Multi-dimensional MR spectroscopy: Towards a better understanding of hepatic encephalopathy

Metabolic Brain Disease

Volumn 26, Issue 3, 2011, Pages 173-184

  Sarma, Manoj K ^a   Huda, Amir ^a,b   Nagarajan, Rajakumar ^a   Hinkin, Charles H ^c,d   Wilson, Neil ^a   Gupta, Rakesh K ^e   Frias Martinez, Enrique ^a   Sayre, James ^a   Guze, Barry ^c   Han, Steven Huy ^c   Thomas, M Albert ^a,c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b CALIFORNIA STATE UNIVERSITY   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d VA GREATER LOS ANGELES HEALTHCARE SYSTEM   (United States)

^e SANJAY GANDHI POSTGRADUATE INSTITUTE OF MEDICAL SCIENCES   (India)

Author keywords

COSY; Glutamate; Glutamine; Hepatic encephalopathy; MRS; Neuropsychological tests

Indexed keywords

4 AMINOBUTYRIC ACID; ALANINE; ASCORBIC ACID; ASPARTIC ACID; CHOLINE; GLUCOSE; GLUTAMIC ACID; GLUTAMINE; GLUTATHIONE; GLYCERYLPHOSPHOCHOLINE; INOSITOL; N ACETYL ASPARTYLGLUTAMATE; N ACETYLASPARTIC ACID; PHOSPHOETHANOLAMINE; SCYLLOINOSITOL; TAURINE; UNCLASSIFIED DRUG;

ADULT; AGED; ALGORITHM; ARTICLE; CLINICAL ARTICLE; COGNITION; CONTROLLED STUDY; EXECUTIVE FUNCTION; HEPATIC ENCEPHALOPATHY; HUMAN; MOTOR PERFORMANCE; NEUROPSYCHOLOGICAL TEST; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIOR KNOWLEDGE FITTING ALGORITHM;

ADULT; BIOLOGICAL MARKERS; BRAIN; BRAIN CHEMISTRY; CASE-CONTROL STUDIES; FEMALE; GLUTAMIC ACID; GLUTAMINE; HEPATIC ENCEPHALOPATHY; HUMANS; IMAGE PROCESSING, COMPUTER-ASSISTED; MAGNETIC RESONANCE SPECTROSCOPY; MALE; METABOLOME; MIDDLE AGED; NEUROPSYCHOLOGICAL TESTS; SENSITIVITY AND SPECIFICITY;

EID: 80052283964     PISSN: 08857490     EISSN: 15737365     Source Type: Journal    
DOI: 10.1007/s11011-011-9250-1     Document Type: Article

References (78)

