Skip to main content

Advertisement

Log in

Perinatal asphyxia: Timing and mechanisms of injury in neonatal encephalopathy

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

This article summarizes the recent medical literature regarding perinatal asphyxia with respect to timing and mechanisms of injury for neonates who were clinically diagnosed with an encephalopathy in the newborn period. Multiple mechanisms of injury are reviewed, including genetic vulnerability, acquired inflammatory responses, and clotting defects that can lead to ischemic-induced brain damage. Before effective treatments for fetal and neonatal brain disorders can be developed, accurate and timely diagnoses of fetal or neonatal brain injury must be achieved. Specific subsets of children can then benefit from neuroprotective strategies that can target the specific developmental aspects of brain adaptation or plasticity relative to the specific etiology and timing of injury after asphyxia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Nelson KB: What proportion of cerebral palsy is related to birth asphyxia? J Pediatr 1988, 112:572–574.

    Article  PubMed  CAS  Google Scholar 

  2. Hagberg H, Mallard C: Antenatal brain injury: etiology and possibilities of prevention. Semin Neonatal 2000, 5:41–51. A useful review of the literature regarding fetal disease that predisposes to brain injury.

    Article  CAS  Google Scholar 

  3. Stevenson DK, Sunshine P: Fetal and Neonatal Brain Injury. Oxford: Oxford University Press; 1997.

    Google Scholar 

  4. Mishra OP, Delivoria-Papadopoulos M: Cellular mechanisms of hypoxic injury in the developing brain. Brain Res Bull 1999, 48:233–238.

    Article  PubMed  CAS  Google Scholar 

  5. Planells-Cases R, Caprini M, Zhang J, et al.: Neuronal death and perinatal lethality in voltage-gated sodium channel alpha (II)-deficient mice. Biophys J 2000, 78:2878–2891.

    PubMed  CAS  Google Scholar 

  6. Hanrahan JD, Cox IJ, Edwards AD, et al.: Persistent increases in cerebral lactate concentration after birth asphyxia. Pediatr Res 1998, 44:304–311.

    Article  PubMed  CAS  Google Scholar 

  7. Niyamoto O, Auer RN: Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology 2000, 54:362–371. Topical review of metabolic disturbances that lead to neuronal injury.

    Google Scholar 

  8. Nagata N, Saji M, Ito T, et al.: Repetitive intermittent hypoxia-ischemia and brain damage in neonatal rats. Brain Dev 2000, 22:315–320.

    Article  PubMed  CAS  Google Scholar 

  9. Vannucci RC, Towfighi J, Vannucci SJ, et al.: Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J Neurol Chem 1998, 71:1215–1220.

    CAS  Google Scholar 

  10. Giffard, RJ, Papadopoulos MC. Mechanisms of ischemic cell injury. In Fetal and Neonatal Brain Injury. Edited by Stevenson DK, Sunshine P. Oxford: Oxford University Press; 1997:24–37.

    Google Scholar 

  11. Fullerton AJ, Ditelberg JS, Chen SV, et al.: Copper/zinc superoxide dimutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia-ischemia. Ann Neurol 1998, 44:357–364.

    Article  PubMed  CAS  Google Scholar 

  12. Ikeda T, Choi BH, Yee S: Oxidative stress, white matter damage and intrauterine asphyxia in fetal lambs. Int J Dev Neurosci 1999, 17:1–14.

    Article  PubMed  CAS  Google Scholar 

  13. Matute C, Sanchez-Gomez MV, Martinez-Millen L: Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA 1997, 94:8830–8835.

    Article  PubMed  CAS  Google Scholar 

  14. Kohlhauser C, Mosgoeller W, Hoeger H, et al.: Cholinergic, monoaminergic and glutamatergic changes following perinatal asphyxia in the rat. Cell Mol Life Sci 1999, 55:1491–1501.

    Article  PubMed  CAS  Google Scholar 

  15. Slotkin TA, Epps TA, Stenger ML, et al.: Cholinergic receptors in heart and brainstem of rats exposed to nicotine during development: implications for hypoxia tolerance and perinatal mortality. Dev Brain Res 1999, 113:1–12.

    Article  CAS  Google Scholar 

  16. Dzhala V, Desferes L, Melyan Z, et al.: Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus. Ann Neurol 1999, 46:95–102.

    Article  PubMed  CAS  Google Scholar 

  17. Gao J, Gross J, Andreeva N, et al.: Hypoxia induces differential changes in dopamine metabolism in mature and immature mesencephalic and diencephalic cell cultures. J Neural Transm 1999, 106:111–122.

