米国発狂牛病１〜３の原文と参考文献リスト

以下は原文です。

「U.S. Version of "Mad Cow"
Known to Authorities Since 1960's

The hungry Sheep look up, and are not fed,
But swoln with wind, and the rank mist they draw
Rot inwardly, and foul contagion spread…
John Milton, Lycidas (1637)

Since the 1960's, US cows have been known to carry a form of mad cow fatal to other animals.

Bovine spongiform encephalopathy (BSE) or "mad cow disease" appears to have originated from scrapie, an endemic "spongiform encephalopathy" of sheep and goats that has been recognized in Europe since the mid-18th century. It has since spread to most sheep-breeding countries and is widespread in the United Kingdom (UK), where until 1988 the rendered carcasses of livestock (including sheep) were fed to ruminants and other animals as a protein-rich nutritional supplement.

Mad cow is one type of "transmissible spongiform encephalopathy" or TSE -- which is a classification of diseases by which abnormal brain proteins called "prions" cause the disintegration of brain tissue, causing physical and psychological devastation, then death. The "T" of TSE means "transmissible" -- meaning capable of being transmitted from one to another.

The current mad cow surveillance program in the US -- such as it is -- is based on the assumption that a native bovine TSE does not exist in the US and that the major threat comes from a British-style BSE.

However, a good deal of indirect evidence, involving studies on transmissible mink encephalopathy as well as on scrapie transmitted to cattle, suggests that a native bovine TSE occurs in the US and may be hiding among the "downer cow" population here.

Evidence from transmissible mink encephalopathy

Transmissible mink encephalopathy (TME) is a rare disease. TME has been seen only in farm-raised mink and was first described in the scientific literature in 1966, in a paper that discussed outbreaks of this disease on 8 or 9 mink farms in Wisconsin over a 16 year period (Hartsough and Burger, 1966a,b). The disease was first recognized on a mink farm in 1947. In 1961, another outbreak of the disease appeared on 5 or 6 mink farms, from three adjoining counties. Since all the farms with affected mink used a ready-mix feed ration which came from the same feed plant, the scientists assumed that the feed was the source of the infectious agent (Hartsough and Burger, 1966a).

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Two years later, in the summer of 1963, TME appeared again, almost simultaneously, on 2 more mink farms. Suspecting a possible feed-based source of contamination, based on the 1961 outbreak, the scientists went through the two farms' feed records.

A striking finding was that, from July through October 1962, meat "from beef carcasses unfit for human consumption (so-called 'downer' cows)" that came from Farm A was fed to minks on both Farms A and B. As the scientists noted, "Since mink on both farms developed the disease almost simultaneously, we believe this feed component has to be incriminated" (Hartsough and Burger, 1966a: 389). Although the authors could not completely rule out the possibility of sheep parts being part of the suspect meat shipment, this was the first suggestion that "downer" cows may be connected to TME. ("Downer" cow is a term that refers to cattle that are killed because they no longer can stand up or have collapsed or died for any of a number of reasons. There are an estimated 100,000 downer cows in the U.S. each year.)

The evidence was convincing enough that, at an NIH-sponsored meeting on TSEs in 1964, Drs. Burger and Hartsough hypothesized that sporadic cases of a bovine TSE occurred in the US under the clinical picture of downer cow (Burger and Hartsough, 1965).

The next recorded outbreak of TME in the U.S. occurred 22 years later, in 1985, on a mink ranch in Stetsonville, Wisconsin. Dr. Richard Marsh and his colleagues (Marsh et al., 1991) studied this outbreak and produced a number of lines of evidence that linked "downer" cows to TME. First, the mink's diet consisted of 95% "downer" cow and 5% horse meat. The minks received no sheep meat, so scrapie can be ruled out as the infectious agent.

Dr. Marsh also performed a number of experiments that further supported the notion that cows were the source of the infectious agent. Dr. Marsh injected brains from Stetsonville mink with TME into the brains of 2 Holstein calves. Within 19 months, both calves had developed a fatal spongiform encephalopathy. They did not act like "mad cows" in Britain; rather they just got a bit lethargic and fell over, i.e. they exhibited symptoms of "downer cow." Furthermore, when brains of these cattle were either injected into mink or simply fed to them, the mink developed TME. The authors concluded that "these results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States" (Marsh et al., 1991: 589).

The evidence is not solely linked to the Stetsonville outbreak. Dr. Marsh's cattle inoculation experiments have been repeated using mink brain isolate from the early 1960s outbreak of TME in Hayward, WI and in Blackfoot, ID. The results of those studies mirror what Dr. Marsh found: the inoculated cattle die of a TSE within two years (Robinson et al., 199?). Furthermore, the cows inoculated with TME do not behave like "mad cows," but exhibit behaviors consistent with "downer cows."

