Aspirin: The mechanism of action revisited in the context of pregnancy complications

Frontiers in Immunology

Volumn 8, Issue MAR, 2017, Pages

  Cadavid, Angela P ^a  

^a UNIVERSIDAD DE ANTIOQUIA   (Colombia)

Author keywords

Anti inflammatory; Aspirin triggered lipoxins; Obstetric antiphospholipid syndrome; Preeclampsia; Pregnancy complications; Pro resolving lipid derived mediators

Indexed keywords

ACETYLSALICYLIC ACID; ENDOGLIN; OMEGA 3 FATTY ACID; PLACENTAL GROWTH FACTOR; PROSTAGLANDIN SYNTHASE; THROMBOXANE A2;

ANTIPHOSPHOLIPID SYNDROME; ATHEROSCLEROSIS; CELL PROTECTION; CHRONIC KIDNEY FAILURE; CYSTIC FIBROSIS; FEMALE; HUMAN; IMMUNOMODULATION; INFLAMMATION; PREECLAMPSIA; PREGNANCY COMPLICATION; SHORT SURVEY; VASCULAR REMODELING;

EID: 85017222974     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.00261     Document Type: Short Survey

References (85)

1. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev (2007) 2:CD004659. doi:10.1002/14651858.CD004659.pub2
2. Bartsch E, Park AL, Kingdom JC, Ray JG. Risk threshold for starting low dose aspirin in pregnancy to prevent preeclampsia: an opportunity at a low cost. PLoS One (2015) 10(3):e0116296. doi:10.1371/journal.pone.0116296
3. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol (2017) 216(2):110-20.e6. doi:10.1016/j.ajog.2016.09.076
4. Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol (2000) 183(4):1008-12. doi:10.1067/mob.2000.106754
5. Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol (2003) 101(6):1333-44. doi:10.1097/00006250-200306000-00031
6. Cadavid A, Lopera J, Gil-Villa A. Potential use of aspirin triggered lipoxins in alterations of the gestation. Placenta. Abstracts for the V Latin American Symposium on Maternal-Fetal Interaction and Placenta and IV Latin American Symposium on Reproductive Immunology Meeting 2013. (Vol. 34), Foz de Iguazu, Brazil (2013). A90 p.
7. Cadavid JAP. Aspirin: the mechanism of action revisited in the context of pregnancy complications. Front Immunol (2015) 5:89; Conference Abstract: IMMUNOCOLOMBIA2015-11th Congress of the Latin American Association of Immunology-10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi:10.3389/conf.fimmu.2015.05.00089
8. Serhan CN. Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators. J Periodontol (2008) 79(8 Suppl):1520-6. doi:10.1902/jop.2008.080231
9. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med (2000) 192(8):1197-204. doi:10.1084/jem.192.8.1197
10. Nicolaou KC, Montagnon T. Molecules that Changed the World. Weinheim: Wiley-VCH (2008).
11. Schrör K. Acetylsalicylic Acid. Weinheim: John Wiley and Sons (2010).
12. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol (1971) 231(25):232-5. doi:10.1038/newbio231232a0
13. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol (1971) 231(25):235-7. doi:10.1038/newbio231235a0
14. Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res (1988) 48(15):4399-404. doi:10.1093/ije/dym193
15. Acheson J, Archibald D, Barnett H, Blakely J, Bousser M-G, Boysen G, et al. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists' Collaboration. Br Med J (Clin Res Ed) (1988) 296(6618):320-31.
16. Hunt D, Varigos J, Carlisle C, Falconer P, Landy T, Smedley A, et al. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. J Am Coll Cardiol (1988) 12(6 Suppl A):3A-13A.
17. Crandon AJ, Isherwood DM. Effect of aspirin on incidence of pre-eclampsia. Lancet (1979) 1(8130):1356. doi:10.1016/S0140-6736(79)91996-2
18. Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci U S A (1995) 92(21):9475-9. doi:10.1073/pnas.92.21.9475
19. Saunders MA, Sansores-Garcia L, Gilroy DW, Wu KK. Selective suppression of CCAAT/enhancer-binding protein beta binding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J Biol Chem (2001) 276(22):18897-904. doi:10.1074/jbc.M011147200
20. Pereira-Leite C, Nunes C, Reis S. Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions. Prog Lipid Res (2013) 52(4):571-84. doi:10.1016/j.plipres.2013.08.003
