• Medication Shortages Hit 267 Drugs in 2011, for 5th Straight Yearly Increase
• Yoga and Stretching Are Better Than Usual Care for Chronic Low Back Pain
• Elders Might Be Overscreened for Cancer
• USPSTF Recommends Against Prostate Cancer Screening
• Good and Bad News About Adolescent Substance Use
• Using Infant Growth Charts to Predict Later Obesity
• Herpes Simplex Vaccine Trial Yields Mixed Results
• TMP-SMX Is Another Option for Treatment of Acute Osteomyelitis
• Statins Don't Lower Risk for Infections
• Yet Another Way to Slow Aging
• The Childhood Obesity Epidemic: More Data but Few Answers
• Alzheimer’s Drug Apes Omega-3s and Berries
• Atypical Femur Fractures with Bisphosphonates
• Ocean Fish May Curb Pancreatic Cancer
MM: The shortage of drugs necessary for surgery, cancer, pain and a variety of oteher emergency and highly necessary procedures is a tragic situation. Mark Drugs is prepared to bridge the gap for many of these products. Our fully accredited compounding labs can make many of these sterile preparations for hospitals, clinics, physician offices and individuals. Please contact us for more information as to how we may assist you.
Medication Shortages Hit 267 Drugs in 2011, for 5th Straight Yearly Increase
Prescription drug shortages in 2011 increased to 267, well above the prior record and about four times the number of medication shortages in the middle of the last decade. As a comparison, there were only 58 drug shortages reported in 2004. The FDA claims it has prevented more than 100 new shortages in 2011. Recently, there have been new shortages of sedatives widely used in surgery, including Valium, Versed, and lorazepam. Another big problem is the recent shortage of the opioid painkiller fentanyl.
Most shortages involve sterile injectables and are normally inexpensive because they've long been available as generics. The FDA states that the main reason for the shortages is manufacturing deficiencies leading to production shutdowns; other reasons include companies ending production of some drugs with narrow profit margins, consolidation in the generic drug industry and limited supplies of some ingredients.
http://www.washingtonpost.com/business/university-new-medication-shortages-hit-267-drugs-in-2011-for-5th-straight-yearly-increase/2012/01/03/gIQA5vUuYP_story.html
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Arch Intern Med 2011 Dec 12/26; 171:2019.
Yoga and Stretching Are Better Than Usual Care for Chronic Low Back Pain
Supervised stretching or exercise of any type is better than self-care.
Numerous treatments have been proposed for chronic low back pain, but none are supported by firm data. In this study from Washington State, 228 adults with back pain for 
3 months, without specific spine pathology, were randomized to one of three treatments: yoga, conventional stretching, or a self-care book. The yoga and stretching groups each received twelve 75-minute sessions and were encouraged to practice on off days. Viniyoga principles, which involve 17 different postures and breathing exercises, were used in the yoga group. Stretching involved aerobic exercise, 10 strengthening exercises, and 12 stretches. In the two intervention groups, 60% to 65% of patients attended at least eight classes.
At 26 weeks, outcomes as measured by standardized assessments were similar and significantly better with yoga and stretching than with self-care. Roughly 51% to 60% of patients in both intervention groups improved by at least 50% compared with 31% of control patients. No serious adverse events were reported in any group.
Comment: The take-home message from this and similar studies (JW Gen Med Nov 17 2011) is that patients benefit more from any type of supervised exercise and stretching than from exhortations to do it on their own. Clinicians should recommend some sort of structured exercise prescription, depending on patient preference and availability of programs.
— Thomas L. Schwenk, MD Published in Journal Watch General Medicine January 5, 2012
Citation(s): Sherman KJ et al. A randomized trial comparing yoga, stretching, and a self-care book for chronic low back pain. Arch Intern Med 2011 Dec 12/26; 171:2019.
(http://dx.doi.org/10.1001/archinternmed.2011.524)
http://www.ncbi.nlm.nih.gov/pubmed/22025101?dopt=Abstract
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Arch Intern Med 2011 Dec 12/26; 171:2031
Elders Might Be Overscreened for Cancer
The prostate cancer screening rate seems particularly excessive.
Exclusion of older adults from many screening studies and the variable benefits derived from screening when underlying chronic diseases are present have led to uncertainty about what cancer screening rates are "right" for elders. Researchers used data from a U.S. nationwide in-person interview survey to assess cancer screening rates in nearly 50,000 adults (including 1697 who were aged 75–79 and 2376 who were 
80)
For breast cancer screening, 50% of women 80 and older underwent mammography versus 62% of those who were 75 to 79 and 74% of those who were 50 to 74. For colorectal cancer screening, rates were 47% for participants who were 80 and older, 57% for those who were 75 to 79, and 48% for those who were 50 to 74. Prostate-specific antigen testing was performed during the previous year in 42% of men who were 80 and older, in 57% of men who were 75 to 79, and in 40% of men who were 50 to 74.
Among participants who were 75 to 79, blacks were less likely to be screened for any of these three cancers than were whites, but this disparity was offset by differences in educational attainment. Patients without high school diplomas were roughly 50% to 60% less likely to be screened than were those with college degrees. More than half of participants who were 75 and older recalled receiving physician recommendations for one or more cancer screenings.
Comment: These cancer screening rates seem inappropriately high, particularly for prostate cancer screening. However, these rates also reflect the known preference by many patients for continued cancer screening, regardless of age or lack of physician recommendation.
— Thomas L. Schwenk, MD Published in Journal Watch General Medicine January 5, 2012
Citation(s):Bellizzi KM et al. Prevalence of cancer screening in older, racially diverse adults: Still screening after all these years. Arch Intern Med 2011 Dec 12/26; 171:2031.
http://www.ncbi.nlm.nih.gov/pubmed/22158573?dopt=Abstract
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USPSTF Recommends Against Prostate Cancer Screening
The Task Force determined that the harms of screening outweighed the benefits for most men.
