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Neurotransmitters in the Nucleus Tractus Solitarius Mediating Cardiovascular Function

  • Hreday N. Sapru
Chapter

Abstract

The importance of the nucleus tractus solitarius (nTS) in the regulation of cardiovascular function has been known for a long time. However, the role of different neurotransmitters in this region in mediating cardiovascular functions is just beginning to be delineated. The carotid chemoreceptor afferents terminate predominantly in a midline area around the calamus scriptorius in the commissural subnucleus of the nTS while the baroreceptor and cardiopulmonary receptor afferents terminate in a region more rostral and lateral to the chemoreceptor projection site. There is a general consensus that glutamate is the neurotransmitter released at the terminals of baroreceptor, cardiopulmonary and chemoreceptor afferents in the nTS. However, cholinergic, GABAergic, and opioidergic mechanisms are also present in the nTS. Activation of glutamatergic and cholinergic mechanisms in the nTS elicits depressor responses while the activation of GABAergic and opioidergic mechanisms elicits pressor responses. Although, the precise physiological role of cholinergic, GABAergic, and opioidergic nTS mechanisms in regulating cardiovascular function remains to be elucidated, there is a general consensus that these mechanisms may play a neuromodulatory role in the nTS.

Key words

Blood pressure bradycardia caudal ventrolateral medullary depressor area chemoreceptor projection site depressor responses heart rate pressor responses rostral ventrolateral medullary pressor area 
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References

  1. Agarwal, S.K., Gelsema, A.J., Calaresu F.R., 1989. Neurons in rostral VLM are inhibited by chemical stimulation of caudal VLM in rats. Am. J. Physiol. 257R265–R270.PubMedGoogle Scholar
  2. Aicher, S.A., Kurucz, O.S., Reis, D.J., Milner, T.A., 1995. Nucleus tractus solitarius efferent terminals synapse on neurons in the caudal ventrolateral medulla that project to the rostral ventrolateral medulla. Brain Res. 69351–63.PubMedCrossRefGoogle Scholar
  3. Andresen, M.C., Yang, M., 1990. Non-NMDA receptors mediate sensory afferent synaptic transmission in medial nucleus tractus solitarius. Am. J. Physiol. 259H1307–H1311.PubMedGoogle Scholar
  4. Aylwin, M.L., Horowitz, J.M., Bonham, A.C., 1997. NMDA receptors contribute to primary visceral afferent transmission in the nucleus of the solitary tract. J. Neurophysiol. 772539–2548.PubMedGoogle Scholar
  5. Bazil, M.K., Gordon, F.J., 1991. Spinal NMDA receptors mediate pressor responses evoked from rostral ventrolateral medulla. Am. J. of Physiol. 260H267–H275.Google Scholar
  6. Bennet, J.A., McWilliam, P.N., Shepheard, S.L., 1987. A gamma-aminobutyric-acid-mediated inhibition of neurones in the nucleus tractus solitarius of the cat. J. Physiol. (Lond.) 392417–430.Google Scholar
  7. Berlin, M.F., Nanopoulos, D., Didier, M., Agüera, M., Steinbusch, H., Verhofstad, A., Maitre, M., Pujol, J.F., 1983. Immunohistochemical evidence for the presence of gamma-aminobutyric acid and serotonin in one nerve cell. A study on the raphe nuclei of the rat using antibodies to glutamate decarboxylase and serotonin. Brain Res. 275329–339.CrossRefGoogle Scholar
  8. Blessing, W.W., Oertel, W.H., Willoughby, J.O., 1984. Glutamic acid decarboxylase immunoreactivity is present in perikariya of neurons in nucleus tractus solitarius of rat. Brain Res. 322346–350.PubMedCrossRefGoogle Scholar
