Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

Top Curr Chem (2011)

DOI: 10.1007/128_2011_161

# Springer-Verlag Berlin Heidelberg 2011

Atypical Prion Diseases in Humans and Animals

Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar


Although prion diseases, such as Creutzfeldt–Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the “scrapie form” (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.

M.A. Tranulis (*)

Norwegian School of Veterinary Science, Oslo, Norway


S.L. Benestad

Norwegian Veterinary Institute, Oslo, Norway

T. Baron

Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France

H. Kretzschmar

Ludwig–Maximilians University of Munich, Munich, Germany

Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type


Classical scrapie in small ruminants, the archetypal animal prion disease [66], and CWD in cervids are the only known prion diseases that spread effectively within a species, under natural (free-ranging wild population) or near-natural (extensive husbandry) conditions [67–70]. Spread may be horizontal through direct contact or shared environments [71, 72], or vertical from mother to offspring during the pre- or neonatal period [73–75]. Although these diseases clearly illustrate that prion diseases can behave as true infectious maladies, they could, ironically, turn out to be exceptions to the rule rather than typical. Predators have the potential to be exposed to ruminant prion disease and, as evident with the BSE-C agent, possibly develop prion disease. A recent study of predators in a CWD endemic area of Wisconsin did not provide evidence of a transmission of CWD prions across species barriers [76]. For a prion disease to be sustained as infectious within a population, it seems that the infectious prion must be present at relatively high levels in the peripheral tissues of affected animals, most notably in the digestive Atypical Prion Diseases in Humans and Animals tract and its associated salivary glands and lymphoid aggregates. CWD transmits effectively, with saliva [71, 72, 77], feces [78], and urine [79] as primary vehicles, either through contact or via the environment. Protease-resistant PrP of cervid origin has been detected in water samples taken from a CWD endemic area [80].


With the discovery of ruminant prion diseases that resemble sporadic human prion disease, a certain element of “balance” in the epidemiology of prion disease could be established. However, the logic of this could also be reversed, and an important question could be raised: might the low level occurrence of spontaneous farm animal prion disease underlie one or more forms of human prion disease, which are currently misinterpreted as spontaneous? This major epidemiological and public-health issue will be the focus of discussion in this chapter.

3 Atypical/Nor98 Scrapie

During a period of enhanced awareness regarding sheep scrapie in the late 1990s, a few suspect scrapie cases, with unusual clinicopathological features, were identified in Norway, and were subsequently named Nor98 [45]. The first case appeared in Eastern Norway, until then considered to be a scrapie-free region. Intriguingly, old and healthy sheep in the same flock were found to be carrying PrP-genotypes conferring high susceptibility to scrapie, while the affected animal had a PrP genotype rarely seen in classical scrapie [117]. The predominant clinical symptom was progressive ataxia. While in classical scrapie the predominance of pathology is in the brain stem, the unusual Nor98 cases showed pathology and PrPSc accumulation in the cerebral and cerebellar cortices. The glycoprofile of proteinase-resistant PrPSc from all the unusual cases also differed from classical scrapie, with multiband pattern and a characteristic lower band of around 11 kDa, not previously described in animal prion diseases (Fig. 1). In the brain stem, pathology and PrPSc accumulation was mild or even below detection limits [45]. This lesion profile has proved to be consistent for atypical/Nor98 scrapie [118–121]. Furthermore, when PrPSc is detectable in the brain stem in atypical cases, it is mainly restricted to the neuropil of the spinal tract nucleus of the trigeminal nerve, as sparse and diffuse staining, and/or as globular staining in the white matter, which is occasionally pronounced along the spinocerebellar tracts.

In addition to the difference in lesion profile, the pattern of PrPSc deposits in such atypical scrapie cases also differs from that seen in classical scrapie cases [109, 122]. In classical scrapie, a stellate pattern of PrPSc deposits is particularly prominent in the granular layer of the cerebellum, while in atypical/Nor98 scrapie a widespread, diffuse, synaptic type of staining can be observed in the molecular or the granular cell layers or both, and may be variably associated with globular staining in the white matter.

In the cerebral cortex, classical cases display a stellate, perivascular, and frequently intraneuronal PrPSc staining, while in atypical/Nor98 cases a diffuse laminar staining dominates. In some atypical/Nor98 cases, multifocal dense plaque-like aggregates can be seen in the white matter tracts [118].

One case of atypical/Nor98 scrapie has been reported in which all brain sections appeared negative for immunohistochemical PrPSc; however, a faint staining could be observed in the granular layer by use of the PET-blot technique [109, 122]. Interestingly, there appears to be no correlation between the degree of PrPSc staining and the disease phenotype, regardless of age and PrP genotype.

Since the obex area and especially the dorsal motoric nucleus of the vagus nerve (DMNV) were previously considered the tissue of choice for scrapie diagnostic purposes, the Nor98 cases might easily have escaped identification. At around the same time that the first atypical/Nor98 cases were discovered, a number of atypical scrapie cases were identified through pan-European screening programs, designed particularly for detecting BSE in small ruminants. Following a report of German and French cases [46], further reports came from many other European countries [120, 123–129], as well as The Falkland Islands [130], USA [131], New Zealand [132], Australia [133], and, most recently, Canada [134]. According to data from the European Surveillance Program for TSE in small ruminants, atypical/Nor98 scrapie has been identified in more than 20 European countries [135], with a surprisingly uniform prevalence (about 6–8 cases per 10 000 tests), which contrasts with the more variable and clustered occurrence of classical scrapie. A study of formalin-fixed archival brain material has back-dated atypical/Nor98 scrapie in the UK to at least 1987 [136], demonstrating that atypical/Nor98 scrapie has existed in the small ruminant population for years without being detected.

