Advertisement

Sleep and Breathing

, Volume 17, Issue 3, pp 905–910 | Cite as

Oxidative stress, cancer, and sleep deprivation: is there a logical link in this association?

  • Juliana Noguti
  • Monica Levy Andersen
  • Chiara Cirelli
  • Daniel Araki RibeiroEmail author
Review

Abstract

Introduction

Sleep disorders are associated with various human pathologies and interfere with biological processes essential for health and quality of life. On the other hand, cancer is one of the most common diseases worldwide with an average of 1,500 deaths per day in the USA. Is there a factor common to both sleep disorders and cancer that serves to link these conditions?

Discussion

It is a normal process for cellular metabolism to produce reactive oxidant series (ROS). However, when the production of ROS overcomes the antioxidant capacity of the cell to eliminate these products, the resulting state is called oxidative stress. Oxidative DNA damage may participate in ROS-induced carcinogenesis. Moreover, ROS are also produced in the sleep deprivation process. The aim of this article is to review pathways and mechanisms that may point to oxidative stress as a link between sleep deprivation and cancer.

Keywords

Sleep deprivation Cancer Oxidative stress 

Notes

Conflict of interest

None.

References

  1. 1.
    Andersen M, Bignotto M, Machado R, Tufik S (2002) Does paradoxical sleep deprivation and cocaine induce penile erection and ejaculation in old rats? Addict Biol 7:285–290PubMedCrossRefGoogle Scholar
  2. 2.
    Andersen M, Bignotto M, Tufik S (2003) Cocaine-induced genital reflexes during paradoxical sleep deprivation and recovery. Physiol Behav 78:255–259PubMedCrossRefGoogle Scholar
  3. 3.
    Blask D, Dauchy R, Sauer L (2005) Putting cancer to sleep at night—the neuroendocrine/ circadian melatonin signal. Endocrine 27:179–188PubMedCrossRefGoogle Scholar
  4. 4.
    Drummond S, Brown G (2001) The effects of total sleep deprivation on cerebral responses to cognitive performance. Neuropsychopharmacology 25:S68–S73PubMedCrossRefGoogle Scholar
  5. 5.
    Gunzman-Marin R, Suntsova N, Methippara M (2005) Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Nuerosci 22:2111–2116CrossRefGoogle Scholar
  6. 6.
    Leibowitz S, Lopes M, Andersen M, Kushida C (2006) Sleep deprivation and sleepiness caused by sleep loss. Sleep Med Clin 1:31–45CrossRefGoogle Scholar
  7. 7.
    Cirelli C, Tononi G (2008) Is sleep essential? PLoS Biol 6:e216PubMedCrossRefGoogle Scholar
  8. 8.
    Sejnowski T, Destexhe A (2000) Why do we sleep? Brain Res 886:208–223PubMedCrossRefGoogle Scholar
  9. 9.
    Pace-Schott E, Hobson J (2002) The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nature 3:591–605Google Scholar
  10. 10.
    Banks S, Dinges D (2007) Behavioral and physiological consequences of sleep restriction. J CLin Sleep Med 3:519–28PubMedGoogle Scholar
  11. 11.
    Andersen M, Bignotto M, Tufik S (2003) The effect of apomorphine on genital reflexes in male rats deprived of paradoxical sleep. Physiol Behav 80:211–215PubMedCrossRefGoogle Scholar
  12. 12.
    Biswas S, Mishra P, Mallick N (2006) Increased apoptosis in rat brain after rapid eye movement sleep loss. Neuroscience 142:315–331PubMedCrossRefGoogle Scholar
  13. 13.
    Graves L, Heller E, Pack A, Abel T (2003) Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn Mem 10:168–176PubMedCrossRefGoogle Scholar
  14. 14.
    Killgore W, Balking T, Wesensten N (2006) Impaired decision making following 49 hours of sleep deprivation. J Sleep Res 15:7–13PubMedCrossRefGoogle Scholar
  15. 15.
    Dinges DF, Pack F, Williams K, Gillen KA, Powell JW, Ott GE, Aptowicz C, Pack AI (1997) Cumulative sleepiness, mood disturbance and psychomotor vigilance performance decrements during sleep restricted to 4–5 hours per night. Sleep 20:267–277PubMedGoogle Scholar
  16. 16.
