Atypical scrapie in sheep from a UK research flock which is free from classical scrapie
Hugh A Simmons , Marion M Simmons , Yvonne I Spencer , Melanie J Chaplin , Gill Povey , Andrew Davis , Angel Ortiz-Pelaez , Nora Hunter , Danny Matthews and Anthony E Wrathall
BMC Veterinary Research 2009, 5:8doi:10.1186/1746-6148-5-8
Published: 10 February 2009
Abstract (provisional) Background In the wake of the epidemic of bovine spongiform encephalopathy the British government established a flock of sheep from which scrapie-free animals are supplied to laboratories for research. Three breeds of sheep carrying a variety of different genotypes associated with scrapie susceptibility/resistance were imported in 1998 and 2001 from New Zealand, a country regarded as free from scrapie. They are kept in a purpose-built Sheep Unit under strict disease security and are monitored clinically and post mortem for evidence of scrapie. It is emphasised that atypical scrapie, as distinct from classical scrapie, has been recognised only relatively recently and differs from classical scrapie in its clinical, neuropathological and biochemical features. Most cases are detected in apparently healthy sheep by post mortem examination.
Results The occurrence of atypical scrapie in three sheep in (or derived from) the Sheep Unit is reported. Significant features of the affected sheep included their relatively high ages (6y 1mo, 7y 9mo, 9y 7mo respectively), their breed (all Cheviots) and their similar PRNP genotypes (AFRQ/AFRQ, AFRQ/ALRQ, and AFRQ/AFRQ, respectively). Two of the three sheep showed no clinical signs prior to death but all were confirmed as having atypical scrapie by immunohistochemistry and Western immunoblotting. Results of epidemiological investigations are presented and possible aetiologies of the cases are discussed.
Conclusions By process of exclusion, a likely explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an exterior source. If correct, this raises challenging issues for countries which are currently regarded as free from scrapie. It would mean that atypical scrapie is liable to occur in flocks worldwide, especially in older sheep of susceptible genotypes. To state confidently that both the classical and atypical forms of scrapie are absent from a population it is necessary for active surveillance to have taken place.
It is noteworthy that a clinical presentation was evident only in the index case, G320, and the other two cases, Y71 and D337, were diagnosed retrospectively after they had been killed. The latter two had apparently been healthy immediately prior to their euthanasia and we do not know if they would have eventually developed clinical disease. The apparent blindness of sheep G320 prior to death was unusual in that previous cases of atypical scrapie have mostly presented with loss of body condition, sometimes with incoordination . There are several possible origins of these atypical scrapie cases: exposure from the environment or infected animals (or, in the case of D337, from the experimental challenge), and spontaneous development of the disease within the sheep themselves. From our own investigations, and the currently available published evidence, none of these possibilities can be ruled out. We must point out, however, that if D337 had been infected by transfusion of blood from the BSE challenged sheep, we would have expected her IHC and WB test results to be characteristic of BSE rather than, as was the case, characteristic of atypical scrapie .
With regard to the possibility of exposure, we are aware that the most important risk factor for introduction of classical scrapie into a flock appears to be the purchase of infected animals  but, as yet, we do not know if this is also the case for introduction of atypical scrapie. Experimental transmission of atypical scrapie by intracranial inoculation of brain homogenate from affected cases has been demonstrated in transgenic (ovinised) mice , and in sheep with the AHQ/AHQ genotype which succumbed after a very variable incubation period ranging from 378 to 1057 days [9; unpublished observations]. This leaves open the question of whether the infection can be transmitted naturally between sheep or via a contaminated environment. To our knowledge, experimental transmission of atypical scrapie has not yet been achieved by the oral route, although studies are ongoing.
Our retrospective analyses and testing did not enable us to determine whether atypical scrapie infection was present among the sheep when they were imported from New Zealand or whether exposure and/or infection occurred after the Sheep Unit was established in the UK. With regard to the latter possibility, we believe that because the Sheep Unit is completely closed with strict biosecurity measures, the risk of introducing scrapie from the outside is very low indeed. At the time of writing (May 2008) only six cases of classical scrapie (and none of atypical scrapie) had been confirmed in the county (Cambridgeshire) in the past ten years, and all of these were beyond a 20 km radius of the Sheep Unit. Furthermore, all sheep and goats tested under the Fallen Stock and Abattoir surveys from holdings in Cambridgeshire have been negative. According to the 2005 agricultural census Cambridgeshire has less than 31 sheep per km2, which is one of the lowest densities in the UK, so contact between sheep in the Unit and other sheep is extremely unlikely. Nevertheless the Unit is not a high-security laboratory premises but a barriered isolation unit where humans (and occasionally wildlife such as birds and rodents) come into contact with its livestock. Therefore we cannot claim that sheep within the Unit are totally isolated from their environment. Comprehensive monitoring by IHC and/or WB is undertaken in animals culled from the flock, and also, where possible, through follow-up of animals leaving for other reasons. However, due to the age and genotype structure of the flock, only a relatively small number of sheep of genotypes that are now known to be at high risk of atypical scrapie [5;15] have been tested, and, of those that have been tested, few were aged four years and over.
Another possible explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an external source. The ‘spontaneous aetiology’ hypothesis for atypical scrapie in sheep has been mentioned by several authors [e.g. 7;10;16;17] but there is no published evidence for it, and it would be difficult to test experimentally. In support of this hypothesis is the relatively consistent prevalence of atypical scrapie in national sheep flocks throughout the European Union (EU), despite significant variations in breed and management methods . This suggests that atypical scrapie is potentially spontaneous at a consistent rate, or, alternatively, that it is poorly contagious.