In October 2011, the U.S. Preventive Services Task Force (USPSTF) ignited controversy when it posted a new recommendation against prostate cancer screening. Tipping the balance against screening was the USPSTF's view that the benefits demonstrated in the two recent randomized screening trials were small at best and insufficient to outweigh the harms of screening (e.g., false-positive prostate-specific antigen [PSA] results, unnecessary biopsies, overdiagnosis of indolent tumors, and psychological effects associated with all these outcomes) and the harms of overtreating men with low-grade disease
(JW Gen Med Oct 27 2011).
During 2011, several analyses expanded on the initial findings from the two major screening trials, which were published in 2009. Although the U.S. Prostate Lung, Colorectal, and Ovarian (PLCO) trial showed no overall difference in 10-year prostate cancer mortality, regardless of screening group, a new post hoc analysis demonstrated that a subgroup of screened men with no comorbidities experienced lower 10-year prostate cancer–specific mortality than unscreened men (0.17% vs. 0.31%; P=0.03). In contrast, screened men with comorbidities had higher prostate cancer–specific mortality than unscreened men
(JW Gen Med Mar 3 2011).
In another analysis, proponents of screening extrapolated from the previously published European Randomized Study of Screening for Prostate Cancer (ERSPC), which had shown that screening was associated with seven fewer prostate cancer deaths per 10,000 men during 9 years of follow-up. These researchers predicted that after several more years of follow-up, the number needed to treat to prevent 1 prostate cancer–related death will drop from 48 to 18 — a more favorable benefit-harm ratio
(JW Gen Med Mar 3 2011).
The USPSTF explicitly does not include costs in its analyses and recommendations. However, cost-effectiveness considerations are unavoidable in any responsible discussion of population-wide screening. One research group — using ERSPC outcomes and U.S. costs — concluded that the cost to prevent one prostate cancer death through screening would be roughly US$5.2 million. This figure includes the cost of screening, diagnostic evaluation, and treatment
(JW Gen Med Mar 3 2011).
Even those who support screening acknowledge that older men and men with substantial comorbidities are unlikely to benefit from screening and aggressive treatment of localized prostate cancer. Nevertheless, in one study, the prevalence of screening during the previous year was 45% among men aged 70 to 79 and 25% among those older than 85. In another study, researchers examined aggressiveness of treatment in men with localized low-risk prostate cancer. Radical prostatectomy or radiation therapy was provided to 15% of men older than 75 and to 54% of men with substantial comorbidities (JW Gen Med May 19 2011).
Back to the USPSTF: Its document was a "draft recommendation," which was made available for public comment for a limited time on the USPSTF website. The final version will presumably be published in the near future; whether public commentary will result in any revisions will be interesting to see. Meanwhile, readers may wish to review three different perspectives on the USPSTF recommendation that were published in the November 24, 2011, issue of the New England Journal of Medicine. (Disclosure: I authored one of those articles.)
— Allan S. Brett, MD Published in Journal Watch General Medicine December 29, 2011
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Good and Bad News About Adolescent Substance Use
Declines in adolescents' use of alcohol and tobacco are offset by a continuing rise in use of marijuana.
Monitoring the Future Survey is a nationwide school-based survey of 47,000 8th-, 10th-, and 12th-grade students. The 37th annual results demonstrate declines among adolescents in all three grades in the use of alcohol, tobacco, and most other illicit drugs, with the notable exception of marijuana.
Alcohol use in the past 30 days was reported by 25% to 50% fewer adolescents in 2011 than 20 years ago, with 13%, 27%, and 40% of 8th, 10th, and 12th graders, respectively, reporting such use in 2011. More important, the reported rate of binge drinking (
5 drinks on 1 occasion in the past 2 weeks) declined from 20% to 14% for the three grades combined.
Smoking among adolescents continued its downward trend from its peak in 1996–1997. In 2011, 2%, 6%, and 10% of 8th, 10th, and 12th graders, respectively, reported smoking daily. The 30-day prevalence of smokeless tobacco use (snuff, dipping or chewing tobacco, and "snus") declined somewhat from 2010 and was reported by <10% of adolescents. Almost 20% of 12th graders reported using a hookah in the past year, but only 10% did so more than twice.
Illicit drugs that have reportedly declined in use include inhalants, cocaine, Vicodin, Adderall, sedatives, tranquilizers, and over-the-counter cough and cold preparations used expressly to get high.
This good news is offset by continued increases in marijuana use, likely fueled by reduced perception that marijuana use is risky. Approximately 7%, 18%, and 23% of 8th, 10th, and 12th graders reported using marijuana in the last 30 days (up from 3%, 9%, and 14%, respectively in 1991), and rates of daily use (1%, 4%, and 7%, respectively) reached the highest levels since 1981. Perceived risk of using marijuana regularly has continued to fall since 2005; less than half of 12th graders agreed that using marijuana regularly carries "great risk" (versus 60% in 2005) About 10% of high school seniors (1 in 9) reported trying synthetic marijuana ("K2" or "spice") during the past year.
Comment: Overall, these results reflect positive trends. Alcohol use, especially binge drinking, is associated with substantial short-term morbidity and mortality (motor vehicle accidents, violence, and sexual assault), and adolescents' developing brains are uniquely susceptible to alcohol-related damage. Rarely do people start smoking after age 19, so efforts to curtail use among adolescents will reap health benefits and healthcare savings down the road. The results of the current study are consistent with another national study) that documented increasing marijuana use among adolescents. It is now more likely that an adolescent will have used marijuana in the last 30 days than smoked a cigarette. Although alcohol and tobacco use cause far more harm, marijuana is not benign (JW Psychiatry Jul 11 2011); the continuing decline in the perceived risk of marijuana use likely portends continuing increases in use in the future.
