 44, 14 ], [ 397, 550, 42, 14 ], [ 442, 550, 60, 14 ], [ 505, 550, 32, 14 ], [ 540, 550, 29, 14 ], [ 572, 550, 64, 14 ], [ 640, 550, 22, 14 ], [ 665, 550, 35, 14 ], [ 703, 550, 28, 14 ], [ 734, 550, 30, 14 ], [ 242, 567, 52, 14 ], [ 297, 567, 80, 14 ], [ 382, 567, 43, 14 ], [ 428, 567, 28, 14 ], [ 460, 567, 43, 14 ], [ 506, 567, 44, 14 ], [ 554, 567, 28, 14 ], [ 585, 567, 30, 14 ], [ 618, 567, 57, 14 ], [ 679, 567, 16, 14 ], [ 699, 567, 20, 14 ], [ 722, 567, 41, 14 ], [ 242, 584, 62, 14 ], [ 308, 584, 69, 14 ], [ 383, 584, 52, 14 ], [ 440, 584, 36, 14 ], [ 481, 584, 36, 14 ], [ 522, 584, 84, 14 ], [ 611, 584, 64, 14 ], [ 680, 584, 83, 14 ], [ 242, 600, 59, 14 ], [ 307, 600, 22, 14 ], [ 335, 600, 106, 14 ], [ 447, 600, 72, 14 ], [ 526, 600, 61, 14 ], [ 594, 600, 65, 14 ], [ 665, 600, 44, 14 ], [ 715, 600, 11, 14 ], [ 733, 600, 30, 14 ], [ 242, 617, 38, 14 ], [ 285, 617, 20, 14 ], [ 310, 617, 82, 14 ], [ 398, 617, 85, 14 ], [ 490, 617, 68, 14 ], [ 564, 617, 19, 14 ], [ 589, 617, 45, 14 ], [ 639, 617, 63, 14 ], [ 708, 617, 22, 14 ], [ 736, 617, 28, 14 ], [ 242, 633, 42, 14 ], [ 286, 633, 50, 14 ], [ 340, 633, 76, 14 ], [ 420, 633, 16, 14 ], [ 439, 633, 31, 14 ], [ 473, 633, 39, 14 ], [ 515, 633, 22, 14 ], [ 540, 633, 41, 14 ], [ 584, 633, 97, 14 ], [ 685, 633, 9, 14 ], [ 696, 633, 10, 14 ], [ 709, 633, 54, 14 ], [ 242, 650, 23, 14 ], [ 272, 650, 19, 14 ], [ 298, 650, 27, 14 ], [ 332, 650, 20, 14 ], [ 359, 650, 15, 14 ], [ 382, 650, 36, 14 ], [ 425, 650, 11, 14 ], [ 442, 650, 20, 14 ], [ 469, 650, 76, 14 ], [ 553, 650, 12, 14 ], [ 572, 650, 95, 14 ], [ 674, 650, 40, 14 ], [ 721, 650, 16, 14 ], [ 744, 650, 19, 14 ], [ 242, 667, 78, 14 ], [ 323, 667, 12, 14 ], [ 338, 667, 33, 14 ], [ 375, 667, 58, 14 ], [ 242, 694, 49, 10 ], [ 295, 694, 37, 10 ], [ 336, 694, 52, 10 ], [ 392, 694, 24, 10 ], [ 420, 694, 24, 10 ], [ 448, 694, 33, 10 ], [ 486, 694, 51, 10 ], [ 541, 694, 54, 10 ], [ 599, 694, 85, 10 ], [ 688, 694, 76, 10 ], [ 242, 708, 36, 10 ], [ 279, 708, 18, 10 ], [ 300, 708, 25, 10 ], [ 62, 739, 90, 14 ], [ 62, 755, 42, 14 ], [ 110, 755, 65, 14 ], [ 180, 755, 19, 14 ], [ 205, 755, 13, 14 ], [ 223, 755, 17, 14 ], [ 246, 755, 61, 14 ], [ 313, 755, 20, 14 ], [ 339, 755, 16, 14 ], [ 361, 755, 6, 14 ], [ 373, 755, 32, 14 ], [ 62, 771, 29, 14 ], [ 94, 771, 11, 14 ], [ 107, 771, 54, 14 ], [ 164, 771, 20, 14 ], [ 187, 771, 50, 14 ], [ 239, 771, 11, 14 ], [ 253, 771, 54, 14 ], [ 310, 771, 40, 14 ], [ 352, 771, 31, 14 ], [ 385, 771, 20, 14 ], [ 62, 787, 32, 14 ], [ 98, 787, 34, 14 ], [ 136, 787, 12, 14 ], [ 152, 787, 28, 14 ], [ 184, 787, 45, 14 ], [ 233, 787, 27, 14 ], [ 264, 787, 60, 14 ], [ 328, 787, 39, 14 ], [ 371, 787, 35, 14 ], [ 62, 803, 30, 14 ], [ 97, 803, 11, 14 ], [ 114, 803, 17, 14 ], [ 136, 803, 35, 14 ], [ 176, 803, 11, 14 ], [ 193, 803, 28, 14 ], [ 226, 803, 47, 14 ], [ 278, 803, 12, 14 ], [ 295, 803, 48, 14 ], [ 348, 803, 32, 14 ], [ 385, 803, 21, 14 ], [ 62, 819, 27, 14 ], [ 93, 819, 34, 14 ], [ 131, 819, 21, 14 ], [ 156, 819, 45, 14 ], [ 205, 819, 34, 14 ], [ 243, 819, 12, 14 ], [ 260, 819, 44, 14 ], [ 307, 819, 45, 14 ], [ 357, 819, 17, 14 ], [ 379, 819, 27, 14 ], [ 62, 835, 46, 14 ], [ 111, 835, 11, 14 ], [ 124, 835, 39, 14 ], [ 165, 835, 60, 14 ], [ 227, 835, 35, 14 ], [ 264, 835, 25, 14 ], [ 291, 835, 13, 14 ], [ 307, 835, 58, 14 ], [ 367, 835, 38, 14 ], [ 62, 851, 29, 14 ], [ 96, 851, 37, 14 ], [ 137, 851, 20, 14 ], [ 162, 851, 44, 14 ], [ 211, 851, 34, 14 ], [ 249, 851, 31, 14 ], [ 285, 851, 19, 14 ], [ 308, 851, 13, 14 ], [ 326, 851, 41, 14 ], [ 371, 851, 34, 14 ], [ 62, 867, 30, 14 ], [ 97, 867, 22, 14 ], [ 124, 867, 29, 14 ], [ 157, 867, 54, 14 ], [ 215, 867, 24, 14 ], [ 244, 867, 52, 14 ], [ 301, 867, 28, 14 ], [ 334, 867, 37, 14 ], [ 376, 867, 30, 14 ], [ 62, 883, 11, 14 ], [ 76, 883, 70, 14 ], [ 148, 883, 91, 14 ], [ 242, 883, 20, 14 ], [ 265, 883, 29, 14 ], [ 296, 883, 54, 14 ], [ 353, 883, 24, 14 ], [ 380, 883, 25, 14 ], [ 62, 898, 28, 14 ], [ 94, 898, 37, 14 ], [ 136, 898, 11, 14 ], [ 151, 898, 17, 14 ], [ 172, 898, 61, 14 ], [ 238, 898, 40, 14 ], [ 282, 898, 28, 14 ], [ 314, 898, 30, 14 ], [ 349, 898, 20, 14 ], [ 373, 898, 32, 14 ], [ 62, 914, 34, 14 ], [ 78, 930, 26, 14 ], [ 111, 930, 17, 14 ], [ 134, 930, 18, 14 ], [ 159, 930, 13, 14 ], [ 178, 930, 30, 14 ], [ 214, 930, 31, 14 ], [ 251, 930, 45, 14 ], [ 302, 930, 18, 14 ], [ 326, 930, 25, 14 ], [ 358, 930, 30, 14 ], [ 394, 930, 11, 14 ], [ 62, 946, 58, 14 ], [ 122, 946, 17, 14 ], [ 141, 946, 38, 14 ], [ 181, 946, 62, 14 ], [ 245, 946, 20, 14 ], [ 268, 946, 39, 14 ], [ 309, 946, 20, 14 ], [ 331, 946, 38, 14 ], [ 371, 946, 34, 14 ], [ 62, 962, 37, 14 ], [ 105, 962, 58, 14 ], [ 168, 962, 17, 14 ], [ 190, 962, 39, 14 ], [ 235, 962, 44, 14 ], [ 283, 962, 57, 14 ], [ 345, 962, 60, 14 ], [ 62, 978, 61, 14 ], [ 127, 978, 51, 14 ], [ 182, 978, 17, 14 ], [ 203, 978, 27, 14 ], [ 234, 978, 18, 14 ], [ 256, 978, 53, 14 ], [ 313, 978, 44, 14 ], [ 360, 978, 45, 14 ], [ 421, 739, 55, 14 ], [ 481, 739, 32, 14 ], [ 518, 739, 21, 14 ], [ 544, 739, 97, 14 ], [ 647, 739, 70, 14 ], [ 722, 739, 42, 14 ], [ 421, 755, 22, 14 ], [ 447, 755, 60, 14 ], [ 513, 755, 43, 14 ], [ 561, 755, 37, 14 ], [ 603, 755, 20, 14 ], [ 628, 755, 45, 14 ], [ 678, 755, 34, 14 ], [ 717, 755, 24, 14 ], [ 745, 755, 18, 14 ], [ 421, 771, 48, 14 ], [ 473, 771, 55, 14 ], [ 532, 771, 41, 14 ], [ 578, 771, 22, 14 ], [ 604, 771, 27, 14 ], [ 635, 771, 49, 14 ], [ 689, 771, 20, 14 ], [ 713, 771, 11, 14 ], [ 729, 771, 6, 14 ], [ 739, 771, 25, 14 ], [ 421, 787, 48, 14 ], [ 474, 787, 51, 14 ], [ 531, 787, 17, 14 ], [ 553, 787, 69, 14 ], [ 628, 787, 11, 14 ], [ 645, 787, 41, 14 ], [ 692, 787, 45, 14 ], [ 742, 787, 21, 14 ], [ 421, 803, 58, 14 ], [ 483, 803, 11, 14 ], [ 499, 803, 38, 14 ], [ 542, 803, 23, 14 ], [ 570, 803, 18, 14 ], [ 593, 803, 33, 14 ], [ 631, 803, 13, 14 ], [ 649, 803, 55, 14 ], [ 709, 803, 55, 14 ], [ 421, 819, 21, 14 ], [ 445, 819, 57, 14 ], [ 505, 819, 26, 14 ], [ 534, 819, 96, 14 ], [ 633, 819, 71, 14 ], [ 707, 819, 11, 14 ], [ 721, 819, 42, 14 ], [ 421, 835, 10, 14 ], [ 436, 835, 20, 14 ], [ 460, 835, 20, 14 ], [ 485, 835, 46, 14 ], [ 535, 835, 16, 14 ], [ 556, 835, 17, 14 ], [ 578, 835, 34, 14 ], [ 616, 835, 86, 14 ], [ 707, 835, 11, 14 ], [ 722, 835, 41, 14 ], [ 421, 851, 19, 14 ], [ 446, 851, 49, 14 ], [ 501, 851, 50, 14 ], [ 557, 851, 10, 14 ], [ 574, 851, 16, 14 ], [ 595, 851, 34, 14 ], [ 635, 851, 39, 14 ], [ 680, 851, 22, 14 ], [ 708, 851, 56, 14 ], [ 421, 867, 57, 14 ], [ 480, 867, 68, 14 ], [ 552, 867, 25, 14 ], [ 579, 867, 55, 14 ], [ 637, 867, 55, 14 ], [ 695, 867, 68, 14 ], [ 421, 883, 38, 14 ], [ 462, 883, 11, 14 ], [ 478, 883, 37, 14 ], [ 519, 883, 20, 14 ], [ 543, 883, 49, 14 ], [ 596, 883, 22, 14 ], [ 622, 883, 38, 14 ], [ 663, 883, 69, 14 ], [ 736, 883, 27, 14 ], [ 421, 899, 22, 14 ], [ 447, 899, 17, 14 ], [ 469, 899, 35, 14 ], [ 508, 899, 11, 14 ], [ 524, 899, 17, 14 ], [ 545, 899, 25, 14 ], [ 574, 899, 41, 14 ], [ 621, 899, 22, 14 ], [ 647, 899, 73, 14 ], [ 724, 899, 40, 14 ], [ 421, 914, 34, 14 ], [ 460, 914, 50, 14 ], [ 515, 914, 27, 14 ], [ 548, 914, 9, 14 ], [ 561, 914, 67, 14 ], [ 633, 914, 48, 14 ], [ 687, 914, 11, 14 ], [ 703, 914, 60, 14 ], [ 421, 930, 56, 14 ], [ 480, 930, 11, 14 ], [ 495, 930, 61, 14 ], [ 558, 930, 58, 14 ], [ 620, 930, 25, 14 ], [ 648, 930, 35, 14 ], [ 686, 930, 41, 14 ], [ 731, 930, 33, 14 ], [ 421, 946, 17, 14 ], [ 440, 946, 17, 14 ], [ 460, 946, 27, 14 ], [ 490, 946, 50, 14 ], [ 542, 946, 50, 14 ], [ 594, 946, 10, 14 ], [ 607, 946, 16, 14 ], [ 625, 946, 34, 14 ], [ 437, 962, 48, 14 ], [ 486, 962, 17, 14 ], [ 506, 962, 105, 14 ], [ 613, 962, 20, 14 ], [ 635, 962, 54, 14 ], [ 691, 962, 72, 14 ], [ 421, 978, 11, 14 ], [ 439, 978, 6, 14 ], [ 452, 978, 50, 14 ], [ 509, 978, 54, 14 ], [ 570, 978, 24, 14 ], [ 601, 978, 38, 14 ], [ 646, 978, 60, 14 ], [ 713, 978, 9, 14 ], [ 729, 978, 35, 14 ], [ 62, 1035, 100, 11 ], [ 594, 1035, 31, 10 ], [ 627, 1035, 21, 10 ], [ 650, 1035, 3, 10 ], [ 655, 1035, 33, 10 ], [ 690, 1035, 6, 10 ], [ 698, 1035, 3, 10 ], [ 703, 1035, 28, 10 ], [ 733, 1035, 17, 10 ], [ 753, 1035, 3, 11 ], [ 758, 1035, 6, 10 ] ]

[ "REVIEW", "ARTICLE", "published:", "31", "August", "2012", "doi:", "10.3389/fphys.2012.00346", "Induced", "pluripotent", "stem", "cell", "derived", "cardiomyocytes", "as", "models", "for", "cardiac", "arrhythmias", "Maaike", "Hoekstra", "1*,", "Christine", "L.", "Mummery", "2,", "Arthur", "A.", "M.", "Wilde", "1,", "Connie", "R.", "Bezzina", "1", "and", "Arie", "O.", "Verkerk", "3", "1", "Department", "of", "Clinical", "and", "Experimental", "Cardiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "Amsterdam,", "Netherlands", "2", "Department", "of", "Anatomy", "and", "Embryology,", "Leiden", "University", "Medical", "Center,", "Leiden,", "Netherlands", "3", "Department", "of", "Anatomy,", "Embryology,", "and", "Physiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "Amsterdam,", "Netherlands", "Edited", "by:", "Carol", "Ann", "Remme,", "University", "of", "Amsterdam,", "Netherlands", "Reviewed", "by:", "Teun", "P.", "De", "Boer,", "University", "Medical", "Center", "Utrecht,", "Netherlands", "Isabelle", "Baro,", "CNRS,", "France", "*Correspondence:", "Maaike", "Hoekstra,", "Department", "of", "Clinical", "and", "Experimental", "Cardiology,", "Heart", "Failure", "Research", "Center,", "Academic", "Medical", "Center,", "University", "of", "Amsterdam,", "room", "K2-113,", "Meibergdreef", "15,", "PO", "Box", "22700,", "1100", "DE", "Amsterdam,", "Netherlands.", "e-mail:", "m.hoekstra@amc.uva.nl", "Cardiac", "arrhythmias", "are", "a", "major", "cause", "of", "morbidity", "and", "mortality.", "In", "younger", "patients,", "the", "majority", "of", "sudden", "cardiac", "deaths", "have", "an", "underlying", "Mendelian", "genetic", "cause.", "Over", "the", "last", "15", "years,", "enormous", "progress", "has", "been", "made", "in", "identifying", "the", "distinct", "clinical", "phenotypes", "and", "in", "studying", "the", "basic", "cellular", "and", "genetic", "mechanisms", "associated", "with", "the", "primary", "Mendelian", "(monogenic)", "arrhythmia", "syndromes.", "Investigation", "of", "the", "electrophysiological", "consequences", "of", "an", "ion", "channel", "mutation", "is", "ideally", "done", "in", "the", "native", "cardiomyocyte", "(CM)", "environment.", "However,", "the", "majority", "of", "such", "studies", "so", "far", "have", "relied", "on", "heterologous", "expression", "systems", "in", "which", "single", "ion", "channel", "genes", "are", "expressed", "in", "non-cardiac", "cells.", "In", "some", "cases,", "transgenic", "mouse", "models", "have", "been", "generated,", "but", "these", "also", "have", "significant", "shortcomings,", "primarily", "related", "to", "species", "differences.", "The", "discovery", "that", "somatic", "cells", "can", "be", "reprogrammed", "to", "pluripotency", "as", "induced", "pluripotent", "stem", "cells", "(iPSC)", "has", "generated", "much", "interest", "since", "it", "presents", "an", "opportunity", "to", "generate", "patient-", "and", "disease-specific", "cell", "lines", "from", "which", "normal", "and", "diseased", "human", "CMs", "can", "be", "obtained", "These", "genetically", "diverse", "human", "model", "systems", "can", "be", "studied", "in", "vitro", "and", "used", "to", "decipher", "mechanisms", "of", "disease", "and", "identify", "strategies", "and", "reagents", "for", "new", "therapies.", "Here,", "we", "review", "the", "present", "state", "of", "the", "art", "with", "respect", "to", "cardiac", "disease", "models", "already", "generated", "using", "IPSC", "technology", "and", "which", "have", "been", "(partially)", "characterized.", "Human", "iPSC", "(hiPSC)", "models", "have", "been", "described", "for", "the", "cardiac", "arrhythmia", "syndromes,", "including", "LQT1,", "LQT2,", "LQT3-Brugada", "Syndrome,", "LQT8/Timothy", "syndrome", "and", "catecholaminergic", "polymorphic", "ventricular", "tachycardia", "(CPVT).", "In", "most", "cases,", "the", "hiPSC-derived", "cardiomyoctes", "recapitulate", "the", "disease", "phenotype", "and", "have", "already", "provided", "opportunities", "for", "novel", "insight", "into", "cardiac", "pathophysiology.", "It", "is", "expected", "that", "the", "lines", "will", "be", "useful", "in", "the", "development", "of", "pharmacological", "agents", "for", "the", "management", "of", "these", "disorders.", "Keywords:", "induced", "pluripotent", "stem", "cells,", "cardiac", "arrhythmia", "syndromes,", "electrophysiology,", "cardiomyocytes,", "human,", "iPS,", "heart", "INTRODUCTION", "Cardiac", "arrhythmias", "can", "be", "life", "threatening", "and", "are", "a", "major", "cause", "of", "morbidity", "and", "mortality", "in", "developed", "nations", "(Wolf", "and", "Berul,", "2008).", "In", "older", "patients,", "most", "arrhythmic", "sudden", "deaths", "occur", "in", "the", "setting", "of", "acute", "ischemia", "or", "coronary", "artery", "dis-", "eases", "(Zipes", "and", "Wellens,", "1998).", "In", "younger", "patients,", "the", "great", "majority", "of", "sudden", "arrhythmic", "deaths", "have", "an", "underlying", "genetic", "cause", "(Wilde", "and", "Bezzina,", "2005).", "These", "can", "be", "broadly", "subdi-", "vided", "into", "those", "associated", "with", "structural", "heart", "disease", "(such", "as", "hypertrophic", "cardiomyopathy)", "and", "those", "associated", "with", "elec-", "trical", "disease", "in", "the", "structurally", "normal", "heart", "(Wolf", "and", "Berul,", "2008).", "Over", "the", "last", "15", "years,", "much", "progress", "has", "been", "made", "in", "identifying", "the", "clinical", "phenotypes", "and", "cellular", "and", "genetic", "mech-", "anisms", "underlying", "the", "various", "primary", "Mendelian", "arrhythmia", "syndromes,", "including", "the", "Long", "QT", "syndrome", "(LQTS),", "Brugada", "Syndrome", "(BrS),", "and", "catecholaminergic", "polymorphic", "ventric-", "ular", "tachycardia", "(CPVT)", "(Wilde", "and", "Bezzina,", "2005).", "This", "has", "provided", "important", "insights", "into", "these", "disorders", "and", "as", "a", "con-", "sequence", "improved", "the", "management", "of", "affected", "patients.", "The", "availability", "of", "genetic", "tests", "has", "added", "an", "important", "diagnostic", "tool", "permitting", "early", "(presymptomatic)", "identification", "of", "patients", "at", "risk", "and", "allowing", "for", "the", "timely", "implementation", "of", "preven-", "tive", "strategies", "(Hofman", "et", "al.,", "2010).", "Studies", "into", "genotype–", "phenotype", "relationships", "have", "uncovered", "important", "gene-specific", "aspects", "of", "disease", "and", "indicated", "that", "patient", "management", "must", "take", "the", "nature", "of", "the", "gene", "affected", "into", "consideration", "(Priori,", "2004).", "However,", "there", "is", "considerable", "variation", "in", "phenotypic", "expression", "of", "arrhythmia", "syndromes", "even", "within", "families", "carry-", "ing", "the", "same", "mutation", "(Scicluna", "et", "al.,", "2008).", "Studying", "the", "electrophysiological", "and", "molecular", "consequences", "of", "a", "mutation", "associated", "with", "cardiac", "arrhythmia", "is", "ideally", "www.frontiersin.org", "August", "2012", "|", "Volume", "3", "|", "Article", "346", "|", "1" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 77, 43, 56, 14 ], [ 138, 43, 35, 14 ], [ 178, 43, 14, 14 ], [ 198, 43, 61, 14 ], [ 264, 43, 28, 14 ], [ 443, 43, 44, 14 ], [ 492, 43, 32, 14 ], [ 529, 43, 57, 14 ], [ 591, 43, 32, 14 ], [ 628, 43, 25, 14 ], [ 658, 43, 18, 14 ], [ 681, 43, 22, 14 ], [ 708, 43, 7, 14 ], [ 729, 43, 63, 14 ], [ 653, 58, 138, 14 ], [ 77, 101, 213, 28 ], [ 300, 101, 77, 28 ], [ 388, 101, 178, 28 ], [ 577, 101, 27, 28 ], [ 615, 101, 170, 28 ], [ 77, 131, 112, 28 ], [ 200, 131, 94, 28 ], [ 305, 131, 201, 28 ], [ 517, 131, 129, 28 ], [ 656, 131, 27, 28 ], [ 77, 162, 162, 28 ], [ 250, 162, 138, 28 ], [ 399, 162, 76, 28 ], [ 77, 204, 53, 17 ], [ 137, 201, 98, 20 ], [ 241, 204, 61, 17 ], [ 308, 201, 96, 20 ], [ 410, 204, 67, 17 ], [ 483, 204, 64, 17 ], [ 547, 201, 7, 12 ], [ 554, 204, 5, 17 ], [ 565, 204, 80, 17 ], [ 651, 201, 85, 20 ], [ 77, 226, 50, 17 ], [ 133, 223, 78, 20 ], [ 217, 226, 30, 17 ], [ 253, 226, 76, 17 ], [ 335, 223, 50, 20 ], [ 77, 259, 55, 17 ], [ 136, 261, 12, 14 ], [ 154, 261, 67, 14 ], [ 226, 261, 58, 14 ], [ 290, 261, 43, 14 ], [ 338, 261, 12, 14 ], [ 355, 261, 73, 14 ], [ 434, 261, 54, 14 ], [ 493, 261, 40, 14 ], [ 538, 261, 65, 14 ], [ 608, 261, 21, 14 ], [ 635, 261, 106, 14 ], [ 77, 278, 65, 14 ], [ 147, 278, 40, 14 ], [ 192, 278, 63, 14 ], [ 260, 275, 64, 17 ], [ 329, 278, 43, 14 ], [ 378, 278, 12, 14 ], [ 395, 278, 48, 14 ], [ 449, 278, 79, 14 ], [ 533, 278, 40, 14 ], [ 578, 278, 65, 14 ], [ 648, 278, 21, 14 ], [ 675, 278, 84, 14 ], [ 77, 294, 36, 14 ], [ 118, 294, 40, 14 ], [ 163, 294, 59, 14 ], [ 227, 294, 24, 14 ], [ 256, 292, 51, 17 ], [ 312, 294, 12, 14 ], [ 330, 294, 54, 14 ], [ 389, 294, 66, 14 ], [ 460, 294, 65, 14 ], [ 530, 294, 34, 14 ], [ 570, 294, 43, 14 ], [ 617, 294, 77, 14 ], [ 699, 294, 38, 14 ], [ 77, 311, 63, 14 ], [ 145, 311, 39, 14 ], [ 77, 346, 47, 11 ], [ 128, 346, 35, 11 ], [ 167, 346, 16, 11 ], [ 186, 346, 28, 11 ], [ 218, 346, 40, 11 ], [ 263, 346, 55, 11 ], [ 322, 346, 10, 11 ], [ 335, 346, 28, 11 ], [ 367, 346, 48, 11 ], [ 420, 346, 55, 11 ], [ 479, 346, 16, 11 ], [ 499, 346, 25, 11 ], [ 77, 393, 75, 14 ], [ 77, 417, 129, 14 ], [ 210, 417, 57, 14 ], [ 272, 417, 25, 14 ], [ 302, 417, 58, 14 ], [ 364, 417, 40, 14 ], [ 408, 417, 12, 14 ], [ 77, 433, 31, 14 ], [ 118, 433, 63, 14 ], [ 191, 433, 8, 14 ], [ 210, 433, 81, 14 ], [ 302, 433, 70, 14 ], [ 382, 433, 38, 14 ], [ 77, 450, 42, 14 ], [ 130, 450, 40, 14 ], [ 180, 450, 12, 14 ], [ 202, 450, 25, 14 ], [ 237, 450, 14, 14 ], [ 262, 450, 21, 14 ], [ 294, 450, 39, 14 ], [ 343, 450, 78, 14 ], [ 77, 466, 31, 14 ], [ 114, 466, 51, 14 ], [ 173, 466, 28, 14 ], [ 208, 466, 38, 14 ], [ 253, 466, 22, 14 ], [ 282, 466, 47, 14 ], [ 336, 466, 14, 14 ], [ 357, 466, 63, 14 ], [ 77, 483, 65, 14 ], [ 155, 483, 13, 14 ], [ 180, 483, 25, 14 ], [ 218, 483, 41, 14 ], [ 272, 483, 20, 14 ], [ 305, 483, 81, 14 ], [ 399, 483, 21, 14 ], [ 77, 500, 106, 14 ], [ 196, 500, 96, 14 ], [ 305, 500, 89, 14 ], [ 407, 500, 14, 14 ], [ 77, 516, 123, 14 ], [ 214, 514, 206, 22 ], [ 77, 533, 159, 14 ], [ 242, 533, 14, 14 ], [ 262, 533, 41, 14 ], [ 308, 533, 22, 14 ], [ 335, 533, 38, 14 ], [ 380, 533, 14, 14 ], [ 399, 533, 21, 14 ], [ 77, 549, 32, 14 ], [ 118, 549, 83, 14 ], [ 209, 549, 17, 14 ], [ 234, 549, 21, 14 ], [ 264, 549, 89, 14 ], [ 362, 549, 59, 14 ], [ 77, 566, 25, 14 ], [ 107, 566, 55, 14 ], [ 167, 566, 54, 14 ], [ 226, 566, 12, 14 ], [ 243, 566, 21, 14 ], [ 270, 566, 101, 14 ], [ 376, 566, 45, 14 ], [ 77, 583, 26, 14 ], [ 107, 583, 14, 14 ], [ 124, 583, 21, 14 ], [ 150, 583, 63, 14 ], [ 217, 583, 34, 14 ], [ 255, 583, 57, 14 ], [ 315, 583, 16, 14 ], [ 335, 583, 68, 14 ], [ 407, 583, 14, 14 ], [ 77, 599, 21, 14 ], [ 110, 599, 81, 14 ], [ 203, 599, 43, 14 ], [ 258, 599, 25, 14 ], [ 295, 599, 36, 14 ], [ 344, 599, 38, 14 ], [ 393, 599, 27, 14 ], [ 77, 616, 59, 14 ], [ 142, 616, 19, 14 ], [ 167, 616, 21, 14 ], [ 194, 616, 128, 14 ], [ 328, 616, 14, 14 ], [ 348, 616, 73, 14 ], [ 77, 630, 230, 22 ], [ 320, 632, 56, 14 ], [ 390, 632, 31, 14 ], [ 77, 649, 21, 14 ], [ 104, 649, 47, 14 ], [ 156, 649, 25, 14 ], [ 187, 649, 63, 14 ], [ 255, 649, 38, 14 ], [ 298, 649, 33, 14 ], [ 336, 649, 48, 14 ], [ 389, 649, 31, 14 ], [ 77, 666, 192, 19 ], [ 292, 666, 46, 14 ], [ 362, 666, 58, 14 ], [ 77, 682, 57, 14 ], [ 142, 682, 26, 14 ], [ 177, 682, 22, 14 ], [ 207, 682, 65, 14 ], [ 281, 682, 45, 14 ], [ 335, 682, 14, 14 ], [ 357, 682, 21, 14 ], [ 387, 682, 34, 14 ], [ 77, 699, 64, 14 ], [ 157, 699, 68, 14 ], [ 241, 699, 12, 14 ], [ 269, 699, 79, 14 ], [ 364, 699, 14, 14 ], [ 394, 699, 26, 14 ], [ 77, 715, 57, 14 ], [ 146, 715, 19, 14 ], [ 176, 715, 22, 14 ], [ 209, 715, 114, 14 ], [ 335, 715, 34, 14 ], [ 380, 715, 40, 14 ], [ 77, 732, 53, 14 ], [ 136, 732, 58, 14 ], [ 200, 732, 8, 14 ], [ 213, 732, 28, 14 ], [ 246, 732, 55, 14 ], [ 306, 732, 19, 14 ], [ 331, 732, 21, 14 ], [ 358, 732, 63, 14 ], [ 77, 749, 14, 14 ], [ 97, 749, 110, 14 ], [ 213, 749, 70, 14 ], [ 289, 749, 22, 14 ], [ 317, 749, 63, 14 ], [ 387, 749, 34, 14 ], [ 77, 765, 39, 14 ], [ 122, 765, 22, 14 ], [ 149, 765, 79, 14 ], [ 235, 765, 106, 14 ], [ 347, 765, 74, 14 ], [ 77, 782, 63, 14 ], [ 153, 782, 16, 14 ], [ 181, 782, 45, 14 ], [ 240, 782, 31, 14 ], [ 283, 782, 77, 14 ], [ 373, 782, 8, 14 ], [ 393, 782, 27, 14 ], [ 77, 798, 63, 14 ], [ 77, 843, 108, 14 ], [ 77, 865, 13, 14 ], [ 96, 865, 19, 14 ], [ 120, 865, 25, 14 ], [ 151, 865, 13, 14 ], [ 169, 865, 45, 14 ], [ 219, 865, 57, 14 ], [ 281, 865, 80, 14 ], [ 367, 865, 54, 14 ], [ 77, 880, 19, 14 ], [ 101, 880, 49, 14 ], [ 156, 880, 23, 14 ], [ 185, 880, 71, 14 ], [ 262, 880, 51, 14 ], [ 318, 880, 13, 14 ], [ 337, 880, 29, 14 ], [ 372, 880, 49, 14 ], [ 77, 895, 42, 14 ], [ 122, 895, 50, 14 ], [ 176, 895, 40, 14 ], [ 220, 895, 30, 14 ], [ 254, 895, 43, 14 ], [ 301, 895, 19, 14 ], [ 324, 895, 36, 14 ], [ 363, 895, 58, 14 ], [ 77, 911, 28, 14 ], [ 112, 911, 15, 14 ], [ 135, 911, 27, 14 ], [ 170, 911, 67, 14 ], [ 245, 911, 19, 14 ], [ 271, 911, 71, 14 ], [ 350, 911, 48, 14 ], [ 406, 911, 15, 14 ], [ 448, 392, 48, 14 ], [ 503, 392, 23, 14 ], [ 533, 392, 19, 14 ], [ 559, 392, 65, 14 ], [ 631, 392, 80, 14 ], [ 719, 392, 32, 14 ], [ 758, 392, 33, 14 ], [ 448, 408, 55, 14 ], [ 506, 408, 45, 14 ], [ 554, 408, 27, 14 ], [ 585, 408, 58, 14 ], [ 646, 408, 19, 14 ], [ 668, 408, 36, 14 ], [ 707, 408, 84, 14 ], [ 448, 423, 12, 14 ], [ 464, 423, 35, 14 ], [ 504, 423, 15, 15 ], [ 524, 423, 53, 14 ], [ 581, 423, 13, 14 ], [ 598, 423, 23, 14 ], [ 625, 423, 41, 14 ], [ 670, 423, 36, 14 ], [ 711, 423, 64, 14 ], [ 780, 423, 12, 14 ], [ 448, 438, 19, 14 ], [ 470, 438, 60, 14 ], [ 534, 438, 13, 14 ], [ 550, 438, 7, 14 ], [ 561, 438, 92, 14 ], [ 656, 438, 28, 14 ], [ 688, 438, 10, 14 ], [ 701, 438, 39, 14 ], [ 743, 438, 27, 14 ], [ 773, 438, 18, 14 ], [ 448, 453, 19, 14 ], [ 469, 453, 74, 14 ], [ 547, 453, 13, 14 ], [ 562, 453, 19, 14 ], [ 584, 453, 25, 14 ], [ 612, 453, 92, 14 ], [ 707, 453, 24, 14 ], [ 734, 453, 12, 14 ], [ 748, 453, 43, 14 ], [ 448, 469, 52, 14 ], [ 504, 469, 23, 14 ], [ 530, 469, 18, 14 ], [ 551, 469, 19, 14 ], [ 574, 469, 74, 14 ], [ 652, 469, 13, 14 ], [ 668, 469, 61, 14 ], [ 732, 469, 41, 14 ], [ 776, 469, 15, 14 ], [ 448, 484, 87, 14 ], [ 539, 484, 18, 14 ], [ 561, 484, 19, 14 ], [ 584, 484, 63, 14 ], [ 651, 484, 48, 14 ], [ 704, 484, 13, 14 ], [ 721, 484, 19, 14 ], [ 744, 484, 48, 14 ], [ 448, 499, 92, 14 ], [ 544, 499, 24, 14 ], [ 572, 499, 34, 14 ], [ 462, 514, 34, 14 ], [ 500, 514, 10, 14 ], [ 514, 514, 15, 14 ], [ 533, 514, 45, 14 ], [ 582, 514, 53, 14 ], [ 639, 514, 24, 14 ], [ 668, 514, 61, 14 ], [ 733, 514, 19, 14 ], [ 756, 514, 36, 14 ], [ 448, 530, 81, 14 ], [ 532, 530, 48, 14 ], [ 584, 530, 13, 14 ], [ 600, 530, 24, 14 ], [ 627, 530, 13, 14 ], [ 643, 530, 32, 14 ], [ 678, 530, 52, 14 ], [ 734, 530, 57, 14 ], [ 448, 545, 23, 14 ], [ 478, 545, 35, 14 ], [ 521, 545, 48, 14 ], [ 576, 545, 39, 14 ], [ 621, 545, 48, 14 ], [ 677, 545, 19, 14 ], [ 703, 545, 41, 14 ], [ 751, 545, 41, 14 ], [ 448, 560, 36, 14 ], [ 495, 560, 13, 14 ], [ 518, 560, 50, 14 ], [ 578, 560, 64, 14 ], [ 653, 560, 32, 14 ], [ 695, 560, 32, 14 ], [ 737, 560, 26, 14 ], [ 773, 560, 19, 14 ], [ 448, 575, 48, 14 ], [ 501, 575, 13, 14 ], [ 519, 575, 86, 14 ], [ 610, 575, 61, 14 ], [ 676, 575, 31, 14 ], [ 712, 575, 35, 14 ], [ 753, 575, 39, 14 ], [ 448, 590, 12, 14 ], [ 470, 590, 19, 14 ], [ 500, 590, 60, 14 ], [ 571, 590, 13, 14 ], [ 594, 590, 71, 14 ], [ 676, 590, 64, 14 ], [ 751, 590, 40, 14 ], [ 448, 605, 48, 14 ], [ 501, 605, 7, 14 ], [ 514, 605, 35, 14 ], [ 554, 605, 26, 14 ], [ 585, 605, 13, 14 ], [ 603, 605, 73, 14 ], [ 680, 605, 44, 14 ], [ 729, 605, 23, 14 ], [ 757, 605, 34, 14 ], [ 448, 621, 24, 14 ], [ 480, 621, 13, 14 ], [ 500, 621, 19, 14 ], [ 527, 621, 30, 14 ], [ 565, 621, 21, 14 ], [ 594, 621, 14, 14 ], [ 616, 621, 67, 14 ], [ 691, 621, 24, 14 ], [ 723, 621, 26, 14 ], [ 757, 621, 35, 14 ], [ 448, 636, 43, 14 ], [ 495, 636, 43, 14 ], [ 543, 636, 57, 14 ], [ 605, 636, 42, 14 ], [ 652, 636, 23, 14 ], [ 679, 636, 60, 14 ], [ 744, 636, 48, 14 ], [ 448, 651, 19, 14 ], [ 470, 651, 16, 14 ], [ 489, 651, 19, 14 ], [ 512, 651, 39, 14 ], [ 555, 651, 59, 14 ], [ 617, 651, 13, 14 ], [ 634, 651, 19, 14 ], [ 656, 651, 23, 14 ], [ 682, 651, 32, 14 ], [ 717, 651, 44, 14 ], [ 765, 651, 26, 14 ], [ 448, 666, 45, 14 ], [ 497, 666, 30, 14 ], [ 531, 666, 26, 14 ], [ 560, 666, 62, 14 ], [ 627, 666, 19, 14 ], [ 650, 666, 39, 14 ], [ 693, 666, 30, 14 ], [ 727, 666, 10, 14 ], [ 741, 666, 51, 14 ], [ 448, 682, 42, 14 ], [ 492, 682, 43, 14 ], [ 538, 682, 12, 14 ], [ 553, 682, 96, 14 ], [ 653, 682, 38, 14 ], [ 693, 682, 22, 14 ], [ 718, 682, 13, 14 ], [ 733, 682, 58, 14 ], [ 448, 697, 65, 14 ], [ 517, 697, 31, 14 ], [ 553, 697, 23, 14 ], [ 580, 697, 53, 14 ], [ 638, 697, 34, 14 ], [ 676, 697, 35, 14 ], [ 715, 697, 10, 14 ], [ 729, 697, 43, 14 ], [ 776, 697, 15, 14 ], [ 448, 712, 31, 14 ], [ 482, 712, 23, 14 ], [ 509, 712, 32, 14 ], [ 544, 712, 12, 14 ], [ 559, 712, 50, 14 ], [ 613, 712, 53, 14 ], [ 670, 712, 43, 14 ], [ 716, 712, 38, 14 ], [ 758, 712, 34, 14 ], [ 448, 727, 41, 14 ], [ 495, 727, 10, 14 ], [ 510, 727, 19, 14 ], [ 535, 727, 41, 14 ], [ 582, 727, 35, 14 ], [ 624, 727, 75, 14 ], [ 705, 727, 13, 14 ], [ 723, 727, 22, 14 ], [ 751, 727, 40, 14 ], [ 448, 743, 51, 14 ], [ 505, 743, 26, 14 ], [ 537, 743, 26, 14 ], [ 569, 743, 13, 14 ], [ 588, 743, 30, 14 ], [ 624, 743, 10, 14 ], [ 639, 743, 61, 14 ], [ 707, 743, 64, 14 ], [ 776, 743, 15, 14 ], [ 448, 758, 48, 14 ], [ 503, 758, 48, 14 ], [ 557, 758, 23, 14 ], [ 587, 758, 53, 14 ], [ 647, 758, 30, 14 ], [ 683, 758, 10, 14 ], [ 699, 758, 7, 14 ], [ 713, 758, 54, 14 ], [ 773, 758, 18, 14 ], [ 448, 773, 34, 14 ], [ 486, 773, 35, 14 ], [ 526, 773, 54, 14 ], [ 584, 773, 27, 14 ], [ 616, 773, 13, 14 ], [ 633, 773, 34, 14 ], [ 672, 773, 65, 14 ], [ 741, 773, 24, 14 ], [ 769, 773, 23, 14 ], [ 448, 788, 17, 14 ], [ 468, 788, 79, 14 ], [ 550, 788, 10, 14 ], [ 563, 788, 27, 14 ], [ 594, 788, 53, 14 ], [ 650, 788, 19, 14 ], [ 672, 788, 35, 14 ], [ 710, 788, 55, 14 ], [ 769, 788, 23, 14 ], [ 448, 803, 33, 14 ], [ 487, 803, 33, 14 ], [ 527, 803, 27, 14 ], [ 561, 803, 24, 14 ], [ 592, 803, 18, 14 ], [ 616, 803, 19, 14 ], [ 641, 803, 39, 14 ], [ 687, 803, 34, 14 ], [ 728, 803, 35, 14 ], [ 769, 803, 23, 14 ], [ 448, 819, 32, 14 ], [ 488, 819, 35, 14 ], [ 532, 819, 19, 14 ], [ 558, 819, 19, 14 ], [ 585, 819, 70, 14 ], [ 663, 819, 23, 14 ], [ 693, 819, 42, 14 ], [ 743, 819, 48, 14 ], [ 448, 834, 51, 14 ], [ 511, 834, 12, 14 ], [ 535, 834, 61, 14 ], [ 608, 834, 48, 14 ], [ 667, 834, 39, 14 ], [ 719, 834, 73, 14 ], [ 448, 849, 39, 14 ], [ 492, 849, 13, 14 ], [ 510, 849, 22, 14 ], [ 538, 849, 30, 14 ], [ 573, 849, 26, 14 ], [ 605, 849, 15, 14 ], [ 626, 849, 43, 14 ], [ 674, 849, 70, 14 ], [ 749, 849, 13, 14 ], [ 767, 849, 24, 14 ], [ 448, 864, 18, 14 ], [ 470, 864, 32, 14 ], [ 506, 864, 22, 14 ], [ 532, 864, 40, 14 ], [ 576, 864, 27, 14 ], [ 608, 864, 35, 14 ], [ 647, 864, 31, 14 ], [ 682, 864, 13, 14 ], [ 699, 864, 30, 14 ], [ 733, 864, 58, 14 ], [ 448, 880, 19, 14 ], [ 470, 880, 61, 14 ], [ 534, 880, 43, 14 ], [ 580, 880, 49, 14 ], [ 631, 880, 78, 14 ], [ 712, 880, 32, 14 ], [ 747, 880, 45, 14 ], [ 448, 895, 22, 14 ], [ 474, 895, 64, 14 ], [ 542, 895, 13, 14 ], [ 559, 895, 7, 14 ], [ 571, 895, 90, 14 ], [ 665, 895, 91, 14 ], [ 760, 895, 12, 14 ], [ 776, 895, 15, 14 ], [ 448, 910, 35, 14 ], [ 487, 910, 48, 14 ], [ 540, 910, 23, 14 ], [ 567, 910, 19, 14 ], [ 590, 910, 55, 14 ], [ 650, 910, 84, 14 ], [ 738, 910, 53, 14 ], [ 77, 952, 20, 12 ], [ 100, 952, 30, 12 ], [ 134, 952, 74, 12 ], [ 212, 952, 32, 12 ], [ 248, 952, 11, 12 ], [ 264, 952, 50, 12 ], [ 318, 952, 19, 12 ], [ 338, 952, 21, 12 ], [ 363, 952, 6, 12 ], [ 373, 952, 23, 12 ], [ 400, 952, 26, 12 ], [ 429, 952, 22, 12 ], [ 453, 952, 21, 12 ], [ 478, 952, 6, 12 ], [ 488, 952, 23, 12 ], [ 515, 952, 26, 12 ], [ 544, 952, 31, 12 ], [ 580, 952, 134, 12 ], [ 77, 965, 35, 12 ], [ 116, 965, 39, 12 ], [ 77, 977, 49, 12 ], [ 130, 977, 49, 12 ], [ 183, 977, 44, 12 ], [ 230, 977, 40, 12 ], [ 275, 977, 10, 12 ], [ 289, 977, 71, 12 ], [ 364, 977, 47, 12 ], [ 415, 977, 38, 12 ], [ 457, 977, 53, 12 ], [ 514, 977, 48, 12 ], [ 566, 977, 59, 12 ], [ 628, 977, 38, 12 ], [ 670, 977, 46, 12 ], [ 720, 977, 32, 12 ], [ 89, 1003, 18, 11 ], [ 109, 1003, 44, 11 ], [ 156, 1003, 24, 11 ], [ 183, 1003, 44, 11 ], [ 230, 1003, 11, 11 ], [ 245, 1003, 33, 11 ], [ 280, 1003, 47, 11 ], [ 330, 1003, 26, 11 ], [ 77, 1015, 20, 11 ], [ 99, 1015, 7, 11 ], [ 109, 1015, 11, 11 ], [ 123, 1015, 24, 11 ], [ 150, 1015, 30, 11 ], [ 183, 1015, 28, 11 ], [ 213, 1015, 48, 11 ], [ 264, 1015, 26, 11 ], [ 293, 1015, 14, 11 ], [ 309, 1015, 25, 11 ], [ 337, 1015, 10, 11 ], [ 349, 1015, 14, 11 ], [ 365, 1015, 38, 11 ], [ 406, 1015, 46, 11 ], [ 454, 1015, 51, 11 ], [ 508, 1015, 78, 11 ], [ 589, 1015, 34, 11 ], [ 625, 1015, 166, 11 ], [ 77, 1028, 48, 11 ], [ 128, 1028, 27, 11 ], [ 158, 1028, 33, 11 ], [ 194, 1028, 53, 11 ], [ 250, 1028, 72, 11 ], [ 326, 1028, 18, 11 ], [ 346, 1028, 55, 11 ], [ 404, 1028, 17, 11 ], [ 425, 1028, 58, 11 ], [ 486, 1028, 9, 11 ], [ 498, 1028, 17, 11 ], [ 517, 1028, 39, 11 ], [ 559, 1028, 40, 11 ], [ 602, 1028, 14, 11 ], [ 620, 1028, 35, 11 ], [ 657, 1028, 23, 11 ], [ 684, 1028, 7, 11 ], [ 694, 1028, 38, 11 ], [ 735, 1028, 24, 11 ] ]

[ "Published", "online", "29", "September", "2010", "Nucleic", "Acids", "Research,", "2011,", "Vol.", "39,", "No.", "3", "1165–1175", "doi:10.1093/nar/gkq855", "Photosensitized", "[2+2]", "cycloaddition", "of", "N-acetylated", "cytosine", "affords", "stereoselective", "formation", "of", "cyclobutane", "pyrimidine", "dimer", "Junpei", "Yamamoto1,", "Kosuke", "Nishiguchi1,", "Koichiro", "Manabe", "1", ",", "Chikahide", "Masutani2,", "Fumio", "Hanaoka3", "and", "Shigenori", "Iwai1,*", "1Division", "of", "Chemistry,", "Graduate", "School", "of", "Engineering", "Science,", "Osaka", "University,", "1-3", "Machikaneyama,", "Toyonaka,", "Osaka", "560-8531,", "2Graduate", "School", "of", "Frontier", "Biosciences,", "Osaka", "University,", "1-3", "Yamada-oka,", "Suita,", "Osaka", "565-0871", "and", "3Faculty", "of", "Science,", "Gakushuin", "University,", "1-5-1", "Mejiro,", "Toshima-ku,", "Tokyo", "171-8588,", "Japan", "Received", "August", "12,", "2010;", "Revised", "September", "9,", "2010;", "Accepted", "September", "10,", "2010", "ABSTRACT", "Photocycloaddition", "between", "two", "adjacent", "bases", "in", "DNA", "produces", "a", "cyclobutane", "pyrimidine", "dimer", "(CPD),", "which", "is", "one", "of", "the", "major", "UV-induced", "DNA", "lesions,", "with", "either", "the", "cis-syn", "or", "trans-syn", "structure.", "In", "this", "study,", "we", "investigated", "the", "photosensitized", "intramolecular", "cycloaddition", "of", "partially-protected", "thymidylyl-(30!50)-N4-acetyl-20-", "deoxy-5-methylcytidine,", "to", "clarify", "the", "effect", "of", "the", "base", "modification", "on", "the", "cycloaddition", "reaction.", "The", "reaction", "resulted", "in", "the", "stereoselective", "forma-", "tion", "of", "the", "trans-syn", "CPD,", "followed", "by", "hydrolysis", "of", "the", "acetylamino", "group.", "The", "same", "result", "was", "obtained", "for", "the", "photocycloaddition", "of", "thymidylyl-", "(30!50)-N4-acetyl-20-deoxycytidine,", "whereas", "both", "the", "cis-syn", "and", "trans-syn", "CPDs", "were", "formed", "from", "thymidylyl-(30!50)-thymidine.", "Kinetic", "analyses", "revealed", "that", "the", "activation", "energy", "of", "the", "acid-", "catalyzed", "hydrolysis", "is", "comparable", "to", "that", "reported", "for", "the", "thymine-cytosine", "CPD.", "These", "findings", "provided", "a", "new", "strategy", "for", "the", "synthesis", "of", "oligonucleotides", "containing", "the", "trans-syn", "CPD.", "Using", "the", "synthesized", "oligonucleotide,", "translesion", "synthesis", "by", "human", "DNA", "polymerase", "g", "was", "analyzed.", "INTRODUCTION", "In", "the", "field", "of", "organic", "synthesis,", "cycloaddition", "reactions", "are", "versatile", "and", "well-studied", "methods", "to", "form", "carbon–", "carbon", "covalent", "bonds.", "They", "include", "the", "[2+2]", "cycloadd-", "ition", "by", "light", "irradiation,", "the", "Diels–Alder", "reaction", "by", "heating,", "and", "the", "1,3-dipolar", "cycloaddition", "using", "metal", "catalysts.", "Among", "such", "reactions,", "the", "[2+2]", "cycloaddition,", "in", "which", "4p", "electrons", "of", "two", "double", "bonds", "participate", "in", "the", "formation", "of", "a", "four-membered", "ring,", "is", "widely", "used", "for", "the", "construction", "of", "the", "core", "four-membered", "ring", "in", "natural", "products", "and", "for", "the", "introduction", "of", "functional", "groups", "by", "rearrangement", "via", "the", "heterolytic", "opening", "of", "the", "strained", "four-membered", "ring", "(1–5).", "DNA", "is", "an", "organic", "molecule", "that", "undergoes", "the", "[2+2]", "cycloaddition", "reaction", "as", "well", "as", "other", "chemical", "reactions.", "The", "major", "reaction", "occurs", "between", "the", "C5–C6", "double", "bonds", "of", "adjacent", "pyrimidine", "bases", "when", "they", "are", "exposed", "to", "environmental", "ultraviolet", "light,", "which", "results", "in", "the", "formation", "of", "cyclobutane", "pyrimidine", "dimers", "(CPDs),", "a", "major", "type", "of", "UV-induced", "lesions.", "The", "struc-", "ture", "of", "the", "CPD", "can", "be", "categorized", "into", "four", "types,", "namely", "cis-syn,", "trans-syn,", "cis-anti", "and", "trans-anti,", "depend-", "ing", "on", "the", "spatial", "alignment", "of", "the", "two", "bases", "(Figure", "1A).", "Among", "these", "four", "structures,", "the", "cis-syn", "CPD", "is", "predom-", "inantly", "formed", "in", "double-stranded", "DNA,", "due", "to", "geometric", "constraints", "(6,7).", "The", "trans-syn", "CPD,", "which", "is", "formed", "by", "UVB", "and", "UVC", "at", "partially", "distorted", "regions", "within", "DNA", "(8–11),", "is", "the", "second", "major", "stereoisomer", "of", "this", "photo-", "product.", "This", "type", "of", "CPD", "is", "reportedly", "recognized", "by", "proteins", "(12–14).", "The", "trans-syn", "CPD", "is", "a", "substrate", "for", "DNA", "repair", "enzymes,", "such", "as", "DNA", "photolyase", "(12)", "and", "T4", "endonuclease", "V", "(13),", "although", "the", "repair", "efficiency", "was", "much", "lower", "than", "that", "for", "the", "cis-syn", "CPD.", "UvrA", "and", "XPE,", "which", "are", "the", "prokaryotic", "and", "human", "proteins", "involved", "in", "nucleotide", "excision", "repair,", "respectively,", "bound", "to", "this", "CPD", "with", "an", "affinity", "comparable", "to", "that", "for", "other", "UV", "lesions", "(14).", "Other", "types", "of", "CPD", "structures", "are", "reportedly", "formed", "between", "non-adjacent", "bases", "(15,16).", "UV", "irradiation", "of", "a", "single-stranded", "oligonucleotide", "in", "an", "acidic", "solution", "and", "the", "telomeric", "G-quadruplex", "structure", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+81", "6", "6850", "6250;", "Fax:", "+81", "6", "6850", "6240;", "Email:", "iwai@chem.es.osaka-u.ac.jp", "Present", "address:", "Chikahide", "Masutani,", "Research", "Institute", "of", "Environmental", "Medicine,", "Nagoya", "University,", "Furo-cho,", "Chikusa-ku,", "Nagoya", "464-8601,", "Japan.", "The", "Author(s)", "2010.", "Published", "by", "Oxford", "University", "Press.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.5),", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 7, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 62, 70, 177, 35 ], [ 250, 70, 31, 35 ], [ 292, 70, 111, 35 ], [ 414, 70, 27, 35 ], [ 453, 70, 149, 35 ], [ 612, 70, 90, 35 ], [ 62, 111, 41, 35 ], [ 114, 111, 135, 35 ], [ 261, 111, 144, 35 ], [ 416, 111, 137, 35 ], [ 62, 161, 41, 13 ], [ 106, 161, 15, 13 ], [ 125, 157, 58, 17 ], [ 187, 161, 34, 13 ], [ 224, 161, 11, 13 ], [ 239, 157, 63, 17 ], [ 306, 161, 34, 13 ], [ 344, 161, 11, 13 ], [ 358, 157, 53, 17 ], [ 415, 161, 35, 13 ], [ 453, 157, 45, 17 ], [ 502, 161, 53, 13 ], [ 560, 161, 12, 13 ], [ 575, 157, 62, 17 ], [ 641, 161, 46, 13 ], [ 690, 157, 39, 17 ], [ 62, 180, 30, 13 ], [ 96, 180, 13, 13 ], [ 113, 177, 50, 17 ], [ 62, 202, 6, 10 ], [ 70, 202, 50, 10 ], [ 123, 202, 9, 10 ], [ 134, 202, 30, 10 ], [ 167, 202, 37, 10 ], [ 207, 202, 41, 10 ], [ 251, 202, 9, 10 ], [ 262, 202, 35, 10 ], [ 300, 202, 36, 10 ], [ 338, 202, 28, 10 ], [ 369, 202, 28, 10 ], [ 400, 202, 25, 10 ], [ 427, 202, 9, 10 ], [ 439, 202, 36, 10 ], [ 477, 202, 6, 10 ], [ 485, 202, 50, 10 ], [ 538, 202, 9, 10 ], [ 549, 202, 50, 10 ], [ 602, 202, 37, 10 ], [ 641, 202, 41, 10 ], [ 685, 202, 9, 10 ], [ 696, 202, 36, 10 ], [ 734, 202, 28, 10 ], [ 62, 216, 28, 10 ], [ 93, 216, 25, 10 ], [ 120, 216, 9, 10 ], [ 132, 216, 34, 10 ], [ 62, 249, 75, 14 ], [ 141, 249, 57, 14 ], [ 201, 249, 23, 14 ], [ 228, 249, 13, 14 ], [ 244, 249, 53, 14 ], [ 301, 249, 12, 14 ], [ 316, 249, 44, 14 ], [ 363, 249, 26, 14 ], [ 392, 249, 15, 14 ], [ 411, 249, 60, 14 ], [ 474, 249, 23, 14 ], [ 501, 249, 12, 14 ], [ 516, 249, 47, 14 ], [ 567, 249, 67, 14 ], [ 638, 249, 53, 14 ], [ 695, 249, 42, 14 ], [ 740, 249, 23, 14 ], [ 62, 265, 38, 14 ], [ 103, 265, 43, 14 ], [ 149, 265, 23, 14 ], [ 174, 265, 29, 14 ], [ 206, 265, 30, 14 ], [ 239, 265, 39, 14 ], [ 281, 265, 13, 14 ], [ 296, 265, 55, 14 ], [ 354, 265, 53, 14 ], [ 410, 265, 12, 14 ], [ 425, 265, 70, 14 ], [ 498, 265, 27, 14 ], [ 528, 265, 13, 14 ], [ 544, 265, 30, 14 ], [ 577, 265, 36, 14 ], [ 616, 265, 23, 14 ], [ 641, 265, 23, 14 ], [ 667, 265, 42, 14 ], [ 711, 265, 51, 14 ], [ 62, 280, 37, 14 ], [ 103, 280, 51, 14 ], [ 158, 280, 12, 14 ], [ 174, 280, 42, 14 ], [ 219, 280, 70, 14 ], [ 293, 280, 19, 14 ], [ 316, 280, 32, 14 ], [ 352, 280, 13, 14 ], [ 369, 280, 15, 14 ], [ 388, 280, 41, 14 ], [ 433, 280, 13, 14 ], [ 450, 280, 27, 14 ], [ 480, 280, 23, 14 ], [ 507, 280, 25, 14 ], [ 536, 280, 59, 14 ], [ 600, 280, 15, 14 ], [ 619, 280, 23, 14 ], [ 645, 280, 20, 14 ], [ 669, 280, 65, 14 ], [ 738, 280, 25, 14 ], [ 62, 295, 44, 14 ], [ 108, 295, 43, 14 ], [ 155, 295, 53, 14 ], [ 211, 295, 12, 14 ], [ 225, 295, 70, 14 ], [ 298, 295, 36, 14 ], [ 336, 295, 12, 14 ], [ 351, 295, 51, 14 ], [ 405, 295, 18, 14 ], [ 425, 295, 29, 14 ], [ 456, 295, 8, 14 ], [ 467, 295, 86, 14 ], [ 555, 295, 56, 14 ], [ 614, 295, 36, 14 ], [ 653, 295, 16, 14 ], [ 671, 295, 49, 14 ], [ 723, 295, 39, 14 ], [ 62, 310, 13, 14 ], [ 80, 310, 34, 14 ], [ 120, 310, 15, 14 ], [ 140, 310, 59, 14 ], [ 204, 310, 35, 14 ], [ 245, 310, 17, 14 ], [ 268, 310, 52, 14 ], [ 325, 310, 59, 14 ], [ 389, 310, 59, 14 ], [ 453, 310, 19, 14 ], [ 477, 310, 64, 14 ], [ 547, 310, 22, 14 ], [ 575, 310, 20, 14 ], [ 600, 310, 30, 14 ], [ 635, 310, 12, 14 ], [ 652, 310, 33, 14 ], [ 690, 310, 35, 14 ], [ 730, 310, 12, 14 ], [ 747, 310, 15, 14 ], [ 62, 325, 63, 14 ], [ 129, 325, 71, 14 ], [ 204, 325, 60, 14 ], [ 267, 325, 20, 14 ], [ 291, 325, 15, 14 ], [ 310, 325, 12, 14 ], [ 326, 325, 20, 14 ], [ 350, 325, 43, 14 ], [ 397, 325, 50, 14 ], [ 450, 325, 53, 14 ], [ 507, 325, 42, 14 ], [ 554, 325, 38, 14 ], [ 595, 325, 23, 14 ], [ 622, 325, 36, 14 ], [ 661, 325, 70, 14 ], [ 736, 325, 26, 14 ], [ 62, 341, 44, 14 ], [ 109, 341, 54, 14 ], [ 165, 341, 33, 14 ], [ 201, 341, 27, 14 ], [ 231, 341, 65, 14 ], [ 299, 341, 48, 14 ], [ 349, 341, 23, 14 ], [ 375, 341, 7, 14 ], [ 385, 341, 36, 14 ], [ 424, 341, 63, 14 ], [ 490, 341, 47, 14 ], [ 539, 341, 43, 14 ], [ 585, 341, 53, 14 ], [ 641, 341, 67, 14 ], [ 711, 341, 51, 14 ], [ 62, 356, 12, 14 ], [ 79, 356, 54, 14 ], [ 137, 356, 17, 14 ], [ 159, 356, 65, 14 ], [ 228, 356, 22, 14 ], [ 255, 356, 51, 14 ], [ 311, 356, 52, 14 ], [ 368, 356, 42, 14 ], [ 415, 356, 30, 14 ], [ 450, 356, 13, 14 ], [ 468, 356, 46, 14 ], [ 518, 356, 15, 14 ], [ 538, 356, 55, 14 ], [ 598, 356, 23, 14 ], [ 626, 356, 70, 14 ], [ 700, 356, 17, 14 ], [ 723, 356, 40, 14 ], [ 62, 371, 50, 14 ], [ 116, 371, 12, 14 ], [ 133, 371, 32, 14 ], [ 169, 371, 60, 14 ], [ 233, 371, 23, 14 ], [ 260, 371, 13, 14 ], [ 277, 371, 65, 14 ], [ 346, 371, 42, 14 ], [ 392, 371, 37, 14 ], [ 433, 371, 20, 14 ], [ 457, 371, 37, 14 ], [ 499, 371, 15, 14 ], [ 517, 371, 44, 14 ], [ 565, 371, 57, 14 ], [ 626, 371, 18, 14 ], [ 648, 371, 36, 14 ], [ 688, 371, 15, 14 ], [ 707, 371, 39, 14 ], [ 750, 371, 13, 14 ], [ 62, 386, 32, 14 ], [ 98, 386, 30, 14 ], [ 131, 386, 12, 14 ], [ 147, 386, 20, 14 ], [ 170, 386, 19, 14 ], [ 193, 386, 12, 14 ], [ 209, 386, 20, 14 ], [ 233, 386, 76, 14 ], [ 312, 386, 12, 14 ], [ 328, 386, 20, 14 ], [ 351, 386, 23, 14 ], [ 378, 386, 52, 14 ], [ 433, 386, 60, 14 ], [ 496, 386, 13, 14 ], [ 513, 386, 20, 14 ], [ 536, 386, 42, 14 ], [ 582, 386, 33, 14 ], [ 619, 386, 52, 14 ], [ 675, 386, 25, 14 ], [ 704, 386, 59, 14 ], [ 62, 401, 35, 14 ], [ 100, 401, 13, 14 ], [ 116, 401, 7, 14 ], [ 126, 401, 36, 14 ], [ 165, 401, 31, 14 ], [ 199, 401, 41, 14 ], [ 243, 401, 12, 14 ], [ 259, 401, 50, 14 ], [ 312, 401, 45, 14 ], [ 359, 401, 57, 14 ], [ 419, 401, 43, 14 ], [ 465, 401, 21, 14 ], [ 488, 401, 56, 14 ], [ 547, 401, 41, 14 ], [ 591, 401, 29, 14 ], [ 623, 401, 43, 14 ], [ 669, 401, 30, 14 ], [ 701, 401, 30, 14 ], [ 734, 401, 29, 14 ], [ 62, 417, 42, 14 ], [ 108, 417, 37, 14 ], [ 150, 417, 35, 14 ], [ 190, 417, 25, 14 ], [ 220, 417, 23, 14 ], [ 247, 417, 62, 14 ], [ 314, 417, 30, 14 ], [ 349, 417, 63, 14 ], [ 416, 417, 26, 14 ], [ 447, 417, 70, 14 ], [ 522, 417, 45, 14 ], [ 572, 417, 43, 14 ], [ 619, 417, 13, 14 ], [ 637, 417, 25, 14 ], [ 667, 417, 59, 14 ], [ 731, 417, 32, 14 ], [ 62, 432, 53, 14 ], [ 120, 432, 12, 14 ], [ 135, 432, 44, 14 ], [ 183, 432, 26, 14 ], [ 213, 432, 15, 14 ], [ 232, 432, 61, 14 ], [ 297, 432, 26, 14 ], [ 327, 432, 32, 14 ], [ 364, 432, 44, 14 ], [ 412, 432, 13, 14 ], [ 429, 432, 87, 14 ], [ 520, 432, 57, 14 ], [ 581, 432, 9, 14 ], [ 594, 432, 10, 14 ], [ 608, 432, 49, 14 ], [ 661, 432, 25, 14 ], [ 690, 432, 32, 14 ], [ 726, 432, 13, 14 ], [ 743, 432, 20, 14 ], [ 62, 447, 41, 14 ], [ 106, 447, 25, 14 ], [ 134, 447, 17, 14 ], [ 154, 447, 53, 14 ], [ 209, 447, 38, 14 ], [ 250, 447, 52, 14 ], [ 304, 447, 57, 14 ], [ 364, 447, 32, 14 ], [ 399, 447, 28, 14 ], [ 429, 447, 47, 14 ], [ 479, 447, 80, 14 ], [ 562, 447, 20, 14 ], [ 585, 447, 40, 14 ], [ 628, 447, 19, 14 ], [ 650, 447, 61, 14 ], [ 713, 447, 26, 14 ], [ 743, 447, 20, 14 ], [ 62, 462, 26, 14 ], [ 90, 462, 25, 14 ], [ 118, 462, 44, 14 ], [ 164, 462, 21, 14 ], [ 188, 462, 30, 14 ], [ 220, 462, 15, 14 ], [ 238, 462, 60, 14 ], [ 301, 462, 52, 14 ], [ 355, 462, 51, 14 ], [ 409, 462, 37, 14 ], [ 449, 462, 16, 14 ], [ 467, 462, 59, 14 ], [ 529, 462, 35, 14 ], [ 567, 462, 17, 14 ], [ 587, 462, 52, 14 ], [ 642, 462, 59, 14 ], [ 704, 462, 59, 14 ], [ 62, 488, 34, 10 ], [ 99, 488, 35, 10 ], [ 136, 488, 16, 10 ], [ 155, 488, 38, 10 ], [ 195, 488, 14, 10 ], [ 212, 488, 31, 10 ], [ 245, 488, 13, 10 ], [ 261, 488, 21, 10 ], [ 285, 488, 9, 10 ], [ 296, 488, 37, 10 ], [ 335, 488, 11, 10 ], [ 349, 488, 9, 10 ], [ 360, 488, 9, 10 ], [ 371, 488, 26, 10 ], [ 399, 488, 50, 10 ], [ 452, 488, 9, 10 ], [ 463, 488, 30, 10 ], [ 495, 488, 8, 10 ], [ 506, 488, 41, 10 ], [ 549, 488, 25, 10 ], [ 576, 488, 12, 10 ], [ 590, 488, 37, 10 ], [ 630, 488, 41, 10 ], [ 673, 488, 40, 10 ], [ 715, 488, 20, 10 ], [ 737, 488, 25, 10 ], [ 62, 500, 18, 10 ], [ 83, 500, 17, 10 ], [ 103, 500, 139, 10 ], [ 62, 539, 82, 15 ], [ 75, 564, 22, 13 ], [ 100, 564, 35, 13 ], [ 139, 564, 12, 13 ], [ 155, 564, 27, 13 ], [ 186, 564, 24, 13 ], [ 215, 564, 24, 13 ], [ 243, 564, 21, 13 ], [ 268, 564, 24, 13 ], [ 296, 564, 30, 13 ], [ 330, 564, 9, 13 ], [ 343, 564, 57, 13 ], [ 62, 580, 17, 13 ], [ 84, 580, 43, 13 ], [ 131, 580, 21, 13 ], [ 157, 580, 74, 13 ], [ 236, 580, 12, 13 ], [ 253, 580, 56, 13 ], [ 314, 580, 12, 13 ], [ 330, 580, 44, 13 ], [ 379, 580, 21, 13 ], [ 62, 595, 53, 13 ], [ 120, 595, 17, 13 ], [ 141, 595, 30, 13 ], [ 175, 595, 45, 13 ], [ 225, 595, 12, 13 ], [ 241, 595, 46, 13 ], [ 291, 595, 74, 13 ], [ 369, 595, 17, 13 ], [ 391, 595, 9, 13 ], [ 62, 610, 64, 13 ], [ 130, 610, 23, 13 ], [ 157, 610, 46, 13 ], [ 208, 610, 24, 13 ], [ 236, 610, 13, 13 ], [ 254, 610, 24, 13 ], [ 282, 610, 52, 13 ], [ 339, 610, 27, 13 ], [ 370, 610, 30, 13 ], [ 62, 626, 29, 13 ], [ 97, 626, 13, 13 ], [ 116, 626, 40, 13 ], [ 162, 626, 52, 13 ], [ 219, 626, 18, 13 ], [ 243, 626, 31, 13 ], [ 280, 626, 63, 13 ], [ 349, 626, 17, 13 ], [ 371, 626, 29, 13 ], [ 62, 641, 64, 13 ], [ 129, 641, 34, 13 ], [ 166, 641, 14, 13 ], [ 183, 641, 50, 13 ], [ 236, 641, 12, 13 ], [ 251, 641, 29, 13 ], [ 283, 641, 57, 13 ], [ 344, 641, 56, 13 ], [ 62, 657, 12, 13 ], [ 79, 657, 49, 13 ], [ 133, 657, 12, 13 ], [ 149, 657, 18, 13 ], [ 173, 657, 36, 13 ], [ 214, 657, 66, 13 ], [ 285, 657, 12, 13 ], [ 302, 657, 40, 13 ], [ 347, 657, 53, 13 ], [ 62, 672, 42, 13 ], [ 111, 672, 58, 13 ], [ 175, 672, 32, 13 ], [ 214, 672, 12, 13 ], [ 233, 672, 29, 13 ], [ 269, 672, 64, 13 ], [ 340, 672, 26, 13 ], [ 373, 672, 27, 13 ], [ 62, 687, 50, 13 ], [ 116, 687, 17, 13 ], [ 137, 687, 38, 13 ], [ 179, 687, 85, 13 ], [ 268, 687, 12, 13 ], [ 284, 687, 44, 13 ], [ 331, 687, 22, 13 ], [ 357, 687, 28, 13 ], [ 389, 687, 11, 13 ], [ 62, 703, 22, 13 ], [ 88, 703, 11, 13 ], [ 102, 703, 12, 13 ], [ 118, 703, 40, 13 ], [ 161, 703, 66, 13 ], [ 231, 703, 12, 13 ], [ 246, 703, 35, 13 ], [ 285, 703, 59, 13 ], [ 347, 703, 53, 13 ], [ 62, 718, 53, 13 ], [ 119, 718, 63, 13 ], [ 185, 718, 22, 13 ], [ 211, 718, 34, 13 ], [ 249, 718, 21, 13 ], [ 274, 718, 57, 13 ], [ 334, 718, 41, 13 ], [ 379, 718, 21, 13 ], [ 62, 734, 24, 13 ], [ 89, 734, 73, 13 ], [ 165, 734, 30, 13 ], [ 198, 734, 12, 13 ], [ 213, 734, 18, 13 ], [ 234, 734, 44, 13 ], [ 280, 734, 24, 13 ], [ 308, 734, 58, 13 ], [ 368, 734, 32, 13 ], [ 62, 749, 12, 13 ], [ 77, 749, 53, 13 ], [ 134, 749, 34, 13 ], [ 171, 749, 12, 13 ], [ 187, 749, 31, 13 ], [ 221, 749, 47, 13 ], [ 272, 749, 12, 13 ], [ 287, 749, 37, 13 ], [ 329, 749, 67, 13 ], [ 75, 765, 68, 13 ], [ 145, 765, 12, 13 ], [ 160, 765, 46, 13 ], [ 209, 765, 41, 13 ], [ 253, 765, 47, 13 ], [ 303, 765, 55, 13 ], [ 360, 765, 25, 13 ], [ 389, 765, 11, 13 ], [ 62, 780, 48, 13 ], [ 116, 780, 23, 13 ], [ 144, 780, 14, 13 ], [ 163, 780, 65, 13 ], [ 233, 780, 57, 13 ], [ 295, 780, 12, 13 ], [ 312, 780, 39, 13 ], [ 357, 780, 43, 13 ], [ 62, 796, 31, 13 ], [ 98, 796, 44, 13 ], [ 149, 796, 18, 13 ], [ 173, 796, 39, 13 ], [ 217, 796, 39, 13 ], [ 262, 796, 22, 13 ], [ 290, 796, 30, 13 ], [ 326, 796, 12, 13 ], [ 343, 796, 57, 13 ], [ 62, 811, 37, 13 ], [ 105, 811, 18, 13 ], [ 129, 811, 35, 13 ], [ 169, 811, 12, 13 ], [ 186, 811, 43, 13 ], [ 235, 811, 25, 13 ], [ 265, 811, 74, 13 ], [ 345, 811, 20, 13 ], [ 370, 811, 30, 13 ], [ 62, 826, 34, 13 ], [ 101, 826, 35, 13 ], [ 142, 826, 55, 13 ], [ 202, 826, 49, 13 ], [ 257, 826, 12, 13 ], [ 274, 826, 50, 13 ], [ 329, 826, 39, 13 ], [ 373, 826, 27, 13 ], [ 62, 842, 47, 13 ], [ 117, 842, 14, 13 ], [ 139, 842, 44, 13 ], [ 190, 842, 37, 13 ], [ 235, 842, 19, 13 ], [ 262, 842, 12, 13 ], [ 281, 842, 57, 13 ], [ 346, 842, 35, 13 ], [ 388, 842, 12, 13 ], [ 62, 857, 41, 13 ], [ 107, 857, 11, 13 ], [ 122, 857, 36, 13 ], [ 163, 857, 50, 13 ], [ 217, 857, 24, 13 ], [ 246, 857, 74, 13 ], [ 324, 857, 30, 13 ], [ 358, 857, 42, 13 ], [ 62, 873, 57, 13 ], [ 125, 873, 47, 13 ], [ 177, 873, 37, 13 ], [ 220, 873, 14, 13 ], [ 239, 873, 7, 13 ], [ 252, 873, 74, 13 ], [ 331, 873, 29, 13 ], [ 366, 873, 34, 13 ], [ 62, 888, 56, 13 ], [ 125, 888, 49, 13 ], [ 180, 888, 11, 13 ], [ 198, 888, 86, 13 ], [ 291, 888, 48, 13 ], [ 345, 888, 23, 13 ], [ 374, 888, 25, 13 ], [ 62, 904, 43, 13 ], [ 108, 904, 62, 13 ], [ 172, 904, 11, 13 ], [ 185, 904, 36, 13 ], [ 224, 904, 50, 13 ], [ 277, 904, 12, 13 ], [ 292, 904, 47, 13 ], [ 342, 904, 12, 13 ], [ 356, 904, 44, 13 ], [ 62, 919, 33, 13 ], [ 100, 919, 20, 13 ], [ 124, 919, 47, 13 ], [ 175, 919, 9, 13 ], [ 189, 919, 30, 13 ], [ 223, 919, 12, 13 ], [ 239, 919, 31, 13 ], [ 274, 919, 12, 13 ], [ 290, 919, 7, 13 ], [ 301, 919, 32, 13 ], [ 337, 919, 12, 13 ], [ 353, 919, 47, 13 ], [ 62, 935, 55, 13 ], [ 123, 935, 19, 13 ], [ 148, 935, 51, 13 ], [ 205, 935, 12, 13 ], [ 223, 935, 19, 13 ], [ 248, 935, 51, 13 ], [ 305, 935, 21, 13 ], [ 333, 935, 12, 13 ], [ 351, 935, 49, 13 ], [ 62, 950, 60, 13 ], [ 127, 950, 33, 13 ], [ 165, 950, 23, 13 ], [ 193, 950, 14, 13 ], [ 211, 950, 42, 13 ], [ 259, 950, 59, 13 ], [ 323, 950, 13, 13 ], [ 341, 950, 21, 13 ], [ 367, 950, 33, 13 ], [ 62, 965, 57, 13 ], [ 123, 965, 24, 13 ], [ 151, 965, 44, 13 ], [ 199, 965, 9, 13 ], [ 212, 965, 42, 13 ], [ 258, 965, 47, 13 ], [ 309, 965, 12, 13 ], [ 324, 965, 60, 13 ], [ 388, 965, 12, 13 ], [ 62, 981, 14, 13 ], [ 79, 981, 81, 13 ], [ 163, 981, 44, 13 ], [ 209, 981, 9, 13 ], [ 221, 981, 50, 13 ], [ 273, 981, 12, 13 ], [ 288, 981, 23, 13 ], [ 313, 981, 78, 13 ], [ 393, 981, 7, 13 ], [ 62, 996, 59, 13 ], [ 127, 996, 37, 13 ], [ 170, 996, 12, 13 ], [ 188, 996, 24, 13 ], [ 217, 996, 58, 13 ], [ 281, 996, 11, 13 ], [ 298, 996, 7, 13 ], [ 310, 996, 48, 13 ], [ 364, 996, 12, 13 ], [ 381, 996, 19, 13 ], [ 425, 533, 51, 13 ], [ 481, 533, 24, 13 ], [ 510, 533, 59, 13 ], [ 574, 533, 24, 13 ], [ 603, 533, 18, 13 ], [ 626, 533, 37, 13 ], [ 668, 533, 23, 13 ], [ 696, 533, 50, 13 ], [ 751, 533, 12, 13 ], [ 425, 549, 24, 13 ], [ 457, 549, 78, 13 ], [ 543, 549, 9, 13 ], [ 560, 549, 52, 13 ], [ 621, 549, 76, 13 ], [ 706, 549, 30, 13 ], [ 745, 549, 18, 13 ], [ 425, 564, 49, 13 ], [ 477, 564, 26, 13 ], [ 507, 564, 48, 13 ], [ 558, 564, 35, 13 ], [ 597, 564, 37, 13 ], [ 638, 564, 11, 13 ], [ 653, 564, 54, 13 ], [ 711, 564, 31, 13 ], [ 745, 564, 17, 13 ], [ 425, 580, 45, 13 ], [ 475, 580, 63, 13 ], [ 544, 580, 21, 13 ], [ 570, 580, 63, 13 ], [ 639, 580, 48, 13 ], [ 693, 580, 43, 13 ], [ 742, 580, 21, 13 ], [ 425, 595, 31, 13 ], [ 463, 595, 45, 13 ], [ 516, 595, 47, 13 ], [ 572, 595, 12, 13 ], [ 592, 595, 37, 13 ], [ 637, 595, 51, 13 ], [ 695, 595, 12, 13 ], [ 715, 595, 47, 13 ], [ 425, 610, 53, 13 ], [ 486, 610, 9, 13 ], [ 503, 610, 42, 13 ], [ 553, 610, 71, 13 ], [ 632, 610, 9, 13 ], [ 650, 610, 20, 13 ], [ 678, 610, 53, 13 ], [ 739, 610, 23, 13 ], [ 425, 626, 84, 13 ], [ 512, 626, 49, 13 ], [ 566, 626, 30, 13 ], [ 600, 626, 15, 13 ], [ 619, 626, 18, 13 ], [ 641, 626, 31, 13 ], [ 676, 626, 63, 13 ], [ 743, 626, 19, 13 ], [ 425, 641, 21, 13 ], [ 451, 641, 31, 13 ], [ 488, 641, 52, 13 ], [ 546, 641, 21, 13 ], [ 572, 641, 22, 13 ], [ 600, 641, 50, 13 ], [ 656, 641, 12, 13 ], [ 673, 641, 18, 13 ], [ 697, 641, 48, 13 ], [ 751, 641, 12, 13 ], [ 425, 657, 49, 13 ], [ 480, 657, 33, 13 ], [ 519, 657, 49, 13 ], [ 574, 657, 17, 13 ], [ 597, 657, 18, 13 ], [ 621, 657, 28, 13 ], [ 655, 657, 66, 13 ], [ 727, 657, 35, 13 ], [ 425, 672, 31, 13 ], [ 458, 672, 12, 13 ], [ 473, 672, 18, 13 ], [ 495, 672, 60, 13 ], [ 558, 672, 12, 13 ], [ 573, 672, 70, 13 ], [ 647, 672, 73, 13 ], [ 723, 672, 40, 13 ], [ 425, 688, 12, 13 ], [ 441, 688, 44, 13 ], [ 489, 688, 12, 13 ], [ 505, 688, 20, 13 ], [ 530, 688, 61, 13 ], [ 595, 688, 20, 13 ], [ 620, 688, 36, 13 ], [ 660, 688, 38, 13 ], [ 702, 688, 49, 13 ], [ 756, 688, 7, 13 ], [ 425, 703, 35, 13 ], [ 464, 703, 62, 13 ], [ 529, 703, 46, 13 ], [ 579, 703, 18, 13 ], [ 601, 703, 64, 13 ], [ 669, 703, 12, 13 ], [ 684, 703, 54, 13 ], [ 742, 703, 21, 13 ], [ 425, 718, 44, 13 ], [ 473, 718, 17, 13 ], [ 495, 718, 73, 13 ], [ 573, 718, 21, 13 ], [ 599, 718, 46, 13 ], [ 650, 718, 20, 13 ], [ 676, 718, 62, 13 ], [ 743, 718, 20, 13 ], [ 425, 734, 58, 13 ], [ 490, 734, 22, 13 ], [ 520, 734, 30, 13 ], [ 558, 734, 56, 13 ], [ 622, 734, 12, 13 ], [ 642, 734, 23, 13 ], [ 673, 734, 50, 13 ], [ 731, 734, 17, 13 ], [ 756, 734, 7, 13 ], [ 425, 749, 74, 13 ], [ 502, 749, 16, 13 ], [ 521, 749, 12, 13 ], [ 537, 749, 44, 13 ], [ 584, 749, 45, 13 ], [ 633, 749, 40, 13 ], [ 437, 765, 12, 13 ], [ 453, 765, 47, 13 ], [ 504, 765, 12, 13 ], [ 519, 765, 23, 13 ], [ 545, 765, 75, 13 ], [ 624, 765, 21, 13 ], [ 649, 765, 41, 13 ], [ 693, 765, 70, 13 ], [ 425, 780, 39, 13 ], [ 469, 780, 27, 13 ], [ 502, 780, 32, 13 ], [ 540, 780, 21, 13 ], [ 567, 780, 20, 13 ], [ 593, 780, 22, 13 ], [ 620, 780, 28, 13 ], [ 654, 780, 32, 13 ], [ 692, 780, 24, 13 ], [ 722, 780, 41, 13 ], [ 425, 796, 52, 13 ], [ 482, 796, 57, 13 ], [ 545, 796, 23, 13 ], [ 573, 796, 44, 13 ], [ 623, 796, 48, 13 ], [ 676, 796, 12, 13 ], [ 694, 796, 18, 13 ], [ 718, 796, 45, 13 ], [ 425, 836, 29, 10 ], [ 456, 836, 26, 10 ], [ 485, 836, 9, 10 ], [ 496, 836, 29, 10 ], [ 528, 836, 35, 10 ], [ 566, 836, 43, 10 ], [ 612, 836, 28, 10 ], [ 642, 836, 25, 10 ], [ 670, 836, 9, 10 ], [ 681, 836, 34, 10 ], [ 425, 855, 40, 10 ], [ 467, 855, 43, 10 ], [ 513, 855, 7, 10 ], [ 524, 855, 22, 10 ], [ 549, 855, 41, 10 ], [ 593, 855, 43, 10 ], [ 639, 855, 12, 10 ], [ 654, 855, 22, 10 ], [ 679, 855, 44, 10 ], [ 726, 855, 36, 10 ], [ 425, 866, 12, 10 ], [ 440, 866, 20, 10 ], [ 425, 885, 46, 10 ], [ 484, 885, 20, 10 ], [ 507, 885, 35, 10 ], [ 545, 885, 9, 10 ], [ 556, 885, 9, 10 ], [ 568, 885, 17, 10 ], [ 587, 885, 6, 10 ], [ 596, 885, 10, 10 ], [ 610, 885, 50, 10 ], [ 662, 885, 25, 10 ], [ 690, 885, 45, 10 ], [ 738, 885, 25, 10 ], [ 425, 897, 14, 10 ], [ 440, 897, 24, 10 ], [ 466, 897, 9, 10 ], [ 476, 897, 14, 10 ], [ 492, 897, 34, 10 ], [ 527, 897, 42, 10 ], [ 571, 897, 45, 10 ], [ 619, 897, 32, 10 ], [ 653, 897, 25, 10 ], [ 680, 897, 31, 10 ], [ 713, 897, 50, 10 ], [ 425, 908, 17, 10 ], [ 444, 908, 50, 10 ], [ 497, 908, 16, 10 ], [ 516, 908, 54, 10 ], [ 574, 908, 8, 10 ], [ 585, 908, 15, 10 ], [ 603, 908, 37, 10 ], [ 643, 908, 37, 10 ], [ 683, 908, 14, 10 ], [ 701, 908, 31, 10 ], [ 735, 908, 28, 10 ], [ 425, 919, 16, 10 ], [ 443, 919, 27, 10 ], [ 473, 919, 13, 10 ], [ 489, 919, 36, 10 ], [ 425, 938, 64, 10 ], [ 491, 938, 27, 10 ], [ 521, 938, 30, 10 ], [ 554, 938, 35, 10 ], [ 592, 938, 36, 10 ], [ 630, 938, 31, 10 ], [ 664, 938, 19, 10 ], [ 686, 938, 19, 10 ], [ 707, 938, 5, 10 ], [ 715, 938, 35, 10 ], [ 425, 957, 5, 10 ], [ 432, 957, 11, 10 ], [ 445, 957, 26, 10 ], [ 474, 957, 66, 10 ], [ 543, 957, 28, 10 ], [ 574, 957, 11, 10 ], [ 588, 957, 44, 10 ], [ 635, 957, 27, 10 ], [ 665, 957, 76, 10 ], [ 425, 968, 55, 10 ], [ 425, 987, 6, 10 ], [ 433, 987, 31, 10 ], [ 466, 987, 34, 10 ], [ 503, 987, 33, 10 ], [ 538, 987, 9, 10 ], [ 549, 987, 33, 10 ], [ 585, 987, 53, 10 ], [ 640, 987, 16, 10 ], [ 659, 987, 49, 10 ], [ 710, 987, 19, 10 ], [ 731, 987, 31, 10 ], [ 425, 998, 8, 10 ], [ 436, 998, 32, 10 ], [ 470, 998, 22, 10 ], [ 495, 998, 23, 10 ], [ 521, 998, 45, 10 ], [ 569, 998, 61, 10 ], [ 633, 998, 28, 10 ], [ 664, 998, 25, 10 ], [ 691, 998, 9, 10 ], [ 703, 998, 34, 10 ], [ 95, 1030, 23, 12 ], [ 121, 1030, 40, 12 ], [ 164, 1030, 3, 12 ], [ 171, 1030, 104, 12 ], [ 401, 1030, 23, 12 ], [ 571, 1030, 42, 12 ], [ 615, 1030, 23, 12 ], [ 642, 1030, 3, 12 ], [ 648, 1030, 36, 12 ], [ 687, 1030, 6, 12 ], [ 696, 1030, 3, 12 ], [ 703, 1030, 24, 12 ], [ 730, 1030, 6, 12 ], [ 739, 1030, 3, 12 ], [ 745, 1030, 17, 12 ] ]

[ "Adaptations", "to", "Climate", "in", "Candidate", "Genes", "for", "Common", "Metabolic", "Disorders", "Angela", "M.", "Hancock1,", "David", "B.", "Witonsky1,", "Adam", "S.", "Gordon1,", "Gidon", "Eshel2¤,", "Jonathan", "K.", "Pritchard1,", "Graham", "Coop1,", "Anna", "Di", "Rienzo1*", "1", "Department", "of", "Human", "Genetics,", "University", "of", "Chicago,", "Chicago,", "Illinois,", "United", "States", "of", "America,", "2", "Department", "of", "Geophysical", "Sciences,", "University", "of", "Chicago,", "Illinois,", "United", "States", "of", "America", "Evolutionary", "pressures", "due", "to", "variation", "in", "climate", "play", "an", "important", "role", "in", "shaping", "phenotypic", "variation", "among", "and", "within", "species", "and", "have", "been", "shown", "to", "influence", "variation", "in", "phenotypes", "such", "as", "body", "shape", "and", "size", "among", "humans.", "Genes", "involved", "in", "energy", "metabolism", "are", "likely", "to", "be", "central", "to", "heat", "and", "cold", "tolerance.", "To", "test", "the", "hypothesis", "that", "climate", "shaped", "variation", "in", "metabolism", "genes", "in", "humans,", "we", "used", "a", "bioinformatics", "approach", "based", "on", "network", "theory", "to", "select", "82", "candidate", "genes", "for", "common", "metabolic", "disorders.", "We", "genotyped", "873", "tag", "SNPs", "in", "these", "genes", "in", "54", "worldwide", "populations", "(including", "the", "52", "in", "the", "Human", "Genome", "Diversity", "Project", "panel)", "and", "found", "correlations", "with", "climate", "variables", "using", "rank", "correlation", "analysis", "and", "a", "newly", "developed", "method", "termed", "Bayesian", "geographic", "analysis.", "In", "addition,", "we", "genotyped", "210", "carefully", "matched", "control", "SNPs", "to", "provide", "an", "empirical", "null", "distribution", "for", "spatial", "patterns", "of", "allele", "frequency", "due", "to", "population", "history", "alone.", "For", "nearly", "all", "climate", "variables,", "we", "found", "an", "excess", "of", "genic", "SNPs", "in", "the", "tail", "of", "the", "distributions", "of", "the", "test", "statistics", "compared", "to", "the", "control", "SNPs,", "implying", "that", "metabolic", "genes", "as", "a", "group", "show", "signals", "of", "spatially", "varying", "selection.", "Among", "our", "strongest", "signals", "were", "several", "SNPs", "(e.g.,", "LEPR", "R109K,", "FABP2", "A54T)", "that", "had", "previously", "been", "associated", "with", "phenotypes", "directly", "related", "to", "cold", "tolerance.", "Since", "variation", "in", "climate", "may", "be", "correlated", "with", "other", "aspects", "of", "environmental", "variation,", "it", "is", "possible", "that", "some", "of", "the", "signals", "that", "we", "detected", "reflect", "selective", "pressures", "other", "than", "climate.", "Nevertheless,", "our", "results", "are", "consistent", "with", "the", "idea", "that", "climate", "has", "been", "an", "important", "selective", "pressure", "acting", "on", "candidate", "genes", "for", "common", "metabolic", "disorders.", "Citation:", "Hancock", "AM,", "Witonsky", "DB,", "Gordon", "AS,", "Eshel", "G,", "Pritchard", "JK,", "et", "al.", "(2008)", "Adaptations", "to", "climate", "in", "candidate", "genes", "for", "common", "metabolic", "disorders.", "PLoS", "Genet", "4(2):", "e32.", "doi:10.1371/journal.pgen.0040032", "Introduction", "The", "ability", "to", "cope", "with", "heat", "and", "cold", "stress", "is", "important", "for", "survival", "and", "reproduction", "of", "organisms", "in", "general,", "and", "especially", "for", "those", "exposed", "to", "extreme", "temperatures", "[1].", "If", "phenotypes", "that", "increase", "heat", "or", "cold", "tolerance", "were", "acted", "upon", "by", "natural", "selection,", "the", "genes", "responsible", "for", "these", "phenotypes", "would", "be", "expected", "to", "carry", "detectable", "signatures", "of", "selection", "in", "the", "spatial", "distribution", "of", "genetic", "variation.", "Indeed,", "latitudinal", "clines", "of", "allele", "frequencies", "have", "been", "observed", "for", "several", "polymorphisms", "in", "humans", "(e.g.", "[2,3])", "as", "well", "as", "in", "natural", "populations", "of", "model", "organisms,", "including", "Drosophila", "melanogaster", "(e.g.", "[4–8]),", "and", "Arabidopsis", "thaliana", "([9–", "11]).", "Interestingly,", "many", "of", "the", "variants", "with", "latitudinal", "clines", "in", "Drosophila", "reside", "in", "genes", "involved", "in", "energy", "metabolism.", "Adaptations", "to", "spatially", "varying", "selective", "pressures,", "such", "as", "climates,", "may", "be", "particularly", "important", "in", "human", "popula-", "tions.", "Because", "the", "human", "species", "first", "arose", "in", "equatorial", "Africa,", "the", "ability", "to", "tolerate", "high", "temperatures", "was", "likely", "under", "strong", "long-term", "selection", "in", "ancestral", "human", "pop-", "ulations.", "As", "humans", "spread", "out", "of", "equatorial", "Africa", "to", "regions", "at", "higher", "latitudes,", "cold", "temperatures", "likely", "became", "important", "selective", "forces.", "As", "a", "consequence,", "traits", "under", "stabilizing", "selection", "at", "near-equatorial", "latitudes", "may", "have", "become", "deleterious", "at", "higher", "latitudes.", "In", "addition", "to", "thermal", "stress,", "this", "scenario", "is", "likely", "to", "apply", "to", "a", "range", "of", "selective", "pressures,", "e.g.", "exposure", "to", "UV", "radiation", "and", "to", "different", "pathogens,", "which", "may", "be", "directly", "influenced", "by", "and", "partly", "correlated", "with", "climate.", "A", "striking", "example", "of", "adaptation", "to", "an", "environmental", "variable", "is", "variation", "in", "skin", "pigmentation,", "a", "phenotype", "known", "to", "vary", "worldwide", "as", "a", "function", "of", "UV", "radiation", "[12].", "Consistent", "with", "the", "notion", "that", "variation", "in", "skin", "pigmentation", "is", "adaptive,", "genome-wide", "scans", "for", "selection", "have", "detected", "strong", "signals", "at", "candidate", "genes", "for", "melanin", "production", "and", "melanocyte", "function", "[13–18].", "An-", "other", "possible", "example", "of", "spatial", "variation", "in", "selective", "pressures", "is", "sodium", "homeostasis.", "It", "was", "proposed", "that", "climate-related", "selection", "acted", "on", "the", "genes", "influencing", "salt", "and", "water", "retention", "and", "that", "variation", "in", "the", "intensity", "of", "selection", "partly", "accounts", "for", "the", "large", "inter-ethnic", "differ-", "ences", "in", "the", "prevalence", "of", "salt-sensitive", "hypertension", "[19,20].", "In", "support", "of", "this", "hypothesis,", "two", "recent", "studies", "reported", "a", "strong", "correlation", "between", "the", "frequencies", "of", "candidate", "risk", "variants", "for", "hypertension", "and", "latitude;", "this", "correlation", "was", "significant", "also", "when", "compared", "to", "that", "observed", "for", "a", "genome-wide", "set", "of", "random", "markers", "[21,22].", "In", "addition", "to", "skin", "pigmentation", "and", "sodium", "homeostasis,", "human", "body", "shape", "and", "size", "also", "show", "clines", "with", "climate", "variables,", "suggesting", "that", "humans", "conform", "to", "the", "classical", "Editor:", "Dmitri", "A.", "Petrov,", "Stanford", "University,", "United", "States", "of", "America", "Received", "November", "5,", "2007;", "Accepted", "December", "26,", "2007;", "Published", "February", "15,", "2008", "Copyright:", "2008", "Hancock", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Abbreviations:", "HGDP,", "Human", "Genome", "Diversity", "Project;", "T2D,", "type", "2", "diabetes", "*", "To", "whom", "correspondence", "should", "be", "addressed.", "E-mail:", "dirienzo@genetics.", "uchicago.edu", "¤", "Current", "address:", "Division", "of", "Science,", "Mathematics", "and", "Computing,", "Bard", "College", "at", "Simon’s", "Rock,", "Great", "Barrington,", "Massachusetts,", "United", "States", "of", "America", "PLoS", "Genetics", "|", "www.plosgenetics.org", "0001", "February", "2008", "|", "Volume", "4", "|", "Issue", "2", "|", "e32" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 12, 12 ], [ 94, 47, 9, 12 ], [ 106, 47, 11, 12 ], [ 120, 47, 21, 12 ], [ 144, 47, 31, 12 ], [ 178, 47, 25, 12 ], [ 207, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 140, 34 ], [ 229, 169, 140, 34 ], [ 379, 169, 51, 34 ], [ 440, 169, 51, 34 ], [ 501, 169, 211, 34 ], [ 78, 205, 137, 34 ], [ 225, 205, 51, 34 ], [ 287, 205, 16, 34 ], [ 313, 205, 140, 34 ], [ 463, 205, 161, 34 ], [ 634, 205, 73, 34 ], [ 717, 205, 25, 34 ], [ 78, 241, 164, 34 ], [ 252, 241, 76, 34 ], [ 78, 288, 49, 16 ], [ 132, 285, 46, 19 ], [ 182, 288, 52, 16 ], [ 239, 285, 42, 19 ], [ 285, 288, 52, 16 ], [ 342, 285, 42, 19 ], [ 389, 288, 60, 16 ], [ 454, 285, 44, 19 ], [ 503, 288, 39, 16 ], [ 546, 285, 32, 19 ], [ 582, 288, 68, 16 ], [ 655, 285, 32, 19 ], [ 78, 307, 40, 16 ], [ 122, 305, 35, 19 ], [ 162, 307, 54, 16 ], [ 220, 305, 44, 19 ], [ 269, 307, 44, 16 ], [ 317, 305, 46, 19 ], [ 367, 307, 45, 16 ], [ 417, 307, 18, 16 ], [ 440, 305, 30, 19 ], [ 474, 307, 34, 16 ], [ 511, 305, 43, 19 ], [ 87, 361, 54, 15 ], [ 87, 386, 76, 14 ], [ 167, 387, 90, 14 ], [ 261, 387, 58, 14 ], [ 323, 387, 31, 14 ], [ 359, 387, 8, 14 ], [ 371, 387, 21, 14 ], [ 397, 387, 11, 14 ], [ 412, 387, 28, 14 ], [ 444, 387, 27, 14 ], [ 476, 387, 11, 14 ], [ 491, 387, 19, 14 ], [ 514, 387, 32, 14 ], [ 550, 387, 20, 14 ], [ 574, 387, 8, 14 ], [ 586, 387, 7, 14 ], [ 597, 387, 51, 14 ], [ 653, 387, 64, 14 ], [ 721, 387, 11, 14 ], [ 87, 403, 50, 14 ], [ 141, 403, 35, 14 ], [ 180, 403, 53, 14 ], [ 237, 403, 11, 14 ], [ 252, 403, 69, 14 ], [ 325, 403, 39, 14 ], [ 369, 403, 29, 14 ], [ 402, 403, 8, 14 ], [ 414, 403, 51, 14 ], [ 469, 403, 12, 14 ], [ 485, 403, 14, 14 ], [ 503, 403, 55, 14 ], [ 563, 403, 47, 14 ], [ 614, 403, 11, 14 ], [ 629, 403, 24, 14 ], [ 657, 403, 18, 14 ], [ 680, 403, 11, 14 ], [ 695, 403, 38, 14 ], [ 87, 420, 49, 14 ], [ 140, 420, 29, 14 ], [ 173, 420, 21, 14 ], [ 199, 420, 24, 14 ], [ 227, 420, 43, 14 ], [ 274, 420, 40, 14 ], [ 318, 420, 19, 14 ], [ 341, 420, 64, 14 ], [ 409, 420, 63, 14 ], [ 477, 420, 11, 14 ], [ 492, 420, 24, 14 ], [ 520, 420, 56, 14 ], [ 581, 420, 11, 14 ], [ 596, 420, 34, 14 ], [ 634, 420, 29, 14 ], [ 667, 420, 55, 14 ], [ 87, 436, 75, 14 ], [ 166, 436, 37, 14 ], [ 207, 436, 19, 14 ], [ 230, 436, 23, 14 ], [ 258, 436, 21, 14 ], [ 282, 436, 46, 14 ], [ 333, 436, 19, 14 ], [ 356, 436, 49, 14 ], [ 409, 436, 19, 14 ], [ 432, 436, 73, 14 ], [ 509, 436, 41, 14 ], [ 555, 436, 21, 14 ], [ 580, 436, 38, 14 ], [ 622, 436, 34, 14 ], [ 660, 436, 11, 14 ], [ 676, 436, 19, 14 ], [ 87, 453, 44, 14 ], [ 136, 453, 72, 14 ], [ 212, 453, 51, 14 ], [ 267, 453, 7, 14 ], [ 278, 453, 74, 14 ], [ 355, 453, 11, 14 ], [ 371, 453, 22, 14 ], [ 397, 453, 22, 14 ], [ 423, 453, 13, 14 ], [ 439, 453, 50, 14 ], [ 493, 453, 51, 14 ], [ 549, 453, 15, 14 ], [ 568, 453, 24, 14 ], [ 596, 453, 18, 14 ], [ 618, 453, 11, 14 ], [ 633, 453, 20, 14 ], [ 657, 453, 76, 14 ], [ 87, 470, 26, 14 ], [ 87, 490, 56, 14 ], [ 148, 490, 14, 14 ], [ 166, 490, 47, 14 ], [ 217, 490, 19, 14 ], [ 240, 490, 61, 14 ], [ 305, 490, 49, 14 ], [ 358, 490, 38, 14 ], [ 400, 490, 37, 14 ], [ 442, 490, 21, 14 ], [ 467, 490, 24, 14 ], [ 496, 490, 18, 14 ], [ 518, 490, 11, 14 ], [ 533, 490, 69, 14 ], [ 606, 490, 34, 14 ], [ 645, 490, 7, 14 ], [ 656, 490, 61, 14 ], [ 87, 507, 81, 14 ], [ 172, 507, 68, 14 ], [ 244, 507, 30, 14 ], [ 279, 507, 22, 14 ], [ 305, 507, 63, 14 ], [ 372, 507, 27, 14 ], [ 403, 507, 40, 14 ], [ 447, 507, 29, 14 ], [ 481, 507, 21, 14 ], [ 506, 507, 27, 14 ], [ 538, 507, 56, 14 ], [ 597, 507, 50, 14 ], [ 651, 507, 45, 14 ], [ 700, 507, 28, 14 ], [ 87, 524, 52, 14 ], [ 143, 524, 30, 14 ], [ 177, 524, 30, 14 ], [ 212, 524, 29, 14 ], [ 245, 524, 21, 14 ], [ 270, 524, 19, 14 ], [ 293, 524, 81, 14 ], [ 379, 524, 24, 14 ], [ 407, 524, 62, 14 ], [ 473, 524, 46, 14 ], [ 523, 524, 23, 14 ], [ 550, 524, 28, 14 ], [ 582, 524, 55, 14 ], [ 642, 524, 30, 14 ], [ 676, 524, 7, 14 ], [ 687, 524, 39, 14 ], [ 87, 540, 57, 14 ], [ 149, 540, 38, 14 ], [ 191, 540, 51, 14 ], [ 246, 540, 15, 14 ], [ 266, 540, 23, 14 ], [ 293, 540, 20, 14 ], [ 318, 540, 58, 14 ], [ 380, 540, 39, 14 ], [ 424, 540, 21, 14 ], [ 449, 540, 57, 14 ], [ 510, 540, 59, 14 ], [ 574, 540, 27, 14 ], [ 87, 561, 46, 14 ], [ 137, 561, 72, 14 ], [ 214, 561, 32, 14 ], [ 250, 561, 41, 14 ], [ 295, 561, 19, 14 ], [ 318, 561, 55, 14 ], [ 377, 561, 11, 14 ], [ 391, 561, 74, 14 ], [ 470, 561, 11, 14 ], [ 485, 561, 68, 14 ], [ 557, 561, 33, 14 ], [ 594, 561, 22, 14 ], [ 620, 561, 55, 14 ], [ 679, 561, 60, 14 ], [ 87, 578, 21, 14 ], [ 113, 578, 91, 14 ], [ 208, 578, 29, 14 ], [ 241, 578, 28, 14 ], [ 273, 578, 66, 14 ], [ 343, 578, 58, 14 ], [ 404, 578, 25, 14 ], [ 433, 578, 53, 14 ], [ 490, 578, 18, 14 ], [ 513, 578, 11, 14 ], [ 528, 578, 26, 14 ], [ 559, 578, 25, 14 ], [ 588, 578, 56, 14 ], [ 648, 578, 28, 14 ], [ 680, 578, 30, 14 ], [ 714, 578, 24, 14 ], [ 87, 594, 11, 14 ], [ 103, 594, 23, 14 ], [ 130, 594, 27, 14 ], [ 161, 594, 13, 14 ], [ 179, 594, 55, 14 ], [ 238, 594, 50, 14 ], [ 292, 594, 14, 14 ], [ 309, 594, 53, 14 ], [ 366, 594, 22, 14 ], [ 392, 594, 23, 14 ], [ 419, 594, 27, 14 ], [ 450, 594, 13, 14 ], [ 468, 594, 53, 14 ], [ 525, 594, 65, 14 ], [ 594, 594, 11, 14 ], [ 609, 594, 19, 14 ], [ 632, 594, 42, 14 ], [ 677, 594, 34, 14 ], [ 87, 611, 55, 14 ], [ 147, 611, 43, 14 ], [ 194, 611, 37, 14 ], [ 235, 611, 59, 14 ], [ 298, 611, 11, 14 ], [ 313, 611, 74, 14 ], [ 391, 611, 11, 14 ], [ 407, 611, 27, 14 ], [ 438, 611, 22, 14 ], [ 465, 611, 22, 14 ], [ 491, 611, 58, 14 ], [ 552, 611, 25, 14 ], [ 581, 611, 46, 14 ], [ 632, 611, 18, 14 ], [ 654, 611, 25, 14 ], [ 683, 611, 7, 14 ], [ 694, 611, 31, 14 ], [ 87, 627, 62, 14 ], [ 153, 627, 65, 14 ], [ 222, 627, 12, 14 ], [ 238, 627, 9, 14 ], [ 251, 627, 35, 14 ], [ 290, 627, 21, 14 ], [ 316, 627, 11, 14 ], [ 331, 627, 74, 14 ], [ 409, 627, 11, 14 ], [ 425, 627, 70, 14 ], [ 498, 627, 35, 14 ], [ 538, 627, 17, 14 ], [ 559, 627, 21, 14 ], [ 585, 627, 35, 14 ], [ 624, 627, 70, 14 ], [ 699, 627, 28, 14 ], [ 87, 644, 22, 14 ], [ 113, 644, 58, 14 ], [ 175, 644, 25, 14 ], [ 204, 644, 57, 14 ], [ 265, 644, 20, 14 ], [ 290, 644, 25, 14 ], [ 319, 644, 22, 14 ], [ 344, 644, 11, 14 ], [ 360, 644, 23, 14 ], [ 387, 644, 27, 14 ], [ 418, 644, 13, 14 ], [ 436, 644, 53, 14 ], [ 493, 644, 21, 14 ], [ 519, 644, 23, 14 ], [ 545, 644, 27, 14 ], [ 577, 644, 13, 14 ], [ 595, 644, 53, 14 ], [ 651, 644, 65, 14 ], [ 721, 644, 11, 14 ], [ 87, 661, 19, 14 ], [ 110, 661, 41, 14 ], [ 156, 661, 34, 14 ], [ 193, 661, 56, 14 ], [ 253, 661, 45, 14 ], [ 302, 661, 11, 14 ], [ 317, 661, 65, 14 ], [ 386, 661, 48, 14 ], [ 439, 661, 30, 14 ], [ 473, 661, 66, 14 ], [ 544, 661, 53, 14 ], [ 601, 661, 59, 14 ], [ 87, 681, 75, 14 ], [ 167, 681, 8, 14 ], [ 179, 681, 20, 14 ], [ 203, 681, 15, 14 ], [ 221, 681, 43, 14 ], [ 269, 681, 22, 14 ], [ 295, 681, 56, 14 ], [ 356, 681, 62, 14 ], [ 423, 681, 38, 14 ], [ 465, 681, 18, 14 ], [ 487, 681, 37, 14 ], [ 528, 681, 11, 14 ], [ 543, 681, 19, 14 ], [ 566, 681, 59, 14 ], [ 629, 681, 61, 14 ], [ 694, 681, 17, 14 ], [ 716, 681, 18, 14 ], [ 87, 698, 33, 14 ], [ 124, 698, 21, 14 ], [ 150, 698, 27, 14 ], [ 181, 698, 66, 14 ], [ 251, 698, 12, 14 ], [ 267, 698, 19, 14 ], [ 290, 698, 54, 14 ], [ 348, 698, 11, 14 ], [ 363, 698, 26, 14 ], [ 78, 744, 77, 15 ], [ 78, 761, 55, 14 ], [ 138, 761, 24, 14 ], [ 166, 761, 12, 14 ], [ 182, 761, 29, 14 ], [ 216, 761, 29, 14 ], [ 250, 761, 12, 14 ], [ 266, 761, 19, 14 ], [ 289, 761, 37, 14 ], [ 331, 761, 73, 14 ], [ 78, 778, 25, 14 ], [ 109, 778, 65, 14 ], [ 180, 778, 39, 14 ], [ 225, 778, 10, 14 ], [ 241, 778, 7, 14 ], [ 254, 778, 54, 14 ], [ 315, 778, 71, 14 ], [ 391, 778, 12, 14 ], [ 78, 794, 52, 14 ], [ 135, 794, 38, 14 ], [ 178, 794, 56, 14 ], [ 239, 794, 12, 14 ], [ 256, 794, 19, 14 ], [ 279, 794, 68, 14 ], [ 352, 794, 51, 14 ], [ 78, 811, 30, 14 ], [ 112, 811, 23, 14 ], [ 140, 811, 55, 14 ], [ 200, 811, 23, 14 ], [ 227, 811, 17, 14 ], [ 248, 811, 33, 14 ], [ 286, 811, 9, 14 ], [ 300, 811, 30, 14 ], [ 335, 811, 26, 14 ], [ 366, 811, 14, 14 ], [ 384, 811, 19, 14 ], [ 78, 827, 48, 14 ], [ 131, 827, 79, 14 ], [ 215, 827, 23, 14 ], [ 243, 827, 10, 14 ], [ 258, 827, 12, 14 ], [ 276, 827, 27, 14 ], [ 308, 827, 12, 14 ], [ 326, 827, 15, 14 ], [ 346, 827, 12, 14 ], [ 364, 827, 15, 14 ], [ 383, 827, 20, 14 ], [ 78, 844, 48, 14 ], [ 133, 844, 80, 14 ], [ 220, 844, 12, 14 ], [ 239, 844, 32, 14 ], [ 278, 844, 32, 14 ], [ 316, 844, 61, 14 ], [ 384, 844, 20, 14 ], [ 78, 861, 42, 14 ], [ 125, 861, 31, 14 ], [ 161, 861, 22, 14 ], [ 187, 861, 19, 14 ], [ 211, 861, 30, 14 ], [ 246, 861, 31, 14 ], [ 281, 861, 32, 14 ], [ 318, 861, 42, 14 ], [ 365, 861, 39, 14 ], [ 78, 877, 20, 14 ], [ 104, 877, 60, 14 ], [ 169, 877, 12, 14 ], [ 186, 877, 29, 14 ], [ 221, 877, 36, 14 ], [ 263, 877, 16, 14 ], [ 284, 877, 13, 14 ], [ 302, 877, 45, 14 ], [ 353, 877, 51, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 103, 11 ], [ 78, 925, 5, 11 ], [ 87, 925, 50, 11 ], [ 140, 925, 30, 11 ], [ 78, 936, 25, 13 ], [ 106, 937, 15, 11 ], [ 124, 937, 45, 11 ], [ 172, 937, 9, 11 ], [ 184, 937, 41, 11 ], [ 227, 937, 8, 11 ], [ 239, 937, 38, 11 ], [ 280, 937, 26, 11 ], [ 309, 937, 50, 11 ], [ 362, 937, 32, 11 ], [ 78, 950, 24, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 16, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 744, 47, 14 ], [ 474, 744, 26, 14 ], [ 505, 744, 29, 14 ], [ 538, 744, 54, 14 ], [ 597, 744, 60, 14 ], [ 662, 744, 29, 14 ], [ 695, 744, 53, 14 ], [ 423, 761, 35, 14 ], [ 462, 761, 27, 14 ], [ 493, 761, 40, 14 ], [ 538, 761, 22, 14 ], [ 564, 761, 46, 14 ], [ 615, 761, 12, 14 ], [ 631, 761, 52, 14 ], [ 687, 761, 38, 14 ], [ 730, 761, 19, 14 ], [ 423, 778, 29, 14 ], [ 457, 778, 12, 14 ], [ 473, 778, 48, 14 ], [ 526, 778, 26, 14 ], [ 557, 778, 12, 14 ], [ 574, 778, 19, 14 ], [ 598, 778, 30, 14 ], [ 632, 778, 53, 14 ], [ 690, 778, 58, 14 ], [ 423, 794, 19, 14 ], [ 447, 794, 16, 14 ], [ 467, 794, 39, 14 ], [ 511, 794, 27, 14 ], [ 544, 794, 7, 14 ], [ 556, 794, 20, 14 ], [ 581, 794, 47, 14 ], [ 634, 794, 78, 14 ], [ 717, 794, 31, 14 ], [ 423, 811, 45, 14 ], [ 472, 811, 46, 14 ], [ 523, 811, 23, 14 ], [ 550, 811, 52, 14 ], [ 607, 811, 47, 14 ], [ 658, 811, 25, 14 ], [ 687, 811, 45, 14 ], [ 736, 811, 12, 14 ], [ 423, 827, 104, 14 ], [ 531, 827, 34, 14 ], [ 570, 827, 28, 14 ], [ 603, 827, 12, 14 ], [ 620, 827, 58, 14 ], [ 683, 827, 30, 14 ], [ 718, 827, 13, 14 ], [ 736, 827, 12, 14 ], [ 423, 844, 48, 14 ], [ 476, 844, 34, 14 ], [ 514, 844, 27, 14 ], [ 546, 844, 12, 14 ], [ 563, 844, 19, 14 ], [ 586, 844, 41, 14 ], [ 632, 844, 58, 14 ], [ 694, 844, 54, 14 ], [ 423, 861, 21, 14 ], [ 448, 861, 18, 14 ], [ 470, 861, 39, 14 ], [ 513, 861, 36, 14 ], [ 554, 861, 50, 14 ], [ 608, 861, 12, 14 ], [ 624, 861, 26, 14 ], [ 654, 861, 7, 14 ], [ 665, 861, 25, 14 ], [ 694, 861, 54, 14 ], [ 423, 877, 11, 14 ], [ 438, 877, 28, 14 ], [ 470, 877, 47, 14 ], [ 521, 877, 54, 14 ], [ 579, 877, 31, 14 ], [ 614, 877, 24, 14 ], [ 643, 877, 34, 14 ], [ 680, 877, 17, 14 ], [ 701, 877, 7, 14 ], [ 712, 877, 36, 14 ], [ 423, 894, 39, 14 ], [ 466, 894, 12, 14 ], [ 483, 894, 27, 14 ], [ 515, 894, 12, 14 ], [ 532, 894, 49, 14 ], [ 586, 894, 31, 14 ], [ 622, 894, 22, 14 ], [ 649, 894, 29, 14 ], [ 682, 894, 66, 14 ], [ 423, 910, 67, 14 ], [ 494, 910, 28, 14 ], [ 526, 910, 12, 14 ], [ 542, 910, 19, 14 ], [ 565, 910, 33, 14 ], [ 602, 910, 27, 14 ], [ 633, 910, 7, 14 ], [ 644, 910, 57, 14 ], [ 705, 910, 21, 14 ], [ 731, 910, 17, 14 ], [ 423, 927, 28, 14 ], [ 456, 927, 40, 14 ], [ 500, 927, 36, 14 ], [ 540, 927, 39, 14 ], [ 585, 927, 44, 14 ], [ 633, 927, 24, 14 ], [ 662, 927, 86, 14 ], [ 423, 944, 42, 14 ], [ 470, 944, 52, 14 ], [ 527, 944, 12, 14 ], [ 545, 944, 20, 14 ], [ 569, 944, 65, 14 ], [ 639, 944, 55, 14 ], [ 699, 944, 49, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 10, 10 ], [ 290, 987, 8, 10 ], [ 301, 987, 8, 10 ], [ 312, 987, 30, 10 ], [ 345, 987, 29, 10 ], [ 376, 987, 27, 10 ], [ 406, 987, 14, 10 ], [ 423, 987, 15, 10 ], [ 441, 987, 6, 10 ], [ 449, 987, 10, 10 ], [ 462, 987, 21, 10 ], [ 485, 987, 25, 10 ], [ 514, 987, 23, 10 ], [ 539, 987, 41, 10 ], [ 583, 987, 23, 10 ], [ 608, 987, 13, 10 ], [ 624, 987, 22, 10 ], [ 648, 987, 8, 10 ], [ 658, 987, 13, 10 ], [ 674, 987, 31, 10 ], [ 707, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Jia", "et", "al.", "BMC", "Cancer", "2010,", "10:446", "http://www.biomedcentral.com/1471-2407/10/446", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Traditional", "Cantonese", "diet", "and", "nasopharyngeal", "carcinoma", "risk:", "a", "large-scale", "case-control", "study", "in", "Guangdong,", "China", "Wei-Hua", "Jia1,2,3*†,", "Xiang-Yu", "Luo1,2†,", "Bing-Jian", "Feng4†,", "Hong-Lian", "Ruan1,3,", "Jin-Xin", "Bei1,2,", "Wen-Sheng", "Liu1,2,", "Hai-De", "Qin1,2,", "Qi-Sheng", "Feng1,2,", "Li-Zhen", "Chen1,2,", "Shugart", "Yin", "Yao5,", "Yi-Xin", "Zeng1,2", "Abstract", "Background:", "Nasopharyngeal", "carcinoma", "(NPC)", "is", "rare", "in", "most", "parts", "of", "the", "world", "but", "is", "a", "common", "malignancy", "in", "southern", "China,", "especially", "in", "Guangdong.", "Dietary", "habit", "is", "regarded", "as", "an", "important", "modifier", "of", "NPC", "risk", "in", "several", "endemic", "areas", "and", "may", "partially", "explain", "the", "geographic", "distribution", "of", "NPC", "incidence.", "In", "China,", "rapid", "economic", "development", "during", "the", "past", "few", "decades", "has", "changed", "the", "predominant", "lifestyle", "and", "dietary", "habits", "of", "the", "Chinese", "considerably,", "requiring", "a", "reassessment", "of", "diet", "and", "its", "potential", "influence", "on", "NPC", "risk", "in", "this", "NPC-endemic", "area.", "Methods:", "To", "evaluate", "the", "association", "between", "dietary", "factors", "and", "NPC", "risk", "in", "Guangdong,", "China,", "a", "large-scale,", "hospital-based", "case-control", "study", "was", "conducted.", "1387", "eligible", "cases", "and", "1459", "frequency", "matched", "controls", "were", "recruited.", "Odds", "ratios", "(ORs)", "and", "the", "corresponding", "95%", "confidence", "intervals", "(CIs)", "were", "estimated", "using", "a", "logistic", "regression", "model,", "adjusting", "for", "age,", "sex,", "education,", "dialect,", "and", "habitation", "household", "type.", "Results:", "Observations", "made", "include", "the", "following:", "1)", "consumption", "of", "canton-style", "salted", "fish,", "preserved", "vegetables", "and", "preserved/cured", "meat", "were", "significantly", "associated", "with", "increased", "risk", "of", "NPC,", "with", "enhanced", "odds", "ratios", "(OR)", "of", "2.45", "(95%", "CI:", "2.03-2.94),", "3.17(95%", "CI:", "2.68-3.77)", "and", "2.09", "(95%", "CI:", "1.22-3.60)", "respectively", "in", "the", "highest", "intake", "frequency", "stratum", "during", "childhood;", "2)", "consumption", "of", "fresh", "fruit", "was", "associated", "with", "reduced", "risk", "with", "a", "dose-", "dependent", "relationship", "(p", "=", "0.001);", "and", "3)", "consumption", "of", "Canton-style", "herbal", "tea", "and", "herbal", "slow-cooked", "soup", "was", "associated", "with", "decreased", "risk,", "with", "ORs", "of", "0.84", "(95%", "CI:", "0.68-1.03)", "and", "0.58", "(95%", "CI:", "0.47-0.72)", "respectively", "in", "the", "highest", "intake", "frequency", "stratum.", "In", "multivariate", "analyses,", "these", "associations", "remained", "significant.", "Conclusions:", "It", "can", "be", "inferred", "that", "previously", "established", "dietary", "risk", "factors", "in", "the", "Cantonese", "population", "are", "still", "stable", "and", "have", "contributed", "to", "the", "incidence", "of", "NPC.", "Background", "Although", "rare", "in", "most", "parts", "of", "the", "world,", "nasopharyn-", "geal", "carcinoma", "(NPC)", "is", "a", "common", "malignancy", "in", "southern", "China,", "especially", "in", "the", "Guangdong", "province", "[1,2].", "The", "incidence", "rate", "for", "males", "is", "more", "than", "20", "per", "100,000", "person-years", "and", "is", "as", "high", "as", "25", "to", "40", "per", "100,000", "person-years", "in", "some", "areas", "bordering", "the", "Xijiang", "River", "and", "the", "Pearl", "River", "[1-4].", "Within", "China,", "the", "incidence", "of", "NPC", "varies", "up", "to", "50-fold", "between", "*", "Correspondence:", "jiaweih@mail.sysu.edu.cn", "†", "Contributed", "equally", "1State", "Key", "Laboratory", "of", "Oncology", "in", "Southern", "China,", "Guangzhou,", "510060,", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "regions,", "with", "rates", "generally", "increasing", "from", "northern", "China", "(e.g.,", "Beijing", "and", "Tianjin)", "to", "southern", "China;", "the", "rates", "in", "Chinese", "men", "in", "the", "most", "northern", "provinces", "are", "no", "higher", "than", "3", "per", "100,000", "person-years", "[1,2].", "Reports", "indicate", "that", "southern", "Chinese", "who", "migrate", "to", "intermediate-risk", "areas,", "such", "as", "Southeast", "Asia,", "or", "to", "low-risk", "areas,", "such", "as", "the", "United", "Kingdom,", "Australia", "and", "the", "United", "States,", "continue", "to", "have", "a", "high", "incidence", "of", "NPC", "[1,5-10].", "However,", "those", "who", "reside", "for", "a", "longer", "period", "of", "time", "in", "low-risk", "areas", "and", "their", "succeeding", "generations", "born", "in", "the", "West,", "have", "a", "decreased", "risk", "for", "NPC", "[8-10].", "These", "results", "suggest", "that", "environmental", "factors", "inherent", "in", "the", "traditional", "southern", "Chinese", "©", "2010", "Jia", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 56, 61, 63, 14 ], [ 133, 61, 43, 14 ], [ 180, 61, 31, 14 ], [ 215, 61, 55, 14 ], [ 275, 61, 32, 14 ], [ 311, 61, 23, 14 ], [ 338, 61, 18, 14 ], [ 360, 61, 20, 14 ], [ 384, 61, 14, 14 ], [ 56, 77, 133, 14 ], [ 56, 112, 157, 28 ], [ 221, 112, 209, 28 ], [ 438, 112, 60, 28 ], [ 506, 112, 221, 28 ], [ 56, 142, 31, 28 ], [ 95, 142, 116, 28 ], [ 219, 142, 257, 28 ], [ 484, 142, 122, 28 ], [ 426, 181, 7, 12 ], [ 542, 181, 7, 12 ], [ 56, 184, 61, 17 ], [ 122, 184, 94, 17 ], [ 220, 184, 39, 17 ], [ 264, 184, 163, 17 ], [ 433, 184, 5, 17 ], [ 443, 184, 49, 17 ], [ 497, 184, 46, 17 ], [ 549, 184, 5, 17 ], [ 559, 184, 62, 17 ], [ 625, 183, 51, 18 ], [ 56, 206, 46, 17 ], [ 107, 203, 51, 20 ], [ 163, 206, 60, 17 ], [ 226, 203, 78, 20 ], [ 309, 206, 30, 17 ], [ 343, 206, 46, 17 ], [ 394, 206, 15, 17 ], [ 414, 206, 85, 17 ], [ 56, 241, 66, 14 ], [ 125, 241, 12, 14 ], [ 139, 241, 63, 14 ], [ 204, 241, 23, 14 ], [ 229, 239, 72, 17 ], [ 303, 241, 12, 14 ], [ 318, 241, 79, 14 ], [ 398, 241, 49, 14 ], [ 449, 241, 12, 14 ], [ 463, 241, 74, 14 ], [ 539, 241, 55, 14 ], [ 596, 241, 42, 14 ], [ 640, 241, 17, 14 ], [ 658, 241, 30, 14 ], [ 691, 241, 65, 14 ], [ 56, 258, 23, 14 ], [ 83, 258, 63, 14 ], [ 150, 258, 32, 14 ], [ 186, 258, 23, 14 ], [ 213, 258, 30, 14 ], [ 247, 258, 92, 14 ], [ 343, 258, 31, 14 ], [ 378, 258, 56, 14 ], [ 437, 258, 31, 14 ], [ 472, 258, 63, 14 ], [ 538, 258, 22, 14 ], [ 564, 258, 43, 14 ], [ 610, 258, 29, 14 ], [ 643, 258, 23, 14 ], [ 56, 272, 72, 17 ], [ 132, 274, 12, 14 ], [ 148, 274, 66, 14 ], [ 217, 274, 66, 14 ], [ 286, 274, 51, 14 ], [ 341, 274, 49, 14 ], [ 394, 274, 12, 14 ], [ 409, 274, 55, 14 ], [ 468, 274, 23, 14 ], [ 495, 274, 57, 14 ], [ 556, 274, 23, 14 ], [ 583, 274, 42, 14 ], [ 630, 274, 61, 14 ], [ 56, 291, 24, 14 ], [ 84, 291, 51, 14 ], [ 139, 291, 56, 14 ], [ 199, 291, 12, 14 ], [ 214, 291, 44, 14 ], [ 262, 291, 31, 14 ], [ 297, 291, 56, 14 ], [ 356, 291, 31, 14 ], [ 391, 291, 63, 14 ], [ 458, 291, 22, 14 ], [ 483, 291, 43, 14 ], [ 530, 291, 29, 14 ], [ 56, 326, 46, 12 ], [ 105, 326, 45, 12 ], [ 153, 326, 16, 12 ], [ 171, 326, 28, 12 ], [ 202, 326, 40, 12 ], [ 245, 326, 21, 12 ], [ 269, 326, 10, 12 ], [ 282, 326, 28, 12 ], [ 312, 326, 47, 12 ], [ 362, 326, 21, 12 ], [ 386, 326, 16, 12 ], [ 405, 326, 25, 12 ], [ 56, 370, 76, 14 ], [ 56, 394, 11, 14 ], [ 73, 394, 105, 14 ], [ 184, 394, 30, 14 ], [ 220, 394, 103, 14 ], [ 330, 394, 71, 14 ], [ 56, 410, 27, 14 ], [ 89, 410, 28, 14 ], [ 123, 410, 21, 14 ], [ 149, 410, 216, 14 ], [ 371, 410, 31, 14 ], [ 56, 427, 71, 14 ], [ 135, 427, 68, 14 ], [ 211, 427, 40, 14 ], [ 259, 427, 34, 14 ], [ 302, 427, 31, 14 ], [ 341, 427, 60, 14 ], [ 56, 443, 27, 14 ], [ 90, 443, 60, 14 ], [ 157, 443, 31, 14 ], [ 196, 443, 121, 14 ], [ 324, 443, 32, 14 ], [ 364, 443, 38, 14 ], [ 56, 460, 78, 14 ], [ 140, 460, 78, 14 ], [ 223, 460, 25, 14 ], [ 255, 460, 103, 14 ], [ 364, 460, 37, 14 ], [ 56, 477, 24, 14 ], [ 88, 477, 16, 14 ], [ 112, 477, 8, 14 ], [ 128, 477, 54, 14 ], [ 189, 477, 17, 14 ], [ 214, 477, 38, 14 ], [ 260, 477, 14, 14 ], [ 281, 477, 17, 14 ], [ 305, 477, 74, 14 ], [ 388, 477, 14, 14 ], [ 56, 493, 21, 14 ], [ 82, 493, 81, 14 ], [ 167, 493, 130, 14 ], [ 301, 493, 30, 14 ], [ 335, 493, 31, 14 ], [ 370, 493, 31, 14 ], [ 56, 510, 53, 14 ], [ 115, 510, 75, 14 ], [ 196, 510, 59, 14 ], [ 261, 510, 14, 14 ], [ 281, 510, 21, 14 ], [ 308, 510, 93, 14 ], [ 56, 526, 123, 14 ], [ 184, 526, 96, 14 ], [ 285, 526, 68, 14 ], [ 357, 526, 44, 14 ], [ 56, 543, 34, 14 ], [ 98, 543, 8, 14 ], [ 113, 543, 74, 14 ], [ 195, 543, 60, 14 ], [ 262, 543, 13, 14 ], [ 282, 543, 16, 14 ], [ 303, 543, 10, 14 ], [ 320, 543, 28, 14 ], [ 356, 543, 8, 14 ], [ 371, 543, 30, 14 ], [ 56, 560, 29, 14 ], [ 90, 560, 14, 14 ], [ 110, 560, 16, 14 ], [ 131, 560, 13, 14 ], [ 149, 560, 25, 14 ], [ 180, 560, 129, 14 ], [ 314, 560, 68, 14 ], [ 388, 560, 14, 14 ], [ 56, 576, 30, 14 ], [ 93, 576, 31, 14 ], [ 131, 576, 55, 14 ], [ 193, 576, 32, 14 ], [ 232, 576, 64, 14 ], [ 303, 576, 13, 14 ], [ 322, 576, 25, 14 ], [ 353, 576, 13, 14 ], [ 373, 576, 28, 14 ], [ 56, 593, 50, 14 ], [ 111, 593, 25, 14 ], [ 141, 593, 14, 14 ], [ 159, 593, 40, 14 ], [ 204, 593, 65, 14 ], [ 273, 593, 14, 14 ], [ 292, 593, 32, 14 ], [ 328, 593, 73, 14 ], [ 56, 610, 13, 14 ], [ 76, 610, 21, 14 ], [ 105, 610, 21, 14 ], [ 134, 610, 28, 14 ], [ 170, 610, 24, 14 ], [ 200, 610, 77, 14 ], [ 285, 610, 38, 14 ], [ 330, 610, 71, 14 ], [ 56, 626, 100, 14 ], [ 162, 626, 37, 14 ], [ 204, 626, 76, 14 ], [ 286, 626, 96, 14 ], [ 388, 626, 14, 14 ], [ 56, 643, 30, 14 ], [ 95, 643, 31, 14 ], [ 136, 643, 56, 14 ], [ 201, 643, 27, 14 ], [ 237, 643, 16, 14 ], [ 262, 643, 57, 14 ], [ 327, 643, 16, 14 ], [ 353, 643, 26, 14 ], [ 388, 643, 14, 14 ], [ 56, 659, 30, 14 ], [ 91, 659, 31, 14 ], [ 128, 659, 31, 14 ], [ 164, 659, 13, 14 ], [ 183, 659, 59, 14 ], [ 247, 659, 21, 14 ], [ 274, 659, 27, 14 ], [ 306, 659, 14, 14 ], [ 325, 659, 77, 14 ], [ 56, 676, 48, 14 ], [ 111, 676, 30, 14 ], [ 147, 676, 33, 14 ], [ 187, 676, 13, 14 ], [ 206, 676, 8, 14 ], [ 221, 676, 56, 14 ], [ 283, 676, 66, 14 ], [ 356, 676, 45, 14 ], [ 56, 692, 30, 14 ], [ 93, 692, 31, 14 ], [ 132, 692, 31, 14 ], [ 171, 692, 67, 14 ], [ 245, 692, 21, 14 ], [ 273, 692, 37, 14 ], [ 318, 692, 14, 14 ], [ 339, 692, 62, 14 ], [ 56, 709, 54, 14 ], [ 119, 709, 32, 14 ], [ 160, 709, 33, 14 ], [ 203, 709, 57, 14 ], [ 269, 709, 36, 14 ], [ 315, 709, 87, 14 ], [ 56, 726, 56, 14 ], [ 117, 726, 24, 14 ], [ 146, 726, 8, 14 ], [ 159, 726, 25, 14 ], [ 189, 726, 8, 14 ], [ 201, 726, 30, 14 ], [ 236, 726, 62, 14 ], [ 303, 726, 98, 14 ], [ 56, 742, 14, 14 ], [ 77, 742, 30, 14 ], [ 113, 742, 31, 14 ], [ 151, 742, 56, 14 ], [ 214, 742, 34, 14 ], [ 255, 742, 32, 14 ], [ 293, 742, 43, 14 ], [ 343, 742, 58, 14 ], [ 56, 759, 54, 14 ], [ 120, 759, 13, 14 ], [ 142, 759, 63, 14 ], [ 214, 759, 122, 14 ], [ 346, 759, 56, 14 ], [ 56, 775, 61, 14 ], [ 123, 775, 67, 14 ], [ 194, 775, 117, 14 ], [ 316, 775, 14, 14 ], [ 335, 775, 30, 14 ], [ 370, 775, 31, 14 ], [ 56, 792, 56, 14 ], [ 118, 792, 25, 14 ], [ 149, 792, 30, 14 ], [ 184, 792, 31, 14 ], [ 221, 792, 31, 14 ], [ 259, 792, 13, 14 ], [ 277, 792, 25, 14 ], [ 308, 792, 41, 14 ], [ 355, 792, 46, 14 ], [ 56, 809, 24, 14 ], [ 87, 809, 21, 14 ], [ 116, 809, 52, 14 ], [ 174, 809, 19, 14 ], [ 200, 809, 75, 14 ], [ 282, 809, 63, 14 ], [ 352, 809, 49, 14 ], [ 56, 825, 57, 14 ], [ 118, 825, 33, 14 ], [ 156, 825, 62, 14 ], [ 223, 825, 25, 14 ], [ 253, 825, 30, 14 ], [ 287, 825, 60, 14 ], [ 351, 825, 21, 14 ], [ 377, 825, 24, 14 ], [ 56, 842, 14, 14 ], [ 75, 842, 75, 14 ], [ 156, 842, 111, 14 ], [ 273, 842, 16, 14 ], [ 294, 842, 61, 14 ], [ 361, 842, 13, 14 ], [ 380, 842, 21, 14 ], [ 56, 859, 56, 14 ], [ 116, 859, 63, 14 ], [ 183, 859, 14, 14 ], [ 200, 859, 66, 14 ], [ 269, 859, 63, 14 ], [ 426, 369, 107, 14 ], [ 426, 391, 28, 14 ], [ 460, 391, 17, 14 ], [ 483, 391, 20, 14 ], [ 509, 391, 21, 14 ], [ 536, 391, 33, 14 ], [ 575, 391, 19, 14 ], [ 599, 391, 47, 14 ], [ 652, 391, 37, 14 ], [ 695, 391, 27, 14 ], [ 727, 391, 44, 14 ], [ 426, 406, 14, 14 ], [ 446, 406, 18, 14 ], [ 470, 406, 37, 14 ], [ 514, 406, 20, 14 ], [ 541, 406, 72, 14 ], [ 620, 406, 12, 14 ], [ 638, 406, 65, 14 ], [ 709, 406, 38, 14 ], [ 754, 406, 17, 14 ], [ 426, 422, 65, 14 ], [ 495, 422, 17, 14 ], [ 515, 422, 20, 14 ], [ 540, 422, 57, 14 ], [ 600, 422, 30, 14 ], [ 635, 422, 57, 14 ], [ 696, 422, 11, 14 ], [ 711, 422, 14, 14 ], [ 728, 422, 42, 14 ], [ 426, 437, 11, 14 ], [ 441, 437, 60, 14 ], [ 505, 437, 7, 14 ], [ 516, 437, 73, 14 ], [ 594, 437, 42, 14 ], [ 640, 437, 17, 14 ], [ 661, 437, 17, 14 ], [ 681, 437, 17, 14 ], [ 703, 437, 51, 14 ], [ 759, 437, 12, 14 ], [ 426, 452, 30, 14 ], [ 462, 452, 93, 14 ], [ 560, 452, 14, 14 ], [ 580, 452, 70, 14 ], [ 656, 452, 12, 14 ], [ 673, 452, 30, 14 ], [ 709, 452, 45, 14 ], [ 759, 452, 11, 14 ], [ 426, 467, 18, 14 ], [ 448, 467, 40, 14 ], [ 492, 467, 48, 14 ], [ 544, 467, 55, 14 ], [ 603, 467, 17, 14 ], [ 625, 467, 87, 14 ], [ 716, 467, 55, 14 ], [ 426, 482, 26, 14 ], [ 458, 482, 7, 14 ], [ 472, 482, 42, 14 ], [ 521, 482, 35, 14 ], [ 563, 482, 42, 14 ], [ 612, 482, 29, 14 ], [ 647, 482, 20, 14 ], [ 675, 482, 46, 14 ], [ 728, 482, 43, 14 ], [ 426, 498, 46, 14 ], [ 478, 498, 12, 14 ], [ 497, 498, 57, 14 ], [ 561, 498, 38, 14 ], [ 605, 498, 27, 14 ], [ 640, 498, 92, 14 ], [ 739, 498, 32, 14 ], [ 426, 513, 39, 14 ], [ 468, 513, 58, 14 ], [ 529, 513, 61, 14 ], [ 594, 513, 31, 14 ], [ 627, 513, 52, 14 ], [ 682, 513, 21, 14 ], [ 706, 513, 25, 14 ], [ 734, 513, 37, 14 ], [ 426, 528, 42, 14 ], [ 474, 528, 70, 14 ], [ 549, 528, 77, 14 ], [ 632, 528, 139, 14 ], [ 426, 543, 57, 14 ], [ 489, 543, 38, 14 ], [ 534, 543, 57, 14 ], [ 598, 543, 38, 14 ], [ 643, 543, 65, 14 ], [ 715, 543, 56, 14 ], [ 426, 559, 27, 14 ], [ 458, 559, 27, 14 ], [ 490, 559, 71, 14 ], [ 566, 559, 22, 14 ], [ 593, 559, 92, 14 ], [ 691, 559, 18, 14 ], [ 714, 559, 57, 14 ], [ 426, 574, 48, 14 ], [ 478, 574, 21, 14 ], [ 503, 574, 49, 14 ], [ 556, 574, 12, 14 ], [ 573, 574, 60, 14 ], [ 637, 574, 64, 14 ], [ 705, 574, 63, 14 ], [ 440, 589, 22, 14 ], [ 464, 589, 70, 14 ], [ 537, 589, 64, 14 ], [ 603, 589, 12, 14 ], [ 618, 589, 26, 14 ], [ 647, 589, 65, 14 ], [ 714, 589, 57, 14 ], [ 426, 604, 57, 14 ], [ 487, 604, 33, 14 ], [ 524, 604, 10, 14 ], [ 538, 604, 56, 14 ], [ 598, 604, 25, 14 ], [ 628, 604, 7, 14 ], [ 639, 604, 69, 14 ], [ 712, 604, 59, 14 ], [ 426, 620, 28, 14 ], [ 460, 620, 116, 14 ], [ 583, 620, 45, 14 ], [ 634, 620, 41, 14 ], [ 682, 620, 34, 14 ], [ 723, 620, 19, 14 ], [ 748, 620, 23, 14 ], [ 426, 635, 27, 14 ], [ 457, 635, 50, 14 ], [ 512, 635, 14, 14 ], [ 531, 635, 34, 14 ], [ 570, 635, 48, 14 ], [ 623, 635, 34, 14 ], [ 662, 635, 17, 14 ], [ 684, 635, 53, 14 ], [ 742, 635, 29, 14 ], [ 426, 650, 57, 14 ], [ 485, 650, 70, 14 ], [ 559, 650, 44, 14 ], [ 605, 650, 12, 14 ], [ 620, 650, 30, 14 ], [ 654, 650, 92, 14 ], [ 749, 650, 21, 14 ], [ 426, 665, 27, 14 ], [ 456, 665, 27, 14 ], [ 487, 665, 49, 14 ], [ 540, 665, 30, 14 ], [ 575, 665, 99, 14 ], [ 678, 665, 11, 15 ], [ 693, 665, 7, 14 ], [ 704, 665, 20, 14 ], [ 729, 665, 7, 14 ], [ 740, 665, 31, 14 ], [ 426, 680, 18, 14 ], [ 459, 680, 65, 14 ], [ 539, 680, 129, 14 ], [ 683, 680, 88, 15 ], [ 426, 696, 132, 14 ], [ 564, 696, 20, 14 ], [ 590, 696, 113, 14 ], [ 710, 696, 38, 14 ], [ 754, 696, 17, 14 ], [ 426, 711, 57, 14 ], [ 490, 711, 57, 14 ], [ 555, 711, 24, 14 ], [ 588, 711, 38, 14 ], [ 633, 711, 22, 14 ], [ 663, 711, 62, 14 ], [ 734, 711, 11, 14 ], [ 753, 711, 17, 14 ], [ 426, 726, 51, 14 ], [ 485, 726, 12, 14 ], [ 506, 726, 92, 14 ], [ 607, 726, 14, 14 ], [ 630, 726, 67, 14 ], [ 705, 726, 65, 14 ], [ 426, 741, 18, 14 ], [ 450, 741, 50, 14 ], [ 506, 741, 12, 14 ], [ 524, 741, 17, 14 ], [ 548, 741, 70, 14 ], [ 625, 741, 58, 14 ], [ 689, 741, 26, 14 ], [ 722, 741, 17, 14 ], [ 745, 741, 26, 14 ], [ 426, 756, 36, 14 ], [ 470, 756, 55, 14 ], [ 532, 756, 92, 14 ], [ 632, 756, 80, 14 ], [ 720, 756, 25, 14 ], [ 753, 756, 17, 14 ], [ 426, 772, 193, 15 ], [ 633, 772, 33, 14 ], [ 679, 772, 17, 14 ], [ 710, 772, 61, 14 ], [ 426, 787, 79, 14 ], [ 509, 787, 57, 14 ], [ 571, 787, 40, 14 ], [ 615, 787, 7, 14 ], [ 627, 787, 31, 14 ], [ 663, 787, 36, 14 ], [ 704, 787, 67, 14 ], [ 426, 802, 19, 14 ], [ 450, 802, 14, 14 ], [ 469, 802, 25, 14 ], [ 499, 802, 7, 14 ], [ 510, 802, 71, 14 ], [ 587, 802, 36, 14 ], [ 627, 802, 36, 14 ], [ 668, 802, 12, 14 ], [ 685, 802, 25, 14 ], [ 715, 802, 5, 14 ], [ 730, 802, 7, 14 ], [ 743, 802, 12, 14 ], [ 759, 802, 11, 14 ], [ 426, 817, 52, 14 ], [ 482, 817, 17, 14 ], [ 505, 817, 65, 14 ], [ 575, 817, 49, 14 ], [ 629, 817, 12, 14 ], [ 647, 817, 20, 14 ], [ 672, 817, 57, 14 ], [ 734, 817, 36, 14 ], [ 426, 833, 53, 14 ], [ 482, 833, 29, 14 ], [ 515, 833, 58, 14 ], [ 576, 833, 17, 14 ], [ 597, 833, 18, 14 ], [ 619, 833, 43, 14 ], [ 666, 833, 17, 14 ], [ 686, 833, 18, 14 ], [ 707, 833, 64, 14 ], [ 426, 848, 12, 14 ], [ 444, 848, 58, 14 ], [ 508, 848, 87, 14 ], [ 601, 848, 70, 14 ], [ 678, 848, 92, 14 ], [ 426, 863, 80, 14 ], [ 516, 863, 25, 14 ], [ 551, 863, 17, 14 ], [ 578, 863, 193, 15 ], [ 56, 900, 18, 12 ], [ 78, 900, 28, 12 ], [ 109, 900, 70, 12 ], [ 182, 900, 30, 12 ], [ 215, 900, 11, 12 ], [ 229, 900, 47, 12 ], [ 279, 900, 19, 12 ], [ 301, 900, 12, 12 ], [ 316, 900, 17, 12 ], [ 336, 900, 17, 12 ], [ 356, 900, 26, 12 ], [ 385, 900, 20, 12 ], [ 409, 900, 12, 12 ], [ 424, 900, 17, 12 ], [ 444, 900, 17, 12 ], [ 464, 900, 26, 12 ], [ 493, 900, 30, 12 ], [ 526, 900, 107, 12 ], [ 56, 913, 20, 12 ], [ 80, 913, 25, 12 ], [ 108, 913, 8, 12 ], [ 119, 913, 43, 12 ], [ 165, 913, 9, 12 ], [ 177, 913, 42, 12 ], [ 223, 913, 43, 12 ], [ 269, 913, 7, 12 ], [ 279, 913, 20, 12 ], [ 302, 913, 12, 12 ], [ 317, 913, 14, 12 ], [ 334, 913, 39, 12 ], [ 376, 913, 10, 12 ], [ 389, 913, 13, 12 ], [ 406, 911, 18, 14 ], [ 427, 913, 40, 12 ], [ 56, 938, 18, 11 ], [ 77, 938, 33, 11 ], [ 113, 938, 21, 11 ], [ 138, 938, 7, 11 ], [ 148, 938, 9, 11 ], [ 160, 938, 11, 11 ], [ 174, 938, 31, 11 ], [ 208, 938, 20, 11 ], [ 231, 938, 9, 11 ], [ 243, 938, 21, 11 ], [ 267, 938, 37, 11 ], [ 307, 938, 14, 11 ], [ 325, 938, 18, 11 ], [ 346, 938, 17, 11 ], [ 366, 938, 33, 11 ], [ 402, 938, 30, 11 ], [ 435, 938, 11, 11 ], [ 450, 938, 39, 11 ], [ 492, 938, 10, 11 ], [ 505, 938, 21, 11 ], [ 529, 938, 21, 11 ], [ 553, 938, 36, 11 ], [ 69, 963, 18, 12 ], [ 90, 963, 32, 12 ], [ 125, 963, 25, 12 ], [ 153, 963, 44, 12 ], [ 200, 963, 12, 12 ], [ 215, 963, 32, 12 ], [ 250, 963, 47, 12 ], [ 301, 963, 27, 12 ], [ 330, 963, 15, 12 ], [ 348, 963, 26, 12 ], [ 377, 963, 41, 12 ], [ 56, 988, 18, 12 ], [ 77, 988, 28, 12 ], [ 108, 988, 33, 12 ], [ 144, 988, 10, 12 ], [ 156, 988, 16, 12 ], [ 176, 988, 28, 12 ], [ 207, 988, 15, 12 ], [ 225, 988, 21, 12 ], [ 249, 988, 44, 12 ], [ 296, 988, 26, 12 ], [ 324, 988, 11, 12 ], [ 338, 988, 22, 12 ], [ 363, 988, 29, 12 ], [ 395, 988, 31, 12 ], [ 429, 988, 25, 12 ], [ 457, 988, 14, 12 ], [ 474, 988, 34, 12 ], [ 510, 988, 9, 12 ], [ 523, 988, 18, 12 ], [ 543, 988, 48, 12 ], [ 594, 988, 56, 12 ], [ 652, 988, 10, 12 ], [ 665, 988, 33, 12 ], [ 700, 988, 14, 12 ], [ 717, 988, 22, 12 ], [ 742, 988, 29, 12 ], [ 56, 1000, 33, 11 ], [ 91, 1000, 10, 11 ], [ 103, 1000, 17, 11 ], [ 122, 1000, 28, 11 ], [ 152, 1000, 13, 11 ], [ 168, 1000, 73, 11 ], [ 243, 1000, 40, 11 ], [ 285, 1000, 40, 11 ], [ 327, 1000, 20, 11 ], [ 350, 1000, 14, 11 ], [ 366, 1000, 35, 11 ], [ 403, 1000, 47, 11 ], [ 452, 1000, 8, 11 ], [ 462, 1000, 38, 11 ], [ 502, 1000, 17, 11 ], [ 521, 1000, 21, 11 ], [ 545, 1000, 46, 11 ], [ 593, 1000, 14, 11 ], [ 609, 1000, 33, 11 ], [ 645, 1000, 16, 11 ], [ 663, 1000, 32, 11 ], [ 698, 1000, 47, 11 ], [ 747, 1000, 24, 11 ], [ 56, 1013, 14, 12 ], [ 72, 1013, 43, 12 ], [ 117, 1013, 10, 12 ], [ 128, 1013, 14, 12 ], [ 144, 1013, 35, 12 ], [ 180, 1013, 24, 12 ], [ 206, 1013, 10, 12 ], [ 217, 1013, 50, 12 ], [ 269, 1013, 20, 12 ], [ 291, 1013, 14, 12 ], [ 307, 1013, 31, 12 ], [ 340, 1013, 34, 12 ], [ 375, 1013, 30, 12 ], [ 406, 1013, 28, 12 ], [ 436, 1013, 7, 12 ], [ 445, 1013, 11, 12 ], [ 458, 1013, 28, 12 ], [ 488, 1013, 8, 12 ], [ 497, 1013, 58, 12 ], [ 557, 1013, 50, 12 ], [ 609, 1013, 10, 12 ], [ 620, 1013, 59, 12 ], [ 680, 1013, 15, 12 ], [ 697, 1013, 9, 12 ], [ 707, 1013, 11, 12 ], [ 720, 1013, 35, 12 ], [ 756, 1013, 15, 12 ], [ 56, 1025, 20, 11 ], [ 80, 1025, 9, 11 ], [ 92, 1025, 18, 11 ], [ 113, 1025, 10, 11 ], [ 126, 1025, 10, 11 ], [ 138, 1025, 5, 11 ], [ 147, 1025, 45, 11 ], [ 195, 1025, 23, 11 ], [ 221, 1025, 16, 11 ], [ 241, 1025, 22, 11 ], [ 266, 1025, 11, 11 ], [ 280, 1025, 31, 11 ], [ 314, 1025, 44, 11 ], [ 361, 1025, 16, 11 ], [ 380, 1025, 53, 11 ], [ 436, 1025, 30, 11 ], [ 470, 1025, 28, 11 ], [ 501, 1025, 33, 11 ], [ 537, 1025, 171, 11 ] ]

