Response: FRONTLINE "Supplements and Safety," 1/19/2016

On January 19th, the PBS program FRONTLINE aired a special entitled "Supplements and Safety," in which the unethical practices of some unscrupulous supplement manufacturers were brought to light. The report also questioned the integrity of the supplement industry in general and the quality of dietary supplements, citing lack of FDA regulation.

We at Life Extension have long respected the journalistic integrity of FRONTLINE. We recommended them to our readers in the early 1990s when they did factual exposés on blood banks that were neglecting to test donated blood for HIV.4 FRONTLINE highlighted the FDA's failure to stop this illegal and deadly malpractice.

We don't know what management changes have occurred over the last 20 years at FRONTLINE to have caused them to produce a grossly misleading, factually inaccurate, and biased attack against the dietary supplement industry.

This paper represents Life Extension's initial rebuttal to the highly prejudicial FRONTLINE report that aired January 19, 2016. >>>

The FRONTLINE episode opened up with an interview of a middle-age woman who described how she started manufacturing dietary supplements for her chiropractor husband in her kitchen. The woman was quite candid on camera, admitting that she had no real world expertise on how to do this but that her husband's chiropractic practice was quite successful in selling the kitchen-made supplements to his patients and other chiropractic offices.

Her chiropractor husband refused to be interviewed for FRONTLINE, possibly because he feared this rather unusual method of manufacturing homemade supplements and selling them in a professional medical practice might not be favorably construed.

As these home-kitchen made supplements became increasingly popular, the woman had to find someone to make them on a larger scale. Again without having any practical expertise, she found a warehouse-based manufacturer to start making them for her. Regrettably, this manufacturer also appeared to be making illegal anabolic steroids for body builders. An apparent failure to properly clean the mixer in his warehouse caused the dietary supplements he made for the chiropractor's wife to become contaminated with anabolic steroids, which resulted in all kinds of non-lethal side effects occurring in some of the chiropractor's patients.

FRONTLINE used this opening segment to portray how terrible the under-regulated dietary supplement industry has become. It of course has nothing to do with how supplements are made under strict good manufacturing practices (GMP) at high-quality manufacturers, but it nonetheless created an opening platform to discredit the entire supplement industry.

The bad actors

Educated dietary supplement consumers usually know who the reputable name brand players are that have a long and consistent track record of producing high-quality supplements using only purified laboratory-tested ingredients.

On the flip side are fly-by-night companies that pretend to sell supplements, but instead spike herbal concoctions with prescription drugs and/or dangerous ingredients that provide a temporary effect (such as stimulation or weight loss) at the cost of serious side effects and potential loss of life.

These unscrupulous companies open and close under different names, aggressively market over the Internet and at some retail outlets, and have emerged as the "bad actors" that journalists point to as representative of the dietary supplement industry. They are in fact mere criminals pretending to be selling natural products.

FRONTLINE interviewed a group of people who suffered permanent liver damage as a result of one of these contaminated herbal concoctions and implied these kinds of problems were pervasive in the legitimate supplement industry, which is blatantly false. Life Extension, for instance, would not have been in business for 36 years if it engaged in these illegal and immoral activities nor would Nature's Plus and other quality brands.

FDA failures

FRONTLINE was particularly critical of the FDA for failing to stop these dangerous supplements from being sold.

The FDA responded with the usual bureaucratic rhetoric that if only Congress would appropriate them more money they could stop these terrible deeds.

These are blatantly false statements that FDA officials have made for decades to increase their budget. The journalist stated there were only 25 employees in the FDA division in charge of the supplement industry to imply not enough personnel were available to stop the bad actors.

Overlooked are the more than 14,000 total employees at the FDA,5 some of whom could have been readily redeployed to stop the outbreak of liver failure that was mostly confined to Hawaii.

