Iberoamerican Journal of Medicine
http://www.iberoamericanjm.periodikos.com.br/article/doi/10.5281/zenodo.4271553
Iberoamerican Journal of Medicine
Review

An Overview of the Physiological and Pathological Role of Mast Cells in the Central Nervous System

Serghei Covantev

Downloads: 1
Views: 928

Abstract

Neurological disorders present a major group of diseases with the global prevalence of 6.3%. They are responsible for 12% global mortality. Mast cells are one of the most abundantly present cell of the immune system in the connective tissue and the central nervous system is not an exception. In this article is presented a review of studies on mast cells regarding their physiological role in cental nervous system. We also disscuss their role in several conditions like: multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, neuropsychiatric disorders, cerebrovascular disorders and central nervous system trauma, epilepsy, seizures and tumors. Finally, we evaluate whether they can be used as a targed for pharmaceutical treatment.

Keywords

Central nervous system; Neuroimmunology; Mast cells; Histamine

References

1. Kandle ER. The Brain/Immune Connection: Progress Report on Brain Research.. New York: The Dana Aliance for Brain Initiatives; 2004.
2. World Health Organization (WHO). Neurological Disorders: Public health challenges. Geneva: WHO Press; 2006.
3. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B; CDBE2010 study group; European Brain Council. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19(1):155-62. doi: 10.1111/j.1468-1331.2011.03590.x.
4. GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-97. doi: 10.1016/S1474-4422(17)30299-5.
5. Neuman J. Ueber das Vorkommen der sogneannten “Mastzellen” bei pathologischen Veraenderungen des Gehirns. Arch Pathol Anat Physiol Virchows. 1890;122:378-81.
6. Olsson Y. Mast cells in plaques of multiple sclerosis. Acta Neurol Scand. 1974;50(5):611-8. doi: 10.1111/j.1600-0404.1974.tb02806.x.
7. Shan L, Bao AM, Swaab DF. The human histaminergic system in neuropsychiatric disorders. Trends Neurosci. 2015;38(3):167-77. doi: 10.1016/j.tins.2014.12.008.
8. Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci. 2003;4(2):121-30. doi: 10.1038/nrn1034.
9. Brady S, Siegel G, Albers RW, Price D. Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology 8th ed. Academic Press; 2011.
10. Riedel G, Platt B. From Messengers to Molecules: Memories are Made of These. Springer Science & Business Media; 2004.
11. Giannoni P, Passani MB, Nosi D, Chazot PL, Shenton FC, Medhurst AD, et al. Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat. Eur J Neurosci. 2009;29(12):2363-74. doi: 10.1111/j.1460-9568.2009.06765.x.
12. Shahid M, Tripathi T, Sobia F, Moin S, Siddiqui M, Khan RA. Histamine, Histamine Receptors, and their Role in Immunomodulation: An Updated Systematic Review. Open Immunol J. 2009;2:9-41. doi: 10.2174/1874226200902010009.
13. Mazurkiewicz-Kwilecki IM, Nsonwah S. Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients. Can J Physiol Pharmacol. 1989;67(1):75-8. doi: 10.1139/y89-013.
14. Costanza M, Colombo MP, Pedotti R. Mast cells in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. Int J Mol Sci. 2012 16;13(11):15107-25. doi: 10.3390/ijms131115107.
15. Khalil M, Ronda J, Weintraub M, Jain K, Silver R, Silverman AJ. Brain mast cell relationship to neurovasculature during development. Brain Res. 2007 26;1171:18-29. doi: 10.1016/j.brainres.2007.07.034.