Although atypical scrapie has been shown to be transmissible by experimental inoculation (see above), if it is a spontaneous genetic disease it may be similar in origin to the familial forms of TSE in man such as Gerstmann-Sträussler-Scheinker syndrome, Creutzfeldt-Jacob disease and fatal familial insomnia in which the resultant diseases can subsequently be transmitted experimentally [18;19]). In a recent article McIntyre  refers to the possibility of a spontaneous aetiology but also restates New Zealand’s position as being free from classical scrapie and other TSEs of ruminants. For suppliers and users of TSE negative control sheep and cattle, and of TSE-free biological materials, the spontaneous aetiology hypothesis raises challenging nomenclature and certification issues. If the hypothesis is correct, one would expect sheep of susceptible genotypes in flocks across the world to be prone to develop atypical scrapie spontaneously, especially in old age. To state confidently that atypical scrapie is absent from a population, specific surveillance is required. It is not sufficient to have shown an absence of the classical disease because atypical scrapie has been shown to exist in sheep populations in which classical scrapie has not been detected [21;22]). Additionally, the low prevalence of atypical scrapie in the EU, and its widespread recognition only following the introduction of certain rapid tests into large surveillance programmes, argues that it may occur below the limit of detection even in countries that do carry out scrapie surveillance. As reported by Lühken et al.  and Moreno et al. , the AFRQ allele appears to confer the highest susceptibility to atypical scrapie, so the probability of detecting the disease is likely to be greatest in sheep of this genotype.
In view of the fact that the three sheep affected with atypical scrapie reported here were carriers of the AFRQ allele, and were of relatively advanced ages, we are of the opinion that the spontaneous origin explanation is the one that should be given the most credence. Disease monitoring, as outlined above, is continuing and the barriers to introduction of disease from outside the Sheep Unit will be maintained. However, with the low recorded incidence of atypical scrapie and the late age at onset, it will be a challenge to establish the true origin of the disease in this flock.
HOW would one explain 'spontaneously', the high morbidity rate 21.05% in these older sheep with scrapie ?
Thursday, March 5, 2009
INVESTIGATION of an OUTBREAK of SCRAPIE in
Clinical studies , Faculty of Veterinary Medicine. An-Najah National University ,
Nablus –Palestie P.O Box 7, e-mail address: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:firstname.lastname@example.org
This study documents an outbreak of scrapie in adult sheep (East – Friesian Breed) in Palestine with high morbidity rate 21.5% . The clinical findings of the disease were abnormal behavior, ataxia, tremor, incoordination of locomotion, pruritus, loss of wool, nibbling, recumbency and hyperaesthesia to noise, movement or touch. The clinical diagnosis is supported by histopathological lesions and immuno-detection of prion proteins in central nervous system by immunohistochemistry using a reference specific staining monoclonal antibody RIDA Mab L42.
Scrapie is a fatal degenerative disease of sheep and goats affecting the central nervous system of an incubation period 2-5 years. The onset of clinical disease is insidious, affected sheep show subtle changes, excitable, tremor of head and neck which may be elicited by sudden noise or movement, shortly thereafter animal develop intense pruritus with wool loss and skin rubbed raw. After 1-3 months of progressive deterioration which characterized by emaciation, weakness, ataxia, staring eyes, recumbence death occur (1). A disease affecting man and some animals known as transmissible spongiform encephalopathy (TSE) and is the prototype of the prion disease, the heterogenons group of PrP-sc associated disorders notably bovine spongiform encephalopathy (BSE), related humans disorders variant creutzfeldot-jakob disease of Captive and free ranging mule deer, white tailed deer and Elk(2). Animal prion diseases all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed(2). The disease is caused by a novel transmissible agent largely composed of prion protein (PrP) Prsc,an abnormal folded isoform of the normal cellular PrP, PrPc. The PrP is very resistant to many environmental insults, chemicals and physical condition that would destroy any virus or microorganism and it does not evoke any detectable immune response or inflammatory reaction in sheep and goats (3,4). The diagnosis of the disease currently based on a clinical history, histopathological changes in the brain and demonstration the presence of PrP – containing Plaque by immunohistochemistry (5). This study deals for the first time with an outbreak of scrapie in sheep ( East –Fresian Breed) recently encountered in Palestine where clinical, pathological and immunohisto_chemistry studies were conducted.
Material and Methods
An outbreak of scrapie occurring in a private Farm with 95 adult sheep age about 2-5 years (East – Fresian Breed) was investigated, the disease appeared in Azzon area –East of Qalqelia Governorate, North Palestine.
Complete clinical examination was performed on the affected animals in April 2005 and Five recumbent animals were euthanized and subjected to thorough post-mortem examination.Specimens from the pons, medulla, Midbrain, thalamus, cerebellum, anterior spinal cord, hippocampus and cerebrum were collected and fixed in 10% neutral buffered formalin for routine scrapie histopathology, Hematoxylin – Eosine stain (6).
Immunohistochemistry assay: slides with samples collected from suspected cases and uninfected control sheep were stained by a standard protocol developed for PrP-sc detection in central nervous system tissues according (7).Briefly slides were dewaxed, rehydrated and treated in 98% formic a cid for 20 min prior to hydreated autoclaving for 30 min at 122c? . After blocking with normal goat serum ( dilution, 1:66) sections staining monoclonal antibody (RIDA MAbL42) the sections were rinsed and treated with biotinylated goat anti-rabbit immunoglobulin G diluted 1:200, followed by treatment with vector Elite ABC and the color was developed with diaminobenzidine.
This study was conducted on a flock of 95 adult sheep (East – Friesian Breed), all animals were treated with Ivermectin and vaccinated annually against the following enzootic infectious diseases Sheeppox, Pest Des Petit Ruminants, Foot and Mouth Disease. The table (1) illustrate the distribution of animals according to clinical signs and their ages.
