Sex differences in lipid peroxidation and fatty acid levels in recent onset schizophrenia

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volumn 44, Issue , 2013, Pages 154-161

  Ramos Loyo, Julieta ^a   Medina Hernández, Virginia ^a,b   Estarrón Espinosa, Mirna ^c   Canales Aguirre, Alejandro ^c   Gómez Pinedo, Ulises ^c,d   Cerdán Sánchez, Luis F ^b  

^a Instituto de Neurociencias   (Mexico)

^b INSTITUTO MEXICANO DEL SEGURO SOCIAL   (Mexico)

^c Center for Research and Assistance in Technology   (Mexico)

^d HOSPITAL CLÍNICO SAN CARLOS   (Spain)

Author keywords

Lipid peroxidation; Oxidative stress; Phospholipid; Schizophrenia; Sex differences

Indexed keywords

4 HYDROXYNONENAL; ARACHIDONIC ACID; DOCOSAHEXAENOIC ACID; FATTY ACID; ICOSAPENTAENOIC ACID; MALONALDEHYDE;

ADULT; AGE DISTRIBUTION; ALCOHOLISM; ARTICLE; CLINICAL ARTICLE; CONTROLLED STUDY; ERYTHROCYTE MEMBRANE; FATTY ACID ANALYSIS; FEMALE; HOSPITALIZATION; HUMAN; LIPID PEROXIDATION; MALE; MENTAL DISEASE; ONSET AGE; OXIDATIVE STRESS; SCHIZOPHRENIA; SENSITIVITY AND SPECIFICITY; SEX DIFFERENCE; SMOKING;

ADOLESCENT; ADULT; ALDEHYDES; ANALYSIS OF VARIANCE; ARACHIDONIC ACID; CHROMATOGRAPHY; DOCOSAHEXAENOIC ACIDS; EICOSAPENTAENOIC ACID; ERYTHROCYTE MEMBRANE; ERYTHROCYTES; FATTY ACIDS; FEMALE; HUMANS; LIPID PEROXIDATION; MALE; MALONDIALDEHYDE; MIDDLE AGED; PSYCHIATRIC STATUS RATING SCALES; SCHIZOPHRENIA; SCHIZOPHRENIA, PARANOID; SEX CHARACTERISTICS; YOUNG ADULT;

EID: 84875265659     PISSN: 02785846     EISSN: 18784216     Source Type: Journal    
DOI: 10.1016/j.pnpbp.2013.02.007     Document Type: Article

References (103)