    Article  PubMed  CAS  Google Scholar 

  18. Meng SZ, Ohyu J, Itoh M, et al.: Dopamine transporter and nitric oxide synthase in hypoxic ischemic brain. Pediatr Neurol 2000, 22:115–121.

    Article  PubMed  CAS  Google Scholar 

  19. Fellman V, Raivio KO: Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 1997, 41:599–607.

    Article  PubMed  CAS  Google Scholar 

  20. Carden DL, Granger DN: Pathophysiology of ischemiareperfusion injury. J Pathol 2000, 190:255–266.

    Article  PubMed  CAS  Google Scholar 

  21. Pourcyrous M, Parfenova H, Bada HS, et al.: Changes in cerebral cyclic nucleotides and cerebral blood flow during prolonged asphyxia and recovery in newborn pigs. Pediatr Res 1997, 41:617–623.

    Article  PubMed  CAS  Google Scholar 

  22. Nakai A, Asakura H, Tanichi Y, et al.: Effect of a phenol-Ntert-Butyl Nitron on fetal cerebral energy metabolism during intrauterine ischemia and reperfusion in rats. Pediatr Res 2000, 47:451–456.

    Article  PubMed  CAS  Google Scholar 

  23. Berger R, Garnier Y: Pathophysiology of perinatal brain damage. Brain Res Rev 1999, 30:107–134.

    Article  PubMed  CAS  Google Scholar 

  24. Banasiaka KJ, Xiab Y, Haddad GG: Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog Neurobiol 2000, 62:215–249.

    Article  Google Scholar 

  25. Edwards AD, Yue X, Cox P, et al.: Apoptosis in the brains of infants suffering intrauterine cerebral palsy. Pediatr Res 1997, 42:684–689.

    Article  PubMed  CAS  Google Scholar 

  26. Mehmet H, Yue X, Squire MV, et al.: Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischemia is related to the degree of high-energy phosphate depletion during the insult. Neurosci Lett 1994, 181:121–125.

    Article  PubMed  CAS  Google Scholar 

  27. Tamatani M, Mitsuda N, Matsuzaki H, et al.: A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: rolls of nuclear factor kappa B and Bcl-2. J Neurochem 2000, 75:683–693.

    Article  PubMed  CAS  Google Scholar 

  28. Bossenmeyer-Poure C, Koziel V, Deval JL.: CPP 32/Caspase-3-like proteases in hypoxia-induced apoptosis in developing brain neurons. Mol Brain Res 1999, 71:225–237.

    Article  Google Scholar 

  29. Zhu C, Wang X, Hagberg H, et al.: Correlation between caspase-3 activation and three different markers of DNA damage in neonatal cerebral hypoxia-ischemia. J Neurochem 2000, 75:819–829.

    Article  PubMed  CAS  Google Scholar 

  30. Rickman DW, Nacke RE, Rickman CB: Characterization of the cell death promoter, BAD, in the developing rat retina and forebrain. Dev Brain Res 1999, 115:41–47.

    Article  CAS  Google Scholar 

  31. Klawson TF, Vannucci SJ, Wang GM, et al.: Hypoxia-ischemiainduced apoptotic cell death correlates with IGF-1 mRNA decrease in neonatal rat brain. Biol Signals Recept 1999, 8:281–293.

    Article  Google Scholar 

  32. Nelson KB, Dambrosia JM, Grether JK, et al.: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 1998, 44:665–675.

    Article  PubMed  CAS  Google Scholar 

  33. Martin-Ancel A, Garcia-Alix A, Pascual-Salcedo D, et al.: Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics 1997, 100:789–794.

    Article  PubMed  CAS  Google Scholar 

  34. Bona E, Andersson AL, Blomgren K, et al.: Cytokine and inflammatory cell response in hypoxia-ischemia in immature rats. Pediatr Res 1999, 45:500–509.

    Article  PubMed  CAS  Google Scholar 

  35. Dammann O, Leviton A: The role of the fetus in perinatal infection and neonatal brain damage. Curr Opin Pediatr 2000, 12:99–104.

    Article  PubMed  CAS  Google Scholar 

  36. Dommergues MA, Patkai J, Renauld JC, et al.: Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol 2000, 47:46–63.

    Article  Google Scholar 

  37. Savman K, Blennow M, Gustafson K, et al.: Cytokine response in cerebral spinal fluid after birth asphyxia. Pediatr Res 1998, 43:746–751.

    Article  PubMed  CAS  Google Scholar 

  38. Debillon T, Garas-Leguen C, Verielle V, et al.: Intrauterine infection induces programmed cell death and rapid periventricular white matter. Pediatr Res 2000, 47:736–742.

