Mechanisms of anesthesia and consciousness

Clinical Anesthesia: Seventh Edition

Volumn , Issue , 2013, Pages

  Crowder, C Michael ^a   Palanca, Ben Julian ^a   Evers, Alex S ^a,b  

^a WASHINGTON UNIVERSITY   (United States)

^b BARNES JEWISH HOSPITAL   (United States)

Author keywords

[No Author keywords available]

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EID: 84976597357     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (255)

1. Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science. 2008; 322(5903):876-880.
2. Tononi G. Consciousness as integrated information: a provisional manifesto. Biol Bull. 2008;215(3):216-242.
3. Balduzzi D. Estimating integrated information with TMS pulses during wakefulness, sleep, and under anesthesia. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:4717-4720.
4. Kelz MB, Sun Y, Chen J, et al. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci USA. 2008;105(4):1309-1314.
5. Quasha AL, Eger EI 2nd, Tinker JH. Determination and applications of MAC. Anesthesiology. 1980;53(4):315-334.
6. White PF, Johnston RR, Eger EI 2nd. Determination of anesthetic requirement in rats. Anesthesiology. 1974;40(1):52-57.
7. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994;367(6464):607-614.
8. Bowdle TA. Depth of anesthesia monitoring. Anesthesiol Clin. 2006;24(4):793-822.
9. Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk surgical population. N Engl J Med. 2011;365(7):591-600.
10. Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. N Engl J Med. 2008;358(11):1097-1108.
11. Palanca BJ, Mashour GA, Avidan MS. Processed electroencephalogram in depth of anesthesia monitoring. Curr Opin Anaesthesiol. 2009;22(5):553-559.
12. Bruhn J, Myles PS, Sneyd R, et al. Depth of anaesthesia monitoring: what's available, what's validated and what's next? Br J Anaesth. 2006;97(1):85-94.
13. Meyer H. Theorie der alkoholnarkose. Arch Exp Pathol Pharmakol. 1899;42:109.
14. Overton CE. Studies of Narcosis. 1st ed. London: Chapman and Hall; 1891.
15. Franks NP, Lieb WR. Where do general anaesthetics act? Nature. 1978;274 (5669):339-342.
16. Larson ER. Fluorine compounds in anesthesiology. In: Tarrant P, ed. Fluorine Chemistry Reviews. Vol. 3. New York, NY: Dekker; 1969.
17. Andrews PR, Jones GP, Poulton DB. Convulsant, anticonvulsant and anaesthetic barbiturates. In vivo activities of oxo-and thiobarbiturates related to pentobarbitone. Eur J Pharmacol. 1982;79(1-2):61-65.
18. Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6(6):2311-2322.
19. Koblin DD, Chortkoff BS, Laster MJ, et al. Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis. Anesth Analg. 1994;79(6):1043-1048.
20. Kandel L, Chortkoff BS, Sonner J, et al. Nonanesthetics can suppress learning. Anesth Analg. 1996;82(2):321-326.
21. Alifimoff JK, Firestone LL, Miller KW. Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site. Br J Pharmacol. 1989;96(1):9-16.
22. Raines DE, Korten SE, Hill AG, et al. Anesthetic cutoff in cycloalkanemethanols. A test of current theories. Anesthesiology. 1993;78(5):918-927.
23. Liu J, Laster MJ, Koblin DD, et al. A cutoff in potency exists in the perfluoroalkanes. Anesth Analg. 1994;79(2):238-244.
24. Andrews PR, Mark LC. Structural specificity of barbiturates and related drugs. Anesthesiology. 1982;57(4):314-320.
25. Richter JA, Holtman JR Jr. Barbiturates: their in vivo effects and potential biochemical mechanisms. Prog Neurobiol. 1982;18(4):275-319.
26. Ryder S, Way WL, Trevor AJ. Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol. 1978;49(1):15-23.
27. Wittmer LL, Hu Y, Kalkbrenner M, et al. Enantioselectivity of steroid-induced gamma-aminobutyric acid A receptor modulation and anesthesia. Mol Pharmacol. 1996;50(6):1581-1586.
28. Tomlin SL, Jenkins A, Lieb WR, et al. Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals. Anesthesiology. 1998;88(3):708-717.
29. Lysko GS, Robinson JL, Casto R, et al. The stereospecific effects of isoflurane isomers in vivo. Eur J Pharmacol. 1994;263(1-2):25-29.
30. Kendig JJ, Grossman Y, MacIver MB. Pressure reversal of anaesthesia: a synaptic mechanism. Br J Anaesth. 1988;60(7):806-816.
31. Smith RA, Porter EG, Miller KW. The solubility of anesthetic gases in lipid bilayers. Biochim Biophys Acta. 1981;645(2):327-338.
32. Franks NP. Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006;147(Suppl 1):S72-S81.
33. Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature. 1984;310(5978):599-601.
34. Franks NP, Lieb WR. Mapping of general anaesthetic target sites provides a molecular basis for cutoff effects. Nature. 1985;316(6026):349-351.
35. Dubois BW, Cherian SF, Evers AS. Volatile anesthetics compete for common binding sites on bovine serum albumin: a 19F-NMR study. Proc Natl Acad Sci USA. 1993;90(14):6478-6482.