1. Abel T., McQueen D. Determinants of selected unhealthy eating behaviours among male and female adults. Eur J Public Health 1994, 4:27-32.
2. Akyol O., Herken H., Uz Efkan E., Fadillioǧlu Ersin E., Unal Süheyla S. The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol Biol Psychiatry 2002, 26:995-1005.
3. Arevalo M.A., Santos-Galindo M., Lagunas N., Azcoitia I., Garcia-Segura L.M. Selective estrogen receptor modulators as brain therapeutic agents. J Mol Endocrinol 2010, 46(1):R1-R9.
4. Arvindakshan M., Sitasawad S., Debsikdar V., Ghate M., Evans D., Horrobin D.F., et al. Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biol Psychiatry 2003, 53:56-64.
5. Berger G.E., Smesny S., Amminger G.P. Bioactive lipids in schizophrenia. Int Rev Psychiatry 2006, 18(2):85-98.
6. Bitanihirwe B.K.Y., Woo T.U. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 2011, 35(3):878-893. [1].
7. Bošković M., Vovk T., Kores Plesničar B., Grabnar I. Oxidative stress in schizophrenia. Curr Neuropharmacol 2011, 9(2):301-312.
8. Buttke T., Sandstrom P. Oxidative stress as a mediator of apoptosis. Immunol Today 1994, 15:7-10.
9. Carver J.D., Benford V.J., Han B., Cantor A.B. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res Bull 2001, 56:79-85.
10. Che Y., Wang J.F., Shao L., Young L.T. Oxidative damage to RNA but not DNA in the hippocampus of patients with major mental illness. J Psychiatry Neurosci 2010, 35(5):296-302.
11. Choi J.S., Chon M.W., Kang D.H., Myung H.J., Jun S.K. Gender Difference in the prodromal symptoms of first-episode schizophrenia. J Korean Med Sci 2009, 24:1083-1088.
12. Christensen O., Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand 1988, 78:587-591.
13. Ciobica A., Padurariu M., Dobrin I., Stefanescu C., Dobrin R. Oxidative stress in schizophrenia - focusing on the main markers. Psychiatr Danub 2011, 23(3):237-245.
14. Dadheech G., Mishra S., Gautam S., Sharma P. Evaluation of antioxidant deficit in schizophrenia. Indian J Psychiatry 2008, 50(1):16-20.
15. Das UN Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog. Neuropsychopharmacol. Biol Psychiatry 2013, 42:122-134.
16. Delion S., Chalon, Hérault J., Guilloteau D., Besnard J.C., Durand G. Chronic dietary a-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats. J Nutr 1994, 124(12):2466-2476.
17. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Masson, S.A. (ed.) Barcelona España; 2003.
18. Dietrich-Muszalska A., Olas B., Rabe-Jablonska J. Oxidative stress in blood platelets from schizophrenic patients. Platelets 2005, 16(7):386-391.
19. Dietrich-Muszalska A., Olas B., Głowacki R., Bald E. Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia. Neuropsychobiology 2009, 59:1-7.
20. du Bois T.M., Deng C., Huang X.F. Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005, 29(6):878-888.
21. Fehsel K., Loeffler S., Krieger K., Henning U., Agelink M., Kolb-Bachofen V., et al. Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. J Clin Psychopharmacol 2005, 25(5):419-426.
22. Fenton W., Hibbeln J., Knable M. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000, 47:8-21.
23. Fusar-Poli P., Berger G. Eicosapentaenoic acid interventions in schizophrenia. Meta-analysis of randomized, placebo- controlled studies. J Clin Psychopharmacol 2012, 32:179-185.
24. Gama C.S., Salvador M., Andreazza A.C., Kapczinski F., Silva Belmonte-de-Abreu P. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine. Prog Neuropsychopharmacol Biol Psychiatry 2006, 30:512-515.
25. 2 activity in schizophrenia. Schizophr Res 1995, 16:1-6.
26. Häfner H. Schizophrenia: do men and women suffer from the same disease?. Rev Psiq Clin 2002, 29:267-292.
27. Häfner H., Maurer K., Loffler W., Riecher-Rossler A. The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry 1993, 162:80-86.
28. Halbreich U., Kahn L.S. Hormonal aspects of schizophrenias: an overview. Psychoneuroendocrinology 2003, 28:1-16.
29. Hibbeln J., Makino K.K., Martin C., Dickenson F., Borono J., Fenton W.S. Smoking, gender and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder. Biol Psychiatry 2003, 53:431-441.
30. Horrobin D.F. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998, 30:193-208.