— Alain Joffe, MD, MPH, FAAP Published in Journal Watch Pediatrics and Adolescent Medicine January 4, 2012
Johnston LD et al. Decline in teen smoking resumes in 2011. Ann Arbor, MI: University of Michigan News Service; Dec 14, 2011.
(http://www.monitoringthefuture.org/pressreleases/11cigpr.pdf
Citation(s): Johnston LD et al. Marijuana use continues to rise among U.S. teens, while alcohol use hits historic lows.Ann Arbor, MI: University of Michigan News Service; Dec 14, 2011. (http://www.monitoringthefuture.org/pressreleases/11drugpr.pdf)
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Arch Pediatr Adolesc Med 2011 Nov; 165:993
Using Infant Growth Charts to Predict Later Obesity
Crossing multiple weight-for-length percentiles before age 2 years is associated with obesity at ages 5 and 10 years.
Studies suggest that excess weight as early as in infancy is related to later obesity and health problems. But what practical tool can pediatricians use in young children to predict future obesity? Researchers in Boston examined the association between weight and length measurements from more than 44,000 children younger than 2 years and follow-up body-mass index (BMI) measurements at ages 5 years (39,000 children) and 10 years (22,000 children).
Children whose weight-for-length percentile on Centers for Disease Control and Prevention growth charts rose by two or more major percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles) during the first 2 years of life had elevated odds of obesity (BMI 
95th percentile for age) at age 5 years (adjusted odds ratio, 2.08; [95% confidence interval, 1.84–2.34]) and at 10 years (AOR, 1.75 [95% CI, 1.53–2.00]), compared with children whose weight-for-length did not rise by at least two major percentiles. Overall, 43% of children crossed two major percentiles during the first 6 months of infancy, and these children were the most likely to be obese at ages 5 and 10 years.
Comment: The authors of this large longitudinal study examined how a practical clinic-based infant assessment used by all pediatricians might predict obesity later in childhood. Editorialists emphasize that the validity, sensitivity, and positive predictive value of this screening tool should be determined before it is used to predict risk for later obesity in individual children. We also need evidence that counseling parents of "upwardly mobile" young children is safe, is cost-effective, and changes the likelihood of later obesity.
— Cornelius W. Van Niel, MD Published in Journal Watch Pediatrics and Adolescent Medicine January 4, 2012
Citation(s):Taveras EM et al. Crossing growth percentiles in infancy and risk of obesity in childhood. Arch Pediatr Adolesc Med 2011 Nov; 165:993.
http://www.ncbi.nlm.nih.gov/pubmed/22065180?dopt=Abstract
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N Engl J Med 2012 Jan 5; 366:34
Herpes Simplex Vaccine Trial Yields Mixed Results
In a large cohort of young women, the vaccine showed efficacy against HSV-1 infection — with or without disease — but not against HSV-2 infection.
The availability of an effective vaccine to protect against infection with herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) would have major public health implications. The results of two earlier trials that involved discordant couples in which one partner had recurrent HSV genital disease suggested that an HSV-2 glycoprotein D–based subunit (gD-2) vaccine provided significant protection against HSV-2 disease in the subset of women who were seronegative for both HSV-1 and HSV-2 antibodies. The current, partially manufacturer-sponsored investigation was conducted to evaluate the efficacy of the gD-2 vaccine in a larger group of HSV-1– and HSV-2–seronegative women.
More than 8000 women aged 18 to 30 from the U.S. and Canada participated in this randomized, double-blind trial. The gD-2 vaccine (or, in controls, inactivated hepatitis A vaccine) was administered by injection at months 0, 1, and 6. The primary endpoint was occurrence of genital herpes disease caused by HSV-1 or HSV-2 from month 2 through month 20.
Efficacy against HSV-2 infection was not seen (–8%; 95% confidence interval, –59% to 26%). In contrast, efficacy against HSV-1 infection, with or without disease, was 35% (95% CI, 13% to 52%). Adverse reactions — both local and systemic — were significantly more common with gD-2 than with the control vaccine.
Comment: The findings of the study were "puzzling" to the authors; I agree. It is difficult to understand the lack of efficacy against HSV-2 disease or infection when such efficacy was shown in two previous trials. Moreover, the vaccine was protective against HSV-1 disease and infection. Unfortunately, an effective HSV vaccine will probably not be available in the near future.
— Larry M. Baddour, MD Published in Journal Watch Infectious Diseases January 4, 2012
Citation(s):Belshe RB et al. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med 2012 Jan 5; 366:34.
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Pediatr Infect Dis J 2011 Dec; 30:1019.
TMP-SMX Is Another Option for Treatment of Acute Osteomyelitis
Treatment with oral trimethoprim-sulfamethoxazole was successful even for MRSA osteomyelitis in children.
Transitioning from intravenous (IV) to oral antibiotic therapy for acute hematogenous osteomyelitis hastens the return to normal activities in children. However, emergence of methicillin-resistant Staphylococcus aureus (MRSA) limits the choice of an oral agent. Clindamycin has a good track record for treatment of MRSA osteomyelitis, but its use is limited by its unpalatable taste and increasing S. aureus resistance. MRSA resistance to trimethoprim-sulfamethoxazole (TMP-SMX) is rare. These investigators report their experience using TMP-SMX for treatment of 20 patients (age, 
18 years) with proven or presumed osteomyelitis caused by S. aureus.
In most cases, patients did not receive TMP-SMX as initial IV therapy but rather as the oral transition drug. Median duration of treatment with TMP-SMX was 40 days; 11 patients received TMP-SMX for most of the treatment duration (median, 31 days). Forty percent of patients experienced adverse effects (rash, neutropenia, and emesis). Erythema multiforme was not reported. All 20 patients were cured at the end of therapy.
