----- Original Message ----- From: Terry S. Singeltary Sr. To: TERRY SINGELTARY Sent: Sunday, November 22, 2009 9:21 PM Subject: A case of atypical scrapie/Nor98 in a sheep from New Zealand
A case of atypical scrapie/Nor98 in a sheep from New Zealand
Abnormal prion protein consistent with atypical scrapie/Nor98 has been detected in the brain of a New Zealand sheep that was part of a large consignment of brains sent to Europe for use as negative control material. Nature of atypical scrapie/Nor98 Accumulated scientific knowledge to date has demonstrated that atypical scrapie, also known as Nor98, is clinically, pathologically, biochemically and epidemiologically different from classical scrapie (1). The majority of atypical scrapie/Nor98 cases have been identified in clinically normal sheep sampled at slaughter (1-3). Cases have been reported from Norway, Sweden, Finland, the UK, Germany, France, Portugal, Belgium, the Netherlands, Ireland, Denmark(4), the United States (5) and Canada (6). The apparent prevalence of the cases in the European Union (EU) Member States is very low, for example for the UK it is less than 0.1%. Active surveillance programmes have led to the detection of atypical scrapie/Nor98 cases even in the absence of any case of classical scrapie in sheep in Portugal, Denmark, Sweden and Finland(4), and in the Falkland Islands(7), the first region in the Southern Hemisphere to report such a case. Atypical scrapie/Nor98 appears to be a non-contagious, sporadic degenerative condition of older sheep. A spontaneous aetiology, possibly with a genetic determinant, environmental influences and metabolic factors, has been suggested in a number of studies based on epidemiological evidence (2-4, 8). Contributing to this suggestion is the observation that atypical scrapie/Nor98 cases have been detected by active surveillance programmes, wherever such programmes have been initiated (4). Most cases which have been detected in a flock have been the only case and this lead to early speculation that the condition is not naturally infectious (1-3). Experimental oral transmission to sheep has been unsuccessful, to date. Experimental oral transmission into standard mice and into bank voles also failed (1). Only experimental intracerebral transmission to transgenic mice expressing the ovine (9, 10) or porcine (11) prion gene and experimental intracerebral challenge in sheep were successful (12). Unlike classical scrapie, abnormal prion protein has not been detected in peripheral tissues of sheep affected by atypical scrapie/Nor98 (1, 4). The OIE Terrestrial Animal Health Code chapter on scrapie specifically excludes atypical scrapie/Nor98 and explicitly states that the condition is unrelated to ‘classical’ scrapie, is probably not contagious and may be a spontaneously occurring condition (13). Draft for submission to Surveillance magazine 27/10/2009 2 It seems that wherever scrapie surveillance in sheep raising countries is intensified and suitable tests are used, atypical scrapie/Nor98 is found. Recently, three cases of atypical scrapie/Nor98 were reported in a UK research sheep flock derived from animals of New Zealand origin (14). Subsequent investigations in the UK did not find any evidence that the condition was either acquired in the UK or introduced from New Zealand. Thus the discovery of an atypical scrapie/Nor98 case in an otherwise healthy New Zealand sheep is not entirely unexpected (15); and reinforces the view that atypical scrapie/Nor 98 occurs spontaneously or naturally in very small numbers of older sheep in every population.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/background-paper.pdf
2009 BSE AND SCRAPIE NZ
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
Nevertheless, the incidence of atypical scrapie is much higher than that of sporadic CJD in humans. Long-term studies on the occurrence and genetics of atypical scrapie, combined with the development of more sensitive methods for detection of infectivity, are needed to elucidate these aspects. Atypical scrapie is not confined to sheep, as it has also been diagnosed in goats in a few European countries including Norway (Benestad et al. 2006). Currently the molecular characteristics of atypical scrapie in goats and sheep are indistinguishable (Le Dur et al. 2005). However, only a few cases have been found in goats to date, so any epidemiological link between the diseases in these two species is presently unknown. 4
http://www.vkm.no/dav/7f33267b4e.pdf
This position has been accepted by the OIE and the Animal Health Code Article 14.9.1 states “The chapter does not cover so-called ‘atypical’ scrapie which is clinically, pathologically, biochemically and epidemiologically unrelated to ‘classical’ scrapie, may not be contagious and may, in fact, be a spontaneous degenerative condition of older sheep.” This position has been supported by the scientific panel on biological hazards of the European Food Safety Authority 3.
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Recent studies have shown experimental transmission of atypical scrapie in sheep and laboratory animals (Simmons et al 2007) but there is as yet no evidence to confirm that transmission can occur naturally in the field. Another recent paper by Espinosa et al (Espinosa, Herva, 2009) has shown that atypical scrapie can be transmitted with low efficiency to genetically engineered mice over expressing the porcine prion protein. They concluded there was a marked species transmission barrier. Further the agent appeared to undergo a strain phenotype shift upon transmission to the transgenic mice. This is the first report of this occurring.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
• Most critical is that atypical scrapie shows higher prevalence in so-called resistant ARR homozygote and heterozygote genotypes, compared with classical scrapie. • Atypical scrapie has not been found naturally in VRQ/VRQ sheep, although such sheep can be infected artificially. VRQ sheep are, in contrast, highly susceptible to classical scrapie. In the UK, one case of atypical scrapie has been found in VRQ heterozygote (AF141RQ/VRQ) sheep. It is important to ascertain whether or not VRQ-carrying sheep are significantly resistant to infection with atypical scrapie or whether the data might result from a failure to detect PrPres in atypical scrapie due to a different pattern of PrP distribution in tissues. • Increased incidence of atypical scrapie in sheep with PrP alleles carrying the variant phenylalanine (F) at position 141 (leucine(L)/phenylalanine) has also been observed compared with classical scrapie. • It will be important to clarify the genotype effect, particularly in relation to ARR and L141F in transmission studies. • In classical scrapie, there is clear evidence for a PrP genotype effect on tissue distribution patterns of PrPres. This might also be true for atypical scrapie although the data are less complete. 4. Transmission of atypical scrapie It has recently18 been demonstrated that atypical scrapie is experimentally transmissible to mice and sheep, primarily through intracerebral injection. There are some data suggesting that it may also be transmissible orally to sheep of different genotypes. The subgroup noted that challenge experiments with atypical scrapie in sheep were underway in the UK, with one successful intracerebral challenge to date. The subgroup was informed that positive transmission of infectivity from atypical scrapie isolated from sheep with a range of genotypes had been observed in mice. This included ovinised transgenic mice overexpressing the VRQ allele. Nor98 atypical scrapie had also transmitted to ARR ovinised mice, with transmission experiments in AF141RQ ovinised mice planned. Biochemical features of the isolates were maintained after transmission, and were distinct from BSE and classical scrapie. High infectivity titres were observed in brain tissue from atypical scrapie, including from ARR/ARR sheep. Brain transmission experiments in mice carrying the human PrP gene were at an early stage. 18 Le Dur A., Béringue V., Andréoletti O., Reine F., Laï T.H., Baron T., Bratberg B., Vilotte J.- L., Sarradin P., Benestad S.L. and Laude H.(2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. PNAS 102, 16031-16036
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,†, Vincent Béringue*,†, Olivier Andréoletti‡, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,†† + Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ‡Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Next Section Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and “cases” that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
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Our study demonstrates that an authentic TSE infectious agent is responsible in sheep and goats of sporadic atypical infections that remained unnoticed until recently. This raises important issues with regard to control of scrapie infection in small ruminants. Of major concern, ARR/ARR sheep can no longer be regarded as free of natural TSE infection. This finding challenges, at least to some extent, the foundation of the selective breeding programs engaged in several European Union member states (47, 48) and may call for a reappraisal of possible consequences of this strategy in the long term. Finally, more information about this newly discovered type of TSE agent, its prevalence in countries free of scrapie or BSE disease, and its potential to across-species transmission would be needed for a comprehensive evaluation of its implications in terms of public health.
http://www.pnas.org/content/102/44/16031.long
http://www.pnas.org/content/102/44/16031.figures-only
Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype
Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
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To add a note, highlight some text. Hide notes Make a general comment Jump to Jean-Noël Arsac1, Dominique Bétemps1, Eric Morignat1, Cécile Féraudet2, Anna Bencsik1, Denise Aubert3, Jacques Grassi2, Thierry Baron1*
1 Agence Française de Sécurité Sanitaire des Aliments, Lyon, France, 2 Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunoanalyse, Gif sur Yvette, France, 3 Ecole Normale Supérieure de Lyon, CNRS/INRA, Lyon, France
Abstract Top Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
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Discussion Top Characterization of the infectious agents involved in TSEs has historically required transmission in inbred wild-type mice, such as C57Bl, VM or RIII [4], [22], [23]. However some TSEs, such as the CH1641 experimental scrapie source [24] or some human TSEs [25] fail to transmit to wild-type mice of any genotype. The recent availability of transgenic mice expressing the prion gene of the natural host of the disease has facilitated TSE transmission studies, as in the use of ovine transgenic mice for scrapie or BSE [5], [20], [21]. The strain-specific molecular diversity of the classical scrapie or BSE sources was faithfully reproduced in the TgOvPrP4 ovine transgenic mouse model that we have developed. However, a novel TSE, called atypical scrapie or Nor98, has recently been identified in sheep and goats throughout Europe [12]. In several countries this disease is now more frequent than classical scrapie and in some countries atypical scrapie has been recognized in the absence of classical scrapie [26]–[28]. The experimental transmissibility of this disease was established in a transgenic mouse model (tg338) that strongly over-expresses (8- to 10-fold) the VRQ allele of ovine prion protein, from a series of 10 French atypical scrapie cases and 2 Norwegian Nor98 isolates [17]. In contrast, experimental transmission was not achieved in wild-type mice [12], [17] or in bank voles [29]. Overall this clearly confirmed that atypical scrapie is a genuine TSE associated with infectious prions.