It is not possible to describe how inefficient the FDA (and other agencies of the government) is when it comes to prioritizing activities. Readers of Life Extension magazine may recall an editorial written (in 2011) in critique of the FDA's attempts to reclassify walnuts as illegal drugs if the grower did not remove health claims from the grower's website. This absurd squandering of FDA resources was occurring at the same time "bad actors" were poisoning Americans with dangerous drugs being disguised as "dietary supplements."

FRONTLINE constantly badgered Daniel Fabricant, formerly in charge of regulating supplements at the FDA, about why the agency was not allocating more resources to stop the sale of what were clearly adulterated supplements.

Fish oil fallacy

Many of you may know that you can ask your doctor to prescribe fish oil and you or your insurance company will pay over $180 for a one-month supply.

While this price is marked up significantly over cost, what you often get is fish oil that contains around 90% EPA/DHA with little residual fish oil in the capsule.6 This enables you to take fewer capsules to get the same potency of EPA/DHA found in dietary supplements. Non-prescription fish oil extracts typically range from 30‒60% EPA/DHA and usually cost less than $32 a month (depending on quality and potency).

You may ask why supplement companies don't use the same 90% concentration as prescription drug makers. One reason is it is exponentially more expensive to produce a 90% EPA/DHA concentration than the 60% EPA/DHA concentrate that Life Extension (and others) produces. Using a 90% concentration could bring the retail price for dietary supplement fish oil to over $60/month, which is beyond the affordability of most consumers. Insurance companies sometimes cover most of the high cost of prescription fish oil, though the co-pays may exceed the cost of an equivalent amount of EPA/DHA from quality dietary supplement sources.

There is, however, another virtue to using lower potency EPA/DHA fish oil blends that might surprise you. There is evidence that other constituents of cold water fish exert cardio-protective benefits.7 While EPA and DHA drive down triglycerides, which is the primary indication for which the FDA has approved them as effective prescription drugs, when a 90% EPA/DHA capsule is used, very little of the other fatty acids naturally contained in fish oil will be obtained.

Since there is such overwhelming evidence that consuming wild caught cold water fish is so beneficial,8,9 and few people have affordable access to wild caught salmon, the other 40% of fish oil constituents in dietary supplement fish oil more naturally represent the composition of wild caught fish.

As it relates to allegations that dietary supplement fish oil is rancid, this has only been found to occur rarely. Quality supplement makers go to extreme lengths to not only guarantee the freshness of their products, but also test them for heavy metals and other toxins to ensure purity.

Evidence of the high quality of many fish oil supplements on the market today is available through the International Fish Oil Standards program, which independently tests fish oil products and reports their potency and purity. Products that meet the most rigorous criteria are awarded the IFOS 5-Star rating; discerning consumers know to look for the IFOS 5-Star rating on the label of the fish oil product they are using.

Pretending food provides sufficient nutrients

FRONTLINE found so-called experts who believe that all the nutrition one needs can come from one's diet.

This is misleading, as widespread deficiencies can easily be seen by what the U.S. Department of Agriculture publishes about the prevalence of inadequate nutrient intake:3

  • 93% of Americans have an inadequate intake of vitamin E
  • 56% of Americans have an inadequate intake of magnesium
  • 44% of Americans have an inadequate intake of vitamin A
  • 31% of Americans have an inadequate intake of vitamin C
  • 14% of Americans have an inadequate intake of vitamin B6
  • 12% of Americans have an inadequate intake of zinc
  • 8% of Americans have an inadequate intake of folate

FRONTLINE partially correct about vitamin D

In response to clinical investigations by Life Extension researchers, and an avalanche of favorable studies on people who had higher levels of vitamin D, Life Extension began recommending higher potency supplements for the majority of the population.

What have proliferated on the marketplace are supplements containing 10,000 IU of vitamin D with no warning to obtain 25-hydroxyvitamin D blood testing. Based on the highly variable individual absorption rates for vitamin D, some of those taking 10,000 IU vitamin D supplements without periodic blood testing are going to have higher blood levels than are needed.