Comment: This small, retrospective case series provides the first published data to show good outcomes in patients with MRSA osteomyelitis treated with TMP-SMX. Oral TMP-SMX is easy to administer and palatable for young children, making it an excellent oral treatment option for children with S. aureus resistant to clindamycin or those with methicillin-susceptible S. aureus and β-lactam allergy. More patients in this series had rash than in my experience. Patients should be counseled to contact their physicians at the first sign of rash.
— Peggy Sue Weintrub, MD Published in Journal Watch Pediatrics and Adolescent Medicine December 21, 2011
Citation(s):Messina AF et al. Trimethoprim-sulfamethoxazole therapy for children with acute osteomyelitis. Pediatr Infect Dis J 2011 Dec; 30:1019.
http://www.ncbi.nlm.nih.gov/pubmed/21817950?dopt=Abstract
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BMJ 2011 Nov 29; 343:d7281
Statins Don't Lower Risk for Infections
A meta-analysis of 11 randomized trials showed no benefit.
Although observational studies have shown that statins are associated with lower risks for infections and infection-related deaths (JW Infect Dis Feb 14 2007 and JW Gen Med Mar 3 2006), such studies are subject to confounding. To assess this association further, investigators conducted a meta-analysis of 11 randomized controlled trials that involved nearly 31,000 participants (mean age, 63).
After a mean follow-up of 3.3 years, statins had no effect on risk for infections (relative risk, 1.00) or infection-related deaths (RR, 0.97).
Comment: This meta-analysis provides no evidence that statins lower risk for infections. However, none of the included trials had predefined infectious outcomes — an important limitation. A related question — whether statin therapy can attenuate the severity of already-acquired infections — currently is being studied in patients with sepsis (e.g., Statins for the Early Treatment of Sepsis trial).
— Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine
December 27, 2011
Citation(s): van den Hoek HL et al. Statins and prevention of infections: Systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011 Nov 29; 343:d7281. (http://dx.doi.org/10.1136/bmj.d7281)
http://www.ncbi.nlm.nih.gov/pubmed/22127443?dopt=Abstract
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MM: Many of us are familiar with the story, “The Portrait of Dorian Gray” but now we may have the potential to live forever! Is this really desirable? So many ethical questions come into play with this potential. Only time will tell if this raw research becomes useful. It certainly is interesting
Nature 2011 Nov 10; 479:232
Yet Another Way to Slow Aging
Eliminating aging cells from the body might be a key.
As cells age, they remain viable and continue their metabolic functions but can no longer divide, and, eventually, they self-destruct. Interestingly, before senescent cells die, they start making a variety of molecules — growth factors, cytokines, proteases, and others — that have harmful biological effects on the cells around them.
A team from Mayo Clinic developed transgenic mice in which cells carrying a particular senescence marker could be destroyed selectively by administration of a drug. These mice then were bred with mice that age prematurely. The resultant offspring suffered from premature aging, and their senescent cells could be eliminated rapidly at any time. When senescent cells were eliminated constantly, starting at a young age, the animals did not develop various age-related disorders. When senescent cells were eliminated for the first time in midlife (in mice that had started to develop various age-related disorders), progression of those disorders slowed dramatically.
Comment: Dying cells secrete factors that might cause age-related disorders. At least in mice, the elimination of dying cells retarded aging. Application of this principle in humans is at least decades away. Nevertheless, this study deserves our attention because it suggests, as do several other recent animal experiments, that the aging process in mammals might not be as inevitable and uncontrollable as we have assumed (JW Gen Med Jan 4 2011 and JW Gen Med May 12 2011).
— Anthony L. Komaroff, MD Published in Journal Watch General Medicine January 3, 2012
Citation(s): Baker DJ et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011 Nov 10; 479:232.
(http://dx.doi.org/10.1038/nature10600)
http://www.ncbi.nlm.nih.gov/pubmed/22048312?dopt=Abstract
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The Childhood Obesity Epidemic: More Data but Few Answers
Risk for obesity in children has been linked with infant feeding practices, media exposure, sleep deprivation, and vitamin D deficiency.
It's not surprising that obesity is linked with what we feed our children, but recent evidence also links the risk for obesity with infant feeding and weaning practices. One study showed that introducing solid foods before age 4 months significantly increases the risk for obesity at age 3 years in formula-fed — but not breast-fed — infants (JW Pediatr Adolesc Med Mar 2 2011). In another study, the risk for obesity was 30% higher in 2-year-olds who still used a bottle compared with those who did not (JW Pediatr Adolesc Med Oct 5 2011). As summarized by one of our editors, "The inconsistent and vacillating recommendations regarding the timing of solid food introduction reflect both the weak evidence and the fact that the ideal recommendation probably is different for different populations." (JW Pediatr Adolesc Med Mar 2 2011)
Regardless of how, when, or what children are fed, obesity occurs when energy intake exceeds caloric expenditure. As discussed in the Year-in-Review essay on Media Use in Children (JW Pediatr Adolesc Med Dec 28 2011, considerable evidence implicates media in altering the relative balance between these two variables, and this year's American Academy of Pediatrics policy statement on Children, Adolescents, Obesity, and the Media (JW Pediatr Adolesc Med Jul 27 2011) addresses the emerging evidence linking increased media time with childhood obesity. Although media, specifically "exergaming," has been shown to increase energy expenditure in children by achieving levels of physical activity intensity comparable to walking on a treadmill at 3 miles per hour (JW Pediatr Adolesc Med Jul 27 2011), playing video games and TV watching also have been positively associated with increased caloric intake, higher-fat diets, drinking more soda, and eating fewer fruits and vegetables (JW Pediatr Adolesc Med Jun 22 2011). Media use can also lead to sleep deprivation and increased sedentary behavior, both of which increase risk for obesity. In a longitudinal study, each additional hour of sleep between ages 3 and 5 years was associated with a 60% reduction in risk of overweight (JW Pediatr Adolesc Med Jul 6 2011).
