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ducted in children with illnesses possibly related to magnesium turnover abnormalities such as ALL. Meanwhile, clinicians must continue to search for the answer to preventing bone mineral loss in ill children. To do that, we must insist that the missing minerals not just be identified as “low bone mass” or hypomagnesemia, but that they be found in the physiology of the children treated for serious illnesses.

Steven A. Abrams, MD US Department of Agriculture/ Agricultural Research Service Children’s Nutrition Research Center Department of Pediatrics Baylor College of Medicine and Texas Children’s Hospital Houston, Texas, USA REFERENCES 1. Perez MD, Abrams SA, Loddeke L, Shypailo R, Ellis KJ. Effects of rheumatic disease and corticosteroid treatment on calcium metabolism and bone density in children assessed 1 year after diagnosis, using stable isotopes and dual-energy X-ray absorptiometry. J Rheumatol 2000;(Suppl 58):38 2. Hoorweg-Nijman JJ, Kardos G, Roos JC, et al. Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol (Oxf) 1999;50:237 3. Wauben IPM, Atkinson Sa, Brandley C, Halton JM, Barr RD. Magnesium absorption using stable isotope tracers in healthy children and children treated for leukemia. Nutrition 2001;17:221. 4. Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl 1998;11:35 5. Wu B, Atkinson SA, Halton JM, Barr RD. Hypermagnesiuria and hypercalciuria in childhood leukemia: an effect of amikacin therapy. J Pediatr Hematol Oncol 1996;18:86 6. Abrams SA. Using stable isotopes to assess mineral requirements in children. Am J Clin Nutr 1999;70:955 7. Abrams SA, Ellis KJ. Multicompartmental analysis of magnesium and calcium kinetics during growth: relationships with body composition. Magnes Res 1998; 11:307 8. Feillet-Coudray C, Coudray C, Bruˆle´ F, et al. Exchangeable magnesium pool masses in rats are related to magnesium status. J Nutr 2000;30:2306

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The Brain–Lipid–Heart Connection ␻-3 Polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA; 20:5 ␻-3), and docosahexaenoic acid (DHA; 22:6 ␻-3) are believed to prevent coronary heart disease (CHD).1– 4 The Diet and Reinfarction Trial,5 the Health Professionals Study,6 the U.S. Physicians’ Health Study,7 the Zutphen study,8 the 30-y follow-up of the Western Electric study,9 the Honolulu Heart program,10 the Lyon Diet Heart Study,11 and the Indian trial by Singh et al.12 have strongly suggested that ␻-3 fatty acids have a protective effect against CHD. The recently concluded GISSI trial also showed that treatment with ␻-3 fatty acids but not with vitamin E lowered the risk of death, non-fatal myocardial infarction, and stroke.13 Some studies have not confirmed these findings.14 –17 ␻-3 Fatty acids can influence eicosanoid metabolism, inflammation, ␤-metabolism, endothelial function, cytokine growth factors, and expression of adhesion molecules, but none of these mechanisms can adequately explain the beneficial actions of EPA and DHA in

Correspondence to: U. N. Das, MD, FAMS, EFA Sciences LLC, 1420 Providence Highway, Suite 266, Norwood, MA 02062, USA. E-mail: [email protected]