    Sateia M (2003) Neuropsychological impairment and quality of life in obstructive sleep apnea. Clin Chest Med 24:249–259PubMedCrossRefGoogle Scholar
  17. 17.
    Shamsuzzaman A, Gersh B, Somers V (2003) Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 290:1906–1914PubMedCrossRefGoogle Scholar
  18. 18.
    Masa J, Rubio M, Findley L (2000) Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep. Am J Respir Crit Care Med 162:1407–1412PubMedCrossRefGoogle Scholar
  19. 19.
    Ingre M, Akerstedt T, Peters B, Anund A, Kecklund G, Pickles A (2006) Subjective sleepiness and accident risk avoiding the ecological fallacy. J Sleep Res 15:142–148PubMedCrossRefGoogle Scholar
  20. 20.
    Connor J, Norton R, Ameratunga S, Robinson E, Civil I, Dunn R, Bailey J, Jackson R (2002) Driver sleepiness and risk of serious injury to car occupants: population based case control study. BMJ 324:1125PubMedCrossRefGoogle Scholar
  21. 21.
    Buscemi D, Kumar A, Nugent R, Nugent K (2007) Short sleep times predict obesity in internal medicine clinic patients. J Clin Sleep Med 3:681–688PubMedGoogle Scholar
  22. 22.
    Irwin M, Mascovich A, Gillin J, Willoughby R, Pike J, Smith T (1994) Partial sleep deprivation reduces natural killer cell activity in humans. Psychom Med 56:493–498Google Scholar
  23. 23.
    Irwin M, McClintick K, Costlow C, Fortner M, White J, Gillin C (1996) Partial night sleep deprivation reduces natural killer and cellular immune response in humans. FASEB J 10:643–653PubMedGoogle Scholar
  24. 24.
    Benca R, Quintas J (1997) Sleep and host defenses: a review. Sleep 20:1027–1037PubMedGoogle Scholar
  25. 25.
    Dinges D, Douglas S, Hamarman S, Zaugg L, Kapoor S (1995) Sleep deprivation and human immune function. Adv Neuroimmunol 5:97–110PubMedCrossRefGoogle Scholar
  26. 26.
    Guariniello L, Vicari P, Lee K, Ad O, Tufik S (2012) Bone marrow and peripheral white blood cells number is affected by sleep deprivation in a murine experimental model. J Cell Physiol 227:361–366PubMedCrossRefGoogle Scholar
  27. 27.
    Wright C, Erblich J, Valdimarsdottir H, Bovbjerg D (2007) Poor sleep the night before an experimental stressor predicts reduced NK cell mobilization and slowed recovery in healthy women. Brain Behav Immun 21:358–363PubMedCrossRefGoogle Scholar
  28. 28.
    Bryant P, Trinder J, Curtis N (2004) Sick and tired: does sleep have a vital role in the immune system? Nat Rev Immunol 4:457–467PubMedCrossRefGoogle Scholar
  29. 29.
    Jemal DA, Siegel R, Xu J, Ward E (2010) Cancer statistics. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  30. 30.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics. CA Cancer J Clin 59:225–249PubMedCrossRefGoogle Scholar
  31. 31.
    Smith R, Cokkinides V, Brooks D, Saslow D, Brawley O (2010) Cancer screening in the United States, 2010: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 60:99–119PubMedCrossRefGoogle Scholar
  32. 32.
    Majumdar S, Buckles E, Estrada J, Koochekpour S (2011) Aberrant DNA methylation and prostate cancer. Curr Genom 12:486–505CrossRefGoogle Scholar
  33. 33.
    Parkin D, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics. CA Cancer J Clin 55:74–108Google Scholar
  34. 34.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M (2007) Cancer statistics. CA Cancer J Clin 57:43–66PubMedCrossRefGoogle Scholar
  35. 35.
    Sies H (1991) Oxidative stress: introduction. In: Sies H (ed) In Oxidants and antioxidants. Academic, San Diego, pp 15–22Google Scholar
  36. 36.
    Valko M, Izakovic M, Mazur M, Rhodes C, Telser J (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56PubMedCrossRefGoogle Scholar
  37. 37.
    D'Almeida V, Hippolide D, Azzalis A, Lobo L, Junqueira V, Tufik S (1997) Absence of oxidative stress following paradoxical sleep deprivation in rats. Neurosci Lett 235:25–28PubMedCrossRefGoogle Scholar
  38. 38.
