id
int64 29.1k
3.5M
| image
unknown | bboxes
sequence | tokens
sequence | ner_tags
sequence |
|---|---|---|---|---|
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] | [
"BMC",
"Genetics",
"Correspondence",
"Minor",
"differences",
"in",
"haplotype",
"frequency",
"estimates",
"can",
"produce",
"very",
"large",
"differences",
"in",
"heterogeneity",
"test",
"statistics",
"David",
"Curtis*1",
"and",
"Ke",
"Xu2",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Academic",
"Department",
"of",
"Psychiatry,",
"Queen",
"Mary's",
"School",
"of",
"Medicine",
"and",
"Dentistry,",
"London",
"E1",
"1BB,",
"UK",
"and",
"2Laboratory",
"of",
"Neurogenetics,",
"National",
"Institute",
"on",
"Alcohol",
"Abuse",
"and",
"Alcoholism,",
"5625",
"Fishers",
"Lane,",
"Room",
"3S32,",
"Bethesda,",
"MD",
"20892-9412,",
"USA",
"Email:",
"David",
"Curtis*",
"-",
"david.curtis@qmul.ac.uk;",
"Ke",
"Xu",
"-",
"ke@mail.nih.gov",
"*",
"Corresponding",
"author",
"Published:",
"27",
"June",
"2007",
"BMC",
"Genetics",
"2007,",
"8:38",
"doi:10.1186/1471-2156-8-38",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2156/8/38",
"Received:",
"12",
"November",
"2006",
"Accepted:",
"27",
"June",
"2007",
"©",
"2007",
"Curtis",
"and",
"Xu;",
"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:",
"Tests",
"for",
"association",
"between",
"a",
"haplotype",
"and",
"disease",
"are",
"commonly",
"performed",
"using",
"a",
"likelihood",
"ratio",
"test",
"for",
"heterogeneity",
"between",
"case",
"and",
"control",
"haplotype",
"frequencies.",
"Using",
"data",
"from",
"a",
"study",
"of",
"association",
"between",
"heroin",
"dependence",
"and",
"the",
"DRD2",
"gene,",
"we",
"obtained",
"estimated",
"haplotype",
"frequencies",
"and",
"the",
"associated",
"likelihood",
"ratio",
"statistic",
"using",
"two",
"different",
"computer",
"programs,",
"MLOCUS",
"and",
"GENECOUNTING.",
"We",
"also",
"carried",
"out",
"permutation",
"testing",
"to",
"assess",
"the",
"empirical",
"significance",
"of",
"the",
"results",
"obtained.",
"Results:",
"Both",
"programs",
"yielded",
"similar,",
"though",
"not",
"identical,",
"estimates",
"for",
"the",
"haplotype",
"frequencies.",
"MLOCUS",
"produced",
"a",
"p",
"value",
"of",
"1.8*10-15",
"and",
"GENECOUNTING",
"produced",
"a",
"p",
"value",
"of",
"5.4*10-4.",
"Permutation",
"testing",
"produced",
"a",
"p",
"value",
"2.8*10-4.",
"Conclusion:",
"The",
"fact",
"that",
"very",
"large",
"differences",
"occur",
"between",
"the",
"likelihood",
"ratio",
"statistics",
"from",
"the",
"two",
"programs",
"may",
"reflect",
"the",
"fact",
"that",
"the",
"haplotype",
"frequencies",
"for",
"the",
"combined",
"group",
"are",
"not",
"constrained",
"to",
"be",
"equal",
"to",
"the",
"weighted",
"averages",
"of",
"the",
"frequencies",
"for",
"the",
"cases",
"and",
"controls,",
"as",
"they",
"would",
"be",
"if",
"they",
"were",
"directly",
"observed",
"rather",
"than",
"being",
"estimated.",
"Minor",
"differences",
"in",
"haplotype",
"frequency",
"estimates",
"can",
"result",
"in",
"very",
"large",
"differences",
"in",
"the",
"likelihood",
"ratio",
"statistic",
"and",
"associated",
"p",
"value.",
"Background",
"We",
"wish",
"to",
"point",
"out",
"a",
"serious",
"and",
"previously",
"unde-",
"scribed",
"problem",
"with",
"using",
"heterogeneity",
"testing",
"to",
"test",
"for",
"differences",
"in",
"haplotype",
"frequencies",
"between",
"cases",
"and",
"controls.",
"As",
"implemented",
"in",
"several",
"applications",
"[1-",
"3]",
"a",
"likelihood",
"ratio",
"statistic",
"(LRS)",
"is",
"calculated",
"as",
"2(LCASE+LCONTROL-LCOMBINED),",
"where",
"the",
"relevant",
"log",
"like-",
"lihoods",
"are",
"produced",
"using",
"maximum",
"likelihood",
"esti-",
"mates",
"of",
"the",
"haplotype",
"frequencies.",
"Although",
"this",
"approach",
"is",
"reasonable",
"in",
"theory,",
"severe",
"problems",
"can",
"arise",
"in",
"practice",
"if",
"the",
"likelihood",
"maximisation",
"process",
"is",
"less",
"than",
"perfect.",
"Although",
"the",
"estimation-maximisation",
"(EM)",
"method",
"usually",
"performs",
"well,",
"it",
"is",
"known",
"that",
"it",
"is",
"not",
"guaranteed",
"always",
"to",
"find",
"a",
"global",
"maximum.",
"In",
"many",
"circumstances",
"small",
"errors",
"in",
"numerical",
"estimates",
"do",
"not",
"have",
"practical",
"signficance.",
"However",
"we",
"have",
"dis-",
"covered",
"that",
"in",
"the",
"context",
"of",
"heterogeneity",
"testing",
"appar-",
"ently",
"trivial",
"differences",
"in",
"estimating",
"the",
"haplotype",
"frequency",
"parameters",
"can",
"have",
"very",
"large",
"impacts",
"on",
"the",
"associated",
"likelihoods",
"and",
"LRS",
"values.",
"Results",
"In",
"Table",
"1",
"we",
"present",
"the",
"haplotype",
"frequency",
"estimates",
"and",
"associated",
"log",
"likelihoods",
"and",
"LRS",
"values",
"obtained",
"Page",
"1",
"of",
"3",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Extended",
"report",
"HSC70",
"blockade",
"by",
"the",
"therapeutic",
"peptide",
"P140",
"affects",
"autophagic",
"processes",
"and",
"endogenous",
"MHCII",
"presentation",
"in",
"murine",
"lupus",
"Nicolas",
"Page,1",
"Frédéric",
"Gros,1",
"Nicolas",
"Schall,1",
"Marion",
"Décossas,1",
"Dominique",
"Bagnard,2",
"Jean-Paul",
"Briand,1",
"Sylviane",
"Muller1",
"▶",
"Additional",
"data",
"(supplementary",
"figures)",
"are",
"published",
"online",
"only.",
"To",
"view",
"these",
"files",
"please",
"visit",
"the",
"journal",
"online",
"at",
"(http://ard.bmj.",
"com).",
"1",
"CNRS",
"UPR9021,",
"Institut",
"de",
"Biologie",
"Moléculaire",
"et",
"Cellulaire,",
"Strasbourg,",
"France",
"2",
"INSERM",
"U682,",
"Université",
"de",
"Strasbourg,",
"Strasbourg,",
"France",
"Correspondence",
"to",
"Sylviane",
"Muller,",
"CNRS",
"UPR9021,",
"Institut",
"de",
"Biologie",
"Moléculaire",
"et",
"Cellulaire,",
"67000",
"Strasbourg,",
"France;",
"s.muller@ibmc-cnrs.unistra.fr",
"Accepted",
"11",
"November",
"2010",
"Published",
"Online",
"First",
"20",
"December",
"2010",
"This",
"paper",
"is",
"freely",
"available",
"online",
"under",
"the",
"BMJ",
"Journals",
"unlocked",
"scheme,",
"see",
"http://",
"ard.bmj.com/info/unlocked.dtl",
"Ann",
"Rheum",
"Dis",
"2011;70:837–843.",
"doi:10.1136/ard.2010.139832",
"ABSTRACT",
"Background",
"The",
"P140",
"phosphopeptide",
"issued",
"from",
"the",
"spliceosomal",
"U1-70K",
"small",
"nuclear",
"ribonucleoprotein",
"protein",
"displays",
"protective",
"properties",
"in",
"MRL/lpr",
"lupus-",
"prone",
"mice.",
"It",
"binds",
"both",
"major",
"histocompatibility",
"class",
"II",
"(MHCII)",
"and",
"HSC70/Hsp73",
"molecules.",
"P140",
"peptide",
"increases",
"MRL/lpr",
"peripheral",
"blood",
"lymphocyte",
"apoptosis",
"and",
"decreases",
"autoepitope",
"recognition",
"by",
"T",
"cells.",
"Objective",
"To",
"explore",
"further",
"the",
"mode",
"of",
"action",
"of",
"P140",
"peptide",
"on",
"HSC70+",
"antigen-presenting",
"cells.",
"Methods",
"P140",
"biodistribution",
"was",
"monitored",
"in",
"real",
"time",
"using",
"an",
"imaging",
"system",
"and",
"by",
"fluorescence",
"and",
"electron",
"microscopy.",
"Fluorescence",
"activated",
"cell",
"sorting",
"and",
"Western",
"blotting",
"experiments",
"were",
"used",
"to",
"evaluate",
"the",
"P140",
"effects",
"on",
"autophagic",
"flux",
"markers.",
"Results",
"P140",
"fluorescence",
"accumulated",
"especially",
"in",
"the",
"lungs",
"and",
"spleen.",
"P140",
"peptide",
"reduced",
"the",
"number",
"of",
"peripheral",
"and",
"splenic",
"T",
"and",
"B",
"cells",
"without",
"affecting",
"these",
"cells",
"in",
"normal",
"mice.",
"Remaining",
"MRL/lpr",
"B",
"cells",
"responded",
"normally",
"to",
"mitogens.",
"P140",
"peptide",
"decreased",
"the",
"expression",
"levels",
"of",
"HSC70/Hsp73",
"chaperone",
"and",
"stable",
"MHCII",
"dimers,",
"which",
"are",
"both",
"increased",
"in",
"MRL/",
"lpr",
"splenic",
"B",
"cells.",
"It",
"impaired",
"refolding",
"properties",
"of",
"chaperone",
"HSC70.",
"In",
"MRL/lpr",
"B",
"cells,",
"it",
"increased",
"the",
"accumulation",
"of",
"the",
"autophagy",
"markers",
"p62/SQSTM1",
"and",
"LC3-II,",
"consistent",
"with",
"a",
"downregulated",
"lysosomal",
"degradation",
"during",
"autophagic",
"flux.",
"Conclusion",
"The",
"study",
"results",
"suggest",
"that",
"after",
"P140",
"peptide",
"binding",
"to",
"HSC70,",
"the",
"endogenous",
"(auto)",
"antigen",
"processing",
"might",
"be",
"greatly",
"affected",
"in",
"MRL/",
"lpr",
"antigen-presenting",
"B",
"cells,",
"leading",
"to",
"the",
"observed",
"decrease",
"of",
"autoreactive",
"T-cell",
"priming",
"and",
"signalling",
"via",
"a",
"mechanism",
"involving",
"a",
"lysosomal",
"degradation",
"pathway.",
"This",
"unexpected",
"mechanism",
"might",
"explain",
"the",
"beneficial",
"effect",
"of",
"P140",
"peptide",
"in",
"treated",
"MRL/lpr",
"mice.",
"INTRODUCTION",
"Systemic",
"lupus",
"erythematosus",
"is",
"a",
"multifacto-",
"rial",
"(multigenic)",
"and",
"highly",
"polymorphic",
"systemic",
"autoimmune",
"disorder.",
"It",
"affects",
"multiple",
"organs,",
"including",
"skin,",
"muscle,",
"joints",
"and",
"vital",
"internal",
"organs",
"such",
"as",
"kidneys",
"and",
"heart.",
"Current",
"pharma-",
"cological",
"treatments",
"are",
"largely",
"palliative",
"and",
"result",
"in",
"non-specific",
"immunosuppression.",
"The",
"goal",
"today",
"is",
"to",
"design",
"more",
"specific",
"and",
"effective",
"treatments.",
"P140",
"peptide",
"is",
"a",
"21-mer",
"fragment",
"of",
"the",
"spli-",
"ceosomal",
"U1-70K",
"small",
"nuclear",
"ribonucleoprotein",
"protein",
"that",
"significantly",
"ameliorates",
"clinical",
"and",
"biological",
"manifestations",
"in",
"autoimmune",
"patients",
"with",
"systemic",
"lupus",
"erythematosus",
"and",
"enhances",
"survival",
"in",
"lupus-prone",
"mice.1",
"2",
"This",
"peptide",
"con-",
"tains",
"a",
"phosphoserine",
"residue",
"at",
"position",
"140,",
"a",
"modification",
"that",
"specifically",
"occurs",
"at",
"an",
"early",
"stage",
"of",
"apoptosis,",
"before",
"the",
"cleavage",
"of",
"the",
"C-terminal",
"part",
"of",
"the",
"protein",
"by",
"caspase-3",
"and",
"the",
"dephosphorylation",
"of",
"other",
"serine",
"residues",
"by",
"a",
"PP1",
"phosphatase-mediated",
"mechanism.3",
"Originally",
"thought",
"to",
"act",
"solely",
"via",
"the",
"modulation",
"of",
"intrac-",
"ellular",
"signalling",
"induced",
"by",
"αβ",
"autoreactive",
"T-cell",
"receptor",
"(TCR)",
"engagement,2",
"4",
"P140",
"was",
"unexpect-",
"edly",
"found",
"to",
"interact",
"selectively",
"with",
"the",
"consti-",
"tutive",
"heat-shock",
"HSC70/Hsp73",
"protein.5",
"By",
"a",
"granzyme-B",
"and",
"caspase-dependent",
"mechanism,",
"it",
"induces",
"in",
"Fas-deficient",
"MRL/lpr",
"lupus",
"mice",
"apopto-",
"sis",
"of",
"B",
"cells",
"and",
"CD4,",
"CD8",
"or",
"double",
"negative",
"(DN)",
"αβTCR+/CD4/CD8/B220+",
"T",
"lymphocytes",
"through",
"a",
"regulatory",
"circuit",
"involving",
"γδT",
"cells.5",
"Intravenous",
"P140",
"peptide",
"administration",
"into",
"young",
"MRL/lpr",
"mice",
"thus",
"causes",
"T-",
"and",
"B-cell",
"egress",
"from",
"periph-",
"eral",
"blood",
"but",
"does",
"not",
"affect",
"T-cell",
"priming,",
"and",
"does",
"not",
"interfere",
"with",
"the",
"ability",
"of",
"P140-treated",
"mice",
"to",
"resist",
"to",
"an",
"infectious",
"viral",
"challenge.6",
"P140",
"also",
"downregulates",
"the",
"expression",
"of",
"programmed",
"death",
"1",
"(PD-1/CD279)",
"receptor,",
"a",
"molecule",
"of",
"the",
"CD28",
"family,",
"which",
"is",
"overexpressed",
"at",
"the",
"sur-",
"face",
"of",
"MRL/lpr",
"CD4",
"T",
"cells.5",
"P140",
"peptide",
"thus",
"displays",
"various",
"effects",
"on",
"the",
"immune",
"system",
"that",
"probably",
"interfere",
"with",
"several,",
"yet",
"unidentified,",
"molecular",
"pathways",
"leading",
"finally",
"to",
"a",
"decreased",
"T-cell",
"autoreactivity",
"and",
"to",
"significantly",
"lower",
"levels",
"of",
"autoantibodies",
"to",
"native",
"DNA.",
"In",
"the",
"postulated",
"P140",
"mode",
"of",
"action,",
"bind-",
"ing",
"to",
"the",
"chaperone",
"HSC70",
"protein",
"seems",
"to",
"be",
"central.",
"The",
"implication",
"of",
"or",
"any",
"defect",
"of",
"the",
"HSC70",
"pathway",
"in",
"regulating",
"immune",
"functions",
"in",
"lupus",
"is",
"not",
"documented.",
"It",
"is",
"not",
"known",
"either",
"if",
"HSC70-chaperoned",
"molecules,",
"such",
"as",
"other",
"Hsps",
"and",
"major",
"histocompatibility",
"complex",
"(MHC)",
"molecules,",
"are",
"affected",
"by",
"P140–HSC70",
"binding.",
"To",
"address",
"these",
"major",
"questions,",
"we",
"evaluated",
"the",
"effect",
"of",
"P140",
"administration",
"on",
"the",
"expres-",
"sion",
"of",
"HSC70",
"and",
"MHCII",
"molecules,",
"and",
"studied",
"the",
"possible",
"influence",
"of",
"P140",
"on",
"autophagosomal",
"pathways",
"implicated",
"in",
"the",
"endogenous",
"MHCII",
"loading.",
"Since",
"HSC70",
"is",
"involved",
"in",
"certain",
"phases",
"of",
"these",
"pathways,",
"we",
"expected",
"that",
"binding",
"of",
"P140",
"to",
"HSC70",
"might",
"alter",
"the",
"delivery",
"of",
"intracel-",
"lular",
"material",
"into",
"the",
"endosomal/lysosomal",
"path-",
"way",
"and",
"therefore",
"thwart",
"the",
"final",
"presentation",
"of",
"self-antigens",
"to",
"autoreactive",
"T",
"cells.",
"METHODS",
"Synthetic",
"peptides",
"and",
"biochemical",
"assays",
"Peptides",
"were",
"assembled",
"and",
"purified",
"as",
"des-",
"cribed.1",
"5",
"The",
"P140",
"peptide",
"was",
"also",
"synthesised",
"837"
] | [
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] | [
"Wang",
"et",
"al.",
"BMC",
"Developmental",
"Biology",
"2010,",
"10:91",
"http://www.biomedcentral.com/1471-213X/10/91",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Commitment",
"of",
"chondrogenic",
"precursors",
"of",
"the",
"avian",
"scapula",
"takes",
"place",
"after",
"epithelial-",
"mesenchymal",
"transition",
"of",
"the",
"dermomyotome",
"Baigang",
"Wang1,2*,",
"Qin",
"Pu3,",
"Raja",
"De2,",
"Ketan",
"Patel4,",
"Bodo",
"Christ2,",
"Jörg",
"Wilting1,",
"Ruijin",
"Huang2,3*",
"Abstract",
"Background:",
"Cells",
"of",
"the",
"epithelially",
"organised",
"dermomyotome",
"are",
"traditionally",
"believed",
"to",
"give",
"rise",
"to",
"skeletal",
"muscle",
"and",
"dermis.",
"We",
"have",
"previously",
"shown",
"that",
"the",
"dermomyotome",
"can",
"undergo",
"epithelial-mesenchymal",
"transition",
"(EMT)",
"and",
"give",
"rise",
"to",
"chondrogenic",
"cells,",
"which",
"go",
"on",
"to",
"form",
"the",
"scapula",
"blade",
"in",
"birds.",
"At",
"present",
"we",
"have",
"little",
"understanding",
"regarding",
"the",
"issue",
"of",
"when",
"the",
"chondrogenic",
"fate",
"of",
"dermomyotomal",
"cells",
"is",
"determined.",
"Using",
"quail-chick",
"grafting",
"experiments,",
"we",
"investigated",
"whether",
"scapula",
"precursor",
"cells",
"are",
"committed",
"to",
"a",
"chondrogenic",
"fate",
"while",
"in",
"an",
"epithelial",
"state",
"or",
"whether",
"commitment",
"is",
"established",
"after",
"EMT.",
"Results:",
"We",
"show",
"that",
"the",
"hypaxial",
"dermomyotome,",
"which",
"normally",
"forms",
"the",
"scapula,",
"does",
"not",
"generate",
"cartilaginous",
"tissue",
"after",
"it",
"is",
"grafted",
"to",
"the",
"epaxial",
"domain.",
"In",
"contrast",
"engraftment",
"of",
"the",
"epaxial",
"dermomyotome",
"to",
"the",
"hypaxial",
"domain",
"gives",
"rise",
"to",
"scapula-like",
"cartilage.",
"However,",
"the",
"hypaxial",
"sub-ectodermal",
"mesenchyme",
"(SEM),",
"which",
"originates",
"from",
"the",
"hypaxial",
"dermomyotome",
"after",
"EMT,",
"generates",
"cartilaginous",
"elements",
"in",
"the",
"epaxial",
"domain,",
"whereas",
"in",
"reciprocal",
"grafting",
"experiments,",
"the",
"epaxial",
"SEM",
"cannot",
"form",
"cartilage",
"in",
"the",
"hypaxial",
"domain.",
"Conclusions:",
"We",
"suggest",
"that",
"the",
"epithelial",
"cells",
"of",
"the",
"dermomyotome",
"are",
"not",
"committed",
"to",
"the",
"chondrogenic",
"lineage.",
"Commitment",
"to",
"this",
"lineage",
"occurs",
"after",
"it",
"has",
"undergone",
"EMT",
"to",
"form",
"the",
"sub-ectodermal",
"mesenchyme.",
"Background",
"Epithelial",
"and",
"mesenchymal",
"cells",
"differ",
"from",
"each",
"other",
"in",
"several",
"aspects.",
"Epithelial",
"cells",
"are",
"connected",
"to",
"each",
"other",
"by",
"cell",
"surface",
"contacts",
"such",
"as",
"desmosomes",
"and",
"gap",
"junctions,",
"form",
"dense",
"cell",
"layers",
"resting",
"on",
"a",
"basal",
"lamina",
"and",
"exhibiting",
"apical-basal",
"polarity.",
"In",
"contrast,",
"mesenchymal",
"cells",
"have",
"no",
"association",
"with",
"the",
"basal",
"lamina",
"and",
"usually",
"do",
"not",
"possess",
"elaborated",
"adhesion",
"complexes",
"with",
"neighbouring",
"cells,",
"which",
"increase",
"their",
"migratory",
"potential.",
"Under",
"certain",
"physiological",
"or",
"pathological",
"conditions",
"epithelial",
"cells",
"lose",
"their",
"charac-",
"teristics",
"and",
"undergo",
"morphological",
"changes",
"to",
"convert",
"into",
"mesenchymal",
"cells,",
"a",
"biological",
"process",
"known",
"as",
"epithelial-mesenchymal",
"transition",
"(EMT)",
"[1].",
"The",
"*",
"Correspondence:",
"baigang.wang@medizin.uni-goettingen.de;",
"ruijin.",
"huang@uni-bonn.de",
"1Department",
"of",
"Anatomy",
"and",
"Cell",
"Biology,",
"University",
"of",
"Goettingen,",
"Kreuzbergring",
"36,",
"37075",
"Goettingen,",
"Germany",
"2Institute",
"of",
"Anatomy",
"and",
"Cell",
"Biology,",
"University",
"of",
"Freiburg,",
"Albertstrasse",
"17,",
"79104",
"Freiburg,",
"Germany",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"process",
"of",
"EMT",
"is",
"reversible",
"and",
"the",
"opposite",
"mechan-",
"ism",
"converts",
"mesenchymal",
"cells",
"into",
"epithelia",
"(mesench-",
"ymal-to-epithelial",
"transition,",
"MET).",
"EMT",
"and",
"MET",
"play",
"key",
"roles",
"not",
"only",
"during",
"early",
"embryonic",
"development,",
"for",
"example",
"during",
"implantation",
"of",
"the",
"embryo",
"into",
"the",
"uterus,",
"gastrulation",
"and",
"de-lamina-",
"tion",
"of",
"neural",
"crest",
"cells,",
"but",
"also",
"during",
"later",
"developmen-",
"tal",
"stages",
"such",
"as",
"in",
"somite",
"development",
"and",
"organogenesis",
"[2].",
"Somites",
"are",
"balls",
"of",
"epithelial",
"cells,",
"which",
"arise",
"from",
"the",
"paraxial",
"mesoderm",
"(mesenchyme)",
"by",
"means",
"of",
"MET.",
"Later,",
"the",
"ventral",
"half",
"of",
"each",
"somite",
"undergoes",
"EMT",
"to",
"give",
"rise",
"to",
"the",
"sclerotome",
"[3],",
"while",
"the",
"dorsal",
"half",
"remains",
"epithe-",
"lial",
"and",
"forms",
"the",
"dermomyotome,",
"source",
"of",
"the",
"skeletal",
"muscle,",
"dermis",
"[4],",
"scapula",
"blade",
"in",
"birds",
"[5]",
"and",
"medial",
"scapula",
"border",
"in",
"mammals",
"[6].",
"The",
"avian",
"dermomyotome",
"in",
"specific",
"axial",
"regions",
"undergoes",
"EMT",
"to",
"form",
"sub-ectodermal",
"mesenchyme",
"which",
"gives",
"rise",
"to",
"scapula",
"[7].",
"This",
"process",
"is",
"con-",
"trolled",
"by",
"signals",
"from",
"the",
"ectoderm",
"and",
"the",
"lateral",
"plate",
"mesoderm",
"[7,8].",
"Furthermore",
"only",
"cells",
"originating",
"©",
"2010",
"Wang",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"International",
"Scholarly",
"Research",
"Network",
"ISRN",
"Nursing",
"Volume",
"2012,",
"Article",
"ID",
"676905,",
"6",
"pages",
"doi:10.5402/2012/676905",
"Research",
"Article",
"Mapping",
"the",
"Diagnosis",
"Axis",
"of",
"an",
"Interface",
"Terminology",
"to",
"the",
"NANDA",
"International",
"Taxonomy",
"Maria-Eul",
"a`lia",
"Juve´",
"Udina,1",
"Maribel",
"Gonzalez",
"Samartino,2",
"and",
"Cristina",
"Matud",
"Calvo2",
"1",
"School",
"of",
"Nursing,",
"University",
"of",
"Barcelona,",
"Campus",
"of",
"Bellvitge,",
"Feixa",
"Llarga",
"s/n,",
"08907",
"Hospitalet",
"de",
"Llobregat,",
"Spain",
"2",
"Nursing",
"Information",
"Systems",
"Department,",
"University",
"Hospital",
"of",
"Bellvitge,",
"08907",
"Hospitalet",
"de",
"Llobregat,",
"Spain",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Maria-Eula`lia",
"Juve´",
"Udina,",
"ejuve@gencat.cat",
"Received",
"11",
"March",
"2012;",
"Accepted",
"8",
"May",
"2012",
"Academic",
"Editors:",
"B.",
"Mandleco",
"and",
"A.",
"Williams",
"Copyright",
"©",
"2012",
"Maria-Eula`lia",
"Juve´",
"Udina",
"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.",
"Nursing",
"terminologies",
"are",
"designed",
"to",
"support",
"nursing",
"practice",
"but,",
"as",
"with",
"any",
"other",
"clinical",
"tool,",
"they",
"should",
"be",
"evaluated.",
"Cross-mapping",
"is",
"a",
"formal",
"method",
"for",
"examining",
"the",
"validity",
"of",
"the",
"existing",
"controlled",
"vocabularies.",
"Objectives.",
"The",
"study",
"aims",
"to",
"assess",
"the",
"inclusiveness",
"and",
"expressiveness",
"of",
"the",
"nursing",
"diagnosis",
"axis",
"of",
"a",
"newly",
"implemented",
"interface",
"terminology",
"by",
"cross-mapping",
"with",
"the",
"NANDA-I",
"taxonomy.",
"Design/Methods.",
"The",
"study",
"applied",
"a",
"descriptive",
"design,",
"using",
"a",
"cross-sectional,",
"bidirectional",
"mapping",
"strategy.",
"The",
"sample",
"included",
"728",
"concepts",
"from",
"both",
"vocabularies.",
"Concept",
"cross-mapping",
"was",
"carried",
"out",
"to",
"identify",
"one-to-one,",
"negative,",
"and",
"hierarchical",
"connections.",
"The",
"analysis",
"was",
"conducted",
"using",
"descriptive",
"statistics.",
"Results.",
"Agreement",
"of",
"the",
"raters’",
"mapping",
"achieved",
"97%.",
"More",
"than",
"60%",
"of",
"the",
"nursing",
"diagnosis",
"concepts",
"in",
"the",
"NANDA-I",
"taxonomy",
"were",
"mapped",
"to",
"concepts",
"in",
"the",
"diagnosis",
"axis",
"of",
"the",
"new",
"interface",
"terminology;",
"71.1%",
"were",
"reversely",
"mapped.",
"Conclusions.",
"Main",
"results",
"for",
"outcome",
"measures",
"suggest",
"that",
"the",
"diagnosis",
"axis",
"of",
"this",
"interface",
"terminology",
"meets",
"the",
"validity",
"criterion",
"of",
"cross-mapping",
"when",
"mapped",
"from",
"and",
"to",
"the",
"NANDA-I",
"taxonomy.",
"1.",
"Introduction",
"Language",
"plays",
"an",
"important",
"role",
"in",
"defining",
"what",
"nurses",
"do",
"and",
"why",
"they",
"do",
"it.",
"In",
"recent",
"decades,",
"language",
"systems",
"have",
"become",
"a",
"priority",
"for",
"international",
"nursing",
"agendas.",
"Standardized",
"controlled",
"vocabularies",
"are",
"a",
"means",
"to",
"develop,",
"express,",
"and",
"understand",
"nursing",
"phenomena",
"and",
"actions",
"through",
"concepts;",
"to",
"quote",
"Matney",
"et",
"al.",
"“structured",
"nursing",
"terminologies",
"are",
"needed",
"to",
"drive,",
"document",
"and",
"evaluate",
"nursing",
"practice”",
"[1].",
"The",
"use",
"of",
"electronic",
"health",
"records",
"and",
"information",
"sys-",
"tems",
"at",
"all",
"levels",
"of",
"the",
"healthcare",
"agencies",
"is",
"now",
"widespread",
"all",
"over",
"the",
"world.",
"In",
"order",
"to",
"optimize",
"the",
"efficiency",
"of",
"these",
"records",
"and",
"systems",
"and",
"to",
"facilitate",
"the",
"exchange",
"of",
"infor-",
"mation",
"among",
"professionals",
"and",
"institutions,",
"they",
"must",
"be",
"based",
"on",
"controlled",
"vocabularies",
"[2,",
"3];",
"as",
"Mu¨",
"ller-Staub",
"et",
"al.",
"explain",
"“standardized",
"computer-compatible",
"professional",
"ter-",
"minology",
"is",
"becoming",
"a",
"requirement,",
"especially",
"by",
"institutions",
"and",
"healthcare",
"systems",
"that",
"bear",
"the",
"costs",
"of",
"health",
"care”",
"[4].",
"Controlled",
"nursing",
"vocabularies",
"can",
"be",
"implemented",
"as",
"interface",
"terminologies",
"at",
"the",
"point",
"of",
"care",
"and",
"as",
"administrative",
"terminologies",
"to",
"retrieve",
"nursing",
"clinical",
"data",
"in",
"order",
"to",
"support",
"decision-making",
"[4–6].",
"To",
"date,",
"twelve",
"nursing",
"terminologies",
"and",
"data",
"sets",
"have",
"been",
"recognized",
"by",
"the",
"American",
"Nurses",
"Association",
"(ANA)",
"for",
"supporting",
"nursing",
"practice:",
"the",
"North",
"American",
"Nursing",
"Diagnosis",
"Association",
"International",
"Taxonomy",
"(NANDA-I),",
"the",
"Nursing",
"Interventions",
"Classification",
"(NIC),",
"the",
"Clinical",
"Care",
"Classification",
"(CCC),",
"the",
"Omaha",
"System,",
"the",
"Nursing",
"Outcomes",
"Classification",
"(NOC),",
"the",
"Nursing",
"Management",
"Minimum",
"Data",
"Set",
"(NMMDS),",
"the",
"Perioperative",
"Nursing",
"Data",
"Set",
"(PNDS),",
"SNOMED",
"Clinical",
"Terms,",
"the",
"Nursing",
"Minimum",
"Data",
"Set",
"(NMDS),",
"the",
"International",
"Classification",
"for",
"Nursing",
"Practice",
"(ICNP)",
"from",
"the",
"International",
"Council",
"of",
"Nurses,",
"the",
"ABCcodes,",
"and",
"the",
"Logical",
"Observation",
"Identifiers",
"Names",
"and",
"Codes",
"(LOINC)",
"[7].",
"The",
"North",
"American",
"Nursing",
"Diagnosis",
"Association",
"International",
"Taxonomy",
"(NANDA-I)",
"is",
"considered",
"the",
"most"
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] | [
"Original",
"Article",
"The",
"Prevalence",
"of",
"Human",
"Papilloma",
"Virus",
"in",
"Esophageal",
"Squamous",
"Cell",
"Carcinoma",
"IJMS",
"Vol",
"37,",
"No",
"2,",
"June",
"2012",
"Sadat",
"Noori1,",
"Ahmad",
"Monabati1,2,",
"Abbasali",
"Ghaderi3",
"1Department",
"of",
"Pathology,",
"School",
"of",
"Medicine,",
"Shiraz",
"University",
"of",
"Medical",
"Sciences,",
"Shiraz,",
"Iran.",
"2Hematology",
"Research",
"Center,",
"Nemazee",
"Hospital,",
"Shiraz",
"University",
"of",
"Medical",
"Sciences,",
"Shiraz,",
"Iran.",
"3Department",
"of",
"Immunology,",
"School",
"of",
"Medicine,",
"Shiraz",
"University",
"of",
"Medical",
"Sciences,",
"Shiraz,",
"Iran.",
"Correspondence:",
"Sadat",
"Noori",
"MD,",
"Department",
"of",
"Pathology,",
"School",
"of",
"Medicine,",
"Shiraz",
"University",
"of",
"Medical",
"Sciences,",
"Zand",
"Avenue,",
"Shiraz,",
"Iran.",
"Tel/Fax:",
"+98",
"711",
"2349521",
"Email:",
"noorisadat@yahoo.com",
"Received:",
"13",
"August",
"2011",
"Revised:",
"29",
"September",
"2011",
"Accepted:",
"13",
"November",
"2011",
"126",
"Abstract",
"Background:",
"Carcinomas",
"of",
"esophagus,",
"mostly",
"squamous",
"cell",
"carcinomas,",
"occur",
"throughout",
"the",
"world.",
"There",
"are",
"a",
"number",
"of",
"suspected",
"genetic",
"or",
"environmental",
"etiologies.",
"Human",
"papilloma",
"virus",
"(HPV)",
"is",
"said",
"to",
"be",
"a",
"major",
"etiology",
"in",
"areas",
"with",
"high",
"incidence",
"of",
"esophageal",
"carcinoma,",
"while",
"it",
"is",
"hardly",
"detectable",
"in",
"low",
"incidence",
"regions.",
"This",
"study",
"was",
"designed",
"to",
"evaluate",
"the",
"prevalence",
"of",
"HPV",
"in",
"esophageal",
"squamous",
"cell",
"carcinoma",
"(ESCC)",
"cases",
"diagnosed",
"in",
"Pathology",
"Department,",
"Medical",
"School,",
"Shiraz",
"University",
"of",
"Medical",
"Sciences.",
"Methods:",
"DNA",
"material",
"for",
"PCR",
"amplification",
"of",
"HPV",
"genome",
"was",
"extracted",
"from",
"formalin-fixed",
"paraffin-embedded",
"tissue",
"blocks",
"of",
"92",
"cases",
"of",
"ESCC,",
"diagnosed",
"during",
"20",
"years",
"from",
"1982",
"to",
"2002.",
"Polymerase",
"chain",
"reaction",
"was",
"performed",
"for",
"amplification",
"and",
"detection",
"of",
"common",
"HPV",
"and",
"type",
"specific",
"HPV-16",
"and",
"HPV-18",
"genomic",
"sequences",
"in",
"the",
"presence",
"of",
"positive",
"control",
"(HPV-18",
"and",
"HPV",
"positive",
"biopsies",
"of",
"uterine",
"exocervix)",
"and",
"additional",
"internal",
"controls",
"i.e.",
"beta-globin",
"and",
"cytotoxic",
"T",
"lymphocyte",
"antigen",
"4",
"(CTLA4).",
"Result:",
"Good",
"amplification",
"of",
"positive",
"control",
"and",
"internal",
"con-",
"trols",
"was",
"observed.",
"However,",
"no",
"amplification",
"of",
"HPV",
"genome",
"was",
"observed.",
"Conclusion:",
"There",
"is",
"no",
"association",
"between",
"HPV",
"infection",
"and",
"the",
"development",
"of",
"esophageal",
"squamous",
"cell",
"carcinoma",
"in",
"the",
"cases",
"evaluated.",
"Please",
"cite",
"this",
"article",
"as:",
"Noori",
"S,",
"Monabati",
"A,",
"Ghaderi",
"AA.",
"The",
"Prevalence",
"of",
"Human",
"Papilloma",
"Virus",
"in",
"Esophageal",
"Squamous",
"Cell",
"Carcinoma.",
"Iran",
"J",
"Med",
"Sci.",
"2012;37(2):126-133.",
"Keywords",
"●",
"Squamous",
"cell",
"carcinoma",
"●",
"esophagus",
"●",
"human",
"papilloma",
"virus",
"●",
"polymerase",
"chain",
"reaction",
"Introduction",
"Malignant",
"esophageal",
"tumors",
"usually",
"arise",
"from",
"epithelial",
"layer",
"of",
"the",
"esophagus.",
"Worldwide,",
"squamous",
"cell",
"carcinomas",
"(SCC)",
"constitute",
"90%",
"of",
"esophageal",
"cancers",
"although",
"in",
"some",
"regions",
"such",
"as",
"United",
"States",
"their",
"incidence",
"is",
"comparable",
"to",
"that",
"of",
"adenocarcinomas.",
"While",
"esophageal",
"SCC",
"(ESCC)",
"occurs",
"throughout",
"the",
"world,",
"its",
"incidence",
"varies",
"widely",
"among",
"countries",
"and",
"within",
"regions",
"of",
"the",
"same",
"country.",
"The",
"region",
"extending",
"from",
"northern",
"Iran",
"across",
"central",
"Asia",
"to",
"northern",
"China",
"exhibits",
"annual",
"incidence",
"rate",
"exceeding",
"100",
"per",
"100,000",
"with",
"deaths",
"from",
"cancer",
"of",
"the",
"esophagus",
"constituting",
"more",
"than",
"20%",
"of",
"all",
"cancer",
"deaths.",
"The",
"death",
"from",
"cancer",
"of",
"the",
"esophagus",
"in",
"this",
"area",
"constitutes",
"more",
"than",
"20%",
"of",
"all",
"cancer",
"deaths.1",
"Fars",
"province",
"in",
"the",
"south",
"of",
"Iran",
"with",
"an",
"average",
"annual",
"Iran",
"J",
"Med",
"Sci",
"June",
"2012;",
"Vol",
"37",
"No",
"2"
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] | [
"International",
"Scholarly",
"Research",
"Network",
"ISRN",
"Dentistry",
"Volume",
"2012,",
"Article",
"ID",
"695151,",
"5",
"pages",
"doi:10.5402/2012/695151",
"Research",
"Article",
"The",
"Effect",
"of",
"Three",
"Different",
"Disinfection",
"Materials",
"on",
"Alginate",
"Impression",
"by",
"Spray",
"Method",
"Hamid",
"Badrian,1",
"Ehsan",
"Ghasemi,2",
"Navid",
"Khalighinejad,1",
"and",
"Nafiseh",
"Hosseini3",
"1",
"Dental",
"Implant",
"Research",
"Center,",
"School",
"of",
"Dentistry,",
"Isfahan",
"University",
"of",
"Medical",
"sciences,",
"81746-73461",
"Isfahan,",
"Iran",
"2",
"Department",
"of",
"Prosthodontic,",
"Torabinezhad",
"Center",
"Research,",
"Dental",
"School,",
"University",
"of",
"Medical",
"Sciences,",
"81746-73461",
"Isfahan,",
"Iran",
"3",
"Department",
"of",
"Microbiology,",
"School",
"of",
"Medicine,",
"Isfahan",
"University",
"of",
"Medical",
"Sciences,",
"81746-73461",
"Isfahan,",
"Iran",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Ehsan",
"Ghasemi,",
"e",
"ghasemi@yahoo.com",
"Received",
"11",
"April",
"2012;",
"Accepted",
"6",
"June",
"2012",
"Academic",
"Editors:",
"M.",
"Behr,",
"M.",
"Del",
"Fabbro,",
"and",
"D.",
"Wray",
"Copyright",
"©",
"2012",
"Hamid",
"Badrian",
"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.",
"Introduction.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"investigate",
"the",
"effect",
"of",
"three",
"different",
"types",
"of",
"disinfectant",
"agents",
"on",
"alginate",
"impression",
"material",
"after",
"5",
"and",
"10",
"minutes.",
"Method",
"and",
"Materials.",
"In",
"this",
"in",
"vitro",
"experimental",
"study,",
"66",
"circular",
"samples",
"of",
"alginate",
"impression",
"material",
"were",
"contaminated",
"with",
"Staphylococcus",
"aureus,",
"Pseudomonas",
"aeruginosa,",
"and",
"Candida",
"albicans",
"fungus.",
"Except",
"for",
"control",
"samples,",
"all",
"of",
"them",
"were",
"disinfected",
"with",
"sodium",
"hypochlorite",
"0.525,",
"Deconex,",
"and",
"Epimax",
"by",
"way",
"of",
"spraying.",
"Afterwards,",
"they",
"were",
"kept",
"in",
"plastic",
"bags",
"with",
"humid",
"rolled",
"cotton",
"for",
"5",
"and",
"10",
"minutes.",
"The",
"number",
"of",
"colonies",
"was",
"counted",
"after",
"24",
"and",
"48",
"hours",
"for",
"bacteria",
"and",
"after",
"72",
"hours",
"for",
"fungus.",
"Statistical",
"Mann-Whitney",
"test",
"was",
"used",
"for",
"data",
"analysis",
"(α",
"=",
"0.05).",
"Results.",
"After",
"5",
"minutes,",
"Epimax",
"showed",
"the",
"highest",
"disinfection",
"action",
"on",
"Staphylococcus",
"aureus",
"as",
"it",
"completely",
"eradicated",
"the",
"bacteria.",
"The",
"disinfection",
"capacity",
"of",
"different",
"agents",
"can",
"be",
"increased",
"as",
"time",
"elapses",
"except",
"for",
"Pseudomonas",
"aeruginosa",
"which",
"was",
"eradicated",
"completely",
"in",
"both",
"5",
"and",
"10",
"minutes.",
"Conclusion.",
"This",
"study",
"revealed",
"that",
"alginate",
"can",
"be",
"effectively",
"disinfected",
"by",
"three",
"types",
"of",
"disinfecting",
"agents",
"by",
"spraying",
"method,",
"although",
"Epimax",
"showed",
"the",
"highest",
"disinfection",
"action",
"after",
"10",
"minutes",
"compared",
"to",
"other",
"agents.",
"1.",
"Introduction",
"Dentists,",
"dental",
"materials,",
"and",
"dental",
"laboratories",
"are",
"exposed",
"to",
"different",
"types",
"of",
"pathogenic",
"microorganisms.",
"Impression",
"materials,",
"impression",
"trays,",
"and",
"poured",
"stone",
"cast",
"have",
"been",
"said",
"to",
"be",
"the",
"main",
"source",
"of",
"cross",
"infection",
"between",
"patients",
"and",
"dentists",
"[1].",
"New",
"researches",
"have",
"shown",
"that",
"67%",
"of",
"materials",
"sent",
"to",
"dental",
"laboratories",
"are",
"infected",
"by",
"various",
"microorganisms",
"[2].",
"The",
"most",
"frequently",
"identified",
"microorganisms",
"are",
"Streptococcus",
"species,",
"Staphylococcus",
"species,",
"Escherichia",
"coli",
"species,",
"Actinomyces",
"species,",
"Antitratus",
"species,",
"Pseudomonas",
"species,",
"Enterobacter",
"species,",
"Klebsiella",
"pneumonia,",
"and",
"Can-",
"dida",
"species",
"[3].",
"Taking",
"this",
"into",
"account,",
"we",
"should",
"make",
"an",
"effort",
"to",
"eliminate",
"most",
"of",
"these",
"microorganisms",
"and",
"reduce",
"the",
"rate",
"of",
"infection",
"transmission",
"in",
"dental",
"laboratories.",
"The",
"International",
"Dental",
"Federation",
"(IDF)",
"insists",
"on",
"disinfecting",
"all",
"impressions",
"taken",
"from",
"patients",
"before",
"sending",
"them",
"to",
"laboratories",
"[4].",
"Also",
"the",
"American",
"Dental",
"Association",
"(ADA)",
"has",
"advised",
"all",
"dental",
"stuffs",
"to",
"disinfect",
"patients’",
"impression",
"trays",
"[5].",
"In",
"some",
"studies,",
"it",
"has",
"been",
"declared",
"that",
"washing",
"the",
"impression",
"materials",
"with",
"tap",
"water",
"only",
"removes",
"40%",
"of",
"bacteria;",
"however,",
"some",
"studies",
"reported",
"that",
"it",
"has",
"the",
"capacity",
"to",
"reduce",
"90%,",
"microorganisms",
"[6].",
"The",
"most",
"common",
"chemical",
"disinfectants",
"which",
"are",
"used",
"by",
"dentists",
"are",
"alcohols,",
"aldehydes,",
"chlorine",
"combination,",
"phenols,",
"biguanides,",
"iodide",
"combinations,",
"and",
"ammonium",
"[7].",
"There",
"are",
"two",
"common",
"methods",
"to",
"disinfect",
"dental",
"materials:",
"(1)",
"immersion",
"and",
"(2)",
"spraying",
"[6].",
"Disinfection",
"by",
"soaking",
"in",
"chemical",
"materials",
"has",
"been",
"shown",
"to",
"cover",
"all",
"surfaces",
"of",
"impression",
"materials",
"in",
"one",
"time",
"[8],",
"while",
"spraying",
"is",
"not",
"capable",
"of",
"disinfecting",
"all",
"surfaces",
"effectively",
"and",
"also",
"cannot",
"cover",
"all",
"undercuts.",
"Contrary",
"to",
"immersing,",
"spraying",
"can",
"significantly",
"reduce",
"the"
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] | [
"Implementation",
"Science",
"Research",
"article",
"Explaining",
"the",
"effects",
"of",
"an",
"intervention",
"designed",
"to",
"promote",
"evidence-based",
"diabetes",
"care:",
"a",
"theory-based",
"process",
"evaluation",
"of",
"a",
"pragmatic",
"cluster",
"randomised",
"controlled",
"trial",
"Jillian",
"J",
"Francis*1,",
"Martin",
"P",
"Eccles2,",
"Marie",
"Johnston3,",
"Paula",
"Whitty2,",
"Jeremy",
"M",
"Grimshaw4,",
"Eileen",
"FS",
"Kaner5,",
"Liz",
"Smith6",
"and",
"Anne",
"Walker1",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Health",
"Services",
"Research",
"Unit,",
"University",
"of",
"Aberdeen,",
"Aberdeen,",
"UK,",
"2Institute",
"of",
"Health",
"and",
"Society,",
"Newcastle",
"University,",
"Newcastle",
"upon",
"Tyne,",
"UK,",
"3College",
"of",
"Life",
"Sciences",
"and",
"Medicine,",
"University",
"of",
"Aberdeen,",
"Aberdeen,",
"UK,",
"4Clinical",
"Epidemiology",
"Program,",
"Ottawa",
"Health",
"Research",
"Institute",
"and",
"Department",
"of",
"Medicine,",
"University",
"of",
"Ottawa,",
"Ontario,",
"Canada,",
"5Faculty",
"of",
"Medical",
"Sciences,",
"Newcastle",
"University,",
"Newcastle",
"upon",
"Tyne,",
"UK",
"and",
"6Manchester",
"Business",
"School,",
"University",
"of",
"Manchester,",
"Manchester,",
"UK",
"Email:",
"Jillian",
"J",
"Francis*",
"-",
"j.francis@abdn.ac.uk;",
"Martin",
"P",
"Eccles",
"-",
"Martin.Eccles@newcastle.ac.uk;",
"Marie",
"Johnston",
"-",
"m.johnston@abdn.ac.uk;",
"Paula",
"Whitty",
"-",
"p.m.whitty@ncl.ac.uk;",
"Jeremy",
"M",
"Grimshaw",
"-",
"jgrimshaw@ohri.ca;",
"Eileen",
"FS",
"Kaner",
"-",
"E.F.S.Kaner@newcastle.ac.uk;",
"Liz",
"Smith",
"-",
"liz.smith@mbs.ac.uk;",
"Anne",
"Walker",
"-",
"anne_walker@yahoo.co.uk",
"*",
"Corresponding",
"author",
"Published:",
"19",
"November",
"2008",
"Implementation",
"Science",
"2008,",
"3:50",
"doi:10.1186/1748-5908-3-50",
"This",
"article",
"is",
"available",
"from:",
"http://www.implementationscience.com/content/3/1/50",
"Received:",
"1",
"May",
"2006",
"Accepted:",
"19",
"November",
"2008",
"©",
"2008",
"Francis",
"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",
"results",
"of",
"randomised",
"controlled",
"trials",
"can",
"be",
"usefully",
"illuminated",
"by",
"studies",
"of",
"the",
"processes",
"by",
"which",
"they",
"achieve",
"their",
"effects.",
"The",
"Theory",
"of",
"Planned",
"Behaviour",
"(TPB)",
"offers",
"a",
"framework",
"for",
"conducting",
"such",
"studies.",
"This",
"study",
"used",
"TPB",
"to",
"explore",
"the",
"observed",
"effects",
"in",
"a",
"pragmatic",
"cluster",
"randomised",
"controlled",
"trial",
"of",
"a",
"structured",
"recall",
"and",
"prompting",
"intervention",
"to",
"increase",
"evidence-based",
"diabetes",
"care",
"that",
"was",
"conducted",
"in",
"three",
"Primary",
"Care",
"Trusts",
"in",
"England.",
"Methods:",
"All",
"general",
"practitioners",
"and",
"nurses",
"in",
"practices",
"involved",
"in",
"the",
"trial",
"were",
"sent",
"a",
"postal",
"questionnaire",
"at",
"the",
"end",
"of",
"the",
"intervention",
"period,",
"based",
"on",
"the",
"TPB",
"(predictor",
"variables:",
"attitude;",
"subjective",
"norm;",
"perceived",
"behavioural",
"control,",
"or",
"PBC).",
"It",
"focussed",
"on",
"three",
"clinical",
"behaviours",
"recommended",
"in",
"diabetes",
"care:",
"measuring",
"blood",
"pressure;",
"inspecting",
"feet;",
"and",
"prescribing",
"statins.",
"Multivariate",
"analyses",
"of",
"variance",
"and",
"multiple",
"regression",
"analyses",
"were",
"used",
"to",
"explore",
"changes",
"in",
"cognitions",
"and",
"thereby",
"better",
"understand",
"trial",
"effects.",
"Results:",
"Fifty-nine",
"general",
"medical",
"practitioners",
"and",
"53",
"practice",
"nurses",
"(intervention:",
"n",
"=",
"55,",
"41.98%",
"of",
"trial",
"participants;",
"control:",
"n",
"=",
"57,",
"38.26%",
"of",
"trial",
"participants)",
"completed",
"the",
"questionnaire.",
"There",
"were",
"no",
"differences",
"between",
"groups",
"in",
"mean",
"scores",
"for",
"attitudes,",
"subjective",
"norms,",
"PBC",
"or",
"intentions.",
"Control",
"group",
"clinicians",
"had",
"'normatively-driven'",
"intentions",
"(i.e.,",
"related",
"to",
"subjective",
"norm",
"scores),",
"whereas",
"intervention",
"group",
"clinicians",
"had",
"'attitudinally-driven'",
"intentions",
"(i.e.,",
"related",
"to",
"attitude",
"scores)",
"for",
"foot",
"inspection",
"and",
"statin",
"prescription.",
"After",
"controlling",
"for",
"effects",
"of",
"the",
"three",
"predictor",
"variables,",
"this",
"group",
"difference",
"was",
"significant",
"for",
"foot",
"inspection",
"behaviour",
"(trial",
"group",
"×",
"attitude",
"interaction,",
"beta",
"=",
"0.72,",
"p",
"<",
"0.05;",
"trial",
"group",
"×",
"subjective",
"norm",
"interaction,",
"beta",
"=",
"-0.65,",
"p",
"<",
"0.05).",
"Conclusion:",
"Attitudinally-driven",
"intentions",
"are",
"proposed",
"to",
"be",
"more",
"consistently",
"translated",
"into",
"action",
"than",
"normatively-driven",
"intentions.",
"This",
"proposition",
"was",
"supported",
"by",
"the",
"findings,",
"thus",
"offering",
"an",
"interpretation",
"of",
"the",
"trial",
"effects.",
"This",
"analytic",
"approach",
"demonstrates",
"the",
"potential",
"of",
"the",
"TPB",
"to",
"explain",
"trial",
"effects",
"in",
"terms",
"of",
"different",
"relationships",
"between",
"variables",
"rather",
"than",
"differences",
"in",
"mean",
"scores.",
"This",
"study",
"illustrates",
"the",
"use",
"of",
"theory-based",
"process",
"evaluation",
"to",
"uncover",
"processes",
"underlying",
"change",
"in",
"implementation",
"trials.",
"Page",
"1",
"of",
"11",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Dempfle",
"et",
"al.",
"Critical",
"Care",
"2011,",
"15:R23",
"http://ccforum.com/content/15/1/R23",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Endogenous",
"plasma",
"activated",
"protein",
"C",
"levels",
"and",
"the",
"effect",
"of",
"enoxaparin",
"and",
"drotrecogin",
"alfa",
"(activated)",
"on",
"markers",
"of",
"coagulation",
"activation",
"and",
"fibrinolysis",
"in",
"pulmonary",
"embolism",
"Carl-Erik",
"H",
"Dempfle1*,",
"Elif",
"Elmas1,",
"Andreas",
"Link2,",
"Nenad",
"Suvajac1,",
"Volker",
"Liebe1,",
"Jonathan",
"Janes3,",
"Martin",
"Borggrefe1",
"Abstract",
"Introduction:",
"There",
"are",
"no",
"published",
"data",
"on",
"the",
"status",
"of",
"endogenous",
"activated",
"protein",
"C",
"(APC)",
"in",
"pulmonary",
"embolism",
"(PE),",
"and",
"no",
"data",
"on",
"the",
"effect",
"of",
"drotrecogin",
"alfa",
"(activated)",
"(DAA)",
"given",
"in",
"addition",
"to",
"therapeutic",
"dose",
"enoxaparin.",
"Methods:",
"In",
"this",
"double-blind",
"clinical",
"trial,",
"47",
"patients",
"with",
"computed",
"tomography",
"(CT)-confirmed",
"acute",
"submassive",
"PE",
"treated",
"with",
"1",
"mg/kg",
"body",
"weight",
"of",
"enoxaparin",
"twice",
"daily",
"were",
"randomized",
"to",
"groups",
"receiving",
"a",
"12-hour",
"intravenous",
"infusion",
"of",
"6,",
"12,",
"18,",
"or",
"24",
"μg/kg/hour",
"of",
"DAA",
"or",
"a",
"placebo.",
"Blood",
"samples",
"were",
"drawn",
"before",
"starting",
"DAA",
"infusion,",
"after",
"4,",
"8",
"and",
"12",
"hours",
"(at",
"the",
"end",
"of",
"the",
"infusion",
"period),",
"and",
"on",
"treatment",
"days",
"2,",
"3,",
"4,",
"5",
"and",
"6.",
"Results:",
"Initial",
"endogenous",
"plasma",
"activated",
"protein",
"C",
"(APC)",
"levels",
"were",
"0.36",
"±",
"0.48",
"ng/ml",
"(<0.10",
"to",
"1.72",
"ng/ml)",
"and",
"remained",
"in",
"the",
"same",
"range",
"in",
"the",
"placebo",
"group.",
"APC",
"levels",
"in",
"patients",
"treated",
"with",
"DAA",
"were",
"13.67",
"±",
"3.57",
"ng/ml,",
"32.71",
"±",
"8.76",
"ng/ml,",
"36.13",
"±",
"7.60",
"ng/ml,",
"and",
"51.79",
"±",
"15.84",
"ng/ml",
"in",
"patients",
"treated",
"with",
"6,",
"12,",
"18,",
"and",
"24",
"μg/kg/hour",
"DAA,",
"respectively.",
"In",
"patients",
"with",
"a",
"D-dimer",
"level",
">4",
"mg/L",
"indicating",
"a",
"high",
"level",
"of",
"acute",
"fibrin",
"formation",
"and",
"dissolution,",
"DAA",
"infusion",
"resulted",
"in",
"a",
"more",
"rapid",
"drop",
"in",
"soluble",
"fibrin,",
"D-dimer,",
"and",
"fibrinogen/",
"fibrin",
"degradation",
"products",
"(FDP)",
"levels,",
"compared",
"to",
"enoxaparin",
"alone.",
"There",
"was",
"a",
"parallel",
"decline",
"of",
"soluble",
"fibrin,",
"D-dimer,",
"FDP,",
"and",
"plasmin-plasmin",
"inhibitor",
"complex",
"(PPIC)",
"in",
"response",
"to",
"treatment",
"with",
"enoxaparin",
"±",
"DAA,",
"with",
"no",
"evidence",
"of",
"a",
"systemic",
"profibrinolytic",
"effect",
"of",
"the",
"treatment.",
"Conclusions:",
"In",
"patients",
"with",
"acute",
"submassive",
"PE",
"endogenous",
"APC",
"levels",
"are",
"low.",
"DAA",
"infusion",
"enhances",
"the",
"inhibition",
"of",
"fibrin",
"formation.",
"Trial",
"registration:",
"ClinicalTrials.gov:",
"NCT00191724",
"Introduction",
"Activated",
"protein",
"C",
"inhibits",
"blood",
"coagulation",
"by",
"inacti-",
"vating",
"factors",
"Va",
"and",
"VIIIa",
"[1].",
"Inactivation",
"of",
"factor",
"VIIIa",
"reduces",
"the",
"activity",
"of",
"the",
"tenase",
"complex",
"and",
"the",
"production",
"of",
"factor",
"Xa.",
"Inactivation",
"of",
"factor",
"Va",
"reduces",
"the",
"activity",
"of",
"the",
"prothrombinase",
"complex",
"and",
"the",
"production",
"of",
"thrombin.",
"Both",
"mechanisms",
"reduce",
"*",
"Correspondence:",
"carl-erik.dempfle@umm.de",
"1I.",
"Department",
"of",
"Medicine,",
"University",
"Medical",
"Center",
"Mannheim,",
"Theodor",
"Kutzer",
"Ufer,",
"Mannheim,",
"D-68167,",
"Germany",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"the",
"amount",
"of",
"thrombin",
"and",
"fibrin",
"generated.",
"In",
"vivo,",
"protein",
"C",
"is",
"activated",
"by",
"the",
"thrombin-thrombomodulin",
"complex,",
"which",
"forms",
"when",
"thrombin",
"binds",
"to",
"throm-",
"bomodulin",
"on",
"intact",
"endothelium.",
"Binding",
"of",
"thrombin",
"to",
"thrombomodulin",
"also",
"changes",
"the",
"specificity",
"of",
"thrombin",
"from",
"a",
"procoagulant",
"to",
"an",
"anticoagulant",
"enzyme",
"[2].",
"In",
"addition",
"to",
"its",
"effects",
"on",
"blood",
"coagula-",
"tion",
"activation,",
"activated",
"protein",
"C",
"when",
"bound",
"to",
"the",
"endothelial",
"protein",
"C",
"receptor",
"(EPCR),",
"activa-",
"tes",
"protease-activated",
"receptors",
"(PARs),",
"inducing",
"a",
"variety",
"of",
"cytoprotective",
"cellular",
"responses,",
"including",
"©",
"2011",
"Dempfle",
"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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] | [
"PSYCHIATRY",
"Hepatitis",
"A",
"virus",
"among",
"drug",
"users",
"and",
"the",
"role",
"of",
"vaccination:",
"a",
"review",
"Fabio",
"Lugoboni",
"*,",
"Benedetta",
"Pajusco,",
"Anna",
"Albiero",
"and",
"Gianluca",
"Quaglio",
"Addiction",
"Unit,",
"Department",
"of",
"Internal",
"Medicine,",
"Verona",
"University",
"Hospital,",
"Verona,",
"Italy",
"REVIEW",
"ARTICLE",
"published:",
"12",
"January",
"2012",
"doi:",
"10.3389/fpsyt.2011.00079",
"Edited",
"by:",
"Lorenzo",
"Leggio,",
"Gemelli",
"Hospital,",
"Italy",
"Reviewed",
"by:",
"Anna",
"Ferrulli,",
"Catholic",
"University",
"of",
"Rome,",
"Italy",
"Giovanni",
"Addolorato,",
"Catholic",
"University",
"of",
"Rome,",
"Italy",
"*Correspondence:",
"Fabio",
"Lugoboni",
",",
"Addiction",
"Unit,",
"Department",
"of",
"Internal",
"Medicine,",
"Verona",
"University",
"Hospital,",
"P.le",
"L.A.",
"Scuro",
"10,",
"37134",
"Verona,",
"Italy.",
"e-mail:",
"fabio.lugoboni@",
"ospedaleuniverona.it",
"In",
"countries",
"with",
"advanced",
"economies",
"better",
"health",
"and",
"hygiene",
"conditions,",
"along",
"with",
"the",
"introduction,",
"in",
"some",
"cases,",
"of",
"global",
"vaccination,",
"have",
"relegated",
"most",
"viral",
"hepatitis",
"to",
"marginal",
"social",
"groups",
"and,",
"in",
"particular,",
"drug",
"users",
"(DUs).",
"The",
"availability",
"of",
"safe",
"and",
"effective",
"vaccines",
"for",
"hepatitis",
"A",
"virus",
"(HAV)",
"and",
"B",
"(HBV)",
"may",
"play",
"a",
"major",
"role",
"in",
"combating",
"this",
"phenomenon.",
"Despite",
"the",
"availability",
"of",
"a",
"safe",
"and",
"effective",
"vaccine",
"for",
"over",
"a",
"decade",
"and",
"the",
"recommendations",
"of",
"international",
"health",
"organizations,",
"vaccinations",
"against",
"HAV",
"among",
"DUs",
"are",
"not",
"as",
"widely",
"known",
"and",
"available",
"as",
"are",
"HBV",
"vaccinations.",
"The",
"purpose",
"of",
"this",
"review",
"article",
"is",
"to",
"present",
"the",
"most",
"significant",
"data",
"in",
"the",
"literature",
"on",
"the",
"preva-",
"lence",
"of",
"HAV",
"among",
"DUs",
"and",
"the",
"role",
"of",
"targeted",
"vaccination.",
"To",
"our",
"knowledge,",
"the",
"present",
"article",
"is",
"the",
"first",
"to",
"solely",
"deal",
"with",
"vaccination",
"against",
"HAV",
"in",
"DUs.",
"Immunization",
"after",
"the",
"administration",
"of",
"anti-HAV",
"vaccine",
"has",
"been",
"demonstrated",
"in",
"DUs",
"even",
"if",
"they",
"have",
"responded",
"significantly",
"less",
"than",
"either",
"the",
"general",
"population",
"or",
"carriers",
"of",
"chronic",
"liver",
"disease.",
"All",
"the",
"vaccines",
"were",
"well",
"tolerated",
"and",
"adherence",
"to",
"the",
"vaccine",
"schedule",
"was",
"good.",
"Further",
"studies",
"are",
"needed",
"to",
"optimize",
"the",
"timing",
"and",
"doses",
"of",
"vaccine",
"to",
"be",
"administered",
"to",
"DUs,",
"especially",
"to",
"assess",
"adherence",
"and",
"antibody",
"persistence.",
"Vaccination",
"campaigns",
"are",
"feasible",
"among",
"DUs",
"and",
"have",
"proven",
"to",
"be",
"highly",
"cost–effective.",
"Keywords:",
"adherence,",
"drug",
"users,",
"hepatitis",
"A",
"vaccination,",
"intravenous,",
"immunization,",
"HAV,",
"vaccine,",
"DUs",
"INTRODUCTION",
"Addiction",
"and",
"diffusion",
"of",
"viral",
"hepatitis",
"are",
"two",
"different",
"phe-",
"nomena",
"but",
"have",
"long",
"been",
"closely",
"correlated.",
"Addiction",
"is",
"a",
"global",
"phenomenon,",
"with",
"geographic",
"location",
"having",
"relatively",
"little",
"to",
"do",
"with",
"its",
"progress",
"in",
"a",
"country,",
"while",
"there",
"are",
"large",
"differences",
"in",
"the",
"spread",
"of",
"viral",
"hepatitis",
"as",
"related",
"to",
"its",
"progression",
"in",
"dif-",
"ferent",
"countries.",
"Such",
"differences",
"tend",
"to",
"decrease",
"significantly",
"among",
"drug",
"users",
"(DUs;",
"United",
"Nations",
"Office",
"on",
"Drug,",
"and",
"Crime,",
"2006;",
"Aceijas",
"et",
"al.,",
"2004).",
"In",
"drug-addicted",
"patients,",
"in",
"conjunction",
"with",
"the",
"decrease",
"of",
"HIV-rate",
"mortality,",
"death",
"from",
"liver",
"diseases",
"have",
"significantly",
"increased",
"(EMCDDA,",
"2003;",
"Schae-",
"fer",
"and",
"Mauss,",
"2008).",
"Counteracting",
"this",
"spread",
"is",
"a",
"priority",
"task,",
"which",
"has",
"to",
"involve",
"all",
"the",
"structures",
"that",
"can",
"interact",
"with",
"drug",
"abusers.",
"Hepatitis",
"C",
"virus",
"(HCV)",
"is",
"surely",
"the",
"most",
"important",
"hepatitis",
"among",
"DUs",
"regarding",
"both",
"its",
"diffusion",
"and",
"its",
"high",
"percentage",
"of",
"chronic",
"disease.",
"Currently,",
"it",
"is",
"the",
"most",
"common",
"cause",
"of",
"chronic",
"hepatitis",
"in",
"developed",
"countries",
"(Centers",
"for",
"Diseases",
"Control",
"and",
"Prevention,",
"2002;",
"Schaefer",
"and",
"Mauss,",
"2008).",
"Health",
"education",
"and",
"harm",
"reduction",
"policies",
"(i.e.,",
"methadone",
"or",
"buprenorphine",
"maintenance",
"therapies",
"and",
"needle-exchange",
"programs)",
"are",
"at",
"the",
"moment",
"the",
"only",
"measure",
"of",
"prevention",
"of",
"HCV,",
"since",
"there",
"is",
"neither",
"specific",
"vaccination",
"nor",
"effective",
"prophylaxis",
"against",
"exposure.",
"Interventions",
"using",
"strategies",
"that",
"Abbreviations:",
"CLD,",
"chronic",
"liver",
"disease;",
"DUs,",
"drug",
"users;",
"GPOP,",
"general",
"popula-",
"tion;",
"HAV,",
"hepatitis",
"A",
"virus;",
"HBV,",
"hepatitis",
"B",
"virus;",
"HCV,",
"hepatitis",
"C",
"virus;",
"HDV,",
"hepatitis",
"D",
"virus.",
"combined",
"substance-use",
"treatment",
"and",
"support",
"for",
"safe",
"injection",
"were",
"most",
"effective",
"at",
"reducing",
"HCV",
"seroconversion",
"(Hagan",
"et",
"al.,",
"2011).",
"Vaccination",
"campaigns",
"targeted",
"at",
"high-risk",
"groups",
"and",
"the",
"introduction",
"of",
"mass",
"vaccination",
"in",
"almost",
"all",
"developed",
"countries",
"has",
"significantly",
"reduced",
"HBV",
"prevalence",
"among",
"the",
"youngest",
"DUs",
"(Baral",
"et",
"al.,",
"2007;",
"Brim",
"et",
"al.,",
"2007).",
"HBV",
"infection",
"through",
"sexual",
"transmission",
"has",
"an",
"important",
"role",
"among",
"non-injective",
"DUs",
"(Gyarmath",
"et",
"al.,",
"2002;",
"Rich",
"et",
"al.,",
"2006).",
"Hepatitis",
"D",
"virus",
"(HDV)",
"is",
"caused",
"by",
"a",
"defective",
"RNA-virus",
"that",
"requires",
"the",
"presence",
"of",
"the",
"HBV",
"Surface",
"Antigen",
"for",
"transmission.",
"HDV",
"can",
"be",
"acquired",
"both",
"as",
"a",
"co-infection",
"with",
"HBV",
"and",
"as",
"an",
"overlap",
"in",
"a",
"chronic",
"HBV",
"carrier.",
"HDV",
"infection",
"can",
"be",
"effec-",
"tively",
"prevented",
"with",
"vaccination",
"against",
"HBV,",
"while",
"protection",
"does",
"not",
"exist",
"for",
"chronic",
"HBV",
"carriers.",
"In",
"Europe",
"and",
"in",
"the",
"USA",
"HDV",
"infection",
"has",
"almost",
"disappeared",
"in",
"the",
"general",
"population",
"(GPOP),",
"remaining",
"confined",
"almost",
"entirely",
"to",
"DUs",
"(Gaeta",
"et",
"al.,",
"2000;",
"Farci,",
"2003).",
"Hepatitis",
"A",
"virus",
"(HAV),",
"the",
"causative",
"agent",
"of",
"type",
"A",
"viral",
"hepatitis,",
"is",
"an",
"ancient",
"picornavirus",
"virus,",
"which",
"was",
"identified",
"almost",
"40",
"years",
"ago.",
"Each",
"year",
"HAV",
"affects",
"1.5",
"million",
"people",
"worldwide.",
"The",
"geography",
"of",
"infection",
"is",
"tightly",
"linked",
"to",
"the",
"quality",
"of",
"sewage",
"water",
"depuration",
"systems.",
"Improved",
"living",
"conditions",
"and",
"subsequent",
"changes",
"in",
"HAV",
"epidemiology",
"have",
"decreased",
"the",
"disease",
"burden",
"of",
"hepatitis",
"A",
"in",
"most",
"developed",
"countries",
"(Martin",
"and",
"Lemon,",
"2006;",
"Koslap-petraco",
"et",
"al.,",
"2008;",
"Jacobsen",
"and",
"Wiersma,",
"2010).",
"The",
"clinical",
"manifestations",
"of",
"HAV",
"infection",
"range",
"from",
"asymptomatic",
"to",
"fulminant",
"hepatitis.",
"The",
"severity",
"of",
"the",
"disease",
"is",
"strongly",
"dependent",
"on",
"the",
"age",
"of",
"the",
"host,",
"being",
"the",
"asymptomatic",
"disease",
"typical",
"of",
"childhood",
"while,",
"www.frontiersin.org",
"January",
"2012",
"|",
"Volume",
"2",
"|",
"Article",
"79",
"|",
"1"
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657,
937,
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685,
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427,
953,
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478,
953,
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490,
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[
539,
953,
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[
554,
953,
48,
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[
606,
953,
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662,
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698,
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427,
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] | [
"JCB",
"Article",
"Dislocation",
"and",
"degradation",
"from",
"the",
"ER",
"are",
"regulated",
"by",
"cytosolic",
"stress",
"Judy",
"K.",
"VanSlyke",
"and",
"Linda",
"S.",
"Musil",
"Division",
"of",
"Molecular",
"Medicine,",
"Oregon",
"Health",
"Sciences",
"University,",
"Portland,",
"OR",
"97201",
"A",
"dislocation",
"of",
"the",
"substrate",
"protein",
"from",
"the",
"ER",
"into",
"key",
"step",
"in",
"ER-associated",
"degradation",
"(ERAD)",
"is",
"the",
"cytosol",
"to",
"gain",
"access",
"to",
"the",
"proteasome.",
"Very",
"little",
"is",
"known",
"about",
"how",
"this",
"process",
"is",
"regulated,",
"especially",
"in",
"the",
"case",
"of",
"polytopic",
"proteins.",
"Using",
"pulse-chase",
"analysis",
"combined",
"with",
"subcellular",
"fractionation,",
"we",
"show",
"that",
"connexins,",
"the",
"four",
"transmembrane",
"structural",
"components",
"of",
"gap",
"junctions,",
"can",
"be",
"chased",
"in",
"an",
"intact",
"form",
"from",
"the",
"ER",
"membrane",
"into",
"the",
"cytosol",
"of",
"proteasome",
"inhibitor–",
"treated",
"cells.",
"Dislocation",
"of",
"endogenously",
"expressed",
"connexin",
"from",
"the",
"ER",
"was",
"reduced",
"50–80%",
"when",
"the",
"cytosolic",
"heat",
"shock",
"response",
"was",
"induced",
"by",
"mild",
"oxidative",
"or",
"thermal",
"stress,",
"but",
"not",
"by",
"treatments",
"that",
"instead",
"upregulate",
"the",
"ER",
"unfolded",
"protein",
"response.",
"Cytosolic",
"but",
"not",
"ER",
"stresses",
"slowed",
"the",
"normally",
"rapid",
"degradation",
"of",
"connexins,",
"and",
"led",
"to",
"a",
"striking",
"increase",
"in",
"gap",
"junction",
"formation",
"and",
"function",
"in",
"otherwise",
"assembly-inefficient",
"cell",
"types.",
"These",
"treatments",
"also",
"inhibited",
"the",
"dislocation",
"and",
"turnover",
"of",
"a",
"connexin-unrelated",
"ERAD",
"substrate,",
"unassembled",
"major",
"histocompatibility",
"complex",
"class",
"I",
"heavy",
"chain.",
"Our",
"findings",
"demonstrate",
"that",
"dislocation",
"is",
"negatively",
"regulated",
"by",
"physiologically",
"relevant,",
"nonlethal",
"stress.",
"They",
"also",
"reveal",
"a",
"previously",
"unrecognized",
"relationship",
"between",
"cytosolic",
"stress",
"and",
"intercellular",
"communication.",
"Introduction",
"After",
"insertion",
"into",
"the",
"ER,",
"nascent",
"secretory",
"proteins",
"can",
"either",
"be",
"exported",
"to",
"the",
"Golgi",
"or",
"destroyed",
"by",
"ER-associated",
"degradation",
"(ERAD)*",
"(McCracken",
"and",
"Brodsky,",
"1996).",
"ERAD",
"is",
"carried",
"out",
"by",
"the",
"26S",
"proteasome,",
"the",
"multicata-",
"lytic",
"protease",
"complex",
"that",
"mediates",
"the",
"majority",
"of",
"protein",
"degradation",
"in",
"the",
"cytosol",
"and",
"nucleus",
"(Plemper",
"and",
"Wolf,",
"1999).",
"It",
"has",
"been",
"demonstrated",
"that",
"ERAD",
"substrates",
"(with",
"certain",
"possible",
"exceptions;",
"Walter",
"et",
"al.,",
"2001)",
"gain",
"access",
"to",
"the",
"proteasome",
"by",
"being",
"extracted",
"from",
"the",
"ER",
"via",
"the",
"Sec61",
"translocon",
"in",
"a",
"process",
"referred",
"to",
"as",
"disloca-",
"tion",
"(Wiertz",
"et",
"al.,",
"1996b;",
"Pilon",
"et",
"al.,",
"1997;",
"Plemper",
"et",
"al.,",
"1997;",
"Zhou",
"and",
"Schekman,",
"1999).",
"Major",
"substrates",
"for",
"ERAD",
"include",
"proteins",
"that",
"are",
"conformationally",
"abnormal",
"as",
"a",
"result",
"of",
"mutation,",
"lack",
"of",
"assembly",
"partners,",
"or",
"imper-",
"fect",
"folding.",
"To",
"date,",
"no",
"mechanism",
"has",
"been",
"described",
"to",
"regulate",
"the",
"dislocation",
"of",
"multiple",
"unrelated",
"proteins",
"under",
"physiologically",
"relevant",
"conditions.",
"Address",
"correspondence",
"to",
"Linda",
"S.",
"Musil,",
"Division",
"of",
"Molecular",
"Medicine",
"NRC3,",
"Oregon",
"Health",
"Sciences",
"University,",
"3181",
"Southwest",
"Sam",
"Jackson",
"Park",
"Rd.,",
"Portland,",
"OR",
"97201.",
"Tel.:",
"(503)",
"494-1300.",
"Fax:",
"(503)",
"494-7368.",
"E-mail:",
"Musill@OHSU.edu",
"*Abbreviations",
"used",
"in",
"this",
"paper:",
"ALLN,",
"acetyl-leu-leu-norleucinal;",
"BFA,",
"brefeldin",
"A;",
"Cx32,",
"connexin32;",
"Cx43,",
"connexin43;",
"ERAD,",
"ER-",
"associated",
"degradation;",
"MHC1,",
"major",
"histocompatibility",
"complex",
"class",
"I;",
"NAC,",
"N-acetyl",
"cysteine.",
"Key",
"words:",
"endoplasmic",
"reticulum;",
"proteasome;",
"heat-shock",
"response;",
"connexins;",
"gap",
"junctions",
"",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2002/04/381/14",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"157,",
"Number",
"3,",
"April",
"29,",
"2002",
"381–394",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200111045",
"Connexins",
"form",
"a",
"family",
"of",
"nonglycosylated,",
"tetra-spanning",
"proteins",
"with",
"both",
"amino",
"and",
"carboxyl",
"termini",
"facing",
"the",
"cytosol.",
"Connexins",
"are",
"the",
"structural",
"components",
"in",
"verte-",
"brates",
"of",
"gap",
"junctions,",
"which",
"are",
"collections",
"of",
"intercellular",
"channels",
"that",
"mediate",
"the",
"regulatable",
"cell-to-cell",
"transfer",
"of",
"low",
"molecular",
"mass",
"substances",
"including",
"ions",
"and",
"second",
"messengers",
"(for",
"review",
"see",
"Goodenough",
"et",
"al.,",
"1996).",
"Cell",
"types",
"differ",
"greatly",
"in",
"the",
"efficiency",
"with",
"which",
"they",
"assem-",
"ble",
"connexins",
"into",
"gap",
"junctions",
"under",
"basal",
"conditions,",
"and",
"have",
"been",
"operationally",
"categorized",
"as",
"either",
"assembly",
"in-",
"competent",
"(no",
"gap",
"junctions),",
"assembly",
"inefficient",
"(few",
"gap",
"junctions",
"relative",
"to",
"the",
"level",
"of",
"connexin",
"expressed",
"on",
"the",
"cell",
"surface),",
"or",
"assembly",
"efficient",
"(Musil",
"et",
"al.,",
"2000).",
"Pulse-chase",
"analysis",
"in",
"tissue",
"culture",
"cells",
"and",
"in",
"whole",
"organs",
"has",
"revealed",
"that",
"both",
"gap",
"junction–assembled",
"and",
"–unassociated",
"forms",
"of",
"connexins",
"turn",
"over",
"remarkably",
"quickly",
"(t1/2",
"1.5–5",
"h),",
"much",
"faster",
"than",
"most",
"other",
"types",
"of",
"plasma",
"membrane",
"proteins",
"(Fallon",
"and",
"Goodenough,",
"1981;",
"Musil",
"et",
"al.,",
"1990;",
"Beardslee",
"et",
"al.,",
"1998).",
"We",
"have",
"recently",
"shown",
"that",
"40%",
"or",
"more",
"of",
"newly",
"synthesized",
"wild-type",
"connexin43",
"(Cx43)",
"and",
"connexin32",
"(Cx32),",
"and",
"up",
"to",
"100%",
"of",
"some",
"mutant",
"forms",
"of",
"Cx32,",
"are",
"rapidly",
"degraded",
"in",
"the",
"cell",
"types",
"examined",
"even",
"if",
"their",
"exit",
"from",
"the",
"ER",
"is",
"blocked",
"(VanSlyke",
"et",
"al.,",
"2000).",
"This",
"ER-associated",
"turnover",
"is",
"sensitive",
"to",
"chemical",
"inhibitors",
"of",
"the",
"proteasome",
"but",
"not",
"of",
"the",
"lysosome,",
"thereby",
"characterizing",
"connexins",
"as",
"substrates",
"for",
"ERAD.",
"It",
"is",
"likely,",
"but",
"has",
"not",
"yet",
"been",
"381"
] | [
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"Hariri",
"and",
"Shin",
"Biology",
"of",
"Mood",
"&",
"Anxiety",
"Disorders",
"2011,",
"1:1",
"http://www.biolmoodanxietydisord.com/content/1/1/1",
"E",
"D",
"I",
"T",
"O",
"R",
"I",
"A",
"L",
"Biology",
"of",
"Mood",
"&",
"Anxiety",
"Disorders",
"Open",
"Access",
"Welcome",
"to",
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"of",
"Mood",
"&",
"Anxiety",
"Disorders",
"Ahmad",
"R",
"Hariri1*",
"and",
"Lisa",
"M",
"Shin2,3",
"We",
"are",
"witnessing",
"dramatic",
"and",
"exciting",
"shifts",
"in",
"the",
"very",
"foundations",
"of",
"mental",
"health",
"and",
"psychiatry",
"[1-3].",
"At",
"this",
"time",
"perhaps",
"more",
"than",
"any",
"other",
"it",
"is",
"impera-",
"tive",
"that",
"research",
"into",
"the",
"biological",
"underpinnings",
"of",
"psychopathology",
"be",
"given",
"a",
"proper",
"outlet",
"to",
"inform,",
"educate",
"and",
"advance",
"these",
"processes",
"in",
"the",
"service",
"of",
"improving",
"the",
"human",
"condition.",
"Indeed,",
"specialized",
"out-",
"lets",
"have",
"been",
"created",
"for",
"biological",
"research",
"in",
"a",
"num-",
"ber",
"of",
"disorders",
"including",
"autism,",
"schizophrenia",
"and",
"bipolar",
"disorder",
"[4-6].",
"Surprisingly,",
"no",
"such",
"dedicated",
"outlet",
"has",
"been",
"available",
"for",
"mood",
"and",
"anxiety",
"disor-",
"ders,",
"the",
"most",
"common",
"forms",
"of",
"psychopathology,",
"until",
"now.",
"Biology",
"of",
"Mood",
"&",
"Anxiety",
"Disorders",
"(BMAD)",
"is",
"a",
"new",
"open",
"access",
"peer-reviewed",
"journal",
"that",
"publishes",
"highly",
"innovative",
"basic,",
"translational",
"and",
"clinical",
"research",
"that",
"advances",
"our",
"understanding",
"of",
"mood",
"and",
"anxiety",
"disor-",
"ders.",
"The",
"journal",
"welcomes",
"research",
"in",
"all",
"areas",
"relevant",
"to",
"the",
"disorders",
"at",
"the",
"level",
"of",
"their",
"underlying",
"mechan-",
"isms.",
"Research",
"areas",
"of",
"interest",
"include",
"but",
"are",
"not",
"lim-",
"ited",
"to:",
"pathophysiology,",
"predictive",
"risk",
"markers,",
"treatment",
"predictors,",
"individual",
"differences",
"and",
"develop-",
"mental",
"trajectories",
"of",
"mood",
"and",
"anxiety",
"disorders.",
"Experimental",
"approaches",
"include",
"but",
"are",
"not",
"limited",
"to:",
"neuroimaging,",
"psychophysiology,",
"behavioral",
"and",
"mole-",
"cular",
"genetics,",
"pharmacology,",
"gene-environment",
"interac-",
"tions,",
"and",
"non-human",
"animal",
"models.",
"Our",
"idea",
"behind",
"BMAD",
"is",
"to",
"create",
"a",
"venue",
"for",
"cut-",
"ting-edge",
"research",
"that",
"will",
"become",
"the",
"destination",
"of",
"choice",
"for",
"the",
"best",
"work",
"in",
"the",
"field.",
"We",
"are",
"dedicated",
"to",
"providing",
"an",
"outlet",
"for",
"contributions",
"that",
"advance",
"the",
"field",
"in",
"any",
"significant",
"way.",
"We",
"believe",
"that",
"BMAD",
"will",
"be",
"an",
"important",
"platform",
"for",
"presenting",
"the",
"findings",
"of",
"those",
"interested",
"in",
"the",
"biology",
"of",
"mood",
"and",
"anxiety",
"dis-",
"orders",
"at",
"any",
"and",
"all",
"levels.",
"The",
"enthusiastic",
"response",
"from",
"colleagues",
"in",
"neuroscience,",
"psychology,",
"psychiatry,",
"psychophysiology,",
"pharmacology",
"and",
"genetics",
"who",
"have",
"graciously",
"committed",
"their",
"time",
"and",
"expertise",
"by",
"joining",
"*",
"Correspondence:",
"ahmad.hariri@duke.edu",
"1Laboratory",
"of",
"NeuroGenetics,",
"Department",
"of",
"Psychology",
"&",
"Neuroscience,",
"Institute",
"for",
"Genome",
"Sciences",
"&",
"Policy,",
"Duke",
"University,",
"Durham,",
"NC",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"the",
"Editorial",
"Board",
"of",
"BMAD",
"[7]",
"is",
"testament",
"to",
"the",
"value",
"of",
"this",
"novel",
"venue.",
"Continued",
"progress",
"in",
"understanding",
"the",
"biology",
"of",
"mood",
"and",
"anxiety",
"disorders",
"is",
"critically",
"dependent",
"on",
"the",
"integration",
"of",
"knowledge",
"gained",
"across",
"many",
"disci-",
"plines,",
"methodologies",
"and",
"model",
"systems;",
"currently",
"such",
"knowledge",
"is",
"divided",
"across",
"publications",
"in",
"many",
"journals,",
"none",
"of",
"which",
"is",
"focused",
"entirely",
"on",
"the",
"biol-",
"ogy",
"of",
"mood",
"and",
"anxiety",
"disorders.",
"The",
"Editors",
"of",
"BMAD",
"thus",
"believe",
"that",
"there",
"is",
"a",
"need",
"for",
"a",
"dedicated",
"journal",
"in",
"this",
"highly",
"diverse",
"field,",
"and",
"given",
"the",
"rising",
"popularity",
"of",
"open",
"access",
"publication,",
"we",
"thought",
"that",
"a",
"new",
"open",
"access",
"journal",
"in",
"our",
"field",
"was",
"particularly",
"timely.",
"The",
"three",
"publications",
"in",
"this",
"inaugural",
"issue",
"highlight",
"the",
"diversity",
"and",
"breadth",
"of",
"relevant",
"research",
"we",
"seek",
"to",
"encourage",
"and",
"promote",
"at",
"BMAD.",
"Fisher",
"and",
"colleagues",
"report",
"on",
"a",
"multimodal",
"PET/fMRI",
"study",
"demonstrating",
"that",
"the",
"balance",
"between",
"excitatory",
"5-HT2A",
"and",
"inhibi-",
"tory",
"5-HT1A",
"receptors",
"in",
"the",
"medial",
"prefrontal",
"cortex",
"determines,",
"at",
"least",
"in",
"part,",
"the",
"functional",
"responsive-",
"ness",
"of",
"the",
"amygdala.",
"These",
"data",
"provide",
"unique",
"insight",
"into",
"specific",
"molecular",
"mechanisms",
"through",
"which",
"a",
"common",
"treatment",
"target,",
"namely",
"5-HT",
"signaling,",
"mod-",
"ulates",
"a",
"corticolimbic",
"circuitry",
"heavily",
"implicated",
"in",
"the",
"pathophysiology",
"of",
"mood",
"and",
"anxiety",
"disorders.",
"Murphy",
"and",
"Frodl",
"present",
"findings",
"of",
"altered",
"white",
"matter",
"path-",
"ways",
"in",
"depression",
"derived",
"from",
"a",
"meta-analysis",
"of",
"dif-",
"fusion",
"tensor",
"imaging",
"studies.",
"Their",
"meta-analysis",
"reveals",
"specific",
"decreases",
"in",
"the",
"functional",
"integrity",
"of",
"the",
"superior",
"longitudinal",
"fasciculus",
"in",
"patients",
"with",
"major",
"depressive",
"disorder.",
"Finally,",
"Waters",
"and",
"McCor-",
"mick",
"describe",
"the",
"challenges",
"involved",
"in",
"examining",
"the",
"effect",
"of",
"exogenous",
"corticosterone",
"on",
"anxiety-like",
"and",
"depressive",
"behavior",
"in",
"adolescent",
"rats.",
"Such",
"diversity",
"will",
"continue",
"to",
"be",
"featured",
"in",
"the",
"forthcoming",
"months,",
"including",
"reviews",
"on",
"facial",
"emotion",
"processing",
"in",
"major",
"depressive",
"disorder,",
"evoked",
"potential",
"studies",
"in",
"post",
"traumatic",
"stress",
"disorder",
"(PTSD),",
"and",
"validation",
"criteria",
"in",
"animal",
"models",
"of",
"anxiety",
"and",
"depression,",
"as",
"well",
"as",
"original",
"research",
"on",
"the",
"involvement",
"of",
"the",
"habenula",
"in",
"PTSD.",
"©",
"2011",
"Hariri",
"and",
"Shin;",
"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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14
],
[
467,
939,
23,
14
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233,
955,
33,
14
],
[
271,
955,
45,
14
],
[
321,
955,
11,
14
],
[
337,
955,
30,
14
],
[
372,
955,
25,
14
],
[
402,
955,
17,
14
],
[
424,
955,
12,
14
],
[
441,
955,
26,
14
],
[
472,
955,
18,
14
],
[
233,
971,
54,
14
],
[
292,
971,
68,
14
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[
365,
971,
6,
14
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376,
971,
40,
14
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[
421,
971,
47,
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474,
971,
17,
14
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233,
988,
37,
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275,
988,
29,
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309,
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8,
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322,
988,
40,
14
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367,
988,
11,
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383,
988,
27,
14
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415,
988,
50,
14
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470,
988,
20,
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233,
1004,
24,
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262,
1004,
35,
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302,
1004,
23,
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331,
1004,
43,
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379,
1004,
54,
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438,
1004,
28,
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472,
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509,
614,
27,
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540,
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591,
614,
21,
14
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616,
614,
12,
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632,
614,
40,
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676,
614,
42,
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722,
614,
11,
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737,
614,
30,
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509,
630,
25,
14
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538,
630,
45,
14
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587,
630,
12,
14
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603,
630,
43,
14
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649,
630,
50,
14
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702,
630,
8,
14
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714,
630,
19,
14
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737,
630,
30,
14
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509,
646,
19,
14
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[
536,
646,
52,
14
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[
597,
646,
54,
14
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[
659,
646,
11,
14
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[
679,
646,
30,
14
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717,
646,
50,
14
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[
509,
663,
27,
14
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[
542,
663,
28,
14
],
[
576,
663,
38,
14
],
[
621,
663,
12,
14
],
[
639,
663,
42,
14
],
[
687,
663,
12,
14
],
[
705,
663,
30,
14
],
[
741,
663,
25,
14
],
[
509,
679,
26,
14
],
[
540,
679,
25,
14
],
[
570,
679,
52,
14
],
[
627,
679,
62,
14
],
[
693,
679,
48,
14
],
[
746,
679,
20,
14
],
[
509,
695,
43,
14
],
[
556,
695,
50,
14
],
[
611,
695,
8,
14
],
[
624,
695,
73,
14
],
[
701,
695,
14,
14
],
[
720,
695,
21,
14
],
[
746,
695,
21,
14
],
[
509,
711,
48,
14
],
[
562,
711,
12,
14
],
[
577,
711,
28,
14
],
[
617,
711,
10,
14
],
[
631,
711,
24,
14
],
[
659,
711,
11,
14
],
[
674,
711,
56,
14
],
[
734,
711,
32,
14
],
[
509,
728,
22,
14
],
[
535,
728,
43,
14
],
[
581,
728,
53,
14
],
[
637,
728,
18,
14
],
[
658,
728,
25,
14
],
[
687,
728,
18,
14
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[
708,
728,
18,
14
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[
729,
728,
38,
14
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[
509,
744,
17,
14
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[
530,
744,
12,
14
],
[
546,
744,
33,
14
],
[
583,
744,
87,
14
],
[
674,
744,
10,
14
],
[
688,
744,
19,
14
],
[
711,
744,
55,
14
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[
509,
760,
77,
14
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[
594,
760,
28,
14
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[
638,
760,
28,
14
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[
673,
760,
25,
14
],
[
706,
760,
26,
14
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[
740,
760,
27,
14
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[
509,
776,
54,
14
],
[
570,
776,
27,
14
],
[
605,
776,
18,
14
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[
630,
776,
25,
14
],
[
662,
776,
12,
14
],
[
681,
776,
62,
14
],
[
750,
776,
17,
14
],
[
509,
793,
34,
14
],
[
547,
793,
43,
14
],
[
595,
793,
20,
14
],
[
620,
793,
74,
14
],
[
699,
793,
20,
14
],
[
723,
793,
44,
14
],
[
509,
809,
22,
14
],
[
534,
809,
64,
14
],
[
601,
809,
12,
14
],
[
616,
809,
77,
14
],
[
696,
809,
70,
14
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[
509,
825,
28,
14
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[
541,
825,
18,
14
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[
564,
825,
25,
14
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[
594,
825,
8,
14
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[
607,
825,
40,
14
],
[
651,
825,
50,
14
],
[
706,
825,
20,
14
],
[
730,
825,
36,
14
],
[
509,
841,
22,
14
],
[
535,
841,
16,
14
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[
555,
841,
31,
14
],
[
590,
841,
60,
14
],
[
655,
841,
47,
14
],
[
706,
841,
45,
14
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[
755,
841,
11,
14
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[
509,
858,
34,
14
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[
548,
858,
37,
14
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[
589,
858,
69,
14
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[
662,
858,
27,
14
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[
701,
858,
30,
14
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[
735,
858,
32,
14
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[
509,
874,
14,
14
],
[
532,
874,
54,
14
],
[
594,
874,
14,
14
],
[
617,
874,
49,
14
],
[
675,
874,
40,
14
],
[
724,
874,
42,
14
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[
509,
890,
52,
14
],
[
570,
890,
77,
14
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[
655,
890,
49,
14
],
[
713,
890,
54,
14
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[
509,
906,
48,
14
],
[
562,
906,
49,
14
],
[
616,
906,
10,
14
],
[
630,
906,
19,
14
],
[
654,
906,
64,
14
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[
723,
906,
12,
14
],
[
740,
906,
26,
14
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[
509,
923,
30,
14
],
[
546,
923,
19,
14
],
[
573,
923,
65,
14
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[
645,
923,
22,
14
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[
675,
923,
43,
14
],
[
725,
923,
10,
14
],
[
743,
923,
24,
14
],
[
509,
939,
55,
14
],
[
571,
939,
8,
14
],
[
585,
939,
21,
14
],
[
613,
939,
60,
14
],
[
679,
939,
8,
14
],
[
693,
939,
54,
14
],
[
753,
939,
14,
14
],
[
509,
955,
25,
14
],
[
540,
955,
54,
14
],
[
599,
955,
25,
14
],
[
630,
955,
18,
14
],
[
654,
955,
36,
14
],
[
696,
955,
12,
14
],
[
713,
955,
53,
14
],
[
509,
971,
47,
14
],
[
562,
971,
35,
14
],
[
603,
971,
14,
14
],
[
622,
971,
51,
14
],
[
678,
971,
12,
14
],
[
695,
971,
20,
14
],
[
721,
971,
46,
14
],
[
509,
988,
45,
14
],
[
558,
988,
14,
14
],
[
575,
988,
10,
14
],
[
589,
988,
74,
14
],
[
666,
988,
62,
14
],
[
731,
988,
36,
14
],
[
509,
1004,
27,
14
],
[
540,
1004,
10,
14
],
[
554,
1004,
19,
14
],
[
578,
1004,
52,
14
],
[
633,
1004,
18,
14
],
[
655,
1004,
27,
14
],
[
686,
1004,
32,
14
],
[
722,
1004,
11,
14
],
[
737,
1004,
29,
14
],
[
745,
1040,
22,
10
]
] | [
"e",
"n",
"i",
"c",
"i",
"d",
"e",
"M",
"l",
"a",
"t",
"n",
"e",
"m",
"i",
"r",
"e",
"p",
"x",
"E",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"CORRESPONDENCE",
"Andrea",
"L.",
"Cox:",
"acox@jhmi.edu",
"Abbreviations",
"used:",
"E1,",
"envelope",
"glycoprotein",
"1;",
"E2,",
"envelope",
"glycoprotein",
"2;",
"HCV,",
"hepatitis",
"C",
"virus;",
"HVR1,",
"hypervariable",
"region",
"1;",
"SFC,",
"spot-forming",
"colony.",
"JEM",
"©",
"The",
"Rockefeller",
"University",
"Press",
"$8.00",
"Vol.",
"201,",
"No.",
"11,",
"June",
"6,",
"2005",
"1741–1752",
"www.jem.org/cgi/doi/10.1084/jem.20050121",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Cellular",
"immune",
"selection",
"with",
"hepatitis",
"C",
"virus",
"persistence",
"in",
"humans",
"Andrea",
"L.",
"Cox,1,2",
"Timothy",
"Mosbruger,1",
"Qing",
"Mao,1",
"Zhi",
"Liu,1",
"Xiao-Hong",
"Wang,1",
"Hung-Chih",
"Yang,1",
"John",
"Sidney,6",
"Alessandro",
"Sette,6",
"Drew",
"Pardoll,1,2,3,4",
"David",
"L.",
"Thomas,1,5",
"and",
"Stuart",
"C.",
"Ray1",
"1Department",
"of",
"Medicine,",
"2Department",
"of",
"Oncology,",
"3Department",
"of",
"Molecular",
"Biology",
"and",
"Genetics,",
"4Department",
"of",
"Pathology,",
"and",
"5Department",
"of",
"Epidemiology,",
"Johns",
"Hopkins",
"Medical",
"Institutions,",
"Baltimore,",
"MD",
"21231",
"6La",
"Jolla",
"Institute",
"for",
"Allergy",
"and",
"Immunology,",
"San",
"Diego,",
"CA",
"92121",
"Hepatitis",
"C",
"virus",
"(HCV)",
"infection",
"frequently",
"persists",
"despite",
"substantial",
"virus-specific",
"cellular",
"immune",
"responses.",
"To",
"determine",
"if",
"immunologically",
"driven",
"sequence",
"variation",
"occurs",
"with",
"HCV",
"persistence,",
"we",
"coordinately",
"analyzed",
"sequence",
"evolution",
"and",
"CD8",
"T",
"cell",
"responses",
"to",
"epitopes",
"covering",
"the",
"entire",
"HCV",
"polyprotein",
"in",
"subjects",
"who",
"were",
"followed",
"prospectively",
"from",
"before",
"infection",
"to",
"beyond",
"the",
"first",
"year.",
"There",
"were",
"no",
"substitutions",
"in",
"T",
"cell",
"epitopes",
"for",
"a",
"year",
"after",
"infection",
"in",
"a",
"subject",
"who",
"cleared",
"viremia.",
"In",
"contrast,",
"in",
"subjects",
"with",
"persistent",
"viremia",
"and",
"detectable",
"T",
"cell",
"responses,",
"we",
"observed",
"substitutions",
"in",
"69%",
"of",
"T",
"cell",
"epitopes,",
"and",
"every",
"subject",
"had",
"a",
"substitution",
"in",
"at",
"least",
"one",
"epitope.",
"In",
"addition,",
"amino",
"acid",
"substitutions",
"occurred",
"13-fold",
"more",
"often",
"within",
"than",
"outside",
"T",
"cell",
"epitopes",
"(P",
"0.001,",
"range",
"5–38).",
"T",
"lymphocyte",
"recognition",
"of",
"8",
"of",
"10",
"mutant",
"peptides",
"was",
"markedly",
"reduced",
"compared",
"with",
"the",
"initial",
"sequence,",
"indicating",
"viral",
"escape.",
"Of",
"16",
"nonenvelope",
"substitutions",
"that",
"occurred",
"outside",
"of",
"known",
"T",
"cell",
"epitopes,",
"8",
"represented",
"conversion",
"to",
"consensus",
"(P",
"0.015).",
"These",
"findings",
"reveal",
"two",
"distinct",
"mechanisms",
"of",
"sequence",
"evolution",
"involved",
"in",
"HCV",
"persistence:",
"viral",
"escape",
"from",
"CD8",
"T",
"cell",
"responses",
"and",
"optimization",
"of",
"replicative",
"capacity.",
"The",
"World",
"Health",
"Organization",
"estimates",
"there",
"are",
"170",
"million",
"persons",
"with",
"hepatitis",
"C",
"virus",
"(HCV)",
"infection",
"worldwide,",
"and",
"an",
"esti-",
"mated",
"4",
"million",
"persons",
"are",
"infected",
"with",
"HCV",
"in",
"the",
"United",
"States",
"(1,",
"2).",
"In",
"most",
"countries,",
"HCV",
"infection",
"is",
"found",
"in",
"1–2%",
"of",
"the",
"general",
"population",
"and",
"may",
"cause",
"cirrhosis",
"or",
"hepatocellular",
"cancer,",
"but",
"only",
"when",
"infec-",
"tion",
"persists",
"(3–7).",
"Patients",
"in",
"the",
"acute",
"phase",
"of",
"HCV",
"infection",
"are",
"much",
"more",
"likely",
"to",
"respond",
"to",
"therapy",
"that",
"is",
"designed",
"to",
"eradicate",
"the",
"virus",
"than",
"are",
"patients",
"after",
"progression",
"to",
"chronicity",
"(8–10).",
"The",
"features",
"unique",
"to",
"acute",
"infection",
"that",
"allow",
"increased",
"responsiveness",
"to",
"interferon",
"therapy",
"remain",
"unknown.",
"Spontaneous",
"clearance",
"of",
"HCV",
"infection",
"occurs",
"in",
"20%",
"of",
"acutely",
"infected",
"individuals",
"and",
"is",
"associated",
"with",
"a",
"broadly",
"specific",
"and",
"vigorous",
"cellular",
"immune",
"response",
"(11–14).",
"Although",
"the",
"cellular",
"immune",
"response",
"is",
"often",
"less",
"vigorous",
"and",
"more",
"nar-",
"rowly",
"directed",
"in",
"those",
"who",
"fail",
"to",
"clear",
"the",
"infection,",
"nonetheless,",
"a",
"cellular",
"immune",
"re-",
"sponse",
"often",
"is",
"present",
"in",
"early",
"infection",
"and",
"may",
"persist",
"into",
"chronic",
"infection.",
"Why",
"the",
"early",
"response",
"fails",
"to",
"control",
"viremia",
"in",
"those",
"who",
"progress",
"to",
"chronic",
"infection",
"is",
"not",
"clear,",
"but",
"responses",
"generated",
"in",
"acute",
"infection",
"have",
"been",
"shown",
"to",
"decline",
"in",
"some",
"sub-",
"jects",
"who",
"remained",
"persistently",
"infected,",
"and",
"chronic",
"infection",
"is",
"characterized",
"by",
"low",
"fre-",
"quencies",
"of",
"CD8",
"T",
"cells",
"in",
"peripheral",
"blood",
"(13,",
"15–20).",
"Although",
"the",
"liver",
"has",
"the",
"poten-",
"tial",
"to",
"delete",
"antigen-specific",
"T",
"cell",
"responses,",
"HCV-specific",
"CD8",
"CTL",
"lines",
"have",
"been",
"generated",
"from",
"the",
"liver",
"of",
"chronically",
"in-",
"fected",
"humans",
"and",
"chimpanzees;",
"this",
"suggests",
"that",
"elimination",
"of",
"HCV-specific",
"lymphocytes",
"from",
"the",
"liver",
"is",
"neither",
"universal",
"nor",
"neces-",
"sary",
"for",
"HCV",
"persistence",
"(21–24).",
"Survival",
"of",
"HCV,",
"despite",
"virus-specific",
"CD8",
"CTL,",
"might",
"be",
"explained",
"by",
"impaired",
"cellular",
"effector",
"functions",
"(proliferation,",
"cytokine",
"secretion,",
"cytolytic",
"activity),",
"T",
"cell",
"exhaustion,",
"or",
"den-",
"dritic",
"cell",
"dysfunction",
"(16,",
"25–27).",
"A",
"final",
"possibility",
"is",
"that",
"persistence",
"is",
"facilitated",
"by",
"viral",
"evolution",
"over",
"the",
"course",
"of",
"infection,",
"enabling",
"escape",
"by",
"mutation",
"of",
"key",
"epitopes",
"targeted",
"by",
"T",
"lymphocytes.",
"Mutational",
"escape",
"from",
"T",
"cell",
"responses",
"has",
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] | [
"Available",
"online",
"at",
"http://www.biij.org/2010/2/e12",
"doi:",
"10.2349/biij.6.2.e12",
"biij",
"Biomedical",
"Imaging",
"and",
"Intervention",
"Journal",
"REVIEW",
"ARTICLE",
"Development",
"and",
"use",
"of",
"iron",
"oxide",
"nanoparticles",
"(Part",
"1):",
"Synthesis",
"of",
"iron",
"oxide",
"nanoparticles",
"for",
"MRI",
"J",
"Lodhia*,1,",
"BAppSci",
"(MedRadSci),",
"G",
"Mandarano1,",
"BAppSci",
"(MedRad),",
"GradCert",
"(Higher",
"Ed.),",
"NJ",
"Ferris2,",
"MBBS,",
"MMed,",
"FRANZCR,",
"P",
"Eu",
"2",
",",
"BSci.,",
"MSci,",
"SF",
"Cowell",
"1",
",",
"PhD,",
"MEd,",
"ANMT",
"1",
"Division",
"of",
"Medical",
"Radiations,",
"School",
"of",
"Medical",
"Sciences,",
"RMIT",
"University,",
"Victoria,",
"Australia",
"2",
"Peter",
"MacCallum",
"Cancer",
"Institute,",
"Melbourne,",
"Victoria,",
"Australia",
"Received",
"5",
"August",
"2009;",
"accepted",
"24",
"November",
"2009",
"ABSTRACT",
"Contrast",
"agents,",
"such",
"as",
"iron",
"oxide,",
"enhance",
"MR",
"images",
"by",
"altering",
"the",
"relaxation",
"times",
"of",
"tissues",
"in",
"which",
"the",
"agent",
"is",
"present.",
"They",
"can",
"also",
"be",
"used",
"to",
"label",
"targeted",
"molecular",
"imaging",
"probes.",
"Unfortunately,",
"no",
"molecular",
"imaging",
"probe",
"is",
"currently",
"available",
"on",
"the",
"clinical",
"MRI",
"market.",
"A",
"promising",
"platform",
"for",
"MRI",
"contrast",
"agent",
"development",
"is",
"nanotechnology,",
"where",
"superparamagnetic",
"iron",
"oxide",
"nanoparticles",
"(SPIONS)",
"are",
"tailored",
"for",
"MR",
"contrast",
"enhancement,",
"and/or",
"for",
"molecular",
"imaging.",
"SPIONs",
"can",
"be",
"produced",
"using",
"a",
"range",
"of",
"methods",
"and",
"the",
"choice",
"of",
"method",
"will",
"be",
"influenced",
"by",
"the",
"characteristics",
"most",
"important",
"for",
"a",
"particular",
"application.",
"In",
"addition,",
"the",
"ability",
"to",
"attach",
"molecular",
"markers",
"to",
"SPIONS",
"heralds",
"their",
"application",
"in",
"molecular",
"imaging.",
"There",
"are",
"many",
"reviews",
"on",
"SPION",
"synthesis",
"for",
"MRI;",
"however,",
"these",
"tend",
"to",
"be",
"targeted",
"to",
"a",
"chemistry",
"audience.",
"The",
"development",
"of",
"MRI",
"contrast",
"agents",
"attracts",
"experienced",
"researchers",
"from",
"many",
"fields",
"including",
"some",
"researchers",
"with",
"little",
"knowledge",
"of",
"medical",
"imaging",
"or",
"MRI.",
"This",
"situation",
"presents",
"medical",
"radiation",
"practitioners",
"with",
"opportunities",
"for",
"involvement,",
"collaboration",
"or",
"leadership",
"in",
"research",
"depending",
"on",
"their",
"level",
"of",
"commitment",
"and",
"their",
"ability",
"to",
"learn.",
"Medical",
"radiation",
"practitioners",
"already",
"possess",
"a",
"large",
"portion",
"of",
"the",
"understanding,",
"knowledge",
"and",
"skills",
"necessary",
"for",
"involvement",
"in",
"MRI",
"development",
"and",
"molecular",
"imaging.",
"Their",
"expertise",
"in",
"imaging",
"technology,",
"patient",
"care",
"and",
"radiation",
"safety",
"provides",
"them",
"with",
"skills",
"that",
"are",
"directly",
"applicable",
"to",
"research",
"on",
"the",
"development",
"and",
"application",
"of",
"SPIONs",
"and",
"MRI.",
"In",
"this",
"paper",
"we",
"argue",
"that",
"MRI",
"SPIONs,",
"currently",
"limited",
"to",
"major",
"research",
"centres,",
"will",
"have",
"widespread",
"clinical",
"use",
"in",
"the",
"future.",
"We",
"believe",
"that",
"knowledge",
"about",
"this",
"growing",
"area",
"of",
"research",
"provides",
"an",
"opportunity",
"for",
"medical",
"radiation",
"practitioners",
"to",
"enhance",
"their",
"specialised",
"expertise",
"to",
"ensure",
"best",
"practice",
"in",
"a",
"truly",
"multi-disciplinary",
"environment.",
"This",
"review",
"outlines",
"how",
"and",
"why",
"SPIONs",
"can",
"be",
"synthesised",
"and",
"examines",
"their",
"characteristics",
"and",
"limitations",
"in",
"the",
"context",
"of",
"MR",
"imaging.",
"©",
"2010",
"Biomedical",
"Imaging",
"and",
"Intervention",
"Journal.",
"All",
"rights",
"reserved.",
"Keywords:",
"Magnetic",
"resonance",
"imaging",
"(MRI),",
"iron",
"oxide,",
"nanoparticles,",
"synthesis",
"*",
"Corresponding",
"author.",
"Present",
"address:",
"Division",
"of",
"Medical",
"Radiations,",
"School",
"of",
"Medical",
"Sciences,",
"RMIT",
"University,",
"Bundoora",
"West",
"campus,",
"PO",
"Box",
"71,",
"Bundoora",
"3083,",
"Victoria",
"Australia.",
"Tel:",
"+",
"61",
"3",
"9925",
"6660;",
"Fax:",
"+61",
"3",
"9925",
"7466;",
"E-mail:",
"jyoti.lodhia@rmit.edu.au",
"(Jyoti",
"Lodhia)."
