Are cheetahs on the run from prion-like amyloidosis?
Byron Caughey* and Gerald S. Baron* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 598940
The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease. Prions are protein-based infectious agents or elements of inheritance that, unlike conventional pathogens, lack agent-specific nucleic acid genomes (5, 6). Prions have been described in both mammals (e.g., bovine spongiform encephalopathy and Creutzfeldt–Jakob disease) and fungi ([URE3], [PSI], and [Het-s]). Replication of prions requires a self-propagating modification of an otherwise non-prion host protein. Usually the mechanism involves the recruitment of the normal form of the protein into a growing amyloid-like prion aggregate. In many cases the presence of prions is a disease state, but some prions play normal physiological roles (7). Although amyloid-like protein aggregation is typical of many important protein misfolding diseases, including Alzheimer’s disease and type 2 diabetes, most of these diseases are not known to be naturally transmissible or heritable because of transfer of the amyloid. However, experimental inoculations of amyloid preparations can enhance amyloidosis in nai¨ve mice that are strongly primed for the development of amyloidosis (8, 9). This suggests that there is potential for amyloidoses, in general, and AA amyloidosis specifically, to be transmissible and, hence, prion-like. For such transmissions to be significant in the real world, there must be practical routes of transmission and the potential for inducing disease in natural, rather than artificially primed, hosts. The shedding of AA amyloid into the feces of cheetahs suggests a potential route of transmission (Fig. 1) (4). Although the fecal amyloid can promote amyloidosis on i.v. inoculation into mice, this is only true in mice that were primed for amyloidosis by injections of an inflammatory chemical (silver nitrate) that dramatically boosts serum SAA levels. The silver nitrate treatment alone causes spontaneous amyloidosis in these mice, albeit at a slower pace than when the mice are inoculated with exogenous amyloid. Thus, it remains to be determined whether fecal amyloid can actually initiate, rather than enhance, amyloidosis in either mice or cheetahs and, if so, by what route of inoculation. One possible mode of entry would be oral because AA amyloid can be active in primed mice when administered orally as well as intravenously (9, 10). Another potential route would be direct inoculation of fecal amyloid into the blood stream through cuts or abrasions. It should be noted that Zhang et al. (4) inoculated mice with highly concentrated preparations of fecal amyloid. Hence, it is unknown whether amyloid concentrations in feces would allow transmission to nai¨ve recipients by any peripheral route. If fecal amyloid can be transmitted to other captive cheetahs, what makes these animals so susceptible to AA amyloidosis? The fact that mice can be primed for AA amyloidosis by inflamm tory stimuli raises the possibility that inflammation is also important in cheetahs. Indeed, inflammatory diseases are prominent in captive cheetahs with AA amyloidosis, and a number of precipitating factors, including chronic infections, diet, and stress, have been identified (2, 3). Other possibilities include genetic predispositions of cheetahs to AA amyloidosis because of their SAA sequence or expression level. Interestingly, a gene polymorphism has been identified in captive cheetahs that flanks the SAA1 gene and strongly affects its transcriptional induction in response to inflammation (11). Expression of other proteins can also profoundly enhance susceptibility of animals to AA amyloidosis, as shown by modulation of pentraxin levels in hamsters (12). The genetic homogeneity of captive cheetahs may enhance these susceptibility problems (11, 13), but does not appear to be the sole issue (3). The very factors that might make cheetahs susceptible to exogenous AA amyloid ‘‘infections’’ should also potentiate spontaneous AA amyloidosis in these animals. There is precedent for this in the spontaneous amyloidosis that occurs in silver nitrate-primed mice. By analogy, it remains possible that the high incidence of AA amyloidosis in cheetahs is caused by spontaneous disease exacerbated by the inflammatory stimuli, stresses, and inbreeding of captivity rather than exposure to fecal amyloid. Further studies will be required to resolve these questions. AA amyloidosis susceptibility issues may have serious implications for cheetah conservation efforts. If the objective is to rescue the wild cheetah population by releasing cheetahs bred in captivity, then it will be important to know the impact of releasing amyloidotic animals into the wild. Will AA amyloidosis continue to progress and affect the survival of released cheetahs? Can the disease be spread to wild cheetahs? One encouraging observation is that, relative to captive cheetahs, wild Namibian cheetahs are remarkably free of disease, including inflammatory diseases such as AA amyloidosis and gastritis (3). Perhaps lower chronic levels of inflammation, and hence serum SAA levels, make them less susceptible than captive cheetahs to AA amyloid shed by other animals. Although major questions remain about the etiology of AA amyloidosis in captive cheetahs, it may be wise to take measures to limit exposure of cheetahs to potential sources of amyloid ‘‘infectivity.’’ The demonstration that cheetah AA amyloid is active in mice indicates that there is cross-species promiscuity in its amyloid-inducing capacity. This promiscuity might also work in reverse, rendering cheetahs susceptible to AAamyloid- laden tissues of other species that might be fed to them. Interestingly, foie gras was recently shown to contain AA amyloid that could accelerate amyloidosis when fed to mice (9). Thus, consideration of a variety of potential sources of exposure for cheetahs seems warranted. Furthermore, if chronic inflammation enhances disease susceptibility, then anti-inflammatory therapies may be helpful. Is AA amyloidosis in cheetahs a prion disease? The answer depends on whether AA amyloidosis in captive cheetahs is caused by spontaneous disease or transmission of amyloid between animals. Environmental influences on AA amyloidosis epidemiology could be due to the presence of either ‘‘infectious’’ amyloid, a prion-like etiology, or to factors that enhance the incidence of spontaneous disease, i.e., a non-prion etiology. Even if transfer of AA amyloid between cheetahs enhances AA amyloidosis, the question would remain as to whether the transferred amyloid initiates the disease de novo or merely accelerates ongoing disease. The latter scenario would place AA amyloidosis into a gray area with respect to the basic prion concept. In this instance, prion transmission would affect the kinetics of the disease without actually initiating it. Regardless of prion semantics, there could be practical consequences of such kinetic phenomena in both animals and humans. For instance, recent studies have shown that in ection of -amyloid can enhance Alzheimer’s-like amyloidosis in transgenic mice (14). This raises the possibility that inadvertent transfer of -amyloid from one person to another could accelerate the neurodegenerative process to the point where it becomes Alzheimer’s disease as opposed to normal aging. In this example, as well as in cheetah AA amyloidosis and many other protein misfolding diseases, the basic problem is likely the outpacing of an organism’s protein quality control mechanisms. This may sometimes be more a problem of the rate, rather than of the instigation, of protein misfolding.
Fig. 1. Diagram of AA amyloid formation and the potential prion-like transmission of AA amyloidosis by fecal shedding and oral uptake of the amyloid. The photo shows an example of Congo red-stained AA amyloid fibril deposits in hamster liver tissue (courtesy of John Coe, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases).
ACKNOWLEDGMENTS. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. 1. Balch WE. Morimoto RI, Dillin A, KellyJW(2008) Adapting proteostasis for disease intervention. Science 319:916–919. 2. Papendick RE, Munson L, O’Brien TD, Johnson KH (1997) Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus). Vet Pathol 34:549–556. 3. MunsonL, et al. (2005) Extrinsic factors significantly affect patterns of disease in free-ranging and captive cheetah (Acinonyx jubatus) populations. J Wildl Dis 41:542–548. 4. Zhang B, et al. (2008) Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci USA 105:7263–7268. 5. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383. 6. Wickner RB, et al. (2004) Prion genetics: New rules for a new kind of gene. Annu Rev Genet 38:681–707. 7. Coustou V, Deleu C, Saupe S, Begueret J (1997) The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc Natl Acad Sci USA 94:9773–9778. 8. Kisilevsky R, Boudreau L (1983) Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy. Lab Invest 48:53–59. 9. Solomon A, et al. (2007) Amyloidogenic potential of foie gras. Proc Natl Acad Sci USA 104:10998–11001. 10. Lundmark K, et al. (2002) Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci USA 99:6979–6984. 11. Zhang B, et al. (March 28, 2008) Characterization of the cheetah serum amyloid A1 gene: Critical role and functional polymorphism of a cis-acting element. J Hered, 10.1093/jhered/esn015. 12. Coe JE, Ross MJ (1990) Amyloidosis and female protein in the Syrian hamster: Concurrent regulation by sex hormones. J Exp Med 171:1257–1267. 13. O’Brien SJ, et al. (1985) Genetic basis for species vulnerability in the cheetah. Science 227:1428 – 1434. 14. Meyer-Luehmann M, et al. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784. 7114 www.pnas.orgcgidoi10.1073pnas.0803438105 Caughey and Baron
Monday, May 12, 2008
Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease
Alzheimer's and CJD
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer’s disease facts and figures
Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c
Sunday, April 27, 2008 re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Greetings,
I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand.