36. Dubois BW, Evers AS. 19F-NMR spin-spin relaxation (T2) method for characterizing volatile anesthetic binding to proteins. Analysis of isoflurane binding to serum albumin. Biochemistry. 1992;31(31):7069-7076.
37. Eckenhoff RG. Amino acid resolution of halothane binding sites in serum albumin. J Biol Chem. 1996;271(26):15521-15526.
38. Eckenhoff RG, Shuman H. Halothane binding to soluble proteins determined by photoaffinity labeling. Anesthesiology. 1993;79(1):96-106.
39. Hall MA, Xi J, Lor C, et al. m-Azipropofol (AziPm) a photoactive analogue of the intravenous general anesthetic propofol. J Med Chem. 2010;53(15):5667-5675.
40. Stewart DS, Savechenkov PY, Dostalova Z, et al. p-(4-Azipentyl)propofol: A potent photoreactive general anesthetic derivative of propofol. J Med Chem. 2011;54(23):8124-8135.
41. Li GD, Chiara DC, Sawyer GW, et al. Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J Neurosci. 2006;26(45):11599-11605.
42. Chiara DC, Dostalova Z, Jayakar SS, et al. Mapping general anesthetic binding site(s) in human alpha1beta3 gamma-aminobutyric acid type A receptors with [(3)H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry. 2012;51 (4):836-847.
43. Franks NP, Jenkins A, Conti E, et al. Structural basis for the inhibition of firefly luciferase by a general anesthetic. Biophys J. 1998;75(5):2205-2211.
44. Bocquet N, Nury H, Baaden M, et al. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature. 2009;457(7225): 111-114.
45. Nury H, Bocquet N, Le Poupon C, et al. Crystal structure of the extracellular domain of a bacterial ligand-gated ion channel. J Mol Biol. 2010;395(5):1114-1127.
46. MacIver MB, Kendig JJ. Anesthetic effects on resting membrane potential are voltage-dependent and agent-specific. Anesthesiology. 1991;74:83-88.
47. Madison DV, Nicoll RA. General anesthetics hyperpolarize neurons in the vertebrate central nervous system. Science. 1982;217:1055-1057.
48. Ries CR, Puil E. Mechanism of anesthesia revealed by shunting actions of isoflurane on thalamocortical neurons. J Neurophysiol. 1999;81(4):1795-1801.
49. Larrabee MG, Posternak JM. Selective action of anesthetics on synapses and axons in mammalian sympathetic ganglia. J Neurophysiol. 1952;15(2):91-114.
50. Richards CD, Russell WJ, Smaje JC. The action of ether and methoxyflurane on synaptic transmission in isolated preparations of the mammalian cortex. J Physiol. 1975;248(1):121-142.
51. Richards CD, White AE. The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus. J Physiol. 1975;252(1):241-257.
52. Langmoen IA, Larsen M, Berg-Johnsen J. Volatile anaesthetics: Cellular mechanisms of action. Eur J Anaesthesiol. 1995;12(1):51-58.
53. Wu XS, Sun JY, Evers AS, et al. Isoflurane inhibits transmitter release and the presynaptic action potential. Anesthesiology. 2004;100(3):663-670.
54. Kullmann DM, Martin RL, Redman SJ. Reduction by general anaesthetics of group Ia excitatory postsynaptic potentials and currents in the cat spinal cord. J Physiol. 1989;412:277-296.
55. Nicoll RA, Eccles JC, Oshima T, et al. Prolongation of inhibitory postsynaptic potentials by barbiturates. Nature. 1975;258:625-627.
56. Proctor WR, Mynlieff M, Dunwiddie TV. Facilitatory action of etomidate and pentobarbital on recurrent inhibition in rat hippocampal pyramidal neurons. J Neurosci. 1986;6(11):3161-3168.
57. Collins GG. Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice. Br J Pharmacol. 1988;95(3):939-949.
58. Nicoll RA. The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb. J Physiol (Lond). 1972;223:803-814.
59. Harrison NL, Vicini S, Barker JL. A steroid anesthetic prolongs inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurosci. 1987;7(2):604-609.
60. Olsen R, Li G-D. GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. Can J Anaesth. 2011;58(2):206-215.
61. Solt K, Forman SA. Correlating the clinical actions and molecular mechanisms of general anesthetics. Curr Opin Anaesthesiol. 2007;20(4):300-306.
62. Fujiwara M, Higashi H, Nishi S, et al. Changes in spontaneous firing patterns of rat hippocampal neurones induced by volatile anaesthetics. J Physiol (Lond). 1988;402:155-175.
63. Mui P, Puil E. Isoflurane-induced impairment of synaptic transmission in hippocampal neurons. Exp Brain Res. 1989;75:354-360.
64. Yoshimura M, Higashi H, Fujita S, et al. Selective depression of hippocampal inhibitory postsynaptic potentials and spontaneous firing by volatile anesthetics. Brain Res. 1985;340:363-368.
65. Takenoshita M, Takahashi T. Mechanisms of halothane action on synaptic transmission in motoneurons of the newborn rat spinal cord in vitro. Brain Res. 1987;402:303-310.
66. Perouansky M, Baranov D, Salman M, et al. Effects of halothane on glutamate receptor-mediated excitatory post-synaptic currents: A patch-clamp study in adult mouse hippocampal slices. Anesthesiology. 1995;83(1):109-119.