1. P Amodio F Del Piccolo P Marchetti P Angeli R Iemmolo L Caregaro C Merkel G Gerunda A Gatta 1999 Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests Hepatology 29 1662 1667 10347105 1:STN:280:DyaK1M3nvVaktQ%3D%3D 10.1002/hep.510290619 (Pubitemid 29247036)
2. P Amodio F Del Piccolo E Pettenò D Mapelli P Angeli R Iemmolo M Muraca C Musto G Gerunda C Rizzo C Merkel A Gatta 2001 Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients J Hepatol 35 37 45 11495040 1:STN:280:DC%2BD3MvkvFeqtQ%3D%3D 10.1016/S0168-8278(01)00129-5 (Pubitemid 32646222)
3. P Amodio S Montagnese A Gatta MY Morgan 2004 Characteristics of minimal hepatic encephalopathy Metab Brain Dis 19 253 267 15554421 10.1023/B:MEBR. 0000043975.01841.de (Pubitemid 39361187)
4. P Amodio L Ridola S Schiff S Montagnese C Pasquale S Nardelli I Pentassuglio M Trezza C Marzano C Flaiban P Angeli G Cona P Bisiacchi A Gatta O Riggio 2010 Improving detection of minimal hepatic encephalopathy using the inhibitory control task Gastroenterology 139 510 518 20470775 10.1053/j.gastro.2010.04.057
5. S Berl G Tokagaki DD Clarke H Waelsch 1962 Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver J Biol Chem 237 2562 2569 13867916 1:CAS:528:DyaF38Xks1Ggurk%3D
6. P Bernthal A Hayes RE Tarter D Van Thiel J Lecky A Hegedus 1987 Cerebral CT scan abnormalities in cholestatic and hepatocellular disease and their relationship to neuropsychologic test performance Hepatology 7 107 114 3804189 1:STN:280:DyaL2s7gslegtg%3D%3D 10.1002/hep.1840070122 (Pubitemid 17019860)
7. 31P nuclear magnetic resonance study in vivo and in vitro Magn Reson Med 41 897 903 10332871 1:CAS:528:DyaK1MXjtF2rsL0%3D 10.1002/(SICI)1522-2594(199905)41:5<897::AID- MRM7>3.0.CO;2-T (Pubitemid 29211131)
8. 1H magnetic resonance spectroscopy of hepatic encephalopathy J Magn Reson Imaging 21 398 405 15779041 10.1002/jmri.20291 (Pubitemid 40446435)
9. N Binesh A Huda MA Thomas N Wyckoff M Bugbee S Han N Rasgon P Davanzo J Sayre B Guze P Martin F Fawzy 2006 Hepatic encephalopathy: a neurochemical, neuroanatomical, and neuropsychological study J Appl Clin Med Phys 7 86 96 16518320 10.1120/jacmp.2027.25374
10. AT Blei J Cordoba 1996 Subclinical encephalopathy Digest Dis 14 2 11 10.1159/000171577
11. Bosman DK, Deutz NE, De Graaf AA, vd Hulst RW, Van Eijk HM, Bovée WM, Maas MA, Jörning GG, Chamuleau RA (1990) Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 12:281-290 (Pubitemid 20285791)
12. RF Butterworth 1995 Hepatic encephalopathy Neurologist 1 95 104
13. RF Butterworth 1996 Taurine in hepatic encephalopathy Adv Exp Med Biol 403 601 606 8915400 1:STN:280:DyaK2s%2Fnt1Kgtw%3D%3D (Pubitemid 26365243)
14. RF Butterworth 2000 Complication of cirrhosis. III. Hepatic encephalopathy J Hepatol 32 171 180 10728803 1:STN:280:DC%2BD3c7ptFWntQ%3D%3D 10.1016/S0168-8278(00)80424-9 (Pubitemid 30123633)
15. N Chalasani N Gitlin 1997 Subclinical hepatic encephalopathy: How best to diagnose? Am J Gastroent 92 905 906 9149218 1:STN:280:DyaK2s3ptlWltw%3D%3D (Pubitemid 27200823)
16. CP Chih EL Roberts Jr 2003 Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis J Cereb Blood Flow Metab 23 1263 1281 14600433 1:CAS:528:DC%2BD3sXos1CmtLg%3D 10.1097/01.WCB.0000081369.51727.6F (Pubitemid 37409789)
17. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW et al (eds) Basic neurochemistry. Lippincott-Raven, Philadelphia, pp 637-669
18. RK Dhiman YK Chawla 2009 Minimal hepatic encephalopathy Indian J Gastroenterol 28 5 16 19529896 10.1007/s12664-009-0003-6
19. JH Duyn J Gillen G Sobering PC van Zijl CTW Moonen 1993 Multisection proton MR spectrosocopic imaging of the brain Radiology 188 277 282 8511313 1:STN:280:DyaK3s3ovVyqsQ%3D%3D (Pubitemid 23183139)
20. 13C resonances Biochim Biophys Acta 805 104 116 6477969 1:CAS:528:DyaL2cXlsV2isrg%3D 10.1016/0167-4889(84)90042-9
