Pathophysiology of Hirschsprung’s Disease

  • P. Puri
  • S. Montedonico


The basic pathophysiological feature in Hirschsprung’s disease (HD) is a functional obstruction caused by a narrowed distal aganglionic colonic segment that prevents the propagation of peristaltic waves. Despite extensive research, the pathophysiology of HD is not fully understood. There is no clear explanation for the occurrence of spastic or tonically contracted aganglionic segment of bowel.


Vasoactive Intestinal Peptide Enteric Nervous System Neural Cell Adhesion Molecule Enteroendocrine Cell NADPH Diaphorase 
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.


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  1. 1.
    Costa M, Brookes SJ, Hennig GW (2000) Anatomy and physiology of the enteric nervous system. Gut 47 [Suppl 4]:iv15–19; discussion iv26Google Scholar
  2. 2.
    Olsson C, Holmgren S (2001) The control of gut motility. Comp Biochem Physiol A Mol Integr Physiol 128:481–503PubMedCrossRefGoogle Scholar
  3. 3.
    Hansen MB (2003) The enteric nervous system I: organisation and classification. Pharmacol Toxicol 92:105–113PubMedCrossRefGoogle Scholar
  4. 4.
    Huizinga JD (1999) Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal. Microsc Res Tech 47:239–247PubMedCrossRefGoogle Scholar
  5. 5.
    Takaki M (2003) Gut pacemaker cells: the interstitial cells of Cajal (ICC). J Smooth Muscle Res 39:137–161PubMedCrossRefGoogle Scholar
  6. 6.
    Ward SM, Sanders KM, Hirst GD (2004) Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles. Neurogastroenterol Motil 16 [Suppl 1]:112–117Google Scholar
  7. 7.
    Sanders KM, Ordog T, Ward SM (2002) Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 282:G747–756PubMedGoogle Scholar
  8. 8.
    Alberti E, Mikkelsen HB, Larsen JO, Jimenez M (2005) Motility patterns and distribution of interstitial cells of Cajal and nitrergic neurons in the proximal, mid- and distal-colon of the rat. Neurogastroenterol Motil 17:133–147PubMedCrossRefGoogle Scholar
  9. 9.
    Berthoud HR, Blackshaw LA, Brookes SJ, Grundy D (2004) Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol Motil 16 [Suppl 1]:28–33Google Scholar
  10. 10.
    Hansen MB (2003) The enteric nervous system II: gastrointestinal functions. Pharmacol Toxicol 92:249–257PubMedCrossRefGoogle Scholar
  11. 11.
    Goyal RK, Hirano I (1996) The enteric nervous system. N Engl J Med 334:1106–1115PubMedCrossRefGoogle Scholar
  12. 12.
    Newgreen D, Young HM (2002) Enteric nervous system: development and developmental disturbances – part 1. Pediatr Dev Pathol 5:224–247PubMedGoogle Scholar
  13. 13.
    Schemann M, Neunlist M (2004) The human enteric nervous system. Neurogastroenterol Motil 16 [Suppl 1]:55–59Google Scholar
  14. 14.
    Furness JB (2000) Types of neurons in the enteric nervous system. J Auton Nerv Syst 81:87–96PubMedCrossRefGoogle Scholar
  15. 15.
    Bornstein JC, Furness JB, Kunze WA (1994) Electrophysiological characterization of myenteric neurons: how do classification schemes relate? J Auton Nerv Syst 48:1–15PubMedCrossRefGoogle Scholar
  16. 16.
    Brehmer A, Schrodl F, Neuhuber W (1999) Morphological classifications of enteric neurons – 100 years after Dogiel. Anat Embryol (Berl) 200:125–135CrossRefGoogle Scholar
  17. 17.
    Costa M, Brookes SJ, Steele PA, Gibbins I, Burcher E, Kandiah CJ (1996) Neurochemical classification of myenteric neurons in the guinea-pig ileum. Neuroscience 75:949–967PubMedCrossRefGoogle Scholar
  18. 18.
