Klamath Lake Algae - Review of the literature regarding neurotoxicity 

Aphanizomenon flos-aquae (Aph. flos-aquae) is a filamentous blue-green algal species harvested each summer from Upper Klamath Lake in Klamath Falls, Oregon. Aph. flos-aquae has been sold as a nutritional food supplement for nearly 20 years. It is known to be rich in certain vitamins (B12, carotenoids, K) and in trace minerals. The nutritional benefits of Aph. flos-aquae have been appreciated by over a million consumers, many of whom reported increased energy levels, heightened mental clarity, improved memory and recall, and an overall feeling of well-being. 
 

Aph. flos-aquae from Upper Klamath Lake
To appreciate Aph. flos-aquae from Klamath Lake, it is important to consider the unique ecosystem in which this alga "blooms." Upper Klamath Lake, which covers approximately 325 km2, has the greatest surface area of any natural water body in Oregon (Gearheart et al. 1995). Numerous springs charged with water filtered through miles of nutrient-rich volcanic soils on the flanks of the Cascade mountains (Gearheart et al. 1995), and six major tributaries, contribute 90% of the annual inflow to the lake (1,527,600 mean acre-feet (1929-1993); Gearheart et al. 1995). Overall, Upper Klamath Lake is described as a very productive eutrophic lake that is marked by high levels of available nutrients and plant life. It is this wealth of nutrients that allows Aph. flos-aquae to grow in such abundance in the wild. Upper Klamath Lake is one of only a few ecosystems which supports the recurrent growth of Aph. flos-aquae in such abundance.

Upper Klamath Lake has sometimes been referred to as polluted because of the lake's incredible bounty of Aph. flos-aquae. The most observable influence of this blue green algae is the change in the chemical properties of the water around the blooming algal masses, namely dissolved oxygen, pH and ammonia. Given summer conditions and a large algal bloom, water chemistry can change drastically and these parameters can reach levels that can directly impact fish species (Monda and Saiki, 1993). Fish will congregate near inflow areas of better water quality, yet their density and stressed condition renders them susceptible to outbreaks of disease and die-offs. In Upper Klamath Lake such fish kills (1971, 1986, 1995) are generally attributed to outbreaks of "Columnaris" disease (Logan and Markle, 1993). These outbreaks have been common in fish hatcheries under crowded, high temperature conditions (Piper et al. 1982). Such impact on the survival of fish has led people unaware of this natural chemistry to state that Klamath Lake is polluted. Various testing for pesticides, petro-chemicals and other contaminants over the past 10 years failed to reveal the presence of any such contaminants. 

Aph. flos-aquae and the issue of neurotoxicity
A few reports of neurotoxicity in the scientific literature have raised unwarranted concern. Aside from these reports, nearly ten years of regular testing (more than 300 samples tested) has failed to reveal the presence of any neurotoxins. In the late 1990's two lawsuits were filed against companies harvesting from Klamath Lake for neurotoxicity. Both cases were dismissed after considerable effort to detect neurotoxins proved unsuccessful. Finally, a study recently published used genetic technologies to determine that the previous reports of neurotoxicity associated with Aph. flos aquae had misidentified the algal species and the toxic algal samples were not Aph. flos aquae but a species of Anabaena. Below is a brief and more detailed account of the evolution of the scientific data regarding the neurotoxicity of Aph. flos aquae.

Klamath Lake
The first article to report toxicity of Aph. flos aquae summarized a 1960 US Department of Health, Education and Welfare seminar in which authors Phinney and Peek (1961) refer to a toxic algal bloom that occurred in Upper Klamath Lake in the late 1950's. A sample of this algal bloom was sent to Dr. Paul Gorham, then at the National Research Council, Ottawa, Canada, for toxicological analysis. Although Phinney and Peek reported: 
"no concrete evidence was obtained as to the effect of this toxin on the biota of the Lake and River, but experiments with mice proved that ingestion of the algal material was quickly lethal and intraperitoneal injection of the aqueous extract almost instantaneous in causing death",
Gorham determined that the sample was not pure Aph. flos-aquae, but actually consisted of equal parts of Aph. flos-aquae and Microcystis - an algae known to produce microcystins. Gorham concluded that the toxicity came not from the Aph. flos-aquae, but from the Microcystis (Gorham, 1964; Carmichael and Gorham, 1980; Gorham, personal communication to W.W.C., 1995).

