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xigris/200-sepsis-management-challenges.jsp

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xigris/200-sepsis-management-challenges.jsp

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  1. In the United States, more than 500,000 patients a year develop sepsis with mortality reported between 30 and 70%. These treatments have been calculated to cost more than 15 billion dollars per year. HMGB1 is a late cytokine mediator in sepsis, and has been linked to cytokine production. Knockout receptor peritoneal macrophages were used to observe varying effects of HMGB1. Knockout TLR2, TLR4, T4R, T2R and RAGE macrophages were treated with LPS, HMGB1 and PGN to observe HMGB1’s cytokine activation. Results suggest that knockout TLR4 receptors significantly reduce cytokine production in a sepsis model. TLR2 knockout macrophages responded with lesser amount of cytokines, however there were still signs of cytokine encroachment. RAGE knockout receptor cells showed best results in the dual knockout receptor trials. Collected data can help shape a clinical model in antagonizing receptors to prevent HMGB1 binding. http://www.xigris.com/200-sepsis-management-challenges.jsp http://blogs.cgdev.org/globalhealth/under_5_deaths.gif Invasive Infection Immune Cells and Cytokines HMGB1 Release Receptor Binding Toll- Like Receptor RAGE Dual Knockout Receptor http://www.uic.edu/classes/bios/bios100/lecturesf04am/inflammation01a.jpg High Mobility Group Box-1 • Pro-Inflammatory • Protection- Critical Illness • Normal –Lethal Response • Appears in 16-24 hrs • Plateaus 24-32 hrs • Late Action-Therapeutic Target in Inflammation TNF Release ELISA Capture Sample Detection Secondary Substrate Yang (2005) • Cytokines and Proteins linked to Sepsis-HMGB1 • Normal/ Septic Conditions. • TLR4, TLR2, RAGE. • Single Knockout Receptors Purpose Yang, 2005 To determine the effectiveness of the dual knockout receptors T2R and TR4, in lowering TNF levels as compared to single knockout receptors. Hypothesis 2 Hypothesis 1 Dual knockout receptor cells will have similar TNF levels as compared to each other and single knockout receptor cells, when exposed to all HMGB1 and LPS concentrations. The dual knockouts will have the lowest TNF levels in both the HMGB1 and TNF Trials.

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