id
int64 37.5k
3.5M
| image
unknown | bboxes
sequence | tokens
sequence | ner_tags
sequence |
---|---|---|---|---|
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] | [
"4686–4703",
"Nucleic",
"Acids",
"Research,",
"2007,",
"Vol.",
"35,",
"No.",
"14",
"doi:10.1093/nar/gkm441",
"Published",
"online",
"29",
"June",
"2007",
"Reconstructing",
"the",
"evolution",
"of",
"the",
"mitochondrial",
"ribosomal",
"proteome",
"Paulien",
"Smits1,",
"Jan",
"A.",
"M.",
"Smeitink",
"1",
",",
"Lambert",
"P.",
"van",
"den",
"Heuvel1,",
"Martijn",
"A.",
"Huynen2",
"and",
"Thijs",
"J.",
"G.",
"Ettema2,*",
"1Nijmegen",
"Center",
"for",
"Mitochondrial",
"Disorders,",
"Nijmegen",
"Center",
"for",
"Molecular",
"Life",
"Sciences,",
"Radboud",
"University",
"Nijmegen",
"Medical",
"Center,",
"Geert–Grooteplein-Zuid",
"10",
"and",
"2Center",
"for",
"Molecular",
"and",
"Biomolecular",
"Informatics,",
"Nijmegen",
"Center",
"for",
"Molecular",
"Life",
"Sciences,",
"Radboud",
"University",
"Nijmegen",
"Medical",
"Center,",
"Geert-Grooteplein",
"28,",
"6525",
"GA",
"Nijmegen,",
"The",
"Netherlands",
"Received",
"March",
"20,",
"2007;",
"Revised",
"May",
"16,",
"2007;",
"Accepted",
"May",
"17,",
"2007",
"ABSTRACT",
"For",
"production",
"of",
"proteins",
"that",
"are",
"encoded",
"by",
"the",
"mitochondrial",
"genome,",
"mitochondria",
"rely",
"on",
"their",
"own",
"mitochondrial",
"translation",
"system,",
"with",
"the",
"mitoribosome",
"as",
"its",
"central",
"component.",
"Using",
"extensive",
"homology",
"searches,",
"we",
"have",
"reconstructed",
"the",
"evolutionary",
"history",
"of",
"the",
"mitoribosomal",
"proteome",
"that",
"is",
"encoded",
"by",
"a",
"diverse",
"subset",
"of",
"eukaryotic",
"genomes,",
"revealing",
"an",
"ancestral",
"ribosome",
"of",
"alpha-proteobacterial",
"descent",
"that",
"more",
"than",
"doubled",
"its",
"protein",
"content",
"in",
"most",
"eukaryotic",
"lineages.",
"We",
"observe",
"large",
"variations",
"in",
"the",
"protein",
"content",
"of",
"mitoribosomes",
"between",
"different",
"eukaryotes,",
"with",
"mammalian",
"mitoribosomes",
"sharing",
"only",
"74",
"and",
"43%",
"of",
"its",
"proteins",
"with",
"yeast",
"and",
"Leishmania",
"mitoribosomes,",
"respectively.",
"We",
"detected",
"many",
"previously",
"unidentified",
"mitochondrial",
"ribosomal",
"proteins",
"(MRPs)",
"and",
"found",
"that",
"several",
"have",
"increased",
"in",
"size",
"compared",
"to",
"their",
"bacterial",
"ancestral",
"counterparts",
"by",
"addition",
"of",
"functional",
"domains.",
"Several",
"new",
"MRPs",
"have",
"originated",
"via",
"duplication",
"of",
"existing",
"MRPs",
"as",
"well",
"as",
"by",
"recruitment",
"from",
"outside",
"of",
"the",
"mitoribosomal",
"proteome.",
"Using",
"sensitive",
"profile–profile",
"homology",
"searches,",
"we",
"found",
"hitherto",
"undetected",
"homology",
"between",
"bacterial",
"and",
"eukaryotic",
"ribosomal",
"proteins,",
"as",
"well",
"as",
"between",
"fungal",
"and",
"mammalian",
"ribosomal",
"proteins,",
"detecting",
"two",
"novel",
"human",
"MRPs.",
"These",
"newly",
"detected",
"MRPs",
"constitute,",
"along",
"with",
"evolu-",
"tionary",
"conserved",
"MRPs,",
"excellent",
"new",
"screening",
"targets",
"for",
"human",
"patients",
"with",
"unresolved",
"mitochondrial",
"oxidative",
"phosphorylation",
"disorders.",
"INTRODUCTION",
"Mitochondria",
"are",
"primary",
"ATP-producing",
"organelles",
"which",
"originated",
"from",
"an",
"ancestral",
"alpha-proteobacterial",
"endosymbiont",
"(1,2).",
"The",
"oxidative",
"phosphorylation",
"(OXPHOS)",
"pathway,",
"consisting",
"of",
"the",
"mitochondrial",
"respiratory",
"chain",
"and",
"the",
"ATP",
"synthase",
"complex,",
"is",
"the",
"final",
"biochemical",
"pathway",
"in",
"energy",
"conversion",
"(3).",
"However,",
"mitochondria",
"have",
"been",
"found",
"to",
"perform",
"pivotal",
"roles",
"in",
"many",
"other",
"metabolic,",
"regulatory",
"and",
"developmental",
"processes.",
"During",
"the",
"evolution",
"of",
"the",
"mitochondria,",
"most",
"genes",
"of",
"the",
"ancestral",
"endosymbiont",
"have",
"been",
"transferred",
"from",
"the",
"mitochondrial",
"to",
"the",
"nuclear",
"genome.",
"The",
"genes",
"that",
"reside",
"on",
"the",
"mitochondrial",
"DNA",
"(mtDNA),",
"e.g.",
"13",
"OXPHOS-related",
"genes",
"in",
"human,",
"are",
"translated",
"into",
"their",
"respective",
"protein",
"products",
"by",
"the",
"mitochondrial",
"translation",
"machin-",
"ery,",
"which",
"resembles",
"the",
"prokaryotic",
"translation",
"system",
"(4),",
"comprising",
"a",
"mitochondrial",
"ribosome",
"(mito-",
"ribosome)",
"and",
"several",
"translation",
"factors.",
"In",
"mammals,",
"all",
"proteins",
"that",
"constitute",
"the",
"mitochondrial",
"translation",
"machinery",
"are",
"encoded",
"by",
"the",
"nuclear",
"genome.",
"Also",
"the",
"mitochondrial",
"genomes",
"of",
"fungi",
"generally",
"encode",
"only",
"very",
"few",
"mitochondrial",
"ribosomal",
"proteins",
"(MRPs).",
"In",
"contrast,",
"the",
"mitochondrial",
"genome",
"of",
"many",
"protozoa",
"and",
"plants",
"encode",
"numerous",
"MRPs.",
"Most",
"notably,",
"the",
"‘primitive’",
"mitochondrial",
"genome",
"of",
"the",
"freshwater",
"protist",
"Reclinomonas",
"americana",
"was",
"found",
"to",
"contain",
"as",
"many",
"as",
"27",
"MRP-encoding",
"genes",
"(5).",
"Mitoribosomes",
"have",
"undergone",
"major",
"remodeling",
"during",
"their",
"evolution.",
"For",
"instance,",
"it",
"has",
"been",
"found",
"that,",
"despite",
"the",
"fact",
"that",
"their",
"rRNA",
"content",
"is",
"only",
"half",
"the",
"content",
"of",
"bacterial",
"ribosomes",
"(6),",
"mitoribosomes",
"generally",
"exceed",
"the",
"bacterial",
"ribosomes",
"both",
"in",
"molecular",
"mass",
"as",
"well",
"as",
"in",
"physical",
"dimensions",
"(6–8).",
"Mass",
"spectrometry",
"studies",
"of",
"the",
"bovine",
"and",
"yeast",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Email:",
"thijs.ettema@ebc.uu.se",
"Present",
"address:",
"Thijs",
"J.",
"G.",
"Ettema,",
"Department",
"of",
"Molecular",
"Evolution,",
"Evolutionary",
"Biology",
"Centre,",
"Uppsala",
"University,",
"Norbyva¨",
"gen",
"18C,",
"752",
"36",
"Uppsala,",
"Sweden.",
"2007",
"The",
"Author(s)",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"ABSTRACT",
"Complications",
"produced",
"by",
"the",
"sectioning",
"of",
"a",
"nonvisu-",
"alized",
"duct",
"of",
"Luschka",
"are",
"uncommon",
"during",
"laparo-",
"scopic",
"cholecystectomy.",
"From",
"1999",
"through",
"2003,",
"we",
"performed",
"1351",
"laparoscopic",
"cholecystectomies",
"in",
"our",
"department",
"and",
"observed",
"2",
"cases",
"(0.15%)",
"of",
"bile",
"leakage",
"due",
"to",
"duct",
"of",
"Luschka",
"injury.",
"Injury",
"during",
"laparoscopic",
"cholecystectomy",
"is",
"usually",
"produced",
"by",
"an",
"excessively",
"deep",
"plane",
"of",
"dissection",
"and",
"by",
"the",
"anatomical",
"localiza-",
"tion",
"of",
"this",
"accessory",
"duct.",
"Clinical",
"symptoms",
"are",
"scarce",
"after",
"duct",
"of",
"Luschka",
"injury.",
"Numerous",
"diagnostic",
"meth-",
"ods",
"have",
"been",
"used",
"to",
"detect",
"these",
"injuries.",
"Nevertheless,",
"careful",
"clinical",
"examination",
"is",
"still",
"of",
"the",
"utmost",
"impor-",
"tance.",
"Noninvasive",
"treatments",
"are",
"usually",
"effective.",
"In",
"patients",
"who",
"present",
"with",
"acute",
"abdomen,",
"as",
"in",
"our",
"cases,",
"or",
"who",
"are",
"not",
"cured",
"by",
"noninvasive",
"treatments,",
"exploratory",
"lap-",
"arotomy",
"is",
"the",
"best",
"approach.",
"The",
"surgical",
"treatment",
"con-",
"sists",
"of",
"a",
"lavage",
"of",
"the",
"abdominal",
"cavity,",
"closure",
"of",
"the",
"duct",
"of",
"Luschka,",
"and",
"intraoperative",
"cholangiography",
"to",
"confirm",
"that",
"the",
"biliary",
"tree",
"is",
"intact.",
"Key",
"Words:",
"Luchska,",
"Laparoscopy,",
"Cholecystectomy,",
"Re-",
"view.",
"Liver",
"Transplantation",
"and",
"Hepatobiliary",
"Unit,",
"Department",
"of",
"Surgery,",
"Hospital",
"Universitario",
"Virgen",
"de",
"las",
"Nieves,",
"Granada,",
"Spain",
"(all",
"authors).",
"Address",
"reprint",
"requests",
"to:",
"J.",
"M.",
"Ramia,",
"PhD,",
"C/Buensuceso",
"6,",
"4D,",
"18002",
"Granada,",
"Spain.",
"Telephone:",
"0034958536859,",
"E-mail:",
"jose_ramia@hotmail.com",
"©",
"2005",
"by",
"JSLS,",
"Journal",
"of",
"the",
"Society",
"of",
"Laparoendoscopic",
"Surgeons.",
"Published",
"by",
"the",
"Society",
"of",
"Laparoendoscopic",
"Surgeons,",
"Inc.",
"216",
"JSLS",
"(2005)9:216",
"–217",
"CASE",
"REPORT",
"Postlaparoscopic",
"Cholecystectomy",
"Bile",
"Leak",
"Secondary",
"to",
"an",
"Accessory",
"Duct",
"of",
"Luschka",
"J.",
"M.",
"Ramia,",
"PhD,",
"K.",
"Muffak,",
"MD,",
"A.",
"Mansilla,",
"PhD,",
"J.",
"Villar,",
"PhD,",
"D.",
"Garrote,",
"PhD,",
"J.",
"A.",
"Ferron,",
"PhD",
"INTRODUCTION",
"The",
"gold",
"standard",
"treatment",
"for",
"cholelithiasis",
"is",
"cur-",
"rently",
"laparoscopic",
"cholecystectomy",
"(LC).",
"During",
"the",
"learning",
"curve",
"phase,",
"LC",
"bile",
"duct",
"injuries",
"appear",
"to",
"be",
"more",
"numerous",
"and",
"severe",
"than",
"those",
"caused",
"by",
"open",
"cholecystectomy.1",
"Currently,",
"the",
"biliary",
"complication",
"rate",
"of",
"these",
"2",
"procedures",
"is",
"similar.2,3",
"Complication",
"produced",
"by",
"the",
"sectioning",
"of",
"a",
"nonvisualized",
"duct",
"of",
"Luschka",
"are",
"uncommon",
"during",
"LC,",
"although",
"the",
"true",
"incidence",
"is",
"unknown,",
"especially",
"because",
"published",
"studies",
"focus",
"on",
"so-called",
"major",
"biliary",
"lesions.1,3,4",
"From",
"1999",
"through",
"2003,",
"we",
"performed",
"1351",
"LCs",
"in",
"our",
"department",
"and",
"observed",
"2",
"cases",
"(0.15%)",
"of",
"bile",
"leak-",
"age",
"due",
"to",
"duct",
"of",
"Luschka",
"injury.",
"We",
"present",
"these",
"2",
"cases",
"and",
"discuss",
"the",
"appropriate",
"diagnostic",
"and",
"ther-",
"apeutic",
"approach.",
"CASE",
"1",
"A",
"51-year-old",
"man",
"was",
"referred",
"to",
"our",
"department",
"for",
"repeated",
"colic",
"abdominal",
"pain",
"in",
"the",
"right",
"hypochon-",
"drium.",
"He",
"had",
"a",
"history",
"of",
"hepatic",
"and",
"renal",
"polycystosis",
"that",
"produced",
"severe",
"chronic",
"renal",
"insufficiency.",
"He",
"un-",
"derwent",
"a",
"surgical",
"laparoscopy",
"that",
"revealed",
"multiple",
"cysts",
"of",
"various",
"sizes",
"on",
"both",
"lobes",
"of",
"the",
"liver.",
"Laparo-",
"scopic",
"defenestration",
"of",
"the",
"dominant",
"hepatic",
"cysts",
"and",
"laparoscopic",
"cholecystectomy",
"were",
"performed.",
"In",
"the",
"postoperative",
"period,",
"the",
"patient",
"was",
"afebrile",
"and",
"expe-",
"rienced",
"diffuse",
"moderate",
"pain",
"of",
"the",
"whole",
"abdomen,",
"with",
"no",
"other",
"symptoms.",
"Two",
"abdominal",
"ultrasound",
"scans",
"showed",
"a",
"small",
"amount",
"of",
"liquid",
"in",
"the",
"abdominal",
"cavity;",
"the",
"blood",
"analysis",
"results",
"were",
"normal.",
"The",
"liquid",
"was",
"assumed",
"to",
"derive",
"from",
"the",
"fenestrated",
"cysts.",
"On",
"the",
"sixth",
"postoperative",
"day,",
"the",
"patient",
"reported",
"the",
"abrupt",
"onset",
"of",
"intense",
"abdominal",
"pain,",
"and",
"a",
"new",
"ultrasound",
"scan",
"showed",
"an",
"increase",
"in",
"the",
"abdominal",
"liquid.",
"An",
"exploratory",
"laparotomy",
"revealed",
"biliary",
"peritonitis",
"due",
"to",
"bile",
"leakage",
"from",
"the",
"duct",
"of",
"Luschka",
"in",
"the",
"liver",
"bed.",
"An",
"intraoperative",
"cholangiography",
"confirmed",
"that",
"the",
"biliary",
"tree",
"was",
"intact.",
"The",
"duct",
"of",
"Luchska",
"was",
"then",
"closed,",
"with",
"thorough",
"lavage",
"of",
"the",
"abdominal",
"cavity.",
"The",
"second",
"postoperative",
"period",
"was",
"free",
"of",
"complications,",
"and",
"the",
"patient",
"was",
"discharged",
"from",
"the",
"hospital",
"5",
"days",
"after",
"the",
"second",
"surgery."
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] | [
"Shenoy",
"et",
"al.",
"Nutrition",
"Journal",
"2010,",
"9:38",
"http://www.nutritionj.com/content/9/1/38",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"The",
"use",
"of",
"a",
"commercial",
"vegetable",
"juice",
"as",
"a",
"practical",
"means",
"to",
"increase",
"vegetable",
"intake:",
"a",
"randomized",
"controlled",
"trial",
"Sonia",
"F",
"Shenoy1,",
"Alexandra",
"G",
"Kazaks2,",
"Roberta",
"R",
"Holt1,",
"Hsin",
"Ju",
"Chen1,",
"Barbara",
"L",
"Winters3,",
"Chor",
"San",
"Khoo4,",
"Walker",
"SC",
"Poston5,",
"C",
"Keith",
"Haddock5,",
"Rebecca",
"S",
"Reeves6,",
"John",
"P",
"Foreyt6,",
"M",
"Eric",
"Gershwin7,",
"Carl",
"L",
"Keen1,8*",
"Abstract",
"Background:",
"Recommendations",
"for",
"daily",
"dietary",
"vegetable",
"intake",
"were",
"increased",
"in",
"the",
"2005",
"USDA",
"Dietary",
"Guidelines",
"as",
"consumption",
"of",
"a",
"diet",
"rich",
"in",
"vegetables",
"has",
"been",
"associated",
"with",
"lower",
"risk",
"of",
"certain",
"chronic",
"health",
"disorders",
"including",
"cardiovascular",
"disease.",
"However,",
"vegetable",
"consumption",
"in",
"the",
"United",
"States",
"has",
"declined",
"over",
"the",
"past",
"decade;",
"consequently,",
"the",
"gap",
"between",
"dietary",
"recommendations",
"and",
"vegetable",
"intake",
"is",
"widening.",
"The",
"primary",
"aim",
"of",
"this",
"study",
"is",
"to",
"determine",
"if",
"drinking",
"vegetable",
"juice",
"is",
"a",
"practical",
"way",
"to",
"help",
"meet",
"daily",
"dietary",
"recommendations",
"for",
"vegetable",
"intake",
"consistent",
"with",
"the",
"2005",
"Dietary",
"Guidelines",
"and",
"the",
"Dietary",
"Approaches",
"to",
"Stop",
"Hypertension",
"(DASH)",
"diet.",
"The",
"secondary",
"aim",
"is",
"to",
"assess",
"the",
"effect",
"of",
"a",
"vegetable",
"juice",
"on",
"measures",
"of",
"cardiovascular",
"health.",
"Methods:",
"We",
"conducted",
"a",
"12-week,",
"randomized,",
"controlled,",
"parallel-arm",
"study",
"consisting",
"of",
"3",
"groups",
"of",
"free-",
"living,",
"healthy",
"volunteers",
"who",
"participated",
"in",
"study",
"visits",
"at",
"the",
"Ragle",
"Human",
"Nutrition",
"Research",
"Center",
"at",
"the",
"University",
"of",
"California,",
"Davis.",
"All",
"subjects",
"received",
"education",
"on",
"the",
"DASH",
"diet",
"and",
"0,",
"8",
"or",
"16",
"fluid",
"ounces",
"of",
"vegetable",
"juice",
"daily.",
"Assessments",
"were",
"completed",
"of",
"daily",
"vegetable",
"servings",
"before",
"and",
"after",
"incorporation",
"of",
"vegetable",
"juice",
"and",
"cardiovascular",
"health",
"parameters",
"including",
"blood",
"pressure.",
"Results:",
"Without",
"the",
"juice,",
"vegetable",
"intake",
"in",
"all",
"groups",
"was",
"lower",
"than",
"the",
"2005",
"Dietary",
"Guidelines",
"and",
"DASH",
"diet",
"recommendations.",
"The",
"consumption",
"of",
"the",
"vegetable",
"juice",
"helped",
"participants",
"reach",
"recommended",
"intake.",
"In",
"general,",
"parameters",
"associated",
"with",
"cardiovascular",
"health",
"did",
"not",
"change",
"over",
"time.",
"However,",
"in",
"the",
"vegetable",
"juice",
"intervention",
"groups,",
"subjects",
"who",
"were",
"pre-hypertensive",
"at",
"the",
"start",
"of",
"the",
"study",
"showed",
"a",
"significant",
"decrease",
"in",
"blood",
"pressure",
"during",
"the",
"12-week",
"intervention",
"period.",
"Conclusion:",
"Including",
"1-2",
"cups",
"of",
"vegetable",
"juice",
"daily",
"was",
"an",
"effective",
"and",
"acceptable",
"way",
"for",
"healthy",
"adults",
"to",
"close",
"the",
"dietary",
"vegetable",
"gap.",
"Increase",
"in",
"daily",
"vegetable",
"intake",
"was",
"associated",
"with",
"a",
"reduction",
"in",
"blood",
"pressure",
"in",
"subjects",
"who",
"were",
"pre-hypertensive",
"at",
"the",
"start",
"of",
"the",
"trial.",
"Trial",
"Registration:",
"Clinicaltrials.gov",
"NCT01161706",
"Background",
"For",
"almost",
"two",
"decades,",
"the",
"United",
"States",
"Department",
"of",
"Agriculture",
"(USDA)",
"has",
"recommended",
"that",
"Ameri-",
"cans",
"consume",
"a",
"minimum",
"of",
"5",
"servings",
"of",
"vegetables",
"and",
"fruits",
"a",
"day",
"[1].",
"These",
"recommendations",
"are",
"based",
"on",
"numerous",
"studies",
"showing",
"that",
"meeting",
"the",
"*",
"Correspondence:",
"clkeen@ucdavis.edu",
"1Department",
"of",
"Nutrition,",
"University",
"of",
"California",
"Davis,",
"One",
"Shields",
"Ave,",
"Davis,",
"California",
"95616,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"recommended",
"daily",
"intake",
"of",
"fruit",
"and",
"vegetables",
"is",
"associated",
"with",
"a",
"reduced",
"risk",
"for",
"a",
"number",
"of",
"chronic",
"diseases,",
"with",
"the",
"evidence",
"for",
"cardiovascular",
"disease",
"and",
"stroke",
"being",
"particularly",
"strong",
"[2-5].",
"In",
"2005",
"the",
"Department",
"of",
"Health",
"and",
"Human",
"Services",
"updated",
"the",
"Dietary",
"Guidelines",
"which",
"recommended",
"an",
"increase",
"in",
"fruit",
"and",
"vegetable",
"intake",
"and",
"changed",
"the",
"recommen-",
"dations",
"from",
"servings",
"to",
"cups",
"[6].",
"The",
"new",
"goal",
"was",
"2-",
"6.5",
"cups",
"(equivalent",
"to",
"4",
"-",
"13",
"servings)",
"according",
"to",
"an",
"individual’s",
"sex,",
"physical",
"activity",
"and",
"age",
"[6].",
"For",
"this",
"©",
"2010",
"Shenoy",
"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."
] | [
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] | [
"Eur",
"J",
"Epidemiol",
"(2010)",
"25:569–580",
"DOI",
"10.1007/s10654-010-9473-1",
"P",
"S",
"Y",
"C",
"H",
"I",
"A",
"T",
"R",
"I",
"C",
"E",
"P",
"I",
"D",
"E",
"M",
"I",
"O",
"L",
"O",
"G",
"Y",
"Cognitive",
"ability,",
"parental",
"socioeconomic",
"position",
"and",
"internalising",
"and",
"externalising",
"problems",
"in",
"adolescence:",
"Findings",
"from",
"two",
"European",
"cohort",
"studies",
"Martijn",
"Huisman",
"•",
"Ricardo",
"Araya",
"•",
"Debbie",
"A.",
"Lawlor",
"•",
"Johan",
"Ormel",
"•",
"Frank",
"C.",
"Verhulst",
"•",
"Albertine",
"J.",
"Oldehinkel",
"Received:",
"28",
"January",
"2010",
"/",
"Accepted:",
"27",
"May",
"2010",
"/",
"Published",
"online:",
"10",
"June",
"2010",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"We",
"investigated",
"whether",
"cognitive",
"ability",
"(CA)",
"may",
"be",
"a",
"moderator",
"of",
"the",
"relationship",
"of",
"parental",
"socio-",
"economic",
"position",
"(SEP)",
"with",
"internalising",
"and",
"external-",
"ising",
"problems",
"in",
"adolescents.",
"We",
"used",
"data",
"from",
"two",
"longitudinal",
"cohort",
"studies;",
"the",
"Avon",
"Longitudinal",
"Study",
"of",
"Parents",
"and",
"Children",
"(ALSPAC)",
"and",
"the",
"Tracking",
"Adolescents’",
"Individual",
"Lives",
"Survey",
"(TRAILS).",
"Indica-",
"tors",
"of",
"SEP",
"were",
"mother’s",
"education",
"and",
"household",
"income.",
"CA",
"was",
"estimated",
"with",
"IQ",
"scores,",
"derived",
"from",
"the",
"Wechsler",
"Intelligence",
"Scale",
"for",
"Children.",
"Internalising",
"and",
"externalising",
"problems",
"were",
"measured",
"with",
"the",
"Strengths",
"and",
"Difficulties",
"Questionnaire",
"in",
"ALSPAC",
"and",
"with",
"the",
"Child",
"Behavior",
"Checklist",
"in",
"TRAILS.",
"Logistic",
"regression",
"analyses",
"were",
"used",
"to",
"estimate",
"the",
"relative",
"index",
"of",
"inequality",
"(RII)",
"for",
"each",
"outcome;",
"the",
"RII",
"provides",
"the",
"odds",
"ratio",
"comparing",
"the",
"most",
"to",
"least",
"deprived",
"for",
"each",
"measure",
"of",
"SEP.",
"In",
"fully",
"adjusted",
"models",
"an",
"association",
"of",
"mother’s",
"education",
"with",
"externalising",
"problems",
"was",
"M.",
"Huisman",
"(&)",
"J.",
"Ormel",
"A.",
"J.",
"Oldehinkel",
"Interdisciplinary",
"Center",
"for",
"Psychiatric",
"Epidemiology,",
"University",
"Medical",
"Center",
"Groningen,",
"Groningen,",
"The",
"Netherlands",
"e-mail:",
"ma.huisman@vumc.nl",
"R.",
"Araya",
"Academic",
"Unit",
"of",
"Psychiatry,",
"Community",
"Based",
"Medicine",
"Department,",
"University",
"of",
"Bristol,",
"Bristol,",
"UK",
"D.",
"A.",
"Lawlor",
"MRC",
"Centre",
"for",
"Causal",
"Analyses",
"in",
"Translational",
"Epidemiology,",
"Department",
"of",
"Social",
"Medicine,",
"University",
"of",
"Bristol,",
"Bristol,",
"UK",
"F.",
"C.",
"Verhulst",
"Department",
"of",
"Child",
"and",
"Adolescent",
"Psychiatry,",
"Erasmus",
"MC-",
"Sophia,",
"University",
"Medical",
"Center,",
"Rotterdam,",
"The",
"Netherlands",
"observed",
"[ALSPAC",
"RII",
"1.42",
"(95%CI:",
"1.01–1.99);",
"TRAILS",
"RII",
"2.21",
"(95%CI:",
"1.37–3.54)],",
"and",
"of",
"household",
"income",
"with",
"internalising",
"and",
"externalising",
"problems",
"[pooled",
"ALSPAC",
"&",
"TRAILS",
"internalising",
"RII",
"1.30",
"(95%CI:",
"0.99–",
"1.71);",
"pooled",
"ALSPAC",
"&",
"TRAILS",
"externalising",
"RII",
"1.38",
"(95%CI:",
"1.03–1.84)].",
"No",
"consistent",
"associations",
"were",
"observed",
"between",
"mother’s",
"education",
"and",
"internalising",
"problems.",
"Results",
"of",
"stratified",
"analyses",
"and",
"interaction-",
"terms",
"showed",
"no",
"evidence",
"that",
"CA",
"moderated",
"the",
"associ-",
"ation",
"of",
"SEP",
"with",
"internalising",
"or",
"externalising",
"problems.",
"Keywords",
"Adolescence",
"Mental",
"health",
"ALSPAC",
"Socioeconomic",
"factors",
"TRAILS",
"Cognitive",
"ability",
"Abbreviations",
"CA",
"Cognitive",
"ability",
"SEP",
"Socioeconomic",
"position",
"Introduction",
"Two",
"important",
"predictors",
"of",
"internalising",
"and",
"externalising",
"problems",
"in",
"adolescents",
"are",
"parental",
"socioeconomic",
"position",
"(SEP)",
"[1–7]",
"and",
"cognitive",
"deficits",
"[8–13]",
"or",
"abilities",
"(CA)",
"in",
"the",
"adolescent",
"[14].",
"Previous",
"studies",
"provided",
"substantial",
"evidence",
"that",
"children",
"and",
"adolescents",
"from",
"lower",
"socio-",
"economic",
"groups",
"more",
"often",
"manifest",
"internalising",
"and",
"externalising",
"problems,",
"although",
"the",
"precise",
"relation",
"between",
"SEP",
"and",
"specific",
"types",
"of",
"problems",
"remains",
"unclear",
"[15].",
"Among",
"adolescents,",
"lower",
"parental",
"SEP",
"is",
"related",
"to",
"most",
"of",
"the",
"common",
"mental",
"health",
"problems,",
"including",
"in-",
"ternalising",
"problems",
"[2],",
"depression",
"[3–5,",
"7]",
"and",
"delinquent",
"and",
"rule-breaking",
"behaviour",
"[1,",
"6,",
"7].",
"123"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Sarcoma",
"Volume",
"2011,",
"Article",
"ID",
"160369,",
"5",
"pages",
"doi:10.1155/2011/160369",
"Case",
"Report",
"Scalp",
"Angiosarcoma",
"Remission",
"with",
"Bevacizumab",
"and",
"Radiotherapy",
"without",
"Surgery:",
"A",
"Case",
"Report",
"and",
"Review",
"of",
"the",
"Literature",
"Jocelyn",
"T.",
"De",
"Yao,1,",
"2",
"Danyu",
"Sun,1,",
"2",
"Angela",
"T.",
"Powell,2,",
"3",
"and",
"Esther",
"H.",
"Rehmus1,",
"2",
"1",
"Department",
"of",
"Medicine,",
"Akron",
"General",
"Medical",
"Center,",
"400",
"Wabash",
"Avenue,",
"Akron,",
"OH",
"44307,",
"USA",
"2",
"Department",
"of",
"Medicine,",
"Northeastern",
"Ohio",
"Universities,",
"College",
"of",
"Medicine",
"and",
"Pharmacy,",
"Rootstown,",
"OH",
"44272,",
"USA",
"3",
"Department",
"of",
"Pathology,",
"Akron",
"General",
"Medical",
"Center,",
"400",
"Wabash",
"Avenue,",
"Akron,",
"OH",
"44307,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Jocelyn",
"T.",
"De",
"Yao,",
"jdeyao@agmc.org",
"Received",
"18",
"October",
"2010;",
"Accepted",
"27",
"February",
"2011",
"Academic",
"Editor:",
"Marcus",
"Schlemmer",
"Copyright",
"©",
"2011",
"Jocelyn",
"T.",
"De",
"Yao",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Angiosarcoma",
"(AS)",
"is",
"a",
"rare",
"and",
"aggressive",
"vascular",
"neoplasm",
"with",
"very",
"poor",
"prognosis.",
"Patients",
"with",
"extensive",
"cutaneous",
"AS",
"who",
"are",
"not",
"surgical",
"candidates",
"have",
"very",
"limited",
"options",
"since",
"there",
"is",
"no",
"standard",
"treatment.",
"Treatment",
"options",
"include",
"radiation,",
"chemotherapy,",
"and",
"angiogenesis",
"inhibitor",
"with",
"varying",
"success",
"rates.",
"Here,",
"we",
"report",
"a",
"case",
"an",
"88",
"year",
"old",
"patient",
"with",
"extensive",
"scalp",
"angiosarcoma",
"having",
"biopsy",
"proven",
"remission",
"with",
"bevacizumab",
"and",
"radiotherapy",
"without",
"undergoing",
"surgery.",
"1.",
"Introduction",
"Angiosarcoma",
"(AS)",
"is",
"a",
"rare",
"and",
"aggressive",
"vascular",
"neo-",
"plasm",
"comprising",
"less",
"than",
"2%",
"of",
"all",
"soft",
"tissue",
"sarcomas",
"[1–",
"3].",
"Angiosarcomas",
"comprise",
"approximately",
"15%",
"of",
"all",
"head",
"and",
"neck",
"sarcomas",
"[4–6]",
"and",
"less",
"than",
"1%",
"of",
"all",
"malignancies",
"in",
"the",
"region",
"[6,",
"7].",
"Head",
"and",
"neck",
"ASs",
"are",
"frequently",
"seen",
"in",
"the",
"scalp",
"[1–3,",
"6–15]",
"and",
"are",
"common",
"in",
"the",
"elderly",
"population",
"with",
"the",
"mean",
"age",
"greater",
"than",
"60",
"years.",
"AS",
"also",
"has",
"a",
"slight",
"predilection",
"for",
"Caucasian",
"patients",
"and",
"the",
"male",
"gender",
"[1,",
"2,",
"7–10,",
"12–14].",
"Prognosis",
"is",
"poor",
"since",
"AS",
"is",
"very",
"aggressive",
"with",
"disease-free",
"survival",
"of",
"less",
"than",
"50%",
"at",
"five",
"years",
"[1,",
"4,",
"5,",
"8–14]",
"due",
"to",
"its",
"high",
"propensity",
"for",
"local",
"recurrence",
"[4,",
"5,",
"8,",
"11].",
"However,",
"some",
"studies",
"report",
"survival",
"of",
"10–20%",
"after",
"five",
"years",
"[1,",
"5,",
"8–11],",
"which",
"may",
"indicate",
"lesions",
"that",
"are",
"located",
"in",
"the",
"scalp",
"and",
"face",
"have",
"a",
"lower",
"survival",
"rate",
"and",
"higher",
"rate",
"of",
"recurrence",
"[10].",
"The",
"most",
"important",
"prognostic",
"factors",
"include",
"tumor",
"size",
"and",
"ability",
"to",
"achieve",
"negative",
"margins",
"with",
"tumor",
"grade",
"also",
"being",
"considered",
"to",
"be",
"a",
"prognostic",
"factor",
"for",
"recurrence",
"[5,",
"12]",
"and",
"overall",
"survival",
"[11].",
"Patients",
"with",
"facial",
"or",
"scalp",
"AS",
"of",
"less",
"than",
"5",
"cm",
"in",
"size",
"tend",
"to",
"do",
"better",
"than",
"those",
"with",
"tumor",
"size",
"greater",
"than",
"5",
"cm",
"[6,",
"10].",
"Patients",
"with",
"cutaneous",
"AS",
"who",
"are",
"not",
"surgical",
"candidates",
"due",
"to",
"multiple",
"comorbid",
"conditions",
"have",
"limited",
"treatment",
"options.",
"Due",
"to",
"its",
"rapid",
"progression,",
"achieving",
"local",
"control",
"and",
"prevention",
"of",
"metastasis",
"in",
"AS",
"has",
"been",
"a",
"challenge.",
"Few",
"reports",
"have",
"described",
"successful",
"treatment",
"of",
"AS",
"using",
"adjuvant",
"chemotherapy",
"with",
"radiotherapy",
"[16].",
"Different",
"treatment",
"modalities",
"used",
"in",
"cutaneous",
"angiosarcoma",
"are",
"depicted",
"in",
"Table",
"1.",
"Here,",
"we",
"report",
"a",
"successful",
"response",
"of",
"AS",
"to",
"bevacizumab",
"with",
"concurrent",
"radiation",
"therapy",
"in",
"a",
"patient",
"not",
"eligible",
"for",
"surgical",
"intervention.",
"2.",
"Case",
"Report",
"An",
"88-year-old",
"Caucasian",
"male",
"with",
"a",
"37-pack-year",
"history",
"of",
"smoking",
"noticed",
"purplish",
"lumps",
"on",
"his",
"scalp",
"with",
"scaling",
"and",
"erythema",
"for",
"two",
"months",
"prior",
"to",
"presentation.",
"He",
"had",
"a",
"complicated",
"past",
"medical",
"history",
"of",
"Stage",
"II",
"prostate",
"cancer",
"treated",
"with",
"radiation",
"treatments,",
"abdominal",
"aortic",
"aneurysm",
"repair,",
"macular",
"degeneration",
"treated",
"with",
"pho-",
"todynamic",
"therapy,",
"torn",
"retina,",
"inguinal",
"hernia",
"repair,",
"and",
"four-vessel",
"coronary",
"artery",
"bypass",
"graft.",
"The",
"patient",
"noted",
"the",
"violaceous",
"papules",
"increasing",
"in",
"size",
"and",
"nodularity",
"and",
"extending",
"down",
"to",
"the",
"level",
"of",
"the",
"eyebrows",
"bilaterally.",
"He"
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] | [
"Zhang",
"et",
"al.",
"Lipids",
"in",
"Health",
"and",
"Disease",
"2010,",
"9:24",
"http://www.lipidworld.com/content/9/1/24",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Fatty",
"acid",
"extracts",
"from",
"Lucilia",
"sericata",
"larvae",
"promote",
"murine",
"cutaneous",
"wound",
"healing",
"by",
"angiogenic",
"activity",
"Zhen",
"Zhang1,",
"Shouyu",
"Wang1,",
"Yunpeng",
"Diao2,",
"Jianing",
"Zhang3,",
"Decheng",
"Lv1*",
"Abstract",
"Background:",
"fatty",
"acids",
"are",
"considered",
"to",
"be",
"effective",
"components",
"to",
"promote",
"wound",
"healing",
"and",
"Lucilia",
"sericata",
"larvae",
"are",
"applied",
"clinically",
"to",
"treat",
"intractable",
"wounds.",
"We",
"aimed",
"to",
"investigat",
"the",
"effect",
"of",
"fatty",
"acid",
"extracts",
"from",
"dried",
"Lucilia",
"sericata",
"larvae",
"on",
"murine",
"cutaneuous",
"wound",
"healing",
"as",
"well",
"as",
"angiogenesis.",
"Results:",
"On",
"day",
"7",
"and",
"10",
"after",
"murine",
"acute",
"excision",
"wounds",
"creation,",
"the",
"percent",
"wound",
"contraction",
"of",
"fatty",
"acid",
"extracts",
"group",
"was",
"higher",
"than",
"that",
"of",
"vaseline",
"group.",
"On",
"day",
"3,",
"7",
"and",
"10",
"after",
"wounds",
"creation,",
"the",
"wound",
"healing",
"quality",
"of",
"fatty",
"acid",
"extracts",
"group",
"was",
"better",
"than",
"that",
"of",
"vaseline",
"group",
"on",
"terms",
"of",
"granulation",
"formation",
"and",
"collagen",
"organization.",
"On",
"day",
"3",
"after",
"wounds",
"creation,",
"the",
"micro",
"vessel",
"density",
"and",
"vascular",
"endothelial",
"growth",
"factor",
"expression",
"of",
"fatty",
"acid",
"extracts",
"group",
"were",
"higher",
"than",
"that",
"of",
"vaseline",
"group.",
"Component",
"analysis",
"of",
"the",
"fatty",
"acid",
"extracts",
"by",
"gas",
"chromatography-mass",
"spectrometry",
"showed",
"there",
"were",
"10",
"kinds",
"of",
"fatty",
"acids",
"in",
"total",
"and",
"the",
"ratio",
"of",
"saturated",
"fatty",
"acid,",
"monounsaturated",
"fatty",
"acid",
"and",
"polyunsaturated",
"fatty",
"acid",
"(PUFA)",
"was:",
"20.57%:60.32%:19.11%.",
"Conclusions:",
"Fatty",
"acid",
"extracts",
"from",
"dried",
"Lucilia",
"sericata",
"larvae,",
"four",
"fifths",
"of",
"which",
"are",
"unsaturated",
"fatty",
"acids,",
"can",
"promote",
"murine",
"cutaneous",
"wound",
"healing",
"probably",
"resulting",
"from",
"the",
"powerful",
"angiogenic",
"activity",
"of",
"the",
"extracts.",
"Background",
"Fatty",
"acids,",
"as",
"a",
"family",
"of",
"bioactive",
"moleculars,",
"partici-",
"pate",
"in",
"many",
"metabolic",
"processes.",
"The",
"deficiency",
"of",
"fatty",
"acids",
"may",
"result",
"in",
"diseases,",
"vice",
"versa",
"supplement-",
"ing",
"fatty",
"acids",
"can",
"treat",
"diseases.",
"Since",
"a",
"kind",
"of",
"disease",
"is",
"a",
"result",
"of",
"multiple",
"etiological",
"factors,",
"it",
"is",
"difficult",
"to",
"get",
"a",
"satisfactory",
"therapeutic",
"outcome",
"using",
"a",
"single",
"compound",
"as",
"drug.",
"Therefore",
"more",
"and",
"more",
"doctors",
"focus",
"on",
"ethnopharmacolgical",
"theory,",
"which",
"records",
"folk",
"plants",
"or",
"animals",
"containing",
"many",
"effective",
"compo-",
"nents.",
"The",
"therapeutic",
"utilization",
"of",
"Lucilia",
"sericata",
"lar-",
"vae",
"commonly",
"called",
"maggot",
"therapy",
"for",
"wound",
"healing",
"can",
"date",
"back",
"to",
"the",
"beginning",
"of",
"civilization",
"[1].",
"According",
"to",
"traditional",
"Chinese",
"medicine",
"principle",
"and",
"the",
"book",
"Compendium",
"of",
"Materia",
"Medica",
"records,",
"Luci-",
"lia",
"sericata",
"larvae",
"which",
"has",
"been",
"given",
"the",
"name",
"of",
"“WuGuChong”",
"is",
"salty",
"in",
"taste,",
"cold",
"in",
"nature",
"and",
"non-",
"*",
"Correspondence:",
"lvdecheng88@sina.com",
"1Department",
"of",
"Orthopedic",
"Surgery,",
"First",
"Affiliated",
"Hospital,",
"Dalian",
"Medical",
"University,",
"Dalian,",
"Liaoning",
"Province,",
"China",
"toxic.",
"It",
"is",
"mainly",
"produced",
"in",
"Guangdong",
"Province",
"in",
"China",
"and",
"local",
"people",
"use",
"“WuGuChong”",
"to",
"treat",
"superficial",
"purulent",
"diseases",
"such",
"as",
"furuncle",
"or",
"carbun-",
"cle.",
"Recently,",
"maggot",
"therapy",
"has",
"been",
"widely",
"used",
"to",
"treat",
"various",
"refractory",
"wounds",
"including",
"diabetes",
"foot",
"and",
"venous",
"ulcers",
"[2-5].",
"The",
"therapeutic",
"action",
"com-",
"prises",
"biological",
"debridement",
"and",
"enhancement",
"of",
"wound",
"healing.",
"The",
"mechanisms",
"of",
"debriding",
"effect",
"of",
"maggots",
"were",
"due",
"to",
"their",
"mechanical",
"wriggling",
"and",
"excretions/secretions",
"degrading",
"extracellular",
"matrix",
"[6,7].",
"However,",
"there",
"are",
"no",
"in",
"vivo",
"reports",
"regarding",
"wound",
"healing",
"mechanisms",
"of",
"maggot",
"therapy.",
"In",
"addi-",
"tion,",
"complications",
"such",
"as",
"larvae",
"loss,",
"persistent",
"pain",
"or",
"severe",
"systemic",
"infection",
"[8]",
"induced",
"by",
"live",
"maggot",
"limits",
"the",
"clinical",
"use",
"of",
"maggot",
"therapy,",
"so",
"the",
"theory",
"and",
"practice",
"of",
"new",
"delivery",
"method",
"is",
"urgent.",
"Cutaneous",
"wound",
"healing",
"is",
"a",
"complex",
"process,",
"con-",
"sisting",
"of",
"an",
"orderly",
"progression",
"of",
"inflammation,",
"angio-",
"genesis,",
"collagen",
"deposition,",
"re-epithlization",
"and",
"tissue",
"remolding",
"[9].",
"The",
"purpose",
"of",
"repairing",
"events",
"is",
"to",
"©",
"2010",
"Zhang",
"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."
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] | [
"Integrated",
"Analyses",
"of",
"microRNAs",
"Demonstrate",
"Their",
"Widespread",
"Influence",
"on",
"Gene",
"Expression",
"in",
"High-Grade",
"Serous",
"Ovarian",
"Carcinoma",
"Chad",
"J.",
"Creighton1,2*.,",
"Anadulce",
"Hernandez-Herrera11.,",
"Anders",
"Jacobsen4.,",
"Douglas",
"A.",
"Levine3,",
"Parminder",
"Mankoo",
"4",
",",
"Nikolaus",
"Schultz4,",
"Ying",
"Du",
"5",
",",
"Yiqun",
"Zhang1,",
"Erik",
"Larsson",
"4",
",",
"Robert",
"Sheridan",
"4",
",",
"Weimin",
"Xiao11,",
"Paul",
"T.",
"Spellman",
"7",
",",
"Gad",
"Getz8,",
"David",
"A.",
"Wheeler9,",
"Charles",
"M.",
"Perou",
"5",
",",
"Richard",
"A.",
"Gibbs9,",
"Chris",
"Sander4,",
"D.",
"Neil",
"Hayes5,6,",
"Preethi",
"H.",
"Gunaratne10,11*,",
"The",
"Cancer",
"Genome",
"Atlas",
"Research",
"Network",
"1",
"Dan",
"L.",
"Duncan",
"Cancer",
"Center,",
"Baylor",
"College",
"of",
"Medicine,",
"Houston,",
"Texas,",
"United",
"States",
"of",
"America",
",",
"2",
"Department",
"of",
"Medicine,",
"Baylor",
"College",
"of",
"Medicine,",
"Houston,",
"Texas,",
"United",
"States",
"of",
"America,",
"3",
"Gynecology",
"Service,",
"Department",
"of",
"Surgery,",
"Memorial",
"Sloan-Kettering",
"Cancer",
"Center,",
"New",
"York,",
"New",
"York,",
"United",
"States",
"of",
"America,",
"4",
"Computational",
"Biology",
"Center,",
"Memorial",
"Sloan-Kettering",
"Cancer",
"Center,",
"New",
"York,",
"New",
"York,",
"United",
"States",
"of",
"America,",
"5",
"Lineberger",
"Comprehensive",
"Cancer",
"Center,",
"University",
"of",
"North",
"Carolina,",
"Chapel",
"Hill,",
"North",
"Carolina,",
"United",
"States",
"of",
"America,",
"6",
"Department",
"of",
"Internal",
"Medicine,",
"Division",
"of",
"Medical",
"Oncology,",
"University",
"of",
"North",
"Carolina,",
"Chapel",
"Hill,",
"North",
"Carolina,",
"United",
"States",
"of",
"America,",
"7",
"Life",
"Sciences",
"Division,",
"Lawrence",
"Berkeley",
"National",
"Laboratory,",
"Berkeley,",
"California,",
"United",
"States",
"of",
"America,",
"8",
"Broad",
"Institute",
"of",
"MIT",
"and",
"Harvard,",
"Cambridge,",
"Massachusetts,",
"United",
"States",
"of",
"America,",
"9",
"Department",
"of",
"Molecular",
"and",
"Human",
"Genetics,",
"Baylor",
"College",
"of",
"Medicine,",
"Houston,",
"Texas,",
"United",
"States",
"of",
"America,",
"10",
"Department",
"of",
"Pathology,",
"Baylor",
"College",
"of",
"Medicine,",
"Houston,",
"Texas,",
"United",
"States",
"of",
"America,",
"11",
"Department",
"of",
"Biology",
"&",
"Biochemistry,",
"University",
"of",
"Houston,",
"Houston,",
"Texas,",
"United",
"States",
"of",
"America",
"Abstract",
"Background:",
"The",
"Cancer",
"Genome",
"Atlas",
"(TCGA)",
"Network",
"recently",
"comprehensively",
"catalogued",
"the",
"molecular",
"aberrations",
"in",
"487",
"high-grade",
"serous",
"ovarian",
"cancers,",
"with",
"much",
"remaining",
"to",
"be",
"elucidated",
"regarding",
"the",
"microRNAs",
"(miRNAs).",
"Here,",
"using",
"TCGA",
"ovarian",
"data,",
"we",
"surveyed",
"the",
"miRNAs,",
"in",
"the",
"context",
"of",
"their",
"predicted",
"gene",
"targets.",
"Methods",
"and",
"Results:",
"Integration",
"of",
"miRNA",
"and",
"gene",
"patterns",
"yielded",
"evidence",
"that",
"proximal",
"pairs",
"of",
"miRNAs",
"are",
"processed",
"from",
"polycistronic",
"primary",
"transcripts,",
"and",
"that",
"intronic",
"miRNAs",
"and",
"their",
"host",
"gene",
"mRNAs",
"derive",
"from",
"common",
"transcripts.",
"Patterns",
"of",
"miRNA",
"expression",
"revealed",
"multiple",
"tumor",
"subtypes",
"and",
"a",
"set",
"of",
"34",
"miRNAs",
"predictive",
"of",
"overall",
"patient",
"survival.",
"In",
"a",
"global",
"analysis,",
"miRNA:mRNA",
"pairs",
"anti-correlated",
"in",
"expression",
"across",
"tumors",
"showed",
"a",
"higher",
"frequency",
"of",
"in",
"silico",
"predicted",
"target",
"sites",
"in",
"the",
"mRNA",
"39-untranslated",
"region",
"(with",
"less",
"frequency",
"observed",
"for",
"coding",
"sequence",
"and",
"59-untranslated",
"regions).",
"The",
"miR-29",
"family",
"and",
"predicted",
"target",
"genes",
"were",
"among",
"the",
"most",
"strongly",
"anti-",
"correlated",
"miRNA:mRNA",
"pairs;",
"over-expression",
"of",
"miR-29a",
"in",
"vitro",
"repressed",
"several",
"anti-correlated",
"genes",
"(including",
"DNMT3A",
"and",
"DNMT3B)",
"and",
"substantially",
"decreased",
"ovarian",
"cancer",
"cell",
"viability.",
"Conclusions:",
"This",
"study",
"establishes",
"miRNAs",
"as",
"having",
"a",
"widespread",
"impact",
"on",
"gene",
"expression",
"programs",
"in",
"ovarian",
"cancer,",
"further",
"strengthening",
"our",
"understanding",
"of",
"miRNA",
"biology",
"as",
"it",
"applies",
"to",
"human",
"cancer.",
"As",
"with",
"gene",
"transcripts,",
"miRNAs",
"exhibit",
"high",
"diversity",
"reflecting",
"the",
"genomic",
"heterogeneity",
"within",
"a",
"clinically",
"homogeneous",
"disease",
"population.",
"Putative",
"miRNA:mRNA",
"interactions,",
"as",
"identified",
"using",
"integrative",
"analysis,",
"can",
"be",
"validated.",
"TCGA",
"data",
"are",
"a",
"valuable",
"resource",
"for",
"the",
"identification",
"of",
"novel",
"tumor",
"suppressive",
"miRNAs",
"in",
"ovarian",
"as",
"well",
"as",
"other",
"cancers.",
"Citation:",
"Creighton",
"CJ,",
"Hernandez-Herrera",
"A,",
"Jacobsen",
"A,",
"Levine",
"DA,",
"Mankoo",
"P,",
"et",
"al.",
"(2012)",
"Integrated",
"Analyses",
"of",
"microRNAs",
"Demonstrate",
"Their",
"Widespread",
"Influence",
"on",
"Gene",
"Expression",
"in",
"High-Grade",
"Serous",
"Ovarian",
"Carcinoma.",
"PLoS",
"ONE",
"7(3):",
"e34546.",
"doi:10.1371/journal.pone.0034546",
"Editor:",
"Aed´ın",
"C.",
"Culhane,",
"Harvard",
"School",
"of",
"Public",
"Health,",
"United",
"States",
"of",
"America",
"Received",
"January",
"10,",
"2012;",
"Accepted",
"March",
"1,",
"2012;",
"Published",
"March",
"29,",
"2012",
"Copyright:",
"2012",
"Creighton",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"in",
"part",
"by",
"the",
"Ovarian",
"Cancer",
"Research",
"Fund",
"(CJC,",
"PHG),",
"National",
"Institutes",
"of",
"Health",
"(NIH)",
"grant",
"P30CA125123",
"(CJC,",
"YZ),",
"TCGA",
"GCC",
"at",
"Baylor:",
"National",
"Cancer",
"Institue",
"(NCI)",
"grant",
"U24CA143843",
"(CJC,",
"DAW,",
"RAG),",
"TCGA",
"GCC",
"at",
"University",
"of",
"North",
"Carolina:",
"NCI-U24CA143848",
"(YD,",
"CMP,",
"DNH),",
"TCGA",
"GDAC",
"at",
"Memorial",
"Sloan-Kettering",
"Cancer",
"Center:",
"NCI-U24CA143840",
"(AJ,",
"PM,",
"NS,",
"EL,",
"RS,",
"CS),",
"CPRIT-RP110355",
"(PHG),",
"a",
"Cullen",
"Foundation",
"Grant",
"(PHG),",
"the",
"Mexican",
"National",
"Council",
"for",
"Science",
"and",
"Technology",
"(CONACyT)",
"(AH),",
"and",
"the",
"Danish",
"Research",
"Council",
"(AJ).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"CJC",
"serves",
"as",
"an",
"Academic",
"Editor",
"for",
"PLoS",
"ONE.",
"This",
"does",
"not",
"alter",
"the",
"authors’",
"adherence",
"to",
"all",
"the",
"PLoS",
"ONE",
"policies",
"on",
"sharing",
"data",
"and",
"materials.",
"*",
"E-mail:",
"creighto@bcm.edu",
"(CJC);",
"phgunaratne@uh.edu",
"(PHG)",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"MicroRNAs",
"(miRNAs",
"or",
"miRs)",
"are",
",22",
"nt",
"noncoding",
"RNAs",
"which",
"target",
"complementary",
"gene",
"transcripts",
"for",
"translational",
"repression",
"or",
"mRNA",
"cleavage",
"[1].",
"Having",
"been",
"implicated",
"in",
"the",
"initiation",
"and",
"progression",
"of",
"human",
"cancers,",
"miRNAs",
"regulate",
"processes",
"such",
"as",
"cell",
"growth,",
"differentiation,",
"and",
"apoptosis",
"[2].",
"A",
"productive",
"miRNA:mRNA",
"interaction",
"can",
"occur",
"with",
"as",
"little",
"as",
"six",
"consecutive",
"nucleotides,",
"through",
"pairing",
"between",
"the",
"59-seed",
"of",
"the",
"miRNA",
"(located",
"in",
"nucleotides",
"2–7)",
"and",
"sequences",
"which",
"are",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"March",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"3",
"|",
"e34546"
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914
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] | [
"Barvkar",
"et",
"al.",
"BMC",
"Genomics",
"2012,",
"13:175",
"http://www.biomedcentral.com/1471-2164/13/175",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Phylogenomic",
"analysis",
"of",
"UDP",
"glycosyltransferase",
"1",
"multigene",
"family",
"in",
"Linum",
"usitatissimum",
"identified",
"genes",
"with",
"varied",
"expression",
"patterns",
"Vitthal",
"T",
"Barvkar,",
"Varsha",
"C",
"Pardeshi,",
"Sandip",
"M",
"Kale,",
"Narendra",
"Y",
"Kadoo",
"and",
"Vidya",
"S",
"Gupta*",
"Abstract",
"Background:",
"The",
"glycosylation",
"process,",
"catalyzed",
"by",
"ubiquitous",
"glycosyltransferase",
"(GT)",
"family",
"enzymes,",
"is",
"a",
"prevalent",
"modification",
"of",
"plant",
"secondary",
"metabolites",
"that",
"regulates",
"various",
"functions",
"such",
"as",
"hormone",
"homeostasis,",
"detoxification",
"of",
"xenobiotics",
"and",
"biosynthesis",
"and",
"storage",
"of",
"secondary",
"metabolites.",
"Flax",
"(Linum",
"usitatissimum",
"L.)",
"is",
"a",
"commercially",
"grown",
"oilseed",
"crop,",
"important",
"because",
"of",
"its",
"essential",
"fatty",
"acids",
"and",
"health",
"promoting",
"lignans.",
"Identification",
"and",
"characterization",
"of",
"UDP",
"glycosyltransferase",
"(UGT)",
"genes",
"from",
"flax",
"could",
"provide",
"valuable",
"basic",
"information",
"about",
"this",
"important",
"gene",
"family",
"and",
"help",
"to",
"explain",
"the",
"seed",
"specific",
"glycosylated",
"metabolite",
"accumulation",
"and",
"other",
"processes",
"in",
"plants.",
"Plant",
"genome",
"sequencing",
"projects",
"are",
"useful",
"to",
"discover",
"complexity",
"within",
"this",
"gene",
"family",
"and",
"also",
"pave",
"way",
"for",
"the",
"development",
"of",
"functional",
"genomics",
"approaches.",
"Results:",
"Taking",
"advantage",
"of",
"the",
"newly",
"assembled",
"draft",
"genome",
"sequence",
"of",
"flax,",
"we",
"identified",
"137",
"UDP",
"glycosyltransferase",
"(UGT)",
"genes",
"from",
"flax",
"using",
"a",
"conserved",
"signature",
"motif.",
"Phylogenetic",
"analysis",
"of",
"these",
"protein",
"sequences",
"clustered",
"them",
"into",
"14",
"major",
"groups",
"(A-N).",
"Expression",
"patterns",
"of",
"these",
"genes",
"were",
"investigated",
"using",
"publicly",
"available",
"expressed",
"sequence",
"tag",
"(EST),",
"microarray",
"data",
"and",
"reverse",
"transcription",
"quantitative",
"real",
"time",
"PCR",
"(RT-qPCR).",
"Seventy-three",
"per",
"cent",
"of",
"these",
"genes",
"(100",
"out",
"of",
"137)",
"showed",
"expression",
"evidence",
"in",
"15",
"tissues",
"examined",
"and",
"indicated",
"varied",
"expression",
"profiles.",
"The",
"RT-qPCR",
"results",
"of",
"10",
"selected",
"genes",
"were",
"also",
"coherent",
"with",
"the",
"digital",
"expression",
"analysis.",
"Interestingly,",
"five",
"duplicated",
"UGT",
"genes",
"were",
"identified,",
"which",
"showed",
"differential",
"expression",
"in",
"various",
"tissues.",
"Of",
"the",
"seven",
"intron",
"loss/gain",
"positions",
"detected,",
"two",
"intron",
"positions",
"were",
"conserved",
"among",
"most",
"of",
"the",
"UGTs,",
"although",
"a",
"clear",
"relationship",
"about",
"the",
"evolution",
"of",
"these",
"genes",
"could",
"not",
"be",
"established.",
"Comparison",
"of",
"the",
"flax",
"UGTs",
"with",
"orthologs",
"from",
"four",
"other",
"sequenced",
"dicot",
"genomes",
"indicated",
"that",
"seven",
"UGTs",
"were",
"flax",
"diverged.",
"Conclusions:",
"Flax",
"has",
"a",
"large",
"number",
"of",
"UGT",
"genes",
"including",
"few",
"flax",
"diverged",
"ones.",
"Phylogenetic",
"analysis",
"and",
"expression",
"profiles",
"of",
"these",
"genes",
"identified",
"tissue",
"and",
"condition",
"specific",
"repertoire",
"of",
"UGT",
"genes",
"from",
"this",
"crop.",
"This",
"study",
"would",
"facilitate",
"precise",
"selection",
"of",
"candidate",
"genes",
"and",
"their",
"further",
"characterization",
"of",
"substrate",
"specificities",
"and",
"in",
"planta",
"functions.",
"Background",
"Flax",
"or",
"linseed",
"(Linum",
"usitatissimum",
"L.)",
"is",
"one",
"of",
"the",
"earliest",
"domesticated",
"crops.",
"It",
"is",
"a",
"self-pollinating",
"diploid",
"species",
"cultivated",
"as",
"a",
"source",
"of",
"fibre,",
"oil",
"and",
"medicinal",
"compounds.",
"Historically",
"it",
"has",
"been",
"used",
"as",
"a",
"model",
"for",
"developmental",
"studies",
"and",
"has",
"a",
"different",
"evolutionary",
"history",
"than",
"other",
"model",
"plants",
"like",
"Arabidopsis",
"[1].",
"Among",
"plant",
"foods,",
"flaxseed",
"has",
"the",
"highest",
"contents",
"of",
"the",
"essential",
"omega-3",
"fatty",
"acid,",
"alpha-linolenic",
"acid",
"*",
"Correspondence:",
"vs.gupta@ncl.res.in",
"Plant",
"Molecular",
"Biology",
"Group,",
"Biochemical",
"Sciences",
"Division,",
"National",
"Chemical",
"Laboratory,",
"Pune,",
"411008,",
"India",
"(ALA)",
"[2]",
"and",
"bioactive",
"phenolic",
"compounds",
"such",
"as",
"lignans,",
"predominantly",
"secoisolariciresinol",
"diglucoside",
"(SDG)",
"[3],",
"phenolic",
"acids",
"and",
"flavonoids",
"[4].",
"ALA",
"dampens",
"inflammatory",
"reactions,",
"thereby",
"reducing",
"a",
"risk",
"of",
"heart",
"attack",
"or",
"stroke;",
"while",
"lignans",
"are",
"strong",
"antioxidants",
"inhibiting",
"breast",
"and",
"prostate",
"cancers.",
"Given",
"the",
"economic",
"and",
"health",
"benefits",
"of",
"these",
"bioactive",
"compounds,",
"it",
"would",
"be",
"useful",
"to",
"comprehensively",
"analyze",
"the",
"genes",
"involved",
"in",
"their",
"biosynthesis.",
"In",
"plants,",
"glycosylation",
"represents",
"the",
"last",
"step",
"in",
"the",
"biosynthesis",
"of",
"numerous",
"natural",
"compounds",
"like",
"terpenes,",
"phenylpropanoids,",
"cyanogenic",
"glucosides",
"and",
"glucosinolates.",
"It",
"is",
"an",
"important",
"©",
"2012",
"Barvkar",
"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."
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] | [
"http://dx.doi.org/10.4110/in.2011.11.6.368",
"pISSN",
"1598-2629",
"eISSN",
"2092-6685",
"ORIGINAL",
"ARTICLE",
"Blockade",
"of",
"Vascular",
"Endothelial",
"Growth",
"Factor",
"(VEGF)",
"Aggravates",
"the",
"Severity",
"of",
"Acute",
"Graft-versus-host",
"Disease",
"(GVHD)",
"after",
"Experimental",
"Allogeneic",
"Hematopoietic",
"Stem",
"Cell",
"Transplantation",
"(allo-HSCT)",
"Ai-Ran",
"Kim1,",
"Ji-Young",
"Lim2,",
"Dae",
"Chul",
"Jeong1,",
"Gyeongsin",
"Park3,",
"Byung",
"Churl",
"Lee1",
"and",
"Chang-Ki",
"Min2*",
"Departments",
"of",
"1Pediatrics,",
"2Internal",
"Medicine,",
"and",
"3Hospital",
"Pathology,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"Seoul",
"137-701,",
"Korea",
"Background:",
"Recent",
"clinical",
"observation",
"reported",
"that",
"there",
"was",
"a",
"significant",
"correlation",
"between",
"change",
"in",
"circulating",
"vascular",
"endothelial",
"growth",
"factor",
"(VEGF)",
"levels",
"and",
"the",
"oc-",
"currence",
"of",
"severe",
"acute",
"graft-versus-host",
"disease",
"(GVHD)",
"following",
"allogeneic",
"hematopoietic",
"stem",
"cell",
"transplantation",
"(allo-HSCT),",
"but",
"the",
"action",
"mechanisms",
"of",
"VEGF",
"in",
"GVHD",
"have",
"not",
"been",
"demonstrated.",
"Methods:",
"This",
"study",
"inves-",
"tigated",
"whether",
"or",
"not",
"blockade",
"of",
"VEGF",
"has",
"an",
"effect",
"on",
"acute",
"GVHD",
"in",
"a",
"lethally",
"irradiated",
"murine",
"allo-HSCT",
"model",
"of",
"B6",
"(H-2b)",
"→B6D2F1",
"(H-2b/d).",
"Syngeneic",
"or",
"allogeneic",
"re-",
"cipient",
"mice",
"were",
"injected",
"subcutaneously",
"with",
"anti-VEGF",
"peptides,",
"dRK6",
"(50μg/dose)",
"or",
"control",
"diluent",
"every",
"other",
"day",
"for",
"2",
"weeks",
"(total",
"7",
"doses).",
"Results:",
"Administration",
"of",
"the",
"dRK6",
"peptide",
"after",
"allo-HSCT",
"significantly",
"reduced",
"sur-",
"vival",
"with",
"greaterclinical",
"GVHD",
"scores",
"and",
"body",
"weight",
"loss.",
"Allogeneic",
"recipients",
"injected",
"with",
"the",
"dRK6",
"peptide",
"ex-",
"hibited",
"significantly",
"increased",
"circulating",
"levels",
"of",
"VEGF",
"and",
"expansion",
"of",
"donor",
"CD3+",
"T",
"cells",
"on",
"day",
"+7",
"compared",
"to",
"control",
"treated",
"animals.",
"The",
"donor",
"CD4+",
"and",
"CD8+",
"T-cell",
"subsets",
"have",
"differential",
"expansion",
"caused",
"by",
"the",
"dRK6",
"injection.",
"The",
"circulating",
"VEGF",
"levels",
"were",
"reduced",
"on",
"day",
"+14",
"regardless",
"of",
"blockade",
"of",
"VEGF.",
"Conclusion:",
"Together",
"these",
"findings",
"demonstrate",
"that",
"the",
"allo-reactive",
"responses",
"after",
"allo-HSCT",
"are",
"exaggerated",
"by",
"the",
"blockade",
"of",
"VEGF.",
"VEGF",
"seems",
"to",
"be",
"consumed",
"during",
"the",
"progression",
"of",
"acute",
"GVHD",
"in",
"this",
"murine",
"allo-HSCT",
"model.",
"[Immune",
"Network",
"2011;11(6):368-375]",
"INTRODUCTION",
"Allogeneic",
"hematopoietic",
"stem",
"cell",
"transplantation",
"(allo-",
"HSCT)",
"is",
"the",
"treatment",
"of",
"choice",
"for",
"manyhematological",
"ma-",
"lignancies",
"as",
"well",
"as",
"for",
"severe",
"immunodeficiency.",
"However,",
"the",
"main",
"causes",
"of",
"patient",
"mortality",
"and",
"morbidity",
"after",
"al-",
"lo-HSCT",
"are",
"relapse,",
"graft-versus-host",
"disease",
"(GVHD),",
"and",
"infections",
"(1,2).",
"Various",
"complications",
"occurring",
"after",
"al-",
"lo-HSCT",
"are",
"believed",
"to",
"be",
"manifestations",
"of",
"systemic",
"in-",
"flammatory",
"response",
"syndrome",
"(SIRS)",
"(3).",
"SIRS",
"is",
"caused",
"by",
"hypercytokinemia",
"with",
"the",
"excess",
"production",
"of",
"proinflam-",
"matory",
"cytokines",
"(4).",
"It",
"is",
"generally",
"recognized",
"that",
"cross-",
"linking",
"of",
"the",
"cytokine",
"network",
"plays",
"an",
"important",
"role",
"in",
"the",
"inflammatory",
"processes.",
"Dysregulation",
"of",
"cytokine",
"pro-",
"duction",
"may",
"initiate",
"and",
"perpetuate",
"tissue",
"damage",
"in",
"those",
"who",
"undergo",
"allo-HSCT.",
"Organ",
"impairment",
"in",
"SIRS",
"is",
"believed",
"to",
"occur",
"as",
"a",
"sequel",
"to",
"vascular",
"endothelial",
"damage",
"(5).",
"Vascular",
"endothelial",
"growth",
"factor",
"(VEGF)",
"is",
"a",
"dimeric",
"glycoprotein",
"that",
"increases",
"the",
"vascular",
"permeability",
"and",
"induces",
"the",
"proliferation",
"and",
"migration",
"of",
"endothelial",
"cells",
"to",
"form",
"new",
"blood",
"vessels",
"(6,7).",
"The",
"role",
"of",
"angiogenesis",
"in",
"sustaining",
"aninflammatory",
"response",
"has",
"recently",
"become",
"evident.",
"VEGF",
"acts",
"as",
"a",
"potent",
"chemo-attractant",
"for",
"leukocytes",
"into",
"neovascularization",
"site",
"and",
"induces",
"endothelial",
"cells",
"to",
"produce",
"collagenase.",
"VEGF",
"has",
"also",
"been",
"implicated",
"in",
"a",
"variety",
"of",
"chronic",
"inflammatory",
"Received",
"on",
"October",
"11,",
"2011.",
"Revised",
"on",
"October",
"28,",
"2011.",
"Accepted",
"on",
"November",
"3,",
"2011.",
"CC",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribu-",
"tion,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"*Corresponding",
"Author.",
"Tel:",
"82-2-2258-6053;",
"Fax:",
"82-2-599-3589;",
"E-mail:",
"ckmin@catholic.ac.kr",
"Keywords:",
"Vascular",
"endothelial",
"growth",
"factors",
"(VEGF),",
"Allogeneic",
"hematopoietic",
"stem",
"cell",
"transplantation,",
"Acute",
"graft-",
"versus-host",
"disease,",
"VEGF",
"blockade,",
"dRK6",
"368",
"IMMUNE",
"NETWORK",
"http://www.ksimm.or.kr",
"Volume",
"11",
"Number",
"6",
"December",
"2011"
] | [
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] | [
"BMC",
"Public",
"Health",
"Study",
"protocol",
"Peripheral",
"Arterial",
"Disease",
"Study",
"(PERART):",
"Prevalence",
"and",
"predictive",
"values",
"of",
"asymptomatic",
"peripheral",
"arterial",
"occlusive",
"disease",
"related",
"to",
"cardiovascular",
"morbidity",
"and",
"mortality",
"María",
"Teresa",
"Alzamora*1,2,3,",
"José",
"Miguel",
"Baena-Díez4,",
"Marta",
"Sorribes5,",
"Rosa",
"Forés1,",
"Pere",
"Toran3,",
"Marisa",
"Vicheto1,",
"Guillem",
"Pera3,",
"María",
"Dolores",
"Reina6,",
"Carlos",
"Albaladejo7,",
"Judith",
"Llussà8,",
"Magda",
"Bundó9,",
"Amparo",
"Sancho10,",
"Antonio",
"Heras1,",
"Joan",
"Rubiés2,6,",
"Juan",
"Francisco",
"Arenillas11",
"for",
"the",
"PERART",
"study",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Primary",
"Healthcare",
"Centre",
"Riu",
"Nord-Riu",
"Sud,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Santa",
"Coloma",
"de",
"Gramenet,,",
"Spain,",
"2Department",
"of",
"Medicine,",
"Universitat",
"Autònoma",
"de",
"Barcelona,",
"Spain,",
"3Research",
"Unit",
"Barcelonés",
"Nord",
"Maresme.",
"ICS-IDIAP",
"Jordi",
"Gol.",
"Mataró,",
"Spain,",
"4Primary",
"Healthcare",
"Centre",
"La",
"Marina,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Barcelona,",
"Spain,",
"5Primary",
"Healthcare",
"Centre",
"Numància,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Barcelona,",
"Spain,",
"6Primary",
"Healthcare",
"Centre",
"Santa",
"Coloma",
"de",
"Gramenet,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Santa",
"Coloma",
"de",
"Gramenet,",
"Spain,",
"7Primary",
"Healthcare",
"Centre",
"Llefià,",
"Institut",
"Català",
"de",
"la",
"Salut",
"Badalona,",
"Spain,",
"8Primary",
"Healthcare",
"Centre",
"Sant",
"Roc,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Badalona,",
"Spain,",
"9Primary",
"Healthcare",
"Centre",
"Ronda",
"Prim,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Mataró,",
"Spain,",
"10Primary",
"Healthcare",
"Centre",
"Can",
"Mariné,",
"Institut",
"Català",
"de",
"la",
"Salut,",
"Santa",
"Coloma",
"de",
"Gramenet,",
"Spain",
"and",
"11Unitat",
"de",
"Neurociències.",
"Hospital",
"Germans",
"Trias",
"i",
"Pujol.",
"Institut",
"Català",
"de",
"la",
"Salut.",
"Badalona,",
"Spain",
"Email:",
"María",
"Teresa",
"Alzamora*",
"-",
"mtalzamora.bnm.ics@gencat.net;",
"José",
"Miguel",
"Baena-Díez",
"-",
"jbaenad@meditex.es;",
"Marta",
"Sorribes",
"-",
"martasorribes.pbcn@ics.scs.es;",
"Rosa",
"Forés",
"-",
"rfores.bnm.ics@gencat.net;",
"Pere",
"Toran",
"-",
"ptoran.bnm.ics@gencat.net;",
"Marisa",
"Vicheto",
"-",
"mvicheto@gmail.com;",
"Guillem",
"Pera",
"-",
"gpera.bnm.ics@gencat.net;",
"María",
"Dolores",
"Reina",
"-",
"dreina.bnm.ics@gencat.net;",
"Carlos",
"Albaladejo",
"-",
"24270cab@comb.es;",
"Judith",
"Llussà",
"-",
"jllussa.bnm.ics@gencat.net;",
"Magda",
"Bundó",
"-",
"mbundo.bnm.ics@gencat.net;",
"Amparo",
"Sancho",
"-",
"asanchop.bnm.ics@gencat.net;",
"Antonio",
"Heras",
"-",
"aheras.bnm.ics@gencat.net;",
"Joan",
"Rubiés",
"-",
"jrubiesp@searteriosclerosis.org;",
"Juan",
"Francisco",
"Arenillas",
"-",
"juanfarenillas@gmail.com",
"*",
"Corresponding",
"author",
"Published:",
"11",
"December",
"2007",
"BMC",
"Public",
"Health",
"2007,",
"7:348",
"doi:10.1186/1471-2458-7-348",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2458/7/348",
"Received:",
"22",
"August",
"2007",
"Accepted:",
"11",
"December",
"2007",
"©",
"2007",
"Alzamora",
"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",
"early",
"diagnosis",
"of",
"atherosclerotic",
"disease",
"is",
"essential",
"for",
"developing",
"preventive",
"strategies",
"in",
"populations",
"at",
"high",
"risk",
"and",
"acting",
"when",
"the",
"disease",
"is",
"still",
"asymptomatic.",
"A",
"low",
"ankle-",
"arm",
"index",
"(AAI)",
"is",
"a",
"good",
"marker",
"of",
"vascular",
"events",
"and",
"may",
"be",
"diminished",
"without",
"presenting",
"symptomatology",
"(silent",
"peripheral",
"arterial",
"disease).",
"The",
"aim",
"of",
"the",
"PERART",
"study",
"(PERipheral",
"ARTerial",
"disease)",
"is",
"to",
"determine",
"the",
"prevalence",
"of",
"peripheral",
"arterial",
"disease",
"(both",
"silent",
"and",
"symptomatic)",
"in",
"a",
"general",
"population",
"of",
"both",
"sexes",
"and",
"determine",
"its",
"predictive",
"value",
"related",
"to",
"morbimortality",
"(cohort",
"study).",
"Methods/Design:",
"This",
"cross-over,",
"cohort",
"study",
"consists",
"of",
"2",
"phases:",
"firstly",
"a",
"descriptive,",
"transversal",
"cross-over",
"study",
"to",
"determine",
"the",
"prevalence",
"of",
"peripheral",
"arterial",
"disease,",
"and",
"secondly,",
"a",
"cohort",
"study",
"to",
"evaluate",
"the",
"predictive",
"value",
"of",
"AAI",
"in",
"relation",
"to",
"cardiovascular",
"morbimortality.",
"From",
"September",
"2006",
"to",
"June",
"2007,",
"a",
"total",
"of",
"3,010",
"patients",
"over",
"the",
"age",
"of",
"50",
"years",
"will",
"be",
"randomly",
"selected",
"from",
"a",
"population",
"adscribed",
"to",
"24",
"healthcare",
"centres",
"in",
"the",
"province",
"of",
"Barcelona",
"(Spain).",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Hindawi",
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"17",
"July",
"2012;",
"Accepted",
"16",
"August",
"2012",
"Academic",
"Editor:",
"Ting",
"Fan",
"Leung",
"Copyright",
"©",
"2012",
"Mahmoud",
"S.",
"Alahwal",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
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"Commons",
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"use,",
"distribution,",
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"in",
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"medium,",
"provided",
"the",
"original",
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"is",
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"a",
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"distinct",
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"and",
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"is",
"the",
"mainstay",
"of",
"treatment.",
"The",
"prognosis",
"of",
"this",
"rare",
"malignancy",
"is",
"poor",
"and",
"the",
"overall",
"5-year",
"survival",
"is",
"around",
"15%.",
"Our",
"patient",
"presented",
"with",
"respiratory",
"symptoms",
"and",
"was",
"found",
"to",
"have",
"right-sided",
"chest",
"wall",
"mass.",
"The",
"patient",
"underwent",
"complete",
"surgical",
"excision",
"followed",
"by",
"6",
"cycles",
"of",
"platinum-",
"based",
"chemotherapy.",
"The",
"patient",
"showed",
"good",
"subjective",
"and",
"objective",
"response",
"with",
"no",
"evidence",
"of",
"disease",
"recurrence.",
"We",
"report",
"this",
"rare",
"malignancy",
"with",
"a",
"review",
"of",
"literature,",
"and",
"the",
"potential",
"to",
"use",
"adjuvant",
"chemotherapy",
"in",
"the",
"management",
"of",
"this",
"condition.",
"1.",
"Introduction",
"Pulmonary",
"blastoma",
"(PB)",
"is",
"classified",
"as",
"one",
"of",
"the",
"rare",
"primary",
"lung",
"malignancies",
"and",
"is",
"considered",
"to",
"be",
"distinct",
"from",
"other",
"lung",
"tumors",
"based",
"on",
"pathological",
"features,",
"clinical",
"course",
"and",
"prognosis.",
"PB",
"is",
"composed",
"of",
"a",
"mixture",
"of",
"epithelial",
"and",
"mesenchymal",
"tissues",
"resembling",
"embryonic",
"lung",
"tissue.",
"Surgery",
"is",
"the",
"standard",
"treatment",
"and",
"the",
"efficacy",
"of",
"adjuvant",
"chemotherapy",
"and",
"radiotherapy",
"has",
"not",
"yet",
"been",
"established.",
"Platinum-based",
"chemotherapy",
"has",
"been",
"used",
"with",
"or",
"without",
"postoperative",
"radiotherapy.",
"The",
"prognosis",
"of",
"this",
"rare",
"tumor",
"is",
"poor.",
"We",
"describe",
"a",
"case",
"of",
"this",
"rare",
"pulmonary",
"malignancy",
"and",
"the",
"role",
"of",
"adjuvant",
"chemotherapy",
"in",
"the",
"management",
"and",
"outcome.",
"2.",
"Case",
"Report",
"A",
"16-year-old",
"young",
"Egyptian",
"female",
"presented",
"with",
"pro-",
"gressive",
"shortness",
"of",
"breath",
"over",
"a",
"period",
"of",
"five",
"years.",
"The",
"dyspnea",
"was",
"gradual",
"in",
"onset,",
"at",
"times",
"precipitated",
"by",
"stress,",
"but",
"most",
"of",
"the",
"time",
"there",
"was",
"no",
"precipitating",
"factor.",
"It",
"was",
"associated",
"with",
"severe",
"nonproductive",
"cough",
"and",
"bilateral",
"headache.",
"There",
"was",
"no",
"significant",
"past",
"medical",
"history.",
"There",
"was",
"no",
"history",
"of",
"fever,",
"night",
"sweats,",
"and",
"wheeze",
"or",
"chest",
"pain.",
"Also,",
"there",
"was",
"no",
"hoarseness",
"of",
"voice",
"or",
"hemop-",
"tysis.",
"The",
"patient",
"sought",
"medical",
"advice",
"at",
"a",
"private",
"health",
"center",
"when",
"the",
"patient’s",
"daily",
"activities",
"gradually",
"started",
"getting",
"affected.",
"The",
"patient",
"was",
"prescribed",
"Salbutamol",
"inhaler",
"which",
"gave",
"her",
"temporary",
"relief.",
"At",
"the",
"same",
"time,",
"the",
"patient",
"was",
"diagnosed",
"to",
"have",
"hyperthyroidism",
"and",
"was",
"started",
"on",
"carbimazole.",
"The",
"patient",
"took",
"these",
"medications",
"for",
"about",
"4",
"weeks",
"and",
"discontinued",
"them",
"against",
"medical",
"advice",
"as",
"she",
"experienced",
"lethargy",
"and",
"easy",
"fatigability",
"due",
"to",
"the",
"sideeffects",
"of",
"the",
"prescribed",
"drugs.",
"After",
"a",
"brief",
"period",
"of",
"relief",
"of",
"symptoms,",
"the",
"patient",
"again",
"started",
"to",
"have",
"dyspnea",
"and",
"presented",
"to",
"the",
"Cardio-",
"thoracic",
"Unit",
"in",
"our",
"hospital",
"for",
"evaluation.",
"Baseline",
"inves-",
"tigations",
"were",
"done,",
"which",
"included",
"complete",
"blood",
"count,",
"renal",
"function",
"tests,",
"and",
"liver",
"function",
"tests;",
"all",
"were",
"within",
"the",
"normal",
"range.",
"Chest",
"X-ray",
"showed",
"a",
"well-demarcated",
"right",
"upper",
"lobe",
"mass",
"close",
"to",
"hilum",
"(Figure",
"1).",
"Chest",
"computed",
"tomography",
"(CT)",
"scan",
"showed",
"bilateral",
"thyroid",
"nodules",
"and",
"a",
"large",
"well-defined",
"heterogeneously",
"enhancing",
"mass",
"measuring",
"11",
"×",
"6",
"cm",
"with",
"a",
"central",
"hypodensity",
"at",
"the",
"right",
"upper",
"lobe",
"with",
"significant",
"compression",
"to",
"the",
"superior",
"vena",
"cava",
"(Figure",
"2).",
"There",
"was",
"no",
"evidence",
"of",
"significant"
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"Hindawi",
"Publishing",
"Corporation",
"Thrombosis",
"Volume",
"2012,",
"Article",
"ID",
"209052,",
"6",
"pages",
"doi:10.1155/2012/209052",
"Research",
"Article",
"Actual",
"Situation",
"of",
"Thromboembolic",
"Prophylaxis",
"in",
"Obesity",
"Surgery:",
"Data",
"of",
"Quality",
"Assurance",
"in",
"Bariatric",
"Surgery",
"in",
"Germany",
"Christine",
"Stroh,1,",
"2",
"D.",
"Luderer,1",
"R.",
"Weiner,3",
"T.",
"Horbach,4,",
"5",
"K.",
"Ludwig,6",
"F.",
"Benedix,7",
"Stefanie",
"Wolff,7",
"C.",
"Knoll,8",
"H.",
"Lippert,2,",
"7",
"and",
"T.",
"Manger1,",
"2",
"1",
"Department",
"of",
"General,",
"Abdominal",
"and",
"Pediatric",
"Surgery,",
"SRH",
"Hospital,",
"Straße",
"des",
"Friedens",
"122,",
"07548",
"Gera,",
"Germany",
"2",
"Institute",
"for",
"Quality",
"Assurance",
"in",
"Operative",
"Medicine,",
"Otto-von-Guericke",
"University,",
"39106",
"Magdeburg,",
"Germany",
"3",
"Municipal",
"Hospital",
"Sachsenhausen,",
"Frankfurt/Main,",
"Germany",
"4",
"Friedrich-Alexander",
"University,",
"91054",
"Erlangen-Nuremberg,",
"Germany",
"5",
"Municipal",
"Hospital,",
"Schwabach,",
"Germany",
"6",
"Municipal",
"Hospital,",
"Rostock",
"Suedstadt,",
"Germany",
"7",
"Otto-von-Guericke",
"Universita¨t",
"Magdeburg,",
"39106",
"Magdeburg,",
"Germany",
"8",
"StatConsult,",
"39112",
"Magdeburg,",
"Germany",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Christine",
"Stroh,",
"christine.stroh@wkg.srh.de",
"Received",
"18",
"March",
"2012;",
"Revised",
"7",
"May",
"2012;",
"Accepted",
"7",
"May",
"2012",
"Academic",
"Editor:",
"Domenico",
"Prisco",
"Copyright",
"©",
"2012",
"Christine",
"Stroh",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Background.",
"Evidence-based",
"data",
"on",
"optimal",
"approach",
"for",
"prophylaxis",
"of",
"deep",
"venous",
"thrombosis",
"(VTE)",
"and",
"pulmonary",
"embolism",
"(PE)",
"in",
"bariatric",
"operations",
"is",
"discussed.",
"Using",
"antithrombotic",
"prophylaxis",
"weight",
"adjusted",
"the",
"risk",
"of",
"VTE",
"and",
"its",
"complications",
"have",
"to",
"be",
"balanced",
"with",
"the",
"increased",
"bleeding",
"risk.",
"Methods.",
"Since",
"2005",
"the",
"current",
"situation",
"for",
"bariatric",
"surgery",
"has",
"been",
"examined",
"by",
"quality",
"assurance",
"study",
"in",
"Germany.",
"As",
"a",
"prospective",
"multicenter",
"observational",
"study,",
"data",
"on",
"the",
"type,",
"regimen,",
"and",
"time",
"course",
"of",
"VTE",
"prophylaxis",
"were",
"documented.",
"The",
"incidences",
"of",
"clinically",
"diagnosed",
"VTE",
"or",
"PE",
"were",
"derived",
"during",
"the",
"in-hospital",
"course",
"and",
"follow",
"up.",
"Results.",
"Overall,",
"11,835",
"bariatric",
"procedures",
"were",
"performed",
"between",
"January",
"2005",
"and",
"December",
"2010.",
"Most",
"performed",
"procedures",
"were",
"2730",
"gastric",
"banding",
"(GB);",
"4901",
"Roux-en-Y-gastric",
"bypass",
"(RYGBP)",
"procedures,",
"and",
"3026",
"sleeve",
"gastrectomies",
"(SG).",
"Study",
"collective",
"includes",
"72.5%",
"(mean",
"BMI",
"48.1",
"kg/m2)",
"female",
"and",
"27.5%",
"(mean",
"BMI",
"50.5",
"kg/m2)",
"male",
"patients.",
"Incidence",
"of",
"VTE",
"was",
"0.06%",
"and",
"of",
"PE",
"0.08%.",
"Conclusion.",
"VTE",
"prophylaxis",
"regimen",
"depends",
"on",
"BMI",
"and",
"the",
"type",
"of",
"procedure.",
"Despite",
"the",
"low",
"incidence",
"of",
"VTE",
"and",
"PE",
"there",
"is",
"a",
"lack",
"of",
"evidence.",
"Therefore,",
"prospective",
"randomized",
"studies",
"are",
"necessary",
"to",
"determine",
"the",
"optimal",
"VTE",
"prophylaxis",
"for",
"bariatric",
"surgical",
"patients.",
"1.",
"Introduction",
"Obesity",
"has",
"developed",
"into",
"an",
"epidemic.",
"Approximately",
"1.7",
"billion",
"people",
"are",
"overweight,",
"and",
"312",
"million",
"are",
"obese",
"[1,",
"2].",
"In",
"Germany",
"in",
"2009,",
"60.1%",
"of",
"male",
"and",
"42.9%",
"of",
"female",
"population",
"were",
"overweight",
"[3].",
"Morbid",
"obesity",
"is",
"associated",
"with",
"increased",
"health",
"costs",
"and",
"an",
"increased",
"mortality",
"risk",
"[4,",
"5].",
"As",
"a",
"result",
"of",
"new",
"technologies",
"with",
"lower",
"risks",
"and",
"better",
"long-term",
"results,",
"bariatric",
"and",
"metabolic",
"surgeries",
"have",
"grown",
"in",
"popularity",
"in",
"recent",
"years.",
"The",
"number",
"of",
"operations",
"performed",
"is",
"rapidly",
"increasing.",
"However,",
"bariatric",
"surgery",
"is",
"associated",
"with",
"numerous",
"peri-",
"and",
"post-",
"operative",
"complications.",
"Venous",
"thromboembolism",
"is",
"the",
"most",
"common",
"postoperative",
"complication.",
"Obesity",
"needs",
"to",
"be",
"considered",
"as",
"one",
"of",
"the",
"most",
"serious",
"factors",
"predisposing",
"patients",
"to",
"the",
"development",
"of",
"thrombosis",
"and",
"pulmonary",
"embolism.",
"In",
"addition,",
"the",
"risk",
"for",
"thromboembolism",
"in",
"metabolic",
"surgery",
"is",
"high,",
"and",
"its",
"detection",
"is",
"complicated.",
"The",
"guidelines",
"of",
"the",
"German",
"Society",
"of",
"Surgery",
"suggest"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Advances",
"in",
"Hematology",
"Volume",
"2011,",
"Article",
"ID",
"258797,",
"6",
"pages",
"doi:10.1155/2011/258797",
"Review",
"Article",
"Role",
"of",
"Radiotherapy",
"in",
"Modern",
"Treatment",
"of",
"Hodgkin’s",
"Lymphoma",
"Kheng-Wei",
"Yeoh",
"and",
"N.",
"George",
"Mikhaeel",
"Department",
"of",
"Clinical",
"Oncology,",
"Guy’s",
"and",
"St.",
"Thomas’",
"Hospital,",
"London,",
"UK",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Kheng-Wei",
"Yeoh,",
"kwyeoh@doctors.org.uk",
"Received",
"21",
"July",
"2010;",
"Accepted",
"16",
"September",
"2010",
"Academic",
"Editor:",
"Nelson",
"J.",
"Chao",
"Copyright",
"©",
"2011",
"K.-W.",
"Yeoh",
"and",
"N.",
"G.",
"Mikhaeel.",
"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.",
"Hodgkin’s",
"Lymphoma",
"was",
"incurable",
"until",
"the",
"advent",
"of",
"effective",
"therapeutic",
"radiation",
"around",
"the",
"first",
"half",
"of",
"the",
"20th",
"century.",
"As",
"survival",
"rates",
"improved,",
"the",
"long-term",
"toxicities",
"from",
"radiotherapy",
"began",
"to",
"emerge.",
"This",
"together",
"with",
"the",
"availability",
"of",
"effective",
"chemotherapy",
"has",
"encouraged",
"a",
"combined",
"modality",
"approach",
"for",
"early-staged",
"disease",
"and",
"the",
"omission",
"of",
"radiotherapy",
"in",
"advanced-staged",
"disease.",
"The",
"differing",
"toxicities",
"of",
"radiotherapy",
"and",
"chemotherapy",
"has",
"promoted",
"ongoing",
"research",
"to",
"identify",
"the",
"utility",
"of",
"each",
"of",
"these",
"modalities",
"in",
"the",
"modern",
"management",
"of",
"Hodgkin’s",
"Lymphoma.",
"This",
"article",
"will",
"provide",
"a",
"critical",
"review",
"of",
"the",
"developments",
"and",
"indications",
"for",
"modern",
"radiotherapy,",
"in",
"context",
"with",
"advances",
"in",
"chemotherapy,",
"for",
"the",
"treatment",
"of",
"Hodgkin’s",
"Lymphoma.",
"1.",
"Introduction",
"During",
"the",
"first",
"half",
"of",
"the",
"20th",
"century,",
"Hodgkin’s",
"Lym-",
"phoma",
"(HL)",
"was",
"incurable",
"until",
"the",
"development",
"of",
"effective",
"therapeutic",
"radiation",
"[1].",
"It",
"involved",
"irradiating",
"beyond",
"the",
"site",
"of",
"disease",
"to",
"include",
"the",
"adjacent",
"nodal",
"groups,",
"the",
"so-called",
"extended",
"field",
"radiotherapy",
"(EFRT)",
"with",
"total",
"or",
"subtotal",
"nodal",
"irradiation",
"[2].",
"With",
"Radiotherapy",
"(RT)",
"alone,",
"10-year",
"relapse-free",
"survival",
"of",
"around",
"70%",
"had",
"been",
"achieved",
"in",
"early-staged",
"HL",
"[3,",
"4].",
"However,",
"advanced",
"stage",
"HL",
"remained",
"less",
"curable",
"with",
"RT",
"even",
"with",
"subtotal",
"or",
"total",
"nodal",
"RT",
"until",
"the",
"introduction",
"of",
"combination",
"chemotherapy.",
"With",
"the",
"advent",
"of",
"effective",
"chemotherapy",
"regimes",
"in",
"the",
"1980s",
"with",
"MOPP",
"[5]",
"and",
"ABVD",
"[6],",
"better",
"cure",
"rates",
"were",
"achieved",
"in",
"advanced",
"disease",
"establishing",
"chemotherapy",
"as",
"the",
"main",
"line",
"of",
"treatment",
"in",
"advanced",
"disease.",
"Gradually,",
"chemotherapy",
"use",
"moved",
"to",
"earlier-stage",
"disease,",
"initially",
"as",
"a",
"pre-RT",
"treatment",
"in",
"bulky",
"mediastinal",
"cases",
"to",
"reduce",
"the",
"extent",
"of",
"mediastinal",
"RT",
"and",
"later",
"to",
"improve",
"the",
"outcome",
"of",
"RT",
"alone.",
"With",
"emerging",
"reports",
"of",
"long-term",
"toxicities",
"from",
"EFRT,",
"namely",
"with",
"pulmonary,",
"cardiac",
"toxicity,",
"and",
"sec-",
"ondary",
"malignancies",
"[7–13]",
"together",
"with",
"studies",
"showing",
"that",
"limited",
"RT",
"was",
"sufficient",
"after",
"prior",
"chemotherapy,",
"combined",
"modality",
"treatment",
"has",
"been",
"established",
"in",
"early",
"disease.",
"More",
"recently,",
"there",
"has",
"been",
"several",
"opinions",
"calling",
"on",
"treating",
"early",
"stage",
"HL",
"with",
"chemotherapy",
"alone",
"without",
"RT,",
"and",
"this",
"remains",
"an",
"interesting",
"research",
"question.",
"The",
"paper",
"below",
"will",
"aim",
"to",
"highlight",
"the",
"developments",
"of",
"RT",
"in",
"HL",
"treatment,",
"with",
"specific",
"focus",
"on",
"its",
"role",
"in",
"early,",
"advanced,",
"and",
"relapsed",
"disease.",
"2.",
"Developments",
"in",
"RT",
"2.1.",
"Background.",
"The",
"concept",
"of",
"RT",
"to",
"cure",
"HL",
"by",
"Gilbert",
"[14]",
"was",
"implemented",
"with",
"kilovoltage",
"[15]",
"and",
"later",
"with",
"megavoltage",
"machines",
"[1].",
"Doses",
"of",
"up",
"to",
"4500",
"rads",
"(1000",
"rads/wk)",
"were",
"commonly",
"used",
"to",
"treat",
"extended",
"fields",
"in",
"order",
"to",
"achieve",
"total",
"lymphoid",
"irradiation",
"(TLI).",
"This",
"included",
"mantle",
"field,",
"inverted-Y",
"techniques,",
"and",
"modifica-",
"tions",
"to",
"include",
"splenic",
"irradiation,",
"delivered",
"with",
"a",
"parallel",
"opposed",
"technique.",
"It",
"was",
"also",
"not",
"uncommon",
"to",
"irradiate",
"liver",
"and",
"lungs",
"involved",
"with",
"disease;",
"all",
"this",
"was",
"done",
"when",
"staging",
"laparotomy",
"and",
"splenectomy",
"were",
"standard",
"practice.",
"In",
"the",
"light",
"of",
"RT",
"toxicities,",
"suboptimal",
"relapse",
"and",
"survival",
"rates",
"together",
"with",
"the",
"introduction",
"of",
"effective",
"chemotherapy,",
"the",
"impetus",
"to",
"rationalise",
"RT",
"delivery",
"became"
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] | [
"Baba",
"et",
"al.",
"Radiation",
"Oncology",
"2010,",
"5:81",
"http://www.ro-journal.com/content/5/1/81",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Clinical",
"outcomes",
"of",
"stereotactic",
"body",
"radiotherapy",
"for",
"stage",
"I",
"non-small",
"cell",
"lung",
"cancer",
"using",
"different",
"doses",
"depending",
"on",
"tumor",
"size",
"Fumiya",
"Baba1,2*,",
"Yuta",
"Shibamoto1,",
"Hiroyuki",
"Ogino1,",
"Rumi",
"Murata1,",
"Chikao",
"Sugie1,",
"Hiromitsu",
"Iwata1,",
"Shinya",
"Otsuka1",
",",
"Katsura",
"Kosaki1,",
"Aiko",
"Nagai1,",
"Taro",
"Murai1,",
"Akifumi",
"Miyakawa1",
"Abstract",
"Background:",
"The",
"treatment",
"schedules",
"for",
"stereotactic",
"body",
"radiotherapy",
"(SBRT)",
"for",
"lung",
"cancer",
"vary",
"from",
"institution",
"to",
"institution.",
"Several",
"reports",
"have",
"indicated",
"that",
"stage",
"IB",
"patients",
"had",
"worse",
"outcomes",
"than",
"stage",
"IA",
"patients",
"when",
"the",
"same",
"dose",
"was",
"used.",
"We",
"evaluated",
"the",
"clinical",
"outcomes",
"of",
"SBRT",
"for",
"stage",
"I",
"non-small",
"cell",
"lung",
"cancer",
"(NSCLC)",
"treated",
"with",
"different",
"doses",
"depending",
"on",
"tumor",
"diameter.",
"Methods:",
"Between",
"February",
"2004",
"and",
"November",
"2008,",
"124",
"patients",
"with",
"stage",
"I",
"NSCLC",
"underwent",
"SBRT.",
"Total",
"doses",
"of",
"44,",
"48,",
"and",
"52",
"Gy",
"were",
"administered",
"for",
"tumors",
"with",
"a",
"longest",
"diameter",
"of",
"less",
"than",
"1.5",
"cm,",
"1.5-3",
"cm,",
"and",
"larger",
"than",
"3",
"cm,",
"respectively.",
"All",
"doses",
"were",
"given",
"in",
"4",
"fractions.",
"Results:",
"For",
"all",
"124",
"patients,",
"overall",
"survival",
"was",
"71%,",
"cause-specific",
"survival",
"was",
"87%,",
"progression-free",
"survival",
"was",
"60%,",
"and",
"local",
"control",
"was",
"80%,",
"at",
"3",
"years.",
"The",
"3-year",
"overall",
"survival",
"was",
"79%",
"for",
"85",
"stage",
"IA",
"patients",
"treated",
"with",
"48",
"Gy",
"and",
"56%",
"for",
"37",
"stage",
"IB",
"patients",
"treated",
"with",
"52",
"Gy",
"(p",
"=",
"0.05).",
"At",
"3",
"years,",
"cause-specific",
"survival",
"was",
"91%",
"for",
"the",
"former",
"group",
"and",
"79%",
"for",
"the",
"latter",
"(p",
"=",
"0.18),",
"and",
"progression-free",
"survival",
"was",
"62%",
"versus",
"54%",
"(p",
"=",
"0.30).",
"The",
"3-year",
"local",
"control",
"rate",
"was",
"81%",
"versus",
"74%",
"(p",
"=",
"0.35).",
"The",
"cumulative",
"incidence",
"of",
"grade",
"2",
"or",
"3",
"radiation",
"pneumonitis",
"was",
"11%",
"in",
"stage",
"IA",
"patients",
"and",
"30%",
"in",
"stage",
"IB",
"patients",
"(p",
"=",
"0.02).",
"Conclusions:",
"There",
"was",
"no",
"difference",
"in",
"local",
"control",
"between",
"stage",
"IA",
"and",
"IB",
"tumors",
"despite",
"the",
"difference",
"in",
"tumor",
"size.",
"The",
"benefit",
"of",
"increasing",
"the",
"SBRT",
"dose",
"for",
"larger",
"tumors",
"should",
"be",
"investigated",
"further.",
"Background",
"Stereotactic",
"body",
"radiotherapy",
"(SBRT)",
"for",
"lung",
"tumors",
"was",
"introduced",
"in",
"the",
"mid",
"1990s",
"[1],",
"and",
"it",
"has",
"been",
"performed",
"in",
"many",
"institutions",
"as",
"a",
"new",
"treatment",
"modality",
"for",
"stage",
"I",
"primary",
"lung",
"cancer",
"and",
"oligometa-",
"static",
"lung",
"cancer.",
"Promising",
"clinical",
"results",
"have",
"been",
"reported",
"despite",
"the",
"use",
"of",
"various",
"treatment",
"protocols",
"[2-9].",
"According",
"to",
"a",
"recently",
"published",
"survey",
"of",
"SBRT",
"in",
"Japan,",
"the",
"treatment",
"techniques",
"and",
"schedules",
"applied",
"for",
"SBRT",
"for",
"lung",
"cancer",
"varied",
"greatly",
"from",
"institution",
"to",
"institution",
"[10].",
"The",
"most",
"frequently",
"used",
"*",
"Correspondence:",
"fbaba@bd5.so-net.ne.jp",
"1Department",
"of",
"Radiology,",
"Nagoya",
"City",
"University",
"Graduate",
"School",
"of",
"Medical",
"Sciences,",
"Nagoya,",
"Japan",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"schedule",
"was",
"48",
"Gy",
"in",
"4",
"fractions",
"for",
"both",
"stage",
"IA",
"and",
"IB",
"primary",
"lung",
"cancer",
"and",
"metastatic",
"lung",
"cancer.",
"As",
"a",
"result,",
"it",
"was",
"found",
"that",
"the",
"outcomes",
"of",
"stage",
"IB",
"patients",
"were",
"worse",
"than",
"those",
"of",
"stage",
"IA",
"patients",
"at",
"the",
"same",
"dose",
"[3-5],",
"which",
"suggests",
"that",
"SBRT",
"doses",
"should",
"be",
"adjusted",
"according",
"to",
"tumor",
"size.",
"We",
"have",
"performed",
"SBRT",
"for",
"lung",
"tumors",
"since",
"2004",
"and",
"changed",
"the",
"pre-",
"scribed",
"dose",
"depending",
"on",
"tumor",
"diameter.",
"In",
"this",
"study,",
"we",
"report",
"the",
"clinical",
"outcomes",
"of",
"SBRT",
"performed",
"with",
"our",
"prospective",
"hypothesis-driven",
"protocol.",
"Methods",
"Eligibility",
"Criteria",
"The",
"eligibility",
"criteria",
"were",
"as",
"follows:",
"histologically-",
"confirmed",
"non-small",
"cell",
"lung",
"cancer",
"(NSCLC)",
"©",
"2010",
"Baba",
"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."