Diagnostic kits for rapid detection of atypical/Nor98 scrapie have recently been evaluated by the European Food Safety Authority (EFSA), with five out of nine tests being approved [137]. Since tests that did not achieve EFSA approval, due to lack of sensitivity, will be in use until the end of 2010, it is reasonable to assume that atypical/Nor98 scrapie is underdiagnosed. The underlying problem of detecting atypical/Nor98 scrapie seems not only related to the selection of tissue for analysis, but also the relative PK-sensitivity of PrPSc generated in this disease [48, 119, 138], a property that continues to be preserved following transmission into mice. In the first study of transmission of atypical/Nor98 scrapie to transgenic mice expressing ovine PrP, similar lesion profiles, PrPSc deposition patterns, incubation periods, and PrP-glycoprofiles were reported following inoculation from isolates obtained from three Norwegian and ten French atypical scrapie cases, suggesting that a single, unique prion strain was responsible for causing the atypical/Nor98 type of scrapie [139]. This study has been extended to British atypical isolates, and the results again confirm the uniformity in transmission characteristics of atypical/Nor98 isolates [140].

Detailed mapping of the PrP-fragments, as revealed in Western Blots after PK treatment, has demonstrated, despite some small discrepancies, a unique banding pattern, with a characteristic lower band (band C after PNGase-F treatment) of about 11 kDa [44, 45, 48] or 7 kDa [138], consisting of an internal PrP-fragment. The N-terminus of the 11-kDa fragment has been accurately mapped to amino acid (aa) 85–90, since several mAbs with known linear epitopes are available for this region of the PrP. The C-terminus of the fragment is predicted to be around aa 185–190, assuming no post-translational modifications. However, there are only few mAb available to the aa 155–200 region in PrP, and thus precise epitope mapping of the C-terminus of this PrP-fragment is currently problematic. The 11- kDa band is a consistent diagnostic hallmark in cases of atypical/Nor98 scrapie, not only in sheep, but also in goats [141].

The occurrence of classical scrapie in sheep is modulated by three polymorphisms, at codons 136 (alanine/valine, A/V), 154 (arginine/histidine, R/H), and 171 (glutamate/arginine/histidine, Q/R/H) in the gene that encodes PrP, PRNP [142–144]. The frequency of these, and other PrP polymorphisms, varies significantly between breeds and the different polymorphisms are generally mutually exclusive. The valine polymorphism at codon 136 results in the major disease promoting allele V136R154Q171 (VRQ), with homozygous VRQ/VRQ animals the most susceptible. The presence of arginine (R) at codon 171 (ARR allele) has been shown to be significantly associated with a reduction in the probability of classical scrapie occurrence, conveying a relative resistance, thereby enabling markerassisted breeding for resistance towards classical scrapie [145, 146].

However, atypical/Nor98 scrapie seems to occur most frequently in sheep with PrP genotypes considered to be less susceptible, while apparently sparing flock-mates carrying high susceptibility PrP genotypes [45]. A large proportion of atypical/Nor98 cases carry at least one AHQ allele. Moreover, the presence of phenylalanine (F) at codon 141 (wt-allele leucine, L), giving rise to the AF141RQ (AFRQ) allele, is also strongly associated with this type of scrapie [147–149]. A schematic presentation of allelic modulation of susceptibility for classical and atypical/Nor98 scrapie is given in Fig. 2. Interestingly, atypical/Nor98 scrapie has been very rarely recorded in sheep carrying the VRQ allele, and only in combination with a disease promoting AHQ or AFRQ allele, while several cases have been seen in sheep with the ARR/ARR genotype [150]. In a study of genetic risk for atypical/Nor98 scrapie involving 248 cases [151], the most susceptible PrP genotypes were found to be ALHQ/ALHQ, ALHQ/AFRQ, and AFRQ/AFRQ, while heterozygotes ALHQ/ALRQ and AFRQ/ALRQ were less susceptible. This result concurs with data from other studies [44, 148, 150] and also highlights the previously reported [150] risk of atypical/Nor98 scrapie in animals with the ALRR/ ALRR genotype, which are enriched in marker-assisted breeding.

Although some data indicate a protective effect of the VRQ allele towards atypical/Nor98 scrapie, the first transmission to transgenic mice (line tg338) was achieved with mice carrying the ovine PrP VRQ/VRQ genotype on a PrP null background. However, these mice over-expressed PrP by eight- to tenfold, compared to the level in sheep brain [139]. In a subsequent study, aimed at defining the transmission characteristics in more detail, three lines of TgOvPrP4 mice were used, with neuron-specific expression of the ovine ARQ/ARQ genotype at approximately 0.25 times, 1.5 times, and 6 times the level in sheep. In this study, transmission of atypical/Nor98 scrapie was shown to be more strongly modulated by host PrP expression level and the genotype of the inoculum than is observed with classical scrapie or BSE-C [152].

Epidemiological analyses of atypical/Nor98 scrapie in different countries [135, 150, 153, 154] have resulted in a fairly uniform epidemiological profile being described. Atypical/Nor98 scrapie is widely distributed geographically, without clustering, and normally only one or very few cases are seen, even in flocks of several hundred animals. Additionally, atypical/Nor98 cases are generally older than classical scrapie cases and a significant proportion of the cases have been identified through screening-programs and/or by analysis of fallen stock, while this is uncommon for classical scrapie [118]. Case-control studies [154, 155] of atypical/ Nor98 scrapie have failed to identify epidemiological evidence to indicate an infectious behavior, whereas contact and purchase are important risk factors for classical scrapie [67]. However, epidemiological analysis and modeling of sheep prion disease is far from trivial. For a comprehensive review of this topic, see [156].