    Clerc N, Furness JB (2004) Intrinsic primary afferent neurons of the digestive tract. Neurogastroenterol Motil 16 [Suppl 1]:24–7Google Scholar
  19. 19.
    Holzer P (2002) Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain. Neurogastroenterol Motil 14:459–475PubMedCrossRefGoogle Scholar
  20. 20.
    Hansen MB (2003) Neurohumoral control of gastrointestinal motility. Physiol Res 52:1–30PubMedGoogle Scholar
  21. 21.
    Dockray GJ (2003) Luminal sensing in the gut: an overview. J Physiol Pharmacol 54 [Suppl 4]:9–17Google Scholar
  22. 22.
    Matini P, Manneschi LI, Mayer B, Faussone-Pellegrini MS (1995) Nitric oxide producing neurons in the human colon: an immunohistochemical and histoenzymatical study. Neurosci Lett 193:17–20PubMedCrossRefGoogle Scholar
  23. 23.
    O’Kelly TJ, Davies JR, Brading AF, Mortensen NJ (1994) Distribution of nitric oxide synthase containing neurons in the rectal myenteric plexus and anal canal. Morphologic evidence that nitric oxide mediates the rectoanal inhibitory reflex. Dis Colon Rectum 37:350–357PubMedCrossRefGoogle Scholar
  24. 24.
    Kunze WA, Furness JB (1999) The enteric nervous system and regulation of intestinal motility. Annu Rev Physiol 61:117–142PubMedCrossRefGoogle Scholar
  25. 25.
    Vantrappen G, Janssens J, Hellemans J, Ghoos Y (1977) The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 59:1158–1166PubMedCrossRefGoogle Scholar
  26. 26.
    Szurszewski JH (1969) A migrating electric complex of canine small intestine. Am J Physiol 217:1757–1763PubMedGoogle Scholar
  27. 27.
    Summers RW, Dusdieker NS (1981) Patterns of spike burst spread and flow in the canine small intestine. Gastroenterology 81:742–750PubMedGoogle Scholar
  28. 28.
    Teitelbaum DH, Coran AG, Weitzman JJ, Ziegler MM, Kane T (1998) Hirschsprung’s disease and related neuromuscular disorders of the intestine. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG (eds) Pediatric surgery, 5th edn. Mosby, St Louis, pp 1381–1424Google Scholar
  29. 29.
    Dasgupta R, Langer JC (2004) Hirschsprung disease. Curr Probl Surg 41:942–988PubMedCrossRefGoogle Scholar
  30. 30.
    Meier-Ruge W (2000) Histological diagnosis and differential diagnosis. In: Holschneider AM, Puri P (eds) Hirschsprung’s disease and allied disorders. Harwood, Amsterdam, pp 252–265Google Scholar
  31. 31.
    Watanabe Y, Ito T, Harada T, Kobayashi S, Ozaki T, Nimura Y (1995) Spatial distribution and pattern of extrinsic nerve strands in the aganglionic segment of congenital aganglionosis: stereoscopic analysis in spotting lethal rats. J Pediatr Surg 30:1471–1476PubMedCrossRefGoogle Scholar
  32. 32.
    Kakita Y, Oshiro K, O’Briain DS, Puri P (2000) Selective demonstration of mural nerves in ganglionic and aganglionic colon by immunohistochemistry for glucose transporter-1: prominent extrinsic nerve pattern staining in Hirschsprung disease. Arch Pathol Lab Med 124:1314–1319PubMedGoogle Scholar
  33. 33.
    Kobayashi H, O’Briain DS, Puri P (1994) Nerve growth factor receptor immunostaining suggests an extrinsic origin for hypertrophic nerves in Hirschsprung’s disease. Gut 35:1605–1607PubMedCrossRefGoogle Scholar
  34. 34.
    Payette RF, Tennyson VM, Pham TD, Mawe GM, Pomeranz HD, Rothman TP, Gershon MD (1987) Origin and morphology of nerve fibers in the aganglionic colon of the lethal spotted (ls/ls) mutant mouse. J Comp Neurol 257:237–252PubMedCrossRefGoogle Scholar
  35. 35.
