Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1995 Oct 16;14(20):4985–4993. doi: 10.1002/j.1460-2075.1995.tb00181.x

Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome.

M Peled-Kamar 1, J Lotem 1, E Okon 1, L Sachs 1, Y Groner 1
PMCID: PMC394602  PMID: 7588627

Abstract

The copper-zinc superoxide dismutase (CuZnSOD) gene resides on chromosome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic CuZnSOD mice with elevated levels of CuZnSOD were used to determine whether, as in DS, overexpression of CuZnSOD was also associated with thymus and bone marrow abnormalities. Three independently derived transgenic CuZnSOD strains had abnormal thymi showing diminution of the cortex and loss of corticomedullary demarcation, resembling thymic defects in children with DS. Transgenic CuZnSOD mice were also more sensitive than control mice to in vivo injection of lipopolysaccharide (LPS), reflected by an earlier onset and enhanced apoptotic cell death in the thymus. This higher susceptibility to LPS-induced apoptosis was associated with an increased production of hydrogen peroxide and a higher degree of lipid peroxidation. When cultured under suboptimal concentrations of interleukin 3 or in the presence of tumour necrosis factor, bone marrow cells from transgenic CuZnSOD mice produced 2- to 3-fold less granulocyte and macrophage colonies than control. The results indicate that transgenic CuZnSOD mice have certain thymus and bone marrow abnormalities which are similar to those found in DS patients, and that the defects are presumably due to an increased oxidative damage resulting in enhanced cell death by apoptosis.

Full text

PDF
4985

Images in this article

4986Image
on p.4986
4987Image
on p.4987
4988Image
on p.4988
4988Image
on p.4988
4990Image
on p.4990

