Transmissible mink encephalopathy - review of the etiology
Folia Neuropathologica 2/2009
full text of the article:
Transmissible mink encephalopathy – review of the etiology
Folia Neuropathol 2009; 47 (2): 195-204
authors: Pawel P. Liberski, Beata Sikorska, Don Guiroy, Richard A. Bessen,
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Folia Neuropathologica 2/2009
full text of the article:
Transmissible mink encephalopathy – review of the etiology
Folia Neuropathol 2009; 47 (2): 195-204
authors: Pawel P. Liberski, Beata Sikorska, Don Guiroy, Richard A. Bessen,
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History of TME
Transmissible mink encephalopathy (TME) is a rare disease of ranch-reared mink (Mustela vision) (Fig. 1) described in 1965 by Hartsough and Burger [15,28]. The first outbreak was noticed in 1947 in a farm in Brown County, Wisconsin, USA and fatality reached almost 100% of the adult mink. Insight into the nature of infection was evident when over 100 pregnant dams sent to another farm in Winona County eventually developed TME, but mink at the recipient ranch did not. This was the first indication that TME was self-limiting and had an incubation period of at least six months. A second TME outbreak occurred simultaneously in several farms in Sheboygan, Calumet and Manitowoc Counties, Wisconsin in 1961. Symptoms were similar to the first outbreak, but the prevalence of TME was limited to 10 to 30% of adult mink among the farms [35]. All of the affected farms were using a ready-mix feed prepared at a common feed plant, demonstrating that TME was likely due to an orally acquired infectious agent. This was followed by another outbreak in 1963 in Sawyer County. A similar pattern emerged with nearly 100% of the 1,100 adult mink affected, but the 4,500 kits did not develop symptoms of TME. There was no evidence of vertical transmission, even to kits that nursed on dams with advanced TME. The term “transmissible mink encephalopathy” was subsequently introduced by Marsh et al. [34] to describe this disease that primarily affects adult mink over one year of age, has an incubation period of at least 6 months, and clinical and neuropathological similarities to scrapie, a fatal neurodegenerative disease in sheep. Fewer than a dozen additional outbreaks of TME have been described in Canada, East Germany, Finland, and the former Soviet Union [1].
The last outbreak of TME was described in 1985 in Stetsonville, Wisconsin, USA [32] and more than 4,300 out of 7,300 adult mink developed TME over a 5-month period, but 600 blue iris kits purchased six months prior to the onset of TME or kits born at this ranch were not affected. This pattern was consistent with previous outbreaks in which exposure to prion/ TSE infection took place from 6 to 12 months prior to clinical symptoms, was due to a single exposure of infection, and affected a large number of mink.
Etiology
TME is an orally acquired TSE/prion disease, but the etiology is uncertain. TME was initially thought to be transmitted by consumption of sheep carcasses or by-products due to similarities between the diseases, but only in one case were sheep products (e.g., heads) linked to mink diet. Although it cannot be conclusively demonstrated that sheep products were not the source of TME, the inclusion of sheep products in mink feed was demonstrated only rarely [35]. Experimental inoculation of mink with several isolates of scrapie resulted in a few examples of transmission to mink in which the distribution of spongiform lesions was similar to natural TME [39]. Seven sources of scrapie from the U.K. were intracerebrally inoculated into 24 mink kits, but only one mink developed TME after 22 months. Three U.S. scrapie isolates inoculated into 16 kits resulted in 100% penetrance with incubation periods ranging from 11 to 24 months. While this indicates that mink are susceptible to TME, it also suggests that the isolates tested were not likely to be the origin of TME since incubation periods are typically less than one year in natural TME. This indicated that either a subset of scrapie strains are the causative agent of TME or that there is an additional unrecognized source of TME.
A possible clue was provided during the Stetsonville TME outbreak in which the rancher fed his mink commercial feed (e.g., poultry, fish, cereal) and fresh meat primarily from sick or downer dairy cattle within a 50-mile radius of his ranch [37]. He did not recall including sheep products in his homemade feed ration. Upon reviewing prior TME outbreaks in the U.S. and Canada, in all four cases in which records were available and were not linked to a commercial feed plant, downer cattle were also included in the mink diet. The Stetsonville TME isolate, and subsequently additional TME isolates, were transmitted to cattle by intracerebral inoculation and the Stetsonville TME isolate was the first confirmed case of experimental transmission of a TSE/prion disease to cattle. What was striking was that upon experimental transmission of cattle TME back into mink by the oral and intracerebral routes, the incubation periods were similar to that found for mink passaged TME. Hence, the pathogenicity of the Stetsonville TME agent in mink was not altered upon passage into cattle, suggesting that a previously unrecognized TSE/prion disease in cattle may be the source of TME infection. Additional studies strongly suggest that TME has similarities to L-type BSE in transgenic mice compared to H-type or classical BSE [2]. Since the L-type BSE does not appear to be an infectious form of TSE/prion disease, the proposal by Marsh [35,37] that a rare TSE in cattle may be the source of TME infection seems plausible. This is particularly the case in Wisconsin, which has had the majority of TME in the USA and is a prominent dairy state with aged cattle being a primary source of fresh meat for mink ration. Since mink are a sentinel host it is not surprising that they may have been a key host in amplifying a rare cattle TSE disease. Another possible explanation for the high incidence of TME in Wisconsin is based on the recent identification of a mutation in the prion protein gene in cattle with atypical BSE. There may be cattle breeding stock in Wisconsin that carry a mutation in the prion protein gene that is linked to late onset disease and are also the source of TSE infection for mink TME outbreaks described in the 1960s and 1985.
To this end, mink were shown to be sensitive to scrapie [23,24]. Of interest, following i.c. inoculation with the UK source of scrapie from a Suffolk sheep only a single animal developed the disease. In contrast, American sources B-834 and B-957 from Suffolk sheep readily transmitted to mink. Also, in another outbreak of TME in Stetsonville, Wisconsin, USA, the affected mink were apparently fed with downer cattle but not scrapie-affected sheep [32], and thus TME may result from BSE transmission from cattle to mink [37]. TME is readily transmitted to cattle [26]. The suggestion that TME may result from transmission from infected cattle but not sheep was supported by recent data on phenotypic similarities of TME in cattle and L-type bovine spongiform encephalopathy (BSE) transmitted to ovine transgenic mice (TgOvPrP4) [2]. To this end, L-type of BSE and TME in TgOvPrP4 presented similar molecular mass of all 3 bands of PrPd. Unglycosylated PrPd in L-type BSE, bovine TME and typical BSE has the same molecular mass of approximately 18 kDa in contrast to that of diglycosylated PrPd species which was lower by 0.5-0.8 kDa in L-type BSE and bovine TME as compared to typical BSE. Furthermore, L-type BSE and bovine TME transmitted to TgOvPrP4 mice presented spongiform change of low intensity but PrPd was strongly expressed including amyloid plaques. Mink were also susceptible to BSE [44]. Exposure by the oral route was ineffective but Marsh and Hanson [35] cited Gajdusek [20] who, in turn, suggested that not the oral route as such but skin and mucosa abrasion are the real port of entry of the agent. The hypothesis was tested experimentally by subcutaneous inoculation of pastel mink with the Idaho source of TME [23]. The infectivity spread from the lymph nodes draining the site of the inoculation (1-4 weeks postinoculation, PI), through the other lymph nodes (98-12 weeks PI, the level 103.0 – 4.0 LD50) to the nervous system stage at 20 week PI (103.0 – 4.5 LD50) to reach the maximum at approximately 28 weeks PI. The sciatic nerve was first affected. The infectivity was detected in both the blood and the thymus, which suggests blood-borne infection. Analogously to scrapie, when the HY TME agent was inoculated into sciatic nerves, hamsters segregated into 2 groups – with a short and a long incubation time [5]. PrPd was first detected in the thoracic spinal cord and then spread rostrally toward the cervical cord. In the brain, PrPd was first detected in the red nucleus, first unilaterally and then bilaterally.
Clinical and neuropathological studies in mink
Clinical description
In the first report by Hartsough and Burger [28], the clinical symptomatology of TME was described in detail. The onset was insidious and animals lost their cleanliness and soiled the boxes with urine and feces. Difficulties in swallowing and eating, excitability and tail arching over the back were noticed. Incoordination followed and typical “jerky stepping action of the hind legs” developed along with epileptic seizures and self-mutilation. The clinical course was longer in females (2 to 6 weeks) than males.
Neuropathology and immunohistochemistry
The first description of TME neuropathology was also descried by Hartsough and Burger [28], who noticed neuronal degeneration and spongiform change (Figs. 2-4). Those authors also stressed similarities with scrapie. However, in TME transmitted to aged mink of the Chediak-Higashi genotype, the spongiform change may be minimal or even absent [40].