Table 1:Distribution of animals on the bases of clinical signs and age.
Number &% of clinically affected animals Number &% of clinically healthy animals
Number of animals 25 (21.05%) 70 (73.7%)
Age in years 3-5 1-2
Clinical findings : The clinical signs of the disease appear at age 3-5 years old, morbidity rate 21.05%, affected animals starts by abnormal behaviour tendency where it separate itself from the flock then return normally if left undisturbed at rest, howere when stimulated by excessive movement like handling or abnormal noise, animals tremble or fall down, ataxia, tremor of the head and neck, incoordination of locomotion, pruritus, loss wool, emaciation despite retention of appetite and recumbency. The recumbent animals are hyperexcitable, tends to carry its head high and has fixed stare, nibble at the affected area of the skin, wool loss and denudation of skin. The course of the disease from onset until recumbency lasts 3-6 months .
Gross Pathology ; There were no characteristic gross lesions.
Histopathology; Vacuolation of neurons in medulla, Pons and midbrain, surrounding cytoplasm showed signs of degeneration and Interstitial spongy degeneration often found and amyloid plaques (sometimes) as in Fig: "(1)
Immunohistochemistry: Positive staining of medulla oblingata, pons and midbrain tissues were identified as strong Particulate and cytoplasmic staining in neurons of tissues as seen in Fig (2) while negative antibody were seen in control tissue.
Fig.1: Vacuolation of several neurons with neuronal degeneration in the medulla oblongata of sheep. Hematoxyline and Eosine. X40.
Fig. 2: Positive immunohistochemistry of medulla oblongata of sheep showed abnormal accumulation of PrP. X40
Scrapie recognized as a distinct disease of sheep in many countries, its distributed widely in Europe, North America and occur sporadically in countries in Africa and Asia (8), According to OIE International Animal Health code, scrapie can be found under list B and within the European Unoin countries, the disease has been a notifiable since January 1993(5). Most breeds of sheep are affected although in some there is a clear genetic basis for resistance or low prevalence of clinical disease, scrapie has also been described in Moufflon (Ovis musimon) a primitive type of sheep such animal incubating the disease and that animal never develop clinical signs may still be a source of infection to others (9). Sheep are considered the natural hosts for scrapie agent, a considerable body of evidence indicate that most sheep with scrapie were infected early in life and the agent has persisted within them in quiescent state during intervening period (1) Most Cases of clinical scrapie occur in sheep 2-5 years of age (10) Rarely Cases present in sheep under one year of age because in some instances the commercial lifespan of sheep may be too short to allow the clinical disease to develop (8) and these findings were similar to that found in comparing with the present study. The encountered clinical findings in sheep were characterized by insidious onset, abnormal behavior, affected animal may lead or trail the rest of flock, tremor, nibbling, ataxia, incoordination of the gait, pruritus, lose weights and recumbency, all these findings, were in accordance with those previously reported(1,5,11,12).A particular interest of this outbreak is its appearance among adult sheep with high morbidity rate 21.05% in comparing with sporadically occurance in Europe(5). The Pathological findings reported in this outbreak were prominent in the medulla, Pons, Mid-brain which characterized by interstitial spongy degeneration and all of these findings were in agreed with those previously reported (13,14,15) . The presence of prion protein in body cells with a high concentration on the surface of nerve cells in the brain due to proteinase K resistance which deposite on to the brain killing other nerve cells which leads to holes in spongiform diseases (16).Immunohistochemistry appears to be useful in detecting scrapie in affected animals and remains promising as it is widely available and inexpensive(17). The final diagnosis was based on the characteristic clinical signs, histopathological findings and identification of the prion by immunohistochemistry.
1- Fraser H. Scrapie in sheep and goats and related diseases. In:Diseases of sheep. Third edition. Martin W.B., and Aitken I.D. Black-well scientific Ltd. Oxford. U.K. 2000, 207-218.
2- Richard T Johnson. .Review. Prion diseases. Lancet Neurol. 2005.4: b35-42.
3- Prusiner S.B. Novel Proteinaceaus infectious Particle Cause Scrapie. 1982, Science: 216:136-44.
4- Prusiner S.B. Prion: Novel infectious Pathogen. 1984 Advance virus. Res. a,29; 1-56.
5- Office International Des Epizootics. Manual of Diagnostic tests and Vaccine for Terrestrial animals- Scrapie. 5th edition, 2004.
6- Luna LG.Manual of histologic staining methods of the Armed Force Institute of Pathology. 3rd .ed. Newyork; M.C.Grow-Hill Book company.
7- Miller J,M., Jenny A,l., Taylor W,D., Race R,E., Ernst D,R., Katz J,B., and Rubenstein R. Detection of prion protein in Formalin-Fixed brain by hydrated autoclaving immunohistochemistry for diagnosis of Scrapie in sheep. 1994 J.vet.Diagn. Investing., 16:366-368.
8- Frederic A Murphy, E Paul J Gibbs, Marinac Hozinek,Michael J studdert. Veterinary virology.3rd ed Academic press Newyork ,2003 P575-576.
9- Wood J L.N., Lund L.J., and Done S.H., The natural occurrence of scrapie in Moufflon. 1992 Vet. Rec-, 130, 25-27.
10- Hoinville L.J.A review of the epidemiology of Scrapie in sheep. Rev. sci tech off. Int.Epiz. 1996, 15, 827-852.
11- Kimberline R.H. Scrapie Disease 1981 Br. Vet .J.. 137, 105-112.
12- Parry H.B. Scrapie Disease in sheep. Historical Clinical Epidemiological, pathological and practical Aspects of the natural disease.Oppenheimer DR, ed. Academic press London . UK, 1983, pp192.
