Building Bone: The Novel Role of Tocotrienols
Biography: The focus of Dr. Ima-Nirwana’s research is the impact of natural products on bone metabolism and osteoporosis, with special emphasis on tocotrienols. Dr. Ima-Nirwana has published 122 articles in scientific journals. Together with her team she has presented her work at over a hundred local and international conferences. The results from her animal studies have consistently shown that tocotrienols can prevent and reverse osteoporosis due to stressors, including menopause, estrogen and androgen deficiency, steroid excess, nicotine exposure and oxidative stress and inflammation. She is currently planning clinical trials on tocotrienols and osteoporosis in the USA and in Malaysia. She is a member of the Malaysian Osteoporosis Society and the Malaysia Endocrine and Metabolic Society. She holds a patent within Malaysia for the use of tocotrienol for bone health in humans.
By the time most of us begin to think about our bones, we may have already suffered significant bone loss. The early stages of osteoporosis can start by age 35. But osteoporosis is not merely the loss of bone structure and strength. Bones are a valuable storehouse of minerals for the body, as well as red and white blood cells. And skeletal tissue undergoes continuous remodeling throughout life, which makes it unique among all body tissues. The bone-immune connection is profound. The field of osteoimmunology has begun to explore how chronic immune system overexertion leads to bone loss. Dr. Soelaiman’s decades of research on tocotrienols and osteoporosis examines many facets of bone loss, including the ways in which it is driven by hormone deficiency, inflammation, inflammatory cytokines, and free radical damage. Tocotrienols interrupt the degeneration to weak, thin bones in several different ways, and show remarkable promise in helping prevent and reverse this process and contribute to bone strength and healthy aging. They may provide a new and safe therapy to prevent bone loss.
Focus: You have produced a remarkable body of work spanning several decades, and of your 122 published studies, forty-eight are on tocotrienols and bone health. You’ve shown that tocotrienol can prevent osteoporosis caused by estrogen deficiency, testosterone deficiency, nicotine, glucocorticoids, and even simple free radical damage. What got you so interested in this subject?
Ima-Nirwana Soelaiman (INS): My PhD thesis was on the antioxidant effects of tocotrienol-rich palm oil. As a young lecturer keen to focus on a research area, I was encouraged by my PhD mentor to study the effects of tocotrienols on osteoporosis. Why osteoporosis? I am interested in osteoporosis because it is a significant medical issue, with profound implications for healthy aging. Around two hundred million people worldwide suffer from osteoporosis, and the United States alone has 44 million. An additional 33.6 million individuals have osteopenia, or low bone mass, which can lead to osteoporosis. In fact, osteoporosis is very serious, and the lifetime risk of fractures for men and women is on par with the risk of cardiovascular disease. Another reason for my interest is that at that time the idea of using an antioxidant to combat osteoporosis was very novel. And tocotrienols from palm oil were the unknown siblings of the more famous alpha-tocopherol. My first research paper on the protective effects of vitamin E tocotrienols against osteoporosis induced by oxidative stress was in 1998. Little did I know that from one idea, many more flowered, leading to 20 years of passionate research thus far.
Palm oil-derived tocotrienol extract contains a mixture of gamma, delta and alpha tocotrienol isomers as well as about 20% alpha-tocopherol. I have been studying tocotrienols and bone health since 1994. The current medical strategies to preserve bone density include calcium, Vitamin D, bisphosphonate drugs, estrogen replacement therapy, and selective estrogen receptor modulators. In addition, it has been shown that the statin drugs, at high doses, increase bone density-but those doses are not well tolerated. What is interesting is that both bisphosphonates and statins seem to help bone health by inhibiting a crucial pathway, the mevalonate pathway-and so do tocotrienols.
Let’s stop and consider how remarkable bone is. It’s a specialized, dynamic, metabolizing connective tissue. We don’t usually think of it that way. It undergoes continuous replenishment throughout life by bone remodeling. This process involves bone resorption by osteoclasts, and bone formation by osteoblasts. Remodeling allows our body to replace old bone tissue with new, regulate calcium and phosphate levels, and provide adaptation to different conditions of load and stress. Bone is a fascinating tissue.