] | [
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596,
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680,
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691,
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732,
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741,
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576,
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656,
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674,
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562,
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758,
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540,
771,
27,
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568,
771,
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578,
771,
30,
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609,
771,
43,
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653,
771,
13,
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668,
771,
29,
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[
699,
771,
9,
11
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709,
771,
17,
11
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[
728,
771,
36,
11
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554,
785,
24,
11
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[
580,
785,
28,
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[
610,
785,
18,
11
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629,
785,
37,
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540,
798,
24,
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566,
798,
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578,
798,
10,
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591,
798,
26,
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620,
798,
12,
11
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634,
798,
15,
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652,
798,
10,
11
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664,
798,
12,
11
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679,
798,
50,
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[
731,
798,
14,
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[
747,
798,
16,
11
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[
554,
811,
39,
11
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[
595,
811,
8,
11
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[
605,
811,
7,
11
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[
614,
811,
30,
11
],
[
645,
811,
37,
11
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[
684,
811,
52,
11
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[
738,
811,
25,
11
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[
554,
824,
35,
11
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592,
824,
16,
11
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[
611,
824,
26,
11
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[
639,
824,
30,
11
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[
672,
824,
31,
11
],
[
705,
824,
58,
11
],
[
554,
837,
41,
11
],
[
597,
837,
17,
11
],
[
617,
837,
9,
11
],
[
627,
837,
55,
11
],
[
685,
837,
9,
11
],
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695,
837,
25,
11
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723,
837,
41,
11
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554,
851,
6,
11
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562,
851,
30,
11
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593,
851,
14,
11
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[
609,
851,
18,
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628,
851,
28,
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540,
864,
111,
11
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653,
864,
111,
11
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554,
877,
51,
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606,
877,
44,
11
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650,
877,
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660,
877,
27,
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688,
877,
22,
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711,
877,
19,
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731,
877,
22,
11
],
[
755,
877,
9,
11
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[
554,
890,
48,
11
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[
604,
890,
31,
11
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[
636,
890,
28,
11
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666,
890,
18,
11
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685,
890,
37,
11
],
[
540,
903,
24,
11
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[
565,
903,
10,
11
],
[
576,
903,
11,
11
],
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588,
903,
35,
11
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[
623,
903,
10,
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],
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634,
903,
17,
11
],
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652,
903,
12,
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[
665,
903,
39,
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704,
903,
10,
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715,
903,
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728,
903,
15,
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[
744,
903,
8,
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753,
903,
11,
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554,
917,
29,
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584,
917,
13,
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599,
917,
16,
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[
616,
917,
20,
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[
637,
917,
9,
11
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[
647,
917,
11,
11
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[
659,
917,
30,
11
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[
690,
917,
41,
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[
732,
917,
31,
11
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[
554,
930,
13,
11
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[
568,
930,
26,
11
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[
594,
930,
67,
11
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[
662,
930,
9,
11
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672,
930,
50,
11
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[
722,
930,
42,
11
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[
554,
943,
14,
11
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[
569,
943,
9,
11
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[
580,
943,
20,
11
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[
603,
943,
51,
11
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[
656,
943,
12,
11
],
[
670,
943,
51,
11
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[
723,
943,
41,
11
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[
554,
956,
9,
11
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[
564,
956,
60,
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[
626,
956,
16,
11
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[
644,
956,
18,
11
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[
663,
956,
37,
11
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[
540,
969,
33,
11
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[
575,
969,
12,
11
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[
588,
969,
11,
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[
601,
969,
16,
11
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[
619,
969,
10,
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[
632,
969,
40,
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[
674,
969,
12,
11
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688,
969,
22,
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712,
969,
13,
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727,
969,
24,
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753,
969,
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554,
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578,
983,
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588,
983,
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623,
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632,
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661,
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671,
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684,
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651,
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707,
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[
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1034,
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751,
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] | [
"Glarne",
"Cyra",
"tnemo",
"published:",
"23",
"April",
"2012",
"doi:",
"10.3389/fneur.2012.00056",
"The",
"“brain–skin",
"connection”",
"in",
"protein",
"misfolding",
"and",
"amyloid",
"deposits:",
"embryological,",
"pathophysiological,",
"and",
"therapeutic",
"common",
"grounds?",
"Philip",
"P.",
"Foster1,2,3,4*",
"1",
"Division",
"of",
"Pulmonary",
"and",
"Critical",
"Care",
"Medicine,",
"Department",
"of",
"Internal",
"Medicine,",
"University",
"ofTexas",
"Medical",
"Branch,",
"Galveston,TX,",
"USA",
"2",
"Division",
"of",
"Cognitive",
"and",
"Behavioral",
"Neurology,",
"Department",
"of",
"Neurology,",
"University",
"ofTexas",
"Medical",
"Branch,",
"Galveston,TX,",
"USA",
"3",
"Encephalogistics,",
"Inc.,",
"Galveston,TX,",
"USA",
"4",
"Brain-Mind",
"Project,",
"Inc.,",
"Galveston,TX,",
"USA",
"*Correspondence:",
"ppfoster@utmb.edu",
"A",
"commentary",
"on",
"Association",
"of",
"skin",
"with",
"the",
"pathogen-",
"esis",
"and",
"treatment",
"of",
"neurodegenerative",
"amyloidosis",
"by",
"Clos,",
"A.",
"L.,",
"Kayed,",
"R.,",
"and",
"Lasagna-",
"Reeves,",
"C.",
"A.",
"(2012).",
"Front.",
"Neur.",
"3:5.",
"doi:",
"10.3389/fneur.2012.00005",
"A",
"brief",
"history",
"of",
"amyloidosis",
"goes",
"back",
"to",
"autopsies",
"of",
"the",
"seventeenth",
"century",
"report-",
"ing",
"a",
"waxing",
"substance",
"(Cordier,",
"2008).",
"Later,",
"in",
"the",
"middle",
"of",
"the",
"nineteenth",
"cen-",
"tury,",
"Rudolph",
"Virchow",
"described",
"an",
"“amy-",
"loid”(starch,",
"amulon,",
"Greek,",
"amylum,",
"Latin)",
"degeneration",
"and",
"infiltration",
"of",
"the",
"lungs",
"within",
"alveoli",
"and",
"small",
"vessels",
"in",
"a",
"patient",
"who",
"presented",
"with",
"systemic",
"amyloidosis",
"(heart,",
"lungs,",
"liver,",
"and",
"kidneys;",
"Cordier,",
"2008).",
"What",
"amyloid-related",
"diseases",
"share",
"is",
"a",
"common",
"molecular",
"ternary",
"structure",
"which",
"involves",
"abnormal",
"aggregation",
"of",
"numerous",
"widespread",
"copies",
"of",
"the",
"same",
"protein",
"into",
"well-ordered",
"filamentous",
"β-sheet",
"rich",
"structures",
"(Friedman,",
"2011)",
"known",
"as",
"amyloid",
"fibrils",
"of",
"10–12",
"nm",
"diam-",
"eters",
"(Plante-Bordeneuve",
"and",
"Said,",
"2011).",
"This",
"abnormal",
"accumulation",
"of",
"amyloid",
"oligomers,",
"protofibrils,",
"or",
"fibrils",
"is",
"con-",
"sidered",
"to",
"be",
"one",
"of",
"the",
"major",
"contributor",
"to",
"neurodegeneration",
"and",
"the",
"hallmark",
"of",
"Alzheimer’s",
"(AD)",
"and",
"Parkinson’s",
"diseases",
"(Arora",
"et",
"al.,",
"2004).",
"A",
"primary",
"cause",
"under-",
"lying",
"these",
"accumulations",
"is",
"the",
"folding",
"of",
"polypeptide",
"chains",
"to",
"specific",
"three-dimen-",
"sional",
"proteins",
"in",
"abnormal",
"ways",
"(Selkoe,",
"2003).",
"The",
"progressive",
"misfolding",
"of",
"spe-",
"cific",
"proteins",
"into",
"aggregation",
"may",
"lead",
"to",
"cell",
"alteration",
"or",
"death.",
"Aggregated",
"forms",
"share",
"many",
"characteristics.",
"One",
"of",
"them",
"is",
"that",
"amyloid",
"deposits",
"show",
"specific",
"optical",
"behavior",
"such",
"as",
"birefringence",
"on",
"binding",
"dyes",
"(Congo",
"red).",
"The",
"systemic",
"distribu-",
"www.frontiersin.org",
"tion",
"of",
"amyloidoses",
"may",
"produce",
"extracel-",
"lular",
"deposits",
"in",
"multiple",
"organs",
"(Joachim",
"et",
"al.,",
"1989).",
"In",
"this",
"paper,",
"Clos,",
"Kayed,",
"and",
"Lasagna-Reeves",
"present",
"a",
"novel",
"perspective",
"about",
"the",
"relation",
"of",
"dermis–epidermis–",
"brain",
"and",
"offer",
"a",
"review",
"about",
"amyloid",
"deposits",
"that",
"are",
"central",
"to",
"the",
"strong“brain–",
"skin”",
"connection.",
"This",
"connection",
"starts",
"as",
"early",
"as",
"the",
"sharing",
"a",
"joint",
"embryological",
"origin.",
"Common",
"multipotent",
"embryonic",
"progenitor",
"stem",
"cells",
"from",
"the",
"ectoderm",
"on",
"the",
"surface",
"of",
"the",
"post-gastrulation",
"embryo",
"receive",
"specific",
"signaling",
"from",
"their",
"envi-",
"ronment",
"that",
"instruct",
"them",
"to",
"commit",
"to",
"a",
"particular",
"differentiation",
"program",
"which",
"will",
"give",
"rise",
"to",
"the",
"nervous",
"system",
"or",
"skin",
"epithelium",
"(Quan",
"and",
"Hassan,",
"2005;",
"Fuchs,",
"2007).",
"Clos,",
"Kayed,",
"and",
"Lasagna-Reeves",
"highlight",
"common",
"“brain–skin”",
"patho-",
"physiological",
"disorders",
"such",
"as",
"the",
"role",
"of",
"presenilin",
"1",
"(PS-1)",
"for",
"proteolytic",
"process-",
"ing",
"of",
"the",
"amyloid",
"precursor",
"protein",
"(APP)",
"which",
"is",
"altered",
"in",
"AD;",
"alteration",
"also",
"found",
"in",
"skin",
"cancers",
"(Xia",
"et",
"al.,",
"2001;",
"Kang",
"et",
"al.,",
"2002).",
"They",
"also",
"draw",
"parallels",
"between",
"neurodegenerative",
"disorders",
"of",
"Parkinson’s",
"disease",
"(Lewy",
"bodies,",
"α-synuclein,",
"mela-",
"nin)",
"and",
"amyotrophic",
"lateral",
"sclerosis",
"(ALS",
"inclusion",
"bodies)",
"which",
"share",
"common",
"fea-",
"tures",
"with",
"skin",
"diseases",
"(Hays",
"et",
"al.,",
"2006).",
"In",
"addition,",
"Clos,",
"Kayed,",
"and",
"Lasagna-Reeves",
"are",
"describing",
"transdermal",
"route-of-entry",
"as",
"an",
"elected",
"administration",
"route",
"for",
"potential",
"medications",
"to",
"patients",
"with",
"neurodegen-",
"erative",
"diseases",
"such",
"as",
"Rivastigmine",
"(AD",
"and",
"Parkinson),",
"Rotigotine",
"(Parkinson).",
"A",
"favorable",
"coefficient",
"of",
"partition",
"(physi-",
"ologically",
"based",
"pharmacokinetics,",
"PBPK;",
"Thrall",
"et",
"al.,",
"2002)",
"to",
"the",
"brain",
"via",
"the",
"skin",
"vector",
"seems",
"promising",
"for",
"potential",
"drugs",
"targeting",
"the",
"brain",
"(Zhao",
"et",
"al.,",
"2011).",
"In",
"PDAPP",
"transgenic",
"mice,",
"the",
"immunization",
"with",
"the",
"42-amino-acid",
"form",
"of",
"the",
"peptide",
"(Aβ42)",
"prevents",
"the",
"development",
"of",
"cere-",
"bral",
"β-amyloid-plaque",
"formation,",
"neuritic",
"dystrophy",
"and",
"astrogliosis",
"(Schenk",
"et",
"al.,",
"1999);",
"the",
"transdermal",
"route",
"has",
"also",
"been",
"successfully",
"used",
"without",
"detrimental",
"side",
"effects",
"such",
"as",
"T",
"cell",
"infiltration",
"and",
"cere-",
"bral",
"microhemorrhage",
"(Nikolic",
"et",
"al.,",
"2007).",
"Occurrence",
"of",
"the",
"systemic",
"deposition",
"of",
"β-amyloid",
"protein",
"in",
"multiple",
"tissues",
"such",
"as",
"skin",
"or",
"brain",
"infers",
"that",
"the",
"initial",
"amy-",
"loid",
"protein",
"may",
"be",
"produced",
"locally",
"in",
"all",
"organs",
"affected",
"or",
"may,",
"as",
"observed",
"in",
"other",
"human",
"amyloidoses,",
"be",
"derived",
"from",
"a",
"com-",
"mon",
"circulating",
"precursor",
"(Joachim",
"et",
"al.,",
"1989).",
"Therefore",
"the",
"transdermal",
"β-amyloid",
"immunization",
"also",
"directly",
"targeting",
"skin",
"β-amyloid",
"deposits",
"may",
"further",
"reduce",
"a",
"potential",
"source",
"for",
"amyloid",
"precursors",
"to",
"other",
"organs",
"such",
"as",
"the",
"brain.",
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"Rscne",
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"and",
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"amyotrophic",
"lateral",
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"breast",
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"S.",
"B.,",
"Zheng,",
"H.,",
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"J.,",
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"J.,",
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"R.",
"D.,",
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"B.,",
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] | [
"J",
"Korean",
"Med",
"Sci",
"2008;",
"23:",
"533-6",
"ISSN",
"1011-8934",
"DOI:",
"10.3346/jkms.2008.23.3.533",
"Copyright",
"The",
"Korean",
"Academy",
"of",
"Medical",
"Sciences",
"A",
"Case",
"of",
"a",
"Patient",
"with",
"Both",
"Chorea",
"and",
"Restless",
"Legs",
"Syndrome",
"The",
"patient",
"was",
"a",
"44-yr-old",
"man",
"with",
"end-stage",
"renal",
"disease",
"who",
"had",
"developed",
"chorea",
"as",
"a",
"result",
"of",
"hypoglycemic",
"injury",
"to",
"the",
"basal",
"ganglia",
"and",
"thalamus",
"and",
"who",
"was",
"subsequently",
"diagnosed",
"with",
"depression",
"and",
"restless",
"legs",
"syndrome",
"(RLS).",
"For",
"proper",
"management,",
"the",
"presence",
"of",
"a",
"complex",
"medical",
"condition",
"including",
"two",
"contrasting",
"diseases,",
"chorea",
"and",
"RLS,",
"had",
"to",
"be",
"considered.",
"Tra-",
"madol",
"improved",
"the",
"pain",
"and",
"dysesthetic",
"restlessness",
"in",
"his",
"feet",
"and",
"legs,",
"and",
"this",
"was",
"gradually",
"followed",
"by",
"improvements",
"in",
"his",
"depressed",
"mood,",
"insomnia,",
"lethar-",
"gy,",
"and",
"feelings",
"of",
"hopelessness.",
"This",
"case",
"suggests",
"that",
"the",
"dopaminergic",
"sys-",
"tem",
"participates",
"intricately",
"with",
"the",
"opioid,",
"serotoninergic,",
"and",
"noradrenergic",
"sys-",
"tems",
"in",
"the",
"pathophysiology",
"of",
"RLS",
"and",
"pain",
"and",
"indirectly",
"of",
"depression",
"and",
"insomnia.",
"Key",
"Words",
":",
"Restless",
"Legs",
"Syndrome;",
"Chorea;",
"Sleep",
"Initiation",
"and",
"Maintenance",
"Disorde;",
"Depression;",
"Tra-",
"madol",
"Yoon-Kyung",
"Shin,",
"Seung-Chul",
"Hong,",
"Yon",
"Kwon",
"Ihn*,",
"Jong-Hyun",
"Jeong,",
"Jin-Hee",
"Han,",
"and",
"Sung-Pil",
"Lee",
"Departments",
"of",
"Psychiatry",
"and",
"Radiology*,",
"St.",
"Vincent’s",
"Hospital,",
"The",
"Catholic",
"University",
"of",
"Korea",
"College",
"of",
"Medicine,",
"Suwon,",
"Korea",
"Received",
":",
"20",
"April",
"2007",
"Accepted",
":",
"20",
"September",
"2007",
"Address",
"for",
"correspondence",
"Seung-Chul",
"Hong,",
"M.D.",
"Department",
"of",
"Psychiatry,",
"St.",
"Vincent",
"Hospital,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"93",
"Ji-dong,",
"Paldal-gu,",
"Suwon",
"442-723,",
"Korea",
"Tel",
":",
"+82.31-249-7161,",
"Fax",
":",
"+82.31-248-6758",
"E-mail",
":",
"hscjohn@hotmail.com",
"INTRODUCTION",
"The",
"patient",
"in",
"this",
"report",
"was",
"suffering",
"from",
"diabetic",
"neu-",
"ropathy,",
"end-stage",
"renal",
"disease,",
"restless",
"legs",
"syndrome",
"(RLS),",
"and",
"depression.",
"He",
"had",
"injuries",
"of",
"both",
"basal",
"ganglia",
"and",
"the",
"thalamus",
"as",
"a",
"result",
"of",
"hypoglycemia,",
"causing",
"chorea",
"and",
"more",
"severe",
"leg",
"pains",
"and",
"dysesthetic",
"sensations.",
"RLS",
"is",
"a",
"sensorimotor",
"disorder",
"characterized",
"by",
"unpleasant",
"leg",
"sen-",
"sations",
"together",
"with",
"an",
"irresistible",
"inner",
"urge",
"to",
"move.",
"Chorea",
"is",
"a",
"neurological",
"syndrome",
"characterized",
"by",
"abrupt",
"involun-",
"tary",
"movements",
"resulting",
"from",
"a",
"continuous",
"flow",
"of",
"random",
"muscle",
"contractions.",
"The",
"first-line",
"pharmacological",
"treat-",
"ment",
"for",
"RLS",
"is",
"a",
"dopaminergic",
"agent,",
"whereas",
"anti-dopamin-",
"ergic",
"drugs",
"are",
"the",
"main",
"pharmacological",
"treatment",
"for",
"chorea.",
"In",
"general,",
"greater",
"D2-receptor",
"blocking",
"action",
"results",
"in",
"greater",
"anti-choreic",
"efficacy",
"(1).",
"Dopaminergic",
"drugs",
"for",
"RLS",
"would",
"aggravate",
"the",
"choreic",
"movements,",
"while",
"anti-",
"dopaminergic",
"agents",
"for",
"the",
"treatment",
"of",
"chorea",
"would",
"exac-",
"erbate",
"the",
"RLS.",
"In",
"this",
"report,",
"the",
"association",
"between",
"the",
"complex",
"medical",
"conditions",
"and",
"symptoms",
"of",
"a",
"patient",
"with",
"two",
"coexisting,",
"opposing",
"diseases",
"is",
"discussed.",
"This",
"report",
"also",
"introduces",
"the",
"process",
"through",
"which",
"proper",
"diagnoses",
"and",
"treatments",
"were",
"sought.",
"CASE",
"REPORT",
"A",
"44-yr-old",
"man",
"with",
"insomnia",
"and",
"depression",
"was",
"referr-",
"ed",
"to",
"the",
"psychiatric",
"department",
"of",
"our",
"institution.",
"He",
"com-",
"plained",
"that",
"he",
"rarely",
"fell",
"asleep",
"because",
"of",
"dysesthetic",
"sen-",
"533",
"sations",
"and",
"pain",
"in",
"the",
"lower",
"legs",
"and",
"feet",
"and",
"that",
"he",
"was",
"depressed",
"and",
"feeling",
"hopeless.",
"Although",
"he",
"was",
"aware",
"of",
"having",
"had",
"a",
"high",
"blood",
"sugar",
"level",
"for",
"10",
"yr,",
"he",
"never",
"sought",
"treatment.",
"About",
"3",
"yr",
"earlier,",
"in",
"summer",
"2003,",
"he",
"began",
"to",
"experience",
"cold,",
"numbing,",
"and",
"pins-and-needles",
"sensations",
"on",
"his",
"toes",
"that",
"eventually",
"spread",
"throughout",
"his",
"feet.",
"About",
"a",
"year",
"later,",
"he",
"started",
"taking",
"hypoglycemic",
"agents.",
"Howev-",
"er,",
"the",
"pain",
"in",
"his",
"feet",
"became",
"severe,",
"and",
"restlessness",
"as",
"a",
"result",
"of",
"creeping",
"sensations",
"in",
"his",
"lower",
"legs",
"gradually",
"start-",
"ed",
"to",
"occur",
"when",
"he",
"was",
"lying",
"down",
"or",
"sitting",
"awake.",
"He",
"tried",
"massaging",
"and",
"beating",
"his",
"legs",
"and",
"walking",
"around.",
"The",
"unpleasant",
"sensations",
"and",
"restlessness",
"were",
"temporarily",
"relieved",
"by",
"massage",
"and",
"walking,",
"but",
"the",
"pain",
"in",
"his",
"feet",
"remained",
"little",
"changed.",
"These",
"dysesthetic",
"sensations",
"were",
"most",
"severe",
"when",
"he",
"lay",
"down",
"to",
"sleep,",
"increasing",
"his",
"sleep",
"latency",
"to",
"longer",
"than",
"one",
"hour.",
"He",
"woke",
"repeatedly",
"and",
"had",
"a",
"difficulty",
"falling",
"back",
"asleep",
"because",
"of",
"further",
"dysesthetic",
"sensations.",
"In",
"July",
"2005,",
"the",
"patient",
"received",
"hemodialysis",
"for",
"end-stage",
"renal",
"disease.",
"In",
"those",
"days",
"his",
"serum",
"hemoglobin,",
"iron,",
"and",
"ferritin",
"levels",
"were",
"7.4",
"g/dL,",
"29",
"μg/dL,",
"and",
"97",
"ng/",
"mL,",
"respectively,",
"so",
"oral",
"iron",
"supplementation",
"was",
"adminis-",
"tered.",
"He",
"gradually",
"became",
"depressed,",
"experienced",
"feelings",
"of",
"worthlessness,",
"lost",
"his",
"appetite,",
"and",
"eventually",
"stopped",
"eating.",
"His",
"speech",
"became",
"slow,",
"and",
"his",
"arms",
"and",
"legs",
"trem-",
"bled",
"and",
"twitched",
"involuntarily.",
"Subsequently,",
"he",
"showed",
"irregular,",
"spasmodic,",
"involuntary",
"movements",
"in",
"his",
"limbs",
"and",
"on",
"his",
"face.",
"He",
"was",
"taken",
"to",
"the",
"emergency",
"center",
"of",
"St.",
"Vincent’s",
"Hospital",
"on",
"26",
"June",
"2006",
"by",
"his",
"son.",
"His",
"blood",
"sugar",
"level",
"was",
"very",
"low",
"(49",
"mg/dL).",
"T2-",
"and",
"fluid-attenuated",
"inversion",
"recovery",
"(FLAIR)-weighted",
"magnetic",
"resonance"
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"I",
"B",
"L",
"L",
"E",
"C",
"F",
"O",
"L",
"A",
"N",
"R",
"U",
"O",
"J",
"E",
"H",
"T",
"utations",
"in",
"the",
"AAA",
"adenosine",
"triphosphatase",
"M",
"(ATPase)",
"Spastin",
"(SPG4)",
"cause",
"an",
"autosomal",
"dominant",
"form",
"of",
"hereditary",
"spastic",
"paraple-",
"gia,",
"which",
"is",
"a",
"retrograde",
"axonopathy",
"primarily",
"charac-",
"terized",
"pathologically",
"by",
"the",
"degeneration",
"of",
"long",
"spi-",
"nal",
"neurons",
"in",
"the",
"corticospinal",
"tracts",
"and",
"the",
"dorsal",
"columns.",
"Using",
"recombinant",
"Spastin,",
"we",
"find",
"that",
"six",
"mu-",
"tant",
"forms",
"of",
"Spastin,",
"including",
"three",
"disease-associated",
"forms,",
"are",
"severely",
"impaired",
"in",
"ATPase",
"activity.",
"In",
"contrast",
"to",
"a",
"mutation",
"designed",
"to",
"prevent",
"adenosine",
"triphosphate",
"(ATP)",
"binding,",
"an",
"ATP",
"hydrolysis–deficient",
"Spastin",
"mutant",
"predicted",
"to",
"remain",
"kinetically",
"trapped",
"on",
"target",
"proteins",
"Introduction",
"Neurons",
"expend",
"considerable",
"effort",
"maintaining",
"and",
"some-",
"times",
"degrading",
"axons",
"in",
"response",
"to",
"a",
"variety",
"of",
"cues.",
"Human",
"genetic",
"phenotypes",
"afforded",
"by",
"diseases",
"that",
"are",
"characterized",
"by",
"axonal",
"degeneration",
"and",
"the",
"study",
"of",
"the",
"corresponding",
"disease",
"genes",
"may",
"shed",
"light",
"into",
"the",
"mechanisms",
"responsible",
"for",
"axonal",
"homeostasis",
"and",
"neurodegenerative",
"disorders.",
"Muta-",
"tions",
"in",
"Spastin,",
"an",
"AAA",
"ATPase",
"that",
"is",
"widely",
"expressed,",
"are",
"the",
"most",
"common",
"cause",
"of",
"the",
"autosomal",
"dominant",
"heredi-",
"tary",
"spastic",
"paraplegia",
"(Hazan",
"et",
"al.,",
"1999),",
"which",
"is",
"a",
"retro-",
"grade",
"axonopathy",
"that",
"primarily",
"affects",
"the",
"corticospinal",
"tracts",
"and",
"the",
"fasciculis",
"gracilis",
"characterized",
"clinically",
"primarily",
"by",
"spastic",
"gait",
"(Fink,",
"2002).",
"The",
"function",
"of",
"Spastin",
"is",
"unclear.",
"Neuronal",
"suppres-",
"sion",
"of",
"Drosophila",
"melanogaster",
"Spastin",
"using",
"RNAi",
"results",
"in",
"undergrowth",
"of",
"the",
"neuromuscular",
"junction",
"and",
"increased",
"synaptic",
"currents,",
"whereas",
"overexpression",
"results",
"in",
"decreased",
"currents",
"(Trotta",
"et",
"al.,",
"2004).",
"AAA",
"proteins",
"often",
"function",
"as",
"oligomers,",
"with",
"each",
"pro-",
"tomer",
"usually",
"containing",
"one",
"or",
"two",
"AAA",
"ATPase",
"modules.",
"Correspondence",
"to",
"Brett",
"P.",
"Lauring:",
"bl320@columbia.edu",
"The",
"online",
"version",
"of",
"this",
"paper",
"contains",
"supplemental",
"material.",
"©",
"The",
"Rockefeller",
"University",
"Press",
"$8.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Vol.",
"168,",
"No.",
"4,",
"February",
"14,",
"2005",
"599–606",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200409058",
"decorates",
"microtubules",
"in",
"transfected",
"cells.",
"Analysis",
"of",
"disease-associated",
"missense",
"mutations",
"shows",
"that",
"some",
"more",
"closely",
"resemble",
"the",
"canonical",
"hydrolysis",
"mutant,",
"whereas",
"others",
"resemble",
"the",
"ATP-binding",
"mutant.",
"Using",
"real-time",
"imaging,",
"we",
"show",
"that",
"Spastin",
"severs",
"microtu-",
"bules",
"when",
"added",
"to",
"permeabilized,",
"cytosol-depleted",
"cells",
"stably",
"expressing",
"GFP-tubulin.",
"Using",
"purified",
"com-",
"ponents,",
"we",
"also",
"show",
"that",
"Spastin",
"interacts",
"directly",
"with",
"microtubules",
"and",
"is",
"sufficient",
"for",
"severing.",
"These",
"studies",
"suggest",
"that",
"defects",
"in",
"microtubule",
"severing",
"are",
"a",
"cause",
"of",
"axonal",
"degeneration",
"in",
"human",
"disease.",
"These",
"domains",
"share",
"several",
"key",
"structural",
"motifs",
"and",
"are",
"homologous",
"to",
"some",
"degree",
"among",
"all",
"AAA",
"proteins.",
"NH2-",
"terminal",
"domains",
"of",
"AAA",
"family",
"members",
"that",
"bind",
"adaptors",
"or",
"directly",
"to",
"target",
"proteins",
"are",
"usually",
"highly",
"divergent",
"and,",
"therefore,",
"are",
"determinant",
"of",
"specificity",
"of",
"cellular",
"function.",
"This",
"portion",
"of",
"Spastin",
"contains",
"an",
"MIT",
"domain—a",
"domain",
"of",
"unknown",
"function",
"(Ciccarelli",
"et",
"al.,",
"2003)",
"found",
"in",
"several",
"proteins",
"that",
"function",
"in",
"the",
"endosome,",
"including",
"VPS4/SKD1",
"(an",
"AAA",
"ATPase",
"involved",
"in",
"endosomal",
"trafficking),",
"and",
"in",
"sorting",
"nexin",
"15.",
"Interestingly,",
"another",
"hereditary",
"spastic",
"para-",
"plegia",
"gene,",
"Spartin,",
"contains",
"an",
"MIT",
"domain.",
"Although",
"the",
"MIT",
"domain",
"mediated",
"interaction",
"of",
"Spastin",
"with",
"the",
"endosomal",
"protein",
"CHMP1B",
"(Reid",
"et",
"al.,",
"2005)",
"raises",
"the",
"possibility",
"an",
"endosome-related",
"function,",
"Spastin’s",
"AAA",
"ATPase",
"domain",
"(Frohlich,",
"2001;",
"Frickey",
"and",
"Lupas,",
"2004)",
"is",
"most",
"homologous",
"to",
"those",
"found",
"in",
"VPS4,",
"Fidegtin,",
"and",
"Katanin,",
"a",
"microtubule-severing",
"AAA",
"ATPase",
"(McNally",
"and",
"Vale,",
"1993).",
"First",
"purified",
"from",
"mitotic",
"sea",
"urchin",
"extracts,",
"Katanin",
"has",
"been",
"shown",
"to",
"play",
"a",
"role",
"in",
"microtubule",
"reorganization",
"at",
"the",
"onset",
"of",
"mitosis",
"(McNally",
"and",
"Vale,",
"1993;",
"McNally",
"and",
"Thomas,",
"1998).",
"In",
"neurons,",
"Katanin",
"appears",
"to",
"be",
"a",
"source",
"of",
"noncentrosomal",
"microtubules",
"(Ahmad",
"et",
"al.,",
"1999).",
"Katanin",
"JCB",
"599"
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"Parameters",
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"Network",
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"Sailu",
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"Cell",
"Biology,",
"Microbiology,",
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"measured,",
"most",
"frequently",
"at",
"steady-state",
"mRNA",
"abundance",
"level",
"using",
"micro-",
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"technology.",
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"used",
"in",
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"the",
"structures",
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"with",
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"exhibit",
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"dynamic",
"profiles.",
"Steady-state",
"mRNA",
"abundance,",
"however,",
"is",
"a",
"composite",
"of",
"two",
"factors:",
"transcription",
"rate",
"and",
"mRNA",
"degradation",
"rate.",
"The",
"question",
"being",
"asked",
"here",
"is",
"therefore",
"whether",
"steady-state",
"mRNA",
"abundance",
"or",
"any",
"of",
"two",
"factors",
"is",
"a",
"more",
"informative",
"measurement",
"target",
"for",
"studying",
"network",
"dynamics.",
"The",
"yeast",
"S.",
"cerevisiae",
"was",
"used",
"as",
"model",
"organism",
"and",
"transcription",
"rate",
"was",
"chosen",
"out",
"of",
"the",
"two",
"factors",
"in",
"this",
"study,",
"because",
"genome-wide",
"determination",
"of",
"transcription",
"rates",
"has",
"been",
"reported",
"for",
"several",
"physiological",
"processes",
"in",
"this",
"species.",
"Our",
"strategy",
"is",
"to",
"test",
"which",
"one",
"is",
"a",
"better",
"measurement",
"of",
"functional",
"relatedness",
"between",
"genes.",
"The",
"analysis",
"was",
"performed",
"on",
"those",
"S.",
"cerevisiae",
"genes",
"that",
"have",
"bacterial",
"orthologs",
"as",
"identified",
"by",
"reciprocal",
"BLAST",
"analysis,",
"so",
"that",
"functional",
"relatedness",
"of",
"a",
"gene",
"pair",
"can",
"be",
"measured",
"by",
"the",
"frequency",
"at",
"which",
"their",
"bacterial",
"orthologs",
"co-occur",
"in",
"the",
"same",
"operon",
"in",
"the",
"collection",
"of",
"bacterial",
"genomes.",
"It",
"is",
"found",
"that",
"transcription",
"rate",
"data",
"is",
"generally",
"a",
"better",
"parameter",
"for",
"functional",
"relatedness",
"than",
"steady",
"state",
"mRNA",
"abundance,",
"suggesting",
"transcription",
"rate",
"data",
"is",
"more",
"informative",
"to",
"use",
"in",
"deciphering",
"the",
"logics",
"used",
"by",
"the",
"cells",
"in",
"dynamic",
"regulation",
"of",
"biochemical",
"network",
"behaviors.",
"The",
"significance",
"of",
"this",
"finding",
"for",
"network",
"and",
"systems",
"biology,",
"as",
"well",
"as",
"biomedical",
"research",
"in",
"general,",
"is",
"discussed.",
"Citation:",
"Hayles",
"B,",
"Yellaboina",
"S,",
"Wang",
"D",
"(2010)",
"Comparing",
"Transcription",
"Rate",
"and",
"mRNA",
"Abundance",
"as",
"Parameters",
"for",
"Biochemical",
"Pathway",
"and",
"Network",
"Analysis.",
"PLoS",
"ONE",
"5(3):",
"e9908.",
"doi:10.1371/journal.pone.0009908",
"Editor:",
"Timothy",
"Ravasi,",
"King",
"Abdullah",
"University",
"of",
"Science",
"and",
"Technology,",
"Saudi",
"Arabia",
"Received",
"January",
"5,",
"2010;",
"Accepted",
"February",
"19,",
"2010;",
"Published",
"March",
"26,",
"2010",
"Copyright:",
"2010",
"Hayles",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"the",
"University",
"of",
"South",
"Florida",
"(USF)",
"Foundation",
"and",
"a",
"USF",
"New",
"Researcher",
"Grant",
"to",
"D.W.",
"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:",
"dwang1@cas.usf.edu",
"¤",
"Current",
"address:",
"Biostatistics",
"Branch,",
"National",
"Institute",
"of",
"Environmental",
"Health",
"Sciences",
"(NIEHS),",
"National",
"Institutes",
"of",
"Health",
"(NIH),",
"Research",
"Triangle",
"Park,",
"North",
"Carolina,",
"United",
"States",
"of",
"America",
"Introduction",
"Biochemical",
"networks",
"underlie",
"essentially",
"all",
"cellular",
"functions.",
"Proteins",
"encoded",
"in",
"the",
"genomic",
"sequences",
"form",
"biochemical",
"pathways",
"and",
"pathways",
"join",
"together",
"to",
"form",
"networks.",
"Cellular",
"biochemical",
"networks",
"are",
"highly",
"modular",
"in",
"that",
"they",
"consist",
"of",
"a",
"hierarchical",
"organization",
"of",
"functional",
"modules",
"[1].",
"For",
"instance,",
"metabolic",
"enzymes",
"form",
"the",
"metabolic",
"network;",
"protein",
"kinases",
"are",
"backbones",
"of",
"the",
"signaling",
"network;",
"and",
"transcription",
"factors",
"are",
"major",
"components",
"of",
"the",
"transcription",
"regulation",
"network.",
"The",
"cells",
"constantly",
"adapt",
"to",
"changes",
"in",
"their",
"environment",
"and",
"internal",
"conditions.",
"Consequently,",
"biochemical",
"networks",
"are",
"never",
"static.",
"The",
"cells",
"respond",
"to",
"extra-",
"and",
"intra-cellular",
"signals",
"by",
"dynamic",
"orchestration",
"of",
"activities",
"of",
"pathways",
"in",
"the",
"networks;",
"activate",
"pathways",
"that",
"are",
"needed",
"and",
"inactivate",
"the",
"others",
"[2].",
"For",
"example,",
"during",
"carbon",
"source",
"shift",
"from",
"glucose",
"to",
"galactose,",
"the",
"yeast",
"cells",
"activate",
"galactose",
"utilization",
"pathways,",
"while",
"inactivating",
"pathways",
"required",
"for",
"glucose",
"metabolism",
"[3,4].",
"Roughly",
"two",
"factors",
"determine",
"how",
"active",
"a",
"pathway",
"is:",
"the",
"abundance",
"and",
"the",
"activity",
"of",
"its",
"components.",
"The",
"activity",
"of",
"many",
"proteins,",
"the",
"latter",
"of",
"the",
"two",
"factors,",
"is",
"under",
"tight",
"post-",
"translational",
"control.",
"There",
"are",
"many",
"forms",
"of",
"post-translational",
"control:",
"covalent",
"chemical",
"modification",
"such",
"as",
"phosphorylation",
"[5]",
"and",
"glycosylation",
"[6],",
"allosteric",
"interaction",
"with",
"regulatory",
"partners",
"[7],",
"etc.",
"The",
"other",
"determining",
"factor",
"of",
"biochemical",
"pathway",
"activity,",
"the",
"abundance",
"of",
"proteins,",
"is",
"also",
"under",
"tight",
"cellular",
"regulation.",
"Gene",
"expression",
"regulation",
"is",
"one",
"of",
"the",
"major",
"regulatory",
"mechanisms.",
"Hence,",
"gene",
"expression",
"has",
"been,",
"and",
"will",
"continue",
"to",
"be,",
"extensively",
"studied.",
"Perhaps",
"due",
"to",
"the",
"availability",
"of",
"reliable",
"and",
"economical",
"measurement",
"methods",
"such",
"as",
"the",
"SAGE",
"[8],",
"the",
"micro-array",
"and",
"the",
"upcoming",
"deep",
"sequencing",
"technologies",
"[9],",
"mRNA",
"transcript",
"levels",
"have",
"been",
"the",
"most",
"frequently",
"studied,",
"even",
"though",
"gene",
"expression",
"process",
"is",
"a",
"multi-stepped",
"process.",
"Measurement",
"targets",
"are",
"usually",
"steady",
"state",
"mRNA",
"abundance.",
"The",
"results",
"are",
"widely",
"used",
"in",
"statistical",
"inference",
"of",
"the",
"structures",
"of",
"underlying",
"biochemical",
"networks",
"[10],",
"as",
"well",
"as",
"in",
"regulatory",
"sequence",
"analysis",
"to",
"detect",
"common",
"sequence",
"motifs",
"that",
"drive",
"transcription",
"of",
"functionally",
"related",
"genes",
"[11,12].",
"The",
"underlying",
"assumption",
"is",
"that",
"functionally",
"related",
"genes",
"should",
"exhibit",
"similar",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"March",
"2010",
"|",
"Volume",
"5",
"|",
"Issue",
"3",
"|",
"e9908"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Ophthalmology",
"Volume",
"2012,",
"Article",
"ID",
"831502,",
"7",
"pages",
"doi:10.1155/2012/831502",
"Review",
"Article",
"New",
"Treatments",
"for",
"Bacterial",
"Keratitis",
"Raymond",
"L.",
"M.",
"Wong,1",
"R.",
"A.",
"Gangwani,1",
"Lester",
"W.",
"H.",
"Yu,2",
"and",
"Jimmy",
"S.",
"M.",
"Lai1",
"1",
"Eye",
"Institute,",
"The",
"University",
"of",
"Hong",
"Kong,",
"Room",
"301,",
"Level",
"3,",
"Block",
"B,",
"100",
"Cyberport",
"Road,",
"Cyberport",
"4,",
"Hong",
"Kong",
"2",
"Department",
"of",
"Ophthalmology,",
"Queen",
"Mary",
"Hospital,",
"Hong",
"Kong",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Jimmy",
"S.",
"M.",
"Lai,",
"laism@hku.hk",
"Received",
"31",
"May",
"2012;",
"Revised",
"30",
"July",
"2012;",
"Accepted",
"19",
"August",
"2012",
"Academic",
"Editor:",
"Rajesh",
"Sinha",
"Copyright",
"©",
"2012",
"Raymond",
"L.",
"M.",
"Wong",
"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.",
"Purpose.",
"To",
"review",
"the",
"newer",
"treatments",
"for",
"bacterial",
"keratitis.",
"Data",
"Sources.",
"PubMed",
"literature",
"search",
"up",
"to",
"April",
"2012.",
"Study",
"Selection.",
"Key",
"words",
"used",
"for",
"literature",
"search:",
"“infectious",
"keratitis”,",
"“microbial",
"keratitis”,",
"“infective",
"keratitis”,",
"“new",
"treatments",
"for",
"infectious",
"keratitis”,",
"“fourth",
"generation",
"fluoroquinolones”,",
"“moxifloxacin”,",
"“gatifloxacin”,",
"“collagen",
"cross-linking”,",
"and",
"“photodynamic",
"therapy”.",
"Data",
"Extraction.",
"Over",
"2400",
"articles",
"were",
"retrieved.",
"Large",
"scale",
"studies",
"or",
"publications",
"at",
"more",
"recent",
"dates",
"were",
"selected.",
"Data",
"Synthesis.",
"Broad",
"spectrum",
"antibiotics",
"have",
"been",
"the",
"main",
"stay",
"of",
"treatment",
"for",
"bacterial",
"keratitis",
"but",
"with",
"the",
"emergence",
"of",
"bacterial",
"resistance;",
"there",
"is",
"a",
"need",
"for",
"newer",
"antimicrobial",
"agents",
"and",
"treatment",
"methods.",
"Fourth-",
"generation",
"fluoroquinolones",
"and",
"corneal",
"collagen",
"cross-linking",
"are",
"amongst",
"the",
"new",
"treatments.",
"In",
"vitro",
"studies",
"and",
"prospective",
"clinical",
"trials",
"have",
"shown",
"that",
"fourth-generation",
"fluoroquinolones",
"are",
"better",
"than",
"the",
"older",
"generation",
"fluoroquinolones",
"and",
"are",
"as",
"potent",
"as",
"combined",
"fortified",
"antibiotics",
"against",
"common",
"pathogens",
"that",
"cause",
"bacterial",
"keratitis.",
"Collagen",
"cross-linking",
"was",
"shown",
"to",
"improve",
"healing",
"of",
"infectious",
"corneal",
"ulcer",
"in",
"treatment-resistant",
"cases",
"or",
"as",
"an",
"adjunct",
"to",
"antibiotics",
"treatment.",
"Conclusion.",
"Fourth-generation",
"fluoroquinolones",
"are",
"good",
"alternatives",
"to",
"standard",
"treatment",
"of",
"bacterial",
"keratitis",
"using",
"combined",
"fortified",
"topical",
"antibiotics.",
"Collagen",
"cross-linking",
"may",
"be",
"considered",
"in",
"treatment-resistant",
"infectious",
"keratitis",
"or",
"as",
"an",
"adjunct",
"to",
"antibiotics",
"therapy.",
"1.",
"Introduction",
"Infectious",
"keratitis",
"is",
"a",
"potentially",
"blinding",
"ocular",
"condition",
"of",
"cornea",
"which",
"can",
"cause",
"severe",
"visual",
"loss",
"if",
"not",
"treated",
"at",
"early",
"stage.",
"If",
"the",
"appropriate",
"antimicrobial",
"treatment",
"is",
"delayed,",
"only",
"50%",
"of",
"the",
"eyes",
"gain",
"good",
"visual",
"recovery",
"[1].",
"It",
"can",
"be",
"caused",
"by",
"bacteria,",
"virus,",
"fungus,",
"protozoa,",
"and",
"parasites.",
"The",
"common",
"risk",
"factors",
"for",
"infectious",
"keratitis",
"include",
"ocular",
"trauma,",
"contact",
"lens",
"wear,",
"recent",
"ocular",
"surgery,",
"preexisting",
"ocular",
"surface",
"disease,",
"dry",
"eyes,",
"lid",
"deformity,",
"corneal",
"sensational",
"impairment,",
"chronic",
"use",
"of",
"topical",
"steroids,",
"and",
"systemic",
"immunosuppression",
"[2–",
"5].",
"The",
"common",
"pathogens",
"include",
"Staphylococcus",
"aureus,",
"coagulase-negative",
"Staphylococcus,",
"Pseudomonas",
"aeruginosa,",
"Streptococcus",
"pneumonia,",
"and",
"Serratia",
"species.",
"The",
"majority",
"of",
"community",
"acquired",
"cases",
"of",
"bacterial",
"keratitis",
"resolve",
"with",
"empiric",
"treatment",
"and",
"do",
"not",
"require",
"culture",
"[6].",
"Corneal",
"scraping",
"for",
"culture",
"and",
"sensitivity",
"is",
"indicated",
"for",
"corneal",
"ulcers",
"that",
"are",
"large",
"in",
"size,",
"central",
"in",
"location,",
"extend",
"from",
"middle",
"to",
"deep",
"stroma,",
"associated",
"with",
"pain,",
"simultaneous",
"presence",
"of",
"anterior",
"chamber",
"reaction",
"or",
"hypopyon,",
"poor",
"vision,",
"and",
"presence",
"of",
"corneal",
"abscess",
"or",
"unresponsive",
"to",
"broad",
"spectrum",
"antibiotic",
"therapy",
"[6].",
"Recent",
"studies",
"have",
"shown",
"increasing",
"evidence",
"of",
"resistance",
"of",
"microbes",
"to",
"antimicrobial",
"agents",
"[7–9].",
"Microorganisms",
"develop",
"resistance",
"due",
"to",
"chromosomal",
"mutation,",
"expression",
"of",
"latent",
"chromosomal",
"genes",
"by",
"induction",
"or",
"exchange",
"of",
"genetic",
"material",
"via",
"transformation",
"[9,",
"10].",
"This",
"can",
"cause",
"continued",
"progression",
"of",
"the",
"disease",
"process",
"despite",
"the",
"use",
"of",
"broad",
"spectrum",
"antibiotics.",
"The",
"purpose",
"of",
"this",
"study",
"was",
"to",
"review",
"the",
"newer",
"treatments",
"available",
"for",
"treating",
"the",
"infectious",
"keratitis",
"including",
"those",
"which",
"are",
"resistant",
"to",
"the",
"antimicrobial",
"therapy.",
"2.",
"Methods",
"A",
"PubMed",
"literature",
"search",
"was",
"conducted",
"up",
"to",
"April",
"2012",
"using",
"the",
"following",
"key",
"words:",
"“infectious",
"keratitis”,",
"“microbial",
"keratitis”,",
"“infective",
"keratitis”,",
"“new",
"treatments",
"for"
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725,
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686,
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445,
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536,
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448,
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464,
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494,
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539,
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577,
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619,
756,
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634,
756,
16,
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654,
756,
29,
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688,
756,
41,
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[
733,
756,
10,
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[
748,
756,
16,
14
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[
421,
772,
29,
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[
452,
772,
27,
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481,
772,
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494,
772,
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511,
772,
31,
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545,
772,
20,
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567,
772,
28,
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597,
772,
23,
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[
622,
772,
45,
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[
670,
772,
10,
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[
683,
772,
16,
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[
701,
772,
34,
14
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[
736,
772,
28,
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421,
788,
54,
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[
479,
788,
39,
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521,
788,
41,
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[
567,
788,
45,
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615,
788,
28,
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[
647,
788,
20,
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[
670,
788,
48,
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723,
788,
40,
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421,
804,
16,
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[
441,
804,
50,
14
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[
495,
804,
16,
14
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514,
804,
43,
14
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[
561,
804,
37,
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[
602,
804,
73,
14
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[
678,
804,
11,
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692,
804,
29,
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725,
804,
39,
14
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421,
820,
10,
14
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[
433,
820,
16,
14
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[
450,
820,
34,
14
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485,
820,
32,
14
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519,
820,
29,
14
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[
550,
820,
50,
14
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602,
820,
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620,
820,
44,
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665,
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704,
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421,
836,
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461,
836,
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437,
852,
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466,
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563,
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620,
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665,
852,
71,
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743,
852,
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484,
868,
50,
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537,
868,
84,
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624,
868,
20,
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647,
868,
9,
14
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659,
868,
41,
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704,
868,
60,
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421,
884,
42,
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467,
884,
27,
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[
498,
884,
11,
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[
513,
884,
53,
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570,
884,
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590,
884,
17,
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611,
884,
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680,
884,
58,
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421,
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480,
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525,
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546,
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621,
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664,
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713,
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442,
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462,
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497,
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542,
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625,
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638,
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657,
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690,
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735,
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] | [
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"30",
"August",
"2011",
"doi:",
"10.3389/fgene.2011.00055",
"Gender-specific",
"hierarchy",
"in",
"nuage",
"localization",
"of",
"PIWI-interacting",
"RNA",
"factors",
"in",
"Drosophila",
"Akihiro",
"Nagao1†,",
"Kaoru",
"Sato1†,",
"Kazumichi",
"M.",
"Nishida1,",
"Haruhiko",
"Siomi",
"1",
"and",
"Mikiko",
"C.",
"Siomi",
"1,2*",
"1",
"Siomi",
"Lab,",
"Department",
"of",
"Molecular",
"Biology,",
"Keio",
"University",
"School",
"of",
"Medicine,",
"Tokyo,",
"Japan",
"2",
"Japan",
"Science",
"and",
"Technology",
"Agency,",
"Core",
"Research",
"for",
"Evolutional",
"Science",
"and",
"Technology,",
"Saitama,",
"Japan",
"Edited",
"by:",
"Muller",
"Fabbri,",
"The",
"Ohio",
"State",
"University,",
"USA",
"Reviewed",
"by:",
"Patrick",
"Provost,",
"Université",
"Laval,",
"Canada",
"Francesca",
"Fanini,",
"Istituto",
"Scientifico",
"Romagnolo",
"per",
"lo",
"Studio",
"e",
"la",
"Cura",
"dei",
"Tumori,",
"Italy",
"Michael",
"Frohman,",
"Stony",
"Brook",
"University,",
"USA",
"*Correspondence:",
"Mikiko",
"C.",
"Siomi,",
"Keio",
"University",
"School",
"of",
"Medicine,",
"3",
"Shinanomachi,",
"Shinjuku-ku,",
"Tokyo",
"160-8582,",
"Japan.",
"e-mail:",
"siomim@z6.keio.jp",
"†Akihiro",
"Nagao",
"and",
"Kaoru",
"Sato",
"have",
"contributed",
"equally",
"to",
"this",
"work.",
"PIWI-interacting",
"RNAs",
"(piRNAs)",
"are",
"germline-specific",
"small",
"non-coding",
"RNAs",
"that",
"form",
"piRNA-induced",
"silencing",
"complexes",
"(piRISCs)",
"by",
"associating",
"with",
"PIWI",
"proteins,",
"a",
"sub-",
"clade",
"of",
"the",
"Argonaute",
"proteins",
"predominantly",
"expressed",
"in",
"the",
"germline.",
"piRISCs",
"protect",
"the",
"integrity",
"of",
"the",
"germline",
"genome",
"from",
"invasive",
"transposable",
"DNA",
"elements",
"by",
"silencing",
"them.",
"Multiple",
"piRNA",
"biogenesis",
"factors",
"have",
"been",
"identified",
"in",
"Drosophila.",
"The",
"majority",
"of",
"piRNA",
"factors",
"are",
"localized",
"in",
"the",
"nuage,",
"electron-dense",
"non-membranous",
"cytoplas-",
"mic",
"structures",
"located",
"in",
"the",
"perinuclear",
"regions",
"of",
"germ",
"cells.",
"Thus,",
"piRNA",
"biogenesis",
"is",
"thought",
"to",
"occur",
"in",
"the",
"nuage",
"in",
"germ",
"cells.",
"Immunofluorescence",
"analyses",
"of",
"ovaries",
"from",
"piRNA",
"factor",
"mutants",
"have",
"revealed",
"a",
"localization",
"hierarchy",
"of",
"piRNA",
"factors",
"in",
"female",
"nuage.",
"However,",
"whether",
"this",
"hierarchy",
"is",
"female-specific",
"or",
"can",
"also",
"be",
"applied",
"in",
"male",
"gonads",
"remains",
"undetermined.",
"Here,",
"we",
"show",
"by",
"immunostaining",
"of",
"both",
"ovaries",
"and",
"testes",
"from",
"piRNA",
"factor",
"mutants",
"that",
"the",
"molecular",
"hierarchy",
"of",
"piRNA",
"factors",
"shows",
"gender-specificity,",
"especially",
"for",
"Krimper",
"(Krimp),",
"a",
"Tudor-domain-containing",
"protein",
"of",
"unknown",
"function(s):",
"Krimp",
"is",
"dispensable",
"for",
"PIWI",
"protein",
"Aubergine",
"(Aub)",
"nuage",
"local-",
"ization",
"in",
"ovaries",
"but",
"Krimp",
"and",
"Aub",
"require",
"each",
"other",
"for",
"their",
"proper",
"nuage",
"localization",
"in",
"testes.",
"This",
"suggests",
"that",
"the",
"functional",
"requirement",
"of",
"Krimp",
"in",
"piRNA",
"biogenesis",
"may",
"be",
"different",
"in",
"male",
"and",
"female",
"gonads.",
"Keywords:",
"nuage,",
"piRNA,",
"PIWI,",
"Drosophila,",
"germline",
"INTRODUCTION",
"PIWI-interacting",
"RNAs",
"(piRNAs)",
"are",
"germline-specific",
"small",
"RNAs",
"that",
"function",
"in",
"RNA",
"silencing.",
"In",
"Drosophila,",
"piRNAs",
"arise",
"mostly",
"from",
"transposable",
"elements",
"and",
"associate",
"with",
"germline-",
"specific",
"Argonaute",
"proteins",
"(PIWI",
"proteins),",
"Aubergine",
"(Aub),",
"Piwi,",
"and",
"Ago3,",
"to",
"guide",
"PIWI",
"proteins",
"to",
"their",
"targets",
"(Saito",
"et",
"al.,",
"2006,",
"2009;",
"Vagin",
"et",
"al.,",
"2006;",
"Aravin",
"et",
"al.,",
"2007;",
"Brennecke",
"et",
"al.,",
"2007;",
"Gunawardane",
"et",
"al.,",
"2007;",
"Nishida",
"et",
"al.,",
"2007).",
"Mutations",
"in",
"the",
"piwi",
"genes",
"lead",
"to",
"de-repression",
"of",
"transposable",
"elements",
"(Cox",
"et",
"al.,",
"1998;",
"Schmidt",
"et",
"al.,",
"1999;",
"Vagin",
"et",
"al.,",
"2004;",
"Kalmykova",
"et",
"al.,",
"2005;",
"Klattenhoff",
"et",
"al.,",
"2007;",
"Li",
"et",
"al.,",
"2009).",
"Mutations",
"in",
"the",
"piRNA-producing",
"genomic",
"loci,",
"the",
"piRNA",
"clusters,",
"show",
"a",
"similar",
"phenotype",
"(Brennecke",
"et",
"al.,",
"2007).",
"Thus,",
"both",
"PIWI",
"and",
"piRNAs",
"are",
"necessary",
"for",
"transposon",
"silencing",
"in",
"the",
"germline.",
"Through",
"this",
"mechanism,",
"the",
"PIWI–piRNA",
"complex,",
"also",
"called",
"the",
"piRNA-",
"induced",
"silencing",
"complex",
"(piRISC),",
"protects",
"the",
"integrity",
"of",
"the",
"germline",
"genome",
"from",
"invasive",
"transposable",
"DNA",
"elements",
"and",
"ensures",
"oogenesis",
"and",
"spermatogenesis.",
"PIWI-interacting",
"RNAs",
"are",
"produced",
"through",
"two",
"mecha-",
"nisms,",
"the",
"primary",
"processing",
"pathway",
"and",
"the",
"amplification",
"loop",
"(or",
"the",
"Ping-Pong",
"cycle;",
"Aravin",
"et",
"al.,",
"2007;",
"Brennecke",
"et",
"al.,",
"2007;",
"Gunawardane",
"et",
"al.,",
"2007;",
"Li",
"et",
"al.,",
"2009;",
"Malone",
"et",
"al.,",
"2009;",
"Siomi",
"et",
"al.,",
"2011).",
"Primary",
"piRNAs",
"are",
"first",
"produced",
"through",
"the",
"pri-",
"mary",
"processing",
"pathway;",
"then,",
"the",
"majority",
"of",
"primary",
"piRNAs",
"are",
"amplified",
"by",
"the",
"Ping-Pong",
"cycle",
"to",
"maintain",
"a",
"high",
"expres-",
"sion",
"level",
"of",
"piRNAs",
"in",
"the",
"germline.",
"Maternally",
"deposited",
"piRNAs",
"also",
"serve",
"as",
"primary",
"piRNAs",
"to",
"induce",
"the",
"Ping-Pong",
"cycle",
"in",
"embryos.",
"Primary",
"piRNAs",
"are",
"mostly",
"antisense",
"to",
"transposon",
"mRNAs,",
"show",
"a",
"strong",
"bias",
"for",
"uracil",
"at",
"the",
"5",
"end",
"(1U",
"bias)",
"and",
"are",
"favor-",
"ably",
"loaded",
"onto",
"Aub",
"and",
"Piwi",
"(Li",
"et",
"al.,",
"2009;",
"Malone",
"et",
"al.,",
"2009).",
"Primary",
"piRNAs",
"in",
"ovarian",
"somatic",
"cells",
"require",
"the",
"female",
"ster-",
"ile",
"(1)",
"Yb",
"(Yb)",
"gene",
"for",
"their",
"accumulation",
"(Olivieri",
"et",
"al.,",
"2010;",
"Saito",
"et",
"al.,",
"2010;",
"Qi",
"et",
"al.,",
"2011).",
"Yb",
"is",
"necessary",
"for",
"self-renewal",
"of",
"germline",
"and",
"somatic",
"stem",
"cells",
"in",
"ovaries",
"(Szakmary",
"et",
"al.,",
"2009).",
"Germ",
"cells",
"do",
"not",
"express",
"Yb",
"and,",
"therefore,",
"Yb",
"is",
"unneces-",
"sary",
"for",
"primary",
"piRNA",
"production",
"in",
"germ",
"cells.",
"Zucchini",
"(zuc)",
"and",
"armitage",
"(armi)",
"are",
"necessary",
"for",
"primary",
"piRNA",
"produc-",
"tion",
"in",
"both",
"ovarian",
"somas",
"(Haase",
"et",
"al.,",
"2010;",
"Olivieri",
"et",
"al.,",
"2010;",
"Saito",
"et",
"al.,",
"2010)",
"and",
"germ",
"cells",
"(Malone",
"et",
"al.,",
"2009).",
"Vasa,",
"maelstrom",
"(mael),",
"krimper",
"(krimp),",
"armi,",
"and",
"spindle-E",
"(spn-E)",
"are",
"necessary",
"for",
"primary",
"piRNA",
"accumulation",
"in",
"testes",
"(Nagao",
"et",
"al.,",
"2010).",
"Other",
"genes",
"necessary",
"for",
"primary",
"piRNA",
"production",
"remain",
"elusive.",
"The",
"Ping-Pong",
"cycle",
"performs",
"piRNA",
"amplification",
"and",
"transposon",
"silencing,",
"simultaneously;",
"this",
"is",
"because",
"transposon",
"mRNAs",
"serve",
"as",
"substrates",
"for",
"the",
"Aub–piRNA",
"complexes.",
"The",
"Aub-Slicer",
"activity,",
"the",
"endonuclease",
"activity",
"required",
"for",
"cleav-",
"ing",
"the",
"target",
"mRNAs",
"(Gunawardane",
"et",
"al.,",
"2007;",
"Nishida",
"et",
"al.,",
"2007),",
"determines",
"the",
"5",
"end",
"of",
"mature",
"piRNAs",
"in",
"the",
"sense",
"orientation.",
"Mature",
"piRNAs",
"are",
"then",
"loaded",
"onto",
"Ago3.",
"Thus,",
"Ago3-associating",
"piRNAs",
"are",
"mostly",
"in",
"the",
"sense",
"orientation.",
"The",
"www.frontiersin.org",
"August",
"2011",
"|",
"Volume",
"2",
"|",
"Article",
"55",
"|",
"1"
] | [
0,
0,
0,
0,
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] | [
"Journal",
"of",
"Carcinogenesis",
"Short",
"paper",
"Comparative",
"study",
"of",
"matrix",
"metalloproteinase",
"expression",
"between",
"African",
"American",
"and",
"Caucasian",
"Women",
"Jacquline",
"A",
"Mason1,",
"Haile",
"F",
"Yancy1,",
"Kerrie",
"Lashley2,",
"Marty",
"Jett3",
"and",
"Agnes",
"A",
"Day*1",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Microbiology,",
"College",
"of",
"Medicine",
"Howard",
"University,",
"Washington,",
"D.C.",
"20059,",
"USA,",
"2Department",
"of",
"Biology",
"Howard",
"University,",
"Washington,",
"D.C.",
"20059,",
"USA",
"and",
"3Division",
"of",
"Pathology,",
"Walter",
"Reed",
"Army",
"Institute",
"of",
"Research,",
"Washington,",
"D.C.",
"20021,",
"USA",
"Email:",
"Jacquline",
"A",
"Mason",
"-",
"Jacquline.A.Mason@comcast.net;",
"Haile",
"F",
"Yancy",
"-",
"Hyancy@aol.com;",
"Kerrie",
"Lashley",
"-",
"kerrielashley@hotmail.com;",
"Marty",
"Jett",
"-",
"marti.jett@na.amedd.army.mil;",
"Agnes",
"A",
"Day*",
"-",
"aday@howard.edu",
"*",
"Corresponding",
"author",
"Published:",
"29",
"October",
"2004",
"Journal",
"of",
"Carcinogenesis",
"2004,",
"3:15",
"doi:10.1186/1477-3163-3-15",
"This",
"article",
"is",
"available",
"from:",
"http://www.carcinogenesis.com/content/3/1/15",
"Received:",
"13",
"September",
"2004",
"Accepted:",
"29",
"October",
"2004",
"©",
"2004",
"Mason",
"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",
"To",
"date",
"there",
"are",
"26",
"human",
"matrix",
"metalloproteinases",
"(MMPs)",
"which",
"are",
"classified",
"according",
"to",
"their",
"substrate",
"specificity",
"and",
"structural",
"similarities.",
"The",
"four",
"major",
"subgroups",
"of",
"MMPs",
"are",
"gelatinases,",
"interstitial",
"collagenases,",
"stromelysins,",
"and",
"membrane-type",
"matrix",
"metalloproteinases",
"(MT-MMPs).",
"This",
"study",
"investigates",
"the",
"expression",
"of",
"26",
"MMPs,",
"which",
"have",
"been",
"shown",
"to",
"play",
"a",
"role",
"in",
"cancer",
"metastasis.",
"Breast",
"tissues",
"and",
"cell",
"lines",
"derived",
"from",
"African",
"American",
"patients",
"and",
"Caucasian",
"patients",
"were",
"assayed",
"to",
"demonstrate",
"alterations",
"in",
"the",
"transcription",
"of",
"genes",
"primarily",
"responsible",
"for",
"degrading",
"the",
"extracellular",
"matrix",
"(ECM).",
"The",
"expression",
"levels",
"of",
"the",
"extracellular",
"matrix",
"and",
"adhesion",
"molecules",
"were",
"analyzed",
"using",
"the",
"gene",
"array",
"technology.",
"Steady",
"state",
"levels",
"of",
"mRNAs",
"were",
"validated",
"by",
"RT-PCR",
"analysis.",
"Total",
"RNA",
"was",
"isolated",
"from",
"tissue",
"and",
"cell",
"lines",
"and",
"used",
"in",
"the",
"RT-PCR",
"assays.",
"From",
"this",
"data,",
"differential",
"expression",
"of",
"MMPs",
"between",
"6",
"breast",
"cancer",
"cell",
"lines",
"and",
"2",
"non-cancer",
"breast",
"cell",
"lines",
"was",
"demonstrated.",
"We",
"have",
"performed",
"an",
"in",
"vitro",
"comparison",
"of",
"MMP",
"expression",
"and",
"established",
"differences",
"in",
"12",
"MMPs",
"(3,",
"7,",
"8,",
"9,",
"11–15,",
"23B,",
"26,",
"and",
"28)",
"expression",
"between",
"African",
"American",
"and",
"Caucasian",
"breast",
"cell",
"lines.",
"Thus,",
"evidence",
"indicates",
"that",
"altered",
"expression",
"of",
"MMPs",
"may",
"play",
"a",
"role",
"in",
"the",
"aggressive",
"phenotype",
"seen",
"in",
"African",
"American",
"women.",
"Introduction",
"In",
"2003,",
"it",
"was",
"estimated",
"that",
"approximately",
"1.3",
"million",
"Americans",
"would",
"be",
"diagnosed",
"with",
"invasive",
"cancer.",
"Of",
"this",
"group,",
"racial/ethnic",
"minorities",
"account",
"for",
"a",
"dispro-",
"portionate",
"number",
"of",
"these",
"cancers",
"[1,2].",
"Invasive",
"breast",
"cancer",
"usually",
"begins",
"in",
"either",
"the",
"lobules",
"or",
"the",
"ducts",
"of",
"the",
"breast.",
"These",
"tumors",
"then",
"metastasize",
"via",
"the",
"breast",
"associated",
"and",
"thoracic",
"lymphatic",
"tissue",
"[3].",
"The",
"inci-",
"dence",
"of",
"breast",
"cancer",
"in",
"Caucasian",
"women",
"(112",
"out",
"of",
"100,000)",
"is",
"higher",
"than",
"in",
"African",
"American",
"women",
"(AA)",
"(95",
"out",
"of",
"100,000)",
"after",
"the",
"age",
"of",
"40,",
"however,",
"the",
"mor-",
"tality",
"suffered",
"by",
"(AA)(37",
"out",
"of",
"100,000)",
"is",
"higher",
"than",
"Caucasian",
"women",
"(CAU)",
"(31",
"out",
"of",
"100,000)",
"at",
"every",
"age",
"[4].",
"Thus",
"a",
"greater",
"percentage",
"of",
"AA",
"women",
"die",
"from",
"breast",
"cancer",
"and",
"resulting",
"metastasis.",
"In",
"2004,",
"an",
"esti-",
"mated",
"215,990",
"new",
"cases",
"of",
"invasive",
"breast",
"cancer",
"is",
"expected",
"to",
"occur",
"among",
"women",
"in",
"the",
"United",
"States",
"[5].",
"Breast",
"cancer",
"is",
"the",
"most",
"common",
"cancer",
"among",
"AA",
"women;",
"however,",
"the",
"rate",
"of",
"newly",
"diagnosed",
"cases",
"is",
"about",
"13%",
"lower",
"than",
"CAU",
"women",
"[6].",
"There",
"is",
"Page",
"1",
"of",
"6",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Lipid",
"mediators",
"in",
"innate",
"immunity",
"against",
"tuberculosis:",
"opposing",
"roles",
"of",
"PGE2",
"and",
"LXA4",
"in",
"the",
"induction",
"of",
"macrophage",
"death",
"A",
"RT",
"I",
"C",
"L",
"E",
"e",
"n",
"i",
"c",
"i",
"d",
"e",
"M",
"l",
"a",
"t",
"n",
"e",
"m",
"i",
"r",
"e",
"p",
"x",
"E",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"CORRESPONDENCE",
"Heinz",
"G.",
"Remold:",
"hremold@rics.bwh.harvard.edu",
"Abbreviations",
"used:",
"5-LO,",
"5-lipoxygenase;",
"AA,",
"arachidonic",
"acid;",
"COX,",
"cyclooxygenase;",
"cPLA2,",
"cytosolic",
"PLA2;",
"EP,",
"E",
"prostanoid;",
"LC-MS-MS,",
"liquid",
"chromatography",
"tandem",
"mass",
"spectrometry;",
"MOI,",
"multi-",
"plicity",
"of",
"infection;",
"mPGES,",
"microsomal",
"prostaglandin",
"E",
"synthase;",
"MPT,",
"mitochondrial",
"permeability",
"transition;",
"PI,",
"propidium",
"iodide;",
"PI3K,",
"phos-",
"phatidylinositol-3",
"kinase;",
"PKA,",
"protein",
"kinase",
"A;",
"siRNA,",
"small",
"interfering",
"RNA.",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Exp.",
"Med.",
"Vol.",
"205",
"No.",
"12",
"2791-2801",
"www.jem.org/cgi/doi/10.1084/jem.20080767",
"Minjian",
"Chen,1",
"Maziar",
"Divangahi,1",
"Huixian",
"Gan,1",
"Daniel",
"S.J.",
"Shin,1",
"Song",
"Hong,2",
"David",
"M.",
"Lee,1",
"Charles",
"N.",
"Serhan,2",
"Samuel",
"M.",
"Behar,1",
"and",
"Heinz",
"G.",
"Remold1",
"1Department",
"of",
"Medicine",
"and",
"Division",
"of",
"Rheumatology,",
"Immunology,",
"and",
"Allergy",
"and",
"2Center",
"for",
"Experimental",
"Therapeutics",
"and",
"Reperfusion",
"Injury,",
"Department",
"of",
"Anesthesiology,",
"Perioperative,",
"and",
"Pain",
"Medicine,",
"Brigham",
"and",
"Women’s",
"Hospital",
"and",
"Harvard",
"Medical",
"School,",
"Boston,",
"MA",
"02115",
"Virulent",
"Mycobacterium",
"tuberculosis",
"(Mtb)",
"induces",
"a",
"maladaptive",
"cytolytic",
"death",
"modality,",
"necrosis,",
"which",
"is",
"advantageous",
"for",
"the",
"pathogen.",
"We",
"report",
"that",
"necrosis",
"of",
"macrophages",
"infected",
"with",
"the",
"virulent",
"Mtb",
"strains",
"H37Rv",
"and",
"Erdmann",
"depends",
"on",
"predominant",
"LXA4",
"production",
"that",
"is",
"part",
"of",
"the",
"antiinflammatory",
"and",
"inflammation-resolving",
"action",
"induced",
"by",
"Mtb.",
"Infection",
"of",
"macrophages",
"with",
"the",
"avirulent",
"H37Ra",
"triggers",
"production",
"of",
"high",
"levels",
"of",
"the",
"prostanoid",
"PGE2,",
"which",
"promotes",
"protection",
"against",
"mitochondrial",
"inner",
"membrane",
"perturbation",
"and",
"necrosis.",
"In",
"contrast",
"to",
"H37Ra",
"infection,",
"PGE2",
"production",
"is",
"significantly",
"reduced",
"in",
"H37Rv-infected",
"macrophages.",
"PGE2",
"acts",
"by",
"engaging",
"the",
"PGE2",
"receptor",
"EP2,",
"which",
"induces",
"cyclic",
"AMP",
"production",
"and",
"protein",
"kinase",
"A",
"activation.",
"To",
"verify",
"a",
"role",
"for",
"PGE2",
"in",
"control",
"of",
"bacterial",
"growth,",
"we",
"show",
"that",
"infection",
"of",
"prostaglan-",
"din",
"E",
"synthase",
"(PGES)",
"/",
"macrophages",
"in",
"vitro",
"with",
"H37Rv",
"resulted",
"in",
"significantly",
"higher",
"bacterial",
"burden",
"compared",
"with",
"wild-type",
"macrophages.",
"More",
"importantly,",
"PGES",
"/",
"mice",
"harbor",
"significantly",
"higher",
"Mtb",
"lung",
"burden",
"5",
"wk",
"after",
"low-dose",
"aerosol",
"infection",
"with",
"virulent",
"Mtb.",
"These",
"in",
"vitro",
"and",
"in",
"vivo",
"data",
"indicate",
"that",
"PGE2",
"plays",
"a",
"critical",
"role",
"in",
"inhibition",
"of",
"Mtb",
"replication.",
"Tuberculosis",
"is",
"the",
"predominant",
"cause",
"for",
"mortal-",
"ity",
"from",
"chronic",
"pulmonary",
"bacterial",
"infections",
"worldwide",
"causing",
"nearly",
"two",
"million",
"deaths",
"yearly.",
"Tuberculosis",
"has",
"become",
"more",
"serious",
"as",
"a",
"consequence",
"of",
"the",
"global",
"AIDS",
"epidemic",
"and",
"the",
"emergence",
"of",
"multidrug-resistant",
"Mycobacte-",
"rium",
"tuberculosis",
"(Mtb),",
"the",
"causative",
"agent",
"of",
"tu-",
"berculosis",
"(1).",
"Natural",
"transmission",
"of",
"Mtb",
"occurs",
"predominantly",
"via",
"inhalation",
"of",
"aerosols",
"contain-",
"ing",
"small",
"numbers",
"of",
"bacteria",
"that",
"are",
"deposited",
"in",
"the",
"distal",
"airways",
"of",
"the",
"lung",
"(2).",
"The",
"pathogens",
"are",
"phagocytosed",
"by",
"pulmonary",
"M",
",",
"which",
"serve",
"as",
"a",
"sanctuary",
"for",
"Mtb",
"(3).",
"Virulent",
"Mtb,",
"which",
"M.",
"Divangahi",
"and",
"H.",
"Gan",
"contributed",
"equally",
"to",
"this",
"study.",
"M.",
"Chen’s",
"present",
"address",
"is",
"Clinical",
"Research",
"Center,",
"The",
"First",
"Affiliated",
"Hospital,",
"Guangxi",
"Medical",
"University,",
"Nanning,",
"Guangxi",
"530021,",
"People’s",
"Republic",
"of",
"China.",
"S.",
"Hong’s",
"present",
"address",
"is",
"Louisiana",
"State",
"University",
"Neuro-",
"science",
"Center,",
"New",
"Orleans,",
"LA",
"70112.",
"The",
"online",
"version",
"of",
"this",
"article",
"contains",
"supplemental",
"material.",
"reside",
"in",
"M",
",",
"initially",
"evade",
"elimination",
"by",
"the",
"immune",
"system",
"via",
"preventing",
"apoptosis",
"and",
"in-",
"hibiting",
"maturation",
"of",
"the",
"phagosome–lysosome",
"organelle",
"of",
"the",
"host",
"M",
"(4,",
"5).",
"The",
"net",
"effect",
"is",
"to",
"diminish",
"entry",
"of",
"bacterial",
"proteins",
"into",
"the",
"class",
"II",
"MHC",
"antigen-processing",
"pathway",
"(4)",
"and",
"to",
"create",
"a",
"protected",
"intracellular",
"milieu",
"where",
"ba-",
"cilli",
"remain",
"metabolically",
"active",
"and",
"replication",
"competent",
"(6).",
"For",
"M",
"infected",
"with",
"virulent",
"H37Rv,",
"necrosis",
"characterized",
"by",
"cytolysis",
"is",
"the",
"dominant",
"form",
"of",
"cell",
"death,",
"which",
"affords",
"a",
"pro-",
"tective",
"milieu",
"for",
"Mtb",
"(7,",
"8).",
"Thus,",
"subversion",
"of",
"cell",
"death",
"toward",
"necrosis",
"is",
"of",
"considerable",
"ad-",
"vantage",
"for",
"the",
"pathogen.",
"©",
"2008",
"Chen",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"an",
"Attribu-",
"tion–Noncommercial–Share",
"Alike–No",
"Mirror",
"Sites",
"license",
"for",
"the",
"first",
"six",
"months",
"after",
"the",
"publication",
"date",
"(see",
"http://www.jem.org/misc/terms.shtml).",
"After",
"six",
"months",
"it",
"is",
"available",
"under",
"a",
"Creative",
"Commons",
"License",
"(Attribution–Noncom-",
"mercial–Share",
"Alike",
"3.0",
"Unported",
"license,",
"as",
"described",
"at",
"http://creativecommons",
".org/licenses/by-nc-sa/3.0/).",
"2791"
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] | [
"REVIEW",
"ARTICLE",
"published:",
"22",
"August",
"2012",
"doi:",
"10.3389/fpls.2012.00203",
"RNA",
"trafficking",
"in",
"parasitic",
"plant",
"systems",
"Megan",
"LeBlanc,",
"Gunjune",
"Kim",
"and",
"James",
"H.",
"Westwood*",
"Department",
"of",
"Plant",
"Pathology,",
"Physiology",
"and",
"Weed",
"Science,",
"Virginia",
"Tech,",
"Blacksburg,",
"VA,",
"USA",
"Edited",
"by:",
"Yiguo",
"Hong,",
"College",
"of",
"Life",
"and",
"Environmental",
"Sciences,",
"Hangzhou",
"Normal",
"University,",
"China",
"Reviewed",
"by:",
"Ralf",
"Kaldenhoff,",
"Technische",
"Universität",
"Darmstadt,",
"Germany",
"Roberto",
"Ruiz-Medrano,",
"CINVESTAV-IPN,",
"Maxico",
"*Correspondence:",
"James",
"H.",
"Westwood,",
"Department",
"of",
"Plant",
"Pathology,",
"Physiology",
"and",
"Weed",
"Science,",
"Virginia",
"Tech,",
"401",
"Latham",
"Hall",
"(0390),",
"Blacksburg,",
"VA",
"24061,",
"USA.",
"e-mail:",
"westwood@vt.edu",
"RNA",
"trafficking",
"in",
"plants",
"contributes",
"to",
"local",
"and",
"long-distance",
"coordination",
"of",
"plant",
"devel-",
"opment",
"and",
"response",
"to",
"the",
"environment.",
"However,",
"investigations",
"of",
"mobile",
"RNA",
"identity",
"and",
"function",
"are",
"hindered",
"by",
"the",
"inherent",
"difficulty",
"of",
"tracing",
"a",
"given",
"molecule",
"of",
"RNA",
"from",
"its",
"cell",
"of",
"origin",
"to",
"its",
"destination.",
"Several",
"methods",
"have",
"been",
"used",
"to",
"address",
"this",
"prob-",
"lem,",
"but",
"all",
"are",
"limited",
"to",
"some",
"extent",
"by",
"constraints",
"associated",
"with",
"accurately",
"sampling",
"phloem",
"sap",
"or",
"detecting",
"trafficked",
"RNA.",
"Certain",
"parasitic",
"plant",
"species",
"form",
"symplastic",
"connections",
"to",
"their",
"hosts",
"and",
"thereby",
"provide",
"an",
"additional",
"system",
"for",
"studying",
"RNA",
"traf-",
"ficking.",
"The",
"haustorial",
"connections",
"of",
"Cuscuta",
"and",
"Phelipanche",
"species",
"are",
"similar",
"to",
"graft",
"junctions",
"in",
"that",
"they",
"are",
"able",
"to",
"transmit",
"mRNAs,",
"viral",
"RNAs,",
"siRNAs,",
"and",
"proteins",
"from",
"the",
"host",
"plants",
"to",
"the",
"parasite.",
"In",
"contrast",
"to",
"other",
"graft",
"systems,",
"these",
"parasites",
"form",
"con-",
"nections",
"with",
"host",
"species",
"that",
"span",
"a",
"wide",
"phylogenetic",
"range,",
"such",
"that",
"a",
"high",
"degree",
"of",
"nucleotide",
"sequence",
"divergence",
"may",
"exist",
"between",
"host",
"and",
"parasites",
"and",
"allow",
"con-",
"fident",
"identification",
"of",
"most",
"host",
"RNAs",
"in",
"the",
"parasite",
"system.",
"The",
"ability",
"to",
"identify",
"host",
"RNAs",
"in",
"parasites,",
"and",
"vice",
"versa,",
"will",
"facilitate",
"genomics",
"approaches",
"to",
"understanding",
"RNA",
"trafficking.",
"This",
"review",
"discusses",
"the",
"nature",
"of",
"host–parasite",