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] | [
"Int.",
"J.",
"Environ.",
"Res.",
"Public",
"Health",
"2012,",
"9,",
"24-32;",
"doi:10.3390/ijerph9010024",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Environmental",
"Research",
"and",
"Public",
"Health",
"ISSN",
"1660-4601",
"www.mdpi.com/journal/ijerph",
"Article",
"Essential",
"Questions",
"on",
"Suicide",
"Bereavement",
"and",
"Postvention",
"Karl",
"Andriessen",
"1,*",
"and",
"Karolina",
"Krysinska",
"2",
"1",
"Suicide",
"Prevention",
"Program",
"of",
"the",
"Flemish",
"Community",
"Mental",
"Health",
"Centres,",
"9000",
"Gent,",
"Belgium",
"2",
"Unit",
"for",
"Clinical",
"Psychology",
"Research,",
"Faculty",
"of",
"Psychology",
"and",
"Educational",
"Sciences,",
"Catholic",
"University",
"Leuven,",
"3000",
"Leuven,",
"Belgium;",
"E-Mail:",
"karolina.krysinska@ppw.kuleuven.be",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"karl.andriessen@pandora.be;",
"Tel.:",
"+32-9-233-5099.",
"Received:",
"8",
"November",
"2011;",
"in",
"revised",
"form:",
"12",
"December",
"2011",
"/",
"Accepted:",
"21",
"December",
"2011",
"/",
"Published:",
"27",
"December",
"2011",
"Abstract:",
"During",
"the",
"past",
"decades",
"public",
"and",
"research",
"interest",
"in",
"postvention,",
"i.e.,",
"support",
"for",
"families",
"and",
"communities",
"after",
"a",
"suicide,",
"has",
"increased.",
"However,",
"the",
"postvention",
"field",
"is",
"still",
"facing",
"a",
"number",
"of",
"important",
"challenges",
"and",
"questions.",
"This",
"article",
"aims",
"to",
"discuss",
"a",
"series",
"of",
"essential",
"issues",
"on",
"suicide",
"bereavement",
"and",
"postvention,",
"regarding",
"the",
"current",
"state",
"of",
"the",
"art",
"and",
"future",
"developments.",
"Who",
"is",
"a",
"suicide",
"survivor",
"and",
"how",
"many",
"suicide",
"survivors",
"are",
"there?",
"Is",
"suicide",
"bereavement",
"different",
"from",
"other",
"types",
"of",
"bereavement?",
"What",
"are",
"the",
"needs",
"of",
"suicide",
"survivors",
"and",
"what",
"is",
"postvention",
"from",
"a",
"clinical",
"perspective",
"and",
"from",
"a",
"public",
"health",
"perspective?",
"Can",
"postvention",
"be",
"prevention?",
"With",
"this",
"last",
"question,",
"the",
"article",
"concludes",
"with",
"a",
"series",
"of",
"recommendations",
"in",
"order",
"to",
"strengthen",
"the",
"potential",
"of",
"postvention",
"as",
"prevention.",
"Keywords:",
"suicide;",
"prevention;",
"postvention;",
"bereavement;",
"public",
"health;",
"policy",
"1.",
"Introduction",
"Any",
"discussion",
"of",
"suicide,",
"a",
"serious",
"public",
"health",
"problem",
"claiming",
"globally",
"approximately",
"one",
"million",
"victims",
"per",
"year,",
"will",
"be",
"incomplete",
"without",
"taking",
"into",
"consideration",
"the",
"perspective",
"of",
"the",
"bereaved,",
"or",
"in",
"other",
"word,",
"the",
"suicide",
"survivors.",
"Their",
"number",
"is",
"significantly",
"higher",
"than",
"the",
"number",
"of",
"suicide",
"victims",
"and",
"some",
"of",
"the",
"survivors",
"have",
"to",
"cope",
"with",
"serious",
"and",
"long",
"lasting",
"psycho-social",
"sequelae",
"of",
"the",
"loss,",
"including",
"increased",
"risk",
"of",
"suicidality.",
"Although",
"a",
"wide",
"range",
"of"
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] | [
"BMC",
"Musculoskeletal",
"Disorders",
"BioMed",
"Central",
"3BR2M0e0Cs2eM,ausrccuhlosakerltetiacllDeisorders",
"x",
"Systemic",
"alendronate",
"prevents",
"resorption",
"of",
"necrotic",
"bone",
"during",
"revascularization.",
"A",
"bone",
"chamber",
"study",
"in",
"rats",
"Jörgen",
"Åstrand*1",
"and",
"Per",
"Aspenberg1,2",
"Address:",
"1Department",
"of",
"Orthopaedics,",
"Lund",
"University",
"Hospital,",
"Lund,",
"Sweden",
"and",
"2Division",
"of",
"Orthopaedics,",
"Department",
"of",
"Neuroscience",
"and",
"Locomotion,",
"Faculty",
"of",
"Medicine,",
"Linköping",
"University,",
"Linköping,",
"Sweden",
"E-mail:",
"Jörgen",
"Åstrand*",
"-",
"jorgen.astrand@ort.lu.se;",
"Per",
"Aspenberg",
"-",
"Per.Aspenberg@inr.liu.se",
"*Corresponding",
"author",
"Published:",
"7",
"August",
"2002",
"BMC",
"Musculoskeletal",
"Disorders",
"2002,",
"3:19",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2474/3/19",
"Received:",
"4",
"March",
"2002",
"Accepted:",
"7",
"August",
"2002",
"©",
"2002",
"Åstrand",
"and",
"Aspenberg;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"article",
"is",
"published",
"in",
"Open",
"Access:",
"verbatim",
"copying",
"and",
"redistribution",
"of",
"this",
"article",
"are",
"permitted",
"in",
"all",
"media",
"for",
"any",
"non-commercial",
"purpose,",
"provided",
"this",
"notice",
"is",
"preserved",
"along",
"with",
"the",
"article's",
"original",
"URL.",
"Abstract",
"Background:",
"Avascular",
"necrosis",
"of",
"bone",
"(osteonecrosis)",
"can",
"cause",
"structural",
"failure",
"and",
"subsequent",
"deformation,",
"leading",
"to",
"joint",
"dysfunction",
"and",
"pain.",
"Structural",
"failure",
"is",
"the",
"result",
"of",
"resorption",
"of",
"necrotic",
"bone",
"during",
"revascularization,",
"before",
"new",
"bone",
"has",
"formed",
"or",
"consolidated",
"enough",
"for",
"loadbearing.",
"Bone",
"resorption",
"can",
"be",
"reduced",
"by",
"bisphosphonates.",
"If",
"resorption",
"of",
"the",
"necrotic",
"bone",
"could",
"be",
"reduced",
"during",
"the",
"revascularization",
"phase",
"until",
"sufficient",
"new",
"bone",
"has",
"formed,",
"it",
"would",
"appear",
"that",
"structural",
"failure",
"could",
"be",
"avoided.",
"Methods:",
"To",
"test",
"whether",
"resorption",
"of",
"necrotic",
"bone",
"can",
"be",
"prevented,",
"structural",
"grafts",
"were",
"subjected",
"to",
"new",
"bone",
"ingrowth",
"during",
"systemic",
"bisphosphonate",
"treatment",
"in",
"a",
"rat",
"model.",
"Results:",
"In",
"rats",
"treated",
"with",
"alendronate",
"the",
"necrotic",
"bone",
"was",
"not",
"resorbed,",
"whereas",
"it",
"was",
"almost",
"entirely",
"resorbed",
"in",
"the",
"controls.",
"Conclusion:",
"Systemic",
"alendronate",
"treatment",
"prevents",
"resorption",
"of",
"necrotic",
"bone",
"during",
"revascularization.",
"In",
"patients",
"with",
"osteonecrosis,",
"bisphosphonates",
"may",
"therefore",
"prevent",
"collapse",
"of",
"the",
"necrotic",
"bone.",
"Background",
"Osteonecrosis",
"is",
"caused",
"by",
"insufficient",
"circulation.",
"This",
"situation",
"can",
"occur",
"after",
"trauma",
"or",
"be",
"the",
"result",
"of",
"other",
"events",
"or",
"conditions",
"that",
"can",
"compromise",
"circulation,",
"such",
"as",
"corticosteroid",
"treatment,",
"scuba",
"diving,",
"sickle",
"cell",
"anaemia,",
"alcoholism",
"and",
"pregnancy.",
"Osteonecrosis",
"can",
"lead",
"to",
"structural",
"failure,",
"with",
"subsequent",
"collapse",
"and",
"de-",
"formation",
"of",
"the",
"bone",
"leading",
"to",
"joint",
"dysfunction",
"and",
"pain.",
"Gardeniers",
"[1]",
"performed",
"a",
"series",
"of",
"experiments,",
"where",
"a",
"section",
"of",
"the",
"femoral",
"head",
"in",
"goats",
"was",
"removed",
"and",
"reattached",
"using",
"bone",
"cement.",
"The",
"cement",
"layer",
"pre-",
"vented",
"revascularization,",
"which",
"was",
"verified",
"with",
"angiog-",
"raphy",
"and",
"histology.",
"No",
"collapse",
"occurred,",
"and",
"mechanical",
"testing",
"of",
"the",
"avascular",
"segment",
"showed",
"no",
"weakening",
"compared",
"to",
"vital",
"controls.",
"However,",
"when",
"a",
"hole",
"was",
"drilled",
"through",
"the",
"cement",
"layer",
"in",
"a",
"second",
"op-",
"eration,",
"revascularization",
"ocurred",
"and",
"collapse",
"of",
"the",
"fem-",
"oral",
"head",
"segment",
"followed.",
"Mechanical",
"testing",
"confirmed",
"weakening",
"of",
"the",
"revascularized",
"segments.",
"Others",
"have",
"confirmed",
"that",
"necrotic",
"bone",
"retains",
"load",
"bearing",
"capacity",
"[2],",
"and",
"evidence",
"can",
"also",
"be",
"found",
"in",
"tools",
"made",
"of",
"bone,",
"which",
"have",
"been",
"known",
"since",
"neo-",
"lithicum.",
"Consequently",
"the",
"death",
"of",
"bone",
"cells",
"per",
"se",
"does",
"not",
"cause",
"structural",
"failure.",
"Rather,",
"it",
"is",
"caused",
"by",
"the",
"re-",
"sorption",
"of",
"necrotic",
"bone",
"[3][1].",
"Resorption",
"is",
"mediated",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Cellular",
"Onc.",
"(2011)",
"34:3–10",
"DOI",
"10.1007/s13402-010-0007-3",
"ORIGINAL",
"PAPER",
"Expression",
"of",
"the",
"stem",
"cell",
"marker",
"ALDH1",
"in",
"BRCA1",
"related",
"breast",
"cancer",
"Marise",
"R.",
"Heerma",
"van",
"Voss",
"&",
"Petra",
"van",
"der",
"Groep",
"&",
"Joost",
"Bart",
"&",
"Elsken",
"van",
"der",
"Wall",
"&",
"Paul",
"J.",
"van",
"Diest",
"Accepted:",
"11",
"December",
"2010",
"/",
"Published",
"online:",
"19",
"February",
"2011",
"#",
"The",
"Author(s)",
"2011.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Introduction",
"The",
"BRCA1",
"protein",
"makes",
"mammary",
"stem",
"cells",
"differentiate",
"into",
"mature",
"luminal",
"and",
"myoepithelial",
"cells.",
"If",
"a",
"BRCA1",
"mutation",
"results",
"in",
"a",
"differentiation",
"block,",
"an",
"enlarged",
"stem",
"cell",
"component",
"might",
"be",
"present",
"in",
"the",
"benign",
"tissue",
"of",
"BRCA1",
"mutation",
"carriers,",
"and",
"these",
"mammary",
"stem",
"cells",
"could",
"be",
"the",
"origin",
"of",
"BRCA1",
"related",
"breast",
"cancer.",
"Since",
"ALDH1",
"is",
"a",
"marker",
"of",
"both",
"mammary",
"stem",
"cells",
"and",
"breast",
"cancer",
"stem",
"cells,",
"we",
"compared",
"ALDH1",
"expression",
"in",
"malignant",
"tissue",
"of",
"BRCA1",
"mutation",
"carriers",
"to",
"non-carriers.",
"Methods",
"Forty-one",
"BRCA1",
"related",
"breast",
"cancers",
"and",
"41",
"age-matched",
"sporadic",
"breast",
"cancers",
"were",
"immunohisto-",
"chemically",
"stained",
"for",
"ALDH1.",
"Expression",
"in",
"epithelium",
"and",
"stroma",
"was",
"scored",
"and",
"compared.",
"Results",
"Epithelial",
"(P=",
"0.001)",
"and",
"peritumoral",
"(P=",
"0.001)",
"ALDH1",
"expression",
"was",
"significantly",
"higher",
"in",
"invasive",
"BRCA1",
"related",
"carcinomas",
"compared",
"to",
"sporadic",
"carcino-",
"mas.",
"Intratumoral",
"stromal",
"ALDH1",
"expression",
"was",
"similarly",
"high",
"in",
"both",
"groups.",
"ALDH1",
"tumor",
"cell",
"expression",
"was",
"an",
"independent",
"predictor",
"of",
"BRCA1",
"mutation",
"status.",
"Conclusion",
"BRCA1",
"related",
"breast",
"cancers",
"showed",
"signifi-",
"cantly",
"more",
"frequent",
"epithelial",
"ALDH1",
"expression,",
"indi-",
"M.",
"R.",
"Heerma",
"van",
"Voss",
":",
"P.",
"J.",
"van",
"Diest",
"(*)",
"Department",
"of",
"Pathology,",
"University",
"Medical",
"Center",
"Utrecht,",
"PO",
"Box",
"85500,",
"3508",
"GA",
"Utrecht,",
"The",
"Netherlands",
"e-mail:",
"p.j.vandiest@umcutrecht.nl",
"P.",
"van",
"der",
"Groep",
":",
"E.",
"van",
"der",
"Wall",
"Department",
"of",
"Internal",
"Medicine,",
"University",
"Medical",
"Center",
"Utrecht,",
"Utrecht,",
"The",
"Netherlands",
"J.",
"Bart",
"Department",
"of",
"Pathology,",
"University",
"Medical",
"Center",
"Groningen,",
"Groningen,",
"The",
"Netherlands",
"cating",
"that",
"these",
"hereditary",
"tumors",
"have",
"an",
"enlarged",
"cancer",
"stem",
"cell",
"component.",
"Besides,",
"(peritumoral)",
"stromal",
"ALDH1",
"expression",
"was",
"also",
"more",
"frequent",
"in",
"BRCA1",
"mutation",
"carriers.",
"ALDH1",
"may",
"therefore",
"be",
"a",
"diagnostic",
"marker",
"and",
"a",
"therapeutic",
"target",
"of",
"BRCA1",
"related",
"breast",
"cancer.",
"Keywords",
"Breast",
"cancer",
".",
"BRCA1",
".",
"ALDH1",
".",
"Stem",
"cells",
".",
"Hereditary",
"breast",
"cancer",
"1",
"Introduction",
"Germline",
"mutation",
"carriers",
"of",
"the",
"BRCA1",
"gene",
"locus",
"harbor",
"a",
"high",
"cumulative",
"risk",
"of",
"developing",
"breast",
"and",
"ovarian",
"cancer",
"of",
"57%",
"and",
"40%",
"by",
"age",
"70,",
"respectively",
"[1].",
"BRCA1",
"related",
"breast",
"cancer",
"shows",
"a",
"distinct",
"histopatho-",
"logical",
"and",
"immunohistochemical",
"phenotype.",
"It",
"has",
"been",
"shown",
"to",
"be",
"more",
"often",
"of",
"the",
"ductal",
"or",
"medullary",
"types,",
"of",
"high",
"grade",
"and",
"to",
"show",
"a",
"high",
"mitotic",
"activity",
"index",
"(MAI)",
"and",
"necrosis",
"[2–4].",
"These",
"tumors",
"usually",
"do",
"not",
"express",
"the",
"estrogen",
"(ER)",
"and",
"progesterone",
"receptors",
"(PR)",
"and",
"are",
"almost",
"always",
"HER-2/neu",
"negative",
"(“triple",
"negative”)",
"[2,",
"3].",
"At",
"the",
"gene-expression",
"level",
"these",
"tumors",
"cluster",
"together",
"with",
"the",
"basal-like",
"subgroup",
"[5].",
"BRCA1",
"seems",
"to",
"play",
"an",
"important",
"role",
"in",
"DNA",
"repair",
"in",
"a",
"common",
"pathway",
"with",
"BRCA2",
"[6].",
"Increasing",
"evidence",
"indicates",
"that",
"BRCA1",
"is",
"necessary",
"for",
"mammary",
"stem",
"cell",
"differen-",
"tiation,",
"a",
"function",
"that",
"could",
"explain",
"its",
"tissue-specificity",
"[7–10].",
"Stem",
"cells",
"play",
"a",
"role",
"in",
"repopulating",
"the",
"breast",
"at",
"several",
"points",
"in",
"the",
"human",
"female",
"lifespan.",
"These",
"primitive",
"cells",
"facilitate",
"rapid",
"expansion",
"and",
"regression",
"in",
"puberty",
"and",
"pregnancy,",
"and",
"during",
"the",
"menstrual",
"cycle.",
"In",
"recent",
"studies",
"mammary",
"stem",
"cells",
"have",
"been",
"isolated,",
"by"
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[
485,
988,
681,
997
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[
750,
1054,
774,
1063
],
[
784,
1054,
809,
1063
]
] | [
"JCB:",
"Article",
"Y",
"G",
"O",
"L",
"O",
"I",
"B",
"L",
"L",
"E",
"C",
"F",
"O",
"L",
"A",
"N",
"R",
"U",
"O",
"J",
"E",
"H",
"T",
"Rb",
"and",
"p130",
"control",
"cell",
"cycle",
"gene",
"silencing",
"to",
"maintain",
"the",
"postmitotic",
"phenotype",
"in",
"cardiac",
"myocytes",
"Patima",
"Sdek,1",
"Peng",
"Zhao,1",
"Yaping",
"Wang,1",
"Chang-jiang",
"Huang,2",
"Christopher",
"Y.",
"Ko,1",
"Peter",
"C.",
"Butler,2",
"James",
"N.",
"Weiss,1",
"and",
"W.",
"Robb",
"MacLellan1",
"1Cardiovascular",
"Research",
"Laboratory,",
"Department",
"of",
"Medicine",
"and",
"Department",
"of",
"Physiology,",
"and",
"2Larry",
"Hillblom",
"Islet",
"Research",
"Center,",
"David",
"Geffen",
"School",
"of",
"Medicine,",
"University",
"of",
"California,",
"Los",
"Angeles,",
"Los",
"Angeles,",
"CA",
"90095",
"T",
"soon",
"after",
"birth.",
"Adult",
"cardiac",
"myocytes",
"(ACMs)",
"he",
"mammalian",
"heart",
"loses",
"its",
"regenerative",
"potential",
"permanently",
"exit",
"the",
"cell",
"cycle,",
"and",
"E2F-dependent",
"genes",
"are",
"stably",
"silenced,",
"although",
"the",
"underlying",
"mech-",
"anism",
"is",
"unclear.",
"Heterochromatin,",
"which",
"silences",
"genes",
"in",
"many",
"biological",
"contexts,",
"accumulates",
"with",
"cardiac",
"differentiation.",
"H3K9me3,",
"a",
"histone",
"methylation",
"charac-",
"teristic",
"of",
"heterochromatin,",
"also",
"increases",
"in",
"ACMs",
"and",
"at",
"E2F-dependent",
"promoters.",
"We",
"hypothesize",
"that",
"genes",
"relevant",
"for",
"cardiac",
"proliferation",
"are",
"targeted",
"to",
"hetero-",
"chromatin",
"by",
"retinoblastoma",
"(Rb)",
"family",
"members",
"inter-",
"acting",
"with",
"E2F",
"transcription",
"factors",
"and",
"recruiting",
"heterochromatin",
"protein",
"1",
"(HP1)",
"proteins.",
"To",
"test",
"this",
"hypothesis,",
"we",
"created",
"cardiac-specific",
"Rb",
"and",
"p130",
"inducible",
"double",
"knockout",
"(IDKO)",
"mice.",
"IDKO",
"ACMs",
"showed",
"a",
"decrease",
"in",
"total",
"heterochromatin,",
"and",
"cell",
"cycle",
"genes",
"were",
"derepressed,",
"leading",
"to",
"proliferation",
"of",
"ACMs.",
"Although",
"Rb/p130",
"deficiency",
"had",
"no",
"effect",
"on",
"total",
"H3K9me3",
"levels,",
"recruitment",
"of",
"HP1-",
"to",
"promoters",
"was",
"lost.",
"Depleting",
"HP1-",
"up-regulated",
"proliferation-promoting",
"genes",
"in",
"ACMs.",
"Thus,",
"Rb",
"and",
"p130",
"have",
"overlapping",
"roles",
"in",
"maintaining",
"the",
"postmitotic",
"state",
"of",
"ACMs",
"through",
"their",
"interaction",
"with",
"HP1-",
"to",
"direct",
"heterochromatin",
"formation",
"and",
"silencing",
"of",
"proliferation-promoting",
"genes.",
"Introduction",
"Some",
"amphibians,",
"as",
"well",
"as",
"teleost",
"fish,",
"have",
"a",
"robust",
"capacity",
"to",
"regenerate",
"their",
"hearts",
"after",
"injury",
"throughout",
"their",
"life",
"(Poss",
"et",
"al.,",
"2002).",
"Adult",
"zebrafish,",
"for",
"example,",
"can",
"fully",
"regenerate",
"their",
"heart",
"without",
"scar",
"formation",
"after",
"up",
"to",
"20%",
"of",
"the",
"ventri-",
"cle",
"has",
"been",
"resected.",
"This",
"regenerative",
"response",
"is",
"thought",
"to",
"occur",
"primarily",
"through",
"dedifferentiation",
"and",
"proliferation",
"of",
"existing",
"myocytes",
"(Jopling",
"et",
"al.,",
"2010;",
"Kikuchi",
"et",
"al.,",
"2010).",
"Recent",
"studies",
"have",
"demonstrated",
"that",
"the",
"embryonic",
"mamma-",
"lian",
"heart",
"is",
"also",
"capable",
"of",
"mounting",
"a",
"hyperplastic",
"response",
"to",
"injury",
"but",
"that",
"this",
"is",
"lost",
"rapidly",
"after",
"birth",
"(Drenckhahn",
"et",
"al.,",
"2008;",
"Porrello",
"et",
"al.,",
"2011).",
"Although",
"some",
"studies",
"have",
"sug-",
"gested",
"that",
"the",
"adult",
"mammalian",
"heart",
"possesses",
"a",
"very",
"limited",
"capacity",
"for",
"new",
"cardiomyocyte",
"formation,",
"the",
"source",
"has",
"been",
"Correspondence",
"to",
"W.",
"Robb",
"MacLellan:",
"rmaclellan@mednet.ucla.edu",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"ACM,",
"adult",
"cardiac",
"myocyte;",
"ANF,",
"atrial",
"natriuretic",
"factor;",
"ChIP,",
"chromatin",
"IP;",
"HP1,",
"heterochromatin",
"protein",
"1;",
"IDKO,",
"inducible",
"double",
"knockout;",
"IP,",
"immunoprecipitation;",
"ITS,",
"insulin-transferrin-",
"selenium;",
"MCM,",
"MerCreMer;",
"MHC,",
"myosin",
"heavy",
"chain;",
"NI,",
"nonionic;",
"NRVM,",
"neonatal",
"rat",
"ventricular",
"myocyte;",
"NS,",
"nonspecific;",
"PSG,",
"penicillin-streptomycin-",
"glutamine;",
"Rb,",
"retinoblastoma;",
"TAC,",
"trans-aortic",
"constriction;",
"TAM,",
"tamoxifen;",
"TLVM,",
"time-lapse",
"video",
"microscopy;",
"WT,",
"wild",
"type.",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Cell",
"Biol.",
"Vol.",
"194",
"No.",
"3",
"407–423",
"www.jcb.org/cgi/doi/10.1083/jcb.201012049",
"postulated",
"to",
"be",
"endogenous",
"cardiac",
"stem",
"cells,",
"not",
"existing",
"myocytes",
"(Pasumarthi",
"and",
"Field,",
"2002;",
"Hsieh",
"et",
"al.,",
"2007;",
"Bergmann",
"et",
"al.,",
"2009).",
"Thus,",
"the",
"vast",
"majority",
"of",
"cardiac",
"myo-",
"cytes",
"permanently",
"exits",
"the",
"cell",
"cycle",
"soon",
"after",
"birth",
"in",
"mam-",
"mals,",
"and,",
"when",
"adult",
"cardiac",
"myocytes",
"(ACMs)",
"are",
"subjected",
"to",
"a",
"growth",
"stimulus,",
"they",
"undergo",
"an",
"increase",
"in",
"cell",
"size",
"(hypertrophy)",
"but",
"do",
"not",
"proliferate.",
"The",
"molecular",
"basis",
"for",
"the",
"postmitotic",
"state",
"of",
"ACMs",
"is",
"unknown,",
"but",
"the",
"subset",
"of",
"E2F-dependent",
"genes",
"specifically",
"involved",
"in",
"regulating",
"G2/M",
"and",
"cytokinesis",
"is",
"not",
"up-regulated",
"after",
"growth",
"stimuli",
"in",
"ACMs.",
"The",
"mechanisms",
"that",
"irreversibly",
"silence",
"these",
"genes",
"are",
"un-",
"known;",
"however,",
"stable",
"transcriptional",
"silencing",
"in",
"eukaryotic",
"cells",
"is",
"often",
"caused",
"by",
"specific",
"histone",
"modifications",
"that",
"result",
"in",
"heterochromatin",
"formation",
"around",
"a",
"gene,",
"making",
"it",
"inacces-",
"sible",
"to",
"transcriptional",
"machinery.",
"©",
"2011",
"Sdek",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"an",
"Attribution–",
"Noncommercial–Share",
"Alike–No",
"Mirror",
"Sites",
"license",
"for",
"the",
"first",
"six",
"months",
"after",
"the",
"pub-",
"lication",
"date",
"(see",
"http://www.rupress.org/terms).",
"After",
"six",
"months",
"it",
"is",
"available",
"under",
"a",
"Creative",
"Commons",
"License",
"(Attribution–Noncommercial–Share",
"Alike",
"3.0",
"Unported",
"license,",
"as",
"described",
"at",
"http://creativecommons.org/licenses/by-nc-sa/3.0/).",
"JCB",
"407"
] | [
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1,
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1,
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1,
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] | [
"Ferreira",
"et",
"al.",
"BMC",
"Genomics",
"2010,",
"11:93",
"http://www.biomedcentral.com/1471-2164/11/93",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Comparative",
"transcriptome",
"analysis",
"coupled",
"to",
"X-ray",
"CT",
"reveals",
"sucrose",
"supply",
"and",
"growth",
"velocity",
"as",
"major",
"determinants",
"of",
"potato",
"tuber",
"starch",
"biosynthesis",
"Stephanus",
"J",
"Ferreira1,",
"Melanie",
"Senning1,",
"Sophia",
"Sonnewald1,",
"Petra-Maria",
"Keßling2,",
"Ralf",
"Goldstein3,",
"Uwe",
"Sonnewald1*",
"Abstract",
"Background:",
"Even",
"though",
"the",
"process",
"of",
"potato",
"tuber",
"starch",
"biosynthesis",
"is",
"well",
"understood,",
"mechanisms",
"regulating",
"biosynthesis",
"are",
"still",
"unclear.",
"Transcriptome",
"analysis",
"provides",
"valuable",
"information",
"as",
"to",
"how",
"genes",
"are",
"regulated.",
"Therefore,",
"this",
"work",
"aimed",
"at",
"investigating",
"transcriptional",
"regulation",
"of",
"starch",
"biosynthetic",
"genes",
"in",
"leaves",
"and",
"tubers",
"of",
"potato",
"plants",
"under",
"various",
"conditions.",
"More",
"specifically",
"we",
"looked",
"at",
"gene",
"expression",
"diurnally",
"in",
"leaves",
"and",
"tubers,",
"during",
"tuber",
"induction",
"and",
"in",
"tubers",
"growing",
"at",
"different",
"velocities.",
"To",
"determine",
"velocity",
"of",
"potato",
"tuber",
"growth",
"a",
"new",
"method",
"based",
"on",
"X-ray",
"Computed",
"Tomography",
"(X-ray",
"CT)",
"was",
"established.",
"Results:",
"Comparative",
"transcriptome",
"analysis",
"between",
"leaves",
"and",
"tubers",
"revealed",
"striking",
"similarities",
"with",
"the",
"same",
"genes",
"being",
"differentially",
"expressed",
"in",
"both",
"tissues.",
"In",
"tubers,",
"oscillation",
"of",
"granule",
"bound",
"starch",
"synthase",
"(GBSS)",
"expression)",
"was",
"observed",
"which",
"could",
"be",
"linked",
"to",
"sucrose",
"supply",
"from",
"source",
"leaves.",
"X-ray",
"CT",
"was",
"used",
"to",
"determine",
"time-dependent",
"changes",
"in",
"tuber",
"volume",
"and",
"the",
"growth",
"velocity",
"was",
"calculated.",
"Although",
"there",
"is",
"not",
"a",
"linear",
"correlation",
"between",
"growth",
"velocity",
"and",
"expression",
"of",
"starch",
"biosynthetic",
"genes,",
"there",
"are",
"significant",
"differences",
"between",
"growing",
"and",
"non-growing",
"tubers.",
"Co-expression",
"analysis",
"was",
"used",
"to",
"identify",
"transcription",
"factors",
"positively",
"correlating",
"with",
"starch",
"biosynthetic",
"genes",
"possibly",
"regulating",
"starch",
"biosynthesis.",
"Conclusion:",
"Most",
"starch",
"biosynthetic",
"enzymes",
"are",
"encoded",
"by",
"gene",
"families.",
"Co-expression",
"analysis",
"revealed",
"that",
"the",
"same",
"members",
"of",
"these",
"gene",
"families",
"are",
"co-regulated",
"in",
"leaves",
"and",
"tubers.",
"This",
"suggests",
"that",
"regulation",
"of",
"transitory",
"and",
"storage",
"starch",
"biosynthesis",
"in",
"leaves",
"and",
"tubers,",
"respectively,",
"is",
"surprisingly",
"similar.",
"X-ray",
"CT",
"can",
"be",
"used",
"to",
"monitor",
"growth",
"and",
"development",
"of",
"belowground",
"organs",
"and",
"allows",
"to",
"link",
"tuber",
"growth",
"to",
"changes",
"in",
"gene",
"expression.",
"Comparative",
"transcriptome",
"analysis",
"provides",
"a",
"useful",
"tool",
"to",
"identify",
"transcription",
"factors",
"possibly",
"involved",
"in",
"the",
"regulation",
"of",
"starch",
"biosynthesis.",
"Background",
"Starch",
"is",
"not",
"only",
"the",
"most",
"important",
"carbohydrate",
"source",
"to",
"the",
"human",
"diet,",
"but",
"has",
"major",
"industrial",
"applications.",
"It",
"consists",
"of",
"two",
"major",
"fractions,",
"amylose",
"and",
"amylopectin.",
"Amylose",
"is",
"essentially",
"a",
"linear",
"polymer",
"of",
"glucose",
"units",
"linked",
"with",
"alpha",
"(1,4)",
"bonds",
"whilst",
"amylopectin",
"has",
"a",
"higher",
"percentage",
"of",
"branched",
"alpha",
"(1,6)",
"bonds.",
"Due",
"to",
"its",
"importance,",
"crop",
"plants",
"*",
"Correspondence:",
"usonne@biologie.uni-erlangen.de",
"1Friedrich-Alexander-University",
"Erlangen-Nuremberg,",
"Department",
"of",
"Biology,",
"Staudtstrasse",
"5,",
"91058",
"Erlangen,",
"Germany",
"producing",
"starch",
"in",
"large",
"quantities",
"have",
"been",
"exten-",
"sively",
"researched.",
"The",
"fourth",
"most",
"important",
"crop",
"in",
"the",
"world",
"in",
"terms",
"of",
"total",
"biomass",
"produced",
"is",
"potato",
"and",
"this",
"is",
"due",
"to",
"its",
"starchy",
"tuber",
"which",
"can",
"store",
"up",
"to",
"80%",
"of",
"its",
"dry",
"weight",
"as",
"starch",
"[1].",
"In",
"potato",
"starch",
"is",
"either",
"accumulated",
"transiently",
"in",
"leaves",
"or",
"as",
"storage",
"starch",
"in",
"tubers.",
"In",
"leaves",
"starch",
"is",
"synthesised",
"in",
"the",
"chloroplast",
"from",
"triose-phosphates",
"produced",
"during",
"photosynthesis.",
"After",
"several",
"inter-",
"mediate",
"steps,",
"glucose",
"6-phosphate",
"is",
"converted",
"to",
"glu-",
"cose",
"1-phosphate",
"by",
"the",
"enzyme",
"phosphoglucomutase",
"(PGM).",
"Glucose",
"1-phosphate,",
"along",
"with",
"ATP",
"serves",
"as",
"©",
"2010",
"Ferreira",
"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."
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] | [
"YALE",
"JOURNAL",
"OF",
"BIOLOGY",
"AND",
"MEDICINE",
"80",
"(2007),",
"pp.",
"95-103",
"Copyright",
"©",
"2007.",
"REVIEW",
"Impact",
"of",
"Placental",
"Plasmodium",
"falciparum",
"Malaria",
"on",
"Pregnancy",
"and",
"Perinatal",
"Outcome",
"in",
"Sub-Saharan",
"Africa",
"II:",
"Effects",
"of",
"Placental",
"Malaria",
"on",
"Perinatal",
"Outcome;",
"Malaria",
"and",
"HIV",
"Chigozie",
"J.",
"Uneke",
"Faculty",
"of",
"Clinical",
"Medicine,",
"Ebonyi",
"State",
"University,",
"Nigeria",
"Placental",
"malaria",
"is",
"recognized",
"as",
"a",
"common",
"complication",
"of",
"malaria",
"in",
"pregnancy",
"in",
"areas",
"of",
"stable",
"transmission,",
"and,",
"as",
"a",
"consequence,",
"serious",
"health",
"problems",
"arise",
"for",
"the",
"mother",
"and",
"especially",
"her",
"baby",
"[1].",
"Although",
"malaria",
"in",
"pregnancy",
"is",
"a",
"major",
"factor",
"associated",
"with",
"adverse",
"perinatal",
"outcome,",
"the",
"link",
"between",
"malaria",
"and",
"perinatal",
"morbidity/mortality",
"is",
"less",
"clear",
"in",
"areas",
"with",
"stable",
"endemic",
"malaria",
"where",
"pregnant",
"women",
"have",
"acquired",
"immunity",
"[2].",
"Histological",
"examination",
"of",
"the",
"placenta",
"is",
"a",
"predictor",
"of",
"fetal",
"morbidity,",
"as",
"well",
"as",
"being",
"the",
"most",
"sensitive",
"detector",
"of",
"maternal",
"infection",
"[3].",
"Adverse",
"perinatal",
"outcome",
"has",
"been",
"described",
"as",
"an",
"important",
"indicator",
"of",
"poor",
"quality",
"of",
"obstetric",
"care",
"and",
"social",
"development",
"[4].",
"A",
"variety",
"of",
"adverse",
"perinatal",
"outcomes",
"associ-",
"ated",
"with",
"placental",
"malaria",
"have",
"been",
"described,",
"including",
"low",
"birth",
"weight,",
"preterm",
"delivery,",
"intrauterine",
"growth",
"retardation,",
"fetal",
"anemia,",
"congenital",
"malaria,",
"and",
"fetal",
"mortality.",
"The",
"most",
"common",
"clinical",
"features",
"in",
"80",
"percent",
"of",
"perinatal",
"cases",
"are",
"fever,",
"anemia,",
"and",
"splenomegaly",
"[5].",
"Other",
"signs",
"and",
"symptoms",
"include",
"hepatomegaly,",
"jaundice,",
"regurgitation,",
"loose",
"stools,",
"poor",
"feeding,",
"and,",
"occasionally,",
"drowsiness,",
"restlessness,",
"and",
"cyanosis",
"also",
"can",
"be",
"seen",
"[5,6].",
"A",
"review",
"of",
"studies",
"that",
"investigated",
"these",
"poor",
"fetal",
"outcomes",
"associated",
"with",
"placental",
"malaria",
"in",
"sub-Saharan",
"Africa",
"is",
"presented",
"here.",
"ADVERSE",
"OUTCOMES",
"OF",
"PLACENTAL",
"MALARIA",
"Congenital",
"malaria",
"Malaria",
"during",
"pregnancy",
"may",
"result",
"in",
"fetal",
"exposure",
"to",
"malaria",
"if",
"parasites",
"are",
"transmitted",
"across",
"the",
"placenta",
"and",
"could",
"re-",
"sult",
"in",
"congenital",
"malaria.",
"Transplacental",
"transmission",
"of",
"P.",
"falciparum",
"has",
"been",
"well",
"described,",
"and",
"the",
"reported",
"frequency",
"of",
"this",
"event",
"in",
"babies",
"born",
"in",
"malaria-exposed",
"pregnancies",
"has",
"ranged",
"from",
"0",
"percent",
"to",
"more",
"than",
"25",
"percent",
"[7-11].",
"Thus,",
"placental",
"malaria",
"is",
"known",
"to",
"be",
"a",
"major",
"determinant",
"To",
"whom",
"all",
"correspondence",
"should",
"be",
"addressed:",
"Chigozie",
"J.",
"Uneke,",
"Department",
"of",
"Med-",
"ical",
"Microbiology/Parasitology,",
"Faculty",
"of",
"Clinical",
"Medicine,",
"Ebonyi",
"State",
"University,",
"PMB",
"053",
"Abakaliki,",
"Nigeria.",
"Tele:",
"234-08038928597;",
"Fax:",
"234-043221093;",
"E-mail:",
"unekecj@",
"yahoo.com.",
"†Abbreviations:",
"LBW,",
"low",
"birth",
"weight;",
"PTD,",
"preterm",
"delivery;",
"IUGR,",
"intrauterine",
"growth",
"re-",
"tardation;",
"MTCT,",
"mother-to-child",
"transmission.",
"95"
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] | [
"SY",
"Park,",
"et",
"al",
"Ann",
"Dermatol",
"Vol.",
"24,",
"No",
"1,",
"2012",
"ORIGINAL",
"ARTICLE",
"http://dx.doi.org/10.5021/ad.2012.24.1.32",
"The",
"Prevalence,",
"Genotype",
"and",
"Antimicrobial",
"Susceptibility",
"of",
"High-",
"and",
"Low-Level",
"Mupirocin",
"Resistant",
"Methicillin-Resistant",
"Staphylococcus",
"aureus",
"Se",
"Young",
"Park,",
"M.D.1,",
"Shin",
"Moo",
"Kim,",
"Ph.D.2,",
"Seok",
"Don",
"Park,",
"M.D.,",
"Ph.D.1,3",
"1Department",
"of",
"Dermatology,",
"Wonkwang",
"University",
"School",
"of",
"Medicine,",
"2Department",
"of",
"Clinical",
"Laboratory",
"Science,",
"Wonkwang",
"Health",
"Science",
"University,",
"3Institute",
"of",
"Wonkwang",
"Medical",
"Science,",
"Wonkwang",
"University",
"School",
"of",
"Medicine,",
"Iksan,",
"Korea",
"Background:",
"Mupirocin",
"has",
"been",
"used",
"for",
"the",
"treatment",
"of",
"skin",
"infections",
"and",
"eradication",
"of",
"nasal",
"carriage",
"of",
"methicil-",
"lin-resistant",
"Staphylococcus",
"aureus",
"(MRSA).",
"The",
"increased",
"use",
"of",
"this",
"antibiotic",
"has",
"been",
"accompanied",
"by",
"outbreaks",
"of",
"MRSA",
"that",
"are",
"resistant",
"to",
"mupirocin.",
"Objective:",
"This",
"study",
"aims",
"to",
"determine",
"the",
"prevalence,",
"genotype",
"and",
"antimicrobial",
"susceptibility",
"of",
"mupirocin-resistant",
"MRSA",
"from",
"4",
"Korean",
"hospitals.",
"Methods:",
"A",
"total",
"193",
"MRSA",
"clinical",
"isolates",
"were",
"collected",
"from",
"four",
"university",
"hospitals.",
"Antimicrobial",
"sus-",
"ceptibility",
"tests,",
"including",
"mupirocin,",
"and",
"pulsed-field",
"gel",
"electrophoresis",
"(PFGE)",
"pattern",
"analysis",
"were",
"performed.",
"Results:",
"Overall,",
"27",
"of",
"the",
"193",
"(14.1%)",
"MRSA",
"isolates",
"were",
"resistant",
"to",
"mupirocin.",
"All",
"of",
"the",
"(A)",
"hospital",
"isolates",
"showed",
"high-level",
"(HL)",
"mupirocin",
"resistance",
"and",
"the",
"low-level",
"(LL)",
"mupirocin",
"resistant",
"strains",
"were",
"from",
"three",
"other",
"hospitals.",
"The",
"PFGE",
"patterns",
"of",
"16",
"mupirocin-resistant",
"isolates",
"were",
"divided",
"into",
"5",
"clusters",
"(1-5),",
"and",
"the",
"nine",
"HL",
"mupirocin-",
"resistant",
"isolates",
"belonged",
"to",
"cluster",
"1.",
"Both",
"the",
"HL",
"and",
"LL",
"mupirocin-resistant",
"MRSA",
"isolates",
"were",
"susceptible",
"to",
"van-",
"comycin",
"and",
"rifampin,",
"but",
"they",
"were",
"resistant",
"to",
"ciproflo-",
"xacin,",
"clindamycin",
"and",
"tetracycline.",
"The",
"erythromycin",
"and",
"fusidic",
"acid",
"resistance",
"rates",
"were",
"different",
"between",
"the",
"HL",
"and",
"LL",
"resistant",
"isolates.",
"Conclusion:",
"HL",
"mupirocin-resistant",
"isolates",
"that",
"could",
"transfer",
"this",
"resistance",
"to",
"other",
"bacteria",
"Received",
"April",
"27,",
"2011,",
"Revised",
"July",
"5,",
"2011,",
"Accepted",
"for",
"publication",
"July",
"7,",
"2011",
"Corresponding",
"author:",
"Seok",
"Don",
"Park,",
"M.D.,",
"Ph.D.,",
"Department",
"of",
"Dermatology,",
"Wonkwang",
"University",
"Hospital,",
"344-2",
"Sinyong-dong,",
"Iksan",
"570-711,",
"Korea.",
"Tel:",
"82-63-859-1601,",
"Fax:",
"82-63-842-1895,",
"E-mail:",
"sdpark@wonkwang.ac.kr",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"32",
"Ann",
"Dermatol",
"were",
"detected",
"and",
"these",
"isolates",
"were",
"clonally",
"related.",
"The",
"emergence",
"of",
"mupirocin",
"resistant",
"isolates",
"emphasizes",
"the",
"importance",
"of",
"using",
"antibiotics",
"judiciously",
"and",
"carefully",
"monitoring",
"the",
"prevalence",
"of",
"mupirocin",
"resistance.",
"(Ann",
"Dermatol",
"24(1)",
"32∼38,",
"2012)",
"-Keywords-",
"Antimicrobial",
"susceptibility,",
"MRSA,",
"Mupirocin,",
"Pulsed",
"field",
"gel",
"electrophoresis",
"INTRODUCTION",
"Mupirocin",
"is",
"a",
"topical",
"antibiotic",
"that",
"was",
"originally",
"isolated",
"from",
"Pseudomonas",
"fluorescens,",
"and",
"it",
"inhibits",
"bacterial",
"protein",
"synthesis",
"by",
"competitively",
"binding",
"to",
"isoleucyl-",
"tRNA",
"synthetase",
"(IleS).",
"This",
"drug",
"is",
"particularly",
"effective",
"against",
"streptococci",
"and",
"staphylococci,",
"including",
"methicil-",
"lin-resistant",
"Staphylococcus",
"aureus",
"(MRSA).",
"Mupirocin",
"is",
"one",
"of",
"the",
"most",
"popular",
"topical",
"agents",
"used",
"for",
"the",
"treat-",
"ment",
"of",
"skin",
"infection",
"and",
"eradication",
"of",
"nasal",
"carriage",
"of",
"MRSA1.",
"The",
"increased",
"use",
"of",
"this",
"antibiotic",
"has",
"been",
"accompanied",
"by",
"outbreaks",
"of",
"MRSA",
"that",
"are",
"resistant",
"to",
"mupirocin2.",
"The",
"mupirocin",
"resistant",
"strains",
"are",
"divided",
"into",
"two",
"groups",
"depending",
"on",
"the",
"minimum",
"inhibitory",
"concentra-",
"tion",
"(MIC)",
"against",
"mupirocin:",
"low-level",
"resistance",
"(MIC=8",
"∼256μg/ml)",
"and",
"high-level",
"resistance",
"(MIC>256μg/",
"ml).",
"High-level",
"mupirocin",
"resistant",
"strains",
"are",
"important",
"in",
"the",
"clinical",
"field",
"because",
"they",
"are",
"able",
"to",
"transfer",
"resistance",
"genes",
"to",
"other",
"bacteria",
"by",
"plasmid",
"conjugation,",
"conse-",
"quently",
"protecting",
"these",
"bacteria",
"from",
"being",
"eradicated",
"with",
"mupirocin3.",
"The",
"use",
"of",
"mupirocin",
"ointment",
"has",
"been",
"increasing",
"in"
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] | [
"www.jkns.or.kr",
"http://dx.doi.org/10.3340/jkns.2012.52.2.80",
"J",
"Korean",
"Neurosurg",
"Soc",
"52",
":",
"80-84,",
"2012",
"Print",
"ISSN",
"2005-3711",
"On-line",
"ISSN",
"1598-7876",
"Copyright",
"©",
"2012",
"The",
"Korean",
"Neurosurgical",
"Society",
"Clinical",
"Article",
"The",
"Meaning",
"of",
"the",
"Prognostic",
"Factors",
"in",
"Ruptured",
"Middle",
"Cerebral",
"Artery",
"Aneurysm",
"with",
"Intracerebral",
"Hemorrhage",
"Ji",
"Woong",
"Oh,",
"M.D.,1",
"Ji-Yong",
"Lee,",
"M.D.,2",
"Myeong",
"Sub",
"Lee,",
"M.D.,3",
"Hyen-Ho",
"Jung,",
"M.D.,1",
"Kum",
"Whang,",
"M.D.;1",
"Brain",
"Research",
"Group",
"Departments",
"of",
"Neurosurgery,1",
"Neurology,2",
"Radiology,3",
"Wonju",
"College",
"of",
"Medicine,",
"Yonsei",
"University,",
"Wonju,",
"Korea",
"Objective",
":",
"This",
"study",
"analyzed",
"the",
"relationship",
"between",
"prognosis",
"and",
"multiple",
"clinical",
"factors",
"of",
"ruptured",
"middle",
"cerebral",
"artery",
"(MCA)",
"aneurysm",
"with",
"intracerebral",
"hemorrhage",
"(ICH),",
"to",
"aid",
"in",
"predicting",
"the",
"results",
"of",
"surgical",
"treatment.",
"Methods",
":",
"Enrolled",
"subjects",
"were",
"41",
"patients",
"with",
"ruptured",
"MCA",
"aneurysm",
"with",
"ICH",
"who",
"were",
"treated",
"with",
"surgical",
"clipping.",
"Clinical",
"factors",
"such",
"as",
"gender,",
"age,",
"and",
"initial",
"Glasgow",
"coma",
"scale",
"were",
"assessed",
"while",
"radiological",
"factors",
"such",
"as",
"the",
"volume",
"and",
"location",
"of",
"hematoma,",
"the",
"degree",
"of",
"a",
"midline",
"shift,",
"and",
"aneurysm",
"size",
"were",
"considered",
"retrospectively.",
"Prognosis",
"was",
"evaluated",
"postoperatively",
"by",
"Glasgow",
"outcome",
"scale.",
"Results",
":",
"Age",
"and",
"prognosis",
"were",
"correlated",
"only",
"in",
"the",
"groups",
"with",
"ICH",
"over",
"31",
"mL",
"or",
"ICH",
"at",
"the",
"frontal",
"lobe",
"or",
"sylvian",
"fissure.",
"When",
"initial",
"mental",
"status",
"was",
"good,",
"only",
"patients",
"with",
"ICH",
"on",
"the",
"temporal",
"lobe",
"had",
"a",
"better",
"prognosis.",
"If",
"the",
"midline",
"shift",
"was",
"less",
"than",
"4.5",
"mm,",
"the",
"probability",
"of",
"better",
"prognosis",
"was",
"95.5%",
"(21",
"of",
"22).",
"If",
"the",
"midline",
"shift",
"was",
"more",
"than",
"4.5",
"mm,",
"the",
"probability",
"of",
"poor",
"prognosis",
"was",
"42.1%",
"(8",
"of",
"19).",
"Patients",
"with",
"ICH",
"less",
"than",
"31",
"mL",
"had",
"higher",
"survival",
"rates,",
"whereas",
"if",
"the",
"ICH",
"was",
"more",
"than",
"31",
"mL,",
"41.2%",
"(7",
"of",
"17)",
"had",
"a",
"poor",
"clinical",
"pathway.",
"Conclusion",
":",
"Even",
"if",
"the",
"initial",
"clinical",
"condition",
"of",
"the",
"patient",
"was",
"not",
"promising,",
"by",
"carefully",
"examining",
"and",
"taking",
"into",
"account",
"all",
"factors,",
"neuro-",
"surgeons",
"can",
"confidently",
"recommend",
"surgical",
"treatment",
"for",
"these",
"patients.",
"Key",
"Words",
":",
"Ruptured",
"middle",
"cerebral",
"artery",
"aneurysm",
"·",
"Intracerebral",
"hemorrhage",
"·",
"Prognostic",
"outcome.",
"INTRODUCTION",
"Middle",
"cerebral",
"artery",
"(MCA)",
"aneurysms",
"are",
"20%",
"of",
"saccular",
"aneurysms.",
"They",
"are",
"occasionally",
"found",
"incidentally",
"or",
"because",
"of",
"a",
"mass",
"effect,",
"but",
"most",
"are",
"found",
"when",
"they",
"rupture8).",
"After",
"Dott2)",
"treated",
"ruptured",
"aneurysms",
"with",
"surgical",
"methods,",
"many",
"treatment",
"modalities",
"have",
"been",
"developed",
"and",
"report-",
"ed17).",
"When",
"MCA",
"aneurysms",
"rupture,",
"approximately",
"30-50%",
"lead",
"to",
"a",
"subarachnoid",
"hemorrhage",
"(SAH)",
"combined",
"with",
"an",
"intracerebral",
"hemorrhage",
"(ICH),",
"with",
"a",
"mortality",
"rate",
"of",
"10-",
"41%4,16).",
"The",
"mechanism",
"of",
"ICH",
"developed",
"by",
"aneurysmal",
"rup-",
"ture",
"is",
"still",
"controversial",
"but",
"the",
"most",
"commonly",
"accepted",
"hy-",
"pothesis",
"is",
"that",
"the",
"ICH",
"develops",
"when",
"fibrin,",
"hematoma,",
"or",
"the",
"fibrosis",
"of",
"the",
"arachnoid",
"membrane",
"obstructs",
"the",
"subarach-",
"noid",
"space,",
"or",
"an",
"aneurysm",
"attached",
"to",
"the",
"pia",
"ruptures16).",
"These",
"ICHs",
"are",
"a",
"risk",
"factor",
"for",
"poor",
"prognosis",
"and",
"surgical",
"complica-",
"tions",
"in",
"ruptured",
"MCA",
"aneurysm",
"patients.",
"However,",
"our",
"clini-",
"cal",
"data",
"suggested",
"that",
"patients",
"with",
"ruptured",
"MCA",
"aneurysms",
"with",
"ICH",
"have",
"a",
"non-classical",
"clinical",
"course",
"that",
"requires",
"fur-",
"ther",
"study.",
"Therefore,",
"authors",
"analyzed",
"the",
"relationship",
"between",
"multiple",
"clinical",
"factors",
"of",
"ruptured",
"MCA",
"aneurysms",
"with",
"ICH",
"and",
"general",
"prognosis,",
"to",
"help",
"predict",
"the",
"results",
"of",
"surgical",
"treatment.",
"MATERIALS",
"AND",
"METHODS",
"We",
"retrospectively",
"reviewed",
"68",
"patients",
"with",
"MCA",
"aneurysm",
"who",
"underwent",
"neck",
"clipping",
"after",
"aneurysm",
"rupture",
"between",
"January",
"2006",
"and",
"December",
"2010.",
"We",
"excluded",
"27",
"patients",
"who",
"did",
"not",
"have",
"accompanying",
"ICH.",
"The",
"remaining",
"41",
"pa-",
"tients",
"with",
"accompanying",
"ICH",
"were",
"evaluated.",
"Aneurysm,",
"SAH",
"and",
"ICH",
"were",
"diagnosed",
"with",
"computed",
"tomography",
"(CT)",
"and",
"conventional",
"cerebral",
"angiography.",
"Of",
"the",
"41",
"total",
"patients,",
"27",
"were",
"evaluated",
"with",
"preoperative",
"angiography",
"(Table",
"1).",
"•",
"Received",
":",
"February",
"15,",
"2012",
"•",
"Revised",
":",
"May",
"30,",
"2012",
"•",
"Accepted",
":",
"August",
"19,",
"2012",
"•",
"Address",
"for",
"reprints",
":",
"Kum",
"Whang,",
"M.D.",
"Departments",
"of",
"Neurosurgery,",
"Wonju",
"College",
"of",
"Medicine,",
"Yonsei",
"University,",
"162",
"Ilsan-dong,",
"Wonju",
"220-701,",
"Korea",
"Tel",
":",
"+82-33-741-0593,",
"Fax",
":",
"+82-33-746-2287,",
"E-mail",
":",
"whangkum@yonsei.ac.kr",
"•",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"80"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Biochemistry",
"Research",
"International",
"Volume",
"2012,",
"Article",
"ID",
"369384,",
"5",
"pages",
"doi:10.1155/2012/369384",
"Review",
"Article",
"Role",
"of",
"Translationally",
"Controlled",
"Tumor",
"Protein",
"in",
"Cancer",
"Progression",
"Tim",
"Hon",
"Man",
"Chan,1,",
"2",
"Leilei",
"Chen,1,",
"2",
"and",
"Xin-Yuan",
"Guan1,",
"2,",
"3",
"1",
"Department",
"of",
"Clinical",
"Oncology,",
"Li",
"Ka",
"Shing",
"Faculty",
"of",
"Medicine,",
"The",
"University",
"of",
"Hong",
"Kong,",
"Hong",
"Kong",
"2",
"State",
"Key",
"Laboratory",
"of",
"Liver",
"Research,",
"The",
"University",
"of",
"Hong",
"Kong,",
"Hong",
"Kong",
"3",
"State",
"Key",
"Laboratory",
"of",
"Oncology",
"in",
"Southern",
"China,",
"Sun",
"Yat-sen",
"University",
"Cancer",
"Center,",
"Guangzhou",
"510060,",
"China",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Xin-Yuan",
"Guan,",
"xyguan@hku.hk",
"Received",
"13",
"January",
"2012;",
"Accepted",
"17",
"February",
"2012",
"Academic",
"Editor:",
"Malgorzata",
"Kloc",
"Copyright",
"©",
"2012",
"Tim",
"Hon",
"Man",
"Chan",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Translationally",
"controlled",
"tumor",
"protein",
"(TCTP)",
"is",
"a",
"highly",
"conserved",
"and",
"ubiquitously",
"expressed",
"protein",
"in",
"all",
"eukaryotes—",
"highlighting",
"its",
"important",
"functions",
"in",
"the",
"cell.",
"Previous",
"studies",
"revealed",
"that",
"TCTP",
"is",
"implicated",
"in",
"many",
"biological",
"processes,",
"including",
"cell",
"growth,",
"tumor",
"reversion,",
"and",
"induction",
"of",
"pluripotent",
"stem",
"cell.",
"A",
"recent",
"study",
"on",
"the",
"solution",
"structure",
"from",
"fission",
"yeast",
"orthologue",
"classifies",
"TCTP",
"under",
"a",
"family",
"of",
"small",
"chaperone",
"proteins.",
"There",
"is",
"growing",
"evidence",
"in",
"the",
"literature",
"that",
"TCTP",
"is",
"a",
"multifunctional",
"protein",
"and",
"exerts",
"its",
"biological",
"activity",
"at",
"the",
"extracellular",
"and",
"intracellular",
"levels.",
"Although",
"TCTP",
"is",
"not",
"a",
"tumor-specific",
"protein,",
"our",
"research",
"group,",
"among",
"several",
"others,",
"focused",
"on",
"the",
"role(s)",
"of",
"TCTP",
"in",
"cancer",
"progression.",
"In",
"this",
"paper,",
"we",
"will",
"summarize",
"the",
"current",
"scientific",
"knowledge",
"of",
"TCTP",
"in",
"different",
"aspects,",
"and",
"the",
"precise",
"oncogenic",
"mechanisms",
"of",
"TCTP",
"will",
"be",
"discussed",
"in",
"detail.",
"1.",
"Introduction",
"Translationally",
"controlled",
"tumor",
"protein",
"(TCTP)",
"is",
"a",
"highly",
"conserved",
"multifunctional",
"protein.",
"Since",
"the",
"discovery",
"of",
"TCTP",
"over",
"two",
"decades",
"ago,",
"the",
"expression",
"level",
"of",
"TCTP",
"has",
"been",
"investigated",
"in",
"more",
"than",
"500",
"tissues",
"and",
"cell",
"types.",
"Expression",
"levels",
"have",
"been",
"found",
"to",
"vary",
"by",
"nearly",
"two",
"orders",
"of",
"magnitude",
"between",
"different",
"types",
"of",
"tissues",
"[1]",
"with",
"preferential",
"expression",
"in",
"mitotically",
"active",
"tissues",
"[2].",
"Two",
"mRNA",
"transcripts",
"have",
"been",
"reported",
"to",
"carry",
"the",
"same",
"5",
"UTR",
"but",
"different",
"3",
"UTR",
"using",
"alternative",
"polyadenylation",
"signals.",
"The",
"solution",
"structure",
"of",
"TCTP",
"from",
"fission",
"yeast",
"also",
"revealed",
"structural",
"similarity",
"with",
"the",
"Mss4/Dss4",
"protein",
"family.",
"The",
"expression",
"of",
"TCTP",
"is",
"highly",
"regulated",
"both",
"at",
"transcriptional",
"and",
"translational",
"levels",
"in",
"addition",
"to",
"a",
"wide",
"range",
"of",
"extracellular",
"signals.",
"It",
"has",
"been",
"implicated",
"in",
"many",
"cellular",
"processes,",
"such",
"as",
"cell",
"growth,",
"cell",
"cycle",
"progression,",
"apoptosis,",
"malignant",
"transformation,",
"and",
"the",
"regulation",
"of",
"pluripotency.",
"Although",
"TCTP",
"is",
"not",
"a",
"tumor-",
"specific",
"protein,",
"the",
"downregulation",
"of",
"TCTP",
"was",
"found",
"in",
"tumor",
"reversion",
"[3].",
"Our",
"research",
"group",
"and",
"others",
"also",
"substantiated",
"the",
"link",
"between",
"TCTP",
"deregulation",
"and",
"cancer",
"progression",
"[4–6].",
"This",
"paper",
"will",
"mainly",
"focus",
"on",
"the",
"biological",
"functions",
"of",
"TCTP",
"and",
"malignant",
"transformation",
"induced",
"by",
"TCTP.",
"Furthermore,",
"the",
"clinical",
"implications",
"of",
"TCTP",
"in",
"human",
"cancers",
"will",
"also",
"be",
"discussed.",
"2.",
"Features",
"of",
"TCTP",
"mRNA",
"and",
"Protein",
"2.1.",
"TCTP",
"mRNA.",
"The",
"human",
"TPT1",
"gene",
"coding",
"for",
"TCTP",
"spanning",
"about",
"4.2",
"kb,",
"consists",
"of",
"six",
"exons",
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"organizers",
"where",
"QTL",
"genotypes",
"were",
"known.",
"Participants",
"submitted",
"estimated",
"breeding",
"values",
"for",
"1000",
"unphenotyped",
"individuals",
"together",
"with",
"a",
"description",
"of",
"the",
"applied",
"method(s).",
"The",
"submitted",
"breeding",
"values",
"were",
"evaluated",
"for",
"correlation",
"with",
"the",
"simulated",
"values",
"(accuracy),",
"rank",
"correlation",
"of",
"the",
"best",
"10%",
"of",
"individuals",
"and",
"error",
"in",
"predictions.",
"Bias",
"was",
"tested",
"by",
"regression",
"of",
"simulated",
"on",
"estimated",
"breeding",
"values.",
"Results:",
"The",
"accuracy",
"obtained",
"from",
"the",
"best",
"case",
"scenario",
"was",
"0.94.",
"Six",
"research",
"groups",
"submitted",
"19",
"sets",
"of",
"estimated",
"breeding",
"values.",
"Methods",
"that",
"assumed",
"the",
"same",
"variance",
"for",
"markers",
"showed",
"accuracies,",
"measured",
"as",
"correlations",
"between",
"estimated",
"and",
"simulated",
"values,",
"ranging",
"from",
"0.75",
"to",
"0.89",
"and",
"rank",
"correlations",
"between",
"0.58",
"and",
"0.70.",
"Methods",
"that",
"allowed",
"different",
"marker",
"variances",
"showed",
"accuracies",
"ranging",
"from",
"0.86",
"to",
"0.94",
"and",
"rank",
"correlations",
"between",
"0.69",
"and",
"0.82.",
"Methods",
"assuming",
"equal",
"marker",
"variances",
"were",
"generally",
"more",
"biased",
"and",
"showed",
"larger",
"prediction",
"errors.",
"Conclusions:",
"The",
"best",
"performing",
"methods",
"achieved",
"very",
"high",
"accuracies,",
"close",
"to",
"accuracies",
"achieved",
"in",
"a",
"best",
"case",
"scenario",
"where",
"QTL",
"genotypes",
"were",
"known",
"without",
"error.",
"Methods",
"that",
"allowed",
"different",
"marker",
"variances",
"generally",
"outperformed",
"methods",
"that",
"assumed",
"equal",
"marker",
"variances.",
"Genomic",
"selection",
"methods",
"performed",
"well",
"compared",
"to",
"traditional,",
"pedigree",
"only,",
"methods;",
"all",
"methods",
"showed",
"higher",
"accuracies",
"than",
"those",
"obtained",
"for",
"breeding",
"values",
"estimated",
"solely",
"on",
"pedigree",
"relationships.",
"Background",
"When",
"methods",
"for",
"selection",
"based",
"on",
"many",
"markers",
"across",
"the",
"genome,",
"or",
"genomic",
"selection,",
"were",
"first",
"described",
"[1]",
"the",
"application",
"of",
"genetic",
"marker",
"data",
"in",
"plant",
"and",
"animal",
"breeding",
"programs",
"was",
"still",
"limited",
"[2].",
"In",
"subsequent",
"years",
"the",
"use",
"of",
"individual",
"markers",
"in",
"breeding",
"programs",
"has",
"increased",
"[3,4].",
"With",
"the",
"avail-",
"ability",
"of",
"assays",
"that",
"provide",
"genotypes",
"for",
"50,000",
"or",
"more",
"markers",
"for",
"each",
"individual,",
"the",
"application",
"of",
"*",
"Correspondence:",
"john.bastiaansen@wur.nl",
"1Animal",
"Breeding",
"and",
"Genomics",
"Centre,",
"Wageningen",
"University,",
"Wageningen,",
"The",
"Netherlands",
"genomic",
"selection",
"has",
"started",
"to",
"take",
"hold",
"in",
"recent",
"years.",
"Especially",
"in",
"dairy",
"cattle",
"the",
"use",
"of",
"genomic",
"selec-",
"tion",
"is",
"becoming",
"common",
"practice",
"[5,6].",
"In",
"other",
"spe-",
"cies",
"the",
"application",
"of",
"genomic",
"selection",
"is",
"being",
"considered",
"or",
"evaluated",
"[7-9].",
"Methods",
"to",
"deal",
"with",
"these",
"large",
"number",
"of",
"markers",
"in",
"breeding",
"programs",
"were",
"first",
"proposed",
"by",
"[1]",
"after",
"which",
"a",
"number",
"of",
"alternatives",
"have",
"been",
"suggested;",
"e.g.",
"[10,11].",
"Most",
"methods",
"have",
"been",
"evaluated",
"in",
"simula-",
"tions",
"and",
"sometimes",
"on",
"real",
"data.",
"Analyses",
"applying",
"genomic",
"BLUP",
"methodology",
"as",
"defined",
"by",
"Meuwissen",
"et",
"al.[1],",
"or",
"applying",
"Ridge",
"Regression",
"(RR)",
"[12],",
"assume",
"©",
"2010",
"Bastiaansen",
"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."
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] | [
"Shi",
"et",
"al.",
"Journal",
"of",
"Cardiothoracic",
"Surgery",
"2012,",
"7:64",
"http://www.cardiothoracicsurgery.org/content/7/1/64",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"Open",
"Access",
"Rare",
"early",
"prosthesis",
"obstruction",
"after",
"mitral",
"valve",
"replacement:",
"a",
"case",
"report",
"and",
"literature",
"review",
"Jun",
"Shi,",
"Zhi-xuan",
"Bai,",
"Jia",
"Hu,",
"Ben-gui",
"Zhang",
"and",
"Ying-qiang",
"Guo*",
"Abstract",
"As",
"a",
"dreadful",
"complication",
"after",
"the",
"mechanical",
"heart",
"valve",
"replacement,",
"prosthetic",
"valve",
"obstruction",
"caused",
"by",
"pannus",
"formation",
"occurs",
"increasingly",
"with",
"time.",
"The",
"authors",
"here",
"present",
"a",
"case",
"of",
"42-year-old",
"woman",
"who",
"was",
"urgently",
"admitted",
"to",
"hospital",
"with",
"acute",
"heart",
"failure",
"symptoms",
"due",
"to",
"the",
"mechanical",
"mitral",
"valve",
"failure",
"only",
"3",
"months",
"after",
"surgery.",
"Transthoracic",
"and",
"transesophageal",
"echocardiography",
"demonstrated",
"that",
"the",
"bileaflet",
"of",
"the",
"mitral",
"prosthesis",
"were",
"completely",
"immobilized",
"with",
"only",
"a",
"small",
"transvalvular",
"jet",
"remained.",
"During",
"the",
"reoperation,",
"the",
"reason",
"of",
"the",
"prosthetic",
"valve",
"obstruction",
"was",
"attributed",
"to",
"the",
"noncircular",
"pannus",
"ingrowth",
"extending",
"from",
"the",
"atrioventricular",
"side.",
"For",
"a",
"better",
"understanding",
"of",
"the",
"prosthetic",
"valve",
"dysfunction",
"caused",
"by",
"pannus",
"formation,",
"the",
"authors",
"then",
"compile",
"a",
"literature",
"review",
"to",
"briefly",
"discuss",
"the",
"status",
"quo",
"of",
"the",
"clinical",
"characteristics",
"of",
"this",
"uncommon",
"complication.",
"Background",
"The",
"evolving",
"design",
"and",
"biomaterials",
"of",
"the",
"mechanical",
"heart",
"valves",
"have",
"greatly",
"advanced",
"their",
"in",
"vivo",
"hemodynamic",
"features",
"and",
"durability",
"over",
"decades",
"[1].",
"However,",
"the",
"anticipated",
"performances",
"of",
"the",
"mechan-",
"ical",
"prostheses",
"are",
"still",
"compromised",
"by",
"the",
"occurrence",
"of",
"various",
"complications,",
"among",
"which",
"pannus-induced",
"prosthetic",
"valve",
"dysfunction",
"(PVD)",
"is",
"relatively",
"uncom-",
"mon",
"but",
"sometimes",
"is",
"the",
"most",
"serious",
"one",
"[2,3].",
"In",
"par-",
"ticular,",
"patients",
"with",
"prosthetic",
"valve",
"obstruction",
"(PVO)",
"due",
"to",
"pannus",
"ingrowth",
"may",
"rapidly",
"develop",
"hemo-",
"dynamic",
"deterioration",
"and",
"crash",
"into",
"a",
"life-threatening",
"condition.",
"According",
"to",
"recent",
"studies",
"[2,4-7],",
"the",
"prevalence",
"of",
"pannus",
"formation",
"in",
"aortic",
"or",
"mit-",
"ral",
"position",
"is",
"controversial.",
"However,",
"pannus",
"is",
"un-",
"doubtedly",
"of",
"later",
"clinical",
"onset",
"than",
"the",
"thrombosis,",
"which",
"is",
"mostly",
"responsible",
"for",
"the",
"early",
"PVD.",
"More-",
"over,",
"the",
"duration",
"from",
"time",
"of",
"prostheses",
"implant-",
"ation",
"to",
"pannus-induced",
"PVD",
"is",
"widely",
"variable",
"and",
"has",
"been",
"reported",
"to",
"be",
"at",
"least",
"6",
"months",
"to",
"12",
"months,",
"during",
"which",
"an",
"ingrowth",
"of",
"periannular",
"tissue",
"would",
"gradually",
"immobilize",
"the",
"moving",
"element",
"of",
"the",
"prostheses",
"[6-8].",
"Here",
"we",
"present",
"a",
"rare",
"case",
"*",
"Correspondence:",
"drguoyq@hotmail.com",
"Department",
"of",
"Cardiovascular",
"Surgery,",
"West",
"China",
"Hospital,",
"Sichuan",
"University,",
"Cheng",
"Du,",
"People’s",
"Republic",
"of",
"China",
"of",
"PVO",
"in",
"the",
"mitral",
"position",
"caused",
"by",
"early",
"pannus",
"formation",
"only",
"3",
"months",
"after",
"surgery.",
"Case",
"presentation",
"A",
"42-year-old",
"woman",
"was",
"admitted",
"to",
"our",
"intensive",
"car-",
"diac",
"care",
"unit",
"with",
"symptoms",
"of",
"acute",
"left",
"heart",
"failure.",
"Three",
"months",
"prior",
"to",
"admission,",
"she",
"underwent",
"the",
"implantation",
"of",
"a",
"mechanical",
"bileaflet",
"mitral",
"valve",
"(25",
"mm",
"SJM",
"Master;",
"St.",
"Paul,",
"MN,",
"USA)",
"due",
"to",
"severe",
"rheumatic",
"valve",
"stenosis.",
"No",
"native",
"valve-",
"or",
"chordal-",
"sparing",
"procedures",
"were",
"performed",
"during",
"the",
"replace-",
"ment.",
"The",
"postoperative",
"course",
"went",
"smoothly",
"and",
"transthoracic",
"echocardiography",
"(TTE)",
"showed",
"proper",
"functioning",
"of",
"the",
"prosthesis.",
"The",
"patient",
"then",
"followed",
"adequate",
"anticoagulation",
"treatment",
"with",
"wafarin",
"and",
"the",
"international",
"normalized",
"ratio",
"maintained",
"above",
"2.0.",
"No",
"episode",
"of",
"atrial",
"fibrillation",
"and",
"other",
"risk",
"factors",
"for",
"thrombus",
"formation",
"were",
"identified.",
"One",
"week",
"before",
"this",
"admission,",
"she",
"had",
"noticed",
"a",
"progressive",
"physical",
"deterioration.",
"After",
"the",
"treatment",
"at",
"local",
"hospital,",
"the",
"patient",
"showed",
"no",
"signs",
"of",
"recovery",
"and",
"finally",
"pre-",
"sented",
"with",
"severe",
"shortness",
"of",
"breath",
"and",
"coughing",
"up",
"pink,",
"foamy",
"mucus",
"on",
"the",
"arrival",
"of",
"our",
"hospital.",
"On",
"admission,",
"the",
"patient",
"was",
"conscious",
"but",
"presented",
"with",
"marked",
"respiratory",
"distress.",
"Initial",
"vital",
"signs",
"showed",
"blood",
"pressure",
"80/40",
"mmHg,",
"sinus",
"rhythm,",
"a",
"regular",
"pulse",
"of",
"140",
"beats/min",
"and",
"a",
"respiratory",
"rate",
"of",
"40",
"breaths/min.",
"Auscultation",
"of",
"the",
"chest",
"revealed",
"©",
"2012",
"Shi",
"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."
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] | [
"CELLULAR",
"AND",
"INFECTION",
"MICROBIOLOGY",
"The",
"influence",
"of",
"early",
"neutrophil-Leishmania",
"interactions",
"on",
"the",
"host",
"immune",
"response",
"to",
"infection",
"Flavia",
"L.",
"Ribeiro-Gomes",
"and",
"David",
"Sacks*",
"Laboratory",
"of",
"Parasitic",
"Diseases,",
"National",
"Institute",
"of",
"Allergy",
"and",
"Infectious",
"Diseases,",
"National",
"Institutes",
"of",
"Health,",
"Bethesda,",
"MD,",
"USA",
"REVIEW",
"ARTICLE",
"published:",
"04",
"May",
"2012",
"doi:",
"10.3389/fcimb.2012.00059",
"Edited",
"by:",
"Stephen",
"M.",
"Beverley,",
"Washington",
"University",
"in",
"St.",
"Louis,",
"USA",
"Reviewed",
"by:",
"Jordi",
"Torrelles,",
"Ohio",
"State",
"University,",
"USA",
"Michael",
"L.",
"Vasil,",
"University",
"of",
"Colorado",
"Medical",
"School,",
"USA",
"*Correspondence:",
"David",
"Sacks,",
"Laboratory",
"of",
"Parasitic",
"Diseases,",
"National",
"Institute",
"of",
"Allergy",
"and",
"Infectious",
"Diseases,",
"National",
"Institutes",
"of",
"Health,",
"4",
"Center",
"Dr.",
"MSC",
"0425,",
"Bethesda,",
"MD",
"20892-0425,",
"USA.",
"e-mail:",
"dsacks@nih.gov",
"Neutrophils",
"are",
"the",
"first",
"cells",
"recruited",
"to",
"the",
"dermal",
"site",
"of",
"Leishmania",
"infection",
"following",
"injection",
"by",
"needle",
"or",
"sand",
"fly",
"bite.",
"The",
"role",
"of",
"neutrophils",
"in",
"either",
"promoting",
"or",
"suppressing",
"host",
"immunity",
"remains",
"controversial.",
"We",
"discuss",
"the",
"events",
"driving",
"neutrophil",
"recruitment,",
"their",
"interaction",
"with",
"the",
"parasite",
"and",
"apoptotic",
"fate,",
"and",
"the",
"nature",
"of",
"their",
"encounters",
"with",
"other",
"innate",
"cells.",
"We",
"suggest",
"that",
"the",
"influence",
"of",
"the",
"neutrophil",
"response",
"on",
"infection",
"outcome",
"critically",
"depends",
"on",
"the",
"timing",
"of",
"their",
"recruitment",
"and",
"the",
"tissue",
"environment",
"in",
"which",
"it",
"occurs.",
"Keywords:",
"neutrophils,",
"Leishmania,",
"inflammation,",
"immune",
"response,",
"sand",
"fly,",
"apoptosis,",
"dendritic",
"cells,",
"macrophages",
"Neutrophils",
"are",
"readily",
"mobilized",
"innate",
"immune",
"cells",
"and",
"essen-",
"tial",
"for",
"host",
"defense",
"against",
"a",
"variety",
"of",
"pathogens",
"(Kobayashi",
"and",
"DeLeo,",
"2009).",
"Patients",
"with",
"severe",
"neutropenia",
"or",
"chronic",
"granulomatous",
"disease",
"(CGD)",
"suffer",
"a",
"wide",
"range",
"of",
"microbial",
"infections",
"(Vento",
"and",
"Cainelli,",
"2003;",
"Segal,",
"2005).",
"Neutrophils",
"are",
"also",
"recruited",
"during",
"acute",
"sterile",
"inflammation",
"where",
"they",
"con-",
"tribute",
"to",
"tissue",
"repair",
"(Kim",
"et",
"al.,",
"2006;",
"McDonald",
"et",
"al.,",
"2010).",
"Given",
"their",
"potent",
"arsenal",
"of",
"constituents",
"used",
"for",
"host",
"defense,",
"including",
"reactive",
"oxygen",
"species",
"(ROS),",
"antimicrobial",
"peptides,",
"and",
"serine",
"proteases,",
"the",
"resolution",
"of",
"inflammation",
"requires",
"that",
"dying",
"neutrophils",
"are",
"removed",
"from",
"the",
"inflammatory",
"site",
"by",
"other",
"phagocytic",
"cells,",
"such",
"as",
"macrophages",
"and",
"dendritic",
"cells",
"(DCs),",
"to",
"avoid",
"their",
"uncontrolled",
"release",
"of",
"injurious",
"con-",
"tents",
"(Segal,",
"2005).",
"It",
"is",
"not",
"surprising",
"that",
"any",
"imbalance",
"in",
"the",
"recruitment",
"and",
"removal",
"of",
"these",
"cells",
"is",
"associated",
"with",
"numer-",
"ous",
"pathologies,",
"including",
"chronic",
"infections",
"and",
"inflammatory",
"disorders",
"(Kono",
"and",
"Rock,",
"2008).",
"Leishmaniasis",
"is",
"a",
"vector-borne",
"disease",
"caused",
"by",
"the",
"intra-",
"cellular",
"protozoan",
"Leishmania.",
"There",
"are",
"an",
"estimated",
"2",
"million",
"new",
"cases",
"annually",
"(1.5",
"million",
"cases",
"of",
"cutaneous",
"leishmaniasis",
"and",
"500,000",
"cases",
"of",
"visceral",
"leishmaniasis),",
"with",
"about",
"12",
"million",
"people",
"currently",
"infected",
"(www.who.int/leishmaniasis/burden).",
"For",
"each",
"Leishmania",
"species",
"studied,",
"neutrophils",
"have",
"been",
"found",
"recruited",
"to",
"the",
"infection",
"site",
"following",
"the",
"delivery",
"of",
"parasites",
"by",
"sand",
"fly",
"bite",
"or",
"by",
"needle",
"injection",
"(Beil",
"et",
"al.,",
"1992;",
"Tacchini-",
"Cottier",
"et",
"al.,",
"2000;",
"Peters",
"et",
"al.,",
"2008;",
"Thalhofer",
"et",
"al.,",
"2011;",
"Ribeiro-Gomes",
"et",
"al.,",
"2012).",
"Numerous",
"in",
"vitro",
"and",
"in",
"vivo",
"stud-",
"ies",
"have",
"been",
"carried",
"out",
"to",
"understand",
"the",
"role",
"of",
"neutrophils",
"in",
"host",
"defense",
"against",
"Leishmaniasis",
"(Tacchini-Cottier",
"et",
"al.,",
"2000;",
"Ribeiro-Gomes",
"et",
"al.,",
"2004,",
"2007;",
"Peters",
"et",
"al.,",
"2008,",
"2009;",
"Charmoy",
"et",
"al.,",
"2010a,b;",
"Filardy",
"et",
"al.,",
"2010).",
"Because",
"of",
"the",
"het-",
"erogeneity",
"of",
"these",
"studies",
"in",
"terms",
"of",
"host",
"species",
"and",
"mouse",
"strain",
"(human,",
"dog,",
"susceptible,",
"or",
"resistant",
"mice),",
"the",
"tissue",
"source",
"and",
"site",
"of",
"recruitment",
"(blood,",
"peritoneum,",
"skin),",
"and",
"the",
"time",
"frame",
"of",
"the",
"recruitment",
"(hours,",
"days,",
"weeks)",
"the",
"impact",
"of",
"the",
"neutrophilic",
"response",
"on",
"promoting",
"host",
"resistance",
"or",
"suscep-",
"tibility",
"to",
"Leishmania",
"infection",
"remains",
"a",
"matter",
"of",
"some",
"debate.",
"In",
"keeping",
"with",
"the",
"theme",
"of",
"this",
"volume,",
"this",
"review",
"will",
"focus",
"on",
"the",
"early",
"events",
"driving",
"neutrophil",
"recruitment,",
"and",
"their",
"fate",
"and",
"immunologic",
"consequences",
"following",
"Leishmania",
"infection",
"initiated",
"by",
"the",
"bite",
"of",
"an",
"infected",
"sand",
"fly",
"or",
"needle",
"inoculation",
"in",
"the",
"skin.",
"RECRUITMENT",
"The",
"first",
"observations",
"concerning",
"the",
"early",
"recruitment",
"of",
"neu-",
"trophils",
"to",
"the",
"site",
"of",
"Leishmania",
"infection",
"were",
"made",
"by",
"Wilson",
"et",
"al.",
"(1987),",
"who",
"described",
"a",
"mixed",
"neutrophil",
"and",
"mono-",
"cytic",
"infiltrate",
"within",
"1",
"h",
"following",
"intra-dermal",
"inoculation",
"of",
"L.",
"donovani",
"promastigotes",
"in",
"hamsters,",
"and",
"by",
"Pompeu",
"et",
"al.",
"(1991)",
"and",
"Beil",
"et",
"al.",
"(1992),",
"who",
"described",
"the",
"predominant",
"neutrophilic",
"infiltrate",
"within",
"3",
"h",
"following",
"high",
"dose",
"subcu-",
"taneous",
"inoculation",
"of",
"Leishmania",
"amazonensis",
"or",
"Leishmania",
"major",
"promastigotes,",
"respectively,",
"into",
"the",
"footpad",
"of",
"BALB/c",
"or",
"C57Bl/6",
"mice.",
"Studies",
"by",
"the",
"group",
"of",
"Laskay",
"confirmed",
"that",
"neu-",
"trophils",
"were",
"the",
"first",
"leukocyte",
"population",
"migrating",
"to",
"the",
"site",
"of",
"L.",
"major",
"infection",
"in",
"the",
"footpad",
"(Muller",
"et",
"al.,",
"2001).",
"These",
"findings",
"have",
"more",
"recently",
"been",
"extended",
"to",
"the",
"ear",
"dermal",
"inoc-",
"ulation",
"site",
"employing",
"L.",
"major",
"(Peters",
"et",
"al.,",
"2008;",
"Charmoy",
"et",
"al.,",
"2010a,b;",
"Ribeiro-Gomes",
"et",
"al.,",
"2012)",
"or",
"L.",
"infantum",
"(Thalhofer",
"et",
"al.,",
"2011).",
"A",
"recent",
"paper",
"suggests",
"that",
"the",
"kinet-",
"ics",
"of",
"myeloid",
"cell",
"recruitment",
"to",
"the",
"L.",
"major",
"injection",
"site",
"might",
"be",
"tissue",
"specific,",
"as",
"neutrophil",
"recruitment",
"into",
"the",
"peritoneal",
"cavity",
"following",
"i.p.",
"injection",
"of",
"L.",
"major",
"was",
"preceded",
"at",
"30",
"min",
"by",
"GR-1+",
"monocytes",
"(Goncalves",
"et",
"al.,",
"2011).",
"Our",
"own",
"stud-",
"ies",
"used",
"two-photon",
"intra-vital",
"microscopy",
"(2P-IVM)",
"to",
"confirm",
"that",
"neutrophils",
"are",
"the",
"first",
"cells",
"to",
"infiltrate",
"(within",
"30",
"min.)",
"Frontiers",
"in",
"Cellular",
"and",
"Infection",
"Microbiology",
"www.frontiersin.org",
"May",
"2012",
"|",
"Volume",
"2",
"|",
"Article",
"59",
"|",
"1"
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"Journal",
"of",
"Chiropractic",
"Humanities",
"(2009)",
"16,",
"1–4",
"Editorial",
"A",
"brief",
"review",
"of",
"the",
"evolution",
"of",
"the",
"Journal",
"of",
"Chiropractic",
"Humanities:",
"a",
"journey",
"beginning",
"in",
"1991",
"Claire",
"Johnson",
"DC,",
"MSEd⁎",
"Professor,",
"National",
"University",
"of",
"Health",
"Sciences,",
"Lombard,",
"IL",
"Editor,",
"Journal",
"of",
"Chiropractic",
"Humanities",
"Abstract",
"This",
"article",
"provides",
"a",
"brief",
"review",
"of",
"the",
"history",
"and",
"origins",
"of",
"the",
"Journal",
"of",
"Chiropractic",
"Humanities.",
"The",
"reason",
"for",
"starting",
"the",
"journal,",
"its",
"purpose,",
"and",
"a",
"timeline",
"from",
"1991",
"to",
"2009",
"are",
"offered.",
"©",
"2009",
"National",
"University",
"of",
"Health",
"Sciences.",
"During",
"the",
"birth",
"of",
"most",
"new",
"journals,",
"hopes",
"are",
"high",
"but",
"the",
"future",
"is",
"uncertain.",
"Success",
"of",
"a",
"peer-reviewed",
"journal",
"requires",
"many",
"factors.",
"Interest",
"and",
"support",
"from",
"the",
"readers,",
"funding",
"for",
"publication,",
"authors",
"submitting",
"meaningful",
"articles,",
"a",
"willing",
"publishing",
"company,",
"indexing",
"systems",
"to",
"include",
"the",
"journal,",
"and",
"an",
"infrastructure",
"to",
"provide",
"the",
"editorial",
"and",
"peer-review",
"process",
"are",
"all",
"necessary",
"to",
"ensure",
"a",
"journal’s",
"success.",
"In",
"the",
"early",
"years",
"of",
"chiropractic,",
"the",
"call",
"for",
"scholarly",
"publication,",
"more",
"legitimate",
"scientific",
"research,",
"and",
"intellectual",
"honesty",
"had",
"been",
"demanded",
"by",
"a",
"few",
"outspoken",
"members",
"of",
"the",
"profession.",
"However,",
"little",
"was",
"done",
"in",
"the",
"first",
"several",
"chiropractic",
"decades.",
"Watkins",
"criticized",
"chiropractic",
"leaders",
"for",
"their",
"misuse",
"and",
"misunderstanding",
"of",
"the",
"term",
"philosophy.",
"Instead",
"of",
"true",
"philosophy",
"they",
"were",
"actually",
"promoting",
"dogma.",
"In",
"1944,",
"Watkins",
"stated,",
"“Many",
"of",
"the",
"old",
"‘philosophical’",
"leaders",
"feel",
"that",
"chiropractic",
"is",
"doomed",
"to",
"failure",
"as",
"a",
"‘healing",
"movement’",
"because",
"in",
"their",
"opinion",
"the",
"average",
"⁎",
"200",
"E.",
"Roosevelt",
"Rd.,",
"Lombard,",
"IL",
"60148.",
"E-mail",
"address:",
"cjohnson@nuhs.edu.",
"1556-3499/$",
"–",
"see",
"front",
"matter",
"©",
"2009",
"National",
"University",
"of",
"Health",
"Sciences.",
"doi:10.1016/j.echu.2010.02.001",
"chiropractor",
"has",
"‘lost",
"the",
"faith’",
"and",
"no",
"longer",
"fervently",
"propounds",
"the",
"doctrine,",
"that",
"he",
"has",
"wandered",
"astray",
"in",
"his",
"therapy,",
"and",
"that",
"he",
"has",
"not",
"kept",
"chiropractic",
"pure",
"so",
"that",
"it",
"may",
"be",
"preserved",
"for",
"posterity.",
"In",
"other",
"words",
"the",
"‘philosophical’",
"leaders",
"regard",
"chiropractic",
"as",
"being",
"based",
"upon",
"doctrine",
"rather",
"than",
"upon",
"science.”1",
"Keating",
"et",
"al",
"suggested",
"that",
"those",
"in",
"the",
"chiropractic",
"profession",
"looked",
"to",
"medicine’s",
"cultural",
"success",
"due",
"to",
"its",
"scientific",
"base",
"as",
"a",
"motivator",
"for",
"becoming",
"more",
"scientific.2",
"The",
"authors",
"found",
"that",
"although",
"the",
"terms",
"research",
"and",
"science",
"were",
"used",
"in",
"chiropractic",
"publications,",
"these",
"terms",
"were",
"often",
"applied",
"to",
"marketing",
"strategies",
"and",
"only",
"rarely",
"used",
"correctly.",
"Though",
"there",
"seemed",
"to",
"be",
"a",
"desire",
"for",
"legitimate",
"research",
"and",
"philosophical",
"discus-",
"sion,",
"little",
"evidence",
"for",
"these",
"were",
"found",
"in",
"the",
"first",
"half",
"of",
"the",
"chiropractic",
"century.",
"Demand",
"for",
"more",
"chiropractic",
"science,",
"research,",
"and",
"publication",
"grew.",
"Between",
"1970",
"and",
"1990,",
"there",
"was",
"an",
"increased",
"interest",
"in",
"creating",
"new",
"scientific",
"and",
"scholarly",
"journals",
"for",
"the",
"chiropractic",
"profession.",
"Some",
"in",
"the",
"profession",
"recognized",
"a",
"need",
"for",
"chiropractic",
"to",
"legitimize",
"itself",
"with",
"research",
"but",
"few",
"had",
"the",
"training"
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] | [
"Zabolotneva",
"et",
"al.",
"Biology",
"Direct",
"2010,",
"5:62",
"http://www.biology-direct.com/content/5/1/62",
"H",
"Y",
"P",
"O",
"T",
"H",
"E",
"S",
"I",
"S",
"Open",
"Access",
"How",
"many",
"antiviral",
"small",
"interfering",
"RNAs",
"may",
"be",
"encoded",
"by",
"the",
"mammalian",
"genomes?",
"Anastasia",
"Zabolotneva1,",
"Victor",
"Tkachev2,",
"Felix",
"Filatov3,",
"Anton",
"Buzdin1*",
"Abstract",
"Background:",
"The",
"discovery",
"of",
"RNA",
"interference",
"phenomenon",
"(RNAi)",
"and",
"understanding",
"of",
"its",
"mechanisms",
"has",
"revolutionized",
"our",
"views",
"on",
"many",
"molecular",
"processes",
"in",
"the",
"living",
"cell.",
"Among",
"the",
"other,",
"RNAi",
"is",
"involved",
"in",
"silencing",
"of",
"transposable",
"elements",
"and",
"in",
"inhibition",
"of",
"virus",
"infection",
"in",
"various",
"eukaryotic",
"organisms.",
"Recent",
"experimental",
"studies",
"demonstrate",
"few",
"cases",
"of",
"viral",
"replication",
"suppression",
"via",
"complementary",
"interactions",
"between",
"the",
"mammalian",
"small",
"RNAs",
"and",
"viral",
"transcripts.",
"Presentation",
"of",
"the",
"hypothesis:",
"It",
"was",
"found",
"that",
">50%",
"of",
"the",
"human",
"genome",
"is",
"transcribed",
"in",
"different",
"cell",
"types",
"and",
"that",
"these",
"transcripts",
"are",
"mainly",
"not",
"associated",
"with",
"known",
"protein",
"coding",
"genes,",
"but",
"represent",
"non-",
"coding",
"RNAs",
"of",
"unknown",
"functions.",
"We",
"propose",
"a",
"hypothesis",
"that",
"mammalian",
"DNAs",
"encode",
"thousands",
"RNA",
"motifs",
"that",
"may",
"serve",
"for",
"antiviral",
"protection.",
"We",
"also",
"presume",
"that",
"the",
"evolutional",
"success",
"of",
"some",
"groups",
"of",
"genomic",
"repeats",
"and,",
"in",
"particular,",
"of",
"transposable",
"elements",
"(TEs)",
"may",
"be",
"due",
"to",
"their",
"ability",
"to",
"provide",
"antiviral",
"RNA",
"motifs",
"to",
"the",
"host",
"organism.",
"Intense",
"genomic",
"repeat",
"propagation",
"into",
"the",
"genome",
"would",
"inevitably",
"cause",
"bidirectional",
"transcription",
"of",
"these",
"sequences,",
"and",
"the",
"resulting",
"double-stranded",
"RNAs",
"may",
"be",
"recognized",
"and",
"processed",
"by",
"the",
"RNA",
"interference",
"enzymatic",
"machinery.",
"Provided",
"that",
"these",
"processed",
"target",
"motifs",
"may",
"be",
"complementary",
"to",
"viral",
"transcripts,",
"fixation",
"of",
"the",
"repeats",
"into",
"the",
"host",
"genome",
"may",
"be",
"of",
"a",
"considerable",
"benefit",
"to",
"the",
"host.",
"It",
"fits",
"with",
"our",
"bioinformatical",
"data",
"revealing",
"thousands",
"of",
"21-28",
"bp",
"long",
"motifs",
"identical",
"between",
"human",
"DNA",
"and",
"human-pathogenic",
"adenoviral",
"and",
"herpesviral",
"genomes.",
"Many",
"of",
"these",
"motifs",
"are",
"transcribed",
"in",
"human",
"cells,",
"and",
"the",
"transcribed",
"part",
"grows",
"proportionally",
"to",
"their",
"lengths.",
"Many",
"such",
"motifs",
"are",
"included",
"in",
"human",
"TEs.",
"For",
"example,",
"one",
"23",
"nt-long",
"motif",
"that",
"is",
"a",
"part",
"of",
"human",
"abundant",
"Alu",
"retrotransposon,",
"shares",
"sequence",
"identity",
"with",
"eight",
"human",
"adenoviral",
"genomes.",
"Testing",
"the",
"hypothesis:",
"This",
"hypothesis",
"could",
"be",
"tested",
"on",
"various",
"mammalian",
"species",
"and",
"viruses",
"infecting",
"mammalian",
"cells.",
"Implications",
"of",
"the",
"hypothesis:",
"This",
"hypothesis",
"proposes",
"that",
"mammalian",
"organisms",
"may",
"use",
"their",
"own",
"genomes",
"as",
"sources",
"of",
"thousands",
"of",
"putative",
"interfering",
"RNA",
"motifs",
"that",
"can",
"be",
"recruited",
"to",
"repress",
"intracellular",
"pathogens",
"like",
"proliferating",
"viruses.",
"Reviewers:",
"This",
"article",
"was",
"reviewed",
"by",
"Eugene",
"V.",
"Koonin,",
"Valerian",
"V.",
"Dolja",
"and",
"Yuri",
"V.",
"Shpakovski.",
"Background",
"The",
"discovery",
"of",
"RNA",
"interference",
"(RNAi)",
"and",
"under-",
"standing",
"of",
"its",
"mechanisms",
"has",
"opened",
"a",
"new",
"era",
"in",
"molecular",
"genetics.",
"It",
"is",
"now",
"clear",
"that",
"very",
"small",
"com-",
"plementary",
"RNAs",
"may",
"modulate",
"expression",
"of",
"large",
"genes.",
"RNAi",
"and",
"related",
"mechanisms",
"may",
"interfere",
"with",
"gene",
"expression",
"at",
"the",
"stages",
"of",
"transcription,",
"processing",
"*",
"Correspondence:",
"bu3din@mail.ru",
"1Shemyakin-Ovchinnikov",
"Institute",
"of",
"Bioorganic",
"Chemistry,",
"Russian",
"Academy",
"of",
"Sciences,",
"16/10",
"Miklukho-Maklaya",
"st,",
"Moscow",
"117997,",
"Russia",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"of",
"mRNA",
"and",
"translation",
"[1,2].",
"They",
"may",
"alter",
"tran-",
"script",
"stability",
"and",
"may",
"even",
"cause",
"methylation",
"of",
"extended",
"genomic",
"loci",
"[3,4].",
"RNAi",
"is",
"a",
"very",
"conservative",
"mechanism",
"that",
"is",
"likely",
"to",
"be",
"active",
"in",
"almost",
"all",
"eukar-",
"yotic",
"taxa.",
"This",
"phenomenon",
"attracts",
"growing",
"attention",
"and",
"studying",
"RNA",
"interference",
"is",
"probably",
"one",
"of",
"the",
"most",
"rapidly",
"developing",
"fields",
"of",
"modern",
"science.",
"Known",
"RNAi",
"pathways",
"are",
"very",
"diverse",
"[2]",
"and",
"many",
"new",
"mechanisms",
"are",
"probably",
"still",
"to",
"be",
"discovered",
"[5].",
"A",
"fundamental",
"step",
"of",
"RNAi",
"is",
"the",
"basepairing",
"of",
"the",
"two",
"interacting",
"RNAs.",
"The",
"resulting",
"duplexes,",
"that",
"may",
"©",
"2010",
"Zabolotneva",
"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."
