Studies conducted in vegetarians tend to show cognitive enhancement in youth, possibly due to a creatine deficiency, as compared to omnivores. Vegetarian diets have lower levels of circulating creatine prior to supplementation, but attain similar circulating levels as omnivores when both groups supplement. Building on the latter, supplementation of creatine monohydrate in a loading protocol (20g daily in orange juice) in omnivores does not alter levels of creatine in white matter tissue in the brain (test subjects: competitive athletes). In most of the parameters that vegetarians experience benefits, omnivores fail to experience statistically significant benefits, except possibly when sleep deprived, where the cognitive improvements rival that seen in vegetarians. Elderly people who are omnivorous may also experience increases in cognition to a similar level, in regard to long-term memory as well as forward number and spatial recall, although the study in question failed to find any significant benefit on backward recall or random number generation, the latter of which is a test for executive working memory.
It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio, and when activated AMPK (active in states of low cellular energy and colocalizes with creatine kinase in muscle tissue) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio. It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.
Contrast loading is the alternation of heavy and light loads. Considered as sets, the heavy load is performed at about 85-95% 1 repetition max; the light load should be considerably lighter at about 30-60% 1RM. Both sets should be performed fast with the lighter set being performed as fast as possible. The joints should not be locked as this inhibits muscle fibre recruitment and reduces the speed at which the exercise can be performed. The lighter set may be a loaded plyometric exercise such as loaded squat jumps or jumps with a trap bar.
JAK2 (Janus-Activating Kinase 2) is a novel protein that has been shown to suppress the activity of the creatine transporter CrT in vitro. The effects of JAK2 on CrT are not well-understood in vivo, however. Given that growth hormone activates both c-src (increases CrT activity) and JAK2- which has been found to decrease CrT activity, it is plausible that JAK2 may function as a negative-feedback regulator of creatine uptake. Future research is needed to better understand the role of JAK2 on CrT activity in vivo.
After all, you’ve probably seen the countless workouts, diets, supplements, programs, products and people claiming that super fast muscle growth is possible. You’ve probably also seen the click-bait headlines (“How To Build 20lbs Of Muscle In Just 6 Weeks!”) and the unbelievable transformations of supposedly “natural” people (bodybuilders, celebrities, athletes, fitness gurus on social media, etc.) that clearly prove it can happen faster than this.
In regard to bioenergetics, phosphorylated cyclocreatine appears to have less affinity for the creatine kinase enzyme than phosphorylated creatine in terms of donating the high energy phosphate group (about 160-fold less affinity) despite the process of receiving phosphorylation being similar. When fed to chickens, phosphorylated cyclocreatine can accumulate up to 60mM in skeletal muscle, which suggests a sequestering of phosphate groups before equilibrium is reached. Cyclocreatine still has the capacity to donate phosphate, however, as beta-adrenergic stimulated skeletal muscle (which depletes ATP and glycogen) exhibits an attenuation of glycogen depletion (indicative of preservation of ATP) with phosphocreatine.
You have to fuel your body with high-quality, real, wholesome food. Eating pizza, burgers, ice cream, and fast food just because it’s high in calories is a really bad plan. You’ll feel terrible, and while the extra calories will help muscle gains to an extent, most of them will turn to fat. It’s not worth it. Your recovery will be slower and you will be riddled with inflammation.
Recommended Dose: In Shannon Clark's article, "6 Ways To Get More Energized For Your Workouts", Dr. Chris Lockwood recommends between 1.36 and 2.5 milligrams of caffeine per pound of bodyweight. That would be 200-375 milligrams for a 150-pound person. If that leaves you jittery, try less. Determine your tolerance and find the dose that works best for you.
