SLA Biomedical & Life Sciences Division Blog

Is Transgenic Introgression Automatically Transgression? Do Genetically Modified Crops Threaten Wild Species (or Ourselves) With Extinction?

Introgression is the process by which one species, usually a plant (although animal models clearly exist), hybridizes with another. Then, the resulting second generation mixed species then hybridizes again with one or the other of the initial parent plants.  If that second generation hybrid is itself able to reproduce and thrive, its existence is said to represent a stable introgression.

Linnaeus , the great classifier of plants and animals, won a prize from the St. Petersburg Academy of Sciences in Russia in the 1700’s when he successfully hybridized two related but nonetheless distinct plants.  The point he was trying to prove at that time was that plants can reproduce sexually (which of course, many or most can), but he also suggested that this hybridization in nature might well be the source of many (or even most ) new species.

Linnaeus was right up to a point.  But as orchid and rose breeders  will tell you, the creation of new hybrids, to say nothing of new species, rarely goes as easily or as planned as that.

A great many hybrids are sterile, that is, they cannot reproduce, even if they can thrive for a single generation.

Other hybrids unravel in terms of their hybrid appearance or in terms of their desirable properties and go right back to being more like their native ancestors. (They revert to being wild.)

A fairly common occurrence among hybrids appears to be that they have seeds that are too small for successful soil penetration, or which will sprout only in well-tilled soil and only under gentle conditions.

Other hybrids are unable to compete with either parent plant once they sprout, and simply go out of existence themselves.

All these points about introgression in plants would be almost purely academic save for a new worry: the effect of genetically modified (hereafter, GM) crops and their nearby wild plant relatives, and both human and wild creature life. 

The most commonly encountered GM crops are soybeans, cotton, corn, canola (rapeseed oil), squash, alfalfa, rice and now, potatoes.

The most common traits which are introduced by GM are increased resistance to harmful insects, decreased susceptibility to weed killers (i.e. enabling weed killers to be used without harming the main crop), the ability to thrive or utilize better what water and fertilizer is available so as to increase yield, and in food crops , the ability to synthesize or maximize other missing or low levels of nutrients for humans.

Will their GM genes introgress into the native species and somehow wipe them out?

Or will there be other and more insidious unintended consequences than can only be imagined at this time.

Current opinion on GM introgression is more politically driven, than experience based, and therefore working assumptions are unsurprisingly diametrically opposed.

A recent  editorial in the June 2, 2008 issue of America’s conservative flagship, The National Review , says that holding GM back retards the ability of Third World countries to feed themselves, and cites Robert Mugabe and Hugo Chavez, as prime examples of GM opponents who are consumed by conspiracy theories of GM, rather than by the existing science concerning GM crops.

But that journal’s  equally prestigious liberal American counterpart, The Nation, warns in its May 12, 2008 issue, that efforts by agribusiness to promote GM crops are deliberately designed to maximize profits, not solve the world food crisis. In fact, the journal suggests that getting poor farmers hooked on GM seeds will eventually impoverish them, and starve their families and produce customers.

The European Union on the whole agrees with the The Nation, and has either bans, or high regulatory barriers, on many GM foods including plants, that are driven by fears of what some commentators refer to as the unpredictable consequences of having Europeans eat “Frankenfood.”

But perhaps the most balanced scientific assessment, and one that merits wider distribution among politicians is found in the May 2008 issue of BioScience (v.58, no.5, p.379). Its essential message is:

"So far, careful scrutiny has found no evidence of health dangers from growing or eating genetically engineered crops. Certainly any ecological or health consequences of these products need to be monitored and prudence observed.”

Have there been unintended outbreaks of GM hybridization?

Yes.

The most common reasons reported for these outbreaks are planting GM crops too close to stands of non-GM or wild varieties so that there is pollen interchange,  and random dispersals of GM seed along truck routes through tire treads or through adherence of seed or pollen to workers clothing.

One example is the hybridization of one GM member of the turnip family (the oil-seed rape plant Brassica napa) with  Brassica olearacea or with Brassica rapa (two turnip top greens favoring varieties ) which thrive better in the wild.

In another case, a ten year study indicated that some GM sunflowers had in fact, hybridized with wild sunflowers.

In yet another, a GM variety of rice had indeed introgressed into a wild rice variety.

In still another, wild lettuce had co-mingled with GM lettuce.

Have those consequences been of any great significance?

No.

Sampling of the Brassica  indicated that at one point in 2002, 85 out of 200 plants sampled near the zone of hybridization, had in fact, shown some evidence of introgression, but by 2005 it had gone down to 5 out of 200.

The GM introgression yielded wild sunflowers that turned out to have greater hardiness, including the ability to withstand better harsher environmental conditions, particularly less water and poorer soil.