    Tam PK, Boyd GP (1990) Origin, course, and endings of abnormal enteric nerve fibres in Hirschsprung’s disease defined by whole-mount immunohistochemistry. J Pediatr Surg 25:457–461PubMedCrossRefGoogle Scholar
  36. 36.
    Weinberg AG (1975) Hirschsprung’s disease — a pa­tho­logist’s view. Perspect Pediatr Pathol 2:207–239PubMedGoogle Scholar
  37. 37.
    Vizi ES, Zseli J, Kontor E, Feher E, Verebelyi T (1990) Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprung’s dis­ease. Gut 31:1046–1050PubMedCrossRefGoogle Scholar
  38. 38.
    Frigo GM, Del Tacca M, Lecchini S, Crema A (1973) Some observations on the intrinsic nervous mechanism in Hirschsprung’s disease. Gut 14:35–40PubMedCrossRefGoogle Scholar
  39. 39.
    Boston VE, Cywes S, Davies MR (1978) Serum and erythrocyte acetylcholinesterase activity in Hirschsprung’s dis­ease. J Pediatr Surg 13:407–410PubMedGoogle Scholar
  40. 40.
    Imamura K, Yamamoto M, Sato A, Kashiki Y, Kunieda T (1975) Pathophysiology of aganglionic colon segment: an experimental study on aganglionosis produced by a new method in the rat. J Pediatr Surg 10:865–873PubMedCrossRefGoogle Scholar
  41. 41.
    Sato A, Yamamoto M, Imamura K, Kashiki Y, Kunieda T, Sakata K (1978) Pathophysiology of aganglionic colon and anorectum: an experimental study on aganglionosis produced by a new method in the rat. J Pediatr Surg 13:399–435PubMedGoogle Scholar
  42. 42.
    Garrett JR, Howard ER, Nixon HH (1969) Autonomic nerves in rectum and colon in Hirschsprung’s disease. A cholinesterase and catecholamine histochemical study. Arch Dis Child 44:406–417PubMedCrossRefGoogle Scholar
  43. 43.
    Touloukian RJ, Aghajanian G, Roth RH (1973) Adrenergic hyperactivity of the aganglionic colon. J Pediatr Surg 8:191–195PubMedCrossRefGoogle Scholar
  44. 44.
    Nirasawa Y, Yokoyama J, Ikawa H, Morikawa Y, Katsumata K (1986) Hirschsprung’s disease: catecholamine content, alpha-adrenoceptors, and the effect of electrical stimulation in aganglionic colon. J Pediatr Surg 21:136–142PubMedCrossRefGoogle Scholar
  45. 45.
    Hiramoto Y, Kiesewetter WB (1974) The response of colonic muscle to drugs: an in vitro study of Hirschsprung’s disease. J Pediatr Surg 9:13–20PubMedCrossRefGoogle Scholar
  46. 46.
    Wright PG, Shepherd JJ (1966) Some observations on the response of normal human sigmoid colon to drugs in vitro. Gut 7:41–51PubMedCrossRefGoogle Scholar
  47. 47.
    Puri P (1997) Hirschsprung disease. In: Oldham KT, Colombani PM, Foglia R (eds) Surgery of infants and children. Scientific principles and practice. Lippincott-Raven, Philadelphia, pp 1277–1299Google Scholar
  48. 48.
    Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG (1990) Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 345:346–347PubMedCrossRefGoogle Scholar
  49. 49.
    Rolle U, Nemeth L, Puri P (2002) Nitrergic innervation of the normal gut and in motility disorders of childhood. J Pediatr Surg 37:551–567PubMedCrossRefGoogle Scholar
  50. 50.
    Dawson TM, Bredt DS, Fotuhi M, Hwang PM, Snyder SH (1991) Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc Natl Acad Sci U S A 88:7797–7801PubMedCrossRefGoogle Scholar
  51. 51.
    Hope BT, Michael GJ, Knigge KM, Vincent SR (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proc Natl Acad Sci U S A 88:2811–2814PubMedCrossRefGoogle Scholar
  52. 52.
