請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74818
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余忠仁(Chong-Jen Yu) | |
dc.contributor.author | Kuei-Pin Chung | en |
dc.contributor.author | 鐘桂彬 | zh_TW |
dc.date.accessioned | 2021-06-17T09:08:10Z | - |
dc.date.available | 2020-03-12 | |
dc.date.copyright | 2020-03-12 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-11-19 | |
dc.identifier.citation | Abraham, E., Laterre, P.F., Garg, R., Levy, H., Talwar, D., Trzaskoma, B.L., Francois, B., Guy, J.S., Bruckmann, M., Rea-Neto, A., et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005 Sep 29; 353(13): 1332-41.
Ahmad, A., Ahmad, R., Iannello, A., Toma, E., Morisset, R., and Sindhu, S.T. IL-15 and HIV infection: lessons for immunotherapy and vaccination. Curr HIV Res 2005 Jul; 3(3): 261-70. Andrejko, K.M., and Deutschman, C.S. Altered hepatic gene expression in fecal peritonitis: changes in transcription of gluconeogenic, beta-oxidative, and ureagenic genes. Shock 1997 Mar; 7(3): 164-9. Annane, D., Renault, A., Brun-Buisson, C., Megarbane, B., Quenot, J.P., Siami, S., Cariou, A., Forceville, X., Schwebel, C., Martin, C., et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018 Mar 1; 378(9): 809-18. Annane, D., Sebille, V., Charpentier, C., Bollaert, P.E., Francois, B., Korach, J.M., Capellier, G., Cohen, Y., Azoulay, E., Troche, G., et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002 Aug 21; 288(7): 862-71. Annane, D., Sebille, V., Troche, G., Raphael, J.C., Gajdos, P., and Bellissant, E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000 Feb 23; 283(8): 1038-45. ARISE, Group, A.C.T., Peake, S.L., Delaney, A., Bailey, M., Bellomo, R., Cameron, P.A., Cooper, D.J., Higgins, A.M., Holdgate, A., et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014 Oct 16; 371(16): 1496-506. Askim, A., Moser, F., Gustad, L.T., Stene, H., Gundersen, M., Asvold, B.O., Dale, J., Bjornsen, L.P., Damas, J.K., and Solligard, E. Poor performance of quick-SOFA (qSOFA) score in predicting severe sepsis and mortality - a prospective study of patients admitted with infection to the emergency department. Scand J Trauma Resusc Emerg Med 2017 Jun 9; 25(1): 56. Belikova, I., Lukaszewicz, A.C., Faivre, V., Damoisel, C., Singer, M., and Payen, D. Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Crit Care Med 2007 Dec; 35(12): 2702-8. Bellomo, R., Reade, M.C., and Warrillow, S.J. The pursuit of a high central venous oxygen saturation in sepsis: growing concerns. Crit Care 2008; 12(2): 130. Bellomo, R., Ronco, C., Kellum, J.A., Mehta, R.L., and Palevsky, P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004 Aug; 8(4): R204-12. Beloborodova, N., Bairamov, I., Olenin, A., Shubina, V., Teplova, V., and Fedotcheva, N. Effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils. J Biomed Sci 2012 Oct 12; 19: 89. Beloborodova, N.V., Khodakova, A.S., Bairamov, I.T., and Olenin, A.Y. Microbial origin of phenylcarboxylic acids in the human body. Biochemistry (Mosc) 2009 Dec; 74(12): 1350-5. Beloborodova, N.V., Olenin, A.Y., and Pautova, A.K. Metabolomic findings in sepsis as a damage of host-microbial metabolism integration. J Crit Care 2018 Feb; 43: 246-55. Bergamaschi, C., Bear, J., Rosati, M., Beach, R.K., Alicea, C., Sowder, R., Chertova, E., Rosenberg, S.A., Felber, B.K., and Pavlakis, G.N. Circulating IL-15 exists as heterodimeric complex with soluble IL-15R in human and mouse serum. Blood 2012 Jul 5; 120(1): e1-8. Bernard, G.R., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., Lopez-Rodriguez, A., Steingrub, J.S., Garber, G.E., Helterbrand, J.D., Ely, E.W., et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001 Mar 8; 344(10): 699-709. Bieche, I., Onody, P., Laurendeau, I., Olivi, M., Vidaud, D., Lidereau, R., and Vidaud, M. Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem 1999 Aug; 45(8 Pt 1): 1148-56. Bilbault, P., Lavaux, T., Lahlou, A., Uring-Lambert, B., Gaub, M.P., Ratomponirina, C., Meyer, N., Oudet, P., and Schneider, F. Transient Bcl-2 gene down-expression in circulating mononuclear cells of severe sepsis patients who died despite appropriate intensive care. Intensive Care Med 2004 Mar; 30(3): 408-15. Bode, R., Lippoldt, A., and Birnbaum, D. Purification and properties of D-aromatic lactate dehydrogenase an enzyme involved in the catabolism of the aromatic amino acids of Candida maltosa. Biochem Physiol Pflanzen 1986; 181(3):189-98. Bone, R.C., Balk, R.A., Cerra, F.B., Dellinger, R.P., Fein, A.M., Knaus, W.A., Schein, R.M., and Sibbald, W.J. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992 Jun; 101(6): 1644-55. Boomer, J.S., To, K., Chang, K.C., Takasu, O., Osborne, D.F., Walton, A.H., Bricker, T.L., Jarman, S.D., 2nd, Kreisel, D., Krupnick, A.S., et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011 Dec 21; 306(23): 2594-605. Bozza, F.A., Salluh, J.I., Japiassu, A.M., Soares, M., Assis, E.F., Gomes, R.N., Bozza, M.T., Castro-Faria-Neto, H.C., and Bozza, P.T. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 2007; 11(2): R49. Brealey, D., Brand, M., Hargreaves, I., Heales, S., Land, J., Smolenski, R., Davies, N.A., Cooper, C.E., and Singer, M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002 Jul 20; 360(9328): 219-23. Brun-Buisson, C. The epidemiology of the systemic inflammatory response. Intensive Care Med 2000; 26 Suppl 1: S64-74. Brun-Buisson, C., Doyon, F., Carlet, J., Dellamonica, P., Gouin, F., Lepoutre, A., Mercier, J.C., Offenstadt, G., and Regnier, B. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995 Sep 27; 274(12): 968-74. Brunkhorst, F.M., Engel, C., Bloos, F., Meier-Hellmann, A., Ragaller, M., Weiler, N., Moerer, O., Gruendling, M., Oppert, M., Grond, S., et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008 Jan 10; 358(2): 125-39. Brunkhorst, F.M., Wegscheider, K., Forycki, Z.F., and Brunkhorst, R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 2000 Mar; 26 Suppl 2: S148-52. Calvano, S.E., Xiao, W., Richards, D.R., Felciano, R.M., Baker, H.V., Cho, R.J., Chen, R.O., Brownstein, B.H., Cobb, J.P., Tschoeke, S.K., et al. A network-based analysis of systemic inflammation in humans. Nature 2005 Oct 13; 437(7061): 1032-7. Casey, L.C., Balk, R.A., and Bone, R.C. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993 Oct 15; 119(8): 771-8. Castelino, D.J., McNair, P., and Kay, T.W. Lymphocytopenia in a hospital population-what does it signify? Aust N Z J Med 1997 Apr; 27(2): 170-4. Castelli, G.P., Pognani, C., Meisner, M., Stuani, A., Bellomi, D., and Sgarbi, L. Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 2004 Aug; 8(4): R234-42. Chandel, N.S. Evolution of mitochondria as signaling organelles. Cell Metab 2015 Aug 4; 22(2): 204-6. Chang, K.C., Unsinger, J., Davis, C.G., Schwulst, S.J., Muenzer, J.T., Strasser, A., and Hotchkiss, R.S. Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis. FASEB J 2007 Mar; 21(3): 708-19. Changsirivathanathamrong, D., Wang, Y., Rajbhandari, D., Maghzal, G.J., Mak, W.M., Woolfe, C., Duflou, J., Gebski, V., dos Remedios, C.G., Celermajer, D.S., et al. Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis. Crit Care Med 2011 Dec; 39(12): 2678-83. Cho, W.H., Park, T., Park, Y.Y., Huh, J.W., Lim, C.M., Koh, Y., Song, D.K., and Hong, S.B. Clinical significance of enzymatic lysophosphatidylcholine (LPC) assay data in patients with sepsis. Eur J Clin Microbiol Infect Dis 2012 Aug; 31(8): 1805-10. Chuang, T.Y., Chang, H.T., Chung, K.P., Cheng, H.S., Liu, C.Y., Liu, Y.C., Huang, H.H., Chou, T.C., Chang, B.L., Lee, M.R., et al. High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis. Int J Infect Dis 2014 Mar; 20:13-7. Chung, K.P., Chang, H.T., Huang, Y.T., Liao, C.H., Ho, C.C., Jerng, J.S., and Yu, C.J. Central venous oxygen saturation under non-protocolized resuscitation is not related to survival in severe sepsis or septic shock. Shock 2012 Dec; 38(6): 584-91. Cooper, M.S., and Stewart, P.M. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003 Feb 20; 348(8): 727-34. Cress, A.P., Fraker, P.J., and Bieber, L.L. Carnitine and acylcarnitine levels of human peripheral blood lymphocytes and mononuclear phagocytes. Biochim Biophys Acta 1989 Aug 18; 992(2): 135-9. Cui, L., Zheng, D., Lee, Y.H., Chan, T.K., Kumar, Y., Ho, W.E., Chen, J.Z., Tannenbaum, S.R., and Ong, C.N. Metabolomics investigation reveals metabolite mediators associated with acute lung injury and repair in a murine model of influenza pneumonia. Sci Rep 2016 May 18; 6: 26076. de Jager, C.P., van Wijk, P.T., Mathoera, R.B., de Jongh-Leuvenink, J., van der Poll, T., and Wever, P.C. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care 2010; 14(5): R192. Dellinger, R.P., Levy, M.M., Carlet, J.M., Bion, J., Parker, M.M., Jaeschke, R., Reinhart, K., Angus, D.C., Brun-Buisson, C., Beale, R., et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Jan; 36(1): 296-327. Dellinger, R.P., Levy, M.M., Rhodes, A., Annane, D., Gerlach, H., Opal, S.M., Sevransky, J.E., Sprung, C.L., Douglas, I.S., Jaeschke, R., et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013 Feb; 41(2): 580-637. Drewry, A.M., Samra, N., Skrupky, L.P., Fuller, B.M., Compton, S.M., and Hotchkiss, R.S. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 2014 Nov; 42(5): 383-91. Drobnik, W., Liebisch, G., Audebert, F.X., Frohlich, D., Gluck, T., Vogel, P., Rothe, G., and Schmitz, G. Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 2003 Apr; 44(4): 754-61. Eiris, J., Ribes, A., Fernandez-Prieto, R., Rodriguez-Garcia, J., Rodriguez-Segade, S., and Castro-Gago, M. 3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome. Rev Neurol 1998 Jun; 26(154): 911-4. Eyenga, P., Roussel, D., Morel, J., Rey, B., Romestaing, C., Gueguen-Chaignon, V., Sheu, S.S., and Viale, J.P. Time course of liver mitochondrial function and intrinsic changes in oxidative phosphorylation in a rat model of sepsis. Intensive Care Med Exp 2018 Sep 5; 6(1): 31. Fedotcheva, N.I., Kazakov, R.E., Kondrashova, M.N., and Beloborodova, N.V. Toxic effects of microbial phenolic acids on the functions of mitochondria. Toxicol Lett 2008 Aug 28; 180(3): 182-8. Feingold, K., Kim, M.S., Shigenaga, J., Moser, A., and Grunfeld, C. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab 2004 Feb; 286(2): E201-7. Feingold, K.R., Wang, Y., Moser, A., Shigenaga, J.K., and Grunfeld, C. LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney. J Lipid Res 2008 Oct; 49(10): 2179-87. Fernando, S.M., Tran, A., Taljaard, M., Cheng, W., Rochwerg, B., Seely, A.J.E., and Perry, J.J. Prognostic accuracy of the quick Sequential Organ Failure Assessment for mortality in patients with suspected infection: a systematic review and meta-analysis. Ann Intern Med 2018 Feb 20; 168(4): 266-75. Ferrario, M., Cambiaghi, A., Brunelli, L., Giordano, S., Caironi, P., Guatteri, L., Raimondi, F., Gattinoni, L., Latini, R., Masson, S., et al. Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach. Sci Rep 2016 Feb 5; 6: 20391. Ferreira da Mota, N.V., Brunialti, M.K.C., Santos, S.S., Machado, F.R., Assuncao, M., Azevedo, L.C.P., and Salomao, R. Immunophenotyping of monocytes during human sepsis shows impairment in antigen presentation: a shift toward nonclassical differentiation and upregulation of FCRi-receptor. Shock 2018 Sep; 50(3): 293-300. Finkelsztein, E.J., Jones, D.S., Ma, K.C., Pabon, M.A., Delgado, T., Nakahira, K., Arbo, J.E., Berlin, D.A., Schenck, E.J., Choi, A.M., et al. Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Crit Care 2017 Mar 26; 21(1): 73. Francois, B., Jeannet, R., Daix, T., Walton, A.H., Shotwell, M.S., Unsinger, J., Monneret, G., Rimmele, T., Blood, T., Morre, M., et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 2018 Mar 8; 3(5): 98960. Freund, H., Atamian, S., Holroyde, J., and Fischer, J.E. Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg 1979 Nov; 190(5): 571-6. Gibault, J.P., Frey, A., Guiraud, M., Schirardin, H., Bouletreau, P., and Bach, A.C. Effects of L-carnitine infusion on intralipid clearance and utilization. Study carried out in septic patients of an intensive care unit. JPEN J Parenter Enteral Nutr 1988 Jan-Feb; 12(1): 29-34. Goek, O.N., Doring, A., Gieger, C., Heier, M., Koenig, W., Prehn, C., Romisch-Margl, W., Wang-Sattler, R., Illig, T., Suhre, K., et al. Serum metabolite concentrations and decreased GFR in the general population. Am J Kidney Dis 2012 Aug; 60(2): 197-206. Goetzman, E.S., Alcorn, J.F., Bharathi, S.S., Uppala, R., McHugh, K.J., Kosmider, B., Chen, R., Zuo, Y.Y., Beck, M.E., McKinney, R.W., et al. Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction. J Biol Chem 2014 Apr 11; 289(15): 10668-79. Grailer, J.J., Fattahi, F., Dick, R.S., Zetoune, F.S., and Ward, P.A. Cutting edge: critical role for C5aRs in the development of septic lymphopenia in mice. J Immunol 2015 Feb 1; 194(3): 868-72. Guignant, C., Lepape, A., Huang, X., Kherouf, H., Denis, L., Poitevin, F., Malcus, C., Cheron, A., Allaouchiche, B., Gueyffier, F., et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 2011; 15(2): R99. Guo, R.F., Huber-Lang, M., Wang, X., Sarma, V., Padgaonkar, V.A., Craig, R.A., Riedemann, N.C., McClintock, S.D., Hlaing, T., Shi, M.M., et al. Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis. J Clin Invest 2000 Nov; 106(10): 1271-80. Guo, Y., Luan, L., Patil, N.K., Wang, J., Bohannon, J.K., Rabacal, W., Fensterheim, B.A., Hernandez, A., and Sherwood, E.R. IL-15 enables septic shock by maintaining NK cell integrity and function. J Immunol 2017 Feb 1; 198(3): 1320-33. Gupta, D.L., Bhoi, S., Mohan, T., Galwnkar, S., and Rao, D.N. Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis. Cytokine 2016 Dec; 88: 214-21. Haydar, S., Spanier, M., Weems, P., Wood, S., and Strout, T. Comparison of qSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. Am J Emerg Med 2017 Nov; 35(11): 1730-33. Heffernan, D.S., Monaghan, S.F., Thakkar, R.K., Machan, J.T., Cioffi, W.G., and Ayala, A. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit Care 2012 Jan 20; 16(1): R12. Hietbrink, F., Besselink, M.G., Renooij, W., de Smet, M.B., Draisma, A., van der Hoeven, H., and Pickkers, P. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock 2009 Oct; 32(4): 374-8. Ho, T.J., Kuo, C.H., Wang, S.Y., Chen, G.Y., and Tseng, Y.J. True ion pick (TIPick): a denoising and peak picking algorithm to extract ion signals from liquid chromatography/mass spectrometry data. J Mass Spectrom 2013 Feb; 48(2): 234-42. Hohlstein, P., Gussen, H., Bartneck, M., Warzecha, K.T., Roderburg, C., Buendgens, L., Trautwein, C., Koch, A., and Tacke, F. Prognostic relevance of altered lymphocyte subpopulations in critical illness and sepsis. J Clin Med 2019 Mar 12; 8(3): E353. Hong, S., Harris, K.A., Fanning, K.D., Sarachan, K.L., Frohlich, K.M., and Agris, P.F. Evidence That antibiotics bind to human mitochondrial ribosomal RNA has implications for aminoglycoside toxicity. J Biol Chem 2015 Jul 31; 290(31): 19273-86. Hotchkiss, R.S., Chang, K.C., Swanson, P.E., Tinsley, K.W., Hui, J.J., Klender, P., Xanthoudakis, S., Roy, S., Black, C., Grimm, E., et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000 Dec; 1(6): 496-501. Hotchkiss, R.S., and Karl, I.E. The pathophysiology and treatment of sepsis. N Engl J Med 2003 Jan 9; 348(2): 138-50. Hotchkiss, R.S., Moldawer, L.L., Opal, S.M., Reinhart, K., Turnbull, I.R., and Vincent, J.L. Sepsis and septic shock. Nat Rev Dis Primers 2016 Jun 30; 2: 16045. Hotchkiss, R.S., and Nicholson, D.W. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006 Nov; 6(11): 813-22. Hotchkiss, R.S., and Opal, S. Immunotherapy for sepsis-a new approach against an ancient foe. N Engl J Med 2010 Jul 1; 363(1): 87-9. Hotchkiss, R.S., Osmon, S.B., Chang, K.C., Wagner, T.H., Coopersmith, C.M., and Karl, I.E. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol 2005 Apr 15; 174(8): 5110-8. Hotchkiss, R.S., Swanson, P.E., Freeman, B.D., Tinsley, K.W., Cobb, J.P., Matuschak, G.M., Buchman, T.G., and Karl, I.E. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999 Jul; 27(7): 1230-51. Hotchkiss, R.S., Swanson, P.E., Knudson, C.M., Chang, K.C., Cobb, J.P., Osborne, D.F., Zollner, K.M., Buchman, T.G., Korsmeyer, S.J., and Karl, I.E. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 1999 Apr 1; 162(7): 4148-56. Hotchkiss, R.S., Tinsley, K.W., Swanson, P.E., Chang, K.C., Cobb, J.P., Buchman, T.G., Korsmeyer, S.J., and Karl, I.E. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci U S A 1999 Dec 7; 96(25): 14541-6. Howie, D., Ten Bokum, A., Necula, A.S., Cobbold, S.P., and Waldmann, H. The role of lipid metabolism in T lymphocyte differentiation and survival. Front Immunol 2017 Jan 12; 8: 1949. Ince, C. The microcirculation is the motor of sepsis. Crit Care 2005; 9 Suppl 4: S13-9. Inokuchi-Shimizu, S., Park, E.J., Roh, Y.S., Yang, L., Zhang, B., Song, J., Liang, S., Pimienta, M., Taniguchi, K., Wu, X., et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest 2014 Aug; 124(8): 3566-78. Inoue, S., Sato, T., Suzuki-Utsunomiya, K., Komori, Y., Hozumi, K., Chiba, T., Yahata, T., Nakai, K., and Inokuchi, S. Sepsis-induced hypercytokinemia and lymphocyte apoptosis in aging-accelerated Klotho knockout mice. Shock 2013 Mar; 39(3): 311-6. Inoue, S., Suzuki-Utsunomiya, K., Okada, Y., Taira, T., Iida, Y., Miura, N., Tsuji, T., Yamagiwa, T., Morita, S., Chiba, T., et al. Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit Care Med 2013 Mar; 41(3): 810-9. Inoue, S., Unsinger, J., Davis, C.G., Muenzer, J.T., Ferguson, T.A., Chang, K., Osborne, D.F., Clark, A.T., Coopersmith, C.M., McDunn, J.E., et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol 2010 Feb 1; 184(3): 1401-9. Investigators, N.-S.S., Finfer, S., Chittock, D.R., Su, S.Y., Blair, D., Foster, D., Dhingra, V., Bellomo, R., Cook, D., Dodek, P., et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009 Mar 26; 360(13): 1283-97. Izquierdo-Garcia, J.L., Nin, N., Jimenez-Clemente, J., Horcajada, J.P., Arenas-Miras, M.D.M., Gea, J., Esteban, A., Ruiz-Cabello, J., and Lorente, J.A. Metabolomic profile of ARDS by nuclear magnetic resonance spectroscopy in patients with H1N1 influenza virus pneumonia. Shock 2017 Dec 29; 50(5): 504-10. Izquierdo-Garcia, J.L., Nin, N., Ruiz-Cabello, J., Rojas, Y., de Paula, M., Lopez-Cuenca, S., Morales, L., Martinez-Caro, L., Fernandez-Segoviano, P., Esteban, A., et al. A metabolomic approach for diagnosis of experimental sepsis. Intensive Care Med 2011 Dec; 37(12): 2023-32. Jameson, S.C. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2002 Aug; 2(8): 547-56. Jansen, T.C., van Bommel, J., and Bakker, J. Blood lactate monitoring in critically ill patients: a systematic health technology assessment. Crit Care Med 2009 Oct; 37(10): 2827-39. Jansen, T.C., van Bommel, J., Woodward, R., Mulder, P.G., and Bakker, J. Association between blood lactate levels, Sequential Organ Failure Assessment subscores, and 28-day mortality during early and late intensive care unit stay: a retrospective observational study. Crit Care Med 2009 Aug; 37(8): 2369-74. Japiassu, A.M., Santiago, A.P., d'Avila, J.C., Garcia-Souza, L.F., Galina, A., Castro Faria-Neto, H.C., Bozza, F.A., and Oliveira, M.F. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5'-triphosphate synthase activity. Crit Care Med 2011 May; 39(5): 1056-63. Jing, Q., Xin, S.M., Zhang, W.B., Wang, P., Qin, Y.W., and Pei, G. Lysophosphatidylcholine activates p38 and p42/44 mitogen-activated protein kinases in monocytic THP-1 cells, but only p38 activation is involved in its stimulated chemotaxis. Circ Res 2000 Jul 7; 87(1): 52-9. Jones, A.E. Point: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? Yes. Chest 2011 Dec; 140(6): 1406-08. Kalil, A.C., and LaRosa, S.P. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis 2012 Sep; 12(9): 678-86. Kang, H.M., Ahn, S.H., Choi, P., Ko, Y.A., Han, S.H., Chinga, F., Park, A.S., Tao, J., Sharma, K., Pullman, J., et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 2015 Jan; 21(1): 37-46. Kasten, K.R., Tschop, J., Goetzman, H.S., England, L.G., Dattilo, J.R., Cave, C.M., Seitz, A.P., Hildeman, D.A., and Caldwell, C.C. T-cell activation differentially mediates the host response to sepsis. Shock 2010 Oct; 34(4): 377-83. Kaukonen, K.M., Bailey, M., Pilcher, D., Cooper, D.J., and Bellomo, R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015 Apr 23; 372(17): 1629-38. Khovidhunkit, W., Kim, M.S., Memon, R.A., Shigenaga, J.K., Moser, A.H., Feingold, K.R., and Grunfeld, C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004 Jul; 45(7): 1169-96. Kim, H.E., Grant, A.R., Simic, M.S., Kohnz, R.A., Nomura, D.K., Durieux, J., Riera, C.E., Sanchez, M., Kapernick, E., Wolff, S., et al. Lipid biosynthesis coordinates a mitochondrial-to-cytosolic stress response. Cell 2016 Sep 8; 166(6): 1539-52. Kim, K.S., Suh, G.J., Kim, K., Kwon, W.Y., Shin, J., Jo, Y.H., Lee, J.H., and Lee, H. Quick sepsis-related organ failure assessment score is not sensitive enough to predict 28-day mortality in emergency department patients with sepsis: a retrospective review. Clin Exp Emerg Med 2019 Mar; 6(1): 77-83. Knaus, W.A., Draper, E.A., Wagner, D.P., and Zimmerman, J.E. APACHE II: a severity of disease classification system. Crit Care Med 1985 Oct; 13(10): 818-29. Krahenbuhl, S., and Reichen, J. Carnitine metabolism in patients with chronic liver disease. Hepatology 1997 Jan; 25(1): 148-53. Kumar, A., Roberts, D., Wood, K.E., Light, B., Parrillo, J.E., Sharma, S., Suppes, R., Feinstein, D., Zanotti, S., Taiberg, L., et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006 Jun; 34(6): 1589-96. Kurth, L., Fraker, P., and Bieber, L. Utilization of intracellular acylcarnitine pools by mononuclear phagocytes. Biochim Biophys Acta 1994 Nov 11; 1201(2): 321-7. Lane, A.N., and Fan, T.W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 2015 Feb 27; 43(4): 2466-85. Langley, R.J., Tsalik, E.L., van Velkinburgh, J.C., Glickman, S.W., Rice, B.J., Wang, C., Chen, B., Carin, L., Suarez, A., Mohney, R.P., et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 2013 Jul 24; 5(195): 195ra95. Le Tulzo, Y., Pangault, C., Gacouin, A., Guilloux, V., Tribut, O., Amiot, L., Tattevin, P., Thomas, R., Fauchet, R., and Drenou, B. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock 2002 Dec; 18(6): 487-94. Lee, C.W., Kou, H.W., Chou, H.S., Chou, H.H., Huang, S.F., Chang, C.H., Wu, C.H., Yu, M.C., and Tsai, H.I. A combination of SOFA score and biomarkers gives a better prediction of septic AKI and in-hospital mortality in critically ill surgical patients: a pilot study. World J Emerg Surg 2018; 13: 41. Levy, M.M., Evans, L.E., and Rhodes, A. The Surviving Sepsis Campaign Bundle: 2018 update. Crit Care Med 2018 Jun; 46(6): 997-1000. Levy, M.M., Fink, M.P., Marshall, J.C., Abraham, E., Angus, D., Cook, D., Cohen, J., Opal, S.M., Vincent, J.L., Ramsay, G., et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003 Apr; 31(4): 1250-6. Li, X., Xu, Z., Pang, X., Huang, Y., Yang, B., Yang, Y., Chen, K., Liu, X., Mao, P., and Li, Y. Interleukin-10/lymphocyte ratio predicts mortality in severe septic patients. PLoS One 2017; 12(6): e0179050. Lin, Z.Y., Xu, P.B., Yan, S.K., Meng, H.B., Yang, G.J., Dai, W.X., Liu, X.R., Li, J.B., Deng, X.M., and Zhang, W.D. A metabonomic approach to early prognostic evaluation of experimental sepsis by (1)H NMR and pattern recognition. NMR Biomed 2009 Jul; 22(6): 601-8. Liu, T.F., Vachharajani, V.T., Yoza, B.K., and McCall, C.E. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 2012 Jul 27; 287(31): 25758-69. Liu, Y., Samuel, B.S., Breen, P.C., and Ruvkun, G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 2014 Apr 17; 508(7496): 406-10. Mackall, C.L., Fry, T.J., and Gress, R.E. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011 May; 11(5): 330-42. Maitra, U., Chang, S., Singh, N., and Li, L. Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia. Mol Immunol 2009 Dec; 47(2-3): 420-5. Marik, P.E., Pastores, S.M., Annane, D., Meduri, G.U., Sprung, C.L., Arlt, W., Keh, D., Briegel, J., Beishuizen, A., Dimopoulou, I., et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008 Jun; 36(6): 1937-49. Martin, G.S., Mannino, D.M., Eaton, S., and Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003 Apr 17; 348(16): 1546-54. Matsumoto, H., Ogura, H., Shimizu, K., Ikeda, M., Hirose, T., Matsuura, H., Kang, S., Takahashi, K., Tanaka, T., and Shimazu, T. The clinical importance of a cytokine network in the acute phase of sepsis. Sci Rep 2018 Sep 18; 8(1): 13995. Mera, S., Tatulescu, D., Cismaru, C., Bondor, C., Slavcovici, A., Zanc, V., Carstina, D., and Oltean, M. Multiplex cytokine profiling in patients with sepsis. APMIS 2011 Feb; 119(2): 155-63. Mickiewicz, B., Duggan, G.E., Winston, B.W., Doig, C., Kubes, P., Vogel, H.J., and Alberta Sepsis, N. Metabolic profiling of serum samples by 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock. Crit Care Med 2014 May; 42(5): 1140-9. Mickiewicz, B., Tam, P., Jenne, C.N., Leger, C., Wong, J., Winston, B.W., Doig, C., Kubes, P., Vogel, H.J., and Alberta Sepsis, N. Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit. Crit Care 2015 Jan 15; 19: 11. Mikkelsen, M.E., Miltiades, A.N., Gaieski, D.F., Goyal, M., Fuchs, B.D., Shah, C.V., Bellamy, S.L., and Christie, J.D. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009 May; 37(5): 1670-7. Minkler, P.E., Kerner, J., North, K.N., and Hoppel, C.L. Quantitation of long-chain acylcarnitines by HPLC/fluorescence detection: application to plasma and tissue specimens from patients with carnitine palmitoyltransferase-II deficiency. Clin Chim Acta 2005 Feb; 352(1-2): 81-92. Moon, J.S., Lee, S., Park, M.A., Siempos, II, Haslip, M., Lee, P.J., Yun, M., Kim, C.K., Howrylak, J., Ryter, S.W., et al. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest 2015 Feb; 125(2): 665-80. Moon, J.S., Nakahira, K., Chung, K.P., DeNicola, G.M., Koo, M.J., Pabon, M.A., Rooney, K.T., Yoon, J.H., Ryter, S.W., Stout-Delgado, H., et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med 2016 Sep; 22(9): 1002-12. Mouncey, P.R., Osborn, T.M., Power, G.S., Harrison, D.A., Sadique, M.Z., Grieve, R.D., Jahan, R., Harvey, S.E., Bell, D., Bion, J.F., et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015 Apr 2; 372(14): 1301-11. Nakahira, K., Haspel, J.A., Rathinam, V.A., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., Kim, H.P., et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011 Mar; 12(3): 222-30. Nanni, G., Pittiruti, M., Giovannini, I., Boldrini, G., Ronconi, P., and Castagneto, M. Plasma carnitine levels and urinary carnitine excretion during sepsis. JPEN J Parenter Enteral Nutr 1985 Jul-Aug; 9(4): 483-90. Napolitano, L.A., Grant, R.M., Deeks, S.G., Schmidt, D., De Rosa, S.C., Herzenberg, L.A., Herndier, B.G., Andersson, J., and McCune, J.M. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med 2001 Jan; 7(1): 73-9. Neugebauer, S., Giamarellos-Bourboulis, E.J., Pelekanou, A., Marioli, A., Baziaka, F., Tsangaris, I., Bauer, M., and Kiehntopf, M. Metabolite profiles in sepsis: developing prognostic tools based on the type of infection. Crit Care Med 2016 Sep; 44(9): 1649-62. Nguyen, H.B., Rivers, E.P., Knoblich, B.P., Jacobsen, G., Muzzin, A., Ressler, J.A., and Tomlanovich, M.C. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004 Aug; 32(8): 1637-42. Nicholson, J.K., and Lindon, J.C. Systems biology: metabonomics. Nature 2008 Oct 23; 455(7216): 1054-6. Numan, Y., Jawaid, Y., Hirzallah, H., Kusmic, D., Megri, M., Aqtash, O., Amro, A., Mezughi, H., Mahe | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74818 | - |
dc.description.abstract | 緒論
敗血症是由微生物感染所引起的臨床症候群,病態生理的主要特徵是異常的系統性免疫反應。敗血症的治療沒有太大的進展,同時,不同臨床試驗間,結果並不完全一致。這可能是因為敗血症患者族群的異質性所導致。因此,我們需要進一步探索和敗血症併發之急性器官功能障礙相關的預後生物指標,以更精準的定義和依疾病嚴重度來分類敗血症患者族群。 研究目的 在本論文中,我們將聚焦於敗血症所引起的免疫功能障礙以及系統性代謝途徑的改變,發現可以於敗血症患者臨床照護應用的潛在預後生物指標。 研究材料與方法 我們進行前瞻性研究,召募轉入內科加護病房,診斷為敗血症合併急性器官功能障礙的成人患者(年齡20歲以上)。對於脂肪酸β氧化反應的目標代謝體研究,我們排除罹患有慢性腎病和肝硬化的患者。敗血症患者若周邊血淋巴球數目小於0.5 × 10^3/μL,則定義為併發嚴重周邊血淋巴球低下。我們同時收集周邊血單核細胞,以萃取核醣核酸(RNA)或是進行流式細胞儀分析。患者血中代謝物濃度則使用高效能液相層析質譜儀進行分析。 結果 我們發現發生嚴重淋巴球低下的敗血症患者,血中腫瘤壞死因子α、介白素6、8和10的濃度較高,並且有較高的28天死亡率(校正後風險比值1.262; 95%信賴區間 1.482~8.416, P = 0.004; 經由考克斯比例風險模式計算)。敗血症引發之嚴重淋巴球低下會伴隨血中介白素15濃度輕度而顯著的升高,但是不會合併血中介白素7濃度的顯著變化,同時也會伴隨周邊血單核細胞的BCL2 信使核醣核酸(messenger RNA, mRNA)的表現量顯著較低。我們發現死亡的敗血症患者其血中效應CD4+ T淋巴球的比例顯著較高,但是,並沒有發現任何和院內感染的風險相關的淋巴球族群或是表面標記的變化。 系統代謝體分析研究結果指出,脂肪酸β氧化反應的相關代謝物,可能是潛在敗血症預後相關的生物指標。經由目標代謝體平台,我們在衍生族群中發現,敗血症患者血中短鏈和中鏈肉毒鹼濃度和敗血症所引起之肝腎功能障礙、血小板低下和高乳酸血症有顯著的正相關。然而,僅有乙酰肉毒鹼的血中濃度是和患者血中不同細胞激素濃度有顯著的正相關,並且和陽性血液培養、以及患者28天存活有顯著的相關。我們於驗證族群中確認衍生族群中的分析結果,並且發現敗血症患者若血中乙酰肉毒鹼濃度大於6000 ng/mL,會有顯著較高的28天死亡率(風險比值5.293, 95%信賴區間2.340~11.975, P < 0.001, 經由考克斯比例風險模式計算)。 結論 總結上述,我們發現嚴重周邊血淋巴球低下,以及CD4+ T淋巴球的活化,和嚴重敗血症的死亡率有顯著的相關性。同時,我們也確認敗血症患者血中乙酰肉毒鹼濃度反映急性器官功能障礙和系統性發炎的嚴重度,以及和陽性血液培養的相關性,並可作為敗血症時的預後生物指標。 | zh_TW |
dc.description.abstract | Introduction
Sepsis is a clinical syndrome caused by micro-organism infection, leading to the hallmark of dysregulated systemic immune responses. The progress of sepsis treatment is lacking, and the results from clinical trials were inconsistent, probably due to heterogeneity of sepsis population. Therefore, it is warranted to explore prognostic biomarkers related to sepsis-related organ dysfunction, for precise definition and risk stratification of sepsis patients. Aims In this thesis, we focused on sepsis-related immune dysfunction and metabolic alternations, and explored the potential prognostic biomarkers for application in clinical care of sepsis patients. Materials and Methods This prospective project enrolled adult patients ( 20 years of age) admitted to medical intensive care units for sepsis with acute organ dysfunction. For metabolomic analyses targeting at fatty acid β-oxidation, patients with chronic kidney disease or cirrhosis will be excluded. Severe lymphopenia was defined as a lymphocyte count < 0.5 × 10^3/μL. Peripheral blood mononuclear cells (PBMCs) were isolated for RNA extraction or for flow cytometric analyses. The levels of plasma metabolites were measured using ultra-high performance liquid chromatography-mass spectrometry after metabolite extraction. Results We found that sepsis-related severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor α, interleukin (IL)6, IL8, and IL10, and was also independently associated with 28-day mortality (adjusted hazard ratio 1.262; 95% confidence interval 1.482~8.416, P = 0.004 by Cox proportional hazard model). In patients with severe lymphopenia, the levels plasma IL15, but not IL7, were modestly but significantly increased, and BCL2 mRNA expression in PBMCs is significantly decreased. We subsequently found that sepsis non-survivors had significantly increased percentages of effector CD4+ T lymphocytes at admission, but none of the lymphocytic features we evaluated were related to the risk of nosocomial infection. Systemic metabolomic profiling suggested that metabolites related to fatty acid β-oxidation may be prognostic biomarkers in sepsis. Through targeted metabolomic analyses, we found in the derivation cohort that increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, only plasma acetylcarnitine levels significantly correlated with various plasma cytokine concentrations, and were also associated with blood culture positivity and 28-day mortality risk. The findings in the deviration cohort were confirmed in the independent validation cohort, and showed that patients with plasma acetylcarnitine levels more than 6000 ng/mL had significantly increased 28-day mortality (hazard ratio 5.293, 95% confidence interval 2.340~11.975, P < 0.001 by Cox proportional hazard model). Conclusion In conclusion, severe lymphopenia and increased activation of CD4+ T lymphocytes were associated with increased mortality in patients with severe sepsis. We further confirmed that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis, and can serve as a prognostic biomarker for mortality prediction. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T09:08:10Z (GMT). No. of bitstreams: 1 ntu-108-D00421009-1.pdf: 7509783 bytes, checksum: e3df092269b1eed291b99e4424f63756 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書............................................i
誌謝.......................................................ii 中文摘要..................................................iii 英文摘要....................................................v 博士論文內容 第一章 緒論(Introduction)..................................1 1-1 敗血症文獻回顧......................................1 1-1.1 敗血症病態生理機轉..................................1 1-1.2 敗血症的流行病學....................................2 1-1.3 敗血症診斷定義的演進................................3 1-1.4 敗血症治療的發展....................................7 1-2 敗血症相關免疫功能障礙.............................11 1-2.1 敗血症患者免疫功能障礙的相關表現...................11 1-2.2 敗血症動物模式於免疫功能障礙的相關研究.............12 1-2.3 敗血症免疫功能障礙未解決問題.......................13 1-3 敗血症患者的系統性代謝體變化.......................14 1-3.1 敗血症所引起之系統性代謝體變化.....................14 1-3.2 敗血症動物模式的代謝體研究.........................15 1-3.3 敗血症患者系統性代謝體研究.........................15 1-3.4 敗血症代謝體和多重器官衰竭的關聯性.................17 1-4 研究假說和目的.....................................17 1-4.1 研究目的1: 周邊血淋巴球數目和敗血症病患多重器官衰竭以及存活的相關性.............................................18 1-4.2 研究目的2: 周邊血淋巴球族群和表面標記變化和敗血症病患存活的相關性...............................................19 1-4.3 研究目的3: 利用系統性代謝體分析探索和敗血症預後相關之代謝途徑...................................................20 1-4.4 研究目的4: 利用代謝體平台探索和敗血症中急性器官功能障礙以及預後相關之代謝生物指標...............................20 第二章 研究材料與方法 (Materials and Methods).............22 2-1 研究族群...........................................22 2-1.1 敗血症患者周邊血淋巴球變化和預後的相關.............22 2-1.2 敗血症患者系統性代謝體分析.........................23 2-1.3 經由目標性代謝體獲得敗血症多重器官衰竭和存活相關的代謝生物指標.................................................23 2-2 臨床資料的收集.....................................23 2-3 臨床檢體的收集.....................................24 2-4 血漿中細胞激素濃度的測量...........................24 2-5 即時定量聚合酶連鎖反應(real-time quantitative polymerase chain reaction).................................25 2-6 活體外內毒素血症模式和體外敗血症淋巴球細胞凋亡模式.25 2-7 免疫墨點法(immunoblots)............................26 2-8 Caspase蛋白活性測量................................27 2-9 流式細胞儀(flow cytometry)分析.....................27 2-10 系統性代謝體分析...................................28 2-11 利用目標性代謝體進行血中肉鹼和肉毒鹼的分析.........29 2-12 統計分析...........................................30 第三章 結果(Results)......................................33 3-1 嚴重周邊血淋巴球低下和敗血症存活的相關性...........33 3-1.1 研究族群...........................................33 3-1.2 嚴重周邊血淋巴球低下和系統性炎症反應以及周邊血單核細胞細胞凋亡的相關性.........................................33 3-1.3 體外敗血症淋巴球細胞凋亡模式的相關結果.............34 3-1.4 嚴重周邊血淋巴球低下和敗血症患者多重器官衰竭以及存活的相關.....................................................35 3-2 周邊血淋巴球族群和表面標記的變化和敗血症存活的相關性 ...........................................................36 3-3 系統性代謝體分析探索敗血症相關之代謝途徑變化.......36 3-3.1 研究族群...........................................36 3-3.2 系統性炎症反應相關之代謝體變化.....................37 3-3.3 敗血症多重器官衰竭及預後相關之代謝體變化...........37 3-3.4 利用敗血症所導致脂肪酸代謝異常探索敗血症相關嶄新之代謝物生物指標...............................................38 3-4 目標性代謝體確認敗血症多重器官衰竭和存活相關的代謝生物指標.....................................................39 3-4.1 研究族群...........................................39 3-4.2 衍生族群目標代謝體分析之結果.......................39 3-4.3 驗證族群目標代謝體分析之結果.......................41 第四章 討論(Discussion)...................................43 4-1 嚴重周邊血淋巴球低下和敗血症存活的相關性...........43 4-1.1 研究結果討論及研究限制.............................43 4-1.2 研究結論...........................................47 4-2 周邊血淋巴球族群和表面標記的變化和敗血症存活的相關性.........................................................48 4-2.1 研究結果討論及研究限制.............................48 4-2.2 研究結論...........................................49 4-3 系統性代謝體分析探索敗血症相關之代謝途徑變化.......49 4-3.1 研究結果討論和研究限制.............................49 4-3.2 研究結論...........................................52 4-4 目標性代謝體確認敗血症多重器官衰竭和存活相關的代謝生物指標.....................................................52 4-4.1 研究結果討論和研究限制.............................52 4-4.2 研究結論...........................................56 第五章 展望(Perspectives) ................................58 5-1 本研究對於敗血症診斷和預後評估的重要性.............58 5-1.1 嚴重周邊血淋巴球低下是敗血症患者的預後因子.........58 5-1.2 淋巴球種類和表面標記於敗血症的臨床重要性...........59 5-1.3 乙酰肉毒鹼是評估敗血症多重器官衰竭和預後的生物指標.59 5-2 敗血症預後評估研究的限制...........................60 5-3 未來的研究方向.....................................61 5-3.1 利用高通量平台測量敗血症患者於不同時期免疫功能障礙的表現與臨床意義.............................................61 5-3.2 釐清糖解反應及脂肪酸β氧化反應下游代謝途徑的改變...62 5-3.3 利用代謝相關生物指標進行敗血症患者的篩檢、診斷和監控急性器官功能障礙的恢復與惡化...............................62 