So, yes, I have been working on this for quite a long time. We have over forty very-detailed studies in animals-all looking at how tocotrienols affect bone health. In the early years, we used a Vitamin E mixture from palm oil, which contained 80% tocotrienols and 20% tocopherol. In more recent years, we have been able to study the impact of individual tocotrienol isomers as well as a palm oil blend.
For decades now, my colleagues and I have looked at everything from the impact of nicotine to sex hormones to Vitamin E deficient diets on bone, and studied how tocotrienols can help in each case. I am so pleased that over all this time, and in so many different studies, our data is remarkably consistent. Tocotrienols increase bone’s microstructural integrity. They increase bone calcium content and bone mechanical strength. They inhibit bone resorption and increase bone formation. And they do this through several novel metabolic pathways, not just one.
We are hoping to embark on human studies soon and translate our findings into definitive clinical benefits.
The Early Work: Vitamin E Deficient Diets
Focus: Let’s start with your early research on the impact of tocotrienols on a Vitamin-E deficient diet, one that contributes to osteoporosis.
INS: We first set out to prove that vitamin E is needed for bone health. In early experiments, we fed animals a Vitamin E deficient diet, which impaired bone calcification and lead to bone loss., Then we supplemented the experimental group with calcium and a Vitamin E-tocotrienol mixture for nine months. We scanned with a bone densitometry x-ray device that we had modified for small animals. It took that long to see changes in the bone using this device. We did find some significant changes in lumbar bone density, in terms of calcium deposition., And when we fed normal rats gamma-tocotrienol isomer, they displayed better structural, static and dynamic bone histomorphometry compared to rats not fed tocotrienols.,
We have since gone on to use more far more sensitive measurements in all our work. Today we use dynamic histomorphometry in all our studies, which allows us to make a sophisticated, quantitative measure of bone and bone changes with a computerized image analyzer system. It is not just observational histology as in the typical bone microscopy. We are also using biomechanical strength testing to determine the strength of the bones of rats treated with tocotrienols. This is important to confirm that the improved structure and density is translated to improved strength. And when we do this, we inevitably find significant improvements with tocotrienols.,,,
Tocotrienols provide significant protection against osteoporosis in an animal model of menopause or andropause, at doses demonstrated safe in both humans and animals.
Reversing Osteoporosis in Menopause
Focus: You have conducted many detailed studies on a post-menopausal animal model, looking at how hormone status affects bone, and how tocotrienols help prevent osteoporosis in this model. Can you review your findings?
INS: This is very important, because we know that post-menopausal osteoporosis is the most common cause of fractures. Our studies have shown that Vitamin E, especially the tocotrienols at a dose of 60 mg/kg/day, provides significant protection against osteoporosis in an animal model of menopause. The human dose calculated from the animal dose has been demonstrated to be safe in both humans and animals. Conversion from human dose to animal dose is not by simple multiplication. Metabolic rate of the human is about 7-10 times slower than the rat. Therefore the calculated human dose per kg is about 7-10 times smaller than the animal dose per kg. It is a safe dose as shown from our safety studies and the dose is comparable to efficacy doses in other clinical parameters.,
In one study, we compared tocotrienols to estrogen, and measured histomorphometric changes in rats whose ovaries had been removed, to mimic menopause in humans. We included sham operated rats, randomly divided into two groups, so that we had a double-blind, controlled study. We treated the rats for two months with estrogen or tocotrienols. Both groups showed improvement in dynamic markers, but the tocotrienol group showed better effects than estrogen on most of those markers. Tocotrienol exhibits bone anabolic actions that actually build bone, and reversed the harmful changes induced by menopause.8,,
We then compared tocotrienols with calcium in post-menopausal rats, with ovaries removed. We looked at bone biomarkers and bone formation rate and showed that palm tocotrienols significantly increased bone formation. We looked at many markers, including rate of mineral deposit and increase in bone formation. These were increased by tocotrienols, but not by calcium alone.8
Tocotrienols exhibit bone anabolic actions that actually build bone, and reverse the harmful changes induced by menopause. In an animal model, they have proved more potent than oestrogen.