13- Jubb K.V.F, Kennedy P.C, and Palmer N. Pathology of Domestic Animals -3rd ed. Vol-I.Academic Prees, Newyork 1985 PP 305-307.
14- Wood J.L.,N,MCGill I.S., Done S.H., and Bradley R. Neuro Pathology of Scrapie: a Study of the distribution patterns of brain lesions in 222 cases of natural scrapie in sheep, 1982-1991 .1997 vet. Rec., 140,167-174.
15- Jeffry M.,Martins., Gonzalezt., Ryder S.J., Bellwothy S.J.,and Jackman R. Differential diagnosis of infections with the Bovine Spongiform Encephalopathy (BSE) and Scrapie agents in sheep. 2001 J. comp. Pathol., 125,271-284.
16- Pousiner S.B. Prions. Proc Natl Acad sci USA. 1998., 95; 13363-83
17- Belt, P.B .G.M, Muileman I.H., Schreuder B.E.C., Gielken A.L.J.,and Smith M.A. Identification of Five allelic, Variants of the sheep PrP gene and their association with natural scrapie. 1995 Journal of general virology, , 76, 509-517.
OR, remember the infamous Louping-ill vaccine that caused some many scrapie cases here ;
From: TSS (216-119-138-163.ipset18.wt.net) Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: September 10, 2000 at 8:57 am PST
Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: Sat, 9 Sep 2000 17:44:57 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946
NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND
ANNUAL CONGRESS, 1946
The annual Congress, 1946, was held at the Royal Veterinary College, Royal College Street, London, N.W.I. from September 22nd to September 27th.
[skip to scrapie vaccine issue...tss]
Papers Presented to Congress
The papers presented to this year's Congress had as their general theme the progressive work of the profession during the war years. Their appeal was clearly demonstrated by the large and remarkably uniform attendance in the Grand Hall of the Royal Veterinary College throughout the series; between 200 and 250 members were present and they showed a keen interest in every paper, which was reflected in the expression of some disappointment that the time available for discussion did not permit of the participation of more than a small proportion of would-be contributors.
In this issue we publish (below) the first to be read and discussed, that by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary Research." Next week's issue will contain the paper on "Some Recent Advances in Veterinary Medicine and Surgery in Large-Animal Practice" by Mr. T. Norman Gold, M.R.C.V.S. In succeeding numbers of the Record will be reproduced, also with reports of discussions, that by Mr. W. L. Weipers, M.R.C.V.S., D.V.S.M., on the same subject as relating to small-animal practice, and the papers by Mr. J. N. Ritchie, B.SC., M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on "War-time Achievements of the British Home Veterinary Services."
The first scientific paper of Congress was read by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946, when Professor J. Basil Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal of the Royal Veterinary College, presided.
Advances in Veterinary Research
W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.
Agriculteral Research Council, Field Station, Compton, Berks.
Louping-ill, Tick-borne Fever and Scrapie
In 1930 Pool, Browniee & Wilson recorded that louping-ill was a transmissible disease. Greig et al, (1931) showed that the infective agent was a filter-passing virus with neurotropic characters and Browniee & Wilson (1932) that the essential pathology was that of an encephalomyelitis. Gordon, Browniee, Wilson & MacLeod (1932) and MacLeod & Gordon (1932) confirmed and extended this work. It was shown that on louping-ill farms the virus was present in the blood of many sheep which did not show clinical symptoms indicating involvement of the central nervous system and that for the perpetuation and spread of the disease these subclinical cases were probably of greater importance that the frank clinical cases because, in Nature, the disease was spread by the tick, lxodes ricinus L. More recently Wilson (1945, 1946) has described the cultivation of the virus in a chick embryo medium, the pathogenic properties of this culture virus and the preparation of louping-ill antiserum.
Between 1931 and 1934 I carried out experiments which resulted in the development of an effective vaccine for the prevention of louping-ill.* This vaccine has been in general use since 1935 and in his annual report to the Animal Diseases Research Association this year, Dr. Greig stated that about 227,000 doses of vaccine had been issued from Moredun alone.
Dr. Gordon illustrated this portion of his paper by means of graphs and diagrams projected by the epidiascope.
This investigation, however, did not begin and end with the study of louping-ill; it had, by good fortune, a more romantic turn and less fortunately a final dramtic twist which led almost to catastrope. After it had been established that a solid immunity to louping-ill could be induced in sheep, a group of immunized and a group of susceptible animals were placed together on the tick-infected pasture of a louping-ill farm. Each day all the animals were gathered and their temperatures were recorded. It was anticipated that febrile reactions with some fatalities would develop in the controls while the louping-ill immunes would remain normal. Contrary to expectation, however, every sheep, both immune and control, developed a febrile reaction. This unexpected result made neccessary further investigation which showed that the febrile reaction in the louping-ill immunes was due to a hitherto undescribed infective agent, a Rickettsia-like organism which could be observed in the cytoplasm of the grannular leucocytes, especially the neutrophil polymorphs (MacLeod (1932), Gordon, Browniee, Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod (1936). MacLeod collected ticks over many widely separated parts of Scotland and all were found to harbour the infective agent of tick-borne fever, and it is probable that all sheep on tick-infested farms develop this disease, at least on the first occasion that they become infested with ticks. When the infection is passed in series through susceptible adult sheep it causes a sever, febrile reaction, dullness and loss of bodily condition but it rarely, if ever, proves fatal. It is clear, however, that it aggravates the harmful effects of a louping-ill infection and it is a serious additional complication to such infections as pyaemia and the anacrobic infections which beset lambs on the hill farms of Northern Britain.
