Life Extension Magazine®

Older couple hiking after balancing their magnesium levels

The National Magnesium Crisis

The majority of Americans do not obtain enough magnesium, which predisposes them to a host of serious illnesses. Human studies show that low magnesium levels accelerate pathological aging, while higher magnesium intake reduces overall mortality.

Scientifically reviewed by: Dr. Amanda Martin, DC, in October 2024. Written by: Stuart Greenfield.

The medical community does not yet understand the life-sustaining properties of magnesium.

In today’s world of high drug prices, it’s hard for physicians to conceive how an inexpensive mineral can provide such diverse health benefits.

Volumes of studies show that those with higher magnesium intake have sharply lower rates of hypertension1 and heart disease,2 fewer strokes,3 better blood sugar control,4 lower rates of kidney disease,5 less risk of cognitive decline,6 healthier bones and teeth,7 and even lower risk of migraine headache.8 As if this weren’t enough, magnesium has also been linked to longevity.9

The majority of Americans do not obtain enough magnesium from dietary sources.10 The result is an epidemic deficiency of a nutrient vital to protecting against degenerative aging.

Magnesium and Longevity

Magnesium and Longevity  

Magnesium is the fourth most abundant mineral in the human body. More than 300 enzymes require magnesium in order to function properly.11

Magnesium is crucial for converting chemical energy from food into useful energy for our bodies, and it has unique functions in regulating blood sugar, blood vessel health, heart function, and brain electrical activity. About half of our total body stores of magnesium are found in bone, which contributes to its strength and integrity.7,11

In fact, virtually every system in the body requires magnesium for its function.

Despite this fact, most of us are not getting enough magnesium to support good health. When humans got their water the old-fashioned way, from natural springs and wells, it was easy to get enough of this naturally-occurring mineral. But today’s world of municipal water supplies and bottled, purified water has left us woefully deficient.

Of people over age 70, 80% of men and 70% of women fail to get the estimated average requirement (350 mg/day for men and 265 mg/day for women) of magnesium from their diets.12,13 Compounding the problem, magnesium levels decline with age, and low magnesium levels are commonly seen in age-related disorders.6,14

To make matters still worse, many common drugs are known to deplete the body of magnesium, further contributing to low levels.15 Of these, the proton-pump inhibitors (PPIs)—drugs used by millions for heartburn relief—are the most notorious and widespread.16,17

Americans’ low magnesium intake—coupled with declining magnesium status with age—represent major obstacles to optimal health and longevity.11

In fact, the risk of death from any cause is significantly higher in people 65 and older who have lower levels of magnesium intake or low blood levels of magnesium.18,19 Basic lab studies show that low magnesium levels accelerate the aging process at the cellular level, increasing the number of senescent cells incapable of further replication or participation in healing.9,20

The good news is that ample magnesium intake and blood levels have been associated with reduced mortality. In one study, higher magnesium blood levels appeared to predict better outcomes among hospitalized patients who were critically ill. While 55% of those who had low blood levels when they were admitted died, that figure was only 35% in those with normal levels.21 (Optimal levels may have conferred greater-life-protective effects.)

Magnesium has been long-neglected by mainstream physicians, much like higher-dose vitamin D. Like vitamin D, however, magnesium is suddenly coming into its own as a result of a multitude of recent studies showing its ability to promote cardiovascular health,2 lower stroke risk,3 regulate blood sugar levels,4 help prevent osteoporosis,7 and more.8

What You Need To Know
The Benefits of Magnesium

The Benefits of Magnesium

  • Magnesium is the fourth most common mineral in our bodies.
  • Although it has been overlooked for years, magnesium is now emerging as a multi-targeted nutrient with myriad functions throughout the body.
  • Magnesium is particularly important in electrically active cells, such as those in the brain, heart, muscles, and artery linings.
  • 70% to 80% of Americans fail to meet the estimated average requirements of magnesium from their diet, leaving them vulnerable to disorders linked to its deficiency.
  • Studies now show that ample magnesium intake is protective against a host of age-related disorders, including cardiovascular disease and stroke, diabetes, osteoporosis, and more.
  • For reliable, consistent daily intake of magnesium, look for a supplement that offers both immediate and extended release.

