id
string
29.1k
3.5M
tokens
sequence
bboxes
sequence
ner_tags
sequence
image
image
2315648
[ "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)" ]
[ [ 76, 47, 160, 81 ], [ 172, 47, 405, 81 ], [ 417, 47, 556, 81 ], [ 76, 118, 146, 138 ], [ 151, 118, 197, 138 ], [ 76, 143, 177, 166 ], [ 182, 143, 220, 166 ], [ 226, 143, 357, 166 ], [ 363, 143, 383, 166 ], [ 389, 143, 502, 166 ], [ 507, 143, 690, 166 ], [ 76, 168, 172, 191 ], [ 178, 168, 243, 191 ], [ 249, 168, 379, 191 ], [ 385, 168, 457, 191 ], [ 464, 168, 484, 191 ], [ 490, 168, 525, 191 ], [ 530, 168, 641, 191 ], [ 76, 193, 259, 216 ], [ 265, 193, 361, 216 ], [ 366, 193, 416, 216 ], [ 422, 193, 475, 216 ], [ 76, 218, 172, 239 ], [ 177, 218, 241, 240 ], [ 246, 218, 295, 239 ], [ 300, 218, 312, 239 ], [ 316, 218, 416, 240 ], [ 421, 218, 486, 239 ], [ 491, 218, 571, 240 ], [ 576, 218, 611, 239 ], [ 76, 243, 150, 264 ], [ 155, 243, 267, 265 ], [ 706, 60, 759, 74 ], [ 761, 60, 798, 74 ], [ 697, 118, 741, 134 ], [ 745, 118, 807, 134 ], [ 76, 293, 117, 305 ], [ 119, 293, 164, 305 ], [ 166, 293, 176, 305 ], [ 179, 293, 228, 305 ], [ 230, 293, 249, 305 ], [ 251, 293, 271, 305 ], [ 274, 293, 314, 305 ], [ 316, 293, 355, 305 ], [ 357, 293, 396, 305 ], [ 399, 293, 413, 305 ], [ 415, 293, 454, 305 ], [ 456, 293, 512, 305 ], [ 515, 293, 534, 305 ], [ 536, 293, 586, 305 ], [ 589, 293, 632, 305 ], [ 634, 293, 674, 305 ], [ 677, 293, 725, 305 ], [ 731, 293, 750, 305 ], [ 76, 306, 126, 318 ], [ 128, 306, 170, 317 ], [ 173, 306, 213, 317 ], [ 215, 306, 224, 317 ], [ 227, 306, 265, 317 ], [ 268, 306, 304, 317 ], [ 306, 306, 341, 317 ], [ 343, 306, 402, 317 ], [ 404, 306, 438, 317 ], [ 441, 306, 462, 317 ], [ 76, 326, 107, 338 ], [ 110, 326, 161, 338 ], [ 164, 326, 191, 338 ], [ 193, 326, 197, 338 ], [ 200, 326, 336, 338 ], [ 338, 326, 364, 338 ], [ 366, 326, 372, 338 ], [ 375, 326, 421, 338 ], [ 424, 326, 428, 338 ], [ 430, 326, 595, 338 ], [ 76, 339, 111, 350 ], [ 113, 339, 151, 350 ], [ 154, 339, 158, 350 ], [ 160, 339, 310, 350 ], [ 313, 339, 353, 350 ], [ 355, 339, 411, 350 ], [ 413, 339, 417, 350 ], [ 419, 339, 550, 350 ], [ 76, 355, 83, 367 ], [ 85, 355, 158, 367 ], [ 160, 355, 193, 367 ], [ 76, 414, 121, 426 ], [ 124, 414, 136, 426 ], [ 138, 414, 167, 426 ], [ 170, 414, 193, 426 ], [ 76, 434, 97, 445 ], [ 100, 434, 151, 445 ], [ 153, 434, 182, 445 ], [ 185, 434, 210, 445 ], [ 213, 434, 233, 446 ], [ 245, 434, 373, 445 ], [ 76, 454, 96, 465 ], [ 98, 454, 126, 465 ], [ 129, 454, 136, 465 ], [ 139, 454, 177, 465 ], [ 179, 454, 204, 465 ], [ 207, 454, 422, 465 ], [ 430, 414, 473, 426 ], [ 476, 414, 488, 426 ], [ 490, 414, 523, 426 ], [ 525, 414, 548, 426 ], [ 430, 427, 476, 438 ], [ 478, 427, 489, 438 ], [ 492, 427, 521, 438 ], [ 523, 427, 546, 438 ], [ 76, 473, 85, 485 ], [ 87, 473, 110, 485 ], [ 113, 473, 140, 485 ], [ 143, 473, 153, 485 ], [ 155, 473, 165, 485 ], [ 167, 473, 203, 485 ], [ 206, 473, 241, 485 ], [ 244, 473, 278, 485 ], [ 281, 473, 299, 485 ], [ 76, 487, 96, 499 ], [ 98, 487, 105, 499 ], [ 108, 487, 119, 499 ], [ 121, 487, 147, 499 ], [ 150, 487, 182, 499 ], [ 184, 487, 212, 499 ], [ 215, 487, 264, 499 ], [ 267, 487, 294, 499 ], [ 296, 487, 311, 499 ], [ 314, 487, 341, 499 ], [ 343, 487, 353, 499 ], [ 355, 487, 370, 499 ], [ 373, 487, 412, 499 ], [ 415, 487, 463, 499 ], [ 465, 487, 516, 499 ], [ 519, 487, 553, 499 ], [ 555, 487, 757, 499 ], [ 76, 500, 103, 512 ], [ 106, 500, 141, 512 ], [ 143, 500, 199, 512 ], [ 201, 500, 219, 512 ], [ 222, 500, 277, 512 ], [ 279, 500, 295, 512 ], [ 298, 500, 358, 512 ], [ 361, 500, 369, 512 ], [ 372, 500, 388, 512 ], [ 390, 500, 429, 512 ], [ 432, 500, 472, 512 ], [ 475, 500, 490, 512 ], [ 493, 500, 527, 512 ], [ 529, 500, 553, 512 ], [ 556, 500, 563, 512 ], [ 565, 500, 604, 512 ], [ 607, 500, 632, 512 ], [ 115, 560, 176, 575 ], [ 115, 581, 195, 595 ], [ 204, 581, 226, 595 ], [ 235, 581, 297, 595 ], [ 306, 581, 403, 595 ], [ 411, 581, 470, 595 ], [ 480, 581, 544, 595 ], [ 552, 581, 572, 595 ], [ 581, 581, 629, 595 ], [ 638, 581, 656, 595 ], [ 665, 581, 711, 595 ], [ 720, 581, 730, 595 ], [ 115, 597, 201, 611 ], [ 205, 597, 225, 611 ], [ 229, 597, 269, 611 ], [ 272, 597, 314, 611 ], [ 318, 597, 356, 611 ], [ 360, 597, 424, 611 ], [ 427, 597, 495, 611 ], [ 499, 597, 515, 611 ], [ 518, 597, 550, 611 ], [ 554, 597, 617, 611 ], [ 621, 597, 662, 611 ], [ 665, 597, 676, 611 ], [ 680, 597, 705, 611 ], [ 709, 597, 730, 611 ], [ 115, 614, 164, 628 ], [ 170, 614, 195, 628 ], [ 202, 614, 213, 628 ], [ 220, 614, 284, 628 ], [ 290, 614, 310, 628 ], [ 316, 614, 364, 628 ], [ 370, 614, 416, 628 ], [ 423, 614, 462, 628 ], [ 468, 614, 531, 628 ], [ 537, 614, 577, 628 ], [ 584, 614, 590, 628 ], [ 597, 614, 628, 628 ], [ 633, 614, 730, 628 ], [ 115, 630, 166, 644 ], [ 169, 630, 200, 644 ], [ 203, 630, 258, 644 ], [ 261, 630, 283, 644 ], [ 285, 630, 349, 644 ], [ 351, 630, 400, 644 ], [ 402, 630, 412, 644 ], [ 415, 630, 502, 644 ], [ 504, 630, 567, 644 ], [ 570, 630, 579, 644 ], [ 581, 630, 636, 644 ], [ 639, 630, 659, 644 ], [ 661, 630, 679, 644 ], [ 682, 630, 730, 644 ], [ 115, 646, 164, 660 ], [ 168, 646, 177, 660 ], [ 180, 646, 238, 660 ], [ 241, 646, 251, 660 ], [ 255, 646, 333, 660 ], [ 336, 646, 392, 660 ], [ 396, 646, 454, 660 ], [ 457, 646, 477, 660 ], [ 481, 646, 573, 660 ], [ 576, 646, 586, 660 ], [ 590, 646, 646, 660 ], [ 649, 646, 669, 660 ], [ 673, 646, 717, 660 ], [ 720, 646, 730, 660 ], [ 115, 663, 170, 677 ], [ 174, 663, 208, 677 ], [ 210, 663, 232, 677 ], [ 235, 663, 266, 677 ], [ 269, 663, 319, 677 ], [ 322, 663, 386, 677 ], [ 388, 663, 408, 677 ], [ 411, 663, 459, 677 ], [ 463, 663, 494, 677 ], [ 497, 663, 515, 677 ], [ 518, 663, 555, 677 ], [ 559, 663, 592, 677 ], [ 595, 663, 605, 677 ], [ 608, 663, 626, 677 ], [ 629, 663, 666, 677 ], [ 669, 663, 689, 677 ], [ 692, 663, 730, 677 ], [ 115, 679, 164, 693 ], [ 167, 679, 177, 693 ], [ 180, 679, 186, 693 ], [ 189, 679, 243, 693 ], [ 246, 679, 311, 693 ], [ 313, 679, 324, 693 ], [ 326, 679, 375, 693 ], [ 378, 679, 405, 693 ], [ 407, 679, 458, 693 ], [ 461, 679, 515, 693 ], [ 518, 679, 575, 693 ], [ 578, 679, 598, 693 ], [ 600, 679, 648, 693 ], [ 651, 679, 669, 693 ], [ 672, 679, 712, 693 ], [ 715, 679, 730, 693 ], [ 115, 695, 133, 709 ], [ 140, 695, 168, 709 ], [ 174, 695, 209, 709 ], [ 215, 695, 226, 709 ], [ 232, 695, 262, 709 ], [ 268, 695, 292, 709 ], [ 299, 695, 343, 709 ], [ 348, 695, 374, 709 ], [ 380, 695, 420, 709 ], [ 427, 695, 479, 709 ], [ 484, 695, 495, 709 ], [ 502, 695, 554, 709 ], [ 560, 695, 586, 709 ], [ 592, 695, 646, 709 ], [ 652, 695, 665, 709 ], [ 671, 695, 690, 709 ], [ 696, 695, 730, 709 ], [ 115, 712, 171, 726 ], [ 175, 712, 197, 726 ], [ 201, 712, 221, 726 ], [ 225, 712, 254, 726 ], [ 257, 712, 275, 726 ], [ 280, 712, 348, 726 ], [ 351, 712, 438, 726 ], [ 442, 712, 452, 726 ], [ 456, 712, 489, 726 ], [ 493, 712, 555, 726 ], [ 559, 712, 572, 726 ], [ 576, 712, 631, 726 ], [ 635, 712, 654, 726 ], [ 658, 712, 699, 726 ], [ 703, 712, 716, 726 ], [ 720, 712, 730, 726 ], [ 115, 728, 141, 742 ], [ 145, 728, 191, 742 ], [ 194, 728, 216, 742 ], [ 219, 728, 283, 742 ], [ 287, 728, 326, 742 ], [ 329, 728, 335, 742 ], [ 339, 728, 376, 742 ], [ 379, 728, 448, 742 ], [ 452, 728, 497, 742 ], [ 500, 728, 529, 742 ], [ 532, 728, 544, 742 ], [ 548, 728, 566, 742 ], [ 569, 728, 629, 742 ], [ 632, 728, 643, 742 ], [ 647, 728, 665, 742 ], [ 668, 728, 730, 742 ], [ 115, 744, 135, 758 ], [ 139, 744, 194, 758 ], [ 197, 744, 216, 758 ], [ 219, 744, 265, 758 ], [ 115, 767, 164, 781 ], [ 176, 768, 197, 782 ], [ 208, 768, 233, 782 ], [ 245, 768, 303, 782 ], [ 314, 768, 320, 782 ], [ 331, 768, 390, 782 ], [ 401, 768, 453, 782 ], [ 465, 768, 535, 782 ], [ 546, 768, 573, 782 ], [ 584, 768, 614, 782 ], [ 625, 768, 701, 782 ], [ 712, 768, 730, 782 ], [ 115, 784, 211, 798 ], [ 216, 784, 267, 798 ], [ 271, 784, 302, 798 ], [ 305, 784, 325, 798 ], [ 329, 784, 394, 798 ], [ 398, 784, 416, 798 ], [ 420, 784, 489, 798 ], [ 492, 784, 531, 798 ], [ 535, 784, 546, 798 ], [ 550, 784, 568, 798 ], [ 572, 784, 630, 798 ], [ 633, 784, 730, 798 ], [ 115, 800, 166, 814 ], [ 174, 800, 200, 814 ], [ 207, 800, 236, 814 ], [ 243, 800, 277, 814 ], [ 284, 800, 290, 814 ], [ 298, 800, 366, 814 ], [ 373, 800, 424, 814 ], [ 431, 800, 495, 814 ], [ 502, 800, 524, 814 ], [ 531, 800, 590, 814 ], [ 598, 800, 644, 814 ], [ 650, 800, 702, 814 ], [ 710, 800, 730, 814 ], [ 115, 816, 173, 830 ], [ 177, 816, 208, 830 ], [ 211, 816, 230, 830 ], [ 234, 816, 321, 830 ], [ 325, 816, 381, 830 ], [ 385, 816, 407, 830 ], [ 410, 816, 469, 830 ], [ 473, 816, 504, 830 ], [ 507, 816, 525, 830 ], [ 529, 816, 571, 830 ], [ 575, 816, 590, 830 ], [ 593, 816, 611, 830 ], [ 615, 816, 643, 830 ], [ 647, 816, 682, 830 ], [ 685, 816, 696, 830 ], [ 700, 816, 730, 830 ], [ 115, 833, 139, 847 ], [ 146, 833, 161, 847 ], [ 167, 833, 228, 847 ], [ 235, 833, 269, 847 ], [ 275, 833, 299, 847 ], [ 306, 833, 324, 847 ], [ 331, 833, 383, 847 ], [ 390, 833, 416, 847 ], [ 422, 833, 462, 847 ], [ 469, 833, 521, 847 ], [ 527, 833, 538, 847 ], [ 545, 833, 563, 847 ], [ 569, 833, 627, 847 ], [ 633, 833, 662, 847 ], [ 669, 833, 730, 847 ], [ 115, 849, 171, 863 ], [ 175, 849, 186, 863 ], [ 189, 849, 207, 863 ], [ 210, 849, 249, 863 ], [ 252, 849, 285, 863 ], [ 288, 849, 299, 863 ], [ 302, 849, 320, 863 ], [ 324, 849, 346, 863 ], [ 349, 849, 380, 863 ], [ 383, 849, 401, 863 ], [ 404, 849, 437, 863 ], [ 439, 849, 486, 863 ], [ 489, 849, 538, 863 ], [ 541, 849, 586, 863 ], [ 589, 849, 595, 863 ], [ 599, 849, 656, 863 ], [ 658, 849, 706, 863 ], [ 709, 849, 730, 863 ], [ 115, 865, 140, 879 ], [ 144, 865, 166, 879 ], [ 170, 865, 217, 879 ], [ 220, 865, 238, 879 ], [ 241, 865, 337, 879 ], [ 341, 865, 392, 879 ], [ 396, 865, 422, 879 ], [ 425, 865, 454, 879 ], [ 457, 865, 467, 879 ], [ 471, 865, 489, 879 ], [ 493, 865, 542, 879 ], [ 545, 865, 556, 879 ], [ 560, 865, 613, 879 ], [ 616, 865, 658, 879 ], [ 661, 865, 681, 879 ], [ 685, 865, 731, 879 ], [ 115, 882, 163, 896 ], [ 169, 882, 191, 896 ], [ 195, 882, 245, 896 ], [ 250, 882, 296, 896 ], [ 301, 882, 323, 896 ], [ 328, 882, 369, 896 ], [ 374, 882, 409, 896 ], [ 415, 882, 426, 896 ], [ 431, 882, 495, 896 ], [ 499, 882, 519, 896 ], [ 524, 882, 582, 896 ], [ 587, 882, 621, 896 ], [ 626, 882, 648, 896 ], [ 653, 882, 705, 896 ], [ 710, 882, 730, 896 ], [ 115, 898, 173, 912 ], [ 176, 898, 207, 912 ], [ 210, 898, 220, 912 ], [ 223, 898, 265, 912 ], [ 268, 898, 288, 912 ], [ 291, 898, 340, 912 ], [ 342, 898, 362, 912 ], [ 365, 898, 383, 912 ], [ 386, 898, 450, 912 ], [ 453, 898, 473, 912 ], [ 475, 898, 533, 912 ], [ 536, 898, 567, 912 ], [ 570, 898, 580, 912 ], [ 583, 898, 633, 912 ], [ 636, 898, 654, 912 ], [ 657, 898, 690, 912 ], [ 693, 898, 730, 912 ], [ 115, 914, 141, 928 ], [ 145, 914, 181, 928 ], [ 184, 914, 196, 928 ], [ 200, 914, 227, 928 ], [ 230, 914, 283, 928 ], [ 287, 914, 297, 928 ], [ 300, 914, 359, 928 ], [ 362, 914, 382, 928 ], [ 385, 914, 418, 928 ], [ 422, 914, 448, 928 ], [ 451, 914, 505, 928 ], [ 509, 914, 519, 928 ], [ 522, 914, 559, 928 ], [ 562, 914, 582, 928 ], [ 586, 914, 632, 928 ], [ 115, 938, 189, 952 ], [ 193, 938, 217, 952 ], [ 220, 938, 257, 952 ], [ 260, 938, 303, 952 ], [ 306, 938, 328, 952 ], [ 332, 938, 350, 952 ], [ 353, 938, 449, 952 ], [ 453, 938, 504, 952 ], [ 508, 938, 534, 952 ], [ 537, 938, 566, 952 ], [ 569, 938, 587, 952 ], [ 591, 938, 659, 952 ], [ 662, 938, 730, 952 ], [ 115, 954, 202, 968 ], [ 205, 954, 215, 968 ], [ 218, 954, 244, 968 ], [ 247, 954, 295, 968 ], [ 299, 954, 350, 968 ], [ 353, 954, 373, 968 ], [ 376, 954, 414, 968 ], [ 417, 954, 450, 968 ], [ 454, 954, 476, 968 ], [ 479, 954, 538, 968 ], [ 540, 954, 584, 968 ], [ 587, 954, 630, 968 ], [ 633, 954, 645, 968 ], [ 648, 954, 662, 968 ], [ 665, 954, 695, 968 ], [ 698, 954, 730, 968 ], [ 115, 970, 139, 984 ], [ 143, 970, 205, 984 ], [ 208, 970, 228, 984 ], [ 231, 970, 269, 984 ], [ 272, 970, 291, 984 ], [ 294, 970, 346, 984 ], [ 350, 970, 365, 984 ], [ 367, 970, 395, 984 ], [ 399, 970, 407, 984 ], [ 410, 970, 445, 984 ], [ 448, 970, 459, 984 ], [ 463, 970, 469, 984 ], [ 472, 970, 516, 984 ], [ 519, 970, 570, 984 ], [ 574, 970, 591, 984 ], [ 594, 970, 639, 984 ], [ 642, 970, 660, 984 ], [ 664, 970, 716, 984 ], [ 719, 970, 730, 984 ], [ 115, 987, 177, 1001 ], [ 180, 987, 200, 1001 ], [ 204, 987, 242, 1001 ], [ 245, 987, 264, 1001 ], [ 267, 987, 319, 1001 ], [ 698, 1052, 728, 1065 ], [ 731, 1052, 738, 1065 ], [ 741, 1052, 752, 1065 ], [ 755, 1052, 769, 1065 ], [ 599, 1070, 624, 1080 ], [ 627, 1070, 660, 1080 ], [ 662, 1070, 676, 1080 ], [ 678, 1070, 690, 1080 ], [ 692, 1070, 723, 1080 ], [ 726, 1070, 770, 1080 ] ]
[ 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 ]
2994856
[ "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." ]
[ [ 78, 47, 97, 59 ], [ 100, 47, 109, 59 ], [ 113, 47, 124, 59 ], [ 127, 47, 148, 59 ], [ 150, 47, 180, 59 ], [ 184, 47, 219, 59 ], [ 222, 47, 262, 59 ], [ 265, 47, 290, 59 ], [ 293, 47, 325, 59 ], [ 78, 61, 311, 73 ], [ 83, 128, 93, 146 ], [ 95, 128, 105, 146 ], [ 106, 128, 119, 146 ], [ 121, 128, 134, 146 ], [ 135, 128, 146, 146 ], [ 154, 128, 165, 146 ], [ 166, 128, 177, 146 ], [ 178, 128, 191, 146 ], [ 193, 128, 203, 146 ], [ 205, 128, 218, 146 ], [ 220, 128, 231, 146 ], [ 232, 128, 245, 146 ], [ 247, 128, 257, 146 ], [ 641, 128, 685, 146 ], [ 691, 128, 744, 146 ], [ 78, 169, 165, 203 ], [ 175, 169, 202, 203 ], [ 212, 169, 370, 203 ], [ 380, 169, 523, 203 ], [ 533, 169, 566, 203 ], [ 576, 169, 735, 203 ], [ 78, 216, 123, 232 ], [ 128, 216, 136, 232 ], [ 140, 213, 176, 232 ], [ 180, 216, 219, 232 ], [ 224, 216, 233, 232 ], [ 237, 213, 290, 232 ], [ 295, 216, 329, 232 ], [ 333, 216, 341, 232 ], [ 345, 213, 412, 232 ], [ 416, 216, 444, 232 ], [ 449, 216, 459, 232 ], [ 463, 213, 499, 232 ], [ 503, 216, 533, 232 ], [ 538, 216, 547, 232 ], [ 551, 213, 589, 232 ], [ 87, 270, 141, 285 ], [ 87, 295, 163, 309 ], [ 167, 295, 216, 309 ], [ 220, 295, 280, 309 ], [ 284, 295, 350, 309 ], [ 355, 295, 374, 309 ], [ 378, 295, 428, 309 ], [ 432, 295, 444, 309 ], [ 448, 295, 499, 309 ], [ 503, 295, 522, 309 ], [ 526, 295, 582, 309 ], [ 587, 295, 654, 309 ], [ 658, 295, 673, 309 ], [ 87, 312, 172, 326 ], [ 177, 312, 198, 326 ], [ 202, 312, 237, 326 ], [ 242, 312, 282, 326 ], [ 286, 312, 339, 326 ], [ 342, 312, 378, 326 ], [ 382, 312, 403, 326 ], [ 408, 312, 445, 326 ], [ 449, 312, 460, 326 ], [ 465, 312, 491, 326 ], [ 495, 312, 537, 326 ], [ 541, 312, 560, 326 ], [ 564, 312, 611, 326 ], [ 615, 312, 660, 326 ], [ 664, 312, 675, 326 ], [ 87, 328, 153, 342 ], [ 157, 328, 179, 342 ], [ 184, 328, 211, 342 ], [ 215, 328, 246, 342 ], [ 250, 328, 316, 342 ], [ 320, 328, 346, 342 ], [ 351, 328, 406, 342 ], [ 410, 328, 439, 342 ], [ 444, 328, 461, 342 ], [ 465, 328, 486, 342 ], [ 490, 328, 536, 342 ], [ 540, 328, 603, 342 ], [ 607, 328, 618, 342 ], [ 622, 328, 652, 342 ], [ 657, 328, 690, 342 ], [ 87, 345, 136, 359 ], [ 140, 345, 162, 359 ], [ 167, 345, 197, 359 ], [ 201, 345, 220, 359 ], [ 225, 345, 272, 359 ], [ 276, 345, 283, 359 ], [ 287, 345, 329, 359 ], [ 333, 345, 360, 359 ], [ 365, 345, 398, 359 ], [ 402, 345, 444, 359 ], [ 448, 345, 459, 359 ], [ 463, 345, 497, 359 ], [ 501, 345, 555, 359 ], [ 558, 345, 583, 359 ], [ 587, 345, 629, 359 ], [ 633, 345, 655, 359 ], [ 660, 345, 704, 359 ], [ 87, 362, 153, 376 ], [ 158, 362, 170, 376 ], [ 174, 362, 255, 376 ], [ 259, 362, 291, 376 ], [ 295, 362, 316, 376 ], [ 321, 362, 356, 376 ], [ 360, 362, 433, 376 ], [ 438, 362, 456, 376 ], [ 460, 362, 527, 376 ], [ 531, 362, 551, 376 ], [ 556, 362, 589, 376 ], [ 593, 362, 646, 376 ], [ 650, 362, 677, 376 ], [ 681, 362, 735, 376 ], [ 87, 378, 108, 392 ], [ 113, 378, 140, 392 ], [ 144, 378, 174, 392 ], [ 179, 378, 232, 392 ], [ 235, 378, 275, 392 ], [ 279, 378, 338, 392 ], [ 342, 378, 354, 392 ], [ 358, 378, 423, 392 ], [ 428, 378, 449, 392 ], [ 453, 378, 499, 392 ], [ 504, 378, 529, 392 ], [ 533, 378, 591, 392 ], [ 595, 378, 642, 392 ], [ 647, 378, 669, 392 ], [ 87, 399, 189, 413 ], [ 194, 399, 212, 413 ], [ 216, 399, 235, 413 ], [ 239, 399, 269, 413 ], [ 274, 399, 281, 413 ], [ 285, 399, 383, 413 ], [ 387, 399, 424, 413 ], [ 428, 399, 439, 413 ], [ 444, 399, 523, 413 ], [ 527, 399, 534, 413 ], [ 538, 399, 576, 413 ], [ 580, 399, 595, 413 ], [ 600, 399, 650, 413 ], [ 654, 399, 681, 413 ], [ 685, 399, 712, 413 ], [ 87, 416, 132, 430 ], [ 137, 416, 166, 430 ], [ 170, 416, 188, 430 ], [ 193, 416, 212, 430 ], [ 216, 416, 235, 430 ], [ 240, 416, 265, 430 ], [ 268, 416, 295, 430 ], [ 299, 416, 314, 430 ], [ 319, 416, 381, 430 ], [ 385, 416, 400, 430 ], [ 404, 416, 416, 430 ], [ 421, 416, 432, 430 ], [ 436, 416, 455, 430 ], [ 459, 416, 530, 430 ], [ 535, 416, 585, 430 ], [ 589, 416, 603, 430 ], [ 607, 416, 627, 430 ], [ 631, 416, 668, 430 ], [ 672, 416, 709, 430 ], [ 713, 416, 732, 430 ], [ 87, 432, 117, 446 ], [ 122, 432, 161, 446 ], [ 165, 432, 186, 446 ], [ 190, 432, 209, 446 ], [ 214, 432, 222, 446 ], [ 226, 432, 238, 446 ], [ 242, 432, 320, 446 ], [ 324, 432, 364, 446 ], [ 368, 432, 395, 446 ], [ 399, 432, 456, 446 ], [ 460, 432, 481, 446 ], [ 485, 432, 529, 446 ], [ 533, 432, 594, 446 ], [ 599, 432, 631, 446 ], [ 635, 432, 698, 446 ], [ 702, 432, 727, 446 ], [ 87, 449, 118, 463 ], [ 122, 449, 167, 463 ], [ 171, 449, 188, 463 ], [ 192, 449, 211, 463 ], [ 215, 449, 245, 463 ], [ 250, 449, 317, 463 ], [ 321, 449, 368, 463 ], [ 372, 449, 383, 463 ], [ 386, 449, 413, 463 ], [ 417, 449, 471, 463 ], [ 476, 449, 497, 463 ], [ 501, 449, 531, 463 ], [ 536, 449, 599, 463 ], [ 603, 449, 664, 463 ], [ 668, 449, 689, 463 ], [ 694, 449, 726, 463 ], [ 87, 465, 113, 479 ], [ 118, 465, 153, 479 ], [ 157, 465, 180, 479 ], [ 185, 465, 207, 479 ], [ 211, 465, 254, 479 ], [ 257, 465, 287, 479 ], [ 292, 465, 355, 479 ], [ 359, 465, 418, 479 ], [ 423, 465, 440, 479 ], [ 444, 465, 463, 479 ], [ 467, 465, 514, 479 ], [ 519, 465, 538, 479 ], [ 541, 465, 578, 479 ], [ 583, 465, 594, 479 ], [ 598, 465, 617, 479 ], [ 620, 465, 668, 479 ], [ 672, 465, 729, 479 ], [ 87, 482, 129, 496 ], [ 133, 482, 154, 496 ], [ 159, 482, 225, 496 ], [ 229, 482, 260, 496 ], [ 264, 482, 286, 496 ], [ 290, 482, 307, 496 ], [ 312, 482, 370, 496 ], [ 374, 482, 399, 496 ], [ 403, 482, 469, 496 ], [ 473, 482, 538, 496 ], [ 542, 482, 564, 496 ], [ 568, 482, 620, 496 ], [ 87, 503, 154, 517 ], [ 158, 503, 169, 517 ], [ 173, 503, 180, 517 ], [ 184, 503, 219, 517 ], [ 224, 503, 260, 517 ], [ 263, 503, 274, 517 ], [ 279, 503, 331, 517 ], [ 335, 503, 410, 517 ], [ 414, 503, 445, 517 ], [ 449, 503, 518, 517 ], [ 523, 503, 561, 517 ], [ 565, 503, 584, 517 ], [ 588, 503, 615, 517 ], [ 619, 503, 630, 517 ], [ 635, 503, 697, 517 ], [ 87, 519, 140, 533 ], [ 144, 519, 156, 533 ], [ 160, 519, 182, 533 ], [ 186, 519, 197, 533 ], [ 202, 519, 227, 533 ], [ 231, 519, 259, 533 ], [ 264, 519, 310, 533 ], [ 315, 519, 348, 533 ], [ 352, 519, 408, 533 ], [ 412, 519, 429, 533 ], [ 433, 519, 470, 533 ], [ 474, 519, 493, 533 ], [ 497, 519, 532, 533 ], [ 536, 519, 547, 533 ], [ 552, 519, 571, 533 ], [ 575, 519, 608, 533 ], [ 612, 519, 637, 533 ], [ 641, 519, 660, 533 ], [ 665, 519, 680, 533 ], [ 683, 519, 738, 533 ], [ 87, 536, 102, 550 ], [ 107, 536, 182, 550 ], [ 186, 536, 198, 550 ], [ 201, 536, 220, 550 ], [ 225, 536, 