Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
Justin J. Greenlee1*, Jodi D. Smith1, M. Heather West Greenlee2, Eric M.
Nicholson1
1 National Animal Disease Center, United States Department of Agriculture,
Agricultural Research Service, Ames, Iowa, United States of America, 2 Iowa
State University, Ames, Iowa, United States of America
Abstract
The majority of bovine spongiform encephalopathy (BSE) cases have been
ascribed to the classical form of the disease. Htype and L-type BSE cases have
atypical molecular profiles compared to classical BSE and are thought to arise
spontaneously. However, one case of H-type BSE was associated with a heritable
E211K mutation in the prion protein gene. The purpose of this study was to
describe transmission of this unique isolate of H-type BSE when inoculated into
a calf of the same genotype by the intracranial route. Electroretinograms were
used to demonstrate preclinical deficits in retinal function, and optical
coherence tomography was used to demonstrate an antemortem decrease in retinal
thickness. The calf rapidly progressed to clinical disease (9.4 months) and was
necropsied. Widespread distribution of abnormal prion protein was demonstrated
within neural tissues by western blot and immunohistochemistry. While this
isolate is categorized as BSE-H due to a higher molecular mass of the
unglycosylated PrPSc isoform, a strong labeling of all 3 PrPSc bands with
monoclonal antibodies 6H4 and P4, and a second unglycosylated band at
approximately 14 kDa when developed with antibodies that bind in the C-terminal
region, it is unique from other described cases of BSE-H because of an
additional band 23 kDa demonstrated on western blots of the cerebellum. This
work demonstrates that this isolate is transmissible, has a BSE-H phenotype when
transmitted to cattle with the K211 polymorphism, and has molecular features
that distinguish it from other cases of BSE-H described in the literature.
snip...
Results and Discussion
Clinical Findings
A calf with the K211 allele was intracranially inoculated with Htype BSE
from the US 2006 BSE case that also had one K211 allele. This calf demonstrated
clinical signs at approximately 9.4 months (288 days) post-inoculation (PI).
Initial signs were nondescript: listlessness, head down in non-physiologic
position with drooping ears, and decreased feed consumption. Within a week,
clinical signs had progressed to the calf separating himself from others in the
pen, head pressing into the wall or gate, and intermittent reluctance to rise
with a stumbling gate for a brief time after rising. The calf began to
demonstrate a lip licking and accentuated chewing behavior that was not
associated with feeding. The lip-licking and chewing behaviors increased in
frequency and severity, and at the time of necropsy at approximately 9.8 months
PI (301 days), the calf was depressed, salivating excessively, and reluctant to
rise.
Progression to severe clinical signs of BSE occurred in this animal after
9.8 months, a faster onset than the 12–18 months described for other
experimental cases of H-type BSE [28,29,30,31]. Previous studies describe the
onset of clinical signs for BSE-H as early as 8 months PI [31], but more
commonly at 12 months PI [30] or later [28] with a 2–7 month progression of
disease to ataxia and inability to rise [28,30,31]. Our findings are similar to
other reports in that the earliest clinical signs appear to be vague: weight
loss, depression, and low head carriage. However, reports of clinical findings
in BSE-H are variable: from ataxia and myoclonus that progresses to an inability
to rise without nervousness or aggression [30] to a nervous disease form that is
characterized by overeactivity to external stimuli, apprehension and anxiety
[31]. This case of E211K BSE-H is different in that the most obvious outward
clinical signs were bizarre licking and chewing behaviors not described
elsewhere. While the calf affected with E211K was reluctant to rise, it was able
to rise when encouraged, however, this animal was younger and smaller than
cattle in other studies that had difficulty getting to their feet, which may
play a role in the difference reported.
snip...
Distribution and Characterization of Lesions in BSE-H
Vacuolar lesions typical of spongiform encephalopathy were present
throughout the brain of this calf. Spongiform change was most severe in the
piriform cortex and hippocampus, but present at all levels of brain examined.
The distribution of lesions suggests sampling at various levels of the brain,
including the obex, would be fruitful for diagnosis. Vacuolation scores ranged
from 1 to 3 (scale of 0 to 4), but the vast majority of regions were scored a 2
or higher, indicating definitive spongiform lesions (Fig. S1). Lesions
predominantly affected gray matter with little to no involvement of white
matter. Vacuoles were primarily present in the neuropil, but were also detected
within the cytoplasm of neurons (Fig. 3). At all levels of the spinal cord,
there were few inconclusive vacuoles present in the neuropil of the dorsal
horns.
