Difference between revisions of "Scrapie"

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Also known as: '''''TSE – Transmissible spongiform encephalopathy''''', '''''Paraplexia enzootica ovium'''''  
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Also known as: '''''Transmissible Spongiform Encephalopathy of Sheep — TSE — Paraplexia enzootica ovium'''''  
 
  
 
==Introduction==  
 
==Introduction==  
  
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Scrapie is a '''progressive, fatal''' and '''non-febrile neurological''' disorder affecting '''sheep''' and '''goats'''.  It belongs to a group of diseases called [[:Category:Transmissible Spongiform Encephalopathies|transmissible spongiform encephalopathy (TSE)]] and [[Prion Disease|other TSE’s]] include Creutzfeldt-Jakob disease in humans, [[BSE]], chronic wasting disease (CWD) in elk and deer, transmissible mink encephalopathy and feline spongiform encephalopathy has been found within cats in the UK.  
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Scrapie is a progressive, fatal and non-febrile neurological disorder affecting sheep and goats.  It belongs to a group of diseases called transmissible spongiform encephalopathy (TSE) and other TSE’s include Creutzfeldt-Jakob disease in humans, BSE, chronic wasting disease (CWD) in elk and deer, transmissible mink encephalopathy and feline spongiform encephalopathy has been found within cats in the UK. The disease is believed to be caused by a conformational change in the prion (PrP).  A prion is a protein that occurs normally in the nervous and lymphoreticular tissues.  It is only when the prion changes conformation into a protease-resistant protein  PrP<sup>sc</sup> that it causes degeneration of neurological tissue. The disease causes astrocyte proliferation and then vacuolization of neurons but demyelination does not occur <ref name=" Dandoy-Dron et al., 1998 ">. Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Lasmézas C, Dormont D, Tovey MG, Dron M, 1998. Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. Journal of Biological Chemistry, 273(13):7691-7697,48 ref.</ref>. The abnormal protein is thought to act as a catalyst to convert more of the host’s protein into this abnormal form.  The disease has been notifiable in the EU since 1993 but unlike BSE there is no evidence to suggest that scrapie is a risk to human health <ref name="Brown et al., 1987">Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P, 1987. The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. Neurology, 37(6):895-904.</ref>, <ref name="Harries et al.,1988">Harries JR, Knight R, Will RG, Cousens SN, Smith PG, Mathews WB, 1988. Creutzfeldt-Jakob disease in England and Wales, 1980-1984: a case-control study of potential risk factors. Journal of Neurology Neurosurgery and Psychiatry, 51(9):1113-1119.</ref>,<ref name="Kondo and Kuriowa, 1982">Kondo K, Kuriowa Y, 1982. A case control study of Creutzfeldt-Jakob disease: association with physical injuries. Annals of Neurology, 11(4):377-381.</ref>, <ref name="WHO, 1999">World Health Organization, 1999. WHO consultation on public health and animal transmissible spongiform encephalopathies: epidemiology, risk and research requirements, with the participation of the Office International des Epizooties. http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000,Accessed 7 March 2005. http://www.who.int/csr/resources/publications/bse/en/whocdscsraph20002.pdf.</ref>. Studies have suggested that after ingestion, PrP<sup>sc</sup> first accumulates in Peyer’s patches of the small intestine, gut-associated lymphoid tissues (GALT) and ganglia of the enteric nervous system <ref name="Beekes and McBride,2000">Beekes M, McBride PA, 2000. Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neuroscience Letters, 278(3):181-184.</ref>,<ref name="Beekes et al., 1998">Beekes M, McBride PA, Baldauf E, 1998. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. Journal of General Virology, 79(3):601-607; 20 ref.</ref>, <ref name="Heggebø et al., 2000">Heggebø R, Press CM, Gunnes G, Lie KaiInge, Tranulis MA, Ulvund M, Groschup MH, Landsverk T, 2000. Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. Journal of General Virology, 81(9):2327-2337; 2 pp. of ref.</ref>, <ref name="Kimberlin and Walker, 1989">Kimberlin RH, Walker CA, 1989. Pathogenesis of scrapie in mice after intragastric infection. Virus Research, 12(3):213-220; 32 ref.</ref>, <ref name="Keulen et al., 1999">Keulen LJMvan, Schreuder BEC, Vromans MEW, Langeveld JPM, Smits MA, 1999. Scrapie-associated prion protein in the gastro-intestinal tract of sheep with natural scrapie. Journal of Comparative Pathology, 121(1):55-63; 24 ref.</ref>, it then spreads throughout the lymph nodes, tonsils, spleen, and into the peripheral nervous tissue.  It finally found in the brain several months later. The disease is thought to have come from imported Merino sheep from Spain and has since spread through the movement of infected sheep. Only Australia and New Zealand are recognized as being currently free of scrapie.
  