Even some of Life Extension clients taking lower doses than 10,000 IU sometimes come back at ranges over 80‒100 ng/mL and are advised to stop or reduce their vitamin D supplementation until levels return to optimal ranges of 50‒80 ng/mL.

This is an important issue that the FDA should warn the public about since Life Extension only reaches a few million people at most. The FDA should make a public announcement that anyone supplementing with more than 2,000 IU of vitamin D per day should have periodic 25-hydroxyvitamin D blood tests.

FRONTLINE Omits Dangers of Drugs

The FRONTLINE episode failed to mention that FDA-approved medications—over-the-counter and prescription—should be of much greater concern because they have a track record of adverse events and associated deaths.25

FRONTLINE omitted the fact that a very common over-the-counter drug, acetaminophen, accounts for more than 56,000 emergency room visits and an estimated 458 deaths due to acute liver failure each year. It is implicated in nearly 50% of all acute liver failure cases in the United States.26 Similarly, non-steroidal anti-inflammatory drugs (NSAIDs) have been estimated to cause as many as 16,500 deaths each year in the U.S.27

On the contrary, there were no deaths related to dietary supplements listed in the 2013 annual report of the National Poison Data System (NPDS).

Prescription drugs that are prescribed properly and used as directed cause 1.9 million hospitalizations a year. These drugs cause a total of 2.74 million serious adverse reactions a year. Adverse reactions to prescribed drugs are the fifth leading cause of death, tied with stroke, causing 128,000 deaths per year.1,2

A recent meta-analysis of data from 22 studies found adverse drug reactions occur in nearly 17% of hospitalized patients.28 Worse yet, a large study published in the Journal of the American Medical Association found patients who experience an adverse drug reaction while hospitalized have an 88% increased risk of dying.29

FRONTLINE quotes misinformed individual

Perhaps the most blatant falsity disseminated by FRONTLINE was the airing of a biased comment that stated there was not a single scientific study that substantiated the health benefits of any supplement.

This can be refuted so easily on PubMed (U.S. National Library of Medicine) that it strains the rational credibility for anyone to state such a glaring prevarication.

There are, of course, flawed studies that the media turns into headline news stories that erroneously state certain supplements are not effective, a conclusion in conflict with considerable existing research.

For example, one study used low-dose fish oil on symptomatic heart failure patients and found no results.10 The media used this study to claim fish oil supplements are worthless. If one waits to develop end-stage congestive heart failure and expects there to be a miraculous reversal of their terminal condition using low-dose fish oil, they are oblivious to what is in the published literature.

The reason to take high-dose fish oil supplements made by quality manufacturers is to prevent vascular,11-14 cognitive,15-19 and chronic inflammatory20-24 problems. Low-dose fish oil was never considered a cure for heart failure.

FRONTLINE attacks Congressional Act of 1994

Back in the 1980–1990's, there was widespread fear that the FDA wanted to turn many supplements into prescription drugs.

The public revolted against the FDA and demanded Congress protect their access to dietary supplements, including the right to be educated about what supplements have been proven to do in scientific studies.

FRONTLINE blamed passage of the Dietary Supplement Health and Education Act of 1994 on a leader in the commercial supplement industry and analogized the dietary supplement industry with tobacco lobbyists.

Comparing dietary supplement users to cigarette smokers is quite a stretch, but FRONTLINE nonetheless sought to create this analogy when blaming Congress for allowing supplements to be so readily accessible.

FRONTLINE Attempted to Undermine Dietary Supplements with Flawed Studies

The FRONTLINE program selectively highlighted flawed studies and used them to unjustly slander supplements by claiming that evidence of benefit is lacking. However, we at Life Extension have already exposed the flaws in studies cited in the FRONTLINE piece.

What follows is a list of specific studies or other relevant materials cited or otherwise described in the FRONTLINE report along with links to Life Extension's corresponding analyses.