    Vanderwinden JM, Rumessen JJ, Liu H, Descamps D, De Laet MH, Vanderhaeghen JJ (1996) Interstitial cells of Cajal in human colon and in Hirschsprung’s disease. Gastroenterology 111:901–910PubMedCrossRefGoogle Scholar
  53. 53.
    Kobayashi H, O’Briain DS, Puri P (1994) Lack of expression of NADPH-diaphorase and neural cell adhesion molecule (NCAM) in colonic muscle of patients with Hirschsprung’s disease. J Pediatr Surg 29:301–304PubMedCrossRefGoogle Scholar
  54. 54.
    Bealer JF, Natuzzi ES, Buscher C, Ursell PC, Flake AW, Adzick NS, Harrison MR (1994) Nitric oxide synthase is deficient in the aganglionic colon of patients with Hirschsprung’s disease. Pediatrics 93:647–651PubMedGoogle Scholar
  55. 55.
    Larsson LT, Shen Z, Ekblad E, Sundler F, Alm P, Andersson KE (1995) Lack of neuronal nitric oxide synthase in nerve fibers of aganglionic intestine: a clue to Hirschsprung’s dis­ease. J Pediatr Gastroenterol Nutr 20:49–53PubMedCrossRefGoogle Scholar
  56. 56.
    Guo R, Nada O, Suita S, Taguchi T, Masumoto K (1997) The distribution and co-localization of nitric oxide synthase and vasoactive intestinal polypeptide in nerves of the colons with Hirschsprung’s disease. Virchows Arch 430:53–61PubMedCrossRefGoogle Scholar
  57. 57.
    Watanabe H, Ikawa H, Masuyama H, Endo M, Yokoyama J, Nakaki T (1995) Non-adrenergic-non-cholinergic relaxation and nitric oxide in the intestines of Hirschsprung disease (in Japanese). J Smooth Muscle Res 31:467–470PubMedGoogle Scholar
  58. 58.
    Kusafuka T, Puri P (1997) Altered mRNA expression of the neuronal nitric oxide synthase gene in Hirschsprung’s dis­ease. J Pediatr Surg 32:1054–1058PubMedCrossRefGoogle Scholar
  59. 59.
    Bealer JF, Natuzzi ES, Flake AW, Adzick NS, Harrison MR (1994) Effect of nitric oxide on the colonic smooth muscle of patients with Hirschsprung’s disease. J Pediatr Surg 29:1025–1029PubMedCrossRefGoogle Scholar
  60. 60.
    Yamataka A, Kato Y, Tibboel D, Murata Y, Sueyoshi N, Fujimoto T, Nishiye H, Miyano T (1995) A lack of intestinal pacemaker (c-kit) in aganglionic bowel of patients with Hirschsprung’s disease. J Pediatr Surg 30:441–444PubMedCrossRefGoogle Scholar
  61. 61.
    Yamataka A, Ohshiro K, Kobayashi H, Fujiwara T, Sunagawa M, Miyano T (1997) Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung’s disorders. J Pediatr Surg 32:1069–1074PubMedCrossRefGoogle Scholar
  62. 62.
    Horisawa M, Watanabe Y, Torihashi S (1998) Distribution of c-Kit immunopositive cells in normal human colon and in Hirschsprung’s disease. J Pediatr Surg 33:1209–1214PubMedCrossRefGoogle Scholar
  63. 63.
    Rolle U, Piotrowska AP, Nemeth L, Puri P (2002) Altered distribution of interstitial cells of Cajal in Hirschsprung dis­ease. Arch Pathol Lab Med 126:928–933PubMedGoogle Scholar
  64. 64.
    Nemeth L, Maddur S, Puri P (2000) Immunolocalization of the gap junction protein connexin43 in the interstitial cells of Cajal in the normal and Hirschsprung’s disease bowel. J Pediatr Surg 35:823–828PubMedCrossRefGoogle Scholar
  65. 65.
    Soeda J, O’Briain DS, Puri P (1992) Mucosal neuroendocrine cell abnormalities in the colon of patients with Hirschsprung’s disease. J Pediatr Surg 27:823–827PubMedCrossRefGoogle Scholar
  66. 66.