In 1980, Gibbs and co-workers [157] transmitted kuru, CJD, and scrapie to squirrel monkeys by the oral route. The scrapie isolate they used had a complex passage history, with nine serial passages from sheep to goat, followed by three serial passages in mice, and finally three serial passages in hamster. Two monkeys were fed brain, kidney, and spleen from scrapie-infected hamsters for 3 days. The monkeys succumbed to spongiform encephalopathy after 25 and 32 months. Notably, the incubation period in a squirrel monkey intracerebrally inoculated with brain material from a scrapie-diseased goat was 31 months and that of intracerebral inoculation of mouse-adapted scrapie isolates varied from 14 to 31 months. Thus the incubation periods observed after oral inoculation were comparatively short, indicating that the oral route of transmission could be effective, at least in combination with large doses of infective material. This significant study demonstrated that a rodent-adapted scrapie strain can be transmitted to non-human primates via the oral route and also provides a pertinent reminder of the pathogenic potential of scrapie. Transmissions of classical and atypical/Nor98 scrapie to mice have produced disease profiles and PrPSc types that are reassuringly different from those seen in BSE and in human prion disease [59, 139, 152, 158]. However, transmission of a primary classical scrapie isolate from Romanov sheep to C57BL/6 mice produced a lesion profile and PrPSc type conspicuously similar to those seen after transmission of sCJD and iCJD to the same line of mice, while this was not the case after transmission of a mouse-adapted scrapie strain included in the same study [158]. Thus, despite the lack of recognized epidemiological connections between sheep scrapie and human prion disease [159], and considering the variability in strain characteristic of sheep scrapie, it should be noted that we currently have no effective experimental models for estimation of human risk related to oral exposure to such pathogens.

4 Atypical BSE

Until 2004 it was believed that BSE was a unique disease, due to a single major strain of TSE agent that was propagated in cattle by recycling in contaminated meat-and-bone meal. This opinion had been strongly supported by the identification of a unique strain of transmissible agent, as defined by its features following transmission of the disease in inbred wt mouse models that had been extensively used in the UK to demonstrate that scrapie in sheep and goats could involve a variety of different strains [160, 161]. Transmission to mouse lines, such as RIII, C57BL, or VM, of different bovine isolates, including those from different countries, revealed a uniform behavior, as shown by incubation periods of the disease, distribution of spongiform changes, and the distribution and features of PrPSc deposits. This uniformity of the disease in cattle was also supported by the findings of the same distribution of lesions in the brains of cattle, with the medulla oblongata predominantly involved, including at different times of the epidemic in cattle in the UK, or in other European countries [162–164].

In 2004, this established “fact” that BSE was a unique single strain infection, was abruptly challenged when two countries reported the occurrence of a few cases of BSE in older cattle that showed deviant features of the disease. In France, three cases were reported that showed an unusually high molecular mass of PrPSc by Western blot studies, indicating a protease cleavage site distinct from that seen in cattle with “classical” BSE (BSE-C) [64]. This was unlikely to be a reflection of phenotypic variations since a number of studies had previously shown that the PrPSc molecular features, notably the protease cleavage site, was a very reliable characteristic of BSE-C, even preserved upon transmission to other species, such as in variant CJD in human [22], or, experimentally, in sheep or in mice [28, 165–168]. A second report from Italy described two cases from cattle, but in these cases the PrPSc molecular mass was slightly lower than that observed in BSE-C, and, more strikingly, the proportion of the diglycosylated band was significantly lower [65]. In this report, the differences from classical BSE were further supported by histopathological analysis that revealed that the distribution and nature of lesions in the cattle brains differed distinctly from those previously described during the BSE-C epizooty. Not only were the lesions much more abundant in the cortical regions of the brain, in contrast with the preferential location in the brain stem in BSE-C, but were also characterized by the presence of amyloid plaques which are not observed in BSE-C. Due to this last characteristic, the disease was termed Bovine Amyloidotic Spongiform Encephalopathy (BASE). As histopathological data are not always available, the two diseases identified in France and Italy were soon referred to as either H-type BSE or L-type BSE, based on the differences in PrPSc molecular masses identified after Western blot analysis [169]. Importantly, in all five cases, analysis of the coding sequence of the PRNP gene did not reveal any unusual features compared with the known PRNP sequence in cattle, and thus a genetic origin of such cases seemed unlikely.

These unexpected observations prompted further investigations, initially directed towards the confirmation of the original findings, including in other countries. Other “atypical” cases of BSE in cattle were rapidly identified in a number of different countries in Europe (Germany, Netherlands, Poland, Denmark, Ireland, United Kingdom, Sweden, Austria) [167, 168, 170–173] and also in Japan [161], USA [174, 175], and Canada [176] (Table 1). Questions immediately arose about the possible origins of such cases. Interestingly, some of the cases had been diagnosed in countries considered at low risk of exposure to contaminated meatand- bone meal such as Sweden in Europe, or the USA. The findings were also confirmed in Italy, where two additional BASE cases (BSE-L) were recognized and, to a larger extent, in France where the highest number of “atypical” cases have been identified to date since the implementation of active surveillance by rapid tests in 2000 (a total of 27 cases, 14 H-type and 13 L-type). Indeed, all cases recognized so far have been identified after initial diagnosis by rapid tests through the active surveillance programs that encompass exhaustive surveillance in adult cattle in Europe since 2001. This large-scale screening has certainly been essential for the discovery of such cases, which hardly would have been identified by passive surveillance, with the only exception being the finding of a single H-type BSE case in a 17-year-old zebu kept in a zoological park in Switzerland, in which clinical signs triggered neurological investigations, including BSE testing [177].

All the available studies to date have demonstrated that the cases identified in different countries have molecular features that are extremely consistent with those of the very first cases diagnosed in France and Italy. Among these studies, a collaborative European network study of atypical cases from six European countries (France, Italy, Netherlands, Germany, Poland, and Sweden) confirmed the migration properties and glycosylation profiles (glycoprofiles) of the H- and L-type isolates (Fig. 3). The presence of H-type BSE could also be detected by the differential binding of mAb specific for N- and more C-terminal PrP regions, indicative of the existence of two PrPSc populations differing by their N-terminal cleavage sites [178] (Fig. 3). In addition, this study revealed that both H-type and L-type BSE have enhanced protease sensitivities at pH 8, compared with BSE-C isolates. These properties appear to be consistent within each BSE type, independent of geographical origin, and although not all these criteria have been investigated in all the studies, this was also confirmed in cases of H-type BSE reported in the UK, USA, and Canada, and for cases of L-type BSE diagnosed in Japan and Canada. Thus, altogether these studies provided reliable criteria for identifying two atypical BSE forms, in addition to classical BSE.