  1. Offit PA. Don't Take Your Vitamins. The New York Times. 6/8/2013.
  2. Vitamin D Excess Is Significantly Associated with Risk of Atrial Fibrillation. Circulation. 2011.
  3. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Journal of the American Medical Association. 2009.
  4. Enough is Enough. Annals of Internal Medicine. 2013.
  5. Fish oil supplements in New Zealand are highly oxidized and do not meet label content of n-3 PUFA. Nature Scientific Reports. 2015.

Life Extension's History of Correcting Media Misrepresentations

For many years, Life Extension has informed the public about the most important scientific discoveries related to integrative healthcare and longevity. We've also consistently provided clarity when mainstream media outlets misinterpret scientific data and confuse consumers. We've included here a list of our Consumer Alerts.

Life Extension’s Commitment to Quality

Long-time Life Extension supporters are well aware of the rigorous criteria we use to ensure industry-leading quality. In fact, we recently described our unrivaled dedication to quality in a Life Extension Magazine® article titled “Relentless Commitment To Quality,” and details about our quality procedures have been available on our website for years.

Although Life Extension adheres to only the most rigorous quality standards, we know some unprincipled profiteers distribute adulterated or otherwise misbranded supplements. Contrary to the implications of the FRONTLINE report, however, this does not mean all dietary supplement companies take advantage of their customers.

Life Extension supporters know that our mission to conquer pathological aging is long-term, and providing anything less than the industry’s pinnacle of product quality and purity in order to increase short-term profits would undermine our goals. Rest assured we spare no expense when it comes to product quality because doing so is of no benefit to our core objective of funding pioneering scientific research aimed at prolonging the healthy human life span.

A Closer Look at Life Extension’s Quality Procedures

All products formulated by Life Extension are produced in accordance with Good Manufacturing Practice (or GMP) as set forth in 21 CFR Part 111 of the Food, Drug, and Cosmetics Act. Manufacturing facilities are periodically inspected by either the FDA or the U.S. Department of Agriculture. Facilities are inspected for their adherence to Standard Operating Procedures (SOPs), employee training, product specifications and supplier/vendor qualification procedures. In addition, Life Extension performs periodic audits of manufacturers to ensure adherence to all regulatory requirements. Life Extension ensures that manufacturing SOPs are followed to ensure consistent product quality.

Raw Materials

Product specification begins with the ingredients we qualify for use in our formulas. We evaluate the source data for these ingredients from well-established vendors with impeccable credentials when formulating our products. Working with high-quality, raw material suppliers allows us the opportunity to select the best options for product formulations.

All sourced raw materials and raw material vendors undergo an extensive qualification process by highly experienced members of our Product Development, Quality Assurance, Quality Control, and Purchasing departments. All raw materials are evaluated according to our internal Raw Material Qualification SOP. Qualification must be approved at multiple steps in the process for each raw material to meet our stringent identity, purity, and potency requirements before a material is approved for use.

Once approved and purchased, all raw materials are received and placed “on hold,” pending release by Quality Control. Release by our Quality Control department occurs only after samples of each lot of raw material passes evaluation according to the raw material specification criteria. Testing includes, but is not limited to, chemical identification (using Fourier transform infrared spectrophotometry [FTIR], ultraviolet [UV] or high performance thin layer chromatography [HPTLC]), physical characteristics, potency/strength confirmation, microbial analysis and analysis for other contaminants including heavy metals to verify and approve the Certificate of Analysis (COA) for each material. Complete COAs that meet our specifications are mandatory for every lot received for use in production. Material can only be released into inventory once it meets the applicable specifications. If materials do not meet our specifications at any step in the process, they are rejected and returned to the material supplier.

GMP (Good Manufacturing Practice) Production

Master production documents (also referred to as Master Manufacturing Records) are approved by Quality Control personnel and kept on file at our manufacturing facilities. They are created from our Finished Product Specification Packets which are on file at Life Extension for every product under our brand.