250, 550 ], [ 253, 536, 272, 550 ], [ 277, 536, 307, 550 ], [ 311, 536, 344, 550 ], [ 349, 536, 400, 550 ], [ 404, 536, 472, 550 ], [ 476, 536, 537, 550 ], [ 542, 536, 604, 550 ], [ 608, 536, 638, 550 ], [ 642, 536, 732, 550 ], [ 78, 582, 155, 597 ], [ 78, 600, 122, 613 ], [ 78, 616, 120, 630 ], [ 125, 616, 137, 630 ], [ 143, 616, 192, 630 ], [ 197, 616, 223, 630 ], [ 228, 616, 238, 630 ], [ 243, 616, 258, 630 ], [ 263, 616, 325, 630 ], [ 331, 616, 381, 630 ], [ 386, 616, 404, 630 ], [ 78, 632, 128, 646 ], [ 135, 632, 147, 646 ], [ 154, 632, 195, 646 ], [ 202, 632, 235, 646 ], [ 242, 632, 314, 646 ], [ 320, 632, 383, 646 ], [ 390, 632, 403, 646 ], [ 78, 649, 124, 663 ], [ 128, 649, 163, 663 ], [ 168, 649, 175, 663 ], [ 179, 649, 220, 663 ], [ 225, 649, 287, 663 ], [ 291, 649, 327, 663 ], [ 331, 649, 351, 663 ], [ 355, 649, 393, 663 ], [ 397, 649, 404, 663 ], [ 78, 665, 118, 679 ], [ 123, 665, 176, 679 ], [ 180, 665, 201, 679 ], [ 205, 665, 230, 679 ], [ 234, 665, 241, 679 ], [ 245, 665, 285, 679 ], [ 290, 665, 325, 679 ], [ 329, 665, 388, 679 ], [ 392, 665, 403, 679 ], [ 78, 682, 132, 696 ], [ 136, 682, 178, 696 ], [ 183, 682, 196, 696 ], [ 200, 682, 247, 696 ], [ 251, 682, 275, 696 ], [ 279, 682, 298, 696 ], [ 303, 682, 323, 696 ], [ 327, 682, 338, 696 ], [ 342, 682, 368, 696 ], [ 373, 682, 404, 696 ], [ 78, 699, 90, 713 ], [ 94, 699, 124, 713 ], [ 129, 699, 195, 713 ], [ 199, 699, 220, 713 ], [ 225, 699, 242, 713 ], [ 246, 699, 286, 713 ], [ 290, 699, 361, 713 ], [ 366, 699, 378, 713 ], [ 382, 699, 404, 713 ], [ 78, 715, 108, 729 ], [ 114, 715, 152, 729 ], [ 157, 715, 186, 729 ], [ 190, 715, 276, 729 ], [ 281, 715, 319, 729 ], [ 324, 715, 403, 729 ], [ 78, 732, 103, 746 ], [ 107, 732, 162, 746 ], [ 167, 732, 238, 746 ], [ 243, 732, 314, 746 ], [ 319, 732, 354, 746 ], [ 358, 732, 368, 746 ], [ 373, 732, 404, 746 ], [ 78, 749, 126, 763 ], [ 130, 749, 179, 763 ], [ 184, 749, 199, 763 ], [ 203, 749, 221, 763 ], [ 225, 749, 275, 763 ], [ 280, 749, 291, 763 ], [ 295, 749, 350, 763 ], [ 355, 749, 404, 763 ], [ 78, 765, 104, 779 ], [ 110, 765, 122, 779 ], [ 126, 765, 173, 779 ], [ 178, 765, 203, 779 ], [ 208, 765, 228, 779 ], [ 233, 765, 257, 779 ], [ 262, 765, 321, 779 ], [ 325, 765, 347, 779 ], [ 352, 765, 404, 779 ], [ 78, 782, 139, 796 ], [ 143, 782, 154, 796 ], [ 159, 782, 189, 796 ], [ 193, 782, 262, 796 ], [ 267, 782, 302, 796 ], [ 306, 782, 318, 796 ], [ 322, 782, 329, 796 ], [ 333, 782, 404, 796 ], [ 78, 798, 123, 812 ], [ 127, 798, 139, 812 ], [ 143, 798, 197, 812 ], [ 201, 798, 265, 812 ], [ 269, 798, 309, 812 ], [ 314, 798, 368, 812 ], [ 372, 798, 403, 812 ], [ 78, 815, 143, 829 ], [ 148, 815, 167, 829 ], [ 172, 815, 206, 829 ], [ 212, 815, 224, 829 ], [ 229, 815, 288, 829 ], [ 294, 815, 343, 829 ], [ 348, 815, 373, 829 ], [ 378, 815, 392, 829 ], [ 397, 815, 403, 829 ], [ 78, 832, 154, 846 ], [ 159, 832, 181, 846 ], [ 186, 832, 198, 846 ], [ 202, 832, 250, 846 ], [ 255, 832, 295, 846 ], [ 299, 832, 335, 846 ], [ 340, 832, 362, 846 ], [ 366, 832, 404, 846 ], [ 78, 848, 104, 862 ], [ 109, 848, 121, 862 ], [ 125, 848, 186, 862 ], [ 190, 848, 211, 862 ], [ 216, 848, 228, 862 ], [ 232, 848, 271, 862 ], [ 275, 848, 293, 862 ], [ 298, 848, 339, 862 ], [ 343, 848, 384, 862 ], [ 388, 848, 403, 862 ], [ 78, 865, 123, 879 ], [ 127, 865, 151, 879 ], [ 155, 865, 216, 879 ], [ 78, 913, 83, 924 ], [ 86, 913, 156, 924 ], [ 159, 913, 240, 924 ], [ 78, 923, 110, 936 ], [ 113, 925, 125, 936 ], [ 128, 925, 155, 936 ], [ 158, 925, 191, 936 ], [ 194, 925, 210, 936 ], [ 214, 925, 239, 936 ], [ 241, 925, 280, 936 ], [ 283, 925, 311, 936 ], [ 315, 925, 324, 936 ], [ 326, 925, 371, 936 ], [ 375, 925, 391, 936 ], [ 78, 937, 103, 948 ], [ 107, 937, 136, 948 ], [ 139, 937, 155, 948 ], [ 158, 937, 199, 948 ], [ 202, 937, 211, 948 ], [ 213, 937, 238, 948 ], [ 242, 937, 284, 948 ], [ 287, 937, 325, 948 ], [ 328, 937, 345, 948 ], [ 348, 937, 367, 948 ], [ 78, 950, 124, 961 ], [ 127, 950, 140, 961 ], [ 143, 950, 158, 961 ], [ 162, 950, 180, 961 ], [ 182, 950, 213, 961 ], [ 78, 962, 93, 973 ], [ 96, 962, 108, 973 ], [ 111, 962, 120, 973 ], [ 123, 962, 151, 973 ], [ 153, 962, 202, 973 ], [ 205, 962, 211, 973 ], [ 215, 962, 251, 973 ], [ 254, 962, 262, 973 ], [ 265, 962, 279, 973 ], [ 282, 962, 298, 973 ], [ 302, 962, 311, 973 ], [ 313, 962, 327, 973 ], [ 330, 962, 355, 973 ], [ 434, 583, 480, 597 ], [ 484, 583, 508, 597 ], [ 513, 583, 525, 597 ], [ 529, 583, 590, 597 ], [ 595, 583, 611, 597 ], [ 615, 583, 637, 597 ], [ 642, 583, 655, 597 ], [ 659, 583, 690, 597 ], [ 695, 583, 748, 597 ], [ 423, 599, 454, 613 ], [ 459, 599, 487, 613 ], [ 492, 599, 521, 613 ], [ 527, 599, 550, 613 ], [ 555, 599, 566, 613 ], [ 572, 599, 600, 613 ], [ 606, 599, 629, 613 ], [ 635, 599, 647, 613 ], [ 652, 599, 684, 613 ], [ 690, 599, 749, 613 ], [ 423, 616, 467, 630 ], [ 471, 616, 540, 630 ], [ 544, 616, 571, 630 ], [ 575, 616, 587, 630 ], [ 591, 616, 635, 630 ], [ 640, 616, 722, 630 ], [ 727, 616, 748, 630 ], [ 423, 632, 462, 646 ], [ 466, 632, 495, 646 ], [ 499, 632, 554, 646 ], [ 558, 632, 586, 646 ], [ 590, 632, 602, 646 ], [ 606, 632, 670, 646 ], [ 675, 632, 694, 646 ], [ 698, 632, 710, 646 ], [ 714, 632, 748, 646 ], [ 423, 649, 452, 663 ], [ 456, 649, 473, 663 ], [ 478, 649, 522, 663 ], [ 526, 649, 587, 663 ], [ 591, 649, 609, 663 ], [ 613, 649, 643, 663 ], [ 648, 649, 717, 663 ], [ 722, 649, 748, 663 ], [ 423, 665, 443, 679 ], [ 447, 665, 472, 679 ], [ 477, 665, 546, 679 ], [ 550, 665, 591, 679 ], [ 595, 665, 635, 679 ], [ 639, 665, 651, 679 ], [ 655, 665, 736, 679 ], [ 741, 665, 748, 679 ], [ 423, 682, 468, 696 ], [ 473, 682, 485, 696 ], [ 489, 682, 519, 696 ], [ 524, 682, 581, 696 ], [ 586, 682, 617, 696 ], [ 622, 682, 637, 696 ], [ 642, 682, 654, 696 ], [ 659, 682, 666, 696 ], [ 671, 682, 705, 696 ], [ 710, 682, 718, 696 ], [ 723, 682, 748, 696 ], [ 423, 699, 442, 713 ], [ 446, 699, 508, 713 ], [ 513, 699, 550, 713 ], [ 556, 699, 568, 713 ], [ 573, 699, 621, 713 ], [ 626, 699, 651, 713 ], [ 656, 699, 701, 713 ], [ 706, 699, 723, 713 ], [ 729, 699, 748, 713 ], [ 423, 715, 472, 729 ], [ 477, 715, 489, 729 ], [ 494, 715, 569, 729 ], [ 574, 715, 622, 729 ], [ 627, 715, 652, 729 ], [ 658, 715, 672, 729 ], [ 677, 715, 684, 729 ], [ 689, 715, 731, 729 ], [ 736, 715, 748, 729 ], [ 423, 732, 493, 746 ], [ 498, 732, 561, 746 ], [ 567, 732, 580, 746 ], [ 585, 732, 647, 746 ], [ 653, 732, 682, 746 ], [ 687, 732, 748, 746 ], [ 423, 749, 457, 763 ], [ 461, 749, 511, 763 ], [ 516, 749, 588, 763 ], [ 592, 749, 659, 763 ], [ 664, 749, 719, 763 ], [ 723, 749, 748, 763 ], [ 423, 765, 474, 779 ], [ 479, 765, 546, 779 ], [ 553, 765, 592, 779 ], [ 597, 765, 610, 779 ], [ 615, 765, 694, 779 ], [ 700, 765, 749, 779 ], [ 423, 782, 493, 796 ], [ 497, 782, 515, 796 ], [ 519, 782, 555, 796 ], [ 559, 782, 600, 796 ], [ 605, 782, 617, 796 ], [ 620, 782, 664, 796 ], [ 669, 782, 709, 796 ], [ 713, 782, 725, 796 ], [ 729, 782, 748, 796 ], [ 423, 798, 464, 812 ], [ 468, 798, 541, 812 ], [ 546, 798, 568, 812 ], [ 572, 798, 640, 812 ], [ 645, 798, 665, 812 ], [ 669, 798, 681, 812 ], [ 686, 798, 748, 812 ], [ 423, 815, 451, 829 ], [ 455, 815, 507, 829 ], [ 511, 815, 521, 829 ], [ 525, 815, 567, 829 ], [ 572, 815, 606, 829 ], [ 610, 815, 640, 829 ], [ 645, 815, 657, 829 ], [ 661, 815, 668, 829 ], [ 672, 815, 722, 829 ], [ 726, 815, 748, 829 ], [ 423, 832, 452, 846 ], [ 456, 832, 491, 846 ], [ 495, 832, 519, 846 ], [ 523, 832, 571, 846 ], [ 575, 832, 586, 846 ], [ 590, 832, 655, 846 ], [ 659, 832, 705, 846 ], [ 434, 848, 488, 862 ], [ 492, 848, 552, 862 ], [ 556, 848, 612, 862 ], [ 616, 848, 673, 862 ], [ 678, 848, 705, 862 ], [ 710, 848, 749, 862 ], [ 423, 865, 466, 879 ], [ 470, 865, 524, 879 ], [ 528, 865, 578, 879 ], [ 582, 865, 594, 879 ], [ 598, 865, 639, 879 ], [ 643, 865, 661, 879 ], [ 665, 865, 697, 879 ], [ 701, 865, 712, 879 ], [ 717, 865, 748, 879 ], [ 423, 881, 455, 895 ], [ 462, 881, 515, 895 ], [ 522, 881, 546, 895 ], [ 553, 881, 578, 895 ], [ 585, 881, 639, 895 ], [ 646, 881, 659, 895 ], [ 666, 881, 699, 895 ], [ 706, 881, 718, 895 ], [ 725, 881, 748, 895 ], [ 423, 898, 474, 912 ], [ 478, 898, 499, 912 ], [ 504, 898, 550, 912 ], [ 554, 898, 589, 912 ], [ 593, 898, 668, 912 ], [ 672, 898, 679, 912 ], [ 683, 898, 732, 912 ], [ 736, 898, 748, 912 ], [ 423, 915, 452, 929 ], [ 456, 915, 480, 929 ], [ 484, 915, 521, 929 ], [ 525, 915, 596, 929 ], [ 601, 915, 613, 929 ], [ 618, 915, 672, 929 ], [ 677, 915, 748, 929 ], [ 423, 931, 445, 945 ], [ 450, 931, 484, 945 ], [ 489, 931, 537, 945 ], [ 543, 931, 624, 945 ], [ 629, 931, 650, 945 ], [ 655, 931, 681, 945 ], [ 686, 931, 711, 945 ], [ 717, 931, 748, 945 ], [ 423, 948, 507, 962 ], [ 511, 948, 523, 962 ], [ 528, 948, 598, 962 ], [ 602, 948, 614, 962 ], [ 619, 948, 638, 962 ], [ 642, 948, 693, 962 ], [ 698, 948, 748, 962 ], [ 248, 987, 255, 997 ], [ 257, 987, 275, 997 ], [ 278, 987, 293, 997 ], [ 296, 987, 304, 997 ], [ 306, 987, 314, 997 ], [ 317, 987, 347, 997 ], [ 350, 987, 379, 997 ], [ 381, 987, 408, 997 ], [ 410, 987, 424, 997 ], [ 427, 987, 442, 997 ], [ 445, 987, 451, 997 ], [ 453, 987, 463, 997 ], [ 465, 987, 486, 997 ], [ 489, 987, 514, 997 ], [ 517, 987, 540, 997 ], [ 542, 987, 583, 997 ], [ 586, 987, 609, 997 ], [ 611, 987, 624, 997 ], [ 626, 987, 648, 997 ], [ 650, 987, 658, 997 ], [ 660, 987, 673, 997 ], [ 676, 987, 707, 997 ], [ 709, 987, 748, 997 ], [ 248, 998, 289, 1008 ], [ 291, 998, 319, 1008 ], [ 322, 998, 493, 1008 ], [ 496, 998, 519, 1008 ], [ 522, 998, 551, 1008 ], [ 553, 998, 598, 1008 ], [ 601, 998, 616, 1008 ], [ 618, 998, 663, 1008 ], [ 666, 998, 681, 1008 ], [ 683, 998, 732, 1008 ], [ 736, 998, 743, 1008 ], [ 248, 1009, 262, 1019 ], [ 264, 1009, 298, 1019 ], [ 300, 1009, 334, 1019 ], [ 337, 1009, 350, 1019 ], [ 352, 1009, 380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]
[ 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 ]
2164954
[ "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)" ]
[ [ 76, 47, 291, 81 ], [ 76, 118, 146, 138 ], [ 76, 143, 139, 166 ], [ 145, 143, 165, 166 ], [ 171, 143, 238, 166 ], [ 243, 143, 262, 166 ], [ 268, 143, 303, 166 ], [ 308, 143, 403, 166 ], [ 408, 143, 428, 166 ], [ 434, 143, 473, 166 ], [ 479, 143, 539, 166 ], [ 544, 143, 645, 166 ], [ 650, 143, 706, 166 ], [ 712, 143, 764, 166 ], [ 76, 168, 88, 191 ], [ 94, 168, 174, 191 ], [ 180, 168, 250, 191 ], [ 255, 168, 334, 191 ], [ 340, 168, 408, 191 ], [ 414, 168, 433, 191 ], [ 439, 168, 490, 191 ], [ 76, 193, 135, 214 ], [ 140, 193, 217, 215 ], [ 222, 193, 260, 214 ], [ 266, 193, 283, 214 ], [ 287, 193, 358, 215 ], [ 363, 193, 431, 214 ], [ 436, 193, 451, 214 ], [ 456, 193, 530, 215 ], [ 535, 193, 570, 214 ], [ 575, 193, 599, 214 ], [ 603, 193, 679, 215 ], [ 706, 60, 759, 74 ], [ 761, 60, 798, 74 ], [ 697, 118, 741, 134 ], [ 745, 118, 807, 134 ], [ 76, 243, 117, 255 ], [ 119, 243, 147, 255 ], [ 150, 243, 160, 255 ], [ 162, 243, 214, 255 ], [ 216, 243, 236, 255 ], [ 239, 243, 287, 255 ], [ 288, 243, 323, 255 ], [ 325, 243, 338, 255 ], [ 340, 243, 350, 255 ], [ 352, 243, 362, 255 ], [ 364, 243, 392, 255 ], [ 394, 243, 421, 255 ], [ 424, 243, 468, 255 ], [ 470, 243, 510, 255 ], [ 513, 243, 539, 255 ], [ 540, 243, 559, 255 ], [ 561, 243, 603, 255 ], [ 606, 243, 633, 255 ], [ 634, 243, 697, 255 ], [ 699, 243, 767, 255 ], [ 76, 256, 84, 267 ], [ 87, 256, 125, 267 ], [ 127, 256, 154, 267 ], [ 156, 256, 178, 267 ], [ 181, 256, 222, 267 ], [ 224, 256, 271, 267 ], [ 274, 256, 306, 267 ], [ 308, 256, 322, 267 ], [ 325, 256, 377, 267 ], [ 380, 256, 423, 267 ], [ 424, 256, 432, 267 ], [ 435, 256, 484, 267 ], [ 487, 256, 497, 267 ], [ 500, 256, 531, 267 ], [ 533, 256, 587, 267 ], [ 589, 256, 610, 267 ], [ 612, 256, 660, 267 ], [ 662, 256, 697, 267 ], [ 700, 256, 740, 267 ], [ 742, 256, 765, 267 ], [ 76, 269, 121, 281 ], [ 123, 269, 149, 281 ], [ 76, 289, 107, 300 ], [ 110, 289, 142, 300 ], [ 144, 289, 178, 300 ], [ 181, 289, 185, 300 ], [ 187, 289, 311, 300 ], [ 313, 289, 334, 300 ], [ 336, 289, 345, 300 ], [ 348, 289, 379, 300 ], [ 381, 289, 385, 300 ], [ 387, 289, 489, 300 ], [ 492, 289, 529, 300 ], [ 531, 289, 539, 300 ], [ 541, 289, 576, 300 ], [ 579, 289, 583, 300 ], [ 585, 289, 698, 300 ], [ 76, 302, 89, 314 ], [ 91, 302, 127, 314 ], [ 130, 302, 134, 314 ], [ 136, 302, 253, 314 ], [ 76, 319, 83, 330 ], [ 85, 319, 158, 330 ], [ 160, 319, 193, 330 ], [ 76, 377, 121, 388 ], [ 124, 377, 136, 388 ], [ 138, 377, 178, 388 ], [ 180, 377, 203, 388 ], [ 76, 397, 124, 409 ], [ 126, 397, 151, 409 ], [ 154, 397, 174, 409 ], [ 186, 397, 314, 409 ], [ 76, 417, 96, 429 ], [ 98, 417, 126, 429 ], [ 129, 417, 136, 429 ], [ 139, 417, 177, 429 ], [ 179, 417, 204, 429 ], [ 207, 417, 403, 429 ], [ 430, 377, 473, 388 ], [ 475, 377, 481, 388 ], [ 484, 377, 516, 388 ], [ 519, 377, 542, 388 ], [ 430, 390, 476, 402 ], [ 478, 390, 490, 402 ], [ 492, 390, 532, 402 ], [ 534, 390, 557, 402 ], [ 76, 437, 85, 449 ], [ 87, 437, 110, 449 ], [ 113, 437, 139, 449 ], [ 141, 437, 151, 449 ], [ 153, 437, 163, 449 ], [ 166, 437, 202, 449 ], [ 205, 437, 240, 449 ], [ 242, 437, 276, 449 ], [ 279, 437, 297, 449 ], [ 76, 450, 96, 462 ], [ 98, 450, 105, 462 ], [ 108, 450, 119, 462 ], [ 121, 450, 147, 462 ], [ 150, 450, 182, 462 ], [ 184, 450, 212, 462 ], [ 215, 450, 264, 462 ], [ 267, 450, 294, 462 ], [ 296, 450, 311, 462 ], [ 314, 450, 341, 462 ], [ 343, 450, 353, 462 ], [ 355, 450, 370, 462 ], [ 373, 450, 412, 462 ], [ 415, 450, 463, 462 ], [ 465, 450, 516, 462 ], [ 519, 450, 553, 462 ], [ 555, 450, 757, 462 ], [ 76, 463, 103, 475 ], [ 106, 463, 141, 475 ], [ 143, 463, 199, 475 ], [ 201, 463, 219, 475 ], [ 222, 463, 277, 475 ], [ 279, 463, 295, 475 ], [ 298, 463, 358, 475 ], [ 361, 463, 369, 475 ], [ 372, 463, 388, 475 ], [ 390, 463, 429, 475 ], [ 432, 463, 472, 475 ], [ 475, 463, 490, 475 ], [ 493, 463, 527, 475 ], [ 529, 463, 553, 475 ], [ 556, 463, 563, 475 ], [ 565, 463, 604, 475 ], [ 607, 463, 632, 475 ], [ 155, 523, 217, 538 ], [ 155, 544, 235, 558 ], [ 239, 544, 262, 558 ], [ 266, 544, 302, 558 ], [ 307, 544, 361, 558 ], [ 365, 544, 411, 558 ], [ 415, 544, 460, 558 ], [ 464, 544, 496, 558 ], [ 501, 544, 522, 558 ], [ 526, 544, 537, 558 ], [ 541, 544, 559, 558 ], [ 564, 544, 586, 558 ], [ 590, 544, 645, 558 ], [ 648, 544, 676, 558 ], [ 681, 544, 691, 558 ], [ 155, 560, 173, 574 ], [ 175, 560, 231, 574 ], [ 234, 560, 245, 574 ], [ 247, 560, 290, 574 ], [ 293, 560, 307, 574 ], [ 309, 560, 332, 574 ], [ 334, 560, 344, 574 ], [ 347, 560, 404, 574 ], [ 406, 560, 427, 574 ], [ 429, 560, 461, 574 ], [ 463, 560, 503, 574 ], [ 506, 560, 538, 574 ], [ 540, 560, 558, 574 ], [ 560, 560, 587, 574 ], [ 590, 560, 617, 574 ], [ 619, 560, 691, 574 ], [ 155, 577, 167, 591 ], [ 170, 577, 193, 591 ], [ 196, 577, 207, 591 ], [ 210, 577, 257, 591 ], [ 261, 577, 303, 591 ], [ 307, 577, 337, 591 ], [ 340, 577, 361, 591 ], [ 364, 577, 397, 591 ], [ 401, 577, 412, 591 ], [ 415, 577, 469, 591 ], [ 472, 577, 485, 591 ], [ 489, 577, 521, 591 ], [ 525, 577, 535, 591 ], [ 538, 577, 595, 591 ], [ 598, 577, 619, 591 ], [ 623, 577, 652, 591 ], [ 655, 577, 666, 591 ], [ 670, 577, 691, 591 ], [ 155, 593, 187, 607 ], [ 190, 593, 233, 607 ], [ 155, 616, 214, 630 ], [ 216, 616, 290, 630 ], [ 292, 616, 312, 630 ], [ 314, 616, 334, 630 ], [ 337, 616, 368, 630 ], [ 370, 616, 411, 630 ], [ 414, 616, 435, 630 ], [ 437, 616, 483, 630 ], [ 485, 616, 495, 630 ], [ 498, 616, 510, 630 ], [ 513, 616, 531, 630 ], [ 533, 616, 565, 630 ], [ 568, 616, 691, 630 ], [ 155, 633, 187, 647 ], [ 190, 633, 211, 647 ], [ 214, 633, 273, 647 ], [ 277, 633, 287, 647 ], [ 290, 633, 304, 647 ], [ 307, 633, 339, 647 ], [ 343, 633, 439, 647 ], [ 442, 633, 477, 647 ], [ 480, 633, 509, 647 ], [ 512, 633, 558, 647 ], [ 561, 633, 571, 647 ], [ 575, 633, 596, 647 ], [ 599, 633, 631, 647 ], [ 155, 656, 204, 670 ], [ 210, 656, 233, 670 ], [ 239, 656, 268, 670 ], [ 273, 656, 302, 670 ], [ 308, 656, 354, 670 ], [ 360, 656, 377, 670 ], [ 382, 656, 388, 670 ], [ 394, 656, 437, 670 ], [ 443, 656, 495, 670 ], [ 501, 656, 530, 670 ], [ 536, 656, 569, 670 ], [ 574, 656, 583, 670 ], [ 589, 656, 622, 670 ], [ 628, 656, 657, 670 ], [ 662, 656, 691, 670 ], [ 155, 672, 207, 686 ], [ 209, 672, 226, 686 ], [ 228, 672, 281, 686 ], [ 284, 672, 304, 686 ], [ 306, 672, 362, 686 ], [ 365, 672, 406, 686 ], [ 408, 672, 477, 686 ], [ 479, 672, 542, 686 ], [ 544, 672, 573, 686 ], [ 575, 672, 593, 686 ], [ 595, 672, 660, 686 ], [ 663, 672, 691, 686 ], [ 155, 689, 173, 703 ], [ 177, 689, 216, 703 ], [ 219, 689, 240, 703 ], [ 243, 689, 272, 703 ], [ 275, 689, 317, 703 ], [ 320, 689, 349, 703 ], [ 352, 689, 391, 703 ], [ 394, 689, 405, 703 ], [ 409, 689, 464, 703 ], [ 468, 689, 514, 703 ], [ 517, 689, 531, 703 ], [ 535, 689, 564, 703 ], [ 567, 689, 602, 703 ], [ 605, 689, 634, 703 ], [ 637, 689, 676, 703 ], [ 680, 689, 691, 703 ], [ 155, 705, 194, 719 ], [ 199, 705, 221, 719 ], [ 227, 705, 281, 719 ], [ 286, 705, 300, 719 ], [ 306, 705, 335, 719 ], [ 341, 705, 373, 719 ], [ 378, 705, 406, 719 ], [ 412, 705, 431, 719 ], [ 437, 705, 501, 719 ], [ 507, 705, 527, 719 ], [ 532, 705, 561, 719 ], [ 566, 705, 605, 719 ], [ 611, 705, 622, 719 ], [ 628, 705, 691, 719 ], [ 155, 721, 208, 735 ], [ 212, 721, 308, 735 ], [ 312, 721, 382, 735 ], [ 386, 721, 396, 735 ], [ 400, 721, 421, 735 ], [ 425, 721, 457, 735 ], [ 461, 721, 485, 735 ], [ 490, 721, 496, 735 ], [ 500, 721, 555, 735 ], [ 559, 721, 607, 735 ], [ 610, 721, 621, 735 ], [ 626, 721, 652, 735 ], [ 656, 721, 680, 735 ], [ 685, 721, 691, 735 ], [ 155, 738, 198, 752 ], [ 200, 738, 255, 752 ], [ 258, 738, 286, 752 ], [ 289, 738, 300, 752 ], [ 303, 738, 326, 752 ], [ 328, 738, 338, 752 ], [ 341, 738, 393, 752 ], [ 396, 738, 425, 752 ], [ 428, 738, 448, 752 ], [ 450, 738, 456, 752 ], [ 459, 738, 504, 752 ], [ 507, 738, 562, 752 ], [ 564, 738, 592, 752 ], [ 595, 738, 606, 752 ], [ 609, 738, 639, 752 ], [ 642, 738, 652, 752 ], [ 655, 738, 691, 752 ], [ 155, 754, 187, 768 ], [ 191, 754, 217, 768 ], [ 220, 754, 249, 768 ], [ 253, 754, 282, 768 ], [ 286, 754, 310, 768 ], [ 314, 754, 360, 768 ], [ 364, 754, 404, 768 ], [ 407, 754, 425, 768 ], [ 429, 754, 469, 768 ], [ 473, 754, 531, 768 ], [ 535, 754, 594, 768 ], [ 598, 754, 612, 768 ], [ 616, 754, 645, 768 ], [ 649, 754, 691, 768 ], [ 155, 770, 184, 784 ], [ 189, 770, 200, 784 ], [ 207, 770, 245, 784 ], [ 251, 770, 270, 784 ], [ 276, 770, 303, 784 ], [ 309, 770, 357, 784 ], [ 362, 770, 375, 784 ], [ 382, 770, 396, 784 ], [ 402, 770, 444, 784 ], [ 449, 770, 460, 784 ], [ 466, 770, 500, 784 ], [ 506, 770, 525, 784 ], [ 531, 770, 555, 784 ], [ 561, 770, 581, 784 ], [ 587, 770, 601, 784 ], [ 607, 770, 636, 784 ], [ 642, 770, 674, 784 ], [ 679, 770, 690, 784 ], [ 155, 787, 216, 801 ], [ 220, 787, 247, 801 ], [ 251, 787, 286, 801 ], [ 290, 787, 304, 801 ], [ 308, 787, 337, 801 ], [ 341, 787, 376, 801 ], [ 380, 787, 409, 801 ], [ 413, 787, 424, 801 ], [ 429, 787, 499, 801 ], [ 503, 787, 530, 801 ], [ 534, 787, 541, 801 ], [ 545, 787, 580, 801 ], [ 584, 787, 613, 801 ], [ 618, 787, 629, 801 ], [ 633, 787, 691, 801 ], [ 155, 803, 179, 817 ], [ 182, 803, 202, 817 ], [ 205, 803, 259, 817 ], [ 262, 803, 269, 817 ], [ 272, 803, 301, 817 ], [ 305, 803, 333, 817 ], [ 336, 803, 347, 817 ], [ 351, 803, 392, 817 ], [ 395, 