Eckroade et al. [10] described the topography of lesions in experimental TME and the sequential development of those lesions following intracerebral inoculation with TME. The incubation period was approximately 31-33 weeks. Spongiform change was severe in the cerebral cortex and an anterior-posterior gradient was observed; the most severe vacuolation was seen in the gyri bordering the cruciate sulcus and within the anterior and the posterior sigmoid gyrus. In the posterior part of the brain, the lesions were minimal. The other parts of the telencephalon were severely affected – caudate nucleus, anterior olfactory tubercle, septal nuclei and putamen – while the globus pallidus was less affected. The diencephalon was affected severely and the hypothalamus was more uniformly vacuolated than the thalamus. The mesencephalon was vacuolated, especially the periaqueductal gray matter. The red nucleus was affected by bizarre intraneuronal vacuoles of great size. The pons, medulla and spinal cord were affected moderately at least.
The earliest spongiform change were observed in the anterior part of the brain 24 weeks postinoculation, sometimes as isolated foci of vacuolation in the cerebral cortex (along the cruciate sulcus) and the thalamus. The caudate nucleus, the periaqueductal gray matter, the central tegmental field of the mesencephalon and the pons were affected minimally at first. Then, spongiform change spread to other neuroanatomical areas; the spreading along the cruciate sulcus was the most rapid.
As already mentioned, from the original Stetsonville TME inoculum, two different strains of TME emerged, i.e. HY and DY, and they differ by topography of lesions [32].The HY strain was characterized by moderate to severe spongiform change in the brain stem, the granule layer of the cerebellum, thalamus, the basal ganglia and the cerebral cortex. In contrast, the DY strain exhibited less severe spongiform change in the brain stem and the cerebellum but more intense vacuolation in the cerebral cortex. The most characteristic lesion of the DY strain in hamsters was focal accumulation of large vacuoles surrounding the pyramidal cell layer of the hippocampus.
The first immunohistochemical studies of TME were published from the laboratory of Gajdusek [2], who used TME-affected mink, TME-infected golden Syrian hamsters and TME-affected squirrel monkeys and ferrets. In sections stained routinely with H & E, typical spongiform change are visible (Fig. 5). Immunohistochemistry for GFAP revealed abundant reactive astrocytic gliosis (Figs. 6-11). Anti-PrP antibodies revealed many different forms of misfolded PrP deposits: plaques (Fig. 9), perineuronal (Fig. 10) and subependymal (Fig. 11) deposits as well as diffuse staining in the cerebellum (Fig. 12) and the hippocampal formation (Fig. 13).
Laser confocal microscopy
Double labeling for both PrPSc and GFAP revealed co-localization of both proteins (Figs. 14-15). For immunofluorescent labeling and multichannel confocal microscopy we used mouse anti-PrP monoclonal antibody (clone 3F4, DAKO, Denmark, dilution 1 : 300) and rabbit anti-GFAP polyclonal antibody (DAKO, Denmark, dilution 1:250). The fluorescent-labeled secondary antibody for the anti-PrP was Alexa Fluor 488 goat anti-mouse IgG (Molecular Probes, USA, 1 : 200) and for anti-GFAP Alexa Fluor 546 goat anti-rabbit IgG (Molecular Probes, 1 : 200). Immunofluorescence labeling was evaluated using an Olympus FluoView1000 laser scanning confocal microscope.
Transmission to different species
The first transmission of TME from mink to mink using intramuscular inoculation, with the incubation period of 183 to 197 days, was performed by Burger and Hartsough [15,28]. Mink infected orally also developed TME. Neuropathological examination revealed astrocytosis and spongiform change. Of note, using filtration, the size of the infectious agent was estimated to be lower than 500 nm.
TME is transmissible to several mammalian species. TME is transmissible to sheep and goats [23], hamsters [36,38], skunks, ferrets and raccoons [17,25,27], American sable (pine marten) and beech marten [26], and squirrel monkeys [18]. The transmission of TME from the Stetsonville source to ferrets resulted in a long incubation period of 28 to 38 months on the primary, and 8 to 9 months on the secondary passage [6]. In contrast, TME was never transmitted to mice [10,34,36,45]. However, TME is readily transmitted to transgenic mice with mink PrP gene [45]. Kimberlin et al. [29] isolated two strains of TME in Chinese hamsters (333K and 333W) that were readily discriminated by the incubation time (130 and 230 days, respectively).
Cloning of the PRNP gene in mink and ferrets
The gene encoding for PrPTME was cloned by Kretzschmar et al. [31]. The open reading frame (ORF) consists of 770 nucleotides (nts) follow by a 3’ untranslated sequence of 1650 nt. The deduced mink PrPTME consists of 257 amino acids (aa); the first 24 aa form a signal peptide. There are two Asp glycosylation sites at positions 185 and 201. Of interest, the “anti-PrP” sequence on the anti-sense DNA strand is interrupted by several stop codons, in contrast to the “anti-PrP” sequence of several other species. The closest species of the mustelids belonging to the weasel family are ferrets, whose PrP gene is one nt longer than that of the mink gene [6]. There are seven differences between ferret and mink PrP gene – 84 (C to A); 231(A to T); 327 (T to C); 354 (T to A), 375 (T to C); 671 (A to G) and 747 (G to A) – but only two differences at the level of aa: 179 (Leu to Phe) and 224 (Glu to Arg).
Molecular biology of TME
The early studies by Marsh et al. [36,41] and others [14] confirmed that the physicochemical properties of the TME agent are similar to those of the scrapie agent. In particular, the TME agent is resistant to formalin: after 4-month exposure the titer dropped from 104.8 ip LD50/ml to 106.5 ip LD50/ml and to 103.8 ip LD50/ml following 20 months.
Molecular basis of TME strain diversity
Experimental transmission of Stetsonville TME into Syrian golden hamsters resulted in the identification of two hamster TME strains upon the third serial passage [33]. One strain had an incubation period of 65 days and was characterized by hyper-excitability (HY TME strain) and tremor of the head and shoulders, while DY (drowsy) TME strain caused progressive lethargy and drowsiness beginning at 168 days post-inoculation. The HY TME strain replicated to a 100-fold higher titer than the DY TME strain in hamster brain, while following additional serial passage, the DY TME strain remained pathogenic upon passage into mink, while the HY TME strain lost its pathogenicity in mink. These findings were consistent with the isolation of two distinct strains of the TME agent upon interspecies passage in hamsters. Additional studies demonstrated that either both TME strains were present in the original Stetsonville TME isolate, or that the short incubation HY TME strain arose upon passage into hamsters and was preferentially selected for since it can replicate faster than DY TME. Serial passage of Stetsonville TME into hamsters at a high dilution resulted in isolation of only the DY TME strain, indicating that this was likely the predominant strain isolated from mink.
Although the HY and DY TME strains were consistent with previous studies that have identified two or more TSE strains upon interspecies transmission, the TME strains also provided the first clues as to the molecular basis of TSE strain diversity [8,9,11,12]. The molecular profiles of PrPTME polypeptides revealed a 1-2 kDa shift in molecular weight following limited proteinase K (PK) treatment (21 kDa vs. 19 kDa), which removes the PK-sensitive N-terminal portion. N-terminal sequencing revealed that PK cleaved further into the N-terminus of DY TME compared to HY TME, which suggested that the two TME strains may have distinct conformations. Differences in sedimentation properties and relative susceptibility to degradation with PK were consistent with this hypothesis. Infrared spectra of the TME PrPSc demonstrated differences in the b-sheet secondary structure content, providing further evidence that these TSE strains had distinct conformations. The ability of these two distinct PrPSc conformations to self-propagate was also demonstrated in an in vitro assay when they were individually incubated with PrPC and the HY TME PrPSc converted PrPC into a 21 kDa PK-resistant PrP, while DY TME PrPSc converted PrPC into a 19 kDa PK-resistant PrP [7,30]. In this cell-free PrP conversion assay, the kinetics of PK-resistant PrP formation was also different between the TME strains, which was consistent with a strain-specific pattern of PrPTME formation in vivo. Overall, these studies suggested that the molecular basis of TME strain diversity is determined by the strain-specific conformation of PrPTME and that each PrPSc conformation can convert the same PrPC molecule into a strain-specific subunit of the PrPSc fibril or aggregate. The formation of each PrPTME conformation may be preferentially favored under specific cellular or subcellular conditions, and the brain distribution of PrPTME may be partially determined by the preferred sites of strain PrPTME formation. Partial evidence for this is provided by the observation that the DY TME strain does not appear to be able to replicate in secondary lymphoid tissue, while the HY TME strain can replicate in lymph nodes and spleen.
