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From: TSS ()
In Reply to: Re: Prohibition of the Use of SRMs for Human Food and Requirements for the Disposition of Non-Ambulatory Disabled Cattle USDA [Docket No. 03-025IFA] posted by TSS on September 8, 2005 at 8:50 am:
I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements for the Disposition of Non-Ambulatory Disabled Cattle Broken bones and such may be the first signs of a sub clinical BSE/TSE Non-Ambulatory Disabled Cattle ; MRC-43-00 NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH A team of researchers led by Professor John Collinge at the Medical The scientists took a closer look at what is known as the ?species Researchers tried to infect laboratory mice with hamster prions3 called In addition the researchers showed that this new sub-clinical infection The height of the species barrier varies widely between different Professor John Collinge said: "These results have a number of important "This is a timely and unexpected result, increasing what we know about ISSUED FRIDAY 25 AUGUST UNDER EMBARGO. PLEASE NOTE THAT THE EMBARGO IS FOR FURTHER INFORMATION CONTACT THE MRC PRESS OFFICE ON 020 7637 6011 NOTES FOR EDITORS Professor Collinge is a consultant neurologist and Director of the newly Prions are unique infectious agents that cause fatal brain diseases such The strain of prion used here to infect the mice is the Sc237 strain This research was funded by the Medical Research Council and Wellcome The Medical Research Council (MRC) is a national organisation funded by The Wellcome Trust is the world's largest medical research charity with http://www.mrc.ac.uk/index/public_interest/public-press_office/public-press_releases_2000/public-mrc-43-00.htm https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument PNAS | August 29, 2000 | vol. 97 | no. 18 | 10248-10253 Neurobiology * Medical Research Council Prion Unit and Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London W2 1PG, United Kingdom; and Department of Neuropathology, Institute of Psychiatry, London SE5 8AF, United Kingdom Communicated by Charles Weissmann, Imperial College of Science, Technology, and Medicine, London, United Kingdom, June 23, 2000 (received for review January 20, 2000) Discussion Implication of Demonstration of Subclinical Prion Infection. In prion diseases, infectious titers in the brain rise progressively throughout prolonged, clinically silent periods that precede the onset of disease. Thus asymptomatic animals may harbor significant infectious titers in brain and other tissues. However, there may be subclinical, as distinct from such preclinical, forms of prion infection, where animals become asymptomatic carriers of infectivity and do not develop clinical disease in their lifetimes (7, 28). Such carrier states are well recognized in other infectious diseases. However, in prion diseases, where incubation periods are extremely prolonged, distinction between subclinical and preclinical states is more difficult. It certainly can be argued that animals dying after a typical lifespan without clinical signs of prion disease but harboring high levels of infectivity represent the late preclinical stage of "transmissions" where the "incubation period" exceeds the normal lifespan (29). The distinction between the terms subclinical and preclinical is essentially a semantic one in this context. Here we use the term subclinical infection operationally to refer to animals in which prion replication is occurring but which have not developed clinical signs of prion disease during a normal lifespan. We have demonstrated that conventional mice inoculated with Sc237 prions harbor high levels of PrPSc and high prion titers in their brains without developing clinical signs of prion disease within their normal lifespan. These results imply the existence of subclinical prion infections that can be induced by challenge with prions from another species. However, whether or not this infectivity is classified as preclinical or subclinical, it has important public health implications. Iatrogenic transmission could occur from apparently healthy humans who may harbor high prion titers and many animal species (including sheep, pigs, and poultry) were exposed to BSE prions via contaminated feed and could have developed subclinical prion infection. It is known that BSE prions retain their distinctive strain characteristics after passage in a number of other species including humans (4, 13), arguing that such BSE passaged in species other than cattle also may be pathogenic to humans. The possibility that subclinical BSE might be present in other species and thereby