Magnesium Promotes Cardiovascular Health

One of magnesium’s most critical benefits is its ability to protect against the number one killer of Americans: cardiovascular disease. Studies show that people with the highest dietary intake of magnesium are 37% less likely to die from a sudden cardiac death.22 Even better, compared to those with the lowest intake, those with the highest intake were found to be 34% less likely to die from any cause at all.23

Magnesium has numerous mechanisms of action that explain its ability to protect against cardiac deaths. The cardioprotective actions include magnesium’s role in maintaining heartbeats and preventing arrhythmias, and in protecting blood vessels against the accumulation of calcium. This can help lower the risk of atherosclerosis, which is a well-known predictor of heart disease, stroke, and death.22,24,25

Studies show that for each 50 mg increase in daily magnesium intake, calcification of the heart’s main arteries decreased by 22%, and calcification of the aorta—the body’s main artery—fell by 12%. As a result, those with the highest magnesium intake were 58% less likely to have any calcification of the coronary arteries and 34% less likely to have any calcification of the abdominal aorta.26

On the other hand, low dietary intakes and blood levels of magnesium are associated with elevated risk for cardiovascular diseases in general, and of arterial calcification specifically.2,25,27,28 One study showed that those with the lowest levels of serum magnesium were 2.1 times more likely to have coronary artery calcification.29

These studies showing the dangers of low magnesium levels—and the incredible benefits of obtaining adequate magnesium levels—make it clear that magnesium is an essential component of cardiovascular health.

Magnesium Supplements Vary
Magnesium Supplements Vary

There is no single “optimal” form of magnesium for supplementation. Instead, it is important to consider the reason for the supplement.

One approach for ideal magnesium supplementation is to use a 2-part supplement composed partly of magne­sium citrate in a quick-release form and magnesium oxide in an extended-release form.

Magnesium oxide is highly concentrated, allowing a lot of magnesium to go into a relatively small pill. Because magnesium oxide is somewhat less bioavailable, it is ideal for an extended-release formulation, which gradually makes its way into the circulation.

Magnesium citrate, on the other hand, is less concentrated but is highly bioavailable, which allows for quick release of the mineral in a form that is readily absorbed.

This kind of innovative combination provides extended magnesium benefits in a single supplement.

Magnesium Lowers Stroke Risk

There are numerous factors that can lead to a stroke. For example, strokes can occur when blood pressure is too high, weakening cerebral arteries in a way that can induce bleeding in the brain (hemorrhagic stroke).

More common strokes occur when artery linings are damaged, setting up conditions for an artery-blocking clot (ischemic stroke). They also commonly occur when a heart arrhythmia or artificial heart valve creates a blood clot that travels into a cerebral artery and blocks vital blood flow (ischemic stroke).30,31

Maintaining consistent magnesium levels may help to prevent all of these processes.

In one study, men with the highest magnesium intake had significantly lower blood pressure and total cholesterol, and were 41% less likely to have a stroke than those with the lowest magnesium intake.3

And according to a 24-year-long study of nearly 43,000 men, subjects with the highest supplemental magnesium intake had a 26% lower stroke risk than those with the lowest intake.32

Studies in women have also shown the dangers of having low blood levels of this mineral. In one of these studies, women with the lowest blood levels of magnesium were found to be 34% more likely to have an ischemic stroke than those with higher levels.33

And in another study, low blood magnesium levels were associated with an approximate 50% greater likelihood of developing atrial fibrillation (a type of irregular heartbeat that can cause a blood clot that can lead to a stroke) compared to those with higher levels.34

Magnesium is so critical for helping maintain a regular heartbeat that hospitals use intravenous magnesium to prevent atrial fibrillation following heart bypass surgery.35

Magnesium Improves Blood Sugar Control

Aging and obesity induce insulin resistance, which elevates blood sugar levels. High, or even “borderline high,” blood sugar inflicts glycation damage to proteins throughout the body that prevents them from functioning properly. Controlling blood sugar—even in nondiabetic people—is a critical approach to preventing age-related diseases.