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The disease is believed to be caused by a '''conformational change in the prion (PrP)'''.  A prion is a protein that occurs normally in the nervous and lymphoreticular tissues. It is only when the prion changes conformation into a protease-resistant protein  PrP<sup>sc</sup> that it causes degeneration of neurological tissue. The disease causes astrocyte proliferation and then vacuolization of neurons but demyelination does not occur <ref name=" Dandoy-Dron et al., 1998 ">. Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Lasmézas C, Dormont D, Tovey MG, Dron M (1998) '''Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts.''''' Journal of Biological Chemistry,'' 273(13):7691-7697,48 ref.</ref>. The abnormal protein is thought to act as a catalyst to convert more of the host’s protein into this abnormal form.  
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==Signalment==
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Scrapie affects the majority of sheep between 3 and 5 years of age and has a long incubation period of two to five years.  It is extremely durable and is able to withstand high temepratures and concentrations of formaldehyde.  Unlike BSE, scrapie is influenced by breed and genetic variation of the PrP gene within sheep populations, which can affect the infectivity and incubation period of the scrapie.  The disease has been shown to be effectively transmitted during lambing  through infected placental tissue <ref name="Dickinson et al., 1974"> Dickinson AG, Stamp JT, Renwick CC, 1974. Maternal and lateral transmission of scrapie in sheep. Journal of Comparative Pathology, 84(1):19-25.</ref>, <ref name="Hourrigan et al., 1979 " /> as placenta and possibly the placental fluids are thought to be a source of infection <ref name="Andréoletti et al., 2002">Andréoletti O, Lacroux C, Chabert A, Monnereau L, Tabouret G, Lantier F, Berthon P, Eychenne F, Lafond-Benestad S, Elsen JM, Schelcher F, 2002. PrP accumulation in placentas of ewes exposed to natural scrapie: influence of foetal PrP genotype and effect on ewe-to-lamb transmission. Journal of General Virology, 83(10):2607-2616; 48 ref.</ref>, <ref name="Onodera et al., 1993"> Onodera T, Ikeda T, Muramatsu Y, Shinagawa M, 1993. Isolation of scrapie agent from the placenta of sheep with natural scrapie in Japan. Microbiology and Immunology, 37(4):311-316. </ref>, <ref name="Race et al., 1998">Race R, Jenny A, Sutton D, 1998. Scrapie infectivity and proteinase K-resistant prion protein in sheep placenta, brain, spleen, and lymph node: implications for transmission and antemortem diagnosis. Journal of Infectious Diseases, 178(4):949-953; 29 ref. </ref>, <ref name="Tuo et al., 2002">Tuo WB, O'Rourke KI, Zhuang DY, Cheevers WP, Spraker TR, Knowles DP, 2002. Pregnancy status and fetal prion genetics determine PrP accumulation in placentomes of scrapie-infected sheep. Proceedings of the National Academy of Sciences of the United States of America, 99(9):6310-6315; 31 ref. </ref>, <ref name="Tuo et al., 2001">Tuo W, Zhuang D, Knowles DP, Cheevers WP, Sy M-S, O’Rourke K, 2001. PrP-C and PrP-Sc at the fetal-maternal interface. Journal of Biological Chemistry, 276(21):18229-18234.</ref> and experimental studies have shown that oral dosing of infected placenta can spread the disease in sheep and goats <ref name="Pattison et al., 1972">Pattison IH, Hoare MN, Jebbett JN, 1972. Spread of scrapie to sheep and goats by oral dosing with foetal membranes from scrapie-affected sheep. Veterinary Record, 90(17):465-468.</ref>.
  
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The disease has been '''notifiable in the EU''' since 1993 but unlike BSE there is no evidence to suggest that scrapie is a risk to human health <ref name="Brown et al., 1987">Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P (1987) '''The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. '''''Neurology, ''37(6):895-904.</ref>, <ref name="Harries et al.,1988">Harries JR, Knight R, Will RG, Cousens SN, Smith PG, Mathews WB (1988) '''Creutzfeldt-Jakob disease in England and Wales, 1980-1984: a case-control study of potential risk factors.''''' Journal of Neurology Neurosurgery and Psychiatry,'' 51(9):1113-1119.</ref>,<ref name="Kondo and Kuriowa, 1982">Kondo K, Kuriowa Y (1982)''' A case control study of Creutzfeldt-Jakob disease: association with physical injuries. '''''Annals of Neurology, 11(4):377-381.</ref>, <ref name="WHO, 1999">World Health Organization, 1999. WHO consultation on public health and animal transmissible spongiform encephalopathies: epidemiology, risk and research requirements, with the participation of the Office International des Epizooties. http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000,Accessed 7 March 2005. http://www.who.int/csr/resources/publications/bse/en/whocdscsraph20002.pdf.</ref>.  
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==Clinical Signs==
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Early clinical signs may include subtle behavioural changes such as staring or fixed gaze, teeth grinding (bruxism), fine tremor, and hyperaesthesia to sound or sudden movements. Affected animals may later become intolerant to exercise and develop ataxia (awkwardness at turning, swaying of the hindquarters and some gait abnormalities such as a high stepping gait in the forelimbs or a bunny hopping gait in the hindlimbs). Some sheep have intense pruritis that leads to compulsive rubbing, nibbling at the skin, or scraping against fixed objects and may lead to wool loss (especially over the hindquarters and lateral thorax). A characteristic lip smacking or nibbling reflex can often be elicited by scratching over the lumbar region. In later stages there can be significant weight loss even without a noticeable decrease in appetite, weakness, recumbency, and death. <ref name="Bradley, 1997"> Bradley R, 1997. Animal prion diseases. In: Collinge J, Palmer MS, eds. Prion diseases. Oxford, UK: Oxford University Press, 89-129.</ref>, <ref name="Dickinson, 1976"> Dickinson AG, 1976. Scrapie in sheep and goats. Frontiers in Biology, 44:209-241</ref>, <ref name="Kimberlin, 1981"> Kimberlin RH, 1981. Scrapie. British Medical Journal, 137:105-112.</ref>, <ref name="Palmer, 1976, "> Palmer AC, 1976. Scrapie. In: Palmer AC, ed. Introduction to animal neurology. Oxford, UK: Blackwell Scientific Publications, 177-178.</ref>, <ref name=" Parry and Oppenheimer, 1983" />. It is important to note that some scrapie-infected sheep may appear healthy until stressed by  transport, shearing, or pregnancy <ref name="Detwiler and Baylis, 2003" />.
  
