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Tumor Necrosis Factor as a Mediator of Sepsis

  • Stephen F. Lowry
  • Kimberly J. VanZee
  • Craig S. Rock
  • William A. Thompson
  • Hester S. A. Oldenburg
  • Michael A. Rogy
  • Lyle L. Moldawer
Conference paper

Abstract

Few recent interfaces between basic biology and clinical therapeutics have evolved as rapidly as those pertaining to the role of cytokine mediators during sepsis and injury. The perceived need for such therapies remains intense, inasmuch as 35–50% of patients with shock attending gram negative or polymicrobial sepsis ultimately succumb to the acute or chronic sequelae of this process.1 While such infections are amenable to anti-microbial chemotherapy, these agents, in addition to advances in systemic hemodynamic and organ system support, have provided only marginal improvements in patient outcome. Current clinical research efforts are now focused upon other recombinant therapeutic agents that might further benefit the septic patient.2

Keywords

Tumor Necrosis Factor Septic Shock Human Tumor Necrosis Factor Endotoxin Administration Plasma Tumor Necrosis Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bone RC (1991) The pathogenesis of sepsis. Ann Intern Med 115:457–469PubMedGoogle Scholar
  2. 2.
    Bone RC (1991) A critical evaluation of new agents for the treatment of sepsis. JAMA 266:1686–1691PubMedCrossRefGoogle Scholar
  3. 3.
    Fong Y, Moldawer LL, Shires GT, Lowry SF (1990) The biological characteristics of cytokines and their implication in surgical injury. Surg Gynecol Obstet 170:363–378PubMedGoogle Scholar
  4. 4.
    Beutler B, Greenwald D, Hulmes JD, Chang M, Pan Y-CE, Mathison J, Ulevitch R, Cerami A (1985) Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316:552–554PubMedCrossRefGoogle Scholar
  5. 5.
    Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ, Zentella A, Albert JD, Shires GT Cerami A (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234:470–474PubMedCrossRefGoogle Scholar
  6. 6.
    Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anticachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330:662–664PubMedCrossRefGoogle Scholar
  7. 7.
    Fong Y, Tracy KJ, Moldawer LL, Hesse DG, Manogue KR, Kenny J, Lee AT, Kuo GC, Allison A, Lowry SF, Cerami A (1989) Antibodies to cachectin/TNF reduce interleukin-1β and interleukin-6 appearance during lethal bacteremia. J Exp Med 170:1627–1633PubMedCrossRefGoogle Scholar
  8. 8.
    Rock CS, Lowry SF (1991) Tumor Necrosis Factor-∝. J Surg Res 57:434–445CrossRefGoogle Scholar
  9. 9.
    Beutler B, Milsark IW, Cerami AC (1985) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229:869–871PubMedCrossRefGoogle Scholar
  10. 10.
    Tracey KJ, Lowry SF, Beutler B, Cerami A, Albert JD, Shires GT (1986) Cachectin/Tumor necrosis factor participates in reduction of in vitro skeletal muscle transmembrane potential. Surg Forum 37:13–15Google Scholar
  11. 11.
    Tracey KJ, Lowry SF, Beutler B, Cerami A, Albert JD, Shires GT (1986) Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential. J Exp Med 164:1368–1373PubMedCrossRefGoogle Scholar
  12. 12.
    Tracey KJ, Lowry SF, Fahey TJ, Albert JD, Fong Y, Hesse D, Beutler B, Manogue K, Calvano SE, Wei H, Cerami A, Shires GT (1987) Cachectin/tumor necrosis factor induces lethal septic shock and stress hormone responses in the dog. Surg Gynecol Obstet 164:415–422PubMedGoogle Scholar
  13. 13.
    Warren RS, Starnes HF Jr, Gabrilove JL, Oettgen HF, Brennan MF (1987) The acute metabolic effects of tumor necrosis factor administration in humans. Archives of Surgery 122:1396–1400PubMedCrossRefGoogle Scholar
  14. 14.