    Article  PubMed  CAS  Google Scholar 

  39. Yoon BH, Ramaro R, Park JS, et al.: Fetal exposure to an intraamniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000, 182:675–681.

    Article  PubMed  CAS  Google Scholar 

  40. Silverstein FS, Barks JD, Hagan P, et al.: Cytokines and perinatal brain injury. Neurochem Int 1997, 30:375–383.

    Article  PubMed  CAS  Google Scholar 

  41. Stanley FJ: Prenatal determinants of motor disorders. Acta Paediatr 1997, 422(suppl):92–102.

    CAS  Google Scholar 

  42. Kupferminc MJ, Eldor A, Steinman N, et al.: Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999, 340:9–13.

    Article  PubMed  CAS  Google Scholar 

  43. Goodwin TM: Clinical implications of perinatal depression in antepartum and intrapartum fetal assessment. Obstet Gynecol Clin North Am 1999, 26:711–723.

    Article  PubMed  CAS  Google Scholar 

  44. Parer JT, King T: Fetal heart rate monitoring: is it salvageable. Am J Obstet Gynecol 2000, 182:982–987.

    Article  PubMed  CAS  Google Scholar 

  45. Strachan B, Sahota D, Wijngaarden WJ, et al.: The fetal electrocardiogram: relationship with acidemia at delivery. Am J Obstet Gynecol 2000, 182:603–606.

    Article  PubMed  CAS  Google Scholar 

  46. Perlman JM: Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: medical legal issues. Pediatrics 1997, 99:851–859.

    Article  PubMed  CAS  Google Scholar 

  47. Allan WC, Vohr B, Makuch RW, et al.: Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage. Arch Pediatr Adolecs Med 1997, 151:580–585.

    CAS  Google Scholar 

  48. Badawi N, Kurinczuk JJ, Keojh JM, et al.: Antepartum risk factors for newborn encephalopathy: the Western Australian case controlled study. BMJ 1998, 317:1549–1553.

    PubMed  CAS  Google Scholar 

  49. American College of Obstetricians and Gynecologists: fetal and neonatal neurological injury. In ACOG technical bulletin No. 163. Washington, DC, American Coll Obstet and Gynecol 1992.

  50. Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976, 33:696–705.

    PubMed  CAS  Google Scholar 

  51. Sorensen LC, Borch K: Neonatal asphyxia-prognosis based on clinical findings during delivery and the first day of life. A retrospective study of 54 newborn infants with asphyxia. Ugeskr Laeger 1999, 161:3094–3098.

    PubMed  CAS  Google Scholar 

  52. Bohr L, Greisen G: Prognosis after perinatal asphyxia in fullterm infants. A literature review. Ugeskr Laeger 1998, 160:2845–2850.

    PubMed  CAS  Google Scholar 

  53. Blackwell SC, Refuerzo JS, Wolfe HM, et al.: The relationship between nucleated red blood cell counts at early onset neonatal seizures. Am J Obstet Gynecol 2000, 182:1452–1457.

    Article  PubMed  CAS  Google Scholar 

  54. Scher MS, Trucco J, Beggarly ME, et al.: Neonates with electrically-confirmed seizures and possible placental associations. Pediatr Neurol 1998, 19:37–41.

    Article  PubMed  CAS  Google Scholar 

  55. Ikeda T, Murata Y, Quilligan EJ, et al.: Histologic and biochemical study of the brain, heart, kidney and liver in asphyxia caused by occlusion of the umbilical cord in near term fetal lambs. Am J Obstet Gynecol 2000, 182:449–457.

    Article  PubMed  CAS  Google Scholar 

  56. Huang C, Wang S, Chang Y, et al.: Measurement of the urinary lactate: creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. N Engl J Med 1999, 341:328–335.

    Article  PubMed  CAS  Google Scholar 

  57. Maschmann J, Heinemann MK, Ziemer G, et al.: Evaluation of protein S-100 serum concentrations in healthy newborns and seven newborns with perinatal acidosis. Acta Paediatr 2000, 89:553–555.

    Article  PubMed  CAS  Google Scholar 

  58. Akisu M, Kultursay N, Coker I, et al.: Plasma platelet-activating factor levels in newborn infants with and without perinatal asphyxia: is it an additional marker of perinatal asphyxia? Acta Paediatr Jpn 1998, 40:427–431.

    PubMed  CAS  Google Scholar 

  59. Buonocore G, Perrone S, Gioia D, et al.: Nucleated red blood cell count at birth as an index of perinatal brain damage. Am J Obstet Gynecol 1999, 181:1500–1505.