Using an in vitro PrPc to PrPd (TME) conversion reaction [7,10,13,30] it was shown that the conversion is “strain-specific”, i.e. HY PrPd only converted PrPc into HY PrPd, and DY PrPd only converted PrPc into DY PrPd. This experiment suggested that certain strain-specificity is encrypted within the conformation of PrPd itself, which, in turn, determines the site of proteinase cleavage and strain-specific size of PrP fragments using Western immunoblot. However, the size of PrPd (either 19 kDa or 21 kDa) is exactly the same as the size of deglycosylated bands purified from human CJD. This may suggest that irrespective of the situation, PrPd may exist only in two major isoforms of 19 kDa and 21 kDa. Whether there are only two strains of every “prion” disease is, in our mind, doubtful.
In a separate study, Mulcahy and Bessen [43] found that conversion of PrPc into PrPd consists of three phases – elongation, depolymerization, and steady-stage phase – and that the elongation phase is that in which strain-specific differences are observed. Those differences between HY and DY strains are the total amount of PrPTME and the time when the reaction peaked. Furthermore, a vast difference in the kinetics of PrPTME accumulation was observed in hamster brains infected with either DY or HY TME strains.
It seems that both DY and HY TME strains are already present as a mixture in the original Stetsonville inoculum and during subsequent passages undergo selection during interspecies transmission [3]. For instance, one of the 4 clones passaged into Syrian golden hamsters bifurcated into a strain characterized by an incubation period ranging from 219 to 522 days and the PrP banding pattern typical of the DY strain of mink, and a second strain with an incubation period of 219 days and PrP pattern that of the DY strain. Upon further passages into hamsters, the incubation periods decreased, the emerging “strain” presented a mixture of HY and DY strains only on subsequent passages, distinct DY strain emerged, and from that, the HY TME strain was selected.
References
1. Barlow RM. Transmissible mink encephalopathy: pathogenesis and nature of aetiological agent. J Clin Pathol 1972; 6 (Suppl): 102-109.
2. Baron T, Bencsik A, Bicabe A-G, Morignat E, Bessen RA. Phenotypic similarity of transmissible mink encephalopathy in cattle and L-type bovine spongiform encephalopathy in a mouse model. Emerging Inf Dis 2007; 13: 1887-1894.
3. Bartz JC, Bessen RA, McKenzie D, Marsh DC, Aiken J. Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. J Virol 2000; 74: 5542-5547.
4. Bartz JC, DeJoia C, Tucker T, Kincaid AE, Bessen RA Extraneural prion neuroinvasion without lymphoreticular system infection. J Virol 2005; 79: 11858-11863.
5. Bartz JC, Kincaid RA, Bessen RA. Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol 2002; 76: 5759-5768.
6. 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; 75: 2947-2953.
7. Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 1995; 22: 698-700.
8. Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 1994; 66: 2096-2101.
9. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis for strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859-7868.
10. Bessen RA, Marsh RF. Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 1992; 73: 329-334.
11. Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 1992; 66: 2096-2101.
12. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859-7868.
13. Bessen RA, Raymond GJ, Caughey B. In situ formation of protease-resistant prion protein in transmissible spongiform encephalopathy-infected brain slices. J Biol Chem 1997; 272: 15227-15231.
14. Burger D, Gorham JR. Observation on the remarkable stability of transmissible mink encephalopathy virus. Res Vet Sci 1977; 22: 131-132.
15. Burger D, Hartsough GR. Transmissible Encephalopathy of Mink. In: Gajdusek DC, Gibbs CJ Jr, Alpers MP (eds.). NINDB Monograph No.2, Slow, Latent and Temperate Virus Infections. US DEPT of Health, Education, and Welfare, Washington 1965; pp 297-306.
16. Caughey B, Raymond GR, Bessen RA Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem 1998; 273: 32230-32235.
17. Eckroade RJ, ZuRhein GM, Hanson RP. Transmissible mink encephalopathy in carnivores: clinical, light, and electron microscopic studies in raccoons, skunks, and ferrets. J Wildlife Dis 1973; 9: 229-239.
18. Eckroade RJ, ZuRhein GM, Marsh CD, Hanson RP. Transmissible mink encephalopathy: experimental transmission to the squirrel monkey. Science 1970; 169: 1088-1090.
19. Ecroade RJ, ZuRhein GM, Hanson RP. Experimental transmissible mink encephalopathy: Brain lesions and their sequential development on mink. In: Prusiner SB, Hadlow WJ (eds.). Slow Transmissible Diseases of the Nervous System, Vol. 1, Academic Press, New York; 409-449.
20. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977; 197: 943-960.
21. 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 Letters 1993; 155: 112-115.
22. Hadlow WJ, Race RE, Kenendy RC. Temporal distribution of transmissible mink encephalopathy virus in mink inoculate subcutaneously. J Virol 2004; 61: 3235-3240.
23. Hadlow WJ, Race RE, Kenendy RC. Experimental infection of sheep and goats with transmissible mink encephalopathy virus. Can J Vet Res 1987; 51: 135-144.
24. Hadlow WJ, Race RE. Cerebroscortical degeneration in goats inoculated with mink-passaged scrapie virus. Vet Pathol 1986; 23: 543-549.
25. Hamir AN, Heidel JR, Picton R, Rupprecht CE. Neuronal vacuolation in raccoons (Procyon lotor). Vet pathol 1997; 34: 250-252.
26. Hamir AN, Kunkle RA, Miller JM, Bartz JC, Richt JA. First and second cattle passage of transmissible mink encephalopathy by intracerebral inoculation. Vet Pathol 2006; 43: 118-126.
27. Hamir AN, Miller JM, O’Rourke KI, bartz JC, Stack MJ, Chaplin MJ. Transmission of transmissible mink encephalopathy to raccoons (Procyon lotor) by intracerebral inoculation. J Vet Diagn Invest 2004: 16: 57-63.
28. Hartsough GR, Burger D. Encephalopathy in mink. I. Epizootiologic and clinical observations. J Inf Dis 1965; 115: 387-392.
29. Kimberlin RH, Cole S, Walker CA. Transmissible mink encephalopathy (TME) in Chinese hamsters: identification of two strains of TME and comparisons with scrapie. Neuropathol appl Neurobiol 1975; 12: 197-206.
30. Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, Caughey B. Cell-free formation of protease-resistant prion protein. Nature 1994; 370: 471-4
31. Kretzschmar HA, Neumann M, Riethmüller G, Prusiner SB. Molecular cloning of a mink prion protein gene. J Gen Virol 1992; 73: 2757-2761.
32. Marsh RF, Bessen RA, Lehmann S, Hartsough GR Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. J Gen Virol 1991; 72: 589-594.
33. Marsh RF, Bessen RA. Physicochemical and biological characterizations of distinct strains of transmissible mink encephalopathy. Phil Trans Roy Soc London: Biol Sci 1994; 343: 413-414.
34. Marsh RF, Burger D, Eckroade R, ZuRhein GM, Hanson RP. A preliminary report on the experimental host range of the transmissible mink encephalopathy agent. J Inf Dis 1969; 120: 713-719.
35. Marsh RF, Hanson RP. On the origin of transmissible mink encephalopathy. In: Prusiner SB, Hadlow WJ (eds.). Slow Transmissible Diseases of the Nervous System, Vol. 1, Academic Press, New York; pp. 451-460.
36. Marsh RF, Hanson RP. Physical and chemical properties of the transmissible mink encephalopathy agent. J Virol 1969; 3: 176-180.
37. Marsh RF, Hartsough GR. Is there a scrapie-like diseases in cattle? In: Proc. of the 89th Annual Meeting of the US Animal Health Ass 1969; pp. 8-9.
38. Marsh RF, Kimberlin RH. Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology and pathogenesis. J Inf Dis 1975; 131: 104-110.
39. Marsh RF, Semancik JS, Medappa KC, Hanson RP, Rueckert RR. Scrapie and transmissible mink encephalopathy: search for infectious nucleic acid. J Virol 1974; 13: 993-996.
40. Marsh RF, Sipe JC, Morse SS, Hanson RP. Transmissible mink encephalopathy. Reduced spongiform degeneration in aged mink of the Chediak-Higashi genotype. Lab Invest 1976; 34: 381-386.
41. Marsh RF. Animal model of human disease. Kuru, Creutzfeldt-Jakob disease (Slow Virus Infection. Am J Pathol 1972; 69: 209-212.
42. Mckenzie D, Bartz JC, Marsh DC. Transmissible mink encephalopathy. Sem Virol 1996; 7: 201-206.
43. Mulcahy ER, Bessen RA. Strain-specific kinetics of prion protein formation in vitro and in vivo. J Biol Chem 2004; 279: 1643-1649.
44. Robinson MM, Hadlow WJ, Huff TP, Wells GAH, Dawson M, Marsh DC, Gorham JR. Experimental infection of mink with bovine spongiform encephalopathy. J Gen Virol 1994; 75: 2151-2155.
45. Taylor DM, Dickinson AG, Fraser H, Marsh RF. Evidence that transmissible mink encephalopathy agent is biologically inactive in mice. Neuropathol appl Neurobiol 1986; 12: 207-215.