A quantitative, comprehensive scientific summary and view of knowledge up to 2007 on the effects of creatine supplementation in athletes and active people was published in a 100 citation review position paper by the International Society of Sports Nutrition. More recent literature has provided greater insight into the anabolic/performance enhancing mechanisms of creatine supplementation [15,25] suggesting that these effects may be due to satellite cell proliferation, myogenic transcription factors and insulin-like growth factor-1 signalling . Saremi et al  reported a change in myogenic transcription factors when creatine supplementation and resistance training are combined in young healthy males. It was found that serum levels of myostatin, a muscle growth inhibitor, were decreased in the creatine group.
^ Jump up to: a b c d e Cooper R, Naclerio F, Allgrove J, Jimenez A (July 2012). "Creatine supplementation with specific view to exercise/sports performance: an update". Journal of the International Society of Sports Nutrition. 9 (1): 33. doi:10.1186/1550-2783-9-33. PMC 3407788. PMID 22817979. Creatine is produced endogenously at an amount of about 1 g/d. Synthesis predominately occurs in the liver, kidneys, and to a lesser extent in the pancreas. The remainder of the creatine available to the body is obtained through the diet at about 1 g/d for an omnivorous diet. 95% of the bodies creatine stores are found in the skeletal muscle and the remaining 5% is distributed in the brain, liver, kidney, and testes .
More recent studies on the regulation of CrT creatine transport activity have identified the protein kinase (Janus-Activating Kinase 2) JAK2, which suppresses the rate of creatine uptake via CrT without affecting creatine binding. JAK2 is a regulatory protein involved in stabilizing the cellular membrane and controlling water concentrations in response to osmotic stress. Similar to c-Src (a positive creatine transport regulator), Jak2 can also be activated by growth hormone signaling. The growth hormone receptor seems to activate these two factors independently, as gh-mediated activation of c-Src does not require JAK2. Given that c-Src is a positive regulator of CrT, JAK2 is a negative regulator, and the fact that downstream signals from both are induced by growth hormone, it is tempting to speculate that JAK2 activation downstream of the gh receptor may function as a homeostatic response to limit c-src induced creatine uptake. This has not been studied, however, and the effects of gh-induced JAK2 signaling on CrT activity have not been examined.
Creatine was first identified in 1832 when Michel Eugène Chevreul isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). In 1928, creatine was shown to exist in equilibrium with creatinine. Studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion. This result pointed to the ability of the body to store creatine, which in turn suggested its use as a dietary supplement.
Another category of muscle-building supplements that lifters and bodybuilders use to improve their results are branched-chained amino acids (BCAAs), or BCAAs. Of the 20 amino acids that make up protein, just three are referred to as BCAAs: leucine, isoleucine, and valine. These are the specific amino acids that have been shown to stimulate protein synthesis and help regulate protein metabolism.
^ Jump up to: a b c d e f g h Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. Wilson et al.  demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al.  showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage .
A typical creatine supplementation protocol consists of a loading phase of 20 g CM/d or 0.3 g CM/kg/d split into 4 daily intakes of 5 g each, followed by a maintenance phase of 3-5 g CM/d or 0.03 g CM/kg/d for the duration of the supplementation period . Other supplementation protocols are also used such as a daily single dose of around 3 – 6 g or between 0.03 to 0.1 g/kg/d [15,55] however this method takes longer (between 21 to 28 days) to produce ergogenic effects . Sale et al  found that a moderate protocol consisting of 20 g CM taken in 1g doses (evenly ingested at 30-min intervals) for 5 days resulted in reduced urinary creatine and methylamine excretion, leading to an estimated increase in whole body retention of creatine (+13%) when compared with a typical loading supplementation protocol of 4 x 5 g/d during 5 days (evenly ingested at 3 hour intervals). This enhancement in creatine retention would lead to a significantly higher weight gain when people follow a moderate protocol ingestion of several doses of small amounts of CM evenly spread along the day.
The incidence of liver damage from herbal and dietary supplements is about 16–20% of all supplement products causing injury, with the occurrence growing globally over the early 21st century. The most common liver injuries from weight loss and bodybuilding supplements involve hepatocellular damage with resulting jaundice, and the most common supplement ingredients attributed to these injuries are catechins from green tea, anabolic steroids, and the herbal extract, aegeline.
