The Role of Complement

  • M. Heideman
  • A. Bengtsson


The bactericidal effect of blood has been known for more than 100 years [1, 2]. As early as the late nineteenth century it was demonstrated that serum contains factors that mediate lysis of bacteria and antibody sensitized cells [3]. Complement is an essential system for protection against invading microorganisms like virus and bacteria. Split products of this cascade will enhance phagocytosis, bacterial killing and promote leukocytosis [4, 5]. Lysis of foreign invaders by complement requires components C5b-C9 from the terminal part of the complement cascade. This complex is also called the membrane attack complex [6]. Individuals with different hereditary complement protein defects suffer from recurrent and sometimes life threatening infections [7–9].


  1. 1.
    Nutall G (1888) Experimente über die bakterienfeindlichen Einflüsse des thierischen Körpers. Z Hyg Infektionskr 4:353.CrossRefGoogle Scholar
  2. 2.
    Buchner H (1889) Ueber die nähere Natur der bakterientödtenden Substanz in Blutserum. Centralbl Bakteriol Parasitenkd 6:561–565.Google Scholar
  3. 3.
    Bordet J (1895) Les leucocytes et les propriétés du sérum chez les vaccines. Ann Inst Pasteur 9:504–506.Google Scholar
  4. 4.
    Ross SC, Rosenthal PJ, Berberich HM, Densen P (1987) Killing of Neisseria meningitidis by human neutrophils: implications for normal and complement-deficient individuals. J Infect Dis 155:1266–1275-.PubMedCrossRefGoogle Scholar
  5. 5.
    Ghebrehiwet B, Müller-Eberhard HJ (1979) C3e: an acidic fragment of human C3 with leukocytosis inducing activity. J Immunol 123:616–621.PubMedGoogle Scholar
  6. 6.
    Mayer MM (1973) The complement system. Sci Am 229:54–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Densen P, Weiler JM, Griffiss JM, Hoffmann LG (1987) Familial properdin deficiency and fatal meningococcemia. N Engl J Med 316:922–926.PubMedCrossRefGoogle Scholar
  8. 8.
    Molad Y, Zimran A, Sidi Y, Pinkhas J (1990) Posttraumatic meningococcemia in a patient with deficiency of the C7 complement component. Isr J Med Sci 26:90–92.PubMedGoogle Scholar
  9. 9.
    Alper CA, Rosen FG (1984) Inherited deficiencies of complement proteins in man. Springer Semin Immunopathol 7:251–261.PubMedCrossRefGoogle Scholar
  10. 10.
    Lachmann PJ (1988) Complement and disease. Recenti Prog Med 79:293–299.PubMedGoogle Scholar
  11. 11.
    Dalmasso AP (1986) Complement in the pathophysiology and diagnosis of human disease. CRC Crit Rev Clin Lab Sci 24:123–183.CrossRefGoogle Scholar
  12. 12.
    McPhaden AR, Whaley K (1985) The complement system in sepsis and trauma. Br Med Bull 41: 281–286.PubMedGoogle Scholar
  13. 13.
    Sundsmo JS (1982) The leukocyte complement system. Fed Proc 41:3094–3098.PubMedGoogle Scholar
  14. 14.
    Byrne K, Carey PD, Sugerman HJ (1987) Adult respiratory distress syndrome. Acute Care 13: 206–234.PubMedGoogle Scholar
  15. 15.
    Schlag G, Redl H (1982) New aspects of shock lung. Anasth Intensivther Notfallmed 17:86–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Müller-Eberhard H (1986) The membrane attack complex of complement. Annu Rev Immunol 4:503–528.PubMedCrossRefGoogle Scholar
  17. 17.
    Hänsch GM, Scitz M, Betz M (1987) Effects of late acting complement components C5b-9 on human monocytes: release of prostanoids, oxygen radicals and a factor which induced cell proliferation. Int Arch Allergy Appl Immunol 82:317–320.PubMedCrossRefGoogle Scholar
  18. 18.