Draft Factual Account #5
10. On 28 June 1986 Mr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo.(S Jeffrey para 6; YB86/7.8/1.1 ) This examination, and subsequent consideration of the report, are described in the CVL DFA.
51. On 10 June 1987 Mr Bradley sent a BSE update to Dr Watson. It discussed, amongst other things, the nyala case and subsequent paper, the work of Mr Wilesmith, the upcoming BCVA meeting and the work of Dr Kimberlin.(YB 87/6.10/1.1 )
63. On 22 June 1987 Mr Bradley sent a memo to Mr Wells detailing actions taken to date. It noted that publication has been discussed with the CVO and halted and that there were now at least 9 suspect herds and a case in a gemsbok at Marwell.(YB 87/6.22/2.1 )
74. On 1 July 1987, Mr Bradley wrote to Mr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/6.29/3.1; YB87/7.1/2.1; YB87/7.1/3.1-3.10 ) This is further discussed in the CVL DFA.
153. On 11 December 1987, Mr Jeffrey's paper on the nyala was submitted for publication in the journal Veterinary Pathology. The paper had first been drafted the paper in autumn 1986. (S 64 Jeffrey para 10) The title of the paper was changed from 'A scrapie-like disorder in a nyala' to 'A spongiform encephalopathy in a nyala.' Other references to scrapie were also amended.( S Jeffrey para 10; S 65 Wells para 55; YB87/11.11/2.1; YB87/11.17/3.1; YB87/11.23/2.1. )
Spongiform encephalopathy in a nyala (Tragelaphus angasi).
Vet Pathol 1988 Sep;25(5):398-9 Jeffrey M, Wells GA Lasswade Veterinary Laboratory, Midlothian.
166. In January 1988, Mr Wilesmith was informed of the June 1987 case of SE in the gemsbok. He discovered from the Winchester VIC that both the >nyala and the gemsbok had received rations containing MBM and this provided further support for his hypothesis.( S Wilesmith para. 37)
Draft Factual Account #4
28. On 28 June 1986 Dr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo. (S Jeffrey para 6; YB86/7.8/1.1 ) The nyala had shown unusual nervous symptoms two weeks prior to being put down on welfare grounds. These symptoms included 'weaving with the head and neck, holding the head on its side and frequent nibbling near the tailbone.'(YB86/6.23/1.1 ) The sections were originally necropsied by Mr Geoff Holmes at the Winchester VIC.(YB86/5.29/1.1; YB86/6.18/1.1 ) The nyala (tragelaphus angasi) is not an antelope but belongs to the same family (species group) as cattle.