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Scrapie is thought to have come from imported Merino sheep from Spain and has since spread through the movement of infected sheep. Only Australia and New Zealand are recognized as being currently free of scrapie.
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==Diagnosis==
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A pre-emptive diagnosis of scrapie may be made from the above clinical signs and history. There are no serological test available for scrapie, as there is no immune or inflammatory response <ref name="Kasper et al., 1982"> Kasper K, Bowman K, Panitch H, Prusiner SB, 1982. Immunological studies of scrapie infection. Journal of Neuroimmunology, 3(3):187-201.</ref>, <ref name="Porter et al., 1973."> Porter D, Porter H, Cox N, 1973. Failure to demonstrate a humoral immune response to scrapie infection in mice. Journal of Immunology, 111(5):1407-1410.</ref>.  
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==Pathophysiology==
 
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Studies have suggested that after ingestion, PrP<sup>sc</sup> first accumulates in [[Peyer's Patches - Anatomy & Physiology|Peyer’s patches]] of the small intestine, [[Regional Lymphoid Tissue - Anatomy & Physiology#Structure|gut-associated lymphoid tissues (GALT)]] and ganglia of the enteric nervous system <ref name="Beekes and McBride,2000">Beekes M, McBride PA (2000) '''Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. '''''Neuroscience Letters,'' 278(3):181-184.</ref>,<ref name="Beekes et al., 1998">Beekes M, McBride PA, Baldauf E (1998) '''Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie.''''' Journal of General Virology,'' 79(3):601-607; 20 ref.</ref>, <ref name="Heggebø et al., 2000">Heggebø R, Press CM, Gunnes G, Lie KaiInge, Tranulis MA, Ulvund M, Groschup MH, Landsverk T (2000) '''Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent.''''' Journal of General Virology,'' 81(9):2327-2337; 2 pp. of ref.</ref>, <ref name="Kimberlin and Walker, 1989">Kimberlin RH, Walker CA (1989) '''Pathogenesis of scrapie in mice after intragastric infection.''''' Virus Research,'' 12(3):213-220; 32 ref.</ref>, <ref name="Keulen et al., 1999">Keulen LJMvan, Schreuder BEC, Vromans MEW, Langeveld JPM, Smits MA (1999) '''Scrapie-associated prion protein in the gastro-intestinal tract of sheep with natural scrapie.''''' Journal of Comparative Pathology,'' 121(1):55-63; 24 ref.</ref>, it then spreads throughout the [[Lymph Nodes - Anatomy & Physiology|lymph nodes]], [[Tonsils - Anatomy & Physiology|tonsils]], [[Spleen - Anatomy & Physiology|spleen]], and into the [[PNS Structure - Anatomy & Physiology|peripheral nervous tissue]]. It is finally found in the brain several months later. It is extremely durable and is able to withstand high temperatures and concentrations of formaldehyde.
 
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==Signalment==
 
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Scrapie affects the majority of sheep between '''3 and 5 years of age''' and has a '''long incubation period''' of two to five years. Unlike BSE, scrapie is influenced by breed and genetic variation of the PrP gene within sheep populations, which can affect the infectivity and incubation period of the scrapie.
 
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The disease has been shown to be effectively '''transmitted during lambing''' <ref name="Dickinson et al., 1974"> Dickinson AG, Stamp JT, Renwick CC (1974) '''Maternal and lateral transmission of scrapie in sheep.''''' Journal of Comparative Pathology,'' 84(1):19-25.</ref>, <ref name="Hourrigan et al., 1979">Hourrigan JL, Klingsporn AI, Clark WW, DeCamp M (1979) '''Epidemiology of scrapie in the US. In: Prusiner SB, Hadlow W, eds. Slow transmissible diseases of the nervous system.''''' New York: Academic Press,'' 331-356.</ref>, and experimental studies have shown that the ingestion of infected placenta can spread the disease in sheep and goats <ref name="Pattison et al., 1972">Pattison IH, Hoare MN, Jebbett JN (1972) '''Spread of scrapie to sheep and goats by oral dosing with foetal membranes from scrapie-affected sheep. '''''Veterinary Record,'' 90(17):465-468.</ref>.
 
  
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==Clinical Signs==
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Pathologic lesions are confined to the CNS. Histology (immunohistochemistry) usually shows vacuolation and an accumulation of prion proteins in various parts of the CNS (medulla, pons, midbrain, and spinal cord). However vacuolation is not completely diagnostic since it may also be present to a lesser extent in the brains of healthy sheep <ref name="Fraser, 1976"> Fraser H, 1976. The pathology of a natural and experimental scrapie. Frontiers of Biology, 44:267-305.</ref>, <ref name="Zlotnik and Rennie, 1958"> Zlotnik I, Rennie JC, 1958. A comparative study of the incidence of vacuolated neurones in the medulla from apparently healthy sheep of various breeds. Journal of Comparative Pathology, 68:411-415.</ref>. In most instances the abnormal prion is resistant to protein kinase digestion, a feature used in diagnostic techniques.  
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[[File:Sheep-scrapie1.jpg|thumb|200px|right|Picture from the rear shows bare patches from rubbing (Sourced from Wiki Commons)]]
 
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Early clinical signs may include subtle '''behavioural and neurological changes'''. Sheep often have a '''fixed gaze''', and suffer from bruxism, fine tremors, and hyperaesthesia to sound or sudden movements. Affected animals may later become exercise intolerant and develop '''progressive ataxia'''.  Sheep often find difficulty in turning, sway on their hind hindquarters and have gait abnormalities such as a high stepping gait in the forelimbs or a bunny hopping gait in the hind limbs. Some sheep have '''intense pruritus''' that leads to compulsive rubbing, nibbling at the skin, or scraping against fixed objects. Wool loss is typically seen over the hindquarters and lateral thorax. Lip smacking or '''nibbling reflex''' can often be elicited by scratching over the lumbar region, which is characteristic of scrapie. Significant weight loss with or without a decrease in appetite, weakness, recumbency, and death are all seen within the later stages of the disease.  
 