    Halliwell B, Gutteridge JMC (1989) Free radicals in biology and medicine, 2nd edn. Oxford, Clarendon PressGoogle Scholar
  39. 39.
    Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664PubMedCrossRefGoogle Scholar
  40. 40.
    Halliwell B and Gutteridge J (1989) Free radicals in Biology and Medicine.(Editor (eds.). ClaredonGoogle Scholar
  41. 41.
    Breimer L (1990) Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: the role of DNA base damage. Mol Carcinog 3:188–197PubMedCrossRefGoogle Scholar
  42. 42.
    Reimund E (1994) The free radical theory of sleep. Med Hypotheses 43:231–233PubMedCrossRefGoogle Scholar
  43. 43.
    Hipólide D, D'Almeida V, Raymond R, Tufik S, Nobrega J (2002) Sleep deprivation does not affect indices of necrosis or apoptosis in rat brain. Int J Neurosci 112:155–166PubMedCrossRefGoogle Scholar
  44. 44.
    D'Almeida V, Lobo L, deliveira A, Nobrega J, Tukik S (1998) Sleep deprivation induces brain region-specific decrease in glutathione levels. Neuroreport 9:2853–2856PubMedCrossRefGoogle Scholar
  45. 45.
    Ikeda M, Ikeda-Sagara M, Okada T, Clement P, Urade Y, Nagai T, Sugiyama T, Yoshioka T, Honda K, Inoué S (2005) Brain oxidation is an initial process in sleep induction. Neuroscience 130:1029–1040PubMedCrossRefGoogle Scholar
  46. 46.
    Horne J (1978) A review of the biological effects of total sleep deprivation in man. Biol Psychol 7:55–102PubMedCrossRefGoogle Scholar
  47. 47.
    Honda K, Kamoda Y, Inoue S (1994) Oxidized glutathione regulates physiological sleep in unrestrained rats. Brain Res 636:253–258PubMedCrossRefGoogle Scholar
  48. 48.
    Blask D, Dauchy R, Sauer L, Krause J (2004) Melatonin uptake and growth prevention in rat hepatoma 7288 CTC in response to dietary melatonin: melatonin receptor-mediated inhibition of tumor linoleic acid metabolism to the growth signaling molecule 13-hydroxydecadienoic acid and the potential role of phytomelatonin. Carcinogenesis 25:951–960PubMedCrossRefGoogle Scholar
  49. 49.
    Blask D, Sauer L, Dauchy R (2002) Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2:113–132PubMedCrossRefGoogle Scholar
  50. 50.
    Almendros I, Montserrat JM, Ramírez J, Torres M, Duran-Cantolla J, Navajas D, Farré R (2012) Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea. Eur Respir J 39:215–217PubMedCrossRefGoogle Scholar
  51. 51.
    Kovacic P, Jacintho J (2001) Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr Med Chem 8:773–796PubMedCrossRefGoogle Scholar
  52. 52.
    Ridnour L, Isenberg J, Espey M, Thomas D, Roberts DD, Wink D (2005) Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc Natl Acad Sci USA 102:13147–13152PubMedCrossRefGoogle Scholar
  53. 53.
    Valko M, Morris H, Mazur M, Rapta P, Bilton R (2001) Oxygen free radical generating mechanisms in the colon: do the semiquinones of Vitamin K play a role in the aetiology of colon cancer? Biochim Biophys Acta 1527:161–166PubMedCrossRefGoogle Scholar
  54. 54.
    Durackova Z (2010) Some current insights into oxidative stress. Physiol Res 59:459–469PubMedGoogle Scholar
  55. 55.
    Nakamura H, Nakamura K, Yodoi J (1997) Redox regulation of cellular activation. Annu Rev Immunol 15:351–369PubMedCrossRefGoogle Scholar
  56. 56.
    Gorbunov N, Elsayed N, Kisin E, Kozlov A, Kagan V (1997) Air blast-induced pulmonary oxidative stress: interplay among hemoglobin, antioxidants, and lipid peroxidation. Am J Physiol 272:L320–334PubMedGoogle Scholar
  57. 57.
    Nakamura K, Hori T, Yodoi J (1996) Alternative binding of p56 and phosphatidylinositol 3-kinase in T cells by sulfhydryl oxidation: implication of aberrant signaling due to oxidative stress in T lymphocytes. Mol Immunol 33:855–865PubMedCrossRefGoogle Scholar
  58. 58.
    Victor V, Rocha M, Fuente MD (2004) Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol 4:327–347PubMedCrossRefGoogle Scholar
  59. 59.