Calcium is often recommended for osteoporosis, and it’s the most abundant mineral in the diet. It is essential for the development and maintenance of strong bones and teeth. In adults with a baseline calcium intake of 500-900 mg/day, increasing or supplementing this intake by a further 500-1000 mg/day has a beneficial effect on bone mineral density. However, the relative risk reduction for osteoporotic fracture is likely to be no more than 10%-20%. Although inadequate calcium intake is likely to be harmful to bone, calcium intake significantly above the recommended level is unlikely to achieve substantive additional benefit for bone health, and high doses can increase the risk of cardiovascular disease. I feel this is reflected perfectly in our animal study, which did not find significant improvement in bone formation in rats supplemented with calcium. I should also note that the rats were supplemented with tocotrienols or calcium only two weeks after their ovaries were removed. They were in an early postmenopausal state.
Since we have shown that tocotrienols increased bone density and bone strength in our post-menopausal rat model, we then looked at the effect of palm oil tocotrienols and alpha-tocopherol on bone fracture healing in post-menopausal rats with osteoporosis. Two months of supplementation with tocotrienol allowed fractured bone to bear significantly more stress, compared to alpha-tocopherol. Fracture healing is a complex process with three distinct phases, the reactive phase, reparative phase, and the remodeling phase. In the reactive phase, inflammation and formation of granulation tissue occur immediately after fracture. This is followed by the reparative phase, where callus is formed and lamellar bone is deposited. In the final or remodeling phase, the bone will be remodeled back to its original bone contour. Osteoporosis can delay and impair fracture healing. Our study found that the bone fractures of rats whose ovaries had been removed healed poorly. We found that while alpha-tocopherol supplementation improved the speed of fracture healing it did not increase strength and quality of the healed fracture. Tocotrienols did, however. We showed that tocotrienols improved late-phase fracture healing by improving callus formation. In fact, supplementation with tocotrienols actually allowed the bones to handle more stress than sham-operated female rats that had normal estrogen profiles.,, That makes sense, since normal male rats supplemented with gamma tocotrienols have better bone biomechanical strength that normal control rats. In addition, male rats put through andropause (testes removed) also suffered bone loss, which was reversed by tocotrienols.
Oxidative Stress and Inflamation Destroy Bone
Focus: One of your most fascinating insights is that osteoporosis may be spurred by oxidative stress and the resulting inflammation that occurs. We think of other bone conditions, such as rheumatoid arthritis, as due to inflammation. But though we know osteoporosis is generally a disorder of aging, we don’t necessarily treat it with antioxidants and anti-inflammatories.
INS: Yes, our work has found that tocotrienols can quench both oxidative stress and inflammation and thereby protect bone.11, An obvious relationship between inflammation and osteoporosis is accepted in rheumatoid arthritis, where proinflammatory cytokines cause bone loss around the affected joints. We also know there is a higher incidence of osteoporosis in ankylosing spondylitis and systemic lupus, which are both driven by inflammation. In fact, research has shown that the degree of osteoporosis is correlated with the extent of inflammation in these diseases.
But the role of oxidative stress and cytokines in osteoporosis is a fairly new view. We’ve begun to realize that elderly patients may be prone to osteoporosis in part because of an elevated level of proinflammatory cytokines that comes with aging-called Inflamm-aging.
We now have good evidence there is indeed a link. If this seems astonishing, it actually opens a window into one means by which tocotrienols repair bones: quenching oxidative stress.11 The osteoblast, which builds bone, is sensitive to oxidative stress. For instance, if you expose an osteoblast to hydrogen peroxide, you reduce differentiation, proliferation, mineralization and antioxidant defenses. You actually stimulate molecules that lead to osteoblast death. Tocotrienols have potent free radical scavenging activities, and may protect the osteoblast from oxidative stress.
A new model of osteoporosis is emerging, as a condition driven by oxidative stress and inflammation. Tocotrienols quench both oxidative stress and inflammation and thereby protect bone.
Oxidative stress and inflammation are tightly linked, and we have abundant evidence that osteoporosis is at least in part due to chronic inflammation as well.14 Free radicals activate one of the most important inflammatory molecules and master switches in the body: NFKappaB. This leads to increases in two inflammatory cytokines, Interleukin-1 and Interleukin-6. Both cause bone resorption. Several studies have shown that tocotrienols are able to suppress these cytokines. In addition, tocotrienols suppress other cytokines (including an important one in remodeling bone, called RANKL) that destroy bone. The level of C-reactive protein, a sensitive marker of systemic inflammation, has also found to be associated with bone mineral density.
Supplementation of palm tocotrienol (100 mg/kg) in normal male rats significantly increases antioxidant enzyme activities in the femur.