  
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==Diagnosis==
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PrP<sup>Sc</sup> from post-mortem brainstem or lymphoid tissues may be detected by Western immunoblot analysis <ref name="Farquhar et al., 1989">Farquhar CF, Somerville RA, Ritchie LA, 1989. Post-mortem immunodiagnosis of scrapie and bovine spongiform encephalopathy. Journal of Virological Methods, 24(1, 2):215-222; 21 ref.</ref>, <ref name="Stack et al., 1996"> Stack MJ, Keyes P, Scott AC, 1996. The diagnosis of bovine spongiform encephalopathy and scrapie by the detection of fibrils and the abnormal protein isoform. In: Baker H, Ridley RM, eds. Methods in molecular medicine: prion diseases. Totowa, New Jersey, USA: Humana Press, 85-103.</ref>, <ref name="Wadsworth et al., 2001 "> Wadsworth JDF, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J, 2001. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet, 358(9277):171-180.</ref> and immunohistochemistry (IHC) <ref name="Miller et al., 1993">Miller JM, Jenny AL, Taylor WD, Marsh RF, Rubenstein R, Race RE, 1993. Immunohistochemical detection of prion protein in sheep with scrapie. Journal of Veterinary Diagnostic Investigation, 5(3):309-316; 38 ref.</ref>, <ref name="Miller et al., 1994">Miller JM, Jenny AL, Taylor WD, Race RE, Ernst DR, Katz JB, Rubenstein R, 1994. Detection of prion protein in formalin-fixed brain by hydrated autoclaving immunohistochemistry for the diagnosis of scrapie in sheep. Journal of Veterinary Diagnostic Investigation, 6(3):366-368; 10 ref</ref>, <ref name="O'Rourke et al., 1998">O'Rourke KI, Baszler TV, Parish SM, Knowles DP, 1998. Preclinical detection of PrP in nictitating membrane lymphoid tissue of sheep. Veterinary Record, 142(18):489-491; 14 ref.</ref>, <ref name="Keulen et al., 1996; ">Keulen LJMvan, Schreuder BEC, Meloen RH, Mooij-Harkes G, Vromans MEW, Langeveld JPM, 1996. Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. Journal of Clinical Microbiology, 34(5):1228-1231; 26 ref.</ref>, <ref name="Keulen et al., 1995">Keulen LJMvan, Schreuder BEC, Meloen RH, Berg MPvan den, Mooij-Harkes G, Vromans MEW, Langeveld JPM, 1995. Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Veterinary Pathology, 32(3):299-308; 35 ref.</ref>. Transmission to mice by injecting suspect tissue can be used to assay infectivity <ref name="OIE, 2000 " />.  IHC staining of tonsil <ref name="Schreuder et al., 1998">Schreuder BEC, Keulen LJMvan, Vromans MEW, Langeveld JPM, Smits MA, 1998. Tonsillar biopsy and PrP detection in the preclinical diagnosis of scrapie. Veterinary Record, 142(21):564-568; 31 ref. </ref>, <ref name="Schreuder et al., 1996 ">Schreuder BEC, Keulen LJMvan, Vromans MEW, Langeveld JPM, Smits MA, 1996. Preclinical test for prion diseases. Nature (London), 381(6583):563; 10 ref.</ref> and lymphoid biopsies <ref name=" Bender et al., 2004"> Bender S, Alverson J, Herrmann LM, O’Rourke KI, 2004. Histamine as an aid to biopsy of third eyelid lymphoid tissue in sheep. Veterinary Record, 154(21):662-663.</ref>, <ref name="Ikegami et al., 1991">Ikegami Y, Ito M, Isomura H, Momotani E, Sasaki K, Muramatsu Y, Ishiguro N, Shinagawa M, 1991. Pre-clinical and clinical diagnosis of scrapie by detection of PrP protein in tissues of sheep. Veterinary Record, 128(12):271-275; 16 ref.</ref>, <ref name="O'Rourke et al., 2000">O'Rourke KI, Baszler TV, Besser TE, Miller JM, Cutlip RC, Wells GAH, Ryder SJ, Parish SM, Hamir AN, Cockett NE, Jenny A, Knowles DP, 2000. Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue. Journal of Clinical Microbiology, 38(9):3254-3259; 33 ref.</ref>, <ref name="O'Rourke et al., 1998">O'Rourke KI, Baszler TV, Miller JM, Spraker TR, Sadler-Riggleman I, Knowles DP, 1998. Monoclonal antibody F89/160.1.5 defines a conserved epitope on the ruminant prion protein. Journal of Clinical Microbiology, 36(6):1750-1755; 41 ref.</ref>, <ref name="Thuring et al., 2000  ">Thuring CMA, Sweeney T, McElroy MC, Weavers E, 2000. Suitability of protuberances on the third eyelids of sheep as a biopsy site for lymphoid follicles. Veterinary Record, 147(22):631-632; 10 ref.</ref> stained for  PrP<sup>sc</sup> habe been used for preclinical scrapie screening.
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[[File:Scrapie lymph node immunoglobulin labeling.png|thumb|200px|right|Immunoglobulin in normal(a) and scrapie-affected (b)follicles - with light microscopy.]]
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A pre-emptive diagnosis of scrapie may be made from the above clinical signs and history. There are no serological test available for scrapie, as is does not evoke an immune or inflammatory response.
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Rapid tests for surveillance that have been approved by the EU include: Western blot test for the detection of the protease-resistant fragment  PrP<sup>Res</sup> (Prionics Check test),
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Chemiluminescent ELISA test involving an extraction method and an ELISA technique, using an enhanced chemiluminescent reagent (Enfer test) and sandwich immunoassay for PrP<sup>Res</sup> carried out following denaturation and concentration steps (Bio-Rad test) <ref name="European Commission, 2001">European Commission, 2001. Commission Regulation (EC) No. 999/2001 of the European Parliament and of the Council of 22 May 2001 laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies. Official Journal of the European Communities, L 147:1-40.</ref>.
  
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Diagnosis is confirmed on '''post-mortem''' and PrP<sup>Sc</sup> can be isolated from brainstem or lymphoid tissues by Western immunoblot, immunohistochemistry (IHC) and [[ELISA testing|Elisa tests]]. Immunohistochemistry usually shows vacuolation and an accumulation of prion proteins in various parts of the CNS (medulla, pons, midbrain, and spinal cord). However vacuolation is not completely diagnostic since it may also be present to a lesser extent in the brains of healthy sheep <ref name="Fraser, 1976"> Fraser H (1976) '''The pathology of a natural and experimental scrapie. '''''Frontiers of Biology,'' 44:267-305.</ref>, <ref name="Zlotnik and Rennie, 1958"> Zlotnik I, Rennie JC (1958) '''A comparative study of the incidence of vacuolated neurones in the medulla from apparently healthy sheep of various breeds.''''' Journal of Comparative Pathology,'' 68:411-415.</ref>. In most instances the abnormal prion is resistant to protein kinase digestion, a feature used in diagnostic techniques. IHC staining of tonsil and lymphoid biopsies have been used for preclinical scrapie testing and the third eyelid lymphoid tissue can be used for diagnosis in sheep.
 