CHD.1 It is important to know how ␻-3 fatty acids act, to develop new drugs and chemicals or newer methods of treatment that will be useful in treating CHD. Further, ␻-3 fatty acids are endogenous substances, so a better understanding of their actions can show how the body protects itself. I suggest that ␻-3 fatty acids in addition to their ability to suppress the production of proinflammatory cytokines can enhance brain acetylcholine levels and parasympathetic tone, resulting in an increase in heart rate variability and, hence, protection from malignant ventricular arrhythmias, the major cause of death from CHD. I also propose that this change in the concentrations of proinflammatory cytokines and increase in parasympathetic tone is the common mechanism by which regular physical exercise and the glucose–insulin–potassium regimen protects against CHD. Tumor necrosis factor-␣ (TNF-␣), which is released early in the course of acute myocardial infarction (AMI),18 can decrease myocardial contractility in a dose-dependent fashion.19 This myocardial depressant action of TNF-␣ can be ameliorated with specific monoclonal antibodies against TNF-␣.19 TNF-␣ stimulates neutrophils, monocytes, T cells, and endothelial cells to generate free radicals, which also can damage the myocardium.20 Further, TNF-␣ causes endothelial dysfunction and apoptosis,21 triggers procoagulant activity and fibrin deposition,22 and enhances freeradical generation and nitric oxide (NO) synthesis in a variety of cells.23 EPA and DHA can inhibit the production of interleukin (IL)–1, IL-2, and TNF-␣ in vitro and in vivo.24 –26 Further, ␻-3 fatty acids can regulate superoxide anion generation and enhance the production of NO,27 a vasodilator and platelet antiaggregator. NO has antiinflammatory actions under certain circumstances.28 The lipid abnormalities found in patients with CHD can also be related to increases in their levels of TNF-␣. For example, elevated plasma levels of TNF-␣ were associated with obesity and insulinresistance syndrome,29 hypertriglyceridemia and glucose intolerance,30 and hyperleptinemia.31 Hence, daily intake of ␻-3 PUFAs can decrease complications such as thrombosis, malignant arrhythmias, and secondary damage to the myocardium and brain caused by excess production of proinflammatory cytokines such as TNF-␣ and free radicals especially after AMI and coronary artery bypass graft surgery. Dietary EPA and DHA can increase heart rate variability in individuals who have had myocardial infarction and thus reduce malignant ventricular arrhythmias and sudden cardiac death.32 In general, increased parasympathetic tone is reflected in increased heart rate variability, which increases the ventricular fibrillation threshold and protects the myocardium against ventricular arrhythmias; increased sympathetic tone has the opposite effect. Therefore, it is important to maintain a normal balance between sympathetic and parasympathetic tones so that the incidence of ventricular fibrillation does not increase. This is especially important immediately after AMI or coronary artery bypass graft surgery. In this context, it is interesting to note that dietary DHA can enhance hippocampal acetylcholine levels.33 Borovikova et al.34 showed that vagus nerve stimulation in vivo inhibits TNF synthesis in the liver and that acetylcholine, the principle vagal neurotransmitter, significantly attenuates the release of proinflammatory cytokines TNF, IL-1␤, IL-6, and IL-18 but not the antiinflammatory cytokine IL-10 in lipopolysaccharide-stimulated human macrophages in vitro. Hence, I suggest that increases in brain acetylcholine levels induced by supplementation with EPA and DHA leads to an increase in the parasympathetic tone and thus an increase in heart rate variability and protection from ventricular arrhythmias. EPA and DHA seem to use two mechanisms to suppress the production of proinflammatory and myocardial depressant cytokines: direct inhibition of their synthesis and augmentation of acetylcholine levels. This possibility suggests that an inverse relationship exists between plasma TNF levels and parasympathetic tone: the higher the TNF levels, the lower the parasympathetic tone, and vice versa.