    Article  PubMed  CAS  Google Scholar 

  60. Juul SE, Stallings SA, Christiansen RD. Erythropoietin in the cerebral spinal fluid of neonates with sustained CNS injury. Pediatr Res 1999, 46:543–547.

    Article  PubMed  CAS  Google Scholar 

  61. Roldan A, Figueras J, Deulofeu R, et al.: Glycine and other neurotransmitter amino acids in cerebrospinal fluid in perinatal asphyxia and neonatal hypoxic ischemic encephalopathy. Acta Paediatr 1999, 88:1137–1141.

    Article  PubMed  CAS  Google Scholar 

  62. Sweet DJ, Bell AH, McClure J, et al.: Comparison between creatinine kinase brain isoenzyme activity and sarnat score for prediction of adverse outcome following perinatal asphyxia. J Perinatal Med 1999, 27:478–483.

    Article  CAS  Google Scholar 

  63. Walker DW, Curtis B, Lace B, et al.: Kynurenic acid in brain and cerebral spinal fluid of fetal, newborn, and adult sheep and effects of placental embolization. Pediatr Res 1999, 45:820–826.

    Article  PubMed  CAS  Google Scholar 

  64. Watanabe K, Hayakawa F, Okumura A: Neonatal EEG: a powerful tool in the assessment of brain damage in preterm infants. Brain Dev 1999, 21:361–372.

    Article  PubMed  CAS  Google Scholar 

  65. Naqeeb N, Edwards AD, Cowan FM, et al.: Assessment of neonatal encephalopathy by amplitude -integrated electroencephalography. Pediatrics 1999, 103:1263–1271.

    Article  PubMed  Google Scholar 

  66. Toet MC, Hellstrom-Westas L, Groenendaal F, et al.: Amplitude and integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 1999, 81:F19-F23.

    Article  PubMed  CAS  Google Scholar 

  67. Scalais E, Adant A, Nuttin C, et al.: Multimodality evoked potentials as a prognostic tool in term asphyxiated newborns. Electroencephalography & Clin Neurophysiol 1998, 108:199–207.

    Article  CAS  Google Scholar 

  68. Taylor GA: Recent advances in neonatal cranial ultrasound and doppler techniques. In Clin Perinatol, Neurological Disorders in the Newborn, Part I. Edited by DuPlessis J. Philadelphia: WB Saunders; 1997:677–691.

    Google Scholar 

  69. Neuman-Haefelin T, Moseley ME, Albers JW: New magnetic resonance imaging methods for cerebrovascular disease: emerging clinical applications. Ann Neurol 2000, 47:559–570.

    Article  Google Scholar 

  70. Huppi PS, Maier SE, Peled S: Microstructural development of human newborn cerebral white matter assessed invivo by diffusion tensor magnetic resonance imaging. Pediatr Res 1998, 44:584–590.

    Article  PubMed  CAS  Google Scholar 

  71. Huppi PS, Warfield S, Kikinis R, et al.: Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann Neurol 1998, 43:224–235.

    Article  PubMed  CAS  Google Scholar 

  72. Mueser U, Rutherford MA, Squier WV, et al.: Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants. Am J Neurol 1999, 20:1349–1357.

    Google Scholar 

  73. Inder TE, Huppi PS, Warfield S, et al.: Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol 1999, 46:755–760.

    Article  PubMed  CAS  Google Scholar 

  74. Lan LM, Yamashita Y, Tang Y, et al.: Normal fetal brain development: MR imaging with half fourier rapid acquisition with relaxation enhancement sequence. Radiol 2000, 215:205–210.

    CAS  Google Scholar 

  75. Levine D, Barnes PD: Cortical maturation in normal and abnormal fetuses as assessed with prenatal MR imaging. Radiology 1999, 210:751–758.

    PubMed  CAS  Google Scholar 

  76. Pavlakis SJ, Kingsley PB, Harper R, et al.: Correlation of basal ganglia magnetic resonance spectroscopy with Apgar score in perinatal asphyxia. Arch Neurol 1999, 56:1476–1481.

    Article  PubMed  CAS  Google Scholar 

  77. Aida N, Nishimura G, Hachiya Y, et al.: MR imaging of perinatal brain damage: comparison of clinical outcome with initial and follow-up MR findings. Am J Neurol Rep 1998, 19:1909–1921.

    CAS  Google Scholar 

  78. Millet V, Bartoli JM, Lacroze V, et al.: Predictive significance of magnetic resonance imaging at four months of adjusted age in infants after perinatal neurologic insult. Biol Neonate 1998, 73:207–219.