21. P Ferenci A Lockwood K Mullen R Tarter K Weissenborn AT Blei 2002 Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998 Hepatology 35 716 721 11870389 10.1053/jhep.2002.31250 (Pubitemid 34183979)
22. BR Foerster LS Conklin M Petrou PB Barker KB Schwarz 2009 Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy AJNR Am J Neuroradiol 30 1610 1613 19509075 1:STN:280:DC%2BD1MnhslSnsA%3D%3D 10.3174/ajnr.A1652
23. CL Fraser AI Arieff 1985 Hepatic encephalopathy New Eng J Med 313 865 873 2993889 1:STN:280:DyaL2M3ps1Wmtg%3D%3D 10.1056/NEJM198510033131406 (Pubitemid 15250202)
24. Frias-Martinez E, Rajakumar N, Liu X, Singhal A, Banakar S, Lipnick S, Verma G, Ramadan S, Kumar A, Thomas MA (2008) ProFit-based Quantitation of Cerebral Metabolites using 2D L-COSY at 3 T Magnetic Resonance. Proc Intl Soc Mag Reson Med 16: 691, Toronto, Canada
25. SJ Gilberstadt H Gilberstadt L Zieve B Buegel RO Collier Jr CJ McClain 1980 Psychomotor performance defects in cirrhotic patients without overt encephalopathy Arch Intern Med 140 519 521 7362383 1:STN:280: DyaL3c7lt1Ghug%3D%3D 10.1001/archinte.140.4.519 (Pubitemid 10156655)
26. Gitlin N (1996) Hepatic encephalopathy. In: Zorkin D, Boyer TD (eds) Hepatology. Saunders, Philadelphia, pp 605-617
27. V Govindaraju K Young AA Maudsley 2000 Proton NMR chemical shifts and coupling constants for brain metabolites NMR Biomed 13 129 153 10861994 1:CAS:528:DC%2BD3cXksFSgtL8%3D 10.1002/1099-1492(200005)13:3<129::AID- NBM619>3.0.CO;2-V (Pubitemid 30414704)
28. 31P-NMR studies of a human tumour in situ Lancet 1 1435 1436 6134191 1:STN:280:DyaL3s3hsl2qtw%3D%3D 10.1016/S0140-6736(83)92375-9 (Pubitemid 13053320)
29. 13C]glucose J Neurochem 63 1377 1385 7931289 1:CAS:528:DyaK2cXmslGktb0%3D 10.1046/j.1471-4159.1994.63041377.x
30. A Haase J Frahm W Haenicke D Matthaei 1985 1H NMR chemical-shift selective (CHESS) imaging Phys Med Biol 30 341 344 4001160 1:CAS:528: DyaL2MXitFOkt7k%3D 10.1088/0031-9155/30/4/008 (Pubitemid 15110036)
31. Heaton RK, Grant I, Matthews CG (1991) Comprehensive norms for an expanded Halstead-Reitan battery: demographic corrections, research findings, and clinical applications. Psychological Assessment Resources, Odessa
32. Hilbe JM (2009) Logistic regression models. Chapman & Hall/CRC Press
33. W Hilgier RO Law M Zielinska 2000 Taurine, glutamine, glutamate, and aspartate content and efflux, cell volume of cerebrocortical minislices of rats with hepatic encephalopathy Adv Exp Med Biol 483 305 312 11787612 1:CAS:528:DC%2BD3MXitFaht74%3D 10.1007/0-306-46838-7-34
34. Hosmer DW, Lemeshow S (1995) Applied Logistic Regression. John Wiley and Sons, Inc Menard, Scott
35. T Kaibara RL Tyson GR Sutherland 1998 Human cerebral neoplasms studied using MR spectroscopy: a review Biochem Cell Biol 76 477 486 9923717 1:CAS:528:DyaK1MXltFejtg%3D%3D 10.1139/o98-048 (Pubitemid 29102033)
36. J Klein R Gonzalez A Koppen K Loffelholz 1993 Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain Neurochem Int 22 293 300 8443570 1:CAS:528:DyaK3sXhs1Gkt78%3D 10.1016/0197-0186(93)90058-D
37. H Koc M Mar A Ranasinghe JA Swenberg SH Zeisel 2002 Quantitation of Choline and its Metabolites in Tissues and Foods by Liquid Chromatography/ Electrospray Ionization-Isotope Dilution Mass Spectrometry Analytical Chemistry 74 4734 4740 12349977 1:CAS:528:DC%2BD38XmtVShsb4%3D 10.1021/ac025624x
38. R Kreis BD Ross NA Farrow Z Ackerman 1992 Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy Radiology 182 19 27 1345760 1:STN:280:DyaK38%2FotVOjsg%3D%3D
39. RE Larzelere SA Mulak 1977 Single-sample tests for many correlations Psychol Bull 84 557 569 10.1037/0033-2909.84.3.557
40. J Lavoie JF Giguere GP Layrargues RF Butterworth 1987 Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy J Neurochem 49 692 697 2886551 1:CAS:528:DyaL2sXlsFahs7Y%3D 10.1111/j.1471-4159. 1987.tb00949.x (Pubitemid 17123714)