67. Buggy DJ, Nicol B, Rowbotham DJ, et al. Effects of intravenous anesthetic agents on glutamate release: a role for GABAA receptor-mediated inhibition. Br J Pharmacol. 1988;95(3):939-949.
68. Kendall TJ, Minchin MC. The effects of anaesthetics on the uptake and release of amino acid neurotransmitters in thalamic slices. Br J Pharmacol. 1982;75: 219-227.
69. Larsen M, Haugstad TS, Berg-Johnsen J, et al. Effect of isoflurane on release and uptake of gamma-aminobutyric acid from rat cortical synaptosomes. Br J Anaesth. 1998;80(5):634-638.
70. Collins GGS. Release of endogenous amino acid neurotransmitter candidates from rat olfactory cortex slices: possible regulatory mechanisms and the effects of pentobarbitone. Brain Res. 1980;190:517-528.
71. Murugaiah KD, Hemmings HC Jr. Effects of intravenous general anesthetics on [3H]GABA release from rat cortical synaptosomes. Anesthesiology. 1998;89 (4):919-928.
72. Mantz J, Lecharny JB, Laudenbach V, et al. Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes. Anesthesiology. 1995;82(2):502-511.
73. Westphalen RI, Hemmings HC Jr. Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals. J Pharmacol Exp Ther. 2003;304(3):1188-1196.
74. Hawasli AH, Saifee O, Liu C, et al. Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release in Caenorhabditis elegans. Genetics. 2004;168(2):831-843.
75. van Swinderen B, Saifee O, Shebester L, et al. A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Proc Natl Acad Sci USA. 1999;96(5):2479-284.
76. Herring BE, Xie Z, Marks J, et al. Isoflurane inhibits the neurotransmitter release machinery. J Neurophysiol. 2009;102(2):1265-1273.
77. Richards CD, Smaje JC. Anaesthetics depress the sensitivity of cortical neurones to L-glutamate. Br J Pharmacol. 1976;58:347-357.
78. Smaje JC. General anaesthetics and the acetylcholine-sensitivity of cortical neurones. Br J Pharmacol. 1976;58:359-366.
79. Akk G, Steinbach JH. Structural studies of the actions of anesthetic drugs on the gamma-aminobutyric acid type A receptor. Anesthesiology. 2011;115(6):1338-1348.
80. - currents in cultured rat hippocampal neurones by three volatile anesthetics. J Physiol. 1992;449:279-293.
81. Haydon DA, Urban BW. The actions of some general anaesthetics on the potassium current of the squid giant axon. J Physiol. 1986;373:311-327.
82. Herrington J, Stern RC, Evers AS, et al. Halothane inhibits two components of calcium current in clonal (GH3) pituitary cells. J Neurosci. 1991;11(7):2226-2240.
83. Hemmings HC Jr. Sodium channels and the synaptic mechanisms of inhaled anaesthetics. Br J Anaesth. 2009;103(1):61-69.
84. Rehberg B, Xiao YH, Duch DS. Central nervous system sodium channels are significantly suppressed at clinical concentrations of volatile anesthetics. Anesthesiology. 1996;84(5):1223-1233.
85. Ratnakumari L, Hemmings HC Jr. Inhibition of presynaptic sodium channels by halothane. Anesthesiology. 1998;88(4):1043-1054.
86. Shiraishi M, Harris RA. Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels. J Pharmacol Exp Ther. 2004;309(3):987-994.
87. Frenkel C, Weckbecker K, Wartenberg HC, et al. Blocking effects of the anaesthetic etomidate on human brain sodium channels. Neurosci Lett. 1998;249(2-3):131-134.
88. Rehberg B, Duch DS. Suppression of central nervous system sodium channels by propofol. Anesthesiology. 1999;91(2):512-520.
89. Eskinder H, Rusch NJ, Supan FD, et al. The effects of volatile anesthetics on L-and T-type calcium channel currents in canine cardiac Purkinje cells. Anesthesiology. 1991;74(5):919-926.
90. Terrar DA. Structure and function of calcium channels and the actions of anaesthetics. Br J Anaesth. 1993;71(1):39-46.
91. Gundersen CB, Umbach JA, Swartz BE. Barbiturates depress currents through human brain calcium channels studied in Xenopus oocytes. J Pharmacol Exp Ther. 1988;247(3):824-829.
92. Hall AC, Lieb WR, Franks NP. Insensitivity of P-type calcium channels to inhalational and intravenous general anesthetics. Anesthesiology. 1994;81:117-123.
93. Study RE. Isoflurane inhibits multiple voltage-gated calcium currents in hippocampal pyramidal neurons. Anesthesiology. 1994;81:104-116.
94. Takenoshita M, Steinbach JH. Halothane blocks low-voltage-activated calcium current in rat sensory neurons. J Neurosci. 1991;11(5):1404-1412.
95. - current. J Neurosci. 1993;13:3211-3221.
96. Correa AM. Gating kinetics of Shaker K+ channels are differentially modified by general anesthetics. Am J Physiol. 1998;275(4 Pt 1):C1009-C1021.