    Nemeth L, Rolle U, Puri P (2002) Altered cytoskeleton in smooth muscle of aganglionic bowel. Arch Pathol Lab Med 126:692–696PubMedGoogle Scholar
  67. 67.
    Covault J, Sanes JR (1986) Distribution of N-CAM in synaptic and extrasynaptic portions of developing and adult skeletal muscle. J Cell Biol 102:716–730PubMedCrossRefGoogle Scholar
  68. 68.
    Thiery JP, Duband JL, Rutishauser U, Edelman GM (1982) Cell adhesion molecules in early chicken embryogenesis. Proc Natl Acad Sci U S A 79:6737–6741PubMedCrossRefGoogle Scholar
  69. 69.
    Moore SE, Walsh FS (1985) Specific regulation of N-CAM/D2-CAM cell adhesion molecule during skeletal muscle development. EMBO J 4:623–630PubMedGoogle Scholar
  70. 70.
    Romanska HM, Bishop AE, Brereton RJ, Spitz L, Polak JM (1993) Increased expression of muscular neural cell adhesion molecule in congenital aganglionosis. Gastroenterology 105:1104–1109PubMedGoogle Scholar
  71. 71.
    Payette RF, Tennyson VM, Pomeranz HD, Pham TD, Rothman TP, Gershon MD (1988) Accumulation of components of basal laminae: association with the failure of neural crest cells to colonize the presumptive aganglionic bowel of ls/ls mutant mice. Dev Biol 125:341–360PubMedCrossRefGoogle Scholar
  72. 72.
    Tennyson VM, Payette RF, Rothman TP, Gershon MD (1990) Distribution of hyaluronic acid and chondroitin sulfate proteoglycans in the presumptive aganglionic terminal bowel of ls/ls fetal mice: an ultrastructural analysis. J Comp Neurol 291:345–362PubMedCrossRefGoogle Scholar
  73. 73.
    Parikh DH, Tam PK, Lloyd DA, Van Velzen D, Edgar DH (1992) Quantitative and qualitative analysis of the extracellular matrix protein, laminin, in Hirschsprung’s disease. J Pediatr Surg 27:991–995; discussion 995–996PubMedCrossRefGoogle Scholar
  74. 74.
    Parikh DH, Tam PK, Van Velzen D, Edgar D (1992) Abnormalities in the distribution of laminin and collagen type IV in Hirschsprung’s disease. Gastroenterology 102:1236–1241PubMedGoogle Scholar
  75. 75.
    Parikh DH, Tam PK, Van Velzen D, Edgar D (1994) The extracellular matrix components, tenascin and fibronectin, in Hirschsprung’s disease: an immunohistochemical study. J Pediatr Surg 29:1302–1306PubMedCrossRefGoogle Scholar
  76. 76.
    Heij HA, de Vries X, Bremer I, Ekkelkamp S, Vos A (1995) Long-term anorectal function after Duhamel operation for Hirschsprung’s disease. J Pediatr Surg 30:430–432PubMedCrossRefGoogle Scholar
  77. 77.
    Moore SW, Albertyn R, Cywes S (1996) Clinical outcome and long-term quality of life after surgical correction of Hirschsprung’s disease. J Pediatr Surg 31:1496–1502PubMedCrossRefGoogle Scholar
  78. 78.
    Baillie CT, Kenny SE, Rintala RJ, Booth JM, Lloyd DA (1999) Long-term outcome and colonic motility after the Duhamel procedure for Hirschsprung’s disease. J Pediatr Surg 34:325–329PubMedCrossRefGoogle Scholar
  79. 79.
    Miele E, Tozzi A, Staiano A, Toraldo C, Esposito C, Clouse RE (2000) Persistence of abnormal gastrointestinal motility after operation for Hirschsprung’s disease. Am J Gastroenterol 95:1226–1230PubMedCrossRefGoogle Scholar
  80. 80.
    Puri P, Rolle U (2004) Variant Hirschsprung’s disease. Semin Pediatr Surg 13:293–299PubMedCrossRefGoogle Scholar
  81. 81.