Although creatine is a natural component of food, the amount of food required to supersaturate the muscle with PCr may not be feasible. For example, it could require 22 pounds of meat daily . If creatine monohydrate is proven to be a safe and effective ergogenic aid, creatine supplementation may be the simplest way to increasing muscle stores. It may be beneficial to avoid caffeine if taking creatine supplements. One study showed that caffeine diminished strength gains seen with creatine use .
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Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) is a synthetic analogue of creatine in a cyclic form. It serves as a substrate for the creatine kinase enzyme system, acting as a creatine mimetic. Cyclocreatine may compete with creatine in the CK enzyme system to transfer phosphate groups to ADP, as coincubation of both can reduce cyclocreatine’s anti-motility effects on some cancer cells.
Maughan RJ, King DS, Lea T. Dietary supplements. J Sports Sci. 2004 Jan;22(1):95-113.Kreider RB. Dietary supplements and the promotion of muscle growth with resistance exercise. Sports Med. 1999 Feb;27(2):97-110.Kerksick CM, Rasmussen CJ, Lancaster SL, et al. The effects of protein and amino acid supplementation on performance and training adaptations during ten weeks of resistance training. J Strength Cond Res. 2006 Aug;20(3):643-53.Update of Cochrane Database Syst Rev. 2001;(1):CD002946. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002946.AIS Sports Nutrition - AIS Sports Supplement Program 2007.
Some of the most common minor side effects include stomach discomfort, nausea, and increased bowel movements. Other potential side effects may include headaches, bloating, and increased thirst. There is always the chance that a supplement could cause an allergic reaction. This can result in rashes, swelling, or difficulty breathing, depending on the severity of the reaction. This is another reason why starting out with lower doses of new products is advisable.
THIS TOOL DOES NOT PROVIDE MEDICAL ADVICE. It is intended for general informational purposes only and does not address individual circumstances. It is not a substitute for professional medical advice, diagnosis or treatment and should not be relied on to make decisions about your health. Never ignore professional medical advice in seeking treatment because of something you have read on the WebMD Site. If you think you may have a medical emergency, immediately call your doctor or dial 911.
Creatine supplementation appears to augment the anti-cancer effects of Vitamin C and methylglyoxal, a metabolic by-product of glycolysis. Methylglycoxal appears to inhibit step 1 of the electron transport chain in isolated mitochondria and cancerous mitochondria, but has not been implicated in doing so in normal tissue, as protective measures in normal cells appear to exist.
Creatine is most commonly found in the basic form of creatine monohydrate, which is the standard form and usually recommended due to the low price. It can also be micronized to improve water solubility, or the monohydrate can be temporarily removed to concentrate creatine in a small volume supplement. Neither alteration changes the properties of creatine.
When looking specifically at human studies, there has been a failure of creatine supplementation to induce or exacerbate kidney damage in people with amyotrophic lateral sclerosis (ALS). Subjects do not experience kidney damage for up to or over a year’s worth of supplementation in the 5-10g range. Postmenopausal women, people with type II diabetes, people on hemodialysis, otherwise healthy elderly, young people, and athletes do not experience kidney damage either. Moreover, numerous scientific reviews on both the long- and short-term safety of supplemental creatine have consistently found no adverse effects on kidney function in a wide range of doses. However, while doses >10 g/day have been found not to impair kidney function, there are fewer long-term trials using such high chronic daily intakes.
The first thing you need is a weight training program that signals the muscle building process to begin. Research has shown that a well designed program will generate this “signal” via a combination of progressive tension overload (as in, getting stronger over time), metabolic stress (as in, fatiguing the muscle and getting “the pump”), and muscular damage (as in, actual damage to the muscle tissue itself).