Nutrition Volume 17, Number 3, 2001 This notion, if true, might explain the beneficial effect of exercise against ischemic heart disease. Yamashita et al.35 showed that exercise significantly reduces the magnitude of myocardial infarction in rats and that this cardioprotective action parallels the change in the activity of manganese superoxide dismutase. In addition to increasing the formation of prostacyclin and the plasma levels of high-density lipoprotein and decreasing that of thromboxane A2,36 regular exercise changed the muscle membrane phospholipid profile such that the unsaturation index was significantly lower in the trained than in the sedentary rats, which largely had lower levels of arachidonic acid and DHA.37 This finding suggests increased use of these fatty acids. Exercise can increase parasympathetic tone and heart rate variability.38,39 Exercise can enhance formation of IL-4, IL-10, and transforming growth factor-␤, which have antiinflammatory actions and inhibit production of proinflammatory cytokines IL-1, IL-2, and TNF-␣ (reviewed by Das27), and reduce serum levels of C-reactive protein.40 Transforming growth factor-␤ has strong cardioprotective actions, especially against ischemia.41 The association of exercise with increased parasympathetic tone and enhanced levels of antiinflammatory cytokines is similar to the actions of EPA and DHA on these parameters. This association suggests that even regular exercise can enhance brain acetylcholine levels reflected in the form of increased parasympathetic tone. The glucose–insulin–potassium (GIK) regimen, used to treat diabetic ketoacidosis and moderate degrees of hyperglycemia, was recommended to patients with acute myocardial infarction, especially those who are poor candidates for thrombolytic therapy and in whom the risk of bleeding is high.42,43 GIK regimen can inhibit TNF-␣, production of macrophage migration inhibitory factor (MIF; a cytokine with proinflammatory actions), and generation of superoxide anions (reviewed by Das44). Insulin enhances the activity of ␦-6-desaturase (reviewed by Das and colleagues45,46) and so can increase formation of gamma linolenic acid and DHA from their respective precursors and also is a potent stimulator of NO synthesis.47 This evidence suggests that insulin can modulate immune response and has antiinflammatory actions.44 Hill et al. showed that the olfactory area and the closely related limbic regions, neocortex, and accessory motor areas of the basal ganglia and the cerebellum are rich in insulin receptors.48 Insulinreceptor tyrosine kinase substrates p58/53 and the insulin receptor are components of synapses in the central nervous system.49 TNF-␣ induces signals that trigger neuronal cell death, which can be antagonized by the survival peptide, insulin-like growth factor-I, and possibly insulin.50,51 However, arachidonic acid, DHA, and other PUFAs have significant neuroprotective action.52 Does this mean that the beneficial effect of GIK regimen in AMI is related to the action of insulin in the brain? Because insulin activates ␦-6-desaturase, suppresses TNF-␣ and MIF (which also might have neurotoxic action) synthesis, and has neuroprotective action, one important function of insulin in the brain is likely protecting neurons from the death signals of TNF-␣ and MIF, similar to their protective action in the heart. Insulin is likely aided in this function by various PUFAs including DHA, which is present in large amounts in the brain. The findings that hyperinsulinemia improves memory in patients with Alzheimer’s disease53 and that dietary DHA increases brain acetycholine levels34 and enhances learning performance in rats54 support this view. Hence, I suggest that insulin protects heart and brain from insults induced by TNF-␣, MIF, and free radicals. Concentrations of DHA can be increased by the action of insulin on ␦-6-desaturase and ␦-5-desaturase, which in turn can increase levels of brain acetylcholine and vagal tone. Increased vagal tone can increase heart rate variability and decrease the incidence of arrhythmias and thus contribute to the beneficial action of GIK regimen in AMI. Recent studies also suggested that administration of insulin can prevent death caused by thrombosis in experimental animals55 and can be attributed to the ability of insulin to enhance NO production.56 Thus, two major functions of insulin in the brain might be to 1)

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FIG. 1. Scheme showing the possible relationships between exercise, insulin, EPA and DHA, the central nervous system, cytokines, free radicals, nitric oxide, PGI2, and CHD. EPA and DHA increase parasympathetic tone, enhance acetylcholine levels in the brain, protect brain neurons from the cytotoxic actions of TNF-␣, increase HRV, decrease the secretion of TNF-␣, IL-1, IL-6, IL-8, and MIF, enhance TGF-␤ levels, inhibit platelet aggregation, preserve endothelial cell function, enhance nitric oxide and PGI2 production, decrease free-radical generation and hyperlipidemia, and thus protect against inflammation, thrombosis, atherosclerosis, and CHD. Exercise decreases sympathetic tone, enhances parasympathetic tone, increases SOD levels, increases production of TGF-␤, IL-4, and IL-10, inhibits platelet aggregation, decreases hyperlipidemia, and thus protects against thrombosis, atherosclerosis, and CHD. Insulin increases parasympathetic tone and thus brain acetylcholine levels, protects neurons from the cytotoxic actions of TNF-␣, decreases production of TNF-␣ and MIF, enhances production of nitric oxide and thus antiinflammation, and prevents thrombosis, atherosclerosis, and CHD. A balance is generally maintained: TNF-␣, IL-1, IL-6, IL-18, and MIF versus TGF-␤, IL-4, and IL-10; free radicals versus nitric oxide and PGI2; platelet function versus endothelial secretion of nitric oxide and PGI2; and sympathetic versus parasympathetic tone. CHD, coronary disease; DHA, docosahexaenoic acid (22:6 ␻-3); EPA, eicosapentaenoic acid (20:5 ␻-3); HRV, heart rate variability; IL, interleukin; MIF, macrophage migration inhibitory factor; PGI2, prostacyclin; SOD, superoxide dismutase; TGF-␤, transforming growth factor-␤; TNF-␣, tumor necrosis factor-␣; TXA2, thromboxane A2.