  
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'''Differential diagnoses''':
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'''Differential diagnosis''': Viral encephalomyelitides (pseudorabies or Aujeszky’s disease, rabies, maedi visna), Bacterial meningoencephalomyelitides (listeriosis), Pregnancy toxemia (ketosis), Hypocalcemis-hypomagnesemia, Toxins (mercury, lead, organophosphates, plant toxins) and Mange, lice, bacterial dermatitis <ref name="OIE, 2000" />.
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:Viral encephalomyelitides ([[Suid Herpesvirus 1|pseudorabies or Aujeszky’s disease]], [[rabies]], [[Visna-Maedi Virus|maedi visna]])
 
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:Bacterial meningoencephalomyelitides ([[listeriosis]])
 
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:[[Pregnancy Toxaemia|Pregnancy toxemia]] (ketosis)
 
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:Hypocalcemia-hypomagnesemia,  
 
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:Toxins (mercury, [[Lead Poisoning|lead]], organophosphates, plant toxins)  
 
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:Mange ([[Psoroptic Mange|psoroptic]], [[Sarcoptic Mange|sarcoptic]], [[Chorioptic Mange|chorioptic]]), [[:Category:Lice - Sheep|lice]], bacterial dermatitis <ref name="OIE, 2000">OIE (2000) '''Scrapie. OIE Manual of Standards for diagnostic tests and vaccines.''' 4 ed. ''Paris, France: Office International des Epizooties,'' 873-880.</ref>.
 
  
 
==Treatment==
 
==Treatment==
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==Control==
 
==Control==
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Good husbandry and hygiene around lambing can greatly reduce the infectious load. It is recommended that individual straw bale pens are used which can be destroyed after each lambing and that contaminated bedding and placenta should be removed immediately.  
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Good husbandry and hygiene around lambing can greatly reduce the infectious load. It is recommended that individual straw bale pens are used which can be destroyed after each lambing and that contaminated bedding and placenta should be removed immediately.   Infection can be minimised by maintaining a closed flock and only obtaining replacement ewes or breeding rams from scrapie-free flocks. Animals of resistant genotypes should be used for breeding to further minimize the risk of scrapie infection in a flock <ref name="CFIA, 2005">Canadian Food Inspection Agency, 2005. Scrapie. http://www.inspection.gc.ca/english/anima/heasan/man/scrtre/scrtree.shtml, Accessed 7 March 2005.</ref>, <ref name="Dawson et al., 1998">Dawson M, Hoinville LJ, Hosie BD, Hunter N, 1998. Guidance on the use of PrP genotyping as an aid to the control of clinical scrapie. Veterinary Record, 142(23):623-625.</ref>, <ref name="European Commission, 2001" />, <ref name="US Department of Agriculture, 2005"> USDA, 2005. Scrapie program. http://www.aphis.usda.gov/vs/nahps/scrapie/, accessed 7 March 2005.</ref>. Genetic resistance to scrapie depends on the prion genotype of the sheep and on the strain of scrapie present. Genotypes of sheep resistant to one strain of scrapie may be susceptible to another strain but on the whole the ARR allele confers resistance in all breeds. The UK government control programme (National Scrapie Plan or NSP) was launched in 2001 and proposes to increase the frequency of the ARR allele in the UK sheep population <ref name="DEFRA, 2001"/>. Many countries use a combination of genetic selection, depopulation of infected sources and sourcing scrapie free flocks to control the spread of scrapie <ref name="US Department of Agriculture, 2005"> Department for Environment Food and Rural Affairs, 2001. National scrapie plan for Great Britain. Schemes brochure. DEFRA, 1-28.</ref>, <ref name="Thorgeirsdottir et al., 2002">Thorgeirsdottir S, Georgsson G, Reynisson E, Sigurdarson S, Palsdottir A, 2002. Search for healthy carriers of scrapie: an assessment of subclinical infection of sheep in an Icelandic scrapie flock by three diagnostic methods and correlation with PrP genotypes. Archives of Virology, 147(4):709-722; 31 ref.</ref>.
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Infection can be minimised by maintaining a closed flock and only obtaining replacement ewes or breeding rams from scrapie-free flocks. Animals of resistant genotypes should be used for breeding to further minimize the risk of scrapie infection in a flock <ref name="CFIA, 2005">Canadian Food Inspection Agency (2005) '''Scrapie'''. http://www.inspection.gc.ca/english/anima/heasan/man/scrtre/scrtree.shtml, Accessed 7 March 2005.</ref>, <ref name="Dawson et al., 1998">Dawson M, Hoinville LJ, Hosie BD, Hunter N (1998) '''Guidance on the use of PrP genotyping as an aid to the control of clinical scrapie.''''' Veterinary Record,'' 142(23):623-625.</ref>, <ref name="European Commission, 2001">European Commission (2001) '''Commission Regulation (EC) No. 999/2001 of the European Parliament and of the Council of 22 May 2001 laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies. '''''Official Journal of the European Communities,'' L 147:1-40.</ref>, <ref name="US Department of Agriculture, 2005"> USDA (2005) '''Scrapie program.''' http://www.aphis.usda.gov/vs/nahps/scrapie/, accessed 7 March 2005.</ref>. Genetic resistance to scrapie depends on the prion genotype of the sheep and on the strain of scrapie present. Genotypes of sheep resistant to one strain of scrapie may be susceptible to another strain but on the whole the ARR allele confers resistance in all breeds. In 2001 the UK government set up the [http://animalhealth.defra.gov.uk/managing-disease/notifiable-disease/scrapie/national-scrapie-plan/ National Scrapie Plan NSP)] which aims to increase the frequency of the ARR allele within UK sheep population. Since 1988 it has been illegal for ruminant derived meat and bone meal to be fed to ruminants.
 