46. Windl O, Buchholz M, Neubauer AN, Schulz-Schaeffer W, Groschup M, Walter S, Arendt A, Neumann M, Voss AK, Kretzschmar HA. Breaking an absolute species barrier: transgenic mice expressing the mink PrP gene are susceptible to transmissible mink encephalopathy. J Virol 2005; 79: 14971-14975.
http://www.termedia.pl/showpdf.php?article_id=12696&filename=Transmissible.pdf&priority=1
YES, I believe I have read that somewhere else before ;
Saturday, December 01, 2007
Saturday, January 24, 2009
NOW, back to those mad mink i.e. TME. let me throw a curve ball here ;
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Thierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* and Richard A. Bessen† Emerging Infectious
Transmissible mink encepholapathy (TME) is a foodborne transmissible spongiform encephalopathy (TSE) of ranch-raised mink; infection with a ruminant TSE has been proposed as the cause, but the precise origin of TME is unknown. To compare the phenotypes of each TSE, bovine- passaged TME isolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents (typical BSE, Htype BSE, and L-type BSE) were inoculated into an ovine transgenic mouse line (TgOvPrP4). Transgenic mice were susceptible to infection with bovine-passaged TME, typical BSE, and L-type BSE but not to H-type BSE. Based on survival periods, brain lesions profi les, disease-associated prion protein brain distribution, and biochemical properties of protease-resistant prion protein, typical BSE had a distint phenotype in ovine transgenic mice compared to L-type BSE and bovine TME. The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4 mice suggest that L-type BSE is a much more likely candidate for the origin of TME than is typical BSE. Transmissible mink encephalopathy (TME) is a rare prion disease in ranch-raised mink (Mustela vison) in North America and Europe (1–4). Six outbreaks have been reported from 1947 through 1985 in North America, and several have been linked to contaminated commercial feed (1). Although contamination of feed with scrapie-infected sheep parts has been proposed as the cause of TME, the origin of the disease remains elusive. The idea that scrapie in sheep may be a source of TME infection is supported by fi ndings that scrapie-infected mink have a similar distribution of vacuolar pathologic features in the brain and the same clinical signs as mink with natural and experimental TME (5). However, mink are not susceptible to scrapie infection following oral exposure for up to 4 years postinoculation, which suggests that either the scrapie agent may not be the source of natural TME infection or that only specifi c strains of the scrapie agent are able to induce TME (6,7). Epidemiologic investigations in the Stetsonville, Wisconsin, outbreak of TME in 1985 suggested a possible cattle origin, since mink were primarily fed downer or dead dairy cattle but not sheep products (8). Experimental transmission of Stetsonville TME into cattle resulted in transmissible spongiform encephalopathy (TSE) disease with an incubation period of 18.5 months. Back passage of bovine TME into mink resulted in incubation periods of 4 and 7 months after oral or intracerebral inoculation, respectively, which was similar to that found following inoculation of Stetsonville TME into mink by these same routes (8). These fi ndings indicated that cattle are susceptible to TME, and that bovine-passaged TME did not result in a reduced pathogenicity for mink. These studies raised the question as to whether an unknown TSE in cattle was the source of TME infection in the Stetsonville outbreak. Several additional TME outbreaks in the United States have been associated with mink diet that contained downer or dead cattle (9). ...
snip...full text ;
http://www.cdc.gov/EID/content/13/12/pdfs/1887.pdf
http://transmissible-mink-encephalopathy.blogspot.com/
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
Saturday, December 01, 2007
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
http://transmissible-mink-encephalopathy.blogspot.com/2007/12/phenotypic-similarity-of-transmissible.html
To be published in the Proceedings of the Fourth International Scientific Congress in Fur Animal Production. Toronto, Canada, August 21-28, 1988
Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
•Department of Veterinary Science, University of Wisconsin-Madison, Madison, Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin 53092
ABSTRACT
Epidemiologic investigation of a new incidence of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin suggests that the disease may have resulted from feeding infected cattle to mink. This observation is supported by the transmission of a TME-like disease to experimentally inoculated cattle, and by the recent report of a new bovine spongiform encephalopathy in England.
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OBSERVATIONS AND RESULTS
A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville, Wisconsin reported that many of his mink were “acting funny”, and some had died. At this time, we visited the farm and found that approximately 10% of all adult mink were showing typical signs of TME: insidious onset characterized by subtle behavioral changes, loss of normal habits of cleanliness, deposition of droppings throughout the pen rather than in a single area, hyperexcitability, difficulty in chewing and swallowing, and tails arched over their _backs like squirrels. These signs were followed by progressive deterioration of neurologic function beginning with locomoior incoordination, long periods of somnolence in which the affected mink would stand motionless with its head in the corner of the cage, complete debilitation, and death.
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME. Since previous incidences of TME were associated with common or shared feeding practices, we obtained a careful history of feed ingredients used over the past 12-18 months. ***The rancher was a “dead stock” feeder using mostly (>95%) downer or dead dairy cattle and a few horses. Sheep had never been fed.***
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http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
Epidemiology Epidemiologic studies suggest that animals contract the disease by external exposure to the infectious agent, such as by eating contaminated feed. No evidence suggests that the TME agent spreads by contact between unrelated mink or from mother to nursing young. The disease has been identified in both genders and all color phases in animals greater than 1 year old. The first documented TME outbreak in the United States occurred in 1947 on one ranch in Wisconsin and then on a ranch in Minnesota that had received mink from the Wisconsin ranch. In 1961, TME outbreaks occurred on five ranches in Wisconsin. In Factsheet Veterinary Services February 2002 APHIS 1963, outbreaks occurred in Idaho, Minnesota, and Wisconsin. Epidemiologic data from the Minnesota and Wisconsin outbreaks trace the cases in those States to one common purchased food source.
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The 1985 Stetsonville Outbreak The most recent TME outbreak occurred on one mink ranch in Stetsonville, WI, in 1985. In the herd of 7,300 adult mink, 60 percent of the animals died. Clinical signs included tail arching, incoordination, and hyperexcitability. At the most advanced stages of the disease, the animals were in trancelike states and eventually died. The outbreak lasted 5 months. Microscopic examination of sections of the brain confirmed the spongelike changes characteristic of TME. Diagnostic tests identified the prion protein. The following year, mink born during the outbreak showed no signs of TME. The late Richard Marsh, a veterinary virologist at the University of Wisconsin who studied the transmission of TME and other TSE’s, investigated this outbreak. Marsh learned that the mink were fed a diet composed of fresh meat products from “downer cattle” and commercial sources of fish, poultry, and cereal. Downer cattle are nonambulatory and cannot rise because they are affected with a condition such as a metabolic disease, broken limbs, or a central nervous system disorder. Marsh theorized that the meat from these downer cattle introduced a TSE agent to the mink in which TME resulted. Although Marsh’s hypothesis is based on speculation and anecdotal evidence, in 1993 APHIS adjusted its national BSE surveillance program to include testing downer cattle for evidence of a TSE. The brains of more than 20,141 cattle have been examined at APHIS’ National Veterinary Services Laboratories and other State diagnostic laboratories. Not a single tissue sample has revealed evidence of BSE or another TSE in cattle.
http://www.aphis.usda.gov/publications/animal_health/content/printable_version/fs_ahtme.pdf
AND as everyone knows, the rest is history, those dead-stock downers, the most high risk cattle, were NOT tested, and in FACT, was a major source of YOUR CHILDRENS SCHOOL LUNCH PROGRAM, all across the Nation. sorry, these are the most high risk cattle for TSE aka mad cow disease, and i am a bit touchy about this topic. ... sorry. ...terry
DOWNER COW SCHOOL LUNCH PROGRAM
http://downercattle.blogspot.com/
IS THERE A SCRAPIE-LIKE DISEASE IN CATTLE ?
In April of 1985, a mink rancher in Wisconsin reported a debilitating neurologic disease in his herd which we diagnosed as TME by histopathologic findings confirmed by experimental transmission to mink and squirrel monkeys. The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle and a few horses. She had never been fed.
We believe that these findings may indicate the presence of a previously unrecognized scrapie-like disease in cattle and wish to alert dairy practitioners to this possibility.