Batch sheets (which are part of the master production documents) list all ingredients and required quantity necessary to produce one batch of product. Each lot number of ingredient, and amount weighed, are recorded on the batch record for traceability. Initials are required by the individual who measured the materials as well as a second individual responsible for review and verification to ensure accuracy. Additional checks and balances follow, including separate quality control inspection processes to ensure consistent product quality.

Weighed ingredients are transferred to the blending department. Material is blended to maintain consistency and continues throughout the specific production process depending on the type of finished product (e.g., softgels, encapsulated hard gelatin [or vegetarian] capsules, tablets, etc.).

In-process controls throughout production processes include line clearance (all production equipment that comes in contact with product must be cleaned according to mandated procedures between all production runs and verified to ensure sanitation has been performed prior to use), lot code verification, weight checks, label and material checks — all of which are performed according to written procedures. Product samples are collected at different stages of production for appropriate chemical and microbiological testing as per the product specifications.

The finished product is transferred to the packaging department, where empty packaging bottles are filled, sealed, labeled, stamped with a lot code and “use by” date, put in cases, and stacked on pallets. Our packaging is designed to protect the integrity of the product and ensure freshness throughout its shelf life.

The finished product is placed on hold until Quality Control completes additional evaluation to ensure adherence to all SOPs. This includes review of the completed batch record and all pertinent tests required on the product specification. This ensures all specifications set within the production process are accurate and within pre-defined parameters. After the evaluation has been completed, and the product has passed all requirements, the test results are indicated on the COA and the product is released. These COAs are maintained on file for each production batch received at Life Extension and are available upon request.

Life Extension Product Labels

Product labels go through a comprehensive review and approval process. Labels comply with all applicable laws and regulations, and are periodically updated based upon the most recent nutritional science parameters for active ingredients. All necessary information is clearly indicated on all our product labels, as well as any pertinent allergen information.

Label storage is tightly controlled with limited access to only authorized personnel. All labeling is checked when initially received for physical size, color variation, wrinkles, condition, and copy versus approved sample. Quality Control personnel are authorized to approve or reject labels per our internal SOP. All labeling is counted and verified upon issuance and on returns for reconciliation purposes.

Finished Product Analysis

Each manufactured lot of finished product is tested using state-of-the-art testing equipment to ensure finished product quality, purity, and potency. Different types of materials such as herbal extracts, minerals, vitamins, etc., require different laboratory testing equipment and/or methodologies to provide the most accurate results. Testing can include, but is not limited to, chemical analysis by high performance liquid chromatography (HPLC), ultraviolet/visible spectrophotometry (UV-Vis), gas chromatography (GC), and gas chromatography mass spectroscopy (GCMS). Physical analysis is performed and active ingredients claimed on the product label are confirmed. Microbiological analysis and heavy metal testing (by ICP-MS) is also completed on every production batch to ensure all specifications are met.

Complete COAs that meet specifications are mandatory for every production lot of product shipped to our customers.

When inspection and testing is performed, Quality Control personnel are authorized to approve or reject product if the finished product does not meet established quality guidelines at any step in the process. Only if the finished product meets specification is the product released for shipment.