803, 422, 817 ], [ 425, 803, 440, 817 ], [ 444, 803, 462, 817 ], [ 465, 803, 499, 817 ], [ 502, 803, 524, 817 ], [ 527, 803, 597, 817 ], [ 600, 803, 620, 817 ], [ 623, 803, 664, 817 ], [ 667, 803, 691, 817 ], [ 155, 819, 166, 833 ], [ 171, 819, 211, 833 ], [ 215, 819, 244, 833 ], [ 248, 819, 303, 833 ], [ 307, 819, 353, 833 ], [ 358, 819, 391, 833 ], [ 395, 819, 424, 833 ], [ 428, 819, 439, 833 ], [ 444, 819, 483, 833 ], [ 487, 819, 506, 833 ], [ 510, 819, 534, 833 ], [ 539, 819, 568, 833 ], [ 571, 819, 610, 833 ], [ 615, 819, 626, 833 ], [ 630, 819, 690, 833 ], [ 155, 836, 185, 850 ], [ 189, 836, 247, 850 ], [ 251, 836, 270, 850 ], [ 274, 836, 307, 850 ], [ 311, 836, 332, 850 ], [ 335, 836, 375, 850 ], [ 379, 836, 389, 850 ], [ 393, 836, 407, 850 ], [ 411, 836, 443, 850 ], [ 447, 836, 471, 850 ], [ 475, 836, 584, 850 ], [ 588, 836, 622, 850 ], [ 626, 836, 637, 850 ], [ 641, 836, 659, 850 ], [ 663, 836, 691, 850 ], [ 155, 852, 211, 866 ], [ 215, 852, 234, 866 ], [ 239, 852, 270, 866 ], [ 275, 852, 313, 866 ], [ 318, 852, 340, 866 ], [ 344, 852, 366, 866 ], [ 371, 852, 395, 866 ], [ 400, 852, 443, 866 ], [ 448, 852, 500, 866 ], [ 504, 852, 533, 866 ], [ 538, 852, 567, 866 ], [ 571, 852, 582, 866 ], [ 587, 852, 655, 866 ], [ 660, 852, 680, 866 ], [ 685, 852, 691, 866 ], [ 155, 868, 213, 882 ], [ 220, 868, 294, 882 ], [ 302, 868, 317, 882 ], [ 324, 868, 363, 882 ], [ 370, 868, 393, 882 ], [ 401, 868, 412, 882 ], [ 420, 868, 434, 882 ], [ 442, 868, 499, 882 ], [ 506, 868, 546, 882 ], [ 554, 868, 587, 882 ], [ 595, 868, 628, 882 ], [ 636, 868, 665, 882 ], [ 673, 868, 691, 882 ], [ 155, 885, 220, 899 ], [ 227, 885, 247, 899 ], [ 254, 885, 271, 899 ], [ 278, 885, 338, 899 ], [ 345, 885, 369, 899 ], [ 376, 885, 434, 899 ], [ 441, 885, 481, 899 ], [ 488, 885, 510, 899 ], [ 518, 885, 558, 899 ], [ 565, 885, 604, 899 ], [ 611, 885, 672, 899 ], [ 680, 885, 691, 899 ], [ 155, 901, 212, 915 ], [ 215, 901, 247, 915 ], [ 155, 924, 229, 938 ], [ 234, 924, 270, 938 ], [ 274, 924, 283, 938 ], [ 288, 924, 315, 938 ], [ 319, 924, 359, 938 ], [ 364, 924, 384, 938 ], [ 389, 924, 436, 938 ], [ 440, 924, 450, 938 ], [ 455, 924, 478, 938 ], [ 483, 924, 536, 938 ], [ 541, 924, 558, 938 ], [ 562, 924, 608, 938 ], [ 613, 924, 666, 938 ], [ 671, 924, 691, 938 ], [ 155, 940, 212, 954 ], [ 215, 940, 255, 954 ], [ 260, 940, 282, 954 ], [ 285, 940, 343, 954 ], [ 347, 940, 379, 954 ], [ 383, 940, 435, 954 ], [ 439, 940, 473, 954 ], [ 476, 940, 495, 954 ], [ 499, 940, 519, 954 ], [ 522, 940, 592, 954 ], [ 596, 940, 651, 954 ], [ 654, 940, 673, 954 ], [ 677, 940, 691, 954 ], [ 155, 957, 193, 971 ], [ 196, 957, 250, 971 ], [ 253, 957, 357, 971 ], [ 361, 957, 423, 971 ], [ 426, 957, 450, 971 ], [ 453, 957, 476, 971 ], [ 479, 957, 490, 971 ], [ 494, 957, 507, 971 ], [ 510, 957, 553, 971 ], [ 556, 957, 574, 971 ], [ 578, 957, 622, 971 ], [ 625, 957, 635, 971 ], [ 638, 957, 668, 971 ], [ 672, 957, 691, 971 ], [ 155, 973, 191, 987 ], [ 698, 1052, 728, 1065 ], [ 731, 1052, 738, 1065 ], [ 741, 1052, 752, 1065 ], [ 755, 1052, 769, 1065 ], [ 599, 1070, 624, 1080 ], [ 627, 1070, 660, 1080 ], [ 662, 1070, 676, 1080 ], [ 678, 1070, 690, 1080 ], [ 692, 1070, 723, 1080 ], [ 726, 1070, 770, 1080 ] ]
[ 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 ]
3211996
[ "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." ]
[ [ 78, 47, 106, 59 ], [ 110, 47, 119, 59 ], [ 122, 47, 133, 59 ], [ 136, 47, 183, 59 ], [ 186, 47, 226, 59 ], [ 229, 47, 259, 59 ], [ 261, 47, 286, 59 ], [ 290, 47, 316, 59 ], [ 78, 61, 309, 73 ], [ 83, 128, 96, 146 ], [ 98, 128, 110, 146 ], [ 111, 128, 124, 146 ], [ 125, 128, 138, 146 ], [ 146, 128, 156, 146 ], [ 158, 128, 169, 146 ], [ 170, 128, 181, 146 ], [ 183, 128, 194, 146 ], [ 195, 128, 205, 146 ], [ 207, 128, 217, 146 ], [ 218, 128, 228, 146 ], [ 641, 128, 685, 146 ], [ 691, 128, 744, 146 ], [ 78, 169, 282, 203 ], [ 292, 169, 329, 203 ], [ 340, 169, 524, 203 ], [ 534, 169, 585, 203 ], [ 595, 169, 699, 203 ], [ 709, 169, 736, 203 ], [ 78, 205, 122, 239 ], [ 132, 205, 250, 239 ], [ 261, 205, 414, 239 ], [ 424, 205, 516, 239 ], [ 526, 205, 738, 239 ], [ 78, 241, 618, 275 ], [ 78, 288, 101, 304 ], [ 106, 288, 113, 304 ], [ 117, 285, 171, 304 ], [ 176, 288, 227, 304 ], [ 231, 288, 249, 304 ], [ 254, 285, 329, 304 ], [ 333, 288, 396, 304 ], [ 400, 288, 415, 304 ], [ 419, 285, 472, 304 ], [ 477, 288, 508, 304 ], [ 512, 288, 530, 304 ], [ 535, 285, 586, 304 ], [ 590, 288, 613, 304 ], [ 617, 288, 626, 304 ], [ 630, 285, 689, 304 ], [ 694, 288, 716, 304 ], [ 78, 307, 124, 323 ], [ 129, 305, 165, 324 ], [ 87, 361, 141, 376 ], [ 87, 382, 96, 396 ], [ 100, 382, 150, 396 ], [ 154, 382, 218, 396 ], [ 222, 382, 283, 396 ], [ 288, 382, 323, 396 ], [ 327, 382, 383, 396 ], [ 388, 382, 427, 396 ], [ 431, 382, 682, 396 ], [ 87, 399, 153, 413 ], [ 157, 399, 179, 413 ], [ 183, 399, 237, 413 ], [ 241, 399, 256, 413 ], [ 261, 399, 280, 413 ], [ 284, 399, 294, 413 ], [ 298, 399, 322, 413 ], [ 326, 399, 345, 413 ], [ 349, 399, 390, 413 ], [ 394, 399, 447, 413 ], [ 452, 399, 467, 413 ], [ 471, 399, 500, 413 ], [ 505, 399, 545, 413 ], [ 549, 399, 584, 413 ], [ 587, 399, 606, 413 ], [ 610, 399, 637, 413 ], [ 642, 399, 678, 413 ], [ 682, 399, 720, 413 ], [ 87, 416, 186, 430 ], [ 190, 416, 237, 430 ], [ 241, 416, 310, 430 ], [ 315, 416, 336, 430 ], [ 340, 416, 393, 430 ], [ 397, 416, 456, 430 ], [ 460, 416, 479, 430 ], [ 483, 416, 508, 430 ], [ 513, 416, 556, 430 ], [ 560, 416, 585, 430 ], [ 589, 416, 596, 430 ], [ 600, 416, 663, 430 ], [ 666, 416, 717, 430 ], [ 721, 416, 732, 430 ], [ 87, 432, 101, 446 ], [ 105, 432, 115, 446 ], [ 119, 432, 175, 446 ], [ 179, 432, 202, 446 ], [ 206, 432, 227, 446 ], [ 231, 432, 253, 447 ], [ 257, 432, 292, 446 ], [ 296, 432, 311, 446 ], [ 315, 432, 327, 446 ], [ 332, 432, 351, 446 ], [ 354, 432, 373, 446 ], [ 377, 432, 402, 446 ], [ 407, 432, 442, 446 ], [ 445, 432, 471, 446 ], [ 476, 432, 488, 446 ], [ 492, 432, 515, 446 ], [ 519, 432, 543, 447 ], [ 547, 432, 569, 446 ], [ 573, 432, 635, 446 ], [ 639, 432, 661, 446 ], [ 665, 432, 739, 446 ], [ 87, 449, 98, 463 ], [ 102, 449, 149, 463 ], [ 153, 449, 209, 463 ], [ 214, 449, 265, 463 ], [ 269, 449, 341, 463 ], [ 346, 449, 406, 463 ], [ 410, 449, 432, 463 ], [ 436, 449, 477, 463 ], [ 481, 449, 531, 463 ], [ 535, 449, 597, 463 ], [ 601, 449, 714, 463 ], [ 87, 465, 127, 479 ], [ 132, 465, 194, 479 ], [ 198, 465, 314, 479 ], [ 318, 465, 359, 479 ], [ 364, 465, 397, 479 ], [ 401, 465, 464, 479 ], [ 468, 465, 534, 479 ], [ 539, 465, 601, 479 ], [ 605, 465, 626, 479 ], [ 630, 465, 687, 479 ], [ 87, 482, 136, 496 ], [ 141, 482, 166, 496 ], [ 170, 482, 225, 496 ], [ 229, 482, 311, 496 ], [ 315, 482, 359, 496 ], [ 364, 482, 386, 496 ], [ 390, 482, 475, 496 ], [ 479, 482, 504, 496 ], [ 508, 482, 527, 496 ], [ 531, 482, 605, 496 ], [ 609, 482, 671, 496 ], [ 675, 482, 692, 496 ], [ 87, 499, 138, 513 ], [ 142, 499, 221, 513 ], [ 225, 499, 246, 513 ], [ 251, 499, 276, 513 ], [ 280, 499, 360, 513 ], [ 365, 499, 420, 513 ], [ 424, 499, 455, 513 ], [ 459, 499, 484, 513 ], [ 489, 499, 509, 513 ], [ 513, 499, 534, 513 ], [ 539, 499, 569, 513 ], [ 573, 499, 615, 513 ], [ 620, 499, 641, 513 ], [ 645, 499, 668, 513 ], [ 673, 499, 723, 513 ], [ 87, 515, 122, 529 ], [ 126, 515, 157, 529 ], [ 162, 515, 188, 529 ], [ 191, 515, 209, 529 ], [ 213, 515, 234, 529 ], [ 238, 515, 279, 529 ], [ 283, 515, 352, 529 ], [ 356, 515, 400, 529 ], [ 404, 515, 416, 529 ], [ 420, 515, 465, 529 ], [ 469, 515, 531, 529 ], [ 535, 515, 583, 529 ], [ 588, 515, 633, 529 ], [ 637, 515, 656, 529 ], [ 660, 515, 684, 529 ], [ 87, 532, 151, 546 ], [ 155, 532, 182, 546 ], [ 186, 532, 253, 546 ], [ 257, 532, 291, 546 ], [ 296, 532, 352, 546 ], [ 356, 532, 368, 546 ], [ 372, 532, 444, 546 ], [ 449, 532, 544, 546 ], [ 549, 532, 598, 546 ], [ 601, 532, 660, 546 ], [ 78, 578, 158, 593 ], [ 78, 595, 139, 609 ], [ 143, 595, 174, 609 ], [ 178, 595, 196, 609 ], [ 199, 595, 237, 609 ], [ 240, 595, 276, 609 ], [ 278, 595, 290, 609 ], [ 293, 595, 311, 609 ], [ 315, 595, 349, 609 ], [ 352, 595, 404, 609 ], [ 78, 612, 90, 626 ], [ 94, 612, 120, 626 ], [ 124, 612, 164, 626 ], [ 168, 612, 240, 626 ], [ 243, 612, 319, 626 ], [ 323, 612, 366, 626 ], [ 369, 612, 375, 626 ], [ 380, 612, 404, 626 ], [ 78, 628, 99, 642 ], [ 103, 628, 150, 642 ], [ 154, 628, 166, 642 ], [ 170, 628, 204, 642 ], [ 208, 628, 245, 642 ], [ 249, 628, 314, 642 ], [ 318, 628, 361, 642 ], [ 365, 628, 404, 642 ], [ 78, 645, 127, 659 ], [ 130, 645, 171, 659 ], [ 175, 645, 196, 659 ], [ 199, 645, 217, 659 ], [ 220, 645, 276, 659 ], [ 278, 645, 290, 659 ], [ 293, 645, 342, 659 ], [ 345, 645, 382, 659 ], [ 385, 645, 403, 659 ], [ 78, 661, 105, 675 ], [ 109, 661, 195, 675 ], [ 198, 661, 216, 675 ], [ 219, 661, 240, 675 ], [ 243, 661, 254, 675 ], [ 258, 661, 276, 675 ], [ 279, 661, 302, 675 ], [ 305, 661, 331, 675 ], [ 335, 661, 379, 675 ], [ 382, 661, 404, 675 ], [ 78, 678, 107, 692 ], [ 111, 678, 129, 692 ], [ 133, 678, 154, 692 ], [ 159, 678, 219, 692 ], [ 223, 678, 263, 692 ], [ 268, 678, 305, 692 ], [ 309, 678, 357, 692 ], [ 362, 678, 404, 692 ], [ 78, 695, 129, 709 ], [ 133, 695, 183, 709 ], [ 187, 695, 208, 709 ], [ 212, 695, 253, 709 ], [ 257, 695, 289, 709 ], [ 293, 695, 382, 709 ], [ 386, 695, 404, 709 ], [ 78, 711, 102, 725 ], [ 106, 711, 118, 725 ], [ 122, 711, 171, 725 ], [ 175, 711, 194, 725 ], [ 198, 711, 273, 725 ], [ 276, 711, 288, 725 ], [ 292, 711, 344, 725 ], [ 348, 711, 386, 725 ], [ 390, 711, 404, 725 ], [ 78, 728, 135, 742 ], [ 139, 728, 165, 742 ], [ 168, 728, 247, 742 ], [ 250, 728, 262, 742 ], [ 265, 728, 291, 742 ], [ 293, 728, 314, 742 ], [ 317, 728, 329, 742 ], [ 332, 728, 354, 742 ], [ 358, 728, 404, 742 ], [ 78, 744, 90, 758 ], [ 95, 744, 119, 758 ], [ 123, 744, 135, 758 ], [ 139, 744, 203, 758 ], [ 207, 744, 235, 758 ], [ 240, 744, 299, 758 ], [ 302, 744, 373, 758 ], [ 377, 744, 403, 758 ], [ 78, 761, 108, 775 ], [ 112, 761, 168, 775 ], [ 172, 761, 203, 775 ], [ 206, 761, 215, 775 ], [ 219, 761, 228, 775 ], [ 231, 761, 277, 775 ], [ 281, 761, 303, 775 ], [ 307, 761, 325, 775 ], [ 328, 761, 373, 775 ], [ 377, 761, 404, 775 ], [ 78, 778, 114, 792 ], [ 118, 778, 160, 792 ], [ 164, 778, 184, 792 ], [ 188, 778, 202, 792 ], [ 206, 778, 263, 792 ], [ 267, 778, 279, 792 ], [ 283, 778, 302, 792 ], [ 305, 778, 354, 792 ], [ 358, 778, 404, 792 ], [ 78, 794, 99, 808 ], [ 103, 794, 121, 808 ], [ 125, 794, 191, 808 ], [ 195, 794, 273, 808 ], [ 276, 794, 288, 808 ], [ 292, 794, 311, 808 ], [ 314, 794, 366, 808 ], [ 370, 794, 404, 808 ], [ 78, 811, 116, 825 ], [ 120, 811, 131, 825 ], [ 135, 811, 153, 825 ], [ 157, 811, 193, 825 ], [ 196, 811, 228, 825 ], [ 232, 811, 248, 825 ], [ 252, 811, 270, 825 ], [ 274, 811, 329, 825 ], [ 333, 811, 404, 825 ], [ 78, 827, 99, 841 ], [ 102, 827, 153, 841 ], [ 156, 827, 186, 841 ], [ 190, 827, 220, 841 ], [ 89, 844, 177, 858 ], [ 181, 844, 205, 858 ], [ 209, 844, 255, 858 ], [ 259, 844, 270, 858 ], [ 275, 844, 322, 858 ], [ 326, 844, 338, 858 ], [ 342, 844, 403, 858 ], [ 78, 861, 105, 875 ], [ 110, 861, 141, 875 ], [ 146, 861, 204, 875 ], [ 208, 861, 235, 875 ], [ 240, 861, 252, 875 ], [ 256, 861, 320, 875 ], [ 324, 861, 350, 875 ], [ 355, 861, 390, 875 ], [ 394, 861, 404, 875 ], [ 78, 877, 92, 891 ], [ 97, 877, 157, 891 ], [ 162, 877, 229, 891 ], [ 234, 877, 246, 891 ], [ 250, 877, 279, 891 ], [ 284, 877, 326, 891 ], [ 331, 877, 403, 891 ], [ 78, 925, 83, 936 ], [ 86, 925, 156, 936 ], [ 159, 925, 279, 936 ], [ 78, 936, 110, 949 ], [ 113, 937, 122, 948 ], [ 125, 937, 155, 948 ], [ 158, 937, 191, 948 ], [ 193, 937, 234, 948 ], [ 237, 937, 246, 948 ], [ 249, 937, 278, 948 ], [ 281, 937, 315, 948 ], [ 318, 937, 329, 948 ], [ 332, 937, 364, 948 ], [ 367, 937, 390, 948 ], [ 78, 950, 93, 961 ], [ 97, 950, 122, 961 ], [ 125, 950, 160, 961 ], [ 78, 962, 93, 973 ], [ 96, 962, 108, 973 ], [ 111, 962, 120, 973 ], [ 123, 962, 151, 973 ], [ 153, 962, 202, 973 ], [ 205, 962, 211, 973 ], [ 215, 962, 251, 973 ], [ 254, 962, 262, 973 ], [ 265, 962, 279, 973 ], [ 282, 962, 299, 973 ], [ 302, 962, 311, 973 ], [ 313, 962, 327, 973 ], [ 330, 962, 355, 973 ], [ 423, 578, 446, 592 ], [ 450, 578, 528, 592 ], [ 532, 578, 544, 592 ], [ 547, 578, 564, 592 ], [ 569, 578, 589, 592 ], [ 593, 578, 639, 592 ], [ 643, 578, 687, 592 ], [ 692, 578, 706, 592 ], [ 710, 578, 749, 592 ], [ 423, 595, 455, 609 ], [ 459, 595, 477, 609 ], [ 481, 595, 521, 609 ], [ 525, 595, 536, 609 ], [ 541, 595, 559, 609 ], [ 563, 595, 588, 609 ], [ 593, 595, 631, 609 ], [ 635, 595, 695, 609 ], [ 699, 595, 748, 609 ], [ 423, 611, 460, 625 ], [ 465, 611, 477, 625 ], [ 482, 611, 501, 625 ], [ 506, 611, 585, 625 ], [ 590, 611, 614, 625 ], [ 619, 611, 658, 625 ], [ 663, 611, 685, 625 ], [ 690, 611, 748, 625 ], [ 423, 628, 454, 642 ], [ 458, 628, 515, 642 ], [ 519, 628, 531, 642 ], [ 535, 628, 562, 642 ], [ 566, 628, 630, 642 ], [ 634, 628, 677, 642 ], [ 681, 628, 732, 642 ], [ 737, 628, 748, 642 ], [ 423, 645, 476, 659 ], [ 480, 645, 529, 659 ], [ 533, 645, 567, 659 ], [ 571, 645, 594, 659 ], [ 599, 645, 640, 659 ], [ 645, 645, 719, 659 ], [ 722, 645, 748, 659 ], [ 423, 661, 498, 675 ], [ 503, 661, 538, 675 ], [ 543, 661, 582, 675 ], [ 587, 661, 623, 675 ], [ 627, 661, 637, 675 ], [ 642, 661, 671, 675 ], [ 675, 661, 687, 675 ], [ 692, 661, 711, 675 ], [ 716, 661, 748, 675 ], [ 423, 678, 474, 692 ], [ 478, 678, 522, 692 ], [ 526, 678, 544, 692 ], [ 549, 678, 602, 692 ], [ 606, 678, 617, 692 ], [ 622, 678, 674, 692 ], [ 678, 678, 692, 692 ], [ 696, 678, 722, 692 ], [ 727, 678, 748, 692 ], [ 423, 695, 475, 709 ], [ 479, 695, 514, 709 ], [ 519, 695, 555, 709 ], [ 559, 695, 620, 709 ], [ 625, 695, 643, 709 ], [ 647, 695, 658, 709 ], [ 662, 695, 680, 709 ], [ 685, 695, 712, 709 ], [ 716, 695, 748, 709 ], [ 423, 711, 441, 725 ], [ 444, 711, 483, 725 ], [ 487, 711, 498, 725 ], [ 503, 711, 521, 725 ], [ 525, 711, 557, 725 ], [ 562, 711, 581, 725 ], [ 585, 711, 639, 725 ], [ 643, 711, 698, 725 ], [ 702, 711, 748, 725 ], [ 423, 728, 454, 742 ], [ 462, 728, 482, 742 ], [ 491, 728, 531, 742 ], [ 539, 728, 570, 742 ], [ 578, 728, 641, 742 ], [ 650, 728, 717, 742 ], [ 725, 728, 748, 742 ], [ 423, 744, 486, 758 ], [ 490, 744, 534, 758 ], [ 539, 744, 551, 758 ], [ 555, 744, 590, 758 ], [ 595, 744, 633, 758 ], [ 638, 744, 696, 758 ], [ 700, 744, 720, 758 ], [ 725, 744, 748, 758 ], [ 423, 761, 442, 775 ], [ 446, 761, 484, 775 ], [ 488, 761, 500, 775 ], [ 504, 761, 590, 775 ], [ 594, 761, 603, 775 ], [ 607, 761, 630, 775 ], [ 634, 761, 648, 775 ], [ 653, 761, 711, 775 ], [ 714, 761, 747, 775 ], [ 423, 778, 445, 792 ], [ 450, 778, 505, 792 ], [ 511, 778, 556, 792 ], [ 561, 778, 583, 792 ], [ 589, 778, 633, 792 ], [ 638, 778, 699, 792 ], [ 704, 778, 748, 792 ], [ 423, 794, 460, 808 ], [ 464, 794, 490, 808 ], [ 495, 794, 541, 808 ], [ 546, 794, 604, 808 ], [ 608, 794, 620, 808 ], [ 625, 794, 644, 808 ], [ 648, 794, 681, 808 ], [ 685, 794, 748, 808 ], [ 423, 811, 449, 825 ], [ 453, 811, 519, 825 ], [ 523, 811, 573, 825 ], [ 577, 811, 606, 825 ], [ 434, 827, 447, 841 ], [ 451, 827, 470, 841 ], [ 475, 827, 520, 841 ], [ 524, 827, 560, 841 ], [ 564, 827, 583, 841 ], [ 588, 827, 660, 841 ], [ 664, 827, 708, 841 ], [ 712, 827, 724, 841 ], [ 729, 827, 748, 841 ], [ 423, 844, 488, 858 ], [ 491, 844, 528, 858 ], [ 532, 844, 589, 858 ], [ 592, 844, 603, 858 ], [ 607, 844, 647, 858 ], [ 651, 844, 748, 858 ], [ 423, 860, 658, 874 ], [ 662, 860, 703, 874 ], [ 706, 860, 721, 874 ], [ 724, 860, 748, 874 ], [ 423, 877, 463, 891 ], [ 467, 877, 533, 891 ], [ 536, 877, 550, 891 ], [ 554, 877, 567, 891 ], [ 570, 877, 596, 891 ], [ 600, 877, 622, 891 ], [ 625, 877, 659, 891 ], [ 664, 877, 681, 891 ], [ 684, 877, 703, 891 ], [ 706, 877, 718, 891 ], [ 721, 877, 748, 891 ], [ 423, 894, 465, 908 ], [ 469, 894, 481, 908 ], [ 486, 894, 517, 908 ], [ 521, 894, 563, 908 ], [ 567, 894, 604, 908 ], [ 608, 894, 629, 908 ], [ 633, 894, 664, 908 ], [ 669, 894, 719, 908 ], [ 723, 894, 748, 908 ], [ 423, 910, 444, 924 ], [ 448, 910, 474, 925 ], [ 478, 910, 518, 924 ], [ 521, 910, 593, 924 ], [ 597, 910, 611, 924 ], [ 615, 910, 675, 924 ], [ 679, 910, 714, 924 ], [ 718, 910, 730, 924 ], [ 734, 910, 748, 924 ], [ 423, 927, 492, 941 ], [ 495, 927, 525, 941 ], [ 529, 927, 592, 941 ], [ 596, 927, 604, 941 ], [ 607, 927, 629, 941 ], [ 633, 927, 708, 941 ], [ 712, 927, 724, 941 ], [ 727, 927, 748, 941 ], [ 423, 944, 457, 958 ], [ 460, 944, 540, 958 ], [ 543, 944, 615, 958 ], [ 618, 944, 639, 958 ], [ 643, 944, 661, 958 ], [ 665, 944, 696, 958 ], [ 699, 944, 723, 958 ], [ 727, 944, 748, 958 ], [ 248, 987, 255, 997 ], [ 256, 987, 274, 997 ], [ 277, 987, 300, 997 ], [ 302, 987, 310, 997 ], [ 312, 987, 320, 997 ], [ 322, 987, 352, 997 ], [ 354, 987, 387, 997 ], [ 390, 987, 405, 997 ], [ 407, 987, 413, 997 ], [ 415, 987, 425, 997 ], [ 427, 987, 448, 997 ], [ 450, 987, 475, 997 ], [ 477, 987, 500, 997 ], [ 502, 987, 543, 997 ], [ 545, 987, 568, 997 ], [ 570, 987, 583, 997 ], [ 585, 987, 607, 997 ], [ 608, 987, 616, 997 ], [ 618, 987, 631, 997 ], [ 633, 987, 664, 997 ], [ 666, 987, 705, 997 ], [ 707, 987, 748, 997 ], [ 248, 998, 276, 1008 ], [ 278, 998, 449, 1008 ], [ 451, 998, 474, 1008 ], [ 477, 998, 506, 1008 ], [ 508, 998, 553, 1008 ], [ 555, 998, 570, 1008 ], [ 573, 998, 618, 1008 ], [ 620, 998, 635, 1008 ], [ 637, 998, 686, 1008 ], [ 689, 998, 696, 1008 ], [ 698, 998, 712, 1008 ], [ 714, 998, 748, 1008 ], [ 248, 1009, 282, 1019 ], [ 284, 1009, 297, 1019 ], [ 300, 1009, 328, 1019 ], [ 331, 1009, 350, 1019 ], [ 352, 1009, 358, 1019 ], [ 361, 1009, 393, 1019 ], [ 395, 1009, 416, 1019 ] ]
[ 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 ]
2593088
[ "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" ]