The second article concerning Klamath Lake was a preliminary summary of a toxicity test on Upper Klamath Lake Aph. flos-aquae published by Gentile (1971) in a review article on blue-green and green algal toxins. A mouse assay (n=1) was performed on a colony isolate of Aph. flos-aquae cultured for a short period of time in a laboratory. Signs of poisoning in the mouse were reported as similar to that of a Kezar Lake, New Hampshire (see below) Aph. flos-aquae sample later shown to produce a toxin with similarities to saxitoxin and its derivatives. 

In both articles, several elements did cast significant uncertainty concerning this possible neurotoxicity of Upper Klamath Lake Aph. flos-aquae. These include:
1) lack of taxonomic verification of Aph. flos-aquae as the dominant alga in the tested culture;
2) lack of a complete mouse bioassay which would have established the minimum lethal dose, LD50 and toxicity compared to known saxitoxin standards; and 
3) lack of a confirmation of toxicity by other laboratories working with these neurotoxins. 

For these reasons, it could not be concluded that Aph. flos-aquae from Upper Klamath Lake produced a neurotoxin. As quoted by Gentile (personal communication to W.W.C., March 27, 1996), "This anecdotal toxicity test on Upper Klamath Lake Aph. flos-aquae should be rigorously restudied before it can be concluded that the alga produces a toxin". Periodic toxicity tests in the 1980's plus frequent regular testing since 1991 have failed to reveal any neurotoxins in Upper Klamath Lake Aph. flos-aquae (Carmichael et al., 2000).

Aph. flos-aquae samples from other locations
In spite of the complete absence of neurotoxicity as tested numerous times using HPLC and mouse bioassay, doubts regarding the possible neurotoxicity of Klamath Lake Aph. flos-aquae persisted because of the discovery of three samples of Aph. flos-aquae found elsewhere (USA and Finland) that contained neurotoxicity.
Sawyer et al. (1968) and Gentile and Maloney (1969) reported toxicity of an atypical non-colony forming Aph. flos-aquae that killed fish and laboratory mice. This Aph. flos-aquae came from Kezar Lake in New Hampshire. More recently, Rapala et al. (1993) reported toxicity of Aph. flos-aquae isolated from water blooms in Finland. These studies establish that Aph. flos-aquae is toxic only in some geographical locations. This study also demonstrated that it was not possible, under the experimental conditions, to manipulate a non-toxic strain of Aph. flos-aquae to become toxic. 
At this point in time, the general consensus among scientists was that some strains of Aph. flos-aquae were capable of producing neurotoxins but most strains, include the Klamath Lake strain, were non-toxic.
One aspect that caught the attention of several scientists was the mention in the aforementioned articles that the toxic samples of Aph. flos-aquae were "atypical non-colony forming Aph. flos-aquae". In other words, the toxic strains that were originally identified and classified as Aph. flos-aquae were not typical of Aph. flos-aquae and the original identification could have been inaccurate. Indeed, the boundary between Aph. flos-aquae and some Anabaena species is very unclear and misidentification of the algal species can be problematic. Anabaena spp. is known to produce various kinds of neurotoxins. 
Recent developments in genetics have provided the tools to determine, using genetic similarities, whether the toxic strains of Aph. flos-aquae are the same species as the strain showed to be non-toxic. Recently, Li et al. (2000) have shown that all the toxic strains of Aph. flos-aquae are genetically dissimilar to the non-toxic strains and most likely belong to the Anabaena genera. 

Court Cases
It is interesting to briefly discuss two instances in which lawsuits were filed around the issue of neurotoxicity of Klamath Lake Aph. flos-aquae. 