Magnesium supplementation improves the body’s response to insulin, which takes sugar out of the bloodstream.

A comprehensive review of 21 smaller clinical trials showed that magnesium supplementation led to significant improvements in insulin resistance.4 For example, after just four months, those supplementing with magnesium had an average of 13 mg/dL lower blood sugar levels compared with placebo recipients. The longer the subjects took the magnesium, the greater the improvements in insulin resistance. The effects were greatest in those subjects whose magnesium levels were lowest at the beginning of the study.

Importantly, these improvements were seen in both diabetic and nondiabetic patients. This is critical because nondiabetics with borderline elevated blood sugar are at increased risk for developing diabetes. This study showed that magnesium is effective both for treating and for preventing diabetes.

Magnesium and Kidney Protection

The kidneys take a beating every day as they filter out waste products from blood. This leaves them particularly vulnerable to the effects of blood pressure and endothelial dysfunction, as well as the ravages of borderline or high glucose levels. Sustained over a lifetime, those factors raise the risk of serious kidney disease.

Kidney disease itself weakens the kidney’s ability to regulate magnesium. This contributes to ongoing losses of magnesium and makes magnesium supplementation that much more critical.36

Researchers studied more than 13,000 middle-aged adults for over 20 years to find out if there was a connection between magnesium levels and kidney disease. They discovered that low magnesium levels are a strong, independent risk factor for chronic kidney disease.5

What they found was that, compared with those with the highest magnesium levels, those with the lowest magnesium levels had a 58% greater risk of developing chronic kidney disease, and a nearly 2.4-fold greater risk of developing end-stage renal disease, requiring dialysis to sustain life.5

Magnesium Supports Bone and Dental Health

While calcium is a well-known bone-protecting nutrient, few people recognize the important role magnesium plays in maintaining healthy bones. In fact, about half of total body magnesium is stored in bones.7,11

Because of that, low levels of magnesium directly lead to osteoporosis by depriving bone tissue of one of its most essential structural components.

Low magnesium also indirectly weakens bones by stimulating inflammatory cytokines that contribute to osteoporosis by increasing the breakdown of bones.37,38

The fact that 70%-80% of Americans don’t meet the daily average requirements of magnesium from their diet puts the large majority of the population at risk for this serious condition. Fortunately, assuring good magnesium intake helps protect against osteoporosis.

A large study of women demonstrated that those whose daily magnesium intake exceeded 423 mg had greater hip and whole-body bone mineral density compared with those getting less than 207 mg daily.39

This protection extends to teeth as well. Like bones, teeth also have high magnesium content and rely on its presence for their structure.40 Because of this connection, magnesium supplementation has been found to improve tooth attachment and help subjects retain more teeth.41

Magnesium and Migraines

Magnesium and Migraines  

Low levels of magnesium are associated with increased risk for migraines.8,42-45 This connection could be related to a genetic inability to properly manage magnesium in the gut and kidneys.42

While there is no cure for migraines, supplementing with magnesium has numerous benefits for those suffering from the condition.

A study of 81 migraine sufferers found that supplementing with magnesium for 12 weeks reduced the frequency of migraines by 41.6%, decreased the number of days with a migraine, and slightly reduced the duration and intensity of the attacks.46

Other studies have shown that oral magnesium may prevent migraines, and that intravenous magnesium may be an effective treatment.45

Researchers have stated: “Intravenous and oral magnesium should be adapted as parts of [a] multimodal approach to reduce migraine.”8

How It Works

Magnesium is an absolute requirement for energy production from fats and carbohydrates and for synthesis of new proteins in our body.47 Magnesium helps regulate the flow of other mineral ions in and out of cells in skeletal and heart muscle, in artery walls, and in brain and nerve cells.