[ [ 70, 61, 109, 73 ], [ 111, 61, 159, 73 ], [ 161, 61, 217, 73 ], [ 70, 75, 96, 86 ], [ 98, 75, 138, 86 ], [ 70, 88, 105, 100 ], [ 107, 88, 131, 100 ], [ 133, 88, 163, 100 ], [ 166, 88, 178, 100 ], [ 180, 88, 215, 100 ], [ 217, 88, 228, 100 ], [ 230, 88, 255, 100 ], [ 70, 101, 182, 113 ], [ 70, 187, 140, 212 ], [ 145, 187, 209, 212 ], [ 70, 220, 111, 245 ], [ 116, 220, 187, 245 ], [ 191, 220, 213, 245 ], [ 218, 220, 423, 245 ], [ 427, 220, 455, 245 ], [ 459, 220, 565, 245 ], [ 570, 220, 725, 245 ], [ 70, 248, 110, 273 ], [ 115, 248, 270, 273 ], [ 274, 248, 296, 273 ], [ 301, 248, 441, 273 ], [ 445, 248, 532, 273 ], [ 120, 316, 154, 333 ], [ 157, 316, 212, 333 ], [ 120, 348, 161, 361 ], [ 164, 348, 173, 361 ], [ 176, 348, 223, 361 ], [ 225, 348, 265, 361 ], [ 268, 348, 287, 361 ], [ 289, 348, 330, 361 ], [ 333, 348, 342, 361 ], [ 345, 348, 390, 361 ], [ 392, 348, 451, 361 ], [ 454, 348, 463, 361 ], [ 466, 348, 514, 361 ], [ 516, 348, 556, 361 ], [ 558, 348, 608, 361 ], [ 611, 348, 648, 361 ], [ 650, 348, 694, 361 ], [ 120, 362, 150, 375 ], [ 153, 362, 181, 375 ], [ 183, 362, 226, 375 ], [ 228, 362, 266, 375 ], [ 120, 390, 203, 403 ], [ 205, 390, 239, 403 ], [ 242, 390, 254, 403 ], [ 256, 390, 305, 403 ], [ 308, 390, 319, 403 ], [ 321, 390, 344, 403 ], [ 346, 390, 388, 403 ], [ 391, 390, 490, 403 ], [ 120, 417, 164, 430 ], [ 166, 417, 178, 430 ], [ 181, 417, 214, 430 ], [ 216, 417, 243, 430 ], [ 246, 417, 292, 430 ], [ 294, 417, 306, 430 ], [ 309, 417, 344, 430 ], [ 347, 417, 371, 430 ], [ 120, 443, 195, 456 ], [ 198, 443, 210, 456 ], [ 213, 443, 265, 456 ], [ 267, 443, 305, 456 ], [ 120, 468, 154, 481 ], [ 159, 468, 188, 481 ], [ 193, 468, 260, 481 ], [ 264, 468, 302, 481 ], [ 307, 468, 412, 481 ], [ 416, 468, 466, 481 ], [ 471, 468, 542, 481 ], [ 546, 468, 583, 481 ], [ 588, 468, 647, 481 ], [ 651, 468, 675, 481 ], [ 679, 468, 690, 481 ], [ 694, 468, 763, 481 ], [ 120, 483, 159, 496 ], [ 161, 483, 190, 496 ], [ 191, 483, 226, 496 ], [ 228, 483, 247, 496 ], [ 249, 483, 284, 496 ], [ 286, 483, 338, 496 ], [ 340, 483, 436, 496 ], [ 438, 483, 453, 496 ], [ 455, 483, 547, 496 ], [ 549, 483, 608, 496 ], [ 610, 483, 642, 496 ], [ 644, 483, 697, 496 ], [ 699, 483, 712, 496 ], [ 714, 483, 763, 496 ], [ 120, 497, 140, 510 ], [ 144, 497, 171, 510 ], [ 174, 497, 184, 510 ], [ 188, 497, 216, 510 ], [ 220, 497, 260, 510 ], [ 264, 497, 356, 510 ], [ 360, 497, 383, 510 ], [ 386, 497, 454, 510 ], [ 457, 497, 517, 510 ], [ 521, 497, 538, 510 ], [ 542, 497, 591, 510 ], [ 594, 497, 653, 510 ], [ 656, 497, 675, 510 ], [ 679, 497, 723, 510 ], [ 726, 497, 763, 510 ], [ 120, 512, 131, 525 ], [ 136, 512, 183, 525 ], [ 189, 512, 229, 525 ], [ 235, 512, 258, 525 ], [ 264, 512, 301, 525 ], [ 307, 512, 337, 525 ], [ 343, 512, 354, 525 ], [ 359, 512, 431, 525 ], [ 437, 512, 467, 525 ], [ 472, 512, 494, 525 ], [ 500, 512, 523, 525 ], [ 528, 512, 543, 525 ], [ 550, 512, 561, 525 ], [ 566, 512, 578, 525 ], [ 584, 512, 620, 525 ], [ 626, 512, 651, 525 ], [ 657, 512, 668, 525 ], [ 674, 512, 716, 525 ], [ 722, 512, 763, 525 ], [ 120, 526, 212, 539 ], [ 216, 526, 244, 539 ], [ 248, 526, 260, 539 ], [ 263, 526, 293, 539 ], [ 297, 526, 308, 539 ], [ 311, 526, 327, 539 ], [ 330, 526, 380, 539 ], [ 383, 526, 394, 539 ], [ 397, 526, 492, 539 ], [ 495, 526, 545, 539 ], [ 549, 526, 623, 539 ], [ 626, 526, 646, 539 ], [ 649, 526, 682, 539 ], [ 685, 526, 695, 539 ], [ 699, 526, 725, 539 ], [ 728, 526, 763, 539 ], [ 120, 541, 160, 554 ], [ 164, 541, 186, 554 ], [ 190, 541, 230, 554 ], [ 234, 541, 242, 554 ], [ 246, 541, 266, 554 ], [ 270, 541, 297, 554 ], [ 301, 541, 315, 554 ], [ 319, 541, 381, 554 ], [ 385, 541, 408, 554 ], [ 412, 541, 457, 554 ], [ 461, 541, 480, 554 ], [ 484, 541, 495, 554 ], [ 498, 541, 540, 554 ], [ 544, 541, 585, 554 ], [ 589, 541, 632, 554 ], [ 636, 541, 652, 554 ], [ 657, 541, 705, 554 ], [ 709, 541, 739, 554 ], [ 743, 541, 763, 554 ], [ 120, 555, 155, 568 ], [ 158, 555, 188, 568 ], [ 191, 555, 203, 568 ], [ 206, 555, 233, 568 ], [ 235, 555, 289, 568 ], [ 292, 555, 302, 568 ], [ 306, 555, 346, 568 ], [ 349, 555, 367, 568 ], [ 369, 555, 401, 568 ], [ 403, 555, 455, 568 ], [ 458, 555, 504, 568 ], [ 507, 555, 545, 568 ], [ 548, 555, 564, 568 ], [ 567, 555, 592, 568 ], [ 594, 555, 621, 568 ], [ 624, 555, 638, 568 ], [ 640, 555, 701, 568 ], [ 704, 555, 763, 568 ], [ 120, 570, 159, 583 ], [ 163, 570, 212, 583 ], [ 216, 570, 251, 583 ], [ 255, 570, 308, 583 ], [ 312, 570, 359, 583 ], [ 364, 570, 412, 583 ], [ 415, 570, 479, 583 ], [ 484, 570, 525, 583 ], [ 529, 570, 570, 583 ], [ 574, 570, 605, 583 ], [ 610, 570, 624, 583 ], [ 628, 570, 658, 583 ], [ 662, 570, 693, 583 ], [ 697, 570, 737, 583 ], [ 741, 570, 763, 583 ], [ 120, 584, 134, 597 ], [ 137, 584, 155, 597 ], [ 158, 584, 197, 597 ], [ 200, 584, 244, 597 ], [ 247, 584, 262, 597 ], [ 266, 584, 282, 597 ], [ 285, 584, 302, 597 ], [ 306, 584, 317, 597 ], [ 320, 584, 412, 597 ], [ 415, 584, 426, 597 ], [ 429, 584, 445, 597 ], [ 449, 584, 499, 597 ], [ 502, 584, 512, 597 ], [ 516, 584, 611, 597 ], [ 614, 584, 675, 597 ], [ 679, 584, 696, 597 ], [ 699, 584, 749, 597 ], [ 752, 584, 763, 597 ], [ 120, 599, 233, 612 ], [ 237, 599, 278, 612 ], [ 281, 599, 302, 612 ], [ 305, 599, 317, 612 ], [ 321, 599, 376, 612 ], [ 378, 599, 398, 612 ], [ 401, 599, 421, 612 ], [ 424, 599, 435, 612 ], [ 438, 599, 530, 612 ], [ 533, 599, 548, 612 ], [ 552, 599, 579, 612 ], [ 582, 599, 641, 612 ], [ 644, 599, 667, 612 ], [ 671, 599, 681, 612 ], [ 684, 599, 763, 612 ], [ 120, 613, 155, 626 ], [ 157, 613, 169, 626 ], [ 171, 613, 208, 626 ], [ 211, 613, 222, 626 ], [ 224, 613, 250, 626 ], [ 252, 613, 295, 626 ], [ 120, 640, 172, 653 ], [ 174, 640, 183, 653 ], [ 186, 640, 210, 653 ], [ 213, 640, 236, 653 ], [ 239, 640, 281, 653 ], [ 282, 640, 304, 653 ], [ 307, 640, 315, 653 ], [ 317, 640, 330, 653 ], [ 332, 640, 358, 653 ], [ 359, 640, 389, 653 ], [ 391, 640, 422, 653 ], [ 425, 640, 480, 653 ], [ 482, 640, 512, 653 ], [ 514, 640, 530, 653 ], [ 532, 640, 573, 653 ], [ 576, 640, 629, 653 ], [ 631, 640, 689, 653 ], [ 690, 640, 730, 653 ], [ 732, 640, 763, 653 ], [ 120, 654, 159, 667 ], [ 161, 654, 222, 667 ], [ 225, 654, 245, 667 ], [ 247, 654, 310, 667 ], [ 312, 654, 331, 667 ], [ 334, 654, 400, 667 ], [ 403, 654, 414, 667 ], [ 416, 654, 434, 667 ], [ 436, 654, 482, 667 ], [ 484, 654, 529, 667 ], [ 532, 654, 548, 667 ], [ 551, 654, 590, 667 ], [ 592, 654, 618, 667 ], [ 621, 654, 629, 667 ], [ 631, 654, 674, 667 ], [ 677, 654, 705, 667 ], [ 70, 715, 83, 732 ], [ 86, 715, 178, 732 ], [ 70, 751, 92, 765 ], [ 100, 751, 154, 765 ], [ 161, 751, 173, 765 ], [ 181, 751, 260, 765 ], [ 267, 751, 286, 765 ], [ 293, 751, 350, 765 ], [ 357, 751, 404, 765 ], [ 70, 767, 96, 781 ], [ 99, 767, 117, 781 ], [ 120, 767, 191, 781 ], [ 195, 767, 207, 781 ], [ 209, 767, 281, 781 ], [ 284, 767, 358, 781 ], [ 362, 767, 404, 781 ], [ 70, 783, 87, 797 ], [ 92, 783, 121, 797 ], [ 126, 783, 170, 797 ], [ 175, 783, 187, 797 ], [ 191, 783, 202, 797 ], [ 207, 783, 242, 797 ], [ 246, 783, 278, 797 ], [ 283, 783, 357, 797 ], [ 362, 783, 404, 797 ], [ 70, 798, 129, 812 ], [ 134, 798, 164, 812 ], [ 168, 798, 186, 812 ], [ 191, 798, 254, 812 ], [ 258, 798, 270, 812 ], [ 275, 798, 293, 812 ], [ 297, 798, 325, 812 ], [ 330, 798, 339, 812 ], [ 344, 798, 404, 812 ], [ 70, 814, 95, 828 ], [ 98, 814, 139, 828 ], [ 141, 814, 197, 828 ], [ 200, 814, 217, 828 ], [ 219, 814, 240, 828 ], [ 243, 814, 271, 828 ], [ 273, 814, 319, 828 ], [ 321, 814, 376, 828 ], [ 379, 814, 404, 828 ], [ 70, 830, 115, 844 ], [ 118, 830, 138, 844 ], [ 140, 830, 153, 844 ], [ 156, 830, 202, 844 ], [ 204, 830, 235, 844 ], [ 238, 830, 294, 844 ], [ 296, 830, 308, 844 ], [ 311, 830, 374, 844 ], [ 376, 830, 404, 844 ], [ 70, 846, 90, 860 ], [ 94, 846, 115, 860 ], [ 119, 846, 163, 860 ], [ 168, 846, 195, 860 ], [ 199, 846, 211, 860 ], [ 215, 846, 264, 860 ], [ 268, 846, 311, 860 ], [ 315, 846, 404, 860 ], [ 70, 861, 91, 875 ], [ 94, 861, 168, 875 ], [ 91, 877, 137, 891 ], [ 141, 877, 191, 891 ], [ 196, 877, 208, 891 ], [ 213, 877, 258, 891 ], [ 263, 877, 287, 891 ], [ 292, 877, 336, 891 ], [ 341, 877, 352, 891 ], [ 357, 877, 364, 891 ], [ 368, 877, 404, 891 ], [ 70, 893, 98, 907 ], [ 103, 893, 124, 907 ], [ 130, 893, 147, 907 ], [ 153, 893, 210, 907 ], [ 215, 893, 270, 907 ], [ 276, 893, 317, 907 ], [ 323, 893, 358, 907 ], [ 363, 893, 404, 907 ], [ 70, 909, 88, 923 ], [ 94, 909, 174, 923 ], [ 180, 909, 219, 923 ], [ 225, 909, 282, 923 ], [ 289, 909, 377, 923 ], [ 383, 909, 404, 923 ], [ 70, 925, 122, 939 ], [ 127, 925, 207, 939 ], [ 212, 925, 269, 939 ], [ 274, 925, 289, 939 ], [ 294, 925, 310, 939 ], [ 315, 925, 337, 939 ], [ 342, 925, 370, 939 ], [ 375, 925, 404, 939 ], [ 70, 940, 120, 954 ], [ 123, 940, 187, 954 ], [ 191, 940, 203, 954 ], [ 205, 940, 311, 954 ], [ 314, 940, 391, 954 ], [ 395, 940, 404, 954 ], [ 70, 956, 88, 970 ], [ 90, 956, 111, 970 ], [ 114, 956, 126, 970 ], [ 128, 956, 204, 970 ], [ 207, 956, 250, 970 ], [ 253, 956, 285, 970 ], [ 287, 956, 304, 970 ], [ 307, 956, 341, 970 ], [ 344, 956, 363, 970 ], [ 365, 956, 404, 970 ], [ 70, 972, 82, 986 ], [ 85, 972, 98, 986 ], [ 101, 972, 125, 986 ], [ 127, 972, 171, 987 ], [ 174, 972, 186, 986 ], [ 188, 972, 214, 986 ], [ 217, 972, 258, 986 ], [ 260, 972, 276, 986 ], [ 91, 988, 197, 1002 ], [ 202, 988, 268, 1002 ], [ 272, 988, 289, 1002 ], [ 294, 988, 316, 1002 ], [ 320, 988, 404, 1002 ], [ 70, 1004, 94, 1018 ], [ 100, 1004, 166, 1018 ], [ 172, 1004, 211, 1018 ], [ 216, 1004, 230, 1018 ], [ 237, 1004, 251, 1018 ], [ 257, 1004, 311, 1018 ], [ 317, 1004, 339, 1018 ], [ 345, 1004, 379, 1019 ], [ 385, 1004, 404, 1018 ], [ 70, 1019, 112, 1033 ], [ 118, 1019, 163, 1033 ], [ 170, 1019, 246, 1033 ], [ 253, 1019, 268, 1033 ], [ 275, 1019, 303, 1033 ], [ 309, 1019, 321, 1033 ], [ 328, 1019, 372, 1033 ], [ 379, 1019, 404, 1033 ], [ 428, 717, 453, 731 ], [ 459, 717, 466, 731 ], [ 472, 717, 517, 731 ], [ 523, 717, 557, 731 ], [ 564, 717, 636, 731 ], [ 641, 717, 653, 731 ], [ 659, 717, 711, 731 ], [ 718, 717, 763, 731 ], [ 428, 733, 472, 747 ], [ 478, 733, 503, 747 ], [ 508, 733, 549, 747 ], [ 555, 733, 588, 747 ], [ 593, 733, 605, 747 ], [ 610, 733, 690, 747 ], [ 695, 733, 762, 747 ], [ 428, 749, 447, 763 ], [ 450, 749, 504, 763 ], [ 507, 749, 562, 763 ], [ 565, 749, 606, 763 ], [ 609, 749, 630, 763 ], [ 633, 749, 709, 763 ], [ 713, 749, 763, 763 ], [ 428, 764, 449, 778 ], [ 453, 764, 480, 778 ], [ 485, 764, 518, 778 ], [ 522, 764, 624, 778 ], [ 628, 764, 649, 778 ], [ 654, 764, 723, 778 ], [ 727, 764, 762, 779 ], [ 428, 780, 440, 794 ], [ 445, 780, 500, 794 ], [ 506, 780, 532, 794 ], [ 537, 780, 560, 794 ], [ 565, 780, 577, 794 ], [ 582, 780, 620, 794 ], [ 625, 780, 665, 794 ], [ 670, 780, 698, 794 ], [ 703, 780, 762, 794 ], [ 428, 796, 474, 810 ], [ 479, 796, 508, 810 ], [ 512, 796, 544, 810 ], [ 548, 796, 579, 810 ], [ 584, 796, 623, 810 ], [ 628, 796, 693, 810 ], [ 698, 796, 719, 810 ], [ 724, 796, 763, 810 ], [ 428, 812, 482, 826 ], [ 485, 812, 497, 826 ], [ 499, 812, 543, 826 ], [ 546, 812, 571, 826 ], [ 574, 812, 680, 826 ], [ 683, 812, 763, 826 ], [ 449, 827, 471, 841 ], [ 478, 827, 522, 841 ], [ 530, 827, 567, 841 ], [ 574, 827, 583, 841 ], [ 590, 827, 633, 841 ], [ 641, 827, 656, 841 ], [ 663, 827, 737, 841 ], [ 744, 827, 762, 841 ], [ 428, 843, 479, 857 ], [ 484, 843, 532, 857 ], [ 536, 843, 576, 857 ], [ 581, 843, 605, 857 ], [ 609, 843, 624, 857 ], [ 629, 843, 647, 857 ], [ 651, 843, 670, 857 ], [ 675, 843, 687, 857 ], [ 691, 843, 746, 857 ], [ 751, 843, 763, 857 ], [ 428, 859, 472, 873 ], [ 475, 859, 500, 873 ], [ 503, 859, 609, 873 ], [ 612, 859, 689, 873 ], [ 428, 895, 441, 912 ], [ 444, 895, 580, 912 ], [ 428, 925, 534, 939 ], [ 543, 925, 560, 939 ], [ 567, 925, 617, 939 ], [ 625, 925, 665, 939 ], [ 673, 925, 690, 939 ], [ 698, 925, 763, 939 ], [ 428, 940, 546, 954 ], [ 550, 940, 596, 954 ], [ 600, 940, 642, 954 ], [ 645, 940, 698, 955 ], [ 701, 940, 740, 955 ], [ 743, 940, 752, 954 ], [ 756, 940, 763, 954 ], [ 428, 956, 469, 970 ], [ 475, 956, 521, 970 ], [ 526, 956, 560, 970 ], [ 564, 956, 594, 970 ], [ 599, 956, 658, 970 ], [ 663, 956, 675, 970 ], [ 679, 956, 726, 970 ], [ 731, 956, 762, 970 ], [ 428, 972, 481, 986 ], [ 488, 972, 518, 986 ], [ 525, 972, 581, 986 ], [ 588, 972, 614, 986 ], [ 620, 972, 641, 986 ], [ 649, 972, 690, 986 ], [ 697, 972, 763, 986 ], [ 428, 988, 455, 1002 ], [ 461, 988, 500, 1003 ], [ 506, 988, 515, 1002 ], [ 520, 988, 574, 1002 ], [ 580, 988, 619, 1002 ], [ 624, 988, 636, 1002 ], [ 641, 988, 684, 1002 ], [ 689, 988, 721, 1002 ], [ 726, 988, 747, 1002 ], [ 753, 988, 762, 1002 ], [ 428, 1004, 450, 1018 ], [ 456, 1004, 490, 1018 ], [ 495, 1004, 507, 1018 ], [ 512, 1004, 570, 1018 ], [ 575, 1004, 599, 1018 ], [ 604, 1004, 631, 1018 ], [ 636, 1004, 682, 1018 ], [ 687, 1004, 762, 1018 ], [ 428, 1019, 449, 1033 ], [ 452, 1019, 529, 1033 ], [ 531, 1019, 552, 1033 ], [ 555, 1019, 567, 1033 ], [ 570, 1019, 590, 1033 ], [ 593, 1019, 648, 1033 ], [ 650, 1019, 662, 1033 ], [ 665, 1019, 695, 1033 ], [ 697, 1019, 734, 1033 ], [ 736, 1019, 762, 1033 ] ]
[ 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 ]
3339391
[ "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." ]
[ [ 78, 47, 138, 59 ], [ 141, 47, 150, 59 ], [ 153, 47, 164, 59 ], [ 168, 47, 189, 59 ], [ 191, 47, 226, 59 ], [ 230, 47, 280, 59 ], [ 283, 47, 301, 59 ], [ 304, 47, 342, 59 ], [ 345, 47, 379, 59 ], [ 382, 47, 407, 59 ], [ 410, 47, 452, 59 ], [ 455, 47, 477, 59 ], [ 78, 61, 320, 73 ], [ 83, 128, 94, 146 ], [ 95, 128, 106, 146 ], [ 108, 128, 121, 146 ], [ 123, 128, 134, 146 ], [ 135, 128, 145, 146 ], [ 147, 128, 157, 146 ], [ 158, 128, 171, 146 ], [ 173, 128, 179, 146 ], [ 180, 128, 193, 146 ], [ 194, 128, 207, 146 ], [ 208, 128, 218, 146 ], [ 641, 128, 685, 146 ], [ 691, 128, 744, 146 ], [ 78, 169, 174, 203 ], [ 185, 169, 201, 203 ], [ 210, 169, 261, 203 ], [ 271, 169, 453, 203 ], [ 463, 169, 620, 203 ], [ 631, 169, 668, 203 ], [ 78, 205, 184, 239 ], [ 195, 205, 281, 239 ], [ 290, 205, 341, 239 ], [ 351, 205, 455, 239 ], [ 465, 205, 572, 239 ], [ 583, 205, 610, 239 ], [ 620, 205, 710, 239 ], [ 78, 241, 141, 275 ], [ 78, 288, 119, 304 ], [ 124, 285, 204, 304 ], [ 209, 288, 258, 304 ], [ 262, 288, 283, 304 ], [ 288, 288, 328, 304 ], [ 332, 288, 395, 304 ], [ 78, 317, 109, 333 ], [ 114, 317, 144, 333 ], [ 148, 317, 175, 333 ], [ 180, 317, 257, 333 ], [ 261, 317, 323, 333 ], [ 327, 317, 344, 333 ], [ 349, 317, 378, 333 ], [ 382, 317, 406, 333 ], [ 410, 317, 436, 333 ], [ 440, 317, 483, 333 ], [ 488, 317, 500, 333 ], [ 504, 317, 571, 333 ], [ 576, 317, 643, 333 ], [ 648, 317, 700, 333 ], [ 704, 317, 738, 333 ], [ 78, 335, 133, 351 ], [ 138, 335, 158, 351 ], [ 163, 335, 178, 351 ], [ 182, 335, 232, 351 ], [ 237, 335, 267, 351 ], [ 87, 389, 141, 404 ], [ 87, 410, 126, 424 ], [ 131, 410, 157, 424 ], [ 161, 410, 178, 424 ], [ 182, 410, 243, 424 ], [ 247, 410, 299, 424 ], [ 304, 410, 362, 424 ], [ 366, 410, 410, 424 ], [ 414, 410, 460, 424 ], [ 464, 410, 479, 424 ], [ 484, 410, 529, 424 ], [ 533, 410, 555, 424 ], [ 558, 410, 598, 424 ], [ 603, 410, 622, 424 ], [ 626, 410, 654, 424 ], [ 658, 410, 704, 424 ], [ 87, 427, 129, 441 ], [ 133, 427, 144, 441 ], [ 149, 427, 193, 441 ], [ 197, 427, 241, 441 ], [ 245, 427, 298, 441 ], [ 302, 427, 357, 441 ], [ 361, 427, 377, 441 ], [ 381, 427, 407, 441 ], [ 411, 427, 456, 441 ], [ 459, 427, 471, 441 ], [ 476, 427, 507, 441 ], [ 510, 427, 542, 441 ], [ 547, 427, 555, 441 ], [ 559, 427, 610, 441 ], [ 614, 427, 636, 441 ], [ 640, 427, 652, 441 ], [ 656, 427, 675, 441 ], [ 679, 427, 730, 441 ], [ 87, 443, 132, 457 ], [ 136, 443, 147, 457 ], [ 151, 443, 194, 457 ], [ 199, 443, 254, 457 ], [ 257, 443, 288, 457 ], [ 292, 443, 319, 457 ], [ 323, 443, 361, 457 ], [ 365, 443, 404, 457 ], [ 409, 443, 433, 457 ], [ 437, 443, 463, 457 ], [ 467, 443, 513, 457 ], [ 517, 443, 580, 457 ], [ 584, 443, 629, 457 ], [ 633, 443, 683, 457 ], [ 687, 443, 727, 457 ], [ 87, 460, 121, 474 ], [ 125, 460, 159, 474 ], [ 163, 460, 178, 474 ], [ 182, 460, 276, 474 ], [ 280, 460, 333, 474 ], [ 338, 460, 353, 474 ], [ 357, 460, 381, 474 ], [ 386, 460, 451, 474 ], [ 455, 460, 466, 474 ], [ 469, 460, 489, 474 ], [ 494, 460, 526, 474 ], [ 530, 460, 547, 474 ], [ 551, 460, 593, 474 ], [ 597, 460, 635, 474 ], [ 640, 460, 654, 474 ], [ 658, 460, 702, 474 ], [ 87, 476, 123, 490 ], [ 127, 476, 189, 490 ], [ 193, 476, 257, 490 ], [ 261, 476, 276, 490 ], [ 280, 476, 318, 490 ], [ 322, 476, 350, 490 ], [ 355, 477, 391, 491 ], [ 395, 476, 419, 490 ], [ 423, 476, 444, 490 ], [ 449, 476, 489, 490 ], [ 493, 476, 514, 490 ], [ 519, 476, 544, 490 ], [ 547, 476, 587, 490 ], [ 591, 476, 641, 490 ], [ 645, 476, 657, 490 ], [ 661, 476, 696, 490 ], [ 700, 476, 738, 490 ], [ 87, 493, 113, 507 ], [ 117, 493, 142, 507 ], [ 146, 493, 201, 507 ], [ 205, 493, 227, 507 ], [ 232, 493, 243, 507 ], [ 247, 493, 270, 507 ], [ 274, 493, 303, 507 ], [ 308, 493, 320, 507 ], [ 323, 493, 370, 507 ], [ 375, 493, 402, 507 ], [ 406, 493, 418, 507 ], [ 422, 493, 462, 507 ], [ 466, 493, 499, 507 ], [ 503, 493, 541, 507 ], [ 545, 493, 556, 507 ], [ 560, 493, 609, 507 ], [ 613, 493, 649, 507 ], [ 653, 493, 708, 507 ], [ 712, 493, 719, 507 ], [ 87, 510, 152, 524 ], [ 157, 510, 172, 524 ], [ 177, 510, 263, 524 ], [ 267, 510, 317, 524 ], [ 321, 510, 358, 524 ], [ 363, 510, 396, 524 ], [ 400, 510, 415, 524 ], [ 419, 510, 426, 524 ], [ 430, 510, 446, 524 ], [ 451, 510, 462, 524 ], [ 466, 510, 512, 524 ], [ 517, 510, 572, 524 ], [ 78, 556, 158, 571 ], [ 78, 573, 125, 587 ], [ 131, 573, 162, 587 ], [ 168, 573, 187, 587 ], [ 192, 573, 278, 587 ], [ 283, 573, 335, 587 ], [ 340, 573, 383, 587 ], [ 388, 573, 404, 587 ], [ 78, 590, 128, 604 ], [ 133, 590, 143, 604 ], [ 147, 590, 213, 604 ], [ 218, 590, 230, 604 ], [ 235, 590, 242, 604 ], [ 246, 590, 288, 604 ], [ 292, 590, 316, 604 ], [ 321, 590, 363, 604 ], [ 368, 590, 375, 604 ], [ 379, 590, 404, 604 ], [ 78, 606, 120, 620 ], [ 125, 606, 173, 620 ], [ 177, 606, 198, 620 ], [ 202, 606, 250, 620 ], [ 254, 606, 295, 620 ], [ 299, 606, 366, 620 ], [ 371, 606, 403, 620 ], [ 78, 623, 97, 637 ], [ 102, 623, 137, 637 ], [ 141, 623, 155, 637 ], [ 160, 623, 187, 637 ], [ 192, 623, 211, 637 ], [ 215, 623, 272, 637 ], [ 276, 623, 311, 637 ], [ 316, 623, 380, 637 ], [ 385, 623, 404, 637 ], [ 78, 639, 114, 653 ], [ 118, 639, 136, 653 ], [ 140, 639, 221, 653 ], [ 225, 639, 237, 653 ], [ 241, 639, 286, 653 ], [ 290, 639, 313, 653 ], [ 316, 639, 336, 653 ], [ 340, 639, 403, 653 ], [ 78, 656, 118, 670 ], [ 124, 656, 159, 670 ], [ 164, 656, 184, 670 ], [ 189, 656, 260, 670 ], [ 265, 656, 290, 670 ], [ 295, 656, 379, 670 ], [ 384, 656, 404, 670 ], [ 78, 672, 113, 686 ], [ 118, 672, 139, 686 ], [ 144, 672, 190, 686 ], [ 194, 672, 224, 686 ], [ 229, 672, 247, 686 ], [ 252, 672, 292, 686 ], [ 297, 672, 316, 686 ], [ 321, 672, 350, 686 ], [ 355, 672, 404, 686 ], [ 78, 689, 121, 703 ], [ 125, 689, 142, 703 ], [ 146, 689, 189, 703 ], [ 193, 689, 279, 703 ], [ 284, 689, 328, 703 ], [ 333, 689, 378, 703 ], [ 382, 689, 403, 703 ], [ 78, 706, 137, 720 ], [ 143, 706, 168, 720 ], [ 173, 706, 208, 720 ], [ 214, 706, 272, 720 ], [ 278, 706, 298, 720 ], [ 303, 706, 327, 720 ], [ 333, 706, 355, 720 ], [ 360, 706, 403, 720 ], [ 78, 722, 126, 736 ], [ 131, 722, 177, 736 ], [ 181, 722, 193, 736 ], [ 198, 722, 244, 736 ], [ 248, 722, 278, 736 ], [ 282, 722, 326, 736 ], [ 331, 722, 350, 736 ], [ 355, 722, 404, 736 ], [ 78, 739, 98, 753 ], [ 104, 739, 116, 753 ], [ 123, 739, 146, 753 ], [ 151, 739, 229, 753 ], [ 235, 739, 302, 753 ], [ 308, 739, 342, 753 ], [ 348, 739, 368, 753 ], [ 374, 739, 403, 753 ], [ 78, 755, 123, 769 ], [ 127, 755, 139, 769 ], [ 143, 755, 189, 769 ], [ 193, 755, 229, 769 ], [ 234, 755, 302, 769 ], [ 306, 755, 323, 769 ], [ 327, 755, 367, 769 ], [ 372, 755, 403, 769 ], [ 78, 772, 117, 786 ], [ 122, 772, 136, 786 ], [ 140, 772, 182, 786 ], [ 187, 772, 243, 786 ], [ 247, 772, 266, 786 ], [ 271, 772, 290, 786 ], [ 294, 772, 314, 786 ], [ 318, 772, 364, 786 ], [ 369, 772, 404, 786 ], [ 78, 789, 128, 803 ], [ 133, 789, 295, 803 ], [ 299, 789, 323, 803 ], [ 328, 789, 403, 803 ], [ 78, 805, 133, 819 ], [ 138, 805, 210, 819 ], [ 215, 805, 278, 819 ], [ 283, 805, 318, 819 ], [ 323, 805, 403, 819 ], [ 78, 822, 102, 836 ], [ 106, 822, 127, 836 ], [ 131, 822, 289, 836 ], [ 293, 822, 347, 836 ], [ 352, 822, 381, 836 ], [ 384, 822, 403, 836 ], [ 78, 838, 141, 852 ], [ 147, 838, 160, 852 ], [ 165, 838, 204, 852 ], [ 210, 838, 230, 852 ], [ 236, 838, 260, 852 ], [ 265, 838, 289, 852 ], [ 295, 838, 371, 852 ], [ 376, 838, 403, 852 ], [ 78, 855, 140, 869 ], [ 145, 855, 199, 869 ], [ 204, 855, 228, 869 ], [ 233, 855, 245, 869 ], [ 250, 855, 295, 869 ], [ 300, 855, 338, 869 ], [ 342, 855, 