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] | [
"Daneault",
"et",
"al.",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2011,",
"5:449",
"http://www.jmedicalcasereports.com/content/5/1/449",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"JOURNAL",
"OF",
"MEDICAL",
"CASE",
"REPORTS",
"Open",
"Access",
"Changes",
"in",
"physiological",
"tremor",
"associated",
"with",
"an",
"epileptic",
"seizure:",
"a",
"case",
"report",
"Jean-François",
"Daneault1,",
"Benoit",
"Carignan2,",
"Maxime",
"Robert3",
"and",
"Christian",
"Duval3*",
"Abstract",
"Introduction:",
"Epileptic",
"seizures",
"are",
"associated",
"with",
"motor,",
"sensory,",
"somatosensory",
"or",
"autonomic",
"symptoms",
"that",
"have",
"all",
"been",
"described",
"in",
"varying",
"detail",
"over",
"the",
"years.",
"Of",
"interest",
"in",
"the",
"present",
"report",
"is",
"a",
"case",
"of",
"normal",
"physiological",
"tremor,",
"which",
"to",
"date",
"has",
"never",
"been",
"evaluated",
"prior",
"to",
"and",
"during",
"an",
"epileptic",
"seizure.",
"In",
"fact,",
"there",
"is",
"only",
"anecdotal",
"mention",
"of",
"pre-ictal",
"and",
"ictal",
"changes",
"in",
"clinically",
"noticeable",
"tremor",
"in",
"the",
"literature.",
"Case",
"presentation:",
"Our",
"patient",
"was",
"a",
"left-handed,",
"27-year-old",
"Caucasian",
"woman",
"diagnosed",
"seven",
"years",
"previously",
"with",
"partial",
"epileptic",
"seizures,",
"secondarily",
"generalized.",
"Physiological",
"tremor",
"was",
"measured",
"simultaneously",
"on",
"the",
"index",
"finger",
"of",
"both",
"hands",
"of",
"our",
"patient.",
"Electromyography",
"as",
"well",
"as",
"heart",
"rate",
"and",
"respiration",
"were",
"also",
"monitored.",
"A",
"previously",
"performed",
"electroencephalography",
"examination",
"revealed",
"abnormal",
"oscillations",
"focalized",
"to",
"the",
"left",
"primary",
"somatosensory",
"cortex.",
"She",
"was",
"also",
"diagnosed",
"with",
"left",
"frontal",
"neuronal",
"heterotopias.",
"We",
"detected",
"subclinical",
"changes",
"in",
"tremor",
"characteristics,",
"such",
"as",
"amplitude,",
"median",
"power",
"frequency",
"and",
"power",
"dispersion,",
"contralateral",
"to",
"the",
"localization",
"of",
"epileptic",
"activity.",
"Tremor",
"characteristics",
"remained",
"relatively",
"steady",
"ipsilateral",
"to",
"the",
"localization",
"of",
"the",
"epileptic",
"activity.",
"Conclusions:",
"Changes",
"in",
"physiological",
"tremor",
"characteristics",
"should",
"be",
"considered",
"as",
"another",
"possible",
"pre-ictal",
"or",
"ictal",
"manifestation.",
"We",
"propose",
"that",
"the",
"network",
"associated",
"with",
"physiological",
"tremor",
"might",
"be",
"more",
"sensitive",
"to",
"abnormal",
"oscillations",
"generated",
"within",
"the",
"central",
"nervous",
"system",
"by",
"epileptic",
"activity",
"from",
"certain",
"structures.",
"Introduction",
"Epilepsy",
"is",
"characterized",
"by",
"a",
"predisposition",
"to",
"abnor-",
"mal",
"brain",
"activity",
"leading",
"to",
"seizures,",
"as",
"well",
"as",
"motor",
"and",
"non-motor",
"symptoms",
"[1].",
"In",
"addition",
"to",
"motor,",
"sensory,",
"somatosensory",
"or",
"autonomic",
"symptoms",
"that",
"can",
"be",
"encountered",
"during",
"the",
"ictal",
"phase",
"[2],",
"physiolo-",
"gical",
"changes",
"have",
"also",
"been",
"observed",
"in",
"the",
"pre-ictal",
"phase.",
"In",
"some",
"cases",
"heart",
"rate",
"variability",
"has",
"been",
"shown",
"to",
"increase",
"in",
"the",
"minutes",
"prior",
"to",
"the",
"clinical",
"onset",
"of",
"seizures",
"[3].",
"There",
"is",
"also",
"anecdotal",
"mention",
"of",
"pre-ictal",
"and",
"ictal",
"changes",
"in",
"clinically",
"noticeable",
"tremor",
"[4].",
"These",
"manifestations",
"are",
"intimately",
"linked",
"to",
"the",
"localization",
"of",
"the",
"seizure",
"activity.",
"In",
"this",
"report,",
"we",
"describe",
"the",
"case",
"of",
"an",
"epileptic",
"patient",
"who",
"had",
"a",
"sei-",
"zure",
"while",
"physiological",
"tremor",
"(PT)",
"was",
"being",
"recorded.",
"PT",
"is",
"commonly",
"described",
"as",
"involuntary",
"rhythmical",
"oscillations",
"with",
"sinusoidal",
"properties.",
"These",
"*",
"Correspondence:",
"duval.christian@uqam.ca",
"3Département",
"de",
"Kinanthropologie,",
"Université",
"du",
"Québec",
"à",
"Montréal,",
"Montréal,",
"Québec,",
"Canada",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"low-amplitude",
"oscillations,",
"normally",
"less",
"than",
"0.5",
"mm",
"[5],",
"stem",
"from",
"mechanical",
"properties",
"of",
"the",
"limb",
"[6]",
"as",
"well",
"as",
"possible",
"central",
"oscillators",
"[7].",
"The",
"characteris-",
"tics",
"of",
"PT",
"have",
"been",
"extensively",
"studied",
"by",
"our",
"group",
"[8,9]",
"and",
"others",
"(see",
"[10]",
"for",
"review).",
"Case",
"presentation",
"Our",
"patient",
"was",
"tested",
"as",
"part",
"of",
"a",
"study",
"on",
"bilateral",
"PT",
"[8].",
"She",
"signed",
"the",
"institutionally",
"approved",
"informed",
"consent",
"form,",
"but",
"omitted",
"to",
"inform",
"us",
"of",
"her",
"condition",
"prior",
"to",
"testing.",
"Detailed",
"procedures",
"for",
"that",
"study",
"can",
"be",
"found",
"in",
"the",
"published",
"work",
"[8],",
"and",
"are",
"described",
"in",
"brief",
"below.",
"A",
"medical",
"history",
"for",
"our",
"patient",
"was",
"gath-",
"ered",
"from",
"her",
"medical",
"records.",
"She",
"was",
"a",
"left-handed,",
"27-year-old",
"Caucasian",
"woman",
"who",
"had",
"been",
"diagnosed",
"seven",
"years",
"previously",
"with",
"partial",
"epileptic",
"seizures,",
"secondarily",
"generalized.",
"Her",
"medical",
"records",
"also",
"described",
"abnormal",
"electroencephalography",
"(EEG)",
"oscil-",
"lations",
"focalized",
"to",
"the",
"left",
"primary",
"somatosensory",
"cor-",
"tex.",
"She",
"was",
"also",
"diagnosed",
"with",
"left",
"frontal",
"neuronal",
"heterotopias.",
"Since",
"her",
"diagnosis,",
"her",
"symptoms",
"had",
"©",
"2011",
"Daneault",
"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."
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"de",
"Lacey2,",
"Michael",
"Chapman3,",
"Julie",
"Ratcliffe4,",
"Robert",
"J",
"Norman5,",
"Neil",
"Johnson6,",
"Gavin",
"Sacks7,",
"Jane",
"Lyttleton8",
"and",
"Clare",
"Boothroyd9",
"Abstract",
"Background:",
"IVF",
"is",
"a",
"costly",
"treatment",
"option",
"for",
"women,",
"their",
"partners,",
"and",
"the",
"public.",
"Therefore",
"new",
"therapies",
"that",
"improve",
"reproductive",
"and",
"health",
"outcomes",
"are",
"highly",
"desirable.",
"There",
"is",
"a",
"growing",
"body",
"of",
"research",
"evaluating",
"the",
"effect",
"of",
"acupuncture",
"administered",
"during",
"IVF,",
"and",
"specifically",
"on",
"the",
"day",
"of",
"embryo",
"transfer",
"(ET).",
"Many",
"trials",
"are",
"heterogeneous",
"and",
"results",
"inconsistent.",
"There",
"remains",
"insufficient",
"evidence",
"to",
"determine",
"if",
"acupuncture",
"can",
"enhance",
"live",
"birth",
"rates",
"when",
"used",
"as",
"an",
"adjunct",
"to",
"IVF",
"treatment.",
"The",
"study",
"will",
"determine",
"the",
"clinical",
"effectiveness",
"of",
"acupuncture",
"with",
"improving",
"the",
"proportion",
"of",
"women",
"undergoing",
"IVF",
"having",
"live",
"births.",
"Other",
"objectives",
"include:",
"determination",
"of",
"the",
"cost",
"effectiveness",
"of",
"IVF",
"with",
"acupuncture;",
"and",
"examination",
"of",
"the",
"personal",
"and",
"social",
"context",
"of",
"acupuncture",
"in",
"IVF",
"patients,",
"and",
"examining",
"the",
"reasons",
"why",
"the",
"acupuncture",
"may",
"or",
"may",
"not",
"have",
"worked.",
"Methods:",
"We",
"will",
"conduct",
"a",
"randomized",
"controlled",
"trial",
"of",
"acupuncture",
"compared",
"to",
"placebo",
"acupuncture.",
"Inclusion",
"criteria",
"include:",
"women",
"aged",
"less",
"than",
"43",
"years;",
"undergoing",
"a",
"fresh",
"IVF",
"or",
"ICSI",
"cycle;",
"and",
"restricted",
"to",
"women",
"with",
"the",
"potential",
"for",
"a",
"lower",
"live",
"birth",
"rate",
"defined",
"as",
"two",
"or",
"more",
"previous",
"unsuccessful",
"ETs;",
"and",
"unsuccessful",
"clinical",
"pregnancies",
"of",
"quality",
"embryos",
"deemed",
"by",
"the",
"embryologist",
"to",
"have",
"been",
"suitable",
"for",
"freezing",
"by",
"standard",
"criteria.",
"Women",
"will",
"be",
"randomized",
"to",
"acupuncture",
"or",
"placebo",
"acupuncture.",
"Treatment",
"is",
"administered",
"on",
"days",
"6",
"to",
"8",
"of",
"the",
"stimulated",
"cycle",
"and",
"two",
"treatments",
"on",
"the",
"day",
"of",
"ET.",
"A",
"non-randomized",
"cohort",
"of",
"women",
"not",
"using",
"acupuncture",
"will",
"be",
"recruited",
"to",
"the",
"study.",
"The",
"primary",
"study",
"outcome",
"is",
"the",
"proportion",
"of",
"women",
"reporting",
"a",
"live",
"birth.",
"Secondary",
"outcomes",
"include",
"the",
"proportion",
"of",
"women",
"reporting",
"a",
"clinical",
"pregnancy",
"miscarriage",
"prior",
"to",
"12",
"weeks,",
"quality",
"of",
"life,",
"and",
"self-efficacy.",
"The",
"sample",
"size",
"of",
"the",
"study",
"is",
"1,168",
"women,",
"with",
"the",
"aim",
"of",
"detecting",
"a",
"7%",
"difference",
"in",
"live",
"births",
"between",
"groups",
"(P",
"=",
"0.05,",
"80%",
"power).",
"Discussion:",
"There",
"remains",
"a",
"need",
"for",
"further",
"research",
"to",
"add",
"significant",
"new",
"knowledge",
"to",
"defining",
"the",
"exact",
"role",
"of",
"certain",
"acupuncture",
"protocols",
"in",
"the",
"management",
"of",
"infertility",
"requiring",
"IVF",
"from",
"a",
"clinical",
"and",
"cost-effectiveness",
"perspective.",
"Clinical",
"Trial",
"Registration:",
"Australian",
"and",
"New",
"Zealand",
"Clinical",
"Trial",
"Registry",
"ACTRN12611000226909",
"*",
"Correspondence:",
"caroline.smith@uws.edu.au",
"1Centre",
"for",
"Complementary",
"Medicine",
"Research,",
"University",
"of",
"Western",
"Sydney,",
"Locked",
"Bag,",
"1797,",
"Penrith",
"South,",
"DC",
"NSW",
"2751,",
"Australia",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2012",
"Smith",
"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."
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"systems.",
"In",
"this",
"study,",
"we",
"have",
"paved",
"the",
"baseline",
"evidence",
"for",
"the",
"cytoplasmic",
"and",
"nuclear",
"localization",
"of",
"Class",
"II",
"HDAs",
"as",
"well",
"as",
"their",
"mRNA",
"expression",
"patterns.",
"RT-PCR",
"analysis",
"on",
"the",
"different",
"vegetative",
"parts",
"and",
"developmental",
"stages",
"reveal",
"that",
"Class",
"II",
"HDAs",
"are",
"ubiquitously",
"expressed",
"in",
"all",
"tissues",
"with",
"minimal",
"developmental",
"specificity.",
"Moreover,",
"stable",
"and",
"transient",
"expression",
"assays",
"using",
"HDA-YFP/GFP",
"fusion",
"constructs",
"indicate",
"cytoplasmic",
"localization",
"of",
"HDA5,",
"HDA8,",
"and",
"HDA14",
"further",
"suggesting",
"their",
"potential",
"for",
"nuclear",
"transport",
"and",
"deacetylating",
"organellar",
"and",
"cytoplasmic",
"proteins.",
"Organelle",
"markers",
"and",
"stains",
"confirm",
"HDA14",
"to",
"abound",
"in",
"the",
"mitochondria",
"and",
"chloroplasts",
"while",
"HDA5",
"localizes",
"in",
"the",
"ER.",
"HDA15,",
"on",
"the",
"other",
"hand,",
"shuttles",
"in",
"and",
"out",
"of",
"the",
"nucleus",
"upon",
"light",
"exposure.",
"In",
"the",
"absence",
"of",
"light,",
"it",
"is",
"exported",
"out",
"of",
"the",
"nucleus",
"where",
"further",
"re-exposition",
"to",
"light",
"treatments",
"signals",
"its",
"nuclear",
"import.",
"Unlike",
"HDA5",
"which",
"binds",
"with",
"14-3-3",
"proteins,",
"HDA15",
"fails",
"to",
"interact",
"with",
"these",
"chaperones.",
"Instead,",
"HDA15",
"relies",
"on",
"its",
"own",
"nuclear",
"localization",
"and",
"export",
"signals",
"to",
"navigate",
"its",
"subcellular",
"compartmentalization",
"classifying",
"it",
"as",
"a",
"Class",
"IIb",
"HDA.",
"Our",
"study",
"indicates",
"that",
"nucleocytoplasmic",
"shuttling",
"is",
"indeed",
"a",
"hallmark",
"for",
"all",
"eukaryotic",
"Class",
"II",
"histone",
"deacetylases.",
"Citation:",
"Alinsug",
"MV,",
"Chen",
"FF,",
"Luo",
"M,",
"Tai",
"R,",
"Jiang",
"L,",
"et",
"al.",
"(2012)",
"Subcellular",
"Localization",
"of",
"Class",
"II",
"HDAs",
"in",
"Arabidopsis",
"thaliana:",
"Nucleocytoplasmic",
"Shuttling",
"of",
"HDA15",
"Is",
"Driven",
"by",
"Light.",
"PLoS",
"ONE",
"7(2):",
"e30846.",
"doi:10.1371/journal.pone.0030846",
"Editor:",
"Qiang",
"Wu,",
"National",
"University",
"of",
"Singapore,",
"Singapore",
"Received",
"July",
"3,",
"2011;",
"Accepted",
"December",
"23,",
"2011;",
"Published",
"February",
"17,",
"2012",
"Copyright:",
"2012",
"Alinsug",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"was",
"funded",
"by",
"grants",
"from",
"the",
"National",
"Science",
"Council",
"of",
"Taiwan",
"(97-2311-B-002-004-MY3,",
"98-2628-B-002-016-MY3",
"and",
"99-2321-B-002-",
"027-MY3)",
"and",
"National",
"Taiwan",
"University",
"(98R0066-36",
"and",
"99R80840).",
"MVA",
"is",
"supported",
"by",
"a",
"grant",
"from",
"the",
"Democratic",
"Pacific",
"Union",
"graduate",
"studies",
"program",
"and",
"research",
"fellowship",
"from",
"NSC.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"kewu@ntu.edu.tw",
"Introduction",
"Histone",
"acetylation",
"has",
"been",
"known",
"to",
"induce",
"an",
"open",
"chromatin",
"configuration",
"leading",
"to",
"transcriptional",
"activation",
"while",
"deacetylation",
"stimulates",
"chromatin",
"condensation",
"triggering",
"transcriptional",
"quies-",
"cence.",
"Plant",
"histone",
"deacetylases",
"(HDA",
"or",
"HDACs)",
"are",
"classified",
"into",
"three",
"distinct",
"families",
"namely",
"RPD3/HDA1",
"superfamily,",
"Sirtuin",
"family,",
"and",
"the",
"HD2",
"family",
"which",
"is",
"unique",
"in",
"plants",
"[1,2,3].",
"Twelve",
"out",
"of",
"the",
"eighteen",
"known",
"HDAs",
"in",
"Arabidopsis",
"belong",
"to",
"the",
"RPD3/HDA1-like",
"histone",
"deacetylase",
"superfamily,",
"which",
"is",
"further",
"subdivided",
"into",
"three",
"classes",
"namely",
"Class",
"I,",
"II,",
"and",
"IV.",
"Recent",
"phylogenetic",
"studies",
"by",
"Alinsug",
"et",
"al.",
"[4]",
"have",
"identified",
"HDA10",
"and",
"HDA17",
"in",
"addition",
"to",
"HDA6,",
"HDA7,",
"HDA9,",
"and",
"HDA19",
"as",
"Class",
"I",
"HDA",
"based",
"on",
"sequence",
"homology.",
"Although",
"HDA8",
"and",
"HDA14",
"are",
"only",
"represented",
"in",
"plants,",
"they",
"exhibit",
"higher",
"sequence",
"similarity",
"with",
"the",
"conserved",
"histone",
"deacetylase",
"domains",
"of",
"HDA5,",
"HDA15,",
"and",
"HDA18,",
"members",
"of",
"the",
"Class",
"II",
"HDAs",
"while",
"HDA2",
"is",
"classified",
"as",
"Class",
"IV.",
"Among",
"the",
"RPD3/HDA1-like",
"superfamily",
"HDAs",
"in",
"Arabidop-",
"sis,",
"HDA6,",
"HDA19,",
"and",
"HDA18",
"have",
"been",
"well",
"elucidated",
"to",
"play",
"crucial",
"roles",
"in",
"plant",
"development",
"and",
"environmental",
"stress",
"response",
"and",
"display",
"tissue-specific",
"expression",
"[5–11,3].",
"HDA6",
"is",
"the",
"most",
"extensively",
"studied",
"plant",
"histone",
"deacetylase",
"acting",
"as",
"a",
"global",
"repressor",
"involved",
"in",
"flowering,",
"freezing",
"tolerance,",
"ABA",
"and",
"salt",
"stress",
"response,",
"senescence,",
"repression",
"of",
"embryonic",
"properties,",
"JA",
"pathway,",
"and",
"establishment",
"of",
"nucleolar",
"dominance",
"[12–16,10].",
"Similarly,",
"HDA19",
"is",
"a",
"global",
"repressor",
"in",
"embryonic",
"and",
"flower",
"development,",
"ABA",
"and",
"abiotic",
"stress",
"response,",
"light-",
"responsive",
"gene",
"expression,",
"JA",
"and",
"ethylene",
"signaling,",
"and",
"regulates",
"basal",
"defense",
"via",
"interaction",
"with",
"WRKY",
"transcription",
"factors",
"[10,5,6,17,8,18,11].",
"HDA18,",
"on",
"the",
"other",
"hand,",
"had",
"been",
"implicated",
"in",
"root",
"epidermal",
"patterning",
"[19].",
"Previous",
"studies",
"by",
"Finkemeier",
"et",
"al.",
"[20]",
"and",
"Wu",
"et",
"al.",
"[21]",
"elaborated",
"on",
"the",
"reversible",
"acetylation",
"of",
"cytoplasmic",
"proteins",
"in",
"Arabidopsis",
"indicating",
"that",
"histones",
"are",
"not",
"the",
"only",
"proteins",
"being",
"acetylated",
"&",
"deacetylated.",
"A",
"substantial",
"proportion",
"of",
"these",
"cytoplasmic",
"proteins",
"are",
"involved",
"in",
"photosynthesis",
"and",
"central",
"metabolism",
"where",
"the",
"deacetylation",
"of",
"rubisco",
"and",
"phosphoglyc-",
"erate",
"kinase",
"using",
"human",
"Sirt3",
"lead",
"to",
"a",
"significant",
"increase",
"in",
"their",
"catalytic",
"activity.",
"However,",
"the",
"use",
"of",
"human",
"Sirt3",
"as",
"a",
"deacetylase",
"may",
"exhibit",
"certain",
"specificities",
"towards",
"plant",
"Lys",
"acetylation",
"sites.",
"Thus,",
"the",
"observed",
"potency",
"may",
"have",
"been",
"underestimated",
"had",
"a",
"plant",
"specific",
"deacetylase",
"been",
"used.",
"Unfortunately,",
"none",
"of",
"the",
"18",
"known",
"histone",
"deacetylases",
"in",
"Arabidopsis",
"have",
"been",
"identified",
"to",
"be",
"cytoplasmic",
"since",
"HDA6",
"and",
"HDA19",
"were",
"established",
"to",
"be",
"exclusively",
"nuclear.",
"In",
"rice,",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"February",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"2",
"|",
"e30846"
] | [
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] | [
"PAPSS2",
"Promotes",
"Alkaline",
"Phosphates",
"Activity",
"and",
"Mineralization",
"of",
"Osteoblastic",
"MC3T3-E1",
"Cells",
"by",
"Crosstalk",
"and",
"Smads",
"Signal",
"Pathways",
"Weizhuo",
"Wang1*,",
"Fang",
"Li2,",
"Kunzheng",
"Wang1,",
"Bin",
"Cheng1,",
"Xiong",
"Guo3",
"1",
"Department",
"of",
"Orthopedics",
"Surgery,",
"the",
"Second",
"Affiliated",
"Hospital,",
"College",
"of",
"Medicine,",
"Xi’an",
"Jiaotong",
"University,",
"Xi’an,",
"Shaanxi,",
"People’s",
"Republic",
"of",
"China,",
"2",
"Department",
"of",
"Prosthodontics,",
"School",
"of",
"Stomatology,",
"The",
"Fourth",
"Military",
"University,",
"Xi’an,",
"Shaanxi,",
"People’s",
"Republic",
"of",
"China,",
"3",
"Faculty",
"of",
"Public",
"Health,",
"College",
"of",
"Medicine,",
"Key",
"Laboratory",
"of",
"Environment",
"and",
"Gene",
"Related",
"Diseases",
"of",
"Ministry",
"Education,",
"Xi’an",
"Jiaotong",
"University,",
"Xi’an,",
"Shaanxi,",
"People’s",
"Republic",
"of",
"China",
"Abstract",
"Several",
"studies",
"have",
"indicated",
"that",
"PAPSS2",
"(39-phosphoadenosine-59-phosphosulfate",
"synthetase",
"2)",
"activity",
"is",
"important",
"to",
"normal",
"skeletal",
"development.",
"Mouse",
"PAPSS2",
"is",
"predominantly",
"expressed",
"during",
"the",
"formation",
"of",
"the",
"skeleton",
"and",
"cartilaginous",
"elements",
"of",
"the",
"mouse",
"embryo",
"and",
"in",
"newborn",
"mice.",
"However,",
"the",
"role",
"and",
"mechanism",
"of",
"PAPSS2",
"in",
"bone",
"formation",
"remains",
"largely",
"unidentified.",
"By",
"analyzing",
"the",
"expression",
"pattern",
"of",
"the",
"PAPSS2",
"gene,",
"we",
"have",
"found",
"that",
"PAPSS2",
"is",
"expressed",
"in",
"bone",
"tissue",
"and",
"bone",
"formation.",
"PAPSS2",
"transcripts",
"increase",
"during",
"osteoblast",
"differentiation",
"and",
"are",
"in",
"less",
"level",
"in",
"RANKL-induced",
"osteoclast",
"like",
"cells.",
"By",
"using",
"lentivirus-mediated",
"RNA",
"interference",
"(RNAi)",
"technology,",
"we",
"knocked",
"down",
"PAPSS2",
"expression",
"in",
"MC3T3-E1",
"osteoblast.",
"Silencing",
"of",
"PAPSS2",
"expression",
"significantly",
"decreases",
"ALP",
"activity",
"and",
"cell",
"mineralization,",
"inhibits",
"expression",
"of",
"osteoblast",
"marker",
"osteopontin",
"(OPN)",
"and",
"collagen",
"I.",
"Conversely,",
"overexpression",
"of",
"PAPSS2",
"promotes",
"the",
"MC3T3-E1",
"to",
"differentiate",
"into",
"osteoblast",
"and",
"mineralization.",
"Moreover,",
"compared",
"to",
"that",
"in",
"the",
"control",
"cells,",
"the",
"mRNA",
"level",
"and",
"protein",
"expression",
"of",
"phosphorylated",
"Smad",
"2/3,",
"which",
"is",
"a",
"key",
"transcriptional",
"factor",
"in",
"the",
"Smad",
"osteoblast",
"differentiation",
"pathway,",
"showed",
"significant",
"decreases",
"in",
"PAPSS2-silenced",
"cells",
"and",
"increases",
"in",
"PAPSS2-",
"overexpression",
"cells.",
"These",
"results",
"suggest",
"that",
"PAPSS2",
"might",
"regulate",
"osteoblast",
"ALP",
"activity",
"and",
"cell",
"mineralization,",
"probably",
"through",
"Smads",
"signal",
"pathways.",
"Citation:",
"Wang",
"W,",
"Li",
"F,",
"Wang",
"K,",
"Cheng",
"B,",
"Guo",
"X",
"(2012)",
"PAPSS2",
"Promotes",
"Alkaline",
"Phosphates",
"Activity",
"and",
"Mineralization",
"of",
"Osteoblastic",
"MC3T3-E1",
"Cells",
"by",
"Crosstalk",
"and",
"Smads",
"Signal",
"Pathways.",
"PLoS",
"ONE",
"7(8):",
"e43475.",
"doi:10.1371/journal.pone.0043475",
"Editor:",
"Brenda",
"Smith,",
"Oklahoma",
"State",
"University,",
"United",
"States",
"of",
"America",
"Received",
"April",
"18,",
"2012;",
"Accepted",
"July",
"20,",
"2012;",
"Published",
"August",
"16,",
"2012",
"Copyright:",
"2012",
"Wang",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"project",
"was",
"supported",
"by",
"the",
"Natural",
"Scientific",
"Fund",
"of",
"China",
"(81001225),",
"the",
"international",
"Co-operative",
"Fund",
"in",
"Xian",
"Jiaotong",
"University,",
"China",
"and",
"US",
"(08143004),",
"and",
"the",
"Fundamental",
"Research",
"Funds",
"for",
"the",
"Central",
"Universities",
"(08140003).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"wangweizhuo@mail.xjtu.edu.cn",
"Introduction",
"Bone",
"is",
"a",
"mineralized",
"tissue",
"that",
"underlies",
"multiple",
"mechanical",
"and",
"metabolic",
"functions",
"of",
"the",
"skeleton",
"[1,2].",
"Formation",
"and",
"maintenance",
"of",
"bone",
"tissue",
"are",
"regulated",
"in",
"a",
"sophisticated",
"fashion",
"by",
"bone-forming",
"osteoblasts",
"and",
"bone-resorbing",
"osteoclasts.",
"Many",
"skeletal",
"diseases,",
"such",
"as",
"osteoporosis,",
"Kashin-Beck",
"disease,",
"Paget’s",
"disease",
"of",
"the",
"bone,",
"rheumatoid",
"arthritis,",
"and",
"bone",
"metastases",
"all",
"arise",
"from",
"an",
"imbalance",
"in",
"the",
"relative",
"activities",
"of",
"osteoblasts",
"and",
"osteoclasts",
"[3].",
"The",
"proliferation",
"and",
"differentiation",
"of",
"those",
"two",
"cell",
"types",
"are",
"controlled",
"by",
"various",
"local",
"growth",
"factors,",
"cytokines",
"produced,",
"in",
"the",
"bone",
"and",
"by",
"systemic",
"enzymes.",
"The",
"presence",
"of",
"PAPS",
"(39-phosphoadenosine-59-phosphosulfate)",
"is",
"a",
"prerequisite",
"for",
"catalytic",
"efficiency",
"in",
"all",
"sulfation",
"reactions.",
"In",
"humans,",
"PAPS",
"is",
"synthesized",
"from",
"ATP",
"and",
"SO422",
"by",
"two",
"isoforms",
"of",
"PAPS",
"synthetase",
"(PAPSS):",
"PAPSS1",
"and",
"PAPSS2.",
"The",
"PAPSS2",
"is",
"one",
"of",
"the",
"principal",
"enzymes",
"required",
"for",
"the",
"sulfation",
"of",
"extracellular",
"matrix",
"molecules",
"in",
"bone",
"formation",
"and",
"other",
"tissues",
"[4–6].",
"A",
"truncation",
"mutation",
"of",
"the",
"human",
"PAPSS2",
"gene",
"was",
"reported",
"in",
"a",
"Pakistani",
"family",
"suffering",
"from",
"a",
"novel",
"form",
"of",
"spondyloepime-",
"taphyseal",
"dysplasia",
"(SEMD)",
"[7,8].",
"A",
"homozygous",
"PAPSS2",
"mutation",
"(S475X)",
"was",
"identified",
"in",
"another",
"large",
"Pakistani",
"family",
"affected",
"by",
"SEMD,",
"Pakistani",
"type",
"[8,9].",
"This",
"manifested",
"as",
"disproportionately",
"short",
"stature",
"with",
"short,",
"bowed",
"lower",
"limbs,",
"enlarged",
"knee",
"joints,",
"kyphoscoliosis,",
"and",
"generalized",
"brachydac-",
"tyly",
"[7].",
"Chondroitin",
"6-O-sulfotransferase",
"requires",
"PAPS",
"for",
"catalytic",
"activity,",
"and",
"the",
"abnormal",
"PAPSS2",
"gene",
"that",
"encodes",
"chondroitin",
"6-O-sulfotransferase",
"can",
"cause",
"SEMD,",
"Omani",
"type",
"[10].",
"Humans",
"lacking",
"normal",
"PAPSS2",
"activity",
"exhibit",
"long",
"bone",
"shortening",
"and",
"bowing,",
"and",
"also",
"show",
"degenerative",
"joint",
"disease,",
"including",
"evidence",
"of",
"knee",
"joint",
"arthrosis.",
"Given",
"the",
"premature",
"development",
"of",
"degenerative",
"knee",
"joint",
"disease",
"in",
"the",
"mutant",
"mice",
"and",
"other",
"similarities",
"between",
"SEMD",
"mice",
"and",
"human",
"lacking",
"normal",
"PAPSS2",
"activity,",
"it",
"has",
"been",
"proposed",
"that",
"this",
"mutant",
"represents",
"a",
"model",
"of",
"human",
"PAPSS2",
"deficiency-associated",
"arthrosis",
"[11].",
"One",
"of",
"our",
"previous",
"studies",
"included",
"a",
"microarray",
"analysis",
"that",
"showed",
"some",
"correlation",
"between",
"PAPSS2",
"genes",
"in",
"individuals",
"afflicted",
"with",
"endemic",
"knee",
"osteoarthritis",
"and",
"those",
"with",
"Kashin-",
"Beck",
"disease",
"exhibiting",
"shortened",
"long",
"bones",
"and",
"enlarged",
"knee",
"and",
"finger",
"joints",
"[12,13].",
"Some",
"features",
"of",
"the",
"bone",
"phenotype",
"in",
"the",
"endemic",
"osteoarthritis",
"patient",
"resemble",
"those",
"observed",
"in",
"SEMD,",
"excepting",
"that",
"the",
"changes",
"in",
"the",
"bone",
"changes",
"were",
"milder",
"for",
"our",
"patients",
"and",
"the",
"changes",
"in",
"the",
"epiphyseal",
"plates",
"of",
"the",
"long",
"bones",
"and",
"metaphyseal",
"changes",
"were",
"detectable",
"in",
"our",
"patients",
"[14,15].",
"However,",
"the",
"absence",
"of",
"the",
"pubertal",
"growth",
"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"August",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"8",
"|",
"e43475"
] | [
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] | [
"Regulation",
"of",
"DNA",
"Replication",
"Timing",
"on",
"Human",
"Chromosome",
"by",
"a",
"Cell-Type",
"Specific",
"DNA",
"Binding",
"Protein",
"SATB1",
"Masako",
"Oda,",
"Yutaka",
"Kanoh,",
"Yoshihisa",
"Watanabe,",
"Hisao",
"Masai*",
"Genome",
"Dynamics",
"Project,",
"Department",
"of",
"Genome",
"Medicine,",
"Tokyo",
"Metropolitan",
"Institute",
"of",
"Medical",
"Science,",
"Tokyo,",
"Japan",
"Abstract",
"Background:",
"Replication",
"timing",
"of",
"metazoan",
"DNA",
"during",
"S-phase",
"may",
"be",
"determined",
"by",
"many",
"factors",
"including",
"chromosome",
"structures,",
"nuclear",
"positioning,",
"patterns",
"of",
"histone",
"modifications,",
"and",
"transcriptional",
"activity.",
"It",
"may",
"be",
"determined",
"by",
"Mb-domain",
"structures,",
"termed",
"as",
"‘‘replication",
"domains’’,",
"and",
"recent",
"findings",
"indicate",
"that",
"replication",
"timing",
"is",
"under",
"developmental",
"and",
"cell",
"type-specific",
"regulation.",
"Methodology/Principal",
"Findings:",
"We",
"examined",
"replication",
"timing",
"on",
"the",
"human",
"5q23/31",
"3.5-Mb",
"segment",
"in",
"T",
"cells",
"and",
"non-T",
"cells.",
"We",
"used",
"two",
"independent",
"methods",
"to",
"determine",
"replication",
"timing.",
"One",
"is",
"quantification",
"of",
"nascent",
"replicating",
"DNA",
"in",
"cell",
"cycle-fractionated",
"stage-specific",
"S",
"phase",
"populations.",
"The",
"other",
"is",
"FISH",
"analyses",
"of",
"replication",
"foci.",
"Although",
"the",
"locations",
"of",
"early-",
"and",
"late-replicating",
"domains",
"were",
"common",
"between",
"the",
"two",
"cell",
"lines,",
"the",
"timing",
"transition",
"region",
"(TTR)",
"between",
"early",
"and",
"late",
"domains",
"were",
"offset",
"by",
"200-kb.",
"We",
"show",
"that",
"Special",
"AT-rich",
"sequence",
"Binding",
"protein",
"1",
"(SATB1),",
"specifically",
"expressed",
"in",
"T-cells,",
"binds",
"to",
"the",
"early",
"domain",
"immediately",
"adjacent",
"to",
"TTR",
"and",
"delays",
"the",
"replication",
"timing",
"of",
"the",
"TTR.",
"Measurement",
"of",
"the",
"chromosome",
"copy",
"number",
"along",
"the",
"TTR",
"during",
"synchronized",
"S",
"phase",
"suggests",
"that",
"the",
"fork",
"movement",
"may",
"be",
"slowed",
"down",
"by",
"SATB1.",
"Conclusions:",
"Our",
"results",
"reveal",
"a",
"novel",
"role",
"of",
"SATB1",
"in",
"cell",
"type-specific",
"regulation",
"of",
"replication",
"timing",
"along",
"the",
"chromosome.",
"Citation:",
"Oda",
"M,",
"Kanoh",
"Y,",
"Watanabe",
"Y,",
"Masai",
"H",
"(2012)",
"Regulation",
"of",
"DNA",
"Replication",
"Timing",
"on",
"Human",
"Chromosome",
"by",
"a",
"Cell-Type",
"Specific",
"DNA",
"Binding",
"Protein",
"SATB1.",
"PLoS",
"ONE",
"7(8):",
"e42375.",
"doi:10.1371/journal.pone.0042375",
"Editor:",
"Marco",
"Muzi-Falconi,",
"Universita’",
"di",
"Milano,",
"Italy",
"Received",
"March",
"22,",
"2012;",
"Accepted",
"July",
"4,",
"2012;",
"Published",
"August",
"7,",
"2012",
"Copyright:",
"2012",
"Oda",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"in",
"part",
"by",
"Grant-in-Aid",
"for",
"Scientific",
"Research",
"(A)",
"(to",
"HM)",
"and",
"Grant-in-Aid",
"for",
"Scientific",
"Research",
"on",
"Priority",
"Area",
"‘‘Chromosome",
"Cycle’’",
"from",
"the",
"Ministry",
"of",
"Education,",
"Culture,",
"Sports,",
"Science,",
"and",
"Technology",
"of",
"Japan",
"(to",
"HM).",
"No",
"additional",
"external",
"funding",
"received",
"for",
"this",
"study.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"masai-hs@igakuken.or.jp",
"Introduction",
"DNA",
"replication",
"occurs",
"once",
"and",
"only",
"once",
"during",
"S",
"phase",
"of",
"cell",
"cycle",
"[1].",
"This",
"strict",
"regulation",
"is",
"achieved",
"by",
"multiple",
"layers",
"of",
"mechanisms.",
"Once",
"DNA",
"replication",
"is",
"initiated,",
"three",
"billion",
"base-",
"pair",
"human",
"genome",
"is",
"replicated",
"in",
"7,8",
"hrs",
"[2].",
"Origins",
"on",
"the",
"eukaryotic",
"chromosomes",
"can",
"be",
"classified",
"according",
"to",
"the",
"timing",
"at",
"which",
"they",
"are",
"programmed",
"to",
"fire",
"during",
"S",
"phase",
"[3].",
"Studies",
"in",
"yeasts",
"have",
"established",
"that",
"intra-S",
"checkpoint",
"negatively",
"regulates",
"the",
"firing",
"of",
"late",
"or",
"dormant",
"origins",
"[4].",
"This",
"is",
"also",
"the",
"case",
"in",
"mammalian",
"cells",
"as",
"well",
"[5–8].",
"Other",
"factors",
"including",
"histone",
"modifiers",
"have",
"also",
"been",
"shown",
"to",
"regulate",
"the",
"timing",
"of",
"origin",
"firing",
"[9–11].",
"On",
"larger",
"genomes",
"of",
"higher",
"eukaryotes,",
"replication",
"is",
"initiated",
"from",
"tens",
"of",
"thousands",
"of",
"loci",
"on",
"the",
"genome",
"[2].",
"It",
"is",
"known",
"that",
"clusters",
"of",
"origins",
"are",
"fired",
"more",
"or",
"less",
"simultaneously,",
"and",
"they",
"may",
"constitute",
"distinct",
"chromosome",
"domains",
"that",
"may",
"be",
"referred",
"to",
"as",
"‘‘replication",
"(timing)",
"domain’’",
"[12–14].",
"The",
"genome-wide",
"landscape",
"of",
"replication",
"timing",
"domains",
"were",
"shown",
"to",
"change",
"during",
"the",
"process",
"of",
"differenti-",
"ation",
"and",
"different",
"cell",
"types",
"may",
"have",
"distinct",
"replication",
"timing",
"domain",
"structures",
"[12,15–17].",
"As",
"much",
"as",
"50%",
"of",
"the",
"genome",
"may",
"be",
"regulated",
"differentially",
"in",
"different",
"cell",
"types",
"[16],",
"and",
"20%",
"of",
"the",
"mouse",
"genome",
"undergoes",
"reorganization",
"during",
"development",
"[12].",
"Replication",
"timing",
"is",
"generally",
"conserved",
"between",
"different",
"species",
"(e.g.",
"between",
"human",
"and",
"mice)",
"[13].",
"Replication",
"domains",
"may",
"be",
"correlated",
"with",
"histone",
"modification",
"marks",
"and",
"most",
"notably",
"with",
"chromosome",
"proximity",
"organization",
"that",
"can",
"be",
"estimated",
"by",
"4C",
"or",
"high-C",
"assays",
"[13,18,19].",
"It",
"would",
"be",
"important",
"to",
"identify",
"factors",
"that",
"may",
"be",
"responsible",
"for",
"cell-type",
"specific",
"regulation",
"of",
"replication",
"timing.",
"We",
"have",
"been",
"using",
"the",
"human",
"chromosome",
"5",
"5q23.3/31.1",
"locus",
"(will",
"be",
"referred",
"to",
"as",
"5q23/31",
"hereafter)",
"containing",
"a",
"cytokine",
"cluster",
"region",
"as",
"a",
"model",
"locus",
"for",
"the",
"study",
"of",
"replication",
"program,",
"since",
"extensive",
"studies",
"have",
"revealed",
"the",
"transcription",
"factors",
"and",
"epigenetic",
"regulation",
"involved",
"in",
"cell-type-specific",
"and",
"simulation-",
"dependent",
"regulation",
"of",
"transcription",
"in",
"this",
"region.",
"We",
"previously",
"mapped",
"an",
"origin",
"near",
"the",
"cytokine",
"cluster",
"and",
"have",
"shown",
"that",
"replication",
"timing",
"regulation",
"is",
"not",
"affected",
"by",
"the",
"activity",
"of",
"local",
"origins",
"[20–22].",
"We",
"have",
"compared",
"replication",
"timing",
"of",
"the",
"3.5",
"Mb",
"segment",
"of",
"5q23/31",
"in",
"T",
"cells",
"and",
"non-T",
"cells,",
"and",
"found",
"that",
"the",
"boundary",
"of",
"the",
"early",
"and",
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] | [
"Estrogen",
"Receptor",
"b",
"Exerts",
"Tumor",
"Repressive",
"Functions",
"in",
"Human",
"Malignant",
"Pleural",
"Mesothelioma",
"via",
"EGFR",
"Inactivation",
"and",
"Affects",
"Response",
"to",
"Gefitinib",
"Giulia",
"Pinton",
"1",
",",
"Warren",
"Thomas2,",
"Paolo",
"Bellini1,",
"Arcangela",
"Gabriella",
"Manente1,",
"Roberto",
"E.",
"Favoni3,",
"Brian",
"J.",
"Harvey2,",
"Luciano",
"Mutti4.,",
"Laura",
"Moro1*.",
"1",
"Department",
"of",
"Chemical,",
"Food,",
"Pharmaceutical",
"and",
"Pharmacological",
"Sciences,",
"Drug",
"and",
"Food",
"Biotechnology",
"Center,",
"University",
"of",
"Piemonte",
"Orientale",
"A.",
"Avogadro,",
"Novara,",
"Italy,",
"2",
"Department",
"of",
"Molecular",
"Medicine,",
"Royal",
"College",
"of",
"Surgeons",
"in",
"Ireland",
"and",
"Education",
"and",
"Research",
"Centre,",
"Beaumont",
"Hospital,",
"Dublin,",
"Ireland,",
"3",
"Laboratory",
"of",
"Experimental",
"Pharmacology,",
"National",
"Cancer",
"Institute,",
"Genoa,",
"Italy,",
"4",
"Department",
"of",
"Medicine,",
"Local",
"Health",
"Unit",
"11,",
"Vercelli,",
"Italy",
"Abstract",
"Background:",
"The",
"role",
"of",
"estrogen",
"and",
"estrogen",
"receptors",
"in",
"oncogenesis",
"has",
"been",
"investigated",
"in",
"various",
"malignancies.",
"Recently",
"our",
"group",
"identified",
"estrogen",
"receptor",
"beta",
"(ERb)",
"expression",
"as",
"an",
"independent",
"prognostic",
"factor",
"in",
"the",
"progression",
"of",
"human",
"Malignant",
"Pleural",
"Mesothelioma",
"(MMe),",
"but",
"the",
"underlying",
"mechanism",
"by",
"which",
"ERb",
"expression",
"in",
"tumors",
"determines",
"clinical",
"outcome",
"remains",
"largely",
"unknown.",
"This",
"study",
"is",
"aimed",
"at",
"investigating",
"the",
"molecular",
"mechanisms",
"of",
"ERb",
"action",
"in",
"MMe",
"cells",
"and",
"disclosing",
"the",
"potential",
"translational",
"implications",
"of",
"these",
"results.",
"Methods:",
"We",
"modulated",
"ERb",
"expression",
"in",
"REN",
"and",
"MSTO-211H",
"MMe",
"cell",
"lines",
"and",
"evaluated",
"cell",
"proliferation",
"and",
"EGF",
"receptor",
"(EGFR)",
"activation.",
"Results:",
"Our",
"data",
"indicate",
"that",
"ERb",
"knockdown",
"in",
"ER",
"positive",
"cells",
"confers",
"a",
"more",
"invasive",
"phenotype,",
"increases",
"anchorage",
"independent",
"proliferation",
"and",
"elevates",
"the",
"constitutive",
"activation",
"of",
"EGFR-coupled",
"signal",
"transduction",
"pathways.",
"Conversely,",
"re-expression",
"of",
"ERb",
"in",
"ER",
"negative",
"cells",
"confers",
"a",
"more",
"epithelioid",
"phenotype,",
"decreases",
"their",
"capacity",
"for",
"anchorage",
"independent",
"growth",
"and",
"down-modulates",
"proliferative",
"signal",
"transduction",
"pathways.",
"We",
"identify",
"a",
"physical",
"interaction",
"between",
"ERb,",
"EGFR",
"and",
"caveolin",
"1",
"that",
"results",
"in",
"an",
"altered",
"internalization",
"and",
"in",
"a",
"selective",
"reduced",
"activation",
"of",
"EGFR-coupled",
"signaling,",
"when",
"ERb",
"is",
"over-expressed.",
"We",
"also",
"demonstrate",
"that",
"differential",
"expression",
"of",
"ERb",
"influences",
"MMe",
"tumor",
"cell",
"responsiveness",
"to",
"the",
"therapeutic",
"agent:",
"Gefitinib.",
"Conclusions:",
"This",
"study",
"describes",
"a",
"role",
"for",
"ERb",
"in",
"the",
"modulation",
"of",
"cell",
"proliferation",
"and",
"EGFR",
"activation",
"and",
"provides",
"a",
"rationale",
"to",
"facilitate",
"the",
"targeting",
"of",
"a",
"subgroup",
"of",
"MMe",
"patients",
"who",
"would",
"benefit",
"most",
"from",
"therapy",
"with",
"Gefitinib",
"alone",
"or",
"in",
"combination",
"with",
"Akt",
"inhibitors.",
"Citation:",
"Pinton",
"G,",
"Thomas",
"W,",
"Bellini",
"P,",
"Manente",
"AG,",
"Favoni",
"RE,",
"et",
"al.",
"(2010)",
"Estrogen",
"Receptor",
"b",
"Exerts",
"Tumor",
"Repressive",
"Functions",
"in",
"Human",
"Malignant",
"Pleural",
"Mesothelioma",
"via",
"EGFR",
"Inactivation",
"and",
"Affects",
"Response",
"to",
"Gefitinib.",
"PLoS",
"ONE",
"5(11):",
"e14110.",
"doi:10.1371/journal.pone.0014110",
"Editor:",
"Joseph",
"Alan",
"Bauer,",
"Bauer",
"Research",
"Foundation,",
"United",
"States",
"of",
"America",
"Received",
"July",
"6,",
"2010;",
"Accepted",
"October",
"22,",
"2010;",
"Published",
"November",
"29,",
"2010",
"Copyright:",
"2010",
"Pinton",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"MARF",
"(Mesothelioma",
"Applied",
"Research",
"Foundation),",
"Fondazione",
"Buzzi",
"Unicem",
"and",
"Higher",
"Education",
"Authority",
"of",
"Ireland",
"(PRTLI4)",
"through",
"the",
"National",
"Biophotonics",
"and",
"Imaging",
"Platform.",
"G.",
"Pinton",
"was",
"supported",
"by",
"a",
"PhD",
"fellowship",
"from",
"Progetto",
"Lagrange",
"(Cassa",
"di",
"Risparmio",
"di",
"Torino).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"moro@pharm.unipmn.it",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"Malignant",
"pleural",
"mesothelioma",
"(MMe)",
"is",
"a",
"highly",
"aggressive",
"tumor,",
"most",
"often",
"associated",
"with",
"asbestos",
"exposure,",
"although",
"a",
"role",
"for",
"SV40",
"and",
"genetic",
"susceptibility",
"have",
"also",
"been",
"proposed",
"[1].",
"The",
"delayed",
"clinical",
"diagnosis",
"of",
"this",
"tumor",
"is",
"due",
"to",
"the",
"slow",
"progression",
"of",
"the",
"malignancy",
"[2].",
"The",
"clinical",
"prognosis",
"is",
"generally",
"poor,",
"with",
"a",
"reported",
"median",
"survival",
"from",
"presentation",
"of",
"9–12",
"months.",
"Several",
"clinical",
"prognostic",
"factors",
"have",
"been",
"tentatively",
"correlated",
"to",
"patient",
"survival;",
"these",
"include",
"histological",
"type",
"(epithelioid,",
"sarcomatoid",
"or",
"biphasic)",
"and",
"tumor",
"grade",
"[3,4].",
"We",
"recently",
"published",
"data",
"demonstrating",
"that",
"estrogen",
"receptor",
"beta",
"(ERb)",
"is",
"linked",
"with",
"better",
"prognosis",
"in",
"MMe",
"patients",
"and",
"is",
"likely",
"to",
"act",
"as",
"tumor",
"repressor",
"[5].",
"Estrogens",
"exert",
"their",
"biological",
"effects",
"through",
"two",
"distinct",
"receptors:",
"ERa",
"and",
"ERb.",
"The",
"ERs",
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] | [
"International",
"Seminars",
"in",
"Surgical",
"Oncology",
"Case",
"report",
"Primary",
"intra-abdominal",
"malignant",
"fibrous",
"histiocytoma",
"presenting",
"as",
"pyrexia",
"of",
"unknown",
"origin",
"–",
"report",
"of",
"a",
"case",
"with",
"review",
"of",
"literature",
"NA",
"Qureshi*,",
"MT",
"Hallissey,",
"JW",
"Fielding",
"and",
"D",
"Gourevitch",
"Address:",
"Department",
"of",
"upper",
"Gastro-intestinal",
"surgery,",
"Queen",
"Elizabeth",
"Hospital,",
"Edgbaston,",
"Birmingham,",
"UK",
"Email:",
"NA",
"Qureshi*",
"-",
"surgeon_1@hotmail.com;",
"MT",
"Hallissey",
"-",
"mike.hallissey@uhb.nhs.uk;",
"JW",
"Fielding",
"-",
"john.fielding@uhb.nhs.uk;",
"D",
"Gourevitch",
"-",
"david.gourevitch@uhb.nhs.uk",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"22",
"June",
"2006",
"International",
"Seminars",
"in",
"Surgical",
"Oncology",
"2006,",
"3:15",
"doi:10.1186/1477-7800-3-15",
"This",
"article",
"is",
"available",
"from:",
"http://www.issoonline.com/content/3/1/15",
"Received:",
"10",
"March",
"2006",
"Accepted:",
"22",
"June",
"2006",
"©",
"2006",
"Qureshi",
"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",
"Primary",
"intra-abdominal",
"malignant",
"mesenchymal",
"tumours",
"are",
"very",
"rare",
"and",
"there",
"are",
"not",
"many",
"cases",
"of",
"visceral",
"malignant",
"fibrous",
"histiocytoma",
"in",
"the",
"English",
"literature.",
"We",
"report",
"a",
"new",
"case",
"of",
"abdominal",
"malignant",
"fibrous",
"histiocytoma",
"presenting",
"as",
"abdominal",
"pain",
"and",
"pyrexia",
"of",
"unknown",
"origin",
"in",
"a",
"54",
"year",
"old",
"female",
"followed",
"by",
"a",
"brief",
"review",
"of",
"literature.",
"Presentation",
"with",
"pyrexia",
"of",
"unknown",
"origin",
"is",
"extremely",
"rare",
"in",
"this",
"condition.",
"Background",
"The",
"term",
"Malignant",
"Fibrous",
"Histiocytoma",
"(MFH)",
"was",
"originally",
"described",
"by",
"O'Brien",
"and",
"Stout",
"in",
"1964",
"[1]",
"to",
"cover",
"a",
"variety",
"of",
"pleomorphic",
"soft",
"tissue",
"sarcomas",
"derived",
"from",
"histiocytes",
"capable",
"of",
"fibroblastic",
"transfor-",
"mation.",
"MFH",
"is",
"a",
"common",
"sarcoma",
"of",
"mesenchymal",
"ori-",
"gin",
"affecting",
"soft",
"tissues",
"of",
"the",
"body,",
"especially",
"the",
"extremities",
"and",
"retroperitoneum.",
"Primary",
"intra-abdomi-",
"nal",
"MFH",
"is",
"a",
"rare",
"disease",
"and",
"few",
"cases",
"are",
"reported",
"in",
"the",
"English",
"literature.",
"Its",
"presentation",
"as",
"high-grade",
"pyrexia",
"of",
"unknown",
"origin",
"(PUO)",
"is",
"extremely",
"unusual.",
"We",
"report",
"a",
"case",
"of",
"malignant",
"fibrous",
"histiocytoma",
"affecting",
"colon,",
"spleen,",
"left",
"hemi",
"diaphragm",
"and",
"distal",
"pancreas",
"in",
"a",
"54",
"year",
"old",
"female,",
"who",
"presented",
"with",
"abdominal",
"pain",
"and",
"pyrexia",
"of",
"unknown",
"origin.",
"Case",
"report",
"A",
"54",
"year",
"old",
"female",
"presented",
"to",
"our",
"surgical",
"outpatient",
"clinic",
"with",
"abdominal",
"pain",
"and",
"pyrexia.",
"Abdominal",
"pain",
"was",
"of",
"recent",
"onset",
"and",
"mainly",
"in",
"the",
"left",
"upper",
"abdomen",
"but",
"she",
"had",
"fever",
"for",
"at",
"least",
"6",
"months.",
"Her",
"pyrexia",
"was",
"high",
"grade",
"(39.5–40",
"C0),",
"intermittent,",
"and",
"most",
"common",
"in",
"the",
"early",
"morning.",
"Clinical",
"examination",
"revealed",
"a",
"firm,",
"vaguely",
"defined,",
"tender",
"mass",
"in",
"the",
"left",
"upper",
"quad-",
"rant",
"of",
"the",
"abdomen.",
"Blood",
"results",
"showed",
"persistently",
"high",
"ESR",
"(>100),",
"high",
"CRP",
"(>240),",
"leukocytosis,",
"mildly",
"raised",
"Alkaline",
"Phosphatase",
"and",
"anaemia",
"(normochro-",
"mic,",
"normocytic).",
"There",
"was",
"no",
"overt",
"source",
"of",
"infection",
"that",
"could",
"account",
"for",
"the",
"fever.",
"Repeated",
"blood",
"cultures",
"did",
"not",
"yield",
"any",
"bacterial",
"growth.",
"NM",
"Leukocyte",
"HMPAO",
"scan",
"showed",
"no",
"convincing",
"abnormality",
"to",
"help",
"localise",
"an",
"infective",
"focus.",
"There",
"was",
"no",
"improvement",
"in",
"pyrexia",
"after",
"treating",
"the",
"patient",
"with",
"broad-spectrum",
"antibiotics.",
"CT",
"scan",
"of",
"the",
"abdomen",
"was",
"performed",
"which",
"showed",
"three",
"heterogeneous",
"masses",
"in",
"left",
"upper",
"abdomen",
"relat-",
"ing",
"to",
"splenic",
"flexure",
"of",
"colon,",
"pancreatic",
"body",
"and",
"tail",
"and",
"left",
"crus",
"of",
"the",
"diaphragm",
"(figure",
"1).",
"There",
"was",
"evi-",
"dence",
"of",
"central",
"necrosis",
"in",
"two",
"of",
"these",
"masses.",
"A",
"trucut",
"biopsy",
"of",
"the",
"mass",
"was",
"performed",
"and",
"histology",
"revealed",
"spindle",
"cell",
"leiomyosarcoma.",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"31",
"August",
"2012",
"doi:",
"10.3389/fpsyg.2012.00303",
"From",
"emotions",
"to",
"consciousness",
"–",
"a",
"neuro-phenomenal",
"and",
"neuro-relational",
"approach",
"Georg",
"Northoff",
"*",
"Mind,",
"Brain",
"Imaging",
"and",
"Neuroethics",
"Research",
"Unit,",
"Institute",
"of",
"Mental",
"Health",
"Research,",
"University",
"of",
"Ottawa,",
"Ottawa,",
"ON,",
"Canada",
"Edited",
"by:",
"Lihong",
"Wang,",
"Duke",
"University,",
"USA",
"Reviewed",
"by:",
"Lihong",
"Wang,",
"Duke",
"University,",
"USA",
"Mauro",
"Adenzato,",
"University",
"of",
"Turin,",
"Italy",
"*Correspondence:",
"Georg",
"Northoff",
",",
"Mind,",
"Brain",
"Imaging",
"and",
"Neuroethics",
"Research",
"Unit,",
"Institute",
"of",
"Mental",
"Health",
"Research,",
"1145",
"Carling",
"Avenue,",
"Ottawa,",
"ON,",
"Canada",
"K1Z",
"7K4.",
"e-mail:",
"georg.northoff@rohcg.on.ca",
"The",
"James–Lange",
"theory",
"considers",
"emotional",
"feelings",
"as",
"perceptions",
"of",
"physiological",
"body",
"changes.",
"This",
"approach",
"has",
"recently",
"resurfaced",
"and",
"modified",
"in",
"both",
"neurosci-",
"entific",
"and",
"philosophical",
"concepts",
"of",
"embodiment",
"of",
"emotional",
"feelings.",
"In",
"addition",
"to",
"the",
"body,",
"the",
"role",
"of",
"the",
"environment",
"in",
"emotional",
"feeling",
"needs",
"to",
"be",
"considered.",
"I",
"here",
"claim",
"that",
"the",
"environment",
"has",
"not",
"merely",
"an",
"indirect",
"and",
"instrumental,",
"i.e.,",
"modulatory",
"role",
"on",
"emotional",
"feelings",
"via",
"the",
"body",
"and",
"its",
"sensorimotor",
"and",
"vegeta-",
"tive",
"functions.",
"Instead,",
"the",
"environment",
"may",
"have",
"a",
"direct",
"and",
"non-instrumental,",
"i.e.,",
"constitutional",
"role",
"in",
"emotional",
"feelings.",
"This",
"implies",
"that",
"the",
"environment",
"itself",
"is",
"con-",
"stitutive",
"of",
"emotional",
"feeling",
"rather",
"than",
"the",
"bodily",
"representation",
"of",
"the",
"environment.",
"I",
"call",
"this",
"the",
"relational",
"concept",
"of",
"emotional",
"feeling.",
"The",
"present",
"paper",
"discusses",
"recent",
"data",
"from",
"neuroimaging",
"that",
"investigate",
"emotions",
"in",
"relation",
"to",
"interoceptive",
"processing",
"and",
"the",
"brain’s",
"intrinsic",
"activity.",
"These",
"data",
"show",
"the",
"intrinsic",
"linkage",
"of",
"interoceptive",
"stimulus",
"processing",
"to",
"both",
"exteroceptive",
"stimuli",
"and",
"the",
"brain’s",
"intrin-",
"sic",
"activity.",
"This",
"is",
"possible",
"only",
"if",
"the",
"differences",
"between",
"intrinsic",
"activity",
"and",
"intero-",
"and",
"exteroceptive",
"stimuli",
"is",
"encoded",
"into",
"neural",
"activity.",
"Such",
"relational",
"coding",
"makes",
"possible",
"the",
"assignment",
"of",
"subjective",
"and",
"affective",
"features",
"to",
"the",
"otherwise",
"objec-",
"tive",
"and",
"non-affective",
"stimulus.",
"I",
"therefore",
"consider",
"emotions",
"to",
"be",
"intrinsically",
"affec-",
"tive",
"and",
"subjective",
"as",
"it",
"is",
"manifest",
"in",
"emotional",
"feelings.",
"The",
"relational",
"approach",
"thus",
"goes",
"together",
"with",
"what",
"may",
"be",
"described",
"as",
"neuro-phenomenal",
"approach.",
"Such",
"neuro-",
"phenomenal",
"approach",
"does",
"not",
"only",
"inform",
"emotions",
"and",
"emotional",
"feeling",
"but",
"is",
"also",
"highly",
"relevant",
"to",
"better",
"understand",
"the",
"neuronal",
"mechanisms",
"underlying",
"consciousness",
"in",
"general.",
"Keywords:",
"consciousness,",
"emotion,",
"emotional",
"feeling,",
"insula,",
"James–Lange",
"theory",
"INTRODUCTION",
"The",
"well-known",
"James–Lange",
"theory",
"determined",
"feelings",
"as",
"per-",
"ceptions",
"of",
"physiological",
"body",
"changes",
"in",
"the",
"autonomic,",
"hor-",
"monal,",
"and",
"motor",
"systems.",
"Once",
"we",
"become",
"aware",
"of",
"phys-",
"iological",
"bodily",
"changes",
"induced",
"by",
"danger,",
"we",
"feel",
"fear",
"and",
"subjectively",
"experience",
"emotional",
"feelings.",
"James",
"(1884,",
"p.",
"190)",
"consequently",
"considered",
"bodily",
"changes",
"as",
"central",
"to",
"emo-",
"tional",
"feelings;",
"“we",
"feel",
"sorry",
"because",
"we",
"cry,",
"angry",
"because",
"we",
"strike,",
"afraid",
"because",
"we",
"tremble,",
"and",
"not",
"that",
"we",
"cry,",
"strike,",
"or",
"tremble,",
"because",
"we",
"are",
"sorry,",
"angry,",
"or",
"fearful,",
"as",
"the",
"case",
"may",
"be.”",
"Modern",
"empirical",
"versions",
"of",
"this",
"the-",
"ory",
"resurface",
"in",
"current",
"neuroscientific",
"models",
"of",
"emotion",
"as,",
"for",
"instance,",
"in",
"Damasio",
"and",
"others",
"(Damasio,",
"1999,",
"2010;",
"Craig,",
"2003,",
"2004,",
"2005,",
"2009,",
"2011;",
"Bechara,",
"2004;",
"Niedenthal,",
"2007).",
"Conceptually,",
"the",
"embodied",
"approach",
"to",
"emotion",
"emphasizes",
"the",
"crucial",
"role",
"of",
"the",
"body",
"in",
"emotional",
"feeling.",
"If",
"the",
"body",
"and",
"its",
"vegetative",
"and",
"sensorimotor",
"function",
"play",
"a",
"crucial",
"role",
"in",
"constituting",
"emotional",
"feelings,",
"the",
"body",
"can",
"no",
"longer",
"be",
"con-",
"sidered",
"in",
"a",
"merely",
"objective",
"way",
"but",
"rather",
"as",
"subjective",
"and",
"experienced",
"–",
"the",
"mere",
"Koerper",
"as",
"objective",
"body",
"must",
"be",
"dis-",
"tinguished",
"from",
"the",
"lived",
"body",
"as",
"subjectively",
"experienced",
"body",
"in",
"emotional",
"feeling",
"(Colombetti",
"and",
"Thompson,",
"2005,",
"2007;",
"Colombetti,",
"2008)1.",
"The",
"emphasis",
"on",
"the",
"body",
"raises",
"the",
"question",
"for",
"the",
"role",
"of",
"the",
"environment",
"in",
"constituting",
"emotional",
"feelings.",
"The",
"body",
"stands",
"in",
"direct",
"contact",
"with",
"the",
"environment",
"via",
"its",
"sensorimotor",
"func-",
"tions",
"which",
"are",
"emphasized",
"in",
"recent",
"body-based,",
"e.g.,",
"embodied",
"concepts",
"of",
"emotional",
"feelings",
"(see",
"Niedenthal",
"et",
"al.,",
"2005;",
"Nieden-",
"thal,",
"2007).",
"The",
"body",
"is",
"supposed",
"to",
"represent",
"the",
"environment",
"in",
"sensorimotor",
"terms",
"and",
"it",
"is",
"these",
"bodily",
"representations",
"that",
"are",
"considered",
"crucial",
"in",
"constituting",
"emotional",
"feelings.",
"The",
"envi-",
"ronment",
"may",
"have",
"then",
"an",
"indirect",
"and",
"modulatory",
"role",
"via",
"the",
"body",
"in",
"the",
"constitution",
"of",
"the",
"emotional",
"feelings.",
"One",
"could",
"also",
"imagine",
"that",
"the",
"environment",
"has",
"a",
"direct",
"and",
"constitutive",
"role",
"in",
"emotional",
"feeling;",
"the",
"environment",
"may",
"then",
"1It",
"should",
"also",
"be",
"pointed",
"out",
"that",
"feelings",
"cannot",
"be",
"considered",
"to",
"be",
"conscious",
"perceptions",
"of",
"the",
"neural",
"activity",
"in",
"those",
"brain",
"regions",
"that",
"induce",
"emotion",
"as",
"for",
"instance",
"LeDoux",
"assumes.",
"We",
"cannot",
"become",
"conscious",
"of",
"neural",
"activity",
"in",
"the",
"first-order",
"emotion",
"regions",
"(see",
"also",
"Bennett",
"and",
"Hacker,",
"2003,",
"208)",
"since",
"we",
"remain",
"principally",
"unable",
"to",
"perceive",
"our",
"brain’s",
"neural",
"activity",
"as",
"such",
"which",
"I",
"recently",
"called",
"“autoepistemic",
"limitation”",
"(Northoff,",
"2004;",
"Northoff",
"and",
"Musholt,",
"2006,",
"see",
"chapter",
"1",
"and",
"2",
"in",
"Northoff,",
"2011).",
"www.frontiersin.org",
"August",
"2012",
"|",
"Volume",
"3",
"|",
"Article",
"303",
"|",
"1"
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] | [
"organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"Dimethylammonium",
"5,5-dimethyl-3-oxo-",
"2-(3,3,6,6-tetramethyl-1,8-dioxo-",
"2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-",
"yl)cyclohex-1-enolate",
"9-(2-hydroxy-4,4-",
"dimethyl-6-oxocyclohex-1-enyl)-3,3,6,6-",
"tetramethyl-3,4,5,6,7,9-hexahydro-1H-",
"xanthene-1,8(2H)-dione",
"n-hexane",
"hemisolvate",
"monohydrate",
"Noorhafizah",
"Hasanudin,a",
"Aisyah",
"Saad",
"Abdul",
"Rahim,a‡",
"Salizawati",
"Muhamad",
"Salhimi,a",
"Jia",
"Hao",
"Gohb§",
"and",
"Hoong-Kun",
"Funb*}",
"aSchool",
"of",
"Pharmaceutical",
"Sciences,",
"Universiti",
"Sains",
"Malaysia,",
"11800",
"USM,",
"Penang,",
"Malaysia,",
"and",
"bX-ray",
"Crystallography",
"Unit,",
"School",
"of",
"Physics,",
"Universiti",
"Sains",
"Malaysia,",
"11800",
"USM,",
"Penang,",
"Malaysia",
"Correspondence",
"e-mail:",
"hkfun@usm.my",
"Received",
"17",
"January",
"2010;",
"accepted",
"25",
"January",
"2010",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"100",
"K;",
"mean",
"(C–C)",
"=",
"0.004",
"A˚;",
"disorder",
"in",
"solvent",
"or",
"counterion;",
"R",
"factor",
"=",
"0.052;",
"wR",
"factor",
"=",
"0.145;",
"data-to-",
"parameter",
"ratio",
"=",
"12.5.",
"The",
"main",
"molecule",
"of",
"the",
"title",
"compound,",
"C2H8N+",
"-",
"C25H31O5",
"C25H32O5",
"0.5C6H14",
"H2O,",
"exists",
"as",
"two",
"crystallo-",
"graphically",
"independent",
"molecules,",
"the",
"hydroxy",
"group",
"of",
"one",
"being",
"deprotonated.",
"The",
"pyran",
"rings",
"of",
"both",
"independent",
"units",
"adopt",
"boat",
"conformations.",
"One",
"of",
"the",
"two",
"cyclohexene",
"rings",
"of",
"the",
"xanthene",
"unit",
"adopts",
"an",
"envelope",
"conformation",
"whereas",
"the",
"other",
"is",
"in",
"a",
"half-chair",
"conformation.",
"The",
"cyclohexene",
"ring",
"attached",
"to",
"the",
"xanthene",
"unit",
"adopts",
"an",
"envelope",
"conformation.",
"The",
"n-hexane",
"solvent",
"molecule",
"is",
"disordered",
"about",
"a",
"crystallographic",
"glide",
"plane",
"and",
"the",
"symmetry-independent",
"components",
"are",
"again",
"disordered",
"over",
"two",
"positions,",
"each",
"with",
"an",
"occupancy",
"of",
"0.25.",
"In",
"the",
"crystal",
"structure,",
"the",
"xanthene",
"derivatives",
"are",
"linked",
"by",
"O—H",
"O,",
"N—H",
"O",
"and",
"C—H",
"O",
"hydrogen",
"bonds,",
"forming",
"a",
"three-",
"dimensional",
"network",
"with",
"channels",
"along",
"the",
"a",
"axis.",
"The",
"dimethylammonium",
"cations",
"and",
"water",
"molecules",
"lie",
"in",
"small",
"channels",
"and",
"are",
"linked",
"to",
"the",
"framework",
"via",
"O—H.",
"O",
"and",
"N—H",
"O",
"hydrogen",
"bonds.",
"The",
"n-hexane",
"solvent",
"molecules",
"occupy",
"large",
"channels.",
"‡",
"Additional",
"corresponding",
"author:",
"aisyah@usm.my.",
"§",
"Thomson",
"Reuters",
"ResearcherID:",
"C-7576-2009.",
"}",
"Thomson",
"Reuters",
"ResearcherID:",
"A-3561-2009.",
"o470",
"Hasanudin",
"et",
"al.",
"Related",
"literature",
"For",
"general",
"background",
"and",
"the",
"preparation",
"and",
"applications",
"of",
"the",
"title",
"compound,",
"see:",
"Ashry",
"et",
"al.",
"(2006);",
"Rubinov",
"et",
"al.",
"(1999);",
"Saitoh",
"et",
"al.",
"(2006).",
"For",
"ring",
"conformations,",
"see:",
"Cremer",
"&",
"Pople",
"(1975).",
"For",
"related",
"structures,",
"see:",
"Jeya-",
"kanthan",
"et",
"al.",
"(1999);",
"Odabas¸og˘",
"lu",
"et",
"al.",
"(2008).",
"For",
"the",
"stability",
"of",
"the",
"temperature",
"controller",
"used",
"for",
"the",
"data",
"collection,",
"see:",
"Cosier",
"&",
"Glazer",
"(1986).",
"Experimental",
"Crystal",
"data",
"C2H8N+",
"C25H31O5",
"C25H32O5",
"-",
"0.5C6H14",
"H2O",
"Mr",
"=",
"931.20",
"Orthorhombic,",
"Pna21",
"a",
"=",
"11.2438",
"(2)",
"A˚",
"b",
"=",
"20.1671",
"(3)",
"A˚",
"c",
"=",
"23.6474",
"(3)",
"A˚",
"Data",
"collection",
"Bruker",
"SMART",
"APEXII",
"CCD",
"area-detector",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(SADABS;",
"Bruker,",
"2009)",
"Tmin",
"=",
"0.963,",
"Tmax",
"=",
"0.984",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.052",
"wR(F",
"2)",
"=",
"0.145",
"S",
"=",
"1.03",
"8021",
"reflections",
"640",
"parameters",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"D—H",
"A",
"O5B—H5OB",
"O1W—H2W1",
"N1—H1N1",
"N1—H2N1",
"C4B—H4C",
"C12A—H12B",
"C12B—H12C",
"C18A—H18A",
"C26—H26C",
"C27—H27B",
"O5A",
"O4Ai",
"O4Aii",
"O1W",
"O2Ai",
"O3Aiii",
"O3Biv",
"O5B",
"O4B",
"O3B",
"0.82",
"0.89",
"0.88",
"0.87",
"0.97",
"0.97",
"0.97",
"0.97",
"0.96",
"0.96",
"1.69",
"2.03",
"1.94",
"2.01",
"2.48",
"2.41",
"2.36",
"2.55",
"2.42",
"2.34",
"V",
"=",
"5362.16",
"(14)",
"A˚3",
"Z",
"=",
"4",
"Mo",
"K",
"radiation",
"=",
"0.08",
"mm",
"1",
"T",
"=",
"100",
"K",
"0.48",
"0.38",
"0.20",
"mm",
"31958",
"measured",
"reflections",
"8021",
"independent",
"reflections",
"6458",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.040",
"19",
"restraints",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.48",
"e",
"A˚",
"3",
"min",
"=",
"0.28",
"e",
"A˚",
"3",
"D",
"A",
"2.488",
"(2)",
"2.918",
"(3)",
"2.755",
"(3)",
"2.860",
"(3)",
"3.353",
"(4)",
"3.261",
"(3)",
"3.238",
"(3)",
"3.227",
"(3)",
"3.244",
"(4)",
"3.055",
"(4)",
"163",
"175",
"155",
"167",
"150",
"146",
"150",
"126",
"144",
"131",
"D—H",
"H",
"A",
"D—H",
"A",
"Symmetry",
"codes:",
"(i)",
"x;",
"y",
"þ",
"1;",
"z",
"þ",
"12;",
"(ii)",
"x",
"þ",
"12;",
"y",
"þ",
"12;",
"z",
"þ",
"12;",
"(iii)",
"x",
"þ",
"21;",
"y",
"þ",
"12;",
"z;",
"(iv)",
"x",
"12;",
"y",
"þ",
"23;",
"z.",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2009);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2009);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"doi:10.1107/S1600536810003107",
"Acta",
"Cryst.",
"(2010).",
"E66,",
"o470–o471"
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"World",
"J",
"Urol",
"(2011)",
"29:199–204",
"DOI",
"10.1007/s00345-010-0612-9",
"T",
"O",
"P",
"I",
"C",
"P",
"A",
"P",
"E",
"R",
"The",
"fish-hook",
"configuration",
"of",
"the",
"distal",
"ureter",
"indicates",
"bladder",
"outlet",
"obstruction",
"due",
"to",
"benign",
"prostatic",
"hyperplasia",
"Charalampos",
"Mamoulakis",
"•",
"Thomas",
"R.",
"W.",
"Herrmann",
"•",
"Klaus",
"Ho¨fner",
"•",
"Matthias",
"Oelke",
"Received:",
"23",
"August",
"2010",
"/",
"Accepted:",
"30",
"October",
"2010",
"/",
"Published",
"online:",
"16",
"November",
"2010",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Purpose",
"The",
"aim",
"of",
"this",
"retrospective",
"study",
"was",
"to",
"evaluate",
"in",
"a",
"historical",
"series",
"of",
"patients",
"whether",
"mor-",
"phological",
"changes",
"of",
"the",
"urinary",
"tract",
"imaged",
"on",
"intra-",
"venous",
"urography",
"(IVU)",
"are",
"associated",
"with",
"clinical",
"or",
"urodynamic",
"data.",
"Methods",
"During",
"a",
"1-year",
"period,",
"every",
"man",
"45",
"years",
"or",
"older",
"with",
"lower",
"urinary",
"tract",
"symptoms",
"suggestive",
"of",
"benign",
"prostatic",
"hyperplasia",
"was",
"systematically",
"evaluated",
"with",
"multi-channel",
"computer-urodynamic",
"investigation",
"and",
"IVU.",
"Men",
"with",
"urinary",
"retention,",
"known",
"bladder",
"stones",
"or",
"diverticula,",
"severely",
"impaired",
"renal",
"function,",
"or",
"allergy",
"to",
"iodine",
"contrast",
"media",
"were",
"excluded.",
"Structural",
"alterations",
"of",
"the",
"urinary",
"tract",
"were",
"correlated",
"with",
"clinical",
"and",
"uro-",
"dynamic",
"data",
"using",
"logistic",
"regression",
"analysis.",
"Results",
"Data",
"on",
"203",
"consecutive",
"patients",
"were",
"available",
"for",
"analysis.",
"Multivariate",
"analysis",
"demonstrated",
"that",
"the",
"‘‘fish-hook’’",
"configuration",
"of",
"the",
"distal",
"ureter",
"(also",
"known",
"as",
"‘‘hockey-stick’’,",
"or",
"‘‘J-shaped’’",
"ureter)",
"was",
"the",
"only",
"sign",
"significantly",
"associated",
"with",
"benign",
"prostatic",
"obstruction",
"(BPO)",
"(odds-ratio",
"3.64;",
"95%",
"confidence",
"interval",
"1.69–7.83;",
"P",
"\\",
"0.001).",
"The",
"sensitivity,",
"specificity,",
"positive",
"and",
"negative",
"predictive",
"values",
"of",
"the",
"‘‘fish-hook’’",
"ureter",
"C.",
"Mamoulakis",
"Department",
"of",
"Urology,",
"University",
"of",
"Crete",
"Medical",
"School,",
"Heraklion,",
"Crete,",
"Greece",
"T.",
"R.",
"W.",
"Herrmann",
"K.",
"Ho¨fner",
"M.",
"Oelke",
"(&)",
"Department",
"of",
"Urology,",
"Hannover",
"Medical",
"School,",
"Carl-Neuberg-Str.",
"1,",
"30625",
"Hannover,",
"Germany",
"e-mail:",
"oelke.matthias@mh-hannover.de",
"K.",
"Ho¨fner",
"Department",
"of",
"Urology,",
"Evangelic",
"Hospital,",
"Oberhausen,",
"Germany",
"configuration",
"sign",
"to",
"detect",
"BPO",
"was",
"53,",
"76,",
"61",
"and",
"70%,",
"respectively.",
"Bladder",
"trabeculation,",
"upper",
"urinary",
"tract",
"dilatation,",
"or",
"bladder",
"base",
"elevation",
"were",
"not",
"associated",
"with",
"BPO,",
"detrusor",
"overactivity,",
"detrusor",
"underactivity,",
"bladder",
"low-compliance",
"or",
"any",
"clinical",
"data.",
"Conclusions",
"The",
"‘‘fish-hook’’",
"shape",
"of",
"the",
"distal",
"ureter(s)",
"indicates",
"BPO",
"and",
"may",
"be",
"a",
"result",
"of",
"prostate",
"median",
"lobe",
"enlargement.",
"Keywords",
"Benign",
"prostatic",
"hyperplasia",
"Bladder",
"outlet",
"obstruction",
"Fish-hook",
"ureter",
"Intravenous",
"urography",
"Lower",
"urinary",
"tract",
"symptoms",
"Sensitivity",
"Specificity",
"Urodynamic",
"investigation",
"Abbreviations",
"BPH",
"Benign",
"prostatic",
"hyperplasia",
"BPO",
"Benign",
"prostatic",
"obstruction",
"BPE",
"Benign",
"prostatic",
"enlargement",
"CI",
"Confidence",
"interval",
"IPP",
"Intravesical",
"prostatic",
"protrusion",
"IPSS",
"International",
"prostate",
"symptom",
"score",
"IVU",
"Intravenous",
"urography",
"LUTS",
"Lower",
"urinary",
"tract",
"symptoms",
"OR",
"Odds",
"ratio",
"PVR",
"Post-void",
"residual",
"urine",
"TRUS",
"Transrectal",
"ultrasound",
"UDI",
"Urodynamic",
"investigation",
"Introduction",
"Benign",
"prostatic",
"hyperplasia",
"(BPH)",
"is",
"the",
"term",
"used",
"to",
"describe",
"the",
"growth",
"of",
"epithelial,",
"muscular",
"and/or",
"fibrotic",
"123"
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] | [
"Leeds",
"et",
"al.",
"BMC",
"Research",
"Notes",
"2011,",
"4:317",
"http://www.biomedcentral.com/1756-0500/4/317",
"P",
"R",
"O",
"J",
"E",
"C",
"T",
"N",
"O",
"T",
"E",
"Open",
"Access",
"Intensive",
"medical",
"student",
"involvement",
"in",
"short-",
"term",
"surgical",
"trips",
"provides",
"safe",
"and",
"effective",
"patient",
"care:",
"a",
"case",
"review",
"Ira",
"L",
"Leeds1*,",
"Francis",
"X",
"Creighton1,",
"Matthew",
"A",
"Wheatley1,2,",
"Jana",
"B",
"Macleod1,3,4,",
"Jahnavi",
"Srinivasan1,4,",
"Marie",
"P",
"Chery5",
"and",
"Viraj",
"A",
"Master1,6",
"Abstract",
"Background:",
"The",
"hierarchical",
"nature",
"of",
"medical",
"education",
"has",
"been",
"thought",
"necessary",
"for",
"the",
"safe",
"care",
"of",
"patients.",
"In",
"this",
"setting,",
"medical",
"students",
"in",
"particular",
"have",
"limited",
"opportunities",
"for",
"experiential",
"learning.",
"We",
"report",
"on",
"a",
"student-faculty",
"collaboration",
"that",
"has",
"successfully",
"operated",
"an",
"annual,",
"short-term",
"surgical",
"intervention",
"in",
"Haiti",
"for",
"the",
"last",
"three",
"years.",
"Medical",
"students",
"were",
"responsible",
"for",
"logistics",
"and",
"were",
"overseen",
"by",
"faculty",
"members",
"for",
"patient",
"care.",
"Substantial",
"planning",
"with",
"local",
"partners",
"ensured",
"that",
"trip",
"activities",
"supplemented",
"existing",
"surgical",
"services.",
"A",
"case",
"review",
"was",
"performed",
"hypothesizing",
"that",
"such",
"trips",
"could",
"provide",
"effective",
"surgical",
"care",
"while",
"also",
"providing",
"a",
"suitable",
"educational",
"experience.",
"Findings:",
"Over",
"three",
"week-long",
"trips,",
"64",
"cases",
"were",
"performed",
"without",
"any",
"reported",
"complications,",
"and",
"no",
"immediate",
"perioperative",
"morbidity",
"or",
"mortality.",
"A",
"plurality",
"of",
"cases",
"were",
"complex",
"urological",
"procedures",
"that",
"required",
"surgical",
"skills",
"that",
"were",
"locally",
"unavailable",
"(43%).",
"Surgical",
"productivity",
"was",
"twice",
"that",
"of",
"comparable",
"peer",
"institutions",
"in",
"the",
"region.",
"Student",
"roles",
"in",
"patient",
"care",
"were",
"greatly",
"expanded",
"in",
"comparison",
"to",
"those",
"at",
"U.S.",
"academic",
"medical",
"centers",
"and",
"appropriate",
"supervision",
"was",
"maintained.",
"Discussion:",
"This",
"demonstration",
"project",
"suggests",
"that",
"a",
"properly",
"designed",
"surgical",
"trip",
"model",
"can",
"effectively",
"balance",
"the",
"surgical",
"needs",
"of",
"the",
"community",
"with",
"an",
"opportunity",
"to",
"expose",
"young",
"trainees",
"to",
"a",
"clinical",
"and",
"cross-",
"cultural",
"experience",
"rarely",
"provided",
"at",
"this",
"early",
"stage",
"of",
"medical",
"education.",
"Few",
"formalized",
"programs",
"currently",
"exist",
"although",
"the",
"experience",
"above",
"suggests",
"the",
"rewarding",
"potential",
"for",
"broad-based",
"adoption.",
"Background",
"Historically,",
"the",
"hierarchical",
"nature",
"of",
"medical",
"education",
"with",
"step-wise",
"progression",
"to",
"greater",
"abilities",
"and",
"responsibilities",
"has",
"been",
"thought",
"necessary",
"for",
"the",
"safe",
"and",
"efficient",
"practice",
"of",
"medical",
"care",
"within",
"the",
"aca-",
"demic",
"learning",
"environment.",
"Although",
"such",
"a",
"system",
"has",
"advantages,",
"one",
"cost",
"of",
"this",
"well-established",
"hierar-",
"chy",
"is",
"that",
"experiential",
"learning",
"only",
"minimally",
"reaches",
"those",
"further",
"down",
"the",
"chain",
"of",
"command.",
"Medical",
"stu-",
"dents",
"in",
"particular",
"have",
"limited",
"clinical",
"responsibilities",
"and",
"therefore",
"limited",
"opportunities",
"for",
"direct",
"hands-on",
"learning",
"considered",
"by",
"some",
"to",
"be",
"the",
"superior",
"form",
"of",
"medical",
"education",
"[1].",
"*",
"Correspondence:",
"ileeds@emory.edu",
"1Emory",
"University",
"School",
"of",
"Medicine,",
"1648",
"Pierce",
"Drive,",
"Atlanta,",
"GA",
"30322",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"In",
"the",
"surgical",
"specialties,",
"this",
"problem",
"is",
"magnified",
"by",
"the",
"nature",
"of",
"procedural",
"medicine.",
"Prior",
"studies[2,3]",
"have",
"demonstrated",
"multiple",
"systemic",
"barriers",
"to",
"surgical",
"skill",
"acquisition",
"by",
"medical",
"students.",
"Given",
"the",
"intrinsic",
"importance",
"of",
"technical",
"acumen",
"and",
"repetition-based",
"learning",
"for",
"surgery,[4]",
"any",
"hierarchy",
"that",
"limits",
"practice",
"of",
"clinical",
"skills",
"may",
"further",
"distance",
"the",
"medical",
"stu-",
"dent",
"from",
"the",
"proven",
"ideal",
"form",
"of",
"surgical",
"skill",
"acquisi-",
"tion",
"-",
"routine",
"reiteration",
"[5,6].",
"One",
"could",
"argue",
"that",
"the",
"rate-limiting",
"step",
"for",
"educa-",
"tion",
"of",
"the",
"medical",
"student",
"is",
"not",
"the",
"student,",
"but",
"a",
"sys-",
"tem",
"that",
"is",
"overloaded",
"with",
"too",
"many",
"intermediaries.",
"Are",
"medical",
"students",
"unable",
"to",
"work",
"more",
"indepen-",
"dently",
"or",
"is",
"this",
"hierarchical",
"construct",
"more",
"a",
"matter",
"of",
"practicality",
"than",
"absolutely",
"necessary",
"supervision?",
"Such",
"inquiry",
"applies",
"not",
"only",
"to",
"student",
"participation",
"in",
"©",
"2010",
"Leeds",
"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."