"connections",
"and",
"the",
"potential",
"significance",
"of",
"host",
"RNAs",
"for",
"the",
"parasite.",
"Additional",
"research",
"on",
"host–parasite",
"interactions",
"is",
"needed",
"to",
"interpret",
"results",
"of",
"RNA",
"trafficking",
"studies,",
"but",
"parasitic",
"plants",
"may",
"provide",
"a",
"fascinating",
"new",
"perspective",
"on",
"RNA",
"trafficking.",
"Keywords:",
"Cuscuta,",
"haustorium,",
"host–parasite",
"interactions,",
"Orobanchaceae,",
"Orobanche,",
"Phelipanche,",
"RNA",
"trafficking",
"INTRODUCTION",
"RNA",
"trafficking",
"in",
"plants",
"has",
"received",
"increasing",
"attention",
"in",
"recent",
"years.",
"It",
"is",
"an",
"important",
"phenomenon",
"in",
"that",
"it",
"suggests",
"that",
"plants",
"operate",
"at",
"the",
"level",
"of",
"supracellular",
"organisms,",
"meaning",
"that",
"mRNA",
"is",
"not",
"restricted",
"to",
"the",
"cell",
"in",
"which",
"it",
"was",
"synthesized,",
"but",
"rather",
"moves",
"from",
"cell-to-cell",
"and",
"even",
"over",
"long",
"distances",
"through",
"the",
"phloem",
"(Lucas",
"and",
"Lee,",
"2004).",
"Under",
"this",
"model",
"mRNAs",
"function",
"in",
"cells",
"distant",
"from",
"their",
"point",
"of",
"origin",
"by",
"car-",
"rying",
"information",
"throughout",
"the",
"plant",
"and",
"act",
"as",
"part",
"of",
"a",
"system",
"for",
"coordinating",
"plant",
"development.",
"However,",
"the",
"study",
"of",
"RNA",
"movement",
"between",
"cells",
"of",
"a",
"single",
"organism",
"presents",
"tremendous",
"challenges.",
"It",
"is",
"difficult",
"to",
"confi-",
"dently",
"determine",
"the",
"cell",
"of",
"origin",
"of",
"an",
"RNA",
"molecule",
"when",
"the",
"genotypes",
"of",
"source",
"and",
"destination",
"cells",
"are",
"identical.",
"This",
"inabil-",
"ity",
"to",
"distinguish",
"mRNA",
"origins",
"hampers",
"research,",
"and",
"while",
"it",
"is",
"currently",
"thought",
"that",
"there",
"are",
"about",
"1,100",
"proteins",
"and",
"hun-",
"dreds",
"of",
"mRNAs",
"that",
"undergo",
"long-distance",
"movement",
"(Atkins",
"et",
"al.,",
"2011),",
"the",
"actual",
"scope",
"of",
"RNA",
"trafficking",
"over",
"short",
"and",
"long",
"distances",
"is",
"unknown.",
"Parasitic",
"plants",
"are",
"relevant",
"to",
"the",
"consideration",
"of",
"RNA",
"traf-",
"ficking",
"because",
"certain",
"species",
"have",
"the",
"ability",
"to",
"form",
"symplastic",
"unions",
"with",
"host",
"species",
"wherein",
"the",
"connections",
"allow",
"the",
"trans-",
"fer",
"of",
"RNA.",
"In",
"the",
"case",
"of",
"lespedeza",
"dodder",
"(Cuscuta",
"pentagona),",
"the",
"connections",
"permit",
"transfer",
"of",
"mRNA",
"from",
"host",
"to",
"parasite",
"(Roney",
"et",
"al.,",
"2007;",
"David-Schwartz",
"et",
"al.,",
"2008),",
"and",
"this",
"raises",
"exciting",
"prospects",
"for",
"understanding",
"RNA",
"trafficking",
"in",
"plants.",
"Because",
"Cuscuta",
"has",
"a",
"relatively",
"wide",
"host",
"range",
"and",
"can",
"effec-",
"tively",
"parasitize",
"a",
"number",
"of",
"species",
"from",
"a",
"diverse",
"range",
"of",
"plant",
"families,",
"this",
"parasite",
"can",
"act",
"as",
"a",
"sink",
"for",
"host",
"mobile",
"RNA",
"from",
"many",
"different",
"species.",
"Furthermore,",
"the",
"evolution-",
"ary",
"distance",
"between",
"Cuscuta",
"and",
"most",
"of",
"its",
"hosts",
"means",
"that",
"the",
"majority",
"of",
"mRNAs",
"synthesized",
"in",
"a",
"host",
"have",
"sequences",
"that",
"are",
"divergent",
"from",
"those",
"of",
"Cuscuta,",
"thus",
"simplifying",
"the",
"process",
"of",
"bioinformatically",
"recognizing",
"host",
"mRNA",
"that",
"has",
"trafficked",
"into",
"the",
"parasite.",
"To",
"the",
"extent",
"that",
"Cuscuta",
"connections",
"to",
"hosts",
"approximate",
"normal",
"cell-to-cell",
"connections",
"within",
"plants,",
"Cus-",
"cuta",
"can",
"serve",
"as",
"an",
"exceptionally",
"wide",
"heterograft",
"to",
"facilitate",
"studies",
"of",
"mobile",
"RNA.",
"This",
"review",
"will",
"examine",
"the",
"nature",
"of",
"host–parasite",
"connections",
"and",
"consider",
"the",
"advantages",
"and",
"dis-",
"advantages",
"of",
"using",
"parasites",
"for",
"studies",
"of",
"RNA",
"trafficking",
"in",
"plants.",
"PARASITIC",
"PLANT",
"CONNECTIONS:",
"THE",
"PERFECT",
"GRAFT?",
"The",
"connection",
"between",
"parasitic",
"plants",
"and",
"their",
"hosts",
"has",
"been",
"compared",
"to",
"“the",
"perfect",
"graft”",
"(Kuijt,",
"1983).",
"The",
"analogy",
"of",
"par-",
"asitic",
"plant",
"connections",
"to",
"graft",
"unions",
"is",
"appropriate",
"in",
"that",
"both",
"involve",
"fusing",
"together",
"separate",
"plants",
"to",
"forge",
"new",
"cellu-",
"lar",
"connections",
"and",
"vascular",
"continuity.",
"Both",
"grafts",
"and",
"parasite",
"connections",
"establish",
"symplastic",
"connections",
"(Although",
"this",
"is",
"not",
"true",
"of",
"all",
"parasite",
"species,",
"it",
"is",
"accepted",
"for",
"Cuscuta",
"and",
"Phelipanche",
"spp.),",
"and",
"have",
"the",
"ability",
"to",
"transmit",
"RNA",
"(West-",
"wood",
"et",
"al.,",
"2009;",
"Harada,",
"2010).",
"However,",
"whereas",
"man-made",
"grafts",
"are",
"the",
"result",
"of",
"joining",
"cut",
"tissues,",
"the",
"parasitic",
"connection",
"involves",
"a",
"highly",
"coordinated",
"biological",
"invasion",
"(Joel",
"and",
"Losner-",
"Goshen,",
"1994;",
"Lee,",
"2007).",
"Although",
"parasitism",
"may",
"elicit",
"defense",
"responses",
"from",
"the",
"host",
"(Borsics",
"and",
"Lados,",
"2002;",
"Griffitts",
"et",
"al.,",
"www.frontiersin.org",
"August",
"2012",
"|",
"Volume",
"3",
"|",
"Article",
"203",
"|",
"1",
"“fpls-03-00203”",
"—",
"2012/8/20",
"—",
"19:45",
"—",
"page",
"1",
"—",
"#1"
] | [
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] | [
"DIABETICMedicine",
"P20BODA37licxMra4uficb2ogEtike-rn3wtdnaoi0,cexa7UlMi1drKPtaAeituacdrlbvietcliscnhlteriensg,Li2nt0dnhy6perglycaemciaY.Miyarzakietael.atic",
"B-cell",
"function",
"is",
"altered",
"by",
"oxidative",
"stress",
"induced",
"by",
"acute",
"hyperglycaemia",
"Y.",
"Miyazaki,",
"H.",
"Kawano,",
"T.",
"Yoshida,",
"S.",
"Miyamoto,",
"J.",
"Hokamaki,",
"Y.",
"Nagayoshi,",
"H.",
"Yamabe,",
"H.",
"Nakamura*,",
"J.",
"Yodoi†",
"and",
"H.",
"Ogawa",
"Department",
"of",
"Cardiovascular",
"Medicine,",
"Graduate",
"School",
"of",
"Medical",
"Sciences,",
"Kumamoto",
"University,",
"Kumamoto,",
"*Thioredoxin",
"Project,",
"Department",
"of",
"Experimental",
"Therapeutics,",
"Translational",
"Research",
"Centre,",
"Kyoto",
"University",
"Hospital",
"and",
"†Department",
"of",
"Biological",
"Responses,",
"Institute",
"for",
"Virus",
"Research,",
"Kyoto",
"University,",
"Kyoto,",
"Japan",
"Accepted",
"29",
"August",
"2006",
"Abstract",
"Aims",
"Type",
"2",
"diabetes",
"is",
"preceded",
"by",
"a",
"symptom-free",
"period",
"of",
"impaired",
"glu-",
"cose",
"tolerance",
"(IGT).",
"Pancreatic",
"B-cell",
"function",
"decreases",
"as",
"glucose",
"intolerance",
"develops.",
"In",
"many",
"patients",
"with",
"IGT,",
"fasting",
"blood",
"glucose",
"is",
"within",
"normal",
"limits",
"and",
"hyperglycaemia",
"occurs",
"only",
"postprandially.",
"We",
"examined",
"whether",
"pancreatic",
"B-cell",
"function",
"changes",
"during",
"acute",
"hyperglycaemia",
"induced",
"by",
"oral",
"glucose",
"loading.",
"Methods",
"We",
"calculated",
"the",
"insulinogenic",
"index",
"(I.I.)",
"as",
"an",
"indicator",
"of",
"pancreatic",
"B-cell",
"function",
"and",
"measured",
"serum",
"levels",
"of",
"thioredoxin,",
"a",
"marker",
"of",
"cellular",
"redox",
"state,",
"and",
"8-hydroxy-2′-deoxyguanosine",
"(8-OHdG),",
"a",
"marker",
"of",
"oxidative",
"stress,",
"during",
"a",
"75-g",
"oral",
"glucose",
"tolerance",
"test",
"(OGTT)",
"in",
"45",
"subjects",
"[24",
"patients",
"with",
"normal",
"glucose",
"tolerance",
"(NGT),",
"14",
"with",
"IGT",
"and",
"seven",
"with",
"Type",
"2",
"diabetes].",
"Results",
"Thioredoxin",
"levels",
"decreased",
"after",
"glucose",
"loading",
"[66.1",
"±",
"23.7,",
"*59.3",
"±",
"22.4,",
"*49.3",
"±",
"21.2",
"and",
"*37.7",
"±",
"18.0",
"ng/ml,",
"fasting",
"(0",
"min)",
"and",
"at",
"30,",
"60",
"and",
"120",
"min,",
"respectively;",
"*P",
"<",
"0.001",
"vs.",
"fasting].",
"In",
"contrast,",
"concentrations",
"of",
"8-OHdG",
"peaked",
"at",
"30",
"min",
"and",
"then",
"gradually",
"decreased",
"(0.402",
"±",
"0.123,",
"*0.440",
"±",
"0.120,",
"†0.362",
"±",
"0.119",
"and",
"†0.355",
"±",
"0.131",
"ng/ml,",
"*P",
"<",
"0.05",
"vs.",
"fasting,",
"†P",
"<",
"0.01",
"vs.",
"30",
"min).",
"The",
"insulinogenic",
"index",
"correlated",
"with",
"the",
"change",
"in",
"thioredoxin",
"levels",
"(r",
"=",
"0.34,",
"P",
"<",
"0.05).",
"However,",
"there",
"was",
"no",
"relationship",
"with",
"the",
"change",
"in",
"8-OHdG",
"levels",
"from",
"0",
"to",
"30",
"min.",
"Conclusions",
"Hyperglycaemia",
"in",
"response",
"to",
"oral",
"glucose",
"impairs",
"pancreatic",
"B-cell",
"function",
"with",
"decreasing",
"thioredoxin",
"levels.",
"The",
"augmented",
"oxidative",
"stress",
"induced",
"by",
"hyperglycaemia",
"may",
"affect",
"the",
"cellular",
"redox",
"state.",
"These",
"findings",
"strongly",
"suggest",
"that",
"repeated",
"postprandial",
"hyperglycaemia",
"may",
"play",
"an",
"important",
"role",
"in",
"the",
"development",
"and",
"progression",
"of",
"diabetes",
"mellitus.",
"Diabet.",
"Med.",
"24,",
"154–160",
"(2007)",
"Keywords",
"blood",
"glucose,",
"impaired",
"glucose",
"tolerance,",
"oxidative",
"stress,",
"post-",
"prandial",
"hyperglycaemia",
"Abbreviations",
"8-OHdG,",
"8-hydroxy-2′-deoxyguanosine;",
"ANOVA,",
"analysis",
"of",
"vari-",
"ance;",
"DM,",
"diabetes",
"mellitus;",
"IGT,",
"impaired",
"glucose",
"tolerance;",
"I.I.,",
"insulinogenic",
"index;",
"NGT,",
"normal",
"glucose",
"tolerance;",
"OGTT,",
"oral",
"glucose",
"tolerance",
"test;",
"TRX,",
"thioredoxin",
"Correspondence",
"to:",
"Hiroaki",
"Kawano",
"MD,",
"PhD,",
"Department",
"of",
"Cardiovascular",
"Medicine,",
"Graduate",
"School",
"of",
"Medical",
"Sciences,",
"Kumamoto",
"University,",
"1-1-1",
"Honjo,",
"Kumamoto",
"City",
"860–8556,",
"Japan.",
"E-mail:",
"koumei@kumamoto-u.ac.jp",
"Re-use",
"of",
"this",
"article",
"is",
"permitted",
"in",
"accordance",
"with",
"the",
"Creative",
"Commons",
"Deed,",
"Attribution",
"2.5,",
"which",
"does",
"not",
"permit",
"commercial",
"exploitation.",
"154",
"Introduction",
"Diabetes",
"mellitus",
"is",
"associated",
"with",
"the",
"development",
"of",
"athero-",
"sclerosis",
"[1].",
"Both",
"macrovascular",
"disease,",
"such",
"as",
"acute",
"coronary",
"syndrome,",
"stroke",
"and",
"claudication,",
"and",
"microvascular",
"disease,",
"such",
"as",
"diabetic",
"nephropathy",
"and",
"retinopathy,",
"are",
"commoner",
"in",
"diabetic",
"than",
"in",
"non-diabetic",
"populations",
"and",
"contribute",
"©",
"2007",
"The",
"Authors.",
"Journal",
"compilation",
"©",
"2007",
"Diabetes",
"UK.",
"Diabetic",
"Medicine,",
"24,",
"154–160"
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] | [
"J",
"Chem",
"Ecol",
"(2007)",
"33:655–668",
"DOI",
"10.1007/s10886-006-9245-2",
"Jasmonic",
"Acid-Induced",
"Changes",
"in",
"Brassica",
"oleracea",
"Affect",
"Oviposition",
"Preference",
"of",
"Two",
"Specialist",
"Herbivores",
"Maaike",
"Bruinsma",
"&",
"Nicole",
"M.",
"Van",
"Dam",
"&",
"Joop",
"J.",
"A.",
"Van",
"Loon",
"&",
"Marcel",
"Dicke",
"Received:",
"6",
"September",
"2006",
"/",
"Accepted:",
"18",
"December",
"2006",
"/",
"Published",
"online:",
"2",
"March",
"2007",
"#",
"Springer",
"Science",
"+",
"Business",
"Media,",
"LLC",
"2007",
"Abstract",
"Jasmonic",
"acid",
"(JA)",
"is",
"a",
"key",
"hormone",
"involved",
"in",
"plant",
"defense",
"responses.",
"The",
"effect",
"of",
"JA",
"treatment",
"of",
"cabbage",
"plants",
"on",
"their",
"acceptability",
"for",
"oviposition",
"by",
"two",
"species",
"of",
"cabbage",
"white",
"butterflies,",
"Pieris",
"rapae",
"and",
"P.",
"brassicae,",
"was",
"investigated.",
"Both",
"butterfly",
"species",
"laid",
"fewer",
"eggs",
"on",
"leaves",
"of",
"JA-treated",
"plants",
"compared",
"to",
"control",
"plants.",
"We",
"show",
"that",
"this",
"is",
"due",
"to",
"processes",
"in",
"the",
"plant",
"after",
"JA",
"treatment",
"rather",
"than",
"an",
"effect",
"of",
"JA",
"itself.",
"The",
"oviposition",
"preference",
"for",
"control",
"plants",
"is",
"adaptive,",
"as",
"development",
"time",
"from",
"larval",
"hatch",
"until",
"pupation",
"of",
"P.",
"rapae",
"caterpillars",
"was",
"longer",
"on",
"JA-treated",
"plants.",
"Total",
"glucosinolate",
"content",
"in",
"leaf",
"surface",
"extracts",
"was",
"similar",
"for",
"control",
"and",
"treated",
"plants;",
"however,",
"two",
"of",
"the",
"five",
"glucosinolates",
"were",
"present",
"in",
"lower",
"amounts",
"in",
"leaf",
"surface",
"extracts",
"of",
"JA-treated",
"plants.",
"When",
"the",
"butterflies",
"were",
"offered",
"a",
"choice",
"between",
"the",
"purified",
"glucosinolate",
"fraction",
"isolated",
"from",
"leaf",
"surface",
"extracts",
"of",
"JA-treated",
"plants",
"and",
"that",
"from",
"control",
"plants,",
"they",
"did",
"not",
"discriminate.",
"Changes",
"in",
"leaf",
"surface",
"glucosinolate",
"profile,",
"therefore,",
"do",
"not",
"seem",
"to",
"explain",
"the",
"change",
"in",
"oviposition",
"preference",
"of",
"the",
"butterflies",
"after",
"JA",
"treatment,",
"suggesting",
"that",
"as",
"yet",
"unknown",
"infochemicals",
"are",
"involved.",
"Keywords",
"Host",
"plant",
"selection",
".",
"Glucosinolates",
".",
"Pieris",
"rapae",
".",
"Pieris",
"brassicae",
".",
"Cabbage",
".",
"Performance",
".",
"Octadecanoid",
"pathway",
"Introduction",
"Plants",
"can",
"be",
"attacked",
"by",
"many",
"herbivorous",
"insects",
"and",
"have",
"evolved",
"a",
"variety",
"of",
"defense",
"strategies,",
"including",
"morphological",
"barriers,",
"synthesis",
"of",
"toxic",
"or",
"repellent",
"secondary",
"metabolites,",
"and",
"the",
"release",
"of",
"synomones",
"that",
"attract",
"natural",
"enemies",
"of",
"the",
"herbivores.",
"M.",
"Bruinsma",
"(*)",
":",
"J.",
"J.",
"A.",
"Van",
"Loon",
":",
"M.",
"Dicke",
"Laboratory",
"of",
"Entomology,",
"Wageningen",
"University,",
"P.O.",
"Box",
"8031,",
"6700",
"EH",
"Wageningen,",
"The",
"Netherlands",
"e-mail:",
"maaike.bruinsma@wur.nl",
"N.",
"M.",
"Van",
"Dam",
"Centre",
"for",
"Terrestrial",
"Ecology,",
"Netherlands",
"Institute",
"of",
"Ecology",
"(NIOO-KNAW),",
"P.O.",
"Box",
"40,",
"6666",
"ZG",
"Heteren,",
"The",
"Netherlands"
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] | [
"Kwon",
"et",
"al.",
"BMC",
"Cancer",
"2010,",
"10:392",
"http://www.biomedcentral.com/1471-2407/10/392",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Cinnamon",
"extract",
"induces",
"tumor",
"cell",
"death",
"through",
"inhibition",
"of",
"NF",
"B",
"and",
"AP1",
"Ho-Keun",
"Kwon1,",
"Ji-Sun",
"Hwang1,",
"Jae-Seon",
"So1,",
"Choong-Gu",
"Lee1,",
"Anupama",
"Sahoo1,",
"Jae-Ha",
"Ryu1,",
"Won",
"Kyung",
"Jeon2,",
"Byoung",
"Seob",
"Ko2,",
"Chang-Rok",
"Im3,",
"Sung",
"Haeng",
"Lee4,",
"Zee",
"Yong",
"Park1,",
"Sin-Hyeog",
"Im1*",
"Abstract",
"Background:",
"Cinnamomum",
"cassia",
"bark",
"is",
"the",
"outer",
"skin",
"of",
"an",
"evergreen",
"tall",
"tree",
"belonging",
"to",
"the",
"family",
"Lauraceae",
"containing",
"several",
"active",
"components",
"such",
"as",
"essential",
"oils",
"(cinnamic",
"aldehyde",
"and",
"cinnamyl",
"aldehyde),",
"tannin,",
"mucus",
"and",
"carbohydrate.",
"They",
"have",
"various",
"biological",
"functions",
"including",
"anti-oxidant,",
"anti-microbial,",
"anti-",
"inflammation,",
"anti-diabetic",
"and",
"anti-tumor",
"activity.",
"Previously,",
"we",
"have",
"reported",
"that",
"anti-cancer",
"effect",
"of",
"cinnamon",
"extracts",
"is",
"associated",
"with",
"modulation",
"of",
"angiogenesis",
"and",
"effector",
"function",
"of",
"CD8+",
"T",
"cells.",
"In",
"this",
"study,",
"we",
"further",
"identified",
"that",
"anti-tumor",
"effect",
"of",
"cinnamon",
"extracts",
"is",
"also",
"link",
"with",
"enhanced",
"pro-apoptotic",
"activity",
"by",
"inhibiting",
"the",
"activities",
"NF",
"B",
"and",
"AP1",
"in",
"mouse",
"melanoma",
"model.",
"Methods:",
"Water",
"soluble",
"cinnamon",
"extract",
"was",
"obtained",
"and",
"quality",
"of",
"cinnamon",
"extract",
"was",
"evaluated",
"by",
"HPLC",
"(High",
"Performance",
"Liquid",
"Chromatography)",
"analysis.",
"In",
"this",
"study,",
"we",
"tested",
"anti-tumor",
"activity",
"and",
"elucidated",
"action",
"mechanism",
"of",
"cinnamon",
"extract",
"using",
"various",
"types",
"of",
"tumor",
"cell",
"lines",
"including",
"lymphoma,",
"melanoma,",
"cervix",
"cancer",
"and",
"colorectal",
"cancer",
"in",
"vitro",
"and",
"in",
"vivo",
"mouse",
"melanoma",
"model.",
"Results:",
"Cinnamon",
"extract",
"strongly",
"inhibited",
"tumor",
"cell",
"proliferation",
"in",
"vitro",
"and",
"induced",
"active",
"cell",
"death",
"of",
"tumor",
"cells",
"by",
"up-regulating",
"pro-apoptotic",
"molecules",
"while",
"inhibiting",
"NF",
"B",
"and",
"AP1",
"activity",
"and",
"their",
"target",
"genes",
"such",
"as",
"Bcl-2,",
"BcL-xL",
"and",
"survivin.",
"Oral",
"administration",
"of",
"cinnamon",
"extract",
"in",
"melanoma",
"transplantation",
"model",
"significantly",
"inhibited",
"tumor",
"growth",
"with",
"the",
"same",
"mechanism",
"of",
"action",
"observed",
"in",
"vitro.",
"Conclusion:",
"Our",
"study",
"suggests",
"that",
"anti-tumor",
"effect",
"of",
"cinnamon",
"extracts",
"is",
"directly",
"linked",
"with",
"enhanced",
"pro-apoptotic",
"activity",
"and",
"inhibition",
"of",
"NF",
"B",
"and",
"AP1",
"activities",
"and",
"their",
"target",
"genes",
"in",
"vitro",
"and",
"in",
"vivo",
"mouse",
"melanoma",
"model.",
"Hence,",
"further",
"elucidation",
"of",
"active",
"components",
"of",
"cinnamon",
"extract",
"could",
"lead",
"to",
"development",
"of",
"potent",
"anti-tumor",
"agent",
"or",
"complementary",
"and",
"alternative",
"medicine",
"for",
"the",
"treatment",
"of",
"diverse",
"cancers.",
"Background",
"Herbal",
"medicines",
"are",
"plant-derived",
"products",
"which",
"have",
"been",
"used",
"as",
"traditional",
"folk",
"medicine",
"and",
"food",
"addi-",
"tives.",
"Recently",
"their",
"medicinal",
"properties",
"are",
"under",
"extensive",
"investigation",
"and",
"become",
"a",
"major",
"part",
"of",
"com-",
"plementary",
"and",
"alternative",
"medicines",
"(CAMs).",
"Their",
"potency",
"for",
"treating",
"different",
"diseases",
"has",
"been",
"reported",
"including",
"cancer,",
"allergy",
"and",
"diabetes",
"[1-4].",
"Cinnamomum",
"cassia",
"bark",
"is",
"the",
"outer",
"skin",
"of",
"an",
"ever-",
"green",
"tall",
"tree",
"belonging",
"to",
"the",
"family",
"Lauraceae.",
"Its",
"extracts",
"contain",
"several",
"active",
"components",
"such",
"as",
"*",
"Correspondence:",
"imsh@gist.ac.kr",
"1School",
"of",
"Life",
"Sciences",
"and",
"Immune",
"Synapse",
"Research",
"Center,",
"Gwangju",
"Institute",
"of",
"Science",
"and",
"Technology",
"(GIST),",
"1",
"Oryong-dong,",
"Puk-ku,",
"Gwangju",
"500-712,",
"Republic",
"of",
"Korea",
"essential",
"oils",
"(cinnamic",
"aldehyde",
"and",
"cinnamyl",
"alde-",
"hyde),",
"tannin,",
"mucus",
"and",
"carbohydrates",
"[5,6].",
"They",
"have",
"various",
"biological",
"functions",
"including",
"anti-oxidant,",
"anti-",
"microbial,",
"anti-inflammation,",
"anti-diabetic",
"effects",
"[7-12],",
"and",
"anti-tumor",
"activity",
"[11,13].",
"However,",
"for",
"the",
"devel-",
"opment",
"of",
"cinnamon",
"as",
"CAMs",
"for",
"cancer",
"treatment,",
"further",
"studies",
"are",
"necessary",
"such",
"as",
"elucidation",
"of",
"working",
"mechanisms",
"and",
"characterization",
"of",
"active",
"compounds",
"directly",
"linked",
"with",
"anti-tumor",
"activity.",
"Cancers",
"are",
"the",
"most",
"life-threatening",
"health",
"problems",
"in",
"the",
"world",
"[14].",
"There",
"have",
"been",
"many",
"trials",
"to",
"treat",
"cancers",
"through",
"modulation",
"of",
"anti-tumor",
"immune",
"response,",
"apoptosis",
"and",
"anti-tumor",
"proteins",
"[15-18].",
"Tumor",
"cells",
"are",
"generally",
"resistant",
"to",
"apoptosis;",
"hence",
"selective",
"killing",
"of",
"tumor",
"cells",
"by",
"promoting",
"apoptosis",
"©",
"2010",
"Kwon",
"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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] | [
"Furrer",
"et",
"al.",
"BMC",
"Ophthalmology",
"2012,",
"12:24",
"http://www.biomedcentral.com/1471-2415/12/24",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Evaluation",
"of",
"filtering",
"blebs",
"using",
"the",
"‘Wuerzburg",
"bleb",
"classification",
"score’",
"compared",
"to",
"clinical",
"findings",
"Sandra",
"Furrer1,",
"Marcel",
"N",
"Menke2,",
"Jens",
"Funk3",
"and",
"Marc",
"Töteberg-Harms3,4*",
"Abstract",
"Background:",
"To",
"determine",
"the",
"agreement",
"between",
"intraocular",
"pressure",
"and",
"the",
"‘Wuerzburg",
"bleb",
"classification",
"score’,",
"as",
"well",
"as",
"between",
"single",
"items",
"of",
"the",
"score",
"and",
"intraocular",
"pressure.",
"Interobserver",
"variability",
"was",
"analyzed.",
"Methods:",
"57",
"post-trabeculectomy",
"eyes",
"were",
"included.",
"Colour",
"photographs",
"were",
"used",
"to",
"score",
"the",
"filtering",
"bleb",
"in",
"accordance",
"to",
"the",
"Wuerzburg",
"bleb",
"classification",
"score",
"by",
"two",
"different",
"examiners.",
"At",
"the",
"same",
"visit,",
"clinical",
"data",
"such",
"as",
"intraocular",
"pressure,",
"best",
"corrected",
"visual",
"acuity,",
"slit",
"lamp",
"biomicroscopy",
"and",
"medical",
"history",
"were",
"obtained",
"by",
"another",
"examiner.",
"Results:",
"After",
"trabeculectomy,",
"42",
"out",
"of",
"57",
"eyes",
"(73.7%)",
"reached",
"the",
"target",
"pressure",
"(≤21mmHg,",
"and",
"intraocular",
"pressure",
"reduction",
"of",
"at",
"least",
"20%,",
"without",
"antiglaucoma",
"medication,",
"and",
"without",
"any",
"additional",
"intervention).",
"Fair",
"agreement",
"was",
"found",
"between",
"intraocular",
"pressure",
"and",
"Wuerzburg",
"bleb",
"classification",
"score",
"≥8",
"points",
"and",
"≥7",
"points",
"(kappa",
"0.24",
"and",
"0.27,",
"respectively).",
"Analyzing",
"the",
"subgroups",
"of",
"the",
"morphological",
"criteria,",
"best",
"agreement",
"was",
"found",
"between",
"occurrence",
"of",
"microcysts",
"and",
"target",
"intraocular",
"pressure",
"(к",
"0.22",
"–",
"0.34).",
"Conclusions:",
"Evaluating",
"filtering",
"blebs",
"after",
"trabeculectomy",
"by",
"using",
"the",
"Wuerzburg",
"bleb",
"classification",
"score",
"is",
"a",
"good",
"technique",
"for",
"predicting",
"intraocular",
"pressure",
"control",
"in",
"eyes",
"attaining",
"a",
"minimum",
"score",
"of",
"seven",
"points.",
"The",
"presence",
"of",
"microcysts",
"on",
"the",
"filtering",
"bleb",
"predicts",
"that",
"the",
"eye",
"is",
"likely",
"to",
"attain",
"target",
"pressure.",
"Keywords:",
"Filtering",
"bleb,",
"Glaucoma,",
"Filtration",
"surgery,",
"Bleb",
"grading,",
"Trabeculectomy",
"Background",
"Since",
"first",
"described",
"by",
"Cairns",
"in",
"1968",
"[1],",
"trabeculect-",
"omy",
"(TE)",
"has",
"been",
"widely",
"used",
"and",
"remains",
"the",
"gold",
"standard",
"in",
"surgical",
"treatment",
"of",
"glaucoma.",
"Long-term",
"success",
"depends",
"on",
"preoperative",
"and",
"intraoperative",
"con-",
"ditions,",
"but",
"long-term",
"success",
"also",
"highly",
"depends",
"on",
"the",
"persistence",
"of",
"filtration",
"efficiency",
"at",
"the",
"bleb",
"site.",
"Therefore,",
"postoperative",
"observation",
"and",
"care",
"of",
"the",
"developing",
"filtering",
"bleb",
"in",
"clinical",
"practice",
"is",
"an",
"import-",
"ant",
"tool",
"in",
"reaching",
"the",
"target",
"pressure",
"after",
"filtration",
"surgery",
"in",
"a",
"higher",
"percentage",
"of",
"the",
"patients",
"[2,3].",
"Since",
"1989,",
"a",
"number",
"of",
"observations",
"and",
"classifica-",
"tions",
"of",
"filtering",
"blebs",
"using",
"morphological",
"criteria",
"*",
"Correspondence:",
"MarcToeteberg@aol.com",
"3Department",
"of",
"Ophthalmology,",
"UniversityHospital",
"of",
"Zurich,",
"Frauenklinikstrasse",
"24,",
"8091",
"Zurich,",
"Switzerland",
"4Massachusetts",
"Eye",
"&",
"Ear",
"Infirmary,",
"Harvard",
"Medical",
"School,",
"Boston,",
"MA,",
"USA",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"have",
"been",
"described",
"[4-7].",
"These",
"early",
"efforts",
"included",
"various",
"assessments",
"of",
"filtering",
"bleb",
"morphology",
"and",
"emphasize",
"a",
"general",
"consensus",
"in",
"the",
"morphologic",
"fea-",
"tures",
"that",
"indicate",
"favourable",
"in",
"contrast",
"to",
"unfavour-",
"able",
"filtering",
"bleb",
"development",
"[8].",
"The",
"most",
"frequent",
"matter",
"of",
"failing",
"filtering",
"surgery",
"is",
"still",
"subconjunctival",
"scarring",
"which",
"needs",
"intensified",
"postoperative",
"care",
"of",
"the",
"filtering",
"bleb",
"even",
"if",
"intraocular",
"pressure",
"(IOP)",
"remains",
"well",
"controlled",
"[9].",
"In",
"order",
"to",
"allow",
"a",
"well-",
"structured",
"assessment",
"of",
"bleb",
"morphology",
"and",
"to",
"pre-",
"dict",
"potential",
"signs",
"of",
"failure",
"early",
"enough",
"(to",
"initiate",
"wound",
"healing",
"modulation",
"therapy),",
"different",
"bleb",
"grading",
"systems",
"including",
"the",
"classification",
"system",
"described",
"by",
"Picht",
"and",
"Grehn",
"[10,11],",
"the",
"Indiana",
"Bleb",
"Appearance",
"Grading",
"Scale",
"(IBAGS)",
"[8]",
"and",
"the",
"Moor-",
"fileds",
"Bleb",
"Grading",
"System",
"(MBGS)",
"[12]",
"were",
"pub-",
"lished.",
"All",
"of",
"them",
"have",
"been",
"developed",
"as",
"stand-alone",
"grading",
"tools.",
"The",
"‘Wuerzburg",
"bleb",
"classification",
"score",
"©",
"2012",
"Furrer",
"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",
"Genomics",
"Research",
"article",
"Comparison",
"of",
"the",
"transcriptomic",
"\"stress",
"response\"",
"evoked",
"by",
"antimycin",
"A",
"and",
"oxygen",
"deprivation",
"in",
"saccharomyces",
"cerevisiae",
"Liang-Chuan",
"Lai1,4,",
"Matthew",
"T",
"Kissinger2,4,",
"Patricia",
"V",
"Burke3,4",
"and",
"Kurt",
"E",
"Kwast*4",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Physiology,",
"National",
"Taiwan",
"University",
"College",
"of",
"Medicine,",
"Taipei,",
"Taiwan",
"(R.O.C.),",
"2Coskata",
"Inc.,",
"4575",
"Weaver",
"Pkwy,",
"Suite",
"100,",
"Warrenville,",
"IL",
"60555,",
"USA,",
"3Department",
"of",
"Microbiology,",
"University",
"of",
"Illinois,",
"Urbana,",
"IL",
"61801,",
"USA",
"and",
"4Department",
"of",
"Molecular",
"&",
"Integrative",
"Physiology,",
"University",
"ofIllinois,",
"Urbana,",
"IL",
"61801,",
"USA",
"Email:",
"Liang-Chuan",
"Lai",
"-",
"llai@ntu.edu.tw;",
"Matthew",
"T",
"Kissinger",
"-",
"mkissi@yahoo.com;",
"Patricia",
"V",
"Burke",
"-",
"burke@life.uiuc.edu;",
"Kurt",
"E",
"Kwast*",
"-",
"kwast@uiuc.edu",
"*",
"Corresponding",
"author",
"Published:",
"23",
"December",
"2008",
"BMC",
"Genomics",
"2008,",
"9:627",
"doi:10.1186/1471-2164-9-627",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2164/9/627",
"Received:",
"22",
"October",
"2007",
"Accepted:",
"23",
"December",
"2008",
"©",
"2008",
"Lai",
"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:",
"Acute",
"changes",
"in",
"environmental",
"parameters",
"(e.g.,",
"O2,",
"pH,",
"UV,",
"osmolarity,",
"nutrients,",
"etc.)",
"evoke",
"a",
"common",
"transcriptomic",
"response",
"in",
"yeast",
"referred",
"to",
"as",
"the",
"\"environmental",
"stress",
"response\"",
"(ESR)",
"or",
"\"common",
"environmental",
"response\"",
"(CER).",
"Why",
"such",
"a",
"diverse",
"array",
"of",
"insults",
"should",
"elicit",
"a",
"common",
"transcriptional",
"response",
"remains",
"enigmatic.",
"Previous",
"functional",
"analyses",
"of",
"the",
"networks",
"involved",
"have",
"found",
"that,",
"in",
"addition",
"to",
"up-regulating",
"those",
"for",
"mitigating",
"the",
"specific",
"stressor,",
"the",
"majority",
"appear",
"to",
"be",
"involved",
"in",
"balancing",
"energetic",
"supply",
"and",
"demand",
"and",
"modulating",
"progression",
"through",
"the",
"cell",
"cycle.",
"Here",
"we",
"compared",
"functional",
"and",
"regulatory",
"aspects",
"of",
"the",
"stress",
"responses",
"elicited",
"by",
"the",
"acute",
"inhibition",
"of",
"respiration",
"with",
"antimycin",
"A",
"and",
"oxygen",
"deprivation",
"under",
"catabolite",
"non-repressed",
"(galactose)",
"conditions.",
"Results:",
"Gene",
"network",
"analyses",
"of",
"the",
"transcriptomic",
"responses",
"revealed",
"both",
"treatments",
"result",
"in",
"the",
"transient",
"(10",
"–",
"60",
"min)",
"down-regulation",
"of",
"MBF-",
"and",
"SBF-regulated",
"networks",
"involved",
"in",
"the",
"G1/S",
"transition",
"of",
"the",
"cell",
"cycle",
"as",
"well",
"as",
"Fhl1",
"and",
"PAC/RRPE-associated",
"networks",
"involved",
"in",
"energetically",
"costly",
"programs",
"of",
"ribosomal",
"biogenesis",
"and",
"protein",
"synthesis.",
"Simultaneously,",
"Msn2/",
"4",
"networks",
"involved",
"in",
"hexose",
"import/dissimilation,",
"reserve",
"energy",
"regulation,",
"and",
"autophagy",
"were",
"transiently",
"up-regulated.",
"Interestingly,",
"when",
"cells",
"were",
"treated",
"with",
"antimycin",
"A",
"well",
"before",
"experiencing",
"anaerobiosis",
"these",
"networks",
"subsequently",
"failed",
"to",
"respond",
"to",
"oxygen",
"deprivation.",
"These",
"results",
"suggest",
"the",
"transient",
"stress",
"response",
"is",
"elicited",
"by",
"the",
"acute",
"inhibition",
"of",
"respiration",
"and,",
"we",
"postulate,",
"changes",
"in",
"cellular",
"energetics",
"and/or",
"the",
"instantaneous",
"growth",
"rate,",
"not",
"oxygen",
"deprivation",
"per",
"se.",
"After",
"a",
"considerable",
"delay",
"(≥",
"1",
"generation)",
"under",
"anoxia,",
"predictable",
"changes",
"in",
"heme-regulated",
"gene",
"networks",
"(e.g.,",
"Hap1,",
"Hap2/3/4/5,",
"Mot3,",
"Rox1",
"and",
"Upc2)",
"were",
"observed",
"both",
"in",
"the",
"presence",
"and",
"absence",
"of",
"antimycin",
"A.",
"Conclusion:",
"This",
"study",
"not",
"only",
"differentiates",
"between",
"the",
"gene",
"networks",
"that",
"respond",
"to",
"respiratory",
"inhibition",
"and",
"those",
"that",
"respond",
"to",
"oxygen",
"deprivation",
"but",
"suggests",
"the",
"function",
"of",
"the",
"ESR",
"or",
"CER",
"is",
"to",
"balance",
"energetic",
"supply/demand",
"and",
"coordinate",
"growth",
"with",
"the",
"cell",
"cycle,",
"whether",
"in",
"response",
"to",
"perturbations",
"that",
"disrupt",
"catabolic",
"pathways",
"or",
"those",
"that",
"require",
"rapidly",
"up-regulating",
"energetically",
"costly",
"programs",
"for",
"combating",
"specific",
"stressors.",
"Page",
"1",
"of",
"14",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"CELLULAR",
"AND",
"INFECTION",
"MICROBIOLOGY",
"Shiga",
"toxin",
"2-induced",
"intestinal",
"pathology",
"in",
"infant",
"rabbits",
"is",
"A-subunit",
"dependent",
"and",
"responsive",
"to",
"the",
"tyrosine",
"kinase",
"and",
"potential",
"ZAK",
"inhibitor",
"imatinib",
"Samuel",
"M.",
"Stone",
"1,",
"Cheleste",
"M.",
"Thorpe",
"1,",
"Amrita",
"Ahluwalia",
"1,2,",
"Arlin",
"B.",
"Rogers",
"3,",
"Fumiko",
"Obata",
"4,",
"Aimee",
"Vozenilek",
"4,",
"Glynis",
"L.",
"Kolling",
"5,",
"Anne",
"V.",
"Kane",
"1,6,",
"Bruce",
"E.",
"Magun",
"7",
"and",
"Dakshina",
"M.",
"Jandhyala",
"1*",
"1",
"Division",
"of",
"Geographic",
"Medicine",
"and",
"Infectious",
"Diseases,",
"Tufts",
"Medical",
"Center,",
"and",
"Tufts",
"University",
"School",
"of",
"Medicine,",
"Boston,",
"MA,",
"USA",
"2",
"VA",
"Long",
"Beach",
"Healthcare",
"System,",
"Long",
"Beach,",
"CA,",
"USA",
"3",
"Department",
"of",
"Pathology",
"and",
"Laboratory",
"Medicine,",
"The",
"University",
"of",
"North",
"Carolina",
"School",
"of",
"Medicine,",
"Chapel",
"Hill,",
"NC,",
"USA",
"4",
"Department",
"of",
"Microbiology",
"and",
"Immunology,",
"University",
"of",
"Maryland",
"School",
"of",
"Medicine,",
"Baltimore,",
"MD,",
"USA",
"5",
"Department",
"of",
"Internal",
"Medicine/Nephrology,",
"University",
"of",
"Virginia,",
"Charlottesville,",
"VA,",
"USA",
"6",
"Phoenix",
"Laboratory,",
"Tufts",
"Medical",
"Center,",
"Boston,",
"MA,",
"USA",
"7",
"Department",
"of",
"Cell",
"and",
"Developmental",
"Biology,",
"Oregon",
"Health",
"and",
"Science",
"University,",
"Portland,",
"OR,",
"USA",
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"08",
"November",
"2012",
"doi:",
"10.3389/fcimb.2012.00135",
"Edited",
"by:",
"Alfredo",
"G.",
"Torres,",
"University",
"of",
"Texas",
"Medical",
"Branch,",
"USA",
"Reviewed",
"by:",
"Vernon",
"L.",
"Tesh,",
"Texas",
"A&M",
"University",
"Health",
"Science",
"Center,",
"USA",
"Jennifer",
"Ritchie,",
"University",
"of",
"Surrey,",
"UK",
"*Correspondence:",
"Dakshina",
"M.",
"Jandhyala,",
"Division",
"of",
"Geographic",
"Medicine",
"and",
"Infectious",
"Disease,",
"Tufts",
"Medical",
"Center,",
"Box",
"041,",
"750",
"Washington",
"Street,",
"Boston,",
"MA",
"02111,",
"USA.",
"e-mail:",
"djandhyala@",
"tuftsmedicalcenter.org",
"Shiga",
"toxin",
"producing",
"Escherichia",
"coli",
"(STEC)",
"are",
"a",
"major",
"cause",
"of",
"food-borne",
"illness",
"worldwide.",
"However,",
"a",
"consensus",
"regarding",
"the",
"role",
"Shiga",
"toxins",
"play",
"in",
"the",
"onset",
"of",
"diarrhea",
"and",
"hemorrhagic",
"colitis",
"(HC)",
"is",
"lacking.",
"One",
"of",
"the",
"obstacles",
"to",
"understanding",
"the",
"role",
"of",
"Shiga",
"toxins",
"to",
"STEC-mediated",
"intestinal",
"pathology",
"is",
"a",
"deficit",
"in",
"small",
"animal",
"models",
"that",
"perfectly",
"mimic",
"human",
"disease.",
"Infant",
"rabbits",
"have",
"been",
"previously",
"used",
"to",
"study",
"STEC",
"and/or",
"Shiga",
"toxin-mediated",
"intestinal",
"inflammation",
"and",
"diarrhea.",
"We",
"demonstrate",
"using",
"infant",
"rabbits",
"that",
"Shiga",
"toxin-mediated",
"intestinal",
"damage",
"requires",
"A-subunit",
"activity,",
"and",
"like",
"the",
"human",
"colon,",
"that",
"of",
"the",
"infant",
"rabbit",
"expresses",
"the",
"Shiga",
"toxin",
"receptor",
"Gb3.",
"We",
"also",
"demonstrate",
"that",
"Shiga",
"toxin",
"treatment",
"of",
"the",
"infant",
"rabbit",
"results",
"in",
"apoptosis",
"and",
"activation",
"of",
"p38",
"within",
"colonic",
"tissues.",
"Finally",
"we",
"demonstrate",
"that",
"the",
"infant",
"rabbit",
"model",
"may",
"be",
"used",
"to",
"test",
"candidate",
"therapeutics",
"against",
"Shiga",
"toxin-mediated",
"intestinal",
"damage.",
"While",
"the",
"p38",
"inhibitor",
"SB203580",
"and",
"the",
"ZAK",
"inhibitor",
"DHP-2",
"were",
"ineffective",
"at",
"preventing",
"Shiga",
"toxin-mediated",
"damage",
"to",
"the",
"colon,",
"pretreatment",
"of",
"infant",
"rabbits",
"with",
"the",
"drug",
"imatinib",
"resulted",
"in",
"a",
"decrease",
"of",
"Shiga",
"toxin-mediated",
"heterophil",
"infiltration",
"of",
"the",
"colon.",
"Therefore,",
"we",
"propose",
"that",
"this",
"model",
"may",
"be",
"useful",
"in",
"elucidating",
"mechanisms",
"by",
"which",
"Shiga",
"toxins",
"could",
"contribute",
"to",
"intestinal",
"damage",
"in",
"the",
"human.",
"Keywords:",
"Shiga",
"toxin,",
"globotriaosylceramide,",
"inflammation,",
"colon,",
"rabbit,",
"p38,",
"imatinib",
"INTRODUCTION",
"Shiga",
"toxin-producing",
"Escherichia",
"coli",
"(STEC)",
"are",
"a",
"heterogenous",
"group",
"of",
"E.",
"coli",
"strains",
"responsible",
"for",
"food-",
"and",
"water-borne",
"ill-",
"ness",
"worldwide.",
"Depending",
"on",
"the",
"strain,",
"approximately",
"5–22%",
"of",
"infected",
"individuals",
"will",
"suffer",
"severe",
"illnesses",
"that",
"can",
"result",
"in",
"permanent",
"disability",
"or",
"death",
"(Paton",
"et",
"al.,",
"1998;",
"Kulasekara",
"et",
"al.,",
"2009;",
"Frank",
"et",
"al.,",
"2011).",
"Severe",
"illnesses",
"attributed",
"to",
"STEC-associated",
"sequelae",
"include",
"hemorrhagic",
"colitis",
"(HC)",
"and",
"the",
"hemolytic",
"uremic",
"syndrome",
"(HUS),",
"the",
"predominant",
"cause",
"of",
"renal",
"failure",
"in",
"US",
"children",
"(Siegler,",
"2003).",
"Other",
"than",
"vol-",
"ume",
"expansion",
"during",
"the",
"diarrheal",
"phase,",
"no",
"approved",
"specific",
"preventative",
"treatments",
"exist",
"for",
"STEC-associated",
"HUS.",
"Shiga",
"toxins",
"(Stxs)",
"are",
"the",
"key",
"virulence",
"factors",
"responsi-",
"ble",
"for",
"promoting",
"severe",
"disease",
"during",
"STEC",
"infection.",
"Stxs",
"are",
"AB5",
"toxins",
"consisting",
"of",
"a",
"single",
"A-subunit",
"non-covalently",
"bound",
"to",
"5",
"B-subunits.",
"The",
"B-subunits",
"are",
"necessary",
"for",
"bind-",
"ing",
"of",
"the",
"toxin",
"to",
"the",
"surface",
"of",
"the",
"host",
"cells",
"via",
"interac-",
"tion",
"with",
"neutral",
"glycolipids",
"with",
"the",
"glycosphingolipid",
"receptor",
"globotriaosylceramide",
"(Gb3)",
"being",
"the",
"major",
"receptor",
"(Lingwood",
"et",
"al.,",
"2010).",
"Once",
"bound,",
"the",
"toxin",
"undergoes",
"receptor-mediated",
"endocytosis",
"and",
"is",
"transported",
"retrograde",
"through",
"the",
"early",
"endosome,",
"the",
"Golgi",
"apparatus,",
"and",
"to",
"the",
"endoplasmic",
"retic-",
"ulum",
"(ER).",
"Somewhere",
"between",
"the",
"early",
"endosome",
"and",
"the",
"trans-Golgi",
"network,",
"the",
"enzymatically",
"active",
"portion",
"of",
"the",
"A-subunit",
"is",
"proteolytically",
"cleaved",
"possibly",
"by",
"furin",
"into",
"an",
"A1",
"fragment",
"which",
"remains",
"bound",
"to",
"the",
"A2",
"fragment",
"and",
"non-covalently",
"associated",
"B-subunits",
"via",
"an",
"intramolecular",
"disul-",
"fide",
"bond",
"(Garred",
"et",
"al.,",
"1995a,b;",
"Tam",
"and",
"Lingwood,",
"2007).",
"Eventually",
"the",
"disulfide",
"bond",
"is",
"reduced,",
"possibly",
"in",
"the",
"ER",
"(Spooner",
"and",
"Lord,",
"2012),",
"and",
"the",
"enzymatically",
"active",
"A1",
"frag-",
"ment",
"is",
"translocated",
"to",
"the",
"cytoplasm,",
"where",
"its",
"N-glycosidase",
"activity",
"results",
"in",
"the",
"depurination",
"of",
"a",
"single",
"adenine",
"residue",
"located",
"in",
"the",
"alpha-sarcin/ricin",
"loop",
"of",
"the",
"28S",
"ribosomal",
"RNA",
"(Endo",
"and",
"Tsurugi,",
"1987;",
"Endo",
"et",
"al.,",
"1987,",
"1988).",
"This",
"depuri-",
"nation",
"event",
"results",
"in",
"the",
"cessation",
"of",
"protein",
"synthesis",
"in",
"the",
"translational",
"elongation",
"phase",
"and",
"activates",
"a",
"proinflammatory",
"signaling",
"cascade",
"referred",
"to",
"as",
"the",
"ribotoxic",
"stress",
"response",
"(RSR)",
"(Iordanov",
"et",
"al.,",
"1997).",
"The",
"RSR",
"is",
"defined",
"as",
"the",
"activation",
"of",
"MAPKinases",
"by",
"cer-",
"tain",
"protein",
"synthesis",
"inhibitors",
"including",
"Shiga",
"toxins,",
"ricin,",
"Frontiers",
"in",
"Cellular",
"and",
"Infection",
"Microbiology",
"www.frontiersin.org",
"November",
"2012",
"|",
"Volume",
"2",
"|",
"Article",
"135",
"|",
"1"
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] | [
"Bousios",
"et",
"al.",
"BMC",
"Genomics",
"2010,",
"11:89",
"http://www.biomedcentral.com/1471-2164/11/89",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Highly",
"conserved",
"motifs",
"in",
"non-coding",
"regions",
"of",
"Sirevirus",
"retrotransposons:",
"the",
"key",
"for",
"their",
"pattern",
"of",
"distribution",
"within",
"and",
"across",
"plants?",
"Alexandros",
"Bousios1*,",
"Nikos",
"Darzentas2,",
"Athanasios",
"Tsaftaris2,3,",
"Stephen",
"R",
"Pearce1",
"Abstract",
"Background:",
"Retrotransposons",
"are",
"key",
"players",
"in",
"the",
"evolution",
"of",
"eukaryotic",
"genomes.",
"Moreover,",
"it",
"is",
"now",
"known",
"that",
"some",
"retrotransposon",
"classes,",
"like",
"the",
"abundant",
"and",
"plant-specific",
"Sireviruses,",
"have",
"intriguingly",
"distinctive",
"host",
"preferences.",
"Yet,",
"it",
"is",
"largely",
"unknown",
"if",
"this",
"bias",
"is",
"supported",
"by",
"different",
"genome",
"structures.",
"Results:",
"We",
"performed",
"sensitive",
"comparative",
"analysis",
"of",
"the",
"genomes",
"of",
"a",
"large",
"set",
"of",
"Ty1/copia",
"retrotransposons.",
"We",
"discovered",
"that",
"Sireviruses",
"are",
"unique",
"among",
"Pseudoviridae",
"in",
"that",
"they",
"constitute",
"an",
"ancient",
"genus",
"characterized",
"by",
"vastly",
"divergent",
"members,",
"which",
"however",
"contain",
"highly",
"conserved",
"motifs",
"in",
"key",
"non-coding",
"regions:",
"multiple",
"polypurine",
"tract",
"(PPT)",
"copies",
"cluster",
"upstream",
"of",
"the",
"3’",
"long",
"terminal",
"repeat",
"(3’LTR),",
"of",
"which",
"the",
"terminal",
"PPT",
"tethers",
"to",
"a",
"distinctive",
"attachment",
"site",
"and",
"is",
"flanked",
"by",
"a",
"precisely",
"positioned",
"inverted",
"repeat.",
"Their",
"LTRs",
"possess",
"a",
"novel",
"type",
"of",
"repeated",
"motif",
"(RM)",
"defined",
"by",
"its",
"exceptionally",
"high",
"copy",
"number,",
"symmetry",
"and",
"core",
"CGG-CCG",
"signature.",
"These",
"RM",
"boxes",
"form",
"CpG",
"islands",
"and",
"lie",
"a",
"short",
"distance",
"upstream",
"of",
"a",
"conserved",
"promoter",
"region",
"thus",
"hinting",
"towards",
"regulatory",
"functions.",
"Intriguingly,",
"in",
"the",
"envelope-containing",
"Sireviruses",
"additional",
"boxes",
"cluster",
"at",
"the",
"5’",
"vicinity",
"of",
"the",
"envelope.",
"The",
"5’LTR/internal",
"domain",
"junction",
"and",
"a",
"polyC-rich",
"integrase",
"signal",
"are",
"also",
"highly",
"conserved",
"domains",
"of",
"the",
"Sirevirus",
"genome.",
"Conclusions:",
"Our",
"comparative",
"analysis",
"of",
"retrotransposon",
"genomes",
"using",
"advanced",
"in",
"silico",
"methods",
"highlighted",
"the",
"unique",
"genome",
"organization",
"of",
"Sireviruses.",
"Their",
"structure",
"may",
"dictate",
"a",
"life",
"cycle",
"with",
"different",
"regulation",
"and",
"transmission",
"strategy",
"compared",
"to",
"other",
"Pseudoviridae,",
"which",
"may",
"contribute",
"towards",
"their",
"pattern",
"of",
"distribution",
"within",
"and",
"across",
"plants.",
"Background",
"Retrotransposons",
"and",
"retroviruses",
"(collectively",
"referred",
"as",
"retroelements)",
"can",
"replicate",
"their",
"genomes",
"via",
"an",
"RNA",
"intermediate",
"and",
"insert",
"the",
"copies",
"into",
"new",
"chro-",
"mosomal",
"locations",
"of",
"the",
"host",
"organism",
"[1,2].",
"This",
"‘copy",
"and",
"paste’",
"process",
"has",
"the",
"potential",
"to",
"greatly",
"amplify",
"their",
"abundance,",
"even",
"over",
"short",
"evolutionary",
"timescales,",
"enabling",
"them",
"to",
"become",
"a",
"major",
"compo-",
"nent",
"of",
"genomes",
"[3-5].",
"Unlike",
"retrotransposons,",
"retro-",
"viruses",
"have",
"additional",
"coding",
"capacity",
"in",
"the",
"form",
"of",
"an",
"envelope",
"(ENV)",
"gene",
"that",
"allows",
"them",
"to",
"enter",
"the",
"extracellular",
"space",
"and",
"infect",
"other",
"individuals.",
"Retro-",
"transposons",
"lack",
"the",
"ENV",
"gene",
"and",
"cannot",
"escape",
"the",
"cell,",
"however",
"they",
"are",
"free",
"to",
"reinfect",
"their",
"host",
"genome.",
"*",
"Correspondence:",
"alexandros.bousios@gmail.com",
"1Department",
"of",
"Biology",
"and",
"Environmental",
"Science,",
"School",
"of",
"Life",
"Sciences,",
"University",
"of",
"Sussex,",
"Brighton,",
"UK",
"Long",
"Terminal",
"Repeat",
"(LTR)",
"retrotransposons",
"form",
"the",
"most",
"abundant",
"transposable",
"element",
"type",
"in",
"plants,",
"lar-",
"gely",
"accounting",
"for",
"the",
"vast",
"differences",
"in",
"genome",
"sizes",
"[6].",
"Small",
"genome",
"plants",
"like",
"Arabidopsis",
"(121",
"Mbp)",
"and",
"rice",
"(389",
"Mbp)",
"are",
"sparsely",
"populated",
"by",
"LTR",
"ret-",
"rotransposons,",
"5.6%",
"[7]",
"and",
"17%",
"[8]",
"respectively.",
"In",
"con-",
"trast,",
"the",
"LTR",
"retrotransposon-derived",
"fraction",
"of",
"medium/large",
"genomes",
"may",
"reach",
"up",
"to",
"75%",
"in",
"maize",
"(2.300",
"Mbp)",
"[9,10]",
"and",
"70%",
"in",
"barley",
"(5439",
"Mbp)",
"[11].",
"The",
"two",
"main",
"superfamilies",
"of",
"LTR",
"retrotransposons",
"are",
"the",
"Ty1/copia",
"(Pseudoviridae)",
"and",
"Ty3/gypsy",
"(Meta-",
"viridae)",
"[12],",
"which",
"differ",
"in",
"the",
"order",
"they",
"package",
"their",
"genes",
"in",
"the",
"coding",
"domains.",
"Both",
"typically",
"con-",
"tain",
"the",
"gag",
"gene",
"and",
"the",
"pol",
"gene",
"region.",
"gag",
"encodes",
"a",
"capsid",
"protein",
"that",
"forms",
"the",
"virus-like",
"particle",
"(VLP),",
"which",
"houses",
"one",
"or",
"two",
"RNA",
"genomes",
"and",
"the",
"enzymes",
"for",
"the",
"cytoplasmic",
"step",
"of",
"reverse",
"©",
"2010",
"Bousios",
"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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] | [
"Gue´",
"ret1,2*",
"Abstract",
"Bloom’s",
"Syndrome",
"and",
"PICH",
"Helicases",
"Cooperate",
"with",
"Topoisomerase",
"IIa",
"in",
"Centromere",
"Disjunction",
"before",
"Anaphase",
"Se´",
"bastien",
"Rouzeau1,2,",
"Fabrice",
"P.",
"Cordelie`",
"res1,2,3,",
"Ge´",
"raldine",
"Buhagiar-Labarche`",
"de1,2,",
"Ilse",
"Hurbain4,5,6,",
"Rosine",
"Onclercq-Delic1,2,",
"Simon",
"Gemble1,2,",
"Laura",
"Magnaghi-Jaulin7,",
"Christian",
"Jaulin7,",
"Mounira",
"Amor-",
"1",
"Institut",
"Curie,",
"Centre",
"de",
"Recherche,",
"Centre",
"Universitaire,",
"Baˆt",
"Orsay,",
"France,",
"2",
"CNRS",
"UMR3348,",
"Stress",
"Ge´notoxiques",
"et",
"Cancer,",
"Orsay,",
"France,",
"3",
"Institut",
"Curie,",
"Centre",
"de",
"Recherche,",
"Plateforme",
"d’Imagerie",
"Cellulaire",
"et",
"Tissulaire",
"IBiSA,",
"Centre",
"Universitaire,",
"Baˆt",
"Orsay,",
"France,",
"4",
"Institut",
"Curie,",
"Centre",
"de",
"Recherche,",
"Paris,",
"France,",
"5",
"Structure",
"et",
"Compartimentation",
"membranaire,",
"CNRS",
"UMR144,",
"Paris,",
"France,",
"6",
"Plateforme",
"d’Imagerie",
"Cellulaire",
"et",
"Tissulaire",
"IBiSA,",
"CNRS",
"UMR",
"144,",
"Paris,",
"France,",
"7",
"Institut",
"de",
"Ge´ne´tique",
"et",
"De´veloppement,",
"CNRS",
"UMR",
"6290,",
"Universite´",
"de",
"Rennes",
"1,",
"Rennes,",
"France",
"Centromeres",
"are",
"specialized",
"chromosome",
"domains",
"that",
"control",
"chromosome",
"segregation",
"during",
"mitosis,",
"but",
"little",
"is",
"known",
"about",
"the",
"mechanisms",
"underlying",
"the",
"maintenance",
"of",
"their",
"integrity.",
"Centromeric",
"ultrafine",
"anaphase",
"bridges",
"are",
"physiological",
"DNA",
"structures",
"thought",
"to",
"contain",
"unresolved",
"DNA",
"catenations",
"between",
"the",
"centromeres",
"separating",
"during",
"anaphase.",
"BLM",
"and",
"PICH",
"helicases",
"colocalize",
"at",
"these",
"ultrafine",
"anaphase",
"bridges",
"and",
"promote",
"their",
"resolution.",
"As",
"PICH",
"is",
"detectable",
"at",
"centromeres",
"from",
"prometaphase",
"onwards,",
"we",
"hypothesized",
"that",
"BLM",
"might",
"also",
"be",
"located",
"at",
"centromeres",
"and",
"that",
"the",
"two",
"proteins",
"might",
"cooperate",
"to",
"resolve",
"DNA",
"catenations",
"before",
"the",
"onset",
"of",
"anaphase.",
"Using",
"immunofluorescence",
"analyses,",
"we",
"demonstrated",
"the",
"recruitment",
"of",
"BLM",
"to",
"centromeres",
"from",
"G2",
"phase",
"to",
"mitosis.",
"With",
"a",
"combination",
"of",
"fluorescence",
"in",
"situ",
"hybridization,",
"electron",
"microscopy,",
"RNA",
"interference,",
"chromosome",
"spreads",
"and",
"chromatin",
"immunoprecipitation,",
"we",
"showed",
"that",
"both",
"BLM-deficient",
"and",
"PICH-deficient",
"prometaphase",
"cells",
"displayed",
"changes",
"in",
"centromere",
"structure.",
"These",
"cells",
"also",
"had",
"a",
"higher",
"frequency",
"of",
"centromeric",
"non",
"disjunction",
"in",
"the",
"absence",
"of",
"cohesin,",
"suggesting",
"the",
"persistence",
"of",
"catenations.",
"Both",
"proteins",
"were",
"required",
"for",
"the",
"correct",
"recruitment",
"to",
"the",
"centromere",
"of",
"active",
"topoisomerase",
"IIa,",
"an",
"enzyme",
"specialized",
"in",
"the",
"catenation/decatenation",
"process.",
"These",
"observations",
"reveal",
"the",
"existence",
"of",
"a",
"functional",
"relationship",
"between",
"BLM,",
"PICH",
"and",
"topoisomerase",
"IIa",
"in",
"the",
"centromere",
"decatenation",
"process.",
"They",
"indicate",
"that",
"the",
"higher",
"frequency",
"of",
"centromeric",
"ultrafine",
"anaphase",
"bridges",
"in",
"BLM-deficient",
"cells",
"and",
"in",
"cells",
"treated",
"with",
"topoisomerase",
"IIa",
"inhibitors",
"is",
"probably",
"due",
"not",
"only",
"to",
"unresolved",
"physiological",
"ultrafine",
"anaphase",
"bridges,",
"but",
"also",
"to",
"newly",
"formed",
"ultrafine",
"anaphase",
"bridges.",
"We",
"suggest",
"that",
"BLM",
"and",
"PICH",
"cooperate",
"in",
"rendering",
"centromeric",
"catenates",
"accessible",
"to",
"topoisomerase",
"IIa,",
"thereby",
"facilitating",
"correct",
"centromere",
"disjunction",
"and",
"preventing",
"the",
"formation",
"of",
"supernumerary",
"centromeric",
"ultrafine",
"anaphase",
"bridges.",
"Citation:",
"Rouzeau",
"S,",
"Cordelie`res",
"FP,",
"Buhagiar-Labarche`de",
"G,",
"Hurbain",
"I,",
"Onclercq-Delic",
"R,",
"et",
"al.",
"(2012)",
"Bloom’s",
"Syndrome",
"and",
"PICH",
"Helicases",
"Cooperate",
"with",
"Topoisomerase",
"IIa",
"in",
"Centromere",
"Disjunction",
"before",
"Anaphase.",
"PLoS",
"ONE",
"7(4):",
"e33905.",
"doi:10.1371/journal.pone.0033905",
"Editor:",
"Beth",
"A.",
"Sullivan,",
"Duke",
"University,",
"United",
"States",
"of",
"America",
"Received",
"November",
"4,",
"2011;",
"Accepted",
"February",
"19,",
"2012;",
"Published",
"April",
"26,",
"2012",
"Copyright:",
"2012",
"Rouzeau",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"grants",
"from",
"the",
"Institut",
"Curie",
"(PIC),",
"the",
"Centre",
"National",
"de",
"la",
"Recherche",
"Scientifique",
"(CNRS),",
"the",
"Cance´ropoˆ",
"le/Re´gion",
"Ile-",
"de-France,",
"the",
"Ligue",
"contre",
"le",
"Cancer",
"Grand-Ouest,",
"the",
"Association",
"pour",
"la",
"Recherche",
"sur",
"le",
"Cancer",
"(1071),",
"the",
"Agence",
"Nationale",
"de",
"la",
"Recherche",
"(EpiCentr)",
"and",
"by",
"fellowships",
"from",
"the",
"Ministe`re",
"de´le´gue´",
"de",
"l’Enseignement",
"Supe´rieur",
"et",
"de",
"la",
"Recherche",
"and",
"from",
"the",
"Ligue",
"Nationale",
"contre",
"le",
"Cancer.",
"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:",
"mounira.amor@curie.fr",
"Introduction",
"The",
"centromere",
"is",
"a",
"highly",
"differentiated",
"chromosomal",
"structure",
"consisting,",
"in",
"human",
"cells,",
"of",
"a-satellite",
"DNA",
"repeats",
"[1].",
"It",
"plays",
"an",
"essential",
"role",
"in",
"cell",
"division,",
"particularly",
"in",
"kinetochore",
"assembly,",
"and",
"in",
"ensuring",
"the",
"segregation",
"of",
"equal",
"number",
"of",
"chromosomes",
"to",
"daughter",
"cells",
"during",
"mitosis",
"[2].",
"The",
"maintenance",
"of",
"centromere",
"stability",
"is",
"thus",
"essential",
"to",
"prevent",
"chromosomal",
"instability",
"and",
"cancer",
"development",
"[3].",
"Our",
"interest",
"in",
"centromere",
"stability",
"began",
"with",
"the",
"unexpected",
"discovery",
"that",
"a",
"helicase-like",
"protein,",
"PICH",
"(Plk1-interacting",
"checkpoint",
"‘‘heli-",
"case’’)",
"and",
"the",
"Bloom",
"syndrome",
"helicase",
"(BLM)",
"colocalized",
"to",
"centromeric",
"ultrathin",
"DNA",
"threads",
"that",
"could",
"not",
"be",
"counter-",
"stained",
"with",
"conventional",
"DNA",
"dyes",
"or",
"antibodies",
"against",
"histones",
"[4,5].",
"These",
"threads",
"were",
"found",
"to",
"be",
"common",
"in",
"all",
"cultured",
"normal",
"cells",
"tested,",
"and",
"are",
"therefore",
"probably",
"physiological",
"structures.",
"These",
"PICH-",
"and",
"BLM-positive",
"DNA",
"threads,",
"which",
"are",
"also",
"called",
"ultrafine",
"anaphase",
"bridges",
"(UFBs),",
"are",
"thought",
"to",
"contain",
"unresolved",
"DNA",
"catenations",
"between",
"the",
"centromeres",
"separating",
"during",
"anaphase",
"or",
"to",
"originate",
"from",
"incompletely",
"replicated",
"DNA",
"[4,5].",
"Almost",
"all",
"the",
"UFBs",
"detected",
"in",
"untreated",
"cells",
"are",
"of",
"centromeric",
"origin",
"and",
"have",
"been",
"proposed",
"to",
"prevent",
"reactivation",
"of",
"the",
"spindle",
"assembly",
"checkpoint",
"(SAC)",
"during",
"early",
"anaphase,",
"by",
"maintaining",
"tension",
"across",
"centromeres",
"[4,6].",
"As",
"cells",
"progress",
"through",
"anaphase,",
"UFBs",
"become",
"progressively",
"longer",
"and",
"decrease",
"in",
"number.",
"They",
"are",
"no",
"longer",
"detectable",
"by",
"telophase.",
"The",
"resolution",
"of",
"centromeric",
"UFBs",
"requires",
"topo-",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"April",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"4",
"|",
"e33905"
] | [
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] | [
"Published",
"online",
"11",
"May",
"2010",
"Nucleic",
"Acids",
"Research,",
"2010,",
"Vol.",
"38,",
"Web",
"Server",
"issue",
"W155–W160",
"doi:10.1093/nar/gkq331",
"The",
"Ontology",
"Lookup",
"Service:",
"bigger",
"and",
"better",
"Richard",
"C",
"oˆte´",
"1,*,",
"Florian",
"Reisinger1,",
"Lennart",
"Martens2,3,",
"Harald",
"Barsnes4,",
"Juan",
"Antonio",
"Vizcaino1",
"and",
"Henning",
"Hermjakob1",
"1European",
"Bioinformatics",
"Institute,",
"Wellcome",
"Trust",
"Genome",
"Campus,",
"Cambridge,",
"CB10",
"1SD,",
"UK,",
"2Department",
"of",
"Medical",
"Protein",
"Research,",
"VIB,",
"Ghent,",
"Belgium,",
"3Department",
"of",
"Biochemistry,",
"Ghent",
"University,",
"Ghent,",
"Belgium",
"and",
"4Department",
"of",
"Informatics,",
"University",
"of",
"Bergen,",
"Norway",
"Received",
"January",
"29,",
"2010;",
"Revised",
"April",
"4,",
"2010;",
"Accepted",
"April",
"17,",
"2010",
"ABSTRACT",
"The",
"Ontology",
"Lookup",
"Service",
"(OLS;",
"http://www.ebi",
".ac.uk/ols)",
"has",
"been",
"providing",
"several",
"means",
"to",
"query,",
"browse",
"and",
"navigate",
"biomedical",
"ontologies",
"and",
"controlled",
"vocabularies",
"since",
"it",
"first",
"went",
"into",
"production",
"4",
"years",
"ago,",
"and",
"usage",
"statistics",
"indicate",
"that",
"it",
"has",
"become",
"a",
"heavily",
"accessed",
"service",
"with",
"millions",
"of",
"hits",
"monthly.",
"The",
"volume",
"of",
"data",
"available",
"for",
"querying",
"has",
"increased",
"7-fold",
"since",
"its",
"inception.",
"OLS",
"functionality",
"has",
"been",
"integrated",
"into",
"several",
"high-usage",
"databases",
"and",
"data",
"entry",
"tools.",
"Improvements",
"in",
"the",
"data",
"model",
"and",
"loaders,",
"as",
"well",
"as",
"interface",
"enhancements",
"have",
"made",
"the",
"OLS",
"easier",
"to",
"use",
"and",
"capture",
"more",
"annotations",
"from",
"the",
"source",
"data.",
"In",
"addition,",
"newly",
"released",
"software",
"packages",
"now",
"provide",
"easy",
"means",
"to",
"fully",
"integrate",
"OLS",
"function-",
"ality",
"in",
"external",
"applications.",
"INTRODUCTION",
"Ontologies",
"and",
"controlled",
"vocabularies",
"(CVs)",
"have",
"more",
"than",
"demonstrated",
"their",
"essential",
"function",
"when",
"dealing",
"with",
"large",
"volumes",
"of",
"complex",
"data",
"currently",
"being",
"generated",
"by",
"high-throughput",
"multi-domain",
"analysis",
"tech-",
"niques",
"(1).",
"They",
"provide",
"a",
"framework",
"around",
"which",
"large",
"data",
"sets",
"can",
"be",
"systematically",
"annotated",
"and",
"queried.",
"For",
"this",
"framework",
"to",
"function",
"efficiently,",
"however,",
"the",
"ontologies",
"and",
"CVs",
"must",
"be",
"made",
"available",
"to",
"the",
"user",
"community.",
"The",
"Ontology",
"Lookup",
"Service",
"(OLS)",
"has",
"been",
"in",
"pro-",
"duction",
"since",
"mid-2005",
"and",
"has",
"quickly",
"become",
"one",
"of",
"the",
"most",
"accessed",
"services",
"in",
"the",
"Proteomics",
"Services",
"team",
"at",
"the",
"EBI,",
"with",
"monthly",
"usage",
"figures",
"in",
"the",
"millions",
"of",
"hits.",
"This",
"includes",
"both",
"the",
"programmatic",
"as",
"well",
"as",
"the",
"inter-",
"active",
"interfaces",
"that",
"the",
"service",
"offers.",
"The",
"OLS",
"has",
"been",
"previously",
"described",
"and",
"readers",
"are",
"invited",
"to",
"refer",
"to",
"the",
"original",
"publication",
"for",
"in-depth",
"information",
"on",
"the",
"tech-",
"nical",
"architecture",
"and",
"data",
"models",
"(2,3).",
"The",
"core",
"functionality",
"of",
"the",
"OLS",
"has",
"remained",
"largely",
"unchanged",
"since",
"its",
"inception,",
"allowing",
"users",
"to",
"query",
"ontologies",
"and",
"CVs",
"by",
"name",
"or",
"identifier",
"as",
"well",
"as",
"ob-",
"taining",
"metadata,",
"such",
"as",
"synonyms,",
"definitions,",
"cross",
"ref-",
"erences",
"and",
"other",
"annotations,",
"for",
"a",
"given",
"term.",
"Users",
"can",
"also",
"traverse",
"the",
"relationships",
"between",
"terms.",
"The",
"usabil-",
"ity",
"and",
"volume",
"of",
"data",
"captured,",
"however,",
"has",
"been",
"enhanced",
"and",
"this",
"will",
"be",
"expanded",
"below.",
"The",
"OLS",
"has",
"always",
"been",
"designed",
"to",
"be",
"used",
"in",
"other",
"projects",
"as",
"a",
"means",
"to",
"integrate",
"ontology",
"and",
"CV",
"anno-",
"tation",
"and",
"query",
"functionality.",
"A",
"SOAP",
"web",
"service",
"has",
"been",
"available",
"since",
"the",
"OLS",
"went",
"into",
"production.",
"A",
"full",
"description",
"of",
"the",
"web",
"service",
"has",
"already",
"been",
"published",
"(2,3)",
"and",
"users",
"who",
"wish",
"to",
"make",
"use",
"of",
"it",
"are",
"encouraged",
"to",
"go",
"to",
"the",
"OLS",
"web",
"service",
"developer",
"section",
"for",
"the",
"most",
"up-to-date",
"documentation",
"and",
"code",
"samples",
"(http://www.ebi.ac.uk/ontology-lookup/WSDLDocument",
"ation.do).",
"AVAILABLE",
"DATA",
"The",
"first",
"OLS",
"publication",
"described",
"it",
"as",
"containing",
"42",
"ontologies,",
"accounting",
"for",
"roughly",
"135",
"000",
"terms.",
"Over",
"a",
"4-year",
"period,",
"the",
"data",
"loaded",
"into",
"the",
"OLS",
"has",
"been",
"expanded",
"to",
"79",
"ontologies,",
"representing",
"over",
"971",
"000",
"unique",
"terms",
"(Figure",
"1).",
"These",
"cover",
"far-ranging",
"topics",
"such",
"as",
"model",
"organism",
"anatomy",
"and",
"development,",
"physi-",
"ology",
"and",
"disease,",
"instrumentation",
"and",
"methods",
"and",
"many",
"others.",
"In",
"the",
"2",
"years",
"since",
"the",
"OLS",
"was",
"previously",
"published",
"in",
"NAR,",
"25",
"new",
"ontologies",
"have",
"been",
"added",
"(Table",
"1).",
"Users",
"are",
"encouraged",
"to",
"go",
"online",
"at",
"http://www.ebi.ac.uk/ontology-lookup/ontologyList.do",
"to",
"access",
"a",
"full",
"listing",
"of",
"currently",
"available",
"ontologies",
"and",
"CVs.",
"The",
"ontologies",
"and",
"CVs",
"loaded",
"in",
"the",
"OLS",
"are",
"main-",
"tained",
"by",
"various",
"external",
"groups",
"that",
"are",
"domain",
"experts",
"in",
"their",
"fields.",
"To",
"maintain",
"the",
"OLS",
"as",
"up-to-date",
"as",
"possible",
"with",
"the",
"current",
"state",
"of",
"knowledge,",
"the",
"ontology",
"providers",
"are",
"polled",
"on",
"a",
"daily",
"basis",
"and",
"updated",
"files",
"are",
"downloaded",
"and",
"parsed",
"to",
"update",
"the",
"core",
"OLS",
"database.",
"Currently,",
"the",
"OLS",
"loaders",
"poll",
"six",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+44",
"1223",
"492",
"610;",
"Fax:",
"+44",
"1223",
"494",
"468;",
"Email:",
"rcote@ebi.ac.uk",
"The",
"Author(s)",
"2010.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.5),",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"The",
"Korean",
"Journal",
"of",
"Internal",
"Medicine",
":",
"22:215-219,",
"2007",
"Mycobacterium",
"Avium",
"Complex",
"Infection",
"Presenting",
"as",
"an",
"Endobronchial",
"Mass",
"in",
"a",
"Patient",
"with",
"Acquired",
"Immune",
"Deficiency",
"Syndrome",
"Ho",
"Cheol",
"Kim,",
"M.D.,",
"In-Gyu",
"Bae,",
"M.D.,",
"Jeong",
"Eun",
"Ma,",
"M.D.,",
"Jong",
"Shil",
"Lee,",
"M.D.2,",
"Kyoung-Nyeo",
"Jeon,",
"M.D.3,",
"Jong",
"Deok",
"Lee,",
"M.D.",
"and",
"Young",
"Sil",
"Hwang,",
"M.D.",
"Departments",
"of",
"Internal",
"Medicine,",
"Pathology2",
"and",
"Diagnostic",
"Radiology3,",
"College",
"of",
"Medicine,",
"Gyeongsang",
"National",
"University,",
"Jinju,",
"Korea",
"Mycobacterium",
"avium",
"complex",
"(MAC)",
"infection",
"is",
"a",
"common",
"opportunistic",
"infection",
"in",
"patients",
"with",
"AIDS",
"(acquired",
"immune",
"deficiency",
"syndrome).",
"Pulmonary",
"involvement",
"of",
"MAC",
"may",
"range",
"from",
"asymptomatic",
"colonization",
"of",
"the",
"respiratory",
"tract",
"to",
"invasive",
"parenchymal",
"or",
"cavitary",
"disease.",
"However,",
"endobronchial",
"lesions",
"with",
"MAC",
"infection",
"are",
"rare",
"in",
"immunocompetent",
"and",
"immunosuppressed",
"hosts.",
"Here,",
"we",
"report",
"MAC",
"infection",
"presenting",
"as",
"an",
"endobronchial",
"mass",
"in",
"a",
"patient",
"with",
"AIDS.",
"Key",
"Words",
":",
"Mycobacterium",
"avium",
"complex,",
"Endobronchial",
"mass,",
"AIDS",
"INTRODUCTION",
"Mycobacterium",
"avium",
"complex",
"(MAC)",
"is",
"well-known",
"as",
"a",
"common",
"opportunistic",
"organism",
"in",
"patients",
"infected",
"with",
"the",
"human",
"immunodeficiency",
"virus",
"(HIV)1).",
"MAC",
"also",
"acts",
"as",
"a",
"pulmonary",
"pathogen",
"in",
"immunocompetent",
"patients",
"with",
"underlying",
"structural",
"lung",
"diseases",
"such",
"as",
"chronic",
"obstructive",
"pulmonary",
"disease",
"(COPD)",
"and",
"bronchiectasis,",
"as",
"well",
"as",
"in",
"destructive",
"lung",
"lesions",
"like",
"those",
"observed",
"previously",
"in",
"diagnosed",
"tuberculosis2).",
"Pulmonary",
"involvement",
"of",
"MAC",
"may",
"range",
"from",
"airway",
"colonization",
"to",
"invasive",
"parenchymal",
"disease.",
"Pulmonary",
"parenchymal",
"disease",
"with",
"MAC",
"occurs",
"rarely",
"in",
"patients",
"with",
"HIV",
"in",
"the",
"absence",
"of",
"dissemination3).",
"Endobronchial",
"involvement",
"due",
"to",
"M.",
"tuberculosis",
"is",
"a",
"well-",
"described",
"and",
"a",
"relatively",
"common",
"manifestation",
"of",
"tuberculosis",
"in",
"the",
"Republic",
"of",
"Korea4).",
"However,",
"endobronchial",
"lesions",
"involved",
"in",
"MAC",
"infection",
"are",
"rarely",
"found",
"in",
"immunocompetent",
"and",
"immunosuppressed",
"hosts5,",
"6).",
"There",
"have",
"been",
"few",
"reports",
"of",
"an",
"endobronchial",
"presentation",
"of",
"MAC",
"infection",
"in",
"patients",
"with",
"acquired",
"immune",
"deficiency",
"syndrome",
"(AIDS)6-11).",
"Here,",
"we",
"report",
"an",
"MAC",
"infection",
"presenting",
"as",
"an",
"endobronchial",
"mass",
"in",
"a",
"patient",
"with",
"AIDS",
"receiving",
"anti-retroviral",
"chemotherapy.",
"CASE",
"REPORT",
"A",
"40-year-old",
"male",
"was",
"admitted",
"to",
"the",
"hospital",
"because",
"of",
"cough",
"with",
"sputum",
"lasting",
"for",
"seven",
"days.",
"He",
"was",
"known",
"to",
"be",
"HIV-positive",
"from",
"a",
"diagnosis",
"made",
"eight",
"months",
"previously.",
"Five",
"months",
"prior",
"to",
"admission,",
"he",
"was",
"diagnosed",
"with",
"Pneumo-",
"cystis",
"carinii",
"(P.",
"carinii)",
"pneumonia",
"(PCP),",
"cytomegalovirus",
"(CMV)",
"pneumonia,",
"and",
"herpes",
"zoster",
"infection",
"on",
"the",
"skin.",
"He",
"was",
"then",
"started",
"on",
"lamivudine,",
"zidovudine,",
"and",
"indinavir",
"as",
"anti-retroviral",
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":",
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"7,",
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"Gyeongsang",
"National",
"University.",
"92",
"Chilam-dong,",
"Jinju",
"660-751,",
"Korea",
"Tel",
":",
"82-55-750-8684,",
"Fax",
":",
"82-55-758-9122,",
"E-mail",
":",
"hochkim@gshp.gsnu.ac.kr"
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] | [
"Malaria",
"Journal",
"Research",
"Analysis",
"of",
"von",
"Willebrand",
"factor",
"A",
"domain-related",
"protein",
"(WARP)",
"polymorphism",
"in",
"temperate",
"and",
"tropical",
"Plasmodium",
"vivax",
"field",
"isolates",
"Saber",
"Gholizadeh1,2,",
"Navid",
"Dinparast",
"Djadid*1,",
"Hamid",
"Reza",
"Basseri2,",
"Sedigheh",
"Zakeri1",
"and",
"Hossein",
"Ladoni2",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Malaria",
"and",
"Vector",
"Research",
"Group",
"(MVRG),",
"Biotechnology",
"Research",
"Center",
"(BRC),",
"Pasteur",
"Institute",
"of",
"Iran",
"(PII),",
"Tehran,",
"Iran,",
"Pasteur",
"Avenue,",
"PO",
"BOX",
"1316943551,",
"Tehran,",
"Iran",
"and",
"2Department",
"of",
"Medical",
"Entomology,",
"School",
"of",
"Public",
"Health,",
"Tehran",
"University",
"of",
"Medical",
"Sciences,",
"Tehran,",
"Iran",
"Email:",
"Saber",
"Gholizadeh",
"-",
"sabergholizadeh@yahoo.com;",
"Navid",
"Dinparast",
"Djadid*",
"-",
"ndinparastdjadid@yahoo.com;",
"Hamid",
"Reza",
"Basseri",
"-",
"basserih@sina.tums.ac.ir;",
"Sedigheh",
"Zakeri",
"-",
"zakeris@yahoo.com;",
"Hossein",
"Ladoni",
"-",
"laddonih@yahoo.com",
"*",
"Corresponding",
"author",
"Published:",
"23",
"June",
"2009",
"Malaria",
"Journal",
"2009,",
"8:137",
"doi:10.1186/1475-2875-8-137",
"This",
"article",
"is",
"available",
"from:",
"http://www.malariajournal.com/content/8/1/137",
"Received:",
"6",
"March",
"2009",
"Accepted:",
"23",
"June",
"2009",
"©",
"2009",
"Gholizadeh",
"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",
"identification",
"of",
"key",
"molecules",
"is",
"crucial",
"for",
"designing",
"transmission-blocking",
"vaccines",
"(TBVs),",
"among",
"those",
"ookinete",
"micronemal",
"proteins",
"are",
"candidate",
"as",
"a",
"general",
"class",
"of",
"malaria",
"transmission-blocking",
"targets.",
"Here,",
"the",
"sequence",
"analysis",
"of",
"an",
"extra-cellular",
"malaria",
"protein",
"expressed",
"in",
"ookinetes,",
"named",
"von",
"Willebrand",
"factor",
"A",
"domain-related",
"protein",
"(WARP),",
"is",
"reported",
"in",
"91",
"Plasmodium",
"vivax",
"isolates",
"circulating",
"in",
"different",
"regions",
"of",
"Iran.",
"Methods:",
"Clinical",
"isolates",
"were",
"collected",
"from",
"north",
"temperate",
"and",
"southern",
"tropical",
"regions",
"in",
"Iran.",
"Primers",
"have",
"been",
"designed",
"based",
"on",
"P.",
"vivax",
"sequence",
"(ctg_6991)",
"which",
"amplified",
"a",
"fragment",
"of",
"about",
"1044",
"bp",
"with",
"no",
"size",
"variation.",
"Direct",
"sequencing",
"of",
"PCR",
"products",
"was",
"used",
"to",
"determine",
"polymorphism",
"and",
"further",
"bioinformatics",
"analysis",
"in",
"P.",
"vivax",
"sexual",
"stage",
"antigen,",
"pvwarp.",
"Results:",
"Amplified",
"pvwarp",
"gene",
"showed",
"886",
"bp",
"in",
"size,",
"with",
"no",
"intron.",
"BLAST",
"analysis",
"showed",
"a",
"similarity",
"of",
"98–100%",
"to",
"P.",
"vivax",
"Sal-I",
"strain;",
"however,",
"Iranian",
"isolates",
"had",
"2",
"bp",
"mismatches",
"in",
"247",
"and",
"531",
"positions",
"that",
"were",
"non-synonymous",
"substitution",
"[T",
"(ACT)",
"to",
"A",
"(GCT)",
"and",
"R",
"(AGA)",
"to",
"S",
"(AGT)]",
"in",
"comparison",
"with",
"the",
"Sal-I",
"sequence.",
"Conclusion:",
"This",
"study",
"presents",
"the",
"first",
"large-scale",
"survey",
"on",
"pvwarp",
"polymorphism",
"in",
"the",
"world,",
"which",
"provides",
"baseline",
"data",
"for",
"developing",
"WARP-based",
"TBV",
"against",
"both",
"temperate",
"and",
"tropical",
"P.",
"vivax",
"isolates.",
"Background",
"Plasmodium",
"vivax",
"is",
"one",
"of",
"the",
"two",
"most",
"prevalent",
"species",
"of",
"human",
"malaria",
"parasites",
"that",
"occurs",
"throughout",
"the",
"tropics,",
"except",
"in",
"western",
"and",
"central",
"sub-Saharan",
"Africa,",
"where",
"the",
"absence",
"of",
"Duffy",
"factor",
"on",
"the",
"surface",
"of",
"red",
"blood",
"cells",
"largely",
"protects",
"the",
"local",
"populations",
"[1].",
"In",
"addition,",
"recent",
"studies",
"have",
"suggested",
"that",
"vivax",
"malaria",
"can",
"become",
"lethal",
"in",
"a",
"similar",
"way",
"to",
"severe",
"falciparum",
"malaria",
"[2-5].",
"To",
"date,",
"the",
"anti-malarial",
"treatment",
"and",
"the",
"vector",
"control",
"measures",
"have",
"not",
"had",
"a",
"significant",
"impact",
"on",
"the",
"transmission",
"of",
"malaria",
"from",
"humans",
"to",
"mosqui-",
"toes.",
"Therefore,",
"vaccine-targeting",
"antigens",
"expressed",
"on",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"J.",
"Cell",
"Commun.",
"Signal.",
"(2009)",
"3:89–94",
"DOI",
"10.1007/s12079-009-0037-7",
"REVIEW",
"Connective",
"tissue",
"growth",
"factor",
"(CTGF,",
"CCN2)",
"gene",
"regulation:",
"a",
"potent",
"clinical",
"bio-marker",
"of",
"fibroproliferative",
"disease?",
"Andrew",
"Leask",
"&",
"Sunil",
"K.",
"Parapuram",
"&",
"Xu",
"Shi-wen",
"&",
"D.",
"J.",
"Abraham",
"Received:",
"25",
"November",
"2008",
"/",
"Accepted:",
"9",
"January",
"2009",
"/",
"Published",
"online:",
"21",
"January",
"2009",
"#",
"The",
"Author(s)",
"2009.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"The",
"CCN",
"(cyr61,",
"ctgf,",
"nov)",
"family",
"of",
"modular",
"proteins",
"regulate",
"diverse",
"biological",
"affects",
"including",
"cell",
"adhesion,",
"matrix",
"production,",
"tissue",
"remodelling,",
"prolifera-",
"tion",
"and",
"differentiation.",
"Recent",
"targeted",
"gene",
"disruption",
"studies",
"have",
"demonstrated",
"the",
"CCN",
"family",
"to",
"be",
"develop-",
"mentally",
"essential",
"for",
"chondrogenesis,",
"osteogenesis",
"and",
"angiogenesis.",
"CCN2",
"is",
"induced",
"by",
"agents",
"such",
"as",
"angio-",
"tensin",
"II,",
"endothelin-1,",
"glucocorticoids,",
"HGF,",
"TGFβ,",
"and",
"VEGF,",
"and",
"by",
"hypoxia",
"and",
"biomechanical",
"and",
"shear",
"stress.",
"Dysregulated",
"expression",
"of",
"CCN2",
"has",
"also",
"been",
"widely",
"documented",
"in",
"many",
"fibroproliferative",
"diseases.",
"This",
"mini-",
"review",
"will",
"focus",
"on",
"CCN2,",
"and",
"the",
"recent",
"progress",
"in",
"understanding",
"CCN2",
"gene",
"regulation",
"in",
"health",
"and",
"disease.",
"That",
"CCN2",
"should",
"be",
"considered",
"a",
"novel",
"and",
"informative",
"surrogate",
"clinical",
"bio-marker",
"for",
"fibroproliferative",
"disease",
"is",
"discussed.",
"Keywords",
"CCN2",
".",
"CTGF",
".",
"Fibrosis",
".",
"Biomarker",
"This",
"article",
"also",
"appears",
"in",
"the",
"newsletter",
"section",
"of",
"the",
"CCN",
"society",
"website:",
"www.ccnsociety.com/.",
"A.",
"Leask",
"(*)",
":",
"S.",
"K.",
"Parapuram",
"CIHR",
"Group",
"in",
"Skeletal",
"Development",
"and",
"Remodeling,",
"Division",
"of",
"Oral",
"Biology",
"and",
"Department",
"of",
"Physiology",
"and",
"Pharmacology,",
"Schulich",
"School",
"of",
"Medicine",
"and",
"Dentistry,",
"University",
"of",
"Western",
"Ontario,",
"Dental",
"Sciences",
"Building,",
"London,",
"ON",
"N6A",
"5C1,",
"Canada",
"e-mail:",
"Andrew.leask@schulich.uwo.ca",
"X.",
"Shi-wen",
":",
"D.",
"J.",
"Abraham",
"Centre",
"for",
"Rheumatology,",
"Royal",
"Free",
"and",
"University",
"College",
"Medical",
"School,",
"University",
"College",
"London",
"(Royal",
"Free",
"Campus),",
"Rowland",
"Hill",
"Street,",
"London",
"NW3",
"2PF,",
"UK",
"Introduction",
"The",
"CCN",
"(cyr61,",
"ctgf,",
"nov)",
"family",
"comprises",
"six",
"members",
"(CCN1–6).",
"These",
"proteins",
"act",
"through",
"integrin-",
"and",
"heparan",
"sulfate",
"proteoglycan-mediated",
"adhesive",
"signaling",
"to",
"directly",
"modulate",
"adhesion",
"and",
"indirectly",
"modulate",
"the",
"functional",
"activities",
"of",
"other",
"extracellular",
"ligands",
"such",
"as",
"cytokines,",
"growth",
"factors,",
"morphogens",
"and",
"matrix",
"compo-",
"nents",
"(Leask",
"and",
"Abraham",
"2006).",
"Of",
"these,",
"connective",
"tissue",
"growth",
"factor",
"(CTGF,",
"CCN2)",
"is",
"perhaps",
"the",
"best",
"studied",
"family",
"member.",
"CCN2",
"was",
"initially",
"identified",
"as",
"a",
"protein",
"secreted",
"by",
"cultured",
"human",
"endothelial",
"cells",
"(Bradham",
"et",
"al.",
"1991).",
"In",
"adult",
"mammals,",
"CCN2",
"exhibits",
"a",
"restricted",
"expression,",
"produced",
"only",
"by",
"hepatic",
"stellate",
"cells",
"(Paradis",
"et",
"al.",
"1999;",
"Chen",
"et",
"al.",
"2001)",
"and",
"kidney",
"mesangial",
"cells",
"(Ito",
"et",
"al.",
"1998;",
"Chen",
"et",
"al.",
"2002).",
"Although",
"CCN2",
"is",
"not",
"normally",
"expressed",
"by",
"other",
"mesenchymal",
"cells,",
"it",
"is",
"rapidly",
"induced",
"during",
"the",
"tissue",
"repair",
"process,",
"for",
"example",
"upon",
"injury",
"(Igarashi",
"et",
"al.",