16. Michaloudi H, Batzios C, Chiotelli M, Papadopoulos GC. Developmental changes of mast cell populations in the cerebral meninges of the rat. J Anat. 2007;211(4):556-66. doi: 10.1111/j.1469-7580.2007.00795.x.
17. Hendrix S, Warnke K, Siebenhaar F, Peters EM, Nitsch R, Maurer M. The majority of brain mast cells in B10.PL mice is present in the hippocampal formation. Neurosci Lett. 2006;392(3):174-7. doi: 10.1016/j.neulet.2005.09.029.
18. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-241. doi: 10.1152/physrev.00043.2007.
19. Zhuang X, Silverman AJ, Silver R. Brain mast cell degranulation regulates blood-brain barrier. J Neurobiol. 1996;31(4):393-403. doi: 10.1002/(SICI)1097-4695(199612)31:4<393::AID-NEU1>3.0.CO;2-4.
20. Matsumoto I, Inoue Y, Shimada T, Aikawa T. Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs. J Exp Med. 2001;194(1):71-8. doi: 10.1084/jem.194.1.71.
21. Matsumoto I, Inoue Y, Shimada T, Matsunaga T, Aikawa T. Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs. Am J Physiol Regul Integr Comp Physiol. 2008;294(3):R689-98. doi: 10.1152/ajpregu.00453.2007.
22. Bianco AC, Nunes MT, Douglas CR. Influence of mast cells on thyroid function. Endocrinol Exp. 1983;17(2):99-106.
23. Khalil MH, Silverman AJ, Silver R. Mast cells in the rat brain synthesize gonadotropin-releasing hormone. J Neurobiol. 2003;56(2):113-24. doi: 10.1002/neu.10220.
24. Wilhelm M, King B, Silverman AJ, Silver R. Gonadal steroids regulate the number and activational state of mast cells in the medial habenula. Endocrinology. 2000;141(3):1178-86. doi: 10.1210/endo.141.3.7352.
25. Silverman AJ, Sutherland AK, Wilhelm M, Silver R. Mast cells migrate from blood to brain. J Neurosci. 2000;20(1):401-8. doi: 10.1523/JNEUROSCI.20-01-00401.2000.
26. Monteforte R, Pinelli C, Santillo A, Rastogi RK, Polese G, Baccari GC. Mast cell population in the frog brain: distribution and influence of thyroid status. J Exp Biol. 2010;213(Pt 10):1762-70. doi: 10.1242/jeb.039628. PMID: 20435827.
27. Van Op den bosch J, Van Nassauw L, Van Marck E, Timmermans JP. Somatostatin modulates mast cell-induced responses in murine spinal neurons and satellite cells. Am J Physiol Gastrointest Liver Physiol. 2009;297(2):G406-17. doi: 10.1152/ajpgi.00059.2009.
28. Leon A, Buriani A, Dal Toso R, Fabris M, Romanello S, Aloe L, et al. Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci U S A. 1994;91(9):3739-43. doi: 10.1073/pnas.91.9.3739.
29. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol. 1995;37(1):63-6. doi: 10.1002/ana.410370112.
30. Bennett JL, Blanchet MR, Zhao L, Zbytnuik L, Antignano F, Gold M, et al. Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis. J Immunol. 2009;182(9):5507-14. doi: 10.4049/jimmunol.0801485.
31. Tanzola MB, Robbie-Ryan M, Gutekunst CA, Brown MA. Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J Immunol. 2003;171(8):4385-91. doi: 10.4049/jimmunol.171.8.4385.
32. Kim DY, Hong GU, Ro JY. Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L. J Neuroinflammation. 2011;8:25. doi: 10.1186/1742-2094-8-25.
33. Sayed BA, Walker ME, Brown MA. Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis. J Immunol. 2011;186(6):3294-8. doi: 10.4049/jimmunol.1003574.
34. Kim DY, Jeoung D, Ro JY. Signaling pathways in the activation of mast cells cocultured with astrocytes and colocalization of both cells in experimental allergic encephalomyelitis. J Immunol. 2010;185(1):273-83. doi: 10.4049/jimmunol.1000991.
35. Christy AL, Walker ME, Hessner MJ, Brown MA. Mast cell activation and neutrophil recruitment promotes early and robust inflammation in the meninges in EAE. J Autoimmun. 2013;42:50-61. doi: 10.1016/j.jaut.2012.11.003.