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] | [
"BMC",
"Medical",
"Informatics",
"and",
"Decision",
"Making",
"Software",
"Doublet",
"method",
"for",
"very",
"fast",
"autocoding",
"Jules",
"J",
"Berman*",
"Address:",
"Cancer",
"Diagnosis",
"Program,",
"National",
"Cancer",
"Institute,",
"National",
"Institutes",
"of",
"Health,",
"Bethesda,",
"MD,",
"USA",
"Email:",
"Jules",
"J",
"Berman*",
"-",
"bermanj@mail.nih.gov",
"*",
"Corresponding",
"author",
"Published:",
"15",
"September",
"2004",
"BMC",
"Medical",
"Informatics",
"and",
"Decision",
"Making",
"2004,",
"4:16",
"doi:10.1186/1472-6947-4-16",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1472-6947/4/16",
"Received:",
"01",
"July",
"2004",
"Accepted:",
"15",
"September",
"2004",
"©",
"2004",
"Berman;",
"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.",
"BioMed",
"Central",
"Open",
"Access",
"Abstract",
"Background:",
"Autocoding",
"(or",
"automatic",
"concept",
"indexing)",
"occurs",
"when",
"a",
"software",
"program",
"extracts",
"terms",
"contained",
"within",
"text",
"and",
"maps",
"them",
"to",
"a",
"standard",
"list",
"of",
"concepts",
"contained",
"in",
"a",
"nomenclature.",
"The",
"purpose",
"of",
"autocoding",
"is",
"to",
"provide",
"a",
"way",
"of",
"organizing",
"large",
"documents",
"by",
"the",
"concepts",
"represented",
"in",
"the",
"text.",
"Because",
"textual",
"data",
"accumulates",
"rapidly",
"in",
"biomedical",
"institutions,",
"the",
"computational",
"methods",
"used",
"to",
"autocode",
"text",
"must",
"be",
"very",
"fast.",
"The",
"purpose",
"of",
"this",
"paper",
"is",
"to",
"describe",
"the",
"doublet",
"method,",
"a",
"new",
"algorithm",
"for",
"very",
"fast",
"autocoding.",
"Methods:",
"An",
"autocoder",
"was",
"written",
"that",
"transforms",
"plain-text",
"into",
"intercalated",
"word",
"doublets",
"(e.g.",
"\"The",
"ciliary",
"body",
"produces",
"aqueous",
"humor\"",
"becomes",
"\"The",
"ciliary,",
"ciliary",
"body,",
"body",
"produces,",
"produces",
"aqueous,",
"aqueous",
"humor\").",
"Each",
"doublet",
"is",
"checked",
"against",
"an",
"index",
"of",
"doublets",
"extracted",
"from",
"a",
"standard",
"nomenclature.",
"Matching",
"doublets",
"are",
"assigned",
"a",
"numeric",
"code",
"specific",
"for",
"each",
"doublet",
"found",
"in",
"the",
"nomenclature.",
"Text",
"doublets",
"that",
"do",
"not",
"match",
"the",
"index",
"of",
"doublets",
"extracted",
"from",
"the",
"nomenclature",
"are",
"not",
"part",
"of",
"valid",
"nomenclature",
"terms.",
"Runs",
"of",
"matching",
"doublets",
"from",
"text",
"are",
"concatenated",
"and",
"matched",
"against",
"nomenclature",
"terms",
"(also",
"represented",
"as",
"runs",
"of",
"doublets).",
"Results:",
"The",
"doublet",
"autocoder",
"was",
"compared",
"for",
"speed",
"and",
"performance",
"against",
"a",
"previously",
"published",
"phrase",
"autocoder.",
"Both",
"autocoders",
"are",
"Perl",
"scripts,",
"and",
"both",
"autocoders",
"used",
"an",
"identical",
"text",
"(a",
"170+",
"Megabyte",
"collection",
"of",
"abstracts",
"collected",
"through",
"a",
"PubMed",
"search)",
"and",
"the",
"same",
"nomenclature",
"(neocl.xml,",
"containing",
"over",
"102,271",
"unique",
"names",
"of",
"neoplasms).",
"In",
"side-by-",
"side",
"comparison",
"on",
"the",
"same",
"computer,",
"the",
"doublet",
"method",
"autocoder",
"was",
"8.4",
"times",
"faster",
"than",
"the",
"phrase",
"autocoder",
"(211",
"seconds",
"versus",
"1,776",
"seconds).",
"The",
"doublet",
"method",
"codes",
"0.8",
"Megabytes",
"of",
"text",
"per",
"second",
"on",
"a",
"desktop",
"computer",
"with",
"a",
"1.6",
"GHz",
"processor.",
"In",
"addition,",
"the",
"doublet",
"autocoder",
"successfully",
"matched",
"terms",
"that",
"were",
"missed",
"by",
"the",
"phrase",
"autocoder,",
"while",
"the",
"phrase",
"autocoder",
"found",
"no",
"terms",
"that",
"were",
"missed",
"by",
"the",
"doublet",
"autocoder.",
"Conclusions:",
"The",
"doublet",
"method",
"of",
"autocoding",
"is",
"a",
"novel",
"algorithm",
"for",
"rapid",
"text",
"autocoding.",
"The",
"method",
"will",
"work",
"with",
"any",
"nomenclature",
"and",
"will",
"parse",
"any",
"ascii",
"plain-text.",
"An",
"implementation",
"of",
"the",
"algorithm",
"in",
"Perl",
"is",
"provided",
"with",
"this",
"article.",
"The",
"algorithm,",
"the",
"Perl",
"implementation,",
"the",
"neoplasm",
"nomenclature,",
"and",
"Perl",
"itself,",
"are",
"all",
"open",
"source",
"materials.",
"Background",
"Autocoding",
"is",
"a",
"specialized",
"form",
"of",
"machine",
"translation.",
"The",
"general",
"idea",
"behind",
"machine",
"translation",
"is",
"that",
"com-",
"puters",
"have",
"the",
"patience,",
"stamina",
"and",
"speed",
"to",
"quickly",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"CLINICS",
"2011;66(7):1177-1182",
"CLINICAL",
"SCIENCE",
"DOI:10.1590/S1807-59322011000700009",
"Risk",
"of",
"herpes",
"zoster",
"in",
"patients",
"with",
"systemic",
"lupus",
"erythematosus:",
"a",
"three-year",
"follow-up",
"study",
"using",
"a",
"nationwide",
"population-based",
"cohort",
"Hsin-Hua",
"Chen,I,II,IV",
"Yi-Ming",
"Chen,I,II",
"Tzeng-Ji",
"Chen,II,III",
"Joung-Liang",
"Lan,I,II,IV,V",
"Ching-Heng",
"Lin,VI",
"Der-Yuan",
"ChenI,II,IV,V",
"I",
"Division",
"of",
"Allergy,",
"Immunology",
"and",
"Rheumatology,",
"Department",
"of",
"Internal",
"Medicine,",
"Taichung",
"Veterans",
"General",
"Hospital,",
"Taichung,",
"Taiwan.",
"II",
"School",
"of",
"Medicine,",
"National",
"Yang-Ming",
"University,",
"Taipei,",
"Taiwan.",
"III",
"Department",
"of",
"Family",
"Medicine,",
"Taipei",
"Veterans",
"General",
"Hospital,",
"Taipei,",
"Taiwan.",
"IV",
"School",
"of",
"Medicine,",
"Chung-Shan",
"Medical",
"University,",
"Taichung,",
"Taiwan.",
"V",
"Institute",
"of",
"Biomedical",
"Science,",
"Chung-Hsing",
"University,",
"Taichung,",
"Taiwan.",
"VI",
"Department",
"of",
"Medical",
"Research,",
"Taichung",
"Veterans",
"General",
"Hospital,",
"Taichung,",
"Taiwan.",
"OBJECTIVE:",
"The",
"goal",
"of",
"the",
"present",
"study",
"was",
"to",
"estimate",
"the",
"risk",
"ratio",
"of",
"herpes",
"zoster",
"among",
"systemic",
"lupus",
"erythematosus",
"patients",
"after",
"disease",
"onset",
"compared",
"with",
"a",
"cohort",
"of",
"patients",
"without",
"systemic",
"lupus",
"erythematosus",
"over",
"a",
"three-year",
"period.",
"METHODS:",
"A",
"nationwide",
"population-based",
"cohort",
"study",
"using",
"the",
"National",
"Health",
"Insurance",
"Research",
"Database",
"identified",
"10,337",
"new",
"cases",
"of",
"systemic",
"lupus",
"erythematosus",
"as",
"the",
"study",
"cohort.",
"In",
"addition,",
"62,022",
"patients",
"without",
"systemic",
"lupus",
"erythematosus,",
"who",
"were",
"matched",
"for",
"age,",
"gender,",
"and",
"date",
"of",
"systemic",
"lupus",
"erythematosus",
"diagnosis,",
"were",
"used",
"as",
"the",
"comparison",
"cohort.",
"These",
"cohorts",
"were",
"followed-up",
"for",
"three",
"years.",
"A",
"Cox",
"proportional",
"hazard",
"regression",
"was",
"performed",
"to",
"estimate",
"the",
"risk",
"ratio",
"of",
"herpes",
"zoster,",
"with",
"adjustments",
"for",
"age,",
"gender,",
"level",
"of",
"insurance,",
"urbanization",
"level,",
"geographic",
"region,",
"comorbid",
"medical",
"conditions,",
"average",
"daily",
"dosage",
"of",
"corticosteroids,",
"and",
"the",
"use",
"of",
"immune-modulation",
"agents.",
"RESULTS:",
"Compared",
"to",
"patients",
"without",
"systemic",
"lupus",
"erythematosus,",
"the",
"crude",
"risk",
"ratio",
"and",
"adjusted",
"risk",
"ratio",
"of",
"herpes",
"zoster",
"among",
"systemic",
"lupus",
"erythematosus",
"patients",
"were",
"7.37",
"(95%",
"confidence",
"interval",
"6.75-8.04)",
"and",
"2.45",
"(95%",
"confidence",
"interval",
"1.77-3.40),",
"respectively.",
"Stratified",
"by",
"gender,",
"the",
"adjusted",
"risk",
"ratio",
"of",
"herpes",
"zoster",
"was",
"2.10",
"(95%",
"confidence",
"interval",
"1.45-2.99)",
"in",
"women",
"and",
"7.51",
"(95%",
"confidence",
"interval",
"2.89-19.52)",
"in",
"men.",
"Stratified",
"by",
"age,",
"the",
"adjusted",
"risk",
"ratio",
"peaked",
"in",
"systemic",
"lupus",
"erythematosus",
"patients",
"who",
"were",
"aged",
"18",
"to",
"24",
"years",
"(risk",
"ratio",
"8.78,",
"95%",
"confidence",
"interval",
"3.08-24.97).",
"CONCLUSION:",
"Based",
"on",
"nationwide",
"population-based",
"data,",
"there",
"is",
"an",
"increased",
"risk",
"of",
"herpes",
"zoster",
"in",
"systemic",
"lupus",
"erythematosus",
"patients",
"compared",
"with",
"non-systemic",
"lupus",
"erythematosus",
"patients,",
"particularly",
"among",
"males",
"and",
"patients",
"aged",
"18",
"to",
"24",
"years.",
"Further",
"research",
"on",
"the",
"associated",
"risk",
"factors",
"for",
"herpes",
"zoster",
"in",
"systemic",
"lupus",
"erythematosus",
"patients",
"is",
"needed.",
"KEYWORDS:",
"Herpes",
"Zoster;",
"Risk;",
"Systemic",
"Lupus",
"Erythematosus;",
"Population-Based",
"Cohort",
"Study;",
"Database.",
"Chen",
"HH,",
"Chen",
"YM,",
"Chen",
"TJ,",
"Lan",
"JL,",
"Lin",
"CH,",
"Chen",
"DY.",
"Risk",
"of",
"herpes",
"zoster",
"in",
"patients",
"with",
"systemic",
"lupus",
"erythematosus:",
"a",
"three-year",
"follow-up",
"study",
"using",
"a",
"nationwide",
"population-based",
"cohort.",
"Clinics.",
"2011;66(7):1177-1182.",
"Received",
"for",
"publication",
"on",
"January",
"26,",
"2011;",
"First",
"review",
"completed",
"on",
"February",
"25,",
"2011;",
"Accepted",
"for",
"publication",
"on",
"May",
"21,",
"2011",
"E-mail:",
"dychen@vghtc.gov.tw",
"Tel.:",
"886-4-23592525",
"ext",
"3336",
"INTRODUCTION",
"Herpes",
"zoster",
"(HZ)",
"is",
"characterized",
"by",
"debilitating",
"painful",
"vesicular",
"eruptions",
"in",
"a",
"dermatomal",
"distribution",
"that",
"are",
"caused",
"by",
"the",
"reactivation",
"of",
"a",
"latent",
"varicella",
"zoster",
"virus",
"(VZV)",
"infection.1",
"This",
"disease",
"is",
"commonly",
"observed",
"in",
"the",
"elderly,",
"in",
"immuno-compromised",
"hosts,",
"and",
"in",
"patients",
"with",
"systemic",
"lupus",
"erythematosus",
"(SLE).2-5",
"Copyright",
"2011",
"CLINICS",
"–",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0/)",
"which",
"permits",
"unrestricted",
"non-",
"commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Cutaneous",
"vesicles",
"can",
"be",
"complicated",
"by",
"a",
"bacterial",
"super-infection,",
"and",
"the",
"dissemination",
"of",
"HZ",
"may",
"be",
"life-",
"threatening.3",
"Post-herpetic",
"neuralgia",
"in",
"the",
"affected",
"areas",
"is",
"the",
"most",
"common",
"complication,",
"which",
"can",
"persist",
"for",
"months",
"or",
"years.",
"The",
"incidence",
"of",
"HZ",
"in",
"the",
"general",
"population",
"is",
"1.2",
"to",
"4.9",
"cases",
"per",
"1000",
"person-years,",
"depending",
"on",
"the",
"ethnic",
"group.6-7",
"The",
"reported",
"incidence",
"of",
"HZ",
"in",
"SLE",
"patients",
"is",
"significantly",
"greater",
"than",
"the",
"incidence",
"in",
"the",
"general",
"population,",
"ranging",
"from",
"16",
"to",
"22",
"cases",
"per",
"1000",
"patient-years",
"in",
"large",
"cohort",
"studies.2-3,8",
"The",
"greater",
"incidence",
"of",
"HZ",
"infection",
"in",
"SLE",
"has",
"been",
"shown",
"to",
"be",
"related",
"to",
"abnormal",
"T-cell-mediated",
"cytotoxi-",
"city",
"that",
"is",
"aggravated",
"by",
"the",
"concomitant",
"use",
"of",
"glucocor-",
"ticoids",
"and",
"immuno-suppressants.4,9-10",
"Disease",
"activity,",
"1177"
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] | [
"Research",
"|",
"Children’s",
"Health",
"Assessing",
"Children’s",
"Dietary",
"Pesticide",
"Exposure:",
"Direct",
"Measurement",
"of",
"Pesticide",
"Residues",
"in",
"24-Hr",
"Duplicate",
"Food",
"Samples",
"Chensheng",
"Lu,1",
"Frank",
"J.",
"Schenck,2",
"Melanie",
"A.",
"Pearson,3",
"and",
"Jon",
"W.",
"Wong",
"4",
"1Exposure,",
"Epidemiology,",
"and",
"Risk",
"Program,",
"Department",
"of",
"Environmental",
"Health,",
"Harvard",
"School",
"of",
"Public",
"Health,",
"Boston,",
"Massachusetts,",
"USA;",
"2U.S.",
"Food",
"and",
"Drug",
"Administration,",
"Southeast",
"Regional",
"Laboratory,",
"Atlanta,",
"Georgia,",
"USA",
"(retired);",
"3Department",
"of",
"Environmental",
"and",
"Occupational",
"Health,",
"Rollins",
"School",
"of",
"Public",
"Health,",
"Emory",
"University,",
"Atlanta,",
"Georgia,",
"USA;",
"4U.S.",
"Food",
"and",
"Drug",
"Administration,",
"Center",
"for",
"Food",
"Safety",
"and",
"Applied",
"Nutrition,",
"College",
"Park,",
"Maryland,",
"USA",
"Background",
":",
"The",
"data",
"presented",
"here",
"are",
"a",
"response",
"to",
"calls",
"for",
"more",
"direct",
"measurements",
"of",
"pesticide",
"residues",
"in",
"foods",
"consumed",
"by",
"children",
"and",
"provide",
"an",
"opportunity",
"to",
"compare",
"direct",
"measures",
"of",
"pesticide",
"residues",
"in",
"foods",
"representing",
"actual",
"consumption",
"with",
"those",
"reported",
"by",
"the",
"U.S.",
"Department",
"of",
"Agriculture",
"Pesticide",
"Data",
"Program.",
"o",
"Bjectiv",
":",
"We",
"measured",
"pesticide",
"residues",
"in",
"24-hr",
"duplicate",
"food",
"samples",
"collected",
"from",
"a",
"group",
"of",
"46",
"young",
"children",
"participating",
"in",
"the",
"Children’s",
"Pesticide",
"Exposure",
"Study",
"(CPES).",
"Methods",
":",
"Parents",
"were",
"instructed",
"to",
"collect",
"24-hr",
"duplicate",
"food",
"samples",
"of",
"all",
"conventional",
"fruits,",
"vegetables,",
"and",
"fruit",
"juices",
"equal",
"to",
"the",
"quantity",
"consumed",
"by",
"their",
"children,",
"similarly",
"prewashed/",
"prepared,",
"and",
"from",
"the",
"same",
"source",
"or",
"batch.",
"Individual",
"or",
"composite",
"food",
"items",
"were",
"analyzed",
"for",
"organophosphate",
"(OP)",
"and",
"pyrethroid",
"insecticide",
"residues.",
"r",
"esult",
":",
"We",
"collected",
"a",
"total",
"of",
"239",
"24-hr",
"duplicate",
"food",
"samples",
"collected",
"from",
"the",
"46",
"CPES",
"chil-",
"dren.",
"We",
"found",
"14%",
"or",
"5%",
"of",
"those",
"food",
"samples",
"contained",
"at",
"least",
"one",
"OP",
"or",
"pyrethroid",
"insecti-",
"cide,",
"respectively.",
"We",
"measured",
"a",
"total",
"of",
"11",
"OP",
"insecticides,",
"at",
"levels",
"ranging",
"from",
"1",
"to",
"387",
"ng/g,",
"and",
"three",
"pyrethroid",
"insecticides,",
"at",
"levels",
"ranging",
"from",
"2",
"to",
"1,133",
"ng/g,",
"in",
"children’s",
"food",
"samples.",
"We",
"found",
"that",
"many",
"of",
"the",
"food",
"items",
"consumed",
"by",
"the",
"CPES",
"children",
"were",
"also",
"on",
"the",
"list",
"of",
"the",
"most",
"contaminated",
"food",
"commodities",
"reported",
"by",
"the",
"Environmental",
"Working",
"Group.",
"c",
"onclusi",
":",
"The",
"frequent",
"consumption",
"of",
"food",
"commodities",
"with",
"episodic",
"presence",
"of",
"pesticide",
"residues",
"that",
"are",
"suspected",
"to",
"cause",
"developmental",
"and",
"neurological",
"effects",
"in",
"young",
"children",
"sup-",
"ports",
"the",
"need",
"for",
"further",
"mitigation.",
"k",
"ey",
"words",
":",
"children’s",
"diets,",
"dietary",
"pesticide",
"exposure,",
"organophosphate",
"pesticides,",
"pesticide",
"residue,",
"pesticide",
"risk",
"assessment,",
"pyrethroid",
"insecticides.",
"Environ",
"Health",
"Perspect",
"118:1625–1630",
"(2010).",
"doi:10.1289/ehp.1002044",
"[Online",
"16",
"July",
"2010]",
"In",
"the",
"1990s,",
"a",
"book",
"published",
"by",
"the",
"National",
"Research",
"Council",
"(NRC)",
"titled",
"Pesticides",
"in",
"the",
"Diets",
"of",
"Infants",
"and",
"Children",
"(NRC",
"1993)",
"and",
"the",
"passage",
"of",
"the",
"Food",
"Quality",
"Protection",
"Act",
"of",
"1996",
"(FQPA",
"1996)",
"were",
"hailed",
"as",
"two",
"major",
"milestones",
"in",
"the",
"United",
"States",
"in",
"recogniz-",
"ing",
"the",
"need",
"for",
"systematic",
"efforts",
"in",
"reducing",
"pesticide",
"exposure",
"in",
"vulnerable",
"populations,",
"especially",
"infants",
"and",
"children.",
"An",
"important",
"summary",
"statement",
"in",
"the",
"NRC",
"report",
"declared",
"that",
"“dietary",
"intake",
"represents",
"the",
"major",
"source",
"of",
"pesticide",
"exposure",
"for",
"infants",
"and",
"children,",
"and",
"the",
"dietary",
"exposure",
"may",
"account",
"for",
"the",
"increased",
"pesticide-related",
"health",
"risks",
"in",
"chil-",
"dren",
"compared",
"with",
"adults.”",
"After",
"the",
"NRC",
"report,",
"the",
"newly",
"enacted",
"FQPA",
"aimed",
"to",
"fundamentally",
"change",
"U.S.",
"policies",
"in",
"govern-",
"ing",
"the",
"acceptability",
"of",
"pesticide",
"residues",
"in",
"foods",
"and",
"required",
"the",
"U.S.",
"Environmental",
"Protection",
"Agency",
"(EPA)",
"to",
"assure",
"the",
"public",
"that",
"there",
"is",
"a",
"“reasonable",
"certainty",
"of",
"no",
"harm”",
"from",
"pesticide",
"exposures",
"for",
"pregnant",
"women,",
"infants,",
"children,",
"and",
"other",
"vulnerable",
"groups.",
"Despite",
"many",
"years",
"of",
"effort",
"in",
"implementing",
"the",
"FQPA,",
"monitoring",
"and",
"managing",
"dietary",
"pesticide",
"exposures",
"and",
"risks",
"are",
"still",
"an",
"ongo-",
"ing",
"challenge.",
"A",
"recent",
"report",
"published",
"by",
"the",
"U.S.",
"Office",
"of",
"Inspector",
"General",
"(2006)",
"has",
"stressed",
"the",
"need",
"for",
"data-driven",
"indicators",
"of",
"pesticide",
"dietary",
"exposures/risks.",
"The",
"data",
"presented",
"here",
"are",
"in",
"response",
"to",
"these",
"calls",
"for",
"more",
"direct",
"measurements",
"of",
"pes-",
"ticide",
"residues",
"in",
"foods",
"consumed",
"by",
"children",
"and",
"provide",
"an",
"initial",
"assessment",
"of",
"the",
"effects",
"of",
"the",
"U.S.",
"EPA’s",
"actions",
"on",
"assessing",
"dietary",
"pesticide",
"risks",
"(U.S.",
"Office",
"of",
"the",
"Inspector",
"General",
"2006).",
"In",
"this",
"study,",
"we",
"measured",
"pes-",
"ticide",
"residues",
"in",
"24-hr",
"duplicate",
"foods",
"from",
"a",
"group",
"of",
"elementary",
"school–age",
"children",
"par-",
"ticipating",
"in",
"the",
"Children’s",
"Pesticide",
"Exposure",
"Study",
"(CPES).",
"In",
"addition,",
"the",
"CPES",
"data",
"pro-",
"vided",
"an",
"opportunity",
"to",
"compare",
"direct",
"mea-",
"sures",
"of",
"pesticide",
"residues",
"in",
"foods",
"representing",
"actual",
"consumption",
"with",
"measured",
"values",
"reported",
"by",
"the",
"Pesticide",
"Data",
"Program",
"[PDP;",
"U.S.",
"Department",
"of",
"Agriculture",
"(USDA)",
"2009],",
"a",
"national",
"database",
"of",
"pesticide",
"residues",
"found",
"on",
"foods",
"that",
"are",
"ready",
"for",
"distribution",
"in",
"the",
"United",
"States.",
"This",
"comparison",
"allows",
"a",
"unique",
"examination",
"of",
"“real-world”",
"applicabil-",
"ity",
"of",
"the",
"national",
"data",
"set.",
"Materials",
"and",
"Methods",
"Children’s",
"Pesticide",
"Exposure",
"Study.",
"CPES",
"was",
"initially",
"conducted",
"in",
"the",
"suburban",
"Seattle,",
"Washington,",
"area",
"(CPES-WA)",
"from",
"summer",
"2003",
"to",
"winter",
"2004",
"and",
"was",
"later",
"repeated",
"in",
"Atlanta,",
"Georgia",
"(CPES-GA),",
"in",
"2006/2007",
"with",
"the",
"same",
"study",
"protocol.",
"Twenty-three",
"children",
"3–11",
"years",
"of",
"age",
"were",
"recruited",
"for",
"Environmental",
"Health",
"Perspectives",
"•",
"volume",
"118",
"|",
"number",
"11",
"|",
"November",
"2010",
"each",
"CPES",
"study",
"from",
"local",
"public",
"elementary",
"schools",
"and",
"Montessori",
"preschools.",
"(One",
"of",
"the",
"children",
"who",
"participated",
"in",
"CPES-GA",
"study",
"was",
"12",
"years",
"old",
"at",
"the",
"beginning",
"of",
"study.)",
"Schools",
"did",
"not",
"provide",
"any",
"assistance",
"in",
"recruiting",
"subjects",
"except",
"for",
"granting",
"permis-",
"sion",
"to",
"send",
"home",
"with",
"the",
"children",
"a",
"letter",
"and",
"a",
"fact",
"sheet",
"describing",
"the",
"study.",
"Families",
"that",
"were",
"interested",
"in",
"participating",
"in",
"this",
"study",
"then",
"contacted",
"the",
"research",
"group",
"directly.",
"A",
"screening",
"questionnaire",
"was",
"conducted",
"over",
"the",
"phone",
"to",
"confirm",
"eligibility,",
"which",
"included",
"children",
"exclusively",
"consuming",
"conventional",
"(nonorganic)",
"diets",
"and",
"spending",
"most",
"of",
"their",
"time",
"in",
"one",
"residence,",
"and",
"the",
"willingness",
"of",
"parents",
"or",
"caregivers",
"to",
"provide",
"assistance",
"in",
"collecting",
"specimen",
"samples.",
"Once",
"a",
"participant",
"was",
"enrolled,",
"an",
"in-house",
"appointment",
"was",
"made",
"to",
"go",
"over",
"the",
"study",
"protocol",
"and",
"train",
"the",
"parents/caregivers",
"on",
"how",
"to",
"collect",
"speci-",
"mens",
"and",
"24-hr",
"duplicate",
"food",
"samples.",
"All",
"parents",
"provided",
"written",
"informed",
"consent,",
"and",
"all",
"children",
"provided",
"written",
"informed",
"consent",
"(if",
"≥",
"10",
"years",
"of",
"age)",
"or",
"oral",
"assent",
"(<",
"10",
"years",
"of",
"age)",
"before",
"data",
"collection",
"began.",
"A",
"ques-",
"tionnaire",
"was",
"also",
"administered",
"by",
"the",
"research",
"staff",
"during",
"this",
"appointment",
"that",
"asked",
"about",
"household",
"pesticide",
"use",
"to",
"account",
"for",
"nondi-",
"etary",
"sources",
"of",
"pesticide",
"exposure.",
"Each",
"CPES",
"child",
"agreed",
"to",
"participate",
"in",
"multiple",
"consecutive",
"days",
"of",
"sampling",
"in",
"four",
"seasons",
"over",
"a",
"12-month",
"period",
"(four",
"seasons).",
"Address",
"correspondence",
"to",
"C.",
"Lu,",
"401",
"Park",
"Dr.,",
"Landmark",
"Center",
"West,",
"Boston,",
"MA",
"02215,",
"USA.",
"Telephone:",
"(617)",
"998-8811.",
"Fax:",
"(617)",
"384-8728.",
"E-mail:",
"cslu@hsph.harvard.edu",
"We",
"thank",
"K.",
"Toepel,",
"R.",
"Irish,",
"and",
"P.",
"Sande",
"(University",
"of",
"Washington);",
"M.",
"Givens,",
"C.",
"Holbrook,",
"D.",
"Gregory,",
"M.",
"Holubar,",
"and",
"Hui-Mien",
"Hsiao",
"(Emory",
"University);",
"and",
"K.",
"Zhang",
"(Food",
"and",
"Drug",
"Administration",
"[FDA],",
"Center",
"for",
"Food",
"Safety",
"and",
"Applied",
"Nutrition)",
"for",
"their",
"contributions",
"in",
"the",
"Children’s",
"Pesticide",
"Exposure",
"Study.",
"This",
"work",
"was",
"supported",
"by",
"the",
"U.S.",
"Environmental",
"Protection",
"Agency",
"(EPA)",
"under",
"the",
"Science",
"to",
"Achieve",
"Results",
"research",
"assistance",
"program",
"(R-832244",
"and",
"R-829364).",
"The",
"content",
"of",
"this",
"publication",
"has",
"not",
"been",
"for-",
"mally",
"reviewed",
"by",
"the",
"U.S.",
"EPA",
"and",
"FDA,",
"and",
"the",
"views",
"expressed",
"in",
"this",
"document",
"are",
"solely",
"those",
"of",
"the",
"authors.",
"Neither",
"the",
"U.S.",
"EPA",
"nor",
"the",
"FDA",
"endorses",
"any",
"products",
"or",
"commercial",
"services",
"men-",
"tioned",
"in",
"this",
"publication.",
"The",
"authors",
"declare",
"they",
"have",
"no",
"actual",
"or",
"potential",
"competing",
"financial",
"interests.",
"Received",
"10",
"February",
"2010;",
"accepted",
"16",
"July",
"2010.",
"1625"
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] | [
"Berg",
"et",
"al.",
"Critical",
"Care",
"2010,",
"14:R16",
"http://ccforum.com/content/14/1/R16",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Cerebral",
"net",
"exchange",
"of",
"large",
"neutral",
"amino",
"acids",
"after",
"lipopolysaccharide",
"infusion",
"in",
"healthy",
"humans",
"Ronan",
"MG",
"Berg1*,",
"Sarah",
"Taudorf1,",
"Damian",
"M",
"Bailey2,",
"Carsten",
"Lundby3,",
"Fin",
"Stolze",
"Larsen4,",
"Bente",
"Klarlund",
"Pedersen1,3,",
"Kirsten",
"Møller1,5",
"Abstract",
"Introduction:",
"Alterations",
"in",
"circulating",
"large",
"neutral",
"amino",
"acids",
"(LNAAs),",
"leading",
"to",
"a",
"decrease",
"in",
"the",
"plasma",
"ratio",
"between",
"branched-chain",
"and",
"aromatic",
"amino",
"acids",
"(BCAA/AAA",
"ratio),",
"may",
"be",
"involved",
"in",
"sepsis-associated",
"encephalopathy.",
"We",
"hypothesised",
"that",
"a",
"decrease",
"in",
"the",
"BCAA/AAA",
"ratio",
"occurs",
"along",
"with",
"a",
"net",
"cerebral",
"influx",
"of",
"the",
"neurotoxic",
"AAA",
"phenylalanine",
"in",
"a",
"human",
"experimental",
"model",
"of",
"systemic",
"inflammation.",
"Methods:",
"The",
"BCAA/AAA",
"ratio,",
"the",
"cerebral",
"delivery,",
"and",
"net",
"exchange",
"of",
"LNAAs",
"and",
"ammonia",
"were",
"measured",
"before",
"and",
"1",
"hour",
"after",
"a",
"4-hour",
"intravenous",
"infusion",
"of",
"Escherichia",
"coli",
"lipopolysaccharide",
"(LPS)",
"in",
"12",
"healthy",
"young",
"men.",
"Results:",
"LPS",
"induced",
"systemic",
"inflammation,",
"reduced",
"the",
"BCAA/AAA",
"ratio,",
"increased",
"the",
"cerebral",
"delivery",
"and",
"unidirectional",
"influx",
"of",
"phenylalanine,",
"and",
"abolished",
"the",
"net",
"cerebral",
"influx",
"of",
"the",
"BCAAs",
"leucine",
"and",
"isoleucine.",
"Furthermore,",
"a",
"net",
"cerebral",
"efflux",
"of",
"glutamine,",
"which",
"was",
"independent",
"of",
"the",
"cerebral",
"net",
"exchange",
"of",
"ammonia,",
"was",
"present",
"after",
"LPS",
"infusion.",
"Conclusions:",
"Systemic",
"inflammation",
"may",
"affect",
"brain",
"function",
"by",
"reducing",
"the",
"BCAA/AAA",
"ratio,",
"thereby",
"changing",
"the",
"cerebral",
"net",
"exchange",
"of",
"LNAAs.",
"Introduction",
"Sepsis-associated",
"encephalopathy",
"(SAE)",
"is",
"often",
"one",
"of",
"the",
"first",
"manifestations",
"of",
"sepsis",
"[1]",
"and",
"is",
"associated",
"with",
"an",
"adverse",
"outcome",
"[2,3].",
"The",
"pathogenesis",
"of",
"SAE",
"is",
"largely",
"unknown,",
"although",
"several",
"potential",
"mechan-",
"isms",
"have",
"been",
"investigated,",
"including",
"cerebral",
"blood",
"flow",
"(CBF)",
"and",
"metabolic",
"alterations,",
"intracranial",
"hyper-",
"tension,",
"cerebral",
"edema,",
"disruption",
"of",
"the",
"blood-brain",
"barrier",
"(BBB),",
"neuronal",
"degeneration,",
"and",
"abnormal",
"neurotransmitter",
"composition",
"[4].",
"Sepsis",
"is",
"characterized",
"by",
"increased",
"peripheral",
"pro-",
"tein",
"breakdown,",
"notably",
"in",
"skeletal",
"muscle",
"[5,6],",
"and",
"hepatic",
"synthesis",
"of",
"acute-phase",
"reactants;",
"the",
"ensuing",
"alterations",
"in",
"plasma",
"amino",
"acids",
"may",
"play",
"a",
"key",
"role",
"in",
"SAE.",
"Thus,",
"the",
"plasma",
"ratio",
"between",
"branched-",
"chain",
"and",
"aromatic",
"amino",
"acids",
"(BCAAs",
"and",
"AAAs,",
"*",
"Correspondence:",
"ronan@dadlnet.dk",
"1Centre",
"of",
"Inflammation",
"and",
"Metabolism,",
"Department",
"of",
"Infectious",
"Diseases,",
"Rigshospitalet,",
"Blegdamsvej",
"9,",
"2100",
"Copenhagen,",
"Denmark",
"respectively)",
"decreases,",
"because",
"the",
"BCAAs",
"are",
"rapidly",
"used",
"in",
"the",
"liver,",
"whereas",
"phenylalanine",
"levels",
"increase",
"[7-9].",
"BCAAs",
"and",
"AAAs",
"belong",
"to",
"the",
"group",
"of",
"large",
"neutral",
"amino",
"acids",
"(LNAAs),",
"which",
"compete",
"for",
"the",
"same",
"saturable",
"carrier",
"across",
"the",
"BBB",
"[10].",
"Hence,",
"a",
"decrease",
"in",
"the",
"BCAA/AAA",
"ratio",
"theoreti-",
"cally",
"implies",
"either",
"a",
"decreased",
"availability",
"of",
"BCAAs",
"to",
"the",
"brain,",
"or",
"an",
"intracerebral",
"accumulation",
"of",
"AAAs,",
"both",
"of",
"which",
"may",
"profoundly",
"affect",
"neuronal",
"function",
"[11].",
"At",
"present,",
"neither",
"the",
"physiological",
"implications",
"of",
"alterations",
"in",
"the",
"BCAA/AAA",
"ratio",
"nor",
"the",
"effects",
"of",
"systemic",
"inflammation",
"on",
"the",
"cerebral",
"net",
"exchange",
"of",
"LNAAs",
"has",
"been",
"investigated",
"in",
"humans.",
"Applying",
"a",
"human",
"experimental",
"model",
"of",
"systemic",
"inflammation,",
"we",
"hypothesised",
"that",
"the",
"BCAA/AAA",
"ratio",
"decreases",
"with",
"a",
"concurrent",
"net",
"cerebral",
"influx",
"of",
"the",
"neurotoxic",
"AAA",
"phenylalanine,",
"and",
"that",
"this",
"attenuates",
"the",
"net",
"cer-",
"ebral",
"influx",
"of",
"BCAAs.",
"©",
"2010",
"Berg",
"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."
] | [
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"Public",
"Health,",
"Beijing,",
"China",
"Abstract",
"Background:",
"There",
"is",
"current",
"interest",
"in",
"understanding",
"the",
"molecular",
"mechanisms",
"of",
"tumor-induced",
"bone",
"pain.",
"Accumulated",
"evidence",
"shows",
"that",
"endogenous",
"formaldehyde",
"concentrations",
"are",
"elevated",
"in",
"the",
"blood",
"or",
"urine",
"of",
"patients",
"with",
"breast,",
"prostate",
"or",
"bladder",
"cancer.",
"These",
"cancers",
"are",
"frequently",
"associated",
"with",
"cancer",
"pain",
"especially",
"after",
"bone",
"metastasis.",
"It",
"is",
"well",
"known",
"that",
"transient",
"receptor",
"potential",
"vanilloid",
"receptor",
"1",
"(TRPV1)",
"participates",
"in",
"cancer",
"pain.",
"The",
"present",
"study",
"aims",
"to",
"demonstrate",
"that",
"the",
"tumor",
"tissue-derived",
"endogenous",
"formaldehyde",
"induces",
"bone",
"cancer",
"pain",
"via",
"TRPV1",
"activation",
"under",
"tumor",
"acidic",
"environment.",
"Methodology/Principal",
"Findings:",
"Endogenous",
"formaldehyde",
"concentration",
"increased",
"significantly",
"in",
"the",
"cultured",
"breast",
"cancer",
"cell",
"lines",
"in",
"vitro,",
"in",
"the",
"bone",
"marrow",
"of",
"breast",
"MRMT-1",
"bone",
"cancer",
"pain",
"model",
"in",
"rats",
"and",
"in",
"tissues",
"from",
"breast",
"cancer",
"and",
"lung",
"cancer",
"patients",
"in",
"vivo.",
"Low",
"concentrations",
"(1,5",
"mM)",
"of",
"formaldehyde",
"induced",
"pain",
"responses",
"in",
"rat",
"via",
"TRPV1",
"and",
"this",
"pain",
"response",
"could",
"be",
"significantly",
"enhanced",
"by",
"pH",
"6.0",
"(mimicking",
"the",
"acidic",
"tumor",
"microenvironment).",
"Formaldehyde",
"at",
"low",
"concentrations",
"(1",
"mM",
"to",
"100",
"mM)",
"induced",
"a",
"concentration-dependent",
"increase",
"of",
"[Ca2+]i",
"in",
"the",
"freshly",
"isolated",
"rat",
"dorsal",
"root",
"ganglion",
"neurons",
"and",
"TRPV1-transfected",
"CHO",
"cells.",
"Furthermore,",
"electrophysiological",
"experiments",
"showed",
"that",
"low",
"concentration",
"formaldehyde-elicited",
"TRPV1",
"currents",
"could",
"be",
"significantly",
"potentiated",
"by",
"low",
"pH",
"(6.0).",
"TRPV1",
"antagonists",
"and",
"formaldehyde",
"scavengers",
"attenuated",
"bone",
"cancer",
"pain",
"responses.",
"Conclusions/Significance:",
"Our",
"data",
"suggest",
"that",
"cancer",
"tissues",
"directly",
"secrete",
"endogenous",
"formaldehyde,",
"and",
"this",
"formaldehyde",
"at",
"low",
"concentration",
"induces",
"metastatic",
"bone",
"cancer",
"pain",
"through",
"TRPV1",
"activation",
"especially",
"under",
"tumor",
"acidic",
"environment.",
"Citation:",
"Tong",
"Z,",
"Luo",
"W,",
"Wang",
"Y,",
"Yang",
"F,",
"Han",
"Y,",
"et",
"al.",
"(2010)",
"Tumor",
"Tissue-Derived",
"Formaldehyde",
"and",
"Acidic",
"Microenvironment",
"Synergistically",
"Induce",
"Bone",
"Cancer",
"Pain.",
"PLoS",
"ONE",
"5(4):",
"e10234.",
"doi:10.1371/journal.pone.0010234",
"Editor:",
"Hiroaki",
"Matsunami,",
"Duke",
"University,",
"United",
"States",
"of",
"America",
"Received",
"November",
"25,",
"2009;",
"Accepted",
"March",
"24,",
"2010;",
"Published",
"April",
"21,",
"2010",
"Copyright:",
"2010",
"Tong",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"research",
"was",
"supported",
"by",
"grants",
"from",
"the",
"National",
"Natural",
"Science",
"Foundation",
"of",
"China",
"(30700206,",
"30800332),",
"the",
"111",
"Project",
"of",
"the",
"Ministry",
"of",
"Education",
"of",
"China",
"(B07001),",
"the",
"National",
"Basic",
"Research",
"Program",
"of",
"the",
"Ministry",
"of",
"Science",
"and",
"Technology",
"of",
"China",
"(2007CB512501)",
"and",
"Beijing",
"Outstanding",
"Ph.D.",
"Program",
"Mentor",
"Grant,",
"Key",
"Project",
"of",
"Chinese",
"Ministry",
"of",
"Education",
"(109003).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"tzq88666883@sina.com",
"(ZT);",
"ywan@hsc.pku.edu.cn",
"(YW)",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"Cancer",
"pain",
"is",
"a",
"severe",
"clinical",
"condition,",
"and",
"about",
"75,90%",
"of",
"advanced",
"or",
"terminal",
"cancer",
"patients",
"experience",
"chronic",
"pain",
"related",
"to",
"treatment",
"failure",
"and/or",
"tumor",
"progression",
"or",
"metastasis.",
"Malignant",
"bone",
"tumors",
"occur",
"in",
"patients",
"with",
"primary",
"bone",
"cancer,",
"but",
"are",
"far",
"more",
"commonly",
"found",
"to",
"be",
"distant",
"metastases",
"from",
"other",
"primary",
"cancers,",
"notably",
"breast,",
"lung",
"and",
"prostate",
"cancers.",
"As",
"such,",
"bone",
"is",
"the",
"most",
"common",
"site",
"of",
"origin",
"of",
"chronic",
"pain",
"in",
"patients",
"with",
"metastatic",
"lung,",
"breast",
"and",
"prostate",
"cancers",
"and",
"myeloma",
"[1].",
"In",
"the",
"development",
"of",
"cancer,",
"it",
"is",
"suggested",
"that",
"tumor",
"tissues",
"secrete",
"different",
"kinds",
"of",
"factors",
"including",
"cytokines",
"such",
"as",
"TNF-a",
"and",
"IL-1",
"[2].",
"Clinical",
"data",
"have",
"shown",
"that",
"formaldehyde",
"concentration",
"is",
"elevated",
"(2,8",
"fold)",
"in",
"the",
"urine",
"of",
"patients",
"with",
"prostate",
"and",
"bladder",
"cancer",
"[3]",
"and",
"in",
"the",
"expired",
"air",
"from",
"tumor-bearing",
"mice",
"and",
"breast",
"cancer",
"patients",
"[4];",
"and",
"these",
"patients",
"frequently",
"suffer",
"from",
"bone",
"cancer",
"pain",
"[5,6].",
"Formaldehyde",
"is",
"considered",
"to",
"be",
"a",
"risk",
"factor",
"of",
"cancer",
"development",
"[7],",
"but",
"for",
"the",
"most",
"part",
"knowledge",
"about",
"formaldehyde",
"secretion",
"by",
"tumor",
"tissue",
"is",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"April",
"2010",
"|",
"Volume",
"5",
"|",
"Issue",
"4",
"|",
"e10234"
] | [
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] | [
"Fujihara",
"et",
"al.",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2012,",
"6:268",
"http://www.jmedicalcasereports.com/content/6/1/268",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"JOURNAL",
"OF",
"MEDICAL",
"CASE",
"REPORTS",
"Open",
"Access",
"Endoscopic",
"hemostasis",
"with",
"endoscopic",
"mucosal",
"resection",
"and",
"multiple",
"synchronous",
"early",
"gastric",
"cancers:",
"a",
"case",
"report",
"Shintaro",
"Fujihara*,",
"Hirohito",
"Mori,",
"Noriko",
"Nishiyama,",
"Mitsuyoshi",
"Kobayashi,",
"Hideki",
"Kobara",
"and",
"Tsutomu",
"Masaki",
"Abstract",
"Introduction:",
"Endoscopic",
"hemostasis",
"for",
"severe",
"upper",
"gastrointestinal",
"bleeding",
"due",
"to",
"tumors,",
"such",
"as",
"gastrointestinal",
"stromal",
"tumors",
"and",
"malignant",
"lymphoma,",
"is",
"temporarily",
"effective.",
"However,",
"permanent",
"hemostasis",
"is",
"difficult",
"in",
"many",
"cases",
"because",
"of",
"diffuse",
"bleeding.",
"Case",
"presentation:",
"A",
"60-year-old",
"Japanese",
"woman",
"was",
"admitted",
"to",
"our",
"hospital",
"with",
"hematemesis.",
"Endoscopy",
"revealed",
"multiple",
"gastric",
"polyps",
"and",
"fresh",
"blood",
"in",
"her",
"stomach.",
"One",
"of",
"the",
"gastric",
"polyps,",
"which",
"was",
"associated",
"with",
"oozing",
"bleeding,",
"was",
"found",
"near",
"the",
"anterior",
"wall",
"of",
"the",
"lower",
"gastric",
"body.",
"We",
"initially",
"applied",
"hemostatic",
"forceps",
"and",
"argon",
"plasma",
"coagulation",
"over",
"the",
"tumor",
"surface,",
"but",
"the",
"bleeding",
"persisted.",
"After",
"endoscopic",
"mucosal",
"resection,",
"exposed",
"vessels",
"were",
"seen",
"at",
"the",
"base",
"of",
"the",
"mucosal",
"resection",
"site",
"with",
"oozing",
"bleeding.",
"Coagulation",
"of",
"the",
"bleeding",
"vessels",
"using",
"hemostatic",
"forceps",
"allowed",
"successful",
"completion",
"of",
"the",
"hemostatic",
"procedure.",
"Our",
"patient",
"also",
"had",
"eight",
"synchronous",
"gastric",
"cancer",
"lesions.",
"Histological",
"examination",
"of",
"the",
"resected",
"specimens",
"showed",
"various",
"types",
"of",
"cancer.",
"Conclusion:",
"This",
"is",
"a",
"case",
"report",
"of",
"gastric",
"cancer",
"associated",
"with",
"eight",
"gastric",
"cancer",
"lesions,",
"confirmed",
"by",
"histology,",
"in",
"which",
"hemostasis",
"was",
"achieved",
"through",
"endoscopy.",
"Introduction",
"Endoscopic",
"hemostasis",
"for",
"severe",
"upper",
"gastrointestinal",
"(GI)",
"bleeding",
"due",
"to",
"tumors,",
"such",
"as",
"GI",
"stromal",
"tumors",
"and",
"malignant",
"lymphoma,",
"is",
"temporarily",
"effective",
"[1].",
"However,",
"permanent",
"hemostasis",
"is",
"difficult",
"in",
"many",
"cases",
"because",
"of",
"diffuse",
"bleeding",
"[2].",
"We",
"here",
"report",
"a",
"case",
"of",
"endoscopic",
"hemostasis",
"with",
"endoscopic",
"mucosal",
"resection",
"(EMR)",
"as",
"a",
"rescue",
"therapy",
"for",
"bleed-",
"ing",
"of",
"a",
"malignant",
"GI",
"tumor",
"after",
"failed",
"conventional",
"therapy.",
"This",
"patient",
"also",
"had",
"multiple",
"synchronous",
"gastric",
"cancers.",
"Case",
"presentation",
"A",
"60-year-old",
"Japanese",
"woman",
"was",
"admitted",
"to",
"our",
"hospital",
"with",
"hematemesis.",
"She",
"had",
"no",
"history",
"of",
"GI",
"hemorrhage,",
"peptic",
"ulcer",
"disease,",
"use",
"of",
"nonsteroidal",
"anti-inflammatory",
"drugs,",
"excessive",
"alcohol",
"ingestion,",
"or",
"*",
"Correspondence:",
"joshin@med.kagawa-u.ac.jp",
"Department",
"of",
"Gastroenterology",
"and",
"Neurology,",
"Kagawa",
"University,",
"Faculty",
"of",
"Medicine,",
"1750-1",
"Ikenobe,",
"Miki-cho,",
"Kita-gun,",
"Kagawa",
"Prefecture",
"761-0793,",
"Japan",
"chronic",
"liver",
"disease.",
"She",
"had",
"no",
"other",
"medical",
"problems",
"and",
"was",
"taking",
"no",
"medications.",
"On",
"presentation,",
"her",
"abdomen",
"was",
"soft,",
"nontender,",
"and",
"nondistended",
"with",
"normal",
"bowel",
"sounds.",
"Her",
"hemoglobin",
"level",
"was",
"8.5g/dL.",
"Contrast-enhanced",
"com-",
"puted",
"tomography",
"(CT)",
"revealed",
"multiple",
"lesions",
"in",
"her",
"stomach.",
"Hematologic",
"tests",
"revealed",
"a",
"total",
"peripheral",
"3",
"white",
"cell",
"count",
"of",
"14,400/mm",
".",
"Biochemical",
"tests",
"yielded",
"elevated",
"serum",
"blood",
"nitrogen",
"(30.7mg/dL),",
"decreased",
"total",
"protein",
"(3.8g/dL),",
"and",
"decreased",
"serum",
"albumin",
"(2.0mg/dL).",
"Endoscopy",
"revealed",
"multiple",
"gastric",
"polyps",
"and",
"fresh",
"blood",
"in",
"her",
"stomach.",
"One",
"of",
"the",
"gastric",
"polyps,",
"which",
"was",
"associated",
"with",
"oozing",
"bleeding,",
"was",
"found",
"near",
"the",
"anterior",
"wall",
"of",
"the",
"lower",
"gastric",
"body.",
"Hemostatic",
"for-",
"ceps",
"(Coagrasper,",
"FD-410LR;",
"Olympus,",
"Tokyo,",
"Japan)",
"were",
"initially",
"applied",
"over",
"the",
"tumor",
"surface,",
"but",
"because",
"the",
"bleeding",
"persisted,",
"argon",
"plasma",
"coagulation",
"(APC)",
"was",
"performed",
"around",
"the",
"bleeding",
"site.",
"Mucosal",
"oozing",
"continued",
"after",
"failed",
"APC",
"and",
"the",
"application",
"of",
"the",
"hemostatic",
"forceps",
"(Figure",
"1).",
"©",
"2012",
"Fujihara",
"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."
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] | [
"Available",
"online",
"http://arthritis-research.com/content/6/4/147",
"Commentary",
"Phosphatidylserine",
"receptor",
"and",
"apoptosis:",
"consequences",
"of",
"a",
"non-ingested",
"meal",
"Marina",
"Botto",
"Rheumatology",
"Section,",
"Eric",
"Bywaters",
"Centre,",
"Faculty",
"of",
"Medicine,",
"Imperial",
"College,",
"London,",
"UK",
"Corresponding",
"author:",
"Marina",
"Botto",
"(e-mail:",
"m.botto@imperial.ac.uk)",
"Received:",
"8",
"Mar",
"2004",
"Revisions",
"requested:",
"5",
"Apr",
"2004",
"Revisions",
"received:",
"19",
"Apr",
"2004",
"Accepted:",
"28",
"Apr",
"2004",
"Published:",
"4",
"Jun",
"2004",
"Arthritis",
"Res",
"Ther",
"2004,",
"6:147-150",
"(DOI",
"10.1186/ar1191)",
"©",
"2004",
"BioMed",
"Central",
"Ltd",
"Abstract",
"Apoptosis,",
"a",
"physiological",
"process",
"of",
"controlled",
"cell",
"death,",
"is",
"essential",
"during",
"embryonic",
"development",
"and",
"for",
"the",
"maintenance",
"of",
"tissue",
"homeostasis.",
"In",
"recent",
"years",
"the",
"view",
"has",
"emerged",
"that",
"dying",
"cells",
"can",
"provide",
"specific",
"signals",
"that",
"enable",
"recruitment",
"and",
"recognition",
"by",
"phagocytes.",
"Exposure",
"of",
"phosphatidylserine,",
"the",
"best",
"characterized",
"of",
"such",
"signals,",
"allows",
"safe",
"clearance",
"of",
"apoptotic",
"waste",
"without",
"induction",
"of",
"inflammation.",
"Here",
"I",
"re-examine",
"some",
"of",
"the",
"arguments",
"that",
"underpin",
"the",
"importance",
"of",
"these",
"clearance",
"mechanisms",
"in",
"light",
"of",
"recent",
"observations",
"from",
"an",
"animal",
"model",
"that",
"lacks",
"the",
"receptor",
"specific",
"for",
"phosphatidylserine.",
"Keywords:",
"apoptosis,",
"autoimmunity,",
"inflammation,",
"phagocytosis",
"Introduction",
"Apoptosis",
"is",
"an",
"active",
"process",
"of",
"cell",
"suicide",
"that",
"leads",
"to",
"ordered",
"destruction",
"of",
"the",
"cells",
"and",
"their",
"safe",
"disposal",
"by",
"professional",
"(macrophages",
"and",
"immature",
"dendritic",
"cells)",
"and",
"nonprofessional",
"(such",
"as",
"fibroblasts",
"and",
"epithelial",
"cells)",
"phagocytes",
"[1].",
"The",
"removal",
"of",
"apoptotic",
"cells",
"is",
"the",
"final",
"step",
"and",
"perhaps",
"the",
"ultimate",
"objective",
"of",
"the",
"apoptotic",
"programme.",
"When",
"apoptosis",
"was",
"initially",
"described",
"by",
"Kerr",
"and",
"coworkers",
"[2],",
"the",
"phenomenon",
"of",
"programmed",
"cell",
"death",
"was",
"greeted",
"with",
"a",
"striking",
"lack",
"of",
"interest.",
"It",
"has",
"now",
"become",
"apparent",
"that",
"the",
"process",
"is",
"ubiquitous",
"and",
"plays",
"a",
"key",
"role",
"in",
"many",
"fundamental",
"biological",
"events,",
"including",
"embryonic",
"development,",
"normal",
"tissue",
"homeostasis,",
"development",
"of",
"the",
"immune",
"system",
"and",
"resolution",
"of",
"inflammation.",
"In",
"addition,",
"apoptotic",
"cells",
"are",
"a",
"potential",
"source",
"of",
"self-antigens",
"[3],",
"and",
"defective",
"clearance",
"of",
"cell",
"corpses",
"has",
"recently",
"been",
"implicated",
"in",
"the",
"pathogenesis",
"of",
"autoimmune",
"diseases",
"[4].",
"Although",
"enormous",
"progress",
"has",
"been",
"made",
"in",
"our",
"understanding",
"of",
"the",
"molecular",
"mechanisms",
"of",
"apoptosis,",
"the",
"events",
"that",
"lead",
"to",
"clearance",
"of",
"apoptotic",
"cells",
"are",
"still",
"undefined.",
"However,",
"it",
"has",
"become",
"increasingly",
"clear",
"that",
"in",
"vivo",
"apoptosis",
"and",
"engulfment",
"are",
"not",
"distinct",
"events,",
"PS",
"=",
"phosphatidylserine;",
"PSR",
"=",
"phosphatidylserine",
"receptor.",
"but",
"rather",
"are",
"two",
"linked",
"stages",
"in",
"the",
"same",
"process.",
"Cells",
"dying",
"by",
"apoptosis",
"provide",
"both",
"‘recruitment’",
"and",
"‘eat",
"me’",
"signals",
"to",
"scavenger",
"cells,",
"facilitating",
"their",
"own",
"uptake",
"[5].",
"The",
"best",
"studied",
"of",
"these",
"signals",
"is",
"exposure",
"of",
"phosphatidylserine",
"(PS),",
"a",
"phospholipid",
"that",
"is",
"normally",
"limited",
"to",
"the",
"inner",
"leaflet",
"of",
"the",
"plasma",
"membrane",
"bilayer.",
"Although",
"it",
"has",
"been",
"well",
"established",
"that",
"PS",
"exposure",
"on",
"apoptotic",
"cells",
"is",
"critically",
"required",
"for",
"their",
"proper",
"uptake,",
"the",
"identification",
"of",
"a",
"single",
"dominant",
"receptor",
"that",
"is",
"capable",
"of",
"recognizing",
"and",
"removing",
"the",
"apoptotic",
"cells",
"has",
"remained",
"controversial.",
"Is",
"a",
"phosphatidylserine-specific",
"receptor",
"required",
"for",
"safe",
"clearance",
"of",
"dying",
"cells?",
"Many",
"receptors",
"and",
"soluble",
"ligands",
"have",
"been",
"proposed",
"to",
"mediate",
"the",
"recognition",
"and",
"uptake",
"of",
"apoptotic",
"cells.",
"These",
"include",
"lectin-like",
"molecules,",
"scavenger",
"receptors,",
"CD14,",
"the",
"thrombospondin",
"receptor",
"CD36,",
"the",
"vitronectin",
"receptor",
"CD51/CD61,",
"the",
"oxidized",
"low-density",
"lipoprotein",
"receptor",
"CD68,",
"the",
"low-density",
"lipoprotein",
"receptor",
"related",
"protein",
"(LRP1,",
"known",
"as",
"CD91)",
"and",
"annexins",
"[6].",
"Some",
"receptors",
"recognize",
"apoptotic",
"cells",
"in",
"the",
"early",
"phase",
"of",
"cell",
"death,",
"whereas",
"others,",
"which",
"recognize",
"later",
"stages",
"of",
"the",
"process,",
"act",
"as",
"backup",
"systems.",
"Some",
"147"
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] | [
"Journal",
"of",
"Cardiovascular",
"Magnetic",
"Resonance",
"Research",
"Infarct",
"evolution",
"in",
"man",
"studied",
"in",
"patients",
"with",
"first-time",
"coronary",
"occlusion",
"in",
"comparison",
"to",
"different",
"species",
"-",
"implications",
"for",
"assessment",
"of",
"myocardial",
"salvage",
"Erik",
"Hedström1,",
"Henrik",
"Engblom1,",
"Fredrik",
"Frogner2,",
"Karin",
"Åström-Olsson3,",
"Hans",
"Öhlin2,",
"Stefan",
"Jovinge2",
"and",
"Håkan",
"Arheden*1",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Clinical",
"Physiology,",
"Lund",
"University",
"Hospital,",
"SE-221",
"85",
"Lund,",
"Sweden,",
"2Department",
"of",
"Cardiology,",
"Lund",
"University",
"Hospital,",
"SE-221",
"85",
"Lund,",
"Sweden",
"and",
"3Department",
"of",
"Cardiology,",
"Sahlgrenska",
"Hospital,",
"SE-413",
"45",
"Gothenburg,",
"Sweden",
"Email:",
"Erik",
"Hedström",
"-",
"erik.hedstrom@med.lu.se;",
"Henrik",
"Engblom",
"-",
"henrik.engblom@med.lu.se;",
"Fredrik",
"Frogner",
"-",
"fredrik.frogner@skane.se;",
"Karin",
"Åström-Olsson",
"-",
"karin.astrom-olsson@vgregion.se;",
"Hans",
"Öhlin",
"-",
"hans.ohlin@skane.se;",
"Stefan",
"Jovinge",
"-",
"stefan.jovinge@med.lu.se;",
"Håkan",
"Arheden*",
"-",
"hakan.arheden@med.lu.se",
"*",
"Corresponding",
"author",
"Published:",
"23",
"September",
"2009",
"Journal",
"of",
"Cardiovascular",
"Magnetic",
"Resonance",
"2009,",
"11:38",
"doi:10.1186/1532-429X-11-38",
"This",
"article",
"is",
"available",
"from:",
"http://www.jcmr-online.com/content/11/1/38",
"Received:",
"13",
"May",
"2009",
"Accepted:",
"23",
"September",
"2009",
"©",
"2009",
"Hedström",
"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",
"time",
"course",
"of",
"infarct",
"evolution,",
"i.e.",
"how",
"fast",
"myocardial",
"infarction",
"(MI)",
"develops",
"during",
"coronary",
"artery",
"occlusion,",
"is",
"well",
"known",
"for",
"several",
"species,",
"whereas",
"no",
"direct",
"evidence",
"exists",
"on",
"the",
"evolution",
"of",
"MI",
"size",
"normalized",
"to",
"myocardium",
"at",
"risk",
"(MaR)",
"in",
"man.",
"Despite",
"the",
"lack",
"of",
"direct",
"evidence,",
"current",
"literature",
"often",
"refers",
"to",
"the",
"\"golden",
"hour\"",
"as",
"the",
"time",
"during",
"which",
"myocardial",
"salvage",
"can",
"be",
"accomplished",
"by",
"reperfusion",
"therapy.",
"Therefore,",
"the",
"aim",
"of",
"the",
"present",
"study",
"was",
"to",
"investigate",
"how",
"duration",
"of",
"myocardial",
"ischemia",
"affects",
"infarct",
"evolution",
"in",
"man",
"in",
"relation",
"to",
"previous",
"animal",
"data.",
"Consecutive",
"patients",
"with",
"clinical",
"signs",
"of",
"acute",
"myocardial",
"ischemia",
"were",
"screened",
"and",
"considered",
"for",
"enrollment.",
"Particular",
"care",
"was",
"taken",
"to",
"assure",
"uniformity",
"of",
"the",
"patients",
"enrolled",
"with",
"regard",
"to",
"old",
"MI,",
"success",
"of",
"revascularization,",
"collateral",
"flow,",
"release",
"of",
"biochemical",
"markers",
"prior",
"to",
"intervention",
"etc.",
"Sixteen",
"patients",
"were",
"ultimately",
"included",
"in",
"the",
"study.",
"Myocardium",
"at",
"risk",
"was",
"assessed",
"acutely",
"by",
"acute",
"Myocardial",
"Perfusion",
"Single",
"photon",
"emission",
"computed",
"tomography",
"(MPS)",
"and",
"by",
"T2",
"imaging",
"(T2-STIR)",
"cardiovascular",
"magnetic",
"resonance",
"(CMR)",
"after",
"one",
"week",
"in",
"10",
"of",
"the",
"16",
"patients.",
"Infarct",
"size",
"was",
"measured",
"by",
"late",
"gadolinium",
"enhancement",
"(LGE)",
"at",
"one",
"week.",
"Results:",
"The",
"time",
"to",
"reach",
"50%",
"MI",
"of",
"the",
"MaR",
"(T50)",
"was",
"significantly",
"shorter",
"in",
"pigs",
"(37",
"min),",
"rats",
"(41",
"min)",
"and",
"dogs",
"(181",
"min)",
"compared",
"to",
"humans",
"(288",
"min).",
"There",
"was",
"no",
"significant",
"difference",
"in",
"T50",
"when",
"using",
"MPS",
"compared",
"to",
"T2-STIR",
"(p",
"=",
"0.53)",
"for",
"assessment",
"of",
"MaR",
"(288",
"±",
"23",
"min",
"vs",
"310",
"±",
"22",
"min,",
"T50",
"±",
"standard",
"error).",
"The",
"transmural",
"extent",
"of",
"MI",
"increased",
"progressively",
"as",
"the",
"duration",
"of",
"ischemia",
"increased",
"(R2",
"=",
"0.56,",
"p",
"<",
"0.001).",
"Conclusion:",
"This",
"is",
"the",
"first",
"study",
"to",
"provide",
"direct",
"evidence",
"of",
"the",
"time",
"course",
"of",
"acute",
"myocardial",
"infarct",
"evolution",
"in",
"relation",
"to",
"MaR",
"in",
"man",
"with",
"first-time",
"MI.",
"Infarct",
"evolution",
"in",
"man",
"is",
"significantly",
"slower",
"than",
"in",
"pigs,",
"rats",
"and",
"dogs.",
"Furthermore,",
"infarct",
"evolution",
"assessments",
"in",
"man",
"are",
"similar",
"when",
"using",
"MPS",
"acutely",
"and",
"T2-STIR",
"one",
"week",
"later",
"for",
"determination",
"of",
"MaR,",
"which",
"significantly",
"facilitates",
"future",
"clinical",
"trials",
"of",
"cardioprotective",
"therapies",
"in",
"acute",
"coronary",
"syndrome",
"by",
"the",
"use",
"of",
"CMR.",
"Page",
"1",
"of",
"10",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"W140–W144",
"Nucleic",
"Acids",
"Research,",
"2008,",
"Vol.",
"36,",
"Web",
"Server",
"issue",
"doi:10.1093/nar/gkn253",
"Published",
"online",
"8",
"May",
"2008",
"OREST:",
"the",
"online",
"resource",
"for",
"EST",
"analysis",
"Brigitte",
"Waegele1,*,",
"Thorsten",
"Schmidt2,",
"H.",
"Werner",
"Mewes1,2",
"and",
"Andreas",
"Ruepp1",
"1Institute",
"for",
"Bioinformatics",
"and",
"Systems",
"Biology",
"(MIPS),",
"Helmholtz",
"Zentrum",
"M",
"u¨nchen",
"-",
"German",
"Research",
"Center",
"for",
"Environmental",
"Health",
"(GmbH),",
"Ingolsta¨",
"dter",
"Landstraße",
"1,",
"D-85764",
"Neuherberg",
"and",
"2Chair",
"of",
"Genome-oriented",
"Bioinformatics,",
"Technische",
"Universita¨",
"t",
"M",
"u¨nchen,",
"Life",
"and",
"Food",
"Science",
"Center",
"Weihenstephan,",
"Am",
"Forum",
"1,",
"D-85354",
"Freising-Weihenstephan,",
"Germany",
"Received",
"January",
"31,",
"2008;",
"Revised",
"April",
"10,",
"2008;",
"Accepted",
"April",
"20,",
"2008",
"ABSTRACT",
"The",
"generation",
"of",
"expressed",
"sequence",
"tag",
"(EST)",
"libraries",
"offers",
"an",
"affordable",
"approach",
"to",
"investi-",
"gate",
"organisms,",
"if",
"no",
"genome",
"sequence",
"is",
"available.",
"OREST",
"(http://mips.gsf.de/genre/proj/orest/index.",
"html)",
"is",
"a",
"server-based",
"EST",
"analysis",
"pipeline,",
"which",
"allows",
"the",
"rapid",
"analysis",
"of",
"large",
"amounts",
"of",
"ESTs",
"or",
"cDNAs",
"from",
"mammalia",
"and",
"fungi.",
"In",
"order",
"to",
"assign",
"the",
"ESTs",
"to",
"genes",
"or",
"proteins",
"OREST",
"maps",
"DNA",
"sequences",
"to",
"reference",
"datasets",
"of",
"gene",
"products",
"and",
"in",
"a",
"second",
"step",
"to",
"complete",
"genome",
"sequences.",
"Mapping",
"against",
"genome",
"sequences",
"recovers",
"additional",
"13%",
"of",
"EST",
"data,",
"which",
"otherwise",
"would",
"escape",
"further",
"analysis.",
"To",
"enable",
"functional",
"analysis",
"of",
"the",
"datasets,",
"ESTs",
"are",
"functionally",
"annotated",
"using",
"the",
"hierarchical",
"FunCat",
"annotation",
"scheme",
"as",
"well",
"as",
"GO",
"annotation",
"terms.",
"OREST",
"also",
"allows",
"to",
"predict",
"the",
"association",
"of",
"gene",
"products",
"and",
"diseases",
"by",
"Morbid",
"Map",
"(OMIM)",
"classification.",
"A",
"statistical",
"analysis",
"of",
"the",
"results",
"of",
"the",
"dataset",
"is",
"possible",
"with",
"the",
"included",
"PROMPT",
"software,",
"which",
"provides",
"information",
"about",
"enrich-",
"ment",
"and",
"depletion",
"of",
"functional",
"and",
"disease",
"annotation",
"terms.",
"OREST",
"was",
"successfully",
"applied",
"for",
"the",
"identification",
"and",
"functional",
"characterization",
"of",
"more",
"than",
"3000",
"EST",
"sequences",
"of",
"the",
"common",
"marmoset",
"monkey",
"(Callithrix",
"jacchus)",
"as",
"part",
"of",
"an",
"international",
"collaboration.",
"INTRODUCTION",
"In",
"spite",
"of",
"considerable",
"genome",
"sequencing",
"efforts",
"during",
"the",
"last",
"years",
"there",
"is",
"still",
"a",
"large",
"number",
"of",
"poorly",
"characterized",
"organisms,",
"which",
"serve",
"as",
"models",
"for",
"the",
"investigation",
"of",
"different",
"phenotypes",
"and",
"diseases.",
"Sequencing",
"of",
"cDNA",
"libraries",
"offers",
"a",
"low-cost",
"approach",
"to",
"obtain",
"information",
"about",
"the",
"protein-coding",
"genes",
"of",
"these",
"organisms.",
"End-sequencing",
"of",
"cDNA",
"clones",
"with",
"standard",
"primers",
"results",
"in",
"expressed",
"sequence",
"tag",
"(EST)",
"libraries",
"with",
"up",
"to",
"thousands",
"of",
"DNA",
"fragments.",
"The",
"dbEST",
"at",
"the",
"NCBI",
"(1),",
"one",
"of",
"the",
"largest",
"resources,",
"contains",
"more",
"than",
"48",
"000",
"000",
"EST",
"sequences",
"from",
"1500",
"organisms.",
"In",
"addition,",
"EST",
"data",
"are",
"used",
"to",
"validate",
"gene",
"models",
"on",
"genome",
"sequences,",
"to",
"analyse",
"results",
"from",
"proteome",
"experiments",
"and",
"to",
"construct",
"organism-specific",
"microarrays",
"(2).",
"High-throughput",
"in",
"silico",
"analysis",
"of",
"thousands",
"of",
"EST",
"sequences",
"for",
"the",
"identification",
"of",
"corresponding",
"gene",
"products",
"and",
"associated",
"information",
"requires",
"an",
"auto-",
"mated",
"EST",
"analysis",
"tool",
"which",
"should",
"fulfil",
"several",
"requirements:",
"(i)",
"it",
"should",
"be",
"designed",
"in",
"a",
"way",
"that",
"it",
"can",
"be",
"operated",
"without",
"in-depth",
"bioinformatics",
"skills;",
"(ii)",
"it",
"should",
"allow",
"the",
"analysis",
"of",
"ESTs",
"from",
"organisms",
"with",
"different",
"phylogenetic",
"background;",
"(iii)",
"the",
"tool",
"has",
"to",
"identify",
"gene",
"products",
"that",
"correspond",
"to",
"ESTs",
"with",
"high",
"accuracy;",
"(iv)",
"in",
"order",
"to",
"provide",
"the",
"user",
"with",
"a",
"primary",
"characterisation",
"about",
"the",
"dataset",
"there",
"is",
"a",
"demand",
"of",
"a",
"systematic",
"functional",
"annotation",
"of",
"the",
"dataset",
"and",
"(v)",
"statistics",
"about",
"functional",
"characteristics",
"that",
"are",
"significantly",
"over-",
"or",
"under-represented",
"within",
"the",
"dataset.",
"There",
"are",
"a",
"number",
"of",
"EST",
"processing",
"systems",
"existing",
"like",
"ESTAnnotator",
"(3),",
"ESTAP",
"(4),",
"ESTExplorer",
"(5),",
"PartiGene",
"(6)",
"or",
"EST2uni",
"(7).",
"However,",
"many",
"of",
"the",
"existing",
"tools",
"require",
"local",
"installation",
"and",
"maintenance",
"of",
"the",
"latest",
"versions",
"of",
"the",
"tools",
"and",
"databases.",
"This",
"hampers",
"an",
"immediate",
"analysis",
"for",
"occasional",
"users",
"and",
"requires",
"investments",
"for",
"disc",
"requirements,",
"database",
"installation",
"and",
"administration.",
"Here,",
"we",
"present",
"OREST",
"(Figure",
"1),",
"a",
"web-based",
"EST",
"analysis",
"pipeline",
"for",
"gene",
"assignment",
"and",
"systematic",
"func-",
"tional",
"annotation",
"of",
"large",
"amounts",
"of",
"DNA",
"sequences.",
"OREST",
"allows",
"mapping",
"of",
"user",
"data",
"to",
"the",
"fungal",
"model",
"organism",
"Saccharomyces",
"cerevisiae",
"as",
"well",
"as",
"to",
"several",
"mammalian",
"datasets.",
"Automated",
"functional",
"assignment",
"of",
"the",
"gene",
"products",
"can",
"be",
"performed",
"via",
"FunCat",
"or",
"GO",
"annotation",
"schemes.",
"Mapping",
"to",
"the",
"human",
"dataset",
"predicts",
"also",
"the",
"association",
"of",
"the",
"ESTs",
"with",
"diseases.",
"Over-",
"und",
"under-represented",
"features",
"from",
"functional",
"annotation",
"and",
"disease",
"relevance",
"are",
"obtained",
"through",
"a",
"statistical",
"analysis.",
"Advantage",
"and",
"usability",
"of",
"the",
"OREST",
"EST",
"analysis",
"pipeline",
"has",
"been",
"shown",
"in",
"a",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+49",
"89",
"3187",
"3640;",
"Fax:",
"+49",
"89",
"3187",
"3585;",
"Email:",
"brigitte.waegele@helmholtz-muenchen.de",
"2008",
"The",
"Author(s)",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Tropical",
"Medicine",
"and",
"Health",
"Vol.",
"39",
"No.",
"4",
"Supplement,",
"2011,",
"pp.",
"17-27",
"doi:10.2149/tmh.2011-S04",
"Copyright",
"2011",
"by",
"The",
"Japanese",
"Society",
"of",
"Tropical",
"Medicine",
"Review",
"TMH",
"9",
"Dengue",
"Vectors",
"and",
"their",
"Spatial",
"Distribution",
"Yukiko",
"Higa",
"Published",
"online",
"25",
"August,",
"2011",
"17",
"©",
"20A1b1stJraapcat:neTsheeSdoicsiteritbyuotifonTroofpdiceanlguMeevdeicctionres,",
"Ae.",
"aegypti",
"and",
"Ae.",
"albopictus,",
"is",
"affected",
"by",
"climatic",
"factors.",
"In",
"addition,",
"since",
"their",
"life",
"cycles",
"are",
"well",
"adapted",
"to",
"the",
"human",
"environment,",
"environmental",
"changes",
"resulting",
"from",
"human",
"activity",
"such",
"as",
"urbanization",
"exert",
"a",
"great",
"impact",
"on",
"vector",
"distribution.",
"The",
"different",
"responses",
"of",
"Ae.",
"aegypti",
"and",
"Ae",
"albopictus",
"to",
"various",
"environments",
"result",
"in",
"a",
"difference",
"in",
"spatial",
"distribution",
"along",
"north-south",
"and",
"urban-rural",
"gradients,",
"and",
"between",
"the",
"indoors",
"and",
"outdoors.",
"In",
"the",
"north-south",
"gradient,",
"climate",
"associated",
"with",
"survival",
"is",
"an",
"important",
"factor",
"in",
"spatial",
"distribution.",
"In",
"the",
"urban-rural",
"gradient,",
"different",
"distribution",
"reflects",
"a",
"difference",
"in",
"adult",
"niches",
"and",
"is",
"modified",
"by",
"geographic",
"and",
"human",
"factors.",
"The",
"direct",
"response",
"of",
"the",
"two",
"species",
"to",
"the",
"environment",
"around",
"houses",
"is",
"related",
"to",
"different",
"spatial",
"distribution",
"indoors",
"and",
"outdoors.",
"Dengue",
"viruses",
"circulate",
"mainly",
"between",
"human",
"and",
"vector",
"mosquitoes,",
"and",
"the",
"vector",
"presence",
"is",
"a",
"limiting",
"factor",
"of",
"transmission.",
"Therefore,",
"spatial",
"distribution",
"of",
"dengue",
"vectors",
"is",
"a",
"significant",
"concern",
"in",
"the",
"epidemiology",
"of",
"the",
"disease.",
"Current",
"technologies",
"such",
"as",
"GIS,",
"satellite",
"imagery",
"and",
"statistical",
"models",
"allow",
"researchers",
"to",
"predict",
"the",
"spatial",
"distribution",
"of",
"vectors",
"in",
"the",
"changing",
"environment.",
"Although",
"it",
"is",
"difficult",
"to",
"confirm",
"the",
"actual",
"effect",
"of",
"environ-",
"mental",
"and",
"climate",
"changes",
"on",
"vector",
"abundance",
"and",
"vector-borne",
"diseases,",
"environmental",
"changes",
"caused",
"by",
"humans",
"and",
"human",
"behavioral",
"changes",
"due",
"to",
"climate",
"change",
"can",
"be",
"expected",
"to",
"exert",
"an",
"impact",
"on",
"dengue",
"vectors.",
"Longitudinal",
"monitoring",
"of",
"dengue",
"vectors",
"and",
"viruses",
"is",
"therefore",
"necessary.",
"Key",
"words:",
"Aedes",
"aegypti,",
"Aedes",
"albopictus,",
"spatial,",
"distribution,",
"environment,",
"dengue",
"INTRODUCTION",
"Humans",
"have",
"experienced",
"dengue",
"fever",
"(DF)",
"since",
"ancient",
"times.",
"Dengue-like",
"illness",
"was",
"already",
"described",
"in",
"Chinese",
"literature",
"in",
"992",
"[1].",
"Since",
"the",
"early",
"20th",
"century",
"when",
"experiments",
"showed",
"that",
"dengue",
"virus",
"was",
"trans-",
"mitted",
"by",
"Aedes",
"aegypti",
"(L.),",
"a",
"great",
"number",
"of",
"studies",
"on",
"the",
"relationship",
"between",
"Ae.",
"aegypti",
"and",
"DF",
"have",
"been",
"conducted",
"[2].",
"Although",
"there",
"are",
"several",
"potential",
"dengue",
"vectors,",
"the",
"field",
"isolation",
"of",
"viruses",
"and",
"epidemiological",
"evidence",
"clearly",
"show",
"that",
"Ae.",
"aegypti",
"and",
"Ae.",
"albopictus",
"are",
"responsible",
"for",
"the",
"majority",
"of",
"dengue",
"transmission",
"[1].",
"Aedes",
"albopictus",
"(Skuse),",
"better",
"known",
"as",
"the",
"“Asian",
"tiger",
"mosquito”,",
"originates",
"in",
"Orient",
"and",
"serves",
"as",
"a",
"second-",
"ary",
"vector",
"of",
"DF",
"[2].",
"This",
"species",
"feeds",
"on",
"humans",
"in",
"gardens,",
"parks",
"and",
"bushes",
"around",
"human",
"dwellings",
"in",
"the",
"daytime",
"and",
"is",
"very",
"common",
"in",
"Japan",
"and",
"other",
"Asian",
"countries.",
"After",
"Ae.",
"albopictus",
"was",
"recognized",
"to",
"be",
"a",
"vector",
"of",
"DF",
"in",
"1931",
"and",
"dengue",
"virus",
"was",
"isolated",
"from",
"Ae.",
"albopictus",
"caught",
"in",
"the",
"wild,",
"many",
"scientists",
"have",
"taken",
"an",
"interest",
"in",
"this",
"species",
"as",
"well",
"as",
"Ae.",
"aegypti",
"[2].",
"There",
"is",
"a",
"wealth",
"of",
"studies",
"on",
"the",
"distribution,",
"mor-",
"phology,",
"genetics,",
"biology",
"and",
"ecology",
"of",
"these",
"two",
"major",
"dengue",
"vectors",
"due",
"to",
"their",
"great",
"medical",
"importance.",
"However,",
"the",
"dengue",
"vector",
"situation",
"has",
"completely",
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"since",
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"of",
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"to",
"New",
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"and",
"Africa",
"by",
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"used",
"tire",
"transportations",
"[3].",
"In",
"addition,",
"recent",
"uncontrolled",
"urbanization",
"in",
"developing",
"countries",
"and",
"global",
"warming,",
"which",
"influence",
"vector",
"mosquitoes",
"and",
"exert",
"an",
"impact",
"on",
"vector-borne",
"diseases,",
"have",
"become",
"topics",
"of",
"concern",
"among",
"scientists.",
"Frequent",
"movement",
"of",
"people",
"by",
"aircraft",
"has",
"resulted",
"in",
"a",
"further",
"introduction",
"of",
"vector",
"mosquitoes",
"to",
"new",
"places.",
"Ae.",
"aegypti",
"and",
"Ae.",
"albopictus",
"were",
"collected",
"from",
"aircraft",
"arriving",
"at",
"Changi",
"International",
"Airport",
"in",
"Singapore",
"[4].",
"Such",
"vector",
"movement",
"will",
"increase",
"the",
"risk",
"of",
"newly",
"emerging",
"vector-",
"borne",
"diseases.",
"Not",
"only",
"the",
"expansion",
"of",
"dengue",
"vector",
"distribution",
"but",
"also",
"behavioral",
"changes",
"of",
"Ae.",
"aegypti",
"and",
"Ae.",
"albopictus",
"are",
"currently",
"reported.",
"Ae.",
"aegypti,",
"which",
"usually",
"breeds",
"in",
"artificial",
"containers",
"in",
"houses,",
"was",
"found",
"Department",
"of",
"Vector",
"Ecology",
"and",
"Environment,",
"Institute",
"of",
"Tropical",
"Medicine",
"(NEKKEN),",
"Nagasaki",
"University,",
"Sakamoto",
"1-12-4,",
"Nagasaki",
"city,",
"Nagasaki",
"852-8523,",
"Japan",
"Tel:",
"+81-95-819-7811",
"Fax:",
"+81-95-819-7812",
"E-mail:",
"yukko@nagasaki-u.ac.jp"
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"being",
"limited",
"to",
"a",
"brief",
"time",
"interval",
"between",
"late",
"G1",
"and",
"early",
"S",
"phase.",
"Human",
"cancers",
"frequently",
"exhibit",
"dereg-",
"ulated",
"cyclin",
"E–associated",
"kinase",
"activity",
"resulting",
"from",
"overexpression",
"of",
"cyclin",
"E",
"and",
"loss",
"of",
"cyclin-dependent",
"kinase",
"inhi-",
"bition",
"(via",
"p53",
"mutations)",
"promoting",
"genetic",
"instability",
"and",
"cell",
"proliferation",
"[1].",
"Increased",
"levels",
"of",
"cyclin",
"E",
"correlate",
"with",
"tumorigenesis",
"and",
"are",
"a",
"poor",
"prog-",
"nostic",
"indicator",
"independent",
"of",
"prolifera-",
"tion",
"rate,",
"suggesting",
"that",
"cyclin",
"E’s",
"role",
"in",
"tumorigenesis",
"is",
"not",
"limited",
"to",
"promoting",
"increased",
"cell",
"proliferation",
"[2,3].",
"By",
"elim-",
"inating",
"regulatory",
"constraints",
"using",
"p53",
"null",
"cells,",
"we",
"and",
"others",
"have",
"shown",
"that",
"overexpression",
"or",
"endogenous",
"expression",
"of",
"stabilizing",
"mutant",
"forms",
"of",
"cyclin",
"E",
"can",
"lead",
"to",
"hyperproliferation,",
"genetic",
"insta-",
"bility,",
"and",
"malignancy",
"in",
"cell",
"culture",
"and",
"murine",
"models",
"[4,5].",
"Normal",
"cells",
"sup-",
"press",
"the",
"effects",
"of",
"excess/stabilized",
"cyclin",
"E",
"via",
"the",
"G1/S",
"checkpoint",
"involving",
"the",
"p53/p21",
"pathway.",
"Five",
"isoforms",
"of",
"cyclin",
"E,",
"ranging",
"in",
"size",
"from",
"33",
"to",
"44",
"kDa,",
"have",
"been",
"identified",
"in",
"tumors",
"over-expressing",
"cyclin",
"E.",
"These",
"low",
"molecular",
"weight",
"forms",
"of",
"cyclin",
"E",
"(LMW-E)",
"are",
"generated",
"through",
"post-",
"translational",
"cleavage",
"of",
"full-length",
"cyclin",
"E",
"by",
"the",
"elastase",
"family",
"of",
"serine",
"proteases",
"in",
"tumor",
"cells",
"[6,7].",
"In",
"comparison",
"to",
"full-",
"length",
"cyclin",
"E",
"(50",
"kDa),",
"LMW-E",
"forms",
"are",
"uniquely",
"expressed",
"in",
"tumor",
"cells,",
"exhibit",
"enhanced",
"CDK2-associated",
"kinase",
"activity,",
"have",
"increased",
"affinity",
"for",
"CDK2",
"[7–9],",
"and",
"exhibit",
"decreased",
"inhibition",
"by",
"CDK2",
"inhibitors,",
"p21",
"and",
"p27",
"(Figure",
"1)",
"[10,11].",
"Ectopic",
"expression",
"of",
"LMW-E",
"isoforms",
"promotes",
"cell",
"proliferation,",
"ge-",
"netic",
"instability,",
"centrosome",
"amplification,",
"and",
"malignancy",
"[12,13].",
"In",
"addition,",
"clinical",
"studies",
"have",
"shown",
"that",
"high",
"LMW-E",
"is",
"strongly",
"associated",
"with",
"poor",
"survival",
"in",
"breast",
"cancer",
"[2],",
"colorectal",
"cancer",
"[14,15],",
"ovarian",
"cancer",
"[16],",
"and",
"melanomas",
"[17].",
"Given",
"its",
"unique",
"prop-",
"erties",
"and",
"distinct",
"function",
"in",
"human",
"cancers,",
"targeting",
"LMW-E",
"could",
"have",
"important",
"therapeutic",
"implications.",
"The",
"study",
"by",
"Duong",
"et",
"al.",
"in",
"this",
"issue",
"of",
"PLoS",
"Genetics",
"[18]",
"convincingly",
"uncovers",
"the",
"tumorigenic",
"potential",
"of",
"LMW-E.",
"The",
"authors",
"used",
"three",
"different",
"model",
"sys-",
"tems—3D",
"acinar",
"cultures,",
"xenograft",
"trans-",
"plantation,",
"and",
"transgenic",
"mice—to",
"show",
"that",
"overexpression",
"of",
"LMW-E",
"is",
"sufficient",
"to",
"induce",
"aberrant",
"acinar",
"morphogenesis",
"in",
"culture",
"and",
"mammary",
"tumors",
"in",
"mice",
"(Figure",
"1).",
"When",
"grown",
"on",
"Matrigel,",
"immortalized",
"human",
"mammary",
"epithelial",
"cells",
"(hMECs)",
"expressing",
"LMW-E",
"exhibit",
"large",
"misshapen",
"multiacinar",
"structures",
"resulting",
"from",
"defective",
"growth",
"arrest",
"and",
"apoptosis",
"that",
"mimic",
"morphologic",
"features",
"of",
"breast",
"carcinomas.",
"Further,",
"ectopic",
"expression",
"of",
"LMW-E",
"in",
"immor-",
"talized",
"hMECs",
"promotes",
"tumorigenesis",
"in",
"xenografts",
"and",
"transgenic",
"mice",
"to",
"a",
"much",
"greater",
"extent",
"than",
"full-length",
"cyclin",
"E.",
"Consistent",
"with",
"the",
"reports",
"by",
"Akli",
"et",
"al.",
"and",
"Nanos-Webb",
"et",
"al.,",
"tumorigenesis",
"associated",
"with",
"LMW-E",
"is",
"dependent",
"on",
"CDK2",
"[19,20].",
"Furthermore,",
"in",
"vivo",
"passaging",
"of",
"tumor",
"cells",
"increases",
"the",
"expression",
"of",
"LMW-E,",
"suggesting",
"that",
"LMW-E",
"provides",
"a",
"selective",
"growth",
"ad-",
"vantage",
"to",
"the",
"tumor.",
"Duong",
"et",
"al.",
"also",
"took",
"advantage",
"of",
"a",
"proteomic",
"analysis",
"termed",
"reverse-phase",
"protein",
"array",
"assay",
"(RPPA)",
"to",
"examine",
"protein",
"expression",
"patterns",
"in",
"cultured",
"tumor",
"cells",
"and",
"in",
"breast",
"tumors",
"expressing",
"high",
"LMW-E",
"levels.",
"Their",
"analyses",
"revealed",
"that",
"multi-",
"ple",
"components",
"of",
"the",
"b-RAF-ERK1/2-",
"mTOR",
"pathway",
"are",
"elevated",
"in",
"these",
"cells.",
"Activation",
"of",
"the",
"b-RAF-ERK1/2-",
"mTOR",
"pathway",
"normally",
"promotes",
"cell",
"division",
"and",
"cell",
"survival.",
"Consistent",
"with",
"this,",
"the",
"authors",
"observed",
"that",
"endogenous",
"cyclin",
"E",
"levels",
"are",
"also",
"increased",
"in",
"cells",
"expressing",
"high",
"LMW-E,",
"indicative",
"of",
"the",
"existence",
"of",
"a",
"positive",
"feedback",
"loop",
"that",
"promotes",
"cell",
"proliferation.",
"Both",
"high",
"LMW-E",
"levels",
"and",
"up-regulation",
"of",
"the",
"b-RAF-ERK1/2-mTOR",
"signaling",
"path-",
"way",
"are",
"associated",
"with",
"poor",
"survival,",
"suggesting",
"functional",
"correlation",
"of",
"these",
"events",
"in",
"aggressive",
"tumors.",
"Importantly,",
"the",
"authors",
"demonstrated",
"that",
"combina-",
"tion",
"therapy",
"targeting",
"LMW-E/CDK2",
"and",
"the",
"b-RAF-ERK1/2-mTOR",
"pathway",
"has",
"a",
"synergistic",
"effect",
"in",
"abrogating",
"the",
"tumorigenic",
"effect",
"of",
"LMW-E.",
"Thus,",
"the",
"identification",
"of",
"these",
"downstream",
"regula-",
"tors",
"may",
"provide",
"novel",
"biomarkers",
"and/or",
"potential",
"therapeutic",
"targets",
"for",
"LMW-E–",
"expressing",
"tumors.",
"The",
"report",
"that",
"LMW-E",
"potentiates",
"tumorigenesis",
"in",
"three",
"independent",
"model",
"systems",
"associated",
"with",
"activation",
"of",
"the",
"b-",
"RAF-ERK1/2-mTOR",
"pathway",
"is",
"intrigu-",
"ing.",
"However,",
"there",
"are",
"many",
"important",
"questions",
"about",
"the",
"role",
"of",
"LMW-E",
"in",
"tumorigenesis",
"that",
"need",
"to",
"be",
"addressed.",
"1)",
"What",
"is",
"the",
"functional",
"relationship",
"be-",
"tween",
"LMW-E",
"and",
"full-length",
"cyclin",
"E?",
"In",
"each",
"tumor",
"model",
"reported",
"by",
"Duong",
"et",
"al.,",
"the",
"effect",
"was",
"examined",
"by",
"over-",
"expressing",
"LMW-E",
"in",
"a",
"background",
"of",
"endogenous",
"full-length",
"cyclin",
"E.",
"Further,",
"the",
"authors",
"show",
"that",
"ectopic",
"expression",
"of",
"LMW-E",
"in",
"transplanted",
"xenografts",
"trig-",
"gers",
"tumor",
"evolution",
"and",
"results",
"in",
"increased",
"levels",
"of",
"endogenous",
"cyclin",
"E.",
"Thus,",
"the",
"contribution",
"of",
"endogenous",
"full-",
"Citation:",
"Loeb",
"KR,",
"Chen",
"X",
"(2012)",
"Too",
"Much",
"Cleavage",
"of",
"Cyclin",
"E",
"Promotes",
"Breast",
"Tumorigenesis.",
"PLoS",
"Genet",
"8(3):",
"e1002623.",
"doi:10.1371/journal.pgen.1002623",
"Editor:",
"Marshall",
"S.",
"Horwitz,",
"University",
"of",
"Washington,",
"United",
"States",
"of",
"America",
"Published",
"March",
"29,",
"2012",
"Copyright:",
"2012",
"Loeb,",
"Chen.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"The",
"authors",
"received",
"no",
"specific",
"funding",
"for",
"this",
"article.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"kloeb@fhcrc.org",
"PLoS",
"Genetics",
"|",
"www.plosgenetics.org",
"1",
"March",
"2012",
"|",
"Volume",
"8",
"|",
"Issue",
"3",
"|",
"e1002623"
] | [
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] | [
"Fornaro",
"Annals",
"of",
"General",
"Psychiatry",
"2011,",
"10:5",
"http://www.annals-general-psychiatry.com/content/10/1/5",
"P",
"R",
"I",
"M",
"A",
"R",
"Y",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Switching",
"from",
"serotonin",
"reuptake",
"inhibitors",
"to",
"agomelatine",
"in",
"patients",
"with",
"refractory",
"obsessive-compulsive",
"disorder:",
"a",
"3",
"month",
"follow-up",
"case",
"series",
"Michele",
"Fornaro",
"Abstract",
"Background:",
"Serotonin",
"reuptake",
"inhibitors",
"(SRIs)",
"currently",
"represent",
"the",
"cornerstone",
"of",
"obsessive-compulsive",
"disorder",
"(OCD)",
"pharmacotherapy.",
"However,",
"OCD",
"is",
"characterized",
"by",
"high",
"rates",
"of",
"partial",
"and/or",
"absent",
"response",
"to",
"standard,",
"recommended",
"treatments,",
"often",
"prompting",
"pharmacological",
"and",
"non-pharmacological",
"augmentation",
"or",
"switching",
"of",
"strategies.",
"Agomelatine,",
"a",
"novel",
"melatonin",
"agonist",
"and",
"selective",
"serotonin",
"antagonist",
"(MASSA)",
"antidepressant",
"approved",
"for",
"major",
"depressive",
"disorder",
"(MDD)",
"has",
"recently",
"been",
"additionally",
"proposed",
"as",
"a",
"treatment",
"for",
"anxiety",
"disorders",
"such",
"as",
"social",
"anxiety",
"disorder",
"(SAD)",
"and",
"panic",
"disorder",
"(PD),",
"but",
"not",
"yet",
"OCD.",
"Nonetheless,",
"agomelatine",
"may",
"have",
"a",
"role",
"in",
"the",
"management",
"of",
"OCD,",
"essentially",
"due",
"to",
"its",
"anxiolytic",
"5-",
"hydroxytryptamine",
"(HT)2C",
"blockade",
"action,",
"while",
"melatonin",
"(MT)1",
"and",
"MT2",
"modulation",
"might",
"contribute",
"to",
"circadian",
"rhythm",
"restoration",
"if",
"impaired.",
"Methods:",
"This",
"case",
"series",
"reports",
"the",
"outcome",
"of",
"six",
"patients",
"with",
"or",
"without",
"comorbid",
"mood",
"and/or",
"other",
"anxiety",
"disorders",
"who",
"were",
"treated",
"with",
"SRIs",
"at",
"adequate",
"doses",
"for",
"at",
"least",
"8",
"weeks,",
"showing",
"partial",
"or",
"no",
"response.",
"Patients",
"were",
"then",
"switched",
"to",
"agomelatine",
"50",
"mg/day,",
"and",
"followed",
"up",
"for",
"12",
"weeks.",
"Results:",
"Three",
"out",
"of",
"six",
"patients,",
"in",
"particular",
"those",
"with",
"relevant",
"circadian",
"rhythm",
"subjective",
"impairment,",
"showed",
"a",
"Yale-Brown",
"Obsessive",
"Compulsive",
"Scale",
"(Y-BOCS)",
"score",
"reduction",
"of",
"≥35%.",
"No",
"relevant",
"side",
"effects",
"were",
"observed,",
"but",
"initial,",
"transient,",
"self-remitting",
"dizziness",
"in",
"one",
"patient",
"and",
"weight",
"gain",
"in",
"another",
"were",
"seen.",
"Conclusions:",
"Although",
"clinical",
"confounding",
"factors",
"(subthreshold",
"bipolarity",
"and",
"eventually",
"the",
"presence",
"of",
"impaired",
"circadian",
"rhythms)",
"and",
"methodological",
"boundaries",
"(lack",
"of",
"control",
"and",
"neurophysiological",
"recording,",
"tiny",
"sample",
"size",
"and",
"short",
"follow-up)",
"limit",
"the",
"validity",
"of",
"this",
"preliminary",
"observation,",
"it",
"does",
"indicate",
"agomelatine",
"may",
"have",
"a",
"role",
"in",
"some",
"SRI-refractory",
"OCD",
"cases,",
"thus",
"prompting",
"the",
"validity",
"of",
"investigation",
"by",
"further",
"controlled",
"studies,",
"even",
"for",
"drug-naïve",
"OCD",
"patients.",
"Introduction",
"Obsessive-compulsive",
"disorder",
"(OCD)",
"is",
"a",
"common",
"con-",
"dition",
"that",
"affects",
"individuals",
"of",
"all",
"ages.",
"This",
"disorder",
"has",
"been",
"listed",
"as",
"one",
"of",
"the",
"10",
"most",
"disabling",
"illnesses",
"by",
"the",
"World",
"Health",
"Organization",
"[1],",
"while",
"the",
"National",
"Comorbidity",
"Survey",
"Replication",
"indicated",
"that",
"OCD",
"is",
"the",
"anxiety",
"disorder",
"with",
"the",
"highest",
"percentage",
"(50.6%)",
"of",
"serious",
"cases",
"[2].",
"Approximately",
"2%",
"to",
"3%",
"of",
"the",
"world’s",
"population",
"will",
"suffer",
"from",
"OCD",
"at",
"some",
"point",
"Correspondence:",
"Dott.Fornaro@gmail.com",
"University",
"of",
"Genova,",
"Department",
"of",
"Psychiatry,",
"Genoa,",
"Italy",
"in",
"their",
"lives",
"[3],",
"and",
"it",
"has",
"been",
"estimated",
"that",
"most",
"individuals",
"with",
"OCD",
"spend",
"an",
"average",
"of",
"17",
"years",
"before",
"receiving",
"an",
"appropriate",
"diagnosis",
"and",
"treatment",
"for",
"their",
"illness",
"[4].",
"Additionally,",
"OCD",
"usually",
"exhibits",
"a",
"waxing",
"and",
"waning",
"course,",
"frequently",
"increasing",
"in",
"severity",
"when",
"left",
"untreated,",
"which",
"causes",
"unnecessary",
"pain",
"to",
"those",
"afflicted",
"and",
"to",
"their",
"families.",
"Hence,",
"the",
"need",
"for",
"appropriate",
"management",
"is",
"imperative.",
"Although",
"serotonin",
"reuptake",
"inhibitors",
"(SRIs),",
"includ-",
"ing",
"the",
"widely",
"prescribed",
"selective",
"SRIs",
"(SSRIs),",
"are",
"con-",
"sidered",
"the",
"cornerstone",
"of",
"pharmacological",
"treatment",
"of",
"©",
"2011",
"Fornaro;",
"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."