In regard to the blood brain barrier (BBB), which is a tightly woven mesh of non-fenestrated microcapillary endothelial cells (MCECs) that prevents passive diffusion of many water-soluble or large compounds into the brain, creatine can be taken into the brain via the SLC6A8 transporter. In contrast, the creatine precursor (guanidinoacetate, or GAA) only appears to enter this transporter during creatine deficiency. More creatine is taken up than effluxed, and more GAA is effluxed rather than taken up, suggesting that creatine utilization in the brain from blood-borne sources is the major source of neural creatine. However, “capable of passage” differs from “unregulated passage” and creatine appears to have tightly regulated entry into the brain in vivo. After injecting rats with a large dose of creatine, creatine levels increased and plateaued at 70uM above baseline levels. These baseline levels are about 10mM, so this equates to an 0.7% increase when superloaded. These kinetics may be a reason for the relative lack of neural effects of creatine supplementation in creatine sufficient populations.
A major benefit of the creatine pills is that they are much more convenient than the powder, so you can just throw a few in your bag without worrying about the mess of a powder spill or having to carry the entire tub around. Reviewers confirm that they’ve seen serious strength and muscle size gains since starting to take this supplement, even after just two weeks of use. One bottle of this creatine includes 90 capsules so you will be set for months of lifting sessions.
The process of phagocytosis (a macrophage consuming a pathogen) in macrophages appears to be associated with an acute reduction in creatine phosphate stores (45%) and an increase in creatine kinase activity, although prolonged stimulation is met with an increase in creatine phosphate (20%). The creatine kinase activity does not appear to be altered based on creatine availability, but since ATP seems to be preserved in these instances, the increase in phosphocreatine may be explained by an overall creatine pool paralleling that found in medium.
Creatine ethyl ester is more a pronutrient for creatinine rather than creatine, and was originally created in an attempt to bypass the creatine transporter. It is currently being studied for its potential as a treatment for situations in which there is a lack of creatine transporters (alongside cyclocreatine as another possible example). Its efficacy may rely on intravenous administration, however.
Another study demonstrated that females receiving 4 days of high-dose creatine intake (20 g/day) followed by low-dose creatine intake (5 g/day) during 10 weeks of resistance training (3hours/week) increased muscle PCr concentrations by 6%. Also, maximal strength of the muscle groups trained increased by 20-25%, maximal intermittent exercise capacity of the arm flexors increased by 10-25% and fat-free mass increased by 60% .
^ Jump up to: a b c Morton RW, Murphy KT, McKellar SR, Schoenfeld BJ, Henselmans M, Helms E, Aragon AA, Devries MC, Banfield L, Krieger JW, Phillips SM (2017). "A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults". Br J Sports Med. 52 (6): bjsports–2017–097608. doi:10.1136/bjsports-2017-097608. PMC 5867436. PMID 28698222.
CONDITIONS OF USE AND IMPORTANT INFORMATION: This information is meant to supplement, not replace advice from your doctor or healthcare provider and is not meant to cover all possible uses, precautions, interactions or adverse effects. This information may not fit your specific health circumstances. Never delay or disregard seeking professional medical advice from your doctor or other qualified health care provider because of something you have read on WebMD. You should always speak with your doctor or health care professional before you start, stop, or change any prescribed part of your health care plan or treatment and to determine what course of therapy is right for you.
It has been argued that purposely overtraining for a brief period can be beneficial. One article published by Muscle & Fitness magazine stated that you can "Overtrain for Big Gains". It suggested that if one is planning a restful holiday and does not wish to inhibit their bodybuilding lifestyle too much, they should overtrain before taking the holiday, so the body can recuperate and grow during the prolonged rest period. Overtraining can be used advantageously, as when a bodybuilder is purposely overtrained for a brief period of time to super compensate during a regeneration phase. These are known as "shock micro-cycles" and were a key training technique used by Soviet athletes.
