Mechanistic Insights into Aspartame-induced Immune Dysregulation

Author(s): Arbind K. Choudhary*, Yeong Y. Lee.

Journal Name: Current Nutrition & Food Science

Volume 15 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background & Objective: Aspartame, (L-aspartyl-L-phenylalanine methyl ester) is a widely used artificial sweetener but studies raise safety concerns regarding the use of aspartame metabolites especially methanol. In this review, we aimed to provide mechanistic insights that may explain aspartame-induced immune dysregulation.

Findings: While evidence is limited, from the available literature, possible mechanisms for immune dysfunction associated with aspartame include (1) alterations in bidirectional communication between neuro-immune-endocrine responses (2) disruption of the brain-gut-microbiota-immune axis (3) induction of oxidative stress in immune cells and organs and lastly (4) the immune-activation effect of methanol.

Conclusion: Further studies are needed to confirm above proposed mechanisms that may explain aspartame- induce immune dysregulation.

Keywords: Aspartame, guts dysbiosis, immune regulation, oxidative stress, methanol, phenylalanine.

[1]
Anton SD, Martin CK, Han H, et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite 2010; 55(1): 37-43.
[http://dx.doi.org/10.1016/j.appet.2010.03.009] [PMID: 20303371]
[2]
Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr 2009; 89(1): 1-14.
[http://dx.doi.org/10.3945/ajcn.2008.26792] [PMID: 19056571]
[3]
Oku T, Nakamura S. Digestion, absorption, fermentation, and metabolism of functional sugar substitutes and their available energy. Pure Appl Chem 2002; 74(7): 1253-61.
[http://dx.doi.org/10.1351/pac200274071253]
[4]
Grenby T. Intense sweeteners for the food industry: an overview. Trends Food Sci Technol 1991; 2: 2-6.
[http://dx.doi.org/10.1016/0924-2244(91)90598-D]
[5]
Butchko HH, Stargel WW. Aspartame: scientific evaluation in the postmarketing period. Regul Toxicol Pharmacol 2001; 34(3): 221-33.
[http://dx.doi.org/10.1006/rtph.2001.1500] [PMID: 11754527]
[6]
Choudhary A. Aspartame: should individuals with Type II Diabetes be taking it? Curr Diabetes Rev 2018; 14(4): 350-62.
[PMID: 28571543]
[7]
Choudhary AK, Pretorius E. Revisiting the safety of aspartame. Nutr Rev 2017; 75(9): 718-30.
[http://dx.doi.org/10.1093/nutrit/nux035] [PMID: 28938797]
[8]
Choudhary AK, Lee YY. Neurophysiological symp-toms and aspartame: What is the connection? Nutr Neurosci 2018; 21(5): 306-16.
[PMID: 28198207]
[9]
Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7(1): 41-53.
[http://dx.doi.org/10.1038/nrn1824] [PMID: 16371949]
[10]
Choudhary AK, Devi RS. Imbalance of the oxidant-antioxidant status by aspartame in the organs of immune system of Wistar albino rats. Afr J Pharm Pharmacol 2014; 8: 220-30.
[http://dx.doi.org/10.5897/AJPP2013.3838]
[11]
Choudhary AK, Sheela Devi R. Longer period of oral administration of aspartame on cytokine response in Wistar albino rats. Endocrinol Nutr 2015; 62(3): 114-22.
[http://dx.doi.org/10.1016/j.endonu.2014.11.004] [PMID: 25681123]
[12]
Choudhary AK, Rathinasamy SD. Aspartame induces alteration in electrolytes homeostasis of immune organs in Wistar albino rats. Biomed Preventive Nutr 2014; 4(2): 181-7.
[http://dx.doi.org/10.1016/j.bionut.2013.12.006]
[13]
Choudhary AK, Rathinasamy SD. Effect of long intake of aspartame on ionic imbalance in immune organs of immunized Wistar albino rats. Biomed Aging Pathol 2014; 4(3): 243-9.
[http://dx.doi.org/10.1016/j.biomag.2014.03.001]
[14]
Choudhary A, Pretorius E. Revisiting the safety of aspartame. Nutr Rev 2017; 75(9): 718-30.
[15]
