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. 2006 Apr 5;14(1):21–33. doi: 10.1111/j.1750-3639.2004.tb00494.x

The Neuropathology of Septic Shock

Tarek Sharshar 1,3, Djillali Annane 1, Geoffroy Lorin de la Gradmaison 2, Jean Philippe Brouland 2, Nicholas S Hopkinson 3, Françoise Gray 2,✉
PMCID: PMC8095740  PMID: 14997934

Abstract

The neuropathological correlates of encephalopathy and autonomic dysfuction in septic shock are unclear. We performed post mortem analysis of 5 brain areas susceptible to ischemia and 5 autonomic nuclei (AN) in 23 pqtients who had died in our intensive care unit (ICU) from septic shock and 8 dying from non‐septic shock as well as 5 controls who had died suddenly from extracranial injury. Proinflammatory cytokine (IL1‐β and TNF‐α) and inducible nitric oxide synthase (iNOS) expressin was assessed by immunocytochemistry. Abnormalities in septic shock were: hemorrhages (26%), hypercoagulability syndrome (9%), micro‐abscessed (9%), multifocal necrotizing leukoencephalopathy (9%) and ischemia (100%). The incidence of cerebral hemorrhage or hypercoagulability syndrome was not related to clotting distrurbances. The intensity of ischemia within susceptible areas was the same on both ICU groups, but more pronounced in the autonomic centers of septic patients (P<0.0001). Neuronal apoptosis assessed using anti‐caspase 3 immunocytochemistry and in situ end labeling was more pronounced in the autonomic nuclei septic patients. (P<0.0001). INF‐alpha expression did not differ between groups but vascular iNOS expression assessed by immunocytochemistry was higher in sepsis (p<0.0001) and correlated with autonomic center neuronal apoptosis (P<0.02). We conclude that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors particularly iNOS.

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References

  • 1. Adamson DC , Wildemann B , Sasaki M , Glsss D , McArthur JC , Christov VI , Dawson TM , Dawson VL ( 1996. ) Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV‐1 gp41 . Science 274 : 1917 – 1921 . [DOI] [PubMed] [Google Scholar]
  • 2. Adle‐Biassette H , Chretien F , Wungertsmann L , Hery C , Ereau T , Scaravilli F , Tardieu M , Gray F ( 1999. ) Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damange . Neuropathol Appl Neurobiol 25 : 123 – 133 . [DOI] [PubMed] [Google Scholar]
  • 3. American College of Chest physicians/Society of, Critical Care Medicine Consensus Conference ( 1998. ) Definitions for sepsis and multiple organ failure, and guidelines for the use of innovative therapies in sepsis , Crit Care Med 26 : 645 – 650 . [PubMed] [Google Scholar]
  • 4. Anders KH , Becker PS , Holden JK , Sharer LR , Cornford ME , Hansen LA , Hsmilton R , Vinters HV ( 1993. ) Multifocal necrotizing leukoencephalopathy with pontine predilection in immunosuppressed patients: a clinicopathologic review of 16 cases . Hum Pathol 24 : 897 – 904 . [DOI] [PubMed] [Google Scholar]
  • 5. Annane D , Baudrie V , Blanc AS , Laude D , Raphael JC , Elghozi JL ( 1999. ) Short‐term variability of blood pressure and heart rate in Guillain‐Barre sydrome without respiratory failure . Clin Sci (Lond) 96 : 613 – 621 . [PubMed] [Google Scholar]