[ "3550–3560", "Nucleic", "Acids", "Research,", "2005,", "Vol.", "33,", "No.", "11", "doi:10.1093/nar/gki657", "Thermolytic", "CpG-containing", "DNA", "oligonucleotides", "as", "potential", "immunotherapeutic", "prodrugs", "1", "1", "Andrzej", "Grajkowski,", "Joao", "Pedras-Vasconcelos", ",", "Vivian", "Wang", ",", "Cristina", "Aus´ın,", "Sonja", "Hess2,", "Daniela", "Verthelyi1", "and", "Serge", "L.", "Beaucage*", "Laboratory", "of", "Chemistry", "and", "1Laboratory", "of", "Immunology,", "Division", "of", "Therapeutic", "Proteins,", "Center", "for", "Drug", "Evaluation", "and", "Research,", "Food", "and", "Drug", "Administration,", "8800", "Rockville", "Pike,", "Bethesda,", "MD", "20892,", "USA", "and", "2Laboratory", "of", "Bioorganic", "Chemistry,", "National", "Institute", "of", "Diabetes", "and", "Digestive", "and", "Kidney", "Diseases,", "The", "National", "Institutes", "of", "Health,", "9000", "Rockville", "Pike,", "Bethesda,", "MD", "20892,", "USA", "Received", "February", "14,", "2005;", "Revised", "May", "9,", "2005;", "Accepted", "May", "26,", "2005", "ABSTRACT", "A", "CpG-containing", "DNA", "oligonucleotide", "functional-", "ized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "thio-", "phosphate", "protecting", "group", "(CpG", "ODN", "fma1555)", "was", "prepared", "from", "phosphoramidites", "1a–d", "using", "solid-phase", "techniques.", "The", "oligonucleotide", "beha-", "ved", "as", "a", "prodrug", "by", "virtue", "of", "its", "conversion", "to", "the", "well-studied", "immunomodulatory", "CpG", "ODN", "1555", "through", "thermolytic", "cleavage", "of", "the", "2-(N-formyl-N-", "methyl)aminoethyl", "thiophosphate", "protecting", "group.", "Such", "a", "conversion", "occurred", "at", "37", "C", "with", "a", "half-", "time", "of", "73", "h.", "The", "immunostimulatory", "properties", "of", "CpG", "ODN", "fma1555", "were", "evaluated", "in", "two", "in", "vivo", "assays,", "one", "of", "which", "consisted", "of", "mice", "challenged", "in", "the", "ear", "with", "live", "Leishmania", "major", "metacyclic", "promastigotes.", "Local", "intradermal", "administration", "of", "CpG", "ODN", "fma1555", "was", "as", "effective", "as", "that", "of", "CpG", "ODN", "1555", "in", "reducing", "the", "size", "of", "Leishmania", "lesions", "over", "time.", "In", "a", "different", "infectious", "model,", "CpG", "ODN", "1555", "prevented", "the", "death", "of", "Tacaribe-", "infected", "mice", "(43%", "survival)", "when", "administered", "between", "day", "0", "and", "3", "post", "infection.", "Administration", "of", "CpG", "ODN", "fma1555", "three", "days", "before", "infection", "resulted", "in", "improved", "immunoprotection", "(60–70%", "survival).", "Moreover,", "co-administration", "of", "CpG", "ODN", "fma1555", "and", "CpG", "ODN", "1555", "in", "this", "model", "increa-", "sed", "the", "window", "for", "therapeutic", "treatment", "against", "Tacaribe", "virus", "infection,", "and", "thus", "supports", "the", "use", "of", "thermolytic", "oligonucleotides", "as", "prodrugs", "in", "the", "effective", "treatment", "of", "infectious", "diseases.", "INTRODUCTION", "Over", "the", "last", "few", "years,", "our", "research", "efforts", "have", "focused", "on", "the", "design", "and", "development", "of", "thermolytic", "groups", "for", "50-hydroxyl", "(1)", "and", "phosphate", "(2–7)", "protection", "in", "an", "attempt", "to", "implement", "a", "‘heat-driven’", "process", "(8)", "for", "the", "synthesis", "of", "DNA", "oligonucleotides", "on", "microarrays.", "In", "sharp", "contrast", "to", "the", "current", "methods", "employed", "for", "oligonucleotide", "synthesis,", "such", "a", "process", "would", "involve", "rapid", "and", "efficient", "thermal", "removal", "of", "protecting", "groups", "from", "oligonucleotides", "under", "neutral", "conditions", "throughout", "chain", "assembly", "and", "final", "depro-", "tection.", "Specifically,", "heat-sensitive", "phosphate/thiophosphate", "protecting", "groups", "exhibiting", "unique", "thermolytic", "properties", "have", "been", "incorporated", "into", "oligonucleotides", "via", "phosphor-", "amidites", "1–6", "(Scheme", "1)", "employing", "solid-phase", "techniques.", "The", "deprotection", "mechanism", "of", "each", "thermolytic", "phosphate", "protecting", "group", "is", "consistent", "with", "a", "well-studied", "intramole-", "cular", "cyclodeesterification", "reaction", "(9–12),", "which", "has", "also", "been", "observed", "by", "others", "(13–16).", "Given", "the", "relatively", "rapid", "phosphate", "deprotection", "kinetics", "of", "DNA", "oligonucleotides", "that", "have", "been", "prepared", "using", "phosphoramidites", "4,", "5", "and", "6", "(6,7),", "the", "thermolytic", "3-(2-pyridyl)-1-propyl,", "2-[N-methyl-N-", "(2-pyridyl)]aminoethyl,", "and", "4-methythio-1-butyl", "groups", "for", "phosphate", "protection", "may", "indeed", "find", "application", "in", "the", "synthesis", "of", "oligonucleotides", "on", "microarrays", "considering", "the", "mildness", "of", "the", "deprotection", "conditions", "used", "for", "each", "group.", "However,", "oligonucleotides", "functionalized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "group", "for", "phosphate/", "thiophosphate", "protection", "require", "a", "much", "higher", "temperature", "(90", "C)", "over", "a", "considerably", "longer", "period", "of", "time", "(", "3", "h)", "to", "complete", "the", "thermolytic", "cleavage", "of", "this", "protecting", "group.", "Although", "these", "conditions", "are", "not", "optimal", "for", "the", "preparation", "of", "diagnostic", "oligonucleotide", "microarrays,", "oligonucleotides", "functionalized", "with", "the", "2-(N-formyl-N-methyl)aminoethyl", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+1", "301", "827", "5162;", "Fax:", "+1", "301", "480", "3256;", "Email:", "beaucage@cber.fda.gov", "This", "paper", "is", "dedicated", "to", "Professor", "Wojciech", "J.", "Stec", "on", "the", "occasion", "of", "his", "65th", "birthday.", "The", "authors", "wish", "it", "to", "be", "known", "that,", "in", "their", "opinion,", "the", "first", "two", "authors", "should", "be", "regarded", "as", "joint", "First", "Authors", "The", "Author", "2005.", "Published", "by", "Oxford", "University", "Press.", "All", "rights", "reserved.", "The", "online", "version", "of", "this", "article", "has", "been", "published", "under", "an", "open", "access", "model.", "Users", "are", "entitled", "to", "use,", "reproduce,", "disseminate,", "or", "display", "the", "open", "access", "version", "of", "this", "article", "for", "non-commercial", "purposes", "provided", "that:", "the", "original", "authorship", "is", "properly", "and", "fully", "attributed;", "the", "Journal", "and", "Oxford", "University", "Press", "are", "attributed", "as", "the", "original", "place", "of", "publication", "with", "the", "correct", "citation", "details", "given;", "if", "an", "article", "is", "subsequently", "reproduced", "or", "disseminated", "not", "in", "its", "entirety", "but", "only", "in", "part", "or", "as", "a", "derivative", "work", "this", "must", "be", "clearly", "indicated.", "For", "commercial", "re-use,", "please", "contact", "journals.permissions@oupjournals.org" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 78, 47, 24, 12 ], [ 105, 47, 9, 12 ], [ 117, 47, 11, 12 ], [ 131, 47, 21, 12 ], [ 155, 47, 30, 12 ], [ 188, 47, 35, 12 ], [ 226, 47, 40, 12 ], [ 269, 47, 25, 12 ], [ 297, 47, 20, 12 ], [ 78, 61, 222, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 86, 34 ], [ 175, 169, 56, 34 ], [ 241, 169, 46, 34 ], [ 296, 169, 51, 34 ], [ 357, 169, 67, 34 ], [ 434, 169, 27, 34 ], [ 471, 169, 103, 34 ], [ 584, 169, 63, 34 ], [ 657, 169, 87, 34 ], [ 78, 205, 128, 34 ], [ 216, 205, 63, 34 ], [ 290, 205, 138, 34 ], [ 438, 205, 131, 34 ], [ 580, 205, 25, 34 ], [ 615, 205, 127, 34 ], [ 78, 241, 20, 34 ], [ 108, 241, 134, 34 ], [ 252, 241, 125, 34 ], [ 78, 288, 36, 16 ], [ 119, 288, 9, 16 ], [ 132, 285, 40, 19 ], [ 177, 288, 40, 16 ], [ 221, 285, 36, 19 ], [ 261, 288, 36, 16 ], [ 302, 288, 28, 16 ], [ 334, 285, 13, 11 ], [ 87, 342, 54, 15 ], [ 87, 367, 76, 14 ], [ 167, 367, 22, 14 ], [ 194, 367, 38, 15 ], [ 235, 367, 21, 14 ], [ 260, 367, 22, 14 ], [ 286, 367, 12, 14 ], [ 303, 367, 45, 14 ], [ 352, 367, 7, 14 ], [ 363, 367, 20, 14 ], [ 387, 367, 77, 14 ], [ 468, 367, 11, 14 ], [ 483, 367, 19, 14 ], [ 506, 367, 56, 14 ], [ 566, 367, 21, 14 ], [ 592, 367, 28, 14 ], [ 624, 367, 11, 14 ], [ 640, 367, 43, 14 ], [ 686, 367, 27, 14 ], [ 87, 384, 37, 14 ], [ 128, 384, 36, 14 ], [ 168, 384, 61, 14 ], [ 233, 384, 11, 14 ], [ 248, 384, 63, 14 ], [ 315, 384, 44, 14 ], [ 364, 384, 44, 14 ], [ 412, 384, 11, 14 ], [ 427, 384, 53, 14 ], [ 87, 405, 56, 14 ], [ 148, 405, 21, 14 ], [ 173, 405, 64, 14 ], [ 241, 405, 21, 14 ], [ 267, 405, 28, 14 ], [ 299, 405, 11, 14 ], [ 315, 405, 29, 14 ], [ 348, 405, 28, 14 ], [ 380, 405, 56, 14 ], [ 440, 405, 15, 14 ], [ 460, 405, 7, 14 ], [ 471, 405, 26, 14 ], [ 501, 405, 27, 14 ], [ 532, 405, 46, 14 ], [ 582, 405, 15, 14 ], [ 601, 405, 14, 14 ], [ 620, 405, 43, 14 ], [ 666, 405, 42, 14 ], [ 87, 421, 33, 14 ], [ 125, 421, 36, 14 ], [ 165, 421, 15, 14 ], [ 184, 421, 31, 14 ], [ 220, 421, 21, 14 ], [ 245, 421, 36, 14 ], [ 285, 421, 55, 14 ], [ 344, 421, 27, 14 ], [ 375, 421, 19, 14 ], [ 398, 421, 20, 14 ], [ 422, 421, 35, 14 ], [ 461, 421, 23, 14 ], [ 489, 421, 41, 14 ], [ 534, 421, 13, 14 ], [ 551, 421, 49, 14 ], [ 604, 421, 11, 14 ], [ 620, 421, 55, 14 ], [ 87, 438, 68, 14 ], [ 160, 438, 33, 14 ], [ 197, 438, 12, 14 ], [ 213, 438, 29, 14 ], [ 246, 438, 22, 14 ], [ 272, 438, 60, 14 ], [ 336, 438, 12, 14 ], [ 352, 438, 53, 14 ], [ 409, 438, 55, 14 ], [ 469, 438, 46, 14 ], [ 519, 438, 33, 14 ], [ 556, 438, 15, 14 ], [ 576, 438, 35, 14 ], [ 615, 438, 65, 14 ], [ 684, 438, 27, 14 ], [ 715, 438, 7, 14 ], [ 87, 454, 49, 14 ], [ 141, 454, 37, 14 ], [ 182, 454, 28, 14 ], [ 214, 454, 27, 14 ], [ 245, 454, 12, 14 ], [ 261, 454, 21, 14 ], [ 286, 454, 19, 14 ], [ 308, 454, 59, 14 ], [ 372, 454, 38, 14 ], [ 87, 475, 46, 14 ], [ 137, 475, 18, 14 ], [ 160, 475, 53, 14 ], [ 217, 475, 19, 14 ], [ 240, 475, 26, 14 ], [ 270, 475, 24, 14 ], [ 298, 475, 59, 14 ], [ 362, 475, 22, 14 ], [ 388, 475, 33, 14 ], [ 425, 475, 7, 14 ], [ 437, 475, 38, 14 ], [ 479, 475, 33, 14 ], [ 516, 475, 52, 14 ], [ 573, 475, 68, 14 ], [ 645, 475, 27, 14 ], [ 676, 475, 19, 14 ], [ 699, 475, 27, 14 ], [ 87, 492, 14, 14 ], [ 105, 492, 24, 14 ], [ 133, 492, 11, 14 ], [ 148, 492, 29, 14 ], [ 182, 492, 36, 14 ], [ 222, 492, 24, 14 ], [ 250, 492, 28, 14 ], [ 282, 492, 39, 14 ], [ 325, 492, 12, 14 ], [ 341, 492, 29, 14 ], [ 374, 492, 11, 14 ], [ 389, 492, 20, 14 ], [ 413, 492, 26, 14 ], [ 443, 492, 25, 14 ], [ 472, 492, 42, 14 ], [ 518, 492, 20, 14 ], [ 543, 492, 38, 14 ], [ 585, 492, 33, 14 ], [ 622, 492, 32, 14 ], [ 658, 492, 28, 14 ], [ 690, 492, 19, 14 ], [ 713, 492, 24, 14 ], [ 87, 508, 28, 14 ], [ 119, 508, 20, 14 ], [ 144, 508, 33, 14 ], [ 181, 508, 35, 14 ], [ 220, 508, 24, 14 ], [ 248, 508, 11, 14 ], [ 263, 508, 28, 14 ], [ 296, 508, 45, 14 ], [ 344, 508, 27, 14 ], [ 375, 508, 87, 14 ], [ 467, 508, 24, 14 ], [ 495, 508, 27, 14 ], [ 526, 508, 63, 14 ], [ 592, 508, 66, 14 ], [ 663, 508, 27, 14 ], [ 694, 508, 21, 14 ], [ 87, 525, 24, 14 ], [ 115, 525, 27, 14 ], [ 146, 525, 56, 14 ], [ 206, 525, 26, 14 ], [ 236, 525, 25, 14 ], [ 265, 525, 24, 14 ], [ 294, 525, 53, 14 ], [ 351, 525, 11, 14 ], [ 366, 525, 56, 14 ], [ 426, 525, 21, 14 ], [ 452, 525, 28, 14 ], [ 484, 525, 11, 14 ], [ 500, 525, 29, 14 ], [ 533, 525, 28, 14 ], [ 565, 525, 31, 14 ], [ 600, 525, 26, 14 ], [ 630, 525, 12, 14 ], [ 647, 525, 53, 14 ], [ 703, 525, 11, 14 ], [ 719, 525, 19, 14 ], [ 87, 542, 54, 14 ], [ 145, 542, 48, 14 ], [ 87, 562, 67, 14 ], [ 158, 562, 21, 14 ], [ 183, 562, 59, 14 ], [ 247, 562, 55, 14 ], [ 306, 562, 21, 14 ], [ 332, 562, 28, 14 ], [ 365, 562, 11, 14 ], [ 380, 562, 29, 14 ], [ 413, 562, 47, 14 ], [ 464, 562, 19, 14 ], [ 487, 562, 45, 14 ], [ 536, 562, 20, 14 ], [ 561, 562, 11, 14 ], [ 576, 562, 19, 14 ], [ 599, 562, 35, 14 ], [ 639, 562, 53, 14 ], [ 695, 562, 21, 14 ], [ 87, 579, 55, 14 ], [ 147, 579, 41, 14 ], [ 192, 579, 38, 14 ], [ 235, 579, 12, 14 ], [ 251, 579, 29, 14 ], [ 284, 579, 11, 14 ], [ 299, 579, 53, 14 ], [ 356, 579, 21, 14 ], [ 381, 579, 39, 14 ], [ 424, 579, 11, 14 ], [ 440, 579, 19, 14 ], [ 463, 579, 20, 14 ], [ 487, 579, 55, 14 ], [ 546, 579, 49, 14 ], [ 599, 579, 27, 14 ], [ 630, 579, 44, 14 ], [ 679, 579, 12, 14 ], [ 695, 579, 15, 14 ], [ 87, 596, 65, 14 ], [ 157, 596, 15, 14 ], [ 176, 596, 53, 14 ], [ 233, 596, 21, 14 ], [ 258, 596, 54, 14 ], [ 316, 596, 42, 14 ], [ 363, 596, 27, 14 ], [ 394, 596, 70, 14 ], [ 467, 596, 27, 14 ], [ 498, 596, 47, 14 ], [ 550, 596, 39, 14 ], [ 593, 596, 22, 14 ], [ 618, 596, 24, 14 ], [ 647, 596, 38, 14 ], [ 87, 612, 56, 14 ], [ 148, 612, 19, 14 ], [ 171, 612, 65, 14 ], [ 240, 612, 22, 14 ], [ 266, 612, 11, 14 ], [ 280, 612, 51, 14 ], [ 335, 612, 54, 14 ], [ 394, 612, 31, 14 ], [ 87, 633, 75, 14 ], [ 167, 633, 22, 14 ], [ 193, 633, 30, 14 ], [ 228, 633, 34, 14 ], [ 265, 633, 28, 14 ], [ 298, 633, 11, 14 ], [ 313, 633, 29, 14 ], [ 346, 633, 11, 14 ], [ 361, 633, 19, 14 ], [ 384, 633, 63, 14 ], [ 452, 633, 38, 14 ], [ 494, 633, 11, 14 ], [ 509, 633, 51, 14 ], [ 564, 633, 12, 14 ], [ 580, 633, 15, 14 ], [ 599, 633, 59, 14 ], [ 662, 633, 23, 14 ], [ 689, 633, 12, 14 ], [ 705, 633, 25, 14 ], [ 87, 650, 43, 14 ], [ 135, 650, 35, 14 ], [ 175, 650, 17, 14 ], [ 196, 650, 24, 14 ], [ 224, 650, 7, 14 ], [ 235, 650, 34, 14 ], [ 273, 650, 57, 14 ], [ 78, 695, 77, 15 ], [ 78, 713, 71, 14 ], [ 154, 713, 18, 14 ], [ 176, 713, 27, 14 ], [ 207, 713, 12, 14 ], [ 223, 713, 25, 14 ], [ 253, 713, 13, 14 ], [ 270, 713, 26, 14 ], [ 301, 713, 41, 14 ], [ 346, 713, 58, 14 ], [ 78, 729, 12, 14 ], [ 95, 729, 40, 14 ], [ 139, 729, 60, 14 ], [ 204, 729, 22, 14 ], [ 230, 729, 12, 14 ], [ 247, 729, 48, 14 ], [ 300, 729, 40, 14 ], [ 345, 729, 12, 14 ], [ 361, 729, 18, 14 ], [ 384, 729, 20, 14 ], [ 78, 746, 58, 14 ], [ 141, 746, 15, 14 ], [ 161, 746, 74, 14 ], [ 240, 746, 25, 14 ], [ 270, 746, 28, 14 ], [ 304, 746, 100, 14 ], [ 78, 762, 40, 14 ], [ 122, 762, 34, 14 ], [ 161, 762, 24, 14 ], [ 189, 762, 14, 14 ], [ 207, 762, 49, 14 ], [ 260, 762, 12, 14 ], [ 276, 762, 27, 14 ], [ 307, 762, 39, 14 ], [ 350, 762, 53, 14 ], [ 78, 779, 41, 14 ], [ 123, 779, 13, 14 ], [ 140, 779, 43, 14 ], [ 188, 779, 27, 14 ], [ 219, 779, 37, 14 ], [ 260, 779, 45, 14 ], [ 310, 779, 42, 14 ], [ 356, 779, 12, 14 ], [ 372, 779, 32, 14 ], [ 78, 796, 36, 14 ], [ 118, 796, 34, 14 ], [ 157, 796, 13, 14 ], [ 174, 796, 51, 14 ], [ 229, 796, 54, 14 ], [ 286, 796, 35, 14 ], [ 325, 796, 49, 14 ], [ 378, 796, 25, 14 ], [ 78, 812, 19, 14 ], [ 102, 812, 43, 14 ], [ 150, 812, 37, 14 ], [ 192, 812, 55, 14 ], [ 252, 812, 7, 14 ], [ 264, 812, 56, 14 ], [ 324, 812, 46, 14 ], [ 374, 812, 29, 14 ], [ 78, 829, 45, 14 ], [ 128, 829, 82, 14 ], [ 215, 829, 32, 14 ], [ 252, 829, 12, 14 ], [ 269, 829, 24, 14 ], [ 297, 829, 43, 14 ], [ 345, 829, 12, 14 ], [ 363, 829, 24, 14 ], [ 392, 829, 12, 14 ], [ 78, 845, 77, 14 ], [ 160, 845, 20, 14 ], [ 185, 845, 13, 14 ], [ 204, 845, 53, 14 ], [ 262, 845, 42, 14 ], [ 309, 845, 12, 14 ], [ 326, 845, 34, 14 ], [ 366, 845, 38, 14 ], [ 78, 862, 43, 14 ], [ 126, 862, 21, 14 ], [ 152, 862, 12, 14 ], [ 168, 862, 19, 14 ], [ 191, 862, 20, 14 ], [ 215, 862, 12, 14 ], [ 231, 862, 6, 14 ], [ 242, 862, 27, 14 ], [ 274, 862, 19, 14 ], [ 298, 862, 33, 14 ], [ 335, 862, 24, 14 ], [ 364, 862, 14, 14 ], [ 382, 862, 21, 14 ], [ 78, 879, 16, 14 ], [ 100, 879, 12, 14 ], [ 119, 879, 69, 14 ], [ 194, 879, 41, 14 ], [ 241, 879, 12, 14 ], [ 260, 879, 46, 14 ], [ 312, 879, 29, 14 ], [ 347, 879, 57, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 133, 11 ], [ 78, 923, 38, 13 ], [ 119, 925, 12, 11 ], [ 134, 925, 27, 11 ], [ 164, 925, 45, 11 ], [ 212, 925, 16, 11 ], [ 231, 925, 27, 11 ], [ 262, 925, 19, 11 ], [ 284, 925, 58, 11 ], [ 345, 925, 43, 11 ], [ 78, 937, 36, 11 ], [ 118, 937, 40, 11 ], [ 161, 937, 4, 11 ], [ 167, 937, 33, 11 ], [ 204, 937, 37, 11 ], [ 244, 937, 28, 11 ], [ 275, 937, 12, 11 ], [ 289, 937, 61, 11 ], [ 353, 937, 29, 11 ], [ 78, 950, 50, 11 ], [ 131, 950, 46, 11 ], [ 180, 950, 7, 11 ], [ 190, 950, 52, 11 ], [ 245, 950, 27, 11 ], [ 275, 950, 38, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 696, 49, 14 ], [ 476, 696, 18, 14 ], [ 499, 696, 70, 14 ], [ 574, 696, 56, 14 ], [ 635, 696, 59, 14 ], [ 699, 696, 11, 14 ], [ 716, 696, 32, 14 ], [ 423, 713, 33, 14 ], [ 460, 713, 20, 14 ], [ 485, 713, 12, 14 ], [ 501, 713, 70, 14 ], [ 576, 713, 26, 14 ], [ 607, 713, 32, 14 ], [ 643, 713, 36, 14 ], [ 685, 713, 63, 14 ], [ 423, 729, 45, 14 ], [ 472, 729, 13, 14 ], [ 489, 729, 18, 14 ], [ 512, 729, 40, 14 ], [ 556, 729, 77, 14 ], [ 637, 729, 52, 14 ], [ 693, 729, 21, 14 ], [ 718, 729, 30, 14 ], [ 423, 746, 27, 14 ], [ 454, 746, 13, 14 ], [ 471, 746, 12, 14 ], [ 487, 746, 35, 14 ], [ 525, 746, 12, 14 ], [ 541, 746, 67, 14 ], [ 613, 746, 64, 14 ], [ 681, 746, 50, 14 ], [ 736, 746, 12, 14 ], [ 423, 762, 21, 14 ], [ 448, 762, 64, 14 ], [ 516, 762, 68, 14 ], [ 588, 762, 29, 14 ], [ 434, 779, 59, 14 ], [ 498, 779, 44, 14 ], [ 547, 779, 57, 14 ], [ 609, 779, 19, 14 ], [ 633, 779, 47, 14 ], [ 684, 779, 12, 14 ], [ 701, 779, 47, 14 ], [ 423, 795, 64, 14 ], [ 492, 795, 22, 14 ], [ 518, 795, 12, 14 ], [ 534, 795, 34, 14 ], [ 573, 795, 27, 14 ], [ 605, 795, 50, 14 ], [ 659, 795, 42, 14 ], [ 706, 795, 42, 14 ], [ 423, 812, 26, 14 ], [ 454, 812, 40, 14 ], [ 498, 812, 12, 14 ], [ 515, 812, 29, 14 ], [ 550, 812, 52, 14 ], [ 607, 812, 24, 14 ], [ 637, 812, 35, 14 ], [ 677, 812, 48, 14 ], [ 730, 812, 18, 14 ], [ 423, 829, 27, 14 ], [ 454, 829, 12, 14 ], [ 470, 829, 46, 14 ], [ 521, 829, 64, 14 ], [ 589, 829, 16, 14 ], [ 610, 829, 47, 14 ], [ 661, 829, 45, 14 ], [ 710, 829, 38, 14 ], [ 423, 845, 12, 14 ], [ 439, 845, 28, 14 ], [ 471, 845, 50, 14 ], [ 525, 845, 23, 14 ], [ 553, 845, 27, 14 ], [ 584, 845, 12, 14 ], [ 600, 845, 14, 14 ], [ 618, 845, 64, 14 ], [ 686, 845, 12, 14 ], [ 703, 845, 45, 14 ], [ 423, 862, 73, 14 ], [ 500, 862, 16, 14 ], [ 520, 862, 28, 14 ], [ 553, 862, 75, 14 ], [ 632, 862, 29, 14 ], [ 665, 862, 7, 14 ], [ 676, 862, 41, 14 ], [ 721, 862, 27, 14 ], [ 423, 879, 50, 14 ], [ 477, 879, 72, 14 ], [ 553, 879, 90, 14 ], [ 648, 879, 12, 14 ], [ 664, 879, 45, 14 ], [ 714, 879, 34, 14 ], [ 423, 895, 24, 14 ], [ 450, 895, 33, 14 ], [ 488, 895, 11, 14 ], [ 504, 895, 56, 14 ], [ 563, 895, 55, 14 ], [ 622, 895, 16, 14 ], [ 642, 895, 49, 14 ], [ 695, 895, 23, 14 ], [ 722, 895, 26, 14 ], [ 423, 912, 12, 14 ], [ 439, 912, 45, 14 ], [ 488, 912, 63, 14 ], [ 556, 912, 28, 14 ], [ 588, 912, 75, 14 ], [ 666, 912, 31, 14 ], [ 702, 912, 46, 14 ], [ 423, 928, 31, 14 ], [ 458, 928, 50, 14 ], [ 512, 928, 23, 14 ], [ 539, 928, 27, 14 ], [ 571, 928, 12, 14 ], [ 587, 928, 14, 14 ], [ 605, 928, 45, 14 ], [ 655, 928, 64, 14 ], [ 723, 928, 25, 14 ], [ 423, 945, 14, 14 ], [ 441, 945, 43, 14 ], [ 488, 945, 27, 14 ], [ 519, 945, 70, 14 ], [ 593, 945, 19, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 19, 10 ], [ 277, 987, 19, 10 ], [ 298, 987, 8, 10 ], [ 308, 987, 8, 10 ], [ 319, 987, 30, 10 ], [ 352, 987, 29, 10 ], [ 383, 987, 27, 10 ], [ 412, 987, 14, 10 ], [ 429, 987, 15, 10 ], [ 446, 987, 6, 10 ], [ 455, 987, 10, 10 ], [ 466, 987, 21, 10 ], [ 490, 987, 25, 10 ], [ 518, 987, 23, 10 ], [ 543, 987, 41, 10 ], [ 586, 987, 23, 10 ], [ 611, 987, 13, 10 ], [ 626, 987, 22, 10 ], [ 650, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Stark", "et", "al.", "BMC", "Health", "Services", "Research", "2011,", "11:9", "http://www.biomedcentral.com/1472-6963/11/9", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Health", "care", "use", "and", "costs", "of", "adverse", "drug", "events", "emerging", "from", "outpatient", "treatment", "in", "Germany:", "A", "modelling", "approach", "Renee", "G", "Stark1*,", "Jürgen", "John1,", "Reiner", "Leidl", "1,2", "Abstract", "Background:", "This", "study’s", "aim", "was", "to", "develop", "a", "first", "quantification", "of", "the", "frequency", "and", "costs", "of", "adverse", "drug", "events", "(ADEs)", "originating", "in", "ambulatory", "medical", "practice", "in", "Germany.", "Methods:", "The", "frequencies", "and", "costs", "of", "ADEs", "were", "quantified", "for", "a", "base", "case,", "building", "on", "an", "existing", "cost-of-", "illness", "model", "for", "ADEs.", "The", "model", "originates", "from", "the", "U.S.", "health", "care", "system,", "its", "structure", "of", "treatment", "probabilities", "linked", "to", "ADEs", "was", "transferred", "to", "Germany.", "Sensitivity", "analyses", "based", "on", "values", "determined", "from", "a", "literature", "review", "were", "used", "to", "test", "the", "postulated", "results.", "Results:", "For", "Germany,", "the", "base", "case", "postulated", "that", "about", "2", "million", "adults", "ingesting", "medications", "have", "will", "have", "an", "ADE", "in", "2007.", "Health", "care", "costs", "related", "to", "ADEs", "in", "this", "base", "case", "totalled", "816", "million", "Euros,", "mean", "costs", "per", "case", "were", "381", "Euros.", "About", "58%", "of", "costs", "resulted", "from", "hospitalisations,", "11%", "from", "emergency", "department", "visits", "and", "21%", "from", "long-term", "care.", "Base", "case", "estimates", "of", "frequency", "and", "costs", "of", "ADEs", "were", "lower", "than", "all", "estimates", "of", "the", "sensitivity", "analyses.", "Discussion:", "The", "postulated", "frequency", "and", "costs", "of", "ADEs", "illustrate", "the", "possible", "size", "of", "the", "health", "problems", "and", "economic", "burden", "related", "to", "ADEs", "in", "Germany.", "The", "validity", "of", "the", "U.S.", "treatment", "structure", "used", "remains", "to", "be", "determined", "for", "Germany.", "The", "sensitivity", "analysis", "used", "assumptions", "from", "different", "studies", "and", "thus", "further", "quantified", "the", "information", "gap", "in", "Germany", "regarding", "ADEs.", "Conclusions:", "This", "study", "found", "costs", "of", "ADEs", "in", "the", "ambulatory", "setting", "in", "Germany", "to", "be", "significant.", "Due", "to", "data", "scarcity,", "results", "are", "only", "a", "rough", "indication.", "Background", "Medications", "are", "used", "to", "cure", "or", "slow", "disease", "processes,", "to", "reduce", "symptoms", "and", "to", "improve", "quality", "of", "life", "[1].", "However,", "all", "medications", "may", "have", "disadvantageous", "effects,", "which", "may", "be", "reported", "as", "drug", "related", "problems", "(DRPs)", "or", "adverse", "drug", "events", "(ADEs).", "Studies", "of", "DRPs", "report", "actual", "or", "potential", "problems", "which", "interfere", "with", "the", "desired", "health", "outcome,", "a", "spectrum", "ranging", "from", "adverse", "consequences", "(such", "as", "side", "effects)", "to", "lack", "of", "effectiveness", "[2].", "In", "contrast,", "studies", "of", "ADEs", "report", "injuries", "due", "to", "the", "use", "of", "a", "drug", "[3].", "ADEs", "may", "be", "due", "to:", "1)", "medication", "errors;", "2)", "adverse", "drug", "reactions", "*", "Correspondence:", "r.stark@helmholtz-muenchen.de", "1Institute", "for", "Health", "Economics", "and", "Health", "Care", "Management,", "Helmholtz", "Zentrum", "München", "-", "German", "Research", "Center", "for", "Environmental", "Health,", "Ingolstädter", "Landstraße", "1,", "Neuherberg,", "85764,", "Germany", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "(ADRs),", "i.e.", "unintended", "reactions", "occurring", "at", "usual", "doses", "[4];", "3)", "interactions", "with", "other", "drugs,", "underlying", "diseases", "or", "the", "patient", "(idiosyncratic", "reactions", "and", "aller-", "gies)", "or", "4)", "errors", "in", "prescribing,", "dispensing,", "adhering", "to", "and", "monitoring", "medications", "[1,5].", "Literature", "reviews", "regarding", "the", "number", "of", "hospital", "admissions", "due", "to", "ADRs", "have", "reported", "various", "results.", "One", "review", "in", "2002", "reported", "that", "ADRs", "account", "for", "4.9%", "of", "hospital", "admissions", "[6]", "whereas", "another", "review", "in", "1997", "reported", "that", "5.8%", "of", "all", "admissions", "to", "medical", "departments", "[4]", "were", "drug-related.", "Only", "2", "studies", "have", "reported", "drug-related", "hospitalisations", "to", "internal", "medi-", "cine", "wards", "in", "Germany.", "Dormann", "[7]", "reported", "that", "3.8%", "of", "medical", "admissions", "were", "drug-related,", "while", "Schnee-", "weiss", "reported", "that", "2.4%", "of", "all", "medical", "admissions", "over", "30", "months", "were", "drug-related", "[8].", "©", "2011", "Stark", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 173, 36, 5, 14 ], [ 183, 36, 6, 14 ], [ 195, 36, 5, 14 ], [ 205, 36, 6, 14 ], [ 216, 36, 6, 14 ], [ 336, 39, 45, 13 ], [ 383, 39, 39, 13 ], [ 424, 39, 30, 13 ], [ 455, 39, 37, 13 ], [ 495, 39, 29, 13 ], [ 526, 39, 58, 13 ], [ 336, 57, 19, 10 ], [ 356, 57, 80, 10 ], [ 569, 57, 7, 10 ], [ 577, 57, 20, 10 ], [ 599, 57, 7, 10 ], [ 608, 57, 28, 10 ], [ 637, 57, 15, 10 ], [ 654, 57, 22, 10 ], [ 336, 68, 42, 10 ], [ 380, 68, 29, 10 ], [ 410, 68, 33, 10 ], [ 445, 68, 12, 10 ], [ 459, 68, 20, 10 ], [ 569, 68, 91, 10 ], [ 336, 86, 17, 10 ], [ 355, 86, 7, 10 ], [ 363, 86, 10, 10 ], [ 375, 86, 23, 10 ], [ 399, 86, 27, 10 ], [ 428, 86, 26, 10 ], [ 455, 86, 34, 10 ], [ 491, 86, 25, 10 ], [ 517, 86, 14, 10 ], [ 533, 86, 24, 10 ], [ 558, 86, 9, 10 ], [ 568, 86, 14, 10 ], [ 584, 86, 34, 10 ], [ 619, 86, 42, 10 ], [ 662, 86, 48, 10 ], [ 336, 97, 106, 10 ], [ 444, 97, 12, 10 ], [ 458, 97, 30, 10 ], [ 490, 97, 123, 10 ], [ 615, 97, 42, 10 ], [ 659, 97, 9, 10 ], [ 669, 97, 14, 10 ], [ 685, 97, 26, 10 ], [ 336, 108, 30, 10 ], [ 368, 108, 9, 10 ], [ 378, 108, 14, 10 ], [ 394, 108, 26, 10 ], [ 421, 108, 20, 10 ], [ 443, 108, 49, 10 ], [ 494, 108, 12, 10 ], [ 507, 108, 68, 10 ], [ 576, 108, 38, 10 ], [ 616, 108, 20, 10 ], [ 750, 69, 8, 16 ], [ 139, 221, 54, 27 ], [ 199, 221, 25, 27 ], [ 228, 221, 137, 27 ], [ 370, 221, 104, 27 ], [ 139, 250, 182, 27 ], [ 326, 250, 15, 27 ], [ 345, 250, 172, 27 ], [ 523, 250, 53, 27 ], [ 139, 279, 47, 27 ], [ 191, 279, 24, 27 ], [ 220, 279, 70, 27 ], [ 295, 279, 25, 27 ], [ 325, 279, 134, 27 ], [ 463, 279, 100, 27 ], [ 139, 309, 116, 27 ], [ 139, 365, 30, 19 ], [ 172, 365, 30, 19 ], [ 206, 363, 36, 21 ], [ 257, 365, 79, 19 ], [ 340, 363, 47, 21 ], [ 402, 365, 23, 19 ], [ 428, 365, 30, 19 ], [ 462, 363, 49, 21 ], [ 139, 395, 71, 15 ], [ 212, 396, 11, 13 ], [ 225, 396, 52, 13 ], [ 280, 396, 43, 13 ], [ 326, 396, 41, 13 ], [ 368, 396, 11, 13 ], [ 382, 396, 39, 13 ], [ 423, 396, 48, 13 ], [ 474, 396, 35, 13 ], [ 511, 396, 56, 13 ], [ 139, 412, 71, 13 ], [ 212, 412, 11, 13 ], [ 225, 410, 60, 15 ], [ 287, 412, 21, 13 ], [ 310, 410, 64, 15 ], [ 376, 412, 36, 13 ], [ 415, 412, 11, 13 ], [ 428, 412, 52, 13 ], [ 482, 412, 44, 13 ], [ 528, 412, 54, 13 ], [ 584, 412, 11, 13 ], [ 139, 427, 38, 13 ], [ 180, 427, 38, 13 ], [ 220, 427, 32, 13 ], [ 254, 427, 31, 13 ], [ 139, 554, 25, 15 ], [ 166, 554, 42, 15 ], [ 139, 572, 69, 15 ], [ 211, 572, 50, 15 ], [ 264, 572, 59, 15 ], [ 333, 572, 71, 15 ], [ 407, 572, 45, 15 ], [ 463, 572, 25, 15 ], [ 490, 572, 12, 15 ], [ 505, 572, 35, 15 ], [ 551, 572, 94, 15 ], [ 647, 572, 8, 15 ], [ 139, 590, 24, 15 ], [ 166, 590, 42, 15 ], [ 219, 590, 36, 15 ], [ 258, 590, 42, 15 ], [ 303, 590, 42, 15 ], [ 139, 645, 56, 15 ], [ 139, 663, 78, 15 ], [ 219, 663, 25, 15 ], [ 246, 663, 56, 15 ], [ 305, 663, 23, 15 ], [ 330, 663, 73, 15 ], [ 405, 663, 55, 15 ], [ 462, 663, 92, 15 ], [ 556, 663, 8, 15 ], [ 565, 663, 41, 15 ], [ 609, 663, 24, 15 ], [ 635, 663, 35, 15 ], [ 671, 663, 13, 15 ], [ 686, 663, 25, 15 ], [ 139, 681, 30, 15 ], [ 174, 681, 59, 15 ], [ 236, 681, 49, 15 ], [ 289, 681, 82, 15 ], [ 375, 681, 23, 15 ], [ 403, 681, 23, 15 ], [ 430, 681, 13, 15 ], [ 447, 681, 23, 15 ], [ 473, 681, 34, 15 ], [ 512, 681, 24, 15 ], [ 540, 681, 13, 15 ], [ 557, 681, 52, 15 ], [ 613, 681, 21, 15 ], [ 638, 681, 73, 15 ], [ 139, 699, 55, 15 ], [ 196, 699, 33, 15 ], [ 231, 699, 90, 15 ], [ 324, 699, 24, 15 ], [ 349, 699, 21, 15 ], [ 372, 699, 35, 15 ], [ 409, 699, 13, 15 ], [ 423, 699, 68, 15 ], [ 493, 699, 50, 15 ], [ 545, 699, 59, 15 ], [ 606, 699, 40, 15 ], [ 648, 699, 63, 15 ], [ 139, 717, 13, 15 ], [ 155, 717, 71, 15 ], [ 229, 717, 45, 15 ], [ 277, 717, 27, 15 ], [ 307, 717, 24, 15 ], [ 334, 717, 44, 15 ], [ 380, 717, 53, 15 ], [ 436, 717, 60, 15 ], [ 499, 717, 23, 15 ], [ 525, 717, 35, 15 ], [ 562, 717, 24, 15 ], [ 589, 717, 65, 15 ], [ 657, 717, 13, 15 ], [ 673, 717, 15, 15 ], [ 690, 717, 21, 15 ], [ 139, 735, 35, 15 ], [ 176, 735, 28, 15 ], [ 206, 735, 32, 15 ], [ 241, 735, 19, 15 ], [ 262, 735, 72, 15 ], [ 336, 735, 31, 15 ], [ 370, 735, 15, 15 ], [ 387, 735, 46, 15 ], [ 434, 735, 32, 15 ], [ 469, 735, 24, 15 ], [ 495, 735, 20, 15 ], [ 518, 735, 50, 15 ], [ 570, 735, 28, 15 ], [ 600, 735, 19, 15 ], [ 621, 735, 18, 15 ], [ 642, 735, 69, 15 ], [ 139, 753, 22, 15 ], [ 163, 753, 15, 15 ], [ 181, 753, 62, 15 ], [ 245, 753, 23, 15 ], [ 270, 753, 13, 15 ], [ 285, 753, 25, 15 ], [ 313, 753, 13, 15 ], [ 328, 753, 23, 15 ], [ 353, 753, 31, 15 ], [ 386, 753, 49, 15 ], [ 437, 753, 24, 15 ], [ 463, 753, 121, 15 ], [ 586, 753, 44, 15 ], [ 632, 753, 53, 15 ], [ 687, 753, 23, 15 ], [ 139, 771, 58, 15 ], [ 201, 771, 13, 15 ], [ 217, 771, 32, 15 ], [ 253, 771, 24, 15 ], [ 280, 771, 37, 15 ], [ 321, 771, 17, 15 ], [ 341, 771, 56, 15 ], [ 401, 771, 82, 15 ], [ 486, 771, 46, 15 ], [ 535, 771, 24, 15 ], [ 562, 771, 21, 15 ], [ 586, 771, 58, 15 ], [ 648, 771, 13, 15 ], [ 664, 771, 19, 15 ], [ 687, 771, 24, 15 ], [ 139, 790, 37, 15 ], [ 180, 790, 17, 15 ], [ 199, 790, 98, 15 ], [ 300, 790, 46, 15 ], [ 349, 790, 33, 15 ], [ 385, 790, 90, 15 ], [ 479, 790, 24, 15 ], [ 505, 790, 69, 15 ], [ 577, 790, 12, 15 ], [ 592, 790, 14, 15 ], [ 610, 790, 76, 15 ], [ 689, 790, 21, 15 ], [ 139, 808, 34, 15 ], [ 176, 808, 34, 15 ], [ 212, 808, 13, 15 ], [ 227, 808, 21, 15 ], [ 250, 808, 33, 15 ], [ 285, 808, 33, 15 ], [ 321, 808, 38, 15 ], [ 361, 808, 24, 15 ], [ 388, 808, 33, 15 ], [ 423, 808, 59, 15 ], [ 484, 808, 12, 15 ], [ 498, 808, 32, 15 ], [ 533, 808, 50, 15 ], [ 585, 808, 63, 15 ], [ 651, 808, 13, 15 ], [ 666, 808, 44, 15 ], [ 139, 826, 53, 15 ], [ 196, 826, 37, 15 ], [ 237, 826, 24, 15 ], [ 265, 826, 21, 15 ], [ 290, 826, 27, 15 ], [ 320, 826, 35, 15 ], [ 359, 826, 30, 15 ], [ 393, 826, 72, 15 ], [ 468, 826, 24, 15 ], [ 496, 826, 46, 15 ], [ 545, 826, 34, 15 ], [ 584, 826, 31, 15 ], [ 618, 826, 55, 15 ], [ 677, 826, 34, 15 ], [ 139, 844, 37, 15 ], [ 180, 844, 33, 15 ], [ 223, 844, 8, 15 ], [ 234, 844, 20, 15 ], [ 258, 844, 22, 15 ], [ 282, 844, 62, 15 ], [ 348, 844, 21, 15 ], [ 371, 844, 35, 15 ], [ 409, 844, 13, 15 ], [ 425, 844, 32, 15 ], [ 460, 844, 22, 15 ], [ 485, 844, 29, 15 ], [ 517, 844, 27, 15 ], [ 547, 844, 15, 15 ], [ 565, 844, 51, 15 ], [ 619, 844, 12, 15 ], [ 634, 844, 50, 15 ], [ 687, 844, 13, 15 ], [ 703, 844, 8, 15 ], [ 139, 862, 64, 15 ], [ 206, 862, 47, 15 ], [ 257, 862, 28, 15 ], [ 288, 862, 62, 15 ], [ 353, 862, 19, 15 ], [ 376, 862, 22, 15 ], [ 401, 862, 29, 15 ], [ 433, 862, 26, 15 ], [ 463, 862, 15, 15 ], [ 481, 862, 51, 15 ], [ 535, 862, 75, 15 ], [ 613, 862, 24, 15 ], [ 640, 862, 40, 15 ], [ 684, 862, 27, 15 ], [ 139, 880, 27, 15 ], [ 169, 880, 25, 15 ], [ 198, 880, 33, 15 ], [ 234, 880, 90, 15 ], [ 327, 880, 10, 15 ], [ 340, 880, 21, 15 ], [ 365, 880, 64, 15 ], [ 433, 880, 28, 15 ], [ 463, 880, 21, 15 ], [ 487, 880, 35, 15 ], [ 525, 880, 13, 15 ], [ 541, 880, 32, 15 ], [ 576, 880, 24, 15 ], [ 603, 880, 25, 15 ], [ 632, 880, 21, 15 ], [ 656, 880, 24, 15 ], [ 683, 880, 27, 15 ], [ 139, 898, 34, 15 ], [ 176, 898, 13, 15 ], [ 192, 898, 32, 15 ], [ 227, 898, 26, 15 ], [ 256, 898, 34, 15 ], [ 292, 898, 40, 15 ], [ 335, 898, 116, 15 ], [ 565, 903, 41, 10 ], [ 607, 903, 7, 10 ], [ 615, 903, 19, 10 ], [ 636, 903, 7, 10 ], [ 645, 903, 27, 10 ], [ 673, 903, 15, 10 ], [ 689, 903, 21, 10 ], [ 139, 981, 14, 12 ], [ 155, 981, 15, 12 ], [ 171, 981, 19, 12 ], [ 192, 981, 27, 12 ], [ 336, 981, 59, 12 ], [ 397, 981, 10, 12 ], [ 409, 981, 53, 12 ], [ 463, 981, 32, 12 ], [ 497, 981, 39, 12 ], [ 538, 981, 48, 12 ], [ 588, 981, 38, 12 ], [ 628, 981, 32, 12 ], [ 336, 995, 39, 12 ], [ 377, 995, 48, 12 ], [ 427, 995, 10, 12 ], [ 439, 995, 32, 12 ], [ 336, 1009, 36, 12 ], [ 374, 1009, 53, 12 ], [ 429, 1009, 38, 12 ], [ 469, 1009, 38, 12 ], [ 508, 1009, 32, 12 ], [ 542, 1009, 32, 12 ], [ 575, 1009, 31, 12 ], [ 336, 1023, 16, 12 ], [ 354, 1023, 19, 12 ], [ 375, 1023, 12, 12 ], [ 389, 1023, 18, 12 ], [ 408, 1023, 26, 12 ], [ 436, 1023, 30, 12 ], [ 467, 1023, 91, 12 ] ]

[ "E", "X", "T", "R", "A", "Dement", "Geriatr", "Cogn", "Disord", "Extra", "2012;2:1–9", "DOI:", "10.1159/000335494", "©", "2012", "S.", "Karger", "AG,", "Basel", "Published", "online:", "January", "19,", "2012", "www.karger.com/dee", "This", "is", "an", "Open", "Access", "article", "licensed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution-", "NonCommercial-NoDerivs", "3.0", "License", "(www.karger.com/OA-license),", "applicable", "to", "the", "online", "version", "of", "the", "article", "only.", "Distribution", "for", "non-commercial", "purposes", "only.", "1", "Lack", "of", "Association", "between", "Apolipoprotein", "E", "Polymorphism", "with", "Age", "at", "Onset", "of", "Subcortical", "Vascular", "Dementia", "Hye", "Guk", "Ryua", "Sung-Won", "Younb", "Oh", "Dae", "Kwonc", "aDepartment", "of", "Biological", "Science,", "College", "of", "Natural", "Sciences,", "Daegu", "University,", "Departments", "of", "bRadiology", "and", "cNeurology,", "School", "of", "Medicine,", "Catholic", "University", "of", "Daegu,", "Daegu,", "South", "Korea", "Key", "Words", "Subcortical", "vascular", "dementia", "Alzheimer’s", "disease", "Age", "at", "onset", "Apolipoprotein", "E", "Risk", "factors", "White", "matter", "lesions", "Abstract", "Background", "and", "Purpose:", "The", "relationship", "between", "apolipoprotein", "E", "(ApoE)", "and", "onset", "of", "vas-", "cular", "dementia", "remains", "controversial.", "The", "aim", "of", "this", "study", "was", "to", "evaluate", "the", "relationship", "between", "ApoE", "polymorphism", "and", "the", "onset", "of", "subcortical", "vascular", "dementia", "(SVaD)", "compared", "to", "Alzheimer’s", "disease", "(AD)", "and", "normal", "controls.", "Methods:", "The", "study", "was", "comprised", "of", "61", "pa-", "tients", "with", "SVaD", "(42", "Binswanger", "type,", "19", "lacunar", "type)", "and", "112", "patients", "with", "AD", "(16", "early-onset", "AD,", "96", "late-onset", "AD)", "as", "well", "as", "284", "age-,", "gender-", "and", "education-matched", "normal", "controls.", "The", "diagnosis", "of", "SVaD", "was", "based", "on", "modified", "NINDS-AIREN", "criteria,", "and", "the", "diagnosis", "of", "AD", "was", "based", "on", "NINCDS-ADRDA", "criteria.", "ApoE", "polymorphism", "was", "genotyped", "in", "all", "participants.", "Re-", "sults:", "None", "of", "the", "three", "ApoE", "alleles", "was", "more", "prevalent", "in", "SVaD", "patients", "compared", "to", "normal", "controls,", "which", "was", "the", "case", "when", "both", "Binswanger", "and", "lacunar", "types", "were", "analyzed", "sepa-", "rately.", "ApoE", "4", "did", "not", "accelerate", "the", "onset", "of", "SVaD", "(OR", "1.66,", "95%", "CI:", "0.8–3.4),", "in", "contrast", "to", "a", "significant", "relation", "with", "late-onset", "AD", "(OR", "3.78,", "95%", "CI:", "2.2–6.5).", "Conclusion:", "Our", "results", "sug-", "gest", "that", "ApoE", "polymorphism", "is", "not", "associated", "with", "the", "onset", "of", "SVaD", "and", "that", "the", "two", "sub-", "types", "of", "SVaD", "may", "share", "similar", "pathophysiologies.", "Copyright", "©", "2012", "S.", "Karger", "AG,", "Basel", "Dr.", "Oh", "Dae", "Kwon", "Department", "of", "Neurology,", "Daegu", "Catholic", "University", "Medical", "Center", "Catholic", "University", "of", "Daegu", "3056-6,", "Daemyung", "4-dong,", "Namgu,", "Daegu", "(South", "Korea)", "Tel.", "+82", "53", "650", "4298,", "E-Mail", "dolbaeke@cu.ac.kr" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 6, 6, 6, 6, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13 ]

[ [ 76, 24, 199, 28 ], [ 285, 24, 113, 28 ], [ 408, 24, 32, 28 ], [ 450, 24, 107, 28 ], [ 76, 52, 100, 28 ], [ 186, 52, 126, 28 ], [ 76, 118, 70, 20 ], [ 706, 60, 54, 14 ], [ 761, 60, 38, 14 ], [ 697, 118, 44, 17 ], [ 745, 118, 62, 17 ], [ 76, 143, 89, 23 ], [ 171, 143, 20, 23 ], [ 197, 143, 63, 23 ], [ 265, 143, 129, 23 ], [ 400, 143, 75, 23 ], [ 481, 143, 88, 23 ], [ 574, 143, 100, 23 ], [ 680, 143, 19, 23 ], [ 76, 168, 112, 23 ], [ 194, 168, 12, 23 ], [ 212, 168, 45, 23 ], [ 263, 168, 85, 23 ], [ 354, 168, 56, 23 ], [ 416, 168, 20, 23 ], [ 441, 168, 57, 23 ], [ 76, 193, 66, 21 ], [ 147, 193, 87, 22 ], [ 240, 193, 58, 21 ], [ 303, 193, 82, 22 ], [ 390, 193, 50, 21 ], [ 445, 193, 79, 22 ], [ 529, 193, 73, 21 ], [ 607, 193, 92, 22 ], [ 76, 218, 64, 21 ], [ 144, 218, 61, 22 ], [ 209, 218, 56, 21 ], [ 270, 218, 116, 22 ], [ 391, 218, 86, 21 ], [ 482, 218, 105, 22 ], [ 591, 218, 82, 21 ], [ 678, 218, 87, 22 ], [ 76, 243, 80, 21 ], [ 161, 243, 56, 22 ], [ 222, 243, 73, 21 ], [ 300, 243, 93, 22 ], [ 399, 243, 65, 21 ], [ 468, 243, 72, 22 ], [ 545, 243, 92, 21 ], [ 642, 243, 99, 22 ], [ 76, 268, 45, 21 ], [ 125, 268, 102, 22 ], [ 233, 268, 35, 21 ], [ 272, 268, 76, 21 ], [ 353, 268, 56, 22 ], [ 76, 318, 41, 12 ], [ 118, 318, 63, 12 ], [ 183, 318, 10, 12 ], [ 195, 318, 83, 12 ], [ 279, 318, 33, 12 ], [ 314, 318, 10, 12 ], [ 326, 318, 48, 12 ], [ 375, 318, 41, 12 ], [ 418, 318, 39, 12 ], [ 458, 318, 52, 12 ], [ 512, 318, 41, 12 ], [ 555, 318, 43, 12 ], [ 599, 318, 46, 12 ], [ 646, 318, 44, 12 ], [ 692, 318, 28, 12 ], [ 721, 318, 47, 12 ], [ 76, 331, 63, 12 ], [ 141, 331, 10, 11 ], [ 154, 331, 52, 11 ], [ 209, 331, 52, 11 ], [ 264, 331, 20, 11 ], [ 286, 331, 52, 11 ], [ 341, 331, 55, 11 ], [ 399, 331, 30, 11 ], [ 432, 331, 63, 12 ], [ 497, 331, 10, 11 ], [ 510, 331, 52, 11 ], [ 564, 331, 49, 11 ], [ 615, 331, 52, 11 ], [ 670, 331, 32, 11 ], [ 704, 331, 40, 11 ], [ 76, 344, 45, 12 ], [ 123, 344, 55, 12 ], [ 181, 344, 31, 12 ], [ 214, 344, 63, 12 ], [ 279, 344, 10, 12 ], [ 292, 344, 52, 12 ], [ 346, 344, 33, 12 ], [ 382, 344, 10, 12 ], [ 395, 344, 48, 12 ], [ 445, 344, 22, 12 ], [ 470, 344, 52, 12 ], [ 524, 344, 33, 12 ], [ 560, 344, 30, 12 ], [ 593, 344, 63, 12 ], [ 658, 344, 10, 12 ], [ 671, 344, 52, 12 ], [ 726, 344, 31, 12 ], [ 76, 357, 45, 12 ], [ 123, 357, 58, 12 ], [ 184, 357, 30, 12 ], [ 216, 357, 63, 12 ], [ 282, 357, 10, 12 ], [ 294, 357, 52, 12 ], [ 349, 357, 49, 12 ], [ 400, 357, 50, 12 ], [ 452, 357, 45, 12 ], [ 499, 357, 33, 12 ], [ 535, 357, 10, 12 ], [ 548, 357, 48, 12 ], [ 598, 357, 44, 12 ], [ 644, 357, 30, 12 ], [ 677, 357, 63, 12 ], [ 742, 357, 10, 12 ], [ 76, 371, 49, 11 ], [ 127, 371, 73, 11 ], [ 203, 371, 38, 11 ], [ 243, 371, 70, 11 ], [ 315, 371, 39, 11 ], [ 356, 371, 43, 11 ], [ 401, 371, 41, 11 ], [ 444, 371, 10, 11 ], [ 457, 371, 60, 11 ], [ 520, 371, 43, 11 ], [ 565, 371, 33, 11 ], [ 600, 371, 30, 11 ], [ 633, 370, 63, 12 ], [ 698, 371, 10, 11 ], [ 76, 384, 83, 12 ], [ 161, 384, 26, 12 ], [ 189, 384, 52, 12 ], [ 244, 384, 34, 12 ], [ 280, 384, 10, 12 ], [ 293, 384, 48, 12 ], [ 343, 384, 33, 12 ], [ 378, 384, 30, 12 ], [ 411, 384, 63, 12 ], [ 476, 384, 10, 12 ], [ 489, 384, 83, 12 ], [ 574, 384, 45, 12 ], [ 621, 384, 32, 12 ], [ 656, 384, 10, 12 ], [ 668, 384, 39, 12 ], [ 709, 384, 43, 12 ], [ 76, 397, 37, 12 ], [ 115, 397, 52, 12 ], [ 170, 397, 45, 12 ], [ 217, 397, 31, 12 ], [ 250, 397, 67, 12 ], [ 320, 397, 10, 12 ], [ 332, 397, 52, 12 ], [ 387, 397, 50, 12 ], [ 439, 397, 10, 12 ], [ 452, 397, 66, 12 ], [ 519, 397, 19, 12 ], [ 541, 397, 72, 12 ], [ 615, 397, 36, 12 ], [ 654, 397, 57, 12 ], [ 713, 397, 30, 12 ], [ 76, 410, 67, 12 ], [ 146, 410, 10, 11 ], [ 158, 410, 82, 11 ], [ 243, 410, 46, 11 ], [ 292, 410, 50, 11 ], [ 344, 410, 45, 11 ], [ 391, 410, 33, 11 ], [ 427, 410, 10, 11 ], [ 440, 410, 48, 11 ], [ 490, 410, 45, 11 ], [ 537, 410, 19, 11 ], [ 559, 410, 74, 11 ], [ 635, 410, 43, 11 ], [ 680, 410, 50, 11 ], [ 732, 410, 28, 11 ], [ 76, 423, 19, 12 ], [ 97, 423, 67, 12 ], [ 167, 423, 10, 12 ], [ 180, 423, 52, 12 ], [ 234, 423, 25, 12 ], [ 261, 423, 45, 12 ], [ 308, 423, 49, 12 ], [ 360, 423, 28, 12 ], [ 76, 444, 31, 11 ], [ 110, 444, 36, 11 ], [ 148, 444, 40, 11 ], [ 190, 444, 4, 11 ], [ 196, 444, 110, 11 ], [ 308, 444, 31, 11 ], [ 342, 444, 37, 11 ], [ 381, 444, 4, 11 ], [ 388, 444, 124, 11 ], [ 514, 444, 27, 11 ], [ 543, 444, 35, 11 ], [ 581, 444, 4, 11 ], [ 587, 444, 128, 11 ], [ 76, 457, 39, 12 ], [ 118, 457, 42, 12 ], [ 162, 457, 4, 12 ], [ 169, 457, 126, 12 ], [ 297, 457, 34, 12 ], [ 334, 457, 25, 12 ], [ 361, 457, 4, 12 ], [ 368, 457, 105, 12 ], [ 475, 457, 30, 12 ], [ 508, 457, 55, 12 ], [ 565, 457, 4, 12 ], [ 571, 457, 128, 12 ], [ 76, 470, 46, 12 ], [ 125, 470, 49, 12 ], [ 176, 470, 4, 12 ], [ 182, 470, 103, 12 ], [ 288, 470, 44, 12 ], [ 334, 470, 39, 12 ], [ 375, 470, 4, 12 ], [ 382, 470, 134, 12 ], [ 518, 470, 43, 12 ], [ 563, 470, 23, 12 ], [ 588, 470, 4, 12 ], [ 595, 470, 75, 12 ], [ 76, 483, 39, 11 ], [ 118, 483, 39, 11 ], [ 159, 483, 4, 11 ], [ 165, 483, 145, 11 ], [ 313, 483, 35, 11 ], [ 350, 483, 27, 11 ], [ 379, 483, 4, 11 ], [ 386, 483, 129, 11 ], [ 517, 483, 49, 11 ], [ 568, 483, 46, 11 ], [ 617, 483, 4, 11 ], [ 623, 483, 128, 11 ], [ 76, 496, 24, 12 ], [ 102, 496, 50, 12 ], [ 155, 496, 4, 12 ], [ 162, 496, 106, 12 ], [ 270, 496, 41, 12 ], [ 313, 496, 21, 12 ], [ 336, 496, 4, 12 ], [ 343, 496, 124, 12 ], [ 76, 512, 7, 11 ], [ 85, 512, 73, 11 ], [ 160, 512, 33, 11 ], [ 76, 571, 45, 11 ], [ 124, 571, 12, 11 ], [ 138, 571, 49, 11 ], [ 190, 571, 23, 11 ], [ 76, 591, 53, 12 ], [ 131, 591, 29, 12 ], [ 163, 591, 8, 12 ], [ 174, 591, 30, 12 ], [ 206, 591, 29, 12 ], [ 237, 591, 34, 12 ], [ 273, 591, 25, 12 ], [ 301, 591, 20, 12 ], [ 333, 591, 128, 12 ], [ 76, 610, 20, 12 ], [ 98, 610, 28, 12 ], [ 129, 610, 7, 12 ], [ 139, 610, 38, 12 ], [ 179, 610, 25, 12 ], [ 207, 610, 169, 12 ], [ 485, 571, 43, 11 ], [ 531, 571, 11, 11 ], [ 545, 571, 19, 11 ], [ 566, 571, 23, 11 ], [ 485, 584, 46, 12 ], [ 533, 584, 12, 12 ], [ 547, 584, 49, 12 ], [ 599, 584, 23, 12 ], [ 76, 630, 9, 12 ], [ 87, 630, 23, 12 ], [ 113, 630, 33, 12 ], [ 148, 630, 9, 12 ], [ 160, 630, 10, 12 ], [ 173, 630, 36, 12 ], [ 211, 630, 35, 12 ], [ 249, 630, 35, 12 ], [ 286, 630, 18, 12 ], [ 76, 644, 20, 12 ], [ 98, 644, 7, 12 ], [ 108, 644, 11, 12 ], [ 121, 644, 26, 12 ], [ 150, 644, 32, 12 ], [ 184, 644, 28, 12 ], [ 215, 644, 49, 12 ], [ 267, 644, 27, 12 ], [ 296, 644, 15, 12 ], [ 314, 644, 27, 12 ], [ 343, 644, 10, 12 ], [ 355, 644, 15, 12 ], [ 373, 644, 39, 12 ], [ 415, 644, 48, 12 ], [ 465, 644, 51, 12 ], [ 519, 644, 34, 12 ], [ 555, 644, 202, 12 ], [ 76, 657, 27, 12 ], [ 106, 657, 35, 12 ], [ 143, 657, 56, 12 ], [ 201, 657, 18, 12 ], [ 222, 657, 55, 12 ], [ 279, 657, 16, 12 ], [ 298, 657, 60, 12 ], [ 361, 657, 8, 12 ], [ 372, 657, 16, 12 ], [ 390, 657, 39, 12 ], [ 432, 657, 40, 12 ], [ 475, 657, 15, 12 ], [ 493, 657, 34, 12 ], [ 529, 657, 24, 12 ], [ 556, 657, 7, 12 ], [ 565, 657, 39, 12 ], [ 607, 657, 25, 12 ], [ 155, 717, 62, 15 ], [ 155, 738, 80, 14 ], [ 239, 738, 31, 14 ], [ 273, 738, 62, 14 ], [ 339, 738, 27, 14 ], [ 370, 738, 19, 14 ], [ 393, 738, 37, 14 ], [ 433, 738, 50, 14 ], [ 487, 738, 12, 14 ], [ 503, 738, 30, 14 ], [ 536, 738, 45, 14 ], [ 585, 738, 37, 14 ], [ 626, 738, 31, 14 ], [ 661, 738, 30, 14 ], [ 155, 754, 46, 14 ], [ 206, 754, 47, 14 ], [ 257, 754, 60, 14 ], [ 322, 754, 25, 14 ], [ 352, 754, 11, 14 ], [ 368, 754, 50, 14 ], [ 423, 754, 20, 14 ], [ 447, 754, 50, 14 ], [ 502, 754, 55, 14 ], [ 561, 754, 30, 14 ], [ 596, 754, 72, 14 ], [ 673, 754, 18, 14 ], [ 155, 771, 73, 14 ], [ 231, 771, 10, 14 ], [ 244, 771, 37, 14 ], [ 285, 771, 59, 14 ], [ 347, 771, 20, 14 ], [ 370, 771, 24, 14 ], [ 397, 771, 18, 14 ], [ 419, 771, 29, 14 ], [ 451, 771, 26, 14 ], [ 480, 771, 11, 14 ], [ 495, 771, 53, 14 ], [ 551, 771, 12, 14 ], [ 567, 771, 27, 14 ], [ 598, 771, 43, 14 ], [ 644, 771, 46, 14 ], [ 155, 787, 11, 14 ], [ 169, 787, 20, 14 ], [ 192, 787, 33, 14 ], [ 228, 787, 17, 14 ], [ 248, 787, 65, 14 ], [ 316, 787, 33, 14 ], [ 352, 787, 70, 14 ], [ 426, 787, 48, 14 ], [ 477, 787, 40, 14 ], [ 520, 787, 59, 14 ], [ 582, 787, 47, 14 ], [ 633, 787, 55, 14 ], [ 155, 810, 59, 14 ], [ 216, 810, 10, 14 ], [ 229, 810, 26, 14 ], [ 258, 810, 11, 14 ], [ 272, 810, 21, 14 ], [ 296, 810, 33, 14 ], [ 332, 810, 67, 14 ], [ 402, 810, 65, 14 ], [ 470, 810, 11, 14 ], [ 485, 810, 44, 14 ], [ 532, 810, 10, 14 ], [ 545, 810, 20, 14 ], [ 568, 810, 33, 14 ], [ 604, 810, 10, 14 ], [ 616, 810, 75, 14 ], [ 155, 826, 25, 14 ], [ 182, 826, 6, 14 ], [ 191, 826, 24, 14 ], [ 218, 826, 44, 14 ], [ 265, 826, 55, 14 ], [ 323, 826, 6, 14 ], [ 332, 826, 38, 14 ], [ 373, 826, 24, 14 ], [ 400, 826, 30, 14 ], [ 433, 826, 52, 14 ], [ 488, 826, 21, 14 ], [ 512, 826, 23, 14 ], [ 538, 826, 12, 14 ], [ 554, 826, 18, 14 ], [ 575, 826, 30, 14 ], [ 607, 826, 44, 14 ], [ 655, 826, 15, 14 ], [ 673, 826, 18, 14 ], [ 155, 843, 45, 14 ], [ 204, 843, 13, 14 ], [ 221, 843, 13, 14 ], [ 238, 843, 25, 14 ], [ 267, 843, 24, 14 ], [ 295, 843, 75, 14 ], [ 373, 843, 46, 14 ], [ 423, 843, 40, 14 ], [ 467, 843, 18, 14 ], [ 489, 843, 50, 14 ], [ 543, 843, 17, 14 ], [ 563, 843, 82, 14 ], [ 649, 843, 20, 14 ], [ 673, 843, 18, 14 ], [ 155, 859, 54, 14 ], [ 214, 859, 11, 14 ], [ 230, 859, 61, 14 ], [ 296, 859, 50, 14 ], [ 351, 859, 36, 14 ], [ 392, 859, 50, 14 ], [ 448, 859, 15, 14 ], [ 467, 859, 6, 14 ], [ 479, 859, 40, 14 ], [ 523, 859, 33, 14 ], [ 561, 859, 27, 14 ], [ 593, 859, 29, 14 ], [ 627, 859, 7, 14 ], [ 639, 859, 52, 14 ], [ 155, 875, 35, 14 ], [ 194, 875, 66, 14 ], [ 155, 899, 49, 14 ], [ 207, 899, 34, 14 ], [ 244, 899, 21, 14 ], [ 268, 899, 40, 14 ], [ 311, 899, 59, 14 ], [ 372, 899, 37, 14 ], [ 412, 899, 18, 14 ], [ 433, 899, 30, 14 ], [ 466, 899, 44, 14 ], [ 513, 899, 22, 14 ], [ 538, 899, 18, 14 ], [ 559, 899, 24, 14 ], [ 586, 899, 37, 14 ], [ 625, 899, 14, 14 ], [ 642, 899, 49, 14 ], [ 155, 915, 12, 14 ], [ 171, 915, 6, 14 ], [ 182, 915, 43, 14 ], [ 229, 915, 28, 14 ], [ 261, 915, 8, 14 ], [ 274, 915, 21, 14 ], [ 299, 915, 20, 14 ], [ 323, 915, 48, 14 ], [ 376, 915, 28, 14 ], [ 408, 915, 8, 14 ], [ 421, 915, 24, 14 ], [ 449, 915, 22, 14 ], [ 475, 915, 54, 14 ], [ 533, 915, 34, 14 ], [ 571, 915, 11, 14 ], [ 587, 915, 79, 14 ], [ 670, 915, 21, 14 ], [ 155, 931, 31, 14 ], [ 188, 931, 8, 14 ], [ 200, 931, 17, 14 ], [ 220, 931, 38, 14 ], [ 260, 931, 55, 14 ], [ 318, 931, 18, 14 ], [ 339, 931, 54, 14 ], [ 396, 931, 11, 14 ], [ 410, 931, 61, 14 ], [ 474, 931, 50, 14 ], [ 527, 931, 37, 14 ], [ 567, 931, 43, 14 ], [ 613, 931, 28, 14 ], [ 644, 931, 47, 14 ], [ 155, 948, 28, 14 ], [ 187, 948, 8, 14 ], [ 199, 948, 17, 14 ], [ 219, 948, 15, 14 ], [ 238, 948, 40, 14 ], [ 281, 948, 34, 14 ], [ 319, 948, 68, 14 ], [ 390, 948, 45, 14 ], [ 439, 948, 11, 14 ], [ 453, 948, 40, 14 ], [ 497, 948, 48, 14 ], [ 549, 948, 38, 14 ], [ 590, 948, 62, 14 ], [ 656, 948, 35, 14 ], [ 155, 964, 28, 14 ], [ 186, 964, 8, 14 ], [ 198, 964, 21, 14 ], [ 222, 964, 24, 14 ], [ 250, 964, 31, 14 ], [ 284, 964, 45, 14 ], [ 332, 964, 11, 14 ], [ 346, 964, 53, 14 ], [ 403, 964, 48, 14 ], [ 454, 964, 28, 14 ], [ 485, 964, 8, 14 ], [ 497, 964, 21, 14 ], [ 521, 964, 13, 14 ], [ 538, 964, 59, 14 ], [ 600, 964, 48, 14 ], [ 651, 964, 28, 14 ], [ 682, 964, 8, 14 ], [ 155, 980, 24, 14 ], [ 185, 980, 10, 14 ], [ 200, 980, 59, 14 ], [ 264, 980, 64, 14 ], [ 334, 980, 11, 14 ], [ 350, 980, 18, 14 ], [ 374, 980, 34, 14 ], [ 414, 980, 11, 14 ], [ 430, 980, 48, 14 ], [ 484, 980, 24, 14 ], [ 513, 980, 47, 14 ], [ 566, 980, 6, 14 ], [ 577, 980, 53, 14 ], [ 636, 980, 55, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "International", "Journal", "of", "Mental", "Health", "Systems", "Research", "BioMed", "Central", "Open", "Access", "Attitude", "of", "young", "psychiatrists", "toward", "coercive", "measures", "in", "psychiatry:", "a", "case", "vignette", "study", "in", "Japan", "Masaru", "Tateno*1,", "Kanna", "Sugiura2,", "Kumi", "Uehara3,", "Daisuke", "Fujisawa4,", "Yueren", "Zhao5,", "Naoki", "Hashimoto6,", "Hidehiko", "Takahashi7,", "Naofumi", "Yoshida8,", "Takahiro", "Kato9,", "Wakako", "Nakano10,", "Yosuke", "Wake11,", "Tomohiro", "Shirasaka1,", "Seiju", "Kobayashi1", "and", "Soichiro", "Sato12", "Address:", "1Department", "of", "Neuropsychiatry,", "School", "of", "Medicine,", "Sapporo", "Medical", "University,", "South-1,", "West-16,", "Chuo-ku,", "Sapporo,", "Japan", "0608543,", "2Department", "of", "Psychiatry,", "Yokohama", "City", "University,", "Yokohama,", "Japan,", "3Department", "of", "Psychiatry,", "Kanagawa", "Psychiatric", "Center", "Serigaya", "Hospital,", "Yokohama,", "Japan,", "4Department", "of", "Psychiatry,", "School", "of", "Medicine,", "Keio", "University,", "Tokyo,", "Japan,", "5Department", "of", "Psychiatry,", "Meisei", "Hospital,", "Kumamoto,", "Japan,", "6Department", "of", "Psychiatry,", "Hokkaido", "University", "Graduate", "School", "of", "Medicine,", "Sapporo,", "Japan,", "7Department", "of", "Molecular", "Neuroimaging,", "Clinical", "Neuroimaging", "Section,", "National", "Institute", "of", "Radiological", "Sciences,", "Chiba,", "Japan,", "8Department", "of", "Neuropsychiatry,", "Toho", "University,", "School", "of", "Medicine,", "Tokyo,", "Japan,", "9Department", "of", "Neuropsychiatry,", "Graduate", "school", "of", "Medical", "Sciences,", "Kyushu", "University,", "Fukuoka,", "Japan,", "10Department", "of", "Psychiatry,", "University", "of", "Occupational", "and", "Environmental", "Health,", "Kitakyushu,", "Japan,", "11Department", "of", "Neuropsychiatry,", "Okayama", "University", "Graduate", "School", "of", "Medicine,", "Dentistry", "and", "Pharmaceutical", "Sciences,", "Okayama,", "Japan", "and", "12Department", "of", "Psychiatry,", "Zikei", "Hospital,", "Okayama,", "Japan", "Email:", "Masaru", "Tateno*", "-", "tatema@sapmed.ac.jp;", "Kanna", "Sugiura", "-", "kannas@fb3.so-net.ne.jp;", "Kumi", "Uehara", "-", "kums@ballade.plala.or.jp;", "Daisuke", "Fujisawa", "-", "fujisawa@sc.itc.keio.ac.jp;", "Yueren", "Zhao", "-", "taipeeyen@ybb.ne.jp;", "Naoki", "Hashimoto", "-", "hashinao@vega.ocn.ne.jp;", "Hidehiko", "Takahashi", "-", "hidehiko@nirs.go.jp;", "Naofumi", "Yoshida", "-", "nao234@med.toho-u.ac.jp;", "Takahiro", "Kato", "-", "med@jap.com;", "Wakako", "Nakano", "-", "wakako-u@med.uoeh-u.ac.jp;", "Yosuke", "Wake", "-", "yosukewake@yahoo.co.jp;", "Tomohiro", "Shirasaka", "-", "shirasaka.t@sapmed.ac.jp;", "Seiju", "Kobayashi", "-", "seij@pastel.ocn.ne.jp;", "Soichiro", "Sato", "-", "soichiro@ja2.so-net.ne.jp", "*", "Corresponding", "author", "Published:", "22", "September", "2009", "International", "Journal", "of", "Mental", "Health", "Systems", "2009,", "3:20", "doi:10.1186/1752-4458-3-20", "This", "article", "is", "available", "from:", "http://www.ijmhs.com/content/3/1/20", "Received:", "20", "May", "2009", "Accepted:", "22", "September", "2009", "©", "2009", "Tateno", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Every", "psychiatrist", "must", "pay", "careful", "attention", "to", "avoid", "violating", "human", "rights", "when", "initiating", "coercive", "treatments", "such", "as", "seclusion", "and", "restraint.", "However,", "these", "interventions", "are", "indispensable", "in", "clinical", "psychiatry,", "and", "they", "are", "often", "used", "as", "strategies", "to", "treat", "agitated", "patients.", "In", "this", "study,", "we", "investigated", "young", "psychiatrists'", "attitudes", "toward", "psychiatric", "coercive", "measures.", "Methods:", "A", "total", "of", "183", "young", "psychiatrists", "participated", "as", "subjects", "in", "our", "study.", "A", "questionnaire", "with", "a", "case", "vignette", "describing", "a", "patient", "with", "acute", "psychosis", "was", "sent", "to", "the", "study", "subjects", "via", "the", "Internet", "or", "by", "mail.", "This", "questionnaire", "included", "scoring", "the", "necessity", "for", "hospitalization,", "and", "the", "likelihood", "of", "prescribing", "seclusion", "and/or", "restraint,", "on", "a", "9-point", "Likert", "scale", "(with", "9", "indicating", "strong", "agreement).", "Results:", "There", "was", "general", "agreement", "among", "the", "study", "subjects", "that", "the", "case", "should", "be", "admitted", "to", "a", "hospital", "(8.91", "±", "0.3)", "and", "secluded", "(8.43", "±", "1.0).", "The", "estimated", "length", "of", "hospitalization", "was", "13.53", "±", "6.4", "weeks.", "Regarding", "the", "likelihood", "of", "prescribing", "restraint,", "results", "showed", "great", "diversity", "(5.14", "±", "2.5", "on", "9-point", "scale);", "psychiatrists", "working", "at", "general", "hospitals", "scored", "significantly", "higher", "(6.25", "±", "2.5)", "than", "those", "working", "at", "university", "hospitals", "(5.02", "±", "2.3)", "or", "psychiatric", "hospitals", "(4.15", "±", "2.6).", "A", "two-group", "comparison", "of", "the", "length", "of", "inpatient", "care", "revealed", "a", "significant", "difference", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 0, 0, 0, 16, 0, 0, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 129, 134, 139, 34 ], [ 276, 134, 113, 34 ], [ 398, 134, 28, 34 ], [ 434, 134, 113, 34 ], [ 555, 134, 169, 34 ], [ 129, 170, 58, 34 ], [ 195, 170, 167, 34 ], [ 371, 170, 156, 34 ], [ 535, 170, 84, 34 ], [ 627, 170, 110, 34 ], [ 129, 206, 56, 34 ], [ 193, 206, 278, 34 ], [ 480, 206, 101, 34 ], [ 139, 366, 50, 14 ], [ 192, 366, 49, 14 ], [ 244, 366, 52, 14 ], [ 139, 384, 47, 14 ], [ 188, 384, 95, 14 ], [ 139, 402, 35, 14 ], [ 177, 402, 57, 14 ], [ 238, 402, 46, 14 ], [ 287, 402, 55, 14 ], [ 139, 420, 57, 14 ], [ 199, 420, 46, 14 ], [ 247, 420, 47, 14 ], [ 139, 438, 29, 14 ], [ 171, 438, 41, 14 ], [ 215, 438, 47, 14 ], [ 139, 456, 45, 14 ], [ 186, 456, 36, 14 ], [ 225, 456, 60, 14 ], [ 288, 456, 47, 14 ], [ 150, 521, 23, 17 ], [ 214, 521, 1, 17 ], [ 150, 543, 69, 14 ], [ 222, 543, 60, 14 ], [ 285, 543, 14, 14 ], [ 302, 543, 52, 14 ], [ 358, 543, 20, 14 ], [ 381, 543, 35, 14 ], [ 419, 543, 12, 14 ], [ 434, 543, 123, 14 ], [ 560, 543, 43, 14 ], [ 606, 543, 37, 14 ], [ 645, 543, 16, 14 ], [ 664, 543, 20, 14 ], [ 687, 543, 53, 14 ], [ 130, 562, 38, 14 ], [ 171, 562, 25, 14 ], [ 199, 562, 23, 14 ], [ 226, 562, 29, 14 ], [ 259, 562, 23, 14 ], [ 285, 562, 34, 14 ], [ 323, 562, 26, 14 ], [ 352, 562, 12, 14 ], [ 368, 562, 34, 14 ], [ 406, 562, 8, 14 ], [ 417, 562, 46, 14 ], [ 466, 562, 75, 14 ], [ 545, 562, 12, 14 ], [ 560, 562, 64, 14 ], [ 628, 562, 34, 14 ], [ 666, 562, 74, 14 ], [ 130, 582, 54, 14 ], [ 190, 582, 55, 14 ], [ 249, 582, 23, 14 ], [ 277, 582, 31, 14 ], [ 313, 582, 52, 14 ], [ 370, 582, 12, 14 ], [ 387, 582, 64, 14 ], [ 455, 582, 75, 14 ], [ 535, 582, 12, 14 ], [ 552, 582, 39, 14 ], [ 596, 582, 42, 14 ], [ 642, 582, 34, 14 ], [ 681, 582, 20, 14 ], [ 706, 582, 34, 14 ], [ 130, 601, 61, 14 ], [ 195, 601, 25, 14 ], [ 223, 601, 26, 14 ], [ 253, 601, 60, 14 ], [ 316, 601, 12, 14 ], [ 331, 601, 29, 14 ], [ 363, 601, 44, 14 ], [ 411, 601, 30, 14 ], [ 444, 601, 35, 14 ], [ 483, 601, 51, 14 ], [ 537, 601, 15, 14 ], [ 555, 601, 8, 14 ], [ 567, 601, 23, 14 ], [ 594, 601, 8, 14 ], [ 605, 601, 51, 14 ], [ 659, 601, 23, 14 ], [ 685, 601, 55, 14 ], [ 130, 621, 70, 14 ], [ 204, 621, 31, 14 ], [ 238, 621, 39, 14 ], [ 279, 621, 18, 14 ], [ 300, 621, 20, 14 ], [ 323, 621, 44, 14 ], [ 370, 621, 12, 14 ], [ 385, 621, 23, 14 ], [ 411, 621, 75, 14 ], [ 488, 621, 61, 14 ], [ 552, 621, 12, 14 ], [ 567, 621, 73, 14 ], [ 643, 621, 34, 14 ], [ 680, 621, 8, 14 ], [ 691, 621, 50, 14 ], [ 130, 640, 35, 14 ], [ 168, 640, 55, 14 ], [ 225, 640, 54, 14 ], [ 282, 640, 25, 14 ], [ 309, 640, 34, 14 ], [ 346, 640, 16, 14 ], [ 364, 640, 20, 14 ], [ 387, 640, 16, 14 ], [ 405, 640, 23, 14 ], [ 431, 640, 18, 14 ], [ 451, 640, 37, 14 ], [ 491, 640, 15, 14 ], [ 509, 640, 37, 14 ], [ 548, 640, 66, 14 ], [ 616, 640, 12, 14 ], [ 631, 640, 32, 14 ], [ 666, 640, 16, 14 ], [ 684, 640, 20, 14 ], [ 707, 640, 33, 14 ], [ 130, 660, 12, 14 ], [ 146, 660, 74, 14 ], [ 223, 660, 61, 14 ], [ 287, 660, 37, 14 ], [ 328, 660, 15, 14 ], [ 346, 660, 42, 14 ], [ 391, 660, 73, 14 ], [ 467, 660, 12, 14 ], [ 482, 660, 64, 14 ], [ 549, 660, 39, 14 ], [ 150, 679, 58, 14 ], [ 212, 679, 30, 14 ], [ 245, 679, 34, 14 ], [ 282, 679, 8, 14 ], [ 294, 679, 64, 14 ], [ 361, 679, 75, 14 ], [ 439, 679, 31, 14 ], [ 473, 679, 35, 14 ], [ 511, 679, 12, 14 ], [ 526, 679, 15, 14 ], [ 545, 679, 64, 14 ], [ 612, 679, 23, 14 ], [ 639, 679, 46, 14 ], [ 688, 679, 26, 14 ], [ 718, 679, 22, 14 ], [ 130, 699, 21, 14 ], [ 155, 699, 39, 14 ], [ 196, 699, 32, 14 ], [ 231, 699, 8, 14 ], [ 242, 699, 45, 14 ], [ 290, 699, 48, 14 ], [ 341, 699, 37, 14 ], [ 381, 699, 23, 14 ], [ 407, 699, 37, 14 ], [ 447, 699, 46, 14 ], [ 497, 699, 38, 14 ], [ 537, 699, 49, 14 ], [ 589, 699, 42, 14 ], [ 634, 699, 41, 14 ], [ 677, 699, 16, 14 ], [ 696, 699, 23, 14 ], [ 722, 699, 18, 14 ], [ 130, 718, 31, 14 ], [ 163, 718, 76, 14 ], [ 242, 718, 62, 14 ], [ 306, 718, 18, 14 ], [ 327, 718, 24, 14 ], [ 353, 718, 12, 14 ], [ 368, 718, 20, 14 ], [ 390, 718, 49, 14 ], [ 442, 718, 23, 14 ], [ 467, 718, 34, 14 ], [ 503, 718, 24, 14 ], [ 530, 718, 25, 14 ], [ 557, 718, 60, 14 ], [ 619, 718, 30, 14 ], [ 651, 718, 32, 14 ], [ 685, 718, 55, 14 ], [ 130, 737, 29, 14 ], [ 164, 737, 44, 14 ], [ 212, 737, 31, 14 ], [ 246, 737, 26, 14 ], [ 277, 737, 52, 14 ], [ 333, 737, 23, 14 ], [ 360, 737, 46, 14 ], [ 410, 737, 34, 14 ], [ 448, 737, 20, 14 ], [ 472, 737, 34, 14 ], [ 510, 737, 61, 14 ], [ 575, 737, 12, 14 ], [ 592, 737, 24, 14 ], [ 619, 737, 20, 14 ], [ 644, 737, 33, 14 ], [ 681, 737, 12, 14 ], [ 697, 737, 43, 14 ], [ 130, 757, 68, 14 ], [ 202, 757, 30, 14 ], [ 235, 757, 60, 14 ], [ 298, 757, 30, 14 ], [ 331, 757, 15, 14 ], [ 349, 757, 8, 14 ], [ 360, 757, 23, 14 ], [ 386, 757, 8, 14 ], [ 397, 757, 47, 14 ], [ 447, 757, 12, 14 ], [ 462, 757, 36, 14 ], [ 501, 757, 51, 14 ], [ 150, 776, 52, 14 ], [ 205, 776, 18, 14 ], [ 226, 776, 69, 14 ], [ 298, 776, 12, 14 ], [ 313, 776, 16, 14 ], [ 332, 776, 23, 14 ], [ 358, 776, 18, 14 ], [ 379, 776, 31, 14 ], [ 413, 776, 35, 14 ], [ 451, 776, 43, 14 ], [ 496, 776, 20, 14 ], [ 520, 776, 43, 14 ], [ 566, 776, 47, 14 ], [ 615, 776, 23, 14 ], [ 642, 776, 33, 14 ], [ 678, 776, 35, 14 ], [ 716, 776, 24, 14 ], [ 130, 796, 23, 14 ], [ 156, 796, 35, 14 ], [ 194, 796, 113, 14 ], [ 310, 796, 47, 14 ], [ 360, 796, 26, 14 ], [ 388, 796, 37, 14 ], [ 429, 796, 39, 14 ], [ 470, 796, 33, 14 ], [ 505, 796, 8, 14 ], [ 516, 796, 62, 14 ], [ 581, 796, 8, 14 ], [ 592, 796, 74, 14 ], [ 669, 796, 35, 14 ], [ 707, 796, 33, 14 ], [ 130, 815, 30, 14 ], [ 163, 815, 35, 14 ], [ 202, 815, 47, 14 ], [ 252, 815, 47, 14 ], [ 150, 835, 81, 14 ], [ 234, 835, 23, 14 ], [ 260, 835, 50, 14 ], [ 313, 835, 58, 14 ], [ 374, 835, 30, 14 ], [ 407, 835, 20, 14 ], [ 430, 835, 57, 14 ], [ 491, 835, 20, 14 ], [ 515, 835, 84, 14 ], [ 602, 835, 23, 14 ], [ 628, 835, 63, 14 ], [ 694, 835, 23, 14 ], [ 720, 835, 20, 14 ], [ 130, 854, 50, 14 ], [ 184, 854, 47, 14 ], [ 235, 854, 20, 14 ], [ 259, 854, 56, 14 ], [ 319, 854, 12, 14 ], [ 334, 854, 20, 14 ], [ 358, 854, 35, 14 ], [ 397, 854, 44, 14 ], [ 445, 854, 20, 14 ], [ 469, 854, 31, 14 ], [ 503, 854, 52, 14 ], [ 559, 854, 12, 14 ], [ 575, 854, 39, 14 ], [ 618, 854, 12, 14 ], [ 634, 854, 20, 14 ], [ 658, 854, 82, 14 ], [ 130, 874, 55, 14 ], [ 188, 874, 54, 14 ], [ 245, 874, 51, 14 ], [ 299, 874, 27, 14 ], [ 329, 874, 30, 14 ], [ 362, 874, 8, 14 ], [ 373, 874, 47, 14 ], [ 423, 874, 12, 14 ], [ 438, 874, 36, 14 ], [ 477, 874, 51, 14 ], [ 530, 874, 27, 14 ], [ 560, 874, 8, 14 ], [ 570, 874, 30, 14 ], [ 603, 874, 99, 14 ], [ 150, 912, 24, 14 ], [ 177, 912, 43, 14 ], [ 222, 912, 96, 14 ], [ 321, 912, 46, 14 ], [ 370, 912, 31, 14 ], [ 404, 912, 56, 14 ], [ 463, 912, 63, 14 ], [ 529, 912, 88, 14 ], [ 141, 987, 4, 7 ], [ 151, 987, 67, 12 ], [ 220, 987, 10, 12 ], [ 232, 987, 57, 12 ], [ 291, 987, 48, 12 ], [ 342, 987, 26, 12 ], [ 370, 987, 50, 12 ], [ 151, 1001, 10, 12 ], [ 164, 1001, 29, 12 ], [ 195, 1001, 38, 12 ], [ 236, 1001, 29, 12 ], [ 268, 1001, 38, 12 ], [ 309, 1001, 39, 12 ], [ 351, 1001, 39, 12 ], [ 141, 1016, 4, 7 ], [ 151, 1016, 23, 12 ], [ 176, 1016, 46, 12 ], [ 225, 1016, 45, 12 ], [ 272, 1016, 10, 12 ], [ 285, 1016, 61, 12 ], [ 348, 1016, 10, 12 ], [ 360, 1016, 57, 12 ], [ 151, 1031, 48, 12 ], [ 202, 1031, 34, 12 ], [ 239, 1031, 10, 12 ], [ 251, 1031, 48, 12 ], [ 302, 1031, 50, 12 ], [ 355, 1031, 10, 12 ], [ 367, 1031, 54, 12 ], [ 151, 1045, 38, 12 ], [ 141, 1060, 4, 7 ], [ 151, 1060, 65, 12 ], [ 219, 1060, 48, 12 ], [ 269, 1060, 34, 12 ], [ 305, 1060, 102, 12 ], [ 151, 1074, 50, 12 ], [ 204, 1074, 38, 12 ], [ 117, 1108, 28, 13 ], [ 148, 1108, 27, 13 ], [ 177, 1108, 6, 13 ], [ 186, 1108, 28, 13 ], [ 461, 985, 4, 7 ], [ 470, 984, 46, 12 ], [ 519, 984, 23, 12 ], [ 545, 984, 46, 12 ], [ 594, 984, 48, 12 ], [ 644, 984, 61, 12 ], [ 707, 984, 10, 12 ], [ 470, 999, 48, 12 ], [ 521, 999, 26, 12 ], [ 550, 999, 50, 12 ], [ 603, 999, 10, 12 ], [ 616, 999, 29, 12 ], [ 648, 999, 38, 12 ], [ 688, 999, 38, 12 ], [ 461, 1014, 73, 12 ], [ 536, 1014, 36, 12 ], [ 575, 1014, 14, 12 ], [ 591, 1014, 39, 12 ], [ 633, 1014, 38, 12 ], [ 673, 1014, 38, 12 ], [ 461, 1028, 23, 12 ], [ 489, 1028, 63, 12 ], [ 556, 1028, 25, 12 ], [ 586, 1028, 18, 12 ], [ 609, 1028, 6, 12 ], [ 620, 1028, 36, 12 ], [ 660, 1028, 24, 12 ], [ 689, 1028, 54, 12 ], [ 461, 1043, 29, 12 ], [ 491, 1043, 37, 12 ], [ 530, 1043, 38, 12 ], [ 570, 1043, 37, 12 ], [ 461, 1057, 18, 12 ], [ 481, 1057, 18, 12 ], [ 500, 1057, 12, 12 ], [ 515, 1057, 23, 12 ], [ 540, 1057, 23, 12 ], [ 461, 1072, 32, 12 ], [ 495, 1072, 154, 12 ], [ 475, 1124, 23, 14 ], [ 502, 1112, 37, 9 ], [ 540, 1112, 29, 9 ], [ 571, 1112, 8, 9 ], [ 580, 1112, 35, 9 ] ]

[ "Interfacial", "integrity", "of", "bonded", "restorations", "with", "self-etching", "adhesives:", "Water", "storage", "and", "thermo-mechanical", "cycling", "Gislaine", "Cristine", "Martins1", "Alfonso", "Sánchez-Ayala2", "Paulo", "Henrique", "Perlatti", "D’Alpino3", "Abraham", "Lincoln", "Calixto4", "João", "Carlos", "Gomes4", "Osnara", "Maria", "Mongruel", "Gomes4", "AbstrA", "tc", "Objectives:", "Objective:", "To", "evaluate", "the", "effect", "of", "thermo-mechanical", "cycling", "(TMC)", "on", "the", "microle-", "akage", "(µL)", "and", "axial", "gap", "width", "(AG)", "of", "Class", "V", "bonded", "restorations", "in", "premolars", "using", "self-etching", "adhesive", "systems.", "The", "bond", "strength", "of", "composite", "restorations", "to", "dentin", "(µTBS)", "using", "the", "same", "adhesives", "was", "also", "evaluated", "in", "third", "molars", "after", "water", "storage:", "24", "h", "and", "6", "months.", "The", "research", "hypotheses", "were", "tested", "for", "the", "results", "of", "two", "self-etching", "adhesives", "in", "comparison", "when", "a", "conven-", "tional", "two-step", "adhesive", "was", "used:", "(1)", "the", "µL", "and", "AG", "would", "be", "lower,", "regardless", "of", "TMC;", "(2)", "the", "µTBS", "of", "self-etching", "adhesives", "would", "be", "higher,", "irrespective", "of", "evaluation", "times.", "Methods:", "Sixty", "Class", "V", "composite", "restorations", "were", "made", "in", "30", "premolars", "and", "bonded", "with", "Ad-", "per", "Single", "Bond", "2", "(ASB2),", "AdheSE", "(ASE),", "and", "Adper", "Prompt", "L-Pop", "(APL-P)", "(n=20).", "Dentin", "µL", "and", "AG", "were", "immediately", "measured", "for", "half", "of", "the", "sample.", "The", "other", "half", "was", "evaluated", "after", "TMC.", "Eighteen", "third", "molars", "were", "also", "selected", "and", "bonded", "using", "the", "same", "adhesives", "to", "test", "the", "µTBS", "to", "dentin.", "Specimens", "were", "evaluated", "after", "24", "h", "and", "6", "months", "of", "water", "storage.", "Results:", "No", "differences", "in", "µL", "and", "AG", "were", "found", "among", "the", "groups", "(P>.05).", "The", "µTBS", "mean", "val-", "ues", "were:", "ASB2>ASE>APL-P", "(P<.05);", "only", "Adper", "Single", "Bond", "2", "presented", "a", "significantly", "lower", "µTBS", "after", "water", "storage", "(P<.05).", "Conclusions:", "The", "bonding", "approach", "does", "not", "influence", "the", "microleakage", "and", "interfacial", "gap", "ex-", "tension.", "Despite", "the", "decrease", "in", "the", "mean", "values,", "the", "bond", "strength", "to", "dentin", "of", "the", "conventional,", "two-step", "adhesive", "remains", "high", "after", "6", "months", "of", "water", "storage.", "(Eur", "J", "Dent", "2012;6:169-177)", "Key", "words:", "Dentin-bonding", "agents;", "bond", "strength;", "durability;", "microleakage.", "1", "Departament", "of", "Restorative", "Dentistry,", "State", "University", "of", "Ponta", "Grossa,", "Ponta", "Grossa,", "Paraná,", "BRASIL", "2", "Post", "Graduate", "Program", "in", "Department", "of", "Prosthetics", "Dentistry,", "School", "of", "Dentistry,", "University", "of", "Campinas,", "BRAZIL", "3", "Biomaterials", "Research", "Group,", "Anhanguera-Uniban", "University", "BRAZIL", "April", "2012", "-", "Vol.6", "4", "Dentistry", "Post", "Graduate", "Program,", "Department", "of", "Dentistry,", "State", "University", "of", "Ponta", "Grossa,", "BRAZIL", "Corresponding", "author:", "Dr.", "Gislaine", "Cristine", "Martins", "Rua:", "Comendador", "Miró,", "711", "–", "Centro,", "CEP:", "84010-160,", "Ponta", "Grossa,", "Paraná,", "BRASIL", "Tel:", "+55", "42", "3224", "5306", "Email:", "gislainecmartins@yahoo.com.br", "169", "European", "Journal", "of", "Dentistry" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 4, 0, 0, 0, 0 ]

[ [ 76, 47, 172, 34 ], [ 260, 47, 33, 34 ], [ 305, 47, 140, 34 ], [ 76, 118, 70, 20 ], [ 76, 143, 142, 23 ], [ 224, 143, 20, 23 ], [ 250, 143, 161, 23 ], [ 417, 143, 103, 23 ], [ 526, 143, 20, 23 ], [ 552, 143, 36, 23 ], [ 594, 143, 19, 23 ], [ 619, 143, 113, 23 ], [ 76, 168, 108, 23 ], [ 190, 168, 90, 23 ], [ 285, 168, 74, 23 ], [ 365, 168, 150, 23 ], [ 520, 168, 59, 23 ], [ 585, 168, 19, 23 ], [ 610, 168, 12, 23 ], [ 628, 168, 122, 23 ], [ 76, 193, 68, 23 ], [ 149, 193, 126, 23 ], [ 281, 193, 97, 23 ], [ 384, 193, 52, 23 ], [ 441, 193, 59, 23 ], [ 506, 193, 52, 23 ], [ 563, 193, 20, 23 ], [ 589, 193, 52, 23 ], [ 647, 193, 50, 23 ], [ 702, 193, 20, 23 ], [ 729, 193, 35, 23 ], [ 76, 218, 86, 23 ], [ 168, 218, 61, 23 ], [ 234, 218, 61, 23 ], [ 76, 243, 42, 21 ], [ 123, 243, 13, 21 ], [ 141, 243, 23, 21 ], [ 169, 243, 31, 21 ], [ 205, 243, 50, 21 ], [ 259, 243, 34, 21 ], [ 298, 243, 12, 21 ], [ 315, 243, 52, 21 ], [ 372, 243, 35, 21 ], [ 411, 243, 36, 21 ], [ 452, 243, 7, 21 ], [ 464, 243, 35, 21 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 293, 41, 12 ], [ 119, 293, 24, 12 ], [ 145, 293, 18, 12 ], [ 165, 293, 53, 12 ], [ 220, 293, 10, 12 ], [ 232, 293, 52, 12 ], [ 286, 293, 38, 12 ], [ 327, 293, 19, 12 ], [ 348, 293, 73, 12 ], [ 423, 293, 40, 12 ], [ 465, 293, 10, 12 ], [ 478, 293, 71, 12 ], [ 550, 293, 39, 12 ], [ 592, 293, 44, 12 ], [ 638, 293, 10, 12 ], [ 651, 293, 43, 12 ], [ 696, 293, 39, 12 ], [ 736, 293, 30, 12 ], [ 76, 306, 42, 11 ], [ 121, 306, 40, 11 ], [ 164, 306, 14, 11 ], [ 180, 306, 30, 11 ], [ 76, 326, 31, 12 ], [ 110, 326, 22, 12 ], [ 135, 326, 7, 12 ], [ 144, 326, 10, 12 ], [ 156, 326, 4, 12 ], [ 163, 326, 78, 12 ], [ 243, 326, 17, 12 ], [ 262, 326, 24, 12 ], [ 288, 326, 4, 12 ], [ 295, 326, 89, 12 ], [ 386, 326, 18, 12 ], [ 407, 326, 6, 12 ], [ 415, 326, 28, 12 ], [ 446, 326, 4, 12 ], [ 452, 326, 92, 12 ], [ 547, 326, 19, 12 ], [ 568, 326, 4, 12 ], [ 575, 326, 18, 12 ], [ 596, 326, 4, 12 ], [ 602, 326, 83, 12 ], [ 76, 342, 7, 12 ], [ 85, 342, 73, 12 ], [ 160, 342, 33, 12 ], [ 76, 401, 45, 12 ], [ 124, 401, 12, 12 ], [ 138, 401, 23, 12 ], [ 164, 401, 23, 12 ], [ 76, 421, 37, 12 ], [ 116, 421, 8, 12 ], [ 127, 421, 31, 12 ], [ 160, 421, 25, 12 ], [ 188, 421, 20, 12 ], [ 220, 421, 128, 12 ], [ 76, 440, 20, 12 ], [ 98, 440, 28, 12 ], [ 129, 440, 7, 12 ], [ 139, 440, 38, 12 ], [ 179, 440, 25, 12 ], [ 207, 440, 235, 12 ], [ 430, 401, 43, 12 ], [ 476, 401, 6, 12 ], [ 484, 401, 40, 12 ], [ 527, 401, 23, 12 ], [ 430, 414, 46, 12 ], [ 478, 414, 12, 12 ], [ 492, 414, 23, 12 ], [ 517, 414, 23, 12 ], [ 76, 460, 9, 12 ], [ 87, 460, 23, 12 ], [ 113, 460, 8, 12 ], [ 124, 460, 10, 12 ], [ 136, 460, 10, 12 ], [ 148, 460, 36, 12 ], [ 187, 460, 35, 12 ], [ 225, 460, 35, 12 ], [ 262, 460, 18, 12 ], [ 76, 473, 20, 12 ], [ 98, 473, 7, 12 ], [ 108, 473, 11, 12 ], [ 121, 473, 26, 12 ], [ 150, 473, 32, 12 ], [ 184, 473, 28, 12 ], [ 215, 473, 49, 12 ], [ 267, 473, 27, 12 ], [ 296, 473, 15, 12 ], [ 314, 473, 27, 12 ], [ 343, 473, 10, 12 ], [ 355, 473, 15, 12 ], [ 373, 473, 39, 12 ], [ 415, 473, 48, 12 ], [ 465, 473, 51, 12 ], [ 519, 473, 34, 12 ], [ 555, 473, 202, 12 ], [ 76, 487, 27, 12 ], [ 106, 487, 35, 12 ], [ 143, 487, 56, 12 ], [ 201, 487, 18, 12 ], [ 222, 487, 55, 12 ], [ 279, 487, 16, 12 ], [ 298, 487, 60, 12 ], [ 361, 487, 8, 12 ], [ 372, 487, 16, 12 ], [ 390, 487, 39, 12 ], [ 432, 487, 40, 12 ], [ 475, 487, 15, 12 ], [ 493, 487, 34, 12 ], [ 529, 487, 24, 12 ], [ 556, 487, 7, 12 ], [ 565, 487, 39, 12 ], [ 607, 487, 25, 12 ], [ 96, 547, 61, 15 ], [ 96, 568, 80, 14 ], [ 181, 568, 41, 14 ], [ 228, 568, 76, 14 ], [ 310, 568, 23, 14 ], [ 338, 568, 32, 14 ], [ 375, 568, 10, 14 ], [ 391, 568, 18, 14 ], [ 415, 568, 54, 14 ], [ 474, 568, 11, 14 ], [ 491, 568, 47, 14 ], [ 544, 568, 11, 14 ], [ 561, 568, 43, 14 ], [ 610, 568, 70, 14 ], [ 686, 568, 13, 14 ], [ 704, 568, 45, 14 ], [ 96, 584, 59, 14 ], [ 157, 584, 21, 14 ], [ 181, 584, 20, 14 ], [ 204, 584, 48, 14 ], [ 255, 584, 41, 14 ], [ 299, 584, 11, 14 ], [ 313, 584, 42, 14 ], [ 359, 584, 11, 14 ], [ 372, 584, 18, 14 ], [ 394, 584, 29, 14 ], [ 425, 584, 26, 14 ], [ 454, 584, 11, 14 ], [ 468, 584, 18, 14 ], [ 489, 584, 44, 14 ], [ 536, 584, 30, 14 ], [ 568, 584, 10, 14 ], [ 582, 584, 35, 14 ], [ 620, 584, 29, 14 ], [ 652, 584, 30, 14 ], [ 686, 584, 33, 14 ], [ 721, 584, 29, 14 ], [ 96, 600, 27, 14 ], [ 127, 600, 58, 14 ], [ 188, 600, 24, 14 ], [ 216, 600, 18, 14 ], [ 239, 600, 30, 14 ], [ 272, 600, 25, 14 ], [ 301, 600, 44, 14 ], [ 349, 600, 43, 14 ], [ 395, 600, 28, 14 ], [ 427, 600, 18, 14 ], [ 449, 600, 33, 14 ], [ 486, 600, 27, 14 ], [ 517, 600, 18, 14 ], [ 539, 600, 27, 14 ], [ 569, 600, 13, 14 ], [ 586, 600, 18, 14 ], [ 608, 600, 70, 14 ], [ 682, 600, 11, 14 ], [ 697, 600, 29, 14 ], [ 730, 600, 20, 14 ], [ 96, 617, 39, 14 ], [ 137, 617, 24, 14 ], [ 164, 617, 29, 14 ], [ 196, 617, 32, 14 ], [ 231, 617, 27, 14 ], [ 260, 617, 58, 14 ], [ 321, 617, 22, 14 ], [ 346, 617, 40, 14 ], [ 388, 617, 26, 14 ], [ 417, 617, 13, 14 ], [ 432, 617, 26, 14 ], [ 461, 617, 80, 14 ], [ 543, 617, 34, 14 ], [ 579, 617, 43, 14 ], [ 624, 617, 44, 14 ], [ 670, 617, 25, 14 ], [ 698, 617, 51, 14 ], [ 96, 633, 60, 14 ], [ 160, 633, 18, 14 ], [ 183, 633, 52, 14 ], [ 240, 633, 11, 14 ], [ 256, 633, 19, 14 ], [ 279, 633, 48, 14 ], [ 331, 633, 18, 14 ], [ 354, 633, 27, 14 ], [ 385, 633, 20, 14 ], [ 409, 633, 27, 14 ], [ 441, 633, 20, 14 ], [ 465, 633, 22, 14 ], [ 491, 633, 37, 14 ], [ 532, 633, 30, 14 ], [ 567, 633, 11, 14 ], [ 582, 633, 20, 14 ], [ 607, 633, 33, 14 ], [ 644, 633, 18, 14 ], [ 666, 633, 83, 14 ], [ 96, 649, 48, 14 ], [ 148, 649, 70, 14 ], [ 222, 649, 29, 14 ], [ 255, 649, 65, 14 ], [ 324, 649, 10, 14 ], [ 338, 649, 6, 14 ], [ 349, 649, 65, 14 ], [ 418, 649, 22, 14 ], [ 444, 649, 18, 14 ], [ 466, 649, 62, 14 ], [ 533, 649, 35, 14 ], [ 572, 649, 65, 14 ], [ 640, 649, 52, 14 ], [ 696, 649, 27, 14 ], [ 728, 649, 22, 14 ], [ 96, 666, 58, 14 ], [ 157, 666, 20, 14 ], [ 181, 666, 19, 14 ], [ 204, 666, 43, 14 ], [ 251, 666, 27, 14 ], [ 282, 666, 10, 14 ], [ 297, 666, 18, 14 ], [ 319, 666, 29, 14 ], [ 351, 666, 26, 14 ], [ 381, 666, 10, 14 ], [ 395, 666, 32, 14 ], [ 431, 666, 12, 14 ], [ 448, 666, 35, 14 ], [ 487, 666, 18, 14 ], [ 509, 666, 31, 14 ], [ 544, 666, 11, 14 ], [ 559, 666, 22, 14 ], [ 585, 666, 76, 14 ], [ 666, 666, 15, 14 ], [ 684, 666, 18, 14 ], [ 706, 666, 43, 14 ], [ 96, 682, 73, 14 ], [ 96, 705, 49, 14 ], [ 148, 705, 10, 14 ], [ 161, 705, 26, 14 ], [ 189, 705, 11, 14 ], [ 204, 705, 14, 14 ], [ 221, 705, 40, 14 ], [ 263, 705, 11, 14 ], [ 277, 705, 53, 14 ], [ 334, 705, 29, 14 ], [ 365, 705, 51, 14 ], [ 419, 705, 10, 14 ], [ 433, 705, 18, 14 ], [ 454, 705, 46, 14 ], [ 504, 705, 20, 14 ], [ 526, 705, 47, 14 ], [ 577, 705, 11, 14 ], [ 591, 705, 9, 14 ], [ 603, 705, 49, 14 ], [ 655, 705, 27, 14 ], [ 685, 705, 31, 14 ], [ 719, 705, 31, 14 ], [ 96, 722, 48, 14 ], [ 147, 722, 22, 14 ], [ 172, 722, 27, 14 ], [ 202, 722, 58, 14 ], [ 262, 722, 24, 14 ], [ 290, 722, 18, 14 ], [ 310, 722, 44, 14 ], [ 357, 722, 32, 14 ], [ 392, 722, 16, 14 ], [ 410, 722, 39, 14 ], [ 452, 722, 20, 14 ], [ 475, 722, 51, 14 ], [ 528, 722, 30, 14 ], [ 561, 722, 20, 14 ], [ 584, 722, 19, 14 ], [ 606, 722, 43, 14 ], [ 651, 722, 30, 14 ], [ 684, 722, 16, 14 ], [ 703, 722, 47, 14 ], [ 96, 738, 40, 14 ], [ 139, 738, 50, 14 ], [ 192, 738, 45, 14 ], [ 241, 738, 20, 14 ], [ 264, 738, 34, 14 ], [ 301, 738, 30, 14 ], [ 335, 738, 30, 14 ], [ 368, 738, 48, 14 ], [ 420, 738, 57, 14 ], [ 480, 738, 20, 14 ], [ 503, 738, 47, 14 ], [ 553, 738, 11, 14 ], [ 567, 738, 48, 14 ], [ 619, 738, 70, 14 ], [ 692, 738, 10, 14 ], [ 706, 738, 44, 14 ], [ 96, 754, 20, 14 ], [ 120, 754, 51, 14 ], [ 174, 754, 27, 14 ], [ 205, 754, 21, 14 ], [ 230, 754, 32, 14 ], [ 266, 754, 24, 14 ], [ 294, 754, 10, 14 ], [ 308, 754, 18, 14 ], [ 330, 754, 31, 14 ], [ 365, 754, 19, 14 ], [ 388, 754, 30, 14 ], [ 422, 754, 22, 14 ], [ 448, 754, 55, 14 ], [ 507, 754, 74, 14 ], [ 585, 754, 62, 14 ], [ 651, 754, 21, 14 ], [ 676, 754, 18, 14 ], [ 698, 754, 52, 14 ], [ 96, 771, 40, 14 ], [ 140, 771, 11, 14 ], [ 157, 771, 70, 14 ], [ 232, 771, 10, 14 ], [ 248, 771, 12, 14 ], [ 265, 771, 18, 14 ], [ 288, 771, 31, 14 ], [ 325, 771, 30, 14 ], [ 360, 771, 19, 14 ], [ 384, 771, 54, 14 ], [ 443, 771, 54, 14 ], [ 502, 771, 10, 14 ], [ 517, 771, 18, 14 ], [ 541, 771, 93, 14 ], [ 639, 771, 30, 14 ], [ 675, 771, 21, 14 ], [ 701, 771, 49, 14 ], [ 96, 787, 48, 14 ], [ 147, 787, 58, 14 ], [ 208, 787, 27, 14 ], [ 238, 787, 32, 14 ], [ 274, 787, 20, 14 ], [ 297, 787, 43, 14 ], [ 343, 787, 27, 14 ], [ 374, 787, 35, 14 ], [ 413, 787, 22, 14 ], [ 438, 787, 50, 14 ], [ 491, 787, 11, 14 ], [ 506, 787, 48, 14 ], [ 557, 787, 70, 14 ], [ 630, 787, 48, 14 ], [ 681, 787, 45, 14 ], [ 730, 787, 20, 14 ], [ 96, 803, 34, 14 ], [ 133, 803, 27, 14 ], [ 164, 803, 21, 14 ], [ 188, 803, 18, 14 ], [ 210, 803, 39, 14 ], [ 252, 803, 49, 14 ], [ 304, 803, 20, 14 ], [ 327, 803, 18, 14 ], [ 349, 803, 37, 14 ], [ 389, 803, 21, 14 ], [ 414, 803, 48, 14 ], [ 464, 803, 47, 14 ], [ 515, 803, 20, 14 ], [ 538, 803, 51, 14 ], [ 592, 803, 27, 14 ], [ 623, 803, 49, 14 ], [ 675, 803, 22, 14 ], [ 700, 803, 50, 14 ], [ 96, 820, 21, 14 ], [ 120, 820, 21, 14 ], [ 144, 820, 48, 14 ], [ 195, 820, 51, 14 ], [ 249, 820, 20, 14 ], [ 273, 820, 18, 14 ], [ 294, 820, 31, 14 ], [ 329, 820, 30, 14 ], [ 362, 820, 20, 14 ], [ 385, 820, 18, 14 ], [ 407, 820, 49, 14 ], [ 460, 820, 56, 14 ], [ 519, 820, 24, 14 ], [ 547, 820, 18, 14 ], [ 569, 820, 60, 14 ], [ 631, 820, 45, 14 ], [ 680, 820, 37, 14 ], [ 720, 820, 30, 14 ], [ 96, 836, 30, 14 ], [ 129, 836, 22, 14 ], [ 153, 836, 48, 14 ], [ 204, 836, 62, 14 ], [ 268, 836, 10, 14 ], [ 281, 836, 21, 14 ], [ 305, 836, 58, 14 ], [ 365, 836, 25, 14 ], [ 393, 836, 39, 14 ], [ 435, 836, 26, 14 ], [ 463, 836, 21, 14 ], [ 487, 836, 51, 14 ], [ 541, 836, 24, 14 ], [ 568, 836, 43, 14 ], [ 613, 836, 30, 14 ], [ 646, 836, 19, 14 ], [ 667, 836, 18, 14 ], [ 688, 836, 62, 14 ], [ 96, 852, 10, 14 ], [ 109, 852, 50, 14 ], [ 163, 852, 26, 14 ], [ 192, 852, 21, 14 ], [ 217, 852, 54, 14 ], [ 274, 852, 10, 14 ], [ 287, 852, 18, 14 ], [ 309, 852, 26, 14 ], [ 96, 875, 74, 14 ], [ 174, 875, 22, 14 ], [ 200, 875, 50, 14 ], [ 254, 875, 10, 14 ], [ 268, 875, 18, 14 ], [ 291, 875, 48, 14 ], [ 343, 875, 70, 14 ], [ 418, 875, 11, 14 ], [ 433, 875, 20, 14 ], [ 457, 875, 19, 14 ], [ 480, 875, 10, 14 ], [ 495, 875, 18, 14 ], [ 517, 875, 58, 14 ], [ 579, 875, 27, 14 ], [ 611, 875, 23, 14 ], [ 638, 875, 14, 14 ], [ 656, 875, 55, 14 ], [ 715, 875, 12, 14 ], [ 732, 875, 18, 14 ], [ 96, 892, 50, 14 ], [ 149, 892, 62, 14 ], [ 214, 892, 11, 14 ], [ 228, 892, 30, 14 ], [ 261, 892, 43, 14 ], [ 307, 892, 20, 14 ], [ 330, 892, 12, 14 ], [ 345, 892, 18, 14 ], [ 367, 892, 62, 14 ], [ 432, 892, 11, 14 ], [ 446, 892, 18, 14 ], [ 468, 892, 53, 14 ], [ 524, 892, 11, 14 ], [ 538, 892, 20, 14 ], [ 561, 892, 19, 14 ], [ 583, 892, 11, 14 ], [ 598, 892, 23, 14 ], [ 623, 892, 11, 14 ], [ 638, 892, 18, 14 ], [ 659, 892, 48, 14 ], [ 710, 892, 40, 14 ], [ 96, 908, 34, 14 ], [ 133, 908, 18, 14 ], [ 155, 908, 65, 14 ], [ 223, 908, 46, 14 ], [ 273, 908, 22, 14 ], [ 298, 908, 47, 14 ], [ 348, 908, 20, 14 ], [ 371, 908, 18, 14 ], [ 393, 908, 48, 14 ], [ 445, 908, 46, 14 ], [ 494, 908, 10, 14 ], [ 508, 908, 18, 14 ], [ 530, 908, 48, 14 ], [ 581, 908, 70, 14 ], [ 655, 908, 19, 14 ], [ 678, 908, 14, 14 ], [ 695, 908, 39, 14 ], [ 737, 908, 12, 14 ], [ 96, 924, 18, 14 ], [ 118, 924, 21, 14 ], [ 143, 924, 11, 14 ], [ 158, 924, 20, 14 ], [ 181, 924, 22, 14 ], [ 207, 924, 20, 14 ], [ 230, 924, 13, 14 ], [ 247, 924, 18, 14 ], [ 269, 924, 53, 14 ], [ 325, 924, 20, 14 ], [ 349, 924, 68, 14 ], [ 421, 924, 57, 14 ], [ 482, 924, 11, 14 ], [ 497, 924, 18, 14 ], [ 519, 924, 46, 14 ], [ 569, 924, 22, 14 ], [ 594, 924, 22, 14 ], [ 620, 924, 46, 14 ], [ 670, 924, 27, 14 ], [ 701, 924, 18, 14 ], [ 723, 924, 26, 14 ], [ 96, 941, 20, 14 ], [ 119, 941, 25, 14 ], [ 147, 941, 57, 14 ], [ 208, 941, 30, 14 ], [ 241, 941, 15, 14 ], [ 259, 941, 18, 14 ], [ 281, 941, 48, 14 ], [ 332, 941, 70, 14 ], [ 406, 941, 11, 14 ], [ 420, 941, 18, 14 ], [ 442, 941, 35, 14 ], [ 480, 941, 10, 14 ], [ 493, 941, 58, 14 ], [ 555, 941, 27, 14 ], [ 586, 941, 11, 14 ], [ 600, 941, 18, 14 ], [ 622, 941, 44, 14 ], [ 668, 941, 32, 14 ], [ 704, 941, 22, 14 ], [ 729, 941, 21, 14 ], [ 96, 957, 58, 14 ], [ 157, 957, 10, 14 ], [ 171, 957, 48, 14 ], [ 222, 957, 70, 14 ], [ 296, 957, 48, 14 ], [ 347, 957, 18, 14 ], [ 368, 957, 50, 14 ], [ 422, 957, 26, 14 ], [ 452, 957, 20, 14 ], [ 475, 957, 36, 14 ], [ 514, 957, 23, 14 ], [ 540, 957, 20, 14 ], [ 564, 957, 14, 14 ], [ 580, 957, 6, 14 ], [ 590, 957, 53, 14 ], [ 646, 957, 11, 14 ], [ 661, 957, 13, 14 ], [ 677, 957, 37, 14 ], [ 718, 957, 32, 14 ], [ 96, 973, 70, 14 ], [ 169, 973, 20, 14 ], [ 193, 973, 79, 14 ], [ 275, 973, 58, 14 ], [ 336, 973, 13, 14 ], [ 353, 973, 76, 14 ], [ 433, 973, 10, 14 ], [ 446, 973, 20, 14 ], [ 469, 973, 25, 14 ], [ 705, 1052, 30, 13 ], [ 738, 1052, 7, 13 ], [ 748, 1052, 11, 13 ], [ 762, 1052, 7, 13 ], [ 599, 1070, 25, 10 ], [ 627, 1070, 33, 10 ], [ 662, 1070, 14, 10 ], [ 678, 1070, 12, 10 ], [ 692, 1070, 31, 10 ], [ 726, 1070, 44, 10 ] ]