The rice study showed that even with close co-planting, the risk for transgenic hybridization was much less than 1%, and that the farther away from the experimental field, the risk diminished to a virtual zero point. Nearby wild grasses that had the theoretical capacity for introgression, were complete unaffected.

The lettuce collision showed that the wild type favoring hybrid was actually more likely to survive than the cultivated one , so the chance of the GM favoring hybrid running amuck seemed unlikely, because it was in fact, less viable outside its intended area of cultivation.

Probably the most serious wildlife consequences any of these hybridizations is alleged to have is on insects and insect eaters.

Butterflies and moths  dependent on one type of flower may not do as well on the GM introgressed hybrid variety.

Streamside plants that have hybridized with GM plants that are insect resistant, may support fewer insects to fall into in the water for fish to eat.

The environmental upsets that have been detected have not been documented as yet to be persistent. And the odds are they will not in fact be so.

There are some rare but somewhat more realistic worries about human health in that  genes for certain proteins -----most commonly mentioned are  nut proteins-----to which some people are allergic may unintentionally migrate through GM to a plant which was previously not known to cause this particular allergic reaction, so that the consumer was taken unaware. Certain soybeans have been found to contains proteins from brazil nuts, for example.

But conversely,  there is already progress on creating allergy medicines using transgenic rice, and vaccines have been made using transgenic potatoes.

In any case, the clearest recommendation about GM and introgression, and its benefits and risks, that can be drawn for biomedical librarians for now, is a very reliable one: Encourage your clientele to read  more of the science.

The very thought alone of GM crops should not make your readers fact-resistant.

Auer C. 2008. Ecological risk assessment and regulation for genetically-modified ornamental  plants. Critical Reviews in Plant Sciences 27 (4): 255-271.

Beardsley TM. 2008. The right fight for biologists. BioScience  58 (5): 379.

Chandler S & Dunwell JM. 2008. Gene flow, risk assessment and the environmental release of transgenic plants. Critical Reviews in Plant Sciences 27 (1): 25-49.

Choo V. 1996. Allergens can be transferred to transgenic products. The Lancet 347 (9004): 819.

Dlugosch KM  & Whitton J. 2008. Can we stop transgenes from talking a walk on the wild side? Molecular Ecology 17 (50; 1167-1169.

Ford CS et al. 2006. Spontaneous gene flow from rapeseed (Brassica napus) to wild  Brassica oleracea.  Proceedings of the Royal Society of London B – Biological Sciences 273 (1605): 3111-3115.

Hooftman DAP et al. 2005. Demographic vital rates determine the performance advantage of crop-wild hybrids in lettuce. Journal of Applied Ecology 42 (6): 1086-1095.

Hooftman DAP et al. 2008. Modelling the long term consequences of crop-wild relative hybridization: A case study using four generations of hybrids. Journal of Applied Ecology 44 (5): 1035-1045.

Hooftman DAP et al. 2008. Modelling the consequences of crop-wild relative gene flow: A sensitivity analysis of the effects of outcrossing rates and hybrid vigor breakdown  in Lactuca. Journal of Applied Ecology 45 (4): 1094-1103.

Liang GH & Skinner DZ.  2004. Genetically Modified Crops: Their Development, Uses, and Risks. Binghamton, NY: Food Products Press, a division of Haworth Press.

Ma S & Jevnikar AM. 2005. Transgenic rice for allergy immunotherapy. Proceedings of the National Academy of Sciences 102 (48):  17255-17256.

McNamee D. 1999. Transgenic potatoes produce oral HBV vaccine. The Lancet 354 (9191): 1707.

Mercer KL et al.  2007. Stress and domestication traits increase the relative fitness of crop-wild hybrids in sunflower. Ecology Letters 10 (5): 383-393.

Moeller L & Wang K. 2008. Engineeering with precision: Tools for the new generation of transgenic crops.

Nichols J. 2008. The world food crisis. The Nation (May 12^th  issue): p.6-7.

Rong J et al.  2005. Low frequency of transgene flow from Bt.Cp TI rice to its non transgenic counterparts planted at close spacing. New Phytologist 168 (3): 559-566.

Rosi-Marshall EJ et al. Toxins in transgenic crop byproducts may affect headwater stream ecosystems. Proceedings of the National Academy Of Sciences 104 (41): 15204-16208.

Schwarz F. 2008. Transgenic travesty. National Review  (June 2^nd issue): 20-21.

Singh O.V, Ghai S & Paul D. 2006. Applied Microbiology and Biotechnology 71: 598-607.

Stewart CN. 2004. Genetically Modified Planet: Environmental Impacts of Genetically Engineered Plants. New York: Oxford University Press.

Thomson JA. 2007. Seeds for the Future: The Impact of Genetically Modified Crops on the Environment. Ithaca, NY: Cornell University Press.

Vonder Leppe M & Kowarik I. 2007. Crop seed spillage along roads: A factor of uncertainty in the containment of GMO. Ecography 30 (4): 483-490.