    Fuente MD, Hernanz A, Vallejo M (2005) The immune system in the oxidative stress conditions of aging and hypertension: favorable effects of antioxidants and physical exercise. Antioxid Redox Signal 9–10:1356–1366CrossRefGoogle Scholar
  60. 60.
    Carr A, McCall M, Frei B (2000) Oxidation of LDL by myeloperoxidase and reactive nitrogen species-reaction pathways and antioxidant protection. Arterioscl Thromb Vasc Biol 20:1716–1723PubMedCrossRefGoogle Scholar
  61. 61.
    Kumar B, Koul S, Khandrika L, Meacham R, Koul H (2008) Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 68:1777–1785PubMedCrossRefGoogle Scholar
  62. 62.
    Fang J, Seki T, Maeda H (2009) Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev 61:290–302PubMedCrossRefGoogle Scholar
  63. 63.
    Schulte-Herman R, Timmermann-Trosiener I, Barthel G, Bursch W (1990) DNA synthesis, apoptosis and phenotypic expression as determinants of growth of altered foci in rat liver durinhg phenobarbital promotion. Cancer Res 50:5127–5135Google Scholar
  64. 64.
    Klaunig JE, Xu Y, Isenberg JS, Bachowski S, Kolaja KL, Jiang J, Stevenson DE, Walborg EF Jr (1998) The role of oxidative stress in chemical carcinogenesis. Environ Health Perspect 106:289–295PubMedGoogle Scholar
  65. 65.
    Ames B, Gold L (1992) Animal cancer tests and cancer prevention. J Natl Cancer Inst 12:125–132Google Scholar
  66. 66.
    Arai T, Kelly V, Minowa O, Noda T, Nishimura S (2002) High accumulation of oxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice by chronic oxidative stress. Carcinogenesis 12:2005–2010CrossRefGoogle Scholar
  67. 67.
    Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, Seeberg E, Lindahl T, Barnes DE (1999) Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 96:13300–13305PubMedCrossRefGoogle Scholar
  68. 68.
    Numonura A, Moreira P, Takeda A, Smith M, Perry G (2007) Oxidative RNA damage and neurodegeneration. Curr Med Chem 14:2968–2975CrossRefGoogle Scholar
  69. 69.
    Gandhi S, Abramov A (2012) Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev 2012:428010PubMedCrossRefGoogle Scholar
  70. 70.
    Casetta I, Govoni V, Granieri E (2005) Oxidative stress, antioxidants and neurodegenerative diseases. Curr Pharm Des 11:2033–2052PubMedCrossRefGoogle Scholar
  71. 71.
    Behl C, Moosmann B (2002) Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds. Biol Chem 383:521–536PubMedCrossRefGoogle Scholar
  72. 72.
    Gopalakrishnan A, Ji L, Cirelli C (2004) Sleep deprivation and cellular responses to oxidative stress. Sleep 27:27–35PubMedGoogle Scholar
  73. 73.
    Cirelli C (2006) Cellular consequences of sleep deprivation in the brain. Sleep Med Rev 10:307–321PubMedCrossRefGoogle Scholar
  74. 74.
    Cirelli C (2006) Sleep disruption, oxidative stress, and aging: new insights from fruit flies. Proc Natl Acad Sci U S A 103:13901–13902PubMedCrossRefGoogle Scholar
  75. 75.
    Singh R, Kiloung J, Singh S, Sharma D (2007) Effect of paradoxical sleep deprivation on oxidative stress parameters in brain regions of adult and old rats. Bioderontology 9:153–162CrossRefGoogle Scholar
  76. 76.
    Spiegel K, Leprout R, Cauter EV (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354:1435–1439PubMedCrossRefGoogle Scholar
  77. 77.
    Prinz P (2004) Age impairments in sleep, metabolic and immune functions. Exp Gerontol 39:1739–1743PubMedCrossRefGoogle Scholar
  78. 78.
    Andersen M, Martins P, D'Almeida V, Santos R, Bignotto M, Tufik S (2004) Effects of paradoxical sleep deprivation on blood parameters associated with cardiovascular risk in aged rats. Exp Gerontol 39:817–824PubMedCrossRefGoogle Scholar
  79. 79.
    Omoi N, Arai M, Saito M, Takatsu H, Shibata A, Fukuzawa K (2006) Influence of oxidative stress on fusion of pre-synaptic plasma membranes of the rat brain with phosphatidylcholine liposomes and protective effect of vitamin E. J Nutr Sci Vitaminol 52:248–255PubMedCrossRefGoogle Scholar