    Article  PubMed  CAS  Google Scholar 

  79. Redline RW: Disorders of the placental parenchyma in pathology of the placenta. In Continuing Issues in Surgical Pathology, edn 2. Edited by Lewis SH, Perrin E. Philadelphia: WB Saunders; 1999:161–184. A useful review of placental pathology that may be relevant to the predisposition of children who suffer with hypoxic ischemic encephalopathy.

    Google Scholar 

  80. Elchalal U, Ezra Y, Levi Y, et al.: Sonographically thick placenta: a marker for increased perinatal risk—a prospective cross sectional study. Placenta 2000, 21:268–272.

    Article  PubMed  CAS  Google Scholar 

  81. Sherer DM, Anyaegbunam A: Prenatal ultrasonographic morphologic assessment of the umbilical cord: a review. Part II. Obstet Gynecol Surg 1997, 52:515–523.

    Article  CAS  Google Scholar 

  82. Kraus FT, Acheen VI: Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Human Pathol 1999, 30:759–769.

    Article  CAS  Google Scholar 

  83. Redline RW, Wilson-Costello D, Borawski E, et al.: The relationship between placental and other perinatal risk factors for the neurologic impairment in very low birth weight children. Pediatr Res 2000, 47:721–726. One of the few papers that correlate placental findings with perinatal risk factors with respect to risk for neurologic impairment in the preterm infant.

    Article  PubMed  CAS  Google Scholar 

  84. Fortunato SJ, Menon R, Bryant C, et al.: Program cell death (apoptosis) as a possible pathway to metallo proteinase activation and fetal membrane degredation in premature rupture of membranes. Am J Obstet Gynecol 2000, 182:1468–1476.

    Article  PubMed  CAS  Google Scholar 

  85. Thoresen M: Cooling the newborn after asphyxia-physiological and experimental background and its clinical use. Semin Neonatol 2000, 5:61–73.

    Article  PubMed  CAS  Google Scholar 

  86. Groenendaal F, DeVries LS: Selection of babies for intervention after birth asphyxia. Semin Neontol 2000, 5:17–32. Excellent review regarding the selected cohort of infants who would potentially benefit from neruologic rescue after birth asphyxia.

    Article  CAS  Google Scholar 

  87. Vannucci RC, Perlman JM: Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997, 100:1004–1014.

    Article  PubMed  CAS  Google Scholar 

  88. Whitelaw A: Systematic review of therapy after hypoxic-ischemic brain injury in the perinatal period. Semin Neonatol 2000, 5:33–40.

    Article  PubMed  CAS  Google Scholar 

  89. Johnston MV, Trescher WH, Ishida A, et al.: Novel treatments after experimental brain injury. Semin Neonatol 2000, 5:75–86.

    Article  PubMed  CAS  Google Scholar 

  90. Nelson KB, Grether JK: Selection of neonates for neuroprotective therapies. Arch Pediatr Adolesc Med 1999, 153:393–398. Well-designed epidemiologic study emphasizing the distinction between intrapartum and neonatal risk factors for hypoxic ischemic encephalopathy versus children who may have suffered brain injury at some time distant from events at birth.

    PubMed  CAS  Google Scholar 

  91. Edwards AD, Azzopardi: Perinatal hypoxia ischemia and brain injury-commentary. Pediatr Res 2000, 47:431–432.

    Article  PubMed  CAS  Google Scholar 

  92. Emerson MR, Sampson FE, Pazdernik TL: Effects of hypoxia preconditioning on expression of metallothioneine — 1–2 and heme oxygenase-1 before and after kainic acid induced seizures. Cell Mol Biol 2000, 46:619–626.

    PubMed  CAS  Google Scholar 

  93. Premkumar DR, Adhikary G, Overhalt JL, et al.: Intracellular pathways linking hypoxia to activation of C-fos and Ap-1. Adv Exp Med Biol 2000, 475:101–109.

    Article  PubMed  CAS  Google Scholar 

  94. Meek DW: The role of P53 in the response to mitotic spindle damage. Pathol Biol 2000, 48:246–254.

    PubMed  CAS  Google Scholar 

  95. Sapolsky RM, Steinberg GK: Gene therapy using viral vectors for acute neurologic insults. Neurology 1999, 53:1922–1931. Provocative and topical review that discusses the use of gene therapy to treat acute neurologic insults.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scher, M. Perinatal asphyxia: Timing and mechanisms of injury in neonatal encephalopathy. Curr Neurol Neurosci Rep 1, 175–184 (2001). https://doi.org/10.1007/s11910-001-0014-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-001-0014-x

Keywords

Navigation