In this study we confirmed the transmissibility of atypical scrapie, after intracerebral challenge, in another ovine transgenic mouse model (TgOvPrP4), but failed to transmit the disease from 2 cases into wild-type mice. Twelve cases, including the 10 French isolates previously transmitted to the tg338 mouse line [17], were successfully transmitted to TgOvPrP4 mice that over-expressed the AL141RQ prion protein. Although this prnp genotype of TgOvPrP4 mice is only rarely identified in sheep with atypical scrapie [13]–[16], [26], [30]–[33], most of the inoculated mice accumulated the pathological prion protein in their brain. Biochemical analysis of PrPres showed a fully conserved pattern comparable to that previously described in the natural host [15], i.e. a similar complex pattern including 5 major bands derived from 3 distinct PrPres products. Both PrPres fragments cleaved at both N- and C-terminal ends, and the uncleaved (or marginally cleaved) PrPres, were consistently maintained after transmission into ovine transgenic mice (Figure 4). The consistency of the Western blot profiles, whatever the isolate, and in line with previous studies in tg338 ovine transgenic mice, does not suggest any diversity in atypical scrapie. This consistent PrPres glycoprofile is somewhat reminiscent of certain PrPres features in patients with Gerstmann-Straüssler-Scheinker syndrome [34]–[36].
This study enabled us to extend the descriptive profile of our TgOvPrP4 mouse model and examine TSE transmission factors in relation to the level of expression of the prion protein by the infected host. After long-term breeding of the mouse line we indeed found three TgOvPrP4 mice subpopulations expressing in their brain ~0.25, 1.5 or 6× the PrPc level measured in a sheep brain control. We then decided to evaluate the possible influence of these differences in PrPc levels in the central nervous system on TSE development, following the inoculation of 3 mouse-adapted strains (BSE, C506M3, 87V), 3 experimental small ruminants isolates (SSBP1, CH1641, BSEOVINE) and 22 small ruminant natural isolates collected by active surveillance of TSEs in sheep and goats (10 classical scrapie isolates, including 3 usual isolates as shown by PrPres molecular analysis and 7 “CH1641-like” isolates; 12 atypical scrapie isolates). This panel of samples thus represents the molecular diversity of TSEs in small ruminants, especially with the three basic PrPres phenotypes possibly demonstrated by Western blot in natural scrapie. Strikingly the influence of the PrPc expression level was much more obvious for the atypical scrapie isolates, and a considerable delay in disease onset was associated with a decrease in PrPc expression levels,. TgOvPrP4 mice with higher PrPc levels (~6×) died after shorter periods (around 400 days) than mice with lower PrPc levels (~1.5×) (around 700 days). Comparisons of different transgenic mouse lines already indicated that the expression levels of the prion protein were inversely related to the incubation period in classical scrapie [6]. Nevertheless, to the best of our knowledge, the variable influence of PrPc expression levels according to the form of prion disease defined by its essential molecular features, has never been described and is here reported between different animals in a same transgenic mouse line. However, although the development of atypical scrapie appears to be much more facilitated by increased PrPc expression, this also suggests that the risk of transmission in animals expressing physiological levels of the protein would be relatively low. This characteristic, in addition to the species barrier, would help to explain the failure to transmit atypical scrapie to wild-type mice (RIII, VM and C56Bl mice) [17] or bank voles [29], unlike classical scrapie. Besides, a major influence of the PrPc expression levels has been demonstrated in transgenic mice over-expressing (i) mutated human prion protein linked to Gerstmann–Sträussler-Scheinker syndrome [37], [38] or (ii) a prion protein with a nine-octapeptide insertion associated with a human familial prion disease [39], [40]. In both cases disease development was strongly conditioned by the levels of transgene expressions, not only following inoculations of brain tissues from affected patients, but also spontaneously.
Our demonstration that atypical scrapie was much more influenced by PrPc expression levels than classical scrapie or BSE was possible in this mouse model solely because our approach was based on serum PrPc measurements. These were indeed found to reflect the levels of PrPc expression in the brain. In this model protein expression was controlled by the neuron-specific enolase promoter and neither RT-PCR or Western blot analyses were able to detect expression of the prnp gene in non nervous tissues [5], [41]. One explanation of the close relationship between serum and cerebral PrPc might be related to a release of PrPc from the central nervous system into the blood, as was also shown for some other neuronal proteins [42]. It is noteworthy that the plasma concentration of PrPc in wild-type C57Bl mice (~70+/-15 ng/ml) is much higher than in TgOvPrP4 mice, even in [TgOvPrP4 (x6)] with the highest level of expression (48+/-10 ng/ml). This suggests that a fraction of the PrPc in the serum of wild-type mice could originate from the nervous system, under physiological conditions. Importantly, direct evidence that PrPc readily crosses the blood brain barrier in both brain-to-blood and blood-to-brain directions has recently been reported [43]. Regarding the TgOvPrP4 mouse line, the presence of [TgOvPrP4 (x0.25)] animals which express low levels of PrPc clearly represents a drawback for transmission studies of TSEs. This can however be circumvented by assessing the PrPc expression levels in each individual mouse prior to its use in animal experiments. Furthermore, although this subpopulation increased following long-term random breeding of the mouse line, blood testing is also used to monitor PrPc expression levels during breeding in order to eliminate those breeders that produce progeny with a high proportion of poorly expressing animals. It should be noted that no indication of variation of transgene expression was found in a similarly produced mouse line (TgOvPrP59) originating from different founders [44], [45], which makes it unlikely that our observations in the TgOvPrP4 mouse line result from factors intrinsic to the transgene construct and/or the genetic background of the mice. However, the loss of transgene expression in a transgenic line is not unprecedented and two types of explanation are generally provided to account for such a loss. These include (1) integration of the transgene in an heterochromatin-rich region which results in silencing of the transgene in some cells (position effect variegation) [46] or (2) the repetitive nature of the transgene arrays which induces the formation of heterochromatin at the sites of integration and leads to gene silencing [47]. In addition, our genetic construction does not contain any insulators, which suggests that heterochromatin propagation might be a cause of transgene extinction in some animals [48].
Concerning the factors involved in the transmission of atypical scrapie, we were also surprised to demonstrate the influence of the prnp genotypes of the sheep or goat donors on development of the disease in TgOvPrP4 inoculated mice. This had not been observed in tg338 mice, which overall showed more rapid incubation of the disease [17]. Lower PrPc expression levels in TgOvPrP4 mice were required to transmit atypical scrapie, when the isolates carried the AF141RQ or AHQ alleles associated with increased susceptibility to the disease in sheep [14]. The same analysis of possible differences associated with the susceptible or resistant genotype, as here reported in atypical scrapie, could not be done for classical scrapie or BSE considering the available isolates. Among these sources only one classical scrapie isolates (Classusual 2) carried the ARR allele known to be associated with resistance to clinical scrapie [49], [50]. Although the ARR allele is rarely observed in classical scrapie we here confirmed, by both PrPres analyses in sheep and bioassays in wild-type and ovine transgenic mice, that it is possible to detect classical scrapie in relatively resistant animals during the implementation of flock analysis of scrapie cases [51]. Overall, given the limited number of samples available we cannot exclude a possible influence of the prnp genotypes for classical scrapie or BSE. The results observed with atypical scrapie are difficult to explain and we cannot exclude differences in infectious titres between the two groups of samples examined, in relation to (i) possible differences in the distribution of infectivity within the CNS [52] and/or (ii) different stages in the incubation periods in sheep and goats. On the other hand the AF141RQ or AHQ prnp alleles were associated with a lower conformational stability of the ovine PrPc protein [53], which might be associated with an increased capacity of the PrPsc of such genotypes to transconform PrPc. It is noteworthy that only one successful experimental transmission of atypical scrapie has so far been reported in sheep, which was obtained in an AHQ homozygous sheep intracerebrally inoculated with an atypical scrapie isolate from an AHQ homozygous sheep [18]. However the apparently spontaneous occurrence of three cases of atypical scrapie in genetically susceptible sheep was also reported in a flock derived from sheep imported from New Zealand, a country regarded as scrapie-free [54].