Importantly, diagnosis of BSE in cattle is not always followed by further analyses to identify whether the case is classical or atypical. This contrasts with the diagnosis of prion disease in sheep and goats in Europe, following which further molecular investigations are undertaken on a regulatory basis, in order to identify possible unusual features that could indicate infection by the BSE agent. This difference in approach suggests that the number of atypical BSE cases in cattle among those reported by the OIE, as shown in Table 1, is certainly underestimated. The largest published study was performed on cattle in France between 2001 and 2007, during which 13 atypical cases (7 H-type and 6 L-type) were identified among 645 BSE cases [179]. During the 6-year period, 17.1 million rapid tests were performed, including 3.6 million animals over 8 years old. Thus, the estimated frequencies of H-type and L-type BSE were 0.41 and 0.35 per million adult cattle tested, respectively (1.9 and 1.7 in cattle over 8 years old). The most important information obtained in this study was the striking difference between the distribution by year of birth of atypical and classical cases detected during 2001–2007. Whereas the cases with classical BSE clearly indicated exposure to the classical BSE agent during 1993–1996 in France, one or two cases born each year were eventually identified as having atypical BSE (both H-type and L-type) at a mean age of 12 years. Overall, whereas the frequency of such atypical cases, although possibly underestimated, is certainly low, another relatively large series of atypical BSE cases (mostly of L-type) was also reported in Poland in cattle over 9 years old [172]. Together with the finding of atypical cases in some countries that were considered at very low risk of foodborne classical BSE, these data strongly argue that such atypical BSE cases represent sporadic TSE, as are most cases of CJD in humans. The PRNP gene has not been characterized for all cattle diagnosed with atypical BSE. However, genetic analyses have so far failed to identify any polymorphisms specifically associated with atypical BSE in the gene that encodes PrP [64, 65, 161, 164, 169, 175, 177]. Interestingly, a single case was reported in the USA with HtypeWestern blot features, which also had an E211K mutation, similar to the mutation E200K in humans, the most frequent mutation associated with gCJD [174]. Although this finding is of interest regarding our basic knowledge about the possible relationship between the PrP sequence and the pathogenesis of such diseases, it is unlikely to be of particular significance in cattle populations, since it seems that this mutation is quite rare, as it was not detected in a study of 6,062 cattle in the USA [180]. As well as the PRNP coding sequence, one or two copies of a distinct PRNP haplotypewere identified in five of six atypical BSE cases from France, Canada, and USA [170, 181]. This haplotype spans a portion of PRNP that includes part of intron 2, the entire coding region of exon 3, and part of the three prime untranslated region of exon 3 (13 kb), suggesting that a genetic determinant in, or near, the PRNP gene may influence susceptibility of cattle to atypical BSE. Also, whereas two regulatory region polymorphisms in the PrP gene of cattle have been reported to be associated with resistance to BSE, it has also been shown that the promoter polymorphism correlationwas specific to classical BSE, and that atypical BSE or experimentally inoculated TSE bypass the site of influence of the polymorphisms [182]. This suggests that genetic features involved in classical or atypical BSE could be linked to the different pathogeneses of the diseases, putatively in relation to either their acquired or sporadic origins.

Another line of investigation that followed the initial discovery of the two atypical forms of BSE was related to the potential transmissibility of the agent from such cases, and biological features of the TSE agents involved. Transmission of H-type BSE through a species barrier was first demonstrated using C57Bl/6 wild-type mice [183]. Detailed studies using transgenic mice expressing bovine or ovine PrP eventually demonstrated that H-type BSE and L-type BSE exhibit different biological and molecular features in these mouse models, and that both also differed from the wellknown strain isolated from classical BSE [169, 184–188]. In particular, the distinct properties of PrPSc in cattle identified by Western blot were maintained following transmission to transgenic mice expressing bovine PrP, in association with distinct incubation periods of the disease, as well as distribution and features of PrPSc deposits in the mouse brains [169, 184–188]. Transmission of H-type BSE into C57Bl/6 wildtype mice demonstrated the presence of a second, more C-terminally cleaved, formof PrPSc (PrPres #2), which, in unglycosylated form, migrated at approximately 14 kDa and could be specifically detected using C-terminal antibodies, as in the cattle brain [189]. Overall, these data clearly indicate that the three phenotypes of BSE in cattle are associated with three different major strains of transmissible agents.

To date, few studies have been published with regard to the transmission of these atypical BSE forms in cattle. Intra-species transmission of an Italian case of L-type BSE between Friesian and Alpine brown cattle was demonstrated using intra-cerebral inoculation, and the L-type molecular features were reproduced, as well as the presence and distribution pattern of amyloid plaques in the cattle brains [190]. This was associated with a disease phenotype characterized by mental dullness and progressive amyotrophy, suggestive of amotor neuron disorder, in contrast with the overreactivity and hypersensitivity in the absence of muscle changes, which are observed in cattle infected by a classical BSE isolate [190]. Transmission between cattle by the intra-cerebral route was also reported from other L-type isolates identified in Japan [191] and Germany [197] also from H-type cases from the Netherlands or Germany [192, 197] that also confirmed that the H-type molecular features were maintained in experimentally infected cattle. However, the extent to which these two atypical forms of BSE could also be transmitted to cattle by the oral route is currently unknown, and this information is essential in order to estimate more precisely the potential risks associated with these rare BSE isolates.