31. Horrobin D.F., Manku M.S., Hillman S., Glen I.A.M. Fatty acid levels in brains of schizophrenics and normal controls. Biol Psychiatry 1991, 30:795-805.
32. Howes O.D., Kapur S. The dopamine hypothesis of schizophrenia: version III-The final common pathway. Schizophr Bull 2009, 35:549-562.
33. Huang Y.S., Horrobin D.F. Sex differences in n-3 and n-6 fatty acid metabolism in EFA-depleted rats. Proc Soc Exp Biol Med (NY) 1987, 185:291-296.
34. John J.P., Shakeel M.K., Jain S. Corpus callosal area differences and gender dimorphism in neuroleptic-naïve, recent-onset schizophrenia and healthy control subjects. Schizophr Res 2008, 103(1-3):11-21.
35. Kale A., Naphade N., Sapkale S., Kamaraju M., Pillai A., Joshi S., et al. Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism. Psychiatry Res 2010, 175:47-53.
36. Kang J.X., Wang J. A simplified method for analysis of polyunsatured fatty acids. BMC Biochem 2005, 1-4.
37. Kay S.R., Opler L.A., Fiszbein A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987, 13:261-276.
38. Keller J., Hanni K., Markesbery W. 4-hydroxynonenal increases neuronal susceptibility to oxidative stress. J Neurosci Res 1999, 58:823-830.
39. Keshavan M.S., Stanley J.A., Pettegrew J.W. Magnetic resonance spectroscopy in schizophrenia methodological issues and findings-Part II. Biol Psychiatry 2000, 48:369-380.
40. Khan M.M., Evans D.R., Gunna V., Scheffer R.E., Parikh V.V., Mahadik S.P. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 2002, 58(1):1-10. [1].
41. Kita T., Miyazaki I., Asanuma M., Takeshima M., Wagner G.C. Dopamine-induced behavioral changes and oxidative stress in methamphetamine-induced neurotoxicity. Int Rev Neurobiol 2009, 88:43-64.
42. Krejsa C.M., Schieven G.L. Impact of oxidative stress on signal transduction control by phosphotyrosine phosphatases. Environ Health Perspect 1998, 106(5):1179-1184.
43. Kropp S., Kern V., Lange K., Degner D., Hajak G., Kornhuber J., et al. Oxidative stress during treatment with first- and second-generation antipsychotics. J Neuropsychiatry Clin Neurosci 2005, 17(2):227-231.
44. Lewine R.R., Gulley L.R., Risch S.C., Jewart R., Houpt J.L. Sexual dimorphism, brain morphology, and schizophrenia. Schizophr Bull 1990, 16:195-203.
45. Li H.C., Chen Q.Z., Ma Y., Zhou J.F. Imbalanced free radicals and antioxidant defense systems in schizophrenia: a comparative study. J Zhejiang Univ Sci B 2006, 7(12):981-986.
46. Longenecker J., Dickinson D., Weinberger D.R., Elvevåg B. Cognitive differences between men and women: a comparison of patients with schizophrenia and healthy volunteers. Schizophr Res 2010, 120(1-3):234-235.
47. Mahadik S.P., Mukherjee S. Free radical pathology and antioxidant defense in schizophrenia: a review. Schizophr Res 1996, 19:1-18.
48. Mahadik S., Mukherjee S., Scheffer R., Corrente E., Mahadik J. Elevated plasma lipid peroxides at the onset of nonaffective psychosis. Biol Psychiatry 1998, 43:674-679.
49. Malaspina D., Keller A., Antonius D., Messinger J.W., Goetz D.M., Harkavy-Friedman J., et al. Olfaction and cognition in schizophrenia: sex matters. Neuropsychiatry Clin Neurosci 2012, 24(2):165-175.
50. Mazza M., Pomponi M., Janiri L., Bria P., Mazza S. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31(1):12-26. [30].
51. McGlashan T.H., Bardenstein K.K. Gender differences in affective, schizoaffective, and schizophrenic disorders. Schizophr Bull 1990, 16:319-329.
52. McNamara R.K., Jandacek R., Rider T., Tso P., Hahn C.G., Richtand N.M., et al. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications. Schizophr Res 2007, 91:37-50.
53. Medina-Hernández V., Ramos-Loyo J., Luquín S., Cerdán-Sánchez L.F., García-Estrada J., Navarro-Ruiz A. Increased lipid peroxidation and neuron specific enolase in treatment refractory schizophrenics. J Psychiatr Res 2007, 41:652-658.
54. Meesters P.D., de Haan L., Comijs H.C., Stek M.L., Smeets-Janssen M.M., Weeda M.R., et al. Schizophrenia spectrum disorders in later life: prevalence and distribution of age at onset and sex in a dutch catchment area. Am J Geriatr Psychiatry 2012, 20(1):18-28.
55. Micó J.A., Rojas-Corrales M.O., Gibert-Rahola J., Parellada M., Moreno D., Fraguas D., et al. Reduced antioxidant defense in early onset first-episode psychosis: a case-control study. BMC Psychiatry 2011, 14:11-26.