Studying the epidemiology of louping-ill on hill farms it became obvious that the pyaemic condition of lambs described by M'Fadyean (1894) was very prevalent on tick infested farms Pyaemia is a crippling condition of lambs associated with tick-bite and is often confused with louping-ill. It is caused by infection with Staphylococcus aureus and affected animals may show abscess formation on the skin, in the joints, viscera, meninges and elsewhere in the body. It was thought that tick-borne fever might have ben a predisposing factor in this disease and unsuccessful attempts were made by Taylor, Holman & Gordon (1941) to reproduce the condition by infecting lambs subcutaneously with the staphylococcus and concurrently produceing infections with tickborne fever and louping-ill in the same lambs. Work on pyaemia was then continued by McDiarmid (1946a, 1946b, 1946c), who succeeded in reproducing a pyaemic disease in mice, guinea-pigs and lambs similar to the naturally occuring condition by intravenous inoculation of Staphylococcus aureus. He also found a bacteraemic form of the disease in which no gross pyaemic lesions were observed. The prevention or treatment of this condition presents a formidable problem. It is unlikely that staphylococcal ???oid will provide an effective immunity and even if penicillin proved to be a successful treatment, the difficulty of applying it in adequate and sustained dosage to young lambs on hill farms would be almost insurmountable.
From 1931 to 1934 field trials to test the immunizing value and harmlessness of the loup-ill vaccine were carried out on a gradually increasing scale. Many thousands of sheep were vaccinated and similar numbers, living under identical conditions were left as controls. The end result showed that an average mortability of about 9 percent in the controls was reduced to less than 1 percent in the vaccinated animals. While the efficiency of the vaccine was obvious after the second year of work, previous bitter experience had shown the wisdom of withholding a biological product from widespread use until it had been successfully produced in bulk, as opposed to small-scale experimental production and until it had been thoroughly tested for immunizing efficiency and freedom from harmful effects. It was thought that after four years testing this stage had been reached in 1935, and in the spring of that year the vaccine was issued for general use. It comprised a 10 percent saline suspension of brain, spinal cord and spleen tissues taken from sheep five days after infection with louping-ill virus by intracerebral inoculation. To this suspension 0-35 percent of formalin was added to inactivate the virus and its safety for use as a vaccine was checked by intracerbral inoculation of mice and sheep and by the inoculation of culture medium. Its protective power was proved by vaccination sheep and later subjecting them, along with controls, to a test dose of living virus.
Vaccine for issue had to be free from detectable, living virus and capable of protecting sheep against a test dose of virus applied subcutaneously. The 1935 vaccine conformed to these standards and was issued for inoculation in March as three separate batches labelled 1, 2, and 3. The tissues of 140 sheep were employed to make batch 1 of which 22,270 doses were used; 114 to make batch 2 of which 18,000 doses were used and 44 to make batch 3 of which 4,360 doses were used. All the sheep tissues incorporated in the vaccine were obtained from yearling sheep. During 1935 and 1936 the vaccine proved highly efficient in the prevention of loup-ill and no user observed an ill-effect in the inoculated animals. In September, 1937, two and a half years after vaccinating the sheep, two owners complained that scrapie, a disease which had not before been observed in the Blackface breed, was appearing in their stock of Blackface sheep and further that it was confined to animals vaccinated with louping-ill vaccine in 1935. At that stage it was difficult to conceive that the occurrence could be associated with the injection of the vaccine but in view of the implications, I visited most of the farms on which sheep had been vaccinated in 1935. It was at this point that the investigation reached its dramatic phase; I shall not forget the profound effect on my emotions when I visited these farms and was warmly welcomed because of the great benefits resulting from the application of louping-ill vaccine, wheras the chief purpose of my visit was to determine if scrapie was appearing in the inoculated sheep. The enquiry made the position clear. Scrapie was developing in the sheep vaccinated in 1935 and it was only in a few instances that the owner was associating the occurrence with louping-ill vaccination. The disease was affecting all breeds and it was confined to the animals vaccinated with batch 2. This was clearly demonstrated on a number of farms on which batch 1 had been used to inoculate the hoggs in 1935 and batch 2 to inoculate the ewes. None of the hoggs, which at this time were three- year-old ewes. At this time it was difficult to forecast whether all of the 18,000 sheep which had received batch 2 vaccine would develop scrapie. It was fortunate, however, that the majority of the sheep vaccinated with batch 2 were ewes and therfore all that were four years old and upwards at the time of vaccination had already been disposed of and there only remained the ewes which had been two to three years old at the time of vaccination, consequently no accurate assessment of the incidence of scrapie could be made. On a few farms, however, where vaccination was confined to hoggs, the incidence ranged from 1 percent, to 35 percent, with an average of about 5 percent. Since batch 2 vaccine had been incriminated as a probable source of scrapie infection, an attempt was made to trace the origin of the 112 sheep whose tissues had been included in the vaccine. It was found that they had been supplied by three owners and that all were of the Blackface or Greyface breed with the exception of eight which were Cheviot lambs born in 1935 from ewes which had been in contact with scrapie infection. Some of these contact ewes developed scrapie in 1936-37 and three surviving fellow lambs to the eight included in the batch 2 vaccine of 1935 developed scrapie, one in September, 1936, one in February, 1937, and one in November, 1937. There was, therefore, strong presumptive evidence that the eight Cheviot lambs included in the vaccine althought apparently healthy were, in fact, in the incubative stage of a scrapie infection and that in their tissues there was an infective agent which had contaminated the batch 2 vaccine, rendering it liable to set up scrapie. If that assumption was correct then the evidence indicated that:-
(1) the infective agent of scrapie was present in the brain, spinal cord and or spleen of infected sheep: (2) it could withstand a concentration of formalin of 0-35 percent, which inactivated the virus of louping-ill: (3) it could be transmitted by subcutaneous inoculation; (4) it had an incubative period of two years and longer.