    Starnes HF, Warren RA, Jeevanandam M, Gabrilove JL, Larchian W, Oettgen HF, Brennan MF (1988) Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest 82:1321–1325PubMedCrossRefGoogle Scholar
  15. 15.
    Revhaug A, Michie HR, Manson JM, Watters JM, Dinarello CA, Wolff SM, Wilmore DW (1988) Inhibition of cyclo-oxygenase attenuates the metabolic response to endotoxin in humans Arch Surg 123:162–170Google Scholar
  16. 16.
    Fong Y, Albert JD, Tracey KJ, Hesse DG, Calvano S, Matthews DE, Lowry SF (1991) The influence of substrate background on the acute metabolic response to epinephrine and Cortisol. J Trauma 31:1467–1476PubMedCrossRefGoogle Scholar
  17. 17.
    Warren RS, Donner DB, Starnes HF, Brennan MF (1987) Modulation of endogenous hormone action by recombinant human tumor necrosis factor. Proc Natl Acad Sci USA 84:8619–8622PubMedCrossRefGoogle Scholar
  18. 18.
    Beutler B, Krochnin N, Milsark IW, Luedke C, Cerami A (1986) Control of cachectin (tumor necrosis factor) synthesis: mechanisms for endotoxin resistance. Science 232:977–980PubMedCrossRefGoogle Scholar
  19. 19.
    Waage A, Halstensen A, Espevik T (1987) Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet i:355–357CrossRefGoogle Scholar
  20. 20.
    Girardin E, Grau GW, Dayer J-M (1988) Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319:397–400PubMedCrossRefGoogle Scholar
  21. 21.
    Debets JMH, Kampmeijer R, van der Linden MPMH, Buurman WA, van der Linden CJ (1989) Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med 17:489–494PubMedCrossRefGoogle Scholar
  22. 22.
    Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock: association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 169:333–338PubMedCrossRefGoogle Scholar
  23. 23.
    de Groote MA, Martin MA, Densen P, Pfalier MA, Wenzel RP (1989) Plasma tumor necrosis factor levels in patients with presumed sepsis: results in those treated with antilipid A antibody vs placebo. JAMA 262:249–251PubMedCrossRefGoogle Scholar
  24. 24.
    Damas P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P (1989) Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 17:975–978PubMedCrossRefGoogle Scholar
  25. 25.
    Marano MA, Fong Y, Moldawer LL, Wei H, Calvano SE, Tracey KJ, Barie PS, Manogue K, Cerami A, Shires GT, Lowry SF (1990) Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 170:32–38PubMedGoogle Scholar
  26. 26.
    Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF (1990) Plasma tumor necrosis factor in patients with septic shock: mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis 141:94–97PubMedGoogle Scholar
  27. 27.
    Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, van der Meer JWM, Endres S, Lonnemann G, Corsetti J, Chernow B, Wilmore DW, Wolff SM, Burke JF, Dinarello CA (1990) Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis 161:79–84PubMedCrossRefGoogle Scholar
  28. 28.
    Calandra T, Baumgartner J-D, Grau GE, Wu M-M, Lambert P-H, Schellekins J, Verhoef J, Glauser MP, and the Swiss-Dutch J5 Immunoglobulin Study Group (1990) Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-∝, and interferon-y in the serum of patients with septic shock. J Infect Dis 161:982–987PubMedCrossRefGoogle Scholar
  29. 29.
    Munoz C, Misset B, Fitting C, Blériot J-P, Carlet J, Cavaillon J-M (1991) Dissociation between plasma and monocyte-associated cytokines during sepsis. Eur J Immunol 21:2177–2184PubMedCrossRefGoogle Scholar
  30. 30.
    Hinshaw LB, Tekamp-Olson P, Chang AC, Lee PA, Taylor FB Jr., Murray CK, Peer GT, Emerson TE Jr., Passey RB, Kuo GC (1990) Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock 30:279–292PubMedGoogle Scholar
  31. 31.
    Beutler BA, Milsark IW, Cerami A (1985) Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 135:3972–3977PubMedGoogle Scholar
  32. 32.