"1993;",
"Kapoor",
"et",
"al.",
"2008).",
"The",
"most",
"potent",
"inducer",
"of",
"CCN2",
"expression",
"thus",
"far",
"identified",
"is",
"TGFβ.",
"The",
"induction",
"of",
"CCN2",
"by",
"TGFβ",
"is",
"restricted",
"to",
"the",
"mesenchymal",
"cell",
"lineages",
"(e.g.",
"tissue",
"fibroblasts,",
"myofi-",
"broblasts,",
"pericytes)",
"and",
"generally",
"not",
"in",
"epithelial",
"cells",
"(Leask",
"et",
"al.",
"2001,",
"2003;",
"Kantarci",
"et",
"al.",
"2006).",
"However,",
"CCN2",
"is",
"expressed",
"in",
"response",
"to",
"TGFβ",
"in",
"renal",
"proximal",
"tubule",
"epithelial",
"cells",
"(Phanish",
"et",
"al.",
"2005).",
"These",
"results",
"indicate",
"that",
"CCN2",
"gene",
"regulation",
"in",
"response",
"to",
"TGFβ",
"can",
"differ",
"based",
"on",
"the",
"cell",
"type",
"examined.",
"CCN2",
"is",
"over-expressed",
"in",
"connective",
"tissue",
"pathologies",
"such",
"as",
"in",
"excessive",
"scarring",
"and",
"fibrosis",
"and",
"in",
"stroma",
"surrounding",
"tumors",
"(Blom",
"et",
"al.",
"2002).",
"Data",
"examining",
"the",
"location",
"of",
"CCN2",
"expression",
"and",
"the",
"use",
"of",
"genetically",
"modified",
"cells",
"has",
"led",
"to",
"a",
"hypothesis",
"that",
"CCN2",
"selectively",
"mediates",
"or",
"sustains",
"the",
"specific",
"actions",
"of",
"DO00037;",
"No",
"of",
"Pages"
] | [
0,
0,
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] | [
"Evaluation",
"of",
"Treatments",
"in",
"Patients",
"with",
"Nocturnal",
"Bruxism",
"on",
"Bite",
"Force",
"and",
"Occlusal",
"Contact",
"Area:",
"A",
"preliminary",
"report",
"Alper",
"Alkana",
"Emel",
"Bulutb",
"Selim",
"Aricic",
"Shuichi",
"Satod",
"Objectives:",
"The",
"purpose",
"of",
"this",
"study",
"was",
"to",
"investigate",
"the",
"short-term",
"effects",
"of",
"occlusal",
"splint",
"therapy",
"and",
"tricyclic",
"antidepressants",
"on",
"the",
"bite",
"force",
"and",
"occlusal",
"contact",
"area",
"of",
"patients",
"presenting",
"with",
"nocturnal",
"bruxism.",
"Methods:",
"A",
"maxillary",
"full-coverage",
"hard",
"acrylic",
"splint",
"was",
"applied",
"to",
"the",
"five",
"patients",
"(Group",
"S).",
"Five",
"patients",
"took",
"a",
"tricyclic",
"antidepressant",
"(Amitriptiline",
"HCl,",
"10",
"mg/day)",
"for",
"3",
"months",
"(Group",
"A)",
"and",
"a",
"control",
"group",
"(Group",
"C)",
"comprising",
"of",
"10",
"dental",
"school",
"students",
"with",
"normal",
"occlusion",
"was",
"also",
"formed.",
"Using",
"a",
"Dental",
"Prescale",
"(Fuji",
"Photo",
"Film",
"Corporation,",
"Tokyo,",
"Japan)",
"and",
"an",
"Occluzer",
"computer",
"(FPD703,",
"Fuji",
"Photo",
"Film",
"Corporation,",
"Tokyo,",
"Japan)",
"the",
"bite",
"force",
"and",
"occlusal",
"contact",
"area",
"were",
"measured.",
"The",
"evaluations",
"were",
"made",
"just",
"before",
"the",
"treatment",
"and",
"at",
"1",
"month",
"and",
"3",
"months",
"of",
"treatment.",
"Results:",
"The",
"bite",
"force",
"and",
"occlusal",
"contact",
"area",
"before",
"treatment",
"in",
"study",
"Groups",
"A",
"and",
"S",
"were",
"found",
"to",
"be",
"higher",
"than",
"those",
"in",
"the",
"Group",
"C.",
"Furthermore,",
"the",
"bite",
"force",
"and",
"occlusal",
"contact",
"area",
"increased",
"during",
"treatment",
"in",
"Group",
"A",
"whilst",
"they",
"decreased",
"in",
"Group",
"S.",
"Bite",
"force",
"and",
"occlusal",
"contact",
"area",
"in",
"Group",
"S",
"were",
"lower",
"at",
"both",
"1",
"month",
"and",
"3",
"months",
"of",
"treatment",
"than",
"in",
"Group",
"C.",
"Conclusions:",
"It",
"could",
"be",
"tentatively",
"suggested",
"that",
"occlusal",
"splint",
"therapy",
"may",
"be",
"more",
"effective",
"than",
"tricyclic",
"antidepressant",
"in",
"the",
"treatment",
"of",
"bruxism.",
"Further",
"investigations",
"of",
"this",
"measurement",
"method",
"involving",
"larger",
"study",
"populations",
"and",
"a",
"longer",
"follow-up",
"period",
"are",
"needed.",
"(Eur",
"J",
"Dent",
"2008;2:276-282)",
"Key",
"words:",
"Antidepressant;",
"Bite",
"force;",
"Bruxism;",
"Occlusal",
"contact",
"area;",
"Splint.",
"a",
"Associate",
"Professor",
"and",
"Chairman,",
"DDS,",
"PhD,",
"Department",
"of",
"Oral",
"and",
"Maxillofacial",
"Surgery,",
"Faculty",
"of",
"Dentistry,",
"Erciyes",
"University,",
"Kayseri,",
"Turkey.",
"b",
"Assistant",
"Professor,",
"DDS,",
"PhD,",
"Department",
"of",
"Oral",
"and",
"Maxillofacial",
"Surgery,",
"Faculty",
"of",
"Dentistry,",
"Ondokuz",
"Mayis",
"University,",
"Samsun,",
"Turkey.",
"c",
"Professor,",
"DDS,",
"MMedSci,",
"PhD,",
"Department",
"of",
"Orthodonthics,",
"Faculty",
"of",
"Dentistry,",
"Ondokuz",
"Mayis",
"University,",
"Samsun,",
"Turkey.",
"d",
"Lecturer,",
"Division",
"of",
"Maxillofacial",
"Surgery,",
"Graduate",
"School",
"of",
"Dentistry,",
"Tohoku",
"University,",
"Sendai,",
"Japan.",
"Corresponding",
"author:",
"Dr.",
"Emel",
"Bulut",
"Ondokuz",
"Mayis",
"Universitesi,",
"Dis",
"Hekimligi",
"Fakultesi",
"55139,",
"Kurupelit,",
"Samsun,",
"Turkey.",
"Phone:",
"+90",
"362",
"3121919-3008",
"Fax:",
"+90",
"362",
"4576032",
"E-mail:",
"euzun@omu.edu.tr",
"276",
"European",
"Journal",
"of",
"Dentistry"
] | [
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] | [
"Wang",
"and",
"Brown",
"Molecular",
"Neurodegeneration",
"2010,",
"5:52",
"http://www.molecularneurodegeneration.com/content/5/1/52",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"A",
"hereditary",
"spastic",
"paraplegia",
"mutation",
"in",
"kinesin-1A/KIF5A",
"disrupts",
"neurofilament",
"transport",
"Lina",
"Wang,",
"Anthony",
"Brown*",
"Abstract",
"Background:",
"Hereditary",
"spastic",
"paraplegias",
"are",
"a",
"group",
"of",
"neurological",
"disorders",
"characterized",
"by",
"progressive",
"distal",
"degeneration",
"of",
"the",
"longest",
"ascending",
"and",
"descending",
"axons",
"in",
"the",
"spinal",
"cord,",
"leading",
"to",
"lower",
"limb",
"spasticity",
"and",
"weakness.",
"One",
"of",
"the",
"dominantly",
"inherited",
"forms",
"of",
"this",
"disease",
"(spastic",
"gait",
"type",
"10,",
"or",
"SPG10)",
"is",
"caused",
"by",
"point",
"mutations",
"in",
"kinesin-1A",
"(also",
"known",
"as",
"KIF5A),",
"which",
"is",
"thought",
"to",
"be",
"an",
"anterograde",
"motor",
"for",
"neurofilaments.",
"Results:",
"We",
"investigated",
"the",
"effect",
"of",
"an",
"SPG10",
"mutation",
"in",
"kinesin-1A",
"(N256S-kinesin-1A)",
"on",
"neurofilament",
"transport",
"in",
"cultured",
"mouse",
"cortical",
"neurons",
"using",
"live-cell",
"fluorescent",
"imaging.",
"N256S-kinesin-1A",
"decreased",
"both",
"anterograde",
"and",
"retrograde",
"neurofilament",
"transport",
"flux",
"by",
"decreasing",
"the",
"frequency",
"of",
"anterograde",
"and",
"retrograde",
"movements.",
"Anterograde",
"velocity",
"was",
"not",
"affected,",
"whereas",
"retrograde",
"velocity",
"actually",
"increased.",
"Conclusions:",
"These",
"data",
"reveal",
"subtle",
"complexities",
"to",
"the",
"functional",
"interdependence",
"of",
"the",
"anterograde",
"and",
"retrograde",
"neurofilament",
"motors",
"and",
"they",
"also",
"raise",
"the",
"possibility",
"that",
"anterograde",
"and",
"retrograde",
"neurofilament",
"transport",
"may",
"be",
"disrupted",
"in",
"patients",
"with",
"SPG10.",
"Background",
"Hereditary",
"spastic",
"paraplegias",
"are",
"a",
"group",
"of",
"neurologi-",
"cal",
"disorders",
"characterized",
"by",
"progressively",
"increasing",
"lower-extremity",
"weakness",
"and",
"spasticity",
"[1].",
"The",
"pri-",
"mary",
"cause",
"appears",
"to",
"be",
"distal",
"degeneration",
"of",
"the",
"longest",
"ascending",
"and",
"descending",
"axons",
"in",
"the",
"spinal",
"cord,",
"though",
"the",
"explanation",
"for",
"this",
"selective",
"vulner-",
"ability",
"is",
"not",
"known.",
"To",
"date,",
"at",
"least",
"41",
"spastic",
"paraple-",
"gia",
"gene",
"loci",
"have",
"been",
"mapped",
"(termed",
"SPG1",
"through",
"SPG",
"41)",
"and",
"17",
"genes",
"have",
"been",
"identified",
"[2].",
"The",
"inheritance",
"can",
"be",
"autosomal",
"dominant,",
"autosomal",
"recessive,",
"or",
"X-linked.",
"One",
"of",
"the",
"autosomal",
"dominant",
"forms,",
"SPG10,",
"is",
"caused",
"by",
"mutations",
"in",
"kinesin-1A,",
"also",
"known",
"as",
"KIF5A,",
"which",
"is",
"a",
"member",
"of",
"the",
"kine-",
"sin-1",
"family",
"of",
"motor",
"proteins.",
"Kinesin-1",
"motor",
"proteins",
"are",
"heterotetramers",
"com-",
"posed",
"of",
"two",
"heavy",
"chains",
"and",
"two",
"light",
"chains",
"[3].",
"There",
"are",
"three",
"kinesin-1",
"heavy",
"chain",
"genes",
"in",
"mam-",
"mals:",
"kinesin-1A,",
"B",
"and",
"C",
"(also",
"known",
"as",
"KIF5A,",
"B",
"and",
"C)",
"[4].",
"Kinesin-1A",
"and",
"kinesin-1C",
"are",
"neuron",
"specific,",
"whereas",
"kinesin-1B",
"(\"conventional",
"kinesin”)",
"is",
"expressed",
"*",
"Correspondence:",
"brown.2302@osu.edu",
"Center",
"for",
"Molecular",
"Neurobiology",
"and",
"Department",
"of",
"Neuroscience,",
"The",
"Ohio",
"State",
"University,",
"Columbus,",
"OH",
"43210,",
"USA",
"ubiquitously",
"[5-7].",
"Little",
"is",
"known",
"about",
"the",
"cargoes",
"of",
"kinesin-1A,",
"though",
"potential",
"cargoes",
"and",
"interactors",
"include",
"HAP-1",
"(huntingtin",
"associated",
"protein-1)",
"[8],",
"DISC-1",
"(disrupted",
"in",
"schizophrenia",
"protein-1)",
"and",
"the",
"NUDEL/LIS1/14-3-3ε",
"complex",
"[9],",
"Grb2",
"(growth",
"factor",
"receptor",
"bound",
"protein-2)",
"[10],",
"and",
"b-dystrobrevin",
"[11,12].",
"Neurofilaments",
"are",
"the",
"intermediate",
"filaments",
"of",
"neu-",
"rons.",
"They",
"are",
"heteropolymers",
"of",
"variable",
"composition",
"and",
"subunit",
"stoichiometry,",
"typically",
"composed",
"of",
"the",
"low,",
"medium",
"and",
"high",
"molecular",
"weight",
"neurofilament",
"triplet",
"proteins",
"(NFL,",
"M",
"and",
"H),",
"as",
"well",
"as",
"peripherin",
"and/or",
"alpha-internexin",
"[13].",
"Live-cell",
"imaging",
"of",
"neuro-",
"filament",
"transport",
"in",
"cultured",
"neurons",
"and",
"computa-",
"tional",
"modeling",
"studies",
"of",
"neurofilament",
"transport",
"in",
"vivo",
"have",
"demonstrated",
"that",
"neurofilaments",
"move",
"along",
"axons",
"in",
"a",
"rapid,",
"intermittent",
"and",
"bidirectional",
"manner",
"[14-17].",
"Studies",
"on",
"kinesin-1A",
"knockout",
"mice",
"have",
"suggested",
"that",
"kinesin-1A",
"may",
"be",
"an",
"anterograde",
"motor",
"for",
"neu-",
"rofilaments",
"in",
"axons",
"[18].",
"In",
"support",
"of",
"this",
"proposal,",
"we",
"observed",
"a",
"75%",
"reduction",
"in",
"the",
"frequency",
"of",
"neuro-",
"filament",
"movement",
"in",
"cultured",
"neurons",
"from",
"kinesin-",
"1A",
"knockout",
"mice",
"[19].",
"Interestingly,",
"both",
"anterograde",
"©",
"2010",
"Wang",
"and",
"Brown;",
"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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] | [
"Byl",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2012,",
"6:216",
"http://www.jmedicalcasereports.com/content/6/1/216",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"JOURNAL",
"OF",
"MEDICAL",
"CASE",
"REPORTS",
"Open",
"Access",
"Mobility",
"training",
"using",
"a",
"bionic",
"knee",
"orthosis",
"in",
"patients",
"in",
"a",
"post-stroke",
"chronic",
"state:",
"a",
"case",
"series",
"Nancy",
"N",
"Byl",
"Abstract",
"Introduction:",
"An",
"emerging",
"area",
"of",
"neurorehabilitation",
"is",
"the",
"use",
"of",
"robotic",
"devices",
"to",
"enhance",
"the",
"efficiency",
"and",
"effectiveness",
"of",
"lower",
"extremity",
"physical",
"therapy",
"post-stroke.",
"Many",
"of",
"the",
"robotic",
"devices",
"currently",
"available",
"rely",
"on",
"computer-driven",
"locomotive",
"algorithms",
"combined",
"with",
"partial",
"bodyweight-supported",
"treadmill",
"training",
"that",
"drive",
"reflex",
"stepping",
"with",
"minimal",
"patient",
"intention",
"during",
"therapy.",
"In",
"this",
"case",
"series,",
"we",
"examined",
"the",
"effect",
"of",
"task-oriented",
"mobility",
"training",
"in",
"patients",
"in",
"a",
"post-stroke",
"chronic",
"state",
"using",
"a",
"novel,",
"wearable,",
"mobile,",
"intention-based",
"robotic",
"leg",
"orthosis.",
"Case",
"presentation:",
"Three",
"individuals,",
"all",
"of",
"whom",
"had",
"reached",
"a",
"plateau",
"with",
"conventional",
"bodyweight-supported",
"treadmill",
"training,",
"participated",
"in",
"task-oriented",
"mobility",
"therapy",
"(1.5",
"hours,",
"two",
"to",
"four",
"times",
"per",
"week",
"for",
"four",
"weeks)",
"with",
"a",
"robotic",
"leg",
"orthosis",
"under",
"supervision",
"by",
"a",
"physical",
"therapist.",
"Participant",
"1",
"was",
"a",
"59-year-old",
"Caucasian",
"man,",
"who",
"had",
"an",
"ischemic",
"left",
"stroke",
"six",
"years",
"previously",
"with",
"resultant",
"right",
"hemiparesis.",
"Participant",
"2",
"was",
"a",
"42-year-old",
"Caucasian",
"woman",
"with",
"left",
"hemiparesis",
"after",
"a",
"right",
"stroke",
"15",
"months",
"previously.",
"Participant",
"3",
"was",
"a",
"62-year-old",
"Caucasian",
"woman",
"with",
"a",
"history",
"of",
"a",
"right",
"middle",
"cerebral",
"artery",
"aneurysm",
"with",
"third",
"degree",
"sub-arachnoid",
"hemorrhage",
"10",
"years",
"ago.",
"Immediately",
"after",
"training,",
"all",
"participants",
"demonstrated",
"improved",
"gait",
"speed",
"(10",
"meter",
"walk),",
"stride",
"length",
"and",
"walking",
"endurance",
"(6",
"minute",
"walk)",
"compared",
"with",
"baseline",
"measurements.",
"Improvements",
"were",
"maintained",
"one",
"month",
"after",
"training.",
"Timed",
"up",
"and",
"go",
"and",
"five",
"times",
"sit-to-stand",
"were",
"maintained",
"for",
"all",
"three",
"participants,",
"with",
"only",
"one",
"individual",
"remaining",
"outside",
"the",
"safety",
"performance",
"norm.",
"Conclusions:",
"Lower",
"extremity",
"training",
"integrating",
"an",
"intention-based",
"robotic",
"leg",
"orthosis",
"may",
"improve",
"gait",
"speed,",
"endurance",
"and",
"community",
"levels",
"of",
"participation",
"in",
"select",
"patients",
"in",
"a",
"post-stroke",
"chronic",
"state",
"after",
"plateauing",
"within",
"a",
"bodyweight-supported",
"treadmill",
"training",
"program.",
"The",
"wearable,",
"mobile",
"assistive",
"robotic",
"device",
"safely",
"supplemented",
"supervised",
"physical",
"therapy",
"including",
"mobility",
"and",
"balance",
"skill",
"training.",
"Introduction",
"Individuals",
"who",
"receive",
"coordinated",
"rehabilitation",
"ser-",
"vices",
"after",
"stroke",
"demonstrate",
"reduced",
"mortality",
"and",
"achieve",
"greater",
"independence",
"than",
"those",
"who",
"do",
"not",
"[1].",
"Although",
"early",
"intervention",
"and",
"rehabilitation",
"are",
"pre-",
"ferred",
"in",
"the",
"recovery",
"process,",
"research",
"indicates",
"late",
"re-",
"covery",
"may",
"also",
"occur",
"for",
"chronic",
"stroke",
"survivors.",
"Late",
"recovery",
"mechanisms",
"require",
"patient",
"effort",
"and",
"attention",
"including",
"progressive",
"repetitive",
"task-specific",
"training",
"to",
"drive",
"neural",
"remodeling",
"and",
"reorganization",
"[2].",
"Correspondence:",
"byln@ptrehab.ucsf.edu",
"Department",
"of",
"Physical",
"Therapy",
"and",
"Rehabilitation",
"Science,",
"School",
"of",
"Medicine,",
"University",
"of",
"California",
"San",
"Francisco",
"(UCSF),",
"PT",
"Health",
"and",
"Wellness",
"Center,",
"Bakar",
"Community",
"Center,",
"1675",
"Owens",
"Street,",
"Box",
"0736,",
"San",
"Francisco",
"94158-2332,",
"USA",
"An",
"emerging",
"area",
"in",
"neurorehabilitation",
"is",
"the",
"use",
"of",
"robotic",
"devices",
"to",
"enhance",
"the",
"efficiency",
"and",
"effective-",
"ness",
"of",
"post-stroke",
"therapy.",
"A",
"number",
"of",
"designs",
"have",
"been",
"commercialized.",
"These",
"wearable,",
"assistive",
"robotic",
"devices",
"typically",
"demand",
"attention",
"and",
"repetition",
"from",
"the",
"patient,",
"while",
"providing",
"feedback",
"through",
"various",
"modes",
"to",
"improve",
"performance.",
"Early",
"studies",
"of",
"upper-",
"limb",
"robotic",
"devices",
"remain",
"inconclusive",
"when",
"evaluating",
"their",
"benefit",
"over",
"conventional",
"physical",
"therapy",
"[3].",
"Robotic",
"systems",
"for",
"lower",
"extremity",
"therapy",
"on",
"a",
"bodyweight-",
"supported",
"treadmill",
"are",
"subject",
"to",
"many",
"of",
"the",
"same",
"limita-",
"tions",
"as",
"conventional",
"bodyweight-supported",
"treadmill",
"training",
"(BWSTT)",
"[4,5]",
"as",
"they",
"do",
"not",
"compensate",
"for",
"the",
"lack",
"of",
"visual",
"flow,",
"balance",
"and",
"intention",
"requirements",
"inherent",
"to",
"this",
"kind",
"of",
"movement",
"training.",
"©",
"2012",
"Byl;",
"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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],
[
605,
738,
26,
13
],
[
638,
738,
22,
13
],
[
666,
738,
45,
13
],
[
718,
738,
44,
13
],
[
425,
754,
53,
13
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[
486,
754,
39,
13
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[
533,
754,
65,
13
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[
606,
754,
54,
13
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[
668,
754,
48,
13
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[
724,
754,
12,
13
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[
744,
754,
18,
13
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[
425,
770,
39,
13
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[
468,
770,
39,
13
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[
511,
770,
39,
13
],
[
555,
770,
21,
13
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[
581,
770,
36,
13
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[
622,
770,
43,
13
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[
670,
770,
43,
13
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[
718,
770,
44,
13
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[
425,
786,
39,
13
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[
471,
786,
17,
13
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[
496,
786,
50,
13
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[
554,
786,
18,
13
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[
580,
786,
27,
13
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[
615,
786,
35,
13
],
[
659,
786,
12,
13
],
[
679,
786,
14,
13
],
[
700,
786,
43,
13
],
[
751,
786,
12,
13
],
[
425,
802,
65,
13
],
[
493,
802,
18,
13
],
[
515,
802,
96,
13
],
[
614,
802,
12,
13
],
[
630,
802,
7,
13
],
[
640,
802,
32,
13
],
[
675,
802,
43,
13
],
[
722,
802,
40,
13
],
[
425,
818,
12,
13
],
[
440,
818,
10,
13
],
[
454,
818,
20,
13
],
[
478,
818,
57,
13
],
[
539,
818,
23,
13
],
[
565,
818,
47,
13
],
[
616,
818,
23,
13
],
[
643,
818,
25,
13
],
[
672,
818,
7,
13
],
[
683,
818,
80,
13
],
[
425,
858,
29,
10
],
[
455,
858,
23,
10
],
[
480,
858,
7,
10
],
[
489,
858,
32,
10
],
[
523,
858,
41,
10
],
[
565,
858,
9,
10
],
[
576,
858,
39,
10
],
[
616,
858,
15,
10
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[
633,
858,
27,
10
],
[
662,
858,
28,
10
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[
692,
858,
25,
10
],
[
718,
858,
9,
10
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[
729,
858,
34,
10
],
[
425,
877,
39,
10
],
[
465,
877,
45,
10
],
[
511,
877,
7,
10
],
[
520,
877,
22,
10
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[
543,
877,
40,
10
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[
585,
877,
16,
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[
602,
877,
12,
10
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[
615,
877,
22,
10
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[
639,
877,
43,
10
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[
683,
877,
45,
10
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[
729,
877,
12,
10
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[
743,
877,
20,
10
],
[
425,
897,
46,
10
],
[
484,
897,
20,
10
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[
507,
897,
33,
10
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[
544,
897,
9,
10
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[
555,
897,
10,
10
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[
567,
897,
17,
10
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[
587,
897,
7,
10
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[
596,
897,
10,
10
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[
609,
897,
50,
10
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[
662,
897,
25,
10
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[
690,
897,
45,
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],
[
738,
897,
25,
10
],
[
425,
908,
14,
10
],
[
440,
908,
24,
10
],
[
466,
908,
9,
10
],
[
476,
908,
14,
10
],
[
492,
908,
34,
10
],
[
527,
908,
42,
10
],
[
571,
908,
45,
10
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[
619,
908,
32,
10
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[
653,
908,
25,
10
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[
680,
908,
31,
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[
713,
908,
50,
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[
425,
919,
17,
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444,
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50,
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497,
919,
16,
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[
516,
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54,
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574,
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585,
919,
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[
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949,
41,
10
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949,
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10
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636,
949,
60,
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949,
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949,
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] | [
"Systems",
"Analysis",
"of",
"Chaperone",
"Networks",
"in",
"the",
"Malarial",
"Parasite",
"Plasmodium",
"falciparum",
"Soundara",
"Raghavan",
"Pavithra[,",
"Ranjit",
"Kumar[,",
"Utpal",
"Tatu*",
"Department",
"of",
"Biochemistry,",
"Indian",
"Institute",
"of",
"Science,",
"Bangalore,",
"Karnataka,",
"India",
"Molecular",
"chaperones",
"participate",
"in",
"the",
"maintenance",
"of",
"cellular",
"protein",
"homeostasis,",
"cell",
"growth",
"and",
"differentiation,",
"signal",
"transduction,",
"and",
"development.",
"Although",
"a",
"vast",
"body",
"of",
"information",
"is",
"available",
"regarding",
"individual",
"chaperones,",
"few",
"studies",
"have",
"attempted",
"a",
"systems",
"level",
"analysis",
"of",
"chaperone",
"function.",
"In",
"this",
"paper,",
"we",
"have",
"constructed",
"a",
"chaperone",
"interaction",
"network",
"for",
"the",
"malarial",
"parasite,",
"Plasmodium",
"falciparum.",
"P.",
"falciparum",
"is",
"responsible",
"for",
"several",
"million",
"deaths",
"every",
"year,",
"and",
"understanding",
"the",
"biology",
"of",
"the",
"parasite",
"is",
"a",
"top",
"priority.",
"The",
"parasite",
"regularly",
"experiences",
"heat",
"shock",
"as",
"part",
"of",
"its",
"life",
"cycle,",
"and",
"chaperones",
"have",
"often",
"been",
"implicated",
"in",
"parasite",
"survival",
"and",
"growth.",
"To",
"better",
"understand",
"the",
"participation",
"of",
"chaperones",
"in",
"cellular",
"processes,",
"we",
"created",
"a",
"parasite",
"chaperone",
"network",
"by",
"combining",
"experimental",
"interactome",
"data",
"with",
"in",
"silico",
"analysis.",
"We",
"used",
"interolog",
"mapping",
"to",
"predict",
"protein–protein",
"interactions",
"for",
"parasite",
"chaperones",
"based",
"on",
"the",
"interactions",
"of",
"corresponding",
"human",
"chaperones.",
"This",
"data",
"was",
"then",
"combined",
"with",
"information",
"derived",
"from",
"existing",
"high-throughput",
"yeast",
"two-",
"hybrid",
"assays.",
"Analysis",
"of",
"the",
"network",
"reveals",
"the",
"broad",
"range",
"of",
"functions",
"regulated",
"by",
"chaperones.",
"The",
"network",
"predicts",
"involvement",
"of",
"chaperones",
"in",
"chromatin",
"remodeling,",
"protein",
"trafficking,",
"and",
"cytoadherence.",
"Importantly,",
"it",
"allows",
"us",
"to",
"make",
"predictions",
"regarding",
"the",
"functions",
"of",
"hypothetical",
"proteins",
"based",
"on",
"their",
"interactions.",
"It",
"allows",
"us",
"to",
"make",
"specific",
"predictions",
"about",
"Hsp70–Hsp40",
"interactions",
"in",
"the",
"parasite",
"and",
"assign",
"functions",
"to",
"members",
"of",
"the",
"Hsp90",
"and",
"Hsp100",
"families.",
"Analysis",
"of",
"the",
"network",
"provides",
"a",
"rational",
"basis",
"for",
"the",
"anti-malarial",
"activity",
"of",
"geldanamycin,",
"a",
"well-known",
"Hsp90",
"inhibitor.",
"Finally,",
"analysis",
"of",
"the",
"network",
"provides",
"a",
"theoretical",
"basis",
"for",
"further",
"experiments",
"designed",
"toward",
"understanding",
"the",
"involvement",
"of",
"this",
"important",
"class",
"of",
"molecules",
"in",
"parasite",
"biology.",
"Citation:",
"Pavithra",
"SR,",
"Kumar",
"R,",
"Tatu",
"U",
"(2007)",
"Systems",
"analysis",
"of",
"chaperone",
"networks",
"in",
"the",
"malarial",
"parasite",
"Plasmodium",
"falciparum.",
"PLoS",
"Comput",
"Biol",
"3(9):",
"e168.",
"doi:10.1371/journal.pcbi.0030168",
"Introduction",
"Molecular",
"chaperones",
"have",
"emerged",
"in",
"recent",
"years",
"as",
"key",
"players",
"in",
"several",
"cellular",
"processes.",
"In",
"addition",
"to",
"assisting",
"in",
"the",
"folding",
"of",
"newly",
"synthesized",
"proteins,",
"they",
"play",
"crucial",
"roles",
"in",
"the",
"translocation",
"of",
"proteins",
"across",
"organelle",
"membranes,",
"quality",
"control",
"in",
"the",
"endoplasmic",
"reticulum",
"(ER),",
"turnover",
"of",
"misfolded",
"proteins,",
"as",
"well",
"as",
"signal",
"transduction",
"[1–3].",
"By",
"chaperoning",
"key",
"signaling",
"proteins",
"such",
"as",
"protein",
"kinases",
"and",
"transcription",
"factors,",
"chaperones",
"such",
"as",
"Hsp90",
"(heat",
"shock",
"protein",
"90)",
"also",
"participate",
"in",
"cell",
"growth,",
"differentiation,",
"apoptosis,",
"and",
"development",
"[4,5].",
"As",
"such,",
"many",
"chaperones",
"are",
"also",
"essential",
"under",
"non-stress",
"conditions",
"and",
"are",
"relatively",
"abundant",
"in",
"the",
"cell.",
"There",
"are",
"different",
"families",
"of",
"stress",
"proteins,",
"the",
"major",
"ones",
"being",
"the",
"Hsp40,",
"Hsp60,",
"Hsp70,",
"Hsp90,",
"Hsp100,",
"TCP-1/CCT,",
"and",
"the",
"small",
"Hsp",
"families",
"[6].",
"These",
"families",
"of",
"chaperones",
"are",
"ubiquitous",
"and",
"conserved",
"in",
"most",
"organisms",
"from",
"bacteria",
"to",
"higher",
"eukaryotes.",
"In",
"recent",
"years,",
"the",
"importance",
"of",
"chaperones",
"in",
"developmental",
"processes",
"has",
"been",
"highlighted",
"by",
"the",
"demonstration",
"of",
"a",
"role",
"for",
"Hsp90",
"in",
"buffering",
"genetic",
"variation",
"[7–9].",
"Despite",
"the",
"important",
"processes",
"in",
"which",
"chaperones",
"have",
"been",
"implicated,",
"most",
"studies",
"have",
"been",
"restricted",
"to",
"the",
"analysis",
"of",
"individual",
"chaperones.",
"There",
"is",
"growing",
"realiza-",
"tion",
"that",
"chaperones",
"function",
"in",
"complexes",
"with",
"partner",
"co-",
"chaperones",
"and",
"other",
"effectors",
"[10,11].",
"These",
"modular",
"complexes",
"participate",
"in",
"multiple",
"pathways",
"in",
"the",
"cell,",
"emphasizing",
"the",
"need",
"to",
"examine",
"protein–protein",
"interac-",
"tion",
"networks",
"for",
"a",
"better",
"understanding",
"of",
"cellular",
"processes.",
"Chaperone",
"interaction",
"networks,",
"for",
"example,",
"may",
"provide",
"a",
"theoretical",
"framework",
"to",
"study",
"the",
"response",
"of",
"a",
"cell",
"to",
"stressful",
"conditions.",
"Keeping",
"in",
"mind",
"the",
"central",
"importance",
"of",
"chaperones",
"in",
"biological",
"processes,",
"we",
"have",
"made",
"an",
"effort",
"at",
"analyzing",
"chaperone",
"interaction",
"networks",
"in",
"human",
"beings,",
"as",
"well",
"as",
"one",
"of",
"the",
"most",
"important",
"human",
"pathogens,",
"the",
"malarial",
"parasite",
"P.",
"falciparum.",
"During",
"its",
"life",
"cycle,",
"the",
"parasite",
"continually",
"cycles",
"between",
"a",
"cold-blooded",
"insect",
"vector",
"and",
"a",
"warm-blooded",
"human",
"host",
"and",
"experiences",
"episodes",
"of",
"heat",
"shock",
"frequently",
"[12].",
"Within",
"the",
"human",
"body,",
"the",
"parasite",
"experiences",
"heat",
"shock",
"periodically",
"during",
"the",
"febrile",
"episodes",
"that",
"are",
"a",
"clinical",
"hallmark",
"of",
"malaria.",
"It",
"is",
"therefore",
"possible",
"that",
"heat",
"shock",
"proteins",
"have",
"a",
"role",
"to",
"play",
"in",
"the",
"adaptation",
"to",
"and",
"survival",
"of",
"the",
"parasite",
"in",
"the",
"human",
"host.",
"The",
"malarial",
"parasite",
"expresses",
"several",
"chaperones",
"including",
"proteins",
"of",
"the",
"Hsp40,",
"Hsp60,",
"Hsp70,",
"and",
"Hsp90",
"families",
"[13–17].",
"Parasite",
"Hsp70,",
"for",
"example,",
"has",
"been",
"shown",
"to",
"be",
"capable",
"of",
"suppressing",
"the",
"thermosensitivity",
"of",
"a",
"DnaK",
"(Hsp70)",
"mutant",
"of",
"E.",
"coli,",
"suggesting",
"that",
"PfHsp70",
"may",
"have",
"a",
"cytoprotective",
"Editor:",
"Philip",
"E.",
"Bourne,",
"University",
"of",
"California",
"San",
"Diego,",
"United",
"States",
"of",
"America",
"Received",
"September",
"5,",
"2006;",
"Accepted",
"July",
"11,",
"2007;",
"Published",
"September",
"14,",
"2007",
"Copyright:",
"2007",
"Pavithra",
"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:",
"ER,",
"endoplasmic",
"reticulum;",
"GA,",
"geldanamycin;",
"HPRD,",
"Human",
"Protein",
"Reference",
"Database;",
"Hsp/HSP,",
"heat",
"shock",
"protein",
"*",
"To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"E-mail:",
"tatu@biochem.iisc.ernet.in",
"[",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"PLoS",
"Computational",
"Biology",
"|",
"www.ploscompbiol.org",
"1701",
"September",
"2007",
"|",
"Volume",
"3",
"|",
"Issue",
"9",
"|",
"e168"
] | [
8,
8,
8,
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] | [
"BMC",
"Cancer",
"Research",
"article",
"BioMed",
"Central",
"Open",
"Access",
"Identification",
"of",
"a",
"panel",
"of",
"tumor-associated",
"antigens",
"from",
"breast",
"carcinoma",
"cell",
"lines,",
"solid",
"tumors",
"and",
"testis",
"cDNA",
"libraries",
"displayed",
"on",
"lambda",
"phage",
"Emiliano",
"Pavoni1,",
"Paola",
"Vaccaro1,",
"Andrea",
"Pucci1,",
"Giorgia",
"Monteriù1,",
"Elisa",
"Beghetto1,",
"Stefano",
"Barca2,",
"Maria",
"Luisa",
"Dupuis2,",
"Adolfo",
"De",
"Pasquale",
"Ceratti3,",
"Antonio",
"Lugini3,",
"Maurizio",
"Cianfriglia2,",
"Enrico",
"Cortesi3,",
"Franco",
"Felici1,4",
"and",
"Olga",
"Minenkova*1",
"Address:",
"1Kenton",
"Labs,",
"c/o",
"Sigma",
"Tau,",
"Pomezia",
"(Rome),",
"00040,",
"Italy,",
"2Laboratorio",
"di",
"Immunologia,",
"Reparto",
"Immunologia",
"dei",
"Tumori,",
"Istituto",
"Superiore",
"di",
"Sanità,",
"Roma,",
"00100,",
"Italy,",
"3Oncologia",
"Medica,",
"Dipartimento",
"di",
"Medicina",
"Sperimentale",
"e",
"Patologia,",
"Facoltà",
"di",
"Medicina",
"e",
"Chirurgia,",
"Università",
"di",
"Roma",
"\"La",
"Sapienza\",",
"Rome,",
"00100,",
"Italy",
"and",
"4Dipartimento",
"di",
"Scienze",
"Microbiologiche,",
"Genetiche",
"e",
"Molecolari,",
"Università",
"di",
"Messina,",
"98100,",
"Italy",
"Email:",
"Emiliano",
"Pavoni",
"-",
"pavoni@kenton.it;",
"Paola",
"Vaccaro",
"-",
"vaccaro@kenton.it;",
"Andrea",
"Pucci",
"-",
"pucci@kenton.it;",
"Giorgia",
"Monteriù",
"-",
"monteriu@kenton.it;",
"Elisa",
"Beghetto",
"-",
"beghetto@kenton.it;",
"Stefano",
"Barca",
"-",
"sbarca@iss.it;",
"Maria",
"Luisa",
"Dupuis",
"-",
"mldupuis@iss.it;",
"Adolfo",
"De",
"Pasquale",
"Ceratti",
"-",
"adolfo.ceratti@tiscali.it;",
"Antonio",
"Lugini",
"-",
"antoniolugini@libero.it;",
"Maurizio",
"Cianfriglia",
"-",
"cianfri@iss.it;",
"Enrico",
"Cortesi",
"-",
"enrico.cortesi@uniroma1.it;",
"Franco",
"Felici",
"-",
"felici@kenton.it;",
"Olga",
"Minenkova*",
"-",
"minenkova@kenton.it",
"*",
"Corresponding",
"author",
"Published:",
"12",
"November",
"2004",
"BMC",
"Cancer",
"2004,",
"4:78",
"doi:10.1186/1471-2407-4-78",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2407/4/78",
"Received:",
"18",
"June",
"2004",
"Accepted:",
"12",
"November",
"2004",
"©",
"2004",
"Pavoni",
"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:",
"Tumor-associated",
"antigens",
"recognized",
"by",
"humoral",
"effectors",
"of",
"the",
"immune",
"system",
"are",
"a",
"very",
"attractive",
"target",
"for",
"human",
"cancer",
"diagnostics",
"and",
"therapy.",
"Recent",
"advances",
"in",
"molecular",
"techniques",
"have",
"led",
"to",
"molecular",
"definition",
"of",
"immunogenic",
"tumor",
"proteins",
"based",
"on",
"their",
"reactivity",
"with",
"autologous",
"patient",
"sera",
"(SEREX).",
"Methods:",
"Several",
"high",
"complexity",
"phage-displayed",
"cDNA",
"libraries",
"from",
"breast",
"carcinomas,",
"human",
"testis",
"and",
"breast",
"carcinoma",
"cell",
"lines",
"MCF-7,",
"MDA-MB-468",
"were",
"constructed.",
"The",
"cDNAs",
"were",
"expressed",
"in",
"the",
"libraries",
"as",
"fusion",
"to",
"bacteriophage",
"lambda",
"protein",
"D.",
"Lambda-displayed",
"libraries",
"were",
"efficiently",
"screened",
"with",
"sera",
"from",
"patients",
"with",
"breast",
"cancer.",
"Results:",
"A",
"panel",
"of",
"21",
"clones",
"representing",
"18",
"different",
"antigens,",
"including",
"eight",
"proteins",
"of",
"unknown",
"function,",
"was",
"identified.",
"Three",
"of",
"these",
"antigens",
"(T7-1,",
"T11-3",
"and",
"T11-9)",
"were",
"found",
"to",
"be",
"overexpressed",
"in",
"tumors",
"as",
"compared",
"to",
"normal",
"breast.",
"A",
"serological",
"analysis",
"of",
"the",
"21",
"different",
"antigens",
"revealed",
"a",
"strong",
"cancer-related",
"profile",
"for",
"at",
"least",
"five",
"clones",
"(T6-2,",
"T6-7,",
"T7-",
"1,",
"T9-21",
"and",
"T9-27).",
"Conclusions:",
"Preliminary",
"results",
"indicate",
"that",
"patient",
"serum",
"reactivity",
"against",
"five",
"of",
"the",
"antigens",
"is",
"associated",
"with",
"tumor",
"disease.",
"The",
"novel",
"T7-1",
"antigen,",
"which",
"is",
"overexpressed",
"in",
"breast",
"tumors",
"and",
"recognized",
"specifically",
"by",
"breast",
"cancer",
"patient",
"sera,",
"is",
"potentially",
"useful",
"in",
"cancer",
"diagnosis.",
"Page",
"1",
"of",
"10",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Tropical",
"Plant",
"Biol.",
"(2010)",
"3:123–135",
"DOI",
"10.1007/s12042-010-9046-1",
"Lablab",
"purpureus—A",
"Crop",
"Lost",
"for",
"Africa?",
"Brigitte",
"L.",
"Maass",
"&",
"Maggie",
"R.",
"Knox",
"&",
"S.",
"C.",
"Venkatesha",
"&",
"Tefera",
"Tolera",
"Angessa",
"&",
"Stefan",
"Ramme",
"&",
"Bruce",
"C.",
"Pengelly",
"Received:",
"11",
"November",
"2009",
"/",
"Accepted:",
"18",
"February",
"2010",
"/",
"Published",
"online:",
"28",
"March",
"2010",
"#",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"In",
"recent",
"years,",
"so-called",
"‘lost",
"crops’",
"have",
"been",
"appraised",
"in",
"a",
"number",
"of",
"reviews,",
"among",
"them",
"Lablab",
"purpureus",
"in",
"the",
"context",
"of",
"African",
"vegetable",
"species.",
"This",
"crop",
"cannot",
"truly",
"be",
"considered",
"‘lost’",
"because",
"worldwide",
"more",
"than",
"150",
"common",
"names",
"are",
"applied",
"to",
"it.",
"Based",
"on",
"a",
"comprehensive",
"literature",
"review,",
"this",
"paper",
"aims",
"to",
"put",
"forward",
"four",
"theses,",
"(i)",
"Lablab",
"is",
"one",
"of",
"the",
"most",
"diverse",
"domesticated",
"legume",
"species",
"and",
"has",
"multiple",
"uses.",
"Although",
"its",
"largest",
"agro-morphological",
"diversity",
"occurs",
"in",
"South",
"Asia,",
"its",
"origin",
"appears",
"to",
"be",
"Africa.",
"(ii)",
"Crop",
"improvement",
"in",
"South",
"Asia",
"is",
"based",
"on",
"limited",
"genetic",
"diversity.",
"(iii)",
"The",
"restricted",
"research",
"and",
"development",
"performed",
"in",
"Africa",
"focuses",
"either",
"on",
"improving",
"forage",
"or",
"soil",
"properties",
"mostly",
"through",
"one",
"popular",
"cultivar,",
"Rongai,",
"Communicated",
"by:",
"Desiree",
"M.",
"Hautea",
"Elaborated",
"from",
"a",
"presentation",
"at",
"the",
"International",
"Symposium",
"“Underutilized",
"plants",
"for",
"food,",
"nutrition,",
"income",
"and",
"sustainable",
"development”,",
"3–7",
"March",
"2008,",
"Arusha,",
"Tanzania;",
"organized",
"by",
"ICUC,",
"GFU,",
"AVRDC,",
"GlobalHort,",
"Bioversity",
"International,",
"PROTA,",
"and",
"ISHS.",
"B.",
"L.",
"Maass",
":",
"TT.eTf.erAanTg.esAs.a",
":",
"S.",
"Ramme",
"Department",
"of",
"Crop",
"Sciences:",
"Agronomy",
"in",
"the",
"Tropics,",
"Georg-August-University",
"Goettingen,",
"Grisebachstr.",
"6,",
"D-37077",
"Goettingen,",
"Germany",
"M.",
"R.",
"Knox",
"John",
"Innes",
"Centre",
"(JIC),",
"Colney",
"Lane,",
"Norwich",
"NR4",
"7UH,",
"UK",
"S.",
"C.",
"Venkatesha",
"University",
"of",
"Agricultural",
"Sciences,",
"GKVK",
"Campus,",
"Bangalore",
"560065",
"Karnataka,",
"India",
"while",
"the",
"available",
"diversity",
"of",
"lablab",
"in",
"Africa",
"might",
"be",
"under",
"threat",
"of",
"genetic",
"erosion.",
"(iv)",
"Lablab",
"is",
"better",
"adapted",
"to",
"drought",
"than",
"common",
"beans",
"(Phaseolus",
"vulgaris)",
"or",
"cowpea",
"(Vigna",
"unguiculata),",
"both",
"of",
"which",
"have",
"been",
"preferred",
"to",
"lablab",
"in",
"African",
"agricultural",
"production",
"systems.",
"Lablab",
"might",
"offer",
"comparable",
"opportunities",
"for",
"African",
"agriculture",
"in",
"the",
"view",
"of",
"global",
"change.",
"Its",
"wide",
"potential",
"for",
"adaptation",
"throughout",
"eastern",
"and",
"southern",
"Africa",
"is",
"shown",
"with",
"a",
"GIS",
"(geographic",
"information",
"systems)",
"approach.",
"Keywords",
"Cover",
"crop",
".",
"Dolichos",
".",
"Forage",
".",
"Genetic",
"diversity",
".",
"Genetic",
"erosion",
".",
"Homegarden",
".",
"Hyacinth",
"bean",
".",
"Landrace",
".",
"Pulse",
".",
"Traditional",
"vegetable",
".",
"Underutilized",
"crop",
"B.",
"C.",
"Pengelly",
"Commwealth",
"Scientific",
"and",
"Industrial",
"Research",
"Organisation",
"(CSIRO):",
"Sustainable",
"Ecosystems,",
"306",
"Carmody",
"Road,",
"St.",
"Lucia,",
"Qld.",
"4067,",
"Australia",
"Present",
"Address:",
"B.",
"L.",
"Maass",
"(*)",
"CIAT-TSBF,",
"ICRAF",
"Campus,",
"PO",
"Box",
"30677-00100,",
"Nairobi,",
"Kenya",
"e-mail:",
"b.maass@cgiar.org",
"Present",
"Address:",
"T.efTe.raATn.geAs.sa",
"The",
"University",
"of",
"Western",
"Australia",
"(M703),",
"35",
"Stirling",
"Highway,",
"Crawley,",
"WA",
"6009,",
"Australia"
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] | [
"Kreider",
"et",
"al.",
"Journal",
"of",
"the",
"International",
"Society",
"of",
"Sports",
"Nutrition",
"2010,",
"7:7",
"http://www.jissn.com/content/7/1/7",
"R",
"E",
"V",
"I",
"E",
"W",
"Open",
"Access",
"ISSN",
"exercise",
"&",
"sport",
"nutrition",
"review:",
"research",
"&",
"recommendations",
"Richard",
"B",
"Kreider1*,",
"Colin",
"D",
"Wilborn2,",
"Lem",
"Taylor2,",
"Bill",
"Campbell3,",
"Anthony",
"L",
"Almada4,",
"Rick",
"Collins5,",
"Mathew",
"Cooke6,",
"Conrad",
"P",
"Earnest7,",
"Mike",
"Greenwood8,",
"Douglas",
"S",
"Kalman9,",
"Chad",
"M",
"Kerksick10,",
"Susan",
"M",
"Kleiner11,",
"Brian",
"Leutholtz8,",
"Hector",
"Lopez12,",
"Lonnie",
"M",
"Lowery13,",
"Ron",
"Mendel14,",
"Abbie",
"Smith10,",
"Marie",
"Spano15,",
"Robert",
"Wildman16,",
"Darryn",
"S",
"Willoughby8,",
"Tim",
"N",
"Ziegenfuss17,",
"Jose",
"Antonio18",
"Abstract",
"Sports",
"nutrition",
"is",
"a",
"constantly",
"evolving",
"field",
"with",
"hundreds",
"of",
"research",
"papers",
"published",
"annually.",
"For",
"this",
"reason,",
"keeping",
"up",
"to",
"date",
"with",
"the",
"literature",
"is",
"often",
"difficult.",
"This",
"paper",
"is",
"a",
"five",
"year",
"update",
"of",
"the",
"sports",
"nutrition",
"review",
"article",
"published",
"as",
"the",
"lead",
"paper",
"to",
"launch",
"the",
"JISSN",
"in",
"2004",
"and",
"presents",
"a",
"well-referenced",
"overview",
"of",
"the",
"current",
"state",
"of",
"the",
"science",
"related",
"to",
"how",
"to",
"optimize",
"training",
"and",
"athletic",
"performance",
"through",
"nutrition.",
"More",
"specifically,",
"this",
"paper",
"provides",
"an",
"overview",
"of:",
"1.)",
"The",
"definitional",
"category",
"of",
"ergogenic",
"aids",
"and",
"dietary",
"supplements;",
"2.)",
"How",
"dietary",
"supplements",
"are",
"legally",
"regulated;",
"3.)",
"How",
"to",
"evaluate",
"the",
"scientific",
"merit",
"of",
"nutri-",
"tional",
"supplements;",
"4.)",
"General",
"nutritional",
"strategies",
"to",
"optimize",
"performance",
"and",
"enhance",
"recovery;",
"and,",
"5.)",
"An",
"overview",
"of",
"our",
"current",
"understanding",
"of",
"the",
"ergogenic",
"value",
"of",
"nutrition",
"and",
"dietary",
"supplementation",
"in",
"regards",
"to",
"weight",
"gain,",
"weight",
"loss,",
"and",
"performance",
"enhancement.",
"Our",
"hope",
"is",
"that",
"ISSN",
"members",
"and",
"individuals",
"inter-",
"ested",
"in",
"sports",
"nutrition",
"find",
"this",
"review",
"useful",
"in",
"their",
"daily",
"practice",
"and",
"consultation",
"with",
"their",
"clients.",
"Introduction",
"Sports",
"nutrition",
"professionals",
"need",
"to",
"know",
"how",
"to",
"evaluate",
"the",
"scientific",
"merit",
"of",
"articles",
"and",
"advertise-",
"ments",
"about",
"exercise",
"and",
"nutrition",
"products",
"so",
"they",
"can",
"separate",
"marketing",
"hype",
"from",
"scientifically-based",
"train-",
"ing",
"and",
"nutritional",
"practices.",
"In",
"order",
"to",
"help",
"ISSN",
"members",
"keep",
"informed",
"about",
"the",
"latest",
"in",
"sports",
"nutri-",
"tion,",
"we",
"have",
"updated",
"the",
"ISSN",
"Exercise",
"&",
"Sports",
"Nutrition",
"Review",
"that",
"was",
"used",
"to",
"help",
"launch",
"the",
"JISSN",
"(originally",
"called",
"the",
"Sports",
"Nutrition",
"Review",
"Journal).",
"This",
"paper",
"provides",
"an",
"overview",
"of:",
"1.)",
"The",
"definitional",
"category",
"of",
"ergogenic",
"aids",
"and",
"dietary",
"sup-",
"plements;",
"2.)",
"How",
"dietary",
"supplements",
"are",
"legally",
"regu-",
"lated;",
"3.)",
"How",
"to",
"evaluate",
"the",
"scientific",
"merit",
"of",
"nutritional",
"supplements;",
"4.)",
"General",
"nutritional",
"strate-",
"gies",
"to",
"optimize",
"performance",
"and",
"enhance",
"recovery;",
"and,",
"5.)",
"An",
"overview",
"of",
"our",
"current",
"understanding",
"of",
"the",
"ergogenic",
"value",
"in",
"regards",
"to",
"weight",
"gain,",
"weight",
"loss,",
"and",
"performance",
"enhancement",
"supplements.",
"We",
"have",
"also",
"categorized",
"nutritional",
"supplements",
"into",
"*",
"Correspondence:",
"rkreider@hlkn.tamu.edu",
"1Exercise",
"&",
"Sports",
"Nutrition",
"Lab,",
"Texas",
"A&M",
"University,",
"College",
"Station,",
"TX,",
"USA",
"‘apparently",
"effective’,",
"‘possibly",
"effective’,",
"‘too",
"early",
"to",
"tell’,",
"and",
"‘apparently",
"ineffective’",
"as",
"well",
"a",
"description",
"of",
"our",
"general",
"approach",
"into",
"educating",
"athletes",
"about",
"sports",
"nutrition.",
"Over",
"the",
"last",
"five",
"years",
"there",
"have",
"been",
"many",
"changes",
"to",
"our",
"original",
"categorization",
"of",
"supple-",
"ments.",
"In",
"addition,",
"a",
"number",
"of",
"new",
"supplements",
"have",
"been",
"introduced",
"to",
"the",
"market",
"are",
"reviewed",
"in",
"this",
"arti-",
"cle.",
"While",
"some",
"may",
"not",
"agree",
"with",
"all",
"of",
"our",
"interpre-",
"tations",
"of",
"the",
"literature",
"and/or",
"categorization",
"of",
"a",
"particular",
"supplement,",
"and",
"some",
"classifications",
"may",
"change",
"over",
"time",
"as",
"more",
"research",
"is",
"forthcoming,",
"these",
"interpretations",
"are",
"based",
"on",
"current",
"available",
"scientific",
"evidence",
"and",
"have",
"been",
"well",
"received",
"within",
"the",
"broader",
"scientific",
"community.",
"Our",
"hope",
"is",
"that",
"ISSN",
"members",
"find",
"this",
"information",
"useful",
"in",
"their",
"daily",
"practice",
"and",
"consultation",
"with",
"their",
"clients.",
"Ergogenic",
"Aid",
"An",
"ergogenic",
"aid",
"is",
"any",
"training",
"technique,",
"mechanical",
"device,",
"nutritional",
"practice,",
"pharmacological",
"method,",
"or",
"psychological",
"technique",
"that",
"can",
"improve",
"exercise",
"per-",
"formance",
"capacity",
"and/or",
"enhance",
"training",
"adaptations",
"[1-3].",
"This",
"includes",
"aids",
"that",
"may",
"help",
"prepare",
"an",
"©",
"2010",
"Kreider",
"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://ccforum.com/content/11/3/R63",
"Research",
"Vol11No3",
"Red",
"blood",
"cell",
"transfusions",
"and",
"the",
"risk",
"of",
"acute",
"respiratory",
"distress",
"syndrome",
"among",
"the",
"critically",
"ill:",
"a",
"cohort",
"study",
"Marya",
"D",
"Zilberberg1,",
"Chureen",
"Carter2,",
"Patrick",
"Lefebvre3,",
"Monika",
"Raut2,",
"Francis",
"Vekeman3,",
"Open",
"Access",
"Mei",
"Sheng",
"Duh4",
"and",
"Andrew",
"F",
"Shorr5",
"1School",
"of",
"Public",
"Health",
"and",
"Health",
"Sciences,",
"University",
"of",
"Massachusetts,",
"Amherst,",
"P.O.",
"Box",
"303,",
"Goshen,",
"MA",
"01032,",
"USA",
"2Ortho",
"Biotech",
"Clinical",
"Affairs,",
"LLC,",
"430",
"Route",
"22",
"East,",
"Bridgewater,",
"NJ",
"08807,",
"USA",
"3Groupe",
"d'analyse,",
"1080",
"Beaver",
"Hall",
"Hill,",
"Suite",
"1810,",
"Montreal,",
"Quebec,",
"H2Z",
"1S8,",
"Canada",
"4Analysis",
"Group,",
"111",
"Huntington",
"Avenue,",
"Tenth",
"Floor,",
"Boston,",
"MA",
"02199,",
"USA",
"5Washington",
"Hospital",
"Center,",
"110",
"Irving",
"Street,",
"NW,",
"Washington,",
"DC",
"20010,",
"USA",
"Corresponding",
"author:",
"Marya",
"D",
"Zilberberg,",
"mzilberb@schoolph.umass.edu",
"Received:",
"28",
"Feb",
"2007",
"Revisions",
"requested:",
"29",
"Mar",
"2007",
"Revisions",
"received:",
"11",
"Apr",
"2007",
"Accepted:",
"6",
"Jun",
"2007",
"Published:",
"6",
"Jun",
"2007",
"Critical",
"Care",
"2007,",
"11:R63",
"(doi:10.1186/cc5934)",
"This",
"article",
"is",
"online",
"at:",
"http://ccforum.com/content/11/3/R63",
"©",
"2007",
"Zilberberg",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Introduction",
"Recent",
"data",
"indicate",
"that",
"transfusion",
"of",
"packed",
"red",
"blood",
"cells",
"(pRBCs)",
"may",
"increase",
"the",
"risk",
"for",
"the",
"development",
"of",
"acute",
"respiratory",
"distress",
"syndrome",
"(ARDS)",
"in",
"critically",
"ill",
"patients.",
"Uncertainty",
"remains",
"regarding",
"the",
"strength",
"of",
"this",
"relationship.",
"Methods",
"To",
"quantify",
"the",
"association",
"between",
"transfusions",
"and",
"intensive",
"care",
"unit",
"(ICU)-onset",
"ARDS,",
"we",
"performed",
"a",
"cohort",
"study",
"within",
"Crit,",
"a",
"multicenter,",
"prospective,",
"observational",
"study",
"of",
"transfusion",
"practice",
"in",
"the",
"ICU",
"which",
"enrolled",
"4,892",
"critically",
"ill",
"patients",
"in",
"284",
"ICUs",
"in",
"the",
"United",
"States.",
"Diagnostic",
"criteria",
"for",
"ARDS",
"were",
"prospectively",
"defined,",
"and",
"we",
"focused",
"on",
"subjects",
"without",
"ARDS",
"at",
"admission.",
"The",
"development",
"of",
"ARDS",
"in",
"the",
"ICU",
"served",
"as",
"the",
"primary",
"endpoint.",
"Results",
"Among",
"the",
"4,730",
"patients",
"without",
"ARDS",
"at",
"admission,",
"246",
"(5.2%)",
"developed",
"ARDS",
"in",
"the",
"ICU.",
"At",
"baseline,",
"ARDS",
"cases",
"were",
"younger,",
"more",
"likely",
"to",
"be",
"in",
"a",
"surgical",
"ICU,",
"and",
"more",
"likely",
"to",
"be",
"admitted",
"with",
"pneumonia",
"or",
"sepsis",
"than",
"controls",
"without",
"ARDS.",
"Cases",
"also",
"were",
"more",
"likely",
"to",
"have",
"a",
"serum",
"creatinine",
"of",
"greater",
"than",
"2.0",
"mg/dl",
"(23%",
"versus",
"18%)",
"and",
"a",
"serum",
"albumin",
"of",
"less",
"than",
"or",
"equal",
"to",
"2.3",
"g/dl",
"(54%",
"versus",
"30%)",
"and",
"were",
"more",
"severely",
"ill",
"upon",
"ICU",
"admission",
"as",
"measured",
"by",
"either",
"the",
"APACHE",
"II",
"(Acute",
"Physiology",
"and",
"Chronic",
"Health",
"Evaluation",
"II)",
"or",
"SOFA",
"(Sequential",
"Organ",
"Failure",
"Assessment)",
"score",
"(p",
"<",
"0.05",
"for",
"all).",
"Sixty-seven",
"percent",
"and",
"42%",
"of",
"cases",
"and",
"controls,",
"respectively,",
"had",
"exposure",
"to",
"pRBC",
"transfusions",
"(p",
"<",
"0.05),",
"and",
"the",
"unadjusted",
"odds",
"ratio",
"(OR)",
"of",
"developing",
"ARDS",
"in",
"transfused",
"patients",
"was",
"2.74",
"(95%",
"confidence",
"interval",
"[CI],",
"2.09",
"to",
"3.59;",
"p",
"<",
"0.0001)",
"compared",
"to",
"those",
"never",
"transfused.",
"After",
"age,",
"baseline",
"severity",
"of",
"illness,",
"admitting",
"diagnosis,",
"and",
"process-of-care",
"factors",
"were",
"adjusted",
"for,",
"the",
"independent",
"relationship",
"between",
"pRBC",
"transfusions",
"and",
"ICU-onset",
"ARDS",
"remained",
"significant",
"(adjusted",
"OR,",
"2.80;",
"95%",
"CI,",
"1.90",
"to",
"4.12;",
"p",
"<",
"0.0001).",
"Conclusion",
"Development",
"of",
"ARDS",
"after",
"ICU",
"admission",
"is",
"common,",
"occurring",
"in",
"approximately",
"5%",
"of",
"critically",
"ill",
"patients.",
"Transfusion",
"of",
"pRBCs",
"is",
"independently",
"associated",
"with",
"the",
"development",
"of",
"ARDS",
"in",
"the",
"ICU.",
"Introduction",
"Acute",
"respiratory",
"distress",
"syndrome",
"(ARDS)",
"remains",
"a",
"fre-",
"quent",
"complication",
"of",
"critical",
"illness",
"and",
"is",
"associated",
"with",
"significant",
"morbidity",
"and",
"mortality.",
"Its",
"age-adjusted",
"incidence",
"rate",
"in",
"the",
"United",
"States",
"exceeds",
"85",
"cases",
"per",
"100,000",
"per-",
"son-years,",
"and",
"the",
"case",
"fatality",
"rate",
"is",
"near",
"40%",
"[1].",
"Illustrating",
"its",
"burden,",
"Rubenfeld",
"and",
"colleagues",
"[1]",
"estimated",
"that",
"ARDS",
"leads",
"to",
"200,000",
"intensive",
"care",
"unit",
"(ICU)",
"admissions",
"annu-",
"ally",
"and",
"necessitates",
"3.6",
"million",
"inpatient",
"days",
"of",
"care.",
"Multiple",
"insults",
"can",
"lead",
"to",
"ARDS",
"and",
"range",
"from",
"sepsis",
"to",
"trauma",
"[2-5].",
"Because",
"the",
"manner",
"in",
"which",
"care",
"is",
"delivered",
"to",
"at-risk",
"patients",
"may",
"contribute",
"to",
"ARDS",
"development,",
"there",
"is",
"a",
"need",
"to",
"better",
"understand",
"process-of-care",
"variables",
"in",
"APACHE",
"II",
"=",
"Acute",
"Physiology",
"and",
"Chronic",
"Health",
"Evaluation",
"II;",
"ARDS",
"=",
"acute",
"respiratory",
"distress",
"syndrome;",
"CI",
"=",
"confidence",
"interval;",
"ICU",
"=",
"inten-",
"sive",
"care",
"unit;",
"OR",
"=",
"odds",
"ratio;",
"pRBC",
"=",
"packed",
"red",
"blood",
"cell;",
"SIRS",
"=",
"systemic",
"inflammatory",
"response",
"syndrome;",
"SOFA",
"=",
"Sequential",
"Organ",
"Failure",
"Assessment;",
"TRALI",
"=",
"transfusion-related",
"acute",
"lung",
"injury.",
"Page",
"1",
"of",
"9",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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233,
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24,
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263,
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49,
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318,
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40,
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364,
820,
11,
14
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380,
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17,
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402,
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314,
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356,
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885,
9,
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617,
885,
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885,
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902,
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546,
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675,
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714,
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] | [
"e",
"n",
"i",
"c",
"i",
"d",
"e",
"M",
"l",
"a",
"t",
"n",
"e",
"m",
"i",
"r",
"e",
"p",
"x",
"E",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"CORRESPONDENCE",
"Tania",
"H.",
"Watts:",
"tania.watts@utoronto.ca",
"Abbreviations",
"used:",
"CHX,",
"cycloheximide;",
"LCMV,",
"lympho-",
"cytic",
"choriomeningitis",
"virus;",
"PD-1,",
"programmed",
"death",
"1;",
"siRNA,",
"small",
"interfering",
"RNA;",
"TRAF,",
"TNFR-associated",
"factor",
"1.",
"A",
"r",
"t",
"i",
"c",
"l",
"e",
"Loss",
"of",
"the",
"signaling",
"adaptor",
"TRAF1",
"causes",
"CD8+",
"T",
"cell",
"dysregulation",
"during",
"human",
"and",
"murine",
"chronic",
"infection",
"Chao",
"Wang,1",
"Ann",
"J.",
"McPherson,1",
"R.",
"Brad",
"Jones,1",
"Kim",
"S.",
"Kawamura,5",
"Gloria",
"H.Y.",
"Lin,1",
"Philipp",
"A.",
"Lang,1,5",
"Thanuja",
"Ambagala,1",
"Marc",
"Pellegrini,5",
"Thomas",
"Calzascia,5",
"Nasra",
"Aidarus,1",
"Alisha",
"R.",
"Elford,5",
"Feng",
"Yun",
"Yue,2",
"Elisabeth",
"Kremmer,6",
"Colin",
"M.",
"Kovacs,7",
"Erika",
"Benko,7",
"Cecile",
"Tremblay,8",
"Jean-Pierre",
"Routy,9",
"Nicole",
"F.",
"Bernard,10",
"Mario",
"A.",
"Ostrowski,1,2,4",
"Pamela",
"S.",
"Ohashi,1,3,5",
"and",
"Tania",
"H.",
"Watts1",
"1Department",
"of",
"Immunology,",
"2Clinical",
"Sciences",
"Division,",
"University",
"of",
"Toronto,",
"Toronto,",
"M5S",
"1A8,",
"Canada",
"3Department",
"of",
"Medical",
"Biophysics,",
"University",
"of",
"Toronto,",
"Toronto,",
"M5G",
"2M9,",
"Canada",
"4Li",
"Ka",
"Shing",
"Knowledge",
"Institute",
"at",
"St.",
"Michael’s",
"Hospital,",
"University",
"of",
"Toronto,",
"Toronto,",
"M5B",
"1W8,",
"Canada",
"5The",
"Campbell",
"Family",
"Cancer",
"Research",
"Institute,",
"Ontario",
"Cancer",
"Institute,",
"University",
"Health",
"Network,",
"Toronto,",
"M5G",
"2M9,",
"Canada",
"6Helmholtz",
"Zentrum",
"München,",
"German",
"Research",
"Center",
"for",
"Environmental",
"Health,",
"Institute",
"of",
"Molecular",
"Immunology,",
"83177",
"Munich,",
"Germany",
"7Maple",
"Leaf",
"Medical",
"Clinic,",
"Toronto,",
"M5B",
"1L6,",
"Canada",
"8Département",
"de",
"microbiologie",
"et",
"immunologie,",
"Université",
"de",
"Montréal,",
"Montréal,",
"H3C",
"3J7,",
"Canada",
"9Immunodeficiency",
"Service",
"and",
"Division",
"of",
"Hematology,",
"Royal",
"Victoria",
"Hospital,",
"and",
"10Research",
"Institute",
"of",
"the",
"McGill",
"University",
"Health",
"Center,",
"Montreal,",
"H3A",
"1A1,",
"Canada",
"The",
"signaling",
"adaptor",
"TNFR-associated",
"factor",
"1",
"(TRAF1)",
"is",
"specifically",
"lost",
"from",
"virus-specific",
"CD8",
"T",
"cells",
"during",
"the",
"chronic",
"phase",
"of",
"infection",
"with",
"HIV",
"in",
"humans",
"or",
"lymphocytic",
"chorio-",
"meningitis",
"virus",
"(LCMV)",
"clone",
"13",
"in",
"mice.",
"In",
"contrast,",
"TRAF1",
"is",
"maintained",
"at",
"higher",
"levels",
"in",
"virus-specific",
"T",
"cells",
"of",
"HIV",
"controllers",
"or",
"after",
"acute",
"LCMV",
"infection.",
"TRAF1",
"expression",
"negatively",
"correlates",
"with",
"programmed",
"death",
"1",
"expression",
"and",
"HIV",
"load",
"and",
"knockdown",
"of",
"TRAF1",
"in",
"CD8",
"T",
"cells",
"from",
"viral",
"controllers",
"results",
"in",
"decreased",
"HIV",
"suppression",
"ex",
"vivo.",
"Consistent",
"with",
"the",
"desensitization",
"of",
"the",
"TRAF1-binding",
"co-stimulatory",
"receptor",
"4-1BB,",
"4-1BBL–deficient",
"mice",
"have",
"defects",
"in",
"viral",
"control",
"early,",
"but",
"not",
"late,",
"in",
"chronic",
"infection.",
"TGF",
"induces",
"the",
"posttranslational",
"loss",
"of",
"TRAF1,",
"whereas",
"IL-7",
"restores",
"TRAF1",
"levels.",
"A",
"combination",
"treatment",
"with",
"IL-7",
"and",
"agonist",
"anti–4-1BB",
"antibody",
"at",
"3",
"wk",
"after",
"LCMV",
"clone",
"13",
"infection",
"expands",
"T",
"cells",
"and",
"reduces",
"viral",
"load",
"in",
"a",
"TRAF1-dependent",
"manner.",
"Moreover,",
"transfer",
"of",
"TRAF1+",
"but",
"not",
"TRAF1",
"memory",
"T",
"cells",
"at",
"the",
"chronic",
"stage",
"of",
"infection",
"reduces",
"viral",
"load.",
"These",
"findings",
"identify",
"TRAF1",
"as",
"a",
"potential",
"biomarker",
"of",
"HIV-specific",
"CD8",
"T",
"cell",
"fitness",
"during",
"the",
"chronic",
"phase",
"of",
"disease",
"and",
"a",
"target",
"for",
"therapy.",
"Immune",
"dysregulation",
"is",
"a",
"hallmark",
"of",
"chronic",
"viral",
"infection",
"(Virgin",
"et",
"al.,",
"2009).",
"Chronic",
"infection",
"with",
"human",
"immunodeficiency",
"virus",
"(HIV)",
"or",
"hepatitis",
"C",
"virus",
"in",
"humans,",
"or",
"with",
"lymphocytic",
"choriomeningitis",
"virus",
"(LCMV)",
"clone",
"13",
"in",
"mice,",
"results",
"in",
"up-regulation",
"of",
"in-",
"hibitory",
"receptors",
"such",
"as",
"programmed",
"death",
"1",
"(PD-1)",
"and",
"TIM-3",
"on",
"effector",
"T",
"cells,",
"as",
"well",
"as",
"the",
"sustained",
"production",
"of",
"immune",
"M.",
"Pellegrini’s",
"present",
"address",
"is",
"Walter",
"and",
"Eliza",
"Hall",
"Insti-",
"tute",
"of",
"Medical",
"Research,",
"Parkville,",
"Australia.",
"T.",
"Calzascia’s",
"present",
"address",
"is",
"Novartis",
"Institute",
"for",
"Bio-",
"medical",
"Research,",
"Basel,",
"Switzerland.",
"regulatory",
"cytokines",
"such",
"as",
"TGF",
"and",
"IL-10",
"(Barber",
"et",
"al.,",
"2006;",
"Day",
"et",
"al.,",
"2006;",
"Freeman",
"et",
"al.,",
"2006;",
"Petrovas",
"et",
"al.,",
"2006;",
"Trautmann",
"et",
"al.,",
"2006;",
"Urbani",
"et",
"al.,",
"2006;",
"Brooks",
"et",
"al.,",
"2008;",
"Jones",
"et",
"al.,",
"2008;",
"Tinoco",
"et",
"al.,",
"2009;",
"Jin",
"et",
"al.,",
"2010).",
"It",
"is",
"thought",
"that",
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"The",
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"University",
"Press",
"$30.00",
"J.",
"Exp.",
"Med.",
"Vol.",
"209",
"No.",
"1",
"77-91",
"www.jem.org/cgi/doi/10.1084/jem.20110675",
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Skin",
"Cancer",
"Volume",
"2012,",
"Article",
"ID",
"820474,",
"5",
"pages",
"doi:10.1155/2012/820474",
"Review",
"Article",
"New",
"Trends",
"in",
"Dermoscopy",
"to",
"Minimize",
"the",
"Risk",
"of",
"Missing",
"Melanoma",
"Aimilios",
"Lallas,1",
"Zoe",
"Apalla,1",
"and",
"Georgios",
"Chaidemenos2",
"1",
"State",
"Clinic",
"of",
"Dermatology,",
"Hospital",
"of",
"Skin",
"and",
"Venereal",
"Diseases,",
"124",
"Delfon",
"Street,",
"54643",
"Thessaloniki,",
"Greece",
"2",
"Private",
"Practice,",
"8",
"Kosma",
"Aitolou",
"Street,",
"54643",
"Thessaloniki,",
"Greece",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Aimilios",
"Lallas,",
"emlallas@gmail.com",
"Received",
"9",
"August",
"2012;",
"Accepted",
"18",
"September",
"2012",
"Academic",
"Editor:",
"Iris",
"Zalaudek",
"Copyright",
"©",
"2012",
"Aimilios",
"Lallas",
"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.",
"During",
"the",
"last",
"decades,",
"induction",
"of",
"dermoscopy",
"in",
"the",
"clinical",
"setting",
"resulted",
"in",
"significant",
"modifications",
"in",
"the",
"management",
"of",
"melanocytic",
"lesions.",
"Indeed,",
"the",
"dermatoscope",
"reveals",
"a",
"fascinating",
"world",
"of",
"morphologic",
"structures",
"invisible",
"to",
"the",
"naked",
"eye,",
"adding",
"valuable",
"information",
"to",
"a",
"clinician",
"evaluating",
"a",
"mole.",
"However,",
"since",
"the",
"technique",
"counts",
"only",
"a",
"couple",
"of",
"decades,",
"new",
"research",
"data",
"are",
"continuously",
"gathering",
"and",
"modify",
"the",
"“optimal”",
"management",
"of",
"melanocytic",
"lesions.",
"In",
"the",
"present",
"paper,",
"we",
"summarize",
"the",
"latest",
"trends",
"in",
"dermoscopy",
"concerning",
"early",
"melanoma",
"diagnosis,",
"management",
"of",
"nodular",
"lesions,",
"diagnosis",
"of",
"mucosal",
"melanoma,",
"and",
"digital",
"followup.",
"1.",
"Introduction",
"During",
"the",
"last",
"decades,",
"induction",
"of",
"dermoscopy",
"in",
"the",
"clin-",
"ical",
"setting",
"resulted",
"in",
"significant",
"modifications",
"in",
"the",
"man-",
"agement",
"of",
"melanocytic",
"lesions",
"[1].",
"Incidence",
"of",
"melanoma",
"increases",
"more",
"rapidly",
"than",
"any",
"other",
"cancer,",
"and",
"this",
"has",
"partially",
"been",
"attributed",
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"the",
"development",
"of",
"highly",
"sen-",
"sitive",
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"techniques—mainly",
"dermoscopy—,",
"which",
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"the",
"detection",
"of",
"clinically",
"not",
"identifiable",
"tumors",
"[2].",
"Indeed,",
"the",
"dermatoscope",
"reveals",
"a",
"fascinating",
"world",
"of",
"morphologic",
"structures",
"invisible",
"to",
"the",
"naked",
"eye,",
"adding",
"valuable",
"information",
"to",
"a",
"clinician",
"evaluating",
"a",
"mole.",
"The",
"controversy",
"whether",
"dermoscopy",
"improves",
"diagnos-",
"tic",
"accuracy",
"when",
"assessing",
"melanocytic",
"lesions",
"belongs",
"to",
"the",
"history,",
"since",
"several",
"lines",
"of",
"evidence",
"clearly",
"demonstrate",
"that",
"use",
"of",
"dermoscopy",
"both",
"enhances",
"melanoma",
"detection",
"and",
"decreases",
"the",
"number",
"of",
"unnecessary",
"excisions",
"[3].",
"Addi-",
"tionally",
"to",
"its",
"use",
"for",
"diagnostic",
"purposes,",
"dermoscopy,",
"by",
"revealing",
"unknown",
"information",
"on",
"morphology,",
"enhanced",
"the",
"understanding",
"of",
"nevogenesis",
"and",
"generated",
"new",
"con-",
"cepts",
"and",
"theories",
"[4].",
"However,",
"since",
"the",
"technique",
"counts",
"only",
"a",
"couple",
"of",
"decades,",
"new",
"research",
"data",
"are",
"continu-",
"ously",
"gathering",
"and",
"modify",
"the",
"“optimal”",
"management",
"of",
"melanocytic",
"lesions.",
"The",
"aim",
"of",
"this",
"paper",
"was",
"to",
"summarize",
"the",
"latest",
"trends",
"in",
"dermoscopy",
"for",
"minimizing",
"the",
"risk",
"to",
"miss",
"melanoma.",
"2.",
"New",
"Trends",
"in",
"Early",
"Melanoma",
"Detection",
"With",
"the",
"introduction",
"of",
"dermoscopy,",
"the",
"new",
"morphologic",
"world",
"of",
"features",
"and",
"structures",
"had",
"to",
"be",
"explored.",
"In",
"order",
"to",
"enhance",
"the",
"utility",
"of",
"the",
"method",
"in",
"the",
"clinical",
"setting,",
"various",
"diagnostic",
"models",
"and",
"algorithms",
"have",
"been",
"developed",
"[5–7].",
"Indeed,",
"application",
"of",
"these",
"algo-",
"rithms",
"resulted",
"in",
"significant",
"improvement",
"of",
"the",
"diagnostic",
"accuracy",
"of",
"clinicians",
"evaluating",
"melanocytic",
"lesions",
"[8–",
"10].",
"Simplified",
"diagnostic",
"approaches",
"were",
"also",
"proposed,",
"aiming",
"to",
"facilitate",
"the",
"use",
"of",
"dermoscopy",
"from",
"less",
"experi-",
"enced",
"clinicians",
"and",
"nondermatologists",
"and",
"thus",
"widen",
"the",
"application",
"field",
"of",
"the",
"method",
"[11].",
"Additionally",
"to",
"their",
"applicability",
"in",
"daily",
"routine,",
"algorithms",
"are",
"also",
"considered",
"of",
"value",
"for",
"educational",
"purposes,",
"providing",
"a",
"mathematic",
"and",
"comprehensive",
"model",
"and",
"guiding",
"the",
"inexperienced",
"clinician",
"on",
"how",
"to",
"deal",
"with",
"the",
"various",
"dermoscopic",
"features.",
"Several",
"lines",
"of",
"evidence,",
"including",
"meta-analyses",
"and",
"randomized",
"trials,",
"have",
"validated",
"the",
"value",
"of",
"dermoscopy"
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] | [
"Predictors",
"of",
"Safe",
"Delivery",
"Service",
"Mulumebet",
"A.",
"et",
"al",
"95",
"ORIGINAL",
"ARTICLE",
"PREDICTORS",
"OF",
"SAFE",
"DELIVERY",
"SERVICE",
"UTILIZATION",
"IN",
"ARSI",
"ZONE,",
"SOUTH-EAST",
"ETHIOPIA",
"Mulumebet",
"Abera1,",
"Abebe",
"G/mariam1,",
"Tefera",
"Belachew1",
"ABSTRACT",
"BACKGROUND:",
"Evidence",
"show",
"that",
"lack",
"of",
"access",
"to",
"and",
"use",
"of,",
"essential",
"obstetric",
"care",
"services",
"to",
"be",
"a",
"crucial",
"factor",
"that",
"contributes",
"to",
"the",
"high",
"maternal",
"morbidity",
"and",
"mortality.",
"Skilled",
"attendance",
"during",
"labor,",
"delivery",
"and",
"early",
"post-partum",
"period",
"could",
"reduce",
"deaths",
"due",
"to",
"obstructed",
"labor,",
"hemorrhage,",
"sepsis",
"and",
"eclampsia.",
"There",
"is",
"limited",
"information",
"on",
"the",
"mothers’",
"use",
"of",
"skilled",
"delivery",
"services",
"in",
"the",
"study",
"area.",
"This",
"study",
"assessed",
"the",
"predictors",
"of",
"safe",
"delivery",
"service",
"utilization",
"in",
"Arsi",
"Zone,",
"Southeast",
"Ethiopia.",
"METHODS:",
"A",
"cross-",
"sectional",
"community",
"based",
"study",
"using",
"quantitative",
"and",
"qualitative",
"methods",
"was",
"conducted",
"from",
"February",
"15th",
"to",
"March",
"15th",
"2006.",
"A",
"total",
"of",
"1089",
"women",
"who",
"had",
"at",
"least",
"one",
"birth",
"one",
"year",
"prior",
"to",
"the",
"study",
"were",
"involved",
"in",
"the",
"study",
"from",
"nine",
"rural",
"and",
"four",
"urban",
"kebeles",
"in",
"three",
"Woredas",
"(Districts)",
"selected",
"using",
"a",
"systematic",
"sampling",
"method",
"from",
"all",
"households",
"in",
"the",
"study",
"area.",
"A",
"pre-tested",
"structured",
"interviewer",
"administered",
"questionnaire",
"was",
"used",
"to",
"collect",
"data.",
"Information",
"on",
"the",
"utilization",
"of",
"safe",
"delivery",
"service",
"and",
"socio-demographic,",
"individual",
"and",
"institutional",
"factors",
"and",
"past",
"obstetric",
"history",
"were",
"collected.",
"Focus",
"Group",
"Discussion",
"guide",
"was",
"used",
"for",
"qualitative",
"data",
"collection.",
"The",
"data",
"were",
"edited,",
"cleaned,",
"and",
"entered",
"into",
"a",
"computer",
"and",
"analyzed",
"using",
"SPSS",
"for",
"windows",
"version",
"12.0.",
"RESULT:",
"One",
"thousand",
"seventy",
"four",
"women",
"who",
"had",
"at",
"least",
"one",
"birth",
"were",
"interviewed",
"making",
"a",
"response",
"rate",
"98.6%.",
"Two",
"hundred",
"seventy",
"one",
"(75.0%)",
"of",
"urban",
"and",
"373(52.0%)",
"rural",
"women",
"received",
"antenatal",
"care",
"from",
"skilled",
"health",
"professional",
"at",
"least",
"once",
"during",
"their",
"last",
"pregnancy.",
"Thirty-one",
"(4.3%)",
"of",
"rural",
"and",
"145",
"(40.4%)",
"of",
"urban",
"women",
"delivered",
"in",
"health",
"institution.",
"In",
"multivariate",
"analysis",
"showed",
"that",
"residential",
"area",
"OR=",
"8.5,",
"95%CI;",
"(5.1,13.9),",
"parity",
"OR=0.18,",
"95%CI;",
"(0.08,",
"0.42),",
"and",
"ANC",
"service",
"use",
"OR=",
"4.5,",
"95%CI;",
"(2.2,8.9),",
"and",
"maternal",
"education",
"OR=4.6,",
"95%CI;",
"(1.7,12.8),",
"were",
"most",
"significant",
"predictors",
"of",
"safe",
"delivery",
"service",
"use",
"by",
"mothers",
"(P<",
"0.01).",
"CONCLUSION:",
"Birth",
"attended",
"by",
"skilled",
"personnel",
"was",
"low",
"in",
"the",
"study",
"area.",
"Maternal",
"education,",
"her",
"birth",
"experience",
"and",
"her",
"use",
"of",
"prenatal",
"services",
"are",
"important",
"predictors.",
"Promoting",
"information,",
"education",
"and",
"communication",
"on",
"safe",
"delivery",
"service",
"utilization,",
"expansion",
"of",
"health",
"service",
"and",
"empowerment",
"of",
"women",
"are",
"needed.",
"KEY",
"WORDS:",
"safe",
"delivery,",
"skilled",
"attendants,",
"and",
"maternal",
"health",
"service",
"utilization.",
"INTRODUCTION",
"Globally",
"about",
"585,000",
"women",
"die",
"each",
"year",
"due",
"to",
"conditions",
"related",
"to",
"pregnancy",
"and",
"child",
"birth",
"99%",
"of",
"which",
"occur",
"in",
"developing",
"countries",
"(1).",
"Over",
"three",
"quarter",
"of",
"maternal",
"deaths",
"are",
"due",
"to",
"causes",
"directly",
"related",
"to",
"pregnancy",
"and",
"childbirth",
"(2).",
"The",
"complications",
"that",
"cause",
"the",
"deaths",
"and",
"disabilities",
"of",
"mothers",
"affect",
"the",
"unborn",
"fetus.",
"These",
"deaths",
"could",
"be",
"avoided",
"if",
"preventive",
"measures",
"were",
"taken",
"and",
"adequate",
"cares",
"available",
"particularly",
"during",
"pregnancy,",
"childbirth",
"and",
"postpartum",
"period",
"through",
"obstetric",
"care",
"services.",
"More",
"than",
"60%",
"of",
"maternal",
"deaths",
"occur",
"immediately",
"following",
"delivery,",
"with",
"more",
"than",
"half",
"occurring",
"within",
"a",
"day",
"of",
"delivery",
"(3-4).",
"--------------------------------------------------------",
"1Department",
"of",
"Population",
"&",
"Family",
"Health,",
"College",
"of",
"Public",
"Health",
"and",
"Medical",
"Sciences,",
"Jimma",
"University"
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] | [
"Int.",
"J.",
"Mol.",
"Sci.",
"2012,",
"13,",
"9959-9970;",
"doi:10.3390/ijms13089959",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Molecular",
"Sciences",
"ISSN",
"1422-0067",
"www.mdpi.com/journal/ijms",
"Article",
"Chick",
"Chorioallantoic",
"Membrane",
"(CAM)",
"Assay",
"as",
"an",
"In",
"Vivo",
"Model",
"to",
"Study",
"the",
"Effect",
"of",
"Newly",
"Identified",
"Molecules",
"on",
"Ovarian",
"Cancer",
"Invasion",
"and",
"Metastasis",
"Noor",
"A.",
"Lokman",
"1,",
"Alison",
"S.",
"F.",
"Elder",
"1,",
"Carmela",
"Ricciardelli",
"1",
"and",
"Martin",
"K.",
"Oehler",
"1,2,*",
"1",
"Research",
"Centre",
"for",
"Reproductive",
"Health,",
"School",
"of",
"Paediatrics",
"and",
"Reproductive",
"Health,",
"Robinson",
"Institute,",
"University",
"of",
"Adelaide,",
"Adelaide,",
"South",
"Australia",
"5000,",
"Australia;",
"E-Mails:",
"noor.lokman@adelaide.edu.au",
"(N.A.L.);",
"alison.elder@adelaide.edu.au",
"(A.S.F.E.);",
"carmela.ricciardelli@adelaide.edu.au",
"(C.R.)",
"2",
"Department",
"of",
"Gynaecological",
"Oncology,",
"Royal",
"Adelaide",
"Hospital,",
"Adelaide,",
"South",
"Australia",
"5000,",
"Australia",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"martin.oehler@adelaide.edu.au;",
"Tel.:",
"+61-8-8222-4816;",
"Fax:",
"+61-8-8222-5952.",
"Received:",
"2",
"July",
"2012;",
"in",
"revised",
"form:",
"27",
"July",
"2012",
"/",
"Accepted:",
"2",
"August",
"2012",
"/",
"Published:",
"10",
"August",
"2012",
"Abstract:",
"The",
"majority",
"of",
"ovarian",
"cancer",
"patients",
"present",
"with",
"advanced",
"disease",
"and",
"despite",
"aggressive",
"treatment,",
"prognosis",
"remains",
"poor.",
"Significant",
"improvement",
"in",
"ovarian",
"cancer",
"survival",
"will",
"require",
"the",
"development",
"of",
"more",
"effective",
"molecularly",
"targeted",
"therapeutics.",
"Commonly,",
"mouse",
"models",
"are",
"used",
"for",
"the",
"in",
"vivo",
"assessment",
"of",
"potential",
"new",
"therapeutic",
"targets",
"in",
"ovarian",
"cancer.",
"However,",
"animal",
"models",
"are",
"costly",
"and",
"time",
"consuming.",
"Other",
"models,",
"such",
"as",
"the",
"chick",
"embryo",
"chorioallantoic",
"membrane",
"(CAM)",
"assay,",
"are",
"therefore",
"an",
"attractive",
"alternative.",
"CAM",
"assays",
"have",
"been",
"widely",
"used",
"to",
"study",
"angiogenesis",
"and",
"tumor",
"invasion",
"of",
"colorectal,",
"prostate",
"and",
"brain",
"cancers.",
"However,",
"there",
"have",
"been",
"limited",
"studies",
"that",
"have",
"used",
"CAM",
"assays",
"to",
"assess",
"ovarian",
"cancer",
"invasion",
"and",
"metastasis.",
"We",
"have",
"therefore",
"developed",
"a",
"CAM",
"assay",
"protocol",
"to",
"monitor",
"the",
"metastatic",
"properties",
"of",
"ovarian",
"cancer",
"cells",
"(OVCAR-3,",
"SKOV-3",
"and",
"OV-90)",
"and",
"to",
"study",
"the",
"effect",
"of",
"potential",
"therapeutic",
"molecules",
"in",
"vivo.",
"The",
"results",
"from",
"the",
"CAM",
"assay",
"are",
"consistent",
"with",
"cancer",
"cell",
"motility",
"and",
"invasion",
"observed",
"in",
"in",
"vitro",
"assays.",
"Our",
"results",
"demonstrate",
"that",
"the",
"CAM",
"assay",
"is",
"a",
"robust",
"and",
"cost",
"effective",
"model",
"to",
"study",
"ovarian",
"cancer",
"cell",
"metastasis.",
"It",
"is",
"therefore",
"a",
"very",
"useful",
"in",
"vivo",
"model",
"for",
"screening",
"of",
"potential",
"novel",
"therapeutics."