In the first one a man, Mr. Fineman, claimed that consumption of Aph. flos-aquae triggered neuropathy. The case revealed that Mr. Fineman had been suffering from diabetes since early childhood and had had many episodes of developing neuropathy. After two years of contracting with various laboratories throughout the world to detect and identify a neurotoxin in Aph. flos-aquae, Mr. Fineman had to withdraw the suit because of lack of evidence. The court obliged Mr. Fineman to published the following statement:
"I, Samuel Fineman, brought a lawsuit against Cell Tech and the Kollmans because I thought I had been harmed by some substance in Cell Tech's products. Testing and investigation (including testing for neurotoxins) did not confirm the presence of any such substance. Accordingly, I have withdrawn my lawsuit in its entirety."

In a second case, the aforementioned company Cell Tech filed a lawsuit against an individual, Mark Thorson, who had relentlessly published over the Internet that Aph. flos-aquae from Klamath Lake contained a neurotoxin similar to cocaine and dangerous to consumers. Once again, after considerable effort to prove his allegations, Mr. Thorson lost his case. He was also asked to published the following statement over the Internet:
"During the last several years, I have from time to time posted to this 
and other newsgroups a file of information called "An Anatoxin-a Primer." I now retract the statements made in the Anatoxin-a Primer.
The Anatoxin-a Primer implied that Super Blue Green Algae from Klamath Lake, produced by Cell Tech, contains anatoxin-a (a neurotoxin I characterized as addictive), and that Cell Tech deliberately avoids testing for this toxin because anatoxin-a is responsible for the effects reported by SBGA users. I have since been advised that Cell Tech conducts regular tests that would disclose anatoxin-a, and that this toxin has never been found in Super Blue Green Algae. I had no basis for the suggestions I made in the Anatoxin-a Primer, and I hereby retract it in full."

These two cases are interesting as they both relied on the explicit demonstration that Aph. flos-aquae from Klamath Lake contained a neurotoxin. In both cases, many laboratories throughout the world with the capability and the expertise to detect and quantify neurotoxins were contracted to find neurotoxins in Aph. flos-aquae from Klamath Lake, with no success. 
 

Summary
In summary, the few instances of reports of neurotoxicity of Aph. flos-aquae pertained not to Aph. flos-aquae but to species believed to be Anabaena spp. All samples shown to be Aph. flos-aquae by PCR technology (genetics) were all reported to be non-toxic. In addition, two significant legal suits failed to detect the presence of any neurotoxin in Aph. flos-aquae from Upper Klamath Lake.
Taken altogether, the available data demonstrate the non-toxicity of Aph. flos-aquae from Upper Klamath Lake.
 
 

REFERENCES

Carmichael, W.W., Drapeau, C., and Anderson, D.M. (2000) Harvesting of Aphanizomenon flos-aquae Ralfs ex Born. & Flah. Var. flos-aquae (Cyanobacteria) from Klamath Lake for human dietary use, J. App. Phyco., vol. 12, pp. 585-595.

Carmichael, W.W., and P.R. Gorham. (1980) Freshwater cyanophyte toxins, In: Algae Biomass, Elsevier, New York, pp. 437-448.

Gearheart, R.A., J.K Anderson, M.G. Forbes, M. Osburn, and D. Oros. (1995) Watershed strategies for improving water quality in Upper Klamath Lake, Oregon. Humboldt State University, Environmental Resources Engineering Department. 3 Volumes.

Gentile, J.H., and T.E. Maloney. (1969) Toxicity and environmental requirements of a strain of Aphanizomenon flos aquae (L.) Ralfs, Can. J. Microbiol., vol. 15 (2), pp. 165-173.

Gentile, J.H. (1971) Blue green and green algal toxins. In: Microbial Toxins, Vol. 7, Academic Press, New York, pp. 27-67.

Gorham, P.R. (1964) Toxic Algae. In: Algae and Man, Plenum Press, New York, pp. 307-306.

Logan, D.J., and D.F. Markle (1993) Fish faunal survey of Agency Lake and northern Upper Klamath Lake, Oregon. In Environmental research in the Klamath Basin, Oregon - 1992 Annual Report. S.G. Campbell (ed.) p. 341.

Monda, D.P. and M.K. Saiki. (1993) Tolerance of Juvenile Lost River and Shortnose suckers to high pH, ammonia concentration, and temperature, and to low dissolved oxygen concentration. In Environmental research in the Klamath Basin, Oregon - 1992 Annual Report. S.G. Campbell (ed.) p. 341.