However, experimental studies in mouse models have already generated the hypothesis that such putatively sporadic cases may have been the origin of the foodborne epizooty of classical BSE, possibly after first recycling through an intermediate species [184, 188, 198]. Inoculations of C57Bl/6 and SJL wild-type mice with an Italian L-type BSE isolate resulted in some intriguing observations [188]. Unlike with inoculation with a classical BSE isolate, in these inoculations no evidence of transmissionwas detected during the first passage; clinical disease and brain lesionswere absent and PrPSc could not be detected either by Western blots or immunohistochemistry. However, a second passage from a pool of brain homogenates from these mice, and inoculated into the same mouse lines by both intra-peritoneal and intra-cerebral routes, resulted in clinical disease associated with brain lesions. Surprisingly, the molecular features, as well as the distribution of spongiform changes and PrPSc deposits, showed considerable similarities with those found in the same mouse lines when infected with classical BSE. It was thus assumed that either (1) classical BSE was present as a minor component in the initial L-type BSE inoculum and had been propagated in these mice or that (2) in the mouse background the L-type BSE had converted into classical BSE. More recently, the emergence of a strain indistinguishable fromclassical BSE has also been described following serial passages of BSE-H in some C57Bl/6 mice, although BSE-H can also be transmitted and maintained with the characteristic H-type properties in this mouse model [189, 198]. Another study of L-type BSE transmitted to a transgenic mouse line (tg338) over-expressing the ovine PrP (VRQ allele), also showed a shift in disease phenotype, with molecular and lesional features similar to those observed in these mice following transmission of classical BSE [184]. These results suggest the theoretical possibility that an early event, preceding the amplification of the classical BSE agent in cattle, could have been recycling of a TSE agent primarily present in cattle but modified through passage in an intermediate host such as sheep. However, it remains to be demonstratedwhether these two series of observations reflect the genuine identification of a common TSE agent present in both L-type and classical BSE in cattle, or if this represents phenotypic convergence following transmission in mouse models. Full characterization of the biological properties of the TSE agents produced in these experiments will help to clarify this issue.

Although, the characteristics of transmission of L-type BSE in sheep still remain to be described, it should be noted that different results were obtained in another transgenic mouse line (TgOvPrP4) expressing the ARQ allele of the ovine PrP at a lower level and under a different promoter [193]. In this mouse line, the molecular and lesional features of L-type BSE remained clearly distinct from those observed following transmission of classical BSE [193]. Results from this study had similarities to those obtained following transmission of the Stetsonville TME isolate in the same mouse model, having first been transmitted to cattle. This has been further supported by a recent study showing the transmissibility in Syrian hamsters of both L-type BSE and TME-in-cattle, and their similar molecular features in this model, as well as in bovine transgenic mice [199]. It can thus be hypothesized that outbreaks of TME in minks, which are occasionally observed in captive minks as a foodborne disease of unknown origin, might actually be caused by the consumption of food derived from cattle affected with L-type BSE. If confirmed, this would demonstrate the oral transmissibility of this atypical BSE form in a non-ruminant species. This hypothesis appears to have gained further credence from the recent observation of phenotypic similarities between TME in cattle and L-type BSE transmitted to macaque monkeys [194]. This recent study [194] belongs to a series of investigations that were initiated to evaluate the potential for transmission of atypical BSE to humans using experimental studies in non-human primates and in transgenic mice expressing the human PrP. This question was first raised following the initial discovery of BASE in Italy, which revealed certain molecular and lesional similarities to a sub-type of sporadic CJD (M/V Type 2) [65]. In another study, some molecular similarities were also emphasized regarding the identification of comparable C-terminally cleaved PrPSc products in both H-type BSE in cattle and in some CJD cases in humans [189]. This was recently reinforced by the observations that the amounts of the 13-kDa C-terminal fragment were specifically increased in CJD Type 1 cases, but this fragment was virtually undetectable in variant CJD and in most sporadic CJD subtypes associated with Type 2 (except the MM2 thalamic sub-type) [195]. While H-type BSE and L-type BSE are already strongly reminiscent of molecular Types 1 and 2, respectively, in sporadic CJD, these observations rather suggest that both cattle and humans could be affected by diseases involving similar molecular mechanisms. However, given the enigmatic origin of such diseases, it is obviously important to investigate any possible causal link between these human and bovine diseases.

In this context, successful transmission of L-type BSE has been reported in a cynomolgus macaque monkey inoculated by the intra-cerebral route. This infection was characterized by a shorter survival period (26 months with 25 mg cattle brain inoculated) than in monkeys infected with classical BSE (40 months with 100 mg cattle brain inoculated), and distinctive clinical, neuropathological, and biochemical features were recorded [194]. Molecular similarities with a rare MM2 cortical subtype of sCJD in humans were also observed, rather than with the MV2 subtype. Transmission of L-type BSE has also been demonstrated by the intra-cerebral route in a transgenic mouse line expressing normal levels of the human M129 PrP protein, and a higher (60%) transmission rate than that observed with classical BSE was reported [196]. Similar conclusions were reached from another study using another transgenic mouse line that over-expresses (about sixfold) M129 human PrP [186]. This study also concluded that there is no significant species barrier for L-type BSE between cattle and humans, as an attack rate of 100% was observed, and the incubation time was not reduced upon secondary passage. In contrast, transmission of the classical BSE agent to the same mice showed a substantial species barrier effect.


Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.

***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat


Rural and Regional Affairs and Transport References Committee

The possible impacts and consequences for public health, trade and agriculture of the Government’s decision to relax import restrictions on beef Final report June 2010

2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49

2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo—has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50

Monday, December 14, 2009

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

(hmmm, this is getting interesting now...TSS)

Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,

see also ;

All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

see full text ;

Monday, December 14, 2009

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

Wednesday, March 9, 2011

27 U.S. Senators want to force feed Japan Highly Potential North America Mad Cow Beef TSE PRION CJD

March 8, 2011

President Barack Obama The White House

1600 Pennsylvania Avenue, W Washington, DC 20500

Dear President Obama:

Friday, May 13,

2011 EFSA Joint Scientific Opinion on any possible epidemiological or molecular association between TSEs in animals and humans

Sunday, May 01, 2011

STUDY OF ATYPICAL BSE 2010 Annual Report May 2011

In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.