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PROCEEDINGS OF THE SEVENTH ANNUAL WESTERN CONFERENCE FOR FOOD ANIMAL VETERINARY MEDICINE, University of Arizona, March 17-19, 1986
http://www.bseinquiry.gov.uk/files/mb/m09a/tab01.pdf
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
http://transmissible-mink-encephalopathy.blogspot.com/2007/12/phenotypic-similarity-of-transmissible.html
Wednesday, July 8, 2009
Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009 Aug; [Epub ahead of print]
http://nor-98.blogspot.com/2009/07/transgenic-mice-expressing-porcine.html
TSS
full text of the article:
Transmissible mink encephalopathy – review of the etiology
Folia Neuropathol 2009; 47 (2): 195-204
authors: Pawel P. Liberski, Beata Sikorska, Don Guiroy, Richard A. Bessen,
Archives of Medical Science
Videosurgery and Other Miniinvasive Techniques
Polish Journal of Pathology
Surgical and Vascular Nursing
Wielkopolska Izba Lekarska - Biuletyn Informacyjny
Medical Problems
Folia Neuropathologica 2/2009
full text of the article:
Transmissible mink encephalopathy – review of the etiology
Folia Neuropathol 2009; 47 (2): 195-204
authors: Pawel P. Liberski, Beata Sikorska, Don Guiroy, Richard A. Bessen,
inform friend about the article
documents in PDF format:
Transmissible.pdf [0.94 MB]
History of TME
Transmissible mink encephalopathy (TME) is a rare disease of ranch-reared mink (Mustela vision) (Fig. 1) described in 1965 by Hartsough and Burger [15,28]. The first outbreak was noticed in 1947 in a farm in Brown County, Wisconsin, USA and fatality reached almost 100% of the adult mink. Insight into the nature of infection was evident when over 100 pregnant dams sent to another farm in Winona County eventually developed TME, but mink at the recipient ranch did not. This was the first indication that TME was self-limiting and had an incubation period of at least six months. A second TME outbreak occurred simultaneously in several farms in Sheboygan, Calumet and Manitowoc Counties, Wisconsin in 1961. Symptoms were similar to the first outbreak, but the prevalence of TME was limited to 10 to 30% of adult mink among the farms [35]. All of the affected farms were using a ready-mix feed prepared at a common feed plant, demonstrating that TME was likely due to an orally acquired infectious agent. This was followed by another outbreak in 1963 in Sawyer County. A similar pattern emerged with nearly 100% of the 1,100 adult mink affected, but the 4,500 kits did not develop symptoms of TME. There was no evidence of vertical transmission, even to kits that nursed on dams with advanced TME. The term “transmissible mink encephalopathy” was subsequently introduced by Marsh et al. [34] to describe this disease that primarily affects adult mink over one year of age, has an incubation period of at least 6 months, and clinical and neuropathological similarities to scrapie, a fatal neurodegenerative disease in sheep. Fewer than a dozen additional outbreaks of TME have been described in Canada, East Germany, Finland, and the former Soviet Union [1].
The last outbreak of TME was described in 1985 in Stetsonville, Wisconsin, USA [32] and more than 4,300 out of 7,300 adult mink developed TME over a 5-month period, but 600 blue iris kits purchased six months prior to the onset of TME or kits born at this ranch were not affected. This pattern was consistent with previous outbreaks in which exposure to prion/ TSE infection took place from 6 to 12 months prior to clinical symptoms, was due to a single exposure of infection, and affected a large number of mink.
Etiology
TME is an orally acquired TSE/prion disease, but the etiology is uncertain. TME was initially thought to be transmitted by consumption of sheep carcasses or by-products due to similarities between the diseases, but only in one case were sheep products (e.g., heads) linked to mink diet. Although it cannot be conclusively demonstrated that sheep products were not the source of TME, the inclusion of sheep products in mink feed was demonstrated only rarely [35]. Experimental inoculation of mink with several isolates of scrapie resulted in a few examples of transmission to mink in which the distribution of spongiform lesions was similar to natural TME [39]. Seven sources of scrapie from the U.K. were intracerebrally inoculated into 24 mink kits, but only one mink developed TME after 22 months. Three U.S. scrapie isolates inoculated into 16 kits resulted in 100% penetrance with incubation periods ranging from 11 to 24 months. While this indicates that mink are susceptible to TME, it also suggests that the isolates tested were not likely to be the origin of TME since incubation periods are typically less than one year in natural TME. This indicated that either a subset of scrapie strains are the causative agent of TME or that there is an additional unrecognized source of TME.
A possible clue was provided during the Stetsonville TME outbreak in which the rancher fed his mink commercial feed (e.g., poultry, fish, cereal) and fresh meat primarily from sick or downer dairy cattle within a 50-mile radius of his ranch [37]. He did not recall including sheep products in his homemade feed ration. Upon reviewing prior TME outbreaks in the U.S. and Canada, in all four cases in which records were available and were not linked to a commercial feed plant, downer cattle were also included in the mink diet. The Stetsonville TME isolate, and subsequently additional TME isolates, were transmitted to cattle by intracerebral inoculation and the Stetsonville TME isolate was the first confirmed case of experimental transmission of a TSE/prion disease to cattle. What was striking was that upon experimental transmission of cattle TME back into mink by the oral and intracerebral routes, the incubation periods were similar to that found for mink passaged TME. Hence, the pathogenicity of the Stetsonville TME agent in mink was not altered upon passage into cattle, suggesting that a previously unrecognized TSE/prion disease in cattle may be the source of TME infection. Additional studies strongly suggest that TME has similarities to L-type BSE in transgenic mice compared to H-type or classical BSE [2]. Since the L-type BSE does not appear to be an infectious form of TSE/prion disease, the proposal by Marsh [35,37] that a rare TSE in cattle may be the source of TME infection seems plausible. This is particularly the case in Wisconsin, which has had the majority of TME in the USA and is a prominent dairy state with aged cattle being a primary source of fresh meat for mink ration. Since mink are a sentinel host it is not surprising that they may have been a key host in amplifying a rare cattle TSE disease. Another possible explanation for the high incidence of TME in Wisconsin is based on the recent identification of a mutation in the prion protein gene in cattle with atypical BSE. There may be cattle breeding stock in Wisconsin that carry a mutation in the prion protein gene that is linked to late onset disease and are also the source of TSE infection for mink TME outbreaks described in the 1960s and 1985.
To this end, mink were shown to be sensitive to scrapie [23,24]. Of interest, following i.c. inoculation with the UK source of scrapie from a Suffolk sheep only a single animal developed the disease. In contrast, American sources B-834 and B-957 from Suffolk sheep readily transmitted to mink. Also, in another outbreak of TME in Stetsonville, Wisconsin, USA, the affected mink were apparently fed with downer cattle but not scrapie-affected sheep [32], and thus TME may result from BSE transmission from cattle to mink [37]. TME is readily transmitted to cattle [26]. The suggestion that TME may result from transmission from infected cattle but not sheep was supported by recent data on phenotypic similarities of TME in cattle and L-type bovine spongiform encephalopathy (BSE) transmitted to ovine transgenic mice (TgOvPrP4) [2]. To this end, L-type of BSE and TME in TgOvPrP4 presented similar molecular mass of all 3 bands of PrPd. Unglycosylated PrPd in L-type BSE, bovine TME and typical BSE has the same molecular mass of approximately 18 kDa in contrast to that of diglycosylated PrPd species which was lower by 0.5-0.8 kDa in L-type BSE and bovine TME as compared to typical BSE. Furthermore, L-type BSE and bovine TME transmitted to TgOvPrP4 mice presented spongiform change of low intensity but PrPd was strongly expressed including amyloid plaques. Mink were also susceptible to BSE [44]. Exposure by the oral route was ineffective but Marsh and Hanson [35] cited Gajdusek [20] who, in turn, suggested that not the oral route as such but skin and mucosa abrasion are the real port of entry of the agent. The hypothesis was tested experimentally by subcutaneous inoculation of pastel mink with the Idaho source of TME [23]. The infectivity spread from the lymph nodes draining the site of the inoculation (1-4 weeks postinoculation, PI), through the other lymph nodes (98-12 weeks PI, the level 103.0 – 4.0 LD50) to the nervous system stage at 20 week PI (103.0 – 4.5 LD50) to reach the maximum at approximately 28 weeks PI. The sciatic nerve was first affected. The infectivity was detected in both the blood and the thymus, which suggests blood-borne infection. Analogously to scrapie, when the HY TME agent was inoculated into sciatic nerves, hamsters segregated into 2 groups – with a short and a long incubation time [5]. PrPd was first detected in the thoracic spinal cord and then spread rostrally toward the cervical cord. In the brain, PrPd was first detected in the red nucleus, first unilaterally and then bilaterally.
Clinical and neuropathological studies in mink
Clinical description
In the first report by Hartsough and Burger [28], the clinical symptomatology of TME was described in detail. The onset was insidious and animals lost their cleanliness and soiled the boxes with urine and feces. Difficulties in swallowing and eating, excitability and tail arching over the back were noticed. Incoordination followed and typical “jerky stepping action of the hind legs” developed along with epileptic seizures and self-mutilation. The clinical course was longer in females (2 to 6 weeks) than males.
Neuropathology and immunohistochemistry
The first description of TME neuropathology was also descried by Hartsough and Burger [28], who noticed neuronal degeneration and spongiform change (Figs. 2-4). Those authors also stressed similarities with scrapie. However, in TME transmitted to aged mink of the Chediak-Higashi genotype, the spongiform change may be minimal or even absent [40].
