Abstract
Background: In addition to the well-known role played in lactation and parturition, Oxytocin (OT) and OT receptor (OTR) are involved in many other aspects such as the control of maternal and social behavior, the regulation of the growth of the neocortex, the maintenance of blood supply to the cortex, the stimulation of limbic olfactory area to mother-infant recognition bond, and the modulation of the autonomic nervous system via the vagal pathway. Moreover, OT and OTR show antiinflammatory, anti-oxidant, anti-pain, anti-diabetic, anti-dyslipidemic and anti-atherogenic effects.
Objective: The aim of this narrative review is to summarize the main data coming from the literature dealing with the role of OT and OTR in physiology and pathologic conditions focusing on the most relevant aspects.
Methods: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined.
Results: We report the most significant and updated data on the role played by OT and OTR in physiology and different clinical contexts.
Conclusion: Emerging evidence indicates the involvement of OT system in several pathophysiological mechanisms influencing brain anatomy, cognition, language, sense of safety and trust and maternal behavior, with the possible use of exogenous administered OT in the treatment of specific neuropsychiatric conditions. Furthermore, it modulates pancreatic β-cell responsiveness and lipid metabolism leading to possible therapeutic use in diabetic and dyslipidemic patients and for limiting and even reversing atherosclerotic lesions.
Keywords: Oxytocin, oxytocin receptor, maternal behavior, social behavior, metabolic homeostasis, atherosclerosis, pain, neuroinflammation, autism, schizophrenia, depression, bipolar disorder.
Graphical Abstract
[http://dx.doi.org/10.1016/S0079-6123(08)64378-2] [PMID: 6198686]
[PMID: 6690342]
[http://dx.doi.org/10.1126/science.6153132] [PMID: 6153132]
[http://dx.doi.org/10.1016/S0301-0082(98)00072-0] [PMID: 10221785]
[http://dx.doi.org/10.1016/S0091-3022(02)00104-8] [PMID: 12609499]
[http://dx.doi.org/10.1677/joe.0.0510347] [PMID: 5166156]
[http://dx.doi.org/10.2174/1381612820666140905150730] [PMID: 25190061]
[http://dx.doi.org/10.1677/joe.0.1320149] [PMID: 1737954]
[http://dx.doi.org/10.1677/joe.0.1410075] [PMID: 8014606]
[http://dx.doi.org/10.1677/JOE-07-0017] [PMID: 17470522]
[http://dx.doi.org/10.1677/JOE-09-0066] [PMID: 19420011]
[http://dx.doi.org/10.1016/0306-4522(95)00186-M] [PMID: 8544991]
[http://dx.doi.org/10.1111/j.1469-7793.2000.t01-2-00457.x] [PMID: 10766926]
[http://dx.doi.org/10.1016/0006-8993(81)90388-7] [PMID: 7317773]
[http://dx.doi.org/10.1002/cne.902100306] [PMID: 7142442]
[http://dx.doi.org/10.1016/0006-8993(83)90999-X] [PMID: 6626987]
[http://dx.doi.org/10.1016/0304-3940(81)90391-8] [PMID: 7290524]
[http://dx.doi.org/10.1002/cne.902180202] [PMID: 6886068]
[http://dx.doi.org/10.1016/j.yfrne.2011.07.002] [PMID: 21802439]