368, 869 ], [ 374, 855, 404, 869 ], [ 78, 872, 158, 886 ], [ 162, 872, 203, 886 ], [ 207, 872, 248, 886 ], [ 251, 872, 268, 886 ], [ 272, 872, 336, 886 ], [ 340, 872, 379, 886 ], [ 89, 888, 114, 902 ], [ 117, 888, 128, 902 ], [ 132, 888, 150, 902 ], [ 154, 888, 182, 902 ], [ 185, 888, 228, 902 ], [ 232, 888, 260, 902 ], [ 264, 888, 275, 902 ], [ 278, 888, 323, 902 ], [ 327, 888, 334, 902 ], [ 337, 888, 361, 902 ], [ 364, 888, 404, 902 ], [ 78, 905, 101, 919 ], [ 105, 905, 114, 919 ], [ 118, 905, 153, 919 ], [ 156, 905, 174, 919 ], [ 178, 905, 230, 919 ], [ 234, 905, 278, 919 ], [ 281, 905, 297, 919 ], [ 300, 905, 318, 919 ], [ 322, 905, 403, 919 ], [ 78, 937, 83, 948 ], [ 86, 937, 156, 948 ], [ 159, 937, 321, 948 ], [ 78, 950, 113, 961 ], [ 116, 950, 144, 961 ], [ 147, 950, 159, 961 ], [ 162, 950, 180, 961 ], [ 183, 950, 213, 961 ], [ 215, 950, 221, 961 ], [ 224, 950, 253, 961 ], [ 256, 950, 265, 961 ], [ 267, 950, 309, 961 ], [ 313, 950, 347, 961 ], [ 350, 950, 366, 961 ], [ 78, 962, 119, 973 ], [ 122, 962, 131, 973 ], [ 134, 962, 184, 973 ], [ 187, 962, 237, 973 ], [ 240, 962, 254, 973 ], [ 257, 962, 277, 973 ], [ 280, 962, 292, 973 ], [ 423, 556, 435, 570 ], [ 438, 556, 510, 570 ], [ 515, 556, 530, 570 ], [ 533, 556, 552, 570 ], [ 556, 556, 586, 570 ], [ 590, 556, 620, 570 ], [ 623, 556, 677, 570 ], [ 681, 556, 723, 570 ], [ 727, 556, 747, 570 ], [ 423, 573, 467, 587 ], [ 470, 573, 502, 587 ], [ 506, 573, 525, 587 ], [ 529, 573, 569, 587 ], [ 572, 573, 584, 587 ], [ 588, 573, 607, 587 ], [ 610, 573, 676, 587 ], [ 680, 573, 702, 587 ], [ 705, 573, 719, 587 ], [ 723, 573, 748, 587 ], [ 423, 589, 458, 603 ], [ 461, 589, 516, 603 ], [ 520, 589, 537, 603 ], [ 541, 589, 611, 603 ], [ 615, 589, 681, 603 ], [ 685, 589, 748, 603 ], [ 423, 606, 442, 620 ], [ 445, 606, 498, 620 ], [ 502, 606, 543, 620 ], [ 547, 606, 559, 620 ], [ 562, 606, 569, 620 ], [ 573, 606, 597, 620 ], [ 600, 606, 634, 620 ], [ 638, 606, 652, 620 ], [ 656, 606, 748, 620 ], [ 423, 623, 440, 637 ], [ 444, 623, 527, 637 ], [ 531, 623, 558, 637 ], [ 563, 623, 572, 637 ], [ 575, 623, 611, 637 ], [ 616, 623, 630, 637 ], [ 634, 623, 734, 637 ], [ 738, 623, 748, 637 ], [ 423, 639, 459, 653 ], [ 463, 639, 496, 653 ], [ 500, 639, 556, 653 ], [ 561, 639, 578, 653 ], [ 582, 639, 629, 653 ], [ 634, 639, 664, 653 ], [ 667, 639, 689, 653 ], [ 693, 639, 748, 653 ], [ 423, 656, 444, 670 ], [ 447, 656, 472, 670 ], [ 475, 656, 534, 670 ], [ 537, 656, 569, 670 ], [ 434, 672, 447, 686 ], [ 450, 672, 471, 686 ], [ 475, 672, 508, 686 ], [ 511, 672, 527, 686 ], [ 531, 672, 574, 686 ], [ 578, 672, 622, 686 ], [ 625, 672, 679, 686 ], [ 683, 672, 722, 686 ], [ 725, 672, 748, 686 ], [ 423, 689, 474, 703 ], [ 478, 689, 492, 703 ], [ 496, 689, 539, 703 ], [ 543, 689, 586, 703 ], [ 590, 689, 604, 703 ], [ 608, 689, 656, 703 ], [ 659, 689, 697, 703 ], [ 701, 689, 748, 703 ], [ 423, 706, 446, 720 ], [ 450, 706, 515, 720 ], [ 518, 706, 530, 720 ], [ 533, 706, 574, 720 ], [ 578, 706, 607, 720 ], [ 610, 706, 633, 720 ], [ 637, 706, 664, 720 ], [ 667, 706, 679, 720 ], [ 683, 706, 726, 720 ], [ 730, 706, 749, 720 ], [ 423, 722, 492, 736 ], [ 496, 722, 546, 736 ], [ 550, 722, 599, 736 ], [ 602, 722, 624, 736 ], [ 628, 722, 640, 736 ], [ 643, 722, 674, 736 ], [ 678, 722, 697, 736 ], [ 700, 722, 748, 736 ], [ 423, 739, 435, 753 ], [ 438, 739, 462, 753 ], [ 466, 739, 525, 753 ], [ 529, 739, 574, 753 ], [ 578, 739, 627, 753 ], [ 631, 739, 721, 753 ], [ 725, 739, 748, 753 ], [ 423, 755, 463, 769 ], [ 466, 755, 540, 769 ], [ 544, 755, 600, 769 ], [ 603, 755, 624, 769 ], [ 628, 755, 655, 769 ], [ 659, 755, 716, 769 ], [ 719, 755, 748, 769 ], [ 423, 772, 463, 786 ], [ 467, 772, 512, 786 ], [ 516, 772, 532, 786 ], [ 537, 772, 567, 786 ], [ 571, 772, 615, 786 ], [ 620, 772, 645, 786 ], [ 650, 772, 720, 786 ], [ 724, 772, 734, 786 ], [ 738, 772, 748, 786 ], [ 423, 789, 472, 803 ], [ 475, 789, 489, 803 ], [ 492, 789, 715, 803 ], [ 434, 805, 447, 819 ], [ 452, 805, 484, 819 ], [ 489, 805, 526, 819 ], [ 531, 805, 570, 819 ], [ 575, 805, 614, 819 ], [ 619, 805, 646, 819 ], [ 651, 805, 658, 819 ], [ 663, 805, 705, 819 ], [ 710, 805, 748, 819 ], [ 423, 822, 456, 836 ], [ 460, 822, 468, 836 ], [ 473, 822, 493, 836 ], [ 497, 822, 511, 836 ], [ 514, 822, 568, 836 ], [ 572, 822, 604, 836 ], [ 608, 822, 620, 836 ], [ 624, 822, 631, 836 ], [ 634, 822, 689, 836 ], [ 694, 822, 705, 836 ], [ 710, 822, 740, 836 ], [ 444, 855, 449, 869 ], [ 453, 855, 467, 869 ], [ 472, 855, 523, 869 ], [ 528, 855, 564, 869 ], [ 568, 855, 585, 869 ], [ 590, 855, 649, 869 ], [ 654, 855, 677, 869 ], [ 682, 855, 748, 869 ], [ 444, 872, 456, 886 ], [ 459, 872, 489, 886 ], [ 494, 872, 524, 886 ], [ 528, 872, 539, 886 ], [ 543, 872, 561, 886 ], [ 565, 872, 605, 886 ], [ 610, 872, 633, 886 ], [ 637, 872, 693, 886 ], [ 444, 888, 449, 902 ], [ 453, 888, 467, 902 ], [ 472, 888, 523, 902 ], [ 527, 888, 548, 902 ], [ 553, 888, 565, 902 ], [ 569, 888, 588, 902 ], [ 592, 888, 670, 902 ], [ 675, 888, 722, 902 ], [ 726, 888, 748, 902 ], [ 444, 905, 488, 919 ], [ 491, 905, 534, 919 ], [ 539, 905, 550, 919 ], [ 554, 905, 594, 919 ], [ 598, 905, 621, 919 ], [ 626, 905, 682, 919 ], [ 444, 921, 449, 935 ], [ 454, 921, 468, 935 ], [ 472, 921, 523, 935 ], [ 528, 921, 534, 935 ], [ 539, 921, 577, 935 ], [ 582, 921, 595, 935 ], [ 599, 921, 657, 935 ], [ 662, 921, 680, 935 ], [ 685, 921, 731, 935 ], [ 736, 921, 748, 935 ], [ 444, 938, 477, 952 ], [ 481, 938, 493, 952 ], [ 498, 938, 517, 952 ], [ 521, 938, 580, 952 ], [ 585, 938, 598, 952 ], [ 602, 938, 662, 952 ], [ 667, 938, 722, 952 ], [ 727, 938, 748, 952 ], [ 444, 955, 470, 969 ], [ 473, 955, 484, 969 ], [ 489, 955, 507, 969 ], [ 511, 955, 551, 969 ], [ 555, 955, 578, 969 ], [ 582, 955, 638, 969 ], [ 248, 987, 255, 997 ], [ 257, 987, 275, 997 ], [ 278, 987, 326, 997 ], [ 329, 987, 337, 997 ], [ 339, 987, 349, 997 ], [ 352, 987, 382, 997 ], [ 385, 987, 414, 997 ], [ 416, 987, 443, 997 ], [ 446, 987, 460, 997 ], [ 463, 987, 478, 997 ], [ 481, 987, 487, 997 ], [ 489, 987, 499, 997 ], [ 502, 987, 522, 997 ], [ 524, 987, 548, 997 ], [ 551, 987, 574, 997 ], [ 577, 987, 618, 997 ], [ 620, 987, 643, 997 ], [ 646, 987, 659, 997 ], [ 661, 987, 683, 997 ], [ 685, 987, 693, 997 ], [ 696, 987, 709, 997 ], [ 711, 987, 742, 997 ], [ 248, 998, 287, 1008 ], [ 289, 998, 330, 1008 ], [ 333, 998, 361, 1008 ], [ 364, 998, 535, 1008 ], [ 538, 998, 561, 1008 ], [ 564, 998, 593, 1008 ], [ 595, 998, 640, 1008 ], [ 643, 998, 658, 1008 ], [ 660, 998, 705, 1008 ], [ 708, 998, 723, 1008 ], [ 248, 1009, 298, 1019 ], [ 300, 1009, 307, 1019 ], [ 310, 1009, 324, 1019 ], [ 326, 1009, 360, 1019 ], [ 362, 1009, 396, 1019 ], [ 399, 1009, 412, 1019 ], [ 415, 1009, 443, 1019 ], [ 446, 1009, 465, 1019 ], [ 467, 1009, 473, 1019 ], [ 476, 1009, 508, 1019 ], [ 510, 1009, 530, 1019 ] ]
[ 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 ]
1281274
[ "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" ]
[ [ 699, 35, 783, 60 ], [ 66, 88, 104, 108 ], [ 109, 88, 235, 108 ], [ 240, 88, 275, 108 ], [ 280, 88, 363, 108 ], [ 368, 88, 471, 108 ], [ 476, 88, 494, 108 ], [ 498, 88, 529, 108 ], [ 534, 88, 586, 108 ], [ 591, 88, 644, 108 ], [ 650, 88, 701, 108 ], [ 66, 116, 113, 130 ], [ 115, 116, 148, 130 ], [ 151, 116, 190, 130 ], [ 193, 116, 264, 130 ], [ 267, 116, 305, 130 ], [ 308, 116, 322, 130 ], [ 325, 116, 390, 130 ], [ 393, 116, 417, 130 ], [ 420, 116, 441, 130 ], [ 444, 116, 480, 130 ], [ 483, 116, 519, 130 ], [ 523, 116, 559, 130 ], [ 562, 116, 588, 130 ], [ 591, 116, 666, 130 ], [ 66, 139, 109, 151 ], [ 112, 139, 123, 151 ], [ 125, 139, 158, 151 ], [ 161, 139, 199, 151 ], [ 201, 139, 256, 151 ], [ 258, 139, 321, 151 ], [ 324, 139, 335, 151 ], [ 337, 139, 371, 151 ], [ 374, 139, 394, 151 ], [ 397, 139, 433, 151 ], [ 435, 139, 483, 151 ], [ 486, 139, 535, 151 ], [ 538, 139, 596, 151 ], [ 598, 139, 623, 151 ], [ 72, 193, 98, 205 ], [ 101, 193, 122, 205 ], [ 125, 193, 137, 205 ], [ 141, 193, 175, 205 ], [ 178, 193, 206, 205 ], [ 209, 193, 225, 205 ], [ 229, 193, 239, 205 ], [ 241, 193, 256, 205 ], [ 260, 193, 284, 205 ], [ 286, 193, 307, 205 ], [ 310, 193, 336, 205 ], [ 339, 193, 385, 205 ], [ 388, 193, 403, 205 ], [ 406, 193, 433, 205 ], [ 436, 193, 465, 205 ], [ 468, 193, 508, 205 ], [ 512, 193, 534, 205 ], [ 72, 207, 96, 219 ], [ 99, 207, 117, 219 ], [ 120, 207, 142, 219 ], [ 145, 207, 172, 219 ], [ 176, 207, 181, 219 ], [ 184, 207, 268, 219 ], [ 271, 207, 354, 219 ], [ 357, 207, 403, 219 ], [ 406, 207, 436, 219 ], [ 439, 207, 449, 219 ], [ 452, 207, 480, 219 ], [ 483, 207, 520, 219 ], [ 523, 207, 533, 219 ], [ 72, 222, 99, 234 ], [ 101, 222, 127, 234 ], [ 131, 222, 154, 234 ], [ 157, 222, 183, 234 ], [ 186, 222, 204, 234 ], [ 206, 222, 254, 234 ], [ 257, 222, 267, 234 ], [ 270, 222, 296, 234 ], [ 300, 222, 361, 234 ], [ 364, 222, 374, 234 ], [ 377, 222, 431, 234 ], [ 434, 222, 452, 234 ], [ 455, 222, 514, 234 ], [ 516, 222, 533, 234 ], [ 72, 236, 90, 248 ], [ 92, 236, 138, 248 ], [ 141, 236, 151, 248 ], [ 153, 236, 206, 248 ], [ 209, 236, 270, 248 ], [ 273, 236, 318, 248 ], [ 321, 236, 335, 248 ], [ 337, 236, 353, 248 ], [ 356, 236, 376, 248 ], [ 378, 236, 394, 248 ], [ 397, 236, 412, 248 ], [ 415, 236, 438, 248 ], [ 440, 236, 450, 248 ], [ 452, 236, 467, 248 ], [ 470, 236, 512, 248 ], [ 515, 236, 533, 248 ], [ 72, 251, 88, 263 ], [ 91, 251, 114, 263 ], [ 117, 251, 183, 263 ], [ 187, 251, 210, 263 ], [ 213, 251, 223, 263 ], [ 226, 251, 241, 263 ], [ 244, 251, 272, 263 ], [ 276, 251, 302, 263 ], [ 305, 251, 315, 263 ], [ 319, 251, 343, 263 ], [ 346, 251, 372, 263 ], [ 375, 251, 415, 263 ], [ 419, 251, 436, 263 ], [ 439, 251, 449, 263 ], [ 452, 251, 474, 263 ], [ 478, 251, 503, 263 ], [ 506, 251, 533, 263 ], [ 72, 265, 107, 277 ], [ 109, 265, 124, 277 ], [ 127, 265, 172, 277 ], [ 175, 265, 190, 277 ], [ 193, 265, 227, 277 ], [ 230, 265, 262, 277 ], [ 264, 265, 311, 277 ], [ 314, 265, 331, 277 ], [ 334, 265, 365, 277 ], [ 368, 265, 391, 277 ], [ 394, 265, 409, 277 ], [ 411, 265, 438, 277 ], [ 441, 265, 470, 277 ], [ 473, 265, 492, 277 ], [ 495, 265, 534, 277 ], [ 72, 280, 88, 292 ], [ 90, 280, 100, 292 ], [ 103, 280, 144, 292 ], [ 147, 280, 167, 292 ], [ 170, 280, 188, 292 ], [ 190, 280, 237, 292 ], [ 240, 280, 299, 292 ], [ 302, 280, 319, 292 ], [ 321, 280, 348, 292 ], [ 351, 280, 368, 292 ], [ 371, 280, 397, 292 ], [ 399, 280, 433, 292 ], [ 436, 280, 464, 292 ], [ 467, 280, 513, 292 ], [ 516, 280, 534, 292 ], [ 72, 295, 90, 307 ], [ 93, 295, 127, 307 ], [ 130, 295, 162, 307 ], [ 166, 295, 191, 307 ], [ 194, 295, 214, 307 ], [ 218, 295, 241, 307 ], [ 244, 295, 254, 307 ], [ 257, 295, 307, 307 ], [ 311, 295, 341, 307 ], [ 345, 295, 363, 307 ], [ 366, 295, 415, 307 ], [ 418, 295, 451, 307 ], [ 455, 295, 520, 307 ], [ 524, 295, 534, 307 ], [ 72, 309, 88, 321 ], [ 91, 309, 115, 321 ], [ 118, 309, 135, 321 ], [ 138, 309, 156, 321 ], [ 159, 309, 193, 321 ], [ 196, 309, 228, 321 ], [ 231, 309, 272, 321 ], [ 275, 309, 285, 321 ], [ 288, 309, 333, 321 ], [ 336, 309, 366, 321 ], [ 369, 309, 387, 321 ], [ 390, 309, 415, 321 ], [ 418, 309, 451, 321 ], [ 454, 309, 489, 321 ], [ 492, 309, 533, 321 ], [ 72, 324, 93, 336 ], [ 96, 324, 114, 336 ], [ 117, 324, 142, 336 ], [ 145, 324, 161, 336 ], [ 165, 324, 185, 336 ], [ 188, 324, 235, 336 ], [ 239, 324, 249, 336 ], [ 252, 324, 314, 336 ], [ 318, 324, 364, 336 ], [ 367, 324, 396, 336 ], [ 400, 324, 412, 336 ], [ 415, 324, 447, 336 ], [ 450, 324, 468, 336 ], [ 472, 324, 491, 336 ], [ 494, 324, 512, 336 ], [ 516, 324, 534, 336 ], [ 72, 338, 102, 350 ], [ 105, 338, 137, 350 ], [ 141, 338, 176, 350 ], [ 179, 338, 209, 350 ], [ 213, 338, 231, 350 ], [ 234, 338, 259, 350 ], [ 263, 338, 305, 350 ], [ 308, 338, 341, 350 ], [ 344, 338, 390, 350 ], [ 394, 338, 417, 350 ], [ 420, 338, 430, 350 ], [ 433, 338, 458, 350 ], [ 462, 338, 482, 350 ], [ 485, 338, 533, 350 ], [ 72, 353, 88, 365 ], [ 91, 353, 150, 365 ], [ 154, 353, 171, 365 ], [ 174, 353, 199, 365 ], [ 202, 353, 207, 365 ], [ 211, 353, 243, 365 ], [ 246, 353, 257, 365 ], [ 260, 353, 285, 365 ], [ 288, 353, 303, 365 ], [ 307, 353, 352, 365 ], [ 355, 353, 395, 365 ], [ 398, 353, 426, 365 ], [ 430, 353, 458, 365 ], [ 462, 353, 473, 365 ], [ 476, 353, 500, 365 ], [ 504, 353, 534, 365 ], [ 72, 368, 94, 380 ], [ 96, 368, 123, 380 ], [ 126, 368, 136, 380 ], [ 139, 368, 154, 380 ], [ 156, 368, 204, 380 ], [ 207, 368, 248, 380 ], [ 251, 368, 274, 380 ], [ 277, 368, 294, 380 ], [ 297, 368, 327, 380 ], [ 329, 368, 366, 380 ], [ 369, 368, 388, 380 ], [ 390, 368, 431, 380 ], [ 434, 368, 444, 380 ], [ 447, 368, 492, 380 ], [ 495, 368, 534, 380 ], [ 72, 382, 101, 394 ], [ 104, 382, 132, 394 ], [ 135, 382, 145, 394 ], [ 148, 382, 164, 394 ], [ 167, 382, 184, 394 ], [ 187, 382, 195, 394 ], [ 198, 382, 223, 394 ], [ 227, 382, 261, 394 ], [ 264, 382, 274, 394 ], [ 277, 382, 282, 394 ], [ 285, 382, 327, 394 ], [ 331, 382, 356, 394 ], [ 359, 382, 426, 394 ], [ 429, 382, 439, 394 ], [ 442, 382, 462, 394 ], [ 465, 382, 509, 394 ], [ 512, 382, 533, 394 ], [ 72, 397, 109, 409 ], [ 112, 397, 147, 409 ], [ 151, 397, 170, 409 ], [ 173, 397, 226, 409 ], [ 229, 397, 245, 409 ], [ 248, 397, 278, 409 ], [ 282, 397, 312, 409 ], [ 316, 397, 371, 409 ], [ 374, 397, 384, 409 ], [ 388, 397, 435, 409 ], [ 438, 397, 452, 409 ], [ 456, 397, 512, 409 ], [ 515, 397, 533, 409 ], [ 72, 411, 108, 423 ], [ 110, 411, 122, 423 ], [ 124, 411, 169, 423 ], [ 172, 411, 187, 423 ], [ 190, 411, 224, 423 ], [ 226, 411, 254, 423 ], [ 257, 411, 283, 423 ], [ 286, 411, 296, 423 ], [ 299, 411, 323, 423 ], [ 325, 411, 351, 423 ], [ 353, 411, 394, 423 ], [ 397, 411, 421, 423 ], [ 424, 411, 446, 423 ], [ 448, 411, 467, 423 ], [ 469, 411, 486, 423 ], [ 489, 411, 516, 423 ], [ 518, 411, 533, 423 ], [ 72, 426, 92, 438 ], [ 96, 426, 114, 438 ], [ 118, 426, 139, 438 ], [ 142, 426, 154, 438 ], [ 157, 426, 167, 438 ], [ 171, 426, 189, 438 ], [ 193, 426, 203, 438 ], [ 206, 426, 254, 438 ], [ 258, 426, 274, 438 ], [ 277, 426, 322, 438 ], [ 326, 426, 352, 438 ], [ 356, 426, 371, 438 ], [ 374, 426, 452, 438 ], [ 456, 426, 533, 438 ], [ 72, 440, 121, 452 ], [ 124, 440, 142, 452 ], [ 146, 440, 171, 452 ], [ 175, 440, 252, 452 ], [ 255, 440, 323, 452 ], [ 327, 441, 345, 453 ], [ 348, 441, 379, 453 ], [ 382, 440, 425, 452 ], [ 428, 440, 478, 452 ], [ 482, 440, 503, 452 ], [ 506, 440, 533, 452 ], [ 72, 455, 101, 467 ], [ 104, 455, 128, 467 ], [ 131, 455, 151, 467 ], [ 153, 455, 191, 467 ], [ 194, 455, 226, 467 ], [ 228, 455, 265, 467 ], [ 268, 455, 343, 467 ], [ 346, 455, 381, 467 ], [ 386, 455, 491, 467 ], [ 493, 455, 533, 467 ], [ 72, 470, 86, 482 ], [ 88, 470, 164, 482 ], [ 167, 470, 204, 482 ], [ 206, 470, 218, 482 ], [ 221, 470, 243, 482 ], [ 245, 470, 273, 482 ], [ 66, 512, 136, 526 ], [ 140, 512, 188, 526 ], [ 191, 512, 206, 526 ], [ 209, 512, 272, 526 ], [ 275, 512, 293, 526 ], [ 66, 527, 90, 541 ], [ 94, 527, 115, 541 ], [ 118, 527, 149, 541 ], [ 153, 527, 166, 541 ], [ 170, 527, 200, 541 ], [ 203, 527, 232, 541 ], [ 236, 527, 262, 541 ], [ 265, 527, 293, 541 ], [ 66, 542, 99, 556 ], [ 102, 542, 118, 556 ], [ 121, 542, 154, 556 ], [ 157, 542, 186, 556 ], [ 190, 542, 237, 556 ], [ 240, 542, 263, 556 ], [ 266, 542, 293, 556 ], [ 66, 556, 79, 570 ], [ 83, 556, 123, 570 ], [ 126, 556, 150, 570 ], [ 153, 556, 219, 570 ], [ 222, 556, 232, 570 ], [ 236, 556, 252, 570 ], [ 255, 556, 293, 570 ], [ 66, 571, 112, 585 ], [ 116, 571, 176, 585 ], [ 179, 571, 201, 585 ], [ 206, 571, 226, 585 ], [ 230, 571, 278, 585 ], [ 282, 571, 293, 585 ], [ 66, 585, 121, 599 ], [ 125, 585, 157, 599 ], [ 160, 585, 179, 599 ], [ 182, 585, 196, 599 ], [ 199, 585, 217, 599 ], [ 221, 585, 249, 599 ], [ 252, 585, 293, 599 ], [ 66, 600, 94, 614 ], [ 98, 600, 119, 614 ], [ 122, 600, 149, 614 ], [ 153, 600, 209, 614 ], [ 212, 600, 236, 614 ], [ 239, 600, 293, 614 ], [ 66, 615, 86, 629 ], [ 89, 615, 95, 629 ], [ 98, 615, 130, 629 ], [ 133, 615, 143, 629 ], [ 146, 615, 172, 629 ], [ 175, 615, 221, 629 ], [ 224, 615, 294, 629 ], [ 66, 629, 141, 643 ], [ 145, 629, 195, 643 ], [ 198, 629, 227, 643 ], [ 231, 629, 293, 643 ], [ 66, 644, 95, 658 ], [ 99, 644, 157, 658 ], [ 161, 644, 191, 658 ], [ 195, 644, 294, 658 ], [ 66, 658, 146, 672 ], [ 149, 658, 168, 672 ], [ 171, 658, 248, 672 ], [ 251, 658, 293, 672 ], [ 66, 673, 100, 687 ], [ 103, 673, 122, 687 ], [ 126, 673, 157, 687 ], [ 160, 673, 184, 687 ], [ 188, 673, 208, 687 ], [ 212, 673, 233, 687 ], [ 237, 673, 253, 687 ], [ 256, 673, 293, 687 ], [ 66, 687, 89, 701 ], [ 93, 687, 121, 701 ], [ 124, 687, 143, 701 ], [ 146, 687, 176, 701 ], [ 180, 687, 202, 701 ], [ 206, 687, 212, 701 ], [ 215, 687, 234, 701 ], [ 237, 687, 248, 701 ], [ 251, 687, 293, 701 ], [ 66, 702, 119, 716 ], [ 122, 702, 132, 716 ], [ 136, 702, 163, 716 ], [ 166, 702, 214, 716 ], [ 217, 702, 238, 716 ], [ 242, 702, 294, 716 ], [ 66, 717, 96, 731 ], [ 99, 717, 159, 731 ], [ 163, 717, 196, 731 ], [ 198, 717, 220, 731 ], [ 223, 717, 293, 731 ], [ 66, 731, 106, 745 ], [ 109, 731, 119, 745 ], [ 123, 731, 136, 745 ], [ 139, 731, 165, 745 ], [ 169, 731, 192, 745 ], [ 195, 731, 260, 745 ], [ 263, 731, 294, 745 ], [ 66, 746, 90, 760 ], [ 93, 746, 108, 760 ], [ 112, 746, 136, 760 ], [ 139, 746, 204, 760 ], [ 208, 746, 258, 760 ], [ 261, 746, 282, 760 ], [ 285, 746, 293, 760 ], [ 66, 760, 99, 774 ], [ 101, 760, 120, 774 ], [ 122, 760, 139, 774 ], [ 141, 760, 193, 774 ], [ 85, 775, 106, 789 ], [ 109, 775, 140, 789 ], [ 143, 775, 219, 789 ], [ 223, 775, 268, 789 ], [ 271, 775, 293, 789 ], [ 66, 789, 105, 803 ], [ 108, 789, 133, 803 ], [ 136, 789, 152, 803 ], [ 156, 789, 199, 803 ], [ 203, 789, 214, 803 ], [ 217, 789, 233, 803 ], [ 237, 789, 280, 803 ], [ 66, 804, 110, 818 ], [ 113, 804, 139, 818 ], [ 143, 804, 154, 818 ], [ 157, 804, 189, 818 ], [ 192, 804, 215, 818 ], [ 219, 804, 265, 818 ], [ 269, 804, 294, 818 ], [ 66, 819, 94, 833 ], [ 98, 819, 117, 833 ], [ 121, 819, 155, 833 ], [ 158, 819, 199, 833 ], [ 204, 819, 215, 833 ], [ 218, 819, 246, 833 ], [ 249, 819, 265, 833 ], [ 269, 819, 293, 833 ], [ 66, 833, 81, 847 ], [ 85, 833, 91, 847 ], [ 95, 833, 155, 847 ], [ 158, 833, 177, 847 ], [ 181, 833, 227, 847 ], [ 231, 833, 243, 847 ], [ 246, 833, 273, 847 ], [ 277, 833, 293, 847 ], [ 66, 848, 89, 862 ], [ 92, 848, 166, 862 ], [ 169, 848, 221, 862 ], [ 223, 848, 259, 862 ], [ 263, 848, 294, 862 ], [ 66, 862, 85, 876 ], [ 89, 862, 105, 876 ], [ 108, 862, 131, 876 ], [ 135, 862, 161, 876 ], [ 165, 862, 184, 876 ], [ 187, 862, 214, 876 ], [ 218, 862, 294, 876 ], [ 66, 877, 100, 891 ], [ 104, 877, 137, 891 ], [ 140, 877, 170, 891 ], [ 174, 877, 240, 891 ], [ 244, 877, 275, 891 ], [ 279, 877, 294, 891 ], [ 66, 892, 124, 906 ], [ 128, 892, 146, 906 ], [ 150, 892, 170, 906 ], [ 173, 892, 191, 906 ], [ 195, 892, 240, 906 ], [ 243, 892, 254, 906 ], [ 258, 892, 294, 906 ], [ 66, 906, 104, 920 ], [ 108, 906, 119, 920 ], [ 122, 906, 186, 920 ], [ 190, 906, 207, 920 ], [ 211, 906, 230, 920 ], [ 234, 906, 266, 920 ], [ 270, 906, 294, 920 ], [ 66, 921, 89, 935 ], [ 92, 921, 126, 935 ], [ 128, 921, 144, 935 ], [ 147, 921, 247, 935 ], [ 250, 921, 281, 935 ], [ 283, 921, 293, 935 ], [ 66, 935, 146, 949 ], [ 150, 935, 159, 949 ], [ 163, 935, 201, 949 ], [ 205, 935, 250, 949 ], [ 253, 935, 264, 949 ], [ 267, 