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ames B. N., Shigenaga M. K., Hagen T. M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915–7922. doi: 10.1073/pnas.90.17.7915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amstad P., Moret R., Cerutti P. Glutathione peroxidase compensates for the hypersensitivity of Cu,Zn-superoxide dismutase overproducers to oxidant stress. J Biol Chem. 1994 Jan 21;269(3):1606–1609. [PubMed] [Google Scholar]
  3. Amstad P., Peskin A., Shah G., Mirault M. E., Moret R., Zbinden I., Cerutti P. The balance between Cu,Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress. Biochemistry. 1991 Sep 24;30(38):9305–9313. doi: 10.1021/bi00102a024. [DOI] [PubMed] [Google Scholar]
  4. Antonarakis S. E. Human chromosome 21: genome mapping and exploration, circa 1993. Trends Genet. 1993 Apr;9(4):142–148. doi: 10.1016/0168-9525(93)90210-9. [DOI] [PubMed] [Google Scholar]
  5. Arends M. J., Wyllie A. H. Apoptosis: mechanisms and roles in pathology. Int Rev Exp Pathol. 1991;32:223–254. doi: 10.1016/b978-0-12-364932-4.50010-1. [DOI] [PubMed] [Google Scholar]
  6. Avraham K. B., Schickler M., Sapoznikov D., Yarom R., Groner Y. Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase. Cell. 1988 Sep 9;54(6):823–829. doi: 10.1016/s0092-8674(88)91153-1. [DOI] [PubMed] [Google Scholar]
  7. Avraham K. B., Sugarman H., Rotshenker S., Groner Y. Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J Neurocytol. 1991 Mar;20(3):208–215. doi: 10.1007/BF01186993. [DOI] [PubMed] [Google Scholar]
  8. Baumgartner J. D., Glauser M. P., McCutchan J. A., Ziegler E. J., van Melle G., Klauber M. R., Vogt M., Muehlen E., Luethy R., Chiolero R. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet. 1985 Jul 13;2(8446):59–63. doi: 10.1016/s0140-6736(85)90176-x. [DOI] [PubMed] [Google Scholar]
  9. Beckman J. S., Carson M., Smith C. D., Koppenol W. H. ALS, SOD and peroxynitrite. Nature. 1993 Aug 12;364(6438):584–584. doi: 10.1038/364584a0. [DOI] [PubMed] [Google Scholar]
  10. Beckman J. S. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol. 1991 Jan;15(1):53–59. [PubMed] [Google Scholar]
  11. Behl C., Davis J. B., Lesley R., Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994 Jun 17;77(6):817–827. doi: 10.1016/0092-8674(94)90131-7. [DOI] [PubMed] [Google Scholar]
  12. Cathcart R., Schwiers E., Ames B. N. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem. 1983 Oct 1;134(1):111–116. doi: 10.1016/0003-2697(83)90270-1. [DOI] [PubMed] [Google Scholar]
  13. Cooper D. N., Hall C. Down's syndrome and the molecular biology of chromosome 21. Prog Neurobiol. 1988;30(6):507–530. doi: 10.1016/0301-0082(88)90033-0. [DOI] [PubMed] [Google Scholar]
  14. Cox D. R., Smith S. A., Epstein L. B., Epstein C. J. Mouse trisomy 16 as an animal model of human trisomy 21 (Down syndrome): production of viable trisomy 16 diploid mouse chimeras. Dev Biol. 1984 Feb;101(2):416–424. doi: 10.1016/0012-1606(84)90156-8. [DOI] [PubMed] [Google Scholar]
  15. Deng H. X., Hentati A., Tainer J. A., Iqbal Z., Cayabyab A., Hung W. Y., Getzoff E. D., Hu P., Herzfeldt B., Roos R. P. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 1993 Aug 20;261(5124):1047–1051. doi: 10.1126/science.8351519. [DOI] [PubMed] [Google Scholar]
  16. Elroy-Stein O., Bernstein Y., Groner Y. Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation. EMBO J. 1986 Mar;5(3):615–622. doi: 10.1002/j.1460-2075.1986.tb04255.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Elroy-Stein O., Groner Y. Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/Zn-superoxide dismutase--implication for gene dosage effects in Down syndrome. Cell. 1988 Jan 29;52(2):259–267. doi: 10.1016/0092-8674(88)90515-6. [DOI] [PubMed] [Google Scholar]
  18. Elson A., Levanon D., Weiss Y., Groner Y. Overexpression of liver-type phosphofructokinase (PFKL) in transgenic-PFKL mice: implication for gene dosage in trisomy 21. Biochem J. 1994 Apr 15;299(Pt 2):409–415. doi: 10.1042/bj2990409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Epstein C. J., Avraham K. B., Lovett M., Smith S., Elroy-Stein O., Rotman G., Bry C., Groner Y. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8044–8048. doi: 10.1073/pnas.84.22.8044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Epstein C. J., Hofmeister B. G., Yee D., Smith S. A., Philip R., Cox D. R., Epstein L. B. Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16. J Exp Med. 1985 Aug 1;162(2):695–712. doi: 10.1084/jem.162.2.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Groner Y., Elroy-Stein O., Avraham K. B., Yarom R., Schickler M., Knobler H., Rotman G. Down syndrome clinical symptoms are manifested in transfected cells and transgenic mice overexpressing the human Cu/Zn-superoxide dismutase gene. J Physiol (Paris) 1990;84(1):53–77. [PubMed] [Google Scholar]
  22. Groner Y., Elroy-Stein O., Bernstein Y., Dafni N., Levanon D., Danciger E., Neer A. Molecular genetics of Down's syndrome: overexpression of transfected human Cu/Zn-superoxide dismutase gene and the consequent physiological changes. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):381–393. doi: 10.1101/sqb.1986.051.01.046. [DOI] [PubMed] [Google Scholar]