Another indication that oxidative stress and bone loss are related is the fracture rate of cigarette smokers. It has long been known that cigarette smoking leads to osteoporosis. One in eight hip fractures is due to smoking. Among 60 year olds with hip fractures, 17% are smokers. But among 80 year olds with hip fractures, 71% are smokers. One cause may be nicotine, which creates oxidative stress. Nicotine reduces bone mineral density, inhibits osteoblasts and delays bone healing.,, In our studies, tocotrienols reversed all the histomorphometric changes induced by nicotine, and protected and restored bone.,
Another study we are doing is on the effects of tocotrienols on steroid-induced osteoporosis. As is well known, osteoporosis is a complication of long-term steroid therapy. So far our early results are promising.
In conclusion, tocotrienols are both antioxidant and anti-inflammatory and uniquely able to protect bone through both mechanisms.
Statins and Tocotrienols: Why Do Both Protect Bone?
Focus: Statins are controversial drugs these days, for many reasons. But they also offer protective health effects. One of the pathways that tocotrienols work on is the same pathway that statins work on, and may offer similar protective effects, without the downsides. Can you talk to us about statins, tocotrienols, bone health and the pathway that they share?
INS: Statins, bisphosphonates and tocotrienols all work on a profoundly important and basic pathway in the body, called the mevalonate pathway. That pathway is important for synthesizing many molecules, including hormones, steroids, and cholesterol. Yes, statins often have serious side effects. But research also shows they also offer protective effects against cardiovascular disease, cancer, diabetic dyslipidemia, Alzheimer’s disease, glomerulonephritis, vitiligo, macular degeneration, polycystic ovary syndrome, influenza, infection and sepsis, rheumatoid arthritis and more. And of course, they work on osteoporosis, however, studies have been mixed, and the doses required may not be tolerated.
Nonetheless, the fact that statins affect this pathway and are so beneficial, makes us take a closer look at tocotrienols, which also inhibit the pathway at a later step, and confer many benefits, including bone health. We have found that statins improve bone health in both intact animals, and those with ovaries removed-but at clinically intolerable doses. Even so, studies of women on long-term statins do show better bone density than those not on statins.
However, in our animal studies, enhancement of bone formation, and reduction of bone resorption, were best achieved by a combination of statins and tocotrienols. By adding tocotrienols to statins, the adverse effects associated with high doses might be avoided, while the bone protective effects might be preserved. This combination strategy might be useful for patients at risk of osteoporosis, cardiovascular disease and high cholesterol. Our study is the only one I know of in the literature looking at both together. Many patients are already on statins worldwide, and adding tocotrienols might enhance their benefit.
Focus: How would you summarize your decades of research on tocotrienols and bone health?
INS: Tocotrienols preserve bone health. They do this in several ways. They quench free radicals and oxidative stress. They reduce inflammation. They work on the mevalonate pathway, which tends to increase osteoclast activity and break down bone. Inhibiting this pathway protects individuals from high cholesterol, cardiovascular disease, and bone loss. Tocotrienols are useful for bone loss triggered by menopause, andropause, and smoking. They help repair fractures in osteoporotic bone at a faster rate. They also enhance the structure and strength of normal, non-osteoporotic bone, increasing bone mass so that there is less risk of osteoporosis later in life. We are in the process of translating our animal studies into human clinical trials. Our new insights into tocotrienols and the way they work are leading us to design other, interesting studies. For instance, we think they may help treat arthritis, and will be studying that soon.
 Arya Khosravi, Alberto Y·Òez, Jeremy G. Price, Andrew Chow, Miriam Merad, Helen S. Goodridge, Sarkis K. Mazmanian. Gut Microbiota Promote Hematopoiesis to Control Bacterial Infection. Cell Host & Microbe, March 2014
 Norazlina M, Ima-Nirwana S. Khalid BAK. 2001. Effects of vitamin E deficiency on bone metabolism in intact and ovariectomised growing female rats. Asia Pacific Journal of Pharmacology. 15(3): 37-46.
 Norazlina M, Chua CW, Ima-Nirwana S. 2004. Vitamin E deficiency reduced lumbar bone calcium content in female rats. Medical Journal of Malaysia, 59(5): 623-630.