Piper, R.G, I.B. McElwain, L.E. Orme, J.P. McCraren, L.G. Fowler, and J.R. Leonard. (1982) Fish Hatchery Management. U.S. Department of the Interior, Fish and Wildlife Service. Washington D.C. p. 517.

Phinney, H.K. and Peek, C.A. (1961) Klamath Lake, an instance of natural enrichment. In Transactions of the seminar on Algae and Metropolitan Wastes. U.S. Public Health Service, pp. 22-27.

Rapala, J., Sivonen, K., Luukkainen, R., and S.I. Niemela. (1993) Anatoxin-a concentration in Anabaena and Aphanizomenon under different environmental conditions and comparison of growth by toxic and non-toxic Anabaena strains - a laboratory study, J. Applied Phycol., vol. 5, pp. 581-591.

Li, R., Carmichael, W.W., Liu, Y., and Watanabe, M.M. (2000) Taxonomic re-evaluation of Aphanizomenon flos-aquae NH-5 based on morphological and 16 rRNA gene sequences, Hydrobiologica, vol. 438, pp. 99-105.

Sawyer, P.J., Gentile J.H., and J.J. Sasner. (1968) Demonstration of a toxin from Aphanizomenon flos-aquae (L.) Ralfs, Can. J. Microbiol., vol. 14, pp. 1199-1204.
 

McPartland response

Townsend Letter for Doctors & Patients
c/o Jonathan Collin, M.D.
Editor-in-Chief
911 Tyler Street
Port Townsend, WA 98368-6541
 

Dr. Collin,

Recently the Townsend Letter for Doctors & Patients (June 1997) published an article entitled "Why Blue Green Algae Makes Me Tired," by John McPartland, DO. The number of inaccuracies and slanderous opinions expressed in this article is overwhelming. Virtually every statement presented by the author is either factually inaccurate, out of context, incomplete or simply libelous. 

One of these statements is McPartland's discussion about the neurotoxicity of Aphanizomenon flos-aquae from Klamath Lake. This concern is certainly appreciated and shared by Cell Tech as it is undisputed that some strains of this particular type of blue-green algae are capable of producing toxins. However, the Upper Klamath Lake strain of Aph. flos-aquae has never been conclusively reported to produce neurotoxins. McPartland cites both Phinney and Peek (1961) and Gentile (1971) as the basis of his conclusion. The algal sample taken by Phinney and Peek was extensively analyzed by Gorham (Gorham, 1964; Carmichael and Gorham, 1980) who concluded that: "The signs of poisoning produced by samples from this bloom, consisting of 50:50 Aphanizomenon, Microcystis, injected i.p. into mice were similar to those of microcystin. It was concluded that Aphanizomenon was either non-toxic or produced a toxin like microcystin." Aph. flos-aquae is not known to produce microcystins. Gentile's report (1971) was a preliminary summary of a toxicity test on Upper Klamath Lake Aph. flos-aquae published in a review article on blue-green and green algal toxins. As quoted by Gentile himself (personal communication to Dr. Wayne W. Carmichael, 1996), "This anecdotal toxicity test on Upper Klamath Lake Aph. flos-aquae should be rigorously restudied before it can be concluded that the alga produces a toxin." Periodic toxicity tests in the 1980's and regular testing since 1991 have failed to reveal any neurotoxins in Upper Klamath Lake Aph. flos-aquae (quality control on Super Blue Green® Algae performed by independent laboratories). McPartland was fully aware of the information mentioned above but chose to disregard the years of laboratory results and the analysis of the scientific literature by experts in algal toxicology.