present a threat to human health has been raised (30) but not yet rigorously investigated. Furthermore, these data argue in favor of screening apparently healthy cattle after slaughter to investigate whether significant levels of subclinical or preclinical BSE are present. A recent report has suggested that hamster scrapie (263K) may persist in the brains of inoculated C57BL/10 mice for prolonged periods without replication (41). Our data are not consistent with infectivity in the PrPSc-positive Sc237-inoculated CD-1 mice being the result of persistence of residual Sc237 hamster scrapie inoculum. High levels of mouse PrPSc (and no hamster PrPSc) are detectable on Western blot, and prions pathogenic for mice are generated. Intracerebral inoculation is known to result in wide distribution of the inoculum outside the brain via the circulation and, presumably as a result of other clearance mechanisms, brain titers fall to undetectable levels within a few days (42). Prion titers present in the brains of these mice (108 LD50/g mouse brain assayed in hamsters) considerably exceed those inoculated (8.5 × 106). Together, these data argue strongly for prion replication in these mice. It is possible that the prions detected in the brains of the C57BL/10 mice in the earlier study were not caused by persistence of inoculated 263K, but by propagation of prions with the properties we describe. The species origin of PrPSc (hamster or mouse) in the 263K-inoculated C57BL/10 mice was not reported. The observation periods postinoculation were generally much shorter than those we report here. That those mice with the longest survival postinoculation produced the shortest incubation periods on passage of infectivity into hamsters is consistent with propagation, rather than simply persistence, of prions in this earlier study (41). The transmission characteristics of prions generated in the brains of Sc237-inoculated CD-1 mice argue that one or more distinct prion strains have been generated. The finding that Sc237-inoculated CD-1 mice in which PrPSc could not be detected on Western blot were the ones that had been culled after shorter periods than mice with detectable PrPSc argues that prion propagation is occurring in all of these mice, but is detectable only after prolonged incubation periods. That high levels of hamster infectivity were present in the PrPSc-negative Sc237-inoculated CD-1 mouse (examined at 463 days postinoculation) in the absence of detectable mouse infectivity, whereas very high and relatively comparable titers of both mouse and hamster infectivity were present in the PrPSc-positive Sc237-inoculated CD-1 mouse (examined at 730 days postinoculation) suggests that more than one strain may be propagating in these mice, with preferential replication of a strain with higher pathogenicity for hamsters early in the incubation period. One possibility is that early replication of a prion strain pathogenic only for hamsters is induced in Sc237-inoculated CD-1 mice, then later followed by the generation of a second strain that is pathogenic for mice. More extensive passage studies, including cloning of strains at end-point dilution in both mice and hamsters, will be required to investigate this further and to characterize the strain(s) of prions generated in the brains of Sc237-inoculated CD-1 mice. http://www.pnas.org/cgi/content/full/97/18/10248 Neurobiology of Disease Joaquín Castilla,1 Alfonso Gutiérrez-Adán,2 Alejandro Brun,1 Deirdre Doyle,3 Belén Pintado,2 Miguel A. Ramírez,2 Francisco J. Salguero,1 Beatriz Parra,1 Fayna Díaz San Segundo,1 José M. Sánchez-Vizcaíno,1 Mark Rogers,3 and Juan M. Torres1 1Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Valdeolmos, 28130 Madrid, Spain, 2Departamento de Reproducción Animal y Conservación de Recursos Zoogenéticos, 28040 Madrid, Spain, and 3Department of Zoology and Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland Abstract The bovine-porcine species barrier to bovine spongiform encephalopathy (BSE) infection was explored by generating transgenic mouse lines expressing the porcine prion protein (PrP) gene. All of the porcine transgenic (poTg) mice showed clinical signs of BSE after intracerebral inoculation with a high-titer BSE inoculum. The protease-resistant PrP (PrPres) was detected in 14% (3 of 22) of the BSE-infected poTg mice by immunohistochemical or immunoblot analysis. Despite being able to infect 42% (5 of 12) of control mice, a low-dose BSE inoculum failed to penetrate the species barrier in our poTg mouse model. The findings of these infectivity studies suggest that there is a strong species barrier between cows and