Based on our findings, the possibility that variations in the expression of ovine PrPc might be factors involved in susceptibility to atypical scrapie in sheep and goats, is open to question. A second proposal could question whether a failure of the protein quality-control systems might also be involved in susceptibility to atypical scrapie. Recent studies have provided new evidence for a role of these systems in the conversion of PrPc to an abnormal form of prion protein, with either impairment of proteasomal degradation or endoplasmic reticulum stress, leading to the generation of a misfolded form of prion protein [55]–[57]. Transgenic mice were also reported to develop a spontaneous neurological disease in the absence of PrPsc when preferentially expressing a transmembrane form of prion protein (PrPCtm) [58], [59], which would imply that CtmPrP is a key component in the pathway of neurodegeneration as in Gerstmann–Sträussler-Scheinker syndrome.
However our data do emphasize the unresolved questions regarding the origin of atypical scrapie, which as yet remains unknown. A spontaneous origin of the disease is suspected, and importantly, no evidence of natural transmissibility in small ruminants has been observed [33], [60]. The results of our novel approach, based on monitoring prion protein expression in animals from the same transgenic mouse line, suggest that the risk of transmission of atypical scrapie is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0007300
P03.141
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.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
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)
http://www.pnas.org/cgi/content/abstract/0502296102v1
>>> So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE.
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
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3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.
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Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
http://physrev.physiology.org/cgi/content/abstract/89/4/1105
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
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. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf
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.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie A] 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 ia 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
SCRAPIE
The United States is unable to support the proposed new draft Code Chapter on Scrapie. The draft chapter, as written, departs significantly from the existing chapter, is confusing and is difficult to understand. This version of the scrapie chapter uses much of the same wording as the BSE chapter and is written as if the predominance of evidence revealed that scrapie was a food-borne disease similar to BSE in cattle which is inappropriate. Moreover, several of the new changes are not supported by current scientific evidence. As a result, detailed comments on individual articles would not meaningful at this time.
The United States is not supportive of the proposed draft chapter for the following reasons:
1. Inclusion of “atypical” scrapie: The scientific evidence indicates that “atypical” scrapie, also referred to as Nor-98, Nor-98-like, or non-classical scrapie, is not the same disease as classical scrapie. Further, “atypical” scrapie does not meet the criteria for listing diseases of trade concern by the OIE, as described in Chapter 2.1.1 of the Code. The United States recommends that the scope of this chapter be limited to classical scrapie in sheep and goats. Further, the United States recommends that OIE clearly adopt the position that “atypical” scrapie represents a distinct disease entity from classical scrapie and that it not be a listed disease.
• There is no evidence that “atypical” scrapie is a contagious disease. If it is contagious, available evidence suggests that it has a much lower transmission efficiency. (Hopp, et al, 2006; Green, et al, 2007; Benestad, et al 2008; McIntyre, et al, 2008)
• The disease appears to be ubiquitous in that it has been found wherever sufficient surveillance has been conducted. (Buschmann et al, 2004; De Bosschere et al, 2004; Orge, et al, 2004; Everest et al, 2006; Arsac, 2007; Benestad, et al 2008; Fediaevsky, et al, 2008)
• The disease does not appear to be economically significant in that the prevalence of clinical disease is low and it typically occurs in older animals. (Luhken, et al., 2007; Benestad, et al 2008).
• The disease is as likely as not to be the result of a spontaneous conversion of normal prion protein. (Benestad, et al 2008, De Bosschere et al 2007)
• Removal of exposed sheep is unlikely to reduce the prevalence of “atypical” scrapie infection and removing only those exposed sheep that are phenylalanine (F) at codon 141 is scientifically unsound since the disease is known to affect sheep of most other genotypes. Further, sheep with AHQ alleles have a similar risk of infection with “atypical” strains as sheep with F at codon 141. (Luhken, et al., 2007).
• If “atypical” scrapie is included as a listed disease, the surveillance and diagnostic requirements which are needed to identify these cases should be described in detail in both this Chapter and the Manual of Diagnostic Tests and Vaccines for Terrestrial
2
Animals. Data from Europe illustrates that using the proper test(s) is essential for the identification of atypical scrapie (Fediaevsky et al., 2008).
SNIP...
6. Overemphasis on importation and use of bovine meat and bone meal as a route of scrapie transmission: Given that the draft Chapter is not intended to address risk mitigation for BSE in small ruminants, we believe there is an over-emphasis on this potential route of transmission in the current draft.
The United States recommends that the requirements in this chapter be limited to the inclusion of products from sheep and goats (instead of from all ruminants) in feed or feed ingredients intended for consumption by animals
• The use of products from sheep and goats as feed or feed ingredients for ruminant or non-ruminant animals represent one possible route of transmission (Philippe, et al, 2005) and a source of environmental contamination with the classical scrapie agent. However, this is not the primary route of transmission for the scrapie agent.
• The need for the exclusion of cattle-derived protein or other animal protein to mitigate BSE risk should be based on a country’s BSE risk status and should be addressed in Chapter 2.3.13 of the Code.
SNIP...
14. Failure to provide scientific justification for the list of permitted commodities in Item 1 of Article 2.4.8.1. .
We recommend that the list be re-evaluated and those items that have not been substantiated as presenting no risk be excluded or those with some risk but where the intended use mitigates the risk the use be specified.
• There is no known human health risk associated with scrapie. As such, if meat and meat products for human consumption are included in this list, sheep and/or goat milk intended for human consumption should also be added to the list of permitted commodities in Item 1 of Article 2.4.8.1.
• In the vast majority of sheep infected with classical scrapie, actual infectivity or PrPres has been identified in most tissues including the lymphoreticular system (tonsils, spleen, lymph nodes), the gastrointestinal tract, brain, and spinal cord (Hadlow et. al. 1979; Hadlow et al., 1980; van Kuelen et al., 1996; van Kuelen et al., 1999, Andreoletti et al., 2000; Heggebø et al., 2002; Caplazi et al., 2004). Infectivity and/or PrPres has also been identified in the placenta (see Hourrigan et al., 1979; Onodera et al., 1993; Pattison et al., 1972; Pattison et al., 1974; Race et al., 1998), blood (Hunter et al., 2002; Houston et al. 2008); peripheral nerves (Groschup et al., 1996), muscle (Pattison and Millson, 1962; Andreoletti et al., 2004; Casalone et al., 2005), salivary gland (Hadlow et al., 1980; Vascellari et al., 2007), kidney (Siso et al., 2006), and skin ( Thomzig et al., 2007). In addition, recent work has shown milk and/or colostrum from scrapie infected ewes transmitted the disease to 17 of 18 lambs (Konold et al., 2008).
• The data on the risk of low protein tallow made from scrapie infected tissues particularly for use in milk replacer is limited and some epidemiologic studies suggest an association of milk replacer use with scrapie risk. Taylor et al., 1997 examined the inactivation capacity of different rendering system in regards to scrapie. The presence of infectivity was determined by bioassay into mice. From the onset of this study, it was assumed that tallow was not the vehicle for the transmission of TSE. Hence only 2 tallow samples were examined.
http://www.aphis.usda.gov/import_export/animals/oie/downloads/tahc_mar-sep08/tahc-scrapie-77-mar08_cmt.pdf
USDA's Deputy Secretary Talks with Sheep Producers
May 1, 2009 - "Life in rural America is intimately integrated with production agriculture," said Kathleen Merrigan, deputy secretary for the U.S. Department of Agriculture (USDA), when she addressed the more than 50 sheep producers from around the country who were in Washington, D.C., this week. "I am very interested in looking for new ways for farmers to market their products and for them to grab a little more of the food dollar. The connection between the food that consumers eat and the farms that the food is grown on must be closer, and I look forward to working with producers to affect that."
snip...
According to Jere Dick, DVM, associate deputy administrator and chief of field operations for the Animal and Plant Health Inspection Service (APHIS), "We anticipate discussions and hopefully revisions of the scrapie chapter at the World Organization for Animal Health meeting this month. The revisions will likely exclude Nor-98 like scrapie from classical scrapie regulations. If this is done, APHIS will be able to exempt flocks with Nor-98 like scrapie cases, should they occur, from extensive flock depopulation actions."
snip...end
http://sheepusa.org/?page=site/newsandevents&nav_id=c806da768c6fcc2652eee0967bc96b5a#772efce63bd783bb5da167cf744f349a
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html
Tuesday, November 17, 2009
SEAC EFFECT OF AGE ON THE PATHOGENESIS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SEAC 103/2
http://downercattle.blogspot.com/2009/11/seac-effect-of-age-on-pathogenesis-of.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
J Neurol Neurosurg Psychiatry 1994;57:757-758 doi:10.1136/jnnp.57.6.757 Research Article
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.