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Obesity",
"Volume",
"2012,",
"Article",
"ID",
"735465,",
"11",
"pages",
"doi:10.1155/2012/735465",
"Research",
"Article",
"Unraveling",
"the",
"Relationship",
"between",
"Smoking",
"and",
"Weight:",
"The",
"Role",
"of",
"Sedentary",
"Behavior",
"Annette",
"Kaufman,1",
"Erik",
"M.",
"Augustson,2",
"and",
"Heather",
"Patrick3",
"1",
"Cancer",
"Prevention",
"Fellowship",
"Program,",
"Office",
"of",
"the",
"Associate",
"Director,",
"Behavioral",
"Research",
"Program,",
"Division",
"of",
"Cancer",
"Control",
"and",
"Population",
"Sciences,",
"National",
"Cancer",
"Institute,",
"Bethesda,",
"MD",
"20852,",
"USA",
"2",
"Tobacco",
"Control",
"Research",
"Branch,",
"Behavioral",
"Research",
"Program,",
"Division",
"of",
"Cancer",
"Control",
"and",
"Population",
"Sciences,",
"National",
"Cancer",
"Institute,",
"Bethesda,",
"MD",
"20852,",
"USA",
"3",
"Health",
"Behaviors",
"Research",
"Branch,",
"Behavioral",
"Research",
"Program,",
"Division",
"of",
"Cancer",
"Control",
"and",
"Population",
"Sciences,",
"National",
"Cancer",
"Institute,",
"Bethesda,",
"MD",
"20852,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Annette",
"Kaufman,",
"kaufmana@mail.nih.gov",
"Received",
"2",
"May",
"2011;",
"Revised",
"1",
"July",
"2011;",
"Accepted",
"5",
"July",
"2011",
"Academic",
"Editor:",
"Susan",
"B.",
"Sisson",
"Copyright",
"©",
"2012",
"Annette",
"Kaufman",
"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.",
"Research",
"has",
"shown",
"that",
"current",
"smokers",
"have",
"a",
"lower",
"mean",
"body",
"mass",
"index",
"(BMI)",
"than",
"never",
"and",
"former",
"smokers,",
"with",
"former",
"smokers",
"having",
"the",
"highest",
"mean",
"BMI.",
"A",
"number",
"of",
"physiological",
"mechanisms",
"have",
"been",
"hypothesized",
"to",
"explain",
"this",
"pattern,",
"but",
"few",
"studies",
"have",
"explored",
"the",
"possible",
"role",
"of",
"behavioral",
"factors.",
"Using",
"data",
"from",
"the",
"cross-sectional",
"National",
"Health",
"and",
"Nutrition",
"Examination",
"Survey",
"1999–2006,",
"this",
"descriptive",
"study",
"explored",
"the",
"associations",
"among",
"smoking",
"status,",
"sedentary",
"behavior,",
"and",
"two",
"anthropometric",
"measures",
"(BMI",
"and",
"waist",
"circumference",
"(WC)).",
"Sedentary",
"behavior",
"was",
"significantly",
"higher",
"among",
"current",
"smokers",
"compared",
"to",
"never",
"and",
"former",
"smokers;",
"former",
"smokers",
"had",
"higher",
"levels",
"of",
"sedentary",
"behavior",
"compared",
"to",
"never",
"smokers.",
"The",
"association",
"between",
"smoking",
"status",
"and",
"anthropometric",
"outcomes",
"was",
"moderated",
"by",
"sedentary",
"behavior,",
"with",
"current",
"smokers",
"evidencing",
"higher",
"BMI",
"and",
"WC",
"at",
"higher",
"levels",
"of",
"sedentary",
"behavior",
"compared",
"to",
"lower",
"levels",
"of",
"sedentary",
"behavior.",
"Results",
"are",
"discussed",
"in",
"terms",
"of",
"their",
"implications",
"for",
"interventions,",
"particularly",
"with",
"respect",
"to",
"postcessation",
"weight",
"gain.",
"1.",
"Background",
"Obesity",
"and",
"tobacco",
"use",
"are",
"the",
"two",
"leading",
"causes",
"of",
"preventable",
"death",
"and",
"disease",
"in",
"the",
"United",
"States",
"[1].",
"Despite",
"declines",
"in",
"smoking",
"prevalence",
"from",
"a",
"peak",
"in",
"the",
"1960s,",
"tobacco",
"use",
"remains",
"the",
"leading",
"cause",
"of",
"preventable",
"death",
"and",
"disease",
"in",
"the",
"USA",
"[2].",
"It",
"is",
"estimated",
"that",
"440,000",
"Americans",
"die",
"prematurely",
"each",
"year",
"as",
"a",
"result",
"of",
"tobacco",
"use",
"and",
"exposure",
"[3].",
"Approximately",
"20.6%",
"of",
"USA",
"adults",
"are",
"current",
"smokers,",
"defined",
"as",
"smoking",
"at",
"least",
"100",
"cigarettes",
"during",
"their",
"lifetime",
"and",
"every",
"day",
"or",
"some",
"days",
"currently",
"[4].",
"As",
"smoking",
"rates",
"have",
"declined,",
"obesity",
"rates",
"(having",
"a",
"body",
"mass",
"index",
"(BMI)",
"of",
"30",
"or",
"higher)",
"have",
"doubled",
"in",
"the",
"USA",
"since",
"1980",
"with",
"recent",
"data",
"indicating",
"that",
"more",
"than",
"33%",
"of",
"USA",
"adults",
"are",
"obese",
"[5].",
"The",
"rate",
"of",
"mortality",
"due",
"to",
"overweight/obesity",
"is",
"estimated",
"to",
"account",
"for",
"approximately",
"365,000",
"deaths",
"yearly",
"[6].",
"Research",
"indicates",
"that",
"smoking",
"and",
"body",
"weight",
"are",
"interrelated,",
"but",
"the",
"relationship",
"is",
"complex",
"and",
"not",
"well",
"understood.",
"In",
"general,",
"cigarette",
"smoking",
"has",
"an",
"inverse",
"association",
"with",
"body",
"weight",
"or",
"BMI",
"[7–9],",
"and",
"smoking",
"cessation",
"has",
"been",
"linked",
"to",
"weight",
"gain",
"[8,",
"10,",
"11].",
"Few",
"studies",
"have",
"examined",
"the",
"relationship",
"between",
"smoking",
"and",
"body",
"shape,",
"specifically",
"central",
"adiposity.",
"Some",
"stud-",
"ies",
"suggest",
"that",
"smokers",
"have",
"greater",
"abdominal",
"obesity",
"compared",
"to",
"nonsmokers",
"[12–14].",
"Independent",
"of",
"overall",
"adiposity,",
"having",
"a",
"larger",
"waist",
"circumference",
"(WC),",
"or",
"android",
"body",
"shape,",
"is",
"associated",
"with",
"mortality",
"in",
"adults",
"age",
"50",
"and",
"older",
"and",
"metabolic",
"disease",
"risk",
"[15–17].",
"Body",
"shape,",
"rather",
"than",
"BMI,",
"may",
"better",
"explain",
"why",
"smokers",
"have",
"a",
"higher",
"risk",
"of",
"metabolic",
"syndrome,",
"in",
"particular",
"type",
"2",
"diabetes",
"[18].",
"A",
"number",
"of",
"biological",
"mechanisms",
"have",
"been",
"proposed",
"to",
"explain",
"this",
"relationship",
"between"
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] | [
"Bradley",
"et",
"al.",
"Arthritis",
"Research",
"&",
"Therapy",
"2010,",
"12:R141",
"http://arthritis-research.com/content/12/4/R141",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Effect",
"of",
"duloxetine",
"in",
"patients",
"with",
"fibromyalgia:",
"tiredness",
"subgroups",
"Laurence",
"A",
"Bradley1,",
"Robert",
"Bennett2,",
"Irwin",
"J",
"Russell3,",
"Madelaine",
"M",
"Wohlreich4*,",
"Amy",
"S",
"Chappell5,6,",
"Fujun",
"Wang7,",
"Deborah",
"N",
"D’Souza8,",
"Harvey",
"Moldofsky9",
"Abstract",
"Introduction:",
"This",
"study",
"tested",
"the",
"hypothesis",
"that",
"baseline",
"ratings",
"of",
"fatigue/tiredness",
"would",
"be",
"negatively",
"associated",
"with",
"the",
"efficacy",
"of",
"duloxetine",
"on",
"measures",
"of",
"pain",
"and",
"functional",
"ability",
"in",
"patients",
"with",
"fibromyalgia.",
"Methods:",
"A",
"post",
"hoc",
"analysis",
"of",
"pooled",
"data",
"from",
"4",
"double-blind,",
"placebo-controlled",
"studies",
"of",
"duloxetine",
"in",
"fibromyalgia",
"was",
"performed.",
"The",
"fibromyalgia",
"impact",
"questionnaire",
"(FIQ)",
"tiredness",
"item",
"score",
"(0",
"to",
"10",
"scale)",
"was",
"used",
"to",
"define",
"tiredness",
"subgroups.",
"Patients",
"were",
"stratified",
"into",
"3",
"subgroups:",
"mild",
"(0",
"to",
"3),",
"moderate",
"(4",
"to",
"6),",
"and",
"severe",
"(7",
"to",
"10)",
"tiredness.",
"Analysis",
"of",
"covariance",
"models",
"and",
"logistic",
"regressions",
"were",
"used",
"to",
"test",
"treatment-by-",
"tiredness",
"subgroup",
"interactions.",
"Results:",
"Data",
"from",
"the",
"first",
"3",
"months",
"are",
"included",
"in",
"this",
"post",
"hoc",
"analysis",
"(duloxetine",
"N",
"=",
"797,",
"placebo",
"N",
"=",
"535).",
"At",
"baseline,",
"the",
"distribution",
"of",
"tiredness",
"severity",
"in",
"the",
"duloxetine",
"and",
"placebo",
"groups",
"respectively",
"was",
"3.64%",
"and",
"3.75%",
"mild,",
"16.71%",
"and",
"15.57%",
"moderate,",
"and",
"79.65%",
"and",
"80.68%",
"severe.",
"Rates",
"of",
"clinically",
"significant",
"(≥30%",
"and",
"≥50%)",
"improvement",
"in",
"brief",
"pain",
"inventory",
"(BPI)",
"average",
"pain",
"were",
"similar",
"across",
"the",
"tiredness",
"subgroups.",
"Tiredness",
"severity",
"at",
"baseline",
"was",
"not",
"negatively",
"associated",
"with",
"the",
"effects",
"of",
"duloxetine",
"on",
"patients’",
"reports",
"of",
"functional",
"ability",
"using",
"the",
"FIQ",
"total",
"score,",
"FIQ",
"measures",
"of",
"physical",
"impairment,",
"interference",
"with",
"work,",
"pain,",
"stiffness,",
"and",
"depression",
"and",
"the",
"medical",
"outcomes",
"study",
"short",
"form-36",
"(SF-36).",
"Conclusions:",
"Studies",
"of",
"duloxetine",
"in",
"fibromyalgia",
"have",
"demonstrated",
"clinically",
"significant",
"improvements",
"in",
"pain",
"and",
"functional",
"ability",
"(FIQ,",
"SF-36).",
"This",
"post",
"hoc",
"analysis",
"of",
"data",
"shows",
"that",
"the",
"efficacy",
"of",
"duloxetine",
"among",
"patients",
"with",
"fibromyalgia",
"does",
"not",
"vary",
"as",
"a",
"function",
"of",
"baseline",
"ratings",
"of",
"fatigue/tiredness.",
"Introduction",
"Fibromyalgia",
"is",
"a",
"disorder",
"that",
"is",
"found",
"in",
"approximately",
"2%",
"of",
"the",
"general",
"population",
"and",
"is",
"characterized",
"by",
"chronic",
"widespread",
"pain",
"and",
"tenderness",
"[1].",
"Additional",
"symptoms",
"that",
"often",
"accompany",
"fibromyalgia",
"are",
"tired-",
"ness",
"or",
"fatigue,",
"depressed",
"mood,",
"sleep",
"disturbance,",
"and",
"headache",
"[2,3].",
"We",
"will",
"use",
"the",
"term",
"‘tiredness’",
"through-",
"out",
"this",
"report,",
"due",
"to",
"our",
"decision",
"to",
"use",
"the",
"fibro-",
"myalgia",
"impact",
"questionnaire",
"(FIQ)",
"outcome",
"measure,",
"unless",
"we",
"refer",
"specifically",
"to",
"studies",
"that",
"have",
"used",
"measures",
"of",
"‘fatigue’.",
"Duloxetine,",
"a",
"potent",
"reuptake",
"inhibitor",
"of",
"serotonin",
"and",
"norepinephrine,",
"was",
"approved",
"in",
"the",
"USA",
"for",
"the",
"management",
"of",
"fibromyalgia",
"in",
"June",
"2008.",
"Preclinical",
"*",
"Correspondence:",
"mwmd@lilly.com",
"4Lilly",
"Research",
"Laboratories,",
"Lilly",
"Corporate",
"Center,",
"Indianapolis,",
"IN",
"46285,",
"USA",
"models",
"of",
"central",
"sensitization",
"suggest",
"that",
"duloxetine",
"is",
"efficacious",
"in",
"the",
"treatment",
"of",
"patients",
"with",
"persistent/",
"chronic",
"pain.",
"In",
"rodents,",
"duloxetine",
"has",
"demonstrated",
"efficacy",
"in",
"the",
"formalin",
"and",
"capsaicin",
"models",
"of",
"persis-",
"tent",
"pain,",
"as",
"well",
"as",
"in",
"the",
"partial",
"sciatic",
"nerve",
"ligation",
"and",
"L5/L6",
"spinal",
"nerve",
"ligation",
"models",
"of",
"neuropathic",
"pain",
"[4,5].",
"Duloxetine",
"is",
"efficacious",
"in",
"the",
"treatment",
"of",
"the",
"painful",
"physical",
"symptoms",
"associated",
"with",
"depres-",
"sion",
"and",
"the",
"pain",
"associated",
"with",
"diabetic",
"neuropathy",
"in",
"nondepressed",
"patients",
"[6,7].",
"The",
"results",
"of",
"four",
"placebo-",
"controlled",
"clinical",
"trials",
"of",
"duloxetine",
"in",
"the",
"treatment",
"of",
"fibromyalgia",
"have",
"been",
"previously",
"reported",
"[8-11].",
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"frequently",
"report",
"moderate",
"to",
"severe",
"fatigue",
"and",
"the",
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"is",
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"literature",
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"found",
"a",
"highly",
"consistent",
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"©",
"2010",
"Bradley",
"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",
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"work",
"is",
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] | [
"Hindawi",
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"PPAR",
"Research",
"Volume",
"2012,",
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"ID",
"513865,",
"12",
"pages",
"doi:10.1155/2012/513865",
"Review",
"Article",
"The",
"Case",
"for",
"the",
"Use",
"of",
"PPARγ",
"Agonists",
"as",
"an",
"Adjunctive",
"Therapy",
"for",
"Cerebral",
"Malaria",
"Lena",
"Serghides",
"Sandra",
"A.",
"Rotman",
"Laboratories,",
"McLaughlin-Rotman",
"Centre",
"for",
"Global",
"Health,",
"Toronto",
"General",
"Hospital",
"University",
"Health",
"Network,",
"101",
"College",
"Street,",
"Suite",
"10-359,",
"Toronto,",
"ON,",
"Canada",
"M5G",
"1L7",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Lena",
"Serghides,",
"lena.serghides@utoronto.ca",
"Received",
"7",
"January",
"2011;",
"Accepted",
"28",
"February",
"2011",
"Academic",
"Editor:",
"Marion",
"M.",
"Chan",
"Copyright",
"©",
"2012",
"Lena",
"Serghides.",
"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.",
"Cerebral",
"malaria",
"is",
"a",
"severe",
"complication",
"of",
"Plasmodium",
"falciparum",
"infection",
"associated",
"with",
"high",
"mortality",
"even",
"when",
"highly",
"effective",
"antiparasitic",
"therapy",
"is",
"used.",
"Adjunctive",
"therapies",
"that",
"modify",
"the",
"pathophysiological",
"processes",
"caused",
"by",
"malaria",
"are",
"a",
"possible",
"way",
"to",
"improve",
"outcome.",
"This",
"review",
"focuses",
"on",
"the",
"utility",
"of",
"PPARγ",
"agonists",
"as",
"an",
"adjunctive",
"therapy",
"for",
"the",
"treatment",
"of",
"cerebral",
"malaria.",
"The",
"current",
"knowledge",
"of",
"PPARγ",
"agonist",
"use",
"in",
"malaria",
"is",
"summarized.",
"Findings",
"from",
"experimental",
"CNS",
"injury",
"and",
"disease",
"models",
"that",
"demonstrate",
"the",
"potential",
"for",
"PPARγ",
"agonists",
"as",
"an",
"adjunctive",
"therapy",
"for",
"cerebral",
"malaria",
"are",
"also",
"discussed.",
"1.",
"Introduction",
"Few",
"diseases",
"have",
"the",
"global",
"health",
"and",
"economic",
"impact",
"of",
"malaria",
"[1].",
"In",
"2009,",
"an",
"estimated",
"225",
"million",
"people",
"were",
"infected",
"with",
"malaria",
"and",
"close",
"to",
"a",
"million",
"people",
"succumbed",
"to",
"their",
"infection",
"[2].",
"Malaria",
"is",
"caused",
"by",
"api-",
"complexan",
"parasites",
"belonging",
"to",
"the",
"genus",
"Plasmodium.",
"Five",
"species",
"infect",
"humans,",
"Plasmodium",
"falciparum,",
"P.",
"vivax,",
"P.",
"ovale,",
"P.",
"malariae,",
"and",
"most",
"recently,",
"P.",
"knowlesi",
"[3].",
"The",
"majority",
"of",
"morbidity",
"and",
"mortality",
"is",
"caused",
"by",
"P.",
"falciparum",
"infection,",
"with",
"the",
"highest",
"burden",
"born",
"by",
"children",
"and",
"pregnant",
"women.",
"In",
"the",
"absence",
"of",
"prompt",
"and",
"effective",
"treatment,",
"P.",
"falciparum",
"infection",
"can",
"progress",
"quickly,",
"rapidly",
"becoming",
"severe",
"and",
"fatal.",
"The",
"rise",
"in",
"drug-",
"resistant",
"parasites",
"complicates",
"the",
"administration",
"of",
"effective",
"treatment.",
"Severe",
"malaria",
"has",
"multiple",
"manifestations",
"that",
"can",
"occur",
"singly",
"or",
"in",
"combination.",
"They",
"include",
"hyperpar-",
"asitemia,",
"high",
"fever,",
"haemoglobinuria,",
"acute",
"renal",
"failure,",
"acute",
"pulmonary",
"edema,",
"metabolic",
"acidosis",
"and",
"respiratory",
"distress,",
"hypoglycemia,",
"anemia,",
"and",
"cerebral",
"malaria,",
"which",
"is",
"characterized",
"by",
"coma",
"and",
"convulsions.",
"Cerebral",
"malaria",
"has",
"the",
"highest",
"mortality",
"rate",
"of",
"all",
"the",
"severe",
"complications",
"and",
"is",
"associated",
"with",
"long-term",
"cognitive",
"and",
"neurological",
"deficits",
"in",
"surviving",
"children",
"[4–6].",
"Intravenous",
"artesunate",
"is",
"now",
"the",
"standard",
"of",
"care",
"for",
"severe",
"malaria",
"in",
"both",
"adults",
"and",
"children",
"following",
"the",
"landmark",
"SEAQUAMAT",
"and",
"AQUAMAT",
"trials",
"that",
"demonstrated",
"the",
"superiority",
"of",
"artesunate",
"over",
"quinine",
"in",
"adults",
"and",
"in",
"children",
"[7,",
"8].",
"However,",
"even",
"with",
"the",
"improved",
"efficacy",
"of",
"artesunate,",
"fatality",
"rates",
"remained",
"high,",
"15%",
"in",
"adults",
"and",
"10.9%",
"in",
"children.",
"Adjunctive",
"therapies,",
"defined",
"as",
"therapies",
"administered",
"in",
"combination",
"with",
"antiparasitic",
"drugs",
"that",
"modify",
"pathophysiological",
"processes",
"caused",
"by",
"malaria,",
"have",
"been",
"pursued",
"as",
"a",
"way",
"to",
"improve",
"the",
"outcome",
"of",
"severe",
"malaria.",
"Adjunctive",
"therapies",
"may",
"also",
"help",
"extend",
"the",
"efficacy",
"of",
"antiparasitic",
"drugs,",
"an",
"important",
"consideration",
"given",
"the",
"emergence",
"of",
"artemisinin",
"resistance",
"[9,",
"10].",
"Several",
"adjunctive",
"therapeutic",
"strategies",
"have",
"been",
"tested",
"in",
"P.",
"falciparum",
"cerebral",
"and",
"severe",
"malaria",
"so",
"far,",
"unfortunately",
"with-out",
"much",
"success",
"(see",
"[11]",
"for",
"a",
"recent",
"review).",
"A",
"number",
"of",
"adjunctive",
"therapies",
"(includ-",
"ing",
"nitric",
"oxide,",
"arginine,",
"erythropoietin,",
"levamisole)",
"have",
"demonstrated",
"encouraging",
"results",
"in",
"experimental",
"models",
"of",
"cerebral",
"malaria",
"or",
"in",
"clinical",
"trials",
"in",
"uncomplicated",
"malaria",
"and",
"are",
"awaiting",
"evaluation",
"in",
"severe",
"malaria",
"[11].",
"This",
"review",
"will",
"focus",
"on",
"the",
"utility",
"of",
"PPARγ",
"agonists",
"as",
"an",
"adjunctive",
"therapy",
"for",
"the",
"treatment",
"of",
"cerebral",
"malaria.",
"The",
"current",
"knowledge",
"of",
"PPARγ",
"agonist",
"use",
"in",
"malaria",
"will",
"be",
"summarized.",
"We",
"will",
"also",
"summarize",
"data",
"on",
"additional"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Sarcoma",
"Volume",
"2010,",
"Article",
"ID",
"353679,",
"3",
"pages",
"doi:10.1155/2010/353679",
"Case",
"Report",
"Recurrent",
"Endometrial",
"Stromal",
"Sarcoma:",
"Treatment",
"with",
"a",
"Progestin",
"and",
"Gonadotropin",
"Releasing",
"Hormone",
"Agonist",
"Nefertiti",
"Chianti",
"duPont",
"and",
"Philip",
"John",
"DiSaia",
"Division",
"of",
"Gynecologic",
"Oncology,",
"Department",
"of",
"Obstetrics",
"and",
"Gynecology,",
"University",
"of",
"California,",
"Irvine",
"College",
"of",
"Medicine,",
"Orange,",
"CA",
"92868,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Nefertiti",
"Chianti",
"duPont,",
"nefertiti.dupont@roswellpark.org",
"Received",
"2",
"September",
"2009;",
"Revised",
"24",
"March",
"2010;",
"Accepted",
"8",
"April",
"2010",
"Academic",
"Editor:",
"Michael",
"Leahy",
"Copyright",
"©",
"2010",
"N.",
"C.",
"duPont",
"and",
"P.",
"J.",
"DiSaia.",
"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.",
"Endometrial",
"stromal",
"sarcoma",
"(ESS)",
"formerly",
"classified",
"as",
"low-grade",
"endometrial",
"stromal",
"sarcoma",
"is",
"a",
"rare",
"uterine",
"malignancy",
"with",
"a",
"good",
"prognosis",
"despite",
"a",
"tendency",
"to",
"recur.",
"Primary",
"surgical",
"management",
"for",
"ESS",
"includes",
"total",
"abdominal",
"hysterectomy",
"and",
"bilateral",
"salpingo-oophorectomy.",
"Patients",
"with",
"ESS",
"have",
"long",
"disease-free",
"survival",
"rates",
"when",
"treated",
"with",
"primary",
"surgical",
"therapy,",
"but",
"nearly",
"fifty",
"percent",
"of",
"these",
"patients",
"will",
"recur.",
"We",
"present",
"the",
"case",
"of",
"a",
"patient",
"with",
"recurrent",
"ESS",
"who",
"had",
"an",
"excellent",
"response",
"to",
"combined",
"therapy",
"with",
"megestrol",
"and",
"leuprolide.",
"1.",
"Introduction",
"First",
"reported",
"in",
"1908,",
"endometrial",
"stromal",
"sarcoma",
"(ESS)",
"is",
"a",
"rare",
"uterine",
"tumor",
"known",
"for",
"its",
"slow",
"growth",
"[1].",
"Originally",
"known",
"as",
"interstitial",
"endometrioma,",
"endolym-",
"phatic",
"stromal",
"myosis,",
"or",
"low-grade",
"endometrial",
"stromal",
"sarcoma",
"ESS",
"is",
"recognized",
"by",
"its",
"infiltrating",
"margins",
"and",
"low",
"mitotic",
"activity",
"[2–4].",
"Endometrial",
"stromal",
"sarcomas",
"represent",
"0.2%",
"of",
"all",
"genital",
"tract",
"malignancies",
"and",
"were",
"previously",
"subdivided",
"into",
"low-",
"or",
"high-grade",
"categories",
"based",
"upon",
"their",
"mitotic",
"index.",
"High-grade",
"endometrial",
"stromal",
"sarcomas",
"are",
"now",
"termed",
"poorly",
"differentiated",
"or",
"undifferentiated",
"uterine",
"sarcomas",
"due",
"to",
"its",
"aggressive",
"clinical",
"course",
"[5–10].",
"Typically",
"diagnosed",
"postoperatively",
"on",
"hysterectomy",
"specimens,",
"ESS",
"has",
"an",
"indolent",
"course",
"and",
"recurrent",
"disease",
"can",
"occur",
"up",
"to",
"twenty",
"years",
"after",
"diagnosis.",
"Primary",
"ESS",
"is",
"treated",
"surgically",
"with",
"a",
"total",
"abdominal",
"hysterectomy",
"and",
"bilateral",
"salpingo-oophorectomy",
"and",
"routine",
"lymphadenec-",
"tomy",
"has",
"not",
"been",
"found",
"to",
"improve",
"overall",
"survival",
"rates",
"[1,",
"3,",
"7,",
"8].",
"Recurrent",
"ESS",
"is",
"commonly",
"treated",
"with",
"progestins",
"like",
"other",
"endometrial",
"cancers",
"but",
"there",
"is",
"no",
"consensus",
"regarding",
"optimal",
"management",
"[5].",
"ESS",
"is",
"hormonally",
"responsive",
"and",
"contains",
"estrogen",
"and",
"progesterone",
"receptors",
"[5,",
"11–13].",
"Patients",
"with",
"retained",
"ovaries",
"after",
"a",
"hysterec-",
"tomy",
"or",
"those",
"who",
"receive",
"estrogen",
"hormone",
"replacement",
"have",
"high",
"recurrence",
"rates;",
"therefore,",
"single",
"agent",
"estrogen",
"replacement",
"therapy",
"is",
"not",
"recommended",
"[5].",
"Progestins",
"however",
"are",
"commonly",
"used",
"in",
"the",
"adjuvant",
"setting",
"to",
"treat",
"ESS",
"[5].",
"The",
"mechanism",
"of",
"action",
"of",
"progestins",
"is",
"to",
"bind",
"progesterone",
"receptors",
"and",
"cause",
"downregulation",
"of",
"gene",
"transcription",
"leading",
"to",
"decreased",
"endometrial",
"gland",
"and",
"stromal",
"proliferation",
"[11,",
"14].",
"Diminished",
"endometrial",
"gland",
"and",
"stromal",
"proliferation",
"make",
"progestins",
"beneficial",
"for",
"use",
"in",
"the",
"adjuvant",
"setting",
"and",
"at",
"the",
"time",
"of",
"disease",
"recurrence.",
"In",
"addition,",
"gonadotropin",
"releasing",
"hormone",
"(GnRH)",
"agonists",
"downregulate",
"GnRH",
"receptors",
"in",
"the",
"anterior",
"pituitary",
"leading",
"to",
"a",
"hypoestrogenic",
"state.",
"Here,",
"we",
"present",
"the",
"long-term",
"followup",
"of",
"a",
"patient",
"with",
"recurrent",
"endometrial",
"stromal",
"sarcoma",
"treated",
"with",
"a",
"progestin",
"and",
"GnRH",
"agonist",
"with",
"excellent",
"results.",
"2.",
"Case",
"Report",
"A",
"41-year-old",
"woman",
"gravida",
"2",
"para",
"1",
"with",
"a",
"body",
"mass",
"index",
"of",
"25",
"presented",
"with",
"menorrhagia,",
"pelvic",
"pain,",
"and",
"dysmenorrhea.",
"Her",
"past",
"medical",
"history",
"was",
"unremarkable.",
"Her",
"past",
"surgical",
"history",
"was",
"pertinent",
"for",
"a",
"bilateral"
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] | [
"Huang",
"et",
"al.",
"Journal",
"of",
"Cardiothoracic",
"Surgery",
"2010,",
"5:88",
"http://www.cardiothoracicsurgery.org/content/5/1/88",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Lung",
"abscess",
"predicts",
"the",
"surgical",
"outcome",
"in",
"patients",
"with",
"pleural",
"empyema",
"Hung-Che",
"Huang1,",
"Heng-Chung",
"Chen1,",
"Hsin-Yuan",
"Fang2*,",
"Yi-Chieh",
"Lin1,",
"Chin-Yen",
"Wu1,",
"Ching-Yuan",
"Cheng1",
"Abstract",
"Objectives:",
"Most",
"cases",
"of",
"pleural",
"empyema",
"are",
"caused",
"by",
"pulmonary",
"infections,",
"which",
"are",
"usually",
"combined",
"with",
"pneumonia",
"or",
"lung",
"abscess.",
"The",
"mortality",
"of",
"patients",
"with",
"pleural",
"empyema",
"remains",
"high",
"(up",
"to",
"20%).",
"It",
"also",
"contributes",
"to",
"higher",
"hospital",
"costs",
"and",
"longer",
"hospital",
"stays.",
"We",
"studied",
"pleural",
"empyema",
"with",
"combined",
"lung",
"abscess",
"to",
"determine",
"if",
"abscess",
"was",
"associated",
"with",
"mortality.",
"Methods:",
"From",
"January",
"2004",
"to",
"December",
"2006,",
"we",
"retrospectively",
"reviewed",
"259",
"patients",
"diagnosed",
"with",
"pleural",
"empyema",
"who",
"received",
"thoracscopic",
"decortications",
"of",
"the",
"pleura",
"in",
"a",
"single",
"medical",
"center.",
"We",
"evaluated",
"their",
"clinical",
"data",
"and",
"analyzed",
"their",
"chest",
"computed",
"tomography",
"scans.",
"Outcomes",
"of",
"pleural",
"empyema",
"were",
"compared",
"between",
"groups",
"with",
"and",
"without",
"lung",
"abscess.",
"Results:",
"Twenty-two",
"pleural",
"empyema",
"patients",
"had",
"lung",
"abscesses.",
"Clinical",
"data",
"showed",
"significantly",
"higher",
"incidences",
"in",
"the",
"lung",
"abscess",
"group",
"of",
"pre-operative",
"leukocytosis,",
"need",
"for",
"an",
"intensive",
"care",
"unit",
"stay",
"and",
"mortality.",
"Conclusion:",
"Patients",
"with",
"pleural",
"empyema",
"and",
"lung",
"abscess",
"have",
"higher",
"intensive",
"care",
"unit",
"admission",
"rate,",
"higher",
"mortality",
"during",
"30",
"days",
"and",
"overall",
"mortality",
"than",
"patients",
"with",
"pleural",
"empyema.",
"The",
"odds",
"ratio",
"of",
"lung",
"abscess",
"is",
"4.685.",
"Physician",
"shall",
"pay",
"more",
"attention",
"on",
"high",
"risk",
"patient",
"of",
"lung",
"abscess",
"for",
"early",
"detection",
"and",
"management.",
"Background",
"Pleural",
"empyema",
"is",
"one",
"of",
"the",
"serious",
"complications",
"of",
"pneumonia,",
"and",
"increases",
"the",
"morbidity",
"and",
"mortality",
"due",
"to",
"pneumonia",
"[1-3].",
"About",
"5%",
"of",
"patients",
"with",
"pneumonia",
"suffer",
"from",
"pleural",
"empyema",
"[4,5].",
"About",
"65,000",
"patients",
"in",
"the",
"United",
"State",
"and",
"the",
"United",
"King-",
"dom",
"suffer",
"annually",
"from",
"pleural",
"empyema",
"or",
"a",
"compli-",
"cated",
"parapneumonic",
"effusion.",
"The",
"mortality",
"of",
"patients",
"with",
"pleural",
"empyema",
"is",
"up",
"to",
"20%",
"and",
"contributes",
"to",
"higher",
"hospital",
"costs.",
"Inflammatory",
"mechanisms",
"and",
"alterations",
"in",
"the",
"balance",
"of",
"pleural",
"fibrinolysis",
"have",
"been",
"implicated",
"in",
"the",
"pathophysiology",
"of",
"infectious",
"pleural",
"effusion.",
"Pleural",
"empyema",
"is",
"associated",
"with",
"fibrin",
"deposition",
"over",
"pleural",
"surfaces",
"due",
"to",
"inhibition",
"of",
"the",
"fibrinolysis",
"system",
"[6,7].",
"Parapneumonic",
"effusions",
"progress",
"through",
"exudative",
"and",
"fibrinopurulent",
"stages",
"and",
"terminate",
"in",
"empyema",
"in",
"the",
"organized",
"stage.",
"The",
"*",
"Correspondence:",
"d93421104@ntu.edu.tw",
"2Department",
"of",
"Surgery,",
"China",
"Medical",
"University",
"Hospital,",
"China",
"Medical",
"University,",
"2",
"Yude",
"Road,",
"Taichung,",
"404,",
"Taiwan",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"clinical",
"courses",
"of",
"patients",
"with",
"parapneumonic",
"effu-",
"sions",
"or",
"pleural",
"empyema",
"are",
"varied.",
"Lung",
"abscess",
"is",
"defined",
"as",
"a",
"circumscribed",
"collection",
"of",
"pus",
"in",
"the",
"lung,",
"which",
"leads",
"to",
"formation",
"of",
"a",
"cavity.",
"It",
"develops",
"when",
"a",
"localized",
"area",
"of",
"parenchymal",
"infection",
"becomes",
"necro-",
"tic",
"and",
"then",
"cavitates.",
"It",
"most",
"commonly",
"occurs",
"second-",
"ary",
"to",
"aspiration",
"in",
"patients",
"with",
"poor",
"dentition",
"or",
"as",
"a",
"complication",
"of",
"necrotizing",
"pneumonia.",
"Lung",
"abscess",
"has",
"previously",
"been",
"thought",
"to",
"be",
"a",
"rare",
"condition",
"of",
"empyema",
"and",
"parapneumonic",
"effusions.",
"About",
"90%",
"of",
"patients",
"with",
"lung",
"abscesses",
"been",
"cured",
"by",
"antibiotics",
"therapies",
"simply",
"[8].",
"Surgical",
"resection",
"of",
"lung",
"abscess",
"is",
"rare",
"when",
"medical",
"treatments",
"fail.",
"Pleural",
"empyema",
"and",
"lung",
"abscess",
"are",
"both",
"a",
"part",
"of",
"low",
"respiratory",
"tract",
"infection.",
"According",
"to",
"the",
"clinical",
"observation,",
"pleural",
"empyema",
"and",
"lung",
"abscesses",
"may",
"happen",
"on",
"the",
"same",
"patient.",
"However,",
"the",
"strategies",
"of",
"these",
"two",
"diseases",
"are",
"so",
"different.",
"It",
"is",
"interesting",
"whether",
"the",
"surgical",
"results",
"are",
"the",
"same",
"of",
"empyema",
"patients",
"with",
"and",
"without",
"lung",
"abscesses.",
"We",
"compared",
"©",
"2010",
"Huang",
"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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515,
780,
11,
13
],
[
533,
780,
22,
13
],
[
562,
780,
47,
13
],
[
617,
780,
11,
13
],
[
635,
780,
26,
13
],
[
669,
780,
10,
13
],
[
687,
780,
33,
13
],
[
727,
780,
43,
13
],
[
437,
794,
58,
13
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[
500,
794,
7,
13
],
[
513,
794,
7,
13
],
[
526,
794,
43,
13
],
[
575,
794,
10,
13
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590,
794,
40,
13
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636,
794,
15,
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794,
53,
13
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794,
55,
13
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[
437,
809,
36,
13
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[
475,
805,
5,
13
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[
484,
809,
44,
13
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[
530,
809,
28,
13
],
[
560,
809,
5,
13
],
[
567,
809,
7,
13
],
[
576,
809,
16,
13
],
[
594,
809,
38,
13
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[
634,
809,
10,
13
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[
646,
809,
49,
13
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[
697,
809,
24,
13
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[
723,
809,
10,
13
],
[
735,
809,
6,
13
],
[
744,
809,
26,
13
],
[
437,
824,
37,
13
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[
477,
824,
19,
13
],
[
499,
824,
17,
13
],
[
519,
824,
8,
13
],
[
529,
824,
16,
13
],
[
548,
824,
52,
13
],
[
602,
824,
55,
13
],
[
660,
824,
40,
13
],
[
703,
824,
29,
13
],
[
734,
824,
10,
13
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[
747,
824,
8,
13
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[
450,
839,
21,
13
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[
475,
839,
47,
13
],
[
527,
839,
55,
13
],
[
587,
839,
58,
13
],
[
649,
839,
22,
13
],
[
675,
839,
15,
13
],
[
694,
839,
29,
13
],
[
728,
839,
30,
13
],
[
762,
839,
8,
13
],
[
437,
854,
33,
13
],
[
474,
854,
10,
13
],
[
488,
854,
19,
13
],
[
511,
854,
18,
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],
[
534,
854,
11,
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549,
854,
18,
13
],
[
571,
854,
32,
13
],
[
607,
854,
19,
13
],
[
630,
854,
41,
13
],
[
675,
854,
29,
13
],
[
708,
854,
44,
13
],
[
756,
854,
13,
13
],
[
437,
869,
34,
13
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[
475,
869,
24,
13
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[
503,
869,
28,
13
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[
535,
869,
20,
13
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[
559,
869,
48,
13
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[
610,
869,
13,
13
],
[
627,
869,
6,
13
],
[
637,
869,
32,
13
],
[
672,
869,
18,
13
],
[
693,
869,
32,
13
],
[
574,
902,
60,
16
],
[
758,
904,
7,
13
],
[
753,
908,
5,
13
],
[
764,
908,
5,
13
],
[
437,
932,
31,
13
],
[
473,
931,
7,
13
],
[
485,
932,
8,
13
],
[
497,
932,
16,
13
],
[
519,
932,
32,
13
],
[
555,
932,
18,
13
],
[
578,
932,
50,
13
],
[
633,
932,
21,
13
],
[
659,
932,
23,
13
],
[
687,
932,
47,
13
],
[
739,
932,
10,
13
],
[
754,
932,
16,
13
],
[
437,
947,
32,
13
],
[
473,
947,
18,
13
],
[
495,
947,
47,
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[
546,
946,
7,
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],
[
556,
947,
8,
13
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[
568,
947,
33,
13
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[
605,
947,
10,
13
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[
619,
947,
19,
13
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[
643,
947,
17,
13
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[
664,
947,
43,
13
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[
711,
947,
20,
13
],
[
735,
946,
7,
13
],
[
746,
947,
24,
13
],
[
437,
961,
73,
13
],
[
514,
961,
46,
13
],
[
563,
961,
80,
14
],
[
647,
961,
15,
13
],
[
665,
961,
13,
13
],
[
682,
961,
26,
13
],
[
450,
976,
18,
13
],
[
473,
976,
30,
13
],
[
508,
976,
30,
13
],
[
543,
976,
19,
13
],
[
566,
976,
47,
13
],
[
619,
976,
40,
13
],
[
664,
976,
25,
13
],
[
694,
976,
16,
13
],
[
715,
976,
32,
13
],
[
752,
976,
18,
13
],
[
437,
991,
44,
13
],
[
485,
991,
80,
13
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[
569,
991,
39,
13
],
[
612,
991,
11,
13
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[
627,
991,
18,
13
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[
649,
991,
32,
13
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[
684,
991,
35,
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[
723,
991,
6,
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[
733,
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36,
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[
437,
1006,
42,
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[
486,
1006,
49,
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[
542,
1006,
58,
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[
607,
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18,
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633,
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19,
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660,
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20,
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[
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627,
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36,
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[
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6,
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[
680,
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3,
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[
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24,
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[
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[
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] | [
"Spreading",
"Patterns",
"of",
"the",
"Influenza",
"A",
"(H1N1)",
"Pandemic",
"Sergio",
"de",
"Picoli",
"Junior1*,",
"Jorge",
"Juarez",
"Vieira",
"Teixeira2,",
"Haroldo",
"Valentin",
"Ribeiro1,3,",
"Luis",
"Carlos",
"Malacarne1,",
"Ricardo",
"Paupitz",
"Barbosa",
"dos",
"Santos1,",
"Renio",
"dos",
"Santos",
"Mendes1,3",
"1",
"Departamento",
"de",
"F´ısica,",
"Universidade",
"Estadual",
"de",
"Maringa´,",
"Maringa´,",
"Parana´,",
"Brazil,",
"2",
"Departamento",
"de",
"Ana´lises",
"Cl´ınicas",
"e",
"Biomedicina,",
"Universidade",
"Estadual",
"de",
"Maringa´,",
"Maringa´,",
"Parana´,",
"Brazil,",
"3",
"National",
"Institute",
"of",
"Science",
"and",
"Technology",
"for",
"Complex",
"Systems,",
"Rio",
"de",
"Janeiro,",
"Rio",
"de",
"Janeiro,",
"Brazil",
"Abstract",
"We",
"investigate",
"the",
"dynamics",
"of",
"the",
"2009",
"influenza",
"A",
"(H1N1/S-OIV)",
"pandemic",
"by",
"analyzing",
"data",
"obtained",
"from",
"World",
"Health",
"Organization",
"containing",
"the",
"total",
"number",
"of",
"laboratory-confirmed",
"cases",
"of",
"infections",
"-",
"by",
"country",
"-",
"in",
"a",
"period",
"of",
"69",
"days,",
"from",
"26",
"April",
"to",
"3",
"July,",
"2009.",
"Specifically,",
"we",
"find",
"evidence",
"of",
"exponential",
"growth",
"in",
"the",
"total",
"number",
"of",
"confirmed",
"cases",
"and",
"linear",
"growth",
"in",
"the",
"number",
"of",
"countries",
"with",
"confirmed",
"cases.",
"We",
"also",
"find",
"that,",
"i)",
"at",
"early",
"stages,",
"the",
"cumulative",
"distribution",
"of",
"cases",
"among",
"countries",
"exhibits",
"linear",
"behavior",
"on",
"log-log",
"scale,",
"being",
"well",
"approximated",
"by",
"a",
"power",
"law",
"decay;",
"ii)",
"for",
"larger",
"times,",
"the",
"cumulative",
"distribution",
"presents",
"a",
"systematic",
"curvature",
"on",
"log-log",
"scale,",
"indicating",
"a",
"gradual",
"change",
"to",
"lognormal",
"behavior.",
"Finally,",
"we",
"compare",
"these",
"empirical",
"findings",
"with",
"the",
"predictions",
"of",
"a",
"simple",
"stochastic",
"model.",
"Our",
"results",
"could",
"help",
"to",
"select",
"more",
"realistic",
"models",
"of",
"the",
"dynamics",
"of",
"influenza-type",
"pandemics.",
"Citation:",
"Picoli",
"Junior",
"Sd,",
"Teixeira",
"JJV,",
"Ribeiro",
"HV,",
"Malacarne",
"LC,",
"Santos",
"RPBd,",
"et",
"al.",
"(2011)",
"Spreading",
"Patterns",
"of",
"the",
"Influenza",
"A",
"(H1N1)",
"Pandemic.",
"PLoS",
"ONE",
"6(3):",
"e17823.",
"doi:10.1371/journal.pone.0017823",
"Editor:",
"Paulo",
"Ho,",
"Instituto",
"Butantan,",
"Brazil",
"Received",
"November",
"8,",
"2010;",
"Accepted",
"February",
"14,",
"2011;",
"Published",
"March",
"31,",
"2011",
"Copyright:",
"2011",
"Picoli",
"Junior",
"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",
"CNPq",
"(Conselho",
"Nacional",
"de",
"Pesquisa)",
"and",
"CAPES",
"(Coordenac¸a˜ode",
"Aperfeic¸",
"oamento",
"de",
"Pessoal",
"de",
"Nı´",
"vel",
"Superior)",
"-",
"Brazilian",
"agencies.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"junior@dfi.uem.br",
"Introduction",
"The",
"spread",
"of",
"infectious",
"diseases",
"is",
"a",
"threat",
"to",
"the",
"world",
"public",
"health",
"and",
"a",
"subject",
"of",
"great",
"scientific",
"interest.",
"Influenza",
"viruses,",
"for",
"example,",
"circulate",
"around",
"the",
"world",
"every",
"year",
"and",
"seasonal",
"influenza",
"is",
"one",
"of",
"the",
"most",
"worrying",
"respiratory",
"infections",
"of",
"humans",
"[1].",
"From",
"time",
"to",
"time",
"new",
"strains",
"of",
"influenza",
"virus",
"emerge",
"and",
"cause",
"large-scale",
"global",
"pandemics",
"–",
"such",
"as",
"the",
"2009",
"influenza",
"A",
"(H1N1/S-OIV).",
"The",
"dynamics",
"of",
"influenza-type",
"pandemics",
"has",
"been",
"the",
"focus",
"of",
"several",
"scientific",
"works",
"which",
"may",
"provide",
"necessary",
"information",
"to",
"deal",
"with",
"future",
"pandemic",
"events",
"[2–9].",
"However,",
"conventional",
"modeling",
"techniques",
"are",
"usually",
"only",
"able",
"to",
"provide",
"a",
"general",
"idea",
"of",
"how",
"a",
"pandemic",
"might",
"evolve,",
"since",
"crucial",
"information",
"concerning",
"model",
"parameters",
"is",
"generally",
"unavailable.",
"Methods",
"Here,",
"we",
"investigate",
"the",
"dynamics",
"of",
"influenza-type",
"pandemics",
"using",
"techniques",
"of",
"statistical",
"physics",
"typically",
"applied",
"in",
"the",
"study",
"of",
"complex",
"systems.",
"We",
"analyze",
"a",
"database",
"-",
"from",
"World",
"Health",
"Organization",
"-",
"containing",
"laboratory-confirmed",
"cases",
"of",
"influenza",
"A",
"(H1N1/S-OIV)",
"infections",
"around",
"the",
"world",
"[10].",
"Specifically,",
"we",
"analyze",
"the",
"total",
"number",
"of",
"laboratory-confirmed",
"cases",
"-",
"by",
"country",
"-",
"in",
"a",
"period",
"of",
"69",
"days,",
"from",
"26",
"April",
"to",
"3",
"July,",
"2009.",
"We",
"search",
"for",
"patterns",
"of",
"spread",
"for",
"the",
"virus",
"influenza",
"A",
"(H1N1/S-OIV).",
"Basically,",
"we",
"investigate",
"the",
"growth",
"in",
"the",
"total",
"number",
"of",
"confirmed",
"cases,",
"the",
"growth",
"in",
"the",
"number",
"of",
"countries",
"with",
"confirmed",
"cases",
"and",
"the",
"cumulative",
"distribution",
"of",
"cases",
"among",
"countries.",
"We",
"also",
"propose",
"a",
"simple",
"stochastic",
"model",
"which",
"reproduces",
"the",
"main",
"empirical",
"findings",
"obtained",
"from",
"the",
"analysis",
"of",
"the",
"database",
"on",
"the",
"2009",
"influenza",
"A",
"(H1N1/S-OIV)",
"pandemic.",
"Results",
"First,",
"we",
"consider",
"the",
"time",
"evolution",
"of",
"the",
"global",
"number",
"of",
"confirmed",
"cases,",
"Y(t).",
"At",
"a",
"given",
"time",
"t,",
"the",
"total",
"number",
"of",
"cases",
"Y",
"is",
"given",
"by",
"the",
"sum",
"of",
"y",
"over",
"all",
"countries.",
"In",
"Fig.",
"1A",
"we",
"show",
"Y(t)",
"in",
"comparison",
"with",
"an",
"exponential",
"curve,",
"given",
"by",
"the",
"equation",
"dY",
"~lY",
",",
"with",
"l~0:05",
"(compare",
"with",
"results",
"reported",
"in",
"ref.",
"dt",
"[11]).",
"This",
"result",
"suggests",
"that",
"the",
"total",
"number",
"of",
"confirmed",
"cases",
"exhibits",
"an",
"exponential",
"growth.",
"However,",
"a",
"systematic",
"deviation",
"of",
"the",
"exponential",
"behavior",
"can",
"be",
"observed",
"for",
"smaller",
"times",
"(t",
",",
"20",
"days).",
"In",
"addition,",
"Fig.",
"1B",
"shows",
"the",
"time",
"evolution",
"of",
"the",
"total",
"number",
"of",
"countries",
"with",
"confirmed",
"cases,",
"W(t).",
"Observe",
"that",
"W(t)",
"exhibits",
"approximately",
"a",
"linear",
"growth",
"in",
"all",
"the",
"period",
"considered.",
"Next,",
"we",
"investigate",
"the",
"distribution",
"of",
"confirmed",
"cases",
"among",
"countries",
"and",
"its",
"time",
"evolution.",
"In",
"order",
"to",
"reduce",
"statistical",
"fluctuations,",
"it",
"is",
"common",
"to",
"consider",
"the",
"cumulative",
"distribution",
"R(y)~",
"Ð",
"P(y’)dy’.",
"Here,",
"y",
"is",
"the",
"number",
"of",
"confirmed",
"cases",
"in",
"a",
"given",
"country",
"and",
"P(y)",
"is",
"the",
"probability",
"distribution",
"function",
"(PDF)",
"of",
"y.",
"The",
"empirical",
"cumulative",
"distribution",
"R(y),",
"for",
"initial",
"times,",
"is",
"shown",
"in",
"Fig.",
"2A.",
"In",
"this",
"range,",
"R(y)",
"presents",
"linear",
"behavior",
"on",
"log-log",
"scale",
"being",
"well",
"described",
"by",
"a",
"power",
"law",
"decay,",
"R(y)*y{a,",
"1",
"ð",
"Þ",
"where",
"a",
"is",
"the",
"power",
"law",
"exponent.",
"The",
"time",
"evolution",
"of",
"the",
"power",
"law",
"exponent",
"a",
"is",
"shown",
"in",
"Fig.",
"2B.",
"Observe",
"that",
"a",
"stays",
"approximately",
"constant,",
"0.35,a,0.040,",
"for",
"21",
"days.",
"For",
"larger",
"times,",
"R(y)",
"gradually",
"deviates",
"from",
"the",
"power",
"law",
"behavior",
"(Supplementary",
"Figure).",
"In",
"this",
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] | [
"Mechanisms",
"of",
"KGF",
"Mediated",
"Signaling",
"in",
"Pancreatic",
"Duct",
"Cell",
"Proliferation",
"and",
"Differentiation",
"Benjamin",
"Uzan,",
"Florence",
"Figeac,",
"Bernard",
"Portha,",
"Jamileh",
"Movassat*",
"Laboratory",
"of",
"Pathophysiology",
"of",
"Nutrition,",
"Paris",
"Diderot-",
"Paris",
"7",
"University,",
"Department",
"of",
"Life",
"Science,",
"CNRS/UMR",
"7059,",
"Paris,",
"France",
"Abstract",
"Background:",
"Keratinocyte",
"growth",
"factor",
"(KGF;",
"palifermin)",
"is",
"a",
"growth",
"factor",
"with",
"a",
"high",
"degree",
"of",
"specificity",
"for",
"epithelial",
"cells.",
"KGF",
"is",
"an",
"important",
"effector",
"of",
"epithelial",
"growth",
"and",
"tissue",
"homeostasis",
"in",
"various",
"organs",
"including",
"the",
"pancreas.",
"Here",
"we",
"investigated",
"the",
"intracellular",
"signaling",
"pathways",
"involved",
"in",
"the",
"mediation",
"of",
"pancreatic",
"ductal",
"cell",
"proliferation",
"and",
"differentiation",
"induced",
"by",
"exogenous",
"KGF",
"during",
"beta-cell",
"regeneration",
"in",
"diabetic",
"rat.",
"Methodology",
"and",
"Results:",
"In",
"vitro",
"and",
"in",
"vivo",
"duct",
"cell",
"proliferation",
"was",
"measured",
"by",
"BrdU",
"incorporation",
"assay.",
"The",
"implication",
"of",
"MAPK-ERK1/2",
"in",
"the",
"mediation",
"of",
"KGF-induced",
"cell",
"proliferation",
"was",
"determined",
"by",
"inactivation",
"of",
"this",
"pathway,",
"using",
"the",
"pharmacological",
"inhibitor",
"or",
"antisense",
"morpholino-oligonucleotides",
"against",
"MEK1.",
"In",
"vivo",
"KGF-induced",
"duct",
"cell",
"differentiation",
"was",
"assessed",
"by",
"the",
"immunolocalization",
"of",
"PDX1",
"and",
"Glut2",
"in",
"ductal",
"cells",
"and",
"the",
"implication",
"of",
"PI3K/AKT",
"in",
"this",
"process",
"was",
"investigated.",
"We",
"showed",
"that",
"KGF",
"exerted",
"a",
"potent",
"mitogenic",
"effect",
"on",
"ductal",
"cells.",
"Both",
"in",
"vitro",
"and",
"in",
"vivo,",
"its",
"effect",
"on",
"cell",
"proliferation",
"was",
"mediated",
"through",
"the",
"activation",
"of",
"ERK1/2",
"as",
"evidenced",
"by",
"the",
"abolition",
"of",
"duct",
"cell",
"proliferation",
"in",
"the",
"context",
"of",
"MEK/ERK",
"inactivation.",
"In",
"vivo,",
"KGF",
"treatment",
"triggered",
"ductal",
"cell",
"differentiation",
"as",
"revealed",
"by",
"the",
"expression",
"of",
"PDX1",
"and",
"Glut2",
"in",
"a",
"subpopulation",
"of",
"ductal",
"cells",
"via",
"a",
"PI3K-dependent",
"mechanism.",
"Conclusion:",
"Here",
"we",
"show",
"that",
"KGF",
"promotes",
"beta-cell",
"regeneration",
"by",
"stimulating",
"duct",
"cell",
"proliferation",
"in",
"vivo.",
"Moreover,",
"we",
"demonstrated",
"for",
"the",
"first",
"time",
"that",
"KGF",
"directly",
"induces",
"the",
"expression",
"of",
"PDX1",
"in",
"some",
"ductal",
"cells",
"thus",
"inducing",
"beta-cell",
"neogenesis.",
"We",
"further",
"explored",
"the",
"molecular",
"mechanisms",
"involved",
"in",
"these",
"processes",
"and",
"showed",
"that",
"the",
"effects",
"of",
"KGF",
"on",
"duct",
"cell",
"proliferation",
"are",
"mediated",
"by",
"the",
"MEK-ERK1/2",
"pathway,",
"while",
"the",
"KGF-induced",
"cell",
"differentiation",
"is",
"mediated",
"by",
"the",
"PI3K/AKT",
"pathway.",
"These",
"findings",
"might",
"have",
"important",
"implications",
"for",
"the",
"in",
"vivo",
"induction",
"of",
"duct-to-beta",
"cell",
"neogenesis",
"in",
"patients",
"with",
"beta-cell",
"deficiency.",
"Citation:",
"Uzan",
"B,",
"Figeac",
"F,",
"Portha",
"B,",
"Movassat",
"J",
"(2009)",
"Mechanisms",
"of",
"KGF",
"Mediated",
"Signaling",
"in",
"Pancreatic",
"Duct",
"Cell",
"Proliferation",
"and",
"Differentiation.",
"PLoS",
"ONE",
"4(3):",
"e4734.",
"doi:10.1371/journal.pone.0004734",
"Editor:",
"Kathrin",
"Maedler,",
"University",
"of",
"Bremen,",
"Germany",
"Received",
"August",
"7,",
"2008;",
"Accepted",
"January",
"13,",
"2009;",
"Published",
"March",
"6,",
"2009",
"Copyright:",
"2009",
"Uzan",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"The",
"authors",
"are",
"supported",
"by",
"grants",
"from",
"the",
"Centre",
"National",
"de",
"la",
"Recherche",
"Scientifique/CNRS.",
"Florence",
"Figeac",
"is",
"a",
"recipient",
"of",
"a",
"fellowship",
"from",
"the",
"Ministe`re",
"de",
"l’Enseignement",
"Supe´rieur",
"et",
"de",
"la",
"Recherche.",
"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:",
"movassat@paris7.jussieu.fr",
"Introduction",
"The",
"shortage",
"of",
"islet",
"for",
"transplantation",
"is",
"a",
"major",
"obstacle",
"for",
"the",
"wide",
"application",
"of",
"beta",
"cell",
"replacement",
"therapy",
"in",
"type",
"1",
"diabetic",
"patients.",
"To",
"make",
"such",
"a",
"therapy",
"readily",
"available,",
"new",
"sources",
"of",
"insulin-producing",
"cells",
"must",
"be",
"identified.",
"Pancreatic",
"duct",
"cells",
"represent",
"such",
"an",
"alternative",
"source",
"for",
"generation",
"of",
"new",
"beta",
"cells",
"in",
"vitro",
"[1].",
"Duct",
"compartment",
"has",
"also",
"implications",
"in",
"type",
"2",
"diabetes",
"(T2D),",
"since",
"T2D",
"is",
"associated",
"with",
"beta",
"cell",
"loss,",
"and",
"the",
"in",
"situ",
"induction",
"of",
"beta",
"cell",
"neogenesis",
"from",
"ductal",
"progenitor",
"cells",
"may",
"help",
"to",
"restore",
"the",
"beta",
"cell",
"mass",
"in",
"the",
"pancreas",
"of",
"type",
"2",
"diabetic",
"patients.",
"Therefore,",
"characterization",
"of",
"stimuli",
"with",
"potential",
"to",
"induce",
"the",
"expansion",
"of",
"duct",
"cells",
"and/or",
"to",
"drive",
"their",
"differentiation",
"into",
"beta",
"cells",
"is",
"of",
"great",
"importance.",
"A",
"variety",
"of",
"growth",
"factors",
"have",
"been",
"described",
"to",
"induce",
"growth",
"and",
"differentiation",
"of",
"ductal",
"cells.",
"Fibroblast",
"growth",
"factors",
"(FGFs)",
"comprise",
"a",
"growing",
"group",
"of",
"structurally",
"related",
"polypeptide",
"mitogens",
"with",
"more",
"than",
"20",
"members,",
"most",
"of",
"which",
"stimulate",
"proliferation",
"of",
"a",
"variety",
"of",
"cell",
"types",
"[2,3].",
"Keratinocyte",
"growth",
"factor,",
"also",
"called",
"FGF7,",
"is",
"a",
"member",
"of",
"the",
"FGF",
"family.",
"KGF",
"is",
"a",
"paracrine-acting",
"mitogen",
"produced",
"by",
"cells",
"of",
"mesenchymal",
"origin.",
"It",
"acts",
"exclusively",
"through",
"a",
"subset",
"of",
"FGF",
"receptor",
"isoforms",
"(FGFR2IIIb)",
"expressed",
"predominantly",
"by",
"epithelial",
"cells",
"and",
"therefore",
"is",
"a",
"specific",
"mitogen",
"for",
"these",
"cells",
"[4].",
"Preclinical",
"data",
"from",
"several",
"animal",
"models",
"have",
"demonstrated",
"that",
"recombinant",
"human",
"KGF",
"could",
"enhance",
"the",
"regenerative",
"capacity",
"of",
"epithelial",
"tissues",
"and",
"protect",
"them",
"from",
"a",
"variety",
"of",
"toxic",
"exposures",
"[3].",
"We",
"and",
"others",
"have",
"previously",
"reported",
"that",
"KGF",
"induces",
"ductal",
"cell",
"proliferation",
"in",
"the",
"pancreas",
"[5–8]",
"and",
"promotes",
"beta",
"cell",
"regeneration",
"in",
"neonatal",
"streptozotocin",
"diabetic",
"rats",
"[6].",
"However",
"the",
"molecular",
"mechanisms",
"underlying",
"the",
"stimulation",
"of",
"beta",
"cell",
"regeneration",
"through",
"the",
"induction",
"of",
"ductal",
"cell",
"proliferation",
"and",
"beta",
"cell",
"neogenesis",
"by",
"KGF",
"are",
"not",
"known.",
"The",
"present",
"study",
"was",
"undertaken",
"to",
"investigate",
"the",
"intracel-",
"lular",
"signaling",
"pathways",
"which",
"mediate",
"the",
"growth",
"promoting",
"effects",
"of",
"KGF",
"(palifermin)",
"in",
"pancreatic",
"ducts",
"and",
"to",
"dissect",
"the",
"key",
"steps",
"of",
"duct-to-beta",
"cell",
"differentiation",
"induced",
"by",
"KGF",
"in",
"a",
"model",
"of",
"neonatal",
"diabetes",
"in",
"rat.",
"In",
"our",
"study,",
"we",
"have",
"established",
"that",
"KGF",
"acts",
"on",
"ductal",
"cells",
"by",
"the",
"the",
"activation",
"of",
"distinct",
"signaling",
"pathways",
"to",
"promote",
"beta",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"March",
"2009",
"|",
"Volume",
"4",
"|",
"Issue",
"3",
"|",
"e4734"
] | [
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"cell",
"migration",
"characteristic",
"of",
"ischemic",
"damages",
"has",
"a",
"dual",
"role",
"providing",
"the",
"tissue",
"with",
"factors",
"needed",
"for",
"tissue",
"injury",
"recovery",
"simultaneously",
"causing",
"deleterious",
"development",
"depending",
"on",
"the",
"quality",
"and",
"the",
"quantity",
"of",
"infiltrated",
"cells.",
"Extracellular",
"superoxide",
"dismutase",
"(SOD3)",
"has",
"been",
"shown",
"to",
"have",
"an",
"anti-inflammatory",
"role",
"in",
"ischemic",
"injuries",
"where",
"it",
"increases",
"the",
"recovery",
"process",
"by",
"activating",
"mitogen",
"signal",
"transduction",
"and",
"increasing",
"cell",
"proliferation.",
"However,",
"SOD3",
"derived",
"effects",
"on",
"inflammatory",
"cytokine",
"and",
"adhesion",
"molecule",
"expression,",
"which",
"would",
"explain",
"reduced",
"inflammation",
"in",
"vascular",
"lesions,",
"has",
"not",
"been",
"properly",
"characterized.",
"In",
"the",
"present",
"work",
"the",
"effect",
"of",
"SOD3",
"on",
"the",
"inflammatory",
"cell",
"extravasation",
"was",
"studied",
"in",
"vivo",
"in",
"rat",
"hind",
"limb",
"ischemia",
"and",
"mouse",
"peritonitis",
"models",
"by",
"identifying",
"the",
"migrated",
"cells",
"and",
"analyzing",
"SOD3-derived",
"response",
"on",
"inflammatory",
"cytokine",
"and",
"adhesion",
"molecule",
"expression.",
"SOD3",
"overexpression",
"significantly",
"reduced",
"TNFa,",
"IL1a,",
"IL6,",
"MIP2,",
"and",
"MCP-1",
"cytokine",
"and",
"VCAM,",
"ICAM,",
"P-selectin,",
"and",
"E-",
"selectin",
"adhesion",
"molecule",
"expressions",
"in",
"injured",
"tissues.",
"Consequently",
"the",
"mononuclear",
"cell,",
"especially",
"CD68+",
"monocyte",
"and",
"CD3+",
"T",
"cell",
"infiltration",
"were",
"significantly",
"decreased",
"whereas",
"granulocyte",
"migration",
"was",
"less",
"affected.",
"According",
"to",
"our",
"data",
"SOD3",
"has",
"a",
"selective",
"anti-inflammatory",
"role",
"in",
"ischemic",
"damages",
"preventing",
"the",
"migration",
"of",
"reactive",
"oxygen",
"producing",
"monocyte/macrophages,",
"which",
"in",
"excessive",
"amounts",
"could",
"potentially",
"further",
"intensify",
"the",
"tissue",
"injuries",
"therefore",
"suggesting",
"potential",
"for",
"SOD3",
"in",
"treatment",
"of",
"inflammatory",
"disorders.",
"Citation:",
"Laurila",
"JP,",
"Laatikainen",
"LE,",
"Castellone",
"MD,",
"Laukkanen",
"MO",
"(2009)",
"SOD3",
"Reduces",
"Inflammatory",
"Cell",
"Migration",
"by",
"Regulating",
"Adhesion",
"Molecule",
"and",
"Cytokine",
"Expression.",
"PLoS",
"ONE",
"4(6):",
"e5786.",
"doi:10.1371/journal.pone.0005786",
"Editor:",
"Eshel",
"Ben-Jacob,",
"Tel",
"Aviv",
"University,",
"Israel",
"Received",
"April",
"15,",
"2009;",
"Accepted",
"May",
"8,",
"2009;",
"Published",
"June",
"4,",
"2009",
"Copyright:",
"2009",
"Laurila",
"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:",
"Academy",
"of",
"Finland,",
"Sigrid",
"Juselius",
"Foundation,",
"Paolo",
"Foundation,",
"TUBS",
"graduation",
"school.",
"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:",
"Mikko.Laukkanen@utu.fi",
"Introduction",
"The",
"inflammatory",
"process",
"is",
"initiated",
"by",
"endothelial",
"cell",
"(EC)",
"activation",
"comprising",
"upregulation",
"of",
"chemokines",
"and",
"cell",
"adhesion",
"molecules,",
"leukocyte",
"activation",
"and",
"transmigration,",
"and",
"secretion",
"of",
"proinflammatory",
"factors",
"by",
"leukocytes",
"[1].",
"The",
"inflammatory",
"reaction",
"is",
"necessary",
"for",
"tissue",
"recovery",
"as",
"it",
"provides",
"the",
"correct",
"cytokine",
"signals",
"and",
"cell",
"machinery",
"to",
"clear",
"up",
"the",
"site",
"for",
"regeneration",
"of",
"the",
"tissue",
"[2].",
"However,",
"uncontrolled",
"inflammation",
"has",
"unfavorable",
"effects",
"on",
"the",
"course",
"of",
"tissue",
"healing",
"since",
"the",
"inflammatory",
"cells",
"are",
"also",
"capable",
"of",
"inducing",
"tissue",
"damage",
"[2]",
"and",
"therefore",
"many",
"conditions",
"involving",
"inflammation,",
"e.g.",
"autoimmune",
"diseases",
"and",
"tissue",
"transplantations,",
"are",
"treated",
"with",
"immunosuppressants",
"to",
"reduce",
"harmful",
"leukocyte",
"infiltration.",
"Among",
"the",
"most",
"potent",
"drugs",
"are",
"glucocorticoids",
"that",
"downregulate",
"the",
"expression",
"of",
"numerous",
"inflammatory",
"chemokines,",
"cytokines",
"and",
"adhesion",
"molecules",
"[3–",
"5],",
"which,",
"however,",
"are",
"not",
"entirely",
"without",
"adverse",
"effects",
"such",
"as",
"delayed",
"myocardial",
"tissue",
"healing,",
"osteoporosis,",
"and",
"blood",
"vessel",
"calcification",
"[6–9].",
"The",
"most",
"prominent",
"outcome",
"in",
"the",
"initial",
"phase",
"of",
"inflammation",
"is",
"the",
"enhanced",
"production",
"of",
"cytokines,",
"such",
"as",
"TNF-a",
"and",
"IL-1,",
"and",
"chemokines,",
"such",
"as",
"monocyte",
"chemoat-",
"tractant",
"protein-1",
"(MCP-1)",
"[10,11],",
"which",
"further",
"induce",
"expression",
"of",
"a",
"number",
"of",
"inflammatory",
"cytokines",
"[4].",
"Many",
"of",
"the",
"stimulus-specific",
"pathways",
"converge",
"in",
"the",
"production",
"of",
"superoxide",
"(O22)",
"and",
"hydrogen",
"peroxide",
"(H2O2)",
"as",
"signal",
"mediators,",
"which",
"in",
"turn",
"result",
"in",
"e.g.",
"NFkB",
"activation",
"responsible",
"for",
"numerous",
"stress-related",
"functions",
"[12–14].",
"Leukocytes",
"are",
"thus",
"recruited",
"by",
"expression",
"of",
"various",
"cell",
"adhesion",
"molecules,",
"e.g.",
"selectins,",
"and",
"intercellular",
"and",
"vascular",
"cell",
"adhesion",
"molecules",
"(ICAM-1",
"and",
"VCAM-1,",
"respectively)",
"[15,16].",
"They",
"promote",
"rolling",
"and",
"firm",
"adhesion",
"of",
"leukocytes",
"to",
"endothelial",
"wall,",
"the",
"necessary",
"interactions",
"preceding",
"transmigration",
"[17].",
"To",
"aid",
"leukocyte",
"migration",
"the",
"vessel",
"wall",
"cells",
"change",
"their",
"morphology",
"by",
"assuming",
"cytoskeletal",
"and",
"cell-cell",
"junction",
"modifications",
"in",
"response",
"to",
"e.g.",
"ligand",
"binding",
"to",
"ICAM-1",
"and",
"VCAM-1",
"[18–20],",
"and",
"when",
"stimulated",
"by",
"O22",
"or",
"TNF-a",
"[21,22].",
"Previously,",
"it",
"has",
"been",
"shown",
"that",
"extracellular",
"superoxide",
"dismutase",
"(SOD3)",
"can",
"attenuate",
"tissue",
"damage",
"and",
"inflammation",
"but",
"so",
"far",
"its",
"mechanism",
"of",
"action",
"has",
"not",
"been",
"completely",
"defined",
"[23–27].",
"Since",
"excess",
"inflammation",
"prevents",
"the",
"tissue",
"injury",
"recovery",
"we",
"investigated",
"in",
"the",
"present",
"study",
"the",
"effect",
"of",
"SOD3",
"overexpression",
"on",
"cell",
"migration.",
"We",
"used",
"two",
"in",
"vivo",
"acute",
"inflammation",
"models",
"to",
"determine",
"how",
"SOD3",
"affects",
"leukocyte",
"extravasation,",
"and",
"compared",
"the",
"results",
"to",
"efficacy",
"of",
"the",
"glucocorticoid",
"immunosuppressant",
"dexamethasone.",
"The",
"mouse",
"peritonitis",
"and",
"rat",
"hind",
"limb",
"ischemia",
"models",
"have",
"been",
"characterized",
"previously:",
"they",
"induce",
"rapid",
"infiltration",
"of",
"leuko-",
"cytes",
"to",
"the",
"peritoneal",
"cavity",
"and",
"large",
"femoral",
"muscles,",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"June",
"2009",
"|",
"Volume",
"4",
"|",
"Issue",
"6",
"|",
"e5786"
] | [
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] | [
"Hindawi",
"Publishing",
"Corporation",
"Dermatology",
"Research",
"and",
"Practice",
"Volume",
"2010,",
"Article",
"ID",
"365173,",
"3",
"pages",
"doi:10.1155/2010/365173",
"Case",
"Report",
"Angiosarcoma",
"Mimicking",
"Rhinophyma",
"Maurizio",
"Lo",
"Presti,1",
"Caterina",
"Mazzella,1",
"Ambra",
"Monfrecola,1",
"and",
"Jessica",
"Falleti2",
"1",
"Department",
"of",
"Pathology",
"Systematics,",
"Section",
"of",
"Dermatology,",
"University",
"Federico",
"II",
"of",
"Naples,",
"via",
"S.",
"Pansini",
"5,",
"80131",
"Naples,",
"Italy",
"2",
"Department",
"of",
"Biomorphological",
"and",
"Functional",
"Science,",
"Section",
"of",
"Pathology,",
"University",
"Federico",
"II",
"of",
"Naples,",
"80131",
"Naples,",
"Italy",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Caterina",
"Mazzella,",
"caterinamazzella@libero.it",
"Received",
"1",
"March",
"2010;",
"Accepted",
"12",
"April",
"2010",
"Academic",
"Editor:",
"Bruce",
"Robert",
"Smoller",
"Copyright",
"©",
"2010",
"Maurizio",
"Lo",
"Presti",
"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.",
"We",
"report",
"the",
"case",
"of",
"a",
"61-year-old",
"man",
"showing",
"persistent",
"erythematous",
"macules,",
"plaques,",
"and",
"partially",
"confluent",
"nodules",
"with",
"irregular",
"borders,",
"developed",
"on",
"his",
"nose",
"for",
"one",
"year.",
"During",
"that",
"time",
"the",
"patient",
"underwent",
"several",
"dermatological",
"consultations,",
"and",
"all",
"produced",
"the",
"same",
"diagnosis:",
"rhinophyma.",
"So",
"antibiotic",
"and",
"steroid",
"treatment",
"was",
"carried",
"out",
"without",
"any",
"improvement",
"while",
"the",
"lesions",
"kept",
"growing.",
"When",
"the",
"patient",
"came",
"to",
"our",
"observation,",
"physical",
"examination",
"revealed",
"large,",
"infiltrative,",
"oedematous,",
"erythematous",
"plaques",
"and",
"rare",
"nodules,",
"with",
"superficial",
"telangiectatic",
"vessels.",
"Cervical",
"lymphadenopathy",
"was",
"not",
"detectable.",
"Routine",
"laboratory",
"analysis",
"was",
"normal.",
"Punch",
"biopsy",
"was",
"performed,",
"and",
"histopathology",
"and",
"immunohistochemical",
"studies",
"were",
"consistent",
"with",
"cutaneous",
"angiosarcoma.",
"This",
"is",
"the",
"report",
"of",
"a",
"face",
"angiosarcoma",
"with",
"an",
"unusual",
"and",
"very",
"deceptive",
"clinical",
"presentation.",
"1.",
"Introduction",
"Angiosarcoma",
"(AS)",
"is",
"a",
"rare",
"malignant",
"vascular",
"tumour",
"that",
"arises",
"in",
"skin",
"or",
"superficial",
"soft",
"tissue",
"in",
"60%",
"of",
"cases",
"[1].",
"It",
"mainly",
"appears",
"on",
"the",
"head",
"and",
"neck",
"of",
"elderly",
"patients.",
"Clinical",
"manifestations",
"of",
"AS",
"are",
"characterized",
"by",
"erythematous",
"plaques,",
"macules,",
"or",
"nodules",
"and",
"sometimes",
"by",
"chronic",
"edema",
"of",
"the",
"face.",
"Diagnosis",
"may",
"often",
"be",
"delayed",
"by",
"the",
"variable",
"presentation",
"and",
"the",
"benign",
"appearance",
"of",
"the",
"lesion,",
"therefore,",
"histological",
"features",
"are",
"fundamental",
"for",
"a",
"correct",
"diagnosis.",
"The",
"prognosis",
"is",
"poor",
"because",
"the",
"tumour",
"is",
"aggressive",
"with",
"high",
"local",
"recurrence",
"and",
"early",
"metastasis.",
"2.",
"Case",
"Report",
"A",
"61-year-old",
"man",
"came",
"to",
"our",
"department",
"with",
"erythema-",
"tous",
"macules,",
"plaques",
"and",
"also",
"rare",
"nodules",
"with",
"irregular",
"borders,",
"localized",
"on",
"the",
"nose,",
"developed",
"for",
"about",
"one",
"year",
"(Figure",
"1).",
"Before",
"examination",
"at",
"our",
"clinic,",
"the",
"patient",
"was",
"repeat-",
"edly",
"treated",
"for",
"rosacea/rhinophyma",
"with",
"oral",
"tetracyclines,",
"metronidazole,",
"and",
"steroids",
"without",
"significant",
"improve-",
"ment.",
"He",
"also",
"suffered",
"of",
"hypertension,",
"ischemic",
"heart",
"disease,",
"and",
"benign",
"prostatic",
"hyperplasia.",
"Histopathologic",
"examination",
"of",
"skin",
"biopsy,",
"taken",
"from",
"a",
"nodule,",
"showed",
"vascular",
"proliferation",
"lined",
"by",
"atypical",
"and",
"plump",
"endothelial",
"cells",
"in",
"the",
"dermis;",
"immunohistochem-",
"istry",
"proved",
"the",
"positivity",
"of",
"neoplastic",
"endothelial",
"cells",
"for",
"CD31",
"and",
"CD34",
"(Figures",
"2(a),",
"2(b)).",
"Based",
"on",
"the",
"clinical",
"and",
"histopathological",
"findings,",
"diagnosis",
"of",
"angiosarcoma",
"of",
"the",
"nose",
"was",
"established.",
"Total",
"body",
"CT,",
"showing",
"no",
"significant",
"findings,",
"was",
"performed,",
"and",
"then,",
"according",
"to",
"consolidated",
"cooperation,",
"and",
"also",
"following",
"his",
"own",
"desire,",
"the",
"patient",
"has",
"been",
"put",
"under",
"oncologists",
"care,",
"undertaking",
"Rx",
"therapy",
"(electron",
"beam).",
"3.",
"Discussion",
"Angiosarcoma",
"(AS)",
"is",
"rare,",
"amounting",
"for",
"less",
"than",
"2%",
"of",
"all",
"sarcomas.",
"Skin",
"and",
"superficial",
"soft",
"tissue",
"are",
"the",
"most",
"common",
"locations",
"(60%",
"of",
"cases)",
"[2]",
"with",
"high",
"rate",
"of",
"lymph",
"node",
"and",
"systemic",
"metastasis",
"and",
"reported",
"5-year",
"survival",
"of",
"10%",
"to",
"35%",
"[3]."
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] | [
"Detection",
"of",
"Gene",
"Expression",
"in",
"an",
"Individual",
"Cell",
"Type",
"within",
"a",
"Cell",
"Mixture",
"Using",
"Microarray",
"Analysis",
"Penelope",
"A.",
"Bryant1,2,3,",
"Gordon",
"K.",
"Smyth4,",
"Roy",
"Robins-Browne2,5,",
"Nigel",
"Curtis1,2,3*",
"1",
"Department",
"of",
"Paediatrics,",
"The",
"University",
"of",
"Melbourne,",
"Royal",
"Children’s",
"Hospital",
"Melbourne,",
"Parkville,",
"Victoria,",
"Australia,",
"2",
"Microbiology",
"&",
"Infectious",
"Diseases",
"Research",
"Group,",
"Murdoch",
"Children’s",
"Research",
"Institute,",
"Royal",
"Children’s",
"Hospital",
"Melbourne,",
"Parkville,",
"Victoria,",
"Australia,",
"3",
"Infectious",
"Diseases",
"Unit,",
"Department",
"of",
"General",
"Medicine,",
"Royal",
"Children’s",
"Hospital",
"Melbourne,",
"Parkville,",
"Victoria,",
"Australia,",
"4",
"Bioinformatics",
"Division,",
"Walter",
"and",
"Eliza",
"Hall",
"Institute",
"of",
"Medical",
"Research,",
"Parkville,",
"Victoria,",
"Australia,",
"5",
"Department",
"of",
"Microbiology",
"&",
"Immunology,",
"University",
"of",
"Melbourne,",
"Parkville,",
"Victoria,",
"Australia",
"Abstract",
"Background:",
"A",
"central",
"issue",
"in",
"the",
"design",
"of",
"microarray-based",
"analysis",
"of",
"global",
"gene",
"expression",
"is",
"the",
"choice",
"between",
"using",
"cells",
"of",
"single",
"type",
"and",
"a",
"mixture",
"of",
"cells.",
"This",
"study",
"quantified",
"the",
"proportion",
"of",
"lipopolysaccharide",
"(LPS)",
"induced",
"differentially",
"expressed",
"monocyte",
"genes",
"that",
"could",
"be",
"measured",
"in",
"peripheral",
"blood",
"mononuclear",
"cells",
"(PBMC),",
"and",
"determined",
"the",
"extent",
"to",
"which",
"gene",
"expression",
"in",
"the",
"non-monocyte",
"cell",
"fraction",
"diluted",
"or",
"obscured",
"fold",
"changes",
"that",
"could",
"be",
"detected",
"in",
"the",
"cell",
"mixture.",
"Methodology/Principal",
"Findings:",
"Human",
"PBMC",
"were",
"stimulated",
"with",
"LPS,",
"and",
"monocytes",
"were",
"then",
"isolated",
"by",
"positive",
"(Mono+)",
"or",
"negative",
"(Mono2)",
"selection.",
"The",
"non-monocyte",
"cell",
"fraction",
"(MonoD)",
"remaining",
"after",
"positive",
"selection",
"of",
"monocytes",
"was",
"used",
"to",
"determine",
"the",
"effect",
"of",
"non-monocyte",
"cells",
"on",
"overall",
"expression.",
"RNA",
"from",
"LPS-stimulated",
"PBMC,",
"Mono+,",
"Mono2",
"and",
"MonoD",
"samples",
"was",
"co-hybridised",
"with",
"unstimulated",
"RNA",
"for",
"each",
"cell",
"type",
"on",
"oligonucleotide",
"microarrays.",
"There",
"was",
"a",
"positive",
"correlation",
"in",
"gene",
"expression",
"between",
"PBMC",
"and",
"both",
"Mono+",
"(0.77)",
"and",
"Mono2",
"(0.61–",
"0.67)",
"samples.",
"Analysis",
"of",
"individual",
"genes",
"that",
"were",
"differentially",
"expressed",
"in",
"Mono+",
"and",
"Mono2",
"samples",
"showed",
"that",
"the",
"ability",
"to",
"detect",
"expression",
"of",
"some",
"genes",
"was",
"similar",
"when",
"analysing",
"PBMC,",
"but",
"for",
"others,",
"differential",
"expression",
"was",
"either",
"not",
"detected",
"or",
"changed",
"in",
"the",
"opposite",
"direction.",
"As",
"a",
"result",
"of",
"the",
"dilutional",
"or",
"obscuring",
"effect",
"of",
"gene",
"expression",
"in",
"non-monocyte",
"cells,",
"overall",
"about",
"half",
"of",
"the",
"statistically",
"significant",
"LPS-induced",
"changes",
"in",
"gene",
"expression",
"in",
"monocytes",
"were",
"not",
"detected",
"in",
"PBMC.",
"However,",
"97%",
"of",
"genes",
"with",
"a",
"four",
"fold",
"or",
"greater",
"change",
"in",
"expression",
"in",
"monocytes",
"after",
"LPS",
"stimulation,",
"and",
"almost",
"all",
"(96–100%)",
"of",
"the",
"top",
"100",
"most",
"differentially",
"expressed",
"monocyte",
"genes",
"were",
"detected",
"in",
"PBMC.",
"Conclusions/Significance:",
"The",
"effect",
"of",
"non-responding",
"cells",
"in",
"a",
"mixture",
"dilutes",
"or",
"obscures",
"the",
"detection",
"of",
"subtle",
"changes",
"in",
"gene",
"expression",
"in",
"an",
"individual",
"cell",
"type.",
"However,",
"for",
"studies",
"in",
"which",
"only",
"the",
"most",
"highly",
"differentially",
"expressed",
"genes",
"are",
"of",
"interest,",
"separating",
"and",
"analysing",
"individual",
"cell",
"types",
"may",
"be",
"unnecessary.",
"Citation:",
"Bryant",
"PA,",
"Smyth",
"GK,",
"Robins-Browne",
"R,",
"Curtis",
"N",
"(2009)",
"Detection",
"of",
"Gene",
"Expression",
"in",
"an",
"Individual",
"Cell",
"Type",
"within",
"a",
"Cell",
"Mixture",
"Using",
"Microarray",
"Analysis.",
"PLoS",
"ONE",
"4(2):",
"e4427.",
"doi:10.1371/journal.pone.0004427",
"Editor:",
"Sui",
"Huang,",
"University",
"of",
"Calgary,",
"Canada",
"Received",
"July",
"17,",
"2008;",
"Accepted",
"December",
"12,",
"2008;",
"Published",
"February",
"12,",
"2009",
"Copyright:",
"2009",
"Bryant",
"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",
"supported",
"by",
"a",
"grant",
"from",
"the",
"National",
"Health",
"and",
"Medical",
"Research",
"Council",
"and",
"National",
"Heart",
"Foundation",
"of",
"Australia.",
"Dr.",
"Bryant",
"was",
"the",
"recipient",
"of",
"a",
"European",
"Society",
"of",
"Paediatric",
"Infectious",
"Diseases",
"Fellowship",
"Award",
"and",
"a",
"University",
"of",
"Melbourne",
"Research",
"Scholarship.",
"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:",
"nigel.curtis@rch.org.au",
"Introduction",
"The",
"choice",
"between",
"using",
"cells",
"of",
"a",
"single",
"type",
"and",
"a",
"mixture",
"of",
"cells",
"in",
"microarray-based",
"analysis",
"of",
"global",
"gene",
"expression",
"is",
"difficult.",
"Analysing",
"cells",
"of",
"one",
"type,",
"such",
"as",
"monocytes[1,2,3],",
"necessitates",
"an",
"isolation",
"step",
"that",
"may",
"be",
"technically",
"difficult[4]",
"and",
"which",
"may",
"induce",
"non-specific",
"changes",
"in",
"gene",
"expression.",
"Analysing",
"a",
"cell",
"mixture,",
"such",
"as",
"peripheral",
"blood",
"mononuclear",
"cells",
"(PBMC)[5,6,7],",
"is",
"simpler",
"but",
"gene",
"expression",
"changes",
"in",
"cells",
"of",
"a",
"specific",
"cell",
"type,",
"particularly",
"if",
"present",
"in",
"small",
"numbers,",
"may",
"not",
"be",
"detected.",
"Specifically,",
"significant",
"changes",
"of",
"gene",
"expression",
"in",
"the",
"cell",
"type",
"of",
"interest",
"may",
"be",
"undetectable",
"as",
"a",
"result",
"of",
"the",
"dilutional",
"effect",
"of",
"a",
"majority",
"of",
"non-responding",
"cells",
"or",
"obscured",
"by",
"opposite",
"responses",
"in",
"other",
"cell",
"types.",
"In",
"addition,",
"it",
"is",
"impossible",
"to",
"attribute",
"observed",
"differential",
"expression",
"to",
"individ-",
"ual",
"cell",
"types.",
"This",
"study",
"compared",
"gene",
"expression",
"in",
"PBMC",
"with",
"expression",
"in",
"monocytes",
"alone",
"after",
"stimulation",
"with",
"lipopolysaccharide",
"(LPS)",
"as",
"a",
"paradigm",
"for",
"determining",
"the",
"extent",
"to",
"which",
"changes",
"in",
"gene",
"expression",
"in",
"a",
"particular",
"cell",
"type",
"can",
"be",
"detected",
"in",
"a",
"cell",
"mixture.",
"A",
"strategy",
"was",
"used",
"that",
"preserved",
"the",
"advantage",
"of",
"the",
"cellular",
"interactions",
"of",
"PBMC",
"but",
"which",
"allowed",
"detection",
"of",
"gene",
"expression",
"from",
"an",
"individual",
"cell",
"type",
"by",
"separating",
"monocytes",
"after",
"stimulation",
"of",
"PBMC",
"ex",
"vivo.",
"Analysis",
"was",
"undertaken",
"in",
"monocytes",
"isolated",
"by",
"both",
"positive",
"and",
"negative",
"selection",
"to",
"control",
"for",
"possible",
"gene",
"expression",
"induced",
"by",
"CD14-mediated",
"pathways.",
"Gene",
"expression",
"was",
"also",
"measured",
"in",
"the",
"non-",
"monocyte",
"cell",
"fraction",
"remaining",
"after",
"positive",
"selection",
"to",
"provide",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"February",
"2009",
"|",
"Volume",
"4",
"|",
"Issue",
"2",
"|",
"e4427"
] | [
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"Percutaneous",
"management",
"of",
"a",
"saphenous",
"vein",
"graft",
"perforation",
"using",
"a",
"covered",
"stent",
"and",
"final",
"coil",
"embolization",
"technique",
"Image",
"Ben",
"Glover,",
"Paul",
"Johnston,",
"Mark",
"Spence",
"Royal",
"Victoria",
"Hospital,",
"Belfast,",
"Great",
"Britain",
"Submitted:",
"23",
"January",
"2010",
"Accepted:",
"28",
"January",
"2010",
"Arch",
"Med",
"Sci",
"2010;",
"6,",
"6:",
"991-992",
"DOI:",
"10.5114/aoms.2010.19317",
"Copyright",
"©",
"2010",
"Termedia",
"&",
"Banach",
"A",
"b",
"s",
"t",
"r",
"a",
"c",
"t",
"Coronary",
"artery",
"perforation",
"as",
"a",
"result",
"of",
"percutaneous",
"coronary",
"intervention",
"is",
"a",
"rare",
"complication",
"which",
"may",
"result",
"in",
"cardiac",
"tamponade,",
"myocardial",
"infarction",
"and",
"death.",
"Perforation",
"of",
"a",
"saphenous",
"vein",
"graft",
"is",
"unusual",
"and",
"generally",
"requires",
"surgical",
"intervention.",
"We",
"describe",
"a",
"novel",
"percutaneous",
"approach",
"that",
"facilitated",
"the",
"successful",
"management",
"of",
"a",
"potentially",
"catastrophic",
"saphenous",
"vein",
"graft",
"(SVG)",
"perforation.",
"Key",
"words:",
"vein",
"graft",
"perforation",
"Coronary",
"artery",
"perforation",
"as",
"a",
"result",
"of",
"percutaneous",
"coronary",
"intervention",
"(PCI)",
"is",
"a",
"rare",
"complication",
"(0.1%)",
"[1]",
"which",
"may",
"result",
"in",
"cardiac",
"tamponade,",
"myocardial",
"infarction",
"and",
"death.",
"The",
"main",
"predictors",
"of",
"coronary",
"perforations",
"are",
"clinical",
"(elderly,",
"female",
"gender),",
"pharma-",
"cological",
"(use",
"of",
"glycoprotein",
"IIb/IIIa",
"inhibitors),",
"angiographic",
"(small",
"tortuous",
"and",
"calcified",
"vessels)",
"and",
"procedural",
"(stiff",
"hydrophilic",
"wires,",
"arte-",
"ry",
"to",
"balloon",
"ratio",
"of",
">",
"1.2-1.3,",
"use",
"of",
"atherectomy",
"device)",
"[1,",
"2].",
"We",
"describe",
"a",
"novel",
"approach",
"that",
"facilitated",
"the",
"successful",
"management",
"of",
"a",
"po-",
"tentially",
"catastrophic",
"saphenous",
"vein",
"graft",
"(SVG)",
"perforation.",
"A",
"68-year-old",
"female",
"treated",
"with",
"CABG",
"5",
"years",
"previously",
"was",
"referred",
"for",
"PCI",
"after",
"angiography",
"demonstrated",
"a",
"significant",
"SVG",
"to",
"the",
"first",
"obtuse",
"marginal",
"(OM)",
"lesion.",
"At",
"PCI",
"(right",
"transradial",
"access,",
"6",
"Fr",
"Left",
"Coronary",
"Bypass",
"(LCB)",
"guide",
"catheter",
"(Cordis",
"Corporation,",
"New",
"Jersey,",
"USA))",
"the",
"SVG",
"was",
"found",
"to",
"be",
"occluded.",
"A",
"Pilot",
"50",
"wire",
"(Abbott",
"Laboratories,",
"Illinois,",
"USA)",
"crossed",
"the",
"occlusion",
"easily",
"and",
"the",
"stenosis",
"was",
"pre-dilated",
"with",
"a",
"2.0",
"mm",
"and",
"a",
"4.0",
"mm",
"balloon.",
"Contrast",
"injection",
"via",
"an",
"Export",
"catheter",
"demonstrated",
"intraluminal",
"wire",
"position",
"and",
"a",
"good",
"sized",
"distal",
"OM.",
"A",
"4.5",
"×",
"24",
"Liberte",
"stent",
"(Boston",
"Scientific,",
"Natick,",
"USA)",
"was",
"deployed",
"at",
"17",
"atmospheres",
"resulting",
"in",
"a",
"class",
"3",
"perforation",
"(Figure",
"1A),",
"tachycardia",
"and",
"hypotension",
"[2].",
"The",
"stent",
"balloon",
"was",
"immediately",
"positioned",
"within",
"the",
"stent",
"and",
"inflated",
"to",
"control",
"the",
"perforation.",
"Intravenous",
"protamine",
"was",
"administered",
"and",
"a",
"transthoracic",
"echocardiogram",
"showed",
"a",
"posterior",
"pericardial",
"effusion",
"with",
"compression",
"of",
"the",
"posterior",
"left",
"atrial",
"wall",
"in",
"a",
"position",
"almost",
"impossible",
"to",
"treat",
"with",
"percutaneous",
"pericardiocentesis",
"(Figure",
"1B).",
"With",
"the",
"inflated",
"balloon",
"controlling",
"the",
"perforation",
"a",
"second",
"8",
"French",
"LCB",
"guide",
"catheter",
"was",
"introduced",
"from",
"the",
"femoral",
"artery",
"and",
"positioned",
"at",
"Corresponding",
"author:",
"Ben",
"Glover,",
"MD",
"Royal",
"Victoria",
"Hospital",
"Grosvenor",
"Road,",
"Belfast,",
"BT12",
"6BA",
"Phone:",
"+44",
"028",
"9024",
"05",
"03",
"E-mail:",
"ben.glover@hotmail.com"
] | [
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] | [
"Wang",
"et",
"al.",
"BMC",
"Immunology",
"2011,",
"12:21",
"http://www.biomedcentral.com/1471-2172/12/21",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"CTLA4",
"is",
"expressed",
"on",
"mature",
"dendritic",
"cells",
"derived",
"from",
"human",
"monocytes",
"and",
"influences",
"their",
"maturation",
"and",
"antigen",
"presentation",
"Xiong",
"B",
"Wang1*†,",
"Zhong",
"Z",
"Fan1†,",
"Doina",
"Anton3,",
"Annika",
"V",
"Vollenhoven3,",
"Zhen",
"H",
"Ni1,",
"Xiao",
"F",
"Chen2,",
"Ann",
"K",
"Lefvert3",
"Abstract",
"Background:",
"Dendritic",
"cells",
"(DCs)",
"initiate",
"immune",
"responses",
"through",
"their",
"direct",
"interaction",
"with",
"effector",
"cells.",
"However,",
"the",
"mechanism",
"by",
"which",
"DC",
"activity",
"is",
"regulated",
"is",
"not",
"well",
"defined.",
"Previous",
"studies",
"have",
"shown",
"that",
"CTLA4",
"on",
"T",
"cells",
"regulates",
"DCs",
"function",
"by",
"“cross-talk”.",
"We",
"investigated",
"whether",
"there",
"is",
"an",
"intrinsic",
"regulatory",
"mechanism",
"in",
"DCs,",
"with",
"CTLA4",
"as",
"a",
"candidate",
"regulator.",
"Results:",
"We",
"confirmed",
"via",
"RT-PCR",
"and",
"flow",
"cytometry",
"the",
"natural",
"expression",
"of",
"CTLA4",
"on",
"mature",
"DCs",
"derived",
"from",
"human",
"monocytes.",
"Approximately",
"8%",
"CD1a-positive",
"cells",
"express",
"CTLA4",
"both",
"on",
"surface",
"and",
"intracellular,",
"whereas",
"10%",
"CD1a-negative",
"cells",
"express",
"CTLA4",
"intracellularly,",
"but",
"little",
"expression",
"was",
"observed",
"on",
"the",
"cell",
"surface.",
"The",
"cross-linking",
"of",
"CTLA4",
"inhibits",
"DCs",
"maturation",
"and",
"antigen",
"presentation",
"in",
"vitro,",
"but",
"does",
"not",
"inhibit",
"endocytosis.",
"Conclusions:",
"CTLA4",
"is",
"expressed",
"by",
"DCs",
"and",
"plays",
"an",
"inhibitory",
"role.",
"CTLA4-expressing",
"DCs",
"may",
"represent",
"a",
"group",
"of",
"regulatory",
"DCs.",
"Because",
"of",
"its",
"wide",
"distribution",
"on",
"different",
"cell",
"types,",
"CTLA4",
"may",
"play",
"a",
"general",
"role",
"in",
"regulating",
"immune",
"responses.",
"Background",
"Dendritic",
"cells",
"(DCs)",
"are",
"sparsely",
"distributed",
"in",
"tissues",
"and",
"the",
"circulation,",
"but",
"they",
"are",
"nevertheless",
"important.",
"They",
"function",
"as",
"professional",
"antigen-presenting",
"cells",
"(APCs)",
"in",
"antigen",
"capture,",
"processing,",
"and",
"presentation",
"to",
"CD4+",
"and",
"CD8+",
"T",
"cells",
"[1].",
"DCs",
"can",
"be",
"produced",
"in",
"vitro",
"by",
"a",
"number",
"of",
"procedures,",
"starting",
"from",
"CD34+",
"hemopoietic",
"progenitor",
"cells",
"(from",
"peripheral",
"blood",
"or",
"bone",
"marrow)",
"cultured",
"with",
"tumor",
"necrosis",
"factor",
"a",
"(TNFa)",
"and",
"granulocyte",
"macrophage-colony-stimulating",
"factor",
"(GM-CSF),",
"or",
"from",
"human",
"blood",
"monocytes",
"cul-",
"tured",
"with",
"GM-CSF,",
"interleukin",
"4",
"(IL-4),",
"or",
"IL-13.",
"Immature",
"DCs",
"(iDCs),",
"which",
"have",
"a",
"high",
"capacity",
"for",
"antigen",
"uptake",
"and",
"processing,",
"but",
"a",
"low",
"capacity",
"to",
"sti-",
"mulate",
"T-cell",
"proliferation,",
"can",
"be",
"further",
"differentiated",
"in",
"vitro",
"to",
"mature",
"DCs",
"(mDCs),",
"which",
"have",
"a",
"high",
"capa-",
"city",
"for",
"antigen",
"presentation,",
"by",
"treatment",
"with",
"TNFa,",
"*",
"Correspondence:",
"xiongbiao6@yahoo.com",
"†",
"Contributed",
"equally",
"1Laboratory",
"center,",
"Putuo",
"Hospital,",
"Shanghai",
"University",
"of",
"Traditional",
"Chinese",
"Medicine.",
"200062,",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"lipopolysaccharide",
"(LPS),",
"IL-1,",
"or",
"CD40L.",
"Many",
"costi-",
"mulatory",
"factors",
"are",
"expressed",
"by",
"DCs",
"and",
"play",
"impor-",
"tant",
"roles",
"in",
"the",
"communication",
"between",
"DCs",
"and",
"immunocompetent",
"cells",
"[2,3].",
"The",
"functions",
"of",
"DCs",
"are",
"also",
"regulated",
"by",
"the",
"mutual",
"cross-talk",
"between",
"costi-",
"mulatory",
"molecules",
"[3].",
"The",
"additional",
"expression",
"of",
"activating",
"costimulatory",
"molecules",
"that",
"favor",
"the",
"inter-",
"action",
"between",
"DCs",
"and",
"T",
"cells",
"further",
"enhances",
"the",
"ability",
"of",
"DCs",
"to",
"generate",
"antitumor",
"immune",
"responses.",
"Activating",
"costimulatory",
"molecules",
"that",
"have",
"been",
"upre-",
"gulated",
"on",
"DCs",
"by",
"genetic",
"engineering",
"include",
"the",
"CD40",
"ligand",
"(CD40L)",
"[4-6],",
"CD70",
"[7],",
"4-1BBL",
"[8],",
"the",
"OX40",
"ligand",
"(OX40L)",
"[9],",
"and",
"the",
"receptor",
"activator",
"of",
"NF-",
"B",
"(RANK)/RANK",
"ligand",
"(RANKL)",
"[10].",
"CTLA4",
"(CD152)",
"is",
"an",
"inhibitory",
"costimulatory",
"mole-",
"cule.",
"The",
"expression",
"and",
"function",
"of",
"CTLA4",
"in",
"T",
"cells",
"have",
"been",
"well",
"studied",
"and",
"the",
"effect",
"of",
"CTLA4",
"on",
"DCs",
"has",
"also",
"been",
"studied.",
"CTLA4",
"acts",
"as",
"a",
"ligand",
"to",
"induce",
"interferon",
"g",
"(IFNg)",
"production",
"by",
"DCs",
"and",
"to",
"prevent",
"T-cell",
"responses",
"via",
"a",
"mechanism",
"that",
"involves",
"trypto-",
"phan",
"catabolism",
"[11].",
"CTLA4-immunoglobulin",
"(Ig)",
"may",
"inhibit",
"DC",
"function",
"through",
"the",
"B7",
"receptor",
"on",
"DCs,",
"©",
"2011",
"Wang",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"BMC",
"Neuroscience",
"Research",
"article",
"Serotonin",
"5-HT2A",
"and",
"5-HT6",
"receptors",
"in",
"the",
"prefrontal",
"cortex",
"of",
"Alzheimer",
"and",
"normal",
"aging",
"patients",
"Dietrich",
"E",
"Lorke1,2,",
"Gang",
"Lu2,3,",
"Eric",
"Cho2",
"and",
"David",
"T",
"Yew*2",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Anatomy,",
"Faculty",
"of",
"Medicine",
"and",
"Health",
"Sciences,",
"UAE",
"University,",
"Box",
"17666,",
"Al",
"Ain,",
"United",
"Arab",
"Emirates,",
"2Department",
"of",
"Anatomy,",
"Chinese",
"University",
"of",
"Hong",
"Kong,",
"Shatin,",
"N.T.,",
"Hong",
"Kong",
"and",
"3Kunming",
"Medical",
"College,",
"Kunming,",
"Yunnan,",
"China",
"Email:",
"Dietrich",
"E",
"Lorke",
"-",
"lorke@uaeu.ac.ae;",
"Gang",
"Lu",
"-",
"lugang@surgery.cuhk.edu.hk;",
"Eric",
"Cho",
"-",
"eric-cho@ana.cuhk.edu.hk;",
"David",
"T",
"Yew*",
"-",
"david-yew@cuhk.edu.hk",
"*",
"Corresponding",
"author",
"Published:",
"27",
"April",
"2006",
"BMC",
"Neuroscience",
"2006,",
"7:36",
"doi:10.1186/1471-2202-7-36",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2202/7/36",
"Received:",
"12",
"December",
"2005",
"Accepted:",
"27",
"April",
"2006",
"©",
"2006",
"Lorke",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"It",
"has",
"been",
"hypothesized",
"that",
"alterations",
"of",
"the",
"serotonergic",
"system",
"contribute",
"to",
"neuropsychiatric",
"symptoms",
"in",
"Alzheimer",
"disease",
"(AD).",
"Cellular",
"expressions",
"of",
"the",
"two",
"serotonergic",
"receptors",
"5-HT2A",
"and",
"5-HT6",
"have",
"therefore",
"been",
"determined",
"by",
"immunohistochemistry",
"in",
"the",
"prefrontal",
"cortex",
"of",
"patients",
"with",
"AD",
"(n=6)",
"and",
"normal",
"age-matched",
"controls",
"(n",
"=",
"7).",
"Results:",
"In",
"normal",
"aging",
"patients,",
"5-HT2A",
"label",
"was",
"mainly",
"observed",
"in",
"large",
"pyramidal",
"cells,",
"but",
"to",
"a",
"lesser",
"extent",
"also",
"in",
"small",
"pyramidal",
"cells",
"and",
"in",
"stellate",
"cells",
"of",
"cortical",
"layers",
"II-VI.",
"In",
"AD,",
"a",
"similar",
"distribution",
"was",
"observed,",
"but",
"density",
"of",
"positive",
"cells",
"was",
"significantly",
"reduced",
"by",
"33%.",
"In",
"aging",
"control",
"patients,",
"the",
"5-HT6",
"receptor",
"was",
"expressed",
"by",
"pyramidal",
"cells",
"and",
"occasional",
"stellate",
"cells,",
"not",
"only",
"of",
"layers",
"II-V,",
"but",
"also",
"of",
"layer",
"I,",
"where",
"a",
"distinct",
"label",
"was",
"observed",
"in",
"neurons",
"and",
"surrounding",
"fibers.",
"5-HT6",
"receptor",
"expression",
"in",
"AD",
"patients",
"had",
"the",
"same",
"pattern,",
"but",
"was",
"significantly",
"decreased",
"by",
"40%.",
"Conclusion:",
"Our",
"results",
"indicate",
"that",
"a",
"decline",
"in",
"neurons",
"expressing",
"5-HT2A,",
"but",
"also",
"5-HT6",
"receptors",
"may",
"play",
"a",
"role",
"in",
"the",
"etiopathology",
"of",
"neuropsychiatric",
"symptoms",
"in",
"AD.",
"Background",
"Alzheimer",
"disease",
"(AD),",
"the",
"most",
"common",
"cause",
"of",
"dementia",
"in",
"the",
"elderly,",
"is",
"clinically",
"characterized",
"by",
"pro-",
"gressive",
"cognitive",
"impairment",
"associated",
"with",
"severe",
"neu-",
"ropsychiatric",
"disturbances.",
"These",
"behavioral",
"and",
"psychological",
"symptoms",
"of",
"dementia",
"(BPSD)",
"include",
"hal-",
"lucinations,",
"delusions,",
"aggressive",
"behavior,",
"overactivity,",
"anxieties",
"and",
"affective",
"disturbances",
"[1,2].",
"Whereas",
"the",
"decline",
"in",
"cognitive",
"functions",
"can",
"be",
"largely",
"related",
"to",
"cholinergic",
"dysfunction",
"arising",
"from",
"disruption",
"of",
"basal",
"forebrain",
"cholinergic",
"pathways",
"(cholinergic",
"hypothesis)",
"[1,3,4],",
"impaired",
"balance",
"between",
"several",
"neurotransmit-",
"ters",
"has",
"been",
"implicated",
"in",
"the",
"pathogenesis",
"of",
"BPSP",
"[2,5-",
"7],",
"with",
"serotonin",
"(5-HT)",
"playing",
"a",
"pivotal",
"role",
"[2,8-10].",
"The",
"actions",
"of",
"5-HT",
"are",
"mediated",
"through",
"seven",
"major",
"receptors",
"classes,",
"5-HT1–7,",
"comprising",
"a",
"total",
"of",
"14",
"distinct",
"mammalian",
"5-HT",
"receptor",
"subtypes",
"(for",
"review,",
"see",
"[11]).",
"The",
"5-HT2A",
"receptor",
"has",
"attracted",
"most",
"interest",
"because",
"of",
"its",
"possible",
"participation",
"in",
"behavioral",
"alterations",
"in",
"AD.",
"5-HT2A",
"is",
"localized",
"in",
"the",
"cortex",
"and",
"caudate",
"and",
"is",
"involved",
"in",
"anxiety",
"[10].",
"5-HT2A",
"receptors",
"mediate",
"the",
"psychotomimetic",
"effects",
"of",
"hallucinogens",
"[11-13],",
"and",
"alterations",
"in",
"binding",
"characteristics",
"to",
"this",
"receptor",
"have",
"been",
"observed",
"in",
"the",
"prefrontal",
"cortex",
"of",
"patients",
"suffer-",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"de",
"Fine",
"Olivarius",
"et",
"al.",
"BMC",
"Public",
"Health",
"2011,",
"11:80",
"http://www.biomedcentral.com/1471-2458/11/80",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Prevalence",
"and",
"progression",
"of",
"visual",
"impairment",
"in",
"patients",
"newly",
"diagnosed",
"with",
"clinical",
"type",
"2",
"diabetes:",
"a",
"6-year",
"follow",
"up",
"study",
"Niels",
"de",
"Fine",
"Olivarius1*,",
"Volkert",
"Siersma1,",
"Gitte",
"Juul",
"Almind1,",
"Niels",
"Vesti",
"Nielsen2",
"Abstract",
"Background:",
"Many",
"diabetic",
"patients",
"fear",
"visual",
"loss",
"as",
"the",
"worst",
"consequence",
"of",
"diabetes.",
"In",
"most",
"studies",
"the",
"main",
"eye",
"pathology",
"is",
"assigned",
"as",
"the",
"cause",
"of",
"visual",
"impairment.",
"This",
"study",
"analysed",
"a",
"broad",
"range",
"of",
"possible",
"ocular",
"and",
"non-ocular",
"predictors",
"of",
"visual",
"impairment",
"prospectively",
"in",
"patients",
"newly",
"diagnosed",
"with",
"clinical",
"type",
"2",
"diabetes.",
"Methods:",
"Data",
"were",
"from",
"a",
"population-based",
"cohort",
"of",
"1,241",
"persons",
"newly",
"diagnosed",
"with",
"clinical,",
"often",
"symptomatic",
"type",
"2",
"diabetes",
"aged",
"≥",
"40",
"years.",
"After",
"6",
"years,",
"807",
"patients",
"were",
"followed",
"up.",
"Standard",
"eye",
"examinations",
"were",
"done",
"by",
"practising",
"ophthalmologists.",
"Results:",
"At",
"diabetes",
"diagnosis",
"median",
"age",
"was",
"65.5",
"years.",
"Over",
"6",
"years,",
"the",
"prevalence",
"of",
"blindness",
"(visual",
"acuity",
"of",
"best",
"seeing",
"eye",
"≤",
"0.1)",
"rose",
"from",
"0.9%",
"(11/1,241)",
"to",
"2.4%",
"(19/807)",
"and",
"the",
"prevalence",
"of",
"moderate",
"visual",
"impairment",
"(>",
"0.1;",
"<",
"0.5)",
"rose",
"from",
"5.4%",
"(67/1,241)",
"to",
"6.7%",
"(54/807).",
"The",
"incidence",
"(95%",
"confidence",
"interval)",
"of",
"blindness",
"was",
"40.2",
"(25.3-63.8)",
"per",
"10,000",
"patient-years.",
"Baseline",
"predictors",
"of",
"level",
"of",
"visual",
"acuity",
"(age,",
"age-related",
"macular",
"degeneration",
"(AMD),",
"cataract,",
"living",
"alone,",
"low",
"self-rated",
"health,",
"and",
"sedentary",
"life-style)",
"and",
"speed",
"of",
"continued",
"visual",
"loss",
"(age,",
"AMD,",
"diabetic",
"retinopathy",
"(DR),",
"cataract,",
"living",
"alone,",
"and",
"high",
"fasting",
"triglycerides)",
"were",
"identified.",
"Conclusions:",
"In",
"a",
"comprehensive",
"assessment",
"of",
"predictors",
"of",
"visual",
"impairment,",
"even",
"in",
"a",
"health",
"care",
"system",
"allowing",
"self-referral",
"to",
"free",
"eye",
"examinations,",
"treatable",
"eye",
"pathologies",
"such",
"as",
"DR",
"and",
"cataract",
"emerge",
"together",
"with",
"age",
"as",
"the",
"most",
"notable",
"predictors",
"of",
"continued",
"visual",
"loss",
"after",
"diabetes",
"diagnosis.",
"Our",
"results",
"underline",
"the",
"importance",
"of",
"eliminating",
"barriers",
"to",
"efficient",
"eye",
"care",
"by",
"increasing",
"patients’",
"and",
"primary",
"care",
"practitioners’",
"awareness",
"of",
"the",
"necessity",
"of",
"regular",
"eye",
"examinations",
"and",
"timely",
"surgical",
"treatment.",
"Background",
"In",
"Europe",
"and",
"the",
"United",
"States",
"severe",
"visual",
"impair-",
"ment",
"may",
"be",
"2-3",
"times",
"more",
"common",
"among",
"people",
"with",
"diabetes",
"than",
"in",
"the",
"general",
"population",
"[1,2],",
"but",
"this",
"difference",
"decreases",
"with",
"age",
"[2].",
"Diabetic",
"retinopa-",
"thy",
"(DR)",
"is",
"regarded",
"as",
"the",
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"of",
"blindness",
"in",
"5-15%",
"of",
"the",
"blind",
"in",
"the",
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"population",
"[3-5]",
"and",
"in",
"30-50%",
"of",
"blind",
"type",
"2",
"diabetic",
"patients",
"[6,7].",
"There",
"are,",
"however,",
"huge",
"regional",
"differences",
"in",
"presumed",
"causes",
"of",
"blindness",
"across",
"the",
"world",
"[8].",
"DR",
"is",
"considered",
"the",
"*",
"Correspondence:",
"olivarius@sund.ku.dk",
"1The",
"Research",
"Unit",
"for",
"General",
"Practice",
"and",
"Section",
"of",
"General",
"Practice,",
"Department",
"of",
"Public",
"Health,",
"University",
"of",
"Copenhagen,",
"Copenhagen,",
"Denmark",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"leading",
"cause",
"of",
"blindness",
"among",
"people",
"of",
"working",
"age",
"in",
"many",
"countries",
"[3-5],",
"while",
"age-related",
"macular",
"degeneration",
"(AMD)",
"is",
"considered",
"the",
"leading",
"cause",
"in",
"people",
"over",
"65",
"years",
"[3-5,9].",
"Diabetes",
"with",
"even",
"mildly",
"to",
"moderately",
"impaired",
"sight",
"has",
"a",
"negative",
"impact",
"on",
"perceived",
"quality",
"of",
"life",
"and",
"psychosocial",
"functioning",
"giving",
"rise",
"to",
"feelings",
"of",
"vulnerability,",
"worries",
"about",
"the",
"future",
"and",
"loss",
"of",
"inde-",
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"and",
"mobility",
"[10-12].",
"A",
"sizeable",
"proportion",
"of",
"type",
"2",
"diabetic",
"patients",
"fear",
"visual",
"loss",
"intensely",
"[13]",
"and",
"consider",
"loss",
"of",
"vision",
"the",
"worst",
"complication",
"of",
"diabetes",
"[10].",
"For",
"the",
"health",
"practitioner",
"visual",
"acuity",
"is",
"a",
"ubiquitous",
"and",
"handy",
"measure",
"of",
"visual",
"function,",
"but",
"visual",
"acuity",
"is",
"not",
"a",
"suitable",
"measure",
"of",
"future",
"visual",
"loss",
"as",
"the",
"sight-threatening",
"eye",
"pathologies",
"often",
"are",
"©",
"2011",
"de",
"Fine",
"Olivarius",
"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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] | [
"Hindawi",
"Publishing",
"Corporation",
"Gastroenterology",
"Research",
"and",
"Practice",
"Volume",
"2011,",
"Article",
"ID",
"410971,",
"6",
"pages",
"doi:10.1155/2011/410971",
"Review",
"Article",
"Refeeding",
"Syndrome:",
"A",
"Literature",
"Review",
"L.",
"U.",
"R.",
"Khan,",
"J.",
"Ahmed,",
"S.",
"Khan,",
"and",
"J.",
"MacFie",
"The",
"Combined",
"Gastroenterology",
"Research",
"Unit,",
"Scarborough",
"Hospital,",
"Woodland",
"Drive,",
"Scarborough",
"YO12",
"6QL,",
"UK",
"Correspondence",
"should",
"be",
"addressed",
"to",
"J.",
"Ahmed,",
"drjag@hotmail.co.uk",
"Received",
"1",
"June",
"2010;",
"Revised",
"21",
"July",
"2010;",
"Accepted",
"3",
"August",
"2010",
"Academic",
"Editor:",
"Re´my",
"Meier",
"Copyright",
"©",
"2011",
"L.",
"U.",
"R.",
"Khan",
"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.",
"Refeeding",
"syndrome",
"(RFS)",
"describes",
"the",
"biochemical",
"changes,",
"clinical",
"manifestations,",
"and",
"complications",
"that",
"can",
"occur",
"as",
"a",
"consequence",
"of",
"feeding",
"a",
"malnourished",
"catabolic",
"individual.",
"RFS",
"has",
"been",
"recognised",
"in",
"the",
"literature",
"for",
"over",
"fifty",
"years",
"and",
"can",
"result",
"in",
"serious",
"harm",
"and",
"death.",
"Crude",
"estimates",
"of",
"incidence,",
"morbidity,",
"and",
"mortality",
"are",
"available",
"for",
"specific",
"populations.",
"RFS",
"can",
"occur",
"in",
"any",
"individual",
"but",
"more",
"commonly",
"occurs",
"in",
"at-risk",
"populations.",
"Increased",
"awareness",
"amongst",
"healthcare",
"professionals",
"is",
"likely",
"to",
"reduce",
"morbidity",
"and",
"mortality.",
"This",
"review",
"examines",
"the",
"physiology",
"of",
"RFS",
"and",
"describes",
"the",
"clinical",
"manifestations.",
"A",
"management",
"strategy",
"is",
"described.",
"The",
"importance",
"of",
"a",
"multidisciplinary",
"approach",
"is",
"emphasized.",
"1.",
"Introduction",
"RFS",
"is",
"well",
"recognised.",
"It",
"occurs",
"after",
"the",
"reintroduction",
"of",
"feeding",
"after",
"a",
"period",
"of",
"starvation",
"or",
"fasting",
"[1].",
"RFS",
"describes",
"a",
"series",
"of",
"metabolic",
"and",
"biochemical",
"changes",
"that",
"occur",
"as",
"a",
"consequence",
"of",
"reintroduction",
"of",
"feeding",
"after",
"a",
"period",
"of",
"starvation",
"or",
"fasting.",
"This",
"unfavorable",
"metabolic",
"response",
"causes",
"nonimmune-mediated",
"harm",
"to",
"the",
"body",
"and",
"can",
"be",
"mild,",
"moderate,",
"or",
"severe.",
"Although,",
"the",
"physiol-",
"ogy",
"and",
"pathophysiology",
"are",
"well",
"known,",
"the",
"circumstances",
"under",
"which",
"RFS",
"occurs,",
"the",
"clinical",
"manifestations,",
"and",
"the",
"management",
"of",
"these",
"patients",
"are",
"less",
"clear",
"[2,",
"3].",
"1.1.",
"Methods.",
"A",
"PubMed",
"search",
"for",
"the",
"terms",
"“refeeding",
"syndrome”",
"AND",
"“hypophosphataemia”",
"generated",
"two",
"hun-",
"dred",
"and",
"seven",
"separate",
"articles.",
"There",
"were",
"no",
"randomized",
"controlled",
"trials",
"identified.",
"1.2.",
"Physiology.",
"With",
"food",
"in",
"abundance,",
"carbohydrates",
"provide",
"for",
"most",
"of",
"our",
"energy",
"requirements.",
"Glucose,",
"the",
"principal",
"product",
"of",
"carbohydrate",
"digestion,",
"is",
"actively",
"cotransported",
"along",
"with",
"sodium",
"at",
"the",
"intestinal",
"brush",
"border",
"against",
"a",
"concentration",
"gradient.",
"Glucose",
"enters",
"the",
"portal",
"circulation",
"by",
"facilitated",
"diffusion",
"and",
"blood",
"sugar",
"levels",
"rise.",
"This",
"stimulates",
"the",
"release",
"of",
"the",
"peptide",
"hormone",
"insulin",
"from",
"pancreatic",
"islet",
"cells.",
"Insulin",
"secretion",
"has",
"several",
"effects.",
"It",
"promotes",
"glucose",
"uptake",
"and",
"storage",
"(glycogenesis),",
"inhibits",
"the",
"breakdown",
"of",
"fats",
"(lipolysis),",
"and",
"increases",
"cellular",
"uptake",
"of",
"potassium.",
"When",
"glycogen",
"stor-",
"age",
"capacity",
"is",
"exceeded,",
"lipogenesis",
"occurs",
"with",
"nonoxidised",
"glucose",
"being",
"converted",
"to",
"fat",
"and",
"stored",
"as",
"triglycerides",
"in",
"adipose",
"tissue.",
"Together,",
"the",
"consequence",
"is",
"for",
"blood",
"glucose",
"levels",
"to",
"fall",
"with",
"a",
"concomitant",
"reduction",
"in",
"insulin",
"secretion",
"[4].",
"With",
"starvation,",
"levels",
"of",
"glucose",
"begin",
"to",
"fall",
"within",
"24",
"to",
"72",
"hours.",
"This",
"results",
"in",
"the",
"release",
"of",
"the",
"peptide",
"hormone",
"glucagon",
"and",
"a",
"reduction",
"in",
"insulin",
"secretion",
"[10].",
"Glucose",
"levels",
"are",
"maintained",
"by",
"glycogenolysis",
"but",
"glycogen",
"stores",
"rarely",
"last",
"more",
"than",
"72",
"hours",
"[11].",
"Glucose",
"homeostasis",
"is",
"essential",
"because",
"certain",
"tissues,",
"such",
"as",
"brain,",
"erythrocytes,",
"and",
"cells",
"of",
"the",
"renal",
"medulla",
"are",
"obligate",
"glucose",
"users",
"[12].",
"These",
"demands",
"for",
"glucose",
"are",
"met",
"by",
"the",
"process",
"of",
"gluconeogenesis",
"by",
"which",
"noncarbohydrate",
"sources",
"are",
"metabolized",
"to",
"glucose.",
"The",
"most",
"important",
"of",
"these",
"is",
"the",
"muscle",
"protein",
"alanine.",
"In",
"addition,",
"fatty",
"acid",
"oxidation",
"in",
"liver",
"hepatocytes",
"generates",
"ketone",
"bodies.",
"These",
"are",
"converted",
"to",
"acetyl-coenzyme-A",
"generating",
"energy",
"via",
"the",
"Kreb’s",
"cycle.",
"Further",
"energy",
"production",
"from",
"lactate",
"and",
"pyruvate",
"(the",
"products",
"of",
"glycolysis)",
"and",
"amino",
"acids",
"occurs",
"via",
"the",
"Cori",
"cycle",
"[4].",
"In",
"summary,",
"metabolic",
"adaptation",
"occurs",
"to",
"ensure",
"survival",
"on",
"fat",
"fuel",
"economy",
"[13].",
"There",
"is",
"a",
"resultant",
"loss",
"of",
"body",
"fat",
"and",
"protein",
"and",
"an",
"accompanying",
"depletion",
"of",
"potassium,",
"phosphate,",
"and",
"magnesium",
"[14,",
"15]."
