Advertisement

Lipoprotein (LDL and HDL) Oxidation in Diabetes Mellitus

Chapter
Part of the Contemporary Diabetes book series (CDI)

Abstract

Diabetes mellitus, in general, and hyperglycemia, in particular, are both linked to premature and accelerated atherogenesis. This is mediated via lipid modifications both quantitatively (mostly increased levels of serum VLDL and decreased HDL concentrations) and qualitatively (lipoproteins oxidation), leading to the accumulation of macrophage foam cells in the arterial wall, the hallmark of early atherogenesis.

Lipoproteins oxidation in diabetes is increased due to the activation of several pro-oxidant systems including: increased formation of advanced glycation end products (AGEs), activation of PKC, and increased activity of the macrophage NADPH oxidase machinery. Furthermore, Diabetes is characterized by a depletion in serum and cellular antioxidants, including: the oxidized lipids hydrolyzing enzyme paraoxonase1 (PON1), reduced glutathione (GSH), vitamin C, and Vitamin E.

Understanding of the above mechanisms which are involved in diabetes-induced lipoproteins oxidation could offer appropriate means to attenuate atherogenesis.

Keywords

NADPH Oxidase Diabetic Mouse PON1 Activity Foam Cell Formation Pomegranate Juice 
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.

References

  1. 1.
    Matthews DR, Matthews PC. Banting Memorial Lecture 2010^. Type 2 diabetes as an ‘infectious’ disease: is this the Black Death of the 21st century? Diabet Med. 2011;28(1):2–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Daneman D. Type 1 diabetes. Lancet. 2006;367(9513): 847–58.PubMedCrossRefGoogle Scholar
  3. 3.
    Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet. 2011;378(9786):169–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Fisher M. Diabetes and atherogenesis. Heart. 2004;90(3):336–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendíc S, Rydén L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002;359(9324):2140–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54: 1615–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.CrossRefGoogle Scholar
  8. 8.
    Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation. 2003;108(12):1527–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care. 1979;2:120–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Prince CT, Becker DJ, Costacou T, Miller RG, Orchard TJ. Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC). Diabetologia. 2007;50:2280–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet. 2008;371:1800–9.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Piga R, Naito Y, Kokura S, Handa O, Yoshikawa T. Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells. Atherosclerosis. 2007;193: 328–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Dasu MR, Devaraj S, Jialal I. High glucose induces IL-1beta expression in human monocytes: mechanistic insights. Am J Physiol Endocrinol Metab. 2007;293:E337–46.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Srivastava AK. High glucose-induced activation of protein kinase signaling pathways in vascular smooth muscle cells: a potential role in the pathogenesis of vascular dysfunction in diabetes. Int J Mol Med. 2002;9(1):85–9.PubMedGoogle Scholar
  16. 16.
    Chait A, Bornfeldt KE. Diabetes and atherosclerosis: is there a role for hyperglycemia? J Lipid Res. 2009;50:S335–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Tomkin GH. Atherosclerosis, diabetes and lipoproteins. Expert Rev Cardiovasc Ther. 2010;8(7): 1015–29.PubMedCrossRefGoogle Scholar
  18. 18.
    Brunzell JD, Deeb SS. Familial lipoprotein lipase deficiency, Apo C-II deficiency, and hepatic lipase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic & molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2789–816.Google Scholar
  19. 19.
    Bos G, Dekker JM, Nijpels G, et al. A combination of high concentrations of serum triglyceride and non-high-density-lipoprotein-cholesterol is a risk factor for cardiovascular disease in subjects with abnormal glucose metabolism—the Hoorn Study. Diabetologia. 2003;46:910–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Jenkins AJ, Rowley KG, Lyons TJ, Best JD, Hill MA, Klein RL. Lipoproteins and diabetic microvascular complications. Curr Pharm Des. 2004;10(27): 3395–418.PubMedCrossRefGoogle Scholar