C J Gibbs, Jr, D M Asher, A Kobrine, H L Amyx, M P Sulima, D C Gajdusek + Author Affiliations
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Abstract Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
http://jnnp.bmj.com/content/57/6/757.abstract
TSS
Monday, November 23, 2009
Tuesday, November 10, 2009
A retrospective immunohistochemical study reveals atypical scrapie has existed in the United Kingdom since at least 1987
Brief Research Reports
A retrospective immunohistochemical study reveals atypical scrapie has existed in the United Kingdom since at least 1987
Paul R. Webb1, Linda Powell, Margaret Denyer, Sarah Marsh, Colin Weaver, Marion M. Simmons, Elizabeth Johns, John Sheehan, Peter Horsfield, Chris Lyth, Christina Wilson, Ann Long, Saira Cawthraw, Ginny C. Saunders and Yvonne I. Spencer Correspondence: 1Corresponding Author: Paul R. Webb, Department of Pathology, Veterinary Laboratories Agency–Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, United Kingdom. p.webb@vla.defra.gsi.gov.uk
Atypical scrapie is a relatively recent discovery, and it was unknown whether it was a new phenomenon or whether it had existed undetected in the United Kingdom national flock. Before 1998, the routine statutory diagnosis of transmissible spongiform encephalopathy (TSE) in sheep relied on the presence of TSE vacuolation in the brainstem. This method would not have been effective for the detection of atypical scrapie. Currently, immunohistochemistry (IHC) and Western blot are commonly used for the differential diagnosis of classical and atypical scrapie. The IHC pattern of PrPd deposition in atypical scrapie is very different from that in classical scrapie using the same antibody. It is thus possible that because of a lack of suitable diagnostic techniques and awareness of this form of the disease, historic cases of atypical scrapie remain undiagnosed. Immunohistochemistry was performed on selected formalin-fixed, paraffin-embedded (FFPE) blocks of ovine brain from the Veterinary Laboratories Agency archives that were submitted for various reasons, including suspect neurological disorders, between 1980 and 1989. It was found that PrPd deposits in a single case were consistent with atypical scrapie. A method was developed to obtain a PrP genotype from FFPE tissues and was applied to material from this single case, which was shown to be AHQ/AHQ. This animal was a scrapie suspect from 1987, but diagnosis was not confirmed by the available techniques at that time.
Key Words: Atypical scrapie • prion • scrapie • transmissible spongiform encephalopathy • United Kingdom
http://jvdi.org/cgi/content/abstract/21/6/826?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=6&resourcetype=HWCIT
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ? August 20, 2008
snip...
another question, just how long have these atypical BSE TSEs been around in the bovine ???
let's look at another case of atypical BSE in Germany way back in 1992 ;
Subject: atypical BSE reported in 1992 and conviently slaughterd and incinerated and then swept under rug for about 12 years Date: April 26, 2007 at 1:08 pm PST 1992
NEW BRAIN DISORDER
3. WHAT ABOUT REPORTS OF NEW FORM OF BSE?
THE VETERINARY RECORD HAS PUBLISHED AN ARTICLE ON A NEW BRAIN DISORDER OF CATTLE DISCOVERED THROUGH OUR CONTROL MEASURES FOR BSE. ALTHOUGH IT PRESENTS SIMILAR CLINICAL SIGNS TO BSE THERE ARE MAJOR DIFFERENCES IN THE HISTOPATHOLOGY AND INCUBATION PERIODS BETWEEN THE TWO. MUST EMPHASISE THAT THIS IS NOT BSE.
4. IS THIS NEW BRAIN DISORDER A THREAT?
WE DO NOT EVEN KNOW WHETHER THE AGENT OF THIS DISEASE IS TRANSMISSIBLE. IN ANY CASE, CASES SO FAR IDENTIFIED HAD SHOWN SIMILAR SYMPTOMS TO THOSE OF BSE, AND THEREFORE HAVE BEEN SLAUGHTERED AND INCINERATED, SO THAT IF A TRANSMISSIBLE AGENT WERE INVOLVED IT WOULD HAVE BEEN ELIMINATED. .......
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/26001001.pdf
2. The Collinge/Will dispute appears to rumble on. Dr. Collinge had told Dr. Tyrrell that Dr. Will's response to his criticism about sharing material had been ''quite unacceptable'' (in spite of it's apparently conciliatory tone). Apparently Professor Allen was now going to try and arrange a meeting to resolve the dispute. No action here for MAFF, although Mr. Murray may be interested.
3. Dr. Tyrrell regretted that the Committee had not seen the article on BBD. However he felt that for the time being NO specific action was called for. The most important need was to consider the possibility that the condition might be transmissible. As we have discussed, I suggested that we might circulate a paper to the members of the committee giving our appreciation of this condition (and perhaps of other non-BSE neurological conditions that had been identified in negative cases) and of any necessary follow up action. IF any Committee member felt strongly about this, or if the issue CAME TO A HEAD, we would call an interim meeting. He was happy with this approach. I would be grateful if Mr. Maslin could, in discussion with CVL and veterinary colleagues draft such a note, which will presumably very largely follow what Mr. Bradley's briefing paper has already said, taking account of DOH comments, We can then clear a final version with DOH before circulating it to Committee members.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/29005001.pdf
IN CONFIDENCE
This is a highly competitive field and it really will be a pity if we allow many of the key findings to be published by overseas groups while we are unable to pursue our research findings because of this disagreement, which I hope we can make every effort to solve.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/26002001.pdf
COLLINGE THREATENS TO GO TO MEDIA
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
2. The discovery might indicate the existence of a different strain of BSE from that present in the general epidemic or an unusual response by an individual host.
3. If further atypical lesion distribution cases are revealed in this herd then implications of misdiagnosis of 'negative' cases in other herds may not be insignificant.
snip...
This minute is re-issued with a wider distribution. The information contained herein should NOT be disseminated further except on the basis of ''NEED TO KNOW''.
R Bradley
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/02/17001001.pdf
IN CONFIDENCE
BSE ATYPICAL LESION DISTRIBUTION
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/03/14001001.pdf
snip...
Visit to USA ... info on BSE and Scrapie
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf
HOUND STUDY
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.
snip...
http://web.archive.org/web/20010305222642/www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
2005 DEFRA Department for Environment, Food & Rural Affairs
Area 307, London, SW1P 4PQ Telephone: 0207 904 6000 Direct line: 0207 904 6287 E-mail: h.mcdonagh.defra.gsi.gov.uk
GTN: FAX:
Mr T S Singeltary P.O. Box 42 Bacliff Texas USA 77518
21 November 2001
Dear Mr Singeltary
TSE IN HOUNDS
Thank you for e-mail regarding the hounds survey. I am sorry for the long delay in responding.
As you note, the hound survey remains unpublished. However the Spongiform Encephalopathy Advisory Committee (SEAC), the UK Government's independent Advisory Committee on all aspects related to BSE-like disease, gave the hound study detailed consideration at their meeting in January 1994. As a summary of this meeting published in the BSE inquiry noted, the Committee were clearly concerned about the work that had been carried out, concluding that there had clearly been problems with it, particularly the control on the histology, and that it was more or less inconclusive. However was agreed that there should be a re-evaluation of the pathological material in the study.
Later, at their meeting in June 95, The Committee re-evaluated the hound study to see if any useful results could be gained from it. The Chairman concluded that there were varying opinions within the Committee on further work. It did not suggest any further transmission studies and thought that the lack of clinical data was a major weakness.
Overall, it is clear that SEAC had major concerns about the survey as conducted. As a result it is likely that the authors felt that it would not stand up to r~eer review and hence it was never published. As noted above, and in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether additional work should be performed to examine dogs for evidence of TSE infection. Although the Committee had mixed views about the merits of conducting further work, the Chairman noted that when the Southwood Committee made their recommendation to complete an assessment of possible spongiform disease in dogs, no TSEs had been identified in other species and hence dogs were perceived as a high risk population and worthy of study. However subsequent to the original recommendation, made in 1990, a number of other species had been identified with TSE ( e.g. cats) so a study in hounds was less
critical. For more details see-
http://web.archive.org/web/20010305223122/www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf
As this study remains unpublished, my understanding is that the ownership of the data essentially remains with the original researchers. Thus unfortunately, I am unable to help with your request to supply information on the hound survey directly. My only suggestion is that you contact one of the researchers originally involved in the project, such as Gerald Wells. He can be contacted at the following address.
Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT 15 3NB, UK
You may also wish to be aware that since November 1994 all suspected cases of spongiform encephalopathy in animals and poultry were made notifiable. Hence since that date there has been a requirement for vets to report any suspect SE in dogs for further investigation. To date there has never been positive identification of a TSE in a dog.