  9. Bonham, A.C., Chen, C.Y., 2002. Glutamatergic neural transmission in the nucleus tractus solitarius: N-methyl-D-aspartate receptors. Clin. Exp. Pharmacol. Physiol. 29497–502.PubMedCrossRefGoogle Scholar
  10. Bowery, N.G., Hudson, A.L., Price, G.W., 1987. GABAA and GABAB receptor binding site distribution in the rat central nervous system. Neurosci. 20365–383.CrossRefGoogle Scholar
  11. Bronstein, D.M., Schafer, M.K.H., Watson, S.J., Akil, H., 1992. Evidence that beta-endorphin is synthesized in cells in the nucleus tractus solitarius: detection of POMC mRNA. Brain Res. 587269–275.PubMedCrossRefGoogle Scholar
  12. Brophy, S., Ford, T.W., Carey, M., Jones, J.F.X., 1999. Activity of aortic chemoreceptors in the anesthetized rat. J. Physiol. (Lond.) 514821–828.CrossRefGoogle Scholar
  13. Brown, D.L., Guyenet, P.G., 1985. Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats. Circ. Res. 56359–369.PubMedCrossRefGoogle Scholar
  14. Chen, C.Y., Ling, E.H., Horowitz, J.M., Bonham, A.C., 2002. Synaptic transmission in nucleus tractus solitarius is depressed by Group II and III but not Group I presynaptic metabotropic glutamate receptors in rats. J. Physiol. (Lond.) 538773–786.CrossRefGoogle Scholar
  15. Cheng, Z., Powley, T.L., Schwaber, J.S., Doyle, F.J., 1997. A laser confocal microscopic study of vagal afferent innervation of rat aortic arch: chemoreceptors as well as baroreceptors. J. Auton. Nerv. Syst. 671–14.PubMedCrossRefGoogle Scholar
  16. Chitravanshi, V.C., Kachroo, A., Sapru, H.N., 1994. A midline area in the nucleus commissuralis of NTS mediates the phrenic nerve responses to carotid chemoreceptor stimulation. Brain Res. 662127–133.PubMedCrossRefGoogle Scholar
  17. Chitravanshi, V.C., Sapru, H.N., 1995. Chemoreceptor-sensitive neurons in commissural subnucleus of nucleus tractus solitarius of the rat. Am. J. Physiol. 268R851–R858.PubMedGoogle Scholar
  18. Chitravanshi, V.C., Sapru, H.N., 1996. NMDA as well as non-NMDA receptors mediate the neurotransmission of inspiratory drive to phrenic motoneurons in the adult rat. Brain Res. 715104–112.PubMedCrossRefGoogle Scholar
  19. Chitravanshi, V.C., Sapru, H.N., 1997. NMDA as well as non-NMDA receptors in phrenic nucleus mediate respiratory effects of carotid chemoreflex. Am. J. Physiol. 272R302–R310.PubMedGoogle Scholar
  20. Criscione, L., Reis, D.J., Taiman, W.T., 1983. Cholinergic mechanisms in the nucleus tractus solitarii and cardiovascular regulation in the rat. Eur. J. Pharmacol. 8847–55.PubMedCrossRefGoogle Scholar
  21. Dhar, S., Nagy, F., Mcintosh, J.M., Sapru, H.N., 2000. Receptor subtypes mediating depressor responses to microinjections of nicotine into the medial nTS of the rat. Am. J. Physiol. 279R132–R140.Google Scholar
  22. Dhruva, A., Bhatnagar, T., Sapru, H.N., 1998. Cardiovascular responses to microinjections of glutamate into the nucleus tractus solitarii of unanesthetized supracollicular decerebrate rats. Brain Res. 81088–100.CrossRefGoogle Scholar
  23. Finley, J.C.W., Katz, D.M., 1992. The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res. 572108–116.PubMedCrossRefGoogle Scholar
  24. Florentino, A., Varga, K., Kunos, G., 1990. Mechanism of the cardiovascular effects of GABAB receptor activation in the nucleus tractus solitarii of the rat. Brain Res. 535264–270.PubMedCrossRefGoogle Scholar