 Norazlina M, Ima-Nirwana S, Abd. Gapor MT, Khalid BAK. 2000. Palm vitamin E is comparable to a-tocopherol in maintaining bone mineral density in ovariectomised female rats. Experimental and Clinical Endocrinology and Diabetes, 108: 305-310. IF: 1.693, Q4.
 Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BAK 2002. Tocotrienols are needed for bone calcification in growing female rats. Asia Pacific Journal of Clinical Nutrition. 11(3): 194-199. IF: 1.133, Q4.
 Shuid AN, Mehat Z, Mohamed N, Muhammad N, Soelaiman IN. Vitamin E exhibits bone anabolic actions in normal male rats. J Bone Miner Metab. 2010 Mar;28(2):149-56. doi: 10.1007/s00774-009-0122-2. PMID: 19779668.
 Zulfadli MM, Nazrun AS, Norazlina M, Norliza M, Ima-Nirwana S. 2010. Beneficial effects of vitamin E isomer supplementation on static and dynamic bone histomorphometry parameters in normal male rats. Journal of Bone and Mineral Metabolism. 28(5): 503-509. IF: 2.268, Q3.
 Ima Nirwana S, Wang M, Roshayati AB Nursyahrina Atiqah H, Hanif MA, Norazlina M, Norliza M, Nazrun AS. 2012. Palm Tocotrienol Supplementation Enhanced Bone Formation in Estrogen-Deficient Rats. International Journal of Endocrinology Volume 2012, Article ID 532862, 7 pages, doi:10.1155/2012/532862. IF: 1.867, Q3.
 Norliza M, Luke DA, Nazrun AS, Norazlina M, Ima Nirwana S. 2012. Two Different Isomers Of Vitamin E On Trabecular Bone In Ovariectomized Rats. Evidence-based Complementary and Alternative Medicine Volume 2012, Article ID 161527, 7 pages, doi:10.1155/2012/161527. IF: 4.774, Q1.
 Nazrun AS, Khalid BAK, Luke DA, Ima-Nirwana S. 2005. Tocotrienols offer better protection than tocopherol from free-radical-induced damage of rat bone. Clinical and Experimental Pharmacology and Physiology, 32(9):761-770. IF: 1.851, Q3.
 Nazrun AS, Luke DA, Khalid BAK, Ima-Nirwana S. 2005. Vitamin E protects from free-radical damage on femur of rats treated with ferric nitrilotriacetate. Current Topics in Pharmacology, 9(2):107-115.
 Ima Nirwana S, Nurshazwani Y, Ahmad NS, Norliza M, Norazlina M. 2011. Subacute and subchronic toxicity of palm vitamin E in mice. Journal of Pharmacology and Toxicology 6(2): 166-173.
 Norazlina M, Norzalyana NMZ, Ima- Nirwana S. 2013. The toxic effects of palm vitamin E on the reproductive system of female mice. Journal of Toxicology Research. 3(1): 25-28.
 Nazrun AS, Norazlina M, Norliza M, Ima Nirwana S. 2012. The anti-inflammatory role of vitamin E in prevention of osteoporosis. Advances in Pharmacological Sciences, Volume 2012, Article ID 142702, 1-7: doi:10.1155/2012/142702.
 Norliza M, Douglas AL, Nazrun AS, Norazlina M, Ima-Nirwana S. 2013. Tocotrienol supplementation in postmenopausal osteoporosis: evidence from a laboratory study. Clinics. 68(10):1338-1343.
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 Aktifanus AT, Nazrun AS, Nurul Hashimah AR, Tam HL, Chua YL, Nurulhayati MS, Norliza M, Norazlina M, Ima-Nirwana S. 2012. Comparison of the Effects of Tocotrienol and Estrogen on the Bone Markers and Dynamic Changes in Postmenopausal Osteoporosis Rat Model. Asian Journal of Animal and Veterinary Advances, 7(3): 225-234. IF: 0.869, Q2.
 18 Nazrun AS, Sharlina M, Norliza M, Fazalina MF, Sabarul AM, Norazlina M, Ima Nirwana S. 2011. Effects of a-tocopherol on the early phase of osteoporotic fracture healing. Journal of Orthopaedic Research, 29(11): 1732-1738. IF: 2.811, Q1.