Some scientists have tried to argue that TME is caused by feeding scrapie-infested sheep to the ranch mink. To test this possibility, Dr. Marsh has tried feeding brains from scrapie-infested sheep to mink. Since there are believed to be at least 20 different strains of scrapie, Dr. Marsh tried feeding brains from a number of different strains of scrapie-infested sheep. In none of these cases was he able to infect mink with TME (Marsh et al., 1991). Indeed, we know of no studies in the scientific literature which demonstrate that mink fed scrapie-infested sheep develop TME.

A second problem with the hypothesis that scrapie is the cause of TME is that the first outbreak of TME in the US could not have involved feeding of scrapie-infested sheep. The first recorded case of scrapie in the US occurred on a ranch in Michigan in 1947, the year of the first TME outbreak in Wisconsin. The infected sheep was a Suffolk that could be traced back to Britain (where scrapie was rampant among the sheep). Indeed, in the first few years after scrapie was identified in the US, virtually all the infested sheep could be shown to have come from Britain (Detwiler, 1992). Thus, when the first case of TME occurred on a farm in Wisconsin in 1947, there were no known scrapie-infested sheep in the state at the time, unless one hypothesizes the existence of a native scrapie that had gone completely undetected.

Scrapie-infested cattle studies

Drs. Marsh, Hartsough and Burger's work suggested that TME may result from consumption of "downer cows." This raises the question of where a TSE which causes "downer cow" behavior might come from. One obvious possibility is scrapie. Thus, in 1979, at the USDA field station in Mission, Texas, researchers inoculated cattle with scrapie to see if cattle were susceptible to it: "It had earlier been observed that the carcasses of 'downer' (paralyzed) cows had been used as food for mink in which transmissible mink encephalopathy developed. Since natural scrapie had never been described in cattle, the study was designed to determine the susceptibility to experimental transmission of this spongiform encephalopathy" (Gibbs et al., 1990: pg. 1275).

Ten animals were injected with scrapie-infested brain homogenates in the brain, muscles and under the skin, as well as fed it. Three of the injected animals developed neurologic symptoms some 2-4 years after inoculation. The clinical symptoms were not those seen in cows with British-style BSE (i.e. the cows did not act "mad"); rather, the symptoms were more similar to those seen in "downer cow" syndrome: "neurological signs 27-48 months after inoculation, consisting of progressive difficulty in rising, a stiff-legged gait, incoordination, abnormal tail position, disorientation, and terminal recumbency" (Gibbs et al., 1990: pg. 1275).

More interesting than the clinical symptoms was the fact that Dr. Hadlow's histopathological analysis of the brains of the three affected cows revealed only diffuse gliosis with little or no vacuolization of the neurons. At the time, this was not considered sufficient evidence to conclude that the animals had a TSE: "Histopathological examination of the brains of affected animals revealed mild diffuse gliosis and few vacuoles, changes which were reported as being insufficient to confirm a clinical diagnosis of scrapie. Attempts to transmit the disease by inoculating homogenates of brain from affected cattle to mice were unsuccessful" (Gibbs et al., 1990: pg. 1275).

However, Dr. Gibbs believed at the time that the three cows had died of a TSE, in large part due to the animals' behavior (Gibbs, pers. com., March 28, 1997).

Ten years later, an immunohistochemical test became available that could detect the supposed infectious agent in scrapie (i.e. PrP27-30). Dr. Gibbs arranged to have the brains of the cattle reexamined using the new probe and found that the three cows with clinical symptoms tested positive while the other cows were negative. Dr. Gibbs et al. published the results of their work in an article entitled "Experimental transmission of scrapie to cattle" in The Lancet (Gibbs et al., 1990). Since publication of the article, another series of mouse inoculation studies using brains from the suspect cows has been done and resulted in passage of disease (Gibbs, pers. com., March 28, 1997).

Dr. Gibbs ended the article by stating that the evidence suggested that a bovine TSE was present at a low level in US cattle and that "downer cows" should be tested: "Susceptibility of cattle to scrapie further suggests the possibility that sporadic cases of BSE may have occurred in the United States under the clinical picture of the downer cow syndrome, as suggested by the work of Burger and Hartsough and Marsh. A search for PrP27-30 in the brains of downer cattle should provide useful information for this hypothesis" italics added (Gibbs et al., 1990: 1275).

After Gibbs et al. were able to show conclusively in 1990 that the Mission cattle Texas had indeed been infected with scrapie, the USDA repeated the experiment at an ARS (Agricultural Research Service) facility in Ames, Iowa under the direction of Randall Cutlip. Dr. Cutlip's results mirrored those found in the earlier study: some of the cows inoculated with scrapie did die of a TSE, but they did not exhibit behaviors associated with "mad cow" disease in Britain (i.e. British BSE). Rather, the behavior is more subtle and could be mistaken as "downer cow." As Cutlip et al. concluded, "Thus, undiagnosed scrapie infection could contribute to the 'downer-cow' syndrome [in the U.S.]" (Cutlip et al., 1994: 814).