Results of microscopic examination for vacuolar change indicate that
additional tools may be required to differentiate E211K BSE from classical BSE
or other isolates of BSE-H that have been described in the literature [30,31].
Similar to other reports, vacuolar change was generally observed in all brain
areas and moderate to severe vacuolar change was detected in cerebral cortex,
cerebellum, basal ganglia, thalamus, and brainstem [30,31]. However, there were
contrasts in the areas with the highest vacuolation scores. The highest levels
of spongiform change were evident in piriform cortex and hippocampus in this
case, whereas the highest levels were in thalamic nuclei and midbrain of other
reports [30]. Profiles developed using larger numbers of animals suggest that
BSE-H may be difficult to distinguish from classical BSE based on spongiform
change in the obex, but may have increased numbers of vacuoles in rostral brain
areas [31]. E211K BSE-H had the lowest scores in pontine and hypoglossal motor
nuclei, which was similar to previous reports of BSE-H [30]. In summary, it
appears that vacuolar change is variable amongst different isolates classified
as BSE-H. Caution should be used when considering the lesion profile of this
single animal as what role individual animal differences or the E211K
polymorphism play cannot be determined without further experimentation.
Microscopic evaluation of the brain of the US 2006 H-type BSE case was
limited to the obex and complicated by freeze artifact, precluding a definitive
microscopic interpretation [18]. Therefore, this is the first description of the
microscopic lesions in the CNS of a bovid affected with H-type BSE associated
with the E211K polymorphism. No amyloid plaques were present in the tissues from
the calf with E211K BSE-H, which is similar to one previous study of BSE-H [31],
but contrasts with another [30].
Immunohistochemical analysis for PrPSc demonstrated widespread
immunoreactivity throughout the brain, spinal cord, and retina with lesser
immunoreactivity in neurohypophysis and the trigeminal ganglia (Fig. S2).
Regardless of the brain region examined, PrPSc immunoreactivity was readily
apparent. Immunoreactivity was most intense in the brainstem and midbrain and
patterns of immunoreactivity were similar to those previously described
[1,18,26,30,31]with an intraglial distribution predominating. The predominant
patterns in the cortex were intraglial and stellate on a background of fine
punctate and granular particulate staining that was multifocally coalescing
(Fig. 4A). Perineuronal staining was also evident, but intraneuronal
immunoreactivity was rare. Immunoreactivity increased in intensity from frontal
cortex caudal to occipital cortex. In the white matter subjacent to the cortex,
there were rare coarse particulate foci of immunoreactivity that were most often
associated with glial cell margins (Fig. S3). This is in contrast to previous
studies where glial staining in the white matter was a more prominent feature in
BSE-H [31]. We did not see PrPSc immunoreactive plaques in the gray or white
matter, but other reports indicate that this occurs as a prominent [30] or
lesser [31] feature. Immunoreactivity in hippocampus, midbrain, and brainstem
was markedly intense and frequently formed coalescing aggregates (Fig. 4B).
While intraneuronal straining was rare in the cortex, it became the most obvious
pattern in the midbrain and brainstem nuclei (Fig. 4D) with notable exception of
the parasympathetic nucleus of the vagus nerve. Intraneuronal staining also was
readily apparent in spinal cord (Fig. S2). Immunoreactivity was scant in the
cerebellum where small, multifocal clumps of granular and particulate staining
occurred in the molecular and granular layers. The cerebellar white matter was
devoid of immunoreactivity except for in association with deep cerebellar nuclei
(Fig. S4), which is in contrast to other studies of BSE-H where the most
prominent staining of the cerebellum was in the white matter [31]. Considering
the strong immunoreactivity in other regions of the brain, the scant
immunoreactivity in cerebellum was surprising. This finding corroborates recent
studies examining PrPSc immunoreactivity in the brainstem and cerebellum of
cases of BSE-H where the cerebellum and caudal brainstem contained less PrPSc
than more rostral regions of the brainstem [31,38]The immunohistochemical
techniques used here failed to demonstrate PrPSc in other tissues examined. This
finding is consisent with other studies of atypical BSE that suggest that no
significant PrPSc depositions occur in peripheral tissues [39]. Other findings
of the lesions described contrast those described for wild-type cattle with
BSE-H [30] in that no PrPSc plaques were noted and that there is less
immunoreactivity in the cerebellum in this case. Whether the E211K polymorphism
influences lesion character or distribution when inoculated with other BSE
isolates will require further study.
snip...