Wang F et al. 2006. A large-scale field study of transgene flow from cultivated rice (Oryza sativa) to common wild rice (O. rufipogon) and barnyard grass (Echinochloa crusgalli).  Plant Biotechnology Journal 4 (6): 667-676.

Warwick  SI et al. 2008. Do escaped transgenes persist in nature? The case of an herbicide resistance transgene in a weedy Brassica rapa population. Molecular Ecology 17 (5): 1387-1395.

Wei W & Darmency H. 2008. Gene flow hampered by low seed size between oilseed rape and five wild varieties. Seed Science Research 18 (2): 115-123. 

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

Are Conjugated Linoleic Acids the Next Omega-3 Fatty Acids? The Serious Promise and the Sometimes Over-the-Top Hype of an Over-the-Counter Supplement: CLA

In 1979 Dr. Michael Pariza of the University of Wisconsin was frying hamburger in his lab with the full intent of proving that ground beef or the process of frying hamburger at high heat would certainly yield cancer-causing compounds.

After all, did it not seem at that time, and this one too, that everything, sooner or later was going to be found to cause cancer?

He took the resulting meat juices and painted them on some nude-skin mice, which were typically used to detect carcinogenic activity. The mice did not get skin cancer nor any other kind of cancer.

He then painted a known cancer causing compound on the mice as well as the hamburger juices, figuring that the hamburger juices might potentiate or stimulate even more cancer-causing damage, even if they were not the prime movers.

  Instead of getting the predicted cancer worse, the mice did not get it at all.

This serendipitous finding, that a category of substances within these hamburgers, called Conjugated Linoleic Acids, possessed potent cancer-inhibitory processes, was soon published in the Proceedings of the American Association for Cancer Research, and began an incredible career for Dr. Pariza and his lab as not only researchers, but maintainers of a clearinghouse for information on these CLAs.

A search of the Web of Science done today (August 25, 2008) disclosed over 2100 articles on CLAs.

While no responsible researchers claim that CLAs are a cure-all for cancer or for a broad variety of ailments, there is a very large body of evidence that some of the isomers in the CLA family do possess fairly marked medicinal or metabolic properties.

What are they?

Weight loss and body fat reduction are two of the most common claims made for the intake of CLAs. While the results are inconsistent, the preponderance of evidence suggests that CLA intake does work in weight loss, particularly among those who are overweight and obese, but otherwise of good health.  There is even some evidence that they can forestall the Thanksgiving-Christmas-New-Year’s holiday weight gain that so many of us experience.

The most commonly proposed mechanism of action for the CLAs is to activate apoptosis, the programmed cell death, of fat cells.

There is much less evidence solidly favoring CLAs as a supplement to combat metabolic syndrome and insulin resistance, although one isomer seems fairly effective in reducing the girth fat that is an important part of this insidious condition.

Once again, the proposed mechanism of action is the promotion of fat cell apoptosis. Unfortunately, some isomers may actually worsen insulin sensitivity; i.e. increase insulin resistance.

Cancer data are promising but also mixed. Breast cancer reduction or avoidance, stomach and colon cancers, and prostate cancers all seem to respond well in the lab to treatments involving CLAs, but these are almost all non-clinical trials.

Cardiovascular health, atherosclerosis, and favorable lipid profiles sometimes result when experimental subjects are taking CLAs, but there are a minority where the opposite occurs.

The promise of these CLAs is such that 2006 sales, the most recent for which we have data, shows that $460 million was spent in over-the-counter supplements of CLAs, largely purchased in nature food stores and over the internet.

While there is little evidence that these CLA preparations are toxic to most people. They are not without their problems.

• First, the most common CLA isomers are cis-9, trans-11, and trans-10, cis-12, but several other types are encountered in nature in lesser amounts, and still others can be prepared in the lab.  So-called all-natural supplements , usually made from various seed oil preparations involving safflower, sunflower, or soybean, tend to vary  in the relative percentage of these ingredients from batch to batch, and from season to season, owing to the natural fluctuation of the isomers in the plant material sources. The consumer is often unaware that what he or she is taking is likely to vary in formulation, which ought to be an important consideration if one isomer does something better physiologically than another isomer.
• Second, there is a distinct possibility that some of these isomers, most commonly the trans-10, cis-12, has been reported as having adverse consequences, particularly in those who have adverse blood lipid profiles. This isomer’s benefits may well outweigh its risks for some patients, but without a firm grasp on which preparations have which concentrations at any given time, an informed judgment cannot be made.
• Third, it is very clear that CLAs often have fabulous curative or preventive results in lab rats. With humans, the picture is far less clear.

Nonetheless, there is absolutely no let up in clinical and animal trials. The people in the beef, dairy, sheep and even pork, poultry & egg businesses have been rapidly developing ways to feed their livestock in a manner that would naturally increase the levels of CLAs within customary proportions, so that one could get their dose as a part of a diet.