  23. Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992 Nov;59(5):1609–1623. doi: 10.1111/j.1471-4159.1992.tb10990.x. [DOI] [PubMed] [Google Scholar]
  24. Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
  25. Holtzman D. M., Bayney R. M., Li Y. W., Khosrovi H., Berger C. N., Epstein C. J., Mobley W. C. Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J. 1992 Feb;11(2):619–627. doi: 10.1002/j.1460-2075.1992.tb05094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kane D. J., Sarafian T. A., Anton R., Hahn H., Gralla E. B., Valentine J. S., Ord T., Bredesen D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. doi: 10.1126/science.8235659. [DOI] [PubMed] [Google Scholar]
  27. Kelner M. J., Bagnell R., Montoya M., Estes L., Uglik S. F., Cerutti P. Transfection with human copper-zinc superoxide dismutase induces bidirectional alterations in other antioxidant enzymes, proteins, growth factor response, and paraquat resistance. Free Radic Biol Med. 1995 Mar;18(3):497–506. doi: 10.1016/0891-5849(94)00167-i. [DOI] [PubMed] [Google Scholar]
  28. Korenberg J. R., Chen X. N., Schipper R., Sun Z., Gonsky R., Gerwehr S., Carpenter N., Daumer C., Dignan P., Disteche C. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4997–5001. doi: 10.1073/pnas.91.11.4997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kubisch H. M., Wang J., Luche R., Carlson E., Bray T. M., Epstein C. J., Phillips J. P. Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9956–9959. doi: 10.1073/pnas.91.21.9956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kuypers F. A., van den Berg J. J., Schalkwijk C., Roelofsen B., Op den Kamp J. A. Parinaric acid as a sensitive fluorescent probe for the determination of lipid peroxidation. Biochim Biophys Acta. 1987 Sep 25;921(2):266–274. doi: 10.1016/0005-2760(87)90027-0. [DOI] [PubMed] [Google Scholar]
  31. Levanon D., Lieman-Hurwitz J., Dafni N., Wigderson M., Sherman L., Bernstein Y., Laver-Rudich Z., Danciger E., Stein O., Groner Y. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J. 1985 Jan;4(1):77–84. doi: 10.1002/j.1460-2075.1985.tb02320.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Levin S., Schlesinger M., Handzel Z., Hahn T., Altman Y., Czernobilsky B., Boss J. Thymic deficiency in Down's syndrome. Pediatrics. 1979 Jan;63(1):80–87. [PubMed] [Google Scholar]
  33. Lotem J., Cragoe E. J., Jr, Sachs L. Rescue from programmed cell death in leukemic and normal myeloid cells. Blood. 1991 Aug 15;78(4):953–960. [PubMed] [Google Scholar]
  34. Lotem J., Sachs L. Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents. Blood. 1993 Aug 15;82(4):1092–1096. [PubMed] [Google Scholar]
  35. Lotem J., Sachs L. Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells. Blood. 1992 Oct 1;80(7):1750–1757. [PubMed] [Google Scholar]
  36. McConkey D. J., Orrenius S. Signal transduction pathways to apoptosis. Trends Cell Biol. 1994 Oct;4(10):370–375. doi: 10.1016/0962-8924(94)90087-6. [DOI] [PubMed] [Google Scholar]
  37. McCord J. M. Mutant mice, Cu,Zn superoxide dismutase, and motor neuron degeneration. Science. 1994 Dec 2;266(5190):1586–1587. [PubMed] [Google Scholar]
  38. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  39. Murphy M., Epstein L. B. Down syndrome (DS) peripheral blood contains phenotypically mature CD3+TCR alpha, beta+ cells but abnormal proportions of TCR alpha, beta+, TCR gamma, delta+, and CD4+ CD45RA+ cells: evidence for an inefficient release of mature T cells by the DS thymus. Clin Immunol Immunopathol. 1992 Feb;62(2):245–251. doi: 10.1016/0090-1229(92)90079-4. [DOI] [PubMed] [Google Scholar]
  40. Nakao N., Frodl E. M., Widner H., Carlson E., Eggerding F. A., Epstein C. J., Brundin P. Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease. Nat Med. 1995 Mar;1(3):226–231. doi: 10.1038/nm0395-226. [DOI] [PubMed] [Google Scholar]
  41. Nelson S. K., Bose S. K., McCord J. M. The toxicity of high-dose superoxide dismutase suggests that superoxide can both initiate and terminate lipid peroxidation in the reperfused heart. Free Radic Biol Med. 1994 Feb;16(2):195–200. doi: 10.1016/0891-5849(94)90143-0. [DOI] [PubMed] [Google Scholar]
  42. Norris K. H., Hornsby P. J. Cytotoxic effects of expression of human superoxide dismutase in bovine adrenocortical cells. Mutat Res. 1990 Mar;237(2):95–106. doi: 10.1016/0921-8734(90)90015-j. [DOI] [PubMed] [Google Scholar]
  43. Olanow C. W. A radical hypothesis for neurodegeneration. Trends Neurosci. 1993 Nov;16(11):439–444. doi: 10.1016/0166-2236(93)90070-3. [DOI] [PubMed] [Google Scholar]
  44. Pluznik D. H., Sachs L. The cloning of normal "mast" cells in tissue culture. J Cell Physiol. 1965 Dec;66(3):319–324. doi: 10.1002/jcp.1030660309. [DOI] [PubMed] [Google Scholar]
  45. Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., Donaldson D., Goto J., O'Regan J. P., Deng H. X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. doi: 10.1038/362059a0. [DOI] [PubMed] [Google Scholar]
  46. Rothstein J. D., Bristol L. A., Hosler B., Brown R. H., Jr, Kuncl R. W. Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4155–4159. doi: 10.1073/pnas.91.10.4155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Royall J. A., Ischiropoulos H. Evaluation of 2',7'-dichlorofluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys. 1993 May;302(2):348–355. doi: 10.1006/abbi.1993.1222. [DOI] [PubMed] [Google Scholar]