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] | [
"Hepat",
"Mon.2012;12(7):430-436.",
"DOI:",
"10.5812/hepatmon.6170",
"KOWSAR",
"www.HepatMon.com",
"Treatment",
"Response",
"and",
"Tolerability",
"of",
"Pegylated",
"Interferon-α",
"Plus",
"Ribavirin",
"Combination",
"Therapy",
"in",
"Elderly",
"Patients",
"(≥",
"65",
"years)",
"With",
"Chronic",
"Hepatitis",
"C",
"in",
"Korea",
"Hyeong",
"Il",
"Kim",
"1,",
"In",
"Hee",
"Kim",
"1*,",
"Byung",
"Jun",
"Jeon",
"1,",
"Seok",
"Lee",
"1,",
"Seong",
"Hun",
"Kim",
"1,",
"Sang",
"Wook",
"Kim",
"1,",
"Seung",
"Ok",
"Lee",
"1,",
"Soo",
"Teik",
"Lee",
"1,",
"Dae",
"Ghon",
"Kim",
"1",
"1",
"Department",
"of",
"Internal",
"Medicine,",
"Chonbuk",
"National",
"University",
"Medical",
"School",
"and",
"Hospital,",
"Jeonju,",
"Jeonbuk,",
"South",
"Korea",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"I",
"N",
"F",
"O",
"A",
"B",
"S",
"T",
"R",
"A",
"C",
"T",
"Article",
"type:",
"Original",
"Article",
"Article",
"history:",
"Received:",
"27",
"Apr",
"2012",
"Revised:",
"07",
"May",
"2012",
"Accepted:",
"17",
"May",
"2012",
"Keywords:",
"Chronic",
"Hepatitis",
"C",
"Ribavirin",
"Korea",
"Background:",
"The",
"prevalence",
"of",
"hepatitis",
"C",
"virus",
"(HCV)",
"infections",
"in",
"elderly",
"patients",
"has",
"been",
"increasing",
"in",
"a",
"number",
"of",
"countries.",
"A",
"few",
"reports",
"concerning",
"pegylated",
"interferon-α",
"(PEG-IFN-α)-based",
"combination",
"treatment",
"in",
"elderly",
"chronic",
"hepatitis",
"C",
"(CHC)",
"patients",
"have",
"been",
"published,",
"with",
"slightly",
"different",
"treatment",
"outcomes.",
"Objectives:",
"We",
"investigated",
"the",
"treatment",
"response",
"and",
"safety",
"of",
"PEG-IFN-α",
"plus",
"ribavirin",
"combination",
"therapy",
"in",
"elderly",
"patients",
"with",
"CHC.",
"Patients",
"and",
"Methods:",
"Among",
"a",
"total",
"of",
"181",
"treatment-naïve",
"CHC",
"patients",
"(60",
"patients",
"with",
"genotype",
"1,",
"121",
"patients",
"with",
"genotype",
"2",
"or",
"3),",
"38",
"were",
"aged",
"≥",
"65",
"years",
"(defined",
"as",
"the",
"elderly",
"group)",
"and",
"143",
"were",
"aged",
"<",
"65",
"years",
"(defined",
"as",
"the",
"non-elderly",
"group).",
"Results:",
"The",
"overall",
"sustained",
"virologic",
"response",
"(SVR)",
"was",
"lower",
"in",
"the",
"elderly",
"group",
"than",
"in",
"the",
"non-elderly",
"group,",
"but",
"it",
"was",
"not",
"significantly",
"different",
"(65.8",
"%vs.",
"76.2",
"%,",
"P",
"=",
"0.15).",
"In",
"a",
"subgroup",
"analysis,",
"among",
"patients",
"with",
"genotype",
"1,",
"the",
"elderly",
"group",
"had",
"a",
"significantly",
"lower",
"SVR",
"rate",
"than",
"the",
"non-elderly",
"group",
"(30.8",
"%",
"vs.",
"66.0",
"%,",
"P",
"=",
"0.03).",
"However,",
"the",
"SVR",
"rate",
"in",
"patients",
"with",
"HCV",
"genotype",
"2",
"or",
"3",
"was",
"comparable",
"between",
"the",
"two",
"groups",
"(84.0",
"%",
"vs.",
"81.3",
"%,",
"P",
"=",
"0.85).",
"HCV",
"genotype",
"was",
"significantly",
"associated",
"with",
"SVR",
"in",
"the",
"elderly",
"patients",
"(genotype",
"1",
"vs.",
"2",
"or",
"3,",
"odds",
"ratio:",
"0.18,",
"95%",
"confidence",
"interval:",
"0.000-0.869,",
"P",
"=",
"0.03).",
"The",
"incidence",
"of",
"premature",
"discontinuation",
"of",
"treatment",
"(21.1",
"%",
"vs.",
"9.1",
"%,",
"P",
"=",
"0.05)",
"and",
"dose",
"modification",
"(52.6",
"%",
"vs.",
"31.5",
"%;",
"P",
"=",
"0.02)",
"due",
"mainly",
"to",
"adverse",
"events",
"or",
"laboratory",
"abnor-",
"malities,",
"were",
"higher",
"in",
"the",
"elderly",
"group",
"than",
"in",
"the",
"non-elderly",
"group.",
"Conclusions:",
"PEG-IFN-α",
"plus",
"ribavirin",
"combination",
"therapy",
"might",
"be",
"considered",
"for",
"elder-",
"ly",
"CHC",
"patients,",
"especially",
"for",
"genotype",
"2",
"or",
"3,",
"with",
"vigilant",
"monitoring",
"of",
"adverse",
"events.",
"Copyright",
"c",
"2012",
"Kowsar",
"Corp.",
"All",
"rights",
"reserved.",
"Implication",
"for",
"health",
"policy/practice/research/medical",
"education:",
"The",
"care",
"of",
"older",
"patients",
"with",
"chronic",
"hepatitis",
"C",
"(CHC)",
"is",
"one",
"of",
"the",
"most",
"important",
"issues",
"confronted",
"by",
"physicians.",
"The",
"results",
"of",
"this",
"study",
"suggest",
"that",
"PEG-IFN-α",
"plus",
"ribavirin",
"combination",
"therapy",
"might",
"be",
"considered",
"for",
"elderly",
"chronic",
"hepatitis",
"C",
"pa-",
"tients,",
"especially",
"for",
"genotype",
"2",
"or",
"3,",
"with",
"vigilant",
"monitoring",
"of",
"adverse",
"events.",
"Please",
"cite",
"this",
"paper",
"as:",
"Kim",
"HI,",
"Kim",
"IH,",
"Jeon",
"BJ,",
"Lee",
"S,",
"Kim",
"SH,",
"Kim",
"SW,",
"et",
"al.",
"Treatment",
"Response",
"and",
"Tolerability",
"of",
"Pegylated",
"Interferon-α",
"Plus",
"Ribavirin",
"Combination",
"Therapy",
"in",
"Elderly",
"Patients",
"(≥",
"65",
"years)",
"With",
"Chronic",
"Hepatitis",
"C",
"in",
"Korea.",
"Hepat",
"Mon.",
"2012;12(7):",
"430-6.",
"DOI:",
"10.5812/",
"hepatmon.6170",
"*",
"Corresponding",
"author:",
"In",
"Hee",
"Kim,",
"Department",
"of",
"Internal",
"Medi-",
"cine,",
"Chonbuk",
"National",
"University",
"Medical",
"School",
"and",
"Hospital,",
"634-18",
"Keumam-dong,",
"Dukjin-gu,",
"Jeonju,",
"Jeonbuk",
"561-712,",
"South",
"Korea.",
"Tel:",
"+82-",
"632501677,",
"Fax:",
"+82-632541609,",
"E-mail:",
"ihkimmd@jbnu.ac.kr",
"DOI:",
"10.5812/hepatmon.6170",
"Copyright",
"c",
"2012",
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702,
740,
748,
754
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753,
740,
764,
754
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421,
756,
442,
770
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445,
756,
456,
770
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458,
756,
475,
770
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756,
506,
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508,
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540,
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542,
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565,
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568,
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597,
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647,
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649,
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695,
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697,
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727,
756,
763,
770
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421,
772,
442,
786
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444,
772,
480,
786
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484,
772,
544,
786
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547,
772,
557,
786
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560,
772,
576,
786
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579,
772,
608,
786
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611,
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659,
786
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662,
772,
672,
786
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676,
772,
692,
786
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[
695,
772,
729,
786
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[
732,
772,
764,
786
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[
421,
788,
442,
802
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[
448,
788,
471,
802
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477,
788,
501,
802
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507,
788,
526,
802
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[
532,
788,
545,
802
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[
550,
788,
601,
802
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607,
788,
618,
802
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[
624,
788,
664,
802
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[
670,
788,
711,
802
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[
717,
788,
764,
802
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[
421,
804,
448,
818
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[
450,
804,
518,
818
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[
521,
804,
546,
818
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[
550,
804,
618,
818
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[
621,
804,
647,
818
],
[
650,
804,
669,
818
],
[
672,
804,
683,
818
],
[
687,
804,
732,
818
],
[
735,
804,
764,
818
],
[
421,
820,
461,
834
],
[
466,
820,
506,
834
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[
511,
820,
564,
834
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[
569,
820,
617,
834
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[
622,
820,
656,
834
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[
661,
820,
670,
834
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[
675,
820,
693,
834
],
[
698,
820,
724,
834
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[
728,
820,
763,
834
],
[
421,
836,
442,
850
],
[
445,
836,
493,
850
],
[
495,
836,
536,
850
],
[
539,
836,
606,
850
],
[
609,
836,
618,
850
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[
621,
836,
709,
850
],
[
711,
836,
763,
850
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[
421,
852,
431,
866
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[
436,
852,
466,
866
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471,
852,
517,
866
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521,
852,
565,
866
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[
570,
852,
579,
866
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584,
852,
601,
866
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[
606,
852,
676,
866
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[
681,
852,
723,
866
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[
727,
852,
763,
866
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[
421,
868,
438,
882
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[
442,
868,
463,
882
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[
468,
868,
475,
882
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479,
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528,
882
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533,
868,
564,
882
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569,
868,
615,
882
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620,
868,
630,
882
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635,
868,
651,
882
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[
655,
868,
689,
882
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[
693,
868,
714,
882
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[
719,
868,
764,
882
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[
421,
883,
463,
897
],
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468,
883,
518,
897
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[
523,
883,
571,
897
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[
576,
883,
600,
897
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[
605,
883,
632,
897
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[
637,
883,
666,
897
],
[
672,
883,
689,
897
],
[
694,
883,
738,
897
],
[
743,
883,
763,
897
],
[
421,
899,
467,
913
],
[
471,
899,
527,
913
],
[
532,
899,
600,
913
],
[
605,
899,
653,
913
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[
657,
899,
681,
913
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[
685,
899,
763,
913
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[
421,
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455,
929
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[
460,
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494,
929
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499,
915,
510,
929
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516,
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522,
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527,
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564,
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569,
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580,
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585,
915,
602,
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607,
915,
648,
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653,
915,
673,
929
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679,
915,
764,
929
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[
421,
931,
484,
945
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490,
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501,
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507,
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555,
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561,
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608,
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615,
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636,
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643,
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679,
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719,
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725,
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421,
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478,
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495,
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453,
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480,
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525,
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532,
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561,
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567,
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620,
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626,
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421,
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] | [
"MOLECULAR",
"NEUROSCIENCE",
"Drug-evoked",
"plasticity:",
"do",
"addictive",
"drugs",
"reopen",
"a",
"critical",
"period",
"of",
"postnatal",
"synaptic",
"development?",
"Camilla",
"Bellone",
"1*",
"and",
"Christian",
"Lüscher",
"1,2",
"1",
"Medical",
"Faculty,",
"Department",
"of",
"Basic",
"Neurosciences,",
"University",
"of",
"Geneva,",
"Geneva,",
"Switzerland",
"2",
"Clinic",
"of",
"Neurology,",
"Department",
"of",
"Clinical",
"Neurosciences,",
"Geneva",
"University",
"Hospital,",
"Geneva,",
"Switzerland",
"REVIEW",
"ARTICLE",
"published:",
"15",
"June",
"2012",
"doi:",
"10.3389/fnmol.2012.00075",
"Edited",
"by:",
"R.",
"Suzanne",
"Zukin,",
"Albert",
"Einstein",
"College",
"of",
"Medicine,",
"USA",
"Reviewed",
"by:",
"Carlo",
"Sala,",
"CNR",
"Institute",
"of",
"Neuroscience,",
"Italy",
"Enrico",
"Tongiorgi,",
"University",
"of",
"Trieste,",
"Italy",
"*Correspondence:",
"Camilla",
"Bellone,",
"Medical",
"Faculty,",
"Department",
"of",
"Basic",
"Neuroscience,",
"University",
"of",
"Geneva,",
"1,",
"Michel-Servet,",
"1211",
"Geneve,",
"Switzerland.",
"e-mail:",
"camilla.bellone@unige.ch",
"As",
"in",
"other",
"parts",
"of",
"the",
"central",
"nervous",
"system",
"(CNS)",
"of",
"the",
"mouse,",
"glutamatergic",
"synapses",
"onto",
"dopamine",
"(DA)",
"neurons",
"in",
"the",
"ventral",
"tegmental",
"area",
"(VTA)",
"mature",
"postnatally.",
"At",
"birth",
"many",
"AMPA",
"receptors",
"(AMPARs)",
"lack",
"GluA2R",
"subunit",
"and",
"most",
"NMDARs",
"contain",
"the",
"GluN2B",
"subunit.",
"Within",
"2",
"weeks",
"these",
"receptors",
"are",
"replaced",
"with",
"GluA2-",
"and",
"GluN2A-",
"containing",
"AMPARs",
"and",
"NMDARs,",
"respectively.",
"Recent",
"data",
"suggest",
"that",
"a",
"single",
"injection",
"of",
"cocaine",
"(or",
"another",
"drug",
"of",
"addiction)",
"triggers",
"glutamate",
"receptor",
"redistribution",
"with",
"the",
"reappearance",
"of",
"the",
"subunits",
"typically",
"present",
"in",
"immature",
"synapses,",
"as",
"if",
"addictive",
"drugs",
"reopen",
"the",
"developmental",
"critical",
"period.",
"Here",
"we",
"review",
"the",
"experimental",
"evidence",
"for",
"this",
"hypothesis",
"and",
"discuss",
"the",
"implications",
"for",
"circuit",
"function.",
"Keywords:",
"CP-AMPARs,",
"VTA,",
"addictive",
"drugs,",
"postnatal",
"development",
"INTRODUCTION",
"Fast",
"excitatory",
"synaptic",
"transmission",
"in",
"the",
"mammalian",
"central",
"nervous",
"system",
"(CNS)",
"is",
"mediated",
"predominantly",
"by",
"ionotropic",
"glutamate",
"receptors",
"of",
"the",
"AMPA-",
"and",
"NMDA-type.",
"These",
"recep-",
"tors",
"are",
"composed",
"of",
"different",
"subunits",
"that",
"determine",
"the",
"bio-",
"physical",
"and",
"trafficking",
"properties",
"of",
"the",
"channel.",
"Depending",
"on",
"the",
"particular",
"subunit",
"composition",
"of",
"the",
"ionotropic",
"receptors",
"both",
"synaptic",
"transmission",
"and",
"synaptic",
"plasticity",
"can",
"vary",
"con-",
"siderably.",
"The",
"AMPA",
"receptors",
"(AMPARs)",
"are",
"the",
"workhorses",
"of",
"fast",
"excitatory",
"transmission",
"in",
"the",
"CNS.",
"They",
"are",
"tetrameric",
"receptor",
"assemblies",
"of",
"GluA1–4",
"subunits,",
"which",
"are",
"differently",
"expressed",
"in",
"the",
"brain",
"and",
"are",
"encoded",
"by",
"separate",
"genes",
"(Hollmann",
"and",
"Heinemann,",
"1994;",
"Kato",
"et",
"al.,",
"2008;",
"Traynelis",
"et",
"al.,",
"2010).",
"The",
"subunits",
"that",
"are",
"predominantly",
"expressed",
"in",
"the",
"CNS",
"are",
"the",
"GluA1",
"and",
"GluA2",
"subunits",
"and",
"the",
"major-",
"ity",
"of",
"receptors",
"at",
"the",
"synapse",
"are",
"heteromers",
"incorporating",
"both.",
"The",
"GluA2",
"subunit",
"is",
"critical",
"in",
"determining",
"the",
"proper-",
"ties",
"of",
"AMPARs;",
"the",
"presence",
"of",
"an",
"arginine",
"(R)",
"residue",
"in",
"its",
"pore",
"membrane",
"domain,",
"introduced",
"by",
"post-translational",
"edit-",
"ing,",
"renders",
"the",
"receptor",
"impermeable",
"to",
"Ca2+",
"(CI-AMPARs)",
"and",
"therefore",
"results",
"in",
"a",
"linear",
"current-voltage",
"(I–V)",
"curve",
"that",
"reverses",
"at",
"0",
"mV.",
"Conversely,",
"when",
"the",
"GluA2",
"subunit",
"is",
"absent,",
"the",
"receptors",
"are",
"Ca2+-permeable",
"(CP-AMPARs)",
"and",
"the",
"I–V",
"curve",
"becomes",
"inwardly",
"rectifying",
"because",
"the",
"currents",
"at",
"positive",
"potentials",
"are",
"inhibited",
"by",
"endogenous",
"polyamines",
"(Donevan",
"and",
"Rogawski,",
"1995;",
"Liu",
"and",
"Zukin,",
"2007)",
"and",
"because",
"the",
"unitary",
"current",
"is",
"larger.",
"Many",
"reversible",
"post-translational",
"modifications",
"of",
"both",
"GluA1",
"and",
"GluA2",
"subunits",
"regulate",
"AMPAR",
"expression",
"and",
"function;",
"among",
"them",
"subunit",
"phosphorylation",
"as",
"well",
"as",
"palmitoylation",
"and",
"ubiquitination",
"have",
"been",
"shown",
"to",
"modu-",
"late",
"both",
"biophysical",
"properties",
"and",
"receptor",
"trafficking",
"(Lu",
"and",
"Roche,",
"2011).",
"How",
"this",
"post-translational",
"modification",
"affects",
"the",
"trafficking",
"of",
"AMPARs",
"in",
"a",
"subunit-specific",
"manner,",
"and",
"how",
"this",
"determines",
"synaptic",
"plasticity,",
"remains",
"elusive.",
"Tight",
"control",
"of",
"CP-AMPAR",
"expression",
"ensures",
"that",
"the",
"majority",
"of",
"cells",
"in",
"the",
"brain",
"contain",
"CI-AMPARs",
"(Shin",
"et",
"al.,",
"2005).",
"Although",
"the",
"CP-AMPARs",
"may",
"mediate",
"excitotoxicity",
"associated",
"with",
"different",
"neurological",
"disorders",
"(Liu",
"and",
"Zukin,",
"2007)",
"it",
"has",
"been",
"shown",
"that",
"these",
"receptors",
"also",
"play",
"an",
"impor-",
"tant",
"role",
"in",
"synaptic",
"plasticity",
"(Plant",
"et",
"al.,",
"2006;",
"Adesnik",
"and",
"Nicoll,",
"2007).",
"Moreover",
"there",
"are",
"several",
"synapses",
"in",
"which",
"CP-",
"AMPARs",
"are",
"developmentally",
"expressed,",
"in",
"contrast",
"to",
"the",
"adult",
"where",
"CP-AMPARs",
"are",
"mainly",
"found",
"on",
"GABAegic",
"interneurons",
"(Goldberg",
"et",
"al.,",
"2003).",
"Because",
"of",
"their",
"characteristics,",
"the",
"CP-",
"AMPARs",
"confer",
"novel",
"properties",
"to",
"the",
"synapses",
"where",
"they",
"are",
"expressed",
"and",
"their",
"specific",
"role",
"in",
"synaptic",
"function",
"as",
"well",
"as",
"synaptic",
"plasticity",
"is",
"beginning",
"to",
"be",
"elucidated.",
"NMDARs",
"are",
"heteromeric",
"receptors",
"containing",
"GluN1",
"as",
"an",
"obligatory",
"subunit.",
"GluN1",
"is",
"expressed",
"both",
"in",
"the",
"neonatal",
"as",
"well",
"as",
"the",
"adult",
"brain.",
"Two",
"other",
"NMDAR",
"subunits",
"exist:",
"GluN2",
"and",
"GluN3",
"(Moriyoshi",
"et",
"al.,",
"1991;",
"Traynelis",
"et",
"al.,",
"2010).",
"Given",
"that",
"they",
"each",
"can",
"be",
"expressed",
"in",
"distinct",
"subunit",
"isoforms",
"(e.g.,",
"GluN2A/2B)",
"their",
"combination",
"gives",
"rise",
"to",
"multiple",
"func-",
"tionally",
"distinct",
"NMDARs",
"(Paoletti,",
"2011).",
"It",
"has",
"been",
"shown",
"that",
"NMDAR",
"subunit",
"composition",
"is",
"developmentally",
"regulated;",
"at",
"many",
"synapses",
"GluN2B",
"is",
"the",
"predominant",
"isoform",
"during",
"the",
"first",
"2",
"postnatal",
"weeks",
"(Monyer",
"et",
"al.,",
"1994).",
"The",
"GluN2A",
"isoform",
"gradually",
"increases",
"after",
"birth",
"while",
"the",
"GluN2B",
"and",
"GluN2D",
"expression",
"progressively",
"decrease.",
"This",
"developmental",
"switch",
"results",
"in",
"a",
"change",
"in",
"the",
"kinetics",
"and",
"subunit-specific",
"modulation",
"of",
"NMDAR",
"currents.",
"The",
"GluN3",
"family",
"can",
"be",
"expressed",
"as",
"two",
"isoforms",
"(GluN3A",
"and",
"GluN3B)",
"that",
"arise",
"from",
"two",
"different",
"genes",
"that",
"have",
"different",
"expression",
"pro-",
"files.",
"GluN3A",
"is",
"mainly",
"expressed",
"during",
"early",
"postnatal",
"life",
"and",
"Frontiers",
"in",
"Molecular",
"Neuroscience",
"www.frontiersin.org",
"June",
"2012",
"|",
"Volume",
"5",
"|",
"Article",
"75",
"|",
"1"
] | [
0,
0,
8,
8,
8,
8,
8,
8,
8,
8,
8,
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] | [
"BioPsychoSocial",
"Medicine",
"Research",
"Altered",
"autonomic",
"nervous",
"system",
"activity",
"as",
"a",
"potential",
"etiological",
"factor",
"of",
"premenstrual",
"syndrome",
"and",
"premenstrual",
"dysphoric",
"disorder",
"Tamaki",
"Matsumoto*1,",
"Takahisa",
"Ushiroyama2,",
"Tetsuya",
"Kimura3,",
"Tatsuya",
"Hayashi3",
"and",
"Toshio",
"Moritani3",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Health",
"Science,",
"International",
"Buddhist",
"University,",
"3-2-1",
"Gakuenmae,",
"Habikino,",
"Osaka,",
"583-8501,",
"Japan,",
"2Department",
"of",
"Nursing,",
"Aino",
"Gakuin",
"College,",
"Ibaragi,",
"Osaka,",
"Japan",
"and",
"3Graduate",
"School",
"of",
"Human",
"and",
"Environmental",
"Studies,",
"Kyoto",
"University,",
"Kyoto,",
"Japan",
"Email:",
"Tamaki",
"Matsumoto*",
"-",
"tamaki@shitennoji.ac.jp;",
"Takahisa",
"Ushiroyama",
"-",
"t-ushiroyama@ns-t.aino.ac.jp;",
"Tetsuya",
"Kimura",
"-",
"kimura@mmg.mbox.media.kyoto-u.ac.jp;",
"Tatsuya",
"Hayashi",
"-",
"tatsuya@kuhp.kyoto-u.ac.jp;",
"Toshio",
"Moritani",
"-",
"t.moritani@neuro.mbox.media.kyoto-u.ac.jp",
"*",
"Corresponding",
"author",
"Published:",
"20",
"December",
"2007",
"BioPsychoSocial",
"Medicine",
"2007,",
"1:24",
"doi:10.1186/1751-0759-1-24",
"This",
"article",
"is",
"available",
"from:",
"http://www.bpsmedicine.com/content/1/1/24",
"Received:",
"25",
"September",
"2007",
"Accepted:",
"20",
"December",
"2007",
"©",
"2007",
"Matsumoto",
"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:",
"Premenstrual",
"syndrome",
"(PMS)",
"encompasses",
"a",
"wide",
"variety",
"of",
"cyclic",
"and",
"recurrent",
"physical,",
"emotional,",
"and",
"behavioral",
"symptoms",
"occurring",
"during",
"the",
"late",
"luteal",
"phase",
"of",
"the",
"menstrual",
"cycle",
"and",
"abating",
"shortly",
"following",
"the",
"beginning",
"of",
"menses.",
"Although",
"PMS",
"is",
"widely",
"recognized,",
"its",
"etiopathogenesis",
"is",
"not",
"yet",
"understood.",
"The",
"present",
"study",
"investigates",
"whether",
"the",
"activity",
"of",
"the",
"autonomic",
"nervous",
"system,",
"which",
"plays",
"a",
"vital",
"role",
"in",
"orchestrating",
"physiological",
"homeostasis",
"within",
"the",
"human",
"body,",
"is",
"altered",
"during",
"the",
"menstrual",
"cycle",
"of",
"women",
"with",
"different",
"degrees",
"of",
"premenstrual",
"symptomatology.",
"Methods:",
"Sixty-two",
"women",
"in",
"their",
"20s",
"to",
"40s",
"with",
"regular",
"menstrual",
"cycles",
"participated",
"in",
"this",
"study.",
"All",
"subjects",
"were",
"examined",
"during",
"the",
"follicular",
"and",
"late",
"luteal",
"phases.",
"Cycle",
"phase",
"was",
"determined",
"by",
"the",
"onset",
"of",
"menstruation",
"and",
"oral",
"temperature",
"and",
"was",
"verified",
"by",
"concentrations",
"of",
"ovarian",
"hormones,",
"estrone,",
"and",
"pregnanediol",
"in",
"a",
"urine",
"sample",
"taken",
"early",
"in",
"the",
"morning.",
"Autonomic",
"nervous",
"system",
"activity",
"was",
"assessed",
"by",
"means",
"of",
"heart-rate",
"variability",
"(HRV)",
"power",
"spectral",
"analysis",
"during",
"supine",
"rest.",
"The",
"Menstrual",
"Distress",
"Questionnaire",
"was",
"used",
"to",
"evaluate",
"physical,",
"emotional,",
"and",
"behavioral",
"symptoms",
"accompanying",
"the",
"menstrual",
"cycle",
"of",
"the",
"subjects.",
"The",
"subjects",
"were",
"categorized",
"in",
"three",
"groups,",
"Control,",
"PMS,",
"and",
"premenstrual",
"dysphoric",
"disorder",
"(PMDD)",
"groups,",
"depending",
"on",
"the",
"severity",
"of",
"premenstrual",
"symptomatology.",
"Results:",
"No",
"intramenstrual",
"cycle",
"difference",
"in",
"any",
"of",
"the",
"parameters",
"of",
"HRV",
"was",
"found",
"in",
"the",
"Control",
"group,",
"which",
"had",
"no",
"or",
"a",
"small",
"increase",
"in",
"premenstrual",
"symptoms.",
"In",
"contrast,",
"Total",
"power",
"and",
"high",
"frequency",
"power,",
"which",
"reflect",
"overall",
"autonomic",
"and",
"parasympathetic",
"nerve",
"activity,",
"respectively,",
"significantly",
"decreased",
"in",
"the",
"late",
"luteal",
"phase",
"from",
"the",
"follicular",
"phase",
"in",
"the",
"PMS",
"group.",
"As",
"for",
"the",
"PMDD",
"group,",
"which",
"had",
"more",
"severe",
"symptoms",
"premenstrually,",
"heart-rate",
"fluctuation",
"as",
"well",
"as",
"all",
"components",
"of",
"the",
"power",
"spectrum",
"of",
"HRV",
"were",
"markedly",
"decreased",
"regardless",
"of",
"the",
"menstrual",
"cycle",
"compared",
"to",
"those",
"of",
"the",
"other",
"two",
"groups.",
"Conclusion:",
"Several",
"theories",
"have",
"been",
"proposed",
"to",
"explain",
"the",
"underlying",
"mechanisms",
"of",
"PMS",
"with",
"its",
"complex",
"web",
"of",
"bio-",
"psycho-social",
"factors.",
"Although",
"causes",
"and",
"consequences",
"continue",
"to",
"elude,",
"the",
"present",
"study",
"provides",
"intriguing",
"and",
"novel",
"findings",
"that",
"the",
"altered",
"functioning",
"of",
"the",
"autonomic",
"nervous",
"system",
"in",
"the",
"late",
"luteal",
"phase",
"could",
"be",
"associated",
"with",
"diverse",
"psychosomatic",
"and",
"behavioral",
"symptoms",
"appearing",
"premenstrually.",
"In",
"addition,",
"when",
"symptoms",
"become",
"more",
"severe",
"(as",
"seen",
"in",
"women",
"with",
"PMDD),",
"the",
"sympathovagal",
"function",
"might",
"be",
"more",
"depressed",
"regardless",
"of",
"the",
"menstrual",
"cycle.",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Journal",
"of",
"Medical",
"Case",
"Reports",
"BioMed",
"Central",
"Case",
"report",
"Severe",
"heparin-induced",
"thrombocytopenia:",
"when",
"the",
"obvious",
"is",
"not",
"obvious,",
"a",
"case",
"report",
"Graham",
"M",
"Cormack",
"and",
"Larry",
"J",
"Kaufman*",
"Open",
"Access",
"Address:",
"Department",
"of",
"Medicine,",
"University",
"of",
"Hawaii,",
"and",
"St.",
"Francis",
"Medical",
"Center,",
"Honolulu,",
"HI,",
"USA",
"Email:",
"Graham",
"M",
"Cormack",
"-",
"grahamcormack@hotmail.com;",
"Larry",
"J",
"Kaufman*",
"-",
"bjammin@hawaii.rr.com",
"*",
"Corresponding",
"author",
"Published:",
"30",
"April",
"2007",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2007,",
"1:13",
"doi:10.1186/1752-1947-1-13",
"This",
"article",
"is",
"available",
"from:",
"http://www.jmedicalcasereports.com/content/1/1/13",
"Received:",
"18",
"December",
"2006",
"Accepted:",
"30",
"April",
"2007",
"©",
"2007",
"Cormack",
"and",
"Kaufman;",
"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",
"Thrombocytopenia",
"commonly",
"occurs",
"in",
"hospitalized",
"patients,",
"particularly",
"critically",
"ill",
"patients.",
"We",
"present",
"an",
"exemplifying",
"case",
"of",
"severe",
"heparin-induced",
"thrombocytopenia",
"(HIT)",
"in",
"an",
"effort",
"to",
"solidify",
"its",
"high",
"priority",
"in",
"the",
"differential",
"diagnosis",
"of",
"thrombocytopenia.",
"A",
"75-year-old",
"female",
"underwent",
"cardiac",
"surgery",
"with",
"intraaortic",
"balloon",
"pump",
"(IABP)",
"placement.",
"A",
"platelet",
"count",
"drop",
"to",
"25",
"×",
"10(9)/L",
"by",
"the",
"third",
"postoperative",
"day",
"was",
"attributed",
"to",
"the",
"IABP,",
"which",
"was",
"removed.",
"Her",
"thrombocytopenia",
"remained",
"refractory",
"to",
"multiple",
"platelet",
"transfusions",
"over",
"several",
"days.",
"Right",
"hand",
"cyanosis",
"then",
"developed,",
"attributed",
"to",
"a",
"right",
"radial",
"arterial",
"catheter,",
"which",
"was",
"removed.",
"All",
"toes",
"and",
"fingers",
"then",
"showed",
"severe",
"ischemic",
"changes.",
"Ten",
"days",
"after",
"the",
"initial",
"platelet",
"count",
"drop,",
"a",
"critical",
"care",
"specialist",
"new",
"to",
"the",
"treating",
"team",
"suspected",
"HIT.",
"Heparin",
"exposure",
"was",
"stopped",
"and",
"argatroban",
"was",
"initiated.",
"A",
"HIT",
"antibody",
"test",
"was",
"subsequently",
"strongly",
"positive.",
"The",
"patients",
"thrombocytopenia",
"gradually",
"resolved.",
"No",
"additional",
"thromboses",
"occurred",
"during",
"a",
"27-day",
"intensive",
"care",
"unit",
"stay.",
"This",
"case",
"underscores",
"the",
"need",
"for",
"vigilance",
"in",
"suspecting",
"HIT",
"in",
"patients",
"with",
"thrombocytopenia",
"and",
"recent",
"heparin",
"exposure.",
"To",
"avoid",
"catastrophic",
"outcomes",
"in",
"such",
"patients,",
"heparin",
"should",
"be",
"stopped",
"and",
"alternative",
"anticoagulation",
"should",
"be",
"initiated,",
"at",
"least",
"until",
"HIT",
"is",
"excluded.",
"Background",
"Thrombocytopenia",
"is",
"a",
"common",
"finding",
"in",
"hospitalized",
"patients,",
"particularly",
"critically",
"ill",
"patients,",
"with",
"readily",
"plausible",
"causes",
"including",
"disseminated",
"intravascular",
"coagulation,",
"dilution",
"from",
"blood",
"transfusions,",
"continu-",
"ous",
"venovenous",
"hemodialysis",
"(CVVHD),",
"liver",
"disease",
"with",
"hypersplenism,",
"and",
"certain",
"medications.",
"Physicians",
"should",
"be",
"vigilant",
"in",
"excluding",
"the",
"more",
"dangerous",
"causes",
"of",
"thrombocytopenia.",
"For",
"example,",
"heparin-induced",
"thrombocytopenia",
"(HIT)",
"warrants",
"serious",
"consideration",
"because",
"it",
"is",
"a",
"potentially",
"devastating,",
"yet",
"underdiag-",
"nosed,",
"complication",
"of",
"one",
"of",
"the",
"most",
"commonly",
"pre-",
"scribed",
"medications",
"worldwide.",
"Approximately",
"one",
"trillion",
"units",
"of",
"heparin",
"are",
"adminis-",
"tered",
"to",
"12",
"million",
"patients",
"per",
"year",
"in",
"the",
"United",
"States",
"[1].",
"HIT",
"is",
"caused",
"by",
"antibodies",
"to",
"a",
"complex",
"of",
"heparin",
"and",
"platelet",
"factor",
"4",
"that",
"activate",
"platelets,",
"resulting",
"in",
"release",
"of",
"procoagulant",
"microparticles,",
"thrombocytope-",
"nia,",
"excessive",
"thrombin",
"generation,",
"and",
"frequently",
"thrombosis",
"[2].",
"HIT",
"occurs",
"in",
"approximately",
"0.5%",
"of",
"patients",
"with",
"occult",
"exposure",
"to",
"heparin",
"(e.g.,",
"catheter",
"flushes),",
"0.1%–1%",
"of",
"patients",
"treated",
"with",
"low-molecu-",
"lar-weight",
"heparin",
"[3],",
"and",
"3%–5%",
"of",
"patients",
"receiving",
"unfractionated",
"heparin",
"[4].",
"Although",
"these",
"are",
"small",
"per-",
"centages,",
"the",
"ubiquitous",
"use",
"of",
"heparin",
"puts",
"an",
"extremely",
"large",
"number",
"of",
"patients",
"at",
"risk.",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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"Acar,2",
"Ahmet",
"Tefekli,2",
"Ahmet",
"Musaog˘lu,2",
"I˙zzet",
"Rozanes,3",
"and",
"Ali",
"Emre4",
"1",
"School",
"of",
"Medicine,",
"Ko¸c",
"University,",
"34450",
"Istanbul,",
"Turkey",
"2",
"Department",
"of",
"Urology,",
"VKF",
"American",
"Hospital,",
"34365",
"Istanbul,",
"Turkey",
"3",
"Department",
"of",
"Radiology,",
"VKF",
"American",
"Hospital,",
"34365",
"Istanbul,",
"Turkey",
"4",
"Department",
"of",
"General",
"Surgery,",
"VKF",
"American",
"Hospital,",
"34365",
"Istanbul,",
"Turkey",
"Correspondence",
"should",
"be",
"addressed",
"to",
"O¨",
"mer",
"Acar,",
"omer",
"acar",
"@hotmail.com",
"Received",
"22",
"June",
"2012;",
"Revised",
"18",
"September",
"2012;",
"Accepted",
"24",
"September",
"2012",
"Academic",
"Editor:",
"Chin-Jung",
"Wang",
"Copyright",
"©",
"2012",
"Tarık",
"Esen",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Pheochromocytomas",
"can",
"be",
"a",
"part",
"of",
"familial",
"neoplastic",
"syndromes,",
"in",
"which",
"case",
"they",
"tend",
"to",
"be",
"multiple",
"and",
"involve",
"both",
"adrenal",
"glands.",
"Therefore,",
"sparing",
"adrenocortical",
"function",
"represents",
"a",
"major",
"concern",
"while",
"dealing",
"with",
"these",
"hereditary",
"lesions.",
"Herein,",
"we",
"describe",
"the",
"clinical",
"characteristics",
"and",
"the",
"management",
"strategy",
"of",
"a",
"patient",
"with",
"von",
"Hippel-Lindau",
"(VHL)",
"disease",
"who",
"had",
"multiple,",
"bilateral",
"pheochromocytomas",
"as",
"well",
"as",
"bilateral",
"renal",
"masses,",
"pancreatic",
"masses,",
"and",
"a",
"paracaval",
"mass.",
"Only",
"a",
"portion",
"of",
"the",
"left",
"adrenal",
"gland",
"has",
"remained",
"in",
"situ",
"after",
"two",
"consecutive",
"open",
"surgeries",
"and",
"a",
"percutaneous",
"radiofrequency",
"ablation",
"which",
"have",
"been",
"performed",
"to",
"treat",
"the",
"various",
"components",
"of",
"this",
"syndrome.",
"No",
"adrenal",
"or",
"extra-",
"adrenal",
"pheochromocytoma",
"recurrences",
"have",
"been",
"detected",
"during",
"a",
"follow-up",
"period",
"of",
"more",
"than",
"2",
"years.",
"Pancreatic",
"and",
"adrenal",
"functions",
"were",
"normal",
"throughout",
"the",
"postoperative",
"period",
"and",
"never",
"necessitated",
"any",
"replacement",
"therapy.",
"Adrenal",
"cortex-",
"sparing",
"surgery",
"is",
"a",
"valid",
"option",
"for",
"VHL",
"disease",
"patients",
"who",
"present",
"with",
"synchronous",
"bilateral",
"adrenal",
"pheochromocytomas.",
"1.",
"Introduction",
"Adrenal",
"surgery",
"has",
"gained",
"popularity",
"throughout",
"the",
"world",
"most",
"probably",
"because",
"of",
"the",
"increased",
"radiologic",
"detection",
"of",
"small,",
"solid,",
"asymptomatic",
"adrenal",
"masses.",
"These",
"inci-",
"dentalomas",
"are",
"mostly",
"small",
"in",
"size",
"and",
"nonfunctioning.",
"However,",
"surgery",
"is",
"needed",
"either",
"because",
"of",
"the",
"size",
"or",
"the",
"hormone-producing",
"nature",
"of",
"the",
"lesion,",
"in",
"at",
"least",
"15%",
"of",
"the",
"cases",
"[1].",
"Adrenal",
"surgery",
"has",
"been",
"accepted",
"as",
"a",
"total",
"adrenal",
"resection",
"per",
"definition.",
"In",
"a",
"patient",
"with",
"unilateral",
"disease",
"and",
"a",
"healthy",
"contralateral",
"adrenal",
"gland,",
"this",
"is",
"mostly",
"not",
"a",
"problem.",
"Yet",
"the",
"radiologic",
"presence",
"of",
"the",
"contralateral",
"gland",
"is",
"not",
"necessarily",
"an",
"evidence",
"for",
"healthy",
"function.",
"Moreover,",
"adrenal",
"masses",
"are",
"common",
"and",
"mostly",
"bilateral",
"and/or",
"multiple",
"in",
"patients",
"with",
"hereditary",
"syndromes,",
"where",
"a",
"bilateral",
"adrenalectomy",
"could",
"have",
"devastating",
"side",
"effects",
"either",
"with",
"the",
"resulting",
"adrenal",
"insufficiency",
"or",
"the",
"need",
"for",
"life-long",
"hormonal",
"replacement",
"[2].",
"Recently,",
"the",
"concept",
"of",
"partial",
"adrenalectomy",
"is",
"intro-",
"duced",
"for",
"the",
"above-mentioned",
"reasons",
"and",
"prompted",
"us",
"to",
"report",
"a",
"case",
"where",
"a",
"staged",
"cortex-sparing",
"adrenal",
"surgery",
"was",
"done",
"in",
"a",
"patient",
"with",
"von",
"Hippel-Lindau",
"(VHL)",
"disease",
"and",
"successfully",
"eliminated",
"multiple",
"bilateral",
"pheochromocytomas",
"without",
"causing",
"adrenal",
"insufficiency.",
"2.",
"Case",
"Report",
"A",
"31-year-old,",
"otherwise",
"healthy,",
"young",
"male",
"patient",
"pre-",
"sented",
"with",
"incidentally",
"detected",
"bilateral",
"small",
"solid",
"renal",
"and",
"adrenal",
"masses,",
"a",
"cystic",
"mass",
"at",
"the",
"head",
"of",
"the",
"pancreas,",
"and",
"a",
"paracaval",
"mass.",
"The",
"patient",
"defined",
"no",
"relevant",
"family",
"history",
"and",
"had",
"no",
"obvious",
"symptoms.",
"Physical",
"examination",
"findings",
"(including",
"serial",
"blood",
"pressure",
"measurements)"
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] | [
"Xhabija",
"et",
"al.",
"Cardiovascular",
"Ultrasound",
"2010,",
"8:44",
"http://www.cardiovascularultrasound.com/content/8/1/44",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"CARDIOVASCULAR",
"ULTRASOUND",
"Open",
"Access",
"Gerbode",
"defect",
"following",
"endocarditis",
"and",
"misinterpreted",
"as",
"severe",
"pulmonary",
"arterial",
"hypertension",
"Nereida",
"Xhabija1*,",
"Edvin",
"Prifti1,",
"Iris",
"Allajbeu2,",
"Fatmir",
"Sula1",
"Abstract",
"A",
"Gerbode",
"-type",
"defect",
"is",
"a",
"ventricular",
"septal",
"defect",
"communicating",
"directly",
"between",
"the",
"left",
"ventricle",
"and",
"right",
"atrium.",
"It",
"is",
"usually",
"congenital,",
"but",
"rarely",
"is",
"acquired,",
"as",
"a",
"complication",
"of",
"endocarditis.",
"This",
"can",
"be",
"anatomically",
"possible",
"because",
"the",
"normal",
"tricuspid",
"valve",
"is",
"more",
"apically",
"displaced",
"than",
"the",
"mitral",
"valve.",
"However,",
"identification",
"of",
"an",
"actual",
"communication",
"is",
"often",
"extremely",
"difficult,",
"so",
"a",
"careful",
"and",
"meticulous",
"echocardiogram",
"should",
"be",
"done",
"in",
"order",
"to",
"prevent",
"echocardiographic",
"misinterpretation",
"of",
"this",
"defect",
"as",
"pulmonary",
"arterial",
"hypertension.",
"The",
"large",
"systolic",
"pressure",
"gradient",
"between",
"the",
"left",
"ventricle",
"and",
"the",
"right",
"atrium",
"would",
"expectedly",
"result",
"in",
"a",
"high",
"velocity",
"systolic",
"Doppler",
"flow",
"signal",
"in",
"right",
"atrium",
"and",
"it",
"can",
"be",
"sometimes",
"mistakably",
"diagnosed",
"as",
"tricus-",
"pid",
"regurgitant",
"jet",
"simulating",
"pulmonary",
"arterial",
"hypertension.",
"We",
"present",
"a",
"rare",
"case",
"of",
"young",
"woman,",
"with",
"endocarditis",
"who",
"presented",
"with",
"severe",
"pulmonary",
"arterial",
"hyper-",
"tension.",
"The",
"preoperative",
"diagnosis",
"of",
"left",
"ventricle",
"to",
"right",
"atrial",
"communication",
"(acquired",
"Gerbode",
"defect)",
"was",
"suspected",
"initially",
"by",
"echocardiogram",
"and",
"confirmed",
"at",
"the",
"time",
"of",
"the",
"surgery.",
"A",
"point",
"of",
"interest,",
"apart",
"from",
"the",
"diagnostic",
"problem,",
"was",
"the",
"explanation",
"for",
"its",
"mechanism",
"and",
"presentation.",
"The",
"probability",
"of",
"a",
"bacterial",
"etiology",
"of",
"the",
"defect",
"is",
"high",
"in",
"this",
"case.",
"Introduction",
"Gerbode’s",
"defect",
"is",
"a",
"rare",
"form",
"of",
"VSD",
"that",
"allows",
"for",
"communication",
"between",
"the",
"LV",
"and",
"RA.",
"Two",
"types",
"of",
"LV-to-RA",
"communication",
"are",
"described:",
"supravalvular",
"and",
"infravalvular,",
"depending",
"on",
"whether",
"the",
"defect",
"in",
"the",
"membranous",
"septum",
"is",
"above",
"or",
"below",
"the",
"tricuspid",
"valve",
"[1,2].",
"Although",
"the",
"majority",
"appears",
"to",
"attribute",
"the",
"Gerbode",
"defect",
"to",
"congenital",
"origins,",
"there",
"have",
"been",
"publication",
"in",
"the",
"past",
"that",
"have",
"credited",
"the",
"defect’s",
"formation",
"secondary",
"to",
"bacterial",
"endocarditis,",
"especially",
"supravalvular",
"form",
"[3].",
"We",
"present",
"a",
"case",
"of",
"our",
"patient",
"with",
"this",
"uncommon",
"complication",
"of",
"endocarditis,",
"simulating",
"severe",
"pulmon-",
"ary",
"hypertension.",
"Case",
"report",
"A",
"41",
"year",
"old",
"lady,",
"from",
"Kosovo,",
"was",
"referred",
"to",
"our",
"hospital",
"for",
"severe",
"pulmonary",
"arterial",
"hypertension",
"and",
"a",
"*",
"Correspondence:",
"nereidaxh@yahoo.fr",
"1Department",
"of",
"Cardiology",
"and",
"Cardiac-Surgery,",
"American",
"Hospital,",
"Department",
"of",
"Cardiology,",
"Tirana,",
"Albania",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"mass",
"in",
"right",
"atrium",
"suspected",
"for",
"vegetation.",
"About",
"one",
"month",
"before,",
"she",
"presented",
"to",
"the",
"ER",
"of",
"her",
"local",
"hospi-",
"tal",
"with",
"pyrexia",
"and",
"malaise.",
"She",
"was",
"given",
"medication",
"and",
"nutrition",
"through",
"the",
"right",
"internal",
"jugular",
"site",
"for",
"a",
"few",
"days",
"since",
"her",
"peripheral",
"venous",
"system",
"was",
"unavail-",
"able.",
"Cardiology",
"was",
"consulted",
"because",
"her",
"blood",
"culture",
"grew",
"methacilin",
"sensitive",
"Staphylococcus",
"aureus",
"and",
"she",
"had",
"persistent",
"fever,",
"despite",
"antibiotics",
"treatment.",
"At",
"that",
"time",
"the",
"echocardiogram",
"was",
"interpreted",
"as",
"following:",
"normal",
"valves",
"and",
"cardiac",
"chambers,",
"but",
"a",
"mobile",
"mass",
"consistent",
"with",
"vegetation",
"in",
"right",
"atrium",
"was",
"present.",
"The",
"tricuspid",
"regurgitation",
"was",
"considered",
"mild-",
"to-",
"moderate",
"with",
"estimated",
"pulmonary",
"arterial",
"systolic",
"pres-",
"sure",
"about",
"80-90",
"mmHg",
"(figure",
"1A).",
"At",
"the",
"time",
"of",
"her",
"presentation",
"she",
"had",
"a",
"40",
"grade",
"fever",
"and",
"complained",
"of",
"fatigue",
"and",
"palpitation.",
"A",
"3/6",
"systolic",
"murmur",
"over",
"the",
"left",
"precordium",
"was",
"audible,",
"while",
"pulmonary",
"auscultation",
"was",
"negative.",
"Her",
"C-reactive",
"pro-",
"tein,",
"white",
"cell",
"count",
"and",
"erythrocyte",
"sedimentation",
"rate",
"were",
"elevated,",
"Hb",
"level",
"was",
"9.6",
"and",
"D-dimer",
"was",
"very",
"high",
"(3088",
"ng/ml).",
"An",
"electrocardiogram",
"revealed",
"sinus",
"tachycardia",
"with",
"right",
"bundle",
"branch",
"block.",
"©",
"2010",
"Xhabija",
"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."
] | [
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686,
871
],
[
693,
858,
714,
871
],
[
722,
858,
732,
871
],
[
739,
858,
769,
871
],
[
437,
873,
519,
886
],
[
524,
873,
548,
886
],
[
553,
873,
577,
886
],
[
582,
873,
618,
886
],
[
623,
873,
636,
886
],
[
640,
873,
720,
886
],
[
725,
873,
770,
886
],
[
437,
888,
456,
901
],
[
463,
888,
469,
901
],
[
476,
888,
509,
901
],
[
516,
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530,
901
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[
537,
888,
547,
901
],
[
554,
888,
577,
901
],
[
584,
888,
605,
901
],
[
611,
888,
641,
901
],
[
648,
888,
678,
901
],
[
685,
888,
693,
901
],
[
700,
888,
734,
901
],
[
740,
888,
750,
901
],
[
757,
888,
769,
901
],
[
437,
903,
515,
916
],
[
518,
903,
531,
916
],
[
534,
903,
568,
916
],
[
570,
903,
610,
916
],
[
613,
903,
623,
916
],
[
626,
903,
648,
916
],
[
651,
903,
673,
916
],
[
676,
903,
698,
916
],
[
701,
903,
723,
916
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[
726,
903,
748,
916
],
[
751,
903,
770,
916
],
[
437,
917,
555,
930
],
[
559,
917,
580,
930
],
[
585,
917,
605,
930
],
[
609,
917,
619,
930
],
[
623,
917,
649,
930
],
[
653,
917,
674,
930
],
[
678,
917,
688,
930
],
[
693,
917,
717,
930
],
[
721,
917,
770,
930
],
[
437,
932,
457,
945
],
[
462,
932,
486,
945
],
[
490,
932,
515,
945
],
[
519,
932,
569,
945
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[
574,
932,
609,
945
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[
613,
932,
626,
945
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[
630,
932,
657,
945
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[
661,
932,
707,
945
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[
712,
932,
746,
945
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932,
769,
945
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947,
463,
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947,
527,
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947,
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592,
947,
674,
960
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677,
947,
687,
960
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690,
947,
720,
960
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722,
947,
744,
960
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[
747,
947,
769,
960
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437,
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962,
473,
975
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962,
495,
975
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498,
962,
516,
975
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519,
962,
552,
975
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554,
962,
578,
975
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581,
962,
645,
975
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648,
962,
719,
975
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962,
748,
975
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962,
769,
975
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976,
463,
989
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547,
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603,
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647,
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573,
1004
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[
576,
991,
586,
1004
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590,
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654,
1004
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670,
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1004
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722,
1004
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1004
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1019
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[
457,
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509,
1019
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1019
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[
578,
1006,
618,
1019
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[
623,
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653,
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683,
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1059
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1059
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1059
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[
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677,
1059
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1059
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[
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] | [
"Protein",
"Kinase",
"A",
"Binds",
"and",
"Activates",
"Heat",
"Shock",
"Factor",
"1",
"Ayesha",
"Murshid1,",
"Shiuh-Dih",
"Chou1,",
"Thomas",
"Prince1,",
"Yue",
"Zhang",
"1",
",",
"Ajit",
"Bharti2,",
"Stuart",
"K.",
"Calderwood",
"1",
"*",
"1",
"Molecular",
"and",
"Cellular",
"Radiation",
"Oncology,",
"Beth",
"Israel",
"Deaconess",
"Medical",
"Center,",
"Harvard",
"Medical",
"School,",
"Boston,",
"Massachusetts,",
"United",
"States",
"of",
"America,",
"2",
"Stress",
"Response",
"Center,",
"Boston",
"University",
"Medical",
"Center,",
"Boston,",
"Massachusetts,",
"United",
"States",
"of",
"America",
"Abstract",
"Background:",
"Many",
"inducible",
"transcription",
"factors",
"are",
"regulated",
"through",
"batteries",
"of",
"posttranslational",
"modifications",
"that",
"couple",
"their",
"activity",
"to",
"inducing",
"stimuli.",
"We",
"have",
"studied",
"such",
"regulation",
"of",
"Heat",
"Shock",
"Factor",
"1",
"(HSF1),",
"a",
"key",
"protein",
"in",
"control",
"of",
"the",
"heat",
"shock",
"response,",
"and",
"a",
"participant",
"in",
"carcinogenisis,",
"neurological",
"health",
"and",
"aging.",
"As",
"the",
"mechanisms",
"involved",
"in",
"the",
"intracellular",
"regulation",
"of",
"HSF1",
"in",
"good",
"health",
"and",
"its",
"dysregulation",
"in",
"disease",
"are",
"still",
"incomplete",
"we",
"are",
"investigating",
"the",
"role",
"of",
"posttranslational",
"modifications",
"in",
"such",
"regulation.",
"Methodology/Principal",
"Findings:",
"In",
"a",
"proteomic",
"study",
"of",
"HSF1",
"binding",
"partners,",
"we",
"have",
"discovered",
"its",
"association",
"with",
"the",
"pleiotropic",
"protein",
"kinase",
"A",
"(PKA).",
"HSF1",
"binds",
"avidly",
"to",
"the",
"catalytic",
"subunit",
"of",
"PKA,",
"(PKAca)",
"and",
"becomes",
"phosphorylated",
"on",
"a",
"novel",
"serine",
"phosphorylation",
"site",
"within",
"its",
"central",
"regulatory",
"domain",
"(serine",
"320",
"or",
"S320),",
"both",
"in",
"vitro",
"and",
"in",
"vivo.",
"Intracellular",
"PKAca",
"levels",
"and",
"phosphorylation",
"of",
"HSF1",
"at",
"S320",
"were",
"both",
"required",
"for",
"HSF1",
"to",
"be",
"localized",
"to",
"the",
"nucleus,",
"bind",
"to",
"response",
"elements",
"in",
"the",
"promoter",
"of",
"an",
"HSF1",
"target",
"gene",
"(hsp70.1)",
"and",
"activate",
"hsp70.1",
"after",
"stress.",
"Reduction",
"in",
"PKAca",
"levels",
"by",
"small",
"hairpin",
"RNA",
"led",
"to",
"HSF1",
"exclusion",
"from",
"the",
"nucleus,",
"its",
"exodus",
"from",
"the",
"hsp70.1",
"promoter",
"and",
"decreased",
"hsp70.1",
"transcription.",
"Likewise,",
"null",
"mutation",
"of",
"HSF1",
"at",
"S320",
"by",
"alanine",
"substitution",
"for",
"serine",
"led",
"to",
"an",
"HSF1",
"species",
"excluded",
"from",
"the",
"nucleus",
"and",
"deficient",
"in",
"hsp70.1",
"activation.",
"Conclusions:",
"These",
"findings",
"of",
"PKA",
"regulation",
"of",
"HSF1",
"through",
"S320",
"phosphorylation",
"add",
"to",
"our",
"knowledge",
"of",
"the",
"signaling",
"networks",
"converging",
"on",
"this",
"factor",
"and",
"may",
"contribute",
"to",
"elucidating",
"its",
"complex",
"roles",
"in",
"the",
"stress",
"response",
"and",
"understanding",
"HSF1",
"dysregulation",
"in",
"disease.",
"Citation:",
"Murshid",
"A,",
"Chou",
"S-D,",
"Prince",
"T,",
"Zhang",
"Y,",
"Bharti",
"A,",
"et",
"al.",
"(2010)",
"Protein",
"Kinase",
"A",
"Binds",
"and",
"Activates",
"Heat",
"Shock",
"Factor",
"1.",
"PLoS",
"ONE",
"5(11):",
"e13830.",
"doi:10.1371/journal.pone.0013830",
"Editor:",
"Mikhail",
"V.",
"Blagosklonny,",
"Roswell",
"Park",
"Cancer",
"Institute,",
"United",
"States",
"of",
"America",
"Received",
"June",
"2,",
"2010;",
"Accepted",
"October",
"18,",
"2010;",
"Published",
"November",
"9,",
"2010",
"Copyright:",
"2010",
"Murshid",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"Studies",
"were",
"supported",
"by",
"NIH",
"research",
"grants",
"2RO1CA047407",
"and",
"RO1CA077465.",
"These",
"are",
"peer-reviewed",
"National",
"Institutes",
"of",
"Health",
"RO-1",
"grants",
"intended",
"to",
"investigate",
"the",
"role",
"of",
"cell",
"signaling",
"in",
"the",
"heat",
"shock/stress",
"response.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection,",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"scalderw@bidmc.harvard.edu",
"Introduction",
"HSF1",
"is",
"a",
"primary",
"regulator",
"of",
"the",
"heat",
"shock",
"response",
"and",
"a",
"factor",
"in",
"a",
"number",
"of",
"human",
"pathologies",
"including",
"cancer",
"and",
"neurodegenerative",
"diseases",
"[1,2,3,4,5].",
"Curiously,",
"although",
"both",
"diseases",
"are",
"associated",
"with",
"advancing",
"age,",
"HSF1",
"loses",
"activity",
"in",
"the",
"progression",
"of",
"neurodegenerative",
"diseases",
"while",
"being",
"activated",
"in",
"cancer",
"[1,2,6].",
"It",
"would",
"seem",
"apparent",
"therefore",
"that",
"understanding",
"the",
"molecular",
"basis",
"of",
"HSF1",
"up-",
"and",
"down-",
"regulation",
"in",
"disease",
"would",
"provide",
"valuable",
"insights.",
"HSF1",
"belongs",
"to",
"the",
"multi-gene",
"HSF",
"family",
"present",
"in",
"all",
"eukaryotes",
"[7].",
"Initial",
"studies",
"were",
"carried",
"out",
"on",
"the",
"single",
"HSF",
"gene",
"of",
"the",
"yeast",
"S.",
"cereviseae",
"[8].",
"These",
"studies",
"indicated",
"that,",
"unique",
"among",
"transcription",
"factors",
"HSF",
"undergoes",
"trimer",
"formation",
"on",
"activation",
"and",
"that",
"such",
"oligomerization",
"governs",
"binding",
"to",
"the",
"heat",
"shock",
"elements",
"(HSE)",
"on",
"the",
"promoters",
"of",
"heat",
"shock",
"protein",
"(HSP)",
"genes",
"[9,10].",
"The",
"findings",
"in",
"yeast",
"were",
"confirmed",
"in",
"mammalian",
"cells",
"in",
"which",
"trimerization",
"was",
"shown",
"to",
"be",
"a",
"requirement",
"for",
"binding",
"to",
"HSP",
"promoters",
"[7].",
"Another",
"unusual",
"feature",
"associated",
"with",
"HSF",
"is",
"that",
"trimerization",
"and",
"binding",
"to",
"HSE",
"can",
"be",
"dissociated",
"from",
"trans-activation",
"in",
"studies",
"carried",
"out",
"both",
"in",
"vitro",
"and",
"in",
"vivo;",
"DNA",
"binding",
"alone",
"is",
"evidently",
"insufficient",
"to",
"drive",
"transcription",
"and",
"other,",
"binding",
"independent",
"processes",
"are",
"involved",
"[11,12,13,14].",
"Early",
"studies",
"suggested",
"that",
"these",
"may",
"include",
"posttranslational",
"modification",
"of",
"HSF1",
"[10,13,15].",
"Indeed",
"yeast",
"HSF",
"and",
"mammalian",
"HSF1",
"appear",
"to",
"undergo",
"heavy",
"phosphorylation",
"on",
"serine",
"and",
"threonine",
"residues",
"when",
"activated",
"[10,15,16].",
"In",
"addition",
"intracellular",
"HSF1",
"under-",
"goes",
"other",
"modifications",
"such",
"as",
"sumoylation",
"and",
"acetylation",
"after",
"stress",
"[17].",
"Alterations",
"in",
"HSF1",
"phosphorylation",
"appear",
"to",
"be",
"important",
"in",
"the",
"‘‘second",
"step’’",
"of",
"HSF1",
"activation",
"and",
"stress",
"and",
"trans-activation",
"of",
"HSP",
"genes",
"can",
"be",
"inhibited",
"by",
"kinase",
"inhibitors,",
"while",
"inactive",
"HSF1",
"trimers",
"can",
"be",
"rendered",
"active",
"in",
"vivo",
"by",
"exposure",
"to",
"phosphatase",
"inhibitors",
"[14].",
"The",
"sites",
"of",
"HSF1",
"phosphorylation",
"have",
"been",
"studied",
"by",
"phosphopeptide",
"mapping",
"and",
"a",
"partial",
"list",
"of",
"such",
"sites",
"exists.",
"HSF1",
"is",
"known",
"to",
"be",
"phosphorylated",
"on",
"serines",
"residues",
"at",
"121,",
"230,",
"303,",
"307,",
"326,",
"363",
"[16,18,19,20,21,22,23].",
"The",
"role",
"of",
"these",
"sites",
"in",
"HSP",
"transcrip-",
"tion",
"have",
"been",
"attributed",
"mainly",
"by",
"point",
"mutation",
"studies",
"and",
"these",
"experiments",
"suggest",
"that",
"phosphorylation",
"of",
"serine",
"121,",
"303,",
"307,",
"or",
"363",
"can",
"inhibit",
"HSP",
"transcription",
"[16,18,24,25].",
"S230",
"and",
"S326",
"are",
"the",
"only",
"currently",
"known",
"phosphorylation",
"sites",
"associated",
"with",
"stimulation",
"of",
"transcription",
"by",
"HSF1.",
"In",
"addition,",
"the",
"regulatory",
"mechanisms",
"through",
"which",
"these",
"posttranslational",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"November",
"2010",
"|",
"Volume",
"5",
"|",
"Issue",
"11",
"|",
"e13830"
] | [
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5,
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] | [
"organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"N-[Amino(azido)methylidene]-4-methyl-",
"benzenesulfonamide",
"Ayyaz",
"Mahmood,",
"Islam",
"Ullah",
"Khan,*",
"Muhammad",
"Nadeem",
"Arshad‡",
"and",
"Jamil",
"Ahmed",
"Materials",
"Chemistry",
"Laboratory,",
"Department",
"of",
"Chemistry,",
"GC",
"University,",
"Lahore",
"54000,",
"Pakistan",
"Correspondence",
"e-mail:",
"iukhan@gcu.edu.pk",
"Received",
"29",
"June",
"2011;",
"accepted",
"6",
"July",
"2011",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"296",
"K;",
"mean",
"(C–C)",
"=",
"0.003",
"A˚;",
"R",
"factor",
"=",
"0.035;",
"wR",
"factor",
"=",
"0.107;",
"data-to-parameter",
"ratio",
"=",
"17.1.",
"In",
"the",
"title",
"molecule,",
"C8H10N5O2S,",
"the",
"amino(azido)methyl",
"and",
"p-toluenesulfonyl",
"moieties",
"are",
"inclined",
"almost",
"at",
"right",
"angles",
"with",
"respect",
"to",
"each",
"other,",
"making",
"a",
"dihedral",
"angle",
"of",
"83.49",
"(6)",
".",
"An",
"intramolecular",
"N—H",
"O",
"hydrogen",
"bond",
"gives",
"rise",
"to",
"the",
"formation",
"of",
"six-membered",
"ring",
"with",
"graph-set",
"motif",
"S(6).",
"In",
"the",
"crystal,",
"intermolecular",
"N—H",
"O",
"hydrogen",
"bonding",
"is",
"responsible",
"for",
"the",
"formation",
"of",
"dimers",
"about",
"inversion",
"centers,",
"which",
"are",
"linked",
"through",
"another",
"N—",
"H",
"O",
"interaction",
"along",
"the",
"b",
"axis.",
"Related",
"literature",
"For",
"the",
"synthesis,",
"see:",
"Arshad",
"et",
"al.",
"(2009).",
"For",
"the",
"biological",
"activity",
"of",
"sulfonamides,",
"see:",
"Moree",
"et",
"al.",
"(1991);",
"Arshad",
"et",
"al.",
"(2008);",
"Gennarti",
"et",
"al.",
"(1994).",
"For",
"related",
"structures,",
"see:",
"Denny",
"et",
"al.",
"(1980);",
"Mu¨",
"ller",
"&",
"Ba¨",
"rnighausen",
"(1970).",
"For",
"graph-",
"set",
"notation,",
"see:",
"Bernstein",
"et",
"al.",
"(1995).",
"Experimental",
"Crystal",
"data",
"C8H9N5O2S",
"Mr",
"=",
"239.26",
"Triclinic,",
"P1",
"a",
"=",
"6.8986",
"(2)",
"A˚",
"b",
"=",
"7.2146",
"(2)",
"A˚",
"c",
"=",
"11.3771",
"(3)",
"A˚",
"=",
"92.244",
"(1)",
"=",
"93.615",
"(1)",
"=",
"110.505",
"(1)",
"V",
"=",
"528.18",
"(3)",
"A˚3",
"Z",
"=",
"2",
"Mo",
"K",
"radiation",
"=",
"0.30",
"mm",
"1",
"T",
"=",
"296",
"K",
"0.34",
"0.17",
"0.17",
"mm",
"Data",
"collection",
"Bruker",
"APEXII",
"CCD",
"diffractometer",
"8664",
"measured",
"reflections",
"Refinement",
"R[F2",
">",
"2",
"(F2)]",
"=",
"0.031",
"wR(F2)",
"=",
"0.088",
"S",
"=",
"1.09",
"2549",
"reflections",
"152",
"parameters",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"D—H",
"A",
"N2—H2N",
"N2—H3N",
"N2—H2N",
"O2i",
"O1ii",
"O2",
"D—H",
"0.80",
"(2)",
"0.89",
"(2)",
"0.80",
"(2)",
"H",
"A",
"2.24",
"(2)",
"2.08",
"(2)",
"2.34",
"(2)",
"Symmetry",
"codes:",
"(i)",
"x",
"þ",
"2;",
"y;",
"z;",
"(ii)",
"x;",
"y",
"1;",
"z.",
"2549",
"independent",
"reflections",
"2343",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.020",
"H",
"atoms",
"treated",
"by",
"a",
"mixture",
"of",
"independent",
"and",
"constrained",
"refinement",
"max",
"=",
"0.30",
"e",
"A˚",
"3",
"min",
"=",
"0.29",
"e",
"A˚",
"3",
"D",
"A",
"2.9459",
"(16)",
"2.9481",
"(15)",
"2.8862",
"(16)",
"D—H",
"A",
"148",
"(2)",
"164",
"(2)",
"127",
"(2)",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2007);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2007);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"ORTEP-3",
"for",
"Windows",
"(Farrugia,",
"1997);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"WinGX",
"(Farrugia,",
"1999).",
"The",
"authors",
"acknowledge",
"the",
"Higher",
"Education",
"Commis-",
"sion",
"of",
"Pakistan",
"for",
"the",
"purchase",
"of",
"the",
"diffractometer",
"under",
"the",
"grant",
"to",
"strengthen",
"the",
"Materials",
"Chemistry",
"Laboratory",
"at",
"GC",
"University,",
"Lahore,",
"and",
"thank",
"Dr",
"Sohail",
"Anjum",
"Shehzad",
"for",
"helpful",
"discussions.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"PV2426).",
"References",
"Arshad,",
"M.",
"N.,",
"Khan,",
"I.",
"U.",
"&",
"Zia-ur-Rehman,",
"M.",
"(2008).",
"Acta",
"Cryst.",
"E64,",
"o2283–o2284.",
"Arshad,",
"M.",
"N.,",
"Tahir,",
"M.",
"N.,",
"Khan,",
"I.",
"U.,",
"Siddiqui,",
"W.",
"A.",
"&",
"Shafiq,",
"M.",
"(2009).",
"Acta",
"Cryst.",
"E65,",
"o281.",
"Bernstein,",
"J.,",
"Davis,",
"R.",
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"Shimoni,",
"L.",
"&",
"Chang,",
"N.-L.",
"(1995).",
"Angew.",
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"34,",
"1555–1573.",
"Bruker",
"(2007).",
"SADABS,",
"APEX2",
"and",
"SAINT.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Denny,",
"G.",
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"E.",
"J.",
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"&",
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"C.",
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"(1980).",
"J.",
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"1665.",
"Farrugia,",
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"Cryst.",
"30,",
"565.",
"Farrugia,",
"L.",
"J.",
"(1999).",
"J.",
"Appl.",
"Cryst.",
"32,",
"837–838.",
"Gennarti,",
"C.,",
"Salom,",
"B.,",
"Potenza,",
"D.",
"&",
"Williams,",
"A.",
"(1994).",
"Angew.",
"Chem.",
"Int.",
"Ed.",
"Engl.",
"33,",
"2067–2069.",
"Moree,",
"W.",
"J.,",
"Van",
"der",
"Marel,",
"G.",
"A.",
"&",
"Liskamp,",
"R.",
"M.",
"(1991).",
"Tetrahedron",
"Lett.",
"32,",
"409–411.",
"Mu¨",
"ller,",
"U.",
"&",
"B",
"a¨rnighausen,",
"H.",
"(1970).",
"Acta",
"Cryst.",
"B26,",
"1671–1679.",
"Sheldrick,",
"G.",
"M.",
"(2008).",
"Acta",
"Cryst.",
"A64,",
"112–122.",
"‡",
"X-ray",
"Diffraction",
"and",
"Physical",
"Laboratory,",
"Department",
"of",
"Physics,",
"School",
"of",
"Physical",
"Sciences,",
"University",
"of",
"the",
"Punjab,",
"Quaid-e-Azam",
"Campus,",
"Lahore",
"54590,",
"Pakistan.",
"o2140",
"Mahmood",
"et",
"al.",
"doi:10.1107/S1600536811026973",
"Acta",
"Cryst.",
"(2011).",
"E67,",
"o2140"
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] | [
"HUMAN",
"NEUROSCIENCE",
"Repetition",
"enhancement",
"and",
"perceptual",
"processing",
"of",
"visual",
"word",
"form",
"Karine",
"Lebreton",
"1,2,3,4*†,",
"Nicolas",
"Villain",
"1,2,3,4†,",
"Gaël",
"Chételat",
"1,2,3,4,",
"Brigitte",
"Landeau",
"1,2,3,4,",
"Mohamed",
"L.",
"Seghier",
"5,6,",
"François",
"Lazeyras",
"5,",
"Francis",
"Eustache",
"1,2,3,4",
"and",
"Vicente",
"Ibanez",
"7",
"1",
"INSERM,",
"U1077,",
"Caen,",
"France",
"2",
"Université",
"de",
"Caen",
"Basse-Normandie,",
"UMR-S1077,",
"Caen,",
"France",
"3",
"Ecole",
"Pratique",
"des",
"Hautes",
"Etudes,",
"UMR-S1077,",
"Caen,",
"France",
"4",
"CHU",
"de",
"Caen,",
"U1077,",
"Caen,",
"France",
"5",
"Department",
"of",
"Radiology,",
"University",
"Hospitals",
"of",
"Geneva,",
"Geneva,",
"Switzerland",
"6",
"Wellcome",
"Trust",
"Centre",
"for",
"Neuroimaging,",
"Institute",
"of",
"Neurology,",
"UCL,",
"London,",
"UK",
"7",
"Psychiatric",
"Neuroimaging",
"Unit,",
"Division",
"of",
"Neuropsychiatry,",
"Department",
"of",
"Psychiatry,",
"University",
"Hospitals",
"of",
"Geneva,",
"Geneva,",
"Switzerland",
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"12",
"July",
"2012",
"doi:",
"10.3389/fnhum.2012.00206",
"Edited",
"by:",
"David",
"Bartrés-Faz,",
"University",
"of",
"Barcelona,",
"Spain",
"Reviewed",
"by:",
"Arun",
"Bokde,",
"Ludwig-Maximilian",
"University,",
"Germany",
"Alfonso",
"Barrós-Loscertales,",
"Universitat",
"Jaume",
"I,",
"Spain",
"*Correspondence:",
"Karine",
"Lebreton,",
"Unité",
"de",
"Recherche",
"U1077,",
"GIP",
"Cyceron,",
"Bd",
"H.",
"Becquerel,",
"BP",
"5229,",
"Caen",
"Cedex,",
"14074,",
"France.",
"e-mail:",
"lebreton@cyceron.fr",
"†These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"The",
"current",
"study",
"investigated",
"the",
"cerebral",
"basis",
"of",
"word",
"perceptual",
"repetition",
"priming",
"with",
"fMRI",
"during",
"a",
"letter",
"detection",
"task",
"that",
"manipulated",
"the",
"familiarity",
"of",
"perceptual",
"word",
"form",
"and",
"the",
"number",
"of",
"repetitions.",
"Some",
"neuroimaging",
"studies",
"have",
"reported",
"increases,",
"instead",
"of",
"decreases,",
"in",
"brain",
"activations",
"(called",
"“repetition",
"enhancement”)",
"associated",
"with",
"repetition",
"priming",
"of",
"unfamiliar",
"stimuli",
"which",
"have",
"been",
"interpreted",
"as",
"the",
"creation",
"of",
"new",
"perceptual",
"representations",
"for",
"unfamiliar",
"items.",
"According",
"to",
"this",
"interpretation,",
"several",
"repetitions",
"of",
"unfamiliar",
"items",
"would",
"then",
"be",
"necessary",
"for",
"the",
"repetition",
"priming",
"to",
"occur,",
"a",
"hypothesis",
"not",
"explicitly",
"tested",
"in",
"prior",
"studies.",
"In",
"the",
"present",
"study,",
"using",
"a",
"letter",
"detection",
"task",
"on",
"briefly",
"flashed",
"words,",
"we",
"explored",
"the",
"effect",
"of",
"familiarity",
"on",
"brain",
"response",
"for",
"word",
"visual",
"perceptual",
"priming",
"using",
"both",
"words",
"with",
"usual",
"(i.e.,",
"familiar)",
"and",
"unusual",
"(i.e.,",
"unfamiliar)",
"font,",
"presented",
"up",
"to",
"four",
"times",
"for",
"stimuli",
"with",
"unusual",
"font.",
"This",
"allows",
"potential",
"changes",
"in",
"the",
"brain",
"responses",
"for",
"unfamiliar",
"items",
"to",
"be",
"assessed",
"over",
"several",
"repetitions,",
"i.e.,",
"repetition",
"enhancement",
"to",
"suppression.",
"Our",
"results",
"reveal",
"significant",
"increases",
"of",
"activity",
"in",
"the",
"bilateral",
"occipital",
"areas",
"related",
"to",
"repetition",
"of",
"words",
"in",
"both",
"familiar",
"and",
"unfamiliar",
"conditions.",
"Our",
"findings",
"support",
"the",
"sharpening",
"hypothesis,",
"showing",
"a",
"lack",
"of",
"cerebral",
"economy",
"with",
"repetition",
"when",
"the",
"task",
"requires",
"the",
"processing",
"of",
"all",
"word",
"features,",
"whatever",
"the",
"familiarity",
"of",
"the",
"material,",
"and",
"emphasize",
"the",
"influence",
"of",
"the",
"nature",
"of",
"stimuli",
"processing",
"on",
"its",
"neuronal",
"manifestation.",
"Keywords:",
"priming,",
"fMRI,",
"repetition",
"suppression,",
"repetition",
"enhancement,",
"sharpening,",
"visual",
"processing",
"INTRODUCTION",
"Priming",
"is",
"generally",
"defined",
"as",
"an",
"improvement",
"or",
"a",
"change",
"in",
"the",
"identification,",
"production",
"or",
"classification",
"of",
"a",
"stimulus",
"as",
"a",
"result",
"of",
"a",
"prior",
"encounter",
"with",
"the",
"same",
"or",
"a",
"similar",
"stimulus",
"(Tulving",
"and",
"Schacter,",
"1990;",
"Schacter",
"and",
"Buckner,",
"1998;",
"Wiggs",
"and",
"Martin,",
"1998;",
"Henson,",
"2003;",
"Schacter",
"et",
"al.,",
"2007).",
"It",
"rep-",
"resents",
"an",
"implicit",
"form",
"of",
"memory",
"which",
"occurs",
"even",
"in",
"the",
"absence",
"of",
"conscious",
"remembering",
"and",
"it",
"may",
"reflect",
"a",
"memory",
"system",
"distinct",
"from",
"explicit",
"memory",
"(Graf",
"and",
"Schacter,",
"1985;",
"Gabrieli,",
"1998;",
"Henson,",
"2003).",
"From",
"a",
"multi-system",
"memory",
"point",
"of",
"view,",
"two",
"kinds",
"of",
"repetition",
"priming",
"have",
"been",
"distin-",
"guished,",
"depending",
"on",
"two",
"distinct",
"memory",
"systems:",
"perceptual",
"and",
"conceptual",
"(or",
"semantic)",
"priming.",
"Perceptual",
"priming",
"(the",
"focus",
"of",
"the",
"present",
"study)",
"is",
"based",
"on",
"the",
"perceptual",
"or",
"phys-",
"ical",
"representations",
"of",
"stimuli",
"and",
"is",
"thought",
"to",
"depend",
"on",
"a",
"perceptual",
"representation",
"system",
"or",
"perceptual",
"memory,",
"which",
"stores",
"and",
"processes",
"perceptual,",
"but",
"not",
"semantic,",
"features",
"of",
"items",
"(Tulving",
"and",
"Schacter,",
"1990;",
"Tulving,",
"1995;",
"Eustache",
"and",
"Desgranges,",
"2008).",
"Perceptual",
"repetition",
"priming",
"is",
"often",
"assessed",
"using",
"identification",
"tasks",
"of",
"degraded",
"items",
"or",
"briefly",
"flashed",
"stimuli",
"which",
"are",
"supposed",
"to",
"further",
"solicit",
"the",
"perceptual",
"mem-",
"ory",
"(Brown",
"et",
"al.,",
"1996;",
"Berry",
"et",
"al.,",
"1997;",
"Lebreton",
"et",
"al.,",
"2001;",
"Gagnepain",
"et",
"al.,",
"2008,",
"2011).",
"This",
"repetition-based",
"processing",
"facilitation",
"has",
"been",
"asso-",
"ciated",
"with",
"reductions",
"in",
"neural",
"activity",
"when",
"an",
"experience",
"is",
"repeated.",
"Several",
"functional",
"neuroimaging",
"studies",
"have",
"con-",
"sistently",
"revealed",
"a",
"decrease",
"in",
"haemodynamic",
"responses",
"for",
"repeated",
"(primed)",
"relative",
"to",
"unrepeated",
"(unprimed)",
"stimuli.",
"This",
"repetition-based",
"neural",
"change",
"has",
"been",
"assigned",
"numer-",
"ous",
"terms",
"such",
"as",
"adaptation,",
"repetition",
"suppression",
"or",
"neural",
"priming",
"(for",
"review",
"see",
"Grill-Spector",
"et",
"al.,",
"2006),",
"and",
"has",
"been",
"observed",
"within",
"a",
"set",
"of",
"specific",
"cortical",
"regions",
"(Schacter",
"et",
"al.,",
"1998,",
"2004,",
"2007;",
"Schacter",
"and",
"Badgaiyan,",
"2001;",
"Henson,",
"2003),",
"depending",
"on",
"the",
"type",
"of",
"stimulus",
"(visual",
"or",
"auditory",
"word,",
"object,",
"face,",
"symbol.",
".",
".)",
"and",
"on",
"the",
"nature",
"of",
"representations",
"across",
"different",
"stages",
"of",
"a",
"processing",
"stream",
"(perceptual",
"or",
"con-",
"ceptual).",
"For",
"example,",
"repetition-related",
"reductions",
"associated",
"with",
"perceptual",
"behavioral",
"priming",
"were",
"reported",
"in",
"brain",
"areas",
"that",
"are",
"significantly",
"active",
"for",
"novel",
"items",
"(or",
"for",
"the",
"first",
"pre-",
"sentation",
"of",
"item),",
"and",
"that",
"are",
"known",
"to",
"be",
"involved",
"in",
"early",
"Frontiers",
"in",
"Human",
"Neuroscience",
"www.frontiersin.org",
"July",
"2012",
"|",
"Volume",
"6",
"|",
"Article",
"206",
"|",
"1"
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] | [
"Latexin",
"Is",
"Down-Regulated",
"in",
"Hematopoietic",
"Malignancies",
"and",
"Restoration",
"of",
"Expression",
"Inhibits",
"Lymphoma",
"Growth",
"Yi",
"Liu2,",
"Dianna",
"Howard1,",
"Kyle",
"Rector2,",
"Carol",
"Swiderski1,",
"Jason",
"Brandon3,",
"Lawrence",
"Schook4,",
"Jayesh",
"Mehta5,",
"J.",
"Scott",
"Bryson1,3,",
"Subbarao",
"Bondada3,",
"Ying",
"Liang",
"1",
"*",
"1",
"Department",
"of",
"Internal",
"Medicine,",
"University",
"of",
"Kentucky",
"College",
"of",
"Medicine,",
"Lexington,",
"Kentucky,",
"United",
"States",
"of",
"America,",
"2",
"Department",
"of",
"Physiology,",
"University",
"of",
"Kentucky",
"College",
"of",
"Medicine,",
"Lexington,",
"Kentucky,",
"United",
"States",
"of",
"America,",
"3",
"Department",
"of",
"Microbiology,",
"Immunology",
"and",
"Molecular",
"Genetics,",
"University",
"of",
"Kentucky",
"College",
"of",
"Medicine,",
"Lexington,",
"Kentucky,",
"United",
"States",
"of",
"America,",
"4",
"Department",
"of",
"Animal",
"Sciences,",
"University",
"of",
"Illinois,",
"Urbana,",
"Illinois,",
"United",
"States",
"of",
"America,",
"5",
"Department",
"of",
"Medicine,",
"The",
"Feinberg",
"School",
"of",
"Medicine,",
"Northwestern",
"University,",
"Chicago,",
"Illinois,",
"United",
"States",
"of",
"America",
"Abstract",
"Latexin",
"is",
"a",
"negative",
"regulator",
"of",
"hematopoietic",
"stem",
"cell",
"number",
"in",
"mice.",
"Its",
"dysregulated",
"expression",
"in",
"other",
"tumors",
"led",
"us",
"to",
"hypothesize",
"that",
"latexin",
"may",
"have",
"tumor",
"suppressor",
"properties",
"in",
"hematological",
"malignancies.",
"We",
"found",
"that",
"latexin",
"was",
"down-regulated",
"in",
"a",
"variety",
"of",
"leukemia",
"and",
"lymphoma",
"cell",
"lines",
"as",
"well",
"as",
"in",
"CD34+",
"cells",
"from",
"the",
"blood",
"and",
"marrow",
"of",
"patients",
"with",
"these",
"malignancies.",
"5-aza-29-deoxycytodine",
"treatment",
"and",
"bisulfite",
"sequencing",
"revealed",
"hypermethylation",
"of",
"latexin",
"promoter",
"in",
"tumor",
"cells.",
"Retrovirus-mediated",
"latexin",
"overexpression",
"in",
"A20",
"mouse",
"lymphoma",
"cells",
"inhibited",
"their",
"in",
"vitro",
"growth",
"by",
"16",
"fold",
"and",
"in",
"vivo",
"tumor",
"volume",
"by",
"2",
"fold.",
"Latexin",
"caused",
"growth",
"inhibition",
"of",
"lymphoma",
"cells",
"by",
"significantly",
"increasing",
"apoptosis",
"through",
"the",
"down-regulation",
"of",
"anti-apoptotic",
"genes",
"Bcl-2",
"and",
"Pim-2.",
"The",
"molecular",
"mechanism",
"underlying",
"latexin-mediated",
"tumor",
"inhibition",
"was",
"not",
"through",
"its",
"canonical",
"carboxypeptidase",
"inhibitor",
"activity.",
"These",
"results",
"are",
"consistent",
"with",
"a",
"tumor",
"suppressor",
"role",
"for",
"latexin",
"and",
"suggest",
"that",
"latexin",
"may",
"have",
"clinical",
"efficacy",
"in",
"the",
"treatment",
"of",
"malignancies.",
"Citation:",
"Liu",
"Y,",
"Howard",
"D,",
"Rector",
"K,",
"Swiderski",
"C,",
"Brandon",
"J,",
"et",
"al.",
"(2012)",
"Latexin",
"Is",
"Down-Regulated",
"in",
"Hematopoietic",
"Malignancies",
"and",
"Restoration",
"of",
"Expression",
"Inhibits",
"Lymphoma",
"Growth.",
"PLoS",
"ONE",
"7(9):",
"e44979.",
"doi:10.1371/journal.pone.0044979",
"Editor:",
"Ilya",
"Ulasov,",
"University",
"of",
"Chicago,",
"United",
"States",
"of",
"America",
"Received",
"April",
"30,",
"2012;",
"Accepted",
"August",
"16,",
"2012;",
"Published",
"September",
"27,",
"2012",
"Copyright:",
"2012",
"Liu",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"American",
"Cancer",
"Society",
"ACS178898",
"(to",
"YL)",
"and",
"BD",
"Biosciences",
"Research",
"Grant",
"Award",
"(to",
"YL)",
"and",
"the",
"support",
"of",
"The",
"Edward",
"P.",
"Evans",
"Foundation.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"ying.liang@uky.edu",
"Introduction",
"Both",
"solid",
"and",
"liquid",
"tumors",
"are",
"now",
"understood",
"to",
"originate",
"from",
"the",
"malignant",
"transformation",
"of",
"resident",
"adult",
"stem",
"and",
"progenitor",
"cells.",
"[1,2]",
"Nowhere",
"is",
"this",
"paradigm",
"better",
"established",
"than",
"in",
"leukemia,",
"yet",
"events",
"causing",
"neoplastic",
"conversion",
"remain",
"poorly",
"understood.",
"[3]",
"We",
"identified",
"latexin",
"(Lxn)",
"as",
"a",
"novel,",
"homeostatic",
"regulator",
"of",
"the",
"size",
"of",
"the",
"hematopoietic",
"stem",
"cell",
"population",
"in",
"mice.",
"[4]",
"The",
"stem",
"cell",
"pool",
"size",
"was",
"inversely",
"related",
"to",
"quantitative",
"Lxn",
"expression",
"at",
"both",
"the",
"levels",
"of",
"transcript",
"and",
"protein.",
"We",
"found",
"that",
"population",
"size",
"was",
"influenced",
"by",
"Lxn",
"in",
"a",
"stem",
"cell-autonomous",
"manner,",
"and",
"acting",
"through",
"the",
"concerted",
"mechanisms",
"of",
"self-renewal",
"and",
"apoptosis,",
"which",
"were",
"decreased",
"and",
"increased,",
"respectively,",
"by",
"Lxn",
"abundance.",
"[4]",
"Thus,",
"Lxn",
"acts",
"as",
"a",
"brake",
"on",
"the",
"expansion",
"of",
"stem",
"cell",
"population.",
"Unrestrained",
"stem",
"cell",
"expansion",
"carries",
"with",
"it",
"the",
"risk",
"of",
"mutations,",
"genomic",
"instability",
"and",
"carcinogenesis.",
"We",
"therefore",
"hypothesized",
"that",
"Lxn",
"expression",
"patterns",
"in",
"stem",
"and",
"progenitor",
"cells",
"may",
"act",
"as",
"a",
"tumor",
"suppressor",
"by",
"inhibiting",
"stem",
"and",
"progenitor",
"cell",
"proliferation,",
"influencing",
"the",
"crucial",
"steps",
"toward",
"malignancy.",
"Lxn",
"was",
"primarily",
"studied",
"in",
"the",
"nervous",
"system,",
"involving",
"the",
"specification",
"of",
"cortical",
"brain",
"regions",
"during",
"development",
"[5,6,7,8,9],",
"as",
"well",
"as",
"the",
"speed",
"of",
"nerve",
"transmission",
"in",
"adult",
"peripheral",
"nervous",
"systems",
"[10].",
"Lxn",
"was",
"found",
"to",
"be",
"involved",
"in",
"the",
"inflammatory",
"response",
"in",
"macrophages",
"owing",
"to",
"its",
"paired",
"cystatin-like",
"domains",
"[11].",
"It",
"was",
"detected",
"in",
"mast",
"cells",
"associated",
"with",
"a",
"unique",
"type",
"of",
"intracellular",
"granule",
"distinct",
"from",
"histamine-",
"containing",
"secretory",
"granules",
"and",
"lysosomes",
"[12].",
"Lxn",
"has",
"about",
"30%",
"sequence",
"homology,",
"but",
"much",
"greater",
"structural",
"homology,",
"with",
"tazarotene-induced",
"gene",
"1",
"(TIG1)",
"(or",
"retinoic",
"acid",
"receptor",
"responder",
"1,",
"RARRES1),",
"whose",
"expression",
"was",
"down-regulated",
"in",
"an",
"extensive",
"list",
"of",
"tumor",
"types",
"in",
"humans.",
"[11,13,14,15,16].",
"Lxn",
"and",
"TIG1",
"are",
"closely",
"linked",
"genetically",
"and",
"may",
"represent",
"members",
"of",
"a",
"family",
"of",
"functionally",
"related",
"genes.",
"Moreover,",
"Lxn",
"was",
"reported",
"to",
"be",
"a",
"TNF-responsive",
"gene",
"in",
"human",
"papillovirus-infected",
"keratinocytes,",
"suggesting",
"that",
"it",
"may",
"contrib-",
"ute",
"to",
"TNF-mediated",
"suppression",
"of",
"cervical",
"cancer",
"development",
"[17].",
"A",
"recent",
"report",
"revealed",
"that",
"Lxn",
"was",
"down-regulated",
"in",
"patients",
"with",
"gastric",
"carcinomas,",
"and",
"overexpression",
"or",
"knock-",
"down",
"of",
"Lxn",
"inhibited",
"or",
"stimulated",
"tumor",
"growth",
"respectively",
"[18].",
"Decreased",
"or",
"absent",
"Lxn",
"expression",
"was",
"observed",
"in",
"several",
"human",
"leukemia",
"and",
"lymphoma",
"cell",
"lines",
"[19],",
"as",
"well",
"as",
"in",
"malignant",
"melanoma",
"patients.",
"[20]",
"However,",
"there",
"is",
"still",
"lack",
"of",
"direct",
"evidence",
"for",
"the",
"cause-effect",
"relationship",
"between",
"Lxn",
"and",
"hematopoietic",
"malignancy.",
"Gene",
"silencing,",
"especially",
"of",
"tumor",
"suppressors,",
"and",
"inappro-",
"priate",
"gene",
"activation,",
"especially",
"of",
"oncogenes,",
"are",
"common",
"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"September",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"9",
"|",
"e44979"
] | [
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] | [
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Impairment",
"of",
"small",
"airways",
"in",
"COPD",
"patients",
"with",
"frequent",
"exacerbations",
"and",
"effects",
"of",
"treatment",
"with",
"tiotropium",
"Cristoforo",
"Incor",
"vaia1",
"Gian",
"Galeazzo",
"Riario-",
"Sforza1",
"Chiara",
"Pravettoni1",
"Mona-Rita",
"Yacoub2",
"Franco",
"Frati3",
"1Pulmonary",
"Rehabilitation",
"Unit,",
"ICP",
"Hospital,",
"Milan,",
"Italy;",
"2Allergy",
"and",
"Rheumatology",
"Unit,",
"IRCCS",
"San",
"Raffaele",
"Hospital,",
"Milan,",
"Italy;",
"3Institute",
"of",
"Pediatrics,",
"Department",
"of",
"Medical",
"and",
"Surgical",
"specialty",
"and",
"Public",
"Health,",
"University",
"of",
"Perugia,",
"Policlinico",
"Monteluce,",
"Perugia,",
"Italy",
"Correspondence:",
"Cristoforo",
"Incorvaia",
"Viale",
"Molise",
"69,",
"20137",
"Milano,",
"Italy",
"Tel/Fax",
"+39",
"2",
"5513852",
"Email",
"cristoforo.incorvaia@fastwebnet.it",
"Abstract:",
"Disease",
"exacerbations",
"are",
"an",
"important",
"aspect",
"of",
"COPD,",
"because",
"they",
"affect",
"its",
"course",
"and",
"are",
"associated",
"with",
"higher",
"lung",
"function",
"decline.",
"On",
"the",
"other",
"hand,",
"data",
"obtained",
"by",
"biopsies",
"have",
"demonstrated",
"that",
"the",
"progression",
"of",
"COPD",
"is",
"related",
"to",
"an",
"increasing",
"impairment",
"of",
"small",
"airways.",
"We",
"sought",
"to",
"evaluate",
"the",
"small",
"airway",
"impairment",
"(FEF25–75)",
"in",
"two",
"groups",
"of",
"COPD",
"patients",
"(each",
"group",
"had",
"37",
"subjects)",
"in",
"relation",
"to",
"the",
"frequency",
"of",
"exacerbations",
"and",
"the",
"effective-",
"ness",
"of",
"treatment",
"with",
"tiotropium",
"bromide",
"on",
"the",
"small",
"airway",
"impairment.",
"The",
"mean",
"number",
"of",
"exacerbations",
"was",
"3.6/year",
"and",
"1.38/year",
"in",
"frequent",
"and",
"in",
"infrequent",
"exacerbators,",
"respectively",
"(p",
"0.001).",
"The",
"mean",
"value",
"of",
"FEF25–75",
"at",
"baseline",
"was",
"624",
"mL",
"and",
"865",
"mL",
"in",
"frequent",
"and",
"in",
"infrequent",
"exacerbators",
"respectively",
"(p",
"=",
"0.002).",
"The",
"changes",
"in",
"respiratory",
"parameters",
"ver-",
"sus",
"baseline",
"showed",
"increases",
"in",
"mean",
"FEV1,",
"FVC,",
"and",
"FEF25–75",
"in",
"both",
"groups",
"but",
"only",
"the",
"increase",
"in",
"FEF25–75",
"in",
"frequent",
"exacerbators",
"was",
"statistically",
"significantly",
"(p",
"=",
"0.013).",
"During",
"the",
"3-month",
"period",
"of",
"the",
"study",
"the",
"mean",
"number",
"of",
"exacerbations",
"was",
"0.66",
"in",
"frequent",
"and",
"0.12",
"in",
"infrequent",
"exacerbators.",
"These",
"findings",
"indicate",
"that",
"COPD",
"patients",
"with",
"frequent",
"exacerbations",
"have",
"a",
"higher",
"impairment",
"of",
"small",
"airways.",
"Treatment",
"with",
"tiotropium",
"in",
"COPD",
"subjects",
"with",
"frequent",
"exacerbations",
"proved",
"to",
"be",
"effective",
"in",
"improving",
"small",
"airway",
"impairment.",
"Keywords:",
"COPD,",
"exacerbations,",
"small",
"airways,",
"FEF25–75,",
"tiotropium",
"Introduction",
"Chronic",
"obstructive",
"pulmonary",
"disease",
"(COPD)",
"is",
"a",
"major",
"health",
"problem.",
"It",
"is",
"char-",
"acterized",
"by",
"a",
"progressive",
"impairment",
"of",
"lung",
"function",
"(Barnes",
"2000)",
"and",
"leads",
"to",
"inability",
"and",
"mortality,",
"which",
"are",
"projected",
"to",
"increase",
"their",
"burden",
"in",
"future",
"(Murray",
"and",
"Lopez",
"1997).",
"This",
"makes",
"the",
"treatment",
"strategies",
"for",
"COPD",
"very",
"important,",
"cur-",
"rently",
"stated",
"as",
"mainly",
"smoking",
"cessation,",
"drug",
"therapy,",
"and",
"pulmonary",
"rehabilitation",
"(Sutherland",
"and",
"Cherniak",
"2004).",
"An",
"important",
"aspect",
"of",
"COPD",
"is",
"the",
"exacerbations,",
"which",
"occur",
"regardless",
"of",
"the",
"stage",
"of",
"disease",
"according",
"to",
"GOLD",
"classification",
"(Pauwels",
"et",
"al",
"2004;",
"Rabe",
"et",
"al",
"2007),",
"and",
"is",
"currently",
"defined",
"as",
"“...",
"a",
"sustained",
"worsening",
"of",
"the",
"patient’s",
"symptoms",
"from",
"his",
"or",
"her",
"usual",
"stable",
"state",
"that",
"is",
"beyond",
"normal",
"day",
"to",
"day",
"variations,",
"and",
"is",
"acute",
"in",
"onset.",
"Commonly",
"reported",
"symptoms",
"are",
"worsening",
"breathlessness,",
"cough,",
"increased",
"sputum",
"production",
"and",
"change",
"in",
"sputum",
"color.",
"The",
"change",
"in",
"these",
"symptoms",
"often",
"necessitates",
"a",
"change",
"in",
"medication.”",
"(The",
"National",
"Collaborating",
"Centre",
"for",
"Chronic",
"Conditions",
"2004).",
"Exacerbations",
"clearly",
"affect",
"the",
"course",
"of",
"the",
"disease,",
"since",
"their",
"frequency",
"is",
"related",
"to",
"lung",
"function",
"decline",
"(Donaldson",
"et",
"al",
"2002).",
"In",
"particular,",
"data",
"obtained",
"by",
"biopsies",
"demonstrated",
"that",
"the",
"progression",
"of",
"COPD",
"is",
"associated",
"with",
"an",
"increasing",
"impairment",
"of",
"small",
"airways",
"which",
"is",
"strongly",
"related",
"to",
"infiltration",
"of",
"inflammatory",
"cells",
"in",
"airways",
"walls",
"and",
"accumulation",
"of",
"exudate",
"in",
"the",
"lumen",
"(Hogg",
"et",
"al",
"2004).",
"International",
"Journal",
"of",
"COPD",
"2008:3(1)",
"123–126",
"©",
"2008",
"Incorvaia",
"et",
"al,",
"publisher",
"and",
"licensee",
"Dove",
"Medical",
"Press",
"Ltd.This",
"is",
"an",
"Open",
"Access",
"article",
"which",
"permits",
"unrestricted",
"noncommercial",
"use,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"123"
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] | [
"Martin",
"et",
"al.",
"BMC",
"Bioinformatics",
"2010,",
"11:91",
"http://www.biomedcentral.com/1471-2105/11/91",
"S",
"O",
"F",
"T",
"W",
"A",
"R",
"E",
"Open",
"Access",
"BisoGenet:",
"a",
"new",
"tool",
"for",
"gene",
"network",
"building,",
"visualization",
"and",
"analysis",
"Alexander",
"Martin,",
"Maria",
"E",
"Ochagavia,",
"Laya",
"C",
"Rabasa,",
"Jamilet",
"Miranda,",
"Jorge",
"Fernandez-de-Cossio,",
"Ricardo",
"Bringas*",
"Abstract",
"Background:",
"The",
"increasing",
"availability",
"and",
"diversity",
"of",
"omics",
"data",
"in",
"the",
"post-genomic",
"era",
"offers",
"new",
"perspectives",
"in",
"most",
"areas",
"of",
"biomedical",
"research.",
"Graph-based",
"biological",
"networks",
"models",
"capture",
"the",
"topology",
"of",
"the",
"functional",
"relationships",
"between",
"molecular",
"entities",
"such",
"as",
"gene,",
"protein",
"and",
"small",
"compounds",
"and",
"provide",
"a",
"suitable",
"framework",
"for",
"integrating",
"and",
"analyzing",
"omics-data.",
"The",
"development",
"of",
"software",
"tools",
"capable",
"of",
"integrating",
"data",
"from",
"different",
"sources",
"and",
"to",
"provide",
"flexible",
"methods",
"to",
"reconstruct,",
"represent",
"and",
"analyze",
"topological",
"networks",
"is",
"an",
"active",
"field",
"of",
"research",
"in",
"bioinformatics.",
"Results:",
"BisoGenet",
"is",
"a",
"multi-tier",
"application",
"for",
"visualization",
"and",
"analysis",
"of",
"biomolecular",
"relationships.",
"The",
"system",
"consists",
"of",
"three",
"tiers.",
"In",
"the",
"data",
"tier,",
"an",
"in-house",
"database",
"stores",
"genomics",
"information,",
"protein-protein",
"interactions,",
"protein-DNA",
"interactions,",
"gene",
"ontology",
"and",
"metabolic",
"pathways.",
"In",
"the",
"middle",
"tier,",
"a",
"global",
"network",
"is",
"created",
"at",
"server",
"startup,",
"representing",
"the",
"whole",
"data",
"on",
"bioentities",
"and",
"their",
"relationships",
"retrieved",
"from",
"the",
"database.",
"The",
"client",
"tier",
"is",
"a",
"Cytoscape",
"plugin,",
"which",
"manages",
"user",
"input,",
"communication",
"with",
"the",
"Web",
"Service,",
"visualization",
"and",
"analysis",
"of",
"the",
"resulting",
"network.",
"Conclusion:",
"BisoGenet",
"is",
"able",
"to",
"build",
"and",
"visualize",
"biological",
"networks",
"in",
"a",
"fast",
"and",
"user-friendly",
"manner.",
"A",
"feature",
"of",
"Bisogenet",
"is",
"the",
"possibility",
"to",
"include",
"coding",
"relations",
"to",
"distinguish",
"between",
"genes",
"and",
"their",
"products.",
"This",
"feature",
"could",
"be",
"instrumental",
"to",
"achieve",
"a",
"finer",
"grain",
"representation",
"of",
"the",
"bioentities",
"and",
"their",
"relationships.",
"The",
"client",
"application",
"includes",
"network",
"analysis",
"tools",
"and",
"interactive",
"network",
"expansion",
"capabilities.",
"In",
"addition,",
"an",
"option",
"is",
"provided",
"to",
"allow",
"other",
"networks",
"to",
"be",
"converted",
"to",
"BisoGenet.",
"This",
"feature",
"facilitates",
"the",
"integration",
"of",
"our",
"software",
"with",
"other",
"tools",
"available",
"in",
"the",
"Cytoscape",
"platform.",
"BisoGenet",
"is",
"available",
"at",
"http://bio.cigb.edu.cu/",
"bisogenet-cytoscape/.",
"Background",
"Network",
"representation",
"of",
"relationships",
"among",
"biomole-",
"cules",
"is",
"an",
"intensive",
"field",
"of",
"research",
"of",
"in",
"silico",
"System",
"Biology.",
"New",
"models",
"for",
"data",
"integration,",
"standard",
"spe-",
"cifications",
"for",
"data",
"exchange",
"and",
"the",
"development",
"of",
"new",
"tools",
"for",
"data",
"visualization",
"and",
"analysis",
"are",
"crucial",
"and",
"represent",
"one",
"of",
"the",
"most",
"challenging",
"tasks",
"for",
"bioinformaticians.",
"Data",
"repositories",
"such",
"as",
"NCBI’s",
"Entrez",
"Gene[1]",
"and",
"Ensembl[2]",
"maintain",
"annotation",
"on",
"whole",
"genomes,",
"including",
"sequences,",
"gene",
"location,",
"transcripts,",
"classifi-",
"cation",
"and",
"links",
"to",
"several",
"external",
"databases.",
"Data",
"retrieved",
"from",
"high-throughput",
"experiments",
"and",
"litera-",
"ture",
"are",
"available",
"from",
"several",
"databases,",
"such",
"as,",
"DIP",
"*",
"Correspondence:",
"bringas@cigb.edu.cu",
"Center",
"for",
"Genetic",
"Engineering",
"and",
"Biotechnology,",
"PO",
"BOX",
"6162,",
"Havana,",
"Cuba",
"[3],",
"BIND[4],",
"HPRD[5],",
"BioGRID[6],",
"MINT[7]",
"and",
"Intact[8],",
"which",
"represent",
"the",
"major",
"repositories",
"of",
"pro-",
"tein-protein",
"interacions",
"from",
"multiple",
"organisms.",
"On",
"the",
"other",
"hand",
"databases",
"like",
"KEGG[9],",
"Reactome[10],",
"BioCyc[11],",
"NCI",
"Nature",
"PID[12]",
"and",
"others",
"provide",
"information",
"on",
"both",
"metabolic",
"and",
"signaling",
"pathways.",
"These",
"databanks",
"can",
"be",
"seen",
"as",
"repositories",
"of",
"biological",
"entities",
"and",
"their",
"functional",
"relations.",
"As",
"the",
"amount",
"of",
"biological",
"data",
"increase,",
"software",
"tools",
"able",
"to",
"visualize",
"biological-meaningful",
"abstract",
"representations",
"of",
"these",
"data",
"at",
"different",
"levels",
"of",
"details",
"are",
"valuable",
"to",
"biologists.",
"Graph-based",
"model",
"has",
"shown",
"to",
"be",
"a",
"convenient",
"model",
"for",
"representing",
"the",
"global",
"picture",
"of",
"protein-pro-",
"tein",
"interactions,",
"transcription",
"regulation,",
"metabolic",
"data",
"and",
"gene",
"co-expression.",
"In",
"this",
"model,",
"bio-entities",
"are",
"represented",
"as",
"nodes",
"in",
"a",
"graph,",
"and",
"functional",
"relations",
"©",
"2010",
"Martin",
"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."