29. Dr Jeffrey observed that the brain showed taxonomic lesions of spongiform encephalopathy and that the similarity of the lesions to natural sheep scrapie was striking, and indeed he thought that in comparison to natural sheep scrapie the lesions were particularly florid.(YB86/7.2/1.1; S Jeffrey para 9 ) The sites (neuroanatomical location) and cellular location (grey matter neuropil and neuronal cytoplasmic vacuolation) were distinctive and characteristic of the TSEs. Dr Jeffrey sent a slide of the nyala brain to Dr Richard Kimberlin at the NPU in the latter quarter of 1986 who 'vividly recollect[ed] seeing the results down the microscope because the pathology was so striking'.(YB 98/11.18/1.1 )
30. Following a field visit to Marwell Zoo on 21 July 1986,(YB86/7.24/1.1 ) a report was compiled by Mr Holmes at Winchester VIC and a scientific paper prepared for publication in a journal.(S Jeffrey para 10 ) Dr Jeffrey conferred with Mr Wells, his line manager at the CVL, in the preparation of the paper.(S Jeffrey para 9; S Wells 1st para 55 ) Dr Jeffrey was not sure of the exact date he submitted the paper to the Animal Health and Veterinary Group (AHVG) for publication but said it was some time in Autumn 1986.(S Jeffrey para 10; YB86/11.00/1.1 ) Dr Jeffrey did not form any conclusions about the origins of the disease in this animal, but he discussed the case with the CVL Epidemiology Department, and they agreed to keep a 'watching brief' on the situation.(S Wilesmith para 11)
89. On 17 June 1987 the Annual Report of the CVO for 1986 was published, having been submitted for publication on 1 June 1987.( M24 Tab 2 at 69 ) The Report described the discovery of a 'Scrapie-like disease in a captive nyala' and noted that 'Transmissible spongiform encephalopathies have been reported in man, sheep and goats (scrapie), mule deer and mink.'
91. On 19 June 1987 Mr Bradley sent Dr Watson a BSE Update. Amongst other things it was noted:(YB 87/6.19/3.1-3.2 )
"The final draft Vet Rec paper has been prepared and submitted for authority to publish. This has been rejected by CVO whilst scrapie is mentioned. For this and other reasons the paper is temporarily withdrawn until further information is available"
92. On 19 June 1987 Dr S.H. Done diagnosed spongiform encephalopathy in a gemsbok from Marwell Park.(YB87/6.19/3.2; YB876.8/3.1; YB87/6.10/3.1; YB87/6.25/1.1 ) This was the zoo was from which the SE-infected nyala had come. While the nyala was from the same species group as cattle, the gemsbok is an African antelope.
100. On 1 July 1987 Mr Bradley wrote to Dr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/7.1/3.2; YB87/6.29/3.1; YB87/7.1/2.1 ) The initial title of the paper was 'Scrapie-like disorder in a nyala'.( S Jeffrey para 12 ) At the request of Tolworth, the title of the paper was eventually changed to 'Spongiform encephalopathy in a nyala'.( YB87/11.00/1.1 ) Because of the original references to the scrapie-like nature of the disorder the paper was delayed for publication and was not published until September 1988.( J/VP/25/398 ) Dr Jeffrey told the BSE Inquiry that he resisted the move to alter his paper because it 'would have been negligent to try and publish that without a reference to scrapie'.(T25 at 32 )
157. On 17 November 1987 Mr Bradley minuted Dr Jeffrey noting that the title to his nyala paper was likely to be unacceptable to "senior management" for "veterinary political reasons". He also recommended that where comparisons were made with scrapie the emphasis ought to be altered.(YB 87/11.17/1.1 )
433. On 23 October 1989 Dr Watson told Mr Wells that the CVL were to supply material from the kudu and nyala to the NPU for transmission to mice. Dr Watson said this was an important transmission experiment designed to establish the relationship between the disease in zoo animals and cattle.(S Watson 1st para 134 ) Mr Bradley provided Dr Watson with a list of tissues that were to be sent to the NPU on 24 November 1989.(YB89/10.24/4.1 )
BSE Inquiry site Draft Factual Account 13 extracts related to zoo animals:
19. On 24 January 1990 Mr Bradley sent to Dr Watson a summary of the main points of a meeting held with the Minister the same day.(20) The minute noted: "The Minister played Devil's advocate in relation to: ... 5. MBM exports unethical. All should be labelled & a letter should be sent to all countries to which MBM was exported should be sent." [No such letter was sent.]