pigs. However, after second-passage infection of poTg mice using brain homogenates of BSE-inoculated mice scoring negative for the incoming prion protein as inoculum, it was possible to detect the presence of the infectious agent. Thus, porcine-adapted BSE inocula were efficient at infecting poTg mice, giving rise to an incubation period substantially reduced from 300 to 177 d after inoculation and to the presence of PrPres in 100% (21 of 21) of the mice. We were therefore able to conclude that initial exposure to the bovine prion may lead to subclinical infection such that brain homogenates from poTg mice classified as uninfected on the basis of the absence of PrPres are infectious when used to reinoculate poTg mice. Collectively, our findings suggest that these poTg mice could be used as a sensitive bioassay model for prion detection in pigs. snip... Discussion We observed that mice expressing higher levels of poPrP spontaneously developed clinical signs. A similar neurological syndrome was described previously by Westaway et al. (1994) in older Tg PrP mice expressing high levels of hamster, ovine, or murine PrP transgenes. This phenomenon may be related to the observed toxicity of overexpressed PrP in certain cell lines, which suggests that lack of physiological PrPC expression may render pathogenic in mice. However, the lifespan of poTg027 mice was much longer than the time needed by porcine prions to propagate in these animals, and the confirmation of infection could be tested using proteinase K (PK)-resistant studies. In none of the cases did the noninoculated animals presenting late clinical signs show PK-resistant protein. We observed substantial evidence of subclinical BSE infection in our poTg mice. PoTg mice inoculated with BSE1 showed no clinical signs of BSE or detectable PrPres protein. However, subsequent passage of brain homogenates from these mice indicated the high level of infectivity of one of these animals. The presence of subclinical infection was particularly evident when we used the poTgBSE1-N2 inoculum (first-passage boTgBSE1 in poTg PrPres-negative mice), which led to a mean incubation time of 269 d and to PrPres that was detectable by Western blotting in two of six mice. The presence of subclinical infection has been reported in other species (Race and Chesebro, 1998; Hill et al., 2000). Although there is no evidence of clinical BSE disease in the domestic pig population, pigs are susceptible to BSE, and our observations raise the possibility of subclinical infection occurring in pigs. The poTg model could be used as an assay for subclinical infection in suspected cases of prion disease in pigs. Three inocula (Fig. 3) were used to infect the poTg mice. These inocula are known to efficiently infect transgenic mice expressing the bovine PrP gene (boTg110 line) (Castilla et al., 2003). We used the same vector to express the porcine and bovine PrP genes under the mouse PrP promoter. In the boTg110 model, increasing the PrPres titer had no effect on the incubation time. When the low-dose BSE1 inoculum was tested in a normal mouse line, the animals showed neurological signs of disease, and 5 of 12 (42%) scored positive for PrPres. These data indicate that the BSE1 inoculum can cross the bovine-murine species barrier, although the expression level of the mouse PrPC is approximately half that shown by our transgenic lines. However, the low-dose BSE1 inoculum provided evidence for a strong bovine-porcine species barrier, because it produced no signs of infection in the poTg001 or poTg027 mice. Survival times were unchanged compared with those observed in control PBS-inoculated poTg001 or poTg027 mice, and no PrPres was detected in any of the 39 inoculated mice (Table 1). In contrast, the higher titer BSE2 and boTgBSE1 inocula were able to breach the bovine-porcine species barrier, and PrPres was detected in 3 of 22 infected poTg mice (14%). Additional evidence for the bovine-porcine species barrier was obtained in second-passage transmission from BSE-infected poTg mice. The survival time dropped from 488 to 198 d postinoculation (dpi) for poTg001 and from 300 to 177 dpi for the poTg027 mice. The presence of a strong barrier may explain the resistance to infection shown by pigs during the BSE epidemic in the United Kingdom. Contrary to the strong species barrier observed when poTg mice were inoculated with BSE, there was little evidence of a species barrier in the opposite direction (i.e., when we infected boTg110 mice with poTgBSE1). All of the boTg mice infected with this inoculum scored positive for PrPres, suggesting that the barrier has different difficulty levels depending on the direction of the infection. Western blotting analysis confirmed that the PrPres observed in the bo110Tg mice displayed the same pattern (band size, glycoform ratio) as the boTgBSE1 or BSE1 inocula but a pattern that is different from that of the newly generated porcine prion (po027Tg) (Fig. 2C). A characteristic feature of the BSE prion is that it retains its biological properties when transmitted to other species such as humans (Collinge and Rossor, 1996; Collinge et al., 1996; Will and Zeidler, 1996; Scott et al., 1999), sheep (Foster et al., 1993, 2001), or mice (Fraser et al., 1992; Lasmezas et al., 1997). Thus, the lack of a strong species barrier observed for transmission in the direction of pig to cow might be explained if the initial BSE inoculum infecting the pig confers BSE-like properties on the porcine prion, although the primary amino acid sequence of this prion is the porcine one. Alternatively, these results could be explained as follows: (1) the bovine PrP is a very permissive protein, more easily transformed by other heterologous prions or (2) the new porcine prion is highly infectious compared with others. This second possibility will be studied using other transgenic mice expressing ovine and human PrP. The species barrier is related to amino acid sequence differences in the globular domain of the PrP protein, which undergoes a conformational change from -helix to -pleated sheet structures. The porcine PrP shows the most unique amino acid sequence (5) in this domain when compared with the mouse, cow, sheep, hamster, and human PrP sequences. Figure 6 compares the globular domains of porcine, bovine, and mouse PrP. It may be observed that four of the five unique amino acids occur in helix 3, and that there are two additional differences in this helix between the porcine and bovine sequence, I to V and R to K. The K residue is known to alter the length and quality of definition of helix 3 (Calzolai et al., 2000), and it is possible that this combination of amino acid variants alters the structure of helix 3 sufficiently to inhibit interactions between porcine PrPC and PrPres. Nuclear magnetic resonance analysis indicates that the global architecture of this region is similar for all species analyzed to date (Riek et al., 1998; Lopez Garcia et al., 2000; Zahn et al., 2000), but individual amino acid changes have been shown to affect local conformation or surface charge (Lopez Garcia et al., 2000). These subtle differences may be sufficient to strengthen or weaken a species barrier. http://www.jneurosci.org/cgi/content/full/24/21/5063 British Medical Bulletin 66:161-170 (2003) MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, London, UK http://bmb.oxfordjournals.org/cgi/content/abstract/66/1/161 Journal of Virology, July 2003, p. 7991-7998, Vol. 77, No. 14 Department of Clinical Veterinary Medicine, Centre for Veterinary Science, University of Cambridge, Cambridge, United Kingdom CB3 OES,1 Prion Research Group, Institute of Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany2 Received 9 January 2003/ Accepted 30 April 2003 Natural transmission of prion disease is believed to occur by peripheral infection such as oral inoculation. Following this route of inoculation, both the peripheral nervous system and the lymphoreticular system may be involved in the subsequent neuroinvasion of the central nervous system by prions, which may not necessarily result in clinical signs of terminal disease. Subclinical prion disease, characterized by the presence of infectivity and PrPSc in the absence of overt clinical signs, may occur. It is not known which host factors contribute to whether infection with prions culminates in a terminal or subclinical disease state. We have investigated whether the level of host PrPc protein expression is a factor in the development of subclinical prion disease. When RML prion inoculum was inoculated by either the i.c. or intraperitoneal route, wild-type and tga20 mice both succumbed to terminal prion disease. In contrast, orally inoculated tga20 mice succumbed to terminal prion disease, whereas wild-type mice showed no clinical signs. However, wild-type mice sacrificed 375 or 525 days after oral inoculation harbored significant levels of brain PrPSc and infectivity. These data show that same-species transmission of prions by the oral route in animals that express normal levels of PrPc can result in subclinical prion disease. This indicates that the level of host PrPc protein expression is a contributing factor to the regulation of development of terminal prion disease. Events that increase PrPc expression may predispose a prion-infected