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] | [
"Liet",
"et",
"al.",
"BMC",
"Pediatrics",
"2011,",
"11:92",
"http://www.biomedcentral.com/1471-2431/11/92",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"Open",
"Access",
"Respiratory",
"support",
"by",
"neurally",
"adjusted",
"ventilatory",
"assist",
"(NAVA)",
"in",
"severe",
"RSV-related",
"bronchiolitis:",
"a",
"case",
"series",
"report",
"Jean-Michel",
"Liet1*,",
"Jean-Marc",
"Dejode1†,",
"Nicolas",
"Joram1†,",
"Bénédicte",
"Gaillard-Le",
"Roux1†,",
"Pierre",
"Bétrémieux2†",
"and",
"Jean-Christophe",
"Rozé1†",
"Abstract",
"Background:",
"Neurally",
"adjusted",
"ventilatory",
"assist",
"(NAVA)",
"is",
"a",
"new",
"mode",
"of",
"mechanical",
"ventilation",
"controlled",
"by",
"diaphragmatic",
"electrical",
"signals.",
"The",
"electrical",
"signals",
"allow",
"synchronization",
"of",
"ventilation",
"to",
"spontaneous",
"breathing",
"efforts",
"of",
"a",
"child,",
"as",
"well",
"as",
"permitting",
"pressure",
"assistance",
"proportional",
"to",
"the",
"electrical",
"signal.",
"NAVA",
"provides",
"equally",
"fine",
"synchronization",
"of",
"respiratory",
"support",
"and",
"pressure",
"assistance",
"varying",
"with",
"the",
"needs",
"of",
"the",
"child.",
"NAVA",
"has",
"mainly",
"been",
"studied",
"in",
"children",
"who",
"underwent",
"cardiac",
"surgery",
"during",
"the",
"period",
"of",
"weaning",
"from",
"a",
"respirator.",
"Case",
"presentation:",
"We",
"report",
"here",
"a",
"series",
"of",
"3",
"children",
"(1",
"month,",
"3",
"years,",
"and",
"28",
"days",
"old)",
"with",
"severe",
"respiratory",
"distress",
"due",
"to",
"RSV-related",
"bronchiolitis",
"requiring",
"invasive",
"mechanical",
"ventilation",
"with",
"a",
"high",
"level",
"of",
"oxygen",
"(FiO2",
"≥50%)",
"for",
"whom",
"NAVA",
"facilitated",
"respiratory",
"support.",
"One",
"of",
"these",
"children",
"had",
"diagnosis",
"criteria",
"for",
"acute",
"lung",
"injury,",
"another",
"for",
"acute",
"respiratory",
"distress",
"syndrome.",
"Establishment",
"of",
"NAVA",
"provided",
"synchronization",
"of",
"mechanical",
"ventilatory",
"support",
"with",
"the",
"breathing",
"efforts",
"of",
"the",
"children.",
"Respiratory",
"rate",
"and",
"inspiratory",
"pressure",
"became",
"extremely",
"variable,",
"varying",
"at",
"each",
"cycle,",
"while",
"children",
"were",
"breathing",
"easily",
"and",
"smoothly.",
"All",
"three",
"children",
"demonstrated",
"less",
"oxygen",
"requirements",
"after",
"introducing",
"NAVA",
"(57",
"±",
"6%",
"to",
"42",
"±",
"18%).",
"This",
"improvement",
"was",
"observed",
"while",
"peak",
"airway",
"pressure",
"decreased",
"(28",
"±",
"3",
"to",
"15",
"±",
"5",
"cm",
"H2O).",
"In",
"one",
"child,",
"NAVA",
"facilitated",
"the",
"management",
"of",
"acute",
"respiratory",
"distress",
"syndrome",
"with",
"extensive",
"subcutaneous",
"emphysema.",
"Conclusions:",
"Our",
"findings",
"highlight",
"the",
"feasibility",
"and",
"benefit",
"of",
"NAVA",
"in",
"children",
"with",
"severe",
"RSV-related",
"bronchiolitis.",
"NAVA",
"provides",
"a",
"less",
"aggressive",
"ventilation",
"requiring",
"lower",
"inspiratory",
"pressures",
"with",
"good",
"results",
"for",
"oxygenation",
"and",
"more",
"comfort",
"for",
"the",
"children.",
"Background",
"Neurally",
"adjusted",
"ventilatory",
"assist",
"(NAVA)",
"is",
"a",
"new",
"method",
"of",
"assisted",
"ventilation",
"that",
"can",
"be",
"used",
"for",
"chil-",
"dren",
"regardless",
"of",
"weight",
"and",
"age.",
"This",
"ventilation",
"mode",
"is",
"controlled",
"by",
"diaphragmatic",
"electrical",
"signals",
"through",
"a",
"gastric",
"tube",
"with",
"specific",
"electrodes",
"on",
"its",
"surface.",
"The",
"collected",
"electrical",
"signals",
"allow",
"synchronization",
"of",
"venti-",
"lation",
"to",
"spontaneous",
"breathing",
"efforts",
"of",
"a",
"child,",
"as",
"well",
"as",
"providing",
"pressure",
"assistance",
"proportional",
"to",
"the",
"*",
"Correspondence:",
"jeanmichel.liet@chu-nantes.fr",
"†",
"Contributed",
"equally",
"1Unité",
"de",
"Réanimation",
"Pédiatrique,",
"Hôpital",
"Mère-Enfant",
"Faïencerie,",
"CHU",
"de",
"Nantes,",
"38",
"Boulevard",
"Jean-Monnet,",
"44093",
"Nantes,",
"France",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"electrical",
"signal",
"and",
"thus",
"to",
"the",
"output",
"of",
"the",
"child’s",
"respiratory",
"centers.",
"NAVA",
"has",
"mainly",
"been",
"studied",
"in",
"children",
"who",
"under-",
"went",
"cardiac",
"surgery",
"[1-3]",
"during",
"the",
"period",
"of",
"weaning",
"from",
"a",
"respirator.",
"We",
"report",
"here",
"a",
"series",
"of",
"3",
"children",
"with",
"severe",
"respiratory",
"distress",
"due",
"to",
"respiratory",
"syncy-",
"tial",
"virus",
"(RSV)",
"bronchiolitis",
"for",
"whom",
"NAVA",
"facilitated",
"respiratory",
"support.",
"Case",
"Presentation",
"Our",
"unit",
"is",
"a",
"12-bed",
"tertiary",
"care",
"university",
"hospital",
"pediatric",
"intensive",
"care",
"unit.",
"Recruitment",
"is",
"both",
"medi-",
"cal",
"and",
"surgical.",
"NAVA",
"has",
"been",
"used",
"in",
"our",
"unit",
"for",
"weaning",
"children",
"from",
"a",
"respirator",
"who",
"were",
"operated",
"©",
"2011",
"Liet",
"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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] | [
"Open",
"Access",
"Renkawitz",
"et",
"al.",
"BMC",
"Musculoskeletal",
"Disorders",
"2011,",
"12:192",
"http://www.biomedcentral.com/1471-2474/12/192",
"S",
"T",
"U",
"D",
"Y",
"P",
"R",
"O",
"T",
"O",
"C",
"O",
"L",
"Minimally",
"invasive",
"computer-navigated",
"total",
"hip",
"arthroplasty,",
"following",
"the",
"concept",
"of",
"femur",
"first",
"and",
"combined",
"anteversion:",
"design",
"of",
"a",
"blinded",
"randomized",
"controlled",
"trial",
"Tobias",
"Renkawitz1*,",
"Martin",
"Haimerl2,",
"Lars",
"Dohmen2,",
"Sabine",
"Gneiting2,",
"Melanie",
"Wegner2,",
"Nicole",
"Ehret2,",
"Claudia",
"Buchele2,",
"Mario",
"Schubert2,",
"Philipp",
"Lechler1,",
"Michael",
"Woerner1,",
"Ernst",
"Sendtner1,",
"Tibor",
"Schuster3,",
"Kurt",
"Ulm3,",
"Robert",
"Springorum1",
"and",
"Joachim",
"Grifka1",
"Abstract",
"Background:",
"Impingement",
"can",
"be",
"a",
"serious",
"complication",
"after",
"total",
"hip",
"arthroplasty",
"(THA),",
"and",
"is",
"one",
"of",
"the",
"major",
"causes",
"of",
"postoperative",
"pain,",
"dislocation,",
"aseptic",
"loosening,",
"and",
"implant",
"breakage.",
"Minimally",
"invasive",
"THA",
"and",
"computer-navigated",
"surgery",
"were",
"introduced",
"several",
"years",
"ago.",
"We",
"have",
"developed",
"a",
"novel,",
"computer-",
"assisted",
"operation",
"method",
"for",
"THA",
"following",
"the",
"concept",
"of",
"“femur",
"first\"/\"combined",
"anteversion”,",
"which",
"incorporates",
"various",
"aspects",
"of",
"performing",
"a",
"functional",
"optimization",
"of",
"the",
"cup",
"position,",
"and",
"comprehensively",
"addresses",
"range",
"of",
"motion",
"(ROM)",
"as",
"well",
"as",
"cup",
"containment",
"and",
"alignment",
"parameters.",
"Hence,",
"the",
"purpose",
"of",
"this",
"study",
"is",
"to",
"assess",
"whether",
"the",
"artificial",
"joint’s",
"ROM",
"can",
"be",
"improved",
"by",
"this",
"computer-assisted",
"operation",
"method.",
"Second,",
"the",
"clinical",
"and",
"radiological",
"outcome",
"will",
"be",
"evaluated.",
"Methods/Design:",
"A",
"registered",
"patient-",
"and",
"observer-blinded",
"randomized",
"controlled",
"trial",
"will",
"be",
"conducted.",
"Patients",
"between",
"the",
"ages",
"of",
"50",
"and",
"75",
"admitted",
"for",
"primary",
"unilateral",
"THA",
"will",
"be",
"included.",
"Patients",
"will",
"be",
"randomly",
"allocated",
"to",
"either",
"receive",
"minimally",
"invasive",
"computer-navigated",
"“femur",
"first”",
"THA",
"or",
"the",
"conventional",
"minimally",
"invasive",
"THA",
"procedure.",
"Self-reported",
"functional",
"status",
"and",
"health-related",
"quality",
"of",
"life",
"(questionnaires)",
"will",
"be",
"assessed",
"both",
"preoperatively",
"and",
"postoperatively.",
"Perioperative",
"complications",
"will",
"be",
"registered.",
"Radiographic",
"evaluation",
"will",
"take",
"place",
"up",
"to",
"6",
"weeks",
"postoperatively",
"with",
"a",
"computed",
"tomography",
"(CT)",
"scan.",
"Component",
"position",
"will",
"be",
"evaluated",
"by",
"an",
"independent",
"external",
"institute",
"on",
"a",
"3D",
"reconstruction",
"of",
"the",
"femur/",
"pelvis",
"using",
"image-processing",
"software.",
"Postoperative",
"ROM",
"will",
"be",
"calculated",
"by",
"an",
"algorithm",
"which",
"automatically",
"determines",
"bony",
"and",
"prosthetic",
"impingements.",
"Discussion:",
"In",
"the",
"past,",
"computer",
"navigation",
"has",
"improved",
"the",
"accuracy",
"of",
"component",
"positioning.",
"So",
"far,",
"there",
"are",
"only",
"few",
"objective",
"data",
"quantifying",
"the",
"risks",
"and",
"benefits",
"of",
"computer",
"navigated",
"THA.",
"Therefore,",
"this",
"study",
"has",
"been",
"designed",
"to",
"compare",
"minimally",
"invasive",
"computer-navigated",
"“femur",
"first”",
"THA",
"with",
"a",
"conventional",
"technique",
"for",
"minimally",
"invasive",
"THA.",
"The",
"results",
"of",
"this",
"trial",
"will",
"be",
"presented",
"as",
"soon",
"as",
"they",
"become",
"available.",
"Trial",
"registration",
"number:",
"DRKS00000739",
"*",
"Correspondence:",
"t.renkawitz@asklepios.com",
"1Department",
"of",
"Orthopaedic",
"Surgery,",
"Regensburg",
"University",
"Medical",
"Center,",
"Germany",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2011",
"Renkawitz",
"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",
"NEUROSCIENCE",
"3D",
"standard",
"brain",
"of",
"the",
"red",
"flour",
"beetle",
"Tribolium",
"castaneum:",
"a",
"tool",
"to",
"study",
"metamorphic",
"development",
"and",
"adult",
"plasticity",
"David",
"Dreyer1,2,",
"Holger",
"Vitt1,",
"Stefan",
"Dippel",
"1,3,",
"Brigitte",
"Goetz1,",
"Basil",
"el",
"Jundi",
"1,",
"Martin",
"Kollmann1,",
"Wolf",
"Huetteroth1,4",
"and",
"Joachim",
"Schachtner",
"1*",
"1",
"Department",
"of",
"Biology,",
"Animal",
"Physiology,",
"Philipps-University",
"Marburg,",
"Marburg,",
"Germany",
"2",
"Department",
"of",
"Biology,",
"Animal",
"Navigation,",
"University",
"of",
"Oldenburg,",
"Oldenburg,",
"Germany",
"3",
"Department",
"of",
"Developmental",
"Biology,",
"Johann-Friedrich-Blumenbach-Institute",
"for",
"Zoology",
"and",
"Anthropol,",
"Georg-August-University",
"Göttingen,",
"Göttingen,",
"Germany",
"4",
"Department",
"of",
"Neurobiology,",
"University",
"of",
"Massachusetts",
"Medical",
"School,",
"Worcester,",
"MA,",
"USA",
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"03",
"March",
"2010",
"doi:",
"10.3389/neuro.06.003.2010",
"Edited",
"by:",
"Randolf",
"Menzel,",
"Freie",
"Universität",
"Berlin,",
"Germany",
"Reviewed",
"by:",
"Monika",
"Stengl,",
"Universität",
"Kassel,",
"Germany",
"*Correspondence:",
"Joachim",
"Schachtner,",
"Department",
"of",
"Biology,",
"Animal",
"Physiology,",
"Philipps-",
"University",
"Marburg,",
"Karl-von-Frisch-Str.",
"8,",
"D-35032",
"Marburg,",
"Germany.",
"e-mail:",
"schachtj@staff.uni-marburg.de",
"The",
"red",
"flour",
"beetleTribolium",
"castaneum",
"is",
"emerging",
"as",
"a",
"further",
"standard",
"insect",
"model",
"beside",
"Drosophila.",
"Its",
"genome",
"is",
"fully",
"sequenced",
"and",
"it",
"is",
"susceptible",
"for",
"genetic",
"manipulations",
"including",
"RNA-interference.",
"We",
"use",
"this",
"beetle",
"to",
"study",
"adult",
"brain",
"development",
"and",
"plasticity",
"primarily",
"with",
"respect",
"to",
"the",
"olfactory",
"system.",
"In",
"the",
"current",
"study,",
"we",
"provide",
"3D",
"standard",
"brain",
"atlases",
"of",
"freshly",
"eclosed",
"adult",
"female",
"and",
"male",
"beetles",
"(A0).The",
"atlases",
"include",
"eight",
"paired",
"and",
"three",
"unpaired",
"neuropils",
"including",
"antennal",
"lobes",
"(ALs),",
"optic",
"lobe",
"neuropils,",
"mushroom",
"body",
"calyces",
"and",
"pedunculi,",
"and",
"central",
"complex.",
"For",
"each",
"of",
"the",
"two",
"standard",
"brains,",
"we",
"averaged",
"brain",
"areas",
"of",
"20",
"individual",
"brains.",
"Additionally,",
"we",
"characterized",
"eight",
"selected",
"olfactory",
"glomeruli",
"from",
"10",
"A0",
"female",
"and",
"male",
"beetles",
"respectively,",
"which",
"we",
"could",
"unequivocally",
"recognize",
"from",
"individual",
"to",
"individual",
"owing",
"to",
"their",
"size",
"and",
"typical",
"position",
"in",
"the",
"ALs.",
"In",
"summary,",
"comparison",
"of",
"the",
"averaged",
"neuropil",
"volumes",
"revealed",
"no",
"sexual",
"dimorphism",
"in",
"any",
"of",
"the",
"reconstructed",
"neuropils",
"in",
"A0",
"Tribolium",
"brains.",
"Both,",
"the",
"female",
"and",
"male",
"3D",
"standard",
"brain",
"are",
"also",
"used",
"for",
"interspecies",
"comparisons,",
"and,",
"importantly,",
"will",
"serve",
"as",
"future",
"volumetric",
"references",
"after",
"genetical",
"manipulation",
"especially",
"regarding",
"metamorphic",
"development",
"and",
"adult",
"plasticity.",
"Keywords:",
"brain,",
"olfactory",
"system,",
"antennal",
"lobe,",
"insect,",
"neuropil,",
"digital",
"neuroanatomy,",
"coleoptera",
"INTRODUCTION",
"The",
"red",
"flour",
"beetle",
"Tribolium",
"castaneum",
"Herbst,",
"1797",
"(Bonneton,",
"2008),",
"which",
"is",
"a",
"major",
"pest",
"of",
"stored",
"grains,",
"grain",
"products,",
"and",
"other",
"dried",
"food,",
"is",
"emerging",
"as",
"a",
"further",
"standard",
"insect",
"model",
"beside",
"Drosophila.",
"It’s",
"powerful",
"reverse",
"genetics",
"(systemic",
"RNA-interference;",
"Bucher",
"et",
"al.,",
"2002;",
"Tomoyasu",
"and",
"Denell,",
"2004;",
"Tomoyasu",
"et",
"al.,",
"2008),",
"the",
"recently",
"published",
"full",
"genomic",
"sequence",
"(Richards",
"et",
"al.,",
"2008)",
"and",
"the",
"established",
"transgenesis",
"systems",
"(Berghammer",
"et",
"al.,",
"1999)",
"transform",
"Tribolium",
"into",
"a",
"primary",
"model",
"system.",
"Since",
"recently,",
"an",
"insertional",
"mutagen-",
"esis",
"screen",
"database",
"provides",
"mutants",
"and",
"enhancer",
"trap",
"lines",
"for",
"the",
"growing",
"Tribolium",
"community",
"(http://134.76.20.145/",
"Default.aspx).",
"Meanwhile,",
"Tribolium",
"has",
"become",
"one",
"of",
"the",
"most",
"important",
"models",
"in",
"the",
"field",
"of",
"evolution",
"and",
"development",
"(“evo-devo”)",
"because",
"its",
"development",
"is",
"more",
"“insect",
"typical”,",
"compared",
"to",
"that",
"of",
"the",
"classical",
"system",
"Drosophila",
"(Klingler,",
"2004).",
"Currently,",
"only",
"little",
"information",
"on",
"the",
"brain",
"or",
"its",
"embryonic",
"and",
"metamorphic",
"development",
"is",
"available.",
"With",
"our",
"pioneering",
"study",
"we",
"provide",
"for",
"the",
"first",
"time",
"anatomical",
"descrip-",
"tions",
"for",
"most",
"of",
"the",
"brain",
"areas",
"of",
"adult",
"Tribolium",
"including",
"3D",
"reconstructions",
"and",
"an",
"average",
"brain",
"atlas",
"for",
"selected",
"brain",
"neuropils.",
"With",
"the",
"latter,",
"we",
"present",
"the",
"first",
"standardization",
"of",
"a",
"coleopteran",
"brain.",
"Brains",
"are",
"typically",
"organized",
"in",
"defined",
"neuropils,",
"which",
"can",
"usually",
"be",
"characterized",
"by",
"their",
"spatial",
"location,",
"gross",
"anatomy,",
"and",
"often",
"by",
"a",
"certain",
"function.",
"For",
"example,",
"the",
"olfactory",
"bulbs",
"of",
"vertebrates",
"and",
"the",
"antennal",
"lobes",
"(ALs)",
"of",
"insects",
"have",
"been",
"attributed",
"to",
"be",
"the",
"first",
"processing",
"centers",
"for",
"olfactory",
"informa-",
"tion",
"(for",
"a",
"review",
"see",
"Hildebrand",
"and",
"Shepherd,",
"1997).",
"Compared",
"to",
"most",
"vertebrate",
"brains,",
"insect",
"brains",
"are",
"miniature",
"versions",
"being",
"typically",
"comprised",
"of",
"a",
"lower",
"number",
"of",
"neurons",
"and",
"neuropils.",
"Owing",
"to",
"the",
"lower",
"complexity",
"and",
"certain",
"technical",
"advantages,",
"insects",
"have",
"been",
"widely",
"used",
"as",
"models",
"to",
"study",
"principal",
"mechanisms",
"of",
"information",
"processing",
"and",
"integra-",
"tion,",
"in",
"the",
"context",
"of",
"defined",
"sensory",
"inputs",
"but",
"also",
"complex",
"behaviors",
"including",
"learning",
"and",
"memory",
"formation",
"(e.g.",
"Menzel,",
"2001;",
"Heisenberg,",
"2003).",
"Brains",
"of",
"animals",
"of",
"the",
"same",
"or",
"of",
"evolutionary",
"related",
"species",
"typically",
"share",
"the",
"same",
"principal",
"organization.",
"For",
"example",
"in",
"neopteran",
"insects,",
"the",
"central",
"olfactory",
"pathway",
"seems",
"to",
"be",
"well",
"conserved",
"(Strausfeld",
"et",
"al.,",
"1998;",
"Schachtner",
"et",
"al.,",
"2005).",
"However,",
"even",
"within",
"the",
"same",
"species,",
"no",
"brain",
"is",
"identical",
"with",
"the",
"next,",
"differing",
"in",
"size",
"and",
"shape",
"of",
"certain",
"brain",
"neuropils.",
"These",
"indi-",
"vidual",
"differences",
"can",
"result",
"from",
"a",
"variety",
"of",
"parameters",
"which",
"are",
"influencing",
"brain",
"organization",
"during",
"development",
"but",
"also",
"during",
"adulthood.",
"In",
"insects,",
"such",
"factors",
"include",
"brood",
"temperature,",
"sex,",
"age,",
"and",
"experience",
"(Groh",
"et",
"al.,",
"2004;",
"Technau,",
"2007;",
"Molina",
"and",
"O’Donnell,",
"2008).",
"To",
"study",
"sexual",
"brain",
"dimorphism",
"or",
"the",
"influence",
"of",
"defined",
"parameters",
"(ranging",
"from",
"single",
"molecules",
"to",
"social",
"experience)",
"on",
"brain",
"development",
"or",
"adult",
"plasticity,",
"average",
"or",
"standardized",
"brains",
"or",
"brain",
"areas",
"are",
"needed",
"to",
"relate",
"individual",
"variations",
"to",
"Frontiers",
"in",
"Systems",
"Neuroscience",
"www.frontiersin.org",
"March",
"2010",
"|",
"Volume",
"4",
"|",
"Article",
"3",
"|",
"1"
] | [
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] | [
"e",
"n",
"i",
"c",
"i",
"d",
"e",
"M",
"l",
"a",
"t",
"n",
"e",
"m",
"i",
"r",
"e",
"p",
"x",
"E",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"CORRESPONDENCE",
"Diane",
"Mathis",
"OR",
"Christophe",
"Benoist:",
"cbdm@hms.harvard.edu",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Exp.",
"Med.",
"Vol.",
"206",
"No.",
"6",
"1245-1252",
"www.jem.org/cgi/doi/10.1084/jem.20090300",
"B",
"R",
"I",
"E",
"F",
"D",
"E",
"F",
"I",
"N",
"I",
"T",
"I",
"V",
"E",
"R",
"E",
"P",
"O",
"RT",
"Neonatal",
"tolerance",
"revisited:",
"a",
"per",
"inatal",
"window",
"for",
"Aire",
"control",
"of",
"autoimmunity",
"Mireia",
"Guerau-de-Arellano,1,2",
"Marianne",
"Martinic,1,2",
"Christophe",
"Benoist,1,2",
"and",
"Diane",
"Mathis1,2",
"1Section",
"on",
"Immunology",
"and",
"Immunogenetics,",
"Joslin",
"Diabetes",
"Center,",
"and",
"2Department",
"of",
"Medicine,",
"Brigham",
"and",
"Women’s",
"Hospital,",
"Harvard",
"Medical",
"School,",
"Boston,",
"MA",
"02215",
"There",
"has",
"long",
"been",
"conceptual",
"and",
"experimental",
"support",
"for,",
"but",
"also",
"challenges",
"to,",
"the",
"notion",
"that",
"the",
"initial",
"period",
"of",
"the",
"immune",
"system’s",
"development",
"is",
"particularly",
"important",
"for",
"the",
"establishment",
"of",
"tolerance",
"to",
"self.",
"The",
"display",
"of",
"self-antigens",
"by",
"thymic",
"epithelial",
"cells",
"is",
"key",
"to",
"inducing",
"tolerance",
"in",
"the",
"T",
"lymphocyte",
"compartment,",
"a",
"process",
"enhanced",
"by",
"the",
"Aire",
"transcription",
"factor.",
"Using",
"a",
"doxycycline-regulated",
"transgene",
"to",
"target",
"Aire",
"expression",
"to",
"the",
"thymic",
"epithelium,",
"complementing",
"the",
"Aire",
"knockout",
"in",
"a",
"temporally",
"controlled",
"manner,",
"we",
"find",
"that",
"Aire",
"is",
"essential",
"in",
"the",
"perinatal",
"period",
"to",
"prevent",
"the",
"multiorgan",
"autoimmunity",
"that",
"is",
"typical",
"of",
"Aire",
"deficiency.",
"Surprisingly,",
"Aire",
"could",
"be",
"shut",
"down",
"soon",
"thereafter",
"and",
"remain",
"off",
"for",
"long",
"periods,",
"with",
"few",
"deleterious",
"consequences.",
"The",
"lymphopenic",
"state",
"present",
"in",
"neonates",
"was",
"a",
"factor",
"in",
"this",
"dichotomy",
"because",
"inducing",
"lymphopenia",
"during",
"Aire",
"turnoff",
"in",
"adults",
"recreated",
"the",
"disease,",
"which,",
"conversely,",
"could",
"be",
"ameliorated",
"by",
"supplementing",
"neonates",
"with",
"adult",
"lymphocytes.",
"In",
"short,",
"Aire",
"expression",
"during",
"the",
"perinatal",
"period",
"is",
"both",
"necessary",
"and",
"sufficient",
"to",
"induce",
"long-lasting",
"tolerance",
"and",
"avoid",
"autoimmunity.",
"Aire-controlled",
"mechanisms",
"of",
"central",
"tolerance",
"are",
"largely",
"dispensable",
"in",
"the",
"adult,",
"as",
"a",
"previously",
"tolerized",
"T",
"cell",
"pool",
"can",
"buffer",
"newly",
"generated",
"autoreactive",
"T",
"cells",
"that",
"might",
"emerge.",
"Adaptive",
"immune",
"systems",
"face",
"the",
"challenge",
"of",
"discriminating",
"between",
"foreign",
"antigens,",
"against",
"which",
"a",
"response",
"may",
"have",
"to",
"be",
"mounted,",
"and",
"self-constituents,",
"which",
"should",
"be",
"ignored",
"or",
"tolerated.",
"Although",
"there",
"are",
"multiple",
"theoret-",
"ical",
"solutions",
"to",
"the",
"challenge",
"of",
"self/nonself",
"discrimination,",
"Burnet",
"and",
"Fenner",
"(1)",
"proposed",
"as",
"a",
"corollary",
"to",
"the",
"clonal",
"selection",
"theory",
"that",
"the",
"problem",
"can",
"be",
"solved",
"on",
"the",
"basis",
"of",
"time",
"considerations;",
"any",
"antigen",
"to",
"which",
"the",
"im-",
"mune",
"system",
"is",
"exposed",
"in",
"the",
"fetal",
"or",
"early",
"neonatal",
"stages",
"is",
"flagged",
"as",
"self",
"and",
"induces",
"long-",
"term",
"tolerance.",
"Lederberg",
"(2)",
"extended",
"this",
"no-",
"tion",
"by",
"postulating",
"that",
"immature",
"lymphocytes",
"have",
"a",
"heightened",
"sensitivity",
"to",
"tolerance",
"in-",
"duction.",
"This",
"“newborn",
"privilege”",
"was",
"tested",
"by",
"introducing",
"foreign",
"molecules",
"as",
"surrogates",
"for",
"self,",
"and,",
"indeed,",
"it",
"did",
"prove",
"possible",
"to",
"in-",
"duce",
"tolerance",
"by",
"administration",
"of",
"allogeneic",
"cells,",
"viruses,",
"or",
"proteins",
"to",
"neonates",
"but",
"not",
"in",
"adults",
"(3–6).",
"However,",
"neonatal",
"exposure",
"was",
"not",
"always",
"tolerogenic,",
"and",
"the",
"outcome",
"was",
"clearly",
"dose",
"dependent",
"(7,",
"8).",
"Although",
"related",
"obser-",
"vations",
"already",
"existed",
"in",
"the",
"literature,",
"the",
"strongest",
"challenge",
"to",
"the",
"notion",
"of",
"neonatal",
"tolerance",
"induction",
"came",
"from",
"a",
"trio",
"of",
"studies",
"published",
"in",
"1996",
"(9–11),",
"which",
"showed",
"that",
"neonatal",
"lymphocytes",
"could",
"mount",
"full",
"im-",
"mune",
"responses",
"under",
"the",
"appropriate",
"conditions.",
"Ridge",
"et",
"al.",
"(9)",
"pointed",
"out",
"that",
"the",
"differential",
"effects",
"of",
"fetal",
"versus",
"adult",
"exposure",
"to",
"alloge-",
"neic",
"cells",
"highlighted",
"by",
"the",
"Medawar",
"group,",
"long",
"a",
"linchpin",
"of",
"neonatal",
"tolerance,",
"may",
"have",
"been",
"due",
"simply",
"to",
"the",
"large",
"disparities",
"in",
"doses",
"(relative",
"to",
"body",
"size)",
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"2009",
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"et",
"al.",
"This",
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"distributed",
"under",
"the",
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"an",
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"Alike–No",
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"for",
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"Creative",
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] | [
"Veerkamp",
"et",
"al.",
"BMC",
"Proceedings",
"2010,",
"4(Suppl",
"1):S9",
"http://www.biomedcentral.com/1753-6561/4/S1/S9",
"P",
"R",
"O",
"C",
"E",
"E",
"D",
"I",
"N",
"G",
"S",
"Open",
"Access",
"Simultaneous",
"QTL",
"detection",
"and",
"genomic",
"breeding",
"value",
"estimation",
"using",
"high",
"density",
"SNP",
"chips",
"Roel",
"F",
"Veerkamp1*,",
"Klara",
"L",
"Verbyla1,2,",
"Han",
"A",
"Mulder1,",
"Mario",
"P",
"L",
"Calus1",
"From",
"13th",
"European",
"workshop",
"on",
"QTL",
"mapping",
"and",
"marker",
"assisted",
"selection",
"Wageningen,",
"The",
"Netherlands.",
"20-21",
"April",
"2009",
"Abstract",
"Background:",
"The",
"simulated",
"dataset",
"of",
"the",
"13th",
"QTL-MAS",
"workshop",
"was",
"analysed",
"to",
"i)",
"detect",
"QTL",
"and",
"ii)",
"predict",
"breeding",
"values",
"for",
"animals",
"without",
"phenotypic",
"information.",
"Several",
"parameterisations",
"considering",
"all",
"SNP",
"simultaneously",
"were",
"applied",
"using",
"Gibbs",
"sampling.",
"Results:",
"Fourteen",
"QTL",
"were",
"detected",
"at",
"the",
"different",
"time",
"points.",
"Correlations",
"between",
"estimated",
"breeding",
"values",
"were",
"high",
"between",
"models,",
"except",
"when",
"the",
"model",
"was",
"used",
"that",
"assumed",
"that",
"all",
"SNP",
"effects",
"came",
"from",
"one",
"distribution.",
"The",
"model",
"that",
"used",
"the",
"selected",
"14",
"SNP",
"found",
"associated",
"with",
"QTL,",
"gave",
"close",
"to",
"unity",
"correlations",
"with",
"the",
"full",
"parameterisations.",
"Conclusions:",
"Nine",
"out",
"of",
"18",
"QTL",
"were",
"detected,",
"however",
"the",
"six",
"QTL",
"for",
"inflection",
"point",
"were",
"missed.",
"Models",
"for",
"genomic",
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"were",
"indicated",
"to",
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"e.g.",
"with",
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"accuracy",
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"estimated",
"breeding",
"values.",
"Still,",
"it",
"is",
"worthwhile",
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"the",
"number",
"QTL",
"underlying",
"the",
"quantitative",
"traits,",
"before",
"choosing",
"the",
"model",
"used",
"for",
"genomic",
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"Background",
"High",
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"SNP",
"chips",
"with",
"~50,000",
"SNPs",
"have",
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"available",
"for",
"most",
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"Breeding",
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"estimation",
"using",
"all",
"these",
"SNPs",
"simultaneously",
"is",
"expected",
"to",
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"the",
"highest",
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"[1].",
"Several",
"para-",
"meterisations",
"of",
"the",
"SNP",
"effects",
"in",
"the",
"statistical",
"model",
"have",
"been",
"suggested",
"[2-5].",
"The",
"objectives",
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"were",
"to",
"accurately",
"identify",
"QTL",
"and",
"predict",
"breeding",
"values",
"in",
"the",
"simulated",
"data",
"of",
"the",
"13th",
"QTL-MAS",
"workshop,",
"using",
"different",
"parameterisations",
"for",
"the",
"SNP",
"effects.",
"Methods",
"The",
"simulated",
"data",
"of",
"the",
"13th",
"QTL-MAS",
"workshop",
"is",
"described",
"Coster",
"et",
"al.",
"[6].",
"Simulated",
"data",
"were",
"analysed",
"per",
"time",
"point,",
"and",
"for",
"QTL",
"detection,",
"the",
"change",
"between",
"traits",
"at",
"subsequent",
"time",
"points",
"was",
"also",
"used.",
"*",
"Correspondence:",
"Roel.Veerkamp@wur.nl",
"1Animal",
"Breeding",
"and",
"Genomics",
"Centre,",
"ASG",
"Wageningen",
"UR,",
"PO",
"Box",
"65,",
"8200",
"AB",
"Lelystad,",
"The",
"Netherlands",
"A",
"pedigree",
"based",
"model",
"was",
"fitted",
"using",
"ASREML",
"[7].",
"The",
"Gibbs",
"sampler",
"described",
"initially",
"by",
"Meuwissen",
"and",
"Goddard",
"[1]",
"and",
"Calus",
"et",
"al.",
"[4,5]",
"was",
"used",
"for",
"models",
"including",
"the",
"SNP",
"parameterisations.",
"The",
"general",
"model",
"used",
"was:",
"nloc",
"2",
"yi",
"",
"",
"",
"animali",
"",
"",
"",
"haplotypeijk",
"",
"ei",
",",
"where",
"yi",
"is",
"j1",
"k1",
"the",
"phenotypic",
"record",
"of",
"animal",
"i,",
"µ",
"is",
"the",
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"phe-",
"notypic",
"performance,",
"animali",
"is",
"the",
"random",
"polygenic",
"effect",
"for",
"animal",
"i,",
"haplotypeijk",
"is",
"a",
"random",
"effect",
"for",
"a",
"paternal",
"(k",
"=",
"1)",
"or",
"maternal",
"(k",
"=",
"2)",
"haplotype",
"at",
"locus",
"j",
"(of",
"nloc",
"loci)",
"of",
"animal",
"i,",
"and",
"ei",
"is",
"a",
"random",
"residual",
"for",
"animal",
"i.",
"The",
"first",
"parameterisation",
"was",
"a",
"simple",
"BLUP",
"model",
"with",
"the",
"additive",
"relationship",
"matrix",
"between",
"the",
"animals",
"only.",
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"parameterisations",
"assumed",
"the",
"SNP",
"effects",
"came",
"from",
"one",
"distribution",
"(SNP1),",
"i.e.",
"BayesA,",
"from",
"two",
"distributions",
"(SNP2",
"i.e.",
"BayesC),",
"or",
"from",
"three",
"distributions",
"allowing",
"for",
"small,",
"medium",
"and",
"large",
"SNP",
"effects",
"(SNP3).",
"A",
"further",
"parameterisation",
"assumed",
"a",
"©",
"2010",
"Veerkamp",
"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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] | [
"Fluch",
"et",
"al.",
"BMC",
"Research",
"Notes",
"2011,",
"4:401",
"http://www.biomedcentral.com/1756-0500/4/401",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Characterization",
"of",
"variable",
"EST",
"SSR",
"markers",
"for",
"Norway",
"spruce",
"(Picea",
"abies",
"L.)",
"Silvia",
"Fluch1*,",
"Agnes",
"Burg1,",
"Dieter",
"Kopecky1,",
"Andreas",
"Homolka1,",
"Nadine",
"Spiess1",
"and",
"Giovanni",
"G",
"Vendramin2",
"Abstract",
"Background:",
"Norway",
"spruce",
"is",
"widely",
"distributed",
"across",
"Europe",
"and",
"the",
"predominant",
"tree",
"of",
"the",
"Alpine",
"region.",
"Fast",
"growth",
"and",
"the",
"fact",
"that",
"timber",
"can",
"be",
"harvested",
"cost-effectively",
"in",
"relatively",
"young",
"populations",
"define",
"its",
"status",
"as",
"one",
"of",
"the",
"economically",
"most",
"important",
"tree",
"species",
"of",
"Northern",
"Europe.",
"In",
"this",
"study,",
"EST",
"derived",
"simple",
"sequence",
"repeat",
"(SSR)",
"markers",
"were",
"developed",
"for",
"the",
"assessment",
"of",
"putative",
"functional",
"diversity",
"in",
"Austrian",
"Norway",
"spruce",
"stands.",
"Results:",
"SSR",
"sequences",
"were",
"identified",
"by",
"analyzing",
"14,022",
"publicly",
"available",
"EST",
"sequences.",
"Tri-nucleotide",
"repeat",
"motifs",
"were",
"most",
"abundant",
"in",
"the",
"data",
"set",
"followed",
"by",
"penta-",
"and",
"hexa-nucleotide",
"repeats.",
"Specific",
"primer",
"pairs",
"were",
"designed",
"for",
"sixty",
"loci.",
"Among",
"these,",
"27",
"displayed",
"polymorphism",
"in",
"a",
"testing",
"population",
"of",
"16",
"P.",
"abies",
"individuals",
"sampled",
"across",
"Austria",
"and",
"in",
"an",
"additional",
"screening",
"population",
"of",
"96",
"P.",
"abies",
"individuals",
"from",
"two",
"geographically",
"distinct",
"Austrian",
"populations.",
"Allele",
"numbers",
"per",
"locus",
"ranged",
"from",
"two",
"to",
"17",
"with",
"observed",
"heterozygosity",
"ranging",
"from",
"0.075",
"to",
"0.99.",
"Conclusions:",
"We",
"have",
"characterized",
"variable",
"EST",
"SSR",
"markers",
"for",
"Norway",
"spruce",
"detected",
"in",
"expressed",
"genes.",
"Due",
"to",
"their",
"moderate",
"to",
"high",
"degree",
"of",
"variability",
"in",
"the",
"two",
"tested",
"screening",
"populations,",
"these",
"newly",
"developed",
"SSR",
"markers",
"are",
"well",
"suited",
"for",
"the",
"analysis",
"of",
"stress",
"related",
"functional",
"variation",
"present",
"in",
"Norway",
"spruce",
"populations.",
"Background",
"Natural",
"populations",
"of",
"Picea",
"abies",
"L.",
"(Norway",
"spruce)",
"are",
"found",
"from",
"north-western",
"Europe",
"outside",
"perma-",
"frost",
"areas",
"down",
"to",
"northern",
"Greece,",
"westwards",
"to",
"the",
"Massif",
"Central",
"(France)",
"and",
"east",
"to",
"the",
"Ural",
"Mountains.",
"Picea",
"abies",
"is",
"growing",
"above",
"400-500",
"m",
"and",
"ascends",
"close",
"to",
"2000",
"m",
"in",
"the",
"Alps.",
"Studies",
"on",
"genetic",
"variation",
"based",
"on",
"allozymes",
"have",
"shown",
"that",
"Picea",
"abies",
"genetic",
"differentiation",
"among",
"populations",
"is",
"rather",
"low",
"over",
"its",
"whole",
"distribution",
"range",
"[1,2].",
"Previous",
"studies",
"on",
"the",
"genetic",
"structure",
"of",
"P.",
"abies",
"using",
"organelle",
"markers",
"showed",
"pronounced",
"differentiation",
"between",
"north-east",
"boreal",
"origins",
"and",
"areas",
"in",
"the",
"central",
"European",
"moun-",
"tains",
"[3,4],",
"supporting",
"the",
"hypothesis",
"of",
"two",
"distinct",
"main",
"glacial",
"refugia",
"as",
"postulated",
"from",
"pollen",
"data",
"[5].",
"Initial",
"reports",
"on",
"the",
"occurrence",
"of",
"SSRs",
"in",
"conifers",
"such",
"as",
"Pinus",
"radiata",
"[6],",
"Pinus",
"sylvestris",
"[7]",
"or",
"Picea",
"*",
"Correspondence:",
"silvia.fluch@ait.ac.at",
"1AIT",
"Austrian",
"Institute",
"of",
"Technology",
"GmbH,",
"Health",
"&",
"Environment",
"Department,",
"Bioresources,",
"3430",
"Tulln,",
"Austria",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"abies",
"[8]",
"have",
"shown",
"that",
"marker",
"development",
"for",
"such",
"complex",
"genomes",
"is",
"difficult.",
"Frequently",
"several",
"DNA",
"fragments",
"in",
"addition",
"to",
"the",
"expected",
"ones",
"are",
"amplified",
"when",
"using",
"primers",
"flanking",
"putative",
"SSR",
"regions.",
"This",
"can",
"be",
"attributed",
"to",
"the",
"very",
"large",
"size",
"of",
"the",
"conifer",
"genomes,",
"with",
"Norway",
"spruce",
"having",
"39.140",
"Mb",
"in",
"the",
"diploid",
"genome",
"(2n",
"=",
"24)",
"as",
"well",
"as",
"the",
"high",
"proportion",
"of",
"repetitive",
"DNA",
"in",
"the",
"conifer",
"genomes",
"[9].",
"These",
"repetitive",
"elements",
"as",
"well",
"as",
"pseudogenes",
"frequently",
"produce",
"complex",
"amplification",
"products",
"from",
"multiple",
"loci",
"[10,11].",
"To",
"overcome",
"this",
"problem,",
"Scotti",
"et",
"al.",
"[12]",
"showed",
"that",
"by",
"isolating",
"di-nucleotide",
"SSRs",
"from",
"cDNA",
"libraries",
"of",
"conifer",
"species",
"this",
"problem",
"can",
"be",
"over-",
"come",
"relying",
"on",
"the",
"fact",
"that",
"expressed",
"genes",
"are",
"less",
"likely",
"to",
"be",
"of",
"repetitive",
"nature",
"in",
"the",
"genome.",
"Following",
"this",
"line",
"of",
"exploiting",
"the",
"advantages",
"of",
"publicly",
"available",
"data",
"on",
"expressed",
"sequences",
"(ESTs)",
"as",
"source",
"for",
"marker",
"development",
"[13]",
"as",
"described",
"also",
"by",
"Rungis",
"et",
"al.",
"[14]",
"for",
"conifers,",
"we",
"used",
"Norway",
"spruce",
"EST",
"sequences",
"from",
"NCBI",
"for",
"in",
"silico",
"identification",
"of",
"SSR",
"regions",
"which",
"could",
"serve",
"for",
"marker",
"development.",
"©",
"2011",
"Fluch",
"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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] | [
"J",
"Neurol",
"(2011)",
"258:212–217",
"DOI",
"10.1007/s00415-010-5712-3",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"C",
"O",
"M",
"M",
"U",
"N",
"I",
"C",
"A",
"T",
"I",
"O",
"N",
"Cold",
"paresis",
"in",
"multifocal",
"motor",
"neuropathy",
"Dirk",
"C.",
"G.",
"Straver",
"•",
"Jan-Thies",
"H.",
"van",
"Asseldonk",
"•",
"Nicolette",
"C.",
"Notermans",
"•",
"John",
"H.",
"J.",
"Wokke",
"•",
"Leonard",
"H.",
"van",
"den",
"Berg",
"•",
"Hessel",
"Franssen",
"Received:",
"25",
"May",
"2010",
"/",
"Revised:",
"9",
"August",
"2010",
"/",
"Accepted:",
"11",
"August",
"2010",
"/",
"Published",
"online:",
"28",
"August",
"2010",
"The",
"Author(s)",
"2010.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Increased",
"weakness",
"during",
"cold",
"(cold",
"paresis)",
"was",
"reported",
"in",
"single",
"cases",
"of",
"multifocal",
"motor",
"neuropa-",
"thy",
"(MMN).",
"This",
"was",
"unexpected",
"because",
"demyelination",
"is",
"a",
"feature",
"of",
"MMN",
"and",
"symptoms",
"of",
"demyelination",
"improve,",
"rather",
"than",
"worsen,",
"in",
"cold.",
"It",
"was",
"hypothesized",
"that",
"cold",
"paresis",
"in",
"MMN",
"does",
"not",
"reflect",
"demyelination",
"only,",
"but",
"may",
"indicate",
"the",
"existence",
"of",
"inflammatory",
"nerve",
"lesions",
"with",
"permanently",
"depolarized",
"axons",
"that",
"only",
"just",
"conduct",
"at",
"normal",
"temperature,",
"but",
"fail",
"at",
"lower",
"tempera-",
"tures.",
"We",
"investigated",
"symptoms",
"of",
"cold",
"paresis",
"in",
"50",
"MMN",
"patients,",
"48",
"chronic",
"inflammatory",
"demyelinating",
"polyneuropathy",
"(CIDP)",
"patients,",
"35",
"progressive",
"spinal",
"muscular",
"atrophy",
"(PSMA)",
"patients,",
"and",
"25",
"chronic",
"idio-",
"pathic",
"axonal",
"polyneuropathy",
"patients.",
"We",
"also",
"investi-",
"gated",
"symptoms",
"of",
"increased",
"weakness",
"during",
"warmth",
"(heat",
"paresis).",
"Cold",
"paresis",
"was",
"reported",
"more",
"often",
"than",
"heat",
"paresis.",
"Cold",
"paresis",
"was",
"most",
"frequently",
"reported",
"in",
"MMN.",
"Multivariate",
"analysis",
"indicated",
"that",
"MMN",
"patients",
"had",
"a",
"4-",
"to",
"6-fold",
"higher",
"risk",
"of",
"reporting",
"cold",
"paresis",
"than",
"CIDP",
"or",
"PSMA",
"patients.",
"Because",
"cold",
"paresis",
"is",
"not",
"consistent",
"with",
"demyelination,",
"the",
"lesions",
"in",
"MMN",
"may",
"involve",
"other",
"mechanisms",
"than",
"demyelination",
"only.",
"In",
"conclusion,",
"symptoms",
"of",
"cold",
"paresis",
"are",
"common",
"in",
"D.",
"C.",
"G.",
"Straver",
"J.-T.",
"H.",
"van",
"Asseldonk",
"N.",
"C.",
"Notermans",
"J.",
"H.",
"J.",
"Wokke",
"L.",
"H.",
"van",
"den",
"Berg",
"H.",
"Franssen",
"Neuromuscular",
"Disease",
"Group,",
"Department",
"of",
"Neurology,",
"Rudolf",
"Magnus",
"Institute",
"of",
"Neuroscience,",
"University",
"Medical",
"Center",
"Utrecht,",
"Heidelberglaan",
"100,",
"3584",
"CX",
"Utrecht,",
"The",
"Netherlands",
"H.",
"Franssen",
"(&)",
"Department",
"of",
"Neurology,",
"F02.230,",
"University",
"Medical",
"Center",
"Utrecht,",
"PO",
"Box",
"85500,",
"3508",
"GA",
"Utrecht,",
"The",
"Netherlands",
"e-mail:",
"H.Franssen@umcutrecht.nl",
"123",
"peripheral",
"nervous",
"system",
"disorders,",
"particularly",
"in",
"MMN.",
"This",
"supports",
"the",
"above-described",
"hypothesis.",
"Keywords",
"Multifocal",
"motor",
"neuropathy",
"Chronic",
"inflammatory",
"demyelinating",
"polyneuropathy",
"Chronic",
"idiopathic",
"axonal",
"polyneuropathy",
"Progressive",
"spinal",
"muscular",
"atrophy",
"Cold",
"paresis",
"Abbreviations",
"CB",
"Conduction",
"block",
"CIAP",
"Chronic",
"idiopathic",
"axonal",
"polyneuropathy",
"CIDP",
"Chronic",
"inflammatory",
"demyelinating",
"polyneuropathy",
"MMN",
"Multifocal",
"motor",
"neuropathy",
"PSMA",
"Progressive",
"spinal",
"muscular",
"atrophy",
"Introduction",
"The",
"effect",
"of",
"temperature",
"on",
"symptoms",
"of",
"neurological",
"disorders",
"is",
"complicated",
"and",
"has",
"not",
"been",
"fully",
"explored,",
"neither",
"in",
"patients,",
"nor",
"in",
"physiological",
"research.",
"A",
"well-",
"known",
"effect",
"is",
"the",
"worsening",
"of",
"symptoms",
"in",
"multiple",
"sclerosis",
"after",
"a",
"hot",
"bath",
"[20,",
"25].",
"In",
"peripheral",
"neuropa-",
"thies,",
"similar",
"effects",
"were",
"described.",
"In",
"a",
"patient",
"with",
"chronic",
"inflammatory",
"demyelinating",
"polyneuropathy",
"(CIDP),",
"symptoms",
"considerably",
"increased",
"during",
"fever",
"and",
"in",
"seven",
"patients",
"with",
"various",
"demyelinating",
"neuropathies,",
"electrophysiological",
"signs",
"of",
"conduction",
"block",
"increased",
"after",
"warming",
"and",
"decreased",
"after",
"cooling",
"[4,",
"8,",
"20].",
"This",
"so-called",
"heat",
"paresis",
"may",
"occur",
"in",
"demyelinating",
"disor-",
"ders",
"and",
"is",
"caused",
"by",
"an",
"unfavorable",
"combination",
"of",
"fac-",
"tors",
"that",
"block",
"saltatory",
"conduction",
"between",
"an",
"active",
"node"
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] | [
"Cancer",
"Cell",
"International",
"ICNATNERCNERATCIOELNLAL",
"Primary",
"research",
"Lack",
"of",
"p53",
"function",
"promotes",
"radiation-induced",
"mitotic",
"catastrophe",
"in",
"mouse",
"embryonic",
"fibroblast",
"cells",
"Fiorenza",
"Ianzini*1,",
"Alessandro",
"Bertoldo2,",
"Elizabeth",
"A",
"Kosmacek2,",
"Stacia",
"L",
"Phillips1",
"and",
"Michael",
"A",
"Mackey3",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Departments",
"of",
"Pathology,",
"Radiation",
"Oncology,",
"and",
"Biomedical",
"Engineering,",
"University",
"of",
"Iowa,",
"Iowa",
"City,",
"IA",
"52242,",
"USA,",
"2Department",
"of",
"Biomedical",
"Engineering,",
"University",
"of",
"Iowa,",
"Iowa",
"City,",
"IA",
"52242,",
"USA",
"and",
"3Departments",
"of",
"Biomedical",
"Engineering",
"and",
"Pathology,",
"University",
"of",
"Iowa,",
"Iowa",
"City,",
"IA",
"52242,",
"USA",
"Email:",
"Fiorenza",
"Ianzini*",
"-",
"fiorenza-ianzini@uiowa.edu;",
"Alessandro",
"Bertoldo",
"-",
"alessandro_bertoldo@yahoo.com;",
"Elizabeth",
"A",
"Kosmacek",
"-",
"ekosmace@engineering.uiowa.edu;",
"Stacia",
"L",
"Phillips",
"-",
"stacia-phillips@uiowa.edu;",
"Michael",
"A",
"Mackey",
"-",
"michael-",
"mackey@uiowa.edu",
"*",
"Corresponding",
"author",
"Published:",
"26",
"April",
"2006",
"Cancer",
"Cell",
"International",
"2006,",
"6:11",
"doi:10.1186/1475-2867-6-11",
"This",
"article",
"is",
"available",
"from:",
"http://www.cancerci.com/content/6/1/11",
"Received:",
"21",
"February",
"2006",
"Accepted:",
"26",
"April",
"2006",
"©",
"2006",
"Ianzini",
"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:",
"We",
"have",
"demonstrated",
"that",
"in",
"some",
"human",
"cancer",
"cells",
"both",
"chronic",
"mild",
"heat",
"and",
"ionizing",
"radiation",
"exposures",
"induce",
"a",
"transient",
"block",
"in",
"S",
"and",
"G2",
"phases",
"of",
"the",
"cell",
"cycle.",
"During",
"this",
"delay,",
"cyclin",
"B1",
"protein",
"accumulates",
"to",
"supranormal",
"levels,",
"cyclin",
"B1-dependent",
"kinase",
"is",
"activated,",
"and",
"abrogation",
"of",
"the",
"G2/M",
"checkpoint",
"control",
"occurs",
"resulting",
"in",
"mitotic",
"catastrophe",
"(MC).",
"Results:",
"Using",
"syngenic",
"mouse",
"embryonic",
"fibroblasts",
"(MEF)",
"with",
"wild-type",
"or",
"mutant",
"p53,",
"we",
"now",
"show",
"that,",
"while",
"both",
"cell",
"lines",
"exhibit",
"delays",
"in",
"S/G2",
"phase",
"post-irradiation,",
"the",
"mutant",
"p53",
"cells",
"show",
"elevated",
"levels",
"of",
"cyclin",
"B1",
"followed",
"by",
"MC,",
"while",
"the",
"wild-type",
"p53",
"cells",
"present",
"both",
"a",
"lower",
"accumulation",
"of",
"cyclin",
"B1",
"and",
"a",
"lower",
"frequency",
"of",
"MC.",
"Conclusion:",
"These",
"results",
"are",
"in",
"line",
"with",
"studies",
"reporting",
"the",
"role",
"of",
"p53",
"as",
"a",
"post-",
"transcriptional",
"regulator",
"of",
"cyclin",
"B1",
"protein",
"and",
"confirm",
"that",
"dysregulation",
"of",
"cyclin",
"B1",
"promote",
"radiation-induced",
"MC.",
"These",
"findings",
"might",
"be",
"exploited",
"to",
"design",
"strategies",
"to",
"augment",
"the",
"yield",
"of",
"MC",
"in",
"tumor",
"cells",
"that",
"are",
"resistant",
"to",
"radiation-induced",
"apoptosis.",
"Introduction",
"Mitotic",
"catastrophe",
"(MC)",
"has",
"been",
"observed",
"following",
"alterations",
"in",
"specific",
"cellular",
"proteins,",
"or",
"by",
"treatment",
"of",
"cells",
"with",
"chemicals,",
"heat,",
"and/or",
"ionizing",
"radiation",
"[1-",
"13].",
"MC",
"is",
"characterized",
"by",
"an",
"aberrant",
"nuclear",
"morphol-",
"ogy",
"observed",
"following",
"premature",
"entry",
"into",
"mitosis",
"[10]",
"and",
"often",
"results",
"in",
"the",
"generation",
"of",
"aneuploid",
"and",
"poly-",
"ploid",
"cell",
"progeny.",
"The",
"initiating",
"event",
"in",
"this",
"process",
"involves",
"the",
"premature",
"entry",
"of",
"cells",
"into",
"mitosis;",
"cells",
"undergo",
"a",
"spontaneous",
"chromosome",
"condensation",
"that",
"produces",
"chromosome",
"morphologies",
"very",
"similar",
"to",
"those",
"observed",
"when",
"metaphase",
"cells",
"are",
"fused",
"with",
"cells",
"located",
"late",
"in",
"the",
"cell",
"cycle",
"[11].",
"Thus",
"we",
"consider",
"these",
"abnormal",
"mitotic",
"figures",
"as",
"indicative",
"of",
"cells",
"undergoing",
"spontaneous",
"premature",
"chromosome",
"condensation",
"(SPCC).",
"These",
"cells",
"entering",
"into",
"mitosis",
"prematurely",
"often",
"either",
"fail",
"to",
"achieve",
"cytokinesis",
"or",
"divide",
"and",
"fuse",
"shortly",
"thereafter,",
"and",
"later",
"exhibit",
"the",
"features",
"of",
"MC.",
"These",
"cells",
"almost",
"always",
"die",
"[9];",
"however,",
"some",
"studies",
"have",
"suggested",
"that",
"a",
"small",
"fraction",
"of",
"cells",
"might",
"survive",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"The",
"Role",
"of",
"Actin",
"Turnover",
"in",
"Retrograde",
"Actin",
"Network",
"Flow",
"in",
"Neuronal",
"Growth",
"Cones",
"David",
"Van",
"Goor,",
"Callen",
"Hyland,",
"Andrew",
"W.",
"Schaefer,",
"Paul",
"Forscher*",
"Department",
"of",
"Molecular,",
"Cellular,",
"and",
"Developmental",
"Biology,",
"Yale",
"University,",
"New",
"Haven,",
"Connecticut,",
"United",
"States",
"of",
"America",
"Abstract",
"The",
"balance",
"of",
"actin",
"filament",
"polymerization",
"and",
"depolymerization",
"maintains",
"a",
"steady",
"state",
"network",
"treadmill",
"in",
"neuronal",
"growth",
"cones",
"essential",
"for",
"motility",
"and",
"guidance.",
"Here",
"we",
"have",
"investigated",
"the",
"connection",
"between",
"depolymerization",
"and",
"treadmilling",
"dynamics.",
"We",
"show",
"that",
"polymerization-competent",
"barbed",
"ends",
"are",
"concentrated",
"at",
"the",
"leading",
"edge",
"and",
"depolymerization",
"is",
"distributed",
"throughout",
"the",
"peripheral",
"domain.",
"We",
"found",
"a",
"high-to-low",
"G-actin",
"gradient",
"between",
"peripheral",
"and",
"central",
"domains.",
"Inhibiting",
"turnover",
"with",
"jasplakinolide",
"collapsed",
"this",
"gradient",
"and",
"lowered",
"leading",
"edge",
"barbed",
"end",
"density.",
"Ultrastructural",
"analysis",
"showed",
"dramatic",
"reduction",
"of",
"leading",
"edge",
"actin",
"filament",
"density",
"and",
"filament",
"accumulation",
"in",
"central",
"regions.",
"Live",
"cell",
"imaging",
"revealed",
"that",
"the",
"leading",
"edge",
"retracted",
"even",
"as",
"retrograde",
"actin",
"flow",
"rate",
"decreased",
"exponentially.",
"Inhibition",
"of",
"myosin",
"II",
"activity",
"before",
"jasplakinolide",
"treatment",
"lowered",
"baseline",
"retrograde",
"flow",
"rates",
"and",
"prevented",
"leading",
"edge",
"retraction.",
"Myosin",
"II",
"activity",
"preferentially",
"affected",
"filopodial",
"bundle",
"disassembly",
"distinct",
"from",
"the",
"global",
"effects",
"of",
"jasplakinolide",
"on",
"network",
"turnover.",
"We",
"propose",
"that",
"growth",
"cone",
"retraction",
"following",
"turnover",
"inhibition",
"resulted",
"from",
"the",
"persistence",
"of",
"myosin",
"II",
"contractility",
"even",
"as",
"leading",
"edge",
"assembly",
"rates",
"decreased.",
"The",
"buildup",
"of",
"actin",
"filaments",
"in",
"central",
"regions",
"combined",
"with",
"monomer",
"depletion",
"and",
"reduced",
"polymerization",
"from",
"barbed",
"ends",
"suggests",
"a",
"mechanism",
"for",
"the",
"observed",
"exponential",
"decay",
"in",
"actin",
"retrograde",
"flow.",
"Our",
"results",
"show",
"that",
"growth",
"cone",
"motility",
"is",
"critically",
"dependent",
"on",
"continuous",
"disassembly",
"of",
"the",
"peripheral",
"actin",
"network.",
"Citation:",
"Van",
"Goor",
"D,",
"Hyland",
"C,",
"Schaefer",
"AW,",
"Forscher",
"P",
"(2012)",
"The",
"Role",
"of",
"Actin",
"Turnover",
"in",
"Retrograde",
"Actin",
"Network",
"Flow",
"in",
"Neuronal",
"Growth",
"Cones.",
"PLoS",
"ONE",
"7(2):",
"e30959.",
"doi:10.1371/journal.pone.0030959",
"Editor:",
"Cara",
"Gottardi,",
"Northwestern",
"University",
"Feinberg",
"School",
"of",
"Medicine,",
"United",
"States",
"of",
"America",
"Received",
"October",
"7,",
"2011;",
"Accepted",
"December",
"28,",
"2011;",
"Published",
"February",
"16,",
"2012",
"Copyright:",
"2012",
"Van",
"Goor",
"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",
"National",
"Institutes",
"of",
"Health",
"grants",
"RO1-NS28695",
"and",
"RO1",
"NS51786",
"to",
"P.F.",
"and",
"the",
"Nikon",
"Partners-in-Research",
"Program.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"Paul",
"Forscher",
"was",
"a",
"‘‘Nikon",
"Partner",
"in",
"Research’’",
"during",
"some",
"of",
"the",
"period",
"this",
"research",
"was",
"conducted.",
"This",
"program",
"gave",
"his",
"group",
"access",
"to",
"loaned",
"imaging",
"equipment",
"for",
"the",
"experiments.",
"There",
"was",
"no",
"personal",
"compensation",
"involved",
"nor",
"did",
"the",
"agreement",
"in",
"any",
"way",
"infringe",
"on",
"the",
"freedom",
"to",
"share",
"and",
"publish",
"the",
"authors’",
"scientific",
"results.",
"Moreover,",
"this",
"agreement",
"does",
"not",
"alter",
"the",
"authors’",
"adherence",
"to",
"all",
"the",
"PLoS",
"ONE",
"policies",
"on",
"sharing",
"data",
"and",
"materials.",
"*",
"E-mail:",
"paul.forscher@yale.edu",
"Introduction",
"Growth",
"cone",
"structure",
"and",
"motility",
"emerge",
"from",
"the",
"balance",
"of",
"actin",
"filament",
"polymerization,",
"depolymerization,",
"transport,",
"and",
"cross-linking",
"into",
"various",
"network",
"architectures.",
"Motile",
"actin",
"structures",
"continuously",
"consume",
"energy",
"and",
"cycle",
"their",
"compo-",
"nents.",
"As",
"structure",
"is",
"continuously",
"turned",
"over,",
"the",
"system",
"can",
"respond",
"rapidly",
"to",
"extracellular",
"guidance",
"cues;",
"small",
"changes",
"affe-",
"cting",
"actin",
"structure",
"may",
"lead",
"to",
"rapid",
"changes",
"in",
"growth",
"cone",
"morphology",
"and",
"behavior.",
"In",
"the",
"absence",
"of",
"changes",
"in",
"substrate",
"or",
"soluble",
"guidance",
"cues,",
"actin",
"filament",
"polymerization,",
"depoly-",
"merization,",
"and",
"transport",
"maintain",
"a",
"steady-state",
"balance",
"where",
"there",
"is",
"little",
"change",
"in",
"position",
"and",
"growth",
"cone",
"morphology",
"despite",
"continuous",
"retrograde",
"actin",
"flux.",
"In",
"such",
"a",
"system,",
"perturbations",
"of",
"a",
"single",
"process",
"can",
"reveal",
"information",
"on",
"the",
"interdependency",
"of",
"the",
"other",
"processes",
"in",
"maintaining",
"the",
"steady-",
"state",
"balance.",
"Actin",
"assembly",
"at",
"the",
"leading",
"edge",
"produces",
"filopodia",
"and",
"veil",
"structures",
"which",
"are",
"transported",
"centripetally",
"by",
"a",
"process",
"called",
"retrograde",
"flow.",
"Both",
"leading",
"edge",
"polymerization",
"and",
"myosin",
"II",
"contractility",
"contribute",
"to",
"retrograde",
"actin",
"movement.",
"Addition",
"of",
"actin",
"subunits",
"between",
"the",
"polymerized",
"actin",
"array",
"and",
"the",
"leading",
"edge",
"membrane",
"pushes",
"the",
"entire",
"network",
"centripetally",
"[1].",
"According",
"to",
"the",
"dynamic",
"network",
"contraction",
"model",
"[2],",
"myosin",
"II",
"localized",
"in",
"the",
"transition",
"zone",
"(Fig.",
"1",
"and",
"Fig.",
"S1D–F)",
"generates",
"contractile",
"force,",
"which",
"propagates",
"through",
"the",
"me-",
"chanical",
"continuum",
"of",
"the",
"actin",
"array",
"and",
"displaces",
"the",
"entire",
"network.",
"Retrograde",
"flow",
"rate",
"is",
"affected",
"by",
"myosin",
"II",
"activity.",
"Flow",
"rates",
"decrease",
"up",
"to",
"50%",
"in",
"growth",
"cones",
"exposed",
"to",
"the",
"myosin",
"II",
"ATPase",
"inhibitor",
"blebbistatin",
"and",
"residual",
"retrograde",
"flow",
"can",
"largely",
"be",
"accounted",
"for",
"by",
"the",
"force",
"of",
"leading",
"edge",
"polymerization",
"[3].",
"Filopodia",
"and",
"veil",
"actin",
"are",
"continuously",
"assembled",
"and",
"tran-",
"sported",
"rearward",
"by",
"retrograde",
"flow.",
"The",
"half-life",
"of",
"growth",
"cone",
"veil",
"actin",
"has",
"been",
"estimated",
"to",
"be",
"1–3",
"min",
"whereas",
"filopodial",
"actin",
"bundles",
"are",
"considerably",
"more",
"stable",
"[4]",
"and",
"their",
"recycling",
"requires",
"non-muscle",
"myosin",
"II",
"[3].",
"To",
"maintain",
"the",
"growth",
"cone",
"periphery",
"in",
"a",
"steady",
"state",
"both",
"of",
"these",
"actin",
"structures",
"must",
"be",
"continuously",
"recycled.",
"Despite",
"the",
"potential",
"mechanistic",
"impor-",
"tance",
"of",
"filament",
"recycling",
"in",
"regulation",
"of",
"growth",
"cone",
"motility,",
"very",
"little",
"is",
"known",
"about",
"the",
"kinetics",
"or",
"spatial",
"characteristics",
"of",
"this",
"processes.",
"In",
"the",
"current",
"study",
"we",
"use",
"jasplakinolide,",
"a",
"cyclic",
"depsipeptide",
"from",
"the",
"marine",
"sponge",
"Jaspis",
"johnstoni,",
"to",
"inhibit",
"network",
"turnover",
"and",
"investigate",
"acute",
"effects",
"on",
"actin",
"filament",
"structure",
"and",
"dynamic",
"behavior.",
"Jasplakinolide",
"cooperatively",
"binds",
"and",
"stabi-",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"February",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"2",
"|",
"e30959"
] | [
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] | [
"Nakanishi-Minami",
"et",
"al.",
"Diabetology",
"&",
"Metabolic",
"Syndrome",
"2012,",
"4:6",
"http://www.dmsjournal.com/content/4/1/6",
"S",
"H",
"O",
"R",
"T",
"R",
"E",
"P",
"O",
"R",
"T",
"DIABETOLOGY",
"&",
"METABOLIC",
"SYNDROME",
"Open",
"Access",
"Metabolic",
"syndrome",
"correlates",
"intracoronary",
"stenosis",
"detected",
"by",
"multislice",
"computed",
"tomography",
"in",
"male",
"subjects",
"with",
"sleep-",
"disordered",
"breathing",
"Tomoko",
"Nakanishi-Minami1,",
"Ken",
"Kishida1,2,6*,",
"Yasuhiko",
"Nakagawa1,",
"Munetaka",
"Nishio3,",
"Chisa",
"Nakagawa4,",
"Yoshiharu",
"Nishida3,",
"Koji",
"Yanagi3,",
"Ryoko",
"Yoshida5,",
"Tohru",
"Funahashi1,2",
"and",
"Iichiro",
"Shimomura1",
"Abstract",
"Background:",
"Sleep-disordered",
"breathing",
"(SDB),",
"especially",
"obstructive",
"sleep",
"apnea",
"(OSA),",
"has",
"frequent",
"complications",
"include",
"hypertension,",
"dyslipidemia",
"and",
"insulin",
"resistance",
"based",
"on",
"abdominal",
"obesity",
"or",
"excess",
"visceral",
"fat",
"(called",
"Syndrome",
"Z).",
"OSA",
"is",
"a",
"potential",
"risk",
"factor",
"for",
"cardiovascular",
"diseases.",
"The",
"clinical",
"characteristics",
"of",
"Japanese",
"OSA",
"subjects",
"with",
"OSA",
"remain",
"unclear.",
"The",
"present",
"study",
"investigated",
"prevalence",
"and",
"predictive",
"factors",
"of",
"intracoronary",
"stenosis",
"detected",
"by",
"multislice",
"computed",
"tomography",
"(MSCT)",
"in",
"Japanese",
"male",
"subjects",
"with",
"SDB/OSA.",
"Findings:",
"The",
"study",
"(O-VFStudy)",
"subjects",
"were",
"39",
"Japanese",
"men",
"with",
"SDB/OSA",
"who",
"underwent",
"all-night",
"cardiorespiratory",
"monitoring",
"with",
"fully",
"attended",
"polysomnography,",
"and",
"moreover",
"both",
"fat",
"computed",
"tomography",
"(CT)",
"scan",
"and",
"64-row",
"MSCT",
"coronary",
"angiography.",
"The",
"prevalence",
"of",
"coronary",
"stenosis",
"in",
"this",
"selected",
"population",
"with",
"SDB/OSA",
"was",
"15%.",
"Logistic",
"regression",
"analysis",
"showed",
"a",
"significant",
"relationship",
"between",
"age-adjusted",
"CAD",
"and",
"metabolic",
"syndrome",
"(p",
"<",
"0.05),",
"but",
"not",
"serum",
"adiponectin",
"levels",
"and",
"nocturnal",
"fall",
"in",
"adiponectin.",
"Subjects",
"with",
"the",
"metabolic",
"syndrome",
"had",
"significantly",
"higher",
"prevalence",
"of",
"CAD",
"(31.3",
"versus",
"4.3%,",
"p",
"=",
"0.033),",
"and",
"lower",
"levels",
"of",
"serum",
"adiponectin",
"(4.5",
"±",
"0.6",
"versus",
"6.4",
"±",
"0.6",
"μg/mL,",
"p",
"=",
"0.014),",
"compared",
"with",
"groups",
"without",
"the",
"metabolic",
"syndrome.",
"Conclusions:",
"The",
"present",
"study",
"describes",
"that",
"the",
"prevalence",
"of",
"greater",
"than",
"50%",
"intracoronary",
"stenotic",
"lesions",
"detected",
"by",
"MSCT",
"was",
"15%",
"and",
"the",
"metabolic",
"syndrome",
"was",
"correlated",
"with",
"intracoronary",
"stenosis",
"detected",
"by",
"MSCT",
"in",
"Japanese",
"SDB/OSA",
"subjects.",
"Trial",
"Registration:",
"UMIN",
"000002997",
"https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?",
"function=brows&action=brows&type=summary&recptno=R000003633&language=E.",
"Keywords:",
"Coronary",
"Stenosis,",
"Sleep",
"apnea-hypopnea,",
"Visceral",
"fat,",
"Adiponectin",
"Background",
"Sleep-disordered",
"breathing",
"(SDB),",
"especially",
"obstructive",
"sleep",
"apnea",
"(OSA),",
"is",
"a",
"potential",
"risk",
"factor",
"for",
"cardio-",
"vascular",
"diseases,",
"including",
"coronary",
"artery",
"disease",
"(CAD)",
"and",
"stroke",
"[1-3].",
"OSA",
"is",
"common",
"in",
"middle-age",
"men",
"[4],",
"and",
"frequent",
"complications",
"include",
"*",
"Correspondence:",
"kkishida@imed2.med.osaka-u.ac.jp",
"1Department",
"of",
"Metabolic",
"Medicine,",
"Graduate",
"School",
"of",
"Medicine,",
"Osaka",
"University,",
"Suita,",
"Osaka",
"565-0871,",
"Japan",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"hypertension,",
"dyslipidemia",
"and",
"insulin",
"resistance",
"based",
"on",
"abdominal",
"obesity",
"or",
"excess",
"visceral",
"fat",
"[5-8].",
"Visc-",
"eral",
"fat",
"is",
"a",
"huge",
"endocrine",
"organ",
"producing",
"a",
"variety",
"of",
"bioactive",
"substances,",
"conceptualized",
"as",
"‘adipocytokines’",
"[9].",
"Our",
"group",
"discovered",
"adiponectin",
"as",
"an",
"adipocyto-",
"kine",
"in",
"the",
"human",
"adipose",
"cDNA",
"library",
"[10],",
"which",
"has",
"anti-atherosclerotic",
"property",
"[11].",
"We",
"have",
"recently",
"demonstrated",
"that,",
"1)",
"production",
"of",
"adiponectin",
"is",
"dys-",
"regulated",
"in",
"intra-abdominal",
"obese",
"patients",
"with",
"severe",
"OSA",
"[12,13],",
"and",
"2)",
"night-time",
"onset",
"of",
"acute",
"coronary",
"©",
"2012",
"Nakanishi-Minami",
"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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238,
724,
45,
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286,
724,
72,
14
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[
362,
724,
62,
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428,
724,
82,
14
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[
513,
724,
59,
14
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576,
724,
26,
14
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[
78,
766,
80,
15
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78,
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125,
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14
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135,
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14
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203,
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248,
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12,
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263,
783,
18,
14
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285,
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54,
14
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344,
783,
38,
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385,
783,
18,
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[
78,
800,
40,
14
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[
126,
800,
21,
14
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156,
800,
11,
14
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176,
800,
18,
14
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[
203,
800,
26,
14
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[
237,
800,
46,
14
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[
291,
800,
38,
14
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[
337,
800,
37,
14
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[
383,
800,
21,
14
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[
78,
817,
45,
14
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[
129,
817,
12,
14
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146,
817,
18,
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170,
817,
36,
14
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211,
817,
29,
14
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245,
817,
51,
14
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301,
817,
38,
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344,
817,
59,
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78,
833,
21,
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106,
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130,
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40,
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176,
833,
29,
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211,
833,
51,
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268,
833,
31,
14
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305,
833,
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323,
833,
81,
14
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78,
850,
32,
14
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114,
850,
19,
14
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136,
850,
38,
14
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178,
850,
59,
14
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241,
850,
12,
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256,
850,
38,
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297,
850,
37,
14
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338,
850,
29,
14
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371,
850,
32,
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78,
867,
11,
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94,
867,
62,
14
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159,
867,
53,
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216,
867,
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242,
867,
24,
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269,
867,
11,
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285,
867,
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323,
867,
31,
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867,
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381,
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312,
883,
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358,
883,
46,
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926,
5,
11
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926,
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11
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159,
926,
70,
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231,
926,
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11
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936,
55,
13
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135,
938,
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11
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43,
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38,
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640,
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55,
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699,
767,
49,
14
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423,
783,
81,
14
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510,
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23,
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668,
783,
36,
14
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783,
38,
14
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423,
800,
44,
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473,
800,
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800,
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540,
800,
40,
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587,
800,
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641,
800,
24,
14
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671,
800,
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689,
800,
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719,
800,
29,
14
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423,
817,
41,
14
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470,
817,
61,
14
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537,
817,
9,
14
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553,
817,
18,
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578,
817,
29,
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613,
817,
31,
14
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651,
817,
12,
14
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669,
817,
18,
14
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[
694,
817,
36,
14
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736,
817,
11,
14
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423,
833,
59,
14
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[
491,
833,
65,
14
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566,
833,
40,
14
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615,
833,
26,
14
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651,
833,
37,
14
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697,
833,
23,
14
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730,
833,
18,
14
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423,
850,
61,
14
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488,
850,
11,
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502,
850,
37,
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542,
850,
37,
14
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582,
850,
21,
14
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607,
850,
28,
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638,
850,
60,
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701,
850,
47,
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423,
867,
25,
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453,
867,
68,
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527,
867,
63,
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595,
867,
87,
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688,
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60,
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594,
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630,
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648,
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673,
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423,
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487,
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538,
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] | [
"Shi",
"et",
"al.",
"Radiation",
"Oncology",
"2012,",
"7:114",
"http://www.ro-journal.com/content/7/1/114",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Computed",
"tomography-guided",
"permanent",
"brachytherapy",
"for",
"locoregional",
"recurrent",
"gastric",
"cancer",
"Liangrong",
"Shi1,",
"Changping",
"Wu1*,",
"Jun",
"Wu1,",
"Wenjie",
"Zhou1,",
"Mei",
"Ji1,",
"Hongyu",
"Zhang1,",
"Jiemin",
"Zhao1,",
"Yuanquan",
"Huang2,",
"Honglei",
"Pei3,",
"Zhong",
"Li4,",
"Jingfang",
"Ju5",
"and",
"Jingting",
"Jiang1*",
"Abstract",
"Background:",
"Locoregional",
"recurrence",
"is",
"the",
"typical",
"pattern",
"of",
"recurrence",
"in",
"gastric",
"cancer,",
"and",
"cannot",
"be",
"removed",
"by",
"surgery",
"in",
"most",
"of",
"the",
"patients.",
"We",
"aimed",
"to",
"evaluate",
"the",
"feasibility",
"and",
"efficacy",
"of",
"computed",
"tomography",
"(CT)-guided",
"brachytherapy",
"for",
"patients",
"with",
"locoregional",
"recurrent",
"gastric",
"cancer.",
"Materials",
"and",
"methods:",
"We",
"reviewed",
"the",
"case",
"histories",
"of",
"28",
"patients",
"with",
"locoregional",
"recurrent",
"gastric",
"cancer",
"that",
"were",
"selected",
"for",
"CT-",
"guided",
"brachytherapy",
"by",
"a",
"multidisciplinary",
"team.",
"The",
"clinical",
"data",
"of",
"the",
"patients",
"including",
"patient",
"characteristics,",
"treatment",
"parameters,",
"short-term",
"effects,",
"and",
"survival",
"data",
"were",
"collected",
"and",
"analyzed.",
"Results:",
"15-75",
"125I",
"seeds",
"were",
"implanted",
"into",
"each",
"patient",
"to",
"produce",
"a",
"minimal",
"peripheral",
"dose",
"(MPD)",
"100-",
"160",
"Gy.",
"Median",
"day",
"0",
"dosimetry",
"was",
"significant",
"for",
"the",
"following:",
"V100",
"(the",
"volume",
"treated",
"with",
"the",
"prescription",
"dose)",
"95.8%",
"(90.2-120.5%)",
"and",
"D90",
"(prescription",
"dose",
"received",
"by",
"at",
"least",
"90%",
"of",
"the",
"volume)",
"105.2%",
"(98.0-124.6%)",
"of",
"prescription",
"dose.",
"No",
"serious",
"complications",
"occurred",
"during",
"the",
"study.",
"Two",
"months",
"after",
"brachytherapy,",
"complete",
"response,",
"partial",
"response",
"and",
"progressive",
"disease",
"were",
"observed",
"in",
"50.0%,",
"28.6%",
"and",
"21.4%",
"of",
"patients,",
"respectively.",
"The",
"median",
"survival",
"time",
"was",
"22.0",
"±",
"5.2",
"months,",
"and",
"the",
"1,",
"2,and",
"3-year",
"survival",
"rate",
"was",
"89",
"±",
"6%,",
"52",
"±",
"10%",
"and",
"11",
"±",
"7%,",
"respectively.",
"A",
"univariate",
"analysis",
"showed",
"that",
"the",
"tumor",
"size",
"was",
"a",
"significant",
"predictor",
"of",
"overall",
"survival",
"(P",
"=",
"0.034).",
"Patients",
"with",
"tumors",
"<3",
"cm",
"had",
"relatively",
"higher",
"complete",
"response",
"rate",
"(66.7%),",
"compared",
"to",
"those",
"with",
"tumors",
">3",
"cm",
"(30.8%).",
"The",
"PTV",
"(planning",
"target",
"volume)",
"smaller",
"than",
"45",
"cm3",
"was",
"significantly",
"correlated",
"with",
"achieving",
"complete",
"tumor",
"eradication",
"in",
"the",
"treated",
"region",
"(P",
"=",
"0.020).",
"Conclusions:",
"For",
"selected",
"patients",
"with",
"limited",
"locoregional",
"recurrent",
"gastric",
"cancer,",
"CT-guided",
"brachytherapy",
"using",
"125I",
"seeds",
"implantation",
"can",
"provide",
"a",
"high",
"local",
"control",
"rate,",
"with",
"minimal",
"trauma.",
"Keywords:",
"Gastric",
"cancer,",
"Surgery,",
"Locoregional",
"recurrence,",
"Brachytherapy,",
"Iodine-125",
"seed",
"Introduction",
"Despite",
"a",
"remarkable",
"decline",
"of",
"the",
"incidence",
"during",
"the",
"second",
"half",
"of",
"the",
"20th",
"century,",
"gastric",
"cancer",
"still",
"remains",
"as",
"the",
"fourth",
"most",
"common",
"cancer",
"worldwide",
"and",
"the",
"second",
"most",
"common",
"cause",
"of",
"cancer-related",
"death",
"[1].",
"Nearly",
"two-thirds",
"of",
"gastric",
"cancer",
"cases",
"occur",
"in",
"developing",
"countries",
"and",
"42%",
"in",
"China",
"alone",
"[2].",
"The",
"prognosis",
"of",
"locally",
"advanced",
"gastric",
"cancer",
"remains",
"*",
"Correspondence:",
"wcpjjt@163.com;",
"jjtnew@163.com",
"1Department",
"of",
"Oncology,",
"The",
"Third",
"Affiliated",
"Hospital,",
"Soochow",
"University,",
"185",
"Juqian",
"Street,",
"Changzhou",
"213003,",
"Jiangsu",
"Province,",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"dismal",
"even",
"after",
"potentially",
"curative",
"resection,",
"adjuvant",
"chemotherapy",
"and",
"radiotherapy",
"[3].",
"The",
"5-year",
"overall",
"survival",
"(OS)",
"rates",
"remain",
"between",
"30%",
"to",
"40%",
"[3,4].",
"Tumor",
"recurrence",
"is",
"the",
"main",
"cause",
"of",
"the",
"failure",
"of",
"treatment.",
"Prospective",
"studies",
"have",
"shown",
"that",
"the",
"recurrence",
"of",
"gastric",
"cancer",
"was",
"most",
"commonly",
"involved",
"with",
"locoregional",
"recurrence,",
"heamatogenous",
"metastasis,",
"and",
"peritoneal",
"lesions",
"[5-7].",
"Most",
"of",
"the",
"patients",
"with",
"recurrent",
"gastric",
"cancer",
"present",
"advanced",
"progression,",
"such",
"as",
"multiple",
"heamatogenous",
"metastasis,",
"extensive",
"lymphatic.",
"In",
"such",
"cases,",
"systemic",
"chemotherapy",
"is",
"the",
"only",
"potential",
"treatment",
"available",
"to",
"patients.",
"However,",
"for",
"©",
"2012",
"Shi",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
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] | [
"The",
"Nitric",
"Oxide",
"Pathway",
"Provides",
"Innate",
"Antiviral",
"Protection",
"in",
"Conjunction",
"with",
"the",
"Type",
"I",
"Interferon",
"Pathway",
"in",
"Fibroblasts",
"Devangi",
"R.",
"Mehta,",
"Ali",
"A.",
"Ashkar,",
"Karen",
"L.",
"Mossman*",
"Department",
"of",
"Pathology",
"and",
"Molecular",
"Medicine,",
"McMaster",
"Immunology",
"Research",
"Centre,",
"Michael",
"DeGroote",
"Institute",
"for",
"Infectious",
"Disease",
"Research,",
"McMaster",
"University,",
"Hamilton,",
"Ontario,",
"Canada",
"Abstract",
"The",
"innate",
"host",
"response",
"to",
"virus",
"infection",
"is",
"largely",
"dominated",
"by",
"the",
"production",
"of",
"type",
"I",
"interferon",
"and",
"interferon",
"stimulated",
"genes.",
"In",
"particular,",
"fibroblasts",
"respond",
"robustly",
"to",
"viral",
"infection",
"and",
"to",
"recognition",
"of",
"viral",
"signatures",
"such",
"as",
"dsRNA",
"with",
"the",
"rapid",
"production",
"of",
"type",
"I",
"interferon;",
"subsequently,",
"fibroblasts",
"are",
"a",
"key",
"cell",
"type",
"in",
"antiviral",
"protection.",
"We",
"recently",
"found,",
"however,",
"that",
"primary",
"fibroblasts",
"deficient",
"for",
"the",
"production",
"of",
"interferon,",
"interferon",
"stimulated",
"genes,",
"and",
"other",
"cytokines",
"and",
"chemokines",
"mount",
"a",
"robust",
"antiviral",
"response",
"against",
"both",
"DNA",
"and",
"RNA",
"viruses",
"following",
"stimulation",
"with",
"dsRNA.",
"Nitric",
"oxide",
"is",
"a",
"chemical",
"compound",
"with",
"pleiotropic",
"functions;",
"its",
"production",
"by",
"phagocytes",
"in",
"response",
"to",
"interferon-c",
"is",
"associated",
"with",
"antimicrobial",
"activity.",
"Here",
"we",
"show",
"that",
"in",
"response",
"to",
"dsRNA,",
"nitric",
"oxide",
"is",
"rapidly",
"produced",
"in",
"primary",
"fibroblasts.",
"In",
"the",
"presence",
"of",
"an",
"intact",
"interferon",
"system,",
"nitric",
"oxide",
"plays",
"a",
"minor",
"but",
"significant",
"role",
"in",
"antiviral",
"protection.",
"However,",
"in",
"the",
"absence",
"of",
"an",
"interferon",
"system,",
"nitric",
"oxide",
"is",
"critical",
"for",
"the",
"protection",
"against",
"DNA",
"viruses.",
"In",
"primary",
"fibroblasts,",
"NF-kB",
"and",
"interferon",
"regulatory",
"factor",
"1",
"participate",
"in",
"the",
"induction",
"of",
"inducible",
"nitric",
"oxide",
"synthase",
"expression,",
"which",
"subsequently",
"produces",
"nitric",
"oxide.",
"As",
"large",
"DNA",
"viruses",
"encode",
"multiple",
"and",
"diverse",
"immune",
"modulators",
"to",
"disable",
"the",
"interferon",
"system,",
"it",
"appears",
"that",
"the",
"nitric",
"oxide",
"pathway",
"serves",
"as",
"a",
"secondary",
"strategy",
"to",
"protect",
"the",
"host",
"against",
"viral",
"infection",
"in",
"key",
"cell",
"types,",
"such",
"as",
"fibroblasts,",
"that",
"largely",
"rely",
"on",
"the",
"type",
"I",
"interferon",
"system",
"for",
"antiviral",
"protection.",
"Citation:",
"Mehta",
"DR,",
"Ashkar",
"AA,",
"Mossman",
"KL",
"(2012)",
"The",
"Nitric",
"Oxide",
"Pathway",
"Provides",
"Innate",
"Antiviral",
"Protection",
"in",
"Conjunction",
"with",
"the",
"Type",
"I",
"Interferon",
"Pathway",
"in",
"Fibroblasts.",
"PLoS",
"ONE",
"7(2):",
"e31688.",
"doi:10.1371/journal.pone.0031688",
"Editor:",
"William",
"P.",
"Halford,",
"Southern",
"Illinois",
"University",
"School",
"of",
"Medicine,",
"United",
"States",
"of",
"America",
"Received",
"January",
"4,",
"2012;",
"Accepted",
"January",
"11,",
"2012;",
"Published",
"February",
"21,",
"2012",
"Copyright:",
"2012",