56. Othmen L.B., Mechri A., Fendri Ch., Bost M., Chazot G., Gaha L., et al. Altered antioxidant defenses system in clinically stable patients with schizophrenia and their unaffected sibilings. Prog Neuropsychopharmacol Biol Psychiatry 2008, 32:155-159.
57. Overrall J.E., Gorham D.R. The brief psychiatric rating scale. Psych Rep 1962, 10:799-812.
58. Oxford Biomedical Research Colorimetric assay for lipid peroxidation product No. FR 12 2003, 1-7.
59. Ozaydin A., Onaran I., Avsar K., Tezcan V., Sultuybek G. Relationship between aging and susceptibility to oxidative damage: an assessment by erythrocyte membrane proteins and lipids. Turk J Med Sci 2001, 31:95-101.
60. Padurariu M., Ciobica A., Dobrin I., Stefanescu C. Evaluation of antioxidant enzymes activities and lipid peroxidation in schizophrenic patients treated with typical and atypical antipsychotics. Neurosci Lett 2010, 479(3):317-320.
61. Pall H., Williams A., Blake D., Lunee J. Evidence of enhanced lipid peroxidation in the cerebrospinal fluid patients taking phenothiazines. Lancet 1987, 12:596-599.
62. Pavlović D., Tamburić V., Stojanović I., Kocić G., Jevtović T., D{stroke}ord{stroke}ević V. Oxidative stress as marker of positive symptoms in schizophrenia. Facta Universitatis 2002, 9(2):157-161.
63. Pawlosky R.J., Salem N. Alcohol consumption in rhesus monkeys depletes tissues of polyunsaturated fatty acids and alters essential fatty acid metabolism. Alcohol Clin Exp Res 1999, 23:311-317.
64. Pazvantoglu O., Selek S., Okay I.T., Sengul C., Karabekiroglu K., Dilbaz N., et al. Oxidative mechanisms in schizophrenia and their relationship with illness subtype and symptom profile. Psychiatry Clin Neurosci 2009, 63(5):693-700.
65. Pedrini M., Massuda R., Fries G.R., de Bittencourt Pasquali M.A., Schnorr C.E., Moreira J.C., et al. Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity. J Psychiatr Res 2012, 46(6):819-824.
66. Peet M., Laugharne J., Rangarajan N., Horrobin D., Reynolds G. Depleted red cell membrane essential fatty acids in drug treated schizophrenic patients. J Psychiatr Res 1995, 29(3):227-232.
67. Peet M., Brind J., Ramchand C.N., Shah S., Vankar G.K. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001, 49(3):243-251.
68. Pettegrew J.W., Keshavan M.S., Panchaligan K. Alterations in brain high energy phosphate and membrane phospholipid metabolism in first episode, drug naïve schizophrenics. Arch Gen Psychiatry 1991, 48:563-568.
69. Rafalowska U., Liu G.J., Floyd R.A. Peroxidation induced changes in synaptosomal transport of dopamine and y-aminobutyric acid. Free Radic Biol Med 1989, 6:485-492.
70. Raffa M., Mechri A., Othman L.B., Fendri C., Gaha L., Kerkeni A. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33:1178-1183.
71. Raffa M., Barhoumi S., Atig F., Fendri C., Kerkeni A., Mechri A. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuropsychopharmacol Biol Psychiatry 2012, 39(2):371-375. [3].
72. Ramos-Loyo J., Mora L., Sánchez L., Medina V. Sex differences in facial, prosodic and social context emotional recognition in early onset schizophrenia. Schizophr Res Treat 2012, [Special Issue: Psychosis and Gender, ID 584725]. 10.1155/2012/584725.
73. Ranjekar P.K., Hinge A., Hegde M.V., Ghate M., Kale A., Sitasawad S., et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res 2003, 121:109-122.
74. Rao M.L., Kölsch H. Effects of estrogen on brain development and neuroprotection-implications for negative symptoms in schizophrenia. Psychoneuroendocrinology 2003, 28:83-96.
75. Reddy R., Yao J.K. Free radical pathology in schizophrenia: a review. Prostaglandins Leukot Essent Fatty Acids 1996, 55(1-2):33-43.
76. Reddy R., Keshavan M., Yao J.K. Reduced plasma antioxidants in first episode patients with schizophrenia. Schizophr Res 2003, 62:205-212.
77. Robinson J.G., Ijioma N., Harris W. Omega-3 fatty acids and cognitive function in women. Womens Health (Lond Engl) 2010, 6(1):119-134.
78. Roşoiu R.D., Verman I.G., Bandrabur D., Basa M., Roşoiu N. Antioxidant status and other biochemical parameters in schizoprenia. J Neural Transm 2007, 114:1121-1128.
79. Ross B.M., Turenne S., Mosezynska A. Differential alteration of phospholipase A2 activities in brains of patients with schizophrenia. Brain Res 1999, 821:407-413.