Stegink LD, Filer L. Effects of aspartame ingestion on plasma aspartate, phenylalanine and methanol concentrations in normal adults. In: Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, Eds. The clinical evaluation of a food additive Assessment of Aspartame. CRC Press FL, United States 1996; pp. 67-86.
[16]
Humphries P, Pretorius E, Naudé H. Direct and indirect cellular effects of aspartame on the brain. Eur J Clin Nutr 2008; 62(4): 451-62.
[http://dx.doi.org/10.1038/sj.ejcn.1602866] [PMID: 17684524]
[17]
Stegink LD, Filer LJ Jr, Baker GL, et al. Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria. Metabolism 1989; 38(1): 78-84.
[http://dx.doi.org/10.1016/0026-0495(89)90184-4] [PMID: 2909831]
[18]
Opperman J. Aspartame metabolism in animals.In: Aspartame Physiology and Biochemistry. Dekker New York 1984; pp. 141-59.
[19]
Magnuson BA, Burdock GA, Doull J, et al. Aspartame: A safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol 2007; 37(8): 629-727.
[http://dx.doi.org/10.1080/10408440701516184] [PMID: 17828671]
[20]
Renwick A. The fate of intense sweeteners in the body. Food Chem 1985; 16(3-4): 281-301.
[http://dx.doi.org/10.1016/0308-8146(85)90122-0]
[21]
Olney JW, Farber NB, Spitznagel E, Robins LN. Increasing brain tumor rates: Is there a link to aspartame? J Neuropathol Exp Neurol 1996; 55(11): 1115-23.
[http://dx.doi.org/10.1097/00005072-199611000-00002] [PMID: 8939194]
[22]
Weihrauch MR, Diehl V. Artificial sweeteners-do they bear a carcinogenic risk? Ann Oncol 2004; 15(10): 1460-5.
[http://dx.doi.org/10.1093/annonc/mdh256] [PMID: 15367404]
[23]
Atkins FM, Metcalfe DD. The diagnosis and treatment of food allergy. Annu Rev Nutr 1984; 4(1): 233-55.
[http://dx.doi.org/10.1146/annurev.nu.04.070184.001313] [PMID: 6205672]
[24]
Szucs EF, Barrett KE, Metcalfe DD. The effects of aspartame on mast cells and basophils. Food Chem Toxicol 1986; 24(2): 171-4.
[http://dx.doi.org/10.1016/0278-6915(86)90353-4] [PMID: 2420690]
[25]
Iyyaswamy A, Rathinasamy S. Effect of chronic exposure to aspartame on oxidative stress in the brain of albino rats. J Biosci 2012; 37(4): 679-88.
[http://dx.doi.org/10.1007/s12038-012-9236-0] [PMID: 22922192]
[26]
Choudhary AK, Sundareswaran L, Devi RS. Aspartame induced cardiac oxidative stress in Wistar albino rats. Nutr Clin Metab 2016; 30(1): 29-37.
[http://dx.doi.org/10.1016/j.nupar.2016.01.071]
[27]
Choudhary AK, Sundareswaran L, Devi RS. Effects of aspartame on the evaluation of electrophysiological responses in Wistar albino rats. J Taibah Univ Sci 2016; 10: 505-12.
[http://dx.doi.org/10.1016/j.jtusci.2015.07.006]
[28]
Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 2005; 5(3): 243-51.
[http://dx.doi.org/10.1038/nri1571] [PMID: 15738954]
[29]
Colosio C, Birindelli S, Corsini E, Galli CL, Maroni M. Low level exposure to chemicals and immune system. Toxicol Appl Pharmacol 2005; 207(2)(Suppl.): 320-8.
[http://dx.doi.org/10.1016/j.taap.2005.01.025] [PMID: 15992843]
[30]
Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3(3): 253-7.
[http://dx.doi.org/10.1038/nri1032] [PMID: 12658273]
[31]
Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005; 122(1): 107-18.
[http://dx.doi.org/10.1016/j.cell.2005.05.007] [PMID: 16009137]
[32]
Choudhary AK, Lee YY. Neurophysiological symptoms and aspartame: what is the connection? Nutritional Neurosci 2018; 21(5): 306-16.
[http://dx.doi.org/10.1080/1028415X.2017.1288340] [PMID: 28198207]
[33]
Abhilash M, Sauganth Paul MV, Varghese MV, Nair RH. Long-term consumption of aspartame and brain antioxidant defense status. Drug Chem Toxicol 2013; 36(2): 135-40.
[http://dx.doi.org/10.3109/01480545.2012.658403] [PMID: 22385158]
[34]