41. L Leybaert 2005 Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J Cereb Blood Flow Metab 25 2 16 15678108 1:CAS:528:DC%2BD2MXht1Kks7k%3D (Pubitemid 40096893)
42. Lezak MD (1995) Neuropsychological assessment. Oxford University Press, New York, pp 333-685
43. AH Lockwood 2000 "What's in a name?" Improving the care of cirrhotics J Hepatol 32 859 861 10845675 1:STN:280:DC%2BD3cvnt12msQ%3D%3D 10.1016/S0168-8278(00)80257-3 (Pubitemid 30262748)
44. AH Lockwood EWH Yap WH Wong 1991 Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy J Cerebral Blood Flow Metabol 11 337 341 1:STN:280:DyaK3M7kslCrsg%3D%3D 10.1038/jcbfm.1991.67
45. AH Lockwood EWH Yap HM Rhodes WH Wong 1991 Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy J Cerebral Blood Flow Metabol 11 331 336 1:STN:280:DyaK3M7kslCkuw%3D%3D 10.1038/jcbfm.1991.66
46. 1H NMR spectroscopy NMR in Biomedicine 18 413 420 16075415 1:CAS:528:DC%2BD2MXhtlWhu7nK 10.1002/nbm.973 (Pubitemid 41646182)
47. PJ Magistretti L Pellerin DL Rothman RG Shulman 1999 Energy on demand Science 283 496 497 9988650 1:CAS:528:DyaK1MXoslagsw%3D%3D 10.1126/science.283. 5401.496 (Pubitemid 29061181)
48. M McCrea I Cordoba G Vessey AT Blei C Randolph 1996 Neuropsychological characterization and detection of subclinical hepatic encephalopathy Arch Neurol 53 758 763 8759982 1:STN:280:DyaK28zis1Wkug%3D%3D (Pubitemid 26266921)
49. MJ McPhail SD Taylor-Robinson 2010 The role of magnetic resonance imaging and spectroscopy in hepatic encephalopathy Metab Brain Dis 25 65 72 20221679 10.1007/s11011-010-9171-4
50. 1H MRS Choline: Correlation with In Vitro Chemistry/Histology Life Sciences 58 1929 1935 8637421 1:CAS:528: DyaK28XivVKntb0%3D 10.1016/0024-3205(96)00182-8
51. KD Mullen 2007 Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy Aliment Pharmacol Ther 25 11 16 17295847 10.1111/j.1746-6342.2006.03216.x (Pubitemid 46148240)
52. RJ Ogg PB Kingsley JS Taylor 1994 WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy J Magn Reson B 104 1 10 8025810 1:CAS:528:DyaK2cXktVCisL4%3D 10.1006/jmrb.1994.1048
53. N Patel DM Forton GA Coutts HC Thomas SD Taylor-Robinson 2000 Intracellular pH measurements of the whole head and the basal ganglia in chronic liver disease: a phosphorus-31 MR spectroscopy study Metab Brain Dis 15 223 240 11206591 1:STN:280:DC%2BD3M7ptlSjuw%3D%3D (Pubitemid 32112944)
54. Pardridge WM, Cornford EM, Braun LD, Oldendorf WH (1979) Transport of choline and choline analogues through the blood-brain barrier. In: Barbeau A, Growdon JH, Wurtman RJ (eds) Nutrition and the Brain. Raven, New York, pp 25-33
55. +-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabian J Neurochem 69 2132 2137 9349559 1:CAS:528:DyaK2sXmvVKkt7o%3D 10.1046/j.1471-4159.1997.69052132.x (Pubitemid 27452761)
56. SW Provencher 1993 Estimation of metabolite concentrations from localized in vivo proton NMR spectra Magn Reson Med 30 672 679 8139448 1:CAS:528:DyaK2cXis1Gjtr0%3D 10.1002/mrm.1910300604 (Pubitemid 23360802)
57. M Romero-Gómez 2007 Critical flicker frequency: it is time to break down barriers surrounding minimal hepatic encephalopathy J Hepatol 47 10 11 17507110 10.1016/j.jhep.2007.04.005 (Pubitemid 46817698)
58. M Romero-Gómez J Córdoba R Jover JA del Olmo M Ramírez R Rey E de Madaria C Montoliu D Nuñez M Flavia L Compañy JM Rodrigo V Felipo 2007 Value of the critical flicker frequency in patients with minimal hepatic encephalopathy Hepatology 45 879 885 17393525 10.1002/hep.21586 (Pubitemid 46631556)
59. BD Ross ER Danielsen S Bluml 1996 Proton magnetic resonance spectroscopy: The new gold standard for diagnosis of clinical and subclinical hepatic encephalopathy? Digest Dis 14 30 39 10.1159/000171581
60. BD Ross S Jacobson F Villamil J Korula R Kreis T Ernst T Shonk RA Moats 1994 Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities Radiology 193 457 463 7972763 1:STN:280:DyaK2M%2Fmt12ruw%3D%3D (Pubitemid 24338334)