    Mathison JC, Wolfson E, Ulevitch RJ (1988) Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 81:1925–1937PubMedCrossRefGoogle Scholar
  33. 33.
    Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladino MA, Cerami A,Shires GT, Lowry SF (1988) Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 166:147–153Google Scholar
  34. 34.
    Fong Y, Marano MA, Moldawer LL, Wei H, Calvano SE, Kenney JS, Allison AC, Cerami A, Shires GT, Lowry SF (1990) The acute splanchnic and peripheral tissue metabolic response to endotoxin in man. J Clin Invest 85:1896–1904PubMedCrossRefGoogle Scholar
  35. 35.
    Richardson RP, Rhyne CD, Fong Y, Hesse DG, Tracey KJ, Marano MA, Lowry SF, Antonacci AC, Calvano SE (1989) Peripheral blood leukocyte kinetics following in vivo lipopolysaccharide (LPS) administration to normal human subjects: influence of elicited hormones and cytokines. Ann Surg 210:239–245PubMedCrossRefGoogle Scholar
  36. 36.
    Calvano SE, Barber AE, Hawes AS, de Riesthal HF, Coyle SM, Lowry SF (1992) Effect of combined cortisol-endotoxin administration on peripheral blood leukocyte counts and phenotype in normal humans. Arch Surg 127:181–186PubMedCrossRefGoogle Scholar
  37. 37.
    Martich GD, Danner RL, Ceska M, Suffredini AF (1991) Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med 173:1021–1024PubMedCrossRefGoogle Scholar
  38. 38.
    van der Poll T, Büller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJH, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW (1990) Activation of coagulation after administration of tumor necrosis factor to normal subjects. New Engl J Med 322:1622–1627PubMedCrossRefGoogle Scholar
  39. 39.
    Michie HR, Spriggs DR, Manogue KR, Sherman ML, Rcvhaug A, O’Dwyer ST, Arthur K, Dinarello CA, Cerami A, Wolff SM, Kufe DW, Wilmore DW (1988) Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. Surgery 104:280–286PubMedGoogle Scholar
  40. 40.
    van der Poll T, Romijn JA, Endert E, Borm JJJ, Büller HR, Sauerwein HP (1991) Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 261:E457-E465Google Scholar
  41. 41.
    Meyer J, Yurt RW, Dehaney R, Hesse DG, Tracey KJ, Fong Y, Richards D, Calvano S, Dineen P, Shires GT, Lowry SF, Davis JM (1988) Differential neutrophil activation before and after endotoxin infusion in enterally versus parenterally fed subjects. Surg Gynecol Obstet 167:501–509PubMedGoogle Scholar
  42. 42.
    Michie HR, Manogue KR, Spriggs DR, Revhaug A, O’Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW (1988) Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 318:1481–1486PubMedCrossRefGoogle Scholar
  43. 43.
    Scales WE, Chensue SW, Otterness I, Kunkel SL (1989) Regulation of monokine gene expression: prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta-mRNA and cell-associated bioactivity. J Leukoc Biol 45:416–421PubMedGoogle Scholar
  44. 44.
    Han J, Thompson P, Beutler B (1990) Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 172:391–394PubMedCrossRefGoogle Scholar
  45. 45.
    Barber AE, Coyle SM, Fong Y, Fischer E, Marano MA, Calvano SE, Moldawer LL, Shires GT, Lowry SF (1990) Impact of hypercortisolemia on the metabolic and hormonal responses to endotoxin in man. Surg Forum 41:74–77Google Scholar
  46. 46.
    Santos AA, Schellinga M, Lynch E, Brown E, Lawton P (1992) Elaboration of IL-1 receptor antagonist is not attenuated by glucocorticoids following endotoxemia in humans. Arch Surg (in press)Google Scholar
  47. 47.
    Marano MA, Moldawcr LL, Fong Y, Wei H, Minei J, Yurt R, Cerami A, Lowry SF (1988) Cachectin/tumor necrosis factor production in experimental burns and Pseudomonas infection. Arch Surg 123:1383–1388PubMedCrossRefGoogle Scholar
  48. 48.