"Mehta",
"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",
"a",
"Canadian",
"Institutes",
"of",
"Health",
"Research",
"operating",
"grant",
"(MOP",
"57669)",
"to",
"KLM.",
"The",
"funder",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"mossk@mcmaster.ca",
"Introduction",
"A",
"central",
"theme",
"today",
"in",
"medical",
"research",
"is",
"understanding",
"the",
"delicate",
"balance",
"of",
"interactions",
"between",
"a",
"pathogen",
"and",
"its",
"host.",
"These",
"interactions",
"dictate",
"the",
"pathological",
"consequences",
"of",
"infections.",
"It",
"is",
"well",
"recognized",
"that",
"the",
"innate",
"immune",
"response",
"against",
"pathogens",
"focuses",
"on",
"detection",
"of",
"highly",
"conserved",
"pathogen-associated",
"molecular",
"patterns",
"(PAMPs)",
"that",
"are",
"distinct",
"from",
"the",
"host.",
"Host",
"pathogen",
"recognition",
"receptors",
"have",
"evolved",
"to",
"recognize",
"patterns",
"such",
"as",
"nucleic",
"acids",
"from",
"pathogens",
"including",
"bacteria",
"and",
"viruses",
"[1].",
"The",
"first",
"line",
"of",
"defence",
"against",
"invading",
"pathogens",
"is",
"the",
"rapid",
"and",
"robust",
"production",
"of",
"type",
"I",
"interferon",
"(IFN),",
"a",
"family",
"of",
"cytokines",
"with",
"potent",
"immune",
"stimulatory",
"and",
"pathogen-controlling",
"properties.",
"Fibroblasts",
"are",
"amongst",
"the",
"first",
"cell",
"types",
"involved",
"in",
"the",
"line",
"of",
"defence",
"against",
"numerous",
"pathogens.",
"Fibroblasts",
"are",
"widely",
"distributed",
"in",
"organisms",
"[2]",
"and",
"play",
"an",
"important",
"role",
"in",
"the",
"transition",
"from",
"innate",
"to",
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"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"February",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"2",
"|",
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"Department",
"of",
"Microbiology,",
"University",
"of",
"Pennsylvania,",
"Philadelphia,",
"Pennsylvania,",
"United",
"States",
"of",
"America,",
"2",
"Department",
"of",
"Chemistry",
"and",
"Biochemistry,",
"University",
"of",
"the",
"Sciences,",
"Philadelphia,",
"Pennsylvania,",
"United",
"States",
"of",
"America,",
"3",
"Institute",
"for",
"Biological",
"Sciences,",
"National",
"Research",
"Council",
"Canada,",
"Ottawa,",
"Ontario,",
"Canada",
"Abstract",
"The",
"human",
"pathogen",
"Haemophilus",
"influenzae",
"has",
"the",
"ability",
"to",
"quickly",
"adapt",
"to",
"different",
"host",
"environments",
"through",
"phase",
"variation",
"of",
"multiple",
"structures",
"on",
"its",
"lipooligosaccharide",
"(LPS),",
"including",
"phosphorylcholine",
"(ChoP).",
"During",
"colonization",
"with",
"H.",
"influenzae,",
"there",
"is",
"a",
"selection",
"for",
"ChoP+",
"phase",
"variants.",
"In",
"a",
"murine",
"model",
"of",
"nasopharyngeal",
"colonization,",
"this",
"selection",
"is",
"lost",
"in",
"the",
"absence",
"of",
"adaptive",
"immunity.",
"Based",
"on",
"previous",
"data",
"highlighting",
"the",
"importance",
"of",
"natural",
"antibody",
"in",
"limiting",
"H.",
"influenzae",
"colonization,",
"the",
"effect",
"of",
"ChoP",
"expression",
"on",
"antibody",
"binding",
"and",
"its",
"bactericidal",
"activity",
"was",
"investigated.",
"Flow",
"cytometric",
"analysis",
"revealed",
"that",
"ChoP+",
"phase",
"variants",
"had",
"decreased",
"binding",
"of",
"antibody",
"to",
"LPS",
"epitopes",
"compared",
"to",
"ChoP2",
"phase",
"variants.",
"This",
"difference",
"in",
"antibody",
"binding",
"correlated",
"with",
"increased",
"survival",
"of",
"ChoP+",
"phase",
"variants",
"in",
"the",
"presence",
"of",
"antibody-dependent,",
"complement-mediated",
"killing.",
"ChoP+",
"phase",
"variants",
"were",
"also",
"more",
"resistant",
"to",
"trypsin",
"digestion,",
"suggesting",
"a",
"general",
"effect",
"on",
"the",
"physical",
"properties",
"of",
"the",
"outer",
"membrane.",
"Moreover,",
"ChoP-mediated",
"protection",
"against",
"antibody",
"binding",
"correlated",
"with",
"increased",
"resilience",
"of",
"outer",
"membrane",
"integrity.",
"Collectively,",
"these",
"data",
"suggest",
"that",
"ChoP",
"expression",
"provides",
"a",
"selective",
"advantage",
"during",
"colonization",
"through",
"ChoP-mediated",
"effects",
"on",
"the",
"accessibility",
"of",
"bactericidal",
"antibody",
"to",
"the",
"cell",
"surface.",
"Citation:",
"Clark",
"SE,",
"Snow",
"J,",
"Li",
"J,",
"Zola",
"TA,",
"Weiser",
"JN",
"(2012)",
"Phosphorylcholine",
"Allows",
"for",
"Evasion",
"of",
"Bactericidal",
"Antibody",
"by",
"Haemophilus",
"influenzae.",
"PLoS",
"Pathog",
"8(3):",
"e1002521.",
"doi:10.1371/journal.ppat.1002521",
"Editor:",
"Nina",
"Salama,",
"Fred",
"Hutchinson",
"Cancer",
"Research",
"Center,",
"United",
"States",
"of",
"America",
"Received",
"September",
"20,",
"2011;",
"Accepted",
"December",
"20,",
"2011;",
"Published",
"March",
"1,",
"2012",
"Copyright:",
"2012",
"Clark",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"the",
"US",
"Public",
"Health",
"Service",
"(AI44231",
"and",
"AI38446)",
"and",
"by",
"the",
"University",
"of",
"Pennsylvania",
"Cell",
"and",
"Molecular",
"Biology",
"Training",
"Grant",
"(T32",
"GM",
"7229-35).",
"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:",
"weiser@mail.med.upenn.edu",
"Introduction",
"Haemophilus",
"influenzae",
"is",
"an",
"extracellular,",
"gram-negative",
"patho-",
"gen",
"that",
"is",
"a",
"primary",
"causative",
"agent",
"of",
"otitis",
"media",
"in",
"children",
"and",
"is",
"also",
"frequently",
"isolated",
"from",
"adults",
"with",
"pneumonia",
"and",
"exacerbations",
"of",
"chronic",
"obstructive",
"pulmonary",
"disease",
"(COPD)",
"[1–5].",
"Colonization",
"of",
"the",
"upper",
"respiratory",
"tract",
"with",
"H.",
"influenzae",
"is",
"common",
"and",
"is",
"the",
"first",
"step",
"in",
"disease",
"development,",
"as",
"H.",
"influenzae",
"carriage",
"is",
"associated",
"with",
"recurrent",
"otitis",
"media",
"episodes",
"in",
"children",
"[6,7].",
"While",
"the",
"Hib",
"conjugate",
"vaccine",
"has",
"greatly",
"reduced",
"the",
"burden",
"of",
"disease",
"caused",
"by",
"type",
"b",
"H.",
"influenzae",
"[8,9],",
"non-typeable",
"H.",
"influenzae",
"(NTHi)",
"strains,",
"which",
"are",
"unencapsu-",
"lated,",
"remain",
"a",
"common",
"source",
"of",
"respiratory",
"tract",
"infections.",
"Vaccine",
"strategies",
"targeting",
"NTHi",
"strains",
"are",
"complicated",
"by",
"the",
"high",
"variability",
"of",
"outer",
"membrane",
"antigens",
"[10,11].",
"One",
"of",
"the",
"structurally",
"diverse",
"molecules",
"on",
"the",
"surface",
"of",
"H.",
"influenzae",
"is",
"the",
"lipopolysaccharide",
"(LPS).",
"The",
"LPS",
"of",
"H.",
"influenzae",
"is",
"truncated",
"compared",
"to",
"the",
"LPS",
"of",
"other",
"gram-negative",
"bacteria.",
"It",
"contains",
"no",
"repetitive",
"O",
"antigen",
"side",
"chains",
"and",
"is",
"also",
"referred",
"to",
"as",
"lipooligosaccharide",
"(LOS)",
"[12,13].",
"H.",
"influenzae",
"LPS",
"consists",
"of",
"lipid",
"A",
"attached",
"to",
"3-deoxy-",
"D-manno-oct-2-ulosonic",
"acid",
"(KDO),",
"with",
"three",
"conserved",
"inner",
"core",
"heptoses",
"to",
"which",
"various",
"oligosaccharide",
"extensions,",
"and",
"other",
"non-carbohydrate",
"molecules,",
"can",
"be",
"attached",
"[14].",
"Mass",
"spectrometry",
"(MS)",
"analysis",
"of",
"different",
"H.",
"influenzae",
"isolates",
"has",
"revealed",
"a",
"significant",
"level",
"of",
"diversity",
"in",
"LPS",
"structures",
"[15–21].",
"For",
"example,",
"the",
"length",
"and",
"composition",
"of",
"the",
"hexose",
"extensions",
"from",
"the",
"inner",
"core",
"heptoses,",
"as",
"well",
"as",
"the",
"attachment",
"of",
"molecules",
"such",
"as",
"sialic",
"acid",
"and",
"glycine,",
"varies",
"both",
"between",
"different",
"strains",
"and",
"within",
"glycoforms",
"of",
"the",
"same",
"isolate.",
"A",
"major",
"source",
"of",
"LPS",
"variability",
"in",
"H.",
"influenzae",
"is",
"on-off",
"switching,",
"or",
"phase",
"variation,",
"involving",
"LPS",
"biosynthesis",
"genes",
"[22,23].",
"One",
"of",
"the",
"phase",
"variable",
"molecules",
"expressed",
"on",
"H.",
"influenzae",
"LPS",
"is",
"phosphorylcholine.",
"Phosphorylcholine",
"[(CH3)3N",
"+",
"CH2CH2PO42],",
"or",
"ChoP,",
"is",
"a",
"small,",
"zwitterionic",
"molecule",
"that",
"is",
"covalently",
"attached",
"to",
"the",
"LPS",
"through",
"its",
"phosphate",
"group.",
"ChoP",
"is",
"a",
"surface",
"structure",
"of",
"a",
"number",
"of",
"bacteria",
"in",
"addition",
"to",
"H.",
"influenzae,",
"particularly",
"those",
"found",
"in",
"the",
"respiratory",
"tract,",
"including",
"Streptococcus",
"pneumoniae,",
"Pseudomonas",
"aeruginosa,",
"and",
"Neisseria",
"species",
"[24–26].",
"ChoP",
"is",
"also",
"a",
"component",
"of",
"eukaryotic",
"membrane",
"lipids",
"in",
"the",
"form",
"of",
"phosphatidylcholine.",
"H.",
"influenzae",
"must",
"acquire",
"choline",
"from",
"the",
"environment,",
"and",
"turnover",
"of",
"host",
"lipids",
"can",
"be",
"a",
"major",
"source",
"of",
"choline",
"during",
"colonization",
"[27,28].",
"Choline",
"import,",
"phosphor-",
"ylation,",
"and",
"attachment",
"to",
"H.",
"influenzae",
"LPS",
"is",
"controlled",
"by",
"genes",
"in",
"the",
"lic1",
"locus.",
"The",
"choline",
"kinase",
"gene",
"lic1A",
"contains",
"a",
"tetranucleotide",
"repeat",
"that",
"is",
"responsible",
"for",
"ChoP",
"phase",
"variation.",
"Slipped-strand",
"mispairing",
"within",
"the",
"repeat",
"region",
"of",
"lic1A",
"creates",
"a",
"translational",
"on-off",
"switch",
"controlling",
"ChoP",
"expression",
"[29].",
"As",
"a",
"result,",
"the",
"control",
"of",
"ChoP",
"attachment",
"to",
"the",
"LPS",
"is",
"stochastic,",
"and",
"phase",
"variation",
"occurs",
"at",
"a",
"high",
"frequency",
"[30].",
"Phase",
"variation",
"of",
"ChoP",
"expression",
"may",
"provide",
"a",
"mechanism",
"for",
"Haemophilus",
"to",
"display",
"a",
"variety",
"of",
"phenotypes,",
"allowing",
"rapid",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"1",
"March",
"2012",
"|",
"Volume",
"8",
"|",
"Issue",
"3",
"|",
"e1002521"
] | [
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] | [
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"3,5-Dimethoxy-N,N-bis(2-pyridyl-",
"methyl)aniline",
"Hongjuan",
"Li,*",
"Xianping",
"Dai",
"and",
"Jufeng",
"Sun",
"School",
"of",
"Pharmacy,",
"Binzhou",
"Medical",
"College,",
"Yantai",
"264003,",
"People’s",
"Republic",
"of",
"China",
"Correspondence",
"e-mail:",
"hjli80@163.com",
"Received",
"12",
"November",
"2009;",
"accepted",
"16",
"November",
"2009",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"113",
"K;",
"mean",
"(C–C)",
"=",
"0.002",
"A˚;",
"R",
"factor",
"=",
"0.041;",
"wR",
"factor",
"=",
"0.113;",
"data-to-parameter",
"ratio",
"=",
"18.0.",
"In",
"the",
"title",
"molecule,",
"C20H21N3O2,",
"the",
"benzene",
"ring",
"forms",
"dihedral",
"angles",
"of",
"80.8",
"(1)",
"and",
"83.5",
"(1)",
"with",
"the",
"two",
"terminal",
"pyridine",
"rings.",
"In",
"the",
"crystal",
"structure,",
"weak",
"intermolecular",
"C—H",
"O",
"hydrogen",
"bonds",
"link",
"the",
"molecules",
"into",
"chains",
"propagating",
"in",
"[001].",
"Related",
"literature",
"For",
"general",
"background",
"to",
"organic",
"ligand-based",
"crystal",
"materials,",
"see:",
"Desiraju",
"(2007);",
"Moulton",
"&",
"Zaworotko",
"(2001).",
"For",
"related",
"structures,",
"see:",
"Frisch",
"&",
"Cahil",
"(2008);",
"Shattock",
"et",
"al.",
"(2008);",
"Shirman",
"et",
"al.",
"(2008).",
"Experimental",
"Crystal",
"data",
"C20H21N3O2",
"Mr",
"=",
"335.40",
"Monoclinic,",
"P21=c",
"a",
"=",
"15.630",
"(3)",
"A˚",
"b",
"=",
"5.9562",
"(12)",
"A˚",
"c",
"=",
"20.088",
"(4)",
"A˚",
"=",
"111.55",
"(3)",
"V",
"=",
"1739.3",
"(6)",
"A˚",
"3",
"Z",
"=",
"4",
"Data",
"collection",
"Rigaku",
"Saturn",
"CCD",
"area-detector",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(CrystalClear;",
"Rigaku/MSC,",
"2005)",
"Tmin",
"=",
"0.978,",
"Tmax",
"=",
"0.983",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.041",
"wR(F",
"2)",
"=",
"0.113",
"S",
"=",
"1.10",
"4106",
"reflections",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"organic",
"compounds",
"Mo",
"K",
"radiation",
"=",
"0.08",
"mm",
"1",
"T",
"=",
"113",
"K",
"0.27",
"0.25",
"0.20",
"mm",
"14749",
"measured",
"reflections",
"4106",
"independent",
"reflections",
"3258",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.038",
"228",
"parameters",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.22",
"e",
"A˚",
"3",
"min",
"=",
"0.21",
"e",
"A˚",
"3",
"D—H",
"A",
"C14—H14",
"O2i",
"D—H",
"0.95",
"H",
"2.49",
"A",
"D",
"A",
"3.3050",
"(15)",
"D—H",
"A",
"144",
"Symmetry",
"code:",
"(i)",
"x;",
"y",
"þ",
"32;",
"z",
"12.",
"Data",
"collection:",
"CrystalClear",
"(Rigaku/MSC,",
"2005);",
"cell",
"refinement:",
"CrystalClear;",
"data",
"reduction:",
"CrystalClear;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"ORTEPIII",
"(Burnett",
"&",
"Johnson,",
"1996);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"SHELXL97",
"and",
"PLATON",
"(Spek,",
"2009).",
"The",
"authors",
"are",
"grateful",
"to",
"the",
"Binzhou",
"Medical",
"College",
"for",
"financial",
"support",
"(grant",
"No.",
"BY2007KJ13).",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"CV2657).",
"References",
"Burnett,",
"M.",
"N.",
"&",
"Johnson,",
"C.",
"K.",
"(1996).",
"ORTEPIII.",
"Report",
"ORNL-6895.",
"Oak",
"Ridge",
"National",
"Laboratory,",
"Tennessee,",
"USA.",
"Desiraju,",
"G.",
"R.",
"(2007).",
"Angew.",
"Chem.",
"Int.",
"Ed.",
"45,",
"8342–8356.",
"Frisch,",
"M.",
"&",
"Cahil,",
"C.",
"L.",
"(2008).",
"Cryst.",
"Growth.",
"Des.",
"8,",
"2921–2928.",
"Moulton,",
"B.",
"&",
"Zaworotko,",
"M.",
"J.",
"(2001).",
"Chem.",
"Rev.",
"101,",
"1629–1658.",
"Rigaku/MSC",
"(2005).",
"CrystalClear.",
"Rigaku/MSC,",
"The",
"Woodlands,",
"Texas,",
"USA.",
"Shattock,",
"T.",
"R.,",
"Arora,",
"K.",
"K.,",
"Vishweshwar,",
"P.",
"&",
"Zaworotko,",
"M.",
"J.",
"(2008).",
"Cryst.",
"Growth.",
"Des.",
"8,",
"4533–4545.",
"Sheldrick,",
"G.",
"M.",
"(2008).",
"Acta",
"Cryst.",
"A64,",
"112–122.",
"Shirman,",
"T.,",
"Lamere,",
"J.-F.,",
"Shimon,",
"L.",
"J.",
"W.,",
"Gupta,",
"T.,",
"Martin,",
"J.",
"M.",
"L.",
"&",
"van",
"der",
"Boom,",
"M.",
"E.",
"(2008).",
"Cryst.",
"Growth.",
"Des.",
"8,",
"3066–3072.",
"Spek,",
"A.",
"L.",
"(2009).",
"Acta",
"Cryst.",
"D65,",
"148–155.",
"Acta",
"Cryst.",
"(2009).",
"E65,",
"o3139",
"doi:10.1107/S1600536809048685",
"Li",
"et",
"al.",
"o3139"
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] | [
"BMC",
"Family",
"Practice",
"Research",
"article",
"The",
"knowledge",
"and",
"expectations",
"of",
"parents",
"about",
"the",
"role",
"of",
"antibiotic",
"treatment",
"in",
"upper",
"respiratory",
"tract",
"infection",
"–",
"a",
"survey",
"among",
"parents",
"attending",
"the",
"primary",
"physician",
"with",
"their",
"sick",
"child",
"Shlomo",
"Vinker*,",
"Adi",
"Ron",
"and",
"Eliezer",
"Kitai",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Department",
"of",
"Family",
"Medicine,",
"Tel",
"Aviv",
"Sackler",
"school",
"of",
"Medicine,",
"Tel",
"Aviv,",
"Israel",
"Email:",
"Shlomo",
"Vinker*",
"-",
"vinker01@inter.net.il;",
"Adi",
"Ron",
"-",
"yoninadi@netvision.net.il;",
"Eliezer",
"Kitai",
"-",
"drkitai@netvision.net.il",
"*",
"Corresponding",
"author",
"Published:",
"30",
"December",
"2003",
"BMC",
"Family",
"Practice",
"2003,",
"4:20",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2296/4/20",
"Received:",
"25",
"June",
"2003",
"Accepted:",
"30",
"December",
"2003",
"©",
"2003",
"Shlomo",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article:",
"verbatim",
"copying",
"and",
"redistribution",
"of",
"this",
"article",
"are",
"permitted",
"in",
"all",
"media",
"for",
"any",
"purpose,",
"provided",
"this",
"notice",
"is",
"preserved",
"along",
"with",
"the",
"article's",
"original",
"URL.",
"Upper",
"respiratory",
"tract",
"infectionantibioticschildrenparentsknowledgeattitude",
"Abstract",
"Background:",
"Upper",
"respiratory",
"tract",
"infections",
"(URTI)",
"are",
"common.",
"The",
"etiologic",
"factor",
"is",
"usually",
"viral,",
"but",
"many",
"physicians",
"prescribe",
"antibiotics.",
"We",
"aimed",
"to",
"evaluate",
"parents'",
"expectations",
"of",
"and",
"knowledge",
"about",
"the",
"role",
"of",
"antibiotics",
"in",
"childhood",
"URTI.",
"Methods:",
"The",
"study",
"was",
"conducted",
"in",
"thirteen",
"primary",
"care",
"pediatric",
"clinics.",
"Parents",
"of",
"children",
"aged",
"3",
"months",
"to",
"6",
"years",
"who",
"attended",
"with",
"URTI",
"symptoms",
"were",
"included",
"when",
"it",
"was",
"the",
"first",
"attendance",
"in",
"the",
"current",
"illness.",
"Questionnaire",
"about",
"the",
"current",
"illness,",
"reasons",
"for",
"attending",
"and",
"expectations",
"from",
"the",
"visit,",
"knowledge",
"about",
"URTI",
"was",
"filled",
"before",
"the",
"visit.",
"Results:",
"In",
"122",
"visits",
"the",
"average",
"age",
"was",
"2.8",
"±",
"1.9",
"years.",
"The",
"main",
"reasons",
"for",
"the",
"visit",
"were",
"to",
"avoid",
"complications",
"(81%)",
"and",
"to",
"be",
"examined",
"(78%).",
"Expected",
"treatment",
"was:",
"cough",
"suppressants",
"(64%),",
"anti-congestants",
"(57%),",
"paracetamol",
"(56%),",
"natural",
"remedies",
"(53%)",
"and",
"antibiotics",
"(25%).",
"In",
"28%",
"the",
"child",
"had",
"received",
"antibiotics",
"in",
"past",
"URTI.",
"Only",
"37%",
"thought",
"that",
"antibiotics",
"would",
"not",
"help",
"in",
"URTI",
"and",
"27%",
"knew",
"that",
"URTI",
"is",
"a",
"self-limited",
"disease.",
"61%",
"knew",
"that",
"URTI",
"is",
"a",
"viral",
"disease.",
"Younger",
"parental",
"age",
"and",
"higher",
"education",
"were",
"associated",
"with",
"lower",
"expectations",
"to",
"receive",
"antibiotics",
"(p",
"=",
"0.01,",
"p",
"<",
"0.005",
"respectively).",
"While",
"previous",
"antibiotic",
"treatment",
"(p",
"<",
"0.001),",
"past",
"perceived",
"complications",
"(p",
"=",
"0.05)",
"and",
"the",
"thought",
"that",
"antibiotics",
"help",
"in",
"URTI",
"(p",
"<",
"0.001)",
"were",
"associated",
"with",
"a",
"greater",
"expectation",
"for",
"antibiotics.",
"Conclusions:",
"A",
"quarter",
"of",
"the",
"parents",
"attending",
"the",
"physician",
"with",
"URTI",
"are",
"expecting",
"to",
"get",
"antibiotics.",
"Predictors",
"were",
"lower",
"education,",
"older",
"parental",
"age,",
"receiving",
"antibiotics",
"in",
"the",
"past",
"and",
"the",
"belief",
"that",
"antibiotics",
"help",
"in",
"URTI.",
"Background",
"Patients",
"with",
"Upper",
"Respiratory",
"Tract",
"Infection",
"(URTI)",
"constitute",
"a",
"major",
"part",
"of",
"the",
"primary",
"care",
"physician's",
"workload",
"during",
"the",
"winter",
"months",
"[1].",
"In",
"most",
"cases",
"the",
"etiologic",
"factor",
"is",
"viral",
"and",
"there",
"is",
"no",
"need",
"for",
"antibiotic",
"treatment",
"[2,3].",
"Many",
"physicians",
"continue",
"to",
"prescribe",
"antibiotic",
"treatment",
"for",
"URTI,",
"knowing",
"that",
"antibiotics",
"do",
"not",
"help",
"viral",
"infection",
"and",
"despite",
"the",
"development",
"of",
"resistant",
"bacterial",
"strains.",
"Page",
"1",
"of",
"6",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Galdeano",
"et",
"al.",
"BMC",
"Gastroenterology",
"2011,",
"11:64",
"http://www.biomedcentral.com/1471-230X/11/64",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Impact",
"of",
"a",
"probiotic",
"fermented",
"milk",
"in",
"the",
"gut",
"ecosystem",
"and",
"in",
"the",
"systemic",
"immunity",
"using",
"a",
"non-severe",
"protein-energy-malnutrition",
"model",
"in",
"mice",
"Carolina",
"Maldonado",
"Galdeano1,2,",
"Ivanna",
"Novotny",
"Núñez1,",
"Alejandra",
"de",
"Moreno",
"de",
"LeBlanc1,",
"Esteban",
"Carmuega3,",
"Ricardo",
"Weill4",
"and",
"Gabriela",
"Perdigón1,2*",
"Abstract",
"Background:",
"Malnutrition",
"affects",
"the",
"immune",
"response,",
"causing",
"a",
"decrease",
"of",
"defence",
"mechanisms",
"and",
"making",
"the",
"host",
"more",
"susceptible",
"to",
"infections.",
"Probiotics",
"can",
"reconstitute",
"the",
"intestinal",
"mucosa",
"and",
"stimulate",
"local",
"and",
"systemic",
"immunity.",
"The",
"aim",
"of",
"this",
"work",
"was",
"evaluate",
"the",
"effects",
"of",
"a",
"probiotic",
"fermented",
"milk",
"as",
"a",
"complement",
"of",
"a",
"re-nutrition",
"diet,",
"on",
"the",
"recovery",
"of",
"the",
"intestinal",
"barrier,",
"and",
"mucosal",
"and",
"systemic",
"immune",
"functions",
"in",
"a",
"murine",
"model",
"of",
"non-severe",
"protein-energy-malnutrition.",
"Its",
"potential",
"protection",
"against",
"Salmonella",
"enterica",
"serovar",
"Typhimurium",
"(S.",
"Typhimurium)",
"infection",
"was",
"also",
"analyzed.",
"Methods:",
"Mice",
"were",
"undernourished",
"and",
"divided",
"into",
"3",
"groups",
"according",
"to",
"the",
"dietary",
"supplement",
"received",
"during",
"re-nutrition",
"(milk,",
"probiotic",
"fermented",
"milk",
"or",
"its",
"bacterial",
"free",
"supernatant)",
"and",
"compared",
"to",
"well-",
"nourished",
"and",
"malnourished",
"mice.",
"They",
"were",
"sacrificed",
"previous",
"to",
"the",
"re-nutrition",
"and",
"5",
"days",
"post",
"re-nutrition.",
"The",
"phagocytic",
"activity",
"of",
"macrophages",
"from",
"spleen",
"and",
"peritoneum",
"and",
"the",
"changes",
"in",
"the",
"intestinal",
"histology",
"and",
"microbiota",
"were",
"evaluated.",
"Different",
"immune",
"cell",
"populations",
"and",
"cytokine",
"productions",
"were",
"analyzed",
"in",
"the",
"small",
"intestine",
"tissues.",
"The",
"effect",
"of",
"the",
"re-nutrition",
"supplements",
"on",
"the",
"systemic",
"immunity",
"using",
"OVA",
"antigen",
"and",
"against",
"an",
"infection",
"with",
"S.",
"Typhimurium",
"was",
"also",
"studied.",
"Results:",
"Probiotic",
"fermented",
"milk",
"was",
"the",
"most",
"effective",
"re-nutrition",
"diet",
"that",
"improved",
"the",
"intestinal",
"microbiota.",
"Its",
"administration",
"also",
"increased",
"the",
"number",
"of",
"IgA+",
"cells,",
"macrophages",
"and",
"dendritic",
"cells.",
"The",
"production",
"of",
"different",
"cytokine",
"(IFN-g,",
"TNF-a,",
"IL-12)",
"by",
"these",
"cells",
"and",
"the",
"phagocytic",
"activity",
"in",
"peritoneum",
"and",
"spleen",
"was",
"also",
"increased.",
"This",
"re-nutrition",
"diet",
"also",
"stimulated",
"the",
"systemic",
"immune",
"response",
"against",
"OVA",
"antigen",
"which",
"was",
"diminished",
"after",
"the",
"malnutrition",
"period",
"and",
"also",
"improved",
"the",
"host",
"response",
"against",
"S.",
"Typhimurium,",
"decreasing",
"the",
"spread",
"of",
"pathogenic",
"bacteria",
"to",
"the",
"liver",
"and",
"the",
"spleen.",
"The",
"importance",
"of",
"the",
"metabolites",
"released",
"during",
"milk",
"fermentation",
"was",
"also",
"demonstrated",
"through",
"the",
"analysis",
"of",
"the",
"bacterial",
"free",
"supernatant",
"obtained",
"from",
"the",
"probiotic",
"fermented",
"milk,",
"but",
"the",
"whole",
"product",
"showed",
"the",
"best",
"effects",
"in",
"the",
"parameters",
"evaluated",
"in",
"this",
"study.",
"Conclusions:",
"The",
"administration",
"of",
"probiotic",
"fermented",
"milk",
"as",
"a",
"dietary",
"supplement",
"during",
"the",
"re-nutrition",
"process",
"in",
"a",
"murine",
"immunodeficiency",
"model",
"by",
"malnutrition",
"could",
"be",
"a",
"good",
"adjuvant",
"diet",
"to",
"improve",
"the",
"gut",
"and",
"systemic",
"immune",
"response",
"for",
"the",
"protection",
"against",
"Salmonella",
"infection.",
"*",
"Correspondence:",
"perdigon@cerela.org.ar",
"1Centro",
"de",
"Referencia",
"para",
"Lactobacilos",
"(CERELA-CONICET).",
"Chacabuco",
"145,",
"San",
"Miguel",
"de",
"Tucumán",
"(T4000ILC)",
"Tucumán.",
"Argentina",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2011",
"Galdeano",
"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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] | [
"Fallani",
"et",
"al.",
"Nonlinear",
"Biomedical",
"Physics",
"2010,",
"4(Suppl",
"1):S8",
"http://www.nonlinearbiomedphys.com/content/4/S1/S8",
"P",
"R",
"O",
"C",
"E",
"E",
"D",
"I",
"N",
"G",
"S",
"Open",
"Access",
"A",
"graph-theoretical",
"approach",
"in",
"brain",
"functional",
"networks.",
"Possible",
"implications",
"in",
"EEG",
"studies",
"Fabrizio",
"De",
"Vico",
"Fallani1,2,",
"Luciano",
"da",
"Fontoura",
"Costa5,",
"Francisco",
"Aparecido",
"Rodriguez5,",
"Laura",
"Astolfi1,3,",
"Giovanni",
"Vecchiato1,2,",
"Jlenia",
"Toppi1,3,",
"Gianluca",
"Borghini1,",
"Febo",
"Cincotti1,",
"Donatella",
"Mattia1,",
"Serenella",
"Salinari3,",
"Roberto",
"Isabella4,",
"Fabio",
"Babiloni1,2*",
"From",
"Consciousness",
"and",
"its",
"Measures:",
"Joint",
"Workshop",
"for",
"COST",
"Actions",
"NeuroMath",
"and",
"Consciousness",
"Limassol,",
"Cyprus.",
"29",
"November",
"–",
"1",
"December",
"2009",
"Abstract",
"Background:",
"Recently,",
"it",
"was",
"realized",
"that",
"the",
"functional",
"connectivity",
"networks",
"estimated",
"from",
"actual",
"brain-",
"imaging",
"technologies",
"(MEG,",
"fMRI",
"and",
"EEG)",
"can",
"be",
"analyzed",
"by",
"means",
"of",
"the",
"graph",
"theory,",
"that",
"is",
"a",
"mathematical",
"representation",
"of",
"a",
"network,",
"which",
"is",
"essentially",
"reduced",
"to",
"nodes",
"and",
"connections",
"between",
"them.",
"Methods:",
"We",
"used",
"high-resolution",
"EEG",
"technology",
"to",
"enhance",
"the",
"poor",
"spatial",
"information",
"of",
"the",
"EEG",
"activity",
"on",
"the",
"scalp",
"and",
"it",
"gives",
"a",
"measure",
"of",
"the",
"electrical",
"activity",
"on",
"the",
"cortical",
"surface.",
"Afterwards,",
"we",
"used",
"the",
"Directed",
"Transfer",
"Function",
"(DTF)",
"that",
"is",
"a",
"multivariate",
"spectral",
"measure",
"for",
"the",
"estimation",
"of",
"the",
"directional",
"influences",
"between",
"any",
"given",
"pair",
"of",
"channels",
"in",
"a",
"multivariate",
"dataset.",
"Finally,",
"a",
"graph",
"theoretical",
"approach",
"was",
"used",
"to",
"model",
"the",
"brain",
"networks",
"as",
"graphs.",
"These",
"methods",
"were",
"used",
"to",
"analyze",
"the",
"structure",
"of",
"cortical",
"connectivity",
"during",
"the",
"attempt",
"to",
"move",
"a",
"paralyzed",
"limb",
"in",
"a",
"group",
"(N=5)",
"of",
"spinal",
"cord",
"injured",
"patients",
"and",
"during",
"the",
"movement",
"execution",
"in",
"a",
"group",
"(N=5)",
"of",
"healthy",
"subjects.",
"Results:",
"Analysis",
"performed",
"on",
"the",
"cortical",
"networks",
"estimated",
"from",
"the",
"group",
"of",
"normal",
"and",
"SCI",
"patients",
"revealed",
"that",
"both",
"groups",
"present",
"few",
"nodes",
"with",
"a",
"high",
"out-degree",
"value",
"(i.e.",
"outgoing",
"links).",
"This",
"property",
"is",
"valid",
"in",
"the",
"networks",
"estimated",
"for",
"all",
"the",
"frequency",
"bands",
"investigated.",
"In",
"particular,",
"cingulate",
"motor",
"areas",
"(CMAs)",
"ROIs",
"act",
"as",
"‘‘hubs’’",
"for",
"the",
"outflow",
"of",
"information",
"in",
"both",
"groups,",
"SCI",
"and",
"healthy.",
"Results",
"also",
"suggest",
"that",
"spinal",
"cord",
"injuries",
"affect",
"the",
"functional",
"architecture",
"of",
"the",
"cortical",
"network",
"sub-serving",
"the",
"volition",
"of",
"motor",
"acts",
"mainly",
"in",
"its",
"local",
"feature",
"property.",
"In",
"particular,",
"a",
"higher",
"local",
"efficiency",
"El",
"can",
"be",
"observed",
"in",
"the",
"SCI",
"patients",
"for",
"three",
"frequency",
"bands,",
"theta",
"(3-6",
"Hz),",
"alpha",
"(7-12",
"Hz)",
"and",
"beta",
"(13-29",
"Hz).",
"By",
"taking",
"into",
"account",
"all",
"the",
"possible",
"pathways",
"between",
"different",
"ROI",
"couples,",
"we",
"were",
"able",
"to",
"separate",
"clearly",
"the",
"network",
"properties",
"of",
"the",
"SCI",
"group",
"from",
"the",
"CTRL",
"group.",
"In",
"particular,",
"we",
"report",
"a",
"sort",
"of",
"compensatory",
"mechanism",
"in",
"the",
"SCI",
"patients",
"for",
"the",
"Theta",
"(3-6",
"Hz)",
"frequency",
"band,",
"indicating",
"a",
"higher",
"level",
"of",
"“activation”",
"Ω",
"within",
"the",
"cortical",
"network",
"during",
"the",
"motor",
"task.",
"The",
"activation",
"index",
"is",
"directly",
"related",
"to",
"diffusion,",
"a",
"type",
"of",
"dynamics",
"that",
"underlies",
"several",
"biological",
"systems",
"including",
"possible",
"spreading",
"of",
"neuronal",
"activation",
"across",
"sev-",
"eral",
"cortical",
"regions.",
"Conclusions:",
"The",
"present",
"study",
"aims",
"at",
"demonstrating",
"the",
"possible",
"applications",
"of",
"graph",
"theoretical",
"approaches",
"in",
"the",
"analyses",
"of",
"brain",
"functional",
"connectivity",
"from",
"EEG",
"signals.",
"In",
"particular,",
"the",
"methodological",
"aspects",
"of",
"the",
"i)",
"cortical",
"activity",
"from",
"scalp",
"EEG",
"signals,",
"ii)",
"functional",
"connectivity",
"estimations",
"iii)",
"graph",
"theoretical",
"indexes",
"are",
"emphasized",
"in",
"the",
"present",
"paper",
"to",
"show",
"their",
"impact",
"in",
"a",
"real",
"application.",
"*",
"Correspondence:",
"fabio.babiloni@uniroma1.it",
"1IRCCS",
"“Fondazione",
"Santa",
"Lucia”,",
"Rome,",
"Italy",
"©",
"2010",
"Babiloni",
"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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] | [
"REVIEW",
"ARTICLE",
"published:",
"09",
"March",
"2012",
"doi:",
"10.3389/fphar.2012.00035",
"Regulation",
"of",
"aldo–keto",
"reductases",
"in",
"human",
"diseases",
"Wei-Dong",
"Chen",
"and",
"Yanqiao",
"Zhang*",
"Department",
"of",
"Integrative",
"Medical",
"Sciences,",
"Northeast",
"Ohio",
"Medical",
"University,",
"Rootstown,",
"OH,",
"USA",
"Edited",
"by:",
"Yi",
"Jin,",
"University",
"of",
"Pennsylvania,",
"USA",
"Reviewed",
"by:",
"Wen",
"Xie,",
"University",
"of",
"Pittsburgh,",
"USA",
"Kwang-Huei",
"Lin,",
"Chang-Gung",
"University,",
"Taiwan",
"*Correspondence:",
"Yanqiao",
"Zhang,",
"Department",
"of",
"Integrative",
"Medical",
"Sciences,",
"Northeast",
"Ohio",
"Medical",
"University,",
"4209",
"State",
"Route",
"44,",
"Rootstown,",
"OH",
"44272,",
"USA.",
"e-mail:",
"yzhang@neomed.edu",
"The",
"aldo–keto",
"reductases",
"(AKRs)",
"are",
"a",
"superfamily",
"of",
"NAD(P)H-linked",
"oxidoreductases,",
"which",
"reduce",
"aldehydes",
"and",
"ketones",
"to",
"their",
"respective",
"primary",
"and",
"secondary",
"alcohols.",
"AKR",
"enzymes",
"are",
"increasingly",
"being",
"recognized",
"to",
"play",
"an",
"important",
"role",
"in",
"the",
"transfor-",
"mation",
"and",
"detoxification",
"of",
"aldehydes",
"and",
"ketones",
"generated",
"during",
"drug",
"detoxification",
"and",
"xenobiotic",
"metabolism.",
"Many",
"transcription",
"factors",
"have",
"been",
"identified",
"to",
"regulate",
"the",
"expression",
"of",
"human",
"AKR",
"genes,",
"which",
"could",
"have",
"profound",
"effects",
"on",
"the",
"metabolism",
"of",
"endogenous",
"mediators",
"and",
"detoxication",
"of",
"chemical",
"carcinogens.",
"This",
"review",
"summarizes",
"the",
"current",
"knowledge",
"on",
"AKR",
"regulation",
"by",
"transcription",
"factors",
"and",
"other",
"mediators",
"in",
"human",
"diseases.",
"Keywords:",
"aldo–keto",
"reductase,",
"regulation,",
"response",
"element,",
"transcription",
"factor,",
"human",
"disease",
"INTRODUCTION",
"The",
"aldo–keto",
"reductases",
"(AKRs)",
"are",
"a",
"superfamily",
"of",
"NAD(P)H-",
"linked",
"oxidoreductases,",
"which",
"primarily",
"catalyze",
"the",
"reduction",
"of",
"aldehydes",
"and",
"ketones",
"to",
"primary",
"and",
"secondary",
"alcohols,",
"respec-",
"tively",
"(Penning",
"and",
"Drury,",
"2007).",
"AKRs",
"are",
"generally",
"soluble,",
"cytosolic",
"monomeric",
"(37",
"kDa)",
"enzymes",
"and",
"are",
"present",
"in",
"both",
"prokaryotes",
"and",
"eukaryotes.",
"These",
"enzymes",
"share",
"a",
"common",
"pro-",
"tein",
"fold,",
"a",
"(β/α)8",
"or",
"a",
"triosephosphate",
"isomerase",
"(TIM)-barrel,",
"and",
"have",
"an",
"active",
"site",
"in",
"the",
"C-terminal",
"face",
"(Jez",
"et",
"al.,",
"1997a,b;",
"Barski",
"et",
"al.,",
"2008).",
"Most",
"AKRs",
"use",
"pyridine",
"nucleotide",
"as",
"cofac-",
"tors",
"and",
"catalyze",
"simple",
"oxidation–reduction",
"reactions",
"involved",
"in",
"the",
"metabolism",
"of",
"sugar",
"aldehydes,",
"reactive",
"lipid",
"aldehydes,",
"ketoprostaglandins,",
"and",
"ketosteroids.",
"Aldo–keto",
"reductases",
"consist",
"of",
"15",
"families",
"which",
"have",
"more",
"than",
"100",
"members",
"(Barski",
"et",
"al.,",
"2008).",
"There",
"are",
"13",
"human",
"AKR",
"proteins",
"that",
"fall",
"into",
"3",
"families",
"AKR1,",
"AKR6,",
"and",
"AKR7",
"(Table",
"1).",
"The",
"detailed",
"information",
"is",
"available",
"at",
"http://www.med.upenn.edu/akr,",
"an",
"AKR",
"superfamily",
"homepage,",
"maintained",
"by",
"Dr.",
"T.",
"Penning",
"at",
"the",
"University",
"of",
"Pennsylvania.",
"The",
"human",
"AKR",
"enzymes",
"include",
"AKR1A1",
"(aldehyde",
"reductase),",
"AKR1B1",
"and",
"AKR1B10",
"(aldose",
"reductases),",
"AKR1C1–C4",
"(hydrox-",
"ysteroid",
"dehydrogenases),",
"AKR1D1",
"(steroid",
"5β-reductase),",
"the",
"AKR6",
"family",
"(AKR6A3,",
"A5,",
"and",
"A9;",
"Kvβ",
"proteins),",
"and",
"the",
"AKR7",
"family",
"(AKR7A2",
"and",
"AKR7A3;",
"aflatoxin",
"aldehyde",
"reduc-",
"tases).",
"These",
"human",
"AKR",
"enzymes",
"can",
"catalyze",
"many",
"meta-",
"bolic",
"oxidation–reduction",
"reactions",
"of",
"numerous",
"endogenous",
"and",
"exogenous",
"substrates,",
"including",
"glucose,",
"steroids,",
"carcino-",
"gens,",
"reactive",
"aldehydes,",
"and",
"a",
"variety",
"of",
"carbonyl-containing",
"drugs.",
"To",
"date,",
"the",
"AKR",
"enzymes",
"have",
"been",
"implicated",
"in",
"a",
"num-",
"ber",
"of",
"human",
"diseases.",
"It",
"is",
"known",
"that",
"AKR1A1,",
"AKR1B10,",
"and",
"AKR1C1–C3",
"are",
"involved",
"in",
"tobacco-induced",
"carcinogen-",
"esis",
"(Hsu",
"et",
"al.,",
"2001;",
"Penning,",
"2005;",
"Jin",
"and",
"Penning,",
"2007;",
"Zhang",
"et",
"al.,",
"2008;",
"Liu",
"et",
"al.,",
"2009a).",
"Inhibition",
"of",
"AKR1B1",
"is",
"able",
"to",
"alleviate",
"diabetic",
"complications.",
"Through",
"mediating",
"oxida-",
"tive",
"stress-induced",
"inflammatory",
"signals,",
"AKR1B1",
"plays",
"a",
"role",
"in",
"inflammation-related",
"diseases",
"such",
"as",
"sepsis",
"and",
"colon",
"cancer",
"(Ramana,",
"2011).",
"AKR1B1",
"and",
"AKR1B10",
"regulate",
"the",
"develop-",
"ment",
"and",
"progression",
"of",
"human",
"liver,",
"breast,",
"and",
"lung",
"cancers",
"through",
"detoxifying",
"reactive",
"carbonyls,",
"retinoic",
"acid",
"homeostatic",
"regulation,",
"and",
"lipid",
"metabolism",
"(Liu",
"et",
"al.,",
"2009a;",
"Diez-Dacal",
"et",
"al.,",
"2011).",
"AKR1C1–C3",
"enzymes",
"are",
"involved",
"in",
"prostate",
"and",
"breast",
"carcinogenesis",
"(Penning",
"and",
"Byrns,",
"2009).",
"Mutations",
"in",
"AKR1D1",
"gene",
"in",
"patients",
"lead",
"to",
"neonatal",
"cholestasis,",
"hepatitis,",
"and",
"liver",
"failure",
"(Lemonde",
"et",
"al.,",
"2003;",
"Barski",
"et",
"al.,",
"2008).",
"AKR7A",
"proteins",
"protect",
"liver",
"from",
"acetaminophen-induced",
"hepatotoxic-",
"ity",
"by",
"enhancing",
"hepatocellular",
"antioxidant",
"defense",
"(Ahmed",
"et",
"al.,",
"2011).",
"Because",
"AKR",
"enzymes",
"are",
"increasingly",
"being",
"recognized",
"to",
"play",
"a",
"role",
"in",
"various",
"diseases,",
"understanding",
"the",
"regulation",
"of",
"human",
"AKR",
"genes",
"may",
"help",
"us",
"develop",
"novel",
"therapeutic",
"approaches.",
"In",
"this",
"review,",
"we",
"summarize",
"the",
"regulation",
"of",
"AKRs",
"by",
"transcription",
"factors,",
"mediators,",
"and",
"pathological",
"conditions.",
"THE",
"REGULATION",
"OF",
"AKRs",
"Many",
"transcription",
"factors",
"have",
"been",
"identified",
"to",
"regulate",
"the",
"expression",
"of",
"human",
"AKR",
"genes,",
"which",
"could",
"have",
"profound",
"effects",
"on",
"the",
"metabolism",
"of",
"endogenous",
"mediators",
"and",
"detox-",
"ication",
"of",
"chemical",
"carcinogens.",
"Several",
"classes",
"of",
"transcription",
"enhancer",
"elements",
"have",
"been",
"identified",
"in",
"the",
"upstream",
"pro-",
"moter",
"region",
"of",
"AKR",
"genes",
"that",
"include",
"nuclear",
"receptor",
"response",
"elements,",
"AP-1",
"binding",
"sites,",
"the",
"xenobiotic",
"response",
"elements",
"(XRE),",
"osmotic",
"response",
"elements",
"(ORE),",
"estrogen",
"response",
"ele-",
"ments",
"(ERE),",
"and",
"antioxidant",
"response",
"elements",
"(ARE;",
"Ko",
"et",
"al.,",
"1997;",
"Burczynski",
"et",
"al.,",
"1999;",
"Lou",
"et",
"al.,",
"2006;",
"Penning",
"and",
"Drury,",
"2007).",
"AKR1A1",
"AKR1A1,",
"a",
"ubiquitously",
"expressed",
"enzyme,",
"is",
"a",
"well-known",
"cytosolic,",
"NADPH-dependent",
"and",
"monomeric",
"oxidoreductase.",
"AKR1A1",
"participates",
"in",
"carbonyl",
"reductions",
"of",
"chemotherapeutic",
"drugs.",
"Protein",
"and",
"mRNA",
"levels",
"of",
"AKR1A1",
"in",
"irinotecan-resistant",
"LoVo",
"cells",
"are",
"higher",
"than",
"in",
"human",
"colon",
"adenocarcinoma",
"LoVo",
"cells",
"(Peng",
"et",
"al.,",
"2010).",
"Recent",
"studies",
"suggest",
"that",
"overexpression",
"www.frontiersin.org",
"March",
"2012",
"|",
"Volume",
"3",
"|",
"Article",
"35",
"|",
"1"
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] | [
"Vascular",
"Health",
"and",
"Risk",
"Management",
"Open",
"Access",
"Full",
"Text",
"Article",
"Dovepress",
"open",
"access",
"to",
"scientific",
"and",
"medical",
"research",
"O",
"R",
"i",
"g",
"i",
"N",
"A",
"L",
"R",
"E",
"s",
"E",
"A",
"R",
"c",
"H",
"costs",
"and",
"outcomes",
"of",
"noncardioembolic",
"ischemic",
"stroke",
"in",
"a",
"managed",
"care",
"population",
"Nicole",
"M",
"Engel-Nitz1",
"stephen",
"D",
"sander",
"2",
"carolyn",
"Harley",
"3",
"gabriel",
"gomez",
"Rey",
"1",
"Hemal",
"shah",
"2",
"1Health",
"Economic",
"and",
"Outcomes",
"Research,",
"i3",
"innovus,",
"Eden",
"Prairie,",
"MN,",
"UsA;",
"2Health",
"Economic",
"and",
"Outcomes",
"Research,",
"Boehringer",
"ingelheim",
"Pharmaceuticals,",
"inc.,",
"Ridgefield,",
"cT,",
"UsA;",
"3Health",
"Economic",
"and",
"Outcomes",
"Research,",
"i3",
"innovus,",
"Palo",
"Alto,",
"c",
"A,",
"UsA",
"correspondence:",
"Nicole",
"M",
"Engel-Nitz",
"i3",
"innovus,",
"Health",
"Economic",
"and",
"Outcomes",
"Research,",
"An",
"ingenix",
"company,",
"12125",
"Technology",
"Drive,",
"Eden",
"Prairie,",
"MN",
"55344,",
"UsA",
"Tel",
"+1",
"952",
"833",
"8048",
"Fax",
"+1",
"952",
"833",
"6045",
"Email",
"nicole.engel-nitz@i3innovus.com",
"submit",
"your",
"manuscript",
"|",
"www.dovepress.com",
"Dovepress",
"DOI:",
"10.2147/VHRM.S10851",
"Purpose:",
"To",
"evaluate",
"the",
"clinical",
"outcomes",
"and",
"incremental",
"health",
"care",
"costs",
"of",
"ischemic",
"stroke",
"in",
"a",
"US",
"managed",
"care",
"population.",
"Patients",
"and",
"methods:",
"A",
"retrospective",
"cohort",
"analysis",
"was",
"done",
"on",
"patients",
"(aged",
"18+",
"years)",
"hospitalized",
"with",
"noncardioembolic",
"ischemic",
"stroke",
"from",
"January",
"1,",
"2002,",
"through",
"December",
"31,",
"2003,",
"identified",
"from",
"commercial",
"health",
"plan",
"administrative",
"claims.",
"New",
"or",
"recurrent",
"stroke",
"was",
"based",
"on",
"history",
"in",
"the",
"previous",
"12",
"months,",
"with",
"index",
"date",
"defined",
"as",
"first",
"date",
"ofindication",
"of",
"stroke.",
"A",
"control",
"group",
"without",
"stroke",
"or",
"transient",
"ischemic",
"attack",
"(TIA)",
"was",
"matched",
"(1:3)",
"on",
"age,",
"sex,",
"and",
"geographic",
"region,",
"with",
"an",
"index",
"date",
"defined",
"as",
"the",
"first",
"medical",
"claim",
"during",
"the",
"patient",
"identification",
"period.",
"Patients",
"with",
"atrial",
"fibrillation",
"or",
"mitral",
"value",
"abnormalities",
"were",
"excluded.",
"Ischemic",
"stroke",
"and",
"control",
"cohorts",
"were",
"compared",
"on",
"4-year",
"clinical",
"outcomes",
"and",
"1-year",
"costs.",
"Results:",
"Of",
"2180",
"ischemic",
"stroke",
"patients,",
"1808",
"(82.9%)",
"had",
"new",
"stroke",
"and",
"372",
"(17.1%)",
"had",
"a",
"recurrent",
"stroke.",
"Stroke",
"patients",
"had",
"higher",
"unadjusted",
"rates",
"of",
"additional",
"stroke,",
"TIA,",
"and",
"fatal",
"outcomes",
"compared",
"with",
"the",
"6540",
"matched",
"controls.",
"Recurrent",
"stroke",
"patients",
"had",
"higher",
"rates",
"of",
"adverse",
"clinical",
"outcomes",
"compared",
"with",
"new",
"stroke",
"patients;",
"costs",
"attributed",
"to",
"recurrent",
"stroke",
"were",
"also",
"higher.",
"Stroke",
"patients",
"were",
"2.4",
"times",
"more",
"likely",
"to",
"be",
"hospitalized",
"in",
"follow-up",
"compared",
"with",
"controls",
"(hazard",
"ratio",
"[HR]",
"2.4,",
"95%",
"confidence",
"interval",
"[CI]:",
"2.2,",
"2.6).",
"Occurrence",
"of",
"stroke",
"following",
"discharge",
"was",
"21",
"times",
"more",
"likely",
"among",
"patients",
"with",
"index",
"stroke",
"compared",
"with",
"controls",
"(HR",
"21.0,",
"95%",
"CI:",
"16.1,",
"27.3).",
"Stroke",
"was",
"also",
"predictive",
"of",
"death",
"(HR",
"1.8,",
"95%",
"CI:",
"1.3,",
"2.5).",
"Controlling",
"for",
"covariates,",
"stroke",
"patients",
"had",
"significantly",
"higher",
"costs",
"compared",
"with",
"control",
"patients",
"in",
"the",
"year",
"following",
"the",
"index",
"event.",
"Conclusion:",
"Noncardioembolic",
"ischemic",
"stroke",
"patients",
"had",
"significantly",
"poorer",
"outcomes",
"and",
"higher",
"costs",
"compared",
"with",
"controls.",
"Recurrent",
"stroke",
"appears",
"to",
"contribute",
"substantially",
"to",
"these",
"higher",
"rates",
"of",
"adverse",
"outcomes",
"and",
"costs.",
"Keywords:",
"burden",
"of",
"illness,",
"stroke/cerebrovascular",
"accident,",
"cardiovascular",
"disease,",
"claims",
"analysis,",
"costs",
"of",
"care,",
"health",
"care",
"outcomes",
"Background",
"Stroke",
"is",
"a",
"major",
"cause",
"of",
"serious,",
"long-term",
"disability,",
"mortality,",
"and",
"institutionalization,",
"and",
"it",
"accounts",
"for",
"substantial",
"use",
"of",
"health",
"care",
"resources.1–4",
"When",
"considered",
"separately",
"from",
"other",
"cardiovascular",
"diseases,",
"stroke",
"ranks",
"third",
"among",
"all",
"causes",
"of",
"death,",
"following",
"diseases",
"of",
"the",
"heart",
"and",
"cancer.5",
"Among",
"survivors,",
"∼15%–30%",
"are",
"permanently",
"disabled",
"and",
"20%",
"require",
"institutional",
"care",
"3",
"months",
"after",
"onset.6",
"As",
"a",
"result,",
"stroke",
"imposes",
"a",
"significant",
"economic",
"impact,",
"with",
"stroke-related",
"costs",
"making",
"up",
"as",
"much",
"as",
"3%–4%",
"of",
"the",
"annual",
"national",
"health",
"care",
"budget.1,2",
"For",
"2009,",
"the",
"estimated",
"direct",
"and",
"indirect",
"cost",
"of",
"stroke",
"in",
"the",
"United",
"States",
"was",
"$68.9",
"billion.6",
"Vascular",
"Health",
"and",
"Risk",
"Management",
"2010:6",
"905–913",
"905",
"©",
"2010",
"Engel-Nitz",
"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."
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] | [
"Aygören-Pürsün",
"et",
"al.",
"Allergy,",
"Asthma",
"&",
"Clinical",
"Immunology",
"2010,",
"6:21",
"http://www.aacijournal.com/content/6/1/21",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"ALLERGY,",
"ASTHMA",
"&",
"CLINICAL",
"IMMUNOLOGY",
"Open",
"Access",
"On",
"demand",
"treatment",
"and",
"home",
"therapy",
"of",
"hereditary",
"angioedema",
"in",
"Germany",
"-",
"the",
"Frankfurt",
"experience",
"Emel",
"Aygören-Pürsün*,",
"Inmaculada",
"Martinez-Saguer,",
"Eva",
"Rusicke,",
"Thomas",
"Klingebiel,",
"Wolfhart",
"Kreuz",
"Abstract",
"Background:",
"Manifestation",
"of",
"acute",
"edema",
"in",
"hereditary",
"angioedema",
"(HAE)",
"is",
"characterized",
"by",
"interindividual",
"and",
"intraindividual",
"variability",
"in",
"symptom",
"expression",
"over",
"time.",
"Flexible",
"therapy",
"options",
"are",
"needed.",
"Methods:",
"We",
"describe",
"and",
"report",
"on",
"the",
"outcomes",
"of",
"the",
"highly",
"individualized",
"approach",
"to",
"HAE",
"therapy",
"practiced",
"at",
"our",
"HAE",
"center",
"in",
"Frankfurt",
"(Germany).",
"Results:",
"The",
"HAE",
"center",
"at",
"the",
"Frankfurt",
"University",
"Hospital",
"currently",
"treats",
"450",
"adults",
"with",
"HAE",
"or",
"AAE",
"and",
"107",
"pediatric",
"HAE",
"patients",
"with",
"highly",
"individualized",
"therapeutic",
"approaches.",
"73.9%",
"of",
"the",
"adult",
"patients",
"treat",
"HAE",
"attacks",
"by",
"on-demand",
"therapy",
"with",
"pasteurized",
"pd",
"C1-INH",
"concentrate,",
"9.8%",
"use",
"additional",
"prophylaxis",
"with",
"attenuated",
"androgens,",
"1%",
"of",
"the",
"total",
"patient",
"population",
"in",
"Frankfurt",
"has",
"been",
"treated",
"with",
"Icatibant",
"up",
"to",
"now.",
"In",
"addition",
"adult",
"and",
"selected",
"pediatric",
"patients",
"with",
"a",
"high",
"frequency",
"of",
"severe",
"attacks",
"are",
"instructed",
"to",
"apply",
"individual",
"replacement",
"therapy",
"(IRT)",
"with",
"pasteurized",
"pd",
"C1-INH",
"concentrate.",
"Improvement",
"on",
"Quality",
"of",
"Life",
"items",
"was",
"shown",
"for",
"these",
"patients",
"compared",
"to",
"previous",
"long-term",
"danazol",
"prophylaxis.",
"Home",
"treatment",
"of",
"HAE",
"patients",
"was",
"developed",
"in",
"the",
"Frankfurt",
"HAE",
"center",
"in",
"line",
"with",
"experiences",
"in",
"hemophilia",
"therapy",
"and",
"has",
"so",
"far",
"been",
"implemented",
"over",
"a",
"period",
"of",
"28",
"years.",
"At",
"present",
"248",
"(55%)",
"of",
"the",
"adult",
"patients",
"and",
"26",
"(24%)",
"of",
"the",
"pediatric",
"patients",
"are",
"practicing",
"home",
"treatment",
"either",
"as",
"on",
"demand",
"or",
"IRT",
"treatment.",
"Conclusions:",
"In",
"conclusion,",
"the",
"individualized",
"home",
"therapies",
"provided",
"by",
"our",
"HAE",
"center,",
"aim",
"to",
"limit",
"the",
"disruption",
"to",
"normal",
"daily",
"activities",
"that",
"occurs",
"for",
"many",
"HAE",
"patients.",
"Furthermore,",
"we",
"seek",
"to",
"optimize",
"the",
"economic",
"burden",
"of",
"the",
"disease",
"while",
"offering",
"a",
"maximum",
"quality",
"of",
"life",
"to",
"our",
"patients.",
"Introduction",
"On",
"demand",
"treatment",
"of",
"acute",
"angioedema",
"in",
"HAE",
"type",
"I",
"and",
"II",
"Hereditary",
"angioedema",
"(HAE)",
"is",
"based",
"on",
"a",
"hereditary,",
"life-long",
"deficiency",
"of",
"C1-esterase-inhibitor",
"(C1-INH).",
"Patients",
"with",
"HAE",
"suffer",
"from",
"recurrent,",
"localized,",
"acute",
"edema",
"attacks",
"that",
"can",
"affect",
"any",
"body",
"location.",
"Mainly",
"affected",
"are",
"subcutaneous",
"tissues",
"or",
"mucous",
"membranes,",
"the",
"gastrointestinal",
"tract,",
"and",
"the",
"throat,",
"the",
"latter",
"leading",
"to",
"potentially",
"life-threatening",
"laryngeal",
"edema.",
"Manifestation",
"of",
"acute",
"edema",
"in",
"hereditary",
"angioedema",
"is",
"characterized",
"by",
"interindividual",
"and",
"intraindividual",
"variability",
"in",
"symptom",
"expression",
"over",
"*",
"Correspondence:",
"eap@em.uni-frankfurt.de",
"Centre",
"of",
"Pediatrics",
"III,",
"Department",
"of",
"Hematology,",
"Oncology",
"and",
"Hemostasis,",
"Comprehensive",
"Care",
"Centre",
"for",
"Thrombosis",
"and",
"Hemostasis,",
"Johann",
"Wolfgang",
"Goethe",
"University",
"Hospital,",
"Frankfurt",
"am",
"Main,",
"Germany",
"time.",
"The",
"onset",
"of",
"the",
"next",
"attack,",
"its",
"location",
"and",
"its",
"severity",
"are",
"unpredictable.",
"Treatment",
"options",
"adapted",
"on",
"the",
"specific",
"needs",
"of",
"the",
"individual",
"patient",
"need",
"to",
"be",
"implemented",
"based",
"on",
"the",
"type",
"and",
"frequency",
"of",
"HAE",
"attacks",
"and",
"should",
"be",
"re-evaluated",
"from",
"time",
"to",
"time",
"[1,2].",
"Worldwide,",
"five",
"different",
"therapy",
"options",
"for",
"on",
"demand",
"therapy",
"of",
"acute",
"attacks",
"based",
"on",
"three",
"distinct",
"pathophysiological",
"approaches",
"are",
"currently",
"under",
"clini-",
"cal",
"investigation",
"or",
"already",
"approved",
"in",
"different",
"coun-",
"tries.",
"For",
"replacement",
"of",
"lacking",
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] | [
"Borel",
"et",
"al.",
"BMC",
"Microbiology",
"2010,",
"10:201",
"http://www.biomedcentral.com/1471-2180/10/201",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Mixed",
"infections",
"with",
"Chlamydia",
"and",
"porcine",
"epidemic",
"diarrhea",
"virus",
"-",
"a",
"new",
"in",
"vitro",
"model",
"of",
"chlamydial",
"persistence",
"Nicole",
"Borel1*,",
"Claudia",
"Dumrese2,",
"Urs",
"Ziegler2,",
"Andrea",
"Schifferli1,",
"Carmen",
"Kaiser1,",
"Andreas",
"Pospischil1",
"Abstract",
"Background:",
"Chlamydiae",
"induce",
"persistent",
"infections,",
"which",
"have",
"been",
"associated",
"with",
"a",
"wide",
"range",
"of",
"chronic",
"diseases",
"in",
"humans",
"and",
"animals.",
"Mixed",
"infections",
"with",
"Chlamydia",
"and",
"porcine",
"epidemic",
"diarrhea",
"virus",
"(PEDV)",
"may",
"result",
"in",
"generation",
"of",
"persistent",
"chlamydial",
"infections.",
"To",
"test",
"this",
"hypothesis,",
"an",
"in",
"vitro",
"model",
"of",
"dual",
"infection",
"with",
"cell",
"culture-adapted",
"PEDV",
"and",
"Chlamydia",
"abortus",
"or",
"Chlamydia",
"pecorum",
"in",
"Vero",
"cells",
"was",
"established.",
"Results:",
"Infected",
"cultures",
"were",
"investigated",
"by",
"immunofluorescence",
"(IF),",
"transmission",
"electron",
"microscopy",
"(TEM)",
"and",
"re-infection",
"experiments.",
"By",
"IF,",
"Chlamydia-infected",
"cells",
"showed",
"normal",
"inclusions",
"after",
"39",
"hpi.",
"Dual",
"infections",
"with",
"Chlamydia",
"abortus",
"revealed",
"a",
"heterogenous",
"mix",
"of",
"inclusion",
"types",
"including",
"small",
"inclusions",
"consisting",
"of",
"aberrant",
"bodies",
"(ABs),",
"medium-sized",
"inclusions",
"consisting",
"of",
"ABs",
"and",
"reticulate",
"bodies",
"and",
"normal",
"inclusions.",
"Only",
"aberrant",
"inclusions",
"were",
"observable",
"in",
"dual",
"infection",
"experiments",
"with",
"Chlamydia",
"pecorum",
"and",
"PEDV.",
"TEM",
"examinations",
"of",
"mixed",
"infections",
"with",
"Chlamydia",
"abortus",
"and",
"Chlamydia",
"pecorum",
"revealed",
"aberrant",
"chlamydial",
"inclusions",
"containing",
"reticulate-like,",
"pleomorphic",
"ABs,",
"which",
"were",
"up",
"to",
"2",
"μm",
"in",
"diameter.",
"No",
"re-differentiation",
"into",
"elementary",
"bodies",
"(EBs)",
"was",
"detected.",
"In",
"re-infection",
"experiments,",
"co-infected",
"cells",
"produced",
"fewer",
"EBs",
"than",
"monoinfected",
"cells.",
"Conclusions:",
"In",
"the",
"present",
"study",
"we",
"confirm",
"that",
"PEDV",
"co-infection",
"alters",
"the",
"developmental",
"cycle",
"of",
"member",
"species",
"of",
"the",
"family",
"Chlamydiaceae,",
"in",
"a",
"similar",
"manner",
"to",
"other",
"well-described",
"persistence",
"induction",
"methods.",
"Interestingly,",
"this",
"effect",
"appears",
"to",
"be",
"partially",
"species-specific",
"as",
"Chlamydia",
"pecorum",
"appears",
"more",
"sensitive",
"to",
"PEDV",
"co-infection",
"than",
"Chlamydia",
"abortus,",
"as",
"evidenced",
"by",
"TEM",
"and",
"IF",
"observations",
"of",
"a",
"homogenous",
"population",
"of",
"aberrant",
"inclusions",
"in",
"PEDV",
"-",
"Chlamydia",
"pecorum",
"co-infections.",
"Background",
"Chlamydiae",
"are",
"implicated",
"in",
"a",
"wide",
"variety",
"of",
"diseases",
"in",
"both",
"animals",
"and",
"humans.",
"Although",
"acute",
"infections",
"in",
"animal",
"chlamydioses",
"are",
"the",
"most",
"commonly",
"reported,",
"chronic",
"chlamydial",
"infections",
"are",
"also",
"asso-",
"ciated",
"with",
"a",
"variety",
"of",
"diseases",
"in",
"humans",
"and",
"animals.",
"These",
"latter",
"infections",
"are",
"characterized",
"by",
"inflamma-",
"tion",
"and",
"scarring",
"resulting",
"in",
"significant",
"damage",
"of",
"the",
"host.",
"A",
"causative",
"role",
"in",
"chronic",
"diseases",
"requires",
"that",
"chlamydiae",
"persist",
"within",
"infected",
"tissue",
"for",
"extended",
"periods",
"of",
"time.",
"Current",
"theories,",
"based",
"primarily",
"on",
"in",
"vitro",
"data,",
"suggest",
"that",
"chlamydial",
"persistence,",
"and",
"the",
"resulting",
"chronic",
"inflammation,",
"is",
"linked",
"to",
"*",
"Correspondence:",
"n.borel@access.uzh.ch",
"1Institute",
"of",
"Veterinary",
"Pathology,",
"Vetsuisse",
"Faculty,",
"University",
"of",
"Zurich,",
"Zurich,",
"Switzerland",
"morphological",
"and",
"metabolic",
"conversion",
"of",
"the",
"actively",
"replicating",
"and",
"intracellular",
"reticulate",
"body",
"(RB)",
"into",
"an",
"alternative,",
"non-replicative",
"form",
"known",
"as",
"an",
"aberrant",
"body",
"(AB)",
"[1].",
"In",
"vitro,",
"alterations",
"of",
"the",
"normal",
"devel-",
"opmental",
"cycle",
"of",
"Chlamydia",
"trachomatis",
"and",
"Chlamy-",
"dia",
"pneumoniae",
"can",
"be",
"induced",
"by",
"Interferon-g",
"(IFN-g),",
"tumor",
"necrosis",
"factor-a",
"(TNF-a)",
"and",
"penicillin",
"G",
"expo-",
"sure",
"as",
"well",
"as",
"amino",
"acid",
"or",
"iron",
"deprivation",
"and",
"monocyte",
"infection",
"[2,3].",
"To",
"date,",
"in",
"vitro",
"models",
"for",
"animal",
"pathogens,",
"Chlamydia",
"abortus",
"and",
"Chlamydia",
"pecorum",
"have",
"not",
"been",
"described",
"although",
"both",
"organ-",
"isms",
"are",
"associated",
"with",
"chronic",
"disease",
"in",
"koalas",
"and",
"small",
"ruminants",
"[1].",
"In",
"pigs,",
"several",
"chlamydial",
"species,",
"including",
"Chlamy-",
"dia",
"abortus,",
"Chlamydia",
"psittaci,",
"Chlamydia",
"pecorum",
"and",
"Chlamydia",
"suis,",
"have",
"been",
"implicated",
"in",
"a",
"variety",
"of",
"©",
"2010",
"Borel",
"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",
"Pregnancy",
"and",
"Childbirth",
"2BC2M0a0Cs2Pe,rergneapncoyratnd",
"Childbirth",
"x",
"Intrauterine",
"pregnancy",
"following",
"low-dose",
"gonadotropin",
"ovulation",
"induction",
"and",
"direct",
"intraperitoneal",
"insemination",
"for",
"severe",
"cervical",
"stenosis",
"E",
"Scott",
"Sills*1,2",
"and",
"Gianpiero",
"D",
"Palermo3",
"Address:",
"1Georgia",
"Reproductive",
"Specialists",
"LLC;",
"Atlanta,",
"Georgia",
"USA,",
"2Division",
"of",
"Reproductive",
"Endocrinology",
"and",
"Infertility,",
"Department",
"of",
"Obstetrics",
"and",
"Gynecology,",
"Atlanta",
"Medical",
"Center;",
"Atlanta,",
"Georgia",
"USA",
"and",
"3Cornell",
"Institute",
"for",
"Reproductive",
"Medicine,",
"Weill",
"Medical",
"College",
"of",
"Cornell",
"University;",
"New",
"York,",
"New",
"York",
"USA",
"E-mail:",
"E",
"Sills*",
"-",
"dr.sills@ivf.com;",
"Gianpiero",
"D",
"Palermo",
"-",
"gdpalerm@med.cornell.edu",
"*Corresponding",
"author",
"BioMed",
"Central",
"Open",
"Access",
"Published:",
"26",
"November",
"2002",
"BMC",
"Pregnancy",
"and",
"Childbirth",
"2002,",
"2:9",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2393/2/9",
"Received:",
"25",
"September",
"2002",
"Accepted:",
"26",
"November",
"2002",
"©",
"2002",
"Sills",
"and",
"Palermo;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article:",
"verbatim",
"copying",
"and",
"redistribution",
"of",
"this",
"article",
"are",
"permitted",
"in",
"all",
"media",
"for",
"any",
"purpose,",
"provided",
"this",
"notice",
"is",
"preserved",
"along",
"with",
"the",
"article's",
"original",
"URL.",
"Keywords:",
"cervical",
"factor",
"infertility,",
"intraperitoneal",
"insemination,",
"ovulation",
"induction",
"Abstract",
"Background:",
"We",
"present",
"a",
"case",
"of",
"primary",
"infertility",
"related",
"to",
"extreme",
"cervical",
"stenosis,",
"a",
"subset",
"of",
"cervical",
"factor",
"infertility",
"which",
"accounts",
"for",
"approximately",
"5%",
"of",
"all",
"clinical",
"infertility",
"referrals.",
"Case",
"presentation:",
"A",
"37",
"year-old",
"nulligravida",
"was",
"successfully",
"treated",
"with",
"ovulation",
"induction",
"via",
"recombinant",
"follicle",
"stimulating",
"hormone",
"(FSH)",
"and",
"direct",
"intraperitoneal",
"insemination",
"(IPI).",
"Anticipating",
"controlled",
"ovarian",
"hyperstimulation",
"with",
"in",
"vitro",
"fertilization/embryo",
"transfer",
"(IVF),",
"the",
"patient",
"underwent",
"hysteroscopy",
"and",
"cervical",
"recanalization,",
"but",
"safe",
"intrauterine",
"access",
"was",
"not",
"possible",
"due",
"to",
"severe",
"proximal",
"cervical",
"stricture.",
"Hysterosalpingogram",
"established",
"bilateral",
"tubal",
"patency",
"and",
"confirmed",
"an",
"irregular",
"cervical",
"contour.",
"Since",
"the",
"cervical",
"canal",
"could",
"not",
"be",
"traversed,",
"neither",
"standard",
"intrauterine",
"insemination",
"nor",
"transcervical",
"embryo",
"transfer",
"could",
"be",
"offered.",
"Prepared",
"spermatozoa",
"were",
"therefore",
"placed",
"intraperitoneally",
"at",
"both",
"tubal",
"fimbria",
"under",
"real-time",
"transvaginal",
"sonographic",
"guidance",
"using",
"a",
"17",
"gage",
"single-lumen",
"IVF",
"needle.",
"Supplementary",
"progesterone",
"was",
"administered",
"as",
"200",
"mg/d",
"lozenge",
"(troche)",
"plus",
"200",
"mg/d",
"rectal",
"suppository,",
"maintained",
"from",
"the",
"day",
"following",
"IPI",
"to",
"the",
"8th",
"gestational",
"week.",
"A",
"singleton",
"intrauterine",
"pregnancy",
"was",
"achieved",
"after",
"the",
"second",
"ovulation",
"induction",
"attempt.",
"Conclusions:",
"In",
"this",
"report,",
"we",
"outline",
"the",
"relevance",
"of",
"cervical",
"factor",
"infertility",
"to",
"reproductive",
"medicine",
"practice.",
"Additionally,",
"our",
"andrology",
"evaluation,",
"ovulation",
"induction",
"approach,",
"spermatozoa",
"preparation,",
"and",
"insemination",
"technique",
"in",
"such",
"cases",
"are",
"described.",
"Background",
"Cervical",
"factor",
"infertility",
"accounts",
"for",
"~5%",
"of",
"all",
"clinical",
"infertility",
"referrals,",
"and",
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"for",
"cervical",
"stenosis",
"include",
"gamete",
"or",
"zygote",
"intrafallopian",
"transfer,",
"and",
"corrective",
"surgical",
"procedures",
"designed",
"to",
"lyse",
"stric-",
"tures",
"responsible",
"for",
"stenosis.",
"However,",
"intrauterine",
"in-",
"semination",
"(IUI)",
"is",
"usually",
"suggested",
"early",
"as",
"an",
"appropriate",
"therapeutic",
"consideration",
"when",
"semen",
"pa-",
"rameters",
"are",
"normal",
"and",
"the",
"suspicion",
"for",
"tubal",
"pathology",
"is",
"low.",
"However,",
"should",
"the",
"cervical",
"canal",
"be",
"tortuous",
"or",
"Page",
"1",
"of",
"5",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Heinrich",
"et",
"al.",
"BMC",
"Cancer",
"2011,",
"11:346",
"http://www.biomedcentral.com/1471-2407/11/346",
"S",
"T",
"U",
"D",
"Y",
"P",
"R",
"O",
"T",
"O",
"C",
"O",
"L",
"Open",
"Access",
"Adjuvant",
"gemcitabine",
"versus",
"NEOadjuvant",
"gemcitabine/oxaliplatin",
"plus",
"adjuvant",
"gemcitabine",
"in",
"resectable",
"pancreatic",
"cancer:",
"a",
"randomized",
"multicenter",
"phase",
"III",
"study",
"(NEOPAC",
"study)",
"Stefan",
"Heinrich1,",
"Bernhard",
"Pestalozzi2,",
"Mickael",
"Lesurtel3,",
"Frederik",
"Berrevoet4,",
"Stéphanie",
"Laurent5,",
"Jean-Robert",
"Delpero6,",
"Jean-Luc",
"Raoul7,",
"Phillippe",
"Bachellier8,",
"Patrick",
"Dufour9,",
"Markus",
"Moehler10,",
"Achim",
"Weber11,",
"Hauke",
"Lang1,",
"Xavier",
"Rogiers4",
"and",
"Pierre-Alain",
"Clavien3*",
"Abstract",
"Background:",
"Despite",
"major",
"improvements",
"in",
"the",
"perioperative",
"outcome",
"of",
"pancreas",
"surgery,",
"the",
"prognosis",
"of",
"pancreatic",
"cancer",
"after",
"curative",
"resection",
"remains",
"poor.",
"Adjuvant",
"chemotherapy",
"increases",
"disease-free",
"and",
"overall",
"survival,",
"but",
"this",
"treatment",
"cannot",
"be",
"offered",
"to",
"a",
"significant",
"proportion",
"of",
"patients",
"due",
"to",
"the",
"surgical",
"morbidity.",
"In",
"contrast,",
"almost",
"all",
"patients",
"can",
"receive",
"(neo)adjuvant",
"chemotherapy",
"before",
"surgery.",
"This",
"treatment",
"is",
"safe",
"and",
"effective,",
"and",
"has",
"resulted",
"in",
"a",
"median",
"survival",
"of",
"26.5",
"months",
"in",
"a",
"recent",
"phase",
"II",
"trial.",
"Moreover,",
"neoadjuvant",
"chemotherapy",
"improves",
"the",
"nutritional",
"status",
"of",
"patients",
"with",
"pancreatic",
"cancer.",
"This",
"multicenter",
"phase",
"III",
"trial",
"(NEOPAC)",
"has",
"been",
"designed",
"to",
"explore",
"the",
"efficacy",
"of",
"neoadjuvant",
"chemotherapy.",
"Methods/Design:",
"This",
"is",
"a",
"prospective",
"randomized",
"phase",
"III",
"trial.",
"Patients",
"with",
"resectable",
"cytologically",
"proven",
"adenocarcinoma",
"of",
"the",
"pancreatic",
"head",
"are",
"eligible",
"for",
"this",
"study.",
"All",
"patients",
"must",
"be",
"at",
"least",
"18",
"years",
"old",
"and",
"must",
"provide",
"written",
"informed",
"consent.",
"An",
"infiltration",
"of",
"the",
"superior",
"mesenteric",
"vein",
">",
"180°",
"or",
"major",
"visceral",
"arteries",
"are",
"considered",
"exclusion",
"criteria.",
"Eligible",
"patients",
"will",
"be",
"randomized",
"to",
"surgery",
"followed",
"by",
"adjuvant",
"gemcitabine",
"(1000",
"mg/m2)",
"for",
"6",
"months",
"or",
"neoadjuvant",
"chemotherapy",
"(gemcitabine",
"1000",
"mg/m2,",
"oxaliplatin",
"100",
"mg/m2)",
"followed",
"by",
"surgery",
"and",
"the",
"same",
"adjuvant",
"treatment.",
"Neoadjuvant",
"chemotherapy",
"is",
"given",
"four",
"times",
"every",
"two",
"weeks.",
"The",
"staging",
"as",
"well",
"as",
"the",
"restaging",
"protocol",
"after",
"neoadjuvant",
"chemotherapy",
"include",
"computed",
"tomography",
"of",
"chest",
"and",
"abdomen",
"and",
"diagnostic",
"laparoscopy.",
"The",
"primary",
"study",
"endpoint",
"is",
"progression-free",
"survival.",
"According",
"to",
"the",
"sample",
"size",
"calculation,",
"155",
"patients",
"need",
"to",
"be",
"randomized",
"to",
"each",
"treatment",
"arm.",
"Disease",
"recurrence",
"will",
"be",
"documented",
"by",
"scheduled",
"computed",
"tomography",
"scans",
"9,",
"12,",
"15,",
"21",
"and",
"thereafter",
"every",
"6",
"months",
"until",
"disease",
"progression.",
"For",
"quality",
"control,",
"circumferential",
"resection",
"margins",
"are",
"marked",
"intraoperatively,",
"and",
"representative",
"histological",
"sections",
"will",
"be",
"centrally",
"reviewed",
"by",
"a",
"dedicated",
"pathologist.",
"Discussion:",
"The",
"NEOPAC",
"study",
"will",
"determine",
"the",
"efficacy",
"of",
"neoadjuvant",
"chemotherapy",
"in",
"pancreatic",
"cancer",
"for",
"the",
"first",
"time",
"and",
"offers",
"a",
"unique",
"potential",
"for",
"translational",
"research.",
"Furthermore,",
"this",
"trial",
"will",
"provide",
"the",
"unbiased",
"overall",
"survival",
"of",
"all",
"patients",
"undergoing",
"surgery",
"for",
"resectable",
"cancer",
"of",
"the",
"pancreatic",
"head.",
"Trial",
"registration:",
"clinicalTrials.gov",
"NCT01314027",
"*",
"Correspondence:",
"clavien@access.uzh.ch",
"3Visceral",
"and",
"Transplantation",
"Surgery,",
"University",
"Hospital",
"of",
"Zurich,",
"Raemistrasse",
"100,",
"8091",
"Zuerich,",
"Switzerland",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2011",
"Heinrich",
"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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] | [
"Nuttall",
"et",
"al.",
"BMC",
"Family",
"Practice",
"2011,",
"12:78",
"http://www.biomedcentral.com/1471-2296/12/78",
"C",
"O",
"R",
"R",
"E",
"S",
"P",
"O",
"N",
"D",
"E",
"N",
"C",
"E",
"Open",
"Access",
"Building",
"an",
"international",
"network",
"for",
"a",
"primary",
"care",
"research",
"program:",
"reflections",
"on",
"challenges",
"and",
"solutions",
"in",
"the",
"set-up",
"and",
"delivery",
"of",
"a",
"prospective",
"observational",
"study",
"of",
"acute",
"cough",
"in",
"13",
"European",
"countries",
"Jacqueline",
"Nuttall1*,",
"Kerenza",
"Hood1,",
"Theo",
"JM",
"Verheij2,",
"Paul",
"Little3,",
"Curt",
"Brugman2,",
"Robert",
"ER",
"Veen2,",
"Herman",
"Goossens4",
"and",
"Christopher",
"C",
"Butler1",
"Abstract",
"Background:",
"Implementing",
"a",
"primary",
"care",
"clinical",
"research",
"study",
"in",
"several",
"countries",
"can",
"make",
"it",
"possible",
"to",
"recruit",
"sufficient",
"patients",
"in",
"a",
"short",
"period",
"of",
"time",
"that",
"allows",
"important",
"clinical",
"questions",
"to",
"be",
"answered.",
"Large",
"multi-country",
"studies",
"in",
"primary",
"care",
"are",
"unusual",
"and",
"are",
"typically",
"associated",
"with",
"challenges",
"requiring",
"innovative",
"solutions.",
"We",
"conducted",
"a",
"multi-country",
"study",
"and",
"through",
"this",
"paper,",
"we",
"share",
"reflections",
"on",
"the",
"challenges",
"we",
"faced",
"and",
"some",
"of",
"the",
"solutions",
"we",
"developed",
"with",
"a",
"special",
"focus",
"on",
"the",
"study",
"set",
"up,",
"structure",
"and",
"development",
"of",
"Primary",
"Care",
"Networks",
"(PCNs).",
"Method:",
"GRACE-01",
"was",
"a",
"multi-European",
"country,",
"investigator-driven",
"prospective",
"observational",
"study",
"implemented",
"by",
"14",
"Primary",
"Care",
"Networks",
"(PCNs)",
"within",
"13",
"European",
"Countries.",
"General",
"Practitioners",
"(GPs)",
"recruited",
"consecutive",
"patients",
"with",
"an",
"acute",
"cough.",
"GPs",
"completed",
"a",
"case",
"report",
"form",
"(CRF)",
"and",
"the",
"patient",
"completed",
"a",
"daily",
"symptom",
"diary.",
"After",
"study",
"completion,",
"the",
"coordinating",
"team",
"discussed",
"the",
"phases",
"of",
"the",
"study",
"and",
"identified",
"challenges",
"and",
"solutions",
"that",
"they",
"considered",
"might",
"be",
"interesting",
"and",
"helpful",
"to",
"researchers",
"setting",
"up",
"a",
"comparable",
"study.",
"Results:",
"The",
"main",
"challenges",
"fell",
"within",
"three",
"domains",
"as",
"follows:",
"i)",
"selecting,",
"setting",
"up",
"and",
"maintaining",
"PCNs;",
"ii)",
"designing",
"local",
"context-appropriate",
"data",
"collection",
"tools",
"and",
"efficient",
"data",
"management",
"systems;",
"and",
"iii)",
"gaining",
"commitment",
"and",
"trust",
"from",
"all",
"involved",
"and",
"maintaining",
"enthusiasm.",
"The",
"main",
"solutions",
"for",
"each",
"domain",
"were:",
"i)",
"appointing",
"key",
"individuals",
"(National",
"Network",
"Facilitator",
"and",
"Coordinator)",
"with",
"clearly",
"defined",
"tasks,",
"involving",
"PCNs",
"early",
"in",
"the",
"development",
"of",
"study",
"materials",
"and",
"procedures.",
"ii)",
"rigorous",
"back",
"translations",
"of",
"all",
"study",
"materials",
"and",
"the",
"use",
"of",
"information",
"systems",
"to",
"closely",
"monitor",
"each",
"PCNs",
"progress;",
"*",
"Correspondence:",
"Nuttallj@cf.ac.uk",
"1South",
"East",
"Wales",
"Trials",
"Unit",
"(SEWTU),",
"Department",
"of",
"Primary",
"Care",
"and",
"Public",
"Health,",
"School",
"of",
"Medicine,",
"Cardiff",
"University,",
"Neuadd",
"Meirionnydd,",
"Heath",
"Park,",
"Cardiff,",
"UK",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2011",
"Nuttall",
"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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[
536,
721,
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14
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562,
721,
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14
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688,
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14
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435,
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] | [
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"Methyl",
"3-(4-bromophenyl)-2-(1H-indol-",
"3-ylmethyl)-5-[1-(4-methoxyphenyl)-4-",
"oxo-2-phenylazetidin-2-yl]-4-nitro-",
"pyrrolidine-2-carboxylate",
"S.",
"Nirmala,a",
"E.",
"Theboral",
"Sugi",
"Kamala,a",
"L.",
"Sudha,b*",
"N.",
"Arumugamc",
"and",
"R.",
"Raghunathanc",
"aDepartment",
"of",
"Physics,",
"Easwari",
"Engineering",
"College,",
"Ramapuram,",
"Chennai",
"600",
"089,",
"India,",
"bDepartment",
"of",
"Physics,",
"SRM",
"University,",
"Ramapuram",
"Campus,",
"Chennai",
"600",
"089,",
"India,",
"and",
"cDepartment",
"of",
"Organic",
"Chemistry,",
"University",
"of",
"Madras,",
"Guindy",
"Campus,",
"Chennai",
"600",
"025,",
"India",
"Correspondence",
"e-mail:",
"sudharose18@gmail.com",
"Received",
"10",
"April",
"2008;",
"accepted",
"12",
"May",
"2008",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"293",
"K;",
"mean",
"(C–C)",
"=",
"0.004",
"A˚;",
"R",
"factor",
"=",
"0.040;",
"wR",
"factor",
"=",
"0.120;",
"data-to-parameter",
"ratio",
"=",
"19.7.",
"In",
"the",
"title",
"compound,",
"C37H33BrN4O6,",
"the",
"pyrrolidine",
"ring",
"adopts",
"an",
"envelope",
"conformation.",
"The",
"-lactam",
"ring",
"is",
"planar",
"and",
"makes",
"dihedral",
"angles",
"of",
"70.16",
"(13)",
"and",
"28.32",
"(13)",
"with",
"the",
"phenyl",
"and",
"4-methoxyphenyl",
"rings,",
"respectively.",
"The",
"molecular",
"packing",
"is",
"stabilized",
"by",
"intramolecular",
"C—H",
"O",
"interactions",
"and",
"the",
"crystal",
"packing",
"is",
"determined",
"by",
"inter-",
"molecular",
"N—H",
"O",
"hydrogen",
"bonds,",
"and",
"C—H",
"O",
"and",
"C—H",
"interactions.",
"Related",
"literature",
"For",
"related",
"literature,",
"see:",
"Kamala",
"et",
"al.",
"(2008);",
"Lukacs",
"&",
"Ohno",
"(1990);",
"Sundari",
"Bhaskaran",
"et",
"al.",
"(2006);",
"Suzuki",
"et",
"al.",
"(1994);",
"Yang",
"et",
"al.",
"(1987);",
"Amal",
"Raj",
"et",
"al.",
"(2003);",
"Cremer",
"&",
"Pople",
"(1975);",
"Nardelli",
"(1995);",
"U¨",
"lku¨",
"et",
"al.",
"(1997).",
"Experimental",
"Crystal",
"data",
"C37H33BrN4O6",
"Mr",
"=",
"709.58",
"Monoclinic,",
"Cc",
"a",
"=",
"11.3988",
"(4)",
"A˚",
"organic",
"compounds",
"b",
"=",
"34.8587",
"(13)",
"A˚",
"c",
"=",
"8.7039",
"(3)",
"A˚",
"=",
"100.982",
"(2)",
"V",
"=",
"3395.1",
"(2)",
"A˚",
"3",
"Z",
"=",
"4",
"Data",
"collection",
"Bruker",
"Kappa",
"APEX2",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(Blessing,",
"1995)",
"Tmin",
"=",
"0.703,",
"Tmax",
"=",
"0.769",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.040",
"wR(F",
"2)",
"=",
"0.120",
"S",
"=",
"1.04",
"8532",
"reflections",
"433",
"parameters",
"2",
"restraints",
"Table",
"1",
"Hydrogen-bond",
"geometry",
"(A˚",
",",
").",
"D—H",
"A",
"C11—H11",
"O4",
"C4—H4",
"O4i",
"C31—H31",
"O4ii",
"N1—H1A",
"O5iii",
"C18—H18",
"Cgiv",
"D—H",
"0.98",
"0.93",
"0.93",
"0.86",
"0.93",
"Mo",
"K",
"radiation",
"=",
"1.26",
"mm",
"1",
"T",
"=",
"293",
"(2)",
"K",
"0.30",
"0.22",
"0.22",
"mm",
"37282",
"measured",
"reflections",
"8532",
"independent",
"reflections",
"6397",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.028",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.43",
"e",
"A˚",
"3",
"0.37",
"e",
"A˚",
"3",
"min",
"=",
"Absolute",
"structure:",
"Flack",
"(1983),",
"4142",
"Friedel",
"pairs",
"Flack",
"parameter:",
"0.008",
"(6)",
"H",
"2.27",
"2.57",
"2.55",
"2.02",
"2.80",
"A",
"D",
"A",
"2.717",
"(3)",
"3.186",
"(3)",
"3.399",
"(3)",
"2.820",
"(3)",
"3.641",
"(4)",
"D—H",
"A",
"107",
"124",
"152",
"155",
"151",
"Symmetry",
"codes:",
"(i)",
"x;",
"y;",
"z",
"1;",
"(ii)",
"x;",
"y",
"þ",
"2;",
"z",
"12;",
"(iii)",
"x",
"þ",
"12;",
"y",
"þ",
"32;",
"z",
"12;",
"(iv)",
"x;",
"y;",
"z",
"þ",
"1.",
"Cg",
"is",
"the",
"centroid",
"of",
"the",
"indole",
"benzene",
"ring.",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2004);",
"cell",
"refinement:",
"APEX2",
"and",
"SAINT",
"(Bruker,",
"2004);",
"data",
"reduction:",
"SAINT",
"and",
"XPREP",
"(Bruker,",
"2004);",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"ORTEP-3",
"(Farrugia,",
"1997);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"PLATON",
"(Spek,",
"2003).",
"SN",
"thanks",
"Professor",
"M.",
"N.",
"Ponnuswamy,",
"Department",
"of",
"Crystallography",
"and",
"Biophysics,",
"University",
"of",
"Madras,",
"India,",
"for",
"his",
"guidance",
"and",
"valuable",
"suggestions.",
"SN",
"thanks",
"SRM",
"management,",
"India,",
"for",
"their",
"support.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"RK2086).",
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"Raj,",
"A.,",
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] | [
"Wang",
"et",
"al.",
"Journal",
"of",
"Neuroinflammation",
"2011,",
"8:134",
"http://www.jneuroinflammation.com/content/8/1/134",
"R",
"E",
"V",
"I",
"E",
"W",
"Toll-like",
"receptors",
"in",
"cerebral",
"ischemic",
"inflammatory",
"injury",
"Yan-Chun",
"Wang1†,",
"Sen",
"Lin2†",
"and",
"Qing-Wu",
"Yang1*",
"JOURNAL",
"OF",
"NEUROINFLAMMATION",
"Open",
"Access",
"Abstract",
"Cerebral",
"ischemia",
"triggers",
"acute",
"inflammation,",
"which",
"has",
"been",
"associated",
"with",
"an",
"increase",
"in",
"brain",
"damage.",
"The",
"mechanisms",
"that",
"regulate",
"the",
"inflammatory",
"response",
"after",
"cerebral",
"ischemia",
"are",
"multifaceted.",
"An",
"important",
"component",
"of",
"this",
"response",
"is",
"the",
"activation",
"of",
"the",
"innate",
"immune",
"system.",
"However,",
"details",
"of",
"the",
"role",
"of",
"the",
"innate",
"immune",
"system",
"within",
"the",
"complex",
"array",
"of",
"mechanisms",
"in",
"cerebral",
"ischemia",
"remain",
"unclear.",
"There",
"have",
"been",
"recent",
"great",
"strides",
"in",
"our",
"understanding",
"of",
"the",
"innate",
"immune",
"system,",
"particularly",
"in",
"regard",
"to",
"the",
"signaling",
"mechanisms",
"of",
"Toll-like",
"receptors",
"(TLRs),",
"whose",
"primary",
"role",
"is",
"the",
"initial",
"activation",
"of",
"immune",
"cell",
"responses.",
"So",
"far,",
"few",
"studies",
"have",
"examined",
"the",
"role",
"of",
"TLRs",
"in",
"cerebral",
"ischemia.",
"However,",
"work",
"with",
"experimental",
"models",
"of",
"ischemia",
"suggests",
"that",
"TLRs",
"are",
"involved",
"in",
"the",
"enhancement",
"of",
"cell",
"damage",
"following",
"ischemia,",
"and",
"their",
"absence",
"is",
"associated",
"with",
"lower",
"infarct",
"volumes.",
"It",
"may",
"be",
"possible",
"that",
"therapeutic",
"targets",
"could",
"be",
"designed",
"to",
"modulate",
"activities",
"of",
"the",
"innate",
"immune",
"system",
"that",
"would",
"attenuate",
"cerebral",
"brain",
"damage.",
"Ischemic",
"tolerance",
"is",
"a",
"protective",
"mechanism",
"induced",
"by",
"a",
"variety",
"of",
"preconditioning",
"stimuli.",
"Interpreting",
"the",
"molecular",
"mechanism",
"of",
"ischemic",
"tolerance",
"will",
"open",
"investigative",
"avenues",
"into",
"the",
"treatment",
"of",
"cerebral",
"ischemia.",
"In",
"this",
"review,",
"we",
"discuss",
"the",
"critical",
"role",
"of",
"TLRs",
"in",
"mediating",
"cerebral",
"ischemic",
"injury.",
"We",
"also",
"summarize",
"evidence",
"demonstrating",
"that",
"cerebral",
"preconditioning",
"downregulates",
"pro-",
"inflammatory",
"TLR",
"signaling,",
"thus",
"reducing",
"the",
"inflammation",
"that",
"exacerbates",
"ischemic",
"brain",
"injury.",
"Keywords:",
"cerebral",
"ischemia,",
"Toll-like",
"receptors",
"(TLRs),",
"inflammation,",
"innate",
"immunity",
"Introduction",
"Cerebral",
"ischemia,",
"the",
"most",
"common",
"cerebrovascular",
"disease,",
"is",
"one",
"of",
"the",
"leading",
"causes",
"of",
"morbidity",
"and",
"mortality",
"around",
"the",
"world.",
"However,",
"many",
"details",
"of",
"the",
"pathogenesis",
"of",
"cerebral",
"ischemia",
"are",
"not",
"fully",
"known.",
"Cerebral",
"ischemia",
"is",
"a",
"condition",
"of",
"complex",
"pathology",
"that",
"includes",
"several",
"inflammatory",
"events,",
"such",
"as",
"aggregation",
"of",
"inflammatory",
"cells",
"and",
"upregula-",
"tion",
"of",
"cytokines.",
"Particularly,",
"accumulating",
"evidence",
"suggests",
"that",
"Toll-like",
"receptors",
"(TLRs)",
"are",
"important",
"mediators",
"of",
"cerebral",
"ischemic",
"injury.",
"Therefore,",
"under-",
"standing",
"TLRs",
"and",
"their",
"relationship",
"to",
"cerebrovascular",
"disease",
"is",
"becoming",
"increasingly",
"important",
"to",
"basic",
"and",
"clinical",
"scientists.",
"TLRs",
"are",
"key",
"receptors",
"in",
"the",
"mammalian",
"innate",
"immune",
"response",
"to",
"infectious",
"microorganisms,",
"but",
"are",
"*",
"Correspondence:",
"yangqwmlys@hotmail.com",
"†",
"Contributed",
"equally",
"1Department",
"of",
"Neurology,",
"Daping",
"Hospital,",
"Third",
"Military",
"Medical",
"University,",
"Changjiang",
"Branch",
"Road",
"No.",
"10,",
"Yuzhong",
"District,",
"Chongqing",
"400042,",
