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The molecular basis of paediatric malarial disease

  • Ian A. Clark
  • Michael J. Griffiths
Part of the Birkhäuser Advances in Infectious Diseases book series (BAID)

Abstract

Severe falciparum malaria is an acute systemic disease that can affect multiple organs, including those in which few parasites are found. The acute disease bears many similarities both clinically and, potentially, mechanistically, to the systemic diseases caused by bacteria, rickettsia, and viruses. Traditionally the morbidity and mortality associated with severe malarial disease has been explained in terms of mechanical obstruction to vascular flow by adherence to endothelium (termed sequestration) of erythrocytes containing mature-stage parasites. However, over the past few decades an alternative ‘cytokine theory of disease’ has also evolved, where malarial pathology is explained in terms of a balance between the pro- and anti-inflammatory cytokines. The final common pathway for this pro-inflammatory imbalance is believed to be a limitation in the supply and mitochondrial utilisation of energy to cells. Different patterns of ensuing energy depletion (both temporal and spatial) throughout the cells in the body present as different clinical syndromes. This chapter draws attention to the over-arching position that inflammatory cytokines are beginning to occupy in the pathogenesis of acute malaria and other acute infections. The influence of inflammatory cytokines on cellular function offers a molecular framework to explain the multiple clinical syndromes that are observed during acute malarial illness, and provides a fresh avenue of investigation for adjunct therapies to ameliorate the malarial disease process.

Keywords

Falciparum Malaria Severe Malaria Cerebral Malaria Ethyl Pyruvate Plasmodium Falciparum Malaria 
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.
    Sachs J, Malaney P (2002) The economic and social burden of malaria. Nature 415: 680–685CrossRefPubMedGoogle Scholar
  2. 2.
    WHO (1986) Severe and complicated malaria. Trans R Soc Trop Med Hyg 80: 3–49Google Scholar
  3. 3.
    Marsh K, Snow RW (1997) Host-parasite interaction and morbidity in malaria endemic areas. Philos Trans R Soc Lond 352: 1385–1394CrossRefGoogle Scholar
  4. 4.
    Cannon PR (1941) Some pathological aspects of human malaria. In: FR Moulton (ed): A symposium on human malaria. American Association for the Advancement of Science, Washington, 214–220Google Scholar
  5. 5.
    Meleney HE (1941) The physiological pathology of malaria. In: FR Moulton (ed): A symposium on human malaria. American Association for the Advancement of Science, Washington, 223–230Google Scholar
  6. 6.
    Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434: 214–217CrossRefPubMedGoogle Scholar
  7. 7.
    Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N et al (1995) Indicators of life-threatening malaria in African children. N Engl J Med 332: 1399–1404CrossRefPubMedGoogle Scholar
  8. 8.
    Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ (2000) The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 28: 1833–1840CrossRefPubMedGoogle Scholar
  9. 9.
    Taylor WRJ, White NJ (2002) Malaria and the lung. Clin Chest Med 23: 457–468CrossRefPubMedGoogle Scholar
  10. 10.
    Robinson T, Mosha F, Grainge M, Madeley R (2006) Indicators of mortality in African adults with malaria. Trans R Soc Trop Med Hyg 100: 719–724CrossRefPubMedGoogle Scholar
  11. 11.
    Newton CR, Krishna S (1998) Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther 79: 1–53CrossRefPubMedGoogle Scholar
  12. 12.
    Calkins CM, Bensard DD, Moore EE, McIntyre RC, Silliman CC, Biffl W, Harken AH, Partrick DA, Offner PJ (2002) The injured child is resistant to multiple organ failure: a different inflammatory response? J Trauma 53: 1058–1063PubMedGoogle Scholar
  13. 13.
    Barsness KA, Bensard DD, Partrick DA, Calkins CM, Hendrickson RJ, McIntyre RC (2004) Endotoxin induces an exaggerated interleukin-10 response in peritoneal macrophages of children compared with adults. J Pediatr Surg 39: 912–915CrossRefPubMedGoogle Scholar
  14. 14.
    Barsness KA, Bensard DD, Partrick DA, Calkins CM, Hendrickson RJ, Banerjee A, McIntyre RC (2004) IL-1 beta induces an exaggerated pro-and anti-inflammatory response in peritoneal macrophages of children compared with adults. Pediatr Surg Int 20: 238–242CrossRefPubMedGoogle Scholar
  15. 15.
    Eiam-Ong S (2002) Current knowledge in falciparum malaria-induced acute renal failure. J Med Assoc Thai 85: S16–S24PubMedGoogle Scholar
  16. 16.
    Parker MM, Hazelzet JA, Carcillo JA (2004) Pediatric considerations. Crit Care Med 32: S591–S594CrossRefPubMedGoogle Scholar
  17. 17.
    Pagliara AS, Karl IE, Haywood M, Kipris DM (1973) Hypoglycemia in infancy and childhood. J Pediatr 82: 365–379CrossRefPubMedGoogle Scholar
  18. 18.
    Dekker E, Romijn JA, Ekberg K, Wahren J, Vanthien H, Ackermans MT, Thuy LTD, Chandramouli V, Kager PA et al (1997) Glucose production and gluconeogenesis in adults with uncomplicated falciparum malaria. Am J Physiol 35: E1059–E1064Google Scholar
  19. 19.
    White NJ, Marsh K, Turner RC, Miller KD, Berry CD, Wiliamson DH, Brown J (1987) Hypoglycaemia in African children with severe malaria. Lancet 1: 708–711CrossRefPubMedGoogle Scholar
  20. 19a.
    Lalloo DG, Trevett AJ, Paul M, Korinhona A, Laurenson IF, Mapao J, Nwokolo N, Dangachristian B, Black J, Saweri A et al (1996) Severe and complicated falciparum malaria in Melanesian adults in Papua New Guinea. Am J Trop Med Hyg 55: 119–124PubMedGoogle Scholar
  21. 20.