935, 293, 949 ], [ 66, 950, 96, 964 ], [ 100, 950, 122, 964 ], [ 127, 950, 155, 964 ], [ 159, 950, 179, 964 ], [ 183, 950, 189, 964 ], [ 193, 950, 219, 964 ], [ 223, 950, 239, 964 ], [ 243, 950, 249, 964 ], [ 253, 950, 294, 964 ], [ 66, 965, 147, 979 ], [ 151, 965, 171, 979 ], [ 175, 965, 245, 979 ], [ 249, 965, 293, 979 ], [ 66, 979, 87, 993 ], [ 91, 979, 143, 993 ], [ 147, 979, 180, 993 ], [ 184, 979, 224, 993 ], [ 227, 979, 293, 993 ], [ 66, 994, 84, 1008 ], [ 88, 994, 107, 1008 ], [ 111, 994, 170, 1008 ], [ 174, 994, 195, 1008 ], [ 199, 994, 216, 1008 ], [ 219, 994, 244, 1008 ], [ 247, 994, 266, 1008 ], [ 270, 994, 293, 1008 ], [ 66, 1008, 132, 1022 ], [ 136, 1008, 155, 1022 ], [ 160, 1008, 211, 1022 ], [ 215, 1008, 250, 1022 ], [ 253, 1008, 293, 1022 ], [ 311, 512, 364, 526 ], [ 368, 512, 395, 526 ], [ 399, 512, 463, 526 ], [ 467, 512, 491, 526 ], [ 495, 512, 539, 526 ], [ 311, 527, 361, 541 ], [ 365, 527, 380, 541 ], [ 384, 527, 430, 541 ], [ 434, 527, 445, 541 ], [ 449, 527, 475, 541 ], [ 479, 527, 515, 541 ], [ 519, 527, 539, 541 ], [ 311, 542, 363, 556 ], [ 366, 542, 376, 556 ], [ 380, 542, 437, 556 ], [ 441, 542, 459, 556 ], [ 462, 542, 472, 556 ], [ 475, 542, 517, 556 ], [ 521, 542, 539, 556 ], [ 311, 556, 330, 570 ], [ 334, 556, 345, 570 ], [ 349, 556, 396, 570 ], [ 401, 556, 474, 570 ], [ 478, 556, 488, 570 ], [ 492, 556, 514, 570 ], [ 518, 556, 529, 570 ], [ 533, 556, 539, 570 ], [ 311, 571, 350, 585 ], [ 353, 571, 396, 585 ], [ 399, 571, 421, 585 ], [ 330, 585, 342, 599 ], [ 345, 585, 371, 599 ], [ 374, 585, 386, 599 ], [ 390, 585, 437, 599 ], [ 441, 585, 464, 599 ], [ 467, 585, 503, 599 ], [ 507, 585, 538, 599 ], [ 311, 600, 334, 614 ], [ 338, 600, 390, 614 ], [ 393, 600, 431, 614 ], [ 435, 600, 446, 614 ], [ 449, 600, 468, 614 ], [ 472, 600, 486, 614 ], [ 489, 600, 505, 614 ], [ 509, 600, 538, 614 ], [ 311, 615, 339, 629 ], [ 341, 615, 367, 629 ], [ 371, 615, 431, 629 ], [ 434, 615, 444, 629 ], [ 447, 615, 463, 629 ], [ 465, 615, 503, 629 ], [ 506, 615, 539, 629 ], [ 311, 629, 360, 643 ], [ 363, 629, 382, 643 ], [ 386, 629, 416, 643 ], [ 420, 629, 456, 643 ], [ 460, 629, 473, 643 ], [ 476, 629, 510, 643 ], [ 514, 629, 539, 643 ], [ 311, 644, 347, 658 ], [ 350, 644, 375, 658 ], [ 379, 644, 402, 658 ], [ 405, 644, 441, 658 ], [ 445, 644, 456, 658 ], [ 459, 644, 489, 658 ], [ 492, 644, 509, 658 ], [ 513, 644, 539, 658 ], [ 311, 658, 345, 672 ], [ 348, 658, 396, 672 ], [ 400, 658, 411, 672 ], [ 414, 658, 426, 672 ], [ 429, 658, 435, 672 ], [ 438, 658, 477, 672 ], [ 481, 658, 539, 672 ], [ 311, 673, 347, 687 ], [ 350, 673, 365, 687 ], [ 369, 673, 397, 687 ], [ 400, 673, 441, 687 ], [ 445, 673, 490, 687 ], [ 493, 673, 538, 687 ], [ 311, 687, 322, 701 ], [ 326, 687, 345, 701 ], [ 348, 687, 374, 701 ], [ 378, 687, 404, 701 ], [ 408, 687, 433, 701 ], [ 437, 687, 454, 701 ], [ 458, 687, 483, 701 ], [ 487, 687, 539, 701 ], [ 311, 702, 333, 716 ], [ 336, 702, 367, 716 ], [ 370, 702, 395, 716 ], [ 397, 702, 436, 716 ], [ 439, 702, 449, 716 ], [ 452, 702, 483, 716 ], [ 485, 702, 517, 716 ], [ 520, 702, 539, 716 ], [ 311, 717, 340, 731 ], [ 344, 717, 538, 731 ], [ 311, 731, 369, 745 ], [ 373, 731, 383, 745 ], [ 387, 731, 400, 745 ], [ 405, 731, 437, 745 ], [ 441, 731, 470, 745 ], [ 474, 731, 484, 745 ], [ 489, 731, 502, 745 ], [ 506, 731, 538, 745 ], [ 311, 746, 372, 760 ], [ 379, 746, 412, 760 ], [ 417, 746, 468, 760 ], [ 474, 746, 480, 760 ], [ 486, 746, 500, 760 ], [ 506, 746, 539, 760 ], [ 311, 760, 361, 774 ], [ 365, 760, 375, 774 ], [ 379, 760, 392, 774 ], [ 396, 760, 427, 774 ], [ 431, 760, 467, 774 ], [ 472, 760, 482, 774 ], [ 485, 760, 498, 774 ], [ 503, 760, 539, 774 ], [ 311, 775, 341, 789 ], [ 345, 775, 393, 789 ], [ 396, 775, 464, 789 ], [ 468, 775, 525, 789 ], [ 528, 775, 539, 789 ], [ 311, 789, 327, 803 ], [ 331, 789, 356, 803 ], [ 360, 789, 382, 803 ], [ 385, 789, 408, 803 ], [ 411, 789, 430, 803 ], [ 434, 789, 474, 803 ], [ 477, 789, 493, 803 ], [ 497, 789, 515, 803 ], [ 519, 789, 529, 803 ], [ 533, 789, 539, 803 ], [ 311, 804, 344, 818 ], [ 347, 804, 357, 818 ], [ 360, 804, 390, 818 ], [ 394, 804, 439, 818 ], [ 442, 804, 464, 818 ], [ 468, 804, 478, 818 ], [ 481, 804, 502, 818 ], [ 505, 804, 538, 818 ], [ 311, 819, 329, 833 ], [ 332, 819, 341, 833 ], [ 344, 819, 356, 833 ], [ 358, 819, 391, 833 ], [ 393, 819, 454, 833 ], [ 457, 819, 481, 833 ], [ 483, 819, 492, 833 ], [ 495, 819, 507, 833 ], [ 510, 819, 539, 833 ], [ 311, 833, 364, 847 ], [ 367, 833, 377, 847 ], [ 380, 833, 392, 847 ], [ 396, 833, 427, 847 ], [ 430, 833, 449, 847 ], [ 453, 833, 507, 847 ], [ 510, 833, 538, 847 ], [ 311, 848, 335, 862 ], [ 339, 848, 378, 862 ], [ 381, 848, 401, 862 ], [ 405, 848, 444, 862 ], [ 447, 848, 482, 862 ], [ 486, 848, 538, 862 ], [ 311, 862, 352, 876 ], [ 355, 862, 406, 876 ], [ 411, 862, 421, 876 ], [ 424, 862, 437, 876 ], [ 440, 862, 471, 876 ], [ 475, 862, 509, 876 ], [ 512, 862, 522, 876 ], [ 526, 862, 539, 876 ], [ 311, 877, 346, 891 ], [ 350, 877, 370, 891 ], [ 373, 877, 449, 891 ], [ 452, 877, 483, 891 ], [ 487, 877, 538, 891 ], [ 311, 892, 321, 906 ], [ 324, 892, 336, 906 ], [ 339, 892, 368, 906 ], [ 372, 892, 417, 906 ], [ 420, 892, 430, 906 ], [ 433, 892, 445, 906 ], [ 448, 892, 477, 906 ], [ 480, 892, 538, 906 ], [ 311, 906, 330, 920 ], [ 334, 906, 380, 920 ], [ 384, 906, 414, 920 ], [ 417, 906, 476, 920 ], [ 480, 906, 490, 920 ], [ 493, 906, 505, 920 ], [ 509, 906, 539, 920 ], [ 311, 921, 345, 935 ], [ 349, 921, 369, 935 ], [ 372, 921, 426, 935 ], [ 430, 921, 465, 935 ], [ 469, 921, 502, 935 ], [ 505, 921, 538, 935 ], [ 311, 935, 331, 949 ], [ 335, 935, 364, 949 ], [ 368, 935, 392, 949 ], [ 396, 935, 421, 949 ], [ 425, 935, 473, 949 ], [ 477, 935, 487, 949 ], [ 491, 935, 538, 949 ], [ 311, 950, 349, 964 ], [ 353, 950, 416, 964 ], [ 420, 950, 433, 964 ], [ 437, 950, 454, 964 ], [ 458, 950, 482, 964 ], [ 487, 950, 515, 964 ], [ 518, 950, 538, 964 ], [ 311, 965, 364, 979 ], [ 368, 965, 440, 979 ], [ 444, 965, 462, 979 ], [ 465, 965, 508, 979 ], [ 513, 965, 539, 979 ], [ 311, 979, 359, 993 ], [ 362, 979, 384, 993 ], [ 388, 979, 400, 993 ], [ 403, 979, 448, 993 ], [ 451, 979, 469, 993 ], [ 472, 979, 482, 993 ], [ 485, 979, 514, 993 ], [ 517, 979, 538, 993 ], [ 311, 994, 327, 1008 ], [ 331, 994, 368, 1008 ], [ 372, 994, 409, 1008 ], [ 413, 994, 495, 1008 ], [ 499, 994, 538, 1008 ], [ 311, 1008, 358, 1022 ], [ 361, 1008, 370, 1022 ], [ 372, 1008, 384, 1022 ], [ 386, 1008, 419, 1022 ], [ 66, 1049, 134, 1062 ], [ 137, 1049, 169, 1062 ], [ 172, 1049, 232, 1062 ], [ 238, 1051, 244, 1061 ], [ 250, 1053, 280, 1062 ], [ 283, 1050, 299, 1062 ], [ 301, 1050, 304, 1062 ], [ 306, 1053, 336, 1062 ], [ 338, 1050, 349, 1062 ], [ 351, 1050, 354, 1062 ], [ 356, 1050, 392, 1062 ], [ 394, 1050, 415, 1062 ], [ 575, 177, 617, 191 ], [ 621, 177, 666, 191 ], [ 670, 177, 681, 191 ], [ 685, 177, 763, 191 ], [ 766, 177, 783, 191 ], [ 556, 192, 581, 206 ], [ 585, 192, 637, 206 ], [ 641, 192, 665, 206 ], [ 669, 192, 700, 206 ], [ 704, 192, 747, 206 ], [ 751, 192, 783, 206 ], [ 556, 206, 575, 220 ], [ 579, 206, 608, 220 ], [ 611, 206, 651, 220 ], [ 655, 206, 694, 220 ], [ 698, 206, 755, 220 ], [ 758, 206, 768, 220 ], [ 771, 206, 783, 220 ], [ 556, 221, 586, 235 ], [ 589, 221, 635, 235 ], [ 639, 221, 649, 235 ], [ 652, 221, 664, 235 ], [ 668, 221, 702, 235 ], [ 705, 221, 783, 235 ], [ 556, 235, 600, 249 ], [ 604, 235, 638, 249 ], [ 641, 235, 693, 249 ], [ 696, 235, 712, 249 ], [ 716, 235, 756, 249 ], [ 760, 235, 784, 249 ], [ 556, 250, 587, 264 ], [ 590, 250, 601, 264 ], [ 603, 250, 635, 264 ], [ 638, 250, 661, 264 ], [ 664, 250, 674, 264 ], [ 677, 250, 747, 264 ], [ 750, 250, 784, 264 ], [ 556, 265, 576, 279 ], [ 580, 265, 609, 279 ], [ 614, 265, 675, 279 ], [ 679, 265, 734, 279 ], [ 737, 265, 783, 279 ], [ 556, 279, 566, 293 ], [ 568, 279, 580, 293 ], [ 583, 279, 612, 293 ], [ 615, 279, 655, 293 ], [ 657, 279, 667, 293 ], [ 669, 279, 681, 293 ], [ 684, 279, 717, 293 ], [ 575, 294, 602, 308 ], [ 605, 294, 621, 308 ], [ 624, 294, 647, 308 ], [ 651, 294, 681, 308 ], [ 684, 294, 730, 308 ], [ 734, 294, 783, 308 ], [ 556, 308, 577, 322 ], [ 580, 308, 628, 322 ], [ 632, 308, 655, 322 ], [ 658, 308, 708, 322 ], [ 712, 308, 783, 322 ], [ 556, 323, 568, 337 ], [ 572, 323, 594, 337 ], [ 597, 323, 622, 337 ], [ 625, 323, 691, 337 ], [ 695, 323, 705, 337 ], [ 709, 323, 734, 337 ], [ 736, 323, 783, 337 ], [ 556, 337, 577, 351 ], [ 580, 337, 603, 351 ], [ 606, 337, 629, 351 ], [ 633, 337, 660, 351 ], [ 664, 337, 677, 351 ], [ 681, 337, 711, 351 ], [ 714, 337, 784, 351 ], [ 556, 352, 567, 366 ], [ 571, 352, 594, 366 ], [ 598, 352, 609, 366 ], [ 613, 352, 657, 366 ], [ 661, 352, 686, 366 ], [ 691, 352, 708, 366 ], [ 712, 352, 723, 366 ], [ 728, 352, 784, 366 ], [ 556, 367, 593, 381 ], [ 597, 367, 657, 381 ], [ 660, 367, 686, 381 ], [ 689, 367, 715, 381 ], [ 719, 367, 763, 381 ], [ 765, 367, 783, 381 ], [ 556, 381, 587, 395 ], [ 591, 381, 625, 395 ], [ 629, 381, 645, 395 ], [ 648, 381, 665, 395 ], [ 669, 381, 699, 395 ], [ 703, 381, 738, 395 ], [ 742, 381, 769, 395 ], [ 772, 381, 783, 395 ], [ 556, 396, 586, 410 ], [ 589, 396, 612, 410 ], [ 615, 396, 658, 410 ], [ 660, 396, 678, 410 ], [ 681, 396, 729, 410 ], [ 732, 396, 746, 410 ], [ 750, 396, 784, 410 ], [ 556, 410, 575, 424 ], [ 578, 410, 599, 424 ], [ 602, 410, 625, 424 ], [ 628, 410, 667, 424 ], [ 670, 410, 723, 424 ], [ 726, 410, 736, 424 ], [ 740, 410, 756, 424 ], [ 759, 410, 784, 424 ], [ 556, 425, 586, 439 ], [ 589, 425, 601, 439 ], [ 604, 425, 620, 439 ], [ 622, 425, 666, 439 ], [ 669, 425, 679, 439 ], [ 681, 425, 697, 439 ], [ 700, 425, 740, 439 ], [ 742, 425, 752, 439 ], [ 755, 425, 783, 439 ], [ 556, 440, 585, 454 ], [ 589, 440, 647, 454 ], [ 651, 440, 668, 454 ], [ 671, 440, 699, 454 ], [ 704, 440, 725, 454 ], [ 728, 440, 763, 454 ], [ 767, 440, 784, 454 ], [ 556, 454, 587, 468 ], [ 591, 454, 622, 468 ], [ 626, 454, 674, 468 ], [ 677, 454, 723, 468 ], [ 727, 454, 783, 468 ], [ 556, 469, 615, 483 ], [ 618, 469, 643, 483 ], [ 647, 469, 675, 483 ], [ 679, 469, 710, 483 ], [ 713, 469, 783, 483 ], [ 556, 483, 576, 497 ], [ 580, 483, 640, 497 ], [ 643, 483, 696, 497 ], [ 700, 483, 706, 497 ], [ 710, 483, 755, 497 ], [ 758, 483, 774, 497 ], [ 778, 483, 784, 497 ], [ 556, 498, 599, 512 ], [ 602, 498, 630, 512 ], [ 632, 498, 659, 512 ], [ 662, 498, 689, 512 ], [ 692, 498, 713, 512 ], [ 715, 498, 783, 512 ], [ 556, 512, 601, 526 ], [ 605, 512, 658, 526 ], [ 661, 512, 671, 526 ], [ 675, 512, 687, 526 ], [ 690, 512, 724, 526 ], [ 728, 512, 753, 526 ], [ 757, 512, 784, 526 ], [ 556, 527, 596, 541 ], [ 600, 527, 641, 541 ], [ 644, 527, 685, 541 ], [ 689, 527, 748, 541 ], [ 751, 527, 764, 541 ], [ 767, 527, 783, 541 ], [ 556, 542, 586, 556 ], [ 589, 542, 626, 556 ], [ 630, 542, 640, 556 ], [ 643, 542, 664, 556 ], [ 667, 542, 702, 556 ], [ 706, 542, 736, 556 ], [ 739, 542, 749, 556 ], [ 752, 542, 783, 556 ], [ 556, 556, 601, 570 ], [ 604, 556, 677, 570 ], [ 680, 556, 726, 570 ], [ 730, 556, 783, 570 ], [ 556, 571, 575, 585 ], [ 579, 571, 605, 585 ], [ 608, 571, 619, 585 ], [ 623, 571, 641, 585 ], [ 644, 571, 655, 585 ], [ 659, 571, 707, 585 ], [ 710, 571, 783, 585 ], [ 556, 585, 589, 599 ], [ 591, 585, 637, 599 ], [ 640, 585, 659, 599 ], [ 661, 585, 716, 599 ], [ 719, 585, 761, 599 ], [ 764, 585, 784, 599 ], [ 556, 600, 573, 614 ], [ 576, 600, 588, 614 ], [ 591, 600, 613, 614 ], [ 617, 600, 627, 614 ], [ 631, 600, 663, 614 ], [ 666, 600, 709, 614 ], [ 712, 600, 723, 614 ], [ 726, 600, 784, 614 ], [ 556, 615, 583, 629 ], [ 587, 615, 656, 629 ], [ 660, 615, 683, 629 ], [ 686, 615, 696, 629 ], [ 700, 615, 729, 629 ], [ 732, 615, 751, 629 ], [ 755, 615, 783, 629 ], [ 556, 629, 607, 643 ], [ 609, 629, 618, 643 ], [ 620, 629, 632, 643 ], [ 634, 629, 666, 643 ], [ 575, 644, 587, 658 ], [ 592, 644, 621, 658 ], [ 626, 644, 644, 658 ], [ 649, 644, 681, 658 ], [ 686, 644, 717, 658 ], [ 723, 644, 754, 658 ], [ 759, 644, 783, 658 ], [ 556, 658, 616, 672 ], [ 618, 658, 628, 672 ], [ 631, 658, 661, 672 ], [ 664, 658, 724, 672 ], [ 726, 658, 736, 672 ], [ 739, 658, 752, 672 ], [ 755, 658, 765, 672 ], [ 767, 658, 783, 672 ], [ 556, 673, 582, 687 ], [ 585, 673, 602, 687 ], [ 606, 673, 634, 687 ], [ 637, 673, 690, 687 ], [ 694, 673, 713, 687 ], [ 717, 673, 783, 687 ], [ 556, 687, 579, 701 ], [ 582, 687, 599, 701 ], [ 602, 687, 647, 701 ], [ 650, 687, 660, 701 ], [ 664, 687, 680, 701 ], [ 683, 687, 720, 701 ], [ 724, 687, 784, 701 ], [ 556, 702, 574, 716 ], [ 578, 702, 614, 716 ], [ 617, 702, 636, 716 ], [ 639, 702, 679, 716 ], [ 683, 702, 741, 716 ], [ 744, 702, 783, 716 ], [ 556, 717, 582, 731 ], [ 586, 717, 603, 731 ], [ 606, 717, 645, 731 ], [ 649, 717, 664, 731 ], [ 668, 717, 699, 731 ], [ 703, 717, 760, 731 ], [ 764, 717, 784, 731 ], [ 556, 731, 593, 745 ], [ 597, 731, 647, 745 ], [ 650, 731, 661, 745 ], [ 665, 731, 723, 745 ], [ 727, 731, 743, 745 ], [ 746, 731, 783, 745 ], [ 556, 746, 580, 760 ], [ 583, 746, 634, 760 ], [ 637, 746, 643, 760 ], [ 646, 746, 732, 760 ], [ 736, 746, 784, 760 ], [ 556, 760, 587, 774 ], [ 590, 760, 600, 774 ], [ 602, 760, 631, 774 ], [ 634, 760, 677, 774 ], [ 679, 760, 689, 774 ], [ 692, 760, 708, 774 ], [ 710, 760, 735, 774 ], [ 737, 760, 754, 774 ], [ 757, 760, 783, 774 ], [ 556, 775, 567, 789 ], [ 570, 775, 611, 789 ], [ 615, 775, 639, 789 ], [ 643, 775, 666, 789 ], [ 670, 775, 688, 789 ], [ 691, 775, 710, 789 ], [ 714, 775, 731, 789 ], [ 735, 775, 783, 789 ], [ 556, 789, 621, 803 ], [ 625, 789, 658, 803 ], [ 660, 789, 690, 803 ], [ 694, 789, 725, 803 ], [ 728, 789, 783, 803 ], [ 556, 804, 583, 818 ], [ 586, 804, 605, 818 ], [ 607, 804, 634, 818 ], [ 636, 804, 652, 818 ], [ 654, 804, 713, 818 ], [ 716, 804, 726, 818 ], [ 728, 804, 783, 818 ], [ 556, 819, 627, 833 ], [ 631, 819, 687, 833 ], [ 691, 819, 755, 833 ], [ 759, 819, 784, 833 ], [ 556, 833, 595, 847 ], [ 598, 833, 611, 847 ], [ 614, 833, 620, 847 ], [ 623, 833, 691, 847 ], [ 695, 833, 784, 847 ], [ 556, 848, 597, 862 ], [ 601, 848, 621, 862 ], [ 626, 848, 639, 862 ], [ 643, 848, 672, 862 ], [ 676, 848, 696, 862 ], [ 700, 848, 725, 862 ], [ 730, 848, 784, 862 ], [ 555, 885, 589, 897 ], [ 593, 885, 661, 897 ], [ 664, 885, 673, 897 ], [ 677, 885, 687, 897 ], [ 689, 885, 714, 897 ], [ 717, 885, 771, 897 ], [ 774, 885, 783, 897 ], [ 555, 897, 588, 909 ], [ 591, 897, 608, 909 ], [ 612, 897, 644, 909 ], [ 648, 897, 688, 909 ], [ 692, 897, 698, 909 ], [ 702, 897, 726, 909 ], [ 730, 897, 764, 909 ], [ 767, 897, 783, 909 ], [ 555, 910, 583, 922 ], [ 586, 910, 606, 922 ], [ 610, 910, 652, 922 ], [ 655, 910, 670, 922 ], [ 673, 910, 702, 922 ], [ 705, 910, 729, 922 ], [ 733, 910, 783, 922 ], [ 555, 922, 582, 934 ], [ 585, 922, 635, 934 ], [ 639, 922, 659, 934 ], [ 663, 922, 690, 934 ], [ 694, 922, 744, 934 ], [ 748, 922, 784, 934 ], [ 555, 935, 661, 947 ], [ 563, 947, 585, 959 ], [ 589, 947, 613, 959 ], [ 617, 947, 634, 959 ], [ 637, 947, 671, 959 ], [ 675, 947, 686, 959 ], [ 690, 947, 711, 959 ], [ 716, 947, 747, 959 ], [ 750, 947, 783, 959 ], [ 555, 960, 587, 972 ], [ 590, 960, 623, 972 ], [ 627, 960, 640, 972 ], [ 643, 960, 669, 972 ], [ 673, 960, 722, 972 ], [ 725, 960, 742, 972 ], [ 746, 960, 784, 972 ], [ 555, 972, 590, 984 ], [ 593, 972, 616, 984 ], [ 618, 972, 707, 984 ], [ 563, 985, 581, 997 ], [ 584, 985, 616, 997 ], [ 619, 985, 649, 997 ], [ 651, 985, 670, 997 ], [ 672, 985, 692, 997 ], [ 695, 985, 707, 997 ], [ 709, 985, 755, 997 ], [ 757, 985, 783, 997 ], [ 555, 997, 570, 1009 ], [ 572, 997, 610, 1009 ], [ 563, 1010, 602, 1022 ], [ 604, 1010, 616, 1022 ], [ 618, 1010, 651, 1022 ], [ 654, 1010, 679, 1022 ], [ 682, 1010, 719, 1022 ], [ 721, 1010, 733, 1022 ], [ 735, 1010, 755, 1022 ], [ 758, 1010, 783, 1022 ], [ 750, 1048, 783, 1062 ] ]
[ 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 ]
3016419
[ "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." ]
[ [ 78, 47, 114, 59 ], [ 117, 47, 126, 59 ], [ 129, 47, 140, 59 ], [ 143, 47, 164, 59 ], [ 167, 47, 211, 59 ], [ 214, 47, 239, 59 ], [ 243, 47, 275, 59 ], [ 78, 61, 311, 73 ], [ 83, 128, 94, 146 ], [ 96, 128, 106, 146 ], [ 107, 128, 117, 146 ], [ 119, 128, 129, 146 ], [ 130, 128, 142, 146 ], [ 144, 128, 155, 146 ], [ 156, 128, 167, 146 ], [ 169, 128, 182, 146 ], [ 189, 128, 201, 146 ], [ 203, 128, 214, 146 ], [ 215, 128, 225, 146 ], [ 227, 128, 232, 146 ], [ 234, 128, 245, 146 ], [ 247, 128, 257, 146 ], [ 258, 128, 268, 146 ], [ 641, 128, 685, 146 ], [ 691, 128, 744, 146 ], [ 78, 169, 199, 203 ], [ 209, 169, 338, 203 ], [ 348, 169, 431, 203 ], [ 441, 169, 461, 203 ], [ 472, 169, 610, 203 ], [ 620, 169, 678, 203 ], [ 688, 169, 704, 203 ], [ 78, 205, 163, 239 ], [ 174, 205, 315, 239 ], [ 325, 205, 369, 239 ], [ 379, 205, 458, 239 ], [ 468, 205, 561, 239 ], [ 571, 205, 622, 239 ], [ 632, 205, 726, 239 ], [ 78, 241, 113, 275 ], [ 123, 241, 223, 275 ], [ 233, 241, 407, 275 ], [ 418, 241, 451, 275 ], [ 78, 288, 102, 304 ], [ 107, 285, 163, 304 ], [ 167, 288, 200, 304 ], [ 205, 285, 251, 304 ], [ 255, 288, 305, 304 ], [ 309, 285, 347, 304 ], [ 351, 288, 392, 304 ], [ 396, 285, 431, 304 ], [ 436, 288, 482, 304 ], [ 487, 285, 556, 304 ], [ 560, 288, 609, 304 ], [ 614, 285, 648, 304 ], [ 87, 342, 141, 357 ], [ 87, 367, 163, 381 ], [ 167, 367, 194, 381 ], [ 198, 367, 246, 381 ], [ 250, 367, 258, 381 ], [ 263, 367, 277, 381 ], [ 281, 367, 337, 381 ], [ 342, 367, 390, 381 ], [ 394, 367, 405, 381 ], [ 409, 367, 421, 381 ], [ 425, 367, 476, 381 ], [ 481, 367, 521, 381 ], [ 525, 367, 577, 381 ], [ 582, 367, 610, 381 ], [ 613, 367, 678, 381 ], [ 683, 367, 704, 381 ], [ 87, 384, 159, 398 ], [ 164, 384, 175, 398 ], [ 180, 384, 214, 398 ], [ 217, 384, 265, 398 ], [ 269, 384, 280, 398 ], [ 284, 384, 324, 398 ], [ 328, 384, 371, 398 ], [ 375, 384, 403, 398 ], [ 407, 384, 455, 398 ], [ 459, 384, 501, 398 ], [ 506, 384, 552, 398 ], [ 556, 384, 621, 398 ], [ 625, 384, 636, 398 ], [ 641, 384, 682, 398 ], [ 686, 384, 722, 398 ], [ 727, 384, 738, 398 ], [ 87, 400, 122, 414 ], [ 126, 400, 203, 414 ], [ 208, 400, 248, 414 ], [ 252, 400, 328, 414 ], [ 332, 400, 343, 414 ], [ 348, 400, 367, 414 ], [ 371, 400, 406, 414 ], [ 410, 400, 438, 414 ], [ 442, 400, 463, 414 ], [ 468, 400, 543, 414 ], [ 547, 400, 558, 414 ], [ 562, 400, 581, 414 ], [ 585, 400, 639, 414 ], [ 644, 400, 661, 414 ], [ 665, 400, 712, 414 ], [ 716, 400, 731, 414 ], [ 87, 417, 118, 431 ], [ 123, 417, 160, 431 ], [ 164, 417, 175, 431 ], [ 179, 417, 198, 431 ], [ 202, 417, 242, 431 ], [ 246, 417, 296, 431 ], [ 300, 417, 318, 431 ], [ 323, 417, 384, 431 ], [ 388, 417, 395, 431 ], [ 399, 417, 449, 431 ], [ 453, 417, 507, 431 ], [ 512, 417, 547, 431 ], [ 551, 417, 582, 431 ], [ 587, 417, 606, 431 ], [ 610, 417, 639, 431 ], [ 643, 417, 691, 431 ], [ 695, 417, 729, 431 ], [ 87, 434, 130, 448 ], [ 135, 434, 147, 448 ], [ 151, 434, 166, 448 ], [ 170, 434, 181, 448 ], [ 186, 434, 228, 448 ], [ 231, 434, 266, 448 ], [ 270, 434, 281, 448 ], [ 285, 434, 332, 448 ], [ 337, 434, 376, 448 ], [ 380, 434, 397, 448 ], [ 401, 434, 428, 448 ], [ 432, 434, 470, 448 ], [ 474, 434, 496, 448 ], [ 501, 434, 508, 448 ], [ 511, 434, 539, 448 ], [ 543, 434, 588, 448 ], [ 592, 434, 603, 448 ], [ 608, 434, 653, 448 ], [ 657, 434, 729, 448 ], [ 87, 450, 114, 464 ], [ 118, 450, 125, 