  • 6. Annane D , Sanquer S , Sebille V , Faye A , Djuranovic D , Raphael JC , Gajdos P , Bellissant E ( 2000. ) Compartmentalised inducible nitric‐oxide synthase activity in septic shock . Lancet 355 : 1143 – 1148 . [DOI] [PubMed] [Google Scholar]
  • 7. Ansari B , Coates P J , Greenstein BD , Hall PA ( 1993. ) In situ endlabelling detects DNA strand breaks in apoptosis and other physiological and pathological states . J Pathol 170 : 18 . [DOI] [PubMed] [Google Scholar]
  • 8. Bleck TP , Smith MC , Pierre‐Louia SJ , Jares JJ , Murray J , Hansen CA ( 1993. ) Neurologic complication of critical medical illnesses . Crit Care Med 21 : 98 – 103 . [DOI] [PubMed] [Google Scholar]
  • 9. Bolton CF , Young GB , Zochodne DW ( 1993. ) The neurological complications of sepsis . Ann Neurol 33 : 94 – 100 . [DOI] [PubMed] [Google Scholar]
  • 10. Bone RC , Balk RA , Cerra FB , Dellinger Rp , Fein AM , Knaus WA , Schein RM , Sibbald WJ ( 1992. ) Definition for sepsis and organ failure and guidelines for use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference.American college of Chest Physician/Society of Critical Care Medicine . Chest 101 : 1644 – 1655 . [DOI] [PubMed] [Google Scholar]
  • 11. Borovikova LV , Ivanova S , Zhang M , Yang H , Botchkina Gl , Watkins LR , Wang H , Abumrad N , Eaton JW , Tracey KJ ( 2000. ) Vagus nerve stimulation attenuates the systemin inflammatory response to endotoxin . Nature 405 : 458 – 462 . [DOI] [PubMed] [Google Scholar]
  • 12. Bouchon A , Facchetti F , Weigand MA , Colonna M ( 2001. ) TREM‐1 amplifies inflammation and is a crucial mediator of septic shock . Nature 410 : 1103 – 1107 . [DOI] [PubMed] [Google Scholar]
  • 13. Bowton DL , Bertels NH , Prough DS , Stump DA ( 1989. ) Cerebral blood flow is reduced in patients with sepsis syndrome . Crit care Med 17 : 399 – 403 . [DOI] [PubMed] [Google Scholar]
  • 14. Breder CD , Dinarello CA , Sapere CB ( 1998. ) Interleukin‐1 immunoreactive innervation of the human hypothalamus . Science 240 : 321 – 324 . [DOI] [PubMed] [Google Scholar]
  • 15. Breder CD , Hazuka C , Ghayur T , Klug C , Huginin M , Yasuda K , Teng M , Saper CB ( 1994. ) Regionsal induction of tumor necrosis factor alphaexpression in the mouse brain after systemic lipololusaccharide administration Proc Natl Acad Sci U S A 91 : 11393 – 11397 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Bredt DS , Hwang PM , Snyder SH ( 1990. ) Localizaion of nitric oxide synthase indicating a neural role for nitric oxide . Nature 347 : 768 – 770 . [DOI] [PubMed] [Google Scholar]
  • 17. Brun‐Buisson C , Doyon F , Carlet J , Dellamonica P , Gouin F , Lepoutre A , Mercier JC , Offenstandt G , Régnier B for the French ICU Grup for servere sepsis ( 1995. ) Incidence, risk factors, and out‐come of severe sepsis and sespic shock in adults A multicenter multicenter prospective study in intensive care units. French ICU Group foe Severe sepsis . JAMA 274 : 968 – 974 . [PubMed] [Google Scholar]
  • 18. Buttini M , Appel K , Sauter A , Gebicke‐ Haerter PJ , Boddeke HW ( 1996. ) Expression of tumor necrosis factor alpha after cerebral ischaemia in the rat . Neuroscience 71 : 1 – 16 . [DOI] [PubMed] [Google Scholar]
  • 19. Christenson JT , Kuikka JT , Owunwanne A , Al‐Sarraf AA ( 1986. ) Cerebral circulation during endotoxin shock with special emphasis on the regional celebral blood flow in vivo . Nucl Med Commun 7 : 531 – 540 . [DOI] [PubMed] [Google Scholar]