  1. Light DW, Lexchin J, Darrow JJ. Institutional corruption of pharmaceuticals and the myth of safe and effective drugs. The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics. Fall 2013;41(3):590-600.
  2. CDC. Centers for Disease Control and Prevention. FastStats. Leading Causes of Death. Last updated 9/30/2015. Accessed 1/20/2016.
  3. USDA. United States Department of Agriculture. What we eat in America, NHANES 2001-2002: Usual nutrient intakes from food compared to dietary reference intakes. 9/2005. Accessed 1/22/2016.
  4. FRONTLINE. Previous Reports. AIDS, BLOOD and POLITICS. Copyright 1993 WGBH Educational Foundation. 11/30/1993. Accessed 1/22/2016.
  5. FDA. Food and Drug Administration: Distribution of Full-Time Equivalent (FTE) Employment Program Level. Accessed 1/22/2016.
  6. Koski RR. Omega-3-acid Ethyl Esters (Lovaza) For Severe Hypertriglyceridemia. Pharmacy and Therapeutics. 2008;33(5):271-303.
  7. Yazdi PG. A review of the biologic and pharmacologic role of docosapentaenoic acid n-3. F1000Research. 2013;2:256.
  8. Nicoll R, Howard JM, Henein MY. A review of the effect of diet on cardiovascular calcification. International journal of molecular sciences. 2015;16(4):8861-8883.
  9. Khankari NK, Bradshaw PT, Steck SE, et al. Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York. Cancer. Mar 24 2015.
  10. Aleksova A, Masson S, Maggioni AP, et al. n-3 polyunsaturated fatty acids and atrial fibrillation in patients with chronic heart failure: the GISSI-HF trial. European journal of heart failure. Nov 2013;15(11):1289-1295.
  11. Naini AE, Keyvandarian N, Mortazavi M, Taheri S, Hosseini SM. Effect of Omega-3 fatty acids on blood pressure and serum lipids in continuous ambulatory peritoneal dialysis patients. Journal of research in pharmacy practice. Jul-Sep 2015;4(3):135-141.
  12. Jain AP, Aggarwal KK, Zhang PY. Omega-3 fatty acids and cardiovascular disease. European review for medical and pharmacological sciences. 2015;19(3):441-445.
  13. Miller PE, Van Elswyk M, Alexander DD. Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. American journal of hypertension. Jul 2014;27(7):885-896.
  14. Casula M, Soranna D, Catapano AL, Corrao G. Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, placebo controlled trials [corrected]. Atherosclerosis. Supplements. Aug 2013;14(2):243-251.
  15. Jerneren F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial. The American journal of clinical nutrition. Jul 2015;102(1):215-221.
  16. Thomas J, Thomas CJ, Radcliffe J, Itsiopoulos C. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer's Disease. BioMed research international. 2015;2015:172801.
  17. Nilsson A, Radeborg K, Salo I, Bjorck I. Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study. Nutrition journal. 2012;11:99.
  18. Strike SC, Carlisle A, Gibson EL, Dyall SC. A High Omega-3 Fatty Acid Multinutrient Supplement Benefits Cognition and Mobility in Older Women: A Randomized, Double-blind, Placebo-controlled Pilot Study. The journals of gerontology. Series A, Biological sciences and medical sciences. Aug 11 2015.
  19. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. The British journal of nutrition. Jun 2012;107(11):1682-1693.
  20. Yan Y, Jiang W, Spinetti T, et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. Jun 27 2013;38(6):1154-1163.
  21. Grenon SM, Owens CD, Nosova EV, et al. Short-Term, High-Dose Fish Oil Supplementation Increases the Production of Omega-3 Fatty Acid-Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA-PAD I Trial). J Am Heart Assoc. 2015;4(8).
  22. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et biophysica acta. Apr 2015;1851(4):469-484.
  23. Proudman SM, Cleland LG, Metcalf RG, Sullivan TR, Spargo LD, James MJ. Plasma n-3 fatty acids and clinical outcomes in recent-onset rheumatoid arthritis. The British journal of nutrition. Aug 18 2015:1-6.
  24. Arriens C, Hynan LS, Lerman RH, Karp DR, Mohan C. Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and disease activity in Systemic Lupus Erythematosus. Nutrition journal. 2015;14(1):82.
  25. James JT. A new, evidence-based estimate of patient harms associated with hospital care. Journal of patient safety. Sep 2013;9(3):122-128.
  26. Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology (Baltimore, Md.). Jul 2004;40(1):6-9.
  27. Food and Drug Administration. Assessment of Safety of aspirin and other Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). 2002.
  28. Miguel A, Azevedo LF, Araujo M, Pereira AC. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiology and drug safety. Nov 2012;21(11):1139-1154.
  29. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA : the journal of the American Medical Association. Jan 22-29 1997;277(4):301-306.