    Betz M, Scitz M, Hänsch GM (1987) Thromboxane B2 synthesis in human platelets induced by the late complement components C5b-9. Int Arch Allergy Appl Immunol 82:313–316.PubMedCrossRefGoogle Scholar
  19. 19.
    Hänsch GM, Scitz M, Martinotti G, Betz M, Rauterberg EW, Gemsa D (1984) Macrophages release arachidonic acid, prostaglandin E2, and thromboxane in response to late complement components. J Immunol 133:2145–2150.PubMedGoogle Scholar
  20. 20.
    Hamilton KK, Hattori R, Esmon CT, Sims PJ (1990) Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 265:3809–3814.PubMedGoogle Scholar
  21. 21.
    Salama A, Hugo F, Heinrich D, Höge R, Müller R, Kiefel V, Müller-Eckhardt C, Bhakdi S (1988) Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass. N Engl J Med 318:408–414.PubMedCrossRefGoogle Scholar
  22. 22.
    Colomb MG, Arlaud GJ, Villiers CL (1984) Structure and activation of Cl: current concepts. Complement 1:69–80.PubMedGoogle Scholar
  23. 23.
    Cooper NR, Morrison DC (1978) Binding and activation of the first component of human complement by the lipid A region of lipopolysaccharides. J Immunol 120:1862–1868.PubMedGoogle Scholar
  24. 24.
    Porter RR, Reid KBM (1979) Activation of the complement system by antibody-antigen complexes: the classical pathway. Adv Protein Chem 33:1–64.PubMedCrossRefGoogle Scholar
  25. 25.
    Tenner AJ, Ziccardi RJ, Cooper NR (1984) Antibody-independent C1 activation by E. coli. J Immunol 133:886–891.PubMedGoogle Scholar
  26. 26.
    Ziccardi RJ (1984) The role of immune complexes in the activation of the first component of human complement. J Immunol 132:283–288.PubMedGoogle Scholar
  27. 27.
    Shastri KA, Phillips MJ, Raza S, Logue GL, Rustagi PK (1988) Effect of RBCs on the activation of human complement by heparin-protamine complexes. Blood 71:36–40.PubMedGoogle Scholar
  28. 28.
    Ghebrihiwet B, Silverberg M, Kaplan AP (1981) Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 153:665–676.CrossRefGoogle Scholar
  29. 29.
    Pangburn MK (1983) Activation of complement via the alternative pathway. Fed Proc 42:139–143.PubMedGoogle Scholar
  30. 30.
    Gelfand JA, Donelan M, Burke JF (1983) Preferential activation and depletion of the alternative complement pathway by burn injury. Ann Surg 198:58–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Joiner KA (1986) Role of complement in infectious disease. In: Ross GD (ed) Immunobiology of the complement system. Academic, New York, pp 183–195.Google Scholar
  32. 32.
    Pangburn MK, Schreiber RD, Müller-Eberhard HJ (1983) C3b deposition during activation of the alternative complement pathway and the effect of deposition on the activating surface. J Immunol 131:1930–1935.PubMedGoogle Scholar
  33. 33.
    Morrison DC, Kline LF (1977) Activation of the classical and properdin pathways of complement by bacterial lipopolysaccharides (LPS). J Immunol 118:362–368.PubMedGoogle Scholar
  34. 34.
    Langlois PF, Gawryl MS (1988) Detection of the terminal complement complex in patient plasma following acute myocardial infarction. Artherosclerosis 70:95–105.CrossRefGoogle Scholar
  35. 35.
    Langlois PF, Sharon GE, Gawryl MS (1989) Plasma concentrations of complement-activation complexes correlated with disease activity in patients diagnosed with isolated central nervous system vasculitis. J Allergy Clin Immunol 83:11–16.PubMedCrossRefGoogle Scholar
  36. 36.