I hope this is helpful
Yours sincerely 4
HUGH MCDONAGH BSE CORRESPONDENCE SECTION
IN CONFIDENCE
CONCEPT NOT FOR FURTHER STUDY OF MATERIAL OBTAINED IN A SURVEY OF HOUNDS FOR EVIDENCE OF A SCRAPIE-LIKE SPONGIFORM ENCEPHALOPATHY (SE)
snip...
b) Fibrillar material closely similar to SAF, found in BSE/Scrapie, was observed in 19 (4.3%) cases, all of which were hounds > 7 years of age. 14/19 of these suspected SAF results correlated with cases in the unresolveable histopathological category.
snip...
The following proposals address the hypothesis that the hound survey observations represent a PrP related or scrapie-like disease of dogs in which the pathological response, and possible the spread of infectivity, is neuroanatomically localized. By inference this could also mean that the disorder is clinically silent and non-progressive.
http://web.archive.org/web/20010305223122/www.bseinquiry.gov.uk/files/yb/1995/02/09001001.pdf
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ? August 20, 2008
see full text ;
http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html
Monday, October 26, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Published online before print October 22, 2009
http://nor-98.blogspot.com/2009/10/similarities-between-forms-of-sheep.html
Published online before print October 22, 2009 This Article
Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
PubMed
PubMed Citation Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
Copyright © 2009 American Society for Investigative Pathology American Journal of Pathology, doi:10.2353/ajpath.2009.090623
Accepted for publication August 19, 2009.
--------------------------------------------------------------------------------
Article
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wiebke M. Wemheuer*, Sylvie L. Benestad, Arne Wrede*, Ulf Schulze-Sturm*, Wilhelm E. Wemheuer, Uwe Hahmann*, Joanna Gawinecka, Ekkehard Schütz, Inga Zerr, Bertram Brenig, Bjørn Bratberg, Olivier Andréoletti¶, and Walter J. Schulz-Schaeffer*@ From the Prion and Dementia Research Unit,* Department of Neuropathology, University Medical Center Goettingen, Goettingen, Germany; National Veterinary Institute, Department of Pathology, Oslo, Norway; Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; and Animal Health,¶ Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
@ To whom correspondence should be addressed. E-mail: wjschulz@med.uni-goettingen.de.
Abstract
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2009.090623v1
P.4.25
Human susceptibility to atypical scrapie
Chris Plinston, Rona Barron, Nora Hunter The Roslin Institute and R(D)SVS, University of Edinburgh, UK
Background: Isolates of classical sheep scrapie are thought to pose little risk to humans as there have been no documented links between presence of sheep scrapie and the development of human TSE disease. However, the link between BSE and the development of vCJD in humans proves that a risk does exist from ruminant TSE disease, and therefore all new ruminant TSEs may potentially be transmissible to humans. Due to increased sensitivity of TSE diagnostic assay systems, a new TSE of sheep termed 'atypical scrapie' has been identified. This disease has been difficult to identify, and is found mainly in sheep which are previously thought to have a genetic makeup that made them resistant to scrapie. It is unclear whether this is a new TSE of sheep, an old disease which has only been identified through increased surveillance, or if it represents the phenotype of classical scrapie in so called 'resistant' sheep PrP genotypes.
Objectives: The objective of the study is to assess relative transmissibility of atypical scrapie isolates to humans and the associated risk to the population.
Methods: In order to determine whether atypical scrapie poses a risk to human health we have transmitted isolates from three different sheep PrP genotypes to our gene targeted transgenic mice which express human PrP with the M129V polymorphism known to be important in human susceptibility to disease. Mice of all three PrP genotypes have been inoculated intracerebrally with atypical scrapie isolates.
Discussion: In order to prevent the emergence of a new human TSE, we need to be able to assess the risk to humans from new emerging TSEs in livestock. The study of atypical scrapie infection in these transgenic lines could therefore provide important information on the host range and disease characteristics associated with such isolates. Preventative measures could then be put in place before this disease gives rise to another human disease variant and an underlying level of infection in the population.
P.5.21
Parallels between different forms of sheep scrapie and types of Creutzfeldt-Jakob disease (CJD)
Wiebke M. Wemheuer1, Sylvie L. Benestad2, Arne Wrede1, Wilhelm E. Wemheuer3, Tatjana Pfander1, Bjørn Bratberg2, Bertram Brenig3,Walter J. Schulz-Schaeffer1 1University Medical Center Goettingen, Germany; 2Institute of Veterinary Medicine Oslo, Norway; 3Institute of Veterinary Medicine Goettingen, Germany
Background: Scrapie in sheep and goats is often regarded as the archetype of prion diseases. In 1998, a new form of scrapie - atypical/Nor98 scrapie - was described that differed from classical scrapie in terms of epidemiology, Western blot profile, the distribution of pathological prion protein (PrPSc) in the body and its stability against proteinase K. In a similar way, distinct disease types exist in sporadic Creutzfeldt-Jakob disease (CJD). They differ with regard to their clinical outcome, Western blot profile and PrPSc deposition pattern in the central nervous system (CNS).
Objectives: The comparison of PrPSc deposits in sheep scrapie and human sporadic CJD. Methods: Tissues of the CNS of sheep with classical scrapie, sheep with atypical/Nor98 scrapie and 20 patients with sporadic CJD were examined using the sensitive Paraffin Embedded Tissue (PET) blot method. The results were compared with those obtained by immunohistochemistry. With the objective of gaining information on the protein conformation, the PrPSc of classical and atypical/Nor98 sheep scrapie and sporadic CJD was tested for its stability against denaturation with guanidine hydrochloride (GdnHCl) using a Membrane Adsorption Assay.
Results: The PrPSc of atypical/Nor98 scrapie cases and of CJD prion type 1 patients exhibits a mainly reticular/synaptic deposition pattern in the brain and is relatively sensitive to denaturation with GdnHCl. In contrast classical scrapie cases and CJD prion type 2 patients have a more complex PrPSc deposition pattern in common that consists of larger PrPSc aggregates and the PrPSc itself is comparatively stable against denaturation.
Discussion: The similarity between CJD types and scrapie types indicates that at least two comparable forms of the misfolded prion protein exist beyond species barriers and can elicit prion diseases. It seems therefore reasonable to classify classical and atypical/Nor98 scrapie - in analogy to the existing CJD types - as different scrapie types.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
P03.141
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.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
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.
Content
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.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
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
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
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.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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 ia 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
Epidemiology of Scrapie in the United States 1977
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://scrapie-usa.blogspot.com/
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
also see ;
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
WHO WILL WATCH THE CHILDREN for CJD over the next 5 decades ?
FOR 4 years, the USDA fed dead stock downer cows, the most high risk cattle for mad cow disease and other dangerous pathogens to children all across the USA via the USDA certified dead stock downer cow school lunch program...
SCHOOL LUNCH PROGRAM FROM DOWNER CATTLE UPDATE
http://downercattle.blogspot.com/2009/05/who-will-watch-children.html
http://downercattle.blogspot.com/
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Sunday, September 6, 2009
MAD COW USA 1997 SECRET VIDEO
http://madcowusda.blogspot.com/2009/09/mad-cow-usa-1997-video.html
U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? see video at bottom
http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.html
DAMNING TESTIMONY FROM STANLEY PRUSINER THE NOBEL PEACE PRIZE WINNER ON PRIONS SPEAKING ABOUT ANN VENEMAN see video
http://maddeer.org/video/embedded/prusinerclip.html
CVM Annual Report Fiscal Year 2008: October 1, 2007-September 30, 2008
PUTTING LIPSTICK ON A PIG AND TAKING HER TO A DANCE...TSS
BSE Feed Rule Enforcement: A Decade of Success OFF TO A FAST START
http://madcowfeed.blogspot.com/2008/06/texas-firm-recalls-cattle-heads-that.html
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
http://bse-atypical.blogspot.com/2006/08/bse-atypical-texas-and-alabama-update.html
Monday, October 26, 2009
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Sent: Tuesday, November 03, 2009 5:14 PM Subject: Re: FOIA REQUEST ON FEED RECALL PRODUCT Bulk Whole Barley, Recall # V-256-2009 DISTRIBUTION TX END OF ENFORCEMENT REPORT FOR AUGUST 26, 2009
http://madcowfeed.blogspot.com/2009/11/re-foia-request-on-feed-recall-product.html
BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?
snip... see full text ;
http://cjdtexas.blogspot.com/
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
Friday, October 23, 2009
Creutzfeldt-Jakob Disease Surveillance Texas Data for Reporting Years 2000-2008
http://cjdtexas.blogspot.com/2009/10/creutzfeldt-jakob-disease-surveillance.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
A retrospective immunohistochemical study reveals atypical scrapie has existed in the United Kingdom since at least 1987
Paul R. Webb1, Linda Powell, Margaret Denyer, Sarah Marsh, Colin Weaver, Marion M. Simmons, Elizabeth Johns, John Sheehan, Peter Horsfield, Chris Lyth, Christina Wilson, Ann Long, Saira Cawthraw, Ginny C. Saunders and Yvonne I. Spencer Correspondence: 1Corresponding Author: Paul R. Webb, Department of Pathology, Veterinary Laboratories Agency–Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, United Kingdom. p.webb@vla.defra.gsi.gov.uk
Atypical scrapie is a relatively recent discovery, and it was unknown whether it was a new phenomenon or whether it had existed undetected in the United Kingdom national flock. Before 1998, the routine statutory diagnosis of transmissible spongiform encephalopathy (TSE) in sheep relied on the presence of TSE vacuolation in the brainstem. This method would not have been effective for the detection of atypical scrapie. Currently, immunohistochemistry (IHC) and Western blot are commonly used for the differential diagnosis of classical and atypical scrapie. The IHC pattern of PrPd deposition in atypical scrapie is very different from that in classical scrapie using the same antibody. It is thus possible that because of a lack of suitable diagnostic techniques and awareness of this form of the disease, historic cases of atypical scrapie remain undiagnosed. Immunohistochemistry was performed on selected formalin-fixed, paraffin-embedded (FFPE) blocks of ovine brain from the Veterinary Laboratories Agency archives that were submitted for various reasons, including suspect neurological disorders, between 1980 and 1989. It was found that PrPd deposits in a single case were consistent with atypical scrapie. A method was developed to obtain a PrP genotype from FFPE tissues and was applied to material from this single case, which was shown to be AHQ/AHQ. This animal was a scrapie suspect from 1987, but diagnosis was not confirmed by the available techniques at that time.