    Keogh CV, Fong Y, Barber A, Marano MA, Wei H, Minei J, Lowry SF, Moldawer LL (1990) Identification of a novel cell-associated murine tumor necrosis factor. Arch Surg 125:79–85PubMedCrossRefGoogle Scholar
  49. 49.
    Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988) A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53:45–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Fong Y, Lowry SF (1990) Cytokines and the cellular response to injury and infection. In: Wilmore DW, Brennan MF, Harken AH, Holcroft JW, Meakins JL (eds) Care of the Surgical Patient vol. 1, Scientific American, New York sec. 4, chap. 7, pp. 1–17Google Scholar
  51. 51.
    Aggarwal BB, Eessalu TE, Hass PE (1985) Characterization of receptors for human tumor necrosis factor and their regulation by gamma interferon. Nature 318:665-PubMedCrossRefGoogle Scholar
  52. 52.
    Baglioni C, McCandless S, Travernier J, Fiers W (1985) Binding of human tumor necrosis factor to high affinity receptors on HeLa and lymphoblastoid cells sensitive to growth inhibition. J Biol Chem 260:13395PubMedGoogle Scholar
  53. 53.
    Kull FC, Jacobs S, Cuatrecasas P (1985) Cellular receptor for 125I-labeled tumor necrosis factor: Specific binding, affinity labeling, and relationship to sensitivity. Proc Natl Acad Sci USA 82:5756PubMedCrossRefGoogle Scholar
  54. 54.
    Tsujimoto M, Yip YK, Vilcek J (1985) Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci USA 82:7626PubMedCrossRefGoogle Scholar
  55. 55.
    Tsujimoto M, Vilcek J (1986) Tumor necrosis factor receptor in HeLa cells and their regulation by interferon Y. J Biol Chem 261:5384PubMedGoogle Scholar
  56. 56.
    Engelmann H, Novick D, Wallach D (1990) Two tumor necrosis factor-binding proteins purified from human urine. J Bio Chem 265:1531–1536.Google Scholar
  57. 57.
    Kohno T, Brewer MT, Baker SL, Schwartz PE, King MW, Hale KK, Squires CH, Thompson RC, Vannice JL (1990) A second tumor necrosis factor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc Natl Acad Sci USA 87:8331–8335PubMedCrossRefGoogle Scholar
  58. 58.
    Ding AH, Sanchez E, Srimal S, Nathan CF (1989) Macrophages rapidly internalize their tumor necrosis factor receptors in response to bacterial lipopolysaccharide. J Biol Chem 264:3924PubMedGoogle Scholar
  59. 59.
    Ding AH, Porteu F, Sanchez E, Nathan CF (1990) Down-regulation of tumor necrosis factor receptors on macrophages and endothelial cells by microtubule depolymerizing agents. J Exp Med 171:715PubMedCrossRefGoogle Scholar
  60. 60.
    Luedke CE, Cerami A (1990) Interferon-gamma overcomes glucocorticoid suppression of cachectin/tumor necrosis factor biosynthesis by murine macrophages. J Clin Invest 86:1234–1240PubMedCrossRefGoogle Scholar
  61. 61.
    Rock CS, Coyle SM, Keogh CV, Lazarus DD, Hawes AS, Leskiw M, Moldawer LL, Stein TP, Lowry SF (1992) Influence of hypercortisolemia on the acute phase protein response to endotoxin in man. Surgery (in press)Google Scholar
  62. 62.
    Lowry SF (1986) The host metabolic response to injury. In: Shires GT and Davis JM (eds) Host Defenses Vol. 6, Academic Press, pp 169–180Google Scholar
  63. 63.
    Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317:653–658PubMedCrossRefGoogle Scholar
  64. 64.
    Burd RS, Cody CS, Raymond CS, Dunn DL (1992) Anti-endotoxin monoclonal antibodies protect by enhancing bacterial and endotoxin clearance during murine gram-negative bacterial sepsis. Arch Surg (in press)Google Scholar
  65. 65.