The disease reported here was true to the molecular characterization of
the case diagnosed in 2006, which is the best approximation of H-type BSE that
may occur later in life in cattle with the E211K polymorphism. Based on the case
history of the original 2006 E211K BSE case and the fact that the vast majority
of naturally-occurring atypical BSE cases involve older cattle (.10 yrs of age),
we speculate that a pre-clinical period of at least 10 years will be required
for BSE-H to naturally occur in E211K cattle without prior exposure to
infectious material. While an inoculation study cannot definitely prove that the
U.S. 2006 BSEH case was due to the E211K polymorphism, i.e. an inherited TSE,
the results of this study do suggest that cattle with the K211 allele are
predisposed to rapid onset of BSE-H when exposed.
Most significantly it must be determined if the molecular phenotype of
this cattle TSE remains stable when transmitted to cattle without the E211K
polymorphism as several other isolates of atypical BSE have been shown to adopt
a molecular profile consistent with classical BSE after passage in transgenic
mice expressing bovine PrPC [40] or multiple passages in wild type mice [23].
Results of ongoing studies, namely passage of the E211K Htype isolate into
wild-type cattle, will lend further insight into what role, if any, genetic and
sporadic forms of BSE may have played in the origins of classical BSE. Atypical
cases presumably of spontaneous or, in the case of E211K BSE-H, genetic origins
highlight that it may not be possible to eradicate BSE entirely and that it
would be hazardous to remove disease control measures such as prohibiting the
feeding of meat and bone meal to ruminants.
snip...
Citation: Greenlee JJ, Smith JD, West Greenlee MH, Nicholson EM (2012)
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism. PLoS ONE 7(6): e38678.
doi:10.1371/journal.pone.0038678
Editor: Corinne Ida Lasmezas, The Scripps Research Institute Scripps
Florida, United States of America
Received January 6, 2012; Accepted May 11, 2012; Published June 8, 2012
This is an open-access article, free of all copyright, and may be freely
reproduced, distributed, transmitted, modified, built upon, or otherwise used by
anyone for any lawful purpose. The work is made available under the Creative
Commons CC0 public domain dedication.
Funding: This research was funded in its entirety by congressionally
appropriated funds to the United States Department of Agriculture, Agriculture
Research Service. The funders of the work did not influence study design, data
collection and analysis, decision to publish, and preparation of the
manuscript.
Competing Interests: The authors have declared that no competing interests
exist. * E-mail: justin.greenlee@ars.usda.gov
see full text ;
thanks again PLOS for open access for the layperson...tss
2011 Annual Report
1a.Objectives (from AD-416) The objective of this cooperative research project is to investigate the influence of the bovine Prnp gene polymorphisms, E211K, on the susceptibility to BSE. Specifically, the research project will provide 134 embryos that will be used to generate approximately 62 animals, 31 of which will contain the rare allele for the purposes BSE research. This ongoing SCA with Iowa State University to produce cattle with the E211K Prnp allele for BSE research has resulted in an E211/K211 heterozygous bull. We are now in the unique position to extend our research on this allele to include animals homozygous for K at position 211. Based upon our understanding of this novel polymorphism one would predict homozygotes would have a more rapid onset of clinical signs associated with genetic BSE than heterozygotes.