    Berendt AR, Turner GDH, Newbold CI (1994) Cerebral malaria: the sequestration hypothesis. Parasitol Today 10: 412–414CrossRefPubMedGoogle Scholar
  22. 21.
    Clark IA, Rockett KA (1994) The cytokine theory of human cerebral malaria. Parasitol Today 10: 410–412CrossRefPubMedGoogle Scholar
  23. 22.
    Golgi C (1886) Sull infezione malarica. Arch Sci Med (Torino) 10: 109–135Google Scholar
  24. 23.
    Ross R (1911) The Prevention of Malaria. John Murray, LondonGoogle Scholar
  25. 24.
    Clark IA, Virelizier JL, Carswell EA, Wood PR (1981) Possible importance of macrophage-derived mediators in acute malaria. Infect Immun 32: 1058–1066PubMedGoogle Scholar
  26. 25.
    Graham AL, Allen JE, Read AF (2005) Evolutionary causes and consequences of immunopathology. Annu Rev Ecol Evol Syst 36: 373–397CrossRefGoogle Scholar
  27. 26.
    Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77: 171–192CrossRefPubMedGoogle Scholar
  28. 27.
    Fernandez-Reyes D, Craig AG, Kyes SA, Peshu N, Snow RW, Berendt AR, Marsh K, Newbold CI (1997) A high frequency African coding polymorphism in the n-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya. Hum Mol Genet 6: 1357–1360CrossRefPubMedGoogle Scholar
  29. 28.
    Beutler B, Kronchin N, Milsark IW, Goldberg A, Cerami A (1986) Induction of cachectin (tumor necrosis factor) synthesis by influenza virus: deficient production by endotoxin-resistant (C3H/HEJ) macrophages. Clin Res 34: 491AGoogle Scholar
  30. 29.
    Cheung CY, Poon LLM, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JSM (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease. Lancet 360: 1831–1837CrossRefPubMedGoogle Scholar
  31. 30.
    Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, Frei E, Kufe DW (1988) Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase 1 and pharmacologic study. J Natl Cancer Inst 80: 1039–1044CrossRefPubMedGoogle Scholar
  32. 31.
    Stevenson MM, Riley EM (2004) Innate immunity to malaria. Nat Rev Immunol 4: 169–180CrossRefPubMedGoogle Scholar
  33. 32.
    Koch O, Awomoyi A, Usen S, Jallow M, Richardson A, Hull J, Pinder M, Newport M, Kwiatkowski D (2002) IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria. J Infect Dis 185: 1684–1687CrossRefPubMedGoogle Scholar
  34. 33.
    Aucan C, Walley AJ, Hennig BJ, Fitness J, Frodsham A, Zhang L, Kwiatkowski D, Hill AV (2003) Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia. Genes Immun 4: 275–282CrossRefPubMedGoogle Scholar
  35. 34.
    Walley AJ, Aucan C, Kwiatkowski D, Hill AVS (2004) Interleukin-1 gene cluster polymorphisms and susceptibility to clinical malaria in a Gambian case-control study. Eur J Hum Genet 12: 132–138CrossRefPubMedGoogle Scholar
  36. 35.
    Luoni G, Verra F, Arca B, Sirima BS, Troye Blomberg M, Coluzzi M, Kwiatkowski D, Modiano D (2001) Antimalarial antibody levels and IL-4 polymorphism in the Fulani of West Africa. Genes Immun 2: 411–414CrossRefPubMedGoogle Scholar
  37. 36.
    Wilson JN, Rockett K, Jallow M, Pinder M, Sisay Joof F, Newport M, Newton J, Kwiatkowski D (2005) Analysis of IL10 haplotypic associations with severe malaria. Genes Immun 6: 462–466CrossRefPubMedGoogle Scholar
  38. 37.
    Wang HC, Bloom O, Zhang MH, Vishnubhakat JM, Ombrellino M, Che JT, Frazier A, Yang H, Ivanova S, Borovikova L et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251CrossRefPubMedGoogle Scholar
  39. 38.
    Andersson U, Wang HC, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang MH, Yang H, Tracey KJ (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192: 565–570CrossRefPubMedGoogle Scholar
  40. 39.
    Ulloa L, Fink MP, Tracey KJ (2003) Ethyl pyruvate protects against lethal systemic inflammation by preventing HMGB1 release. Ann NY Acad Sci 987: 319–321Google Scholar
  41. 40.
    Mantell LL, Parrish WR, Ulloa L (2006) HMGB-1 as a therapeutic target for infectious and inflammatory disorders. Shock 25: 4–11CrossRefPubMedGoogle Scholar
  42. 41.
    Alleva LM, Yang H, Tracey KJ, Clark IA (2005) High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria. Trans R Soc Trop Med Hyg 99: 171–175CrossRefPubMedGoogle Scholar
  43. 42.
    Clark IA, Hunt NH, Butcher GA, Cowden WB (1987) Inhibition of murine malaria (Plasmodium chabaudi) in vivo by recombinant interferon-gamma or tumor necrosis factor, and its enhancement by butylated hydroxyanisole. J Immunol 139: 3493–3496PubMedGoogle Scholar
  44. 43.
    Rockett KA, Awburn MM, Cowden WB, Clark IA (1991) Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun 59: 3280–3283PubMedGoogle Scholar
  45. 44.
    Muniz-Junqueira MI, dos Santos-Neto LL, Tosta CE (2001) Influence of tumor necrosis factor-alpha on the ability of monocytes and lymphocytes to destroy intraerythrocytic Plasmodium falciparum in vitro. Cell Immunol 208: 73–79CrossRefPubMedGoogle Scholar
  46. 45.
    Pombo DJ, Lawrence G, Hirunpetcharat C, Rzepczyk C, Bryden M, Cloonan N, Anderson K, Mahakunkijcharoen Y, Martin LB, Wilson D (2002) Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum. Lancet 360: 610–617CrossRefPubMedGoogle Scholar
  47. 46.
    Van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S et al (1996) The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis 174: 1091–1097PubMedGoogle Scholar
  48. 47.