Ashok I, Sheeladevi R. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain. Redox Biol 2014; 2: 820-31.
[http://dx.doi.org/10.1016/j.redox.2014.04.011] [PMID: 25009784]
[35]
Ashok I, Sheeladevi R. Neurobehavioral changes and activation of neurodegenerative apoptosis on long-term consumption of aspartame in the rat brain. J Nutr Intermed Metab 2015; 2(3): 76-85.
[http://dx.doi.org/10.1016/j.jnim.2015.09.001]
[36]
Ashok I, Sheeladevi R, Wankhar D. Long term effect of aspartame (artificial sweetener) on membrane homeostatic imbalance and histopathology in the rat brain. Free Radic Antioxid 2013; 3: S42-9.
[37]
Alleva R, Borghi B, Santarelli L, et al. In vitro effect of aspartame in angiogenesis induction. Toxicol In Vitro 2011; 25(1): 286-93.
[http://dx.doi.org/10.1016/j.tiv.2010.09.002] [PMID: 20837131]
[38]
Kaestner F, Hettich M, Peters M, et al. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 2005; 87(2-3): 305-11.
[http://dx.doi.org/10.1016/j.jad.2005.03.012] [PMID: 15951024]
[39]
Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006; 6(4): 318-28.
[http://dx.doi.org/10.1038/nri1810] [PMID: 16557263]
[40]
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009; 136(6): 2003-14.
[http://dx.doi.org/10.1053/j.gastro.2009.01.075] [PMID: 19457424]
[41]
Romijn JA, Corssmit EP, Havekes LM, Pijl H. Gut-brain axis. Curr Opin Clin Nutr Metab Care 2008; 11(4): 518-21.
[http://dx.doi.org/10.1097/MCO.0b013e328302c9b0] [PMID: 18542016]
[42]
Choudhary AK, Lee Y. Dysregulated microbiota-gut-brain axis: does it explain aspartame metabolic and other side-effects? Nutr Food Sci 2017; 47(5): 648-58.
[http://dx.doi.org/10.1108/NFS-03-2017-0034]
[43]
Groot J, Bijlsma P, Van Kalkeren A, Kiliaan A, Saunders P, Perdue M. Stress-induced decrease of the intestinal barrier function. The role of muscarinic receptor activation. Ann N Y Acad Sci 2000; 915(1): 237-46.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb05247.x] [PMID: 11193581]
[44]
Palmnäs MS, Cowan TE, Bomhof MR, et al. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One 2014; 9(10)e109841
[http://dx.doi.org/10.1371/journal.pone.0109841] [PMID: 25313461]
[45]
Frankenfeld CL, Sikaroodi M, Lamb E, Shoemaker S, Gillevet PM. High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States 2015. Ann Epidemiol 2015; 25(10): 736-42.e4.
[46]
Bonaz B, Sabaté J-M. Brain-gut axis dysfunction. Gastroenterol Clin Biol 2009; 33(Suppl. 1): S48-58.
[http://dx.doi.org/10.1016/S0399-8320(09)71525-8] [PMID: 19303539]
[47]
Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science 2012; 336(6086): 1268-73.
[http://dx.doi.org/10.1126/science.1223490] [PMID: 22674334]
[48]
Mulak A, Bonaz B. Irritable bowel syndrome: a model of the brain-gut interactions. Med Sci Monit 2004; 10(4): RA55-62.
[PMID: 15260348]
[49]
Thakur AK, Shakya A, Husain GH, Emerald M. Gut-microbiota and mental health: current and future perspectives. J Pharmacol Clin Toxicol 2014; 2: 1016-31.
[50]
Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000; 408(6809): 239-47.
[http://dx.doi.org/10.1038/35041687] [PMID: 11089981]
[51]
Victor VM, Rocha M, De la Fuente M. Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol 2004; 4(3): 327-47.
[http://dx.doi.org/10.1016/j.intimp.2004.01.020]
[52]
Arbind K, Sheela Devi R, Sundareswaran L. Role of antioxidant enzymes in oxidative stress and immune response evaluation of aspartame in blood cells of Wistar albino rats. Int Food Res J 2014; 21(6): 2263-72.
[53]
Choudhary AK, Devi RS. Exposures of long intake of aspartame on free radical scavenging enzymes in blood cells and neutrophil functions of immunized Wistar albino rats. Am J PharmTech Res 2014; 4(1): 1014-29.
[54]