  21. 21.
    Ohgami N, Miyazaki A, Sakai M, Kuniyasu A, Nakayama H, Horiuchi S. Advanced glycation end products (AGE) inhibit scavenger receptor class B type I-mediated reverse cholesterol transport: a new crossroad of AGE to cholesterol metabolism. J Atheroscler Thromb. 2003;10:1–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms: oxidation. Inflammation and genetics. Circulation. 1995;91: 2488–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Aviram M. Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins. Antioxid Redox Signal. 1999;1(4):585–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaplan M, Aviram M. Ox-LDL atherogenic and proinflammatory characteristics during macrophage foam cell formation: an inhibitory role for nutritional antioxidants and serum paraoxonase. Clin Chem Lab Med. 1999;37:777–87.PubMedCrossRefGoogle Scholar
  25. 25.
    Ylä-Herttuala S, Rosenfeld ME, Parthasarathy S, Glass CK, Sigal E, Witztum JL, Steinberg D. Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions. Proc Natl Acad Sci USA. 1990;87(18):6959–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Parthasarathy S, Wieland E, Steinberg D. A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc Natl Acad Sci USA. 1989;86:1046–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Stocker R, Keaney JF. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:1381–478.PubMedCrossRefGoogle Scholar
  29. 29.
    Steinberg D. The LDL modification hypothesis of atherogenesis: an update. J Lipid Res. 2009;50: S376–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Yoshida H, Kisugi R. Mechanisms of LDL oxidation. Clin Chim Acta. 2010;411(23–24):1875–82.PubMedCrossRefGoogle Scholar
  31. 31.
    Parthasarathy S, Steinberg D. Cell-induced oxidation of LDL. Curr Opin Lipidol. 1992;3:313–7.CrossRefGoogle Scholar
  32. 32.
    Aviram M. Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. Eur J Clin Chem Clin Biochem. 1996;34(8):599–608.PubMedGoogle Scholar
  33. 33.
    Aviram M, Rosenblat M, Etzioni A, Levy R. Activation of NADPH oxidase required for macrophage-mediated oxidation of low-density lipoprotein. Metabolism. 1996;45(9):1069–79.PubMedCrossRefGoogle Scholar
  34. 34.
    Bey EA, Cathcart MK. In vitro knockout of human p47phox blocks superoxide anion production and LDL oxidation by activated human monocytes. J Lipid Res. 2000;41(3):489–95.PubMedGoogle Scholar
  35. 35.
    Carr AC, Myzak MC, Stocker R, McCall MR, Frei B. Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis. FEBS Lett. 2000;487:176–80.PubMedCrossRefGoogle Scholar
  36. 36.
    Klebanoff SJ. Myeloperoxidase: friend or foe. J Leukoc Biol. 2005;77:598–625.PubMedCrossRefGoogle Scholar
  37. 37.
    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol. 1996;271:C1424–37; Cell Physiol 40.PubMedGoogle Scholar
  38. 38.
    Hogg N, Struck A, Goss SP, et al. Inhibition of macrophage-dependent low density lipoprotein oxidation by nitric-oxide donors. J Lipid Res. 1995;36:1756–62.PubMedGoogle Scholar
  39. 39.
    Ng CJ, Shih DM, Hama SY, Villa N, Navab M, Reddy ST. The paraoxonase gene family and atherosclerosis. Free Radic Biol Med. 2005;38:153–63.PubMedCrossRefGoogle Scholar
  40. 40.
    Ng CJ, Wadleigh DJ, Gangopadhyay A, Hama S, Grijalva VR, Navab M, Fogelman AM, Reddy ST. Paraoxonase-2 is an ubiquitously expressed protein with antioxidant properties, and is capable of preventing cell-mediated oxidative modification of low-density lipoprotein. J Biol Chem. 2001;276:44444–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Rosenblat M. M. Aviram. Paraoxonases role in the prevention of cardiovascular diseases. Biofactors. 2009;35(1):98–104.PubMedCrossRefGoogle Scholar
  42. 42.
    Maritim AC, Sanders RA, Watkins III JB. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17(1):24–38.PubMedCrossRefGoogle Scholar
  43. 43.
    Gökkusu C, Palanduz S, Ademoğlu E, Tamer S. Oxidant and antioxidant systems in niddm patients: influence of vitamin E supplementation. Endocr Res. 2001;27(3):377–86.PubMedCrossRefGoogle Scholar
  44. 44.