] | [
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] | [
"PLoS",
"BIOLOGY",
"Expanding",
"the",
"Neuron’s",
"Calcium",
"Signaling",
"Repertoire:",
"Intracellular",
"Calcium",
"Release",
"via",
"Voltage-Induced",
"PLC",
"and",
"IP3R",
"Activation",
"Stefanie",
"Ryglewski1,",
"Hans",
"J.",
"Pflueger1,",
"Carsten",
"Duch2*",
"1",
"Institute",
"of",
"Biology/Neurobiology,",
"Free",
"University",
"of",
"Berlin,",
"Berlin,",
"Germany,",
"2",
"School",
"of",
"Life",
"Sciences,",
"Arizona",
"State",
"University,",
"Tempe,",
"Arizona,",
"United",
"States",
"of",
"America",
"Neuronal",
"calcium",
"acts",
"as",
"a",
"charge",
"carrier",
"during",
"information",
"processing",
"and",
"as",
"a",
"ubiquitous",
"intracellular",
"messenger.",
"Calcium",
"signals",
"are",
"fundamental",
"to",
"numerous",
"aspects",
"of",
"neuronal",
"development",
"and",
"plasticity.",
"Specific",
"and",
"independent",
"regulation",
"of",
"these",
"vital",
"cellular",
"processes",
"is",
"achieved",
"by",
"a",
"rich",
"bouquet",
"of",
"different",
"calcium",
"signaling",
"mechanisms",
"within",
"the",
"neuron,",
"which",
"either",
"can",
"operate",
"independently",
"or",
"may",
"act",
"in",
"concert.",
"This",
"study",
"demonstrates",
"the",
"existence",
"of",
"a",
"novel",
"calcium",
"signaling",
"mechanism",
"by",
"simultaneous",
"patch",
"clamping",
"and",
"calcium",
"imaging",
"from",
"acutely",
"isolated",
"central",
"neurons.",
"These",
"neurons",
"possess",
"a",
"membrane",
"voltage",
"sensor",
"that,",
"independent",
"of",
"calcium",
"influx,",
"causes",
"G-protein",
"activation,",
"which",
"subsequently",
"leads",
"to",
"calcium",
"release",
"from",
"intracellular",
"stores",
"via",
"phospholipase",
"C",
"and",
"inositol",
"1,4,5-trisphosphate",
"receptor",
"activation.",
"This",
"allows",
"neurons",
"to",
"monitor",
"activity",
"by",
"intracellular",
"calcium",
"release",
"without",
"relying",
"on",
"calcium",
"as",
"the",
"input",
"signal",
"and",
"opens",
"up",
"new",
"insights",
"into",
"intracellular",
"signaling,",
"developmental",
"regulation,",
"and",
"information",
"processing",
"in",
"neuronal",
"compartments",
"lacking",
"calcium",
"channels.",
"Citation:",
"Ryglewski",
"S,",
"Pflueger",
"HJ,",
"Duch",
"C",
"(2007)",
"Expanding",
"the",
"neuron’s",
"calcium",
"signaling",
"repertoire:",
"Intracellular",
"calcium",
"release",
"via",
"voltage-induced",
"PLC",
"and",
"IP3R",
"activation.",
"PLoS",
"Biol",
"5(4):",
"e66.",
"doi:10.1371/journal.pbio.0050066",
"Introduction",
"Neuronal",
"calcium",
"plays",
"a",
"dual",
"role",
"as",
"a",
"charge",
"carrier",
"and",
"as",
"an",
"intracellular",
"messenger.",
"Calcium",
"signals",
"regulate",
"various",
"developmental",
"processes,",
"such",
"as",
"migration",
"in",
"the",
"central",
"nervous",
"system",
"(CNS)",
"[1],",
"growth-cone",
"behavior",
"[2],",
"dendritic",
"development",
"[3,4],",
"and",
"synaptogenesis",
"[5],",
"but",
"calcium",
"is",
"also",
"involved",
"in",
"apoptosis",
"[6],",
"and",
"it",
"regulates",
"neurotransmitter",
"release",
"and",
"membrane",
"excitability",
"[7].",
"How",
"can",
"one",
"ubiquitous",
"intracellular",
"messenger",
"regulate",
"so",
"many",
"different",
"vital",
"processes",
"in",
"parallel,",
"but",
"independently?",
"The",
"answer",
"lies",
"in",
"the",
"versatility",
"of",
"the",
"calcium",
"signaling",
"mechanisms",
"in",
"terms",
"of",
"amplitude",
"and",
"spatiotemporal",
"patterning",
"within",
"a",
"neuron",
"[8],",
"and",
"the",
"present",
"study",
"adds",
"a",
"novel",
"mechanism",
"to",
"the",
"bouquet",
"of",
"neuronal",
"calcium",
"signals.",
"The",
"neuronal",
"plasma",
"membrane",
"contains",
"numerous",
"voltage-operated",
"(VOCs),",
"receptor-operated",
"(ROCs)",
"and",
"store-operated",
"(SOCs)",
"calcium",
"channels",
"carrying",
"out",
"differ-",
"ent",
"functions",
"in",
"different",
"parts",
"of",
"the",
"cell.",
"For",
"example,",
"in",
"vertebrate",
"neurons,",
"N-",
"and",
"P/Q-type",
"VOCs",
"trigger",
"vesicle",
"fusion",
"at",
"synaptic",
"terminals,",
"whereas",
"L-type",
"VOCs",
"are",
"located",
"proximally",
"to",
"provide",
"calcium",
"signals",
"regulating",
"gene",
"tran-",
"scription.",
"Structural",
"plasticity",
"of",
"dendrites",
"and",
"filopodia",
"is",
"mediated",
"via",
"calcium",
"influx",
"through",
"VOCs",
"and",
"ROCs",
"and",
"also",
"by",
"local",
"release",
"from",
"internal",
"stores",
"[5,9].",
"Internal",
"calcium",
"stores",
"are",
"held",
"within",
"the",
"membrane",
"system",
"of",
"the",
"endoplasmic",
"reticulum",
"(ER).",
"Release",
"from",
"the",
"ER",
"is",
"mediated",
"by",
"the",
"inositol",
"1,4,5-trisphosphate",
"receptor",
"(IP3R)",
"and",
"the",
"ryanodine",
"receptor",
"(RYR)",
"families,",
"both",
"of",
"which",
"depend",
"on",
"the",
"concentration",
"of",
"free",
"intracellular",
"calcium",
"([Ca2þ]i",
"[10]).",
"The",
"patterns",
"of",
"calcium",
"signals",
"depend",
"on",
"the",
"distributions",
"of",
"the",
"calcium",
"entry",
"mechanisms",
"and",
"calcium-binding",
"proteins",
"within",
"a",
"specific",
"neuronal",
"compartment",
"[8].",
"Calcium",
"buffers,",
"such",
"as",
"parvalbumin",
"and",
"calbindin,",
"can",
"locally",
"confine",
"calcium",
"signals",
"even",
"to",
"individual",
"synapses",
"[11].",
"Calcium-sensing",
"proteins",
"translate",
"elevation",
"or",
"even",
"tempo-",
"ral",
"patterns",
"in",
"[Ca2þ]i",
"into",
"diverse",
"cellular",
"processes",
"[7,12].",
"In",
"summary,",
"different",
"spatiotemporal",
"distributions",
"of",
"calcium",
"signals,",
"buffers,",
"and",
"sensors",
"in",
"various",
"neuronal",
"compartments",
"allow",
"distinct",
"calcium",
"signals",
"to",
"be",
"assigned",
"separately",
"to",
"specific",
"cellular",
"processes.",
"Conversely,",
"multiple",
"calcium",
"signals",
"can",
"act",
"as",
"coincidence",
"detectors",
"[13].",
"Never-",
"theless,",
"to",
"date,",
"no",
"mechanism",
"is",
"known",
"by",
"which",
"a",
"neuron",
"can",
"monitor",
"its",
"own",
"activity",
"by",
"ER",
"calcium",
"release",
"in",
"the",
"absence",
"of",
"both",
"metabotropic",
"receptor",
"activation",
"and",
"calcium",
"influx",
"from",
"the",
"extracellular",
"space.",
"Consequently,",
"influx",
"and",
"store",
"activation",
"are",
"thought",
"to",
"be",
"irrevocably",
"linked,",
"such",
"that",
"they",
"neither",
"operate",
"independently",
"from",
"each",
"other,",
"nor",
"work",
"in",
"concert",
"for",
"coincidence",
"detection.",
"In",
"the",
"present",
"study,",
"we",
"use",
"well-characterized",
"and",
"identified",
"insect",
"central",
"neurons,",
"the",
"dorsal",
"unpaired",
"median",
"(DUM)",
"neurons,",
"as",
"a",
"model",
"to",
"analyze",
"a",
"novel",
"calcium-release",
"mechanism",
"in",
"neurons.",
"DUM",
"neurons",
"are",
"among",
"the",
"best-",
"studied",
"insect",
"neurons",
"that",
"can",
"be",
"individually",
"identified",
"in",
"culture",
"[14,15].",
"Therefore,",
"they",
"are",
"well",
"suited",
"for",
"pharmaco-",
"logical",
"analysis",
"of",
"cellular",
"signaling",
"mechanisms.",
"We",
"demon-",
"strate",
"the",
"existence",
"of",
"a",
"novel",
"voltage-dependent,",
"but",
"not",
"Academic",
"Editor:",
"Nick",
"C.",
"Spitzer,",
"University",
"of",
"California",
"San",
"Diego,",
"United",
"States",
"of",
"America",
"Received",
"July",
"28,",
"2006;",
"Accepted",
"December",
"29,",
"2006;",
"Published",
"March",
"6,",
"2007",
"Copyright:",
"2007",
"Ryglewski",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Abbreviations:",
"[Ca2þ]i,",
"free",
"intracellular",
"calcium;",
"DUM,",
"dorsal",
"unpaired",
"median;",
"ER,",
"endoplasmic",
"reticulum;",
"IP3R,",
"inositol",
"1,4,5-trisphosphate",
"receptor;",
"PLC,",
"phospho-",
"lipase",
"C;",
"RYR,",
"ryanodine",
"receptor;",
"VOC,",
"voltage-operated",
"calcium",
"channel",
"*",
"To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"E-mail:",
"carsten.duch@asu.edu",
"PLoS",
"Biology",
"|",
"www.plosbiology.org",
"0818",
"April",
"2007",
"|",
"Volume",
"5",
"|",
"Issue",
"4",
"|",
"e66"
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] | [
"Int",
"Urogynecol",
"J",
"(2011)",
"22:557–561",
"DOI",
"10.1007/s00192-010-1353-4",
"ORIGINAL",
"ARTICLE",
"Technique",
"of",
"anterior",
"colporrhaphy:",
"a",
"Dutch",
"evaluation",
"Ellen",
"J.",
"M.",
"Lensen",
"&",
"Jackie",
"A.",
"Stoutjesdijk",
"&",
"Mariella",
"I.",
"J.",
"Withagen",
"&",
"Kirsten",
"B.",
"Kluivers",
"&",
"Mark",
"E.",
"Vierhout",
"Received:",
"7",
"October",
"2010",
"/",
"Accepted:",
"16",
"December",
"2010",
"/",
"Published",
"online:",
"25",
"February",
"2011",
"#",
"The",
"Author(s)",
"2011.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Introduction",
"and",
"hypothesis",
"To",
"evaluate",
"the",
"variation",
"in",
"techniques",
"of",
"anterior",
"colporrhaphy",
"among",
"members",
"of",
"the",
"Dutch",
"Urogynecologic",
"Society.",
"Methods",
"A",
"questionnaire",
"evaluating",
"the",
"technique",
"of",
"anterior",
"colporrhaphy,",
"preoperative",
"and",
"postoperative",
"care,",
"and",
"use",
"of",
"the",
"POP-Q",
"score",
"was",
"sent",
"out",
"by",
"e-mail.",
"Results",
"One",
"hundred",
"thirty-three",
"completed",
"questionnaires",
"were",
"received.",
"The",
"response",
"rate",
"was",
"65%.",
"There",
"are",
"large",
"variations",
"in",
"incisions,",
"use",
"of",
"hydrodissection,",
"method",
"of",
"plication,",
"and",
"excision",
"of",
"redundant",
"vaginal",
"epithelium.",
"The",
"urinary",
"catheter",
"was",
"generally",
"removed",
"on",
"day",
"2",
"after",
"surgery",
"and",
"the",
"vaginal",
"pack",
"on",
"day",
"1.",
"Less",
"than",
"half",
"of",
"the",
"respondents",
"used",
"the",
"POP-Q",
"score",
"routinely.",
"Conclusions",
"Dutch",
"gynecologists",
"use",
"a",
"variety",
"of",
"surgical",
"techniques",
"to",
"operate",
"on",
"a",
"cystocele.",
"This",
"suggests",
"that",
"there",
"is",
"no",
"widely",
"accepted",
"opinion",
"on",
"the",
"best",
"surgical",
"approach.",
"The",
"lack",
"of",
"differentiation",
"between",
"central",
"and",
"lateral",
"defects",
"is",
"striking",
"and",
"in",
"contrast",
"with",
"the,",
"mostly,",
"American",
"literature.",
"Keywords",
"Anterior",
"colporrhaphy",
".",
"Cystocele",
".",
"Pelvic",
"organ",
"prolapse",
".",
"POP-Q",
"E.",
"J.",
"M.",
"Lensen",
":",
"J.",
"A.",
"Stoutjesdijk",
"Obstetrics",
"and",
"Gynecology,",
"Canisius-Wilhelmina",
"Hospital,",
"Nijmegen,",
"Netherlands",
"M.",
"I.",
"J.",
"Withagen",
":",
"K.",
"B.",
"Kluivers",
":",
"M.",
"E.",
"Vierhout",
"Obstetrics",
"and",
"Gynecology,",
"UMC",
"St.",
"Radboud,",
"Nijmegen,",
"Netherlands",
"E.",
"J.",
"M.",
"Lensen",
"(*)",
"Kersenlaan",
"45,",
"5345",
"JL",
"Oss,",
"The",
"Netherlands",
"e-mail:",
"ellen@lensen.nu",
"Abbreviations",
"AUGS",
"American",
"Urogynecologic",
"Society",
"POP",
"Pelvic",
"organ",
"prolapse",
"POP-Q",
"Pelvic",
"organ",
"prolapse",
"quantification",
"Introduction",
"Pelvic",
"organ",
"prolapse",
"(POP)",
"is",
"known",
"to",
"affect",
"up",
"to",
"50%",
"of",
"women",
"with",
"a",
"lifetime",
"risk",
"of",
"undergoing",
"surgery",
"for",
"POP",
"or",
"incontinence",
"of",
"11%",
"[1].",
"Recurrence",
"rates",
"after",
"surgery",
"are",
"high",
"and",
"especially",
"anterior",
"vaginal",
"wall",
"prolapse",
"is",
"known",
"to",
"recur",
"frequently,",
"with",
"recurrence",
"rates",
"following",
"anterior",
"colporrhaphy",
"anywhere",
"between",
"0%",
"and",
"92%",
"[2].",
"To",
"prevent",
"recurrence",
"of",
"a",
"cystocele",
"after",
"repair,",
"different",
"techniques",
"have",
"been",
"used,",
"for",
"example",
"paravaginal",
"repair",
"(abdominal",
"or",
"vaginal),",
"ultralateral",
"anterior",
"colporrha-",
"phy,",
"and",
"the",
"use",
"of",
"different",
"grafts",
"and",
"meshes.",
"All",
"these",
"different",
"techniques,",
"except",
"the",
"use",
"of",
"grafts,",
"have",
"had",
"disappointing",
"results",
"to",
"date.",
"Studies",
"comparing",
"techniques",
"have",
"shown",
"no",
"differences",
"in",
"the",
"risk",
"of",
"recurrence",
"[3].",
"In",
"2008,",
"Shippey",
"described",
"a",
"survey",
"of",
"the",
"American",
"Urogynecologic",
"Society",
"(AUGS)",
"members",
"of",
"the",
"contem-",
"porary",
"approaches",
"to",
"cystocele",
"repair",
"[4].",
"Their",
"research",
"mainly",
"compared",
"the",
"differences",
"between",
"generalist",
"and",
"fellowship-trained",
"urogynecologists.",
"Since",
"a",
"number",
"of",
"Dutch",
"studies",
"also",
"showed",
"comparable",
"poor",
"anatomical",
"outcome",
"of",
"anterior",
"colporrhaphy,",
"we",
"decided",
"to",
"evaluate",
"the",
"variation",
"in",
"techniques",
"of",
"anterior",
"colporraphy",
"among",
"members",
"of",
"the",
"Dutch",
"Urogynecologic",
"Society",
"in",
"an",
"attempt",
"to",
"get",
"more",
"insight",
"in",
"the",
"variation",
"of",
"techniques",
"and",
"potentially",
"find",
"a",
"reason",
"for",
"the",
"high",
"recurrence",
"[5,",
"6]."
] | [
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] | [
"HUMAN",
"NEUROSCIENCE",
"Is",
"analogical",
"reasoning",
"just",
"another",
"measure",
"of",
"executive",
"functioning?",
"GENERAL",
"COMMENTARY",
"published:",
"20",
"September",
"2010",
"doi:",
"10.3389/fnhum.2010.00180",
"Lindsey",
"Engle",
"Richland1*",
"and",
"Robert",
"G.",
"Morrison",
"2",
"1",
"Department",
"of",
"Education,",
"University",
"of",
"California,",
"Irvine,",
"CA,",
"USA",
"2",
"Department",
"of",
"Psychology,",
"Loyola",
"University",
"Chicago,",
"Chicago,",
"IL,",
"USA",
"*Correspondence:",
"l.e.richland@uci.edu",
"A",
"commentary",
"on",
"Deficits",
"in",
"analogical",
"reasoning",
"in",
"adoles",
"-",
"cents",
"with",
"traumatic",
"brain",
"injury.",
"by",
"Krawczyk,",
"D.",
"C.,",
"Hanten,",
"G.,",
"Wilde,",
"E.",
"A.,",
"Li,",
"X.,",
"Schnelle,",
"K.",
"P.,",
"Merkley,",
"T.",
"L.,",
"Vasquez,",
"A.",
"C.,",
"Cook,",
"L.",
"G.,",
"McClelland,",
"M.,",
"Chapman,",
"S.",
"B.,",
"and",
"Levin,",
"H.",
"S.",
"(2010).",
"Front.",
"Hum.",
"Neurosci.4:62.",
"doi:",
"10.3389/",
"fnhum.2010.00062",
"The",
"present",
"paper",
"by",
"Krawczyk",
"et",
"al.",
"(2010)",
"adds",
"to",
"a",
"growing",
"list",
"of",
"studies",
"that",
"have",
"shown",
"analogical",
"reasoning",
"to",
"be",
"critically",
"dependent",
"on",
"what",
"is",
"known",
"as",
"executive",
"functioning",
"in",
"the",
"neuropsychological",
"lit-",
"erature,",
"and",
"working",
"memory",
"in",
"the",
"cogni-",
"tive",
"(neuro)science",
"literature.",
"Specifically,",
"analogy",
"requires",
"the",
"maintenance,",
"manipu-",
"lation,",
"and",
"selective",
"activation",
"(or",
"inhibi-",
"tion)",
"of",
"mental",
"representations",
"to",
"identify,",
"map",
"correspondences,",
"and",
"draw",
"inferences",
"about",
"higher-order",
"similarity",
"relationships",
"(e.g.,",
"Waltz",
"et",
"al.,",
"2000;",
"Morrison",
"et",
"al.,",
"2004;",
"Bunge",
"et",
"al.,",
"2005,",
"2009;",
"Morrison,",
"2005;",
"Green",
"et",
"al.,",
"2006;",
"Cho",
"et",
"al.,",
"2007,",
"2010;",
"Krawczyk",
"et",
"al.,",
"2008;",
"Morrison",
"and",
"Cho,",
"2008).",
"Consistent",
"with",
"this,",
"popula-",
"tions",
"with",
"limited",
"executive",
"functioning",
"resources",
"have",
"shown",
"reduced",
"analogy",
"performance",
"when",
"required",
"to",
"integrate",
"multiple",
"relations",
"and/or",
"inhibit",
"featural",
"distractors",
"in",
"favor",
"of",
"relational",
"similar-",
"ity",
"(e.g.,",
"TBI",
"adolescents:",
"Krawczyk",
"et",
"al.,",
"2010;",
"children:",
"Richland",
"et",
"al.,",
"2006,",
"2010;",
"Wright",
"et",
"al.,",
"2008;",
"Thibaut",
"et",
"al.,",
"2010;",
"older",
"adults:",
"Viskontas",
"et",
"al.,",
"2004;",
"and",
"brain",
"damaged",
"adults:",
"Morrison",
"et",
"al.,",
"2004;",
"Krawczyk",
"et",
"al.,",
"2008).",
"So",
"is",
"analogical",
"reasoning",
"simply",
"another",
"measure",
"of",
"execu-",
"tive",
"function?",
"Analogy",
"is",
"pervasive",
"in",
"everyday",
"learn-",
"ing",
"and",
"discovery.",
"Importantly",
"it",
"allows",
"us",
"to",
"make",
"sense",
"of",
"and",
"make",
"inferences",
"about",
"new",
"situations",
"and",
"information",
"with",
"respect",
"to",
"things",
"we",
"already",
"know",
"and",
"understand",
"(Holyoak",
"and",
"Thagard,",
"1995;",
"Dunbar",
"and",
"Blanchette,",
"2001).",
"Thus,",
"theories",
"of",
"the",
"development",
"of",
"analogy",
"in",
"children",
"have",
"frequently",
"focused",
"on",
"rela-",
"tional",
"knowledge",
"as",
"a",
"necessary",
"precondi-",
"tion",
"for",
"analogy",
"(Rattermann",
"and",
"Gentner,",
"1998;",
"Goswami,",
"2001).",
"The",
"importance",
"of",
"relational",
"knowledge",
"may",
"also",
"be",
"seen",
"in",
"patients",
"with",
"damage",
"to",
"the",
"temporal",
"lobe.",
"Morrison",
"et",
"al.",
"(2004)",
"and",
"Krawczyk",
"et",
"al.",
"(2008)",
"and",
"colleagues",
"have",
"previously",
"found",
"that",
"patients",
"with",
"broad",
"damage",
"to",
"anterior",
"temporal",
"lobe,",
"an",
"area",
"associated",
"with",
"semantic",
"knowledge,",
"have",
"difficulty",
"with",
"both",
"verbal",
"and",
"visual",
"analogies",
"in",
"spite",
"of",
"having",
"preserved",
"executive",
"func-",
"tions;",
"however,",
"the",
"patterns",
"of",
"deficit",
"are",
"different",
"than",
"those",
"of",
"patients",
"with",
"dam-",
"age",
"to",
"prefrontal",
"cortex",
"and",
"their",
"associated",
"executive",
"dysfunction.",
"These",
"findings",
"are",
"consistent",
"with",
"the",
"current",
"paper’s",
"finding",
"that",
"cortical",
"differences",
"in",
"both",
"prefrontal",
"and",
"temporal",
"regions",
"were",
"associated",
"with",
"lower",
"analogy",
"performance.",
"We",
"have",
"recently",
"begun",
"to",
"explore",
"how",
"executive",
"functions",
"and",
"relational",
"knowl-",
"edge,",
"and",
"their",
"underlying",
"brain",
"networks,",
"may",
"work",
"together",
"in",
"the",
"service",
"of",
"anal-",
"ogy.",
"In",
"one",
"study,",
"Richland",
"et",
"al.",
"(2010),",
"we",
"exploited",
"cross-cultural",
"differences",
"in",
"relational",
"knowledge",
"and",
"discovered",
"a",
"dissociation",
"between",
"the",
"ability",
"to",
"inhibit",
"featural",
"distractors",
"and",
"integrate",
"relations",
"in",
"analogy,",
"two",
"functions",
"associated",
"with",
"executive",
"functions",
"which",
"have",
"traditionally",
"correlated",
"in",
"studies",
"of",
"analogy",
"(see",
"Cho",
"et",
"al.,",
"2010",
"for",
"an",
"exception",
"using",
"neu-",
"roimaging).",
"Using",
"a",
"computational",
"model",
"of",
"analogy",
"we",
"offered",
"an",
"explanation",
"of",
"the",
"results,",
"suggesting",
"that",
"more",
"advanced",
"relational",
"knowledge",
"structures",
"reduce",
"the",
"demands",
"for",
"executive",
"functions",
"in",
"analogy",
"(Morrison",
"et",
"al.,",
"in",
"press).",
"Thus,",
"prefrontal",
"and",
"temporal",
"networks",
"work",
"together",
"in",
"analogy",
"and",
"the",
"development",
"or",
"advanced",
"functioning",
"on",
"one",
"area",
"affect",
"demands",
"on",
"the",
"other.",
"In",
"fact,",
"we",
"have",
"also",
"shown",
"via",
"modeling",
"that",
"the",
"development",
"of",
"such",
"advanced",
"relational",
"knowledge",
"networks",
"themselves",
"may",
"be",
"dependent",
"on",
"executive",
"functions",
"(Doumas",
"et",
"al.,",
"2010).",
"Thus,",
"analogy",
"is",
"not",
"simply",
"another",
"measure",
"of",
"executive",
"functions,",
"rather",
"it",
"is",
"a",
"whole",
"brain",
"activity,",
"that",
"is",
"a",
"profound",
"test",
"of",
"our",
"ability",
"to",
"think",
"in",
"everyday",
"life,",
"and",
"as",
"such",
"is",
"an",
"excellent",
"measure",
"to",
"evalu-",
"ate",
"the",
"impact",
"of",
"traumatic",
"brain",
"injury",
"on",
"patients’",
"ability",
"to",
"function.",
"RRfescne",
"Bunge,",
"S.",
"A.,",
"Wendelken,",
"C.,",
"Badre,",
"D.,",
"and",
"Wagner,",
"A.",
"D.",
"(2005).",
"Analogical",
"reasoning",
"and",
"prefrontal",
"cor-",
"tex:",
"evidence",
"for",
"separable",
"retrieval",
"and",
"integration",
"mechanisms.",
"Cereb.",
"Cortex",
"15,",
"239–249.",
"Bunge,",
"S.",
"A.,",
"Wendelken,",
"C.,",
"and",
"Helskog,",
"E.",
"H.",
"(2009).",
"Left,",
"but",
"not",
"right,",
"rostrolateral",
"prefrontal",
"cortex",
"meets",
"a",
"stringent",
"test",
"of",
"the",
"relational",
"integration",
"hypothesis.",
"Neuroimage",
"46,",
"338–342.",
"Cho,",
"S.,",
"Holyoak,",
"K.",
"J.,",
"and",
"Cannon,",
"T.",
"D.",
"(2007).",
"Analogical",
"reasoning",
"in",
"working",
"memory:",
"resources",
"shared",
"among",
"relational",
"integration,",
"interference",
"resolution,",
"and",
"maintenance.",
"Mem.",
"Cognit.",
"35,",
"1445–1455.",
"Cho,",
"S.,",
"Moody,",
"T.",
"D.,",
"Fernandino,",
"L.,",
"Mumford,",
"J.",
"A.,",
"Poldrack,",
"R.",
"A.,",
"Cannon,",
"T.",
"D.,",
"Knowlton,",
"B.",
"J.,",
"and",
"Holyoak,",
"K.",
"J.",
"(2010).",
"Common",
"and",
"dis-",
"sociable",
"prefrontal",
"loci",
"associated",
"with",
"component",
"mechanisms",
"of",
"analogical",
"reasoning.",
"Cereb.",
"Cortex",
"20,",
"524–533.",
"Dunbar,",
"K.,",
"and",
"Blanchette,",
"I.",
"(2001).",
"The",
"in",
"vivo/in",
"vitro",
"approach",
"to",
"cognition:",
"the",
"case",
"of",
"analogy.",
"Trends",
"Cogn.",
"Sci.",
"5,",
"335–339.",
"Doumas,",
"L.",
"A.",
"A.,",
"Morrison,",
"R.",
"G.,",
"&",
"Richland,",
"L.",
"E.",
"(2010).“Differences",
"in",
"development",
"of",
"analogy",
"across",
"cultures:",
"a",
"computational",
"account,”",
"in",
"Proceedings",
"of",
"the",
"32nd",
"Annual",
"Conference",
"of",
"the",
"Cognitive",
"Science",
"Society,",
"Portland,",
"Oregon.",
"Goswami,",
"U.",
"(2001).“Analogical",
"reasoning",
"in",
"children,”",
"in",
"The",
"Analogical",
"mind:",
"Perspectives",
"from",
"Cognitive",
"Science,",
"eds.",
"D.",
"Gentner,",
"K.",
"J.",
"Holyoak,",
"and",
"B.",
"N.",
"Kokinov",
"(Cambridge,",
"MA:",
"MIT",
"Press),",
"437–470.",
"Green,A.",
"E.,",
"Fugelsang,",
"J.A.,",
"Kraemer,",
"D.",
"J.",
"M.,",
"Shamosh,",
"N.",
"A.,",
"and",
"Dunbar,",
"K.",
"N.",
"(2006).",
"Frontopolar",
"cortex",
"mediates",
"abstract",
"integration",
"in",
"analogy.",
"Brain",
"Res.",
"1096,",
"125–137.",
"Holyoak,",
"K.",
"J.,",
"and",
"Thagard,",
"P.",
"(1995).",
"Mental",
"Leaps:",
"Analogy",
"in",
"Creative",
"Thought.",
"Cambridge,",
"MA:",
"The",
"MIT",
"Press.",
"Krawczyk,",
"D.",
"C.,",
"Hanten,",
"G.,Wilde,",
"E.A.,",
"Li,",
"X.,",
"Schnelle,",
"K.",
"P.,",
"Merkley,",
"T.",
"L.,",
"Vasquez,",
"A.",
"C.,",
"Cook,",
"L.",
"G.,",
"Frontiers",
"in",
"Human",
"Neuroscience",
"www.frontiersin.org",
"September",
"2010",
"|",
"Volume",
"4",
"|",
"Article",
"180",
"|",
"1"
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] | [
"Olangir",
"r",
"e",
"hcraes",
"a",
"r",
"elcit",
"published:",
"11",
"March",
"2011",
"doi:",
"10.3389/fphys.2011.00010",
"The",
"driving",
"force",
"of",
"the",
"Na+/Ca2+-exchanger",
"during",
"metabolic",
"inhibition",
"Antonius",
"Baartscheer*,",
"Cees",
"A.",
"Schumacher,",
"Ruben",
"Coronel",
"and",
"Jan",
"W.T.",
"Fiolet",
"Experimental",
"Cardiology,",
"Heart",
"Failure",
"Research",
"Center,",
"Academic",
"Medical",
"Center,",
"University",
"of",
"Amsterdam,",
"Amsterdam,",
"Netherlands",
"Edited",
"by:",
"Marcel",
"V.",
"D.",
"Heyden,",
"University",
"Medical",
"Center,",
"Netherlands",
"Reviewed",
"by:",
"Teun",
"P.",
"De",
"Boer,",
"University",
"Medical",
"Center",
"Utrecht,",
"Netherlands",
"Gudrun",
"Antoons,",
"Katholieke",
"Unversiteit",
"Leuven,",
"Belgium",
"YukiomiTsuji,",
"Nagoya",
"University,",
"Japan",
"*Correspondence:",
"Antonius",
"Baartscheer,",
"Experimental",
"Cardiology,",
"Heart",
"failure",
"Research",
"Center,",
"Academic",
"Medical",
"Center,",
"University",
"of",
"Amsterdam,",
"Room",
"K2-104,",
"1105",
"AZ,",
"Amsterdam,",
"Netherlands.",
"e-mail:",
"a.baartscheer@amc.uva.nl",
"Objective:",
"Metabolic",
"inhibition",
"causes",
"a",
"decline",
"in",
"mechanical",
"performance",
"and,",
"if",
"prolonged,",
"myocardial",
"contracture",
"and",
"cell",
"death.The",
"decline",
"in",
"mechanical",
"performance",
"is",
"mainly",
"due",
"to",
"altered",
"intracellular",
"calcium",
"handling,",
"which",
"is",
"under",
"control",
"of",
"the",
"Na+/Ca2+-exchanger",
"(NCX)",
"The",
"driving",
"force",
"of",
"the",
"NCX",
"(∆",
"Gncx)",
"determines",
"the",
"activity",
"of",
"NCX.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"describe",
"the",
"relation",
"between",
"∆",
"Gncx",
"and",
"calcium",
"homeostasis",
"during",
"metabolic",
"inhibition.",
"Methods:",
"In",
"left",
"ventricular",
"rabbit",
"myocytes,",
"during",
"metabolic",
"inhibition",
"(2",
"mmol/L",
"sodium",
"cyanide),",
"sodium",
"([Na+]i),",
"calcium",
"([Ca2+]i),",
"and",
"action",
"potentials",
"were",
"determined",
"with",
"SBFI,",
"indo-",
"1,",
"and",
"the",
"patch",
"clamp",
"technique.",
"Changes",
"of",
"∆",
"Gncx",
"were",
"calculated.",
"Results:",
"During",
"metabolic",
"inhibition:",
"The",
"first",
"8",
"min",
"[Na+]i",
"remained",
"constant,",
"systolic",
"calcium",
"decreased",
"from",
"532",
"±",
"28",
"to",
"82",
"±",
"13",
"nM,",
"diastolic",
"calcium",
"decreased",
"from",
"121",
"±",
"12",
"to",
"36",
"±",
"10",
"nM",
"and",
"the",
"sarcoplasmic",
"reticulum",
"(SR)",
"calcium",
"content",
"was",
"depleted",
"for",
"85",
"±",
"3%.",
"After",
"8",
"min",
"[Na+]i",
"and",
"diastolic",
"calcium",
"started",
"to",
"increase",
"to",
"30",
"±",
"1.3",
"mmol/L",
"and",
"500",
"±",
"31",
"nM",
"after",
"30",
"min",
"respectively.The",
"action",
"potential",
"duration",
"shortened",
"biphasically.",
"In",
"the",
"first",
"5",
"min",
"it",
"shortened",
"from",
"225",
"±",
"12",
"to",
"153",
"±",
"11",
"ms",
"and",
"remained",
"almost",
"constant",
"until",
"it",
"shortened",
"again",
"after",
"10",
"min.",
"After",
"14",
"min",
"action",
"potential",
"and",
"calcium",
"transients",
"disappeared",
"due",
"to",
"unexcitability",
"of",
"the",
"myocytes.",
"This",
"resulted",
"in",
"an",
"increased",
"of",
"the",
"time",
"average",
"of",
"∆",
"Gncx",
"from",
"6.2",
"±",
"0.2",
"to",
"7.7",
"±",
"0.3",
"kJ/mol",
"during",
"the",
"first",
"3",
"min,",
"where",
"after",
"it",
"decreased",
"and",
"became",
"negative",
"after",
"about",
"15",
"min.",
"Conclusion:",
"Metabolic",
"inhibition",
"caused",
"an",
"early",
"increase",
"of",
"∆",
"Gncx",
"caused",
"by",
"shortening",
"of",
"the",
"action",
"potential.The",
"increase",
"of",
"∆",
"Gncx",
"contributed",
"to",
"decrease",
"of",
"diastolic",
"calcium,",
"calcium",
"transient",
"amplitude,",
"SR",
"calcium",
"content,",
"and",
"contractility.",
"The",
"increase",
"of",
"diastolic",
"calcium",
"started",
"after",
"∆",
"Gncx",
"became",
"lower",
"than",
"under",
"aerobic",
"conditions.",
"Keywords:",
"Na/Ca-exchanger,",
"myocytes,",
"calcium,",
"sodium,",
"action",
"potential,",
"metabolic",
"inhibition,",
"SR,",
"driving",
"force",
"Incudortt",
"Io",
"n",
"The",
"sarcolemmal",
"Na+/Ca2+-exchanger",
"(NCX)",
"is",
"a",
"passive",
"ion",
"transport",
"mechanism,",
"which",
"directly",
"couples",
"transmembrane",
"movements",
"of",
"Ca2+",
"to",
"reciprocal",
"movements",
"of",
"Na+",
"with",
"a",
"stoi-",
"chiometric",
"ratio",
"of",
"three",
"sodium",
"per",
"calcium",
"(Reeves",
"and",
"Hale,",
"1984).",
"The",
"direction",
"of",
"action",
"(forward",
"mode,",
"Ca2+",
"efflux",
"or",
"reversed",
"mode,",
"Ca2+",
"influx)",
"depends",
"on",
"the",
"driving",
"force",
"of",
"NCX",
"(∆",
"Gncx).",
"A",
"passive",
"transporter",
"such",
"as",
"NCX",
"must",
"be",
"out",
"of",
"ther-",
"modynamic",
"equilibrium",
"in",
"order",
"to",
"operate.",
"This",
"requires",
"a",
"non-",
"zero",
"driving",
"force",
"and",
"the",
"continuous",
"input",
"of",
"metabolic",
"energy.",
"The",
"energy",
"required",
"to",
"maintain",
"a",
"non-equilibrium",
"state",
"is",
"pro-",
"vided",
"by",
"the",
"Na+/K+-ATPase,",
"which",
"channels",
"metabolic",
"energy",
"derived",
"from",
"ATP",
"hydrolysis",
"into",
"the",
"trans-sarcolemmal",
"electro-",
"chemical",
"potential",
"differences",
"of",
"sodium.",
"Therefore,",
"NCX",
"is",
"indi-",
"rectly",
"under",
"thermodynamic",
"control",
"of",
"myocardial",
"metabolism",
"and",
"the",
"phosphorylation",
"potential,",
"∆",
"GATP",
"(Fiolet",
"et",
"al.,",
"1984).",
"The",
"∆",
"Gncx",
"can",
"be",
"calculated",
"from",
"the",
"difference",
"of",
"three",
"times",
"the",
"trans-sarcolemmal",
"electrochemical",
"potential",
"of",
"sodium",
"and",
"once",
"that",
"of",
"calcium",
"(Chapman",
"et",
"al.,",
"1983;",
"Fiolet",
"et",
"al.,",
"1995).",
"Thus,",
"measurement",
"of",
"concentration",
"gradients",
"of",
"the",
"respective",
"ions",
"and",
"membrane",
"potential",
"allows",
"calculation",
"of",
"∆",
"Gncx.",
"Under",
"physiological",
"resting",
"conditions",
"in",
"cardiac",
"myocytes",
"the",
"reversal",
"potential",
"of",
"NCX",
"is",
"about",
"−20",
"mV.",
"Therefore,",
"at",
"a",
"resting",
"membrane",
"potential",
"of",
"−90",
"mV",
"∆",
"Gncx",
"deviates",
"70",
"mV",
"from",
"thermodynamic",
"equilibrium,",
"corresponding",
"to",
"a",
"free",
"energy",
"of",
"about",
"7",
"kJ/mol",
"(Bers",
"et",
"al.,",
"1988;",
"Barry",
"and",
"Bridge,",
"1993).",
"This",
"favors",
"transport",
"of",
"calcium",
"coupled",
"to",
"inward",
"transport",
"of",
"sodium.",
"However,",
"in",
"dynamic",
"conditions,",
"such",
"as",
"during",
"electrical",
"stimulation,",
"∆",
"Gncx",
"continuously",
"changes",
"due",
"to",
"changes",
"of",
"membrane",
"potential",
"and",
"[Ca2+]i",
"and",
"even",
"operates",
"in",
"reversed",
"mode",
"(calcium",
"influx)",
"for",
"a",
"short",
"period",
"after",
"the",
"upstroke",
"of",
"the",
"action",
"potential",
"(Despa",
"et",
"al.,",
"2002;",
"Baartscheer",
"et",
"al.,",
"2003a).",
"Nevertheless,",
"it",
"is",
"unanimously",
"agreed",
"that",
"the",
"NCX",
"is",
"the",
"main",
"pathway",
"for",
"Ca2+",
"extrusion",
"from",
"ventricular",
"myocytes",
"(Noble",
"et",
"al.,",
"1991;",
"Egger",
"and",
"Niggli,",
"1999;",
"Bers,",
"2001;",
"Weber",
"et",
"al.,",
"2002)",
"and",
"contributes",
"to",
"contraction",
"by",
"regulating",
"the",
"overall",
"calcium",
"balance",
"(Mullins,",
"1979;",
"Barry",
"and",
"Bridge,",
"1993).",
"In",
"pathophysiological",
"conditions",
"in",
"which",
"myocardial",
"metab-",
"olism",
"is",
"disturbed,",
"such",
"as",
"ischemia",
"and",
"anoxia,",
"∆",
"Gncx",
"must",
"adapt",
"to",
"reduced",
"metabolic",
"energy",
"derived",
"from",
"ATP",
"hydroly-",
"sis",
"(∆",
"GATP),",
"which",
"influence",
"[Ca2+]i",
"homeostasis",
"and",
"contractil-",
"ity",
"(Fiolet",
"et",
"al.,",
"1984;",
"Baartscheer",
"et",
"al.,",
"2003b).",
"Indeed,",
"It",
"has",
"been",
"shown",
"that",
"during",
"metabolic",
"inhibition",
"∆",
"Gncx",
"is",
"shifted",
"toward",
"more",
"reversed",
"and",
"less",
"forward",
"mode",
"resulting",
"in",
"an",
"increase",
"of",
"[Ca2+]i",
"(Boston",
"et",
"al.,",
"1998;",
"Sugishita",
"et",
"al.,",
"2001;",
"Ju",
"and",
"Allen,",
"2005;",
"Barry",
"et",
"al.,",
"2009).",
"www.frontiersin.org",
"March",
"2011",
"|",
"Volume",
"2",
"|",
"Article",
"10",
"|",
"1"
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] | [
"Clin",
"Transl",
"Oncol",
"(2012)",
"14:606–612",
"DOI",
"10.1007/s12094-012-0843-x",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"A",
"randomized",
"phase",
"II",
"study",
"to",
"compare",
"oxaliplatin",
"plus",
"5-fluorouracil",
"and",
"leucovorin",
"(FOLFOX4)",
"versus",
"oxaliplatin",
"plus",
"raltitrexed",
"(TOMOX)",
"as",
"first-line",
"chemotherapy",
"for",
"advanced",
"colorectal",
"cancer",
"Cristina",
"Gravalos",
"•",
"Antonieta",
"Salut",
"•",
"Carlos",
"Garc´ıa-Giro´",
"n",
"•",
"Roc´ıo",
"Garc´ıa-Carbonero",
"•",
"Ana",
"Isabel",
"Le",
"o´n",
"•",
"Isabel",
"Sevilla",
"•",
"Joan",
"Maurel",
"•",
"Beatriz",
"Esteban",
"•",
"Eduardo",
"Garc´ıa-Rico",
"•",
"Adolfo",
"Murias",
"•",
"Herna´",
"n",
"Corte´s-Funes",
"Received:",
"28",
"March",
"2011",
"/",
"Accepted:",
"14",
"November",
"2011",
"/",
"Published",
"online:",
"19",
"July",
"2012",
"The",
"Author(s)",
"2012.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Introduction",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"compare",
"TOMOX",
"versus",
"FOLFOX4",
"as",
"first-line",
"treatment",
"of",
"advanced",
"colorectal",
"cancer",
"(CRC).",
"Materials",
"and",
"methods",
"191",
"chemotherapy-na¨ıve",
"patients",
"were",
"randomized",
"to",
"receive",
"TOMOX",
"or",
"FOLFOX4.",
"Patients",
"were",
"evaluated",
"every",
"3",
"months",
"and",
"chemotherapy",
"C.",
"Gravalos",
"(&)",
"H.",
"Corte´s-Funes",
"Medical",
"Oncology",
"Department,",
"University",
"Hospital",
"12",
"de",
"Octubre,",
"Avda.",
"de",
"Andaluc´ıa",
"s/n",
"Km",
"5.400,",
"28041",
"Madrid,",
"Spain",
"e-mail:",
"cgravalos@telefonica.net",
"A.",
"Salut",
"Hospital",
"Arnau",
"de",
"la",
"Villanova,",
"Lleida,",
"Spain",
"C.",
"Garc´ıa-Giro´n",
"Hospital",
"General",
"Yagu¨e,",
"Burgos,",
"Spain",
"R.",
"Garc´ıa-Carbonero",
"Hospital",
"Severo",
"Ochoa,",
"Legane´s,",
"Spain",
"A.",
"I.",
"Leo´n",
"Fundacio´n",
"Jime´nez",
"D´ıaz,",
"Madrid,",
"Spain",
"I.",
"Sevilla",
"Hospital",
"Virgen",
"de",
"la",
"Victoria,",
"Ma´laga,",
"Spain",
"J.",
"Maurel",
"Hospital",
"Clinic",
"i",
"Provincial,",
"Barcelona,",
"Spain",
"B.",
"Esteban",
"Hospital",
"General",
"de",
"Segovia,",
"Segovia,",
"Spain",
"E.",
"Garc´ıa-Rico",
"Hospital",
"de",
"Monteprincipe,",
"Madrid,",
"Spain",
"A.",
"Murias",
"Hospital",
"Insular",
"de",
"Las",
"Palmas,",
"Gran",
"Canaria,",
"Spain",
"123",
"was",
"continued",
"until",
"disease",
"progression",
"or",
"unacceptable",
"toxicity.",
"Overall",
"response",
"rate",
"was",
"the",
"primary",
"endpoint.",
"Results",
"183",
"patients",
"were",
"included",
"in",
"the",
"intent-to-treat",
"analysis",
"(92",
"TOMOX",
"and",
"91",
"FOLFOX4).",
"Overall",
"response",
"rate",
"was",
"45.6",
"and",
"36.3",
"%",
"(p",
"=",
"0.003)",
"for",
"TOMOX",
"and",
"FOLFOX4,",
"respectively.",
"No",
"statistically",
"significant",
"dif-",
"ferences",
"were",
"observed",
"in",
"overall",
"survival",
"(15.6",
"and",
"17.2",
"months;",
"p",
"=",
"0.475);",
"progression-free",
"survival",
"(7.7",
"and",
"8.7",
"months;",
"p",
"=",
"0.292),",
"and",
"response",
"duration",
"(6.4",
"and",
"7.6",
"months;",
"p",
"=",
"0.372)",
"for",
"TOMOX",
"and",
"FOLFOX4,",
"respectively.",
"Grades",
"3",
"and",
"4",
"neutropenia",
"(p",
"\\",
"0.0001)",
"and",
"leukopenia",
"(p",
"=",
"0.028)",
"were",
"more",
"common",
"with",
"the",
"FOLFOX4",
"regimen,",
"while",
"hepatic",
"disorders",
"and",
"asthenia",
"were",
"higher",
"in",
"TOMOX",
"group",
"(p",
"=",
"ns).",
"There",
"were",
"two",
"treatment-related",
"deaths",
"in",
"the",
"FOLFOX4",
"arm",
"and",
"one",
"in",
"the",
"TOMOX",
"arm.",
"Quality",
"of",
"life",
"analysis",
"based",
"on",
"the",
"SF-",
"36",
"revealed",
"differences",
"between",
"the",
"two",
"regimens",
"for",
"physical",
"and",
"mental",
"composite",
"scores",
"after",
"6",
"weeks,",
"and",
"for",
"body",
"pain",
"and",
"emotional",
"role",
"functioning",
"after",
"6",
"and",
"12",
"weeks;",
"all",
"of",
"these",
"favored",
"the",
"FOLFOX4",
"arm",
"(p",
"B",
"0.05).",
"Conclusions",
"TOMOX",
"and",
"FOLFOX4",
"seem",
"to",
"have",
"similar",
"efficacy",
"and",
"are",
"well",
"tolerated",
"in",
"the",
"first-line",
"treatment",
"for",
"advanced",
"CRC",
"with",
"different",
"profiles",
"of",
"toxicity.",
"The",
"convenient",
"TOMOX",
"regimen",
"may",
"offer",
"an",
"alternative",
"to",
"fluoropyrimidine-based",
"regimens.",
"Colorectal",
"cancer",
"Raltitrexed",
"Oxaliplatin",
"Keywords",
"Fluorouracil",
"Introduction",
"Colorectal",
"cancer",
"(CRC)",
"is",
"the",
"second",
"most",
"prevalent",
"cancer",
"worldwide,",
"with",
"more",
"than",
"1",
"million",
"new",
"cases"
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] | [
"Bai",
"et",
"al.",
"Journal",
"of",
"Animal",
"Science",
"and",
"Biotechnology",
"2012,",
"3:8",
"http://www.jasbsci.com/content/3/1/8",
"R",
"E",
"V",
"I",
"E",
"W",
"JOURNAL",
"OF",
"ANIMAL",
"SCIENCE",
"AND",
"BIOTECHNOLOGY",
"Open",
"Access",
"Current",
"status",
"and",
"future",
"perspectives",
"for",
"sequencing",
"livestock",
"genomes",
"Yongsheng",
"Bai1*,",
"Maureen",
"Sartor1,2",
"and",
"James",
"Cavalcoli1",
"Abstract",
"Only",
"in",
"recent",
"years,",
"the",
"draft",
"sequences",
"for",
"several",
"agricultural",
"animals",
"have",
"been",
"assembled.",
"Assembling",
"an",
"individual",
"animal’s",
"entire",
"genome",
"sequence",
"or",
"specific",
"region(s)",
"of",
"interest",
"is",
"increasingly",
"important",
"for",
"agricultural",
"researchers",
"to",
"perform",
"genetic",
"comparisons",
"between",
"animals",
"with",
"different",
"performance.",
"We",
"review",
"the",
"current",
"status",
"for",
"several",
"sequenced",
"agricultural",
"species",
"and",
"suggest",
"that",
"next",
"generation",
"sequencing",
"(NGS)",
"technology",
"with",
"decreased",
"sequencing",
"cost",
"and",
"increased",
"speed",
"of",
"sequencing",
"can",
"benefit",
"agricultural",
"researchers.",
"By",
"taking",
"advantage",
"of",
"advanced",
"NGS",
"technologies,",
"genes",
"and",
"chromosomal",
"regions",
"that",
"are",
"more",
"labile",
"to",
"the",
"influence",
"of",
"environmental",
"factors",
"could",
"be",
"pinpointed.",
"A",
"more",
"long",
"term",
"goal",
"would",
"be",
"addressing",
"the",
"question",
"of",
"how",
"animals",
"respond",
"at",
"the",
"molecular",
"and",
"cellular",
"levels",
"to",
"different",
"environmental",
"models",
"(e.g.",
"nutrition).",
"Upon",
"revealing",
"important",
"genes",
"and",
"gene-environment",
"interactions,",
"the",
"rate",
"of",
"genetic",
"improvement",
"can",
"also",
"be",
"accelerated.",
"It",
"is",
"clear",
"that",
"NGS",
"technologies",
"will",
"be",
"able",
"to",
"assist",
"animal",
"scientists",
"to",
"efficiently",
"raise",
"animals",
"and",
"to",
"better",
"prevent",
"infectious",
"diseases",
"so",
"that",
"overall",
"costs",
"of",
"animal",
"production",
"can",
"be",
"decreased.",
"Keywords:",
"livestock",
"genomes,",
"next-generation",
"sequencing",
"technology,",
"nutrition",
"1.",
"Current",
"Status",
"of",
"Domestic",
"Animal",
"Reference",
"Sequences",
"As",
"the",
"new",
"genomics",
"era",
"matures,",
"with",
"large-scale",
"gen-",
"ome",
"research",
"and",
"the",
"development",
"of",
"sophisticated",
"bioinformatics",
"tools",
"that",
"can",
"be",
"applied",
"to",
"the",
"agricul-",
"tural",
"field,",
"agricultural",
"researchers",
"should",
"take",
"advan-",
"tage",
"of",
"and",
"benefit",
"from",
"new",
"sequencing",
"and",
"mapping",
"technologies.",
"In",
"recent",
"years,",
"the",
"genomes",
"of",
"several",
"domesticated",
"livestock",
"animals",
"(chicken,",
"pig,",
"cow,",
"sheep,",
"and",
"horse)",
"have",
"been",
"partially",
"or",
"completely",
"sequenced.",
"In",
"this",
"review,",
"we",
"first",
"examine",
"the",
"current",
"sequencing",
"status",
"for",
"several",
"sequenced",
"agricultural",
"spe-",
"cies.",
"Next,",
"we",
"discuss",
"the",
"different",
"platforms",
"used",
"for",
"genome",
"sequencing,",
"tools",
"available",
"for",
"mapping",
"sequences",
"to",
"the",
"genome,",
"and",
"several",
"additional",
"applica-",
"tions",
"for",
"which",
"next",
"generation",
"sequencing",
"can",
"be",
"used.",
"We",
"also",
"list",
"tools",
"available",
"for",
"analyzing",
"data",
"from",
"these",
"additional",
"applications.",
"*",
"Correspondence:",
"ybai@umich.edu",
"1Center",
"for",
"Computational",
"Medicine",
"and",
"Bioinformatics",
"and",
"Department",
"of",
"Computational",
"Medicine",
"and",
"Bioinformatics,",
"The",
"University",
"of",
"Michigan,",
"100",
"Washtenaw",
"Ave.,",
"2017",
"Palmer",
"Commons,",
"Ann",
"Arbor,",
"Michigan",
"48109-2218,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"Due",
"to",
"the",
"high",
"recombination",
"rate",
"of",
"its",
"micro-chro-",
"mosomes,",
"the",
"chicken",
"is",
"an",
"ideal",
"model",
"for",
"studying",
"genetic",
"linkage",
"[1].",
"The",
"chicken",
"genome",
"sequence",
"of",
"Red",
"Junglefowl",
"(RJF)",
"was",
"the",
"first",
"livestock",
"species",
"to",
"be",
"sequenced.",
"The",
"first",
"draft",
"of",
"the",
"chicken",
"genome",
"was",
"built",
"from",
"an",
"assembly",
"with",
"6.6-fold",
"whole-genome",
"shotgun",
"coverage,",
"although",
"sex",
"chromosomes",
"were",
"poorly",
"annotated",
"in",
"the",
"initial",
"assembly",
"[1,2].",
"The",
"updated",
"version",
"of",
"NCBI",
"build",
"2.1",
"was",
"released",
"recently",
"with",
"a",
"significant",
"improvement",
"on",
"the",
"annotation",
"of",
"the",
"sex",
"chromosomes.",
"Roughly",
"2.8",
"million",
"SNPs",
"for",
"chicken",
"were",
"identified",
"[1,3,4]",
"between",
"the",
"base",
"(wild",
"type)",
"RJF",
"sequence",
"assembly",
"and",
"a",
"partial",
"genome",
"scan",
"of",
"three",
"chicken",
"breeds:",
"a",
"female",
"layer",
"(White",
"Leghorn);",
"a",
"male",
"broiler",
"(Cornish);",
"and",
"a",
"female",
"Silkie.",
"A",
"moderate",
"den-",
"sity",
"(60",
"k)",
"Illumina",
"SNP",
"BeadChip",
"for",
"commercial",
"chicken",
"(broilers",
"and",
"layers)",
"containing",
"352,303",
"SNPs",
"was",
"designed",
"and",
"additional",
"SNPs",
"not",
"covered",
"by",
"the",
"current",
"chicken",
"genome",
"assembly",
"(Gallus_gallus-2.1)",
"were",
"identified",
"and",
"selected",
"recently",
"[5].",
"The",
"BBSRC",
"ChickenEST",
"Database",
"(http://www.chick.manchester.ac.",
"uk/)",
"provides",
"the",
"most",
"comprehensive",
"database",
"[6,7]",
"of",
"ESTs/cDNAs",
"for",
"the",
"chicken",
"genome.",
"Chicken",
"Varia-",
"tion",
"Database",
"(ChickVD)",
"(http://chicken.genomics.org.",
"©",
"2012",
"Bai",
"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."
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] | [
"BMC",
"Evolutionary",
"Biology",
"Research",
"article",
"Pupal",
"remodeling",
"and",
"the",
"evolution",
"and",
"development",
"of",
"alternative",
"male",
"morphologies",
"in",
"horned",
"beetles",
"Armin",
"P",
"Moczek",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Department",
"of",
"Biology,",
"Indiana",
"University,",
"Bloomington",
"IN,",
"USA",
"Email:",
"Armin",
"P",
"Moczek",
"-",
"armin@indiana.edu",
"Published:",
"29",
"August",
"2007",
"BMC",
"Evolutionary",
"Biology",
"2007,",
"7:151",
"doi:10.1186/1471-2148-7-151",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2148/7/151",
"Received:",
"2",
"May",
"2007",
"Accepted:",
"29",
"August",
"2007",
"©",
"2007",
"Moczek;",
"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:",
"How",
"novel",
"morphological",
"traits",
"originate",
"and",
"diversify",
"represents",
"a",
"major",
"frontier",
"in",
"evolutionary",
"biology.",
"Horned",
"beetles",
"are",
"emerging",
"as",
"an",
"increasingly",
"popular",
"model",
"system",
"to",
"explore",
"the",
"genetic,",
"developmental,",
"and",
"ecological",
"mechanisms,",
"as",
"well",
"as",
"the",
"interplay",
"between",
"them,",
"in",
"the",
"genesis",
"of",
"novelty",
"and",
"diversity.",
"The",
"horns",
"of",
"beetles",
"originate",
"during",
"a",
"rapid",
"growth",
"phase",
"during",
"the",
"prepupal",
"stage",
"of",
"larval",
"development.",
"Differential",
"growth",
"during",
"this",
"period",
"is",
"either",
"implicitly",
"or",
"explicitly",
"assumed",
"to",
"be",
"the",
"sole",
"mechanism",
"underlying",
"differences",
"in",
"horn",
"expression",
"within",
"and",
"between",
"species.",
"Here",
"I",
"focus",
"on",
"male",
"horn",
"dimorphisms,",
"a",
"phenomenon",
"at",
"the",
"center",
"of",
"many",
"studies",
"in",
"behavioral",
"ecology",
"and",
"evolutionary",
"development,",
"and",
"quantify",
"the",
"relative",
"contributions",
"of",
"a",
"previously",
"ignored",
"developmental",
"process,",
"pupal",
"remodeling,",
"to",
"the",
"expression",
"of",
"male",
"dimorphism",
"in",
"three",
"horned",
"beetle",
"species.",
"Results:",
"Prepupal",
"growth",
"is",
"not",
"the",
"only",
"determinant",
"of",
"differences",
"in",
"male",
"horn",
"expression.",
"Instead,",
"following",
"their",
"initial",
"prepupal",
"growth",
"phase,",
"beetles",
"may",
"be",
"extensively",
"remodeled",
"during",
"the",
"subsequent",
"pupal",
"stage",
"in",
"a",
"sex",
"and",
"size-dependent",
"manner.",
"Specifically,",
"male",
"dimorphism",
"in",
"the",
"three",
"Onthophagus",
"species",
"studied",
"here",
"was",
"shaped",
"not",
"at",
"all,",
"partly",
"or",
"entirely",
"by",
"such",
"pupal",
"remodeling",
"rather",
"than",
"differential",
"growth,",
"suggesting",
"that",
"pupal",
"remodeling",
"is",
"phylogenetically",
"widespread,",
"evolutionarily",
"labile,",
"and",
"developmentally",
"flexible.",
"Conclusion:",
"This",
"study",
"is",
"the",
"first",
"to",
"document",
"that",
"male",
"dimorphism",
"in",
"horned",
"beetles",
"is",
"the",
"product",
"of",
"two",
"developmentaly",
"dissociated",
"processes:",
"prepupal",
"growth",
"and",
"pupal",
"remodeling.",
"More",
"generally,",
"adult",
"morphology",
"alone",
"appears",
"to",
"provide",
"few",
"clues,",
"if",
"any,",
"as",
"to",
"the",
"relative",
"contributions",
"of",
"both",
"processes",
"to",
"the",
"expression",
"of",
"alternative",
"male",
"morphs,",
"underscoring",
"the",
"importance",
"of",
"developmental",
"studies",
"in",
"efforts",
"aimed",
"at",
"understanding",
"the",
"evolution",
"of",
"adult",
"diversity",
"patterns.",
"Background",
"Phenotypic",
"diversity",
"is",
"produced",
"by",
"changes",
"in",
"ontoge-",
"netic",
"processes",
"occurring",
"at",
"earlier",
"developmental",
"stages.",
"Such",
"changes",
"may",
"be",
"brought",
"about",
"by",
"allelic",
"differences",
"among",
"individuals,",
"differences",
"in",
"ontogenetic",
"environ-",
"ment,",
"or",
"as",
"is",
"probably",
"the",
"case",
"for",
"the",
"majority",
"of",
"pheno-",
"typic",
"traits,",
"both.",
"Evolutionary",
"biologists",
"are",
"accustomed",
"to",
"deducing",
"ontogenetic",
"properties",
"based",
"on",
"ontogenetic",
"outputs",
"rather",
"than",
"by",
"studying",
"development",
"as",
"a",
"process.",
"For",
"example,",
"the",
"degree",
"of",
"fluctuating",
"asymmetry",
"between",
"paired",
"adult",
"structures",
"has",
"been",
"assumed",
"by",
"many",
"studies",
"to",
"be",
"indicative",
"of",
"degree",
"of",
"developmental",
"instability",
"and",
"integration",
"[1-3],",
"even",
"though",
"few",
"studies",
"made",
"the",
"effort",
"to",
"investigate",
"the",
"developmental",
"underpinnings",
"of",
"asym-",
"Page",
"1",
"of",
"12",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Lipids",
"Volume",
"2011,",
"Article",
"ID",
"575840,",
"9",
"pages",
"doi:10.1155/2011/575840",
"Review",
"Article",
"Lipid",
"Abnormalities",
"and",
"Cardiometabolic",
"Risk",
"in",
"Patients",
"with",
"Overt",
"and",
"Subclinical",
"Thyroid",
"Disease",
"Melpomeni",
"Peppa,1",
"Grigoria",
"Betsi,1",
"and",
"George",
"Dimitriadis2",
"1",
"Endocrine",
"Unit,",
"Second",
"Department",
"of",
"Internal",
"Medicine-Propaedeutic,",
"Research",
"Institute",
"and",
"Diabetes",
"Center,",
"Athens",
"University",
"Medical",
"School,",
"Attikon",
"University",
"Hospital,",
"Athens,",
"Greece",
"2",
"Second",
"Department",
"of",
"Internal",
"Medicine-Propaedeutic,",
"Research",
"Institute",
"and",
"Diabetes",
"Center,",
"Athens",
"University",
"Medical",
"School,",
"Attikon",
"University",
"Hospital,",
"Athens,",
"Greece",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Melpomeni",
"Peppa,",
"molypepa@otenet.gr",
"Received",
"3",
"May",
"2011;",
"Revised",
"17",
"May",
"2011;",
"Accepted",
"17",
"May",
"2011",
"Academic",
"Editor:",
"Angeliki",
"Chroni",
"Copyright",
"©",
"2011",
"Melpomeni",
"Peppa",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Dyslipidemia",
"is",
"a",
"common",
"finding",
"in",
"patients",
"with",
"thyroid",
"disease,",
"explained",
"by",
"the",
"adverse",
"effects",
"of",
"thyroid",
"hormones",
"in",
"almost",
"all",
"steps",
"of",
"lipid",
"metabolism.",
"Not",
"only",
"overt",
"but",
"also",
"subclinical",
"hypo-",
"and",
"hyperthyroidism,",
"through",
"different",
"mechanisms,",
"are",
"associated",
"with",
"lipid",
"alterations,",
"mainly",
"concerning",
"total",
"and",
"LDL",
"cholesterol",
"and",
"less",
"often",
"HDL",
"cholesterol,",
"triglycerides,",
"lipoprotein",
"(a),",
"apolipoprotein",
"A1,",
"and",
"apolipoprotein",
"B.",
"In",
"addition",
"to",
"quantitative,",
"qualitative",
"alterations",
"of",
"lipids",
"have",
"been",
"also",
"reported,",
"including",
"atherogenic",
"and",
"oxidized",
"LDL",
"and",
"HDL",
"particles.",
"In",
"thyroid",
"disease,",
"dyslipidemia",
"coexists",
"with",
"various",
"metabolic",
"abnormalities",
"and",
"induce",
"insulin",
"resistance",
"and",
"oxidative",
"stress",
"via",
"a",
"vice-vicious",
"cycle.",
"The",
"above",
"associations",
"in",
"combination",
"with",
"the",
"thyroid",
"hormone",
"induced",
"hemodynamic",
"alterations,",
"might",
"explain",
"the",
"increased",
"risk",
"of",
"coronary",
"artery",
"disease,",
"cerebral",
"ischemia",
"risk,",
"and",
"angina",
"pectoris",
"in",
"older,",
"and",
"possibly",
"ischemic",
"stroke",
"in",
"younger",
"patients",
"with",
"overt",
"or",
"subclinical",
"hyperthyroidism.",
"1.",
"Introduction",
"Thyroid",
"disease,",
"namely",
"hypothyroidism",
"and",
"hyperthyroid-",
"ism,",
"constitutes",
"the",
"most",
"common",
"endocrine",
"abnormality",
"in",
"recent",
"years,",
"diagnosed",
"either",
"in",
"subclinical",
"or",
"clinical",
"form.",
"According",
"to",
"the",
"6-year",
"duration",
"NHANES",
"III",
"Study,",
"the",
"prevalence",
"of",
"hypothyroidism",
"was",
"4.6%",
"(0.3%",
"clinical",
"and",
"4.3%",
"subclinical)",
"and",
"of",
"hyperthyroidism",
"1.3%",
"(0.5%",
"clinical",
"and",
"0.7%",
"subclinical),",
"in",
"population",
"aged",
"at",
"least",
"12",
"years,",
"showing",
"an",
"age",
"and",
"sex",
"dependence",
"[1].",
"Thyroid",
"disease",
"is",
"associated",
"with",
"various",
"metabolic",
"ab-",
"normalities,",
"due",
"to",
"the",
"effects",
"of",
"thyroid",
"hormones",
"on",
"nearly",
"all",
"major",
"metabolic",
"pathways.",
"Thyroid",
"hormones",
"regulate",
"the",
"basal",
"energy",
"expenditure",
"through",
"their",
"effect",
"on",
"protein,",
"carbohydrate,",
"and",
"lipid",
"metabolism.",
"This",
"might",
"be",
"a",
"direct",
"effect",
"or",
"an",
"indirect",
"effect",
"by",
"modification",
"of",
"other",
"regulatory",
"hormones",
"such",
"as",
"insulin",
"or",
"catecholamines",
"[2].",
"Dyslipi-",
"demia",
"is",
"a",
"common",
"metabolic",
"abnormality",
"in",
"patients",
"with",
"thyroid",
"disease,",
"either",
"in",
"the",
"overt",
"or",
"subclinical",
"forms",
"of",
"the",
"disease,",
"and",
"constitutes",
"the",
"end",
"result",
"of",
"the",
"effect",
"of",
"thyroid",
"hormones",
"in",
"all",
"aspects",
"of",
"lipid",
"metabolism",
"leading",
"to",
"var-",
"ious",
"quantitative",
"and/or",
"qualitative",
"changes",
"of",
"triglycerides,",
"phospholipids,",
"cholesterol,",
"and",
"other",
"lipoproteins",
"[3].",
"In",
"thyroid",
"disease,",
"dyslipidemia",
"and",
"the",
"coexisting",
"met-",
"abolic",
"abnormalities,",
"in",
"combination",
"with",
"the",
"thyroid",
"hor-",
"mone-induced",
"hemodynamic",
"alterations,",
"explain",
"the",
"high",
"risk",
"for",
"cardiovascular",
"disease",
"[4–7].",
"2.",
"Effects",
"of",
"Thyroid",
"Hormones",
"on",
"Lipid",
"Metabolism",
"Thyroid",
"hormones",
"influence",
"all",
"aspects",
"of",
"lipid",
"metabolism",
"including",
"synthesis,",
"mobilization,",
"and",
"degradation",
"[3].",
"Thy-",
"roid",
"hormones",
"stimulate",
"cholesterol",
"synthesis",
"by",
"inducing",
"3-hydroxy-3-methyl-glutaryl",
"coenzyme",
"A",
"reductase",
"in",
"the",
"liver",
"[8].",
"Thyroid",
"hormones",
"affect",
"lipoprotein",
"lipase",
"activity",
"and",
"thus,",
"the",
"hydrolysis",
"of",
"triglycerides",
"into",
"very-low,",
"density",
"lipoprotein",
"(VLDL)",
"and",
"chylomicrons",
"into",
"fatty"
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] | [
"Knee",
"Surg",
"Sports",
"Traumatol",
"Arthrosc",
"(2007)",
"15:465–471",
"DOI",
"10.1007/s00167-006-0275-7",
"A",
"N",
"K",
"L",
"E",
"The",
"distal",
"fascicle",
"of",
"the",
"anterior",
"inferior",
"tibiofibular",
"ligament",
"as",
"a",
"cause",
"of",
"tibiotalar",
"impingement",
"syndrome:",
"a",
"current",
"concepts",
"review",
"Michel",
"P.",
"J.",
"van",
"den",
"Bekerom",
"Æ",
"Eric",
"E.",
"J.",
"Raven",
"Received:",
"12",
"August",
"2006",
"/",
"Accepted:",
"11",
"December",
"2006",
"/",
"Published",
"online:",
"20",
"January",
"2007",
"Springer-Verlag",
"2007",
"Abstract",
"Impingement",
"syndromes",
"of",
"the",
"ankle",
"in-",
"volve",
"either",
"osseous",
"or",
"soft",
"tissue",
"impingement",
"and",
"can",
"be",
"anterior,",
"anterolateral,",
"or",
"posterior.",
"Ankle",
"impingement",
"syndromes",
"are",
"painful",
"conditions",
"caused",
"by",
"the",
"friction",
"of",
"joint",
"tissues,",
"which",
"are",
"both",
"the",
"cause",
"and",
"the",
"effect",
"of",
"altered",
"joint",
"biomechanics.",
"The",
"distal",
"fascicle",
"of",
"the",
"anterior",
"inferior",
"tibiofibular",
"ligament",
"(AITFL)",
"is",
"possible",
"cause",
"of",
"anterior",
"impingement.",
"The",
"objective",
"of",
"this",
"article",
"was",
"to",
"review",
"the",
"literature",
"concerning",
"the",
"anatomy,",
"pathogenesis,",
"symptoms",
"and",
"treatment",
"of",
"the",
"AITFL",
"impingement",
"and",
"finally",
"to",
"formulate",
"treatment",
"recommendations.",
"The",
"AITFL",
"starts",
"from",
"the",
"distal",
"tibia,",
"5",
"mm",
"in",
"average",
"above",
"the",
"articular",
"surface,",
"and",
"descends",
"obliquely",
"between",
"the",
"adjacent",
"margins",
"of",
"the",
"tibia",
"and",
"fibula,",
"anterior",
"to",
"the",
"syndesmosis",
"to",
"the",
"anterior",
"aspect",
"of",
"the",
"lateral",
"malleolus.",
"The",
"incidence",
"of",
"the",
"accessory",
"fascicle",
"differs",
"very",
"widely",
"in",
"the",
"several",
"studies.",
"The",
"presence",
"of",
"the",
"distal",
"fascicle",
"of",
"the",
"AITFL",
"and",
"also",
"the",
"contact",
"with",
"the",
"anterolateral",
"talus",
"is",
"probably",
"a",
"normal",
"find-",
"ing.",
"It",
"may",
"become",
"pathological,",
"due",
"to",
"anatomical",
"variations",
"and/or",
"anterolateral",
"instability",
"of",
"the",
"ankle",
"resulting",
"from",
"an",
"anterior",
"talofibular",
"ligament",
"injury.",
"When",
"observed",
"during",
"an",
"ankle",
"arthroscopy,",
"the",
"sur-",
"geon",
"should",
"look",
"for",
"the",
"criteria",
"described",
"to",
"decide",
"whether",
"it",
"is",
"pathological",
"and",
"considering",
"resection",
"M.",
"P.",
"J.",
"van",
"den",
"Bekerom",
"E.",
"E.",
"J.",
"Raven",
"Department",
"of",
"Orthopaedic",
"Surgery,",
"Gelre",
"Hospitals,",
"Apeldoorn,",
"The",
"Netherlands",
"M.",
"P.",
"J.",
"van",
"den",
"Bekerom",
"(&)",
"Department",
"of",
"Surgery",
"and",
"Traumatology,",
"Gelre",
"Hospitals,",
"Location",
"Lukas,",
"P.O.",
"Box",
"9014,",
"7300",
"Apeldoorn,",
"The",
"Netherlands",
"e-mail:",
"Bekerom@gmail.com",
"of",
"the",
"distal",
"fascicle.",
"The",
"presence",
"of",
"the",
"AITFL",
"and",
"the",
"contact",
"with",
"the",
"talus",
"is",
"a",
"normal",
"finding.",
"An",
"impingement",
"of",
"the",
"AITFL",
"can",
"result",
"from",
"an",
"ana-",
"tomical",
"variant",
"or",
"anteroposterior",
"instability",
"of",
"the",
"ankle.",
"The",
"diagnosis",
"of",
"ligamentous",
"impingement",
"in",
"the",
"anterior",
"aspect",
"of",
"the",
"ankle",
"should",
"be",
"considered",
"in",
"patients",
"who",
"have",
"chronic",
"ankle",
"pain",
"in",
"the",
"antero-",
"lateral",
"aspect",
"of",
"the",
"ankle",
"after",
"an",
"inversion",
"injury",
"and",
"have",
"a",
"stable",
"ankle,",
"normal",
"plain",
"radiographs,",
"and",
"isolated",
"point",
"tenderness",
"on",
"the",
"anterolateral",
"aspect",
"of",
"the",
"talar",
"dome",
"and",
"in",
"the",
"anteroinferior",
"tibiofibular",
"ligament.",
"The",
"impingement",
"syndrome",
"can",
"be",
"treated",
"arthroscopically.",
"Keywords",
"Ankle",
"Impingement",
"syndrome",
"Anterior",
"inferior",
"tibiofibular",
"ligament",
"Accessory",
"fascicle",
"Introduction",
"Impingement",
"syndromes",
"of",
"the",
"ankle",
"involve",
"either",
"osseous",
"or",
"soft",
"tissue",
"impingement",
"and",
"can",
"be",
"anterior,",
"anterolateral,",
"or",
"posterior",
"[5,",
"25].",
"Ankle",
"impingement",
"syndromes",
"are",
"painful",
"conditions",
"caused",
"by",
"the",
"friction",
"of",
"joint",
"tissues,",
"which",
"are",
"both",
"the",
"cause",
"and",
"the",
"effect",
"of",
"altered",
"joint",
"biomechanics",
"[14].",
"The",
"leading",
"causes",
"of",
"impingement",
"lesions",
"are",
"post-traumatic",
"ankle",
"injuries,",
"usually",
"ankle",
"sprains,",
"resulting",
"in",
"chronic",
"ankle",
"pain",
"[33].",
"According",
"to",
"the",
"ISAKOS",
"definition,",
"anterior",
"ankle",
"impingement",
"is",
"a",
"pain",
"syndrome",
"char-",
"acterised",
"by",
"anterior",
"ankle",
"pain",
"on",
"activity.",
"Recurrent",
"dorsiflexion",
"is",
"often",
"the",
"cause.",
"On",
"investigation,",
"there",
"is",
"pain",
"on",
"palpation",
"at",
"the",
"antero/medial",
"and/or",
"ante-",
"rolateral",
"aspect",
"of",
"the",
"ankle",
"joint.",
"Some",
"swelling",
"and/",
"123"
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815,
594,
828
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[
600,
815,
621,
828
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[
626,
815,
643,
828
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[
649,
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656,
828
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[
661,
815,
697,
828
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[
702,
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745,
828
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[
750,
815,
762,
828
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425,
855,
454,
865
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458,
855,
489,
865
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493,
855,
501,
865
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[
506,
855,
539,
865
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543,
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558,
865
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[
563,
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616,
865
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620,
855,
641,
865
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646,
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689,
865
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721,
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725,
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750,
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425,
866,
459,
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425,
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491,
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746,
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425,
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445,
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425,
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589,
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590,
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597,
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599,
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610,
926
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611,
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661,
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664,
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689,
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691,
916,
736,
926
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738,
916,
763,
926
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[
425,
927,
439,
937
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440,
927,
464,
937
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[
466,
927,
475,
937
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476,
927,
490,
937
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492,
927,
526,
937
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[
527,
927,
569,
937
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571,
927,
616,
937
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619,
927,
651,
937
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653,
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678,
937
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927,
711,
937
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713,
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763,
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938,
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948
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948
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] | [
"Theme",
"and",
"Variations",
"in",
"the",
"Evolutionary",
"Pathways",
"to",
"Virulence",
"of",
"an",
"RNA",
"Plant",
"Virus",
"Species",
"Agn",
"e`s",
"Pinel-Galzi1,",
"Mbolarinosy",
"Rakotomalala2,",
"Emmanuel",
"Sangu3,",
"Fatogoma",
"Sorho4,",
"Zakaria",
"Kanyeka3,",
"Oumar",
"Traor",
"e´5,",
"Drissa",
"Se´",
"r",
"e´m",
"e´5,",
"Nils",
"Poulicard1,",
"Yvonne",
"Rabenantoandro6,",
"Yacouba",
"Se´",
"r",
"e´4,",
"Gnissa",
"Konat",
"e´5,",
"Alain",
"Ghesquie`",
"re7,",
"Euge´",
"nie",
"He´",
"brard1,",
"Denis",
"Fargette1*",
"1",
"Institut",
"de",
"Recherche",
"pour",
"le",
"De´veloppement",
"(IRD),",
"UMR",
"RPB,",
"Montpellier,",
"France,",
"2",
"Centre",
"National",
"de",
"la",
"Recherche",
"Applique´e",
"au",
"De´veloppement",
"Rural",
"(FOFIFA),",
"Mahajanga,",
"Madagascar,",
"3",
"Botany",
"Department,",
"Dar",
"es",
"Salaam",
"University,",
"Dar",
"es",
"Salaam,",
"Tanzania,",
"4",
"Africa",
"Rice",
"Center",
"(WARDA),",
"Cotonou,",
"Be´nin,",
"5",
"Institut",
"de",
"l’Environnement",
"et",
"de",
"Recherches",
"Agricoles",
"(INERA),",
"Laboratoire",
"de",
"Biotechnologie",
"et",
"de",
"Virologie",
"Ve´ge´tale,",
"Kamboinse´,",
"Ouagadougou,",
"Burkina",
"Faso,",
"6",
"Centre",
"National",
"de",
"la",
"Recherche",
"Applique´e",
"au",
"De´veloppement",
"Rural",
"(FOFIFA),",
"Antananarivo,",
"Madagascar,",
"7",
"Institut",
"de",
"Recherche",
"pour",
"le",
"De´veloppement",
"(IRD),",
"UMR",
"GDP,",
"Montpellier,",
"France",
"The",
"diversity",
"of",
"a",
"highly",
"variable",
"RNA",
"plant",
"virus",
"was",
"considered",
"to",
"determine",
"the",
"range",
"of",
"virulence",
"substitutions,",
"the",
"evolutionary",
"pathways",
"to",
"virulence,",
"and",
"whether",
"intraspecific",
"diversity",
"modulates",
"virulence",
"pathways",
"and",
"propensity.",
"In",
"all,",
"114",
"isolates",
"representative",
"of",
"the",
"genetic",
"and",
"geographic",
"diversity",
"of",
"Rice",
"yellow",
"mottle",
"virus",
"(RYMV)",
"in",
"Africa",
"were",
"inoculated",
"to",
"several",
"cultivars",
"with",
"eIF(iso)4G-mediated",
"Rymv1-2",
"resistance.",
"Altogether,",
"41",
"virulent",
"variants",
"generated",
"from",
"ten",
"wild",
"isolates",
"were",
"analyzed.",
"Nonconservative",
"amino",
"acid",
"replacements",
"at",
"five",
"positions",
"located",
"within",
"a",
"stretch",
"of",
"15",
"codons",
"in",
"the",
"central",
"region",
"of",
"the",
"79-aa-long",
"protein",
"VPg",
"were",
"associated",
"with",
"virulence.",
"Virulence",
"substitutions",
"were",
"fixed",
"predominantly",
"at",
"codon",
"48",
"in",
"most",
"strains,",
"whatever",
"the",
"host",
"genetic",
"background",
"or",
"the",
"experimental",
"conditions.",
"There",
"were",
"one",
"major",
"and",
"two",
"isolate-specific",
"mutational",
"pathways",
"conferring",
"virulence",
"at",
"codon",
"48.",
"In",
"the",
"prevalent",
"mutational",
"pathway",
"I,",
"arginine",
"(AGA)",
"was",
"successively",
"displaced",
"by",
"glycine",
"(GGA)",
"and",
"glutamic",
"acid",
"(GAA).",
"Substitutions",
"in",
"the",
"other",
"virulence",
"codons",
"were",
"displaced",
"when",
"E48",
"was",
"fixed.",
"In",
"the",
"isolate-specific",
"mutational",
"pathway",
"II,",
"isoleucine",
"(ATA)",
"emerged",
"and",
"often",
"later",
"coexisted",
"with",
"valine",
"(GTA).",
"In",
"mutational",
"pathway",
"III,",
"arginine,",
"with",
"the",
"specific",
"S2/S3",
"strain",
"codon",
"usage",
"AGG,",
"was",
"displaced",
"by",
"tryptophane",
"(TGG).",
"Mutational",
"pathway",
"I",
"never",
"arose",
"in",
"the",
"widely",
"spread",
"West",
"African",
"S2/S3",
"strain",
"because",
"G48",
"was",
"not",
"infectious",
"in",
"the",
"S2/S3",
"genetic",
"context.",
"Strain",
"S2/S3",
"least",
"frequently",
"overcame",
"resistance,",
"whereas",
"two",
"geographically",
"localized",
"variants",
"of",
"the",
"strain",
"S4",
"had",
"a",
"high",
"propensity",
"to",
"virulence.",
"Codons",
"49",
"and",
"26",
"of",
"the",
"VPg,",
"under",
"diversifying",
"selection,",
"are",
"candidate",
"positions",
"in",
"modulating",
"the",
"genetic",
"barriers",
"to",
"virulence.",
"The",
"theme",
"and",
"variations",
"in",
"the",
"evolutionary",
"pathways",
"to",
"virulence",
"of",
"RYMV",
"illustrates",
"the",
"extent",
"of",
"parallel",
"evolution",
"within",
"a",
"highly",
"variable",
"RNA",
"plant",
"virus",
"species.",
"Citation:",
"Pinel-Galzi",
"A,",
"Rakotomalala",
"M,",
"Sangu",
"E,",
"Sorho",
"F,",
"Kanyeka",
"Z,",
"et",
"al.",
"(2007)",
"Theme",
"and",
"variations",
"in",
"the",
"evolutionary",
"pathways",
"to",
"virulence",
"of",
"an",
"RNA",
"plant",
"virus",
"species.",
"PLoS",
"Pathog",
"3(11):",
"e180.",
"doi:10.1371/journal.ppat.0030180",
"Introduction",
"Parallel",
"evolution",
"is",
"the",
"evolution",
"of",
"similar",
"or",
"identical",
"features",
"independently",
"in",
"related",
"lineages",
"when",
"subjected",
"to",
"similar",
"selection",
"pressures",
"[1,2].",
"Parallel",
"evolution",
"has",
"been",
"reported",
"extensively",
"both",
"in",
"natural",
"isolates",
"and",
"in",
"exper-",
"imental",
"populations",
"of",
"many",
"microbes,",
"most",
"often",
"viruses",
"[2–",
"4],",
"but",
"also",
"bacteria",
"[5],",
"yeast",
"[6],",
"and",
"protozoa",
"[7].",
"With",
"viruses,",
"similar",
"amino",
"acid",
"replacements",
"often",
"occurred",
"in",
"immune",
"or",
"antiviral",
"escape",
"variants.",
"This",
"is",
"usually",
"inter-",
"preted",
"as",
"the",
"fixation",
"of",
"a",
"mutation",
"with",
"a",
"beneficial",
"effect.",
"However,",
"differences",
"in",
"founding",
"genotypes",
"may",
"result",
"in",
"divergent",
"evolutionary",
"trajectories",
"[5].",
"So,",
"patterns",
"of",
"adaptation",
"to",
"selective",
"constraints",
"may",
"also",
"be",
"dependent",
"on",
"intraspecific",
"polymorphisms.",
"This",
"is",
"well",
"documented",
"for",
"HIV",
"resistance",
"to",
"antiretroviral",
"agents,",
"where",
"pathways",
"of",
"viral",
"evolution",
"towards",
"drug",
"resistance",
"may",
"proceed",
"through",
"distinct",
"steps",
"and",
"at",
"different",
"rates",
"among",
"different",
"HIV",
"subtypes",
"[8,9].",
"The",
"objective",
"of",
"this",
"article",
"is",
"to",
"assess",
"the",
"extent",
"of",
"parallel",
"evolution",
"in",
"a",
"highly",
"variable",
"RNA",
"plant",
"virus",
"species.",
"Then,",
"the",
"diversity",
"of",
"Rice",
"yellow",
"mottle",
"virus",
"(RYMV)",
"was",
"considered",
"to",
"determine",
"the",
"range",
"of",
"virulence",
"substitutions,",
"to",
"reconstruct",
"the",
"evolutionary",
"pathways",
"to",
"virulence,",
"and",
"to",
"test",
"whether",
"intraspecific",
"diversity",
"modu-",
"lates",
"virulence",
"pathways",
"and",
"propensity.",
"The",
"breakdown",
"of",
"host",
"plant",
"resistance",
"is",
"a",
"well-docu-",
"mented",
"case",
"of",
"virus",
"adaptation",
"[10].",
"Translation",
"initiation",
"factors",
"of",
"the",
"eIF4E",
"and",
"eIF4G",
"families",
"are",
"major",
"determi-",
"nants",
"of",
"recessive",
"resistance",
"to",
"plant",
"viruses",
"[11,12].",
"Several",
"studies",
"showed",
"that",
"one",
"or",
"a",
"few",
"amino",
"acid",
"substitutions",
"in",
"the",
"genome-linked",
"viral",
"protein",
"VPg",
"are",
"independently",
"responsible",
"for",
"virulence",
"(see",
"[12]",
"for",
"a",
"recent",
"review).",
"In",
"Editor:",
"Edward",
"C.",
"Holmes,",
"The",
"Pennsylvania",
"State",
"University,",
"United",
"States",
"of",
"America",
"Received",
"June",
"11,",
"2007;",
"Accepted",
"October",
"12,",
"2007;",
"Published",
"November",
"23,",
"2007",
"Copyright:",
"2007",
"Pinel-Galzi",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Abbreviations:",
"NIL,",
"nearly",
"isogenic",
"line;",
"ORF,",
"open",
"reading",
"frame;",
"PI,",
"protease",
"inhibitor;",
"RYMV,",
"Rice",
"yellow",
"mottle",
"virus",
"*",
"To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"E-mail:",
"Denis.Fargette@mpl.ird.fr",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"1761",
"November",
"2007",
"|",
"Volume",
"3",
"|",
"Issue",
"11",
"|",
"e180"
] | [
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3,
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3,
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3,
3,
3,
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3,
3,
3,
3,
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3,
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3,
3,
3,
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3,
3,
3,
3,
3,
3,
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5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
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] | [
"BMC",
"Genomics",
"Research",
"article",
"The",
"trypanosome",
"transcriptome",
"is",
"remodelled",
"during",
"differentiation",
"but",
"displays",
"limited",
"responsiveness",
"within",
"life",
"stages",
"V",
"Lila",
"Koumandou,",
"Senthil",
"Kumar",
"A",
"Natesan,",
"Tatiana",
"Sergeenko",
"and",
"Mark",
"C",
"Field*",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"The",
"Molteno",
"Building,",
"Department",
"of",
"Pathology,",
"University",
"of",
"Cambridge,",
"Tennis",
"Court",
"Road,",
"Cambridge,",
"CB2",
"1QP,",
"UK",
"Email:",
"V",
"Lila",
"Koumandou",
"-",
"vk219@cam.ac.uk;",
"Senthil",
"Kumar",
"A",
"Natesan",
"-",
"ska23@mole.bio.cam.ac.uk;",
"Tatiana",
"Sergeenko",
"-",
"ts329@cam.ac.uk;",
"Mark",
"C",
"Field*",
"-",
"mcf34@cam.ac.uk",
"*",
"Corresponding",
"author",
"Published:",
"23",
"June",
"2008",
"BMC",
"Genomics",
"2008,",
"9:298",
"doi:10.1186/1471-2164-9-298",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2164/9/298",
"Received:",
"3",
"March",
"2008",
"Accepted:",
"23",
"June",
"2008",
"©",
"2008",
"Koumandou",
"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:",
"Trypanosomatids",
"utilise",
"polycistronic",
"transcription",
"for",
"production",
"of",
"the",
"vast",
"majority",
"of",
"protein-coding",
"mRNAs,",
"which",
"operates",
"in",
"the",
"absence",
"of",
"gene-specific",
"promoters.",
"Resolution",
"of",
"nascent",
"transcripts",
"by",
"polyadenylation",
"and",
"trans-splicing,",
"together",
"with",
"specific",
"rates",
"of",
"mRNA",
"turnover,",
"serve",
"to",
"generate",
"steady",
"state",
"transcript",
"levels",
"that",
"can",
"differ",
"in",
"abundance",
"across",
"several",
"orders",
"of",
"magnitude",
"and",
"can",
"be",
"developmentally",
"regulated.",
"We",
"used",
"a",
"targeted",
"oligonucleotide",
"microarray,",
"representing",
"the",
"strongly",
"developmentally-regulated",
"T.",
"brucei",
"membrane",
"trafficking",
"system",
"and",
"~10%",
"of",
"the",
"Trypanosoma",
"brucei",
"genome,",
"to",
"investigate",
"both",
"between-stage,",
"or",
"differentiation-dependent,",
"transcriptome",
"changes",
"and",
"within-stage",
"flexibility",
"in",
"response",
"to",
"various",
"challenges.",
"Results:",
"6%",
"of",
"the",
"gene",
"cohort",
"are",
"developmentally",
"regulated,",
"including",
"several",
"small",
"GTPases,",
"SNAREs,",
"vesicle",
"coat",
"factors",
"and",
"protein",
"kinases",
"both",
"consistent",
"with",
"and",
"extending",
"previous",
"data.",
"Therefore",
"substantial",
"differentiation-dependent",
"remodeling",
"of",
"the",
"trypanosome",
"transcriptome",
"is",
"associated",
"with",
"membrane",
"transport.",
"Both",
"the",
"microarray",
"and",
"qRT-PCR",
"were",
"then",
"used",
"to",
"analyse",
"transcriptome",
"changes",
"resulting",
"from",
"specific",
"gene",
"over-expression,",
"knockdown,",
"altered",
"culture",
"conditions",
"and",
"chemical",
"stress.",
"Firstly,",
"manipulation",
"of",
"Rab5",
"expression",
"results",
"in",
"co-ordinate",
"changes",
"to",
"clathrin",
"protein",
"expression",
"levels",
"and",
"endocytotic",
"activity,",
"but",
"no",
"detectable",
"changes",
"to",
"steady-state",
"mRNA",
"levels,",
"which",
"indicates",
"that",
"the",
"effect",
"is",
"mediated",
"post-transcriptionally.",
"Secondly,",
"knockdown",
"of",
"clathrin",
"or",
"the",
"variant",
"surface",
"glycoprotein",
"failed",
"to",
"perturb",
"transcription.",
"Thirdly,",
"exposure",
"to",
"dithiothreitol",
"or",
"tunicamycin",
"revealed",
"no",
"evidence",
"for",
"a",
"classical",
"unfolded",
"protein",
"response,",
"mediated",
"in",
"higher",
"eukaryotes",
"by",
"transcriptional",
"changes.",
"Finally,",
"altered",
"serum",
"levels",
"invoked",
"little",
"transcriptome",
"alteration",
"beyond",
"changes",
"to",
"expression",
"of",
"ESAG6/7,",
"the",
"transferrin",
"receptor.",
"Conclusion:",
"While",
"trypanosomes",
"regulate",
"mRNA",
"abundance",
"to",
"effect",
"the",
"major",
"changes",
"accompanying",
"differentiation,",
"a",
"given",
"differentiated",
"state",
"appears",
"transcriptionally",
"inflexible.",
"The",
"implications",
"of",
"the",
"absence",
"of",
"a",
"transcriptome",
"response",
"in",
"trypanosomes",
"for",
"both",
"virulence",
"and",
"models",
"of",
"life",
"cycle",
"progression",
"are",
"discussed.",
"Page",
"1",
"of",
"28",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Oxidative",
"Medicine",
"and",
"Cellular",
"Longevity",
"Volume",
"2012,",
"Article",
"ID",
"428010,",
"11",
"pages",
"doi:10.1155/2012/428010",
"Review",
"Article",
"Mechanism",
"of",
"Oxidative",
"Stress",
"in",
"Neurodegeneration",
"Sonia",
"Gandhi",
"and",
"Andrey",
"Y.",
"Abramov",
"Department",
"of",
"Molecular",
"Neuroscience,",
"UCL",
"Institute",
"of",
"Neurology,",
"Queen",
"Square,",
"London",
"WC1N",
"3BG,",
"UK",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Andrey",
"Y.",
"Abramov,",
"a.abramov@ucl.ac.uk",
"Received",
"13",
"December",
"2011;",
"Accepted",
"14",
"March",
"2012",
"Academic",
"Editor:",
"Krzysztof",
"Ksiazek",
"Copyright",
"©",
"2012",
"S.",
"Gandhi",
"and",
"A.",
"Y.",
"Abramov.",
"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.",
"Biological",
"tissues",
"require",
"oxygen",
"to",
"meet",
"their",
"energetic",
"demands.",
"However,",
"the",
"consumption",
"of",
"oxygen",
"also",
"results",
"in",
"the",
"generation",
"of",
"free",
"radicals",
"that",
"may",
"have",
"damaging",
"effects",
"on",
"cells.",
"The",
"brain",
"is",
"particularly",
"vulnerable",
"to",
"the",
"effects",
"of",
"reactive",
"oxygen",
"species",
"due",
"to",
"its",
"high",
"demand",
"for",
"oxygen,",
"and",
"its",
"abundance",
"of",
"highly",
"peroxidisable",
"substrates.",
"Oxidative",
"stress",
"is",
"caused",
"by",
"an",
"imbalance",
"in",
"the",
"redox",
"state",
"of",
"the",
"cell,",
"either",
"by",
"overproduction",
"of",
"reactive",
"oxygen",
"species,",
"or",
"by",
"dysfunction",
"of",
"the",
"antioxidant",
"systems.",
"Oxidative",
"stress",
"has",
"been",
"detected",
"in",
"a",
"range",
"of",
"neurodegenerative",
"disease,",
"and",
"emerging",
"evidence",
"from",
"in",
"vitro",
"and",
"in",
"vivo",
"disease",
"models",
"suggests",
"that",
"oxidative",
"stress",
"may",
"play",
"a",
"role",
"in",
"disease",
"pathogenesis.",
"However,",
"the",
"promise",
"of",
"antioxidants",
"as",
"novel",
"therapies",
"for",
"neurodegenerative",
"diseases",
"has",
"not",
"been",
"borne",
"out",
"in",
"clinical",
"studies.",
"In",
"this",
"review,",
"we",
"critically",
"assess",
"the",
"hypothesis",
"that",
"oxidative",
"stress",
"is",
"a",
"crucial",
"player",
"in",
"common",
"neurodegenerative",
"disease",
"and",
"discuss",
"the",
"source",
"of",
"free",
"radicals",
"in",
"such",
"diseases.",
"Furthermore,",
"we",
"examine",
"the",
"issues",
"surrounding",
"the",
"failure",
"to",
"translate",
"this",
"hypothesis",
"into",
"an",
"effective",
"clinical",
"treatment.",
"1.",
"Introduction",
"1.1.",
"Oxidative",
"Stress",
"and",
"Neurodegeneration.",
"It",
"has",
"been",
"long",
"recognised",
"that",
"oxidative",
"stress",
"may",
"be",
"important",
"in",
"the",
"aeti-",
"ology",
"of",
"a",
"variety",
"of",
"late",
"onset",
"neurodegenerative",
"diseases.",
"Aging",
"has",
"been",
"established",
"as",
"the",
"most",
"important",
"risk",
"factor",
"for",
"the",
"common",
"neurodegenerative",
"diseases,",
"Alzheimer’s",
"disease",
"(AD),",
"and",
"Parkinson’s",
"disease",
"(PD).",
"Most",
"theories",
"of",
"aging",
"centre",
"are",
"on",
"the",
"idea",
"that",
"cumulative",
"oxidative",
"stress",
"leads",
"to",
"mitochondrial",
"mutations,",
"mitochondrial",
"dysfunc-",
"tion,",
"and",
"oxidative",
"damage",
"[1].",
"However,",
"as",
"the",
"role",
"of",
"ROS",
"becomes",
"increasingly",
"recognised",
"in",
"aging",
"and",
"age-related",
"diseases,",
"a",
"number",
"of",
"controversies",
"begin",
"to",
"emerge",
"in",
"this",
"field.",
"Is",
"oxidative",
"stress",
"an",
"epiphenomenon",
"of",
"dysfunctional",
"and",
"dying",
"neurons,",
"or",
"does",
"oxidative",
"stress",
"itself",
"cause",
"the",
"dysfunctionality/death",
"of",
"neurons?",
"How",
"does",
"a",
"global",
"event",
"such",
"as",
"oxidative",
"stress",
"result",
"in",
"the",
"selective",
"neuronal",
"vulnerability",
"seen",
"in",
"most",
"neurodegenerative",
"diseases?",
"And",
"finally,",
"if",
"oxidative",
"stress",
"is",
"truly",
"fundamental",
"to",
"pathogenesis",
"then",
"why",
"has",
"the",
"use",
"of",
"antioxidant",
"therapy",
"been",
"thus",
"far",
"largely",
"unsuccessful",
"in",
"such",
"diseases?",
"In",
"order",
"to",
"address",
"these",
"questions,",
"we",
"first",
"outline",
"the",
"definition",
"of",
"oxidative",
"stress",
"and",
"show",
"how",
"ROS",
"is",
"generated",
"in",
"the",
"human",
"brain",
"(Box",
"1),",
"as",
"well",
"as",
"the",
"antioxidant",
"defence",
"mechanisms",
"that",
"exist",
"to",
"counteract",
"it",
"(Box",
"2).",
"We",
"present",
"the",
"evidence",
"that",
"oxidative",
"stress",
"can",
"be",
"found",
"in",
"ne-",
"urodegenerative",
"disease.",
"Next",
"we",
"address",
"the",
"issue",
"of",
"whe-",
"ther",
"oxidative",
"stress",
"is",
"truly",
"pathogenic",
"in",
"disease",
"models.",
"In",
"order",
"to",
"prove",
"a",
"crucial",
"of",
"ROS,",
"it",
"is",
"necessary",
"to",
"observe",
"oxidative",
"stress",
"as",
"an",
"early",
"event",
"in",
"the",
"disease",
"process,",
"and",
"to",
"further",
"demonstrate",
"that",
"inhibition",
"of",
"ROS",
"production",
"is",
"able",
"to",
"prevent",
"the",
"pathogenic",
"process.",
"We",
"describe",
"the",
"evidence",
"from",
"animal",
"and",
"cellular",
"models",
"of",
"the",
"role",
"of",
"ROS",
"in",
"the",
"major",
"neurodegenerative",
"diseases.",
"We",
"present",
"hypotheses",
"for",
"the",
"interplay",
"between",
"oxidative",
"stress",
"and",
"selective",
"cell",
"death.",
"Finally",
"we",
"study",
"the",
"rationale",
"for",
"the",
"use",
"of",
"antioxidant",
"therapy",
"and",
"the",
"outcome",
"of",
"its",
"use",
"in",
"human",
"disease.",
"Although",
"oxidative",
"stress",
"has",
"been",
"implicated",
"in",
"a",
"range",
"of",
"chronic",
"neurodegenerative",
"disorders,",
"including",
"Alzheimer’s",
"disease,",
"Parkinson’s",
"disease,",
"Huntington’s",
"dis-",
"ease,",
"and",
"Amyotrophic",
"Lateral",
"Sclerosis,",
"the",
"two",
"commonest",
"of",
"these",
"diseases,",
"AD",
"and",
"PD,",
"will",
"be",
"discussed",
"in",
"detail"
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] | [
"W540–W543",
"Nucleic",
"Acids",
"Research,",
"2005,",
"Vol.",
"33,",
"Web",
"Server",
"issue",
"doi:10.1093/nar/gki478",
"YASS:",
"enhancing",
"the",
"sensitivity",
"of",
"DNA",
"similarity",
"search",
"Laurent",
"Noe´",
"*",
"and",
"Gregory",
"Kucherov",
"LORIA/INRIA-Lorraine,",
"615",
"rue",
"du",
"Jardin",
"Botanique,",
"54602",
"Villers-les-Nancy,",
"France",
"Received",
"March",
"23,",
"2005;",
"Accepted",
"April",
"15,",
"2005",
"ABSTRACT",
"YASS",
"is",
"a",
"DNA",
"local",
"alignment",
"tool",
"based",
"on",
"an",
"effi-",
"cient",
"and",
"sensitive",
"filtering",
"algorithm.",
"It",
"applies",
"transition-constrained",
"seeds",
"to",
"specify",
"the",
"most",
"probable",
"conserved",
"motifs",
"between",
"homologous",
"sequences,",
"combined",
"with",
"a",
"flexible",
"hit",
"criterion",
"used",
"to",
"identify",
"groups",
"of",
"seeds",
"that",
"are",
"likely",
"to",
"exhibit",
"significant",
"alignments.",
"A",
"web",
"interface",
"(http://www.loria.fr/projects/YASS/)",
"is",
"available",
"to",
"upload",
"input",
"sequences",
"in",
"fasta",
"format,",
"query",
"the",
"program",
"and",
"visualize",
"the",
"results",
"obtained",
"in",
"several",
"forms",
"(dot-plot,",
"tabular",
"output",
"and",
"others).",
"A",
"stan-",
"dalone",
"version",
"is",
"available",
"for",
"download",
"from",
"the",
"web",
"page.",
"INTRODUCTION",
"Modern",
"bioinformatics",
"relies",
"heavily",
"on",
"alignment",
"programs",
"and",
"motif",
"discovery",
"tools,",
"and",
"numerous",
"comparative",
"genomics",
"projects",
"need",
"ever",
"more",
"precise",
"and",
"faster",
"tools",
"for",
"comparing",
"two",
"or",
"several",
"genomic",
"sequences",
"with",
"differ-",
"ent",
"resolutions.",
"Except",
"for",
"small",
"sequences,",
"the",
"exact",
"local",
"alignment",
"algo-",
"rithm",
"of",
"Smith",
"and",
"Waterman",
"(1)",
"is",
"not",
"frequently",
"used,",
"and",
"most",
"alignments",
"are",
"obtained",
"using",
"heuristic",
"alignment",
"tools",
"such",
"as",
"FASTA",
"(2),",
"FLASH",
"(3),",
"BLAST",
"(4,5),",
"BLASTZ",
"(6)",
"and",
"PatternHunter",
"(7,8).",
"All",
"these",
"methods",
"introduce",
"a",
"trade-",
"off",
"between",
"two",
"competing",
"parameters:",
"selectivity",
"(or",
"speci-",
"ficity)",
"directly",
"affecting",
"the",
"speed",
"of",
"the",
"algorithm",
"and",
"sensitivity",
"affecting",
"its",
"precision",
"(i.e.",
"the",
"number",
"of",
"relevant",
"alignments",
"missed).",
"Achieving",
"a",
"good",
"trade-off",
"between",
"sens-",
"itivity",
"and",
"selectivity",
"is",
"the",
"key",
"issue",
"in",
"local",
"alignment",
"tools.",
"The",
"recently",
"introduced",
"spaced",
"seeds",
"technique",
"(7,8)",
"allows",
"an",
"increase",
"in",
"sensitivity",
"without",
"loss",
"in",
"selectivity.",
"This",
"innovation",
"triggered",
"various",
"studies",
"(9–15)",
"related",
"to",
"the",
"usage,",
"design",
"and",
"generalizations",
"of",
"spaced",
"seeds.",
"In",
"this",
"note,",
"we",
"present",
"YASS",
"(Yet",
"Another",
"Similarity",
"Searcher)—a",
"new",
"software",
"for",
"computing",
"local",
"alignments",
"of",
"two",
"DNA",
"sequences—and",
"its",
"web",
"server",
"(http://yass.",
"loria.fr/interface.php).",
"Compared",
"with",
"other",
"tools,",
"YASS",
"is",
"based",
"on",
"two",
"innovations.",
"The",
"first",
"is",
"a",
"new",
"spaced",
"seed",
"model",
"called",
"transition-constrained",
"seeds",
"that",
"takes",
"advantage",
"of",
"statistical",
"properties",
"of",
"real",
"genomic",
"sequences.",
"The",
"second",
"feature",
"is",
"a",
"new",
"statistically",
"founded",
"hit",
"criterion",
"that",
"controls",
"the",
"formation",
"of",
"groups",
"of",
"closely",
"located",
"seeds",
"that",
"are",
"likely",
"to",
"belong",
"to",
"the",
"same",
"alignment.",
"An",
"implementation",
"of",
"these",
"improvements,",
"reported",
"here,",
"provides",
"a",
"fast",
"and",
"sensitive",
"tool",
"for",
"local",
"alignment",
"of",
"large",
"genomic",
"sequences.",
"DESCRIPTION",
"Web",
"interface",
"The",
"main",
"user",
"input",
"(Figure",
"1A)",
"consists",
"of",
"one",
"or",
"two",
"sequences",
"in",
"fasta",
"format",
"either",
"chosen",
"from",
"a",
"predefined",
"database",
"or",
"uploaded",
"to",
"the",
"web",
"server.",
"Once",
"sequences",
"have",
"been",
"selected,",
"the",
"user",
"can",
"run",
"the",
"program",
"right",
"away",
"with",
"all",
"other",
"parameters",
"set",
"by",
"default.",
"Alternatively,",
"the",
"user",
"can",
"set",
"other",
"parameters",
"such",
"as",
"the",
"scoring",
"matrix",
"or",
"gap",
"penalties",
"(preselected",
"matrices",
"are",
"pro-",
"posed),",
"and",
"specify",
"the",
"DNA",
"strain",
"to",
"be",
"processed",
"(direct,",
"complementary",
"or",
"both).",
"The",
"user",
"can",
"also",
"choose",
"to",
"display",
"complete",
"alignments",
"rather",
"than",
"only",
"alignment",
"positions.",
"More",
"advanced",
"parameters",
"are",
"available",
"for",
"expert",
"users.",
"For",
"example,",
"the",
"right",
"choice",
"of",
"the",
"seed",
"pattern",
"can",
"increase",
"the",
"search",
"sensitivity",
"considerably",
"provided",
"that",
"some",
"knowledge",
"of",
"target",
"alignments",
"is",
"available",
"(10–14).",
"The",
"web",
"interface",
"provides",
"a",
"preselection",
"of",
"seeds",
"including",
"three",
"transition-constrained",
"seeds,",
"one",
"providing",
"a",
"good",
"perform-",
"ance",
"compromise",
"between",
"coding",
"and",
"non-coding",
"sequences,",
"and",
"the",
"other",
"two",
"tuned",
"respectively",
"for",
"non-coding",
"and",
"coding",
"regions.",
"The",
"accompanying",
"Hedera",
"program",
"(http://",
"www.loria.fr/projects/YASS/hedera.html)",
"is",
"also",
"provided",
"for",
"advanced",
"users",
"in",
"order",
"to",
"design",
"new",
"seed",
"patterns",
"according",
"to",
"different",
"probabilistic",
"models",
"of",
"alignments",
"(15).",
"Finally,",
"the",
"user",
"can",
"specify",
"some",
"statistical",
"parameters",
"of",
"target",
"alignments,",
"such",
"as",
"the",
"assumed",
"substitution",
"rate",
"or",
"indel",
"rate.",
"These",
"parameters",
"control",
"the",
"hit",
"criterion,",
"i.e.",
"the",
"rules",
"for",
"grouping",
"together",
"closely",
"located",
"seeds",
"to",
"detect",
"similarities.",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+33",
"3",
"83",
"59",
"30",
"11;",
"Fax:",
"+33",
"3",
"83",
"27",
"83",
"19;",
"Email:",
"Laurent.Noe@loria.fr",
"The",
"Author",
"2005.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"All",
"rights",
"reserved.",
"The",
"online",
"version",
"of",
"this",
"article",
"has",
"been",
"published",
"under",
"an",
"open",
"access",
"model.",
"Users",
"are",
"entitled",
"to",
"use,",
"reproduce,",
"disseminate,",
"or",
"display",
"the",
"open",
"access",
"version",
"of",
"this",
"article",
"for",
"non-commercial",
"purposes",
"provided",
"that:",
"the",
"original",
"authorship",
"is",
"properly",
"and",
"fully",
"attributed;",
"the",
"Journal",
"and",
"Oxford",
"University",
"Press",
"are",
"attributed",
"as",
"the",
"original",
"place",
"of",
"publication",
"with",
"the",
"correct",
"citation",
"details",
"given;",
"if",
"an",
"article",
"is",
"subsequently",
"reproduced",
"or",
"disseminated",
"not",
"in",
"its",
"entirety",
"but",
"only",
"in",
"part",
"or",
"as",
"a",
"derivative",
"work",
"this",
"must",
"be",
"clearly",
"indicated.",
"For",
"commercial",
"re-use,",
"please",
"contact",
"journals.permissions@oupjournals.org"
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] | [
"Acta",
"Neuropathol",
"(2011)",
"122:293–311",
"DOI",
"10.1007/s00401-011-0834-y",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"P",
"A",
"P",
"E",
"R",
"Vascular",
"b-amyloid",
"and",
"early",
"astrocyte",
"alterations",
"impair",
"cerebrovascular",
"function",
"and",
"cerebral",
"metabolism",
"in",
"transgenic",
"arcAb",
"mice",
"Mario",
"Merlini",
"•",
"Eric",
"P.",
"Meyer",
"•",
"Alexandra",
"Ulmann-Schuler",
"•",
"Roger",
"M.",
"Nitsch",
"Received:",
"10",
"December",
"2010",
"/",
"Revised:",
"11",
"April",
"2011",
"/",
"Accepted:",
"4",
"May",
"2011",
"/",
"Published",
"online:",
"19",
"June",
"2011",
"The",
"Author(s)",
"2011.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Cerebrovascular",
"lesions",
"related",
"to",
"congophilic",
"amyloid",
"angiopathy",
"(CAA)",
"often",
"accompany",
"deposition",
"of",
"b-amyloid",
"(Ab)",
"in",
"Alzheimer’s",
"disease",
"(AD),",
"leading",
"to",
"disturbed",
"cerebral",
"blood",
"flow",
"and",
"cognitive",
"dysfunction,",
"posing",
"the",
"question",
"how",
"cerebrovascular",
"pathology",
"con-",
"tributes",
"to",
"the",
"pathology",
"of",
"AD.",
"To",
"address",
"this",
"question,",
"we",
"characterised",
"the",
"morphology,",
"biochemistry",
"and",
"func-",
"tionality",
"of",
"brain",
"blood",
"vessels",
"in",
"transgenic",
"arctic",
"b-amyloid",
"(arcAb)",
"mice",
"expressing",
"human",
"amyloid",
"pre-",
"cursor",
"protein",
"(APP)",
"with",
"both",
"the",
"familial",
"AD-causing",
"Swedish",
"and",
"Arctic",
"mutations;",
"these",
"mice",
"are",
"characterised",
"by",
"strong",
"CAA",
"pathology.",
"Mice",
"were",
"analysed",
"at",
"early,",
"mid",
"and",
"late-stage",
"pathology.",
"Expression",
"of",
"the",
"glucose",
"transporter",
"GLUT1",
"at",
"the",
"blood–brain",
"barrier",
"(BBB)",
"was",
"significantly",
"decreased",
"and",
"paralleled",
"by",
"impaired",
"in",
"vivo",
"blood-to-brain",
"glucose",
"transport",
"and",
"reduced",
"cerebral",
"lac-",
"tate",
"release",
"during",
"neuronal",
"activation",
"from",
"mid-stage",
"pathology",
"onwards.",
"Reductions",
"in",
"astrocytic",
"GLUT1",
"and",
"lactate",
"transporters,",
"as",
"well",
"as",
"retraction",
"of",
"astrocyte",
"end-",
"feet",
"and",
"swelling",
"consistent",
"with",
"neurovascular",
"uncoupling,",
"preceded",
"wide-spread",
"b-amyloid",
"plaque",
"pathology.",
"We",
"M.",
"Merlini",
"(&)",
"R.",
"M.",
"Nitsch",
"(&)",
"Division",
"of",
"Psychiatry",
"Research,",
"University",
"of",
"Zu¨rich,",
"August",
"Forel-Strasse",
"1,",
"8008",
"Zurich,",
"Switzerland",
"e-mail:",
"mario.merlini@gladstone.ucsf.edu",
"R.",
"M.",
"Nitsch",
"e-mail:",
"nitsch@bli.uzh.ch",
"E.",
"P.",
"Meyer",
"A.",
"Ulmann-Schuler",
"Institute",
"of",
"Molecular",
"Life",
"Sciences,",
"University",
"of",
"Zu¨rich,",
"Winterthurerstrasse",
"190,",
"8057",
"Zurich,",
"Switzerland",
"Present",
"Address:",
"M.",
"Merlini",
"Gladstone",
"Institute",
"of",
"Neurological",
"Disease,",
"1650",
"Owens",
"Street,",
"San",
"Francisco,",
"CA",
"94158,",
"USA",
"show",
"that",
"CAA",
"at",
"later",
"disease",
"stages",
"is",
"accompanied",
"by",
"severe",
"morphological",
"alterations",
"of",
"brain",
"blood",
"vessels",
"including",
"stenoses,",
"BBB",
"leakages",
"and",
"the",
"loss",
"of",
"vascular",
"smooth",
"muscle",
"cells",
"(SMCs).",
"Together,",
"our",
"data",
"establish",
"that",
"cerebrovascular",
"and",
"astrocytic",
"pathology",
"are",
"paralleled",
"by",
"impaired",
"cerebral",
"metabolism",
"in",
"arcAb",
"mice,",
"and",
"that",
"astrocyte",
"alterations",
"occur",
"already",
"at",
"premature",
"stages",
"of",
"pathology,",
"suggesting",
"that",
"astrocyte",
"dysfunction",
"can",
"con-",
"tribute",
"to",
"early",
"behavioural",
"and",
"cognitive",
"impairments",
"seen",
"in",
"these",
"mice.",
"Keywords",
"Alzheimer’s",
"disease",
"Congophilic",
"amyloid",
"angiopathy",
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] | [
"Gagliardi",
"et",
"al.",
"Implementation",
"Science",
"2011,",
"6:26",
"http://www.implementationscience.com/content/6/1/26",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Implementation",
"Science",
"Open",
"Access",
"How",
"can",
"we",
"improve",
"guideline",
"use?",
"A",
"conceptual",
"framework",
"of",
"implementability",
"Anna",
"R",
"Gagliardi1*,",
"Melissa",
"C",
"Brouwers2,",
"Valerie",
"A",
"Palda3,",
"Louise",
"Lemieux-Charles4",
"and",
"Jeremy",
"M",
"Grimshaw5",
"Abstract",
"Background:",
"Guidelines",
"continue",
"to",
"be",
"underutilized,",
"and",
"a",
"variety",
"of",
"strategies",
"to",
"improve",
"their",
"use",
"have",
"been",
"suboptimal.",
"Modifying",
"guideline",
"features",
"represents",
"an",
"alternative,",
"but",
"untested",
"way",
"to",
"promote",
"their",
"use.",
"The",
"purpose",
"of",
"this",
"study",
"was",
"to",
"identify",
"and",
"define",
"features",
"that",
"facilitate",
"guideline",
"use,",
"and",
"examine",
"whether",
"and",
"how",
"they",
"are",
"included",
"in",
"current",
"guidelines.",
"Methods:",
"A",
"guideline",
"implementability",
"framework",
"was",
"developed",
"by",
"reviewing",
"the",
"implementation",
"science",
"literature.",
"We",
"then",
"examined",
"whether",
"guidelines",
"included",
"these,",
"or",
"additional",
"implementability",
"elements.",
"Data",
"were",
"extracted",
"from",
"publicly",
"available",
"high",
"quality",
"guidelines",
"reflecting",
"primary",
"and",
"institutional",
"care,",
"reviewed",
"independently",
"by",
"two",
"individuals,",
"who",
"through",
"discussion",
"resolved",
"conflicts,",
"then",
"by",
"the",
"research",
"team.",
"Results:",
"The",
"final",
"implementability",
"framework",
"included",
"22",
"elements",
"organized",
"in",
"the",
"domains",
"of",
"adaptability,",
"usability,",
"validity,",
"applicability,",
"communicability,",
"accommodation,",
"implementation,",
"and",
"evaluation.",
"Data",
"were",
"extracted",
"from",
"20",
"guidelines",
"on",
"the",
"management",
"of",
"diabetes,",
"hypertension,",
"leg",
"ulcer,",
"and",
"heart",
"failure.",
"Most",
"contained",
"a",
"large",
"volume",
"of",
"graded,",
"narrative",
"evidence,",
"and",
"tables",
"featuring",
"complementary",
"clinical",
"information.",
"Few",
"contained",
"additional",
"features",
"that",
"could",
"improve",
"guideline",
"use.",
"These",
"included",
"alternate",
"versions",
"for",
"different",
"users",
"and",
"purposes,",
"summaries",
"of",
"evidence",
"and",
"recommendations,",
"information",
"to",
"facilitate",
"interaction",
"with",
"and",
"involvement",
"of",
"patients,",
"details",
"of",
"resource",
"implications,",
"and",
"instructions",
"on",
"how",
"to",
"locally",
"promote",
"and",
"monitor",
"guideline",
"use.",
"There",
"were",
"no",
"consistent",
"trends",
"by",
"guideline",
"topic.",
"Conclusions:",
"Numerous",
"opportunities",
"were",
"identified",
"by",
"which",
"guidelines",
"could",
"be",
"modified",
"to",
"support",
"various",
"types",
"of",
"decision",
"making",
"by",
"different",
"users.",
"New",
"governance",
"structures",
"may",
"be",
"required",
"to",
"accommodate",
"development",
"of",
"guidelines",
"with",
"these",
"features.",
"Further",
"research",
"is",
"needed",
"to",
"validate",
"the",
"proposed",
"framework",
"of",
"guideline",
"implementability,",
"develop",
"methods",
"for",
"preparing",
"this",
"information,",
"and",
"evaluate",
"how",
"inclusion",
"of",
"this",
"information",
"influences",
"guideline",
"use.",
"Background",
"Guidelines",
"are",
"syntheses",
"of",
"best",
"available",
"evidence",
"that",
"support",
"decision",
"making",
"by",
"clinicians,",
"managers,",
"and",
"policy",
"makers",
"about",
"the",
"organization",
"and",
"delivery",
"of",
"healthcare,",
"but",
"continue",
"to",
"be",
"underused.",
"Numerous",
"population-based",
"studies",
"demonstrate",
"low",
"compliance",
"with",
"guidelines",
"produced",
"by",
"prominent",
"government",
"and",
"professional",
"agencies",
"for",
"chronic",
"and",
"acute",
"conditions",
"[1-7].",
"It",
"has",
"been",
"proposed",
"that",
"for",
"a",
"condition",
"such",
"as",
"cancer,",
"a",
"third",
"of",
"cases",
"could",
"be",
"prevented,",
"another",
"*",
"Correspondence:",
"anna.gagliardi@uhnresearch.ca",
"1Departments",
"of",
"Surgery;",
"and",
"Department",
"of",
"Health",
"Policy,",
"Management",
"and",
"Evaluation;",
"and",
"Institute",
"of",
"Medical",
"Science,",
"Faculty",
"of",
"Medicine,",
"University",
"of",
"Toronto,",
"Toronto,",
"Ontario,",
"Canada",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"third",
"cured,",
"and",
"the",
"remainder",
"effectively",
"treated",
"if",
"management",
"consistently",
"complied",
"with",
"existing",
"guide-",
"lines",
"[8].",
"Thus,",
"it",
"is",
"imperative",
"that",
"we",
"better",
"implement",
"guidelines.",
"Many",
"existing",
"implementation",
"strategies",
"have",
"limited",
"effectiveness",
"and",
"are",
"not",
"routinely",
"applied",
"outside",
"of",
"experimental",
"research",
"due",
"to",
"their",
"cost",
"and",
"complexity",
"[9-18].",
"As",
"a",
"result",
"many",
"guidelines",
"are",
"passively",
"distrib-",
"uted",
"[19-21].",
"Surveys",
"of",
"international",
"guideline",
"develo-",
"pers",
"found",
"that",
"few",
"developers",
"implemented",
"their",
"own",
"guidelines,",
"had",
"dedicated",
"implementation",
"staff,",
"or",
"evalu-",
"ated",
"use",
"of",
"their",
"guidelines,",
"and",
"many",
"believed",
"that",
"tar-",
"get",
"users",
"should",
"be",
"responsible",
"for",
"implementation",
"[22-25].",
"Accountability",
"for",
"guideline",
"implementation",
"may",
"differ",
"by",
"jurisdiction",
"and",
"organization",
"depending",
"©",
"2011",
"Gagliardi",
"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."