animal to the more deleterious effects of prion pathology. -------------------------------------------------------------------------------- * Corresponding author. Mailing address: Centre for Veterinary Science, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd., Cambridge, United Kingdom CB3 OES. Phone: 44-1223-337655. Fax: 44-1223-337610. E-mail: rb202@cam.ac.uk . Journal of Virology, July 2003, p. 7991-7998, Vol. 77, No. 14 http://jvi.asm.org/cgi/content/abstract/77/14/7991 Journal of Virology, March 2002, p. 2510-2517, Vol. 76, No. 5 Centre for Veterinary Science, Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom,1 University Hospital Basel, Institute of Pathology, CH-4003 Basel,2 Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland3 Received 24 September 2001/ Accepted 16 November 2001 We have compared the transmission characteristics of the two mouse-adapted scrapie isolates, ME7 and Rocky Mountain Laboratory (RML), in tga20 mice. These mice express elevated levels of PrP protein compared to wild-type mice and display a relatively short disease incubation period following intracerebral prion inoculation. Terminal prion disease in tga20 mice induced by ME7 or RML was characterized by a distinct pattern of clinical signs and different incubation times. High-dose RML inoculated intracerebrally into tga20 mice induced the most rapid onset of clinical signs, with mice succumbing to terminal disease after only 58 ± 3 days. In contrast, high-dose ME7 gave a mean time to terminal disease of 74 ± 0 days. Histological examination of brain sections from prion-inoculated tga20 mice at terminal disease showed that ME7 gave rise to a more general and extensive pattern of vacuolation than RML. Low-dose inoculum failed to induce terminal disease but did cause preclinical symptoms, including the appearance of reversible clinical signs. Some mice oscillated between showing no clinical signs and early clinical signs for many months but never progressed to terminal disease. Brain tissue from these mice with chronic subclinical prion disease, sacrificed at >200 days postinoculation, contained high levels of infectivity and showed the presence of PrPSc. Parallel analysis of brain tissue from mice with terminal disease showed similar levels of infectivity and detectable PrPSc. These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation. -------------------------------------------------------------------------------- * Corresponding author. Mailing address: Centre for Veterinary Science, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd., Cambridge CB3 0ES, United Kingdom. Phone: 44-1223-337655. Fax: 44-1223-337610. E-mail: rb202@cam.ac.uk . Journal of Virology, March 2002, p. 2510-2517, Vol. 76, No. 5 Journal of Virology, November 2001, p. 10106-10112, Vol. 75, No. 21 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840 Cattle infected with bovine spongiform encephalopathy (BSE) appear to be a reservoir for transmission of variant Creutzfeldt-Jakob disease (vCJD) to humans. Although just over 100 people have developed clinical vCJD, millions have probably been exposed to the infectivity by consumption of BSE-infected beef. It is currently not known whether some of these individuals will develop disease themselves or act as asymptomatic carriers of infectivity which might infect others in the future. We have studied agent persistence and adaptation after cross-species infection using a model of mice inoculated with hamster scrapie strain 263K. Although mice inoculated with hamster scrapie do not develop clinical disease after inoculation with 10 million hamster infectious doses, hamster scrapie infectivity persists in brain and spleen for the life span of the mice. In the present study, we were surprised to find a 1-year period postinfection with hamster scrapie where there was no evidence for replication of infectivity in mouse brain. In contrast, this period of inactive persistence was followed by a period of active replication of infectivity as well as adaptation of new strains of agent capable of causing disease in mice. In most mice, neither the early persistent phase nor the later replicative phase could be detected by immunoblot assay for protease-resistant prion protein (PrP). If similar asymptomatic carriers of infection arise after exposure of humans or animals to BSE, this could markedly increase the danger of additional spread of BSE or vCJD infection by contaminated blood, surgical instruments, or meat. If such subclinical carriers were negative for protease-resistant PrP, similar to our mice, then the recently proposed screening of brain, tonsils, or other tissues of