Datasets:

SotiriosKastanas

/

trygroto

like 0

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

[ 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 ]

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

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

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