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"Trop",
"Anim",
"Health",
"Prod",
"(2010)",
"42:1705–1710",
"DOI",
"10.1007/s11250-010-9623-1",
"ORIGINAL",
"RESEARCH",
"Feed",
"intake",
"and",
"production",
"parameters",
"of",
"lactating",
"crossbred",
"cows",
"fed",
"maize-based",
"diets",
"of",
"stover,",
"silage",
"or",
"quality",
"protein",
"silage",
"Efrem",
"Gebrehawariat",
"&",
"Berhan",
"Tamir",
"&",
"Azage",
"Tegegne",
"Accepted:",
"13",
"June",
"2010",
"/",
"Published",
"online:",
"25",
"June",
"2010",
"#",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Thirty-six",
"Boran",
"×",
"Friesian",
"dairy",
"cows",
"(392",
"±",
"12",
"kg;",
"mean",
"±",
"SD)",
"in",
"early",
"parity",
"were",
"used",
"in",
"a",
"randomised",
"complete",
"block",
"design.",
"Cows",
"were",
"blocked",
"by",
"parity",
"into",
"three",
"blocks",
"of",
"12",
"animals",
"and",
"offered",
"normal",
"maize",
"(NM)",
"stover",
"(T1),",
"NM",
"silage",
"(T2)",
"or",
"quality",
"protein",
"maize",
"(QPM)",
"silage",
"(T3)",
"basal",
"diets",
"supplemented",
"with",
"a",
"similar",
"concentrate",
"mix.",
"Feed",
"intake,",
"body",
"weight",
"and",
"condition",
"changes",
"and",
"milk",
"yield",
"and",
"composition",
"were",
"assessed.",
"The",
"daily",
"intake",
"of",
"DM,",
"OM,",
"NDF",
"and",
"ADF",
"for",
"cows",
"fed",
"the",
"NM",
"stover-based",
"diet",
"was",
"higher",
"(P<",
"0.05)",
"than",
"for",
"the",
"cows",
"fed",
"the",
"NM",
"silage",
"and",
"QPM",
"silage-based",
"diets.",
"However,",
"the",
"daily",
"intake",
"of",
"DOM",
"(9.3",
"kg)",
"and",
"ME",
"(140.8",
"MJ)",
"for",
"cows",
"on",
"QPM",
"silage-based",
"diet",
"was",
"higher",
"(P<",
"0.05)",
"than",
"for",
"cows",
"on",
"NM",
"stover-",
"based",
"diet",
"(8.4",
"kg",
"and",
"124.2",
"MJ)",
"and",
"NM",
"silage-based",
"diet",
"(7.9",
"kg",
"and",
"119.1",
"MJ).",
"Body",
"weight",
"of",
"cows",
"was",
"affected",
"(P<",
"0.05)",
"by",
"the",
"diet,",
"but",
"diet",
"had",
"no",
"effect",
"(P>",
"0.05)",
"on",
"body",
"condition",
"score,",
"milk",
"yield",
"and",
"milk",
"composition.",
"The",
"digestible",
"organic",
"matter",
"in",
"the",
"NM",
"stover-based",
"diet",
"(724",
"g/kg",
"DM)",
"was",
"lower",
"(P<",
"0.05)",
"than",
"that",
"in",
"the",
"NM",
"(770",
"g/kg",
"DM)",
"and",
"QPM",
"silage-based",
"diet",
"(762",
"g/kg",
"DM).",
"It",
"was",
"concluded",
"that",
"the",
"performances",
"of",
"the",
"cows",
"on",
"the",
"NM",
"silage",
"and",
"QPM",
"silage",
"diets",
"were",
"similar",
"and",
"were",
"not",
"superior",
"to",
"that",
"of",
"the",
"NM",
"stover-based",
"diet.",
"E.",
"Gebrehawariat",
"Faculty",
"of",
"Agriculture,",
"Wellega",
"University,",
"Nekemte,",
"Ethiopia",
"B.",
"Tamir",
"(*)",
"Faculty",
"of",
"Veterinary",
"Medicine,",
"Addis",
"Ababa",
"University,",
"P.O.",
"Box",
"34,",
"Debre-Zeit,",
"Ethiopia",
"e-mail:",
"berhantamir@yahoo.com",
"A.",
"Tegegne",
"International",
"Livestock",
"Research",
"Institute,",
"Addis",
"Ababa,",
"Ethiopia",
"Keywords",
"Body",
"condition",
"score",
".",
"Body",
"weight",
"change",
".",
"Feed",
"intake",
".",
"Production",
"parameter",
".",
"Quality",
"protein",
"maize",
"silage",
".",
"Normal",
"maize",
"stover",
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"ADF",
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"detergent",
"fibre",
"CP",
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"protein",
"DM",
"Dry",
"matter",
"DOM",
"Digestible",
"organic",
"matter",
"NDF",
"Neutral",
"detergent",
"fibre",
"NM",
"Normal",
"maize",
"QPM",
"Quality",
"protein",
"maize",
"Introduction",
"The",
"major",
"constraint",
"to",
"cattle",
"production",
"in",
"Ethiopia",
"is",
"nutrition.",
"Cattle",
"are",
"predominantly",
"fed",
"on",
"natural",
"pastures",
"and",
"crop",
"residues.",
"However,",
"due",
"to",
"rising",
"human",
"popula-",
"tion,",
"traditional",
"grazing",
"lands",
"are",
"widely",
"being",
"converted",
"to",
"croplands,",
"forcing",
"cattle",
"to",
"graze",
"on",
"marginal",
"and",
"over-",
"grazed",
"lands",
"with",
"poor",
"quality",
"forge",
"(Kitaba",
"and",
"Tamir",
"2007).",
"Maize",
"is",
"a",
"major",
"source",
"of",
"food",
"for",
"millions",
"of",
"poor",
"Africans.",
"According",
"to",
"CIMMYT",
"(2000),",
"three",
"systems",
"of",
"maize",
"utilisation",
"as",
"food/feed",
"can",
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"envisaged.",
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"the",
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"grain",
"maturity",
"and",
"using",
"the",
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"for",
"human",
"consumption",
"while",
"the",
"stover",
"is",
"used",
"as",
"livestock",
"feed—this",
"is",
"the",
"most",
"common",
"use",
"of",
"maize",
"in",
"developing",
"countries;",
"second,",
"harvesting",
"the",
"plant",
"at",
"the",
"dent",
"stage,",
"marketing",
"the",
"ears",
"for",
"human",
"consumption",
"and",
"using",
"the",
"greener",
"forage",
"as",
"feed;",
"third,",
"harvesting",
"the",
"whole",
"plant",
"at",
"the",
"dent",
"stage",
"and",
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"it",
"as",
"livestock",
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] | [
"Dynamic",
"Medicine",
"Research",
"A",
"new",
"evaluation",
"method",
"for",
"+Gz",
"tolerance",
"with",
"loratadine",
"by",
"using",
"a",
"near-infrared",
"spectroscopy",
"Akihiko",
"Onozawa†,",
"Azusa",
"Kikukawa†",
"and",
"Yoshinori",
"Miyamoto*",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Aeromedical",
"Laboratory,",
"Japan",
"Air",
"Self-Defense",
"Force,",
"Tachikawa,",
"Tokyo,",
"Japan",
"Email:",
"Akihiko",
"Onozawa",
"-",
"akihikoonozawa@ybb.ne.jp;",
"Azusa",
"Kikukawa",
"-",
"kikukawa4232@inet.asdf.mod.go.jp;",
"Yoshinori",
"Miyamoto*",
"-",
"ymiyamo@rivo.mediatti.net",
"*",
"Corresponding",
"author",
"†Equal",
"contributors",
"Published:",
"28",
"January",
"2008",
"Dynamic",
"Medicine",
"2008,",
"7:3",
"doi:10.1186/1476-5918-7-3",
"This",
"article",
"is",
"available",
"from:",
"http://www.dynamic-med.com/content/7/1/3",
"Received:",
"19",
"October",
"2007",
"Accepted:",
"28",
"January",
"2008",
"©",
"2008",
"Onozawa",
"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:",
"Loratadine",
"(Claritin®),",
"an",
"over",
"the",
"counter",
"antihistamine",
"in",
"U.S.",
"and",
"UK,",
"is",
"acceptable",
"for",
"use",
"without",
"adverse",
"side",
"effects",
"by",
"aircrew",
"with",
"mild",
"or",
"moderate",
"allergic",
"or",
"other",
"situations",
"requiring",
"an",
"antihistamine.",
"Although",
"+Gz",
"(head",
"to",
"foot",
"direction)",
"tolerance",
"testing",
"for",
"aircrew",
"with",
"loratadine",
"has",
"not",
"been",
"documented",
"in",
"the",
"published",
"literature,",
"it",
"is",
"commonly",
"accepted",
"that",
"loratadine",
"dose",
"not",
"effect",
"+Gz",
"tolerance.",
"The",
"purpose",
"of",
"this",
"study",
"was",
"to",
"offer",
"and",
"validate",
"a",
"new",
"evaluation",
"method",
"for",
"+Gz",
"tolerance",
"testing",
"with",
"loratadine",
"by",
"using",
"a",
"near-infrared",
"spectroscopy",
"(NIRS).",
"Methods:",
"A",
"double-blind,",
"placebo-controlled,",
"randomized,",
"crossover",
"protocol",
"was",
"used",
"to",
"administer",
"10",
"mg",
"of",
"loratadine",
"or",
"placebo",
"in",
"nine",
"healthy",
"subjects.",
"The",
"subjects",
"didn't",
"wear",
"anti-G",
"suit.",
"The",
"+Gz",
"exposure",
"profiles",
"consisted",
"of,",
"in",
"series,",
"a",
"gradual",
"onset",
"ran",
"(0.1",
"G·sec-1)",
"to",
"the",
"subject's",
"visual",
"end-point",
"(peripheral",
"light",
"loss)",
"or",
"loss",
"of",
"consciousness",
"(GLOC),",
"and",
"rapid",
"onset",
"run",
"(1.0",
"G·sec-1)",
"to",
"the",
"subject's",
"same",
"end-point.",
"In",
"this",
"study,",
"G-level",
"tolerance",
"was",
"defined",
"as",
"the",
"+Gz",
"level",
"at",
"visual",
"end-point",
"and/or",
"at",
"GLOC.",
"As",
"a",
"subject's",
"G-duration",
"tolerance,",
"we",
"measured",
"the",
"total",
"time",
"(seconds)",
"during",
"rapid",
"onset",
"run.",
"Otherwise,",
"to",
"confirm",
"the",
"effect",
"of",
"loratadine",
"on",
"+Gz",
"tolerance,",
"we",
"measured",
"the",
"cerebral",
"NIRS",
"variables",
"(hemoglobin",
"concentration",
"changes",
"and",
"tissue",
"oxygenation",
"index)",
"as",
"a",
"new",
"quantitative",
"method",
"for",
"+Gz",
"tolerance",
"during",
"a",
"centrifuge",
"experiments.",
"Results:",
"No",
"significant",
"differences",
"were",
"observed",
"in",
"+Gz",
"tolerance",
"(+Gz",
"level,",
"duration",
"time",
"and",
"NIRS",
"variables)",
"between",
"subjects",
"taking",
"loratadine",
"and",
"placebo.",
"Conclusion:",
"Our",
"results",
"demonstrate",
"that",
"loratadine",
"has",
"no",
"detectable",
"effect",
"on",
"+Gz",
"tolerance",
"by",
"using",
"a",
"new",
"method",
"with",
"cerebral",
"NIRS",
"variables",
"and",
"the",
"traditional",
"method",
"with",
"+Gz",
"level",
"and",
"duration",
"time.",
"This",
"study",
"represents",
"the",
"first",
"use",
"of",
"a",
"quantitative",
"parameter",
"such",
"as",
"cerebral",
"NIRS",
"variables",
"to",
"assess",
"the",
"effects",
"of",
"a",
"drug",
"on",
"acceleration",
"tolerance.",
"Background",
"Older",
"first-generation",
"antihistamines,",
"such",
"as",
"diphenhy-",
"dramine",
"and",
"chlorpheniramine,",
"are",
"unsuitable",
"for",
"use",
"by",
"aircrew",
"during",
"flight",
"duties",
"due",
"to",
"their",
"well-documented",
"sedating",
"side",
"effects.",
"Loratadine",
"(Claritin®)",
"is",
"a",
"newer,",
"sec-",
"ond-generation",
"antihistamine",
"available",
"over-the-counter",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Gatherer",
"BMC",
"Systems",
"Biology",
"2010,",
"4:22",
"http://www.biomedcentral.com/1752-0509/4/22",
"C",
"O",
"R",
"R",
"E",
"S",
"P",
"O",
"N",
"D",
"E",
"N",
"C",
"E",
"Open",
"Access",
"So",
"what",
"do",
"we",
"really",
"mean",
"when",
"we",
"say",
"that",
"systems",
"biology",
"is",
"holistic?",
"Derek",
"Gatherer",
"Abstract",
"Background:",
"An",
"old",
"debate",
"has",
"undergone",
"a",
"resurgence",
"in",
"systems",
"biology:",
"that",
"of",
"reductionism",
"versus",
"holism.",
"At",
"least",
"35",
"articles",
"in",
"the",
"systems",
"biology",
"literature",
"since",
"2003",
"have",
"touched",
"on",
"this",
"issue.",
"The",
"histories",
"of",
"holism",
"and",
"reductionism",
"in",
"the",
"philosophy",
"of",
"biology",
"are",
"reviewed,",
"and",
"the",
"current",
"debate",
"in",
"systems",
"biology",
"is",
"placed",
"in",
"context.",
"Results:",
"Inter-theoretic",
"reductionism",
"in",
"the",
"strict",
"sense",
"envisaged",
"by",
"its",
"creators",
"from",
"the",
"1930s",
"to",
"the",
"1960s",
"is",
"largely",
"impractical",
"in",
"biology,",
"and",
"was",
"effectively",
"abandoned",
"by",
"the",
"early",
"1970s",
"in",
"favour",
"of",
"a",
"more",
"piecemeal",
"approach",
"using",
"individual",
"reductive",
"explanations.",
"Classical",
"holism",
"was",
"a",
"stillborn",
"theory",
"of",
"the",
"1920s,",
"but",
"the",
"term",
"survived",
"in",
"several",
"fields",
"as",
"a",
"loose",
"umbrella",
"designation",
"for",
"various",
"kinds",
"of",
"anti-reductionism",
"which",
"often",
"differ",
"markedly.",
"Several",
"of",
"these",
"different",
"anti-reductionisms",
"are",
"on",
"display",
"in",
"the",
"holistic",
"rhetoric",
"of",
"the",
"recent",
"systems",
"biology",
"literature.",
"This",
"debate",
"also",
"coincides",
"with",
"a",
"time",
"when",
"interesting",
"arguments",
"are",
"being",
"proposed",
"within",
"the",
"philosophy",
"of",
"biology",
"for",
"a",
"new",
"kind",
"of",
"reductionism.",
"Conclusions:",
"Engaging",
"more",
"deeply",
"with",
"these",
"issues",
"should",
"sharpen",
"our",
"ideas",
"concerning",
"the",
"philosophy",
"of",
"systems",
"biology",
"and",
"its",
"future",
"best",
"methodology.",
"As",
"with",
"previous",
"decisive",
"moments",
"in",
"the",
"history",
"of",
"biology,",
"only",
"those",
"theories",
"that",
"immediately",
"suggest",
"relatively",
"easy",
"experiments",
"will",
"be",
"winners.",
"Introduction",
"An",
"old",
"debate",
"has",
"made",
"a",
"surprising,",
"or",
"perhaps",
"not",
"so",
"surprising,",
"reappearance",
"in",
"systems",
"biology:",
"that",
"of",
"reductionism",
"versus",
"holism.",
"Surprising:",
"in",
"the",
"sense",
"that",
"the",
"mainstream",
"of",
"molecular",
"biology",
"has",
"for",
"at",
"least",
"30",
"years",
"been",
"relatively",
"uninterested",
"in",
"the",
"matter,",
"content",
"with",
"a",
"compromise",
"that",
"allows",
"lab",
"work",
"to",
"proceed",
"without",
"too",
"much",
"philosophical",
"agonizing.",
"Unsurprising:",
"in",
"that",
"general",
"systems",
"theory",
"has",
"churned",
"with",
"the",
"debate",
"for",
"nearly",
"75",
"years.",
"Once",
"systems",
"theory",
"met",
"molecular",
"biology,",
"it",
"was",
"probably",
"only",
"a",
"matter",
"of",
"time",
"before",
"the",
"controversy",
"went",
"pandemic.",
"At",
"least",
"35",
"arti-",
"cles",
"in",
"the",
"systems",
"biology",
"literature",
"from",
"2003",
"to",
"the",
"early",
"part",
"of",
"2009",
"touched",
"on",
"this",
"issue",
"[1-35].",
"How-",
"ever,",
"much",
"confusion",
"is",
"apparent",
"in",
"the",
"variation",
"in",
"what",
"is",
"understood",
"by",
"the",
"term",
"holistic,",
"and",
"also",
"from",
"overstatements",
"as",
"to",
"the",
"degree",
"that",
"“traditional”",
"mole-",
"cular",
"biology",
"is",
"truly",
"reductionist.",
"Some",
"of",
"the",
"systems",
"biology",
"articles",
"give",
"the",
"impression",
"that",
"this",
"is",
"the",
"first",
"Correspondence:",
"d.gatherer@mrcvu.gla.ac.uk",
"MRC",
"Virology",
"Unit,",
"Institute",
"of",
"Virology,",
"University",
"of",
"Glasgow,",
"Church",
"Street,",
"Glasgow",
"G11",
"5JR,",
"UK",
"time",
"this",
"argument",
"has",
"arisen,",
"but",
"we",
"have",
"been",
"here",
"before",
"on",
"several",
"occasions.",
"The",
"reductionist-holist",
"debate",
"emerged",
"in",
"biology",
"in",
"the",
"1920s",
"out",
"of",
"the",
"ear-",
"lier",
"disputes",
"between",
"mechanists",
"and",
"vitalists,",
"and",
"between",
"neo-Darwinians",
"and",
"neo-Lamarckians,",
"although",
"it",
"should",
"not",
"be",
"thought",
"that",
"all",
"the",
"corresponding",
"terms",
"on",
"the",
"left",
"or",
"right",
"sides",
"of",
"each",
"pair",
"are",
"in",
"any",
"way",
"necessarily",
"equivalent.",
"One",
"would",
"not",
"expect",
"any",
"aspiring",
"modern",
"holist",
"within",
"the",
"systems",
"biology",
"com-",
"munity",
"to",
"be",
"a",
"vitalist",
"or",
"a",
"neo-Lamarckian.",
"Neverthe-",
"less,",
"broadly",
"speaking,",
"it",
"is",
"possible",
"to",
"see",
"general",
"continuities",
"that",
"allow",
"one",
"to",
"posit",
"what",
"might",
"be",
"called",
"mechanist-Darwinian-reductionist",
"and",
"vitalist-Lamarck-",
"ian-holist",
"lineages,",
"respectively,",
"and",
"an",
"understanding",
"of",
"how",
"these",
"debates",
"unfolded",
"serves",
"to",
"illuminate",
"how",
"any",
"modern",
"reductionist-holist",
"conversation",
"within",
"sys-",
"tems",
"biology",
"may",
"develop.",
"Those",
"systems",
"biologists",
"who",
"see",
"themselves",
"as",
"holists",
"need",
"to",
"know",
"what",
"kind",
"of",
"holists",
"they",
"are.",
"Then",
"they",
"can",
"be",
"more",
"explicit",
"about",
"what",
"aspects",
"of",
"reductionism",
"they",
"are",
"opposed",
"to.",
"Many",
"holistically",
"inclined",
"systems",
"biologists",
"seem",
"to",
"be",
"arguing",
"against",
"a",
"classical",
"and",
"now",
"rather",
"outdated",
"©",
"2010",
"Gatherer;",
"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."
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] | [
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"4-[1-(4-Hydroxy-3-methoxybenzyl)-1H-",
"benzimidazol-2-yl]-2-methoxyphenol",
"Zuo-an",
"Xiao,*",
"Tao",
"Gao,",
"Fa-jun",
"Huang",
"and",
"Ting-ting",
"Jiang",
"School",
"of",
"Chemical",
"Engineering",
"and",
"Food",
"Science,",
"Xiangfan",
"University,",
"Xiangfan",
"441053,",
"People’s",
"Republic",
"of",
"China",
"Correspondence",
"e-mail:",
"blueice8250@yahoo.com.cn",
"Received",
"17",
"October",
"2011;",
"accepted",
"23",
"October",
"2011",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"298",
"K;",
"mean",
"(C–C)",
"=",
"0.002",
"A˚;",
"R",
"factor",
"=",
"0.058;",
"wR",
"factor",
"=",
"0.154;",
"data-to-parameter",
"ratio",
"=",
"17.7.",
"In",
"the",
"title",
"molecule,",
"C22H20N2O4,",
"the",
"dihedral",
"angles",
"between",
"the",
"benzimidazole",
"ring",
"system",
"and",
"the",
"benzene",
"rings",
"are",
"44.26",
"(2)",
"and",
"82.91",
"(2)",
".",
"Intramolecular",
"O—H",
"O",
"hydrogen",
"bonds",
"occur.",
"In",
"the",
"crystal,",
"O—H",
"N",
"and",
"O—H",
"O",
"hydrogen",
"bonds",
"connect",
"the",
"molecules",
"into",
"a",
"two-dimension",
"network",
"parallel",
"to",
"(102)",
"and",
"weak",
"intermolecular",
"C—H",
"O",
"hydrogen",
"bonds",
"complete",
"the",
"formation",
"of",
"a",
"three-dimen-",
"sional",
"network.",
"Related",
"literature",
"For",
"the",
"biological",
"appications",
"of",
"benzimidazole",
"compounds,",
"see:",
"Santoro",
"et",
"al.",
"(2000);",
"Sundberg",
"et",
"al.",
"(1977).",
"For",
"related",
"structures,",
"see:",
"Li",
"et",
"al.",
"(2005);",
"Liu",
"et",
"al.",
"(2003);",
"Xi",
"et",
"al.",
"(2006).",
"Experimental",
"Crystal",
"data",
"C22H20N2O4",
"Mr",
"=",
"376.40",
"Monoclinic,",
"P21=c",
"a",
"=",
"7.9717",
"(9)",
"A˚",
"b",
"=",
"16.4327",
"(19)",
"A˚",
"c",
"=",
"14.3560",
"(16)",
"A˚",
"=",
"95.133",
"(2)",
"V",
"=",
"1873.0",
"(4)",
"A˚3",
"Z",
"=",
"4",
"Mo",
"K",
"radiation",
"organic",
"compounds",
"=",
"0.09",
"mm",
"1",
"T",
"=",
"298",
"K",
"Data",
"collection",
"Bruker",
"SMART",
"CCD",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(SADABS;",
"Sheldrick,",
"1996)",
"Tmin",
"=",
"0.966,",
"Tmax",
"=",
"0.983",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.058",
"wR(F",
"2)",
"=",
"0.154",
"S",
"=",
"1.06",
"4625",
"reflections",
"261",
"parameters",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"D—H",
"A",
"O4—H4A",
"O1—H1A",
"O4—H4A",
"O1—H1A",
"C15—H15B",
"O3",
"O2",
"N2i",
"O4ii",
"O4iii",
"D—H",
"0.89",
"(2)",
"0.85",
"(3)",
"0.89",
"(2)",
"0.85",
"(3)",
"0.97",
"0.20",
"0.20",
"0.20",
"mm",
"14067",
"measured",
"reflections",
"4625",
"independent",
"reflections",
"3718",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.064",
"H",
"atoms",
"treated",
"by",
"a",
"mixture",
"of",
"independent",
"and",
"constrained",
"refinement",
"max",
"=",
"0.30",
"e",
"A˚",
"3",
"min",
"=",
"0.23",
"e",
"A˚",
"3",
"H",
"A",
"2.25",
"(2)",
"2.22",
"(3)",
"1.90",
"(2)",
"2.07",
"(3)",
"2.59",
"D",
"A",
"2.6598",
"(18)",
"2.6631",
"(18)",
"2.7671",
"(18)",
"2.7934",
"(17)",
"3.402",
"(2)",
"D—H",
"A",
"108.0",
"(18)",
"113",
"(2)",
"165",
"(2)",
"143",
"(2)",
"141",
"Symmetry",
"codes:",
"(i)",
"x",
"þ",
"1;",
"y",
"þ",
"12;",
"z",
"þ",
"12;",
"(ii)",
"x;",
"y",
"þ",
"21;",
"z",
"12.",
"x",
"þ",
"2;",
"y",
"12;",
"z",
"þ",
"32;",
"(iii)",
"Data",
"collection:",
"SMART",
"(Bruker,",
"2001);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2001);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"PLATON",
"(Spek,",
"2009);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"SHELXTL",
"(Sheldrick,",
"2008).",
"The",
"authors",
"are",
"grateful",
"to",
"the",
"Science",
"Technology",
"Research",
"Programme",
"of",
"the",
"Education",
"Office",
"of",
"Hubei",
"Province",
"(grant",
"No.",
"Q20092503)",
"for",
"financial",
"support.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"LH5356).",
"References",
"Bruker",
"(2001).",
"SAINT",
"and",
"SMART.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Li,",
"J.,",
"Meng,",
"X.-G.",
"&",
"Liao,",
"Z.-R.",
"(2005).",
"Acta",
"Cryst.",
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"o3421–o3423.",
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"Ma,",
"J.-F.,",
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"N.-H.",
"&",
"Jia,",
"H.-Q.",
"(2003).",
"Acta",
"Cryst.",
"E59,",
"m361–",
"m363.",
"Santoro,",
"S.",
"W.,",
"Joyce,",
"G.",
"F.,",
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"A64,",
"112–122.",
"Spek,",
"A.",
"L.",
"(2009).",
"Acta",
"Cryst.",
"D65,",
"148–155.",
"Sundberg,",
"R.",
"J.,",
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"&",
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"(2006).",
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"64,",
"1183–1188.",
"Acta",
"Cryst.",
"(2011).",
"E67,",
"o3087",
"doi:10.1107/S1600536811043935",
"Xiao",
"et",
"al.",
"o3087"
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] | [
"BMC",
"Psychiatry",
"Research",
"article",
"The",
"factor",
"structure",
"and",
"reliability",
"of",
"the",
"Illness",
"Attitude",
"Scales",
"in",
"a",
"student",
"and",
"a",
"patient",
"sample",
"Alexander",
"Crössmann*",
"and",
"Paul",
"Pauli",
"Address:",
"Department",
"of",
"Psychology",
"I,",
"University",
"of",
"Wuerzburg,",
"Marcusstr.",
"9-11,",
"97070",
"Wuerzburg,",
"Germany",
"Email:",
"Alexander",
"Crössmann*",
"-",
"alexander@croessmann.org;",
"Paul",
"Pauli",
"-",
"pauli@psychologie.uni-wuerzburg.de",
"*",
"Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"26",
"October",
"2006",
"BMC",
"Psychiatry",
"2006,",
"6:46",
"doi:10.1186/1471-244X-6-46",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-244X/6/46",
"Received:",
"05",
"May",
"2006",
"Accepted:",
"26",
"October",
"2006",
"©",
"2006",
"Crössmann",
"and",
"Pauli;",
"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",
"Illness",
"Attitude",
"Scales",
"(IAS),",
"designed",
"by",
"Kellner",
"in",
"1986,",
"assesses",
"fears,",
"beliefs,",
"and",
"attitudes",
"associated",
"with",
"hypochondriasis",
"and",
"abnormal",
"illness",
"behaviour.",
"However,",
"its",
"factor",
"structure",
"is,",
"especially",
"for",
"translations",
"of",
"the",
"IAS,",
"not",
"sufficiently",
"explored.",
"Thus,",
"the",
"present",
"Study",
"aimed",
"to",
"analyse",
"the",
"factor",
"structure",
"of",
"the",
"IAS",
"in",
"a",
"German",
"student",
"and",
"a",
"patient",
"population",
"using",
"exploratory",
"factor",
"analysis.",
"Methods:",
"A",
"mixed",
"student",
"(N",
"=",
"296)",
"and",
"a",
"mixed",
"patient",
"(N",
"=",
"130)",
"sample",
"completed",
"the",
"IAS.",
"The",
"data",
"was",
"submitted",
"to",
"principal",
"components",
"analyses",
"(PCA)",
"with",
"subsequent",
"oblique",
"rotations.",
"From",
"identified",
"factor",
"structures,",
"scales",
"were",
"derived",
"and",
"submitted",
"to",
"reliability",
"analyses",
"as",
"well",
"as",
"to",
"a",
"preliminary",
"validity",
"analysis.",
"Results:",
"The",
"PCA",
"revealed",
"a",
"four-factor",
"solution",
"in",
"the",
"student",
"sample:",
"(1)",
"fear",
"of",
"illness",
"and",
"death;",
"(2)",
"treatment",
"experience;",
"(3)",
"hypochondriacal",
"beliefs;",
"and",
"(4)",
"effect",
"of",
"symptoms.",
"In",
"the",
"patient",
"sample,",
"the",
"data",
"was",
"best",
"explained",
"by",
"a",
"two-factor",
"solution:",
"(1)",
"health",
"related",
"anxiety",
"and",
"(2)",
"effect",
"of",
"symptoms",
"and",
"treatment",
"experience.",
"All",
"scales",
"reached",
"good",
"to",
"acceptable",
"reliability",
"coefficients.",
"The",
"scales",
"derived",
"from",
"the",
"student",
"sample",
"and",
"those",
"derived",
"from",
"the",
"patient",
"sample",
"were",
"able",
"to",
"distinguish",
"between",
"pain",
"patients",
"and",
"a",
"matched",
"group",
"of",
"normal",
"controls.",
"Conclusion:",
"Our",
"data",
"suggests",
"that",
"the",
"IAS",
"is",
"in",
"student",
"samples",
"best",
"represented",
"by",
"a",
"four",
"factor-solution",
"and",
"in",
"patient",
"samples",
"by",
"a",
"two-factor-solution.",
"Background",
"Hypochondriasis",
"as",
"described",
"in",
"DSM-IV",
"is",
"a",
"mental",
"dis-",
"order",
"characterized",
"by",
"excessive",
"fear",
"of",
"or",
"preoccupation",
"with",
"a",
"serious",
"illness,",
"despite",
"medical",
"testing",
"and",
"reassur-",
"ance",
"to",
"the",
"contrary",
"[1].",
"In",
"primary",
"care",
"users",
"its",
"preva-",
"lence",
"is",
"estimated",
"at",
"3%",
"[2].",
"The",
"disorder",
"can",
"significantly",
"interfere",
"with",
"an",
"individual's",
"functioning",
"and",
"can",
"be",
"very",
"costly",
"to",
"the",
"health",
"care",
"system",
"when",
"it",
"results",
"in",
"high",
"lev-",
"els",
"of",
"medical",
"services",
"utilization.",
"To",
"detect",
"hypochon-",
"driasis",
"in",
"an",
"early",
"stage,",
"it",
"is",
"very",
"important",
"that",
"self-report",
"questionnaires",
"are",
"developed",
"and",
"thoroughly",
"evaluated.",
"One",
"of",
"the",
"most",
"popular",
"self-report",
"measures",
"of",
"hypo-",
"chondriasis",
"is",
"the",
"Illness",
"Attitude",
"Scales",
"(IAS)",
"by",
"Kellner",
"[3].",
"The",
"questionnaire,",
"which",
"consists",
"of",
"29",
"self-rated",
"items,",
"is",
"designed",
"to",
"measure",
"abnormal",
"illness",
"behaviour",
"and",
"hypochondriasis.",
"Twenty-seven",
"items",
"are",
"answered",
"on",
"a",
"five-point",
"scale,",
"two",
"items",
"are",
"answered",
"differently.",
"For",
"24",
"of",
"the",
"27",
"items,",
"the",
"steps",
"of",
"the",
"scale",
"are",
"labelled:",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Diagnosis",
"of",
"Recurrent",
"Uterine",
"Cervical",
"Cancer:",
"Computed",
"Tomography",
"versus",
"Positron",
"Emission",
"Tomography",
"Dong",
"Hee",
"Park,",
"MD1",
"Kie",
"Hwan",
"Kim,",
"MD1",
"Sang",
"Yoon",
"Park,",
"MD2",
"Byung",
"Hee",
"Lee,",
"MD1",
"Chang",
"Woon",
"Choi,",
"MD3",
"Soo",
"Yil",
"Chin,",
"MD1",
"Index",
"words:",
"Uterine",
"neoplasms,",
"CT",
"Uterine",
"neoplasms,",
"radionuclide",
"studies",
"Positron",
"emission",
"tomography",
"(PET),",
"comparative",
"studies",
"Korean",
"J",
"Radiol",
"2000;1",
":51-55",
"Received",
"October",
"13,",
"1999;",
"accepted",
"after",
"revision",
"January",
"6,",
"2000.",
"Departments",
"of",
"1Diagnostic",
"Radiology,",
"2Obstetrics",
"and",
"Gynecology,",
"and",
"3Nuclear",
"Medicine,",
"Korea",
"Cancer",
"Center",
"Hospital.",
"Address",
"reprint",
"requests",
"to:",
"Dong",
"Hee",
"Park,",
"MD,",
"Department",
"of",
"Diagnostic",
"Radiology,",
"Korea",
"Cancer",
"Center",
"Hospital,",
"215-4,",
"Gongneung-Dong,",
"Nowon-Gu,",
"Seoul",
"139-240,",
"Korea.",
"Telephone:",
"(822)",
"974-2501",
"Fax:",
"(822)",
"972-3093",
"Objective:",
"To",
"determine",
"the",
"accuracy",
"of",
"CT",
"and",
"positron",
"emission",
"tomogra-",
"phy",
"(PET)",
"in",
"the",
"diagnosis",
"of",
"recurrent",
"uterine",
"cervical",
"cancer.",
"Materials",
"and",
"Methods:",
"Imaging",
"findings",
"of",
"CT",
"and",
"PET",
"in",
"36",
"patients",
"(mean",
"age,",
"53",
"years)",
"in",
"whom",
"recurrent",
"uterine",
"cervical",
"cancer",
"was",
"suspected",
"were",
"analyzed",
"retrospectively.",
"Between",
"October",
"1997",
"and",
"May",
"1998,",
"they",
"had",
"under-",
"gone",
"surgery",
"and/or",
"radiation",
"therapy.",
"Tumor",
"recurrence",
"was",
"confirmed",
"by",
"pathologic",
"examination",
"or",
"follow-up",
"studies.",
"Results:",
"In",
"detecting",
"recurrent",
"uterine",
"cervical",
"cancer,",
"the",
"sensitivity,",
"specifici-",
"ty,",
"and",
"accuracy",
"of",
"CT",
"were",
"77.8%,",
"83.3%,",
"and",
"80.5%,",
"respectively,",
"while",
"for",
"PET,",
"the",
"corresponding",
"figures",
"were",
"100%,",
"94.4%,",
"and",
"97.2%.",
"The",
"Chi-square",
"test",
"revealed",
"no",
"significant",
"difference",
"in",
"specificity",
"(p",
"=",
".2888),",
"but",
"significant",
"dif-",
"ferences",
"in",
"sensitivity",
"(p",
"=",
".0339)",
"and",
"accuracy",
"(p",
"=",
".0244).",
"Conclusion:",
"PET",
"proved",
"to",
"be",
"a",
"reliable",
"screening",
"method",
"for",
"detecting",
"recur-",
"rent",
"uterine",
"cervical",
"cancer,",
"but",
"to",
"determine",
"the",
"anatomical",
"localization",
"of",
"recur-",
"rent",
"tumors,",
"and",
"thus",
"decide",
"an",
"adequate",
"treatment",
"plan,",
"CT",
"was",
"eventually",
"needed.",
"T",
"he",
"recurrence",
"rate",
"of",
"uterine",
"cervical",
"cancer",
"is",
"reported",
"to",
"be",
"6.5%",
"after",
"surgery",
"and",
"26.2%",
"after",
"radiation",
"therapy",
"alone",
"(1).",
"Radiological",
"studies",
"such",
"as",
"intravenous",
"urography",
"(IVU),",
"US,",
"CT,",
"and",
"MR",
"imaging",
"are",
"used",
"to",
"detect",
"recurrent",
"cervical",
"cancer",
"(2).",
"It",
"is",
"difficult,",
"however,",
"for",
"these",
"imaging",
"modali-",
"ties",
"to",
"differentiate",
"recurrent",
"tumor",
"from",
"postoperative",
"or",
"radiation",
"fibrosis,",
"and",
"to",
"de-",
"tect",
"metastatic",
"normal-sized",
"lymph",
"nodes",
"and",
"extrapelvic",
"metastases",
"(2",
"7).",
"Since",
"Di",
"Chiro",
"et",
"al.",
"(8)",
"first",
"used",
"it",
"to",
"detect",
"recurrent",
"brain",
"tumors,",
"positron",
"emis-",
"sion",
"tomography",
"(PET),",
"the",
"diagnostic",
"modality",
"which",
"makes",
"use",
"of",
"increased",
"glycoly-",
"sis",
"in",
"tumor",
"cells,",
"has",
"been",
"used",
"to",
"detect",
"recurrent",
"tumors",
"in",
"many",
"organs.",
"To",
"our",
"knowledge,",
"no",
"report",
"has",
"described",
"the",
"diagnosis",
"of",
"recurrent",
"cervical",
"cancer",
"using",
"PET.",
"The",
"purpose",
"of",
"this",
"study",
"is",
"to",
"compare",
"the",
"accuracy",
"of",
"CT",
"with",
"that",
"of",
"PET",
"in",
"the",
"detection",
"of",
"recurrent",
"cervical",
"cancer.",
"MATERIALS",
"AND",
"METHODS",
"Among",
"patients",
"with",
"uterine",
"cervical",
"cancer",
"who",
"had",
"undergone",
"initial",
"treatment",
"between",
"October",
"1997",
"and",
"May",
"1998,",
"CT",
"and",
"PET",
"were",
"performed",
"in",
"36",
"in",
"whom",
"recurrence",
"was",
"clinically",
"suspected.",
"As",
"initial",
"treatment,",
"13",
"patients",
"had",
"undergone",
"surgery",
"alone,",
"14",
"radiation",
"therapy",
"alone,",
"and",
"nine",
"surgery",
"and",
"postoperative",
"radia-",
"tion",
"therapy.",
"Recurrence",
"was",
"suspected",
"on",
"the",
"basis",
"of",
"increased",
"levels",
"of",
"serum",
"squa-",
"Korean",
"J",
"Radiol",
"1(1),",
"March",
"2000",
"51"
] | [
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] | [
"Guerrero",
"et",
"al.",
"International",
"Journal",
"of",
"Emergency",
"Medicine",
"2012,",
"5:4",
"http://www.intjem.com/content/5/1/4",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"Open",
"Access",
"The",
"role",
"of",
"perfusion",
"CT",
"in",
"identifying",
"stroke",
"mimics",
"in",
"the",
"emergency",
"room:",
"a",
"case",
"of",
"status",
"epilepticus",
"presenting",
"with",
"perfusion",
"CT",
"alterations",
"Waldo",
"R",
"Guerrero*,",
"Haitham",
"Dababneh",
"and",
"Stephan",
"Eisenschenk",
"Abstract",
"Emergency",
"medicine",
"physicians",
"are",
"often",
"faced",
"with",
"the",
"challenging",
"task",
"of",
"differentiating",
"true",
"acute",
"ischemic",
"strokes",
"from",
"stroke",
"mimics.",
"We",
"present",
"a",
"case",
"that",
"was",
"initially",
"diagnosed",
"as",
"acute",
"stroke.",
"However,",
"perfusion",
"CT",
"and",
"EEG",
"eventually",
"led",
"to",
"the",
"final",
"diagnosis",
"of",
"status",
"epilepticus.",
"This",
"case",
"further",
"asserts",
"the",
"role",
"of",
"CT",
"perfusion",
"in",
"the",
"evaluation",
"of",
"patients",
"with",
"stroke",
"mimics",
"in",
"the",
"emergency",
"room",
"setting.",
"Background",
"The",
"differentiation",
"between",
"stroke",
"and",
"seizure",
"can",
"be",
"a",
"clinically",
"arduous",
"task",
"for",
"both",
"emergency",
"medicine",
"physicians",
"and",
"neurologists",
"[1,2].",
"Patients",
"with",
"diseases",
"that",
"mimic",
"stroke",
"account",
"for",
"one-fifth",
"of",
"patients",
"with",
"brain",
"attacks",
"[1].",
"Imaging",
"may",
"therefore",
"be",
"critical",
"in",
"making",
"a",
"diagnosis",
"in",
"the",
"acute",
"setting.",
"Seizure",
"is",
"one",
"condition",
"that",
"can",
"mimic",
"a",
"stroke.",
"Commonly,",
"patients",
"with",
"Todd’s",
"paralysis",
"or",
"those",
"with",
"nonconvulsive",
"status",
"epilepticus",
"can",
"be",
"clinically",
"indistinct",
"from",
"those",
"with",
"acute",
"stroke.",
"Further",
"complicating",
"the",
"clinical",
"scenario,",
"seizure",
"may",
"also",
"be",
"a",
"presenting",
"sign",
"of",
"stroke",
"[3].",
"Recently",
"the",
"time",
"frame",
"for",
"standard",
"treatment",
"of",
"acute",
"stroke",
"with",
"IV",
"tissue",
"plasminogen",
"activator",
"was",
"expanded",
"from",
"3",
"h",
"to",
"4.5",
"h",
"from",
"ictus",
"onset",
"[4].",
"Although",
"this",
"extension",
"of",
"time",
"is",
"supported",
"by",
"the",
"American",
"Heart",
"Association,",
"it",
"is",
"not",
"FDA",
"approved",
"and",
"comes",
"with",
"a",
"different",
"set",
"of",
"relative",
"contraindica-",
"tions.",
"Intravenous",
"thrombolytics",
"are",
"not",
"without",
"the",
"risk",
"of",
"complications,",
"including",
"intracranial",
"hemorrhage",
"[5].",
"Non-contrast",
"CT",
"(NCCT)",
"of",
"the",
"head",
"is",
"the",
"current",
"gold",
"standard",
"in",
"excluding",
"intracranial",
"hemorrhage",
"prior",
"to",
"administration",
"of",
"intravenous",
"thrombolysis.",
"However,",
"NCCT",
"has",
"a",
"limited",
"role",
"in",
"differentiating",
"those",
"patients",
"with",
"stroke",
"from",
"those",
"with",
"seizure.",
"*",
"Correspondence:",
"waldo.guerrero@neurology.ufl.edu",
"Department",
"of",
"Neurology,",
"College",
"of",
"Medicine,",
"University",
"of",
"Florida,",
"1601",
"Archer",
"Road",
"Gainesville,",
"32610-0236",
"FL,",
"USA",
"Although",
"current",
"guidelines",
"advocate",
"only",
"NCCT",
"as",
"the",
"imaging",
"modality",
"of",
"choice",
"in",
"the",
"initial",
"evaluation",
"of",
"acute",
"stroke,",
"this",
"case",
"illustrates",
"the",
"importance",
"of",
"CT",
"perfusion",
"studies",
"in",
"the",
"radiographic",
"evaluation",
"of",
"brain",
"attack",
"patients",
"in",
"order",
"to",
"avoid",
"misdiagnosis",
"and",
"inad-",
"vertent",
"treatment",
"of",
"non-stroke",
"patients",
"with",
"thrombo-",
"lytic",
"therapy.",
"Furthermore,",
"whereas",
"hypoperfusion",
"related",
"to",
"strokes",
"has",
"been",
"widely",
"investigated",
"by",
"CT-",
"perfusion",
"imaging",
"[6,7],",
"this",
"case",
"demonstrates",
"the",
"hyperperfusion",
"state",
"often",
"seen",
"on",
"perfusion",
"CT",
"in",
"emergency",
"room",
"patients",
"with",
"epilepsy.",
"We",
"describe",
"an",
"interesting",
"case",
"of",
"a",
"patient",
"presenting",
"to",
"the",
"Shands",
"Hospital",
"at",
"the",
"University",
"of",
"Florida",
"emergency",
"room",
"with",
"a",
"homonymous",
"hemianopsia",
"and",
"alterations",
"on",
"perfusion",
"CT",
"related",
"to",
"hyperglycemia-induced",
"occipital",
"status",
"epilepticus.",
"Case",
"presentation",
"A",
"72-year-old",
"man",
"with",
"a",
"past",
"medical",
"history",
"signifi-",
"cant",
"for",
"diabetes",
"mellitus",
"type",
"2",
"presented",
"to",
"the",
"Shands",
"Hospital",
"at",
"the",
"University",
"of",
"Florida",
"emergency",
"room",
"with",
"sudden",
"onset",
"of",
"visual",
"changes.",
"The",
"patient",
"had",
"noted",
"that",
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"licensee",
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"distribution,",
"and",
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"in",
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] | [
"INTEGRATIVE",
"NEUROSCIENCE",
"GENERAL",
"COMMENTARY",
"published:",
"18",
"May",
"2009",
"doi:",
"10.3389/neuro.07.006.2009",
"Retina",
"or",
"visual",
"cortex?The",
"site",
"of",
"phosphene",
"induction",
"by",
"transcranial",
"alternating",
"current",
"stimulation",
"Caspar",
"M.",
"Schwiedrzik*",
"Department",
"of",
"Neurophysiology,",
"Max",
"Planck",
"Institute",
"for",
"Brain",
"Research,",
"Frankfurt",
"am",
"Main,",
"Germany",
"*Correspondence:",
"schwiedrzik@mpih-frankfurt.mpg.de",
"A",
"commentary",
"on",
"Frequency-dependent",
"electrical",
"stimula-",
"tion",
"of",
"the",
"visual",
"cortex.",
"Kanai,",
"R.,",
"Chaieb,",
"L.,",
"Antal,",
"A.,",
"Walsh,",
"V.,",
"and",
"Paulus,",
"W.",
"(2008).",
"Curr.",
"Biol.",
"18,",
"1839–1843.",
"Since",
"the",
"first",
"descriptions",
"of",
"oscillatory",
"synchrony",
"in",
"the",
"cortex,",
"a",
"plethora",
"of",
"stud-",
"ies",
"have",
"provided",
"empirical",
"evidence",
"for",
"correlations",
"between",
"cortical",
"oscillations",
"and",
"perception,",
"attention,",
"and",
"other",
"cog-",
"nitive",
"functions",
"(Tallon-Baudry,",
"2009).",
"However,",
"it",
"has",
"remained",
"difficult",
"to",
"obtain",
"causal",
"evidence",
"for",
"a",
"role",
"of",
"oscil-",
"latory",
"synchrony",
"in",
"cortical",
"processing.",
"Recent",
"developments",
"in",
"noninvasive",
"brain",
"stimulation",
"techniques",
"might",
"constitute",
"a",
"new",
"approach",
"to",
"this",
"problem",
"(Thut",
"and",
"Miniussi,",
"2009).",
"In",
"a",
"recent",
"paper",
"employ-",
"ing",
"such",
"a",
"technique,",
"Kanai",
"et",
"al.",
"(2008)",
"report",
"that",
"the",
"visibility",
"of",
"phosphenes",
"elicited",
"by",
"transcranial",
"alternating",
"cur-",
"rent",
"stimulation",
"(tACS)",
"depends",
"on",
"the",
"frequency",
"of",
"stimulation.",
"Specifically,",
"at",
"a",
"frequency",
"of",
"about",
"20",
"Hz",
"the",
"lowest",
"intensity",
"was",
"needed",
"to",
"produce",
"periph-",
"eral",
"phosphenes.",
"Furthermore,",
"when",
"the",
"eyes",
"of",
"the",
"subjects",
"were",
"closed,",
"this",
"opti-",
"mum",
"frequency",
"shifted",
"to",
"a",
"frequency",
"of",
"about",
"10",
"Hz.",
"Interestingly,",
"these",
"stimula-",
"tion",
"frequencies",
"seem",
"to",
"correspond",
"to",
"the",
"well",
"known",
"beta",
"(12–30",
"Hz)",
"and",
"alpha",
"(8–12",
"Hz)",
"frequency",
"bands",
"in",
"the",
"electro-",
"encephalogram",
"(EEG),",
"and",
"alpha",
"power",
"in",
"the",
"EEG",
"indeed",
"increases",
"when",
"subjects",
"close",
"their",
"eyes.",
"Based",
"on",
"these",
"ostensible",
"similarities,",
"the",
"authors",
"concluded",
"that",
"“the",
"frequency",
"dependency",
"is",
"caused",
"by",
"inter-",
"actions",
"with",
"ongoing",
"oscillatory",
"activity",
"in",
"the",
"stimulated",
"cortex”,",
"and",
"that",
"“tACS",
"can",
"be",
"used",
"as",
"a",
"noninvasive",
"tool",
"for",
"establish-",
"ing",
"a",
"causal",
"link",
"between",
"rhythmic",
"cortical",
"activities",
"and",
"their",
"functions”.",
"If",
"this",
"were",
"the",
"case,",
"tACS",
"would",
"poten-",
"tially",
"be",
"an",
"interesting",
"tool",
"to",
"inquire",
"the",
"causal",
"role",
"of",
"oscillatory",
"synchrony",
"in",
"cor-",
"tical",
"processing.",
"However,",
"previously",
"pub-",
"lished",
"evidence",
"renders",
"the",
"interpretation",
"that",
"tACS",
"interacts",
"directly",
"with",
"cortical",
"activity",
"questionable:",
"It",
"has",
"been",
"suggested",
"that",
"peripheral",
"phosphenes",
"as",
"observed",
"by",
"Kanai",
"et",
"al.",
"(2008)",
"are",
"elicited",
"on",
"the",
"level",
"of",
"the",
"retina,",
"and",
"not",
"in",
"cortical",
"structures.",
"The",
"first",
"successful",
"attempts",
"to",
"stimulate",
"the",
"visual",
"system",
"by",
"alternating",
"current",
"(AC)",
"were",
"already",
"introduced",
"in",
"the",
"first",
"half",
"of",
"the",
"last",
"century",
"by",
"one",
"of",
"the",
"pioneers",
"of",
"the",
"EEG,",
"Rohracher",
"(1935).",
"He",
"described",
"that",
"peripheral",
"phosphenes",
"could",
"reliably",
"be",
"elicited",
"by",
"AC",
"stimulation",
"with",
"differ-",
"ent",
"electrode",
"configurations",
"on",
"the",
"head.",
"The",
"most",
"consistent",
"finding",
"was",
"a",
"frequency",
"optimum",
"in",
"the",
"beta",
"range",
"(15–20",
"Hz),",
"irrespective",
"of",
"electrode",
"arrangement.",
"This",
"finding",
"corresponds",
"well",
"to",
"the",
"more",
"recent",
"results",
"of",
"Kanai",
"et",
"al.",
"(2008),",
"which",
"were",
"obtained",
"only",
"with",
"a",
"fronto-occipital",
"mon-",
"tage.",
"Based",
"on",
"the",
"result",
"that",
"the",
"intensity",
"needed",
"to",
"elicit",
"phosphenes",
"increased",
"with",
"distance",
"from",
"the",
"eye,",
"Rohracher",
"concluded",
"that",
"the",
"most",
"likely",
"site",
"of",
"stimulation",
"was",
"the",
"retina",
"(although",
"he",
"also",
"considered",
"an",
"effect",
"of",
"AC",
"stimulation",
"on",
"the",
"cortex).",
"A",
"few",
"years",
"later,",
"Schwarz",
"(1947)",
"showed",
"that",
"the",
"intensity",
"needed",
"to",
"elicit",
"phos-",
"phenes",
"by",
"AC",
"stimulation",
"depends",
"on",
"the",
"adaptational",
"state",
"of",
"the",
"eye.",
"The",
"initial",
"adjustment",
"of",
"retinal",
"sensitivity",
"to",
"back-",
"ground",
"illumination",
"only",
"takes",
"fractions",
"of",
"a",
"second",
"(Meister",
"and",
"Berry,",
"1999),",
"thus",
"5",
"s",
"of",
"eyes",
"closed",
"as",
"in",
"Kanai",
"et",
"al.",
"(2008)",
"can",
"be",
"considered",
"a",
"case",
"of",
"dark",
"adaptation.",
"During",
"dark",
"adaptation,",
"the",
"susceptibility",
"to",
"AC",
"stimulation",
"shifts",
"to",
"lower",
"frequencies",
"(see",
"Figure",
"1).",
"These",
"findings",
"were",
"replicated",
"by",
"Meyer-Schwickerath",
"and",
"Magun",
"(1951),",
"and",
"expanded",
"to",
"the",
"field",
"of",
"color",
"vision",
"by",
"Motokawa",
"and",
"Ebe",
"(1952).",
"More",
"definite",
"proof",
"that",
"the",
"site",
"of",
"stimulation",
"was",
"indeed",
"the",
"retina",
"was",
"obtained",
"by",
"Brindley",
"(1955).",
"Brindley",
"used",
"conjunctival",
"electrodes",
"which",
"render",
"volume",
"conduction",
"to",
"the",
"occipital",
"cortex",
"highly",
"unlikely.",
"More",
"importantly,",
"he",
"FIGURE",
"1",
"|",
"In",
"his",
"experiments,",
"Schwarz",
"(1947)",
"varied",
"the",
"duration",
"of",
"dark",
"adaptation",
"and",
"the",
"frequency",
"of",
"alternating",
"current",
"stimulation.",
"Without",
"dark",
"adaptation,",
"a",
"clear",
"frequency",
"optimum",
"is",
"seen",
"at",
"20",
"Hz,",
"whereas",
"differing",
"durations",
"of",
"dark",
"adaptation",
"shift",
"this",
"optimum",
"to",
"lower",
"frequencies",
"(10",
"Hz)",
"(adapted",
"from",
"Schwarz,",
"1947,",
"with",
"kind",
"permission",
"from",
"Springer",
"Science",
"+",
"Business",
"Media).",
"Frontiers",
"in",
"Integrative",
"Neuroscience",
"www.frontiersin.org",
"April",
"2009",
"|",
"Volume",
"3",
"|",
"Article",
"6",
"|",
"1"
] | [
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] | [
"Ann",
"Dermatol",
"Vol.",
"23,",
"Suppl.",
"2,",
"2011",
"CASE",
"REPORT",
"Linear",
"Focal",
"Elastosis",
"Following",
"Striae",
"Distensae",
"http://dx.doi.org/10.5021/ad.2011.23.S2.S141",
"Linear",
"Focal",
"Elastosis",
"Following",
"Striae",
"Distensae:",
"Further",
"Evidence",
"of",
"Keloidal",
"Repair",
"Process",
"in",
"the",
"Pathogenesis",
"of",
"Linear",
"Focal",
"Elastosis",
"Jin",
"Seob",
"Jeong,",
"M.D.,",
"Ji",
"Yeoun",
"Lee,",
"M.D.,",
"Mi",
"Kyeong",
"Kim,",
"M.D.1,",
"Tae",
"Young",
"Yoon,",
"M.D.",
"Departments",
"of",
"Dermatology",
"and",
"1Internal",
"Medicine,",
"School",
"of",
"Medicine",
"and",
"Medical",
"Research",
"Institute,",
"Chungbuk",
"National",
"University,",
"Cheongju,",
"Korea",
"Linear",
"focal",
"elastosis",
"(LFE)",
"is",
"a",
"rare",
"dermal",
"elastosis",
"characterized",
"by",
"hypertrophic",
"yellowish",
"linear",
"plaques",
"and",
"increased",
"abnormal",
"elastic",
"tissues",
"in",
"the",
"lumbosacral",
"area.",
"Although",
"the",
"pathogenesis",
"of",
"this",
"disorder",
"remains",
"unknown,",
"it",
"may",
"be",
"associated",
"with",
"keloidal",
"repair",
"process",
"(KRP)",
"of",
"elastic",
"tissues",
"in",
"striae",
"distensae",
"(SD),",
"because",
"there",
"have",
"been",
"some",
"reported",
"cases",
"of",
"LFE",
"accompanied",
"by",
"SD.",
"We",
"herein",
"report",
"a",
"14-year-old",
"boy",
"with",
"LFE",
"following",
"SD",
"in",
"the",
"lumbar",
"region.",
"Our",
"case",
"supports",
"the",
"hypothesis",
"of",
"KRP",
"in",
"the",
"pathogenesis",
"of",
"LFE.",
"Immunohistochemical",
"study",
"for",
"transforming",
"growth",
"factor-beta",
"(TGF-β)",
"was",
"negative.",
"Therefore,",
"we",
"assume",
"that",
"the",
"pathogenesis",
"of",
"KRP",
"in",
"LFE",
"is",
"different",
"from",
"that",
"of",
"keloid",
"development,",
"which",
"is",
"the",
"TGF-",
"β",
"signaling",
"pathway.",
"(Ann",
"Dermatol",
"23(S2)",
"S141∼S143,",
"2011)",
"-Keywords-",
"Keloidal",
"repair",
"process,",
"Linear",
"focal",
"elastosis,",
"Striae",
"dis-",
"tensae,",
"Transforming",
"growth",
"factor-beta",
"Received",
"January",
"22,",
"2010,",
"Revised",
"May",
"13,",
"2010,",
"Accepted",
"for",
"publication",
"July",
"14,",
"2010",
"Corresponding",
"author:",
"Tae",
"Young",
"Yoon,",
"M.D.,",
"Department",
"of",
"Derma-",
"tology,",
"School",
"of",
"Medicine",
"and",
"Medical",
"Research",
"Institute,",
"Chungbuk",
"National",
"University,",
"52",
"Naesoodong-ro,",
"Heungdeok-gu,",
"Cheongju",
"361-763,",
"Korea.",
"Tel:",
"82-43-269-6369,",
"Fax:",
"82-43-266-1698,",
"E-mail:",
"tyyoon@chungbuk.ac.kr",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"INTRODUCTION",
"Since",
"Burket",
"et",
"al.1",
"described",
"three",
"white",
"elderly",
"men",
"with",
"palpable",
"yellow",
"lines",
"on",
"their",
"back",
"and",
"named",
"the",
"disorder,",
"linear",
"focal",
"elastosis",
"(LFE),",
"in",
"1989,",
"many",
"cases",
"of",
"LFE",
"have",
"been",
"reported.",
"It",
"usually",
"occurs",
"in",
"the",
"lumbosacral",
"area,",
"characterized",
"by",
"hypertrophic",
"yellowish",
"linear",
"bands",
"and",
"an",
"increase",
"of",
"abnormal",
"elastic",
"tissues2.",
"Although",
"the",
"pathogenesis",
"of",
"LFE",
"remains",
"unknown,",
"it",
"may",
"be",
"associated",
"with",
"keloidal",
"repair",
"process",
"(KRP)",
"of",
"elastic",
"tissue",
"in",
"striae",
"distensae",
"(SD),",
"because",
"some",
"cases",
"of",
"LFE",
"have",
"presented",
"with",
"features",
"of",
"SD3-5.",
"Several",
"cases",
"of",
"LFE,",
"including",
"two",
"cases",
"of",
"LFE",
"with",
"SD,",
"have",
"been",
"reported",
"since",
"we",
"first",
"reported",
"two",
"patients",
"with",
"LFE",
"in",
"the",
"Korean",
"dermatologic",
"literature6-8.",
"We",
"herein",
"report",
"a",
"14-year-old",
"boy",
"with",
"LFE",
"following",
"SD",
"in",
"the",
"same",
"region.",
"Our",
"case",
"supports",
"the",
"hypothesis",
"of",
"KRP",
"in",
"the",
"patho-",
"genesis",
"of",
"LFE.",
"Additionally,",
"in",
"order",
"to",
"elucidate",
"the",
"role",
"of",
"transforming",
"growth",
"factor-beta",
"(TGF-β)",
"in",
"the",
"patho-",
"genesis",
"of",
"LFE,",
"we",
"performed",
"immunohistochemical",
"study",
"for",
"TGF-β.",
" ",
"CASE",
"REPORT",
"A",
"14-year-old",
"Korean",
"boy",
"presented",
"with",
"a",
"2-year",
"history",
"of",
"asymptomatic",
"multiple",
"horizontal",
"linear",
"lesions",
"on",
"his",
"lumbar",
"area.",
"His",
"familial",
"and",
"personal",
"histories",
"were",
"unremarkable,",
"and",
"he",
"did",
"not",
"take",
"any",
"significant",
"medi-",
"cations",
"such",
"as",
"steroids.",
"He",
"denied",
"any",
"history",
"of",
"trauma",
"on",
"his",
"lumbar",
"area,",
"obesity,",
"rapid",
"growth,",
"and",
"systemic",
"illness.",
"He",
"recalled",
"that",
"the",
"hypertrophic",
"lesions",
"arose",
"from",
"the",
"atrophic",
"bands,",
"and",
"the",
"atrophic",
"bands",
"on",
"the",
"upper",
"back",
"occurred",
"recently.",
"Physical",
"examination",
"revealed",
"several",
"palpable",
"hypertrophic",
"yellowish",
"bands",
"Vol.",
"23,",
"Suppl.",
"2,",
"2011",
"S141"
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] | [
"Zintl",
"et",
"al.",
"Veterinary",
"Research",
"2011,",
"42:7",
"http://www.veterinaryresearch.org/content/42/1/7",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"VETERINARY",
"RESEARCH",
"Open",
"Access",
"Babesias",
"of",
"red",
"deer",
"(Cervus",
"elaphus)",
"in",
"Ireland",
"Annetta",
"Zintl1,",
"Eugene",
"J",
"Finnerty2,",
"Thomas",
"M",
"Murphy3,",
"Theo",
"de",
"Waal1,",
"Jeremy",
"S",
"Gray2*",
"Abstract",
"Blood",
"samples",
"were",
"obtained",
"from",
"38",
"wild",
"red",
"deer",
"(Cervus",
"elaphus)",
"at",
"two",
"sites",
"in",
"Ireland",
"and",
"subjected",
"to",
"PCR",
"analysis",
"of",
"the",
"18S",
"rRNA",
"gene",
"followed",
"by",
"sequencing.",
"Two",
"fragments",
"of",
"the",
"18S",
"rRNA",
"gene",
"were",
"generated",
"by",
"two",
"different",
"PCR",
"protocols",
"and",
"subsequent",
"sequencing",
"suggested",
"that",
"at",
"least",
"six",
"of",
"the",
"deer",
"were",
"infected",
"by",
"a",
"babesia",
"that,",
"in",
"those",
"loci,",
"is",
"indistinguishable",
"from",
"Babesia",
"divergens,",
"an",
"important",
"tick-borne",
"pathogen",
"of",
"cattle",
"and",
"of",
"zoonotic",
"significance.",
"Additionally,",
"a",
"B.",
"odocoilei-like",
"parasite",
"was",
"detected",
"in",
"three",
"samples",
"and",
"a",
"babesia",
"that",
"did",
"not",
"match",
"any",
"sequences",
"in",
"the",
"GenBank",
"database",
"was",
"found",
"in",
"five",
"samples.",
"Neither",
"B.",
"capreoli",
"nor",
"B.",
"venatorum",
"(EU1)",
"were",
"found.",
"There",
"have",
"been",
"several",
"reports",
"of",
"B.",
"divergens",
"occurring",
"in",
"deer",
"species,",
"including",
"red",
"deer,",
"roe",
"deer",
"(Capreolus",
"capreolus)",
"and",
"reindeer",
"(Rangifer",
"tarandus).",
"However,",
"in",
"view",
"of",
"recent",
"re-sequencing",
"of",
"bovine-origin",
"samples",
"deposited",
"previously",
"in",
"GenBank,",
"it",
"is",
"unlikely",
"that",
"any",
"of",
"these",
"sequences",
"from",
"deer",
"are",
"B.",
"divergens.",
"The",
"present",
"study",
"describes",
"the",
"only",
"deer",
"piroplasm",
"detected",
"so",
"far",
"that",
"shows",
"complete",
"identity",
"with",
"B.",
"divergens,",
"in",
"just",
"over",
"half",
"of",
"the",
"18S",
"rRNA",
"gene.",
"The",
"entire",
"gene",
"of",
"this",
"deer",
"parasite",
"should",
"be",
"analysed",
"and",
"transmission",
"experiments",
"undertaken",
"before",
"the",
"infectivity",
"of",
"B.",
"divergens",
"for",
"red",
"deer",
"can",
"be",
"confirmed.",
"Introduction",
"There",
"has",
"been",
"considerable",
"recent",
"interest",
"in",
"the",
"iden-",
"tity",
"of",
"Babesia",
"spp.",
"in",
"deer,",
"because",
"of",
"concerns",
"about",
"the",
"health",
"of",
"endangered",
"host",
"species",
"such",
"as",
"chamois",
"(Rupicapra",
"r.",
"rupicapra)",
"[1]",
"and",
"also",
"because",
"of",
"the",
"possibility",
"of",
"deer",
"acting",
"as",
"reservoirs",
"for",
"important",
"cat-",
"tle",
"parasites",
"such",
"as",
"Babesia",
"divergens",
"[2].",
"Earlier",
"stu-",
"dies",
"on",
"red",
"(Cervus",
"elaphus)",
"and",
"sika",
"(C.",
"nippon)",
"deer",
"babesias",
"in",
"Europe",
"suggested",
"that",
"they",
"were",
"morpholo-",
"gically",
"and",
"antigenically",
"indistinguishable",
"from",
"B.",
"diver-",
"gens,",
"but",
"were",
"not",
"transmissible",
"to",
"splenectomised",
"calves.",
"They",
"were",
"therefore",
"tentatively",
"identified",
"as",
"B.",
"capreoli",
"[3,4],",
"which",
"was",
"first",
"observed",
"in",
"roe",
"deer",
"(Capreolus",
"capreolus)",
"[5].",
"With",
"the",
"advent",
"of",
"molecular",
"taxonomy",
"based",
"on",
"analysis",
"of",
"DNA",
"sequences,",
"several",
"authors",
"described",
"parasites",
"in",
"roe,",
"red",
"or",
"reindeer",
"as",
"B.",
"divergens",
"or",
"B.",
"divergens-like",
"[2,6-12].",
"These",
"authors",
"based",
"their",
"conclusions",
"on",
"18S",
"rRNA",
"gene",
"sequence",
"alignment,",
"but",
"none",
"of",
"their",
"samples",
"showed",
"100%",
"simi-",
"larity",
"with",
"B.",
"divergens",
"sequences",
"of",
"bovine",
"origin",
"in",
"GenBank.",
"Resequencing",
"of",
"the",
"18S",
"rRNA",
"gene",
"from",
"the",
"same",
"strains",
"of",
"B.",
"divergens",
"originally",
"deposited",
"in",
"Gen-",
"Bank",
"showed",
"that",
"all",
"were",
"in",
"fact",
"identical",
"and",
"that",
"*",
"Correspondence:",
"Jeremy.gray@ucd.ie",
"2UCD",
"School",
"of",
"Biology",
"and",
"Environmental",
"Science,",
"University",
"College",
"Dublin,",
"Ireland",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"there",
"were",
"errors",
"in",
"the",
"original",
"sequences",
"(Slemenda",
"et",
"al.,",
"unpublished,",
"cited",
"in",
"[13]).",
"This",
"suggests",
"that",
"parasites",
"showing",
"less",
"than",
"100%",
"similarity",
"for",
"this",
"gene",
"should",
"not",
"be",
"designated",
"B.",
"divergens",
"and",
"to",
"date",
"there",
"are",
"no",
"studies",
"showing",
"that",
"B.",
"divergens",
"occurs",
"naturally",
"in",
"ruminant",
"hosts",
"other",
"than",
"cattle.",
"An",
"opportunity",
"to",
"re-examine",
"this",
"situation",
"arose",
"dur-",
"ing",
"a",
"serosurvey",
"of",
"deer",
"parasites",
"in",
"free-ranging",
"wild",
"Irish",
"deer.",
"Blood",
"samples",
"from",
"38",
"red",
"deer",
"from",
"two",
"National",
"Parks",
"in",
"different",
"geographical",
"locations",
"were",
"analysed",
"by",
"two",
"PCR",
"protocols",
"targeting",
"the",
"18S",
"rRNA",
"gene,",
"and",
"the",
"products",
"then",
"sequenced",
"and",
"aligned",
"for",
"identification",
"purposes.",
"Materials",
"and",
"methods",
"Blood",
"samples",
"were",
"collected",
"from",
"red",
"deer",
"shot",
"by",
"the",
"National",
"Parks",
"and",
"Wildlife",
"Service",
"as",
"part",
"of",
"the",
"seaso-",
"nal",
"cull",
"in",
"Glenveagh",
"(n",
"=",
"27)",
"and",
"Killarney",
"(n",
"=",
"11)",
"(Figure",
"1).",
"From",
"each",
"animal",
"3",
"to",
"4",
"mL",
"whole",
"blood",
"were",
"collected",
"into",
"EDTA.",
"Following",
"centrifugation",
"and",
"removal",
"of",
"plasma,",
"the",
"packed",
"cell",
"component",
"was",
"stored",
"at",
"-20°C.",
"DNA",
"was",
"subsequently",
"extracted",
"from",
"thawed",
"and",
"mixed",
"100",
"mg",
"packed",
"cells",
"of",
"each",
"sample",
"using",
"the",
"High",
"Pure",
"PCR",
"Template",
"Preparation",
"Kit",
"(Roche,",
"Burgess",
"Hill,",
"UK).",
"A",
"nested",
"PCR",
"protocol",
"was",
"used",
"initially",
"to",
"screen",
"all",
"samples",
"(protocol",
"I).",
"The",
"positive",
"samples",
"were",
"then",
"additionally",
"analysed",
"using",
"a",
"©",
"2011",
"Zintl",
"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."