    Fisher CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RMH, Benjamin E (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N Engl J Med 334: 1697–1702CrossRefPubMedGoogle Scholar
  49. 48.
    Clark IA, Alleva LE, Mills AC, Cowden WB (2004) Disease pathogenesis in malaria and clinically similar conditions. Clin Microbiol Rev 17: 509–539CrossRefPubMedGoogle Scholar
  50. 49.
    Spriggs DR, Sherman ML, Kufe DW, Frei E (1987) Tumour necrosis factor and related cytokines. Ciba Found Symp 131: 206–227PubMedGoogle Scholar
  51. 50.
    Creagan ET, Kovach JS, Moertel CG, Frytak S, Kvols LK (1988) A phase 1 clinical trial of recombinant human tumor necrosis factor. Cancer 62: 2467–2471CrossRefPubMedGoogle Scholar
  52. 51.
    Luxemburger C, Nosten F, Kyle DE, Kiricharoen L, Chongsuphajaisiddhi T, White NJ (1998) Clinical features cannot predict a diagnosis of malaria or differentiate the infecting species in children living in an area of low transmission. Trans R Soc Trop Med Hyg 92: 45–49CrossRefPubMedGoogle Scholar
  53. 52.
    Barnwell JW, Asch AS, Nachman RL, Yamaya M, Aikawa M, Ingravallo P (1989) A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes. J Clin Invest 84: 765–772PubMedGoogle Scholar
  54. 53.
    Roberts DD, Sherwood JA, Spitalnik SL, Panton LJ, Howard RJ, Dixit VM, Frazier WA, Miller LH, Ginsburg V (1985) Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence. Nature 318: 64–66CrossRefPubMedGoogle Scholar
  55. 54.
    Newbold C, Warn P, Black G, Berendt A, Craig A, Snow B, Msobo M, Peshu N, Marsh K (1997) Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg 57: 389–398PubMedGoogle Scholar
  56. 55.
    Berendt AR, Simmons DL, Tansey J, Newbold CI, Marsh K (1989) Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature 341: 57–59CrossRefPubMedGoogle Scholar
  57. 56.
    Ockenhouse CF, Tegoshi T, Maeno Y, Benjamin C, Ho M, Kan KE, Thway Y, Win K, Aikawa M, Lobb RR (1992) Human vascular endothelial cell adhesion receptors for Plasmodium falciparum-infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1. J Exp Med 176: 1183–1189CrossRefPubMedGoogle Scholar
  58. 57.
    Carlson J, Helmby H, Hill AVS, Brewster D, Greenwood BM, Wahlgren M (1990) Human cerebral malaria: associated with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet 336: 1457–1460CrossRefPubMedGoogle Scholar
  59. 58.
    Pain A, Ferguson DJP, Kai O, Urban BC, Lowe B, Marsh K, Roberts DJ (2001) Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phonotype and is associated with severe malaria. Proc Natl Acad Sci USA 98: 1805–1810CrossRefPubMedGoogle Scholar
  60. 59.
    Pain A, Urban BC, Kai O, Casals-Pascual C, Shafi J, Marsh K, Roberts DJ (2001) A non-sense mutation in Cd36 gene is associated with protection from severe malaria. Lancet 357: 1502–1503CrossRefPubMedGoogle Scholar
  61. 60.
    Jakobsen PH, Morris-Jones S, Hviid L, Theander TG, Elhassan IM, Bygbjerg IC, Greenwood BM, Ronn A (1994) Increased plasma concentrations of sICAM-1, sVCAM-1 and sELAM-1 in patients with Plasmodium falciparum or P. vivax malaria and association with disease severity. Immunology 83: 665–669PubMedGoogle Scholar
  62. 61.
    Esmon CT (1999) Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Baill Best Pract Clin Haematol 12: 343–359CrossRefGoogle Scholar
  63. 62.
    Levi M, van der Poll T, ten Cate H (2006) Tissue factor in infection and severe inflammation. Semin Thromb Hemost 32: 33–39CrossRefPubMedGoogle Scholar
  64. 63.
    Bajaj MS, Kuppuswamy MN, Manepalli AN, Bajaj SP (1999) Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost 82: 1047–1052PubMedGoogle Scholar
  65. 64.
    Kaplanski G, Marin V, Fabrigoule M, Boulay V, Benoliel AM, Bongrand P, Kaplanski S, Farnarier C (1998) Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intercellular adhesion molecule-1 (ICAM-1 CD54) and vascular cell adhesion molecule-1 (VCAM-1 CD106). Blood 92: 1259–1267PubMedGoogle Scholar
  66. 65.
    Marra F, Grandaliano G, Valente AJ, Abboud HE (1995) Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 22: 780–787PubMedGoogle Scholar
  67. 66.
    English M, Muambi B, Mithwani S, Marsh K (1997) Lactic acidosis and oxygen debt in African children with severe anaemia. Q J Med 90: 563–569Google Scholar
  68. 67.
    Scharte M, Fink MP (2003) Red blood cell physiology in critical illness. Crit Care Med 31: S651–S657CrossRefPubMedGoogle Scholar
  69. 68.
    Taverne J, Sheikh N, Desouza JB, Playfair JHL, Probert L, Kollias J (1994) Anaemia and resistance to malaria in transgenic mice expressing human tumour necrosis factor. Immunology 82: 397–403PubMedGoogle Scholar
  70. 69.
    Overmann RR, Hill TS, Wong YT (1949) Physiological studies in the human malarial host. J Nat Malaria Soc 8: 14–31Google Scholar
  71. 70.
    Dunn MJ (1969) Alterations in red blood cell sodium transport during malaria. J Clin Invest 48: 674–684PubMedGoogle Scholar
  72. 71.
    Illner H, Shires GT (1982) Changes in sodium, potassium, and adenosine triphosphate contents of red blood cells in sepsis and septic shock. Circ Shock 9: 259–267PubMedGoogle Scholar
  73. 72.