BSE Surveillance Program

In sum, the indirect evidence from the TME studies, as well as from the scrapie-inoculated cattle studies, points to the existence of a native bovine TSE in downer cows in the U.S.

This native BSE could arise spontaneously in cattle; it seems unlikely that all cases are linked to scrapie. But USDA's Surveillance has only recently started looking at downer cows. In 1965, Drs. Burger and Hartsough were hypothesizing the existence of a native BSE strain in the US that could be hiding in the downer cow population. In 1987, Dr. Marsh began hypothesizing the same thing and calling on USDA to look at downer cows for potential TSEs. By 1990, even NIH (in the person of Dr. Clarence Gibbs) was calling for testing of downer cows for the presence of the mutant prion using an immunohistochemical probe (Gibbs et al., 1990). The same year, USDA set up an advisory committee called the Scrapie/BSE consultants committee. Dr. Richard Marsh was one of the members. This committee designed and began the BSE monitoring program done by the USDA.

At the start, the BSE Monitoring program did not look at brains from downer cows. There were two selection criteria for animals to be chosen for testing. First were rabies-suspect but rabies negative cattle. Second were animals that had gotten at least two years worth of animal protein (energy-dense feeds) in the diet and had died of obvious neurologic symptoms. Dr. Marsh argued that the CNS symptomology exhibited by "downer cows" would go unrecognized by these two selection screens and therefore argued that downer cows be added to the selection criteria. For at least two years, 1991 and 1992, the committee declined to follow Dr. Marsh's suggestion. At approximately the same time, Dr. Marsh was trying to secure funding to sample downer cows and test them, both pathologically and imuunohistologically, for evidence of a TSE. In the early 1990s, Dr. Marsh submitted grant proposals for two years in a row to USDA; both proposals were turned down.

The net result has been that very few downer cows have been included in the BSE Surveillance program. They were first included in the program in 1996. As of January 23, 1997, some 5,342 cattle brains had been tested. Yet only a couple hundred of the brains came from downer cows. While we applaud USDA for finally deciding to include downer cows in their surveillance, USDA needs to focus more strongly on the downer cows.

Given that the USDA tested only 1,000 cows for BSE in 1999 and 2,000 cows in 2000 -- this is a miniscule number. Also, the number of downer cows examined out of the 2,000 test is even smaller. Remember that it's commonly expected that 100,000 U.S. cows are "downer cows" each year, meaning the U.S. is testing a fraction of a percent of this population.

Since the USDA has not publicly admitted that we could have a native bovine TSE already present in the US, the BSE Surveillance program has focused on looking for British-style BSE.

The USDA must admit that there is a strong likelihood that a native TSE exists in US cattle. Once the USDA makes this admission, the other changes needed in the Surveillance program will logically follow. First, the veterinarians and pathologists who are looking at the brain samples have been trained with slides and materials from British cattle with BSE, so that they are looking for the characteristics of the British strain of BSE. The brain damage characterisitic of British style BSE is easily seen as there is lots of vacuolization of the nerves.

However, the work of the USDA and ARS on transmission of US scrapie to cattle suggest that a US strain of a TSE in cattle probably could show only subtle changes in brain morphology with very little, if any, vacuolization of nerves. Thus, the U.S. vets may not may not be looking for the right brain characteristics. Consequently, vets should be trained using materials that show TSEs with subtle characteristics, such as the pathology slides from the three affected cattle from the original Mission, Texas studies or from the affected cattle in Dr. Cutlip et al.'s repeat study. Furthermore, USDA should make greater use of the immunohistochemical probe. Indeed, all suspect brains should be examined using the probe.

In addition, the USDA needs to focus more heavily on the downer cow population. At present, only a few of hundred downer cows have been examined. This is completely inadequate. If the disease were occuring at a rate of one in 1,000 animals, it might not show up at all in this sample. Yet this is a rate that would be of great public health concern. Likewise, there are approximately 100,000 downer cows each year in the US (Marsh, 1992). If just one-half of one percent (0.5%) of these cows had a TSE, that would mean 500 infected cows. One would have to look at 5,000 cows just to see 25 cases.

Consequently, we believe that USDA should expand the BSE Surveillance Program, modify the selection criteria and focus far more heavily on downer cows. In fact, the major selection criterion should be downer cows. For example, USDA could try to sample at least 500-1,000 downer cows every year. Furthermore, among downer cows, USDA should focus on those that exhibit CNS symptoms and not downer cows that have broken legs, milk fever, etc. The USDA could also focus on states which make the largest use of rendered ruminant protein in their cattle feed and that have some of the oldest cows. This would mean focusing on the larger dairy states such as Wisconsin, California and New York.