In the continued search for interventions that can prevent and treat childhood obesity, Australian investigators found that a 6-month child-centered physical activity program and a parent-centered dietary modification program each reduced body-mass index (BMI) z scores and waist circumference in prepubertal overweight children and that combining the interventions was more effective than either program alone (JW Pediatr Adolesc Med Apr 27 2011). However, in a randomized controlled trial, restructuring primary care practices to adopt a chronic disease management approach to obesity failed to result in lower BMIs in children compared with usual care (JW Pediatr Adolesc Med May 25 2011). Fortunately, a combined analysis of four large long-term studies indicates that children can lower their risk for cardiovascular disease if they achieve normal BMIs as adults, suggesting that it's never too late to encourage healthy lifestyles in our patients (JW Pediatr Adolesc Med Nov 16 2011). Finally, vitamin D deficiency (<50 nmol/L) was marginally associated with greater increases in BMI in school-age children during a 2.5-year period (JW Pediatr Adolesc Med Dec 8 2010). If only the solution to childhood obesity were that simple.
— Alain Joffe, MD, MPH, FAAP Published in Journal Watch Pediatrics and Adolescent Medicine December 28, 2011
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Alzheimer’s Drug Apes Omega-3s and Berries
Promising experimental drug yields brain benefits in rodents, similar to those seen in animals given omega-3 fish oil or blueberries
by Craig Weatherby
More than five million Americans suffer from Alzheimer's, according to the National Institutes of Health. And more than 16 million will have the disease by 2050, according to Alzheimer's Association estimates, resulting in medical costs of over $1 trillion per year.
Alzheimer's typically appears after age 60, although a small percentage of families carry a genetic risk for earlier onset. Among the top ten causes of death, Alzheimer's is the only one without a way to prevent, cure, or slow down disease progression. Over the past decade, studies in rodents have found that omega-3 fish oil and blueberries exert beneficial effects in these animals’ brains … benefits that may be relevant to prevention or amelioration of Alzheimer's disease. These rat and mouse studies also showed that one omega-3 in particular – DHA, which is essential to animal and human brain structure and functions alike – helped rodents’ brains withstand physical or psychological brain trauma more resiliently. Specifically, these experiments revealed that even short-term feeding of omega-3 fish oil “up-regulated” growth of new brain cells (Beltz BS et al. 2007) in rodents.
Another team found that adding omega-3 DHA to brain cells taken from the hippocampus – the brain’s memory-forming center – enhanced connectivity among these neurons via increased “extension and branching” (Calderon F et al. 2004).
And a third group reported that fish oil raised rodents’ brain levels of brain-derived neurotrophic factor (BDNF) … a key compound that promotes survival and growth of brain cells (Wu A et al. 2004).
On a cellular level, a DHA-enriched diet increased levels of six beneficial chemicals, which enhance the brain “plasticity” needed for memory and learning:
- BDNF (brain-derived neurotrophic factor)
- Mature BDNF
- CREB (cAMP responsive element-binding protein)
- Synapsin I
- Hippocampal Akt
- Hippocampal CaMKII
For more on these studies, see “Omega-3s May Deter PTSD” and “Fish Fats Boost Brain Resilience” and “Berries Give Aged Rats' Brains a Big Boost”.
Berries and company yield similar brain benefits
Blueberries produced similar benefits in the brains of rodents: see “Blueberries Reversed Rodents' Brain Decline”. And the authors of this research believe that these effects extend to most berries, because they flow from certain polyphenols (antioxidants) called anthocyanins and flavanols, which abound in almost all berries … as well as in dark chocolate, natural (non-Dutched) cocoa, and grapes. We also know that these particular polyphenols exert beneficial “nutrigenomic” effects on genetic switches called nuclear transcription factors, such as Nf-kappaB (Goyarzu P et al. 2004). Specifically, they tend to “turn off” pro-inflammatory genetic switches, and may thereby inhibit the chronic low-level inflammation associated with Alzheimer’s and other degenerative diseases.
What about humans? The outcomes of two small, “pilot” clinical trials suggest that berries may provide similar brain benefits to people. (See “Blueberries Score in Two Brain-Health Trials”.) In both trials, people who drank blueberry juice or smoothies showed significant improvements in learning and memory, compared with the control groups, and showed a statistical trend towards fewer signs of depression, and lower blood sugar (glucose) levels.
New Alzheimer's drug may prevent disease progression
Now, scientists at the Salk Institute for Biological Studies say they’ve developed a new drug that improves memory and prevents brain damage in mice. Remarkably, it works by exerting effects similar to those that omega-3 fish oil and blueberries displayed in rodent studies. When given to mice with Alzheimer's, an experimental drug called J147 improved memory and prevented brain damage caused by the disease (Chen Q et al. 2011).
According to David Schubert, director of Salk’s Cellular Neurobiology Laboratory, “J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections. No drugs on the market for Alzheimer’s have both of these properties.” That is certainly true of current Alzheimer’s drugs … but as we’ve just described, berries and omega-3 DHA seem to bring these same benefits to rodents’ brains. So far, the drugs developed to treat the disease – such as Aricept, Razadyne, and Exelon – only produce slight, fleeting memory improvements and do nothing to slow the overall course of the disease.
All of these drugs belong to a family called “cholinesterase inhibitors”, which reduce breakdown of a brain compound called acetylcholine that mediates communication between neurons (brain cells), and whose production is reduced by the presence of amyloid plaque (Pedersen WA et al. 1996). To date, academic and pharmaceutical industry researchers have focused almost exclusively on drugs that block the actions of cholinesterase … an enzyme that the brain uses to break down excess acetylcholine. Since the brain cells of Alzheimer's patients don’t produce enough acetylcholine, the goal of using cholinesterase inhibitor drugs is to curb the enzymatic process by which the brain normally breaks down acetylcholine.