[ "Parasites", "&", "Vectors", "Research", "Communities", "of", "gastrointestinal", "helminths", "of", "fish", "in", "historically", "connected", "habitats:", "habitat", "fragmentation", "effect", "in", "a", "carnivorous", "catfish", "Pelteobagrus", "fulvidraco", "from", "seven", "lakes", "in", "flood", "plain", "of", "the", "Yangtze", "River,", "China", "Wen", "X", "Li,", "Pin", "Nie*,", "Gui", "T", "Wang", "and", "Wei", "J", "Yao", "BioMed", "Central", "Open", "Access", "Address:", "State", "Key", "Laboratory", "of", "Freshwater", "Ecology", "and", "Biotechnology,", "Institute", "of", "Hydrobiology,", "Chinese", "Academy", "of", "Sciences,", "Wuhan,", "Hubei", "Province", "430072,", "PR", "China", "Email:", "Wen", "X", "Li", "-", "liwx@ihb.ac.cn;", "Pin", "Nie*", "-", "pinnie@ihb.ac.cn;", "Gui", "T", "Wang", "-", "gtwang@ihb.ac.cn;", "Wei", "J", "Yao", "-", "wjyao@ihb.ac.cn", "*", "Corresponding", "author", "Published:", "27", "April", "2009", "Parasites", "&", "Vectors", "2009,", "2:22", "doi:10.1186/1756-3305-2-22", "This", "article", "is", "available", "from:", "http://www.parasitesandvectors.com/content/2/1/22", "Received:", "4", "February", "2009", "Accepted:", "27", "April", "2009", "©", "2009", "Li", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Background:", "Habitat", "fragmentation", "may", "result", "in", "the", "reduction", "of", "diversity", "of", "parasite", "communities", "by", "affecting", "population", "size", "and", "dispersal", "pattern", "of", "species.", "In", "the", "flood", "plain", "of", "the", "Yangtze", "River", "in", "China,", "many", "lakes,", "which", "were", "once", "connected", "with", "the", "river,", "have", "become", "isolated", "since", "the", "1950s", "from", "the", "river", "by", "the", "construction", "of", "dams", "and", "sluices,", "with", "many", "larger", "lakes", "subdivided", "into", "smaller", "ones", "by", "road", "embankments.", "These", "artificial", "barriers", "have", "inevitably", "obstructed", "the", "migration", "of", "fish", "between", "the", "river", "and", "lakes", "and", "also", "among", "lakes.", "In", "this", "study,", "the", "gastrointestinal", "helminth", "communities", "were", "investigated", "in", "a", "carnivorous", "fish,", "the", "yellowhead", "catfish", "Pelteobagrus", "fulvidraco,", "from", "two", "connected", "and", "five", "isolated", "lakes", "in", "the", "flood", "plain", "in", "order", "to", "detect", "the", "effect", "of", "lake", "fragmentation", "on", "the", "parasite", "communities.", "Results:", "A", "total", "of", "11", "species", "of", "helminths", "were", "recorded", "in", "the", "stomach", "and", "intestine", "of", "P.", "fulvidraco", "from", "seven", "lakes,", "including", "two", "lakes", "connected", "with", "the", "Yangtze", "River,", "i.e.", "Poyang", "and", "Dongting", "lakes,", "and", "five", "isolated", "lakes,", "i.e.", "Honghu,", "Liangzi,", "Tangxun,", "Niushan", "and", "Baoan", "lakes.", "Mean", "helminth", "individuals", "and", "diversity", "of", "helminth", "communities", "in", "Honghu", "and", "Dongting", "lakes", "was", "lower", "than", "in", "the", "other", "five", "lakes.", "The", "nematode", "Procamallanus", "fulvidraconis", "was", "the", "dominant", "species", "of", "communities", "in", "all", "the", "seven", "lakes.", "No", "significant", "difference", "in", "the", "Shannon-Wiener", "index", "was", "detected", "between", "connected", "lakes", "(0.48)", "and", "isolated", "lakes", "(0.50).", "The", "similarity", "of", "helminth", "communities", "between", "Niushan", "and", "Baoan", "lakes", "was", "the", "highest", "(0.6708),", "and", "the", "lowest", "was", "between", "Tangxun", "and", "Dongting", "lakes", "(0.1807).", "The", "similarity", "was", "low", "between", "Dongting", "and", "the", "other", "lakes,", "and", "the", "similarity", "decreased", "with", "the", "geographic", "distance", "among", "these", "lakes.", "The", "helminth", "community", "in", "one", "connected", "lake,", "Poyang", "Lake", "was", "clustered", "with", "isolated", "lakes,", "but", "the", "community", "in", "Dongting", "Lake", "was", "separated", "in", "the", "tree.", "Conclusion:", "The", "similarity", "in", "the", "helminth", "communities", "of", "this", "fish", "in", "the", "flood-plain", "lakes", "may", "be", "attributed", "to", "the", "historical", "connection", "of", "these", "habitats", "and", "to", "the", "completion", "of", "the", "life-cycles", "of", "this", "fish", "as", "well", "as", "the", "helminth", "species", "within", "the", "investigated", "habitats.", "The", "diversity", "and", "the", "digenean", "majority", "in", "the", "helminth", "communities", "can", "be", "related", "to", "the", "diet", "of", "this", "fish,", "and", "to", "the", "lacustrine", "and", "macrophytic", "characters", "of", "the", "habitats.", "The", "lake", "isolation", "from", "the", "river", "had", "little", "detectable", "effect", "on", "the", "helminth", "communities", "of", "the", "catfish", "in", "flood-plain", "lakes", "of", "the", "Yangtze", "River.", "The", "low", "similarities", "in", "helminth", "communities", "between", "the", "Dongting", "Lake", "and", "others", "may", "just", "be", "a", "reflection", "of", "its", "unique", "water", "environment", "and", "anthropogenic", "alterations", "or", "fragmentation", "in", "this", "lake.", "Page", "1", "of", "7", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 9, 9, 9, 9, 9, 9, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 64, 118, 9, 12 ], [ 78, 118, 20, 12 ], [ 104, 118, 19, 12 ], [ 128, 118, 36, 12 ], [ 169, 118, 30, 12 ], [ 213, 117, 19, 13 ], [ 237, 118, 19, 12 ], [ 64, 135, 26, 12 ], [ 95, 135, 131, 12 ], [ 65, 169, 34, 17 ], [ 101, 169, 49, 17 ], [ 636, 122, 5, 11 ], [ 643, 122, 10, 11 ], [ 657, 122, 9, 11 ], [ 670, 122, 9, 11 ], [ 683, 122, 10, 11 ], [ 697, 122, 9, 11 ], [ 710, 122, 7, 11 ], [ 728, 122, 10, 11 ], [ 742, 122, 7, 11 ], [ 638, 140, 110, 23 ], [ 654, 160, 77, 23 ], [ 65, 226, 140, 23 ], [ 209, 226, 19, 23 ], [ 234, 226, 51, 23 ], [ 290, 226, 52, 23 ], [ 347, 226, 56, 23 ], [ 408, 226, 44, 23 ], [ 457, 226, 98, 23 ], [ 560, 226, 19, 23 ], [ 585, 226, 106, 23 ], [ 65, 250, 141, 23 ], [ 211, 250, 69, 23 ], [ 285, 250, 37, 23 ], [ 327, 250, 98, 23 ], [ 431, 250, 78, 23 ], [ 65, 294, 33, 16 ], [ 101, 290, 41, 19 ], [ 145, 294, 86, 16 ], [ 235, 290, 45, 19 ], [ 283, 294, 73, 16 ], [ 360, 290, 35, 19 ], [ 399, 294, 78, 16 ], [ 479, 290, 48, 20 ], [ 65, 325, 71, 17 ], [ 139, 328, 11, 14 ], [ 153, 328, 52, 14 ], [ 208, 328, 21, 14 ], [ 233, 328, 81, 14 ], [ 317, 328, 38, 14 ], [ 358, 328, 11, 14 ], [ 372, 328, 60, 14 ], [ 435, 328, 56, 14 ], [ 493, 328, 58, 14 ], [ 555, 328, 11, 14 ], [ 569, 328, 62, 14 ], [ 634, 328, 36, 14 ], [ 673, 328, 18, 14 ], [ 694, 328, 39, 14 ], [ 736, 328, 26, 14 ], [ 65, 341, 37, 18 ], [ 104, 344, 31, 14 ], [ 139, 344, 11, 14 ], [ 153, 344, 61, 14 ], [ 217, 344, 60, 14 ], [ 280, 344, 54, 14 ], [ 338, 344, 51, 14 ], [ 391, 344, 17, 14 ], [ 411, 344, 40, 14 ], [ 454, 344, 50, 14 ], [ 507, 344, 21, 14 ], [ 531, 344, 67, 14 ], [ 601, 344, 11, 14 ], [ 616, 344, 60, 14 ], [ 679, 344, 45, 14 ], [ 65, 360, 56, 14 ], [ 123, 360, 44, 14 ], [ 170, 360, 11, 14 ], [ 184, 360, 60, 14 ], [ 247, 360, 56, 14 ], [ 306, 360, 43, 14 ], [ 352, 360, 62, 14 ], [ 416, 360, 31, 14 ], [ 451, 360, 50, 14 ], [ 504, 360, 35, 14 ], [ 71, 405, 35, 14 ], [ 108, 405, 31, 14 ], [ 141, 405, 33, 14 ], [ 177, 405, 26, 14 ], [ 205, 405, 28, 14 ], [ 235, 405, 48, 14 ], [ 286, 405, 18, 14 ], [ 305, 405, 18, 14 ], [ 326, 405, 60, 14 ], [ 388, 405, 12, 14 ], [ 65, 421, 58, 14 ], [ 124, 421, 42, 14 ], [ 168, 421, 30, 14 ], [ 200, 421, 45, 14 ], [ 247, 421, 21, 14 ], [ 270, 421, 58, 14 ], [ 329, 421, 70, 14 ], [ 65, 438, 15, 14 ], [ 83, 438, 26, 14 ], [ 114, 438, 55, 14 ], [ 173, 438, 82, 14 ], [ 259, 438, 29, 14 ], [ 292, 438, 22, 14 ], [ 318, 438, 27, 14 ], [ 350, 438, 50, 14 ], [ 65, 455, 54, 14 ], [ 123, 455, 58, 14 ], [ 184, 455, 46, 14 ], [ 235, 455, 22, 14 ], [ 261, 455, 61, 14 ], [ 327, 455, 15, 14 ], [ 345, 455, 18, 14 ], [ 368, 455, 32, 14 ], [ 65, 471, 22, 14 ], [ 90, 471, 35, 14 ], [ 129, 471, 30, 14 ], [ 163, 471, 22, 14 ], [ 189, 471, 15, 14 ], [ 207, 471, 30, 14 ], [ 242, 471, 26, 14 ], [ 272, 471, 56, 14 ], [ 332, 471, 42, 14 ], [ 378, 471, 21, 14 ], [ 65, 488, 84, 14 ], [ 151, 488, 22, 14 ], [ 176, 488, 84, 14 ], [ 262, 488, 34, 14 ], [ 299, 488, 27, 14 ], [ 328, 488, 28, 14 ], [ 358, 488, 41, 14 ], [ 65, 505, 26, 14 ], [ 98, 505, 74, 14 ], [ 181, 505, 22, 14 ], [ 211, 505, 68, 14 ], [ 287, 505, 22, 14 ], [ 317, 505, 43, 14 ], [ 368, 505, 32, 14 ], [ 65, 521, 77, 14 ], [ 146, 521, 12, 14 ], [ 163, 521, 41, 14 ], [ 209, 521, 32, 14 ], [ 246, 521, 38, 14 ], [ 288, 521, 85, 14 ], [ 378, 521, 22, 14 ], [ 65, 538, 81, 14 ], [ 151, 538, 28, 14 ], [ 185, 538, 19, 14 ], [ 210, 538, 55, 14 ], [ 272, 538, 45, 14 ], [ 323, 538, 12, 14 ], [ 340, 538, 59, 14 ], [ 65, 555, 57, 14 ], [ 126, 555, 26, 14 ], [ 157, 555, 24, 14 ], [ 186, 555, 37, 14 ], [ 227, 555, 77, 14 ], [ 309, 555, 18, 14 ], [ 332, 555, 41, 14 ], [ 378, 555, 22, 14 ], [ 65, 571, 58, 14 ], [ 133, 571, 47, 14 ], [ 189, 571, 12, 14 ], [ 211, 571, 63, 14 ], [ 283, 571, 84, 14 ], [ 378, 571, 22, 14 ], [ 65, 588, 81, 14 ], [ 148, 588, 12, 14 ], [ 163, 588, 30, 14 ], [ 196, 588, 31, 14 ], [ 229, 588, 33, 14 ], [ 265, 588, 30, 14 ], [ 65, 612, 63, 14 ], [ 130, 611, 38, 14 ], [ 171, 611, 58, 14 ], [ 231, 611, 75, 14 ], [ 310, 611, 76, 14 ], [ 72, 661, 86, 15 ], [ 161, 661, 31, 15 ], [ 196, 661, 13, 15 ], [ 211, 661, 55, 15 ], [ 269, 661, 48, 15 ], [ 321, 661, 10, 15 ], [ 334, 661, 7, 15 ], [ 344, 661, 55, 15 ], [ 65, 678, 12, 15 ], [ 79, 678, 36, 15 ], [ 117, 678, 28, 15 ], [ 147, 678, 61, 15 ], [ 210, 678, 44, 15 ], [ 257, 678, 46, 15 ], [ 305, 678, 37, 15 ], [ 345, 678, 18, 15 ], [ 365, 678, 35, 15 ], [ 65, 695, 25, 15 ], [ 92, 695, 69, 15 ], [ 163, 695, 20, 15 ], [ 186, 695, 53, 15 ], [ 241, 695, 18, 15 ], [ 261, 695, 32, 15 ], [ 295, 695, 12, 15 ], [ 309, 695, 21, 15 ], [ 332, 695, 10, 15 ], [ 344, 695, 56, 15 ], [ 65, 711, 18, 15 ], [ 90, 711, 55, 15 ], [ 154, 711, 26, 15 ], [ 187, 711, 33, 15 ], [ 227, 711, 29, 15 ], [ 264, 711, 42, 15 ], [ 313, 711, 66, 15 ], [ 387, 711, 13, 15 ], [ 65, 728, 63, 15 ], [ 134, 728, 13, 15 ], [ 152, 728, 25, 15 ], [ 184, 728, 14, 15 ], [ 204, 728, 21, 15 ], [ 231, 728, 12, 15 ], [ 249, 728, 67, 15 ], [ 321, 728, 60, 15 ], [ 387, 728, 13, 15 ], [ 65, 745, 50, 15 ], [ 117, 745, 13, 15 ], [ 132, 745, 35, 15 ], [ 170, 745, 26, 15 ], [ 199, 745, 34, 15 ], [ 235, 745, 38, 15 ], [ 276, 745, 21, 15 ], [ 299, 745, 50, 15 ], [ 352, 745, 26, 15 ], [ 380, 745, 10, 15 ], [ 393, 745, 7, 15 ], [ 65, 761, 74, 15 ], [ 141, 761, 43, 15 ], [ 186, 761, 25, 15 ], [ 213, 761, 13, 15 ], [ 228, 761, 21, 15 ], [ 252, 761, 46, 15 ], [ 301, 761, 36, 15 ], [ 339, 761, 10, 15 ], [ 351, 761, 49, 15 ], [ 65, 778, 12, 15 ], [ 82, 778, 85, 15 ], [ 172, 778, 27, 15 ], [ 205, 778, 13, 15 ], [ 223, 778, 47, 15 ], [ 276, 778, 46, 15 ], [ 327, 778, 22, 15 ], [ 354, 778, 27, 15 ], [ 387, 778, 13, 15 ], [ 65, 795, 47, 15 ], [ 114, 795, 28, 15 ], [ 144, 795, 39, 15 ], [ 185, 795, 51, 15 ], [ 239, 795, 29, 15 ], [ 270, 795, 10, 15 ], [ 283, 795, 31, 15 ], [ 316, 795, 69, 15 ], [ 387, 795, 13, 15 ], [ 65, 811, 12, 15 ], [ 79, 811, 25, 15 ], [ 107, 811, 21, 15 ], [ 130, 811, 42, 15 ], [ 175, 811, 38, 15 ], [ 216, 811, 12, 15 ], [ 230, 811, 29, 15 ], [ 261, 811, 13, 15 ], [ 276, 811, 48, 15 ], [ 327, 811, 12, 15 ], [ 341, 811, 29, 15 ], [ 372, 811, 28, 15 ], [ 65, 828, 26, 15 ], [ 93, 828, 22, 15 ], [ 117, 828, 30, 15 ], [ 150, 828, 41, 15 ], [ 193, 828, 11, 15 ], [ 207, 828, 21, 15 ], [ 230, 828, 25, 15 ], [ 257, 828, 13, 15 ], [ 272, 828, 18, 15 ], [ 293, 828, 53, 15 ], [ 348, 828, 21, 15 ], [ 372, 828, 28, 15 ], [ 65, 845, 13, 15 ], [ 80, 845, 51, 15 ], [ 134, 845, 22, 15 ], [ 158, 845, 26, 15 ], [ 186, 845, 28, 15 ], [ 217, 845, 31, 15 ], [ 250, 845, 73, 15 ], [ 326, 845, 43, 15 ], [ 372, 845, 27, 15 ], [ 65, 861, 13, 15 ], [ 81, 861, 47, 15 ], [ 132, 861, 54, 15 ], [ 191, 861, 47, 15 ], [ 242, 861, 27, 15 ], [ 274, 861, 60, 15 ], [ 338, 861, 21, 15 ], [ 364, 861, 36, 15 ], [ 65, 878, 27, 15 ], [ 95, 878, 35, 15 ], [ 133, 878, 21, 15 ], [ 72, 895, 47, 15 ], [ 122, 895, 55, 15 ], [ 179, 895, 20, 15 ], [ 202, 895, 29, 15 ], [ 233, 895, 19, 15 ], [ 254, 895, 51, 15 ], [ 307, 895, 27, 15 ], [ 337, 895, 19, 15 ], [ 358, 895, 42, 15 ], [ 65, 911, 18, 15 ], [ 86, 911, 43, 15 ], [ 133, 911, 34, 15 ], [ 170, 911, 80, 15 ], [ 254, 911, 106, 15 ], [ 363, 911, 36, 15 ], [ 65, 928, 90, 15 ], [ 158, 928, 68, 15 ], [ 230, 928, 21, 15 ], [ 255, 928, 23, 15 ], [ 282, 928, 44, 15 ], [ 330, 928, 21, 15 ], [ 354, 928, 14, 15 ], [ 372, 928, 27, 15 ], [ 65, 945, 17, 15 ], [ 85, 945, 18, 15 ], [ 106, 945, 55, 15 ], [ 164, 945, 13, 15 ], [ 180, 945, 21, 15 ], [ 204, 945, 28, 15 ], [ 236, 945, 22, 15 ], [ 261, 945, 28, 15 ], [ 291, 945, 50, 15 ], [ 343, 945, 57, 15 ], [ 65, 961, 59, 15 ], [ 127, 961, 10, 15 ], [ 141, 961, 47, 15 ], [ 192, 961, 50, 15 ], [ 246, 961, 91, 15 ], [ 341, 961, 36, 15 ], [ 381, 961, 18, 15 ], [ 66, 1006, 76, 12 ], [ 145, 1006, 31, 12 ], [ 66, 1020, 19, 12 ], [ 88, 1020, 81, 12 ], [ 171, 1020, 21, 12 ], [ 195, 1020, 78, 12 ], [ 66, 1034, 36, 12 ], [ 105, 1034, 110, 12 ], [ 427, 405, 66, 15 ], [ 495, 405, 50, 15 ], [ 547, 405, 28, 15 ], [ 578, 405, 21, 15 ], [ 601, 405, 62, 15 ], [ 665, 405, 18, 15 ], [ 685, 405, 39, 15 ], [ 727, 405, 35, 15 ], [ 427, 421, 44, 15 ], [ 473, 421, 12, 15 ], [ 487, 421, 18, 15 ], [ 506, 421, 26, 15 ], [ 534, 421, 18, 15 ], [ 553, 421, 49, 15 ], [ 604, 421, 30, 15 ], [ 636, 421, 12, 15 ], [ 650, 421, 43, 15 ], [ 695, 421, 7, 15 ], [ 704, 421, 59, 15 ], [ 427, 438, 12, 15 ], [ 442, 438, 69, 15 ], [ 514, 438, 18, 15 ], [ 535, 438, 49, 15 ], [ 588, 438, 51, 15 ], [ 642, 438, 32, 15 ], [ 434, 455, 25, 15 ], [ 461, 455, 25, 15 ], [ 488, 455, 34, 15 ], [ 524, 455, 74, 15 ], [ 599, 455, 85, 15 ], [ 686, 455, 76, 15 ], [ 427, 471, 33, 15 ], [ 469, 471, 12, 15 ], [ 490, 471, 30, 15 ], [ 528, 471, 32, 15 ], [ 569, 471, 33, 15 ], [ 611, 471, 28, 15 ], [ 648, 471, 55, 15 ], [ 712, 471, 50, 15 ], [ 427, 488, 83, 15 ], [ 515, 488, 29, 15 ], [ 549, 488, 21, 15 ], [ 575, 488, 28, 15 ], [ 607, 488, 49, 15 ], [ 660, 488, 34, 15 ], [ 699, 488, 15, 15 ], [ 718, 488, 43, 15 ], [ 427, 505, 21, 15 ], [ 451, 505, 60, 15 ], [ 515, 505, 52, 15 ], [ 434, 521, 29, 15 ], [ 469, 521, 22, 15 ], [ 496, 521, 13, 15 ], [ 514, 521, 11, 15 ], [ 530, 521, 64, 15 ], [ 600, 521, 41, 15 ], [ 647, 521, 40, 15 ], [ 693, 521, 41, 15 ], [ 739, 521, 22, 15 ], [ 427, 538, 55, 15 ], [ 490, 538, 19, 15 ], [ 518, 538, 15, 15 ], [ 542, 538, 23, 15 ], [ 574, 538, 56, 15 ], [ 639, 538, 26, 15 ], [ 674, 538, 28, 15 ], [ 711, 538, 51, 15 ], [ 427, 555, 77, 15 ], [ 508, 555, 21, 15 ], [ 533, 555, 26, 15 ], [ 562, 555, 27, 15 ], [ 592, 555, 38, 15 ], [ 634, 555, 85, 15 ], [ 723, 555, 22, 15 ], [ 749, 555, 13, 15 ], [ 427, 571, 26, 15 ], [ 460, 571, 27, 15 ], [ 494, 571, 23, 15 ], [ 523, 571, 43, 15 ], [ 573, 571, 56, 15 ], [ 635, 571, 8, 15 ], [ 650, 571, 27, 15 ], [ 684, 571, 21, 15 ], [ 712, 571, 21, 15 ], [ 740, 571, 21, 15 ], [ 427, 588, 65, 15 ], [ 505, 588, 46, 15 ], [ 563, 588, 27, 15 ], [ 603, 588, 18, 15 ], [ 634, 588, 60, 15 ], [ 707, 588, 24, 15 ], [ 744, 588, 18, 15 ], [ 427, 605, 80, 15 ], [ 512, 605, 15, 15 ], [ 533, 605, 18, 15 ], [ 557, 605, 54, 15 ], [ 617, 605, 34, 15 ], [ 656, 605, 33, 15 ], [ 695, 605, 39, 15 ], [ 740, 605, 22, 15 ], [ 427, 621, 36, 15 ], [ 469, 621, 72, 15 ], [ 546, 621, 39, 15 ], [ 592, 621, 29, 15 ], [ 627, 621, 53, 15 ], [ 685, 621, 76, 15 ], [ 427, 638, 72, 15 ], [ 502, 638, 50, 15 ], [ 554, 638, 58, 15 ], [ 615, 638, 47, 15 ], [ 665, 638, 53, 15 ], [ 721, 638, 12, 15 ], [ 735, 638, 26, 15 ], [ 427, 655, 26, 15 ], [ 456, 655, 36, 15 ], [ 495, 655, 41, 15 ], [ 538, 655, 40, 15 ], [ 581, 655, 38, 15 ], [ 622, 655, 21, 15 ], [ 646, 655, 35, 15 ], [ 684, 655, 46, 15 ], [ 733, 655, 29, 15 ], [ 427, 671, 44, 15 ], [ 473, 671, 35, 15 ], [ 510, 671, 15, 15 ], [ 527, 671, 18, 15 ], [ 547, 671, 74, 15 ], [ 623, 671, 67, 15 ], [ 692, 671, 12, 15 ], [ 706, 671, 56, 15 ], [ 427, 688, 48, 15 ], [ 482, 688, 29, 15 ], [ 518, 688, 61, 15 ], [ 585, 688, 55, 15 ], [ 648, 688, 59, 15 ], [ 714, 688, 48, 15 ], [ 427, 705, 37, 15 ], [ 466, 705, 26, 15 ], [ 495, 705, 13, 15 ], [ 510, 705, 18, 15 ], [ 530, 705, 30, 15 ], [ 563, 705, 21, 15 ], [ 586, 705, 35, 15 ], [ 624, 705, 26, 15 ], [ 652, 705, 23, 15 ], [ 678, 705, 50, 15 ], [ 730, 705, 32, 15 ], [ 427, 721, 7, 15 ], [ 438, 721, 19, 15 ], [ 460, 721, 31, 15 ], [ 495, 721, 51, 15 ], [ 550, 721, 43, 15 ], [ 597, 721, 32, 15 ], [ 633, 721, 12, 15 ], [ 649, 721, 63, 15 ], [ 716, 721, 46, 15 ], [ 427, 738, 21, 15 ], [ 450, 738, 39, 15 ], [ 492, 738, 21, 15 ], [ 515, 738, 21, 15 ], [ 539, 738, 74, 15 ], [ 615, 738, 45, 15 ], [ 662, 738, 41, 15 ], [ 705, 738, 57, 15 ], [ 427, 755, 60, 15 ], [ 489, 755, 46, 15 ], [ 538, 755, 18, 15 ], [ 559, 755, 49, 15 ], [ 610, 755, 51, 15 ], [ 665, 755, 21, 15 ], [ 689, 755, 37, 15 ], [ 729, 755, 12, 15 ], [ 744, 755, 18, 15 ], [ 427, 771, 35, 15 ], [ 465, 771, 26, 15 ], [ 495, 771, 49, 15 ], [ 548, 771, 41, 15 ], [ 592, 771, 21, 15 ], [ 617, 771, 36, 15 ], [ 657, 771, 46, 15 ], [ 707, 771, 55, 15 ], [ 427, 788, 29, 15 ], [ 459, 788, 33, 15 ], [ 495, 788, 28, 15 ], [ 526, 788, 16, 15 ], [ 434, 805, 36, 15 ], [ 476, 805, 15, 15 ], [ 496, 805, 30, 15 ], [ 532, 805, 52, 15 ], [ 590, 805, 18, 15 ], [ 614, 805, 22, 15 ], [ 641, 805, 23, 15 ], [ 670, 805, 60, 15 ], [ 735, 805, 26, 15 ], [ 427, 821, 64, 15 ], [ 495, 821, 85, 15 ], [ 585, 821, 22, 15 ], [ 612, 821, 84, 15 ], [ 700, 821, 62, 15 ], [ 427, 838, 23, 15 ], [ 452, 838, 22, 15 ], [ 477, 838, 23, 15 ], [ 502, 838, 40, 15 ], [ 545, 838, 26, 15 ], [ 574, 838, 66, 15 ], [ 642, 838, 41, 15 ], [ 685, 838, 8, 15 ], [ 696, 838, 41, 15 ], [ 739, 838, 23, 15 ], [ 427, 855, 29, 15 ], [ 457, 855, 45, 15 ], [ 504, 855, 36, 15 ], [ 542, 855, 39, 15 ], [ 583, 855, 21, 15 ], [ 606, 855, 73, 15 ], [ 681, 855, 81, 15 ], [ 427, 871, 8, 15 ], [ 436, 871, 40, 15 ], [ 478, 871, 22, 15 ], [ 503, 871, 29, 15 ], [ 533, 871, 35, 15 ], [ 570, 871, 47, 15 ], [ 619, 871, 43, 15 ], [ 664, 871, 22, 15 ], [ 689, 871, 34, 15 ], [ 725, 871, 37, 15 ], [ 427, 888, 56, 15 ], [ 486, 888, 15, 15 ], [ 504, 888, 18, 15 ], [ 525, 888, 28, 15 ], [ 556, 888, 22, 15 ], [ 581, 888, 22, 15 ], [ 606, 888, 65, 15 ], [ 674, 888, 70, 15 ], [ 747, 888, 15, 15 ], [ 427, 905, 18, 15 ], [ 448, 905, 41, 15 ], [ 493, 905, 35, 15 ], [ 531, 905, 67, 15 ], [ 601, 905, 21, 15 ], [ 626, 905, 28, 15 ], [ 657, 905, 43, 15 ], [ 704, 905, 17, 15 ], [ 724, 905, 26, 15 ], [ 754, 905, 8, 15 ], [ 427, 921, 47, 15 ], [ 480, 921, 34, 15 ], [ 521, 921, 23, 15 ], [ 550, 921, 15, 15 ], [ 572, 921, 42, 15 ], [ 620, 921, 17, 15 ], [ 644, 921, 8, 15 ], [ 658, 921, 44, 15 ], [ 708, 921, 27, 15 ], [ 741, 921, 21, 15 ], [ 427, 938, 67, 15 ], [ 434, 955, 29, 15 ], [ 470, 955, 22, 15 ], [ 500, 955, 13, 15 ], [ 519, 955, 11, 15 ], [ 537, 955, 64, 15 ], [ 609, 955, 33, 15 ], [ 649, 955, 29, 15 ], [ 685, 955, 47, 15 ], [ 739, 955, 22, 15 ], [ 427, 971, 55, 15 ], [ 489, 971, 26, 15 ], [ 522, 971, 15, 15 ], [ 544, 971, 23, 15 ], [ 575, 971, 56, 15 ], [ 638, 971, 26, 15 ], [ 672, 971, 18, 15 ], [ 697, 971, 28, 15 ], [ 733, 971, 29, 15 ], [ 427, 988, 52, 15 ], [ 483, 988, 21, 15 ], [ 509, 988, 56, 15 ], [ 569, 988, 12, 15 ], [ 585, 988, 18, 15 ], [ 607, 988, 59, 15 ], [ 670, 988, 17, 15 ], [ 692, 988, 8, 15 ], [ 704, 988, 31, 15 ], [ 739, 988, 23, 15 ], [ 427, 1005, 42, 15 ], [ 473, 1005, 24, 15 ], [ 500, 1005, 49, 15 ], [ 553, 1005, 22, 15 ], [ 579, 1005, 18, 15 ], [ 601, 1005, 22, 15 ], [ 627, 1005, 22, 15 ], [ 652, 1005, 7, 15 ], [ 662, 1005, 27, 15 ], [ 693, 1005, 53, 15 ], [ 750, 1005, 12, 15 ], [ 427, 1021, 42, 15 ], [ 473, 1021, 11, 15 ], [ 489, 1021, 14, 15 ], [ 507, 1021, 74, 15 ], [ 586, 1021, 25, 15 ], [ 615, 1021, 22, 15 ], [ 641, 1021, 23, 15 ], [ 669, 1021, 58, 15 ], [ 731, 1021, 30, 15 ] ]

[ "J.", "Vet.", "Sci.", "(2009),", "10(4),", "365?", "367", "DOI:", "10.4142/jvs.2009.10.4.365", "Case", "Report", "J", "O", "U", "R", "N", "A", "L", "O", "F", "Veterinary", "Science", "Syringomyelia", "in", "three", "small", "breed", "dogs", "secondary", "to", "Chiari-like", "malformation:", "clinical", "and", "diagnostic", "findings", "Chul", "Park1,", "Byeong-Teck", "Kang2,", "Jong-Hyun", "Yoo2,", "Hee-Myung", "Park2,*", "1Department", "of", "Medicine", "and", "Epidemiology,", "School", "of", "Veterinary", "Medicine,", "University", "of", "California,", "Davis,", "CA", "95616,", "USA", "2BK21", "Basic", "&", "Diagnostic", "Veterinary", "Specialist", "Program", "for", "Animal", "Diseases", "and", "Department", "of", "Veterinary", "Internal", "Medicine,", "College", "of", "Veterinary", "Medicine,", "Konkuk", "University,", "Seoul", "143-701,", "Korea", "Three", "small", "breed", "dogs", "were", "referred", "for", "the", "evaluation", "of", "neurologic", "deficits.", "Upon", "physical", "and", "neurologic", "examination,", "all", "dogs", "displayed", "hyperesthesia,", "pain,", "and", "neck", "stiffness.", "Magnetic", "resonance", "imaging", "was", "performed", "on", "the", "brain", "and", "spinal", "cord,", "and", "all", "three", "dogs", "presented", "Chiari-", "like", "malformations", "and", "syringomyelia.", "These", "dogs", "were", "treated", "with", "prednisolone", "and", "furosemide,", "and", "showed", "rapid", "improvement", "of", "clinical", "signs.", "Chiari", "malformations", "and", "syringomyelia", "were", "not", "improved", "because", "of", "congenital", "disorders.", "This", "case", "report", "demonstrates", "the", "clinical", "and", "diagnostic", "features", "of", "Chiari-like", "malformations", "and", "syringomyelia", "in", "three", "small", "breed", "dogs.", "Keywords:", "canine,", "Chiari-like", "malformation,", "syringomyelia", "Syringomyelia", "(SM)", "of", "unknown", "etiology", "is", "a", "condition", "in", "which", "fluid", "containing", "cavities", "develop", "within", "the", "spinal", "cord", "parenchyma", "[9].", "Although", "the", "cause", "of", "SM", "is", "unknown,", "the", "condition", "may", "result", "from", "venous", "obstruction", "or", "distension,", "or", "may", "be", "due", "to", "mechanical", "disruption", "or", "shearing", "of", "spinal", "cord", "tissue", "planes", "[9].", "Cervical", "pain", "is", "a", "predominant", "clinical", "sign", "of", "this", "disease,", "which", "is", "reported", "in", "approximately", "80%", "of", "affected", "humans", "and", "35%", "of", "affected", "dogs", "[7,10],", "although", "there", "is", "some", "controversy", "as", "to", "how", "this", "disease", "results", "in", "pain.", "In", "addition", "to", "pain,", "dogs", "with", "SM", "often", "scratch", "at", "one", "area", "of", "the", "shoulder,", "ear,", "neck", "or", "sternum,", "and", "may", "have", "other", "neurological", "deficits", "such", "as", "cervical", "scoliosis,", "thoracic", "limb", "weakness,", "and", "pelvic", "limb", "ataxia", "[6].", "Medical", "treatment", "can", "help,", "but", "typically", "does", "not", "resolve", "the", "clinical", "signs.", "Non-steroidal", "anti-inflammatory", "drugs,", "corticosteroids,", "gabapentin,", "and", "oral", "opioids", "can", "be", "used", "for", "the", "treatment", "of", "SM", "[10].", "The", "most", "common", "procedure", "performed", "is", "foramen", "magnum", "decompression,", "where", "the", "*Corresponding", "author", "Tel:", "+82-2-450-4140;", "Fax:", "+82-2-444-4396", "E-mail:", "parkhee@konkuk.ac.kr", "hypoplastic", "occipital", "bone", "and", "sometimes", "the", "cranial", "dorsal", "laminae", "of", "the", "atlas", "are", "removed", "(with", "or", "without", "a", "durotomy)", "to", "decompress", "the", "foramen", "magnum", "[1,3].", "This", "case", "report", "demonstrates", "SM/Chiari-like", "malformation", "(CM)", "in", "three", "small", "breed", "dogs", "primarily", "showing", "hyperesthesia,", "pain,", "and", "neck", "stiffness", "based", "on", "clinical", "and", "diagnostic", "findings.", "Case", "No.", "1:", "A", "6-year-old,", "spayed", "female", "Poodle", "dog", "weighing", "4.1", "kg", "was", "presented", "with", "neck", "stiffness,", "hyperesthesia", "and", "hind", "limb", "ataxia.", "Uncoordinated", "gait", "of", "hind", "limb", "was", "acutely", "presented", "3", "days", "ago", "and", "had", "maintained", "steadily", "until", "the", "admission", "day.", "No", "abnormalities", "on", "the", "complete", "blood", "count", "(CBC)", "and", "serum", "biochemical", "profile", "were", "detected.", "Neurological", "examination", "revealed", "decreased", "postural", "reactions", "in", "both", "hind", "limbs,", "though", "cranial", "nerves", "and", "spinal", "reflexes", "were", "normal.", "Based", "on", "the", "examination,", "myelopathy", "or", "cerebellar", "diseases", "were", "suspected.", "Magnetic", "resonance", "imaging", "(MRI)", "scan", "of", "the", "brain", "and", "spinal", "cord", "was", "obtained", "using", "a", "0.2", "Tesla", "(E-Scan;", "Esaote,", "Italy)", "in", "transverse,", "sagittal,", "and", "dorsal,", "T1-", "and", "T2-weighted", "images.", "Caudal", "cerebellar", "herniation", "through", "the", "foramen", "magnum", "and", "syrinx", "in", "the", "spinal", "cord", "between", "second", "and", "fourth", "cervical", "vertebrae", "were", "noted", "(Fig.", "1).", "Based", "on", "these", "findings,", "the", "dog", "was", "diagnosed", "with", "Chiari-like", "malformations", "and", "syringomyelia", "(CM/SM).", "The", "dog", "was", "treated", "with", "furosemide", "(Lasix,", "2", "mg/kg,", "PO,", "BID;", "Handok", "Pham,", "Korea)", "and", "prednisolone", "(Prednisolone,", "1", "mg/kg,", "PO,", "BID;", "Korea", "Pharma,", "Korea).", "The", "ataxia", "mildly", "improved", "on", "the", "third", "day", "and", "completely", "disappeared", "by", "the", "second", "week.", "Medication", "had", "been", "tapered", "off", "over", "2", "months.", "There", "was", "no", "relapse", "for", "6", "months", "until", "last", "follow-ups.", "Case", "No.", "2:", "A", "3-year-old,", "intact", "male", "Maltese", "dog", "weighing", "4.16", "kg", "was", "presented", "with", "the", "neck", "pain,", "stiffness,", "and", "weakness", "in", "the", "hindlimbs", "for", "7", "days.", "The", "owners", "also", "reported", "that", "the", "dog", "had", "a", "mild", "tendency", "to", "scratch", "at", "its", "mid-cervical", "area", "and", "was", "becoming", "more" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 11, 11, 11, 11, 11, 11, 11, 11, 11, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 78, 47, 48, 12 ], [ 129, 47, 18, 12 ], [ 151, 47, 28, 12 ], [ 182, 47, 33, 12 ], [ 218, 47, 9, 12 ], [ 231, 47, 59, 12 ], [ 293, 47, 18, 12 ], [ 314, 47, 66, 12 ], [ 384, 47, 25, 12 ], [ 412, 47, 20, 12 ], [ 78, 61, 214, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 78, 169, 128, 34 ], [ 216, 169, 80, 34 ], [ 307, 169, 63, 34 ], [ 380, 169, 25, 34 ], [ 415, 169, 119, 34 ], [ 545, 169, 60, 34 ], [ 615, 169, 37, 34 ], [ 78, 205, 169, 34 ], [ 257, 205, 125, 34 ], [ 392, 205, 51, 34 ], [ 453, 205, 90, 34 ], [ 553, 205, 84, 34 ], [ 78, 252, 36, 16 ], [ 119, 252, 12, 16 ], [ 135, 249, 66, 18 ], [ 206, 252, 38, 16 ], [ 248, 252, 35, 16 ], [ 604, 63, 44, 11 ], [ 650, 63, 14, 11 ], [ 666, 63, 79, 11 ], [ 604, 75, 23, 11 ], [ 629, 75, 81, 11 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 87, 306, 54, 15 ], [ 87, 327, 54, 14 ], [ 145, 327, 11, 14 ], [ 161, 327, 19, 14 ], [ 184, 327, 71, 14 ], [ 259, 327, 27, 14 ], [ 290, 327, 78, 14 ], [ 372, 327, 25, 14 ], [ 401, 327, 55, 14 ], [ 461, 327, 22, 14 ], [ 487, 327, 71, 14 ], [ 562, 327, 53, 14 ], [ 618, 327, 50, 14 ], [ 672, 327, 12, 14 ], [ 688, 327, 15, 14 ], [ 707, 327, 7, 14 ], [ 87, 344, 32, 14 ], [ 124, 344, 35, 14 ], [ 163, 344, 54, 14 ], [ 221, 344, 62, 14 ], [ 287, 344, 16, 14 ], [ 307, 344, 59, 14 ], [ 370, 344, 45, 14 ], [ 418, 344, 11, 14 ], [ 434, 344, 29, 14 ], [ 467, 344, 40, 14 ], [ 511, 344, 8, 14 ], [ 524, 344, 65, 14 ], [ 593, 344, 27, 14 ], [ 624, 344, 12, 14 ], [ 640, 344, 43, 14 ], [ 687, 344, 26, 14 ], [ 87, 360, 55, 14 ], [ 146, 360, 21, 14 ], [ 172, 360, 31, 14 ], [ 207, 360, 27, 14 ], [ 238, 360, 29, 14 ], [ 271, 360, 68, 14 ], [ 343, 360, 15, 14 ], [ 362, 360, 25, 14 ], [ 392, 360, 42, 14 ], [ 438, 360, 25, 14 ], [ 467, 360, 43, 14 ], [ 514, 360, 38, 14 ], [ 556, 360, 9, 14 ], [ 569, 360, 25, 14 ], [ 598, 360, 11, 14 ], [ 614, 360, 20, 14 ], [ 639, 360, 29, 14 ], [ 671, 360, 40, 14 ], [ 87, 377, 57, 14 ], [ 149, 377, 12, 14 ], [ 165, 377, 14, 14 ], [ 183, 377, 39, 14 ], [ 226, 377, 22, 14 ], [ 252, 377, 14, 14 ], [ 270, 377, 42, 14 ], [ 316, 377, 28, 14 ], [ 348, 377, 72, 14 ], [ 424, 377, 21, 14 ], [ 450, 377, 53, 14 ], [ 506, 377, 12, 14 ], [ 522, 377, 35, 14 ], [ 561, 377, 51, 14 ], [ 617, 377, 15, 14 ], [ 636, 377, 71, 14 ], [ 87, 394, 53, 14 ], [ 144, 394, 11, 14 ], [ 159, 394, 50, 14 ], [ 213, 394, 28, 14 ], [ 245, 394, 28, 14 ], [ 277, 394, 40, 14 ], [ 322, 394, 27, 14 ], [ 353, 394, 28, 14 ], [ 385, 394, 60, 14 ], [ 449, 394, 42, 14 ], [ 495, 394, 49, 14 ], [ 548, 394, 14, 14 ], [ 566, 394, 59, 14 ], [ 629, 394, 22, 14 ], [ 655, 394, 52, 14 ], [ 87, 410, 36, 14 ], [ 128, 410, 21, 14 ], [ 154, 410, 39, 14 ], [ 196, 410, 21, 14 ], [ 221, 410, 28, 14 ], [ 254, 410, 55, 14 ], [ 313, 410, 42, 14 ], [ 360, 410, 17, 14 ], [ 381, 410, 35, 14 ], [ 420, 410, 67, 14 ], [ 491, 410, 23, 14 ], [ 519, 410, 45, 14 ], [ 568, 410, 12, 14 ], [ 584, 410, 25, 14 ], [ 614, 410, 37, 14 ], [ 655, 410, 64, 14 ], [ 723, 410, 11, 14 ], [ 87, 427, 19, 14 ], [ 110, 427, 26, 14 ], [ 140, 427, 89, 14 ], [ 234, 427, 21, 14 ], [ 259, 427, 45, 14 ], [ 308, 427, 11, 14 ], [ 324, 427, 35, 14 ], [ 363, 427, 69, 14 ], [ 437, 427, 15, 14 ], [ 456, 427, 71, 14 ], [ 531, 427, 53, 14 ], [ 588, 427, 28, 14 ], [ 620, 427, 50, 14 ], [ 675, 427, 27, 14 ], [ 705, 427, 19, 14 ], [ 87, 443, 34, 14 ], [ 125, 443, 11, 14 ], [ 141, 443, 34, 14 ], [ 179, 443, 49, 14 ], [ 232, 443, 19, 14 ], [ 255, 443, 35, 14 ], [ 294, 443, 29, 14 ], [ 326, 443, 49, 14 ], [ 380, 443, 21, 14 ], [ 405, 443, 33, 14 ], [ 442, 443, 49, 14 ], [ 495, 443, 30, 14 ], [ 530, 443, 30, 14 ], [ 564, 443, 29, 14 ], [ 597, 443, 27, 14 ], [ 628, 443, 28, 14 ], [ 660, 443, 27, 14 ], [ 691, 443, 20, 14 ], [ 87, 460, 59, 14 ], [ 150, 460, 29, 14 ], [ 184, 460, 25, 14 ], [ 213, 460, 24, 14 ], [ 241, 460, 11, 14 ], [ 257, 460, 19, 14 ], [ 280, 460, 30, 14 ], [ 313, 460, 27, 14 ], [ 345, 460, 29, 14 ], [ 378, 460, 45, 14 ], [ 426, 460, 22, 14 ], [ 452, 460, 27, 14 ], [ 483, 460, 12, 14 ], [ 500, 460, 43, 14 ], [ 547, 460, 54, 14 ], [ 604, 460, 27, 14 ], [ 635, 460, 24, 14 ], [ 663, 460, 11, 14 ], [ 679, 460, 19, 14 ], [ 87, 476, 51, 14 ], [ 143, 476, 28, 14 ], [ 175, 476, 41, 14 ], [ 220, 476, 32, 14 ], [ 257, 476, 30, 14 ], [ 291, 476, 19, 14 ], [ 314, 476, 57, 14 ], [ 375, 476, 27, 14 ], [ 406, 476, 28, 14 ], [ 438, 476, 41, 14 ], [ 483, 476, 49, 14 ], [ 536, 476, 31, 14 ], [ 571, 476, 51, 14 ], [ 626, 476, 28, 14 ], [ 658, 476, 51, 14 ], [ 713, 476, 12, 14 ], [ 87, 493, 48, 14 ], [ 139, 493, 11, 14 ], [ 155, 493, 46, 14 ], [ 205, 493, 65, 14 ], [ 87, 510, 27, 14 ], [ 119, 510, 48, 14 ], [ 171, 510, 50, 14 ], [ 226, 510, 30, 14 ], [ 260, 510, 12, 14 ], [ 276, 510, 32, 14 ], [ 313, 510, 19, 14 ], [ 335, 510, 42, 14 ], [ 381, 510, 11, 14 ], [ 397, 510, 19, 14 ], [ 420, 510, 40, 14 ], [ 464, 510, 56, 14 ], [ 525, 510, 12, 14 ], [ 540, 510, 71, 14 ], [ 615, 510, 45, 14 ], [ 665, 510, 51, 14 ], [ 720, 510, 11, 14 ], [ 87, 526, 50, 14 ], [ 142, 526, 28, 14 ], [ 173, 526, 26, 14 ], [ 204, 526, 24, 14 ], [ 232, 526, 11, 14 ], [ 247, 526, 19, 14 ], [ 270, 526, 34, 14 ], [ 308, 526, 33, 14 ], [ 345, 526, 12, 14 ], [ 362, 526, 25, 14 ], [ 391, 526, 59, 14 ], [ 454, 526, 27, 14 ], [ 485, 526, 29, 14 ], [ 518, 526, 41, 14 ], [ 563, 526, 11, 14 ], [ 578, 526, 12, 14 ], [ 595, 526, 15, 14 ], [ 615, 526, 25, 14 ], [ 644, 526, 54, 14 ], [ 87, 543, 59, 14 ], [ 150, 543, 21, 14 ], [ 175, 543, 65, 14 ], [ 244, 543, 39, 14 ], [ 287, 543, 15, 14 ], [ 306, 543, 57, 14 ], [ 367, 543, 27, 14 ], [ 398, 543, 56, 14 ], [ 459, 543, 51, 14 ], [ 514, 543, 34, 14 ], [ 552, 543, 24, 14 ], [ 579, 543, 31, 14 ], [ 614, 543, 29, 14 ], [ 647, 543, 15, 14 ], [ 667, 543, 33, 14 ], [ 87, 560, 38, 14 ], [ 130, 560, 15, 14 ], [ 149, 560, 37, 14 ], [ 191, 560, 42, 14 ], [ 237, 560, 11, 14 ], [ 252, 560, 30, 14 ], [ 286, 560, 12, 14 ], [ 303, 560, 45, 14 ], [ 352, 560, 24, 14 ], [ 381, 560, 34, 14 ], [ 78, 605, 77, 15 ], [ 78, 623, 63, 14 ], [ 145, 623, 12, 14 ], [ 162, 623, 29, 14 ], [ 195, 623, 36, 14 ], [ 235, 623, 56, 14 ], [ 296, 623, 77, 14 ], [ 377, 623, 26, 14 ], [ 78, 639, 37, 14 ], [ 119, 639, 57, 14 ], [ 180, 639, 21, 14 ], [ 204, 639, 41, 14 ], [ 249, 639, 24, 14 ], [ 276, 639, 30, 14 ], [ 310, 639, 12, 14 ], [ 325, 639, 42, 14 ], [ 371, 639, 33, 14 ], [ 78, 656, 21, 14 ], [ 104, 656, 75, 14 ], [ 183, 656, 51, 14 ], [ 238, 656, 36, 14 ], [ 278, 656, 49, 14 ], [ 331, 656, 73, 14 ], [ 78, 672, 59, 14 ], [ 141, 672, 22, 14 ], [ 167, 672, 91, 14 ], [ 261, 672, 33, 14 ], [ 298, 672, 50, 14 ], [ 351, 672, 52, 14 ], [ 78, 689, 20, 14 ], [ 102, 689, 19, 14 ], [ 125, 689, 34, 14 ], [ 162, 689, 12, 14 ], [ 178, 689, 36, 14 ], [ 217, 689, 27, 14 ], [ 249, 689, 34, 14 ], [ 286, 689, 33, 14 ], [ 323, 689, 13, 14 ], [ 340, 689, 64, 14 ], [ 78, 706, 58, 14 ], [ 140, 706, 27, 14 ], [ 171, 706, 22, 14 ], [ 197, 706, 28, 14 ], [ 229, 706, 82, 14 ], [ 315, 706, 27, 14 ], [ 345, 706, 12, 14 ], [ 361, 706, 19, 14 ], [ 384, 706, 20, 14 ], [ 78, 722, 21, 14 ], [ 103, 722, 41, 14 ], [ 147, 722, 58, 14 ], [ 209, 722, 17, 14 ], [ 230, 722, 35, 14 ], [ 269, 722, 35, 14 ], [ 307, 722, 25, 14 ], [ 336, 722, 36, 14 ], [ 376, 722, 28, 14 ], [ 78, 739, 52, 14 ], [ 134, 739, 25, 14 ], [ 163, 739, 26, 14 ], [ 193, 739, 20, 14 ], [ 217, 739, 24, 14 ], [ 244, 739, 12, 14 ], [ 260, 739, 31, 14 ], [ 294, 739, 62, 14 ], [ 360, 739, 44, 14 ], [ 78, 755, 50, 14 ], [ 132, 755, 21, 14 ], [ 156, 755, 40, 14 ], [ 200, 755, 43, 14 ], [ 246, 755, 78, 14 ], [ 327, 755, 26, 14 ], [ 357, 755, 12, 14 ], [ 372, 755, 31, 14 ], [ 78, 772, 29, 14 ], [ 110, 772, 41, 14 ], [ 155, 772, 62, 14 ], [ 220, 772, 43, 14 ], [ 266, 772, 37, 14 ], [ 307, 772, 21, 14 ], [ 332, 772, 18, 14 ], [ 353, 772, 50, 14 ], [ 78, 789, 31, 14 ], [ 113, 789, 11, 14 ], [ 128, 789, 39, 14 ], [ 170, 789, 21, 14 ], [ 194, 789, 34, 14 ], [ 232, 789, 19, 14 ], [ 89, 805, 70, 14 ], [ 164, 805, 58, 14 ], [ 227, 805, 33, 14 ], [ 265, 805, 10, 14 ], [ 280, 805, 28, 14 ], [ 313, 805, 49, 14 ], [ 366, 805, 23, 14 ], [ 394, 805, 10, 14 ], [ 78, 822, 40, 14 ], [ 123, 822, 47, 14 ], [ 174, 822, 12, 14 ], [ 189, 822, 57, 14 ], [ 250, 822, 70, 14 ], [ 324, 822, 13, 14 ], [ 340, 822, 63, 14 ], [ 78, 839, 57, 14 ], [ 138, 839, 22, 14 ], [ 164, 839, 9, 14 ], [ 177, 839, 30, 14 ], [ 211, 839, 18, 14 ], [ 233, 839, 25, 14 ], [ 261, 839, 56, 14 ], [ 321, 839, 21, 14 ], [ 346, 839, 58, 14 ], [ 78, 855, 59, 14 ], [ 141, 855, 55, 14 ], [ 201, 855, 24, 14 ], [ 229, 855, 36, 14 ], [ 269, 855, 43, 14 ], [ 316, 855, 24, 14 ], [ 344, 855, 23, 14 ], [ 371, 855, 10, 14 ], [ 385, 855, 19, 14 ], [ 78, 872, 46, 14 ], [ 128, 872, 36, 14 ], [ 168, 872, 24, 14 ], [ 196, 872, 40, 14 ], [ 239, 872, 17, 14 ], [ 260, 872, 24, 14 ], [ 287, 872, 12, 14 ], [ 303, 872, 19, 14 ], [ 325, 872, 63, 14 ], [ 392, 872, 12, 14 ], [ 78, 888, 62, 14 ], [ 143, 888, 56, 14 ], [ 202, 888, 12, 14 ], [ 218, 888, 30, 14 ], [ 251, 888, 51, 14 ], [ 306, 888, 18, 14 ], [ 328, 888, 35, 14 ], [ 366, 888, 37, 14 ], [ 78, 905, 18, 14 ], [ 100, 905, 35, 14 ], [ 138, 905, 17, 14 ], [ 158, 905, 19, 14 ], [ 180, 905, 54, 14 ], [ 238, 905, 94, 14 ], [ 336, 905, 41, 14 ], [ 381, 905, 23, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 120, 11 ], [ 78, 950, 31, 11 ], [ 112, 950, 7, 11 ], [ 122, 950, 27, 11 ], [ 152, 950, 30, 11 ], [ 185, 950, 34, 11 ], [ 222, 950, 38, 11 ], [ 263, 950, 32, 11 ], [ 298, 950, 16, 11 ], [ 317, 950, 16, 11 ], [ 336, 950, 17, 11 ], [ 356, 950, 10, 11 ], [ 369, 950, 24, 11 ], [ 78, 962, 15, 11 ], [ 97, 962, 50, 11 ], [ 150, 962, 18, 11 ], [ 423, 606, 24, 14 ], [ 450, 606, 11, 14 ], [ 464, 606, 18, 14 ], [ 486, 606, 61, 14 ], [ 551, 606, 11, 14 ], [ 565, 606, 30, 14 ], [ 599, 606, 21, 14 ], [ 623, 606, 24, 14 ], [ 650, 606, 11, 14 ], [ 665, 606, 18, 14 ], [ 687, 606, 61, 14 ], [ 423, 623, 12, 14 ], [ 438, 623, 56, 14 ], [ 498, 623, 27, 14 ], [ 529, 623, 27, 14 ], [ 559, 623, 25, 14 ], [ 588, 623, 23, 14 ], [ 615, 623, 36, 14 ], [ 654, 623, 51, 14 ], [ 710, 623, 23, 14 ], [ 736, 623, 12, 14 ], [ 423, 639, 32, 14 ], [ 459, 639, 34, 14 ], [ 497, 639, 56, 14 ], [ 557, 639, 22, 14 ], [ 584, 639, 10, 14 ], [ 597, 639, 38, 14 ], [ 640, 639, 31, 14 ], [ 674, 639, 27, 14 ], [ 706, 639, 42, 14 ], [ 423, 656, 49, 14 ], [ 475, 656, 52, 14 ], [ 530, 656, 9, 14 ], [ 543, 656, 30, 14 ], [ 576, 656, 38, 14 ], [ 618, 656, 52, 14 ], [ 674, 656, 21, 14 ], [ 698, 656, 12, 14 ], [ 713, 656, 35, 14 ], [ 423, 672, 45, 14 ], [ 472, 672, 12, 14 ], [ 489, 672, 60, 14 ], [ 553, 672, 46, 14 ], [ 603, 672, 56, 14 ], [ 664, 672, 28, 14 ], [ 697, 672, 18, 14 ], [ 719, 672, 29, 14 ], [ 423, 689, 45, 14 ], [ 471, 689, 19, 14 ], [ 434, 706, 94, 14 ], [ 532, 706, 65, 14 ], [ 601, 706, 55, 14 ], [ 659, 706, 41, 14 ], [ 705, 706, 10, 14 ], [ 718, 706, 30, 14 ], [ 423, 722, 19, 14 ], [ 445, 722, 61, 14 ], [ 510, 722, 12, 14 ], [ 526, 722, 33, 14 ], [ 563, 722, 60, 14 ], [ 627, 722, 59, 14 ], [ 689, 722, 59, 14 ], [ 423, 739, 45, 14 ], [ 471, 739, 12, 14 ], [ 487, 739, 19, 14 ], [ 510, 739, 64, 14 ], [ 578, 739, 12, 14 ], [ 594, 739, 19, 14 ], [ 616, 739, 18, 14 ], [ 638, 739, 27, 14 ], [ 669, 739, 27, 14 ], [ 700, 739, 32, 14 ], [ 737, 739, 11, 14 ], [ 423, 755, 26, 14 ], [ 452, 755, 27, 14 ], [ 482, 755, 19, 14 ], [ 505, 755, 21, 14 ], [ 529, 755, 18, 14 ], [ 551, 755, 19, 14 ], [ 574, 755, 11, 14 ], [ 588, 755, 11, 14 ], [ 603, 755, 26, 14 ], [ 632, 755, 21, 14 ], [ 656, 755, 11, 14 ], [ 671, 755, 14, 14 ], [ 689, 755, 60, 14 ], [ 423, 772, 52, 14 ], [ 478, 772, 54, 14 ], [ 535, 772, 28, 14 ], [ 567, 772, 24, 14 ], [ 594, 772, 12, 14 ], [ 609, 772, 28, 14 ], [ 640, 772, 12, 14 ], [ 656, 772, 24, 14 ], [ 683, 772, 11, 14 ], [ 698, 772, 28, 14 ], [ 729, 772, 19, 14 ], [ 423, 789, 23, 14 ], [ 450, 789, 46, 14 ], [ 500, 789, 12, 14 ], [ 515, 789, 30, 14 ], [ 548, 789, 12, 14 ], [ 564, 789, 55, 14 ], [ 623, 789, 12, 14 ], [ 638, 789, 32, 14 ], [ 674, 789, 25, 14 ], [ 703, 789, 45, 14 ], [ 423, 805, 14, 14 ], [ 440, 805, 16, 14 ], [ 460, 805, 19, 14 ], [ 482, 805, 45, 14 ], [ 531, 805, 12, 14 ], [ 546, 805, 29, 14 ], [ 579, 805, 12, 14 ], [ 594, 805, 14, 14 ], [ 612, 805, 45, 14 ], [ 661, 805, 24, 14 ], [ 689, 805, 59, 14 ], [ 423, 822, 12, 14 ], [ 439, 822, 20, 14 ], [ 463, 822, 18, 14 ], [ 486, 822, 32, 14 ], [ 522, 822, 24, 14 ], [ 551, 822, 55, 14 ], [ 610, 822, 18, 14 ], [ 633, 822, 20, 14 ], [ 657, 822, 20, 14 ], [ 682, 822, 12, 14 ], [ 698, 822, 23, 14 ], [ 726, 822, 22, 14 ], [ 423, 839, 33, 14 ], [ 460, 839, 19, 14 ], [ 483, 839, 82, 14 ], [ 570, 839, 49, 14 ], [ 623, 839, 12, 14 ], [ 640, 839, 33, 14 ], [ 677, 839, 30, 14 ], [ 712, 839, 12, 14 ], [ 729, 839, 19, 14 ], [ 423, 855, 38, 14 ], [ 465, 855, 24, 14 ], [ 493, 855, 29, 14 ], [ 526, 855, 83, 14 ], [ 613, 855, 33, 14 ], [ 650, 855, 72, 14 ], [ 726, 855, 22, 14 ], [ 423, 872, 57, 14 ], [ 484, 872, 11, 14 ], [ 499, 872, 25, 14 ], [ 528, 872, 18, 14 ], [ 549, 872, 38, 14 ], [ 592, 872, 12, 14 ], [ 607, 872, 19, 14 ], [ 630, 872, 31, 14 ], [ 665, 872, 22, 14 ], [ 691, 872, 19, 14 ], [ 714, 872, 34, 14 ], [ 423, 888, 41, 14 ], [ 467, 888, 17, 14 ], [ 488, 888, 36, 14 ], [ 527, 888, 58, 14 ], [ 589, 888, 32, 14 ], [ 625, 888, 15, 14 ], [ 644, 888, 60, 14 ], [ 708, 888, 40, 14 ], [ 423, 905, 26, 14 ], [ 452, 905, 9, 14 ], [ 465, 905, 25, 14 ], [ 493, 905, 55, 14 ], [ 551, 905, 11, 14 ], [ 565, 905, 24, 14 ], [ 592, 905, 14, 14 ], [ 610, 905, 36, 14 ], [ 649, 905, 19, 14 ], [ 434, 921, 53, 14 ], [ 491, 921, 27, 14 ], [ 522, 921, 9, 14 ], [ 535, 921, 46, 14 ], [ 586, 921, 12, 14 ], [ 602, 921, 14, 14 ], [ 620, 921, 18, 14 ], [ 642, 921, 36, 14 ], [ 682, 921, 12, 14 ], [ 697, 921, 18, 14 ], [ 720, 921, 28, 14 ], [ 423, 938, 21, 14 ], [ 448, 938, 46, 14 ], [ 498, 938, 40, 14 ], [ 543, 938, 26, 14 ], [ 574, 938, 20, 14 ], [ 598, 938, 22, 14 ], [ 624, 938, 62, 14 ], [ 690, 938, 58, 14 ], [ 423, 955, 50, 14 ], [ 477, 955, 12, 14 ], [ 493, 955, 21, 14 ], [ 518, 955, 36, 14 ], [ 559, 955, 40, 14 ], [ 603, 955, 14, 14 ], [ 622, 955, 57, 14 ], [ 683, 955, 65, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 277, 987, 39, 10 ], [ 318, 987, 15, 10 ], [ 335, 987, 24, 10 ], [ 361, 987, 30, 10 ], [ 394, 987, 29, 10 ], [ 425, 987, 27, 10 ], [ 455, 987, 14, 10 ], [ 471, 987, 15, 10 ], [ 489, 987, 6, 10 ], [ 497, 987, 10, 10 ], [ 509, 987, 21, 10 ], [ 532, 987, 25, 10 ], [ 560, 987, 23, 10 ], [ 585, 987, 41, 10 ], [ 628, 987, 23, 10 ], [ 653, 987, 13, 10 ], [ 668, 987, 22, 10 ], [ 692, 987, 8, 10 ], [ 702, 987, 13, 10 ], [ 717, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 49, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Bussmann", "and", "Glenn", "Journal", "of", "Ethnobiology", "and", "Ethnomedicine", "2010,", "6:30", "http://www.ethnobiomed.com/content/6/1/30", "R", "E", "S", "E", "A", "R", "C", "H", "Medicinal", "plants", "used", "in", "Northern", "Peru", "for", "reproductive", "problems", "and", "female", "health", "Rainer", "W", "Bussmann*,", "Ashley", "Glenn", "JOURNAL", "OF", "ETHNOBIOLOGY", "AND", "ETHNOMEDICINE", "Open", "Access", "Abstract", "Infections", "of", "the", "reproductive", "tract,", "complications", "after", "childbirth,", "and", "reproductive", "problems", "continue", "to", "be", "a", "major", "health", "challenge", "worldwide.", "An", "impressive", "number", "of", "plant", "species", "is", "traditionally", "used", "to", "remedy", "such", "afflictions,", "and", "some", "have", "been", "investigated", "for", "their", "efficacy", "with", "positive", "results.", "A", "total", "of", "105", "plant", "species", "belonging", "to", "91", "genera", "and", "62", "families", "were", "documented", "and", "identified", "as", "herbal", "remedies", "for", "reproductive", "problems", "in", "Northern", "Peru.", "Most", "species", "used", "were", "Asteraceae", "(9.52%),", "followed", "by", "Lamiaceae", "and", "Fabaceae", "(8.57%", "and", "6.67%).", "The", "most", "important", "families", "are", "clearly", "represented", "very", "similarly", "to", "their", "overall", "importance", "in", "the", "local", "pharmacopoeia.", "The", "majority", "of", "herbal", "preparations", "for", "reproductive", "afflictions", "were", "prepared", "from", "the", "leaves", "of", "plants", "(22.72%),", "the", "whole", "plant", "(21.97%),", "and", "stems", "(21.21%),", "while", "other", "plant", "parts", "were", "used", "less", "frequently.", "More", "than", "60%", "of", "the", "cases", "fresh", "plant", "material", "was", "used", "to", "prepare", "remedies.", "Over", "70%", "of", "the", "remedies", "were", "applied", "orally,", "while", "the", "remaining", "ones", "were", "applied", "topically.", "Many", "remedies", "were", "prepared", "as", "mixtures", "of", "multiple", "ingredients.", "Little", "scientific", "evidence", "exists", "to", "prove", "the", "efficacy", "of", "the", "species", "employed", "as", "reproductive", "disorder", "remedies", "in", "Northern", "Peru.", "Only", "34%", "of", "the", "plants", "found", "or", "their", "congeners", "have", "been", "studied", "at", "all", "for", "their", "medicinal", "properties.", "The", "information", "gained", "on", "frequently", "used", "traditional", "remedies", "might", "give", "some", "leads", "for", "future", "targets", "for", "further", "analysis", "in", "order", "to", "develop", "new", "drugs.", "Background", "According", "to", "1999", "WHO", "estimates", "reproductive", "pro-", "blems,", "including,", "340", "million", "new", "cases", "of", "curable", "Sexu-", "ally", "Transmitted", "Diseases", "(STIs;", "syphilis,", "gonorrhoea,", "chlamydia", "and", "trichomoniasis)", "occur", "annually", "through-", "out", "the", "world", "in", "adults", "aged", "15-49", "years.", "In", "developing", "countries,", "STIs", "and", "their", "complications", "rank", "in", "the", "top", "five", "disease", "categories", "for", "which", "adults", "seek", "health", "care.", "Infection", "with", "STIs", "can", "lead", "to", "acute", "symptoms,", "chronic", "infection", "and", "serious", "delayed", "consequences", "such", "as", "infer-", "tility,", "ectopic", "pregnancy,", "cervical", "cancer", "and", "the", "untimely", "death", "of", "infants", "and", "adults", "[1].", "Traditional", "Medicine", "(TM)", "is", "used", "globally", "and", "is", "rapidly", "growing", "in", "economic", "importance.", "In", "developing", "countries,", "TM", "is", "often", "the", "only", "accessible", "and", "affordable", "treatment", "available.", "The", "WHO", "reports", "that", "TM", "is", "the", "primary", "health", "care", "system", "for", "80%", "of", "the", "population", "in", "developing", "countries.", "In", "Latin", "America,", "the", "WHO", "Regio-", "nal", "Office", "for", "the", "Americas", "(AMRO/PAHO)", "reports", "that", "*", "Correspondence:", "rainer.bussmann@mobot.org", "William", "L.", "Brown", "Center,", "Missouri", "Botanical", "Garden,", "P.O.", "Box", "299,", "St.", "Louis,", "MO", "63166-0299,", "USA", "71%", "of", "the", "population", "in", "Chile", "and", "40%", "of", "the", "population", "in", "Colombia", "have", "used", "TM.", "The", "WHO", "indicates", "that", "in", "many", "Asian", "countries", "TM", "is", "widely", "used,", "even", "though", "Western", "medicine", "is", "often", "readily", "available,", "and", "in", "Japan,", "60-70%", "of", "allopathic", "doctors", "prescribe", "TMs", "for", "their", "patients", "[2].", "Complementary", "Alternative", "Medicine", "(CAM)", "is", "gain-", "ing", "popularity", "in", "many", "developed", "countries.", "Forty-two", "percent", "of", "the", "population", "in", "the", "US", "have", "used", "CAM", "at", "least", "once", "[3],", "and", "the", "use", "of", "at", "least", "one", "of", "16", "alternative", "therapies", "increased", "from", "34%", "in", "1990", "to", "42%", "in", "1997", "[4].", "The", "number", "of", "visits", "to", "providers", "of", "CAM", "now", "exceeds", "by", "far", "the", "number", "of", "visits", "to", "all", "primary", "care", "physicians", "in", "the", "US", "[5,6].", "The", "expenses", "for", "the", "use", "of", "TM", "and", "CAM", "are", "exponentially", "growing", "in", "many", "parts", "of", "the", "world.", "The", "1997", "out-of-pocket", "CAM", "expenditure", "was", "estimated", "at", "US$", "2,7", "billion", "in", "the", "USA,", "and", "the", "world", "market", "for", "herbal", "medicines", "based", "on", "traditional", "knowl-", "edge", "is", "now", "estimated", "at", "US$", "60", "billion", "[7].", "Northern", "Peru", "is", "believed", "to", "be", "the", "center", "of", "the", "Cen-", "tral", "Andean", "Health", "Axis", "[8],", "and", "traditional", "medicinal", "practices", "in", "this", "region", "remain", "an", "important", "component", "©", "2010", "Bussmann", "and", "Glenn;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 0, 0, 0, 0, 0, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 70, 61, 39, 12 ], [ 111, 61, 48, 12 ], [ 161, 61, 56, 12 ], [ 70, 75, 23, 11 ], [ 95, 75, 22, 11 ], [ 119, 75, 59, 11 ], [ 70, 88, 35, 12 ], [ 107, 88, 24, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 112, 12 ], [ 70, 187, 70, 25 ], [ 145, 187, 64, 25 ], [ 70, 220, 67, 25 ], [ 142, 220, 22, 25 ], [ 168, 220, 84, 25 ], [ 256, 220, 22, 25 ], [ 283, 220, 73, 25 ], [ 360, 220, 54, 25 ], [ 418, 220, 42, 25 ], [ 465, 220, 22, 25 ], [ 492, 220, 110, 25 ], [ 606, 220, 61, 25 ], [ 671, 220, 68, 25 ], [ 120, 289, 64, 17 ], [ 186, 289, 16, 17 ], [ 205, 289, 44, 17 ], [ 252, 289, 27, 17 ], [ 282, 289, 29, 17 ], [ 314, 289, 19, 17 ], [ 120, 320, 51, 13 ], [ 174, 320, 31, 13 ], [ 208, 320, 9, 13 ], [ 220, 320, 47, 13 ], [ 270, 320, 48, 13 ], [ 320, 320, 53, 13 ], [ 375, 320, 52, 13 ], [ 430, 320, 6, 13 ], [ 438, 320, 54, 13 ], [ 495, 320, 29, 13 ], [ 526, 320, 29, 13 ], [ 558, 320, 27, 13 ], [ 587, 320, 37, 13 ], [ 626, 320, 27, 13 ], [ 655, 320, 27, 13 ], [ 685, 320, 45, 13 ], [ 120, 347, 83, 13 ], [ 205, 347, 34, 13 ], [ 242, 347, 12, 13 ], [ 256, 347, 49, 13 ], [ 308, 347, 11, 13 ], [ 321, 347, 20, 13 ], [ 343, 347, 16, 13 ], [ 362, 347, 105, 13 ], [ 120, 374, 44, 13 ], [ 166, 374, 6, 13 ], [ 175, 374, 23, 13 ], [ 200, 374, 27, 13 ], [ 230, 374, 39, 13 ], [ 271, 374, 12, 13 ], [ 286, 374, 35, 13 ], [ 324, 374, 27, 13 ], [ 354, 374, 46, 13 ], [ 402, 374, 12, 13 ], [ 417, 374, 35, 13 ], [ 454, 374, 24, 13 ], [ 120, 399, 49, 13 ], [ 172, 399, 35, 13 ], [ 209, 399, 30, 13 ], [ 241, 399, 10, 13 ], [ 254, 399, 102, 13 ], [ 120, 425, 52, 13 ], [ 174, 425, 9, 13 ], [ 186, 425, 24, 13 ], [ 213, 425, 9, 13 ], [ 225, 425, 12, 13 ], [ 240, 425, 32, 13 ], [ 274, 425, 19, 13 ], [ 295, 425, 7, 13 ], [ 305, 425, 16, 13 ], [ 326, 425, 22, 13 ], [ 353, 425, 8, 13 ], [ 366, 425, 13, 13 ], [ 384, 425, 26, 13 ], [ 414, 425, 30, 13 ], [ 449, 425, 31, 13 ], [ 485, 425, 55, 13 ], [ 545, 425, 30, 13 ], [ 580, 425, 16, 13 ], [ 601, 425, 41, 13 ], [ 647, 425, 53, 13 ], [ 705, 425, 57, 13 ], [ 120, 439, 40, 13 ], [ 163, 439, 31, 13 ], [ 197, 439, 39, 13 ], [ 239, 439, 61, 13 ], [ 303, 439, 20, 13 ], [ 326, 439, 63, 13 ], [ 393, 439, 19, 13 ], [ 415, 439, 66, 13 ], [ 485, 439, 11, 13 ], [ 499, 439, 18, 13 ], [ 520, 439, 46, 13 ], [ 569, 439, 45, 13 ], [ 617, 439, 16, 13 ], [ 637, 439, 39, 13 ], [ 680, 439, 26, 13 ], [ 709, 439, 8, 13 ], [ 720, 439, 43, 13 ], [ 120, 454, 28, 13 ], [ 120, 480, 52, 13 ], [ 174, 480, 27, 13 ], [ 204, 480, 31, 13 ], [ 237, 480, 29, 13 ], [ 269, 480, 8, 13 ], [ 280, 480, 19, 13 ], [ 301, 480, 10, 13 ], [ 314, 480, 16, 13 ], [ 333, 480, 37, 13 ], [ 372, 480, 32, 13 ], [ 407, 480, 10, 13 ], [ 420, 480, 30, 13 ], [ 453, 480, 46, 13 ], [ 501, 480, 19, 13 ], [ 523, 480, 28, 13 ], [ 554, 480, 56, 13 ], [ 612, 480, 35, 13 ], [ 649, 480, 24, 13 ], [ 676, 480, 21, 13 ], [ 700, 480, 38, 13 ], [ 740, 480, 23, 13 ], [ 120, 495, 40, 13 ], [ 164, 495, 24, 13 ], [ 192, 495, 33, 13 ], [ 229, 495, 11, 13 ], [ 243, 495, 53, 13 ], [ 300, 495, 11, 13 ], [ 314, 495, 16, 13 ], [ 334, 495, 37, 13 ], [ 375, 495, 61, 13 ], [ 439, 495, 20, 13 ], [ 463, 495, 33, 13 ], [ 500, 495, 48, 13 ], [ 551, 495, 20, 13 ], [ 575, 495, 19, 13 ], [ 598, 495, 46, 13 ], [ 647, 495, 17, 13 ], [ 668, 495, 24, 13 ], [ 696, 495, 32, 13 ], [ 732, 495, 11, 13 ], [ 747, 495, 16, 13 ], [ 120, 509, 21, 13 ], [ 144, 509, 11, 13 ], [ 158, 509, 32, 13 ], [ 193, 509, 24, 13 ], [ 221, 509, 17, 13 ], [ 241, 509, 10, 13 ], [ 254, 509, 40, 13 ], [ 298, 509, 38, 13 ], [ 339, 509, 15, 13 ], [ 357, 509, 22, 13 ], [ 383, 509, 20, 13 ], [ 406, 509, 28, 13 ], [ 437, 509, 22, 13 ], [ 462, 509, 21, 13 ], [ 486, 509, 13, 13 ], [ 502, 509, 52, 13 ], [ 557, 509, 20, 13 ], [ 579, 509, 11, 13 ], [ 593, 509, 16, 13 ], [ 612, 509, 50, 13 ], [ 665, 509, 11, 13 ], [ 679, 509, 20, 13 ], [ 701, 509, 12, 13 ], [ 717, 509, 46, 13 ], [ 120, 524, 16, 13 ], [ 139, 524, 46, 13 ], [ 188, 524, 21, 13 ], [ 212, 524, 19, 13 ], [ 235, 524, 42, 13 ], [ 280, 524, 73, 13 ], [ 356, 524, 22, 13 ], [ 381, 524, 29, 13 ], [ 413, 524, 62, 13 ], [ 478, 524, 6, 13 ], [ 487, 524, 35, 13 ], [ 525, 524, 55, 13 ], [ 582, 524, 11, 13 ], [ 596, 524, 31, 13 ], [ 630, 524, 22, 13 ], [ 655, 524, 19, 13 ], [ 677, 524, 51, 13 ], [ 731, 524, 6, 13 ], [ 740, 524, 23, 13 ], [ 120, 538, 57, 13 ], [ 180, 538, 11, 13 ], [ 192, 538, 14, 13 ], [ 209, 538, 32, 13 ], [ 243, 538, 11, 13 ], [ 256, 538, 40, 13 ], [ 299, 538, 35, 13 ], [ 336, 538, 55, 13 ], [ 393, 538, 10, 13 ], [ 406, 538, 28, 13 ], [ 437, 538, 10, 13 ], [ 450, 538, 23, 13 ], [ 70, 607, 13, 17 ], [ 89, 607, 92, 17 ], [ 70, 640, 57, 14 ], [ 132, 640, 30, 14 ], [ 167, 640, 34, 14 ], [ 206, 640, 32, 14 ], [ 243, 640, 19, 14 ], [ 266, 640, 53, 14 ], [ 324, 640, 7, 14 ], [ 335, 640, 34, 14 ], [ 374, 640, 31, 14 ], [ 70, 656, 12, 14 ], [ 85, 656, 55, 14 ], [ 143, 656, 57, 14 ], [ 203, 656, 21, 14 ], [ 228, 656, 41, 14 ], [ 272, 656, 30, 14 ], [ 306, 656, 12, 14 ], [ 321, 656, 58, 14 ], [ 383, 656, 21, 14 ], [ 70, 672, 43, 14 ], [ 117, 672, 62, 14 ], [ 183, 672, 22, 14 ], [ 208, 672, 36, 14 ], [ 248, 672, 12, 14 ], [ 263, 672, 6, 14 ], [ 273, 672, 27, 14 ], [ 304, 672, 45, 14 ], [ 353, 672, 12, 14 ], [ 368, 672, 36, 14 ], [ 70, 688, 21, 14 ], [ 95, 688, 6, 14 ], [ 105, 688, 31, 14 ], [ 139, 688, 12, 14 ], [ 155, 688, 61, 14 ], [ 220, 688, 59, 14 ], [ 283, 688, 25, 14 ], [ 312, 688, 57, 14 ], [ 372, 688, 32, 14 ], [ 70, 704, 12, 14 ], [ 85, 704, 65, 14 ], [ 153, 704, 47, 14 ], [ 203, 704, 21, 14 ], [ 228, 704, 73, 14 ], [ 304, 704, 21, 14 ], [ 328, 704, 35, 14 ], [ 366, 704, 38, 14 ], [ 70, 719, 74, 14 ], [ 149, 719, 48, 14 ], [ 202, 719, 12, 14 ], [ 218, 719, 30, 14 ], [ 253, 719, 19, 14 ], [ 276, 719, 54, 14 ], [ 335, 719, 22, 14 ], [ 362, 719, 25, 14 ], [ 392, 719, 12, 14 ], [ 70, 735, 26, 14 ], [ 100, 735, 33, 15 ], [ 136, 735, 52, 14 ], [ 192, 735, 52, 14 ], [ 248, 735, 57, 14 ], [ 308, 735, 12, 14 ], [ 324, 735, 6, 14 ], [ 334, 735, 45, 14 ], [ 382, 735, 22, 14 ], [ 70, 751, 28, 14 ], [ 101, 751, 22, 14 ], [ 125, 751, 34, 14 ], [ 91, 767, 57, 14 ], [ 150, 767, 35, 14 ], [ 187, 767, 19, 14 ], [ 208, 767, 62, 14 ], [ 273, 767, 18, 14 ], [ 293, 767, 23, 14 ], [ 319, 767, 37, 14 ], [ 358, 767, 26, 14 ], [ 386, 767, 18, 14 ], [ 70, 783, 103, 14 ], [ 179, 783, 18, 14 ], [ 202, 783, 23, 14 ], [ 232, 783, 47, 14 ], [ 285, 783, 34, 14 ], [ 325, 783, 55, 14 ], [ 386, 783, 18, 14 ], [ 70, 798, 41, 14 ], [ 114, 798, 12, 14 ], [ 129, 798, 47, 14 ], [ 180, 798, 42, 14 ], [ 226, 798, 21, 14 ], [ 250, 798, 21, 14 ], [ 275, 798, 41, 14 ], [ 320, 798, 22, 14 ], [ 345, 798, 59, 14 ], [ 70, 814, 41, 14 ], [ 113, 814, 35, 14 ], [ 151, 814, 12, 14 ], [ 166, 814, 22, 14 ], [ 190, 814, 41, 14 ], [ 234, 814, 26, 14 ], [ 263, 814, 33, 15 ], [ 299, 814, 51, 14 ], [ 353, 814, 22, 14 ], [ 378, 814, 26, 14 ], [ 70, 830, 54, 14 ], [ 127, 830, 31, 14 ], [ 162, 830, 24, 14 ], [ 189, 830, 41, 14 ], [ 233, 830, 38, 14 ], [ 275, 830, 12, 14 ], [ 290, 830, 30, 14 ], [ 324, 830, 46, 14 ], [ 373, 830, 31, 14 ], [ 70, 846, 63, 14 ], [ 135, 846, 17, 14 ], [ 154, 846, 24, 14 ], [ 180, 846, 41, 14 ], [ 223, 846, 42, 14 ], [ 267, 846, 21, 14 ], [ 290, 846, 69, 14 ], [ 362, 846, 42, 14 ], [ 70, 861, 31, 14 ], [ 105, 861, 24, 14 ], [ 134, 861, 41, 14 ], [ 179, 861, 42, 14 ], [ 225, 861, 67, 14 ], [ 297, 861, 16, 14 ], [ 318, 861, 29, 14 ], [ 351, 861, 21, 14 ], [ 377, 861, 27, 14 ], [ 70, 877, 51, 14 ], [ 124, 877, 56, 14 ], [ 183, 877, 25, 14 ], [ 211, 877, 22, 14 ], [ 235, 877, 12, 14 ], [ 250, 877, 51, 14 ], [ 304, 877, 15, 14 ], [ 322, 877, 16, 14 ], [ 91, 893, 52, 14 ], [ 146, 893, 15, 14 ], [ 164, 893, 46, 14 ], [ 212, 893, 43, 14 ], [ 257, 893, 13, 14 ], [ 273, 893, 49, 14 ], [ 325, 893, 9, 14 ], [ 336, 893, 48, 14 ], [ 387, 893, 17, 14 ], [ 70, 909, 55, 14 ], [ 129, 909, 12, 14 ], [ 145, 909, 62, 14 ], [ 211, 909, 25, 14 ], [ 241, 909, 25, 14 ], [ 270, 909, 68, 14 ], [ 342, 909, 62, 14 ], [ 70, 925, 21, 14 ], [ 96, 925, 27, 14 ], [ 127, 925, 30, 14 ], [ 161, 925, 63, 14 ], [ 229, 925, 35, 14 ], [ 269, 925, 20, 14 ], [ 293, 925, 111, 14 ], [ 70, 940, 21, 14 ], [ 93, 940, 30, 14 ], [ 125, 940, 74, 14 ], [ 201, 940, 38, 14 ], [ 241, 940, 12, 14 ], [ 254, 940, 30, 14 ], [ 286, 940, 34, 14 ], [ 323, 940, 25, 14 ], [ 350, 940, 54, 14 ], [ 70, 956, 55, 14 ], [ 128, 956, 26, 14 ], [ 156, 956, 25, 14 ], [ 185, 956, 18, 14 ], [ 206, 956, 22, 14 ], [ 231, 956, 12, 14 ], [ 245, 956, 67, 14 ], [ 316, 956, 21, 14 ], [ 340, 956, 43, 14 ], [ 386, 956, 18, 14 ], [ 70, 972, 65, 14 ], [ 138, 972, 28, 14 ], [ 168, 972, 54, 14 ], [ 225, 972, 55, 14 ], [ 282, 972, 26, 14 ], [ 310, 972, 23, 14 ], [ 335, 972, 30, 14 ], [ 367, 972, 37, 14 ], [ 70, 988, 12, 14 ], [ 84, 988, 81, 14 ], [ 167, 988, 25, 14 ], [ 194, 988, 20, 14 ], [ 217, 988, 32, 14 ], [ 251, 988, 92, 14 ], [ 345, 988, 12, 14 ], [ 359, 988, 45, 14 ], [ 70, 1004, 8, 14 ], [ 81, 1004, 29, 14 ], [ 112, 1004, 56, 14 ], [ 172, 1004, 59, 14 ], [ 233, 1004, 21, 14 ], [ 257, 1004, 30, 14 ], [ 290, 1004, 74, 14 ], [ 366, 1004, 38, 14 ], [ 70, 1019, 26, 14 ], [ 103, 1019, 20, 14 ], [ 131, 1019, 22, 14 ], [ 160, 1019, 12, 14 ], [ 180, 1019, 25, 14 ], [ 212, 1019, 40, 14 ], [ 260, 1019, 30, 14 ], [ 298, 1019, 63, 14 ], [ 369, 1019, 35, 14 ], [ 428, 609, 20, 14 ], [ 452, 609, 70, 14 ], [ 526, 609, 72, 14 ], [ 602, 609, 85, 14 ], [ 690, 609, 21, 14 ], [ 715, 609, 47, 14 ], [ 428, 625, 93, 14 ], [ 523, 625, 27, 14 ], [ 553, 625, 26, 14 ], [ 581, 625, 26, 14 ], [ 609, 625, 14, 14 ], [ 624, 625, 37, 14 ], [ 663, 625, 12, 14 ], [ 677, 625, 26, 14 ], [ 705, 625, 57, 14 ], [ 428, 640, 36, 14 ], [ 466, 640, 30, 15 ], [ 498, 640, 12, 14 ], [ 512, 640, 40, 14 ], [ 554, 640, 11, 14 ], [ 567, 640, 73, 14 ], [ 642, 640, 28, 14 ], [ 672, 640, 25, 14 ], [ 699, 640, 63, 14 ], [ 428, 656, 76, 14 ], [ 507, 656, 12, 14 ], [ 521, 656, 50, 14 ], [ 574, 656, 49, 14 ], [ 626, 656, 34, 14 ], [ 449, 672, 50, 14 ], [ 503, 672, 30, 14 ], [ 537, 672, 51, 14 ], [ 592, 672, 19, 14 ], [ 615, 672, 27, 14 ], [ 645, 672, 36, 14 ], [ 685, 672, 12, 14 ], [ 701, 672, 18, 14 ], [ 723, 672, 23, 14 ], [ 750, 672, 12, 14 ], [ 428, 688, 27, 14 ], [ 459, 688, 19, 14 ], [ 481, 688, 45, 14 ], [ 530, 688, 37, 14 ], [ 570, 688, 21, 14 ], [ 595, 688, 12, 14 ], [ 610, 688, 52, 14 ], [ 666, 688, 60, 14 ], [ 730, 688, 32, 14 ], [ 428, 704, 27, 14 ], [ 458, 704, 27, 14 ], [ 489, 704, 22, 14 ], [ 514, 704, 27, 14 ], [ 545, 704, 24, 14 ], [ 572, 704, 24, 14 ], [ 599, 704, 23, 14 ], [ 626, 704, 14, 14 ], [ 643, 704, 57, 14 ], [ 704, 704, 22, 14 ], [ 729, 704, 12, 14 ], [ 744, 704, 18, 14 ], [ 428, 719, 55, 14 ], [ 488, 719, 12, 14 ], [ 505, 719, 22, 14 ], [ 531, 719, 14, 14 ], [ 550, 719, 51, 14 ], [ 606, 719, 51, 14 ], [ 662, 719, 27, 14 ], [ 694, 719, 21, 14 ], [ 720, 719, 42, 14 ], [ 428, 735, 58, 14 ], [ 489, 735, 50, 14 ], [ 541, 735, 22, 14 ], [ 566, 735, 35, 14 ], [ 605, 735, 17, 14 ], [ 624, 735, 27, 14 ], [ 654, 735, 19, 14 ], [ 676, 735, 43, 14 ], [ 721, 735, 17, 14 ], [ 741, 735, 22, 14 ], [ 428, 751, 9, 14 ], [ 442, 751, 68, 14 ], [ 515, 751, 30, 14 ], [ 549, 751, 18, 14 ], [ 572, 751, 92, 14 ], [ 669, 751, 12, 14 ], [ 685, 751, 22, 14 ], [ 712, 751, 9, 14 ], [ 725, 751, 37, 14 ], [ 428, 767, 57, 14 ], [ 488, 767, 8, 14 ], [ 499, 767, 35, 14 ], [ 537, 767, 6, 14 ], [ 546, 767, 35, 14 ], [ 584, 767, 17, 14 ], [ 604, 767, 14, 14 ], [ 620, 767, 46, 14 ], [ 669, 767, 27, 14 ], [ 698, 767, 19, 14 ], [ 720, 767, 43, 14 ], [ 428, 782, 47, 15 ], [ 481, 782, 25, 14 ], [ 511, 782, 9, 14 ], [ 526, 782, 43, 14 ], [ 574, 782, 47, 14 ], [ 627, 782, 19, 14 ], [ 652, 782, 30, 14 ], [ 686, 782, 20, 14 ], [ 712, 782, 50, 14 ], [ 428, 798, 27, 14 ], [ 459, 798, 27, 14 ], [ 489, 798, 21, 14 ], [ 514, 798, 62, 14 ], [ 580, 798, 24, 14 ], [ 608, 798, 17, 14 ], [ 628, 798, 40, 14 ], [ 671, 798, 47, 14 ], [ 722, 798, 12, 14 ], [ 737, 798, 25, 14 ], [ 428, 814, 75, 14 ], [ 506, 814, 44, 14 ], [ 553, 814, 66, 14 ], [ 621, 814, 53, 14 ], [ 677, 814, 18, 14 ], [ 697, 814, 33, 14 ], [ 732, 814, 30, 14 ], [ 428, 830, 39, 14 ], [ 472, 830, 38, 14 ], [ 515, 830, 24, 14 ], [ 543, 830, 13, 14 ], [ 561, 830, 43, 15 ], [ 610, 830, 12, 14 ], [ 626, 830, 25, 14 ], [ 656, 830, 21, 14 ], [ 681, 830, 34, 14 ], [ 720, 830, 24, 14 ], [ 749, 830, 13, 14 ], [ 428, 846, 27, 14 ], [ 458, 846, 13, 14 ], [ 474, 846, 38, 15 ], [ 515, 846, 37, 14 ], [ 555, 846, 34, 14 ], [ 593, 846, 37, 14 ], [ 633, 846, 42, 14 ], [ 678, 846, 29, 14 ], [ 710, 846, 52, 14 ], [ 428, 861, 18, 14 ], [ 450, 861, 35, 14 ], [ 489, 861, 12, 14 ], [ 504, 861, 22, 14 ], [ 530, 861, 21, 14 ], [ 554, 861, 40, 14 ], [ 598, 861, 31, 14 ], [ 633, 861, 34, 14 ], [ 671, 861, 20, 14 ], [ 695, 861, 67, 14 ], [ 428, 877, 23, 14 ], [ 459, 877, 46, 14 ], [ 512, 877, 21, 14 ], [ 541, 877, 24, 14 ], [ 572, 877, 27, 14 ], [ 607, 877, 9, 14 ], [ 623, 877, 19, 14 ], [ 650, 877, 27, 14 ], [ 684, 877, 48, 14 ], [ 740, 877, 22, 14 ], [ 428, 893, 59, 14 ], [ 490, 893, 24, 14 ], [ 517, 893, 75, 15 ], [ 594, 893, 23, 14 ], [ 620, 893, 46, 14 ], [ 668, 893, 21, 14 ], [ 693, 893, 24, 14 ], [ 719, 893, 12, 14 ], [ 733, 893, 29, 14 ], [ 428, 909, 33, 14 ], [ 468, 909, 21, 14 ], [ 497, 909, 14, 14 ], [ 518, 909, 45, 14 ], [ 569, 909, 12, 14 ], [ 588, 909, 54, 14 ], [ 648, 909, 45, 14 ], [ 701, 909, 9, 14 ], [ 716, 909, 46, 14 ], [ 428, 925, 43, 14 ], [ 477, 925, 55, 14 ], [ 538, 925, 12, 14 ], [ 556, 925, 53, 14 ], [ 614, 925, 27, 14 ], [ 647, 925, 22, 14 ], [ 675, 925, 70, 14 ], [ 751, 925, 12, 14 ], [ 428, 940, 78, 14 ], [ 509, 940, 78, 14 ], [ 590, 940, 41, 14 ], [ 449, 956, 25, 14 ], [ 477, 956, 37, 14 ], [ 518, 956, 9, 14 ], [ 530, 956, 14, 14 ], [ 548, 956, 47, 14 ], [ 599, 956, 28, 14 ], [ 631, 956, 12, 14 ], [ 646, 956, 17, 14 ], [ 667, 956, 8, 14 ], [ 679, 956, 16, 14 ], [ 698, 956, 20, 14 ], [ 721, 956, 41, 14 ], [ 428, 972, 18, 14 ], [ 453, 972, 61, 14 ], [ 521, 972, 12, 14 ], [ 540, 972, 28, 14 ], [ 575, 972, 60, 14 ], [ 642, 972, 12, 14 ], [ 661, 972, 36, 14 ], [ 704, 972, 27, 14 ], [ 738, 972, 24, 14 ], [ 428, 988, 23, 14 ], [ 455, 988, 63, 14 ], [ 523, 988, 42, 14 ], [ 569, 988, 12, 14 ], [ 585, 988, 43, 14 ], [ 632, 988, 25, 14 ], [ 661, 988, 22, 14 ], [ 687, 988, 14, 14 ], [ 704, 988, 58, 14 ], [ 428, 1004, 21, 14 ], [ 454, 1004, 61, 14 ], [ 520, 1004, 29, 14 ], [ 554, 1004, 36, 14 ], [ 595, 1004, 60, 14 ], [ 659, 1004, 24, 14 ], [ 688, 1004, 43, 14 ], [ 735, 1004, 27, 14 ], [ 428, 1019, 72, 14 ], [ 503, 1019, 21, 14 ], [ 527, 1019, 50, 14 ], [ 580, 1019, 29, 14 ], [ 612, 1019, 24, 14 ], [ 638, 1019, 12, 14 ], [ 653, 1019, 18, 14 ], [ 674, 1019, 49, 14 ], [ 725, 1019, 37, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Stem", "Cells", "International", "Volume", "2012,", "Article", "ID", "141624,", "8", "pages", "doi:10.1155/2012/141624", "Review", "Article", "Bench", "to", "Bedside", "of", "Neural", "Stem", "Cell", "in", "Traumatic", "Brain", "Injury", "Solomon", "O.", "Ugoya", "and", "Jian", "Tu", "Australian", "School", "of", "Advanced", "Medicine,", "Macquarie", "University,", "2", "Technology", "Place,", "North", "Ryde,", "Sydney,", "NSW", "2109,", "Australia", "Correspondence", "should", "be", "addressed", "to", "Jian", "Tu,", "james.tu@mq.edu.au", "Received", "1", "June", "2012;", "Revised", "10", "August", "2012;", "Accepted", "21", "August", "2012", "Academic", "Editor:", "Rocio", "E.", "Gonzalez-Castaneda", "Copyright", "©", "2012", "S.", "O.", "Ugoya", "and", "J.", "Tu.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Traumatic", "brain", "injury", "(TBI)", "is", "one", "of", "the", "leading", "causes", "of", "major", "disability", "and", "death", "worldwide.", "Neural", "stem", "cells", "(NSCs)", "have", "recently", "been", "shown", "to", "contribute", "to", "the", "cellular", "remodelling", "that", "occurs", "following", "TBI", "and", "attention", "has", "been", "drawn", "to", "the", "area", "of", "neural", "stem", "cell", "as", "possible", "therapy", "for", "TBI.", "The", "NSCs", "may", "play", "an", "important", "role", "in", "the", "treatment", "of", "TBI", "by", "replacing", "the", "damaged", "cells", "and", "eventual", "remyelination.", "This", "paper", "summarized", "a", "critical", "assessment", "of", "recent", "data", "and", "developed", "a", "view", "comprising", "of", "six", "points", "to", "possible", "quality", "translation", "of", "NSCs", "in", "TBI.", "1.", "Introduction", "Traumatic", "brain", "injury", "(TBI)", "has", "remained", "a", "major", "cause", "of", "mortality,", "morbidity", "and", "leading", "cause", "of", "large-scale", "dis-", "abilities", "worldwide.", "TBI", "results", "in", "a", "large", "number", "of", "deaths", "and", "a", "cause", "of", "permanent", "disabilities", "with", "enormous", "losses", "to", "individuals,", "families,", "and", "communities", "[1].", "World", "Health", "Organization", "(WHO),", "in", "2004,", "has", "estimated", "that", "25%", "of", "road", "traffic", "collisions", "requiring", "admission", "to", "a", "hospital", "suf-", "fered", "TBI", "[1–3].", "Moreover,", "WHO", "has", "introduced", "the", "new", "metric", "tool,", "the", "disability-adjusted", "life", "year", "(DALY),", "which", "quantifies", "the", "burden", "of", "diseases,", "injuries", "and", "risk", "factors.", "The", "worldwide", "leading", "causes", "of", "TBI", "include", "road", "traffic", "accidents", "that", "were", "estimated", "being", "41.2", "million", "DALYs", "in", "2008,", "violence", "being", "responsible", "for", "21.7", "million", "DALYs,", "and", "self-inflicted", "injuries", "being", "19.6", "million", "DALYs,", "respectively.", "All", "these", "will", "leave", "disability", "associated", "with", "TBI", "in", "survivors", "[2,", "3].", "However,", "no", "effective", "therapy", "or", "program", "is", "available", "for", "treatment", "of", "individuals", "with", "TBI;", "nonetheless,", "researchers", "had", "tried", "some", "therapeutic", "agents", "like", "levodopa/carbidopa", "and", "some", "neurotrophic", "factors", "in", "brain", "injury", "with", "persistent", "vegetative", "state", "with", "the", "aim", "of", "augmenting", "and", "slowing", "the", "progression", "from", "persistent", "vegetative", "state", "into", "some", "degree", "of", "consciousness.", "This", "still", "needs", "experimentation", "to", "confirm", "if", "these", "dopamine", "precursors", "and", "other", "neurotrophic", "factors", "have", "any", "role", "in", "TBI.", "Several", "other", "therapeutic", "agents", "like", "cannabinoid", "dexanabinol,", "erythropoietin,", "and", "gamma-", "glutamylcysteine", "ethyl", "ester", "have", "all", "shown", "to", "have", "neuropro-", "tective", "effect", "in", "human", "at", "experimental", "stage", "with", "remarkable", "improvement", "in", "post-TBI", "outcome", "[4–8].", "Recently,", "more", "attention", "has", "been", "drawn", "to", "the", "area", "of", "stem", "cell", "therapy,", "largely", "due", "to", "advanced", "knowledge", "about", "stem", "cells.", "The", "stem", "cells", "may", "play", "an", "important", "role", "in", "the", "treatment", "of", "TBI", "by", "replacing", "damaged", "cells,", "and", "helping", "functional", "recovery.", "The", "search", "for", "stem", "cell", "therapy", "for", "TBI", "is", "progressing.", "Since", "the", "pathophysiology", "of", "TBI", "is", "largely", "unknown,", "it", "makes", "a", "search", "for", "an", "effective", "stem", "cell", "therapy", "difficult.", "This", "is", "because", "multiple", "cell", "types", "like", "neuronal", "cells,", "glial,", "and", "endothelial", "cells", "are", "usually", "involved", "in", "TBI.", "Furthermore,", "cerebral", "vasculature,", "especially", "the", "blood", "brain", "barrier", "(BBB),", "may", "be", "affected", "in", "TBI;", "this", "injury", "may", "be", "focal", "or", "diffuse", "axonal", "injury", "(DAI).", "Taming", "these", "burgeon-", "ing", "effects", "of", "TBI", "will", "require", "NSCs", "which", "can", "differentiate", "into", "neurons", "and", "glial", "cells.", "It", "has", "been", "reported", "that", "progenitor", "cells", "differentiated", "into", "neurons", "and", "glial", "in", "adult", "brain,", "and", "an", "increase", "in", "astrocytic", "progeny", "is", "forming", "reactive", "astrocytes", "to", "primarily", "limit", "cyst", "enlargement", "in", "posttraumatic", "syringomyelia", "[9–12].", "This", "review", "is", "an", "optional", "extra", "to", "see", "if", "we", "can", "achieve", "the", "translation", "of", "basic", "knowledge", "of", "neural", "stem", "cells", "into", "therapeutic", "options", "in", "persons", "with", "TBI", "by", "enhancing", "and", "integrating", "these", "neural", "progenitor", "cells", "(NPCs)", "unto", "neurogenesis", "and", "directing", "these", "cells", "to", "the", "specified", "targets" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 18, 18, 18, 18, 18, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 80, 78, 170, 28 ], [ 260, 78, 25, 28 ], [ 293, 78, 173, 28 ], [ 475, 78, 130, 28 ], [ 614, 78, 24, 28 ], [ 646, 78, 64, 28 ], [ 719, 78, 47, 28 ], [ 80, 109, 60, 28 ], [ 147, 109, 127, 28 ], [ 281, 109, 45, 28 ], [ 334, 109, 129, 28 ], [ 470, 109, 116, 28 ], [ 593, 109, 79, 28 ], [ 679, 109, 91, 28 ], [ 80, 139, 46, 28 ], [ 136, 139, 79, 28 ], [ 224, 139, 163, 28 ], [ 80, 183, 50, 14 ], [ 135, 180, 63, 17 ], [ 202, 183, 25, 14 ], [ 232, 180, 52, 17 ], [ 288, 183, 42, 14 ], [ 334, 180, 52, 17 ], [ 390, 183, 72, 14 ], [ 466, 183, 15, 14 ], [ 485, 180, 68, 17 ], [ 557, 183, 45, 14 ], [ 605, 180, 65, 17 ], [ 80, 205, 6, 10 ], [ 88, 205, 50, 10 ], [ 143, 205, 9, 10 ], [ 156, 205, 88, 10 ], [ 250, 205, 16, 10 ], [ 271, 205, 21, 10 ], [ 296, 205, 34, 10 ], [ 335, 205, 15, 10 ], [ 356, 205, 20, 10 ], [ 381, 205, 21, 10 ], [ 407, 205, 43, 10 ], [ 455, 205, 44, 10 ], [ 505, 205, 22, 10 ], [ 532, 205, 28, 10 ], [ 565, 205, 25, 10 ], [ 595, 205, 9, 10 ], [ 609, 205, 36, 10 ], [ 649, 205, 6, 10 ], [ 657, 205, 15, 10 ], [ 677, 205, 20, 10 ], [ 703, 205, 21, 10 ], [ 729, 205, 41, 10 ], [ 80, 219, 64, 10 ], [ 147, 219, 28, 10 ], [ 178, 219, 30, 10 ], [ 211, 219, 15, 10 ], [ 229, 219, 20, 10 ], [ 252, 219, 21, 10 ], [ 276, 219, 43, 10 ], [ 321, 219, 44, 10 ], [ 368, 219, 22, 10 ], [ 393, 219, 28, 10 ], [ 423, 219, 25, 10 ], [ 451, 219, 9, 10 ], [ 463, 219, 34, 10 ], [ 102, 258, 57, 14 ], [ 101, 285, 69, 13 ], [ 174, 285, 57, 13 ], [ 235, 285, 32, 13 ], [ 270, 285, 17, 13 ], [ 290, 285, 27, 13 ], [ 321, 285, 61, 13 ], [ 385, 285, 28, 13 ], [ 416, 285, 22, 13 ], [ 441, 285, 22, 13 ], [ 467, 285, 13, 13 ], [ 483, 285, 53, 13 ], [ 539, 285, 20, 13 ], [ 563, 285, 10, 13 ], [ 576, 285, 35, 13 ], [ 615, 285, 70, 13 ], [ 688, 285, 33, 13 ], [ 724, 285, 24, 13 ], [ 102, 299, 19, 13 ], [ 123, 299, 16, 13 ], [ 142, 299, 11, 13 ], [ 156, 299, 58, 13 ], [ 216, 299, 11, 13 ], [ 230, 299, 11, 13 ], [ 244, 299, 101, 13 ], [ 348, 299, 43, 13 ], [ 393, 299, 8, 13 ], [ 404, 299, 6, 13 ], [ 413, 299, 94, 13 ], [ 509, 299, 22, 13 ], [ 533, 299, 8, 13 ], [ 544, 299, 54, 13 ], [ 601, 299, 81, 13 ], [ 684, 299, 10, 13 ], [ 697, 299, 6, 13 ], [ 706, 299, 42, 13 ], [ 102, 313, 11, 13 ], [ 117, 313, 33, 13 ], [ 153, 313, 31, 13 ], [ 188, 313, 50, 13 ], [ 242, 313, 24, 13 ], [ 269, 313, 8, 13 ], [ 281, 313, 36, 13 ], [ 320, 313, 31, 13 ], [ 356, 313, 18, 13 ], [ 377, 313, 21, 13 ], [ 401, 313, 11, 13 ], [ 416, 313, 43, 13 ], [ 462, 313, 10, 13 ], [ 476, 313, 27, 13 ], [ 506, 313, 20, 13 ], [ 530, 313, 25, 13 ], [ 559, 313, 54, 13 ], [ 617, 313, 18, 13 ], [ 639, 313, 55, 13 ], [ 697, 313, 47, 13 ], [ 101, 339, 48, 13 ], [ 153, 339, 21, 13 ], [ 178, 339, 42, 13 ], [ 224, 339, 43, 13 ], [ 270, 339, 56, 13 ], [ 330, 339, 10, 13 ], [ 344, 339, 33, 13 ], [ 380, 339, 45, 13 ], [ 429, 339, 37, 13 ], [ 470, 339, 18, 13 ], [ 492, 339, 24, 13 ], [ 519, 339, 20, 13 ], [ 543, 339, 59, 13 ], [ 606, 339, 23, 13 ], [ 632, 339, 20, 13 ], [ 656, 339, 52, 13 ], [ 711, 339, 13, 13 ], [ 728, 339, 20, 13 ], [ 102, 353, 24, 13 ], [ 132, 353, 24, 13 ], [ 161, 353, 104, 13 ], [ 271, 353, 21, 13 ], [ 298, 353, 25, 13 ], [ 329, 353, 12, 13 ], [ 346, 353, 46, 13 ], [ 398, 353, 43, 13 ], [ 446, 353, 10, 13 ], [ 462, 353, 37, 13 ], [ 505, 353, 18, 13 ], [ 529, 353, 24, 13 ], [ 559, 353, 20, 13 ], [ 585, 353, 37, 13 ], [ 628, 353, 59, 13 ], [ 693, 353, 26, 13 ], [ 724, 353, 23, 13 ], [ 102, 367, 67, 13 ], [ 175, 367, 51, 13 ], [ 232, 367, 20, 13 ], [ 258, 367, 58, 13 ], [ 321, 367, 40, 13 ], [ 367, 367, 21, 13 ], [ 393, 367, 52, 13 ], [ 450, 367, 13, 13 ], [ 469, 367, 25, 13 ], [ 500, 367, 60, 13 ], [ 565, 367, 40, 13 ], [ 610, 367, 38, 13 ], [ 653, 367, 28, 13 ], [ 687, 367, 20, 13 ], [ 712, 367, 35, 13 ], [ 102, 381, 52, 13 ], [ 157, 381, 31, 13 ], [ 191, 381, 43, 13 ], [ 237, 381, 30, 13 ], [ 270, 381, 14, 13 ], [ 288, 381, 33, 13 ], [ 324, 381, 39, 13 ], [ 365, 381, 20, 13 ], [ 389, 381, 33, 13 ], [ 425, 381, 69, 13 ], [ 497, 381, 20, 13 ], [ 521, 381, 52, 13 ], [ 576, 381, 13, 13 ], [ 592, 381, 10, 13 ], [ 605, 381, 21, 13 ], [ 630, 381, 25, 13 ], [ 658, 381, 36, 13 ], [ 697, 381, 51, 13 ], [ 102, 395, 36, 13 ], [ 144, 395, 20, 13 ], [ 169, 395, 34, 13 ], [ 209, 395, 67, 13 ], [ 282, 395, 22, 13 ], [ 309, 395, 43, 13 ], [ 358, 395, 8, 13 ], [ 371, 395, 63, 13 ], [ 440, 395, 81, 13 ], [ 526, 395, 10, 13 ], [ 541, 395, 37, 13 ], [ 584, 395, 38, 13 ], [ 628, 395, 20, 13 ], [ 653, 395, 18, 13 ], [ 677, 395, 27, 13 ], [ 709, 395, 39, 13 ], [ 102, 409, 56, 13 ], [ 162, 409, 11, 13 ], [ 177, 409, 43, 13 ], [ 223, 409, 10, 13 ], [ 237, 409, 37, 13 ], [ 278, 409, 18, 13 ], [ 300, 409, 24, 13 ], [ 328, 409, 63, 13 ], [ 394, 409, 47, 13 ], [ 446, 409, 33, 13 ], [ 482, 409, 18, 13 ], [ 504, 409, 67, 13 ], [ 575, 409, 35, 13 ], [ 614, 409, 52, 13 ], [ 670, 409, 20, 13 ], [ 694, 409, 54, 13 ], [ 102, 422, 43, 13 ], [ 151, 422, 79, 13 ], [ 236, 422, 21, 13 ], [ 263, 422, 49, 13 ], [ 317, 422, 81, 13 ], [ 404, 422, 25, 13 ], [ 435, 422, 20, 13 ], [ 462, 422, 41, 13 ], [ 508, 422, 32, 13 ], [ 546, 422, 37, 13 ], [ 589, 422, 65, 13 ], [ 660, 422, 29, 13 ], [ 695, 422, 53, 13 ], [ 102, 436, 45, 13 ], [ 155, 436, 26, 13 ], [ 189, 436, 46, 13 ], [ 242, 436, 42, 13 ], [ 293, 436, 22, 13 ], [ 322, 436, 98, 13 ], [ 428, 436, 51, 13 ], [ 487, 436, 11, 13 ], [ 506, 436, 18, 13 ], [ 533, 436, 66, 13 ], [ 606, 436, 20, 13 ], [ 635, 436, 36, 13 ], [ 679, 436, 53, 13 ], [ 739, 436, 8, 13 ], [ 102, 450, 78, 13 ], [ 187, 450, 50, 13 ], [ 244, 450, 13, 13 ], [ 265, 450, 31, 13 ], [ 303, 450, 43, 13 ], [ 353, 450, 10, 13 ], [ 370, 450, 47, 13 ], [ 424, 450, 33, 13 ], [ 464, 450, 43, 13 ], [ 514, 450, 25, 13 ], [ 547, 450, 38, 13 ], [ 591, 450, 43, 13 ], [ 641, 450, 42, 13 ], [ 690, 450, 13, 13 ], [ 710, 450, 37, 13 ], [ 102, 464, 62, 13 ], [ 167, 464, 47, 13 ], [ 216, 464, 43, 13 ], [ 262, 464, 20, 13 ], [ 285, 464, 41, 13 ], [ 329, 464, 11, 13 ], [ 343, 464, 22, 13 ], [ 367, 464, 11, 13 ], [ 381, 464, 43, 13 ], [ 427, 464, 20, 13 ], [ 450, 464, 25, 13 ], [ 479, 464, 32, 13 ], [ 513, 464, 81, 13 ], [ 597, 464, 11, 13 ], [ 611, 464, 31, 13 ], [ 645, 464, 59, 13 ], [ 706, 464, 41, 13 ], [ 102, 478, 41, 13 ], [ 146, 478, 56, 13 ], [ 205, 478, 10, 13 ], [ 219, 478, 43, 13 ], [ 265, 478, 56, 13 ], [ 324, 478, 25, 13 ], [ 353, 478, 41, 13 ], [ 397, 478, 58, 13 ], [ 458, 478, 22, 13 ], [ 483, 478, 43, 13 ], [ 529, 478, 23, 13 ], [ 555, 478, 14, 13 ], [ 572, 478, 54, 13 ], [ 629, 478, 41, 13 ], [ 673, 478, 56, 13 ], [ 733, 478, 15, 13 ], [ 102, 492, 34, 13 ], [ 140, 492, 39, 13 ], [ 182, 492, 56, 13 ], [ 242, 492, 11, 13 ], [ 257, 492, 43, 13 ], [ 304, 492, 21, 13 ], [ 329, 492, 63, 13 ], [ 395, 492, 47, 13 ], [ 446, 492, 33, 13 ], [ 483, 492, 39, 13 ], [ 525, 492, 20, 13 ], [ 549, 492, 33, 13 ], [ 586, 492, 69, 13 ], [ 659, 492, 10, 13 ], [ 673, 492, 6, 13 ], [ 683, 492, 25, 13 ], [ 712, 492, 36, 13 ], [ 102, 505, 51, 13 ], [ 155, 505, 36, 13 ], [ 194, 505, 68, 13 ], [ 265, 505, 43, 13 ], [ 310, 505, 47, 13 ], [ 360, 505, 33, 13 ], [ 395, 505, 69, 13 ], [ 467, 505, 13, 13 ], [ 483, 505, 45, 13 ], [ 531, 505, 28, 13 ], [ 561, 505, 59, 13 ], [ 622, 505, 13, 13 ], [ 638, 505, 33, 13 ], [ 673, 505, 23, 13 ], [ 699, 505, 11, 13 ], [ 712, 505, 22, 13 ], [ 736, 505, 11, 13 ], [ 102, 519, 39, 13 ], [ 145, 519, 51, 13 ], [ 199, 519, 59, 13 ], [ 262, 519, 18, 13 ], [ 284, 519, 52, 13 ], [ 101, 545, 68, 13 ], [ 174, 545, 32, 13 ], [ 210, 545, 49, 13 ], [ 262, 545, 29, 13 ], [ 295, 545, 42, 13 ], [ 341, 545, 42, 13 ], [ 386, 545, 22, 13 ], [ 412, 545, 72, 13 ], [ 488, 545, 11, 13 ], [ 502, 545, 43, 13 ], [ 549, 545, 56, 13 ], [ 609, 545, 8, 13 ], [ 621, 545, 47, 13 ], [ 672, 545, 10, 13 ], [ 686, 545, 37, 13 ], [ 728, 545, 20, 13 ], [ 102, 559, 61, 13 ], [ 167, 559, 11, 13 ], [ 182, 559, 39, 13 ], [ 224, 559, 38, 13 ], [ 266, 559, 32, 13 ], [ 301, 559, 50, 13 ], [ 355, 559, 6, 13 ], [ 365, 559, 29, 13 ], [ 398, 559, 60, 13 ], [ 462, 559, 43, 13 ], [ 509, 559, 15, 13 ], [ 528, 559, 18, 13 ], [ 549, 559, 53, 13 ], [ 605, 559, 11, 13 ], [ 620, 559, 40, 13 ], [ 92, 594, 40, 10 ], [ 134, 594, 27, 10 ], [ 163, 594, 8, 10 ], [ 173, 594, 25, 10 ], [ 200, 594, 8, 10 ], [ 210, 594, 20, 10 ], [ 232, 594, 6, 10 ], [ 240, 594, 29, 10 ], [ 271, 594, 14, 10 ], [ 287, 594, 27, 10 ], [ 316, 594, 6, 10 ], [ 323, 594, 26, 10 ], [ 351, 594, 57, 10 ], [ 410, 594, 9, 10 ], [ 421, 594, 58, 10 ], [ 481, 594, 44, 10 ], [ 527, 594, 8, 10 ], [ 537, 594, 22, 10 ], [ 560, 594, 16, 10 ], [ 578, 594, 21, 10 ], [ 600, 594, 43, 10 ], [ 646, 594, 15, 10 ], [ 663, 594, 44, 10 ], [ 709, 594, 40, 10 ], [ 92, 605, 27, 10 ], [ 122, 605, 31, 10 ], [ 156, 605, 16, 10 ], [ 174, 605, 27, 10 ], [ 204, 605, 57, 10 ], [ 264, 605, 20, 10 ], [ 287, 605, 18, 10 ], [ 308, 605, 18, 10 ], [ 329, 605, 32, 10 ], [ 364, 605, 139, 10 ], [ 92, 623, 31, 10 ], [ 126, 623, 18, 10 ], [ 147, 623, 8, 10 ], [ 158, 623, 42, 10 ], [ 203, 623, 20, 10 ], [ 225, 623, 15, 10 ], [ 243, 623, 37, 10 ], [ 283, 623, 17, 10 ], [ 302, 623, 28, 10 ], [ 333, 623, 25, 10 ], [ 360, 623, 9, 10 ], [ 372, 623, 34, 10 ], [ 92, 640, 42, 10 ], [ 137, 640, 30, 10 ], [ 170, 640, 12, 10 ], [ 185, 640, 22, 10 ], [ 210, 640, 44, 10 ], [ 257, 640, 20, 10 ], [ 279, 640, 12, 10 ], [ 294, 640, 22, 10 ], [ 319, 640, 47, 10 ], [ 369, 640, 17, 10 ], [ 389, 640, 12, 10 ], [ 404, 640, 20, 10 ], [ 92, 657, 50, 10 ], [ 158, 657, 20, 10 ], [ 182, 657, 27, 10 ], [ 213, 657, 9, 10 ], [ 225, 657, 9, 10 ], [ 238, 657, 17, 10 ], [ 259, 657, 6, 10 ], [ 269, 657, 10, 10 ], [ 283, 657, 50, 10 ], [ 338, 657, 25, 10 ], [ 367, 657, 45, 10 ], [ 415, 657, 25, 10 ], [ 444, 657, 14, 10 ], [ 462, 657, 24, 10 ], [ 489, 657, 9, 10 ], [ 501, 657, 14, 10 ], [ 519, 657, 34, 10 ], [ 557, 657, 42, 10 ], [ 603, 657, 45, 10 ], [ 652, 657, 32, 10 ], [ 688, 657, 25, 10 ], [ 717, 657, 31, 10 ], [ 92, 668, 49, 10 ], [ 144, 668, 17, 10 ], [ 163, 668, 50, 10 ], [ 216, 668, 16, 10 ], [ 235, 668, 54, 10 ], [ 291, 668, 8, 10 ], [ 302, 668, 15, 10 ], [ 320, 668, 37, 10 ], [ 359, 668, 37, 10 ], [ 399, 668, 14, 10 ], [ 416, 668, 31, 10 ], [ 450, 668, 28, 10 ], [ 480, 668, 16, 10 ], [ 499, 668, 27, 10 ], [ 529, 668, 13, 10 ], [ 545, 668, 36, 10 ], [ 92, 686, 42, 10 ], [ 136, 686, 17, 10 ], [ 155, 686, 21, 10 ], [ 178, 686, 16, 10 ], [ 196, 686, 30, 10 ], [ 228, 686, 10, 10 ], [ 240, 686, 35, 10 ], [ 277, 686, 38, 10 ], [ 317, 686, 9, 10 ], [ 328, 686, 64, 10 ], [ 394, 686, 28, 10 ], [ 425, 686, 34, 10 ], [ 461, 686, 22, 10 ], [ 486, 686, 42, 10 ], [ 530, 686, 16, 10 ], [ 548, 686, 16, 10 ], [ 566, 686, 25, 10 ], [ 594, 686, 21, 10 ], [ 617, 686, 37, 10 ], [ 656, 686, 23, 10 ], [ 681, 686, 14, 10 ], [ 697, 686, 16, 10 ], [ 715, 686, 16, 10 ], [ 733, 686, 16, 10 ], [ 92, 697, 31, 10 ], [ 126, 697, 16, 10 ], [ 145, 697, 11, 10 ], [ 159, 697, 16, 10 ], [ 177, 697, 8, 10 ], [ 188, 697, 23, 10 ], [ 214, 697, 30, 10 ], [ 246, 697, 18, 10 ], [ 268, 697, 40, 10 ], [ 310, 697, 16, 10 ], [ 329, 697, 34, 10 ], [ 365, 697, 34, 10 ], [ 402, 697, 9, 10 ], [ 414, 697, 33, 10 ], [ 450, 697, 9, 10 ], [ 461, 697, 48, 10 ], [ 512, 697, 9, 10 ], [ 524, 697, 14, 10 ], [ 540, 697, 48, 10 ], [ 92, 714, 52, 10 ], [ 147, 714, 44, 10 ], [ 193, 714, 16, 10 ], [ 212, 714, 31, 10 ], [ 246, 714, 20, 10 ], [ 268, 714, 35, 10 ], [ 307, 714, 17, 10 ], [ 326, 714, 11, 10 ], [ 340, 714, 45, 10 ], [ 388, 714, 35, 10 ], [ 426, 714, 21, 10 ], [ 92, 731, 5, 10 ], [ 99, 731, 27, 10 ], [ 129, 731, 108, 10 ], [ 80, 774, 84, 14 ], [ 93, 799, 28, 13 ], [ 127, 799, 19, 13 ], [ 153, 799, 24, 13 ], [ 183, 799, 50, 13 ], [ 239, 799, 17, 13 ], [ 263, 799, 53, 13 ], [ 322, 799, 54, 13 ], [ 382, 799, 31, 13 ], [ 80, 814, 41, 13 ], [ 127, 814, 38, 13 ], [ 170, 814, 10, 13 ], [ 186, 814, 20, 13 ], [ 211, 814, 33, 13 ], [ 250, 814, 62, 13 ], [ 318, 814, 35, 13 ], [ 358, 814, 19, 13 ], [ 383, 814, 29, 13 ], [ 80, 829, 42, 13 ], [ 125, 829, 44, 13 ], [ 172, 829, 15, 13 ], [ 189, 829, 73, 13 ], [ 265, 829, 41, 13 ], [ 309, 829, 21, 13 ], [ 332, 829, 25, 13 ], [ 361, 829, 27, 13 ], [ 391, 829, 22, 13 ], [ 80, 843, 19, 13 ], [ 103, 843, 8, 13 ], [ 114, 843, 24, 13 ], [ 141, 843, 37, 13 ], [ 182, 843, 34, 13 ], [ 219, 843, 13, 13 ], [ 235, 843, 48, 13 ], [ 286, 843, 53, 13 ], [ 342, 843, 18, 13 ], [ 364, 843, 21, 13 ], [ 388, 843, 25, 13 ], [ 80, 858, 51, 13 ], [ 134, 858, 18, 13 ], [ 155, 858, 34, 13 ], [ 191, 858, 47, 13 ], [ 241, 858, 11, 13 ], [ 255, 858, 14, 13 ], [ 272, 858, 16, 13 ], [ 292, 858, 40, 13 ], [ 334, 858, 17, 13 ], [ 354, 858, 19, 13 ], [ 376, 858, 37, 13 ], [ 80, 873, 68, 13 ], [ 151, 873, 31, 13 ], [ 184, 873, 25, 13 ], [ 213, 873, 10, 13 ], [ 226, 873, 24, 13 ], [ 253, 873, 6, 13 ], [ 261, 873, 52, 13 ], [ 316, 873, 27, 13 ], [ 346, 873, 18, 13 ], [ 367, 873, 12, 13 ], [ 381, 873, 31, 13 ], [ 80, 888, 29, 13 ], [ 113, 888, 16, 13 ], [ 133, 888, 48, 13 ], [ 185, 888, 10, 13 ], [ 199, 888, 73, 13 ], [ 276, 888, 41, 13 ], [ 321, 888, 58, 13 ], [ 382, 888, 10, 13 ], [ 397, 888, 16, 13 ], [ 80, 903, 39, 13 ], [ 123, 903, 32, 13 ], [ 159, 903, 17, 13 ], [ 180, 903, 47, 13 ], [ 232, 903, 50, 13 ], [ 286, 903, 30, 13 ], [ 321, 903, 22, 13 ], [ 347, 903, 12, 13 ], [ 363, 903, 35, 13 ], [ 402, 903, 10, 13 ], [ 80, 917, 41, 13 ], [ 125, 917, 10, 13 ], [ 139, 917, 20, 13 ], [ 162, 917, 20, 13 ], [ 185, 917, 73, 13 ], [ 263, 917, 36, 13 ], [ 302, 917, 74, 13 ], [ 380, 917, 33, 13 ], [ 80, 932, 48, 13 ], [ 137, 932, 18, 13 ], [ 164, 932, 38, 13 ], [ 211, 932, 71, 13 ], [ 291, 932, 10, 13 ], [ 310, 932, 39, 13 ], [ 358, 932, 20, 13 ], [ 386, 932, 27, 13 ], [ 80, 947, 57, 13 ], [ 143, 947, 49, 13 ], [ 198, 947, 7, 13 ], [ 210, 947, 22, 13 ], [ 238, 947, 39, 13 ], [ 283, 947, 24, 13 ], [ 313, 947, 15, 13 ], [ 333, 947, 25, 13 ], [ 364, 947, 19, 13 ], [ 389, 947, 24, 13 ], [ 80, 962, 39, 13 ], [ 123, 962, 24, 13 ], [ 150, 962, 32, 13 ], [ 185, 962, 37, 13 ], [ 225, 962, 24, 13 ], [ 253, 962, 33, 13 ], [ 289, 962, 16, 13 ], [ 309, 962, 17, 13 ], [ 329, 962, 19, 13 ], [ 351, 962, 40, 13 ], [ 394, 962, 18, 13 ], [ 80, 977, 40, 13 ], [ 130, 977, 20, 13 ], [ 159, 977, 36, 13 ], [ 205, 977, 22, 13 ], [ 236, 977, 37, 13 ], [ 283, 977, 37, 13 ], [ 329, 977, 83, 13 ], [ 80, 991, 49, 13 ], [ 132, 991, 33, 13 ], [ 167, 991, 26, 13 ], [ 196, 991, 18, 13 ], [ 216, 991, 22, 13 ], [ 240, 991, 51, 13 ], [ 294, 991, 44, 13 ], [ 340, 991, 19, 13 ], [ 362, 991, 51, 13 ], [ 80, 1006, 37, 13 ], [ 125, 1006, 21, 13 ], [ 154, 1006, 35, 13 ], [ 197, 1006, 60, 13 ], [ 265, 1006, 45, 13 ], [ 317, 1006, 13, 13 ], [ 339, 1006, 16, 13 ], [ 362, 1006, 50, 13 ], [ 437, 773, 72, 13 ], [ 519, 773, 10, 13 ], [ 538, 773, 44, 13 ], [ 592, 773, 20, 13 ], [ 621, 773, 16, 13 ], [ 647, 773, 36, 13 ], [ 692, 773, 19, 13 ], [ 721, 773, 49, 13 ], [ 437, 788, 68, 13 ], [ 511, 788, 10, 13 ], [ 526, 788, 16, 13 ], [ 548, 788, 35, 13 ], [ 588, 788, 17, 13 ], [ 611, 788, 51, 13 ], [ 668, 788, 16, 13 ], [ 689, 788, 65, 13 ], [ 760, 788, 10, 13 ], [ 437, 803, 27, 13 ], [ 468, 803, 57, 13 ], [ 529, 803, 49, 13 ], [ 450, 817, 37, 13 ], [ 491, 817, 8, 13 ], [ 503, 817, 6, 13 ], [ 514, 817, 43, 13 ], [ 561, 817, 36, 13 ], [ 601, 817, 35, 13 ], [ 640, 817, 10, 13 ], [ 654, 817, 31, 13 ], [ 689, 817, 59, 13 ], [ 753, 817, 17, 13 ], [ 437, 832, 36, 13 ], [ 482, 832, 28, 13 ], [ 519, 832, 19, 13 ], [ 547, 832, 10, 13 ], [ 566, 832, 34, 13 ], [ 609, 832, 10, 13 ], [ 629, 832, 30, 13 ], [ 668, 832, 47, 13 ], [ 724, 832, 20, 13 ], [ 753, 832, 16, 13 ], [ 437, 846, 64, 13 ], [ 506, 846, 15, 13 ], [ 526, 846, 37, 13 ], [ 568, 846, 60, 13 ], [ 634, 846, 18, 13 ], [ 658, 846, 46, 13 ], [ 709, 846, 8, 13 ], [ 722, 846, 47, 13 ], [ 437, 861, 20, 13 ], [ 464, 861, 52, 13 ], [ 524, 861, 10, 13 ], [ 541, 861, 16, 13 ], [ 564, 861, 53, 13 ], [ 623, 861, 10, 13 ], [ 640, 861, 61, 13 ], [ 708, 861, 33, 13 ], [ 748, 861, 22, 13 ], [ 437, 875, 21, 13 ], [ 466, 875, 6, 13 ], [ 479, 875, 17, 13 ], [ 503, 875, 20, 13 ], [ 530, 875, 10, 13 ], [ 547, 875, 34, 13 ], [ 588, 875, 65, 13 ], [ 660, 875, 19, 13 ], [ 686, 875, 58, 13 ], [ 751, 875, 18, 13 ], [ 437, 890, 62, 13 ], [ 508, 890, 36, 13 ], [ 553, 890, 19, 13 ], [ 581, 890, 48, 13 ], [ 638, 890, 29, 13 ], [ 676, 890, 13, 13 ], [ 697, 890, 26, 13 ], [ 732, 890, 18, 13 ], [ 760, 890, 10, 13 ], [ 437, 905, 64, 13 ], [ 506, 905, 30, 13 ], [ 540, 905, 18, 13 ], [ 564, 905, 16, 13 ], [ 585, 905, 26, 13 ], [ 616, 905, 57, 13 ], [ 678, 905, 31, 13 ], [ 714, 905, 20, 13 ], [ 739, 905, 15, 13 ], [ 760, 905, 10, 13 ], [ 437, 919, 38, 13 ], [ 480, 919, 10, 13 ], [ 495, 919, 41, 13 ], [ 540, 919, 53, 13 ], [ 597, 919, 10, 13 ], [ 612, 919, 36, 13 ], [ 653, 919, 29, 13 ], [ 687, 919, 44, 13 ], [ 736, 919, 33, 13 ], [ 437, 934, 27, 13 ], [ 470, 934, 23, 13 ], [ 499, 934, 32, 13 ], [ 536, 934, 64, 13 ], [ 606, 934, 10, 13 ], [ 622, 934, 22, 13 ], [ 650, 934, 19, 13 ], [ 675, 934, 35, 13 ], [ 715, 934, 24, 13 ], [ 745, 934, 25, 13 ], [ 437, 948, 47, 13 ], [ 492, 948, 49, 13 ], [ 548, 948, 48, 13 ], [ 604, 948, 47, 13 ], [ 659, 948, 4, 13 ], [ 671, 948, 39, 13 ], [ 717, 948, 16, 13 ], [ 741, 948, 29, 13 ], [ 437, 963, 70, 13 ], [ 512, 963, 10, 13 ], [ 526, 963, 31, 13 ], [ 560, 963, 37, 13 ], [ 601, 963, 25, 13 ], [ 631, 963, 16, 13 ], [ 651, 963, 10, 13 ], [ 665, 963, 43, 13 ], [ 713, 963, 26, 13 ], [ 743, 963, 27, 13 ], [ 437, 977, 16, 13 ], [ 458, 977, 69, 13 ], [ 533, 977, 50, 13 ], [ 588, 977, 19, 13 ], [ 612, 977, 26, 13 ], [ 643, 977, 30, 13 ], [ 678, 977, 10, 13 ], [ 693, 977, 37, 13 ], [ 735, 977, 18, 13 ], [ 758, 977, 11, 13 ], [ 437, 992, 52, 13 ], [ 495, 992, 36, 13 ], [ 537, 992, 27, 13 ], [ 570, 992, 16, 13 ], [ 592, 992, 55, 13 ], [ 652, 992, 13, 13 ], [ 670, 992, 37, 13 ], [ 713, 992, 41, 13 ], [ 759, 992, 10, 13 ], [ 437, 1006, 25, 13 ], [ 470, 1006, 75, 13 ], [ 552, 1006, 44, 13 ], [ 604, 1006, 43, 13 ], [ 655, 1006, 36, 13 ], [ 698, 1006, 19, 13 ], [ 726, 1006, 44, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 21, 12 ], [ 165, 1047, 3, 12 ], [ 174, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 568, 1047, 20, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "Dysregulation", "of", "MicroRNA-34a", "Expression", "in", "Head", "and", "Neck", "Squamous", "Cell", "Carcinoma", "Promotes", "Tumor", "Growth", "and", "Tumor", "Angiogenesis", "Bhavna", "Kumar1,2,", "Arti", "Yadav2,", "James", "Lang1,2,", "Theodoros", "N.", "Teknos1,2,", "Pawan", "Kumar1,2*", "1", "Department", "of", "Otolaryngology-Head", "and", "Neck", "Surgery,", "The", "Ohio", "State", "University,", "Columbus,", "Ohio,", "United", "States", "of", "America,", "2", "The", "Ohio", "State", "University", "Comprehensive", "Cancer", "Center,", "The", "Ohio", "State", "University,", "Columbus,", "Ohio,", "United", "States", "of", "America", "Abstract", "Background:", "MicroRNAs", "(miRs)", "are", "small", "non-coding", "RNAs", "that", "play", "an", "important", "role", "in", "cancer", "development", "where", "they", "can", "act", "as", "oncogenes", "or", "as", "tumor-suppressors.", "miR-34a", "is", "a", "tumor-suppressor", "that", "is", "frequently", "downregulated", "in", "a", "number", "of", "tumor", "types.", "However,", "little", "is", "known", "about", "the", "role", "of", "miR-34a", "in", "head", "and", "neck", "squamous", "cell", "carcinoma", "(HNSCC).", "Methods", "and", "Results:", "miR-34a", "expression", "in", "tumor", "samples,", "HNSCC", "cell", "lines", "and", "endothelial", "cells", "was", "examined", "by", "real", "time", "PCR.", "Lipofectamine-2000", "was", "used", "to", "transfect", "miR-34a", "in", "HNSCC", "cell", "lines", "and", "human", "endothelial", "cells.", "Cell-", "proliferation,", "migration", "and", "clonogenic", "survival", "was", "examined", "by", "MTT,", "Xcelligence", "system,", "scratch", "assay", "and", "colony", "formation", "assay.", "miR-34a", "effect", "on", "tumor", "growth", "and", "tumor", "angiogenesis", "was", "examined", "by", "in", "vivo", "SCID", "mouse", "xenograft", "model.", "Our", "results", "demonstrate", "that", "miR-34a", "is", "significantly", "downregulated", "in", "HNSCC", "tumors", "and", "cell", "lines.", "Ectopic", "expression", "of", "miR-34a", "in", "HNSCC", "cell", "lines", "significantly", "inhibited", "tumor", "cell", "proliferation,", "colony", "formation", "and", "migration.", "miR-34a", "overexpression", "also", "markedly", "downregulated", "E2F3", "and", "survivin", "levels.", "Rescue", "experiments", "using", "microRNA", "resistant", "E2F3", "isoforms", "suggest", "that", "miR-34a-mediated", "inhibition", "of", "cell", "proliferation", "and", "colony", "formation", "is", "predominantly", "mediated", "by", "E2F3a", "isoform.", "In", "addition,", "tumor", "samples", "from", "HNSCC", "patients", "showed", "an", "inverse", "relationship", "between", "miR-34a", "and", "survivin", "as", "well", "as", "miR-34a", "and", "E2F3", "levels.", "Overexpression", "of", "E2F3a", "completely", "rescued", "survivin", "expression", "in", "miR-34a", "expressing", "cells,", "thereby", "suggesting", "that", "miR-34a", "may", "be", "regulating", "survivin", "expression", "via", "E2F3a.", "Ectopic", "expression", "of", "miR-34a", "also", "significantly", "inhibited", "tumor", "growth", "and", "tumor", "angiogenesis", "in", "a", "SCID", "mouse", "xenograft", "model.", "Interestingly,", "miR-34a", "inhibited", "tumor", "angiogenesis", "by", "blocking", "VEGF", "production", "by", "tumor", "cells", "as", "well", "as", "directly", "inhibiting", "endothelial", "cell", "functions.", "Conclusions:", "Taken", "together,", "these", "findings", "suggest", "that", "dysregulation", "of", "miR-34a", "expression", "is", "common", "in", "HNSCC", "and", "modulation", "of", "miR34a", "activity", "might", "represent", "a", "novel", "therapeutic", "strategy", "for", "the", "treatment", "of", "HNSCC.", "Citation:", "Kumar", "B,", "Yadav", "A,", "Lang", "J,", "Teknos", "TN,", "Kumar", "P", "(2012)", "Dysregulation", "of", "MicroRNA-34a", "Expression", "in", "Head", "and", "Neck", "Squamous", "Cell", "Carcinoma", "Promotes", "Tumor", "Growth", "and", "Tumor", "Angiogenesis.", "PLoS", "ONE", "7(5):", "e37601.", "doi:10.1371/journal.pone.0037601", "Editor:", "Irina", "V.", "Lebedeva,", "Enzo", "Life", "Sciences,", "Inc.,", "United", "States", "of", "America", "Received", "August", "16,", "2011;", "Accepted", "April", "26,", "2012;", "Published", "May", "22,", "2012", "Copyright:", "2012", "Kumar", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "funded", "by", "National", "Institutes", "of", "Health/National", "Cancer", "Institute", "grant", "CA133250", "(PK)", "and", "Joan’s", "Fund", "Research", "Grant", "(BK", "and", "PK).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "pawan.kumar@osumc.edu", "Introduction", "Head", "and", "neck", "squamous", "cell", "carcinoma", "(HNSCC),", "which", "includes", "cancers", "of", "oral", "cavity,", "oropharynx,", "larynx,", "and", "hypo-", "pharynx", "accounts", "for", "approximately", "600,000", "new", "cases", "every", "year", "and", "is", "sixth", "leading", "cancer", "by", "incidence", "worldwide", "[1].", "The", "most", "important", "risk", "factors", "identified", "so", "far", "are", "tobacco", "use", "and", "alcohol", "consumption,", "which", "seem", "to", "have", "a", "synergistic", "effect", "[2].", "In", "recent", "years,", "the", "incidence", "of", "oropharyngeal", "cancers,", "particularly", "in", "the", "western", "world,", "has", "markedly", "increased,", "which", "may", "be", "related", "to", "increase", "in", "oral", "and", "oropharyngeal", "human", "papillomavirus", "(HPV)", "infections", "[3].", "Despite", "advancements", "in", "surgical", "and", "other", "therapeutic", "regimens,", "5", "year", "survival", "rates", "for", "head", "and", "neck", "patients", "have", "stayed", "around", "50%", "during", "the", "last", "two", "decades", "[4].", "Patients", "that", "survive", "with", "surgery", "and/or", "chemo-radiation", "treatment", "(CRT)", "often", "live", "with", "significant", "cosmetic", "and", "functional", "defects.", "The", "limited", "information", "available", "on", "the", "molecular", "carcinogenesis", "of", "HNSCC", "and", "the", "genetic", "and", "biological", "heterogeneity", "of", "the", "disease", "has", "hampered", "the", "development", "of", "novel", "therapeutic", "strategies.", "Cancer", "is", "a", "complex", "genetic", "disease", "in", "which", "deregulated", "cell", "growth", "arises", "due", "to", "defects", "in", "major", "pathways", "that", "are", "fundamental", "for", "normal", "homeostasis", "[1].", "Evidence", "is", "emerging", "that", "alterations", "in", "the", "expression", "of", "microRNAs", "(miRs)", "may", "play", "a", "key", "role", "in", "cancer", "development", "and", "progression", "[5].", "MicroRNAs", "(miRs),", "first", "described", "about", "18", "years", "ago", "in", "Caenorhabditis", "elegans", "[6],", "are", "small", "non-coding", "RNAs", "that", "act", "in", "concert", "to", "regulate", "expression", "of", "myriad", "target", "Proteins.", "Today", "more", "than", "17000", "microRNA’s", "in", "over", "153", "species", "have", "been", "identified", "(miRBase", "Sequence", "Database", "-", "Release", "17;", "www.", "miRbase.org),", "of", "which", "around", "1400", "are", "in", "humans.", "Most", "miRs", "are", "evolutionarily", "conserved", "and", "often", "found", "in", "clusters", "[7].", "In", "mammals,", "mature", "miRs", "are", "recognized", "by", "specific", "proteins", "to", "form", "RNA-inducing", "silencing", "complex", "(RISC)", "and", "associate", "PLoS", "ONE", "|", "www.plosone.org", "1", "May", "2012", "|", "Volume", "7", "|", "Issue", "5", "|", "e37601" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 80, 78, 45, 28 ], [ 134, 78, 101, 28 ], [ 243, 78, 96, 28 ], [ 348, 78, 93, 28 ], [ 449, 78, 110, 28 ], [ 568, 78, 103, 28 ], [ 80, 109, 164, 28 ], [ 253, 109, 128, 28 ], [ 390, 109, 56, 28 ], [ 455, 109, 100, 28 ], [ 564, 109, 127, 28 ], [ 700, 109, 24, 28 ], [ 732, 109, 15, 28 ], [ 80, 139, 93, 28 ], [ 182, 139, 50, 28 ], [ 241, 139, 116, 28 ], [ 366, 139, 45, 28 ], [ 419, 139, 54, 28 ], [ 482, 139, 126, 28 ], [ 617, 139, 82, 28 ], [ 80, 183, 57, 14 ], [ 140, 180, 144, 18 ], [ 288, 183, 46, 14 ], [ 337, 180, 110, 18 ], [ 450, 183, 45, 14 ], [ 498, 180, 56, 17 ], [ 557, 183, 48, 14 ], [ 608, 180, 47, 17 ], [ 657, 183, 35, 14 ], [ 695, 180, 75, 17 ], [ 80, 202, 47, 14 ], [ 132, 200, 85, 17 ], [ 221, 202, 61, 14 ], [ 287, 202, 15, 14 ], [ 305, 200, 76, 17 ], [ 80, 225, 6, 10 ], [ 88, 225, 50, 10 ], [ 140, 225, 9, 10 ], [ 151, 225, 34, 10 ], [ 187, 225, 33, 10 ], [ 222, 225, 32, 10 ], [ 257, 225, 28, 10 ], [ 287, 225, 16, 10 ], [ 306, 225, 59, 10 ], [ 367, 225, 32, 10 ], [ 402, 225, 36, 10 ], [ 440, 225, 31, 10 ], [ 474, 225, 61, 10 ], [ 537, 225, 28, 10 ], [ 568, 225, 25, 10 ], [ 595, 225, 9, 10 ], [ 606, 225, 36, 10 ], [ 645, 225, 6, 10 ], [ 652, 225, 50, 10 ], [ 705, 225, 9, 10 ], [ 716, 225, 54, 10 ], [ 80, 238, 16, 10 ], [ 99, 238, 68, 10 ], [ 169, 238, 32, 10 ], [ 204, 238, 32, 10 ], [ 239, 238, 30, 10 ], [ 271, 238, 31, 10 ], [ 305, 238, 61, 10 ], [ 368, 238, 28, 10 ], [ 399, 238, 25, 10 ], [ 426, 238, 9, 10 ], [ 438, 238, 36, 10 ], [ 476, 238, 6, 10 ], [ 483, 238, 33, 10 ], [ 519, 238, 38, 10 ], [ 559, 238, 12, 10 ], [ 574, 238, 35, 10 ], [ 611, 238, 31, 10 ], [ 645, 238, 31, 10 ], [ 678, 238, 61, 10 ], [ 742, 238, 28, 10 ], [ 80, 252, 25, 10 ], [ 108, 252, 9, 10 ], [ 119, 252, 34, 10 ], [ 102, 291, 57, 14 ], [ 102, 313, 54, 13 ], [ 160, 313, 47, 13 ], [ 211, 313, 47, 13 ], [ 261, 313, 22, 13 ], [ 287, 313, 45, 13 ], [ 336, 313, 42, 13 ], [ 382, 313, 40, 13 ], [ 426, 313, 22, 13 ], [ 452, 313, 36, 13 ], [ 491, 313, 17, 13 ], [ 512, 313, 53, 13 ], [ 569, 313, 53, 13 ], [ 625, 313, 11, 13 ], [ 640, 313, 108, 13 ], [ 102, 327, 50, 13 ], [ 155, 327, 44, 13 ], [ 203, 327, 48, 13 ], [ 254, 327, 32, 13 ], [ 289, 327, 29, 13 ], [ 322, 327, 105, 13 ], [ 430, 327, 36, 13 ], [ 470, 327, 11, 13 ], [ 485, 327, 46, 13 ], [ 534, 327, 46, 13 ], [ 584, 327, 37, 13 ], [ 624, 327, 41, 13 ], [ 669, 327, 28, 13 ], [ 700, 327, 16, 13 ], [ 720, 327, 28, 13 ], [ 102, 340, 22, 13 ], [ 126, 340, 18, 13 ], [ 147, 340, 71, 13 ], [ 220, 340, 57, 13 ], [ 280, 340, 69, 13 ], [ 352, 340, 48, 13 ], [ 403, 340, 44, 13 ], [ 449, 340, 76, 13 ], [ 528, 340, 33, 13 ], [ 564, 340, 56, 13 ], [ 622, 340, 23, 13 ], [ 649, 340, 44, 13 ], [ 695, 340, 53, 13 ], [ 102, 354, 10, 13 ], [ 116, 354, 6, 13 ], [ 126, 354, 41, 13 ], [ 171, 354, 22, 13 ], [ 197, 354, 48, 13 ], [ 249, 354, 23, 13 ], [ 276, 354, 32, 13 ], [ 312, 354, 11, 13 ], [ 328, 354, 26, 13 ], [ 358, 354, 24, 13 ], [ 385, 354, 19, 13 ], [ 409, 354, 54, 13 ], [ 467, 354, 25, 13 ], [ 496, 354, 38, 13 ], [ 538, 354, 24, 13 ], [ 565, 354, 26, 13 ], [ 595, 354, 25, 13 ], [ 625, 354, 11, 13 ], [ 640, 354, 46, 13 ], [ 690, 354, 20, 13 ], [ 714, 354, 6, 13 ], [ 725, 354, 23, 13 ], [ 102, 368, 40, 13 ], [ 145, 368, 54, 13 ], [ 201, 368, 11, 13 ], [ 216, 368, 23, 13 ], [ 242, 368, 40, 13 ], [ 285, 368, 21, 13 ], [ 308, 368, 49, 13 ], [ 360, 368, 10, 13 ], [ 373, 368, 18, 13 ], [ 394, 368, 80, 13 ], [ 477, 368, 43, 13 ], [ 523, 368, 28, 13 ], [ 554, 368, 33, 13 ], [ 589, 368, 26, 13 ], [ 618, 368, 59, 13 ], [ 680, 368, 46, 13 ], [ 730, 368, 18, 13 ], [ 102, 382, 33, 13 ], [ 139, 382, 44, 13 ], [ 187, 382, 48, 13 ], [ 238, 382, 51, 13 ], [ 293, 382, 49, 13 ], [ 345, 382, 96, 13 ], [ 445, 382, 39, 13 ], [ 488, 382, 38, 13 ], [ 529, 382, 46, 13 ], [ 579, 382, 39, 13 ], [ 622, 382, 31, 13 ], [ 656, 382, 42, 13 ], [ 702, 382, 20, 13 ], [ 726, 382, 22, 13 ], [ 102, 396, 70, 13 ], [ 177, 396, 52, 13 ], [ 233, 396, 7, 13 ], [ 245, 396, 56, 13 ], [ 305, 396, 44, 13 ], [ 354, 396, 48, 13 ], [ 406, 396, 52, 13 ], [ 462, 396, 28, 13 ], [ 494, 396, 73, 13 ], [ 571, 396, 27, 13 ], [ 602, 396, 27, 13 ], [ 633, 396, 13, 13 ], [ 651, 396, 68, 13 ], [ 724, 396, 24, 13 ], [ 102, 410, 70, 13 ], [ 175, 410, 52, 13 ], [ 231, 410, 26, 13 ], [ 260, 410, 23, 13 ], [ 286, 410, 70, 13 ], [ 360, 410, 8, 13 ], [ 371, 410, 70, 13 ], [ 444, 410, 13, 13 ], [ 461, 410, 6, 13 ], [ 471, 410, 84, 13 ], [ 558, 410, 51, 13 ], [ 612, 410, 29, 13 ], [ 644, 410, 11, 13 ], [ 658, 410, 31, 13 ], [ 692, 410, 56, 13 ], [ 102, 424, 33, 13 ], [ 140, 424, 27, 13 ], [ 171, 424, 20, 13 ], [ 196, 424, 32, 13 ], [ 233, 424, 54, 13 ], [ 291, 424, 24, 13 ], [ 319, 424, 47, 13 ], [ 371, 424, 52, 13 ], [ 428, 424, 52, 13 ], [ 484, 424, 11, 13 ], [ 500, 424, 64, 13 ], [ 568, 424, 51, 13 ], [ 623, 424, 33, 13 ], [ 661, 424, 27, 13 ], [ 692, 424, 20, 13 ], [ 717, 424, 31, 13 ], [ 102, 437, 33, 13 ], [ 139, 437, 44, 13 ], [ 187, 437, 23, 13 ], [ 213, 437, 11, 13 ], [ 228, 437, 134, 13 ], [ 366, 437, 49, 13 ], [ 419, 437, 44, 13 ], [ 467, 437, 52, 13 ], [ 522, 437, 20, 13 ], [ 546, 437, 52, 13 ], [ 602, 437, 11, 13 ], [ 617, 437, 18, 13 ], [ 639, 437, 60, 13 ], [ 703, 437, 45, 13 ], [ 102, 451, 22, 13 ], [ 127, 451, 46, 13 ], [ 177, 451, 32, 13 ], [ 213, 451, 54, 13 ], [ 271, 451, 33, 13 ], [ 309, 451, 45, 13 ], [ 357, 451, 15, 13 ], [ 376, 451, 61, 13 ], [ 440, 451, 18, 13 ], [ 462, 451, 70, 13 ], [ 536, 451, 51, 13 ], [ 591, 451, 28, 13 ], [ 623, 451, 54, 13 ], [ 681, 451, 23, 13 ], [ 708, 451, 40, 13 ], [ 102, 465, 20, 13 ], [ 125, 465, 51, 13 ], [ 179, 465, 60, 13 ], [ 242, 465, 41, 13 ], [ 286, 465, 24, 13 ], [ 312, 465, 12, 13 ], [ 327, 465, 32, 13 ], [ 362, 465, 12, 13 ], [ 376, 465, 31, 13 ], [ 410, 465, 42, 13 ], [ 455, 465, 11, 13 ], [ 469, 465, 34, 13 ], [ 506, 465, 11, 13 ], [ 520, 465, 6, 13 ], [ 529, 465, 39, 13 ], [ 571, 465, 46, 13 ], [ 620, 465, 34, 13 ], [ 656, 465, 20, 13 ], [ 679, 465, 34, 13 ], [ 716, 465, 32, 13 ], [ 102, 479, 6, 13 ], [ 113, 479, 15, 13 ], [ 133, 479, 105, 13 ], [ 243, 479, 31, 13 ], [ 279, 479, 22, 13 ], [ 305, 479, 51, 13 ], [ 361, 479, 40, 13 ], [ 406, 479, 39, 13 ], [ 450, 479, 11, 13 ], [ 466, 479, 71, 13 ], [ 542, 479, 85, 13 ], [ 632, 479, 17, 13 ], [ 654, 479, 44, 13 ], [ 702, 479, 22, 13 ], [ 729, 479, 19, 13 ], [ 102, 493, 83, 13 ], [ 188, 493, 50, 13 ], [ 242, 493, 51, 13 ], [ 297, 493, 62, 13 ], [ 363, 493, 29, 13 ], [ 395, 493, 46, 13 ], [ 445, 493, 23, 13 ], [ 472, 493, 49, 13 ], [ 525, 493, 12, 13 ], [ 540, 493, 49, 13 ], [ 92, 528, 40, 10 ], [ 135, 528, 66, 10 ], [ 203, 528, 8, 10 ], [ 213, 528, 42, 10 ], [ 257, 528, 10, 10 ], [ 270, 528, 17, 10 ], [ 289, 528, 17, 10 ], [ 308, 528, 12, 10 ], [ 322, 528, 6, 10 ], [ 330, 528, 33, 10 ], [ 366, 528, 8, 10 ], [ 376, 528, 9, 10 ], [ 387, 528, 9, 10 ], [ 398, 528, 26, 10 ], [ 426, 528, 16, 10 ], [ 444, 528, 34, 10 ], [ 481, 528, 32, 10 ], [ 515, 528, 31, 10 ], [ 548, 528, 38, 10 ], [ 588, 528, 35, 10 ], [ 625, 528, 56, 10 ], [ 684, 528, 43, 10 ], [ 729, 528, 19, 10 ], [ 92, 539, 34, 10 ], [ 129, 539, 43, 10 ], [ 175, 539, 8, 10 ], [ 186, 539, 5, 10 ], [ 194, 539, 32, 10 ], [ 228, 539, 17, 10 ], [ 248, 539, 39, 10 ], [ 290, 539, 15, 10 ], [ 308, 539, 18, 10 ], [ 329, 539, 43, 10 ], [ 375, 539, 30, 10 ], [ 407, 539, 20, 10 ], [ 430, 539, 30, 10 ], [ 463, 539, 23, 10 ], [ 488, 539, 42, 10 ], [ 533, 539, 137, 10 ], [ 92, 556, 31, 10 ], [ 126, 556, 31, 10 ], [ 160, 556, 5, 10 ], [ 168, 556, 53, 10 ], [ 223, 556, 17, 10 ], [ 244, 556, 43, 10 ], [ 289, 556, 28, 10 ], [ 320, 556, 25, 10 ], [ 348, 556, 9, 10 ], [ 359, 556, 34, 10 ], [ 92, 573, 42, 10 ], [ 137, 573, 17, 10 ], [ 157, 573, 12, 10 ], [ 172, 573, 22, 10 ], [ 198, 573, 44, 10 ], [ 244, 573, 45, 10 ], [ 293, 573, 12, 10 ], [ 308, 573, 22, 10 ], [ 333, 573, 47, 10 ], [ 382, 573, 43, 10 ], [ 428, 573, 12, 10 ], [ 444, 573, 20, 10 ], [ 92, 591, 50, 10 ], [ 154, 591, 20, 10 ], [ 177, 591, 66, 10 ], [ 245, 591, 9, 10 ], [ 255, 591, 9, 10 ], [ 267, 591, 17, 10 ], [ 285, 591, 7, 10 ], [ 294, 591, 10, 10 ], [ 306, 591, 50, 10 ], [ 359, 591, 25, 10 ], [ 386, 591, 45, 10 ], [ 433, 591, 25, 10 ], [ 460, 591, 14, 10 ], [ 476, 591, 24, 10 ], [ 501, 591, 9, 10 ], [ 512, 591, 14, 10 ], [ 528, 591, 34, 10 ], [ 564, 591, 42, 10 ], [ 608, 591, 45, 10 ], [ 655, 591, 32, 10 ], [ 690, 591, 25, 10 ], [ 717, 591, 31, 10 ], [ 92, 602, 49, 10 ], [ 144, 602, 17, 10 ], [ 163, 602, 50, 10 ], [ 216, 602, 16, 10 ], [ 235, 602, 54, 10 ], [ 291, 602, 8, 10 ], [ 302, 602, 15, 10 ], [ 320, 602, 37, 10 ], [ 359, 602, 37, 10 ], [ 399, 602, 14, 10 ], [ 416, 602, 31, 10 ], [ 450, 602, 27, 10 ], [ 480, 602, 16, 10 ], [ 498, 602, 27, 10 ], [ 529, 602, 13, 10 ], [ 545, 602, 36, 10 ], [ 92, 619, 42, 10 ], [ 136, 619, 17, 10 ], [ 155, 619, 21, 10 ], [ 178, 619, 16, 10 ], [ 196, 619, 43, 10 ], [ 241, 619, 11, 10 ], [ 254, 619, 33, 10 ], [ 289, 619, 35, 10 ], [ 326, 619, 22, 10 ], [ 350, 619, 33, 10 ], [ 386, 619, 9, 10 ], [ 397, 619, 18, 10 ], [ 418, 619, 16, 10 ], [ 436, 619, 31, 10 ], [ 469, 619, 16, 10 ], [ 487, 619, 11, 10 ], [ 501, 619, 16, 10 ], [ 519, 619, 8, 10 ], [ 529, 619, 23, 10 ], [ 554, 619, 30, 10 ], [ 586, 619, 19, 10 ], [ 607, 619, 40, 10 ], [ 649, 619, 16, 10 ], [ 667, 619, 34, 10 ], [ 703, 619, 34, 10 ], [ 739, 619, 9, 10 ], [ 92, 630, 32, 10 ], [ 127, 630, 9, 10 ], [ 139, 630, 48, 10 ], [ 190, 630, 9, 10 ], [ 201, 630, 14, 10 ], [ 218, 630, 48, 10 ], [ 92, 648, 52, 10 ], [ 147, 648, 44, 10 ], [ 193, 648, 16, 10 ], [ 212, 648, 31, 10 ], [ 246, 648, 20, 10 ], [ 268, 648, 35, 10 ], [ 307, 648, 17, 10 ], [ 326, 648, 11, 10 ], [ 340, 648, 45, 10 ], [ 388, 648, 35, 10 ], [ 426, 648, 21, 10 ], [ 92, 665, 5, 10 ], [ 99, 665, 27, 10 ], [ 129, 665, 134, 10 ], [ 92, 682, 5, 10 ], [ 100, 682, 31, 10 ], [ 134, 682, 34, 10 ], [ 170, 682, 41, 10 ], [ 214, 682, 41, 10 ], [ 258, 682, 34, 10 ], [ 294, 682, 16, 10 ], [ 313, 682, 32, 10 ], [ 348, 682, 30, 10 ], [ 380, 682, 43, 10 ], [ 426, 682, 22, 10 ], [ 451, 682, 28, 10 ], [ 481, 682, 25, 10 ], [ 509, 682, 9, 10 ], [ 521, 682, 36, 10 ], [ 92, 699, 7, 10 ], [ 102, 699, 24, 10 ], [ 129, 699, 31, 10 ], [ 163, 699, 49, 10 ], [ 215, 699, 30, 10 ], [ 247, 699, 9, 10 ], [ 259, 699, 15, 10 ], [ 277, 699, 23, 10 ], [ 80, 742, 84, 14 ], [ 93, 768, 75, 13 ], [ 170, 768, 59, 13 ], [ 232, 768, 16, 13 ], [ 251, 768, 68, 13 ], [ 321, 768, 13, 13 ], [ 337, 768, 13, 13 ], [ 352, 768, 60, 13 ], [ 80, 783, 45, 13 ], [ 128, 783, 42, 13 ], [ 172, 783, 44, 13 ], [ 219, 783, 19, 13 ], [ 241, 783, 21, 13 ], [ 265, 783, 37, 13 ], [ 304, 783, 21, 13 ], [ 328, 783, 34, 13 ], [ 365, 783, 35, 13 ], [ 403, 783, 10, 13 ], [ 80, 798, 6, 13 ], [ 91, 798, 47, 13 ], [ 142, 798, 41, 13 ], [ 188, 798, 13, 13 ], [ 205, 798, 16, 13 ], [ 226, 798, 38, 13 ], [ 268, 798, 10, 13 ], [ 282, 798, 11, 13 ], [ 298, 798, 46, 13 ], [ 348, 798, 37, 13 ], [ 389, 798, 24, 13 ], [ 80, 813, 42, 13 ], [ 127, 813, 47, 13 ], [ 179, 813, 19, 13 ], [ 203, 813, 16, 13 ], [ 224, 813, 42, 13 ], [ 271, 813, 28, 13 ], [ 304, 813, 10, 13 ], [ 319, 813, 16, 13 ], [ 340, 813, 24, 13 ], [ 369, 813, 43, 13 ], [ 80, 828, 48, 13 ], [ 132, 828, 47, 13 ], [ 183, 828, 31, 13 ], [ 217, 828, 37, 13 ], [ 258, 828, 29, 13 ], [ 290, 828, 46, 13 ], [ 340, 828, 37, 13 ], [ 381, 828, 21, 13 ], [ 406, 828, 6, 13 ], [ 80, 842, 34, 13 ], [ 122, 842, 20, 13 ], [ 150, 842, 10, 13 ], [ 168, 842, 16, 13 ], [ 192, 842, 44, 13 ], [ 243, 842, 10, 13 ], [ 261, 842, 18, 13 ], [ 287, 842, 60, 13 ], [ 355, 842, 58, 13 ], [ 80, 857, 45, 13 ], [ 129, 857, 41, 13 ], [ 174, 857, 36, 13 ], [ 215, 857, 23, 13 ], [ 243, 857, 45, 13 ], [ 292, 857, 29, 13 ], [ 325, 857, 10, 13 ], [ 339, 857, 26, 13 ], [ 369, 857, 44, 13 ], [ 80, 872, 18, 13 ], [ 101, 872, 18, 13 ], [ 123, 872, 17, 13 ], [ 143, 872, 8, 13 ], [ 154, 872, 6, 13 ], [ 163, 872, 79, 13 ], [ 245, 872, 34, 13 ], [ 281, 872, 33, 13 ], [ 317, 872, 37, 13 ], [ 356, 872, 13, 13 ], [ 372, 872, 41, 13 ], [ 80, 887, 10, 13 ], [ 97, 887, 42, 13 ], [ 145, 887, 19, 13 ], [ 171, 887, 43, 13 ], [ 221, 887, 47, 13 ], [ 274, 887, 49, 13 ], [ 329, 887, 20, 13 ], [ 355, 887, 37, 13 ], [ 399, 887, 13, 13 ], [ 80, 902, 55, 13 ], [ 138, 902, 36, 13 ], [ 177, 902, 48, 13 ], [ 228, 902, 23, 13 ], [ 254, 902, 17, 13 ], [ 275, 902, 92, 13 ], [ 370, 902, 42, 13 ], [ 80, 916, 41, 13 ], [ 124, 916, 34, 13 ], [ 160, 916, 8, 13 ], [ 171, 916, 45, 13 ], [ 218, 916, 40, 13 ], [ 262, 916, 16, 13 ], [ 281, 916, 56, 13 ], [ 339, 916, 19, 13 ], [ 362, 916, 51, 13 ], [ 80, 931, 10, 13 ], [ 95, 931, 112, 13 ], [ 212, 931, 43, 13 ], [ 260, 931, 29, 13 ], [ 293, 931, 49, 13 ], [ 348, 931, 18, 13 ], [ 371, 931, 15, 13 ], [ 391, 931, 11, 13 ], [ 406, 931, 6, 13 ], [ 80, 946, 32, 13 ], [ 117, 946, 15, 13 ], [ 136, 946, 51, 13 ], [ 192, 946, 10, 13 ], [ 207, 946, 39, 13 ], [ 251, 946, 46, 13 ], [ 301, 946, 34, 13 ], [ 339, 946, 15, 13 ], [ 359, 946, 34, 13 ], [ 398, 946, 15, 13 ], [ 80, 961, 43, 13 ], [ 131, 961, 49, 13 ], [ 188, 961, 31, 13 ], [ 227, 961, 37, 13 ], [ 272, 961, 23, 13 ], [ 303, 961, 29, 13 ], [ 339, 961, 49, 13 ], [ 396, 961, 16, 13 ], [ 80, 976, 49, 13 ], [ 135, 976, 27, 13 ], [ 167, 976, 59, 13 ], [ 231, 976, 40, 13 ], [ 276, 976, 10, 13 ], [ 292, 976, 50, 13 ], [ 348, 976, 65, 13 ], [ 80, 990, 44, 13 ], [ 130, 990, 19, 13 ], [ 155, 990, 50, 13 ], [ 210, 990, 10, 13 ], [ 226, 990, 72, 13 ], [ 304, 990, 61, 13 ], [ 370, 990, 43, 13 ], [ 80, 1005, 18, 13 ], [ 450, 742, 23, 13 ], [ 480, 742, 10, 13 ], [ 497, 742, 16, 13 ], [ 521, 742, 20, 13 ], [ 548, 742, 68, 13 ], [ 624, 742, 17, 13 ], [ 648, 742, 38, 13 ], [ 693, 742, 8, 13 ], [ 709, 742, 20, 13 ], [ 736, 742, 10, 13 ], [ 754, 742, 16, 13 ], [ 437, 756, 57, 13 ], [ 500, 756, 76, 13 ], [ 582, 756, 51, 13 ], [ 639, 756, 57, 13 ], [ 701, 756, 45, 13 ], [ 751, 756, 18, 13 ], [ 437, 771, 18, 13 ], [ 460, 771, 23, 13 ], [ 487, 771, 66, 13 ], [ 557, 771, 47, 13 ], [ 608, 771, 28, 13 ], [ 641, 771, 57, 13 ], [ 701, 771, 13, 13 ], [ 718, 771, 52, 13 ], [ 437, 786, 19, 13 ], [ 460, 786, 8, 13 ], [ 470, 786, 13, 13 ], [ 486, 786, 47, 13 ], [ 537, 786, 10, 13 ], [ 550, 786, 41, 13 ], [ 594, 786, 20, 13 ], [ 617, 786, 41, 13 ], [ 662, 786, 45, 13 ], [ 709, 786, 61, 13 ], [ 437, 800, 27, 13 ], [ 467, 800, 19, 13 ], [ 490, 800, 38, 13 ], [ 531, 800, 51, 13 ], [ 585, 800, 9, 13 ], [ 596, 800, 32, 13 ], [ 631, 800, 58, 13 ], [ 692, 800, 38, 13 ], [ 733, 800, 10, 13 ], [ 746, 800, 24, 13 ], [ 437, 815, 48, 13 ], [ 488, 815, 10, 13 ], [ 501, 815, 34, 13 ], [ 537, 815, 22, 13 ], [ 562, 815, 28, 13 ], [ 592, 815, 36, 13 ], [ 630, 815, 25, 13 ], [ 658, 815, 25, 13 ], [ 685, 815, 42, 13 ], [ 730, 815, 40, 13 ], [ 437, 830, 19, 13 ], [ 459, 830, 68, 13 ], [ 530, 830, 42, 13 ], [ 575, 830, 38, 13 ], [ 615, 830, 25, 13 ], [ 642, 830, 25, 13 ], [ 670, 830, 10, 13 ], [ 682, 830, 45, 13 ], [ 730, 830, 40, 13 ], [ 437, 844, 16, 13 ], [ 457, 844, 24, 13 ], [ 485, 844, 53, 13 ], [ 542, 844, 10, 13 ], [ 556, 844, 29, 13 ], [ 589, 844, 46, 13 ], [ 640, 844, 33, 13 ], [ 677, 844, 40, 13 ], [ 722, 844, 26, 13 ], [ 752, 844, 17, 13 ], [ 437, 859, 41, 13 ], [ 482, 859, 30, 13 ], [ 516, 859, 31, 13 ], [ 551, 859, 19, 13 ], [ 574, 859, 30, 13 ], [ 608, 859, 33, 13 ], [ 645, 859, 18, 13 ], [ 667, 859, 27, 13 ], [ 698, 859, 20, 13 ], [ 721, 859, 28, 13 ], [ 753, 859, 16, 13 ], [ 437, 874, 45, 13 ], [ 491, 874, 13, 13 ], [ 512, 874, 16, 13 ], [ 536, 874, 96, 13 ], [ 640, 874, 36, 13 ], [ 685, 874, 32, 13 ], [ 725, 874, 45, 13 ], [ 437, 888, 50, 13 ], [ 494, 888, 100, 13 ], [ 601, 888, 59, 13 ], [ 668, 888, 37, 13 ], [ 712, 888, 58, 14 ], [ 437, 903, 28, 13 ], [ 472, 903, 19, 13 ], [ 498, 903, 149, 13 ], [ 653, 903, 36, 13 ], [ 696, 903, 48, 14 ], [ 751, 903, 18, 13 ], [ 437, 918, 60, 13 ], [ 506, 918, 30, 13 ], [ 545, 918, 33, 13 ], [ 586, 918, 8, 13 ], [ 603, 918, 45, 13 ], [ 657, 918, 13, 13 ], [ 679, 918, 16, 13 ], [ 704, 918, 66, 13 ], [ 437, 933, 75, 13 ], [ 519, 933, 39, 13 ], [ 564, 933, 45, 13 ], [ 615, 933, 50, 13 ], [ 671, 933, 25, 13 ], [ 702, 933, 68, 13 ], [ 437, 947, 98, 13 ], [ 540, 947, 72, 13 ], [ 617, 947, 54, 13 ], [ 676, 947, 35, 13 ], [ 715, 947, 19, 13 ], [ 739, 947, 31, 13 ], [ 437, 962, 150, 13 ], [ 592, 962, 18, 13 ], [ 616, 962, 18, 13 ], [ 640, 962, 18, 13 ], [ 665, 962, 25, 13 ], [ 695, 962, 12, 13 ], [ 712, 962, 42, 13 ], [ 759, 962, 10, 13 ], [ 437, 977, 24, 13 ], [ 464, 977, 20, 13 ], [ 486, 977, 10, 13 ], [ 500, 977, 17, 13 ], [ 520, 977, 29, 13 ], [ 552, 977, 53, 13 ], [ 608, 977, 31, 13 ], [ 641, 977, 19, 13 ], [ 663, 977, 33, 13 ], [ 700, 977, 20, 13 ], [ 722, 977, 48, 13 ], [ 437, 991, 68, 13 ], [ 509, 991, 19, 13 ], [ 532, 991, 42, 13 ], [ 578, 991, 48, 13 ], [ 630, 991, 10, 13 ], [ 644, 991, 49, 13 ], [ 698, 991, 18, 13 ], [ 720, 991, 25, 13 ], [ 749, 991, 21, 13 ], [ 437, 1006, 79, 14 ], [ 521, 1006, 29, 13 ], [ 554, 1006, 45, 13 ], [ 604, 1006, 37, 13 ], [ 645, 1006, 45, 13 ], [ 695, 1006, 17, 13 ], [ 716, 1006, 19, 13 ], [ 740, 1006, 30, 13 ], [ 80, 1047, 25, 12 ], [ 108, 1047, 50, 12 ], [ 163, 1047, 3, 12 ], [ 171, 1047, 114, 12 ], [ 422, 1047, 6, 12 ], [ 522, 1047, 49, 12 ], [ 574, 1047, 23, 12 ], [ 602, 1047, 3, 12 ], [ 610, 1047, 36, 12 ], [ 651, 1047, 6, 12 ], [ 663, 1047, 3, 12 ], [ 671, 1047, 23, 12 ], [ 699, 1047, 12, 12 ], [ 716, 1047, 3, 12 ], [ 724, 1047, 45, 12 ] ]