97. Friederich P, Urban BW. Interaction of intravenous anesthetics with human neuronal potassium currents in relation to clinical concentrations. Anesthesiology. 1999;91(6):1853-1860.
98. Gerstin KM, Gong DH, Abdallah M, et al. Mutation of KCNK5 or Kir3.2 potassium channels in mice does not change minimum alveolar anesthetic concentration. Anesth Analg. 2003;96(5):1345-1349.
99. Gibbons SJ, Núñez-Hernández R, Mazé G, et al. Inhibition of a fast inwardly rectifying potassium conductance by barbiturates. Anesth Analg. 1996;82(6): 1242-1246.
100. Stadnicka A, Bosnjak ZJ, Kampine JP, et al. Effects of sevoflurane on inward rectifier K+ current in guinea pig ventricular cardiomyocytes. Am J Physiol. 1997; 273(1 Pt 2):H324-H332.
101. Patel AJ, Honore E. Anesthetic-sensitive 2P domain K+ channels. Anesthesiology. 2001;95(4):1013-1021.
102. Franks NP, Lieb WR. Volatile general anaesthetics activate a novel neuronal K +current. Nature. 1988;333:662-664.
103. + channels in aplysia neurons. Brain Res. 1998;807(1-2):255-262.
104. Honore E. The neuronal background K2P channels: Focus on TREK1. Nat Rev Neurosci. 2007;8(4):251-261.
105. + channels. Nat Neurosci. 1999;2(5):422-426.
106. Gruss M, Bushell TJ, Bright DP, et al. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol. 2004;65(2):443-452.
107. Postea O, Biel M. Exploring HCN channels as novel drug targets. Nat Rev Drug Discov. 2011;10(12):903-914.
108. Chen X, Sirois JE, Lei Q, et al. HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents. J Neurosci. 2005;25(24):5803-5814.
109. Chen X, Shu S, Bayliss DA. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci. 2009;29(3):600-609.
110. Cacheaux LP, Topf N, Tibbs GR, et al. Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol. J Pharmacol Exp Ther. 2005;315(2):517-525.
111. Akk G, Mennerick S, Steinbach JH. Actions of anesthetics on excitatory transmitter-gated channels. Handb Exp Pharmacol 2008;(182):53-84.
112. Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999;55(10):1278-1303.
113. Wakamori M, Ikemoto Y, Akaike N. Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat. J Neurophysiol. 1991;66(6):2014-2021.
114. Lin L, Chen LL, Harris RA. Enflurane inhibits NMDA, AMPA and kainate-induced currents in Xenopus oocytes expressing mouse and human brain mRNA. FASEB J. 1992;7:479-485.
115. Weight FF, Lovinger DM, White G, et al. Alcohol and anesthetic actions on excitatory amino acid-activated ion channels. Ann N Y Acad Sci. 1991;625:97-107.
116. Dildy-Mayfield JE, Eger EI 2nd, Harris RA. Anesthetics produce subunit-selective actions on glutamate receptors. J Pharmacol Exp Ther. 1996;276(3):1058-1065.
117. Minami K, Wick MJ, Stern-Bach Y, et al. Sites of volatile anesthetic action on kainate (glutamate receptor 6) receptors. J Biol Chem. 1998;273(14):8248-8255.
118. Aronstam RS, Martin DC, Dennison RL. Volatile anesthetics inhibit NMDA-stimulated Ca uptake by rat brain microvesicles. Neurochem Res. 1994;19(12): 1515-1520.
119. Anis NA, Berry SC, Burton NR, et al. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79:565-575.
120. Lodge D, Anis NA, Burton NR. Effects of optical isomers of ketamine on excitation of cat and rat spinal neurons by amino acids and acetylcholine. Neurosci Lett. 1982;29:281-286.
121. Zeilhofer HU, Swandulla D, Geisslinger G, et al. Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. Eur J Pharmacol. 1992;213(1):155-158.
122. Jevtović-Todorović V, Todorović SM, Mennerick S, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;4(4):460-463.
123. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, et al. Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci. 1998;18(23):9716-9726.
124. Franks NP, Dickinson R, de Sousa SL, et al. How does xenon produce anaesthesia? [letter]. Nature. 1998;396:324.
125. Barker JL, Harrison NL, Lange GD, et al. Potentiation of gamma-aminobutyric-acid-activated chloride conductance by a steroid anesthetic in cultured rat spinal neurons. J Physiol. 1987;386:485-501.
126. Hales TH, Lambert JJ. Modulation of the GABAA receptor by propofol. Br J Pharmacol. 1988;93:84P.
127. Macdonald RL, Olsen RW. GABAA receptor channels. Annu Rev Neurosci. 1994;17:569-602.
128. Macdonald RL, Rogers CJ, Twyman RE. Barbiturate regulation of kinetic properties of the GABAA receptor channels of mouse spinal neurones in culture. J Physiol. 1989;417:483-500.
129. Hall AC, Lieb WR, Franks NP. Stereoselective and non-stereoselective actions of isoflurane on the GABAA receptor. Br J Pharmacol. 1994;112(3):906-910.
130. Nakahiro M, Yeh JZ, Brunner E, et al. General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons. FASEB J. 1989;3: 1850-1854.