61. N Saxena M Bhatia YK Joshi PK Garg SN Dwivedi RK Tandon 2002 Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy Liver 22 190 197 12100568 10.1034/j.1600-0676.2002.01431.x (Pubitemid 34846356)
62. H Schomerus W Hamster 1998 Neuropsychological aspects of portalsystemic encephalopathy Metab Brain Dis 13 361 377 10206827 1:STN:280: DyaK1M7jvF2qsA%3D%3D 10.1023/A:1020645110880 (Pubitemid 29063735)
63. H Schomerus W Hamster H Blunck U Reinhard K Mayer W Dolle 1981 Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive Dig Dis Sci 26 622 630 7249898 1:STN:280: DyaL3M3js1Wjsg%3D%3D 10.1007/BF01367675 (Pubitemid 11093388)
64. RF Schulte P Boesiger 2006 ProFit: two-dimensional prior-knowledge fitting of J-resolved spectra NMR Biomed 19 255 263 16541464 1:CAS:528:DC%2BD28XktlShsr4%3D 10.1002/nbm.1026
65. A Singhal R Nagarajan CH Hinkin R Kumar J Sayre V Elderkin-Thompson A Huda RK Gupta SH Han MA Thomas 2010 Two-dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo J Magn Reson Imaging 32 35 43 20578008 10.1002/jmri.22216
66. SA Smith TO Levante BH Meier RR Ernst 1994 Computer-simulations in magnetic-resonance-an object-oriented programming approach J Magn Reson A 106 75 105 1:CAS:528:DyaK2cXhvVWgs7w%3D 10.1006/jmra.1994.1008
67. J Solivera S Cerdan JM Pascual L Barrios JM Roda 2009 Assessment of 31P-NMR analysis of phospholipid profiles for potential differential diagnosis of human cerebral tumors NMR in Biomedicine 22 663 674 19378301 1:CAS:528:DC%2BD1MXhtVSnurvO 10.1002/nbm.1387
68. CA Stewart GE Smith 2007 Minimal hepatic encephalopathy Nat Clin Pract Gastroenterol Hepatol 4 677 685 18043677 10.1038/ncpgasthep0999 (Pubitemid 350193817)
69. RE Tarter AM Hegedus DH Van Thiel RR Schade JS Gavaler TE Starzl 1984 Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy Gastroenterology 86 1421 1427 6714571 1:STN:280:DyaL2c7otlChuw%3D%3D (Pubitemid 14147933)
70. SD Taylor-Robinson J Sargentoni RJ Mallalieu JD Bell DJ Bryant GA Coutts MY Morgan 1994 Cerebral phosphorus-31 magnetic resonance spectroscopy in patients with chronic hepatic encephalopathy Hepatology 20 1173 1178 7927249 1:STN:280:DyaK2M%2Fht1Wgsg%3D%3D 10.1002/hep.1840200511 (Pubitemid 24323562)
71. SD Taylor-Robinson C Buckley KK Changani HJ Hodgson JD Bell 1999 Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy Liver 19 389 398 10533796 1:STN:280:DC%2BD3c%2FgtFelsQ%3D%3D 10.1111/j.1478-3231.1999.tb00067.x (Pubitemid 29457216)
72. MA Thomas K Yue N Binesh P Davanzo A Kumar B Siegel M Frye J Curran R Lufkin P Martin B Guze 2001 Localized two-dimensional shift correlated MR spectroscopy of human brain Magn Reson Med 46 58 67 11443711 1:CAS:528:DC%2BD3MXltlShsro%3D 10.1002/mrm.1160 (Pubitemid 32594777)
73. J Vaquero RF Butterworth 2006 The brain glutamate system in liver failure J Neurochem 98 661 669 16771837 1:CAS:528:DC%2BD28XovFGhsLw%3D 10.1111/j.1471-4159.2006.03918.x (Pubitemid 44051268)
74. YM Wang 2004 The definition, nomenclature and diagnosis of hepatic encephalopathy Zhonghua Gan Zang Bing Za Zhi 12 305 306 15161513
75. K Weissenborn B Ahl D Fischer-Wasels J van den Hoff H Hecker W Burchert H Köstler 2007 Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy Gut 56 1736 1742 17660226 10.1136/gut.2006.110569 (Pubitemid 350206301)
76. K Weissenborn JC Ennen H Schomerus N Ruckert H Hecker 2001 Neuropsychological characterization of hepatic encephalopathy J Hepatol 34 768 773 11434627 1:STN:280:DC%2BD38%2Fhslehtg%3D%3D 10.1016/S0168-8278(01)00026-5 (Pubitemid 32488796)
77. C Zimmerman K Winnefeld S Streck M Roskosb RL Haberla 2004 Antioxidant status in acute stroke patients and patients at stroke risk Eur Neurol 51 157 161 10.1159/000077662 (Pubitemid 38608316)
78. C Zwingmann N Chaturet D Leibiritz RF Butterworth 2003 Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study Hepatology 37 420 428 12540793 1:CAS:528:DC%2BD3sXhsFeltrs%3D 10.1053/jhep.2003.50052 (Pubitemid 36152542)