[ "The", "Quorum", "Sensing", "Volatile", "Molecule", "2-Amino", "Acetophenon", "Modulates", "Host", "Immune", "Responses", "in", "a", "Manner", "that", "Promotes", "Life", "with", "Unwanted", "Guests", "Arunava", "Bandyopadhaya1,2,3.,", "Meenu", "Kesarwani1,2,3.¤,", "Yok-Ai", "Que1,2,3,", "Jianxin", "He1,2,3,", "Katie", "Padfield1,3,", "Ronald", "Tompkins1,3,", "Laurence", "G.", "Rahme1,2,3*", "1", "Department", "of", "Surgery,", "Harvard", "Medical", "School", "and", "Massachusetts", "General", "Hospital,", "Boston,", "Massachusetts,", "United", "States", "of", "America,", "2", "Department", "of", "Microbiology", "and", "Immunobiology,", "Harvard", "Medical", "School,", "Boston,", "Massachusetts,", "United", "States", "of", "America,", "3", "Shriners", "Hospitals", "for", "Children", "Boston,", "Boston,", "Massachusetts,", "United", "States", "of", "America", "Abstract", "Increasing", "evidence", "indicates", "that", "bacterial", "quorum", "sensing", "(QS)", "signals", "are", "important", "mediators", "of", "immunomodulation.", "However,", "whether", "microbes", "utilize", "these", "immunomodulatory", "signals", "to", "maintain", "infection", "remain", "unclear.", "Here,", "we", "show", "that", "the", "Pseudomonas", "aeruginosa", "QS-regulated", "molecule", "2-amino", "acetophenone", "(2-AA)", "modulates", "host", "immune", "responses", "in", "a", "manner", "that", "increases", "host", "ability", "to", "cope", "with", "this", "pathogen.", "Mice", "treated", "with", "2-AA", "prior", "to", "infection", "had", "a", "90%", "survival", "compared", "to", "10%", "survival", "rate", "observed", "in", "the", "non-pretreated", "infected", "mice.", "Whilst", "2-AA", "stimulation", "activates", "key", "innate", "immune", "response", "pathways", "involving", "mitogen-activated", "protein", "kinases", "(MAPKs),", "nuclear", "factor", "(NF)-kB,", "and", "pro-", "inflammatory", "cytokines,", "it", "attenuates", "immune", "response", "activation", "upon", "pretreatment,", "most", "likely", "by", "upregulating", "anti-", "inflammatory", "cytokines.", "2-AA", "host", "pretreatment", "is", "characterized", "by", "a", "transcriptionally", "regulated", "block", "of", "c-JUN", "N-terminal", "kinase", "(JNK)", "and", "NF-kB", "activation,", "with", "relatively", "preserved", "activation", "of", "extracellular", "regulated", "kinase", "(ERK)", "1/2.", "These", "kinase", "changes", "lead", "to", "CCAAT/enhancer-binding", "protein-b", "(c/EBPb)", "activation", "and", "formation", "of", "the", "c/EBPb-p65", "complex", "that", "prevents", "NF-kB", "activation.", "2-AA’s", "aptitude", "for", "dampening", "the", "inflammatory", "processes", "while", "increasing", "host", "survival", "and", "pathogen", "persistence", "concurs", "with", "its", "ability", "to", "signal", "bacteria", "to", "switch", "to", "a", "chronic", "infection", "mode.", "Our", "results", "reveal", "a", "QS", "immunomodulatory", "signal", "that", "promotes", "original", "aspects", "of", "interkingdom", "communication.", "We", "propose", "that", "this", "communication", "facilitates", "pathogen", "persistence,", "while", "enabling", "host", "tolerance", "to", "infection.", "Citation:", "Bandyopadhaya", "A,", "Kesarwani", "M,", "Que", "Y-A,", "He", "J,", "Padfield", "K,", "et", "al.", "(2012)", "The", "Quorum", "Sensing", "Volatile", "Molecule", "2-Amino", "Acetophenon", "Modulates", "Host", "Immune", "Responses", "in", "a", "Manner", "that", "Promotes", "Life", "with", "Unwanted", "Guests.", "PLoS", "Pathog", "8(11):", "e1003024.", "doi:10.1371/journal.ppat.1003024", "Editor:", "Barbara", "I.", "Kazmierczak,", "Yale", "University,", "United", "States", "of", "America", "Received", "May", "21,", "2012;", "Accepted", "September", "26,", "2012;", "Published", "November", "15,", "2012", "Copyright:", "2012", "Bandyopadhaya", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "Shriners", "research", "grant", "#87100", "to", "LGR.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "rahme@molbio.mgh.harvard.edu", "¤", "Current", "address:", "Cincinnati", "Children’s", "Hospital", "and", "Medical", "Center,", "Cincinnati,", "Ohio,", "United", "States", "of", "America.", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "Host-pathogen", "interactions", "are", "characterized", "by", "an", "antagonistic", "interplay", "between", "bacterial", "and", "host", "factors.", "The", "overall", "success", "of", "a", "pathogen", "depends", "on", "the", "efficacy", "of", "its", "virulence", "factors,", "anti-", "immune", "weapons,", "and", "the", "immune", "status", "of", "the", "host.", "Secreted", "microbial", "products,", "which", "include", "many", "virulence", "factors,", "play", "a", "critical", "role", "in", "the", "outcome", "of", "this", "antagonistic", "interaction.", "Bacterial", "quorum", "sensing", "(QS)", "regulates", "many", "of", "these", "products", "[1],", "[2].", "QS", "is", "a", "communication", "system", "widely", "utilized", "by", "bacteria", "to", "perceive", "and", "promote", "collective", "behaviors", "that", "depend", "on", "population", "density", "signaling.", "This", "cell", "density-dependent", "commu-", "nication", "system", "is", "achieved", "through", "the", "production", "and", "regulation", "of", "low-molecular-weight,", "excreted", "signal", "molecules", "[1],", "[3]", "as", "a", "means", "for", "pathogens", "to", "activate", "virulence", "factors", "[4]", "critical", "for", "infecting", "mammals", "[4–6].", "Several", "such", "signal", "molecules", "are", "becoming", "more", "appreciated", "recently", "as", "important", "anti-immune", "weapons", "and", "mediators", "of", "inter-kingdom", "antagonistic", "relations", "[7].", "One", "of", "the", "best", "characterized", "QS", "systems", "is", "that", "of", "the", "recalcitrant", "Gram-negative", "bacterium", "Pseudomonas", "aeruginosa", "[8],", "[9].", "This", "opportunistic", "pathogen", "defies", "eradication", "by", "antibiotics", "and", "is", "an", "exemplar", "of", "bacteria", "that", "produce", "clinically", "problematic", "acute", "and", "chronic", "infections.", "It", "causes", "particularly", "difficult", "to", "treat", "infections", "in", "people", "with", "cystic", "fibrosis", "(CF),", "burn", "wounds,", "trauma,", "and", "compromised", "immune", "systems", "[10],", "[11].", "P.", "aeruginosa", "controls", "the", "gene", "expression", "of", "many", "virulence", "factors", "through", "three", "QS", "systems:", "LasR,", "RhlR,", "and", "MvfR", "(PqsR)", "[9].", "LasR", "and", "RhlR", "are", "activated", "by", "the", "N-acyl-homoserine", "lactone", "(AHL)", "signaling", "molecules", "N-3-oxododecanoyl", "homoserine", "lactone", "(3-oxo-C12-", "HSL)", "and", "N-3-butanoyl-DL-homoserine", "lactone", "(C4-HSL)", "[9].", "Meanwhile,", "MvfR", "(PqsR)", "is", "activated", "by", "the", "4-hydroxy-2-", "alkylquinolines", "(HAQs)", "signaling", "molecules", "PQS", "(2-heptyl-3,4-", "dihydroxyquinoline", "(Pseudomonas", "Quinolone", "Signal)", "and", "HHQ", "(4-hydroxy-2-heptylquinoline)", "[5],", "[6],", "[8],", "[12].", "In", "addition", "to", "their", "role", "as", "QS", "signal", "molecules,", "AHLs", "and", "HAQs", "also", "modulate", "inflammation", "and", "immune", "responses", "in", "mammals", "[7],", "[13].", "The", "3-oxo-C12-HSL", "signal", "molecule", "inhibits", "dendritic", "cell", "and", "T-cell", "PLOS", "Pathogens", "|", "www.plospathogens.org", "1", "November", "2012", "|", "Volume", "8", "|", "Issue", "11", "|", "e1003024" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 30, 12 ], [ 112, 47, 9, 12 ], [ 124, 47, 11, 12 ], [ 138, 47, 33, 12 ], [ 175, 47, 9, 12 ], [ 187, 47, 55, 12 ], [ 245, 47, 7, 12 ], [ 255, 47, 43, 12 ], [ 301, 47, 25, 12 ], [ 330, 47, 20, 12 ], [ 78, 61, 190, 12 ], [ 83, 128, 10, 18 ], [ 95, 128, 13, 18 ], [ 109, 128, 13, 18 ], [ 124, 128, 11, 18 ], [ 136, 128, 10, 18 ], [ 154, 128, 11, 18 ], [ 166, 128, 10, 18 ], [ 178, 128, 11, 18 ], [ 190, 128, 13, 18 ], [ 205, 128, 11, 18 ], [ 217, 128, 10, 18 ], [ 660, 65, 30, 7 ], [ 691, 65, 9, 7 ], [ 702, 65, 46, 7 ], [ 660, 74, 5, 7 ], [ 666, 74, 38, 7 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 141, 34 ], [ 229, 169, 51, 34 ], [ 290, 169, 152, 34 ], [ 452, 169, 27, 34 ], [ 489, 169, 112, 34 ], [ 612, 169, 67, 34 ], [ 78, 205, 25, 34 ], [ 113, 205, 120, 34 ], [ 78, 252, 37, 16 ], [ 120, 249, 51, 19 ], [ 176, 252, 15, 16 ], [ 195, 249, 51, 19 ], [ 250, 252, 51, 16 ], [ 305, 249, 39, 18 ], [ 348, 252, 35, 16 ], [ 388, 249, 35, 18 ], [ 427, 252, 30, 16 ], [ 462, 249, 37, 18 ], [ 504, 252, 16, 16 ], [ 523, 249, 18, 18 ], [ 545, 252, 46, 16 ], [ 596, 249, 22, 18 ], [ 622, 252, 30, 16 ], [ 657, 249, 40, 18 ], [ 701, 252, 19, 16 ], [ 724, 249, 23, 18 ], [ 78, 271, 22, 16 ], [ 105, 271, 48, 16 ], [ 158, 269, 26, 19 ], [ 87, 325, 54, 15 ], [ 87, 350, 76, 14 ], [ 167, 351, 50, 14 ], [ 221, 351, 17, 14 ], [ 242, 351, 43, 14 ], [ 290, 351, 11, 14 ], [ 305, 351, 19, 14 ], [ 327, 351, 55, 14 ], [ 386, 351, 26, 14 ], [ 416, 351, 31, 14 ], [ 451, 351, 77, 14 ], [ 532, 351, 72, 14 ], [ 608, 351, 92, 14 ], [ 704, 351, 11, 14 ], [ 719, 351, 7, 14 ], [ 87, 367, 24, 14 ], [ 116, 367, 11, 14 ], [ 131, 367, 35, 14 ], [ 171, 367, 58, 14 ], [ 233, 367, 34, 14 ], [ 271, 367, 39, 14 ], [ 315, 367, 7, 14 ], [ 325, 367, 83, 14 ], [ 412, 367, 27, 14 ], [ 443, 367, 33, 14 ], [ 481, 367, 12, 14 ], [ 497, 367, 19, 14 ], [ 520, 367, 47, 14 ], [ 570, 367, 31, 14 ], [ 605, 367, 47, 14 ], [ 656, 367, 8, 14 ], [ 669, 367, 22, 14 ], [ 695, 367, 11, 14 ], [ 710, 367, 19, 14 ], [ 87, 384, 57, 14 ], [ 148, 384, 7, 14 ], [ 160, 384, 47, 14 ], [ 211, 384, 11, 14 ], [ 226, 384, 40, 14 ], [ 271, 384, 71, 14 ], [ 346, 384, 15, 14 ], [ 365, 384, 39, 14 ], [ 408, 384, 7, 14 ], [ 420, 384, 28, 14 ], [ 452, 384, 7, 14 ], [ 463, 384, 36, 14 ], [ 503, 384, 21, 14 ], [ 528, 384, 11, 14 ], [ 543, 384, 19, 14 ], [ 566, 384, 70, 14 ], [ 640, 384, 80, 14 ], [ 87, 400, 22, 14 ], [ 113, 400, 84, 14 ], [ 201, 400, 14, 14 ], [ 219, 400, 66, 14 ], [ 290, 400, 19, 14 ], [ 313, 400, 59, 14 ], [ 376, 400, 21, 14 ], [ 401, 400, 64, 14 ], [ 469, 400, 11, 14 ], [ 485, 400, 20, 14 ], [ 509, 400, 47, 14 ], [ 560, 400, 52, 14 ], [ 616, 400, 43, 14 ], [ 663, 400, 11, 14 ], [ 678, 400, 19, 14 ], [ 87, 417, 47, 14 ], [ 138, 417, 29, 14 ], [ 171, 417, 11, 14 ], [ 186, 417, 52, 14 ], [ 242, 417, 17, 14 ], [ 263, 417, 49, 14 ], [ 316, 417, 19, 14 ], [ 339, 417, 59, 14 ], [ 402, 417, 26, 14 ], [ 432, 417, 11, 14 ], [ 448, 417, 47, 14 ], [ 499, 417, 11, 14 ], [ 513, 417, 56, 14 ], [ 574, 417, 33, 14 ], [ 611, 417, 74, 14 ], [ 689, 417, 24, 14 ], [ 87, 434, 27, 14 ], [ 118, 434, 14, 14 ], [ 136, 434, 44, 14 ], [ 185, 434, 25, 14 ], [ 214, 434, 13, 14 ], [ 231, 434, 27, 14 ], [ 262, 434, 52, 14 ], [ 319, 434, 14, 14 ], [ 337, 434, 44, 14 ], [ 385, 434, 25, 14 ], [ 414, 434, 50, 14 ], [ 469, 434, 11, 14 ], [ 483, 434, 53, 14 ], [ 541, 434, 53, 14 ], [ 598, 434, 25, 14 ], [ 627, 434, 21, 14 ], [ 652, 434, 14, 14 ], [ 670, 434, 41, 14 ], [ 87, 450, 59, 14 ], [ 150, 450, 14, 14 ], [ 169, 450, 49, 14 ], [ 222, 450, 22, 14 ], [ 248, 450, 21, 14 ], [ 274, 450, 53, 14 ], [ 331, 450, 19, 14 ], [ 354, 450, 47, 14 ], [ 405, 450, 43, 14 ], [ 451, 450, 11, 14 ], [ 467, 450, 47, 14 ], [ 518, 450, 14, 14 ], [ 536, 450, 42, 14 ], [ 87, 471, 55, 14 ], [ 146, 471, 67, 14 ], [ 217, 471, 36, 14 ], [ 257, 471, 59, 14 ], [ 321, 471, 11, 14 ], [ 336, 471, 47, 14 ], [ 387, 471, 22, 14 ], [ 413, 471, 33, 14 ], [ 450, 471, 11, 14 ], [ 465, 471, 28, 14 ], [ 497, 471, 27, 14 ], [ 529, 471, 34, 14 ], [ 567, 471, 21, 14 ], [ 592, 471, 32, 14 ], [ 628, 471, 39, 14 ], [ 671, 471, 11, 14 ], [ 87, 488, 66, 14 ], [ 157, 488, 25, 14 ], [ 186, 488, 41, 14 ], [ 231, 488, 47, 14 ], [ 283, 488, 27, 14 ], [ 314, 488, 59, 14 ], [ 377, 488, 11, 14 ], [ 392, 488, 47, 14 ], [ 443, 488, 22, 14 ], [ 469, 488, 50, 14 ], [ 523, 488, 11, 14 ], [ 538, 488, 19, 14 ], [ 561, 488, 32, 14 ], [ 597, 488, 36, 14 ], [ 637, 488, 51, 14 ], [ 692, 488, 15, 14 ], [ 87, 504, 56, 14 ], [ 148, 504, 55, 14 ], [ 208, 504, 22, 14 ], [ 233, 504, 33, 14 ], [ 271, 504, 57, 14 ], [ 332, 504, 25, 14 ], [ 361, 504, 19, 14 ], [ 384, 504, 41, 14 ], [ 429, 504, 36, 14 ], [ 470, 504, 21, 14 ], [ 495, 504, 59, 14 ], [ 558, 504, 26, 14 ], [ 588, 504, 11, 14 ], [ 604, 504, 47, 14 ], [ 654, 504, 11, 14 ], [ 669, 504, 19, 14 ], [ 692, 504, 44, 14 ], [ 87, 521, 34, 14 ], [ 125, 521, 57, 14 ], [ 186, 521, 65, 14 ], [ 256, 521, 57, 14 ], [ 317, 521, 25, 14 ], [ 346, 521, 22, 14 ], [ 373, 521, 11, 14 ], [ 388, 521, 19, 14 ], [ 410, 521, 13, 14 ], [ 428, 521, 27, 14 ], [ 459, 521, 25, 14 ], [ 488, 521, 34, 14 ], [ 527, 521, 21, 14 ], [ 552, 521, 22, 14 ], [ 578, 521, 19, 14 ], [ 602, 521, 65, 14 ], [ 671, 521, 47, 14 ], [ 87, 537, 27, 14 ], [ 118, 537, 19, 14 ], [ 141, 537, 26, 14 ], [ 171, 537, 11, 14 ], [ 186, 537, 19, 14 ], [ 208, 537, 41, 14 ], [ 254, 537, 36, 14 ], [ 294, 537, 13, 14 ], [ 312, 537, 30, 14 ], [ 347, 537, 47, 14 ], [ 398, 537, 37, 14 ], [ 439, 537, 26, 14 ], [ 469, 537, 22, 14 ], [ 496, 537, 45, 14 ], [ 545, 537, 47, 14 ], [ 596, 537, 35, 14 ], [ 635, 537, 20, 14 ], [ 659, 537, 52, 14 ], [ 87, 554, 43, 14 ], [ 134, 554, 11, 14 ], [ 150, 554, 47, 14 ], [ 200, 554, 31, 14 ], [ 236, 554, 15, 14 ], [ 255, 554, 55, 14 ], [ 314, 554, 14, 14 ], [ 332, 554, 42, 14 ], [ 379, 554, 31, 14 ], [ 415, 554, 15, 14 ], [ 434, 554, 50, 14 ], [ 488, 554, 11, 14 ], [ 502, 554, 41, 14 ], [ 548, 554, 45, 14 ], [ 597, 554, 12, 14 ], [ 613, 554, 23, 14 ], [ 640, 554, 12, 14 ], [ 656, 554, 11, 14 ], [ 670, 554, 12, 14 ], [ 687, 554, 19, 14 ], [ 87, 571, 50, 14 ], [ 141, 571, 47, 14 ], [ 193, 571, 21, 14 ], [ 219, 571, 35, 14 ], [ 258, 571, 64, 14 ], [ 327, 571, 21, 14 ], [ 352, 571, 69, 14 ], [ 425, 571, 11, 14 ], [ 441, 571, 47, 14 ], [ 492, 571, 28, 14 ], [ 524, 571, 54, 14 ], [ 87, 591, 75, 14 ], [ 167, 591, 85, 14 ], [ 256, 591, 11, 14 ], [ 272, 591, 47, 14 ], [ 322, 591, 11, 14 ], [ 337, 591, 29, 14 ], [ 371, 591, 64, 14 ], [ 439, 591, 12, 14 ], [ 455, 591, 23, 14 ], [ 482, 591, 12, 14 ], [ 498, 591, 11, 14 ], [ 513, 591, 45, 14 ], [ 562, 591, 50, 14 ], [ 616, 591, 24, 14 ], [ 644, 591, 34, 14 ], [ 682, 591, 31, 14 ], [ 717, 591, 12, 14 ], [ 87, 608, 13, 14 ], [ 104, 608, 67, 14 ], [ 175, 608, 22, 14 ], [ 201, 608, 80, 14 ], [ 286, 608, 71, 14 ], [ 361, 608, 11, 14 ], [ 377, 608, 19, 14 ], [ 399, 608, 31, 14 ], [ 435, 608, 11, 14 ], [ 450, 608, 33, 14 ], [ 488, 608, 53, 14 ], [ 545, 608, 11, 14 ], [ 561, 608, 20, 14 ], [ 585, 608, 29, 14 ], [ 618, 608, 34, 14 ], [ 655, 608, 15, 14 ], [ 674, 608, 53, 14 ], [ 87, 625, 12, 14 ], [ 103, 625, 37, 14 ], [ 145, 625, 88, 14 ], [ 237, 625, 11, 14 ], [ 253, 625, 55, 14 ], [ 312, 625, 70, 14 ], [ 385, 625, 22, 14 ], [ 411, 625, 47, 14 ], [ 463, 625, 42, 14 ], [ 509, 625, 11, 14 ], [ 524, 625, 52, 14 ], [ 87, 648, 62, 14 ], [ 154, 648, 46, 14 ], [ 204, 648, 52, 14 ], [ 261, 648, 29, 14 ], [ 294, 648, 61, 14 ], [ 359, 648, 52, 14 ], [ 415, 648, 38, 14 ], [ 78, 694, 77, 15 ], [ 78, 711, 61, 14 ], [ 144, 711, 43, 14 ], [ 191, 711, 67, 14 ], [ 263, 711, 33, 14 ], [ 301, 711, 45, 14 ], [ 351, 711, 19, 14 ], [ 375, 711, 29, 14 ], [ 78, 728, 18, 14 ], [ 103, 728, 38, 14 ], [ 147, 728, 25, 14 ], [ 178, 728, 21, 14 ], [ 205, 728, 44, 14 ], [ 256, 728, 60, 14 ], [ 323, 728, 12, 14 ], [ 341, 728, 62, 14 ], [ 78, 744, 46, 14 ], [ 129, 744, 12, 14 ], [ 145, 744, 24, 14 ], [ 173, 744, 12, 14 ], [ 189, 744, 51, 14 ], [ 245, 744, 58, 14 ], [ 307, 744, 39, 14 ], [ 351, 744, 17, 14 ], [ 372, 744, 31, 14 ], [ 78, 761, 51, 14 ], [ 134, 761, 31, 14 ], [ 169, 761, 23, 14 ], [ 196, 761, 42, 14 ], [ 242, 761, 11, 14 ], [ 258, 761, 57, 14 ], [ 319, 761, 85, 14 ], [ 78, 778, 12, 14 ], [ 97, 778, 56, 14 ], [ 159, 778, 10, 14 ], [ 176, 778, 56, 14 ], [ 238, 778, 23, 14 ], [ 267, 778, 33, 14 ], [ 307, 778, 42, 14 ], [ 356, 778, 29, 14 ], [ 391, 778, 12, 14 ], [ 78, 794, 56, 14 ], [ 138, 794, 27, 14 ], [ 170, 794, 62, 14 ], [ 237, 794, 22, 14 ], [ 263, 794, 57, 14 ], [ 324, 794, 80, 14 ], [ 78, 811, 71, 14 ], [ 154, 811, 76, 14 ], [ 235, 811, 12, 14 ], [ 252, 811, 44, 14 ], [ 300, 811, 45, 14 ], [ 350, 811, 54, 14 ], [ 78, 827, 57, 14 ], [ 139, 827, 22, 14 ], [ 165, 827, 73, 14 ], [ 243, 827, 12, 14 ], [ 259, 827, 59, 14 ], [ 322, 827, 59, 14 ], [ 385, 827, 18, 14 ], [ 78, 844, 48, 14 ], [ 131, 844, 12, 14 ], [ 147, 844, 18, 14 ], [ 170, 844, 74, 14 ], [ 248, 844, 12, 14 ], [ 264, 844, 52, 14 ], [ 320, 844, 19, 14 ], [ 343, 844, 60, 14 ], [ 78, 861, 25, 14 ], [ 108, 861, 26, 14 ], [ 139, 861, 58, 14 ], [ 202, 861, 61, 14 ], [ 268, 861, 44, 14 ], [ 317, 861, 69, 14 ], [ 391, 861, 12, 14 ], [ 78, 913, 5, 11 ], [ 86, 913, 70, 11 ], [ 159, 913, 97, 11 ], [ 78, 925, 5, 11 ], [ 87, 925, 50, 11 ], [ 140, 925, 30, 11 ], [ 78, 936, 38, 13 ], [ 119, 937, 9, 11 ], [ 130, 937, 53, 11 ], [ 187, 937, 33, 11 ], [ 222, 937, 33, 11 ], [ 259, 937, 22, 11 ], [ 284, 937, 43, 11 ], [ 330, 937, 50, 11 ], [ 383, 937, 14, 11 ], [ 78, 950, 24, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 17, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 695, 54, 14 ], [ 483, 695, 32, 14 ], [ 522, 695, 12, 14 ], [ 541, 695, 56, 14 ], [ 603, 695, 19, 14 ], [ 629, 695, 44, 14 ], [ 680, 695, 18, 14 ], [ 704, 695, 44, 14 ], [ 423, 711, 94, 14 ], [ 434, 728, 58, 14 ], [ 499, 728, 10, 14 ], [ 515, 728, 23, 14 ], [ 545, 728, 12, 14 ], [ 564, 728, 20, 14 ], [ 590, 728, 64, 14 ], [ 661, 728, 9, 14 ], [ 676, 728, 53, 14 ], [ 736, 728, 12, 14 ], [ 423, 744, 42, 14 ], [ 469, 744, 71, 14 ], [ 544, 744, 17, 14 ], [ 565, 744, 45, 14 ], [ 614, 744, 35, 14 ], [ 653, 744, 9, 14 ], [ 667, 744, 7, 14 ], [ 677, 744, 34, 14 ], [ 715, 744, 32, 14 ], [ 423, 761, 16, 14 ], [ 443, 761, 97, 14 ], [ 545, 761, 72, 14 ], [ 621, 761, 24, 14 ], [ 649, 761, 38, 14 ], [ 691, 761, 19, 14 ], [ 715, 761, 33, 14 ], [ 423, 778, 68, 14 ], [ 495, 778, 34, 14 ], [ 534, 778, 12, 14 ], [ 550, 778, 32, 14 ], [ 587, 778, 48, 14 ], [ 640, 778, 20, 14 ], [ 665, 778, 23, 14 ], [ 693, 778, 55, 14 ], [ 423, 794, 27, 14 ], [ 455, 794, 47, 14 ], [ 506, 794, 21, 14 ], [ 532, 794, 74, 14 ], [ 610, 794, 41, 14 ], [ 655, 794, 49, 14 ], [ 710, 794, 39, 15 ], [ 423, 810, 40, 15 ], [ 468, 810, 40, 15 ], [ 514, 810, 40, 15 ], [ 559, 811, 22, 14 ], [ 587, 810, 37, 15 ], [ 629, 811, 44, 14 ], [ 678, 811, 16, 14 ], [ 699, 811, 49, 14 ], [ 423, 827, 37, 15 ], [ 468, 827, 10, 14 ], [ 487, 827, 60, 14 ], [ 555, 827, 27, 14 ], [ 590, 827, 12, 14 ], [ 610, 827, 33, 14 ], [ 652, 827, 24, 14 ], [ 685, 827, 64, 14 ], [ 423, 844, 55, 14 ], [ 482, 844, 27, 14 ], [ 513, 844, 30, 14 ], [ 547, 844, 40, 14 ], [ 591, 844, 11, 14 ], [ 606, 844, 48, 14 ], [ 659, 844, 46, 14 ], [ 709, 844, 7, 14 ], [ 720, 844, 28, 14 ], [ 423, 861, 62, 14 ], [ 490, 860, 37, 15 ], [ 532, 861, 72, 14 ], [ 609, 860, 57, 14 ], [ 671, 861, 10, 14 ], [ 686, 861, 45, 14 ], [ 736, 861, 12, 14 ], [ 423, 877, 38, 14 ], [ 465, 877, 29, 14 ], [ 499, 877, 55, 14 ], [ 558, 877, 29, 14 ], [ 591, 877, 7, 14 ], [ 602, 877, 39, 14 ], [ 645, 877, 23, 14 ], [ 671, 877, 12, 14 ], [ 687, 877, 20, 14 ], [ 712, 877, 36, 14 ], [ 423, 894, 44, 14 ], [ 471, 894, 85, 14 ], [ 559, 894, 21, 14 ], [ 585, 894, 89, 14 ], [ 678, 894, 32, 14 ], [ 715, 894, 15, 14 ], [ 734, 894, 14, 14 ], [ 423, 910, 57, 14 ], [ 484, 910, 12, 14 ], [ 501, 910, 110, 14 ], [ 615, 910, 12, 14 ], [ 632, 910, 22, 14 ], [ 658, 910, 11, 14 ], [ 674, 910, 43, 14 ], [ 722, 910, 26, 14 ], [ 423, 927, 27, 14 ], [ 454, 927, 19, 14 ], [ 478, 927, 10, 14 ], [ 491, 927, 19, 14 ], [ 515, 927, 28, 14 ], [ 547, 927, 50, 14 ], [ 601, 927, 23, 14 ], [ 629, 927, 19, 14 ], [ 652, 927, 49, 14 ], [ 705, 927, 43, 14 ], [ 423, 944, 71, 14 ], [ 499, 944, 12, 14 ], [ 516, 944, 19, 14 ], [ 540, 943, 36, 15 ], [ 581, 944, 62, 14 ], [ 648, 944, 46, 14 ], [ 698, 944, 50, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 277, 987, 25, 10 ], [ 304, 987, 8, 10 ], [ 314, 987, 8, 10 ], [ 324, 987, 30, 10 ], [ 356, 987, 29, 10 ], [ 387, 987, 27, 10 ], [ 416, 987, 14, 10 ], [ 433, 987, 15, 10 ], [ 450, 987, 6, 10 ], [ 458, 987, 10, 10 ], [ 469, 987, 21, 10 ], [ 493, 987, 25, 10 ], [ 520, 987, 23, 10 ], [ 545, 987, 41, 10 ], [ 588, 987, 23, 10 ], [ 613, 987, 13, 10 ], [ 628, 987, 22, 10 ], [ 651, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Zheng", "et", "al.", "Journal", "of", "Hematology", "&", "Oncology", "2011,", "4:21", "http://www.jhoonline.org/content/4/1/21", "S", "H", "O", "R", "T", "R", "E", "P", "O", "R", "T", "JOURNAL", "OF", "HEMATOLOGY", "&", "ONCOLOGY", "Open", "Access", "Expression", "and", "distribution", "of", "PPP2R5C", "gene", "in", "leukemia", "Haitao", "Zheng1†,", "Yu", "Chen1,2†,", "Shaohua", "Chen1,", "Yuzhe", "Niu1,2,", "Lijian", "Yang1,", "Bo", "Li1,", "Yuhong", "Lu1,", "Suxia", "Geng3,", "Xin", "Du3", "and", "Yangqiu", "Li1,2*", "Abstract", "Background:", "Recently,", "we", "clarified", "at", "the", "molecular", "level", "novel", "chromosomal", "translocation", "t(14;14)(q11;q32)", "in", "a", "case", "of", "Sézary", "syndrome,", "which", "caused", "a", "rearrangement", "from", "TRAJ7", "to", "the", "PPP2R5C", "gene.", "PPP2R5C", "is", "one", "of", "the", "regulatory", "B", "subunits", "of", "protein", "phosphatase", "2A", "(PP2A).", "It", "plays", "a", "crucial", "role", "in", "cell", "proliferation,", "differentiation,", "and", "transformation.", "To", "characterize", "the", "expression", "and", "distribution", "of", "five", "different", "transcript", "variants", "of", "the", "PPP2R5C", "gene", "in", "leukemia,", "we", "analyzed", "the", "expression", "level", "of", "PPP2R5C", "in", "peripheral", "blood", "mononuclear", "cells", "from", "77", "patients", "with", "de", "novo", "leukemia,", "26", "patients", "with", "leukemia", "in", "complete", "remission", "(CR),", "and", "20", "healthy", "individuals", "by", "real-time", "PCR", "and", "identified", "the", "different", "variants", "of", "PPP2R5C", "by", "RT-PCR.", "Findings:", "Significantly", "higher", "expression", "of", "PPP2R5C", "was", "found", "in", "AML,", "CML,", "T-ALL,", "and", "B-CLL", "groups", "in", "comparison", "with", "healthy", "controls.", "High", "expression", "of", "PPP2R5C", "was", "detected", "in", "the", "B-ALL", "group;", "however,", "no", "significant", "difference", "was", "found", "compared", "with", "the", "healthy", "group.", "The", "expression", "level", "of", "PPP2R5C", "in", "the", "CML-CR", "group", "decreased", "significantly", "compared", "with", "that", "in", "the", "de", "novo", "CML", "group", "and", "was", "not", "significantly", "different", "from", "the", "level", "in", "the", "healthy", "group.", "By", "using", "different", "primer", "pairs", "that", "covered", "different", "exons,", "five", "transcript", "variants", "of", "PPP2R5C", "could", "be", "identified.", "All", "variants", "could", "be", "detected", "in", "healthy", "samples", "as", "well", "as", "in", "all", "the", "leukemia", "samples,", "and", "similar", "frequencies", "and", "distributions", "of", "PPP2R5C", "were", "indicated.", "Conclusions:", "Overexpression", "of", "PPP2R5C", "in", "T-cell", "malignancy", "as", "well", "as", "in", "myeloid", "leukemia", "cells", "might", "relate", "to", "its", "proliferation", "and", "differentiation.", "Investigation", "of", "the", "effect", "of", "target", "inhibition", "of", "this", "gene", "might", "be", "beneficial", "to", "further", "characterization", "of", "molecular", "mechanisms", "and", "targeted", "therapy", "in", "leukemia.", "Keywords:", "PPP2R5C", "leukemia,", "gene", "expression,", "transcript", "variant", "Background", "Molecular", "genetic", "aberrations", "could", "provide", "the", "basis", "for", "assays", "that", "can", "predict", "prognosis", "of", "individual", "patients", "as", "well", "as", "potential", "molecular", "targets", "for", "novel", "therapies", "[1-3].", "The", "process", "of", "malignant", "transformation", "in", "leukemia", "is", "complex,", "and", "many", "factors", "such", "as", "abnormal", "gene", "expression", "and", "mutation,", "chromosomal", "aberrations,", "deregulation", "of", "various", "cellular", "signaling", "pathways,", "and", "deregulation", "of", "epigenetic", "regulation", "are", "involved", "in", "the", "development", "of", "leukemia", "[1].", "Therefore,", "new", "data", "regarding", "molecular", "genetic", "aberrations", "in", "*", "Correspondence:", "yangqiuli@hotmail.com", "†", "Contributed", "equally", "1Institute", "of", "Hematology,", "Medical", "College,", "Jinan", "University,", "Guangzhou,", "P.R.", "China", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "different", "types", "of", "leukemia", "are", "needed", "for", "further", "characterization.", "PPP2R5C", "is", "one", "of", "the", "regulatory", "B", "subunits", "of", "protein", "phosphatase", "2A", "(PP2A),", "which", "is", "a", "major", "cellu-", "lar", "serine/threonine", "phosphatase", "that", "affects", "the", "phos-", "phorylation", "status", "of", "many", "proteins", "[4].", "The", "PPP2R5C", "gene", "encodes", "five", "differentially", "spliced", "variants:", "B56g1,", "B56g2,", "B56g3,", "B56g5,", "and", "B56g6", "(Figure", "1),", "whereas", "B56g4", "is", "identified", "only", "in", "mice.", "The", "functional", "PPP2R5C", "gene", "locus", "resides", "at", "14q32.2,", "whereas", "a", "non-", "functional", "B56g1", "pseudogene", "PPP2R5C", "is", "present", "at", "3p21.3", "[4,5].", "PPP2R5C", "plays", "a", "crucial", "role", "in", "cell", "prolif-", "eration,", "differentiation,", "and", "transformation,", "based", "on", "its", "induction", "of", "dephosphorylation", "of", "P53", "at", "various", "resi-", "dues", "[6].", "It", "has", "been", "reported", "that", "the", "dynamic", "nuclear", "distribution", "of", "the", "B56g3", "regulatory", "subunit", "controls", "©", "2011", "Zheng", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 69, 75, 52, 17 ], [ 125, 75, 38, 17 ], [ 166, 75, 21, 17 ], [ 191, 76, 61, 17 ], [ 255, 76, 167, 17 ], [ 654, 101, 39, 14 ], [ 696, 101, 55, 14 ], [ 622, 122, 136, 45 ], [ 644, 168, 38, 17 ], [ 686, 168, 73, 17 ], [ 545, 187, 213, 17 ], [ 69, 211, 46, 17 ], [ 69, 248, 112, 25 ], [ 186, 248, 116, 25 ], [ 307, 248, 92, 25 ], [ 405, 248, 84, 25 ], [ 495, 248, 117, 25 ], [ 69, 297, 46, 17 ], [ 118, 297, 67, 17 ], [ 189, 294, 21, 20 ], [ 214, 297, 58, 17 ], [ 275, 297, 40, 17 ], [ 319, 297, 17, 17 ], [ 339, 294, 10, 20 ], [ 353, 297, 53, 17 ], [ 410, 297, 17, 17 ], [ 431, 297, 54, 17 ], [ 489, 294, 10, 20 ], [ 503, 297, 45, 17 ], [ 551, 297, 58, 17 ], [ 613, 294, 14, 11 ], [ 631, 297, 27, 17 ], [ 662, 297, 39, 17 ], [ 705, 297, 28, 17 ], [ 737, 294, 17, 20 ], [ 69, 334, 6, 12 ], [ 69, 381, 6, 11 ], [ 69, 428, 6, 12 ], [ 69, 452, 6, 11 ], [ 89, 337, 79, 17 ], [ 171, 337, 14, 17 ], [ 189, 337, 78, 17 ], [ 271, 337, 86, 17 ], [ 361, 337, 71, 17 ], [ 436, 337, 14, 17 ], [ 454, 337, 39, 17 ], [ 497, 337, 53, 17 ], [ 553, 337, 51, 17 ], [ 608, 337, 20, 17 ], [ 632, 337, 46, 17 ], [ 682, 337, 38, 17 ], [ 89, 361, 59, 17 ], [ 151, 361, 124, 17 ], [ 279, 361, 61, 17 ], [ 344, 361, 118, 17 ], [ 465, 361, 60, 17 ], [ 89, 384, 45, 17 ], [ 137, 384, 20, 17 ], [ 161, 384, 77, 17 ], [ 242, 384, 86, 17 ], [ 332, 384, 79, 17 ], [ 414, 384, 14, 17 ], [ 432, 384, 68, 17 ], [ 504, 384, 59, 17 ], [ 566, 384, 25, 17 ], [ 595, 384, 65, 17 ], [ 663, 384, 61, 17 ], [ 89, 408, 55, 17 ], [ 147, 408, 55, 17 ], [ 206, 408, 51, 17 ], [ 261, 408, 52, 17 ], [ 316, 408, 27, 17 ], [ 347, 408, 46, 17 ], [ 397, 408, 38, 17 ], [ 439, 408, 52, 17 ], [ 495, 408, 103, 17 ], [ 89, 431, 91, 17 ], [ 183, 431, 45, 17 ], [ 232, 431, 59, 17 ], [ 295, 431, 25, 17 ], [ 323, 431, 84, 17 ], [ 411, 431, 79, 17 ], [ 493, 431, 27, 17 ], [ 524, 431, 46, 17 ], [ 574, 431, 34, 17 ], [ 89, 455, 79, 17 ], [ 171, 455, 14, 17 ], [ 189, 455, 78, 17 ], [ 271, 455, 86, 17 ], [ 361, 455, 71, 17 ], [ 436, 455, 14, 17 ], [ 454, 455, 47, 17 ], [ 505, 455, 47, 17 ], [ 555, 455, 25, 17 ], [ 584, 455, 46, 17 ], [ 634, 455, 34, 17 ], [ 69, 495, 9, 17 ], [ 88, 495, 54, 17 ], [ 146, 495, 13, 17 ], [ 163, 495, 42, 17 ], [ 209, 495, 105, 17 ], [ 318, 495, 45, 17 ], [ 367, 495, 16, 17 ], [ 386, 495, 71, 17 ], [ 461, 495, 59, 17 ], [ 523, 495, 123, 17 ], [ 650, 495, 48, 17 ], [ 88, 519, 118, 17 ], [ 210, 519, 41, 17 ], [ 255, 519, 31, 17 ], [ 290, 519, 118, 17 ], [ 412, 519, 48, 17 ], [ 463, 519, 30, 17 ], [ 497, 519, 118, 17 ], [ 619, 519, 48, 17 ], [ 88, 543, 31, 17 ], [ 123, 543, 118, 17 ], [ 245, 543, 41, 17 ], [ 290, 543, 30, 17 ], [ 324, 543, 118, 17 ], [ 446, 543, 41, 17 ], [ 69, 583, 66, 17 ], [ 138, 583, 17, 17 ], [ 159, 583, 69, 17 ], [ 232, 583, 40, 17 ], [ 275, 583, 13, 17 ], [ 292, 583, 49, 17 ], [ 344, 583, 38, 17 ], [ 386, 583, 9, 17 ], [ 398, 583, 55, 17 ], [ 457, 583, 34, 17 ], [ 494, 583, 5, 17 ], [ 503, 583, 67, 17 ], [ 574, 583, 17, 17 ], [ 595, 583, 55, 17 ], [ 654, 583, 34, 17 ], [ 691, 583, 5, 17 ], [ 69, 606, 73, 17 ], [ 145, 606, 17, 17 ], [ 166, 606, 55, 17 ], [ 225, 606, 34, 17 ], [ 108, 673, 68, 17 ], [ 184, 673, 52, 17 ], [ 245, 673, 69, 17 ], [ 323, 673, 12, 17 ], [ 343, 673, 14, 17 ], [ 366, 673, 34, 17 ], [ 409, 673, 50, 17 ], [ 467, 673, 14, 17 ], [ 489, 673, 37, 17 ], [ 535, 673, 67, 17 ], [ 611, 673, 25, 17 ], [ 645, 673, 75, 17 ], [ 108, 696, 85, 17 ], [ 197, 696, 78, 17 ], [ 280, 696, 57, 17 ], [ 341, 696, 32, 17 ], [ 378, 696, 32, 17 ], [ 414, 696, 31, 17 ], [ 450, 696, 13, 17 ], [ 468, 696, 25, 17 ], [ 498, 696, 57, 17 ], [ 559, 696, 25, 17 ], [ 588, 696, 35, 17 ], [ 628, 696, 66, 17 ], [ 698, 696, 21, 17 ], [ 108, 720, 34, 17 ], [ 147, 720, 64, 17 ], [ 216, 720, 30, 17 ], [ 252, 720, 31, 17 ], [ 288, 720, 39, 17 ], [ 332, 720, 50, 17 ], [ 388, 720, 69, 17 ], [ 462, 720, 53, 17 ], [ 521, 720, 12, 17 ], [ 538, 720, 21, 17 ], [ 564, 720, 32, 17 ], [ 601, 720, 20, 17 ], [ 626, 720, 8, 17 ], [ 640, 720, 43, 17 ], [ 688, 720, 31, 17 ], [ 108, 744, 20, 17 ], [ 134, 744, 69, 17 ], [ 210, 744, 68, 17 ], [ 284, 744, 65, 17 ], [ 356, 744, 14, 17 ], [ 378, 744, 21, 17 ], [ 405, 744, 43, 17 ], [ 455, 744, 39, 17 ], [ 501, 744, 45, 17 ], [ 553, 744, 21, 17 ], [ 580, 744, 53, 17 ], [ 640, 744, 79, 17 ], [ 108, 767, 48, 17 ], [ 162, 767, 31, 17 ], [ 199, 767, 48, 17 ], [ 253, 767, 56, 17 ], [ 316, 767, 48, 17 ], [ 370, 767, 25, 17 ], [ 401, 767, 43, 17 ], [ 450, 767, 35, 17 ], [ 492, 767, 54, 17 ], [ 553, 767, 8, 17 ], [ 567, 767, 82, 17 ], [ 655, 767, 44, 17 ], [ 706, 767, 13, 17 ], [ 108, 791, 40, 17 ], [ 153, 791, 43, 17 ], [ 201, 791, 31, 17 ], [ 237, 791, 25, 17 ], [ 266, 791, 69, 17 ], [ 340, 791, 67, 17 ], [ 412, 791, 55, 17 ], [ 472, 791, 17, 17 ], [ 495, 791, 21, 17 ], [ 520, 791, 43, 17 ], [ 569, 791, 39, 17 ], [ 613, 791, 87, 17 ], [ 705, 791, 14, 17 ], [ 108, 814, 25, 17 ], [ 140, 814, 42, 17 ], [ 189, 814, 20, 17 ], [ 217, 814, 49, 17 ], [ 273, 814, 8, 17 ], [ 289, 814, 83, 17 ], [ 379, 814, 58, 17 ], [ 444, 814, 20, 17 ], [ 472, 814, 68, 17 ], [ 548, 814, 50, 17 ], [ 606, 814, 69, 17 ], [ 683, 814, 37, 17 ], [ 108, 838, 57, 17 ], [ 168, 838, 49, 17 ], [ 221, 838, 55, 17 ], [ 280, 838, 46, 17 ], [ 330, 838, 14, 17 ], [ 348, 838, 25, 17 ], [ 377, 838, 62, 17 ], [ 443, 838, 57, 17 ], [ 504, 838, 21, 17 ], [ 528, 838, 27, 17 ], [ 560, 838, 34, 17 ], [ 597, 838, 17, 17 ], [ 619, 838, 12, 17 ], [ 635, 838, 21, 17 ], [ 660, 838, 41, 17 ], [ 705, 838, 15, 17 ], [ 108, 862, 21, 17 ], [ 134, 862, 52, 17 ], [ 192, 862, 51, 17 ], [ 250, 862, 77, 17 ], [ 333, 862, 25, 17 ], [ 363, 862, 54, 17 ], [ 423, 862, 43, 17 ], [ 472, 862, 35, 17 ], [ 513, 862, 26, 17 ], [ 545, 862, 57, 17 ], [ 608, 862, 21, 17 ], [ 635, 862, 29, 17 ], [ 670, 862, 50, 17 ], [ 108, 885, 26, 17 ], [ 139, 885, 21, 17 ], [ 165, 885, 47, 17 ], [ 216, 885, 35, 17 ], [ 255, 885, 41, 17 ], [ 302, 885, 57, 17 ], [ 364, 885, 21, 17 ], [ 390, 885, 43, 17 ], [ 438, 885, 53, 17 ], [ 496, 885, 21, 17 ], [ 522, 885, 66, 17 ], [ 594, 885, 56, 17 ], [ 655, 885, 39, 17 ], [ 699, 885, 20, 17 ], [ 108, 909, 26, 17 ], [ 139, 909, 39, 17 ], [ 182, 909, 73, 17 ], [ 260, 909, 26, 17 ], [ 291, 909, 39, 17 ], [ 335, 909, 57, 17 ], [ 397, 909, 21, 17 ], [ 423, 909, 55, 17 ], [ 482, 909, 13, 17 ], [ 500, 909, 35, 17 ], [ 540, 909, 42, 17 ], [ 587, 909, 88, 17 ], [ 680, 909, 13, 17 ], [ 698, 909, 21, 17 ], [ 108, 932, 52, 17 ], [ 167, 932, 25, 17 ], [ 198, 932, 14, 17 ], [ 219, 932, 21, 17 ], [ 246, 932, 55, 17 ], [ 308, 932, 35, 17 ], [ 350, 932, 79, 17 ], [ 435, 932, 96, 17 ], [ 538, 932, 89, 17 ], [ 635, 932, 57, 17 ], [ 698, 932, 21, 17 ], [ 108, 956, 63, 17 ], [ 175, 956, 26, 17 ], [ 205, 956, 56, 17 ], [ 265, 956, 66, 17 ], [ 335, 956, 49, 17 ], [ 388, 956, 26, 17 ], [ 418, 956, 69, 17 ], [ 491, 956, 47, 17 ], [ 541, 956, 14, 17 ], [ 559, 956, 21, 17 ], [ 584, 956, 49, 17 ], [ 637, 956, 83, 17 ], [ 108, 980, 58, 17 ], [ 170, 980, 12, 17 ], [ 187, 980, 25, 17 ], [ 217, 980, 21, 17 ], [ 243, 980, 44, 17 ], [ 292, 980, 31, 17 ], [ 328, 980, 22, 17 ], [ 355, 980, 48, 17 ], [ 407, 980, 21, 17 ], [ 433, 980, 23, 17 ], [ 460, 980, 14, 17 ], [ 480, 980, 21, 17 ], [ 505, 980, 43, 17 ], [ 554, 980, 31, 17 ], [ 590, 980, 20, 17 ], [ 614, 980, 75, 17 ], [ 695, 980, 25, 17 ], [ 108, 1003, 55, 17 ], [ 169, 1003, 14, 17 ], [ 190, 1003, 61, 17 ], [ 257, 1003, 53, 17 ], [ 316, 1003, 21, 17 ], [ 343, 1003, 68, 17 ], [ 417, 1003, 31, 17 ], [ 455, 1003, 58, 17 ], [ 519, 1003, 25, 17 ], [ 550, 1003, 69, 17 ], [ 625, 1003, 21, 17 ], [ 652, 1003, 67, 17 ], [ 108, 1027, 43, 17 ], [ 157, 1027, 8, 17 ], [ 171, 1027, 40, 17 ], [ 218, 1027, 83, 17 ], [ 307, 1027, 44, 17 ], [ 358, 1027, 25, 17 ], [ 389, 1027, 92, 17 ], [ 487, 1027, 105, 17 ], [ 599, 1027, 14, 17 ], [ 620, 1027, 25, 17 ], [ 651, 1027, 42, 17 ], [ 699, 1027, 20, 17 ], [ 108, 1050, 90, 17 ], [ 203, 1050, 25, 17 ], [ 235, 1050, 58, 17 ], [ 298, 1050, 50, 17 ], [ 354, 1050, 99, 17 ], [ 458, 1050, 80, 17 ], [ 544, 1050, 20, 17 ], [ 570, 1050, 9, 17 ], [ 584, 1050, 23, 17 ], [ 613, 1050, 25, 17 ], [ 643, 1050, 17, 17 ], [ 666, 1050, 23, 17 ], [ 695, 1050, 25, 17 ], [ 108, 1074, 20, 17 ], [ 135, 1074, 9, 17 ], [ 151, 1074, 23, 17 ], [ 181, 1074, 25, 17 ], [ 213, 1074, 9, 17 ], [ 229, 1074, 27, 17 ], [ 264, 1074, 36, 17 ], [ 307, 1074, 21, 17 ], [ 336, 1074, 45, 17 ], [ 388, 1074, 14, 17 ], [ 410, 1074, 21, 17 ], [ 438, 1074, 35, 17 ], [ 480, 1074, 46, 17 ], [ 533, 1074, 21, 17 ], [ 561, 1074, 31, 17 ], [ 600, 1074, 30, 17 ], [ 637, 1074, 25, 17 ], [ 669, 1074, 50, 17 ] ]

[ "Sensors", "2012,", "12,", "905-922;", "doi:10.3390/s120100905", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "Sheathless", "Size-Based", "Acoustic", "Particle", "Separation", "Rasim", "Guldiken", "1,*,", "Myeong", "Chan", "Jo", "1,", "Nathan", "D.", "Gallant", "1,", "Utkan", "Demirci", "2,3", "and", "Jiang", "Zhe", "4,*", "1", "2", "3", "4", "Department", "of", "Mechanical", "Engineering,", "University", "of", "South", "Florida,", "Tampa,", "FL", "33620,", "USA;", "E-Mails:", "mjo@mail.usf.edu", "(M.C.J.);", "ngallant@usf.edu", "(N.D.G.)", "Center", "for", "Biomedical", "Engineering,", "Department", "of", "Medicine,", "Brigham", "and", "Women’s", "Hospital,", "Harvard", "Medical", "School,", "Boston,", "MA", "02115,", "USA;", "E-Mail:", "utkan@mit.edu", "Harvard-MIT", "Health", "Sciences", "and", "Technology,", "Cambridge,", "MA", "02139,", "USA", "Department", "of", "Mechanical", "Engineering,", "University", "of", "Akron,", "Akron,", "OH", "44325,", "USA", "*", "Authors", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mails:", "guldiken@usf.edu", "(R.G.);", "jzhe@uakron.edu", "(J.Z.);", "Tel.:", "+1-813-974-5628", "(R.G.);", "Fax:", "+1-813-974-3539", "(R.G.);", "Tel.:", "+1-330-972-7737", "(J.Z.);", "Fax:", "+1-330-972-6027", "(J.Z.).", "Received:", "23", "November", "2011;", "in", "revised", "form:", "4", "January", "2012", "/", "Accepted:", "14", "January", "2012", "/", "Published:", "16", "January", "2012", "Abstract:", "Particle", "separation", "is", "of", "great", "interest", "in", "many", "biological", "and", "biomedical", "applications.", "Flow-based", "methods", "have", "been", "used", "to", "sort", "particles", "and", "cells.", "However,", "the", "main", "challenge", "with", "flow", "based", "particle", "separation", "systems", "is", "the", "need", "for", "a", "sheath", "flow", "for", "successful", "operation.", "Existence", "of", "the", "sheath", "liquid", "dilutes", "the", "analyte,", "necessitates", "precise", "flow", "control", "between", "sample", "and", "sheath", "flow,", "requires", "a", "complicated", "design", "to", "create", "sheath", "flow", "and", "separation", "efficiency", "depends", "on", "the", "sheath", "liquid", "composition.", "In", "this", "paper,", "we", "present", "a", "microfluidic", "platform", "for", "sheathless", "particle", "separation", "using", "standing", "surface", "acoustic", "waves.", "In", "this", "platform,", "particles", "are", "first", "lined", "up", "at", "the", "center", "of", "the", "channel", "without", "introducing", "any", "external", "sheath", "flow.", "The", "particles", "are", "then", "entered", "into", "the", "second", "stage", "where", "particles", "are", "driven", "towards", "the", "off-center", "pressure", "nodes", "for", "size", "based", "separation.", "The", "larger", "particles", "are", "exposed", "to", "more", "lateral", "displacement", "in", "the", "channel", "due", "to", "the", "acoustic", "force", "differences.", "Consequently,", "different-size", "particles", "are", "separated", "into", "multiple", "collection", "outlets.", "The", "prominent", "feature", "of", "the", "present", "microfluidic", "platform", "is", "that", "the", "device", "does", "not", "require", "the", "use", "of", "the", "sheath", "flow", "for", "positioning", "and", "aligning", "of", "particles.", "Instead,", "the", "sheathless", "flow", "focusing", "and", "separation", "are", "integrated", "within", "a", "single", "microfluidic", "device", "and", "accomplished", "simultaneously.", "In", "this", "paper,", "we", "demonstrated", "two", "different", "particle", "size-resolution", "separations;", "(1)", "3", "µm", "and", "10", "µm", "and", "(2)", "3", "µm", "and", "5", "µm.", "Also,", "the", "effects", "of", "the", "input", "power,", "the", "flow", "rate,", "and", "particle" ]

[ 0, 0, 0, 0, 0, 9, 9, 0, 0, 0, 0, 16, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 11, 11, 11, 11, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5 ]

[ [ 80, 78, 137, 28 ], [ 226, 78, 84, 28 ], [ 319, 78, 100, 28 ], [ 428, 78, 35, 28 ], [ 471, 78, 106, 28 ], [ 586, 78, 125, 28 ], [ 720, 78, 24, 28 ], [ 80, 109, 40, 28 ], [ 130, 109, 94, 28 ], [ 232, 109, 73, 28 ], [ 314, 109, 80, 28 ], [ 80, 152, 44, 14 ], [ 129, 152, 46, 15 ], [ 175, 149, 33, 18 ], [ 211, 152, 43, 14 ], [ 259, 152, 19, 15 ], [ 277, 149, 51, 18 ], [ 332, 152, 31, 14 ], [ 367, 150, 62, 17 ], [ 434, 152, 65, 14 ], [ 503, 150, 57, 17 ], [ 80, 175, 6, 10 ], [ 88, 175, 50, 10 ], [ 141, 175, 9, 10 ], [ 154, 175, 72, 10 ], [ 229, 175, 83, 10 ], [ 316, 175, 12, 10 ], [ 332, 175, 21, 10 ], [ 357, 175, 39, 10 ], [ 399, 175, 40, 10 ], [ 442, 175, 39, 10 ], [ 485, 175, 6, 10 ], [ 493, 175, 37, 10 ], [ 534, 175, 34, 10 ], [ 572, 175, 12, 10 ], [ 587, 175, 41, 10 ], [ 632, 175, 30, 10 ], [ 666, 175, 26, 10 ], [ 696, 175, 30, 10 ], [ 730, 175, 40, 10 ], [ 80, 189, 30, 10 ], [ 113, 189, 43, 10 ], [ 159, 189, 40, 10 ], [ 201, 189, 40, 10 ], [ 243, 189, 6, 10 ], [ 251, 189, 34, 10 ], [ 287, 189, 12, 10 ], [ 302, 189, 45, 10 ], [ 350, 189, 42, 10 ], [ 395, 189, 33, 10 ], [ 431, 189, 19, 10 ], [ 452, 189, 41, 10 ], [ 496, 189, 9, 10 ], [ 507, 189, 50, 10 ], [ 560, 189, 21, 10 ], [ 584, 189, 29, 10 ], [ 102, 227, 57, 14 ], [ 102, 249, 8, 13 ], [ 114, 249, 8, 13 ], [ 126, 249, 47, 13 ], [ 176, 249, 18, 13 ], [ 199, 249, 36, 13 ], [ 239, 249, 24, 13 ], [ 266, 249, 58, 13 ], [ 328, 249, 47, 13 ], [ 379, 249, 53, 13 ], [ 435, 249, 10, 13 ], [ 449, 249, 25, 13 ], [ 479, 249, 30, 13 ], [ 513, 249, 28, 13 ], [ 544, 249, 26, 13 ], [ 574, 249, 84, 13 ], [ 662, 249, 64, 13 ], [ 731, 249, 17, 13 ], [ 102, 263, 30, 13 ], [ 136, 263, 77, 13 ], [ 217, 263, 56, 13 ], [ 277, 263, 25, 13 ], [ 307, 263, 16, 13 ], [ 327, 263, 41, 13 ], [ 372, 263, 30, 13 ], [ 406, 263, 33, 13 ], [ 443, 263, 20, 13 ], [ 468, 263, 40, 13 ], [ 512, 263, 47, 13 ], [ 563, 263, 25, 13 ], [ 592, 263, 45, 13 ], [ 642, 263, 43, 13 ], [ 689, 263, 10, 13 ], [ 704, 263, 29, 13 ], [ 736, 263, 12, 13 ], [ 102, 277, 40, 13 ], [ 146, 277, 18, 13 ], [ 168, 277, 48, 13 ], [ 220, 277, 50, 13 ], [ 274, 277, 11, 13 ], [ 289, 277, 85, 13 ], [ 378, 277, 62, 13 ], [ 444, 277, 10, 13 ], [ 458, 277, 18, 13 ], [ 480, 277, 38, 13 ], [ 522, 277, 38, 13 ], [ 565, 277, 11, 13 ], [ 580, 277, 27, 13 ], [ 610, 277, 56, 13 ], [ 671, 277, 11, 13 ], [ 686, 277, 38, 13 ], [ 728, 277, 20, 13 ], [ 102, 291, 46, 13 ], [ 151, 291, 17, 13 ], [ 171, 291, 25, 13 ], [ 200, 291, 55, 13 ], [ 259, 291, 11, 13 ], [ 273, 291, 15, 13 ], [ 290, 291, 11, 13 ], [ 305, 291, 28, 13 ], [ 336, 291, 45, 13 ], [ 384, 291, 30, 13 ], [ 417, 291, 35, 13 ], [ 456, 291, 36, 13 ], [ 496, 291, 11, 13 ], [ 510, 291, 18, 13 ], [ 531, 291, 50, 13 ], [ 584, 291, 53, 13 ], [ 640, 291, 15, 13 ], [ 659, 291, 20, 13 ], [ 682, 291, 16, 13 ], [ 701, 291, 20, 13 ], [ 724, 291, 24, 13 ], [ 102, 305, 44, 13 ], [ 149, 305, 11, 13 ], [ 163, 305, 20, 13 ], [ 186, 305, 16, 13 ], [ 205, 305, 11, 13 ], [ 219, 305, 33, 13 ], [ 255, 305, 26, 13 ], [ 284, 305, 11, 13 ], [ 298, 305, 18, 13 ], [ 319, 305, 62, 13 ], [ 383, 305, 31, 13 ], [ 418, 305, 30, 13 ], [ 450, 305, 35, 13 ], [ 489, 305, 58, 13 ], [ 550, 305, 14, 13 ], [ 566, 305, 70, 13 ], [ 639, 305, 47, 13 ], [ 689, 305, 11, 13 ], [ 703, 305, 45, 13 ], [ 102, 318, 46, 13 ], [ 151, 318, 17, 13 ], [ 173, 318, 42, 13 ], [ 218, 318, 33, 13 ], [ 255, 318, 50, 13 ], [ 309, 318, 24, 13 ], [ 336, 318, 50, 13 ], [ 390, 318, 32, 13 ], [ 426, 318, 52, 13 ], [ 481, 318, 20, 13 ], [ 506, 318, 21, 13 ], [ 530, 318, 58, 13 ], [ 593, 318, 13, 13 ], [ 610, 318, 35, 13 ], [ 648, 318, 29, 13 ], [ 681, 318, 66, 13 ], [ 102, 332, 25, 13 ], [ 129, 332, 11, 13 ], [ 143, 332, 19, 13 ], [ 165, 332, 14, 13 ], [ 181, 332, 47, 13 ], [ 231, 332, 14, 13 ], [ 247, 332, 52, 13 ], [ 301, 332, 46, 13 ], [ 350, 332, 24, 13 ], [ 376, 332, 35, 13 ], [ 414, 332, 17, 13 ], [ 434, 332, 18, 13 ], [ 455, 332, 28, 13 ], [ 486, 332, 62, 13 ], [ 550, 332, 31, 13 ], [ 584, 332, 45, 13 ], [ 632, 332, 38, 13 ], [ 673, 332, 20, 13 ], [ 695, 332, 53, 13 ], [ 102, 346, 11, 13 ], [ 117, 346, 18, 13 ], [ 139, 346, 27, 13 ], [ 169, 346, 34, 13 ], [ 207, 346, 44, 13 ], [ 255, 346, 53, 13 ], [ 311, 346, 31, 13 ], [ 347, 346, 29, 13 ], [ 380, 346, 46, 13 ], [ 430, 346, 11, 13 ], [ 445, 346, 62, 13 ], [ 510, 346, 31, 13 ], [ 546, 346, 25, 13 ], [ 575, 346, 19, 13 ], [ 598, 346, 20, 13 ], [ 622, 346, 18, 13 ], [ 644, 346, 53, 13 ], [ 701, 346, 47, 13 ], [ 102, 360, 21, 13 ], [ 127, 360, 62, 13 ], [ 193, 360, 21, 13 ], [ 217, 360, 46, 13 ], [ 267, 360, 25, 13 ], [ 297, 360, 10, 13 ], [ 311, 360, 18, 13 ], [ 332, 360, 51, 13 ], [ 387, 360, 26, 13 ], [ 417, 360, 51, 13 ], [ 472, 360, 62, 13 ], [ 538, 360, 11, 13 ], [ 553, 360, 18, 13 ], [ 575, 360, 51, 13 ], [ 630, 360, 11, 13 ], [ 645, 360, 43, 13 ], [ 691, 360, 23, 13 ], [ 718, 360, 30, 13 ], [ 102, 374, 29, 13 ], [ 134, 374, 27, 13 ], [ 164, 374, 24, 13 ], [ 191, 374, 51, 13 ], [ 245, 374, 15, 13 ], [ 263, 374, 58, 13 ], [ 325, 374, 25, 13 ], [ 353, 374, 13, 13 ], [ 370, 374, 22, 13 ], [ 394, 374, 10, 13 ], [ 408, 374, 18, 13 ], [ 429, 374, 37, 13 ], [ 469, 374, 35, 13 ], [ 506, 374, 11, 13 ], [ 520, 374, 52, 13 ], [ 575, 374, 32, 13 ], [ 610, 373, 37, 13 ], [ 652, 374, 22, 13 ], [ 677, 374, 20, 13 ], [ 700, 374, 48, 13 ], [ 102, 388, 15, 13 ], [ 120, 388, 37, 13 ], [ 160, 388, 20, 13 ], [ 183, 388, 16, 13 ], [ 202, 388, 40, 13 ], [ 246, 388, 18, 13 ], [ 267, 388, 30, 13 ], [ 300, 388, 11, 13 ], [ 314, 388, 38, 13 ], [ 355, 388, 20, 13 ], [ 378, 388, 35, 13 ], [ 416, 388, 42, 13 ], [ 461, 388, 22, 13 ], [ 486, 388, 18, 13 ], [ 506, 388, 44, 13 ], [ 553, 388, 25, 13 ], [ 582, 388, 32, 13 ], [ 617, 388, 16, 13 ], [ 636, 388, 47, 13 ], [ 686, 388, 8, 13 ], [ 698, 388, 50, 13 ], [ 102, 401, 24, 13 ], [ 129, 401, 34, 13 ], [ 167, 401, 44, 13 ], [ 215, 401, 20, 13 ], [ 239, 401, 8, 13 ], [ 250, 401, 41, 13 ], [ 295, 401, 11, 13 ], [ 310, 401, 59, 13 ], [ 373, 401, 33, 13 ], [ 410, 401, 73, 13 ], [ 487, 401, 42, 13 ], [ 532, 401, 62, 13 ], [ 598, 401, 31, 13 ], [ 633, 401, 57, 13 ], [ 693, 401, 55, 13 ], [ 102, 415, 38, 13 ], [ 144, 415, 21, 13 ], [ 169, 415, 30, 13 ], [ 202, 415, 56, 13 ], [ 261, 415, 39, 13 ], [ 304, 415, 50, 13 ], [ 358, 415, 81, 13 ], [ 443, 415, 44, 13 ], [ 491, 415, 11, 13 ], [ 505, 415, 55, 13 ], [ 563, 415, 36, 13 ], [ 92, 450, 40, 10 ], [ 136, 450, 28, 10 ], [ 167, 450, 9, 10 ], [ 180, 450, 31, 10 ], [ 214, 450, 7, 10 ], [ 225, 450, 26, 10 ], [ 255, 450, 11, 10 ], [ 269, 450, 25, 10 ], [ 298, 450, 9, 10 ], [ 310, 450, 26, 10 ], [ 339, 450, 46, 10 ], [ 389, 450, 28, 10 ], [ 420, 450, 34, 10 ], [ 458, 450, 12, 10 ], [ 474, 450, 35, 10 ], [ 513, 450, 42, 10 ], [ 558, 450, 8, 10 ], [ 570, 450, 14, 10 ], [ 587, 450, 31, 10 ], [ 622, 450, 24, 10 ], [ 650, 450, 29, 10 ], [ 683, 450, 20, 10 ], [ 706, 450, 16, 10 ], [ 725, 450, 23, 10 ], [ 92, 461, 42, 10 ], [ 137, 461, 136, 10 ], [ 92, 479, 46, 10 ], [ 140, 479, 32, 10 ], [ 175, 479, 38, 10 ], [ 216, 479, 9, 10 ], [ 227, 479, 26, 10 ], [ 256, 479, 20, 10 ], [ 279, 479, 29, 10 ], [ 311, 479, 32, 10 ], [ 346, 479, 33, 10 ], [ 382, 479, 28, 10 ], [ 413, 479, 25, 10 ], [ 440, 479, 9, 10 ], [ 452, 479, 34, 10 ], [ 92, 496, 42, 10 ], [ 137, 496, 20, 10 ], [ 160, 496, 12, 10 ], [ 175, 496, 22, 10 ], [ 200, 496, 44, 10 ], [ 247, 496, 43, 10 ], [ 293, 496, 12, 10 ], [ 308, 496, 22, 10 ], [ 333, 496, 47, 10 ], [ 383, 496, 42, 10 ], [ 428, 496, 12, 10 ], [ 443, 496, 20, 10 ], [ 92, 513, 50, 10 ], [ 158, 513, 20, 10 ], [ 182, 513, 28, 10 ], [ 213, 513, 9, 10 ], [ 226, 513, 9, 10 ], [ 239, 513, 17, 10 ], [ 259, 513, 6, 10 ], [ 270, 513, 10, 10 ], [ 284, 513, 50, 10 ], [ 338, 513, 25, 10 ], [ 367, 513, 45, 10 ], [ 416, 513, 25, 10 ], [ 444, 513, 14, 10 ], [ 462, 513, 24, 10 ], [ 489, 513, 9, 10 ], [ 502, 513, 14, 10 ], [ 519, 513, 34, 10 ], [ 557, 513, 42, 10 ], [ 603, 513, 45, 10 ], [ 652, 513, 33, 10 ], [ 688, 513, 25, 10 ], [ 717, 513, 31, 10 ], [ 92, 524, 49, 10 ], [ 144, 524, 17, 10 ], [ 163, 524, 50, 10 ], [ 216, 524, 16, 10 ], [ 235, 524, 54, 10 ], [ 291, 524, 8, 10 ], [ 302, 524, 15, 10 ], [ 320, 524, 37, 10 ], [ 359, 524, 37, 10 ], [ 399, 524, 14, 10 ], [ 416, 524, 31, 10 ], [ 450, 524, 27, 10 ], [ 480, 524, 16, 10 ], [ 498, 524, 27, 10 ], [ 529, 524, 13, 10 ], [ 545, 524, 36, 10 ], [ 92, 542, 42, 10 ], [ 136, 542, 17, 10 ], [ 155, 542, 21, 10 ], [ 178, 542, 16, 10 ], [ 197, 542, 43, 10 ], [ 242, 542, 10, 10 ], [ 255, 542, 5, 10 ], [ 262, 542, 22, 10 ], [ 286, 542, 20, 10 ], [ 309, 542, 39, 10 ], [ 350, 542, 102, 10 ], [ 454, 542, 12, 10 ], [ 468, 542, 36, 10 ], [ 507, 542, 10, 10 ], [ 520, 542, 14, 10 ], [ 536, 542, 33, 10 ], [ 571, 542, 30, 10 ], [ 604, 542, 33, 10 ], [ 639, 542, 9, 10 ], [ 650, 542, 41, 10 ], [ 693, 542, 16, 10 ], [ 711, 542, 37, 10 ], [ 92, 553, 29, 10 ], [ 124, 553, 26, 10 ], [ 153, 553, 14, 10 ], [ 170, 553, 43, 10 ], [ 216, 553, 26, 10 ], [ 245, 553, 78, 10 ], [ 326, 553, 34, 10 ], [ 363, 553, 35, 10 ], [ 400, 553, 22, 10 ], [ 426, 553, 45, 10 ], [ 474, 553, 41, 10 ], [ 518, 553, 16, 10 ], [ 537, 553, 42, 10 ], [ 582, 553, 35, 10 ], [ 620, 553, 16, 10 ], [ 639, 553, 25, 10 ], [ 668, 553, 35, 10 ], [ 706, 553, 43, 10 ], [ 92, 564, 26, 10 ], [ 121, 564, 32, 10 ], [ 156, 564, 16, 10 ], [ 176, 564, 37, 10 ], [ 216, 564, 17, 10 ], [ 235, 564, 20, 10 ], [ 258, 564, 14, 10 ], [ 275, 564, 34, 10 ], [ 312, 564, 31, 10 ], [ 346, 564, 21, 10 ], [ 370, 564, 18, 10 ], [ 392, 564, 8, 10 ], [ 403, 564, 44, 10 ], [ 450, 564, 16, 10 ], [ 469, 564, 29, 10 ], [ 501, 564, 8, 10 ], [ 513, 564, 48, 10 ], [ 563, 564, 39, 10 ], [ 605, 564, 29, 10 ], [ 637, 564, 8, 10 ], [ 649, 564, 48, 10 ], [ 700, 564, 30, 10 ], [ 732, 564, 16, 10 ], [ 92, 575, 29, 10 ], [ 123, 575, 8, 10 ], [ 134, 575, 48, 10 ], [ 184, 575, 43, 10 ], [ 228, 575, 9, 10 ], [ 239, 575, 14, 10 ], [ 255, 575, 40, 10 ], [ 296, 575, 27, 10 ], [ 325, 575, 16, 10 ], [ 343, 575, 31, 10 ], [ 376, 575, 16, 10 ], [ 394, 575, 11, 10 ], [ 407, 575, 16, 10 ], [ 425, 575, 8, 10 ], [ 435, 575, 23, 10 ], [ 460, 575, 30, 10 ], [ 492, 575, 18, 10 ], [ 512, 575, 40, 10 ], [ 554, 575, 16, 10 ], [ 572, 575, 34, 10 ], [ 608, 575, 34, 10 ], [ 644, 575, 9, 10 ], [ 655, 575, 32, 10 ], [ 689, 575, 9, 10 ], [ 700, 575, 48, 10 ], [ 92, 586, 9, 10 ], [ 103, 586, 14, 10 ], [ 120, 586, 48, 10 ], [ 92, 603, 52, 10 ], [ 147, 603, 44, 10 ], [ 193, 603, 16, 10 ], [ 212, 603, 31, 10 ], [ 246, 603, 20, 10 ], [ 268, 603, 35, 10 ], [ 307, 603, 17, 10 ], [ 326, 603, 11, 10 ], [ 340, 603, 45, 10 ], [ 388, 603, 35, 10 ], [ 426, 603, 21, 10 ], [ 92, 620, 69, 10 ], [ 163, 620, 20, 10 ], [ 186, 620, 18, 10 ], [ 206, 620, 25, 10 ], [ 233, 620, 75, 10 ], [ 310, 620, 60, 10 ], [ 373, 620, 15, 10 ], [ 390, 620, 74, 10 ], [ 466, 620, 12, 10 ], [ 481, 620, 40, 10 ], [ 523, 620, 33, 10 ], [ 558, 620, 10, 10 ], [ 570, 620, 63, 10 ], [ 636, 620, 16, 10 ], [ 654, 620, 23, 10 ], [ 680, 620, 22, 10 ], [ 704, 620, 18, 10 ], [ 725, 620, 24, 10 ], [ 92, 632, 50, 10 ], [ 145, 632, 19, 10 ], [ 167, 632, 44, 10 ], [ 213, 632, 18, 10 ], [ 234, 632, 23, 10 ], [ 259, 632, 20, 10 ], [ 283, 632, 36, 10 ], [ 322, 632, 13, 10 ], [ 337, 632, 38, 10 ], [ 378, 632, 20, 10 ], [ 401, 632, 14, 10 ], [ 417, 632, 36, 10 ], [ 456, 632, 40, 10 ], [ 500, 632, 20, 10 ], [ 523, 632, 32, 10 ], [ 558, 632, 26, 10 ], [ 587, 632, 37, 10 ], [ 627, 632, 20, 10 ], [ 650, 632, 37, 10 ], [ 690, 632, 12, 10 ], [ 92, 649, 5, 10 ], [ 99, 649, 27, 10 ], [ 129, 649, 104, 10 ], [ 92, 665, 7, 10 ], [ 102, 666, 24, 10 ], [ 129, 666, 31, 10 ], [ 163, 666, 49, 10 ], [ 215, 666, 30, 10 ], [ 247, 666, 9, 10 ], [ 259, 666, 15, 10 ], [ 277, 666, 23, 10 ], [ 80, 711, 84, 14 ], [ 93, 740, 9, 13 ], [ 104, 740, 40, 13 ], [ 147, 740, 10, 13 ], [ 159, 740, 39, 13 ], [ 201, 740, 43, 13 ], [ 246, 740, 24, 13 ], [ 273, 740, 25, 13 ], [ 300, 740, 44, 13 ], [ 347, 740, 10, 13 ], [ 360, 740, 53, 13 ], [ 80, 755, 22, 13 ], [ 106, 755, 45, 13 ], [ 155, 755, 35, 13 ], [ 194, 755, 37, 13 ], [ 234, 755, 49, 13 ], [ 286, 755, 10, 13 ], [ 300, 755, 37, 13 ], [ 341, 755, 56, 13 ], [ 401, 755, 11, 13 ], [ 80, 770, 44, 13 ], [ 128, 770, 22, 13 ], [ 153, 770, 10, 13 ], [ 166, 770, 48, 13 ], [ 217, 770, 29, 13 ], [ 249, 770, 43, 13 ], [ 295, 770, 24, 13 ], [ 322, 770, 24, 13 ], [ 349, 770, 33, 13 ], [ 385, 770, 15, 13 ], [ 403, 770, 10, 13 ], [ 80, 784, 16, 13 ], [ 99, 784, 46, 13 ], [ 148, 784, 84, 13 ], [ 234, 784, 24, 13 ], [ 261, 784, 28, 13 ], [ 292, 784, 19, 13 ], [ 314, 784, 16, 13 ], [ 333, 784, 80, 13 ], [ 80, 799, 28, 13 ], [ 112, 799, 20, 13 ], [ 135, 799, 16, 13 ], [ 155, 799, 54, 13 ], [ 213, 799, 33, 13 ], [ 249, 799, 10, 13 ], [ 263, 799, 35, 13 ], [ 302, 799, 36, 13 ], [ 343, 799, 70, 13 ], [ 80, 814, 24, 13 ], [ 108, 814, 43, 13 ], [ 154, 814, 10, 13 ], [ 168, 814, 47, 13 ], [ 219, 814, 19, 13 ], [ 240, 814, 20, 13 ], [ 264, 814, 11, 13 ], [ 279, 814, 43, 13 ], [ 324, 814, 22, 13 ], [ 350, 814, 34, 13 ], [ 387, 814, 26, 13 ], [ 80, 829, 11, 13 ], [ 98, 829, 22, 13 ], [ 127, 829, 48, 13 ], [ 182, 829, 26, 13 ], [ 215, 829, 10, 13 ], [ 232, 829, 16, 13 ], [ 255, 829, 31, 13 ], [ 293, 829, 10, 13 ], [ 310, 829, 54, 13 ], [ 371, 829, 42, 13 ], [ 80, 843, 41, 13 ], [ 125, 843, 19, 13 ], [ 147, 843, 78, 13 ], [ 229, 843, 45, 13 ], [ 277, 843, 20, 13 ], [ 301, 843, 16, 13 ], [ 321, 843, 43, 13 ], [ 367, 843, 20, 13 ], [ 391, 843, 22, 13 ], [ 80, 858, 24, 13 ], [ 109, 858, 10, 13 ], [ 125, 858, 19, 13 ], [ 149, 858, 13, 13 ], [ 168, 858, 53, 13 ], [ 226, 858, 31, 13 ], [ 263, 858, 23, 13 ], [ 291, 858, 31, 13 ], [ 327, 858, 47, 13 ], [ 380, 858, 12, 13 ], [ 397, 858, 16, 13 ], [ 80, 873, 40, 13 ], [ 124, 873, 10, 13 ], [ 138, 873, 29, 13 ], [ 171, 873, 31, 13 ], [ 206, 873, 10, 13 ], [ 220, 873, 16, 13 ], [ 241, 873, 60, 13 ], [ 305, 873, 10, 13 ], [ 319, 873, 31, 13 ], [ 354, 873, 36, 13 ], [ 394, 873, 19, 13 ], [ 80, 888, 20, 13 ], [ 106, 888, 10, 13 ], [ 121, 888, 28, 13 ], [ 154, 888, 53, 13 ], [ 212, 888, 18, 13 ], [ 235, 888, 24, 13 ], [ 264, 888, 8, 13 ], [ 277, 888, 10, 13 ], [ 293, 888, 63, 13 ], [ 360, 888, 16, 13 ], [ 381, 888, 31, 13 ], [ 80, 903, 54, 13 ], [ 138, 903, 46, 13 ], [ 187, 903, 43, 13 ], [ 234, 903, 20, 13 ], [ 258, 903, 24, 13 ], [ 285, 903, 25, 13 ], [ 314, 903, 51, 13 ], [ 368, 903, 10, 13 ], [ 382, 903, 30, 13 ], [ 80, 917, 37, 13 ], [ 125, 917, 80, 13 ], [ 212, 917, 40, 13 ], [ 260, 917, 10, 13 ], [ 278, 917, 48, 13 ], [ 333, 917, 50, 13 ], [ 390, 917, 22, 13 ], [ 80, 932, 41, 13 ], [ 127, 932, 20, 13 ], [ 154, 932, 28, 13 ], [ 187, 932, 42, 13 ], [ 235, 932, 61, 13 ], [ 303, 932, 29, 13 ], [ 338, 932, 41, 13 ], [ 385, 932, 28, 13 ], [ 80, 947, 43, 13 ], [ 126, 947, 20, 13 ], [ 149, 947, 43, 13 ], [ 195, 947, 22, 13 ], [ 219, 947, 29, 13 ], [ 251, 947, 60, 13 ], [ 314, 947, 18, 13 ], [ 335, 947, 12, 13 ], [ 350, 947, 47, 13 ], [ 400, 947, 13, 13 ], [ 80, 962, 6, 13 ], [ 90, 962, 29, 13 ], [ 122, 962, 37, 13 ], [ 162, 962, 36, 13 ], [ 202, 962, 25, 13 ], [ 230, 962, 16, 13 ], [ 249, 962, 23, 13 ], [ 276, 962, 48, 13 ], [ 327, 962, 10, 13 ], [ 340, 962, 11, 13 ], [ 355, 962, 58, 13 ], [ 80, 976, 40, 13 ], [ 127, 976, 19, 13 ], [ 152, 976, 23, 13 ], [ 181, 976, 20, 13 ], [ 208, 976, 17, 13 ], [ 230, 976, 31, 13 ], [ 267, 976, 45, 13 ], [ 318, 976, 24, 13 ], [ 348, 976, 42, 13 ], [ 397, 976, 16, 13 ], [ 80, 991, 41, 13 ], [ 126, 991, 60, 13 ], [ 190, 991, 40, 13 ], [ 235, 991, 15, 13 ], [ 255, 991, 30, 13 ], [ 290, 991, 10, 13 ], [ 305, 991, 16, 13 ], [ 326, 991, 52, 13 ], [ 383, 991, 30, 13 ], [ 80, 1006, 30, 13 ], [ 115, 1006, 26, 13 ], [ 145, 1006, 37, 13 ], [ 186, 1006, 52, 13 ], [ 242, 1006, 41, 13 ], [ 286, 1006, 16, 13 ], [ 306, 1006, 26, 13 ], [ 337, 1006, 10, 13 ], [ 351, 1006, 41, 13 ], [ 397, 1006, 16, 13 ], [ 437, 710, 22, 13 ], [ 464, 710, 25, 13 ], [ 493, 710, 12, 13 ], [ 510, 710, 49, 13 ], [ 563, 710, 10, 13 ], [ 578, 710, 16, 13 ], [ 599, 710, 39, 13 ], [ 642, 710, 25, 13 ], [ 671, 710, 10, 13 ], [ 686, 710, 41, 13 ], [ 731, 710, 18, 13 ], [ 754, 710, 16, 13 ], [ 437, 725, 48, 13 ], [ 492, 725, 10, 13 ], [ 510, 725, 16, 13 ], [ 533, 725, 41, 13 ], [ 581, 725, 37, 13 ], [ 625, 725, 40, 13 ], [ 673, 725, 25, 13 ], [ 705, 725, 12, 13 ], [ 725, 725, 45, 13 ], [ 437, 740, 77, 13 ], [ 521, 740, 25, 13 ], [ 552, 740, 39, 13 ], [ 597, 740, 19, 13 ], [ 623, 740, 63, 13 ], [ 692, 740, 10, 13 ], [ 708, 740, 22, 13 ], [ 736, 740, 33, 13 ], [ 437, 755, 56, 13 ], [ 500, 755, 10, 13 ], [ 517, 755, 20, 13 ], [ 544, 755, 52, 13 ], [ 603, 755, 10, 13 ], [ 620, 755, 19, 13 ], [ 646, 755, 26, 13 ], [ 679, 755, 30, 13 ], [ 715, 755, 16, 13 ], [ 738, 755, 32, 13 ], [ 437, 770, 33, 13 ], [ 474, 770, 12, 13 ], [ 490, 770, 45, 13 ], [ 538, 770, 22, 13 ], [ 563, 770, 26, 13 ], [ 592, 770, 34, 13 ], [ 630, 770, 36, 13 ], [ 669, 770, 16, 13 ], [ 689, 770, 39, 13 ], [ 731, 770, 39, 13 ], [ 437, 784, 33, 13 ], [ 473, 784, 12, 13 ], [ 489, 784, 39, 13 ], [ 530, 784, 13, 13 ], [ 546, 784, 27, 13 ], [ 576, 784, 23, 13 ], [ 601, 784, 15, 13 ], [ 619, 784, 68, 13 ], [ 689, 784, 44, 13 ], [ 736, 784, 23, 13 ], [ 762, 784, 8, 13 ], [ 437, 799, 45, 13 ], [ 486, 799, 15, 13 ], [ 505, 799, 37, 13 ], [ 547, 799, 40, 13 ], [ 593, 799, 10, 13 ], [ 607, 799, 56, 13 ], [ 668, 799, 24, 13 ], [ 697, 799, 23, 13 ], [ 724, 799, 15, 13 ], [ 744, 799, 26, 13 ], [ 437, 814, 26, 13 ], [ 468, 814, 70, 13 ], [ 542, 814, 39, 13 ], [ 586, 814, 40, 13 ], [ 631, 814, 24, 13 ], [ 660, 814, 10, 13 ], [ 675, 814, 12, 13 ], [ 692, 814, 49, 13 ], [ 745, 814, 13, 13 ], [ 763, 814, 6, 13 ], [ 437, 829, 49, 13 ], [ 490, 829, 19, 13 ], [ 513, 829, 16, 13 ], [ 533, 829, 22, 13 ], [ 559, 829, 22, 13 ], [ 585, 829, 44, 13 ], [ 633, 829, 10, 13 ], [ 647, 829, 38, 13 ], [ 689, 829, 53, 13 ], [ 745, 829, 25, 13 ], [ 437, 843, 6, 13 ], [ 448, 843, 25, 13 ], [ 477, 843, 40, 13 ], [ 521, 843, 10, 13 ], [ 536, 843, 37, 13 ], [ 577, 843, 44, 13 ], [ 625, 843, 16, 13 ], [ 645, 843, 57, 13 ], [ 707, 843, 28, 13 ], [ 739, 843, 20, 13 ], [ 763, 843, 6, 13 ], [ 437, 858, 35, 13 ], [ 479, 858, 39, 13 ], [ 525, 858, 10, 13 ], [ 543, 858, 26, 13 ], [ 576, 858, 41, 13 ], [ 623, 858, 43, 13 ], [ 673, 858, 27, 13 ], [ 707, 858, 10, 13 ], [ 725, 858, 45, 13 ], [ 437, 873, 66, 13 ], [ 450, 888, 21, 13 ], [ 479, 888, 37, 13 ], [ 524, 888, 27, 13 ], [ 558, 888, 19, 13 ], [ 585, 888, 44, 13 ], [ 637, 888, 10, 13 ], [ 655, 888, 26, 13 ], [ 689, 888, 26, 13 ], [ 723, 888, 47, 13 ], [ 437, 903, 46, 13 ], [ 488, 903, 72, 13 ], [ 565, 903, 58, 13 ], [ 627, 903, 14, 13 ], [ 646, 903, 45, 13 ], [ 695, 903, 74, 13 ], [ 437, 917, 25, 13 ], [ 465, 917, 6, 13 ], [ 475, 917, 25, 13 ], [ 503, 917, 40, 13 ], [ 547, 917, 10, 13 ], [ 560, 917, 40, 13 ], [ 604, 917, 10, 13 ], [ 618, 917, 22, 13 ], [ 643, 917, 13, 13 ], [ 659, 917, 10, 13 ], [ 673, 917, 31, 13 ], [ 708, 917, 62, 13 ], [ 437, 932, 19, 13 ], [ 464, 932, 20, 13 ], [ 491, 932, 35, 13 ], [ 534, 932, 48, 13 ], [ 589, 932, 22, 13 ], [ 618, 932, 23, 13 ], [ 649, 932, 50, 13 ], [ 707, 932, 10, 13 ], [ 724, 932, 45, 13 ], [ 437, 947, 50, 13 ], [ 490, 947, 35, 13 ], [ 529, 947, 34, 13 ], [ 566, 947, 33, 13 ], [ 602, 947, 10, 13 ], [ 616, 947, 16, 13 ], [ 635, 947, 50, 13 ], [ 688, 947, 31, 13 ], [ 722, 947, 48, 13 ], [ 437, 962, 24, 13 ], [ 464, 962, 23, 13 ], [ 490, 962, 16, 13 ], [ 508, 962, 11, 13 ], [ 521, 962, 31, 13 ], [ 555, 962, 10, 13 ], [ 567, 962, 41, 13 ], [ 611, 962, 39, 13 ], [ 653, 962, 40, 13 ], [ 696, 962, 49, 13 ], [ 747, 962, 13, 13 ], [ 763, 962, 6, 13 ], [ 437, 976, 49, 13 ], [ 493, 976, 23, 13 ], [ 523, 976, 40, 13 ], [ 570, 976, 10, 13 ], [ 587, 976, 10, 13 ], [ 605, 976, 47, 13 ], [ 659, 976, 18, 13 ], [ 684, 976, 19, 13 ], [ 710, 976, 36, 13 ], [ 754, 976, 16, 13 ], [ 437, 991, 41, 13 ], [ 482, 991, 40, 13 ], [ 526, 991, 10, 13 ], [ 540, 991, 35, 13 ], [ 579, 991, 16, 13 ], [ 599, 991, 29, 13 ], [ 631, 991, 34, 13 ], [ 669, 991, 20, 13 ], [ 692, 991, 24, 13 ], [ 720, 991, 50, 13 ], [ 437, 1006, 16, 13 ], [ 456, 1006, 51, 13 ], [ 509, 1006, 19, 13 ], [ 531, 1006, 24, 13 ], [ 558, 1006, 16, 13 ], [ 576, 1006, 63, 13 ], [ 642, 1006, 19, 13 ], [ 664, 1006, 40, 13 ], [ 707, 1006, 46, 13 ], [ 755, 1006, 14, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 35, 12 ], [ 180, 1047, 3, 12 ], [ 188, 1047, 100, 12 ], [ 422, 1047, 6, 12 ], [ 523, 1047, 48, 12 ], [ 574, 1047, 23, 12 ], [ 602, 1047, 3, 12 ], [ 610, 1047, 36, 12 ], [ 651, 1047, 6, 12 ], [ 663, 1047, 3, 12 ], [ 671, 1047, 23, 12 ], [ 699, 1047, 12, 12 ], [ 716, 1047, 3, 12 ], [ 724, 1047, 45, 12 ] ]