[http://dx.doi.org/10.1111/j.1365-2826.2011.02268.x] [PMID: 22151700]
[http://dx.doi.org/10.1615/CritRevNeurobiol.v10.i1.60] [PMID: 8853957]
[PMID: 16468232]
[PMID: 9316462]
[http://dx.doi.org/10.1152/ajpendo.90590.2008] [PMID: 19126785]
[http://dx.doi.org/10.1074/jbc.272.23.14800] [PMID: 9169447]
[http://dx.doi.org/10.1038/nature14402] [PMID: 25874674]
[http://dx.doi.org/10.1002/1097-4547(20001201)62:5<750:AID-JNR15>3.0.CO;2-8] [PMID: 11104514]
[http://dx.doi.org/10.4172/2471-2663.1000113]
[http://dx.doi.org/10.1089/gg.2017.0017]
[http://dx.doi.org/10.1152/ajpregu.00773.2005] [PMID: 16357093]
[http://dx.doi.org/10.1523/JNEUROSCI.3164-04.2004] [PMID: 15537880]
[http://dx.doi.org/10.1016/j.neuroscience.2010.08.015] [PMID: 20709160]
[http://dx.doi.org/10.1152/ajpregu.00709.2005]
[http://dx.doi.org/10.1152/physiolgenomics.90218.2008] [PMID: 18765859]
[http://dx.doi.org/10.1046/j.1460-9568.2003.02877.x] [PMID: 14511331]
[http://dx.doi.org/10.1523/JNEUROSCI.22-03-00959.2002] [PMID: 11826124]
[http://dx.doi.org/10.1016/S0079-6123(08)00404-4] [PMID: 18655870]
[http://dx.doi.org/10.1111/j.1365-2826.2004.01119.x] [PMID: 14962074]
[http://dx.doi.org/10.1111/j.1365-2826.2007.01640.x] [PMID: 18088359]
[http://dx.doi.org/10.1523/JNEUROSCI.22-01-00265.2002] [PMID: 11756510]
[http://dx.doi.org/10.2174/138161212802651607]
[http://dx.doi.org/10.1111/j.1460-9568.1996.tb01600.x] [PMID: 8758945]
[http://dx.doi.org/10.1007/BF00222774] [PMID: 880623]
[http://dx.doi.org/10.1016/0306-4522(81)90173-1] [PMID: 7242921]
[http://dx.doi.org/10.1046/j.1460-9568.1998.00221.x] [PMID: 9753099]
[http://dx.doi.org/10.1038/nn1849] [PMID: 17310248]
[http://dx.doi.org/10.1073/pnas.97.15.8629] [PMID: 10900020]
[http://dx.doi.org/10.1073/pnas.97.15.8629] [PMID: 10900020]
[http://dx.doi.org/10.1016/j.neuron.2008.11.024] [PMID: 19186164]
[http://dx.doi.org/10.1038/nn1498] [PMID: 15995701]
[http://dx.doi.org/10.1016/j.cell.2006.02.051] [PMID: 16713567]
[http://dx.doi.org/10.1038/nature04671] [PMID: 16547515]
[http://dx.doi.org/10.1007/BF00171316] [PMID: 9053729]
[http://dx.doi.org/10.1016/j.cub.2003.12.009] [PMID: 14711422]
[http://dx.doi.org/10.1016/j.neuropharm.2008.06.067] [PMID: 18657557]
[http://dx.doi.org/10.1038/nature04886] [PMID: 16885977]
[http://dx.doi.org/10.1111/j.1365-2826.2011.02259.x] [PMID: 22128866]
[http://dx.doi.org/10.1073/pnas.0308408100] [PMID: 14766975]
[http://dx.doi.org/10.1210/en.2006-0218] [PMID: 16675519]
[http://dx.doi.org/10.1113/jphysiol.2009.173435] [PMID: 19703969]
[http://dx.doi.org/10.1523/JNEUROSCI.3936-12.2013] [PMID: 23303942]
[http://dx.doi.org/10.1016/j.neuron.2013.04.025] [PMID: 23791197]
[http://dx.doi.org/10.1523/JNEUROSCI.3389-09.2010] [PMID: 20089907]
[http://dx.doi.org/10.1016/S0079-6123(02)39020-4] [PMID: 12436939]
[http://dx.doi.org/10.1016/j.tins.2009.11.004] [PMID: 19963290]
[http://dx.doi.org/10.1007/BF00249215] [PMID: 6894105]
[http://dx.doi.org/10.1007/400_2009_15] [PMID: 19582412]