Eckroade et al. [10] described the topography of lesions in experimental TME and the sequential development of those lesions following intracerebral inoculation with TME. The incubation period was approximately 31-33 weeks. Spongiform change was severe in the cerebral cortex and an anterior-posterior gradient was observed; the most severe vacuolation was seen in the gyri bordering the cruciate sulcus and within the anterior and the posterior sigmoid gyrus. In the posterior part of the brain, the lesions were minimal. The other parts of the telencephalon were severely affected – caudate nucleus, anterior olfactory tubercle, septal nuclei and putamen – while the globus pallidus was less affected. The diencephalon was affected severely and the hypothalamus was more uniformly vacuolated than the thalamus. The mesencephalon was vacuolated, especially the periaqueductal gray matter. The red nucleus was affected by bizarre intraneuronal vacuoles of great size. The pons, medulla and spinal cord were affected moderately at least.
The earliest spongiform change were observed in the anterior part of the brain 24 weeks postinoculation, sometimes as isolated foci of vacuolation in the cerebral cortex (along the cruciate sulcus) and the thalamus. The caudate nucleus, the periaqueductal gray matter, the central tegmental field of the mesencephalon and the pons were affected minimally at first. Then, spongiform change spread to other neuroanatomical areas; the spreading along the cruciate sulcus was the most rapid.
As already mentioned, from the original Stetsonville TME inoculum, two different strains of TME emerged, i.e. HY and DY, and they differ by topography of lesions [32].The HY strain was characterized by moderate to severe spongiform change in the brain stem, the granule layer of the cerebellum, thalamus, the basal ganglia and the cerebral cortex. In contrast, the DY strain exhibited less severe spongiform change in the brain stem and the cerebellum but more intense vacuolation in the cerebral cortex. The most characteristic lesion of the DY strain in hamsters was focal accumulation of large vacuoles surrounding the pyramidal cell layer of the hippocampus.
The first immunohistochemical studies of TME were published from the laboratory of Gajdusek [2], who used TME-affected mink, TME-infected golden Syrian hamsters and TME-affected squirrel monkeys and ferrets. In sections stained routinely with H & E, typical spongiform change are visible (Fig. 5). Immunohistochemistry for GFAP revealed abundant reactive astrocytic gliosis (Figs. 6-11). Anti-PrP antibodies revealed many different forms of misfolded PrP deposits: plaques (Fig. 9), perineuronal (Fig. 10) and subependymal (Fig. 11) deposits as well as diffuse staining in the cerebellum (Fig. 12) and the hippocampal formation (Fig. 13).
Laser confocal microscopy
Double labeling for both PrPSc and GFAP revealed co-localization of both proteins (Figs. 14-15). For immunofluorescent labeling and multichannel confocal microscopy we used mouse anti-PrP monoclonal antibody (clone 3F4, DAKO, Denmark, dilution 1 : 300) and rabbit anti-GFAP polyclonal antibody (DAKO, Denmark, dilution 1:250). The fluorescent-labeled secondary antibody for the anti-PrP was Alexa Fluor 488 goat anti-mouse IgG (Molecular Probes, USA, 1 : 200) and for anti-GFAP Alexa Fluor 546 goat anti-rabbit IgG (Molecular Probes, 1 : 200). Immunofluorescence labeling was evaluated using an Olympus FluoView1000 laser scanning confocal microscope.
Transmission to different species
The first transmission of TME from mink to mink using intramuscular inoculation, with the incubation period of 183 to 197 days, was performed by Burger and Hartsough [15,28]. Mink infected orally also developed TME. Neuropathological examination revealed astrocytosis and spongiform change. Of note, using filtration, the size of the infectious agent was estimated to be lower than 500 nm.
TME is transmissible to several mammalian species. TME is transmissible to sheep and goats [23], hamsters [36,38], skunks, ferrets and raccoons [17,25,27], American sable (pine marten) and beech marten [26], and squirrel monkeys [18]. The transmission of TME from the Stetsonville source to ferrets resulted in a long incubation period of 28 to 38 months on the primary, and 8 to 9 months on the secondary passage [6]. In contrast, TME was never transmitted to mice [10,34,36,45]. However, TME is readily transmitted to transgenic mice with mink PrP gene [45]. Kimberlin et al. [29] isolated two strains of TME in Chinese hamsters (333K and 333W) that were readily discriminated by the incubation time (130 and 230 days, respectively).
Cloning of the PRNP gene in mink and ferrets
The gene encoding for PrPTME was cloned by Kretzschmar et al. [31]. The open reading frame (ORF) consists of 770 nucleotides (nts) follow by a 3’ untranslated sequence of 1650 nt. The deduced mink PrPTME consists of 257 amino acids (aa); the first 24 aa form a signal peptide. There are two Asp glycosylation sites at positions 185 and 201. Of interest, the “anti-PrP” sequence on the anti-sense DNA strand is interrupted by several stop codons, in contrast to the “anti-PrP” sequence of several other species. The closest species of the mustelids belonging to the weasel family are ferrets, whose PrP gene is one nt longer than that of the mink gene [6]. There are seven differences between ferret and mink PrP gene – 84 (C to A); 231(A to T); 327 (T to C); 354 (T to A), 375 (T to C); 671 (A to G) and 747 (G to A) – but only two differences at the level of aa: 179 (Leu to Phe) and 224 (Glu to Arg).
Molecular biology of TME
The early studies by Marsh et al. [36,41] and others [14] confirmed that the physicochemical properties of the TME agent are similar to those of the scrapie agent. In particular, the TME agent is resistant to formalin: after 4-month exposure the titer dropped from 104.8 ip LD50/ml to 106.5 ip LD50/ml and to 103.8 ip LD50/ml following 20 months.
Molecular basis of TME strain diversity
Experimental transmission of Stetsonville TME into Syrian golden hamsters resulted in the identification of two hamster TME strains upon the third serial passage [33]. One strain had an incubation period of 65 days and was characterized by hyper-excitability (HY TME strain) and tremor of the head and shoulders, while DY (drowsy) TME strain caused progressive lethargy and drowsiness beginning at 168 days post-inoculation. The HY TME strain replicated to a 100-fold higher titer than the DY TME strain in hamster brain, while following additional serial passage, the DY TME strain remained pathogenic upon passage into mink, while the HY TME strain lost its pathogenicity in mink. These findings were consistent with the isolation of two distinct strains of the TME agent upon interspecies passage in hamsters. Additional studies demonstrated that either both TME strains were present in the original Stetsonville TME isolate, or that the short incubation HY TME strain arose upon passage into hamsters and was preferentially selected for since it can replicate faster than DY TME. Serial passage of Stetsonville TME into hamsters at a high dilution resulted in isolation of only the DY TME strain, indicating that this was likely the predominant strain isolated from mink.
Although the HY and DY TME strains were consistent with previous studies that have identified two or more TSE strains upon interspecies transmission, the TME strains also provided the first clues as to the molecular basis of TSE strain diversity [8,9,11,12]. The molecular profiles of PrPTME polypeptides revealed a 1-2 kDa shift in molecular weight following limited proteinase K (PK) treatment (21 kDa vs. 19 kDa), which removes the PK-sensitive N-terminal portion. N-terminal sequencing revealed that PK cleaved further into the N-terminus of DY TME compared to HY TME, which suggested that the two TME strains may have distinct conformations. Differences in sedimentation properties and relative susceptibility to degradation with PK were consistent with this hypothesis. Infrared spectra of the TME PrPSc demonstrated differences in the b-sheet secondary structure content, providing further evidence that these TSE strains had distinct conformations. The ability of these two distinct PrPSc conformations to self-propagate was also demonstrated in an in vitro assay when they were individually incubated with PrPC and the HY TME PrPSc converted PrPC into a 21 kDa PK-resistant PrP, while DY TME PrPSc converted PrPC into a 19 kDa PK-resistant PrP [7,30]. In this cell-free PrP conversion assay, the kinetics of PK-resistant PrP formation was also different between the TME strains, which was consistent with a strain-specific pattern of PrPTME formation in vivo. Overall, these studies suggested that the molecular basis of TME strain diversity is determined by the strain-specific conformation of PrPTME and that each PrPSc conformation can convert the same PrPC molecule into a strain-specific subunit of the PrPSc fibril or aggregate. The formation of each PrPTME conformation may be preferentially favored under specific cellular or subcellular conditions, and the brain distribution of PrPTME may be partially determined by the preferred sites of strain PrPTME formation. Partial evidence for this is provided by the observation that the DY TME strain does not appear to be able to replicate in secondary lymphoid tissue, while the HY TME strain can replicate in lymph nodes and spleen.