  25. Foley, C.M., Vogl, H.W., Mueller, P.J., Hay, M., Hasser, E.M., 1999. Cardiovascular response to group I metabotropic glutamate receptor activation in NTS. Am. J. Physiol. 276R1469–R1478.PubMedGoogle Scholar
  26. Gordon, F.J., 1987. Aortic baroreceptor reflexes are mediated by NMDA receptors in caudal ventrolateral medulla. Am. J. Physiol. 252R628–R633.PubMedGoogle Scholar
  27. Gordon, F.J., 1990. Opioids and central baroreflex control. A site of action in the nucleus tractus solitarius. Peptides 11305–309.PubMedCrossRefGoogle Scholar
  28. Gordon, F.J., 1994. Opioids and the nucleus of the tractus solitarius: effects on cardiovascular and baroreflex function. In: Barraco, I.R.A. (Ed.), Nucleus of the Solitary Tract. CRC Press, Boca Raton, pp. 283–287.Google Scholar
  29. Gordon, F.J., Leone, C., 1991. Non-NMDA receptors in the nucleus of the tractus solitarius play the predominant role in mediating aortic baroreceptor reflexes. Brain Res. 568319–322.PubMedCrossRefGoogle Scholar
  30. Gordon, F.J., Sved, A.F., 2002. Neurotransmitters in central cardiovascular regulation: Glutamate and GABA. Clin. Exp. Pharmacol. Physiol. 29522–524.PubMedCrossRefGoogle Scholar
  31. Guyenet, P.G., Filtz, T.M., Donaldson, S.R., 1987. Role of excitatory amino acids in rat vagal and sympathetic baroreflexes. Brain Res. 407272–284.PubMedCrossRefGoogle Scholar
  32. Guyenet, P.G., Koshiya, N., 1995. Working model of the sympathetic chemoreflex in rats. Clin. Exp. Hypertension 17167–179.CrossRefGoogle Scholar
  33. Hassen, A.H., Feuerstein, G., Faden, A.I., 1983. Differential cardiovascular effects mediated by mu and kappa opiate receptors in hindbrain nuclei. Peptides 4621–625.PubMedCrossRefGoogle Scholar
  34. Heike, C.J., Sohl, B.D., Jacobowitz, D.M., 1980. Choline acetyltransferase activity in discrete brain nuclei of DOCA-salt hypertensive rats. Brain Res. 193293–298.CrossRefGoogle Scholar
  35. Jordan, D., Mifflin, S.W., Spyer, K.M., 1988. Hypothalamic inhibition of neurones in the nucleus tractus solitarius of the cat is GABA mediated. J. Physiol. (Lond.) 399389–404.Google Scholar
  36. Klausmair, A., Philippu, A., 1989. Carotid occlusion increases the release of endogenous GABA in the nucleus of the solitary tract. Naunyn-Schmiedeberg’s Arch. Pharmacol. 340764–766.CrossRefGoogle Scholar
  37. Kobayashi, M., Cheng, Z.B., Tanaka, K., Nosaka, S., 1999. Is the aortic depressor nerve involved in arterial chemoreflexes in rats? J. Auton. Nerv. Syst. 7838–48.PubMedCrossRefGoogle Scholar
  38. Koshiya, N., Guyenet, P.G., 1996. NTS neurons with carotid chemoreceptor inputs arborize in the rostral ventrolateral medulla. Am. J. Physiol. 270R1273–R1278.PubMedGoogle Scholar
  39. Kubo, T., Kihara, M., 1987. Evidence for the presence of GABAergic and glycine-like systems responsible for cardiovascular control in the nucleus tractus solitarii of the rat. Neurosci. Lett. 74331–336.PubMedCrossRefGoogle Scholar
  40. Kubo, T., Amano, M., Asari, T., 1993. N-methyl-D-aspartate receptors but not non-N-methyl-D-aspartate receptors mediate hypertension induced by carotid body chemoreceptor stimulation in the rostral ventrolateral medulla of the rat. Neurosci. Lett. 164113–116.PubMedCrossRefGoogle Scholar
  41. Kwok, E.H., Dun, N.J., 1998. Endomorphins decrease heart rate and blood pressure possibly by activating vagal afferents in anesthetized rats. Brain Res. 803204–207.PubMedCrossRefGoogle Scholar
  42. Liu, Z., Chen, C.Y., Bonham, A.C., 1998. Metabotropic glutamate receptors depress vagal and aortic baroreceptor signal transmission in the NTS. Am. J. Physiol. 275H1682–H1694.PubMedGoogle Scholar