"PR",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"also",
"activated",
"by",
"host-derived",
"molecules.",
"The",
"associa-",
"tion",
"between",
"TLRs",
"and",
"the",
"activation",
"of",
"a",
"variety",
"of",
"downstream",
"inflammatory",
"cascades",
"has",
"been",
"established",
"in",
"cerebral",
"ischemia,",
"as",
"well",
"as",
"an",
"involvement",
"in",
"inflammatory",
"injury.",
"Additionally,",
"many",
"diverse",
"neuro-",
"protective",
"networks",
"may",
"redirect",
"TLR",
"signaling",
"as",
"one",
"mechanism",
"of",
"endogenous",
"protection.",
"The",
"purpose",
"of",
"this",
"review",
"is",
"to",
"(1)",
"summarize",
"cur-",
"rent",
"knowledge",
"on",
"TLR",
"signaling;",
"(2)",
"examine",
"the",
"evi-",
"dence",
"implicating",
"TLRs",
"in",
"cerebral",
"ischemia",
"injury,",
"(3)",
"outline",
"known",
"mechanisms",
"of",
"TLR-mediated",
"neuronal",
"damage,",
"and",
"(4)",
"summarize",
"the",
"information",
"on",
"other",
"molecules",
"involved",
"in",
"TLR",
"signaling.",
"The",
"latter",
"may",
"help",
"identify",
"potential",
"clinical",
"targets",
"for",
"preventing",
"TLR-mediated",
"cerebral",
"ischemic",
"injury.",
"The",
"innate",
"immune",
"response",
"in",
"the",
"central",
"nervous",
"system",
"(CNS)",
"It",
"was",
"initially",
"believed",
"that",
"innate",
"immunity",
"was",
"an",
"immunological",
"program",
"engaged",
"by",
"peripheral",
"organs",
"to",
"maintain",
"homeostasis",
"after",
"nonspecific",
"stress",
"and",
"©",
"2011",
"Wang",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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"Rehman",
"-",
"aamir.rehman@aku.edu;",
"Masood",
"Umer",
"-",
"masood.umer@aku.edu;",
"Yasir",
"J",
"Sepah*",
"-",
"jamalyasir@gmail.com;",
"Muhammad",
"A",
"Wajid",
"-",
"muhammad.wajid@aku.edu",
"*",
"Corresponding",
"author",
"Published:",
"5",
"December",
"2007",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2007,",
"1:171",
"doi:10.1186/1752-1947-1-171",
"Received:",
"17",
"May",
"2007",
"Accepted:",
"5",
"December",
"2007",
"This",
"article",
"is",
"available",
"from:",
"http://www.jmedicalcasereports.com/content/1/1/171",
"©",
"2007",
"Rehman",
"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:",
"With",
"increasing",
"prevalence",
"of",
"gunshot",
"injuries",
"we",
"are",
"seeing",
"more",
"patients",
"with",
"retained",
"bullet",
"fragments",
"lodged",
"in",
"their",
"bodies.",
"Embedded",
"lead",
"bullets",
"are",
"usually",
"considered",
"inert",
"after",
"their",
"kinetic",
"energy",
"has",
"dissipated",
"hence",
"these",
"are",
"not",
"removed",
"routinely.",
"However,",
"exposure",
"of",
"any",
"foreign",
"body",
"to",
"synovial",
"fluid",
"may",
"lead",
"to",
"rapid",
"degradation",
"and",
"hence",
"result",
"in",
"systemic",
"absorption,",
"causing",
"local",
"and",
"systemic",
"symptoms.",
"We",
"present",
"the",
"case",
"of",
"a",
"thirty",
"year",
"old",
"man",
"who",
"came",
"to",
"our",
"out",
"patient",
"department",
"with",
"a",
"history",
"of",
"progressive,",
"severe",
"hip",
"pain",
"ten",
"years",
"after",
"a",
"gun",
"shot",
"injury",
"to",
"his",
"right",
"hip.",
"Conclusion:",
"The",
"common",
"belief",
"that",
"intraarticular",
"bullets",
"should",
"not",
"be",
"removed",
"has",
"no",
"benefit",
"and",
"may",
"result",
"in",
"unwanted",
"long",
"term",
"complications.",
"Introduction",
"With",
"increasing",
"prevalence",
"of",
"gunshot",
"injuries",
"we",
"are",
"see-",
"ing",
"more",
"and",
"more",
"patients",
"with",
"retained",
"bullet",
"frag-",
"ments",
"lodged",
"in",
"their",
"bodies",
"[1].",
"Embedded",
"lead",
"particles",
"are",
"usually",
"considered",
"inert",
"after",
"their",
"kinetic",
"energy",
"has",
"dissipated",
"hence",
"these",
"are",
"not",
"removed",
"routinely.",
"Removal",
"is",
"indicated",
"if",
"they",
"impinge",
"on",
"vital",
"structures",
"or",
"are",
"easily",
"accessible",
"during",
"operation",
"for",
"other",
"reasons",
"[2-",
"5].",
"A",
"review",
"of",
"literature",
"shows",
"that",
"retained",
"intra-articu-",
"lar",
"bullets",
"have",
"been",
"associated",
"with",
"significant",
"morbidity",
"[6-9],",
"joint",
"degeneration",
"and",
"ultimately",
"resulting",
"in",
"joint",
"replacement.",
"Intra-articular",
"bullet",
"fragments",
"behave",
"differently",
"due",
"to",
"direct",
"contact",
"with",
"synovial",
"fluid.",
"Lead",
"being",
"soluble",
"in",
"synovial",
"fluid",
"[3,10]",
"can",
"cause",
"both",
"local",
"and",
"systemic",
"effects.",
"Lead",
"poisoning",
"from",
"retained",
"intra",
"articular",
"bul-",
"lets",
"has",
"been",
"recognized",
"in",
"the",
"literature",
"since",
"1867",
"[3,11-",
"13].",
"Although",
"in",
"most",
"of",
"the",
"cases",
"the",
"cause",
"of",
"arthropa-",
"thy",
"is",
"not",
"known",
"but",
"it's",
"attributed",
"mainly",
"to",
"mechanical",
"forces",
"along",
"with",
"local",
"effects",
"of",
"lead",
"poisoning",
"[3,4,6,7,10,14].",
"A",
"retained",
"bullet",
"can",
"not",
"only",
"produce",
"foreign",
"body",
"reaction,",
"mechanical",
"articular",
"cartilage",
"dam-",
"age",
"and",
"proliferative",
"synovitis,",
"leading",
"to",
"destructive",
"arthritis",
"but",
"can",
"also",
"lead",
"to",
"systemic",
"absorption",
"of",
"lead.",
"However,",
"there",
"is",
"considerable",
"variation",
"in",
"extent",
"of",
"lead",
"absorption,",
"onset",
"of",
"time",
"to",
"symptoms,",
"severity",
"of",
"symp-",
"toms",
"and",
"toxicity",
"[13].",
"Symptoms",
"of",
"systemic",
"lead",
"poi-",
"soning",
"are",
"usually",
"vague;",
"headache,",
"nausea,",
"fatigue",
"and",
"abdominal",
"pain",
"[15].",
"Page",
"1",
"of",
"4",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Epidemiology",
"1",
"London",
"School",
"of",
"Hygiene",
"&",
"Tropical",
"Medicine,",
"London,",
"UK;",
"2",
"National",
"Institute",
"for",
"Medical",
"Research",
"(NIMR),",
"Mwanza,",
"Tanzania;",
"3",
"African",
"Medical",
"and",
"Research",
"Foundation",
"(AMREF),",
"Mwanza,",
"Tanzania;",
"4",
"St",
"George’s",
"Hospital,",
"London,",
"UK",
"Correspondence",
"to:",
"Kathy",
"Baisley,",
"Department",
"of",
"Epidemiology",
"&",
"Population",
"Health,",
"Keppel",
"Street,",
"London,",
"WC1E",
"7HT,",
"UK;",
"kathy.baisley@",
"lshtm.ac.uk",
"Accepted",
"15",
"May",
"2009",
"Published",
"Online",
"First",
"26",
"May",
"2009",
"This",
"paper",
"is",
"freely",
"available",
"online",
"under",
"the",
"BMJ",
"Journals",
"unlocked",
"scheme,",
"see",
"http://",
"sti.bmj.com/info/unlocked.dtl",
"370",
"Bacterial",
"vaginosis",
"in",
"female",
"facility",
"workers",
"in",
"north-western",
"Tanzania:",
"prevalence",
"and",
"risk",
"factors",
"K",
"Baisley,1,2",
"J",
"Changalucha,2",
"H",
"A",
"Weiss,1",
"K",
"Mugeye,3",
"D",
"Everett,1,2",
"I",
"Hambleton,1,2",
"P",
"Hay,4",
"D",
"Ross,1",
"C",
"Tanton,1,2",
"T",
"Chirwa,1,2",
"R",
"Hayes,1",
"D",
"Watson-Jones1,3",
"ABSTRACT",
"Objectives:",
"To",
"determine",
"prevalence",
"of,",
"and",
"risk",
"factors",
"for,",
"bacterial",
"vaginosis",
"(BV)",
"among",
"herpes",
"simplex",
"virus",
"(HSV)",
"2",
"seropositive",
"Tanzanian",
"women",
"at",
"enrolment",
"into",
"a",
"randomised,",
"placebo-controlled",
"trial",
"of",
"HSV",
"suppressive",
"treatment.",
"Methods:",
"1305",
"HSV-2",
"seropositive",
"women",
"aged",
"16–35",
"years",
"working",
"in",
"bars,",
"guesthouses",
"and",
"similar",
"facilities",
"were",
"interviewed,",
"examined",
"and",
"tested",
"for",
"HIV,",
"syphilis,",
"Neisseria",
"gonorrhoeae,",
"Chlamydia",
"trachomatis,",
"BV,",
"candidiasis",
"and",
"trichomoniasis.",
"Factors",
"associated",
"with",
"BV",
"were",
"analysed",
"using",
"logistic",
"regression",
"to",
"estimate",
"odds",
"ratios",
"and",
"95%",
"confidence",
"intervals.",
"Results:",
"BV",
"prevalence",
"was",
"62.9%;",
"prevalence",
"of",
"Nugent",
"score",
"9–10",
"was",
"16.1%.",
"Independent",
"risk",
"factors",
"for",
"BV",
"were",
"work",
"facility",
"type,",
"fewer",
"dependents,",
"increasing",
"alcohol",
"consumption,",
"sex",
"in",
"the",
"last",
"week",
"(adjusted",
"OR",
"2.03;",
"95%",
"CI",
"1.57",
"to",
"2.62),",
"using",
"cloths",
"or",
"cotton",
"wool",
"for",
"menstrual",
"hygiene,",
"HIV",
"(adjusted",
"OR",
"1.41;",
"95%",
"CI",
"1.09",
"to",
"1.83)",
"and",
"Trichomonas",
"vaginalis",
"infection.",
"There",
"was",
"no",
"association",
"between",
"BV",
"and",
"the",
"frequency",
"or",
"method",
"of",
"vaginal",
"cleansing.",
"However,",
"BV",
"was",
"less",
"prevalent",
"among",
"women",
"who",
"reported",
"inserting",
"sub-",
"stances",
"to",
"dry",
"the",
"vagina",
"for",
"sex",
"(adjusted",
"OR",
"0.44;",
"95%",
"CI",
"0.25",
"to",
"0.75).",
"Conclusion:",
"BV",
"was",
"extremely",
"prevalent",
"among",
"our",
"study",
"population",
"of",
"HSV-2",
"positive",
"female",
"facility",
"workers",
"in",
"North-western",
"Tanzania.",
"Although",
"recent",
"sex",
"was",
"associated",
"with",
"increased",
"BV",
"prevalence,",
"vaginal",
"drying",
"was",
"associated",
"with",
"lower",
"BV",
"prevalence.",
"Further",
"studies",
"of",
"the",
"effects",
"of",
"specific",
"practices",
"on",
"vaginal",
"flora",
"are",
"warranted.",
"Bacterial",
"vaginosis",
"(BV)",
"is",
"one",
"of",
"the",
"most",
"common",
"vaginal",
"infections",
"worldwide.",
"It",
"is",
"char-",
"acterised",
"by",
"vaginal",
"flora",
"changes,",
"including",
"a",
"decrease",
"in",
"lactobacilli,",
"particularly",
"those",
"that",
"produce",
"hydrogen",
"peroxide,",
"and",
"an",
"increase",
"in",
"anaerobic",
"and",
"facultative",
"anaerobic",
"bacteria.",
"BV",
"has",
"been",
"associated",
"with",
"a",
"variety",
"of",
"adverse",
"health",
"outcomes,",
"including",
"preterm",
"delivery,1",
"intrauterine",
"infection,1",
"pelvic",
"inflammatory",
"disease",
"(PID)2",
"and",
"other",
"gynaecological",
"complications.3",
"BV",
"may",
"also",
"increase",
"susceptibility",
"to",
"HIV",
"and",
"other",
"sexually",
"transmitted",
"infections",
"(STIs),4–6",
"and",
"in",
"prospective",
"studies",
"BV",
"has",
"been",
"associated",
"with",
"the",
"acquisition",
"of",
"HIV",
"and",
"herpes",
"simplex",
"virus",
"(HSV)",
"type",
"2.7–11",
"BV",
"may",
"also",
"facilitate",
"HIV",
"and",
"HSV-2",
"transmission",
"by",
"increasing",
"the",
"frequency",
"of",
"genital",
"shedding",
"of",
"the",
"virus.12",
"The",
"aetiology",
"of",
"BV",
"remains",
"poorly",
"understood,",
"although",
"sexual",
"activity",
"and",
"vaginal",
"hygiene",
"practices",
"have",
"been",
"associated",
"with",
"BV.4",
"13–16",
"Reproductive",
"hormones",
"are",
"also",
"thought",
"to",
"play",
"a",
"role",
"in",
"the",
"regulation",
"of",
"vaginal",
"flora.17",
"18",
"In",
"sub-",
"Saharan",
"Africa,",
"the",
"prevalence",
"of",
"BV",
"is",
"very",
"high,",
"ranging",
"from",
"30–51%",
"in",
"community",
"based",
"stu-",
"dies.6",
"10",
"A",
"high",
"prevalence",
"has",
"also",
"been",
"reported",
"among",
"African–American",
"women",
"with",
"estimates",
"of",
"up",
"to",
"50%",
"in",
"population-based",
"surveys.19",
"The",
"reasons",
"for",
"this",
"are",
"unclear.",
"Prevention",
"of",
"BV,",
"and",
"any",
"impact",
"that",
"this",
"might",
"have",
"on",
"reducing",
"the",
"risk",
"of",
"HIV",
"acquisition,",
"will",
"depend",
"in",
"part",
"on",
"identification",
"of",
"risk",
"factors",
"for",
"BV",
"that",
"are",
"susceptible",
"to",
"interventions.",
"We",
"report",
"on",
"the",
"factors",
"associated",
"with",
"BV",
"prevalence",
"at",
"baseline",
"in",
"a",
"cohort",
"of",
"women",
"at",
"high",
"risk",
"of",
"STI",
"working",
"in",
"bars,",
"guesthouses",
"and",
"similar",
"facilities",
"in",
"Tanzania.",
"These",
"women",
"were",
"enrolled",
"into",
"a",
"trial",
"of",
"the",
"effect",
"of",
"HSV-2",
"suppressive",
"treatment",
"on",
"HIV",
"incidence,",
"and",
"on",
"genital",
"HIV",
"and",
"HSV-2",
"viral",
"shedding",
"in",
"women",
"who",
"are",
"HIV",
"positive.",
"MATERIALS",
"AND",
"METHODS",
"Study",
"population",
"A",
"randomised,",
"double-blind,",
"placebo-controlled",
"trial",
"of",
"acyclovir",
"400",
"mg",
"twice",
"daily",
"suppressive",
"treatment",
"was",
"conducted",
"in",
"women",
"HSV-2",
"seropositive",
"in",
"the",
"Lake",
"Victoria",
"region",
"of",
"Tanzania.",
"In",
"total,",
"1305",
"women",
"aged",
"16–35",
"years",
"working",
"in",
"bars,",
"guesthouses",
"and",
"similar",
"facilities",
"were",
"enrolled",
"in",
"three",
"phases",
"from",
"January",
"2004",
"to",
"May",
"2006.",
"Trial",
"procedures",
"have",
"been",
"described",
"previously.20",
"Screening,",
"enrolment",
"and",
"3-monthly",
"follow-up",
"visits",
"were",
"conducted",
"at",
"mobile",
"clinics",
"established",
"in",
"19",
"communities",
"in",
"high",
"HIV-",
"transmission",
"areas.",
"Women",
"were",
"followed",
"for",
"12–",
"30",
"months",
"depending",
"on",
"phase",
"of",
"enrolment.",
"At",
"screening,",
"after",
"informed",
"consent,",
"partici-",
"pants",
"were",
"tested",
"for",
"antibodies",
"to",
"HSV-2",
"and",
"HIV,",
"and",
"interviewed",
"about",
"sociodemographic",
"details,",
"sexual",
"behaviour",
"and",
"intravaginal",
"practices",
"(IVP).",
"Eligible",
"women",
"were",
"given",
"an",
"appointment",
"to",
"attend",
"the",
"mobile",
"clinic",
"8–12",
"weeks",
"later;",
"women",
"were",
"asked",
"to",
"avoid",
"vaginal",
"cleansing",
"before",
"attending",
"the",
"visit.",
"To",
"be",
"eligible,",
"women",
"had",
"to",
"be",
"HSV-2",
"seropositive,",
"have",
"no",
"history",
"of",
"epilepsy,",
"able",
"to",
"give",
"informed",
"consent,",
"not",
"planning",
"to",
"move",
"out",
"of",
"the",
"study",
"site,",
"not",
"breastfeeding",
"and",
"not",
"pregnant",
"or",
"planning",
"preg-",
"nancy",
"during",
"follow-up.",
"At",
"enrolment,",
"participants",
"were",
"tested",
"for",
"pregnancy",
"and",
"were",
"asked",
"about",
"recent",
"sexual",
"behaviour",
"and",
"IVP.",
"Women",
"were",
"examined",
"for",
"symptoms",
"of",
"reproductive",
"tract",
"infections",
"(RTI),",
"and",
"blood",
"and",
"genital",
"samples",
"were",
"collected.",
"Participants",
"were",
"offered",
"syndromic",
"management",
"Sex",
"Transm",
"Infect",
"2009;85:370–375.",
"doi:10.1136/sti.2008.035543"
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] | [
"BMC",
"Infectious",
"Diseases",
"Research",
"article",
"Geographic",
"distribution",
"and",
"genetic",
"diversity",
"of",
"the",
"Ehrlichia",
"sp.",
"from",
"Panola",
"Mountain",
"in",
"Amblyomma",
"americanum",
"Amanda",
"D",
"Loftis*1,9,",
"Tonya",
"R",
"Mixson1,",
"Ellen",
"Y",
"Stromdahl2,",
"Michael",
"J",
"Yabsley3,4,",
"Laurel",
"E",
"Garrison5,",
"Phillip",
"C",
"Williamson6,",
"Robert",
"R",
"Fitak7,",
"Paul",
"A",
"Fuerst7,",
"Daryl",
"J",
"Kelly7",
"and",
"Keith",
"W",
"Blount8",
"Address:",
"1Centers",
"for",
"Disease",
"Control",
"and",
"Prevention,",
"Atlanta,",
"GA",
"30333,",
"USA,",
"2U.S.",
"Army",
"Center",
"for",
"Health",
"Promotion",
"and",
"Preventive",
"Medicine,",
"Entomological",
"Sciences",
"Program,",
"Aberdeen",
"Proving",
"Ground,",
"MD",
"21010-5403,",
"USA,",
"3Daniel",
"B.",
"Warnell",
"School",
"of",
"Forestry",
"and",
"Natural",
"Resources,",
"University",
"of",
"Georgia,",
"Athens,",
"GA",
"30602,",
"USA,",
"4Southeastern",
"Cooperative",
"Wildlife",
"Disease",
"Study,",
"Department",
"of",
"Population",
"Health,",
"College",
"of",
"Veterinary",
"Medicine,",
"University",
"of",
"Georgia,",
"Athens,",
"GA",
"30602,",
"USA,",
"5Georgia",
"Division",
"of",
"Public",
"Health,",
"Atlanta,",
"GA",
"30303-3186,",
"USA,",
"6DNA/",
"Identity",
"Laboratory,",
"Department",
"of",
"Pathology",
"and",
"Human",
"Identification,",
"University",
"of",
"North",
"Texas",
"Health",
"Science",
"Center,",
"Ft.",
"Worth,",
"TX",
"76107-",
"2699,",
"USA,",
"7Department",
"of",
"Evolution,",
"Ecology",
"and",
"Organismal",
"Biology,",
"The",
"Ohio",
"State",
"University,",
"Columbus,",
"OH",
"43210-1293,",
"USA,",
"8Air",
"Force",
"Research",
"Laboratory,",
"Brooks",
"City-Base,",
"TX",
"78235,",
"USA",
"and",
"9266",
"N.",
"Lincoln",
"St.,",
"Laramie,",
"WY",
"82070,",
"USA",
"Email:",
"Amanda",
"D",
"Loftis*",
"-",
"adloftis@gmail.com;",
"Tonya",
"R",
"Mixson",
"-",
"zdy0@cdc.gov;",
"Ellen",
"Y",
"Stromdahl",
"-",
"ellen.stromdahl@us.army.mil;",
"Michael",
"J",
"Yabsley",
"-",
"myabsley@vet.uga.edu;",
"Laurel",
"E",
"Garrison",
"-",
"legarrison@dhr.state.ga.us;",
"Phillip",
"C",
"Williamson",
"-",
"phwilliam@hsc.unt.edu;",
"Robert",
"R",
"Fitak",
"-",
"fitak.2@osu.edu;",
"Paul",
"A",
"Fuerst",
"-",
"fuerst.1@osu.edu;",
"Daryl",
"J",
"Kelly",
"-",
"kelly.350@osu.edu;",
"Keith",
"W",
"Blount",
"-",
"keith.blount@brooks.af.mil",
"BioMed",
"Central",
"Open",
"Access",
"*",
"Corresponding",
"author",
"Published:",
"23",
"April",
"2008",
"BMC",
"Infectious",
"Diseases",
"2008,",
"8:54",
"doi:10.1186/1471-2334-8-54",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2334/8/54",
"Received:",
"9",
"November",
"2007",
"Accepted:",
"23",
"April",
"2008",
"©",
"2008",
"Loftis",
"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:",
"A",
"novel",
"Ehrlichia,",
"closely",
"related",
"to",
"Ehrlichia",
"ruminantium,",
"was",
"recently",
"discovered",
"from",
"Panola",
"Mountain",
"State",
"Park,",
"GA,",
"USA.",
"We",
"conducted",
"a",
"study",
"to",
"determine",
"if",
"this",
"agent",
"was",
"recently",
"introduced",
"into",
"the",
"United",
"States.",
"Methods:",
"We",
"developed",
"a",
"sensitive",
"PCR",
"assay",
"based",
"on",
"the",
"conserved",
"gltA",
"(citrate",
"synthase)",
"gene",
"and",
"tested",
"DNA",
"samples",
"extracted",
"from",
"1964",
"field-collected",
"and",
"1835",
"human-biting",
"Amblyomma",
"americanum",
"from",
"23",
"eastern",
"states",
"of",
"the",
"USA.",
"Results:",
"The",
"novel",
"agent",
"was",
"detected",
"in",
"36",
"ticks",
"collected",
"from",
"10",
"states",
"between",
"1998",
"and",
"2006.",
"Infected",
"ticks",
"were",
"collected",
"both",
"from",
"vegetation",
"(n",
"=",
"14,",
"0.7%)",
"and",
"from",
"humans",
"(n",
"=",
"22,",
"1.2%).",
"Fragments",
"of",
"the",
"conserved",
"gltA",
"gene",
"and",
"the",
"variable",
"map1",
"gene",
"were",
"sequenced",
"from",
"positive",
"samples.",
"Two",
"distinct",
"clades,",
"with",
"10.5%",
"nucleic",
"acid",
"divergence",
"over",
"the",
"730",
"bp",
"map1",
"sequence,",
"were",
"identified.",
"Conclusion:",
"These",
"data",
"suggest",
"that",
"the",
"Panola",
"Mountain",
"Ehrlichia",
"was",
"not",
"recently",
"introduced",
"to",
"the",
"United",
"States;",
"this",
"agent",
"has",
"an",
"extensive",
"distribution",
"throughout",
"the",
"range",
"of",
"its",
"tick",
"vector,",
"has",
"been",
"present",
"in",
"some",
"locations",
"for",
"several",
"years,",
"and",
"displays",
"genetic",
"variability.",
"Furthermore,",
"people",
"in",
"several",
"states",
"were",
"exposed",
"to",
"this",
"agent",
"through",
"the",
"bite",
"of",
"infected",
"ticks,",
"underscoring",
"the",
"potential",
"public",
"health",
"risk",
"of",
"this",
"emerging",
"ehrlichiosis.",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Erez",
"et",
"al.",
"BMC",
"Pregnancy",
"and",
"Childbirth",
"2012,",
"12:82",
"http://www.biomedcentral.com/1471-2393/12/82",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Early",
"preterm",
"delivery",
"due",
"to",
"placenta",
"previa",
"is",
"an",
"independent",
"risk",
"factor",
"for",
"a",
"subsequent",
"spontaneous",
"preterm",
"birth",
"Offer",
"Erez1*,",
"Lena",
"Novack2,",
"Vered",
"Klaitman1,",
"Idit",
"Erez-Weiss3,",
"Ruthy",
"Beer-Weisel1,",
"Doron",
"Dukler1",
"and",
"Moshe",
"Mazor1",
"Abstract",
"Background:",
"To",
"determine",
"whether",
"patients",
"with",
"placenta",
"previa",
"who",
"delivered",
"preterm",
"have",
"an",
"increased",
"risk",
"for",
"recurrent",
"spontaneous",
"preterm",
"birth.",
"Methods:",
"This",
"retrospective",
"population",
"based",
"cohort",
"study",
"included",
"patients",
"who",
"delivered",
"after",
"a",
"primary",
"cesarean",
"section",
"(n",
"=",
"9983).",
"The",
"rate",
"of",
"placenta",
"previa,",
"its",
"recurrence,",
"and",
"the",
"risk",
"for",
"recurrent",
"preterm",
"birth",
"were",
"determined.",
"Results:",
"Patients",
"who",
"had",
"a",
"placenta",
"previa",
"at",
"the",
"primary",
"CS",
"pregnancy",
"had",
"an",
"increased",
"risk",
"for",
"its",
"recurrence",
"[crude",
"OR",
"of",
"2.65",
"(95%",
"CI",
"1.3-5.5)].",
"The",
"rate",
"of",
"preterm",
"birth",
"in",
"patients",
"with",
"placenta",
"previa",
"in",
"the",
"primary",
"CS",
"pregnancy",
"was",
"55.9%;",
"and",
"these",
"patients",
"had",
"a",
"higher",
"rate",
"of",
"recurrent",
"preterm",
"delivery",
"than",
"the",
"rest",
"of",
"the",
"study",
"population",
"(p",
"<",
".001).",
"Among",
"patients",
"with",
"placenta",
"previa",
"in",
"the",
"primary",
"CS",
"pregnancy,",
"those",
"who",
"delivered",
"preterm",
"had",
"a",
"higher",
"rate",
"of",
"recurrent",
"spontaneous",
"preterm",
"birth",
"regardless",
"of",
"the",
"location",
"of",
"their",
"placenta",
"in",
"the",
"subsequent",
"delivery",
"[OR",
"3.09",
"(95%",
"CI",
"2.1-4.6)].",
"In",
"comparison",
"to",
"all",
"patients",
"with",
"who",
"had",
"a",
"primary",
"cesarean",
"section,",
"patients",
"who",
"had",
"placenta",
"previa",
"and",
"delivered",
"preterm",
"had",
"an",
"independent",
"increased",
"risk",
"for",
"recurrent",
"preterm",
"birth",
"[OR",
"of",
"3.6",
"(95%",
"CI",
"1.5-8.5)].",
"Conclusions:",
"Women",
"with",
"placenta",
"previa,",
"who",
"deliver",
"preterm,",
"especially",
"before",
"34",
"weeks",
"of",
"gestation,",
"are",
"at",
"increased",
"risk",
"for",
"recurrent",
"spontaneous",
"preterm",
"birth",
"regardless",
"to",
"the",
"site",
"of",
"placental",
"implantation",
"in",
"the",
"subsequent",
"pregnancy.",
"Thus,",
"strict",
"follow",
"up",
"by",
"high",
"risk",
"pregnancies",
"specialist",
"is",
"recommended.",
"Keywords:",
"Preterm",
"birth,",
"Placenta,",
"Recurrent",
"preterm",
"delivery,",
"Vaginal",
"bleeding,",
"Short",
"cervix,",
"Placenta",
"previa",
"Background",
"Placenta",
"previa",
"is",
"a",
"risk",
"factor",
"for",
"preterm",
"birth,",
"and",
"contributes",
"to",
"about",
"5%",
"of",
"all",
"preterm",
"deliveries.",
"[1]",
"The",
"prevalence",
"of",
"placenta",
"previa",
"is",
"0.3-0.5%",
"of",
"pregnancies",
"[2-10],",
"and",
"the",
"risk",
"for",
"this",
"complication",
"increases",
"according",
"to",
"the",
"number",
"of",
"prior",
"cesarean",
"deliveries",
"[11-14].",
"Placenta",
"previa",
"is",
"associated",
"with",
"an",
"increased",
"maternal",
"morbidity",
"including",
"the",
"need",
"for",
"blood",
"and",
"blood",
"products",
"transfusion,",
"urgent",
"cesarean",
"section,",
"and",
"cesarean",
"hysterectomy.",
"Moreover,",
"a",
"higher",
"rate",
"of",
"peri-",
"natal",
"mortality",
"and",
"morbidity,",
"especially",
"respiratory",
"*",
"Correspondence:",
"erezof@bgu.ac.il",
"1Department",
"of",
"Obstetrics",
"and",
"Gynecology,",
"Soroka",
"University",
"Medical",
"Center,",
"School",
"of",
"Medicine,",
"Faculty",
"of",
"Health",
"Sciences,",
"Ben",
"Gurion",
"University",
"of",
"the",
"Negev,",
"P",
"O",
"Box",
"151,",
"Beer",
"Sheva",
"84101,",
"Israel",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"distress",
"syndrome",
"and",
"anemia",
"are",
"associated",
"with",
"this",
"abnormal",
"placentation",
"[15,16].",
"Most",
"of",
"the",
"patients",
"with",
"placenta",
"previa",
"are",
"delivered",
"preterm",
"[4,17],",
"and",
"these",
"deliveries",
"are",
"regarded",
"as",
"indi-",
"cated",
"preterm",
"births",
"due",
"to",
"excessive",
"maternal",
"hemorrhage.",
"Nevertheless,",
"recent",
"evidence",
"suggests",
"that",
"other",
"mechanisms",
"aside",
"bleeding",
"may",
"lead",
"to",
"preterm",
"birth",
"in",
"women",
"with",
"placenta",
"previa",
"[18,19].",
"Patients",
"with",
"placenta",
"previa",
"who",
"delivered",
"preterm",
"had",
"a",
"higher",
"rate",
"of",
"intra-amniotic",
"infection/inflammation",
"than",
"those",
"who",
"delivered",
"at",
"term",
"[18],",
"suggesting",
"that",
"similarly",
"to",
"spontaneous",
"preterm",
"birth,",
"intra-amniotic",
"infection",
"or",
"inflammation",
"may",
"contribute",
"to",
"the",
"process",
"of",
"preterm",
"parturition",
"in",
"patients",
"with",
"placenta",
"previa.",
"Moreover,",
"women",
"with",
"this",
"complication",
"who",
"had",
"a",
"short",
"cervical",
"length",
"have",
"an",
"increased",
"risk",
"to",
"deliver",
"preterm",
"[20-22].",
"©",
"2012",
"Erez",
"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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] | [
"Hindawi",
"Publishing",
"Corporation",
"Journal",
"of",
"Biomedicine",
"and",
"Biotechnology",
"Volume",
"2012,",
"Article",
"ID",
"274150,",
"8",
"pages",
"doi:10.1155/2012/274150",
"Review",
"Article",
"Are",
"Basophils",
"Important",
"Mediators",
"for",
"Helminth-Induced",
"Th2",
"Immune",
"Responses?",
"A",
"Debate",
"Sonia",
"Leon-Cabrera",
"and",
"Ana",
"Flisser",
"Departamento",
"de",
"Microbiolog´ıa",
"y",
"Parasitolog´ıa,",
"Facultad",
"de",
"Medicina,",
"Universidad",
"Nacional",
"Auto´noma",
"de",
"M´exico,",
"04510",
"M´exico,",
"DF,",
"Mexico",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Ana",
"Flisser,",
"flisser@unam.mx",
"Received",
"27",
"May",
"2011;",
"Accepted",
"8",
"December",
"2011",
"Academic",
"Editor:",
"Abhay",
"R.",
"Satoskar",
"Copyright",
"©",
"2012",
"S.",
"Leon-Cabrera",
"and",
"A.",
"Flisser.",
"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.",
"Helminth",
"parasites",
"induce",
"Th2",
"immune",
"responses.",
"Immunological",
"mechanisms",
"leading",
"to",
"Th2",
"induction",
"are",
"mainly",
"dependent",
"on",
"IL-4.",
"However,",
"early",
"source",
"of",
"IL-4",
"has",
"not",
"been",
"precisely",
"identified.",
"Noticeably,",
"basophils",
"seem",
"to",
"be",
"important",
"mediators",
"for",
"inducing",
"and",
"maintaining",
"the",
"Th2",
"response",
"probably",
"because",
"they",
"secrete",
"IL-4",
"and",
"exert",
"functions",
"similar",
"to",
"APCs.",
"Nevertheless,",
"recent",
"experimental",
"evidence",
"points",
"that",
"DCs",
"could",
"be",
"also",
"significant",
"participants",
"during",
"this",
"process.",
"The",
"involvement",
"of",
"basophils",
"during",
"memory",
"responses",
"is",
"also",
"discussed.",
"1.",
"Introduction",
"Intestinal",
"helminth",
"infections",
"still",
"represent",
"a",
"public",
"health",
"problem",
"in",
"many",
"developing",
"tropical",
"and",
"subtropical",
"coun-",
"tries",
"affecting",
"the",
"health",
"of",
"human",
"beings",
"and",
"of",
"livestock",
"[1,",
"2].",
"CD4+",
"T",
"cells",
"are",
"the",
"main",
"cellular",
"mediators",
"in",
"host",
"helminth",
"interactions.",
"In",
"response",
"to",
"different",
"antigens,",
"these",
"cells",
"differentiate",
"in",
"four",
"types",
"of",
"T-helper",
"cells",
"Th1,",
"Th2,",
"Th17,",
"and",
"regulatory",
"T",
"cells.",
"Helminths",
"and",
"their",
"anti-",
"gens",
"induce",
"Th2",
"immune",
"responses,",
"and",
"protection",
"against",
"these",
"parasites",
"seems",
"to",
"be",
"dependent",
"on",
"this",
"polarization.",
"Th2-cells",
"secrete",
"type",
"2",
"cytokines",
"such",
"as",
"interleukin-4",
"(IL-4),",
"IL-5,",
"IL-9,",
"IL-13,",
"but",
"non-T",
"cells",
"including",
"basophils,",
"mast",
"cells,",
"B",
"cells,",
"and",
"eosinophils",
"can",
"also",
"produce",
"them.",
"The",
"initial",
"priming",
"for",
"Th2",
"differentiation",
"is",
"dependent",
"on",
"the",
"IL-4",
"receptor",
"α",
"chain",
"(IL-4R)",
"and",
"transcription",
"factors",
"STAT6",
"and",
"GATA3,",
"as",
"well",
"as",
"processing",
"and",
"presenting",
"anti-",
"gens",
"from",
"antigen",
"presenting",
"cells",
"(APCs)",
"and",
"upregulation",
"of",
"costimulatory",
"molecules",
"[3].",
"A",
"type",
"2",
"immune",
"response",
"is",
"characterized",
"by",
"activation",
"and",
"expansion",
"of",
"CD4+",
"Th2-",
"cells,",
"mucosal",
"epithelial",
"cells,",
"eosinophils,",
"basophils,",
"produc-",
"tion",
"of",
"immunoglobulin",
"E",
"(IgE)",
"and",
"mast",
"cell,",
"and",
"goblet",
"cell",
"hyperplasia",
"[4].",
"Moreover,",
"basophils",
"and",
"mast",
"cells",
"are",
"activated",
"by",
"IgE-immune",
"complexes",
"through",
"crosslinked-",
"high-affinity",
"Fc",
"receptors",
"(FcRs)",
"for",
"IgE",
"located",
"on",
"the",
"cell",
"surface.",
"Then,",
"these",
"cells",
"are",
"able",
"to",
"degranulate",
"and",
"release",
"cytokines,",
"chemokines,",
"proteases,",
"serotonin,",
"histamine,",
"and",
"heparin,",
"resulting",
"in",
"smooth",
"muscle",
"hypercontractibility,",
"in-",
"creased",
"permeability,",
"and",
"inflammatory",
"cell",
"recruitment",
"that,",
"accompanied",
"by",
"mucus",
"production,",
"will",
"facilitate",
"clear-",
"ance",
"of",
"parasites",
"(Figure",
"1).",
"Basic",
"aspects",
"about",
"activation",
"of",
"Th1-",
"and",
"Th17-type",
"immune",
"responses",
"are",
"well",
"characterized.",
"Nevertheless,",
"the",
"immunological",
"mechanisms",
"leading",
"towards",
"induction",
"of",
"Th2",
"immune",
"responses",
"remain",
"to",
"be",
"elucidated.",
"Early",
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"[3].",
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"secreting",
"IL-4",
"in",
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"helminth",
"antigens",
"and",
"by",
"crosslinking",
"of",
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"IgE",
"complex-",
"es.",
"Furthermore,",
"it",
"has",
"been",
"suggested",
"the",
"possible",
"role",
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"APCs,",
"since",
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"constitutively",
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"MHC-",
"class-II,",
"costimulatory",
"molecules",
"such",
"as",
"CD40,",
"CD80,",
"and",
"CD86,",
"and",
"the",
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"receptor",
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"[6–8]."
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] | [
"JCB",
"Report",
"A",
"novel",
"Apaf-1–independent",
"putative",
"caspase-2",
"activation",
"complex",
"Stuart",
"H.",
"Read,1",
"Belinda",
"C.",
"Baliga,1",
"Paul",
"G.",
"Ekert,2",
"David",
"L.",
"Vaux,2",
"and",
"Sharad",
"Kumar1,3",
"1Hanson",
"Institute,",
"Frome",
"Road,",
"Adelaide,",
"Australia",
"5000",
"2Walter",
"and",
"Eliza",
"Hall",
"Institute",
"of",
"Medical",
"Research,",
"Melbourne,",
"Australia",
"3050",
"3Department",
"of",
"Medicine,",
"Adelaide",
"University,",
"Adelaide,",
"Australia",
"5005",
"C",
"tion.",
"In",
"stress-induced",
"apoptosis,",
"the",
"mitochondrial",
"aspase",
"activation",
"is",
"a",
"key",
"event",
"in",
"apoptosis",
"execu-",
"pathway",
"of",
"caspase",
"activation",
"is",
"believed",
"to",
"be",
"of",
"central",
"importance.",
"In",
"this",
"pathway,",
"cytochrome",
"c",
"released",
"from",
"mitochondria",
"facilitates",
"the",
"formation",
"of",
"an",
"Apaf-1",
"apoptosome",
"that",
"recruits",
"and",
"activates",
"caspase-9.",
"Recent",
"data",
"indicate",
"that",
"in",
"some",
"cells",
"caspase-9",
"may",
"not",
"be",
"the",
"initiator",
"caspase",
"in",
"stress-mediated",
"apoptosis",
"because",
"caspase-2",
"is",
"required",
"upstream",
"of",
"mitochondria",
"for",
"the",
"release",
"of",
"cytochrome",
"c",
"and",
"other",
"apoptogenic",
"factors.",
"To",
"determine",
"how",
"caspase-2",
"is",
"activated,",
"we",
"have",
"studied",
"the",
"formation",
"of",
"a",
"complex",
"that",
"mediates",
"caspase-2",
"activation.",
"Using",
"gel",
"filtration",
"analysis",
"of",
"cell",
"lysates,",
"we",
"show",
"that",
"caspase-2",
"is",
"spontaneously",
"recruited",
"to",
"a",
"large",
"protein",
"complex",
"independent",
"of",
"cytochrome",
"c",
"and",
"Apaf-1",
"and",
"that",
"recruitment",
"of",
"caspase-2",
"to",
"this",
"complex",
"is",
"sufficient",
"to",
"mediate",
"its",
"activation.",
"Using",
"substrate-binding",
"assays,",
"we",
"also",
"provide",
"the",
"first",
"evidence",
"that",
"caspase-2",
"activation",
"may",
"occur",
"without",
"processing",
"of",
"the",
"precursor",
"molecule.",
"Our",
"data",
"are",
"consistent",
"with",
"a",
"model",
"where",
"caspase-2",
"activation",
"occurs",
"by",
"oligomerization,",
"independent",
"of",
"the",
"Apaf-1",
"apoptosome.",
"Introduction",
"The",
"execution",
"of",
"apoptosis",
"is",
"performed",
"by",
"a",
"family",
"of",
"cysteine",
"proteases",
"known",
"as",
"caspases",
"(for",
"review",
"see",
"Nicholson,",
"1999).",
"Caspases",
"are",
"present",
"as",
"zymogens",
"in",
"most",
"animal",
"cells",
"and",
"are",
"activated",
"in",
"response",
"to",
"apoptotic",
"signals.",
"The",
"apoptotic",
"signals",
"first",
"lead",
"to",
"the",
"activation",
"of",
"so",
"called",
"“initiator",
"caspases,”",
"such",
"as",
"caspase-8",
"and",
"caspase-9.",
"These",
"caspases",
"contain",
"specific",
"protein–protein",
"interaction",
"domains",
"in",
"their",
"NH2",
"termini",
"that",
"allow",
"them",
"to",
"be",
"recruited",
"to",
"death-signaling",
"complexes",
"promoting",
"their",
"activation",
"by",
"an",
"autocatalytic",
"mechanism",
"(for",
"review",
"see",
"Kumar,",
"1999).",
"Once",
"the",
"initiator",
"caspases",
"are",
"activated,",
"they",
"process",
"and",
"activate",
"downstream",
"effector",
"caspases,",
"such",
"as",
"caspase-3,",
"-6",
"and",
"-7,",
"which",
"are",
"responsible",
"for",
"the",
"cleavage",
"of",
"several",
"proteins",
"in",
"dying",
"cells",
"(Nicholson,",
"1999).",
"In",
"mammals,",
"there",
"are",
"two",
"main",
"caspase",
"activation",
"pathways:",
"the",
"death",
"receptor",
"pathway",
"and",
"the",
"mitochondrial",
"pathway",
"(Kumar,",
"1999;",
"Nicholson,",
"1999).",
"In",
"the",
"first",
"pathway,",
"TNF",
"Address",
"correspondence",
"to",
"Sharad",
"Kumar,",
"Hanson",
"Institute,",
"P.O.",
"Box",
"14,",
"Rundle",
"Mall,",
"Adelaide,",
"Australia",
"5000.",
"Tel.:",
"61-8-8222-3738.",
"Fax:",
"61-8-8222-3139.",
"E-mail:",
"sharad.kumar@imvs.sa.gov.au",
"*Abbreviations",
"used",
"in",
"this",
"paper:",
"CARD,",
"caspase",
"recruitment",
"domain;",
"DISC,",
"death-inducing",
"signaling",
"complex;",
"FADD,",
"Fas-associated",
"protein",
"with",
"death",
"domain.",
"Key",
"words:",
"apoptosis;",
"caspase",
"activation;",
"apoptosome;",
"caspase-9;",
"initiator",
"caspase",
"",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2002/12/739/7",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"159,",
"Number",
"5,",
"December",
"9,",
"2002",
"739–745",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200209004",
"receptor",
"family",
"members",
"recruit",
"Fas-associated",
"protein",
"with",
"death",
"domain",
"(FADD),*",
"an",
"adaptor",
"molecule",
"that",
"in",
"turn",
"recruits",
"caspase-8",
"to",
"the",
"death-inducing",
"signaling",
"complex",
"(DISC).",
"Recruitment",
"of",
"caspase-8",
"to",
"DISC",
"results",
"in",
"its",
"activation.",
"The",
"mitochondrial",
"pathway",
"of",
"caspase",
"activation",
"is",
"regulated",
"by",
"the",
"Bcl-2",
"family",
"of",
"proteins",
"and",
"involves",
"cyto-",
"chrome",
"c",
"and",
"Apaf-1–mediated",
"activation",
"of",
"caspase-9.",
"During",
"stress",
"signaling,",
"cytochrome",
"c",
"released",
"from",
"mito-",
"chondria",
"binds",
"Apaf-1,",
"resulting",
"in",
"a",
"conformational",
"change",
"that",
"facilitates",
"oligomerization",
"of",
"Apaf-1",
"into",
"an",
"apoptosome",
"and",
"subsequent",
"caspase",
"recruitment",
"domain",
"(CARD)–mediated",
"recruitment",
"and",
"activation",
"of",
"caspase-9",
"(Acehan",
"et",
"al.,",
"2002).",
"Interestingly,",
"initiator",
"caspase",
"DRONC",
"activation",
"in",
"Drosophila",
"cells",
"does",
"not",
"seem",
"to",
"require",
"release",
"of",
"cytochrome",
"c",
"from",
"mitochondria",
"(Dorstyn",
"et",
"al.,",
"2002).",
"Although",
"caspase-9",
"is",
"generally",
"believed",
"to",
"be",
"the",
"initiator",
"caspase",
"in",
"stress-induced",
"apoptosis,",
"recent",
"studies",
"suggest",
"that",
"caspase-2",
"can",
"act",
"upstream",
"of",
"mitochondria",
"(Lassus",
"et",
"al.,",
"2002;",
"Robertson",
"et",
"al.,",
"2002).",
"The",
"new",
"findings",
"indicate",
"that",
"caspase-2",
"is",
"the",
"initiator",
"caspase",
"in",
"stress-induced",
"apoptosis,",
"whereas",
"apoptosome",
"mediated",
"caspase-9,",
"and",
"subsequently",
"caspase-3,",
"activation",
"may",
"mainly",
"serve",
"as",
"an",
"amplification",
"loop",
"(Kumar",
"and",
"Vaux,",
"2002).",
"Caspase-2,",
"the",
"first",
"discovered",
"apoptotic",
"mammalian",
"caspase,",
"has",
"been",
"implicated",
"in",
"a",
"variety",
"of",
"cell",
"death",
"pathways,",
"and",
"consistent",
"with",
"an",
"initiator",
"role",
"it",
"is",
"activated",
"rapidly",
"in",
"response",
"to",
"diverse",
"death",
"stimuli",
"(Kumar",
"et",
"739"
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] | [
"Iranian",
"J",
"Publ",
"Health,",
"Vol.",
"40,",
"No.4,",
"2011,",
"pp.89-98",
"Original",
"Article",
"Physical",
"Activity,",
"Nutrition,",
"and",
"Dyslipidemia",
"in",
"Middle-Aged",
"Women",
"MA",
"Delavar",
"1,",
"*MS",
"Lye",
"2,",
"STBS",
"Hassan",
"2,",
"GL",
"Khor",
"3,",
"P",
"Hanachi4",
"1Fatemezahra",
"Infertility",
"and",
"Reproductive",
"Health",
"Research",
"Center,",
"Department",
"of",
"Midwifery,",
"Babol",
"University",
"of",
"Medical",
"Sciences,",
"Babol,",
"Iran",
"2Dept.",
"of",
"Community",
"Health,",
"Faculty",
"of",
"Medicine",
"and",
"Health",
"Sciences,",
"Universiti",
"Putra",
"Malaysia",
"3School",
"of",
"Pharmacy",
"and",
"Health",
"Sciences,",
"International",
"Medical",
"University,",
"Malaysia",
"4Dept.",
"of",
"Women",
"Research,",
"Alzahra",
"University,",
"Tehran,",
"Iran",
"(Received",
"28",
"Mar",
"2011;",
"accepted",
"12",
"Oct",
"2011)",
"Abstract",
"Background:",
"Cardiovascular",
"disease",
"is",
"a",
"major",
"cause",
"of",
"death",
"throughout",
"the",
"world.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"as-",
"sess",
"the",
"prevalence",
"of",
"overweight/obesity,",
"central",
"obesity,",
"hypertension",
"and",
"dyslipidemia,",
"as",
"well",
"as",
"dietary",
"factors",
"contributing",
"to",
"the",
"development",
"of",
"dyslipidemia",
"among",
"middle-aged",
"women.",
"Methods:",
"The",
"research",
"design",
"of",
"the",
"present",
"study",
"was",
"a",
"population-based",
"cross-sectional",
"study;",
"anthropometric",
"meas-",
"ures",
"and",
"blood",
"chemistry",
"were",
"obtained.",
"Physical",
"activity",
"was",
"measured",
"using",
"the",
"original",
"International",
"Physical",
"Activity",
"Questionnaires",
"Long",
"Form",
"while",
"food",
"frequency",
"questionnaire",
"(FFQ)",
"was",
"used",
"in",
"assessing",
"individual’s",
"habit-",
"ual",
"intake.",
"Overall,",
"809",
"women,",
"30-50",
"years",
"of",
"age",
"from",
"fourteen",
"active",
"urban",
"Primary",
"Healthcare",
"Centers",
"(PHC)",
"in",
"Babol",
"City,",
"northern",
"Iran,",
"were",
"obtained",
"from",
"1,905",
"households",
"across",
"operational",
"areas",
"of",
"14",
"PHC",
"using",
"systematic",
"random",
"sampling",
"method.",
"Results:",
"The",
"prevalence",
"rates",
"of",
"women",
"classified",
"as",
"overweight/obese,",
"with",
"central",
"obesity,",
"hypertension",
"and",
"dyslip-",
"idemia",
"were",
"82.8%,",
"75.5%,",
"14.6%",
"and",
"63.4%,",
"respectively.",
"Total",
"physical",
"activity",
"did",
"not",
"correlate",
"with",
"cholesterol",
"ratio.",
"Soybean",
"protein",
"was",
"inversely",
"associated",
"with",
"cholesterol",
"ratio",
"(rho=-0.18,",
"P≤",
"0.001).",
"The",
"adjusted",
"OR",
"for",
"dyslipidemia",
"in",
"women",
"with",
"moderate",
"protein",
"intake",
"was",
"significantly",
"higher",
"than",
"in",
"women",
"with",
"high",
"and",
"low",
"intake",
"(OR=2.31;",
"95%",
"CI=",
"1.61,",
"3.30).",
"No",
"significant",
"associations",
"were",
"found",
"between",
"dyslipidemia",
"and",
"carbohydrate,",
"fat",
"intake",
"or",
"physical",
"activity.",
"Conclusion:",
"This",
"study",
"showed",
"very",
"high",
"prevalence",
"of",
"cardiovascular",
"disease",
"risk",
"factors",
"among",
"Iranian",
"middle-aged",
"women.",
"A",
"more",
"detailed",
"study",
"is",
"suggested",
"to",
"develop",
"definitively",
"recommendations",
"for",
"the",
"primary",
"and",
"secondary",
"prevention",
"of",
"cardiovascular",
"disease",
"for",
"the",
"Iranian",
"population.",
"Keywords:",
"Nutrition,",
"Physical",
"activity,",
"Dyslipidemia,",
"Women's",
"health",
"Introduction",
"Cardiovascular",
"disease",
"is",
"recognized",
"as",
"the",
"most",
"common",
"cause",
"of",
"death",
"worldwide",
"(1).",
"Over-",
"weight/obesity,",
"hypertension,",
"dyslipidemia,",
"and",
"other",
"manifestations",
"are",
"major",
"risk",
"factors",
"(2).",
"Improved",
"long-term",
"outcomes",
"have",
"been",
"at-",
"tained",
"as",
"a",
"result",
"of",
"physicians'",
"recommendations",
"for",
"dietary",
"practices",
"and",
"physical",
"activity",
"that",
"lead",
"to",
"several",
"favorable",
"parameters",
"such",
"as",
"a",
"healthier",
"waist",
"circumference",
"and",
"improved",
"body",
"mass",
"index,",
"lower",
"blood",
"pressure,",
"improved",
"HDL-",
"cholesterol,",
"and",
"triglyceride",
"levels",
"(3).",
"HDL-",
"cholesterol",
"is",
"protective",
"against",
"cardiovascular",
"disease",
"and",
"decreases",
"cardiovascular",
"morbidity",
"and",
"mortality",
"(4).",
"A",
"meta-analysis",
"has",
"shown",
"*Corresponding",
"Author:",
"Tel:",
"+60",
"3",
"89472410,",
"Fax:",
"+60",
"3",
"8945",
"0151,",
"E-mail",
"address:lyems9@yahoo.com",
"Published",
"by",
"Tehran",
"University",
"of",
"Medical",
"Sciences",
"(www.tums.ac.ir)"
] | [
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634,
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21,
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659,
859,
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673,
859,
47,
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723,
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427,
876,
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461,
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511,
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526,
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584,
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427,
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479,
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556,
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606,
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626,
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668,
893,
58,
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730,
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745,
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427,
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461,
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] | [
"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",
"Bub1",
"overexpression",
"induces",
"aneuploidy",
"and",
"tumor",
"formation",
"through",
"Aurora",
"B",
"kinase",
"hyperactivation",
"Robin",
"M.",
"Ricke,1",
"Karthik",
"B.",
"Jeganathan,1",
"and",
"Jan",
"M.",
"van",
"Deursen1,2",
"1Department",
"of",
"Pediatric",
"and",
"Adolescent",
"Medicine,",
"2Biochemistry",
"and",
"Molecular",
"Biology,",
"Mayo",
"Clinic,",
"Rochester,",
"MN",
"55905",
"H",
"been",
"observed",
"in",
"a",
"variety",
"of",
"human",
"tumors",
"and",
"igh",
"expression",
"of",
"the",
"protein",
"kinase",
"Bub1",
"has",
"often",
"correlates",
"with",
"poor",
"clinical",
"prognosis,",
"but",
"its",
"molecular",
"and",
"cellular",
"consequences",
"and",
"role",
"in",
"tu-",
"morigenesis",
"are",
"unknown.",
"Here,",
"we",
"demonstrate",
"that",
"overexpression",
"of",
"Bub1",
"in",
"mice",
"leads",
"to",
"near-diploid",
"an-",
"euploidies",
"and",
"tumor",
"formation.",
"We",
"found",
"that",
"chromo-",
"some",
"misalignment",
"and",
"lagging",
"are",
"the",
"primary",
"mitotic",
"errors",
"responsible",
"for",
"the",
"observed",
"aneuploidization.",
"High",
"Bub1",
"levels",
"resulted",
"in",
"aberrant",
"Bub1",
"kinase",
"activity",
"and",
"hyperactivation",
"of",
"Aurora",
"B",
"kinase.",
"When",
"Aurora",
"B",
"activity",
"is",
"suppressed,",
"pharmacologically",
"or",
"via",
"BubR1",
"overexpression,",
"chromosome",
"segregation",
"errors",
"caused",
"by",
"Bub1",
"overexpression",
"are",
"largely",
"corrected.",
"Impor-",
"tantly,",
"Bub1",
"transgenic",
"mice",
"overexpressing",
"Bub1",
"devel-",
"oped",
"various",
"kinds",
"of",
"spontaneous",
"tumors",
"and",
"showed",
"accelerated",
"Myc-induced",
"lymphomagenesis.",
"Our",
"results",
"establish",
"that",
"Bub1",
"has",
"oncogenic",
"properties",
"and",
"suggest",
"that",
"Aurora",
"B",
"is",
"a",
"critical",
"target",
"through",
"which",
"over-",
"expressed",
"Bub1",
"drives",
"aneuploidization",
"and",
"tumorigenesis.",
"Introduction",
"During",
"M",
"phase,",
"replicated",
"chromosomes",
"are",
"evenly",
"distributed",
"into",
"daughter",
"cells.",
"Inaccurate",
"chromosome",
"segregation",
"can",
"re-",
"sult",
"in",
"the",
"loss",
"or",
"gain",
"of",
"whole",
"chromosomes,",
"a",
"status",
"referred",
"to",
"as",
"aneuploidy",
"(Ricke",
"et",
"al.,",
"2008).",
"Aneuploidy",
"is",
"observed",
"in",
"80–90%",
"of",
"human",
"cancers",
"and",
"associated",
"with",
"poor",
"clinical",
"outcome,",
"but",
"its",
"role",
"in",
"malignant",
"cell",
"transformation",
"remains",
"ambiguous",
"(Holland",
"and",
"Cleveland,",
"2009;",
"Schvartzman",
"et",
"al.,",
"2010).",
"To",
"ensure",
"faithful",
"chromosome",
"segregation,",
"eukaryotic",
"cells",
"have",
"developed",
"a",
"surveillance",
"system,",
"the",
"mitotic",
"checkpoint,",
"which",
"delays",
"anaphase",
"onset",
"until",
"all",
"kinetochores",
"are",
"properly",
"attached",
"to",
"microtubules",
"emanating",
"from",
"opposite",
"spindle",
"poles",
"(Nezi",
"and",
"Musacchio,",
"2009).",
"One",
"of",
"the",
"core",
"components",
"of",
"this",
"checkpoint",
"is",
"Bub1",
"(Roberts",
"et",
"al.,",
"1994;",
"Taylor",
"and",
"McKeon,",
"1997).",
"In",
"prophase,",
"this",
"serine/threonine",
"protein",
"kinase",
"accumulates",
"at",
"unattached",
"kinetochores",
"where",
"it",
"mediates",
"the",
"recruitment",
"of",
"Mad1–Mad2",
"dimers",
"(Sharp-Baker",
"and",
"Chen,",
"2001;",
"Meraldi",
"and",
"Sorger,",
"2005;",
"Jeganathan",
"et",
"al.,",
"2007).",
"These",
"Mad1–Mad2",
"dimers",
"produce",
"a",
"diffusible",
"anaphase",
"wait",
"signal",
"consisting",
"of",
"protein",
"complexes",
"of",
"Bub3,",
"BubR1,",
"and",
"Mad2",
"(Sudakin",
"et",
"al.,",
"2001;",
"Luo",
"et",
"al.,",
"2002;",
"Sironi",
"et",
"al.,",
"2002;",
"Kulukian",
"et",
"al.,",
"2009).",
"These",
"complexes",
"bind",
"to",
"and",
"inhibit",
"Cdc20,",
"the",
"activating",
"subunit",
"of",
"the",
"anaphase-promoting",
"complex/cyclosome",
"(APC/C),",
"an",
"E3",
"ubiquitin",
"ligase",
"that",
"regulates",
"orderly",
"separation",
"of",
"chromosomes",
"by",
"targeting",
"various",
"cell",
"cycle",
"regulators",
"for",
"degradation",
"by",
"the",
"26S",
"proteasome",
"at",
"specific",
"mitotic",
"stages",
"(Peters,",
"2006).",
"Bub1",
"not",
"only",
"regulates",
"APC/C",
"activity",
"via",
"kinetochore",
"recruitment",
"of",
"Mad1–Mad2,",
"but",
"has",
"also",
"been",
"pro-",
"posed",
"to",
"inhibit",
"APC/C",
"activity",
"directly",
"through",
"phosphorylation",
"of",
"Cdc20",
"(Chung",
"and",
"Chen,",
"2003;",
"Tang",
"et",
"al.,",
"2004a).",
"In",
"addition",
"to",
"the",
"Mad",
"proteins,",
"several",
"other",
"mitotic",
"pro-",
"teins",
"are",
"dependent",
"on",
"Bub1",
"for",
"efficient",
"recruitment",
"to",
"un-",
"attached",
"kinetochores,",
"including",
"BubR1,",
"Cenp-E,",
"and",
"Sgo1",
"(Sharp-Baker",
"and",
"Chen,",
"2001;",
"Tang",
"et",
"al.,",
"2004b;",
"Morrow",
"et",
"al.,",
"2005;",
"Jeganathan",
"et",
"al.,",
"2007;",
"Perera",
"et",
"al.,",
"2007).",
"BubR1",
"and",
"Cenp-E",
"both",
"function",
"in",
"microtubule–kinetochore",
"attachment",
"and",
"failure",
"to",
"recruit",
"these",
"proteins",
"at",
"unattached",
"kinetochores",
"is",
"known",
"to",
"cause",
"chromosome",
"missegregation",
"(Wood",
"et",
"al.,",
"1997;",
"Yao",
"et",
"al.,",
"2000;",
"Lampson",
"and",
"Kapoor,",
"2005;",
"Malureanu",
"et",
"al.,",
"2009).",
"Sgo1,",
"on",
"the",
"other",
"hand,",
"acts",
"to",
"maintain",
"centro-",
"meric",
"cohesion",
"of",
"duplicated",
"chromosomes",
"until",
"bi-orientation",
"has",
"been",
"accomplished",
"(Tang",
"et",
"al.,",
"2004b;",
"Boyarchuk",
"et",
"al.,",
"2007;",
"Kawashima",
"et",
"al.,",
"2010).",
"The",
"current",
"model",
"is",
"that",
"Bub1",
"Correspondence",
"to",
"Jan",
"van",
"Deursen:",
"vandeursen.jan@mayo.edu",
"Abbreviations",
"used",
"in",
"this",
"paper:",
"CAGGS,",
"CMV",
"early",
"enhancer/chicken",
"-actin;",
"CPC,",
"chromosome",
"passenger",
"complex;",
"HA,",
"hemagglutinin;",
"MEF,",
"mouse",
"embryonic",
"fibroblast;",
"PMSCS,",
"premature",
"sister",
"chromatid",
"separation.",
"©",
"2011",
"Ricke",
"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/).",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Cell",
"Biol.",
"Vol.",
"193",
"No.",
"6",
"1049–1064",
"www.jcb.org/cgi/doi/10.1083/jcb.201012035",
"JCB",
"1049"
] | [
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1,
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] | [
"Ishida",
"et",
"al.",
"Annals",
"of",
"Clinical",
"Microbiology",
"and",
"Antimicrobials",
"2011,",
"10:3",
"http://www.ann-clinmicrob.com/content/10/1/3",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Synthetic",
"arylquinuclidine",
"derivatives",
"exhibit",
"antifungal",
"activity",
"against",
"Candida",
"albicans,",
"Candida",
"tropicalis",
"and",
"Candida",
"parapsilopsis",
"Kelly",
"Ishida1,",
"Juliany",
"Cola",
"Fernandes",
"Rodrigues2,",
"Simon",
"Cammerer3,",
"Julio",
"A",
"Urbina4,",
"Ian",
"Gilbert3,",
"Wanderley",
"de",
"Souza2,5,",
"Sonia",
"Rozental1*",
"Abstract",
"Background:",
"Sterol",
"biosynthesis",
"is",
"an",
"essential",
"pathway",
"for",
"fungal",
"survival,",
"and",
"is",
"the",
"biochemical",
"target",
"of",
"many",
"antifungal",
"agents.",
"The",
"antifungal",
"drugs",
"most",
"widely",
"used",
"to",
"treated",
"fungal",
"infections",
"are",
"compounds",
"that",
"inhibit",
"cytochrome",
"P450-dependent",
"C14a-demethylase",
"(CYP51),",
"but",
"other",
"enzymes",
"of",
"this",
"pathway,",
"such",
"as",
"squalene",
"synthase",
"(SQS)",
"which",
"catalyses",
"the",
"first",
"committed",
"step",
"in",
"sterol",
"biosynthesis,",
"could",
"be",
"viable",
"targets.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"evaluate",
"the",
"antifungal",
"activity",
"of",
"SQS",
"inhibitors",
"on",
"Candida",
"albicans,",
"Candida",
"tropicalis",
"and",
"Candida",
"parapsilopsis",
"strains.",
"Methods:",
"Ten",
"arylquinuclidines",
"that",
"act",
"as",
"SQS",
"inhibitors",
"were",
"tested",
"as",
"antiproliferative",
"agents",
"against",
"three",
"ATCC",
"strains",
"and",
"54",
"clinical",
"isolates",
"of",
"Candida",
"albicans,",
"Candida",
"tropicalis",
"and",
"Candida",
"parapsilopsis.",
"Also,",
"the",
"morphological",
"alterations",
"induced",
"in",
"the",
"yeasts",
"by",
"the",
"experimental",
"compounds",
"were",
"evaluated",
"by",
"fluorescence",
"and",
"transmission",
"electron",
"microscopy.",
"Results:",
"The",
"most",
"potent",
"arylquinuclidine",
"derivative",
"(3-[1’-{4’-(benzyloxy)-phenyl}]-quinuclidine-2-ene)",
"(WSP1267)",
"had",
"a",
"MIC50",
"of",
"2",
"μg/ml",
"for",
"all",
"species",
"tested",
"and",
"MIC90",
"varying",
"from",
"4",
"μg/ml",
"to",
"8",
"μg/ml.",
"Ultrathin",
"sections",
"of",
"C.",
"albicans",
"treated",
"with",
"1",
"μg/ml",
"of",
"WSP1267",
"showed",
"several",
"ultrastructural",
"alterations,",
"including",
"(a)",
"loss",
"of",
"cell",
"wall",
"integrity,",
"(b)",
"detachment",
"of",
"the",
"plasma",
"membrane",
"from",
"the",
"fungal",
"cell",
"wall,",
"(c)",
"accumulation",
"of",
"small",
"vesicles",
"in",
"the",
"periplasmic",
"region,",
"(d)",
"presence",
"of",
"large",
"electron-dense",
"vacuoles",
"and",
"(e)",
"significantly",
"increased",
"cell",
"size",
"and",
"cell",
"wall",
"thickness.",
"In",
"addition,",
"fluorescence",
"microscopy",
"of",
"cells",
"labelled",
"with",
"Nile",
"Red",
"showed",
"an",
"accumulation",
"of",
"lipid",
"droplets",
"in",
"the",
"cytoplasm",
"of",
"treated",
"yeasts.",
"Nuclear",
"staining",
"with",
"DAPI",
"revealed",
"the",
"appearance",
"of",
"uncommon",
"yeast",
"buds",
"without",
"a",
"nucleus",
"or",
"with",
"two",
"nuclei.",
"Conclusion:",
"Taken",
"together,",
"our",
"data",
"demonstrate",
"that",
"arylquinuclidine",
"derivatives",
"could",
"be",
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"as",
"lead",
"compounds",
"for",
"the",
"rational",
"synthesis",
"of",
"new",
"antifungal",
"drugs.",
"Background",
"Candidiasis",
"is",
"the",
"most",
"common",
"fungal",
"infection;",
"it",
"is",
"found",
"all",
"over",
"the",
"world.",
"Candida",
"spp.",
"isolates",
"are",
"the",
"fourth",
"most",
"common",
"microorganisms",
"found",
"in",
"blood-",
"stream",
"infections",
"and",
"are",
"particularly",
"prevalent",
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"patients",
"hospitalised",
"for",
"long",
"periods",
"who",
"have",
"been",
"exposed",
"to",
"antibiotics,",
"immunosuppressive",
"therapy,",
"*",
"Correspondence:",
"rozental@biof.ufrj.br",
"1Laboratório",
"de",
"Biologia",
"Celular",
"de",
"Fungos,",
"Instituto",
"de",
"Biofísica",
"Carlos",
"Chagas",
"Filho,",
"Universidade",
"Federal",
"do",
"Rio",
"de",
"Janeiro,",
"Avenida",
"Carlos",
"Chagas",
"Filho",
"373,",
"Bloco",
"C,",
"Sala",
"C0-026,",
"Cidade",
"Universitária,",
"21.941-902,",
"Rio",
"de",
"Janeiro/RJ,",
"Brazil",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"parenteral",
"nutrition,",
"and",
"multiple",
"invasive",
"medical",
"pro-",
"cedures",
"[1].",
"Systemic",
"fungal",
"infections",
"are",
"generally",
"dif-",
"ficult",
"to",
"diagnose",
"and",
"hard",
"to",
"treat,",
"having",
"an",
"attributable",
"mortality",
"rate",
"of",
"near",
"40%",
"[1].",
"Although",
"Candida",
"albicans",
"is",
"the",
"species",
"most",
"frequently",
"isolated",
"from",
"those",
"patients,",
"being",
"responsible",
"for",
"more",
"than",
"half",
"of",
"candidiasis",
"cases,",
"the",
"incidence",
"of",
"other",
"species,",
"such",
"as",
"Candida",
"parapsilopsis",
"and",
"Candida",
"tropicalis,",
"is",
"increasing",
"[2].",
"Most",
"current",
"therapies",
"to",
"treat",
"fungal",
"infections",
"are",
"based",
"on",
"disrupting",
"fungal",
"membrane",
"homeostasis.",
"The",
"most",
"commonly",
"used",
"groups",
"of",
"antifungal",
"agents",
"are",
"©",
"2011",
"Ishida",
"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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] | [
"JCB",
"Article",
"Activation",
"of",
"ErbB2",
"receptor",
"tyrosine",
"kinase",
"supports",
"invasion",
"of",
"endothelial",
"cells",
"by",
"Neisseria",
"meningitidis",
"Isabelle",
"Hoffmann,1",
"Emmanuel",
"Eugène,2",
"Xavier",
"Nassif,2",
"Pierre-Olivier",
"Couraud,1",
"and",
"Sandrine",
"Bourdoulous1",
"1Laboratoire",
"d’Immuno-Pharmacologie",
"Moléculaire,",
"Centre",
"National",
"de",
"la",
"Recherche",
"Scientifique,",
"Institut",
"Cochin",
"de",
"Génétique",
"Moléculaire,",
"75014",
"Paris,",
"France",
"2Laboratoire",
"de",
"Microbiologie,",
"Institut",
"National",
"de",
"la",
"Santé",
"et",
"de",
"la",
"Recherche",
"Médicale,",
"Faculté",
"de",
"Médecine",
"Necker-Enfants",
"Malades,",
"75015",
"Paris,",
"France",
"Efamily",
"of",
"epidermal",
"growth",
"factor",
"(EGF)",
"receptors",
"rbB2",
"is",
"a",
"receptor",
"tyrosine",
"kinase",
"belonging",
"to",
"the",
"which",
"is",
"generally",
"involved",
"in",
"cell",
"differentiation,",
"proliferation,",
"and",
"tumor",
"growth,",
"and",
"activated",
"by",
"het-",
"erodimerization",
"with",
"the",
"other",
"members",
"of",
"the",
"family.",
"We",
"show",
"here",
"that",
"type",
"IV",
"pilus–mediated",
"adhesion",
"of",
"Neisseria",
"meningitidis",
"onto",
"endothelial",
"cells",
"induces",
"tyrosyl",
"phos-",
"phorylation",
"and",
"massive",
"recruitment",
"of",
"ErbB2",
"underneath",
"the",
"bacterial",
"colonies.",
"However,",
"neither",
"the",
"phosphorylation",
"status",
"nor",
"the",
"cellular",
"localization",
"of",
"the",
"EGF",
"receptors,",
"ErbB3",
"or",
"ErbB4,",
"were",
"affected",
"in",
"infected",
"cells.",
"ErbB2",
"phosphorylation",
"induced",
"by",
"N.",
"meningitidis",
"provides",
"docking",
"sites",
"for",
"the",
"kinase",
"src",
"and",
"leads",
"to",
"its",
"subsequent",
"activation.",
"Specific",
"inhibition",
"of",
"either",
"ErbB2",
"and/or",
"src",
"activity",
"reduces",
"bacterial",
"internalization",
"into",
"endothelial",
"cells",
"without",
"affecting",
"bacteria-induced",
"actin",
"cytoskeleton",
"reorganization",
"or",
"ErbB2",
"recruitment.",
"Moreover,",
"inhibition",
"of",
"both",
"actin",
"polymerization",
"and",
"the",
"ErbB2/src",
"pathway",
"totally",
"prevents",
"bacterial",
"entry.",
"Altogether,",
"our",
"results",
"pro-",
"vide",
"new",
"insight",
"into",
"ErbB2",
"function",
"by",
"bringing",
"evidence",
"of",
"a",
"bacteria-induced",
"ErbB2",
"clustering",
"leading",
"to",
"src",
"kinase",
"phosphorylation",
"and",
"activation.",
"This",
"pathway,",
"in",
"cooperation",
"with",
"the",
"bacteria-induced",
"reorganization",
"of",
"the",
"actin",
"cytoskeleton,",
"is",
"required",
"for",
"the",
"efficient",
"internalization",
"of",
"N.",
"meningitidis",
"into",
"endothelial",
"cells,",
"an",
"essential",
"process",
"enabling",
"this",
"pathogen",
"to",
"cross",
"host",
"cell",
"barriers.",
"Introduction",
"The",
"ErbB",
"family",
"of",
"receptor",
"tyrosine",
"kinases",
"(RTKs)*",
"com-",
"prises",
"four",
"closely",
"related",
"members:",
"EGF",
"receptor",
"(EGFR;",
"also",
"termed",
"ErbB1),",
"ErbB2/Neu,",
"ErbB3,",
"and",
"ErbB4.",
"These",
"receptors",
"are",
"activated",
"by",
"numerous",
"ErbB-specific",
"ligands,",
"each",
"containing",
"an",
"EGF-like",
"domain",
"which",
"confers",
"binding",
"specificity",
"(for",
"review",
"see",
"Olayioye",
"et",
"al.,",
"2000).",
"These",
"ligands,",
"which",
"are",
"produced",
"as",
"transmembrane",
"precursors",
"and",
"are",
"processed",
"and",
"released",
"by",
"proteolysis,",
"bind",
"the",
"extra-",
"cellular",
"domain",
"of",
"ErbB",
"receptors",
"and",
"lead",
"to",
"the",
"formation",
"of",
"both",
"homo-",
"and",
"heterodimers.",
"No",
"soluble",
"ligand",
"for",
"ErbB2",
"has",
"yet",
"been",
"discovered.",
"However,",
"increasing",
"evi-",
"dence",
"suggests",
"that",
"the",
"primary",
"function",
"of",
"ErbB2",
"is",
"as",
"a",
"Address",
"correspondence",
"to",
"Sandrine",
"Bourdoulous,",
"Laboratoire",
"d’Im-",
"muno-Pharmacologie",
"Moléculaire,",
"Centre",
"National",
"de",
"la",
"Recherche",
"Sci-",
"entifique",
"UPR",
"415,",
"Institut",
"Cochin",
"de",
"Génétique",
"Moléculaire,",
"22",
"rue",
"Méchain,",
"75014",
"Paris,",
"France.",
"Tel.:",
"(33)",
"1-40-51-64-34.",
"Fax:",
"(33)",
"1-40-",
"51-64-30.",
"E-mail:",
"bourdoulous@cochin.inserm.fr",
"*Abbreviations",
"used",
"in",
"this",
"paper:",
"EGFR,",
"EGF",
"receptor;",
"GST,",
"glu-",
"tathione",
"S-transferase;",
"HBMEC,",
"human",
"bone",
"marrow",
"endothelial",
"cell;",
"MAPK,",
"mitogen-activated",
"protein",
"kinase;",
"RTK,",
"receptor",
"tyrosine",
"kinase;",
"SH2,",
"src",
"homology",
"2.",
"Key",
"words:",
"ErbB2;",
"homodimerization;",
"src;",
"Neisseria",
"meningitidis;",
"invasion",
"",
"The",
"Rockefeller",
"University",
"Press,",
"0021-9525/2001/10/133/11",
"$5.00",
"The",
"Journal",
"of",
"Cell",
"Biology,",
"Volume",
"155,",
"Number",
"1,",
"October",
"1,",
"2001",
"133–143",
"http://www.jcb.org/cgi/doi/10.1083/jcb.200106148",
"coreceptor,",
"since",
"ErbB2",
"is",
"the",
"preferred",
"heterodimerization",
"partner",
"for",
"all",
"other",
"ErbB",
"family",
"members",
"(Tzahar",
"et",
"al.,",
"1996;",
"Graus-Porta",
"et",
"al.,",
"1997)",
"and",
"plays",
"a",
"role",
"in",
"the",
"po-",
"tentiation",
"of",
"ErbB",
"receptor",
"signaling",
"(Beerli",
"et",
"al.,",
"1995;",
"Graus-Porta",
"et",
"al.,",
"1995).",
"Dimerization",
"stimulates",
"the",
"in-",
"trinsic",
"tyrosine",
"kinase",
"activity",
"of",
"the",
"receptors",
"and",
"triggers",
"autophosphorylation",
"of",
"specific",
"tyrosine",
"residues",
"within",
"the",
"cytoplasmic",
"domains.",
"These",
"phosphorylated",
"residues",
"pro-",
"vide",
"docking",
"sites",
"for",
"proteins",
"which",
"contain",
"src",
"homology",
"2",
"(SH2)",
"or",
"phosphotyrosine",
"binding",
"domains",
"and",
"which",
"are",
"involved",
"in",
"the",
"regulation",
"of",
"intracellular",
"signaling",
"cascades.",
"All",
"ErbB",
"family",
"members",
"couple",
"via",
"the",
"adaptors",
"Shc",
"and/or",
"Grb2",
"to",
"the",
"mitogen-activated",
"protein",
"kinase",
"(MAPK)",
"path-",
"way.",
"However,",
"preferential",
"modulation",
"of",
"specific",
"pathways",
"linked",
"to",
"specific",
"homo-",
"or",
"heterodimers,",
"or",
"to",
"specific",
"cell",
"surface",
"sites,",
"have",
"been",
"described",
"(Olayioye",
"et",
"al.,",
"2000;",
"Carraway",
"and",
"Sweeney,",
"2001).",
"Therefore,",
"the",
"signaling",
"di-",
"versity",
"associated",
"with",
"the",
"ErbB",
"family",
"is",
"dependent",
"upon",
"the",
"repertoire",
"of",
"ErbB",
"ligands,",
"the",
"combinatorial",
"properties",
"of",
"induced",
"receptor",
"dimers,",
"and",
"receptor",
"localization.",
"Ulti-",
"mately,",
"downstream",
"effects",
"on",
"gene",
"expression",
"determine",
"the",
"biological",
"response",
"to",
"receptor",
"activation.",
"ErbB",
"recep-",
"tors",
"are",
"expressed",
"in",
"a",
"variety",
"of",
"tissues",
"of",
"epithelial,",
"mesen-",
"133"
] | [
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2,714,112 | null | [
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] | [
"Available",
"online",
"http://arthritis-research.com/content/11/3/R66",
"Research",
"article",
"Vol11No3",
"Identification",
"of",
"novel",
"genetic",
"susceptibility",
"loci",
"for",
"Behçet's",
"disease",
"using",
"a",
"genome-wide",
"association",
"study",
"Open",
"Access",
"Yiping",
"Fei1,2,",
"Ryan",
"Webb2,3,",
"Beth",
"L",
"Cobb2,4,",
"Haner",
"Direskeneli5,",
"Güher",
"Saruhan-Direskeneli6",
"and",
"Amr",
"H",
"Sawalha1,2,7",
"1Department",
"of",
"Medicine,",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"825",
"NE",
"13th",
"Street,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"2Arthritis",
"&",
"Immunology",
"Program,",
"Oklahoma",
"Medical",
"Research",
"Foundation,",
"825",
"NE",
"13th",
"Street,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"3College",
"of",
"Public",
"Health,",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"825",
"NE",
"13th",
"Street,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"4JK",
"Autoimmunity",
"Inc.,",
"755",
"Research",
"Parkway,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"5Division",
"of",
"Rheumatology,",
"Department",
"of",
"Internal",
"Medicine,",
"Marmara",
"University",
"Medical",
"School,",
"Tophanelioglu",
"Cad.",
"13/15,",
"34662,",
"Uskudar,",
"Istanbul,",
"Turkey",
"6Department",
"of",
"Physiology,",
"Istanbul",
"Faculty",
"of",
"Medicine,",
"Istanbul",
"University,",
"Capa",
"34093,",
"Istanbul,",
"Turkey",
"7US",
"Department",
"of",
"Veterans",
"Affairs",
"Medical",
"Center,",
"921",
"NE",
"13th",
"Street,",
"Oklahoma",
"City,",
"OK",
"73104,",
"USA",
"Corresponding",
"author:",
"Amr",
"H",
"Sawalha,",
"amr-sawalha@ouhsc.edu",
"Received:",
"31",
"Mar",
"2009",
"Revisions",
"requested:",
"28",
"Apr",
"2009",
"Revisions",
"received:",
"3",
"May",
"2009",
"Accepted:",
"14",
"May",
"2009",
"Published:",
"14",
"May",
"2009",
"Arthritis",
"Research",
"&",
"Therapy",
"2009,",
"11:R66",
"(doi:10.1186/ar2695)",
"This",
"article",
"is",
"online",
"at:",
"http://arthritis-research.com/content/11/3/R66",
"©",
"2009",
"Fei",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Introduction",
"Behçet's",
"disease",
"is",
"a",
"chronic",
"systemic",
"inflammatory",
"disease",
"that",
"remains",
"incompletely",
"understood.",
"Herein,",
"we",
"perform",
"the",
"first",
"genome-wide",
"association",
"study",
"in",
"Behçet's",
"disease.",
"Methods",
"Using",
"DNA",
"pooling",
"technology",
"and",
"the",
"Affymetrix",
"500K",
"arrays,",
"we",
"identified",
"possible",
"candidate",
"gene",
"associations",
"with",
"Behçet's",
"disease",
"in",
"a",
"cohort",
"of",
"152",
"Behçet's",
"disease",
"patients",
"and",
"172",
"healthy",
"ethnically",
"matched",
"controls.",
"Genetic",
"loci",
"that",
"were",
"identified",
"in",
"the",
"pooling",
"study",
"were",
"genotyped",
"in",
"patients",
"and",
"controls",
"using",
"TaqMan",
"genotyping",
"technology.",
"Results",
"We",
"identified",
"genetic",
"associations",
"between",
"Behçet's",
"disease",
"and",
"single-nucleotide",
"polymorphisms",
"(SNPs)",
"in",
"KIAA1529,",
"CPVL,",
"LOC100129342,",
"UBASH3B,",
"and",
"UBAC2",
"(odds",
"ratio",
"=",
"2.04,",
"2.26,",
"1.84,",
"1.71,",
"and",
"1.61,",
"respectively;",
"P",
"value",
"=",
"4.2",
"×",
"10-5,",
"1.0",
"×",
"10-4,",
"3.0",
"×",
"10-4,",
"1.5",
"×",
"10-3,",
"and",
"5.8",
"×",
"10-3,",
"respectively).",
"Among",
"the",
"associated",
"SNPs,",
"the",
"Behçet's",
"disease-risk",
"allele",
"in",
"rs2061634",
"leads",
"to",
"substitution",
"of",
"serine",
"to",
"cysteine",
"at",
"amino",
"acid",
"position",
"995",
"(S995C)",
"in",
"the",
"KIAA1529",
"protein.",
"Conclusions",
"Using",
"an",
"unbiased",
"whole-genome",
"genetic",
"association",
"approach,",
"we",
"identified",
"novel",
"candidate",
"genetic",
"loci",
"that",
"are",
"associated",
"with",
"increased",
"susceptibility",
"for",
"Behçet's",
"disease.",
"These",
"findings",
"will",
"help",
"to",
"better",
"understand",
"the",
"pathogenesis",
"of",
"Behçet's",
"disease",
"and",
"identify",
"novel",
"targets",
"for",
"therapeutic",
"intervention.",
"Introduction",
"Behçet's",
"disease",
"is",
"a",
"chronic",
"relapsing",
"systemic",
"inflammatory",
"disease",
"characterized",
"by",
"the",
"presence",
"of",
"oro-genital",
"ulcers,",
"cutaneous",
"manifestations,",
"and",
"uveitis.",
"The",
"disease",
"can",
"also",
"lead",
"to",
"vascular",
"complications",
"such",
"as",
"arterial",
"and",
"venous",
"thrombosis,",
"central",
"nervous",
"system",
"vasculitis,",
"arthritis,",
"and",
"gastrointestinal",
"involvement",
"[1].",
"The",
"etiology",
"of",
"Behçet's",
"dis-",
"ease",
"is",
"not",
"fully",
"understood.",
"Therefore,",
"treatment",
"remains",
"insufficient",
"and",
"relies",
"on",
"non-specific",
"immunosuppressive",
"medications,",
"with",
"significant",
"side",
"effects.",
"Evidence",
"for",
"a",
"genetic",
"contribution",
"to",
"the",
"pathogenesis",
"of",
"the",
"disease",
"comes",
"from",
"strong",
"familial",
"aggregation,",
"the",
"strong",
"predominance",
"in",
"patients",
"with",
"Mediterranean",
"or",
"Asian",
"ancestry,",
"and",
"the",
"con-",
"firmed",
"association",
"with",
"HLA-B51",
"in",
"several",
"ethnic",
"groups",
"[2-",
"4].",
"It",
"is",
"estimated",
"that",
"the",
"association",
"with",
"HLA-B51",
"in",
"Behçet's",
"disease",
"accounts",
"for",
"only",
"~20%",
"of",
"the",
"relative",
"risk",
"in",
"siblings",
"CI:",
"confidence",
"interval;",
"CPVL:",
"carboxypeptidase,",
"vitellogenic-like;",
"HWE:",
"Hardy-Weinberg",
"equilibrium;",
"OR:",
"odds",
"ratio;",
"SD:",
"standard",
"deviation;",
"SNP:",
"single-nucleotide",
"polymorphism;",
"UBA:",
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] | [
"organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"2-(o-Tolyloxy)pyrimidine",
"Nasir",
"Shah",
"Bakhtiar,",
"Zanariah",
"Abdullah",
"and",
"Seik",
"Weng",
"Ng*",
"Department",
"of",
"Chemistry,",
"University",
"of",
"Malaya,",
"50603",
"Kuala",
"Lumpur,",
"Malaysia",
"Correspondence",
"e-mail:",
"seikweng@um.edu.my",
"Received",
"7",
"July",
"2009;",
"accepted",
"8",
"July",
"2009",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"153",
"K;",
"mean",
"(C–C)",
"=",
"0.003",
"A˚;",
"R",
"factor",
"=",
"0.033;",
"wR",
"factor",
"=",
"0.088;",
"data-to-parameter",
"ratio",
"=",
"9.1.",
"The",
"title",
"compound,",
"C11H10N2O,",
"crystallizes",
"with",
"two",
"mol-",
"ecules",
"in",
"the",
"asymmetric",
"unit.",
"The",
"angle",
"at",
"the",
"ether",
"O",
"atom",
"is",
"widened",
"to",
"118.13",
"(15)",
"[117.89",
"(16)",
"for",
"the",
"second",
"molecule",
"in",
"the",
"asymmetric",
"unit];",
"the",
"six-membered",
"rings",
"subtend",
"a",
"dihedral",
"angle",
"of",
"84.3",
"(1)",
"[87.4",
"(1)",
"in",
"the",
"second",
"molecule].",
"Related",
"literature",
"For",
"2-phenoxypyrimidine,",
"see:",
"Shah",
"Bakhtiar",
"et",
"al.",
"(2009).",
"Experimental",
"Crystal",
"data",
"C11H10N2O",
"Mr",
"=",
"186.21",
"Orthorhombic,",
"Pca21",
"a",
"=",
"7.5197",
"(2)",
"A˚",
"b",
"=",
"12.7997",
"(3)",
"A˚",
"c",
"=",
"20.3238",
"(4)",
"A˚",
"Data",
"collection",
"Bruker",
"SMART",
"APEX",
"diffractometer",
"Absorption",
"correction:",
"none",
"12792",
"measured",
"reflections",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.033",
"wR(F",
"2)",
"=",
"0.088",
"S",
"=",
"1.02",
"2317",
"reflections",
"255",
"parameters",
"V",
"=",
"1956.16",
"(8)",
"A˚",
"3",
"Z",
"=",
"8",
"Mo",
"K",
"radiation",
"=",
"0.08",
"mm",
"1",
"T",
"=",
"153",
"K",
"0.35",
"0.25",
"0.15",
"mm",
"2317",
"independent",
"reflections",
"2030",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.028",
"1",
"restraint",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.16",
"e",
"A˚",
"3",
"min",
"=",
"0.19",
"e",
"A˚",
"3",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2008);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2008);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"X-",
"SEED",
"(Barbour,",
"2001);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"publCIF",
"(Westrip,",
"2009).",
"We",
"thank",
"the",
"University",
"of",
"Malaya",
"(FP047/2008",
"C,",
"RG027/",
"09AFR)",
"for",
"supporting",
"this",
"study.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"BT2995).",
"References",
"Barbour,",
"L.",
"J.",
"(2001).",
"J.",
"Supramol.",
"Chem.",
"1,",
"189–191.",
"Bruker",
"(2008).",
"APEX2",
"and",
"SAINT.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Shah",
"Bakhtiar,",
"N.,",
"Abdullah,",
"Z.",
"&",
"Ng,",
"S.",
"W.",
"(2009).",
"Acta",
"Cryst.",
"E65,",
"o114.",
"Sheldrick,",
"G.",
"M.",
"(2008).",
"Acta",
"Cryst.",
"A64,",
"112–122.",
"Westrip,",
"S.",
"P.",
"(2009).",
"publCIF.",
"In",
"preparation.",
"o1880",
"Shah",
"Bakhtiar",
"et",
"al.",
"doi:10.1107/S1600536809026609",
"Acta",
"Cryst.",
"(2009).",
"E65,",
"o1880"
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] | [
"www.impactjournals.com/oncotarget/",
"Oncotarget,",
"March,",
"Vol.2,",
"No",
"3",
"Personalizing",
"Therapy",
"with",
"Targeted",
"Agents",
"in",
"Non-Small",
"Cell",
"Lung",
"Cancer",
"Rodrigo",
"Dienstmann1,",
"Pablo",
"Martinez2,",
"Enriqueta",
"Felip2",
"1",
"Molecular",
"Therapeutic",
"Research",
"Unit,",
"Medical",
"Oncology",
"Service,",
"Vall",
"d’Hebron",
"University",
"Hospital",
"and",
"Vall",
"d’Hebron",
"Institute",
"of",
"Oncology,",
"Barcelona",
"2",
"Thoracic",
"Neoplasms",
"Unit,",
"Medical",
"Oncology",
"Service,",
"Vall",
"d’Hebron",
"University",
"Hospital",
"and",
"Vall",
"d’Hebron",
"Institute",
"of",
"Oncology,",
"Barcelona,",
"Spain",
"Correspondence",
"to:",
"Enriqueta",
"Felip,",
"email:",
"efelip@vhebron.net",
"Keywords:",
"ALK,",
"EGFR,",
"KRAS,",
"lung",
"cancer,",
"targeted",
"therapy",
"Received:",
"March",
"12,",
"2011,",
"Accepted:",
"March",
"23,",
"2011,",
"Published:",
"March",
"23,",
"2011",
"Copyright:",
"©",
"Dienstmann",
"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.",
"AbstrAct:",
"In",
"the",
"last",
"6",
"years,",
"since",
"the",
"first",
"reports",
"of",
"an",
"association",
"between",
"somatic",
"mutations",
"in",
"epidermal",
"growth",
"factor",
"receptor",
"(EGFR)",
"exons",
"19",
"and",
"21",
"and",
"response",
"to",
"EGFR",
"tyrosine",
"kinase",
"inhibitors",
"(TKIs),",
"treatment",
"of",
"non-small",
"cell",
"lung",
"cancer",
"(NSCLC)",
"has",
"changed",
"dramatically.",
"Based",
"on",
"laboratory",
"and",
"clinical",
"observations,",
"investigators",
"have",
"anticipated",
"that",
"these",
"mutations",
"could",
"be",
"predictive",
"of",
"response",
"to",
"EGFR",
"TKIs",
"and",
"numerous",
"studies",
"have",
"confirmed",
"that",
"the",
"presence",
"of",
"mutation",
"was",
"associated",
"with",
"longer",
"survival",
"in",
"patients",
"receiving",
"targeted",
"therapy.",
"Prospective",
"trials",
"comparing",
"standard",
"platinum-based",
"chemotherapy",
"with",
"EGFR",
"TKIs",
"in",
"patients",
"with",
"and",
"without",
"activating",
"EGFR",
"mutations",
"validated",
"the",
"predictive",
"value",
"of",
"molecular",
"selection",
"of",
"patients",
"for",
"first-line",
"treatment",
"of",
"advanced",
"NSCLC.",
"Recently,",
"preclinical",
"and",
"first-",
"in-human",
"studies",
"have",
"demonstrated",
"impressive",
"activity",
"of",
"ALK",
"TKI",
"in",
"tumors",
"harboring",
"ALK",
"rearrangement.",
"In",
"this",
"article,",
"we",
"review",
"current",
"data",
"on",
"molecular",
"biology",
"of",
"lung",
"cancer",
"and",
"evidence-based",
"patient",
"selection",
"for",
"targeted",
"therapy.",
"IntroductIon",
"Lung",
"cancer",
"is",
"the",
"most",
"frequent",
"cause",
"of",
"cancer-",
"related",
"death",
"worldwide.",
"Non-small",
"cell",
"lung",
"cancer",
"(NSCLC)",
"accounts",
"for",
"85%",
"of",
"all",
"lung",
"cancers",
"[1].",
"Only",
"a",
"minority",
"of",
"NSCLC",
"patients",
"is",
"suitable",
"for",
"radical",
"treatment",
"as",
"curative",
"care.",
"Most",
"patients",
"have",
"advanced",
"disease",
"at",
"diagnosis",
"and",
"palliative",
"therapy",
"is",
"the",
"mainstay",
"of",
"management.",
"Conventional",
"chemotherapy",
"of",
"NSCLC",
"has",
"apparently",
"reached",
"a",
"plateau",
"of",
"effectiveness",
"in",
"improving",
"survival",
"of",
"lung",
"cancer",
"patients,",
"and",
"treatment",
"outcomes",
"must",
"still",
"be",
"considered",
"disappointing",
"[2].",
"Based",
"on",
"a",
"better",
"understanding",
"of",
"the",
"biology",
"of",
"lung",
"cancer,",
"targeted",
"therapies",
"are",
"also",
"available",
"to",
"treat",
"patients",
"with",
"NSCLC.",
"Predictive",
"markers",
"of",
"response",
"to",
"these",
"agents",
"are",
"undergoing",
"prospective",
"validation",
"and",
"promising",
"results",
"have",
"been",
"reported.",
"The",
"epidermal",
"growth",
"factor",
"receptor",
"(EGFR)",
"signaling",
"pathway",
"is",
"importantly",
"implicated",
"in",
"tumor",
"cell",
"growth,",
"local",
"invasion,",
"angiogenesis,",
"metastasis,",
"protein",
"translation",
"and",
"cell",
"metabolism.",
"It",
"activates",
"two",
"major",
"pathways",
"in",
"solid",
"tumors,",
"RAS/RAF/MAPK/ERK",
"and",
"PI3K/AKT/mTOR,",
"as",
"seen",
"in",
"Figure",
"1",
"[3].",
"Molecular",
"aberrations",
"on",
"the",
"EGFR",
"pathway",
"are",
"the",
"most",
"commonly",
"studied",
"predictive",
"biomarkers",
"of",
"response/",
"resistance",
"to",
"targeted",
"agents",
"in",
"lung",
"cancer.",
"This",
"review",
"delineates",
"the",
"current",
"role",
"of",
"EGFR",
"inhibitors",
"in",
"the",
"treatment",
"of",
"advanced",
"NSCLC",
"according",
"to",
"EGFR",
"and",
"KRAS",
"status",
"of",
"the",
"tumor,",
"strategies",
"to",
"overcome",
"resistance",
"to",
"agents",
"targeting",
"EGFR",
"and",
"also",
"discusses",
"other",
"recently",
"discovered",
"molecular",
"aberration",
"in",
"lung",
"cancer,",
"ALK",
"rearrangement,",
"which",
"is",
"being",
"efficiently",
"targeted",
"with",
"ALK",
"inhibitors.",
"EGFr",
"p",
"Athw",
"Ay:",
"molEculAr",
"AbErrA",
"tIons,",
"AntI-EGFr",
"thErApy",
"And",
"prEdIctIvE",
"mArkErs",
"oF",
"rEsponsE",
"NSCLC",
"is",
"associated",
"with",
"EGFR",
"overexpression",
"in",
"up",
"to",
"80%",
"of",
"the",
"patients",
"and",
"a",
"high",
"EGFR",
"gene",
"copy",
"number",
"is",
"found",
"in",
"nearly",
"60%",
"of",
"the",
"cases",
"[4-6].",
"Mutation",
"of",
"the",
"EGFR",
"proto-oncogene",
"is",
"found",
"in",
"10%",
"to",
"20%",
"of",
"www.impactjournals.com/oncotarget",
"165",
"Oncotarget",
"2011;",
"2:",
"165",
"-",
"177"
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