    Haeger M, Bengtsson A, Karlsson K, Heideman M (1989) Complement activation and anaphylatoxin (C3a and C5a) formation in preeclampsia and by amniotic fluid. Obstet Gynecol 73:551–556.PubMedGoogle Scholar
  37. 37.
    Kapp A, Meske-Brand S, Maly FE, Müller W (1984) Komplementaktivierung bei Patienten mit chronischer Polyarthritis gemessen anhand des Komplement Bruckstückes C3a im Plasma. Z Rheumatol 43:103–105.PubMedGoogle Scholar
  38. 38.
    Roxvall L, Bengtsson A, Heideman M (1989) Anaphylatoxin generation in acute pancreatitis. J Surg Res 47:138–143.PubMedCrossRefGoogle Scholar
  39. 39.
    Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW (1981) Complement activation during cardiopulmonary bypass. Evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 304:497–503.PubMedCrossRefGoogle Scholar
  40. 40.
    Hugli TE (1979) Complement anaphylatoxins as plasma mediators, spasmogens and chemotaxins. In: Bing DH (ed) The chemistry and physiology of human plasma proteins. Pergamon, New York, pp 255–280.Google Scholar
  41. 41.
    Grant JA, Dupree E, Goldman AS, Schultz DR, Jackson AL (1975) Complement-mediated release of histamine from human leukocytes. J Immunol 114:1101–1106.PubMedGoogle Scholar
  42. 42.
    Hugli TE, Marceau F (1985) Effects of the C5a anaphylatoxin and its relationship to cyclo-oxygenase metabolites in rabbit vascular strips. Br J Pharmacol 84:725–733.PubMedGoogle Scholar
  43. 43.
    Stimler NP, Brocklehurst WE, Bloor CM, Hugli TE (1981) Anaphylatoxin-mediated contraction of guinea pig lung strips: a non-histamine tissue responses. J Immunol 126:2258–2261.PubMedGoogle Scholar
  44. 44.
    Hugli TE, Marceau F, Lundberg C (1987) Effect of complement fragments on pulmonary and vascular smooth muscle. Am Rev Respir Dis 135:S9–S13.PubMedGoogle Scholar
  45. 45.
    Hachfeld del Balzo U, Levi R, Polley MJ (1985) Cardiac dysfunction caused by purified human C3a anaphylatoxin. Proc Natl Acad Sci USA 82:886–890.CrossRefGoogle Scholar
  46. 46.
    Yancey KB, Hammer CH, Harvath L, Renfer L, Frank MM, Lawley TJ (1985) Studies of human C5a as a mediator of inflammation in normal human skin. J Clin Invest 75:486–495.PubMedCrossRefGoogle Scholar
  47. 47.
    Webster RO, Hong SR, Johnston Jr RB, Henson PM (1980) Biological effects of the human complement fragments C5a and C5adesArg on neutrophil function. Immunopharmacology 2:201–219.PubMedCrossRefGoogle Scholar
  48. 48.
    Hugli TE (1984) Structure and function of the anaphylatoxins. Springer Semin Immunopathol 7: 193–219.PubMedCrossRefGoogle Scholar
  49. 49.
    Goldstein IM, Brai M, Osler AG, Weissmann G (1973) Lysosomal enzyme release from human leukocytes: mediation by the alternate pathway of complement activation. J Immunol 111:33–37.PubMedGoogle Scholar
  50. 50.
    Goodman MG, Chenoweth DE, Weigle WO (1982) Induction of interleukin 1 secretion and enhancement of humoral immunity by binding of human C5a to macrophage surface C5a receptors. J Exp Med 1156:912–917.CrossRefGoogle Scholar
  51. 51.
    Scholz W, McClurg MR, Cardenas GJ, Smith M, Noonan DJ, Hugli TE, Morgan EL (1990) C5a-mediated release of interleukin 6 by human monocytes. Clin Immun Immunopathol 57:297–307.CrossRefGoogle Scholar
  52. 52.