 Sharlina M, Ahmad NS, Sabarul AM, Shahrum A, Soelaiman IM. 2012. Tocotrienol supplementation improves healing compared to alpha-Tocopherol on late phase fracture healing in postmenopausal osteoporosis rat model. Evidence-based Complementary and Alternative Medicine, Volume 2012, Article ID 372878, 7 pages, doi:10.1155/2012/372878. IF: 4.774, Q1.
 Sharlina_M, Nazrun AS, Norazlina M, Fazalina MF, Sabarul AM, Shahrum A, Faizah O, Farihah S, Norliza M, Ima-Nirwana S. 2012. Effects of Alpha-Tocopherol Supplementation on Fracture Healing in Postmenopausal Osteoporotic Rat Model. Clinics 67(9):1077-1085. IF: 2.058, Q2.
 Nazrun AS, Zulfadli M, Norazlina M, Norliza M, Ima-Nirwana S. 2010. Vitamin E exhibits bone anabolic actions in normal male rats. Journal of Bone and Mineral Metabolism. 28(2):149-156. IF: 2.268, Q3.
 Ima-Nirwana S, Kiftiah A, Zainal AG, Norazlina M, Abd Gapor MT, Khalid BAK. 2000. Palm vitamin E prevents osteoporosis in orchidectomised growing male rats. Natural Product Sciences, 6(4): 155-160.
 Nazrun AS, Khalid BAK, Ima-Nirwana S, 2004. Effects of vitamin E on interleukin-1 in ferric nitrilotriacetate treated rats. Malaysian Journal of Biochemistry and Molecular Biology, 9: 43-47.
 Nizar AM, Nazrun AS, Norazlina M, Norliza M, Ima-Nirwana S. 2011. Low dose of tocotrienols protects osteoblasts against oxidative stress. La Clinica Terapeutica, 162(6):533-8. IF: 0.266, Q4.
 Maniam S, Norazlina M, Nazrun AS, Ima-Nirwana S. 2008. Palm tocotrienol exerted better antioxidant activities in bone than ?-tocopherol. Basic and Clinical Pharmacology and Toxicology. 103(1):55-60. IF: 2.179, Q2.
 Hermizi H, Faizah O, Ima-Nirwana S, Ahmad Nazrun S, Luke DA, Norazlina M. 2007. Nicotine impaired bone histomorphometric parameters and bone remodeling biomarkers in Sprague-Dawley male rats. Journal of Annals Microscopy, 7: 10-24.
 Hermizi H, Faizah O, Ima-Nirwana S, Ahmad Nazrun S, Luke DA, Norazlina M. 2007. Negative effects of nicotine on bone resorbing cytokines and bone histomorphometric parameters in male rats. Journal of Bone and Mineral Metabolism, 25 (2). 93-98. IF: 2.268, Q3.
 Hermizi, H., Faizah, O., Ima-Nirwana, S., Ahmad Nazrun, S., Norazlina, M. 2009. Beneficial Effects of Tocotrienol and Tocopherol on Bone Histomorphometric Parameters in Sprague-Dawley Male Rats After Nicotine Cessation. Calcified Tissue International, 84: 65-74. IF: 2.376, Q3.
 Norazlina M, Hermizi H, Faizah O, Nazrun AS, Norliza M, Ima-Nirwana S. 2010. Vitamin E reversed nicotine-induced toxic effects on bone biochemial markers in male rats. Archives of Medical Science, 6 (4): 505-512. IF: 1.214, Q2
 Norazlina M, Maizatul-Neza J, Azarina A, Nazrun AS, Norliza M, Ima-Nirwana S. 2010. Effects of vitamin E on receptor-activator of nuclear facyor kappa B ligand (RANKL) and osteoprotegerin (OPG) in rats treated with nicotine. Medical Journal of Malaysia, 65(1): 14-17.
 Ima-Nirwana S, Fakhrurazi H. 2002. Palm vitamin E protects bone against Dexamethasone-induced osteoporosis in male rats. Medical Journal of Malaysia, 57(2):136-144.
 Abdul-Majeed S, Norazlina M, Ima-Nirwana S. Effects Of Tocotrienol And Lovastatin Combination On Osteoblast And Osteoclast Activity In Estrogen-Deficient Osteoporosis. Evidence-based Complementary and Alternative Medicine, Volume 2012, Article ID 960742, 9 pages, doi:10.1155/2012/960742. IF: 4.774, Q1.
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