    Guzman NJ, Fang MZ, Tang SS, Ingelfinger JR, Garg LC (1995) Autocrine inhibition of Na+/K+-ATPase by nitric oxide in mouse proximal tubule epithelial cells. J Clin Invest 95: 2083–2088PubMedGoogle Scholar
  74. 73.
    Bateman RM, Jagger JE, Sharpe MD, Ellsworth ML, Mehta S, Ellis CG (2001) Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. Am J Physiol 280: H2848–H2856Google Scholar
  75. 74.
    Wambach G, Overhoff U, Hossmann V (1985) Sodium transport and red cell deformability. Klin Wochenschr 3: 35–37Google Scholar
  76. 75.
    Scharte M, Fink MP (2003) Red blood cell physiology in critical illness. Crit Care Med 31: S651–S657CrossRefPubMedGoogle Scholar
  77. 76.
    Lee MV, Ambrus JL, DeSouza JM, Lee RV (1982) Diminished red blood cell deformability in uncomplicated human malaria. A preliminary report. J Med 13: 479–485PubMedGoogle Scholar
  78. 77.
    Rogers F, Dunn R, Barrett J, Merlotti G, Sheaff C, Nolan P (1985) Alterations of capillary flow during sepsis. Circ Shock 15: 105–110PubMedGoogle Scholar
  79. 78.
    Hurd TC, Dasmahapatra KS, Rush BF Jr, Machiedo GW (1988) Red blood cell deformability in human and experimental sepsis. Arch Surg 123: 217–220PubMedGoogle Scholar
  80. 79.
    Dondorp AM, Angus BJ, Hardeman MR, Chotivanich KT, Silamut K, Ruangveerayuth R, Kager PA, White NJ, Vreeken J (1997) Prognostic significance of reduced red blood cell deformability in severe falciparum malaria. Am J Trop Med Hyg 57: 507–511PubMedGoogle Scholar
  81. 80.
    Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ (1999) Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg 60: 733–737PubMedGoogle Scholar
  82. 81.
    Srichaikul T, Panikbutr N, Jeumtrakul P (1967) Bone marrow changes in human malaria. Ann Trop Med Parasitol 61: 40–51PubMedGoogle Scholar
  83. 82.
    Dörmer P, Dietrich M, Kern P, Horstmann RD (1983) Ineffective erythropoiesis in acute human P. falciparum malaria. Blut 46: 279–288CrossRefPubMedGoogle Scholar
  84. 83.
    Wickramasinghe SN, Phillips RE, Looareesuwan S, Warrell DA, Hughes M (1987) The bone marrow in human cerebral malaria: parasite sequestration within sinusoids. Br J Haematol 66: 295–306PubMedGoogle Scholar
  85. 84.
    Wickramasinghe SN, Looareesuwan S, Nagachinta B, White NJ (1989) Dyserythropoiesis and ineffective erythropoiesis in Plasmodium vivax malaria. Br J Haematol 72: 91–99PubMedGoogle Scholar
  86. 85.
    Sassa S, Kawakami M, Cerami A (1983) Inhibiton of the growth and differentiation of erythroid precursor cells by an endotoxin-induced mediator from peritoneal macrophages. Proc Natl Acad Sci USA 80: 1717–1720CrossRefPubMedGoogle Scholar
  87. 86.
    Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A (1985) Identity of tumour necrosis factor and the macrophagesecreted factor cachectin. Nature 316: 552–554CrossRefPubMedGoogle Scholar
  88. 87.
    Clark IA, Chaudhri G (1988) Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis. Br J Haematol 70: 99–103PubMedGoogle Scholar
  89. 88.
    Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V (1999) A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 179: 279–282CrossRefPubMedGoogle Scholar
  90. 89.
    Perkins DJ, Weinberg JB, Kremsner PG (2000) Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity. J Infect Dis 182: 988–992CrossRefPubMedGoogle Scholar
  91. 90.
    May J, Lell B, Luty AJ, Meyer CG, Kremsner PG (2000) Plasma interleukin-10: tumor necrosis factor (TNF)-alpha ratio is associated with TNF promoter variants and predicts malarial complications. J Infect Dis 182: 1570–1573CrossRefPubMedGoogle Scholar
  92. 91.
    Dodoo D, Omer FM, Todd J, Akanmori BD, Koram KA, Riley EM (2002) Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria. J Infect Dis 185: 971–979CrossRefPubMedGoogle Scholar
  93. 92.
    Luty AJ, Perkins DJ, Lell B, Schmidt Ott R, Lehman LG, Luckner D, Greve B, Matousek P, Herbich K, Schmid D et al (2000) Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect Immun 68: 3909–3915CrossRefPubMedGoogle Scholar
  94. 93.
    Issifou S, Mavoungou E, Borrmann S, Bouyou Akotet MK, Matsiegui PB, Kremsner PG, Ntoumi F (2003) Severe malarial anemia associated with increased soluble Fas ligand (sFasL) concentrations in Gabonese children. Eur Cytokine Netw 14: 238–241PubMedGoogle Scholar
  95. 94.
    Helleberg M, Goka BQ, Akanmori BD, Obeng Adjei G, Rodriques O, Kurtzhals JA (2005) Bone marrow suppression and severe anaemia associated with persistent Plasmodium falciparum infection in African children with microscopically undetectable parasitaemia. Malaria J 4: 56CrossRefGoogle Scholar
  96. 95.
    Martiney JA, Sherry B, Metz CN, Espinoza M, Ferrer AS, Calandra T, Broxmeyer HE, Bucala R (2000) Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: Possible role in the pathogenesis of malarial anemia. Infect Immun 68: 2259–2267CrossRefPubMedGoogle Scholar
  97. 96.
    McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R et al (2006) A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203: 1185–1196CrossRefPubMedGoogle Scholar
  98. 97.
    Fink MP (2001) Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin 17: 219–237CrossRefPubMedGoogle Scholar
  99. 98.