28. By 12 February 1990 the nyala and kudu tissues and the placenta had been inoculated into mice at the NPU.(33) After his investigations into the alimentary tract, ... Mr Bradley said in a minute dated 12 February 1990 that:(36) "It is very clear that it is important to initiate studies now in a much wider range of tissues and in multiple specimens than can be accommodated in the annual quota of 30 for the next two years." Mr Bradley attached a table showing the progress of infectivity studies:..fixed nyala brain, fixed kudu brain, buffy coat.
57. On 17 September 1990 Mr Bradley circulated a minute with regards to an offer by Dr Schellekers of the Netherlands to collaborate on attempting to transmit BSE to chimpanzees.(YB90/9.17/1.1) Mr Wells and Dr Rosalind Ridley, who was conducting the marmoset experiment, told Mr Bradley that they did not feel there was any greater justification for an attempted transmission in chimpanzees than marmosets.(S Bradley 3rd para 40 ) Mr Bradley passed on this view to the CVO.(YB90/9.23/1.1; YB90/9.26/3.1 ). [This is ignorant beyond belief.]
67. In Spring 1991 Mr McGill performed a review of 200 brains that had, using the obex histopathological method, been deemed BSE-negative.(110) This diagnostic approach, that had been developed for use within the VIS, used a single section from the medulla to look for spongiform change. In his review Mr McGill examined other parts of the brain.(111) In his statement to the BSE Inquiry Mr McGill said:
Upon closer examination, three of the 200 'BSE-negative' brains proved positive for spongiform changes diagnostic of BSE.(112) This represents an overall diagnostic accuracy of 99.85%, exceeding the 99.6% previously published for the same standard diagnostic technique. Despite this, at the behest of MAFF managers, the emphasis of the study and its provisional title had to be changed, from accurately representing the whole negative 10%, to a study examining this 10% minus any mention whatsoever of BSE-affected cattle going undiagnosed. I therefore had to reluctantly locate and analyse three new BSE-negative suspect brains.(113)
76. In mid-1991 it was decided that a proposed survey of 300 deer brains would proceed.(124) As with the hound survey, there were difficulties in collecting the material in a manner optimal for histopathological examinations.(See YB92/11.4/2.1) During the period 1986 to 1996, 26 deer brains were referred for examination to the Consultant Pathology Unit at the CVL, but none of these showed evidence of an SE.
103. On 16 July 1992 a meeting was held at CVL to discuss the research proposals relating to the studies on SEs in a greater kudu at a zoo. (S Bradley 3rd para 65 ) Three main experiments were proposed: to determine the distribution of agent in tissues; to study the epidemiology; and to strain type isolates from a brain of a new case of spongiform encephalopathy. Formal proposals were later drawn up and Mr Bradley became the Project Officer for the experiments.
108. Mr Bradley and Mr Dawson met staff at London Zoo on 23 March 1993 to discuss tissue selection for the proposed transmission studies on BSE-infected kudu material.(166) The Zoo did not want to keep the kudu, but moving them to the CVL was ruled out because of inadequate facilities to care for them. The investigations into the distribution of the SE agent in various tissues began in June 1993.
121. On 9 October 1993 Mr Wilesmith and others published a paper on the additional cases of TSE in the herd of greater kudu at London Zoo.(S Wilesmith 2nd para 95 ) On the basis of feeding histories, the authors concluded that horizontal transmission had occurred. However, subsequent investigations based at the zoo revealed that the affected animals were most likely to have been infected from the feedborne source.
143. On 3 July 1994 Mr Bradley was informed that two more kudu were to be culled.( Bradley 3rd para 86 ) He visited the London Zoo on 21 July 1994 to review the progress of the studies on TSEs in zoo animals. Necropsies were to be carried out on the kudu and tissues collected for further transmission studies. At this stage the mice that had been inoculated with kudu tissues in August and September 1993 had not succumbed to spongiform encephalopathy. The Zoo authorities wanted to move the kudu because of the possibility of bad publicity.(YB95/2.10/1.6) This was discussed at a SEAC meeting on 2 February 1995. The meeting agreed that the risk to Zoo visitors was minuscule or non-existent. Mr Bradley's case control study indicated that infected feed was the most probable cause of the BAB kudu SE cases.