80. Ruiz-Litago F., Seco J., Echevarría E., Martínez-Cengotitabengoa M., Gil J., Irazusta J., González-Pinto A.M. Adaptive response in the antioxidant defense system in the course and outcome in first-episode schizophrenia patients: A 12-months follow-up study. Psychiatry Res 2012, 200(2-3):218-222.
81. Sánchez R., Téllez G., Jaramillo L.E. Age of onset symptoms and gender in schizophrenic spectrum disorders. Biomedica 2012, 32(2):206-213.
82. Sarandol A., Kirli S., Akkaya C., Altin A., Demirci M., Sarandol E. Oxidative-antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: effects of short term antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31(6):1164-1169. [15].
83. Sartori-Valinotti J.C., Iliescu R., Fortepiani L.A., Yanes L.L., Reckelhoff J.F. Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease. Clin Exp Pharmacol Physiol 2007, 34:938-945.
84. Seidman L.J., Goldstein J.M., Goodman D., Koren W.M., Turner S.V., Faraone M., et al. Sex differences in olfactory identification and Wisconsin Card Sorting performance in schizophrenia: relationship to attention and verbal ability. Biol Psychiatry 1997, 42:104-115.
85. Simonian N.A., Coyle J.T. Oxidative stress in neurodegenerative diseases. Pharmacol Toxicol 1996, 36:82-106.
86. Skosnik P.D., Yao J.K. From membrane phospholipid defects to altered neurotransmission: is arachidonic acid a nexus in the pathophysiology of schizophrenia?. Prostaglandins Leukot Essent Fatty Acids 2003, 69:367-384.
87. Soldin O.P., Mattison D.R. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009, 48:143-157.
88. Song C., Zhao S. Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations. Expert Opin Investig Drugs 2007, 16(10):1627-1638.
89. Sparkes R.S., Zollman S., Klisak I. Human genes involved in lipolysis of plasma lipoproteins: mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15q21. Genomics 1987, 1:138-143.
90. Thara R., Eaton W.W. Outcome of schizophrenia: the Madras longitudinal study. Aust N Z J Psychiatry 1996, 30:516-522.
91. Torniainen M., Suvisaari J., Partonen T., Castaneda S.E., Kuha A., Perälä J., et al. Sex differences in cognition among persons with schizophrenia and healthy first-degree relatives. Psychiatry Res 2011, 188:7-12.
92. Ustundag B., Atmaca M., Kirtas O., Selek S., Metin K., Tezcan E. Total antioxidant response in patients with schizophrenia. Psychiatry Clin Neurosci 2006, 60(4):458-464.
93. van der Kemp W.J., Klomp D.W., Kahn R.S., Luijten P.R., Hulshoff Pol H.E. A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia. Schizophr Res 2012, 141(2-3):153-161.
94. Virit O., Altindag A., Yumru M., Dalkilic A., Savas H.A., Selek S., et al. A defect in the antioxidant defense system in schizophrenia. Neuropsychobiology 2009, 60(2):87-93.
95. Wei Z., Bai O., Richardson J.S., Mousseau D.D., Li X.M. Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide. J Neurosci Res 2003, 73(3):364-368. [1].
96. Wu Z., Zhang X.Y., Wang H., Tang W., Xia Y., Zhang F., et al. Elevated plasma superoxide dismutase in first-episode and drug naive patients with schizophrenia: inverse association with positive symptoms. Prog Neuropsychopharmacol Biol Psychiatry 2012, 36(1):34-38. [10].
97. 31P-spectroscopy of frontal lobe in schizophrenia: alterations in phospolipid and high-energy phosphate metabolism. Schizophr Res 2002, 58:117-122.
98. Yao J.K., Reddy R.D., Van Kammen D.P. Reduced level of plasma antioxidant uric acid. Psychiatry Res 1998, 80:29-30.
99. Yao J.K., Reddy R., Van Kammen D.P. Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatry Res 2000, 97:137-151.
100. Yao J., Stanley J.A., Reddy R.D., Keshavan M.S., Pettegrew W. Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 2002, 52:823-830.
101. Zhang X.Y., Tan Y.L., Cao L.Y., Wu G.Y., Xu Q., Shen Y., et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res 2006, 81:291-300.
102. Zhang M., Zhao Z., He L., Wan Ch. A meta-analysis of oxidative stress markers in schizophrenia. Sci China Life Sci 2010, 53(1):112-124.
103. Zhang X.Y., Chen da C., Xiu M.H., Tang W., Zhang F., Liu L., et al. Plasma total antioxidant status and cognitive impairments in schizophrenia. Schizophr Res 2012, 139(1-3):66-72.