464 ], [ 129, 450, 160, 464 ], [ 164, 450, 209, 464 ], [ 214, 450, 257, 464 ], [ 261, 450, 273, 464 ], [ 277, 450, 296, 464 ], [ 300, 450, 332, 464 ], [ 337, 450, 359, 464 ], [ 363, 450, 374, 464 ], [ 379, 450, 398, 464 ], [ 402, 450, 459, 464 ], [ 87, 471, 133, 485 ], [ 137, 471, 227, 485 ], [ 231, 471, 242, 485 ], [ 247, 471, 266, 485 ], [ 269, 471, 319, 485 ], [ 324, 471, 378, 485 ], [ 382, 471, 427, 485 ], [ 431, 471, 466, 485 ], [ 471, 471, 518, 485 ], [ 522, 471, 544, 485 ], [ 549, 471, 576, 485 ], [ 580, 471, 599, 485 ], [ 602, 471, 659, 485 ], [ 663, 471, 710, 485 ], [ 715, 471, 736, 485 ], [ 87, 488, 144, 502 ], [ 149, 488, 166, 502 ], [ 170, 488, 217, 502 ], [ 222, 488, 244, 502 ], [ 248, 488, 273, 502 ], [ 277, 488, 288, 502 ], [ 292, 488, 316, 502 ], [ 321, 488, 364, 502 ], [ 369, 488, 381, 502 ], [ 385, 488, 400, 502 ], [ 404, 488, 411, 502 ], [ 414, 488, 470, 502 ], [ 475, 488, 528, 502 ], [ 532, 488, 553, 502 ], [ 558, 488, 597, 502 ], [ 600, 488, 627, 502 ], [ 631, 488, 642, 502 ], [ 647, 488, 666, 502 ], [ 670, 488, 707, 502 ], [ 711, 488, 720, 502 ], [ 87, 504, 134, 518 ], [ 139, 504, 166, 518 ], [ 170, 504, 195, 518 ], [ 200, 504, 225, 518 ], [ 229, 504, 306, 518 ], [ 310, 504, 376, 518 ], [ 380, 504, 433, 518 ], [ 437, 504, 479, 518 ], [ 484, 504, 503, 518 ], [ 507, 504, 531, 518 ], [ 535, 504, 593, 518 ], [ 597, 504, 633, 518 ], [ 638, 504, 673, 518 ], [ 677, 504, 693, 518 ], [ 697, 504, 723, 518 ], [ 87, 521, 102, 535 ], [ 107, 521, 149, 535 ], [ 153, 521, 227, 535 ], [ 231, 521, 247, 535 ], [ 252, 521, 276, 535 ], [ 280, 521, 316, 535 ], [ 320, 521, 359, 535 ], [ 363, 521, 384, 535 ], [ 389, 521, 431, 535 ], [ 435, 521, 476, 535 ], [ 480, 521, 515, 535 ], [ 520, 521, 540, 535 ], [ 544, 521, 580, 535 ], [ 584, 521, 612, 535 ], [ 616, 521, 680, 535 ], [ 684, 521, 705, 535 ], [ 87, 537, 146, 551 ], [ 150, 537, 161, 551 ], [ 166, 537, 196, 551 ], [ 200, 537, 234, 551 ], [ 238, 537, 291, 551 ], [ 295, 537, 361, 551 ], [ 365, 537, 376, 551 ], [ 380, 537, 444, 551 ], [ 448, 537, 470, 551 ], [ 474, 537, 514, 551 ], [ 518, 537, 551, 551 ], [ 555, 537, 576, 551 ], [ 580, 537, 618, 551 ], [ 622, 537, 669, 551 ], [ 673, 537, 684, 551 ], [ 689, 537, 730, 551 ], [ 87, 554, 98, 568 ], [ 102, 554, 157, 568 ], [ 161, 554, 236, 568 ], [ 240, 554, 305, 568 ], [ 308, 554, 328, 568 ], [ 332, 554, 361, 568 ], [ 365, 554, 377, 568 ], [ 381, 554, 388, 568 ], [ 392, 554, 422, 568 ], [ 426, 554, 481, 568 ], [ 485, 554, 548, 568 ], [ 553, 554, 568, 568 ], [ 573, 554, 592, 568 ], [ 595, 554, 622, 568 ], [ 626, 554, 650, 568 ], [ 87, 571, 180, 585 ], [ 184, 571, 207, 585 ], [ 211, 571, 233, 585 ], [ 237, 571, 290, 585 ], [ 293, 571, 328, 585 ], [ 333, 571, 352, 585 ], [ 355, 571, 395, 585 ], [ 399, 571, 430, 585 ], [ 434, 571, 486, 585 ], [ 491, 571, 503, 585 ], [ 507, 571, 527, 585 ], [ 531, 571, 582, 585 ], [ 586, 571, 608, 585 ], [ 612, 571, 645, 585 ], [ 650, 571, 661, 585 ], [ 665, 571, 737, 585 ], [ 87, 587, 114, 601 ], [ 118, 587, 129, 601 ], [ 133, 587, 192, 601 ], [ 196, 587, 221, 601 ], [ 225, 587, 265, 601 ], [ 269, 587, 306, 601 ], [ 310, 587, 330, 601 ], [ 335, 587, 343, 601 ], [ 347, 587, 366, 601 ], [ 371, 587, 399, 601 ], [ 402, 587, 414, 601 ], [ 419, 587, 434, 601 ], [ 437, 587, 456, 601 ], [ 460, 587, 494, 601 ], [ 498, 587, 551, 601 ], [ 87, 608, 162, 622 ], [ 167, 608, 178, 622 ], [ 182, 608, 202, 622 ], [ 206, 608, 236, 622 ], [ 240, 608, 257, 622 ], [ 262, 608, 315, 622 ], [ 318, 608, 340, 622 ], [ 345, 608, 400, 622 ], [ 404, 608, 438, 622 ], [ 442, 608, 457, 622 ], [ 461, 608, 468, 622 ], [ 472, 608, 508, 622 ], [ 512, 608, 547, 622 ], [ 551, 608, 600, 622 ], [ 604, 608, 631, 622 ], [ 635, 608, 654, 622 ], [ 658, 608, 693, 622 ], [ 87, 625, 141, 639 ], [ 146, 625, 167, 639 ], [ 172, 625, 229, 639 ], [ 233, 625, 255, 639 ], [ 260, 625, 297, 639 ], [ 300, 625, 350, 639 ], [ 355, 625, 379, 639 ], [ 383, 625, 394, 639 ], [ 398, 625, 428, 639 ], [ 433, 625, 469, 639 ], [ 473, 625, 515, 639 ], [ 519, 625, 547, 639 ], [ 551, 625, 565, 639 ], [ 570, 625, 625, 639 ], [ 629, 625, 650, 639 ], [ 655, 625, 666, 639 ], [ 87, 641, 167, 655 ], [ 172, 641, 179, 655 ], [ 183, 641, 249, 655 ], [ 253, 641, 268, 655 ], [ 272, 641, 329, 655 ], [ 334, 641, 401, 655 ], [ 405, 641, 426, 655 ], [ 431, 641, 485, 655 ], [ 490, 641, 547, 655 ], [ 551, 641, 619, 655 ], [ 623, 641, 642, 655 ], [ 646, 641, 716, 655 ], [ 720, 641, 731, 655 ], [ 87, 658, 107, 672 ], [ 111, 658, 140, 672 ], [ 144, 658, 155, 672 ], [ 159, 658, 178, 672 ], [ 182, 658, 232, 672 ], [ 236, 658, 290, 672 ], [ 295, 658, 330, 672 ], [ 334, 658, 356, 672 ], [ 360, 658, 387, 672 ], [ 391, 658, 441, 672 ], [ 78, 704, 155, 719 ], [ 78, 721, 107, 735 ], [ 111, 721, 163, 735 ], [ 168, 721, 177, 735 ], [ 181, 721, 237, 735 ], [ 241, 721, 309, 735 ], [ 313, 721, 366, 735 ], [ 370, 721, 403, 735 ], [ 78, 737, 100, 751 ], [ 107, 737, 120, 751 ], [ 126, 737, 217, 751 ], [ 223, 737, 269, 751 ], [ 275, 737, 295, 751 ], [ 302, 737, 336, 751 ], [ 342, 737, 386, 751 ], [ 391, 737, 403, 751 ], [ 78, 754, 113, 768 ], [ 118, 754, 191, 768 ], [ 195, 754, 221, 768 ], [ 225, 754, 253, 768 ], [ 257, 754, 263, 768 ], [ 267, 754, 307, 768 ], [ 312, 754, 346, 768 ], [ 350, 754, 403, 768 ], [ 78, 771, 89, 785 ], [ 94, 771, 112, 785 ], [ 116, 771, 179, 785 ], [ 183, 771, 204, 785 ], [ 209, 771, 272, 785 ], [ 276, 771, 287, 785 ], [ 291, 771, 326, 785 ], [ 331, 771, 349, 785 ], [ 353, 771, 371, 785 ], [ 375, 771, 403, 785 ], [ 78, 787, 132, 801 ], [ 138, 787, 178, 801 ], [ 184, 787, 196, 801 ], [ 202, 787, 232, 801 ], [ 238, 787, 297, 801 ], [ 303, 787, 358, 801 ], [ 364, 787, 376, 801 ], [ 382, 787, 404, 801 ], [ 78, 804, 115, 818 ], [ 120, 804, 176, 818 ], [ 182, 804, 280, 818 ], [ 285, 804, 343, 818 ], [ 348, 804, 385, 818 ], [ 390, 804, 403, 818 ], [ 78, 820, 99, 834 ], [ 104, 820, 141, 834 ], [ 146, 820, 193, 834 ], [ 197, 820, 230, 834 ], [ 235, 820, 280, 834 ], [ 284, 820, 322, 834 ], [ 327, 820, 339, 834 ], [ 345, 820, 380, 834 ], [ 385, 820, 404, 834 ], [ 78, 837, 111, 851 ], [ 117, 837, 139, 851 ], [ 143, 837, 171, 851 ], [ 177, 837, 233, 851 ], [ 238, 837, 250, 851 ], [ 255, 837, 357, 851 ], [ 361, 837, 389, 851 ], [ 394, 837, 404, 851 ], [ 78, 854, 118, 868 ], [ 123, 854, 157, 868 ], [ 161, 854, 180, 868 ], [ 185, 854, 249, 868 ], [ 253, 854, 291, 868 ], [ 296, 854, 308, 868 ], [ 312, 854, 340, 868 ], [ 345, 854, 403, 868 ], [ 78, 870, 140, 884 ], [ 145, 870, 164, 884 ], [ 169, 870, 237, 884 ], [ 241, 870, 263, 884 ], [ 268, 870, 347, 884 ], [ 351, 870, 363, 884 ], [ 368, 870, 404, 884 ], [ 78, 887, 109, 901 ], [ 115, 887, 184, 901 ], [ 189, 887, 243, 901 ], [ 249, 887, 352, 901 ], [ 357, 887, 404, 901 ], [ 78, 925, 83, 936 ], [ 86, 925, 156, 936 ], [ 159, 925, 236, 936 ], [ 78, 936, 118, 949 ], [ 122, 937, 159, 948 ], [ 162, 937, 195, 948 ], [ 197, 937, 217, 948 ], [ 220, 937, 280, 948 ], [ 284, 937, 300, 948 ], [ 303, 937, 325, 948 ], [ 328, 937, 367, 948 ], [ 78, 950, 121, 961 ], [ 125, 950, 160, 961 ], [ 163, 950, 204, 961 ], [ 208, 950, 239, 961 ], [ 78, 962, 93, 973 ], [ 96, 962, 108, 973 ], [ 111, 962, 120, 973 ], [ 123, 962, 151, 973 ], [ 153, 962, 202, 973 ], [ 205, 962, 211, 973 ], [ 215, 962, 251, 973 ], [ 254, 962, 262, 973 ], [ 265, 962, 279, 973 ], [ 282, 962, 299, 973 ], [ 302, 962, 311, 973 ], [ 313, 962, 327, 973 ], [ 330, 962, 355, 973 ], [ 423, 704, 484, 718 ], [ 489, 704, 561, 718 ], [ 565, 704, 582, 718 ], [ 587, 704, 663, 718 ], [ 669, 704, 688, 718 ], [ 693, 704, 732, 718 ], [ 736, 704, 748, 718 ], [ 423, 721, 450, 735 ], [ 454, 721, 509, 735 ], [ 434, 737, 507, 751 ], [ 511, 737, 611, 751 ], [ 617, 737, 627, 751 ], [ 631, 737, 638, 751 ], [ 643, 737, 695, 751 ], [ 699, 737, 748, 751 ], [ 423, 754, 458, 768 ], [ 461, 754, 501, 768 ], [ 504, 754, 588, 768 ], [ 591, 754, 635, 768 ], [ 638, 754, 661, 768 ], [ 665, 754, 710, 768 ], [ 713, 754, 748, 768 ], [ 423, 771, 484, 785 ], [ 488, 771, 563, 785 ], [ 567, 771, 662, 785 ], [ 666, 771, 713, 785 ], [ 716, 771, 747, 785 ], [ 423, 787, 503, 801 ], [ 506, 787, 562, 801 ], [ 566, 787, 589, 801 ], [ 594, 787, 612, 801 ], [ 616, 787, 676, 801 ], [ 680, 787, 694, 801 ], [ 698, 787, 748, 801 ], [ 423, 804, 480, 818 ], [ 483, 804, 553, 818 ], [ 556, 804, 584, 818 ], [ 588, 804, 628, 818 ], [ 631, 804, 719, 818 ], [ 722, 804, 748, 818 ], [ 423, 820, 445, 834 ], [ 448, 820, 483, 834 ], [ 486, 820, 548, 834 ], [ 551, 820, 598, 834 ], [ 602, 820, 652, 834 ], [ 655, 820, 723, 834 ], [ 727, 820, 748, 834 ], [ 423, 837, 507, 851 ], [ 511, 837, 557, 851 ], [ 561, 837, 584, 851 ], [ 588, 837, 606, 851 ], [ 610, 837, 664, 851 ], [ 667, 837, 681, 851 ], [ 685, 837, 748, 851 ], [ 423, 854, 450, 868 ], [ 454, 854, 516, 868 ], [ 519, 854, 541, 868 ], [ 545, 854, 614, 868 ], [ 618, 854, 666, 868 ], [ 670, 854, 712, 868 ], [ 716, 854, 748, 868 ], [ 423, 870, 445, 884 ], [ 449, 870, 478, 884 ], [ 482, 870, 526, 884 ], [ 530, 870, 583, 884 ], [ 588, 870, 608, 884 ], [ 613, 870, 694, 884 ], [ 698, 870, 710, 884 ], [ 714, 870, 748, 884 ], [ 423, 887, 470, 901 ], [ 473, 887, 484, 901 ], [ 488, 887, 523, 901 ], [ 527, 887, 599, 901 ], [ 602, 887, 611, 901 ], [ 615, 887, 622, 901 ], [ 625, 887, 692, 901 ], [ 695, 887, 707, 901 ], [ 710, 887, 748, 901 ], [ 423, 904, 471, 918 ], [ 473, 904, 491, 918 ], [ 495, 904, 550, 918 ], [ 553, 904, 622, 918 ], [ 625, 904, 637, 918 ], [ 640, 904, 734, 918 ], [ 434, 920, 472, 934 ], [ 476, 920, 551, 934 ], [ 556, 920, 566, 934 ], [ 570, 920, 610, 934 ], [ 614, 920, 626, 934 ], [ 631, 920, 645, 934 ], [ 649, 920, 704, 934 ], [ 709, 920, 748, 934 ], [ 423, 937, 511, 951 ], [ 515, 937, 527, 951 ], [ 531, 937, 571, 951 ], [ 575, 937, 634, 951 ], [ 639, 937, 682, 951 ], [ 687, 937, 707, 951 ], [ 711, 937, 748, 951 ], [ 423, 953, 494, 967 ], [ 500, 953, 512, 967 ], [ 517, 953, 569, 967 ], [ 575, 953, 612, 967 ], [ 618, 953, 697, 967 ], [ 703, 953, 728, 967 ], [ 733, 953, 748, 967 ], [ 248, 987, 255, 997 ], [ 256, 987, 274, 997 ], [ 276, 987, 305, 997 ], [ 307, 987, 315, 997 ], [ 317, 987, 325, 997 ], [ 327, 987, 357, 997 ], [ 359, 987, 388, 997 ], [ 390, 987, 417, 997 ], [ 419, 987, 433, 997 ], [ 435, 987, 450, 997 ], [ 452, 987, 458, 997 ], [ 460, 987, 470, 997 ], [ 471, 987, 492, 997 ], [ 494, 987, 519, 997 ], [ 522, 987, 545, 997 ], [ 546, 987, 587, 997 ], [ 589, 987, 612, 997 ], [ 614, 987, 627, 997 ], [ 628, 987, 650, 997 ], [ 652, 987, 660, 997 ], [ 662, 987, 675, 997 ], [ 676, 987, 707, 997 ], [ 709, 987, 748, 997 ], [ 248, 998, 289, 1008 ], [ 291, 998, 319, 1008 ], [ 322, 998, 493, 1008 ], [ 496, 998, 519, 1008 ], [ 522, 998, 551, 1008 ], [ 553, 998, 598, 1008 ], [ 601, 998, 616, 1008 ], [ 618, 998, 663, 1008 ], [ 666, 998, 681, 1008 ], [ 683, 998, 732, 1008 ], [ 736, 998, 743, 1008 ], [ 248, 1009, 262, 1019 ], [ 264, 1009, 298, 1019 ], [ 300, 1009, 334, 1019 ], [ 337, 1009, 350, 1019 ], [ 352, 1009, 380, 1019 ], [ 384, 1009, 403, 1019 ], [ 405, 1009, 411, 1019 ], [ 414, 1009, 446, 1019 ], [ 448, 1009, 469, 1019 ] ]
[ 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 ]
2596294
[ "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" ]
[ [ 70, 45, 90, 57 ], [ 93, 45, 122, 57 ], [ 124, 45, 172, 57 ], [ 175, 45, 207, 57 ], [ 209, 45, 272, 57 ], [ 70, 61, 91, 73 ], [ 95, 61, 230, 73 ], [ 78, 90, 88, 104 ], [ 89, 90, 98, 104 ], [ 99, 90, 104, 104 ], [ 105, 90, 115, 104 ], [ 116, 90, 121, 104 ], [ 122, 90, 132, 104 ], [ 132, 90, 142, 104 ], [ 143, 90, 152, 104 ], [ 157, 90, 165, 104 ], [ 166, 90, 176, 104 ], [ 177, 90, 185, 104 ], [ 185, 90, 194, 104 ], [ 195, 90, 204, 104 ], [ 70, 146, 200, 169 ], [ 206, 146, 288, 169 ], [ 293, 146, 322, 169 ], [ 327, 146, 400, 169 ], [ 405, 146, 424, 169 ], [ 429, 146, 596, 169 ], [ 70, 171, 174, 194 ], [ 180, 171, 199, 194 ], [ 204, 171, 254, 194 ], [ 259, 171, 305, 194 ], [ 310, 171, 463, 194 ], [ 468, 171, 514, 194 ], [ 70, 219, 126, 233 ], [ 130, 219, 216, 233 ], [ 219, 219, 223, 233 ], [ 225, 219, 258, 233 ], [ 261, 219, 319, 233 ], [ 323, 219, 327, 233 ], [ 330, 219, 350, 235 ], [ 353, 219, 392, 233 ], [ 70, 338, 118, 350 ], [ 121, 338, 127, 350 ], [ 130, 338, 150, 350 ], [ 152, 338, 176, 350 ], [ 179, 338, 183, 350 ], [ 185, 338, 233, 350 ], [ 236, 338, 248, 350 ], [ 250, 338, 285, 350 ], [ 288, 338, 312, 350 ], [ 314, 338, 318, 350 ], [ 320, 338, 367, 350 ], [ 370, 338, 403, 350 ], [ 406, 338, 412, 350 ], [ 415, 338, 466, 350 ], [ 468, 338, 492, 350 ], [ 70, 353, 70, 365 ], [ 84, 352, 161, 364 ], [ 164, 352, 188, 364 ], [ 70, 391, 122, 405 ], [ 136, 391, 165, 405 ], [ 168, 391, 218, 405 ], [ 220, 391, 237, 405 ], [ 240, 391, 247, 405 ], [ 250, 391, 291, 405 ], [ 294, 391, 327, 405 ], [ 329, 391, 341, 405 ], [ 344, 391, 372, 405 ], [ 375, 391, 402, 405 ], [ 70, 409, 129, 423 ], [ 135, 409, 227, 423 ], [ 233, 409, 308, 423 ], [ 313, 409, 327, 423 ], [ 333, 409, 373, 423 ], [ 378, 409, 402, 423 ], [ 70, 423, 94, 440 ], [ 99, 426, 147, 440 ], [ 152, 426, 172, 440 ], [ 177, 426, 189, 440 ], [ 193, 426, 227, 440 ], [ 232, 426, 242, 440 ], [ 246, 426, 253, 440 ], [ 257, 426, 315, 440 ], [ 320, 426, 332, 440 ], [ 336, 426, 353, 440 ], [ 358, 426, 402, 440 ], [ 70, 443, 106, 457 ], [ 115, 443, 137, 457 ], [ 145, 443, 166, 457 ], [ 174, 443, 266, 457 ], [ 274, 443, 301, 457 ], [ 309, 443, 351, 457 ], [ 360, 443, 402, 457 ], [ 70, 461, 104, 475 ], [ 109, 461, 147, 475 ], [ 152, 461, 169, 475 ], [ 173, 461, 224, 475 ], [ 228, 461, 249, 475 ], [ 253, 461, 288, 475 ], [ 292, 461, 330, 475 ], [ 335, 461, 352, 475 ], [ 356, 461, 402, 475 ], [ 70, 478, 94, 492 ], [ 99, 478, 148, 492 ], [ 153, 478, 202, 492 ], [ 207, 478, 296, 492 ], [ 301, 478, 313, 492 ], [ 318, 478, 347, 492 ], [ 352, 478, 402, 492 ], [ 70, 495, 97, 509 ], [ 102, 495, 142, 509 ], [ 146, 495, 174, 509 ], [ 179, 495, 220, 509 ], [ 224, 495, 271, 509 ], [ 276, 495, 297, 509 ], [ 302, 495, 324, 509 ], [ 328, 495, 340, 509 ], [ 345, 495, 371, 509 ], [ 375, 495, 402, 509 ], [ 70, 513, 107, 527 ], [ 110, 513, 139, 527 ], [ 143, 513, 161, 527 ], [ 163, 513, 199, 527 ], [ 203, 513, 250, 527 ], [ 253, 513, 287, 527 ], [ 290, 513, 310, 527 ], [ 314, 513, 352, 527 ], [ 355, 513, 402, 527 ], [ 70, 530, 90, 544 ], [ 96, 530, 171, 544 ], [ 176, 530, 204, 544 ], [ 209, 530, 252, 544 ], [ 257, 530, 269, 544 ], [ 275, 530, 295, 544 ], [ 300, 530, 333, 544 ], [ 338, 530, 355, 544 ], [ 360, 530, 402, 544 ], [ 70, 548, 101, 562 ], [ 104, 548, 111, 562 ], [ 115, 548, 175, 562 ], [ 178, 548, 199, 562 ], [ 203, 548, 224, 562 ], [ 227, 548, 263, 562 ], [ 266, 548, 323, 562 ], [ 326, 548, 340, 562 ], [ 343, 548, 377, 562 ], [ 380, 548, 401, 562 ], [ 70, 565, 80, 579 ], [ 84, 565, 124, 579 ], [ 128, 565, 146, 579 ], [ 150, 565, 177, 579 ], [ 181, 565, 203, 579 ], [ 207, 565, 219, 579 ], [ 223, 565, 241, 579 ], [ 244, 565, 273, 579 ], [ 277, 565, 335, 579 ], [ 339, 565, 351, 579 ], [ 355, 565, 362, 579 ], [ 366, 565, 402, 579 ], [ 70, 582, 87, 596 ], [ 91, 582, 155, 596 ], [ 159, 582, 219, 596 ], [ 223, 582, 235, 596 ], [ 239, 582, 324, 596 ], [ 328, 582, 373, 596 ], [ 377, 582, 402, 596 ], [ 70, 600, 100, 614 ], [ 105, 600, 152, 614 ], [ 157, 600, 171, 614 ], [ 176, 600, 193, 614 ], [ 199, 600, 250, 614 ], [ 255, 600, 330, 614 ], [ 335, 600, 374, 614 ], [ 380, 600, 402, 614 ], [ 70, 617, 138, 631 ], [ 144, 617, 193, 631 ], [ 198, 617, 243, 631 ], [ 248, 617, 260, 631 ], [ 265, 617, 336, 631 ], [ 340, 617, 384, 631 ], [ 390, 617, 402, 631 ], [ 70, 632, 140, 649 ], [ 145, 634, 174, 648 ], [ 178, 634, 243, 648 ], [ 247, 634, 258, 648 ], [ 263, 634, 270, 648 ], [ 274, 634, 309, 648 ], [ 313, 634, 341, 648 ], [ 346, 634, 402, 648 ], [ 70, 652, 128, 666 ], [ 136, 652, 156, 666 ], [ 164, 652, 233, 666 ], [ 241, 652, 253, 666 ], [ 260, 652, 318, 666 ], [ 326, 652, 373, 666 ], [ 380, 652, 401, 666 ], [ 70, 669, 105, 683 ], [ 109, 669, 129, 683 ], [ 132, 669, 161, 683 ], [ 164, 669, 198, 683 ], [ 201, 669, 256, 683 ], [ 260, 669, 296, 683 ], [ 299, 669, 306, 683 ], [ 309, 669, 347, 683 ], [ 350, 669, 401, 683 ], [ 70, 686, 82, 700 ], [ 88, 686, 137, 700 ], [ 142, 686, 187, 700 ], [ 192, 686, 222, 700 ], [ 228, 686, 255, 700 ], [ 260, 686, 333, 700 ], [ 339, 686, 402, 700 ], [ 70, 704, 109, 718 ], [ 113, 704, 134, 718 ], [ 138, 704, 155, 718 ], [ 159, 704, 195, 718 ], [ 198, 704, 245, 718 ], [ 249, 704, 284, 718 ], [ 287, 704, 307, 718 ], [ 310, 704, 345, 718 ], [ 349, 704, 359, 718 ], [ 362, 704, 402, 718 ], [ 70, 721, 97, 735 ], [ 102, 721, 131, 735 ], [ 135, 721, 193, 735 ], [ 197, 721, 218, 735 ], [ 221, 721, 264, 735 ], [ 268, 721, 289, 735 ], [ 293, 721, 314, 735 ], [ 317, 721, 359, 735 ], [ 363, 721, 373, 735 ], [ 376, 721, 401, 735 ], [ 70, 775, 143, 787 ], [ 145, 775, 157, 787 ], [ 160, 775, 189, 787 ], [ 192, 775, 258, 787 ], [ 70, 804, 122, 816 ], [ 125, 804, 201, 816 ], [ 203, 804, 246, 816 ], [ 258, 804, 277, 816 ], [ 279, 804, 309, 816 ], [ 312, 804, 347, 816 ], [ 350, 804, 360, 816 ], [ 362, 804, 379, 816 ], [ 70, 818, 100, 830 ], [ 103, 818, 265, 830 ], [ 267, 818, 307, 830 ], [ 309, 818, 379, 830 ], [ 70, 832, 112, 844 ], [ 115, 832, 144, 844 ], [ 147, 832, 155, 844 ], [ 158, 832, 201, 844 ], [ 203, 832, 213, 844 ], [ 215, 832, 265, 844 ], [ 268, 832, 296, 844 ], [ 70, 860, 82, 872 ], [ 85, 860, 153, 872 ], [ 155, 860, 158, 872 ], [ 161, 860, 171, 872 ], [ 174, 860, 220, 872 ], [ 223, 860, 226, 872 ], [ 229, 860, 237, 872 ], [ 239, 860, 270, 872 ], [ 273, 860, 295, 873 ], [ 70, 874, 109, 886 ], [ 112, 874, 122, 886 ], [ 125, 874, 150, 886 ], [ 152, 874, 201, 886 ], [ 204, 874, 246, 886 ], [ 70, 888, 109, 900 ], [ 112, 888, 144, 900 ], [ 146, 888, 180, 900 ], [ 183, 888, 242, 901 ], [ 244, 888, 259, 900 ], [ 70, 902, 100, 914 ], [ 103, 902, 133, 915 ], [ 135, 902, 192, 914 ], [ 195, 902, 225, 914 ], [ 227, 902, 270, 914 ], [ 70, 916, 104, 928 ], [ 107, 916, 204, 928 ], [ 70, 930, 97, 942 ], [ 100, 930, 255, 942 ], [ 70, 957, 82, 969 ], [ 85, 957, 153, 969 ], [ 70, 971, 106, 983 ], [ 109, 971, 119, 983 ], [ 122, 971, 162, 983 ], [ 164, 971, 214, 983 ], [ 217, 971, 227, 983 ], [ 230, 971, 258, 983 ], [ 260, 971, 306, 983 ], [ 70, 985, 100, 998 ], [ 103, 985, 160, 997 ], [ 163, 985, 193, 997 ], [ 195, 985, 238, 997 ], [ 425, 391, 465, 405 ], [ 468, 391, 518, 405 ], [ 522, 391, 542, 405 ], [ 546, 391, 557, 405 ], [ 561, 391, 591, 405 ], [ 595, 391, 628, 405 ], [ 631, 391, 673, 405 ], [ 677, 391, 702, 405 ], [ 706, 391, 716, 405 ], [ 720, 391, 740, 405 ], [ 744, 391, 756, 405 ], [ 425, 409, 450, 423 ], [ 453, 409, 474, 423 ], [ 478, 409, 516, 423 ], [ 519, 409, 549, 423 ], [ 552, 409, 564, 423 ], [ 567, 409, 607, 423 ], [ 610, 409, 637, 423 ], [ 640, 409, 732, 423 ], [ 735, 409, 756, 423 ], [ 425, 426, 443, 440 ], [ 447, 426, 472, 440 ], [ 477, 426, 497, 440 ], [ 502, 426, 536, 440 ], [ 541, 426, 585, 440 ], [ 590, 426, 616, 440 ], [ 620, 426, 638, 440 ], [ 643, 426, 685, 440 ], [ 690, 426, 718, 440 ], [ 722, 426, 734, 440 ], [ 739, 426, 756, 440 ], [ 425, 443, 480, 457 ], [ 484, 443, 522, 457 ], [ 527, 443, 587, 457 ], [ 591, 443, 615, 457 ], [ 620, 443, 682, 457 ], [ 686, 443, 720, 457 ], [ 725, 443, 756, 457 ], [ 425, 461, 443, 475 ], [ 446, 461, 479, 475 ], [ 482, 461, 493, 475 ], [ 496, 461, 524, 475 ], [ 527, 461, 569, 475 ], [ 572, 461, 608, 