46. On 28 June 1990 Mr Bradley informed Mr Wells that a survey of hounds was to commence.(68) The hound survey arose because the Tyrrell Committee had recognised that domestic pets might prove susceptible to the unconventional agent of BSE and recommended monitoring the health of animals fed offal, carcases or meat and bone meal.(M11a Tab 8 )
47. A total of 444 hound brains of mixed breeds from 101 kennels across the United Kingdom were collected and examined. Histopathological changes consistent with a florid spongiform encephalopathy similar to that reported in cats was not observed. However, the report of the survey identified serious flaws in the survey's design. Mr Wells said in a minute to Mr Bradley in October 1991 that 'the survey as designed has little to offer scientifically'.(YB91/10.17/1.1)
54. On 20 August 1990 Mr Wells confirmed the parenteral transmission of BSE to a pig.(YB90/7.20/2.1) The pig was inoculated in February/March of 1989 and was slaughtered in July 1990.(S Wells 2nd para 40) An interim report was prepared for SEAC(84) and a press conference was held on 24 September 1990 to announce the parenteral transmission of BSE to pigs.(85) The transmission of BSE to pigs was a major factor in the ban on SBOs being extended to all animal feed. Experiments were also conducted by orally dosing pigs with BSE infected material but when the pigs were killed after seven years they were not found to be incubating the disease.(S Wells 2nd para 40 )
55. By August 1990 a total of 10 cases of FSE in domestic cats had been confirmed.(S Wilesmith 2nd para 109 ) Mr Wilesmith designed a questionnaire to be completed by the veterinarians who clinically identified FSE for the purposes of an epidemiological investigation. In addition to this investigation, the University of Bristol was subsequently granted a MAFF contract for a study in collaboration with the NPU to ascertain whether the condition in cats was transmissible to mice and, if so, to undertake strain typing of the agent.(S Wells 2nd para 104; YB 92/6.19/5.1 ) Mr Wells was appointed Project Officer to monitor the study. When the study was completed it showed that the disease in cats was transmissible and that similarities in the biological characteristics of FSE and BSE on transmission to mice indicated that the two diseases probably arose from a common source.(J/VR/134/449 )
64. In February 1991 Mr Mark Robinson began studies on the transmission of BSE to mink.(S Wilesmith 2nd paras 117-118 ) This study was done in collaboration with the United States Department of Agriculture (USDA), the Agricultural Research Service (ARS), and the Department of Veterinary Science at the University of Wisconsin, USA. The results of this study were discussed at the 10th CVL/NPU BSE R&D meeting held on 27 April 1993.(YB93/4.27/1.1) The results indicated that mink were susceptible to BSE, and in contrast to previous attempts to transmit scrapie to the species, were susceptible by the oral route of challenge.(J/JVIR /75/2151)
99. On 11 April 1992 Mr Bradley prepared a paper for the Lamming Expert Committee on Animal Feedingstuffs.(153) Some of the areas covered in the paper were tallow, the danger of BSE to pigs, the effect of the species barrier, tissue infectivity of lambs and calves, scrapie incidence and the danger of dogs developing SEs.
116. In July 1993 studies involving the oral exposure of pigs to scrapie were started the CVL.(179) Such studies were recommended by the expert committee on feedingstuffs chaired by Professor Lamming, because it was found that pigs had been orally exposed not only to BSE but also to scrapie. The pigs were orally exposed to scrapie-infected brain material in November 1993 and while the experiment remains in progress, no pigs have been shown to have developed the disease to date.
123. In December 1993 Dr Ken Charlton of the Animal Disease Research Institute, Nepean, Ontario, Canada, visited the CVL bringing material from a suspect case of BSE in Canada. The CVL confirmed that the case was a BSE case and reported it to the Canadian authorities.(189) in 1994.
152. On 13-16 February 1995 ... ...BSE to pigs - Further work to clarify the finding of non-specific vacuolation in the brains of control pigs was needed.
...BSE to chickens - Sub-passage in chickens and mice of various tissues from experimentally infected birds was needed to clarify the findings of neurological signs without neuropathology in inoculated birds.
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