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] | [
"Time-Dependent",
"Effect",
"of",
"Refrigeration",
"on",
"Viscosity",
"and",
"Conversion",
"Kinetics",
"of",
"Dental",
"Adhesive",
"Resins",
"André",
"L",
"Faria-e-Silvaa",
"Evandro",
"Pivab",
"Rafael",
"R",
"Moraesb",
"AbstrAct",
"Objectives:",
"This",
"study",
"evaluated",
"the",
"effect",
"of",
"refrigeration",
"at",
"4oC",
"and",
"post-refrigeration",
"times",
"(immediate,",
"5,",
"10,",
"15,",
"or",
"20",
"min)",
"on",
"the",
"viscosity",
"and",
"conversion",
"kinetics",
"of",
"adhesive",
"bonding",
"resins.",
"Methods:",
"Scotchbond",
"Dual-Cure",
"(3M",
"ESPE)",
"and",
"Clearfil",
"SE",
"Bond",
"(Kuraray)",
"were",
"tested.",
"Control",
"samples",
"were",
"kept",
"at",
"25oC",
"for",
"24",
"h.",
"At",
"each",
"post-refrigeration",
"time,",
"the",
"temperature",
"was",
"checked",
"with",
"a",
"K-type",
"thermocouple.",
"Viscosity",
"measurements",
"as",
"a",
"function",
"of",
"temperature",
"were",
"performed",
"using",
"a",
"cone-plate",
"viscometer.",
"Real-time",
"polymerization",
"was",
"monitored",
"by",
"infrared",
"spectroscopy.",
"Degree",
"of",
"conversion",
"(DC)",
"was",
"calculated",
"for",
"each",
"second",
"during",
"polymerization,",
"and",
"the",
"rate",
"of",
"po-",
"lymerization",
"analyzed.",
"Data",
"were",
"separately",
"submitted",
"to",
"two-way",
"ANOVA",
"and",
"Tukey’s",
"test",
"(P<.05).",
"Results:",
"Clearfil",
"presented",
"faster",
"increase",
"in",
"temperature",
"after",
"exposure",
"to",
"room",
"temperature",
"than",
"Scotchbond.",
"A",
"continuous",
"decrease",
"in",
"viscosity",
"(Pa.s)",
"was",
"observed",
"for",
"both",
"Scotchbond",
"(0.49,",
"0.34,",
"0.30,",
"0.26,",
"0.23,",
"0.23)",
"and",
"Clearfil",
"(0.38,",
"0.37,",
"0.34,",
"0.25,",
"0.24,",
"0.22).",
"For",
"Scotchbond,",
"higher",
"final",
"DC",
"was",
"detected",
"for",
"the",
"control",
"(62.7%)",
"compared",
"with",
"the",
"immediate",
"(53.3%)",
"and",
"5",
"min",
"(54.7%)",
"groups.",
"For",
"Clearfil,",
"the",
"control",
"sample",
"(81.4%)",
"showed",
"higher",
"DC",
"than",
"all",
"refrigerated",
"groups",
"(68.8–",
"69.5%).",
"Clearfil",
"always",
"showed",
"significantly",
"higher",
"DC",
"than",
"Scotchbond.",
"Conclusions:",
"Refrigeration",
"presented",
"a",
"significant",
"time-",
"and",
"material-dependent",
"effect",
"on",
"the",
"viscosity",
"and",
"polymerization",
"kinetics",
"of",
"the",
"bonding",
"resins.",
"Under",
"clinical",
"conditions,",
"adhesive",
"agents",
"should",
"be",
"removed",
"from",
"the",
"refrigerator",
"at",
"least",
"20",
"min",
"before",
"being",
"used.",
"(Eur",
"J",
"Dent",
"2010;4:150-",
"155)",
"Key",
"words:",
"Bonding",
"resins;",
"Degree",
"of",
"conversion;",
"Polymerization",
"kinetics;",
"Refrigeration;",
"Viscosity.",
"a",
"Professor,",
"Department",
"of",
"Dentistry,",
"School",
"of",
"Dentistry,",
"State",
"University",
"of",
"Montes",
"Claros,",
"MG,",
"Brasil.",
"b",
"Department",
"of",
"Restorative",
"Dentistry,",
"School",
"of",
"Dentistry,",
"Federal",
"University",
"of",
"Pelotas,",
"RS,",
"Brasil.",
"Corresponding",
"author:",
"Prof.",
"André",
"L.",
"Faria-e-Silva",
"Department",
"of",
"Dentistry,",
"School",
"of",
"Dentistry",
"State",
"Uni-",
"versity",
"of",
"Montes",
"Claros,",
"MG,",
"Brazil",
"Campus",
"Universi-",
"tário",
"Prof.",
"Darcy",
"Ribeiro,",
"Vila",
"Mauricéia",
"Montes",
"Claros,",
"MG,",
"Brasil",
"-",
"39401-089",
"Phone/Fax:",
"+55",
"38",
"3229.8284",
"E-mail:",
"andrelfsilva@hotmail.com",
"IntroductIon",
"The",
"main",
"goal",
"of",
"the",
"adhesion",
"of",
"restoratives",
"materials",
"to",
"dental",
"hard",
"tissues",
"is",
"to",
"obtain",
"high",
"bond",
"strengths",
"and",
"a",
"satisfactory,",
"long-lasting",
"seal.1-3",
"Over",
"the",
"last",
"decade,",
"a",
"number",
"of",
"inves-",
"tigations",
"have",
"reported",
"that",
"several",
"factors",
"might",
"interfere",
"with",
"the",
"bonding",
"ability",
"of",
"adhesive",
"sys-",
"tems",
"to",
"enamel",
"or",
"dentin,",
"including",
"the",
"adhesion",
"strategy,4",
"conditioning",
"time,5",
"solvent",
"removal",
"method,6,7",
"thickness",
"of",
"the",
"adhesive",
"layer,8",
"and",
"even",
"the",
"environmental",
"humidity.9,10",
"150",
"European",
"Journal",
"of",
"Dentistry"
] | [
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] | [
"Background:",
"Material/Methods:",
"Results:",
"Conclusions:",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"The",
"hyperdense",
"posterior",
"cerebral",
"artery",
"sign",
"in",
"CT",
"is",
"related",
"to",
"larger",
"ischemic",
"lesion",
"volume",
"Wojciech",
"Ambrosius1,2,",
"Varsha",
"Gupta1,",
"Radoslaw",
"Kazmierski3,",
"Agnieszka",
"Hellmann2,",
"GuoYu",
"Qian1,",
"Wieslaw",
"L.",
"Nowinski1",
"1",
"Biomedical",
"Imaging",
"Lab,",
"Agency",
"for",
"Science",
"Technology",
"and",
"Research,",
"Singapore",
"2",
"Department",
"of",
"Neurology",
"Poznań",
"University",
"of",
"Medical",
"Sciences,",
"Poznań,",
"Poland",
"3",
"Department",
"of",
"Neurology",
"and",
"Cerebrovascular",
"Disorders,",
"Poznań",
"University",
"of",
"Medical",
"Sciences,",
"L.",
"Bierkowski",
"Hospital,",
"Poznań,",
"Poland",
"Author’s",
"address:",
"Wojciech",
"Ambrosius,",
"Department",
"of",
"Neurology,",
"Poznan",
"University",
"of",
"Medical",
"Sciences,",
"Przybyszewskiego",
"49",
"Str.,",
"60-645,",
"Poznań,",
"Poland,",
"e-mail:",
"wambrosius@ump.edu.pl",
"Source",
"of",
"support:",
"This",
"study",
"is",
"a",
"part",
"of",
"the",
"joined",
"Singaporean-Polish",
"project",
"focused",
"on",
"development",
"of",
"the",
"computer-",
"aided",
"decision",
"support",
"system",
"for",
"assessment",
"of",
"thrombolytic",
"therapy",
"in",
"acute",
"ischemic",
"stroke",
"in",
"Emergency",
"Department",
"funded",
"by",
"Agency",
"for",
"Science,",
"Technology",
"and",
"Research,",
"Singapore",
"and",
"Ministry",
"of",
"Science",
"and",
"Higher",
"Education,",
"Poland",
"(project",
"no.",
"072-134",
"0049)",
"Summary",
"Hyperdensity",
"of",
"the",
"middle",
"cerebral",
"artery",
"(MCA)",
"on",
"unenhanced",
"CT",
"is",
"a",
"recognized",
"sign",
"associated",
"with",
"brain’s",
"early",
"ischemia.",
"The",
"number",
"of",
"studies",
"which",
"showed",
"a",
"hyperdense",
"posterior",
"cerebral",
"artery",
"(HPCA)",
"sign",
"in",
"posterior",
"circulation",
"infarct",
"is",
"relatively",
"small.",
"We",
"investigated",
"the",
"prevalence",
"of",
"the",
"HPCA",
"sign,",
"correlations",
"with",
"ischemic",
"lesion",
"volume,",
"and",
"stroke",
"risk",
"factors.",
"We",
"also",
"determined",
"the",
"association",
"with",
"prothrombotic",
"and",
"inflammatory",
"markers",
"which",
"have",
"not",
"been",
"studied",
"before.",
"In",
"the",
"group",
"of",
"376",
"patients",
"with",
"a",
"first",
"acute",
"stroke",
"consecutively",
"admitted",
"to",
"Emergency",
"Department,",
"early",
"signs",
"of",
"brain",
"infarction",
"were",
"visible",
"in",
"221",
"(58%)",
"cases.",
"Fifty",
"five",
"(25%)",
"subjects",
"had",
"ischemic",
"lesions",
"in",
"the",
"brain",
"supplied",
"by",
"the",
"posterior",
"circulation.",
"We",
"analyzed",
"the",
"unenhanced",
"CT",
"scans,",
"calculated",
"the",
"density",
"of",
"the",
"posterior",
"cerebral",
"arteries,",
"infarct",
"volume,",
"and",
"assessed",
"the",
"relation",
"of",
"the",
"HPCA",
"sign",
"to",
"other",
"factors.",
"The",
"HPCA",
"sign",
"appeared",
"on",
"CT",
"scans",
"of",
"12",
"(22%)",
"patients",
"with",
"evidence",
"of",
"the",
"posterior",
"circulation",
"infarct.",
"The",
"density",
"(in",
"Hounsfield",
"units)",
"of",
"the",
"affected",
"PCA",
"was",
"46.5",
"comparing",
"to",
"20.2",
"of",
"an",
"intact",
"vessel",
"(p<0.0001).",
"The",
"stroke",
"volume",
"was",
"larger",
"when",
"the",
"HPCA",
"sign",
"was",
"observed",
"(medians:",
"17.6",
"vs.",
"4.3",
"cm3,",
"p=0.02);",
"in",
"multivariate",
"analysis",
"this",
"association",
"was",
"still",
"significant",
"(OR=1.07;",
"95%",
"CI,",
"0.99–1.13).",
"The",
"C-reactive",
"protein",
"and",
"fibrinogen",
"levels",
"were",
"significantly",
"higher",
"(p=0.02",
"for",
"both",
"factors)",
"in",
"patients",
"with",
"the",
"HPCA",
"sign",
"in",
"the",
"univariate",
"analysis.",
"The",
"HPCA",
"may",
"be",
"considered",
"as",
"an",
"additional",
"marker",
"of",
"early",
"brain",
"infarct,",
"especially",
"with",
"large",
"lesion",
"volume.",
"Signature:",
"©",
"Pol",
"J",
"Radiol,",
"2011;",
"76(2):",
"13-17",
"Received:",
"2011.04.12",
"Accepted:",
"2011.05.11",
"Key",
"words:",
"stroke",
"•",
"imaging",
"•",
"computed",
"tomography",
"•",
"hyperdense",
"artery",
"sign",
"PDF",
"file:",
"http://www.polradiol.com/fulltxt.php?ICID=881814",
"Background",
"Visualization",
"of",
"acute",
"signs",
"of",
"ischemic",
"stroke",
"is",
"still",
"a",
"challenging",
"aspect",
"of",
"neuroimaging.",
"Every",
"year",
"new",
"sophisticated",
"imaging",
"methods",
"are",
"introduced",
"and",
"their",
"results",
"are",
"published",
"showing",
"brain",
"ischemic",
"lesions",
"much",
"more",
"accurately.",
"Most",
"of",
"these",
"trials",
"employ",
"MRI",
"techni-",
"ques",
"[1,2].",
"Practically,",
"in",
"routine",
"emergency",
"neurological",
"13"
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] | [
"Upsala",
"Journal",
"of",
"Medical",
"Sciences.",
"2011;",
"116:",
"285–288",
"CASE",
"REPORT",
"Recurrent",
"dislocation",
"of",
"the",
"patella",
"accompanying",
"hypotrochlea",
"of",
"the",
"femur",
"and",
"malalignment",
"of",
"the",
"patella",
"AKIRA",
"HORIKAWA1,",
"HIROYUKI",
"KODAMA1,",
"NAOHISA",
"MIYAKOSHI2,",
"SHIN",
"YAMADA2",
"&",
"SEIYA",
"MIYAMOTO3",
"1South",
"Akita",
"Orthopedic",
"Clinic,",
"Seiwakai,",
"96-2",
"Kaidousita,",
"Syowa-Ookubo,",
"Katagami",
"018-1401,",
"Japan,",
"2Department",
"of",
"Orthopedic",
"Surgery,",
"Akita",
"University",
"Graduate",
"School",
"of",
"Medicine,",
"1-1-1",
"Hondo,",
"Akita",
"010-8543,",
"Japan,",
"and",
"3Department",
"of",
"Orthopedic",
"Surgery,",
"Nakadori",
"General",
"Hospital,",
"3-15",
"Minamidoori-Misono,",
"Akita",
"010-8577,",
"Japan",
"Abstract",
"This",
"case",
"report",
"describes",
"a",
"rare",
"case",
"of",
"recurrent",
"dislocation",
"of",
"the",
"patella",
"which",
"was",
"accompanied",
"with",
"trochlear",
"dysplasia",
"and",
"malalignment",
"of",
"the",
"patella",
"in",
"a",
"15-year-old",
"girl.",
"She",
"complained",
"of",
"hemoarthrosis",
"and",
"recurrent",
"patellar",
"dislocation",
"in",
"the",
"early",
"knee",
"flexion",
"phase.",
"Plain",
"radiography",
"and",
"computed",
"tomography",
"(CT)",
"showed",
"patellar",
"malalignment",
"(quadriceps",
"angle",
"20",
")",
"and",
"severe",
"dysplasia",
"of",
"the",
"trochlea",
"of",
"the",
"femur",
"(sulcus",
"angle",
"170",
").",
"Surgery",
"was",
"performed,",
"consisting",
"of",
"trochleoplasty",
"in",
"addition",
"to",
"proximal",
"and",
"distal",
"realignment.",
"Trochleoplasty",
"was",
"undertaken",
"using",
"a",
"modified",
"Dejour",
"technique.",
"After",
"surgery,",
"the",
"patient",
"complained",
"of",
"joint",
"contracture.",
"Arthroscopic",
"release",
"of",
"fibrous",
"tissue",
"relieved",
"symptoms",
"and",
"obtained",
"normal",
"range",
"of",
"motion",
"without",
"patellar",
"dislocation.",
"Postoperative",
"radiography",
"and",
"CT",
"demonstrated",
"improvement",
"of",
"the",
"quadriceps",
"angle",
"(10",
")",
"and",
"sulcus",
"angle",
"(140",
").",
"Key",
"words:",
"Dislocations,",
"knee,",
"patella",
"Introduction",
"Although",
"biomechanics",
"and",
"surgical",
"treatments",
"have",
"been",
"examined",
"for",
"recurrent",
"dislocation",
"of",
"the",
"patella,",
"few",
"studies",
"have",
"reported",
"on",
"the",
"combination",
"of",
"troch-",
"lear",
"dysplasia",
"and",
"recurrent",
"patellar",
"instability.",
"In",
"addi-",
"tion,",
"treatment",
"methods",
"have",
"only",
"been",
"reported",
"in",
"a",
"few",
"cases.",
"We",
"present",
"herein",
"a",
"case",
"with",
"successful",
"surgical",
"outcomes",
"for",
"the",
"treatment",
"of",
"recurrent",
"dislocation",
"of",
"the",
"patella",
"with",
"trochlear",
"dysplasia",
"and",
"malalignment",
"of",
"the",
"patella.",
"Case",
"report",
"A",
"15-year-old",
"girl",
"who",
"had",
"complained",
"of",
"recurrent",
"patellar",
"dislocation",
"for",
"more",
"than",
"5",
"years",
"presented",
"with",
"left",
"knee",
"hemoarthrosis.",
"Physical",
"examination",
"revealed",
"patellar",
"dislocation",
"at",
"slight",
"knee",
"flexion",
"of",
"approximately",
"30",
"that",
"was",
"easily",
"reduced",
"without",
"pain.",
"No",
"signs",
"of",
"apprehension,",
"joint",
"laxities,",
"or",
"sys-",
"tematic",
"disease",
"were",
"observed.",
"Plain",
"radiography",
"showed",
"a",
"lateralized",
"tibial",
"tubercle",
"with",
"increased",
"quad-",
"riceps",
"angle",
"(Q",
"angle)",
"of",
"20",
"and",
"dysplasia",
"of",
"the",
"trochlea",
"as",
"defined",
"by",
"the",
"‘crossing",
"sign’",
"(1)",
"without",
"patella",
"alta.",
"Computed",
"tomography",
"(CT)",
"also",
"demon-",
"strated",
"marked",
"trochleodysplasia",
"of",
"the",
"femur,",
"with",
"a",
"sulcus",
"angle",
"of",
"170",
"(Figure",
"1).",
"Arthroscopic",
"examination",
"showed",
"a",
"flat,",
"hypoplastic",
"trochlea",
"of",
"the",
"femur",
"and",
"frequent",
"patellar",
"dislocation",
"with",
"knee",
"motion.",
"Surgery",
"consisted",
"of",
"trochleoplasty,",
"followed",
"by",
"proximal",
"and",
"distal",
"realignment.",
"Tro-",
"chleoplasty",
"was",
"performed",
"as",
"a",
"modified",
"Dejour",
"tech-",
"nique",
"(2).",
"This",
"technique",
"involved:",
"1)",
"shaving",
"of",
"the",
"subchondral",
"bone;",
"2)",
"making",
"an",
"incision",
"from",
"the",
"aspect",
"of",
"the",
"groove",
"to",
"the",
"anterior",
"femoral",
"cortex;",
"3)",
"cutting",
"a",
"subchondral",
"trench;",
"4)",
"undermining",
"the",
"flap",
"to",
"allow",
"collapse",
"of",
"the",
"osteochondral",
"flap;",
"5)",
"impaction",
"using",
"finger",
"pressure;",
"and",
"6)",
"fixation",
"of",
"Correspondence:",
"Akira",
"Horikawa,",
"MD,",
"South",
"Akita",
"Orthopedic",
"Clinic,",
"Seiwakai,",
"96-2",
"Kaidousita,",
"Syowa-Ookubo,",
"Katagami",
"018-1401,",
"Japan.",
"E-mail:",
"horikawa@virgo.interq.or.jp",
"(Received",
"19",
"February",
"2011;",
"accepted",
"8",
"June",
"2011)",
"ISSN",
"0300-9734",
"print/ISSN",
"2000-1967",
"online",
"2011",
"Informa",
"Healthcare",
"DOI:",
"10.3109/03009734.2011.596291"
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] | [
"y",
"g",
"o",
"l",
"o",
"i",
"s",
"y",
"h",
"P",
"l",
"a",
"r",
"e",
"n",
"e",
"G",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"EF",
"hands",
"at",
"the",
"N-lobe",
"of",
"calmodulin",
"are",
"required",
"for",
"both",
"SK",
"channel",
"gating",
"and",
"stable",
"SK–calmodulin",
"interaction",
"Weiyan",
"Li,",
"David",
"B.",
"Halling,",
"Amelia",
"W.",
"Hall,",
"and",
"Richard",
"W.",
"Aldrich",
"Section",
"of",
"Neurobiology,",
"Center",
"for",
"Learning",
"and",
"Memory,",
"The",
"University",
"of",
"Texas",
"at",
"Austin,",
"Austin,",
"TX",
"78712",
"Small",
"conductance",
"calcium-activated",
"potassium",
"(SK)",
"channels",
"respond",
"to",
"intracellular",
"Ca2+",
"via",
"constitutively",
"asso-",
"ciated",
"calmodulin",
"(CaM).",
"Previous",
"studies",
"have",
"proposed",
"a",
"modular",
"design",
"for",
"the",
"interaction",
"between",
"CaM",
"and",
"SK",
"channels.",
"The",
"C-lobe",
"and",
"the",
"linker",
"of",
"CaM",
"are",
"thought",
"to",
"regulate",
"the",
"constitutive",
"binding,",
"whereas",
"the",
"N-lobe",
"binds",
"Ca2+",
"and",
"gates",
"SK",
"channels.",
"However,",
"we",
"found",
"that",
"coexpression",
"of",
"mutant",
"CaM",
"(E/Q)",
"where",
"the",
"N-lobe",
"has",
"only",
"one",
"functional",
"EF",
"hand",
"leads",
"to",
"rapid",
"rundown",
"of",
"SK",
"channel",
"activity,",
"which",
"can",
"be",
"recovered",
"with",
"exogenously",
"applied",
"wild-type",
"(WT),",
"but",
"not",
"mutant,",
"CaM.",
"Our",
"results",
"suggest",
"that",
"the",
"mutation",
"at",
"the",
"N-lobe",
"EF",
"hand",
"disrupts",
"the",
"stable",
"interaction",
"between",
"CaM",
"and",
"SK",
"channel",
"subunits,",
"such",
"that",
"mutant",
"CaM",
"dissociates",
"from",
"the",
"channel",
"complex",
"when",
"the",
"inside",
"of",
"the",
"membrane",
"is",
"exposed",
"to",
"CaM-free",
"solution.",
"The",
"disruption",
"of",
"the",
"stable",
"interaction",
"does",
"not",
"directly",
"result",
"from",
"the",
"loss",
"of",
"Ca2+-binding",
"capacity",
"because",
"SK",
"channels",
"and",
"WT",
"CaM",
"can",
"stably",
"interact",
"in",
"the",
"absence",
"of",
"Ca2+.",
"These",
"findings",
"question",
"a",
"previous",
"conclusion",
"that",
"CaM",
"where",
"the",
"N-lobe",
"has",
"only",
"one",
"functional",
"EF",
"hand",
"can",
"stably",
"support",
"the",
"gating",
"of",
"SK",
"channels.",
"They",
"cannot",
"be",
"explained",
"by",
"the",
"current",
"model",
"of",
"modular",
"interaction",
"between",
"CaM",
"and",
"SK",
"channels,",
"and",
"they",
"imply",
"a",
"role",
"for",
"N-lobe",
"EF",
"hand",
"residues",
"in",
"binding",
"to",
"the",
"channel",
"subunits.",
"Additionally,",
"we",
"found",
"that",
"a",
"potent",
"enhancer",
"for",
"SK",
"channels,",
"3-oxime-6,7-dichloro-1H-indole-2,3-dione",
"(NS309),",
"enables",
"the",
"recovery",
"of",
"channel",
"activity",
"with",
"CaM",
"(E/Q),",
"sug-",
"gesting",
"that",
"NS309",
"stabilizes",
"the",
"interaction",
"between",
"CaM",
"and",
"SK",
"channels.",
"CaM",
"(E/Q)",
"can",
"regulate",
"Ca2+-depen-",
"dent",
"gating",
"of",
"SK",
"channels",
"in",
"the",
"presence",
"of",
"NS309,",
"but",
"with",
"a",
"lower",
"apparent",
"Ca2+",
"affinity",
"than",
"WT",
"CaM.",
"I",
"N",
"T",
"R",
"O",
"D",
"U",
"C",
"T",
"I",
"O",
"N",
"By",
"responding",
"to",
"elevated",
"intracellular",
"Ca2+",
"concentra-",
"tion,",
"small",
"conductance",
"calcium-activated",
"potassium",
"(SK;",
"KCa2,",
"KCNN)",
"channels",
"play",
"critical",
"roles",
"in",
"regulat-",
"ing",
"neuronal",
"excitability",
"(Stocker",
"et",
"al.,",
"1999),",
"hor-",
"mone",
"release",
"(Tse",
"and",
"Hille,",
"1992),",
"and",
"smooth",
"muscle",
"tone",
"(Doughty",
"et",
"al.,",
"1999;",
"Herrera",
"et",
"al.,",
"2000).",
"SK",
"channel",
"subunits",
"do",
"not",
"directly",
"bind",
"Ca2+",
"but",
"detect",
"Ca2+",
"concentration",
"via",
"associated",
"calmodulin",
"(CaM)",
"(Xia",
"et",
"al.,",
"1998).",
"Different",
"from",
"many",
"other",
"CaM-interact-",
"ing",
"proteins",
"that",
"only",
"bind",
"with",
"Ca2+-loaded",
"CaM",
"(Yam-",
"niuk",
"and",
"Vogel,",
"2004),",
"SK",
"channels",
"are",
"constitutively",
"associated",
"with",
"CaM,",
"even",
"in",
"the",
"absence",
"of",
"Ca2+",
"(Xia",
"et",
"al.,",
"1998).",
"This",
"intimate",
"association",
"likely",
"enables",
"the",
"fast",
"activation",
"of",
"SK",
"channels",
"in",
"response",
"to",
"Ca2+",
"as",
"es-",
"sential",
"for",
"their",
"physiological",
"functions",
"(Xia",
"et",
"al.,",
"1998).",
"CaM",
"consists",
"of",
"two",
"globular",
"domains",
"(the",
"C-",
"and",
"N-lobe)",
"connected",
"by",
"a",
"flexible",
"linker.",
"Each",
"lobe",
"con-",
"tains",
"two",
"EF",
"hand",
"structures",
"that",
"serve",
"as",
"the",
"Ca2+-binding",
"sites.",
"Structural,",
"functional,",
"and",
"biochemical",
"studies",
"on",
"SK",
"channel–CaM",
"complexes",
"have",
"suggested",
"a",
"modular",
"mechanism",
"for",
"the",
"molecular",
"interaction",
"between",
"SK",
"channels",
"and",
"CaM.",
"The",
"C-lobe",
"and",
"the",
"linker",
"of",
"CaM",
"are",
"thought",
"to",
"be",
"responsible",
"for",
"the",
"constitutive",
"asso-",
"ciation",
"between",
"CaM",
"and",
"SK",
"channels,",
"but",
"C-lobe",
"EF",
"hands",
"do",
"not",
"bind",
"Ca2+.",
"On",
"the",
"other",
"hand,",
"the",
"N-lobe",
"of",
"CaM",
"is",
"considered",
"not",
"involved",
"in",
"the",
"constitutive",
"bind-",
"ing,",
"but",
"EF",
"hands",
"in",
"the",
"N-lobe",
"bind",
"Ca2+",
"and",
"gate",
"SK",
"channels",
"(Xia",
"et",
"al.,",
"1998;",
"Keen",
"et",
"al.,",
"1999;",
"Schumacher",
"et",
"al.,",
"2001;",
"Li",
"and",
"Aldrich,",
"2009).",
"A",
"thorough",
"understanding",
"of",
"the",
"activation",
"mecha-",
"nism",
"for",
"SK",
"channels",
"is",
"not",
"yet",
"available,",
"partly",
"result-",
"ing",
"from",
"the",
"fact",
"that",
"each",
"SK",
"channel",
"complex",
"has",
"up",
"to",
"four",
"CaM",
"molecules,",
"each",
"with",
"at",
"least",
"two",
"Ca2+-bind-",
"ing",
"sites",
"(EF",
"hands)",
"that",
"likely",
"bind",
"Ca2+",
"cooperatively",
"(Xia",
"et",
"al.,",
"1998;",
"Keen",
"et",
"al.,",
"1999).",
"The",
"contribution",
"of",
"individual",
"EF",
"hands",
"to",
"the",
"opening",
"of",
"SK",
"channels",
"has",
"been",
"difficult",
"to",
"evaluate.",
"To",
"establish",
"a",
"quantitative",
"framework",
"for",
"the",
"characterization",
"of",
"the",
"coupling",
"be-",
"tween",
"Ca2+",
"binding",
"and",
"channel",
"activation,",
"it",
"is",
"useful",
"to",
"study",
"SK",
"channels",
"associated",
"with",
"CaMs",
"in",
"which",
"only",
"one",
"of",
"the",
"N-lobe",
"EF",
"hands",
"binds",
"Ca2+.",
"A",
"previous",
"study",
"suggested",
"that",
"when",
"one",
"of",
"the",
"EF",
"hands",
"at",
"the",
"N-lobe",
"of",
"CaM",
"loses",
"its",
"Ca2+-binding",
"capacity",
"by",
"mutation,",
"CaM",
"can",
"still",
"stably",
"support",
"SK",
"channel",
"gating,",
"albeit",
"with",
"a",
"reduced",
"apparent",
"affinity",
"for",
"Ca2+",
"(Keen",
"et",
"al.,",
"1999).",
"This",
"mutation",
"in",
"CaM",
"would",
"greatly",
"reduce",
"the",
"com-",
"plexity",
"of",
"the",
"SK",
"channel",
"gating",
"scheme;",
"therefore,",
"we",
"Correspondence",
"to",
"Richard",
"W.",
"Aldrich:",
"raldrich@mail.utexas.edu",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"CaM,",
"calmodulin;",
"NS309,",
"3-oxime-6,7-",
"dichloro-1H-indole-2,3-dione;",
"SK,",
"small",
"conductance",
"calcium-activated",
"potassium;",
"WT,",
"wild-type.",
"©",
"2009",
"Li",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"an",
"Attribution–Noncommer-",
"cial–Share",
"Alike–No",
"Mirror",
"Sites",
"license",
"for",
"the",
"first",
"six",
"months",
"after",
"the",
"publication",
"date",
"(see",
"http://www.jgp.org/misc/terms.shtml).",
"After",
"six",
"months",
"it",
"is",
"available",
"under",
"a",
"Creative",
"Commons",
"License",
"(Attribution–Noncommercial–Share",
"Alike",
"3.0",
"Unported",
"license,",
"as",
"de-",
"scribed",
"at",
"http://creativecommons.org/licenses/by-nc-sa/3.0/).",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Gen.",
"Physiol.",
"Vol.",
"134",
"No.",
"4",
"281–293",
"www.jgp.org/cgi/doi/10.1085/jgp.200910295",
"281"
] | [
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] | [
"Psychon",
"Bull",
"Rev",
"(2011)",
"18:364–370",
"DOI",
"10.3758/s13423-010-0044-y",
"When",
"bicycle",
"pump",
"is",
"harder",
"to",
"read",
"than",
"bicycle",
"bell:",
"effects",
"of",
"parsing",
"cues",
"in",
"first",
"and",
"second",
"language",
"compound",
"reading",
"Kristin",
"Lemhöfer",
"&",
"Dirk",
"Koester",
"&",
"Robert",
"Schreuder",
"Published",
"online:",
"5",
"January",
"2011",
"#",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Reading",
"and",
"understanding",
"morphologically",
"com-",
"plex",
"words",
"can",
"sometimes",
"be",
"a",
"particular",
"challenge",
"to",
"nonnative",
"speakers.",
"For",
"example,",
"compound",
"words",
"consist",
"of",
"multiple",
"free",
"morphemes,",
"oftentimes",
"without",
"explicit",
"marking",
"of",
"the",
"morpheme",
"boundaries.",
"In",
"a",
"lexical",
"decision",
"task,",
"we",
"investigated",
"compound",
"reading",
"in",
"native",
"and",
"nonnative",
"speakers",
"of",
"Dutch.",
"The",
"compounds",
"differed",
"in",
"that",
"the",
"letter",
"bigram",
"that",
"formed",
"the",
"morpheme",
"boundary",
"could",
"or",
"could",
"not",
"occur",
"within",
"a",
"Dutch",
"morpheme,",
"thus",
"providing",
"an",
"orthotactic",
"cue",
"as",
"to",
"the",
"position",
"of",
"the",
"morpheme",
"boundary.",
"Native",
"and",
"nonnative",
"speakers",
"responded",
"faster",
"to",
"compounds",
"that",
"contained",
"such",
"an",
"orthotactic",
"cue.",
"Additional",
"analyses",
"showed",
"that",
"although",
"native",
"speakers",
"used",
"this",
"cue",
"for",
"long,",
"but",
"not",
"for",
"short",
"compounds,",
"no",
"such",
"word",
"length",
"modulation",
"was",
"observed",
"for",
"nonnative",
"speakers.",
"It",
"is",
"suggested",
"that",
"orthotactic",
"parsing",
"cues",
"are",
"used",
"during",
"compound",
"reading",
"and",
"possibly",
"even",
"more",
"so",
"in",
"nonnative",
"speakers.",
"Keywords",
"Visual",
"word",
"recognition",
".",
"compound",
"reading",
".",
"Orthotactic",
"parsing",
"cues",
".",
"Second",
"language",
"speakers",
"Learning",
"a",
"second",
"language",
"(L2)",
"can",
"be",
"a",
"tedious",
"enterprise,",
"and",
"each",
"language",
"has",
"its",
"own",
"hurdles",
"that",
"Electronic",
"supplementary",
"material",
"The",
"online",
"version",
"of",
"this",
"article",
"(doi:10.3758/s13423-010-0044-y)",
"contains",
"supplementary",
"material,",
"which",
"is",
"available",
"to",
"authorized",
"users.",
"K.",
"Lemhöfer",
"(*)",
":",
"R.",
"Schreuder",
"Donders",
"Institute",
"for",
"Brain,",
"Cognition,",
"and",
"Behaviour",
"-",
"Centre",
"for",
"Cognition,",
"Radboud",
"University",
"Nijmegen,",
"P.O.",
"Box",
"9104,",
"6500",
"HE",
"Nijmegen,",
"The",
"Netherlands",
"e-mail:",
"k.lemhofer@donders.ru.nl",
"D.",
"Koester",
"Cognitive",
"Interaction",
"Technology",
"-",
"Center",
"of",
"Excellence,",
"University",
"of",
"Bielefeld,",
"Bielefeld,",
"Germany",
"make",
"life",
"hard",
"for",
"nonnative",
"speakers.",
"In",
"languages",
"such",
"as",
"Dutch",
"or",
"German,",
"for",
"instance,",
"reading",
"compounds",
"(words",
"with",
"more",
"than",
"one",
"free",
"morpheme,",
"such",
"as",
"doghouse)",
"can",
"be",
"problematic,",
"because",
"they",
"are",
"written",
"without",
"interspa-",
"ces",
"or",
"hyphens.",
"An",
"extreme",
"example",
"from",
"German",
"is",
"Selbstbedienungskontoauszugsdrucker",
"(“self-service",
"printer",
"for",
"account",
"statements”),",
"but",
"even",
"in",
"two-constituent",
"compounds,",
"it",
"can",
"be",
"difficult",
"to",
"identify",
"the",
"constituent",
"boundary.",
"In",
"the",
"Dutch",
"example",
"fiets-pomp",
"(“bicycle",
"pump”;",
"hyphens",
"are",
"included",
"only",
"to",
"indicate",
"constituent",
"boundaries),",
"the",
"location",
"of",
"the",
"boundary",
"does",
"not",
"follow",
"from",
"orthotactic",
"constraints—that",
"is,",
"from",
"the",
"rules",
"spec-",
"ifying",
"which",
"letter",
"sequences",
"are",
"well",
"formed",
"for",
"a",
"given",
"language.",
"The",
"incorrect",
"parsing",
"*fiet-spomp",
"also",
"results",
"in",
"two",
"legal",
"and",
"pronounceable",
"letter",
"strings",
"and",
"can",
"thus",
"not",
"be",
"rejected",
"immediately.",
"In",
"contrast,",
"in",
"fiets-bel",
"(“bicycle",
"bell”),",
"the",
"morpheme",
"boundary",
"is",
"easier",
"to",
"detect,",
"since",
"the",
"bigram",
"“sb”",
"cannot",
"occur",
"within",
"Dutch",
"morphemes.",
"Whether",
"or",
"not",
"orthotactic",
"parsing",
"cues",
"such",
"as",
"the",
"legality",
"of",
"the",
"boundary",
"bigram",
"are",
"used",
"in",
"compound",
"processing",
"is",
"not",
"only",
"unknown",
"for",
"L2",
"speakers,",
"it",
"has",
"also",
"rarely",
"been",
"investigated",
"in",
"native",
"speakers.",
"Of",
"course,",
"not",
"only",
"nonnative,",
"but",
"also",
"native",
"Dutch",
"readers",
"might",
"be",
"slowed",
"down",
"when",
"orthotactic",
"cues",
"that",
"indicate",
"the",
"boundary",
"are",
"missing.",
"The",
"few",
"studies",
"on",
"effects",
"of",
"orthotactic",
"boundary",
"cues",
"in",
"native",
"speakers",
"have",
"yielded",
"controversial",
"results.",
"Taft",
"and",
"Forster",
"(1976)",
"used",
"nonwords",
"with",
"clear",
"(e.g.,",
"bonchmip)",
"versus",
"unclear",
"constituent",
"boundaries",
"(e.g.,",
"glicerax)",
"in",
"lexical",
"decision",
"and",
"found",
"no",
"effect",
"of",
"boundary",
"type.",
"However,",
"rejecting",
"nonwords",
"might",
"involve",
"quite",
"different",
"mecha-",
"nisms",
"than",
"word",
"recognition.",
"Libben",
"(1994)",
"showed",
"that",
"parsing",
"preferences",
"for",
"novel",
"English",
"compounds",
"with",
"ambiguous",
"parsings",
"(e.g.,",
"busheater)",
"are",
"influenced",
"by",
"orthographic",
"factors.",
"In",
"a",
"study",
"using",
"eye-movement",
"measures",
"during",
"sentence",
"reading,",
"Bertram,",
"Pollatsek,"
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945
],
[
659,
936,
680,
945
],
[
682,
936,
690,
945
],
[
692,
936,
702,
945
],
[
703,
936,
767,
945
],
[
433,
946,
501,
955
],
[
503,
946,
537,
955
],
[
538,
946,
561,
955
],
[
563,
946,
581,
955
],
[
582,
946,
608,
955
],
[
610,
946,
621,
955
],
[
622,
946,
635,
955
],
[
636,
946,
650,
955
],
[
651,
946,
661,
955
],
[
662,
946,
690,
955
],
[
692,
946,
709,
955
],
[
711,
946,
723,
955
],
[
725,
946,
767,
955
],
[
433,
956,
450,
965
],
[
452,
956,
467,
965
],
[
468,
956,
609,
965
],
[
610,
956,
629,
965
],
[
631,
956,
641,
965
],
[
642,
956,
670,
965
],
[
672,
956,
677,
965
],
[
678,
956,
684,
965
],
[
686,
956,
719,
965
],
[
720,
956,
742,
965
],
[
744,
956,
749,
965
],
[
750,
956,
766,
965
],
[
433,
966,
451,
975
],
[
453,
966,
492,
975
],
[
493,
966,
521,
975
],
[
523,
966,
654,
975
],
[
656,
966,
675,
975
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[
677,
966,
688,
975
],
[
690,
966,
726,
975
],
[
728,
966,
756,
975
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[
758,
966,
766,
975
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[
433,
976,
470,
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[
472,
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985
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[
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] | [
"y",
"g",
"o",
"l",
"o",
"i",
"s",
"y",
"h",
"P",
"l",
"a",
"r",
"e",
"n",
"e",
"G",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Inhibition",
"of",
"KCa2.2",
"and",
"KCa2.3",
"channel",
"currents",
"by",
"protonation",
"of",
"outer",
"pore",
"histidine",
"residues",
"Samuel",
"J.",
"Goodchild,1",
"Cedric",
"Lamy,2",
"Vincent",
"Seutin,2",
"and",
"Neil",
"V.",
"Marrion1",
"1Department",
"of",
"Physiology",
"and",
"Pharmacology,",
"School",
"of",
"Medical",
"Sciences,",
"University",
"of",
"Bristol,",
"Bristol",
"BS8",
"1TD,",
"England,",
"UK",
"2Laboratory",
"of",
"Pharmacology,",
"Giga-Neurosciences,",
"University",
"of",
"Liège,",
"4000",
"Liège,",
"Belgium",
"Ion",
"channels",
"are",
"often",
"modulated",
"by",
"changes",
"in",
"extracellular",
"pH,",
"with",
"most",
"examples",
"resulting",
"from",
"shifts",
"in",
"the",
"ionization",
"state",
"of",
"histidine",
"residue(s)",
"in",
"the",
"channel",
"pore.",
"The",
"application",
"of",
"acidic",
"extracellular",
"solution",
"inhib-",
"ited",
"expressed",
"KCa2.2",
"(SK2)",
"and",
"KCa2.3",
"(SK3)",
"channel",
"currents,",
"with",
"KCa2.3",
"(pIC50",
"of",
"6.8)",
"being",
"approximately",
"fourfold",
"more",
"sensitive",
"than",
"KCa2.2",
"(pIC50",
"of",
"6.2).",
"Inhibition",
"was",
"found",
"to",
"be",
"voltage",
"dependent,",
"resulting",
"from",
"a",
"shift",
"in",
"the",
"affinity",
"for",
"the",
"rectifying",
"intracellular",
"divalent",
"cation(s)",
"at",
"the",
"inner",
"mouth",
"of",
"the",
"selectivity",
"filter.",
"The",
"inhibition",
"by",
"extracellular",
"protons",
"resulted",
"from",
"a",
"reduction",
"in",
"the",
"single-channel",
"conductance,",
"without",
"signifi-",
"cant",
"changes",
"in",
"open-state",
"kinetics",
"or",
"open",
"probability.",
"KCa2.2",
"and",
"KCa2.3",
"subunits",
"both",
"possess",
"a",
"histidine",
"residue",
"in",
"their",
"outer",
"pore",
"region",
"between",
"the",
"transmembrane",
"S5",
"segment",
"and",
"the",
"pore",
"helix,",
"with",
"KCa2.3",
"also",
"exhibiting",
"an",
"additional",
"histidine",
"residue",
"between",
"the",
"selectivity",
"filter",
"and",
"S6.",
"Mutagenesis",
"revealed",
"that",
"the",
"outer",
"pore",
"histi-",
"dine",
"common",
"to",
"both",
"channels",
"was",
"critical",
"for",
"inhibition.",
"The",
"greater",
"sensitivity",
"of",
"KCa2.3",
"currents",
"to",
"protons",
"arose",
"from",
"the",
"additional",
"histidine",
"residue",
"in",
"the",
"pore,",
"which",
"was",
"more",
"proximal",
"to",
"the",
"conduction",
"pathway",
"and",
"in",
"the",
"electrostatic",
"vicinity",
"of",
"the",
"ion",
"conduction",
"pathway.",
"The",
"decrease",
"of",
"channel",
"conductance",
"by",
"extracellular",
"protons",
"was",
"mimicked",
"by",
"mutation",
"of",
"the",
"outer",
"pore",
"histidine",
"in",
"KCa2.2",
"to",
"an",
"asparagine",
"residue.",
"These",
"data",
"sug-",
"gest",
"that",
"local",
"interactions",
"involving",
"the",
"outer",
"turret",
"histidine",
"residues",
"are",
"crucial",
"to",
"enable",
"high",
"conductance",
"openings,",
"with",
"protonation",
"inhibiting",
"current",
"by",
"changing",
"pore",
"shape.",
"I",
"N",
"T",
"R",
"O",
"D",
"U",
"C",
"T",
"I",
"O",
"N",
"The",
"KCa2.2",
"(SK2)",
"and",
"KCa2.3",
"(SK3)",
"potassium",
"channels",
"are",
"characterized",
"by",
"their",
"activation",
"by",
"intracellular",
"calcium",
"(Ca2+;",
"half-maximal",
"activation",
"of",
"0.3–0.7",
"µM),",
"voltage",
"independence,",
"and",
"small",
"single-channel",
"con-",
"ductance",
"of",
"10–20",
"pS",
"(Köhler",
"et",
"al.,",
"1996;",
"Hirschberg",
"et",
"al.,",
"1998;",
"Xia",
"et",
"al.,",
"1998).",
"Because",
"of",
"the",
"distinct",
"spatial",
"distribution",
"of",
"the",
"channel",
"subtypes",
"in",
"the",
"mammalian",
"brain",
"and",
"their",
"involvement",
"in",
"the",
"genera-",
"tion",
"of",
"afterhyperpolarization",
"currents,",
"there",
"has",
"been",
"considerable",
"interest",
"in",
"developing",
"subtype-selective",
"pharmacological",
"tools",
"to",
"study",
"these",
"channels",
"(Stocker",
"and",
"Pedarzani,",
"2000;",
"Shakkottai",
"et",
"al.,",
"2001;",
"Sailer",
"et",
"al.,",
"2002,",
"2004;",
"Stocker",
"et",
"al.,",
"2004;",
"Dilly",
"et",
"al.,",
"2005).",
"The",
"predicted",
"pore",
"regions",
"of",
"KCa2.2",
"and",
"KCa2.3",
"display",
"high",
"sequence",
"homology.",
"Each",
"channel",
"subunit",
"pos-",
"sesses",
"a",
"histidine",
"(H)",
"residue",
"that",
"is",
"predicted",
"to",
"reside",
"within",
"the",
"extracellular-facing",
"region",
"of",
"the",
"outer",
"pore",
"(H337",
"in",
"KCa2.2",
"and",
"H491",
"in",
"KCa2.3).",
"In",
"addition,",
"the",
"KCa2.3",
"subunit",
"exhibits",
"an",
"additional",
"H",
"(H522)",
"that",
"is",
"seen",
"as",
"asparagine",
"(N368)",
"in",
"KCa2.2.",
"Histidine",
"residues",
"in",
"channels’",
"outer",
"pore",
"regions",
"have",
"been",
"reported",
"to",
"be",
"proton",
"interaction",
"sites",
"that",
"mediate",
"inhibition",
"of",
"currents.",
"For",
"example,",
"proton-induced",
"inhibition",
"is",
"ob-",
"V.",
"Seutin",
"and",
"N.V.",
"Marrion",
"contributed",
"equally",
"to",
"this",
"paper.",
"Correspondence",
"to",
"Neil",
"V.",
"Marrion:",
"N.V.Marrion@bris.ac.uk",
"Abbreviation",
"used",
"in",
"this",
"paper:",
"GHK,",
"Goldman-Hodgkin-Katz.",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Gen.",
"Physiol.",
"Vol.",
"134",
"No.",
"4",
"295–308",
"www.jgp.org/cgi/doi/10.1085/jgp.200910252",
"served",
"for",
"several",
"different",
"potassium",
"channels,",
"includ-",
"ing",
"the",
"voltage-gated",
"Shaker-like",
"plant",
"channel",
"ATK3",
"(Geiger",
"et",
"al.,",
"2002),",
"Kv1.5",
"(Steidl",
"and",
"Yool,",
"1999;",
"Jäger",
"and",
"Grissmer,",
"2001;",
"Kehl",
"et",
"al.,",
"2002),",
"Kv1.4",
"(Claydon",
"et",
"al.,",
"2000),",
"Kv7.2/7.3",
"(Prole",
"et",
"al.,",
"2003),",
"K2P2.1",
"(Cohen",
"et",
"al.,",
"2008),",
"and",
"the",
"inward-rectifying",
"channel",
"Kir2.3",
"(Coulter",
"et",
"al.,",
"1995;",
"Ureche",
"et",
"al.,",
"2008).",
"Several",
"mechanisms",
"have",
"been",
"proposed",
"to",
"explain",
"this",
"inhi-",
"bition.",
"For",
"example,",
"Kv1.5",
"macroscopic",
"current",
"block",
"is",
"mediated",
"through",
"modifying",
"gating",
"and",
"enhancing",
"inactivation",
"without",
"any",
"effect",
"on",
"single-channel",
"con-",
"ductance",
"(Kwan",
"et",
"al.,",
"2006).",
"Macroscopic",
"inhibition",
"of",
"both",
"ATK3",
"and",
"Kir2.3",
"channel",
"currents",
"resulted",
"from",
"a",
"reduction",
"in",
"single-channel",
"conductance",
"(Coulter",
"et",
"al.,",
"1995;",
"Geiger",
"et",
"al.,",
"2002),",
"whereas",
"inhibition",
"of",
"Kv7.2/7.3",
"heteromeric",
"channel",
"currents",
"resulted",
"from",
"both",
"effects",
"on",
"gating",
"and",
"single-channel",
"conductance",
"(Prole",
"et",
"al.,",
"2003).",
"We",
"demonstrate",
"that",
"macroscopic",
"KCa2.2",
"and",
"KCa2.3",
"current",
"is",
"inhibited",
"by",
"extracellular",
"protons,",
"with",
"KCa2.3",
"being",
"more",
"sensitive.",
"Inhibition",
"resulted",
"from",
"a",
"reduc-",
"tion",
"in",
"single-channel",
"conductance",
"and,",
"in",
"particular",
"for",
"KCa2.3,",
"a",
"shift",
"of",
"inward",
"rectification.",
"We",
"show",
"that",
"©",
"2009",
"Goodchild",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"an",
"Attribution–Non-",
"commercial–Share",
"Alike–No",
"Mirror",
"Sites",
"license",
"for",
"the",
"first",
"six",
"months",
"after",
"the",
"publication",
"date",
"(see",
"http://www.jgp.org/misc/terms.shtml).",
"After",
"six",
"months",
"it",
"is",
"available",
"under",
"a",
"Cre-",
"ative",
"Commons",
"License",
"(Attribution–Noncommercial–Share",
"Alike",
"3.0",
"Unported",
"license,",
"as",
"described",
"at",
"http://creativecommons.org/licenses/by-nc-sa/3.0/).",
"295"
] | [
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5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
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5,
5,
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5,
5,
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5,
5,
5,
5,
5,
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5,
5,
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5,
5,
5,
5,
5,
5,
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5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
5,
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1,
1,
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1,
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1,
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13,
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] | [
"DISPATCH",
"CLINICAL",
"STUDIES",
"Atypical",
"SARS",
"and",
"Escherichia",
"coli",
"Bacteremia",
"Thuan",
"Tong",
"Tan,*",
"Ban",
"Hock",
"Tan,*",
"Asok",
"Kurup,*",
"Lynette",
"Lin",
"Ean",
"Oon,*",
"Derrick",
"Heng,*",
"Su",
"Yun",
"Se",
"Thoe,*",
"Xin",
"Lai",
"Bai,*",
"Kwai",
"Peng",
"Chan,*",
"and",
"Ai",
"Ee",
"Ling*",
"We",
"describe",
"a",
"patient",
"with",
"severe",
"acute",
"respiratory",
"syndrome",
"(SARS)",
"whose",
"clinical",
"symptoms",
"were",
"masked",
"by",
"Escherichia",
"coli",
"bacteremia.",
"SARS",
"developed",
"in",
"a",
"clus-",
"ter",
"of",
"healthcare",
"workers",
"who",
"had",
"contact",
"with",
"this",
"patient.",
"SARS",
"was",
"diagnosed",
"when",
"a",
"chest",
"infiltrate",
"developed",
"and",
"when",
"the",
"patient’s",
"brother",
"was",
"hospitalized",
"with",
"acute",
"respiratory",
"failure.",
"We",
"highlight",
"problems",
"in",
"atypical",
"cases",
"and",
"offer",
"infection",
"control",
"suggestions.",
"Srecognized",
"condition.",
"In",
"early",
"March",
"2003,",
"the",
"World",
"evere",
"acute",
"respiratory",
"syndrome",
"(SARS)",
"is",
"a",
"newly",
"Health",
"Organization",
"(WHO)",
"issued",
"case",
"definitions",
"for",
"SARS",
"(1).",
"In",
"most",
"studies,",
"the",
"clinical",
"syndrome",
"includes",
"fever",
"in",
"100%",
"of",
"patients",
"(2–4).",
"Other",
"common",
"clinical",
"features",
"include",
"chills",
"and",
"rigors",
"(73%),",
"myalgia",
"(60%),",
"and",
"cough",
"(>50%).",
"Some",
"patients",
"initially",
"thought",
"to",
"have",
"SARS",
"have",
"been",
"excluded",
"when",
"tests",
"showed",
"other",
"caus-",
"es",
"(5).",
"We",
"report",
"a",
"patient",
"whose",
"coexisting",
"conditions",
"masked",
"the",
"diagnosis",
"of",
"SARS,",
"leading",
"to",
"a",
"cluster",
"of",
"sus-",
"pect",
"and",
"probable",
"cases.",
"Case",
"Report",
"A",
"59-year-old",
"Chinese",
"man",
"was",
"admitted",
"on",
"March",
"24,",
"2003,",
"to",
"the",
"Singapore",
"General",
"Hospital.",
"He",
"had",
"previous-",
"ly",
"been",
"hospitalized",
"in",
"Tan",
"Tock",
"Seng",
"Hospital,",
"the",
"hospi-",
"tal",
"in",
"which",
"the",
"first",
"SARS",
"outbreak",
"in",
"Singapore",
"occurred",
"(6),",
"from",
"March",
"5",
"to",
"March",
"20",
"for",
"diabetic",
"nephropathy.",
"The",
"patient",
"had",
"multiple",
"coexisting",
"conditions",
"includ-",
"ing",
"ischemic",
"heart",
"disease",
"with",
"atrial",
"fibrillation,",
"previous",
"stroke",
"with",
"scar",
"epilepsy,",
"diabetes",
"mellitus",
"with",
"nephropa-",
"thy",
"(creatinine",
"242",
"µ",
"mol/L),",
"and",
"peripheral",
"vascular",
"dis-",
"ease.",
"He",
"was",
"not",
"on",
"steroids",
"or",
"traditional",
"medications.",
"Clinical",
"signs",
"and",
"symptoms",
"were",
"melena",
"and",
"dizzi-",
"ness.",
"He",
"was",
"pale,",
"temperature",
"was",
"36.5°C,",
"blood",
"pressure",
"was",
"126/70",
"mm",
"Hg,",
"and",
"pulse",
"rate",
"was",
"110/min.",
"Chest",
"examination",
"was",
"normal,",
"and",
"the",
"abdomen",
"was",
"soft.",
"Rectal",
"examination",
"showed",
"melena.",
"The",
"patient",
"also",
"had",
"a",
"sloughy",
"right",
"heel",
"ulcer.",
"Laboratory",
"values",
"are",
"shown",
"in",
"the",
"Table.",
"Antral",
"gastritis",
"was",
"diagnosed",
"on",
"gastroscopy.",
"*Singapore",
"General",
"Hospital,",
"Singapore",
"Colonoscopy",
"and",
"barium",
"enema",
"were",
"unsuccessful",
"because",
"of",
"excessive",
"fecal",
"residue.",
"The",
"patient",
"had",
"a",
"temperature",
"spike",
"(38.4°C)",
"on",
"March",
"26,",
"and",
"intravenous",
"(IV)",
"amoxicillin/clavulanic",
"acid",
"was",
"started.",
"His",
"temperature",
"spiked",
"again",
"(38.8°C)",
"on",
"March",
"28.",
"The",
"source",
"of",
"sepsis",
"was",
"thought",
"to",
"be",
"the",
"necrotic",
"heel",
"ulcer;",
"wound",
"débridement",
"was",
"performed",
"on",
"March",
"30.",
"The",
"fever",
"persisted",
"from",
"March",
"28",
"until",
"April",
"2.",
"Blood",
"cultures",
"drawn",
"on",
"March",
"28",
"isolated",
"E.",
"coli",
"of",
"intermedi-",
"ate",
"sensitivity",
"to",
"amoxicillin/clavulanic",
"acid.",
"Further",
"eval-",
"uation",
"for",
"the",
"source",
"of",
"bacteremia",
"included",
"urinalysis,",
"which",
"indicated",
"a",
"leukocyte",
"count",
"of",
"4",
"and",
"erythrocyte",
"count",
"of",
"165.",
"Ultrasonography",
"showed",
"a",
"2.8-cm",
"abscess",
"at",
"the",
"midpole",
"of",
"the",
"right",
"kidney.",
"Urine",
"culture",
"yielded",
"mixed",
"bacteria",
"growth.",
"The",
"patient’s",
"medication",
"was",
"changed",
"to",
"IV",
"ceftriaxone",
"(to",
"which",
"the",
"organism",
"was",
"sus-",
"ceptible)",
"on",
"April",
"1.",
"Tissue",
"cultures",
"from",
"the",
"necrotic",
"heel",
"yielded",
"Pseudomonas",
"aeruginosa",
"sensitive",
"only",
"to",
"imipenem.",
"Although",
"fever",
"was",
"lower",
"after",
"1",
"day",
"of",
"ceftri-",
"axone,",
"the",
"patient’s",
"medication",
"was",
"switched",
"to",
"IV",
"imipenem",
"on",
"April",
"2.",
"He",
"remained",
"afebrile",
"thereafter.",
"On",
"April",
"1",
"(6",
"days",
"after",
"the",
"patient’s",
"first",
"spike",
"of",
"tem-",
"perature),",
"three",
"healthcare",
"workers",
"from",
"the",
"ward",
"into",
"which",
"he",
"had",
"first",
"been",
"admitted",
"became",
"febrile.",
"At",
"this",
"time,",
"physicians",
"were",
"notified",
"that",
"the",
"patient",
"was",
"on",
"a",
"surveillance",
"program",
"for",
"SARS.",
"He",
"was",
"transferred",
"from",
"the",
"general",
"surgical",
"ward",
"to",
"an",
"isolation",
"room,",
"and",
"health-",
"care",
"workers",
"used",
"a",
"combination",
"of",
"airborne,",
"contact,",
"and",
"droplet",
"precautions.",
"His",
"clinical",
"course",
"was",
"scrutinized",
"for",
"evidence",
"of",
"SARS.",
"Despite",
"the",
"positive",
"contact",
"history,",
"he",
"did",
"not",
"have",
"any",
"respiratory",
"symptoms.",
"Three",
"chest",
"x-rays",
"performed",
"on",
"days",
"1,",
"5,",
"and",
"7",
"of",
"hospitalization",
"were",
"nor-",
"mal",
"(Figure",
"1A,",
"B,",
"and",
"C).",
"The",
"fever",
"could",
"have",
"been",
"attributed",
"to",
"the",
"E.",
"coli",
"bacteremia",
"because",
"it",
"subsided",
"after",
"the",
"patient’s",
"antimicrobial",
"drug",
"was",
"changed",
"to",
"an",
"appropriate",
"one.",
"Over",
"the",
"subsequent",
"days,",
"16",
"healthcare",
"workers",
"from",
"the",
"two",
"wards",
"where",
"this",
"patient",
"was",
"treated",
"became",
"febrile.",
"On",
"day",
"11",
"of",
"hospitalization",
"(April",
"3,",
"14",
"days",
"after",
"the",
"patient’s",
"last",
"day",
"in",
"Tan",
"Tock",
"Seng",
"Hospital),",
"an",
"ill-",
"defined",
"air",
"space",
"shadow",
"was",
"noted",
"in",
"the",
"right",
"lower",
"zone",
"Emerging",
"Infectious",
"Diseases",
"•",
"www.cdc.gov/eid",
"•",
"Vol.",
"10,",
"No.",
"2,",
"February",
"2004",
"349"
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] | [
"Pearls",
"Five",
"Questions",
"on",
"Prion",
"Diseases",
"Adriano",
"Aguzzi*,",
"Caihong",
"Zhu",
"Institute",
"of",
"Neuropathology,",
"University",
"Hospital",
"of",
"Zu¨",
"rich,",
"Zu¨",
"rich,",
"Switzerland",
"Introduction",
"Prion",
"diseases",
"are",
"characterized",
"by",
"deposition",
"of",
"PrPSc,",
"a",
"misfolded",
"and",
"aggregated",
"isoform",
"of",
"the",
"host-encoded",
"cellular",
"prion",
"protein",
"(PrPC),",
"within",
"the",
"central",
"nervous",
"system",
"(CNS)",
"and",
"other",
"organs.",
"Here",
"we",
"review",
"the",
"current",
"knowledge",
"on",
"five",
"issues",
"relevant",
"to",
"prion",
"diseases:",
"(1)",
"how",
"do",
"prions",
"enter",
"the",
"body,",
"(2)",
"how",
"do",
"prions",
"reach",
"the",
"central",
"nervous",
"system,",
"(3)",
"how",
"do",
"prions",
"damage",
"the",
"CNS,",
"(4)",
"do",
"mammals",
"have",
"an",
"antiprion",
"defense",
"system,",
"and",
"(5)",
"how",
"can",
"the",
"prion",
"problem",
"be",
"resolved",
"for",
"good.",
"How",
"Do",
"Prions",
"Enter",
"the",
"Body?",
"Most",
"cases",
"of",
"human",
"prion",
"disease",
"occur",
"for",
"unknown",
"reasons,",
"and",
".20",
"mutations",
"in",
"the",
"prion",
"gene",
"(PRNP)",
"may",
"lead",
"to",
"inherited",
"prion",
"disease.",
"In",
"other",
"instances,",
"prion",
"diseases",
"are",
"contracted",
"by",
"exposure",
"to",
"prion",
"infectivity.",
"Save",
"for",
"direct",
"brain",
"exposure",
"by",
"neurosurgery,",
"prions",
"typically",
"enter",
"the",
"body",
"through",
"extraneural",
"pathways.",
"This",
"raises",
"the",
"intriguing",
"question",
"of",
"how",
"a",
"mere",
"protein",
"aggregate",
"can",
"trespass",
"mucosal",
"barriers,",
"circumvent",
"innate",
"and",
"adaptive",
"immunity,",
"and",
"travel",
"across",
"the",
"blood–brain",
"barrier",
"to",
"eventually",
"provoke",
"brain",
"disease.",
"Oral",
"Uptake",
"There",
"is",
"no",
"doubt",
"that",
"prion",
"infections",
"can",
"be",
"efficaciously",
"transmitted",
"under",
"both",
"natural",
"and",
"human-made",
"conditions.",
"While",
"some",
"aspects",
"of",
"the",
"natural",
"transmission",
"of",
"scrapie",
"and",
"chronic",
"wasting",
"disease",
"(CWD)",
"remain",
"unexplained,",
"oral",
"transmission",
"of",
"prions",
"has",
"caused",
"large",
"epidemics",
"and",
"epizootics.",
"Kuru,",
"a",
"human",
"prion",
"disease",
"transmitted",
"through",
"ritual",
"cannibalism,",
"has",
"afflicted",
"the",
"Fore",
"people",
"of",
"Northern",
"Papua",
"New",
"Guinea",
"at",
"extraordinarily",
"high",
"rates.",
"Bovine",
"spongiform",
"encephalopathy",
"(BSE),",
"which",
"has",
"killed",
"more",
"than",
"280,000",
"cattle",
"worldwide,",
"is",
"a",
"prion",
"disease",
"caused",
"by",
"the",
"feeding",
"of",
"recycled",
"prion-infected",
"foodstuff",
"to",
"cattle",
"[1].",
"In",
"turn,",
"variant",
"Creutzfeldt-",
"Jacob",
"Disease",
"(vCJD),",
"which",
"has",
"claimed",
"over",
"200",
"victims,",
"appears",
"to",
"be",
"caused",
"by",
"consumption",
"of",
"BSE-contaminated",
"beef",
"products",
"[2].",
"Parenteral",
"Uptake",
"Prions",
"can",
"also",
"enter",
"the",
"body",
"via",
"parenteral",
"uptake.",
"Most",
"worryingly,",
"vCJD",
"has",
"been",
"transmitted",
"from",
"subclinically",
"vCJD-",
"infected",
"donors",
"to",
"recipients",
"of",
"transfused",
"non-leukocyte-reduced",
"red",
"cells",
"and",
"of",
"purified",
"factor",
"VIII",
"preparations",
"[3].",
"By",
"far",
"the",
"largest",
"incident",
"involving",
"iatrogenic",
"prion",
"transmission",
"involved",
"human",
"pituitary",
"hormones.",
"Before",
"the",
"advent",
"of",
"recombinant",
"DNA",
"technology,",
"growth",
"hormone",
"(used",
"to",
"treat",
"dwarfism)",
"and",
"fertility",
"hormones",
"were",
"recovered",
"from",
"human",
"cadaveric",
"pituitary",
"glands.",
"The",
"prevalence",
"of",
"subclinically",
"CJD-affected",
"donors,",
"probably",
"coupled",
"with",
"brain-tissue",
"contamination",
"of",
"pituitary",
"extracts,",
"led",
"to",
"over",
"160",
"prion",
"deaths",
"in",
"mostly",
"young",
"recipients.",
"Experimentally,",
"the",
"parenteral",
"route",
"of",
"prion",
"transmission",
"is",
"very",
"effective",
"and,",
"e.g.,",
"intraperitoneal",
"(i.p)",
"inoculation",
"of",
"prions",
"to",
"laboratory",
"animals",
"is",
"a",
"widely",
"used",
"route",
"for",
"studies",
"of",
"peripheral",
"prion",
"replication",
"and",
"neuroinvasion.",
"Intracerebral",
"Administration",
"The",
"most",
"efficient",
"way",
"of",
"prion",
"transmission",
"is",
"intracerebral",
"(i.c)",
"administration.",
"This",
"is",
"not",
"unexpected,",
"since",
"the",
"brain",
"is",
"the",
"main",
"target",
"of",
"prion",
"toxicity",
"and",
"administration",
"to",
"the",
"brain",
"bypasses",
"all",
"natural",
"barriers",
"to",
"prion",
"neuroinvasion,",
"such",
"as",
"the",
"innate",
"and",
"adaptive",
"immune",
"system,",
"as",
"well",
"as",
"the",
"blood–brain",
"barrier.",
"Several",
"iatrogenic",
"CJD",
"(iCJD)",
"transmissions",
"occurred",
"via",
"neurosurgery",
"and",
"dura",
"mater",
"grafts.",
"These",
"cases",
"were",
"particularly",
"tragic",
"for",
"all",
"those",
"involved",
"because",
"they",
"were",
"inadvertently",
"caused",
"by",
"medical",
"personnel",
"and",
"represented",
"an",
"untoward",
"effect",
"of",
"the",
"intent",
"to",
"treat",
"other",
"ailments.",
"Some",
"of",
"the",
"first",
"well-",
"documented",
"instances",
"of",
"intracerebral",
"prion",
"transmission",
"to",
"humans",
"occurred",
"in",
"Zu¨",
"rich",
"in",
"the",
"1970s",
"[4].",
"Electrodes",
"were",
"used",
"for",
"stereotactic",
"electroencephalographic",
"(EEG)",
"recordings",
"in",
"a",
"CJD",
"patient,",
"and",
"reused",
"after",
"sterilization",
"with",
"ethanol",
"and",
"formaldehyde",
"vapors—a",
"procedure",
"that",
"reliably",
"inactivates",
"viruses",
"and",
"bacteria,",
"but",
"is",
"ineffective",
"against",
"prions.",
"This",
"resulted",
"in",
"fatal",
"prion",
"transmission",
"to",
"two",
"young",
"patients.",
"The",
"infectivity",
"on",
"these",
"electrodes",
"was",
"later",
"confirmed",
"by",
"transmission",
"of",
"CJD",
"to",
"a",
"chimpanzee.",
"Aerosols",
"Prion",
"transmission",
"is",
"usually",
"not",
"considered",
"to",
"be",
"airborne",
"like",
"influenza",
"or",
"chicken",
"pox.",
"But",
"we",
"and",
"others",
"recently",
"have",
"found",
"that",
"prions",
"can",
"also",
"be",
"efficiently",
"transmitted",
"to",
"mice",
"through",
"aerosols",
"[5,6].",
"Although",
"aerosol-transmitted",
"prions",
"have",
"never",
"been",
"found",
"under",
"natural",
"conditions,",
"this",
"finding",
"highlights",
"the",
"necessity",
"of",
"revising",
"the",
"current",
"prion-related",
"biosafety",
"guidelines",
"and",
"health",
"standards",
"in",
"diagnostic",
"and",
"scientific",
"laboratories",
"being",
"potentially",
"confronted",
"with",
"prion-",
"infected",
"materials.",
"Citation:",
"Aguzzi",
"A,",
"Zhu",
"C",
"(2012)",
"Five",
"Questions",
"on",
"Prion",
"Diseases.",
"PLoS",
"Pathog",
"8(5):",
"e1002651.",
"doi:10.1371/journal.ppat.1002651",
"Editor:",
"Heather",
"True-Krob,",
"Washington",
"University",
"School",
"of",
"Medicine,",
"United",
"States",
"of",
"America",
"Published",
"May",
"3,",
"2012",
"Copyright:",
"2012",
"Aguzzi,",
"Zhu.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"funded",
"by",
"European",
"Research",
"Council",
"(ERC)",
"Advanced",
"Grant",
"to",
"Adriano",
"Aguzzi",
"(#",
"250356),",
"by",
"the",
"Swiss",
"National",
"Science",
"Foundation",
"(#",
"3100A0-125927/1),",
"the",
"Center",
"of",
"Transgenesis",
"Expertise",
"of",
"the",
"National",
"Center",
"of",
"Competence",
"in",
"Research",
"‘‘Neural",
"Plasticity",
"and",
"Repair’’,",
"by",
"a",
"Sinergia",
"grant",
"from",
"Swiss",
"National",
"Science",
"Foundation",
"(#",
"CRSI33_125073),",
"by",
"an",
"unrestricted",
"grant",
"of",
"the",
"Novartis",
"Research",
"Foundation,",
"and",
"by",
"the",
"European",
"Union",
"Framework",
"7",
"programs",
"PRIORITY",
"(#",
"222887),",
"LUPAS",
"(#",
"242098)",
"and",
"NeuriNox",
"(#",
"278611).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"adriano.aguzzi@usz.ch",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"1",
"May",
"2012",
"|",
"Volume",
"8",
"|",
"Issue",
"5",
"|",
"e1002651"
] | [
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] | [
"Endow",
"and",
"Hallen",
"BMC",
"Cell",
"Biology",
"2011,",
"12:1",
"http://www.biomedcentral.com/1471-2121/12/1",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Anastral",
"spindle",
"assembly",
"and",
"g-tubulin",
"in",
"Drosophila",
"oocytes",
"Sharyn",
"A",
"Endow*,",
"Mark",
"A",
"Hallen",
"Abstract",
"Background:",
"Anastral",
"spindles",
"assemble",
"by",
"a",
"mechanism",
"that",
"involves",
"microtubule",
"nucleation",
"and",
"growth",
"from",
"chromatin.",
"It",
"is",
"still",
"uncertain",
"whether",
"g-tubulin,",
"a",
"microtubule",
"nucleator",
"essential",
"for",
"mitotic",
"spindle",
"assembly",
"and",
"maintenance,",
"plays",
"a",
"role.",
"Not",
"only",
"is",
"the",
"requirement",
"for",
"g-tubulin",
"to",
"form",
"anastral",
"Drosophila",
"oocyte",
"meiosis",
"I",
"spindles",
"controversial,",
"but",
"its",
"presence",
"in",
"oocyte",
"meiosis",
"I",
"spindles",
"has",
"not",
"been",
"demonstrated",
"and",
"is",
"uncertain.",
"Results:",
"We",
"show,",
"for",
"the",
"first",
"time,",
"using",
"a",
"bright",
"GFP",
"fusion",
"protein",
"and",
"live",
"imaging,",
"that",
"the",
"Drosophila",
"maternally-expressed",
"gTub37C",
"is",
"present",
"at",
"low",
"levels",
"in",
"oocyte",
"meiosis",
"I",
"spindles.",
"Despite",
"this,",
"we",
"find",
"that",
"formation",
"of",
"bipolar",
"meiosis",
"I",
"spindles",
"does",
"not",
"require",
"functional",
"gTub37C,",
"extending",
"previous",
"findings",
"by",
"others.",
"Fluorescence",
"photobleaching",
"assays",
"show",
"rapid",
"recovery",
"of",
"gTub37C",
"in",
"the",
"meiosis",
"I",
"spindle,",
"similar",
"to",
"the",
"cytoplasm,",
"indicating",
"weak",
"binding",
"by",
"gTub37C",
"to",
"spindles,",
"and",
"fits",
"of",
"a",
"new,",
"potentially",
"more",
"accurate",
"model",
"for",
"fluorescence",
"recovery",
"yield",
"kinetic",
"parameters",
"consistent",
"with",
"transient,",
"diffusional",
"binding.",
"Conclusions:",
"The",
"FRAP",
"results,",
"together",
"with",
"its",
"mutant",
"effects",
"late",
"in",
"meiosis",
"I,",
"indicate",
"that",
"gTub37C",
"may",
"perform",
"a",
"role",
"subsequent",
"to",
"metaphase",
"I,",
"rather",
"than",
"nucleating",
"microtubules",
"for",
"meiosis",
"I",
"spindle",
"formation.",
"Weak",
"binding",
"to",
"the",
"meiosis",
"I",
"spindle",
"could",
"stabilize",
"pre-existing",
"microtubules",
"or",
"position",
"g-tubulin",
"for",
"function",
"during",
"meiosis",
"II",
"spindle",
"assembly,",
"which",
"follows",
"rapidly",
"upon",
"oocyte",
"activation",
"and",
"completion",
"of",
"the",
"meiosis",
"I",
"division.",
"Background",
"Anastral",
"spindles",
"assemble",
"without",
"centrosomes",
"by",
"a",
"pathway",
"that",
"is",
"still",
"not",
"fully",
"understood.",
"In",
"particular,",
"the",
"mechanism",
"by",
"which",
"microtubule",
"nucleation",
"occurs",
"has",
"not",
"been",
"well",
"defined.",
"Although",
"chromatin",
"has",
"been",
"shown",
"to",
"play",
"an",
"essential",
"role",
"[1],",
"the",
"involvement",
"of",
"the",
"microtubule",
"nucleator,",
"g-tubulin,",
"is",
"still",
"an",
"open",
"question.",
"g-Tubulin",
"localizes",
"to",
"centrosomes",
"and",
"other",
"microtubule",
"organizing",
"centers",
"in",
"mitosis",
"and",
"is",
"essential",
"for",
"nucleating",
"microtubules",
"in",
"organisms",
"as",
"diverse",
"as",
"yeast,",
"Drosophila,",
"Xenopus,",
"humans,",
"and",
"higher",
"plants",
"[2-5].",
"g-Tubulin",
"is",
"also",
"found",
"on",
"spindle",
"microtubules,",
"where",
"it",
"has",
"been",
"proposed",
"to",
"nucleate",
"microtubules",
"for",
"spindle",
"maintenance",
"by",
"functioning",
"in",
"a",
"chromatin-",
"mediated",
"nucleation",
"pathway",
"that",
"augments",
"the",
"domi-",
"nant",
"pathway",
"of",
"nucleation",
"by",
"centrosomes",
"[6,7].",
"g-Tubulin",
"is",
"present",
"in",
"cells",
"as",
"a",
"large",
"ring",
"complex,",
"gTuRC,",
"comprising",
"12-13",
"g-tubulin",
"molecules",
"associated",
"*",
"Correspondence:",
"endow@duke.edu",
"Department",
"of",
"Cell",
"Biology",
"and",
"Structural",
"Biology",
"&",
"Biophysics",
"Program,",
"Duke",
"University",
"with",
"as",
"many",
"as",
"~7-8",
"other",
"proteins",
"[8,9].",
"gTuRC",
"forms",
"from",
"a",
"small",
"complex,",
"gTuSC,",
"consisting",
"of",
"g-tubulin",
"bound",
"to",
"two",
"other",
"proteins",
"[10-12].",
"The",
"mechanism",
"by",
"which",
"gTuRC",
"nucleates",
"microtubules",
"is",
"uncertain",
"-",
"it",
"could",
"serve",
"as",
"a",
"ring-like",
"template",
"for",
"a",
"12-or",
"13-",
"protofilament",
"microtubule",
"[13,14]",
"or,",
"alternatively,",
"a/b",
"tubulin",
"dimers",
"could",
"assemble",
"onto",
"an",
"end",
"of",
"the",
"large",
"ring",
"complex",
"to",
"form",
"individual",
"protofilaments",
"[15].",
"Although",
"g-tubulin",
"is",
"believed",
"to",
"play",
"a",
"central",
"role",
"in",
"mitotic",
"spindle",
"assembly",
"and",
"maintenance",
"in",
"many",
"organisms,",
"its",
"role",
"in",
"anastral",
"spindles",
"that",
"lack",
"centro-",
"somes",
"is",
"less",
"certain.",
"Analysis",
"of",
"mutants",
"that",
"affect",
"the",
"Drosophila",
"oocyte-",
"and",
"early",
"embryo-specific",
"gTub37C",
"[16]",
"has",
"led",
"to",
"the",
"conclusion",
"that",
"g-tubulin",
"plays",
"an",
"essential",
"role",
"in",
"nucleating",
"microtubules",
"for",
"anastral",
"oocyte",
"meiosis",
"I",
"(MI)",
"spindle",
"assembly",
"[17].",
"Conflict-",
"ingly,",
"another",
"study",
"of",
"the",
"same",
"mutants",
"concluded",
"that",
"g-tubulin",
"is",
"not",
"required",
"for",
"oocyte",
"MI",
"spindle",
"forma-",
"tion",
"[18].",
"Moreover,",
"attempts",
"by",
"several",
"groups",
"to",
"stain",
"oocyte",
"MI",
"spindles",
"using",
"anti-gTub37C",
"antibodies",
"have",
"©",
"2011",
"Endow",
"and",
"Hallen;",
"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."
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] | [
"Ubiquitous",
"Expression",
"of",
"CUG",
"or",
"CAG",
"Trinucleotide",
"Repeat",
"RNA",
"Causes",
"Common",
"Morphological",
"Defects",
"in",
"a",
"Drosophila",
"Model",
"of",
"RNA-Mediated",
"Pathology",
"Kynan",
"T.",
"Lawlor,",
"Louise",
"V.",
"O’Keefe,",
"Saumya",
"E.",
"Samaraweera,",
"Clare",
"L.",
"van",
"Eyk,",
"Robert",
"I.",
"Richards*",
"Discipline",
"of",
"Genetics,",
"School",
"of",
"Molecular",
"and",
"Biomedical",
"Science",
"and",
"Australian",
"Research",
"Council",
"Special",
"Research",
"Centre",
"for",
"the",
"Molecular",
"Genetics",
"of",
"Development,",
"The",
"University",
"of",
"Adelaide,",
"Adelaide,",
"South",
"Australia,",
"Australia",
"Abstract",
"Expanded",
"DNA",
"repeat",
"sequences",
"are",
"known",
"to",
"cause",
"over",
"20",
"diseases,",
"including",
"Huntington’s",
"disease,",
"several",
"types",
"of",
"spinocerebellar",
"ataxia",
"and",
"myotonic",
"dystrophy",
"type",
"1",
"and",
"2.",
"A",
"shared",
"genetic",
"basis,",
"and",
"overlapping",
"clinical",
"features",
"for",
"some",
"of",
"these",
"diseases,",
"indicate",
"that",
"common",
"pathways",
"may",
"contribute",
"to",
"pathology.",
"Multiple",
"mechanisms,",
"mediated",
"by",
"both",
"expanded",
"homopolymeric",
"proteins",
"and",
"expanded",
"repeat",
"RNA,",
"have",
"been",
"identified",
"by",
"the",
"use",
"of",
"model",
"systems,",
"that",
"may",
"account",
"for",
"shared",
"pathology.",
"The",
"use",
"of",
"such",
"animal",
"models",
"enables",
"identification",
"of",
"distinct",
"pathways",
"and",
"their",
"‘molecular",
"hallmarks’",
"that",
"can",
"be",
"used",
"to",
"determine",
"the",
"contribution",
"of",
"each",
"pathway",
"in",
"human",
"pathology.",
"Here",
"we",
"characterise",
"a",
"tergite",
"disruption",
"phenotype",
"in",
"adult",
"flies,",
"caused",
"by",
"ubiquitous",
"expression",
"of",
"either",
"untranslated",
"CUG",
"or",
"CAG",
"expanded",
"repeat",
"RNA.",
"Using",
"the",
"tergite",
"phenotype",
"as",
"a",
"quantitative",
"trait",
"we",
"define",
"a",
"new",
"genetic",
"system",
"in",
"which",
"to",
"examine",
"‘hairpin’",
"repeat",
"RNA-mediated",
"cellular",
"perturbation.",
"Further",
"experiments",
"use",
"this",
"system",
"to",
"examine",
"whether",
"pathways",
"involving",
"Muscleblind",
"sequestration",
"or",
"Dicer",
"processing,",
"which",
"have",
"been",
"shown",
"to",
"mediate",
"repeat",
"RNA-",
"mediated",
"pathology",
"in",
"other",
"model",
"systems,",
"contribute",
"to",
"cellular",
"perturbation",
"in",
"this",
"model.",
"Citation:",
"Lawlor",
"KT,",
"O’Keefe",
"LV,",
"Samaraweera",
"SE,",
"van",
"Eyk",
"CL,",
"Richards",
"RI",
"(2012)",
"Ubiquitous",
"Expression",
"of",
"CUG",
"or",
"CAG",
"Trinucleotide",
"Repeat",
"RNA",
"Causes",
"Common",
"Morphological",
"Defects",
"in",
"a",
"Drosophila",
"Model",
"of",
"RNA-Mediated",
"Pathology.",
"PLoS",
"ONE",
"7(6):",
"e38516.",
"doi:10.1371/journal.pone.0038516",
"Editor:",
"Diego",
"E.",
"Rincon-Limas,",
"University",
"of",
"Florida,",
"United",
"States",
"of",
"America",
"Received",
"February",
"9,",
"2012;",
"Accepted",
"May",
"8,",
"2012;",
"Published",
"June",
"8,",
"2012",
"Copyright:",
"2012",
"Lawlor",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"Australian",
"Postgraduate",
"Awards",
"(to",
"KTL,",
"SES",
"and",
"CLvE);",
"a",
"National",
"Health",
"and",
"Medical",
"Research",
"Council",
"Peter",
"Doherty",
"Fellowship",
"(fellowship",
"number",
"207830",
"to",
"LVO);",
"project",
"grants",
"from",
"the",
"National",
"Health",
"and",
"Medical",
"Research",
"Council",
"(grant",
"numbers",
"453674,",
"627183",
"to",
"RIR",
"and",
"LVO);",
"and",
"the",
"Australian",
"Research",
"Council",
"Special",
"Research",
"Centre",
"for",
"the",
"Molecular",
"Genetics",
"of",
"Development.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"robert.richards@adelaide.edu.au",
"Introduction",
"The",
"expansion",
"of",
"polymorphic",
"repeat",
"sequences",
"(dynamic",
"mutation)",
"is",
"responsible",
"for",
"over",
"20",
"human",
"diseases,",
"including",
"Huntington’s",
"disease",
"(HD),",
"myotonic",
"dystrophy",
"and",
"several",
"types",
"of",
"spinocerebellar",
"ataxia",
"(SCA)",
"[1–3].",
"In",
"all",
"cases",
"affected",
"individuals",
"inherit",
"a",
"repeat",
"number",
"that",
"exceeds",
"a",
"pathogenic",
"threshold.",
"Increased",
"disease",
"severity",
"and",
"earlier",
"age-of-onset",
"are",
"correlated",
"with",
"repeat",
"length",
"expansion,",
"which",
"occurs",
"within",
"successive",
"generations",
"[1–3].",
"Expansion",
"is",
"associated",
"with",
"loss",
"of",
"repeat-containing",
"gene",
"function",
"and",
"recessive",
"inheritance",
"in",
"a",
"few",
"cases",
"[4,5],",
"however",
"the",
"majority",
"of",
"diseases",
"appear",
"to",
"be",
"caused",
"by",
"dominant,",
"repeat-mediated",
"mechanisms.",
"As",
"well",
"as",
"a",
"shared",
"genetic",
"basis,",
"many",
"diseases",
"show",
"similar",
"clinical",
"features,",
"including",
"late",
"onset",
"neurodegeneration",
"and",
"movement",
"disorder,",
"highlighting",
"the",
"possibility",
"that",
"common",
"pathways",
"contribute",
"to",
"pathology",
"in",
"most,",
"if",
"not",
"all",
"cases",
"of",
"dominantly",
"inherited",
"dynamic",
"mutation",
"[1–3,6].",
"In",
"diseases",
"including",
"HD",
"and",
"some",
"types",
"of",
"SCA,",
"expanded",
"CAG",
"trinucleotide",
"repeats",
"are",
"found",
"within",
"a",
"coding",
"region,",
"producing",
"an",
"expanded",
"polyglutamine",
"tract",
"within",
"the",
"final",
"protein",
"[2].",
"Polyglutamine",
"is",
"able",
"to",
"cause",
"pathology",
"through",
"multiple",
"possible",
"pathways,",
"including",
"gain-of-function",
"interactions",
"inherent",
"to",
"the",
"expanded",
"protein",
"tract",
"and",
"alterations",
"to",
"normal",
"protein",
"function",
"[3,7,8].",
"Nevertheless,",
"polyglutamine",
"protein-",
"mediated",
"pathology",
"is",
"not",
"able",
"to",
"account",
"for",
"diseases",
"where",
"repeats",
"are",
"unable",
"to",
"encode",
"polyglutamine,",
"due",
"to",
"the",
"repeat",
"sequence",
"composition",
"and/or",
"presence",
"of",
"the",
"repeat",
"tract",
"within",
"non-coding",
"regions",
"of",
"the",
"associated",
"gene.",
"This",
"class",
"of",
"‘untranslated’",
"repeat",
"diseases",
"share",
"similar",
"repeat",
"sequences,",
"pathogenic",
"thresholds",
"and",
"clinical",
"features",
"with",
"the",
"‘polygluta-",
"mine’",
"diseases",
"and",
"includes",
"myotonic",
"dystrophy",
"type",
"1",
"(DM1)",
"and",
"2",
"(DM2),",
"Huntington’s",
"disease-like-2",
"(HDL-2),",
"fragile",
"X",
"tremor/",
"ataxia",
"syndrome",
"(FXTAS)",
"and",
"SCA8,",
"10",
"and",
"12.",
"In",
"these",
"diseases,",
"gain-of-function",
"properties",
"of",
"the",
"expanded",
"repeat",
"RNA",
"transcript",
"appear",
"to",
"be",
"responsible",
"for",
"dominant",
"pathology",
"[9–11].",
"Since",
"repeat-containing",
"RNA",
"is",
"present",
"whether",
"repeats",
"are",
"coding",
"or",
"non-coding,",
"it",
"may",
"also",
"represent",
"a",
"common",
"contributor",
"to",
"all",
"the",
"dominant",
"expanded",
"repeat",
"diseases.",
"Studies",
"have",
"reported",
"the",
"ability",
"of",
"repeat",
"RNA",
"to",
"cause",
"pathology",
"in",
"animal",
"and",
"cellular",
"model",
"systems,",
"via",
"multiple,",
"and",
"likely",
"distinct",
"pathways",
"[12–21].",
"Pathology",
"due",
"to",
"expanded",
"repeat",
"RNA",
"was",
"first",
"attributed",
"in",
"DM1,",
"caused",
"by",
"a",
"non-coding",
"CUG",
"repeat",
"within",
"the",
"39UTR",
"of",
"the",
"dystrophia",
"myotonica-protein",
"kinase",
"(DMPK)",
"gene,",
"and",
"DM2,",
"caused",
"by",
"a",
"non-coding",
"CCUG",
"repeat",
"within",
"an",
"intron",
"of",
"ZNF9",
"(now",
"called",
"CNBP)",
"[22,23].",
"Expanded",
"repeat",
"RNA",
"transcripts",
"form",
"a",
"‘hairpin’",
"secondary",
"structure,",
"which",
"is",
"able",
"to",
"bind",
"and",
"sequester",
"specific",
"RNA-binding",
"proteins",
"[24–26].",
"The",
"most",
"extensively",
"characterised",
"of",
"these",
"is",
"Muscleblind-like",
"1",
"(MBNL-1),",
"which",
"is",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"June",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"6",
"|",
"e38516"
] | [
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] | [
"Liguori",
"et",
"al.",
"BMC",
"Microbiology",
"2010,",
"10:19",
"http://www.biomedcentral.com/1471-2180/10/19",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Microbiological",
"quality",
"of",
"drinking",
"water",
"from",
"dispensers",
"in",
"Italy",
"Giorgio",
"Liguori,",
"Ivan",
"Cavallotti,",
"Antonio",
"Arnese,",
"Ciro",
"Amiranda,",
"Daniela",
"Anastasi,",
"Italo",
"F",
"Angelillo*",
"Abstract",
"Background:",
"Water",
"coolers",
"are",
"popular",
"in",
"office",
"buildings",
"and",
"commercial",
"stores",
"and",
"the",
"quality",
"of",
"this",
"source",
"of",
"drinking",
"water",
"has",
"the",
"potential",
"to",
"cause",
"waterborne",
"outbreaks,",
"especially",
"in",
"sensitive",
"and",
"immunocompromised",
"subjects.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"determine",
"the",
"quality",
"of",
"water",
"plumbed",
"in",
"coolers",
"from",
"commercial",
"stores",
"in",
"comparison",
"with",
"tap",
"water",
"in",
"Italy.",
"Methods:",
"For",
"each",
"sample,",
"microbial",
"parameters",
"and",
"chemical",
"indicators",
"of",
"contamination",
"were",
"evaluated",
"and",
"information",
"about",
"the",
"date",
"of",
"installation,",
"time",
"since",
"last",
"ordinary",
"and",
"extraordinary",
"maintenance",
"of",
"water",
"coolers",
"was",
"collected.",
"Results:",
"In",
"all",
"samples",
"the",
"chemical",
"parameters",
"(nitrite,",
"ammonium,",
"free",
"active",
"chlorine",
"residual)",
"did",
"not",
"exceed",
"the",
"reference",
"values",
"of",
"the",
"drinking",
"water",
"regulation;",
"the",
"pH",
"value",
"in",
"86.8%",
"samples",
"of",
"the",
"carbonated",
"waters",
"was",
"lower",
"than",
"the",
"reference",
"limit.",
"The",
"microbiological",
"results",
"indicated",
"that",
"the",
"bacteria",
"count",
"at",
"22°C",
"and",
"37°C",
"was",
"higher",
"than",
"the",
"required",
"values",
"in",
"71%",
"and",
"81%",
"for",
"the",
"non-carbonated",
"water",
"and",
"in",
"86%",
"and",
"88%",
"for",
"the",
"carbonated",
"one,",
"respectively.",
"Enterococcus",
"spp.",
"and",
"Escherichia",
"coli",
"were",
"not",
"detected",
"in",
"any",
"of",
"the",
"water",
"samples.",
"Pseudomonas",
"aeruginosa",
"was",
"found",
"in",
"only",
"one",
"sample",
"of",
"the",
"tap",
"water",
"and",
"in",
"28.9%",
"and",
"23.7%",
"of",
"the",
"non-",
"carbonated",
"and",
"carbonated",
"water",
"samples,",
"respectively.",
"No",
"statistically",
"significant",
"differences",
"in",
"bacterial",
"counts",
"at",
"22°C",
"and",
"37°C",
"have",
"been",
"found",
"between",
"the",
"non-carbonated",
"and",
"carbonated",
"water",
"from",
"the",
"sampled",
"coolers",
"in",
"relation",
"with",
"the",
"time",
"since",
"the",
"last",
"filter",
"was",
"substituted.",
"The",
"bacteriological",
"quality",
"of",
"tap",
"water",
"was",
"superior",
"to",
"that",
"of",
"non-carbonated",
"and",
"carbonated",
"water",
"from",
"coolers.",
"Conclusion:",
"The",
"results",
"emphasize",
"the",
"importance",
"of",
"adopting",
"appropriate",
"routinely",
"monitoring",
"system",
"in",
"order",
"to",
"prevent",
"or",
"to",
"diminish",
"the",
"chances",
"of",
"contamination",
"of",
"this",
"water",
"source.",
"Background",
"It",
"is",
"well",
"known",
"that",
"the",
"quality",
"and",
"safety",
"of",
"the",
"drink-",
"ing",
"water",
"continues",
"to",
"be",
"an",
"important",
"public",
"health",
"issue",
"[1,2],",
"because",
"its",
"contamination",
"has",
"been",
"fre-",
"quently",
"described",
"as",
"responsible",
"for",
"the",
"transmission",
"of",
"infectious",
"diseases",
"that",
"have",
"caused",
"serious",
"illnesses",
"and",
"associated",
"mortality",
"worldwide",
"[3-6].",
"Clearly,",
"point-of-",
"use",
"water",
"quality",
"is",
"a",
"critical",
"public",
"health",
"indicator",
"[2].",
"Over",
"the",
"past",
"decade,",
"there",
"has",
"been",
"a",
"markedly",
"increase",
"in",
"the",
"consumption",
"of",
"water",
"derived",
"from",
"dif-",
"ferent",
"sources",
"in",
"place",
"of",
"tap",
"water",
"for",
"drinking",
"use",
"in",
"many",
"regions",
"of",
"the",
"world.",
"One",
"of",
"these",
"alternative",
"sources",
"is",
"the",
"water",
"from",
"dispensers,",
"which",
"is",
"popular",
"mainly",
"in",
"office",
"buildings",
"and",
"commercial",
"stores,",
"that",
"*",
"Correspondence:",
"italof.angelillo@unina2.it",
"Department",
"of",
"Public,",
"Clinical",
"and",
"Preventive",
"Medicine,",
"Second",
"University",
"of",
"Naples,",
"Naples,",
"Italy",
"are",
"often",
"presented",
"as",
"systems",
"that",
"are",
"able",
"to",
"improve",
"some",
"characteristics",
"of",
"water",
"and",
"easy",
"to",
"use",
"and",
"to",
"maintain.",
"However,",
"concerns",
"have",
"been",
"sometimes",
"raised",
"about",
"the",
"quality",
"of",
"this",
"source",
"due",
"to",
"its",
"poten-",
"tial",
"to",
"cause",
"waterborne",
"outbreaks",
"associated",
"with",
"drinking",
"water,",
"particularly",
"in",
"sensitive",
"and",
"immuno-",
"compromised",
"populations",
"[2].",
"International",
"drinking",
"water-quality",
"monitoring",
"pro-",
"grams",
"have",
"been",
"established",
"in",
"order",
"to",
"prevent",
"or",
"to",
"reduce",
"the",
"risk",
"of",
"contracting",
"water",
"related",
"infections.",
"In",
"Italy,",
"the",
"water",
"for",
"human",
"consumption,",
"including",
"the",
"water",
"coming",
"from",
"dispensers,",
"according",
"to",
"the",
"Eur-",
"opean",
"Community",
"Directive",
"guidelines,",
"is",
"required",
"to",
"be",
"free",
"from",
"any",
"pathogenic",
"microorganism",
"as",
"well",
"as",
"che-",
"mical",
"contaminations,",
"which",
"may",
"be",
"hazardous",
"to",
"the",
"human",
"health",
"[7,8].",
"©",
"2010",
"Liguori",
"et",
"al;",
"licensee",
"BioMed",
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] | [
"Pflugers",
"Arch",
"-",
"Eur",
"J",
"Physiol",
"(2010)",
"460:223–237",
"DOI",
"10.1007/s00424-009-0761-0",
"ION",
"CHANNELS,",
"RECEPTORS",
"AND",
"TRANSPORTERS",
"Cardiac",
"sodium",
"channelopathies",
"Ahmad",
"S.",
"Amin",
"&",
"Alaleh",
"Asghari-Roodsari",
"&",
"Hanno",
"L.",
"Tan",
"Received:",
"12",
"October",
"2009",
"/",
"Revised:",
"9",
"November",
"2009",
"/",
"Accepted:",
"11",
"November",
"2009",
"/",
"Published",
"online:",
"29",
"November",
"2009",
"#",
"The",
"Author(s)",
"2009.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Cardiac",
"sodium",
"channel",
"are",
"protein",
"complexes",
"that",
"are",
"expressed",
"in",
"the",
"sarcolemma",
"of",
"cardiomyocytes",
"to",
"carry",
"a",
"large",
"inward",
"depolarizing",
"current",
"(INa)",
"during",
"phase",
"0",
"of",
"the",
"cardiac",
"action",
"potential.",
"The",
"importance",
"of",
"INa",
"for",
"normal",
"cardiac",
"electrical",
"activity",
"is",
"reflected",
"by",
"the",
"high",
"incidence",
"of",
"arrhythmias",
"in",
"cardiac",
"sodium",
"channelopathies,",
"i.e.,",
"arrhythmogenic",
"diseases",
"in",
"patients",
"with",
"mutations",
"in",
"SCN5A,",
"the",
"gene",
"responsible",
"for",
"the",
"pore-forming",
"ion-",
"conducting",
"α-subunit,",
"or",
"in",
"genes",
"that",
"encode",
"the",
"ancillary",
"β-subunits",
"or",
"regulatory",
"proteins",
"of",
"the",
"cardiac",
"sodium",
"channel.",
"While",
"clinical",
"and",
"genetic",
"studies",
"have",
"laid",
"the",
"foundation",
"for",
"our",
"understanding",
"of",
"cardiac",
"sodium",
"channe-",
"lopathies",
"by",
"establishing",
"links",
"between",
"arrhythmogenic",
"diseases",
"and",
"mutations",
"in",
"genes",
"that",
"encode",
"various",
"subunits",
"of",
"the",
"cardiac",
"sodium",
"channel,",
"biophysical",
"studies",
"(particularly",
"in",
"heterologous",
"expression",
"systems",
"and",
"transgenic",
"mouse",
"models)",
"have",
"provided",
"insights",
"into",
"the",
"mechanisms",
"by",
"which",
"INa",
"dysfunction",
"causes",
"disease",
"in",
"such",
"channelopathies.",
"It",
"is",
"now",
"recognized",
"that",
"mutations",
"that",
"increase",
"INa",
"delay",
"cardiac",
"repolarization,",
"prolong",
"action",
"potential",
"duration,",
"and",
"cause",
"long",
"QT",
"syndrome,",
"while",
"mutations",
"that",
"reduce",
"INa",
"decrease",
"cardiac",
"excitability,",
"reduce",
"electrical",
"conduction",
"velocity,",
"and",
"Grant",
"support",
"Dr.",
"Tan",
"was",
"supported",
"by",
"the",
"Netherlands",
"Organization",
"for",
"Scientific",
"Research",
"(NWO,",
"grant",
"ZonMW",
"Vici",
"918.86.616).",
"A.",
"S.",
"Amin",
":",
"A.",
"Asghari-Roodsari",
"Heart",
"Failure",
"Research",
"Center,",
"Academic",
"Medical",
"Center,",
"University",
"of",
"Amsterdam,",
"Amsterdam,",
"the",
"Netherlands",
"H.",
"L.",
"Tan",
"(*)",
"Department",
"of",
"Cardiology,",
"Heart",
"Failure",
"Research",
"Center,",
"Academic",
"Medical",
"Center,",
"University",
"of",
"Amsterdam,",
"Room",
"K2-109,",
"Meibergdreef",
"9,",
"Amsterdam,",
"1105",
"AZ,",
"the",
"Netherlands",
"e-mail:",
"h.l.tan@amc.nl",
"induce",
"Brugada",
"syndrome,",
"progressive",
"cardiac",
"conduction",
"disease,",
"sick",
"sinus",
"syndrome,",
"or",
"combinations",
"thereof.",
"Recently,",
"mutation-induced",
"INa",
"dysfunction",
"was",
"also",
"linked",
"to",
"dilated",
"cardiomyopathy,",
"atrial",
"fibrillation,",
"and",
"sudden",
"infant",
"death",
"syndrome.",
"This",
"review",
"describes",
"the",
"structure",
"and",
"function",
"of",
"the",
"cardiac",
"sodium",
"channel",
"and",
"its",
"various",
"subunits,",
"summarizes",
"major",
"cardiac",
"sodium",
"channelopathies",
"and",
"the",
"current",
"knowledge",
"concerning",
"their",
"genetic",
"back-",
"ground",
"and",
"underlying",
"molecular",
"mechanisms,",
"and",
"discusses",
"recent",
"advances",
"in",
"the",
"discovery",
"of",
"mutation-specific",
"therapies",
"in",
"the",
"management",
"of",
"these",
"channelopathies.",
"Keywords",
"Arrhythmia",
".",
"Action",
"potential",
".",
"Cardiac",
"electrophysiology",
".",
"Cardiomyocyte",
".",
"Ion",
"channels",
"Introduction",
"Cardiac",
"sodium",
"channels",
"are",
"transmembrane",
"proteins",
"that",
"are",
"located",
"in",
"the",
"sarcolemma",
"of",
"atrial",
"and",
"ventricular",
"myocytes",
"and",
"the",
"Purkinje",
"fibers.",
"They",
"enable",
"a",
"large",
"and",
"rapid",
"influx",
"of",
"sodium",
"ions",
"(sodium",
"current;",
"INa)",
"during",
"the",
"rapid",
"upstroke",
"(phase",
"0)",
"of",
"the",
"cardiac",
"action",
"potential.",
"INa",
"underlies",
"the",
"initiation",
"and",
"propagation",
"of",
"action",
"potentials,",
"and,",
"by",
"doing",
"so,",
"it",
"determines",
"cardiac",
"excitability",
"and",
"conduction",
"velocity",
"of",
"electrical",
"stimuli",
"through",
"the",
"heart",
"(Fig.",
"1a,",
"b)",
"[9].",
"To",
"a",
"lesser",
"extent,",
"cardiac",
"sodium",
"channels",
"are",
"also",
"present",
"in",
"the",
"sinoatrial",
"node",
"and",
"the",
"atrioventric-",
"ular",
"node,",
"where",
"they",
"contribute",
"to",
"pacemaker",
"activity",
"[45].",
"The",
"importance",
"of",
"sodium",
"channels",
"for",
"normal",
"electrical",
"activity",
"of",
"the",
"heart",
"is",
"emphasized",
"in",
"arrhythmogenic",
"diseases",
"caused",
"by",
"inherited",
"or",
"de",
"novo",
"(mostly",
"heterozy-",
"gous)",
"mutations",
"in",
"SCN5A,",
"the",
"gene",
"that",
"encodes",
"the",
"cardiac",
"sodium",
"channel",
"(“cardiac",
"sodium",
"channelopathies”).",
"These",
"diseases",
"include",
"long",
"QT",
"syndrome",
"type",
"3",
"(LQT-3),",
"Brugada"
] | [
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