As a result, it is related to conditions as diverse as depression (involving brain cells), muscle cramps (involving skeletal muscle), heart arrhythmias (involving heart muscle cells), and hypertension (often involving cells in arterial walls).1,48-52

Magnesium also fights against the chronic, low-grade inflammation associated with aging and unhealthy lifestyles.53-55 This effect has been traced to magnesium’s ability to reduce the activity of the “master inflammation regulator” called NF-kB, which results in downstream shutdown of cytokines and other pro-inflammation signaling molecules.56

Inflammation is a major contributor to a wide range of chronic, age-related diseases. This explains in part why poor magnesium status is so closely associated with diabesity (diabetes and obesity) and metabolic syndrome, with cardiovascular disease, and neurodegenerative disorders such as Alzheimer’s.57-59

The role of magnesium deficiency in chronic inflammatory stress led researchers to conclude that it should be considered a significant nutrient for health and well-being.54

Magnesium’s Underappreciated Role in Healthy Longevity
Healthy Longevity

When Life Extension® raised awareness of the need for higher-dose vitamin D, it was thought of only as a nutrient added to milk for strong bones and teeth.

Physicians are just now realizing that vitamin D plays a key role in everything from immunity and brain function to heart disease and diabetes.

Today, Life Extension continues to raise awareness of the essential nature of another nutrient that is vastly underappreciated, i.e., magnesium.

Since 1981, Life Extension has recommended higher magnesium intake, despite conventional medical authorities seeing little or no value to it.

This is regrettable, since magnesium is perhaps the most deficient mineral in the American diet.

Summary

Magnesium has been described as an “orphan nutrient,” because so few people really understand its importance. Yet it is involved in hundreds of critical body processes.

Few Americans get adequate magnesium to support all of those processes, leaving them vulnerable to a host of potentially serious diseases. Fortunately, magnesium is a low-cost supplement available without the need of a doctor’s prescription.

Magnesium is emerging as this generation’s vitamin D—an overlooked nutrient that favorably alters human disease risk and improves quality of life.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

Editor's Note

Science continues to evolve, and new research is published daily. As such, we have a more recent article on this topic: Magnesium: The Overlooked Mineral