Creatine helps create essential adenosine triphosphate (ATP). This is the energy source of muscle contractions. By upping your levels, you can increase the amount of energy available to your muscles, boosting your performance. Because your muscle strength and size increases when you add weight and reps, improving your performance can be a game changer in terms of increasing your muscle mass. If you’re able to lift longer and harder, your muscles will grow. Creatine is certainly a winner among muscle building supplements.
A: Start with the calculations above but don’t be afraid to adjust up or down. Your metabolism and physiology will adapt to more food by trying to maintain homeostasis and regulate your bodyweight. Some may have to increase more than others but the number on the scale doesn’t lie. If it’s not going up, then you probably need to increase your calories.
Beginners are advised to build up slowly to a weight training program. Untrained individuals may have some muscles that are comparatively stronger than others; nevertheless, an injury can result if (in a particular exercise) the primary muscle is stronger than its stabilizing muscles. Building up slowly allows muscles time to develop appropriate strengths relative to each other. This can also help to minimize delayed onset muscle soreness. A sudden start to an intense program can cause significant muscular soreness. Unexercised muscles contain cross-linkages that are torn during intense exercise. A regimen of flexibility exercises should be implemented before weight training begins, to help avoid soft tissue pain and injuries.
AAOS does not endorse any treatments, procedures, products, or physicians referenced herein. This information is provided as an educational service and is not intended to serve as medical advice. Anyone seeking specific orthopaedic advice or assistance should consult his or her orthopaedic surgeon, or locate one in your area through the AAOS Find an Orthopaedist program on this website.
There have also been concerns that creatine can cause kidney damage, and doctors warn that people with a history of kidney disease or conditions, such as diabetes, that increase the risk of kidney problems should steer clear of the supplement. Combining creatine with nephrotoxic drugs — drugs that might damage the kidneys — like nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (advil or motrin) and naproxen sodium (Aleve), should also be avoided, according to the U.S. Department of Health and Human Services. (1)
^ Jump up to: a b Barcelos RP, Stefanello ST, Mauriz JL, Gonzalez-Gallego J, Soares FA (2016). "Creatine and the Liver: Metabolism and Possible Interactions". Mini Reviews in Medicinal Chemistry. 16 (1): 12–8. doi:10.2174/1389557515666150722102613. PMID 26202197. The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis.
Wilkinson, S. B., Tarnopolsky, M. A., MacDonald, M. J., MacDonald, J. R., Armstrong, D., & Phillips, S. M. (2007). Consumption of fluid skim milk promotes greater muscle protein accretion after resistance exercise than does consumption of an isonitrogenous and isoenergetic soy-protein beverage. The American Journal of Clinical Nutrition, 85(4), 1031-1040.
When combined with an appropriate exercise program, dietary supplementation with β-hydroxy β-methylbutyrate (HMB) has been shown to dose-dependently augment gains in muscle hypertrophy (i.e., the size of a muscle), muscle strength, and lean body mass, reduce exercise-induced skeletal muscle damage,[note 1] and expedite recovery from high-intensity exercise. HMB is believed to produce these effects by increasing muscle protein synthesis and decreasing muscle protein breakdown by various mechanisms, including activation of the mechanistic target of rapamycin (mTOR) and inhibition of the proteasome in skeletal muscles.
In regard to practical interventions, concurrent glycogen loading has been noted to increase creatine stores by 37-46% regardless of whether the tissue was exercised prior to loading phase. It is important to note, however, that creatine levels in response to the creatine loading protocol were compared in one glycogen-depleted leg to the contralateral control leg, which was not exercised. This does not rule out a possible systemic exercise-driven increase in creatine uptake, and the increase in creatine noted above was larger than typically seen with a loading protocol (usually in the 20-25% range). Consistent with an exercise-effect, others have reported that exercise itself increases creatine uptake into muscle, reporting 68% greater creatine uptake in an exercised limb, relative to 14% without exercise.