  • 20. Chrousos GP ( 1995. ) The hypothalamic‐pitu‐itary‐adrenal‐axis and immune‐mediated inflammation . N EnglJ Med 332 : 1351 – 1362 . [DOI] [PubMed] [Google Scholar]
  • 21. Clawson CC , Hartmann JF , Vernier RL ( 1966. ) Electron microscopy of the effect of gram‐negative endotoxin on the blood‐brain barrier . J Comp Neurol 127 : 183 – 198 . [DOI] [PubMed] [Google Scholar]
  • 22. Colasanti M , Persichini T , Pucchio TD , Gremo F , Lauro GM ( 1995. ) Human remified microglial cells produce nitric oxide upon Escherichi coli lipopolysaccharide and tumor necrosis factor alpha stimulation . NeurosciLett 200 : 144 – 146 . [DOI] [PubMed] [Google Scholar]
  • 23. Combs CK , Karlo CK , Karlo JC , Kao SC , Landreth GE ( 2001. ) Beta‐amyloid stimulation of microglia and monocytes results in TNFalpha‐dependent expression of inducible nitric oxide synthase and neuronal apoptosis . J Neurosci Res 21 : 1179 – 1188 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Deng X , Wang X , Andersson R ( 1995. ) Endothelial barrier resistance in multiple organs after septic and nonseptic challenges in the rat . J Appl Physiol 78 : 2052 – 2061 . [DOI] [PubMed] [Google Scholar]
  • 25. Dunn AJ ( 1992. ) Endotoxin‐induced activation of celebral catecholamine and serotonin metabolism: comparison with interleukin‐1 . J Pharmacol Exp Ther 261 : 964 – 969 . [PubMed] [Google Scholar]
  • 26. Dunn AJ ( 2000. ) Cytokine activation of the HPA axis . Ann N Y Acad Sci 917 : 608 – 617 . [DOI] [PubMed] [Google Scholar]
  • 27. Eidelman LA , Putterman D , Putterman C , Sprung CL ( 1996. ) The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities . JAMA 275 : 470 – 473 . [PubMed] [Google Scholar]
  • 28. Ekstrom‐Jodal B , Larsson LE ( 1982. ) Effects of dopamine of cerebral circulation and oxygen metabolism in endotoxic shock: an.experimental study in dogs . Crit care Med 10 : 375 – 377 . [DOI] [PubMed] [Google Scholar]
  • 29. Galea E , Reis DJ , Fox ES , Xu H , Feinstein DL ( 1996. ) CD14 mediate endotoxin inducton of nitric oxide synthase in cultured brain glial cell . J Neuroimmunol 64 : 19 – 28 . [DOI] [PubMed] [Google Scholar]
  • 30. Giusti‐Paiva A , De Castro M , Antunes‐Ro‐drigues J , Carnio EC ( 2002. ) Inducible nitric oxide synthase pathway in the central nervous system and vasopressin release during experimental septic shock . Crit Care Med 30 : 1306 – 1310 . [DOI] [PubMed] [Google Scholar]
  • 31. Gray F , Belec L , Chretien F , Dubreuil‐Lemaire ML , Ricolfi F , Wingertsmann L , Poron F. R. G ( 1998. ) Acute, relapsing brain edema with diffuse blood‐brain barrier alteration and axonal damage in the acquired immunodeficiency syndrome . Neuro-pathol Appl Neurobiol 24 : 209 – 216 . [DOI] [PubMed] [Google Scholar]
  • 32. Iadecola C , Zhang F , Casey R , Clark HB , Ross ME ( 1996. ) Inducible nitric oxide synthase gene expression in vascular cell after transient focal ischemia . Stroke 27 : 1373 – 1380 . [DOI] [PubMed] [Google Scholar]
  • 33. Jackson AC , Gilbert JJ , Young GB , Bolton CF ( 1985. ) The encephalopathy of sepsis . Can J Neurol 12 : 303 – 307 . [DOI] [PubMed] [Google Scholar]