Two Frenchmen, Cuille & Chelle (1939) as the result of experiments commenced in 1932, reported the successful infection of sheep by inoculation of emulsions of spinal cord or brain material by the intracerebral, epidural, intraocular and subcutaneous routes The incubation period varied according to the route employed, being one year intracerebrally, 15 months intraocularly and 20 months subcutaneously. They failed to infect rabbits but succeeded in infecting goats. Another important part of their work showed that the infective agent could pass throught a chamberland 1.3 filter, thus demonstrating that the infective agent was a filtrable virus. It was a curious coincidence that while they were doing their transmission experiments their work was being confirmed by the unforeseeable infectivity of a formalinized tissue vaccine.
As a result of this experience a large-scale transmision experiment involving the ue of 788 sheep was commenced in 1938 on a farm specially taken for the purpose by the Animal Diseases Research Association with funds provided by the Agricultural Research Council. The experiment was designed to determine the nature of the infective agent and the pathogenesis of the disease. It is only possible here to give a summary of the result which showed that (1) saline suspensions of brain and spinal cord tissue of sheep affected with scrapie were infective to normal sheep when inoculatted intracerebrally or subcutaneously; (2) the incubation period after intracerebral inoculation was seven months and upwards and only 60 percent of the inoculated sheep developed scrapie during a period of four and a half years; (3) the incubation period after subcutaneous inoculation was 15 months and upwards and only about 30 percent of the inoculated sheep developed the disease during the four and a half years: (4) the infective agent was of small size and probably a filtrable virus.
The prolonged incubative period of the disease and the remarkable resistance of the causal agent to formalin are features of distinct interest. It still remains to determine if a biological test can be devised to detect infected animals so that they can be killed for food before they develop clinical symptoms and to explore the possibilities of producing an immunity to the disease. ==================================================================
Greetings List Members,
pretty disturbing document. now, what would stop this from happening with the vaccineCJD in children???
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
Subject: VACCINES/CHILDREN/TSE'S -- 'CONFIDENTIAL' From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:email@example.com> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 5 Sep 2000 12:00:34 -0700 Content-Type: text/plain Parts/Attachments: text/plain (148 lines)
######### Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> #########
Greetings list members,
this document is very disturbing, considering if they continued to use these vaccines, the U.K. could loose a generation of children. If they continue to force these vaccines on children, they could loose more than just one generation, looking at the inventory. I did not know, that a Government body or bodies, if you include the United States, could be so stupid to this disease, with the evidence they have to date. It's as blatant and negligent as you can get. You may think the BSE Inquiry is almost over, but that was only the beginning.
The Truth Will Come... (just hope i'm alive to see it)
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA ============================================
Dr Harris (MED)
From: Dr Adams (MB3B)
cc - Dr. Pickles
Date: 14 February 1989
BOVINE SPONGIFORM ENCEPHALOPATHY
This minute details the information received on human vaccines in response to telephone enquires, and details of forthcoming expert group meetings during February 1989.
Subject: VACCINES and CJD -- FDA says Mothers to stupid to understand... 7/27/2000 TSE Advisory Committee From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:firstname.lastname@example.org> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 19 Sep 2000 11:12:39 -0700
######### Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> #########
Greetings List Members,
"Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map." We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels."
But I think the Mothers are smart enough to know, that the scrapie agent has been the model for CJD research since day one. So, I think the Louping-ill vaccine and Scrapie episode, which killed many sheep, from a vaccine made from scrapie-infected brain, is most important, and I think these Mothers are smart enough to understand that...
TSE Advisory Committee 7/27/2000
259 I feel the need to say something. It's theoretical. I agree with your sense of how often it's going to occur totally. What could we do? What could they do?
DR. SNIDER: This is Dixie Snider. Yeah, we can hear from him, but you made a criticism of my comment, and I just want -- I thought it might be useful to have something to go along with their U.S. Today story that they were reading. That's all. Something that's authoritative from the FDA.
CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this committee.
DR. RATZAN: If I could try to answer that, there is a scientific nature to how do you look at communication. You don't overreact to infinitesimal risks, and at the same time you don't under-react when there is a real risk that's involved, because that does undermine the public trust.
What I heard today were some of the steps that were being taken by some of the manufacturers, the two that presented, that they are trying to embody the public trust in terms of their processes. I think more of the open nature, even meetings like this of being able to have advisory meetings, meetings also that might have the professional associations where you have opinion leaders who might be able to defuse the information appropriately.
A blanket communication -- We often say Marshall McCluhan, a Canadian scholar in media, said, if you try to reach everybody, you reach nobody. By doing that, it's really key in thinking about communicating with the people that need to know.
Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map. We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels.
So I'm answering in a circuitous way, because I think we've heard some of the right steps being taken today, the open hearing, some of the voluntary efforts that are being done in good faith by the manufacturers, and some of the other ways that continue to monitor the open disclosure. I think the surveillance systems that we've put in place not only here in the United States but now abroad in looking at BSE and looking at the CJD that we heard from CDC and others where the numbers are.
So I would say, by all means, keep the surveillance. Keep the voluntary efforts. Continue to focus upon the science, and communicate that appropriately on, whether it's a quarterly basis, or use the different channels, the Institute of Medicine channels that are out there.
I think there's a variety of different expert committees as well. So, thank you.
CHAIRMAN BROWN: Thank you very much. Yes?
MS. FISHER: You may not want to communicate this theoretical risk to the public, but that doesn't mean it's the right thing to do. I think that part of what the National Childhood Injury Act of 1986 was all about, the safety provisions, was communicating risk to parents before they get their children vaccinated.