    Henson PM, Larsen GL, Webster RO, Mitchell BC, Goins AJ, Henson J (1982) Pulmonary microvascular alterations and injury induced by complement fragments: synergistic effect of complement activation, neutrophil sequestration, and prostaglandins. Ann NY Acad Sci USA 384:287–300-.CrossRefGoogle Scholar
  53. 53.
    Fearon DT, Collins LA (1983) Increased expression of C3b receptors on polymorphonuclear leukocytes induced by chemotactic factors and by purification procedures. J Immunol 130:370–375.PubMedGoogle Scholar
  54. 54.
    Lee J, Hakim RM, Fearon DT (1984) Increased expression of the C3b receptor and complement activation during hemodialysis. Clin Exp Immunol 56:205–214.PubMedGoogle Scholar
  55. 55.
    Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A (1992) Complement, neutrophil and macrophage activation in women with severe preclampsia and HELLP syndrome. Obstet Gynecol (in press).Google Scholar
  56. 56.
    Dwenger A, Schweitzer G, Regel G (1986) Bronchoalveolar lavage fluid and plasma proteins, chemiluminescence response and protein contents of polymorphonuclear leukocytes from blood and lavage fluid in traumatized patients. J Clin Chem Clin Biochem 24:73–88.PubMedGoogle Scholar
  57. 57.
    Habal FM, Movat HZ, Burrows CE (1974) Isolation of two functionally different kininogens from human plasma separation from proteinase inhibitors and interaction with plasma kallikrein. Biochem Pharmacol 23:2291–2303.PubMedCrossRefGoogle Scholar
  58. 58.
    Kaplan AP (1978) Initiation of the intrinsic pathways of man: the role of surfaces, Hageman factor, prekallikrein, high-molecular-weight kininogen, and factor XI. Prog Hemost Thromb 4:127–175.PubMedGoogle Scholar
  59. 59.
    Sundsmo JS, Fair DS (1983) Relationship among the complement, kinin, coagulation and fibrinolytic systems. Springer Semin Immunopathol 6:231–258.PubMedCrossRefGoogle Scholar
  60. 60.
    Slotman GJ, Burchard KW, Williams JJ, D’Arezzo A, Yellin SA (1986) Interaction of prostaglandins, activated complement, and granulocytes in clinical sepsis and hypotension. Surgery 99:744–751.PubMedGoogle Scholar
  61. 61.
    Kongsgaard UE, Smith-Erichsen N, Geiran O, Björkskau L (1989) Different activation patterns in the plasma kallikrein-kinin and complement systems during coronary bypass surgery. Acta Anesthesiol Scand 33:343–347.CrossRefGoogle Scholar
  62. 62.
    Pottemeyer E, Vassar MJ, Holcroft JW (1986) Coagulation, inflammation and response to injury. Crit Care Clin 2:683–702.Google Scholar
  63. 63.
    Dahlén S-E, Björk J, Hedqvist P, Arfors KE, Hammarström S, Lindgren JA, Samuelsson B (1981) Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules. In vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci USA 78:3887–3891.PubMedCrossRefGoogle Scholar
  64. 64.
    Björk J, Hedqvist P, Arfors KE (1982) Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation 6:189–200.PubMedCrossRefGoogle Scholar
  65. 65.
    Fantone JC, Ward PA (1982) Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107:397–418.Google Scholar
  66. 66.
    Bengtsson A, Holmberg P, Heideman M (1987) The ischaemic leg as a source of complement activation. Br J Surg 74:697–700.CrossRefGoogle Scholar
  67. 67.
    Kapur MM, Jain P, Gidh M (1988) Estimation of serum complement and its role in management of trauma. World J Surg 12:211–216.PubMedCrossRefGoogle Scholar
  68. 68.
    Pacher R, Redl H, Frass M, Petzl DH, Schuster E, Woloszczuk W (1989) Relationship between neopterin and granulocyte elastase plasma levels and the severity of multiple organ failure. Crit Care Med 17:221–226.PubMedCrossRefGoogle Scholar
  69. 69.