[http://dx.doi.org/10.1152/physrev.00036.2009] [PMID: 20086078]
[http://dx.doi.org/10.1016/0165-0173(82)90010-8] [PMID: 6756545]
[http://dx.doi.org/10.1159/000123215] [PMID: 6167889]
[http://dx.doi.org/10.1016/0006-8993(82)91061-7] [PMID: 7104713]
[http://dx.doi.org/10.1113/jphysiol.1991.sp018840] [PMID: 1688025]
[PMID: 14229500]
[http://dx.doi.org/10.1113/jphysiol.1984.sp015416] [PMID: 6436476]
[http://dx.doi.org/10.1016/0006-8993(85)90496-2] [PMID: 2988698]
[http://dx.doi.org/10.1210/endo.140.8.6891] [PMID: 10433231]
[http://dx.doi.org/10.1523/JNEUROSCI.20-23-08868.2000] [PMID: 11102496]
[PMID: 7284125]
[http://dx.doi.org/10.1016/S0028-3908(99)00010-6] [PMID: 10462127]
[http://dx.doi.org/10.1016/j.brainres.2014.03.006] [PMID: 24642272]
[PMID: 18208678]
[http://dx.doi.org/10.1016/j.regpep.2004.12.009] [PMID: 15680491]
[http://dx.doi.org/10.1046/j.1365-2826.2003.00978.x] [PMID: 12588512]
[http://dx.doi.org/10.1152/jn.1996.76.2.1166] [PMID: 8871228]
[http://dx.doi.org/10.1016/j.brainresbull.2008.04.009] [PMID: 18639747]
[http://dx.doi.org/10.1016/0306-4522(86)90016-3] [PMID: 3537841]
[http://dx.doi.org/10.1002/cne.903020423] [PMID: 2081813]
[http://dx.doi.org/10.1016/0006-8993(79)91049-7] [PMID: 476481]
[http://dx.doi.org/10.1152/ajplegacy.1972.223.2.310] [PMID: 4558378]
[http://dx.doi.org/10.1016/0006-8993(71)90491-4] [PMID: 4400088]
[http://dx.doi.org/10.1161/CIRCRESAHA.113.301814] [PMID: 24103391]
[http://dx.doi.org/10.1016/S0168-0102(99)00121-2] [PMID: 10711808]
[http://dx.doi.org/10.1002/cne.902240102] [PMID: 6715573]
[http://dx.doi.org/10.1002/cne.20956] [PMID: 16628615]
[http://dx.doi.org/10.1016/0306-4522(84)90027-7] [PMID: 6201778]
[PMID: 6103825]
[http://dx.doi.org/10.1016/0006-8993(84)90605-X] [PMID: 6541075]
[http://dx.doi.org/10.1016/0014-2999(91)90518-U] [PMID: 1680708]
[http://dx.doi.org/10.1159/000125364] [PMID: 1971712]
[http://dx.doi.org/10.1159/000126797] [PMID: 7700499]
[http://dx.doi.org/10.1016/0006-8993(84)90574-2] [PMID: 6722545]
[http://dx.doi.org/10.1046/j.1365-2826.2001.00650.x] [PMID: 11328453]
[http://dx.doi.org/10.1530/JOE-15-0087] [PMID: 25901040]
[http://dx.doi.org/10.1152/ajpregu.00478.2003] [PMID: 14604844]
[http://dx.doi.org/10.1016/S0169-328X(02)00525-9] [PMID: 12531518]
[http://dx.doi.org/10.1523/JNEUROSCI.23-10-04261.2003] [PMID: 12764114]
[http://dx.doi.org/10.1210/endo.136.1.7828526] [PMID: 7828526]
[http://dx.doi.org/10.1016/0006-8993(94)91946-1] [PMID: 7895018]
[http://dx.doi.org/10.1002/cne.901930210] [PMID: 7440777]
[http://dx.doi.org/10.1016/0306-4522(78)90102-1] [PMID: 733004]
[http://dx.doi.org/10.1126/science.3715453]
[PMID: 3661761]
[http://dx.doi.org/10.1111/j.1365-2826.1991.tb00264.x] [PMID: 19215523]
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb13820.x] [PMID: 8220899]
[http://dx.doi.org/10.1016/0167-0115(93)90413-3] [PMID: 8426907]
[http://dx.doi.org/10.1016/0091-3057(90)90568-3] [PMID: 1982697]
[http://dx.doi.org/10.1159/000125917] [PMID: 1758580]