This would essentially turn a glass of milk or a hamburger into a kind of CLA nutraceutical. 

Don’t laugh, eggs have had a fairly dramatic rebound in sales over the last few years once it was found how a farmer might be able to increase naturally their levels of highly beneficial omega-3 fatty acids, perhaps even offsetting the now somewhat discredited egg-eating-cholesterol- raising dilemma. (Genetics raises cholesterol at least as much as eating eggs, in many, many patients. Eating a limited number of eggs per week is now seen as much less threatening than before, and eggs are frankly otherwise excellent nutritionally.)

Even now, there are numerous announcements of agricultural experimental station scientists being able to increase naturally through animal nutrition methods both CLAs and omega-3s at the same time, hoping perhaps to double their sales, as they improve the overall healthiness of their products.

For a longer review written especially for librarians, one with over a 100 references, see the article below by this blogger.

Cachaldora, P et al. 2008. Double enrichment of chicken eggs with conjugated linoleic acid and n-3 fatty acids through dietary fat supplementation. Animal Feed Science & Technology 144 (3-4): 315-326.

Plourde, M. et al. Conjugated linoleic acids: Why the discrepancy between animal and human studies? Nutrition Reviews 66 (7): 415-421.

Stankus, T. 2008. Turning meat, poultry, eggs, and dairy products into nutraceuticals through increasing their conjugated linoleic acid levels, Part one: Reviewing the literature of benefits claimed for conjugated linoleic acids in human health. Journal of Agricultural & Food Information 9 (3): 229-255.

Watras, AC et al. 2007. The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain. International Journal of Obesity 31 (3): 481-487.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

H5N1: Update on Avian-to-Avian & Avian-to-Human FluTransmission, Testing, Vaccines, Mortality Rates, Symptomatology, Hospitalization Rates

The years 2003-2004 saw outbreaks of what we now know as H5N1 Avian flu virus in eight East Asian countries: Cambodia, China, Indonesia,   Japan, Laos, South Korea, Thailand,  and Vietnam.  It has since spread to Egypt, India, Kazakhstan, Russia and the US, but at much, much lower rates, sometimes with only a few cases per country. This blog will update the reader with some of what has been newly learned, or more strongly confirmed, since then, without “The Pandemic Will Wipe Us Out Tomorrow” hype that has the potential for desensitizing a community that has grown skeptical that Avian flu is much of  a threat to anyone, when, in fact it is.

What Birds (“Avians”) Transmit the Virus That Causes the Disease?

Thus far it is pretty clear that two categories of poultry seem to be responsible for most of the outbreaks that spread to humans.

Domestic poultry, basically chickens and ducks grown for home consumption or the marketplace, seem to be the primary carriers from which most humans contract the disease.

These birds can get it from one another, or from migratory waterfowl.

Which Migratory Waterfowl Appear to Be The Culprits?

The family of birds called Anatidae, which consists of ducks, geese and swans are the most likely international vectors. Seagulls have been implicated, but not to as great a degree.

This bit of detective work has primarily used two pieces of evidence: Finding infected migratory birds and then tracking paths of infection along migratory flyways. The match up is good, although trucking of poultry infected by wildlife to cities that are not part of the migratory birds’ flyway can complicate the picture.

The means of transmission from migratory to domestic fowl seems to be through the migratory birds fouling the water and land with their often copious and virus-shedding feces.

The domestic fowl incorporate the viruses through contact or ingestion, and then pass it to on to other members of the domestic flocks through contact and their own virus-laden defecation.

One of the most imaginative studies of risk evaluation   from migratory birds comes from Australia, where scientists have co-mapped the locations of poultry farms and the breeding grounds of sea birds and water fowl, and found only a narrow overlap. This will allow them to focus better their preventive efforts.

What about other animals? Rats and pigs can be infected with the virus, but only in experimental settings, and seem not to be likely to become vectors.

Is H5N1 Everywhere Identical?

No, there are at least five different strains, (and a number of related viruses since discovered, like H5N2 ) most of which get named after the location from which they were first isolated, or from where the most cases were reported.

There has already been  some rate of mutation among these.

The good news is that most respond to the same drugs.

The bad news is that some of the newer strains appear more virulent.

How Can We Tell the Strains Apart?

Probably the most rapidly progressing area in the field is the differentially diagnostic molecular sequencing of these viruses. Tests are becoming more reliable, faster, more portable, and even cheaper.

False positives remain a problem, but by and large, that is better than false negatives, which would leave patients without any treatment.

What Are The Current Treatments?

By far, the most common treatment is with oseltamivir carboxylate, whose brand name is Tamiflu™. While it is not equally effective against all H5N1 strains, it has been able to be prepared in the multimillions of doses and to have some activity against virtually all of them.