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BSE in cattle has been linked to the practice of incorporating rendered ruminant byproducts into cattle feed. Meat and bone meal(MBM)contaminated feeds have not been shown to be involved in scrapie transmission, but prohibiting the use of feeds that contain ruminant animal products in sheep and goats is a prudent measure. In the UK, a feed ban was issued in 1988 prohibiting the feeding of ruminant-derived meat and bone meal to ruminants (HMSO, 2002) and was adopted by the EU in 1994 and USA in 1997 <ref name="European Commission, 2001" />, <ref name="FDA, 1997">Food and Drug Administration, 1997. 21 CFR Part 589 [Docket No. 96N–0135] RIN 0910–AA91 substances prohibited from use in animal food or feed; animal proteins prohibited in ruminant feed. DHHS, 30935-30978.</ref>.
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[[Category:Transmissible Spongiform Encephalopathies]]
 
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Revision as of 11:48, 8 June 2011

Also known as: TSE – Transmissible spongiform encephalopathy, Paraplexia enzootica ovium

Introduction

Scrapie is a progressive, fatal and non-febrile neurological disorder affecting sheep and goats. It belongs to a group of diseases called transmissible spongiform encephalopathy (TSE) and other TSE’s include Creutzfeldt-Jakob disease in humans, BSE, chronic wasting disease (CWD) in elk and deer, transmissible mink encephalopathy and feline spongiform encephalopathy has been found within cats in the UK. The disease is believed to be caused by a conformational change in the prion (PrP). A prion is a protein that occurs normally in the nervous and lymphoreticular tissues. It is only when the prion changes conformation into a protease-resistant protein PrPsc that it causes degeneration of neurological tissue. The disease causes astrocyte proliferation and then vacuolization of neurons but demyelination does not occur [1]. The abnormal protein is thought to act as a catalyst to convert more of the host’s protein into this abnormal form. The disease has been notifiable in the EU since 1993 but unlike BSE there is no evidence to suggest that scrapie is a risk to human health [2], [3],[4], [5]. Studies have suggested that after ingestion, PrPsc first accumulates in Peyer’s patches of the small intestine, gut-associated lymphoid tissues (GALT) and ganglia of the enteric nervous system [6],[7], [8], [9], [10], it then spreads throughout the lymph nodes, tonsils, spleen, and into the peripheral nervous tissue. It finally found in the brain several months later. The disease is thought to have come from imported Merino sheep from Spain and has since spread through the movement of infected sheep. Only Australia and New Zealand are recognized as being currently free of scrapie.

Signalment

Scrapie affects the majority of sheep between 3 and 5 years of age and has a long incubation period of two to five years. It is extremely durable and is able to withstand high temepratures and concentrations of formaldehyde. Unlike BSE, scrapie is influenced by breed and genetic variation of the PrP gene within sheep populations, which can affect the infectivity and incubation period of the scrapie. The disease has been shown to be effectively transmitted during lambing through infected placental tissue [11], [12] as placenta and possibly the placental fluids are thought to be a source of infection [13], [14], [15], [16], [17] and experimental studies have shown that oral dosing of infected placenta can spread the disease in sheep and goats [18].

Clinical Signs

Early clinical signs may include subtle behavioural changes such as staring or fixed gaze, teeth grinding (bruxism), fine tremor, and hyperaesthesia to sound or sudden movements. Affected animals may later become intolerant to exercise and develop ataxia (awkwardness at turning, swaying of the hindquarters and some gait abnormalities such as a high stepping gait in the forelimbs or a bunny hopping gait in the hindlimbs). Some sheep have intense pruritis that leads to compulsive rubbing, nibbling at the skin, or scraping against fixed objects and may lead to wool loss (especially over the hindquarters and lateral thorax). A characteristic lip smacking or nibbling reflex can often be elicited by scratching over the lumbar region. In later stages there can be significant weight loss even without a noticeable decrease in appetite, weakness, recumbency, and death. [19], [20], [21], [22], [23]. It is important to note that some scrapie-infected sheep may appear healthy until stressed by transport, shearing, or pregnancy [24].

Diagnosis

A pre-emptive diagnosis of scrapie may be made from the above clinical signs and history. There are no serological test available for scrapie, as there is no immune or inflammatory response [25], [26].

Pathologic lesions are confined to the CNS. Histology (immunohistochemistry) usually shows vacuolation and an accumulation of prion proteins in various parts of the CNS (medulla, pons, midbrain, and spinal cord). However vacuolation is not completely diagnostic since it may also be present to a lesser extent in the brains of healthy sheep [27], [28]. In most instances the abnormal prion is resistant to protein kinase digestion, a feature used in diagnostic techniques.

PrPSc from post-mortem brainstem or lymphoid tissues may be detected by Western immunoblot analysis [29], [30], [31] and immunohistochemistry (IHC) [32], [33], [34], [35], [36]. Transmission to mice by injecting suspect tissue can be used to assay infectivity [37]. IHC staining of tonsil [38], [39] and lymphoid biopsies [40], [41], [42], [34], [43] stained for PrPsc habe been used for preclinical scrapie screening.

Rapid tests for surveillance that have been approved by the EU include: Western blot test for the detection of the protease-resistant fragment PrPRes (Prionics Check test), Chemiluminescent ELISA test involving an extraction method and an ELISA technique, using an enhanced chemiluminescent reagent (Enfer test) and sandwich immunoassay for PrPRes carried out following denaturation and concentration steps (Bio-Rad test) [44].


Differential diagnosis: Viral encephalomyelitides (pseudorabies or Aujeszky’s disease, rabies, maedi visna), Bacterial meningoencephalomyelitides (listeriosis), Pregnancy toxemia (ketosis), Hypocalcemis-hypomagnesemia, Toxins (mercury, lead, organophosphates, plant toxins) and Mange, lice, bacterial dermatitis [37].