21. Urra FA, Cordova-Delgado M, Lapier M, Orellana-Manzano A, Acevedo-Arevalo L, Pessoa-Mahana H, et al. Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral oxidative phosphorylation. Toxicol Appl Pharmacol (2016) 291:46-57. doi:10.1016/j.taap.2015.12.005
22. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature (1998) 396(6706):77-80. doi:10.1038/23948
23. Shi X, Ding M, Dong Z, Chen F, Ye J, Wang S, et al. Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Mol Cell Biochem (1999) 199(1-2):93-102.
24. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U S A (1975) 72(8):3073-6. doi:10.1073/pnas.72.8.3073
25. Taubert D, Berkels R, Grosser N, Schroder H, Grundemann D, Schomig E. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol (2004) 143(1):159-65. doi:10.1038/sj.bjp.0705907
26. Grosser N, Abate A, Oberle S, Vreman HJ, Dennery PA, Becker JC, et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun (2003) 308(4):956-60. doi:10.1016/S0006-291X(03)01504-3
27. Schroder H. New signaling routes for an old drug: lipoxin A4 might mediate heme oxygenase-1 induction by aspirin. Focus on "Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells". Am J Physiol Cell Physiol (2005) 289(3):C507-8. doi:10.1152/ajpcell.00230.2005
28. Pinckard RN, Hawkins D, Farr RS. In vitro acetylation of plasma proteins, enzymes and DNA by aspirin. Nature (1968) 219(5149):68-9. doi:10.1038/219068a0
29. Alfonso LF, Srivenugopal KS, Bhat GJ. Does aspirin acetylate multiple cellular proteins? (Review). Mol Med Rep (2009) 2(4):533-7. doi:10.3892/mmr_00000132
30. Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke (1992) 23(10):1400-3. doi:10.1161/01.STR.23.10.1400
31. American College of Obstetricians and Gynecologists. Task force on hypertension in P. hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' task force on hypertension in pregnancy. Obstet Gynecol (2013) 122(5):1122-31. doi:10.1097/01.AOG.0000437382.03963.88
32. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science (2005) 308(5728):1592-4. doi:10.1126/science.1111726
33. Redman C. Pre-eclampsia and the placenta. Placenta (1991) 12(4):301-8. doi:10.1016/0143-4004(91)90339-H
34. Sanchez-Aranguren LC, Prada CE, Riano-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia: role of oxidative stress. Front Physiol (2014) 5:372. doi:10.3389/fphys.2014.00372
35. Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N Engl J Med (1993) 329(17):1213-8.
36. Beroyz G, Casale R, Farreiros A, Palermo M, Margulies M, Voto L, et al. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet (1988) 2(8607):349-60. doi:10.1016/S0140-6736(88)92833-4
37. Villa PM, Kajantie E, Raikkonen K, Pesonen AK, Hamalainen E, Vainio M, et al. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG (2013) 120(1):64-74. doi:10.1111/j.1471-0528.2012.03493.x
38. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks' gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol (2017) 216(2):121-8.e2. doi:10.1016/j.ajog.2016.10.016
39. Norgard B, Puho E, Czeizel AE, Skriver MV, Sorensen HT. Aspirin use during early pregnancy and the risk of congenital abnormalities: a population-based case-control study. Am J Obstet Gynecol (2005) 192(3):922-3. doi:10.1016/j.ajog.2004.10.598
40. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol (2010) 116(2 Pt 1):402-14. doi:10.1097/AOG.0b013e3181e9322a
41. Schisterman EF, Silver RM, Lesher LL, Faraggi D, Wactawski-Wende J, Townsend JM, et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet (2014) 384(9937):29-36. doi:10.1016/S0140-6736(14)60157-4
42. Mone F, Mulcahy C, McParland P, McAuliffe FM. Should we recommend universal aspirin for all pregnant women? Am J Obstet Gynecol (2017) 216(2):141.e1-e5. doi:10.1016/j.ajog.2016.09.086
43. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost (2006) 4(2):295-306. doi:10.1111/j.1538-7836.2006.01753.x