[ "Distributed", "Fading", "Memory", "for", "Stimulus", "Properties", "in", "the", "Primary", "Visual", "Cortex", "Danko", "Nikolic´", "1,2.*,", "Stefan", "Ha¨", "usler3.,", "Wolf", "Singer1,2,", "Wolfgang", "Maass2,3", "1", "Department", "of", "Neurophysiology,", "Max-Planck-Institute", "for", "Brain", "Research,", "Frankfurt,", "Germany,", "2", "Frankfurt", "Institute", "for", "Advanced", "Studies", "(FIAS),", "Johann", "Wolfgang", "Goethe", "University,", "Frankfurt,", "Germany,", "3", "Institute", "for", "Theoretical", "Computer", "Science,", "Graz", "University", "of", "Technology,", "Graz,", "Austria", "Abstract", "It", "is", "currently", "not", "known", "how", "distributed", "neuronal", "responses", "in", "early", "visual", "areas", "carry", "stimulus-related", "information.", "We", "made", "multielectrode", "recordings", "from", "cat", "primary", "visual", "cortex", "and", "applied", "methods", "from", "machine", "learning", "in", "order", "to", "analyze", "the", "temporal", "evolution", "of", "stimulus-related", "information", "in", "the", "spiking", "activity", "of", "large", "ensembles", "of", "around", "100", "neurons.", "We", "used", "sequences", "of", "up", "to", "three", "different", "visual", "stimuli", "(letters", "of", "the", "alphabet)", "presented", "for", "100", "ms", "and", "with", "intervals", "of", "100", "ms", "or", "larger.", "Most", "of", "the", "information", "about", "visual", "stimuli", "extractable", "by", "sophisticated", "methods", "of", "machine", "learning,", "i.e.,", "support", "vector", "machines", "with", "nonlinear", "kernel", "functions,", "was", "also", "extractable", "by", "simple", "linear", "classification", "such", "as", "can", "be", "achieved", "by", "individual", "neurons.", "New", "stimuli", "did", "not", "erase", "information", "about", "previous", "stimuli.", "The", "responses", "to", "the", "most", "recent", "stimulus", "contained", "about", "equal", "amounts", "of", "information", "about", "both", "this", "and", "the", "preceding", "stimulus.", "This", "information", "was", "encoded", "both", "in", "the", "discharge", "rates", "(response", "amplitudes)", "of", "the", "ensemble", "of", "neurons", "and,", "when", "using", "short", "time", "constants", "for", "integration", "(e.g.,", "20", "ms),", "in", "the", "precise", "timing", "of", "individual", "spikes", "(#,20", "ms),", "and", "persisted", "for", "several", "100", "ms", "beyond", "the", "offset", "of", "stimuli.", "The", "results", "indicate", "that", "the", "network", "from", "which", "we", "recorded", "is", "endowed", "with", "fading", "memory", "and", "is", "capable", "of", "performing", "online", "computations", "utilizing", "information", "about", "temporally", "sequential", "stimuli.", "This", "result", "challenges", "models", "assuming", "frame-by-frame", "analyses", "of", "sequential", "inputs.", "Citation:", "Nikolic´", "D,", "Ha¨usler", "S,", "Singer", "W,", "Maass", "W", "(2009)", "Distributed", "Fading", "Memory", "for", "Stimulus", "Properties", "in", "the", "Primary", "Visual", "Cortex.", "PLoS", "Biol", "7(12):", "e1000260.", "doi:10.1371/journal.pbio.1000260", "Academic", "Editor:", "Jonathan", "D.", "Victor,", "Weill", "Cornell", "Medical", "College,", "United", "States", "of", "America", "Received", "June", "22,", "2009;", "Accepted", "November", "10,", "2009;", "Published", "December", "22,", "2009", "Copyright:", "2009", "Nikolic", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "a", "grant", "from", "Deutsche", "Forschungsgemeinschaft", "(NI", "708/2-1),", "by", "the", "German", "Federal", "Ministry", "of", "Education", "and", "Research", "(BMBF)", "within", "the", "‘‘Bernstein", "Focus:", "Neurotechnology’’,", "through", "research", "grant", "01GQ0840,", "Alexander", "von", "Humboldt", "Stiftung,", "and", "Hertie", "Stiftung.", "Additional", "partial", "support", "was", "obtained", "also", "from", "the", "Austrian", "Science", "Fund", "FWF", "#", "S9102-N13", "and", "project", "#", "FP6-015879", "(FACETS),", "project", "#", "FP7-216593", "(SECO),", "and", "project", "#", "FP7-506778", "(PASCAL2)", "of", "the", "European", "Union.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "Abbreviations:", "AUC,", "area", "under", "receiver-operating", "characteristics;", "I&F,", "integrate-and-fire;", "ISI,", "interspike", "interval;", "IT,", "inferotemporal;", "Mfr,", "mean", "firing", "rate;", "PSTH,", "peristimulus", "time", "histogram;", "RBF,", "radial", "basis", "function;", "RF,", "receptive", "field;", "SD,", "standard", "deviation;", "SVM,", "support", "vector", "machine;", "XOR,", "exclusive", "OR", "*", "E-mail:", "danko.nikolic@gmail.com", ".", "These", "authors", "contributed", "equally", "to", "this", "work.", "Introduction", "A", "number", "of", "analysis", "methods", "have", "been", "designed", "to", "investigate", "how", "neuronal", "spiking", "activity", "correlates", "to", "sensory", "stimulation", "or", "behavior", "and,", "as", "expected,", "many", "relations", "have", "been", "found.", "All", "of", "the", "following", "variables—firing", "rates", "[1–4]", "and", "the", "synchronization", "[4–7]", "and", "the", "differential", "timing", "of", "spiking", "activity", "[8–10]—have", "been", "reported", "to", "correlate,", "one", "way", "or", "another,", "with", "stimuli", "and/", "or", "with", "behavior.", "Most", "of", "the", "efforts", "to", "distinguish", "between", "relevant", "and", "epiphenomenal", "variables", "face", "the", "problem", "that", "they", "have", "to", "rely", "on", "correlative", "rather", "than", "causal", "evidence.", "In", "the", "absence", "of", "direct", "access", "to", "the", "information", "of", "causal", "nature,", "one", "way", "to", "begin", "addressing", "this", "issue", "is", "to", "complement", "the", "highly", "specialized", "statistical", "methods", "that", "have", "been", "developed", "to", "detect", "specific", "stimulus-related", "changes", "in", "responses", "[9,11–18]", "with", "analyses", "that", "make", "minimal", "assumptions", "about", "putative", "codes", "[19–21],", "and", "examine", "how", "much", "information", "can", "be", "extracted", "by", "a", "single", "cortical", "neuron", "from", "the", "joint", "responses", "of", "its", "presynaptic", "neurons", "and", "then", "find", "out", "which", "variables", "were", "carrying", "the", "relevant", "information", "[22,23].", "To", "adjust", "to", "the", "conditions", "under", "which", "these", "cortical", "‘‘readout’’", "neurons", "are", "likely", "to", "operate,", "the", "data", "must", "be", "presented", "to", "the", "readout", "units", "in", "parallel,", "i.e.,", "the", "responses", "of", "the", "putative", "feeding", "neurons", "must", "be", "recorded", "simultaneously.", "Also,", "analysis", "and", "classification", "of", "data", "should", "correspond", "to", "that", "conducted", "in", "real", "time.", "Thus,", "the", "results", "should", "be", "available", "with", "short", "delays.", "Hence,", "the", "analysis", "method", "should", "be", "allowed", "no", "more", "time", "for", "accumulating", "evidence", "than", "is", "available", "for", "cortical", "neurons", "to", "accomplish", "their", "task.", "To", "fulfill", "these", "requirements,", "readout", "neurons", "need", "to", "be", "simulated", "on", "a", "computer", "and", "fed", "with", "data", "obtained", "in", "parallel", "recordings", "from", "a", "large", "number", "of", "cortical", "neurons,", "the", "assumption", "being", "that", "a", "certain", "fraction", "of", "these", "neurons", "provides", "input", "to", "neuronal", "classification.", "The", "present", "study", "was", "designed", "to", "fulfill", "these", "premises.", "Applying", "multielectrode", "technology,", "we", "recorded", "simultaneously", "from", "a", "large", "number", "of", "neurons", "in", "area", "17", "of", "lightly", "anesthetized", "cats", "and", "evoked", "responses", "with", "brief", "sequences", "of", "different,", "stationary", "flashed", "stimuli", "(letters", "of", "the", "alphabet).", "These", "responses", "were", "then", "fed", "as", "inputs", "to", "artificial", "readout", "neurons", "simulated", "on", "a", "computer", "(also", "referred", "to", "as", "classifiers).", "We", "first", "trained", "the", "artificial", "neurons", "to", "classify", "the", "visual", "stimuli", "that", "have", "generated", "the", "responses,", "and", "once", "the", "classification", "had", "reached", "criterion,", "we", "PLoS", "Biology", "|", "www.plosbiology.org", "1", "December", "2009", "|", "Volume", "7", "|", "Issue", "12", "|", "e1000260" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 20, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 80, 78, 69, 28 ], [ 158, 78, 25, 28 ], [ 192, 78, 109, 28 ], [ 309, 78, 118, 28 ], [ 436, 78, 185, 28 ], [ 629, 78, 32, 28 ], [ 80, 109, 141, 28 ], [ 230, 109, 131, 28 ], [ 371, 109, 25, 28 ], [ 405, 109, 237, 28 ], [ 80, 139, 193, 28 ], [ 282, 139, 24, 28 ], [ 314, 139, 15, 28 ], [ 338, 139, 123, 28 ], [ 470, 139, 76, 28 ], [ 555, 139, 45, 28 ], [ 608, 139, 94, 28 ], [ 80, 183, 20, 14 ], [ 104, 183, 50, 14 ], [ 158, 183, 21, 14 ], [ 183, 183, 42, 14 ], [ 229, 183, 34, 14 ], [ 267, 183, 51, 14 ], [ 322, 183, 43, 14 ], [ 369, 183, 34, 14 ], [ 407, 183, 19, 14 ], [ 430, 183, 76, 14 ], [ 510, 183, 25, 14 ], [ 540, 183, 48, 14 ], [ 80, 205, 50, 10 ], [ 133, 205, 9, 10 ], [ 144, 205, 60, 10 ], [ 207, 205, 51, 10 ], [ 261, 205, 36, 10 ], [ 300, 205, 43, 10 ], [ 345, 205, 45, 10 ], [ 393, 205, 38, 10 ], [ 433, 205, 24, 10 ], [ 102, 244, 57, 14 ], [ 102, 266, 51, 13 ], [ 158, 266, 50, 13 ], [ 212, 266, 8, 13 ], [ 225, 266, 56, 13 ], [ 285, 266, 14, 13 ], [ 303, 266, 25, 13 ], [ 333, 266, 101, 13 ], [ 439, 266, 42, 13 ], [ 485, 266, 30, 13 ], [ 520, 266, 20, 13 ], [ 545, 266, 101, 13 ], [ 650, 266, 41, 13 ], [ 696, 266, 34, 13 ], [ 734, 266, 14, 13 ], [ 102, 280, 40, 13 ], [ 145, 280, 18, 13 ], [ 166, 280, 30, 13 ], [ 200, 280, 11, 13 ], [ 215, 280, 50, 13 ], [ 268, 280, 73, 13 ], [ 345, 280, 14, 13 ], [ 363, 280, 18, 13 ], [ 384, 280, 58, 13 ], [ 446, 280, 45, 13 ], [ 495, 280, 44, 13 ], [ 542, 280, 11, 13 ], [ 557, 280, 101, 13 ], [ 661, 280, 87, 13 ], [ 102, 294, 16, 13 ], [ 122, 294, 52, 13 ], [ 178, 294, 44, 13 ], [ 227, 294, 10, 13 ], [ 241, 294, 18, 13 ], [ 263, 294, 59, 13 ], [ 327, 294, 20, 13 ], [ 351, 294, 60, 13 ], [ 416, 294, 66, 13 ], [ 486, 294, 11, 13 ], [ 502, 294, 24, 13 ], [ 530, 294, 20, 13 ], [ 555, 294, 23, 13 ], [ 583, 294, 10, 13 ], [ 597, 294, 45, 13 ], [ 647, 294, 33, 13 ], [ 684, 294, 26, 13 ], [ 715, 294, 11, 13 ], [ 730, 294, 18, 13 ], [ 102, 307, 44, 13 ], [ 149, 307, 31, 13 ], [ 183, 307, 55, 13 ], [ 241, 307, 26, 13 ], [ 270, 307, 102, 13 ], [ 376, 307, 20, 13 ], [ 399, 307, 18, 13 ], [ 420, 307, 57, 13 ], [ 480, 307, 22, 13 ], [ 505, 307, 62, 13 ], [ 570, 307, 35, 13 ], [ 609, 307, 49, 13 ], [ 660, 307, 54, 13 ], [ 717, 307, 10, 13 ], [ 730, 307, 18, 13 ], [ 102, 321, 38, 13 ], [ 144, 321, 25, 13 ], [ 173, 321, 20, 13 ], [ 197, 321, 50, 13 ], [ 251, 321, 10, 13 ], [ 266, 321, 18, 13 ], [ 287, 321, 27, 13 ], [ 318, 321, 25, 13 ], [ 348, 321, 35, 13 ], [ 387, 321, 18, 13 ], [ 408, 321, 55, 13 ], [ 468, 321, 43, 13 ], [ 515, 321, 117, 13 ], [ 635, 321, 55, 13 ], [ 695, 321, 26, 13 ], [ 725, 321, 23, 13 ], [ 102, 335, 47, 13 ], [ 152, 335, 10, 13 ], [ 165, 335, 18, 13 ], [ 185, 335, 27, 13 ], [ 215, 335, 25, 13 ], [ 243, 335, 10, 13 ], [ 256, 335, 18, 13 ], [ 276, 335, 20, 13 ], [ 299, 335, 29, 13 ], [ 330, 335, 20, 13 ], [ 353, 335, 65, 13 ], [ 421, 335, 26, 13 ], [ 450, 335, 25, 13 ], [ 478, 335, 69, 13 ], [ 549, 335, 20, 13 ], [ 572, 335, 64, 13 ], [ 639, 335, 41, 13 ], [ 682, 335, 42, 13 ], [ 726, 335, 22, 13 ], [ 102, 349, 28, 13 ], [ 133, 349, 26, 13 ], [ 162, 349, 50, 13 ], [ 215, 349, 111, 13 ], [ 329, 349, 55, 13 ], [ 387, 349, 50, 13 ], [ 440, 349, 10, 13 ], [ 453, 349, 18, 13 ], [ 474, 349, 38, 13 ], [ 514, 349, 25, 13 ], [ 542, 349, 33, 13 ], [ 578, 349, 18, 13 ], [ 599, 349, 50, 13 ], [ 651, 349, 73, 13 ], [ 727, 349, 21, 13 ], [ 102, 363, 18, 13 ], [ 123, 363, 42, 13 ], [ 169, 363, 25, 13 ], [ 198, 363, 24, 13 ], [ 226, 363, 20, 13 ], [ 250, 363, 23, 13 ], [ 277, 363, 23, 13 ], [ 304, 363, 47, 13 ], [ 354, 363, 10, 13 ], [ 368, 363, 45, 13 ], [ 417, 363, 30, 13 ], [ 451, 363, 54, 13 ], [ 508, 363, 31, 13 ], [ 543, 363, 45, 13 ], [ 592, 363, 45, 13 ], [ 640, 363, 20, 13 ], [ 665, 363, 25, 13 ], [ 693, 363, 55, 13 ], [ 102, 376, 20, 13 ], [ 125, 376, 48, 13 ], [ 175, 376, 60, 13 ], [ 238, 376, 26, 13 ], [ 266, 376, 26, 13 ], [ 295, 376, 28, 13 ], [ 328, 374, 73, 15 ], [ 403, 376, 17, 13 ], [ 423, 374, 41, 15 ], [ 468, 376, 10, 13 ], [ 481, 376, 18, 13 ], [ 501, 376, 21, 13 ], [ 525, 376, 25, 13 ], [ 553, 376, 32, 13 ], [ 588, 376, 20, 13 ], [ 611, 376, 34, 13 ], [ 648, 376, 24, 13 ], [ 675, 376, 18, 13 ], [ 696, 376, 29, 13 ], [ 727, 376, 21, 13 ], [ 102, 390, 33, 13 ], [ 138, 390, 10, 13 ], [ 151, 390, 42, 13 ], [ 197, 390, 42, 13 ], [ 242, 390, 58, 13 ], [ 303, 390, 45, 13 ], [ 351, 390, 44, 13 ], [ 398, 390, 26, 13 ], [ 427, 390, 32, 13 ], [ 462, 390, 15, 13 ], [ 480, 390, 26, 13 ], [ 508, 390, 24, 13 ], [ 535, 390, 20, 13 ], [ 559, 390, 23, 13 ], [ 585, 390, 31, 13 ], [ 620, 390, 18, 13 ], [ 640, 390, 45, 13 ], [ 689, 390, 45, 13 ], [ 737, 390, 11, 13 ], [ 102, 404, 58, 13 ], [ 164, 404, 50, 13 ], [ 217, 404, 20, 13 ], [ 241, 404, 18, 13 ], [ 263, 404, 44, 13 ], [ 310, 404, 26, 13 ], [ 340, 404, 45, 13 ], [ 389, 404, 10, 13 ], [ 403, 404, 28, 13 ], [ 434, 404, 30, 13 ], [ 468, 404, 11, 13 ], [ 483, 404, 18, 13 ], [ 504, 404, 18, 13 ], [ 526, 404, 42, 13 ], [ 92, 439, 40, 10 ], [ 135, 439, 28, 10 ], [ 166, 439, 9, 10 ], [ 177, 439, 23, 10 ], [ 203, 439, 7, 10 ], [ 213, 439, 29, 10 ], [ 245, 439, 7, 10 ], [ 255, 439, 19, 10 ], [ 276, 439, 8, 10 ], [ 287, 439, 44, 10 ], [ 333, 439, 8, 10 ], [ 344, 439, 9, 10 ], [ 355, 439, 9, 10 ], [ 368, 439, 26, 10 ], [ 396, 439, 23, 10 ], [ 422, 439, 9, 10 ], [ 434, 439, 36, 10 ], [ 473, 439, 40, 10 ], [ 516, 439, 62, 10 ], [ 581, 439, 11, 10 ], [ 595, 439, 48, 10 ], [ 646, 439, 45, 10 ], [ 694, 439, 9, 10 ], [ 705, 439, 43, 10 ], [ 92, 450, 37, 10 ], [ 132, 450, 65, 10 ], [ 200, 450, 8, 10 ], [ 211, 450, 5, 10 ], [ 219, 450, 41, 10 ], [ 263, 450, 26, 10 ], [ 291, 450, 15, 10 ], [ 309, 450, 35, 10 ], [ 346, 450, 20, 10 ], [ 369, 450, 18, 10 ], [ 390, 450, 18, 10 ], [ 411, 450, 32, 10 ], [ 446, 450, 139, 10 ], [ 92, 468, 31, 10 ], [ 126, 468, 35, 10 ], [ 165, 468, 23, 10 ], [ 190, 468, 41, 10 ], [ 233, 468, 9, 10 ], [ 245, 468, 30, 10 ], [ 278, 468, 29, 10 ], [ 92, 485, 42, 10 ], [ 137, 485, 37, 10 ], [ 176, 485, 12, 10 ], [ 191, 485, 22, 10 ], [ 216, 485, 44, 10 ], [ 263, 485, 16, 10 ], [ 282, 485, 12, 10 ], [ 298, 485, 22, 10 ], [ 323, 485, 47, 10 ], [ 372, 485, 30, 10 ], [ 405, 485, 12, 10 ], [ 420, 485, 20, 10 ], [ 92, 502, 50, 10 ], [ 158, 502, 20, 10 ], [ 182, 502, 28, 10 ], [ 214, 502, 9, 10 ], [ 226, 502, 9, 10 ], [ 239, 502, 17, 10 ], [ 260, 502, 6, 10 ], [ 270, 502, 10, 10 ], [ 284, 502, 50, 10 ], [ 338, 502, 25, 10 ], [ 367, 502, 45, 10 ], [ 416, 502, 25, 10 ], [ 444, 502, 14, 10 ], [ 462, 502, 24, 10 ], [ 489, 502, 9, 10 ], [ 502, 502, 14, 10 ], [ 519, 502, 34, 10 ], [ 557, 502, 42, 10 ], [ 603, 502, 45, 10 ], [ 652, 502, 32, 10 ], [ 688, 502, 25, 10 ], [ 717, 502, 31, 10 ], [ 92, 513, 49, 10 ], [ 144, 513, 17, 10 ], [ 163, 513, 50, 10 ], [ 216, 513, 16, 10 ], [ 235, 513, 54, 10 ], [ 291, 513, 8, 10 ], [ 302, 513, 15, 10 ], [ 320, 513, 37, 10 ], [ 359, 513, 37, 10 ], [ 399, 513, 14, 10 ], [ 416, 513, 31, 10 ], [ 450, 513, 27, 10 ], [ 480, 513, 16, 10 ], [ 498, 513, 27, 10 ], [ 529, 513, 13, 10 ], [ 545, 513, 36, 10 ], [ 92, 531, 42, 10 ], [ 137, 531, 15, 10 ], [ 156, 531, 31, 10 ], [ 191, 531, 19, 10 ], [ 214, 531, 9, 10 ], [ 226, 531, 24, 10 ], [ 253, 531, 14, 10 ], [ 271, 531, 35, 10 ], [ 309, 531, 30, 10 ], [ 342, 531, 31, 10 ], [ 377, 531, 48, 10 ], [ 428, 531, 9, 10 ], [ 440, 531, 24, 10 ], [ 467, 531, 48, 10 ], [ 518, 531, 35, 10 ], [ 556, 531, 15, 10 ], [ 575, 531, 55, 10 ], [ 633, 531, 37, 10 ], [ 673, 531, 16, 10 ], [ 692, 531, 56, 10 ], [ 92, 542, 36, 10 ], [ 130, 542, 9, 10 ], [ 141, 542, 24, 10 ], [ 167, 542, 66, 10 ], [ 235, 542, 16, 10 ], [ 253, 542, 14, 10 ], [ 270, 542, 30, 10 ], [ 302, 542, 31, 10 ], [ 335, 542, 48, 10 ], [ 385, 542, 9, 10 ], [ 396, 542, 36, 10 ], [ 435, 542, 36, 10 ], [ 473, 542, 43, 10 ], [ 518, 542, 15, 10 ], [ 536, 542, 31, 10 ], [ 570, 542, 16, 10 ], [ 588, 542, 11, 10 ], [ 602, 542, 16, 10 ], [ 620, 542, 8, 10 ], [ 630, 542, 23, 10 ], [ 655, 542, 30, 10 ], [ 688, 542, 18, 10 ], [ 708, 542, 40, 10 ], [ 92, 553, 16, 10 ], [ 111, 553, 34, 10 ], [ 147, 553, 34, 10 ], [ 184, 553, 9, 10 ], [ 196, 553, 33, 10 ], [ 231, 553, 9, 10 ], [ 243, 553, 48, 10 ], [ 294, 553, 9, 10 ], [ 305, 553, 14, 10 ], [ 322, 553, 48, 10 ], [ 92, 570, 52, 10 ], [ 147, 570, 44, 10 ], [ 193, 570, 16, 10 ], [ 212, 570, 31, 10 ], [ 246, 570, 20, 10 ], [ 268, 570, 35, 10 ], [ 307, 570, 17, 10 ], [ 326, 570, 11, 10 ], [ 340, 570, 45, 10 ], [ 388, 570, 35, 10 ], [ 426, 570, 21, 10 ], [ 92, 587, 5, 10 ], [ 99, 587, 27, 10 ], [ 129, 587, 96, 10 ], [ 80, 630, 84, 14 ], [ 93, 655, 61, 13 ], [ 160, 655, 8, 13 ], [ 173, 655, 34, 13 ], [ 214, 655, 10, 13 ], [ 230, 655, 16, 13 ], [ 252, 655, 31, 13 ], [ 288, 655, 42, 13 ], [ 336, 655, 25, 13 ], [ 368, 655, 20, 13 ], [ 393, 655, 8, 13 ], [ 406, 655, 6, 13 ], [ 80, 670, 35, 13 ], [ 119, 670, 43, 13 ], [ 166, 670, 34, 13 ], [ 204, 670, 41, 13 ], [ 248, 670, 48, 13 ], [ 299, 670, 43, 13 ], [ 345, 670, 22, 13 ], [ 371, 670, 41, 13 ], [ 80, 684, 48, 13 ], [ 132, 684, 43, 13 ], [ 179, 684, 10, 13 ], [ 194, 684, 33, 13 ], [ 231, 684, 18, 13 ], [ 254, 684, 51, 13 ], [ 309, 684, 48, 13 ], [ 361, 684, 8, 13 ], [ 373, 684, 16, 13 ], [ 393, 684, 19, 13 ], [ 80, 699, 19, 13 ], [ 106, 699, 62, 13 ], [ 174, 699, 20, 13 ], [ 201, 699, 10, 13 ], [ 217, 699, 62, 13 ], [ 285, 699, 9, 13 ], [ 300, 699, 19, 13 ], [ 325, 699, 43, 13 ], [ 374, 699, 20, 13 ], [ 400, 699, 12, 13 ], [ 80, 713, 48, 13 ], [ 131, 713, 44, 13 ], [ 177, 713, 24, 13 ], [ 204, 713, 41, 13 ], [ 247, 713, 23, 13 ], [ 273, 713, 98, 13 ], [ 373, 713, 40, 13 ], [ 80, 728, 24, 13 ], [ 108, 728, 33, 13 ], [ 143, 728, 21, 13 ], [ 168, 728, 40, 13 ], [ 210, 728, 10, 13 ], [ 224, 728, 35, 13 ], [ 262, 728, 7, 13 ], [ 272, 728, 12, 13 ], [ 287, 728, 15, 13 ], [ 305, 728, 19, 13 ], [ 328, 728, 42, 13 ], [ 372, 728, 7, 13 ], [ 383, 728, 12, 13 ], [ 397, 728, 15, 13 ], [ 80, 743, 46, 13 ], [ 129, 743, 16, 13 ], [ 148, 743, 45, 13 ], [ 197, 743, 10, 13 ], [ 209, 743, 40, 13 ], [ 252, 743, 46, 13 ], [ 301, 743, 10, 13 ], [ 314, 743, 48, 13 ], [ 365, 743, 48, 13 ], [ 80, 757, 19, 13 ], [ 104, 757, 16, 13 ], [ 124, 757, 23, 13 ], [ 151, 757, 10, 13 ], [ 166, 757, 99, 13 ], [ 269, 757, 40, 13 ], [ 313, 757, 19, 13 ], [ 336, 757, 31, 13 ], [ 372, 757, 41, 13 ], [ 80, 772, 13, 13 ], [ 95, 772, 16, 13 ], [ 114, 772, 62, 13 ], [ 178, 772, 19, 13 ], [ 200, 772, 23, 13 ], [ 226, 772, 39, 13 ], [ 268, 772, 10, 13 ], [ 281, 772, 35, 13 ], [ 318, 772, 32, 13 ], [ 353, 772, 10, 13 ], [ 365, 772, 28, 13 ], [ 395, 772, 17, 13 ], [ 80, 786, 20, 13 ], [ 105, 786, 36, 13 ], [ 146, 786, 42, 13 ], [ 194, 786, 17, 13 ], [ 216, 786, 69, 13 ], [ 290, 786, 20, 13 ], [ 315, 786, 98, 13 ], [ 80, 801, 40, 13 ], [ 125, 801, 22, 13 ], [ 152, 801, 25, 13 ], [ 182, 801, 6, 13 ], [ 194, 801, 42, 13 ], [ 241, 801, 19, 13 ], [ 265, 801, 79, 13 ], [ 350, 801, 42, 13 ], [ 397, 801, 16, 13 ], [ 80, 816, 87, 13 ], [ 171, 816, 43, 13 ], [ 93, 831, 52, 13 ], [ 151, 831, 49, 13 ], [ 206, 831, 42, 13 ], [ 255, 831, 29, 13 ], [ 290, 831, 13, 13 ], [ 309, 831, 16, 13 ], [ 332, 831, 51, 13 ], [ 389, 831, 24, 13 ], [ 80, 845, 25, 13 ], [ 115, 845, 20, 13 ], [ 143, 845, 16, 13 ], [ 169, 845, 51, 13 ], [ 229, 845, 24, 13 ], [ 262, 845, 17, 13 ], [ 289, 845, 42, 13 ], [ 340, 845, 6, 13 ], [ 356, 845, 57, 13 ], [ 80, 860, 58, 13 ], [ 143, 860, 10, 13 ], [ 158, 860, 28, 13 ], [ 190, 860, 43, 13 ], [ 238, 860, 64, 13 ], [ 307, 860, 25, 13 ], [ 337, 860, 41, 13 ], [ 383, 860, 30, 13 ], [ 80, 875, 20, 13 ], [ 103, 875, 28, 13 ], [ 133, 875, 45, 13 ], [ 181, 875, 68, 13 ], [ 251, 875, 24, 13 ], [ 278, 875, 45, 13 ], [ 325, 875, 62, 13 ], [ 390, 875, 23, 13 ], [ 80, 889, 10, 13 ], [ 98, 889, 30, 13 ], [ 135, 889, 10, 13 ], [ 152, 889, 23, 13 ], [ 182, 889, 17, 13 ], [ 206, 889, 21, 13 ], [ 235, 889, 19, 13 ], [ 261, 889, 28, 13 ], [ 297, 889, 25, 13 ], [ 328, 889, 17, 13 ], [ 352, 889, 16, 13 ], [ 376, 889, 37, 13 ], [ 80, 904, 66, 13 ], [ 155, 904, 10, 13 ], [ 173, 904, 28, 13 ], [ 208, 904, 19, 13 ], [ 235, 904, 27, 13 ], [ 270, 904, 10, 13 ], [ 288, 904, 16, 13 ], [ 312, 904, 17, 13 ], [ 337, 904, 43, 13 ], [ 387, 904, 25, 13 ], [ 80, 918, 48, 13 ], [ 134, 918, 74, 13 ], [ 214, 918, 29, 13 ], [ 249, 918, 56, 13 ], [ 312, 918, 42, 13 ], [ 360, 918, 20, 13 ], [ 386, 918, 27, 13 ], [ 80, 933, 33, 13 ], [ 118, 933, 6, 13 ], [ 128, 933, 27, 13 ], [ 159, 933, 50, 13 ], [ 214, 933, 20, 13 ], [ 238, 933, 23, 13 ], [ 265, 933, 28, 13 ], [ 297, 933, 10, 13 ], [ 312, 933, 17, 13 ], [ 333, 933, 62, 13 ], [ 399, 933, 14, 13 ], [ 80, 948, 19, 13 ], [ 102, 948, 39, 13 ], [ 144, 948, 21, 13 ], [ 169, 948, 30, 13 ], [ 201, 948, 20, 13 ], [ 224, 948, 40, 13 ], [ 267, 948, 10, 13 ], [ 280, 948, 45, 13 ], [ 327, 948, 59, 13 ], [ 389, 948, 24, 13 ], [ 80, 962, 24, 13 ], [ 108, 962, 22, 13 ], [ 134, 962, 51, 13 ], [ 189, 962, 22, 13 ], [ 215, 962, 16, 13 ], [ 235, 962, 40, 13 ], [ 279, 962, 10, 13 ], [ 293, 962, 27, 13 ], [ 324, 962, 25, 13 ], [ 353, 962, 28, 13 ], [ 385, 962, 28, 13 ], [ 80, 977, 22, 13 ], [ 109, 977, 31, 13 ], [ 147, 977, 45, 13 ], [ 199, 977, 31, 14 ], [ 237, 977, 11, 13 ], [ 255, 977, 44, 13 ], [ 306, 977, 35, 14 ], [ 348, 977, 10, 13 ], [ 365, 977, 48, 13 ], [ 80, 991, 48, 13 ], [ 132, 991, 10, 13 ], [ 147, 991, 16, 13 ], [ 168, 991, 20, 13 ], [ 192, 991, 70, 13 ], [ 267, 991, 13, 13 ], [ 285, 991, 7, 13 ], [ 296, 991, 12, 13 ], [ 313, 991, 21, 13 ], [ 339, 991, 53, 13 ], [ 396, 991, 16, 13 ], [ 80, 1006, 26, 13 ], [ 110, 1006, 67, 13 ], [ 181, 1006, 10, 13 ], [ 195, 1006, 24, 13 ], [ 223, 1006, 42, 13 ], [ 269, 1006, 50, 13 ], [ 323, 1006, 11, 13 ], [ 338, 1006, 44, 13 ], [ 386, 1006, 27, 13 ], [ 437, 629, 56, 13 ], [ 501, 629, 45, 13 ], [ 553, 629, 28, 13 ], [ 588, 629, 10, 13 ], [ 606, 629, 16, 13 ], [ 629, 629, 26, 13 ], [ 663, 629, 34, 13 ], [ 704, 629, 10, 13 ], [ 722, 629, 48, 13 ], [ 437, 644, 48, 13 ], [ 492, 644, 10, 13 ], [ 508, 644, 20, 13 ], [ 535, 644, 74, 13 ], [ 616, 644, 7, 13 ], [ 630, 644, 12, 13 ], [ 649, 644, 21, 13 ], [ 677, 644, 43, 13 ], [ 727, 644, 20, 13 ], [ 754, 644, 16, 13 ], [ 437, 659, 44, 13 ], [ 488, 659, 59, 13 ], [ 553, 659, 24, 13 ], [ 584, 659, 24, 13 ], [ 614, 659, 47, 13 ], [ 668, 659, 51, 13 ], [ 725, 659, 22, 13 ], [ 754, 659, 16, 13 ], [ 437, 674, 40, 13 ], [ 482, 674, 19, 13 ], [ 506, 674, 73, 13 ], [ 583, 674, 37, 13 ], [ 624, 674, 10, 13 ], [ 639, 674, 28, 13 ], [ 671, 674, 25, 13 ], [ 701, 674, 31, 13 ], [ 736, 674, 33, 13 ], [ 437, 689, 7, 13 ], [ 448, 689, 12, 13 ], [ 463, 689, 21, 13 ], [ 487, 689, 52, 13 ], [ 541, 689, 16, 13 ], [ 560, 689, 49, 13 ], [ 612, 689, 20, 13 ], [ 635, 689, 10, 13 ], [ 648, 689, 28, 13 ], [ 678, 689, 10, 13 ], [ 691, 689, 17, 13 ], [ 711, 689, 59, 13 ], [ 437, 703, 13, 13 ], [ 454, 703, 33, 13 ], [ 490, 703, 10, 13 ], [ 504, 703, 29, 13 ], [ 537, 703, 36, 13 ], [ 576, 703, 30, 13 ], [ 610, 703, 19, 13 ], [ 633, 703, 16, 13 ], [ 653, 703, 60, 13 ], [ 717, 703, 39, 13 ], [ 760, 703, 10, 13 ], [ 437, 718, 42, 13 ], [ 483, 718, 25, 13 ], [ 513, 718, 31, 13 ], [ 548, 718, 27, 13 ], [ 579, 718, 7, 13 ], [ 591, 718, 12, 13 ], [ 607, 718, 21, 13 ], [ 632, 718, 20, 13 ], [ 656, 718, 69, 13 ], [ 729, 718, 20, 13 ], [ 754, 718, 16, 13 ], [ 437, 733, 36, 13 ], [ 479, 733, 10, 13 ], [ 496, 733, 22, 13 ], [ 524, 733, 43, 13 ], [ 574, 733, 17, 13 ], [ 597, 733, 17, 13 ], [ 620, 733, 44, 13 ], [ 670, 733, 48, 13 ], [ 725, 733, 45, 13 ], [ 437, 748, 45, 13 ], [ 485, 748, 10, 13 ], [ 497, 748, 59, 13 ], [ 559, 748, 22, 13 ], [ 584, 748, 30, 13 ], [ 616, 748, 62, 13 ], [ 680, 748, 57, 13 ], [ 740, 748, 10, 13 ], [ 752, 748, 17, 13 ], [ 437, 763, 22, 13 ], [ 464, 763, 37, 13 ], [ 506, 763, 17, 13 ], [ 529, 763, 36, 13 ], [ 571, 763, 19, 13 ], [ 596, 763, 27, 13 ], [ 628, 763, 65, 13 ], [ 699, 763, 71, 13 ], [ 437, 778, 22, 13 ], [ 463, 778, 37, 13 ], [ 504, 778, 16, 13 ], [ 523, 778, 42, 13 ], [ 570, 778, 67, 13 ], [ 640, 778, 10, 13 ], [ 654, 778, 28, 13 ], [ 685, 778, 19, 13 ], [ 708, 778, 27, 13 ], [ 739, 778, 10, 13 ], [ 753, 778, 17, 13 ], [ 437, 792, 62, 13 ], [ 503, 792, 11, 13 ], [ 518, 792, 45, 13 ], [ 567, 792, 28, 13 ], [ 599, 792, 19, 13 ], [ 622, 792, 27, 13 ], [ 652, 792, 22, 13 ], [ 678, 792, 43, 13 ], [ 725, 792, 45, 13 ], [ 437, 807, 11, 13 ], [ 452, 807, 35, 13 ], [ 490, 807, 51, 13 ], [ 544, 807, 60, 13 ], [ 607, 807, 30, 13 ], [ 641, 807, 26, 13 ], [ 670, 807, 55, 13 ], [ 729, 807, 41, 13 ], [ 437, 822, 30, 13 ], [ 471, 822, 27, 13 ], [ 502, 822, 52, 13 ], [ 559, 822, 16, 13 ], [ 579, 822, 64, 13 ], [ 647, 822, 65, 13 ], [ 716, 822, 54, 13 ], [ 437, 837, 42, 13 ], [ 484, 837, 26, 13 ], [ 514, 837, 51, 13 ], [ 570, 837, 22, 13 ], [ 597, 837, 21, 13 ], [ 623, 837, 10, 13 ], [ 638, 837, 28, 13 ], [ 670, 837, 52, 13 ], [ 727, 837, 10, 13 ], [ 742, 837, 28, 13 ], [ 437, 852, 19, 13 ], [ 460, 852, 27, 13 ], [ 489, 852, 25, 13 ], [ 517, 852, 54, 13 ], [ 574, 852, 73, 13 ], [ 650, 852, 34, 13 ], [ 687, 852, 16, 13 ], [ 706, 852, 51, 13 ], [ 760, 852, 10, 13 ], [ 437, 866, 61, 13 ], [ 507, 866, 16, 13 ], [ 533, 866, 42, 13 ], [ 584, 866, 59, 13 ], [ 652, 866, 44, 13 ], [ 704, 866, 20, 13 ], [ 732, 866, 37, 13 ], [ 437, 881, 67, 13 ], [ 507, 881, 10, 13 ], [ 521, 881, 28, 13 ], [ 552, 881, 19, 13 ], [ 576, 881, 30, 13 ], [ 450, 896, 38, 13 ], [ 491, 896, 12, 13 ], [ 508, 896, 73, 13 ], [ 585, 896, 37, 13 ], [ 626, 896, 48, 13 ], [ 678, 896, 8, 13 ], [ 690, 896, 16, 13 ], [ 711, 896, 45, 13 ], [ 760, 896, 10, 13 ], [ 437, 911, 48, 13 ], [ 490, 911, 48, 13 ], [ 543, 911, 15, 13 ], [ 562, 911, 31, 13 ], [ 598, 911, 74, 13 ], [ 677, 911, 18, 13 ], [ 700, 911, 38, 13 ], [ 742, 911, 27, 13 ], [ 437, 926, 59, 13 ], [ 498, 926, 40, 13 ], [ 540, 926, 9, 13 ], [ 552, 926, 19, 13 ], [ 573, 926, 30, 13 ], [ 605, 926, 20, 13 ], [ 628, 926, 28, 13 ], [ 658, 926, 24, 13 ], [ 685, 926, 21, 13 ], [ 709, 926, 10, 13 ], [ 721, 926, 25, 13 ], [ 749, 926, 20, 13 ], [ 437, 941, 19, 13 ], [ 460, 941, 16, 13 ], [ 481, 941, 36, 13 ], [ 520, 941, 10, 13 ], [ 534, 941, 28, 13 ], [ 566, 941, 19, 13 ], [ 589, 941, 40, 13 ], [ 632, 941, 22, 13 ], [ 659, 941, 17, 13 ], [ 680, 941, 59, 13 ], [ 742, 941, 28, 13 ], [ 437, 955, 16, 13 ], [ 457, 955, 70, 13 ], [ 530, 955, 10, 13 ], [ 544, 955, 48, 13 ], [ 595, 955, 19, 13 ], [ 618, 955, 46, 13 ], [ 667, 955, 18, 13 ], [ 689, 955, 11, 13 ], [ 704, 955, 16, 13 ], [ 723, 955, 33, 13 ], [ 760, 955, 10, 13 ], [ 437, 970, 48, 13 ], [ 493, 970, 19, 13 ], [ 519, 970, 40, 13 ], [ 567, 970, 16, 13 ], [ 590, 970, 73, 13 ], [ 670, 970, 10, 13 ], [ 688, 970, 38, 13 ], [ 733, 970, 37, 13 ], [ 437, 985, 46, 13 ], [ 486, 985, 27, 13 ], [ 516, 985, 24, 13 ], [ 544, 985, 27, 13 ], [ 574, 985, 59, 13 ], [ 635, 985, 10, 13 ], [ 649, 985, 17, 13 ], [ 669, 985, 59, 13 ], [ 731, 985, 19, 13 ], [ 754, 985, 16, 13 ], [ 437, 1000, 40, 13 ], [ 481, 1000, 10, 13 ], [ 495, 1000, 27, 13 ], [ 525, 1000, 25, 13 ], [ 554, 1000, 24, 13 ], [ 581, 1000, 31, 13 ], [ 616, 1000, 19, 13 ], [ 639, 1000, 36, 13 ], [ 678, 1000, 23, 13 ], [ 705, 1000, 20, 13 ], [ 729, 1000, 10, 13 ], [ 742, 1000, 28, 13 ], [ 80, 1047, 25, 12 ], [ 108, 1047, 21, 12 ], [ 134, 1047, 3, 12 ], [ 142, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 554, 1047, 34, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "Effect", "of", "Different", "Ammonia", "Concentrations", "on", "Community", "Succession", "of", "Ammonia-oxidizing", "Microorganisms", "in", "a", "Simulated", "Paddy", "Soil", "Column", "Hu", "Baolan,", "Liu", "Shuai,", "Shen", "Lidong,", "Zheng", "Ping,", "Xu", "Xiangyang,", "Lou", "Liping*", "Department", "of", "Environmental", "Engineering,", "Zhejiang", "University,", "Hangzhou,", "Zhejiang,", "China", "Abstract", "Ammonia", "oxidation", "is", "performed", "by", "both", "ammonia-oxidizing", "bacteria", "(AOB)", "and", "ammonia-oxidizing", "archaea", "(AOA).", "To", "explore", "the", "effect", "of", "ammonia", "concentration", "on", "the", "population", "dynamic", "changes", "of", "ammonia-oxidizing", "microorganisms,", "we", "examined", "changes", "in", "the", "abundance", "and", "community", "composition", "of", "AOA", "and", "AOB", "in", "different", "layers.", "Most", "of", "the", "archaeal", "amoA", "sequences", "were", "Nitrosotalea-related", "and", "the", "proportion", "that", "Nitrosotalea", "cluster", "occupied", "decreased", "in", "the", "surface", "layer", "and", "increased", "in", "the", "deep", "layer", "during", "the", "cultivation", "process.", "Nitrosopumilus-related", "sequences", "were", "only", "detected", "in", "the", "deep", "layer", "in", "the", "first", "stage", "and", "disappeared", "later.", "Both", "phylogenetic", "and", "quantitative", "analysis", "showed", "that", "there", "were", "increased", "Nitrosomonas-related", "sequences", "appeared", "in", "the", "surface", "layer", "where", "the", "ammonia", "concentration", "was", "the", "highest.", "Both", "AOA", "and", "AOB", "OTU", "numbers", "in", "different", "layers", "decreased", "under", "selective", "pressure", "and", "then", "recovered.", "The", "potential", "nitrification", "rates", "were", "25.06", "mg?N?L21?g21", "dry", "soil?h21", "in", "the", "mid", "layer", "which", "was", "higher", "than", "the", "other", "two", "layers.", "In", "general,", "obvious", "population", "dynamic", "changes", "were", "found", "for", "both", "AOA", "and", "AOB", "under", "the", "selective", "pressure", "of", "exogenous", "ammonia", "and", "the", "changes", "were", "different", "in", "three", "layers", "of", "the", "soil", "column.", "Citation:", "Baolan", "H,", "Shuai", "L,", "Lidong", "S,", "Ping", "Z,", "Xiangyang", "X,", "et", "al.", "(2012)", "Effect", "of", "Different", "Ammonia", "Concentrations", "on", "Community", "Succession", "of", "Ammonia-", "oxidizing", "Microorganisms", "in", "a", "Simulated", "Paddy", "Soil", "Column.", "PLoS", "ONE", "7(8):", "e44122.", "doi:10.1371/journal.pone.0044122", "Editor:", "Matthias", "Horn,", "University", "of", "Vienna,", "Austria", "Received", "February", "15,", "2012;", "Accepted", "July", "30,", "2012;", "Published", "August", "31,", "2012", "Copyright:", "2012", "Baolan", "et", "al.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "The", "authors", "wish", "to", "thank", "the", "National", "Natural", "Science", "Foundation", "of", "China", "(40801198),", "National", "Key", "Technologies", "Research", "and", "Development", "program", "of", "China", "(2012BAJ25B00)", "and", "the", "Natural", "Science", "Foundation", "of", "Zhejiang", "province", "(Y507227).", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "baolanhz@hotmail.com", "Introduction", "Nitrification", "is", "critical", "in", "the", "global", "nitrogen", "cycle", "and", "is", "a", "unique", "pathway", "linking", "reduced", "inorganic", "nitrogen", "with", "oxidised", "inorganic", "nitrogen", "in", "nature", "[1].", "Ammonia", "oxidation", "is", "the", "first", "and", "rate-limiting", "step", "of", "nitrification.", "It", "was", "assumed", "that", "all", "ammonia", "oxidisers", "were", "bacteria", "until", "ammonia-oxidizing", "archaea", "were", "found.", "The", "findings", "of", "Venter", "et", "al.", "[2]", "and", "Treusch", "et", "al.", "[3]", "indicated", "the", "posibility", "of", "archaea", "involving", "in", "ammonia", "oxidation", "and", "the", "exist", "of", "ammonia-oxidation", "archaea", "was", "finally", "certified", "by", "the", "enrichments", "and", "pure", "cultures", "of", "several", "strains", "of", "AOA", "[4–", "10].", "Recent", "research", "has", "demonstrated", "that", "ammonia-oxidizing", "archaea", "may", "form", "a", "separate", "and", "deep-branching", "phylum,", "the", "Thaumarchaeota", "[11–13].", "Molecular", "biological", "research", "based", "on", "the", "functional", "gene", "amoA", "and", "the", "16SrRNA", "gene", "has", "revealed", "a", "widespread", "distribution", "of", "AOA", "[14–17].", "Quantitative", "PCR", "analyses", "found", "that", "AOA", "normally", "outnumbered", "their", "substrate", "competitors,", "such", "as", "AOB,", "in", "both", "soil", "[17]", "and", "water", "[18],", "but", "the", "relative", "contributions", "of", "AOA", "and", "AOB", "in", "the", "soil", "nitrogen", "cycle", "remained", "undetermined.", "Some", "researchers", "believed", "that", "AOB", "played", "a", "more", "important", "role", "than", "AOA", "in", "soil", "nitrification.", "Jia", "and", "Conrad", "[19]", "found", "that", "changes", "in", "potential", "nitrification", "rates", "were", "only", "correlated", "with", "the", "number", "of", "AOB", "amoA", "genes", "when", "they", "added", "substrate", "(NH3)", "or", "inhibitor", "(C2H2)", "of", "ammonia", "oxidation", "to", "the", "soil.", "Subsequently,", "Di", "et", "al.", "[20]", "discovered", "the", "same", "phenomenon", "in", "New", "Zealand", "grassland.", "In", "contrast,", "other", "researchers", "regarded", "AOA", "as", "the", "main", "drivers", "of", "ammonia", "oxidation", "in", "soil.", "Gubry-Rangin", "et", "al.", "[21]", "reported", "that", "the", "potential", "nitrification", "rates", "were", "positively", "correlated", "with", "the", "number", "and", "transcriptional", "activity", "of", "AOA", "amoA", "genes.", "Zhang", "et", "al.", "[22]", "confirmed", "the", "dominant", "role", "of", "AOA", "in", "soil", "nitrification", "by", "means", "of", "stable", "isotope", "probe", "and", "the", "quantitative", "analysis", "of", "archaral", "amoA", "genes.", "Offre", "et", "al.", "[23]", "also", "demonstrated", "that", "the", "growth", "of", "only", "archaeal", "but", "not", "bacterial", "ammonia", "oxidizers", "occurred", "in", "microcosms", "with", "active", "nitrification.", "Differences", "in", "cell", "size,", "specific", "cell", "activity", "and", "other", "physiological", "characteristics", "may", "explain", "the", "different", "contributions", "of", "AOA", "and", "AOB", "to", "soil", "nitrification.", "In", "addition,", "AOA", "and", "AOB", "may", "compete", "mutually", "or", "exhibit", "functional", "redundancy", "under", "some", "conditions,", "whereas", "under", "other", "conditions", "the", "fundamental", "physiological", "differences", "between", "these", "organisms", "may", "lead", "to", "niche", "separation", "of", "AOA", "and", "AOB", "[24].", "Therefore,", "environmental", "factors", "are", "important", "in", "determining", "the", "different", "nitrification", "activities", "and", "relative", "contributions", "of", "AOA", "and", "AOB.", "Among", "all", "environmental", "factors,", "ammonia", "is", "the", "substrate", "of", "ammonia", "oxidation", "for", "which", "concentrations", "will", "directly", "affect", "nitrification", "activity.", "It", "was", "found", "that", "AOA", "were", "able", "to", "grow", "well", "and", "the", "growth", "of", "AOA", "was", "coupled", "with", "soil", "nitrification", "when", "the", "concentration", "of", "ammonia", "was", "relatively", "low", "or", "the", "supply", "of", "ammonia", "was", "through", "the", "mineralization", "of", "organic", "matter;", "however,", "AOB", "were", "more", "competitive", "in", "soil", "nitrification", "and", "the", "number", "of", "AOB", "amoA", "gene", "copies", "was", "greater", "than", "that", "of", "AOA", "PLOS", "ONE", "|", "www.plosone.org", "1", "August", "2012", "|", "Volume", "7", "|", "Issue", "8", "|", "e44122" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 46, 12 ], [ 128, 47, 9, 12 ], [ 140, 47, 11, 12 ], [ 154, 47, 21, 12 ], [ 178, 47, 56, 12 ], [ 237, 47, 33, 12 ], [ 273, 47, 25, 12 ], [ 302, 47, 20, 12 ], [ 78, 61, 222, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 172, 34 ], [ 260, 169, 159, 34 ], [ 429, 169, 27, 34 ], [ 466, 169, 153, 34 ], [ 629, 169, 63, 34 ], [ 78, 205, 178, 34 ], [ 266, 205, 123, 34 ], [ 399, 205, 139, 34 ], [ 548, 205, 25, 34 ], [ 583, 205, 16, 34 ], [ 609, 205, 102, 34 ], [ 78, 241, 61, 34 ], [ 149, 241, 80, 34 ], [ 240, 241, 27, 34 ], [ 276, 241, 163, 34 ], [ 450, 241, 60, 34 ], [ 520, 241, 99, 34 ], [ 78, 277, 161, 34 ], [ 249, 277, 254, 34 ], [ 78, 324, 28, 16 ], [ 111, 321, 65, 19 ], [ 180, 324, 27, 16 ], [ 212, 321, 56, 19 ], [ 272, 324, 49, 16 ], [ 325, 321, 69, 19 ], [ 398, 324, 25, 16 ], [ 427, 321, 71, 19 ], [ 87, 378, 54, 15 ], [ 87, 403, 76, 14 ], [ 167, 403, 21, 14 ], [ 192, 403, 29, 14 ], [ 225, 403, 37, 14 ], [ 266, 403, 11, 14 ], [ 281, 403, 56, 14 ], [ 341, 403, 39, 14 ], [ 384, 403, 64, 14 ], [ 452, 403, 22, 14 ], [ 478, 403, 63, 14 ], [ 544, 403, 11, 14 ], [ 560, 403, 42, 14 ], [ 606, 403, 26, 14 ], [ 636, 403, 19, 14 ], [ 660, 403, 32, 14 ], [ 696, 403, 8, 14 ], [ 87, 420, 41, 14 ], [ 133, 420, 12, 14 ], [ 149, 420, 39, 14 ], [ 192, 420, 20, 14 ], [ 216, 420, 46, 14 ], [ 267, 420, 12, 14 ], [ 283, 420, 20, 14 ], [ 307, 420, 47, 14 ], [ 359, 420, 68, 14 ], [ 431, 420, 38, 14 ], [ 473, 420, 39, 14 ], [ 516, 420, 27, 14 ], [ 547, 420, 37, 14 ], [ 589, 420, 22, 14 ], [ 615, 420, 42, 14 ], [ 662, 420, 26, 14 ], [ 692, 420, 20, 14 ], [ 716, 420, 15, 14 ], [ 87, 436, 62, 14 ], [ 153, 436, 21, 14 ], [ 179, 436, 15, 14 ], [ 198, 436, 47, 14 ], [ 250, 436, 11, 14 ], [ 264, 436, 57, 14 ], [ 325, 436, 11, 14 ], [ 341, 436, 57, 14 ], [ 402, 436, 49, 14 ], [ 456, 436, 21, 14 ], [ 481, 436, 29, 14 ], [ 514, 436, 61, 14 ], [ 579, 436, 32, 14 ], [ 616, 436, 42, 14 ], [ 662, 436, 34, 14 ], [ 700, 436, 26, 14 ], [ 87, 453, 12, 14 ], [ 103, 453, 19, 14 ], [ 126, 453, 42, 14 ], [ 172, 453, 54, 14 ], [ 230, 453, 33, 14 ], [ 267, 453, 11, 14 ], [ 282, 453, 69, 14 ], [ 355, 453, 25, 14 ], [ 385, 453, 43, 14 ], [ 433, 453, 27, 14 ], [ 464, 453, 7, 14 ], [ 475, 453, 45, 14 ], [ 524, 453, 75, 14 ], [ 603, 453, 25, 14 ], [ 632, 453, 52, 14 ], [ 688, 453, 49, 14 ], [ 87, 470, 21, 14 ], [ 113, 470, 39, 14 ], [ 156, 470, 62, 14 ], [ 222, 470, 35, 14 ], [ 261, 470, 27, 14 ], [ 292, 470, 38, 14 ], [ 87, 490, 46, 14 ], [ 137, 490, 18, 14 ], [ 160, 490, 48, 14 ], [ 212, 490, 19, 14 ], [ 235, 490, 73, 14 ], [ 312, 490, 54, 14 ], [ 370, 490, 11, 14 ], [ 386, 490, 19, 14 ], [ 408, 490, 18, 14 ], [ 430, 490, 52, 14 ], [ 486, 490, 35, 14 ], [ 525, 490, 19, 14 ], [ 548, 490, 42, 14 ], [ 595, 490, 59, 14 ], [ 657, 490, 27, 14 ], [ 688, 490, 14, 14 ], [ 87, 507, 47, 14 ], [ 138, 507, 66, 14 ], [ 208, 507, 70, 14 ], [ 283, 507, 14, 14 ], [ 301, 507, 40, 14 ], [ 345, 507, 11, 14 ], [ 360, 507, 71, 14 ], [ 436, 507, 21, 14 ], [ 461, 507, 18, 14 ], [ 483, 507, 36, 14 ], [ 523, 507, 22, 14 ], [ 549, 507, 65, 14 ], [ 618, 507, 30, 14 ], [ 652, 507, 57, 14 ], [ 713, 507, 26, 14 ], [ 87, 524, 19, 14 ], [ 110, 524, 101, 14 ], [ 215, 524, 34, 14 ], [ 253, 524, 36, 14 ], [ 294, 524, 11, 14 ], [ 309, 524, 19, 14 ], [ 332, 524, 42, 14 ], [ 378, 524, 38, 14 ], [ 420, 524, 11, 14 ], [ 435, 524, 49, 14 ], [ 488, 524, 33, 14 ], [ 525, 524, 28, 14 ], [ 557, 524, 30, 14 ], [ 591, 524, 57, 14 ], [ 652, 524, 26, 14 ], [ 682, 524, 33, 14 ], [ 719, 524, 11, 14 ], [ 87, 540, 35, 14 ], [ 126, 540, 38, 14 ], [ 169, 540, 80, 14 ], [ 252, 540, 56, 14 ], [ 313, 540, 28, 14 ], [ 345, 540, 50, 14 ], [ 399, 540, 22, 14 ], [ 425, 540, 49, 14 ], [ 478, 540, 26, 14 ], [ 508, 540, 41, 14 ], [ 554, 540, 21, 14 ], [ 579, 540, 25, 14 ], [ 607, 540, 36, 14 ], [ 648, 540, 11, 14 ], [ 663, 540, 19, 14 ], [ 686, 540, 18, 14 ], [ 87, 557, 52, 14 ], [ 143, 557, 22, 14 ], [ 169, 557, 45, 14 ], [ 218, 557, 14, 14 ], [ 236, 557, 24, 14 ], [ 264, 557, 21, 14 ], [ 289, 557, 59, 14 ], [ 352, 557, 71, 14 ], [ 427, 557, 21, 14 ], [ 453, 557, 19, 14 ], [ 475, 557, 49, 14 ], [ 528, 557, 45, 14 ], [ 578, 557, 22, 14 ], [ 603, 557, 39, 14 ], [ 646, 557, 24, 14 ], [ 674, 557, 28, 14 ], [ 87, 573, 40, 14 ], [ 132, 573, 20, 14 ], [ 156, 573, 61, 14 ], [ 221, 573, 24, 14 ], [ 250, 573, 40, 14 ], [ 293, 573, 11, 14 ], [ 309, 573, 19, 14 ], [ 332, 573, 18, 14 ], [ 354, 573, 59, 14 ], [ 417, 573, 47, 14 ], [ 468, 573, 22, 14 ], [ 495, 573, 7, 14 ], [ 505, 573, 59, 14 ], [ 568, 573, 33, 14 ], [ 605, 573, 18, 14 ], [ 627, 573, 52, 14 ], [ 683, 573, 20, 14 ], [ 707, 573, 15, 14 ], [ 87, 590, 33, 14 ], [ 125, 590, 11, 14 ], [ 140, 590, 28, 14 ], [ 172, 590, 11, 14 ], [ 188, 590, 19, 14 ], [ 211, 590, 69, 14 ], [ 284, 590, 66, 14 ], [ 354, 590, 21, 14 ], [ 380, 590, 43, 14 ], [ 87, 611, 75, 14 ], [ 167, 611, 21, 14 ], [ 192, 611, 73, 14 ], [ 269, 611, 54, 14 ], [ 327, 611, 44, 14 ], [ 375, 611, 22, 14 ], [ 401, 611, 19, 14 ], [ 424, 611, 18, 14 ], [ 446, 611, 36, 14 ], [ 487, 611, 11, 14 ], [ 502, 611, 19, 14 ], [ 525, 611, 42, 14 ], [ 571, 611, 54, 14 ], [ 629, 611, 33, 14 ], [ 666, 611, 8, 14 ], [ 679, 611, 46, 14 ], [ 87, 627, 15, 14 ], [ 107, 627, 46, 14 ], [ 158, 627, 11, 14 ], [ 172, 627, 69, 14 ], [ 245, 627, 25, 14 ], [ 275, 627, 43, 14 ], [ 323, 627, 52, 14 ], [ 379, 627, 19, 14 ], [ 402, 627, 56, 14 ], [ 462, 627, 21, 14 ], [ 487, 627, 11, 14 ], [ 503, 627, 18, 14 ], [ 525, 627, 57, 14 ], [ 586, 627, 11, 14 ], [ 601, 627, 57, 14 ], [ 662, 627, 57, 14 ], [ 723, 627, 8, 14 ], [ 87, 644, 43, 14 ], [ 135, 644, 21, 14 ], [ 160, 644, 45, 14 ], [ 209, 644, 52, 14 ], [ 265, 644, 27, 14 ], [ 296, 644, 29, 14 ], [ 329, 644, 38, 14 ], [ 371, 644, 12, 14 ], [ 388, 644, 27, 14 ], [ 419, 644, 49, 14 ], [ 472, 644, 11, 14 ], [ 487, 644, 14, 14 ], [ 506, 644, 24, 14 ], [ 534, 644, 33, 14 ], [ 571, 644, 14, 14 ], [ 590, 644, 7, 14 ], [ 600, 644, 100, 14 ], [ 705, 644, 21, 14 ], [ 87, 661, 57, 14 ], [ 148, 661, 11, 14 ], [ 164, 661, 29, 14 ], [ 196, 661, 61, 14 ], [ 262, 661, 48, 14 ], [ 314, 661, 19, 14 ], [ 337, 661, 18, 14 ], [ 359, 661, 52, 14 ], [ 415, 661, 11, 14 ], [ 430, 661, 69, 14 ], [ 503, 661, 8, 14 ], [ 515, 661, 48, 14 ], [ 567, 661, 11, 14 ], [ 582, 661, 36, 14 ], [ 622, 661, 52, 14 ], [ 677, 661, 44, 14 ], [ 725, 661, 12, 14 ], [ 87, 677, 15, 14 ], [ 106, 677, 70, 14 ], [ 180, 677, 36, 14 ], [ 220, 677, 39, 14 ], [ 264, 677, 29, 14 ], [ 296, 677, 12, 14 ], [ 313, 677, 71, 14 ], [ 388, 677, 25, 14 ], [ 417, 677, 19, 14 ], [ 440, 677, 51, 14 ], [ 495, 677, 59, 14 ], [ 559, 677, 47, 14 ], [ 610, 677, 21, 14 ], [ 635, 677, 69, 14 ], [ 87, 694, 55, 14 ], [ 147, 694, 27, 14 ], [ 178, 694, 45, 14 ], [ 227, 694, 19, 14 ], [ 250, 694, 45, 14 ], [ 299, 694, 52, 14 ], [ 355, 694, 11, 14 ], [ 371, 694, 19, 14 ], [ 394, 694, 77, 14 ], [ 78, 740, 77, 15 ], [ 78, 757, 66, 14 ], [ 149, 757, 106, 14 ], [ 260, 757, 46, 14 ], [ 311, 757, 31, 14 ], [ 346, 757, 57, 14 ], [ 78, 773, 20, 14 ], [ 103, 773, 26, 14 ], [ 135, 773, 28, 14 ], [ 168, 773, 40, 14 ], [ 213, 773, 12, 14 ], [ 231, 773, 60, 14 ], [ 296, 773, 7, 14 ], [ 307, 773, 30, 14 ], [ 342, 773, 45, 14 ], [ 391, 773, 12, 14 ], [ 78, 790, 20, 14 ], [ 103, 790, 59, 14 ], [ 166, 790, 45, 14 ], [ 215, 790, 19, 14 ], [ 239, 790, 39, 14 ], [ 282, 790, 40, 14 ], [ 326, 790, 12, 14 ], [ 341, 790, 62, 14 ], [ 78, 807, 46, 14 ], [ 129, 807, 96, 14 ], [ 230, 807, 72, 14 ], [ 306, 807, 7, 14 ], [ 317, 807, 37, 14 ], [ 359, 807, 45, 14 ], [ 78, 823, 67, 14 ], [ 151, 823, 50, 14 ], [ 206, 823, 48, 14 ], [ 259, 823, 23, 14 ], [ 287, 823, 22, 14 ], [ 315, 823, 19, 14 ], [ 340, 823, 47, 14 ], [ 392, 823, 12, 14 ], [ 78, 840, 48, 14 ], [ 131, 840, 20, 14 ], [ 156, 840, 50, 14 ], [ 210, 840, 10, 14 ], [ 225, 840, 42, 14 ], [ 271, 840, 43, 14 ], [ 319, 840, 12, 14 ], [ 336, 840, 19, 14 ], [ 360, 840, 44, 14 ], [ 78, 856, 63, 14 ], [ 148, 856, 31, 14 ], [ 186, 856, 12, 14 ], [ 206, 856, 20, 14 ], [ 233, 856, 86, 14 ], [ 326, 856, 31, 14 ], [ 364, 856, 13, 14 ], [ 384, 856, 20, 14 ], [ 78, 873, 71, 14 ], [ 153, 873, 21, 14 ], [ 179, 873, 59, 14 ], [ 242, 873, 23, 14 ], [ 269, 873, 25, 14 ], [ 299, 873, 71, 14 ], [ 374, 873, 30, 14 ], [ 78, 890, 27, 14 ], [ 113, 890, 12, 14 ], [ 132, 890, 49, 14 ], [ 189, 890, 23, 14 ], [ 219, 890, 20, 14 ], [ 246, 890, 53, 14 ], [ 307, 890, 97, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 116, 11 ], [ 78, 948, 34, 13 ], [ 115, 950, 29, 11 ], [ 147, 950, 38, 11 ], [ 188, 950, 51, 11 ], [ 242, 950, 12, 11 ], [ 257, 950, 37, 11 ], [ 297, 950, 16, 11 ], [ 316, 950, 47, 11 ], [ 78, 962, 41, 11 ], [ 122, 962, 9, 11 ], [ 134, 962, 21, 11 ], [ 157, 962, 20, 11 ], [ 181, 962, 20, 11 ], [ 204, 962, 32, 11 ], [ 423, 740, 48, 14 ], [ 475, 740, 27, 14 ], [ 506, 740, 45, 14 ], [ 555, 740, 66, 14 ], [ 625, 740, 17, 14 ], [ 646, 740, 32, 14 ], [ 682, 740, 33, 14 ], [ 719, 740, 29, 14 ], [ 423, 757, 24, 14 ], [ 451, 757, 53, 14 ], [ 509, 757, 18, 14 ], [ 531, 757, 60, 14 ], [ 595, 757, 23, 14 ], [ 622, 757, 30, 14 ], [ 655, 757, 9, 14 ], [ 669, 757, 7, 14 ], [ 679, 757, 41, 14 ], [ 725, 757, 23, 14 ], [ 423, 773, 38, 14 ], [ 465, 773, 49, 14 ], [ 520, 773, 12, 14 ], [ 536, 773, 50, 14 ], [ 591, 773, 23, 14 ], [ 619, 773, 59, 14 ], [ 682, 773, 50, 14 ], [ 736, 773, 12, 14 ], [ 423, 790, 46, 14 ], [ 473, 790, 12, 14 ], [ 489, 790, 60, 14 ], [ 553, 790, 56, 14 ], [ 613, 790, 36, 14 ], [ 654, 790, 12, 14 ], [ 670, 790, 44, 14 ], [ 718, 790, 30, 14 ], [ 423, 807, 42, 14 ], [ 470, 807, 22, 14 ], [ 496, 807, 50, 14 ], [ 550, 807, 66, 14 ], [ 620, 807, 42, 14 ], [ 666, 807, 43, 14 ], [ 714, 807, 23, 14 ], [ 742, 807, 6, 14 ], [ 423, 823, 42, 14 ], [ 469, 823, 48, 14 ], [ 521, 823, 39, 14 ], [ 564, 823, 14, 14 ], [ 581, 823, 47, 14 ], [ 632, 823, 12, 14 ], [ 648, 823, 49, 14 ], [ 434, 840, 54, 14 ], [ 492, 840, 73, 14 ], [ 569, 840, 11, 14 ], [ 585, 840, 46, 14 ], [ 635, 840, 21, 14 ], [ 660, 840, 31, 14 ], [ 695, 840, 53, 14 ], [ 423, 856, 19, 14 ], [ 446, 856, 31, 14 ], [ 481, 856, 20, 14 ], [ 505, 856, 28, 14 ], [ 538, 856, 35, 14 ], [ 577, 856, 12, 14 ], [ 593, 856, 32, 14 ], [ 630, 856, 41, 14 ], [ 676, 856, 24, 14 ], [ 704, 856, 44, 14 ], [ 423, 873, 23, 14 ], [ 450, 873, 49, 14 ], [ 503, 873, 12, 14 ], [ 519, 873, 19, 14 ], [ 542, 873, 23, 14 ], [ 569, 873, 48, 14 ], [ 622, 873, 12, 14 ], [ 638, 873, 30, 14 ], [ 673, 873, 62, 14 ], [ 739, 873, 9, 14 ], [ 423, 890, 46, 14 ], [ 473, 890, 19, 14 ], [ 496, 890, 36, 14 ], [ 536, 890, 40, 14 ], [ 580, 890, 31, 14 ], [ 616, 890, 29, 14 ], [ 649, 890, 69, 14 ], [ 722, 890, 26, 14 ], [ 423, 906, 72, 14 ], [ 499, 906, 19, 14 ], [ 522, 906, 22, 14 ], [ 548, 906, 12, 14 ], [ 564, 906, 66, 14 ], [ 635, 906, 34, 14 ], [ 674, 906, 12, 14 ], [ 689, 906, 59, 14 ], [ 423, 923, 11, 14 ], [ 438, 923, 27, 14 ], [ 469, 923, 63, 14 ], [ 536, 923, 59, 14 ], [ 600, 923, 74, 14 ], [ 678, 923, 21, 14 ], [ 703, 923, 45, 14 ], [ 423, 940, 67, 14 ], [ 494, 940, 21, 14 ], [ 520, 940, 6, 14 ], [ 531, 940, 41, 14 ], [ 577, 940, 18, 14 ], [ 600, 940, 31, 14 ], [ 635, 940, 20, 14 ], [ 660, 940, 52, 14 ], [ 715, 940, 9, 14 ], [ 729, 940, 20, 14 ], [ 423, 956, 29, 14 ], [ 456, 956, 84, 14 ], [ 545, 956, 24, 14 ], [ 574, 956, 32, 14 ], [ 611, 956, 70, 14 ], [ 686, 956, 35, 14 ], [ 727, 956, 21, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 37, 10 ], [ 318, 987, 8, 10 ], [ 328, 987, 8, 10 ], [ 339, 987, 30, 10 ], [ 372, 987, 29, 10 ], [ 404, 987, 27, 10 ], [ 434, 987, 14, 10 ], [ 450, 987, 15, 10 ], [ 468, 987, 6, 10 ], [ 477, 987, 10, 10 ], [ 489, 987, 21, 10 ], [ 513, 987, 25, 10 ], [ 541, 987, 23, 10 ], [ 567, 987, 41, 10 ], [ 610, 987, 23, 10 ], [ 636, 987, 13, 10 ], [ 651, 987, 22, 10 ], [ 675, 987, 8, 10 ], [ 686, 987, 13, 10 ], [ 701, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 49, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Martinsen", "et", "al.", "BMC", "Evolutionary", "Biology", "2010,", "10:3", "http://www.biomedcentral.com/1471-2148/10/3", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Phylogenetic", "footprinting", "of", "non-coding", "RNA:", "hammerhead", "ribozyme", "sequences", "in", "a", "satellite", "DNA", "family", "of", "Dolichopoda", "cave", "crickets", "(Orthoptera,", "Rhaphidophoridae)", "Lene", "Martinsen1,", "Arild", "Johnsen1,", "Federica", "Venanzetti2,", "Lutz", "Bachmann1*", "Abstract", "Background:", "The", "great", "variety", "in", "sequence,", "length,", "complexity,", "and", "abundance", "of", "satellite", "DNA", "has", "made", "it", "difficult", "to", "ascribe", "any", "function", "to", "this", "genome", "component.", "Recent", "studies", "have", "shown", "that", "satellite", "DNA", "can", "be", "transcribed", "and", "be", "involved", "in", "regulation", "of", "chromatin", "structure", "and", "gene", "expression.", "Some", "satellite", "DNAs,", "such", "as", "the", "pDo500", "sequence", "family", "in", "Dolichopoda", "cave", "crickets,", "have", "a", "catalytic", "hammerhead", "(HH)", "ribozyme", "structure", "and", "activity", "embedded", "within", "each", "repeat.", "Results:", "We", "assessed", "the", "phylogenetic", "footprints", "of", "the", "HH", "ribozyme", "within", "the", "pDo500", "sequences", "from", "38", "different", "populations", "representing", "12", "species", "of", "Dolichopoda.", "The", "HH", "region", "was", "significantly", "more", "conserved", "than", "the", "non-hammerhead", "(NHH)", "region", "of", "the", "pDo500", "repeat.", "In", "addition,", "stems", "were", "more", "conserved", "than", "loops.", "In", "stems,", "several", "compensatory", "mutations", "were", "detected", "that", "maintain", "base", "pairing.", "The", "core", "region", "of", "the", "HH", "ribozyme", "was", "affected", "by", "very", "few", "nucleotide", "substitutions", "and", "the", "cleavage", "position", "was", "altered", "only", "once", "among", "198", "sequences.", "RNA", "folding", "of", "the", "HH", "sequences", "revealed", "that", "a", "potentially", "active", "HH", "ribozyme", "can", "be", "found", "in", "most", "of", "the", "Dolichopoda", "populations", "and", "species.", "Conclusions:", "The", "phylogenetic", "footprints", "suggest", "that", "the", "HH", "region", "of", "the", "pDo500", "sequence", "family", "is", "selected", "for", "function", "in", "Dolichopoda", "cave", "crickets.", "However,", "the", "functional", "role", "of", "HH", "ribozymes", "in", "eukaryotic", "organisms", "is", "unclear.", "The", "possible", "functions", "have", "been", "related", "to", "trans", "cleavage", "of", "an", "RNA", "target", "by", "a", "ribonucleoprotein", "and", "regulation", "of", "gene", "expression.", "Whether", "the", "HH", "ribozyme", "in", "Dolichopoda", "is", "involved", "in", "similar", "functions", "remains", "to", "be", "investigated.", "Future", "studies", "need", "to", "demonstrate", "how", "the", "observed", "nucleotide", "changes", "and", "evolutionary", "constraint", "have", "affected", "the", "catalytic", "efficiency", "of", "the", "hammerhead.", "Background", "Noncoding", "tandem-repetitive", "satellite", "DNA", "(satDNA)", "has", "long", "been", "known", "to", "constitute", "a", "large", "portion", "of", "any", "eukaryotic", "genome", "[1].", "Recent", "studies", "in", "Drosophila", "through", "underreplication", "documented", "a", "strong", "positive", "correlation", "between", "genome", "size", "and", "the", "amount", "of", "satDNA", "[2].", "SatDNA", "is", "usually", "located", "in", "the", "hetero-", "chromatic", "parts", "of", "the", "chromosomes", "close", "to", "the", "centromeres", "and", "telomeres.", "The", "high", "evolutionary", "turn-", "over", "of", "satDNA", "and", "the", "frequent", "species-specific", "*", "Correspondence:", "lutz.bachmann@nhm.uio.no", "1Natural", "History", "Museum,", "Department", "for", "Research", "and", "Collections,", "University", "of", "Oslo,", "0318", "Oslo,", "Norway", "patterns", "have", "puzzled", "researchers", "for", "many", "years.", "Such", "data", "challenge", "the", "hypothesis", "that", "there", "is", "a", "general", "bio-", "logical", "function", "of", "satDNA.", "The", "enormous", "diversity", "of", "satDNA", "in", "nucleotide", "sequence,", "length", "of", "repeats,", "com-", "plexity,", "and", "genomic", "abundance,", "instead", "suggest", "that", "a", "specific", "function", "cannot", "be", "ascribed", "to", "satDNA.", "However,", "transcription", "of", "satDNA", "and", "other", "non-cod-", "ing", "DNA", "has", "been", "found", "in", "many", "species", "(e.g.", "[3-10]).", "The", "function", "of", "the", "vast", "majority", "of", "these", "transcripts", "is", "unclear,", "but", "recent", "studies", "using", "RNA", "interference", "have", "documented", "the", "role", "of", "non-coding", "RNAs", "in", "regulation", "of", "gene", "expression,", "chromatin", "organization,", "and", "genome", "functioning", "(for", "a", "review,", "see", "[11]).", "For", "example,", "it", "has", "been", "demonstrated", "that", "small", "non-coding", "RNAs", "can", "©", "2010", "Martinsen", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 62, 98, 19, 10 ], [ 84, 98, 72, 10 ], [ 158, 98, 31, 10 ], [ 192, 98, 5, 10 ], [ 62, 112, 57, 14 ], [ 122, 112, 46, 14 ], [ 62, 128, 42, 14 ], [ 62, 151, 20, 10 ], [ 85, 151, 46, 10 ], [ 62, 188, 330, 20 ], [ 62, 210, 329, 20 ], [ 62, 232, 32, 20 ], [ 62, 272, 75, 14 ], [ 141, 272, 40, 14 ], [ 185, 272, 36, 14 ], [ 225, 272, 19, 14 ], [ 249, 272, 58, 14 ], [ 311, 272, 38, 14 ], [ 353, 272, 23, 14 ], [ 380, 272, 28, 14 ], [ 62, 290, 38, 14 ], [ 62, 320, 29, 10 ], [ 93, 320, 8, 10 ], [ 104, 320, 42, 10 ], [ 149, 320, 16, 10 ], [ 168, 320, 40, 10 ], [ 210, 320, 52, 10 ], [ 265, 320, 43, 10 ], [ 310, 320, 45, 10 ], [ 358, 320, 46, 10 ], [ 62, 334, 36, 10 ], [ 100, 334, 35, 10 ], [ 138, 334, 37, 10 ], [ 178, 334, 8, 10 ], [ 189, 334, 25, 10 ], [ 62, 348, 68, 10 ], [ 133, 348, 29, 10 ], [ 165, 348, 87, 10 ], [ 62, 375, 38, 10 ], [ 103, 375, 11, 10 ], [ 116, 375, 21, 10 ], [ 140, 375, 25, 10 ], [ 168, 375, 38, 10 ], [ 208, 375, 11, 10 ], [ 222, 375, 20, 10 ], [ 245, 375, 22, 10 ], [ 62, 401, 16, 10 ], [ 80, 401, 44, 10 ], [ 127, 401, 54, 10 ], [ 184, 401, 22, 10 ], [ 209, 401, 25, 10 ], [ 237, 401, 6, 10 ], [ 245, 401, 6, 10 ], [ 254, 401, 17, 10 ], [ 273, 401, 9, 10 ], [ 285, 401, 23, 10 ], [ 316, 401, 24, 10 ], [ 343, 401, 6, 10 ], [ 352, 401, 25, 10 ], [ 379, 399, 10, 11 ], [ 62, 415, 6, 10 ], [ 71, 415, 24, 10 ], [ 97, 415, 6, 10 ], [ 106, 415, 28, 10 ], [ 137, 415, 14, 10 ], [ 154, 415, 24, 10 ], [ 180, 415, 6, 10 ], [ 190, 415, 28, 10 ], [ 220, 415, 73, 10 ], [ 297, 415, 19, 10 ], [ 318, 415, 6, 10 ], [ 327, 415, 23, 10 ], [ 62, 456, 13, 14 ], [ 82, 456, 19, 14 ], [ 107, 456, 23, 14 ], [ 137, 456, 63, 14 ], [ 208, 456, 85, 15 ], [ 300, 456, 18, 14 ], [ 326, 456, 47, 14 ], [ 380, 456, 31, 14 ], [ 62, 473, 48, 14 ], [ 116, 473, 18, 14 ], [ 140, 473, 63, 14 ], [ 209, 473, 31, 14 ], [ 247, 473, 31, 14 ], [ 284, 473, 21, 14 ], [ 312, 473, 55, 14 ], [ 373, 473, 23, 14 ], [ 402, 473, 9, 14 ], [ 62, 490, 30, 14 ], [ 94, 490, 17, 14 ], [ 116, 490, 4, 14 ], [ 122, 490, 13, 14 ], [ 138, 490, 18, 14 ], [ 159, 490, 40, 14 ], [ 210, 490, 7, 14 ], [ 228, 490, 67, 14 ], [ 297, 490, 48, 14 ], [ 348, 490, 63, 14 ], [ 62, 506, 56, 14 ], [ 127, 506, 24, 14 ], [ 159, 506, 12, 14 ], [ 179, 506, 19, 14 ], [ 206, 506, 57, 14 ], [ 271, 506, 12, 14 ], [ 291, 506, 34, 14 ], [ 334, 506, 12, 14 ], [ 354, 506, 57, 14 ], [ 62, 523, 68, 14 ], [ 133, 523, 11, 14 ], [ 147, 523, 32, 14 ], [ 182, 523, 22, 14 ], [ 207, 523, 29, 14 ], [ 240, 523, 46, 14 ], [ 289, 523, 48, 14 ], [ 340, 523, 19, 14 ], [ 361, 523, 49, 14 ], [ 62, 540, 39, 14 ], [ 105, 540, 12, 14 ], [ 121, 540, 100, 14 ], [ 225, 540, 57, 14 ], [ 285, 540, 14, 14 ], [ 315, 540, 11, 14 ], [ 330, 540, 8, 14 ], [ 343, 540, 30, 14 ], [ 375, 540, 17, 14 ], [ 395, 536, 11, 18 ], [ 406, 540, 5, 14 ], [ 62, 556, 50, 14 ], [ 120, 556, 19, 14 ], [ 146, 556, 52, 14 ], [ 206, 556, 12, 14 ], [ 226, 556, 78, 14 ], [ 311, 556, 69, 14 ], [ 389, 556, 22, 14 ], [ 62, 573, 37, 14 ], [ 106, 573, 45, 14 ], [ 157, 573, 23, 14 ], [ 187, 573, 44, 14 ], [ 238, 573, 29, 14 ], [ 274, 573, 83, 14 ], [ 364, 573, 47, 14 ], [ 62, 589, 48, 14 ], [ 112, 589, 19, 14 ], [ 133, 589, 28, 14 ], [ 164, 589, 39, 14 ], [ 205, 589, 21, 14 ], [ 229, 589, 13, 14 ], [ 245, 589, 34, 14 ], [ 282, 589, 18, 14 ], [ 315, 589, 11, 14 ], [ 329, 589, 8, 14 ], [ 339, 589, 30, 14 ], [ 372, 589, 17, 14 ], [ 392, 586, 11, 18 ], [ 403, 589, 8, 14 ], [ 62, 630, 48, 15 ], [ 114, 630, 59, 15 ], [ 62, 653, 20, 14 ], [ 85, 653, 42, 14 ], [ 131, 653, 71, 14 ], [ 205, 653, 22, 14 ], [ 230, 653, 27, 14 ], [ 256, 652, 13, 15 ], [ 273, 653, 10, 14 ], [ 286, 653, 14, 14 ], [ 303, 653, 40, 14 ], [ 346, 653, 65, 14 ], [ 62, 669, 10, 14 ], [ 75, 669, 14, 14 ], [ 93, 670, 40, 14 ], [ 137, 670, 61, 14 ], [ 202, 669, 10, 14 ], [ 215, 669, 14, 14 ], [ 233, 670, 40, 14 ], [ 276, 670, 33, 14 ], [ 314, 669, 10, 14 ], [ 327, 669, 14, 14 ], [ 345, 670, 40, 14 ], [ 389, 670, 22, 14 ], [ 62, 686, 51, 14 ], [ 116, 686, 21, 14 ], [ 141, 686, 55, 14 ], [ 200, 686, 14, 14 ], [ 218, 686, 45, 14 ], [ 266, 686, 10, 14 ], [ 280, 686, 14, 14 ], [ 297, 686, 40, 14 ], [ 62, 917, 83, 15 ], [ 62, 940, 36, 13 ], [ 101, 940, 22, 13 ], [ 62, 960, 65, 12 ], [ 62, 972, 13, 12 ], [ 78, 972, 7, 11 ], [ 87, 972, 29, 11 ], [ 249, 960, 39, 12 ], [ 290, 959, 13, 12 ], [ 249, 972, 6, 11 ], [ 257, 972, 7, 11 ], [ 267, 972, 29, 11 ], [ 298, 972, 14, 11 ], [ 315, 969, 9, 14 ], [ 591, 49, 73, 23 ], [ 671, 49, 112, 23 ], [ 435, 98, 6, 12 ], [ 444, 98, 7, 12 ], [ 454, 98, 34, 12 ], [ 491, 98, 19, 12 ], [ 513, 95, 9, 15 ], [ 435, 110, 5, 12 ], [ 443, 110, 7, 12 ], [ 453, 110, 34, 12 ], [ 490, 110, 19, 12 ], [ 511, 108, 9, 15 ], [ 445, 123, 7, 12 ], [ 455, 123, 29, 12 ], [ 486, 123, 14, 12 ], [ 445, 135, 7, 12 ], [ 455, 135, 29, 12 ], [ 486, 135, 14, 12 ], [ 445, 148, 7, 12 ], [ 455, 148, 29, 12 ], [ 486, 148, 14, 12 ], [ 435, 160, 8, 12 ], [ 446, 160, 7, 11 ], [ 456, 160, 29, 11 ], [ 487, 160, 14, 11 ], [ 504, 157, 9, 14 ], [ 513, 159, 4, 8 ], [ 435, 187, 25, 13 ], [ 464, 187, 48, 13 ], [ 435, 206, 33, 12 ], [ 471, 206, 39, 12 ], [ 512, 206, 31, 12 ], [ 545, 206, 24, 12 ], [ 572, 206, 23, 12 ], [ 446, 219, 38, 12 ], [ 487, 219, 65, 12 ], [ 435, 231, 52, 12 ], [ 490, 231, 49, 12 ], [ 542, 231, 47, 12 ], [ 446, 244, 50, 12 ], [ 500, 244, 46, 12 ], [ 548, 244, 25, 12 ], [ 446, 256, 20, 12 ], [ 469, 256, 7, 11 ], [ 479, 256, 26, 11 ], [ 508, 256, 21, 12 ], [ 531, 256, 7, 11 ], [ 541, 256, 24, 11 ], [ 435, 283, 57, 13 ], [ 435, 302, 18, 12 ], [ 454, 300, 4, 8 ], [ 461, 302, 7, 11 ], [ 470, 302, 6, 11 ], [ 482, 302, 11, 12 ], [ 494, 300, 12, 13 ], [ 508, 302, 7, 11 ], [ 518, 302, 24, 11 ], [ 435, 314, 26, 12 ], [ 462, 313, 8, 13 ], [ 473, 315, 7, 12 ], [ 482, 315, 24, 12 ], [ 435, 327, 6, 12 ], [ 444, 327, 7, 12 ], [ 454, 327, 19, 12 ], [ 435, 340, 21, 11 ], [ 459, 340, 47, 11 ], [ 622, 98, 8, 12 ], [ 633, 98, 7, 12 ], [ 642, 98, 6, 12 ], [ 622, 110, 16, 12 ], [ 641, 110, 9, 12 ], [ 659, 110, 41, 12 ], [ 633, 123, 7, 12 ], [ 643, 123, 19, 12 ], [ 664, 123, 18, 12 ], [ 687, 121, 4, 8 ], [ 622, 135, 7, 12 ], [ 632, 135, 7, 12 ], [ 642, 135, 16, 12 ], [ 661, 135, 9, 12 ], [ 622, 148, 19, 12 ], [ 655, 148, 19, 12 ], [ 689, 148, 19, 12 ], [ 710, 148, 18, 12 ], [ 622, 206, 21, 12 ], [ 646, 206, 44, 12 ], [ 693, 206, 47, 12 ], [ 622, 219, 21, 12 ], [ 646, 219, 57, 12 ], [ 706, 219, 47, 12 ], [ 622, 231, 21, 12 ], [ 646, 231, 47, 12 ], [ 696, 231, 20, 12 ], [ 719, 231, 5, 12 ], [ 726, 231, 7, 12 ], [ 736, 231, 6, 12 ], [ 747, 231, 12, 12 ], [ 622, 244, 17, 13 ], [ 642, 244, 7, 12 ], [ 651, 244, 24, 12 ], [ 622, 302, 16, 11 ], [ 641, 302, 51, 11 ], [ 622, 315, 35, 12 ], [ 660, 315, 51, 12 ], [ 714, 315, 53, 12 ], [ 637, 332, 14, 8 ], [ 654, 327, 7, 12 ], [ 663, 327, 19, 12 ], [ 685, 327, 6, 12 ], [ 693, 324, 9, 14 ], [ 708, 325, 4, 8 ], [ 637, 344, 13, 8 ], [ 653, 340, 7, 11 ], [ 671, 340, 19, 11 ], [ 692, 340, 6, 11 ], [ 700, 337, 9, 14 ], [ 715, 338, 4, 8 ], [ 747, 422, 22, 11 ], [ 772, 422, 13, 11 ], [ 747, 434, 22, 11 ], [ 772, 434, 13, 11 ], [ 435, 385, 30, 13 ], [ 469, 385, 7, 13 ], [ 435, 399, 41, 12 ], [ 479, 399, 55, 12 ], [ 538, 399, 44, 12 ], [ 585, 399, 5, 12 ], [ 589, 395, 17, 15 ], [ 435, 422, 17, 11 ], [ 435, 434, 15, 11 ], [ 464, 421, 15, 12 ], [ 462, 432, 17, 12 ], [ 560, 422, 22, 11 ], [ 585, 422, 13, 11 ], [ 560, 434, 22, 11 ], [ 585, 434, 13, 11 ], [ 622, 422, 17, 11 ], [ 622, 434, 17, 11 ], [ 651, 421, 23, 12 ], [ 651, 432, 23, 12 ], [ 435, 452, 41, 10 ], [ 494, 452, 25, 10 ], [ 536, 452, 10, 10 ], [ 572, 452, 5, 10 ], [ 578, 455, 8, 10 ], [ 588, 452, 8, 10 ], [ 605, 452, 5, 10 ], [ 611, 455, 8, 10 ], [ 621, 452, 8, 10 ], [ 638, 452, 7, 10 ], [ 663, 452, 13, 10 ], [ 693, 452, 5, 10 ], [ 700, 455, 8, 10 ], [ 710, 452, 8, 10 ], [ 719, 452, 5, 10 ], [ 725, 455, 8, 10 ], [ 735, 452, 8, 10 ], [ 745, 452, 7, 10 ], [ 769, 452, 15, 10 ], [ 443, 463, 5, 10 ], [ 450, 466, 8, 10 ], [ 459, 463, 8, 10 ], [ 476, 463, 5, 10 ], [ 483, 466, 8, 10 ], [ 492, 463, 8, 10 ], [ 509, 463, 5, 10 ], [ 516, 466, 8, 10 ], [ 525, 463, 7, 10 ], [ 537, 463, 15, 10 ], [ 563, 463, 8, 10 ], [ 580, 463, 5, 10 ], [ 586, 466, 8, 10 ], [ 596, 463, 8, 10 ], [ 613, 463, 5, 10 ], [ 620, 466, 8, 10 ], [ 629, 463, 7, 10 ], [ 641, 463, 16, 10 ], [ 661, 463, 15, 10 ], [ 680, 463, 16, 10 ], [ 700, 463, 13, 10 ], [ 718, 463, 13, 10 ], [ 735, 463, 37, 10 ], [ 776, 463, 9, 10 ], [ 435, 474, 24, 10 ], [ 462, 474, 72, 10 ], [ 537, 474, 15, 10 ], [ 554, 474, 29, 10 ], [ 586, 474, 49, 10 ], [ 449, 504, 26, 13 ], [ 479, 504, 52, 13 ], [ 535, 504, 43, 13 ], [ 581, 504, 44, 13 ], [ 629, 504, 31, 13 ], [ 664, 504, 18, 13 ], [ 685, 504, 58, 13 ], [ 747, 504, 37, 13 ], [ 435, 519, 44, 13 ], [ 484, 519, 31, 13 ], [ 521, 519, 23, 13 ], [ 548, 519, 52, 13 ], [ 605, 519, 40, 13 ], [ 651, 519, 57, 13 ], [ 713, 519, 24, 13 ], [ 742, 519, 11, 13 ], [ 758, 519, 26, 13 ], [ 435, 534, 49, 13 ], [ 489, 534, 60, 13 ], [ 553, 534, 56, 13 ], [ 614, 534, 31, 13 ], [ 649, 534, 57, 13 ], [ 711, 534, 24, 13 ], [ 740, 534, 11, 13 ], [ 755, 534, 30, 13 ], [ 435, 550, 49, 13 ], [ 495, 549, 62, 13 ], [ 568, 550, 56, 13 ], [ 635, 550, 31, 13 ], [ 677, 550, 51, 13 ], [ 739, 550, 45, 13 ], [ 435, 565, 52, 13 ], [ 495, 565, 33, 13 ], [ 535, 565, 31, 13 ], [ 573, 565, 44, 13 ], [ 624, 565, 24, 13 ], [ 655, 565, 11, 13 ], [ 673, 565, 40, 13 ], [ 720, 565, 42, 13 ], [ 769, 565, 15, 13 ], [ 435, 580, 60, 13 ], [ 499, 580, 55, 13 ], [ 449, 612, 19, 14 ], [ 471, 612, 33, 14 ], [ 506, 612, 59, 14 ], [ 568, 612, 60, 14 ], [ 630, 612, 35, 14 ], [ 667, 612, 25, 14 ], [ 695, 612, 89, 14 ], [ 435, 628, 65, 14 ], [ 508, 628, 21, 14 ], [ 537, 628, 90, 14 ], [ 634, 628, 21, 14 ], [ 664, 628, 19, 14 ], [ 690, 628, 44, 14 ], [ 741, 628, 43, 14 ], [ 435, 645, 65, 14 ], [ 505, 645, 12, 14 ], [ 521, 645, 62, 14 ], [ 587, 645, 35, 14 ], [ 626, 645, 20, 14 ], [ 651, 645, 76, 14 ], [ 730, 645, 17, 14 ], [ 752, 645, 33, 14 ], [ 435, 662, 20, 14 ], [ 459, 662, 47, 14 ], [ 435, 698, 73, 12 ], [ 513, 698, 21, 12 ], [ 539, 698, 18, 12 ], [ 562, 698, 32, 12 ], [ 599, 698, 15, 12 ], [ 618, 698, 18, 12 ], [ 640, 698, 28, 12 ], [ 672, 698, 16, 12 ], [ 693, 698, 43, 12 ], [ 741, 698, 24, 12 ], [ 769, 698, 16, 12 ], [ 435, 711, 26, 12 ], [ 464, 711, 48, 12 ], [ 515, 711, 40, 12 ], [ 558, 711, 57, 12 ], [ 618, 711, 46, 12 ], [ 435, 749, 70, 15 ], [ 435, 770, 33, 12 ], [ 475, 770, 32, 12 ], [ 513, 770, 56, 12 ], [ 576, 770, 17, 12 ], [ 600, 770, 41, 12 ], [ 647, 770, 33, 12 ], [ 686, 770, 23, 12 ], [ 716, 770, 20, 12 ], [ 743, 770, 42, 12 ], [ 446, 783, 49, 11 ], [ 498, 783, 26, 11 ], [ 435, 795, 27, 12 ], [ 462, 795, 8, 12 ], [ 473, 795, 14, 12 ], [ 490, 795, 36, 12 ], [ 529, 795, 13, 12 ], [ 545, 795, 12, 12 ], [ 560, 795, 11, 12 ], [ 575, 795, 32, 12 ], [ 610, 795, 10, 12 ], [ 624, 795, 13, 12 ], [ 640, 795, 26, 12 ], [ 670, 795, 10, 12 ], [ 683, 795, 13, 12 ], [ 699, 795, 32, 12 ], [ 735, 795, 12, 12 ], [ 750, 795, 11, 12 ], [ 764, 795, 8, 12 ], [ 776, 795, 9, 12 ], [ 446, 807, 31, 11 ], [ 480, 807, 11, 11 ], [ 494, 807, 7, 11 ], [ 504, 807, 32, 11 ], [ 539, 807, 25, 12 ], [ 567, 807, 33, 12 ], [ 603, 807, 33, 12 ], [ 639, 807, 23, 12 ], [ 665, 807, 29, 12 ], [ 697, 807, 19, 12 ], [ 719, 807, 39, 11 ], [ 435, 820, 54, 12 ], [ 492, 820, 7, 12 ], [ 501, 820, 12, 12 ], [ 516, 820, 40, 12 ], [ 559, 820, 11, 12 ], [ 572, 820, 43, 12 ], [ 617, 820, 12, 12 ], [ 632, 820, 29, 12 ], [ 664, 820, 13, 12 ], [ 680, 820, 40, 12 ], [ 723, 820, 11, 12 ], [ 736, 820, 13, 12 ], [ 752, 820, 33, 12 ], [ 446, 832, 13, 12 ], [ 463, 832, 22, 12 ], [ 488, 832, 7, 12 ], [ 498, 832, 15, 12 ], [ 517, 832, 40, 12 ], [ 560, 832, 7, 12 ], [ 571, 832, 12, 12 ], [ 586, 832, 37, 12 ], [ 626, 832, 14, 12 ], [ 643, 832, 62, 12 ], [ 708, 832, 11, 12 ], [ 723, 832, 9, 12 ], [ 735, 832, 35, 12 ], [ 774, 832, 11, 12 ], [ 446, 845, 32, 12 ], [ 481, 845, 8, 12 ], [ 491, 845, 23, 12 ], [ 517, 845, 29, 12 ], [ 549, 845, 13, 12 ], [ 566, 845, 50, 12 ], [ 435, 857, 39, 11 ], [ 476, 857, 14, 11 ], [ 493, 857, 64, 11 ], [ 559, 857, 14, 11 ], [ 575, 857, 36, 11 ], [ 614, 857, 14, 11 ], [ 630, 857, 33, 11 ], [ 665, 857, 12, 11 ], [ 680, 857, 29, 11 ], [ 711, 857, 8, 11 ], [ 721, 857, 9, 11 ], [ 732, 857, 14, 12 ], [ 745, 857, 25, 11 ], [ 773, 857, 11, 11 ], [ 446, 870, 32, 12 ], [ 481, 870, 38, 12 ], [ 521, 870, 30, 12 ], [ 554, 870, 17, 12 ], [ 573, 870, 55, 12 ], [ 435, 882, 46, 11 ], [ 485, 882, 11, 11 ], [ 500, 882, 13, 11 ], [ 516, 882, 32, 11 ], [ 552, 882, 46, 12 ], [ 603, 882, 33, 11 ], [ 639, 882, 23, 11 ], [ 666, 882, 20, 11 ], [ 690, 882, 42, 11 ], [ 736, 882, 49, 11 ], [ 446, 895, 26, 12 ], [ 435, 907, 46, 12 ], [ 484, 907, 11, 12 ], [ 497, 907, 13, 12 ], [ 513, 907, 32, 12 ], [ 547, 907, 21, 11 ], [ 571, 907, 27, 11 ], [ 601, 907, 22, 12 ], [ 626, 907, 39, 12 ], [ 435, 920, 51, 12 ], [ 488, 920, 8, 12 ], [ 498, 920, 15, 12 ], [ 515, 920, 27, 12 ], [ 544, 920, 8, 12 ], [ 554, 920, 9, 12 ], [ 565, 920, 31, 12 ], [ 597, 920, 13, 12 ], [ 612, 920, 32, 12 ], [ 645, 919, 29, 12 ], [ 676, 919, 22, 12 ], [ 700, 919, 24, 12 ], [ 726, 919, 20, 12 ], [ 748, 920, 13, 12 ], [ 763, 920, 21, 12 ], [ 446, 932, 19, 11 ], [ 435, 944, 25, 12 ], [ 464, 944, 12, 12 ], [ 478, 944, 10, 12 ], [ 491, 944, 32, 12 ], [ 525, 944, 21, 12 ], [ 550, 944, 26, 12 ], [ 579, 944, 22, 12 ], [ 604, 944, 39, 12 ], [ 435, 957, 29, 11 ], [ 469, 957, 11, 11 ], [ 484, 957, 45, 11 ], [ 534, 957, 11, 11 ], [ 549, 957, 41, 11 ], [ 595, 957, 11, 11 ], [ 610, 957, 9, 11 ], [ 623, 957, 48, 11 ], [ 675, 957, 7, 11 ], [ 687, 957, 32, 11 ], [ 723, 957, 34, 12 ], [ 762, 957, 23, 12 ], [ 446, 969, 29, 12 ], [ 479, 969, 13, 12 ], [ 495, 969, 50, 12 ], [ 62, 1062, 22, 12 ], [ 87, 1062, 28, 12 ], [ 118, 1062, 35, 12 ], [ 155, 1062, 22, 12 ], [ 180, 1062, 31, 12 ], [ 356, 1062, 165, 12 ], [ 666, 1062, 28, 12 ], [ 698, 1062, 9, 12 ], [ 710, 1062, 12, 12 ], [ 738, 1058, 46, 17 ] ]

[ "Acta", "Crystallographica", "Section", "E", "Structure", "Reports", "Online", "ISSN", "1600-5368", "(Z)-3-(9-Anthryl)-1-(4-chlorophenyl)-2-", "(4-nitro-1H-imidazol-1-yl)prop-2-en-1-", "one", "Guang-zhou", "Wang,", "Yi-hui", "Lu,", "Cheng-he", "Zhou*", "and", "Yi-yi", "Zhang", "School", "of", "Chemistry", "and", "Chemical", "Engineering,", "Southwest", "University,", "Chongqing", "400715,", "People’s", "Republic", "of", "China", "Correspondence", "e-mail:", "zhouch@swu.edu.cn", "Received", "10", "April", "2009;", "accepted", "20", "April", "2009", "Key", "indicators:", "single-crystal", "X-ray", "study;", "T", "=", "292", "K;", "mean", "(C–C)", "=", "0.003", "A˚;", "R", "factor", "=", "0.044;", "wR", "factor", "=", "0.113;", "data-to-parameter", "ratio", "=", "13.6.", "In", "the", "title", "compound,", "C26H16ClN3O3,", "the", "dihedral", "angle", "between", "the", "anthracene", "mean", "plane", "and", "imidazole", "ring", "is", "64.75", "(2)", ".", "In", "the", "crystal,", "–", "interactions", "between", "anthracene", "fragments", "lead", "to", "the", "formation", "of", "stacks", "of", "molecules", "propagating", "in", "[100].", "The", "short", "distance", "between", "the", "carbonyl", "groups", "of", "symmetry-related", "molecules", "[C", "O", "=", "2.985", "(2)", "A˚", "]", "indicates", "the", "existence", "of", "dipole–dipole", "interactions.", "The", "crystal", "packing", "also", "exhibits", "short", "intermolecular", "contacts", "between", "the", "nitro", "groups", "and", "Cl", "atoms", "[Cl", "O", "=", "3.181", "(2)", "A˚", "].", "Related", "literature", "For", "general", "background,", "see:", "Corr", "eˆa", "et", "al.", "(2001);", "Daskiewicz", "et", "al.", "(2005);", "Sivakumar", "et", "al.", "(2009);", "Vogel", "et", "al.", "(2008).", "The", "synthesis", "was", "described", "by", "Erhardt", "et", "al.", "(1985).", "Experimental", "Crystal", "data", "C26H16ClN3O3", "Mr", "=", "453.87", "Triclinic,", "P1", "a", "=", "8.0511", "(9)", "A˚", "organic", "compounds", "b", "=", "11.0406", "(12)", "A˚", "c", "=", "12.9274", "(14)", "A˚", "=", "76.065", "(2)", "=", "85.974", "(2)", "=", "71.258", "(2)", "V", "=", "1056.1", "(2)", "A˚", "3", "Data", "collection", "Bruker", "SMART", "APEX", "CCD", "area-", "detector", "diffractometer", "Absorption", "correction:", "multi-scan", "(SADABS;", "Sheldrick,", "1997)", "Tmin", "=", "0.956,", "Tmax", "=", "0.979", "Refinement", "R[F", "2", ">", "2", "(F", "2)]", "=", "0.044", "wR(F", "2)", "=", "0.113", "S", "=", "1.04", "4070", "reflections", "Z", "=", "2", "Mo", "K", "radiation", "=", "0.22", "mm", "1", "T", "=", "292", "K", "0.16", "0.12", "0.10", "mm", "6168", "measured", "reflections", "4070", "independent", "reflections", "3354", "reflections", "with", "I", ">", "2", "(I)", "Rint", "=", "0.014", "299", "parameters", "H-atom", "parameters", "constrained", "max", "=", "0.56", "e", "A˚", "3", "min", "=", "0.50", "e", "A˚", "3", "3.746", "(7)", "3.863", "(8)", "Table", "1", "Selected", "interatomic", "distances", "(", "A˚).", "C17", "Cl1", "O1i", "O3ii", "2.985", "(2)", "3.181", "(3)", "Cg1", "Cg2", "Cg2iii", "Cg2iv", "Symmetry", "codes:", "(i)", "x", "þ", "1;", "y", "þ", "2;", "z;", "(ii)", "x", "þ", "1;", "y", "þ", "1;", "z;", "(iii)", "x", "þ", "1;", "y", "þ", "2;", "z", "þ", "1;", "(iv)", "x;", "y", "þ", "2;", "z", "þ", "1.", "Cg1", "and", "Cg2", "are", "the", "centroids", "of", "atoms", "C1/C2/C14/C7–C9", "and", "C2–C7,", "respectively.", "Data", "collection:", "SMART", "(Bruker,", "2001);", "cell", "refinement:", "SAINT", "(Bruker,", "2001);", "data", "reduction:", "SAINT;", "program(s)", "used", "to", "solve", "structure:", "SHELXS97", "(Sheldrick,", "2008);", "program(s)", "used", "to", "refine", "structure:", "SHELXL97", "(Sheldrick,", "2008);", "molecular", "graphics:", "PLATON", "(Spek,", "2009);", "software", "used", "to", "prepare", "material", "for", "publication:", "PLATON.", "We", "thank", "Southwest", "University", "(grant", "Nos.", "SWUB2006018,", "XSGX0602", "and", "SWUF2007023)", "and", "the", "Natural", "Science", "Foundation", "of", "Chongqing", "(grant", "No.", "2007BB5369)", "for", "finan-", "cial", "support.", "Supplementary", "data", "and", "figures", "for", "this", "paper", "are", "available", "from", "the", "IUCr", "electronic", "archives", "(Reference:", "CV2548).", "References", "Bruker", "(2001).", "SAINT-Plus", "and", "SMART.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Correˆ", "a,", "R.,", "Pereira,", "M.", "A.", "S.,", "Santos,", "L.", "D.,", "Filho,", "V.", "C.,", "Santos,", "A.", "R.", "S.", "&", "Nunes,", "R.", "J.", "(2001).", "Arch.", "Pharm.", "Pharm.", "Med.", "Chem.", "334,", "332–334.", "Daskiewicz,", "J.", "B.,", "Depeint,", "F.,", "Viornery,", "L.,", "Bayet,", "C.,", "Sarrazin,", "G.", "C.,", "Comte,", "G.,", "Gee,", "J.", "M.,", "Johnson,", "I.", "T.,", "Ndjoko,", "K.,", "Hostettmann,", "K.", "&", "Barron,", "D.", "(2005).", "J.", "Med.", "Chem.", "48,", "2790–2804.", "Erhardt,", "H.,", "Mildenberger,", "H.,", "Handte,", "R.,", "Sachse,", "B.,", "Hartz,", "P.", "&", "Bu¨", "rstell,", "H.", "(1985).", "German", "Patent", "No.", "DE3406908.", "Sheldrick,", "G.", "M.", "(1997).", "SADABS.", "Bruker", "AXS", "Inc.,", "Madison,", "Wisconsin,", "USA.", "Sheldrick,", "G.", "M.", "(2008).", "Acta", "Cryst.", "A64,", "112–122.", "Sivakumar,", "P.", "M.,", "Priya,", "S.", "&", "Doble,", "M.", "(2009).", "Chem.", "Biol.", "Drug", "Des.", "73,", "403–", "415.", "Spek,", "A.", "L.", "(2009).", "Acta", "Cryst.", "D65,", "148–155.", "Vogel,", "S.,", "Ohmayer,", "S.,", "Brunner,", "G.", "&", "Heilmann,", "J.", "(2008).", "Bioorg.", "Med.", "Chem.", "16,", "4286–4293.", "Acta", "Cryst.", "(2009).", "E65,", "o1113", "doi:10.1107/S1600536809014676", "Wang", "et", "al.", "o1113" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 7, 7, 7, 7, 7, 0, 9, 9, 9, 4 ]

[ [ 80, 78, 173, 28 ], [ 262, 78, 122, 28 ], [ 393, 78, 143, 28 ], [ 544, 78, 25, 28 ], [ 578, 78, 40, 28 ], [ 627, 78, 88, 28 ], [ 80, 109, 88, 28 ], [ 176, 109, 109, 28 ], [ 295, 109, 133, 28 ], [ 436, 109, 92, 28 ], [ 537, 109, 100, 28 ], [ 645, 109, 65, 28 ], [ 719, 109, 25, 28 ], [ 80, 139, 40, 28 ], [ 130, 139, 236, 28 ], [ 375, 139, 96, 28 ], [ 479, 139, 24, 28 ], [ 511, 139, 204, 28 ], [ 80, 183, 52, 14 ], [ 137, 183, 44, 14 ], [ 185, 183, 36, 14 ], [ 225, 183, 81, 14 ], [ 80, 205, 50, 10 ], [ 133, 205, 9, 10 ], [ 144, 205, 55, 10 ], [ 202, 205, 28, 10 ], [ 233, 205, 21, 10 ], [ 257, 205, 43, 10 ], [ 302, 205, 47, 10 ], [ 352, 205, 30, 10 ], [ 385, 205, 28, 10 ], [ 415, 205, 25, 10 ], [ 443, 205, 9, 10 ], [ 454, 205, 34, 10 ], [ 102, 244, 57, 14 ], [ 102, 266, 32, 13 ], [ 138, 266, 50, 13 ], [ 191, 266, 17, 13 ], [ 211, 266, 23, 13 ], [ 237, 266, 66, 13 ], [ 307, 266, 11, 13 ], [ 322, 266, 18, 13 ], [ 343, 266, 32, 13 ], [ 379, 266, 48, 13 ], [ 430, 266, 46, 13 ], [ 479, 266, 20, 13 ], [ 502, 266, 22, 13 ], [ 528, 266, 6, 13 ], [ 538, 266, 36, 13 ], [ 578, 266, 20, 13 ], [ 602, 266, 10, 13 ], [ 615, 266, 18, 13 ], [ 637, 266, 20, 13 ], [ 661, 266, 49, 13 ], [ 713, 266, 35, 13 ], [ 102, 280, 70, 13 ], [ 176, 280, 11, 13 ], [ 190, 280, 22, 13 ], [ 215, 280, 11, 13 ], [ 230, 280, 30, 13 ], [ 264, 280, 68, 13 ], [ 335, 280, 30, 13 ], [ 367, 280, 33, 13 ], [ 404, 280, 44, 13 ], [ 451, 280, 32, 13 ], [ 486, 280, 8, 13 ], [ 498, 280, 63, 13 ], [ 564, 280, 40, 13 ], [ 608, 280, 11, 13 ], [ 621, 280, 18, 13 ], [ 642, 280, 13, 13 ], [ 659, 280, 19, 13 ], [ 680, 280, 13, 13 ], [ 697, 280, 13, 13 ], [ 714, 280, 34, 13 ], [ 102, 294, 46, 13 ], [ 151, 294, 20, 13 ], [ 175, 294, 10, 13 ], [ 189, 294, 18, 13 ], [ 210, 294, 13, 13 ], [ 226, 294, 19, 13 ], [ 248, 294, 14, 13 ], [ 265, 294, 18, 13 ], [ 286, 294, 59, 13 ], [ 348, 294, 48, 13 ], [ 399, 294, 36, 13 ], [ 439, 294, 27, 13 ], [ 469, 294, 52, 13 ], [ 525, 294, 11, 13 ], [ 539, 294, 18, 13 ], [ 560, 294, 46, 13 ], [ 609, 294, 54, 13 ], [ 667, 294, 34, 13 ], [ 704, 294, 29, 13 ], [ 737, 294, 11, 13 ], [ 102, 307, 18, 13 ], [ 123, 307, 32, 13 ], [ 158, 307, 45, 13 ], [ 205, 307, 32, 13 ], [ 240, 307, 13, 13 ], [ 256, 307, 75, 13 ], [ 334, 307, 21, 13 ], [ 357, 307, 33, 13 ], [ 393, 307, 28, 13 ], [ 424, 307, 54, 13 ], [ 480, 307, 65, 13 ], [ 548, 307, 39, 13 ], [ 590, 307, 28, 13 ], [ 621, 307, 11, 13 ], [ 635, 307, 18, 13 ], [ 655, 307, 22, 13 ], [ 680, 307, 31, 13 ], [ 714, 307, 18, 13 ], [ 735, 307, 13, 13 ], [ 102, 321, 46, 13 ], [ 152, 321, 19, 13 ], [ 173, 321, 39, 13 ], [ 216, 321, 10, 13 ], [ 229, 321, 18, 13 ], [ 250, 321, 100, 13 ], [ 354, 321, 24, 13 ], [ 381, 321, 43, 13 ], [ 427, 321, 22, 13 ], [ 453, 321, 11, 13 ], [ 467, 321, 18, 13 ], [ 488, 321, 39, 13 ], [ 530, 321, 55, 13 ], [ 588, 321, 23, 13 ], [ 615, 321, 33, 13 ], [ 651, 321, 41, 13 ], [ 695, 321, 31, 13 ], [ 730, 321, 18, 13 ], [ 102, 335, 22, 13 ], [ 128, 335, 71, 13 ], [ 203, 335, 25, 13 ], [ 233, 335, 6, 13 ], [ 243, 335, 94, 13 ], [ 341, 335, 26, 13 ], [ 371, 335, 12, 13 ], [ 386, 335, 6, 13 ], [ 396, 335, 95, 13 ], [ 495, 335, 20, 13 ], [ 520, 335, 40, 13 ], [ 563, 335, 6, 13 ], [ 574, 335, 60, 13 ], [ 637, 335, 27, 13 ], [ 668, 335, 40, 13 ], [ 712, 335, 14, 13 ], [ 730, 335, 18, 13 ], [ 102, 349, 22, 13 ], [ 127, 349, 28, 13 ], [ 159, 349, 33, 13 ], [ 195, 349, 65, 13 ], [ 263, 349, 28, 13 ], [ 294, 349, 16, 13 ], [ 313, 349, 53, 13 ], [ 369, 349, 74, 13 ], [ 446, 349, 48, 13 ], [ 497, 349, 60, 13 ], [ 560, 349, 20, 13 ], [ 584, 349, 83, 13 ], [ 670, 349, 78, 13 ], [ 102, 363, 50, 13 ], [ 156, 363, 12, 13 ], [ 170, 363, 58, 13 ], [ 231, 363, 18, 13 ], [ 252, 363, 41, 13 ], [ 296, 363, 20, 13 ], [ 320, 363, 73, 13 ], [ 396, 363, 38, 13 ], [ 437, 363, 20, 13 ], [ 460, 363, 51, 13 ], [ 515, 363, 65, 13 ], [ 583, 363, 11, 13 ], [ 597, 363, 18, 13 ], [ 618, 363, 37, 13 ], [ 659, 363, 38, 13 ], [ 700, 363, 25, 13 ], [ 728, 363, 20, 13 ], [ 102, 376, 60, 13 ], [ 168, 376, 42, 13 ], [ 216, 376, 22, 13 ], [ 244, 376, 43, 13 ], [ 293, 376, 27, 13 ], [ 326, 376, 40, 13 ], [ 372, 376, 12, 13 ], [ 390, 376, 18, 13 ], [ 415, 376, 38, 13 ], [ 459, 376, 11, 13 ], [ 476, 376, 18, 13 ], [ 500, 376, 22, 13 ], [ 529, 376, 60, 13 ], [ 595, 376, 18, 13 ], [ 619, 376, 21, 13 ], [ 646, 376, 46, 13 ], [ 698, 376, 25, 13 ], [ 730, 376, 18, 13 ], [ 102, 390, 100, 13 ], [ 205, 390, 24, 13 ], [ 232, 390, 40, 13 ], [ 275, 390, 10, 13 ], [ 288, 390, 6, 13 ], [ 298, 390, 68, 13 ], [ 368, 390, 35, 13 ], [ 406, 390, 55, 13 ], [ 464, 390, 43, 13 ], [ 510, 390, 64, 13 ], [ 577, 390, 18, 13 ], [ 598, 390, 60, 13 ], [ 660, 390, 27, 13 ], [ 690, 390, 19, 13 ], [ 712, 390, 36, 13 ], [ 102, 404, 27, 13 ], [ 131, 404, 25, 13 ], [ 158, 404, 51, 13 ], [ 212, 404, 11, 13 ], [ 226, 404, 18, 13 ], [ 246, 404, 17, 13 ], [ 266, 404, 40, 13 ], [ 309, 404, 10, 13 ], [ 322, 404, 6, 13 ], [ 331, 404, 62, 13 ], [ 395, 404, 43, 13 ], [ 441, 404, 39, 13 ], [ 482, 404, 22, 13 ], [ 506, 404, 33, 13 ], [ 542, 404, 41, 13 ], [ 585, 404, 17, 13 ], [ 605, 404, 57, 13 ], [ 664, 404, 34, 13 ], [ 700, 404, 11, 13 ], [ 714, 404, 18, 13 ], [ 735, 404, 13, 13 ], [ 102, 418, 19, 13 ], [ 124, 418, 25, 13 ], [ 153, 418, 11, 13 ], [ 167, 418, 65, 13 ], [ 236, 418, 76, 13 ], [ 315, 418, 17, 13 ], [ 335, 418, 36, 13 ], [ 375, 418, 47, 13 ], [ 424, 418, 25, 13 ], [ 452, 418, 50, 13 ], [ 505, 418, 45, 13 ], [ 554, 418, 41, 13 ], [ 598, 418, 38, 13 ], [ 639, 418, 21, 13 ], [ 663, 418, 37, 13 ], [ 703, 418, 45, 13 ], [ 102, 432, 20, 13 ], [ 127, 432, 53, 13 ], [ 184, 432, 43, 13 ], [ 232, 432, 11, 13 ], [ 248, 432, 18, 13 ], [ 270, 432, 17, 13 ], [ 291, 432, 43, 13 ], [ 338, 432, 20, 13 ], [ 362, 432, 34, 13 ], [ 401, 432, 17, 13 ], [ 422, 432, 54, 13 ], [ 480, 432, 24, 13 ], [ 508, 432, 6, 13 ], [ 519, 432, 34, 13 ], [ 557, 432, 10, 13 ], [ 572, 432, 32, 13 ], [ 608, 432, 18, 13 ], [ 630, 432, 17, 13 ], [ 651, 432, 40, 13 ], [ 696, 432, 51, 13 ], [ 102, 446, 45, 13 ], [ 152, 446, 89, 13 ], [ 246, 446, 74, 13 ], [ 325, 446, 22, 13 ], [ 352, 446, 30, 13 ], [ 387, 446, 14, 13 ], [ 406, 446, 39, 13 ], [ 450, 446, 35, 13 ], [ 490, 446, 32, 13 ], [ 527, 446, 54, 13 ], [ 587, 446, 21, 13 ], [ 613, 446, 48, 13 ], [ 666, 446, 20, 13 ], [ 692, 446, 11, 13 ], [ 708, 446, 18, 13 ], [ 731, 446, 17, 13 ], [ 102, 460, 40, 13 ], [ 149, 460, 10, 13 ], [ 165, 460, 95, 13 ], [ 265, 460, 32, 13 ], [ 303, 460, 52, 13 ], [ 361, 460, 23, 13 ], [ 390, 460, 25, 13 ], [ 421, 460, 64, 13 ], [ 491, 460, 15, 13 ], [ 512, 460, 77, 13 ], [ 595, 460, 37, 13 ], [ 639, 460, 20, 13 ], [ 665, 460, 45, 13 ], [ 716, 460, 32, 13 ], [ 102, 473, 50, 13 ], [ 92, 508, 40, 10 ], [ 137, 508, 22, 10 ], [ 163, 508, 6, 10 ], [ 174, 508, 45, 10 ], [ 224, 508, 6, 10 ], [ 235, 508, 26, 10 ], [ 266, 508, 59, 10 ], [ 330, 508, 41, 10 ], [ 375, 508, 48, 10 ], [ 428, 508, 9, 10 ], [ 441, 508, 14, 10 ], [ 460, 508, 30, 10 ], [ 495, 508, 30, 10 ], [ 530, 508, 37, 10 ], [ 571, 508, 44, 10 ], [ 620, 508, 31, 10 ], [ 656, 508, 33, 10 ], [ 694, 508, 22, 10 ], [ 721, 508, 9, 10 ], [ 734, 508, 14, 10 ], [ 92, 520, 79, 10 ], [ 174, 520, 33, 10 ], [ 209, 520, 8, 10 ], [ 220, 520, 71, 10 ], [ 294, 520, 20, 10 ], [ 317, 520, 18, 10 ], [ 338, 520, 18, 10 ], [ 359, 520, 32, 10 ], [ 393, 520, 139, 10 ], [ 92, 537, 31, 10 ], [ 126, 537, 30, 10 ], [ 159, 537, 6, 10 ], [ 168, 537, 33, 10 ], [ 204, 537, 59, 10 ], [ 266, 537, 34, 10 ], [ 303, 537, 9, 10 ], [ 314, 537, 50, 10 ], [ 367, 537, 28, 10 ], [ 398, 537, 25, 10 ], [ 426, 537, 9, 10 ], [ 437, 537, 34, 10 ], [ 92, 554, 42, 10 ], [ 137, 554, 37, 10 ], [ 176, 554, 12, 10 ], [ 191, 554, 22, 10 ], [ 216, 554, 44, 10 ], [ 263, 554, 20, 10 ], [ 286, 554, 12, 10 ], [ 301, 554, 22, 10 ], [ 326, 554, 47, 10 ], [ 376, 554, 16, 10 ], [ 395, 554, 12, 10 ], [ 410, 554, 20, 10 ], [ 92, 571, 50, 10 ], [ 156, 571, 20, 10 ], [ 179, 571, 24, 10 ], [ 205, 571, 47, 10 ], [ 255, 571, 17, 10 ], [ 275, 571, 7, 10 ], [ 284, 571, 10, 10 ], [ 297, 571, 50, 10 ], [ 350, 571, 25, 10 ], [ 378, 571, 45, 10 ], [ 426, 571, 25, 10 ], [ 453, 571, 14, 10 ], [ 470, 571, 24, 10 ], [ 496, 571, 9, 10 ], [ 508, 571, 14, 10 ], [ 525, 571, 34, 10 ], [ 561, 571, 42, 10 ], [ 606, 571, 45, 10 ], [ 654, 571, 32, 10 ], [ 689, 571, 25, 10 ], [ 717, 571, 31, 10 ], [ 92, 582, 49, 10 ], [ 144, 582, 17, 10 ], [ 163, 582, 50, 10 ], [ 216, 582, 16, 10 ], [ 235, 582, 54, 10 ], [ 291, 582, 8, 10 ], [ 302, 582, 15, 10 ], [ 320, 582, 37, 10 ], [ 359, 582, 37, 10 ], [ 399, 582, 14, 10 ], [ 416, 582, 31, 10 ], [ 450, 582, 27, 10 ], [ 480, 582, 16, 10 ], [ 498, 582, 27, 10 ], [ 529, 582, 13, 10 ], [ 545, 582, 36, 10 ], [ 92, 600, 42, 10 ], [ 137, 600, 17, 10 ], [ 157, 600, 21, 10 ], [ 181, 600, 16, 10 ], [ 200, 600, 43, 10 ], [ 246, 600, 11, 10 ], [ 260, 600, 16, 10 ], [ 279, 600, 34, 10 ], [ 316, 600, 5, 10 ], [ 325, 600, 32, 10 ], [ 360, 600, 27, 10 ], [ 390, 600, 22, 10 ], [ 415, 600, 38, 10 ], [ 456, 600, 9, 10 ], [ 468, 600, 10, 10 ], [ 481, 600, 16, 10 ], [ 500, 600, 10, 10 ], [ 514, 600, 14, 10 ], [ 531, 600, 35, 10 ], [ 569, 600, 38, 10 ], [ 610, 600, 9, 10 ], [ 622, 600, 27, 10 ], [ 652, 600, 34, 10 ], [ 689, 600, 10, 10 ], [ 703, 600, 16, 10 ], [ 721, 600, 27, 10 ], [ 92, 611, 47, 10 ], [ 141, 611, 9, 10 ], [ 152, 611, 14, 10 ], [ 167, 611, 17, 10 ], [ 186, 611, 21, 10 ], [ 209, 611, 7, 10 ], [ 217, 611, 51, 10 ], [ 270, 611, 35, 10 ], [ 306, 611, 20, 10 ], [ 328, 611, 14, 10 ], [ 344, 611, 28, 10 ], [ 374, 611, 48, 10 ], [ 423, 611, 47, 10 ], [ 472, 611, 31, 10 ], [ 505, 611, 15, 10 ], [ 522, 611, 31, 10 ], [ 556, 611, 16, 10 ], [ 573, 611, 11, 10 ], [ 586, 611, 16, 10 ], [ 604, 611, 8, 10 ], [ 614, 611, 23, 10 ], [ 639, 611, 30, 10 ], [ 670, 611, 19, 10 ], [ 690, 611, 40, 10 ], [ 732, 611, 16, 10 ], [ 92, 622, 34, 10 ], [ 129, 622, 34, 10 ], [ 165, 622, 9, 10 ], [ 177, 622, 32, 10 ], [ 213, 622, 9, 10 ], [ 224, 622, 48, 10 ], [ 275, 622, 9, 10 ], [ 287, 622, 14, 10 ], [ 303, 622, 48, 10 ], [ 92, 639, 52, 10 ], [ 147, 639, 44, 10 ], [ 193, 639, 16, 10 ], [ 212, 639, 31, 10 ], [ 246, 639, 20, 10 ], [ 268, 639, 35, 10 ], [ 307, 639, 17, 10 ], [ 326, 639, 11, 10 ], [ 340, 639, 45, 10 ], [ 388, 639, 35, 10 ], [ 426, 639, 21, 10 ], [ 92, 656, 5, 10 ], [ 99, 656, 27, 10 ], [ 129, 656, 73, 10 ], [ 205, 656, 17, 10 ], [ 225, 656, 67, 10 ], [ 295, 656, 17, 10 ], [ 80, 699, 84, 14 ], [ 93, 724, 32, 13 ], [ 129, 724, 45, 13 ], [ 178, 724, 8, 13 ], [ 190, 724, 6, 13 ], [ 201, 724, 31, 13 ], [ 237, 724, 50, 13 ], [ 292, 724, 64, 13 ], [ 361, 724, 52, 13 ], [ 80, 739, 31, 13 ], [ 115, 739, 43, 13 ], [ 161, 739, 20, 13 ], [ 184, 739, 26, 13 ], [ 213, 739, 34, 13 ], [ 250, 739, 24, 13 ], [ 277, 739, 10, 13 ], [ 291, 739, 54, 13 ], [ 348, 739, 65, 13 ], [ 80, 754, 19, 13 ], [ 106, 754, 10, 13 ], [ 122, 754, 27, 13 ], [ 156, 754, 60, 13 ], [ 222, 754, 31, 13 ], [ 259, 754, 52, 13 ], [ 316, 754, 32, 13 ], [ 354, 754, 45, 13 ], [ 405, 754, 8, 13 ], [ 80, 768, 51, 13 ], [ 135, 768, 51, 13 ], [ 189, 768, 22, 13 ], [ 214, 768, 6, 13 ], [ 224, 768, 40, 13 ], [ 267, 768, 10, 13 ], [ 281, 768, 36, 13 ], [ 320, 768, 42, 13 ], [ 366, 768, 47, 13 ], [ 80, 783, 30, 13 ], [ 112, 783, 27, 13 ], [ 142, 783, 61, 13 ], [ 206, 783, 45, 13 ], [ 254, 783, 43, 13 ], [ 299, 783, 19, 13 ], [ 321, 783, 23, 13 ], [ 347, 783, 35, 13 ], [ 385, 783, 28, 13 ], [ 80, 798, 12, 13 ], [ 95, 798, 16, 13 ], [ 114, 798, 27, 13 ], [ 143, 798, 10, 13 ], [ 155, 798, 32, 13 ], [ 190, 798, 45, 13 ], [ 236, 798, 16, 13 ], [ 255, 798, 16, 13 ], [ 274, 798, 32, 13 ], [ 308, 798, 49, 13 ], [ 360, 798, 6, 13 ], [ 369, 798, 31, 13 ], [ 403, 798, 10, 13 ], [ 80, 813, 31, 13 ], [ 115, 813, 46, 13 ], [ 165, 813, 53, 13 ], [ 222, 813, 80, 13 ], [ 306, 813, 41, 13 ], [ 350, 813, 28, 13 ], [ 381, 813, 31, 13 ], [ 80, 828, 16, 13 ], [ 99, 828, 21, 13 ], [ 123, 828, 32, 13 ], [ 157, 828, 46, 13 ], [ 205, 828, 10, 13 ], [ 218, 828, 52, 13 ], [ 273, 828, 53, 13 ], [ 329, 828, 10, 13 ], [ 342, 828, 53, 13 ], [ 398, 828, 15, 13 ], [ 80, 842, 32, 13 ], [ 115, 842, 46, 13 ], [ 164, 842, 24, 13 ], [ 191, 842, 6, 13 ], [ 200, 842, 34, 13 ], [ 237, 842, 43, 13 ], [ 283, 842, 63, 13 ], [ 350, 842, 10, 13 ], [ 363, 842, 50, 13 ], [ 80, 857, 10, 13 ], [ 96, 857, 20, 13 ], [ 122, 857, 13, 13 ], [ 141, 857, 15, 13 ], [ 161, 857, 36, 13 ], [ 204, 857, 41, 13 ], [ 251, 857, 36, 13 ], [ 293, 857, 59, 13 ], [ 359, 857, 16, 13 ], [ 381, 857, 32, 13 ], [ 80, 872, 42, 13 ], [ 127, 872, 8, 13 ], [ 139, 872, 38, 13 ], [ 181, 872, 10, 13 ], [ 195, 872, 16, 13 ], [ 216, 872, 14, 13 ], [ 233, 872, 17, 13 ], [ 255, 872, 13, 13 ], [ 272, 872, 6, 13 ], [ 282, 872, 46, 13 ], [ 332, 872, 45, 13 ], [ 382, 872, 31, 13 ], [ 80, 887, 28, 13 ], [ 113, 887, 6, 13 ], [ 124, 887, 62, 13 ], [ 190, 887, 22, 13 ], [ 217, 887, 74, 13 ], [ 295, 887, 51, 13 ], [ 350, 887, 62, 13 ], [ 80, 902, 19, 13 ], [ 103, 902, 80, 13 ], [ 186, 902, 42, 13 ], [ 231, 902, 28, 13 ], [ 262, 902, 52, 13 ], [ 317, 902, 32, 13 ], [ 352, 902, 49, 13 ], [ 405, 902, 8, 13 ], [ 80, 917, 41, 13 ], [ 127, 917, 13, 13 ], [ 146, 917, 39, 13 ], [ 190, 917, 10, 13 ], [ 206, 917, 6, 13 ], [ 218, 917, 80, 13 ], [ 304, 917, 31, 13 ], [ 341, 917, 10, 13 ], [ 356, 917, 16, 13 ], [ 378, 917, 34, 13 ], [ 80, 931, 79, 13 ], [ 162, 931, 30, 13 ], [ 195, 931, 31, 13 ], [ 229, 931, 13, 13 ], [ 245, 931, 16, 13 ], [ 265, 931, 71, 13 ], [ 339, 931, 17, 13 ], [ 359, 931, 10, 13 ], [ 372, 931, 6, 13 ], [ 381, 931, 32, 13 ], [ 80, 946, 42, 13 ], [ 125, 946, 13, 13 ], [ 140, 946, 16, 13 ], [ 159, 946, 35, 13 ], [ 197, 946, 10, 13 ], [ 210, 946, 16, 13 ], [ 229, 946, 29, 13 ], [ 260, 946, 46, 13 ], [ 308, 946, 17, 13 ], [ 328, 946, 37, 13 ], [ 367, 946, 45, 13 ], [ 80, 961, 62, 13 ], [ 147, 961, 15, 13 ], [ 167, 961, 10, 13 ], [ 183, 961, 12, 13 ], [ 200, 961, 44, 13 ], [ 249, 961, 61, 13 ], [ 315, 961, 31, 13 ], [ 352, 961, 61, 13 ], [ 80, 976, 37, 13 ], [ 123, 976, 47, 13 ], [ 176, 976, 82, 13 ], [ 264, 976, 53, 13 ], [ 323, 976, 31, 13 ], [ 359, 976, 16, 13 ], [ 381, 976, 32, 13 ], [ 80, 991, 42, 13 ], [ 126, 991, 8, 13 ], [ 138, 991, 19, 13 ], [ 162, 991, 38, 13 ], [ 203, 991, 10, 13 ], [ 217, 991, 6, 13 ], [ 228, 991, 80, 13 ], [ 312, 991, 62, 13 ], [ 378, 991, 17, 13 ], [ 399, 991, 14, 13 ], [ 80, 1005, 13, 13 ], [ 96, 1005, 51, 13 ], [ 150, 1005, 11, 13 ], [ 164, 1005, 51, 13 ], [ 218, 1005, 83, 13 ], [ 305, 1005, 43, 13 ], [ 351, 1005, 26, 13 ], [ 380, 1005, 16, 13 ], [ 399, 1005, 14, 13 ], [ 437, 699, 46, 13 ], [ 490, 699, 16, 13 ], [ 514, 699, 32, 13 ], [ 553, 699, 42, 13 ], [ 602, 699, 8, 13 ], [ 617, 699, 35, 13 ], [ 659, 699, 38, 13 ], [ 704, 699, 10, 13 ], [ 721, 699, 13, 13 ], [ 742, 699, 28, 13 ], [ 437, 713, 55, 13 ], [ 497, 713, 14, 13 ], [ 515, 713, 17, 13 ], [ 537, 713, 13, 13 ], [ 554, 713, 16, 13 ], [ 575, 713, 55, 13 ], [ 635, 713, 43, 13 ], [ 682, 713, 43, 13 ], [ 730, 713, 21, 13 ], [ 756, 713, 13, 13 ], [ 437, 728, 43, 13 ], [ 486, 728, 38, 13 ], [ 530, 728, 16, 13 ], [ 552, 728, 61, 13 ], [ 619, 728, 37, 13 ], [ 662, 728, 10, 13 ], [ 678, 728, 32, 13 ], [ 715, 728, 29, 13 ], [ 750, 728, 19, 13 ], [ 437, 742, 31, 13 ], [ 474, 742, 7, 13 ], [ 487, 742, 10, 13 ], [ 503, 742, 55, 13 ], [ 563, 742, 10, 13 ], [ 579, 742, 16, 13 ], [ 601, 742, 38, 13 ], [ 644, 742, 19, 13 ], [ 669, 742, 54, 13 ], [ 729, 742, 10, 13 ], [ 745, 742, 25, 13 ], [ 437, 757, 44, 13 ], [ 484, 757, 51, 13 ], [ 538, 757, 10, 13 ], [ 551, 757, 6, 13 ], [ 560, 757, 37, 13 ], [ 600, 757, 19, 13 ], [ 622, 757, 24, 13 ], [ 649, 757, 23, 13 ], [ 674, 757, 53, 13 ], [ 730, 757, 40, 13 ], [ 437, 772, 40, 13 ], [ 450, 787, 52, 13 ], [ 505, 787, 51, 13 ], [ 559, 787, 24, 13 ], [ 586, 787, 24, 13 ], [ 614, 787, 28, 13 ], [ 645, 787, 40, 13 ], [ 688, 787, 72, 13 ], [ 763, 787, 6, 13 ], [ 437, 801, 48, 13 ], [ 489, 801, 24, 13 ], [ 518, 801, 10, 13 ], [ 532, 801, 32, 13 ], [ 567, 801, 45, 13 ], [ 616, 801, 19, 13 ], [ 640, 801, 51, 13 ], [ 695, 801, 34, 13 ], [ 733, 801, 23, 13 ], [ 760, 801, 10, 13 ], [ 437, 816, 16, 13 ], [ 456, 816, 17, 13 ], [ 477, 816, 46, 13 ], [ 525, 816, 8, 13 ], [ 536, 816, 16, 13 ], [ 555, 816, 31, 13 ], [ 590, 816, 71, 13 ], [ 664, 816, 10, 13 ], [ 677, 816, 76, 13 ], [ 756, 816, 14, 13 ], [ 437, 831, 17, 13 ], [ 457, 831, 49, 13 ], [ 509, 831, 10, 13 ], [ 523, 831, 16, 13 ], [ 542, 831, 42, 13 ], [ 588, 831, 52, 13 ], [ 643, 831, 36, 13 ], [ 683, 831, 34, 13 ], [ 720, 831, 10, 13 ], [ 734, 831, 36, 13 ], [ 437, 845, 38, 13 ], [ 479, 845, 19, 13 ], [ 503, 845, 38, 13 ], [ 545, 845, 40, 13 ], [ 589, 845, 21, 13 ], [ 614, 845, 28, 13 ], [ 646, 845, 38, 13 ], [ 689, 845, 10, 13 ], [ 703, 845, 26, 13 ], [ 733, 845, 37, 13 ], [ 437, 860, 32, 13 ], [ 474, 860, 36, 13 ], [ 514, 860, 32, 13 ], [ 551, 860, 19, 13 ], [ 576, 860, 16, 13 ], [ 597, 860, 96, 13 ], [ 697, 860, 26, 13 ], [ 728, 860, 42, 13 ], [ 437, 875, 21, 13 ], [ 462, 875, 23, 13 ], [ 489, 875, 42, 13 ], [ 535, 875, 23, 13 ], [ 562, 875, 16, 13 ], [ 582, 875, 13, 13 ], [ 599, 875, 19, 13 ], [ 623, 875, 13, 13 ], [ 640, 875, 21, 13 ], [ 665, 875, 23, 13 ], [ 691, 875, 16, 13 ], [ 711, 875, 35, 13 ], [ 750, 875, 19, 13 ], [ 437, 889, 16, 13 ], [ 456, 889, 60, 13 ], [ 520, 889, 58, 13 ], [ 581, 889, 22, 13 ], [ 607, 889, 13, 13 ], [ 623, 889, 21, 13 ], [ 647, 889, 30, 13 ], [ 680, 889, 45, 13 ], [ 728, 889, 22, 13 ], [ 754, 889, 16, 13 ], [ 437, 904, 35, 13 ], [ 476, 904, 20, 13 ], [ 500, 904, 16, 13 ], [ 521, 904, 28, 13 ], [ 553, 904, 49, 13 ], [ 607, 904, 13, 13 ], [ 624, 904, 74, 13 ], [ 703, 904, 43, 13 ], [ 750, 904, 20, 13 ], [ 437, 918, 31, 13 ], [ 471, 918, 16, 13 ], [ 490, 918, 26, 13 ], [ 520, 918, 42, 13 ], [ 565, 918, 26, 13 ], [ 594, 918, 37, 13 ], [ 634, 918, 16, 13 ], [ 653, 918, 20, 13 ], [ 676, 918, 39, 13 ], [ 718, 918, 19, 13 ], [ 740, 918, 29, 13 ], [ 437, 933, 16, 13 ], [ 461, 933, 14, 13 ], [ 483, 933, 17, 13 ], [ 507, 933, 25, 13 ], [ 540, 933, 79, 13 ], [ 627, 933, 34, 13 ], [ 669, 933, 40, 13 ], [ 717, 933, 53, 13 ], [ 437, 948, 77, 13 ], [ 519, 948, 58, 13 ], [ 581, 948, 46, 13 ], [ 632, 948, 6, 13 ], [ 643, 948, 66, 13 ], [ 713, 948, 10, 13 ], [ 728, 948, 42, 13 ], [ 437, 962, 16, 13 ], [ 460, 962, 46, 13 ], [ 514, 962, 32, 13 ], [ 553, 962, 19, 13 ], [ 580, 962, 38, 13 ], [ 625, 962, 25, 13 ], [ 657, 962, 16, 13 ], [ 680, 962, 20, 13 ], [ 707, 962, 39, 13 ], [ 753, 962, 16, 13 ], [ 437, 977, 48, 13 ], [ 490, 977, 15, 13 ], [ 509, 977, 13, 13 ], [ 527, 977, 38, 13 ], [ 570, 977, 42, 13 ], [ 618, 977, 10, 13 ], [ 633, 977, 22, 13 ], [ 660, 977, 31, 13 ], [ 695, 977, 10, 13 ], [ 710, 977, 16, 13 ], [ 731, 977, 13, 13 ], [ 750, 977, 20, 13 ], [ 437, 991, 37, 13 ], [ 477, 991, 36, 13 ], [ 516, 991, 24, 13 ], [ 543, 991, 24, 13 ], [ 570, 991, 47, 13 ], [ 619, 991, 10, 13 ], [ 633, 991, 37, 13 ], [ 672, 991, 22, 13 ], [ 697, 991, 31, 13 ], [ 731, 991, 39, 13 ], [ 437, 1006, 30, 13 ], [ 472, 1006, 43, 13 ], [ 520, 1006, 25, 13 ], [ 551, 1006, 77, 13 ], [ 634, 1006, 40, 13 ], [ 680, 1006, 32, 13 ], [ 717, 1006, 16, 13 ], [ 739, 1006, 31, 13 ], [ 113, 1047, 23, 12 ], [ 140, 1047, 21, 12 ], [ 165, 1047, 3, 12 ], [ 174, 1047, 83, 12 ], [ 422, 1047, 6, 12 ], [ 569, 1047, 19, 12 ], [ 591, 1047, 23, 12 ], [ 619, 1047, 3, 12 ], [ 627, 1047, 36, 12 ], [ 668, 1047, 6, 12 ], [ 680, 1047, 3, 12 ], [ 688, 1047, 24, 12 ], [ 716, 1047, 6, 12 ], [ 727, 1047, 3, 12 ], [ 736, 1047, 34, 12 ] ]