475 ], [ 425, 495, 486, 509 ], [ 499, 495, 580, 509 ], [ 583, 495, 587, 509 ], [ 590, 495, 665, 509 ], [ 668, 495, 672, 509 ], [ 675, 495, 722, 509 ], [ 725, 495, 729, 509 ], [ 425, 513, 481, 527 ], [ 484, 513, 542, 527 ], [ 545, 513, 549, 527 ], [ 552, 513, 587, 527 ], [ 590, 513, 634, 527 ], [ 425, 566, 501, 580 ], [ 425, 601, 455, 615 ], [ 461, 601, 507, 615 ], [ 513, 601, 547, 615 ], [ 553, 601, 589, 615 ], [ 595, 601, 686, 615 ], [ 692, 601, 743, 615 ], [ 750, 601, 757, 615 ], [ 425, 618, 458, 632 ], [ 460, 618, 472, 632 ], [ 475, 618, 514, 632 ], [ 516, 618, 556, 632 ], [ 559, 618, 609, 632 ], [ 611, 618, 685, 632 ], [ 687, 618, 701, 632 ], [ 704, 618, 711, 632 ], [ 714, 618, 756, 632 ], [ 425, 636, 446, 650 ], [ 450, 636, 544, 650 ], [ 547, 636, 578, 650 ], [ 582, 636, 594, 650 ], [ 598, 636, 669, 650 ], [ 673, 636, 726, 650 ], [ 730, 636, 756, 650 ], [ 425, 653, 473, 667 ], [ 476, 653, 488, 667 ], [ 491, 653, 508, 667 ], [ 511, 653, 556, 667 ], [ 558, 653, 606, 667 ], [ 608, 653, 648, 667 ], [ 651, 653, 721, 667 ], [ 724, 653, 736, 667 ], [ 739, 653, 756, 667 ], [ 425, 670, 474, 684 ], [ 478, 670, 508, 684 ], [ 512, 670, 534, 684 ], [ 539, 670, 573, 684 ], [ 577, 670, 597, 684 ], [ 602, 670, 664, 684 ], [ 668, 670, 728, 684 ], [ 733, 670, 745, 684 ], [ 750, 670, 757, 684 ], [ 425, 688, 449, 702 ], [ 454, 688, 498, 702 ], [ 504, 688, 526, 702 ], [ 531, 688, 548, 702 ], [ 554, 688, 601, 702 ], [ 607, 688, 629, 702 ], [ 635, 688, 670, 702 ], [ 675, 688, 709, 702 ], [ 715, 688, 756, 702 ], [ 425, 705, 482, 719 ], [ 488, 705, 544, 719 ], [ 551, 705, 567, 719 ], [ 575, 705, 648, 719 ], [ 655, 703, 683, 720 ], [ 690, 705, 707, 719 ], [ 714, 705, 756, 719 ], [ 425, 723, 461, 737 ], [ 464, 723, 516, 737 ], [ 521, 723, 572, 737 ], [ 575, 723, 620, 737 ], [ 624, 723, 649, 737 ], [ 653, 723, 705, 737 ], [ 709, 723, 721, 737 ], [ 725, 723, 756, 737 ], [ 425, 740, 456, 754 ], [ 459, 740, 514, 754 ], [ 517, 740, 539, 754 ], [ 542, 740, 563, 754 ], [ 566, 740, 592, 754 ], [ 595, 740, 627, 754 ], [ 630, 740, 647, 754 ], [ 650, 740, 695, 754 ], [ 697, 740, 736, 754 ], [ 739, 740, 756, 754 ], [ 425, 757, 439, 771 ], [ 441, 757, 492, 771 ], [ 495, 757, 507, 771 ], [ 510, 757, 563, 771 ], [ 566, 757, 613, 771 ], [ 616, 757, 636, 771 ], [ 639, 757, 668, 771 ], [ 671, 757, 731, 771 ], [ 734, 757, 756, 771 ], [ 425, 775, 443, 789 ], [ 446, 775, 472, 789 ], [ 476, 775, 521, 789 ], [ 524, 775, 573, 789 ], [ 575, 775, 621, 789 ], [ 625, 775, 657, 789 ], [ 660, 775, 700, 789 ], [ 703, 775, 756, 789 ], [ 425, 792, 497, 806 ], [ 499, 792, 549, 806 ], [ 552, 792, 572, 806 ], [ 575, 792, 625, 806 ], [ 628, 792, 664, 806 ], [ 666, 792, 707, 806 ], [ 710, 792, 730, 806 ], [ 732, 792, 756, 806 ], [ 425, 809, 467, 823 ], [ 470, 809, 487, 823 ], [ 491, 809, 576, 823 ], [ 580, 809, 610, 823 ], [ 613, 809, 635, 823 ], [ 638, 809, 668, 823 ], [ 672, 809, 692, 823 ], [ 696, 809, 745, 823 ], [ 748, 809, 756, 823 ], [ 425, 827, 447, 841 ], [ 452, 827, 469, 841 ], [ 475, 827, 522, 841 ], [ 528, 827, 598, 841 ], [ 604, 827, 667, 841 ], [ 672, 827, 684, 841 ], [ 690, 827, 707, 841 ], [ 713, 827, 756, 841 ], [ 425, 844, 461, 858 ], [ 464, 844, 474, 858 ], [ 476, 844, 521, 858 ], [ 525, 844, 552, 858 ], [ 555, 844, 562, 858 ], [ 565, 844, 598, 858 ], [ 601, 844, 621, 858 ], [ 624, 844, 638, 858 ], [ 642, 844, 700, 858 ], [ 703, 844, 733, 858 ], [ 736, 844, 756, 858 ], [ 425, 861, 481, 875 ], [ 485, 861, 541, 875 ], [ 544, 861, 589, 875 ], [ 593, 861, 610, 875 ], [ 613, 861, 659, 875 ], [ 663, 861, 690, 875 ], [ 694, 861, 701, 875 ], [ 704, 861, 756, 875 ], [ 425, 879, 489, 893 ], [ 491, 879, 506, 893 ], [ 508, 879, 525, 893 ], [ 528, 879, 562, 893 ], [ 565, 879, 577, 893 ], [ 580, 879, 626, 893 ], [ 629, 879, 672, 893 ], [ 675, 879, 695, 893 ], [ 698, 879, 756, 893 ], [ 425, 896, 457, 910 ], [ 460, 896, 513, 910 ], [ 515, 896, 525, 910 ], [ 529, 896, 543, 910 ], [ 545, 896, 581, 910 ], [ 440, 914, 474, 928 ], [ 478, 914, 496, 928 ], [ 499, 914, 543, 928 ], [ 546, 914, 578, 928 ], [ 582, 914, 599, 928 ], [ 603, 914, 652, 928 ], [ 655, 914, 666, 928 ], [ 670, 914, 685, 928 ], [ 688, 914, 756, 928 ], [ 425, 931, 452, 945 ], [ 455, 931, 551, 945 ], [ 554, 931, 582, 945 ], [ 586, 931, 603, 945 ], [ 607, 928, 668, 945 ], [ 671, 931, 682, 945 ], [ 686, 931, 703, 945 ], [ 707, 931, 756, 945 ], [ 425, 948, 437, 962 ], [ 443, 948, 469, 962 ], [ 475, 948, 513, 962 ], [ 519, 948, 564, 962 ], [ 569, 948, 604, 962 ], [ 609, 948, 626, 962 ], [ 633, 948, 682, 962 ], [ 688, 948, 699, 962 ], [ 705, 948, 739, 962 ], [ 744, 948, 756, 962 ], [ 425, 966, 472, 980 ], [ 477, 966, 548, 980 ], [ 555, 966, 567, 980 ], [ 572, 966, 623, 980 ], [ 629, 966, 671, 980 ], [ 677, 966, 719, 980 ], [ 725, 966, 756, 980 ], [ 425, 983, 443, 997 ], [ 450, 983, 503, 997 ], [ 512, 983, 557, 997 ], [ 565, 983, 612, 997 ], [ 620, 983, 631, 997 ], [ 639, 983, 656, 997 ], [ 665, 983, 686, 997 ], [ 695, 983, 731, 997 ], [ 739, 983, 756, 997 ], [ 699, 1017, 755, 1038 ] ]
[ 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 ]
3093610
[ "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" ]
[ [ 90, 71, 165, 90 ], [ 171, 71, 209, 90 ], [ 90, 93, 280, 127 ], [ 291, 93, 345, 127 ], [ 356, 93, 488, 127 ], [ 498, 93, 622, 127 ], [ 633, 93, 725, 127 ], [ 90, 129, 273, 163 ], [ 284, 129, 418, 163 ], [ 429, 129, 457, 163 ], [ 468, 129, 567, 163 ], [ 90, 165, 280, 199 ], [ 90, 221, 121, 241 ], [ 127, 218, 199, 241 ], [ 205, 221, 252, 241 ], [ 257, 218, 305, 241 ], [ 311, 221, 366, 241 ], [ 373, 218, 449, 241 ], [ 455, 221, 515, 241 ], [ 520, 221, 550, 241 ], [ 557, 221, 597, 241 ], [ 596, 218, 603, 231 ], [ 602, 221, 608, 241 ], [ 614, 220, 648, 241 ], [ 653, 221, 703, 241 ], [ 90, 240, 160, 263 ], [ 166, 244, 230, 264 ], [ 237, 244, 285, 264 ], [ 284, 240, 291, 253 ], [ 290, 244, 296, 264 ], [ 302, 244, 352, 264 ], [ 359, 240, 443, 263 ], [ 90, 277, 164, 294 ], [ 168, 280, 180, 294 ], [ 184, 280, 264, 294 ], [ 269, 280, 292, 294 ], [ 296, 280, 380, 294 ], [ 383, 280, 406, 294 ], [ 410, 277, 485, 294 ], [ 490, 280, 502, 294 ], [ 506, 280, 591, 294 ], [ 595, 280, 618, 294 ], [ 621, 280, 665, 294 ], [ 669, 280, 746, 294 ], [ 90, 296, 132, 311 ], [ 137, 296, 142, 310 ], [ 145, 296, 266, 311 ], [ 271, 296, 310, 310 ], [ 314, 296, 367, 310 ], [ 90, 340, 113, 354 ], [ 119, 340, 142, 354 ], [ 147, 340, 159, 354 ], [ 165, 340, 195, 354 ], [ 200, 340, 267, 354 ], [ 273, 340, 283, 354 ], [ 288, 340, 296, 354 ], [ 302, 340, 356, 354 ], [ 362, 340, 409, 354 ], [ 415, 340, 426, 354 ], [ 431, 340, 469, 354 ], [ 475, 340, 501, 354 ], [ 506, 340, 557, 354 ], [ 563, 340, 583, 354 ], [ 589, 340, 628, 354 ], [ 633, 340, 716, 354 ], [ 722, 340, 746, 354 ], [ 90, 357, 150, 371 ], [ 155, 357, 214, 371 ], [ 219, 357, 241, 371 ], [ 246, 357, 258, 371 ], [ 263, 357, 283, 371 ], [ 288, 357, 318, 371 ], [ 323, 357, 385, 371 ], [ 390, 357, 421, 371 ], [ 426, 357, 493, 371 ], [ 499, 357, 524, 371 ], [ 529, 357, 556, 371 ], [ 561, 357, 610, 371 ], [ 615, 357, 639, 371 ], [ 644, 357, 665, 371 ], [ 670, 357, 717, 371 ], [ 723, 357, 746, 371 ], [ 90, 374, 142, 388 ], [ 145, 374, 157, 388 ], [ 160, 374, 182, 388 ], [ 185, 374, 219, 388 ], [ 223, 374, 248, 388 ], [ 251, 374, 263, 388 ], [ 266, 374, 319, 388 ], [ 321, 374, 341, 388 ], [ 344, 374, 386, 388 ], [ 389, 374, 401, 388 ], [ 404, 374, 432, 388 ], [ 435, 374, 502, 388 ], [ 506, 374, 522, 388 ], [ 525, 374, 545, 388 ], [ 547, 374, 623, 388 ], [ 626, 374, 706, 388 ], [ 708, 374, 746, 388 ], [ 90, 390, 148, 404 ], [ 157, 390, 169, 404 ], [ 178, 390, 221, 404 ], [ 230, 390, 319, 404 ], [ 327, 390, 415, 404 ], [ 424, 390, 455, 404 ], [ 463, 390, 512, 404 ], [ 521, 390, 549, 404 ], [ 558, 390, 610, 404 ], [ 619, 390, 662, 404 ], [ 670, 390, 700, 404 ], [ 710, 390, 747, 404 ], [ 90, 407, 159, 421 ], [ 163, 407, 174, 421 ], [ 178, 407, 228, 421 ], [ 231, 407, 275, 421 ], [ 279, 407, 303, 421 ], [ 307, 407, 370, 421 ], [ 373, 407, 390, 421 ], [ 394, 407, 410, 421 ], [ 413, 407, 437, 421 ], [ 442, 407, 458, 421 ], [ 461, 407, 510, 421 ], [ 514, 407, 539, 421 ], [ 543, 407, 626, 421 ], [ 630, 407, 683, 421 ], [ 687, 407, 747, 421 ], [ 90, 424, 145, 438 ], [ 153, 424, 187, 438 ], [ 194, 424, 207, 438 ], [ 214, 424, 338, 438 ], [ 345, 424, 381, 438 ], [ 389, 424, 425, 438 ], [ 433, 424, 450, 438 ], [ 457, 424, 503, 438 ], [ 511, 424, 593, 438 ], [ 601, 424, 639, 438 ], [ 646, 424, 713, 438 ], [ 721, 424, 746, 438 ], [ 90, 440, 152, 454 ], [ 157, 440, 205, 454 ], [ 209, 440, 236, 454 ], [ 241, 440, 317, 454 ], [ 322, 440, 372, 454 ], [ 377, 440, 389, 454 ], [ 394, 440, 433, 454 ], [ 437, 440, 464, 454 ], [ 469, 440, 522, 454 ], [ 526, 440, 550, 454 ], [ 555, 440, 603, 454 ], [ 608, 440, 632, 454 ], [ 637, 440, 711, 454 ], [ 716, 440, 746, 454 ], [ 90, 457, 146, 471 ], [ 152, 457, 168, 471 ], [ 174, 457, 244, 471 ], [ 250, 457, 304, 471 ], [ 310, 457, 397, 471 ], [ 404, 457, 453, 471 ], [ 458, 457, 466, 471 ], [ 473, 457, 540, 471 ], [ 546, 457, 597, 471 ], [ 603, 457, 615, 471 ], [ 621, 457, 648, 471 ], [ 654, 457, 712, 471 ], [ 718, 457, 746, 471 ], [ 90, 473, 150, 487 ], [ 156, 473, 215, 487 ], [ 220, 473, 261, 487 ], [ 267, 473, 298, 487 ], [ 303, 473, 315, 487 ], [ 321, 473, 371, 487 ], [ 377, 473, 389, 487 ], [ 394, 473, 421, 487 ], [ 427, 473, 470, 487 ], [ 475, 473, 495, 487 ], [ 500, 473, 522, 487 ], [ 528, 473, 576, 487 ], [ 581, 473, 602, 487 ], [ 608, 473, 636, 487 ], [ 641, 473, 668, 487 ], [ 674, 473, 694, 487 ], [ 699, 473, 719, 487 ], [ 725, 473, 747, 487 ], [ 90, 490, 164, 504 ], [ 168, 490, 216, 504 ], [ 220, 490, 273, 504 ], [ 277, 490, 297, 504 ], [ 301, 490, 349, 504 ], [ 353, 490, 436, 504 ], [ 440, 490, 463, 504 ], [ 466, 490, 498, 504 ], [ 502, 490, 532, 504 ], [ 536, 490, 590, 504 ], [ 593, 490, 620, 504 ], [ 624, 490, 684, 504 ], [ 687, 490, 746, 504 ], [ 90, 507, 130, 521 ], [ 134, 507, 150, 521 ], [ 153, 507, 173, 521 ], [ 175, 507, 199, 521 ], [ 202, 507, 226, 521 ], [ 229, 507, 249, 521 ], [ 252, 507, 274, 521 ], [ 277, 507, 325, 521 ], [ 328, 507, 352, 521 ], [ 355, 507, 429, 521 ], [ 433, 507, 458, 521 ], [ 461, 507, 481, 521 ], [ 484, 507, 528, 521 ], [ 530, 507, 546, 521 ], [ 549, 507, 569, 521 ], [ 572, 507, 644, 521 ], [ 647, 507, 659, 521 ], [ 662, 507, 682, 521 ], [ 685, 507, 746, 521 ], [ 90, 523, 186, 537 ], [ 190, 523, 210, 537 ], [ 214, 523, 248, 537 ], [ 252, 523, 303, 537 ], [ 307, 523, 319, 537 ], [ 324, 523, 363, 537 ], [ 367, 523, 394, 537 ], [ 398, 523, 447, 537 ], [ 451, 523, 463, 537 ], [ 468, 523, 512, 537 ], [ 516, 523, 601, 537 ], [ 606, 523, 663, 537 ], [ 667, 523, 675, 537 ], [ 679, 523, 746, 537 ], [ 90, 540, 197, 554 ], [ 201, 540, 239, 554 ], [ 244, 540, 302, 554 ], [ 306, 540, 322, 554 ], [ 326, 540, 409, 554 ], [ 414, 540, 446, 554 ], [ 450, 540, 477, 554 ], [ 481, 540, 497, 554 ], [ 501, 540, 561, 554 ], [ 565, 540, 620, 554 ], [ 624, 540, 648, 554 ], [ 653, 540, 700, 554 ], [ 90, 567, 140, 577 ], [ 142, 567, 192, 577 ], [ 195, 567, 227, 577 ], [ 230, 567, 291, 577 ], [ 293, 567, 335, 577 ], [ 338, 567, 378, 577 ], [ 381, 567, 442, 577 ], [ 445, 567, 507, 577 ], [ 90, 611, 171, 627 ], [ 90, 631, 144, 645 ], [ 148, 631, 188, 645 ], [ 191, 631, 236, 645 ], [ 239, 631, 263, 645 ], [ 267, 631, 318, 645 ], [ 321, 631, 344, 645 ], [ 347, 631, 375, 645 ], [ 378, 631, 406, 645 ], [ 90, 649, 147, 663 ], [ 154, 649, 185, 663 ], [ 192, 649, 225, 663 ], [ 232, 649, 261, 663 ], [ 269, 649, 338, 663 ], [ 344, 649, 370, 663 ], [ 378, 649, 406, 663 ], [ 90, 667, 165, 681 ], [ 169, 667, 262, 681 ], [ 266, 667, 280, 681 ], [ 284, 667, 347, 681 ], [ 351, 667, 376, 681 ], [ 380, 667, 406, 681 ], [ 90, 685, 119, 699 ], [ 122, 685, 135, 699 ], [ 138, 685, 158, 699 ], [ 160, 685, 188, 699 ], [ 191, 685, 248, 699 ], [ 251, 685, 286, 699 ], [ 289, 685, 308, 699 ], [ 311, 685, 346, 699 ], [ 348, 685, 406, 699 ], [ 90, 703, 108, 717 ], [ 111, 703, 171, 717 ], [ 174, 703, 187, 717 ], [ 190, 703, 256, 717 ], [ 259, 700, 323, 717 ], [ 325, 703, 338, 717 ], [ 341, 703, 391, 717 ], [ 393, 703, 406, 717 ], [ 90, 721, 164, 735 ], [ 168, 721, 181, 735 ], [ 185, 721, 214, 735 ], [ 219, 721, 296, 735 ], [ 300, 721, 319, 735 ], [ 323, 721, 389, 735 ], [ 393, 721, 406, 735 ], [ 90, 739, 118, 753 ], [ 128, 739, 188, 753 ], [ 199, 739, 208, 753 ], [ 218, 739, 225, 753 ], [ 236, 739, 287, 753 ], [ 297, 739, 356, 753 ], [ 366, 739, 378, 753 ], [ 388, 739, 406, 753 ], [ 90, 757, 147, 771 ], [ 155, 757, 168, 771 ], [ 175, 757, 203, 771 ], [ 210, 757, 271, 771 ], [ 278, 757, 301, 771 ], [ 309, 757, 338, 771 ], [ 346, 757, 406, 771 ], [ 90, 775, 117, 789 ], [ 120, 775, 182, 789 ], [ 184, 775, 197, 789 ], [ 199, 775, 227, 789 ], [ 230, 775, 258, 789 ], [ 260, 775, 283, 789 ], [ 285, 775, 326, 789 ], [ 328, 775, 385, 789 ], [ 387, 775, 406, 789 ], [ 90, 793, 172, 807 ], [ 176, 793, 199, 807 ], [ 204, 793, 260, 807 ], [ 264, 793, 319, 807 ], [ 323, 793, 336, 807 ], [ 341, 793, 389, 807 ], [ 393, 793, 406, 807 ], [ 90, 811, 145, 825 ], [ 155, 811, 220, 825 ], [ 229, 811, 254, 825 ], [ 263, 811, 278, 825 ], [ 288, 811, 308, 825 ], [ 318, 811, 349, 825 ], [ 359, 811, 406, 825 ], [ 90, 829, 161, 843 ], [ 170, 829, 192, 843 ], [ 202, 829, 271, 843 ], [ 280, 829, 308, 843 ], [ 318, 829, 378, 843 ], [ 388, 829, 406, 843 ], [ 90, 847, 122, 861 ], [ 132, 847, 175, 861 ], [ 184, 847, 197, 861 ], [ 206, 847, 261, 861 ], [ 270, 847, 331, 861 ], [ 341, 847, 361, 861 ], [ 370, 847, 382, 861 ], [ 392, 847, 406, 861 ], [ 90, 865, 155, 879 ], [ 165, 865, 183, 879 ], [ 192, 865, 223, 879 ], [ 232, 865, 264, 879 ], [ 274, 865, 317, 879 ], [ 326, 865, 350, 879 ], [ 360, 865, 406, 879 ], [ 90, 883, 125, 897 ], [ 130, 883, 140, 897 ], [ 145, 883, 160, 897 ], [ 166, 883, 214, 897 ], [ 220, 883, 280, 897 ], [ 285, 883, 333, 897 ], [ 339, 883, 406, 897 ], [ 90, 901, 103, 915 ], [ 110, 901, 157, 915 ], [ 164, 901, 187, 915 ], [ 193, 901, 237, 915 ], [ 245, 901, 287, 915 ], [ 294, 899, 389, 916 ], [ 395, 901, 405, 915 ], [ 90, 919, 131, 933 ], [ 137, 919, 151, 933 ], [ 158, 919, 209, 933 ], [ 216, 919, 241, 933 ], [ 248, 919, 267, 933 ], [ 273, 919, 300, 933 ], [ 306, 919, 319, 933 ], [ 326, 919, 406, 933 ], [ 90, 958, 162, 968 ], [ 167, 958, 178, 968 ], [ 183, 958, 200, 968 ], [ 205, 958, 240, 968 ], [ 244, 958, 273, 968 ], [ 279, 958, 291, 968 ], [ 295, 958, 364, 968 ], [ 369, 958, 406, 968 ], [ 90, 969, 143, 979 ], [ 146, 969, 200, 979 ], [ 203, 969, 234, 979 ], [ 237, 969, 280, 979 ], [ 283, 969, 321, 979 ], [ 323, 969, 351, 979 ], [ 354, 969, 406, 979 ], [ 90, 980, 99, 990 ], [ 101, 980, 128, 990 ], [ 131, 980, 159, 990 ], [ 162, 980, 205, 990 ], [ 208, 980, 235, 990 ], [ 238, 980, 342, 990 ], [ 430, 615, 474, 629 ], [ 480, 615, 507, 629 ], [ 512, 615, 541, 629 ], [ 545, 615, 608, 629 ], [ 613, 615, 653, 629 ], [ 659, 615, 673, 629 ], [ 678, 615, 727, 629 ], [ 732, 615, 746, 629 ], [ 430, 633, 453, 647 ], [ 465, 633, 479, 647 ], [ 483, 633, 529, 647 ], [ 542, 633, 555, 647 ], [ 567, 633, 621, 647 ], [ 633, 633, 662, 647 ], [ 674, 633, 722, 647 ], [ 734, 633, 747, 647 ], [ 430, 651, 478, 665 ], [ 485, 651, 508, 665 ], [ 514, 651, 557, 665 ], [ 563, 651, 576, 665 ], [ 582, 651, 610, 665 ], [ 616, 651, 691, 665 ], [ 697, 651, 746, 665 ], [ 430, 670, 454, 684 ], [ 460, 670, 490, 684 ], [ 496, 670, 546, 684 ], [ 553, 670, 605, 684 ], [ 612, 670, 648, 684 ], [ 654, 670, 673, 684 ], [ 679, 670, 746, 684 ], [ 430, 688, 448, 702 ], [ 455, 688, 496, 702 ], [ 503, 688, 526, 702 ], [ 532, 688, 560, 702 ], [ 567, 688, 629, 702 ], [ 636, 688, 655, 702 ], [ 661, 688, 746, 702 ], [ 430, 706, 506, 720 ], [ 514, 706, 537, 720 ], [ 545, 706, 635, 720 ], [ 642, 703, 718, 720 ], [ 726, 706, 746, 720 ], [ 430, 724, 459, 738 ], [ 464, 724, 516, 738 ], [ 521, 724, 541, 738 ], [ 547, 724, 584, 738 ], [ 589, 724, 646, 738 ], [ 652, 724, 716, 738 ], [ 720, 724, 746, 738 ], [ 430, 742, 457, 756 ], [ 463, 742, 482, 756 ], [ 487, 742, 586, 756 ], [ 591, 742, 645, 756 ], [ 650, 742, 663, 756 ], [ 668, 742, 746, 756 ], [ 430, 760, 442, 774 ], [ 451, 760, 531, 774 ], [ 540, 760, 563, 774 ], [ 571, 760, 616, 774 ], [ 625, 760, 659, 774 ], [ 667, 760, 686, 774 ], [ 695, 760, 746, 774 ], [ 430, 778, 467, 792 ], [ 478, 778, 501, 792 ], [ 512, 778, 583, 792 ], [ 594, 778, 658, 792 ], [ 669, 778, 717, 792 ], [ 728, 778, 747, 792 ], [ 430, 796, 510, 810 ], [ 516, 796, 539, 810 ], [ 544, 796, 618, 810 ], [ 624, 796, 664, 810 ], [ 669, 796, 700, 810 ], [ 706, 796, 721, 810 ], [ 726, 796, 746, 810 ], [ 430, 814, 475, 828 ], [ 486, 814, 509, 828 ], [ 520, 814, 538, 828 ], [ 549, 814, 568, 828 ], [ 579, 814, 639, 828 ], [ 650, 814, 663, 828 ], [ 673, 814, 746, 828 ], [ 430, 832, 507, 846 ], [ 515, 832, 551, 846 ], [ 560, 832, 570, 846 ], [ 578, 832, 639, 846 ], [ 647, 832, 665, 846 ], [ 673, 832, 692, 846 ], [ 700, 832, 746, 846 ], [ 430, 850, 469, 864 ], [ 478, 850, 497, 864 ], [ 505, 850, 585, 864 ], [ 594, 850, 617, 864 ], [ 625, 850, 644, 864 ], [ 652, 850, 725, 864 ], [ 734, 850, 747, 864 ], [ 430, 868, 504, 882 ], [ 510, 866, 598, 883 ], [ 603, 868, 689, 882 ], [ 694, 868, 709, 882 ], [ 714, 868, 747, 882 ], [ 430, 886, 475, 900 ], [ 480, 886, 493, 900 ], [ 496, 886, 574, 900 ], [ 579, 886, 633, 900 ], [ 636, 886, 675, 900 ], [ 679, 886, 691, 900 ], [ 695, 886, 746, 900 ], [ 430, 905, 477, 919 ], [ 482, 905, 509, 919 ], [ 513, 905, 532, 919 ], [ 536, 905, 559, 919 ], [ 563, 905, 576, 919 ], [ 581, 902, 683, 919 ], [ 444, 923, 471, 937 ], [ 479, 923, 492, 937 ], [ 499, 923, 518, 937 ], [ 524, 923, 554, 937 ], [ 561, 923, 624, 937 ], [ 631, 923, 658, 937 ], [ 665, 923, 727, 937 ], [ 735, 923, 747, 937 ], [ 430, 941, 464, 955 ], [ 470, 941, 498, 955 ], [ 503, 941, 547, 955 ], [ 553, 941, 572, 955 ], [ 577, 941, 656, 955 ], [ 662, 941, 685, 955 ], [ 690, 941, 746, 955 ], [ 430, 959, 485, 973 ], [ 493, 959, 553, 973 ], [ 559, 959, 603, 973 ], [ 610, 959, 641, 973 ], [ 648, 959, 713, 973 ], [ 720, 959, 747, 973 ], [ 430, 977, 465, 991 ], [ 471, 977, 490, 991 ], [ 495, 977, 533, 991 ], [ 538, 977, 551, 991 ], [ 556, 977, 618, 991 ], [ 624, 977, 640, 991 ], [ 645, 977, 687, 991 ], [ 692, 977, 747, 991 ], [ 100, 1020, 118, 1029 ], [ 121, 1020, 155, 1029 ], [ 158, 1020, 188, 1029 ], [ 190, 1020, 201, 1029 ], [ 205, 1020, 271, 1029 ], [ 90, 1030, 113, 1039 ], [ 116, 1030, 164, 1039 ], [ 167, 1030, 197, 1039 ], [ 200, 1030, 213, 1039 ], [ 216, 1030, 236, 1039 ], [ 238, 1030, 265, 1039 ], [ 268, 1030, 283, 1039 ], [ 285, 1030, 330, 1039 ], [ 333, 1030, 356, 1039 ], [ 359, 1030, 372, 1039 ], [ 375, 1030, 398, 1039 ], [ 400, 1030, 408, 1039 ], [ 411, 1030, 424, 1039 ], [ 427, 1030, 460, 1039 ], [ 463, 1030, 502, 1039 ], [ 505, 1030, 549, 1039 ], [ 551, 1030, 581, 1039 ], [ 584, 1030, 597, 1039 ], [ 90, 1040, 105, 1049 ], [ 107, 1040, 257, 1049 ], [ 489, 1039, 522, 1049 ], [ 526, 1039, 535, 1049 ], [ 538, 1039, 615, 1049 ], [ 635, 1039, 659, 1049 ], [ 678, 1041, 694, 1049 ], [ 696, 1039, 708, 1049 ], [ 727, 1041, 739, 1049 ], [ 741, 1039, 747, 1049 ], [ 775, 1038, 788, 1049 ] ]
[ 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 ]

No dataset card yet

New: Create and edit this dataset card directly on the website!

Contribute a Dataset Card
Downloads last month
9
Add dataset card