    Ceriello A. Oxidative stress and glycemic regulation. Metabolism. 2000;49(2, Suppl 1):27–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Hayek T, Hussein K, Aviram M, Coleman R, Keidar S, Pavoltzky E, Kaplan M. Macrophage-foam cell formation in streptozotocin-induced diabetic mice: stimulatory effect of glucose. Atherosclerosis. 2005;183: 25–33.PubMedCrossRefGoogle Scholar
  46. 46.
    Coleman R, Hayek T, Keidar S, Aviram M. A mouse model for human atherosclerosis: long-term histopathological study of lesion development in the aortic arch of apolipoprotein E-deficient (E0) mice. Acta Histochem. 2006;108(6):415–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996;19:257–67.PubMedCrossRefGoogle Scholar
  48. 48.
    Folli F, Corradi D, Fanti P, Davalli A, Paez A, Giaccari A, Perego C, Muscogiuri G. The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: avenues for a mechanistic-based therapeutic approach. Curr Diabetes Rev. 2011;7(5):313–24.PubMedCrossRefGoogle Scholar
  49. 49.
    Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47:859–66.PubMedCrossRefGoogle Scholar
  50. 50.
    Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 1999;13:23–30.PubMedGoogle Scholar
  51. 51.
    Hunt JV, Dean RT, Wolff SP. Hydroxyl radical production and autooxidative glycosylation. Biochem J. 1988;256:205–12.PubMedGoogle Scholar
  52. 52.
    Yao D, Brownlee M. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 2010;59(1):249–55.PubMedCrossRefGoogle Scholar
  53. 53.
    Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.PubMedCrossRefGoogle Scholar
  54. 54.
    Stitt AW, Jenkins AJ, Cooper ME. Advanced glycation end products and diabetic complications. Expert Opin Investig Drugs. 2002;11(9):1205–23.PubMedCrossRefGoogle Scholar
  55. 55.
    Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA. 1992;89:11059–63.PubMedCrossRefGoogle Scholar
  56. 56.
    Scivittaro V, Ganz MB, Weiss MF. AGEs induce oxidative stress and activate protein kinase C-beta (II) in neonatal mesangial cells. Am J Physiol. 2000;278:F676–83.Google Scholar
  57. 57.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000; 404:787–90.PubMedCrossRefGoogle Scholar
  58. 58.
    Hayek T, Kaplan M, Kerry R, Aviram M. Macrophage NADPH oxidase activation, impaired cholesterol fluxes, and increased cholesterol biosynthesis in diabetic mice: a stimulatory role for D-glucose. Atherosclerosis. 2007;195(2):277–86.PubMedCrossRefGoogle Scholar
  59. 59.
    Sonta T, Inoguchi T, Tsubouchi H, Sekiguchi N, Kobayashi K, Matsumoto S, Utsumi H, Nawata H. Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med. 2004; 37(1):115–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Iwashima Y, Eto M, Hata A, Kaku K, Horiuchi S, Ushikubi F, Sano H. Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages. Biochem Biophys Res Commun. 2000;277(2): 368–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Aviram M. Review of human studies on oxidative damage and antioxidant protection related to cardiovascular diseases. Free Radic Res. 2000;33(Suppl): S85–97.PubMedGoogle Scholar
  62. 62.
    Aviram M, Kaplan M, Rosenblat M, Fuhrman B. Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development. Handb Exp Pharmacol. 2005;170:263–300.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosenblat M, Aviram M. Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Radic Biol Med. 1998;24(2):305–17.PubMedCrossRefGoogle Scholar
  64. 64.
    Fuhrman B, Aviram M. Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol. 2001;12(1):41–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Chertow B. Advances in diabetes for the millennium: vitamins and oxidant stress in diabetes and its complications. MedGenMed. 2004;6(3 Suppl):4.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Dagenais GR, Marchioli R, Yusuf S, Tognoni G. Beta-carotene, vitamin C, and vitamin E and cardiovascular diseases. Curr Cardiol Rep. 2000;2:293–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Arai K, Iizuka S, Tada Y, Oikawa K, Taniguchi N. Increase in the glycosylated form of erythrocyte Cu-Zn-superoxide dismutase in diabetes and close association of the nonenzymatic glucosylation with the enzyme activity. Biochim Biophys Acta. 1987;924:292–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Aviram M, Fuhrman B. Wine flavonoids protect against LDL oxidation and atherosclerosis. Ann N Y Acad Sci. 2002;957:146–61.PubMedCrossRefGoogle Scholar