animals and humans by present methods such as immunoblotting or immunohistochemistry might be too insensitive to identify these individuals. * Corresponding author. Mailing address: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, 903 South Fourth St., Hamilton, MT 59840-2999. Phone: (406) 363-9354. Fax: (406) 363-9286. E-mail: bchesebro@nih.gov . Journal of Virology, November 2001, p. 10106-10112, Vol. 75, No. 21 http://jvi.asm.org/cgi/content/abstract/75/21/10106 From: TSS () PrPSc distribution of a natural case of bovine Yoshifumi Iwamaru, Yuka Okubo, Tamako Ikeda, Hiroko Hayashi, Mori- Priori Disease Research Center, National Institute of Animal Health, 3-1-5 Abstract Bovine spongiform encephalopathy (BSE) is a disease of cattle that causes The specified risk materials (SRM) are tissues potentially carrying BSE The 11th BSE case in Japan was detected in fallen stock surveillance. PrPSc was detected in brain, spinal cord, dorsal root ganglia, trigeminal Our results suggest that the currently accepted definitions of SRM in 179 T. Kitamoto (Ed.) ALSO from the International Symposium of Prion Diseases held in Sendai, October 31, to "Furthermore, current studies into transmission of cases of BSE that are Tetsuyuki Kitamoto From: TSS () Atypical Proteinase K-Resistant Prion Protein (PrPres) observed in an Apparently Healthy 23-Month-Old Holstein Steer Jpn. J. Infect. Dis., 56, 221-222, 2003 Atypical Proteinase K-Resistant Prion Protein (PrPres) Observed in an Apparently Healthy 23-Month-Old Holstein Steer Yoshio Yamakawa*, KenÕichi Hagiwara, Kyoko Nohtomi, Yuko Nakamura, Masahiro Nishizima ,Yoshimi Higuchi1, Yuko Sato1, Tetsutaro Sata1 and the Expert Committee for BSE Diagnosis, Ministry of Health, Labour and Welfare of Japan2 Department of Biochemistry & Cell Biology and 1Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640 and 2Miistry of Health, Labour and Welfare, Tokyo 100-8916 Communicated by Tetsutaro Sata (Accepted December 2, 2003) An ELISA-positive specimen from a 23 month-old Holstein steer slaughtered on September 29, 2003, in Ibaraki Prefecture (Ibaraki case) was sent to the NIID for confirmation. The animal was reportedly healthy before slaughter. The OD titer in ELISA was slightly higher than the 'cut-off' level given by the manufacturer. The histology showed no spongiform changes and IHC revealed no signal of PrPSc accumulation typical for BSE. However, WB analysis of the homogenate that was prepared from the obex region and used for ELISA revealed a small amount of PrPSc with an electrophoretic profile different from that of typical BSE-associated PrPSc (1-3). The characteristics were (i) low content of the di-glycosylated molecular form of PrPSc, (ii) a faster migration of the non-glycosylated form of PrPSc on SDS-PAGE, and (iii) less resistance against PK digestion as compared with an authentic PrPSc specimen derived from an 83-month-old Holstein (Wakayama case) (Fig. 1). Table 1 summarizes the relative amounts of three distinctive glycoforms (di-, mono, non-glycosylated) of PrPSc calculated by densitometric analysis of the blot shown in Fig. 1. As 2.5 mg wet weight obex-equivalent homogenate of the Ibaraki case (Fig. 1, lane 4) gave slightly stronger band intensities of PrPSc than an 8 mg wet weight obex-equivqlent homogenate of a typical BSE-affected Wakayama case (Fig. 1, lane 2), the amount of PrPSc accumulated in the Ibaraki case was calculated to be 1/500 - 1/1000 of the Wakayama case. In the Ibaraki case, the PrPSc bands were not detectable in the homogenates of the proximal surrounding region of the obex. These findings were consistent with the low OD value in ELISA, i.e., 0.2 - 0.3 for the Ibaraki case versus over 3.0 for the Wakayama case. The DNA sequence of the PrP coding region of the Ibaraki case was the same as that appearing in the database (GenBank accession number: AJ298878). More recently, we encountered another case that resembled the Ibaraki case. It was a 21-month-old Holstein steer from Hiroshima Prefecture. WB showed typical BSE-specific PrPSc deposition though IHC did not detect positive signals of PrPSc (data not shown). Though the clinical onset of BSE is usually at around 5 years of age or later, a 20-month-old case showing the clinical signs has been reported (4). Variant forms of BSE similar to our cases, i.e., with atypical histopathological and/or biochemical phenotype, have been recently reported in Italy (5) and in France (6). Such variant BSE was not associated with mutations in the prion protein (PrP) coding region as in our case (5,6). The Ministry of Agriculture, Forestry and Fisheries of Japan (MAFF) announced a ban of feeding