    Fosse E, Mollnes TE, Ingvaldsen B (1987) Complement activation during major operations with or without cardiopulmonary bypass. J Thorac Cardiovasc Surg 93:860–866.PubMedGoogle Scholar
  70. 70.
    Fosse E, Mollnes TE, Ingvaldsen B (1987) Complement activation during major operations with or without cardiopulmonary bypass. J Thorac Cardiovasc Surg 93:860–866.PubMedGoogle Scholar
  71. 71.
    Bengtsson A, Heideman M (1986) Altered anaphylatoxin activity during induced hypoperfusion in acute and elective abdominal aortic surgery. J Trauma 26:631–636.CrossRefGoogle Scholar
  72. 72.
    Heideman M (1979) Complement activation in vitro induced by endotoxin and injured tissue. J Surg Res 26:670–675.PubMedCrossRefGoogle Scholar
  73. 73.
    Hansson GK, Lagerstedt E, Bengtsson A, Heideman M (1987) IgG binding to cytoskeletal intermediate filaments activates the complement cascade. Exp Cell Res 70:338–350.CrossRefGoogle Scholar
  74. 74.
    Cavarocchi NC, Pluth JR, Schaff HV, Orszulak TA, Homburger HA, Solis E, Kaye MP, Clancy MS, Kolff J, Deeb GM (1986) Complement activation during cardiopulmonary bypass. Comparison of bubble and membrane oxygenators. J Thorac Cardiovasc Surg 91:252–258.PubMedGoogle Scholar
  75. 75.
    Lee J, Hakim RM, Fearon DT (1984) Increased expression of the C3b receptor and complement activation during hemodialysis. Clin Exp Immunol 56:205–214.PubMedGoogle Scholar
  76. 76.
    Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW (1981) Complement activation during cardiopulmonary bypass. Evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 304:497–503.PubMedCrossRefGoogle Scholar
  77. 77.
    Herzlinger GA, Bing DH, Stein R, Cumming RD (1981) Quantitative measurement of C3 activation at polymer surfaces. Blood 57:764–770.PubMedGoogle Scholar
  78. 78.
    Westaby S, Dawson P, Turner MW, Pridie RB (1985) Angiography and complement activation. Evidence for generation of C3a anaphylatoxin by intravascular contrast agents. Cardiovasc Res 19:85–88.PubMedCrossRefGoogle Scholar
  79. 79.
    Bengtsson A, Milocco I, Heideman M, Berggren H (1989) Altered concentrations of terminal complement complexes, anaphylatoxins and leukotrienes in the coronary sinus during cardiopulmonary bypass. J Cardiothorac Anesthesiol 3:305–310.CrossRefGoogle Scholar
  80. 80.
    Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD (1983) Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 86:845–857.PubMedGoogle Scholar
  81. 81.
    Kirklin JK, Chenoweth DE, Naftel DC, Blackstone EH, Kirklin JW, Bitran DD, Curd JG, Reves JG, Samuelson PN (1986) Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg 41:193–199.PubMedCrossRefGoogle Scholar
  82. 82.
    Ausman RK, Aust JB (1959) Isolated perfusion of the liver with HN2. Proceedings of the Forum Sessions 45th Clinical Congress of the American College of Surgeons, Atlantic City, New Jersey.Google Scholar
  83. 83.
    Aigner K, Walther H, Tonn J, Wenzl A, Hechtel R, Merker G, Schwemmle K (1983) First experimental and clinical results of isolated liver perfusion with cytotoxins in metastases from colorectal primary. In: Schwemmle K, Aigner K (eds) Vascular perfusion in cancer therapy. Springer, Berlin Heidelberg New York, pp 99–102 (Recent results in cancer research, vol 86).CrossRefGoogle Scholar
  84. 84.
    Quebbeman EJ, Skibba JL, Petroff RJ (1984) A technique for isolated hyperthermic liver perfusion. J Surg Oncol 27:141–145.PubMedCrossRefGoogle Scholar
  85. 85.