In brief, a test called enzyme-linked immunosorbent assay (ELISA) is used to detect microcystins, a specific type of hepatotoxin (An and Carmichael 1994). ELISAs are among the most sensitive detection techniques available. In addition, the levels of hepatotoxins are also accurately determined by a protein phosphatase inhibition assay (Takai and Mieskes 1991; An and Carmichael 1994) which measures the actual toxicity. Neurotoxins, which are commonly produced by some Anabaenas, some dinoflagellates and some strains of Aph. flos-aquae are detected by using an anticholinesterase enzyme assay (Matsunaga et al. 1989) and an FDA-approved assay for saxitoxins (AOAC, 1990) and/or high performance liquid chromatography (Oshima et al. 1989). All of these testing procedures are performed on every batch of freeze-dried Super Blue Green® Algae by external laboratories to ensure an unbiased and independent evaluation. Absolutely no batch of algae is processed without having undergone analysis and met the standards. Neurotoxins have never been detected after 6 years of rigorous testing of every batch of algae harvested by Cell Tech.

Again, it is indisputable that some strains of Aph. flos-aquae were shown to produce neurotoxins in Europe as well as in lakes in New Hampshire and Canada, but the extrapolation that all strains are toxic shows a lack of scientific background or a lack of integrity. Actually, after testing many blooms of Aph. flos-aquae in North America for neurotoxicity, Carmichael and Gorham (1980) concluded that, "All blooms and isolates from blooms of Aphanizomenon flos-aquae that we have collected from lakes of Ontario, Saskatchewan and Alberta, Canada have been nontoxic." Gorham (1964) further concluded that, "A decision as to whether fast-death-producing strains of Aphanizomenon exist must be left in abeyance, but the suspicion we now have is that the final answer may be negative."

With this in mind, the author's opinion that the reason why people eating Aph. flos-aquae feel energized is due to anatoxin's similarities to cocaine is totally groundless. First and foremost, anatoxin is not produced by nor present in the algae harvested from Klamath Lake. With little objective and honest research, McPartland could have found many plausible scientific explanations for the energy felt by people eating Aph. flos-aquae. He preferred to slander Cell Tech and deceive the readers by suggesting that Super Blue Green® Algae contained an analog to an illegal drug.

McPartland wrote, "I received a nasty phone call from Cell Tech in Oregon..." The only individuals within Cell Tech who would personally contact McPartland by telephone did not, in fact, do so. We have never accused the author of having been "paid off" nor has Cell Tech "slammed" Spirulina. These are shameless lies. Cell Tech produces an entirely safe, extremely high quality product which has brought numerous benefits to thousands of people and we market our products as such, without slander or defamation.

Without any knowledge of Cell Tech's philanthropic activities, McPartland writes, "The concept of doing something for nothing is foreign to them." Cell Tech is deeply involved with humanitarian projects to which we donate a significant amount of product, time and commitment. We are assisting with projects located in Nicaragua, Argentina, Dominican Republic, Guatemala, Cambodia, Tibet as well as projects within the United States including Los Angeles, the Navahos in Arizona, The American Indian Family Healing Center in Oakland, California, and Klamath Falls, Oregon. Yet, very few of these projects have been used for marketing purposes. McPartland's comment ridiculing Cell Tech's humanitarianism is a clear demonstration of his unsubstantiated bias. 

McPartland implied that the fish kills (1894, 1971, 1986, 1995, 1996) occurred because of pollution or toxicity. A very simple investigation with the local agencies in the Klamath Basin would have revealed to the author that these fish kills occurred simply because of poor water quality, indirectly caused by the biodynamics of algae blooms, not toxicity or pollution. He further mentions that, "... SBGA, like many species of blue-green algae, is encased by mucilaginous sheath, which provides a strong anchor for adhering bacterial contaminants. One such bacterium associated with blue-green algae is Legionella pneumophila, the cause of legionnaire disease. Another bug, Vibrio cholerae, can actually live inside blue-green algae." Here McPartland's intention to discredit Cell Tech and to mislead the reader is indisputable. Does McPartland know of any case of cholera or legionnaire disease linked to the consumption of Super Blue Green® Algae? 

Any food can be a medium for bacterial growth and Cell Tech's Quality Control procedure fully ensures that Super Blue Green® Algae meets all the standards established by the Department of Agriculture. McPartland writes, "Cell Tech substitutes expensive pasteurization with "heat-sanitize" process." Pasteurization is a heat-sanitation process. Cell Tech's pasteurization process differs from classic pasteurization in that it preserves the enzymatic activity and the nutritional value of the algae. Everyone who visited Cell Tech's harvesting and production facilities, including state inspectors, have been unanimously impressed by the quality of the process and the investment made by Cell Tech to ensure quality and safety of its products. 