44. La Rosa L, Meroni PL, Tincani A, Balestrieri G, Faden D, Lojacono A, et al. Beta 2 glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome. J Rheumatol (1994) 21(9):1684-93.
45. Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest (2003) 112(11):1644-54. doi:10.1172/JCI18817
46. Girardi G, Salmon JB. The role of complement in pregnancy and fetal loss. Autoimmunity (2003) 36(1):19-26. doi:10.1080/0891693031000067322
47. Di Simone N, Ferrazzani S, Castellani R, De Carolis S, Mancuso S, Caruso A. Heparin and low-dose aspirin restore placental human chorionic gonadotrophin secretion abolished by antiphospholipid antibody-containing sera. Hum Reprod (1997) 12(9):2061-5. doi:10.1093/humrep/12.9.2061
48. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol (2011) 7(6):330-9. doi:10.1038/nrrheum.2011.52
49. Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol (2009) 62(2):96-111. doi:10.1111/j.1600-0897.2009.00717.x
50. Di Simone N, Caliandro D, Castellani R, Ferrazzani S, De Carolis S, Caruso A. Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Hum Reprod (1999) 14(2):489-95. doi:10.1093/humrep/14.2.489
51. Mulla MJ, Myrtolli K, Brosens JJ, Chamley LW, Kwak-Kim JY, Paidas MJ, et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol (2010) 63(5):339-48. doi:10.1111/j.1600-0897.2009.00805.x
52. Chamley LW, Duncalf AM, Mitchell MD, Johnson PM. Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet (1998) 352(9133):1037-8. doi:10.1016/S0140-6736(05)60080-3
53. Jovanovic M, Bozic M, Kovacevic T, Radojcic L, Petronijevic M, Vicovac L. Effects of anti-phospholipid antibodies on a human trophoblast cell line (HTR-8/SVneo). Acta Histochem (2010) 112(1):34-41. doi:10.1016/j.acthis.2008.07.001
54. Adler RR, Ng AK, Rote NS. Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR. Biol Reprod (1995) 53(4):905-10. doi:10.1095/biolreprod53.4.905
55. Bose P, Kadyrov M, Goldin R, Hahn S, Backos M, Regan L, et al. Aberrations of early trophoblast differentiation predispose to pregnancy failure: lessons from the anti-phospholipid syndrome. Placenta (2006) 27(8):869-75. doi:10.1016/j.placenta.2005.09.007
56. Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote NS. Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod (1997) 56(1):50-8. doi:10.1095/biolreprod56.1.50
57. Di Simone N, Luigi MP, Marco D, Fiorella DN, Silvia D, Clara DM, et al. Pregnancies complicated with antiphospholipid syndrome: the pathogenic mechanism of antiphospholipid antibodies: a review of the literature. Ann N Y Acad Sci (2007) 1108:505-14. doi:10.1196/annals.1422.054
58. Mineo C, Shaul PW. New insights into the molecular basis of the antiphospholipid syndrome. Drug Discov Today Dis Mech (2011) 8(1-2):e47-52. doi:10.1016/j.ddmec.2011.12.002
59. Alvarez AM, Mulla MJ, Chamley LW, Cadavid AP, Abrahams VM. Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions. Arthritis Rheumatol (2015) 67(2):488-97. doi:10.1002/art.38934
60. Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol (2009) 36(2):279-87. doi:10.3899/jrheum.080763
61. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev (2005) 2:CD002859. doi:10.1002/14651858.CD002859.pub2
62. Andrade D, Tektonidou M. Emerging therapies in antiphospholipid syndrome. Curr Rheumatol Rep (2016) 18(4):22. doi:10.1007/s11926-016-0566-z
63. Ruffatti A, Hoxha A, Favaro M, Tonello M, Colpo A, Cucchini U, et al. Additional treatments for high-risk obstetric antiphospholipid syndrome: a comprehensive review. Clin Rev Allergy Immunol (2016). doi:10.1007/s12016-016-8571-6
64. Krause I, Blank M, Gilbrut B, Shoenfeld Y. The effect of aspirin on recurrent fetal loss in experimental antiphospholipid syndrome. Am J Reprod Immunol (1993) 29(3):155-61. doi:10.1111/j.1600-0897.1993.tb00581.x
65. Cadavid A, Sanchez F, Botero J, Peña B, Castañeda A, Ossa JE. Coadjuvant effect of aspirin in the treatment of recurrent spontaneous abortion. Am J Reprod Immunol (1996) 35:465; Abstract for the 16th American Society Reproductive Immunology Meeting, June-26-29, 1996. Knoxville, USA.