  43. Marchenko, V., Sapru, H.N., 2000. Different patterns of respiratory and cardiovascular responses elicited by chemical stimulation of dorsal medulla in the rat. Brain Res. 85799–109.PubMedCrossRefGoogle Scholar
  44. Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guillemot, J.C., Ferrara, P., Monsarrat, B., Mazargull, H., Vassaart, G., Parmentier, M., Costentin, J., 1995. Isolation and structure of the endogenous agonist of opioid receptorlike ORLI receptor. Nature 377532–535.PubMedCrossRefGoogle Scholar
  45. Miyawaki, T., Minson, J., Amolda, L., Llewellyn-Smith, I., Chalmers, J., Pilowsky, P., 1996. AMPA/kainate receptors mediate sympathetic chemoreceptor reflex in the rostral ventrolateral medulla. Brain Res. 72664–68.PubMedGoogle Scholar
  46. Miyawaki, T., Suzuki, S., Minson, J., Amolda, L., Chalmers, J., Llewellyn-Smith, I., Pilowsky, P., 1997. Role of AMPA/kainate receptors in transmission of the sympathetic baroreflex in rat CVLM. Am. J. Physiol. 272R800–R812.PubMedGoogle Scholar
  47. Neal, C.R., Mansour, A., Reinscheid, R., Nothacker, H-P., Civelli, O., Watson, S.J., 1999. Localization of orphanin FQ (Nociceptin) peptide and messenger RNA in the central nervous system of the rat. J. Comp. Neurol. 406503–547.PubMedCrossRefGoogle Scholar
  48. Neff, R.A., Mihalevich, M., Mendelowitz, D., 1998. Stimulation of NTS activates NMDA and non-NMDA receptors in rat cardiac vagal neurons in the nucleus ambiguus. Brain Res. 792277–282.PubMedCrossRefGoogle Scholar
  49. Numao, Y., Siato, M., Terui, N., Kumada, M., 1985. The aortic nerve-sympathetic reflex in the rat. J. Auton. Nerv. Syst. 1365–79.PubMedCrossRefGoogle Scholar
  50. Ohta, H., Taiman, W.T., 1994. Both NMDA and non-NMDA receptors in the NTS participate in the baroreceptor reflex in rats. Am. J. Physiol. 267R1065–R1070.PubMedGoogle Scholar
  51. Ohta, H., Li, X., Taiman, W.T., 1996. Release of glutamate in the nucleus tractus solitarii in response to baroreflex activation in rats. Neurosci. 7429–37.CrossRefGoogle Scholar
  52. Patón, J.F.R., De Paula, P.M., Spyer, K.M., Machado, B.H., Boscan, P., 2002. Sensory afferent selective role of P2 receptors in the nucleus tractus solitarii for mediating the cardiac component of the peripheral chemoreceptor reflex in rats. J. Physiol. (Lond.) 543995–1005.CrossRefGoogle Scholar
  53. Pilowsky, P.M., Goodchild, A.K., 2002. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J. Hypertension 201675–1688.CrossRefGoogle Scholar
  54. Ross, C.A., Ruggiero, D.A., Park, D.H., Joh, T.H., Sved, A.F., Fernandez-Pardal, J., Saavedra, J.M., Reis, D.J., 1984. Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J. Neurosci. 4474–494.PubMedGoogle Scholar
  55. Sapru, H.N., 1994. Transmitter/receptor mechanisms in cardiovascular control by the NTS: excitatory amino acids, acetylcholine and substance P. In: Barraco, I.R.A. (Ed.), Nucleus of the Solitary Tract. CRC Press; Boca Raton, pp. 267–281.Google Scholar
  56. Sapru, H.N., 2002. Glutamate circuits in selected medullo-spinal areas regulating cardiovascular function. Clin. Exp. Pharmacol. Physiol. 29491–496.PubMedCrossRefGoogle Scholar
  57. Sapru, H.N., Chitravanshi, V.C., 2002. Responses to microinjections of endomorphin and nociceptin into the medullary cardiovascular areas. Clin. Exp. Pharmacol. Physiol. 29243–247.PubMedCrossRefGoogle Scholar