The use of adjuvants (chemicals that seem to boost vaccine performance) and the timing of the injections seem to be more important to current successful treatment  than the lack of specificity to all strains at this time of vaccines like Tamiflu™, although the development of cheap, and quickly scalable production of  strain-specific vaccines or the development of multivalent vaccines that can inhibit the entire class of H5N1 are ultimately the long term goal.

Curiously, there is a good news/ bad news dichotomy with regard to the longer lasting nature of the drug in waterways. Apparently, it lasts up to two weeks in ponds and rivers. This might seem to suggest that treated humans who wash, void, or defecate nearby could actually decrease the water’s viral load. More likely, however, over-exposure of the drug could induce drug resistance as susceptible strains quickly fall prey, leaving only resistant mutants.

What Are Today’s Mortality Rates?

The most on-point study thus far is Kundun et al. below, from August 14^th, 2008 issue of  The Lancet . They reported 127 cases in Indonesia, occurring between June 2005 – February 2008.

The mortality was a whopping 81%.

What Are the Common Factors in Exposure to the Virus?

Living in an area where poultry had died with avian flu (30%)

Handling sick or dead poultry (21%)

Being around healthy poultry (15%)

Slaughtering or processing the meat of sick poultry (15%)

H5N1 positive poultry in the home or neighborhood, even if the poultry were apparently healthy at the time (5%).

Visited “wet” market where poultry was slaughtered at point of purchase. (3%)

Handled H5N1 positive poultry feces (perhaps as part of  an attempt to clean it out.) (1%)

Symptomatology

Fever (93% of patients), cough (32%), runny nose (17%), nausea/vomiting (7%-13%), vertigo (10%), diarrhea (7%0, headache (6%),  muscle aches (1%).

Rates of Admission to Hospital & Effectiveness of Treatment

125 patients were admitted to a hospital. One recovered with treatment at home; the other refused treatment and died. The sooner a patient was admitted to a hospital, the better were his or her chances. Likewise with the onset of treatment with Tamiflu™.

Nonetheless, most patients did die, typically of pneumonia.

The study suggests that the reason for the high death rate was that the hospital admission was too late after the onset  of the disease, likewise with the administration of the Tamiflu™. 

A curious result was the fact that patients who were part of a group that got ill, had better chances of recovery, than did patients who came down sick with the virus with no apparently sick  neighbors, co-workers or family members. This could be because public health workers or primary care physicians were less alert to the possibility that this patient’s cold or flu was in fact, H5N1 based, until   it was too late.

Bartels P & von Tumpling W. 2008. The environmental fate of the antiviral drug oseltamivir carboxylate in different waters. The Science Of The Total Environment epub ahead of print, no volume or pagination yet assigned. DOI: 10.1016/j.scitotenv.2008.06.032

Chantratita W, et al. 2008. Qualitative detection of avian influenza A (H5N1) viruses: A comparative evaluation of four real-time nucleic acid amplification methods. Molecular And Cellular Probes epub ahead of print, no volume or pagination yet assigned. DOI: 10.1016/j.mcp.2008.06.005

East IJ, Hamilton S & Garner G. 2008. Identifying areas of Australia at risk of H5N1 avian influenza infection from exposure to migratory birds: a spatial analysis. Geospatial Health 2 (2): 203-213.

Gaidet N, et al. 2008.Evidence of infection by H5N2 highly pathogenic avian influenza viruses in healthy wild waterfowl. PLoS Pathogens 4(8):e1000127.

Gilbert M, et al. 2006. Anatidae migration in the western Palearctic and spread of highly pathogenic avian influenza H5NI virus. Emerging Infectious Diseases 12 (11):1650-1656.

Goji NA, et al. 2008. Immune responses of healthy subjects to a single dose of intramuscular inactivated influenza A/Vietnam/1203/2004 (H5N1) vaccine after priming with an antigenic variant. The Journal Of Infectious Diseases198 (5): 635-641.

Isoda N, et al. 2008. Potency of an inactivated avian influenza vaccine prepared from a non-pathogenic H5N1 reassortant virus generated between isolates from migratory ducks in Asia. Archives of Virology epub ahead of print, no volume or pagination yet assigned.

Kalthoff D, et al. 2008.Highly pathogenic avian influenza virus (H5N1) in experimentally infected adult mute swans. Emerging Infectious Diseases 14(8):1267-1270.

Kandun, IN et al. 2008. Factors associated with case fatality of human H5N1 virus infections in Indonesia: A case series. The Lancet epub ahead of print, no volume or pagination yet assigned

Nagarajan S, et al. 2008.Isolation and pathotyping of H9N2 avian influenza viruses in Indian poultry. Veterinary microbiology epub ahead of print, no volume or pagination yet assigned. DOI: 10.1016/j.vetmic.2008.06.013

Perrone LA, et al. 2008. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PloS Pathogens 4 (8):e1000115.