[ "Force-Induced", "Unfolding", "Simulations", "of", "the", "Human", "Notch1", "Negative", "Regulatory", "Region:", "Possible", "Roles", "of", "the", "Heterodimerization", "Domain", "in", "Mechanosensing", "Jianhan", "Chen*,", "Anna", "Zolkiewska*", "Department", "of", "Biochemistry,", "Kansas", "State", "University,", "Manhattan,", "Kansas,", "United", "States", "of", "America", "Abstract", "Notch", "receptors", "are", "core", "components", "of", "the", "Notch", "signaling", "pathway", "and", "play", "a", "central", "role", "in", "cell", "fate", "decisions", "during", "development", "as", "well", "as", "tissue", "homeostasis.", "Upon", "ligand", "binding,", "Notch", "is", "sequentially", "cleaved", "at", "the", "S2", "site", "by", "an", "ADAM", "protease", "and", "at", "the", "S3", "site", "by", "the", "c-secretase", "complex.", "Recent", "X-ray", "structures", "of", "the", "negative", "regulatory", "region", "(NRR)", "of", "the", "Notch", "receptor", "reveal", "an", "auto-inhibited", "fold", "where", "three", "protective", "Lin12/Notch", "repeats", "(LNR)", "of", "the", "NRR", "shield", "the", "S2", "cleavage", "site", "housed", "in", "the", "heterodimerization", "(HD)", "domain.", "One", "of", "the", "models", "explaining", "how", "ligand", "binding", "drives", "the", "NRR", "conformation", "from", "a", "protease-resistant", "state", "to", "a", "protease-sensitive", "one", "invokes", "a", "mechanical", "force", "exerted", "on", "the", "NRR", "upon", "ligand", "endocytosis.", "Here,", "we", "combined", "physics-based", "atomistic", "simulations", "and", "topology-based", "coarse-grained", "modeling", "to", "investigate", "the", "intrinsic", "and", "force-induced", "folding", "and", "unfolding", "mechanisms", "of", "the", "human", "Notch1", "NRR.", "The", "simulations", "support", "that", "external", "force", "applied", "to", "the", "termini", "of", "the", "NRR", "disengages", "the", "LNR", "modules", "from", "the", "heterodimerization", "(HD)", "domain", "in", "a", "well-defined,", "largely", "sequential", "manner.", "Importantly,", "the", "mechanical", "force", "can", "further", "drive", "local", "unfolding", "of", "the", "HD", "domain", "in", "a", "functionally", "relevant", "fashion", "that", "would", "provide", "full", "proteolytic", "access", "to", "the", "S2", "site", "prior", "to", "heterodimer", "disassociation.", "We", "further", "analyzed", "local", "structural", "features,", "intrinsic", "folding", "free", "energy", "surfaces,", "and", "correlated", "motions", "of", "the", "HD", "domain.", "The", "results", "are", "consistent", "with", "a", "model", "in", "which", "the", "HD", "domain", "possesses", "inherent", "mechanosensing", "characteristics", "that", "could", "be", "utilized", "during", "Notch", "activation.", "This", "potential", "role", "of", "the", "HD", "domain", "in", "ligand-dependent", "Notch", "activation", "may", "have", "implications", "for", "understanding", "normal", "and", "aberrant", "Notch", "signaling.", "Citation:", "Chen", "J,", "Zolkiewska", "A", "(2011)", "Force-Induced", "Unfolding", "Simulations", "of", "the", "Human", "Notch1", "Negative", "Regulatory", "Region:", "Possible", "Roles", "of", "the", "Heterodimerization", "Domain", "in", "Mechanosensing.", "PLoS", "ONE", "6(7):", "e22837.", "doi:10.1371/journal.pone.0022837", "Editor:", "Markus", "J.", "Buehler,", "Massachusetts", "Institute", "of", "Technology,", "United", "States", "of", "America", "Received", "February", "14,", "2011;", "Accepted", "June", "30,", "2011;", "Published", "July", "28,", "2011", "Copyright:", "2011", "Chen,", "Zolkiewska.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "author", "and", "source", "are", "credited.", "Funding:", "This", "work", "was", "supported", "by", "NSF", "through", "a", "CAREER", "Award", "(MCB", "0952514)", "to", "JC", "and", "by", "the", "National", "Institutes", "of", "Health", "through", "an", "R15", "Award", "(CA151065)", "to", "AZ.", "This", "work", "is", "contribution", "11-225-J", "from", "the", "Kansas", "Agricultural", "Experiment", "Station.", "The", "funders", "had", "no", "role", "in", "study", "design,", "data", "collection", "and", "analysis,", "decision", "to", "publish,", "or", "preparation", "of", "the", "manuscript.", "Competing", "Interests:", "The", "authors", "have", "declared", "that", "no", "competing", "interests", "exist.", "*", "E-mail:", "jianhanc@ksu.edu", "(JC);", "zolkiea@ksu.edu", "(AZ)", "Introduction", "Notch", "signaling", "is", "a", "highly", "conserved", "inter-cellular", "communi-", "cation", "pathway", "that", "plays", "critical", "roles", "in", "embryonic", "development", "and", "in", "tissue", "homeostasis", "[1–3].", "Abnormal", "Notch", "signaling", "is", "frequently", "associated", "with", "a", "number", "of", "human", "diseases,", "including", "T-cell", "acute", "lymphocytic", "leukemia", "(T-ALL)", "and", "solid", "tumors", "[4,5].", "At", "the", "heart", "of", "Notch", "signaling", "are", "the", "Notch", "receptors,", "a", "family", "of", "highly", "modular,", "single-pass", "transmembrane", "proteins", "[6,7].", "There", "are", "four", "Notch", "receptors", "in", "mammals,", "designated", "as", "Notch1–4.", "All", "Notch", "receptors", "have", "a", "similar", "modular", "architecture,", "as", "illustrated", "in", "Fig.", "1a", "for", "human", "Notch1.", "During", "maturation,", "the", "Notch", "receptor", "is", "cleaved", "at", "the", "S1", "site", "by", "a", "furin-like", "protease,", "which", "yields", "a", "heterodimer", "with", "non-covalently", "associated", "extracellular", "and", "transmembrane", "subunits", "[8,9].", "Canonical", "Notch", "activation", "is", "initiated", "by", "binding", "of", "a", "transmembrane", "ligand", "of", "the", "Delta/", "Serrate/LAG-2", "(DSL)", "family", "on", "the", "signal-sending", "cell", "to", "a", "Notch", "receptor", "on", "the", "surface", "of", "the", "signal", "receiving", "cell", "[2,6,7].", "Through", "mechanisms", "yet", "to", "be", "precisely", "determined,", "ligand", "engagement", "triggers", "regulated", "intra-membrane", "proteolysis", "where", "the", "Notch", "receptor", "is", "first", "cleaved", "at", "a", "juxtamembrane", "extracellular", "site", "S2", "by", "ADAM10", "or", "ADAM17", "metalloproteases", "[10–14].", "After", "the", "S2", "cleavage,", "the", "Notch", "receptor", "is", "further", "cleaved", "at", "an", "intra-", "membrane", "S3", "site", "by", "the", "c-secretase", "complex", "[15–17].", "The", "S3", "cleavage", "releases", "the", "intracellular", "portion", "of", "Notch", "(ICN)", "and", "allows", "it", "to", "translocate", "to", "the", "nucleus", "and", "participate", "in", "tran-", "scription", "regulation", "in", "a", "context", "and", "gene", "dose", "dependent", "manner", "[18,19].", "Important", "progresses", "have", "been", "made", "towards", "understanding", "a", "structural", "basis", "of", "Notch", "signaling", "and", "regulation", "[7,20].", "One", "of", "the", "key", "advances", "is", "the", "recent", "determination", "of", "high-resolution", "X-", "ray", "structures", "of", "the", "negative", "regulatory", "regions", "(NRR)", "of", "human", "Notch1", "and", "Notch2", "[21,22].", "The", "NRR", "consists", "of", "three", "Lin12/", "Notch", "repeats", "(LNR)", "and", "the", "heterodimerization", "(HD)", "domain.", "The", "later", "contains", "both", "the", "S1", "and", "S2", "sites", "near", "the", "middle", "and", "the", "C-terminus,", "respectively", "(Fig.", "1).", "The", "X-ray", "structure", "(Fig.", "1b)", "reveals", "that", "the", "NRR", "maintains", "an", "auto-inhibited,", "compact", "fold", "where", "the", "LNR", "modules", "wrap", "around", "the", "HD", "domain", "and", "shield", "the", "S2", "site", "from", "metalloprotease", "access.", "Clearly,", "large-scale", "conformational", "movements", "involving", "a", "displacement", "of", "LNR-A,", "the", "LNR-AB", "linker,", "and", "LNR-B", "from", "the", "HD", "domain", "are", "necessary", "for", "an", "ADAM", "protease", "to", "gain", "access", "to", "the", "S2", "site.", "Several", "models", "have", "been", "proposed", "to", "explain", "how", "ligand", "binding", "might", "facilitate", "large", "conformational", "changes", "within", "the", "NRR,", "PLoS", "ONE", "|", "www.plosone.org", "1", "July", "2011", "|", "Volume", "6", "|", "Issue", "7", "|", "e22837" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 18, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 70, 61, 39, 11 ], [ 111, 61, 48, 11 ], [ 161, 61, 56, 11 ], [ 70, 74, 70, 12 ], [ 142, 74, 73, 12 ], [ 217, 74, 17, 12 ], [ 236, 74, 49, 12 ], [ 287, 74, 42, 12 ], [ 70, 88, 35, 12 ], [ 107, 88, 25, 12 ], [ 133, 88, 30, 12 ], [ 166, 88, 12, 12 ], [ 180, 88, 35, 12 ], [ 217, 88, 6, 12 ], [ 225, 88, 25, 12 ], [ 70, 101, 115, 12 ], [ 70, 187, 83, 25 ], [ 158, 187, 64, 25 ], [ 70, 220, 17, 25 ], [ 91, 220, 85, 25 ], [ 181, 220, 74, 25 ], [ 259, 220, 128, 25 ], [ 392, 220, 120, 25 ], [ 516, 220, 62, 25 ], [ 583, 220, 75, 25 ], [ 70, 248, 149, 25 ], [ 224, 248, 62, 25 ], [ 290, 248, 134, 25 ], [ 429, 248, 40, 25 ], [ 474, 248, 121, 25 ], [ 600, 248, 135, 25 ], [ 70, 275, 86, 25 ], [ 161, 275, 120, 25 ], [ 286, 275, 100, 25 ], [ 391, 275, 106, 25 ], [ 120, 346, 36, 17 ], [ 159, 346, 15, 17 ], [ 177, 345, 68, 18 ], [ 247, 345, 6, 12 ], [ 256, 346, 72, 17 ], [ 331, 345, 42, 18 ], [ 377, 346, 47, 17 ], [ 426, 345, 53, 18 ], [ 483, 346, 41, 17 ], [ 527, 345, 35, 18 ], [ 566, 346, 70, 17 ], [ 639, 345, 55, 18 ], [ 120, 365, 31, 17 ], [ 154, 365, 46, 17 ], [ 203, 363, 50, 18 ], [ 256, 365, 34, 17 ], [ 292, 363, 93, 18 ], [ 389, 365, 47, 17 ], [ 440, 363, 37, 18 ], [ 480, 365, 57, 17 ], [ 539, 363, 40, 18 ], [ 583, 365, 27, 17 ], [ 613, 365, 32, 17 ], [ 648, 365, 15, 17 ], [ 666, 363, 88, 18 ], [ 120, 395, 4, 9 ], [ 126, 396, 40, 13 ], [ 168, 396, 50, 13 ], [ 220, 396, 59, 13 ], [ 282, 396, 9, 13 ], [ 294, 396, 48, 13 ], [ 344, 396, 30, 13 ], [ 376, 396, 44, 13 ], [ 423, 396, 56, 13 ], [ 481, 396, 44, 13 ], [ 120, 409, 4, 9 ], [ 126, 410, 36, 13 ], [ 164, 410, 9, 13 ], [ 176, 410, 36, 13 ], [ 215, 410, 58, 13 ], [ 275, 410, 19, 13 ], [ 297, 410, 38, 13 ], [ 337, 410, 39, 13 ], [ 379, 410, 52, 13 ], [ 434, 410, 21, 13 ], [ 457, 410, 19, 13 ], [ 478, 410, 33, 13 ], [ 513, 410, 56, 13 ], [ 571, 410, 21, 13 ], [ 594, 410, 27, 13 ], [ 624, 410, 44, 13 ], [ 120, 424, 4, 9 ], [ 126, 425, 41, 13 ], [ 170, 425, 9, 13 ], [ 181, 425, 38, 13 ], [ 222, 425, 48, 13 ], [ 272, 425, 32, 13 ], [ 306, 425, 9, 13 ], [ 318, 425, 33, 13 ], [ 354, 425, 42, 13 ], [ 398, 425, 31, 13 ], [ 431, 425, 52, 13 ], [ 486, 425, 56, 13 ], [ 544, 425, 44, 13 ], [ 120, 438, 4, 9 ], [ 126, 439, 49, 13 ], [ 178, 439, 38, 13 ], [ 218, 439, 44, 13 ], [ 265, 439, 57, 13 ], [ 324, 439, 10, 13 ], [ 336, 439, 34, 13 ], [ 373, 439, 41, 13 ], [ 416, 439, 43, 13 ], [ 462, 439, 24, 13 ], [ 488, 439, 44, 13 ], [ 120, 452, 4, 9 ], [ 126, 453, 43, 13 ], [ 172, 453, 41, 13 ], [ 215, 453, 9, 13 ], [ 227, 453, 78, 13 ], [ 307, 453, 48, 13 ], [ 358, 453, 50, 13 ], [ 410, 453, 9, 13 ], [ 422, 453, 39, 13 ], [ 463, 453, 37, 13 ], [ 503, 453, 37, 13 ], [ 542, 453, 44, 13 ], [ 120, 467, 4, 9 ], [ 126, 468, 41, 13 ], [ 169, 468, 9, 13 ], [ 181, 468, 42, 13 ], [ 226, 468, 19, 13 ], [ 247, 468, 67, 13 ], [ 317, 468, 36, 13 ], [ 355, 468, 25, 13 ], [ 383, 468, 76, 13 ], [ 461, 468, 62, 13 ], [ 526, 468, 39, 13 ], [ 568, 468, 30, 13 ], [ 120, 493, 82, 13 ], [ 205, 493, 35, 13 ], [ 241, 493, 12, 13 ], [ 256, 493, 49, 13 ], [ 308, 493, 11, 13 ], [ 321, 493, 25, 13 ], [ 348, 493, 11, 13 ], [ 362, 493, 43, 13 ], [ 408, 493, 118, 13 ], [ 120, 519, 44, 13 ], [ 166, 519, 13, 13 ], [ 181, 519, 51, 13 ], [ 235, 519, 28, 13 ], [ 265, 519, 45, 13 ], [ 313, 519, 12, 13 ], [ 328, 519, 35, 13 ], [ 365, 519, 25, 13 ], [ 120, 542, 51, 13 ], [ 174, 542, 9, 13 ], [ 186, 542, 25, 13 ], [ 213, 542, 25, 13 ], [ 241, 542, 11, 13 ], [ 255, 542, 40, 13 ], [ 297, 542, 10, 13 ], [ 309, 542, 12, 13 ], [ 326, 542, 22, 13 ], [ 353, 542, 8, 13 ], [ 366, 542, 13, 13 ], [ 384, 542, 25, 13 ], [ 414, 542, 30, 13 ], [ 449, 542, 31, 13 ], [ 485, 542, 55, 13 ], [ 545, 542, 30, 13 ], [ 580, 542, 16, 13 ], [ 601, 542, 41, 13 ], [ 648, 542, 53, 13 ], [ 705, 542, 57, 13 ], [ 120, 556, 40, 13 ], [ 164, 556, 31, 13 ], [ 197, 556, 39, 13 ], [ 239, 556, 60, 13 ], [ 303, 556, 20, 13 ], [ 326, 556, 63, 13 ], [ 393, 556, 19, 13 ], [ 415, 556, 66, 13 ], [ 485, 556, 11, 13 ], [ 499, 556, 18, 13 ], [ 520, 556, 46, 13 ], [ 569, 556, 45, 13 ], [ 618, 556, 16, 13 ], [ 637, 556, 40, 13 ], [ 680, 556, 26, 13 ], [ 709, 556, 8, 13 ], [ 720, 556, 43, 13 ], [ 120, 571, 27, 13 ], [ 120, 597, 56, 13 ], [ 179, 597, 46, 13 ], [ 227, 597, 50, 13 ], [ 280, 597, 45, 13 ], [ 327, 597, 35, 13 ], [ 365, 597, 41, 13 ], [ 409, 597, 48, 13 ], [ 460, 597, 11, 13 ], [ 473, 597, 16, 13 ], [ 492, 597, 41, 13 ], [ 535, 597, 68, 13 ], [ 605, 597, 23, 13 ], [ 631, 597, 43, 13 ], [ 677, 597, 10, 13 ], [ 690, 597, 19, 13 ], [ 711, 597, 34, 13 ], [ 748, 597, 15, 13 ], [ 120, 612, 72, 13 ], [ 195, 612, 35, 13 ], [ 232, 612, 38, 13 ], [ 272, 612, 32, 13 ], [ 306, 612, 16, 13 ], [ 324, 612, 43, 13 ], [ 368, 612, 11, 13 ], [ 381, 612, 60, 13 ], [ 443, 612, 81, 13 ], [ 526, 612, 20, 13 ], [ 548, 612, 15, 13 ], [ 566, 612, 41, 13 ], [ 609, 612, 10, 13 ], [ 622, 612, 21, 13 ], [ 645, 612, 6, 13 ], [ 652, 612, 20, 13 ], [ 674, 612, 11, 13 ], [ 687, 612, 77, 13 ], [ 120, 626, 9, 13 ], [ 132, 626, 40, 13 ], [ 175, 626, 49, 13 ], [ 228, 626, 16, 13 ], [ 247, 626, 53, 13 ], [ 303, 626, 23, 13 ], [ 328, 626, 26, 13 ], [ 357, 626, 25, 13 ], [ 385, 626, 35, 13 ], [ 423, 626, 10, 13 ], [ 436, 626, 16, 13 ], [ 455, 626, 65, 13 ], [ 524, 626, 30, 13 ], [ 557, 626, 54, 13 ], [ 614, 626, 26, 13 ], [ 643, 626, 40, 13 ], [ 686, 626, 32, 13 ], [ 722, 626, 42, 13 ], [ 120, 641, 39, 13 ], [ 162, 641, 29, 13 ], [ 194, 641, 35, 13 ], [ 231, 641, 70, 13 ], [ 304, 641, 29, 13 ], [ 336, 641, 64, 13 ], [ 402, 641, 19, 13 ], [ 424, 641, 58, 13 ], [ 484, 641, 67, 13 ], [ 553, 641, 17, 13 ], [ 573, 641, 24, 13 ], [ 600, 641, 23, 13 ], [ 625, 641, 11, 13 ], [ 639, 641, 31, 13 ], [ 672, 641, 15, 13 ], [ 690, 641, 16, 13 ], [ 708, 641, 55, 13 ], [ 120, 655, 19, 13 ], [ 142, 655, 66, 13 ], [ 209, 655, 11, 13 ], [ 222, 655, 28, 13 ], [ 253, 655, 44, 13 ], [ 299, 655, 53, 13 ], [ 353, 655, 19, 13 ], [ 375, 655, 35, 13 ], [ 412, 655, 35, 13 ], [ 449, 655, 23, 13 ], [ 474, 655, 48, 13 ], [ 525, 655, 20, 13 ], [ 547, 655, 19, 13 ], [ 568, 655, 59, 13 ], [ 629, 655, 38, 13 ], [ 669, 655, 24, 13 ], [ 695, 655, 68, 13 ], [ 120, 670, 19, 13 ], [ 143, 670, 45, 13 ], [ 193, 670, 46, 13 ], [ 242, 670, 56, 13 ], [ 302, 670, 8, 13 ], [ 315, 670, 37, 13 ], [ 356, 670, 35, 13 ], [ 395, 670, 27, 13 ], [ 426, 670, 61, 13 ], [ 490, 670, 94, 13 ], [ 589, 670, 27, 13 ], [ 620, 670, 19, 13 ], [ 643, 670, 53, 13 ], [ 700, 670, 11, 13 ], [ 714, 670, 29, 13 ], [ 747, 670, 16, 13 ], [ 120, 685, 31, 13 ], [ 154, 685, 11, 13 ], [ 166, 685, 16, 13 ], [ 185, 685, 16, 13 ], [ 203, 685, 14, 13 ], [ 219, 685, 26, 13 ], [ 247, 685, 35, 13 ], [ 284, 685, 11, 13 ], [ 297, 685, 28, 13 ], [ 326, 685, 65, 13 ], [ 394, 685, 17, 13 ], [ 413, 685, 45, 13 ], [ 460, 685, 56, 13 ], [ 519, 685, 55, 13 ], [ 575, 685, 41, 13 ], [ 619, 685, 17, 13 ], [ 638, 685, 45, 13 ], [ 685, 685, 56, 13 ], [ 744, 685, 19, 13 ], [ 120, 699, 56, 13 ], [ 180, 699, 17, 13 ], [ 201, 699, 38, 13 ], [ 243, 699, 63, 13 ], [ 310, 699, 11, 13 ], [ 324, 699, 60, 13 ], [ 388, 699, 23, 13 ], [ 415, 699, 76, 13 ], [ 495, 699, 110, 13 ], [ 608, 699, 52, 13 ], [ 665, 699, 50, 13 ], [ 719, 699, 44, 13 ], [ 120, 714, 61, 13 ], [ 184, 714, 19, 13 ], [ 207, 714, 71, 13 ], [ 281, 714, 44, 13 ], [ 328, 714, 19, 13 ], [ 351, 714, 36, 13 ], [ 390, 714, 34, 13 ], [ 428, 714, 27, 13 ], [ 458, 714, 60, 13 ], [ 522, 714, 24, 13 ], [ 549, 714, 61, 13 ], [ 613, 714, 11, 13 ], [ 627, 714, 29, 13 ], [ 659, 714, 49, 13 ], [ 712, 714, 12, 13 ], [ 726, 714, 37, 13 ], [ 120, 728, 15, 13 ], [ 139, 728, 12, 13 ], [ 155, 728, 33, 13 ], [ 191, 728, 52, 13 ], [ 246, 728, 23, 13 ], [ 273, 728, 16, 13 ], [ 292, 728, 19, 13 ], [ 315, 728, 51, 13 ], [ 369, 728, 23, 13 ], [ 395, 728, 6, 13 ], [ 405, 728, 56, 13 ], [ 463, 728, 53, 13 ], [ 519, 728, 42, 13 ], [ 565, 728, 11, 13 ], [ 579, 728, 42, 13 ], [ 625, 728, 22, 13 ], [ 650, 728, 45, 13 ], [ 698, 728, 7, 13 ], [ 709, 729, 8, 12 ], [ 720, 728, 20, 13 ], [ 744, 728, 19, 13 ], [ 120, 743, 51, 13 ], [ 174, 743, 28, 13 ], [ 203, 743, 45, 13 ], [ 251, 743, 7, 13 ], [ 261, 743, 8, 12 ], [ 271, 743, 29, 13 ], [ 303, 743, 29, 13 ], [ 335, 743, 19, 13 ], [ 356, 743, 14, 13 ], [ 373, 743, 53, 13 ], [ 427, 743, 35, 13 ], [ 465, 743, 11, 13 ], [ 479, 743, 25, 13 ], [ 506, 743, 44, 13 ], [ 552, 743, 25, 13 ], [ 580, 743, 22, 13 ], [ 605, 743, 43, 13 ], [ 651, 743, 25, 13 ], [ 678, 743, 40, 13 ], [ 721, 743, 28, 13 ], [ 752, 743, 11, 13 ], [ 120, 757, 51, 13 ], [ 173, 757, 37, 13 ], [ 212, 757, 27, 13 ], [ 241, 757, 19, 13 ], [ 262, 757, 36, 13 ], [ 300, 757, 37, 13 ], [ 339, 757, 31, 13 ], [ 373, 757, 17, 13 ], [ 392, 757, 18, 13 ], [ 411, 757, 27, 13 ], [ 440, 757, 41, 13 ], [ 484, 757, 16, 13 ], [ 502, 757, 29, 13 ], [ 533, 757, 19, 13 ], [ 554, 757, 16, 13 ], [ 572, 757, 37, 13 ], [ 610, 757, 38, 13 ], [ 650, 757, 29, 13 ], [ 682, 757, 24, 13 ], [ 707, 757, 14, 13 ], [ 723, 757, 40, 13 ], [ 120, 772, 40, 13 ], [ 162, 772, 11, 13 ], [ 176, 772, 60, 13 ], [ 238, 772, 45, 13 ], [ 286, 772, 41, 13 ], [ 330, 772, 30, 13 ], [ 363, 772, 33, 13 ], [ 398, 772, 36, 13 ], [ 437, 772, 20, 13 ], [ 460, 772, 19, 13 ], [ 481, 772, 32, 13 ], [ 516, 772, 46, 13 ], [ 565, 772, 22, 13 ], [ 589, 772, 52, 13 ], [ 644, 772, 10, 13 ], [ 657, 772, 16, 13 ], [ 676, 772, 65, 13 ], [ 744, 772, 11, 13 ], [ 757, 772, 6, 13 ], [ 120, 786, 27, 13 ], [ 150, 786, 47, 13 ], [ 200, 786, 11, 13 ], [ 213, 786, 72, 13 ], [ 287, 786, 19, 13 ], [ 309, 786, 52, 13 ], [ 70, 847, 13, 17 ], [ 86, 847, 93, 17 ], [ 70, 880, 63, 14 ], [ 139, 880, 50, 14 ], [ 196, 880, 56, 14 ], [ 258, 880, 46, 14 ], [ 310, 880, 17, 14 ], [ 334, 880, 46, 14 ], [ 386, 880, 18, 14 ], [ 70, 896, 41, 14 ], [ 114, 896, 14, 14 ], [ 130, 896, 18, 14 ], [ 151, 896, 46, 14 ], [ 199, 896, 72, 14 ], [ 273, 896, 47, 14 ], [ 323, 896, 12, 14 ], [ 337, 896, 67, 14 ], [ 70, 912, 89, 14 ], [ 166, 912, 22, 14 ], [ 196, 912, 17, 14 ], [ 221, 912, 46, 14 ], [ 274, 912, 12, 14 ], [ 293, 912, 23, 14 ], [ 324, 912, 6, 14 ], [ 338, 912, 22, 14 ], [ 367, 912, 12, 14 ], [ 386, 912, 18, 14 ], [ 70, 928, 52, 14 ], [ 128, 928, 12, 14 ], [ 145, 928, 18, 14 ], [ 168, 928, 82, 14 ], [ 255, 928, 44, 14 ], [ 305, 928, 33, 14 ], [ 344, 928, 17, 14 ], [ 366, 928, 38, 14 ], [ 70, 944, 43, 14 ], [ 119, 944, 12, 14 ], [ 135, 944, 39, 14 ], [ 179, 944, 53, 14 ], [ 237, 944, 53, 14 ], [ 295, 944, 57, 14 ], [ 357, 944, 47, 14 ], [ 70, 960, 21, 14 ], [ 96, 960, 95, 14 ], [ 196, 960, 66, 14 ], [ 267, 960, 52, 14 ], [ 324, 960, 21, 14 ], [ 349, 960, 22, 14 ], [ 376, 960, 28, 14 ], [ 70, 975, 57, 14 ], [ 134, 975, 50, 14 ], [ 190, 975, 56, 14 ], [ 252, 975, 47, 14 ], [ 305, 975, 12, 14 ], [ 323, 975, 81, 14 ], [ 70, 991, 38, 14 ], [ 112, 991, 12, 14 ], [ 127, 991, 13, 14 ], [ 145, 991, 67, 14 ], [ 215, 991, 19, 14 ], [ 238, 991, 50, 14 ], [ 292, 991, 63, 14 ], [ 358, 991, 46, 14 ], [ 70, 1007, 15, 14 ], [ 92, 1007, 63, 14 ], [ 161, 1007, 19, 14 ], [ 186, 1007, 42, 14 ], [ 234, 1007, 65, 14 ], [ 305, 1007, 21, 14 ], [ 333, 1007, 46, 14 ], [ 385, 1007, 19, 14 ], [ 428, 849, 50, 14 ], [ 485, 849, 63, 14 ], [ 553, 849, 65, 14 ], [ 624, 849, 37, 14 ], [ 668, 849, 30, 14 ], [ 704, 849, 12, 14 ], [ 722, 849, 41, 14 ], [ 428, 864, 7, 14 ], [ 442, 864, 26, 14 ], [ 474, 864, 27, 14 ], [ 507, 864, 34, 14 ], [ 547, 864, 12, 14 ], [ 565, 864, 13, 14 ], [ 585, 864, 55, 14 ], [ 646, 864, 12, 14 ], [ 665, 864, 52, 14 ], [ 723, 864, 21, 14 ], [ 751, 864, 12, 14 ], [ 428, 880, 80, 14 ], [ 511, 880, 35, 14 ], [ 549, 880, 15, 14 ], [ 568, 880, 16, 14 ], [ 586, 880, 53, 14 ], [ 642, 880, 12, 14 ], [ 657, 880, 41, 14 ], [ 700, 880, 62, 14 ], [ 428, 896, 21, 14 ], [ 455, 896, 34, 14 ], [ 496, 896, 12, 14 ], [ 514, 896, 54, 14 ], [ 574, 896, 21, 14 ], [ 602, 896, 55, 14 ], [ 663, 896, 26, 14 ], [ 695, 896, 27, 14 ], [ 728, 896, 34, 14 ], [ 428, 912, 12, 14 ], [ 447, 912, 40, 14 ], [ 494, 912, 80, 14 ], [ 582, 912, 39, 14 ], [ 628, 912, 39, 14 ], [ 674, 912, 21, 14 ], [ 703, 912, 12, 14 ], [ 722, 912, 41, 14 ], [ 428, 928, 42, 14 ], [ 476, 928, 21, 14 ], [ 504, 928, 21, 14 ], [ 532, 928, 12, 14 ], [ 550, 928, 44, 14 ], [ 601, 928, 25, 14 ], [ 633, 928, 32, 14 ], [ 672, 928, 50, 14 ], [ 729, 928, 33, 14 ], [ 428, 943, 39, 14 ], [ 474, 943, 40, 14 ], [ 521, 943, 30, 14 ], [ 558, 943, 12, 14 ], [ 577, 943, 55, 14 ], [ 639, 943, 38, 14 ], [ 684, 943, 12, 14 ], [ 703, 943, 35, 14 ], [ 744, 943, 18, 14 ], [ 428, 959, 43, 14 ], [ 475, 959, 12, 14 ], [ 492, 959, 47, 14 ], [ 543, 959, 81, 14 ], [ 629, 959, 21, 14 ], [ 654, 959, 51, 14 ], [ 710, 959, 24, 14 ], [ 738, 959, 13, 14 ], [ 756, 959, 6, 14 ], [ 428, 975, 30, 14 ], [ 461, 975, 41, 14 ], [ 505, 975, 40, 14 ], [ 549, 975, 17, 14 ], [ 568, 975, 52, 14 ], [ 623, 975, 85, 14 ], [ 711, 975, 28, 14 ], [ 742, 975, 8, 14 ], [ 753, 975, 9, 14 ], [ 428, 991, 40, 14 ], [ 472, 991, 54, 14 ], [ 530, 991, 12, 14 ], [ 546, 991, 82, 14 ], [ 632, 991, 43, 14 ], [ 679, 991, 17, 14 ], [ 700, 991, 21, 14 ], [ 726, 991, 36, 14 ], [ 428, 1007, 30, 14 ], [ 463, 1007, 17, 14 ], [ 484, 1007, 56, 14 ], [ 545, 1007, 25, 14 ], [ 575, 1007, 52, 14 ], [ 631, 1007, 21, 14 ], [ 657, 1007, 12, 14 ], [ 672, 1007, 50, 14 ], [ 727, 1007, 35, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "Evidence-Based", "Complementary", "and", "Alternative", "Medicine", "Volume", "2011,", "Article", "ID", "790784,", "6", "pages", "doi:10.1093/ecam/nen060", "Original", "Article", "A", "Chinese", "Herbal", "Preparation", "Containing", "Radix", "Salviae", "Miltiorrhizae,", "Radix", "Notoginseng", "and", "Borneolum", "Syntheticum", "Reduces", "Circulating", "Adhesion", "Molecules", "Kylie", "A.", "O’Brien,1,", "2", "Shanhong", "Ling,1", "Estelle", "Abbas,1", "Aozhi", "Dai,1", "Jiansheng", "Zhang,3", "Wen", "Cheng", "Wang,4", "Alan", "Bensoussan,5", "Ruizhi", "Luo,6", "Zhi-Xin", "Guo,6", "and", "Paul", "A.", "Komesaroff1", "1", "Monash", "University", "Department", "of", "Medicine,", "Alfred", "Hospital,", "Melbourne,", "Australia", "2", "Faculty", "of", "Health,", "Engineering", "and", "Science,", "Victoria", "University,", "P.O.", "Box", "14428,", "Melbourne,", "VIC", "8001,", "Australia", "3", "Division", "of", "Chinese", "Medicine,", "School", "of", "Health", "Sciences,", "RMIT", "University,", "Melbourne,", "Australia", "4", "Registered", "Chinese", "medicine", "practitioner", "in", "private", "practice,", "Prahran,", "VIC,", "Australia", "5", "National", "Institute", "of", "Complementary", "Medicine,", "University", "of", "Western", "Sydney,", "Sydney,", "Australia", "6", "Institute", "of", "Research", "and", "Development,", "Tianjin", "Tasly", "Pharmaceutical", "Corporation,", "Tianjin,", "China", "Correspondence", "should", "be", "addressed", "to", "Kylie", "A.", "O’Brien,", "kylie.obrien@vu.edu.au", "Received", "13", "December", "2007;", "Accepted", "21", "August", "2008", "Copyright", "©", "2011", "Kylie", "A.", "O’Brien", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Circulating", "adhesion", "molecules", "(CAMs),", "surface", "proteins", "expressed", "in", "the", "vascular", "endothelium,", "have", "emerged", "as", "risk", "factors", "for", "cardiovascular", "disease", "(CVD).", "CAMs", "are", "involved", "in", "intercellular", "communication", "that", "are", "believed", "to", "play", "a", "role", "in", "atherosclerosis.", "A", "Chinese", "medicine,", "the", "“Dantonic", "Pill”", "(DP)", "(also", "known", "as", "the", "“Cardiotonic", "Pill”),", "containing", "three", "Chinese", "herbal", "material", "medica,", "Radix", "Salviae", "Miltiorrhizae,", "Radix", "Notoginseng", "and", "Borneolum", "Syntheticum,", "has", "been", "used", "in", "China", "for", "the", "prevention", "and", "management", "of", "CVD.", "Previous", "laboratory", "and", "animal", "studies", "have", "suggested", "that", "this", "preparation", "reduces", "both", "atherogenesis", "and", "adhesion", "molecule", "expression.", "A", "parallel", "double", "blind", "randomized", "placebo-controlled", "study", "was", "conducted", "to", "assess", "the", "effects", "of", "the", "DP", "on", "three", "species", "of", "CAM", "(intercellular", "cell", "adhesion", "molecule-1", "(ICAM-1),", "vascular", "cell", "adhesion", "molecule-1", "and", "endothelial", "cell", "selectin", "(E-selectin))", "in", "participants", "with", "mild-moderate", "hypercholesterolemia.", "Secondary", "endpoints", "included", "biochemical", "and", "hematological", "variables", "and", "clinical", "effects.", "Forty", "participants", "were", "randomized", "to", "either", "treatment", "or", "control", "for", "12", "weeks.", "Treatment", "with", "DP", "was", "associated", "with", "a", "statistically", "significant", "decrease", "in", "ICAM-1", "(9%", "decrease,", "P", "=", ".03)", "and", "E-Selectin", "(15%", "decrease,", "P", "=", ".004).", "There", "was", "no", "significant", "change", "in", "renal", "function", "tests,", "liver", "function", "tests,", "glucose,", "lipids", "or", "C-reactive", "protein", "levels", "and", "clinical", "adverse", "effects", "did", "not", "differ", "between", "the", "active", "and", "the", "control", "groups.", "There", "were", "no", "relevant", "changes", "in", "participants", "receiving", "placebo.", "These", "results", "suggest", "that", "this", "herbal", "medicine", "may", "contribute", "to", "the", "development", "of", "a", "novel", "approach", "to", "cardiovascular", "risk", "reduction.", "1.", "Introduction", "Circulating", "adhesion", "molecules", "(CAMs)", "are", "proteins", "ex-", "pressed", "by", "the", "vascular", "endothelium", "involved", "in", "intercellular", "communication", "that", "are", "believed", "to", "play", "a", "role", "in", "the", "initiation", "of", "the", "atherosclerotic", "process.", "There", "are", "several", "families", "of", "CAMs,", "including", "integrins,", "cadherins,", "selectins", "and", "immunoglobulin", "superfamily", "members", "[1].", "The", "most", "important", "adhesion", "molecules", "involved", "in", "atherosclerosis", "appear", "to", "be", "intercellular", "cell", "adhesion", "molecule-1", "(ICAM-", "1),", "endothelial", "cell", "selectin", "(E-selectin)", "and", "vascular", "cell", "adhesion", "molecule-1", "(VCAM-1).", "Raised", "levels", "of", "ICAM-", "1", "have", "been", "found", "to", "be", "predictive", "of", "increased", "risk", "of", "cardiovascular", "events", "[2,", "3],", "including", "in", "healthy", "individuals", "[4].", "Levels", "of", "P-selectin", "and", "E-selectin", "have", "been", "found", "to", "predict", "cardiovascular", "disease", "(CVD)", "risk", "in", "healthy", "women", "[5],", "and", "in", "patients", "with", "stable", "coronary", "artery", "disease", "plasma", "levels", "of", "E-selectin", "appear", "to", "reflect", "the", "severity", "of", "systemic", "atherosclerosis", "[6].", "VCAM-1", "may", "be", "a", "more", "specific", "marker", "for", "advanced", "atherosclerosis,", "since", "it", "is", "usually", "expressed", "in", "atherosclerotic", "plaques", "[7]", "and", "higher", "levels", "are", "associated", "with", "increased", "risk", "of", "coronary", "events" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 59, 43, 63, 14 ], [ 135, 43, 44, 14 ], [ 183, 43, 32, 14 ], [ 221, 43, 57, 14 ], [ 283, 43, 32, 14 ], [ 320, 43, 25, 14 ], [ 350, 43, 18, 14 ], [ 373, 43, 22, 14 ], [ 400, 43, 14, 14 ], [ 59, 58, 142, 14 ], [ 572, 43, 56, 14 ], [ 633, 43, 35, 14 ], [ 673, 43, 14, 14 ], [ 693, 43, 47, 14 ], [ 745, 43, 28, 14 ], [ 59, 101, 87, 28 ], [ 156, 101, 16, 28 ], [ 183, 101, 203, 28 ], [ 397, 101, 80, 28 ], [ 488, 101, 118, 28 ], [ 616, 101, 37, 28 ], [ 664, 101, 88, 28 ], [ 59, 131, 113, 28 ], [ 182, 131, 50, 28 ], [ 243, 131, 97, 28 ], [ 350, 131, 132, 28 ], [ 493, 131, 60, 28 ], [ 564, 131, 129, 28 ], [ 703, 131, 59, 28 ], [ 59, 162, 148, 28 ], [ 217, 162, 56, 28 ], [ 284, 162, 59, 28 ], [ 59, 203, 46, 17 ], [ 111, 200, 87, 20 ], [ 204, 203, 72, 17 ], [ 282, 200, 70, 20 ], [ 358, 203, 48, 17 ], [ 412, 200, 64, 20 ], [ 482, 203, 74, 17 ], [ 563, 203, 20, 17 ], [ 589, 200, 60, 20 ], [ 59, 226, 76, 17 ], [ 141, 223, 70, 20 ], [ 217, 225, 20, 18 ], [ 236, 226, 17, 17 ], [ 259, 223, 65, 20 ], [ 331, 226, 30, 17 ], [ 367, 226, 46, 17 ], [ 419, 226, 47, 17 ], [ 472, 225, 28, 18 ], [ 499, 223, 73, 20 ], [ 59, 258, 63, 17 ], [ 127, 261, 63, 14 ], [ 195, 261, 43, 14 ], [ 243, 261, 27, 14 ], [ 276, 261, 42, 14 ], [ 323, 261, 50, 14 ], [ 378, 261, 17, 14 ], [ 400, 261, 43, 14 ], [ 448, 261, 84, 14 ], [ 537, 258, 67, 17 ], [ 610, 261, 53, 14 ], [ 668, 261, 42, 14 ], [ 715, 261, 17, 14 ], [ 59, 277, 69, 14 ], [ 132, 277, 87, 14 ], [ 224, 277, 58, 14 ], [ 287, 275, 51, 17 ], [ 344, 277, 61, 14 ], [ 410, 277, 49, 14 ], [ 464, 277, 53, 14 ], [ 522, 277, 58, 14 ], [ 585, 275, 80, 17 ], [ 669, 277, 12, 14 ], [ 687, 277, 61, 14 ], [ 59, 294, 54, 14 ], [ 118, 294, 27, 14 ], [ 150, 294, 42, 14 ], [ 197, 294, 50, 14 ], [ 252, 294, 17, 14 ], [ 274, 294, 43, 14 ], [ 322, 294, 84, 14 ], [ 412, 294, 54, 14 ], [ 470, 294, 53, 14 ], [ 529, 291, 79, 17 ], [ 613, 294, 17, 14 ], [ 635, 294, 84, 14 ], [ 59, 311, 60, 14 ], [ 123, 311, 61, 14 ], [ 190, 311, 50, 14 ], [ 245, 311, 54, 14 ], [ 303, 311, 49, 14 ], [ 358, 311, 24, 14 ], [ 386, 308, 58, 17 ], [ 449, 311, 45, 14 ], [ 499, 311, 54, 14 ], [ 558, 311, 49, 14 ], [ 59, 346, 46, 12 ], [ 109, 346, 22, 12 ], [ 135, 346, 16, 12 ], [ 154, 346, 28, 12 ], [ 186, 346, 40, 12 ], [ 230, 346, 35, 12 ], [ 270, 346, 16, 12 ], [ 289, 346, 28, 12 ], [ 321, 346, 48, 12 ], [ 374, 346, 55, 12 ], [ 433, 346, 16, 12 ], [ 453, 346, 25, 12 ], [ 59, 394, 75, 14 ], [ 59, 417, 78, 14 ], [ 145, 417, 66, 14 ], [ 219, 417, 30, 14 ], [ 256, 417, 44, 14 ], [ 307, 417, 40, 14 ], [ 355, 417, 12, 14 ], [ 375, 417, 28, 14 ], [ 59, 433, 38, 14 ], [ 108, 433, 21, 14 ], [ 141, 433, 51, 14 ], [ 204, 433, 14, 14 ], [ 229, 433, 45, 14 ], [ 286, 433, 19, 14 ], [ 316, 433, 85, 14 ], [ 59, 450, 101, 14 ], [ 167, 450, 48, 14 ], [ 223, 450, 28, 14 ], [ 258, 450, 41, 14 ], [ 307, 450, 63, 14 ], [ 377, 450, 25, 14 ], [ 59, 467, 91, 14 ], [ 155, 467, 14, 14 ], [ 173, 467, 62, 14 ], [ 240, 467, 60, 14 ], [ 305, 467, 25, 14 ], [ 336, 467, 30, 14 ], [ 370, 467, 32, 14 ], [ 59, 483, 33, 14 ], [ 99, 483, 33, 14 ], [ 138, 483, 29, 14 ], [ 174, 483, 16, 14 ], [ 198, 483, 97, 14 ], [ 302, 483, 35, 14 ], [ 345, 483, 58, 14 ], [ 59, 500, 24, 14 ], [ 90, 500, 33, 14 ], [ 130, 500, 62, 14 ], [ 200, 500, 16, 14 ], [ 223, 500, 79, 14 ], [ 310, 500, 69, 14 ], [ 386, 500, 16, 14 ], [ 59, 516, 8, 14 ], [ 77, 516, 59, 14 ], [ 146, 516, 26, 14 ], [ 181, 516, 19, 14 ], [ 210, 516, 34, 14 ], [ 254, 516, 35, 14 ], [ 299, 516, 35, 14 ], [ 344, 516, 58, 14 ], [ 59, 533, 63, 14 ], [ 129, 533, 22, 14 ], [ 157, 533, 34, 14 ], [ 199, 533, 57, 14 ], [ 263, 533, 14, 14 ], [ 284, 533, 52, 14 ], [ 343, 533, 59, 14 ], [ 59, 550, 35, 14 ], [ 102, 550, 65, 14 ], [ 174, 550, 30, 14 ], [ 212, 550, 24, 14 ], [ 244, 550, 53, 14 ], [ 305, 550, 67, 14 ], [ 380, 550, 22, 14 ], [ 59, 566, 86, 14 ], [ 150, 566, 14, 14 ], [ 170, 566, 102, 14 ], [ 278, 566, 25, 14 ], [ 309, 566, 51, 14 ], [ 367, 566, 35, 14 ], [ 59, 583, 73, 14 ], [ 145, 583, 73, 14 ], [ 232, 583, 10, 14 ], [ 255, 583, 28, 14 ], [ 297, 583, 52, 14 ], [ 362, 583, 40, 14 ], [ 59, 599, 35, 14 ], [ 105, 599, 33, 14 ], [ 149, 599, 34, 14 ], [ 194, 599, 47, 14 ], [ 252, 599, 27, 14 ], [ 290, 599, 87, 14 ], [ 388, 599, 14, 14 ], [ 59, 616, 50, 14 ], [ 114, 616, 8, 14 ], [ 127, 616, 46, 14 ], [ 179, 616, 102, 14 ], [ 286, 616, 28, 14 ], [ 319, 616, 59, 14 ], [ 383, 616, 19, 14 ], [ 59, 633, 17, 14 ], [ 81, 633, 14, 14 ], [ 100, 633, 34, 14 ], [ 138, 633, 44, 14 ], [ 188, 633, 67, 14 ], [ 260, 633, 69, 14 ], [ 335, 633, 14, 14 ], [ 353, 633, 49, 14 ], [ 59, 649, 35, 14 ], [ 101, 649, 72, 14 ], [ 180, 649, 31, 14 ], [ 219, 649, 21, 14 ], [ 248, 649, 60, 14 ], [ 315, 649, 55, 14 ], [ 377, 649, 25, 14 ], [ 59, 666, 54, 14 ], [ 120, 666, 61, 14 ], [ 188, 666, 17, 14 ], [ 212, 666, 72, 14 ], [ 291, 666, 22, 14 ], [ 319, 666, 57, 14 ], [ 383, 666, 19, 14 ], [ 59, 682, 72, 14 ], [ 135, 682, 34, 14 ], [ 174, 682, 8, 14 ], [ 187, 682, 25, 14 ], [ 217, 682, 21, 14 ], [ 242, 682, 14, 14 ], [ 260, 682, 65, 14 ], [ 329, 682, 73, 14 ], [ 59, 699, 70, 14 ], [ 138, 699, 80, 14 ], [ 228, 699, 32, 14 ], [ 269, 699, 53, 14 ], [ 332, 699, 70, 14 ], [ 59, 716, 99, 14 ], [ 168, 716, 25, 14 ], [ 204, 716, 21, 14 ], [ 236, 716, 37, 14 ], [ 283, 716, 42, 14 ], [ 336, 716, 66, 14 ], [ 59, 732, 95, 14 ], [ 172, 732, 87, 14 ], [ 276, 732, 25, 14 ], [ 319, 732, 83, 14 ], [ 59, 749, 65, 14 ], [ 126, 749, 57, 14 ], [ 187, 749, 74, 14 ], [ 265, 749, 29, 14 ], [ 296, 749, 30, 14 ], [ 329, 749, 22, 14 ], [ 354, 749, 48, 14 ], [ 59, 765, 19, 14 ], [ 81, 765, 65, 14 ], [ 150, 765, 17, 14 ], [ 170, 765, 22, 14 ], [ 195, 765, 40, 14 ], [ 239, 765, 56, 14 ], [ 298, 765, 12, 14 ], [ 314, 765, 21, 14 ], [ 339, 765, 63, 14 ], [ 59, 782, 31, 14 ], [ 95, 782, 61, 14 ], [ 161, 782, 75, 14 ], [ 241, 782, 28, 14 ], [ 274, 782, 29, 14 ], [ 308, 782, 48, 14 ], [ 361, 782, 41, 14 ], [ 59, 799, 20, 14 ], [ 83, 799, 42, 14 ], [ 129, 799, 72, 14 ], [ 205, 799, 53, 14 ], [ 261, 799, 19, 14 ], [ 284, 799, 56, 14 ], [ 344, 799, 59, 14 ], [ 59, 815, 33, 14 ], [ 104, 815, 54, 14 ], [ 170, 815, 25, 14 ], [ 207, 815, 39, 14 ], [ 259, 815, 45, 14 ], [ 315, 815, 25, 14 ], [ 353, 815, 16, 14 ], [ 380, 815, 22, 14 ], [ 59, 832, 102, 14 ], [ 172, 832, 31, 14 ], [ 214, 832, 57, 14 ], [ 283, 832, 28, 14 ], [ 323, 832, 16, 14 ], [ 350, 832, 52, 14 ], [ 59, 848, 59, 14 ], [ 122, 848, 35, 14 ], [ 163, 848, 72, 14 ], [ 240, 848, 43, 14 ], [ 288, 848, 30, 14 ], [ 323, 848, 23, 14 ], [ 352, 848, 50, 14 ], [ 59, 865, 33, 14 ], [ 98, 865, 53, 14 ], [ 157, 865, 19, 14 ], [ 182, 865, 77, 14 ], [ 265, 865, 62, 14 ], [ 333, 865, 25, 14 ], [ 365, 865, 37, 14 ], [ 59, 882, 52, 14 ], [ 114, 882, 59, 14 ], [ 176, 882, 62, 14 ], [ 241, 882, 49, 14 ], [ 293, 882, 16, 14 ], [ 312, 882, 51, 14 ], [ 367, 882, 35, 14 ], [ 59, 898, 37, 14 ], [ 103, 898, 23, 14 ], [ 129, 898, 23, 14 ], [ 160, 898, 72, 14 ], [ 240, 898, 29, 14 ], [ 276, 898, 26, 14 ], [ 310, 898, 23, 14 ], [ 335, 898, 23, 14 ], [ 366, 898, 36, 14 ], [ 59, 915, 50, 14 ], [ 112, 915, 25, 14 ], [ 141, 915, 16, 14 ], [ 159, 915, 23, 14 ], [ 187, 915, 34, 14 ], [ 225, 915, 50, 14 ], [ 278, 915, 47, 14 ], [ 429, 392, 108, 14 ], [ 429, 415, 51, 14 ], [ 485, 415, 15, 14 ], [ 504, 415, 19, 14 ], [ 527, 415, 63, 14 ], [ 595, 415, 41, 14 ], [ 640, 415, 13, 14 ], [ 657, 415, 24, 14 ], [ 686, 415, 23, 14 ], [ 713, 415, 39, 14 ], [ 756, 415, 17, 14 ], [ 429, 430, 14, 14 ], [ 452, 430, 31, 14 ], [ 492, 430, 22, 14 ], [ 523, 430, 23, 14 ], [ 554, 430, 27, 14 ], [ 590, 430, 16, 14 ], [ 615, 430, 48, 14 ], [ 671, 430, 15, 14 ], [ 695, 430, 31, 14 ], [ 735, 430, 38, 14 ], [ 429, 446, 75, 14 ], [ 515, 446, 23, 14 ], [ 549, 446, 34, 14 ], [ 594, 446, 34, 14 ], [ 639, 446, 19, 14 ], [ 669, 446, 60, 14 ], [ 740, 446, 33, 14 ], [ 429, 461, 48, 14 ], [ 486, 461, 53, 14 ], [ 548, 461, 20, 14 ], [ 577, 461, 28, 14 ], [ 614, 461, 65, 14 ], [ 689, 461, 13, 14 ], [ 710, 461, 19, 14 ], [ 738, 461, 35, 14 ], [ 429, 477, 56, 14 ], [ 494, 477, 18, 14 ], [ 520, 477, 19, 14 ], [ 548, 477, 76, 14 ], [ 632, 477, 13, 14 ], [ 653, 477, 19, 14 ], [ 680, 477, 61, 14 ], [ 750, 477, 23, 14 ], [ 429, 492, 46, 14 ], [ 481, 492, 13, 14 ], [ 500, 492, 95, 14 ], [ 601, 492, 31, 14 ], [ 638, 492, 39, 14 ], [ 683, 492, 19, 14 ], [ 709, 492, 31, 14 ], [ 746, 492, 27, 14 ], [ 429, 508, 21, 14 ], [ 452, 508, 21, 14 ], [ 479, 508, 48, 14 ], [ 532, 508, 53, 14 ], [ 591, 508, 32, 14 ], [ 628, 508, 23, 14 ], [ 656, 508, 29, 14 ], [ 691, 508, 45, 14 ], [ 741, 508, 32, 14 ], [ 429, 523, 23, 14 ], [ 459, 523, 33, 14 ], [ 499, 523, 39, 14 ], [ 544, 523, 58, 14 ], [ 609, 523, 20, 14 ], [ 636, 523, 18, 14 ], [ 661, 523, 63, 14 ], [ 731, 523, 42, 14 ], [ 429, 539, 61, 14 ], [ 500, 539, 58, 14 ], [ 567, 539, 23, 14 ], [ 599, 539, 70, 14 ], [ 679, 539, 51, 14 ], [ 740, 539, 33, 14 ], [ 429, 555, 14, 14 ], [ 448, 555, 71, 14 ], [ 525, 555, 13, 14 ], [ 542, 555, 22, 14 ], [ 569, 555, 63, 14 ], [ 637, 555, 38, 14 ], [ 681, 555, 13, 14 ], [ 699, 555, 39, 14 ], [ 743, 555, 30, 14 ], [ 429, 570, 19, 14 ], [ 456, 570, 76, 14 ], [ 540, 570, 13, 14 ], [ 561, 570, 19, 14 ], [ 589, 570, 31, 14 ], [ 628, 570, 51, 14 ], [ 687, 570, 28, 14 ], [ 723, 570, 23, 14 ], [ 754, 570, 19, 14 ], [ 429, 586, 50, 14 ], [ 484, 586, 13, 14 ], [ 502, 586, 14, 14 ], [ 521, 586, 61, 14 ], [ 587, 586, 58, 14 ], [ 650, 586, 36, 14 ], [ 690, 586, 31, 14 ], [ 726, 586, 27, 14 ], [ 759, 586, 14, 14 ], [ 429, 601, 31, 14 ], [ 466, 601, 22, 14 ], [ 493, 601, 20, 14 ], [ 518, 601, 23, 14 ], [ 547, 601, 51, 14 ], [ 603, 601, 28, 14 ], [ 636, 601, 33, 14 ], [ 675, 601, 7, 14 ], [ 687, 601, 55, 14 ], [ 748, 601, 25, 14 ], [ 429, 617, 51, 14 ], [ 485, 617, 23, 14 ], [ 513, 617, 7, 14 ], [ 525, 617, 28, 14 ], [ 557, 617, 41, 14 ], [ 602, 617, 13, 14 ], [ 620, 617, 64, 14 ], [ 688, 617, 51, 14 ], [ 743, 617, 30, 14 ], [ 429, 632, 28, 14 ], [ 461, 632, 43, 14 ], [ 508, 632, 7, 14 ], [ 519, 632, 52, 14 ], [ 575, 632, 56, 14 ], [ 635, 632, 81, 14 ], [ 719, 632, 19, 14 ], [ 742, 632, 31, 14 ], [ 429, 648, 42, 14 ], [ 477, 648, 51, 14 ], [ 533, 648, 64, 14 ], [ 603, 648, 63, 14 ], [ 672, 648, 64, 14 ], [ 742, 648, 31, 14 ], [ 429, 664, 32, 14 ], [ 469, 664, 18, 14 ], [ 496, 664, 32, 14 ], [ 536, 664, 23, 14 ], [ 567, 664, 29, 14 ], [ 604, 664, 45, 14 ], [ 657, 664, 48, 14 ], [ 713, 664, 36, 14 ], [ 757, 664, 16, 14 ], [ 429, 679, 53, 14 ], [ 488, 679, 41, 14 ], [ 536, 679, 77, 14 ], [ 618, 679, 65, 14 ], [ 689, 679, 23, 14 ], [ 717, 679, 19, 14 ], [ 742, 679, 31, 14 ], [ 429, 695, 45, 14 ], [ 477, 695, 18, 14 ], [ 498, 695, 9, 14 ], [ 510, 695, 10, 14 ], [ 522, 695, 54, 14 ], [ 579, 695, 57, 14 ], [ 639, 695, 24, 14 ], [ 666, 695, 19, 14 ], [ 688, 695, 31, 14 ], [ 722, 695, 51, 14 ], [ 429, 710, 28, 14 ], [ 460, 710, 23, 14 ], [ 486, 710, 14, 14 ], [ 504, 710, 58, 14 ], [ 565, 710, 19, 14 ], [ 587, 710, 58, 14 ], [ 648, 710, 62, 14 ], [ 714, 710, 15, 14 ], [ 732, 710, 41, 14 ], [ 429, 726, 56, 14 ], [ 490, 726, 30, 14 ], [ 525, 726, 29, 14 ], [ 559, 726, 56, 14 ], [ 619, 726, 23, 14 ], [ 647, 726, 53, 14 ], [ 705, 726, 14, 14 ], [ 723, 726, 50, 14 ], [ 429, 741, 13, 14 ], [ 447, 741, 19, 14 ], [ 471, 741, 31, 14 ], [ 507, 741, 60, 14 ], [ 573, 741, 30, 14 ], [ 608, 741, 19, 14 ], [ 632, 741, 54, 14 ], [ 691, 741, 30, 14 ], [ 726, 741, 47, 14 ], [ 429, 757, 46, 14 ], [ 485, 757, 36, 14 ], [ 530, 757, 13, 14 ], [ 552, 757, 7, 14 ], [ 569, 757, 16, 14 ], [ 595, 757, 13, 14 ], [ 617, 757, 45, 14 ], [ 671, 757, 60, 14 ], [ 740, 757, 33, 14 ], [ 429, 773, 53, 14 ], [ 487, 773, 23, 14 ], [ 515, 773, 59, 14 ], [ 580, 773, 61, 14 ], [ 647, 773, 19, 14 ], [ 671, 773, 59, 14 ], [ 734, 773, 39, 14 ], [ 429, 788, 56, 14 ], [ 494, 788, 12, 14 ], [ 515, 788, 19, 14 ], [ 542, 788, 62, 14 ], [ 613, 788, 13, 14 ], [ 634, 788, 30, 14 ], [ 672, 788, 100, 14 ], [ 429, 804, 103, 14 ], [ 536, 804, 20, 14 ], [ 561, 804, 19, 14 ], [ 585, 804, 65, 14 ], [ 654, 804, 56, 14 ], [ 715, 804, 42, 14 ], [ 762, 804, 11, 14 ], [ 429, 819, 153, 14 ], [ 586, 819, 12, 14 ], [ 601, 819, 57, 14 ], [ 662, 819, 30, 14 ], [ 695, 819, 62, 14 ], [ 761, 819, 12, 14 ], [ 429, 835, 27, 14 ], [ 464, 835, 52, 14 ], [ 523, 835, 20, 14 ], [ 550, 835, 45, 14 ], [ 603, 835, 23, 14 ], [ 633, 835, 19, 14 ], [ 659, 835, 65, 14 ], [ 731, 835, 41, 14 ], [ 429, 850, 160, 14 ], [ 596, 850, 67, 14 ], [ 669, 850, 15, 14 ], [ 690, 850, 19, 14 ], [ 715, 850, 58, 14 ], [ 429, 866, 51, 14 ], [ 486, 866, 53, 14 ], [ 544, 866, 69, 14 ], [ 618, 866, 12, 14 ], [ 635, 866, 55, 14 ], [ 696, 866, 21, 14 ], [ 722, 866, 27, 14 ], [ 754, 866, 19, 14 ], [ 429, 881, 26, 14 ], [ 458, 881, 47, 14 ], [ 508, 881, 28, 14 ], [ 538, 881, 12, 14 ], [ 553, 881, 27, 14 ], [ 583, 881, 22, 14 ], [ 608, 881, 22, 14 ], [ 633, 881, 39, 14 ], [ 674, 881, 46, 14 ], [ 723, 881, 20, 14 ], [ 746, 881, 27, 14 ], [ 429, 897, 12, 14 ], [ 447, 897, 19, 14 ], [ 471, 897, 46, 14 ], [ 523, 897, 13, 14 ], [ 541, 897, 62, 14 ], [ 609, 897, 42, 14 ], [ 656, 897, 43, 14 ], [ 705, 897, 68, 14 ], [ 429, 913, 23, 14 ], [ 456, 913, 41, 14 ], [ 501, 913, 69, 14 ], [ 575, 913, 58, 14 ], [ 636, 913, 19, 14 ], [ 659, 913, 31, 14 ], [ 695, 913, 42, 14 ], [ 740, 913, 10, 14 ], [ 754, 913, 19, 14 ], [ 59, 953, 20, 12 ], [ 82, 953, 30, 12 ], [ 116, 953, 74, 12 ], [ 194, 953, 32, 12 ], [ 230, 953, 11, 12 ], [ 245, 953, 50, 12 ], [ 299, 953, 19, 12 ], [ 322, 953, 23, 12 ], [ 348, 953, 17, 12 ], [ 369, 953, 42, 12 ], [ 415, 953, 22, 12 ], [ 441, 953, 23, 12 ], [ 468, 953, 17, 12 ], [ 489, 953, 42, 12 ], [ 535, 953, 31, 12 ], [ 570, 953, 98, 12 ], [ 59, 978, 19, 11 ], [ 81, 978, 37, 11 ], [ 122, 978, 22, 11 ], [ 147, 978, 7, 11 ], [ 159, 978, 10, 11 ], [ 173, 978, 11, 11 ], [ 188, 978, 33, 11 ], [ 225, 978, 22, 11 ], [ 251, 978, 10, 11 ], [ 265, 978, 22, 11 ], [ 291, 978, 40, 11 ], [ 335, 978, 15, 11 ], [ 354, 978, 19, 11 ], [ 378, 978, 18, 11 ], [ 400, 978, 37, 11 ], [ 440, 978, 32, 11 ], [ 477, 978, 11, 11 ], [ 492, 978, 42, 11 ], [ 538, 978, 10, 11 ], [ 552, 978, 22, 11 ], [ 579, 978, 23, 11 ], [ 605, 978, 43, 11 ], [ 70, 1003, 21, 11 ], [ 94, 1003, 18, 11 ], [ 115, 1003, 44, 11 ], [ 59, 1016, 20, 11 ], [ 81, 1016, 7, 11 ], [ 91, 1016, 11, 11 ], [ 104, 1016, 24, 11 ], [ 131, 1016, 30, 11 ], [ 164, 1016, 28, 11 ], [ 194, 1016, 48, 11 ], [ 245, 1016, 26, 11 ], [ 274, 1016, 14, 11 ], [ 291, 1016, 25, 11 ], [ 318, 1016, 10, 11 ], [ 330, 1016, 14, 11 ], [ 347, 1016, 38, 11 ], [ 387, 1016, 46, 11 ], [ 436, 1016, 51, 11 ], [ 490, 1016, 78, 11 ], [ 570, 1016, 33, 11 ], [ 606, 1016, 167, 11 ], [ 59, 1029, 64, 11 ], [ 125, 1029, 27, 11 ], [ 155, 1029, 34, 11 ], [ 191, 1029, 53, 11 ], [ 247, 1029, 72, 11 ], [ 323, 1029, 18, 11 ], [ 343, 1029, 55, 11 ], [ 401, 1029, 17, 11 ], [ 422, 1029, 58, 11 ], [ 483, 1029, 9, 11 ], [ 495, 1029, 17, 11 ], [ 514, 1029, 39, 11 ], [ 556, 1029, 40, 11 ], [ 599, 1029, 14, 11 ], [ 617, 1029, 35, 11 ], [ 654, 1029, 23, 11 ], [ 681, 1029, 7, 11 ], [ 691, 1029, 38, 11 ], [ 732, 1029, 24, 11 ] ]

[ "7188–7196", "Nucleic", "Acids", "Research,", "2007,", "Vol.", "35,", "No.", "21", "doi:10.1093/nar/gkm864", "Published", "online", "18", "October", "2007", "SILVA:", "a", "comprehensive", "online", "resource", "for", "quality", "checked", "and", "aligned", "ribosomal", "RNA", "sequence", "data", "compatible", "with", "ARB", "Elmar", "Pruesse1,2,", "Christian", "Quast1,3,", "Katrin", "Knittel4,", "Bernhard", "M.", "Fuchs4,", "Wolfgang", "Ludwig5,", "Jo¨", "rg", "Peplies6", "and", "Frank", "Oliver", "Glo¨", "ckner1,3,*", "1Microbial", "Genomics", "Group,", "Max", "Planck", "Institute", "for", "Marine", "Microbiology,", "2University", "Bremen,", "Center", "for", "Computing", "Technologies,", "D-28359,", "3Jacobs", "University", "Bremen", "gGmbH,", "D-28759,", "4Department", "of", "Molecular", "Ecology,", "Max", "Planck", "Institute", "for", "Marine", "Microbiology,", "D-28359", "Bremen,", "5Department", "for", "Microbiology,", "Technical", "University", "Munich,", "D-85354", "Freising", "and", "6Ribocon", "GmbH,", "D-28359", "Bremen", "Received", "May", "26,", "2007;", "Revised", "August", "18,", "2007;", "Accepted", "September", "14,", "2007", "ABSTRACT", "Sequencing", "ribosomal", "RNA", "(rRNA)", "genes", "is", "cur-", "rently", "the", "method", "of", "choice", "for", "phylogenetic", "reconstruction,", "nucleic", "acid", "based", "detection", "and", "quantification", "of", "microbial", "diversity.", "The", "ARB", "soft-", "ware", "suite", "with", "its", "corresponding", "rRNA", "datasets", "has", "been", "accepted", "by", "researchers", "worldwide", "as", "a", "standard", "tool", "for", "large", "scale", "rRNA", "analysis.", "However,", "the", "rapid", "increase", "of", "publicly", "available", "rRNA", "sequence", "data", "has", "recently", "hampered", "the", "maintenance", "of", "comprehensive", "and", "curated", "rRNA", "knowledge", "databases.", "A", "new", "system,", "SILVA", "(from", "Latin", "silva,", "forest),", "was", "implemented", "to", "provide", "a", "central", "comprehensive", "web", "resource", "for", "up", "to", "date,", "quality", "controlled", "databases", "of", "aligned", "rRNA", "sequences", "from", "the", "Bacteria,", "Archaea", "and", "Eukarya", "domains.", "All", "sequences", "are", "checked", "for", "anomalies,", "carry", "a", "rich", "set", "of", "sequence", "associated", "contextual", "information,", "have", "multiple", "taxonomic", "classifications,", "and", "the", "latest", "validly", "described", "nomenclature.", "Furthermore,", "two", "precompiled", "sequence", "datasets", "compatible", "with", "ARB", "are", "offered", "for", "download", "on", "the", "SILVA", "website:", "(i)", "the", "reference", "(Ref)", "datasets,", "comprising", "only", "high", "quality,", "nearly", "full", "length", "sequences", "suitable", "for", "in-depth", "phyloge-", "netic", "analysis", "and", "probe", "design", "and", "(ii)", "the", "comprehensive", "Parc", "datasets", "with", "all", "publicly", "available", "rRNA", "sequences", "longer", "than", "300", "nucleo-", "tides", "suitable", "for", "biodiversity", "analyses.", "The", "latest", "publicly", "available", "database", "release", "91", "(August", "2007)", "hosts", "547", "521", "sequences", "split", "into", "461", "823", "small", "subunit", "and", "85", "689", "large", "subunit", "rRNAs.", "INTRODUCTION", "Initiated", "by", "the", "pioneering", "studies", "of", "Fox", "and", "Woese", "(1)", "30", "years", "ago", "and", "later", "on", "pursued", "by", "Pace,", "Olsen,", "Giovannoni,", "and", "Ward", "(2–5),", "the", "ribosomal", "RNA", "(rRNA)", "molecule", "has", "been", "established", "as", "the", "‘gold-", "standard’", "for", "the", "investigation", "of", "the", "phylogeny", "and", "ecology", "of", "microorganisms", "(6,7).", "Today", "the", "more", "than", "500", "000", "publicly", "available", "small", "and", "large", "subunit", "(SSU", "and", "LSU)", "rRNA", "sequences", "ask", "for", "specialized", "quality", "controlled", "databases", "and", "appropriate", "software", "tools.", "In", "anticipation", "of", "this", "impending", "deluge", "of", "rRNA", "data,", "the", "development", "of", "the", "ARB", "software", "suite", "and", "the", "curation", "of", "its", "associated", "databases", "began", "more", "than", "12", "years", "ago", "(8).", "The", "software", "suite", "offers", "a", "graphical", "user", "interface", "and", "a", "wide", "variety", "of", "interacting", "software", "tools", "built", "around", "a", "common", "database.", "Furthermore,", "the", "ARB", "project", "provides", "structured,", "integrative", "knowledge", "data-", "bases", "for", "small", "and", "large", "subunit", "rRNAs.", "Based", "on", "regularly", "offered", "international", "workshops", "and", "the", "ARB", "mailing", "list", "it", "is", "currently", "estimated", "that", "the", "ARB", "software", "suite", "and", "its", "databases", "are", "employed", "worldwide", "by", "several", "thousand", "users", "from", "academia", "and", "industry.", "In", "addition", "to", "the", "ARB", "approach,", "there", "are", "currently", "three", "projects", "offering", "access", "to", "a", "set", "of", "curated", "ribosomal", "RNA", "sequence", "and", "alignment", "databases:", "the", "European", "rRNA", "databank", "at", "the", "University", "of", "Gent", "(http://www.psb.", "ugent.be/rRNA/)", "(9),", "the", "Ribosomal", "Database", "Project", "II", "(http://rdp.cme.msu.edu/)", "at", "Michigan", "State", "University", "in", "East", "Lansing,", "MI", "(10,11),", "and", "the", "greengenes", "project", "(http://greengenes.lbl.gov/)", "maintained", "by", "the", "Lawrence", "Berkeley", "National", "Laboratory", "in", "Berkeley,", "CA", "(12).", "All", "four", "projects", "offer", "at", "least", "one", "16S", "rRNA", "dataset,", "but", "vary", "in", "the", "amount", "of", "sequences,", "quality", "checks,", "alignments,", "and", "update", "procedures.", "However,", "the", "ARB", "project", "is", "the", "*To", "whom", "correspondence", "should", "be", "addressed.", "Tel:", "+49", "421", "2028970;", "Fax:", "+49", "421", "2028580;", "Email:", "fog@mpi-bremen.de", "The", "authors", "wish", "it", "to", "be", "known", "that,", "in", "their", "opinion,", "the", "first", "two", "authors", "should", "be", "regarded", "as", "joint", "First", "Authors.", "2007", "The", "Author(s)", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/", "by-nc/2.0/uk/)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 68, 74, 52, 17 ], [ 124, 74, 38, 17 ], [ 166, 74, 21, 17 ], [ 191, 74, 94, 17 ], [ 289, 74, 167, 17 ], [ 654, 100, 39, 14 ], [ 696, 100, 55, 14 ], [ 622, 114, 136, 45 ], [ 645, 161, 38, 17 ], [ 686, 161, 73, 17 ], [ 545, 180, 213, 17 ], [ 68, 215, 46, 17 ], [ 68, 253, 63, 25 ], [ 137, 253, 21, 25 ], [ 164, 253, 34, 25 ], [ 204, 253, 118, 25 ], [ 328, 253, 45, 25 ], [ 379, 253, 60, 25 ], [ 445, 253, 77, 25 ], [ 528, 253, 61, 25 ], [ 595, 253, 92, 25 ], [ 68, 281, 73, 25 ], [ 147, 281, 103, 25 ], [ 256, 281, 32, 25 ], [ 294, 281, 162, 25 ], [ 461, 281, 123, 25 ], [ 590, 281, 41, 25 ], [ 636, 281, 96, 25 ], [ 68, 310, 84, 25 ], [ 68, 359, 81, 17 ], [ 153, 359, 51, 17 ], [ 208, 359, 27, 17 ], [ 239, 359, 40, 17 ], [ 283, 359, 28, 17 ], [ 315, 359, 9, 17 ], [ 68, 399, 47, 17 ], [ 119, 399, 14, 17 ], [ 137, 399, 80, 17 ], [ 220, 399, 25, 17 ], [ 249, 399, 108, 17 ], [ 360, 399, 86, 17 ], [ 450, 399, 59, 17 ], [ 513, 399, 58, 17 ], [ 574, 399, 75, 17 ], [ 653, 399, 98, 17 ], [ 68, 423, 87, 17 ], [ 159, 423, 95, 17 ], [ 257, 423, 46, 17 ], [ 307, 423, 52, 17 ], [ 363, 423, 158, 17 ], [ 68, 463, 9, 17 ], [ 88, 463, 48, 17 ], [ 139, 463, 13, 17 ], [ 156, 463, 42, 17 ], [ 202, 463, 105, 17 ], [ 311, 463, 45, 17 ], [ 360, 463, 16, 17 ], [ 380, 463, 71, 17 ], [ 454, 463, 52, 17 ], [ 510, 463, 154, 17 ], [ 88, 486, 31, 17 ], [ 123, 486, 123, 17 ], [ 250, 486, 30, 17 ], [ 284, 486, 122, 17 ], [ 68, 527, 66, 17 ], [ 138, 527, 9, 17 ], [ 150, 527, 69, 17 ], [ 223, 527, 40, 17 ], [ 266, 527, 14, 17 ], [ 284, 527, 49, 17 ], [ 336, 527, 37, 17 ], [ 377, 527, 17, 17 ], [ 398, 527, 69, 17 ], [ 470, 527, 34, 17 ], [ 508, 527, 5, 17 ], [ 517, 527, 67, 17 ], [ 588, 527, 17, 17 ], [ 609, 527, 69, 17 ], [ 681, 527, 34, 17 ], [ 719, 527, 5, 17 ], [ 68, 550, 73, 17 ], [ 145, 550, 9, 17 ], [ 157, 550, 69, 17 ], [ 230, 550, 34, 17 ], [ 107, 617, 68, 17 ], [ 183, 617, 40, 17 ], [ 230, 617, 26, 17 ], [ 264, 617, 51, 17 ], [ 323, 617, 21, 17 ], [ 351, 617, 29, 17 ], [ 388, 617, 61, 17 ], [ 456, 617, 33, 17 ], [ 497, 617, 30, 17 ], [ 535, 617, 22, 17 ], [ 565, 617, 62, 17 ], [ 634, 617, 32, 17 ], [ 674, 617, 25, 17 ], [ 706, 617, 13, 17 ], [ 107, 640, 49, 17 ], [ 161, 640, 52, 17 ], [ 217, 640, 55, 17 ], [ 276, 640, 25, 17 ], [ 305, 640, 63, 17 ], [ 372, 640, 59, 17 ], [ 435, 640, 38, 17 ], [ 478, 640, 24, 17 ], [ 506, 640, 10, 17 ], [ 520, 640, 12, 17 ], [ 536, 640, 61, 17 ], [ 601, 640, 66, 17 ], [ 670, 640, 20, 17 ], [ 694, 640, 26, 17 ], [ 107, 664, 38, 17 ], [ 155, 664, 13, 17 ], [ 178, 664, 72, 17 ], [ 259, 664, 71, 17 ], [ 339, 664, 25, 17 ], [ 373, 664, 62, 17 ], [ 444, 664, 22, 17 ], [ 475, 664, 73, 17 ], [ 558, 664, 75, 17 ], [ 641, 664, 14, 17 ], [ 664, 664, 55, 17 ], [ 107, 688, 82, 17 ], [ 194, 688, 25, 17 ], [ 223, 688, 54, 17 ], [ 282, 688, 30, 17 ], [ 316, 688, 47, 17 ], [ 368, 688, 31, 17 ], [ 403, 688, 13, 17 ], [ 421, 688, 36, 17 ], [ 462, 688, 13, 17 ], [ 480, 688, 36, 17 ], [ 520, 688, 35, 17 ], [ 559, 688, 67, 17 ], [ 631, 688, 14, 17 ], [ 650, 688, 25, 17 ], [ 679, 688, 41, 17 ], [ 107, 711, 20, 17 ], [ 132, 711, 56, 17 ], [ 193, 711, 31, 17 ], [ 229, 711, 8, 17 ], [ 241, 711, 75, 17 ], [ 320, 711, 17, 17 ], [ 342, 711, 72, 17 ], [ 419, 711, 8, 17 ], [ 432, 711, 71, 17 ], [ 507, 711, 25, 17 ], [ 537, 711, 32, 17 ], [ 574, 711, 47, 17 ], [ 626, 711, 41, 17 ], [ 671, 711, 48, 17 ], [ 107, 735, 38, 17 ], [ 150, 735, 64, 17 ], [ 219, 735, 46, 17 ], [ 270, 735, 64, 17 ], [ 339, 735, 75, 17 ], [ 419, 735, 13, 17 ], [ 437, 735, 21, 17 ], [ 463, 735, 22, 17 ], [ 490, 735, 59, 17 ], [ 554, 735, 24, 17 ], [ 583, 735, 50, 17 ], [ 638, 735, 25, 17 ], [ 669, 735, 8, 17 ], [ 682, 735, 38, 17 ], [ 107, 758, 24, 17 ], [ 142, 758, 45, 17 ], [ 198, 758, 100, 17 ], [ 308, 758, 71, 17 ], [ 390, 758, 45, 17 ], [ 445, 758, 16, 17 ], [ 471, 758, 57, 17 ], [ 539, 758, 17, 17 ], [ 566, 758, 25, 17 ], [ 602, 758, 38, 17 ], [ 651, 758, 14, 17 ], [ 675, 758, 45, 17 ], [ 107, 782, 97, 17 ], [ 214, 782, 25, 17 ], [ 248, 782, 41, 17 ], [ 299, 782, 79, 17 ], [ 388, 782, 41, 17 ], [ 439, 782, 32, 17 ], [ 481, 782, 29, 17 ], [ 520, 782, 29, 17 ], [ 559, 782, 66, 17 ], [ 635, 782, 22, 17 ], [ 666, 782, 30, 17 ], [ 706, 782, 13, 17 ], [ 107, 806, 75, 17 ], [ 186, 806, 21, 17 ], [ 212, 806, 26, 17 ], [ 242, 806, 32, 17 ], [ 279, 806, 21, 17 ], [ 304, 806, 21, 17 ], [ 330, 806, 32, 17 ], [ 367, 806, 33, 17 ], [ 404, 806, 49, 17 ], [ 458, 806, 21, 17 ], [ 483, 806, 36, 17 ], [ 524, 806, 22, 17 ], [ 551, 806, 27, 17 ], [ 583, 806, 59, 17 ], [ 646, 806, 21, 17 ], [ 672, 806, 48, 17 ], [ 107, 829, 14, 17 ], [ 130, 829, 26, 17 ], [ 163, 829, 32, 17 ], [ 203, 829, 58, 17 ], [ 269, 829, 14, 17 ], [ 290, 829, 47, 17 ], [ 344, 829, 65, 17 ], [ 417, 829, 14, 17 ], [ 440, 829, 59, 17 ], [ 507, 829, 58, 17 ], [ 572, 829, 24, 17 ], [ 604, 829, 16, 17 ], [ 628, 829, 91, 17 ], [ 107, 853, 68, 17 ], [ 180, 853, 38, 17 ], [ 222, 853, 17, 17 ], [ 244, 853, 59, 17 ], [ 307, 853, 85, 17 ], [ 396, 853, 74, 17 ], [ 475, 853, 41, 17 ], [ 520, 853, 21, 17 ], [ 545, 853, 50, 17 ], [ 599, 853, 19, 17 ], [ 623, 853, 17, 17 ], [ 644, 853, 25, 17 ], [ 673, 853, 8, 17 ], [ 685, 853, 34, 17 ], [ 107, 876, 41, 17 ], [ 154, 876, 48, 17 ], [ 208, 876, 14, 17 ], [ 227, 876, 40, 17 ], [ 273, 876, 14, 17 ], [ 293, 876, 69, 17 ], [ 368, 876, 32, 17 ], [ 406, 876, 51, 17 ], [ 463, 876, 35, 17 ], [ 503, 876, 30, 17 ], [ 539, 876, 88, 17 ], [ 633, 876, 29, 17 ], [ 668, 876, 51, 17 ], [ 107, 900, 29, 17 ], [ 140, 900, 55, 17 ], [ 199, 900, 73, 17 ], [ 275, 900, 25, 17 ], [ 304, 900, 56, 17 ], [ 363, 900, 31, 17 ], [ 398, 900, 47, 17 ], [ 449, 900, 52, 17 ], [ 505, 900, 25, 17 ], [ 533, 900, 71, 17 ], [ 608, 900, 26, 17 ], [ 637, 900, 32, 17 ], [ 672, 900, 47, 17 ], [ 107, 924, 24, 17 ], [ 136, 924, 51, 17 ], [ 191, 924, 8, 17 ], [ 204, 924, 58, 17 ], [ 266, 924, 30, 17 ], [ 301, 924, 79, 17 ], [ 385, 924, 61, 17 ], [ 450, 924, 33, 17 ], [ 487, 924, 97, 17 ], [ 589, 924, 46, 17 ], [ 639, 924, 25, 17 ], [ 669, 924, 21, 17 ], [ 694, 924, 26, 17 ], [ 107, 947, 32, 17 ], [ 147, 947, 48, 17 ], [ 202, 947, 55, 17 ], [ 264, 947, 41, 17 ], [ 313, 947, 12, 17 ], [ 333, 947, 60, 17 ], [ 400, 947, 13, 17 ], [ 421, 947, 51, 17 ], [ 480, 947, 79, 17 ], [ 567, 947, 48, 17 ], [ 622, 947, 13, 17 ], [ 643, 947, 44, 17 ], [ 695, 947, 25, 17 ], [ 107, 971, 72, 17 ], [ 183, 971, 52, 17 ], [ 239, 971, 48, 17 ], [ 290, 971, 63, 17 ], [ 357, 971, 20, 17 ], [ 381, 971, 26, 17 ], [ 410, 971, 32, 17 ], [ 446, 971, 67, 17 ], [ 107, 1011, 78, 17 ], [ 189, 1011, 42, 17 ], [ 235, 1011, 75, 17 ], [ 314, 1011, 77, 17 ], [ 395, 1011, 26, 17 ], [ 425, 1011, 26, 17 ], [ 454, 1011, 32, 17 ] ]

[ "Sensors", "2010,", "10,", "10752-10777;", "doi:10.3390/s101210752", "OPEN", "ACCESS", "sensors", "ISSN", "1424-8220", "www.mdpi.com/journal/sensors", "Article", "Study", "of", "the", "Ubiquitous", "Hog", "Farm", "System", "Using", "Wireless", "Sensor", "Networks", "for", "Environmental", "Monitoring", "and", "Facilities", "Control", "Jeonghwan", "Hwang", "and", "Hyun", "Yoe", "*", "School", "of", "Information", "and", "Communication", "Engineering,", "Sunchon", "National", "University,", "Maegok-dong,", "Suncheon-si,", "Jeollanam-do,", "Korea;", "E-Mail:", "jhwang@sunchon.ac.kr", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "yhyun@sunchon.ac.kr;", "Tel.:", "+82-61-750-3591;", "Fax:", "+82-61-750-3590.", "Received:", "2", "November", "2010;", "in", "revised", "form:", "16", "November", "2010", "/", "Accepted:", "26", "November", "2010", "/", "Published:", "2", "December", "2010", "Abstract:", "Many", "hog", "farmers", "are", "now", "suffering", "from", "high", "pig", "mortality", "rates", "due", "to", "various", "wasting", "diseases", "and", "increased", "breeding", "costs,", "etc.", "It", "is", "therefore", "necessary", "for", "hog", "farms", "to", "implement", "systematic", "and", "scientific", "pig", "production", "technology", "to", "increase", "productivity", "and", "produce", "high", "quality", "pork", "in", "order", "to", "solve", "these", "problems.", "In", "this", "study,", "we", "describe", "such", "a", "technology", "by", "suggesting", "a", "ubiquitous", "hog", "farm", "system", "which", "applies", "WSN", "(Wireless", "Sensor", "Network)", "technology", "to", "the", "pig", "industry.", "We", "suggest", "that", "a", "WSN", "and", "CCTV", "(Closed-circuit", "television)", "should", "be", "installed", "on", "hog", "farms", "to", "collect", "environmental", "and", "image", "information", "which", "shall", "then", "help", "producers", "not", "only", "in", "monitoring", "the", "hog", "farm", "via", "the", "Web", "from", "outside", "the", "farm,", "but", "also", "facilitate", "the", "control", "of", "hog", "farm", "facilities", "in", "remote", "locations.", "In", "addition,", "facilities", "can", "be", "automatically", "controlled", "based", "on", "breeding", "environment", "parameters", "which", "are", "already", "set", "up", "and", "a", "SMS", "notice", "service", "to", "notify", "of", "deviations", "shall", "provide", "users", "with", "convenience.", "Hog", "farmers", "may", "increase", "production", "and", "improve", "pork", "quality", "through", "this", "ubiquitous", "hog", "farm", "system", "and", "prepare", "a", "database", "with", "information", "collected", "from", "environmental", "factors", "and", "the", "hog", "farm", "control", "devices,", "which", "is", "expected", "to", "provide", "information", "needed", "to", "design", "and", "implement", "suitable", "control", "strategies", "for", "hog", "farm", "operation.", "Keywords:", "WSN;", "ubiquitous;", "agriculture;", "pig;", "hog", "farm" ]

[ 0, 0, 0, 0, 0, 9, 9, 1, 0, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17 ]

[ [ 78, 47, 48, 12 ], [ 130, 47, 9, 12 ], [ 142, 47, 11, 12 ], [ 156, 47, 50, 12 ], [ 209, 47, 40, 12 ], [ 252, 47, 25, 12 ], [ 280, 47, 32, 12 ], [ 78, 61, 228, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 49, 34 ], [ 137, 169, 219, 34 ], [ 366, 169, 60, 34 ], [ 436, 169, 20, 34 ], [ 466, 169, 149, 34 ], [ 625, 169, 114, 34 ], [ 78, 205, 28, 34 ], [ 116, 205, 209, 34 ], [ 335, 205, 128, 34 ], [ 78, 252, 48, 16 ], [ 130, 252, 9, 16 ], [ 143, 252, 62, 16 ], [ 210, 252, 26, 16 ], [ 240, 252, 37, 16 ], [ 282, 252, 23, 16 ], [ 309, 252, 26, 16 ], [ 339, 249, 34, 18 ], [ 87, 306, 54, 15 ], [ 87, 331, 76, 14 ], [ 167, 331, 45, 14 ], [ 216, 331, 54, 14 ], [ 274, 331, 8, 14 ], [ 286, 331, 53, 14 ], [ 344, 331, 11, 14 ], [ 358, 331, 19, 14 ], [ 381, 331, 92, 14 ], [ 478, 331, 28, 14 ], [ 510, 331, 52, 14 ], [ 566, 331, 70, 14 ], [ 640, 331, 47, 14 ], [ 691, 331, 17, 14 ], [ 713, 331, 19, 14 ], [ 87, 348, 23, 14 ], [ 115, 348, 67, 14 ], [ 186, 348, 49, 14 ], [ 239, 348, 17, 14 ], [ 261, 348, 78, 14 ], [ 343, 348, 22, 14 ], [ 370, 348, 31, 14 ], [ 405, 348, 11, 14 ], [ 420, 348, 31, 14 ], [ 455, 348, 47, 14 ], [ 506, 348, 7, 14 ], [ 518, 348, 22, 14 ], [ 543, 348, 10, 14 ], [ 557, 348, 31, 14 ], [ 592, 348, 11, 14 ], [ 608, 348, 24, 14 ], [ 635, 348, 22, 14 ], [ 661, 348, 55, 16 ], [ 87, 365, 25, 14 ], [ 116, 365, 28, 14 ], [ 149, 365, 47, 14 ], [ 200, 365, 11, 14 ], [ 215, 365, 19, 14 ], [ 238, 365, 25, 14 ], [ 267, 365, 11, 14 ], [ 283, 365, 45, 14 ], [ 332, 365, 25, 14 ], [ 361, 365, 71, 14 ], [ 436, 365, 41, 14 ], [ 481, 365, 48, 14 ], [ 533, 365, 54, 14 ], [ 591, 365, 29, 14 ], [ 624, 365, 17, 14 ], [ 645, 365, 52, 14 ], [ 701, 365, 22, 14 ], [ 87, 381, 22, 14 ], [ 113, 381, 12, 14 ], [ 129, 381, 42, 14 ], [ 175, 381, 60, 14 ], [ 240, 381, 50, 14 ], [ 294, 381, 33, 14 ], [ 331, 381, 19, 14 ], [ 354, 381, 92, 14 ], [ 450, 381, 25, 14 ], [ 480, 381, 35, 14 ], [ 520, 381, 15, 14 ], [ 538, 381, 62, 14 ], [ 605, 381, 47, 14 ], [ 656, 381, 12, 14 ], [ 672, 381, 35, 14 ], [ 87, 398, 53, 14 ], [ 145, 398, 56, 14 ], [ 87, 418, 84, 14 ], [ 176, 418, 29, 14 ], [ 208, 418, 24, 14 ], [ 236, 418, 28, 14 ], [ 268, 418, 47, 14 ], [ 320, 418, 12, 14 ], [ 336, 418, 37, 14 ], [ 377, 418, 49, 14 ], [ 430, 418, 36, 14 ], [ 471, 418, 40, 14 ], [ 515, 418, 38, 14 ], [ 557, 418, 28, 16 ], [ 590, 418, 26, 14 ], [ 620, 418, 12, 14 ], [ 636, 418, 54, 14 ], [ 694, 418, 39, 14 ], [ 87, 435, 77, 14 ], [ 168, 435, 21, 14 ], [ 194, 435, 44, 14 ], [ 242, 435, 7, 14 ], [ 254, 435, 44, 14 ], [ 302, 435, 65, 14 ], [ 372, 435, 11, 14 ], [ 386, 435, 49, 14 ], [ 439, 435, 36, 14 ], [ 480, 435, 47, 14 ], [ 531, 435, 25, 14 ], [ 560, 435, 45, 14 ], [ 610, 435, 28, 14 ], [ 642, 435, 50, 14 ], [ 696, 435, 27, 14 ], [ 87, 452, 118, 14 ], [ 210, 452, 22, 14 ], [ 236, 452, 92, 14 ], [ 332, 452, 45, 14 ], [ 381, 452, 22, 14 ], [ 407, 452, 47, 14 ], [ 458, 452, 12, 14 ], [ 474, 452, 22, 14 ], [ 500, 452, 12, 14 ], [ 516, 452, 35, 14 ], [ 555, 452, 15, 14 ], [ 575, 452, 15, 14 ], [ 594, 452, 12, 14 ], [ 610, 452, 14, 14 ], [ 628, 452, 34, 14 ], [ 666, 452, 29, 14 ], [ 87, 468, 45, 14 ], [ 136, 468, 28, 14 ], [ 168, 468, 54, 14 ], [ 227, 468, 21, 14 ], [ 253, 468, 31, 14 ], [ 287, 468, 11, 14 ], [ 303, 468, 33, 14 ], [ 340, 468, 54, 14 ], [ 398, 468, 21, 14 ], [ 424, 468, 54, 14 ], [ 482, 468, 28, 14 ], [ 514, 468, 55, 14 ], [ 573, 468, 27, 14 ], [ 604, 468, 31, 14 ], [ 639, 468, 39, 14 ], [ 87, 489, 46, 14 ], [ 137, 489, 26, 14 ], [ 168, 489, 49, 14 ], [ 221, 489, 36, 14 ], [ 262, 489, 38, 14 ], [ 304, 489, 21, 14 ], [ 329, 489, 28, 16 ], [ 362, 489, 28, 14 ], [ 394, 489, 24, 14 ], [ 421, 489, 12, 14 ], [ 438, 489, 47, 14 ], [ 489, 489, 28, 14 ], [ 521, 489, 24, 14 ], [ 549, 489, 12, 14 ], [ 565, 489, 88, 14 ], [ 657, 489, 56, 14 ], [ 87, 506, 56, 14 ], [ 147, 506, 52, 14 ], [ 204, 506, 51, 14 ], [ 259, 506, 12, 14 ], [ 275, 506, 37, 14 ], [ 316, 506, 54, 14 ], [ 374, 506, 21, 14 ], [ 400, 506, 11, 14 ], [ 415, 506, 28, 14 ], [ 447, 506, 51, 14 ], [ 502, 506, 11, 14 ], [ 517, 506, 25, 14 ], [ 546, 506, 46, 14 ], [ 597, 506, 27, 14 ], [ 628, 506, 92, 14 ], [ 87, 522, 45, 14 ], [ 136, 522, 30, 14 ], [ 171, 522, 32, 14 ], [ 207, 522, 57, 14 ], [ 268, 522, 11, 14 ], [ 283, 522, 25, 14 ], [ 313, 522, 46, 14 ], [ 363, 522, 27, 14 ], [ 394, 522, 118, 14 ], [ 517, 522, 47, 14 ], [ 87, 543, 72, 14 ], [ 164, 543, 13, 14 ], [ 180, 543, 20, 14 ], [ 205, 543, 37, 14 ], [ 246, 543, 45, 14 ], [ 295, 543, 54, 14 ], [ 353, 543, 12, 14 ], [ 369, 543, 88, 14 ], [ 461, 543, 54, 14 ], [ 519, 543, 8, 14 ], [ 531, 543, 45, 14 ], [ 580, 543, 53, 14 ], [ 637, 543, 11, 14 ], [ 652, 543, 19, 14 ], [ 87, 560, 92, 14 ], [ 184, 560, 25, 14 ], [ 213, 560, 22, 14 ], [ 239, 560, 12, 14 ], [ 255, 560, 19, 14 ], [ 278, 560, 50, 14 ], [ 333, 560, 11, 14 ], [ 348, 560, 50, 14 ], [ 403, 560, 33, 14 ], [ 440, 560, 22, 14 ], [ 466, 560, 34, 14 ], [ 504, 560, 15, 14 ], [ 523, 560, 7, 14 ], [ 534, 560, 24, 14 ], [ 562, 560, 65, 14 ], [ 631, 560, 41, 14 ], [ 676, 560, 12, 14 ], [ 87, 576, 53, 14 ], [ 144, 576, 43, 14 ], [ 191, 576, 54, 14 ], [ 249, 576, 21, 14 ], [ 275, 576, 54, 14 ], [ 333, 576, 43, 14 ], [ 380, 576, 63, 14 ], [ 447, 576, 52, 14 ], [ 504, 576, 48, 14 ], [ 555, 576, 54, 14 ], [ 87, 600, 62, 14 ], [ 154, 600, 58, 14 ], [ 216, 600, 36, 14 ], [ 255, 600, 50, 14 ], [ 310, 600, 33, 14 ], [ 347, 600, 24, 14 ], [ 375, 600, 31, 14 ], [ 78, 646, 80, 15 ], [ 78, 663, 77, 14 ], [ 161, 663, 41, 14 ], [ 207, 663, 42, 14 ], [ 254, 663, 14, 14 ], [ 274, 663, 54, 14 ], [ 332, 663, 56, 14 ], [ 394, 663, 10, 14 ], [ 78, 679, 39, 14 ], [ 121, 679, 77, 14 ], [ 202, 679, 14, 14 ], [ 220, 679, 7, 14 ], [ 231, 679, 22, 14 ], [ 257, 679, 12, 14 ], [ 273, 679, 45, 14 ], [ 322, 679, 48, 14 ], [ 375, 679, 29, 14 ], [ 78, 696, 19, 14 ], [ 102, 696, 12, 14 ], [ 120, 696, 28, 14 ], [ 153, 696, 19, 14 ], [ 177, 696, 56, 14 ], [ 239, 696, 50, 14 ], [ 294, 696, 19, 14 ], [ 318, 696, 47, 14 ], [ 370, 696, 33, 14 ], [ 78, 713, 22, 14 ], [ 104, 713, 63, 14 ], [ 172, 713, 59, 14 ], [ 235, 713, 20, 14 ], [ 259, 713, 60, 14 ], [ 324, 713, 19, 14 ], [ 347, 713, 56, 14 ], [ 78, 729, 44, 14 ], [ 128, 729, 27, 14 ], [ 159, 729, 10, 14 ], [ 174, 729, 15, 14 ], [ 194, 729, 53, 14 ], [ 251, 729, 35, 14 ], [ 291, 729, 12, 14 ], [ 308, 729, 36, 14 ], [ 349, 729, 54, 14 ], [ 78, 746, 70, 14 ], [ 152, 746, 45, 14 ], [ 202, 746, 76, 14 ], [ 283, 746, 22, 14 ], [ 309, 746, 72, 14 ], [ 385, 746, 18, 14 ], [ 78, 762, 34, 14 ], [ 116, 762, 11, 14 ], [ 132, 762, 28, 14 ], [ 164, 762, 50, 14 ], [ 218, 762, 19, 14 ], [ 241, 762, 13, 14 ], [ 258, 762, 47, 14 ], [ 309, 762, 12, 14 ], [ 325, 762, 53, 14 ], [ 382, 762, 21, 14 ], [ 78, 779, 79, 14 ], [ 162, 779, 62, 14 ], [ 228, 779, 67, 14 ], [ 300, 779, 22, 14 ], [ 327, 779, 77, 14 ], [ 78, 796, 49, 14 ], [ 132, 796, 45, 14 ], [ 181, 796, 41, 14 ], [ 227, 796, 41, 14 ], [ 272, 796, 36, 14 ], [ 312, 796, 30, 14 ], [ 346, 796, 26, 14 ], [ 377, 796, 27, 14 ], [ 78, 812, 12, 14 ], [ 95, 812, 52, 14 ], [ 151, 812, 32, 14 ], [ 187, 812, 60, 14 ], [ 252, 812, 46, 14 ], [ 302, 812, 14, 14 ], [ 320, 812, 46, 14 ], [ 370, 812, 33, 14 ], [ 78, 829, 22, 14 ], [ 105, 829, 38, 14 ], [ 148, 829, 53, 14 ], [ 206, 829, 22, 14 ], [ 233, 829, 10, 14 ], [ 247, 829, 67, 14 ], [ 319, 829, 17, 14 ], [ 340, 829, 19, 14 ], [ 364, 829, 40, 14 ], [ 78, 845, 30, 14 ], [ 113, 845, 11, 14 ], [ 128, 845, 51, 14 ], [ 184, 845, 32, 14 ], [ 219, 845, 26, 14 ], [ 250, 845, 48, 14 ], [ 302, 845, 51, 14 ], [ 358, 845, 19, 14 ], [ 89, 862, 29, 14 ], [ 122, 862, 52, 14 ], [ 179, 862, 32, 14 ], [ 216, 862, 20, 14 ], [ 241, 862, 45, 14 ], [ 290, 862, 20, 14 ], [ 314, 862, 35, 14 ], [ 353, 862, 51, 14 ], [ 78, 879, 22, 14 ], [ 105, 879, 43, 14 ], [ 153, 879, 30, 14 ], [ 188, 879, 20, 14 ], [ 214, 879, 9, 14 ], [ 228, 879, 20, 14 ], [ 253, 879, 41, 14 ], [ 298, 879, 28, 14 ], [ 331, 879, 46, 14 ], [ 382, 879, 22, 14 ], [ 78, 895, 31, 14 ], [ 115, 895, 28, 14 ], [ 149, 895, 13, 14 ], [ 167, 895, 48, 14 ], [ 221, 895, 30, 14 ], [ 256, 895, 80, 14 ], [ 342, 895, 22, 14 ], [ 369, 895, 34, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 117, 11 ], [ 78, 950, 28, 11 ], [ 109, 950, 11, 11 ], [ 123, 950, 42, 11 ], [ 168, 950, 11, 11 ], [ 182, 950, 33, 11 ], [ 218, 950, 50, 11 ], [ 271, 950, 11, 11 ], [ 285, 950, 46, 11 ], [ 334, 950, 9, 11 ], [ 346, 950, 11, 11 ], [ 78, 962, 56, 11 ], [ 138, 962, 11, 11 ], [ 152, 962, 33, 11 ], [ 188, 962, 45, 11 ], [ 236, 962, 35, 11 ], [ 274, 962, 31, 11 ], [ 423, 646, 62, 14 ], [ 489, 646, 19, 14 ], [ 512, 646, 53, 14 ], [ 569, 646, 12, 14 ], [ 585, 646, 60, 14 ], [ 649, 646, 26, 14 ], [ 680, 646, 22, 14 ], [ 706, 646, 15, 14 ], [ 725, 646, 23, 14 ], [ 423, 663, 22, 14 ], [ 449, 663, 151, 14 ], [ 605, 663, 52, 14 ], [ 662, 663, 54, 14 ], [ 721, 663, 27, 14 ], [ 423, 679, 12, 14 ], [ 442, 679, 45, 14 ], [ 494, 679, 33, 14 ], [ 534, 679, 71, 14 ], [ 613, 679, 24, 14 ], [ 645, 679, 9, 14 ], [ 660, 679, 23, 14 ], [ 690, 679, 20, 14 ], [ 716, 679, 32, 14 ], [ 423, 696, 44, 14 ], [ 470, 696, 62, 14 ], [ 537, 696, 52, 14 ], [ 593, 696, 21, 14 ], [ 618, 696, 19, 14 ], [ 434, 713, 23, 14 ], [ 461, 713, 75, 14 ], [ 541, 713, 34, 14 ], [ 579, 713, 21, 14 ], [ 605, 713, 9, 14 ], [ 619, 713, 14, 14 ], [ 637, 713, 58, 14 ], [ 700, 713, 48, 14 ], [ 423, 729, 12, 14 ], [ 439, 729, 18, 14 ], [ 461, 729, 42, 14 ], [ 508, 729, 51, 14 ], [ 563, 729, 12, 14 ], [ 579, 729, 30, 14 ], [ 614, 729, 47, 14 ], [ 666, 729, 63, 14 ], [ 733, 729, 15, 14 ], [ 423, 746, 19, 14 ], [ 447, 746, 47, 14 ], [ 499, 746, 12, 14 ], [ 516, 746, 19, 14 ], [ 541, 746, 31, 14 ], [ 577, 746, 49, 14 ], [ 632, 746, 22, 14 ], [ 660, 746, 22, 14 ], [ 687, 746, 61, 14 ], [ 423, 762, 32, 14 ], [ 459, 762, 23, 14 ], [ 486, 762, 21, 14 ], [ 511, 762, 25, 14 ], [ 540, 762, 18, 14 ], [ 563, 762, 20, 14 ], [ 587, 762, 29, 14 ], [ 619, 762, 20, 14 ], [ 644, 762, 24, 14 ], [ 673, 762, 50, 14 ], [ 727, 762, 21, 14 ], [ 423, 779, 31, 14 ], [ 458, 779, 31, 14 ], [ 494, 779, 38, 14 ], [ 536, 779, 55, 14 ], [ 596, 779, 22, 14 ], [ 622, 779, 21, 14 ], [ 647, 779, 23, 14 ], [ 675, 779, 50, 14 ], [ 729, 779, 19, 14 ], [ 423, 796, 77, 14 ], [ 505, 796, 12, 14 ], [ 522, 796, 82, 14 ], [ 608, 796, 33, 14 ], [ 646, 795, 22, 14 ], [ 673, 795, 26, 14 ], [ 704, 795, 44, 14 ], [ 423, 812, 42, 14 ], [ 469, 812, 23, 14 ], [ 496, 812, 95, 14 ], [ 595, 812, 7, 14 ], [ 607, 812, 23, 14 ], [ 634, 812, 12, 14 ], [ 650, 812, 23, 14 ], [ 678, 812, 21, 14 ], [ 704, 812, 45, 14 ], [ 423, 829, 53, 14 ], [ 480, 829, 21, 14 ], [ 505, 829, 23, 14 ], [ 533, 829, 12, 14 ], [ 549, 829, 20, 14 ], [ 573, 829, 32, 14 ], [ 608, 829, 19, 14 ], [ 434, 845, 10, 14 ], [ 448, 845, 9, 14 ], [ 462, 845, 25, 14 ], [ 491, 845, 24, 14 ], [ 520, 845, 51, 14 ], [ 575, 845, 23, 14 ], [ 603, 845, 55, 14 ], [ 663, 845, 10, 14 ], [ 677, 845, 55, 14 ], [ 736, 845, 12, 14 ], [ 423, 862, 19, 14 ], [ 446, 862, 95, 14 ], [ 546, 862, 26, 14 ], [ 576, 862, 39, 14 ], [ 620, 862, 53, 14 ], [ 678, 862, 19, 14 ], [ 701, 862, 32, 14 ], [ 739, 862, 10, 14 ], [ 423, 879, 21, 14 ], [ 449, 879, 27, 14 ], [ 481, 879, 74, 14 ], [ 560, 879, 25, 14 ], [ 590, 879, 63, 14 ], [ 659, 879, 20, 14 ], [ 685, 879, 63, 14 ], [ 423, 895, 79, 14 ], [ 506, 895, 23, 14 ], [ 533, 895, 6, 14 ], [ 544, 895, 57, 14 ], [ 605, 895, 26, 14 ], [ 636, 895, 12, 14 ], [ 652, 895, 54, 14 ], [ 710, 895, 38, 14 ], [ 423, 912, 18, 14 ], [ 444, 912, 41, 15 ], [ 490, 912, 50, 14 ], [ 544, 912, 21, 14 ], [ 570, 912, 21, 14 ], [ 595, 912, 71, 14 ], [ 671, 912, 22, 14 ], [ 697, 912, 21, 14 ], [ 723, 912, 25, 14 ], [ 423, 928, 55, 14 ], [ 482, 928, 99, 14 ], [ 585, 928, 68, 14 ], [ 657, 928, 7, 14 ], [ 669, 928, 22, 14 ], [ 695, 928, 7, 14 ], [ 706, 928, 12, 14 ], [ 722, 928, 26, 14 ], [ 423, 945, 93, 14 ], [ 520, 945, 25, 14 ], [ 549, 945, 30, 14 ], [ 584, 945, 26, 14 ], [ 614, 945, 34, 14 ], [ 652, 945, 53, 14 ], [ 710, 945, 38, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 39, 10 ], [ 320, 987, 8, 10 ], [ 330, 987, 8, 10 ], [ 341, 987, 30, 10 ], [ 374, 987, 29, 10 ], [ 406, 987, 27, 10 ], [ 435, 987, 14, 10 ], [ 452, 987, 15, 10 ], [ 470, 987, 6, 10 ], [ 479, 987, 9, 10 ], [ 491, 987, 21, 10 ], [ 515, 987, 25, 10 ], [ 543, 987, 23, 10 ], [ 568, 987, 41, 10 ], [ 612, 987, 23, 10 ], [ 637, 987, 13, 10 ], [ 653, 987, 22, 10 ], [ 677, 987, 8, 10 ], [ 687, 987, 13, 10 ], [ 703, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 49, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Morissette", "et", "al.", "Respiratory", "Research", "2011,", "12:105", "http://respiratory-research.com/content/12/1/105", "R", "E", "S", "E", "A", "R", "C", "H", "Open", "Access", "The", "emphysematous", "lung", "is", "abnormally", "sensitive", "to", "TRAIL-mediated", "apoptosis", "Mathieu", "C", "Morissette,", "Julie", "Parent", "and", "Julie", "Milot*", "Abstract", "Background:", "Alveolar", "apoptosis", "is", "increased", "in", "the", "emphysematous", "lung.", "However,", "mechanisms", "involved", "are", "not", "fully", "understood.", "Recently,", "we", "demonstrated", "that", "levels", "of", "TRAIL", "receptor", "1", "and", "2,", "levels", "of", "p53,", "and", "Bax/Bcl-xL", "ratio", "were", "elevated", "in", "the", "lung", "of", "subjects", "with", "emphysema,", "despite", "smoking", "cessation.", "Thus,", "we", "postulate", "that", "due", "to", "chronic", "pulmonary", "oxidative", "stress,", "the", "emphysematous", "lung", "would", "be", "abnormally", "sensitive", "to", "TRAIL-", "mediated", "apoptosis.", "Methodology:", "A549", "cells", "were", "exposed", "to", "rTRAIL,", "cigarette", "smoke", "extract,", "and/or", "H2O2", "prior", "to", "caspase-3", "activity", "measurement", "and", "annexin", "V", "staining", "assessment.", "In", "addition,", "freshly", "resected", "lung", "samples", "were", "obtained", "from", "non-emphysematous", "and", "emphysematous", "subjects", "and", "exposed", "ex", "vivo", "to", "rTRAIL", "for", "up", "to", "18", "hours.", "Lung", "samples", "were", "harvested", "and", "levels", "of", "active", "caspase-3", "and", "caspase-8", "were", "measured", "from", "tissue", "lysates.", "Results:", "Both", "cigarette", "smoke", "extract", "and", "H2O2", "were", "able", "to", "sensitize", "A549", "cells", "to", "TRAIL-mediated", "apoptosis.", "Moreover,", "following", "exposure", "to", "rTRAIL,", "caspase-3", "and", "-8", "were", "activated", "in", "lung", "explants", "from", "emphysematous", "subjects", "while", "being", "decreased", "in", "lung", "explants", "from", "non-emphysematous", "subjects.", "Significance", "of", "the", "study:", "Alveolar", "sensitivity", "to", "TRAIL-mediated", "apoptosis", "is", "strongly", "increased", "in", "the", "emphysematous", "lung", "due", "to", "the", "presence", "of", "oxidative", "stress.", "This", "might", "be", "a", "new", "mechanism", "leading", "to", "increased", "alveolar", "apoptosis", "and", "persistent", "alveolar", "destruction", "following", "smoking", "cessation.", "Keywords:", "Apoptosis,", "COPD,", "oxidative", "stress,", "p53,", "TRAIL", "Introduction", "Emphysema,", "largely", "caused", "by", "cigarette", "smoking,", "is", "mainly", "characterized", "by", "a", "loss", "of", "alveolar", "integrity", "lead-", "ing", "to", "poor", "gas", "exchange", "between", "the", "alveolar", "space", "and", "pulmonary", "capillaries", "[1].", "Moreover,", "the", "emphyse-", "matous", "lung", "is", "an", "inflamed", "tissue", "in", "which", "activated", "neutrophils,", "alveolar", "macrophages", "and", "lymphocytes", "are", "found", "in", "large", "numbers", "[2].", "In", "addition", "to", "proteases", "and", "inflammatory", "mediators,", "neutrophils", "and", "macrophages", "generate", "reactive", "oxygen", "species", "(ROS)", "[3,4].", "This", "adds", "to", "oxidative", "stress", "aggression", "induced", "by", "primary", "cigar-", "ette", "smoke", "exposure", "and", "is", "responsible", "for", "the", "persis-", "tence", "of", "oxidative", "stress", "after", "smoking", "cessation", "[5].", "High", "oxidative", "stress", "can", "damage", "cell", "lipids,", "proteins,", "and", "nucleic", "acids", "[6].", "If", "too", "severe,", "such", "damage", "will", "force", "cells", "to", "activate", "their", "programmed", "cell", "death", "*", "Correspondence:", "Julie.milot@criucpq.ulaval.ca", "Centre", "de", "recherche", "de", "l’Institut", "universitaire", "de", "cardiologie", "et", "de", "pneumologie", "de", "Québec", "(CRIUCPQ),", "Québec,", "Canada", "(apoptosis)", "[7].", "Exposure", "to", "exogenous", "ROS", "acts", "on", "sev-", "eral", "apoptosis/survival-related", "signaling", "pathways", "such", "as", "MAPK,", "AKT,", "JAK/STAT,", "NF-", "B", "and", "the", "DNA", "damage", "checkpoint", "involving", "p53", "[7].", "The", "transcription", "factor", "p53", "is", "an", "important", "member", "of", "the", "cellular", "response", "to", "DNA", "damage.", "Depending", "on", "the", "severity", "of", "the", "DNA", "injuries,", "p53", "will", "transcribe", "genes", "that", "will", "stop", "the", "cell", "cycle", "(i.e.", "p21,", "14-3-3s)", "and", "allow", "DNA", "repair.", "However,", "p53", "can", "also", "promote", "the", "transcription", "of", "pro-apoptotic", "genes", "(i.e.", "Bax,", "PUMA,", "NOXA,", "Fas,", "TRAIL-receptors", "1", "and", "2)", "that", "will", "activate", "apoptosis", "and", "lead", "to", "cell", "death", "[8].", "It", "is", "now", "well", "accepted", "that", "apoptosis", "is", "increased", "in", "the", "emphysematous", "lung", "[9-12],", "however,", "the", "cause", "is", "not", "fully", "understood.", "Our", "laboratory", "has", "previously", "demonstrated", "that", "a", "sub-lethal", "dose", "of", "hydrogen", "perox-", "ide", "(H2O2)", "activates", "p53", "and", "up-regulates", "Bax", "and", "pro-", "apoptotic", "TRAIL-receptors", "(TRAIL-Rs)", "1", "and", "2", "in", "lung", "adenocarcinoma", "cells", "A549", "[13].", "These", "apoptotic", "factors", "©", "2011", "Morissette", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 76, 47, 135, 34 ], [ 223, 47, 39, 34 ], [ 274, 47, 245, 34 ], [ 530, 47, 166, 34 ], [ 76, 118, 70, 20 ], [ 76, 143, 219, 23 ], [ 301, 143, 60, 23 ], [ 76, 168, 35, 21 ], [ 115, 168, 66, 22 ], [ 186, 168, 68, 21 ], [ 259, 168, 15, 21 ], [ 279, 168, 76, 22 ], [ 360, 168, 46, 21 ], [ 412, 168, 89, 22 ], [ 505, 168, 76, 21 ], [ 586, 168, 134, 22 ], [ 76, 193, 39, 21 ], [ 120, 193, 42, 22 ], [ 167, 193, 37, 21 ], [ 209, 193, 13, 21 ], [ 228, 193, 71, 22 ], [ 303, 193, 70, 21 ], [ 378, 193, 74, 22 ], [ 456, 193, 51, 21 ], [ 511, 193, 105, 22 ], [ 76, 218, 54, 21 ], [ 135, 218, 11, 21 ], [ 150, 218, 99, 22 ], [ 254, 218, 35, 21 ], [ 294, 218, 88, 21 ], [ 387, 218, 19, 21 ], [ 410, 218, 112, 22 ], [ 706, 60, 53, 14 ], [ 761, 60, 37, 14 ], [ 697, 118, 44, 16 ], [ 745, 118, 62, 16 ], [ 76, 268, 41, 12 ], [ 119, 268, 86, 12 ], [ 207, 268, 39, 12 ], [ 248, 268, 59, 12 ], [ 309, 268, 10, 12 ], [ 322, 268, 57, 12 ], [ 381, 268, 48, 12 ], [ 431, 268, 38, 12 ], [ 472, 268, 35, 12 ], [ 509, 268, 43, 12 ], [ 555, 268, 45, 12 ], [ 602, 268, 10, 12 ], [ 614, 268, 36, 12 ], [ 653, 268, 46, 12 ], [ 702, 268, 47, 12 ], [ 76, 281, 34, 11 ], [ 113, 281, 24, 11 ], [ 139, 281, 63, 12 ], [ 204, 281, 10, 11 ], [ 217, 281, 48, 11 ], [ 267, 281, 19, 11 ], [ 288, 281, 38, 11 ], [ 328, 281, 43, 11 ], [ 373, 281, 48, 11 ], [ 423, 281, 39, 11 ], [ 464, 281, 50, 11 ], [ 515, 281, 10, 11 ], [ 528, 281, 39, 11 ], [ 569, 281, 38, 11 ], [ 610, 281, 25, 11 ], [ 636, 281, 38, 12 ], [ 677, 281, 53, 11 ], [ 732, 281, 35, 11 ], [ 76, 294, 37, 12 ], [ 116, 294, 32, 12 ], [ 150, 294, 14, 12 ], [ 167, 294, 34, 12 ], [ 203, 294, 45, 12 ], [ 251, 294, 43, 12 ], [ 296, 294, 34, 12 ], [ 332, 294, 43, 12 ], [ 378, 294, 43, 12 ], [ 423, 294, 45, 12 ], [ 470, 294, 10, 12 ], [ 483, 294, 36, 12 ], [ 522, 294, 46, 12 ], [ 570, 294, 19, 12 ], [ 592, 294, 34, 12 ], [ 628, 294, 24, 12 ], [ 655, 294, 45, 12 ], [ 702, 294, 10, 12 ], [ 715, 294, 39, 12 ], [ 76, 307, 66, 12 ], [ 145, 307, 33, 12 ], [ 180, 307, 32, 12 ], [ 214, 307, 50, 12 ], [ 266, 307, 86, 12 ], [ 355, 307, 31, 12 ], [ 389, 307, 29, 12 ], [ 420, 307, 45, 12 ], [ 468, 307, 19, 12 ], [ 489, 307, 63, 12 ], [ 554, 307, 10, 12 ], [ 567, 307, 60, 12 ], [ 629, 307, 50, 12 ], [ 682, 307, 18, 12 ], [ 702, 307, 50, 12 ], [ 754, 307, 10, 12 ], [ 76, 321, 29, 11 ], [ 108, 321, 19, 11 ], [ 129, 321, 47, 11 ], [ 178, 321, 34, 11 ], [ 214, 321, 35, 11 ], [ 252, 321, 46, 11 ], [ 300, 321, 16, 11 ], [ 319, 321, 21, 11 ], [ 76, 341, 31, 12 ], [ 110, 341, 19, 12 ], [ 131, 341, 28, 12 ], [ 161, 341, 4, 12 ], [ 168, 341, 119, 12 ], [ 288, 341, 37, 12 ], [ 328, 341, 8, 12 ], [ 338, 341, 34, 12 ], [ 374, 341, 4, 12 ], [ 380, 341, 131, 12 ], [ 514, 341, 25, 12 ], [ 541, 341, 40, 12 ], [ 584, 341, 4, 12 ], [ 590, 341, 107, 12 ], [ 76, 354, 41, 11 ], [ 119, 354, 65, 11 ], [ 186, 354, 4, 11 ], [ 192, 354, 159, 11 ], [ 354, 354, 21, 11 ], [ 377, 354, 16, 11 ], [ 395, 354, 4, 11 ], [ 401, 354, 131, 11 ], [ 535, 354, 20, 11 ], [ 557, 354, 7, 11 ], [ 567, 354, 31, 11 ], [ 600, 354, 4, 11 ], [ 606, 354, 146, 11 ], [ 76, 367, 37, 12 ], [ 116, 367, 32, 12 ], [ 150, 367, 4, 12 ], [ 157, 367, 185, 12 ], [ 344, 367, 27, 12 ], [ 373, 367, 49, 12 ], [ 425, 367, 4, 12 ], [ 431, 367, 130, 12 ], [ 76, 380, 29, 12 ], [ 107, 380, 6, 12 ], [ 116, 380, 48, 12 ], [ 167, 380, 4, 12 ], [ 173, 380, 137, 12 ], [ 312, 380, 47, 12 ], [ 362, 380, 10, 12 ], [ 375, 380, 55, 12 ], [ 433, 380, 4, 12 ], [ 439, 380, 115, 12 ], [ 76, 396, 7, 12 ], [ 85, 396, 73, 12 ], [ 160, 396, 33, 12 ], [ 76, 455, 45, 12 ], [ 124, 455, 12, 12 ], [ 138, 455, 40, 12 ], [ 180, 455, 23, 12 ], [ 76, 475, 29, 12 ], [ 108, 475, 9, 12 ], [ 119, 475, 54, 12 ], [ 176, 475, 38, 12 ], [ 216, 475, 25, 12 ], [ 244, 475, 20, 12 ], [ 276, 475, 128, 12 ], [ 430, 455, 43, 12 ], [ 476, 455, 11, 12 ], [ 490, 455, 49, 12 ], [ 542, 455, 23, 12 ], [ 430, 468, 46, 12 ], [ 478, 468, 12, 12 ], [ 492, 468, 40, 12 ], [ 534, 468, 23, 12 ], [ 76, 495, 20, 12 ], [ 98, 495, 28, 12 ], [ 129, 495, 7, 12 ], [ 139, 495, 38, 12 ], [ 179, 495, 25, 12 ], [ 207, 495, 244, 12 ], [ 76, 514, 9, 12 ], [ 87, 514, 23, 12 ], [ 113, 514, 27, 12 ], [ 142, 514, 10, 12 ], [ 155, 514, 10, 12 ], [ 167, 514, 36, 12 ], [ 206, 514, 35, 12 ], [ 243, 514, 35, 12 ], [ 280, 514, 18, 12 ], [ 76, 528, 20, 12 ], [ 98, 528, 7, 12 ], [ 108, 528, 11, 12 ], [ 121, 528, 55, 12 ], [ 179, 528, 28, 12 ], [ 210, 528, 49, 12 ], [ 262, 528, 27, 12 ], [ 291, 528, 15, 12 ], [ 309, 528, 27, 12 ], [ 338, 528, 9, 12 ], [ 350, 528, 15, 12 ], [ 368, 528, 39, 12 ], [ 410, 528, 48, 12 ], [ 460, 528, 51, 12 ], [ 513, 528, 34, 12 ], [ 550, 528, 202, 12 ], [ 76, 541, 27, 12 ], [ 106, 541, 35, 12 ], [ 143, 541, 56, 12 ], [ 201, 541, 18, 12 ], [ 222, 541, 55, 12 ], [ 279, 541, 16, 12 ], [ 298, 541, 60, 12 ], [ 361, 541, 8, 12 ], [ 372, 541, 16, 12 ], [ 390, 541, 39, 12 ], [ 432, 541, 40, 12 ], [ 475, 541, 15, 12 ], [ 493, 541, 34, 12 ], [ 529, 541, 24, 12 ], [ 556, 541, 7, 12 ], [ 565, 541, 39, 12 ], [ 607, 541, 25, 12 ], [ 155, 601, 62, 15 ], [ 155, 622, 40, 14 ], [ 200, 622, 57, 14 ], [ 262, 622, 56, 14 ], [ 323, 622, 56, 14 ], [ 385, 622, 18, 14 ], [ 408, 622, 35, 14 ], [ 449, 622, 6, 14 ], [ 460, 622, 23, 14 ], [ 488, 622, 50, 14 ], [ 543, 622, 58, 14 ], [ 606, 622, 17, 14 ], [ 628, 622, 13, 14 ], [ 646, 622, 44, 14 ], [ 155, 638, 86, 14 ], [ 247, 638, 22, 14 ], [ 275, 638, 51, 14 ], [ 333, 638, 52, 14 ], [ 391, 638, 54, 14 ], [ 452, 638, 21, 14 ], [ 479, 638, 57, 14 ], [ 542, 638, 56, 14 ], [ 605, 638, 12, 14 ], [ 623, 638, 67, 14 ], [ 155, 655, 39, 14 ], [ 197, 655, 48, 14 ], [ 248, 655, 22, 14 ], [ 273, 655, 23, 14 ], [ 299, 655, 30, 14 ], [ 332, 655, 18, 14 ], [ 353, 655, 65, 14 ], [ 421, 655, 48, 14 ], [ 472, 655, 35, 14 ], [ 510, 655, 20, 14 ], [ 533, 655, 24, 14 ], [ 561, 655, 44, 14 ], [ 608, 655, 24, 14 ], [ 636, 655, 21, 14 ], [ 660, 655, 30, 14 ], [ 155, 671, 21, 14 ], [ 183, 671, 11, 14 ], [ 202, 671, 18, 14 ], [ 227, 671, 28, 14 ], [ 263, 671, 28, 14 ], [ 298, 671, 39, 14 ], [ 344, 671, 6, 14 ], [ 358, 671, 58, 14 ], [ 423, 671, 67, 14 ], [ 497, 671, 29, 14 ], [ 534, 671, 62, 14 ], [ 603, 671, 53, 14 ], [ 664, 671, 27, 14 ], [ 155, 687, 62, 14 ], [ 223, 687, 61, 14 ], [ 290, 687, 21, 14 ], [ 318, 687, 39, 14 ], [ 364, 687, 25, 14 ], [ 396, 687, 12, 14 ], [ 415, 687, 42, 14 ], [ 463, 687, 80, 14 ], [ 549, 687, 79, 14 ], [ 635, 687, 37, 14 ], [ 678, 687, 12, 14 ], [ 155, 704, 57, 14 ], [ 216, 704, 56, 14 ], [ 276, 704, 57, 14 ], [ 337, 704, 22, 14 ], [ 364, 704, 23, 14 ], [ 391, 704, 13, 14 ], [ 409, 704, 23, 14 ], [ 436, 704, 19, 14 ], [ 460, 704, 14, 14 ], [ 478, 704, 45, 14 ], [ 527, 704, 12, 14 ], [ 544, 704, 13, 14 ], [ 562, 704, 73, 14 ], [ 639, 704, 52, 14 ], [ 155, 720, 40, 14 ], [ 202, 720, 54, 14 ], [ 263, 720, 55, 14 ], [ 326, 720, 30, 14 ], [ 363, 720, 14, 14 ], [ 385, 720, 51, 14 ], [ 443, 720, 60, 14 ], [ 510, 720, 11, 14 ], [ 529, 720, 44, 14 ], [ 580, 720, 13, 14 ], [ 601, 720, 31, 14 ], [ 639, 720, 51, 14 ], [ 155, 736, 53, 14 ], [ 212, 736, 11, 14 ], [ 226, 736, 48, 14 ], [ 277, 736, 18, 14 ], [ 299, 736, 80, 14 ], [ 382, 736, 36, 14 ], [ 422, 736, 11, 14 ], [ 436, 736, 57, 14 ], [ 497, 736, 57, 14 ], [ 557, 736, 21, 14 ], [ 582, 736, 56, 14 ], [ 641, 736, 25, 14 ], [ 669, 736, 22, 14 ], [ 155, 753, 11, 14 ], [ 169, 753, 43, 14 ], [ 215, 753, 28, 14 ], [ 245, 753, 19, 14 ], [ 266, 753, 42, 14 ], [ 311, 753, 36, 14 ], [ 350, 753, 56, 14 ], [ 409, 753, 39, 14 ], [ 450, 753, 31, 14 ], [ 484, 753, 87, 14 ], [ 573, 753, 56, 14 ], [ 632, 753, 13, 14 ], [ 648, 753, 18, 14 ], [ 669, 753, 22, 14 ], [ 155, 769, 35, 14 ], [ 194, 769, 32, 14 ], [ 229, 769, 29, 14 ], [ 262, 769, 28, 14 ], [ 293, 769, 9, 14 ], [ 305, 769, 44, 14 ], [ 353, 769, 44, 14 ], [ 400, 769, 59, 14 ], [ 463, 769, 38, 14 ], [ 505, 769, 80, 14 ], [ 588, 769, 48, 14 ], [ 639, 769, 28, 14 ], [ 671, 769, 20, 14 ], [ 155, 785, 57, 14 ], [ 216, 785, 23, 14 ], [ 243, 785, 23, 14 ], [ 271, 785, 46, 14 ], [ 322, 785, 18, 14 ], [ 345, 785, 39, 14 ], [ 388, 785, 11, 14 ], [ 404, 785, 26, 14 ], [ 435, 785, 49, 14 ], [ 489, 785, 44, 14 ], [ 538, 785, 86, 14 ], [ 628, 785, 24, 14 ], [ 656, 785, 35, 14 ], [ 155, 801, 60, 14 ], [ 218, 801, 30, 14 ], [ 250, 801, 50, 14 ], [ 304, 801, 56, 14 ], [ 363, 801, 6, 14 ], [ 372, 801, 23, 14 ], [ 398, 801, 17, 14 ], [ 418, 801, 18, 14 ], [ 439, 801, 69, 14 ], [ 511, 801, 11, 14 ], [ 525, 801, 56, 14 ], [ 584, 801, 56, 14 ], [ 644, 801, 10, 14 ], [ 657, 801, 34, 14 ], [ 155, 818, 37, 14 ], [ 195, 818, 27, 14 ], [ 225, 818, 20, 14 ], [ 249, 818, 11, 14 ], [ 263, 818, 18, 14 ], [ 284, 818, 28, 14 ], [ 316, 818, 25, 14 ], [ 344, 818, 23, 14 ], [ 370, 818, 30, 14 ], [ 403, 818, 75, 14 ], [ 481, 818, 11, 14 ], [ 496, 818, 30, 14 ], [ 529, 818, 63, 14 ], [ 595, 818, 41, 14 ], [ 76, 886, 84, 15 ], [ 76, 903, 46, 14 ], [ 125, 903, 60, 14 ], [ 188, 903, 60, 14 ], [ 251, 903, 64, 14 ], [ 318, 903, 43, 14 ], [ 364, 903, 13, 14 ], [ 380, 903, 31, 14 ], [ 76, 919, 54, 14 ], [ 132, 919, 29, 14 ], [ 164, 919, 42, 14 ], [ 209, 919, 36, 14 ], [ 248, 919, 27, 14 ], [ 277, 919, 30, 14 ], [ 310, 919, 20, 14 ], [ 333, 919, 38, 14 ], [ 373, 919, 38, 14 ], [ 76, 935, 19, 14 ], [ 103, 935, 25, 14 ], [ 136, 935, 51, 14 ], [ 196, 935, 62, 14 ], [ 266, 935, 12, 14 ], [ 287, 935, 33, 14 ], [ 328, 935, 62, 14 ], [ 399, 935, 12, 14 ], [ 76, 952, 51, 14 ], [ 131, 952, 81, 14 ], [ 216, 952, 32, 14 ], [ 252, 952, 56, 14 ], [ 312, 952, 19, 14 ], [ 335, 952, 55, 14 ], [ 394, 952, 17, 14 ], [ 76, 968, 22, 14 ], [ 102, 968, 80, 14 ], [ 186, 968, 58, 14 ], [ 248, 968, 39, 14 ], [ 291, 968, 57, 14 ], [ 352, 968, 21, 14 ], [ 377, 968, 35, 14 ], [ 76, 985, 22, 14 ], [ 104, 985, 60, 14 ], [ 170, 985, 60, 14 ], [ 236, 985, 64, 14 ], [ 305, 985, 10, 14 ], [ 321, 985, 54, 14 ], [ 381, 985, 30, 14 ], [ 76, 1001, 34, 14 ], [ 113, 1001, 12, 14 ], [ 129, 1001, 32, 14 ], [ 163, 1001, 42, 14 ], [ 209, 1001, 27, 14 ], [ 239, 1001, 7, 14 ], [ 249, 1001, 39, 14 ], [ 292, 1001, 13, 14 ], [ 308, 1001, 43, 14 ], [ 354, 1001, 57, 14 ], [ 434, 887, 49, 14 ], [ 488, 887, 12, 14 ], [ 506, 887, 42, 14 ], [ 552, 887, 83, 14 ], [ 640, 887, 57, 14 ], [ 701, 887, 45, 14 ], [ 750, 887, 19, 14 ], [ 434, 903, 25, 14 ], [ 462, 903, 13, 14 ], [ 478, 903, 36, 14 ], [ 517, 903, 37, 14 ], [ 557, 903, 63, 14 ], [ 623, 903, 75, 14 ], [ 701, 903, 68, 14 ], [ 434, 919, 66, 14 ], [ 505, 919, 37, 14 ], [ 546, 919, 26, 14 ], [ 577, 919, 21, 14 ], [ 602, 919, 14, 14 ], [ 621, 919, 46, 14 ], [ 672, 919, 29, 14 ], [ 706, 919, 64, 14 ], [ 434, 935, 62, 14 ], [ 500, 935, 48, 14 ], [ 550, 935, 15, 14 ], [ 568, 935, 79, 14 ], [ 650, 935, 37, 14 ], [ 690, 935, 13, 14 ], [ 706, 935, 64, 14 ], [ 434, 952, 26, 14 ], [ 462, 952, 13, 14 ], [ 477, 952, 29, 14 ], [ 508, 952, 54, 14 ], [ 564, 952, 8, 14 ], [ 574, 952, 20, 14 ], [ 596, 952, 57, 14 ], [ 656, 952, 21, 14 ], [ 679, 952, 13, 14 ], [ 694, 952, 54, 14 ], [ 750, 952, 19, 14 ], [ 434, 968, 35, 14 ], [ 473, 968, 57, 14 ], [ 535, 968, 12, 14 ], [ 551, 968, 127, 14 ], [ 683, 968, 49, 14 ], [ 736, 968, 14, 14 ], [ 753, 968, 16, 14 ], [ 434, 985, 63, 14 ], [ 501, 985, 39, 14 ], [ 544, 985, 72, 14 ], [ 620, 985, 23, 14 ], [ 647, 985, 13, 14 ], [ 664, 985, 32, 14 ], [ 699, 985, 42, 14 ], [ 745, 985, 24, 14 ], [ 434, 1001, 41, 14 ], [ 481, 1001, 7, 14 ], [ 493, 1001, 48, 14 ], [ 546, 1001, 97, 14 ], [ 649, 1001, 12, 14 ], [ 667, 1001, 22, 14 ], [ 694, 1001, 37, 14 ], [ 737, 1001, 33, 14 ], [ 698, 1052, 30, 13 ], [ 731, 1052, 7, 13 ], [ 741, 1052, 11, 13 ], [ 755, 1052, 14, 13 ], [ 599, 1069, 25, 10 ], [ 627, 1069, 33, 10 ], [ 662, 1069, 14, 10 ], [ 678, 1069, 12, 10 ], [ 692, 1069, 31, 10 ], [ 726, 1069, 44, 10 ] ]

[ "Journal", "of", "Translational", "Medicine", "Research", "Melanoma-restricted", "genes", "Ena", "Wang1,", "Monica", "C", "Panelli1,", "Katia", "Zavaglia1,", "Susanna", "Mandruzzato2,", "Nan", "Hu3,", "Phil", "R", "Taylor3,", "Barbara", "Seliger4,", "Paola", "Zanovello2,", "Ralph", "S", "Freedman5", "and", "Francesco", "M", "Marincola*1", "BioMed", "Central", "Open", "Access", "Address:", "1Immunogenetics", "Section,", "Department", "of", "Transfusion", "Medicine,", "Clinical", "Center,", "National", "Institutes", "of", "Health,", "Bethesda,", "Maryland", "20892,", "USA,", "2Department", "of", "Oncology", "and", "Surgical", "Sciences,", "Oncology", "Section,", "University", "of", "Padova,", "Padova,", "Italy,", "3Cancer", "Prevention", "Studies", "Branch,", "Center", "for", "Cancer", "Research,", "National", "Cancer", "Institute,", "National", "Institutes", "of", "Health,", "Bethesda,", "MD", "20892,", "USA,", "4Institute", "of", "Medical", "Immunology,", "Martin", "Luther", "University", "Halle-Wittenberg,", "06112", "Halle,", "Germany", "and", "5Department", "of", "Gynecologic", "Oncology,", "The", "University", "of", "Texas,", "MD", "Anderson", "Cancer", "Center,", "Houston,", "TX,", "USA", "Email:", "Ena", "Wang", "-", "ewang@mail.cc.nih.gov;", "Monica", "C", "Panelli", "-", "MPanelli@mail.cc.nih.gov;", "Katia", "Zavaglia", "-", "kzavaglia@cc.nih.gov;", "Susanna", "Mandruzzato", "-", "susanna.mandruzzato@unipd.it;", "Nan", "Hu", "-", "hun@dcpcepn.nci.nih.gov;", "Phil", "R", "Taylor", "-", "taylorp@dcpcepn.nci.nih.gov;", "Barbara", "Seliger", "-", "barbara.seliger@medizin.uni-halle.de;", "Paola", "Zanovello", "-", "paola.zanovello@unipd.it;", "Ralph", "S", "Freedman", "-", "rfreedma@mdanderson.org;", "Francesco", "M", "Marincola*", "-", "FMarincola@cc.nih.gov", "*", "Corresponding", "author", "Published:", "15", "October", "2004", "Journal", "of", "Translational", "Medicine", "2004,", "2:34", "doi:10.1186/1479-5876-2-34", "Received:", "16", "September", "2004", "Accepted:", "15", "October", "2004", "This", "article", "is", "available", "from:", "http://www.translational-medicine.com/content/2/1/34", "©", "2004", "Wang", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "open-access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "Abstract", "Human", "metastatic", "cutaneous", "melanoma", "has", "gained", "a", "well", "deserved", "reputation", "for", "its", "immune", "responsiveness.", "The", "reason(s)", "remain(s)", "unknown.", "We", "attempted", "previously", "to", "characterize", "several", "variables", "that", "may", "affect", "the", "relationship", "between", "tumor", "and", "host", "immune", "cells", "but,", "taken", "one", "at", "the", "time,", "none", "yielded", "a", "convincing", "explanation.", "With", "explorative", "purposes,", "high-", "throughput", "technology", "was", "applied", "here", "to", "portray", "transcriptional", "characteristics", "unique", "to", "metastatic", "cutaneous", "melanoma", "that", "may", "or", "may", "not", "be", "relevant", "to", "its", "immunogenic", "potential.", "Several", "functional", "signatures", "could", "be", "identified", "descriptive", "of", "immune", "or", "other", "biological", "functions.", "In", "addition,", "the", "transcriptional", "profile", "of", "metastatic", "melanoma", "was", "compared", "with", "that", "of", "primary", "renal", "cell", "cancers", "(RCC)", "identifying", "several", "genes", "co-coordinately", "expressed", "by", "the", "two", "tumor", "types.", "Since", "RCC", "is", "another", "immune", "responsive", "tumor,", "commonalities", "between", "RCC", "and", "melanoma", "may", "help", "untangle", "the", "enigma", "of", "their", "potential", "immune", "responsiveness.", "This", "purely", "descriptive", "study", "provides,", "therefore,", "a", "map", "for", "the", "investigation", "of", "metastatic", "melanoma", "in", "future", "clinical", "trials", "and", "at", "the", "same", "time", "may", "invite", "consideration", "of", "novel", "therapeutic", "targets.", "Background", "Human", "metastatic", "cutaneous", "melanoma", "relative", "to", "other", "common", "solid", "tumors", "shares", "with", "renal", "cell", "cancer", "(RCC)", "the", "well", "deserved", "reputation", "of", "being", "responsive", "to", "immune", "manipulation", "[1,2].", "However,", "the", "reason(s)", "for", "this", "phenomenon", "remain(s)", "largely", "unknown", "[3].", "Possi-", "bly,", "metastatic", "cutaneous", "melanoma", "is", "endowed", "com-", "pared", "to", "other", "tumors", "with", "a", "wealth", "of", "\"tumor", "rejection\"", "antigens", "of", "unique", "immunogenic", "potential.", "Indeed,", "the", "ease", "in", "which", "tumor", "infiltrating", "lymphocytes", "recognizing", "autologous", "tumor", "cells", "can", "be", "isolated", "from", "melanoma", "metastases", "suggests", "an", "extraordinary", "ability", "of", "melanoma", "cells", "to", "elicit", "cognitive", "T", "cell", "responses", "[4].", "In", "addition,", "the", "broad", "repertoire", "of", "melanoma-associated", "antigens", "so", "far", "discovered", "largely", "outnumbers", "that", "of", "other", "tumors", "sug-", "gesting", "a", "stronger", "immunogenicity", "of", "this", "cancer", "[5-7].", "Page", "1", "of", "14", "(page", "number", "not", "for", "citation", "purposes)" ]

[ 0, 0, 0, 0, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 0, 0, 9, 9, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 0, 0, 0, 0, 0, 0, 0, 7, 7, 7, 7, 7, 7, 7, 7, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 ]

[ [ 512, 68, 17, 12 ], [ 532, 68, 18, 12 ], [ 553, 68, 26, 12 ], [ 582, 68, 20, 12 ], [ 604, 68, 9, 12 ], [ 616, 68, 16, 12 ], [ 635, 68, 9, 12 ], [ 647, 68, 22, 12 ], [ 673, 68, 26, 12 ], [ 702, 68, 15, 12 ], [ 720, 68, 40, 12 ], [ 94, 91, 67, 13 ], [ 162, 91, 55, 13 ], [ 90, 159, 67, 21 ], [ 161, 159, 135, 21 ], [ 301, 159, 18, 21 ], [ 323, 159, 108, 21 ], [ 436, 159, 56, 21 ], [ 497, 159, 17, 21 ], [ 519, 159, 57, 21 ], [ 581, 159, 104, 21 ], [ 90, 183, 103, 21 ], [ 198, 183, 50, 21 ], [ 252, 183, 20, 21 ], [ 277, 183, 56, 21 ], [ 90, 231, 34, 14 ], [ 128, 231, 28, 14 ], [ 160, 229, 47, 16 ], [ 211, 231, 23, 14 ], [ 237, 231, 29, 14 ], [ 270, 231, 40, 14 ], [ 314, 231, 25, 14 ], [ 342, 231, 16, 14 ], [ 362, 229, 41, 16 ], [ 406, 231, 19, 14 ], [ 429, 231, 29, 14 ], [ 462, 229, 41, 16 ], [ 506, 231, 52, 14 ], [ 562, 229, 45, 16 ], [ 611, 231, 46, 14 ], [ 661, 229, 46, 16 ], [ 711, 231, 35, 14 ], [ 750, 231, 10, 14 ], [ 90, 245, 45, 16 ], [ 138, 247, 36, 14 ], [ 178, 247, 32, 14 ], [ 214, 245, 43, 16 ], [ 261, 247, 30, 14 ], [ 294, 247, 22, 14 ], [ 320, 245, 52, 16 ], [ 376, 247, 53, 14 ], [ 433, 245, 45, 16 ], [ 482, 247, 27, 14 ], [ 513, 247, 25, 14 ], [ 541, 245, 59, 16 ], [ 604, 247, 29, 14 ], [ 636, 247, 25, 14 ], [ 665, 245, 45, 16 ], [ 714, 247, 22, 14 ], [ 739, 247, 20, 14 ], [ 90, 263, 22, 14 ], [ 115, 260, 43, 16 ], [ 88, 287, 59, 12 ], [ 151, 287, 10, 12 ], [ 164, 287, 37, 12 ], [ 205, 287, 45, 12 ], [ 254, 287, 26, 12 ], [ 283, 287, 48, 12 ], [ 335, 287, 35, 12 ], [ 373, 287, 10, 12 ], [ 387, 287, 45, 12 ], [ 442, 287, 32, 12 ], [ 477, 287, 48, 12 ], [ 529, 287, 34, 12 ], [ 567, 287, 10, 12 ], [ 581, 287, 45, 12 ], [ 636, 287, 26, 12 ], [ 666, 287, 40, 12 ], [ 710, 287, 48, 12 ], [ 88, 300, 34, 12 ], [ 126, 300, 10, 12 ], [ 139, 300, 45, 12 ], [ 189, 298, 51, 13 ], [ 243, 300, 10, 12 ], [ 256, 300, 27, 12 ], [ 286, 300, 34, 12 ], [ 324, 300, 10, 12 ], [ 337, 300, 45, 12 ], [ 387, 298, 31, 14 ], [ 421, 300, 41, 12 ], [ 466, 300, 48, 12 ], [ 517, 300, 32, 12 ], [ 553, 300, 10, 12 ], [ 566, 300, 45, 12 ], [ 615, 298, 53, 13 ], [ 672, 300, 48, 12 ], [ 724, 300, 35, 12 ], [ 88, 313, 10, 12 ], [ 102, 313, 46, 12 ], [ 153, 311, 34, 13 ], [ 191, 313, 20, 12 ], [ 216, 313, 49, 12 ], [ 269, 313, 35, 12 ], [ 308, 313, 10, 12 ], [ 322, 313, 46, 12 ], [ 372, 313, 51, 12 ], [ 427, 313, 49, 12 ], [ 480, 313, 35, 12 ], [ 519, 313, 10, 12 ], [ 533, 313, 46, 12 ], [ 595, 313, 74, 12 ], [ 673, 313, 49, 12 ], [ 726, 313, 32, 12 ], [ 88, 327, 10, 12 ], [ 102, 327, 46, 12 ], [ 163, 327, 34, 12 ], [ 201, 327, 49, 12 ], [ 254, 327, 35, 12 ], [ 292, 327, 10, 12 ], [ 306, 327, 38, 12 ], [ 349, 325, 24, 13 ], [ 377, 327, 49, 12 ], [ 429, 327, 35, 12 ], [ 468, 327, 10, 12 ], [ 482, 327, 46, 12 ], [ 531, 327, 18, 12 ], [ 554, 324, 44, 14 ], [ 602, 327, 55, 12 ], [ 661, 327, 14, 12 ], [ 679, 327, 15, 12 ], [ 698, 327, 28, 12 ], [ 729, 327, 10, 12 ], [ 743, 327, 15, 12 ], [ 88, 340, 44, 12 ], [ 135, 340, 35, 12 ], [ 173, 340, 40, 12 ], [ 216, 340, 27, 12 ], [ 90, 382, 107, 14 ], [ 201, 382, 65, 14 ], [ 269, 382, 32, 14 ], [ 304, 382, 26, 14 ], [ 334, 382, 75, 14 ], [ 90, 400, 67, 14 ], [ 161, 400, 22, 14 ], [ 187, 400, 66, 14 ], [ 257, 400, 33, 14 ], [ 294, 400, 22, 14 ], [ 320, 400, 10, 14 ], [ 333, 400, 76, 14 ], [ 90, 418, 13, 14 ], [ 106, 418, 40, 14 ], [ 150, 418, 50, 14 ], [ 204, 418, 11, 14 ], [ 218, 418, 32, 14 ], [ 254, 418, 11, 14 ], [ 269, 418, 22, 14 ], [ 294, 418, 39, 14 ], [ 337, 418, 51, 14 ], [ 391, 418, 18, 14 ], [ 90, 436, 89, 14 ], [ 182, 436, 43, 14 ], [ 229, 436, 22, 14 ], [ 254, 436, 57, 14 ], [ 315, 436, 94, 14 ], [ 90, 455, 45, 14 ], [ 139, 455, 18, 14 ], [ 160, 455, 51, 14 ], [ 214, 455, 22, 14 ], [ 240, 455, 28, 14 ], [ 272, 455, 65, 14 ], [ 340, 455, 70, 14 ], [ 90, 473, 18, 14 ], [ 111, 473, 50, 14 ], [ 165, 473, 7, 14 ], [ 175, 473, 62, 14 ], [ 241, 473, 62, 14 ], [ 306, 473, 30, 14 ], [ 340, 473, 11, 14 ], [ 354, 473, 56, 14 ], [ 90, 491, 18, 14 ], [ 112, 491, 38, 14 ], [ 154, 491, 49, 14 ], [ 207, 491, 67, 14 ], [ 277, 491, 62, 14 ], [ 343, 491, 10, 14 ], [ 357, 491, 18, 14 ], [ 379, 491, 30, 14 ], [ 90, 509, 21, 14 ], [ 114, 509, 59, 14 ], [ 176, 509, 11, 14 ], [ 190, 509, 19, 14 ], [ 212, 509, 10, 14 ], [ 226, 509, 35, 14 ], [ 264, 509, 52, 14 ], [ 320, 509, 18, 14 ], [ 340, 509, 69, 14 ], [ 90, 527, 45, 14 ], [ 139, 527, 45, 14 ], [ 189, 527, 37, 14 ], [ 229, 527, 37, 14 ], [ 270, 527, 47, 14 ], [ 320, 527, 15, 14 ], [ 339, 527, 29, 14 ], [ 372, 527, 26, 14 ], [ 401, 527, 8, 14 ], [ 90, 545, 30, 14 ], [ 124, 545, 8, 14 ], [ 135, 545, 19, 14 ], [ 157, 545, 46, 14 ], [ 207, 545, 35, 14 ], [ 245, 545, 31, 14 ], [ 279, 545, 21, 14 ], [ 304, 545, 48, 14 ], [ 355, 545, 34, 14 ], [ 392, 545, 18, 14 ], [ 90, 563, 47, 14 ], [ 140, 563, 38, 14 ], [ 180, 563, 45, 14 ], [ 227, 563, 21, 14 ], [ 251, 563, 56, 14 ], [ 309, 563, 76, 14 ], [ 387, 563, 22, 14 ], [ 90, 581, 42, 14 ], [ 135, 581, 44, 14 ], [ 183, 581, 11, 14 ], [ 197, 581, 27, 14 ], [ 227, 581, 29, 14 ], [ 260, 581, 50, 14 ], [ 313, 581, 45, 14 ], [ 361, 581, 8, 14 ], [ 371, 581, 24, 14 ], [ 399, 581, 11, 14 ], [ 90, 599, 23, 14 ], [ 116, 599, 44, 14 ], [ 164, 599, 23, 14 ], [ 190, 599, 40, 14 ], [ 233, 599, 45, 14 ], [ 282, 599, 26, 14 ], [ 312, 599, 44, 14 ], [ 359, 599, 15, 14 ], [ 378, 599, 7, 14 ], [ 389, 599, 21, 14 ], [ 90, 617, 21, 14 ], [ 113, 617, 66, 14 ], [ 180, 617, 21, 14 ], [ 204, 617, 26, 14 ], [ 232, 617, 32, 14 ], [ 266, 617, 19, 14 ], [ 287, 617, 21, 14 ], [ 310, 617, 50, 14 ], [ 362, 617, 10, 14 ], [ 375, 617, 16, 14 ], [ 392, 617, 17, 14 ], [ 90, 635, 30, 14 ], [ 123, 635, 32, 14 ], [ 158, 635, 24, 14 ], [ 185, 635, 32, 14 ], [ 220, 635, 31, 14 ], [ 254, 635, 23, 14 ], [ 280, 635, 24, 14 ], [ 307, 635, 35, 14 ], [ 345, 635, 12, 14 ], [ 361, 635, 30, 14 ], [ 394, 635, 16, 14 ], [ 90, 653, 47, 14 ], [ 140, 653, 16, 14 ], [ 159, 653, 21, 14 ], [ 184, 653, 63, 14 ], [ 250, 653, 31, 14 ], [ 284, 653, 21, 14 ], [ 309, 653, 8, 14 ], [ 320, 653, 21, 14 ], [ 345, 653, 65, 14 ], [ 90, 671, 34, 14 ], [ 126, 671, 20, 14 ], [ 149, 671, 31, 14 ], [ 182, 671, 29, 14 ], [ 213, 671, 22, 14 ], [ 237, 671, 44, 14 ], [ 283, 671, 10, 14 ], [ 296, 671, 22, 14 ], [ 320, 671, 8, 14 ], [ 331, 671, 31, 14 ], [ 364, 671, 45, 14 ], [ 90, 689, 18, 14 ], [ 110, 689, 55, 14 ], [ 168, 689, 29, 14 ], [ 199, 689, 10, 14 ], [ 212, 689, 8, 14 ], [ 222, 689, 31, 14 ], [ 256, 689, 43, 14 ], [ 301, 689, 18, 14 ], [ 322, 689, 56, 14 ], [ 380, 689, 29, 14 ], [ 90, 707, 11, 14 ], [ 104, 707, 8, 14 ], [ 116, 707, 32, 14 ], [ 151, 707, 46, 14 ], [ 201, 707, 21, 14 ], [ 226, 707, 18, 14 ], [ 247, 707, 18, 14 ], [ 269, 707, 30, 14 ], [ 302, 707, 10, 14 ], [ 316, 707, 8, 14 ], [ 328, 707, 32, 14 ], [ 363, 707, 46, 14 ], [ 90, 725, 29, 14 ], [ 123, 725, 26, 14 ], [ 152, 725, 8, 14 ], [ 164, 725, 54, 14 ], [ 222, 725, 27, 14 ], [ 252, 725, 46, 14 ], [ 301, 725, 11, 14 ], [ 316, 725, 8, 14 ], [ 328, 725, 32, 14 ], [ 364, 725, 46, 14 ], [ 90, 743, 70, 14 ], [ 163, 743, 97, 14 ], [ 264, 743, 87, 14 ], [ 355, 743, 25, 14 ], [ 383, 743, 27, 14 ], [ 90, 761, 50, 14 ], [ 144, 761, 10, 14 ], [ 157, 761, 8, 14 ], [ 169, 761, 32, 14 ], [ 204, 761, 46, 14 ], [ 253, 761, 8, 14 ], [ 265, 761, 11, 14 ], [ 279, 761, 32, 14 ], [ 314, 761, 42, 14 ], [ 360, 761, 50, 14 ], [ 90, 780, 45, 14 ], [ 138, 780, 55, 14 ], [ 197, 780, 47, 14 ], [ 246, 780, 82, 14 ], [ 331, 780, 11, 14 ], [ 346, 780, 18, 14 ], [ 367, 780, 43, 14 ], [ 90, 798, 24, 14 ], [ 117, 798, 56, 14 ], [ 176, 798, 58, 14 ], [ 237, 798, 55, 14 ], [ 296, 798, 26, 14 ], [ 325, 798, 57, 14 ], [ 386, 798, 24, 14 ], [ 90, 816, 22, 14 ], [ 115, 816, 36, 14 ], [ 156, 816, 26, 14 ], [ 185, 816, 70, 14 ], [ 260, 816, 50, 14 ], [ 313, 816, 27, 14 ], [ 344, 816, 51, 14 ], [ 399, 816, 11, 14 ], [ 90, 834, 8, 14 ], [ 102, 834, 32, 14 ], [ 136, 834, 45, 14 ], [ 185, 834, 22, 14 ], [ 210, 834, 11, 14 ], [ 225, 834, 18, 14 ], [ 246, 834, 16, 14 ], [ 265, 834, 44, 14 ], [ 312, 834, 23, 14 ], [ 338, 834, 19, 14 ], [ 360, 834, 50, 14 ], [ 90, 852, 23, 14 ], [ 116, 852, 68, 14 ], [ 187, 852, 24, 14 ], [ 214, 852, 13, 14 ], [ 230, 852, 61, 14 ], [ 294, 852, 11, 14 ], [ 309, 852, 55, 14 ], [ 367, 852, 42, 14 ], [ 90, 870, 33, 14 ], [ 126, 870, 11, 14 ], [ 139, 870, 7, 14 ], [ 150, 870, 61, 14 ], [ 214, 870, 60, 14 ], [ 278, 870, 29, 14 ], [ 310, 870, 11, 14 ], [ 324, 870, 39, 14 ], [ 366, 870, 44, 14 ], [ 90, 888, 23, 14 ], [ 117, 888, 41, 14 ], [ 162, 888, 50, 14 ], [ 217, 888, 19, 14 ], [ 239, 888, 55, 14 ], [ 298, 888, 11, 14 ], [ 313, 888, 19, 14 ], [ 336, 888, 22, 14 ], [ 362, 888, 32, 14 ], [ 398, 888, 11, 14 ], [ 440, 382, 14, 14 ], [ 458, 382, 75, 14 ], [ 537, 382, 28, 14 ], [ 569, 382, 36, 14 ], [ 609, 382, 11, 14 ], [ 623, 382, 18, 14 ], [ 645, 382, 61, 14 ], [ 710, 382, 50, 14 ], [ 440, 400, 10, 14 ], [ 454, 400, 45, 14 ], [ 503, 400, 54, 14 ], [ 560, 400, 55, 14 ], [ 619, 400, 18, 14 ], [ 640, 400, 70, 14 ], [ 714, 400, 11, 14 ], [ 729, 400, 19, 14 ], [ 750, 400, 10, 14 ], [ 440, 418, 52, 14 ], [ 496, 418, 15, 14 ], [ 513, 418, 18, 14 ], [ 533, 418, 51, 14 ], [ 587, 418, 72, 14 ], [ 661, 418, 11, 14 ], [ 675, 418, 39, 14 ], [ 716, 418, 44, 14 ], [ 440, 436, 22, 14 ], [ 465, 436, 39, 14 ], [ 506, 436, 48, 14 ], [ 556, 436, 24, 14 ], [ 582, 436, 27, 14 ], [ 611, 436, 95, 14 ], [ 440, 473, 21, 14 ], [ 466, 473, 40, 14 ], [ 510, 473, 43, 14 ], [ 556, 473, 51, 14 ], [ 611, 473, 67, 14 ], [ 682, 473, 36, 14 ], [ 722, 473, 38, 14 ], [ 440, 491, 33, 14 ], [ 476, 491, 34, 14 ], [ 512, 491, 65, 14 ], [ 579, 491, 31, 14 ], [ 440, 527, 90, 14 ], [ 452, 563, 19, 13 ], [ 475, 563, 26, 13 ], [ 505, 563, 47, 13 ], [ 556, 563, 11, 13 ], [ 571, 563, 60, 13 ], [ 636, 563, 30, 13 ], [ 670, 563, 9, 13 ], [ 683, 563, 38, 13 ], [ 725, 563, 35, 13 ], [ 440, 581, 44, 13 ], [ 488, 581, 37, 13 ], [ 528, 581, 16, 13 ], [ 548, 581, 36, 13 ], [ 587, 581, 36, 13 ], [ 626, 581, 41, 13 ], [ 671, 581, 8, 13 ], [ 682, 581, 40, 13 ], [ 726, 581, 34, 13 ], [ 440, 599, 49, 13 ], [ 493, 599, 70, 13 ], [ 567, 599, 60, 13 ], [ 630, 599, 30, 13 ], [ 664, 599, 9, 13 ], [ 676, 599, 46, 13 ], [ 725, 599, 11, 13 ], [ 740, 599, 20, 13 ], [ 440, 617, 45, 13 ], [ 489, 617, 33, 13 ], [ 526, 617, 11, 13 ], [ 540, 617, 31, 13 ], [ 575, 617, 63, 13 ], [ 642, 617, 43, 13 ], [ 689, 617, 25, 13 ], [ 718, 617, 42, 13 ], [ 440, 635, 36, 13 ], [ 480, 635, 13, 13 ], [ 496, 635, 10, 13 ], [ 510, 635, 19, 13 ], [ 533, 635, 17, 13 ], [ 554, 635, 19, 13 ], [ 576, 635, 62, 13 ], [ 641, 635, 33, 13 ], [ 677, 635, 66, 13 ], [ 747, 635, 13, 13 ], [ 440, 654, 16, 13 ], [ 461, 654, 44, 13 ], [ 508, 654, 11, 13 ], [ 523, 654, 7, 13 ], [ 533, 654, 64, 13 ], [ 601, 654, 26, 13 ], [ 631, 654, 23, 13 ], [ 658, 654, 13, 13 ], [ 676, 654, 11, 13 ], [ 690, 654, 20, 13 ], [ 714, 654, 46, 13 ], [ 440, 670, 28, 15 ], [ 452, 690, 11, 13 ], [ 466, 690, 41, 13 ], [ 510, 690, 49, 13 ], [ 562, 690, 8, 13 ], [ 572, 690, 17, 13 ], [ 592, 690, 39, 13 ], [ 634, 690, 44, 13 ], [ 681, 690, 20, 13 ], [ 704, 690, 56, 13 ], [ 440, 708, 9, 13 ], [ 453, 708, 30, 13 ], [ 486, 708, 8, 13 ], [ 497, 708, 6, 13 ], [ 507, 708, 44, 13 ], [ 554, 708, 28, 13 ], [ 585, 708, 11, 13 ], [ 599, 708, 44, 13 ], [ 646, 708, 57, 13 ], [ 707, 708, 11, 13 ], [ 721, 708, 39, 13 ], [ 440, 726, 25, 13 ], [ 470, 726, 11, 13 ], [ 486, 726, 36, 13 ], [ 527, 724, 49, 15 ], [ 581, 726, 13, 13 ], [ 599, 726, 43, 13 ], [ 647, 726, 20, 13 ], [ 671, 726, 89, 13 ], [ 440, 744, 18, 13 ], [ 462, 744, 17, 13 ], [ 483, 744, 24, 13 ], [ 512, 744, 36, 13 ], [ 551, 744, 19, 13 ], [ 574, 744, 17, 13 ], [ 595, 744, 8, 13 ], [ 607, 744, 30, 13 ], [ 641, 744, 11, 13 ], [ 656, 744, 45, 13 ], [ 705, 744, 23, 13 ], [ 732, 744, 28, 13 ], [ 440, 762, 11, 13 ], [ 455, 762, 38, 13 ], [ 497, 762, 56, 13 ], [ 558, 762, 24, 13 ], [ 585, 762, 11, 13 ], [ 600, 762, 64, 13 ], [ 668, 762, 20, 13 ], [ 692, 762, 68, 13 ], [ 440, 780, 20, 13 ], [ 464, 780, 69, 13 ], [ 537, 780, 28, 13 ], [ 569, 778, 57, 15 ], [ 630, 780, 23, 13 ], [ 657, 780, 29, 13 ], [ 690, 780, 35, 13 ], [ 729, 780, 31, 13 ], [ 440, 798, 60, 13 ], [ 503, 798, 30, 13 ], [ 536, 798, 9, 13 ], [ 548, 798, 51, 13 ], [ 601, 798, 23, 13 ], [ 627, 798, 29, 13 ], [ 659, 798, 35, 13 ], [ 697, 798, 19, 13 ], [ 720, 798, 40, 13 ], [ 440, 816, 29, 13 ], [ 472, 816, 43, 13 ], [ 517, 816, 23, 13 ], [ 543, 816, 11, 13 ], [ 557, 816, 25, 13 ], [ 584, 816, 4, 13 ], [ 591, 816, 41, 13 ], [ 634, 816, 19, 13 ], [ 656, 816, 37, 13 ], [ 695, 814, 42, 15 ], [ 452, 834, 29, 13 ], [ 485, 834, 18, 13 ], [ 507, 834, 25, 13 ], [ 535, 834, 6, 13 ], [ 546, 834, 27, 13 ], [ 577, 834, 42, 13 ], [ 622, 834, 11, 13 ], [ 637, 834, 52, 13 ], [ 694, 834, 20, 13 ], [ 717, 834, 43, 13 ], [ 440, 852, 25, 13 ], [ 468, 852, 14, 13 ], [ 485, 852, 19, 13 ], [ 506, 852, 35, 13 ], [ 545, 852, 32, 13 ], [ 580, 852, 11, 13 ], [ 593, 852, 32, 13 ], [ 628, 852, 37, 13 ], [ 668, 852, 29, 13 ], [ 700, 852, 60, 13 ], [ 440, 870, 30, 13 ], [ 474, 870, 18, 13 ], [ 495, 870, 24, 13 ], [ 523, 870, 54, 13 ], [ 581, 870, 19, 13 ], [ 604, 870, 26, 13 ], [ 635, 870, 36, 13 ], [ 675, 870, 35, 13 ], [ 713, 870, 13, 13 ], [ 730, 870, 30, 13 ], [ 440, 888, 31, 13 ], [ 474, 888, 16, 13 ], [ 492, 888, 48, 13 ], [ 543, 888, 50, 13 ], [ 595, 888, 36, 13 ], [ 634, 888, 58, 13 ], [ 694, 888, 15, 13 ], [ 712, 888, 16, 13 ], [ 730, 888, 30, 13 ], [ 92, 940, 71, 12 ], [ 165, 940, 12, 12 ], [ 180, 940, 30, 12 ], [ 212, 940, 23, 12 ], [ 237, 940, 21, 12 ], [ 104, 954, 52, 12 ], [ 158, 954, 10, 12 ], [ 169, 954, 35, 12 ], [ 206, 954, 43, 12 ], [ 251, 954, 20, 12 ], [ 274, 954, 35, 12 ], [ 311, 954, 31, 12 ], [ 344, 954, 20, 12 ], [ 366, 954, 45, 12 ], [ 414, 954, 32, 12 ], [ 448, 954, 10, 12 ], [ 460, 954, 43, 12 ], [ 505, 954, 12, 12 ], [ 519, 954, 82, 12 ], [ 603, 954, 50, 12 ], [ 655, 954, 25, 12 ], [ 682, 954, 40, 12 ], [ 724, 954, 26, 12 ], [ 104, 968, 17, 12 ], [ 123, 968, 77, 12 ], [ 202, 968, 20, 12 ], [ 225, 968, 77, 12 ], [ 304, 968, 33, 12 ], [ 339, 968, 91, 12 ], [ 92, 982, 40, 12 ], [ 134, 982, 12, 12 ], [ 148, 982, 19, 12 ], [ 170, 982, 14, 12 ], [ 186, 982, 25, 12 ], [ 214, 982, 41, 12 ], [ 257, 982, 12, 12 ], [ 271, 982, 36, 12 ], [ 310, 982, 9, 12 ], [ 320, 982, 25, 12 ], [ 92, 996, 28, 12 ], [ 122, 996, 49, 12 ], [ 173, 996, 27, 12 ], [ 203, 996, 49, 12 ], [ 254, 996, 21, 12 ], [ 276, 996, 113, 12 ], [ 105, 1010, 16, 10 ], [ 124, 1010, 7, 10 ], [ 132, 1010, 10, 10 ], [ 145, 1010, 21, 10 ], [ 167, 1010, 26, 10 ], [ 195, 1010, 24, 10 ], [ 222, 1010, 41, 10 ], [ 265, 1010, 23, 10 ], [ 290, 1010, 13, 10 ], [ 304, 1010, 22, 10 ], [ 328, 1010, 9, 10 ], [ 338, 1010, 13, 10 ], [ 353, 1010, 32, 10 ], [ 387, 1010, 39, 10 ], [ 428, 1010, 43, 10 ], [ 473, 1010, 66, 10 ], [ 541, 1010, 29, 10 ], [ 572, 1010, 184, 10 ], [ 93, 1020, 24, 10 ], [ 119, 1020, 29, 10 ], [ 149, 1020, 46, 10 ], [ 197, 1020, 64, 10 ], [ 263, 1020, 15, 10 ], [ 280, 1020, 47, 10 ], [ 329, 1020, 15, 10 ], [ 346, 1020, 50, 10 ], [ 397, 1020, 8, 10 ], [ 408, 1020, 15, 10 ], [ 425, 1020, 34, 10 ], [ 460, 1020, 34, 10 ], [ 497, 1020, 13, 10 ], [ 511, 1020, 30, 10 ], [ 543, 1020, 20, 10 ], [ 565, 1020, 7, 10 ], [ 574, 1020, 33, 10 ], [ 608, 1020, 21, 10 ] ]