    Hotchkiss RS, Rust RS, Dence CS, Wasserman TH, Song SK, Hwang DR, Karl IE, Welch MJ (1991) Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am J Physiol 261: R965–R972PubMedGoogle Scholar
  100. 99.
    Boekstegers P, Weidenhofer S, Kapsner T, Werdan K (1994) Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 22: 640–650CrossRefPubMedGoogle Scholar
  101. 100.
    Fink M (1997) Cytopathic hypoxia in sepsis. Acta Anaesthesiol Scand 110: 87–95Google Scholar
  102. 101.
    L’Her E, Sebert P (2001) A global approach to energy metabolism in an experimental model of sepsis. Am J Respir Crit Care Med 164: 1444–1447PubMedGoogle Scholar
  103. 102.
    Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol 286: R491–497Google Scholar
  104. 103.
    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360: 219–223CrossRefPubMedGoogle Scholar
  105. 104.
    Svistunenko DA, Davies N, Brealey D, Singer M, Cooper CE (2006) Mitochondrial dysfunction in patients with severe sepsis: An EPR interrogation of individual respiratory chain components. Biochim Biophys Acta 1757: 262–272CrossRefPubMedGoogle Scholar
  106. 105.
    Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M (1989) Elevated tumour necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am J Med 87: 139–143PubMedCrossRefGoogle Scholar
  107. 106.
    Kwiatkowski D, Hill AVS, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM (1990) TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 336: 1201–1204CrossRefPubMedGoogle Scholar
  108. 107.
    Nicholls DG (2004) Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr Mol Med 4: 149–177CrossRefPubMedGoogle Scholar
  109. 108.
    Riley MV, Maegraith BG (1962) A factor in the serum of malaria-infected animals capable of inhibiting the in vitro oxidative metabolism of normal liver mitochondria. Ann Trop Med Parasitol 55: 489–497Google Scholar
  110. 109.
    Thurnham DI, Fletcher KA, Maegraith BG (1971) The inhibition of mitochondrial respiration and oxidative phosphorylation by serum from malaria-infected animals. II. The inhibitory activity of serum ultrafitrates from Plasmodium knowlesi-infected monkeys. Ann Trop Med Parasitol 65: 287–295PubMedGoogle Scholar
  111. 110.
    Maegraith B, Fletcher A (1972) The pathogenesis of mammalian malaria. Adv Parasitol 10: 49–75PubMedGoogle Scholar
  112. 111.
    Taylor TE, Borgstein A, Molyneux ME (1993) Acid-base status in paediatric Plasmodium falciparum malaria. Q J Med 86: 99–109PubMedGoogle Scholar
  113. 112.
    Krishna S, Waller DW, Terkuile F, Kwiatkowski D, Crawley J, Craddock CFC, Nosten F, Chapman D, Brewster D, Holloway PA, White NJ (1994) Lactic acidosis and hypoglycaemia in children with severe malaria — pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg 88: 67–73CrossRefPubMedGoogle Scholar
  114. 113.
    Aiyathurai JE, Wong HB, Quak SH, Jacob E, Chio LF, Sothy SP (1983) The significance of type B hyperlactataemia in infective encephalopathy. Ann Acad Med Singapore 12: 115–125PubMedGoogle Scholar
  115. 114.
    Sasi P, English M, Berkley J, Lowe B, Shebe M, Mwakesi R, Kokwaro G (2006) Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions. Trans R Soc Trop Med Hyg 100: 401–409CrossRefPubMedGoogle Scholar
  116. 115.
    Dennis SC, Gevers W, Opie LH (1991) Protons in ischemia: where do they come from; where do they go to? J Mol Cell Cardiol 23: 1077–1086CrossRefPubMedGoogle Scholar
  117. 116.
    Hotchkiss RS, Karl IE (1992) Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 267: 1503–1510CrossRefPubMedGoogle Scholar
  118. 117.
    Fink MP (1996) Does tissue acidosis in sepsis indicate tissue hypoperfusion? Intens Care Med 22: 1144–1146Google Scholar
  119. 118.
    Deshpande SA, Platt MP (1997) Association between blood lactate and acidbase status and mortality in ventilated babies. Arch Dis Child 76: F15–F20Google Scholar
  120. 119.
    Azimi G, Vincent JL (1986) Ultimate survival from septic shock. Resuscitation 14: 245–53CrossRefPubMedGoogle Scholar
  121. 120.
    White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, Williamson DH, Turner RC (1983) Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 309: 61–66PubMedCrossRefGoogle Scholar
  122. 121.
    Planche T (2005) Malaria and fluids — balancing acts. Trends Parasitol 21: 562–567CrossRefPubMedGoogle Scholar
  123. 122.
    Krishna S, Taylor AM, Supanaranond W, Pukrittayakamee S, ter Kuile F, Tawfiq KM, Holloway PAH, White NJ (1999) Thiamine deficiency and malaria in adults from southeast Asia. Lancet 353: 546–549CrossRefPubMedGoogle Scholar
  124. 123.
    Kreisberg RA (1980) Lactate homeostasis and lactic acidosis. Ann Intern Med 92: 227–237PubMedGoogle Scholar
  125. 124.
    Gutierrez G, Wulf ME (2005) Lactic acidosis in sepsis: another commentary. Crit Care Med 33: 2420–2422CrossRefPubMedGoogle Scholar
  126. 125.
    Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Supputamongkol Y, Davis TM, Holloway PA, White NJ (1994) Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. Metabolism 43: 974–981CrossRefPubMedGoogle Scholar
  127. 126.
    Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S et al (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med 327: 1564–1569PubMedCrossRefGoogle Scholar
  128. 127.
    Maran A, Cranston I, Lomas J, Macdonald I, Amiel SA (1994) Protection by lactate of cerebral function during hypoglycaemia. Lancet 343: 16–20CrossRefPubMedGoogle Scholar
  129. 128.
    Schurr A, Payne RS, Miller JJ, Rigor BM (1997) Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study. Brain Res 744: 105–111CrossRefPubMedGoogle Scholar
  130. 129.