This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.

Tuesday, November 02, 2010

BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992

let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.

This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$


In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.

her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008).

This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine–human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks.

Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA

NATURE|Vol 457|26 February 2009

Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health

Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY

(see mad cow feed in COMMERCE IN ALABAMA...TSS)

Saturday, June 12, 2010

PUBLICATION REQUEST AND FOIA REQUEST Project Number: 3625-32000-086-05 Study of Atypical Bse

Wednesday, July 28, 2010

re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010


Molecular characterization of BSE in Canada

Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada

Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.

Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.

Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal- specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.

Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada. *It also suggests a similar cause or source for atypical BSE in these countries.

Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada. *It also suggests a similar cause or source for atypical BSE in these countries.

(see mad cow feed in COMMERCE IN ALABAMA...TSS)

Archive Number 20101206.4364 Published Date 06-DEC-2010 Subject PRO/AH/EDR> Prion disease update 2010 (11)



TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010 TAFS


Saturday, November 6, 2010

TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010 TAFS


"Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement."


Date: March 21, 2007 at 2:27 pm PST




Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007


Cattle feed delivered between 01/12/2007 and 01/26/2007


Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.

Firm initiated recall is ongoing.


Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.


42,090 lbs.







The firm does not utilize a code - only shipping documentation with commodity and weights identified.


Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete.


Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.


9,997,976 lbs.


ID and NV


Tuesday, May 3, 2011

PRION, TSE, typical, atypical BSE, aka mad cow disease, spray dried blood, feed, and a recipe for disaster

Tuesday, September 14, 2010

Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)

Sunday, May 10, 2009

Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)

TO :

May 8, 2009

Greetings again Dr. Freas, TSEAC et al,

In response to the Washington State case, we announced in January, 2004 our intention to strengthen the >97 feed ban by banning the use of blood products, poultry litter and plate waste, and this was one of the changes in the plan.


We did not follow through with this set of measures.

After considering the recommendations of the international review PAPER MILL REPORTING 301 495-5831 263 team we, instead, published an advance notice of proposed rule-making in July, 2004 jointly with USDA. In that proposal we tentatively proposed to ban SRMs from all animal feed. What we actually proposed in October, 2005 was a partial SRM ban, limited to brain and spinal cord tissues. It took us until April 25, 2008 to finalize the proposal because we significantly underestimated the costs associated with the measures. Also, commensurate with USDA’s surveillance results and prevalence estimates, and the high level of compliance with our >97 rule, we modified the rule to apply only to brains and spinal cords from cattle 30 months of age and older, rather than cattle of all ages.

(Response) FDA agrees that the prevalence of BSE in the United States is very low, and that compliance with the current feed ban by the U.S. animal feed industry is at a high level...

suppressed peer review of Harvard study October 31, 2002

Harvard Risk Assessment of Bovine Spongiform Encephalopathy Update, October 31, 2005 INTRODUCTION The United States Department of Agriculture’s Food Safety and Inspection Service (FSIS) held a public meeting on July 25, 2006 in Washington, D.C. to present findings from the Harvard Risk Assessment of Bovine Spongiform Encephalopathy Update, October 31, 2005 (report and model located on the FSIS website:

Comments on technical aspects of the risk assessment were then submitted to FSIS. Comments were received from Food and Water Watch, Food Animal Concerns Trust (FACT), Farm Sanctuary, R-CALF USA, Linda A Detwiler, and Terry S. Singeltary.

This document provides itemized replies to the public comments received on the 2005 updated Harvard BSE risk assessment. Please bear the following points in mind:

Monday, April 25, 2011

Experimental Oral Transmission of Atypical Scrapie to Sheep

Volume 17, Number 5–May 2011

putting the cart before the horse OIE TSE policy. ...TSS

Monday, November 30, 2009


Published online 11 February 2011 | Nature | doi:10.1038/news.2011.87


Livestock plagues are spreading As farming intensifies, researchers warn that the developing world is "dangerously behind" on controlling animal diseases.

Natasha Gilbert

Friday, February 11, 2011

Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues

Friday, February 04, 2011

NMLB and USDA allow scrapie prion infected mutton to enter food chain on the Navajo Reservation in New Mexico

Sunday, December 12, 2010

EFSA reviews BSE/TSE infectivity in small ruminant tissues News Story 2 December 2010

Thursday, December 23, 2010

Molecular Typing of Protease-Resistant Prion Protein in Transmissible Spongiform Encephalopathies of Small Ruminants, France, 2002-2009 Volume 17, Number 1 January 2011

Thursday, November 18, 2010

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep

Sunday, October 3, 2010

Scrapie, Nor-98 atypical Scrapie, and BSE in sheep and goats North America, who's looking ?

Sunday, March 27, 2011


Wednesday, February 16, 2011




Sunday, April 18, 2010


Wednesday, January 19, 2011

EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011

Tuesday, January 18, 2011

Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease


This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........


Wednesday, September 08, 2010


Thursday, April 28, 2011

Chronic Wasting Disease Testing and Prevalence Wisconsin April 2011

Wednesday, January 5, 2011



David W. Colby1,* and Stanley B. Prusiner1,2

Creutzfeldt Jakob Disease (s)

Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein 17 May 2011

Wednesday, May 18, 2011

Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein 17 May 2011 Journal of Molecular Neuroscience DOI: 10.1007/s12031-011-9543-1



In 2008, we reported 11 cases affected by a disease that differed from typical human prion diseases such as sporadic and familial Creutzfeldt-Jakob diseae (CJD) clinically, pathologically, and more importantly for the characteristics of the abnormal, disease-related prion protein (PrPDis) present in the brain of the cases (Gambetti et al. 2008). A striking feature of the PrPDis was the apparent lack of resistance to treatment with proteases as opposed to the protease resistance that is a prominent feature of atypical prion diseases.