  69. 69.
    Suksomboon N, Poolsup N, Sinprasert S. Effects of vitamin E supplementation on glycaemic control in type 2 diabetes: systematic review of randomized controlled trials. J Clin Pharm Ther. 2011;36(1): 53–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev. 2011;7(2):106–25.PubMedCrossRefGoogle Scholar
  71. 71.
    Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60.PubMedCrossRefGoogle Scholar
  72. 72.
    American Diabetes Association. Nutrition principles and recommendations in diabetes. Diabetes Care. 2004;27 suppl 1:s36.Google Scholar
  73. 73.
    Aviram M, Dornfeld L, Kaplan M, Coleman R, Gaitini D, Nitecki S, Hofman A, Rosenblat M, Volkova N, Presser D, Attias J, Hayek T, Fuhrman B. Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans. Drugs Exp Clin Res. 2002;28(2–3):49–62.PubMedGoogle Scholar
  74. 74.
    Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L, Volkova N, Presser D, Attias J, Liker H, Hayek T. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004;23(3):423–33.PubMedCrossRefGoogle Scholar
  75. 75.
    Rosenblat M, Hayek T, Aviram M. Anti-oxidative effects of pomegranate juice (PJ) consumption by diabetic patients on serum and on macrophages. Atherosclerosis. 2006;187(2):363–71.PubMedCrossRefGoogle Scholar
  76. 76.
    Tzulker R, Glazer I, Bar-Ilan I, Holland D, Aviram M, Amir R. Antioxidant activity, polyphenol content, and related compounds in different fruit juices and homogenates prepared from 29 different pomegranate accessions. J Agric Food Chem. 2007;55(23): 9559–70.PubMedCrossRefGoogle Scholar
  77. 77.
    Rock W, Rosenblat M, Miller-Lotan R, Levy AP, Elias M, Aviram M. Consumption of wonderful variety pomegranate juice and extract by diabetic patients increases paraoxonase 1 association with high-density lipoprotein and stimulates its catalytic activities. J Agric Food Chem. 2008;56(18):8704–13.PubMedCrossRefGoogle Scholar
  78. 78.
    Rosenblat M, Volkova N, Coleman R, Aviram M. Pomegranate byproduct administration to apolipoprotein e-deficient mice attenuates atherosclerosis development as a result of decreased macrophage oxidative stress and reduced cellular uptake of oxidized low-density lipoprotein. J Agric Food Chem. 2006;54(5): 1928–35.PubMedCrossRefGoogle Scholar
  79. 79.
    Rozenberg O, Shiner M, Aviram M, Hayek T. Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties. Free Radic Biol Med. 2008;44(11):1951–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Mackness MI, Durrington PN. Paraoxonase: another factor in NIDDM cardiovascular disease (letter). Lancet. 1995;346:856.PubMedCrossRefGoogle Scholar
  81. 81.
    Abbott CA, Mackness MI, Kumar S, Boulton AJ, Durrington PN. Serum paraoxonase activity, concentration and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoprotein. Arterioscler Thromb Vasc Biol. 1995;11:1812–8.CrossRefGoogle Scholar
  82. 82.
    Rosenblat M, Karry R, Aviram M. Paraoxonase 1 (PON1) is a more potent antioxidant and stimulant of macrophage cholesterol efflux, when present in HDL than in lipoprotein-deficient serum: relevance to diabetes. Atherosclerosis. 2006;187:74–81.PubMedGoogle Scholar
  83. 83.
    Mastorikou M, Mackness B, Liu Y, Mackness M. Glycation of paraoxonase 1 inhibits its activity and impairs the ability of high-density lipoprotein to metabolize membrane lipid hydroperoxides. Diabet Med. 2008;25:1049–55.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Mastorikou M, Mackness M, Mackness B. Defective metabolism of oxidized phospholipid by HDL from people with type 2 diabetes. Diabetes. 2006;55: 3099–103.PubMedCrossRefGoogle Scholar
  85. 85.
    Koren-Gluzer M, Aviram M, Meilin E, Hayek T. The antioxidant HDL-associated paraoxonase-1 (PON1) attenuates diabetes development and stimulates β-cell insulin release. Atherosclerosis. 2011;219(2):510–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.The Laboratory of Clinical Biochemistry, Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical CenterHaifaIsrael
  2. 2.The Lipid Research LaboratoryTechnion Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical CenterHaifaIsrael

Personalised recommendations