ruminants with meat bone meal (MBM) on September 18, 2001, and a complete ban was made on October 15 of the same year. According to the recent MAFF report, the previous seven cases of BSE in Japan were cattle born in 1995 - 1996 and possibly fed with cross-contaminated feed. However, the two cattle in this report were born after the complete ban. Whether contaminated MBM was implicated in the present cases remains to be investigated. REFERENCES Collinge, J., Sidle, K. C. L., Meads, J., Ironside, J. and Hill, A. F. (1996): Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature, 383, 685-690. SEE SLIDES IN PDF FILE; http://www.nih.go.jp/JJID/56/221.pdf Published online January 27, 2005 Risk of oral infection with bovine spongiform encephalopathy agent in primates Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys The uncertain extent of human exposure to bovine spongiform encephalopathy (BSE)—which can lead to variant Creutzfeldt-Jakob disease (vCJD)—is compounded by incomplete knowledge about the ef.ciency of oral infection and the magnitude of any bovine-to-human biological barrier to transmission. We therefore investigated oral transmission of BSE to non-human primates. We gave two macaques a 5 g oral dose of brain homogenate from a BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months after exposure, whereas the other remained free of disease at 76 months. On the basis of these .ndings and data from other studies, we made a preliminary estimate of the food exposure risk for man, which provides additional assurance that existing public health measures can prevent transmission of BSE to man. snip... BSE bovine brain inoculum 100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg Primate (oral route)* 1/2 (50%) Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%) 1/15 (7%) RIII mice (icip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%) PrPres biochemical detection The comparison is made on the basis of calibration of the bovine inoculum used in our study with primates against a bovine brain inoculum with a similar PrPres concentration that was inoculated into mice and cattle.8 *Data are number of animals positive/number of animals surviving at the time of clinical onset of disease in the .rst positive animal (%). The accuracy of bioassays is generally judged to be about plus or minus 1 log. icip=intracerebral and intraperitoneal. Table 1: Comparison of transmission rates in primates and cattle infected orally with similar BSE brain inocula snip...end www.thelancet.com Published online January 27, 2005 http://www.bseinquiry.gov.uk/files/ws/s014.pdf [PDF] The BSE Inquiry / Statement No 76F (Supplementary) Mr Alan ... http://www.bseinquiry.gov.uk/files/ws/s076f.pdf 03-025IF 03-025IF-631 Linda A. Detwiler [PDF] http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-631.pdf Specified Risk Materials (SRMs) I am in full support of the interim final rule which prohibits SRMs from Dr. Linda Detwiler comments in full; http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-634.pdf http://www.usda.gov/wps/portal/usdahome?contentidonly=true&contentid=2005/07/0280.xml IN CONFIDENCE PERCEPTION OF UNCONVENTENTIONAL SLOW VIRUS DISEASES OF ANIMALS IN THE USA 1985 The Stetsonville outbreak (farmer's name: Brecke). In addition to the downer cows and horses Brecke's mink recieved a cereal supplement. Hartsough's view was that this would contain bone meal and would be from a commercial source. If this were so and it was contaminated with a TME agent why were no other ranches affected? Many mink ranches now feed a commerical pelleted diet. Brecke was equipped to process LARGE CARCASSES USING A CRUSHER/MIXER WHICH COULD ACCOMMODATE A WHOLE COW! snip... Dead mink go for rendering but are used only in poultry feed. In the fall at pelting time the skinned carcasses of the mink are placed in large barrels which are left in the open to freeze. When full, a renderer collects ''for use in poultry feeds''. Sections from the brains of the two Brecke TME inoculated cattle were examined and Marsh provided all the blocks from the 2nd steer for study at CVL and comparison with BSE. In general the vacuolar changes were more severe than in most cases of BSE but very similar in distribution. Unfortunately material aken fro histopathology from those anials omitted representaion of most of the brain stem. ........... Wilbur Clarke (reference the Mission, Texas scrapie transmission transmission to cattle study) is now the State Veterinarian for Montana based at Helena. I was given confidential access to sections from the Clarke scrapie-cattle transmission experiment. Details of the experimental