antagonize the neurotoxic actions of TNF-␣ and prevent neurodegenerative conditions and 2) induce production of adequate amounts of NO from the vascular endothelial cells to prevent inappropriate thrombosis and maintain cerebral blood flow. This notion suggests a close interaction between insulin and insulinbinding receptors, TNF-␣, MIF, PUFAs, and neurotransmitters such as acetylcholine (Fig. 1). From the preceding discussion, it is evident that regular supplementation with DHA and EPA, regular but not necessarily

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severe exercise, and GIK regimen have common pathways for their beneficial actions including alterations in the cytokine profile, balance between oxidants and antioxidants, upregulation of parasympathetic tone, and induction of vasodilator substances prostacyclin and NO. Regular intake of EPA and DHA is unlikely to produce gross increases in parasympathetic tone that would depress myocardial contractility. The very fact that regular and long-term intake of EPA and DHA can prevent CHD1–13 suggests that these fatty acids also are less unlikely to have significant side effects. In addition, supplementation with EPA and DHA lowers serum levels of plasma triacylglycerol, cholesterol, and lowdensity lipoprotein, enhances concentrations of high-density lipoprotein, prevents platelet aggregation and thrombosis, and arrests, prevents, or postpones atherosclerosis (reviewed by Das57,58), effects that contribute to the prevention of CHD. That supplementation with EPA and DHA (in addition to GIK regimen and regular exercise) can increase cerebral acetycholine levels is particularly interesting and suggests a potential mechanism by which dietary factors can influence parasympathetic tone, heart rate variability, malignant ventricular arrhythmias, and sudden cardiac death. The actions of EPA and DHA on the synthesis of cytokines and parasympathetic tone also might explain their beneficial actions in various inflammatory conditions such as systemic lupus erythematosus,27 rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease,44 and neurodegenerative conditions.52,59

U. N. Das, MD, FAMS EFA Sciences LLC Norwood, Massachusetts, USA

15.

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REFERENCES 28. 1. Prichard BNC, Smith CCT, Ling KLE, Betteridge DJ. Fish oils and cardiovascular disease. BMJ 1995;310:819 2. Kagawa Y, Nishizawa M, Suzuki M, et al. Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular diseases. J Nutr Sci Vitaminol (Tokyo) 1982;28:441 3. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205 4. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med 1992;200:177 5. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;ii:757 6. Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. Dietary intake of marine n-3 fatty acids, fish intake and the risk of coronary disease among men. N Engl J Med 1995;332:977 7. Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:23 8. Kromhout D, Bosschieter EB, de Lezenne CC. The inverse relationship between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205 9. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336:1046 10. Rodriguez BL, Sharp DS, Abbott RD, et al. Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers: the Honolulu Heart Program. Circulation 1996;94:952 11. De Lorgeril M, Salen P, Martin J-L, Moniaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779 12. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMJ 1992;304:1015 13. GISSI Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999;354:447 14. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart

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disease, part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765 Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease, part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827 Goodnight SH, Cairns JA, Fisher M, Fitzerald GA. Assessment of the therapeutic use of n-3 fatty acids in vascular disease and thrombosis. Chest 1992;102:374 Israel DH, Gorlin R. Fish oils in the prevention of atherosclerosis. J Am Coll Cardiol 1992;19:174 Cain BS, Harken AH, Meldrum DR. Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and perfusion. J Mol Cell Cardiol 1999;31:931 Li D, Zhao L, Liu M, et al. Kinetics of tumor necrosis factor alpha in plasma and the cardioprotective effect of a monoclonal antibody to tumor necrosis factor alpha in acute myocardial infarction. Am Heart J 1999;137:1145 Das UN. Can free radicals cause acute myocardial infarction? Med Hypotheses 1992;39:90 Fujita H, Morita I, Murota S. A possible involvement of ion transporters in tumor necrosis factor alpha and cycloheximide-induced apoptosis of endothelial cells. Mediat Inflamm 1999;8:211 Meldrom DR, Donnahoo KK. Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a post bypass cardiorenal syndrome. J Surg Res 1999;85:185 Ferrari R. Tumor necrosis factor in CHF: a double facet cytokine. Cardiovasc Res 1998;37:554 Kumar SG, Das UN, Kumar KV, et al. Effect of n-6 and n-3 fatty acids on the proliferation and secretion of TNF and IL-2 by human lymphocytes in vitro. Nutr Res 1992;12:815 Kumar GS, Das UN. Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins. Prostaglandins Leukot Essent Fatty Acids 1994;50:331 Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989;320:265 Das UN. Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine net work. Prostaglandins Leukot Essent Fatty Acids 1994;51:207 Guidot DM, Hybertson BM, Kitlowski RP, Repine JE. Inhaled nitric oxide prevents IL-1 induced neutrophil accumulation and associated acute edema in isolated rat lungs. Am J Physiol 1996;271:L225 Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med 1999;245:621 Jovinge S, Hamsten A, Tornvall P, et al. Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism 1998;47:113 Corica F, Allegra A, Corsonello A, et al. Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int J Obes Metab Disord 1999;23:355 Christensen JH, Gustenhoff P, Korup E, et al. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomized controlled trial. BMJ 1996;312:677 Minami M, Kimura S, Endo T, et al. Dietary docosahexaenoic acid increases cerebral acetylcholine levels and improves passive avoidance performance in stroke-prone spontaneously hypertensive rats. Pharmacol Biochem Behav 1997; 58:1123 Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458 Yamashita N, Hoshida S, Otsu K, et al. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med 1999;189:1699 Rauramaa R, Salonen JT, Harjula KK, et al. Effects of mild physical exercise on serum lipoproteins and metabolites of arachidonic acid: a controlled randomized trial in middle aged men. BMJ 1984;288:603 Helge JW, Ayre KJ, Hulbert AJ, et al. Regular exercise modulates muscle membrane phospholipid profile in rats. J Nutr 1999;129:1636 Fujimoto S, Uemura S, Tomoda Y, et al. Effects of exercise training on the heart rate variability and QT dispersion of patients with acute myocardial infarction. Jpn Circ J 1999;63:577 Jensen-Urstad K, Saltin B, Ericson M, et al. Pronounced resting bradycardia in male elite runners is associated with high heart rate variability. Scand J Med Sci Sports 1997;7:274 Smith JK, Dykes R, Douglas JE, et al. Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of ischemic heart disease. JAMA 1999;281:1722 Das UN. Transforming growth factor-beta: Is it an endogenous cardioprotector? Med Sci Res 1993;21:373

Nutrition Volume 17, Number 3, 2001 42. Ryan TJ, Antman EM, Brooks NH, et al. for the Committee on Management of Acute Myocardial Infarction 1999. Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 1999;100:1016 43. Ryan TJ, Antman EM, Brooks NH, et al. for the Committee on Management of Acute Myocardial Infarction 1999. Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1999; 34:890 44. Das UN. Possible beneficial action(s) of glucose-insulin-potassium regimen in acute myocardial infarction and inflammatory conditions: a hypothesis. Diabetologia 2001;43:1081 45. Das UN. Nutrients, essential fatty acids and prostaglandins interact to augment immune responses and prevent genetic damage and cancer. Nutrition 1989;5:106 46. Das UN, Horrobin DF, Begin ME, et al. Clinical significance of essential fatty acids. Nutrition 1988;4:337 47. Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000;101:676 48. Hill JM, Lesniak MA, Pert CB, Roth J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 1986;17:1127 49. Abbott MA, Wells DG, Fallon JR. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci 1999;19:7300 50. Venters HD, Tang Q, Liu Q, et al. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci USA 1999;96:9879 51. Venters HD, Dantzer R, Kelley KW. A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci 2000;23:175 52. Lauritzen I, Blondeau N, Heurteaux C, et al. Polyunsaturated fatty acids are potent neuroprotectors. EMBO J 2000;19:1784 53. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging 1996;17:123 54. Zhao W, Chen H, Xu H, et al. Brain insulin receptors and spatial memory: correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 1999; 274:34893 55. Sinha AK, Bhattacharya S, Acharya K, Mazumdar S. Administration of insulin prevents death due to thrombosis in mice. Ind J Physiol Allied Sci 1998;52:46 56. Kahn NN, Acharya K, Bhattacharya S, et al. Nitric oxide: the “second messenger” of insulin. IUBMB Life 2000;49:441 57. Das UN. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukot Essent Fatty Acids 2001;63:351 58. Das UN. Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol Cell Biochem 2001;215:145 59. Kyle DJ, Schaefer E, Patton G, Beiser A. Low serum docosahexaenoic acid is a significant risk factor for Alzheimer’s dementia. Lipids 1999;34(suppl): S245