References

  1. Kass L, Weekes J, Carpenter L. Effect of magnesium supplementation on blood pressure: a meta-analysis. Eur J Clin Nutr. 2012;66(4):411-8.
  2. Del Gobbo LC, Imamura F, Wu JH, et al. Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2013;98(1):160-73.
  3. Bain LK, Myint PK, Jennings A, et al. The relationship between dietary magnesium intake, stroke and its major risk factors, blood pressure and cholesterol, in the EPIC-Norfolk cohort. Int J Cardiol. 2015;196:108-14.
  4. Simental-Mendia LE, Sahebkar A, Rodriguez-Moran M, et al. A systematic review and meta-analysis of randomized controlled trials on the effects of magnesium supplementation on insulin sensitivity and glucose control. Pharmacol Res. 2016;111:272-82.
  5. Tin A, Grams ME, Maruthur NM, et al. Results from the Atherosclerosis Risk in Communities study suggest that low serum magnesium is associated with incident kidney disease. Kidney Int. 2015;87(4):820-7.
  6. Veronese N, Zurlo A, Solmi M, et al. Magnesium Status in Alzheimer’s Disease: A Systematic Review. Am J Alzheimers Dis Other Demen. 2016;31(3):208-13.
  7. Castiglioni S, Cazzaniga A, Albisetti W, et al. Magnesium and Osteoporosis: Current State of Knowledge and Future Research Directions. Nutrients. 2013;5(8):3022-33.
  8. Chiu HY, Yeh TH, Huang YC, et al. Effects of Intravenous and Oral Magnesium on Reducing Migraine: A Meta-analysis of Randomized Controlled Trials. Pain Physician. 2016;19(1):E97-112.
  9. Killilea DW, Ames BN. Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. Proc Natl Acad Sci U S A. 2008;105(15):5768-73.
  10. Available at: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/. Accessed August 29, 2016.
  11. Grober U, Schmidt J, Kisters K. Magnesium in Prevention and Therapy. Nutrients. 2015;7(9):8199-226.
  12. Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev. 2012;70(3):153-64.
  13. Available at: http://www.ncbi.nlm.nih.gov/books/NBK109816/. Accessed August 30, 2016.
  14. Veronese N, Zanforlini BM, Manzato E, et al. Magnesium and healthy aging. Magnes Res. 2015;28(3):112-5.
  15. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95(1):1-46.
  16. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69(2):338-41.
  17. Atkinson NS, Reynolds DJ, Travis SP. ‘Lemonade Legs’: Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intest Res. 2015;13(3):227-32.
  18. Huang YC, Wahlqvist ML, Kao MD, et al. Optimal Dietary and Plasma Magnesium Statuses Depend on Dietary Quality for a Reduction in the Risk of All-Cause Mortality in Older Adults. Nutrients. 2015;7(7):5664-83.
  19. Reffelmann T, Ittermann T, Dorr M, et al. Low serum magnesium concentrations predict cardiovascular and all-cause mortality. Atherosclerosis. 2011;219(1):280-4.
  20. Bhatia-Dey N, R. KR, Stair SE, et al. Cellular Senescence as the Causal Nexus of Aging. Frontiers in Genetics. 2016;7(13):doi:10.3389/fgene.2016.00013.
  21. Safavi M, Honarmand A. Admission hypomagnesemia--impact on mortality or morbidity in critically ill patients. Middle East J Anaesthesiol. 2007;19(3):645-60.
  22. Chiuve SE, Korngold EC, Januzzi JL, Jr., et al. Plasma and dietary magnesium and risk of sudden cardiac death in women. Am J Clin Nutr. 2011;93(2):253-60.
  23. Guasch-Ferre M, Bullo M, Estruch R, et al. Dietary magnesium intake is inversely associated with mortality in adults at high cardiovascular disease risk. J Nutr. 2014;144(1):55-60.
  24. Demer LL, Tintut Y. Vascular Calcification: Pathobiology of a Multifaceted Disease. Circulation. 2008;117(22):2938-48.
  25. Nicoll R, Howard JM, Henein MY. A review of the effect of diet on cardiovascular calcification. Int J Mol Sci. 2015;16(4):8861-83.
  26. Hruby A, O’Donnell CJ, Jacques PF, et al. Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study. JACC Cardiovasc Imaging. 2014;7(1):59-69.
  27. Tzanakis IP, Stamataki EE, Papadaki AN, et al. Magnesium retards the progress of the arterial calcifications in hemodialysis patients: a pilot study. Int Urol Nephrol. 2014;46(11):2199-205.
  28. Yamori Y, Sagara M, Mizushima S, et al. An inverse association between magnesium in 24-h urine and cardiovascular risk factors in middle-aged subjects in 50 CARDIAC Study populations. Hypertens Res. 2015;38(3):219-25.