    Dcitch EA (1990) The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch Surg 125:403–404CrossRefGoogle Scholar
  66. 66.
    Fong Y, Marano MA, Barber A, Wei H, Moldawer LL, Bushman ED, Coyle SM, Shires GT, Lowry SF (1989) Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in man. Ann Surg 210:449–457PubMedCrossRefGoogle Scholar
  67. 67.
    Lowry SF (1990) The route of feeding influences injury responses. J Trauma 30:510–515Google Scholar
  68. 68.
    Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM (1989) TEN versus TPN following major abdominal trauma-reduced septic morbidity. J Trauma 29:916–923PubMedCrossRefGoogle Scholar
  69. 69.
    McDonald WS, Sharp CW, Deitch EA (1991) Immediate enteral feeding in burn patients is safe and effective. Ann Surg 213:177–183PubMedCrossRefGoogle Scholar
  70. 70.
    Zanetti G, Heumann D, Gérain J, Kohler J, Abbet P, Barras C, Lucas R, Glauser M-P, Baumgartner J-D (1992) Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice 148:1890–1897PubMedGoogle Scholar
  71. 71.
    Eskandari MK, Bolgos G, Miller C, Nguyen DT, DeForge LE, Remick DG (1992) Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J Immunol 143:2724–2730Google Scholar
  72. 72.
    Peetre C, Thysell H, Grubb A, Olsson I (1988) A tumor necrosis factor binding protein is present in human biological fluids. Eur J Haematol 41:414–419PubMedCrossRefGoogle Scholar
  73. 73.
    Seckinger P, Isaaz S, Dayer J-M (1988) A human inhibitor of tumor necrosis factor ∝. J Exp Med 167:1511–1516PubMedCrossRefGoogle Scholar
  74. 74.
    Gatanaga T, Hwang C, Kohr W, Cappuccini F, Lucci JA III, Jeffes EWB, Lentz R, Tomich J, Yamamota RS, Granger GA (1990) Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proc Natl Acad Sci USA 87:8781–8784PubMedCrossRefGoogle Scholar
  75. 75.
    Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D (1989) A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. J Biol Chem 264:11974–11980PubMedGoogle Scholar
  76. 76.
    VanZee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF (1992) Tumor necrosis factor (TNF) soluble receptors circulate during experimental and clinical inflammation and can protect against excessive TNF∝ in vitro and in vivo. Proc Natl Acad Sci (in press)Google Scholar
  77. 77.
    Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 175:323–329PubMedCrossRefGoogle Scholar
  78. 78.
    Lowry SF (1992) Modulating the metabolic response to injury and infection. Proceedings of the Nutrition Society (in press)Google Scholar
  79. 79.
    Lowry SF Moldawer LL (1992) Cytokines and cytokine antagonists in sepsis and critical illness. Yearbook of Intensive Care and Emergency Medicine, Update 1992, Springer-Verlag, Berlin, pp. 36–43Google Scholar
  80. 80.
    Lesslauer W, Tabuchi H, Gentz R, Brockhaus M, Schlacger EJ, Grau G, Piguet PF, Pointaire P, Vassalli P, Loetscher H (1991) Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol 21:2883–2886PubMedCrossRefGoogle Scholar
  81. 81.
    Vassalli P (1992) The pathophysiology of tumor necrosis factors. Ann Rev Immunol 10:411–452CrossRefGoogle Scholar
  82. 82.
    Exley AR, Cohen J, Buurman W, Owen R, Hanson G, Lumley J, Aulakh JM, Bodmer M, Riddell A, Stephens S (1990) Monoclonal antibody to TNF in severe septic shock. Lancet 335:1275–1277PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Stephen F. Lowry
    • 1
  • Kimberly J. VanZee
    • 1
  • Craig S. Rock
    • 1
  • William A. Thompson
    • 1
  • Hester S. A. Oldenburg
    • 1
  • Michael A. Rogy
    • 1
  • Lyle L. Moldawer
    • 1
  1. 1.Department of Surgery, Laboratory of Surgical MetabolismNew York Hospital-Cornell Medical CenterNew YorkUSA

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