Ashok I, Sheeladevi R, Wankhar D. Acute effect of aspartame-induced oxidative stress in Wistar albino rat brain. J Biomed Res 2015; 29(5): 390-6.
[PMID: 26445572]
[55]
Abdel-Salam OM, Salem NA, Hussein JS. Effect of aspartame on oxidative stress and monoamine neurotransmitter levels in lipopoly-saccharide-treated mice. Neurotox Res 2012; 21(3): 245-55.
[http://dx.doi.org/10.1007/s12640-011-9264-9] [PMID: 21822758]
[56]
Knight JA. Review: free radicals, antioxidants, and the immune system. Ann Clin Lab Sci 2000; 30(2): 145-58.
[PMID: 10807157]
[57]
Roy S, Sen CK, Packer L. Determination of cell-cell adhesion in response to oxidants and antioxidants. Methods Enzymol 1999; 300: 395-401.
[http://dx.doi.org/10.1016/S0076-6879(99)00144-5] [PMID: 9919540]
[58]
Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J 1994; 8(8): 504-12.
[http://dx.doi.org/10.1096/fasebj.8.8.8181668] [PMID: 8181668]
[59]
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1): 44-84.
[http://dx.doi.org/10.1016/j.biocel.2006.07.001] [PMID: 16978905]
[60]
Bautista AP. Neutrophilic infiltration in alcoholic hepatitis. Alcohol 2002; 27(1): 17-21.
[http://dx.doi.org/10.1016/S0741-8329(02)00206-9] [PMID: 12062632]
[61]
Parthasarathy NJ, Kumar RS, Devi RS. Effect of methanol intoxication on rat neutrophil functions. J Immunotoxicol 2005; 2(2): 115-21.
[http://dx.doi.org/10.1080/15476910500187425] [PMID: 18958665]
[62]
Abhilash M, Paul MV, Varghese MV, Nair RH. Effect of long term intake of aspartame on antioxidant defense status in liver. Food Chem Toxicol 2011; 49(6): 1203-7.
[http://dx.doi.org/10.1016/j.fct.2011.02.019] [PMID: 21376768]
[63]
Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006; 8(2)(Suppl. 2): S3.
[http://dx.doi.org/10.1186/ar1917] [PMID: 16899107]
[64]
Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 1987; 84(20): 7251-5.
[http://dx.doi.org/10.1073/pnas.84.20.7251] [PMID: 2444978]
[65]
Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7(9): 678-89.
[http://dx.doi.org/10.1038/nri2156] [PMID: 17717539]
[66]
Choudhary AK, Devi RS. Effect of long intake of as-partame on oxidative stress and cell and humoral immune response in immunized wistar albino rats. Am J PharmTech Res 2014; 4(2): 235-50.
[67]
Choudhary AK, Devi RS. Effects of aspartame on hsp70, bcl-2 and bax expression in immune organs of Wistar albino rats. J Biomed Res 2016; 30(5): 427-35.
[PMID: 27845306]
[68]
Pandurangan M, Enkhtaivan G, Mistry B, Chandrasekaran M, Noorzai R, Kim DH. Investigation of role of aspartame on apoptosis process in HeLa cells. Saudi J Biol Sci 2016; 23(4): 503-6.
[http://dx.doi.org/10.1016/j.sjbs.2015.06.001] [PMID: 27298583]
[69]
Villareal LMA, Cruz RAM, Ples MB, Santos RJ. Neurotropic effects of aspartame, stevia and sucralose on memory retention and on the histology of the hippocampus of the ICR mice (Mus musculus). Asian Pac J Trop Biomed 2016; 6(2): 114-8.
[http://dx.doi.org/10.1016/j.apjtb.2015.11.001]
[70]
Ramsland PA, Movafagh BF, Reichlin M, Edmundson AB. Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester. J Mol Recognit 1999; 12(4): 249-57.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199907/08)12:4<249:AID-JMR463>3.0.CO;2-B] [PMID: 10440996]
[71]
Monte WC. Aspartame: Methanol and the public health. J Appl Nutr 1984; 36: 42-54.
[72]
Stegink F. Aspartame: physiology and biochemistry. Vol. 12. CRC Press: FL, United States 1984
[73]
Stegink LD, Brummel MC, McMartin K, et al. Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. J Toxicol Environ Health 1981; 7(2): 281-90.
[http://dx.doi.org/10.1080/15287398109529979] [PMID: 7230276]
[74]
Franz M, Franz M. Is aspartame safe? Diabetes Educ 1984; 10(2): 56-7.