One thing that McPartland did not dare report is the well known stimulating effect of blue-green algae on the immune system (Lahitova et al., 1994). A study performed by a reputed university provided strong evidence, obtained by traditional immunological assay, that Aph. flos-aquae significantly increases, among other things, the phagocytic and microbicidal activity of macrophages, and the recruitment of natural killer (NK) cells (Manoukian et al., 1997). In addition, Aph. flos-aquae contains nearly 2% chlorophyll which was shown to accelerate healing of wounds and burns (Gruskin, 1940; Sano and Smith, 1942; Goldberg, 1943; Gahan et al., 1943) and to act as a precursor for the synthesis of other compounds such as hemoglobin (Hughes et al., 1936) and vitamin K (Hansen, 1980; Borowitzka, 1988). Furthermore, recent studies have demonstrated the ability of chlorophyllin to provide protection against certain forms of liver toxicity (Breinholt et al., 1995a,b). Finally, Aph. flos-aquae is an exceptional source of essential fatty acids (more than 40% of lipid content) whose deficiency is increasingly linked to decreased cardiovascular health (Simopoulos, 1989, 1991; Spielmann et al., 1989; Kromhout, 1989; Renaud et al., 1989; Wood et al., 1987), reduced immunity (DeWille et al., 1979), certain forms of cancer (Anti et al., 1992; Wargovich, 1992), arthritis (Kremer et al., 1989), mental problems (Hibbeln and Salem, 1995; Stevens et al., 1995), and skin problems (Wright and Burton, 1982).

In summary, it is quite deplorable to see the ease with which someone can publish such inaccurate information and slanderous opinions. Super Blue Green® Algae is extensively tested and all independent laboratory results demonstrate its safety for human consumption. It is certainly unfortunate that McPartland feels he has been bombarded by individuals attempting to share their information and the benefits they experienced by eating blue-green algae. However, it is both disturbing and scandalous that he is utilizing his doctoral degree to make slanderous claims about something unrelated to his field of expertise, and it is even more disturbing that he has been allowed to utilize the Townsend Letter as a bulletin board for his personal vendetta. 
 

Sincerely,

Christian Drapeau
Director of Research and Development

Reference
 

An, J.S., and W.W. Carmichael. 1994. Use of a colorimetric protein phosphatase inhibition assay and enzyme linked immunosorbent assay for the study of microcystins and nodularins, Toxicon, vol. 32 (12), pp. 1495-1507.

Anti M., Marra G., and Armelao F. (1992) Effect of -3 fatty acids on rectal proliferation on subjects at risk for colon cancer. Gastroenterology 103:883-801.

AOAC. 1990. Hollingworth T., and M.M. Wekell. Paralytic shellfish poison biological method final action. In: Official Methods of Analysis, 15th edition, K. Hellrich (Ed.), AOAC, Arlington VA, pp. 881-882

Carmichael, W.W., and Gorham, P.R. (1980). Freshwater cyanophite toxins, In: Algae Biomass, Elsevier, New York, pp. 437-448.

DeWille et al. (1979) Effects of essential fatty acid deficiency, and various levels of dietary polyunsaturated fatty acids, on humoral immunity in mice. J. Nutr. 109(6): 1018-1027.

Gahan, E., Kline, P.R. and Finkle, T.H. (1943) Chlorophyll in the treatment of ulcers. Arch. of Dermatology and Syphilology, #49:848-851.

Gentile, J.H. 1971. Blue green and green algal toxins. In: Microbial Toxins, Vol. 7, Academic Press, New York, pp. 27-67.

Goldberg, S.L. (1943) The use of water soluble chlorophyll in oral sepsis. Am. J. of Surg., (October): 117-123.

Gorham, P.R. 1964. Toxic Algae. In: Algae and Man, Plenum Press, New York, pp. 307-306.

Gruskin, B. (1940) Chlorophyll its therapeutic place in acute and suppurative disease. Am. J. Surg., 49: 49-55.