131. Yeh JZ, Quandt FN, Tanguy J, et al. General anesthetic action on gamma-aminobutyric acid-activated channels. Ann N Y Acad Sci. 1991;625:155-173.
132. Banks MI, Pearce RA. Dual actions of volatile anesthetics on GABA(A) IPSCs: Dissociation of blocking and prolonging effects. Anesthesiology. 1999;90(1):120-134.
133. Pritchett DB, Sontheimer H, Shivers BD. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature. 1989;338:582-585.
134. Hill-Venning C, Belelli D, Peters JA, et al. Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br J Pharmacol. 1997;120(5):749-756.
135. Davies PA, Hanna MC, Hales TG, et al. Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit. Nature. 1997;385:820-823.
136. Zhu WJ, Wang JF, Krueger KE, et al. Delta subunit inhibits neurosteroid modulation of GABAA receptors. J Neurosci. 1996;16:6648-6656.
137. Mihic SJ, Harris RA. Inhibition of rho1 receptor GABAergic currents by alcohols and volatile anesthetics. J Pharmacol Exp Ther. 1996;277:411-416.
138. Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature. 1997;389(6649):385-389.
139. Belelli D, Lambert JJ, Peters JA, et al. The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci USA. 1997;94(20):11031-11036.
140. Krasowski MD, Koltchine VV, Rick CE, et al. Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane. Mol Pharmacol. 1998;53(3):530-538.
141. Hosie AM, Wilkins ME, da Silva HM, et al. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006;444(7118):486-489.
142. Forman S, Miller K. Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels. Can J Anaesth. 2011;58(2):191-205.
143. Dilger JP, Vidal AM, Mody HI, et al. Evidence for direct actions of general anesthetics on an ion channel protein. An new look at a unified mode of action. Anesthesiology. 1994;81:431-442.
144. Firestone LL, Sauter JF, Braswell LM, et al. Actions of general anesthetics on acetylcholine receptor-rich membranes from Torpedo californica. Anesthesiology. 1986;64:694-702.
145. Franks NP, Lieb WR. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science. 1991;254:427-430.
146. Charlesworth P, Richards CD. Anaesthetic modulation of nicotinic ion channel kinetics in bovine chromaffin cells. Br J Pharmacol. 1995;114(4):909-917.
147. Violet JM, Downie DL, Nakisa RC, et al. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics [see comments]. Anesthesiology. 1997;86(4):866-874.
148. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected [see comments]. Anesthesiology. 1997;86(4):859-865.
149. Evers AS, Steinbach JH. Supersensitive sites in the central nervous system: Anesthetics block brain nicotinic receptors. Anesthesiology. 1997;86:760-762.
150. Eger EI 2nd, Zhang Y, Laster M, et al. Acetylcholine receptors do not mediate the immobilization produced by inhaled anesthetics. Anesth Analg. 2002;94(6): 1500-1504.
151. Wong SM, Sonner JM, Kendig JJ. Acetylcholine receptors do not mediate isoflurane's actions on spinal cord in vitro. Anesth Analg. 2002;94(6):1495-1499.
152. Raines DE, Claycomb RJ, Forman SA. Nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes inhibit alpha(4)beta(2) neuronal nicotinic acetylcholine receptors. Anesth Analg. 2002;95(3):573-577.
153. Downie DL, Hall AC, Lieb WR, et al. Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurons and recombinant glycine receptors in Xenopus oocytes. Br J Pharmacol. 1996;118:493-502.
154. Mascia MP, Machu TK, Harris RA. Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics. Br J Pharmacol. 1996;119(7):1331-1336.
155. Jenkins A, Franks NP, Lieb WR. Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells. Br J Pharmacol. 1996;117:1507-1515.
156. Machu TK, Harris RA. Alcohols and anesthetics enhance the function of 5-hydroxytryptamine3 receptors expressed in Xenopus laevis oocytes. J Pharmacol Exp Ther. 1994;271:898-905.
157. Segal IS, Vickery RG, Walton JK, et al. Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha 2 adrenergic receptor. Anesthesiology. 1988;69:818-823.
158. Moody EJ, Harris BD, Skolnick P. The potential for safer anaesthesia using stereoselective anaesthetics. Trends Pharmacol Sci. 1994;15(10):387-391.
159. Zhang Y, Laster MJ, Hara K, et al. Glycine receptors mediate part of the immobility produced by inhaled anesthetics. Anesth Analg. 2003;96(1):97-101.
160. Zhang Y, Sonner JM, Eger EI 2nd, et al. Gamma-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane. Anesth Analg. 2004; 99(1):85-90.
161. Zhang Y, Wu S, Eger EI 2nd, et al. Neither GABA(A) nor strychnine-sensitive glycine receptors are the sole mediators of MAC for isoflurane. Anesth Analg. 2001;92(1):123-127.
162. Morgan PG, Cascorbi HF. Effect of anesthetics and a convulsant on normal and mutant Caenorhabditis elegans. Anesthesiology. 1985;62:738-744.
163. Sedensky MM, Meneely PM. Genetic analysis of halothane sensitivity in Caenorhabditis elegans. Science. 1987;236(4804):952-954.
164. Humphrey JA, Hamming KS, Thacker CM, et al. A putative cation channel and its novel regulator: Cross-species conservation of effects on general anesthesia. Curr Biol. 2007;17(7):624-629.