Using an in vitro PrPc to PrPd (TME) conversion reaction [7,10,13,30] it was shown that the conversion is “strain-specific”, i.e. HY PrPd only converted PrPc into HY PrPd, and DY PrPd only converted PrPc into DY PrPd. This experiment suggested that certain strain-specificity is encrypted within the conformation of PrPd itself, which, in turn, determines the site of proteinase cleavage and strain-specific size of PrP fragments using Western immunoblot. However, the size of PrPd (either 19 kDa or 21 kDa) is exactly the same as the size of deglycosylated bands purified from human CJD. This may suggest that irrespective of the situation, PrPd may exist only in two major isoforms of 19 kDa and 21 kDa. Whether there are only two strains of every “prion” disease is, in our mind, doubtful.
In a separate study, Mulcahy and Bessen [43] found that conversion of PrPc into PrPd consists of three phases – elongation, depolymerization, and steady-stage phase – and that the elongation phase is that in which strain-specific differences are observed. Those differences between HY and DY strains are the total amount of PrPTME and the time when the reaction peaked. Furthermore, a vast difference in the kinetics of PrPTME accumulation was observed in hamster brains infected with either DY or HY TME strains.
It seems that both DY and HY TME strains are already present as a mixture in the original Stetsonville inoculum and during subsequent passages undergo selection during interspecies transmission [3]. For instance, one of the 4 clones passaged into Syrian golden hamsters bifurcated into a strain characterized by an incubation period ranging from 219 to 522 days and the PrP banding pattern typical of the DY strain of mink, and a second strain with an incubation period of 219 days and PrP pattern that of the DY strain. Upon further passages into hamsters, the incubation periods decreased, the emerging “strain” presented a mixture of HY and DY strains only on subsequent passages, distinct DY strain emerged, and from that, the HY TME strain was selected.
References
1. Barlow RM. Transmissible mink encephalopathy: pathogenesis and nature of aetiological agent. J Clin Pathol 1972; 6 (Suppl): 102-109.
2. Baron T, Bencsik A, Bicabe A-G, Morignat E, Bessen RA. Phenotypic similarity of transmissible mink encephalopathy in cattle and L-type bovine spongiform encephalopathy in a mouse model. Emerging Inf Dis 2007; 13: 1887-1894.
3. Bartz JC, Bessen RA, McKenzie D, Marsh DC, Aiken J. Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. J Virol 2000; 74: 5542-5547.
4. Bartz JC, DeJoia C, Tucker T, Kincaid AE, Bessen RA Extraneural prion neuroinvasion without lymphoreticular system infection. J Virol 2005; 79: 11858-11863.
5. Bartz JC, Kincaid RA, Bessen RA. Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol 2002; 76: 5759-5768.
6. 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; 75: 2947-2953.
7. Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 1995; 22: 698-700.
8. Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 1994; 66: 2096-2101.
9. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis for strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859-7868.
10. Bessen RA, Marsh RF. Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 1992; 73: 329-334.
11. Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 1992; 66: 2096-2101.
12. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859-7868.
13. Bessen RA, Raymond GJ, Caughey B. In situ formation of protease-resistant prion protein in transmissible spongiform encephalopathy-infected brain slices. J Biol Chem 1997; 272: 15227-15231.
14. Burger D, Gorham JR. Observation on the remarkable stability of transmissible mink encephalopathy virus. Res Vet Sci 1977; 22: 131-132.
15. Burger D, Hartsough GR. Transmissible Encephalopathy of Mink. In: Gajdusek DC, Gibbs CJ Jr, Alpers MP (eds.). NINDB Monograph No.2, Slow, Latent and Temperate Virus Infections. US DEPT of Health, Education, and Welfare, Washington 1965; pp 297-306.
16. Caughey B, Raymond GR, Bessen RA Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem 1998; 273: 32230-32235.
17. Eckroade RJ, ZuRhein GM, Hanson RP. Transmissible mink encephalopathy in carnivores: clinical, light, and electron microscopic studies in raccoons, skunks, and ferrets. J Wildlife Dis 1973; 9: 229-239.
18. Eckroade RJ, ZuRhein GM, Marsh CD, Hanson RP. Transmissible mink encephalopathy: experimental transmission to the squirrel monkey. Science 1970; 169: 1088-1090.
19. Ecroade RJ, ZuRhein GM, Hanson RP. Experimental transmissible mink encephalopathy: Brain lesions and their sequential development on mink. In: Prusiner SB, Hadlow WJ (eds.). Slow Transmissible Diseases of the Nervous System, Vol. 1, Academic Press, New York; 409-449.
20. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977; 197: 943-960.
21. 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 Letters 1993; 155: 112-115.
22. Hadlow WJ, Race RE, Kenendy RC. Temporal distribution of transmissible mink encephalopathy virus in mink inoculate subcutaneously. J Virol 2004; 61: 3235-3240.
23. Hadlow WJ, Race RE, Kenendy RC. Experimental infection of sheep and goats with transmissible mink encephalopathy virus. Can J Vet Res 1987; 51: 135-144.
24. Hadlow WJ, Race RE. Cerebroscortical degeneration in goats inoculated with mink-passaged scrapie virus. Vet Pathol 1986; 23: 543-549.
25. Hamir AN, Heidel JR, Picton R, Rupprecht CE. Neuronal vacuolation in raccoons (Procyon lotor). Vet pathol 1997; 34: 250-252.
26. Hamir AN, Kunkle RA, Miller JM, Bartz JC, Richt JA. First and second cattle passage of transmissible mink encephalopathy by intracerebral inoculation. Vet Pathol 2006; 43: 118-126.
27. Hamir AN, Miller JM, O’Rourke KI, bartz JC, Stack MJ, Chaplin MJ. Transmission of transmissible mink encephalopathy to raccoons (Procyon lotor) by intracerebral inoculation. J Vet Diagn Invest 2004: 16: 57-63.
28. Hartsough GR, Burger D. Encephalopathy in mink. I. Epizootiologic and clinical observations. J Inf Dis 1965; 115: 387-392.
29. Kimberlin RH, Cole S, Walker CA. Transmissible mink encephalopathy (TME) in Chinese hamsters: identification of two strains of TME and comparisons with scrapie. Neuropathol appl Neurobiol 1975; 12: 197-206.
30. Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, Caughey B. Cell-free formation of protease-resistant prion protein. Nature 1994; 370: 471-4
31. Kretzschmar HA, Neumann M, Riethmüller G, Prusiner SB. Molecular cloning of a mink prion protein gene. J Gen Virol 1992; 73: 2757-2761.
32. Marsh RF, Bessen RA, Lehmann S, Hartsough GR Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. J Gen Virol 1991; 72: 589-594.
33. Marsh RF, Bessen RA. Physicochemical and biological characterizations of distinct strains of transmissible mink encephalopathy. Phil Trans Roy Soc London: Biol Sci 1994; 343: 413-414.
34. Marsh RF, Burger D, Eckroade R, ZuRhein GM, Hanson RP. A preliminary report on the experimental host range of the transmissible mink encephalopathy agent. J Inf Dis 1969; 120: 713-719.
35. Marsh RF, Hanson RP. On the origin of transmissible mink encephalopathy. In: Prusiner SB, Hadlow WJ (eds.). Slow Transmissible Diseases of the Nervous System, Vol. 1, Academic Press, New York; pp. 451-460.
36. Marsh RF, Hanson RP. Physical and chemical properties of the transmissible mink encephalopathy agent. J Virol 1969; 3: 176-180.
37. Marsh RF, Hartsough GR. Is there a scrapie-like diseases in cattle? In: Proc. of the 89th Annual Meeting of the US Animal Health Ass 1969; pp. 8-9.
38. Marsh RF, Kimberlin RH. Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology and pathogenesis. J Inf Dis 1975; 131: 104-110.
39. Marsh RF, Semancik JS, Medappa KC, Hanson RP, Rueckert RR. Scrapie and transmissible mink encephalopathy: search for infectious nucleic acid. J Virol 1974; 13: 993-996.
40. Marsh RF, Sipe JC, Morse SS, Hanson RP. Transmissible mink encephalopathy. Reduced spongiform degeneration in aged mink of the Chediak-Higashi genotype. Lab Invest 1976; 34: 381-386.
41. Marsh RF. Animal model of human disease. Kuru, Creutzfeldt-Jakob disease (Slow Virus Infection. Am J Pathol 1972; 69: 209-212.
42. Mckenzie D, Bartz JC, Marsh DC. Transmissible mink encephalopathy. Sem Virol 1996; 7: 201-206.
43. Mulcahy ER, Bessen RA. Strain-specific kinetics of prion protein formation in vitro and in vivo. J Biol Chem 2004; 279: 1643-1649.
44. Robinson MM, Hadlow WJ, Huff TP, Wells GAH, Dawson M, Marsh DC, Gorham JR. Experimental infection of mink with bovine spongiform encephalopathy. J Gen Virol 1994; 75: 2151-2155.
45. Taylor DM, Dickinson AG, Fraser H, Marsh RF. Evidence that transmissible mink encephalopathy agent is biologically inactive in mice. Neuropathol appl Neurobiol 1986; 12: 207-215.