Treatment

Scrapie is a fatal condition and no effective treatment is currently available

Control

Good husbandry and hygiene around lambing can greatly reduce the infectious load. It is recommended that individual straw bale pens are used which can be destroyed after each lambing and that contaminated bedding and placenta should be removed immediately. Infection can be minimised by maintaining a closed flock and only obtaining replacement ewes or breeding rams from scrapie-free flocks. Animals of resistant genotypes should be used for breeding to further minimize the risk of scrapie infection in a flock [45], [46], [44], [47]. Genetic resistance to scrapie depends on the prion genotype of the sheep and on the strain of scrapie present. Genotypes of sheep resistant to one strain of scrapie may be susceptible to another strain but on the whole the ARR allele confers resistance in all breeds. The UK government control programme (National Scrapie Plan or NSP) was launched in 2001 and proposes to increase the frequency of the ARR allele in the UK sheep population [48]. Many countries use a combination of genetic selection, depopulation of infected sources and sourcing scrapie free flocks to control the spread of scrapie [47], [49].

BSE in cattle has been linked to the practice of incorporating rendered ruminant byproducts into cattle feed. Meat and bone meal(MBM)contaminated feeds have not been shown to be involved in scrapie transmission, but prohibiting the use of feeds that contain ruminant animal products in sheep and goats is a prudent measure. In the UK, a feed ban was issued in 1988 prohibiting the feeding of ruminant-derived meat and bone meal to ruminants (HMSO, 2002) and was adopted by the EU in 1994 and USA in 1997 [44], [50].