design were as supplied previously by Dr. Wrathall (copy of relevant information appended). Only 3 animals (2 inoculated with 2nd pass Suffolk scrapie and 1 inoculated with Angora goat passaged scrapie) showed clinical signs. Clinical signs were characterised by weakness, ''a stilted hindlimb gait'', disorientation, ataxia and, terminally, lateral recumbency. The two cattle from which I examined material were inocluated at 8 months of age and developed signs 36 months pi (goat scrapie inoculum) and 49 months pi (one of the Suffolk scrapie inoculated) respectively. This latter animal was killed at 58 months of age and so the clinical duration was only 1 month. The neuropathology was somewhat different from BSE or the Stetsonville TME in cattle. Vacuolar changes were minimal, to the extent that detection REQUIRED CAREFUL SEARCHING. Conversely astrocyte hypertrophy was a widespread and prominent feature. The material requires DETAILED NEUROPATHOLOGICAL ASSESSMENT BUT WHETHER OR NOT THIS WILL BE DONE REMAINS A QUESTION. Transmission Studies Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}...TSS resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest snip... Appendix 3 VISIT TO USA - DR A E WRATHALL - INFO OH BSE AND SCRAPIE 1. Dr Clark lately of the Scrapie Research Unit, Mission Texas has Expt A Expt B Expt C Diagnosis in A, B, C was by histopath. No reports on SAT were given. 2. Dr Warren Foote indicated success so far in eliminating scrapie in 3. Prof. A Robertson gave a brief account of BSE. The US approach was to 5. Scrapie agent was reported to have been isolated from a solitary 6. A western blotting diagnostic technique (? on PrP) shows some promise. 7. Results of a questionnaire sent to 33 states on the subject of the 6/33 wished to develop it 8/33 had few sheep and were neutral 33 end...TSS full text 33 PAGES ; http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf http://www.bseinquiry.gov.uk/ 1: J Infect Dis. 1994 Apr;169(4):814-20. Cutlip RC, Miller JM, Race RE, Jenny AL, Katz JB, Lehmkuhl HD, DeBey BM, Robinson MM. USDA, Agriculture Research Service, National Animal Disease Center, Ames, IA 50010. To determine if sheep scrapie agent(s) in the United States would induce a disease in cattle resembling bovine spongiform encephalopathy, 18 newborn calves were inoculated intracerebrally with a pooled suspension of brain from 9 sheep with scrapie. Half of the calves were euthanatized 1 year after inoculation. All calves kept longer than 1 year became severely lethargic and demonstrated clinical signs of motor neuron dysfunction that were manifest as progressive stiffness, posterior paresis, general weakness, and permanent recumbency. The incubation period was 14-18 months, and the clinical course was 1-5 months. The brain from each calf was examined for lesions and for protease-resistant prion protein. Lesions were subtle, but a disease-specific isoform of the prion protein was present in the brain of all calves. Neither signs nor lesions were characteristic of those for bovine spongiform encephalopathy. MeSH Terms: Substances: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8133096&dopt=Citation SNIP... http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf 12/10/76 snip... A The Present Position with respect to Scrapie Scrapie is a natural disease of sheep and goats. It is a slow The field problem has been reviewed by a MAFF working group It is clear that scrapie in sheep is important commercially and Recently the question has again been brought up as to whether Whether true or not. the hypothesis that these agents might be snip... 76/10.12/4.6 http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf THE infamous USA SPORADIC CJDs, something to ponder; over 20 strains of scrapie documented to date with new atypical strains now being documented in sheep and goat i.e. BSE. atypical strains of BSE/TSE showing up in cattle in different countries? ALL human TSEs must be made reportable Nationally and Internationally, OF ALL AGES... IN a time when FSIS/APHIS/USDA/FDA et al should be strengthening the TSE regulations, it seems corporate interest has won out again over sound science and consumer protection from an agent that is 100% fatal for the ones that go clinical. With the many different atypical TSEs showing up in different parts of the world, and with GWs BSE MRR policy (the legal policy of trading all strains of TSEs), the battle that has waged for the last 25 years to eradicate this agent from this planet will be set back decades, if not lost for good. ... Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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