[http://dx.doi.org/10.1159/000124794] [PMID: 3614554]
[http://dx.doi.org/10.1111/j.1749-6632.1992.tb34364.x] [PMID: 1626836]
[http://dx.doi.org/10.1210/en.2007-0615] [PMID: 17628000]
[http://dx.doi.org/10.1126/science.7071605] [PMID: 7071605]
[http://dx.doi.org/10.2174/1871530319666190131155310] [PMID: 30706797]
[http://dx.doi.org/10.1016/j.neuron.2017.06.003] [PMID: 28669546]
[http://dx.doi.org/10.1016/j.cell.2014.05.017] [PMID: 24949967]
[http://dx.doi.org/10.1038/ncomms2144] [PMID: 23132022]
[http://dx.doi.org/10.1016/j.pbb.2005.06.001] [PMID: 15996723]
[http://dx.doi.org/10.1073/pnas.221224598] [PMID: 11606726]
[http://dx.doi.org/10.1111/j.1749-6632.1997.tb51916.x] [PMID: 9071347]
[http://dx.doi.org/10.1046/j.1365-2826.1996.05266.x] [PMID: 8933362]
[http://dx.doi.org/10.1111/j.1601-183X.2005.00162.x] [PMID: 16594980]
[http://dx.doi.org/10.1016/j.neuropharm.2018.02.019] [PMID: 29477300]
[http://dx.doi.org/10.1016/j.psyneuen.2011.03.003] [PMID: 21481539]
[http://dx.doi.org/10.3389/fnins.2018.00183] [PMID: 29618970]
[http://dx.doi.org/10.1007/s00441-018-2889-8] [PMID: 30054732]
[http://dx.doi.org/10.5661/RDR-VI-191] [PMID: 17491148]
[http://dx.doi.org/10.1111/j.1749-6632.1997.tb51918.x] [PMID: 9071349]
[http://dx.doi.org/10.1126/science.1133212] [PMID: 17170309]
[http://dx.doi.org/10.1016/j.neuron.2007.03.007] [PMID: 17408581]
[http://dx.doi.org/10.1016/S0079-6123(08)00421-4] [PMID: 18655887]
[http://dx.doi.org/10.1002/hup.2402] [PMID: 24911580]
[http://dx.doi.org/10.3389/fnbeh.2014.00191] [PMID: 24904342]
[http://dx.doi.org/10.1093/scan/nsr100] [PMID: 22446301]
[http://dx.doi.org/10.1002/hbm.22605] [PMID: 25094043]
[http://dx.doi.org/10.1523/JNEUROSCI.2755-12.2012] [PMID: 23152592]
[http://dx.doi.org/10.1093/scan/nss083] [PMID: 22842905]
[http://dx.doi.org/10.1523/JNEUROSCI.21-07-02546.2001] [PMID: 11264328]
[http://dx.doi.org/10.1523/JNEUROSCI.3984-05.2005] [PMID: 16339042]
[http://dx.doi.org/10.1016/j.neuropsychologia.2012.03.011] [PMID: 22450197]
[http://dx.doi.org/10.1073/pnas.1602620113] [PMID: 27325780]
[http://dx.doi.org/10.1007/s00429-005-0025-5] [PMID: 16208455]
[http://dx.doi.org/10.1111/j.1749-6632.2010.05445.x] [PMID: 20392275]
[http://dx.doi.org/10.1146/annurev.neuro.28.051804.101459] [PMID: 16022595]
[http://dx.doi.org/10.1016/j.bbi.2011.04.013] [PMID: 21536123]
[http://dx.doi.org/10.1097/CCM.0b013e3181a592b3] [PMID: 19885996]
[http://dx.doi.org/10.1186/1742-2094-9-71] [PMID: 22520439]
[http://dx.doi.org/10.3389/fncel.2015.00082] [PMID: 25814933]
[http://dx.doi.org/10.1016/0306-4530(90)90046-C] [PMID: 2367615]
[http://dx.doi.org/10.1046/j.1365-2826.2000.00442.x] [PMID: 10718919]
[http://dx.doi.org/10.1016/j.biopsych.2008.10.011] [PMID: 19027101]
[http://dx.doi.org/10.1210/endo.138.7.5255] [PMID: 9202224]
[http://dx.doi.org/10.1161/STROKEAHA.111.628008] [PMID: 21960564]
[http://dx.doi.org/10.1097/PSY.0b013e3181de8678] [PMID: 20466999]