36. Walker-Caulfield ME, Hatfield JK, Brown MA. Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis. J Neuroimmunol. 2015;278:112-22. doi: 10.1016/j.jneuroim.2014.12.009.
37. Piconese S, Costanza M, Musio S, Tripodo C, Poliani PL, Gri G, et al. Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient Kit W-sh/W-sh mice. Lab Invest. 2011;91(4):627-41. doi: 10.1038/labinvest.2011.3.
38. Mayo L, Quintana FJ, Weiner HL. The innate immune system in demyelinating disease. Immunol Rev. 2012;248(1):170-87. doi: 10.1111/j.1600-065X.2012.01135.x.
39. Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012;12:36. doi: 10.1186/1471-2377-12-36.
40. Förster A, Preussner LM, Seeger JM, Rabenhorst A, Kashkar H, Mrowietz U, et al. Dimethylfumarate induces apoptosis in human mast cells. Exp Dermatol. 2013;22(11):719-24. doi: 10.1111/exd.12247.
41. Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A, et al. Impact of mast cells on multiple sclerosis: inhibitory effect of natalizumab. Int J Immunopathol Pharmacol. 2014;27(3):331-5. doi: 10.1177/039463201402700303.
42. Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140(3):691-707.
43. Fiala M, Chattopadhay M, La Cava A, Tse E, Liu G, Lourenco E, et al. IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients. J Neuroinflammation. 2010;7:76. doi: 10.1186/1742-2094-7-76.
44. Mizwicki MT, Fiala M, Magpantay L, Aziz N, Sayre J, Liu G, et al. Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis. 2012;1(3):305-15.
45. Apolloni S, Fabbrizio P, Parisi C, Amadio S, Volonté C. Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2016;53(1):518-31. doi: 10.1007/s12035-014-9019-8.
46. Clemente S. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report. CNS Neurol Disord Drug Targets. 2012;11(7):933-6. doi: 10.2174/1871527311201070933.
47. Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, et al. Neuronal histamine deficit in Alzheimer's disease. Neuroscience. 1998;82(4):993-7. doi: 10.1016/s0306-4522(97)00353-9.
48. Motawaj M, Peoc'h K, Callebert J, Arrang JM. CSF levels of the histamine metabolite tele-methylhistamine are only slightly decreased in Alzheimer's disease. J Alzheimers Dis. 2010;22(3):861-71. doi: 10.3233/JAD-2010-100381.
49. Niederhoffer N, Levy R, Sick E, Andre P, Coupin G, Lombard Y, et al. Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses. Int J Immunopathol Pharmacol. 2009;22(2):473-83. doi: 10.1177/039463200902200224.
50. Nelson RB, Siman R, Iqbal MA, Potter H. Identification of a chymotrypsin-like mast cell protease in rat brain capable of generating the N-terminus of the Alzheimer amyloid beta-protein. J Neurochem. 1993;61(2):567-77. doi: 10.1111/j.1471-4159.1993.tb02160.x.
51. Kalsheker NA. Alpha 1-antichymotrypsin. Int J Biochem Cell Biol. 1996;28(9):961-4. doi: 10.1016/1357-2725(96)00032-5.
52. Folch J, Petrov D, Ettcheto M, Pedrós I, Abad S, Beas-Zarate C, et al. Masitinib for the treatment of mild to moderate Alzheimer's disease. Expert Rev Neurother. 2015;15(6):587-96. doi: 10.1586/14737175.2015.1045419.
53. Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011;3(2):16. doi: 10.1186/alzrt75.
54. Moura DS, Sultan S, Georgin-Lavialle S, Pillet N, Montestruc F, Gineste P, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One. 2011;6(10):e26375. doi: 10.1371/journal.pone.0026375.
55. Angelidou A, Francis K, Vasiadi M, Alysandratos KD, Zhang B, Theoharides A, et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010;7:48. doi: 10.1186/1742-2094-7-48.