[http://dx.doi.org/10.1177/014572178401000211] [PMID: 6564954]
[75]
Trocho C, Pardo R, Rafecas I, et al. Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 1998; 63(5): 337-49.
[http://dx.doi.org/10.1016/S0024-3205(98)00282-3] [PMID: 9714421]
[76]
Makar AB, Tephly TR. Methanol poisoning in the folate-deficient rat. Nature 1976; 261(5562): 715-6.
[http://dx.doi.org/10.1038/261715a0] [PMID: 6915]
[77]
Black KA, Eells JT, Noker PE, Hawtrey CA, Tephly TR. Role of hepatic tetrahydrofolate in the species difference in methanol toxicity. Proc Natl Acad Sci USA 1985; 82(11): 3854-8.
[http://dx.doi.org/10.1073/pnas.82.11.3854] [PMID: 3923481]
[78]
Makar AB, Tephly TR. Methanol poisoning in the folate-deficient rat. Nature 1976; 261(5562): 715-6.
[http://dx.doi.org/10.1038/261715a0] [PMID: 6915]
[79]
Tephly TR. The toxicity of methanol. Life Sci 1991; 48(11): 1031-41.
[http://dx.doi.org/10.1016/0024-3205(91)90504-5] [PMID: 1997785]
[80]
Ranney RE, Oppermann JA, Muldoon E, McMahon FG. Comparative metabolism of aspartame in experimental animals and humans. J Toxicol Environ Health 1976; 2(2): 441-51.
[http://dx.doi.org/10.1080/15287397609529445] [PMID: 827618]
[81]
Röe O, Enoksson P. Species differences in methanol poisoning. Crit Rev Toxicol 1982; 10(4): 275-86.
[http://dx.doi.org/10.3109/10408448209003368] [PMID: 6756793]
[82]
Roberts HJ. Aspartame as a cause of allergic reactions, including anaphylaxis. Arch Intern Med 1996; 156(9): 1027-8.
[http://dx.doi.org/10.1001/archinte.1996.00440090139016] [PMID: 8624169]
[83]
Roberts HJ. Reactions attributed to aspartame-containing products: 551 cases. J Appl Nutr 1988; 40: 85-94.
[84]
Roberts HJ. Sweet’ner Dearest: Bittersweet Vignettes About Aspartame (NutraSweet). Sunshine Sentinel Press FL, United States 1992.
[85]
Hill AM, Belsito DV. Systemic contact dermatitis of the eyelids caused by formaldehyde derived from aspartame? Contact Dermat 2003; 49(5): 258-9.
[http://dx.doi.org/10.1111/j.0105-1873.2003.0225a.x] [PMID: 14996049]
[86]
Jacob SE, Stechschulte S. Formaldehyde, aspartame, and migraines: a possible connection. Dermatitis 2008; 19(3): E10-1.
[PMID: 18627677]
[87]
Abegaz EG, Bursey RG. Formaldehyde, aspartame, migraines: a possible connection. Dermatitis 2009; 20(3): 176-7.
[http://dx.doi.org/10.2310/6620.2009.08082] [PMID: 19470307]
[88]
Thrasher JD, Broughton A, Madison R. Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde. Arch Environ Health 1990; 45(4): 217-23.
[http://dx.doi.org/10.1080/00039896.1990.9940805] [PMID: 2400243]
[89]
Stegink LD, Brummel MC, Filer LJ Jr, Baker GL. Blood methanol concentrations in one-year-old infants administered graded doses of aspartame. J Nutr 1983; 113(8): 1600-6.
[http://dx.doi.org/10.1093/jn/113.8.1600] [PMID: 6875695]
[90]
Davoli E, Cappellini L, Airoldi L, Fanelli R. Serum methanol concentrations in rats and in men after a single dose of aspartame. Food Chem Toxicol 1986; 24(3): 187-9.
[http://dx.doi.org/10.1016/0278-6915(86)90227-9] [PMID: 3957170]
[91]
Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR. Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. Metabolism 1989; 38(4): 357-63.
[http://dx.doi.org/10.1016/0026-0495(89)90125-X] [PMID: 2566887]
[92]
Oyama Y, Sakai H, Arata T, et al. Cytotoxic effects of methanol, formaldehyde, and formate on dissociated rat thymocytes: a possibility of aspartame toxicity. Cell Biol Toxicol 2002; 18(1): 43-50.
[http://dx.doi.org/10.1023/A:1014419229301] [PMID: 11991085]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [653 - 661]
Pages: 9
DOI: 10.2174/1573401314666181016124250
Price: $65

Article Metrics

PDF: 23
HTML: 2
EPUB: 1
PRC: 1

Special-new-year-discount