  58. Sapru, H.N., Krieger, A.J., 1977. Carotid and aortic chemoreceptor function in the rat. J. Appl. Physiol. 42344–348.PubMedGoogle Scholar
  59. Sapru, H.N., Willette, R.N., Krieger, A.J., 1981a. Stimulation of pulmonary J receptors by an enkephalin-analog. J. Pharmacol. Exp. Ther. 217228–234.PubMedGoogle Scholar
  60. Sapru, H.N., Gonzalez, E.R., Krieger, A.J., 1981b. Aortic nerve stimulation in the rat: cardiovascular and respiratory responses. Brain Res. Bull. 6393–398.PubMedCrossRefGoogle Scholar
  61. Seagard, J.L., Dean, C., Hopp, F.A., 2001. Properties of NTS neurons receiving input from barosensitive receptors. Ann. NY Acad. Sci. 940142–156.PubMedCrossRefGoogle Scholar
  62. Schreihofer, A.M., Guyenet, P.G., 2002. The baroreflex and beyond: Control of sympathetic vasomotor tone by GABAergic neurons in the ventrolateral medulla. Clin. Exp. Pharmacol. Physiol. 29514–521.PubMedCrossRefGoogle Scholar
  63. Stornetta, R.L., Guyenet, P.G., McCarty, R.C., 1987. Autonomic nervous system control of heart rate during baroreceptor activation in conscious and anesthetized rats. J. Auton. Nerv. Syst. 20121–127.PubMedCrossRefGoogle Scholar
  64. Sun, M.K., Guyenet, P.G., 1985. GABA-mediated baroreceptor inhibition of reticulospinal neurons. Am. J. Physiol. 249R672–R680.PubMedGoogle Scholar
  65. Sun, M.K., Reis, D.J., 1995. NMDA receptor-mediated sympathetic chemoreflex excitation of RVL-spinal vasomotor neurones in rats. J. Physiol. (Lond.) 48253–68.Google Scholar
  66. Sun, M.K., Reis, D.J., 1996. Excitatory amino acid-mediated chemoreflex excitation of respiratory neurones in rostral ventrolateral medulla in rats. J. Physiol. (Lond.) 492559–571.Google Scholar
  67. Sundaram, K., Watson, M., Sapru, H.N., 1989. M2 muscarinic receptor agonists produce hypotension and bradycardia when injected into the nucleus tractus solitarii. Brain Res. 477358–362.PubMedCrossRefGoogle Scholar
  68. Sundaram, K., Sapru, H.N., 1991. NMDA receptors in the intermediolateral column of the spinal cord mediate sympathoexcitatory responses elicited from the ventrolateral medullary pressor area. Brain Res. 54433–41.PubMedCrossRefGoogle Scholar
  69. Suzuki, T., Takayama, K., Miura, M., 1997. Distribution and projection of the medullary cardiovascular control neurons containing glutamate, glutamic acid decarboxylase, tyrosine hydroxylase and phenylethanolamine N-methyltransferase in rats. Neurosci. Res. 279–19.PubMedCrossRefGoogle Scholar
  70. Sved, A.F., 1994. GABA-mediated neural transmission in mechanisms of cardiovascular control by the NTS. In: Barraco, I.R.A. (Ed.), Nucleus of the Solitary Tract. CRC Press, Boca Raton, pp. 245–253.Google Scholar
  71. Sved, A. F., Tsukamoto, K., 1992. Tonic stimulation of GAB A B receptors in the nucleus tractus solitarius modulates the baroreceptor reflex. Brain Res. 59237–43.PubMedCrossRefGoogle Scholar
  72. Taiman, W.T., Perrone, M.H., Reis, D.J., 1980. Evidence for L-glutamate as the neurotransmitter of baroreceptor afferent nerve fibers. Science 209813–815.CrossRefGoogle Scholar
  73. Tsukamoto, K., Yin, M., Sved, A.F., 1994. Effect of atropine injected into the nucleus tractus solitarius on the regulation of blood pressure. Brain Res. 6489–15.PubMedCrossRefGoogle Scholar
  74. Uhl, G.R., Childers, S., Pasternak, G., 1994. An opiate-receptor gene family reunion. Trends Neurosci. 1789–93.PubMedCrossRefGoogle Scholar
  75. Urbanski, R., Sapru, H.N., 1988a. Evidence for a sympathoexcitatory pathway from the nucleus tractus solitarius to the ventrolateral medullary pressor area, J. Auton. Nerv. Syst. 23161–174.CrossRefGoogle Scholar