  • 34. Jeppsson B , Freund HR. Z G , James JH , von Meyenfeldt MF , Fischer JE ( 1981. ) Blood‐brain barrier derangement in sepsis: cause of septicencephalopathy ? Am J Surg 141 : 136 – 142 . [DOI] [PubMed] [Google Scholar]
  • 35. Kadoi Y , Saito S ( 1996. ) An alteration in the gamma‐aminobutyric acid receptor system in experimentally induced septic shock in rats . Crit Care Med 24 : 298 – 305 . [DOI] [PubMed] [Google Scholar]
  • 36. Kadoi Y , Saito S , Kunimoto F , Imai T , Fujita T ( 1996. ) Impairment of the brain beta‐adrenergic system during experimental endotoxemia . J Surg Res 61 : 496 – 502 . [DOI] [PubMed] [Google Scholar]
  • 37. Karima R , Matsumoto S , Higshi H , Matsushima K ( 1999. ) The molecular pathogenesis of endotoxic shock and organ failure . Mol Med Today 5 : 123 – 132 . [DOI] [PubMed] [Google Scholar]
  • 38. Knaus WA , Draper EA , Wagner DP , Zimmer‐man JE ( 1985. ) Prognosis in acute organ‐system failure . Ann Surg 202 : 685 – 693 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Konsman JP , Kelley K , Dantzer R ( 1999. ) Temporal and spatial relationships between lipopoly‐saccharide‐induced expression of Fos, interleukin‐1 beta and inclucible nitric oxide synthase in rat brain . Neuroscience 89 : 535 – 548 . [DOI] [PubMed] [Google Scholar]
  • 40. Koyama S , Manning J ( 1984. ) Role of sympathetic nerve activity in endotoxin induced hypotension in cats . Cardiovasc Res 19 : 32 – 37 . [DOI] [PubMed] [Google Scholar]
  • 41. Koyama S , Manning J ( 1986. ) Central impairment of renal nerve response to stimulation of medullary pressor area in rabbit endotoxic hypotension . Brain Res 366 : 217 – 223 . [DOI] [PubMed] [Google Scholar]
  • 42. Koyama S , Santiesteban HL , Ammons WS , Mannig JW ( 1982. ) Centrally mediated hypotensive effect of E Coli in the anesthetized cat . Circulatory Shock 9 : 557 – 570 . [PubMed] [Google Scholar]
  • 43. Kunze K ( 2002. ) Metabolic encephalopathies . J Neurol 249 : 1150 – 1159 . [DOI] [PubMed] [Google Scholar]
  • 44. Lacroix S , Feinstein D , Rivest ( 1998. ) The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations . Brain Pathol 8 : 625 – 640 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Le Gall JR , Lemeshow S. F S ( 1993. ) A new simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study . JAMA 270 : 2957 – 2963 . [DOI] [PubMed] [Google Scholar]
  • 46. Lee P , Lee J , Kim S , Lee MS , Yagita H , Kim SY , Kim H , Suk K ( 2001. ) NO as an autocrine mediator in the apoptosis of activated microglial cell: correlation between activation and apoptosis of microglial cells . Brain Res 892 : 380 – 385 . [DOI] [PubMed] [Google Scholar]
  • 47. Levi M , Cate HT ( 1999. ) Disseminated intravascular coagulation . N Engl J Med 341 : 586 – 592 . [DOI] [PubMed] [Google Scholar]
  • 48. Li H , Forstermann U ( 2000. ) Nitric oxide in the pathogenesis of vascular disease . J Pathol 190 : 244 – 254 . [DOI] [PubMed] [Google Scholar]
  • 49. Maekawa T , Fujii Y , Sadamitsu D , Yokota K , Soejima Y , Ishikawa T , Miyauchi Y , Takeshita H ( 1991. ) Cerebral circulation and metabolism in patients with septic encephalopathy . Am J Emerg Med 9 : 139 – 143 . [DOI] [PubMed] [Google Scholar]
  • 50. Matta BF , Stow P ( 1996. ) Sepsis‐induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies . Br J Anaesth 76 : 790 – 794 . [DOI] [PubMed] [Google Scholar]
  • 51. Oberholzer C , Oberholzer A , Clare‐Salzler M , Moldawer LL ( 2001. ) Apoptosis in sepsis: a new target for therapeutic exploration . Faseb J 15 : 879 – 892 . [DOI] [PubMed] [Google Scholar]
  • 52. Papadopoulos MC , Davies DC , Moss RF , Tighe D , Bennett ED ( 2000. ) Pathophysiology of septic encephalopathy: a review . Crit Care Med 28 : 3019 – 3024 . [DOI] [PubMed] [Google Scholar]
  • 53. Papadopoulos MC , Lamb FJ , Moss RF , Davies DC , Tighe D , Bennett ED ( 1999. ) Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex . Clin Sci (Lond) 96 : 461 – 466 . [PubMed] [Google Scholar]
  • 54. Pendlebury WW , Perl DP , Munoz DG ( 1989. ) Multiple microabscesses in the central nervous system: a clinicopathologic study . J Neuropathol Exp Neurol 48 : 290 – 300 . [DOI] [PubMed] [Google Scholar]
  • 55. Persson PB ( 1996. ) Modulation of cardiovascular control mechanisms and their interaction . Physiol Rev 76 : 193 – 232 . [DOI] [PubMed] [Google Scholar]
  • 56. Poirier J , Gray F , Escourolle R ( 1990. ) Manual of Basic Neuropathology , W.B. Saunderns Company; , Philadelphia , pp 276 . [Google Scholar]
  • 57. Pollard V , Prough DS , Deyo DJ , Conroy B , Uchida T , Daye A , Traber LD , Traber DL ( 1997. ). Cerebral blood flow during experimental endotoxemia in volunteers . Crit Care Med 25 : 1700 – 1706 . [DOI] [PubMed] [Google Scholar]
  • 58. Quan N , Stern EL , Whiteside MB , Herkenham M ( 1999. ) Induction of pro‐inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat . J Neuroimmunol 93 : 72 – 80 . [DOI] [PubMed] [Google Scholar]
  • 59. Reinhart K , Bayer O , Brunkhorst F , Meisner M ( 2002. ) Markers of endothelial damage in organ dysfunction and sepsis . Crit Care Med 30 : S302 – S312 . [DOI] [PubMed] [Google Scholar]
  • 60. Sakahira H , Enari H , Enari M , Nagata S ( 1998. ) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis . Nature 391 : 969 . [DOI] [PubMed] [Google Scholar]
  • 61. Schwenk J , Gosztonyi G ( 1987. ) Purpura cerebri in gram‐negative septicaemia. A histological and immunohiistochemical study . Histol Histopathol 2 : 57 – 66 . [PubMed] [Google Scholar]
  • 62. Sessler CN , Shepherd W ( 2000. ) New concepts in sepsis . Curr Opin Crit Care 8 : 465 – 472 . [DOI] [PubMed] [Google Scholar]
  • 63. Sharshar T , Gray F , Lorin de la Grandmaison G , Hopkinson NS , Dorandeu A , Orlikowski D , Raphael J‐C , Gajdos P , Annane D ( 2003. ) Inducible Niric Oxide synthase triggered neuronal apoptosis in cardiovscular autonomic centers in septic Lancet ( in press ). [DOI] [PubMed] [Google Scholar]
  • 64. Sharshar T , Gray F , Poron F , Raphael JC , Gajdos P , Annane D ( 2002. ) Multifocal necrotizing leukoencephalopathy in septic shock . Crit Care Med 30 : 2371 – 2375 . [DOI] [PubMed] [Google Scholar]
  • 65. Soejima Y , Fujii Y , Ishikawa T , Takeshita H , Maekawa T ( 1990. ) Local cerebral glucose utilization in septic rats . Crit Care Med 18 : 423 – 427 . [DOI] [PubMed] [Google Scholar]
  • 66. Sprung CL , Cerra FB , Freund HR , Schein RM , Konstantinides FN , Marcoa; EH , Pena M ( 1991. ) Amino acid alterations and encephalopathy in the sepsis syndrome . Crit Care Med 19 : 753 – 757 . [DOI] [PubMed] [Google Scholar]
  • 67. Sprung CL , Peduzzi PN , Shatney CH , Schein RMH , Wilson MF , Sheagren JN , Hinshaw LB , The Veterans Administration System sepsis Cooperative Study Group ( 1990. ) Impact of encephalopathy on mortality of sepsic . Crit Care Med 18 : 801 – 806 . [DOI] [PubMed] [Google Scholar]
  • 68. Straver JS , Keunen RW , Stam CJ , Tavy DL , De Ruiter GR , Smith SJ , Thijs LG , Schellens RG , Gielen G ( 1998. ) Nonlinear analysis of EEG in septic encephalopathy . Neurol Res 20 : 100 – 106 . [DOI] [PubMed] [Google Scholar]
  • 69. Terborg C , Schummer W , Albrecht M , Reinhart K , Weiller C , Rother J ( 2001. ) Dysfunction of vasomotor reactivity in severe sepsis and septic shock . Intensive Care Med 27 : 1231 – 1234 . [DOI] [PubMed] [Google Scholar]
  • 70. Turnbull AW , Rivier CL ( 1999. ) Regulation of the hypothalamic‐Pituitary‐Adrenal axis cytokines: actions and mechanisms of action . Physiol Rev 79 : 1 – 71 . [DOI] [PubMed] [Google Scholar]
  • 71. Vincent JL , Zang H , Szabo C , Preiser J‐C ( 2001. ) Effects of nitric oxide in septic shock . Am J Respir Crit Care Med 161 : 1781 – 1785 . [DOI] [PubMed] [Google Scholar]
  • 72. Wang H , Yu M , Ochani M , Amella CA , Tanovic M , Susarla S , Li JH , Yang H , Ulloa L , AI‐Abed Y , Czura CJ , Tracey KJ ( 2003. ) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation . Nature 421 : 384 – 388 . [DOI] [PubMed] [Google Scholar]
  • 73. Westerlind A , Laesson LE , Haggendal J , Ekstrom‐Jodal B ( 1991. ) Prevention of endotoxinducedincrease of cerebral oxygen consumption in dogs by propranolol pretreatment . Acta Anaesthesiol Scand 35 : 745 – 749 . [DOI] [PubMed] [Google Scholar]
  • 74. Winkler F , Koedel U , Kastengauer S , Pfister HW ( 2001. ) Differential Expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood‐brain breakdown . J Infect Dis 183 : 1749 – 1759 . [DOI] [PubMed] [Google Scholar]
  • 75. Wong ML , Bongiorno PB , Rettori V , McCann SM , Licinio J ( 1997. ) Intereukin (IL)‐1β, IL‐1 receptor antagonist, IL‐10, and IL‐13 gene expression in the central nervous system during systemic inflammation: pathophysiological implications . Proc Natl Acad Sci U S A 94 : 227 – 232 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76. Wong ML , Rettori V , Shekhlee Aa , Bongiorno PB , Canteros G , McCann SM , Gold PW , Licinio J ( 1996. ) Inducible nitric oxide synthase gene expression in the brain during systemic inflammation . Nat Med 2 : 581 – 584 . [DOI] [PubMed] [Google Scholar]
  • 77. Young GB , Bolton CF , Archibald YM , Austin TW , Wells GA ( 1992. ) The electroencephalogram in sepsis‐associated encephalopathy . J Clin Neurophysiol 9 : 145 – 152 . [DOI] [PubMed] [Google Scholar]
  • 78. Young GB , Bolton CF , Austin TW , Archibald YM , Gonder J , Wells GA ( 1990. ) The encephalopathy associated with septic illness . Clin Invest Med 13 : 297 – 304 . [PubMed] [Google Scholar]
  • 79. Yuan J , Yankner BA ( 2000. ) Apoptosis in the nervous system . Nature 407 : 802 – 809 . [DOI] [PubMed] [Google Scholar]
  • 80. Zauner C , Gendo A , Kramer L , Kranz A , Grimm G , Madl C ( 2000. ) Metabolic encephalopathy in critically ill patients organ failure . Crit Care Med 28 : 1310 – 1315 . [DOI] [PubMed] [Google Scholar]

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