Hibbeln, J.R. and Salem, N.J. (1995) Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 62:1-9.

Kremer, J.M., Lawrence, D.A., and Jubiz, W. (1989) Different doses of fish-oil fatty acid ingestion in active rheumatoid arthritis: a prospective study of clinical and immunological parameters. In: Dietary -3 and -6 Fatty Acids: Biological Effects and Nutritional Essentiality, Galli, C. and Simopoulos, A.P., eds., Plenum Publishing, New York, p. 343-350.

Kromhout, D. (1989) Fish (oil) consumption and coronary heart disease. In: Dietary -3 and -6 Fatty Acids: Biological Effects and Nutritional Essentiality, Galli, C. and Simopoulos, A.P., eds., Plenum Publishing, New York, p. 273-282.

Lahitova, N., Doupovcova, M., Zvonar, J., Chandoga, J., and Hocman, G. (1994) Antimutagenic properties of fresh-water blue-green algae. Folia Microbiol 39(4):301-303. 

Manoukian, R., Citton, M., Huerta, P., Rhode, B., Drapeau, C., and Jensen, G.S. (1997) Effects of the blue-green alga Aphanizomenon flos-aquae (AFA) on Natural Killer cells, in preparation.

Matsunaga, S., Moore, R.E., Niernezura, W.P., and W.W. Carmichael. (1989) Anatoxin-a(s) a potent anticholinesterase from Anabaena flos-aquae, J. Amer. Chem. Soc., vol. 111, pp. 8021-8023. 

Oshima, Y., Sugino, K., and T. Yasumoto. (1989) Latest advances in HPLC analysis of paralytic shellfish toxins. In: Mycotoxins and phycotoxins, Natoris, S., Hashimoto, K., and Ueno, T. [Eds], Elsevier, New York, pp. 319-326.

Phinney, H.K. and Peek, C.A. (1961) Klamath Lake, an instance of natural enrichment. In Transactions of the seminar on Algae and Metropolitan Wastes. U.S. Public Health Service, pp. 22-27.

Renaud, S., Godsey, F., Dumont, E., Thevenon, C., Ortchanian, E., and Martin J. (1989) Influence of long-term diet modification on platelet function and composition in Moselle farmers. Am. J. Clin. Nutr. 43: 136-150.

Sano, M.E. and Smith, L.W. (1942) The effect of lowered temperatures upon the growth of the fibroblast in vitro: its application to wound healing. J. Lab. & Clin. Med., 27: 460-464.

Simopoulos, A.P. (1989) Summary of the NATO advanced research workshop on dietary w3 and w6 fatty acids: biological effects and nutritional essentiality. Am Inst Nutr :521-527. 

Simopoulos, A.P. (1991) Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr 54:438-463.

Spielmann, D., Traitler, H., Crozier, G., Fleith, M., Bracco, U., Finot, P.A., Berger, M., and Holman. R.T. (1989) Biochemical and bioclinical aspects of blackcurrant seed oil: 3- 6 balanced oil. In: Dietary -3 and -6 Fatty Acids: Biological Effects and Nutritional Essentiality, Galli, C. and Simopoulos, A.P., eds., Plenum Publishing, New York, p. 309-322.

Stevens, L.J., Zentall, S.S., Deck, J.L., Abate, M.L., Watkins, B.A., Lipp, S.R., and Burgess, J.R. (1995) Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 62:761-768. 

Takai, A., and Mieskes, G. (1991). Inhibitory effect of okadaic acid on the P-nitrophenyl phosphate phosphatase activity of protein phosphatases, Biochemical Journal, vol. 275, pp. 233-239.

Wargovich M.J. (1992) Fish oil and colon cancer. Gastroenterology 103:1096-1101.

Wood, D.A., Butler, S., MacIntyre, C., Riemersma, R.A., Thomson, M., and Elton, R.A. (1987) Linoleic and eicosapentaenoic acids in adipose tissue and platelets and risk of coronary heart disease. The Lancet (Jan 24):177-183.

Wright, S. and Burton, J.L. (1982) Oral evening-primrose-seed oil improves atopic eczema. Lancet (Sept 20):1120-1122.