References

  1. ↑ . Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Lasmézas C, Dormont D, Tovey MG, Dron M, 1998. Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. Journal of Biological Chemistry, 273(13):7691-7697,48 ref.
  2. ↑ Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P, 1987. The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. Neurology, 37(6):895-904.
  3. ↑ Harries JR, Knight R, Will RG, Cousens SN, Smith PG, Mathews WB, 1988. Creutzfeldt-Jakob disease in England and Wales, 1980-1984: a case-control study of potential risk factors. Journal of Neurology Neurosurgery and Psychiatry, 51(9):1113-1119.
  4. ↑ Kondo K, Kuriowa Y, 1982. A case control study of Creutzfeldt-Jakob disease: association with physical injuries. Annals of Neurology, 11(4):377-381.
  5. ↑ World Health Organization, 1999. WHO consultation on public health and animal transmissible spongiform encephalopathies: epidemiology, risk and research requirements, with the participation of the Office International des Epizooties. http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000,Accessed 7 March 2005. http://www.who.int/csr/resources/publications/bse/en/whocdscsraph20002.pdf.
  6. ↑ Beekes M, McBride PA, 2000. Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neuroscience Letters, 278(3):181-184.
  7. ↑ Beekes M, McBride PA, Baldauf E, 1998. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. Journal of General Virology, 79(3):601-607; 20 ref.
  8. ↑ Heggebø R, Press CM, Gunnes G, Lie KaiInge, Tranulis MA, Ulvund M, Groschup MH, Landsverk T, 2000. Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. Journal of General Virology, 81(9):2327-2337; 2 pp. of ref.
  9. ↑ Kimberlin RH, Walker CA, 1989. Pathogenesis of scrapie in mice after intragastric infection. Virus Research, 12(3):213-220; 32 ref.
  10. ↑ Keulen LJMvan, Schreuder BEC, Vromans MEW, Langeveld JPM, Smits MA, 1999. Scrapie-associated prion protein in the gastro-intestinal tract of sheep with natural scrapie. Journal of Comparative Pathology, 121(1):55-63; 24 ref.
  11. ↑ Dickinson AG, Stamp JT, Renwick CC, 1974. Maternal and lateral transmission of scrapie in sheep. Journal of Comparative Pathology, 84(1):19-25.
  12. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Hourrigan et al., 1979
  13. ↑ Andréoletti O, Lacroux C, Chabert A, Monnereau L, Tabouret G, Lantier F, Berthon P, Eychenne F, Lafond-Benestad S, Elsen JM, Schelcher F, 2002. PrP accumulation in placentas of ewes exposed to natural scrapie: influence of foetal PrP genotype and effect on ewe-to-lamb transmission. Journal of General Virology, 83(10):2607-2616; 48 ref.
  14. ↑ Onodera T, Ikeda T, Muramatsu Y, Shinagawa M, 1993. Isolation of scrapie agent from the placenta of sheep with natural scrapie in Japan. Microbiology and Immunology, 37(4):311-316.
  15. ↑ Race R, Jenny A, Sutton D, 1998. Scrapie infectivity and proteinase K-resistant prion protein in sheep placenta, brain, spleen, and lymph node: implications for transmission and antemortem diagnosis. Journal of Infectious Diseases, 178(4):949-953; 29 ref.
  16. ↑ Tuo WB, O'Rourke KI, Zhuang DY, Cheevers WP, Spraker TR, Knowles DP, 2002. Pregnancy status and fetal prion genetics determine PrP accumulation in placentomes of scrapie-infected sheep. Proceedings of the National Academy of Sciences of the United States of America, 99(9):6310-6315; 31 ref.
  17. ↑ Tuo W, Zhuang D, Knowles DP, Cheevers WP, Sy M-S, O’Rourke K, 2001. PrP-C and PrP-Sc at the fetal-maternal interface. Journal of Biological Chemistry, 276(21):18229-18234.
  18. ↑ Pattison IH, Hoare MN, Jebbett JN, 1972. Spread of scrapie to sheep and goats by oral dosing with foetal membranes from scrapie-affected sheep. Veterinary Record, 90(17):465-468.
  19. ↑ Bradley R, 1997. Animal prion diseases. In: Collinge J, Palmer MS, eds. Prion diseases. Oxford, UK: Oxford University Press, 89-129.
  20. ↑ Dickinson AG, 1976. Scrapie in sheep and goats. Frontiers in Biology, 44:209-241
  21. ↑ Kimberlin RH, 1981. Scrapie. British Medical Journal, 137:105-112.
  22. ↑ Palmer AC, 1976. Scrapie. In: Palmer AC, ed. Introduction to animal neurology. Oxford, UK: Blackwell Scientific Publications, 177-178.
  23. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Parry and Oppenheimer, 1983
  24. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Detwiler and Baylis, 2003
  25. ↑ Kasper K, Bowman K, Panitch H, Prusiner SB, 1982. Immunological studies of scrapie infection. Journal of Neuroimmunology, 3(3):187-201.
  26. ↑ Porter D, Porter H, Cox N, 1973. Failure to demonstrate a humoral immune response to scrapie infection in mice. Journal of Immunology, 111(5):1407-1410.
  27. ↑ Fraser H, 1976. The pathology of a natural and experimental scrapie. Frontiers of Biology, 44:267-305.
  28. ↑ Zlotnik I, Rennie JC, 1958. A comparative study of the incidence of vacuolated neurones in the medulla from apparently healthy sheep of various breeds. Journal of Comparative Pathology, 68:411-415.
  29. ↑ Farquhar CF, Somerville RA, Ritchie LA, 1989. Post-mortem immunodiagnosis of scrapie and bovine spongiform encephalopathy. Journal of Virological Methods, 24(1, 2):215-222; 21 ref.
  30. ↑ Stack MJ, Keyes P, Scott AC, 1996. The diagnosis of bovine spongiform encephalopathy and scrapie by the detection of fibrils and the abnormal protein isoform. In: Baker H, Ridley RM, eds. Methods in molecular medicine: prion diseases. Totowa, New Jersey, USA: Humana Press, 85-103.
  31. ↑ Wadsworth JDF, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J, 2001. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet, 358(9277):171-180.
  32. ↑ Miller JM, Jenny AL, Taylor WD, Marsh RF, Rubenstein R, Race RE, 1993. Immunohistochemical detection of prion protein in sheep with scrapie. Journal of Veterinary Diagnostic Investigation, 5(3):309-316; 38 ref.
  33. ↑ Miller JM, Jenny AL, Taylor WD, Race RE, Ernst DR, Katz JB, Rubenstein R, 1994. Detection of prion protein in formalin-fixed brain by hydrated autoclaving immunohistochemistry for the diagnosis of scrapie in sheep. Journal of Veterinary Diagnostic Investigation, 6(3):366-368; 10 ref
  34. ↑ 34.0 34.1 O'Rourke KI, Baszler TV, Parish SM, Knowles DP, 1998. Preclinical detection of PrP in nictitating membrane lymphoid tissue of sheep. Veterinary Record, 142(18):489-491; 14 ref. Cite error: Invalid <ref> tag; name "O'Rourke et al., 1998" defined multiple times with different content
  35. ↑ Keulen LJMvan, Schreuder BEC, Meloen RH, Mooij-Harkes G, Vromans MEW, Langeveld JPM, 1996. Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. Journal of Clinical Microbiology, 34(5):1228-1231; 26 ref.
  36. ↑ Keulen LJMvan, Schreuder BEC, Meloen RH, Berg MPvan den, Mooij-Harkes G, Vromans MEW, Langeveld JPM, 1995. Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Veterinary Pathology, 32(3):299-308; 35 ref.
  37. ↑ 37.0 37.1 Cite error: Invalid <ref> tag; no text was provided for refs named OIE, 2000
  38. ↑ Schreuder BEC, Keulen LJMvan, Vromans MEW, Langeveld JPM, Smits MA, 1998. Tonsillar biopsy and PrP detection in the preclinical diagnosis of scrapie. Veterinary Record, 142(21):564-568; 31 ref.
  39. ↑ Schreuder BEC, Keulen LJMvan, Vromans MEW, Langeveld JPM, Smits MA, 1996. Preclinical test for prion diseases. Nature (London), 381(6583):563; 10 ref.
  40. ↑ Bender S, Alverson J, Herrmann LM, O’Rourke KI, 2004. Histamine as an aid to biopsy of third eyelid lymphoid tissue in sheep. Veterinary Record, 154(21):662-663.
  41. ↑ Ikegami Y, Ito M, Isomura H, Momotani E, Sasaki K, Muramatsu Y, Ishiguro N, Shinagawa M, 1991. Pre-clinical and clinical diagnosis of scrapie by detection of PrP protein in tissues of sheep. Veterinary Record, 128(12):271-275; 16 ref.
  42. ↑ O'Rourke KI, Baszler TV, Besser TE, Miller JM, Cutlip RC, Wells GAH, Ryder SJ, Parish SM, Hamir AN, Cockett NE, Jenny A, Knowles DP, 2000. Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue. Journal of Clinical Microbiology, 38(9):3254-3259; 33 ref.
  43. ↑ Thuring CMA, Sweeney T, McElroy MC, Weavers E, 2000. Suitability of protuberances on the third eyelids of sheep as a biopsy site for lymphoid follicles. Veterinary Record, 147(22):631-632; 10 ref.
  44. ↑ 44.0 44.1 44.2 European Commission, 2001. Commission Regulation (EC) No. 999/2001 of the European Parliament and of the Council of 22 May 2001 laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies. Official Journal of the European Communities, L 147:1-40.
  45. ↑ Canadian Food Inspection Agency, 2005. Scrapie. http://www.inspection.gc.ca/english/anima/heasan/man/scrtre/scrtree.shtml, Accessed 7 March 2005.
  46. ↑ Dawson M, Hoinville LJ, Hosie BD, Hunter N, 1998. Guidance on the use of PrP genotyping as an aid to the control of clinical scrapie. Veterinary Record, 142(23):623-625.
  47. ↑ 47.0 47.1 USDA, 2005. Scrapie program. http://www.aphis.usda.gov/vs/nahps/scrapie/, accessed 7 March 2005. Cite error: Invalid <ref> tag; name "US Department of Agriculture, 2005" defined multiple times with different content
  48. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named DEFRA, 2001
  49. ↑ Thorgeirsdottir S, Georgsson G, Reynisson E, Sigurdarson S, Palsdottir A, 2002. Search for healthy carriers of scrapie: an assessment of subclinical infection of sheep in an Icelandic scrapie flock by three diagnostic methods and correlation with PrP genotypes. Archives of Virology, 147(4):709-722; 31 ref.
  50. ↑ Food and Drug Administration, 1997. 21 CFR Part 589 [Docket No. 96N–0135] RIN 0910–AA91 substances prohibited from use in animal food or feed; animal proteins prohibited in ruminant feed. DHHS, 30935-30978.



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