46. Windl O, Buchholz M, Neubauer AN, Schulz-Schaeffer W, Groschup M, Walter S, Arendt A, Neumann M, Voss AK, Kretzschmar HA. Breaking an absolute species barrier: transgenic mice expressing the mink PrP gene are susceptible to transmissible mink encephalopathy. J Virol 2005; 79: 14971-14975.
http://www.termedia.pl/showpdf.php?article_id=12696&filename=Transmissible.pdf&priority=1
YES, I believe I have read that somewhere else before ;
Saturday, December 01, 2007
Saturday, January 24, 2009
NOW, back to those mad mink i.e. TME. let me throw a curve ball here ;
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model Thierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* and Richard A. Bessen† Emerging Infectious
Transmissible mink encepholapathy (TME) is a foodborne transmissible spongiform encephalopathy (TSE) of ranch-raised mink; infection with a ruminant TSE has been proposed as the cause, but the precise origin of TME is unknown. To compare the phenotypes of each TSE, bovine- passaged TME isolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents (typical BSE, Htype BSE, and L-type BSE) were inoculated into an ovine transgenic mouse line (TgOvPrP4). Transgenic mice were susceptible to infection with bovine-passaged TME, typical BSE, and L-type BSE but not to H-type BSE. Based on survival periods, brain lesions profi les, disease-associated prion protein brain distribution, and biochemical properties of protease-resistant prion protein, typical BSE had a distint phenotype in ovine transgenic mice compared to L-type BSE and bovine TME. The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4 mice suggest that L-type BSE is a much more likely candidate for the origin of TME than is typical BSE. Transmissible mink encephalopathy (TME) is a rare prion disease in ranch-raised mink (Mustela vison) in North America and Europe (1–4). Six outbreaks have been reported from 1947 through 1985 in North America, and several have been linked to contaminated commercial feed (1). Although contamination of feed with scrapie-infected sheep parts has been proposed as the cause of TME, the origin of the disease remains elusive. The idea that scrapie in sheep may be a source of TME infection is supported by fi ndings that scrapie-infected mink have a similar distribution of vacuolar pathologic features in the brain and the same clinical signs as mink with natural and experimental TME (5). However, mink are not susceptible to scrapie infection following oral exposure for up to 4 years postinoculation, which suggests that either the scrapie agent may not be the source of natural TME infection or that only specifi c strains of the scrapie agent are able to induce TME (6,7). Epidemiologic investigations in the Stetsonville, Wisconsin, outbreak of TME in 1985 suggested a possible cattle origin, since mink were primarily fed downer or dead dairy cattle but not sheep products (8). Experimental transmission of Stetsonville TME into cattle resulted in transmissible spongiform encephalopathy (TSE) disease with an incubation period of 18.5 months. Back passage of bovine TME into mink resulted in incubation periods of 4 and 7 months after oral or intracerebral inoculation, respectively, which was similar to that found following inoculation of Stetsonville TME into mink by these same routes (8). These fi ndings indicated that cattle are susceptible to TME, and that bovine-passaged TME did not result in a reduced pathogenicity for mink. These studies raised the question as to whether an unknown TSE in cattle was the source of TME infection in the Stetsonville outbreak. Several additional TME outbreaks in the United States have been associated with mink diet that contained downer or dead cattle (9). ...
snip...full text ;
http://www.cdc.gov/EID/content/13/12/pdfs/1887.pdf
http://transmissible-mink-encephalopathy.blogspot.com/
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
Saturday, December 01, 2007
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
http://transmissible-mink-encephalopathy.blogspot.com/2007/12/phenotypic-similarity-of-transmissible.html
To be published in the Proceedings of the Fourth International Scientific Congress in Fur Animal Production. Toronto, Canada, August 21-28, 1988
Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
•Department of Veterinary Science, University of Wisconsin-Madison, Madison, Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin 53092
ABSTRACT
Epidemiologic investigation of a new incidence of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin suggests that the disease may have resulted from feeding infected cattle to mink. This observation is supported by the transmission of a TME-like disease to experimentally inoculated cattle, and by the recent report of a new bovine spongiform encephalopathy in England.
snip...
OBSERVATIONS AND RESULTS
A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville, Wisconsin reported that many of his mink were “acting funny”, and some had died. At this time, we visited the farm and found that approximately 10% of all adult mink were showing typical signs of TME: insidious onset characterized by subtle behavioral changes, loss of normal habits of cleanliness, deposition of droppings throughout the pen rather than in a single area, hyperexcitability, difficulty in chewing and swallowing, and tails arched over their _backs like squirrels. These signs were followed by progressive deterioration of neurologic function beginning with locomoior incoordination, long periods of somnolence in which the affected mink would stand motionless with its head in the corner of the cage, complete debilitation, and death.
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME. Since previous incidences of TME were associated with common or shared feeding practices, we obtained a careful history of feed ingredients used over the past 12-18 months. ***The rancher was a “dead stock” feeder using mostly (>95%) downer or dead dairy cattle and a few horses. Sheep had never been fed.***
snip...end
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
Epidemiology Epidemiologic studies suggest that animals contract the disease by external exposure to the infectious agent, such as by eating contaminated feed. No evidence suggests that the TME agent spreads by contact between unrelated mink or from mother to nursing young. The disease has been identified in both genders and all color phases in animals greater than 1 year old. The first documented TME outbreak in the United States occurred in 1947 on one ranch in Wisconsin and then on a ranch in Minnesota that had received mink from the Wisconsin ranch. In 1961, TME outbreaks occurred on five ranches in Wisconsin. In Factsheet Veterinary Services February 2002 APHIS 1963, outbreaks occurred in Idaho, Minnesota, and Wisconsin. Epidemiologic data from the Minnesota and Wisconsin outbreaks trace the cases in those States to one common purchased food source.
snip...
The 1985 Stetsonville Outbreak The most recent TME outbreak occurred on one mink ranch in Stetsonville, WI, in 1985. In the herd of 7,300 adult mink, 60 percent of the animals died. Clinical signs included tail arching, incoordination, and hyperexcitability. At the most advanced stages of the disease, the animals were in trancelike states and eventually died. The outbreak lasted 5 months. Microscopic examination of sections of the brain confirmed the spongelike changes characteristic of TME. Diagnostic tests identified the prion protein. The following year, mink born during the outbreak showed no signs of TME. The late Richard Marsh, a veterinary virologist at the University of Wisconsin who studied the transmission of TME and other TSE’s, investigated this outbreak. Marsh learned that the mink were fed a diet composed of fresh meat products from “downer cattle” and commercial sources of fish, poultry, and cereal. Downer cattle are nonambulatory and cannot rise because they are affected with a condition such as a metabolic disease, broken limbs, or a central nervous system disorder. Marsh theorized that the meat from these downer cattle introduced a TSE agent to the mink in which TME resulted. Although Marsh’s hypothesis is based on speculation and anecdotal evidence, in 1993 APHIS adjusted its national BSE surveillance program to include testing downer cattle for evidence of a TSE. The brains of more than 20,141 cattle have been examined at APHIS’ National Veterinary Services Laboratories and other State diagnostic laboratories. Not a single tissue sample has revealed evidence of BSE or another TSE in cattle.
http://www.aphis.usda.gov/publications/animal_health/content/printable_version/fs_ahtme.pdf
AND as everyone knows, the rest is history, those dead-stock downers, the most high risk cattle, were NOT tested, and in FACT, was a major source of YOUR CHILDRENS SCHOOL LUNCH PROGRAM, all across the Nation. sorry, these are the most high risk cattle for TSE aka mad cow disease, and i am a bit touchy about this topic. ... sorry. ...terry
DOWNER COW SCHOOL LUNCH PROGRAM
http://downercattle.blogspot.com/
IS THERE A SCRAPIE-LIKE DISEASE IN CATTLE ?
In April of 1985, a mink rancher in Wisconsin reported a debilitating neurologic disease in his herd which we diagnosed as TME by histopathologic findings confirmed by experimental transmission to mink and squirrel monkeys. The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle and a few horses. She had never been fed.
We believe that these findings may indicate the presence of a previously unrecognized scrapie-like disease in cattle and wish to alert dairy practitioners to this possibility.
snip...
PROCEEDINGS OF THE SEVENTH ANNUAL WESTERN CONFERENCE FOR FOOD ANIMAL VETERINARY MEDICINE, University of Arizona, March 17-19, 1986
http://www.bseinquiry.gov.uk/files/mb/m09a/tab01.pdf
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
http://transmissible-mink-encephalopathy.blogspot.com/2007/12/phenotypic-similarity-of-transmissible.html
Wednesday, July 8, 2009
Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009 Aug; [Epub ahead of print]
http://nor-98.blogspot.com/2009/07/transgenic-mice-expressing-porcine.html
TSS
Labels: COVER-UP, L-BSE, MAD COW USA, SPORADIC CJD, TME
posted by Terry S. Singeltary Sr. at
9:47 PM
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