  76. Urbanski, R., Sapru, H.N., 1988b. Putative neurotransmitters involved in medullary cardiovascular regulation. J. Auton. Nerv. Syst. 25181–193.PubMedCrossRefGoogle Scholar
  77. Van Giersbergen, P.L.M., Palkovits, M., De Jong, W., 1992. Involvement of neurotransmitters in the nucleus tractus solitarii in cardiovascular regulation. Physiol. Rev. 72789–824.PubMedGoogle Scholar
  78. Vardhan, A., Kachroo, A., Sapru, H.N., 1993a. Excitatory amino acid receptors in the commissural nucleus of the NTS mediate carotid chemoreceptor responses. Am. J. Physiol.264R41–R50.PubMedGoogle Scholar
  79. Vardhan, A., Kachroo, A., Sapru, H.N., 1993b. Excitatory amino acid receptors in the nTS mediate the responses to the stimulation of cardio-pulmonary vagal C fiber endings. Brain Res. 61823–31.PubMedCrossRefGoogle Scholar
  80. Velley, L., Milner, T.A., Chan, J., Morrison, S.F., Pickel, V.M., 1991. Relationship of met-enkephalin-like immunoreactivity to vagal afferents and motor dendrites in the nucleus of the solitary tract: A light and electron microscopic dual labeling study. Brain Res. 550298–312.PubMedCrossRefGoogle Scholar
  81. Verberne, A.J.M., Guyenet, P.G., 1992. Medullary pathway of the Bezold-Jarisch reflex in the rat. Am. J. Physiol. 263R1195–R1202.PubMedGoogle Scholar
  82. Viard, E., Sapru, H.N., 2002. Cardiovascular responses to activation of metabotropic glutamate receptors in the nTS of the rat. Brain Res. 952308–332.PubMedCrossRefGoogle Scholar
  83. Watson, M., Roeske, W.R., Vickroy, T.W., Smith, T.L., Akiyami, K., Gulya, K., Duckies, S.P., Serra, M., Adern, A., Nordberg, A., Gehlert, D.R., Wamsley, J.K., Yamamura, H.I., 1986. Biochemical and functional basis of putative muscarinic receptor subtypes and its implications. Trends Pharmacol. Sci. Suppl. 46–55.Google Scholar
  84. Willette, R.N., Barcas, P.P., Krieger, A.J., Sapru, H.N., 1983a. Vasopressor and depressor areas in the rat medulla: identification by L-glutamate microinjections. Neuropharmacol. 221071–1079.CrossRefGoogle Scholar
  85. Willette, R.N., Krieger, A.J., Barcas, P.P., Sapru, H.N., 1983b. Medullary GABA receptors and the regulation of blood pressure in the rat. J. Pharmacol. Exp. Ther. 226893–899.PubMedGoogle Scholar
  86. Willette, R.N., Krieger, A.J., Barcas, P.P., Sapru, H.N., 1984a. Endogenous GABAergic mechanisms in the medulla and the regulation of blood pressure. J. Pharmacol. Exp. Ther. 23034–39.PubMedGoogle Scholar
  87. Willette, R.N., Punnen, S., Krieger, A.J., Sapru, A.J., 1984b. Interdependence of rostral and caudal ventrolateral medullary areas in the control of blood pressure. Brain Res. 321169–174.PubMedCrossRefGoogle Scholar
  88. Xia, Y., Haddad, G.G., 1991. Ontogeny and distribution of opioid receptors in the rat brainstem. Brain Res. 549181–193.PubMedCrossRefGoogle Scholar
  89. Zadina, J.E., Hackler, L., Ge, L.J., Kastin, A.J., 1997. A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386499–502.PubMedCrossRefGoogle Scholar
  90. Zhang, J., Mifflin, S.W., 1998. Differential roles for NMDA and non-NMDA receptor subtypes in baroreceptor afferent integration in the nucleus of the solitary tract of the rat. J. Physiol. (Lond.) 511.3733–745.CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Hreday N. Sapru
    • 1
  1. 1.UMDNJ — New Jersey Medical SchoolNewarkUSA

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