[http://dx.doi.org/10.1016/j.pnpbp.2017.02.022] [PMID: 28259722]
[http://dx.doi.org/10.3389/fncel.2011.00003]
[http://dx.doi.org/10.1089/jwh.2012.3768] [PMID: 23586800]
[http://dx.doi.org/10.1038/npp.2011.117] [PMID: 21734650]
[http://dx.doi.org/10.1016/j.jpain.2006.07.001] [PMID: 17097925]
[http://dx.doi.org/10.1016/j.peptides.2012.08.005] [PMID: 22917880]
[http://dx.doi.org/10.1002/cne.902050306] [PMID: 6122696]
[http://dx.doi.org/10.1016/j.pain.2013.05.003] [PMID: 23707282]
[http://dx.doi.org/10.1523/JNEUROSCI.3084-12.2013] [PMID: 24133265]
[http://dx.doi.org/10.1016/j.neuron.2016.01.041] [PMID: 26948889]
[http://dx.doi.org/10.1002/hipo.20947] [PMID: 21692136]
[http://dx.doi.org/10.1111/j.1365-2826.2011.02235.x] [PMID: 21981277]
[http://dx.doi.org/10.1016/j.neulet.2014.02.012] [PMID: 24548623]
[http://dx.doi.org/10.1038/s41467-017-00675-5] [PMID: 28912554]
[http://dx.doi.org/10.1016/S0079-6123(02)39024-1] [PMID: 12436943]
[http://dx.doi.org/10.1152/physrev.2001.81.2.629] [PMID: 11274341]
[http://dx.doi.org/10.1002/cne.21872] [PMID: 19003903]
[http://dx.doi.org/10.1016/j.pbb.2010.05.026] [PMID: 20595062]
[http://dx.doi.org/10.1046/j.1365-201X.1997.00162.x] [PMID: 9338510]
[http://dx.doi.org/10.1152/ajpheart.00808.2015] [PMID: 27016581]
[http://dx.doi.org/10.1016/j.jneuroim.2015.11.001] [PMID: 26616885]
[http://dx.doi.org/10.2174/1871530319666190617160934] [PMID: 31237219]
[http://dx.doi.org/10.1016/j.physbeh.2015.05.023]
[http://dx.doi.org/10.2174/1871530318666180212095235] [PMID: 29437026]
[http://dx.doi.org/10.2174/1871530318666180220104900] [PMID: 29468985]
[http://dx.doi.org/10.1186/s12902-016-0110-1]
[http://dx.doi.org/10.1210/en.2011-1415] [PMID: 21971157]
[http://dx.doi.org/10.1186/cc7930] [PMID: 19549333]
[http://dx.doi.org/10.1210/en.2014-1718] [PMID: 25562615]
[http://dx.doi.org/10.1016/S0006-3223(97)00439-3] [PMID: 9513736]
[http://dx.doi.org/10.1016/S0006-3223(01)01139-8] [PMID: 11690596]
[http://dx.doi.org/10.1007/s10803-006-0124-z] [PMID: 16865550]
[http://dx.doi.org/10.1038/mp.2014.77] [PMID: 25092245]
[http://dx.doi.org/10.1152/physrev.00035.2007] [PMID: 18626062]
[http://dx.doi.org/10.1016/j.neulet.2008.09.084] [PMID: 18926879]
[http://dx.doi.org/10.1016/j.yhbeh.2011.12.011] [PMID: 22227279]
[http://dx.doi.org/10.1248/bpb.34.1369] [PMID: 21881219]
[http://dx.doi.org/10.1016/j.neuropharm.2009.06.012] [PMID: 19540855]
[http://dx.doi.org/10.1038/nature05526] [PMID: 17287729]
[http://dx.doi.org/10.1016/j.neures.2010.03.004] [PMID: 20435366]
[http://dx.doi.org/10.1038/mp.2008.14] [PMID: 18283277]
[http://dx.doi.org/10.1111/j.1749-6632.2009.04541.x] [PMID: 19580556]
[http://dx.doi.org/10.1080/17470919.2014.897995] [PMID: 24635660]
[http://dx.doi.org/10.3389/fnins.2016.00195] [PMID: 27242401]
[http://dx.doi.org/10.1111/gbb.12069] [PMID: 23941164]
[http://dx.doi.org/10.1016/j.neulet.2007.02.001] [PMID: 17383819]
[http://dx.doi.org/10.1038/sj.mp.4002087] [PMID: 17893705]