論文英文簡述(Summary in English)...........................64 參考文獻(References).......................................79 表目錄 表1、肉毒鹼分析的質譜儀多重反應監測參數設定(transitions for profiling acylcarnitines)..................................99 表2、敗血症中周邊血淋巴球低下之研究族群臨床資料...........100 表3、研究族群周邊血白血球、中性球、淋巴球和單核球的數目和比例........................................................101 表4、活體外內毒素血症模式所造成細胞培養液中細胞激素濃度的變化........................................................102 表5、研究族群中和敗血症 28 天存活相關的預後因子...........103 表6、多變數考克斯比例風險模式分析顯示嚴重淋巴球低下和敗血症 28 天死亡有顯著且獨立的相關性.............................104 表7、敗血症周邊血淋巴球族群和表面標記之研究族群臨床資料...105 表8、系統性代謝體分析探索敗血症相關代謝生物指標之研究族群臨床資料......................................................106 表9、和敗血症系統性炎症反應相關之血中代謝物...............107 表10、和敗血症多重器官衰竭以及 28 天存活相關之血中代謝物..108 表11、敗血症患者血中肉鹼及肉毒鹼目標性代謝體研究: 衍生族群和驗證族群的臨床資料........................................109 表12、經由線性迴歸模式對衍生族群的臨床連續變項進行年齡和性別的校正....................................................110 表13、衍生族群病患血中肉鹼及肉毒鹼濃度和急性器官功能障礙及系統性炎症反應之相關性......................................111 表14、衍生族群不同參數對於陽性血液培養和 28 天死亡率預測的接收者操作特徵曲線的曲線下面積..............................113 表15、單變數分析衍生族群和陽性血液培養顯著相關之臨床參數..114 表16、探索和陽性血液培養(經由邏輯迴歸模式)和 28 天死亡(經由考克斯比例風險模式)統計相關的參數...........................115 表17、單變數分析衍生族群和 28 天存活顯著相關之臨床參數....117 表18、經由線性迴歸模式對驗證族群的臨床連續變項進行年齡和性別的校正....................................................118 表19、驗證族群病患血中乙酰肉毒鹼和己酰肉毒鹼濃度和急性器官功能障礙及系統性炎症反應之相關性............................119 圖目錄 圖1、活體外內毒素血症(Ex vivo endotoxemia)和體外敗血症相關淋巴球細胞凋亡模式(In vitro model simulating lymphocytic apoptosis in sepsis)的實驗流程圖..........................120 圖2、周邊血淋巴球表面標記流式細胞儀分析代表圖.............121 圖3、研究族群血中細胞激素濃度以及周邊血單核細胞中BCL2和BIM mRNA的表現量..............................................122 圖4、研究族群中 65 歲以上和以下的患者,周邊血單核細胞中BCL2和BIM mRNA的表現量差異......................................123 圖5、細胞中BCL2和BIM mRNA表現量於體外敗血症相關淋巴球凋亡模式中的變化..................................................124 圖6、擬敗血症培養液(Sepsis medium)經由Caspase的活化以及粒腺體膜電位的喪失造成Jurkat淋巴球細胞株的細胞凋亡..............125 圖7、擬敗血症培養液(Sepsis medium)造成健康受試者T淋巴球和B淋巴球的細胞凋亡............................................127 圖8、擬敗血症培養液(Sepsis medium)和介白素7對於淋巴球BCL2和BIM蛋白質表現量的影響.....................................128 圖9、介白素7抑制擬敗血症培養液(Sepsis medium)所造成的細胞凋亡........................................................129 圖10、介白素15抑制擬敗血症培養液(Sepsis medium)所造成的細胞凋亡........................................................130 圖11、介白素7和15抑制擬敗血症培養液(Sepsis medium)所造成的細胞凋亡: 流式細胞分析示意圖................................131 圖12、Kaplan-Meier存活曲線顯示合併嚴重淋巴球低下的敗血症患者有較高的28天死亡率........................................132 圖13、周邊血淋巴球族群和表面標記於敗血症患者轉入加護病房後一週內的變化................................................133 圖14、周邊血TH1/TH2/TH17 T細胞和敗血症患者28天存活以及院內感染發生的相關性............................................134 圖15、淋巴球不同活化階段和敗血症患者28天存活以及院內感染發生的相關性..................................................135 圖16、不同淋巴球表面標記的表現和敗血症患者28天存活以及院內感染發生的相關性............................................136 圖17、系統性代謝體分析研究: 衍生族群和驗證族群的28天死亡率Kaplan-Meier曲線..........................................137 圖18、系統性代謝體分析研究: 衍生族群和驗證族群病患血中細胞激素濃度隨時間的變化........................................138 圖19、敗血症患者系統性炎症反應以及血中代謝物濃度變化的相關性........................................................139 圖20、系統性代謝體分析: 敗血症病患血中與系統性炎症反應相關之代謝物....................................................140 圖21、系統性代謝體分析: 敗血症病患血中與多重器官衰竭相關之代謝物......................................................141 圖22、系統性代謝體分析: 敗血症病患血中與28天存活相關之代謝物........................................................142 圖23、敗血症系統性代謝體分析結果顯示代謝物和粒腺體功能障礙之相關性....................................................143 圖24、衍生族群中敗血症患者嚴重周邊血淋巴球低下和乙酰肉毒鹼血中濃度之相關性............................................144 圖25、衍生族群的敗血症患者血中肉毒鹼濃度和陽性血液培養或是28天死亡率的相關性..........................................145 圖26、衍生族群患者血中經疾病嚴重度校正後乙酰肉毒鹼濃度與陽性血液培養及28天存活之相關性................................146 圖27、衍生族群患者血中經疾病嚴重度校正後己酰肉毒鹼濃度與陽性血液培養及28天存活之相關性................................147 圖28、研究族群之肉毒鹼濃度預測陽性血液培養或28天死亡率之接收者操作特徵曲線............................................148 圖29、衍生族群依血中乙酰肉毒鹼或己酰肉毒鹼血中濃度分組後之28天 KaplanMeier 存活曲線...................................149 圖30、非敗血症重症患者血中乙酰肉毒鹼濃度分布以及和腎功能相關性........................................................150 圖31、驗證族群之敗血症患者血中乙酰肉毒鹼和多重器官衰竭、陽性血液培養以及28天存活的相關性..............................151 圖32、驗證族群之敗血症患者血中己酰肉毒鹼和多重器官衰竭、陽性血液培養以及28天存活的相關性..............................152 圖33、敗血症患者周邊血嚴重淋巴球低下以及血中乙酰肉毒鹼濃度和SOFA評分以及病患存活之相關性..............................153 附錄: 個人在修業期間所發表之論文清冊......................154 | |
dc.language.iso | zh-TW | |
dc.title | 經由系統性發炎至多重器官衰竭的嶄新觀點來探討敗血症患者預後生物指標 | zh_TW |
dc.title | Explore prognostic factors in sepsis patients from systemic inflammation to novel insights of multi-organ dysfunction | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 郭錦樺(Ching-Hua Kuo) | |
dc.contributor.oralexamcommittee | 江伯倫,黃坤崙,李岡遠 | |
dc.subject.keyword | 敗血症,介白素7,介白素15,淋巴球低下,乙?肉毒鹼,肉鹼,多重器官衰竭,菌血症,死亡率, | zh_TW |
dc.subject.keyword | sepsis,interleukin 7,interleukin 15,lymphopenia,acetylcarnitine,carnitine,multiple organ failure,bacteremia,mortality, | en |
dc.relation.page | 154 | |
dc.identifier.doi | 10.6342/NTU201904291 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-11-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 7.33 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。