Key Words: Atypical scrapie • prion • scrapie • transmissible spongiform encephalopathy • United Kingdom
http://jvdi.org/cgi/content/abstract/21/6/826?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=6&resourcetype=HWCIT
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ? August 20, 2008
snip...
another question, just how long have these atypical BSE TSEs been around in the bovine ???
let's look at another case of atypical BSE in Germany way back in 1992 ;
Subject: atypical BSE reported in 1992 and conviently slaughterd and incinerated and then swept under rug for about 12 years Date: April 26, 2007 at 1:08 pm PST 1992
NEW BRAIN DISORDER
3. WHAT ABOUT REPORTS OF NEW FORM OF BSE?
THE VETERINARY RECORD HAS PUBLISHED AN ARTICLE ON A NEW BRAIN DISORDER OF CATTLE DISCOVERED THROUGH OUR CONTROL MEASURES FOR BSE. ALTHOUGH IT PRESENTS SIMILAR CLINICAL SIGNS TO BSE THERE ARE MAJOR DIFFERENCES IN THE HISTOPATHOLOGY AND INCUBATION PERIODS BETWEEN THE TWO. MUST EMPHASISE THAT THIS IS NOT BSE.
4. IS THIS NEW BRAIN DISORDER A THREAT?
WE DO NOT EVEN KNOW WHETHER THE AGENT OF THIS DISEASE IS TRANSMISSIBLE. IN ANY CASE, CASES SO FAR IDENTIFIED HAD SHOWN SIMILAR SYMPTOMS TO THOSE OF BSE, AND THEREFORE HAVE BEEN SLAUGHTERED AND INCINERATED, SO THAT IF A TRANSMISSIBLE AGENT WERE INVOLVED IT WOULD HAVE BEEN ELIMINATED. .......
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/26001001.pdf
2. The Collinge/Will dispute appears to rumble on. Dr. Collinge had told Dr. Tyrrell that Dr. Will's response to his criticism about sharing material had been ''quite unacceptable'' (in spite of it's apparently conciliatory tone). Apparently Professor Allen was now going to try and arrange a meeting to resolve the dispute. No action here for MAFF, although Mr. Murray may be interested.
3. Dr. Tyrrell regretted that the Committee had not seen the article on BBD. However he felt that for the time being NO specific action was called for. The most important need was to consider the possibility that the condition might be transmissible. As we have discussed, I suggested that we might circulate a paper to the members of the committee giving our appreciation of this condition (and perhaps of other non-BSE neurological conditions that had been identified in negative cases) and of any necessary follow up action. IF any Committee member felt strongly about this, or if the issue CAME TO A HEAD, we would call an interim meeting. He was happy with this approach. I would be grateful if Mr. Maslin could, in discussion with CVL and veterinary colleagues draft such a note, which will presumably very largely follow what Mr. Bradley's briefing paper has already said, taking account of DOH comments, We can then clear a final version with DOH before circulating it to Committee members.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/29005001.pdf
IN CONFIDENCE
This is a highly competitive field and it really will be a pity if we allow many of the key findings to be published by overseas groups while we are unable to pursue our research findings because of this disagreement, which I hope we can make every effort to solve.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/26002001.pdf
COLLINGE THREATENS TO GO TO MEDIA
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
2. The discovery might indicate the existence of a different strain of BSE from that present in the general epidemic or an unusual response by an individual host.
3. If further atypical lesion distribution cases are revealed in this herd then implications of misdiagnosis of 'negative' cases in other herds may not be insignificant.
snip...
This minute is re-issued with a wider distribution. The information contained herein should NOT be disseminated further except on the basis of ''NEED TO KNOW''.
R Bradley
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/02/17001001.pdf
IN CONFIDENCE
BSE ATYPICAL LESION DISTRIBUTION
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/03/14001001.pdf
snip...
Visit to USA ... info on BSE and Scrapie
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf
HOUND STUDY
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.
snip...
http://web.archive.org/web/20010305222642/www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
2005 DEFRA Department for Environment, Food & Rural Affairs
Area 307, London, SW1P 4PQ Telephone: 0207 904 6000 Direct line: 0207 904 6287 E-mail: h.mcdonagh.defra.gsi.gov.uk
GTN: FAX:
Mr T S Singeltary P.O. Box 42 Bacliff Texas USA 77518
21 November 2001
Dear Mr Singeltary
TSE IN HOUNDS
Thank you for e-mail regarding the hounds survey. I am sorry for the long delay in responding.
As you note, the hound survey remains unpublished. However the Spongiform Encephalopathy Advisory Committee (SEAC), the UK Government's independent Advisory Committee on all aspects related to BSE-like disease, gave the hound study detailed consideration at their meeting in January 1994. As a summary of this meeting published in the BSE inquiry noted, the Committee were clearly concerned about the work that had been carried out, concluding that there had clearly been problems with it, particularly the control on the histology, and that it was more or less inconclusive. However was agreed that there should be a re-evaluation of the pathological material in the study.
Later, at their meeting in June 95, The Committee re-evaluated the hound study to see if any useful results could be gained from it. The Chairman concluded that there were varying opinions within the Committee on further work. It did not suggest any further transmission studies and thought that the lack of clinical data was a major weakness.
Overall, it is clear that SEAC had major concerns about the survey as conducted. As a result it is likely that the authors felt that it would not stand up to r~eer review and hence it was never published. As noted above, and in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether additional work should be performed to examine dogs for evidence of TSE infection. Although the Committee had mixed views about the merits of conducting further work, the Chairman noted that when the Southwood Committee made their recommendation to complete an assessment of possible spongiform disease in dogs, no TSEs had been identified in other species and hence dogs were perceived as a high risk population and worthy of study. However subsequent to the original recommendation, made in 1990, a number of other species had been identified with TSE ( e.g. cats) so a study in hounds was less
critical. For more details see-
http://web.archive.org/web/20010305223122/www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf
As this study remains unpublished, my understanding is that the ownership of the data essentially remains with the original researchers. Thus unfortunately, I am unable to help with your request to supply information on the hound survey directly. My only suggestion is that you contact one of the researchers originally involved in the project, such as Gerald Wells. He can be contacted at the following address.
Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT 15 3NB, UK
You may also wish to be aware that since November 1994 all suspected cases of spongiform encephalopathy in animals and poultry were made notifiable. Hence since that date there has been a requirement for vets to report any suspect SE in dogs for further investigation. To date there has never been positive identification of a TSE in a dog.
I hope this is helpful
Yours sincerely 4
HUGH MCDONAGH BSE CORRESPONDENCE SECTION
IN CONFIDENCE
CONCEPT NOT FOR FURTHER STUDY OF MATERIAL OBTAINED IN A SURVEY OF HOUNDS FOR EVIDENCE OF A SCRAPIE-LIKE SPONGIFORM ENCEPHALOPATHY (SE)
snip...
b) Fibrillar material closely similar to SAF, found in BSE/Scrapie, was observed in 19 (4.3%) cases, all of which were hounds > 7 years of age. 14/19 of these suspected SAF results correlated with cases in the unresolveable histopathological category.
snip...
The following proposals address the hypothesis that the hound survey observations represent a PrP related or scrapie-like disease of dogs in which the pathological response, and possible the spread of infectivity, is neuroanatomically localized. By inference this could also mean that the disorder is clinically silent and non-progressive.
http://web.archive.org/web/20010305223122/www.bseinquiry.gov.uk/files/yb/1995/02/09001001.pdf
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ? August 20, 2008
see full text ;
http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html
Monday, October 26, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Published online before print October 22, 2009
http://nor-98.blogspot.com/2009/10/similarities-between-forms-of-sheep.html
Published online before print October 22, 2009 This Article
Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
PubMed
PubMed Citation Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
Copyright © 2009 American Society for Investigative Pathology American Journal of Pathology, doi:10.2353/ajpath.2009.090623
Accepted for publication August 19, 2009.