[http://dx.doi.org/10.1186/2040-2392-5-48] [PMID: 25264479]
[http://dx.doi.org/10.1186/2040-2392-4-22] [PMID: 23815867]
[http://dx.doi.org/10.1073/pnas.1003296107] [PMID: 20647384]
[http://dx.doi.org/10.1016/j.neuroimage.2013.05.029] [PMID: 23684879]
[http://dx.doi.org/10.1016/j.neuroimage.2016.04.009] [PMID: 27109357]
[http://dx.doi.org/10.1073/pnas.0910249107] [PMID: 20160081]
[http://dx.doi.org/10.1038/mp.2015.162] [PMID: 26503762]
[http://dx.doi.org/10.1186/1471-244X-12-110] [PMID: 22888794]
[http://dx.doi.org/10.1093/brain/awv249] [PMID: 26336909]
[http://dx.doi.org/10.1007/s10803-013-1899-3] [PMID: 23888359]
[http://dx.doi.org/10.1111/jcpp.12305] [PMID: 25087908]
[http://dx.doi.org/10.1038/tp.2016.152] [PMID: 27552585]
[http://dx.doi.org/10.1016/S0306-4530(98)00055-9] [PMID: 9924738]
[http://dx.doi.org/10.1016/S0031-9384(03)00151-3] [PMID: 12954433]
[http://dx.doi.org/10.1196/annals.1384.006] [PMID: 17435137]
[http://dx.doi.org/10.1016/j.tins.2012.08.004] [PMID: 22974560]
[http://dx.doi.org/10.1080/1025389031000104193]
[http://dx.doi.org/10.1016/S0031-9384(98)00119-X] [PMID: 9761230]
[http://dx.doi.org/10.1016/S0006-3223(03)00465-7] [PMID: 14675803]
[http://dx.doi.org/10.1016/j.biopsych.2007.03.025] [PMID: 17617382]
[http://dx.doi.org/10.1038/nature03701] [PMID: 15931222]
[http://dx.doi.org/10.1111/j.1601-5215.2011.00634.x] [PMID: 22736892]
[http://dx.doi.org/10.1007/BF00461555] [PMID: 6489403]
[http://dx.doi.org/10.1016/0306-4530(85)90056-3] [PMID: 4034849]
[http://dx.doi.org/10.1016/0306-4530(92)90019-4] [PMID: 1287681]
[http://dx.doi.org/10.1093/schbul/13.2.261] [PMID: 3616518]
[http://dx.doi.org/10.1016/j.schres.2010.09.014] [PMID: 20947304]
[http://dx.doi.org/10.1016/j.schres.2010.04.019] [PMID: 20547038]
[http://dx.doi.org/10.1017/S1461145711001374] [PMID: 21899794]
[http://dx.doi.org/10.1017/S1461145710000167] [PMID: 20196918]
[http://dx.doi.org/10.1136/bmj.4.5835.298-c] [PMID: 5083904]
[http://dx.doi.org/10.1177/070674377401900323] [PMID: 4841051]
[http://dx.doi.org/10.1007/BF01186517] [PMID: 3748373]
[http://dx.doi.org/10.1007/s00213-011-2193-8] [PMID: 21301811]
[http://dx.doi.org/10.1016/j.biopsych.2010.04.039] [PMID: 20615494]
[http://dx.doi.org/10.1016/j.schres.2012.05.018] [PMID: 22682705]
[http://dx.doi.org/10.1016/j.schres.2011.07.027] [PMID: 21840177]
[http://dx.doi.org/10.1007/s40263-012-0022-1] [PMID: 23233269]
[http://dx.doi.org/10.1016/j.peptides.2009.12.015] [PMID: 20026211]
[http://dx.doi.org/10.1016/0006-3223(96)84235-1]
[http://dx.doi.org/10.1007/s003930070045] [PMID: 11201002]
[http://dx.doi.org/10.1016/j.psychres.2008.06.034] [PMID: 19732960]
[http://dx.doi.org/10.1097/PSY.0b013e318188ade4] [PMID: 19005082]
[http://dx.doi.org/10.1038/npp.2011.74] [PMID: 21562482]
[http://dx.doi.org/10.1016/j.psyneuen.2009.05.006] [PMID: 19515497]
[http://dx.doi.org/10.1016/j.psyneuen.2010.07.003] [PMID: 20708845]
[http://dx.doi.org/10.1176/jnp.23.2.jnpe5] [PMID: 21677229]