Another striking feature of these cases was the genotype of the prion protein (PrP) gene which is characterized by a common methionine (Met)/valine (Val) polymorphism at codon 129 (Collinge et al. 1991). All the 11 cases were homozygous for Val at codon 129 of the PrP gene although the prevalence of this PrP genotype in the general Caueasian population is approximately 12% (Collinge et al. 1991).

Furthermore, none of the cases had a mutation in the open reading frame (ORF) of the PrP gene where all the known mutation have been found (Kong et al, 2004) although six of the ten informative cases had family history of dementia.

In 2010. we reported 15 new case affected by a condition similar to that previously described for clinical and histopathological features as well as for the character­istics of the abnormal prion protein, but these cases included not only patients who were homozygous Val at codon 129 of the PrP gene like the previous ones but also cases that were homozygous Met (Met/Met) and heterozygous (Met/Val) (Zou et al. 2010a). Because the 129 Met/Met and Metl/Val cases PrPDis presented less and disimilar senitivity to protease digestion, the condition was renamed variably protease-sensitive prionopathy or VPSPr.

Currently, a total of 30 cases of VPSPr have been publihed (Head et al. 2009, 2010; Jansen et al. 20I0; Rodriguez­-Martinez et al. 2010; Zou et al. 2010a). These 30 cases are not equally distributed among the three 129 genotypes: 19 are Val/Val, 8 are Met/Val, and 3 are Met/Met. These findings prompt three considerations. ...

DEEP THROAT TO TSS 2000-2001 (take these old snips of emails with how ever many grains of salt you wish. ...tss)

The most frightening thing I have read all day is the report of Gambetti's finding of a new strain of sporadic cjd in young people...Dear God, what in the name of all that is holy is that!!! If the US has different strains of scrapie.....why????than the UK...then would the same mechanisms that make different strains of scrapie here make different strains of BSE...if the patterns are different in sheep and mice for scrapie.....could not the BSE be different in the cattle, in the mink, in the humans.......I really think the slides or tissues and everything from these young people with the new strain of sporadic cjd should be put up to be analyzed by many, many experts in cjd........bse.....scrapie Scrape the damn slide and put it into mice.....wait.....chop up the mouse brain and and spinal cord........put into some more mice.....dammit amplify the thing and start the damned research.....This is NOT rocket science...we need to use what we know and get off our butts and move....the whining about how long everything takes.....well it takes a whole lot longer if you whine for a year and then start the research!!! Not sure where I read this but it was a recent press release or something like that: I thought I would fall out of my chair when I read about how there was no worry about infectivity from a histopath slide or tissues because they are preserved in formic acid, or formalin or formaldehyde.....for God's sake........ Ask any pathologist in the UK what the brain tissues in the formalin looks like after a is a big fat sponge...the agent continues to eat the brain can't make slides anymore because the agent has never stopped........and the old slides that are stained with Hemolysin and Eosin......they get holier and holier and degenerate and continue...what you looked at 6 months ago is not there........Gambetti better be photographing every damned thing he is looking at.....

Okay, you need to know. You don't need to pass it on as nothing will come of it and there is not a damned thing anyone can do about it. Don't even hint at it as it will be denied and laughed at.......... USDA is gonna do as little as possible until there is actually a human case in the USA of the nvcjd........if you want to move this thing along and shake the earth....then we gotta get the victims families to make sure whoever is doing the autopsy is credible, trustworthy, and a saint with the courage of Joan of Arc........I am not kidding!!!! so, unless we get a human death from EXACTLY the same form with EXACTLY the same histopath lesions as seen in the UK nvcjd........forget any is ALL gonna be sporadic!!!

And, if there is a case.......there is gonna be every effort to link it to international travel, international food, etc. etc. etc. etc. etc. They will go so far as to find out if a sex partner had ever traveled to the UK/europe, etc. etc. .... It is gonna be a long, lonely, dangerous twisted journey to the truth. They have all the cards, all the money, and are willing to threaten and carry out those threats....and this may be their biggest downfall...

Thanks as always for your help. (Recently had a very startling revelation from a rather senior person in government here..........knocked me out of my must keep pushing. If I was a power person....I would be demanding that there be a least a million bovine tested as soon as possible and agressively seeking this disease. The big players are coming out of the woodwork as there is money to be made!!! In short: "FIRE AT WILL"!!! for the very dumb....who's "will"! "Will be the burden to bare if there is any coverup!"

again it was said years ago and it should be taken seriously....BSE will NEVER be found in the US! As for the BSE conference call...I think you did a great service to freedom of information and making some people feign integrity...I find it scary to see that most of the "experts" are employed by the federal government or are supported on the "teat" of federal funds. A scary picture! I hope there is a confidential panel organized by the new government to really investigate this thing.

You need to watch your back........but keep picking at a buzzard to the just may get to the truth!!! (You probably have more support than you know. Too many people are afraid to show you or let anyone else know. I have heard a few things myself... you ask the questions that everyone else is too afraid to ask.)


Asante/Collinge et al, that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest _sporadic_ CJD;

Asante/Collinge et al have major findings on sporadic CJD, why in the hell is this not making big news in the USA? ($$$) the fact that with the new findings from Collinge et al, that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc, the commonest sporadic CJD, i only ponder how many of the sporadic CJDs in the USA are tied to this alternate phenotype? these new findings are very serious, and should have a major impact on the way sporadic CJDs are now treated as opposed to the vCJD that was thought to be the only TSE tied to ingesting beef, in the medical/surgical arena. these new findings should have a major impact on the way sporadic CJD is ignored, and should now be moved to the forefront of research as with vCJD/nvCJD.

2011 - Here are my considerations, and they have not changed ;

Thursday, July 10, 2008

A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008

Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.

Thursday, July 10, 2008

A New Prionopathy update July 10, 2008


Thursday, July 10, 2008

A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008 Friday, June 20, 2008

Here we go folks. AS predicted. THIS JUST OUT !