Peyre M, et al. 2008. Avian influenza vaccines: A practical review in relation to their application in the field with a focus on the Asian experience. Epidemiology And Infection 14: 1-21.

Poland GA &S Ambhara S. 2008.Vaccines against Influenza A (H5N1): Evidence of Progress. The Journal Of Infectious Diseases 198(5):629-631.

Rappole JH & Hubalek Z. 2006. Birds and influenza H5NI virus movement to and within North America. Emerging Infectious Diseases 12 (10):1486-1492.

Saito T, et al. 2008.Pathogenicity of highly pathogenic avian influenza viruses of H5N1 subtype isolated in Thailand for different poultry species. Veterinary Microbiology epub ahead of print, no volume or pagination yet assigned. DOI: 10.1016/j.vetmic.2008.06.020

Stelzer-Braid S, et al. 2008.A commercial ELISA detects high levels of human H5 antibody but cross-reacts with influenza A antibodies. Journal of Clinical Virology epub ahead of print, no volume or pagination yet assigned. DOI: 10.1016/j.jcv.2008.06.012

Stevens J, et al. 2008. Recent avian H5N1 viruses exhibit increased propensity for acquiring human receptor specificity. Journal of Molecular Biology 381(5):1382-1394.

Suriya R, et al. 2008.Seroprevalence and risk factors for influenza a viruses in pigs in peninsular Malaysia .Zoonoses And Public Health 55 (7):342-351.

van der Laan JW, et al. 2008. Animal models in influenza vaccine testing. Expert Review Of Vaccines 7 (6): 783-793.

Vong S, et al. 2006.Low frequency of poultry-to-human H5NI virus transmission, southern Cambodia, 2005. Emerging Infectious Diseases 12 (10): 1542-1547.

Vong S, et al. 2008. Environmental contamination during influenza A virus (H5N1) outbreaks, Cambodia, 2006. Emerging Infectious Diseases 14 (8): 1303-1305.

Waicharoen S, et al. 2008.Influenza viruses circulating in Thailand in 2004 and 2005.Japanese Journal of Infectious Diseases 61 (4): 321-323.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Bibliographer

University of Arkansas Libraries MULN 233 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

HIV/AIDS: Progress in Prevention As Reported in The Lancet.

A great service is being provided to readers of The Lancet via a number of highly readable review articles and commentaries on HIV/AIDS prevention strategies and their relative success rates. See full references below for a full and careful reading, but until then, here are some highlights.

Condoms for Men

The first line of defense, apart from abstention, continues to be the use of the male condom.  It appears to be 85%-95%  effective when used consistently. The problem with the missing percentage points appears to be mostly their selective use, in the sense that many men who are having sex with prostitutes will use them  all the time, but will only use them with their wives when they feel there is a good chance of the wife becoming pregnant otherwise. In other words, many men eschew their use during their wives menstruations, when they perceive the chance of pregnancy are minimal. Not only is this a somewhat shaky proposition in terms of birth control, but it exposes the men to HIV picked up by the wife from other means, or it allows HIV which the men picked up , but of which the men were unaware, to be transmitted to their wives.

Condoms for Women

While many are unacquainted with them, female condoms  are in use as both contraceptive and HIV preventive  methods.  They are somewhat less effective, not so much because their construction in theory is in any notable way highly penetrable to the AIDS virus, but because  female condoms can be somewhat awkward  to insert and keep in place.  Female condoms   generally consist of a  flexible cylinder  or sheath of thin latex or polyurethane, with a reinforced ring, largely of the same material as the rest of the sheath, and somewhat reinforced material at the tip that goes into the vagina. Those structures help the female condom stay in place during intercourse.  At the opposite end, at the  vagina’s entrance, is another ring of reinforced material, acting as an anchor , or it might be in something like a  triangle shape. In either case it is open, as opposed to closed off as its opposite end,  and it is through this entryway where the man inserts his penis and into into the connected tunnel or barrel of which, the man ejaculates his semen, and any concomitant viruses.  The greatest advantage of the system is that the woman is in charge of the insertion and use, and can place it inside her even before her partner has an erection.  Women have generally reported either no decline in their sexual enjoyment in using them, and some have reported enhanced sensation. Perhaps unfortunately, their costs are greater, and field trials have generally shown that training women to insist on their partner’s use of  male condoms has about the same level of AIDS preventive effectiveness.

Diaphragms and Cervical Caps with Antiviral Lotions or Lubricants

While there is little doubt that these would not be as effective as either male or female condom use, because they expose more internal tissue to possible viral penetration, use of diaphragms or cervical caps with antimicrobials and newly developed antiretroviral  gels or creams may yet prove to be a reasonably effective strategy. Its advantage for women is similar to that of the female condom, but without the chance  of having the male partner see the external ring at the vulva (and presumably have an opportunity  to object).