165. Crowder CM, Shebester LD, Schedl T. Behavioral effects of volatile anesthetics in Caenorhabditis elegans. Anesthesiology. 1996;85(4):901-912.
166. Metz LB, Dasgupta N, Liu C, et al. An evolutionarily conserved presynaptic protein is required for isoflurane sensitivity in Caenorhabditis elegans. Anesthesiology. 2007;107(6):971-982.
167. Nagele P, Metz LB, Crowder CM. Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci USA. 2004;101(23):8791-8796.
168. Nagele P, Metz LB, Crowder CM. Xenon acts by inhibition of non-N-methyl-D-aspartate receptor-mediated glutamatergic neurotransmission in Caenorhabditis elegans. Anesthesiology. 2005;103(3):508-513.
169. Campbell DB, Nash HA. Use of Drosophila mutants to distinguish among volatile general anesthetics. Proc Natl Acad Sci USA. 1994;91(6):2135-2139.
170. Campbell JL, Nash HA. The visually-induced jump response of Drosophila melanogaster is sensitive to volatile anesthetics. J Neurogenet. 1998;12(4):241-251.
171. Krishnan KS, Nash HA. A genetic study of the anesthetic response: mutants of Drosophila melanogaster altered in sensitivity to halothane. Proc Natl Acad Sci USA. 1990;87:8632-8636.
172. Drexler B, Antkowiak B, Engin E, et al. Identification and characterization of anesthetic targets by mouse molecular genetics approaches. Can J Anaesth. 2011; 58(2):178-190.
173. Blednov YA, Jung S, Alva H, et al. Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther. 2003;304(1):30-36.
174. Rau V, Iyer SV, Oh I, et al. Gamma-aminobutyric acid type A receptor alpha 4 subunit knockout mice are resistant to the amnestic effect of isoflurane. Anesth Analg. 2009;109(6):1816-1822.
175. Sonner JM, Cascio M, Xing Y, et al. Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol Pharmacol. 2005;68(1):61-68.
176. Cheng VY, Martin LJ, Elliott EM, et al. Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J Neurosci. 2006;26(14):3713-3720.
177. Homanics GE, Ferguson C, Quinlan JJ, et al. Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: Lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol Pharmacol. 1997;51(4):588-596.
178. Borghese CM, Werner DF, Topf N, et al. An isoflurane-and alcohol-insensitive mutant GABA(A) receptor alpha(1) subunit with near-normal apparent affinity for GABA: Characterization in heterologous systems and production of knockin mice. J Pharmacol Exp Ther. 2006;319(1):208-218.
179. Sonner JM, Werner DF, Elsen FP, et al. Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane. Anesthesiology. 2007;106(1):107-113.
180. Werner DF, Blednov YA, Ariwodola OJ, et al. Knockin mice with ethanol-insensitive alpha1-containing gamma-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol. J Pharmacol Exp Ther. 2006; 319(1):219-227.
181. Nishikawa K, Jenkins A, Paraskevakis I, et al. Volatile anesthetic actions on the GABAA receptors: Contrasting effects of alpha 1(S270) and beta 2(N265) point mutations. Neuropharmacology. 2002;42(3):337-345.
182. Homanics GE, Elsen FP, Ying SW, et al. A gain-of-function mutation in the GABA receptor produces synaptic and behavioral abnormalities in the mouse. Genes Brain Behav. 2005;4(1):10-19.
183. Siegwart R, Jurd R, Rudolph U. Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors. J Neurochem. 2002;80(1):140-148.
184. Jurd R, Arras M, Lambert S, et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J. 2003;17(2):250-252.
185. Zeller A, Arras M, Jurd R, et al. Identification of a molecular target mediating the general anesthetic actions of pentobarbital. Mol Pharmacol. 2007;71(3):852-859.
186. Zeller A, Arras M, Jurd R, et al. Mapping the contribution of beta3-containing GABAA receptors to volatile and intravenous general anesthetic actions. BMC Pharmacol. 2007;7:2.
187. Zeller A, Arras M, Lazaris A, et al. Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol. FASEB J. 2005;19(12):1677-1679.
188. Liao M, Sonner JM, Jurd R, et al. Beta3-containing gamma-aminobutyric acidA receptors are not major targets for the amnesic and immobilizing actions of isoflurane. Anesth Analg. 2005;101(2):412-418, table of contents.
189. Cirone J, Rosahl TW, Reynolds DS, et al. Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice. Anesthesiology. 2004;100(6):1438-1445.
190. Reynolds DS, Rosahl TW, Cirone J, et al. Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci. 2003;23(24):8608-8617.
191. Mihalek RM, Banerjee PK, Korpi ER, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA. 1999;96(22):12905-12910.
192. Heurteaux C, Guy N, Laigle C, et al. TREK-1, a K(+) channel involved in neuroprotection and general anesthesia. EMBO J. 2004;23(13):2684-2695.
193. Westphalen RI, Krivitski M, Amarosa A, et al. Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1. Br J Pharmacol. 2007;152(6):939-945.
194. Linden AM, Aller MI, Leppä E, et al. The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists. J Pharmacol Exp Ther. 2006; 317(2):615-626.