  29. Lee SY, Hyun YY, Lee KB, et al. Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease. Nutr Metab Cardiovasc Dis. 2015;25(11):1056-61.
  30. Keach JW, Bradley SM, Turakhia MP, et al. Early detection of occult atrial fibrillation and stroke prevention. Heart. 2015;101(14):1097-102.
  31. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023162/. Accessed August 30, 2016.
  32. Adebamowo SN, Spiegelman D, Flint AJ, et al. Intakes of magnesium, potassium, and calcium and the risk of stroke among men. Int J Stroke. 2015;10(7):1093-100.
  33. Akarolo-Anthony SN, Jimenez MC, Chiuve SE, et al. Plasma magnesium and risk of ischemic stroke among women. Stroke. 2014;45(10):2881-6.
  34. Khan AM, Lubitz SA, Sullivan LM, et al. Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study. Circulation. 2013;127(1):33-8.
  35. Gu WJ, Wu ZJ, Wang PF, et al. Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. Trials. 2012;13:41.
  36. Cunningham J, Rodríguez M, Messa P. Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients. Clinical Kidney Journal. 2012;5(Suppl 1):i39-i51.
  37. Rude RK, Singer FR, Gruber HE. Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr. 2009;28(2):131-41.
  38. Ishii A, Imanishi Y. Magnesium disorder in metabolic bone diseases. Clin Calcium. 2012;22(8):1251-6.
  39. rchard TS, Larson JC, Alghothani N, et al. Magnesium intake, bone mineral density, and fractures: results from the Women’s Health Initiative Observational Study. Am J Clin Nutr. 2014;99(4):926-33.
  40. Steinfort J, Driessens FC, Heijligers HJ, et al. The distribution of magnesium in developing rat incisor dentin. J Dent Res. 1991;70(3):187-91.
  41. Meisel P, Schwahn C, Luedemann J, et al. Magnesium deficiency is associated with periodontal disease. J Dent Res. 2005;84(10):937-41.
  42. Mauskop A, Varughese J. Why all migraine patients should be treated with magnesium. J Neural Transm (Vienna). 2012;119(5):575-9.
  43. Talebi M, Savadi-Oskouei D, Farhoudi M, et al. Relation between serum magnesium level and migraine attacks. Neurosciences (Riyadh). 2011;16(4):320-3.
  44. Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9(11):637-44.
  45. Sun-Edelstein C, Mauskop A. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother. 2009;9(3):369-79.
  46. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-63.
  47. Available at: http://lpi.oregonstate.edu/mic/minerals/magnesium. Accessed August 31, 2016.
  48. Kanbay M, Yilmaz MI, Apetrii M, et al. Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients. Am J Nephrol. 2012;36(3):228-37.
  49. Kolte D, Vijayaraghavan K, Khera S, et al. Role of magnesium in cardiovascular diseases. Cardiol Rev. 2014;22(4):182-92.
  50. Haigney MC, Berger R, Schulman S, et al. Tissue magnesium levels and the arrhythmic substrate in humans. J Cardiovasc Electrophysiol. 1997;8(9):980-6.
  51. Available at: http://emedicine.medscape.com/article/2038394-overview#a4. Accessed August 31, 2016.
  52. Rajizadeh A, Mozaffari-Khosravi H, Yassini-Ardakani M, et al. Serum Magnesium Status in Patients Subjects with Depression in the City of Yazd in Iran 2013-2014. Biol Trace Elem Res. 2016;171(2):275-82.
  53. Kharitonova M, Iezhitsa I, Zheltova A, et al. Comparative angioprotective effects of magnesium compounds. J Trace Elem Med Biol. 2015;29:227-34.
  54. Nielsen FH. Effects of magnesium depletion on inflammation in chronic disease. Curr Opin Clin Nutr Metab Care. 2014;17(6):525-30.
  55. Lamhot VB, Khatib N, Ginsberg Y, et al. Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring. Am J Obstet Gynecol. 2015;213(6):851 e1-8.
  56. Sugimoto J, Romani AM, Valentin-Torres AM, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012;188(12):6338-46.
  57. Chandrasekaran NC, Weir C, Alfraji S, et al. Effects of magnesium deficiency--more than skin deep. Exp Biol Med (Maywood). 2014;239(10):1280-91.
  58. Blaszczyk U, Duda-Chodak A. Magnesium: its role in nutrition and carcinogenesis. Rocz Panstw Zakl Hig. 2013;64(3):165-71.
  59. Hata A, Doi Y, Ninomiya T, et al. Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study. Diabet Med. 2013;30(12):1487-94.