  80. 80.
    Petursdottir A, Farr S, Morley J, Banks W, Skuladottir G (2006) Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM). Neurobiol Aging 28:1170–1178PubMedCrossRefGoogle Scholar
  81. 81.
    Tsuda T, Yoshimura H, Hamasaki N (2006) Effect of phosphatidylcholine, phosphatidylethanolamine and lysophosphatidylcholine on the activated factor X-prothrombin system. Blood Coagul Fibrinolysis 17:465–469PubMedCrossRefGoogle Scholar
  82. 82.
    Hicks D (2011) Obstructive sleep apnoea: its link with diabetes. Nurs Times 107:31–32PubMedGoogle Scholar
  83. 83.
    Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi H (2009) Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 122:1122–1127PubMedCrossRefGoogle Scholar
  84. 84.
    Bardwell W, Ancoli-Israel S, Berry C, Dimsdale J (2001) Neuropsychological effects for one-week continuous positive airway pressure treatment in patients with obstructive sleep apnea: a placebo-controlled study. Psychol Med 63:579–584Google Scholar
  85. 85.
    Fogel R, Malhotra A, White D (2004) Sleep 2 Pathophysiology of obstructive sleep apnea/hypopnea syndrome. Thorax 59:159–163PubMedCrossRefGoogle Scholar
  86. 86.
    Young T, Peppard P, Gottlieb D (2002) Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 165:1217–1239PubMedCrossRefGoogle Scholar
  87. 87.
    Lavie L (2003) Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev 7:35–51PubMedCrossRefGoogle Scholar
  88. 88.
    Bradley T, Floras J (2009) Obstructive sleep apnoea and its cardiovascular consequences. Lancet 373:82–93PubMedCrossRefGoogle Scholar
  89. 89.
    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1a in hypoxiamediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRefGoogle Scholar
  90. 90.
    Knowles H, Harris A (2001) Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis. Breast Cancer Res 3:318–322PubMedCrossRefGoogle Scholar
  91. 91.
    Pugh C, Gleadle J, Maxwell P (2001) Hypoxia and oxidative stress in breast cancer. Hypoxia signalling pathways. Breast Cancer Res 3:313–7Google Scholar
  92. 92.
    Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R (2012) Sleep-disordered breathing and cancer mortality results from the Wisconsin Sleep Cohort Study. Am J Resp Crit C Med 186:190–194CrossRefGoogle Scholar
  93. 93.
    Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ (2009) Genome-wide association of hypoxia-inducible factor (HIF)-1a and HIF-2a DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284:16767–16775PubMedCrossRefGoogle Scholar
  94. 94.
    Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumours: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  95. 95.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedCrossRefGoogle Scholar
  96. 96.
    Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395PubMedCrossRefGoogle Scholar
  97. 97.
    Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS (2000) Hypoxia-inducible factor-1α is a positive factor in solid tumour growth. Cancer Res 60:4010–4015PubMedGoogle Scholar
  98. 98.
    Franco CM, Lima AM, Ataíde L Jr, Lins OG, Castro CM, Bezerra AA, de Oliveira MF, Oliveira JR (2012) Obstructive sleep apnea severity correlates with cellular and plasma oxidative stress parameters and affective symptoms. J Mol Neurosci 47:300–310PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Juliana Noguti
    • 1
  • Monica Levy Andersen
    • 2
  • Chiara Cirelli
    • 3
  • Daniel Araki Ribeiro
    • 1
    • 4
    Email author
  1. 1.Department of PathologyFederal University of São Paulo–UNIFESPSao PauloBrazil
  2. 2.Department of PsychobiologyFederal University of São Paulo–UNIFESPSao PauloBrazil
  3. 3.Department of PsychiatryUniversity of WisconsinMadisonUSA
  4. 4.Department of BiosciencesFederal University of São Paulo–UNIFESPSantosBrazil

Personalised recommendations