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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EIn a nonhuman primate model of hemolytic uremic syndrome, complement was not activated despite clear microvascular thrombosis and cellular injury. Complement is an important immune defense mechanism. This article presents outcomes from a study on the role of complement in HUS and thrombotic microangiography induced by \u003Cem\u003EEscherichia coli\u003C\/em\u003E (\u003Cem\u003EE. coli\u003C\/em\u003E) Shiga toxins.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAnemias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAnemias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EIn a nonhuman primate model of hemolytic uremic syndrome (HUS), complement was not activated despite clear microvascular thrombosis and cellular injury. Complement is an important immune defense mechanism. Shinichiro Kurosawa, MD, PhD, Boston University School of Medicine, Boston, Massachusetts, USA, presented outcomes from a study on the role of complement in HUS and thrombotic microangiography induced by \u003Cem\u003EEscherichia coli (E. coli)\u003C\/em\u003E Shiga toxins.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EEnterohemorrhagic Shiga toxin-producing \u003Cem\u003EE. coli\u003C\/em\u003E (EHEC), the leading cause of acute renal failure in otherwise healthy children, is associated with the potentially lethal complication of HUS. EHEC are food- and water-borne bacteria, contributing to the estimated 76 million illnesses, 325,000 hospitalizations, and 5200 deaths each year in the United States attributable to foodborne outbreaks, with a total annual cost of $10 to $83 billion [Bavaro MF. \u003Cem\u003ECurr Gastroenterol Rep\u003C\/em\u003E 2012]. Toxins from these bacteria cause kidney, intestinal, and neurologic damage.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EA 2011 outbreak of an \u003Cem\u003EE. coli\u003C\/em\u003E strain secreting Shiga toxin type-2 in Germany infected 3842 individuals, many after consuming contaminated fenugreek sprouts. More than 50% of them required hospitalization; 855 developed HUS; and 54 died [Werber D et al. \u003Cem\u003EBMC Med\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn order to develop a clinically-relevant animal model of HUS, Stearns-Kurosawa and colleagues \u003Cem\u003E[Infect Immun\u003C\/em\u003E 2010] studied the effects of Shiga toxin types 1 and 2 (Stx1, Stx2) in nonhuman primates, comparing the \u003Cem\u003Ein vivo\u003C\/em\u003E consequences of the toxins in a parallel and reproducible manner. They found that the time course, pathology, and cytokine profiles differed between Stx1 and Stx 2, but that both induced HUS (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Time Course, Pathology, and Cytokine Profiles Differ Between Stx1 and Stx2\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-79790424\u0022 data-figure-caption=\u0022Time Course, Pathology, and Cytokine Profiles Differ Between Stx1 and Stx2\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13651\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003ETime Course, Pathology, and Cytokine Profiles Differ Between Stx1 and Stx2\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from S Kurosawa, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003EIn a subsequent study, Lee and colleagues [\u003Cem\u003EBlood\u003C\/em\u003E 2013] asked whether complement activation is a major pathway for HUS development in this animal model. Some patients show evidence of complement activation during EHEC infection, raising the possibility of therapeutic targeting of complement for relief. Nonhuman primate models indicate otherwise. They found that platelet levels declined in a dose-dependent manner after Stx1 and Stx2 (thrombocytopenia). Evidence of coagulation and full HUS development was clear. D-dimer was elevated, indicating that both coagulation and fibrinolysis took place. Damage-associated molecular patterns (DAMPs; HMGB1 and histones) were also elevated, indicating tissue damage. However, complement was not activated. There were no significant increases in soluble terminal complement complex (C5b-9) levels after challenge with lethal Stx1 (n=6) or Stx2 (n=5) in plasma samples from TO to euthanasia at 49.5 to 128 hours post challenge (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). This contrasts with robust complement activation in bacteria sepsis models (\u003Cem\u003EBacillus anthracis\u003C\/em\u003E, nontoxin \u003Cem\u003EE. coli\u003C\/em\u003E), which have disseminated intravascular coagulation, rather than HUS.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Complement Activation Is Not the Major Pathway for HUS Development.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-79790424\u0022 data-figure-caption=\u0022Complement Activation Is Not the Major Pathway for HUS Development.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/16\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13652\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EComplement Activation Is Not the Major Pathway for HUS Development.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from S Kurosawa, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EThese studies found that in preclinical models, complement activation is not required for the development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins. The global nature of food processing and distribution raises the stakes in the study of EHEC, heightening the imperative to recognize, treat, and report it. To date, no specific treatment is available.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/13\/16.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznp5p\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznp5p\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}