Treating Other STDs

Public  health programs where examination, testing, and treatment for other STDs are made readily available, has some effectiveness in HIV prevention, largely because HIV appears to become more readily established or better established in persons with STDs. This is particularly the case if the region is not already saturated with HIV positive patients. 

Encouraging Circumcision of Men

(and Stopping the Detestable Practice of Female Genital Mutilation Masquerading as Circumcision)

Males who are uncircumcised have a somewhat greater risk of developing both sexually acquired and fairly routine bacterial and yeast infections of their foreskins and the underlying penis. This risk increases in countries where daily bathing and hygienic washing of the foreskin-retracted and exposed penis are not   common.  Secondary HIV virus penetration is more likely when even small surface ulcerations emerge, even if the primary infection is self-limiting.   Of course, the use of truly sterile technique is required for any cutting procedure, and this is particularly rarely observed in countries where female genital mutilation is practiced. The latter procedure may well cause a greater risk of HIV owing to both the operation itself, and owing to the follow on infections and chronic irritations. Male circumcision by contrast leads to a penis whose skin is actually toughened after healing and less likely to be penetrable by the virus.

Treating the HIV Infected Partner May Reduce the Risk to an Uninfected Partner

There is some thought and a few clinical trials that suggest that aggressively treating the HIV infected partner and keeping that partner down to a clinically very low or undetectable HIV load significantly reduces the chances of the uninfected partner getting the disease, but this seems to depend on a highly conscientious prescription medication regimen being maintained by the HIV-positive partner, even though the viral load seems extremely low.  Alternatively, it has been suggested that giving the non-positive partner antiretrovirals may be of some use, although this raises the risk of increasing strains of HIV that are drug resistant, and may have other adverse consequences.

Vaccines

There is no easy way to say it. Things are not promising.

The Idea that Retrovirals Will Simply Wipe AIDS Out Making Prevention Unnecessary.

Even with the massive infusion of monies today, five new cases emerge for every two that are started on retrovirals. We cannot, one article in this series quotes, “treat our way out of this crisis.”

Horton R & Das P. 2008. Putting   prevention at the forefront of HIV/AIDS. The Lancet 372 (9637): 421-422.

Merson MH et al. 2008. The history  and challenge of HIV prevention. The Lancet 372 (9637): 475-488.

Padian NS et al.  2008. Biomedical interventions to prevent HIV infection: Evidence, challenges, and way forward.  The Lancet (9638): 585-599.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 233 E

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Tryptophan: Much More Than Something in Turkey That Allegedly Makes You Sleepy After Thanksgiving Dinner

Tryptophan is an amino acid that is not readily synthesized in the body, but it is an important ingredient in the synthesis of some vital proteins, and therefore must be obtained through dietary intake.

The most common notion most of us have with respect to tryptophan is that it is present in turkey ----which is correct---- and that it makes us sleepy after it is eaten. 

This is not quite the whole truth if you consider that it is the tryptophan that is acting alone. Particularly if you think that the alcohol, copious carbs and fats in need of digestion, and the exhaustion of most holidays, play no significant  supporting role.

The demonstration of this sort of benevolent half-truth  of turkey as a particularly effective sleep-inducer lies in the fact that other foods actually have more tryptophan.

Trypophan is more abundant in edamame (salad bar soybeans), several aged cow’s milk cheeses (most notably Parmesan), and pork chops. Moreover, beef, salmon and lamb have only about 5% less tryptophan; a few bites more of them, and you’re at the same level of tryptophan.

If the tryptophan in turkey was the sole sleep-inducer, you might expect that there would be accounts of a similar effect from consumers of  soy, cheese, roast beef, and pork and lamb chops. This is particularly since there is absolutely no structural or metabolic differences in the tryptophan from any of these sources.

Nonetheless, there is some clinical evidence that the somewhat more concentrated doses found in over-the-counter tryptophan have helped people with insomnia fall, and stay asleep. Nonetheless, those largely loosely-structured   studies fail to cause it be widely recommended by most sleep clinicians and researchers.

But tryptophan deserves more and better press than it gets around the holiday season in any case.

Tryptophan plays other very serious roles in psychiatric disorders, immunology in both cases of infection and in transplant rejection, in smooth function of the gastrointestinal system, and perhaps even in cardiovascular disease.

Tryptophan can do all these things for two very good reasons.

First, tryptophan is a key player in cell membrane biology.  The gateways through the cell, ionopores, tend to be ringed with proteins whose tryptophan-rich heads are prominent, and they are seemingly important to the cell’s input/output balance and function. The tryptophan-based protein most studied of late has been gramicidin, and it has yielded some interesting results.

Second, tryptophan is the most notable precursor to a number of other, better known regulatory proteins.

The Tryptophan/Serotonin Connection

The first of these tryptophan-based regulators is serotonin, the most important player in the management of depression and a number of other brain disorders. These include various types of dementia and Alzheimer’s Disease.