Sadly, none of the existing amyloid-based drugs have produced substantial benefits in clinical trials … probably because reduced production of acetylcholine isn’t the primary problem in Alzheimer's disease. As the authors of one evidence review wrote, “The debate on whether donepezil [Aricept] is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice.” (Birks J, Harvey RJ 2006)
Experimental drug echoes omega-3s’ brain effects
Instead of targeting cholinesterase, the Salk team used living neurons to test whether or not new synthetic compounds were effective at protecting the brain cells against changes associated with Alzheimer’s. Based on the results of testing chemical variations on a compound originally developed for treatment of stroke and traumatic brain injury, they were able to make it into a much more potent anti-Alzheimer’s drug … at least in animals. The Salk researchers conducted a range of behavioral tests, which showed that J147 improved memory in normal rodents. The scientists went on to show that it prevented cognitive decline in animals with Alzheimer's and that mice and rats treated with the drug produced more brain-derived neurotrophic factor (BDNF).
As we said, omega-3 DHA is also shown to raise brain levels of BDNF, which protects neurons from damage, helps new neurons grow and connect with other brain cells, and is involved in memory formation. Because of the broad ability of J147 to protect nerve cells, the researchers believe that it may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), as well as stroke.
The Salk team hopes to test the new compound in humans in the near future. The Salk team’s research was supported by the National Institutes of Health and the Alzheimer’s Association, among funders. In the meantime, it seems logical to fill your diet with fatty fish and/or fish oil, as well as berries and other sources of the flavanol-type antioxidants that appear to produce their brain benefits … including tea, dark chocolate, natural, non-Dutched cocoa, and grapes. While it may well be that none of these foods can produce brain-protective effects as potent as a synthetic drug like J147 – assuming it actually works in people – they bring multiple health benefits and have no adverse effects. We should also note that animal experiments support the possible efficacy of Krill oil (Lee B et al. 2010) … and of a traditional Chinese herb called Rehmannia (Rehmannia glutinosa or “Chinese Foxglove”).
Like omega-3 DHA, flavanols, and J147, Rhemannia root boosts brain levels of BDNF. It’s shown to significantly improve memory deficits in rodents with Alzheimer’s (Liu J et al. 2006; Wang Z et al. 2009; Lee B et al. 2011)
Sources: Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA. Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci. 2005 Apr;8(2):111-20. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001190. Review. Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F, Cicchetti F. Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;33(8):1401-8. Epub 2009 Jul 24. Calderon F, Kim HY. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem. 2004;90(4):979-988. Cantu RC. Chronic traumatic encephalopathy in the National Football League. Neurosurgery. 2007 Aug;61(2):223-5. Review. Chance R. Food for Thought. British Science Association, September 14, 2009. Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D. A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. PLoS One. 2011;6(12):e27865. Epub 2011 Dec 14. Cotman CW, Engesser-Cesar C. Exercise enhances and protects brain function. Exerc Sport Sci Rev. 2002 Apr;30(2):75-9. Review. Cysneiros RM, Ferrari D, Arida RM, Terra VC, de Almeida AC, Cavalheiro EA, Scorza FA. Qualitative analysis of hippocampal plastic changes in rats with epilepsy supplemented with oral omega-3 fatty acids. Epilepsy Behav. 2010 Jan;17(1):33-8. Epub 2009 Dec 6. Derbyshire D. A bowl of blueberries keeps the brain active in the afternoon. The Daily Mail UK, September 14, 2009. Accessed at:
http://www.dailymail.co.uk/health/article-1212579/A-bowl-blueberries-day-keeps-brain-active-afternoon.html Dishman RK, Berthoud HR, Booth FW, Cotman CW, Edgerton VR, Fleshner MR, Gandevia SC, Gomez-Pinilla F, Greenwood BN, Hillman CH, Kramer AF, Levin BE, Moran TH, Russo- Feng R, Rampon C, Tang YP, et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001;32(5):911-926. Garcia P, Youssef I, Utvik JK, Florent-Béchard S, Barthélémy V, Malaplate-Armand C, Kriem B, Stenger C, Koziel V, Olivier JL, Escanye MC, Hanse M, Allouche A, Desbène C, Yen FT, Bjerkvig R, Oster T, Niclou SP, Pillot T. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease. J Neurosci. 2010 Jun 2;30(22):7516-27. Kitamura T, Saitoh Y, Takeshima N, et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009;139(4):814-827. Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br J Nutr. 2009 Dec 23:1-5. [Epub ahead of print] Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, Joseph JA. Blueberry Supplementation Improves Memory in Older Adults (dagger). J Agric Food Chem. 2010 Jan 4. [Epub ahead of print] Lee B, Shim I, Lee H, Hahm DH. Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats. J Microbiol Biotechnol. 2011 Aug;21(8):874-83. Lee B, Sur BJ, Han JJ, Shim I, Her S, Lee HJ, Hahm DH. Krill phosphatidylserine improves learning and memory in Morris water maze in aged rats. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):1085-93. Liu J, He QJ, Zou W, Wang HX, Bao YM, Liu YX, An LJ. Catalpol increases hippocampal neuroplasticity and up-regulates PKC and BDNF in the aged rats. Brain Res. 2006 Dec 6;1123(1):68-79. Epub 2006 Oct 31. Logan AC. Omega-3 and BDNF regulation: eicosapentaenoic acid may play a key role in limitation of CNS injury. J Neurotrauma. 2008 Dec;25(12):1499. No abstract available. Macready AL, Kennedy OB, Ellis JA, Williams CM, Spencer JP, Butler LT. Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr. 2009 Dec;4(4):227-42. Epub 2009 Aug 13. Matsuoka Y, Nishi D, Nakajima S, Yonemoto N, Hashimoto K, Noguchi H, Homma M, Otomo Y, Kim Y. The Tachikawa cohort of motor vehicle accident study investigating psychological distress: design, methods and cohort profiles. Soc Psychiatry Psychiatr Epidemiol 2009, 44:341. Matsuoka Y, Nishi D, Yonemoto N, Hamazaki K, Hamazaki T, Hashimoto K. Potential role of BDNF in the omega-3 fatty acid supplementation to prevent posttraumatic distress after accidental injury: An open-label pilot study. Psychothear Psychosom in press. Matsuoka Y, Nishi D, Yonemoto N, Hamazaki K, Hashimoto K, Hamazaki T. Omega-3 fatty acids for secondary prevention of posttraumatic stress disorder after accidental injury: an open-label pilot study. J Clin Psychopharmacol. 2010 Apr;30(2):217-9. Neustadt AA, Salamone JD, Van Hoomissen JD, Wade CE, York DA, Zigmond MJ. Neurobiology of exercise. Obesity (Silver Spring). 2006 Mar;14(3):345-56. Review. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of Fear Extinction with Hippocampal-Infralimbic BDNF. Science 2010, 328:1288-1290. Rao JS, Ertley RN, Lee HJ, DeMar JC Jr, Arnold JT, Rapoport SI, Bazinet RP. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry. 2007 Jan;12(1):36-46. Epub 2006 Sep 19. Spencer JP. Flavonoids and brain health: multiple effects underpinned by common mechanisms. Genes Nutr. 2009 Dec;4(4):243-50. Epub 2009 Aug 15. Squire LR. Memory and Brain. Oxford: Oxford University Press; 1987. Venna VR, Deplanque D, Allet C, Belarbi K, Hamdane M, Bordet R. PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus. Psychoneuroendocrinology. 2009 Feb;34(2):199-211. Epub 2008 Oct 10. Wang Z, Liu Q, Zhang R, Liu S, Xia Z, Hu Y. Catalpol ameliorates beta amyloid-induced degeneration of cholinergic neurons by elevating brain-derived neurotrophic factors. Neuroscience. 2009 Nov 10;163(4):1363-72. Epub 2009 Jul 24. Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, Whiteman M, Spencer JP. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med. 2008 Aug 1;45(3):295-305. Epub 2008 May 5. Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma. 2004;21(10):1457-1467.
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Atypical Femur Fractures with Bisphosphonates
Risk is low but not inconsequential.
Bisphosphonate drugs (alendronate, risedronate, and others) are typically prescribed to prevent osteoporotic hip fractures involving the femoral neck or intertrochanteric region. However, several small case series show that long-term users of bisphosphonates could be at excess risk for subtrochanteric or femoral shaft fractures with atypical characteristics, including transverse orientation and thickening of the cortex at the fracture site (see image). In addition, these fractures sometimes are "low-energy" (i.e., not associated with trauma) and preceded by prodromal thigh pain. The incidence of bisphosphonate-associated femur fractures has been unclear, but two large studies published in 2011 shed some light on the matter.
In a population-based Canadian case-control study of bisphosphonate users, older women who suffered subtrochanteric or femoral shaft fractures were compared with age-matched women who didn't have such fractures. Bisphosphonate use for >5 years, compared with transient use (<100 days), was associated with significant excess risk for subtrochanteric or shaft fracture (odds ratio, 2.74). However, absolute risk was low — roughly 1 fracture per 1000 bisphosphonate users annually, during the 2 years following a 5-year course of bisphosphonate therapy (JW Gen Med Mar 3 2011).
In a cohort study of all older Swedish women, researchers focused specifically on atypical femur fractures with transverse orientation and cortical thickening. During a 12-month period, the incidence of such fractures was considerably higher among women who had used bisphosphonates anytime during the preceding 3 years than among women who had not (5.5 vs. 0.1 per 10,000 patient-years). Risk was even higher in those who had used bisphosphonates for at least 2 years (8.4 per 10,000 patient-years). Moreover, 78% of women with atypical fractures, but only 10% of controls, were bisphosphonate users (JW Womens Health May 4 2011).
These studies allow us to estimate tentatively that the annual risk for a subtrochanteric or femoral shaft fracture is about 1 per 1000 among long-term bisphosphonate users. Among women with FDA-approved, evidence-based indications for bisphosphonate therapy (i.e., documented osteoporosis or a previous osteoporotic fracture), the number of typical hip fractures prevented by bisphosphonate therapy would outnumber the number of atypical femur fractures caused by treatment. However, many women without those indications take bisphosphonates; for such women, inappropriate bisphosphonate therapy might confer risk for atypical fractures without offsetting benefit. For patients with indications for bisphosphonate therapy, so-called "drug holidays" after several years of treatment might result in an optimal balance of benefits and harms.
— Allan S. Brett, MD Published in Journal Watch General Medicine December 29, 2011
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December 27, 2011
Ocean Fish May Curb Pancreatic Cancer
Selenium is linked to lower risk, and ocean fish are the richest source
by Craig Weatherby
As we’ve noted in several past articles, most seafood is rich in selenium, which is essential to the body’s key antioxidant enzymes. In fact, mercury is toxic primarily because it binds to selenium and thereby disables key antioxidant enzymes, allowing oxygen free radicals to damage brain, nerve, and other cells. As long as people consume substantially more selenium than mercury, the latter can’t do much, if any, harm. Almost every commercial ocean fish species contains lots of selenium, and much more selenium than mercury. (The very few exceptions include shark, swordfish, tilefish, and large King mackerel … fresh water fish vary widely in both mercury and selenium content.) This explains why there is virtually no evidence of mercury-related harm found in children and adults who eat ocean fish far more frequently than Americans do. (See “Fish-Mercury Fears Hyped, Despite Pesky Facts” and related articles in the “Mercury Issues” section of our news archive.)
Selenium and cancer: A mixed picture
There have been some indications that dietary selenium might reduce cancer risk … a possibility attributed to the mineral’s key supporting role in the human antioxidant network. Conversely, when it comes to combating cancer cells, selenium acts as a pro-oxidant that induces apoptosis (suicide) among cancer cells. In other words, when cancer is present, selenium helps generate oxygen free radicals, and compared with healthy cells, malignant cells are more vulnerable to the resulting “oxidative stress”.