Adapted from Michael K. Hansen, Ph.D., Research Associate Consumer's Union letter to USDA.

References

Bobowick, A.R., Brody, J.A., Matthews, M.R., Roos, R. and D.C. Gajdusek. 1973. Creutzfeldt-Jakob disease: A case-control study. American Journal of Epidemiology 98: 381-394.

Boller, F., Lopez, O.L. and J. Moossy. 1989. Diagnosis of dementia: Clinicopathologic correlations. Neurology, 39: 76-79.

Davanipour, Z., Alter, M., Sobel, E., Asher, D.M. and D.C. Gajdusek. 1989. A case-control study of Creutzfeldt-Jakob disease: Dietary risk factors. American Journal of Epidemiology 122: 433-451.

Detwiler, L.A. 1992. Scrapie, Revue Scientifique et Technique. Office Internationale Epizootics, 11(2): 491-537.

Gibbs, C.J., Safar, J., Ceroni, M., Di Martino, A., Clark, W.W. and J.L. Hourrigan. 1990. Experimental transmission of scrapie to cattle. Lancet, 335: 1275.

-------------- 1997. Statement to the Committee on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations, U.S. House of Representatives. January 29, 1997.

Hadlow, W.J. 1996. Letter to Patrick McCaskey, USDA/FSIS/Eastern Lab, dated November 10, 1996.

--------------------1997. Letter to Patrick McCaskey, USDA/FSIS/Eastern Lab, dated April 10, 1997.

Hartsough, G.R. and D. Burger. 1966a. Encephalopathy of mink. I. Epizootiologic and clinical observations. Journal of Infectious Diseases 115: 387-392.

----------------------------------------------------b. Encephalopathy of mink. II. Experimental and natural transmission. Journal of Infectious Diseases 115: 393-399.

Manuelidis, E.F. and L. Manuelidis. 1989. Suggested links between different types of dementias: Creutzfeldt-Jakob disease, Alzheimer disease, and rteroviral CNS infections. Alzheimer Disease and Associated Disorders, 2: 100-109.

Marsh, R.F. 1992. Transmissible mink encephalopathy, scrapie and downer cow disease: potential links. paper presented at the Third International Workshop on Bovine Spongiform Encephalopathy, Bethesda, Maryland, December 9-10, 1992. 7 pp.

----------------, Bessen, R.A., Lehmann, S. and G.R. Hartsough. 1991. Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. Journal of Genetics and Virology, 72: 589-594.

VegSource Articles on Mad Cow:

Read USDA Mad Cow Strategy: Don't Look, Don't Find
Read Cattlemen Respond to Article
Read Dr. Moser of Prionics Responds to Cattlemen
Read Mad Cow Disease: Is the U.S. a different case than Europe?
Read U.S. Version of "Mad Cow" Known to Authorities Since 1960's
Editorial The Unthinkable: Alzheimers Caused by Meat?

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以下はさらなる追加文献です

「Bartz JC, Bessen RA, McKenzie D, Marsh RF, Aiken JM. Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. J Virol. 2000 Jun;74(12):5542-7.

Robinson MM, Hadlow WJ, Knowles DP, Huff TP, Lacy PA, Marsh RF, Gorham JR. Experimental infection of cattle with the agents of transmissible mink encephalopathy and scrapie. J Comp Pathol. 1995 Oct;113(3):241-51.

Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol. 1994 Dec;68(12):7859-68.

Bartz JC, McKenzie DI, Bessen RA, Marsh RF, Aiken JM. Transmissible mink encephalopathy species barrier effect between ferret and mink: PrP gene and protein analysis. J Gen Virol. 1994 Nov;75 ( Pt 11):2947-53

Marsh RF, Bessen RA. Physicochemical and biological characterizations of distinct strains of the transmissible mink encephalopathy agent. Philos Trans R Soc Lond B Biol Sci. 1994 Mar 29;343(1306):413-4.

Guiroy DC, Marsh RF, Yanagihara R, Gajdusek DC. Immunolocalization of scrapie amyloid in non-congophilic, non-birefringent deposits in golden Syrian hamsters with experimental transmissible mink encephalopathy. Neurosci Lett. 1993 May 28;155(1):112-5.

Marsh RF, Bessen RA. Epidemiologic and experimental studies on transmissible mink encephalopathy. Dev Biol Stand. 1993;80:111-8.

Marsh RF, Hadlow WJ. Transmissible mink encephalopathy. Rev Sci Tech. 1992 Jun;11(2):539-50. Review. 」

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