    Puri P, Lake BD, Nixon HH, Mishalany H, Claireaux AE (1977) Neuronal colonic dysplasia: an unusual association of Hirschsprung’s disease. J Pediatr Surg 12:681–685PubMedCrossRefGoogle Scholar
  82. 82.
    Fadda B, Maier WA, Meier-Ruge W, Scharli A, Daum R (1983) Neuronal intestinal dysplasia. Critical 10-years’ analysis of clinical and biopsy diagnosis (in German). Z Kinderchir 38:305–311PubMedGoogle Scholar
  83. 83.
    Scharli AF (1992) Intestinal neuronal dysplasia (in Spanish). Cir Pediatr 5:64–65PubMedGoogle Scholar
  84. 84.
    Kobayashi H, Hirakawa H, Surana R, O’Briain DS, Puri P (1995) Intestinal neuronal dysplasia is a possible cause of persistent bowel symptoms after pull-through operation for Hirschsprung’s disease. J Pediatr Surg 30:253–257; discussion 257–259PubMedCrossRefGoogle Scholar
  85. 85.
    Schmittenbecher PP, Sacher P, Cholewa D, Haberlik A, Menardi G, Moczulski J, Rumlova E, Schuppert W, Ure B (1999) Hirschsprung’s disease and intestinal neuronal dysplasia – a frequent association with implications for the postoperative course. Pediatr Surg Int 15:553–558PubMedCrossRefGoogle Scholar
  86. 86.
    Banani SA, Forootan HR, Kumar PV (1996) Intestinal neuronal dysplasia as a cause of surgical failure in Hirschsprung’s disease: a new modality for surgical management. J Pediatr Surg 31:572–574PubMedCrossRefGoogle Scholar
  87. 87.
    Sandgren K, Larsson LT, Ekblad E (2002) Widespread changes in neurotransmitter expression and number of enteric neurons and interstitial cells of Cajal in lethal spotted mice: an explanation for persisting dysmotility after operation for Hirschsprung’s disease? Dig Dis Sci 47:1049–1064PubMedCrossRefGoogle Scholar
  88. 88.
    Swenson O, Rheinlander H, Diamond I (1949) Hirschsprung’s disease: a new concept of the etiology. N Engl J Med 241:551–556PubMedCrossRefGoogle Scholar
  89. 89.
    Swenson O, Bill A (1948) Resection of the rectum and rectosigmoid with preservation of the sphincter for benign spastic lesions producing megacolon. Surgery 24:212–220PubMedGoogle Scholar
  90. 90.
    Kubota M, Ito Y, Ikeda K (1983) Membrane properties and innervation of smooth muscle cells in Hirschsprung’s dis­ease. Am J Physiol 244:G406–415PubMedGoogle Scholar
  91. 91.
    Kubota M, Ito Y, Taguchi T, Ikeda K, Ikadai H (1989) Regional differences in the pattern of neurogenic responses in the aganglionic colon from congenitally aganglionic rats. J Pediatr Surg 24:911–919PubMedCrossRefGoogle Scholar
  92. 92.
    Kubota M, Kamimura T, Suita S (1997) External anal sphincter dysfunction and postoperative bowel habits of patients with Hirschsprung’s disease. J Pediatr Surg 32:22–24PubMedCrossRefGoogle Scholar
  93. 93.
    Kubota M, Suita S, Ito Y, Szurszewski JH (2001) Membrane properties and innervation of the aganglionic segment of smooth muscle in Hirschsprung’s disease (in Japanese). Fukuoka Igaku Zasshi 92:341–346PubMedGoogle Scholar
  94. 94.
    Kubota M, Suita S, Kamimura T, Ito Y, Szurszewski JH (2002) Electrophysiological properties of the aganglionic segment in Hirschsprung’s disease. Surgery 131 [1 Suppl]:S288–293Google Scholar

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© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • P. Puri
    • 1
  • S. Montedonico
    • 1
  1. 1.Children’s Research Centre, Our Lady’s Children’s HospitalUniversity College of DublinCrumlinIreland

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