Tuesday, August 03, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein

Monday, August 9, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?

snip...see full text ;

Tuesday, April 26, 2011

sporadic CJD RISING Text and figures of the latest annual report of the NCJDRSU covering the period 1990-2009 (published 11th March 2011)

Saturday, March 5, 2011


Wednesday, April 27, 2011




"which includes the ___elimination___ of Prion activities ($5,473,000),"

All Other Emerging and Zoonotic Infectious Diseases CDC‘s FY 2012 request of $52,658,000 for all other emerging and zoonotic infectious disease activities is a decrease of $13,607,000 below the FY 2010 level, which includes the elimination of Prion activities ($5,473,000), a reduction for other cross-cutting infectious disease activities, and administrative savings. These funds support a range of critical emerging and zoonotic infectious disease programs such Lyme Disease, Chronic Fatigue Syndrome, and Special Pathogens, as well as other activities described below.


BY Philip Yam

Yam Philip Yam News Editor Scientific American

Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.


Laying Odds

Are prion diseases more prevalent than we thought?

Researchers and government officials badly underestimated the threat that mad cow disease posed when it first appeared in Britain. They didn't think bovine spongiform encephalopathy was a zoonosis-an animal disease that can sicken people. The 1996 news that BSE could infect humans with a new form of Creutzfeldt-Jakob disease stunned the world. It also got some biomedical researchers wondering whether sporadic CJD may really be a manifestation of a zoonotic sickness. Might it be caused by the ingestion of prions, as variant CJD is?

Revisiting Sporadic CJD

It's not hard to get Terry Singeltary going. "I have my conspiracy theories," admitted the 49-year-old Texan.1 Singeltary is probably the nation's most relentless consumer advocate when it comes to issues in prion diseases. He has helped families learn about the sickness and coordinated efforts with support groups such as CJD Voice and the CJD Foundation. He has also connected with others who are critical of the American way of handling the threat of prion diseases. Such critics include Consumers Union's Michael Hansen, journalist John Stauber, and Thomas Pringle, who used to run the voluminous www.madcow. org Web site. These three lend their expertise to newspaper and magazine stories about prion diseases, and they usually argue that prions represent more of a threat than people realize, and that the government has responded poorly to the dangers because it is more concerned about protecting the beef industry than people's health.

Singeltary has similar inclinations. ...



Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

Newsdesk The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003 doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI

Tracking spongiform encephalopathies in North America

Xavier Bosch

"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." 49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of documents on transmissible spongiform encephalopathies (TSE) and realised that if Britons could get variant CJD from bovine spongiform encephalopathy (BSE), Americans might get a similar disorder from chronic wasting disease (CWD)-the relative of mad cow disease seen among deer and elk in the USA. Although his feverish.

Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT

DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen) USA: Loch in der Mauer Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehördensind lax.Link auf diesen Artikel im Archiv:

"Löcher wie in einem Schweizer Käse" hat auch Terry Singeltary im Regelwerk der FDA ausgemacht. Der Texaner kam auf einem tragischen Umweg zu dem Thema: Nachdem seine Mutter 1997 binnen weniger Wochen an der Creutzfeldt-Jakob-Krankheit gestorben war, versuchte er, die Ursachen der Infektion aufzuspüren. Er klagte auf die Herausgabe von Regierungsdokumenten und arbeitete sich durch Fachliteratur; heute ist er überzeugt, dass seine Mutter durch die stetige Einnahme von angeblich kräftigenden Mitteln erkrankte, in denen - völlig legal - Anteile aus Rinderprodukten enthalten sind.

Von der Fachwelt wurde Singeltary lange als versponnener Außenseiter belächelt. Doch mittlerweile sorgen sich auch Experten, dass ausgerechnet diese verschreibungsfreien Wundercocktails zur Stärkung von Intelligenz, Immunsystem oder Libido von den Importbeschränkungen ausgenommen sind. Dabei enthalten die Pillen und Ampullen, die in Supermärkten verkauft werden, exotische Mixturen aus Rinderaugen; dazu Extrakte von Hypophyse oder Kälberföten, Prostata, Lymphknoten und gefriergetrocknetem Schweinemagen. In die USA hereingelassen werden auch Blut, Fett, Gelatine und Samen. Diese Stoffe tauchen noch immer in US-Produkten auf, inklusive Medizin und Kosmetika. Selbst in Impfstoffen waren möglicherweise gefährliche Rinderprodukte enthalten. Zwar fordert die FDA schon seit acht Jahren die US-Pharmaindustrie auf, keine Stoffe aus Ländern zu benutzen, in denen die Gefahr einer BSE-Infizierung besteht. Aber erst kürzlich verpflichteten sich fünf Unternehmen, darunter Branchenführer wie GlaxoSmithKline, Aventis und American Home Products, ihre Seren nur noch aus unverdächtigem Material herzustellen.

"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...

Suspect symptoms

What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?

28 Mar 01

Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284. Subscribe and get 4 free issues. 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 mice as sCJD.

"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris. Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb.

Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health. But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.

Deslys and colleagues were originally studying vCJD, not sCJD. They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three. Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.

As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain. As expected, they all affected the brain in a different way from BSE and vCJD. But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology.

"The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys. "You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie." In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar.

But there are more than 20 strains of scrapie, and six of sCJD. "You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys. Bruce is cautious about the mouse results, but agrees they require further investigation. Other trials of scrapie and sCJD in mice, she says, are in progress.

People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways. Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD.

But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD. "If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."

There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere. Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain. Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.

Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE. And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.

2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.


USA sporadic CJD cases rising ;

There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.


5 Includes 41 cases in which the diagnosis is pending, and 17 inconclusive cases;

*** 6 Includes 46 cases with type determination pending in which the diagnosis of vCJD has been excluded.

Saturday, January 2, 2010

Human Prion Diseases in the United States January 1, 2010 ***FINAL***

Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.

my comments to PLosone here ;

Monday, May 23, 2011

CDC Assesses Potential Human Exposure to Prion Diseases Travel Warning

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518



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