--------------------------------------------------------------------------------
Article
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wiebke M. Wemheuer*, Sylvie L. Benestad, Arne Wrede*, Ulf Schulze-Sturm*, Wilhelm E. Wemheuer, Uwe Hahmann*, Joanna Gawinecka, Ekkehard Schütz, Inga Zerr, Bertram Brenig, Bjørn Bratberg, Olivier Andréoletti¶, and Walter J. Schulz-Schaeffer*@ From the Prion and Dementia Research Unit,* Department of Neuropathology, University Medical Center Goettingen, Goettingen, Germany; National Veterinary Institute, Department of Pathology, Oslo, Norway; Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; and Animal Health,¶ Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
@ To whom correspondence should be addressed. E-mail: wjschulz@med.uni-goettingen.de.
Abstract
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2009.090623v1
P.4.25
Human susceptibility to atypical scrapie
Chris Plinston, Rona Barron, Nora Hunter The Roslin Institute and R(D)SVS, University of Edinburgh, UK
Background: Isolates of classical sheep scrapie are thought to pose little risk to humans as there have been no documented links between presence of sheep scrapie and the development of human TSE disease. However, the link between BSE and the development of vCJD in humans proves that a risk does exist from ruminant TSE disease, and therefore all new ruminant TSEs may potentially be transmissible to humans. Due to increased sensitivity of TSE diagnostic assay systems, a new TSE of sheep termed 'atypical scrapie' has been identified. This disease has been difficult to identify, and is found mainly in sheep which are previously thought to have a genetic makeup that made them resistant to scrapie. It is unclear whether this is a new TSE of sheep, an old disease which has only been identified through increased surveillance, or if it represents the phenotype of classical scrapie in so called 'resistant' sheep PrP genotypes.
Objectives: The objective of the study is to assess relative transmissibility of atypical scrapie isolates to humans and the associated risk to the population.
Methods: In order to determine whether atypical scrapie poses a risk to human health we have transmitted isolates from three different sheep PrP genotypes to our gene targeted transgenic mice which express human PrP with the M129V polymorphism known to be important in human susceptibility to disease. Mice of all three PrP genotypes have been inoculated intracerebrally with atypical scrapie isolates.
Discussion: In order to prevent the emergence of a new human TSE, we need to be able to assess the risk to humans from new emerging TSEs in livestock. The study of atypical scrapie infection in these transgenic lines could therefore provide important information on the host range and disease characteristics associated with such isolates. Preventative measures could then be put in place before this disease gives rise to another human disease variant and an underlying level of infection in the population.
P.5.21
Parallels between different forms of sheep scrapie and types of Creutzfeldt-Jakob disease (CJD)
Wiebke M. Wemheuer1, Sylvie L. Benestad2, Arne Wrede1, Wilhelm E. Wemheuer3, Tatjana Pfander1, Bjørn Bratberg2, Bertram Brenig3,Walter J. Schulz-Schaeffer1 1University Medical Center Goettingen, Germany; 2Institute of Veterinary Medicine Oslo, Norway; 3Institute of Veterinary Medicine Goettingen, Germany
Background: Scrapie in sheep and goats is often regarded as the archetype of prion diseases. In 1998, a new form of scrapie - atypical/Nor98 scrapie - was described that differed from classical scrapie in terms of epidemiology, Western blot profile, the distribution of pathological prion protein (PrPSc) in the body and its stability against proteinase K. In a similar way, distinct disease types exist in sporadic Creutzfeldt-Jakob disease (CJD). They differ with regard to their clinical outcome, Western blot profile and PrPSc deposition pattern in the central nervous system (CNS).
Objectives: The comparison of PrPSc deposits in sheep scrapie and human sporadic CJD. Methods: Tissues of the CNS of sheep with classical scrapie, sheep with atypical/Nor98 scrapie and 20 patients with sporadic CJD were examined using the sensitive Paraffin Embedded Tissue (PET) blot method. The results were compared with those obtained by immunohistochemistry. With the objective of gaining information on the protein conformation, the PrPSc of classical and atypical/Nor98 sheep scrapie and sporadic CJD was tested for its stability against denaturation with guanidine hydrochloride (GdnHCl) using a Membrane Adsorption Assay.
Results: The PrPSc of atypical/Nor98 scrapie cases and of CJD prion type 1 patients exhibits a mainly reticular/synaptic deposition pattern in the brain and is relatively sensitive to denaturation with GdnHCl. In contrast classical scrapie cases and CJD prion type 2 patients have a more complex PrPSc deposition pattern in common that consists of larger PrPSc aggregates and the PrPSc itself is comparatively stable against denaturation.
Discussion: The similarity between CJD types and scrapie types indicates that at least two comparable forms of the misfolded prion protein exist beyond species barriers and can elicit prion diseases. It seems therefore reasonable to classify classical and atypical/Nor98 scrapie - in analogy to the existing CJD types - as different scrapie types.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
P03.141
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.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
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.
Content
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.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
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
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
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.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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 ia 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
Epidemiology of Scrapie in the United States 1977
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://scrapie-usa.blogspot.com/
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
also see ;
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
WHO WILL WATCH THE CHILDREN for CJD over the next 5 decades ?
FOR 4 years, the USDA fed dead stock downer cows, the most high risk cattle for mad cow disease and other dangerous pathogens to children all across the USA via the USDA certified dead stock downer cow school lunch program...
SCHOOL LUNCH PROGRAM FROM DOWNER CATTLE UPDATE
http://downercattle.blogspot.com/2009/05/who-will-watch-children.html
http://downercattle.blogspot.com/
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Sunday, September 6, 2009
MAD COW USA 1997 SECRET VIDEO
http://madcowusda.blogspot.com/2009/09/mad-cow-usa-1997-video.html
U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? see video at bottom
http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.html
DAMNING TESTIMONY FROM STANLEY PRUSINER THE NOBEL PEACE PRIZE WINNER ON PRIONS SPEAKING ABOUT ANN VENEMAN see video
http://maddeer.org/video/embedded/prusinerclip.html
CVM Annual Report Fiscal Year 2008: October 1, 2007-September 30, 2008
PUTTING LIPSTICK ON A PIG AND TAKING HER TO A DANCE...TSS
BSE Feed Rule Enforcement: A Decade of Success OFF TO A FAST START
http://madcowfeed.blogspot.com/2008/06/texas-firm-recalls-cattle-heads-that.html
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
http://bse-atypical.blogspot.com/2006/08/bse-atypical-texas-and-alabama-update.html
Monday, October 26, 2009
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Sent: Tuesday, November 03, 2009 5:14 PM Subject: Re: FOIA REQUEST ON FEED RECALL PRODUCT Bulk Whole Barley, Recall # V-256-2009 DISTRIBUTION TX END OF ENFORCEMENT REPORT FOR AUGUST 26, 2009
http://madcowfeed.blogspot.com/2009/11/re-foia-request-on-feed-recall-product.html
BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?
snip... see full text ;
http://cjdtexas.blogspot.com/
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
Friday, October 23, 2009
Creutzfeldt-Jakob Disease Surveillance Texas Data for Reporting Years 2000-2008
http://cjdtexas.blogspot.com/2009/10/creutzfeldt-jakob-disease-surveillance.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Monday, October 26, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Published online before print October 22, 2009 This Article
Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
PubMed
PubMed Citation Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
Copyright © 2009 American Society for Investigative Pathology American Journal of Pathology, doi:10.2353/ajpath.2009.090623
Accepted for publication August 19, 2009.
--------------------------------------------------------------------------------
Article
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wiebke M. Wemheuer*, Sylvie L. Benestad, Arne Wrede*, Ulf Schulze-Sturm*, Wilhelm E. Wemheuer, Uwe Hahmann*, Joanna Gawinecka, Ekkehard Schütz, Inga Zerr, Bertram Brenig, Bjørn Bratberg, Olivier Andréoletti¶, and Walter J. Schulz-Schaeffer*@ From the Prion and Dementia Research Unit,* Department of Neuropathology, University Medical Center Goettingen, Goettingen, Germany; National Veterinary Institute, Department of Pathology, Oslo, Norway; Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; and Animal Health,¶ Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
@ To whom correspondence should be addressed. E-mail: wjschulz@med.uni-goettingen.de.