Overall, the evidence that selenium prevents cancer ranges from mixed to negative (Garland M et al.1995; Garland M et al.1996; Peters U et al. 2007; Marshall JR et al. 2011; Jiang L et al. 2010). And as the authors of a recent evidence review wrote, “To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.” (Dennert G et al. 2011) But the trials conducted to date have had flaws that preclude definite conclusions (Goodman M et al. 2011). And some evidence suggests that adding selenium to the diet – either as supplements or in foods such as fish – might help curb certain cancer risks among people whose dietary intakes are low (Brozmanová J 2011; Lee KH, Jeong D 2012) Now, a team of international researchers reports findings that suggest a pancreas-protecting role for selenium … and, by extension, for seafood.
Study finds new links between trace metals and pancreatic cancer
This “case-control” study was conducted by scientists from the U.S. National Cancer Institute, Dartmouth College, the Spanish National Cancer Research Centre, and the University of Barcelona (Amaral AF et al. 2011). They measured the levels of 12 trace elements in the toenails of 118 hospital patients with exocrine pancreatic cancer – the most common form – and 399 patients free of cancer. (Toenails provide the most reliable measure of body levels of trace metals, because they reflect people’s intakes from all sources over the long term.) After comparing the subjects’ metal levels to their cancer status, high body levels of nickel and selenium were associated with absence of pancreatic cancer.
Specifically, the subjects with the highest levels of nickel and selenium were 33 to 95 percent less likely to have the disease, compared with those showing the lowest levels. In contrast, the pancreatic cancer patients tended to have high levels of lead, arsenic, and cadmium. The subjects with the highest levels of arsenic and cadmium in their nails were between two and 3.5 times more likely to have pancreatic cancer, compared to those with the lowest levels.
Even worse, the subjects with the highest levels of lead were more than six times as likely to have the disease. Of course, we cannot be certain whether these differences in metal levels result from the presence or absence of pancreatic cancer. But it appears quite implausible that having pancreatic cancer would result in lead, arsenic, and cadmium accumulating in the body. The team’s findings held true even after taking into account other known risk factors, such as diabetes, overweight, and smoking.
Smoking is thought to account for about one-third of all cases of pancreatic cancer. Tobacco contains trace metals, including cadmium, which is a known carcinogen, and has been associated with an increased risk of lung, kidney, and prostate cancers. The authors noted that high body levels of selenium have been linked to lower risk of certain cancers, and that selenium may counter the harmful effects of cadmium, arsenic, and lead. And as they concluded, “Our results support an increased risk of pancreatic cancer associated with higher levels of cadmium, arsenic, and lead, as well as an inverse association with higher levels of selenium and nickel.” (Amaral AF et al. 2011)
Sources: Amaral AF, Porta M, Silverman DT, Milne RL, Kogevinas M, Rothman N, Cantor KP, Jackson BP, Pumarega JA, López T, Carrato A, Guarner L, Real FX, Malats N. Pancreatic cancer risk and levels of trace elements. Gut. 2011 Dec 19. [Epub ahead of print] Arslan AA, Helzlsouer KJ, Kooperberg C, et al. Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med. 2010 May 10;170(9):791-802. Brozmanová J. [Selenium and cancer: from prevention to treatment]. Klin Onkol. 2011;24(3):171-9. Review. Slovak. Dennert G, Zwahlen M, Brinkman M, Vinceti M, Zeegers MP, Horneber M. Selenium for preventing cancer. Cochrane Database Syst Rev. 2011 May 11;(5):CD005195. Review. Garland M, Morris JS, Colditz GA, Stampfer MJ, Spate VL, Baskett CK, Rosner B, Speizer FE, Willett WC, Hunter DJ. Toenail trace element levels and breast cancer: a prospective study. Am J Epidemiol. 1996 Oct 1;144(7):653-60. Garland M, Morris JS, Stampfer MJ, Colditz GA, Spate VL, Baskett CK, Rosner B, Speizer FE, Willett WC, Hunter DJ. Prospective study of toenail selenium levels and cancer among women. J Natl Cancer Inst. 1995 Apr 5;87(7):497-505. Review. Goodman M, Bostick RM, Kucuk O, Jones DP. Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic Biol Med. 2011 Sep 1;51(5):1068-84. Epub 2011 May 24. Review. Jiang L, Yang KH, Tian JH, Guan QL, Yao N, Cao N, Mi DH, Wu J, Ma B, Yang SH. Efficacy of antioxidant vitamins and selenium supplement in prostate cancer prevention: a meta-analysis of randomized controlled trials. Nutr Cancer. 2010;62(6):719-27. Lee KH, Jeong D. Bimodal actions of selenium essential for antioxidant and toxic pro-oxidant activities: The selenium paradox (Review). Mol Med Report. 2012 Feb;5(2):299-304. doi: 10.3892/mmr.2011.651. Epub 2011 Oct 31. Marshall JR, Tangen CM, Sakr WA, Wood DP Jr, Berry DL, Klein EA, Lippman SM, Parnes HL, Alberts DS, Jarrard DF, Lee WR, Gaziano JM, Crawford ED, Ely B, Ray M, Davis W, Minasian LM, Thompson IM Jr. Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila). 2011 Nov;4(11):1761-9. Epub 2011 Sep 6. Peters U, Foster CB, Chatterjee N, Schatzkin A, Reding D, Andriole GL, Crawford ED, Sturup S, Chanock SJ, Hayes RB. Serum selenium and risk of prostate cancer-a nested case-control study. Am J Clin Nutr. 2007 Jan;85(1):209-17. Erratum in: Am J Clin Nutr. 2007 Sep;86(3):808.