Abnormalities in the body’s handling of tryptophan have also been found in patients with anorexia and bulimia, as well as those made sick to their stomachs and unlikely to want to eat, owing to liver toxicity, kidney failure, or advanced wasting diseases such as seen in cancer patients. Curiously, the relative lack of tryptophan in these cases, sometimes reduces the normal breakdown of serotonin, sometimes giving the afflicted person a peculiar sense of well-being.

Unfortunately, this effect wears off until even more self-starvation or binge-purging takes place, to such a degree that the momentary serotonin lift is once again realized.  The price for this deprivation is ultimately protein starvation owing to a lack of the essential tryptophan needed for other purposes.

There has been growing interest in the use of the Acute Tryptophan Depletion or ATD  test as a challenge of the brain’s ability to manage its serotonin levels.  A  cocktail is given that is deficient in tryptophan, after which in the course of a few hours, generally causes a competition within the body for the remaining tryptophan.

In these cases, the serotonin levels also plummet, deprived of their most direct precursor, tryptophan, by the body using it up for other purposes.

Nonetheless,  most of the mentally healthy volunteers no significant shift of mood downward was observed.

However, in depressed patients   that had been doing quite well based on serotonin modulating antidepressants, mood notably sank.

The surprise was that notably depressed patients who had gained no relief from those drugs, did not have their mood change notably . In other words, they did not get even more depressed, nor did their mood improve. Their form of depression might not be amenable to an adjustment of the tryptophan/serotonin metabolic pathway.

There were some peculiarities. Women tended to be represented more heavily among those whose mood sank with the ATD test, as did persons who had prior thoughts or attempts of suicide.

Most significantly, the small number of persons who were mentally healthy, but whose ATD test caused a severe mood shift downward, contained a high percentage of persons whose family members had depression, or were persons for whom genetics tests had indicated an anomaly that would predispose them to tryptophan-serotonin miscues that might sooner or later trigger depression in them, despite their current upbeat state. It has been recently suggested in a 2008  review  by Fisher et al. in the American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, that a propensity for mistakes in the metabolic pathways by which tryptophan is managed,  has a strong genetic component and may indeed be hereditable.

The ATD test may prove to be a good indicator test, then, of people who would be helped or not, with serotonin-modulating drugs.

It has also been shown that the ATD test increases aggression in hyperactive children, suggesting that this condition too might involve a tryptophan-based metabolic disorder.

Further, after an ATD challenge test in healthy adults, tests of memory and task performance that required the subjects to  make corrective movements or to adjust their responses, showed that the subjects did not seem willing to listen to advice, or otherwise adjust their behavior to improve on their generally dismal  performance.  

That may say something about the ability of people who are depressed being able to take advantage of counseling or psychotherapy in improving their outlook or job performance. Until their tryptophan/serotonin pathway has been fixed, they cannot adapt as well as they should.

The Tryptophan/Melatonin Connection

The second major tryptophan based protein of note is melatonin, which was first found in the pineal gland, a structure very near the brain. Both the pineal and melatonin are best known as a sleep-wake cycle regulators (thereby gaining a modicum of support for tryptophan as a sleep aid, although serotonin which is not made in the pineal, probably play sat least as important a role.) But melatonin is also an antioxidant, and plays a major role in the management of inflammation.

Many of the insights into the anti-inflammatory roles played by melatonin were gained when it was found that melatonin was still being made even after the pineal was surgically removed.

It turns out that the GI tract actually makes much more melatonin, and that melatonin not only plays a role in the regulation of normal (non-spastic, non-ulcerative) colon function, but serves as a cancer protective substance for other visceral organs, most notably the pancreas.

It also  turns out that the aorta of the heart also makes melatonin, and maintaining the correct balance is thought to be a key to avoidance of catastrophic aortic aneurysms.

The Tryptophan/IDO Connection

Some of the body’s biochemicals made with tryptophan have checkered records. The most important of these is indoleamine 2,3-dioxygenase, which is typically abbreviated as IDO.

On the plus side, IDO appears to help the body modulate its immune function in two important instances. First, it plays a role in keeping a mother from immunologically attacking her fetus as an alien invader. Second, stimulation of IDO production has been shown to reduce both bone marrow and other tissue transplantation.

Most intriguingly, having just the right levels of IDO (and therefore just about the right levels of tryptophan) is seen as important to the quelling of autoimmune diseases, particularly certain ones which cause severe nerve pain. Indeed, tryptophan is sometimes suggested as an adjuvant to boost the power of painkillers and antidepressants prescribed for nerve pain.

One proposed beneficial function of IDO is to use up as much tryptophan as possible, so as to deny it to invading organisms, who could use that essential amino acid for their own protein synthesis needs.

Unfortunately, it also appears that the HIV viruses can also stimulate IDO production, and through IDO’s immunomodulatory effect, limit the ability of the body’s T-cells to go on the attack against the invaders.