[ "Gut", "and", "Liver,", "Vol.", "5,", "No.", "2,", "June", "2011,", "pp.", "181-186", "ORiginal", "Article", "Clinical", "Characteristics", "of", "Microscopic", "Colitis", "in", "Korea:", "Prospective", "Multicenter", "Study", "by", "KASID", "Young", "Sook", "Park*,∥∥,", "Dae", "Hyun", "Baek*,", "Won", "Ho", "Kim†,∥∥,", "Joo", "Sung", "Kim‡,∥∥,", "Suk-Kyun", "Yang§,∥∥,", "Sung-Ae", "Jung∥,∥∥,", "Byung", "Ik", "Jang¶,∥∥,", "Chnag", "Hwan", "Choi#,∥∥,", "Dong", "Soo", "Han**,∥∥,", "Young-Ho", "Kim††,∥∥,", "Yong", "Woo", "Chung‡‡,∥∥,", "Sang", "Woo", "Kim‡‡,∥∥,", "and", "You", "Sun", "Kim§§,∥∥", "Departments", "of", "Internal", "Medicine,", "*Eulji", "University", "College", "of", "Medicine,", "Yonsei", "University", "College", "of", "Medicine,", "Seoul", "National", "University", "College", "of", "Medicine,", "§University", "of", "Ulsan", "College", "of", "Medicine,", "∥Ehwa", "Womans", "University", "School", "of", "Medicine,", "¶Yeungnam", "University", "College", "of", "Medicine,", "#Chung", "Ang", "University", "College", "of", "Medicine,", "**Hanyang", "University", "College", "of", "Medicine,", "Sungkyunkwan", "University", "School", "of", "Medicine,", "Hallym", "University", "College", "of", "Medine,", "§§Inje", "University", "College", "of", "Medicine,", "and", "∥∥Korean", "Association", "for", "the", "Study", "of", "the", "Intestinal", "Disease", "(KASID),", "Korea", "Background/Aims:", "Microscopic", "colitis", "(MC)", "encompasses", "collagenous", "and", "lymphocytic", "colitis", "and", "is", "characterized", "by", "chronic", "diarrhea.", "In", "cases", "of", "MC,", "colonic", "mucosae", "are", "macroscopically", "normal,", "and", "diagnostic", "histopathological", "features", "are", "observed", "only", "upon", "microscopic", "examination.", "We", "designed", "a", "prospective", "multicenter", "study", "to", "determine", "the", "clinical", "features,", "pathological", "distribution", "in", "the", "colon", "and", "prevalence", "of", "MC", "in", "Korea.", "Methods:", "We", "prospectively", "enrolled", "patients", "having", "watery", "diarrhea", "no", "more", "than", "3", "times", "a", "day", "between", "March", "2008", "and", "February", "2009.", "We", "obtained", "patient", "histories", "and", "performed", "colonoscopies", "with", "random", "biopsies", "at", "each", "colon", "segment.", "Results:", "A", "total", "of", "100", "patients", "with", "chronic", "diarrhea", "were", "enrolled", "for", "a", "nor-", "mal", "colonoscopy", "and", "stool", "exam.", "MC", "was", "observed", "in", "22", "pa-", "tients", "(22%)", "(M:F", "1.2:1;", "mean", "age,", "47.5", "years).", "Of", "those", "22", "patients,", "18", "had", "lymphocytic", "colitis", "and", "4", "had", "collagenous", "colitis.", "The", "entire", "colon", "was", "affected", "in", "only", "3", "cases", "(13.6%),", "the", "ascending", "colon", "in", "6", "cases", "(27.2%),", "the", "transverse", "colon", "in", "3", "cases", "(13.6%),", "and", "the", "left", "colon", "in", "3", "cases", "(13.6%).", "More", "than", "2", "segments", "were", "affected", "in", "7", "cases", "(31.8%).", "Nonsteroidal", "anti-inflammatory", "drug-associated", "MCs", "were", "observed", "in", "4", "cases", "(18.2%),", "3", "of", "which", "showed", "improved", "diarrhea", "symptoms", "following", "discontinuation", "of", "the", "medica-", "tion.", "Frequently", "associated", "symptoms", "were", "abdominal", "pain", "and", "weight", "loss.", "Autoimmune", "diseases", "were", "observed", "in", "4", "cases", "(18.2%).", "Half", "of", "the", "22", "patients", "with", "MC", "improved", "with", "conservative", "care", "by", "loperamide", "or", "probiotics.", "Conclu-", "sions:", "In", "a", "prospective", "multicenter", "study", "of", "Korean", "patients", "with", "chronic", "diarrhea,", "the", "frequency", "of", "MC", "was", "found", "to", "be", "approximately", "20%,", "similar", "to", "the", "percentage", "observed", "in", "Western", "countries.", "Therefore,", "the", "identification", "of", "MC", "is", "important", "for", "the", "adequate", "management", "of", "Korean", "patients", "with", "chronic", "diarrhea.", "(Gut", "Liver", "2011;5:181-186)", "Key", "Words:", "Chronic", "diarrhea;", "Microscopic", "colitis;", "Collag-", "enous", "colitis;", "Lymphocytic", "colitis", "INTRODUCTION", "The", "main", "symptom", "of", "microscopic", "colitis", "is", "chronic", "watery", "diarrhea.", "Despite", "the", "grossly", "normal", "mucosa,", "it", "displays", "typical", "histologic", "abnormalities.", "Microscopic", "colitis", "is", "classified", "as", "col-", "lagenous", "colitis,", "in", "which", "subepithelial", "collagen", "layer", "thickens", "around", "10", "to", "100", "μm", "and", "lymphocytic", "colitis,", "characterized", "by", "the", "presence", "of", "a", "lymphocytes", "more", "than", "20", "in", "100", "epithelial", "cells.1", "In", "Western", "countries,", "it", "has", "become", "apparent", "that", "microscop-", "ic", "colitis", "is", "a", "common", "cause", "of", "diarrhea,", "particularly", "in", "middle-", "aged", "or", "elderly", "patients.2", "Its", "etiology", "and", "pathophysiology", "has", "not", "been", "proven", "yet,", "but", "it", "seems", "to", "associate", "with", "using", "of", "various", "medication", "such", "as", "lansoprazole", "and", "non-steroidal", "anti", "inflammatory", "drugs", "(NSAIDs).3,4", "Also", "many", "reports", "shows", "microscopic", "colitis", "is", "associated", "with", "celiac", "disease", "and", "autoim-", "mune", "diseases,", "such", "as", "Type", "I", "diabetes", "and", "thyroid", "disease.2", "There", "has", "been", "a", "rapid", "increase", "in", "researches", "and", "publica-", "tions", "on", "this", "disease", "entity.", "In", "Korea,", "interest", "about", "microscopic", "colitis", "has", "been", "increasing,", "and", "some", "clinical", "reports", "by", "single", "center", "are", "available.", "Therefore,", "Korean", "Association", "for", "the", "Study", "Correspondence", "to:", "Young", "Sook", "Park", "Department", "of", "Internal", "Medicine,", "Eulji", "Medical", "Center,", "Eulji", "University", "College", "of", "Medicine,", "14", "Hangeulbiseok-gil,", "Nowon-gu,", "Seoul", "139-872,", "Korea", "Tel:", "+82-2-970-8207,", "Fax:", "+82-2-970-8621,", "E-mail:", "Pys1109@eulji.ac.kr", "Received", "on", "July", "23,", "2010.", "Accepted", "on", "January", "3,", "2011.", "pISSN", "1976-2283", "eISSN", "2005-1212", "DOI:", "10.5009/gnl.2011.5.2.181", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "Non-Commercial", "License", "(http://creativecommons.org/licenses/by-nc/3.0)", "which", "permits", "unrestricted", "non-commercial", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 78, 47, 41, 12 ], [ 122, 47, 9, 12 ], [ 134, 47, 11, 12 ], [ 148, 47, 21, 12 ], [ 172, 47, 66, 12 ], [ 242, 47, 41, 12 ], [ 286, 47, 25, 12 ], [ 315, 47, 26, 12 ], [ 78, 61, 227, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 12, 18 ], [ 109, 128, 10, 18 ], [ 121, 128, 10, 18 ], [ 139, 128, 11, 18 ], [ 151, 128, 10, 18 ], [ 163, 128, 11, 18 ], [ 175, 128, 13, 18 ], [ 190, 128, 11, 18 ], [ 202, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 142, 34 ], [ 231, 169, 79, 34 ], [ 320, 169, 83, 34 ], [ 413, 169, 25, 34 ], [ 448, 169, 16, 34 ], [ 474, 169, 64, 34 ], [ 548, 169, 58, 34 ], [ 617, 169, 82, 34 ], [ 78, 205, 138, 34 ], [ 227, 205, 16, 34 ], [ 252, 205, 58, 34 ], [ 320, 205, 81, 34 ], [ 78, 252, 22, 16 ], [ 104, 252, 33, 16 ], [ 141, 249, 62, 18 ], [ 208, 252, 42, 16 ], [ 254, 252, 45, 16 ], [ 304, 249, 46, 18 ], [ 354, 252, 55, 16 ], [ 413, 249, 54, 18 ], [ 87, 306, 54, 15 ], [ 87, 331, 76, 14 ], [ 167, 331, 35, 14 ], [ 206, 331, 56, 14 ], [ 266, 331, 22, 14 ], [ 292, 331, 8, 14 ], [ 305, 331, 7, 14 ], [ 315, 331, 21, 14 ], [ 341, 331, 50, 14 ], [ 395, 331, 46, 14 ], [ 445, 331, 74, 14 ], [ 523, 331, 14, 14 ], [ 541, 331, 14, 14 ], [ 559, 331, 74, 14 ], [ 637, 331, 11, 14 ], [ 653, 331, 19, 14 ], [ 676, 331, 42, 14 ], [ 87, 348, 21, 14 ], [ 113, 348, 46, 14 ], [ 163, 348, 12, 14 ], [ 179, 348, 19, 14 ], [ 202, 348, 60, 14 ], [ 267, 348, 56, 14 ], [ 327, 348, 55, 14 ], [ 386, 348, 42, 14 ], [ 431, 348, 12, 14 ], [ 448, 348, 28, 14 ], [ 479, 348, 34, 14 ], [ 517, 348, 11, 14 ], [ 533, 348, 14, 14 ], [ 551, 348, 26, 14 ], [ 581, 348, 23, 14 ], [ 608, 348, 14, 14 ], [ 627, 348, 27, 14 ], [ 658, 348, 21, 14 ], [ 684, 348, 39, 14 ], [ 727, 348, 11, 14 ], [ 87, 365, 39, 14 ], [ 131, 365, 69, 14 ], [ 204, 365, 11, 14 ], [ 219, 365, 15, 14 ], [ 238, 365, 27, 14 ], [ 269, 365, 29, 14 ], [ 302, 365, 57, 14 ], [ 363, 365, 22, 14 ], [ 389, 365, 11, 14 ], [ 404, 365, 19, 14 ], [ 426, 365, 45, 14 ], [ 476, 365, 11, 14 ], [ 491, 365, 30, 14 ], [ 525, 365, 12, 14 ], [ 541, 365, 19, 14 ], [ 564, 365, 36, 14 ], [ 604, 365, 18, 14 ], [ 627, 365, 11, 14 ], [ 642, 365, 29, 14 ], [ 675, 365, 64, 14 ], [ 87, 381, 75, 14 ], [ 166, 381, 11, 14 ], [ 181, 381, 30, 14 ], [ 216, 381, 47, 14 ], [ 267, 381, 11, 14 ], [ 282, 381, 30, 14 ], [ 316, 381, 50, 14 ], [ 371, 381, 71, 14 ], [ 446, 381, 11, 14 ], [ 461, 381, 7, 14 ], [ 472, 381, 85, 14 ], [ 561, 381, 63, 14 ], [ 628, 381, 16, 14 ], [ 648, 381, 53, 14 ], [ 705, 381, 18, 14 ], [ 728, 381, 11, 14 ], [ 87, 398, 73, 14 ], [ 164, 398, 8, 14 ], [ 177, 398, 43, 14 ], [ 224, 398, 60, 14 ], [ 289, 398, 49, 14 ], [ 87, 418, 28, 14 ], [ 120, 418, 80, 14 ], [ 204, 418, 18, 14 ], [ 226, 418, 34, 14 ], [ 265, 418, 19, 14 ], [ 287, 418, 25, 14 ], [ 316, 418, 11, 14 ], [ 332, 418, 7, 14 ], [ 343, 418, 62, 14 ], [ 409, 418, 38, 14 ], [ 451, 418, 45, 14 ], [ 500, 418, 14, 14 ], [ 518, 418, 7, 14 ], [ 529, 418, 23, 14 ], [ 557, 418, 36, 14 ], [ 597, 418, 26, 14 ], [ 627, 418, 27, 14 ], [ 658, 418, 11, 14 ], [ 674, 418, 17, 14 ], [ 87, 435, 9, 14 ], [ 100, 435, 56, 14 ], [ 160, 435, 63, 14 ], [ 228, 435, 61, 14 ], [ 293, 435, 11, 14 ], [ 308, 435, 19, 14 ], [ 331, 435, 56, 14 ], [ 391, 435, 25, 14 ], [ 420, 435, 59, 14 ], [ 483, 435, 29, 14 ], [ 516, 435, 40, 14 ], [ 561, 435, 35, 14 ], [ 600, 435, 14, 14 ], [ 619, 435, 20, 14 ], [ 643, 435, 24, 14 ], [ 87, 452, 74, 14 ], [ 166, 452, 58, 14 ], [ 228, 452, 33, 14 ], [ 265, 452, 41, 14 ], [ 310, 452, 8, 14 ], [ 323, 452, 22, 14 ], [ 349, 452, 51, 14 ], [ 404, 452, 9, 14 ], [ 417, 452, 45, 14 ], [ 466, 452, 105, 14 ], [ 576, 452, 65, 14 ], [ 644, 452, 60, 14 ], [ 708, 452, 19, 14 ], [ 87, 468, 71, 14 ], [ 162, 468, 76, 14 ], [ 242, 468, 11, 14 ], [ 258, 468, 30, 14 ], [ 292, 468, 22, 14 ], [ 318, 468, 51, 14 ], [ 373, 468, 8, 14 ], [ 386, 468, 60, 14 ], [ 450, 468, 79, 14 ], [ 533, 468, 58, 14 ], [ 596, 468, 11, 14 ], [ 611, 468, 42, 14 ], [ 657, 468, 55, 14 ], [ 717, 468, 11, 14 ], [ 87, 485, 26, 14 ], [ 117, 485, 17, 14 ], [ 139, 485, 57, 14 ], [ 200, 485, 39, 14 ], [ 243, 485, 21, 14 ], [ 269, 485, 63, 14 ], [ 336, 485, 75, 14 ], [ 416, 485, 11, 14 ], [ 431, 485, 15, 14 ], [ 450, 485, 25, 14 ], [ 479, 485, 78, 14 ], [ 562, 485, 69, 14 ], [ 636, 485, 17, 14 ], [ 657, 485, 56, 14 ], [ 717, 485, 22, 14 ], [ 87, 501, 7, 14 ], [ 98, 501, 28, 14 ], [ 131, 501, 49, 14 ], [ 184, 501, 37, 14 ], [ 225, 501, 61, 14 ], [ 87, 522, 75, 14 ], [ 167, 522, 22, 14 ], [ 193, 522, 20, 14 ], [ 217, 522, 34, 14 ], [ 256, 522, 11, 14 ], [ 271, 522, 7, 14 ], [ 282, 522, 78, 14 ], [ 365, 522, 61, 14 ], [ 430, 522, 55, 14 ], [ 490, 522, 19, 14 ], [ 513, 522, 45, 14 ], [ 562, 522, 69, 14 ], [ 636, 522, 11, 14 ], [ 651, 522, 47, 14 ], [ 87, 539, 56, 14 ], [ 148, 539, 11, 14 ], [ 163, 539, 19, 14 ], [ 185, 539, 22, 14 ], [ 211, 539, 68, 14 ], [ 283, 539, 27, 14 ], [ 315, 539, 32, 14 ], [ 350, 539, 85, 14 ], [ 440, 539, 44, 14 ], [ 487, 539, 12, 14 ], [ 504, 539, 15, 14 ], [ 522, 539, 63, 14 ], [ 590, 539, 15, 14 ], [ 609, 539, 19, 14 ], [ 632, 539, 34, 14 ], [ 670, 539, 12, 14 ], [ 686, 539, 40, 14 ], [ 87, 555, 57, 14 ], [ 148, 555, 73, 14 ], [ 225, 555, 11, 14 ], [ 240, 555, 17, 14 ], [ 261, 555, 51, 14 ], [ 317, 555, 24, 14 ], [ 345, 555, 53, 14 ], [ 402, 555, 7, 14 ], [ 413, 555, 24, 14 ], [ 441, 555, 47, 14 ], [ 492, 555, 37, 14 ], [ 534, 555, 11, 14 ], [ 549, 555, 19, 14 ], [ 571, 555, 76, 14 ], [ 651, 555, 11, 14 ], [ 667, 555, 26, 14 ], [ 697, 555, 33, 14 ], [ 87, 572, 49, 14 ], [ 78, 618, 77, 15 ], [ 78, 635, 37, 14 ], [ 120, 635, 56, 14 ], [ 180, 635, 29, 14 ], [ 213, 635, 23, 14 ], [ 240, 635, 54, 14 ], [ 298, 635, 14, 14 ], [ 316, 635, 29, 14 ], [ 349, 635, 13, 14 ], [ 366, 635, 37, 14 ], [ 78, 652, 12, 14 ], [ 95, 652, 32, 14 ], [ 131, 652, 10, 14 ], [ 145, 652, 7, 14 ], [ 157, 652, 24, 14 ], [ 185, 652, 54, 14 ], [ 243, 652, 29, 14 ], [ 277, 652, 12, 14 ], [ 293, 652, 67, 14 ], [ 364, 652, 39, 14 ], [ 78, 668, 82, 14 ], [ 165, 668, 23, 14 ], [ 193, 668, 5, 14 ], [ 204, 668, 28, 14 ], [ 237, 668, 12, 14 ], [ 254, 668, 48, 14 ], [ 308, 668, 64, 14 ], [ 377, 668, 27, 14 ], [ 78, 685, 56, 14 ], [ 139, 685, 29, 14 ], [ 173, 685, 46, 14 ], [ 223, 685, 50, 14 ], [ 277, 685, 85, 14 ], [ 367, 685, 37, 14 ], [ 78, 701, 23, 14 ], [ 106, 701, 47, 14 ], [ 157, 701, 9, 14 ], [ 171, 701, 39, 14 ], [ 214, 701, 14, 14 ], [ 232, 701, 40, 14 ], [ 276, 701, 12, 14 ], [ 292, 701, 18, 14 ], [ 315, 701, 32, 14 ], [ 351, 701, 52, 14 ], [ 78, 718, 7, 14 ], [ 89, 718, 63, 14 ], [ 156, 718, 33, 14 ], [ 194, 718, 46, 14 ], [ 244, 718, 21, 14 ], [ 270, 718, 12, 14 ], [ 286, 718, 19, 14 ], [ 310, 718, 40, 14 ], [ 354, 718, 49, 14 ], [ 78, 735, 12, 14 ], [ 95, 735, 49, 14 ], [ 148, 735, 72, 14 ], [ 225, 735, 25, 14 ], [ 254, 735, 22, 14 ], [ 281, 735, 22, 14 ], [ 308, 735, 6, 14 ], [ 319, 735, 35, 14 ], [ 358, 735, 45, 14 ], [ 78, 751, 28, 14 ], [ 111, 751, 12, 14 ], [ 129, 751, 19, 14 ], [ 154, 751, 31, 14 ], [ 190, 751, 68, 14 ], [ 263, 751, 31, 14 ], [ 299, 751, 65, 14 ], [ 370, 751, 34, 14 ], [ 78, 768, 46, 14 ], [ 128, 768, 59, 14 ], [ 192, 768, 24, 14 ], [ 221, 768, 12, 14 ], [ 237, 768, 6, 14 ], [ 249, 768, 34, 14 ], [ 287, 768, 55, 14 ], [ 346, 768, 12, 14 ], [ 363, 768, 41, 14 ], [ 78, 785, 34, 14 ], [ 117, 785, 48, 14 ], [ 169, 785, 40, 14 ], [ 213, 785, 68, 14 ], [ 285, 785, 43, 14 ], [ 333, 785, 28, 14 ], [ 365, 785, 39, 14 ], [ 78, 801, 26, 14 ], [ 109, 801, 29, 14 ], [ 142, 801, 71, 14 ], [ 217, 801, 12, 14 ], [ 234, 801, 55, 14 ], [ 293, 801, 29, 14 ], [ 326, 801, 43, 14 ], [ 373, 801, 17, 14 ], [ 394, 801, 9, 14 ], [ 78, 818, 52, 14 ], [ 134, 818, 14, 14 ], [ 152, 818, 18, 14 ], [ 175, 818, 48, 14 ], [ 227, 818, 11, 14 ], [ 243, 818, 45, 14 ], [ 292, 818, 45, 14 ], [ 341, 818, 28, 14 ], [ 373, 818, 12, 14 ], [ 390, 818, 14, 14 ], [ 78, 834, 49, 14 ], [ 132, 834, 27, 14 ], [ 163, 834, 50, 14 ], [ 217, 834, 30, 14 ], [ 251, 834, 45, 14 ], [ 300, 834, 39, 14 ], [ 343, 834, 14, 14 ], [ 361, 834, 42, 14 ], [ 78, 851, 22, 14 ], [ 105, 851, 53, 14 ], [ 164, 851, 54, 14 ], [ 222, 851, 13, 14 ], [ 240, 851, 62, 14 ], [ 307, 851, 58, 14 ], [ 370, 851, 34, 14 ], [ 78, 868, 43, 14 ], [ 126, 868, 76, 14 ], [ 206, 868, 20, 14 ], [ 231, 868, 16, 14 ], [ 251, 868, 7, 14 ], [ 262, 868, 43, 14 ], [ 310, 868, 27, 14 ], [ 342, 868, 45, 14 ], [ 392, 868, 12, 14 ], [ 78, 884, 19, 14 ], [ 101, 884, 41, 14 ], [ 147, 884, 10, 14 ], [ 161, 884, 41, 14 ], [ 207, 884, 12, 14 ], [ 223, 884, 34, 14 ], [ 261, 884, 26, 14 ], [ 291, 884, 51, 14 ], [ 347, 884, 20, 14 ], [ 372, 884, 32, 14 ], [ 78, 925, 5, 11 ], [ 86, 925, 70, 11 ], [ 159, 925, 77, 11 ], [ 78, 936, 54, 13 ], [ 136, 937, 9, 11 ], [ 147, 937, 60, 11 ], [ 210, 937, 16, 11 ], [ 230, 937, 53, 11 ], [ 286, 937, 37, 11 ], [ 326, 937, 41, 11 ], [ 370, 937, 9, 11 ], [ 78, 950, 32, 11 ], [ 114, 950, 32, 11 ], [ 149, 950, 17, 11 ], [ 78, 962, 15, 11 ], [ 96, 962, 12, 11 ], [ 111, 962, 9, 11 ], [ 123, 962, 28, 11 ], [ 153, 962, 49, 11 ], [ 205, 962, 6, 11 ], [ 215, 962, 36, 11 ], [ 254, 962, 8, 11 ], [ 265, 962, 14, 11 ], [ 282, 962, 16, 11 ], [ 302, 962, 9, 11 ], [ 313, 962, 14, 11 ], [ 330, 962, 25, 11 ], [ 423, 619, 42, 14 ], [ 469, 619, 36, 14 ], [ 510, 619, 12, 14 ], [ 526, 619, 28, 14 ], [ 558, 619, 22, 14 ], [ 584, 619, 39, 14 ], [ 627, 619, 76, 14 ], [ 708, 619, 40, 14 ], [ 423, 635, 19, 14 ], [ 447, 635, 19, 14 ], [ 471, 635, 62, 14 ], [ 538, 635, 54, 14 ], [ 596, 635, 29, 14 ], [ 630, 635, 31, 14 ], [ 666, 635, 18, 14 ], [ 689, 635, 40, 14 ], [ 734, 635, 14, 14 ], [ 423, 652, 77, 14 ], [ 504, 652, 28, 14 ], [ 537, 652, 31, 14 ], [ 572, 652, 30, 14 ], [ 606, 652, 12, 14 ], [ 622, 652, 44, 14 ], [ 670, 652, 78, 14 ], [ 423, 668, 28, 14 ], [ 456, 668, 20, 14 ], [ 480, 668, 17, 14 ], [ 502, 668, 22, 14 ], [ 528, 668, 41, 14 ], [ 574, 668, 72, 14 ], [ 650, 668, 30, 14 ], [ 685, 668, 47, 14 ], [ 736, 668, 12, 14 ], [ 423, 685, 17, 14 ], [ 444, 685, 18, 14 ], [ 466, 685, 58, 14 ], [ 529, 685, 51, 14 ], [ 584, 685, 12, 14 ], [ 600, 685, 28, 14 ], [ 632, 685, 37, 14 ], [ 673, 685, 59, 14 ], [ 736, 685, 12, 14 ], [ 423, 701, 29, 14 ], [ 456, 701, 32, 14 ], [ 492, 701, 51, 14 ], [ 547, 701, 52, 14 ], [ 603, 701, 69, 14 ], [ 677, 701, 21, 14 ], [ 702, 701, 46, 14 ], [ 423, 718, 11, 14 ], [ 438, 718, 18, 14 ], [ 461, 718, 48, 14 ], [ 513, 718, 26, 14 ], [ 544, 718, 58, 14 ], [ 605, 718, 13, 14 ], [ 622, 718, 20, 14 ], [ 646, 718, 25, 14 ], [ 675, 718, 18, 14 ], [ 698, 718, 50, 14 ], [ 423, 735, 12, 14 ], [ 440, 735, 45, 14 ], [ 490, 735, 20, 14 ], [ 515, 735, 35, 14 ], [ 555, 735, 21, 14 ], [ 582, 735, 33, 14 ], [ 621, 735, 33, 14 ], [ 659, 735, 22, 14 ], [ 686, 735, 62, 14 ], [ 423, 751, 61, 14 ], [ 489, 751, 12, 14 ], [ 505, 751, 19, 14 ], [ 528, 751, 64, 14 ], [ 596, 751, 29, 14 ], [ 630, 751, 62, 14 ], [ 696, 751, 24, 14 ], [ 725, 751, 23, 14 ], [ 423, 768, 11, 14 ], [ 438, 768, 31, 14 ], [ 473, 768, 42, 14 ], [ 519, 768, 25, 14 ], [ 548, 768, 64, 14 ], [ 616, 768, 71, 14 ], [ 691, 768, 11, 14 ], [ 706, 768, 42, 14 ], [ 423, 785, 20, 14 ], [ 447, 785, 35, 14 ], [ 487, 785, 76, 14 ], [ 567, 785, 12, 14 ], [ 583, 785, 61, 14 ], [ 648, 785, 21, 14 ], [ 674, 785, 74, 14 ], [ 423, 801, 42, 14 ], [ 469, 801, 63, 14 ], [ 536, 801, 49, 14 ], [ 589, 801, 12, 14 ], [ 605, 801, 14, 14 ], [ 624, 801, 59, 14 ], [ 687, 801, 45, 14 ], [ 736, 801, 12, 14 ], [ 423, 818, 58, 14 ], [ 486, 818, 30, 14 ], [ 521, 818, 12, 14 ], [ 539, 818, 55, 14 ], [ 599, 818, 55, 14 ], [ 659, 818, 18, 14 ], [ 682, 818, 49, 14 ], [ 736, 818, 12, 14 ], [ 423, 834, 21, 14 ], [ 448, 834, 21, 14 ], [ 474, 834, 43, 14 ], [ 521, 834, 11, 14 ], [ 536, 834, 21, 14 ], [ 562, 834, 12, 14 ], [ 577, 834, 100, 14 ], [ 681, 834, 39, 14 ], [ 724, 834, 24, 14 ], [ 423, 851, 44, 14 ], [ 471, 851, 43, 14 ], [ 518, 851, 62, 14 ], [ 584, 851, 48, 14 ], [ 637, 851, 46, 14 ], [ 687, 851, 11, 14 ], [ 703, 851, 45, 14 ], [ 423, 868, 19, 14 ], [ 446, 868, 30, 14 ], [ 480, 868, 26, 14 ], [ 511, 868, 60, 14 ], [ 575, 868, 35, 14 ], [ 615, 868, 12, 14 ], [ 631, 868, 66, 14 ], [ 701, 868, 47, 14 ], [ 423, 884, 26, 14 ], [ 454, 884, 12, 14 ], [ 470, 884, 50, 14 ], [ 525, 884, 12, 14 ], [ 541, 884, 56, 14 ], [ 602, 884, 30, 14 ], [ 636, 884, 45, 14 ], [ 685, 884, 18, 14 ], [ 707, 884, 41, 14 ], [ 423, 901, 25, 14 ], [ 453, 901, 43, 14 ], [ 500, 901, 47, 14 ], [ 552, 901, 18, 14 ], [ 575, 901, 45, 14 ], [ 625, 901, 53, 14 ], [ 683, 901, 20, 14 ], [ 707, 901, 41, 14 ], [ 423, 917, 32, 14 ], [ 459, 917, 19, 14 ], [ 483, 917, 30, 14 ], [ 518, 917, 53, 14 ], [ 575, 917, 22, 14 ], [ 602, 917, 43, 14 ], [ 650, 917, 82, 14 ], [ 736, 917, 12, 14 ], [ 423, 934, 20, 14 ], [ 447, 934, 40, 14 ], [ 492, 934, 38, 14 ], [ 534, 934, 12, 14 ], [ 549, 934, 18, 14 ], [ 572, 934, 23, 14 ], [ 599, 934, 29, 14 ], [ 633, 934, 12, 14 ], [ 649, 934, 21, 14 ], [ 674, 934, 31, 14 ], [ 709, 934, 39, 14 ], [ 423, 950, 30, 14 ], [ 457, 950, 9, 14 ], [ 471, 950, 37, 14 ], [ 513, 950, 21, 14 ], [ 539, 950, 50, 14 ], [ 593, 950, 65, 14 ], [ 663, 950, 58, 14 ], [ 725, 950, 23, 14 ], [ 248, 987, 7, 10 ], [ 257, 987, 18, 10 ], [ 278, 987, 33, 10 ], [ 313, 987, 8, 10 ], [ 324, 987, 8, 10 ], [ 335, 987, 30, 10 ], [ 368, 987, 29, 10 ], [ 399, 987, 27, 10 ], [ 429, 987, 14, 10 ], [ 446, 987, 15, 10 ], [ 464, 987, 6, 10 ], [ 472, 987, 10, 10 ], [ 484, 987, 21, 10 ], [ 508, 987, 25, 10 ], [ 536, 987, 23, 10 ], [ 562, 987, 41, 10 ], [ 606, 987, 23, 10 ], [ 631, 987, 13, 10 ], [ 646, 987, 22, 10 ], [ 671, 987, 8, 10 ], [ 681, 987, 13, 10 ], [ 697, 987, 31, 10 ], [ 248, 998, 39, 10 ], [ 289, 998, 41, 10 ], [ 333, 998, 28, 10 ], [ 364, 998, 171, 10 ], [ 538, 998, 23, 10 ], [ 564, 998, 29, 10 ], [ 595, 998, 45, 10 ], [ 643, 998, 15, 10 ], [ 660, 998, 45, 10 ], [ 708, 998, 15, 10 ], [ 248, 1009, 49, 10 ], [ 300, 1009, 7, 10 ], [ 310, 1009, 14, 10 ], [ 326, 1009, 34, 10 ], [ 362, 1009, 34, 10 ], [ 399, 1009, 13, 10 ], [ 415, 1009, 28, 10 ], [ 446, 1009, 19, 10 ], [ 467, 1009, 6, 10 ], [ 476, 1009, 32, 10 ], [ 510, 1009, 20, 10 ] ]

[ "Bassareo", "et", "al.", "BMC", "Cardiovascular", "Disorders", "2010,", "10:48", "http://www.biomedcentral.com/1471-2261/10/48", "C", "A", "S", "E", "R", "E", "P", "O", "R", "T", "Open", "Access", "Ventricular", "septal", "defect", "in", "a", "child", "with", "Alport", "syndrome:", "a", "case", "report", "Pier", "Paolo", "Bassareo1*,", "Andrea", "Raffaele", "Marras2,", "Giuseppe", "Mercuro1", "Abstract", "Background:", "Alport", "syndrome", "(AS)", "is", "a", "rare", "inherited", "disorder", "characterized", "by", "an", "inflammation", "of", "the", "kidneys", "and", "damage", "to", "the", "glomerular", "capillaries,", "ultimately", "leading", "to", "renal", "failure", "at", "an", "early", "age.", "To", "date,", "rare", "reports", "of", "cardiac", "involvement", "in", "AS", "have", "been", "described,", "due", "in", "the", "majority", "of", "cases", "to", "the", "higher", "risk", "of", "heart", "conduction", "abnormalities", "in", "these", "patients,", "at", "times", "requiring", "implantation", "of", "a", "transcutaneous", "pacemaker.", "An", "increased", "risk", "of", "hypertension", "is", "likewise", "commonly", "featured.", "Case", "presentation:", "We", "report", "the", "case", "of", "a", "17-year-old", "female", "affected", "by", "a", "very", "severe", "early", "form", "of", "AS.", "A", "previously", "unreported", "association", "of", "the", "syndrome", "with", "congenital", "heart", "disease", "(CHD),", "(in", "this", "case", "membranous", "ventricular", "septal", "defect),", "is", "also", "reported.", "A", "possible", "pathophysiological", "mechanism", "underlying", "the", "concomitant", "manifestation", "of", "these", "two", "disorders", "is", "suggested.", "Complications", "implicated", "in", "surgical", "treatment", "of", "CHD", "are", "described.", "Clinical", "and", "therapeutic", "management", "of", "AS", "with", "cardiovascular", "involvement", "are", "discussed,", "and", "a", "short", "literature", "review", "performed.", "Conclusions:", "This", "first", "report", "of", "a", "cardiovascular", "association", "highlights", "the", "possible", "involvement", "of", "collagen", "mutations", "in", "the", "two", "pathologies.", "Even", "when", "drug-resistance", "appears", "to", "be", "responsible", "for", "the", "failure", "to", "control", "secondary", "hypertension", "in", "AS,", "clonidine", "may", "represent", "a", "safe,", "effective", "option", "in", "the", "normalization", "of", "high", "blood", "pressure.", "Background", "Alport", "syndrome", "(AS),", "first", "described", "by", "Cecil", "A.", "Alport", "in", "1927,", "is", "a", "rare", "inherited", "form", "of", "progressive", "kidney", "inflammation", "(0.3", "-", "2.3%", "of", "patients", "presenting", "with", "end-stage", "renal", "disease)", "affecting", "predominantly", "males.", "The", "disorder", "is", "caused", "by", "defects", "in", "the", "genes", "encoding", "a", "connective", "tissue", "protein,", "one", "of", "the", "several", "subunits", "of", "collagen", "(particularly", "type", "IV),", "and", "a", "major", "compo-", "nent", "of", "the", "renal", "glomerular", "basal", "membrane", "[1-5].", "Various", "mutations", "lead", "to", "a", "broad", "spectrum", "of", "signifi-", "cantly", "different", "disease", "phenotypes,", "ranging", "from", "benign", "mild", "renal", "insufficiency", "to", "end-stage", "renal", "disease.", "AS", "is", "inherited", "by", "the", "majority", "of", "patients", "(approx", "85%)", "as", "an", "X-linked", "trait,", "although", "some", "patients", "display", "an", "autoso-", "mal", "recessive", "(10-15%)", "or", "autosomal", "dominant", "(rare)", "genetic", "transmission", "[6].", "As", "a", "general", "rule,", "severity", "of", "the", "disease", "is", "greater", "in", "males", "with", "X-linked", "AS,", "being", "*", "Correspondence:", "piercard@inwind.it", "1Department", "of", "Cardiovascular", "and", "Neurological", "Sciences,", "University", "of", "Cagliari,", "Cagliari,", "Italy", "Full", "list", "of", "author", "information", "is", "available", "at", "the", "end", "of", "the", "article", "equally", "severe", "in", "male", "and", "female", "homozygotes", "featur-", "ing", "the", "autosomal", "recessive", "form", "[7,8].", "AS", "should", "be", "differentiated", "from", "other", "types", "of", "chronic", "glomerulopa-", "thies", "[9].", "To", "this", "regard,", "microscopic", "renal", "changes", "in", "AS", "are", "frequently", "observed", "in", "early", "biopsy", "specimens", "of", "renal", "tissue", "featuring", "podocyte", "hypertrophy", "and", "stiffness", "of", "the", "capillary", "wall,", "associated", "or", "not", "with", "the", "presence", "of", "tubular", "red", "blood", "cell", "casts.", "Focal", "and", "segmental", "thickening", "of", "the", "glomerular", "basal", "membrane", "may", "also", "at", "times", "present", "with", "progressive", "enlargement", "of", "mesan-", "gial", "stalks.", "Development", "of", "segmental,", "and", "subsequently", "diffuse,", "glomerular", "sclerosis", "in", "an", "increasing", "number", "of", "glomeruli", "leads", "to", "complete", "sclerosis.", "An", "increase", "in", "size", "and", "severity", "of", "foci", "of", "tubulo-interstitial", "lesions", "may", "precede", "marked", "glomerular", "changes.", "Clusters", "of", "intersti-", "tial", "foam", "cells", "frequently", "found", "in", "proteinuric", "patients", "tend", "to", "decrease", "in", "end-stage", "renal", "disease.", "No", "signifi-", "cant", "arterial", "changes", "are", "initially", "observed", "[3].", "Hema-", "turia,", "the", "most", "common", "and", "earliest", "manifestation", "of", "AS,", "usually", "occurs", "in", "the", "first", "years", "of", "life,", "while", "protei-", "nuria", "is", "absent", "and", "develops", "throughout", "childhood", "into", "©", "2010", "Bassareo", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 78, 47, 23, 12 ], [ 104, 47, 9, 12 ], [ 116, 47, 11, 12 ], [ 130, 47, 21, 12 ], [ 154, 47, 44, 12 ], [ 201, 47, 25, 12 ], [ 230, 47, 32, 12 ], [ 78, 61, 233, 12 ], [ 83, 128, 11, 18 ], [ 96, 128, 10, 18 ], [ 107, 128, 10, 18 ], [ 119, 128, 10, 18 ], [ 130, 128, 12, 18 ], [ 144, 128, 11, 18 ], [ 156, 128, 11, 18 ], [ 169, 128, 13, 18 ], [ 189, 128, 12, 18 ], [ 203, 128, 11, 18 ], [ 215, 128, 10, 18 ], [ 227, 128, 5, 18 ], [ 234, 128, 11, 18 ], [ 247, 128, 10, 18 ], [ 258, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 183, 34 ], [ 270, 169, 84, 34 ], [ 362, 169, 26, 34 ], [ 396, 169, 67, 34 ], [ 472, 169, 131, 34 ], [ 611, 169, 96, 34 ], [ 716, 169, 27, 34 ], [ 78, 205, 126, 34 ], [ 213, 205, 26, 34 ], [ 247, 205, 43, 34 ], [ 298, 205, 68, 34 ], [ 374, 205, 44, 34 ], [ 426, 205, 108, 34 ], [ 542, 205, 78, 34 ], [ 628, 205, 118, 34 ], [ 78, 241, 75, 34 ], [ 161, 241, 100, 34 ], [ 270, 241, 51, 34 ], [ 329, 241, 93, 34 ], [ 430, 241, 78, 34 ], [ 516, 241, 128, 34 ], [ 78, 288, 42, 16 ], [ 124, 288, 30, 16 ], [ 159, 288, 32, 16 ], [ 195, 288, 67, 16 ], [ 267, 288, 25, 16 ], [ 296, 288, 38, 16 ], [ 339, 288, 31, 16 ], [ 375, 288, 56, 16 ], [ 435, 288, 25, 16 ], [ 464, 288, 12, 16 ], [ 480, 285, 95, 19 ], [ 580, 288, 22, 16 ], [ 607, 288, 33, 16 ], [ 644, 288, 39, 16 ], [ 87, 342, 54, 15 ], [ 87, 367, 76, 14 ], [ 167, 367, 21, 14 ], [ 192, 367, 29, 14 ], [ 225, 367, 19, 14 ], [ 248, 367, 22, 14 ], [ 275, 367, 46, 14 ], [ 325, 367, 102, 14 ], [ 431, 367, 40, 14 ], [ 476, 367, 35, 14 ], [ 514, 367, 66, 14 ], [ 585, 367, 48, 14 ], [ 637, 367, 8, 14 ], [ 649, 367, 19, 14 ], [ 672, 367, 28, 14 ], [ 87, 384, 50, 14 ], [ 142, 384, 11, 14 ], [ 158, 384, 60, 14 ], [ 222, 384, 55, 14 ], [ 281, 384, 12, 14 ], [ 297, 384, 19, 14 ], [ 320, 384, 23, 14 ], [ 347, 384, 30, 14 ], [ 382, 384, 11, 14 ], [ 396, 384, 31, 14 ], [ 432, 384, 29, 14 ], [ 465, 384, 17, 14 ], [ 486, 384, 33, 14 ], [ 523, 384, 7, 14 ], [ 534, 384, 50, 14 ], [ 588, 384, 53, 14 ], [ 645, 384, 12, 14 ], [ 661, 384, 27, 14 ], [ 692, 384, 25, 14 ], [ 721, 384, 15, 14 ], [ 87, 400, 22, 14 ], [ 113, 400, 41, 14 ], [ 159, 400, 22, 14 ], [ 185, 400, 17, 14 ], [ 207, 400, 24, 14 ], [ 235, 400, 43, 14 ], [ 283, 400, 67, 14 ], [ 354, 400, 43, 14 ], [ 401, 400, 19, 14 ], [ 424, 400, 88, 14 ], [ 516, 400, 11, 14 ], [ 531, 400, 19, 14 ], [ 554, 400, 29, 14 ], [ 587, 400, 56, 14 ], [ 647, 400, 41, 14 ], [ 87, 417, 58, 14 ], [ 149, 417, 25, 14 ], [ 178, 417, 22, 14 ], [ 205, 417, 48, 14 ], [ 257, 417, 54, 14 ], [ 315, 417, 22, 14 ], [ 341, 417, 19, 14 ], [ 363, 417, 35, 14 ], [ 403, 417, 12, 14 ], [ 419, 417, 34, 14 ], [ 457, 417, 33, 14 ], [ 495, 417, 54, 14 ], [ 553, 417, 54, 14 ], [ 610, 417, 25, 14 ], [ 640, 417, 79, 14 ], [ 87, 434, 58, 14 ], [ 87, 454, 46, 14 ], [ 137, 454, 9, 14 ], [ 149, 454, 56, 14 ], [ 209, 454, 28, 14 ], [ 240, 454, 40, 14 ], [ 283, 454, 45, 14 ], [ 330, 454, 33, 14 ], [ 366, 454, 21, 14 ], [ 391, 454, 49, 14 ], [ 443, 454, 15, 14 ], [ 461, 454, 62, 14 ], [ 527, 454, 76, 14 ], [ 606, 454, 52, 14 ], [ 661, 454, 11, 14 ], [ 676, 454, 18, 14 ], [ 697, 454, 26, 14 ], [ 87, 471, 37, 14 ], [ 128, 471, 43, 14 ], [ 175, 471, 28, 14 ], [ 206, 471, 31, 14 ], [ 240, 471, 60, 14 ], [ 303, 471, 106, 14 ], [ 412, 471, 30, 14 ], [ 445, 471, 11, 14 ], [ 459, 471, 18, 14 ], [ 481, 471, 51, 14 ], [ 535, 471, 45, 14 ], [ 583, 471, 46, 14 ], [ 632, 471, 49, 14 ], [ 684, 471, 49, 14 ], [ 87, 488, 24, 14 ], [ 115, 488, 25, 14 ], [ 143, 488, 30, 14 ], [ 176, 488, 11, 14 ], [ 190, 488, 88, 14 ], [ 282, 488, 11, 14 ], [ 296, 488, 19, 14 ], [ 319, 488, 35, 14 ], [ 356, 488, 50, 14 ], [ 410, 488, 36, 14 ], [ 449, 488, 33, 14 ], [ 485, 488, 37, 14 ], [ 526, 488, 12, 14 ], [ 541, 488, 18, 14 ], [ 562, 488, 22, 14 ], [ 587, 488, 67, 14 ], [ 658, 488, 21, 14 ], [ 87, 504, 86, 14 ], [ 177, 504, 51, 14 ], [ 230, 504, 21, 14 ], [ 255, 504, 30, 14 ], [ 288, 504, 24, 14 ], [ 316, 504, 52, 14 ], [ 370, 504, 47, 14 ], [ 421, 504, 61, 14 ], [ 485, 504, 41, 14 ], [ 529, 504, 11, 14 ], [ 543, 504, 18, 14 ], [ 565, 504, 18, 14 ], [ 586, 504, 33, 14 ], [ 623, 504, 11, 14 ], [ 637, 504, 45, 14 ], [ 685, 504, 47, 14 ], [ 87, 521, 25, 14 ], [ 115, 521, 67, 14 ], [ 186, 521, 11, 14 ], [ 200, 521, 18, 14 ], [ 221, 521, 22, 14 ], [ 246, 521, 69, 14 ], [ 318, 521, 9, 14 ], [ 330, 521, 30, 14 ], [ 363, 521, 58, 14 ], [ 424, 521, 48, 14 ], [ 475, 521, 30, 14 ], [ 508, 521, 11, 14 ], [ 522, 521, 20, 14 ], [ 545, 521, 88, 14 ], [ 637, 521, 21, 14 ], [ 661, 521, 18, 14 ], [ 87, 537, 60, 14 ], [ 150, 537, 11, 14 ], [ 165, 537, 18, 14 ], [ 186, 537, 76, 14 ], [ 265, 537, 49, 14 ], [ 317, 537, 21, 14 ], [ 341, 537, 33, 14 ], [ 377, 537, 10, 14 ], [ 391, 537, 28, 14 ], [ 422, 537, 31, 14 ], [ 456, 537, 51, 14 ], [ 510, 537, 18, 14 ], [ 531, 537, 57, 14 ], [ 592, 537, 11, 14 ], [ 606, 537, 22, 14 ], [ 631, 537, 87, 14 ], [ 87, 554, 33, 14 ], [ 123, 554, 21, 14 ], [ 148, 554, 54, 14 ], [ 205, 554, 10, 14 ], [ 219, 554, 30, 14 ], [ 252, 554, 45, 14 ], [ 300, 554, 10, 14 ], [ 314, 554, 18, 14 ], [ 335, 554, 45, 14 ], [ 383, 554, 11, 14 ], [ 398, 554, 54, 14 ], [ 455, 554, 20, 14 ], [ 478, 554, 90, 14 ], [ 572, 554, 40, 14 ], [ 615, 554, 18, 14 ], [ 636, 554, 20, 14 ], [ 659, 554, 22, 14 ], [ 684, 554, 54, 14 ], [ 87, 571, 32, 14 ], [ 123, 571, 49, 14 ], [ 175, 571, 44, 14 ], [ 222, 571, 18, 14 ], [ 243, 571, 47, 14 ], [ 293, 571, 21, 14 ], [ 318, 571, 48, 14 ], [ 369, 571, 22, 14 ], [ 394, 571, 47, 14 ], [ 444, 571, 52, 14 ], [ 499, 571, 21, 14 ], [ 524, 571, 56, 14 ], [ 583, 571, 12, 14 ], [ 598, 571, 51, 14 ], [ 652, 571, 57, 14 ], [ 713, 571, 11, 14 ], [ 87, 587, 30, 14 ], [ 121, 587, 11, 14 ], [ 134, 587, 18, 14 ], [ 156, 587, 18, 14 ], [ 177, 587, 22, 14 ], [ 202, 587, 5, 14 ], [ 210, 587, 7, 14 ], [ 220, 587, 37, 14 ], [ 261, 587, 40, 14 ], [ 304, 587, 77, 14 ], [ 384, 587, 63, 14 ], [ 450, 587, 5, 14 ], [ 458, 587, 10, 14 ], [ 472, 587, 32, 14 ], [ 507, 587, 24, 14 ], [ 534, 587, 11, 14 ], [ 548, 587, 18, 14 ], [ 569, 587, 45, 14 ], [ 617, 587, 53, 14 ], [ 87, 608, 70, 14 ], [ 161, 608, 18, 14 ], [ 184, 608, 43, 14 ], [ 230, 608, 24, 14 ], [ 259, 608, 43, 14 ], [ 306, 608, 22, 14 ], [ 332, 608, 29, 14 ], [ 365, 608, 34, 14 ], [ 403, 608, 39, 14 ], [ 446, 608, 12, 14 ], [ 462, 608, 19, 14 ], [ 485, 608, 22, 14 ], [ 511, 608, 48, 14 ], [ 563, 608, 21, 14 ], [ 589, 608, 22, 14 ], [ 615, 608, 25, 14 ], [ 645, 608, 19, 14 ], [ 667, 608, 27, 14 ], [ 698, 608, 11, 14 ], [ 87, 625, 54, 14 ], [ 145, 625, 11, 14 ], [ 161, 625, 19, 14 ], [ 184, 625, 20, 14 ], [ 209, 625, 33, 14 ], [ 246, 625, 29, 14 ], [ 279, 625, 12, 14 ], [ 295, 625, 47, 14 ], [ 346, 625, 58, 14 ], [ 408, 625, 64, 14 ], [ 476, 625, 19, 14 ], [ 499, 625, 52, 14 ], [ 555, 625, 11, 14 ], [ 570, 625, 20, 14 ], [ 595, 625, 24, 14 ], [ 623, 625, 11, 14 ], [ 638, 625, 50, 14 ], [ 87, 641, 55, 14 ], [ 147, 641, 32, 14 ], [ 183, 641, 45, 14 ], [ 232, 641, 59, 14 ], [ 295, 641, 27, 14 ], [ 326, 641, 33, 14 ], [ 363, 641, 67, 14 ], [ 435, 641, 15, 14 ], [ 454, 641, 81, 14 ], [ 540, 641, 19, 14 ], [ 562, 641, 64, 14 ], [ 631, 641, 11, 14 ], [ 646, 641, 30, 14 ], [ 681, 641, 57, 14 ], [ 87, 658, 40, 14 ], [ 78, 704, 77, 15 ], [ 78, 721, 23, 14 ], [ 106, 721, 48, 14 ], [ 157, 721, 12, 14 ], [ 173, 721, 47, 14 ], [ 225, 721, 50, 14 ], [ 278, 721, 12, 14 ], [ 294, 721, 48, 14 ], [ 346, 721, 41, 14 ], [ 391, 721, 13, 14 ], [ 78, 737, 84, 14 ], [ 166, 737, 61, 14 ], [ 231, 737, 10, 14 ], [ 244, 737, 49, 14 ], [ 297, 737, 17, 14 ], [ 318, 737, 71, 14 ], [ 392, 737, 12, 14 ], [ 78, 754, 70, 14 ], [ 155, 754, 57, 14 ], [ 218, 754, 61, 14 ], [ 285, 754, 12, 14 ], [ 303, 754, 61, 14 ], [ 370, 754, 33, 14 ], [ 78, 771, 53, 14 ], [ 134, 771, 14, 14 ], [ 151, 771, 102, 14 ], [ 257, 771, 42, 14 ], [ 302, 771, 41, 14 ], [ 347, 771, 57, 14 ], [ 78, 787, 24, 14 ], [ 106, 787, 7, 14 ], [ 117, 787, 20, 14 ], [ 140, 787, 23, 14 ], [ 167, 787, 12, 14 ], [ 183, 787, 30, 14 ], [ 217, 787, 59, 14 ], [ 280, 787, 10, 14 ], [ 294, 787, 61, 14 ], [ 358, 787, 45, 14 ], [ 78, 804, 11, 14 ], [ 93, 804, 47, 14 ], [ 144, 804, 19, 14 ], [ 166, 804, 27, 14 ], [ 197, 804, 59, 14 ], [ 260, 804, 12, 14 ], [ 275, 804, 36, 14 ], [ 314, 804, 29, 14 ], [ 346, 804, 12, 14 ], [ 361, 804, 42, 14 ], [ 78, 820, 33, 14 ], [ 115, 820, 30, 14 ], [ 150, 820, 34, 14 ], [ 188, 820, 75, 14 ], [ 266, 820, 57, 14 ], [ 327, 820, 33, 14 ], [ 365, 820, 39, 14 ], [ 78, 837, 15, 14 ], [ 97, 837, 18, 14 ], [ 118, 837, 36, 14 ], [ 158, 837, 28, 14 ], [ 189, 837, 84, 14 ], [ 277, 837, 54, 14 ], [ 335, 837, 27, 14 ], [ 365, 837, 39, 14 ], [ 78, 854, 12, 14 ], [ 94, 854, 41, 14 ], [ 139, 854, 13, 14 ], [ 155, 854, 48, 14 ], [ 208, 854, 37, 14 ], [ 248, 854, 32, 14 ], [ 284, 854, 40, 14 ], [ 328, 854, 54, 14 ], [ 385, 854, 18, 14 ], [ 78, 870, 79, 14 ], [ 160, 870, 61, 14 ], [ 225, 870, 44, 14 ], [ 272, 870, 38, 14 ], [ 313, 870, 28, 14 ], [ 345, 870, 29, 14 ], [ 377, 870, 26, 14 ], [ 78, 887, 41, 14 ], [ 123, 887, 12, 14 ], [ 139, 887, 7, 14 ], [ 150, 887, 35, 14 ], [ 190, 887, 86, 14 ], [ 280, 887, 12, 14 ], [ 296, 887, 72, 14 ], [ 372, 887, 32, 14 ], [ 78, 904, 28, 14 ], [ 110, 904, 12, 14 ], [ 125, 904, 37, 14 ], [ 166, 904, 63, 14 ], [ 232, 904, 23, 14 ], [ 259, 904, 29, 14 ], [ 292, 904, 52, 14 ], [ 348, 904, 12, 14 ], [ 364, 904, 40, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 98, 11 ], [ 78, 950, 61, 11 ], [ 142, 950, 11, 11 ], [ 156, 950, 57, 11 ], [ 216, 950, 6, 11 ], [ 226, 950, 35, 11 ], [ 264, 950, 11, 11 ], [ 278, 950, 39, 11 ], [ 320, 950, 49, 11 ], [ 78, 962, 56, 11 ], [ 137, 962, 11, 11 ], [ 151, 962, 31, 11 ], [ 185, 962, 28, 11 ], [ 216, 962, 25, 11 ], [ 244, 962, 31, 11 ], [ 279, 962, 23, 11 ], [ 423, 704, 54, 14 ], [ 480, 704, 9, 14 ], [ 494, 704, 7, 14 ], [ 504, 704, 101, 14 ], [ 609, 704, 44, 14 ], [ 657, 704, 59, 14 ], [ 719, 704, 29, 14 ], [ 423, 721, 28, 14 ], [ 454, 721, 12, 14 ], [ 470, 721, 48, 14 ], [ 521, 721, 57, 14 ], [ 581, 721, 11, 14 ], [ 596, 721, 29, 14 ], [ 629, 721, 41, 14 ], [ 673, 721, 23, 14 ], [ 699, 721, 49, 14 ], [ 423, 737, 7, 14 ], [ 433, 737, 57, 14 ], [ 493, 737, 55, 14 ], [ 552, 737, 47, 14 ], [ 602, 737, 14, 14 ], [ 619, 737, 37, 14 ], [ 659, 737, 11, 14 ], [ 673, 737, 75, 14 ], [ 423, 754, 23, 14 ], [ 449, 754, 36, 14 ], [ 489, 754, 19, 14 ], [ 511, 754, 23, 14 ], [ 538, 754, 58, 14 ], [ 599, 754, 11, 14 ], [ 614, 754, 39, 14 ], [ 657, 754, 33, 14 ], [ 693, 754, 55, 14 ], [ 423, 771, 25, 14 ], [ 453, 771, 51, 14 ], [ 510, 771, 16, 14 ], [ 531, 771, 7, 14 ], [ 543, 771, 42, 14 ], [ 590, 771, 12, 14 ], [ 608, 771, 76, 14 ], [ 689, 771, 59, 14 ], [ 423, 787, 44, 14 ], [ 470, 787, 50, 14 ], [ 524, 787, 62, 14 ], [ 590, 787, 66, 14 ], [ 659, 787, 11, 14 ], [ 674, 787, 49, 14 ], [ 727, 787, 21, 14 ], [ 423, 804, 35, 14 ], [ 461, 804, 21, 14 ], [ 486, 804, 18, 14 ], [ 507, 804, 35, 14 ], [ 546, 804, 11, 14 ], [ 560, 804, 41, 14 ], [ 605, 804, 75, 14 ], [ 683, 804, 19, 14 ], [ 434, 820, 13, 14 ], [ 450, 820, 32, 14 ], [ 486, 820, 16, 14 ], [ 506, 820, 40, 14 ], [ 550, 820, 50, 14 ], [ 604, 820, 27, 14 ], [ 634, 820, 28, 14 ], [ 666, 820, 55, 14 ], [ 725, 820, 23, 14 ], [ 423, 837, 45, 14 ], [ 472, 837, 18, 14 ], [ 494, 837, 50, 14 ], [ 547, 837, 12, 14 ], [ 563, 837, 49, 14 ], [ 615, 837, 43, 14 ], [ 661, 837, 13, 14 ], [ 677, 837, 71, 14 ], [ 423, 854, 72, 14 ], [ 499, 854, 52, 14 ], [ 554, 854, 56, 14 ], [ 615, 854, 17, 14 ], [ 636, 854, 50, 14 ], [ 690, 854, 58, 14 ], [ 423, 870, 71, 14 ], [ 497, 870, 40, 14 ], [ 541, 870, 55, 14 ], [ 599, 870, 20, 14 ], [ 623, 870, 92, 14 ], [ 718, 870, 30, 14 ], [ 423, 887, 111, 14 ], [ 537, 887, 55, 14 ], [ 596, 887, 19, 14 ], [ 619, 887, 24, 14 ], [ 646, 887, 57, 14 ], [ 707, 887, 41, 14 ], [ 423, 903, 50, 14 ], [ 477, 903, 37, 14 ], [ 518, 903, 20, 14 ], [ 543, 903, 16, 14 ], [ 564, 903, 49, 14 ], [ 617, 903, 60, 14 ], [ 682, 903, 38, 14 ], [ 724, 903, 24, 14 ], [ 423, 920, 51, 14 ], [ 477, 920, 54, 14 ], [ 534, 920, 21, 14 ], [ 558, 920, 19, 14 ], [ 580, 920, 20, 14 ], [ 603, 920, 23, 14 ], [ 629, 920, 31, 14 ], [ 664, 920, 35, 14 ], [ 702, 920, 20, 14 ], [ 725, 920, 23, 14 ], [ 423, 937, 46, 14 ], [ 472, 937, 51, 14 ], [ 526, 937, 22, 14 ], [ 551, 937, 14, 14 ], [ 568, 937, 51, 14 ], [ 622, 937, 36, 14 ], [ 661, 937, 12, 14 ], [ 676, 937, 39, 14 ], [ 718, 937, 30, 14 ], [ 423, 953, 27, 14 ], [ 453, 953, 11, 14 ], [ 467, 953, 23, 14 ], [ 493, 953, 23, 14 ], [ 519, 953, 28, 14 ], [ 550, 953, 46, 14 ], [ 600, 953, 9, 14 ], [ 612, 953, 47, 14 ], [ 662, 953, 16, 14 ], [ 682, 953, 66, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 19, 10 ], [ 277, 987, 18, 10 ], [ 298, 987, 8, 10 ], [ 308, 987, 8, 10 ], [ 319, 987, 30, 10 ], [ 352, 987, 29, 10 ], [ 383, 987, 27, 10 ], [ 412, 987, 14, 10 ], [ 429, 987, 15, 10 ], [ 446, 987, 6, 10 ], [ 454, 987, 10, 10 ], [ 466, 987, 21, 10 ], [ 490, 987, 25, 10 ], [ 518, 987, 23, 10 ], [ 543, 987, 41, 10 ], [ 586, 987, 23, 10 ], [ 611, 987, 13, 10 ], [ 626, 987, 21, 10 ], [ 650, 987, 8, 10 ], [ 661, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "Arias", "et", "al.", "BMC", "Genomics", "2011,", "12:390", "http://www.biomedcentral.com/1471-2164/12/390", "R", "E", "S", "E", "A", "R", "C", "H", "A", "R", "T", "I", "C", "L", "E", "Open", "Access", "Genome-wide", "survey", "of", "yeast", "mutations", "leading", "to", "activation", "of", "the", "yeast", "cell", "integrity", "MAPK", "pathway:", "Novel", "insights", "into", "diverse", "MAPK", "outcomes", "Patricia", "Arias,", "Sonia", "Díez-Muñiz,", "Raúl", "García,", "César", "Nombela,", "José", "M", "Rodríguez-Peña*", "and", "Javier", "Arroyo", "Abstract", "Background:", "The", "yeast", "cell", "wall", "integrity", "mitogen-activated", "protein", "kinase", "(CWI-MAPK)", "pathway", "is", "the", "main", "regulator", "of", "adaptation", "responses", "to", "cell", "wall", "stress", "in", "yeast.", "Here,", "we", "adopt", "a", "genomic", "approach", "to", "shed", "light", "on", "two", "aspects", "that", "are", "only", "partially", "understood,", "namely,", "the", "characterization", "of", "the", "gene", "functional", "catalog", "associated", "with", "CWI", "pathway", "activation", "and", "the", "extent", "to", "which", "MAPK", "activation", "correlates", "with", "transcriptional", "outcomes.", "Results:", "A", "systematic", "yeast", "mutant", "deletion", "library", "was", "screened", "for", "constitutive", "transcriptional", "activation", "of", "the", "CWI-", "related", "reporter", "gene", "MLP1.", "Monitoring", "phospho-Slt2/Mpk1", "levels", "in", "the", "identified", "mutants", "revealed", "sixty-four", "deletants", "with", "high", "levels", "of", "phosphorylation", "of", "this", "MAPK,", "including", "mainly", "genes", "related", "to", "cell", "wall", "construction", "and", "morphogenesis,", "signaling,", "and", "those", "with", "unknown", "function.", "Phenotypic", "analysis", "of", "the", "last", "group", "of", "mutants", "suggests", "their", "involvement", "in", "cell", "wall", "homeostasis.", "A", "good", "correlation", "between", "levels", "of", "Slt2", "phosphorylation", "and", "the", "magnitude", "of", "the", "transcriptional", "response", "was", "found", "in", "most", "cases.", "However,", "the", "expression", "of", "CWI", "pathway-related", "genes", "was", "enhanced", "in", "some", "mutants", "in", "the", "absence", "of", "significant", "Slt2", "phosphorylation,", "despite", "the", "fact", "that", "functional", "MAPK", "signaling", "through", "the", "pathway", "was", "required.", "CWI", "pathway", "activation", "was", "associated", "to", "increased", "deposition", "of", "chitin", "in", "the", "cell", "wall", "-", "a", "known", "survival", "compensatory", "mechanism", "-", "in", "about", "30%", "of", "the", "mutants", "identified.", "Conclusion:", "We", "provide", "new", "insights", "into", "yeast", "genes", "related", "to", "the", "CWI", "pathway", "and", "into", "how", "the", "state", "of", "activation", "of", "the", "Slt2", "MAPK", "leads", "to", "different", "outcomes,", "discovering", "the", "versatility", "of", "this", "kind", "of", "signaling", "pathways.", "These", "findings", "potentially", "have", "broad", "implications", "for", "understanding", "the", "functioning", "of", "other", "eukaryotic", "MAPKs.", "Background", "The", "capacity", "to", "respond", "properly", "to", "external", "stimuli", "or", "environmental", "conditions", "is", "essential", "for", "homeostasis", "in", "eukaryotes.", "Signaling", "pathways,", "in", "particular", "those", "mediated", "by", "mitogen-activated", "protein", "kinases", "(MAPKs),", "play", "a", "key", "role", "in", "these", "processes.", "A", "significant", "amount", "of", "research", "has", "been", "conducted", "in", "recent", "years", "to", "charac-", "terize", "these", "signal", "transduction", "pathways,", "based", "largely", "on", "the", "model", "yeast", "Saccharomyces", "cerevisiae", "(also", "known", "as", "baker’s", "or", "budding", "yeast).", "Since", "MAPK", "pathways", "are", "evolutionarily", "conserved,", "insights", "gained", "from", "yeast", "con-", "tribute", "to", "a", "better", "understanding", "of", "orthologous", "path-", "ways", "in", "higher", "organisms.", "The", "basic", "assembly", "of", "MAPK", "*", "Correspondence:", "josemanu@farm.ucm.es", "Departamento", "de", "Microbiología", "II,", "Facultad", "de", "Farmacia,", "Universidad", "Complutense", "de", "Madrid,", "IRYCIS,", "28040", "Madrid,", "Spain", "pathways", "is", "a", "three-component", "module", "conserved", "from", "yeast", "to", "humans,", "consisting", "of", "three", "kinases", "that", "establish", "a", "sequential", "activation", "pathway", "by", "means", "of", "phosphoryla-", "tion", "events", "[1].", "The", "regulation", "of", "MAPK", "signal", "transduc-", "tion", "depends", "on", "a", "variety", "of", "mechanisms", "including", "scaffold", "proteins,", "subcellular", "localization", "of", "different", "ele-", "ments", "and", "the", "action", "of", "protein", "phosphatases", "[2].", "In", "yeast,", "six", "MAPK", "cascades", "have", "been", "identified", "that", "mediate", "the", "response", "to", "different", "stimuli:", "(i)", "pheromones", "(pheromone", "response", "pathway);", "(ii)", "nitrogen", "starvation", "(filamentous", "growth", "pathway);", "(iii)", "hyperosmolarity", "(high", "osmolarity/glycerol", "pathway);", "(iv)", "STE", "vegetative", "growth", "pathway", "(SVG)", "[3];", "(v)", "nutrient", "starvation", "(spore", "wall", "assembly", "pathway);", "and", "(vi)", "cell", "wall", "stress", "(CWI:", "cell", "wall", "integrity", "pathway)", "(see", "an", "extensive", "review", "of", "MAPK", "path-", "ways", "in", "[2]).", "The", "CWI", "pathway", "is", "essential", "for", "maintaining", "©", "2011", "Arias", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]

[ [ 66, 72, 85, 20 ], [ 157, 72, 72, 20 ], [ 651, 55, 112, 46 ], [ 66, 128, 159, 28 ], [ 233, 128, 62, 28 ], [ 302, 128, 52, 28 ], [ 363, 128, 63, 28 ], [ 433, 128, 121, 28 ], [ 563, 128, 47, 28 ], [ 618, 128, 59, 28 ], [ 685, 128, 24, 28 ], [ 66, 157, 205, 28 ], [ 278, 157, 102, 28 ], [ 388, 157, 107, 28 ], [ 503, 157, 65, 28 ], [ 575, 157, 41, 28 ], [ 624, 157, 114, 28 ], [ 66, 186, 82, 28 ], [ 156, 186, 110, 28 ], [ 274, 186, 69, 28 ], [ 66, 232, 39, 17 ], [ 110, 232, 11, 17 ], [ 127, 232, 59, 17 ], [ 187, 231, 17, 18 ], [ 210, 232, 40, 17 ], [ 256, 232, 10, 17 ], [ 271, 232, 59, 17 ], [ 331, 231, 10, 18 ], [ 346, 232, 34, 17 ], [ 386, 232, 56, 17 ], [ 444, 231, 10, 18 ], [ 459, 232, 49, 17 ], [ 513, 232, 10, 17 ], [ 529, 232, 46, 17 ], [ 577, 231, 10, 18 ], [ 592, 232, 7, 17 ], [ 604, 232, 40, 17 ], [ 650, 232, 34, 17 ], [ 685, 231, 10, 18 ], [ 66, 251, 62, 17 ], [ 133, 251, 52, 17 ], [ 187, 251, 10, 18 ], [ 202, 251, 58, 17 ], [ 265, 251, 32, 17 ], [ 299, 251, 10, 18 ], [ 314, 251, 27, 17 ], [ 347, 251, 51, 17 ], [ 403, 251, 10, 17 ], [ 418, 251, 57, 18 ], [ 71, 273, 69, 15 ], [ 143, 275, 11, 13 ], [ 157, 275, 46, 13 ], [ 206, 275, 33, 13 ], [ 242, 275, 41, 13 ], [ 286, 275, 37, 13 ], [ 327, 275, 51, 13 ], [ 382, 275, 17, 13 ], [ 402, 275, 22, 13 ], [ 71, 289, 69, 15 ], [ 143, 291, 11, 13 ], [ 157, 291, 51, 13 ], [ 211, 291, 52, 13 ], [ 266, 291, 11, 13 ], [ 280, 291, 55, 13 ], [ 339, 291, 35, 13 ], [ 376, 291, 40, 13 ], [ 419, 291, 37, 13 ], [ 460, 291, 51, 13 ], [ 515, 291, 17, 13 ], [ 535, 291, 22, 13 ], [ 71, 305, 69, 15 ], [ 143, 307, 11, 13 ], [ 157, 307, 55, 13 ], [ 216, 307, 51, 13 ], [ 270, 307, 52, 13 ], [ 325, 307, 11, 13 ], [ 339, 307, 55, 13 ], [ 397, 307, 34, 13 ], [ 435, 307, 40, 13 ], [ 478, 307, 37, 13 ], [ 519, 307, 51, 13 ], [ 573, 307, 17, 13 ], [ 594, 307, 22, 13 ], [ 71, 321, 69, 15 ], [ 143, 323, 11, 13 ], [ 157, 323, 51, 13 ], [ 211, 323, 52, 13 ], [ 266, 323, 11, 13 ], [ 280, 323, 52, 13 ], [ 335, 323, 31, 13 ], [ 369, 323, 18, 13 ], [ 390, 323, 22, 13 ], [ 71, 337, 29, 15 ], [ 103, 339, 60, 13 ], [ 167, 339, 36, 13 ], [ 206, 339, 47, 13 ], [ 256, 339, 37, 13 ], [ 297, 339, 38, 13 ], [ 339, 339, 21, 13 ], [ 363, 339, 22, 13 ], [ 71, 353, 69, 15 ], [ 143, 355, 11, 13 ], [ 157, 355, 44, 13 ], [ 204, 355, 50, 13 ], [ 258, 355, 25, 13 ], [ 287, 355, 8, 13 ], [ 298, 355, 30, 13 ], [ 331, 355, 35, 13 ], [ 370, 355, 11, 13 ], [ 384, 355, 51, 13 ], [ 438, 355, 52, 13 ], [ 493, 355, 11, 13 ], [ 507, 355, 38, 13 ], [ 548, 355, 50, 13 ], [ 602, 355, 14, 13 ], [ 619, 355, 22, 13 ], [ 71, 368, 57, 15 ], [ 132, 371, 11, 13 ], [ 146, 371, 65, 13 ], [ 215, 371, 38, 13 ], [ 256, 371, 21, 13 ], [ 280, 371, 22, 13 ], [ 71, 384, 57, 15 ], [ 132, 387, 11, 13 ], [ 146, 387, 55, 13 ], [ 204, 387, 55, 13 ], [ 262, 387, 20, 13 ], [ 285, 387, 22, 13 ], [ 66, 419, 65, 14 ], [ 66, 436, 66, 13 ], [ 135, 436, 30, 13 ], [ 168, 436, 34, 13 ], [ 205, 436, 17, 13 ], [ 224, 436, 25, 13 ], [ 252, 436, 62, 13 ], [ 317, 436, 10, 13 ], [ 330, 436, 36, 13 ], [ 368, 436, 42, 13 ], [ 413, 436, 11, 13 ], [ 427, 436, 25, 13 ], [ 454, 436, 6, 13 ], [ 463, 436, 42, 13 ], [ 507, 436, 11, 13 ], [ 521, 436, 57, 13 ], [ 581, 436, 49, 13 ], [ 633, 436, 18, 13 ], [ 653, 436, 62, 13 ], [ 718, 436, 46, 13 ], [ 66, 453, 18, 13 ], [ 87, 453, 18, 13 ], [ 109, 453, 11, 13 ], [ 123, 453, 29, 13 ], [ 155, 453, 66, 13 ], [ 225, 453, 58, 13 ], [ 287, 453, 18, 13 ], [ 308, 453, 33, 13 ], [ 344, 453, 30, 13 ], [ 377, 453, 20, 13 ], [ 401, 453, 41, 13 ], [ 445, 453, 18, 13 ], [ 467, 453, 18, 13 ], [ 488, 453, 18, 13 ], [ 510, 453, 27, 13 ], [ 540, 453, 21, 13 ], [ 565, 453, 73, 13 ], [ 641, 453, 17, 13 ], [ 662, 453, 25, 13 ], [ 691, 453, 23, 13 ], [ 718, 453, 25, 13 ], [ 746, 453, 18, 13 ], [ 66, 470, 49, 13 ], [ 118, 470, 35, 13 ], [ 155, 470, 45, 13 ], [ 203, 470, 29, 13 ], [ 235, 470, 11, 13 ], [ 250, 470, 54, 13 ], [ 307, 470, 18, 13 ], [ 328, 470, 62, 13 ], [ 392, 470, 46, 13 ], [ 442, 470, 18, 13 ], [ 462, 470, 18, 13 ], [ 484, 470, 11, 13 ], [ 498, 470, 27, 13 ], [ 528, 470, 20, 13 ], [ 552, 470, 23, 13 ], [ 578, 470, 48, 13 ], [ 629, 470, 20, 13 ], [ 652, 470, 27, 13 ], [ 683, 470, 40, 13 ], [ 726, 470, 38, 13 ], [ 66, 486, 32, 13 ], [ 101, 486, 23, 13 ], [ 126, 486, 13, 13 ], [ 142, 486, 42, 13 ], [ 186, 486, 11, 13 ], [ 199, 486, 16, 13 ], [ 217, 486, 27, 13 ], [ 247, 486, 11, 13 ], [ 260, 486, 52, 13 ], [ 314, 486, 17, 13 ], [ 334, 486, 46, 13 ], [ 382, 486, 41, 13 ], [ 425, 486, 40, 13 ], [ 467, 486, 32, 13 ], [ 501, 486, 27, 13 ], [ 531, 486, 11, 13 ], [ 544, 486, 27, 13 ], [ 573, 486, 20, 13 ], [ 596, 486, 41, 13 ], [ 639, 486, 51, 13 ], [ 693, 486, 26, 13 ], [ 722, 486, 13, 13 ], [ 737, 486, 11, 13 ], [ 751, 486, 13, 13 ], [ 66, 503, 28, 13 ], [ 97, 503, 10, 13 ], [ 111, 503, 19, 13 ], [ 134, 503, 63, 13 ], [ 201, 503, 35, 13 ], [ 239, 503, 47, 13 ], [ 289, 503, 26, 13 ], [ 319, 503, 60, 13 ], [ 382, 503, 15, 13 ], [ 401, 503, 55, 13 ], [ 460, 503, 18, 13 ], [ 482, 503, 11, 13 ], [ 496, 503, 27, 13 ], [ 527, 503, 20, 13 ], [ 551, 503, 50, 13 ], [ 605, 503, 55, 13 ], [ 663, 503, 23, 13 ], [ 690, 503, 24, 13 ], [ 718, 503, 46, 13 ], [ 66, 520, 39, 13 ], [ 107, 520, 24, 13 ], [ 133, 520, 22, 13 ], [ 157, 523, 10, 13 ], [ 168, 520, 25, 13 ], [ 195, 520, 23, 13 ], [ 220, 520, 58, 13 ], [ 280, 520, 39, 13 ], [ 321, 520, 18, 13 ], [ 340, 520, 56, 13 ], [ 398, 520, 12, 13 ], [ 412, 520, 61, 13 ], [ 475, 520, 46, 13 ], [ 523, 520, 49, 13 ], [ 574, 520, 18, 13 ], [ 593, 520, 17, 13 ], [ 612, 520, 19, 13 ], [ 633, 523, 10, 13 ], [ 644, 520, 25, 13 ], [ 671, 520, 23, 13 ], [ 696, 520, 10, 13 ], [ 708, 520, 56, 13 ], [ 66, 536, 36, 13 ], [ 105, 536, 47, 13 ], [ 155, 536, 46, 13 ], [ 204, 536, 19, 13 ], [ 225, 540, 10, 13 ], [ 236, 536, 25, 13 ], [ 264, 536, 23, 13 ], [ 291, 536, 10, 13 ], [ 305, 536, 56, 13 ], [ 364, 536, 29, 13 ], [ 396, 536, 21, 13 ], [ 421, 536, 11, 13 ], [ 435, 536, 25, 13 ], [ 464, 536, 46, 13 ], [ 513, 536, 19, 13 ], [ 533, 540, 10, 13 ], [ 545, 536, 25, 13 ], [ 573, 536, 23, 13 ], [ 599, 536, 10, 13 ], [ 613, 536, 56, 13 ], [ 672, 536, 20, 13 ], [ 696, 536, 28, 13 ], [ 728, 536, 36, 13 ], [ 66, 553, 46, 13 ], [ 114, 553, 19, 13 ], [ 134, 556, 10, 13 ], [ 146, 553, 24, 13 ], [ 172, 553, 23, 13 ], [ 197, 553, 10, 13 ], [ 210, 553, 53, 13 ], [ 265, 553, 20, 13 ], [ 288, 553, 20, 13 ], [ 310, 553, 11, 13 ], [ 323, 553, 28, 13 ], [ 353, 553, 21, 13 ], [ 376, 553, 19, 13 ], [ 396, 556, 10, 13 ], [ 408, 553, 25, 13 ], [ 435, 553, 23, 13 ], [ 460, 553, 10, 13 ], [ 472, 553, 53, 13 ], [ 528, 553, 18, 13 ], [ 548, 553, 18, 13 ], [ 568, 553, 23, 13 ], [ 594, 553, 43, 13 ], [ 639, 553, 25, 13 ], [ 667, 553, 11, 13 ], [ 680, 553, 44, 13 ], [ 726, 553, 10, 13 ], [ 738, 553, 25, 13 ], [ 66, 569, 4, 13 ], [ 71, 569, 7, 13 ], [ 91, 569, 22, 13 ], [ 118, 569, 15, 13 ], [ 137, 569, 12, 13 ], [ 154, 569, 29, 13 ], [ 188, 569, 20, 13 ], [ 212, 569, 11, 13 ], [ 228, 569, 28, 13 ], [ 260, 569, 24, 13 ], [ 289, 569, 20, 13 ], [ 314, 569, 20, 13 ], [ 339, 569, 18, 13 ], [ 362, 569, 11, 13 ], [ 377, 569, 91, 13 ], [ 473, 569, 27, 13 ], [ 505, 569, 26, 13 ], [ 535, 569, 62, 13 ], [ 602, 569, 55, 13 ], [ 662, 569, 23, 13 ], [ 690, 569, 24, 13 ], [ 718, 569, 46, 13 ], [ 66, 586, 19, 13 ], [ 86, 590, 10, 13 ], [ 98, 586, 25, 13 ], [ 126, 586, 23, 13 ], [ 154, 586, 10, 13 ], [ 168, 586, 50, 13 ], [ 222, 586, 20, 13 ], [ 247, 586, 15, 13 ], [ 264, 590, 10, 13 ], [ 275, 586, 24, 13 ], [ 304, 586, 23, 13 ], [ 331, 586, 10, 13 ], [ 346, 586, 52, 13 ], [ 402, 586, 68, 13 ], [ 475, 586, 17, 13 ], [ 496, 586, 48, 13 ], [ 549, 586, 21, 13 ], [ 574, 586, 10, 13 ], [ 589, 586, 36, 13 ], [ 629, 586, 44, 13 ], [ 677, 586, 87, 13 ], [ 66, 602, 40, 13 ], [ 108, 602, 23, 13 ], [ 133, 602, 18, 13 ], [ 154, 602, 27, 13 ], [ 184, 602, 36, 13 ], [ 221, 602, 14, 13 ], [ 237, 602, 58, 13 ], [ 298, 602, 10, 13 ], [ 310, 602, 50, 13 ], [ 363, 602, 18, 13 ], [ 383, 602, 15, 13 ], [ 400, 602, 43, 13 ], [ 446, 602, 20, 13 ], [ 469, 602, 48, 13 ], [ 519, 602, 11, 13 ], [ 532, 602, 16, 13 ], [ 550, 602, 57, 13 ], [ 610, 602, 23, 13 ], [ 635, 602, 14, 13 ], [ 651, 602, 58, 13 ], [ 711, 602, 52, 13 ], [ 66, 619, 10, 13 ], [ 80, 619, 29, 13 ], [ 112, 619, 42, 13 ], [ 173, 619, 26, 13 ], [ 202, 619, 50, 13 ], [ 256, 619, 38, 13 ], [ 297, 619, 15, 13 ], [ 316, 619, 27, 13 ], [ 347, 619, 20, 13 ], [ 371, 619, 39, 13 ], [ 414, 619, 49, 13 ], [ 66, 654, 22, 13 ], [ 92, 654, 46, 13 ], [ 143, 655, 62, 11 ], [ 207, 655, 41, 11 ], [ 252, 655, 33, 11 ], [ 288, 655, 60, 11 ], [ 66, 739, 93, 17 ], [ 66, 775, 75, 38 ], [ 151, 793, 18, 13 ], [ 179, 793, 65, 13 ], [ 253, 793, 30, 13 ], [ 293, 791, 47, 15 ], [ 349, 793, 49, 13 ], [ 98, 777, 49, 13 ], [ 150, 777, 13, 13 ], [ 167, 777, 36, 13 ], [ 206, 777, 36, 13 ], [ 246, 777, 30, 13 ], [ 279, 777, 25, 13 ], [ 308, 777, 46, 13 ], [ 357, 777, 20, 13 ], [ 381, 777, 18, 13 ], [ 66, 810, 65, 13 ], [ 135, 810, 26, 13 ], [ 165, 810, 37, 13 ], [ 206, 810, 29, 13 ], [ 239, 810, 41, 13 ], [ 284, 810, 46, 13 ], [ 334, 810, 18, 13 ], [ 356, 810, 11, 13 ], [ 371, 810, 27, 13 ], [ 66, 826, 8, 13 ], [ 79, 826, 53, 13 ], [ 136, 826, 28, 13 ], [ 169, 824, 69, 15 ], [ 242, 826, 53, 13 ], [ 299, 826, 18, 13 ], [ 321, 826, 62, 13 ], [ 388, 826, 11, 13 ], [ 66, 843, 22, 13 ], [ 92, 843, 18, 13 ], [ 114, 843, 11, 13 ], [ 129, 843, 66, 13 ], [ 199, 843, 8, 13 ], [ 211, 843, 11, 13 ], [ 225, 843, 42, 13 ], [ 78, 860, 20, 13 ], [ 101, 860, 62, 13 ], [ 166, 860, 11, 13 ], [ 180, 860, 22, 13 ], [ 206, 860, 18, 13 ], [ 227, 860, 11, 13 ], [ 242, 860, 45, 13 ], [ 291, 860, 8, 13 ], [ 302, 860, 70, 13 ], [ 375, 860, 23, 13 ], [ 66, 874, 48, 15 ], [ 116, 876, 47, 13 ], [ 166, 876, 18, 13 ], [ 187, 874, 25, 15 ], [ 214, 876, 37, 13 ], [ 253, 876, 58, 13 ], [ 313, 876, 21, 13 ], [ 337, 876, 41, 13 ], [ 380, 876, 18, 13 ], [ 66, 893, 8, 13 ], [ 77, 893, 53, 13 ], [ 133, 893, 49, 13 ], [ 186, 893, 29, 13 ], [ 218, 893, 37, 13 ], [ 259, 893, 17, 13 ], [ 279, 893, 37, 13 ], [ 319, 893, 13, 13 ], [ 335, 893, 38, 13 ], [ 376, 893, 22, 13 ], [ 66, 910, 47, 13 ], [ 115, 910, 11, 13 ], [ 128, 910, 45, 13 ], [ 175, 910, 20, 13 ], [ 198, 910, 26, 13 ], [ 227, 910, 55, 13 ], [ 284, 910, 18, 13 ], [ 304, 910, 33, 13 ], [ 339, 910, 11, 13 ], [ 353, 910, 22, 13 ], [ 378, 910, 21, 13 ], [ 431, 742, 42, 13 ], [ 475, 742, 47, 13 ], [ 524, 742, 67, 13 ], [ 593, 740, 54, 16 ], [ 650, 742, 26, 13 ], [ 677, 742, 6, 13 ], [ 685, 742, 26, 13 ], [ 714, 742, 50, 13 ], [ 431, 759, 81, 13 ], [ 515, 759, 48, 13 ], [ 565, 759, 21, 13 ], [ 589, 759, 52, 13 ], [ 644, 759, 18, 13 ], [ 664, 759, 62, 13 ], [ 728, 759, 11, 13 ], [ 742, 759, 22, 13 ], [ 431, 775, 18, 13 ], [ 453, 775, 20, 13 ], [ 476, 775, 46, 13 ], [ 525, 775, 20, 13 ], [ 549, 775, 36, 13 ], [ 588, 775, 11, 13 ], [ 603, 775, 37, 13 ], [ 643, 775, 15, 13 ], [ 661, 775, 52, 13 ], [ 717, 775, 47, 13 ], [ 431, 792, 68, 13 ], [ 507, 792, 49, 13 ], [ 563, 792, 32, 13 ], [ 602, 792, 36, 13 ], [ 645, 792, 11, 13 ], [ 663, 792, 48, 13 ], [ 719, 792, 45, 13 ], [ 431, 809, 38, 13 ], [ 474, 809, 20, 13 ], [ 498, 809, 83, 13 ], [ 585, 809, 9, 13 ], [ 598, 806, 45, 15 ], [ 647, 809, 32, 13 ], [ 683, 809, 17, 13 ], [ 703, 809, 46, 13 ], [ 754, 809, 10, 13 ], [ 431, 825, 18, 13 ], [ 452, 825, 49, 13 ], [ 503, 825, 35, 13 ], [ 540, 825, 45, 13 ], [ 588, 825, 31, 13 ], [ 622, 825, 10, 13 ], [ 635, 825, 46, 13 ], [ 684, 825, 26, 13 ], [ 713, 825, 37, 13 ], [ 753, 825, 11, 13 ], [ 431, 842, 18, 13 ], [ 453, 842, 62, 13 ], [ 518, 842, 11, 13 ], [ 533, 842, 22, 13 ], [ 559, 842, 18, 13 ], [ 581, 842, 20, 13 ], [ 606, 842, 45, 13 ], [ 655, 842, 25, 13 ], [ 684, 842, 48, 13 ], [ 736, 842, 28, 13 ], [ 431, 858, 37, 13 ], [ 472, 858, 28, 13 ], [ 505, 858, 24, 13 ], [ 534, 856, 76, 15 ], [ 615, 858, 49, 13 ], [ 668, 858, 43, 13 ], [ 716, 858, 25, 13 ], [ 746, 858, 18, 13 ], [ 431, 875, 26, 13 ], [ 459, 875, 6, 13 ], [ 468, 875, 50, 13 ], [ 520, 875, 28, 13 ], [ 549, 873, 75, 15 ], [ 627, 875, 22, 13 ], [ 651, 875, 37, 13 ], [ 690, 875, 25, 13 ], [ 718, 875, 46, 13 ], [ 431, 891, 18, 13 ], [ 451, 891, 115, 13 ], [ 569, 891, 46, 13 ], [ 617, 891, 11, 13 ], [ 630, 891, 29, 13 ], [ 662, 889, 65, 15 ], [ 729, 891, 34, 13 ], [ 431, 908, 18, 13 ], [ 455, 908, 8, 13 ], [ 468, 908, 54, 13 ], [ 527, 908, 38, 13 ], [ 570, 908, 49, 13 ], [ 624, 908, 15, 13 ], [ 644, 908, 57, 13 ], [ 706, 908, 28, 13 ], [ 740, 908, 24, 13 ], [ 66, 942, 40, 11 ], [ 108, 942, 9, 11 ], [ 120, 942, 33, 11 ], [ 156, 942, 21, 11 ], [ 180, 942, 21, 11 ], [ 204, 942, 13, 11 ], [ 220, 942, 24, 11 ], [ 247, 942, 31, 11 ], [ 281, 942, 21, 11 ], [ 305, 942, 48, 11 ], [ 356, 942, 13, 11 ], [ 373, 942, 24, 11 ], [ 399, 942, 40, 11 ], [ 443, 942, 36, 11 ], [ 481, 942, 13, 11 ], [ 497, 942, 24, 11 ], [ 524, 942, 43, 11 ], [ 570, 942, 28, 11 ], [ 601, 942, 35, 11 ], [ 639, 942, 13, 11 ], [ 655, 942, 24, 11 ], [ 66, 956, 35, 11 ], [ 104, 956, 71, 11 ], [ 178, 956, 11, 11 ], [ 192, 956, 24, 11 ], [ 219, 956, 7, 11 ], [ 230, 956, 39, 11 ], [ 272, 956, 18, 11 ], [ 293, 956, 16, 11 ], [ 312, 956, 43, 11 ], [ 358, 956, 9, 11 ], [ 370, 956, 46, 11 ], [ 419, 956, 29, 11 ], [ 451, 956, 33, 11 ], [ 487, 956, 31, 11 ], [ 522, 956, 16, 11 ], [ 541, 956, 24, 11 ], [ 568, 956, 41, 11 ], [ 612, 956, 43, 11 ], [ 658, 956, 12, 11 ], [ 673, 956, 29, 11 ], [ 705, 956, 21, 11 ], [ 66, 970, 29, 11 ], [ 98, 970, 88, 11 ], [ 66, 988, 32, 11 ], [ 101, 988, 9, 11 ], [ 113, 988, 23, 11 ], [ 139, 988, 17, 11 ], [ 159, 988, 33, 11 ], [ 195, 988, 41, 11 ], [ 239, 988, 16, 11 ], [ 258, 988, 13, 11 ], [ 274, 988, 15, 11 ], [ 292, 988, 8, 11 ], [ 303, 988, 21, 11 ], [ 327, 988, 24, 11 ], [ 353, 988, 12, 11 ], [ 368, 988, 38, 11 ], [ 66, 1002, 19, 11 ], [ 88, 1002, 92, 11 ], [ 78, 1016, 22, 11 ], [ 103, 1016, 42, 11 ], [ 148, 1016, 32, 11 ], [ 182, 1016, 12, 11 ], [ 198, 1016, 23, 11 ], [ 223, 1016, 17, 11 ], [ 243, 1016, 33, 11 ], [ 279, 1016, 39, 11 ], [ 721, 1044, 22, 14 ] ]

[ "ORIGINAL", "ARTICLE", "JBMR", "Antiepileptic", "Drug", "Use,", "Falls,", "Fractures,", "and", "BMD", "in", "Postmenopausal", "Women:", "Findings", "From", "the", "Women’s", "Health", "Initiative", "(WHI)", "Laura", "D", "Carbone", ",1,2", "Karen", "C", "Johnson", ",3", "John", "Robbins", ",4", "Joseph", "C", "Larson", ",5", "J", "David", "Curb", ",6", "Kathleen", "Watson", ",7", "Margery", "Gass", ",8", "and", "Andrea", "Z", "LaCroix5", "1Department", "of", "Veterans", "Affairs", "Medical", "Center,", "Memphis,", "TN,", "USA", "2Department", "of", "Medicine,", "University", "of", "Tennessee", "Health", "Science", "Center,", "Memphis,", "TN,", "USA", "3Department", "of", "Preventive", "Medicine,", "University", "of", "Tennessee", "Health", "Science", "Center,", "Memphis,", "TN,", "USA", "4Department", "of", "Medicine,", "University", "of", "California,", "Davis,", "CA,", "USA", "5Fred", "Hutchinson", "Cancer", "Research", "Center,", "Seattle,", "WA,", "USA", "6Department", "of", "Geriatric", "Medicine,", "John", "A", "Burns", "School", "of", "Medicine,", "University", "of", "Hawaii,", "Honolulu,", "HI,", "USA", "7University", "of", "Washington,", "Seattle,", "WA,", "USA", "8University", "of", "Cincinnati,", "Cincinnati,", "OH,", "USA", "ABSTRACT", "Antiepileptic", "drugs", "(AEDs)", "are", "used", "increasingly", "in", "clinical", "practice", "to", "treat", "a", "number", "of", "conditions.", "However,", "the", "relationship", "between", "the", "use", "of", "these", "medications,", "particularly", "the", "newer", "AEDs,", "and", "fracture", "risk", "has", "not", "been", "well", "characterized.", "We", "used", "data", "from", "the", "Women’s", "Health", "Initiative", "(WHI)", "to", "determine", "the", "relationship", "bewteen", "the", "use", "of", "AEDs", "and", "falls,", "fractures,", "and", "bone", "mineral", "density", "(BMD)", "over", "an", "average", "of", "7.7", "years", "of", "follow-up.", "We", "included", "138,667", "women", "(1,385", "users", "of", "AEDs", "and", "137,282", "nonusers)", "aged", "50", "to", "79", "years", "in", "this", "longitudinal", "cohort", "analyses.", "After", "adjustment", "for", "covariates,", "use", "of", "AEDs", "was", "positively", "associated", "with", "total", "fractures", "[hazard", "ratio", "(HR)", "¼", "1.44,", "95%", "confidence", "interval", "(CI)", "1.30–1.61],", "all", "site-specific", "fractures", "including", "the", "hip", "(HR", "¼", "1.51,", "95%", "CI", "1.05–2.17),", "clinical", "vertebral", "fractures", "(HR", "¼", "1.60,", "95%", "CI", "1.20–2.12),", "lower", "arm", "or", "wrist", "fractures", "(HR", "¼", "1.40,", "95%", "CI", "1.11–1.76),", "and", "other", "clinical", "fractures", "(HR", "¼", "1.46,", "95%", "CI", "1.29–1.65)", "and", "two", "or", "more", "falls", "(HR", "¼", "1.62,", "95%", "CI", "1.50–1.74)", "but", "not", "with", "baseline", "BMD", "or", "changes", "in", "BMD", "(", "p", ".064", "for", "all", "sites).", "Use", "of", "more", "than", "one", "and", "use", "of", "enzyme-inducing", "AEDs", "were", "significantly", "associated", "with", "total", "fractures", "(HR", "¼", "1.55,", "95%", "CI", "1.15–2.09", "and", "HR", "¼", "1.36,", "95%", "CI", "1.09–1.69,", "respectively).", "We", "conclude", "that", "in", "clinical", "practice,", "postmenopausal", "women", "who", "use", "AEDs", "should", "be", "considered", "at", "increased", "risk", "for", "fracture,", "and", "attention", "to", "fall", "prevention", "may", "be", "particularly", "important", "in", "these", "women.", "2010", "American", "Society", "for", "Bone", "and", "Mineral", "Research.", "KEY", "WORDS:", "POPULATION", "STUDIES;", "AGING;", "MENOPAUSE", "Introduction", "Wmajority", "use", "antiepileptic", "drugs", "(AEDs).(1)", "However,", "orldwide,", "50", "million", "people", "suffer", "from", "epilepsy,", "and", "the", "increasingly,", "even", "among", "those", "without", "epilepsy,", "use", "of", "AEDs", "is", "becoming", "more", "prevalent.(2,3)", "Therefore,", "the", "relationship", "of", "AED", "use", "to", "osteoporosis", "is", "of", "interest.", "The", "relationship", "of", "AED", "use", "to", "fractures", "is", "controversial,", "with", "some,(4,5)", "although", "not", "all,(6)", "studies", "suggesting", "that", "fracture", "risk", "is", "increased.", "However,", "these", "reports", "are", "limited", "by", "sample", "size,", "selection", "of", "controls,", "and", "most", "important,", "the", "failure", "to", "take", "into", "account", "potential", "confounding", "factors.(4,5)", "Even", "a", "large", "pharmac-", "oepidemiologic", "database", "that", "examined", "the", "relationship", "of", "AED", "use", "and", "fractures", "was", "unable", "to", "control", "for", "important", "potential", "confounders,", "including", "family", "history", "of", "fractures,", "smoking", "history,", "and", "calcium/vitamin", "D", "intake,(7)", "which", "are", "available", "in", "the", "Women’s", "Health", "Initiative", "(WHI).", "In", "addition,", "most", "studies", "of", "the", "relationship", "of", "AED", "use", "and", "fractures", "have", "excluded", "racial", "groups", "other", "than", "Caucasians.(6,8)", "However,", "epilepsy", "does", "not", "have", "a", "particular", "racial", "predilection.(9)", "Few", "studies", "have", "included", "the", "non-enzyme-inducing", "category", "of", "these", "drugs,(7,10,11)", "whose", "use", "is", "increasing", "rapidly,", "including", "for", "indications", "other", "than", "Received", "in", "original", "form", "June", "16,", "2009;", "revised", "form", "September", "14,", "2009;", "accepted", "October", "15,", "2009.", "Published", "online", "October", "17,", "2009.", "Address", "correspondence", "to:", "Laura", "D", "Carbone,", "MD,", "MS,", "University", "of", "Tennessee", "Health", "Science", "Center,", "956", "Court", "Aveenue,", "Memphis,", "TN", "38163,", "USA.", "E-mail:", "lcarbone@uthsc.edu", "Journal", "of", "Bone", "and", "Mineral", "Research,", "Vol.", "25,", "No.", "4,", "April", "2010,", "pp", "873–881", "DOI:", "10.1359/jbmr.091027", "2010", "American", "Society", "for", "Bone", "and", "Mineral", "Research", "873" ]

[ 16, 16, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4 ]

[ [ 130, 78, 155, 24 ], [ 130, 103, 143, 15 ], [ 642, 87, 29, 15 ], [ 674, 87, 38, 15 ], [ 656, 103, 56, 15 ], [ 138, 136, 30, 24 ], [ 174, 136, 104, 24 ], [ 283, 136, 89, 24 ], [ 378, 136, 31, 24 ], [ 414, 136, 32, 24 ], [ 451, 136, 96, 24 ], [ 552, 136, 134, 24 ], [ 691, 136, 20, 24 ], [ 301, 164, 95, 24 ], [ 401, 164, 46, 24 ], [ 453, 164, 96, 24 ], [ 167, 200, 49, 11 ], [ 218, 199, 26, 12 ], [ 247, 200, 47, 11 ], [ 296, 199, 26, 12 ], [ 324, 200, 42, 11 ], [ 368, 199, 28, 12 ], [ 399, 200, 46, 11 ], [ 447, 199, 25, 12 ], [ 474, 200, 35, 11 ], [ 511, 199, 31, 12 ], [ 545, 200, 39, 11 ], [ 586, 199, 29, 12 ], [ 616, 200, 31, 11 ], [ 650, 199, 33, 12 ], [ 140, 223, 46, 12 ], [ 188, 224, 39, 11 ], [ 230, 224, 36, 11 ], [ 268, 224, 40, 11 ], [ 311, 224, 9, 11 ], [ 322, 224, 51, 11 ], [ 376, 224, 33, 11 ], [ 411, 224, 39, 11 ], [ 452, 224, 30, 11 ], [ 483, 224, 38, 11 ], [ 523, 224, 29, 11 ], [ 554, 223, 52, 12 ], [ 609, 224, 9, 11 ], [ 619, 224, 48, 11 ], [ 670, 224, 40, 11 ], [ 139, 236, 39, 11 ], [ 180, 236, 36, 11 ], [ 219, 236, 40, 11 ], [ 261, 236, 9, 11 ], [ 273, 236, 52, 11 ], [ 326, 236, 33, 11 ], [ 361, 236, 39, 11 ], [ 402, 236, 29, 11 ], [ 433, 236, 30, 11 ], [ 465, 236, 51, 11 ], [ 519, 236, 12, 11 ], [ 533, 236, 81, 11 ], [ 616, 236, 66, 11 ], [ 684, 236, 27, 11 ], [ 263, 260, 39, 11 ], [ 304, 260, 28, 11 ], [ 334, 260, 14, 11 ], [ 350, 260, 24, 11 ], [ 376, 260, 37, 11 ], [ 415, 260, 23, 11 ], [ 440, 260, 14, 11 ], [ 456, 260, 24, 11 ], [ 482, 260, 41, 11 ], [ 525, 260, 23, 11 ], [ 550, 260, 14, 11 ], [ 566, 260, 21, 11 ], [ 130, 273, 43, 11 ], [ 130, 285, 17, 11 ], [ 150, 285, 36, 11 ], [ 190, 285, 40, 11 ], [ 234, 285, 9, 11 ], [ 246, 285, 52, 11 ], [ 301, 285, 33, 11 ], [ 338, 285, 36, 11 ], [ 377, 285, 14, 11 ], [ 395, 285, 43, 11 ], [ 442, 285, 5, 11 ], [ 451, 285, 45, 11 ], [ 499, 285, 37, 11 ], [ 539, 285, 9, 11 ], [ 551, 285, 33, 11 ], [ 587, 285, 67, 11 ], [ 658, 285, 50, 11 ], [ 711, 285, 9, 11 ], [ 130, 296, 43, 11 ], [ 176, 296, 17, 11 ], [ 197, 296, 40, 11 ], [ 240, 296, 37, 11 ], [ 281, 296, 14, 11 ], [ 299, 296, 18, 11 ], [ 321, 296, 25, 11 ], [ 350, 296, 35, 11 ], [ 389, 296, 31, 11 ], [ 423, 296, 30, 11 ], [ 457, 296, 43, 11 ], [ 504, 296, 67, 11 ], [ 575, 296, 37, 11 ], [ 615, 296, 31, 11 ], [ 651, 296, 50, 11 ], [ 704, 296, 16, 11 ], [ 130, 309, 24, 11 ], [ 157, 309, 32, 11 ], [ 191, 309, 7, 11 ], [ 201, 309, 36, 11 ], [ 240, 309, 16, 11 ], [ 259, 309, 40, 11 ], [ 302, 309, 36, 11 ], [ 340, 309, 67, 11 ], [ 410, 309, 50, 11 ], [ 463, 309, 13, 11 ], [ 479, 309, 13, 11 ], [ 494, 309, 36, 11 ], [ 533, 309, 31, 11 ], [ 567, 309, 34, 11 ], [ 604, 309, 34, 11 ], [ 640, 309, 40, 11 ], [ 683, 309, 37, 11 ], [ 130, 321, 43, 11 ], [ 177, 321, 36, 11 ], [ 218, 321, 15, 11 ], [ 237, 321, 59, 11 ], [ 301, 321, 28, 11 ], [ 333, 321, 56, 11 ], [ 393, 321, 13, 11 ], [ 411, 321, 36, 11 ], [ 452, 321, 37, 11 ], [ 493, 321, 24, 11 ], [ 521, 321, 24, 11 ], [ 550, 321, 30, 11 ], [ 584, 321, 41, 11 ], [ 629, 321, 14, 11 ], [ 648, 321, 23, 11 ], [ 675, 321, 9, 11 ], [ 689, 321, 31, 11 ], [ 130, 333, 40, 11 ], [ 172, 333, 39, 11 ], [ 213, 333, 8, 11 ], [ 223, 333, 33, 11 ], [ 259, 333, 67, 11 ], [ 328, 333, 50, 11 ], [ 381, 333, 21, 11 ], [ 404, 333, 36, 11 ], [ 443, 333, 41, 11 ], [ 486, 333, 35, 11 ], [ 523, 333, 32, 11 ], [ 558, 333, 24, 11 ], [ 584, 333, 16, 11 ], [ 602, 333, 24, 11 ], [ 628, 333, 38, 11 ], [ 669, 333, 24, 11 ], [ 695, 333, 25, 11 ], [ 130, 345, 31, 11 ], [ 163, 345, 25, 11 ], [ 190, 345, 31, 11 ], [ 223, 345, 27, 11 ], [ 252, 345, 15, 11 ], [ 270, 345, 29, 11 ], [ 301, 345, 34, 11 ], [ 337, 345, 15, 11 ], [ 355, 345, 26, 11 ], [ 384, 345, 21, 11 ], [ 407, 345, 36, 11 ], [ 446, 345, 29, 11 ], [ 476, 345, 26, 11 ], [ 505, 345, 29, 11 ], [ 537, 345, 9, 11 ], [ 548, 345, 24, 11 ], [ 575, 345, 15, 11 ], [ 593, 345, 22, 11 ], [ 617, 345, 9, 11 ], [ 628, 345, 13, 11 ], [ 644, 345, 36, 11 ], [ 682, 345, 26, 11 ], [ 711, 345, 9, 11 ], [ 130, 357, 27, 11 ], [ 159, 357, 15, 11 ], [ 176, 357, 15, 11 ], [ 194, 357, 31, 11 ], [ 227, 357, 29, 11 ], [ 130, 381, 56, 11 ], [ 188, 381, 17, 11 ], [ 207, 381, 36, 11 ], [ 245, 381, 7, 11 ], [ 255, 381, 38, 11 ], [ 295, 381, 13, 11 ], [ 310, 381, 17, 11 ], [ 329, 381, 8, 11 ], [ 339, 381, 172, 11 ], [ 130, 405, 49, 11 ], [ 181, 405, 40, 11 ], [ 223, 405, 32, 11 ], [ 257, 405, 20, 11 ], [ 280, 405, 43, 11 ], [ 324, 405, 40, 11 ], [ 367, 405, 25, 11 ], [ 393, 405, 40, 11 ], [ 435, 405, 36, 11 ], [ 130, 429, 59, 11 ], [ 130, 441, 17, 11 ], [ 149, 441, 40, 11 ], [ 191, 441, 7, 11 ], [ 201, 441, 16, 11 ], [ 219, 441, 9, 11 ], [ 231, 441, 13, 11 ], [ 247, 441, 21, 11 ], [ 270, 441, 57, 11 ], [ 329, 441, 44, 11 ], [ 375, 441, 42, 11 ], [ 130, 453, 29, 11 ], [ 162, 453, 9, 11 ], [ 174, 453, 24, 11 ], [ 201, 453, 47, 11 ], [ 252, 453, 39, 11 ], [ 294, 453, 27, 11 ], [ 324, 453, 9, 11 ], [ 336, 453, 13, 11 ], [ 352, 453, 15, 11 ], [ 371, 453, 46, 11 ], [ 130, 465, 16, 11 ], [ 148, 465, 28, 11 ], [ 178, 465, 9, 11 ], [ 189, 465, 55, 11 ], [ 246, 465, 21, 11 ], [ 270, 465, 39, 11 ], [ 311, 465, 9, 11 ], [ 322, 465, 36, 11 ], [ 361, 465, 56, 11 ], [ 130, 477, 21, 11 ], [ 154, 477, 7, 11 ], [ 164, 477, 5, 11 ], [ 172, 477, 22, 11 ], [ 197, 477, 35, 11 ], [ 234, 477, 9, 11 ], [ 245, 477, 72, 11 ], [ 320, 477, 18, 11 ], [ 341, 477, 40, 11 ], [ 384, 477, 33, 11 ], [ 130, 489, 43, 11 ], [ 175, 489, 16, 11 ], [ 192, 489, 31, 11 ], [ 225, 489, 37, 11 ], [ 264, 489, 17, 11 ], [ 283, 489, 32, 11 ], [ 317, 489, 37, 11 ], [ 356, 489, 7, 11 ], [ 365, 489, 5, 11 ], [ 373, 489, 18, 11 ], [ 393, 489, 24, 11 ], [ 130, 501, 43, 11 ], [ 179, 501, 13, 11 ], [ 197, 501, 13, 11 ], [ 216, 501, 37, 11 ], [ 260, 501, 46, 11 ], [ 311, 501, 16, 11 ], [ 333, 501, 23, 11 ], [ 362, 501, 9, 11 ], [ 377, 501, 40, 11 ], [ 130, 513, 31, 11 ], [ 168, 513, 15, 11 ], [ 191, 513, 36, 11 ], [ 234, 513, 18, 11 ], [ 260, 513, 15, 11 ], [ 282, 513, 53, 11 ], [ 342, 513, 7, 11 ], [ 357, 513, 10, 11 ], [ 375, 513, 42, 11 ], [ 130, 525, 40, 11 ], [ 175, 525, 34, 11 ], [ 215, 525, 36, 11 ], [ 258, 525, 16, 11 ], [ 279, 525, 18, 11 ], [ 303, 525, 30, 11 ], [ 339, 525, 17, 11 ], [ 362, 525, 19, 11 ], [ 387, 525, 6, 11 ], [ 399, 525, 18, 11 ], [ 130, 537, 41, 11 ], [ 175, 537, 6, 11 ], [ 186, 537, 20, 11 ], [ 211, 537, 31, 11 ], [ 247, 537, 16, 11 ], [ 268, 537, 6, 11 ], [ 278, 537, 51, 11 ], [ 335, 537, 40, 11 ], [ 380, 537, 15, 11 ], [ 400, 537, 17, 11 ], [ 130, 549, 31, 11 ], [ 170, 549, 49, 11 ], [ 228, 549, 49, 11 ], [ 286, 549, 43, 11 ], [ 338, 549, 28, 11 ], [ 375, 549, 42, 11 ], [ 130, 561, 36, 11 ], [ 170, 561, 24, 11 ], [ 199, 561, 39, 11 ], [ 242, 561, 15, 11 ], [ 261, 561, 16, 11 ], [ 282, 561, 40, 11 ], [ 326, 561, 47, 11 ], [ 377, 561, 40, 11 ], [ 130, 573, 15, 11 ], [ 151, 573, 17, 11 ], [ 174, 573, 57, 11 ], [ 237, 573, 36, 11 ], [ 279, 573, 13, 11 ], [ 298, 573, 37, 11 ], [ 341, 573, 8, 11 ], [ 354, 573, 37, 11 ], [ 398, 573, 19, 11 ], [ 130, 585, 29, 11 ], [ 162, 585, 23, 11 ], [ 188, 585, 26, 11 ], [ 217, 585, 13, 11 ], [ 233, 585, 38, 11 ], [ 274, 585, 16, 11 ], [ 293, 585, 44, 11 ], [ 340, 585, 17, 11 ], [ 359, 585, 24, 11 ], [ 386, 585, 31, 11 ], [ 130, 597, 16, 11 ], [ 148, 597, 29, 11 ], [ 180, 597, 43, 11 ], [ 225, 597, 32, 11 ], [ 259, 597, 21, 11 ], [ 282, 597, 6, 11 ], [ 291, 597, 25, 11 ], [ 318, 597, 19, 11 ], [ 340, 597, 41, 11 ], [ 382, 597, 15, 11 ], [ 400, 597, 17, 11 ], [ 130, 609, 43, 11 ], [ 176, 609, 7, 11 ], [ 187, 609, 5, 11 ], [ 195, 609, 40, 11 ], [ 238, 609, 37, 11 ], [ 278, 609, 9, 11 ], [ 290, 609, 61, 11 ], [ 354, 609, 39, 11 ], [ 396, 609, 21, 11 ], [ 130, 621, 13, 11 ], [ 147, 621, 38, 11 ], [ 189, 621, 42, 11 ], [ 234, 621, 39, 11 ], [ 276, 621, 17, 11 ], [ 297, 621, 15, 11 ], [ 317, 621, 26, 11 ], [ 346, 621, 34, 11 ], [ 383, 621, 34, 11 ], [ 130, 633, 43, 11 ], [ 180, 633, 9, 11 ], [ 198, 633, 13, 11 ], [ 219, 633, 41, 11 ], [ 267, 633, 15, 11 ], [ 290, 633, 17, 11 ], [ 315, 633, 37, 11 ], [ 359, 633, 40, 11 ], [ 408, 633, 9, 11 ], [ 130, 645, 52, 11 ], [ 185, 645, 33, 11 ], [ 222, 645, 36, 11 ], [ 261, 645, 14, 11 ], [ 279, 645, 43, 11 ], [ 326, 645, 5, 11 ], [ 335, 645, 36, 11 ], [ 375, 645, 30, 11 ], [ 408, 645, 9, 11 ], [ 433, 429, 32, 11 ], [ 469, 429, 42, 11 ], [ 515, 429, 50, 11 ], [ 568, 429, 24, 11 ], [ 596, 429, 31, 11 ], [ 631, 429, 20, 11 ], [ 655, 429, 40, 11 ], [ 698, 429, 21, 11 ], [ 433, 441, 16, 11 ], [ 451, 441, 14, 11 ], [ 468, 441, 38, 11 ], [ 509, 441, 13, 11 ], [ 525, 441, 40, 11 ], [ 567, 441, 20, 11 ], [ 590, 441, 40, 11 ], [ 633, 441, 30, 11 ], [ 665, 441, 15, 11 ], [ 683, 441, 37, 11 ], [ 433, 453, 16, 11 ], [ 456, 453, 26, 11 ], [ 490, 453, 13, 11 ], [ 510, 453, 43, 11 ], [ 561, 453, 5, 11 ], [ 574, 453, 45, 11 ], [ 627, 453, 36, 11 ], [ 671, 453, 9, 11 ], [ 688, 453, 32, 11 ], [ 433, 465, 67, 11 ], [ 502, 465, 15, 11 ], [ 520, 465, 30, 11 ], [ 552, 465, 50, 11 ], [ 604, 465, 9, 11 ], [ 615, 465, 42, 11 ], [ 433, 489, 63, 11 ], [ 433, 501, 38, 11 ], [ 433, 513, 17, 11 ], [ 452, 513, 40, 11 ], [ 495, 513, 36, 11 ], [ 534, 513, 38, 11 ], [ 574, 513, 21, 11 ], [ 598, 513, 13, 11 ], [ 614, 513, 40, 11 ], [ 657, 513, 20, 11 ], [ 680, 513, 40, 11 ], [ 433, 525, 29, 11 ], [ 465, 525, 9, 11 ], [ 478, 525, 32, 11 ], [ 512, 525, 12, 11 ], [ 528, 525, 5, 11 ], [ 536, 525, 24, 11 ], [ 563, 525, 9, 11 ], [ 575, 525, 15, 11 ], [ 594, 525, 32, 11 ], [ 630, 525, 13, 11 ], [ 645, 525, 20, 11 ], [ 669, 525, 51, 11 ], [ 433, 537, 13, 11 ], [ 452, 537, 67, 11 ], [ 525, 537, 9, 11 ], [ 541, 537, 44, 11 ], [ 591, 537, 9, 11 ], [ 606, 537, 32, 11 ], [ 644, 537, 24, 11 ], [ 674, 537, 15, 11 ], [ 696, 537, 24, 11 ], [ 433, 549, 35, 11 ], [ 472, 549, 40, 11 ], [ 516, 549, 24, 11 ], [ 545, 549, 15, 11 ], [ 564, 549, 22, 11 ], [ 590, 549, 9, 11 ], [ 603, 549, 13, 11 ], [ 620, 549, 36, 11 ], [ 661, 549, 22, 11 ], [ 687, 549, 33, 11 ], [ 433, 561, 17, 11 ], [ 452, 561, 40, 11 ], [ 496, 561, 36, 11 ], [ 535, 561, 36, 11 ], [ 575, 561, 16, 11 ], [ 594, 561, 40, 11 ], [ 637, 561, 30, 11 ], [ 670, 561, 50, 11 ], [ 433, 573, 13, 11 ], [ 448, 573, 13, 11 ], [ 464, 573, 36, 11 ], [ 503, 573, 31, 11 ], [ 537, 573, 34, 11 ], [ 574, 573, 31, 11 ], [ 608, 573, 9, 11 ], [ 620, 573, 42, 11 ], [ 665, 573, 38, 11 ], [ 705, 573, 14, 11 ], [ 433, 585, 42, 11 ], [ 478, 585, 34, 11 ], [ 515, 585, 15, 11 ], [ 533, 585, 42, 11 ], [ 578, 585, 40, 11 ], [ 621, 585, 15, 11 ], [ 639, 585, 42, 11 ], [ 684, 585, 36, 11 ], [ 433, 597, 9, 11 ], [ 447, 597, 39, 11 ], [ 492, 597, 15, 11 ], [ 513, 597, 59, 11 ], [ 577, 597, 15, 11 ], [ 597, 597, 42, 11 ], [ 644, 597, 17, 11 ], [ 666, 597, 24, 11 ], [ 696, 597, 24, 11 ], [ 433, 609, 30, 11 ], [ 465, 609, 9, 11 ], [ 477, 609, 24, 11 ], [ 504, 609, 16, 11 ], [ 523, 609, 22, 11 ], [ 547, 609, 50, 11 ], [ 600, 609, 38, 11 ], [ 641, 609, 21, 11 ], [ 664, 609, 13, 11 ], [ 680, 609, 15, 11 ], [ 697, 609, 23, 11 ], [ 433, 621, 9, 11 ], [ 448, 621, 31, 11 ], [ 486, 621, 40, 11 ], [ 533, 621, 39, 11 ], [ 578, 621, 56, 11 ], [ 640, 621, 13, 11 ], [ 660, 621, 36, 11 ], [ 703, 621, 17, 11 ], [ 433, 633, 56, 11 ], [ 491, 633, 18, 11 ], [ 511, 633, 36, 11 ], [ 550, 633, 18, 11 ], [ 570, 633, 25, 11 ], [ 597, 633, 31, 11 ], [ 630, 633, 43, 11 ], [ 675, 633, 15, 11 ], [ 692, 633, 28, 11 ], [ 433, 645, 38, 11 ], [ 472, 645, 20, 11 ], [ 494, 645, 28, 11 ], [ 524, 645, 51, 11 ], [ 578, 645, 14, 11 ], [ 595, 645, 25, 11 ], [ 622, 645, 16, 11 ], [ 640, 645, 26, 11 ], [ 668, 645, 15, 11 ], [ 684, 645, 28, 11 ], [ 130, 969, 30, 11 ], [ 164, 969, 9, 11 ], [ 178, 969, 8, 11 ], [ 190, 969, 20, 11 ], [ 214, 969, 18, 11 ], [ 236, 969, 9, 11 ], [ 250, 969, 13, 11 ], [ 268, 969, 33, 11 ], [ 305, 969, 67, 11 ], [ 377, 969, 50, 11 ], [ 431, 969, 21, 11 ], [ 456, 969, 33, 11 ], [ 494, 969, 40, 11 ], [ 538, 969, 39, 11 ], [ 581, 969, 17, 11 ], [ 602, 969, 67, 11 ], [ 674, 969, 15, 11 ], [ 694, 969, 26, 11 ], [ 130, 981, 50, 11 ], [ 182, 981, 21, 11 ], [ 205, 981, 23, 11 ], [ 229, 981, 30, 11 ], [ 261, 981, 41, 11 ], [ 305, 981, 38, 11 ], [ 345, 981, 11, 11 ], [ 358, 981, 34, 11 ], [ 394, 981, 5, 11 ], [ 401, 981, 33, 11 ], [ 436, 981, 56, 11 ], [ 495, 981, 32, 11 ], [ 529, 981, 19, 11 ], [ 551, 981, 22, 11 ], [ 131, 1005, 23, 11 ], [ 156, 1005, 46, 11 ], [ 204, 1005, 34, 11 ], [ 240, 1005, 46, 11 ], [ 288, 1005, 27, 11 ], [ 131, 1017, 65, 11 ], [ 198, 1017, 26, 11 ], [ 226, 1017, 35, 11 ], [ 263, 1017, 28, 11 ], [ 424, 1012, 16, 11 ], [ 592, 1017, 8, 11 ], [ 603, 1017, 21, 11 ], [ 626, 1017, 49, 11 ], [ 677, 1017, 49, 11 ] ]

[ "Bioinformation", "www.bioinformation.net", "open", "access", "Database", "An", "integrated", "database", "for", "the", "enhanced", "identification", "of", "silkworm", "gene", "resources", "ChangKug", "Kim1,", "KeeYoung", "Kim2,", "DongSuk", "Park1,", "YoungJoo", "Seol1,", "JangHo", "Hahn1,", "SooChul", "Park1,", "PilDon", "Kang2,*", "1Genomics", "Division,", "National", "Academy", "of", "Agricultural", "Science", "(NAAS),", "Suwon", "441-707,", "Korea,", "2Sericultural", "&", "Apicultural", "Materials", "Division,", "National", "Academy", "of", "Agricultural", "Science", "(NAAS),", "Korea.", "PilDon", "Kang-Email", "id:", "kangpd@rda.go.kr.", "*corresponding", "author", "Received", "March", "03,", "2010;", "accepted", "April", "09,", "2010;", "published", "April", "30,", "2010", "Abstract:", "The", "National", "Academy", "of", "Agricultural", "Science", "(NAAS)", "has", "developed", "a", "web-based", "database", "to", "provide", "characterization", "information", "in", "silkworm.", "The", "silkworm", "database", "has", "four", "major", "function", "menus:", "variety", "searching,", "characterization", "viewing,", "general", "information", "and", "photo", "gallery.", "It", "provides", "321", "silkworm", "varieties", "characterization", "information", "for", "six", "different", "regions", "namely,", "Korean,", "Japanese,", "Chinese,", "European,", "Tropical", "and", "non-classified", "group.", "Additionally,", "the", "database", "provides", "1,132", "photo", "images", "regarding", "life", "cycle", "of", "various", "silkworm", "varieties.", "A", "specific", "characterization", "information", "table", "provides", "accession", "number,", "variety,", "strain", "and", "larval", "marking,", "blood", "color,", "cocoon", "color,", "cocoon", "shape,", "egg", "colors,", "remarks", "and", "image", "table", "provides", "photos", "which", "consist", "of", "shape", "and", "color", "in", "the", "different", "stages", "of", "larval,", "egg", "and", "cocoon", "stages.", "Availability:", "The", "database", "is", "available", "for", "free", "at", "http://www.naas.go.kr/silkworm/english/", "Keywords:", "silkworm", "variety,", "gene", "resources,", "silkworm", "races,", "silkworm", "database", "Background:", "The", "silkworm", "is", "one", "of", "the", "most", "economically", "important,", "beneficial", "insects", "in", "many", "developing", "countries", "owing", "to", "for", "silk", "production", "and", "source", "of", "biomaterials.", "With", "advances", "in", "genomic", "technologies,", "there", "is", "a", "rapid", "increase", "in", "silkworm-related", "data", "including", "genome", "sequences", "and", "genetic", "markers.", "The", "SilkDB", "database", "is", "a", "web", "based", "repository", "for", "the", "curation,", "integration", "and", "study", "of", "silkworm", "genetic", "and", "genomic", "data", "[1].", "KAIKObase", "is", "an", "integrated", "silkworm", "genome", "database", "and", "data", "mining", "tool", "with", "4", "map", "browsers,", "1", "gene", "viewer,", "and", "2", "independent", "databases", "[2].", "The", "Central", "Sericultural", "Germplasm", "Resources", "Centre", "(CSGRC)", "provides", "1,120", "mulberry", "and", "432", "silkworm", "germplasm", "resources", "[3].", "The", "WildSilkbase", "provides", "the", "database", "is", "provided", "with", "57,113", "ESTs", "which", "are", "clustered", "and", "assembled", "into", "4,019", "contigs", "and", "10,019", "singletons", "derived", "from", "3", "major", "wild", "silk-moth", "[4].", "The", "SilkSatDb", "is", "a", "relational", "database", "of", "microsatellites", "extracted", "from", "the", "available", "expressed", "sequence", "tags", "and", "whole", "genome", "shotgun", "sequences", "of", "the", "silk-moth", "[5].", "The", "National", "Academy", "of", "Agricultural", "Science", "(NAAS)", "has", "developed", "a", "database", "system", "to", "provide", "integrated", "information", "about", "various", "gene", "resources", "[6-8]", "and", "has", "launched", "the", "silkworm", "gene", "resources", "project", "[9].", "Towards", "this", "effort,", "we", "developed", "a", "web-based", "database", "to", "provide", "characterization", "and", "images", "information", "in", "silkworm.", "Methodology:", "Dataset:", "The", "silkworm", "varieties", "collected", "from", "the", "silkworm", "gene", "resources", "project", "of", "NAAS.", "As", "a", "result", "of", "this", "project,", "we", "have", "investigated", "the", "characterization", "of", "silkworms", "as", "variety,", "strain", "and", "larval", "marking", "including", "shape", "and", "color", "in", "the", "different", "stage", "images.", "The", "silkworm", "database", "provides", "321", "silkworm", "variety", "information", "for", "six", "different", "regions", "namely,", "Korean", "(4", "varieties),", "Japanese", "(90", "varieties),", "Chinese", "(96", "varieties),", "European", "(32", "varieties),", "Tropical", "(9", "varieties)", "and", "non-classified", "(90", "varieties).", "The", "1,132", "photo", "images", "of", "shape", "and", "color", "information", "collected", "from", "the", "life", "cycle", "of", "various", "silkworm", "varieties.", "Additionally,", "the", "database", "was", "distinguished", "four", "different", "race", "types,", "namely", "univoltine", "(32", "races),", "bivoltine", "(188", "races),", "multivoltine", "(11", "races)", "and", "others", "(90", "races).", "Figure", "1:", "A", "snap", "shot", "of", "the", "specific", "characterization", "information", "table", "through", "silkworm", "database.", "The", "characterization", "and", "image", "information", "table", "show", "sample", "(Hansung", "banmun)", "by", "clicking", "a", "specific", "identification", "number", "(No.", "143).", "ISSN", "0973-2063", "(online)", "0973-8894", "(print)", "Bioinformation", "4(10):", "436-437", "(2010)", "436", "©", "2010", "Biomedical", "Informatics" ]

[ 0, 0, 9, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 0, 0, 0, 0, 0, 0, 0, 0, 0, 4, 9, 9, 9, 9 ]

[ [ 70, 45, 32, 12 ], [ 106, 45, 24, 12 ], [ 133, 45, 31, 12 ], [ 167, 45, 58, 12 ], [ 70, 61, 21, 12 ], [ 95, 61, 134, 12 ], [ 78, 89, 76, 15 ], [ 159, 89, 60, 15 ], [ 70, 148, 66, 25 ], [ 142, 148, 105, 25 ], [ 253, 148, 20, 25 ], [ 279, 148, 121, 25 ], [ 405, 148, 104, 25 ], [ 515, 148, 56, 25 ], [ 577, 148, 39, 25 ], [ 622, 148, 75, 25 ], [ 70, 176, 33, 25 ], [ 111, 176, 161, 25 ], [ 280, 176, 20, 25 ], [ 307, 176, 124, 25 ], [ 439, 176, 68, 25 ], [ 70, 225, 33, 14 ], [ 107, 225, 39, 14 ], [ 149, 227, 4, 11 ], [ 156, 225, 37, 14 ], [ 197, 225, 39, 14 ], [ 239, 227, 4, 11 ], [ 246, 225, 45, 14 ], [ 296, 225, 69, 14 ], [ 367, 227, 4, 11 ], [ 70, 242, 50, 14 ], [ 125, 242, 114, 14 ], [ 242, 245, 4, 11 ], [ 249, 242, 45, 14 ], [ 299, 242, 75, 14 ], [ 376, 245, 5, 11 ], [ 70, 260, 48, 14 ], [ 123, 260, 47, 14 ], [ 173, 262, 4, 12 ], [ 180, 260, 49, 14 ], [ 233, 260, 74, 14 ], [ 70, 337, 47, 12 ], [ 121, 337, 12, 12 ], [ 136, 337, 42, 12 ], [ 182, 337, 24, 12 ], [ 208, 337, 4, 12 ], [ 213, 337, 48, 12 ], [ 264, 337, 12, 12 ], [ 280, 337, 25, 12 ], [ 308, 337, 24, 12 ], [ 334, 337, 4, 12 ], [ 339, 337, 46, 12 ], [ 388, 337, 33, 12 ], [ 425, 337, 12, 12 ], [ 440, 337, 22, 12 ], [ 465, 337, 24, 12 ], [ 70, 351, 12, 12 ], [ 86, 350, 19, 12 ], [ 108, 350, 46, 12 ], [ 157, 350, 27, 12 ], [ 187, 350, 21, 12 ], [ 212, 350, 29, 12 ], [ 244, 350, 8, 12 ], [ 256, 350, 46, 12 ], [ 305, 350, 21, 12 ], [ 330, 350, 23, 12 ], [ 357, 350, 30, 12 ], [ 390, 350, 9, 12 ], [ 402, 350, 82, 12 ], [ 70, 392, 51, 14 ], [ 128, 392, 61, 14 ], [ 194, 392, 11, 14 ], [ 209, 392, 67, 14 ], [ 281, 392, 59, 14 ], [ 344, 392, 26, 14 ], [ 375, 392, 26, 14 ], [ 70, 409, 51, 14 ], [ 126, 409, 11, 14 ], [ 143, 409, 24, 14 ], [ 172, 409, 22, 14 ], [ 198, 409, 11, 14 ], [ 215, 409, 66, 14 ], [ 285, 409, 36, 14 ], [ 327, 409, 75, 14 ], [ 70, 426, 31, 14 ], [ 110, 426, 21, 14 ], [ 140, 426, 41, 14 ], [ 190, 426, 17, 14 ], [ 216, 426, 28, 14 ], [ 253, 426, 57, 14 ], [ 318, 426, 12, 14 ], [ 339, 426, 63, 14 ], [ 70, 444, 59, 14 ], [ 135, 444, 20, 14 ], [ 161, 444, 69, 14 ], [ 236, 444, 12, 14 ], [ 254, 444, 25, 14 ], [ 285, 444, 59, 14 ], [ 350, 444, 19, 14 ], [ 375, 444, 26, 14 ], [ 70, 461, 51, 14 ], [ 128, 461, 12, 14 ], [ 147, 461, 7, 14 ], [ 161, 461, 46, 14 ], [ 213, 461, 31, 14 ], [ 251, 461, 12, 14 ], [ 270, 461, 67, 14 ], [ 344, 461, 57, 14 ], [ 70, 478, 50, 14 ], [ 124, 478, 11, 14 ], [ 138, 478, 41, 14 ], [ 182, 478, 45, 14 ], [ 230, 478, 22, 14 ], [ 255, 478, 50, 14 ], [ 308, 478, 12, 14 ], [ 323, 478, 20, 14 ], [ 346, 478, 30, 14 ], [ 380, 478, 22, 14 ], [ 70, 495, 11, 14 ], [ 90, 495, 61, 14 ], [ 160, 495, 32, 14 ], [ 201, 495, 21, 14 ], [ 230, 495, 42, 14 ], [ 280, 495, 32, 14 ], [ 321, 495, 60, 14 ], [ 390, 495, 11, 14 ], [ 70, 513, 66, 14 ], [ 142, 513, 36, 14 ], [ 184, 513, 20, 14 ], [ 210, 513, 11, 14 ], [ 227, 513, 42, 14 ], [ 275, 513, 17, 14 ], [ 298, 513, 38, 14 ], [ 342, 513, 12, 14 ], [ 359, 513, 42, 14 ], [ 70, 530, 68, 14 ], [ 142, 530, 78, 14 ], [ 224, 530, 14, 14 ], [ 241, 530, 25, 14 ], [ 270, 530, 63, 14 ], [ 336, 530, 31, 14 ], [ 370, 530, 32, 14 ], [ 70, 572, 51, 12 ], [ 124, 572, 75, 12 ], [ 202, 572, 42, 12 ], [ 249, 572, 19, 12 ], [ 270, 572, 30, 12 ], [ 302, 572, 35, 12 ], [ 340, 572, 10, 12 ], [ 353, 572, 17, 12 ], [ 372, 572, 29, 12 ], [ 70, 585, 160, 12 ], [ 233, 585, 39, 12 ], [ 276, 585, 69, 12 ], [ 349, 585, 41, 12 ], [ 70, 599, 29, 12 ], [ 103, 599, 8, 12 ], [ 114, 599, 42, 12 ], [ 160, 599, 10, 12 ], [ 173, 599, 50, 12 ], [ 226, 599, 27, 12 ], [ 70, 622, 12, 12 ], [ 86, 622, 30, 12 ], [ 117, 615, 5, 17 ], [ 124, 622, 12, 12 ], [ 139, 622, 30, 12 ], [ 171, 615, 5, 17 ], [ 178, 622, 11, 12 ], [ 193, 622, 60, 12 ], [ 70, 635, 52, 12 ], [ 126, 635, 10, 12 ], [ 140, 635, 61, 12 ], [ 204, 635, 55, 12 ], [ 263, 635, 10, 12 ], [ 276, 635, 35, 12 ], [ 315, 635, 46, 12 ], [ 70, 649, 39, 12 ], [ 112, 649, 50, 12 ], [ 165, 649, 10, 12 ], [ 179, 649, 35, 12 ], [ 70, 663, 13, 12 ], [ 86, 663, 65, 12 ], [ 154, 663, 9, 12 ], [ 70, 677, 36, 12 ], [ 110, 677, 35, 12 ], [ 147, 677, 33, 12 ], [ 70, 705, 12, 12 ], [ 86, 705, 30, 12 ], [ 117, 698, 5, 17 ], [ 124, 705, 10, 12 ], [ 137, 705, 56, 12 ], [ 195, 698, 5, 17 ], [ 201, 705, 10, 12 ], [ 214, 705, 59, 12 ], [ 70, 719, 12, 12 ], [ 86, 719, 55, 12 ], [ 144, 719, 10, 12 ], [ 158, 719, 60, 12 ], [ 221, 719, 39, 12 ], [ 263, 719, 50, 12 ], [ 316, 719, 10, 12 ], [ 330, 719, 35, 12 ], [ 70, 732, 13, 12 ], [ 86, 732, 65, 12 ], [ 154, 732, 9, 12 ], [ 70, 746, 36, 12 ], [ 110, 746, 35, 12 ], [ 147, 746, 33, 12 ], [ 70, 774, 12, 12 ], [ 86, 774, 30, 12 ], [ 70, 788, 37, 12 ], [ 111, 788, 17, 12 ], [ 132, 788, 49, 12 ], [ 184, 788, 37, 12 ], [ 225, 788, 58, 12 ], [ 287, 788, 31, 12 ], [ 322, 788, 35, 12 ], [ 70, 801, 45, 12 ], [ 119, 801, 43, 12 ], [ 70, 815, 13, 12 ], [ 86, 815, 48, 12 ], [ 137, 815, 21, 12 ], [ 70, 829, 35, 12 ], [ 108, 829, 33, 12 ], [ 70, 857, 11, 12 ], [ 85, 857, 90, 12 ], [ 70, 871, 55, 12 ], [ 129, 871, 10, 12 ], [ 143, 871, 47, 12 ], [ 193, 871, 17, 12 ], [ 213, 871, 59, 12 ], [ 276, 871, 21, 12 ], [ 300, 871, 63, 12 ], [ 70, 885, 44, 12 ], [ 118, 885, 24, 12 ], [ 145, 885, 39, 12 ], [ 187, 885, 50, 12 ], [ 240, 885, 10, 12 ], [ 254, 885, 35, 12 ], [ 70, 898, 13, 12 ], [ 86, 898, 75, 12 ], [ 165, 898, 15, 12 ], [ 70, 912, 36, 12 ], [ 110, 912, 35, 12 ], [ 147, 912, 33, 12 ], [ 70, 940, 12, 12 ], [ 86, 940, 38, 12 ], [ 70, 954, 55, 12 ], [ 129, 954, 10, 12 ], [ 143, 954, 59, 12 ], [ 205, 954, 39, 12 ], [ 247, 954, 50, 12 ], [ 300, 954, 10, 12 ], [ 313, 954, 35, 12 ], [ 70, 968, 13, 12 ], [ 86, 968, 65, 12 ], [ 154, 968, 9, 12 ], [ 70, 981, 34, 12 ], [ 107, 981, 35, 12 ], [ 145, 981, 33, 12 ], [ 425, 392, 45, 14 ], [ 475, 392, 27, 14 ], [ 507, 392, 50, 14 ], [ 562, 392, 27, 14 ], [ 594, 392, 14, 14 ], [ 614, 392, 43, 14 ], [ 662, 392, 19, 14 ], [ 686, 392, 70, 14 ], [ 425, 409, 67, 14 ], [ 500, 409, 59, 14 ], [ 567, 409, 21, 14 ], [ 597, 409, 15, 14 ], [ 620, 409, 54, 14 ], [ 682, 409, 45, 14 ], [ 735, 409, 21, 14 ], [ 425, 426, 68, 14 ], [ 498, 426, 23, 14 ], [ 526, 426, 27, 14 ], [ 558, 426, 48, 14 ], [ 610, 426, 27, 14 ], [ 642, 426, 44, 14 ], [ 691, 426, 65, 14 ], [ 425, 444, 25, 14 ], [ 453, 444, 32, 14 ], [ 489, 444, 20, 14 ], [ 512, 444, 41, 14 ], [ 557, 444, 32, 14 ], [ 593, 444, 65, 14 ], [ 661, 444, 27, 14 ], [ 691, 444, 47, 14 ], [ 742, 444, 14, 14 ], [ 425, 461, 55, 14 ], [ 488, 461, 31, 14 ], [ 528, 461, 52, 14 ], [ 588, 461, 52, 14 ], [ 650, 461, 36, 14 ], [ 694, 461, 32, 14 ], [ 735, 461, 21, 14 ], [ 425, 478, 42, 14 ], [ 476, 478, 61, 14 ], [ 545, 478, 33, 14 ], [ 587, 478, 28, 14 ], [ 624, 478, 71, 14 ], [ 703, 478, 32, 14 ], [ 745, 478, 11, 14 ], [ 425, 495, 66, 14 ], [ 496, 495, 36, 14 ], [ 538, 495, 45, 14 ], [ 589, 495, 59, 14 ], [ 654, 495, 11, 14 ], [ 670, 495, 48, 14 ], [ 724, 495, 32, 14 ], [ 425, 513, 22, 14 ], [ 452, 513, 87, 14 ], [ 544, 513, 14, 14 ], [ 564, 513, 17, 14 ], [ 587, 513, 32, 14 ], [ 625, 513, 12, 14 ], [ 642, 513, 25, 14 ], [ 672, 513, 12, 14 ], [ 685, 513, 8, 14 ], [ 694, 513, 36, 14 ], [ 735, 513, 20, 14 ], [ 425, 530, 41, 14 ], [ 470, 530, 26, 14 ], [ 500, 530, 30, 14 ], [ 533, 530, 59, 14 ], [ 596, 530, 30, 14 ], [ 630, 530, 22, 14 ], [ 655, 530, 18, 14 ], [ 676, 530, 30, 14 ], [ 710, 530, 32, 14 ], [ 745, 530, 11, 14 ], [ 425, 622, 11, 12 ], [ 439, 622, 60, 12 ], [ 425, 636, 8, 12 ], [ 436, 636, 55, 12 ], [ 495, 636, 10, 12 ], [ 509, 636, 39, 12 ], [ 551, 636, 39, 12 ], [ 593, 636, 50, 12 ], [ 646, 636, 10, 12 ], [ 660, 636, 35, 12 ], [ 425, 650, 13, 12 ], [ 441, 650, 38, 12 ], [ 483, 650, 15, 12 ], [ 425, 663, 34, 12 ], [ 462, 663, 35, 12 ], [ 500, 663, 33, 12 ], [ 425, 727, 11, 12 ], [ 439, 727, 60, 12 ], [ 425, 741, 39, 12 ], [ 467, 741, 53, 12 ], [ 524, 741, 58, 12 ], [ 585, 741, 30, 12 ], [ 618, 741, 10, 12 ], [ 631, 741, 45, 12 ], [ 425, 755, 13, 12 ], [ 441, 755, 63, 12 ], [ 507, 755, 9, 12 ], [ 425, 769, 34, 12 ], [ 462, 769, 45, 12 ], [ 510, 769, 33, 12 ], [ 425, 832, 12, 12 ], [ 440, 832, 30, 12 ], [ 472, 832, 21, 12 ], [ 425, 846, 37, 12 ], [ 465, 846, 4, 12 ], [ 472, 846, 33, 12 ], [ 509, 846, 44, 12 ], [ 556, 846, 59, 12 ], [ 619, 846, 53, 12 ], [ 425, 860, 57, 12 ], [ 485, 860, 50, 12 ], [ 539, 860, 9, 12 ], [ 551, 860, 43, 12 ], [ 425, 874, 13, 12 ], [ 441, 874, 65, 12 ], [ 509, 874, 9, 12 ], [ 425, 887, 34, 12 ], [ 462, 887, 35, 12 ], [ 500, 887, 33, 12 ], [ 425, 901, 33, 12 ], [ 461, 901, 89, 12 ], [ 425, 968, 12, 12 ], [ 440, 968, 30, 12 ], [ 425, 982, 33, 12 ], [ 461, 982, 104, 12 ] ]

[ "Tumor", "Biol.", "(2011)", "32:769–776", "DOI", "10.1007/s13277-011-0179-0", "RESEARCH", "ARTICLE", "Major", "regulators", "of", "microRNAs", "biogenesis", "Dicer", "and", "Drosha", "are", "down-regulated", "in", "endometrial", "cancer", "Anna", "Torres", "&", "Kamil", "Torres", "&", "Tomasz", "Paszkowski", "&", "Barbara", "Jodłowska-Jędrych", "&", "Tomasz", "Radomański", "&", "Andrzej", "Książek", "&", "Ryszard", "Maciejewski", "Received:", "28", "February", "2011", "/", "Accepted:", "13", "April", "2011", "/", "Published", "online:", "11", "May", "2011", "#", "The", "Author(s)", "2011.", "This", "article", "is", "published", "with", "open", "access", "at", "Springerlink.com", "Abstract", "Alterations", "in", "microRNAs", "expression", "have", "been", "proposed", "to", "play", "role", "in", "endometrial", "cancer", "pathogenesis.", "Dicer", "and", "Drosha", "are", "main", "regulators", "of", "microRNA", "biogenesis", "and", "deregulation", "of", "their", "expression", "has", "been", "indicated", "as", "a", "possible", "cause", "of", "microRNAs", "alterations", "observed", "in", "various", "cancers.", "The", "objective", "of", "this", "study", "was", "to", "investigate", "Dicer", "and", "Drosha", "genes", "expression", "in", "endometrial", "cancer", "and", "to", "analyze", "the", "impact", "of", "clinico-", "pathological", "characteristics", "on", "their", "expression.", "Fresh", "tissue", "Electronic", "supplementary", "material", "The", "online", "version", "of", "this", "article", "(doi:10.1007/s13277-011-0179-0)", "contains", "supplementary", "material,", "which", "is", "available", "to", "authorized", "users.", "A.", "Torres", ":", "K.", "Torres", ":", "R.", "Maciejewski", "Laboratory", "of", "Biostructure,", "Department", "of", "Human", "Anatomy,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "4,", "20–094", "Lublin,", "Poland", "A.", "Torres", ":", "T.", "Paszkowski", ":", "T.", "Radomański", "III", "Department", "of", "Gynecology,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "8,", "20–094", "Lublin,", "Poland", "K.", "Torres", "General", "and", "Oncologic", "Surgery", "Department,", "Lublin", "County", "Specialist", "Hospital,", "ul.", "Kraśnicka", "100,", "Lublin,", "Poland", "B.", "Jodłowska-Jędrych", "Department", "of", "Histology", "and", "Embryology", "with", "Experimental", "Cytology", "Unit,", "Medical", "University", "of", "Lublin,", "ul.", "Radziwiłłowska", "11,", "20–080", "Lublin,", "Poland", "A.", "Książek", "Department", "of", "Nephrology,", "Medical", "University", "of", "Lublin,", "ul.", "Jaczewskiego", "8,", "20-094", "Lublin,", "Poland", "samples", "were", "collected", "from", "44", "patients", "(26", "endometroid", "endometrial", "carcinoma", "and", "18", "controls).", "Clinical", "and", "pathological", "data", "were", "acquired", "from", "medical", "documenta-", "tion.", "Dicer", "and", "Drosha", "genes", "expressions", "were", "assessed", "by", "qRT-PCR", "using", "validated", "reference", "genes.", "Dicer", "and", "Drosha", "expression", "levels", "were", "significantly", "lower", "in", "endometrial", "cancer", "samples", "comparing", "to", "controls.", "Dicer", "was", "down-regulated", "by", "the", "factor", "of", "1.54", "(p", "=", "0.009)", "and", "Drosha", "gene", "mean", "expression", "value", "was", "1.4", "times", "lower", "in", "R.", "Maciejewski", "II", "Department", "of", "Surgery,", "Medical", "University", "of", "Lublin,", "ul.", "Staszica", "16,", "20-081", "Lublin,", "Poland", "R.", "Maciejewski", "Medical", "Emergency", "Department,", "UlTM", "in", "Rzeszów,", "ul.", "Sucharskiego", "2,", "35-225", "Rzeszów,", "Poland", "A.", "Torres", "(*)", "Katedra", "i", "Zakład", "Anatomii", "Prawidłowej", "Człowieka,", "Uniwersytet", "Medyczny", "w", "Lublinie,", "ul.", "Jaczewskiego", "4,", "20-094", "Lublin,", "Poland", "e-mail:", "anna.torres@wp.pl", "A.", "Torres", "e-mail:", "anna.torres@umlub.pl" ]

[ 0, 0, 0, 0, 0, 0, 16, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 11, 11, 11 ]