    Aigner KR, Walther H, Tonn JC, Link KH, Schock P, Schwemmle K (1984) Die isolierte Leberperfusion bei fortgeschrittenen Metastasen kolorektaler Karzinome. Onkologie 1:13–21.CrossRefGoogle Scholar
  86. 86.
    Bengtsson A, Arnestad J-P, Bengtson J-P, Henriksson BÅ, Stenqvist O, Naredi P, Hafström LO (1991) Formation of anaphylatoxins and terminal complement complexes by perfusion of limbs with malignant melanoma. Reg Cancer Treat 3:308–311.Google Scholar
  87. 87.
    Arnestad J-P, Bengtsson A, Bengtson J-P, Henriksson BÅ, Stenqvist O, Naredi P, Hafström LO (1992) Isolated hyperthermic liver perfusion with cytostatic-containing perfusate activates the complement cascade. Br J Surg 79:948–951.PubMedCrossRefGoogle Scholar
  88. 88.
    Sieunarine K, Langton S, Lawrence-Brown MMD, Goodman MA, Prendergast FJ, Hellings M (1990) Elastase levels in salvaged blood and the effect of cell washing. Aust N Z J Surg 60:613–616.PubMedCrossRefGoogle Scholar
  89. 89.
    Ketai LH, Grum CM (1986) C3a and adult respiratory distress syndrome after massive transfusion. Crit Care Med 14:1001–1003.PubMedCrossRefGoogle Scholar
  90. 90.
    Bull MH, Bull BS, Van Arsdell GS, Smith LL (1988) Clinical implication of procoagulant and leukoattractant formation during intraoperative blood salvage. Arch Surg 123:1073–1078.PubMedCrossRefGoogle Scholar
  91. 91.
    Keeling MM, Gray LA Jr, Bring MA, Hillerich VK, Bland KI (1983) Intraoperative autotransfusion. Experience in consecutive 725 cases. Ann Surg 197:536–540.PubMedCrossRefGoogle Scholar
  92. 92.
    Hallowell P, Bland JHL, Buckley MJ (1972) Transfusion of fresh autologous blood in open-heart surgery. J Thorac Cardiovasc Surg 64:941–945.PubMedGoogle Scholar
  93. 93.
    Tedesco F, Radillo O, Candussi G, Nazzaro A, Mollnes TE, Pecorari D (1990) Immunohistochemical detection of terminal complement complex and S protein in normal and pre-eclamptic placentae. Clin Exp Immunol 80:236–240.PubMedCrossRefGoogle Scholar
  94. 94.
    Haeger M, Bengtsson A, Karlsson K, Heideman M (1989) Complement activation and anaphylatoxin (C3a and C5a) formation in preeclampsia and by amniotic fluid. Obstet Gynecol 73:551–556.PubMedGoogle Scholar
  95. 95.
    Haeger M, Unander M, Bengtsson A (1990) Enhanced anaphylatoxin and terminal C5b-9 complement complex formation in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 76:698–702.PubMedGoogle Scholar
  96. 96.
    Carmichael FJ, Lindop MJ, Farman JV (1985) Anesthesia for hepatic transplantation: cardiovascular and metabolic alterations and their management. Anesth Analg 64:108–116.PubMedCrossRefGoogle Scholar
  97. 97.
    Aggerwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR (1987) Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 19: 54–55.Google Scholar
  98. 98.
    Bengtsson A, Holmberg P, Heideman M (1983) The ischemic limb as a source of complement activation. Br J Surg 74:697–700.CrossRefGoogle Scholar
  99. 99.
    Heideman M, Hugli TE (1984) Anaphylatoxin generation in multisystem organ failure. J Trauma 24:1038–1043.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • M. Heideman
    • 1
  • A. Bengtsson
    • 2
  1. 1.Department of SurgeryBorås HospitalBoråsSweden
  2. 2.Department of Anesthesiology & Intensive CareSahlgren’s HospitalGothenburgSweden

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