195. Linden AM, Sandu C, Aller MI, et al. TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J Pharmacol Exp Ther. 2007;323(3):924-934.
196. Pang DS, Robledo CJ, Carr DR, et al. An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action. Proc Natl Acad Sci USA. 2009;106(41):17546-17551.
197. Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology. 1993;78(4):707-712.
198. Rampil IJ. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology. 1994;80(3):606-610.
199. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology. 1993;79(6):1244-1249.
200. Borges M, Antognini JF. Does the brain influence somatic responses to noxious stimuli during isoflurane anesthesia? Anesthesiology. 1994;81(6):1511-1515.
201. Zorychta E, Esplin DW, Capek R. Action of halothane on transmitter release in the spinal monosynaptic pathway. Fed Proc Am Soc Exp Biol. 1975;34:2999.
202. Takenoshita M, Takahashi T. Mechanisms of halothane action on synaptic transmission in motoneurons of the newborn rat spinal cord in vitro. Brain Res 1987;402:303-310.
203. Jinks SL, Bravo M, Satter O, et al. Brainstem regions affecting minimum alveolar concentration and movement pattern during isoflurane anesthesia. Anesthesiology. 2010;112(2):316-324.
204. Kungys G, Kim J, Jinks SL, et al. Propofol produces immobility via action in the ventral horn of the spinal cord by a GABAergic mechanism. Anesth Analg. 2009;108(5):1531-1537.
205. Jinks SL, Atherley RJ, Dominguez CL, et al. Isoflurane disrupts central pattern generator activity and coordination in the lamprey isolated spinal cord. Anesthesiology. 2005;103(3):567-575.
206. Stucke AG, Zuperku EJ, Tonkovic-Capin V, et al. Halothane depresses glutamatergic neurotransmission to brain stem inspiratory premotor neurons in a decerebrate dog model. Anesthesiology. 2003;98(4):897-905.
207. Wang X. Propofol and isoflurane enhancement of tonic gamma-aminobutyric acid type a current in cardiac vagal neurons in the nucleus ambiguus. Anesth Analg. 2009;108(1):142-148.
208. McDougall SJ, Bailey TW, Mendelowitz D, et al. Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS). Neuropharmacology. 2008;54(3):552-563.
209. Peters JH, McDougall SJ, Mendelowitz D, et al. Isoflurane differentially modulates inhibitory and excitatory synaptic transmission to the solitary tract nucleus. Anesthesiology. 2008;108(4):675-683.
210. Kushikata T, Hirota K, Kotani N, et al. Isoflurane increases norepinephrine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro: Relevance to thermoregulation during anesthesia. Neuroscience. 2005;131(1): 79-86.
211. Collinson N, Kuenzi FM, Jarolimek W, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci. 2002;22(13):5572-5580.
212. Zurek AA, Bridgwater EM, Orser BA. Inhibition of alpha5 gamma-aminobutyric acid type A receptors restores recognition memory after general anesthesia. Anesth Analg. 2012;114(4):845-855.
213. Laureys S. The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci. 2005;9(12):556-559.
214. French JD, Verzeano M, Magoun HW. A neural basis of the anesthetic state. AMA Arch Neurol Psychiatry. 1953;69(4):519-529.
215. Orth M, Bravo E, Barter L, et al. The differential effects of halothane and isoflurane on electroencephalographic responses to electrical microstimulation of the reticular formation. Anesth Analg. 2006;102(6):1709-1714.
216. Vanini G, Wathen BL, Lydic R, et al. Endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during rapid eye movement sleep. J Neurosci. 2011;31(7):2649-2656.
217. Vanini G, Watson CJ, Lydic R, et al. Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia. Anesthesiology. 2008;109(6):978-988.
218. Luo T, Leung LS. Involvement of tuberomamillary histaminergic neurons in isoflurane anesthesia. Anesthesiology. 2011;115(1):36-43.
219. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci. 2002;5(10):979-984.
220. Zecharia AY, Nelson LE, Gent TC, et al. The involvement of hypothalamic sleep pathways in general anesthesia: Testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse. J Neurosci. 2009;29(7):2177-2187.
221. Eikermann M, Vetrivelan R, Grosse-Sundrup M, et al. The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia. Brain Res. 2011;1426:30-37.
222. Yasuda Y, Takeda A, Fukuda S, et al. Orexin a elicits arousal electroencephalography without sympathetic cardiovascular activation in isoflurane-anesthetized rats. Anesth Analg. 2003;97(6):1663-1666.
223. Pillay S, Vizuete JA, McCallum JB, et al. Norepinephrine infusion into nucleus basalis elicits microarousal in desflurane-anesthetized rats. Anesthesiology. 2011;115(4):733-742.
224. Luo T, Leung LS. Basal forebrain histaminergic transmission modulates electroencephalographic activity and emergence from isoflurane anesthesia. Anesthesiology. 2009;111(4):725-733.
225. Solt K, Cotten JF, Cimenser A, et al. Methylphenidate actively induces emergence from general anesthesia. Anesthesiology. 2011;115(4):791-803.
226. Alkire MT, Haier RJ, Fallon JH. Toward a unified theory of narcosis: Brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn. 2000;9(3):370-386.