[ [ 76, 115, 65, 22 ], [ 145, 115, 76, 22 ], [ 225, 115, 20, 22 ], [ 249, 115, 59, 22 ], [ 313, 115, 188, 22 ], [ 505, 115, 133, 23 ], [ 643, 115, 26, 23 ], [ 674, 115, 90, 22 ], [ 76, 146, 20, 22 ], [ 101, 146, 49, 22 ], [ 155, 145, 45, 23 ], [ 205, 146, 73, 22 ], [ 284, 146, 11, 22 ], [ 300, 146, 108, 22 ], [ 413, 146, 90, 22 ], [ 509, 146, 65, 22 ], [ 579, 145, 110, 23 ], [ 118, 197, 37, 16 ], [ 158, 197, 12, 16 ], [ 174, 197, 73, 16 ], [ 250, 197, 26, 16 ], [ 279, 197, 35, 16 ], [ 318, 197, 14, 16 ], [ 335, 197, 64, 16 ], [ 118, 222, 27, 12 ], [ 147, 222, 16, 12 ], [ 165, 222, 59, 12 ], [ 227, 222, 10, 12 ], [ 240, 222, 51, 12 ], [ 294, 222, 19, 12 ], [ 315, 222, 54, 12 ], [ 371, 222, 49, 12 ], [ 422, 222, 10, 12 ], [ 435, 222, 31, 12 ], [ 469, 222, 34, 12 ], [ 505, 222, 10, 12 ], [ 518, 222, 49, 12 ], [ 569, 222, 34, 12 ], [ 605, 222, 35, 12 ], [ 643, 222, 55, 12 ], [ 118, 260, 8, 14 ], [ 126, 260, 8, 14 ], [ 135, 260, 6, 14 ], [ 142, 260, 8, 14 ], [ 151, 260, 8, 14 ], [ 159, 260, 8, 14 ], [ 168, 260, 8, 14 ], [ 177, 260, 8, 14 ], [ 193, 260, 24, 14 ], [ 221, 259, 93, 14 ], [ 319, 260, 36, 14 ], [ 360, 260, 66, 14 ], [ 431, 260, 12, 14 ], [ 448, 260, 106, 14 ], [ 559, 260, 99, 14 ], [ 662, 259, 16, 14 ], [ 683, 260, 29, 14 ], [ 716, 260, 52, 14 ], [ 118, 275, 29, 14 ], [ 149, 275, 49, 14 ], [ 201, 275, 16, 14 ], [ 221, 275, 43, 14 ], [ 267, 275, 41, 14 ], [ 310, 275, 20, 14 ], [ 333, 275, 57, 14 ], [ 394, 275, 29, 14 ], [ 425, 275, 20, 14 ], [ 448, 275, 13, 14 ], [ 464, 274, 27, 14 ], [ 494, 275, 12, 14 ], [ 509, 275, 27, 14 ], [ 539, 275, 37, 14 ], [ 579, 274, 27, 14 ], [ 608, 275, 71, 14 ], [ 682, 275, 86, 14 ], [ 118, 289, 12, 14 ], [ 134, 289, 45, 14 ], [ 184, 289, 33, 14 ], [ 219, 289, 6, 14 ], [ 230, 289, 31, 14 ], [ 266, 289, 84, 14 ], [ 355, 289, 61, 14 ], [ 420, 289, 34, 14 ], [ 458, 289, 63, 14 ], [ 525, 289, 24, 15 ], [ 554, 289, 55, 14 ], [ 614, 289, 25, 14 ], [ 643, 289, 60, 14 ], [ 708, 289, 30, 16 ], [ 742, 289, 26, 15 ], [ 217, 295, 3, 9 ], [ 118, 304, 25, 14 ], [ 146, 303, 11, 14 ], [ 161, 304, 18, 14 ], [ 182, 303, 21, 14 ], [ 206, 304, 11, 14 ], [ 221, 303, 25, 14 ], [ 250, 304, 23, 14 ], [ 276, 304, 22, 14 ], [ 302, 304, 61, 14 ], [ 366, 304, 12, 14 ], [ 382, 304, 18, 14 ], [ 403, 303, 11, 14 ], [ 418, 304, 27, 14 ], [ 449, 304, 51, 14 ], [ 504, 304, 7, 14 ], [ 514, 304, 59, 14 ], [ 577, 304, 12, 14 ], [ 592, 304, 35, 14 ], [ 631, 304, 17, 14 ], [ 652, 303, 30, 16 ], [ 684, 304, 11, 14 ], [ 699, 304, 21, 14 ], [ 724, 303, 24, 14 ], [ 752, 304, 16, 14 ], [ 118, 318, 48, 14 ], [ 170, 318, 30, 16 ], [ 204, 318, 42, 14 ], [ 250, 318, 12, 14 ], [ 267, 318, 31, 14 ], [ 303, 318, 21, 14 ], [ 328, 318, 22, 14 ], [ 355, 318, 27, 14 ], [ 386, 318, 59, 14 ], [ 450, 318, 32, 14 ], [ 486, 318, 16, 14 ], [ 507, 318, 35, 14 ], [ 546, 318, 13, 15 ], [ 563, 318, 13, 14 ], [ 581, 318, 19, 14 ], [ 604, 318, 84, 14 ], [ 692, 318, 48, 14 ], [ 745, 318, 24, 14 ], [ 118, 333, 52, 14 ], [ 172, 333, 32, 14 ], [ 208, 333, 40, 14 ], [ 251, 333, 11, 14 ], [ 265, 333, 26, 14 ], [ 294, 333, 31, 14 ], [ 328, 333, 12, 14 ], [ 344, 333, 25, 14 ], [ 372, 333, 30, 14 ], [ 405, 333, 22, 14 ], [ 430, 333, 25, 14 ], [ 458, 333, 12, 14 ], [ 473, 333, 20, 14 ], [ 497, 333, 37, 14 ], [ 536, 333, 31, 14 ], [ 571, 333, 11, 14 ], [ 585, 333, 27, 14 ], [ 615, 333, 31, 14 ], [ 649, 333, 12, 14 ], [ 664, 332, 30, 16 ], [ 697, 333, 38, 14 ], [ 738, 333, 30, 14 ], [ 118, 347, 59, 14 ], [ 180, 347, 25, 14 ], [ 208, 347, 31, 14 ], [ 242, 347, 12, 14 ], [ 258, 347, 25, 14 ], [ 286, 347, 30, 14 ], [ 320, 347, 22, 14 ], [ 345, 347, 20, 14 ], [ 369, 347, 12, 14 ], [ 385, 347, 32, 14 ], [ 420, 347, 37, 14 ], [ 460, 347, 31, 14 ], [ 495, 347, 11, 14 ], [ 509, 347, 32, 14 ], [ 544, 347, 33, 16 ], [ 580, 347, 24, 14 ], [ 608, 347, 35, 14 ], [ 646, 347, 12, 14 ], [ 661, 347, 40, 14 ], [ 704, 347, 48, 14 ], [ 756, 347, 12, 14 ], [ 118, 362, 46, 14 ], [ 169, 362, 17, 14 ], [ 192, 362, 19, 14 ], [ 217, 362, 84, 14 ], [ 306, 362, 44, 14 ], [ 356, 362, 20, 14 ], [ 382, 362, 57, 14 ], [ 445, 362, 25, 14 ], [ 475, 362, 77, 14 ], [ 557, 362, 59, 14 ], [ 622, 362, 59, 14 ], [ 686, 362, 35, 14 ], [ 727, 362, 12, 14 ], [ 745, 362, 24, 14 ], [ 118, 377, 71, 14 ], [ 192, 377, 32, 14 ], [ 228, 377, 60, 14 ], [ 291, 377, 73, 14 ], [ 367, 377, 52, 14 ], [ 422, 377, 29, 14 ], [ 454, 377, 20, 14 ], [ 478, 377, 12, 14 ], [ 493, 377, 27, 14 ], [ 524, 376, 33, 16 ], [ 560, 377, 41, 14 ], [ 605, 377, 49, 14 ], [ 657, 377, 36, 14 ], [ 696, 377, 29, 14 ], [ 728, 377, 19, 14 ], [ 751, 377, 17, 14 ], [ 118, 391, 27, 14 ], [ 147, 391, 151, 14 ], [ 302, 391, 37, 14 ], [ 342, 391, 33, 14 ], [ 378, 391, 20, 14 ], [ 402, 391, 49, 14 ], [ 454, 391, 19, 14 ], [ 476, 391, 60, 14 ], [ 539, 391, 73, 14 ], [ 615, 391, 29, 14 ], [ 647, 391, 20, 14 ], [ 670, 391, 12, 14 ], [ 686, 391, 27, 14 ], [ 716, 391, 33, 16 ], [ 752, 391, 16, 14 ], [ 118, 406, 29, 14 ], [ 150, 406, 49, 14 ], [ 201, 406, 36, 14 ], [ 240, 406, 29, 14 ], [ 272, 406, 42, 14 ], [ 317, 406, 44, 14 ], [ 363, 406, 37, 14 ], [ 404, 406, 17, 14 ], [ 424, 406, 7, 14 ], [ 434, 406, 90, 14 ], [ 527, 406, 60, 14 ], [ 590, 406, 43, 14 ], [ 637, 406, 33, 14 ], [ 672, 406, 74, 14 ], [ 749, 406, 19, 14 ], [ 118, 420, 60, 14 ], [ 180, 420, 73, 14 ], [ 256, 420, 20, 14 ], [ 278, 420, 20, 14 ], [ 301, 420, 19, 14 ], [ 323, 420, 71, 14 ], [ 397, 420, 81, 14 ], [ 481, 420, 48, 14 ], [ 532, 420, 49, 14 ], [ 584, 420, 48, 14 ], [ 635, 420, 11, 14 ], [ 649, 420, 27, 14 ], [ 679, 420, 33, 16 ], [ 715, 420, 53, 14 ], [ 118, 435, 42, 14 ], [ 163, 435, 36, 14 ], [ 203, 435, 29, 14 ], [ 235, 435, 7, 14 ], [ 246, 435, 44, 14 ], [ 293, 435, 14, 14 ], [ 311, 435, 27, 14 ], [ 342, 435, 58, 14 ], [ 403, 435, 47, 14 ], [ 454, 435, 12, 14 ], [ 470, 435, 35, 14 ], [ 508, 435, 31, 14 ], [ 543, 435, 27, 14 ], [ 574, 435, 14, 14 ], [ 592, 435, 37, 14 ], [ 632, 435, 31, 14 ], [ 667, 435, 16, 14 ], [ 687, 435, 19, 14 ], [ 710, 435, 35, 14 ], [ 749, 435, 20, 14 ], [ 118, 450, 22, 14 ], [ 144, 450, 14, 14 ], [ 162, 450, 30, 14 ], [ 196, 450, 31, 14 ], [ 232, 450, 16, 14 ], [ 252, 450, 19, 14 ], [ 275, 450, 32, 14 ], [ 311, 450, 22, 14 ], [ 338, 450, 33, 14 ], [ 375, 450, 74, 14 ], [ 453, 450, 27, 14 ], [ 484, 450, 19, 14 ], [ 508, 450, 60, 14 ], [ 571, 450, 73, 14 ], [ 648, 450, 22, 14 ], [ 675, 450, 19, 14 ], [ 698, 450, 71, 14 ], [ 118, 464, 29, 14 ], [ 150, 464, 20, 14 ], [ 173, 464, 12, 14 ], [ 189, 464, 27, 14 ], [ 219, 464, 33, 16 ], [ 256, 464, 13, 14 ], [ 272, 464, 19, 14 ], [ 295, 464, 58, 14 ], [ 356, 464, 41, 14 ], [ 400, 464, 19, 14 ], [ 423, 464, 18, 14 ], [ 444, 464, 47, 14 ], [ 495, 464, 21, 14 ], [ 519, 464, 30, 14 ], [ 553, 464, 43, 14 ], [ 599, 464, 29, 14 ], [ 631, 464, 27, 14 ], [ 662, 464, 37, 14 ], [ 702, 464, 30, 14 ], [ 736, 464, 22, 14 ], [ 762, 464, 7, 14 ], [ 118, 479, 57, 14 ], [ 178, 479, 12, 14 ], [ 193, 479, 21, 14 ], [ 217, 479, 30, 14 ], [ 250, 479, 22, 14 ], [ 275, 479, 20, 14 ], [ 298, 479, 37, 14 ], [ 338, 479, 31, 14 ], [ 372, 479, 19, 14 ], [ 394, 479, 50, 14 ], [ 447, 479, 17, 14 ], [ 467, 479, 36, 14 ], [ 507, 479, 11, 14 ], [ 521, 479, 20, 14 ], [ 544, 479, 31, 14 ], [ 578, 478, 33, 16 ], [ 614, 479, 9, 14 ], [ 626, 479, 37, 14 ], [ 666, 479, 23, 14 ], [ 693, 479, 50, 14 ], [ 745, 479, 23, 14 ], [ 118, 493, 19, 14 ], [ 140, 493, 53, 14 ], [ 195, 493, 76, 14 ], [ 274, 493, 29, 14 ], [ 305, 493, 21, 14 ], [ 329, 493, 33, 14 ], [ 365, 493, 7, 14 ], [ 375, 493, 59, 14 ], [ 437, 493, 23, 14 ], [ 463, 493, 11, 14 ], [ 477, 493, 27, 14 ], [ 507, 493, 30, 16 ], [ 539, 493, 33, 14 ], [ 575, 493, 23, 14 ], [ 601, 493, 74, 14 ], [ 678, 493, 19, 14 ], [ 700, 493, 36, 14 ], [ 740, 493, 29, 14 ], [ 118, 508, 20, 14 ], [ 140, 508, 12, 14 ], [ 156, 508, 27, 14 ], [ 185, 507, 33, 16 ], [ 221, 508, 24, 14 ], [ 248, 508, 64, 14 ], [ 315, 508, 42, 14 ], [ 360, 508, 21, 14 ], [ 384, 508, 29, 14 ], [ 416, 508, 12, 14 ], [ 431, 508, 47, 14 ], [ 480, 508, 64, 14 ], [ 547, 508, 17, 14 ], [ 568, 508, 19, 14 ], [ 590, 508, 36, 14 ], [ 629, 508, 12, 14 ], [ 644, 508, 18, 14 ], [ 665, 508, 55, 14 ], [ 118, 532, 8, 14 ], [ 126, 532, 7, 14 ], [ 134, 532, 8, 14 ], [ 148, 532, 11, 14 ], [ 159, 532, 9, 14 ], [ 169, 532, 8, 14 ], [ 177, 532, 9, 14 ], [ 187, 532, 6, 14 ], [ 194, 532, 4, 14 ], [ 213, 532, 18, 14 ], [ 234, 532, 47, 14 ], [ 283, 532, 7, 14 ], [ 293, 532, 19, 15 ], [ 315, 532, 47, 14 ], [ 365, 532, 6, 14 ], [ 374, 532, 151, 14 ], [ 528, 532, 7, 14 ], [ 538, 532, 34, 14 ], [ 574, 532, 6, 14 ], [ 584, 532, 44, 14 ], [ 75, 585, 5, 14 ], [ 82, 585, 9, 14 ], [ 93, 585, 8, 14 ], [ 104, 585, 8, 14 ], [ 114, 585, 9, 14 ], [ 125, 585, 9, 14 ], [ 137, 585, 9, 14 ], [ 148, 585, 8, 14 ], [ 158, 585, 8, 14 ], [ 169, 585, 5, 14 ], [ 176, 585, 9, 14 ], [ 188, 585, 9, 14 ], [ 75, 609, 117, 14 ], [ 196, 609, 85, 15 ], [ 287, 609, 17, 15 ], [ 310, 609, 35, 15 ], [ 350, 609, 58, 14 ], [ 75, 626, 36, 14 ], [ 117, 626, 20, 14 ], [ 142, 626, 54, 14 ], [ 202, 626, 14, 14 ], [ 221, 626, 72, 14 ], [ 299, 626, 91, 14 ], [ 396, 626, 13, 14 ], [ 75, 643, 75, 14 ], [ 154, 642, 29, 15 ], [ 188, 642, 44, 17 ], [ 237, 643, 24, 14 ], [ 265, 643, 14, 14 ], [ 284, 643, 88, 14 ], [ 378, 643, 31, 14 ], [ 75, 659, 22, 14 ], [ 100, 659, 12, 14 ], [ 116, 659, 18, 14 ], [ 138, 659, 35, 14 ], [ 177, 659, 20, 14 ], [ 201, 659, 46, 14 ], [ 250, 659, 13, 14 ], [ 267, 659, 7, 14 ], [ 278, 659, 28, 14 ], [ 310, 659, 40, 14 ], [ 353, 659, 13, 14 ], [ 370, 659, 39, 14 ], [ 75, 676, 60, 14 ], [ 138, 676, 14, 14 ], [ 156, 676, 34, 14 ], [ 194, 676, 33, 14 ], [ 230, 676, 38, 14 ], [ 272, 676, 33, 14 ], [ 309, 676, 63, 14 ], [ 375, 676, 33, 14 ], [ 75, 693, 50, 14 ], [ 128, 693, 33, 14 ], [ 165, 693, 38, 14 ], [ 208, 693, 39, 14 ], [ 251, 693, 56, 14 ], [ 311, 693, 19, 14 ], [ 334, 693, 54, 14 ], [ 392, 693, 16, 14 ], [ 75, 709, 30, 14 ], [ 113, 709, 67, 14 ], [ 189, 709, 66, 14 ], [ 264, 709, 14, 14 ], [ 287, 709, 51, 14 ], [ 346, 709, 17, 15 ], [ 373, 709, 36, 14 ], [ 75, 726, 50, 14 ], [ 131, 726, 30, 14 ], [ 167, 726, 47, 14 ], [ 219, 726, 37, 14 ], [ 263, 726, 36, 14 ], [ 305, 726, 36, 14 ], [ 347, 726, 20, 14 ], [ 374, 726, 35, 14 ], [ 75, 743, 36, 14 ], [ 117, 743, 55, 14 ], [ 178, 743, 33, 14 ], [ 217, 743, 54, 14 ], [ 278, 743, 44, 14 ], [ 329, 743, 19, 14 ], [ 354, 743, 54, 14 ], [ 75, 759, 30, 14 ], [ 108, 759, 7, 14 ], [ 119, 759, 24, 14 ], [ 147, 759, 13, 14 ], [ 163, 759, 7, 14 ], [ 174, 759, 51, 14 ], [ 229, 759, 58, 14 ], [ 291, 759, 28, 14 ], [ 322, 759, 24, 14 ], [ 350, 759, 58, 14 ], [ 75, 776, 66, 14 ], [ 144, 776, 13, 14 ], [ 160, 776, 54, 14 ], [ 218, 776, 13, 14 ], [ 234, 776, 29, 14 ], [ 266, 776, 58, 14 ], [ 328, 775, 31, 17 ], [ 363, 776, 24, 14 ], [ 390, 776, 19, 14 ], [ 75, 793, 77, 14 ], [ 87, 809, 74, 14 ], [ 164, 809, 35, 14 ], [ 202, 809, 20, 14 ], [ 225, 809, 38, 14 ], [ 266, 809, 70, 14 ], [ 338, 809, 13, 14 ], [ 354, 809, 18, 14 ], [ 375, 809, 33, 14 ], [ 75, 826, 25, 14 ], [ 102, 826, 21, 14 ], [ 125, 826, 78, 14 ], [ 205, 826, 30, 14 ], [ 238, 826, 41, 14 ], [ 282, 826, 42, 14 ], [ 326, 826, 17, 14 ], [ 346, 826, 36, 14 ], [ 385, 826, 24, 14 ], [ 75, 843, 89, 14 ], [ 171, 843, 60, 14 ], [ 238, 843, 58, 14 ], [ 302, 843, 19, 14 ], [ 328, 843, 54, 14 ], [ 389, 843, 20, 14 ], [ 75, 889, 39, 12 ], [ 116, 889, 79, 12 ], [ 198, 889, 10, 12 ], [ 211, 889, 16, 12 ], [ 230, 889, 21, 12 ], [ 254, 889, 10, 12 ], [ 267, 889, 44, 12 ], [ 314, 889, 27, 12 ], [ 344, 889, 10, 12 ], [ 357, 889, 51, 12 ], [ 75, 903, 19, 12 ], [ 98, 903, 52, 12 ], [ 154, 903, 41, 12 ], [ 200, 903, 50, 12 ], [ 254, 903, 10, 12 ], [ 269, 903, 32, 12 ], [ 305, 903, 34, 12 ], [ 344, 903, 10, 12 ], [ 358, 903, 50, 12 ], [ 75, 917, 35, 12 ], [ 118, 917, 13, 12 ], [ 140, 917, 58, 12 ], [ 206, 917, 21, 12 ], [ 235, 917, 66, 12 ], [ 310, 917, 34, 12 ], [ 353, 917, 56, 12 ], [ 75, 931, 52, 12 ], [ 87, 944, 0, 8 ], [ 93, 945, 20, 12 ], [ 115, 945, 32, 12 ], [ 149, 945, 35, 12 ], [ 187, 945, 10, 12 ], [ 199, 945, 18, 12 ], [ 220, 945, 31, 12 ], [ 253, 945, 41, 12 ], [ 296, 945, 66, 12 ], [ 365, 945, 43, 12 ], [ 87, 958, 63, 12 ], [ 155, 958, 20, 12 ], [ 179, 958, 10, 12 ], [ 193, 958, 16, 12 ], [ 214, 958, 27, 12 ], [ 246, 958, 20, 12 ], [ 270, 958, 72, 12 ], [ 346, 958, 15, 12 ], [ 366, 958, 42, 12 ], [ 75, 972, 90, 12 ], [ 171, 972, 84, 12 ], [ 262, 972, 14, 12 ], [ 283, 972, 43, 12 ], [ 332, 972, 31, 12 ], [ 370, 972, 38, 12 ], [ 75, 986, 92, 12 ], [ 169, 986, 41, 13 ], [ 212, 986, 56, 12 ], [ 270, 986, 50, 12 ], [ 323, 986, 26, 12 ], [ 433, 585, 97, 14 ], [ 540, 585, 45, 14 ], [ 595, 585, 30, 14 ], [ 635, 585, 26, 14 ], [ 672, 585, 34, 14 ], [ 716, 585, 51, 14 ], [ 433, 601, 37, 14 ], [ 473, 601, 12, 14 ], [ 488, 601, 18, 14 ], [ 509, 601, 39, 14 ], [ 551, 601, 26, 14 ], [ 580, 601, 23, 14 ], [ 606, 601, 14, 14 ], [ 623, 601, 33, 14 ], [ 659, 600, 79, 15 ], [ 741, 601, 26, 14 ], [ 433, 618, 21, 14 ], [ 457, 618, 46, 14 ], [ 506, 618, 65, 14 ], [ 574, 618, 24, 14 ], [ 600, 618, 45, 14 ], [ 649, 618, 39, 14 ], [ 691, 618, 18, 14 ], [ 712, 618, 54, 14 ], [ 433, 635, 49, 14 ], [ 489, 635, 42, 14 ], [ 538, 635, 7, 14 ], [ 553, 635, 32, 14 ], [ 592, 635, 48, 14 ], [ 647, 635, 50, 14 ], [ 705, 634, 31, 17 ], [ 743, 635, 23, 14 ], [ 433, 651, 31, 14 ], [ 467, 651, 68, 14 ], [ 539, 651, 17, 16 ], [ 559, 651, 26, 14 ], [ 588, 651, 23, 14 ], [ 614, 651, 69, 14 ], [ 686, 651, 42, 14 ], [ 731, 651, 13, 14 ], [ 746, 651, 20, 14 ], [ 433, 668, 35, 14 ], [ 474, 668, 13, 14 ], [ 492, 668, 22, 14 ], [ 520, 668, 49, 14 ], [ 574, 668, 12, 14 ], [ 592, 668, 15, 14 ], [ 612, 668, 33, 14 ], [ 651, 668, 35, 14 ], [ 692, 668, 12, 14 ], [ 710, 668, 18, 14 ], [ 734, 668, 33, 14 ], [ 433, 685, 65, 14 ], [ 503, 685, 12, 14 ], [ 520, 685, 18, 14 ], [ 543, 685, 33, 14 ], [ 580, 685, 72, 14 ], [ 657, 685, 12, 14 ], [ 674, 685, 18, 14 ], [ 697, 685, 33, 14 ], [ 735, 685, 32, 14 ], [ 433, 701, 25, 14 ], [ 461, 701, 12, 14 ], [ 475, 701, 18, 14 ], [ 496, 701, 33, 14 ], [ 532, 701, 59, 14 ], [ 594, 701, 24, 14 ], [ 620, 701, 53, 14 ], [ 676, 701, 33, 14 ], [ 711, 701, 20, 14 ], [ 734, 701, 12, 14 ], [ 748, 701, 18, 14 ], [ 433, 718, 33, 14 ], [ 471, 718, 55, 14 ], [ 531, 718, 23, 14 ], [ 560, 718, 57, 14 ], [ 622, 718, 33, 14 ], [ 660, 718, 22, 14 ], [ 687, 718, 12, 14 ], [ 704, 718, 18, 14 ], [ 728, 718, 39, 14 ], [ 433, 735, 23, 14 ], [ 463, 735, 69, 14 ], [ 540, 734, 19, 15 ], [ 566, 735, 44, 14 ], [ 617, 735, 7, 14 ], [ 631, 735, 70, 14 ], [ 709, 735, 38, 14 ], [ 754, 735, 13, 14 ], [ 433, 750, 29, 15 ], [ 468, 751, 17, 14 ], [ 492, 751, 8, 14 ], [ 505, 751, 4, 14 ], [ 516, 751, 23, 14 ], [ 546, 751, 20, 14 ], [ 572, 751, 32, 14 ], [ 611, 751, 61, 14 ], [ 679, 751, 26, 14 ], [ 712, 751, 55, 14 ], [ 500, 758, 5, 10 ], [ 433, 768, 71, 14 ], [ 507, 768, 13, 14 ], [ 523, 768, 42, 14 ], [ 567, 768, 76, 14 ], [ 646, 768, 33, 14 ], [ 682, 768, 38, 14 ], [ 723, 768, 39, 14 ], [ 445, 785, 44, 14 ], [ 497, 785, 38, 14 ], [ 543, 785, 30, 14 ], [ 581, 785, 20, 14 ], [ 608, 785, 158, 14 ], [ 433, 801, 47, 14 ], [ 487, 801, 39, 14 ], [ 532, 801, 51, 14 ], [ 590, 801, 12, 14 ], [ 609, 801, 18, 14 ], [ 634, 801, 35, 14 ], [ 676, 801, 63, 14 ], [ 746, 801, 20, 14 ], [ 433, 818, 63, 14 ], [ 501, 818, 13, 14 ], [ 519, 818, 63, 14 ], [ 587, 818, 55, 14 ], [ 646, 818, 50, 14 ], [ 701, 818, 28, 14 ], [ 734, 818, 32, 14 ], [ 433, 835, 30, 14 ], [ 466, 835, 29, 14 ], [ 498, 835, 13, 14 ], [ 513, 835, 51, 14 ], [ 567, 835, 20, 14 ], [ 590, 834, 98, 15 ], [ 691, 835, 38, 14 ], [ 732, 835, 13, 14 ], [ 748, 835, 19, 14 ], [ 433, 851, 58, 14 ], [ 495, 851, 21, 14 ], [ 520, 851, 55, 14 ], [ 580, 851, 59, 14 ], [ 643, 851, 23, 14 ], [ 670, 851, 51, 14 ], [ 725, 851, 41, 14 ], [ 433, 868, 37, 14 ], [ 476, 868, 24, 14 ], [ 506, 868, 7, 14 ], [ 519, 868, 39, 14 ], [ 564, 868, 26, 14 ], [ 596, 868, 33, 14 ], [ 634, 868, 31, 14 ], [ 671, 868, 23, 14 ], [ 701, 868, 21, 14 ], [ 728, 868, 38, 14 ], [ 433, 885, 33, 14 ], [ 470, 885, 38, 14 ], [ 513, 885, 30, 14 ], [ 548, 885, 20, 14 ], [ 573, 885, 35, 14 ], [ 612, 885, 39, 14 ], [ 656, 885, 34, 14 ], [ 695, 885, 48, 14 ], [ 748, 885, 18, 14 ], [ 433, 901, 33, 14 ], [ 470, 901, 13, 14 ], [ 488, 901, 20, 14 ], [ 512, 901, 30, 14 ], [ 547, 901, 48, 14 ], [ 599, 901, 13, 14 ], [ 616, 901, 20, 14 ], [ 641, 900, 29, 15 ], [ 674, 901, 75, 14 ], [ 754, 901, 13, 14 ], [ 433, 918, 20, 14 ], [ 457, 918, 87, 14 ], [ 548, 918, 38, 14 ], [ 590, 918, 46, 14 ], [ 640, 918, 30, 14 ], [ 674, 918, 21, 14 ], [ 699, 918, 13, 14 ], [ 715, 918, 52, 14 ], [ 433, 935, 30, 14 ], [ 466, 935, 33, 14 ], [ 502, 935, 13, 14 ], [ 517, 935, 44, 14 ], [ 564, 935, 23, 14 ], [ 590, 935, 25, 14 ], [ 618, 935, 12, 14 ], [ 633, 935, 15, 14 ], [ 650, 935, 49, 14 ], [ 702, 935, 37, 14 ], [ 742, 935, 24, 14 ], [ 433, 951, 20, 14 ], [ 456, 951, 21, 14 ], [ 480, 951, 45, 14 ], [ 529, 951, 35, 14 ], [ 567, 951, 39, 14 ], [ 609, 951, 30, 14 ], [ 642, 951, 24, 14 ], [ 669, 951, 15, 14 ], [ 688, 951, 57, 14 ], [ 748, 951, 18, 14 ], [ 433, 968, 28, 14 ], [ 467, 968, 45, 14 ], [ 517, 968, 35, 14 ], [ 558, 968, 48, 14 ], [ 612, 968, 18, 14 ], [ 636, 968, 76, 14 ], [ 718, 968, 49, 14 ], [ 433, 985, 82, 14 ], [ 518, 985, 53, 14 ], [ 574, 985, 26, 14 ], [ 604, 985, 7, 14 ], [ 614, 985, 28, 14 ], [ 645, 985, 35, 14 ], [ 683, 985, 13, 14 ], [ 699, 984, 35, 17 ], [ 233, 1013, 14, 13 ], [ 268, 1014, 7, 11 ], [ 277, 1014, 22, 11 ], [ 302, 1014, 42, 11 ], [ 346, 1014, 9, 12 ], [ 357, 1014, 20, 12 ], [ 379, 1014, 56, 12 ], [ 438, 1014, 49, 12 ], [ 489, 1014, 25, 12 ], [ 516, 1015, 5, 10 ], [ 524, 1014, 121, 12 ], [ 647, 1014, 26, 12 ], [ 266, 1028, 39, 12 ], [ 307, 1028, 18, 12 ], [ 335, 1028, 19, 12 ], [ 356, 1028, 24, 12 ], [ 391, 1028, 35, 12 ], [ 266, 1042, 95, 12 ] ]

[ "Gating", "Kinetics", "of", "Single", "Large-Conductance", "Ca21-activated", "K1", "Channels", "in", "High", "Ca21", "Suggest", "a", "Two-Tiered", "Allosteric", "Gating", "MechanismJ", "Brad", "S.", "Rothberg", "and", "Karl", "L.", "Magleby", "From", "the", "Department", "of", "Physiology", "and", "Biophysics,", "University", "of", "Miami", "School", "of", "Medicine,", "Miami,", "Florida", "33101-6430", "a", "b", "s", "t", "r", "a", "c", "t", "The", "Ca21-dependent", "gating", "mechanism", "of", "large-conductance", "calcium-activated", "K1", "(BK)", "channels", "from", "cultured", "rat", "skeletal", "muscle", "was", "examined", "from", "low", "(4", "mM)", "to", "high", "(1,024", "mM)", "intracellular", "concentrations", "of", "calcium", "(Ca21", ")", "using", "single-channel", "recording.", "Open", "probability", "(Po)", "increased", "with", "increasing", "Ca21i", "(K0.5", "i", "11.2", "6", "0.3", "mM", "at", "130", "mV,", "Hill", "coefficient", "of", "3.5", "6", "0.3),", "reaching", "a", "maximum", "of", "z0.97", "for", "Ca21i", "z", "100", "mM.", "In-", "creasing", "Ca21i", "further", "to", "1,024", "mM", "had", "little", "additional", "effect", "on", "either", "Po", "or", "the", "single-channel", "kinetics.", "The", "channels", "gated", "among", "at", "least", "three", "to", "four", "open", "and", "four", "to", "five", "closed", "states", "at", "high", "levels", "of", "Ca21i", "(.100", "mM),", "compared", "with", "three", "to", "four", "open", "and", "five", "to", "seven", "closed", "states", "at", "lower", "Ca21i.", "The", "ability", "of", "kinetic", "schemes", "to", "account", "for", "the", "single-channel", "kinetics", "was", "examined", "with", "simultaneous", "maximum", "likelihood", "fitting", "of", "two-", "dimensional", "(2-D)", "dwell-time", "distributions", "obtained", "from", "low", "to", "high", "Ca21i.", "Kinetic", "schemes", "drawn", "from", "the", "10-", "state", "Monod-Wyman-Changeux", "model", "could", "not", "describe", "the", "dwell-time", "distributions", "from", "low", "to", "high", "Ca21i.", "Ki-", "netic", "schemes", "drawn", "from", "Eigen’s", "general", "model", "for", "a", "ligand-activated", "tetrameric", "protein", "could", "approximate", "the", "dwell-time", "distributions", "but", "not", "the", "dependency", "(correlations)", "between", "adjacent", "intervals", "at", "high", "Ca21i.", "However,", "models", "drawn", "from", "a", "general", "50", "state", "two-tiered", "scheme,", "in", "which", "there", "were", "25", "closed", "states", "on", "the", "upper", "tier", "and", "25", "open", "states", "on", "the", "lower", "tier,", "could", "approximate", "both", "the", "dwell-time", "distributions", "and", "the", "dependency", "from", "low", "to", "high", "Ca21i.", "In", "the", "two-tiered", "model,", "the", "BK", "channel", "can", "open", "directly", "from", "each", "closed", "state,", "and", "a", "minimum", "of", "five", "open", "and", "five", "closed", "states", "are", "available", "for", "gating", "at", "any", "given", "Ca21i.", "A", "model", "that", "assumed", "that", "the", "apparent", "Ca21-binding", "steps", "can", "reach", "a", "maximum", "rate", "at", "high", "Ca21i", "could", "also", "approximate", "the", "gating", "from", "low", "to", "high", "Ca21i.", "The", "considered", "models", "can", "serve", "as", "working", "hypotheses", "for", "the", "gating", "of", "BK", "channels.", "k", "e", "y", "w", "o", "r", "d", "s", ":", "BK", "channel", "•", "KCa", "channel", "•", "Monod-Wyman-Changeux", "•", "Eigen", "•", "Markov", "i", "n", "t", "r", "o", "d", "u", "c", "t", "i", "o", "n", "Large-conductance", "Ca21-activated", "K1", "(BK)1", "channels,", "which", "are", "activated", "by", "micromolar", "concentrations", "of", "intracellular", "Ca21", "(Ca21i)", "and", "by", "depolarization", "(Bar-", "rett", "et", "al.,", "1982)", "are", "present", "in", "a", "wide", "variety", "of", "tissues", "(reviewed", "by", "Rudy,", "1988;", "Marty,", "1989;", "McManus,", "1991;", "Latorre,", "1994;", "Conly,", "1996).", "Activated", "BK", "channels", "re-", "duce", "membrane", "excitability", "by", "allowing", "K1", "efflux", "through", "their", "opened", "pores,", "which", "drives", "the", "mem-", "brane", "potential", "more", "negative.", "Hence,", "BK", "channels", "form", "a", "link", "in", "a", "negative", "feed-back", "loop", "that", "decreases", "excitability", "in", "response", "to", "both", "increased", "Ca21i", "and", "de-", "polarization.", "Information", "about", "the", "gating", "mechanism", "of", "BK", "chan-", "nels", "has", "accumulated", "from", "kinetic", "studies", "on", "native", "and", "heterologously", "expressed", "channels.", "BK", "channels", "are", "Address", "correspondence", "to", "Dr.", "Karl", "L.", "Magleby,", "Dept.", "of", "Physiology", "and", "Biophysics", "(R-430),", "University", "of", "Miami", "School", "of", "Medicine,", "Miami,", "FL", "33101-6430.", "Fax:", "305-243-6898;", "E-mail:", "kmagleby@", "miami.edu", "J", "The", "online", "version", "of", "this", "article", "contains", "supplemental", "material.", "1Abbreviations", "used", "in", "this", "paper:", "1-D,", "1-dimensional;", "BK", "channel,", "large-conductance", "calcium-activated", "K1", "channel;", "MWC,", "Monod-", "Wyman-Changeux;", "NLR1000,", "normalized", "likelihood", "ratio.", "homotetramers,", "formed", "from", "four", "alpha", "subunits", "(Shen", "et", "al.,", "1994),", "with", "one", "or", "more", "Ca21-binding", "sites", "per", "subunit", "(Schreiber", "and", "Salkoff,", "1997).", "BK", "channels", "typically", "display", "a", "steep", "relation", "between", "Ca21i", "and", "open", "probability,", "Po,", "with", "Hill", "coefficients", "usually", "in", "the", "range", "of", "2–4", "(Barrett", "et", "al.", "1982;", "Wong", "et", "al.,", "1982;", "Golowasch", "et", "al.,", "1986;", "Oberhauser", "et", "al.,", "1988;", "Rein-", "hart", "et", "al.,", "1989;", "McManus", "and", "Magleby,", "1991;", "Art", "et", "al.,", "1995;", "DiChiara", "and", "Reinhart,", "1995;", "Cui", "et", "al.,", "1997).", "Hill", "coefficients", ".1", "suggest", "a", "cooperative", "action", "of", "Ca21", "on", "P", ",", "and", "are", "often", "associated", "with", "allosteric", "o", "modulation", "of", "activity", "(Colquhoun", "1973;", "Fersht", "1985).", "Models", "drawn", "from", "the", "Monod-Wyman-Changeux", "(MWC)", "model", "(Monod", "et", "al.,", "1965)", "describing", "the", "transitions", "of", "tetrameric", "allosteric", "proteins", "have", "often", "been", "used", "to", "describe", "the", "Ca21-dependent", "gating", "of", "BK", "channels.", "For", "example,", "McManus", "and", "Magleby", "(1991)", "found", "that", "a", "model", "with", "three", "open", "and", "five", "closed", "states", "drawn", "from", "the", "MWC", "model", "could", "account", "for", "many", "of", "the", "basic", "features", "of", "the", "Ca21", "dependence", "of", "the", "single-channel", "gating", "kinetics", "from", "low", "to", "interme-", "diate", "levels", "of", "activity,", "and", "Cox", "et", "al.", "(1997b)", "found", "that", "the", "full", "10-state", "MWC", "model", "(and", "also", "an", "extended", "12-", "state", "model)", "could", "account", "for", "macroscopic", "conduc-", "tance–voltage", "relations", "over", "a", "wide", "range", "of", "Ca21i.", "93", "J.", "Gen.", "Physiol.", "©", "The", "Rockefeller", "University", "Press", "•", "0022-1295/99/07/93/32", "$5.00", "Volume", "114", "July", "1999", "93–124", "http://www.jgp.org" ]

[ 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 11, 11, 11, 11, 11, 11, 11, 11, 11, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ [ 69, 75, 45, 17 ], [ 117, 75, 38, 17 ], [ 159, 75, 13, 17 ], [ 175, 76, 77, 17 ], [ 257, 76, 185, 17 ], [ 654, 102, 39, 14 ], [ 696, 102, 55, 14 ], [ 633, 124, 126, 50 ], [ 644, 180, 38, 17 ], [ 686, 180, 73, 17 ], [ 553, 204, 205, 17 ], [ 69, 227, 46, 17 ], [ 69, 265, 308, 25 ], [ 382, 265, 84, 25 ], [ 472, 265, 137, 25 ], [ 614, 265, 81, 25 ], [ 701, 265, 41, 25 ], [ 69, 293, 110, 25 ], [ 184, 293, 44, 25 ], [ 234, 293, 55, 25 ], [ 294, 293, 21, 25 ], [ 321, 293, 116, 25 ], [ 69, 342, 77, 17 ], [ 150, 342, 38, 17 ], [ 191, 339, 10, 20 ], [ 205, 342, 65, 17 ], [ 274, 342, 47, 17 ], [ 324, 339, 10, 20 ], [ 338, 342, 66, 17 ], [ 408, 342, 121, 17 ], [ 532, 339, 6, 12 ], [ 542, 342, 27, 17 ], [ 573, 342, 17, 17 ], [ 594, 342, 44, 17 ], [ 641, 342, 34, 17 ], [ 679, 339, 17, 20 ], [ 69, 379, 6, 12 ], [ 69, 426, 6, 11 ], [ 69, 473, 6, 12 ], [ 89, 382, 79, 17 ], [ 171, 382, 14, 17 ], [ 189, 382, 69, 17 ], [ 262, 382, 25, 17 ], [ 290, 382, 54, 17 ], [ 348, 382, 101, 17 ], [ 453, 382, 42, 17 ], [ 499, 382, 47, 17 ], [ 550, 382, 14, 17 ], [ 568, 382, 68, 17 ], [ 639, 382, 71, 17 ], [ 714, 382, 14, 17 ], [ 89, 406, 49, 17 ], [ 141, 406, 49, 17 ], [ 194, 406, 49, 17 ], [ 246, 406, 46, 17 ], [ 296, 406, 38, 17 ], [ 339, 406, 52, 17 ], [ 395, 406, 168, 17 ], [ 89, 429, 71, 17 ], [ 163, 429, 14, 17 ], [ 181, 429, 45, 17 ], [ 230, 429, 52, 17 ], [ 286, 429, 13, 17 ], [ 303, 429, 21, 17 ], [ 328, 429, 44, 17 ], [ 375, 429, 62, 17 ], [ 441, 429, 45, 17 ], [ 490, 429, 36, 17 ], [ 529, 429, 50, 17 ], [ 582, 429, 57, 17 ], [ 643, 429, 49, 17 ], [ 695, 429, 49, 17 ], [ 89, 453, 46, 17 ], [ 139, 453, 39, 17 ], [ 181, 453, 52, 17 ], [ 237, 453, 188, 17 ], [ 89, 476, 79, 17 ], [ 171, 476, 14, 17 ], [ 189, 476, 76, 17 ], [ 269, 476, 42, 17 ], [ 315, 476, 47, 17 ], [ 365, 476, 14, 17 ], [ 384, 476, 68, 17 ], [ 455, 476, 71, 17 ], [ 530, 476, 14, 17 ], [ 548, 476, 49, 17 ], [ 600, 476, 49, 17 ], [ 653, 476, 49, 17 ], [ 705, 476, 46, 17 ], [ 89, 500, 38, 17 ], [ 131, 500, 52, 17 ], [ 187, 500, 236, 17 ], [ 69, 540, 9, 17 ], [ 89, 540, 48, 17 ], [ 140, 540, 14, 17 ], [ 157, 540, 42, 17 ], [ 203, 540, 105, 17 ], [ 312, 540, 45, 17 ], [ 360, 540, 16, 17 ], [ 380, 540, 71, 17 ], [ 455, 540, 52, 17 ], [ 511, 540, 160, 17 ], [ 89, 564, 31, 17 ], [ 124, 564, 123, 17 ], [ 250, 564, 30, 17 ], [ 284, 564, 123, 17 ], [ 69, 604, 66, 17 ], [ 138, 604, 17, 17 ], [ 159, 604, 71, 17 ], [ 234, 604, 39, 17 ], [ 277, 604, 14, 17 ], [ 294, 604, 49, 17 ], [ 347, 604, 38, 17 ], [ 388, 604, 17, 17 ], [ 409, 604, 55, 17 ], [ 468, 604, 34, 17 ], [ 505, 604, 5, 17 ], [ 514, 604, 67, 17 ], [ 585, 604, 9, 17 ], [ 597, 604, 69, 17 ], [ 670, 604, 34, 17 ], [ 708, 604, 5, 17 ], [ 69, 628, 73, 17 ], [ 145, 628, 9, 17 ], [ 157, 628, 69, 17 ], [ 230, 628, 34, 17 ], [ 108, 694, 67, 17 ], [ 181, 694, 26, 17 ], [ 214, 694, 70, 17 ], [ 292, 694, 77, 17 ], [ 375, 694, 41, 17 ], [ 424, 694, 32, 17 ], [ 462, 694, 186, 17 ], [ 655, 694, 65, 17 ], [ 108, 717, 26, 17 ], [ 138, 717, 27, 17 ], [ 170, 717, 68, 17 ], [ 242, 717, 30, 17 ], [ 276, 717, 20, 17 ], [ 302, 717, 30, 17 ], [ 336, 717, 63, 17 ], [ 404, 717, 14, 17 ], [ 423, 717, 88, 17 ], [ 515, 717, 47, 17 ], [ 567, 717, 153, 17 ], [ 108, 741, 64, 17 ], [ 176, 741, 60, 17 ], [ 241, 741, 79, 17 ], [ 325, 741, 13, 17 ], [ 343, 741, 45, 17 ], [ 392, 741, 63, 17 ], [ 459, 741, 50, 17 ], [ 514, 741, 22, 17 ], [ 541, 741, 31, 17 ], [ 577, 741, 69, 17 ], [ 651, 741, 14, 17 ], [ 669, 741, 8, 17 ], [ 682, 741, 38, 17 ], [ 108, 764, 95, 17 ], [ 206, 764, 39, 17 ], [ 248, 764, 25, 17 ], [ 276, 764, 73, 17 ], [ 352, 764, 13, 17 ], [ 369, 764, 20, 17 ], [ 393, 764, 54, 17 ], [ 450, 764, 14, 17 ], [ 468, 764, 81, 17 ], [ 553, 764, 24, 17 ], [ 580, 764, 78, 17 ], [ 661, 764, 58, 17 ], [ 108, 788, 13, 17 ], [ 130, 788, 54, 17 ], [ 194, 788, 13, 17 ], [ 217, 788, 36, 17 ], [ 262, 788, 65, 17 ], [ 336, 788, 20, 17 ], [ 367, 788, 50, 17 ], [ 426, 788, 14, 17 ], [ 450, 788, 50, 17 ], [ 510, 788, 13, 17 ], [ 533, 788, 28, 17 ], [ 570, 788, 22, 17 ], [ 602, 788, 21, 17 ], [ 633, 788, 31, 17 ], [ 675, 788, 45, 17 ], [ 108, 812, 92, 17 ], [ 204, 812, 32, 17 ], [ 239, 812, 20, 17 ], [ 263, 812, 40, 17 ], [ 306, 812, 22, 17 ], [ 331, 812, 85, 17 ], [ 420, 812, 14, 17 ], [ 437, 812, 21, 17 ], [ 461, 812, 87, 17 ], [ 552, 812, 14, 17 ], [ 570, 812, 50, 17 ], [ 624, 812, 13, 17 ], [ 640, 812, 79, 17 ], [ 108, 835, 23, 17 ], [ 135, 835, 39, 17 ], [ 178, 835, 25, 17 ], [ 207, 835, 46, 17 ], [ 257, 835, 40, 17 ], [ 302, 835, 14, 17 ], [ 320, 835, 50, 17 ], [ 374, 835, 52, 17 ], [ 430, 835, 22, 17 ], [ 457, 835, 35, 17 ], [ 496, 835, 68, 17 ], [ 568, 835, 65, 17 ], [ 637, 835, 24, 17 ], [ 665, 835, 54, 17 ], [ 108, 859, 24, 17 ], [ 136, 859, 55, 17 ], [ 196, 859, 52, 17 ], [ 253, 859, 13, 17 ], [ 270, 859, 33, 17 ], [ 308, 859, 26, 17 ], [ 338, 859, 52, 17 ], [ 395, 859, 14, 17 ], [ 414, 859, 21, 17 ], [ 439, 859, 69, 17 ], [ 512, 859, 13, 17 ], [ 530, 859, 69, 17 ], [ 603, 859, 11, 17 ], [ 619, 859, 66, 17 ], [ 690, 859, 30, 17 ], [ 108, 882, 20, 17 ], [ 136, 882, 89, 17 ], [ 234, 882, 14, 17 ], [ 256, 882, 50, 17 ], [ 314, 882, 55, 17 ], [ 377, 882, 13, 17 ], [ 398, 882, 33, 17 ], [ 439, 882, 87, 17 ], [ 534, 882, 97, 17 ], [ 639, 882, 60, 17 ], [ 706, 882, 13, 17 ], [ 108, 906, 50, 17 ], [ 164, 906, 24, 17 ], [ 195, 906, 47, 17 ], [ 248, 906, 45, 17 ], [ 300, 906, 17, 17 ], [ 324, 906, 53, 17 ], [ 383, 906, 29, 17 ], [ 419, 906, 22, 17 ], [ 447, 906, 52, 17 ], [ 506, 906, 49, 17 ], [ 562, 906, 13, 17 ], [ 582, 906, 55, 17 ], [ 644, 906, 24, 17 ], [ 674, 906, 45, 17 ], [ 108, 930, 51, 17 ], [ 164, 930, 82, 17 ], [ 251, 930, 76, 17 ], [ 332, 930, 13, 17 ], [ 350, 930, 31, 17 ], [ 387, 930, 43, 17 ], [ 435, 930, 26, 17 ], [ 466, 930, 46, 17 ], [ 517, 930, 52, 17 ], [ 575, 930, 25, 17 ], [ 605, 930, 50, 17 ], [ 660, 930, 60, 17 ], [ 108, 953, 43, 17 ], [ 155, 953, 50, 17 ], [ 209, 953, 91, 17 ], [ 305, 953, 24, 17 ], [ 334, 953, 25, 17 ], [ 363, 953, 75, 17 ], [ 443, 953, 41, 17 ], [ 489, 953, 14, 17 ], [ 507, 953, 8, 17 ], [ 520, 953, 40, 17 ], [ 565, 953, 41, 17 ], [ 611, 953, 13, 17 ], [ 629, 953, 66, 17 ], [ 699, 953, 20, 17 ], [ 108, 977, 85, 17 ], [ 196, 977, 14, 17 ], [ 213, 977, 72, 17 ], [ 104, 1017, 78, 17 ], [ 186, 1017, 89, 17 ], [ 279, 1017, 48, 17 ], [ 330, 1017, 65, 17 ], [ 400, 1017, 66, 17 ], [ 469, 1017, 125, 17 ] ]

[ "Toxins", "2010,", "2,", "2663-2679;", "doi:10.3390/toxins2112663", "OPEN", "ACCESS", "toxins", "ISSN", "2072-6651", "www.mdpi.com/journal/toxins", "Article", "β-N-Methylamino-L-Alanine", "Induces", "Neurological", "Deficits", "and", "Shortened", "Life", "Span", "in", "Drosophila", "Xianchong", "Zhou", "1,", "Wilfredo", "Escala", "2,", "Spyridon", "Papapetropoulos", "3", "and", "R.", "Grace", "Zhai", "1,*", "1", "2", "3", "Department", "of", "Molecular", "and", "Cellular", "Pharmacology,", "Miller", "School", "of", "Medicine,", "University", "of", "Miami,", "Miami,", "Florida", "33136,", "USA;", "E-Mail:", "zhouxchong@gmail.com", "University", "of", "Miami", "Bridges", "to", "the", "Future", "Program,", "Miami", "Dade", "Honors", "College,", "Miami,", "Florida", "33132,", "USA;", "E-Mail:", "wilfredo.escala@gmail.com", "Department", "of", "Neurology,", "Miller", "School", "of", "Medicine,", "University", "of", "Miami,", "Miami,", "Florida", "33136,", "USA;", "E-Mail:", "spapapetropoulos@med.miami.edu", "*", "Author", "to", "whom", "correspondence", "should", "be", "addressed;", "E-Mail:", "gzhai@med.miami.edu;", "Tel.:", "+1-305-243-6316;", "Fax:", "+1-305-243-4555.", "Received:", "29", "September", "2010;", "in", "revised", "form:", "28", "October", "2010", "/", "Accepted:", "1", "November", "2010", "/", "Published:", "3", "November", "2010", "Abstract:", "The", "neurotoxic", "non-protein", "amino", "acid,", "β-N-methylamino-L-alanine", "(BMAA),", "was", "first", "associated", "with", "the", "high", "incidence", "of", "Amyotrophic", "Lateral", "Sclerosis/Parkinsonism", "Dementia", "Complex", "(ALS/PDC)", "in", "Guam.", "Recently,", "BMAA", "has", "been", "implicated", "as", "a", "fierce", "environmental", "factor", "that", "contributes", "to", "the", "etiology", "of", "Alzheimer’s", "and", "Parkinson’s", "diseases,", "in", "addition", "to", "ALS.", "However,", "the", "toxicity", "of", "BMAA", "in", "vivo", "has", "not", "been", "clearly", "demonstrated.", "Here", "we", "report", "our", "investigation", "of", "the", "neurotoxicity", "of", "BMAA", "in", "Drosophila.", "We", "found", "that", "dietary", "intake", "of", "BMAA", "reduced", "life", "span,", "locomotor", "functions,", "and", "learning", "and", "memory", "abilities", "in", "flies.", "The", "severity", "of", "the", "alterations", "in", "phenotype", "is", "correlated", "with", "the", "concentration", "of", "BMAA", "detected", "in", "flies.", "Interestingly,", "developmental", "exposure", "to", "BMAA", "had", "limited", "impact", "on", "survival", "rate,", "but", "reduced", "fertility", "in", "females,", "and", "caused", "delayed", "neurological", "impairment", "in", "aged", "adults.", "Our", "studies", "indicate", "that", "BMAA", "exposure", "causes", "chronic", "neurotoxicity,", "and", "that", "Drosophila", "serves", "as", "a", "useful", "model", "in", "dissecting", "the", "pathogenesis", "of", "ALS/PDC.", "Keywords:", "Amyotrophic", "Lateral", "Sclerosis;", "dementia;", "neurodegeneration" ]

[ 0, 0, 0, 0, 0, 9, 9, 0, 0, 0, 0, 16, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 11, 11, 11, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17 ]

[ [ 72, 61, 39, 12 ], [ 113, 61, 48, 12 ], [ 163, 61, 56, 12 ], [ 72, 75, 26, 11 ], [ 100, 75, 40, 11 ], [ 72, 88, 35, 12 ], [ 109, 88, 24, 12 ], [ 135, 88, 30, 12 ], [ 168, 88, 12, 12 ], [ 182, 88, 30, 12 ], [ 214, 88, 11, 12 ], [ 227, 88, 25, 12 ], [ 72, 101, 107, 12 ], [ 72, 177, 71, 25 ], [ 147, 177, 64, 25 ], [ 72, 210, 70, 25 ], [ 146, 210, 22, 25 ], [ 173, 210, 93, 25 ], [ 270, 210, 140, 25 ], [ 415, 210, 85, 25 ], [ 120, 285, 46, 14 ], [ 168, 285, 12, 14 ], [ 183, 285, 41, 14 ], [ 226, 285, 60, 14 ], [ 288, 285, 10, 14 ], [ 300, 285, 70, 14 ], [ 372, 285, 24, 14 ], [ 398, 285, 28, 14 ], [ 429, 285, 12, 14 ], [ 444, 285, 40, 14 ], [ 121, 315, 41, 13 ], [ 165, 315, 9, 13 ], [ 176, 315, 55, 13 ], [ 233, 315, 19, 13 ], [ 255, 315, 37, 13 ], [ 294, 315, 24, 13 ], [ 320, 315, 48, 13 ], [ 370, 315, 59, 13 ], [ 432, 315, 9, 13 ], [ 444, 315, 40, 13 ], [ 485, 315, 48, 13 ], [ 121, 330, 50, 13 ], [ 174, 330, 9, 13 ], [ 185, 330, 46, 13 ], [ 234, 330, 39, 13 ], [ 275, 330, 35, 13 ], [ 313, 330, 21, 13 ], [ 336, 330, 31, 13 ], [ 369, 330, 15, 13 ], [ 387, 330, 61, 13 ], [ 450, 330, 23, 13 ], [ 120, 358, 82, 13 ], [ 205, 358, 35, 13 ], [ 242, 358, 12, 13 ], [ 256, 358, 49, 13 ], [ 308, 358, 11, 13 ], [ 321, 358, 24, 13 ], [ 347, 358, 12, 13 ], [ 361, 358, 34, 13 ], [ 398, 358, 88, 13 ], [ 121, 385, 44, 13 ], [ 167, 385, 12, 13 ], [ 182, 385, 33, 13 ], [ 217, 385, 27, 13 ], [ 247, 385, 46, 13 ], [ 295, 385, 13, 13 ], [ 310, 385, 22, 13 ], [ 334, 385, 24, 13 ], [ 121, 410, 75, 13 ], [ 199, 410, 12, 13 ], [ 213, 410, 24, 13 ], [ 239, 410, 37, 13 ], [ 121, 435, 36, 13 ], [ 161, 435, 26, 13 ], [ 190, 435, 38, 13 ], [ 232, 435, 42, 13 ], [ 278, 435, 21, 13 ], [ 302, 435, 6, 13 ], [ 312, 435, 34, 13 ], [ 349, 435, 20, 13 ], [ 373, 435, 11, 13 ], [ 387, 435, 51, 13 ], [ 441, 435, 16, 13 ], [ 461, 435, 50, 13 ], [ 514, 435, 10, 13 ], [ 528, 435, 39, 13 ], [ 571, 435, 69, 13 ], [ 644, 435, 31, 13 ], [ 678, 435, 11, 13 ], [ 692, 435, 23, 13 ], [ 718, 435, 36, 13 ], [ 758, 435, 6, 13 ], [ 121, 450, 35, 13 ], [ 158, 450, 26, 13 ], [ 186, 450, 11, 13 ], [ 199, 450, 16, 13 ], [ 217, 450, 43, 13 ], [ 262, 450, 44, 13 ], [ 308, 450, 11, 13 ], [ 321, 450, 51, 13 ], [ 375, 450, 19, 13 ], [ 396, 450, 58, 13 ], [ 457, 450, 32, 13 ], [ 491, 450, 11, 13 ], [ 504, 450, 23, 13 ], [ 529, 450, 41, 13 ], [ 573, 450, 16, 13 ], [ 591, 450, 11, 13 ], [ 604, 450, 19, 13 ], [ 625, 450, 35, 13 ], [ 663, 450, 14, 13 ], [ 679, 450, 42, 13 ], [ 723, 450, 16, 13 ], [ 741, 450, 22, 13 ], [ 121, 465, 20, 13 ], [ 144, 465, 11, 13 ], [ 157, 465, 16, 13 ], [ 176, 465, 39, 13 ], [ 218, 465, 62, 13 ], [ 283, 465, 10, 13 ], [ 296, 465, 24, 13 ], [ 323, 465, 6, 13 ], [ 331, 465, 43, 13 ], [ 377, 465, 44, 13 ], [ 425, 465, 41, 13 ], [ 469, 465, 12, 13 ], [ 484, 465, 65, 13 ], [ 551, 465, 37, 13 ], [ 591, 465, 19, 13 ], [ 613, 465, 6, 13 ], [ 622, 465, 46, 13 ], [ 670, 465, 11, 13 ], [ 684, 465, 16, 13 ], [ 703, 465, 43, 13 ], [ 749, 465, 15, 13 ], [ 121, 479, 37, 13 ], [ 161, 479, 56, 13 ], [ 219, 479, 14, 13 ], [ 235, 479, 12, 13 ], [ 249, 479, 23, 13 ], [ 274, 479, 11, 13 ], [ 287, 479, 53, 13 ], [ 342, 479, 16, 13 ], [ 361, 479, 39, 13 ], [ 402, 479, 62, 13 ], [ 466, 479, 22, 13 ], [ 490, 479, 29, 13 ], [ 521, 479, 42, 13 ], [ 565, 479, 11, 13 ], [ 579, 479, 43, 13 ], [ 625, 479, 43, 13 ], [ 670, 479, 36, 13 ], [ 708, 479, 10, 13 ], [ 720, 479, 43, 13 ], [ 121, 494, 43, 13 ], [ 167, 494, 11, 13 ], [ 180, 494, 16, 13 ], [ 200, 494, 26, 13 ], [ 228, 494, 16, 13 ], [ 247, 494, 23, 13 ], [ 273, 494, 33, 13 ], [ 309, 494, 16, 13 ], [ 328, 494, 20, 13 ], [ 351, 494, 11, 13 ], [ 364, 494, 39, 13 ], [ 406, 494, 19, 13 ], [ 429, 494, 12, 13 ], [ 443, 494, 36, 13 ], [ 482, 494, 11, 13 ], [ 496, 494, 61, 13 ], [ 559, 494, 39, 13 ], [ 601, 494, 100, 13 ], [ 704, 494, 40, 13 ], [ 747, 494, 16, 13 ], [ 121, 508, 69, 13 ], [ 194, 508, 44, 13 ], [ 241, 508, 23, 13 ], [ 267, 508, 7, 13 ], [ 278, 508, 57, 13 ], [ 338, 508, 28, 13 ], [ 369, 508, 42, 13 ], [ 414, 508, 16, 13 ], [ 433, 508, 42, 13 ], [ 479, 508, 55, 13 ], [ 537, 508, 43, 13 ], [ 584, 508, 11, 13 ], [ 597, 508, 16, 13 ], [ 617, 508, 80, 13 ], [ 699, 508, 64, 13 ], [ 121, 523, 16, 13 ], [ 140, 523, 24, 13 ], [ 168, 523, 65, 13 ], [ 236, 523, 39, 13 ], [ 278, 523, 37, 13 ], [ 318, 523, 14, 13 ], [ 336, 523, 42, 13 ], [ 381, 523, 16, 13 ], [ 401, 523, 20, 13 ], [ 424, 523, 20, 13 ], [ 448, 523, 55, 13 ], [ 506, 523, 11, 13 ], [ 521, 523, 69, 13 ], [ 593, 523, 39, 13 ], [ 636, 523, 49, 13 ], [ 688, 523, 21, 13 ], [ 712, 523, 11, 13 ], [ 726, 523, 37, 13 ], [ 121, 537, 23, 13 ], [ 146, 537, 42, 13 ], [ 121, 563, 51, 13 ], [ 175, 563, 9, 13 ], [ 187, 563, 24, 13 ], [ 214, 563, 39, 13 ], [ 255, 563, 11, 13 ], [ 268, 563, 30, 13 ], [ 301, 563, 10, 13 ], [ 313, 563, 12, 13 ], [ 330, 563, 22, 13 ], [ 357, 563, 8, 13 ], [ 369, 563, 13, 13 ], [ 386, 563, 26, 13 ], [ 417, 563, 30, 13 ], [ 451, 563, 31, 13 ], [ 487, 563, 55, 13 ], [ 547, 563, 30, 13 ], [ 582, 563, 16, 13 ], [ 602, 563, 41, 13 ], [ 648, 563, 53, 13 ], [ 706, 563, 58, 13 ], [ 121, 578, 40, 13 ], [ 164, 578, 31, 13 ], [ 198, 578, 39, 13 ], [ 240, 578, 61, 13 ], [ 304, 578, 20, 13 ], [ 327, 578, 63, 13 ], [ 394, 578, 19, 13 ], [ 416, 578, 66, 13 ], [ 486, 578, 11, 13 ], [ 499, 578, 18, 13 ], [ 521, 578, 46, 13 ], [ 570, 578, 45, 13 ], [ 618, 578, 16, 13 ], [ 637, 578, 39, 13 ], [ 680, 578, 26, 13 ], [ 709, 578, 8, 13 ], [ 721, 578, 43, 13 ], [ 121, 593, 28, 13 ], [ 72, 640, 12, 14 ], [ 97, 640, 98, 14 ], [ 72, 672, 65, 14 ], [ 145, 672, 119, 14 ], [ 272, 672, 51, 14 ], [ 332, 672, 47, 14 ], [ 389, 672, 17, 14 ], [ 72, 688, 52, 14 ], [ 129, 688, 12, 14 ], [ 145, 688, 18, 14 ], [ 168, 688, 92, 14 ], [ 265, 688, 69, 14 ], [ 339, 688, 31, 14 ], [ 375, 688, 31, 14 ], [ 72, 704, 39, 14 ], [ 114, 704, 28, 14 ], [ 144, 704, 18, 14 ], [ 165, 704, 86, 14 ], [ 253, 704, 47, 14 ], [ 303, 704, 12, 14 ], [ 317, 704, 18, 14 ], [ 338, 704, 29, 14 ], [ 369, 704, 37, 14 ], [ 72, 719, 11, 15 ], [ 87, 719, 35, 14 ], [ 126, 719, 55, 14 ], [ 184, 719, 43, 14 ], [ 231, 719, 71, 14 ], [ 305, 719, 12, 14 ], [ 321, 719, 70, 14 ], [ 394, 719, 12, 14 ], [ 72, 735, 18, 14 ], [ 95, 735, 28, 14 ], [ 128, 735, 15, 14 ], [ 148, 735, 39, 14 ], [ 192, 735, 30, 15 ], [ 227, 735, 9, 14 ], [ 241, 735, 25, 14 ], [ 271, 735, 25, 14 ], [ 302, 735, 30, 14 ], [ 337, 735, 52, 14 ], [ 394, 735, 12, 14 ], [ 72, 751, 18, 14 ], [ 94, 751, 29, 14 ], [ 126, 751, 49, 14 ], [ 180, 751, 33, 14 ], [ 216, 751, 51, 14 ], [ 271, 751, 17, 14 ], [ 292, 751, 11, 14 ], [ 307, 751, 73, 14 ], [ 384, 751, 21, 14 ], [ 72, 767, 25, 14 ], [ 100, 767, 46, 14 ], [ 149, 767, 74, 14 ], [ 225, 767, 26, 14 ], [ 254, 767, 18, 14 ], [ 275, 767, 45, 14 ], [ 323, 767, 10, 14 ], [ 335, 767, 46, 14 ], [ 384, 767, 21, 14 ], [ 72, 783, 25, 14 ], [ 102, 783, 44, 14 ], [ 150, 783, 12, 14 ], [ 166, 783, 41, 14 ], [ 212, 783, 49, 14 ], [ 266, 783, 50, 14 ], [ 320, 783, 47, 14 ], [ 372, 783, 12, 14 ], [ 388, 783, 18, 14 ], [ 72, 798, 53, 14 ], [ 128, 798, 41, 14 ], [ 172, 798, 12, 14 ], [ 187, 798, 18, 14 ], [ 208, 798, 31, 14 ], [ 241, 798, 24, 14 ], [ 269, 798, 48, 14 ], [ 319, 798, 34, 14 ], [ 356, 798, 50, 14 ], [ 72, 814, 14, 14 ], [ 91, 814, 65, 14 ], [ 162, 814, 43, 14 ], [ 211, 814, 37, 14 ], [ 254, 814, 47, 14 ], [ 307, 814, 6, 14 ], [ 319, 814, 87, 14 ], [ 72, 830, 39, 14 ], [ 115, 830, 22, 14 ], [ 142, 830, 28, 14 ], [ 174, 830, 12, 14 ], [ 190, 830, 37, 14 ], [ 232, 830, 12, 14 ], [ 248, 830, 69, 14 ], [ 321, 830, 21, 14 ], [ 346, 830, 44, 14 ], [ 394, 830, 12, 14 ], [ 72, 846, 62, 14 ], [ 139, 846, 59, 14 ], [ 204, 846, 25, 14 ], [ 235, 846, 64, 14 ], [ 304, 846, 50, 14 ], [ 360, 846, 12, 14 ], [ 377, 846, 29, 14 ], [ 72, 861, 50, 14 ], [ 125, 861, 12, 14 ], [ 140, 861, 18, 14 ], [ 161, 861, 31, 14 ], [ 195, 861, 51, 14 ], [ 249, 861, 31, 14 ], [ 283, 861, 49, 14 ], [ 335, 861, 45, 14 ], [ 383, 861, 22, 14 ], [ 72, 877, 12, 14 ], [ 88, 877, 18, 14 ], [ 109, 877, 43, 14 ], [ 157, 877, 12, 14 ], [ 172, 877, 55, 14 ], [ 231, 877, 43, 14 ], [ 278, 877, 37, 14 ], [ 319, 877, 24, 14 ], [ 347, 877, 26, 14 ], [ 377, 877, 29, 14 ], [ 72, 893, 45, 14 ], [ 121, 893, 21, 14 ], [ 146, 893, 76, 14 ], [ 226, 893, 59, 14 ], [ 289, 893, 12, 14 ], [ 305, 893, 31, 14 ], [ 339, 893, 25, 14 ], [ 369, 893, 37, 14 ], [ 72, 909, 60, 14 ], [ 134, 909, 58, 14 ], [ 195, 909, 21, 14 ], [ 93, 925, 33, 14 ], [ 130, 925, 17, 14 ], [ 152, 925, 29, 14 ], [ 186, 925, 32, 14 ], [ 223, 925, 52, 14 ], [ 280, 925, 47, 15 ], [ 333, 925, 47, 15 ], [ 384, 925, 21, 14 ], [ 72, 940, 59, 15 ], [ 135, 940, 27, 14 ], [ 167, 940, 12, 14 ], [ 183, 940, 18, 14 ], [ 205, 940, 49, 14 ], [ 259, 940, 9, 14 ], [ 272, 940, 18, 14 ], [ 295, 940, 45, 14 ], [ 344, 940, 12, 14 ], [ 360, 940, 6, 14 ], [ 371, 940, 35, 14 ], [ 72, 956, 18, 14 ], [ 93, 956, 29, 14 ], [ 125, 956, 55, 15 ], [ 183, 956, 9, 14 ], [ 195, 956, 54, 14 ], [ 251, 956, 12, 14 ], [ 266, 956, 38, 14 ], [ 306, 956, 30, 14 ], [ 339, 956, 31, 14 ], [ 373, 956, 12, 14 ], [ 388, 956, 18, 14 ], [ 72, 972, 31, 14 ], [ 106, 972, 44, 15 ], [ 154, 972, 9, 14 ], [ 167, 972, 28, 14 ], [ 199, 972, 60, 14 ], [ 263, 972, 45, 14 ], [ 312, 972, 12, 14 ], [ 328, 972, 12, 14 ], [ 343, 972, 63, 14 ], [ 72, 988, 25, 14 ], [ 102, 988, 65, 14 ], [ 172, 988, 21, 14 ], [ 199, 988, 43, 15 ], [ 247, 988, 25, 14 ], [ 277, 988, 62, 14 ], [ 344, 988, 19, 14 ], [ 369, 988, 12, 14 ], [ 385, 988, 21, 14 ], [ 72, 1004, 26, 14 ], [ 102, 1004, 17, 14 ], [ 124, 1004, 54, 14 ], [ 181, 1004, 12, 14 ], [ 197, 1004, 6, 14 ], [ 207, 1004, 38, 14 ], [ 250, 1004, 12, 14 ], [ 265, 1004, 24, 14 ], [ 293, 1004, 21, 14 ], [ 318, 1004, 40, 14 ], [ 362, 1004, 44, 14 ], [ 72, 1019, 52, 14 ], [ 130, 1019, 44, 15 ], [ 180, 1019, 50, 14 ], [ 236, 1019, 26, 14 ], [ 268, 1019, 69, 14 ], [ 343, 1019, 63, 14 ], [ 430, 640, 57, 14 ], [ 490, 640, 21, 14 ], [ 514, 640, 53, 14 ], [ 570, 640, 11, 14 ], [ 584, 640, 23, 14 ], [ 610, 640, 11, 14 ], [ 624, 640, 26, 14 ], [ 653, 640, 64, 14 ], [ 719, 640, 45, 14 ], [ 430, 656, 55, 15 ], [ 490, 656, 53, 14 ], [ 547, 656, 26, 14 ], [ 577, 656, 57, 14 ], [ 638, 656, 21, 14 ], [ 663, 656, 43, 15 ], [ 711, 656, 53, 14 ], [ 430, 672, 71, 14 ], [ 506, 672, 21, 14 ], [ 532, 672, 27, 14 ], [ 565, 672, 19, 14 ], [ 589, 672, 30, 14 ], [ 624, 672, 53, 14 ], [ 682, 672, 12, 14 ], [ 699, 672, 41, 14 ], [ 746, 672, 18, 14 ], [ 430, 687, 27, 14 ], [ 462, 687, 50, 14 ], [ 517, 687, 20, 14 ], [ 541, 687, 50, 14 ], [ 596, 687, 44, 15 ], [ 646, 687, 43, 14 ], [ 694, 687, 71, 14 ], [ 430, 703, 12, 14 ], [ 447, 703, 46, 14 ], [ 498, 703, 43, 14 ], [ 546, 703, 39, 14 ], [ 590, 703, 24, 14 ], [ 619, 703, 12, 14 ], [ 636, 703, 49, 14 ], [ 690, 703, 12, 14 ], [ 707, 703, 34, 14 ], [ 747, 703, 17, 14 ], [ 430, 719, 21, 14 ], [ 457, 719, 65, 14 ], [ 529, 719, 18, 14 ], [ 552, 719, 35, 14 ], [ 593, 719, 12, 14 ], [ 610, 719, 65, 14 ], [ 681, 719, 10, 14 ], [ 697, 719, 15, 14 ], [ 718, 719, 18, 14 ], [ 741, 719, 23, 14 ], [ 430, 735, 28, 14 ], [ 464, 735, 23, 14 ], [ 492, 735, 21, 14 ], [ 518, 735, 13, 14 ], [ 535, 735, 27, 14 ], [ 568, 735, 55, 15 ], [ 628, 735, 43, 14 ], [ 676, 735, 48, 14 ], [ 729, 735, 35, 15 ], [ 430, 750, 50, 14 ], [ 485, 750, 12, 14 ], [ 501, 750, 74, 14 ], [ 579, 750, 21, 14 ], [ 604, 750, 58, 14 ], [ 666, 750, 12, 14 ], [ 682, 750, 43, 15 ], [ 729, 750, 12, 14 ], [ 745, 750, 19, 14 ], [ 430, 766, 49, 14 ], [ 483, 766, 21, 14 ], [ 508, 766, 46, 14 ], [ 557, 766, 43, 14 ], [ 604, 766, 39, 14 ], [ 646, 766, 24, 14 ], [ 674, 766, 44, 14 ], [ 721, 766, 43, 14 ], [ 430, 782, 59, 14 ], [ 495, 782, 12, 14 ], [ 513, 782, 18, 14 ], [ 537, 782, 65, 14 ], [ 609, 782, 10, 14 ], [ 625, 782, 46, 14 ], [ 677, 782, 17, 14 ], [ 701, 782, 21, 14 ], [ 728, 782, 36, 14 ], [ 430, 798, 33, 14 ], [ 468, 798, 46, 14 ], [ 520, 798, 12, 14 ], [ 537, 798, 70, 14 ], [ 612, 798, 27, 14 ], [ 644, 798, 21, 14 ], [ 670, 798, 43, 15 ], [ 719, 798, 45, 14 ], [ 430, 814, 26, 14 ], [ 461, 814, 22, 14 ], [ 489, 814, 27, 14 ], [ 521, 814, 37, 14 ], [ 563, 814, 12, 14 ], [ 580, 814, 28, 14 ], [ 614, 814, 89, 14 ], [ 709, 814, 35, 14 ], [ 749, 814, 15, 14 ], [ 430, 829, 7, 14 ], [ 443, 829, 38, 14 ], [ 487, 829, 12, 14 ], [ 505, 829, 36, 14 ], [ 547, 829, 24, 14 ], [ 577, 829, 21, 14 ], [ 604, 829, 25, 14 ], [ 635, 829, 19, 14 ], [ 660, 829, 17, 14 ], [ 683, 829, 12, 14 ], [ 701, 829, 63, 14 ], [ 430, 845, 58, 14 ], [ 495, 845, 12, 14 ], [ 513, 845, 27, 14 ], [ 546, 845, 45, 14 ], [ 597, 845, 57, 14 ], [ 661, 845, 12, 14 ], [ 679, 845, 36, 14 ], [ 722, 845, 43, 14 ], [ 430, 861, 28, 14 ], [ 462, 861, 17, 14 ], [ 483, 861, 34, 14 ], [ 521, 861, 36, 14 ], [ 561, 861, 22, 14 ], [ 588, 861, 21, 14 ], [ 613, 861, 26, 14 ], [ 643, 861, 12, 14 ], [ 659, 861, 7, 14 ], [ 669, 861, 20, 14 ], [ 693, 861, 27, 14 ], [ 724, 861, 40, 14 ], [ 430, 877, 32, 14 ], [ 451, 893, 16, 14 ], [ 476, 893, 29, 14 ], [ 514, 893, 37, 14 ], [ 560, 893, 26, 14 ], [ 594, 893, 58, 14 ], [ 660, 893, 104, 14 ], [ 430, 908, 27, 14 ], [ 464, 908, 12, 14 ], [ 483, 908, 24, 14 ], [ 514, 908, 12, 14 ], [ 533, 908, 18, 14 ], [ 558, 908, 48, 14 ], [ 612, 908, 41, 14 ], [ 661, 908, 43, 15 ], [ 711, 908, 19, 14 ], [ 737, 908, 27, 14 ], [ 430, 924, 34, 14 ], [ 467, 924, 12, 14 ], [ 481, 924, 138, 14 ], [ 621, 924, 22, 14 ], [ 646, 924, 22, 14 ], [ 670, 924, 64, 14 ], [ 737, 924, 27, 14 ], [ 430, 940, 51, 14 ], [ 488, 940, 24, 14 ], [ 518, 940, 27, 14 ], [ 551, 940, 9, 14 ], [ 566, 940, 24, 14 ], [ 597, 940, 21, 14 ], [ 625, 940, 9, 14 ], [ 640, 940, 44, 14 ], [ 690, 940, 74, 14 ], [ 430, 956, 63, 14 ], [ 500, 956, 27, 14 ], [ 534, 956, 40, 14 ], [ 580, 956, 29, 14 ], [ 615, 956, 24, 14 ], [ 646, 956, 27, 14 ], [ 679, 956, 21, 14 ], [ 707, 956, 27, 14 ], [ 740, 956, 24, 14 ], [ 430, 971, 27, 14 ], [ 465, 971, 43, 15 ], [ 515, 971, 81, 14 ], [ 603, 971, 59, 14 ], [ 669, 971, 12, 14 ], [ 687, 971, 6, 14 ], [ 701, 971, 45, 14 ], [ 752, 971, 12, 14 ], [ 430, 987, 96, 14 ], [ 532, 987, 56, 14 ], [ 593, 987, 30, 14 ], [ 629, 987, 71, 14 ], [ 705, 987, 59, 14 ], [ 430, 1003, 12, 14 ], [ 446, 1003, 104, 14 ], [ 555, 1003, 56, 14 ], [ 615, 1003, 55, 14 ], [ 674, 1003, 12, 14 ], [ 690, 1003, 32, 14 ], [ 727, 1003, 37, 14 ], [ 430, 1019, 8, 14 ], [ 443, 1019, 9, 14 ], [ 456, 1019, 34, 14 ], [ 495, 1019, 12, 14 ], [ 511, 1019, 57, 14 ], [ 572, 1019, 14, 14 ], [ 590, 1019, 18, 14 ], [ 613, 1019, 29, 14 ], [ 646, 1019, 24, 14 ], [ 675, 1019, 11, 14 ], [ 691, 1019, 43, 15 ], [ 739, 1019, 25, 14 ] ]

[ "Hindawi", "Publishing", "Corporation", "PPAR", "Research", "Volume", "2007,", "Article", "ID", "23812,", "12", "pages", "doi:10.1155/2007/23812", "Review", "Article", "PPARs", "in", "Alveolar", "Macrophage", "Biology", "Monica", "R.", "Smith,", "Theodore", "J.", "Standiford,", "and", "Raju", "C.", "Reddy", "Division", "of", "Pulmonary", "and", "Critical", "Care", "Medicine,", "Department", "of", "Internal", "Medicine,", "University", "of", "Michigan", "Medical", "Center,", "Ann", "Arbor,", "MI", "48109-2200,", "USA", "Correspondence", "should", "be", "addressed", "to", "Raju", "C.", "Reddy,", "rajuc@umich.edu", "Received", "13", "March", "2007;", "Accepted", "18", "May", "2007", "Recommended", "by", "Jesse", "Roman", "PPARs,", "most", "notably", "PPAR-γ,", "play", "a", "crucial", "role", "in", "regulating", "the", "activation", "of", "alveolar", "macrophages,", "which", "in", "turn", "occupy", "a", "pivotal", "place", "in", "the", "immune", "response", "to", "pathogens", "and", "particulates", "drawn", "in", "with", "inspired", "air.", "In", "this", "review,", "we", "describe", "the", "dual", "role", "of", "the", "alveolar", "macrophage", "as", "both", "a", "first-line", "defender", "through", "its", "phagocytotic", "activity", "and", "a", "regulator", "of", "the", "immune", "re-", "sponse.", "Depending", "on", "its", "state", "of", "activation,", "the", "alveolar", "macrophage", "may", "either", "enhance", "or", "suppress", "different", "aspects", "of", "immune", "function", "in", "the", "lung.", "We", "then", "review", "the", "role", "of", "PPAR-γ", "and", "its", "ligands", "in", "deactivating", "alveolar", "macrophages—thus", "limiting", "the", "inflammatory", "response", "that,", "if", "unchecked,", "could", "threaten", "the", "essential", "respiratory", "function", "of", "the", "alveolus—while", "upregulating", "the", "cell’s", "phagocytotic", "activity.", "Finally,", "we", "examine", "the", "role", "that", "inadequate", "or", "inappropriate", "PPAR-γ", "responses", "play", "in", "specific", "lung", "diseases.", "Copyright", "©", "2007", "Monica", "R.", "Smith", "et", "al.", "This", "is", "an", "open", "access", "article", "distributed", "under", "the", "Creative", "Commons", "Attribution", "License,", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited.", "1.", "INTRODUCTION", "Peroxisome", "proliferator-activated", "receptors", "(PPARs)", "are", "members", "of", "the", "nuclear-receptor", "superfamily.", "Their", "name", "derives", "from", "the", "first-discovered", "member", "of", "the", "class,", "PPAR-", "α,", "whose", "activation", "induces", "proliferation", "of", "peroxisomes", "in", "the", "liver;", "no", "similar", "effect", "is", "seen", "with", "other", "members", "of", "the", "class,", "however.", "These", "receptors", "act", "as", "transcription", "fac-", "tors,", "forming", "heterodimers", "with", "the", "retinoid", "X", "receptor", "and", "then", "binding", "to", "specific", "response", "elements", "(PPREs)", "in", "the", "promoter", "regions", "of", "the", "genes", "they", "regulate.", "When", "activated", "by", "appropriate", "ligands,", "PPARs", "undergo", "a", "conformational", "change", "that", "leads", "to", "release", "of", "corepressors", "and", "binding", "of", "coactivator", "molecules,", "with", "consequent", "increases", "in", "tran-", "scription", "of", "the", "genes", "involved.", "Some", "evidence", "suggests", "that", "in", "the", "absence", "of", "activating", "ligands,", "PPARs", "may", "bind", "core-", "pressors", "and", "downregulate", "expression", "of", "genes", "with", "PPRE-", "containing", "promoters", "[1].", "There", "are", "three", "PPAR", "isoforms:", "PPAR-α,", "PPAR-γ,", "and", "PPAR-β/δ.", "Each", "of", "the", "isoforms", "is", "the", "product", "of", "a", "differ-", "ent", "gene.", "PPAR-β/δ", "is", "expressed", "in", "almost", "every", "tissue", "of", "the", "body.", "PPAR-α", "is", "most", "commonly", "thought", "of", "in", "connection", "with", "hepatocytes", "and", "PPAR-γ", "with", "adipocytes,", "but", "in", "fact", "both", "are", "expressed", "in", "a", "variety", "of", "cells", "and", "tissues.", "Broadly", "speaking,", "PPAR-α", "regulates", "lipid", "metabolism,", "lipoprotein", "formation", "and", "transport", "as", "well", "as", "lipid", "catabolism,", "whereas", "PPAR-β/δ", "promotes", "lipid", "oxidation,", "and", "PPAR-γ", "promotes", "adipogenesis", "[2].", "Each", "has", "other", "functions", "in", "specific", "tis-", "sues,", "however.", "For", "example,", "PPAR-α", "inhibits", "proliferation", "of", "vascular", "smooth", "muscle", "cells", "in", "response", "to", "injury", "[3]", "and", "antagonizes", "the", "effects", "of", "angiotensin", "II", "on", "the", "vas-", "cular", "wall", "[4].", "In", "skin,", "PPAR-β/δ", "induces", "terminal", "differ-", "entiation", "of", "keratinocytes", "[5].", "Activation", "of", "PPAR-γ", "in", "en-", "dothelial", "and", "vascular", "smooth", "muscle", "cells", "likewise", "inhibits", "expression", "of", "the", "angiotensin", "II", "receptor", "[6]", "and", "lowers", "blood", "pressure", "in", "hypertensive", "mice", "[7].", "PPAR-γ", "agonists", "have", "also", "been", "shown", "to", "exert", "antiproliferative", "effects", "on", "a", "variety", "of", "cancer", "cells", "[8].", "This", "has", "led", "to", "widespread", "discussion", "of", "their", "possible", "usefulness", "in", "cancer", "therapy", "(e.g.,", "for", "breast", "cancer", "[9])", "and", "even", "to", "a", "few", "early", "clinical", "trials.", "All", "three", "PPARs", "have", "significant", "anti-inflammatory", "roles", "in", "cells", "of", "the", "immune", "system.", "PPAR-γ", "has", "been", "found", "in", "monocytes/macrophages", "[10,", "11],", "neutrophils", "[12],", "dendritic", "cells", "[13],", "B", "[14]", "and", "T", "[15–17]", "lymphocytes,", "eosinophils", "[18],", "natural", "killer", "cells", "[19],", "and", "mast", "cells", "[20].", "PPAR-γ", "downregulates", "expression", "of", "a", "number", "of", "proinflammatory", "mediators", "while", "upregulating", "expression", "of", "anti-inflammatory", "mediators", "(reviewed", "in", "[21]).", "PPAR-", "α", "is", "found", "in", "essentially", "all", "the", "same", "cells", "as", "PPAR-γ", "with" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 13, 13, 13, 13, 13, 13, 13, 13, 13, 7, 7, 7, 7, 7, 7, 7, 7, 11, 11, 11, 11, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ [ 74, 65, 38, 12 ], [ 115, 65, 60, 12 ], [ 178, 65, 26, 12 ], [ 206, 65, 15, 12 ], [ 224, 65, 41, 12 ], [ 554, 65, 25, 12 ], [ 582, 65, 159, 12 ], [ 74, 124, 128, 23 ], [ 208, 124, 36, 23 ], [ 251, 124, 89, 23 ], [ 348, 124, 78, 23 ], [ 433, 124, 19, 23 ], [ 459, 124, 68, 23 ], [ 534, 124, 92, 23 ], [ 633, 124, 54, 23 ], [ 694, 124, 19, 23 ], [ 74, 157, 73, 23 ], [ 154, 157, 134, 23 ], [ 294, 157, 15, 23 ], [ 316, 157, 51, 23 ], [ 374, 157, 25, 23 ], [ 406, 157, 84, 23 ], [ 497, 157, 77, 23 ], [ 581, 157, 45, 23 ], [ 74, 215, 11, 12 ], [ 88, 215, 11, 12 ], [ 102, 214, 64, 13 ], [ 170, 215, 7, 12 ], [ 180, 214, 66, 13 ], [ 249, 215, 11, 12 ], [ 263, 215, 12, 12 ], [ 279, 215, 12, 12 ], [ 294, 215, 17, 12 ], [ 314, 214, 57, 13 ], [ 374, 215, 12, 12 ], [ 389, 215, 12, 12 ], [ 404, 215, 9, 12 ], [ 416, 214, 65, 13 ], [ 484, 215, 11, 12 ], [ 498, 215, 11, 12 ], [ 512, 214, 137, 13 ], [ 653, 215, 9, 12 ], [ 74, 229, 13, 12 ], [ 89, 229, 11, 12 ], [ 103, 229, 11, 12 ], [ 118, 228, 78, 13 ], [ 74, 261, 37, 13 ], [ 114, 262, 12, 12 ], [ 128, 262, 45, 12 ], [ 176, 262, 41, 12 ], [ 221, 262, 35, 12 ], [ 258, 262, 48, 12 ], [ 309, 262, 41, 12 ], [ 354, 262, 27, 12 ], [ 383, 262, 48, 12 ], [ 435, 262, 41, 12 ], [ 479, 262, 27, 12 ], [ 509, 262, 43, 12 ], [ 554, 262, 45, 12 ], [ 602, 262, 31, 12 ], [ 636, 262, 32, 12 ], [ 74, 275, 53, 13 ], [ 130, 276, 11, 12 ], [ 144, 276, 40, 12 ], [ 187, 276, 43, 12 ], [ 233, 276, 63, 12 ], [ 299, 276, 12, 12 ], [ 313, 276, 51, 12 ], [ 367, 276, 34, 12 ], [ 404, 276, 63, 12 ], [ 469, 276, 44, 12 ], [ 516, 276, 24, 12 ], [ 543, 276, 51, 12 ], [ 596, 276, 18, 12 ], [ 618, 276, 30, 12 ], [ 651, 276, 29, 12 ], [ 74, 380, 73, 14 ], [ 74, 405, 20, 13 ], [ 96, 405, 19, 13 ], [ 116, 405, 10, 13 ], [ 129, 405, 18, 13 ], [ 149, 405, 26, 13 ], [ 177, 405, 18, 13 ], [ 197, 405, 10, 13 ], [ 210, 405, 36, 13 ], [ 248, 405, 33, 13 ], [ 282, 405, 108, 13 ], [ 74, 421, 45, 13 ], [ 124, 421, 57, 13 ], [ 185, 421, 24, 13 ], [ 214, 421, 40, 13 ], [ 259, 421, 48, 13 ], [ 311, 421, 13, 13 ], [ 328, 421, 63, 13 ], [ 74, 438, 43, 13 ], [ 122, 438, 35, 13 ], [ 162, 438, 41, 13 ], [ 208, 438, 24, 13 ], [ 237, 438, 45, 13 ], [ 287, 438, 25, 13 ], [ 317, 438, 13, 13 ], [ 335, 438, 26, 13 ], [ 367, 438, 24, 13 ], [ 74, 455, 25, 13 ], [ 102, 455, 13, 13 ], [ 119, 455, 42, 13 ], [ 165, 455, 23, 13 ], [ 192, 455, 11, 13 ], [ 208, 455, 39, 13 ], [ 251, 455, 72, 13 ], [ 326, 455, 20, 13 ], [ 350, 455, 40, 13 ], [ 74, 471, 24, 13 ], [ 102, 471, 42, 13 ], [ 147, 471, 20, 13 ], [ 172, 471, 22, 13 ], [ 198, 471, 52, 13 ], [ 254, 471, 12, 13 ], [ 270, 471, 41, 13 ], [ 315, 471, 16, 13 ], [ 335, 471, 55, 13 ], [ 74, 488, 44, 13 ], [ 122, 488, 11, 13 ], [ 137, 488, 39, 13 ], [ 180, 488, 71, 13 ], [ 255, 488, 23, 13 ], [ 281, 488, 7, 13 ], [ 292, 488, 40, 13 ], [ 335, 488, 56, 13 ], [ 74, 505, 21, 13 ], [ 99, 505, 19, 13 ], [ 123, 505, 32, 13 ], [ 159, 505, 19, 13 ], [ 182, 505, 42, 13 ], [ 229, 505, 35, 13 ], [ 269, 505, 36, 13 ], [ 309, 505, 15, 13 ], [ 328, 505, 63, 13 ], [ 74, 521, 44, 13 ], [ 119, 521, 19, 13 ], [ 140, 521, 52, 13 ], [ 194, 521, 53, 13 ], [ 249, 521, 10, 13 ], [ 261, 521, 37, 13 ], [ 300, 521, 67, 13 ], [ 369, 521, 22, 13 ], [ 74, 538, 7, 13 ], [ 84, 538, 45, 13 ], [ 133, 538, 59, 13 ], [ 195, 538, 23, 13 ], [ 221, 538, 20, 13 ], [ 245, 538, 20, 13 ], [ 268, 538, 42, 13 ], [ 314, 538, 38, 13 ], [ 355, 538, 36, 13 ], [ 74, 555, 15, 13 ], [ 95, 555, 63, 13 ], [ 163, 555, 23, 13 ], [ 192, 555, 40, 13 ], [ 239, 555, 23, 13 ], [ 267, 555, 50, 13 ], [ 323, 555, 68, 13 ], [ 74, 571, 34, 13 ], [ 110, 571, 23, 13 ], [ 135, 571, 7, 13 ], [ 145, 571, 40, 13 ], [ 187, 571, 55, 13 ], [ 245, 571, 22, 13 ], [ 269, 571, 19, 13 ], [ 291, 571, 19, 13 ], [ 313, 571, 39, 13 ], [ 355, 571, 36, 13 ], [ 74, 588, 36, 13 ], [ 113, 588, 15, 13 ], [ 131, 588, 66, 13 ], [ 200, 588, 19, 13 ], [ 222, 588, 22, 13 ], [ 247, 588, 63, 13 ], [ 313, 588, 23, 13 ], [ 339, 588, 7, 13 ], [ 348, 588, 43, 13 ], [ 74, 605, 55, 13 ], [ 132, 605, 22, 13 ], [ 156, 605, 22, 13 ], [ 182, 605, 42, 13 ], [ 227, 605, 36, 13 ], [ 265, 605, 36, 13 ], [ 304, 605, 15, 13 ], [ 322, 605, 68, 13 ], [ 74, 621, 20, 13 ], [ 102, 621, 45, 13 ], [ 154, 621, 46, 13 ], [ 208, 621, 16, 13 ], [ 232, 621, 91, 13 ], [ 331, 621, 59, 13 ], [ 74, 638, 98, 13 ], [ 175, 638, 46, 13 ], [ 224, 638, 39, 13 ], [ 266, 638, 22, 13 ], [ 292, 638, 28, 13 ], [ 323, 638, 20, 13 ], [ 346, 638, 7, 13 ], [ 356, 638, 34, 13 ], [ 74, 655, 48, 13 ], [ 124, 655, 11, 13 ], [ 138, 655, 59, 13 ], [ 200, 655, 37, 13 ], [ 240, 655, 8, 13 ], [ 250, 655, 9, 13 ], [ 260, 655, 43, 13 ], [ 305, 655, 53, 13 ], [ 360, 655, 31, 13 ], [ 74, 671, 8, 13 ], [ 84, 671, 9, 13 ], [ 95, 671, 44, 13 ], [ 145, 671, 49, 13 ], [ 199, 671, 77, 13 ], [ 282, 671, 38, 13 ], [ 325, 671, 8, 13 ], [ 336, 671, 9, 13 ], [ 347, 671, 44, 13 ], [ 74, 688, 19, 13 ], [ 95, 688, 40, 13 ], [ 138, 688, 11, 13 ], [ 153, 688, 16, 13 ], [ 172, 688, 48, 13 ], [ 222, 688, 40, 13 ], [ 264, 688, 39, 13 ], [ 305, 688, 8, 13 ], [ 316, 688, 9, 13 ], [ 328, 688, 41, 13 ], [ 372, 688, 19, 13 ], [ 74, 705, 11, 13 ], [ 90, 705, 16, 13 ], [ 110, 705, 46, 13 ], [ 161, 705, 24, 13 ], [ 189, 705, 39, 13 ], [ 232, 705, 8, 13 ], [ 243, 705, 9, 13 ], [ 254, 705, 41, 13 ], [ 300, 705, 10, 13 ], [ 315, 705, 16, 13 ], [ 335, 705, 55, 13 ], [ 74, 721, 56, 13 ], [ 132, 721, 30, 13 ], [ 165, 721, 23, 13 ], [ 191, 721, 10, 13 ], [ 203, 721, 16, 13 ], [ 222, 721, 28, 13 ], [ 252, 721, 38, 13 ], [ 293, 721, 21, 13 ], [ 316, 721, 23, 13 ], [ 342, 721, 49, 13 ], [ 74, 738, 22, 13 ], [ 101, 738, 26, 13 ], [ 131, 738, 41, 13 ], [ 177, 738, 10, 13 ], [ 192, 738, 16, 13 ], [ 213, 738, 28, 13 ], [ 246, 738, 23, 13 ], [ 273, 738, 11, 13 ], [ 290, 738, 16, 13 ], [ 311, 738, 32, 13 ], [ 348, 738, 21, 13 ], [ 374, 738, 17, 13 ], [ 74, 755, 54, 13 ], [ 130, 755, 23, 13 ], [ 156, 755, 47, 13 ], [ 206, 755, 44, 13 ], [ 254, 755, 39, 13 ], [ 296, 755, 72, 13 ], [ 74, 788, 50, 13 ], [ 130, 788, 34, 13 ], [ 166, 788, 39, 13 ], [ 208, 788, 72, 13 ], [ 283, 788, 62, 13 ], [ 348, 788, 43, 13 ], [ 74, 805, 62, 13 ], [ 139, 805, 53, 13 ], [ 195, 805, 48, 13 ], [ 247, 805, 33, 13 ], [ 283, 805, 35, 13 ], [ 74, 846, 77, 12 ], [ 153, 846, 27, 12 ], [ 183, 846, 56, 12 ], [ 241, 846, 57, 12 ], [ 301, 846, 16, 12 ], [ 320, 846, 55, 12 ], [ 74, 860, 33, 12 ], [ 110, 860, 11, 12 ], [ 124, 860, 46, 12 ], [ 172, 860, 41, 12 ], [ 217, 860, 90, 12 ], [ 310, 860, 20, 12 ], [ 333, 860, 49, 12 ], [ 74, 873, 32, 12 ], [ 109, 873, 20, 12 ], [ 132, 873, 43, 12 ], [ 177, 873, 56, 12 ], [ 237, 873, 45, 12 ], [ 284, 873, 31, 12 ], [ 318, 873, 29, 12 ], [ 74, 887, 36, 12 ], [ 113, 887, 117, 12 ], [ 74, 901, 32, 12 ], [ 109, 901, 10, 12 ], [ 123, 901, 18, 12 ], [ 143, 901, 30, 12 ], [ 176, 901, 8, 12 ], [ 186, 901, 46, 12 ], [ 235, 901, 10, 12 ], [ 248, 901, 54, 12 ], [ 304, 901, 21, 12 ], [ 328, 901, 15, 12 ], [ 74, 915, 40, 12 ], [ 116, 915, 49, 12 ], [ 168, 915, 29, 12 ], [ 200, 915, 55, 12 ], [ 257, 915, 18, 12 ], [ 278, 915, 28, 12 ], [ 309, 915, 22, 12 ], [ 334, 915, 16, 12 ], [ 353, 915, 32, 12 ], [ 74, 929, 55, 12 ], [ 132, 929, 60, 12 ], [ 74, 943, 45, 12 ], [ 121, 943, 12, 12 ], [ 136, 943, 31, 12 ], [ 170, 943, 23, 12 ], [ 74, 957, 43, 12 ], [ 119, 957, 14, 12 ], [ 136, 957, 55, 12 ], [ 194, 957, 12, 12 ], [ 208, 957, 23, 12 ], [ 233, 957, 23, 12 ], [ 74, 990, 9, 12 ], [ 85, 990, 23, 12 ], [ 111, 990, 19, 12 ], [ 133, 990, 39, 12 ], [ 74, 1004, 36, 12 ], [ 112, 1004, 57, 12 ], [ 172, 1004, 9, 12 ], [ 184, 1004, 23, 12 ], [ 210, 1004, 46, 12 ], [ 259, 1004, 50, 12 ], [ 312, 1004, 18, 12 ], [ 424, 380, 115, 14 ], [ 424, 405, 43, 13 ], [ 473, 405, 72, 13 ], [ 551, 405, 9, 13 ], [ 565, 405, 25, 13 ], [ 596, 405, 12, 13 ], [ 613, 405, 45, 13 ], [ 664, 405, 20, 13 ], [ 690, 405, 51, 13 ], [ 424, 422, 88, 13 ], [ 518, 422, 20, 13 ], [ 544, 422, 93, 13 ], [ 644, 422, 45, 13 ], [ 695, 422, 46, 13 ], [ 424, 439, 70, 13 ], [ 498, 439, 40, 13 ], [ 543, 439, 73, 13 ], [ 621, 439, 36, 13 ], [ 662, 439, 13, 13 ], [ 680, 439, 61, 13 ], [ 424, 455, 50, 13 ], [ 477, 455, 21, 13 ], [ 502, 455, 47, 13 ], [ 552, 455, 40, 13 ], [ 596, 455, 71, 13 ], [ 671, 455, 30, 13 ], [ 705, 455, 36, 13 ], [ 424, 472, 13, 13 ], [ 441, 472, 12, 13 ], [ 457, 472, 54, 13 ], [ 515, 472, 50, 13 ], [ 569, 472, 21, 13 ], [ 595, 472, 28, 13 ], [ 627, 472, 38, 13 ], [ 669, 472, 9, 13 ], [ 681, 472, 44, 13 ], [ 730, 472, 11, 13 ], [ 424, 489, 80, 13 ], [ 507, 489, 49, 13 ], [ 560, 489, 20, 13 ], [ 585, 489, 17, 13 ], [ 606, 489, 53, 13 ], [ 662, 489, 54, 13 ], [ 720, 489, 21, 13 ], [ 424, 505, 13, 13 ], [ 442, 505, 34, 13 ], [ 480, 505, 34, 13 ], [ 520, 505, 17, 13 ], [ 542, 505, 62, 13 ], [ 609, 505, 11, 13 ], [ 625, 505, 64, 13 ], [ 694, 505, 28, 13 ], [ 727, 505, 13, 13 ], [ 424, 522, 25, 13 ], [ 454, 522, 21, 13 ], [ 481, 522, 12, 13 ], [ 499, 522, 17, 13 ], [ 521, 522, 68, 13 ], [ 594, 522, 20, 13 ], [ 620, 522, 56, 13 ], [ 681, 522, 36, 13 ], [ 722, 522, 19, 13 ], [ 424, 539, 61, 13 ], [ 489, 539, 54, 13 ], [ 548, 539, 46, 13 ], [ 600, 539, 47, 13 ], [ 652, 539, 25, 13 ], [ 682, 539, 18, 13 ], [ 705, 539, 36, 13 ], [ 424, 555, 22, 13 ], [ 450, 555, 11, 13 ], [ 466, 555, 18, 13 ], [ 488, 555, 19, 13 ], [ 511, 555, 29, 13 ], [ 544, 555, 42, 13 ], [ 590, 555, 43, 13 ], [ 637, 555, 25, 13 ], [ 666, 555, 21, 13 ], [ 691, 555, 10, 13 ], [ 705, 555, 25, 13 ], [ 734, 555, 7, 13 ], [ 424, 572, 59, 13 ], [ 486, 572, 12, 13 ], [ 503, 572, 42, 13 ], [ 550, 572, 25, 13 ], [ 579, 572, 25, 13 ], [ 608, 572, 37, 13 ], [ 649, 572, 75, 13 ], [ 729, 572, 12, 13 ], [ 424, 589, 43, 13 ], [ 473, 589, 7, 13 ], [ 486, 589, 25, 13 ], [ 517, 589, 42, 13 ], [ 566, 589, 33, 13 ], [ 605, 589, 9, 13 ], [ 620, 589, 80, 13 ], [ 706, 589, 35, 13 ], [ 424, 605, 71, 13 ], [ 497, 605, 25, 13 ], [ 524, 605, 21, 13 ], [ 547, 605, 43, 13 ], [ 592, 605, 41, 13 ], [ 635, 605, 7, 13 ], [ 645, 605, 32, 13 ], [ 679, 605, 26, 13 ], [ 708, 605, 11, 13 ], [ 723, 605, 18, 13 ], [ 424, 622, 25, 13 ], [ 451, 622, 22, 13 ], [ 475, 622, 9, 13 ], [ 487, 622, 38, 13 ], [ 527, 622, 30, 13 ], [ 560, 622, 8, 13 ], [ 572, 622, 18, 13 ], [ 592, 622, 54, 13 ], [ 649, 622, 12, 13 ], [ 664, 622, 20, 13 ], [ 687, 622, 37, 13 ], [ 726, 622, 15, 13 ], [ 424, 639, 18, 13 ], [ 445, 639, 17, 13 ], [ 465, 639, 25, 13 ], [ 495, 639, 18, 13 ], [ 516, 639, 12, 13 ], [ 531, 639, 25, 13 ], [ 560, 639, 12, 13 ], [ 575, 639, 20, 13 ], [ 598, 639, 32, 13 ], [ 634, 639, 26, 13 ], [ 664, 639, 12, 13 ], [ 680, 639, 17, 13 ], [ 700, 639, 40, 13 ], [ 424, 655, 12, 13 ], [ 437, 655, 24, 13 ], [ 464, 655, 41, 13 ], [ 506, 655, 20, 13 ], [ 528, 655, 26, 13 ], [ 556, 655, 16, 13 ], [ 574, 655, 35, 13 ], [ 612, 655, 44, 13 ], [ 658, 655, 23, 13 ], [ 683, 655, 58, 13 ], [ 424, 672, 66, 13 ], [ 492, 672, 12, 13 ], [ 508, 672, 17, 13 ], [ 529, 672, 23, 13 ], [ 555, 672, 21, 13 ], [ 579, 672, 37, 13 ], [ 620, 672, 29, 13 ], [ 651, 672, 49, 13 ], [ 703, 672, 21, 13 ], [ 727, 672, 14, 13 ], [ 424, 689, 50, 13 ], [ 478, 689, 76, 13 ], [ 558, 689, 12, 13 ], [ 574, 689, 47, 13 ], [ 625, 689, 47, 13 ], [ 677, 689, 47, 13 ], [ 729, 689, 12, 13 ], [ 424, 705, 28, 13 ], [ 456, 705, 25, 13 ], [ 485, 705, 27, 13 ], [ 517, 705, 11, 13 ], [ 534, 705, 38, 13 ], [ 577, 705, 17, 13 ], [ 598, 705, 38, 13 ], [ 641, 705, 71, 13 ], [ 716, 705, 13, 13 ], [ 734, 705, 7, 13 ], [ 424, 722, 37, 13 ], [ 464, 722, 12, 13 ], [ 480, 722, 22, 13 ], [ 507, 722, 21, 13 ], [ 531, 722, 34, 13 ], [ 569, 722, 36, 13 ], [ 609, 722, 18, 13 ], [ 631, 722, 32, 13 ], [ 666, 722, 22, 13 ], [ 692, 722, 9, 13 ], [ 704, 722, 37, 13 ], [ 424, 739, 31, 13 ], [ 460, 739, 17, 13 ], [ 482, 739, 43, 13 ], [ 531, 739, 46, 13 ], [ 582, 739, 12, 13 ], [ 599, 739, 60, 13 ], [ 665, 739, 50, 13 ], [ 720, 739, 21, 13 ], [ 424, 755, 24, 13 ], [ 451, 755, 17, 13 ], [ 471, 755, 44, 13 ], [ 517, 755, 46, 13 ], [ 566, 755, 11, 13 ], [ 580, 755, 39, 13 ], [ 622, 755, 18, 13 ], [ 643, 755, 29, 13 ], [ 675, 755, 26, 13 ], [ 704, 755, 37, 13 ], [ 424, 772, 11, 13 ], [ 439, 772, 38, 13 ], [ 480, 772, 38, 13 ], [ 523, 772, 12, 13 ], [ 540, 772, 73, 13 ], [ 616, 772, 44, 13 ], [ 664, 772, 29, 13 ], [ 697, 772, 11, 13 ], [ 714, 772, 27, 13 ], [ 424, 789, 40, 13 ], [ 465, 789, 45, 13 ], [ 512, 789, 16, 13 ], [ 531, 789, 60, 13 ], [ 593, 789, 70, 13 ], [ 665, 789, 13, 13 ], [ 680, 789, 17, 13 ], [ 699, 789, 42, 13 ], [ 424, 805, 33, 13 ], [ 460, 805, 11, 13 ], [ 476, 805, 17, 13 ], [ 497, 805, 43, 13 ], [ 543, 805, 41, 13 ], [ 588, 805, 38, 13 ], [ 630, 805, 11, 13 ], [ 646, 805, 51, 13 ], [ 701, 805, 24, 13 ], [ 729, 805, 12, 13 ], [ 424, 822, 48, 13 ], [ 476, 822, 48, 13 ], [ 528, 822, 56, 13 ], [ 588, 822, 78, 13 ], [ 670, 822, 27, 13 ], [ 701, 822, 40, 13 ], [ 424, 839, 36, 13 ], [ 461, 839, 38, 13 ], [ 501, 839, 11, 13 ], [ 515, 839, 29, 13 ], [ 546, 839, 45, 13 ], [ 592, 839, 25, 13 ], [ 619, 839, 39, 13 ], [ 660, 839, 11, 13 ], [ 675, 839, 66, 13 ], [ 424, 855, 32, 13 ], [ 459, 855, 63, 13 ], [ 525, 855, 46, 13 ], [ 573, 855, 72, 13 ], [ 648, 855, 40, 13 ], [ 692, 855, 49, 13 ], [ 424, 872, 16, 13 ], [ 442, 872, 28, 13 ], [ 473, 872, 25, 13 ], [ 500, 872, 23, 13 ], [ 526, 872, 11, 13 ], [ 541, 872, 17, 13 ], [ 561, 872, 55, 13 ], [ 618, 872, 21, 13 ], [ 642, 872, 12, 13 ], [ 657, 872, 16, 13 ], [ 675, 872, 66, 13 ], [ 424, 889, 31, 13 ], [ 457, 889, 16, 13 ], [ 475, 889, 18, 13 ], [ 496, 889, 17, 13 ], [ 515, 889, 28, 13 ], [ 545, 889, 50, 13 ], [ 597, 889, 26, 13 ], [ 625, 889, 11, 13 ], [ 640, 889, 16, 13 ], [ 658, 889, 43, 13 ], [ 704, 889, 37, 13 ], [ 424, 905, 21, 13 ], [ 448, 905, 36, 13 ], [ 486, 905, 26, 13 ], [ 515, 905, 39, 13 ], [ 557, 905, 47, 13 ], [ 607, 905, 13, 13 ], [ 623, 905, 12, 13 ], [ 638, 905, 42, 13 ], [ 682, 905, 9, 13 ], [ 694, 905, 7, 13 ], [ 703, 905, 38, 13 ], [ 424, 922, 37, 13 ], [ 464, 922, 19, 13 ], [ 485, 922, 24, 13 ], [ 512, 922, 12, 13 ], [ 528, 922, 29, 13 ], [ 560, 922, 11, 13 ], [ 574, 922, 13, 13 ], [ 590, 922, 23, 13 ], [ 615, 922, 26, 13 ], [ 644, 922, 16, 13 ], [ 663, 922, 54, 13 ], [ 720, 922, 21, 13 ], [ 424, 939, 84, 13 ], [ 512, 939, 40, 13 ], [ 556, 939, 25, 13 ], [ 585, 939, 18, 13 ], [ 607, 939, 22, 13 ], [ 633, 939, 16, 13 ], [ 653, 939, 72, 13 ], [ 729, 939, 12, 13 ], [ 424, 955, 14, 13 ], [ 441, 955, 50, 13 ], [ 495, 955, 37, 13 ], [ 536, 955, 33, 13 ], [ 573, 955, 16, 13 ], [ 593, 955, 17, 13 ], [ 613, 955, 38, 13 ], [ 655, 955, 40, 13 ], [ 699, 955, 42, 13 ], [ 720, 988, 21, 14 ] ]

[ "Parasite", "Immunology,", "2008,", "30,", "515–524", "DOI:", "10.1111/j.1365-3024.2008.01051.x", "SBOIplRaecInkGniwcINeclhAaPLnugbAeliRsflhnTiIvnCigscLeErtadSllaeishmaniamsismation", "and", "structural", "changes", "of", "splenic", "lymphoid", "tissue", "in", "visceral", "leishmaniasis:", "A", "study", "on", "naturally", "infected", "dogs", "C.", "C.", "SANTANA,1", "J.", "VASSALLO,2", "L.", "A.", "R.", "DE", "FREITAS,1", "G.", "G.", "S.", "OLIVEIRA,1", "L.", "C.", "PONTES-DE-CARVALHO1", "&", "W.", "L.", "C.", "DOS-SANTOS1", "1Centro", "de", "Pesquisas", "Gonçalo", "Moniz,", "Fundação", "Oswaldo", "Cruz,", "Fundação", "Oswaldo", "Cruz,", "Candeal,", "Salvador,", "Bahia,", "Brazil,", "2Faculdade", "de", "Ciências", "Médicas,", "Universidade", "de", "Campinas,", "Cidade", "Universitária", "‘Zeferino", "Vaz’,", "Campinas,", "São", "Paulo,", "Brazil", "SUMMARY", "The", "aim", "of", "this", "study", "was", "to", "identify", "splenic", "immuno-inflammatory", "patterns", "associated", "with", "natural", "infection", "by", "Leishmania", "chagasi.", "Spleen", "samples", "were", "obtained", "from", "72", "stray", "dogs", "from", "an", "endemic", "area", "of", "visceral", "leishmaniasis.", "The", "animals", "were", "grouped", "into", "four", "categories", "as", "follows:", "(i)", "potentially", "resistant", "to", "visceral", "leishmaniasis,", "with", "a", "positive", "leishmanin", "skin", "test", "result,", "and", "negative", "splenic", "culture", "for", "Leishmania", "parasites", "(ii)", "potentially", "susceptible", "to", "visceral", "leishmaniasis,", "with", "a", "negative", "leishmanin", "skin", "test", "and", "positive", "splenic", "culture", "for", "Leishmania", "(iii)", "infected", "with", "undefined", "susceptibility", "status,", "with", "a", "positive", "leishmanin", "skin", "test", "and", "positive", "splenic", "culture", "for", "Leishmania,", "and", "(iv)", "noninfected,", "with", "a", "negative", "leishmanin", "skin", "test,", "negative", "splenic", "culture", "for", "Leishmania,", "and", "negative", "serology", "for", "anti-Leishmania", "antibodies.", "Histopathological", "analyses", "showed", "that", "there", "was", "a", "higher", "frequency", "of", "perisplenitis", "(18/25,", "P", "<", "0·0001),", "granuloma", "(7/25,", "P", "=", "0·0102),", "structural", "disorganization", "(14/25,", "P", "<", "0·0001),", "and", "atrophy", "of", "the", "lymphoid", "follicles", "(20/25,", "P", "=", "0·0036)", "and", "of", "the", "marginal", "zone", "(15/25,", "P", "=", "0·0025)", "in", "the", "potentially", "susceptible", "group", "than", "in", "the", "other", "groups.", "The", "data", "presented", "here", "show", "changes", "in", "the", "white", "pulp", "of", "the", "spleen", "that", "are", "associated", "with", "naturally", "acquired", "visceral", "leishmaniasis.", "Keywords", "canine", "visceral", "leishmaniasis,", "Leishmania", "chagasi,", "Leishmania", "infantum,", "lymphoid", "tissue,", "Spleen", "Correspondence:", "WLC", "Dos-Santos", "Washington", "LC", "dos-Santos,", "Centro", "de", "Pesquisas", "Gonçalo", "Moniz-FIOCRUZ,", "Rua", "Waldemar", "Falcão", "121,", "Candeal,", "40·296–710,", "Salvador,", "Bahia,", "Brazil", "(e-mail:", "wluis@bahia.fiocruz.br).", "Re-use", "of", "this", "article", "is", "permitted", "in", "accordance", "with", "the", "Creative", "Commons", "Deed,", "Attribution", "2·5,", "which", "does", "not", "permit", "commercial", "exploitation.", "Received:", "10", "March", "2008", "Accepted", "for", "publication:", "28", "May", "2008", "©", "2008", "The", "Authors", "Journal", "compilation", "©", "2008", "Blackwell", "Publishing", "Ltd", "INTRODUCTION", "Visceral", "leishmaniasis", "is", "used", "to", "describe", "two", "clinically,", "parasitologically", "and", "epidemiologically", "different", "diseases:", "antroponotic", "visceral", "leishmaniasis,", "caused", "by", "Leishmania", "donovani,", "and", "zoonotic", "visceral", "leishmaniasis", "(VL),", "caused", "by", "L.", "chagasi/L.", "infantum.", "The", "latter", "disease", "is", "endemic", "in", "Mediterranean", "countries", "and", "the", "American", "continent,", "and", "its", "causal", "agents", "are", "transmitted", "to", "mammalian", "hosts", "by", "sand", "flies", "of", "the", "Phlebotomus", "and", "Lutzomyia", "genera", "(1).", "Leishmania", "chagasi/L.", "infantum", "infection", "does", "not", "always", "lead", "to", "VL", "(2).", "Most", "infected", "humans", "(2,3)", "and", "at", "least", "a", "proportion", "of", "infected", "dogs", "(4,5)", "remain", "asymptomatic", "or", "develop", "a", "mild", "disease,", "which", "is", "spontaneously", "cured.", "Occasionally,", "dogs", "and", "humans", "develop", "a", "severe", "form", "of", "VL", "(2,6)", "that", "is", "usually", "lethal", "if", "left", "untreated.", "In", "this", "report,", "we", "use", "the", "term", "VL", "to", "refer", "to", "this", "severe", "form", "of", "the", "disease.", "In", "both", "humans", "and", "dogs,", "the", "disease", "proceeds", "with", "emaciation,", "enlargement", "of", "the", "liver", "and", "spleen,", "fever,", "anaemia,", "and", "an", "increased", "predisposition", "to", "bacterial", "infection", "(2,7–10).", "In", "dogs,", "such", "signs", "of", "disease", "are", "further", "accompanied", "by", "a", "variety", "of", "skin", "and", "ocular", "lesions", "(9).", "Much", "that", "is", "known", "about", "the", "immune", "response", "to", "Leishmania", "parasites,", "and", "even", "the", "immune", "response", "in", "general", "has", "come", "from", "studies", "in", "murine", "models", "of", "leishmaniases", "(11–13).", "Most", "of", "these", "models,", "however,", "are", "intrinsically", "compromised", "by", "the", "artificial", "nature", "of", "the", "infective", "inocula.", "Instead", "of", "consisting", "only", "of", "naturally", "infective,", "metacyclic", "promastigotes,", "these", "inocula", "usually", "contain", "(i)", "either", "relatively", "large", "number", "of", "complement-", "fixing,", "noninfective", "procyclic", "promastigotes", "(usually", "constitut-", "ing", "more", "than", "70%", "of", "the", "inoculum)", "(14)", "or", "(ii)", "amastigotes,", "which", "are", "not", "the", "usual", "infectious", "form", "of", "the", "parasite.", "Canine", "VL,", "arising", "from", "natural", "infection", "by", "L.", "chagasi,", "is", "a", "disease", "worthy", "not", "only", "of", "study", "in", "its", "own", "right", "for", "veterinary", "and", "epidemiological", "reasons", "(15),", "but", "also", "for", "consideration", "as", "an", "attractive", "animal", "model", "for", "the", "human", "disease,", "because", "515" ]

[ 0, 0, 0, 0, 0, 0, 0, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 11, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4 ]

[ [ 78, 47, 17, 12 ], [ 99, 47, 16, 12 ], [ 118, 47, 9, 12 ], [ 130, 47, 11, 12 ], [ 144, 47, 21, 12 ], [ 168, 47, 64, 12 ], [ 235, 47, 25, 12 ], [ 264, 47, 26, 12 ], [ 78, 61, 227, 12 ], [ 83, 128, 10, 18 ], [ 95, 128, 13, 18 ], [ 109, 128, 10, 18 ], [ 121, 128, 10, 18 ], [ 133, 128, 16, 18 ], [ 150, 128, 12, 18 ], [ 164, 128, 11, 18 ], [ 176, 128, 10, 18 ], [ 641, 128, 44, 18 ], [ 691, 128, 53, 18 ], [ 78, 169, 130, 34 ], [ 218, 169, 36, 34 ], [ 264, 169, 72, 34 ], [ 346, 169, 181, 34 ], [ 537, 169, 33, 34 ], [ 580, 169, 137, 34 ], [ 78, 205, 125, 34 ], [ 213, 205, 37, 34 ], [ 260, 205, 44, 34 ], [ 314, 205, 109, 34 ], [ 433, 205, 161, 34 ], [ 604, 205, 51, 34 ], [ 665, 205, 59, 34 ], [ 78, 241, 177, 34 ], [ 266, 241, 27, 34 ], [ 302, 241, 123, 34 ], [ 435, 241, 262, 34 ], [ 78, 277, 78, 34 ], [ 166, 277, 175, 34 ], [ 78, 324, 40, 16 ], [ 123, 324, 21, 16 ], [ 149, 321, 27, 19 ], [ 180, 324, 25, 16 ], [ 209, 324, 18, 16 ], [ 231, 321, 37, 19 ], [ 272, 324, 40, 16 ], [ 317, 321, 40, 19 ], [ 361, 324, 67, 16 ], [ 432, 321, 89, 19 ], [ 526, 324, 29, 16 ], [ 559, 321, 56, 19 ], [ 620, 324, 27, 16 ], [ 651, 324, 21, 16 ], [ 676, 324, 37, 16 ], [ 78, 343, 20, 16 ], [ 102, 340, 55, 19 ], [ 87, 397, 54, 15 ], [ 87, 423, 76, 14 ], [ 167, 423, 51, 14 ], [ 223, 423, 112, 14 ], [ 339, 423, 33, 14 ], [ 376, 423, 74, 14 ], [ 454, 423, 40, 14 ], [ 497, 423, 8, 14 ], [ 510, 423, 14, 14 ], [ 528, 423, 62, 14 ], [ 594, 423, 22, 14 ], [ 620, 423, 20, 14 ], [ 645, 423, 15, 14 ], [ 663, 423, 27, 14 ], [ 695, 423, 15, 14 ], [ 714, 423, 19, 14 ], [ 87, 439, 53, 14 ], [ 145, 439, 11, 14 ], [ 160, 439, 46, 14 ], [ 210, 439, 77, 14 ], [ 291, 439, 62, 14 ], [ 357, 439, 11, 14 ], [ 372, 439, 7, 14 ], [ 383, 439, 33, 14 ], [ 420, 439, 66, 14 ], [ 490, 439, 11, 14 ], [ 505, 439, 22, 14 ], [ 531, 439, 47, 14 ], [ 583, 439, 15, 14 ], [ 602, 439, 12, 14 ], [ 618, 439, 14, 14 ], [ 636, 439, 47, 14 ], [ 687, 439, 50, 14 ], [ 87, 456, 59, 14 ], [ 150, 456, 20, 14 ], [ 174, 456, 15, 14 ], [ 193, 456, 51, 14 ], [ 248, 456, 18, 14 ], [ 270, 456, 7, 14 ], [ 281, 456, 40, 14 ], [ 325, 456, 58, 14 ], [ 387, 456, 27, 14 ], [ 419, 456, 17, 14 ], [ 440, 456, 43, 14 ], [ 487, 456, 15, 14 ], [ 507, 456, 78, 14 ], [ 589, 456, 46, 14 ], [ 639, 456, 25, 14 ], [ 87, 472, 77, 14 ], [ 169, 472, 78, 14 ], [ 251, 472, 69, 14 ], [ 324, 472, 52, 14 ], [ 380, 472, 22, 14 ], [ 406, 472, 78, 14 ], [ 87, 493, 46, 14 ], [ 137, 493, 29, 14 ], [ 170, 493, 17, 14 ], [ 192, 493, 59, 14 ], [ 255, 493, 7, 14 ], [ 266, 493, 25, 14 ], [ 295, 493, 75, 14 ], [ 374, 493, 41, 14 ], [ 419, 493, 54, 14 ], [ 477, 493, 15, 14 ], [ 497, 493, 32, 14 ], [ 533, 493, 78, 14 ], [ 616, 493, 22, 14 ], [ 642, 493, 8, 14 ], [ 655, 493, 51, 14 ], [ 87, 510, 60, 14 ], [ 152, 510, 22, 14 ], [ 177, 510, 19, 14 ], [ 201, 510, 7, 14 ], [ 212, 510, 65, 14 ], [ 281, 510, 50, 14 ], [ 335, 510, 15, 14 ], [ 355, 510, 63, 14 ], [ 422, 510, 22, 14 ], [ 447, 510, 66, 14 ], [ 517, 510, 19, 14 ], [ 540, 510, 32, 14 ], [ 576, 510, 25, 14 ], [ 605, 510, 38, 14 ], [ 647, 510, 22, 14 ], [ 674, 510, 8, 14 ], [ 87, 526, 57, 14 ], [ 149, 526, 27, 14 ], [ 180, 526, 19, 14 ], [ 202, 526, 73, 14 ], [ 279, 526, 31, 14 ], [ 314, 526, 12, 14 ], [ 330, 526, 45, 14 ], [ 379, 526, 37, 14 ], [ 421, 526, 40, 14 ], [ 465, 526, 21, 14 ], [ 490, 526, 69, 14 ], [ 564, 526, 9, 14 ], [ 576, 526, 50, 14 ], [ 631, 526, 53, 14 ], [ 688, 526, 8, 14 ], [ 87, 543, 42, 14 ], [ 133, 543, 15, 14 ], [ 153, 543, 19, 14 ], [ 175, 543, 76, 14 ], [ 255, 543, 21, 14 ], [ 281, 543, 42, 14 ], [ 327, 543, 11, 14 ], [ 343, 543, 28, 14 ], [ 375, 543, 31, 14 ], [ 410, 543, 11, 14 ], [ 425, 543, 32, 14 ], [ 462, 543, 35, 14 ], [ 501, 543, 41, 14 ], [ 546, 543, 19, 14 ], [ 570, 543, 11, 14 ], [ 586, 543, 46, 14 ], [ 636, 543, 40, 14 ], [ 680, 543, 45, 14 ], [ 87, 560, 21, 14 ], [ 113, 560, 42, 14 ], [ 159, 560, 47, 14 ], [ 87, 580, 75, 14 ], [ 167, 580, 54, 14 ], [ 225, 580, 50, 14 ], [ 280, 580, 32, 14 ], [ 316, 580, 25, 14 ], [ 345, 580, 11, 14 ], [ 360, 580, 27, 14 ], [ 391, 580, 25, 14 ], [ 420, 580, 65, 14 ], [ 490, 580, 33, 14 ], [ 527, 580, 40, 14 ], [ 571, 580, 55, 14 ], [ 630, 580, 75, 14 ], [ 87, 597, 46, 14 ], [ 137, 597, 22, 14 ], [ 163, 597, 40, 14 ], [ 207, 597, 80, 14 ], [ 291, 597, 22, 14 ], [ 317, 597, 58, 14 ], [ 379, 597, 53, 14 ], [ 436, 597, 30, 14 ], [ 470, 597, 11, 14 ], [ 485, 597, 19, 14 ], [ 508, 597, 61, 14 ], [ 573, 597, 49, 14 ], [ 627, 597, 11, 14 ], [ 642, 597, 28, 14 ], [ 674, 597, 31, 14 ], [ 709, 597, 11, 14 ], [ 87, 614, 32, 14 ], [ 124, 614, 25, 14 ], [ 153, 614, 21, 14 ], [ 178, 614, 62, 14 ], [ 244, 614, 7, 14 ], [ 255, 614, 30, 14 ], [ 289, 614, 21, 14 ], [ 315, 614, 65, 14 ], [ 384, 614, 48, 14 ], [ 436, 614, 27, 14 ], [ 467, 614, 19, 14 ], [ 490, 614, 57, 14 ], [ 552, 614, 11, 14 ], [ 567, 614, 14, 14 ], [ 585, 614, 64, 14 ], [ 653, 614, 12, 14 ], [ 669, 614, 14, 14 ], [ 87, 630, 59, 14 ], [ 150, 630, 36, 14 ], [ 78, 676, 77, 15 ], [ 78, 693, 13, 14 ], [ 96, 693, 46, 14 ], [ 147, 693, 53, 14 ], [ 204, 693, 63, 14 ], [ 272, 693, 12, 14 ], [ 289, 693, 81, 14 ], [ 374, 693, 30, 14 ], [ 78, 710, 28, 14 ], [ 110, 710, 13, 14 ], [ 127, 710, 79, 14 ], [ 211, 710, 9, 14 ], [ 224, 710, 12, 14 ], [ 240, 710, 29, 14 ], [ 272, 710, 68, 14 ], [ 344, 710, 20, 14 ], [ 368, 710, 35, 14 ], [ 78, 726, 21, 14 ], [ 103, 726, 9, 14 ], [ 116, 726, 20, 14 ], [ 141, 726, 25, 14 ], [ 171, 726, 13, 14 ], [ 188, 726, 34, 14 ], [ 227, 726, 66, 14 ], [ 297, 726, 19, 14 ], [ 320, 726, 42, 14 ], [ 366, 726, 37, 14 ], [ 78, 743, 12, 14 ], [ 95, 743, 41, 14 ], [ 141, 743, 47, 14 ], [ 193, 743, 22, 14 ], [ 219, 743, 12, 14 ], [ 236, 743, 6, 14 ], [ 247, 743, 79, 14 ], [ 331, 743, 49, 14 ], [ 385, 743, 19, 14 ], [ 78, 760, 58, 14 ], [ 141, 760, 22, 14 ], [ 167, 760, 57, 14 ], [ 229, 760, 12, 14 ], [ 245, 760, 59, 14 ], [ 308, 760, 50, 14 ], [ 363, 760, 41, 14 ], [ 78, 776, 62, 14 ], [ 144, 776, 17, 14 ], [ 165, 776, 18, 14 ], [ 188, 776, 53, 14 ], [ 245, 776, 12, 14 ], [ 261, 776, 78, 14 ], [ 344, 776, 60, 14 ], [ 78, 793, 24, 14 ], [ 106, 793, 42, 14 ], [ 153, 793, 71, 14 ], [ 227, 793, 53, 14 ], [ 285, 793, 48, 14 ], [ 337, 793, 67, 14 ], [ 78, 810, 13, 14 ], [ 96, 810, 24, 14 ], [ 125, 810, 83, 14 ], [ 213, 810, 44, 14 ], [ 262, 810, 63, 14 ], [ 330, 810, 47, 14 ], [ 381, 810, 22, 14 ], [ 78, 826, 72, 14 ], [ 155, 826, 35, 14 ], [ 195, 826, 47, 14 ], [ 247, 826, 47, 14 ], [ 298, 826, 14, 14 ], [ 317, 826, 55, 14 ], [ 377, 826, 26, 14 ], [ 78, 843, 32, 14 ], [ 115, 843, 13, 14 ], [ 133, 843, 37, 14 ], [ 174, 843, 33, 14 ], [ 212, 843, 98, 14 ], [ 315, 843, 51, 14 ], [ 370, 843, 33, 14 ], [ 78, 859, 15, 14 ], [ 98, 859, 28, 14 ], [ 130, 859, 38, 14 ], [ 172, 859, 26, 14 ], [ 202, 859, 35, 14 ], [ 241, 859, 21, 14 ], [ 266, 859, 40, 14 ], [ 310, 859, 62, 14 ], [ 377, 859, 27, 14 ], [ 78, 876, 39, 14 ], [ 122, 876, 71, 14 ], [ 197, 876, 30, 14 ], [ 232, 876, 56, 14 ], [ 292, 876, 31, 14 ], [ 328, 876, 18, 14 ], [ 351, 876, 53, 14 ], [ 78, 892, 29, 14 ], [ 112, 892, 17, 14 ], [ 134, 892, 35, 14 ], [ 174, 892, 47, 14 ], [ 226, 892, 50, 14 ], [ 280, 892, 31, 14 ], [ 316, 892, 64, 14 ], [ 385, 892, 19, 14 ], [ 78, 937, 5, 11 ], [ 86, 937, 70, 11 ], [ 159, 937, 73, 11 ], [ 78, 948, 54, 13 ], [ 136, 950, 9, 11 ], [ 147, 950, 44, 11 ], [ 194, 950, 28, 11 ], [ 226, 950, 41, 11 ], [ 270, 950, 33, 11 ], [ 305, 950, 30, 11 ], [ 338, 950, 30, 11 ], [ 371, 950, 16, 11 ], [ 78, 962, 50, 11 ], [ 423, 677, 62, 14 ], [ 491, 677, 105, 14 ], [ 603, 677, 49, 14 ], [ 659, 677, 13, 14 ], [ 678, 677, 70, 14 ], [ 423, 693, 55, 14 ], [ 482, 693, 21, 14 ], [ 507, 693, 48, 14 ], [ 559, 693, 28, 14 ], [ 591, 693, 24, 14 ], [ 619, 693, 24, 14 ], [ 648, 693, 23, 14 ], [ 675, 693, 73, 14 ], [ 423, 710, 21, 14 ], [ 448, 710, 78, 14 ], [ 530, 710, 11, 14 ], [ 546, 710, 26, 14 ], [ 576, 710, 66, 14 ], [ 647, 710, 24, 14 ], [ 675, 710, 9, 14 ], [ 688, 710, 19, 14 ], [ 712, 710, 7, 14 ], [ 722, 710, 26, 14 ], [ 423, 726, 26, 14 ], [ 453, 726, 56, 14 ], [ 514, 726, 113, 14 ], [ 631, 726, 34, 14 ], [ 669, 726, 79, 14 ], [ 423, 743, 49, 14 ], [ 476, 743, 17, 14 ], [ 498, 743, 20, 14 ], [ 522, 743, 28, 14 ], [ 556, 743, 65, 14 ], [ 626, 743, 12, 14 ], [ 643, 743, 7, 14 ], [ 654, 743, 54, 14 ], [ 713, 743, 35, 14 ], [ 423, 760, 22, 14 ], [ 449, 760, 21, 14 ], [ 475, 760, 45, 14 ], [ 524, 760, 12, 14 ], [ 541, 760, 48, 14 ], [ 593, 760, 70, 14 ], [ 668, 760, 80, 14 ], [ 423, 776, 48, 14 ], [ 478, 776, 12, 14 ], [ 496, 776, 16, 14 ], [ 519, 776, 13, 14 ], [ 538, 776, 35, 14 ], [ 580, 776, 15, 14 ], [ 601, 776, 53, 14 ], [ 660, 776, 32, 14 ], [ 698, 776, 13, 14 ], [ 718, 776, 30, 14 ], [ 423, 793, 61, 14 ], [ 488, 793, 34, 14 ], [ 526, 793, 9, 14 ], [ 540, 793, 23, 14 ], [ 568, 793, 12, 14 ], [ 584, 793, 62, 14 ], [ 650, 793, 58, 14 ], [ 712, 793, 36, 14 ], [ 423, 810, 18, 14 ], [ 446, 810, 12, 14 ], [ 462, 810, 25, 14 ], [ 491, 810, 21, 14 ], [ 517, 810, 64, 14 ], [ 586, 810, 26, 14 ], [ 617, 810, 58, 14 ], [ 679, 810, 21, 14 ], [ 704, 810, 19, 14 ], [ 727, 810, 21, 14 ], [ 423, 826, 48, 14 ], [ 475, 826, 18, 14 ], [ 497, 826, 50, 14 ], [ 551, 826, 23, 14 ], [ 579, 826, 61, 14 ], [ 644, 826, 6, 14 ], [ 655, 826, 33, 14 ], [ 692, 826, 30, 14 ], [ 727, 826, 21, 14 ], [ 423, 843, 18, 14 ], [ 445, 843, 61, 14 ], [ 510, 843, 23, 14 ], [ 537, 843, 62, 14 ], [ 603, 843, 58, 14 ], [ 665, 843, 11, 14 ], [ 681, 843, 24, 14 ], [ 434, 859, 38, 14 ], [ 476, 859, 9, 14 ], [ 489, 859, 7, 14 ], [ 499, 859, 31, 14 ], [ 535, 859, 21, 14 ], [ 560, 859, 23, 14 ], [ 587, 859, 47, 14 ], [ 638, 859, 53, 14 ], [ 694, 859, 12, 14 ], [ 710, 859, 38, 14 ], [ 423, 876, 17, 14 ], [ 444, 876, 19, 14 ], [ 467, 876, 51, 14 ], [ 523, 876, 12, 14 ], [ 539, 876, 27, 14 ], [ 570, 876, 52, 14 ], [ 627, 876, 13, 14 ], [ 645, 876, 55, 14 ], [ 704, 876, 44, 14 ], [ 423, 892, 46, 14 ], [ 474, 892, 16, 14 ], [ 495, 892, 51, 14 ], [ 552, 892, 22, 14 ], [ 579, 892, 12, 14 ], [ 597, 892, 6, 14 ], [ 608, 892, 36, 14 ], [ 649, 892, 30, 14 ], [ 685, 892, 36, 14 ], [ 727, 892, 21, 14 ], [ 423, 909, 32, 14 ], [ 460, 909, 14, 14 ], [ 478, 909, 43, 14 ], [ 525, 909, 12, 14 ], [ 542, 909, 58, 14 ], [ 605, 909, 61, 14 ], [ 670, 909, 78, 14 ], [ 423, 926, 38, 14 ], [ 465, 926, 25, 14 ], [ 495, 926, 47, 14 ], [ 546, 926, 31, 14 ], [ 580, 926, 50, 14 ], [ 635, 926, 12, 14 ], [ 651, 926, 34, 14 ], [ 689, 926, 60, 14 ], [ 423, 942, 31, 14 ], [ 458, 942, 51, 14 ], [ 514, 942, 29, 14 ], [ 548, 942, 51, 14 ], [ 603, 942, 29, 14 ], [ 637, 942, 46, 14 ], [ 687, 942, 61, 14 ], [ 423, 959, 48, 14 ], [ 476, 959, 21, 14 ], [ 501, 959, 14, 14 ], [ 519, 959, 30, 14 ], [ 554, 959, 60, 14 ], [ 619, 959, 39, 14 ], [ 662, 959, 10, 14 ], [ 676, 959, 27, 14 ], [ 708, 959, 17, 14 ], [ 729, 959, 19, 14 ], [ 248, 987, 7, 10 ], [ 256, 987, 18, 10 ], [ 276, 987, 14, 10 ], [ 292, 987, 13, 10 ], [ 307, 987, 8, 10 ], [ 316, 987, 8, 10 ], [ 326, 987, 30, 10 ], [ 359, 987, 29, 10 ], [ 390, 987, 27, 10 ], [ 419, 987, 14, 10 ], [ 435, 987, 15, 10 ], [ 452, 987, 6, 10 ], [ 459, 987, 10, 10 ], [ 471, 987, 21, 10 ], [ 494, 987, 25, 10 ], [ 521, 987, 23, 10 ], [ 546, 987, 41, 10 ], [ 589, 987, 23, 10 ], [ 614, 987, 13, 10 ], [ 628, 987, 22, 10 ], [ 652, 987, 8, 10 ], [ 662, 987, 13, 10 ], [ 676, 987, 31, 10 ], [ 709, 987, 39, 10 ], [ 248, 998, 41, 10 ], [ 291, 998, 28, 10 ], [ 322, 998, 171, 10 ], [ 496, 998, 23, 10 ], [ 522, 998, 29, 10 ], [ 553, 998, 45, 10 ], [ 601, 998, 15, 10 ], [ 618, 998, 45, 10 ], [ 666, 998, 15, 10 ], [ 683, 998, 49, 10 ], [ 736, 998, 7, 10 ], [ 248, 1009, 14, 10 ], [ 264, 1009, 34, 10 ], [ 300, 1009, 34, 10 ], [ 337, 1009, 13, 10 ], [ 352, 1009, 28, 10 ], [ 384, 1009, 19, 10 ], [ 405, 1009, 6, 10 ], [ 414, 1009, 32, 10 ], [ 448, 1009, 21, 10 ] ]

[ "van", "Eijk", "et", "al.", "BMC", "Bioinformatics", "2010,", "11:67", "http://www.biomedcentral.com/1471-2105/11/67", "S", "O", "F", "T", "W", "A", "R", "E", "Open", "Access", "MLPAinter", "for", "MLPA", "interpretation:", "an", "integrated", "approach", "for", "the", "analysis,", "visualisation", "and", "data", "management", "of", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "Ronald", "van", "Eijk1,", "Paul", "HC", "Eilers2,", "Remco", "Natté1,", "Anne-Marie", "Cleton-Jansen1,", "Hans", "Morreau1,", "Tom", "van", "Wezel,", "Jan", "Oosting1*", "Abstract", "Background:", "Multiplex", "Ligation-Dependent", "Probe", "Amplification", "(MLPA)", "is", "an", "application", "that", "can", "be", "used", "for", "the", "detection", "of", "multiple", "chromosomal", "aberrations", "in", "a", "single", "experiment.", "In", "one", "reaction,", "up", "to", "50", "different", "genomic", "sequences", "can", "be", "analysed.", "For", "a", "reliable", "work-flow,", "tools", "are", "needed", "for", "administrative", "support,", "data", "management,", "normalisation,", "visualisation,", "reporting", "and", "interpretation.", "Results:", "Here,", "we", "developed", "a", "data", "management", "system,", "MLPAInter", "for", "MLPA", "interpretation,", "that", "is", "windows", "executable", "and", "has", "a", "stand-alone", "database", "for", "monitoring", "and", "interpreting", "the", "MLPA", "data", "stream", "that", "is", "generated", "from", "the", "experimental", "setup", "to", "analysis,", "quality", "control", "and", "visualisation.", "A", "statistical", "approach", "is", "applied", "for", "the", "normalisation", "and", "analysis", "of", "large", "series", "of", "MLPA", "traces,", "making", "use", "of", "multiple", "control", "samples", "and", "internal", "controls.", "Conclusions:", "MLPAinter", "visualises", "MLPA", "data", "in", "plots", "with", "information", "about", "sample", "replicates,", "normalisation", "settings,", "and", "sample", "characteristics.", "This", "integrated", "approach", "helps", "in", "the", "automated", "handling", "of", "large", "series", "of", "MLPA", "data", "and", "guarantees", "a", "quick", "and", "streamlined", "dataflow", "from", "the", "beginning", "of", "an", "experiment", "to", "an", "authorised", "report.", "Background", "In", "medical", "research,", "knowledge", "of", "chromosomal", "dele-", "tions", "or", "amplifications", "is", "of", "great", "importance.", "For", "exam-", "ple,", "it", "can", "help", "us", "better", "understand", "the", "genetic", "causes", "of", "certain", "diseases", "and", "as", "a", "consequence,", "improve", "the", "treatment", "and", "prognosis", "of", "individual", "patients.", "Classic", "techniques", "for", "the", "detection", "of", "chromosomal", "abnormal-", "ities", "include", "karyotyping,", "Southern", "blotting,", "Fluorescent", "In", "Situ", "Hybridisation", "(FISH),", "CA-repeat", "analysis", "and", "quantitative", "micro", "satellite", "analysis", "by", "real-time", "PCR", "[1-4].", "In", "recent", "years,", "high-throughput", "methods", "based", "on", "BAC", "arrays,", "SNP", "arrays", "and", "related", "techniques", "have", "gained", "prominence", "[5,6].", "Although", "these", "are", "excellent", "tools", "for", "whole", "genome", "analysis,", "these", "techniques", "are", "*", "Correspondence:", "j.oosting@lumc.nl", "1Department", "of", "Pathology,", "Leiden", "University", "Medical", "Center,", "Leiden,", "The", "Netherlands", "laborious,", "time-consuming,", "difficult", "to", "implement,", "expensive", "and", "generate", "large", "data", "sets.", "The", "management", "and", "interpretation", "of", "such", "voluminous", "data", "is", "not", "a", "light", "task.", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "(MLPA)", "[7]", "has", "been", "introduced", "as", "a", "relatively", "cheap", "and", "fast", "method", "to", "perform", "quantitative", "chromosomal", "analysis", "of", "up", "to", "about", "50", "genomic", "DNA", "or", "RNA", "sequences,", "which", "is", "able", "to", "distinguish", "sequences", "differ-", "ing", "in", "only", "one", "nucleotide.", "This", "technique", "fills", "the", "gap", "between", "the", "methods", "that", "investigate", "a", "single", "locus", "and", "the", "techniques", "that", "interrogate", "thousands", "of", "loci.", "MLPA", "is", "a", "quick", "and", "cost", "effective", "approach", "to", "testing", "for", "the", "presence", "of", "gene", "deletions", "or", "obtaining", "tumour", "profiles", "on", "multiple", "loci", "in", "a", "single", "tube,", "which", "can", "easily", "be", "applied", "in", "molecular", "pathology.", "Furthermore,", "MLPA", "only", "requires", "small", "amounts", "of", "DNA.", "Moreover,", "DNA", "obtained", "from", "formalin", "fixed", "paraffin", "embedded", "material", "can", "be", "used.", "Currently,", "MLPA", "is", "used", "for", "the", "©", "2010", "van", "Eijk", "et", "al;", "licensee", "BioMed", "Central", "Ltd.", "This", "is", "an", "Open", "Access", "article", "distributed", "under", "the", "terms", "of", "the", "Creative", "Commons", "Attribution", "License", "(http://creativecommons.org/licenses/by/2.0),", "which", "permits", "unrestricted", "use,", "distribution,", "and", "reproduction", "in", "any", "medium,", "provided", "the", "original", "work", "is", "properly", "cited." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 16, 16, 16, 16, 16, 16, 16, 16, 9, 9, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 ]