Bodybuilding developed in the late 19th century, promoted in England by German Eugen Sandow, now considered as the "Father of Bodybuilding". He allowed audiences to enjoy viewing his physique in "muscle display performances". Although audiences were thrilled to see a well-developed physique, the men simply displayed their bodies as part of strength demonstrations or wrestling matches. Sandow had a stage show built around these displays through his manager, Florenz Ziegfeld. The Oscar-winning 1936 musical film The Great Ziegfeld depicts the beginning of modern bodybuilding, when Sandow began to display his body for carnivals.
It is suggested [16,37] that another mechanism for the effect of creatine could be enhanced muscle glycogen accumulation and GLUT4 expression, when creatine supplementation is combined with a glycogen depleting exercise. Whereas it has been observed  that creatine supplementation alone does not enhance muscle glycogen storage. Hickner et al  observed positive effects of creatine supplementation for enhancing initial and maintaining a higher level of muscle glycogen during 2 hours of cycling. In general, it is accepted that glycogen depleting exercises, such as high intensity or long duration exercise should combine high carbohydrate diets with creatine supplementation to achieve heightened muscle glycogen stores .
Despite the popularity of creatine among young people, there has been very little research conducted in children under age 18. Of those studies, a few have suggested a positive effect but the overall evidence is inconclusive. In one study, teenage swimmers performed better after taking creatine; in another study, it helped high school soccer players sprint, dribble, and jump more effectively.
Healthy sources of fat include: cold water oily fish (such as salmon, mackerel, and sardines), extra-virgin olive oil, peanuts (unsalted), avocado, pecans, almonds, hazelnuts, walnuts or flaxseed. Nuts (any sort, just make sure they are unsalted) are a great food to snack on if you're having trouble gaining weight, as they are not only high in calories, but they contain monounsaturated fats, a good source of protein, fibre and contain a number of essential minerals that are needed for health. For those not consuming any oily fish, you may want to consider taking a fish oil supplement, such as cod liver oil or flaxseeds.
Fish oils are an excellent source of omega-3 fatty acids, which provide myriad benefits for the body. For strength athletes and bodybuilders, we're most concerned with their anti-inflammatory and antioxidant properties. Intense resistance training can cause microscopic tears in your muscle fibers, leading to muscle damage and inflammation. While some inflammation is desirable, too much can delay the post-exercise recovery process.
Nutricost's BCAA packs a powerful punch when it comes to quality for the price. With 6 grams of L-Leucine, L-Isoleucine, and L-Valine in every serving, and 83 servings per bottle, each scoop equates to just 23 cents. These high quality branched chain amino acids help support protein synthesis, muscle recovery, while boosting endurance and stamina. This straight forward formula is free of calories and comes in several natural, easily mixed fruit flavors. Keep Reading »
Carducci, C., Birarelli, M., Leuzzi, V., Carducci, C., Battini, R., Cioni, G., and Antonozzi, I. Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: an effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies. Clin Chem 2002;48:1772-1778. View abstract.
We’re confident you’ll love your Onnit supplements. If the product doesn't perform for you, however, we’re not gonna play games with you. Order any of our entry size supplements, and if you don’t like it, you can keep it! Notify our team, telling us why it wasn't a fit for you, and we’ll get you a refund right there on the spot - no return necessary. We just ask that you try it out for at least two weeks to give it a fair shot.
Gordon, P. H., Cheung, Y. K., Levin, B., Andrews, H., Doorish, C., Macarthur, R. B., Montes, J., Bednarz, K., Florence, J., Rowin, J., Boylan, K., Mozaffar, T., Tandan, R., Mitsumoto, H., Kelvin, E. A., Chapin, J., Bedlack, R., Rivner, M., McCluskey, L. F., Pestronk, A., Graves, M., Sorenson, E. J., Barohn, R. J., Belsh, J. M., Lou, J. S., Levine, T., Saperstein, D., Miller, R. G., and Scelsa, S. N. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph.Lateral.Scler. 2008;9:212-222. View abstract.