227. Alkire MT, Asher CD, Franciscus AM, et al. Thalamic microinfusion of antibody to a voltage-gated potassium channel restores consciousness during anesthesia. Anesthesiology. 2009;110(4):766-773.
228. Alkire MT, McReynolds JR, Hahn EL, et al. Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat. Anesthesiology. 2007;107(2):264-272.
229. Yen CT, Shaw FZ. Reticular thalamic responses to nociceptive inputs in anesthetized rats. Brain Res. 2003;968(2):179-191.
230. Imas OA, Ropella KM, Wood JD, et al. Halothane augments event-related gamma oscillations in rat visual cortex. Neuroscience. 2004;123(1):269-278.
231. Hudetz AG, Imas OA. Burst activation of the cerebral cortex by flash stimuli during isoflurane anesthesia in rats. Anesthesiology. 2007;107(6):983-991.
232. Velly LJ, Rey MF, Bruder NJ, et al. Differential dynamic of action on cortical and subcortical structures of anesthetic agents during induction of anesthesia. Anesthesiology. 2007;107(2):202-212.
233. Hudetz AG, Vizuete JA, Imas OA. Desflurane selectively suppresses long-latency cortical neuronal response to flash in the rat. Anesthesiology. 2009;111(2): 231-239.
234. Imas OA, Ropella KM, Ward BD, et al. Volatile anesthetics disrupt frontal-posterior recurrent information transfer at gamma frequencies in rat. Neurosci Lett. 2005;387(3):145-150.
235. Lee U, Mashour GA, Kim S, et al. Propofol induction reduces the capacity for neural information integration: Implications for the mechanism of consciousness and general anesthesia. Conscious Cogn. 2009;18(1):56-64.
236. Ku SW, Lee U, Noh GJ, et al. Preferential inhibition of frontal-to-parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS One. 2011;6(10):e25155.
237. Lee U, Kim S, Noh GJ, et al. The directionality and functional organization of frontoparietal connectivity during consciousness and anesthesia in humans. Conscious Cogn. 2009;18(4):1069-1078.
238. Schrouff J, Perlbarg V, Boly M, et al. Brain functional integration decreases during propofol-induced loss of consciousness. Neuroimage. 2011;57(1):198-205.
239. Boveroux P, Vanhaudenhuyse A, Bruno MA, et al. Breakdown of within-and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology. 2010; 113(5):1038-1053.
240. Raichle ME, MacLeod AM, Snyder AZ, et al. A default mode of brain function. Proc Natl Acad Sci USA. 2001;98(2):676-682.
241. Greicius MD, Krasnow B, Reiss AL, et al. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA. 2003;100(1):253-258.
242. Samann PG, Wehrle R, Hoehn D, et al. Development of the brain's default mode network from wakefulness to slow wave sleep. Cereb Cortex. 2011;21(9):2082-2093.
243. Horovitz SG, Braun AR, Carr WS, et al. Decoupling of the brain's default mode network during deep sleep. Proc Natl Acad Sci USA. 2009;106(27):11376-11381.
244. Larson-Prior LJ, Power JD, Vincent JL, et al. Modulation of the brain's functional network architecture in the transition from wake to sleep. Prog Brain Res. 2011;193:277-294.
245. Mashour GA Consciousness unbound: toward a paradigm of general anesthesia. Anesthesiology. 2004;100(2):428-433.
246. Hudetz AG, Vizuete JA, Pillay S. Differential effects of isoflurane on high-frequency and low-frequency gamma oscillations in the cerebral cortex and hippocampus in freely moving rats. Anesthesiology. 2011;114(3):588-595.
247. Breshears JD, Roland JL, Sharma M, et al. Stable and dynamic cortical electrophysiology of induction and emergence with propofol anesthesia. Proc Natl Acad Sci USA. 2010;107(49):21170-21175.
248. John ER, Prichep LS, Kox W, et al. Invariant reversible QEEG effects of anesthetics. Conscious Cogn. 2001;10(2):165-183.
249. Martin LJ, Orser BA. Etomidate targets alpha5 gamma-aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade. Anesthesiology. 2009;111(5):1025-1035.
250. O'Meara GF, Newman RJ, Fradley RL, et al. The GABA-A beta3 subunit mediates anaesthesia induced by etomidate. Neuroreport;15(10):1653-1656.
251. Quinlan JJ, Homanics GE, Firestone LL. Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid receptor. Anesthesiology;88(3):775-780.
252. Rau V, Oh I, Liao M, et al. Gamma-aminobutyric acid type A receptor beta3 subunit forebrain-specific knockout mice are resistant to the amnestic effect of isoflurane. Anesth Analg. 2011;113(3):500-504.
253. Lambert S, Arras M, Vogt KE, et al. Isoflurane-induced surgical tolerance mediated only in part by beta3-containing GABA(A) receptors. Eur J Pharmacol. 2005; 516(1):23-27.
254. Linden AM, Aller MI, Leppa E, et al. K+ channel TASK-1 knockout mice show enhanced sensitivities to ataxic and hypnotic effects of GABA(A) receptor ligands. J Pharmacol Exp Ther. 2008;327(1):277-286.
255. Chen X, Shu S., Kennedy DP, et al. Subunit-specific effects of isoflurane on neuronal Ih in HCN1 knockout mice. J Neurophysiol. 2009;101(1):129-140.