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Malnutrition in the Critically Ill After more than 2 decades of nutritional awareness, malnutrition is still a noticeable common problem for hospitalized patients.1– 8 The prevalence of malnutrition varies from 30% to 50% in different studies according to the various criteria used: 50% of the patients were in abnormal nutritional status indices 1 wk after major surgery in the study of Hill et al.1; 38% of medical patients receiving ventilatory support appeared malnourished on their initial physical examination at the Omaha Veterans Administration Medical Center2; 30 –57% of the hospitalized patients were in protein-calorie malnutrition in National Taiwan University Hospi-

Correspondence to: Yi-Chia Huang, RD, PhD, No. 110 Sec. 1 Chien-Kuo N. Road, Chung-Shan Medical and Dental College, School of Nutrition and Institute of Nutritional Science, Taichung, Taiwan, 402. E-mail: [email protected]

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tal4; 30 –32% of the hospitalized patients were considered to be malnourished according to the method of a group-based reference at Bridgeport Hospital5; and 43% of the patients in an intensive care unit (ICU) were malnourished in another study.7 Startling findings in our study8 were that almost 100% of the mechanically ventilated critically ill patients were malnourished at admission to the ICU of Taichung Veteran General Hospital, Taiwan, but the prevalence of malnutrition decreased to 94% through nutrition support 14 d later according to one combination of objective nutritional parameters, the Maastricht Index.9 It is notable that the frequency of malnutrition was higher than that reported by others.1–7 The reasons might be that the patients from our study were receiving mechanical ventilation support and were from the ICU. Thus, the medical condition of our patients was probably more severe than that in other reports.1–7 The prevalence of malnutrition seems a serious worldwide problem for the critically ill. It has been hypothesized that malnutrition is one of the contributing factors of organ failure in the hospital.10 –12 Malnutrition may compromise the intestinal barrier function, which prevents bacteria from translocating to the blood and other organs; prolongs ventilator dependency as a result of failing to restore respiratory muscle strength and endurance6,13; increases the length of hospital stay14,15; and leads to increased morbidity and mortality rates.16 Critically ill patients are a particularly vulnerable group to be malnourished resulting from the severity and complications of illness, the complexity of ICU care, the inability to express hunger and eat normally, and potentially the physician’s inability to recognize the nutritional risk of patients. Ideally, early identification of nutritional status and provision of appropriate and aggressive nutritional support for critically ill patients may reduce the length of ventilator dependence, ICU or hospital stay, and mortality. Larca and Greenbaum3 found that 8 of 14 mechanically ventilated patients showing a good response to nutritional support were weaned from mechanical ventilation. Bassili and Deitel17 found that 54% of the patients receiving insufficient nutritional support, compared with 93% of the patients receiving sufficient nutritional support, were weaned from mechanical ventilation. In our study,8 results also showed a slight improvement in nutritional status after critically ill patients received nutritional support for 14 d. Nutritional support is essential in hospitalized patients, especially in those who are critically ill. The advantages and disadvantages of enteral, total parenteral, or combined nutritional support (enteral plus total parenteral) have been reviewed and discussed in many studies. Determining the optimal route of nutritional support for critically ill patients is complicated. However, enteral nutrition is more favorable than total parenteral nutrition because of the beneficial effects on the integrity of the intestinal mucosa of patients, lower cost, and fewer risks of complications. Although providing early and appropriate nutritional intervention for critically ill patients has been recognized to prevent malnutrition, physicians are often unaware which patients are at nutritional risk at admission.18 Butterworth19 noted more than 20 y ago that malnutrition was common and unrecognized by the physicians in the hospital. Driver and LeBrun2 examined the nutritional management of patients requiring prolonged ventilatory supplementation, and found that only 3 of 26 patients received sufficient nutritional support to satisfy minimum metabolic needs. A study by Roubenoff et al.18 indicated that only 12.5% of patients were correctly identified as being malnourished by hospital house staff. Iatrogenic malnutrition in critically ill patients apparently occurs in the hospital. Although clinical dietitians help physicians to assess nutritional status and manage nutritional therapeutic plan for hospitalized patients, critically ill patients are totally dependent on doctors to provide most or all of their nutrients. Unfortunately, physicians usually do not receive sufficient training to recognize and prevent malnutrition. To solve this problem, Roubenoff et al.18 suggested that physician education should effectively improve the nutritional care of patients without undue difficulty or expense.