    King P, Parkin H, Macdonald IA, Barber C, Tattersall RB (1997) The effect of intravenous lactate on cerebral function during hypoglycaemia. Diabet Med 14: 19–28CrossRefPubMedGoogle Scholar
  131. 130.
    Pellerin L (2003) Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem Int 43: 331–338CrossRefPubMedGoogle Scholar
  132. 131.
    Mecher C, Rackow EC, Astiz ME, Weil MH (1991) Unaccounted for anion in metabolic acidosis during severe sepsis in humans. Crit Care Med 19: 705–711CrossRefPubMedGoogle Scholar
  133. 132.
    Balasubramanyan N, Havens PL, Hoffman GM (1999) Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med 27: 1577–1581CrossRefPubMedGoogle Scholar
  134. 133.
    Dondorp AM, Chau TTH, Phu NH, Mai NTH, Loc PP, Van Chuong L, Sinh DX, Taylor A, Hien TT, White NJ, Day NPJ (2004) Unidentified acids of strong prognostic significance in severe malaria. Crit Care Med 32: 1683–1688CrossRefPubMedGoogle Scholar
  135. 134.
    Dekker E, Hellerstein MK, Romijn JA, Neese RA, Peshu N, Endert E, Marsh K, Sauerwein HP (1997) Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production. J Clin Endocrinol Metab 82: 2514–2521CrossRefPubMedGoogle Scholar
  136. 135.
    Miller SI, Wallace RJ, Musher DM, Septimus EJ, Kohl S, Baughn RE (1980) Hypoglycemia as a manifestation of sepsis. Am J Med 68: 649–654CrossRefPubMedGoogle Scholar
  137. 136.
    Phillips RE (1989) Hypoglycaemia is an important complication of falciparum malaria. Q J Med 71: 477–483PubMedGoogle Scholar
  138. 137.
    Beales PF, Brabin B, Dorman E, Gilles HM, Loutain L, Marsh K, Molyneux ME, Olliaro P, Schapira A, Touze JE et al (2000) Severe falciparum malaria. Trans R Soc Trop Med Hyg 94: S1–S90Google Scholar
  139. 138.
    Waller D, Crawley J, Nosten F, Chapman D, Krishna S, Craddock C, Brewster D, White NJ (1991) Intracranial pressure in childhood cerebral malaria. Trans R Soc Trop Med Hyg 85: 362–364CrossRefPubMedGoogle Scholar
  140. 139.
    Newton CRJC, Crawley J, Sowumni A, Waruiru C, Mwangi I, English M, Murphy S, Winstanley PA, Marsh K, Kirkham FJ (1997) Intracranial hypertension in Africans with cerebral malaria. Arch Dis Child 76: 219–226PubMedGoogle Scholar
  141. 140.
    Beare NA, Southern C, Chalira C, Taylor TE, Molyneux ME, Harding SP (2004) Prognostic significance and course of retinopathy in children with severe malaria. Arch Ophthalmol 122: 1141–1147CrossRefPubMedGoogle Scholar
  142. 141.
    Gitau EN, Newton CR (2005) Blood-brain barrier in falciparum malaria. Trop Med Int Health 10: 285–292CrossRefPubMedGoogle Scholar
  143. 142.
    Adams S, Brown H, Turner G (2002) Breaking down the blood-brain barrier: signaling a path to cerebral malaria? Trends Parasitol 18: 360–366CrossRefPubMedGoogle Scholar
  144. 143.
    Brown H, Hien TT, Day N, Mai N, Chuong LV, Chau T, Loc PP, Phu NH, Bethell D, Farrar J et al (1999) Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol 25: 331–340CrossRefPubMedGoogle Scholar
  145. 144.
    Warrell DA, Looareesuwan S, Phillips RE, White NJ, Warrell MJ, Chapel HM, Areekul S, Tharavanij S (1986) Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis. Am J Trop Med Hyg 35: 882–889PubMedGoogle Scholar
  146. 145.
    Brown HC, Chau TTH, Mai NTH, Day NPJ, Sinh DX, White NJ, Hien TT, Farrar J, Turner GDH (2000) Blood-brain barrier function in cerebral malaria and CNS infections in Vietnam. Neurology 55: 104–111PubMedGoogle Scholar
  147. 146.
    Unterberg AW, Stover J, Kress B, Kiening KL (2004) Edema and brain trauma. Neuroscience 129: 1021–1029CrossRefPubMedGoogle Scholar
  148. 147.
    Idro R, Bitarakwate E, Tumwesigire S, John CC (2005) Clinical manifestations of severe malaria in the highlands of southwestern Uganda. Am J Trop Med Hyg 72: 561–567PubMedGoogle Scholar
  149. 148.
    English M, Newton CR (2002) Malaria: pathogenicity and disease. Chem Immunol 80: 50–69PubMedCrossRefGoogle Scholar
  150. 149.
    Salih MA, Abdel Gader AG, Al Jarallah AA, Kentab AY, Al Nasser MN (2006) Outcome of stroke in Saudi children. Saudi Med J 27: S91–S96PubMedGoogle Scholar
  151. 150.
    Newton CRJC, Peshu N, Kendall B, Kirkham FJ, Sowunmi A, Waruiru C, Mwangi I, Murphy SA, Marsh K (1994) Brain swelling and ischaemia in Kenyans with cerebral malaria. Arch Dis Child 70: 281–287PubMedCrossRefGoogle Scholar
  152. 151.
    Clark IA, Awburn MM, Whitten RO, Harper CG, Liomba NG, Molyneux ME, Taylor TE (2003) Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children. Malaria J 2: 6CrossRefGoogle Scholar
  153. 152.
    Clark IA, Awburn MM, Harper CG, Liomba NG, Molyneux ME (2003) Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis. Malaria J 2: 41CrossRefGoogle Scholar
  154. 153.
    Kwiatkowski D, Cannon JG, Manogue KR, Cerami A, Dinarello CA, Greenwood BM (1989) Tumor necrosis factor production in falciparum malaria and its association with schizont rupture. Clin Exp Immunol 77: 361–366PubMedGoogle Scholar
  155. 154.