56. Theoharides TC, Angelidou A, Alysandratos KD, Zhang B, Asadi S, Francis K, et al. Mast cell activation and autism. Biochim Biophys Acta. 2012;1822(1):34-41. doi: 10.1016/j.bbadis.2010.12.017.
57. Theoharides TC, Zhang B. Neuro-inflammation, blood-brain barrier, seizures and autism. J Neuroinflammation. 2011;8:168. doi: 10.1186/1742-2094-8-168.
58. Theoharides TC, Asadi S, Patel AB. Focal brain inflammation and autism. J Neuroinflammation. 2013;10:46. doi: 10.1186/1742-2094-10-46.
59. Nishino S, Sakurai E, Nevsimalova S, Yoshida Y, Watanabe T, Yanai K, et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep. 2009;32(2):175-80. doi: 10.1093/sleep/32.2.175.
60. Xanthos DN, Gaderer S, Drdla R, Nuro E, Abramova A, Ellmeier W, et al. Central nervous system mast cells in peripheral inflammatory nociception. Mol Pain. 2011;7:42. doi: 10.1186/1744-8069-7-42.
61. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab. 2010;30(4):689-702. doi: 10.1038/jcbfm.2009.282.
62. Strbian D, Karjalainen-Lindsberg ML, Kovanen PT, Tatlisumak T, Lindsberg PJ. Mast cell stabilization reduces hemorrhage formation and mortality after administration of thrombolytics in experimental ischemic stroke. Circulation. 2007;116(4):411-8. doi: 10.1161/CIRCULATIONAHA.106.655423.
63. Jin Y, Silverman AJ, Vannucci SJ. Mast cell stabilization limits hypoxic-ischemic brain damage in the immature rat. Dev Neurosci. 2007;29(4-5):373-84. doi: 10.1159/000105478.
64. Strbian D, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ. Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab. 2006;26(5):605-12. doi: 10.1038/sj.jcbfm.9600228.
65. Arac A, Grimbaldeston MA, Nepomuceno AR, Olayiwola O, Pereira MP, Nishiyama Y, et al. Evidence that meningeal mast cells can worsen stroke pathology in mice. Am J Pathol. 2014;184(9):2493-504. doi: 10.1016/j.ajpath.2014.06.003.
66. Jin Y, Silverman AJ, Vannucci SJ. Mast cells are early responders after hypoxia-ischemia in immature rat brain. Stroke. 2009;40(9):3107-12. doi: 10.1161/STROKEAHA.109.549691.
67. Strbian D, Tatlisumak T, Ramadan UA, Lindsberg PJ. Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27(4):795-802. doi: 10.1038/sj.jcbfm.9600387.
68. Abrams MB, Nilsson I, Lewandowski SA, Kjell J, Codeluppi S, Olson L, et al. Imatinib enhances functional outcome after spinal cord injury. PLoS One. 2012;7(6):e38760. doi: 10.1371/journal.pone.0038760.
69. Nelissen S, Vangansewinkel T, Geurts N, Geboes L, Lemmens E, Vidal PM, et al. Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4. Neurobiol Dis. 2014;62:260-72. doi: 10.1016/j.nbd.2013.09.012.
70. Hendrix S, Kramer P, Pehl D, Warnke K, Boato F, Nelissen S, et al. Mast cells protect from post-traumatic brain inflammation by the mast cell-specific chymase mouse mast cell protease-4. FASEB J. 2013;27(3):920-9. doi: 10.1096/fj.12-204800.
71. Stokely ME, Orr EL. Acute effects of calvarial damage on dural mast cells, pial vascular permeability, and cerebral cortical histamine levels in rats and mice. J Neurotrauma. 2008;25(1):52-61. doi: 10.1089/neu.2007.0397.
72. Valle-Dorado MG, Santana-Gómez CE, Orozco-Suárez SA, Rocha L. The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus. Neuropharmacology. 2015;92:49-55. doi: 10.1016/j.neuropharm.2014.12.032.
73. Yillar DO, Küçükhüseyin C. The effects of compound 48/80, morphine, and mast cell depletion on electroshock seizure in mice. J Basic Clin Physiol Pharmacol. 2008;19(1):1-14. doi: 10.1515/jbcpp.2008.19.1.1.
74. Rehni AK, Singh TG, Singh N, Arora S. Tramadol-induced seizurogenic effect: a possible role of opioid-dependent histamine H1 receptor activation-linked mechanism. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(1):11-9. doi: 10.1007/s00210-009-0476-y.
75. Swiader M, Wielosz M, Czuczwar SJ. Interaction of astemizole, an H1 receptor antagonist, with conventional antiepileptic drugs in mice. Pharmacol Biochem Behav. 2003;76(1):169-78. doi: 10.1016/s0091-3057(03)00212-0.
76. Yokoyama H, Onodera K, Iinuma K, Watanabe T. 2-Thiazolylethylamine, a selective histamine H1 agonist, decreases seizure susceptibility in mice. Pharmacol Biochem Behav. 1994;47(3):503-7. doi: 10.1016/0091-3057(94)90151-1.
77. Yokoyama H, Onodera K, Maeyama K, Sakurai E, Iinuma K, Leurs R, et al. Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice. Eur J Pharmacol. 1994;260(1):23-8. doi: 10.1016/0014-2999(94)90005-1.
78. Põlajeva J, Sjösten AM, Lager N, Kastemar M, Waern I, Alafuzoff I, et al. Mast cell accumulation in glioblastoma with a potential role for stem cell factor and chemokine CXCL12. PLoS One. 2011;6(9):e25222. doi: 10.1371/journal.pone.0025222.
79. Põlajeva J, Bergström T, Edqvist PH, Lundequist A, Sjösten A, Nilsson G, et al. Glioma-derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5-dependent manner. Mol Oncol. 2014;8(1):50-8. doi: 10.1016/j.molonc.2013.09.002.
80. Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, et al. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. J Clin Invest. 2003;112(12):1851-61. doi: 10.1172/JCI19195.
81. Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008;135(3):437-48. doi: 10.1016/j.cell.2008.08.041.
82. Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood. 2010;116(2):157-64. doi: 10.1182/blood-2009-09-242875.
83. Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C. Subependymal giant cell astrocytoma--a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol Oncol Res. 2004;10(4):219-24. doi: 10.1007/BF03033764.
84. Broholm H, Laursen H. Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. APMIS. 2004;112(4-5):257-63. doi: 10.1111/j.1600-0463.2004.apm11204-0505.x.
85. Maślińska D, Woźniak R, Kaliszek A, Schmidt-Sidor B, Lipska A, Woolley DE. Phenotype of mast cells in the brain tumor. Capillary hemangioblastoma. Folia Neuropathol. 1999;37(3):138-42.
86. Reszec J, Hermanowicz A, Kochanowicz J, Turek G, Mariak Z, Chyczewski L. Mast cells evaluation in meningioma of various grades. Folia Histochem Cytobiol. 2012;50(4):542-6. doi: 10.5603/14744.
87. Reszec J, Hermanowicz A, Rutkowski R, Bernaczyk P, Mariak Z, Chyczewski L. Evaluation of mast cells and hypoxia inducible factor-1 expression in meningiomas of various grades in correlation with peritumoral brain edema. J Neurooncol. 2013;115(1):119-25. doi: 10.1007/s11060-013-1208-1.
88. Tirakotai W, Mennel HD, Celik I, Hellwig D, Bertalanffy H, Riegel T. Secretory meningioma: immunohistochemical findings and evaluation of mast cell infiltration. Neurosurg Rev. 2006;29(1):41-8. doi: 10.1007/s10143-005-0402-9.
89. Theoharides TC, Rozniecki JJ, Sahagian G, Jocobson S, Kempuraj D, Conti P, et al. Impact of stress and mast cells on brain metastases. J Neuroimmunol. 2008;205(1-2):1-7. doi: 10.1016/j.jneuroim.2008.09.014.
90. Rozniecki JJ, Sahagian GG, Kempuraj D, Tao K, Jocobson S, Zhang B, et al. Brain metastases of mouse mammary adenocarcinoma is increased by acute stress. Brain Res. 2010;1366:204-10. doi: 10.1016/j.brainres.2010.09.085.


Submitted date:
10/31/2020

Reviewed date:
12/02/2020

Accepted date:
12/02/2020

Publication date:
12/02/2020

5fc7eba70e8825193223ae0f iberoamericanjm Articles
Links & Downloads

Iberoam J Med

Share this page
Page Sections