66. Cadavid A, Pena B, Garcia G, Botero J, Sanchez F, Ossa J, et al. Heparin plus aspirin as a "single" therapy for recurrent spontaneous abortion associated with both allo-and autoimmunity. Am J Reprod Immunol (1999) 41(4):271-8. doi:10.1111/j.1600-0897.1999.tb00438.x
67. Parkinson JF. Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation. Inflamm Allergy Drug Targets (2006) 5(2):91-106. doi:10.2174/187152806776383125
68. Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol (2000) 164(4):1663-7. doi:10.4049/jimmunol.164.4.1663
69. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thromb Haemost (2007) 97(1):88-98. doi:10.1160/TH06-06-0315
70. Bandeira-Melo C, Bozza PT, Diaz BL, Cordeiro RS, Jose PJ, Martins MA, et al. Cutting edge: lipoxin (LX) A4 and aspirin-triggered 15-epi-LXA4 block allergen-induced eosinophil trafficking. J Immunol (2000) 164(5):2267-71. doi:10.4049/jimmunol.164.5.2267
71. Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE, et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev (2006) 58(3):463-87. doi:10.1124/pr.58.3.4
72. Levy BD, Lukacs NW, Berlin AA, Schmidt B, Guilford WJ, Serhan CN, et al. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J (2007) 21(14):3877-84. doi:10.1096/fj.07-8653com
73. Gilroy DW. The role of aspirin-triggered lipoxins in the mechanism of action of aspirin. Prostaglandins Leukot Essent Fatty Acids (2005) 73(3-4):203-10. doi:10.1016/j.plefa.2005.05.007
74. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Villela CG, Fierro IM. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. Am J Physiol Cell Physiol (2005) 289(3):C557-63. doi:10.1152/ajpcell.00045.2005
75. Schroder H. Nitric oxide and aspirin: a new mediator for an old drug. Am J Ther (2009) 16(1):17-23. doi:10.1097/MJT.0b013e318164bd60
76. Macdonald LJ, Boddy SC, Denison FC, Sales KJ, Jabbour HN. A role for lipoxin A(4) as an anti-inflammatory mediator in the human endometrium. Reproduction (2011) 142(2):345-52. doi:10.1530/REP-11-0021
77. Gil-Villa AM, Norling LV, Serhan CN, Cordero D, Rojas M, Cadavid A. Aspirin triggered-lipoxin A4 reduces the adhesion of human polymorphonuclear neutrophils to endothelial cells initiated by preeclamptic plasma. Prostaglandins Leukot Essent Fatty Acids (2012) 87(4-5):127-34. doi:10.1016/j.plefa.2012.08.003
78. Greenberg JA, Bell SJ, Ausdal WV. Omega-3 fatty acid supplementation during pregnancy. Rev Obstet Gynecol (2008) 1(4):162-9.
79. Keelan JA, Mas E, D'Vaz N, Dunstan JA, Li S, Barden AE, et al. Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors. Reproduction (2015) 149(2):171-8. doi:10.1530/REP-14-0549
80. Coletta JM, Bell SJ, Roman AS. Omega-3 Fatty acids and pregnancy. Rev Obstet Gynecol (2010) 3(4):163-71.
81. Pettit LK, Varsanyi C, Tadros J, Vassiliou E. Modulating the inflammatory properties of activated microglia with docosahexaenoic acid and aspirin. Lipids Health Dis (2013) 12:16. doi:10.1186/1476-511X-12-16
82. Hirahashi J, Hanafusa N, Wada T, Arita M, Hishikawa K, Hayashi M, et al. Aspirin and eicosapentaenoic acid may arrest progressive IgA nephropathy: a potential alternative to immunosuppression. Intern Med (2015) 54(18):2377-82. doi:10.2169/internalmedicine.54.4623
83. Sorokin AV, Yang ZH, Vaisman BL, Thacker S, Yu ZX, Sampson M, et al. Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice. J Nutr Biochem (2016) 35:58-65. doi:10.1016/j.jnutbio.2016.05.012
84. Barden A, Mas E, Croft KD, Phillips M, Mori TA. Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation. J Lipid Res (2014) 55(11):2401-7. doi:10.1194/jlr.M045583
85. Block RC, Dier U, Calderonartero P, Shearer GC, Kakinami L, Larson MK, et al. The effects of EPA+DHA and aspirin on inflammatory cytokines and angiogenesis factors. World J Cardiovasc Dis (2012) 2(1):14-9. doi:10.4236/wjcd.2012.21003