I think that, you know, the FDA's charge is to ensure the purity and potency of vaccines. It seems to me that the least that we can do at this juncture when we know something is to let the people know we know, rather than keeping it from them.
CHAIRMAN BROWN: Hold on, Dave. Shirley?
MS. WALKER: There's an old German proverb, "Don't point the devil on the wall; otherwise, he will jump off." I think the devil has already jumped off.
The inserts in the packets for pharmaceuticals are great. Notification to the doctor is great. But I represent something like 79,000 mothers who have children in Dallas County who we actively promote to get vaccinated.
So Monday morning when I go back to work, I'm going to have to tell someone, a percentage of these young mothers, that, hey, your child is at risk for whatever that minute amount is for CJD. So what do we do at this particular point? Do we remain mute and say nothing or do we promote and give some type of information?
So I am saying to FDA that we do need some kind of general information that we can impart to our constituents.
CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more comments in this discussion, and then in the event that a number of people on the committee may have to leave, there are two or three very specific questions that the FDA would like some discussion-on, and I want to move to them. We've touched on some of them already, but if there's anything more to say on this -- Yes, go ahead.
263 DR. STEPHENS: I guess I'm really concerned that this discussion is kind of spinning out of control in terms of the risk. I must agree with the consumer advocate who spoke a minute ago --
CHAIRMAN BROWN: Dr. Ratzan.
DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a duty, in my view, to protect the vaccine system in this country. I think that this discussion has gotten to the point of at least suggesting that we believe that this is a significant problem. The data suggests that the risk is in the billions, that there have not -- there's not been a single case of new variant CJD in this country, despite the use of vaccines manufactured in this way for years.
So I think the issue is we need public disclosure. That's not the question. I think we all are in agreement on this committee, but I think to emphasize this point where you're concerned about going back to your group of mothers and saying there's a risk -- I think that's something we don't want to send. That's a message we do not want to send.
CHAIRMAN BROWN: I opened this whole seminar with the notion that we're starting from a very, very small amount of infectivity, if there is any, and that there is a tradeoff between, as several people have said, a theoretical risk and a real risk, which would be discrediting in some way vaccines or causing vaccine shortages or difficulties or refusal to get vaccines.
In other words, this is the tradeoff. Right at the outset, this was the scene that I hoped to set. But you're right. All of our committee discussion meetings tend to spin out of control at about this time of the afternoon, and sometimes it's in one direction, and sometimes it's in another direction.
I think the word risk has enlarged as the afternoon has progressed, and maybe we should shrink it down a little bit and get a little better perspective or a little different perspective. So I tend to agree with you. Let me --
DR. BOLTON: Paul, can I get in my comment?
CHAIRMAN BROWN: I'm sorry? Go ahead.
BOLTON: I agree that it would be important to communicate known risks or even good estimates of risk to the public, but I'm not sure what that estimate would be at this point. I don't think that we really have enough information to communicate to the public and have it be meaningful and not simply scare people away.
I can't imagine the negative impact on the program in this country if parents started thinking that, if I vaccinate my child, he or she may come down with new variant CJD.
To me, the other way that we communicate is by action. It seems to me that there are actions that can be taken in terms of looking at the process of vaccine manufacture and where the real -- the greatest of the theoretical risks are. It seems to me that the viral/bacterial master seeds are really at the very lowest end, as are the master cell banks, and also trying to change those creates the biggest problem.
From that point on, from the working seeds on down through production, I think that the manufacturers have issues that they can address in terms of removing the use of at-risk bovine materials from that point on.
I guess my question to anybody at the FDA is: Are at-risk bovine materials currently in use at the -- certainly from the production step on, and even at the production of the working seeds and working cell lines, are they in use now, and how long before they will be phased out?
CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of anything currently coming from BSE designated countries?
DR. STEPHENS: When I say at risk, I really mean those bovine materials are coming from Europe or at-risk countries.
CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --
DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines there was bovine derived fermentation media where that skeletal muscle and pancreas derived from several European countries. I think it was Germany, Denmark, Poland, the Netherlands.
CHAIRMAN BROWN: Right. So they are currently in use in this country.
DR. EGAN: They have all agreed to -- That will be changed, but as I mentioned, by the time -- You know, they've gotten new sources, but that comes into new vaccines -- What?
DR. BOLTON: Is that the only material that's now sourced from at-risk countries?
DR. EGAN: That's used in the production. I think I also mentioned hemin. I think that was it, but I'd have to go back to it.
DR. BOLTON: So I guess my recommendation would be that the FDA work with the manufacturers to set a definite timeline to phase out all those materials. In terms of the master virus seeds and the bacterial stocks and the master cell lines, I think that the risk is so small as to be really counterproductive to try to change those, because the risk of changing the product by changing those is much, much greater than any risk that there would be from proceeding.
CHAIRMAN BROWN: One of the questions that the FDA specifically wanted some judgment on was: Is it necessary to re-derive bacterial master seeds? I mean, I'm getting the sense -- Every time I get the sense of something, the sense changes. You know, we had a consensus about informed consent, and now we have a consensus about not smother it, but be awfully, awfully, awfully careful.
Now I thought we had pretty much decided that, at least for current products, that it will not be necessary to re-derive bacterial master seeds. That was my sense. Dr. Huang?
DR. HUANG: I completely agree. I think that the derivation of new master seed stocks would be more dangerous than this perceived danger that we are facing now.
CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ from that opinion? All right. We have answered one definitive question that the FDA wanted to asked.
They also want an answer to a question I think should be very easy to answer. That is: Is 1980, form all that you have heard, an appropriate cutoff date before which one need not worry about anything in terms of sourcing of the products we are talking about?