  48. Sachs L., Lotem J. Control of programmed cell death in normal and leukemic cells: new implications for therapy. Blood. 1993 Jul 1;82(1):15–21. [PubMed] [Google Scholar]
  49. Sachs L. The adventures of a biologist: prenatal diagnosis, hematopoiesis, leukemia, carcinogenesis, and tumor suppression. Adv Cancer Res. 1995;66:1–40. [PubMed] [Google Scholar]
  50. Sachs L. The molecular control of blood cell development. Science. 1987 Dec 4;238(4832):1374–1379. doi: 10.1126/science.3317831. [DOI] [PubMed] [Google Scholar]
  51. Sakashita A., Epstein C. J., Carlson E., Koeffler H. P. Hematopoietic progenitor cells of transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to tumor necrosis factor. J Cell Physiol. 1994 Aug;160(2):233–238. doi: 10.1002/jcp.1041600204. [DOI] [PubMed] [Google Scholar]
  52. Sandstrom P. A., Buttke T. M. Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4708–4712. doi: 10.1073/pnas.90.10.4708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sandstrom P. A., Mannie M. D., Buttke T. M. Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis. J Leukoc Biol. 1994 Feb;55(2):221–226. doi: 10.1002/jlb.55.2.221. [DOI] [PubMed] [Google Scholar]
  54. Schickler M., Knobler H., Avraham K. B., Elroy-Stein O., Groner Y. Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity. EMBO J. 1989 May;8(5):1385–1392. doi: 10.1002/j.1460-2075.1989.tb03519.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Schreck R., Baeuerle P. A. A role for oxygen radicals as second messengers. Trends Cell Biol. 1991 Aug;1(2-3):39–42. doi: 10.1016/0962-8924(91)90072-h. [DOI] [PubMed] [Google Scholar]
  56. Schulze-Osthoff K., Bakker A. C., Vanhaesebroeck B., Beyaert R., Jacob W. A., Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem. 1992 Mar 15;267(8):5317–5323. [PubMed] [Google Scholar]
  57. Schulze-Osthoff K., Beyaert R., Vandevoorde V., Haegeman G., Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 1993 Aug;12(8):3095–3104. doi: 10.1002/j.1460-2075.1993.tb05978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Standen G., Philip M. A., Fletcher J. Reduced number of peripheral blood granulocytic progenitor cells in patients with Down's syndrome. Br J Haematol. 1979 Jul;42(3):417–423. doi: 10.1111/j.1365-2141.1979.tb01150.x. [DOI] [PubMed] [Google Scholar]
  59. Steinman H. M. The Bcl-2 oncoprotein functions as a pro-oxidant. J Biol Chem. 1995 Feb 24;270(8):3487–3490. [PubMed] [Google Scholar]
  60. Tolksdorf M., Wiedemann H. R. Clinical aspects of Down's syndrome from infancy to adult life. Hum Genet Suppl. 1981;2:3–31. doi: 10.1007/978-3-642-68006-9_2. [DOI] [PubMed] [Google Scholar]
  61. Troy C. M., Shelanski M. L. Down-regulation of copper/zinc superoxide dismutase causes apoptotic death in PC12 neuronal cells. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6384–6387. doi: 10.1073/pnas.91.14.6384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wang S. D., Huang K. J., Lin Y. S., Lei H. Y. Sepsis-induced apoptosis of the thymocytes in mice. J Immunol. 1994 May 15;152(10):5014–5021. [PubMed] [Google Scholar]
  63. White C. W., Avraham K. B., Shanley P. F., Groner Y. Transgenic mice with expression of elevated levels of copper-zinc superoxide dismutase in the lungs are resistant to pulmonary oxygen toxicity. J Clin Invest. 1991 Jun;87(6):2162–2168. doi: 10.1172/JCI115249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Williams G. T., Smith C. A., Spooncer E., Dexter T. M., Taylor D. R. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature. 1990 Jan 4;343(6253):76–79. doi: 10.1038/343076a0. [DOI] [PubMed] [Google Scholar]
  65. Yarom R., Sapoznikov D., Havivi Y., Avraham K. B., Schickler M., Groner Y. Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome. J Neurol Sci. 1988 Dec;88(1-3):41–53. doi: 10.1016/0022-510x(88)90204-3. [DOI] [PubMed] [Google Scholar]
  66. Yim M. B., Chock P. B., Stadtman E. R. Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5006–5010. doi: 10.1073/pnas.87.13.5006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yim M. B., Chock P. B., Stadtman E. R. Enzyme function of copper, zinc superoxide dismutase as a free radical generator. J Biol Chem. 1993 Feb 25;268(6):4099–4105. [PubMed] [Google Scholar]
  68. Zhang Y. H., Takahashi K., Jiang G. Z., Kawai M., Fukada M., Yokochi T. In vivo induction of apoptosis (programmed cell death) in mouse thymus by administration of lipopolysaccharide. Infect Immun. 1993 Dec;61(12):5044–5048. doi: 10.1128/iai.61.12.5044-5048.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. de Vos S., Epstein C. J., Carlson E., Cho S. K., Koeffler H. P. Transgenic mice overexpressing human copper/zinc-superoxide dismutase (Cu/Zn SOD) are not resistant to endotoxic shock. Biochem Biophys Res Commun. 1995 Mar 17;208(2):523–531. doi: 10.1006/bbrc.1995.1370. [DOI] [PubMed] [Google Scholar]
  70. van Deventer S. J., Buller H. R., ten Cate J. W., Sturk A., Pauw W. Endotoxaemia: an early predictor of septicaemia in febrile patients. Lancet. 1988 Mar 19;1(8586):605–609. doi: 10.1016/s0140-6736(88)91412-2. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES