Zena Vexler, PhD

Zinaida Vexler, PhD, is Professor in the Department of Neurology at UCSF and Director of Research at the Neonatal Brain Disorder Center. She has multi-disciplinary training in chemistry, biochemistry, pharmacology, and physiology and has served as Director of MRI Core on PPG since 2002, and as the Director of Research of Neonatal Brain Disorders Center at UCSF since 2003.

Over the last twenty five years, her research has been centered on the mechanisms of experimental stroke with the long-term goal of developing effective therapies. She has contributed to the fields of brain vascular and cellular injury after experimental stroke first in the adult and, over more than seventeen years, in the neonate. Dr. Vexler’s lab was the first to establish and characterize the in vivo models of focal arterial stroke in neonatal rodents. With these age-appropriate models of perinatal stroke, she defined that the “signature” of neurovascular integrity after stroke is markedly different after neonatal stroke than after adult stroke. Her studies of microglial cell function in injured neonatal brain have been critical for the improved understanding of neuroinflammation as modifier of perinatal stroke.
Honors and Awards
  • The Thomas Willis Award, The American Heart Association/American Stroke Association, 2023
Websites

  1. Vecchiarelli HA, Bisht K, Sharma K, Weiser Novak S, Traetta ME, Garcia-Segura ME, St-Pierre MK, Savage JC, Willis C, Picard K, Bordeleau M, Vernoux N, Khakpour M, Garg R, Loewen SM, Murray CJ, Grinberg YY, Faustino J, Halvorson T, Lau V, Pluchino S, Vexler ZS, Carson MJ, Manor U, Peruzzotti-Jametti L, Tremblay MÈ. Dark Microglia Are Abundant in Normal Postnatal Development, where they Remodel Synapses via Phagocytosis and Trogocytosis, and Are Dependent on TREM2. bioRxiv : the preprint server for biology 2024. PMID: 39463930


  2. Chumak T, Jullienne A, Ek CJ, Ardalan M, Svedin P, Quan R, Salehi A, Salari S, Obenaus A, Vexler ZS, Mallard C. Maternal n-3 enriched diet reprograms the offspring neurovascular transcriptome and blunts inflammation induced by endotoxin in the neonate. Journal of neuroinflammation 2024. PMID: 39128994


  3. Mallard C, Ferriero DM, Vexler ZS. Immune-Neurovascular Interactions in Experimental Perinatal and Childhood Arterial Ischemic Stroke. Stroke 2024. PMID: 38252757


  4. Chumak T, Jullienne A, Joakim Ek C, Ardalan M, Svedin P, Quan R, Salehi A, Salari S, Obenaus A, Vexler ZS, Mallard C. Maternal n-3 enriched diet reprograms neurovascular transcriptome and blunts inflammation in neonate. bioRxiv : the preprint server for biology 2024. PMID: 38328227


  5. Fukuzaki Y, Faustino J, Lecuyer M, Rayasam A, Vexler ZS. Global sphingosine-1-phosphate receptor 2 deficiency attenuates neuroinflammation and ischemic-reperfusion injury after neonatal stroke. iScience 2023. PMID: 37009213


  6. Gadagkar SG, Lalancette-H?bert M, Thammisetty SS, Vexler ZS, Kriz J. CD36 neutralisation blunts TLR2-IRF7 but not IRF3 pathway in neonatal mouse brain and immature human microglia following innate immune challenge. Scientific Reports 2023. PMID: 36759676


  7. Di Martino E, Rayasam A, Vexler ZS. Brain Maturation as a Fundamental Factor in Immune-Neurovascular Interactions in Stroke. Translational stroke research 2023. PMID: 36705821


  8. Cornet MC, Grose C, Vexler Z, Wu YW, Fullerton HJ. The Role of Infection and Inflammation in the Pathogenesis of Pediatric Arterial Ischemic Stroke. Seminars in pediatric neurology 2022. PMID: 36456035


  9. Rayasam A, Mottahedin A, Faustino J, Mallard C, Vexler ZS. Scavenger receptor CD36 governs recruitment of myeloid cells to the blood-CSF barrier after stroke in neonatal mice. 2022. PMID: 35148760


  10. Chumak T, Lecuyer MJ, Nilsson AK, Faustino J, Ardalan M, Svedin P, Sjöbom U, Ek J, Obenaus A, Vexler ZS, Mallard C. Maternal n-3 Polyunsaturated Fatty Acid Enriched Diet Commands Fatty Acid Composition in Postnatal Brain and Protects from Neonatal Arterial Focal Stroke. 2021. PMID: 34674145


  11. Rayasam A, Jullienne A, Chumak T, Faustino J, Szu J, Hamer M, Ek CJ, Mallard C, Obenaus A, Vexler ZS. Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2021. PMID: 34293939


  12. Pathipati P, Lecuyer M, Faustino J, Strivelli J, Phinney DG, Vexler ZS. Mesenchymal Stem Cell (MSC)-Derived Extracellular Vesicles Protect from Neonatal Stroke by Interacting with Microglial Cells. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2021. PMID: 34235636


  13. Lecuyer M, Pathipati P, Faustino J, Vexler ZS. Neonatal stroke enhances interaction of microglia-derived extracellular vesicles with microglial cells. Neurobiology of disease 2021. PMID: 34153465


  14. Rayasam A, Fukuzaki Y, Vexler ZS. Microglia-leucocyte axis in cerebral ischaemia and inflammation in the developing brain. Acta physiologica (Oxford, England) 2021. PMID: 33991400


  15. Rayasam A, Faustino J, Lecuyer M, Vexler ZS. Neonatal Stroke and TLR1/2 Ligand Recruit Myeloid Cells through the Choroid Plexus in a CX3CR1-CCR2- and Context-Specific Manner. The Journal of neuroscience : the official journal of the Society for Neuroscience 2020. PMID: 32269105


  16. Ardalan M, Chumak T, Vexler Z, Mallard C. Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders. International journal of molecular sciences 2019. PMID: 31071949


  17. Faustino J, Chip S, Derugin N, Jullienne A, Hamer M, Haddad E, Butovsky O, Obenaus A, Vexler ZS. CX3CR1-CCR2-dependent monocyte-microglial signaling modulates neurovascular leakage and acute injury in a mouse model of childhood stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2019. PMID: 30628839


  18. Vexler ZS, Mallard C, Hagberg H. Positive and negative conditioning in the neonatal brain. Conditioning medicine 2018. PMID: 31214666


  19. Salehi A, Jullienne A, Wendel KM, Hamer M, Tang J, Zhang JH, Pearce WJ, DeFazio RA, Vexler ZS, Obenaus A. A Novel Technique for Visualizing and Analyzing the Cerebral Vasculature in Rodents. Translational stroke research 2018. PMID: 29766452


  20. Mallard C, Ek CJ, Vexler ZS. The myth of the immature barrier systems in the developing brain: role in perinatal brain injury. The Journal of physiology 2018. PMID: 29528501


  21. Mallard C, Tremblay ME, Vexler ZS. Microglia and Neonatal Brain Injury. Neuroscience 2018. PMID: 29352997


  22. Lalancette-Hébert M, Faustino J, Thammisetty SS, Chip S, Vexler ZS, Kriz J. Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection. Brain, behavior, and immunity 2017. PMID: 28579520


  23. Koo E, Sheldon RA, Lee BS, Vexler ZS, Ferriero DM. Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia-ischemia. Pediatric research 2017. PMID: 28561815


  24. Chip S, Fernández-López D, Li F, Faustino J, Derugin N, Vexler ZS. Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke. Brain, behavior, and immunity 2016. PMID: 27836669


  25. Bosetti F, Galis ZS, Bynoe MS, Charette M, Cipolla MJ, Del Zoppo GJ, Gould D, Hatsukami TS, Jones TL, Koenig JI, Lutty GA, Maric-Bilkan C, Stevens T, Tolunay HE, Koroshetz W, “Small Blood Vessels: Big Health Problems” Workshop Participants. "Small Blood Vessels: Big Health Problems?": Scientific Recommendations of the National Institutes of Health Workshop. Journal of the American Heart Association 2016. PMID: 27815267


  26. van Velthoven CT, Dzietko M, Wendland MF, Derugin N, Faustino J, Heijnen CJ, Ferriero DM, Vexler ZS. Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. Journal of neuroscience research 2016. PMID: 27781299


  27. Fernández-López D, Faustino J, Klibanov AL, Derugin N, Blanchard E, Simon F, Leib SL, Vexler ZS. Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience 2016. PMID: 26961944


  28. Li F, Faustino J, Woo MS, Derugin N, Vexler ZS. Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke. Journal of neurochemistry 2015. PMID: 26223273


  29. Mallard C, Vexler ZS. Modeling Ischemia in the Immature Brain: How Translational Are Animal Models? Stroke 2015. PMID: 26272384


  30. Sohet F, Lin C, Munji RN, Lee SY, Ruderisch N, Soung A, Arnold TD, Derugin N, Vexler ZS, Yen FT, Daneman R. LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation. The Journal of cell biology 2015. PMID: 25753034


  31. Hagberg H, Mallard C, Ferriero DM, Vannucci SJ, Levison SW, Vexler ZS, Gressens P. The role of inflammation in perinatal brain injury. Nature reviews. Neurology 2015. PMID: 25686754


  32. Titomanlio L, Fernández-López D, Manganozzi L, Moretti R, Vexler ZS, Gressens P. Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models. Pediatric neurology 2015. PMID: 26002050


  33. Kratzer I, Chip S, Vexler ZS. Barrier mechanisms in neonatal stroke. Frontiers in neuroscience 2014. PMID: 25426016


  34. van Velthoven CT, Gonzalez F, Vexler ZS, Ferriero DM. Stem cells for neonatal stroke- the future is here. Frontiers in cellular neuroscience 2014. PMID: 25120432


  35. Fernández-López D, Natarajan N, Ashwal S, Vexler ZS. Mechanisms of perinatal arterial ischemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2014. PMID: 24667913


  36. Fernández-López D, Faustino J, Derugin N, Vexler ZS. Acute and chronic vascular responses to experimental focal arterial stroke in the neonate rat. Translational stroke research 2013. PMID: 23730350


  37. Dzietko M, Derugin N, Wendland MF, Vexler ZS, Ferriero DM. Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Translational stroke research 2013. PMID: 23926451


  38. van Velthoven CT, Sheldon RA, Kavelaars A, Derugin N, Vexler ZS, Willemen HL, Maas M, Heijnen CJ, Ferriero DM. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke 2013. PMID: 23539530


  39. Woo MS, Wang X, Faustino JV, Derugin N, Wendland MF, Zhou P, Iadecola C, Vexler ZS. Genetic deletion of CD36 enhances injury after acute neonatal stroke. Annals of neurology 2012. PMID: 23280844


  40. Fernández-López D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, Wendland MF, Vexler ZS. Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012. PMID: 22787045


  41. Fernández-López D, Faustino J, Derugin N, Wendland M, Lizasoain I, Moro MA, Vexler ZS. Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke. Neuroscience 2012. PMID: 22285309


  42. Faustino JV, Wang X, Johnson CE, Klibanov A, Derugin N, Wendland MF, Vexler ZS. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience 2011. PMID: 21900578


  43. Bowers KJ, Deveber GA, Ferriero DM, Roach ES, Vexler ZS, Maria BL. Cerebrovascular disease in children: recent advances in diagnosis and management. Journal of child neurology 2011. PMID: 21778188


  44. Dzietko M, Wendland M, Derugin N, Ferriero DM, Vexler ZS. Magnetic resonance imaging (MRI) as a translational tool for the study of neonatal stroke. Journal of child neurology 2011. PMID: 21670390


  45. Biran V, Heine VM, Verney C, Sheldon RA, Spadafora R, Vexler ZS, Rowitch DH, Ferriero DM. Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain. Neurobiology of disease 2010. PMID: 20843479


  46. Davis B, Tang J, Zhang L, Mu D, Jiang X, Biran V, Vexler Z, Ferriero DM. Role of vasodilator stimulated phosphoprotein in VEGF induced blood-brain barrier permeability in endothelial cell monolayers. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 2010. PMID: 20599605


  47. Shimotake J, Derugin N, Wendland M, Vexler ZS, Ferriero DM. Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke 2010. PMID: 20101028


  48. Vexler ZS, Yenari MA. Does inflammation after stroke affect the developing brain differently than adult brain? Developmental neuroscience 2009. PMID: 19672067


  49. Wendland MF, Faustino J, West T, Manabat C, Holtzman DM, Vexler ZS. Early diffusion-weighted MRI as a predictor of caspase-3 activation after hypoxic-ischemic insult in neonatal rodents. Stroke 2008. PMID: 18420950


  50. Gonzalez FF, McQuillen P, Mu D, Chang Y, Wendland M, Vexler Z, Ferriero DM. Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Developmental neuroscience 2007. PMID: 17762200


  51. Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS. Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. Journal of neurochemistry 2006. PMID: 17212701


  52. Vexler ZS, Tang XN, Yenari MA. Inflammation in adult and neonatal stroke. Clinical neuroscience research 2006. PMID: 20300490


  53. Vexler ZS, Sharp FR, Feuerstein GZ, Ashwal S, Thoresen M, Yager JY, Ferriero DM. Translational stroke research in the developing brain. Pediatric neurology 2006. PMID: 16765824


  54. Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS. Aminoguanidine inhibits caspase-3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia. Journal of neurochemistry 2006. PMID: 16464234


  55. Matsumori Y, Northington FJ, Hong SM, Kayama T, Sheldon RA, Vexler ZS, Ferriero DM, Weinstein PR, Liu J. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke 2006. PMID: 16397188


  56. Derugin N, Dingman A, Wendland MF, Fox C, Bollen A, Vexler ZS. Magnetic resonance imaging as a surrogate measure for histological sub-chronic endpoint in a neonatal rat stroke model. Brain research 2005. PMID: 16336947


  57. Mu D, Chang YS, Vexler ZS, Ferriero DM. Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke. Experimental neurology 2005. PMID: 16023639


  58. Fox C, Dingman A, Derugin N, Wendland MF, Manabat C, Ji S, Ferriero DM, Vexler ZS. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2005. PMID: 15874975


  59. Yenari MA, Liu J, Zheng Z, Vexler ZS, Lee JE, Giffard RG. Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Annals of the New York Academy of Sciences 2005. PMID: 16179510


  60. Matsumori Y, Hong SM, Aoyama K, Fan Y, Kayama T, Sheldon RA, Vexler ZS, Ferriero DM, Weinstein PR, Liu J. Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2005. PMID: 15744251


  61. Chang YS, Mu D, Wendland M, Sheldon RA, Vexler ZS, McQuillen PS, Ferriero DM. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatric research 2005. PMID: 15879287


  62. Jiang X, Mu D, Manabat C, Koshy AA, Christen S, Täuber MG, Vexler ZS, Ferriero DM. Differential vulnerability of immature murine neurons to oxygen-glucose deprivation. Experimental neurology 2004. PMID: 15473995


  63. Sheldon RA, Jiang X, Francisco C, Christen S, Vexler ZS, Täuber MG, Ferriero DM. Manipulation of antioxidant pathways in neonatal murine brain. Pediatric research 2004. PMID: 15295091


  64. Mu D, Jiang X, Sheldon RA, Fox CK, Hamrick SE, Vexler ZS, Ferriero DM. Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiology of disease 2003. PMID: 14678768


  65. Vexler ZS, Wong A, Francisco C, Manabat C, Christen S, Täuber M, Ferriero DM, Gregory G. Fructose-1,6-bisphosphate preserves intracellular glutathione and protects cortical neurons against oxidative stress. Brain research 2003. PMID: 12505661


  66. Manabat C, Han BH, Wendland M, Derugin N, Fox CK, Choi J, Holtzman DM, Ferriero DM, Vexler ZS. Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 2003. PMID: 12511776


  67. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Annals of neurology 2002. PMID: 12447935


  68. Donohoe PH, Fahlman CS, Bickler PE, Vexler ZS, Gregory GA. Neuroprotection and intracellular Ca2+ modulation with fructose-1,6-bisphosphate during in vitro hypoxia-ischemia involves phospholipase C-dependent signaling. Brain research 2001. PMID: 11640901


  69. Vexler ZS, Ferriero DM. Molecular and biochemical mechanisms of perinatal brain injury. Seminars in neonatology : SN 2001. PMID: 11483016


  70. Derugin N, Wendland M, Muramatsu K, Roberts TP, Gregory G, Ferriero DM, Vexler ZS. Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. Stroke 2000. PMID: 10884483


  71. Vexler Z, Berrios M, Ursell PC, Sola A, Ferriero DM, Gregory GA. Toxicity of fructose-1,6-bisphosphate in developing normoxic rats. Pharmacology & toxicology 1999. PMID: 10193671


  72. Derugin N, Ferriero DM, Vexler ZS. Neonatal reversible focal cerebral ischemia: a new model. Neuroscience research 1998. PMID: 9950062


  73. Vexler ZS, Roberts TP, Bollen AW, Derugin N, Arieff AI. Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion. The Journal of clinical investigation 1997. PMID: 9077555


  74. Vexler ZS, Symons M, Barber DL. Activation of Na+-H+ exchange is necessary for RhoA-induced stress fiber formation. The Journal of biological chemistry 1996. PMID: 8798382


  75. Roberts TP, Vexler ZS, Vexler V, Derugin N, Kucharczyk J. Sensitivity of high-speed "perfusion-sensitive" magnetic resonance imaging to mild cerebral ischemia. European radiology 1996. PMID: 8934128


  76. Roberts TP, Vexler ZS, Derugin N, Kozniewska E, Kucharczyk J, Emmett CJ. Evaluation of recombinant human basic fibroblast growth factor (rhbFGF) as a cerebroprotective agent using high speed MR imaging. Brain research 1995. PMID: 8616613


  77. Arieff AI, Kozniewska E, Roberts TP, Vexler ZS, Ayus JC, Kucharczyk J. Age, gender, and vasopressin affect survival and brain adaptation in rats with metabolic encephalopathy. The American journal of physiology 1995. PMID: 7771574


  78. Kozniewska E, Roberts TP, Vexler ZS, Oseka M, Kucharczyk J, Arieff AI. Hormonal dependence of the effects of metabolic encephalopathy on cerebral perfusion and oxygen utilization in the rat. Circulation research 1995. PMID: 7895330


  79. Vexler ZS, Ayus JC, Roberts TP, Fraser CL, Kucharczyk J, Arieff AI. Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals. The Journal of clinical investigation 1994. PMID: 8282795


  80. Vexler ZS, Roberts TP, Derugin N, Kozniewska E, Arieff AI, Kucharczyk J. Mechanisms of brain injury associated with partial and complete occlusion of the MCA in cat. Acta neurochirurgica. Supplementum 1994. PMID: 7976549


  81. Vexler ZS, Roberts TP, Kucharczyk J, Arieff AI. Severe brain edema associated with cumulative effects of hyponatremic encephalopathy and ischemic hypoxia. Acta neurochirurgica. Supplementum 1994. PMID: 7976557


  82. Roberts TP, Vexler Z, Derugin N, Moseley ME, Kucharczyk J. High-speed MR imaging of ischemic brain injury following stenosis of the middle cerebral artery. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 1993. PMID: 7691853


  83. Kucharczyk J, Vexler ZS, Roberts TP, Asgari HS, Mintorovitch J, Derugin N, Watson AD, Moseley ME. Echo-planar perfusion-sensitive MR imaging of acute cerebral ischemia. Radiology 1993. PMID: 8351338


  84. de Crespigny AJ, Wendland MF, Derugin N, Vexler ZS, Moseley ME. Rapid MR imaging of a vascular challenge to focal ischemia in cat brain. Journal of magnetic resonance imaging : JMRI 1993. PMID: 8324306


  85. Kucharczyk J, Asgari H, Mintorovitch J, Vexler Z, Rocklage S, Watson A, Moseley M. Cerebrovascular transit characteristics of DyDTPA-BMA and GdDTPA-BMA on normal and ischemic cat brain. AJNR. American journal of neuroradiology 1993. PMID: 8456701


  86. Moseley ME, Vexler Z, Asgari HS, Mintorovitch J, Derugin N, Rocklage S, Kucharczyk J. Comparison of Gd- and Dy-chelates for T2 contrast-enhanced imaging. Magnetic resonance in medicine 1991. PMID: 1812356


  87. Kucharczyk J, Asgari H, Mintorovitch J, Vexler Z, Moseley M, Watson A, Rocklage S. Magnetic resonance imaging of brain perfusion using the nonionic contrast agents Dy-DTPA-BMA and Gd-DTPA-BMA. Investigative radiology 1991. PMID: 1808141