    Akanmori BD, Kurtzhals JAL, Goka BQ, Adabayeri V, Ofori MF, Nkrumah FK, Behr C, Hviid L (2000) Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria. Eur Cytokine Net 11: 113–118Google Scholar
  156. 155.
    Gimenez F, de Lagerie SB, Fernandez C, Pino P, Mazier D (2003) Tumor necrosis factor alpha in the pathogenesis of cerebral malaria. Cell Mol Life Sci 60: 1623–1635CrossRefPubMedGoogle Scholar
  157. 156.
    McGuire W, Hill AVS, Allsopp CEM, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371: 508–511CrossRefPubMedGoogle Scholar
  158. 157.
    Clark IA, Rockett KA, Cowden WB (1992) Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. Lancet 340: 894–896CrossRefPubMedGoogle Scholar
  159. 158.
    Schweizer M, Richter C (1994) Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension. Biochem Biophys Res Commun 204: 169–175CrossRefPubMedGoogle Scholar
  160. 159.
    Currier AR, Ziegler MH, Riley MM, Babcock TA, Telbis VP, Carlin JM (2000) Tumor necrosis factor-alpha and lipopolysaccharide enhance interferoninduced antichlamydial indoleamine dioxygenase activity independently. J Interferon Cytokine Res 20: 369–376CrossRefPubMedGoogle Scholar
  161. 160.
    Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H, Wada H, Noma A, Seishima M (2001) Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism. Eur J Immunol 31: 2313–2318CrossRefPubMedGoogle Scholar
  162. 161.
    Medana IM, Day NPJ, Salahifar-Sabet H, Stocker R, Smythe G, Bwanaisa L, Njobvu A, Kayira K, Turner GDH, Taylor TE, Hunt NH (2003) Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria. J Infect Dis 188: 844–849CrossRefPubMedGoogle Scholar
  163. 162.
    Dobbie M, Crawley J, Waruiru C, Marsh K, Surtees R (2000) Cerebrospinal fluid studies in children with cerebral malaria: An excitotoxic mechanism? Am J Trop Med Hyg 62: 284–290PubMedGoogle Scholar
  164. 163.
    Clark IA, Al Yaman FM, Cowden WB, Rockett KA (1996) Does malarial tolerance, through nitric oxide, explain the low incidence of autoimmune disease in tropical Africa. Lancet 348: 1492–1494CrossRefPubMedGoogle Scholar
  165. 164.
    Mendis KN, Carter R (1992) The role of cytokines in Plasmodium vivax malaria. Mem Inst Oswaldo Cruz 87: 51–55PubMedGoogle Scholar
  166. 165.
    Young GB, Bolton CF, Austin TW, Archibald YM, Gonder J, Wells GA (1990) The encephalopathy associated with septic illness. Clin Invest Med 13: 297–304PubMedGoogle Scholar
  167. 166.
    Yang YL, Li JP, Li KZ, Dou KF (2004) Tumor necrosis factor alpha antibody prevents brain damage of rats with acute necrotizing pancreatitis. World J Gastroenterol 10: 2898–2900PubMedGoogle Scholar
  168. 167.
    Wilson JX, Young GB (2003) Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts. Can J Neurol Sci 30: 98–105PubMedGoogle Scholar
  169. 168.
    van Zeijl JH, Bakkers J, Wilbrink B, Melchers WJG, Mullaart RA, Galama JMD (2005) Influenza-associated encephalopathy: No evidence for neuroinvasion by influenza virus nor for reactivation of human herpesvirus 6 or 7. Clin Infect Dis 40: 483–485CrossRefPubMedGoogle Scholar
  170. 169.
    Morishima T, Togashi T, Yokota S, Okuno Y, Miyazaki C, Tashiro M, Okabe N (2002) Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 35: 512–517CrossRefPubMedGoogle Scholar
  171. 170.
    Ichiyama T, Isumi H, Ozawa H, Matsubara T, Morishima T, Furukawa S (2003) Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy. Scand J Infect Dis 35: 59–61CrossRefPubMedGoogle Scholar
  172. 171.
    Ichiyama T, Morishima T, Isumi H, Matsufuji H, Matsubara T, Furukawa S (2004) Analysis of cytokine levels and NF-[kappa]B activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine 27: 31–37CrossRefPubMedGoogle Scholar
  173. 172.
    Hosoya M, Nunoi H, Aoyama M, Kawasaki Y, Suzuki H (2005) Cytochrome c and tumor necrosis factor-alpha values in serum and cerebrospinal fluid of patients with influenza-associated encephalopathy. Pediatr Infect Dis J 24: 467–470CrossRefPubMedGoogle Scholar
  174. 173.
    Kawashima H, Watanabe Y, Ichiyama T, Mizuguchi M, Yamada N, Kashiwagi Y, Takekuma K, Hoshika A, Mori T (2002) High concentration of serum nitrite/nitrate obtained from patients with influenza-associated encephalopathy. Pediatr Int 44: 705–707CrossRefPubMedGoogle Scholar
  175. 174.
    Nakai Y, Itoh M, Mizuguchi M, Ozawa H, Okazaki E, Kobayashi Y, Takahashi M, Ohtani K, Ogawa A, Narita M (2003) Apoptosis and microglial activation in influenza encephalopathy. Acta Neuropathol (Berl) 105: 233–239Google Scholar
  176. 175.
    Idro R, Jenkins NE, Newton CR (2005) Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 4: 827–840CrossRefPubMedGoogle Scholar
  177. 176.
    Lang B, Newbold CI, Williams G, Peshu N, Marsh K, Newton C (2005) Antibodies to voltage-gated calcium channels in children with falciparum malaria. J Infect Dis 191: 117–121CrossRefPubMedGoogle Scholar
  178. 177.
    Haldane JBS (1948) The rate of mutation of human genes. Hereditas 35(Suppl): 267–273Google Scholar
  179. 178.
    Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM (1991) Common west African HLA antigens are associated with protection from severe malaria. Nature 352: 595–600CrossRefPubMedGoogle Scholar
  180. 179.
    Agarwal A, Guindo A, Cissoko Y, Taylor JG, Coulibaly D, Kone A, Kayentao K, Djimde A, Plowe CV, Doumbo O et al (2000) Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96: 2358–2363PubMedGoogle Scholar
  181. 180.
    Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM et al (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305–308CrossRefPubMedGoogle Scholar
  182. 181.
    Hutagalung R, Wilairatana P, Looareesuwan S, Brittenham GM, Aikawa H, Gordeuk VR (1999) Influence of hemoglobin E trait on the severity of falciparum malaria. J Infect Dis 179: 283–286CrossRefPubMedGoogle Scholar
  183. 182.
    Ruwende C, Khoo SC, Snow AW, Yates SNR, Kwiatkowski D, Gupta S, Warn P, Allsopp CEM, Gilbert SC, Peschu N et al (1995) Natural selection of hemi-and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376: 246–249CrossRefPubMedGoogle Scholar
  184. 183.
    Pasvol G, Weatherall DJ, Wilson RJ (1978) Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274: 701–703CrossRefPubMedGoogle Scholar
  185. 184.
    Cappadoro M, Giribaldi G, O’Brien E, Turrini F, Mannu F, Ulliers D, Simula G, Luzzatto L, Arese P (1998) Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 92: 2527–2534PubMedGoogle Scholar
  186. 185.
    Abu-Zeid YA, Abdulhadi NH, Hviid L, Theander TG, Saeed BO, Jepsen S, Jensen JB, Bayoumi RA (1991) Lymphoproliferative responses to Plasmodium falciparum antigens in children with and without the sickle cell trait. Scand J Immunol 34: 237–242CrossRefPubMedGoogle Scholar
  187. 186.
    Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL, Hayton K, Guindo A, Makobongo MO, Schwartz OM et al (2005) Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 435: 1117–1121CrossRefPubMedGoogle Scholar
  188. 187.
    Ringelhann B, Hathorn MK, Jilly P, Grant F, Parniczky G (1976) A new look at the protection of hemoglobin AS and AC genotypes against Plasmodium falciparum infection: a census tract approach. Am J Hum Genet 28: 270–279PubMedGoogle Scholar
  189. 188.
    Mockenhaupt FP, Ehrhardt S, Cramer JP, Otchwemah RN, Anemana SD, Goltz K, Mylius F, Dietz E, Eggelte TA, Bienzle U (2004) Hemoglobin C and resistance to severe malaria in Ghanaian children. J Infect Dis 190: 1006–1009CrossRefPubMedGoogle Scholar
  190. 189.
    Duffy PE, Fried M (2006) Red blood cells that do and red blood cells that don’t: how to resist a persistent parasite. Trends Parasitol 22: 99–101CrossRefPubMedGoogle Scholar
  191. 190.
    Wambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, Mwacharo JK, Weatherall DJ, Snow RW, Marsh K, Williams TN (2006) The effect of alpha+− thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya. PLoS Med 3: e158CrossRefPubMedGoogle Scholar
  192. 191.
    Williams TN, Maitland K, Bennett S, Ganczakowski M, Peto TEA, Newbold CI, Bowden DK, Weatherall DJ, Clegg JB (1996) High incidence of malaria in alpha-thalassaemic children. Nature 383: 522–525CrossRefPubMedGoogle Scholar
  193. 192.
    Oguariri RM, Borrmann S, Klinkert MQ, Kremsner PG, Kun JFJ (2001) High prevalence of human antibodies to recombinant Duffy binding-like alpha domains of the Plasmodium falciparum-infected erythrocyte membrane protein 1 in semi-immune adults compared to that in non-immune children. Infect Immun 69: 7603–7609CrossRefPubMedGoogle Scholar
  194. 193.
    Atkinson SH, Rockett K, Sirugo G, Bejon PA, Fulford A, O’Connell MA, Bailey R, Kwiatkowski DP, Prentice AM (2006) Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype. PLoS Med 3: e172CrossRefPubMedGoogle Scholar
  195. 194.
    Williams TN, Mwangi TW, Wambua S, Peto TEA, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, Macharia A et al (2005) Negative epistasis between the malaria-protective effects of alpha(+)-thalassemia and the sickle cell trait. Nat Genet 37: 1253–1257CrossRefPubMedGoogle Scholar
  196. 195.
    Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R et al (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 101: 296–301CrossRefPubMedGoogle Scholar
  197. 196.
    Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP, Tracey KJ (2002) Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 99: 12351–12356CrossRefPubMedGoogle Scholar
  198. 197.
    Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton C, Levin M (2005) Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 40: 538–545CrossRefPubMedGoogle Scholar
  199. 198.
    Krishna S, Agbenyega T, Angus BJ, Beduaddo G, Oforiamanfo G, Henderson G, Szwandt ISF, O’Brien R, Stacpoole PW (1995) Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria. Q J Med 88: 341–349Google Scholar
  200. 199.
    Dondorp AM, Omodeo Sale F, Chotivanich K, Taramelli D, White NJ (2003) Oxidative stress and rheology in severe malaria. Redox Rep 8: 292–294CrossRefPubMedGoogle Scholar
  201. 200.
    Watt G, Jongsakul K, Ruangvirayuth R (2002) A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria. Q J Med 95: 285–290Google Scholar
  202. 201.
    Wassmer SC, Cianciolo GJ, Combes V, Grau GE (2005) Inhibition of endothelial activation: a new way to treat cerebral malaria? PLoS Med 2: 885–890CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • Ian A. Clark
    • 1
  • Michael J. Griffiths
    • 2
  1. 1.School of Biochemistry and Molecular BiologyAustralian National UniversityCanberraAustralia
  2. 2.Department of PaediatricsNewcastle General HospitalNewcastle upon TyneUK

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