We always worry about something, but 1980 -- is that an appropriate date before which not to be concerned? That's a pretty focused question. Is there anybody that feels that one should be concerned about products produced before 1980 from anywhere? Yes?
DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect to our blood donation pool in the United States,'we were concerned about BSE and started with 1980.
CHAIRMAN BROWN: It has the merit of consistency as well. All right. That's two questions.
The third question they were concerned about was: Do we think that the small amount of fetal calf serum from the U.K. around 1985 used in the production of master cell banks constitutes a negligible or -- well, the phrase was "a negligible or a significant risk"? Again, a question about fetal calf serum, sourced from the U.K. in the middle of the 1980s, use in the production of master cell banks constitutes any kind of significant risk? Yes?
DR. CLIVER: May I start by saying negligible. We'll see if anybody disagrees.
CHAIRMAN BROWN: Do I hear significant? Negligible?
[[[sounds like a damn auction...tss]]]
DR. BOLTON: I agree that it's negligible.
CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used for the production -- just for this specific purpose, used in the production of master cell banks? Well, that answers the three questions that you most wanted some judgment on Dr. Ewenstein?
Dr. EWENSTEIN: There was also the products that are still under investigation. I think, you know, we should address that. I think one of the comments before was, I think, right on the point. That is that it's different if you have a licensed drug or product that has, therefore, documented benefit versus recruited volunteers.
I think we should think about what we should answer for number 3. I think that it's appropriate to include again, with the correct caveat, about theoretical and negligibly small risk in a consent form. but I certainly wouldn't like to see all clinical trials stopped of such vaccines.
CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We haven't touched on that, and we might just continue that discussion a bit. Peter?
DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him correctly. I think that it is indeed a different situation. For one thing, not only is the benefit of the vaccine unknown, but for another, one actually does know the name of the patients, and one is personal contact with those patients on a semi-regular basis.
I think that the ethical responsibility toward those people is quite different than is owed to the population at large......
FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
The Old Days
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
Sunday, May 18, 2008 BSE, CJD, and Baby foods (the great debate 1999 to 2005)
Back to reality
When Atypical Scrapie cross species barriers
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
INFECTED AND SOURCE FLOCKS
There were 20 scrapie infected and source flocks with open statuses (Figure 3) as of April, 30, 2008. Twenty eight new infected and source flocks have been designated in FY 2008 (Figure 4); three source flocks were reported in April. ...snip
POSITIVE SCRAPIE CASES
As of April 30, 2008, 122 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 6). Of these, 103 were field cases and 19* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by May 20, 2008). Positive cases reported for April 2008 are depicted in Figure 7. Eighteen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 8). The most recent positive goat case was confirmed in February 2008 and originated from the same herd in Michigan as the other FY 2008 goat cases. ...snip
CAPRINE SCRAPIE PREVALENCE STUDY (CSPS)
However, four positive goats have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and the other three originated from the birth herd of the clinical case.
ANIMALS SAMPLED FOR SCRAPIE TESTING
As of April 30, 2008, 26,703 animals have been sampled for scrapie testing: 23,378 RSSS, 1,517 goats for the CSPS study, 1,466 regulatory field cases, 270 regulatory third eyelid biopsies, and 72 regulatory rectal biopsies (chart 8).
TESTING OF LYMPHOID TISSUE OBTAINED BY RECTAL BIOPSY WAS APPROVED BY USDA AS AN OFFICIAL LIVE-ANIMAL TEST ON JANUARY 11, 2008. ...
PLEASE NOTE, (FIGURE 6), Scrapie Confirmed Cases in FY 2008 MAP, PA 3, 1**, Two cases-state of ID UNKNOWN, 1 case Nor98-like**
CHAPTER 3 Animal Disease Eradication Programs and Control and Certification Programs
In FY 2007, two field cases, one validation study case, and two RSSS cases were consistent with a variant of the disease known as Nor98 scrapie.1 These five cases originated from flocks in California, Minnesota, Colorado, Wyoming, and Indiana, respectively.
NOR-98 Scrapie FY 2008 to date 1
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1]
September 1, 2008
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute,
Norway Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
Monday, December 1, 2008 When Atypical Scrapie cross species barriers
CONFIDENTIAL PAPER No: SEAC 78/9 Amendment 2 2 In March 2002, a SEAC Sub-Group considered the risks associated with certain genotypes entering the food chain if BSE were ever isolated from sheep. In contrast to the SSC opinion, SEAC concluded that: • In line with previous SEAC advice, only animals carrying the ARR allele should enter the food chain • On a precautionary basis, the 12 month cut off previously advised by SEAC remained appropriate for ARR heterozygotes. However, in view of existing SRM regulations there was no justification for any age cut off in ARR homozygotes • In line with SEAC advice in 2001, only milk from ARR homozygous sheep could be considered as highly unlikely to contain the infectious agent. Further experimental work was required before potential risks from small ruminant milk from goats and semi-resistant or susceptible sheep could be excluded. There is therefore a disparity of opinion between the SSC and SEAC on this issue. Whilst recognising the uncertainties relating to the science in this area, it is important that contingency planning is based on the most up to date scientific developments and assessments of risk that are available. SEAC will be presented with an update on the ongoing BSE in sheep studies, funded by Defra (Annex 31). This covering paper also provides a history of previous SEAC advice on this issue. BACKGROUND...snip...end
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
A The Present Position with respect to Scrapie The Problem
Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it is fatal. It is enzootic in the United Kingdom but not in all countries.
The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep.
It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible.
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the scrapie problem urgent if the sheep industry is not to suffer grievously.
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
Wednesday, January 28, 2009TAFS1 Position Paper on BSE in small ruminants (January 2009)