Abstract
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2009.090623v1
P.4.25
Human susceptibility to atypical scrapie
Chris Plinston, Rona Barron, Nora Hunter The Roslin Institute and R(D)SVS, University of Edinburgh, UK
Background: Isolates of classical sheep scrapie are thought to pose little risk to humans as there have been no documented links between presence of sheep scrapie and the development of human TSE disease. However, the link between BSE and the development of vCJD in humans proves that a risk does exist from ruminant TSE disease, and therefore all new ruminant TSEs may potentially be transmissible to humans. Due to increased sensitivity of TSE diagnostic assay systems, a new TSE of sheep termed 'atypical scrapie' has been identified. This disease has been difficult to identify, and is found mainly in sheep which are previously thought to have a genetic makeup that made them resistant to scrapie. It is unclear whether this is a new TSE of sheep, an old disease which has only been identified through increased surveillance, or if it represents the phenotype of classical scrapie in so called 'resistant' sheep PrP genotypes.
Objectives: The objective of the study is to assess relative transmissibility of atypical scrapie isolates to humans and the associated risk to the population.
Methods: In order to determine whether atypical scrapie poses a risk to human health we have transmitted isolates from three different sheep PrP genotypes to our gene targeted transgenic mice which express human PrP with the M129V polymorphism known to be important in human susceptibility to disease. Mice of all three PrP genotypes have been inoculated intracerebrally with atypical scrapie isolates.
Discussion: In order to prevent the emergence of a new human TSE, we need to be able to assess the risk to humans from new emerging TSEs in livestock. The study of atypical scrapie infection in these transgenic lines could therefore provide important information on the host range and disease characteristics associated with such isolates. Preventative measures could then be put in place before this disease gives rise to another human disease variant and an underlying level of infection in the population.
P.5.21
Parallels between different forms of sheep scrapie and types of Creutzfeldt-Jakob disease (CJD)
Wiebke M. Wemheuer1, Sylvie L. Benestad2, Arne Wrede1, Wilhelm E. Wemheuer3, Tatjana Pfander1, Bjørn Bratberg2, Bertram Brenig3,Walter J. Schulz-Schaeffer1 1University Medical Center Goettingen, Germany; 2Institute of Veterinary Medicine Oslo, Norway; 3Institute of Veterinary Medicine Goettingen, Germany
Background: Scrapie in sheep and goats is often regarded as the archetype of prion diseases. In 1998, a new form of scrapie - atypical/Nor98 scrapie - was described that differed from classical scrapie in terms of epidemiology, Western blot profile, the distribution of pathological prion protein (PrPSc) in the body and its stability against proteinase K. In a similar way, distinct disease types exist in sporadic Creutzfeldt-Jakob disease (CJD). They differ with regard to their clinical outcome, Western blot profile and PrPSc deposition pattern in the central nervous system (CNS).
Objectives: The comparison of PrPSc deposits in sheep scrapie and human sporadic CJD. Methods: Tissues of the CNS of sheep with classical scrapie, sheep with atypical/Nor98 scrapie and 20 patients with sporadic CJD were examined using the sensitive Paraffin Embedded Tissue (PET) blot method. The results were compared with those obtained by immunohistochemistry. With the objective of gaining information on the protein conformation, the PrPSc of classical and atypical/Nor98 sheep scrapie and sporadic CJD was tested for its stability against denaturation with guanidine hydrochloride (GdnHCl) using a Membrane Adsorption Assay.
Results: The PrPSc of atypical/Nor98 scrapie cases and of CJD prion type 1 patients exhibits a mainly reticular/synaptic deposition pattern in the brain and is relatively sensitive to denaturation with GdnHCl. In contrast classical scrapie cases and CJD prion type 2 patients have a more complex PrPSc deposition pattern in common that consists of larger PrPSc aggregates and the PrPSc itself is comparatively stable against denaturation.
Discussion: The similarity between CJD types and scrapie types indicates that at least two comparable forms of the misfolded prion protein exist beyond species barriers and can elicit prion diseases. It seems therefore reasonable to classify classical and atypical/Nor98 scrapie - in analogy to the existing CJD types - as different scrapie types.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
P03.141
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.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
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.
Content
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.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
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
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
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.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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 ia 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://scrapie-usa.blogspot.com/
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
PubMed
PubMed Citation Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
Copyright © 2009 American Society for Investigative Pathology American Journal of Pathology, doi:10.2353/ajpath.2009.090623
Accepted for publication August 19, 2009.
--------------------------------------------------------------------------------
Article
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wiebke M. Wemheuer*, Sylvie L. Benestad, Arne Wrede*, Ulf Schulze-Sturm*, Wilhelm E. Wemheuer, Uwe Hahmann*, Joanna Gawinecka, Ekkehard Schütz, Inga Zerr, Bertram Brenig, Bjørn Bratberg, Olivier Andréoletti¶, and Walter J. Schulz-Schaeffer*@ From the Prion and Dementia Research Unit,* Department of Neuropathology, University Medical Center Goettingen, Goettingen, Germany; National Veterinary Institute, Department of Pathology, Oslo, Norway; Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; and Animal Health,¶ Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
@ To whom correspondence should be addressed. E-mail: wjschulz@med.uni-goettingen.de.
Abstract
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2009.090623v1
P.4.25
Human susceptibility to atypical scrapie
Chris Plinston, Rona Barron, Nora Hunter The Roslin Institute and R(D)SVS, University of Edinburgh, UK
Background: Isolates of classical sheep scrapie are thought to pose little risk to humans as there have been no documented links between presence of sheep scrapie and the development of human TSE disease. However, the link between BSE and the development of vCJD in humans proves that a risk does exist from ruminant TSE disease, and therefore all new ruminant TSEs may potentially be transmissible to humans. Due to increased sensitivity of TSE diagnostic assay systems, a new TSE of sheep termed 'atypical scrapie' has been identified. This disease has been difficult to identify, and is found mainly in sheep which are previously thought to have a genetic makeup that made them resistant to scrapie. It is unclear whether this is a new TSE of sheep, an old disease which has only been identified through increased surveillance, or if it represents the phenotype of classical scrapie in so called 'resistant' sheep PrP genotypes.
Objectives: The objective of the study is to assess relative transmissibility of atypical scrapie isolates to humans and the associated risk to the population.
Methods: In order to determine whether atypical scrapie poses a risk to human health we have transmitted isolates from three different sheep PrP genotypes to our gene targeted transgenic mice which express human PrP with the M129V polymorphism known to be important in human susceptibility to disease. Mice of all three PrP genotypes have been inoculated intracerebrally with atypical scrapie isolates.
Discussion: In order to prevent the emergence of a new human TSE, we need to be able to assess the risk to humans from new emerging TSEs in livestock. The study of atypical scrapie infection in these transgenic lines could therefore provide important information on the host range and disease characteristics associated with such isolates. Preventative measures could then be put in place before this disease gives rise to another human disease variant and an underlying level of infection in the population.
P.5.21
Parallels between different forms of sheep scrapie and types of Creutzfeldt-Jakob disease (CJD)
Wiebke M. Wemheuer1, Sylvie L. Benestad2, Arne Wrede1, Wilhelm E. Wemheuer3, Tatjana Pfander1, Bjørn Bratberg2, Bertram Brenig3,Walter J. Schulz-Schaeffer1 1University Medical Center Goettingen, Germany; 2Institute of Veterinary Medicine Oslo, Norway; 3Institute of Veterinary Medicine Goettingen, Germany
Background: Scrapie in sheep and goats is often regarded as the archetype of prion diseases. In 1998, a new form of scrapie - atypical/Nor98 scrapie - was described that differed from classical scrapie in terms of epidemiology, Western blot profile, the distribution of pathological prion protein (PrPSc) in the body and its stability against proteinase K. In a similar way, distinct disease types exist in sporadic Creutzfeldt-Jakob disease (CJD). They differ with regard to their clinical outcome, Western blot profile and PrPSc deposition pattern in the central nervous system (CNS).
Objectives: The comparison of PrPSc deposits in sheep scrapie and human sporadic CJD. Methods: Tissues of the CNS of sheep with classical scrapie, sheep with atypical/Nor98 scrapie and 20 patients with sporadic CJD were examined using the sensitive Paraffin Embedded Tissue (PET) blot method. The results were compared with those obtained by immunohistochemistry. With the objective of gaining information on the protein conformation, the PrPSc of classical and atypical/Nor98 sheep scrapie and sporadic CJD was tested for its stability against denaturation with guanidine hydrochloride (GdnHCl) using a Membrane Adsorption Assay.
Results: The PrPSc of atypical/Nor98 scrapie cases and of CJD prion type 1 patients exhibits a mainly reticular/synaptic deposition pattern in the brain and is relatively sensitive to denaturation with GdnHCl. In contrast classical scrapie cases and CJD prion type 2 patients have a more complex PrPSc deposition pattern in common that consists of larger PrPSc aggregates and the PrPSc itself is comparatively stable against denaturation.
Discussion: The similarity between CJD types and scrapie types indicates that at least two comparable forms of the misfolded prion protein exist beyond species barriers and can elicit prion diseases. It seems therefore reasonable to classify classical and atypical/Nor98 scrapie - in analogy to the existing CJD types - as different scrapie types.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
P03.141
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.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
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.
Content
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.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
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
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
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.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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 ia 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://scrapie-usa.blogspot.com/
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
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