1b.Approach (from AD-416) To achieve the research goals it is imperative to increase the number of animals available to study this Prnp polymorphism. One female calf of the 2006 BSE case was identified and carries the E211K allele. The specific objectives are to be accomplished through the production of multiple offspring from this E211K heifer through superovulation and embryo transfer. Approximately 50% of the offspring will be heterozygous for the E211K polymorphism while the others will serve as genetically matched non-E211K controls. Collection of semen from an E211K heterozygous bull will allow creation of E211K homozygotes. To protect this unique resource immediate collection of embryos is necessary. The initial goal is to harvest 134 embryos that should result in approximately 62 pregnancies (half of which will carry the E211K polymorphism) for immediate use in the studies to amplify the E211K material, test for genetic susceptibility to TSE, and develop a breeding group to produce calves for transmissibility studies. To achieve the goal of understanding the role of the E211K polymorphism with regard to genetic BSE we have utilized superovulation and embryo transfer obtaining a E211/K211 containing bull. We are now in a position to collect semen from the E211/K211 heterozygous bull to create K211/K211 homozygotes. To accomplish this goal we plan to collect semen from this bull and through artificial insemination using semen from the E211/K211 bull with superovulation and embryo transplantation using other E211/K211 heterzygotes generate 30-40 embryos resulting in 15-20 pregnancies yielding approximately 5 K211/K211 homozygous animals and 10 E211/K211 heterozyous animals as well as 5 E211/E211 homozygous controls.
3.Progress Report
The objective of this cooperative research is to protect the unique resource afforded us in the form of the only known cow possessing the 211K PRNP allele and to produce offspring containing this allele for research purposes. To date, 18 pregnancies have resulted from the harvested embryos. From these, 13 live calves have been delivered, 8 of which contain the 211K PRNP allele and an additional 8 calves are due in FY2012. One of the 8 211K-containing animals produced to date is a bull from which semen has been collected and embryos are now being produced from sibling matings that may provide 211K homozygous animals. As a derivative of this work we have been able to define the upstream regulatory elements associated with the 211K PRNP allele. Communication with the collaborator has been through a combination of email and face-to-face communication.
PO-183: Association of dna polymorphisms within the regulatory regions of the bovine PRNP gene with atypical BSE
Simone Peletto,1 Maria Grazia Maniaci,1 Miroslaw Pawel Polak,2 Jan Langeveld,3 Stefanie Czub,4 Alex Bossers,3 Wilfred Goldmann,5 Pier Luigi Acutis1 1Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy; 2National Veterinary Research Institute; Pulawy, Poland; 3Central Veterinary Institute of Wageningen UR (CVI ); Lelystad, The Netherlands; 4Canadian and OIE Reference Laboratories for BSE; Canadian Food Inspection Agency; Alberta, AB Canada; 5The Roslin Institute & Royal (Dick) School of Veterinary Studies; Edinburgh, UK
Background. Atypical bovine spongiform encephalopathy (atypical BSE) is a recently recognized form of prion disease in cattle. Atypical BSE cases are rare but have been identified worldwide. They have been classified as so-called H-type and L-type on the basis of the prion protein’s immunobiochemical signature. The etiology of atypical BSE is unclear, however, its epidemiology suggests that, unlike classical BSE, it may have originated spontaneously as a sporadic disease. In 2006, an atypical BSE case was found in the United States, carrying a PRNP mutation (E211K) homologous to the human E200K polymorphism, a risk factor for genetic CJD. To date, the K211 allele has not been detected in other atypical BSE cases or healthy cattle.
Objectives. In this study, the analysis of regulatory regions outside the open reading frame of the PRNP gene was performed on a panel of atypical BSE cases and negative controls with the aim to identify potential genetic determinants of susceptibility. Methods. DNA samples were obtained from 20 cases confirmed as atypical H-type (n = 4) or L-type (n = 16) BSE by Western Blot profile. They originated from Italy, Poland, the Netherlands and Canada. The control group comprised 108 BSE negative cattle which were frequency matched to cases by breed. A 5.2 Kb region of high linkage disequilibrium (LD) was selected from the promoter through exon 2 of the PRNP gene. Association analysis was performed comparing allele/genotype/ haplotype frequencies between cases and controls by computing Fisher exact test. H-type and L-type BSE cases were analyzed both as one group and separately.
Results. Sequence analysis revealed 46 single nucleotide polymorphisms (SNPs), three multiple nucleotide and five insertion/ deletion (indel) polymorphisms. Two SNP variants, being in complete LD and located upstream the transcription start site (47238-C and 47450-C; ref. seq. AJ298878), were associated with susceptibility to atypical BSE in both allele and genotype distributions (p = 0.0004 and p = 0.0005, respectively). In intron I, the 12-bp deletion allele and one SNP (50743-G) resulted to be significantly more frequent in the atypical BSE cases (p = 0.0002). Finally, one haplotype was found to be underrepresented in the BSE group compared with controls (p = 0.0002), with the exception of the Italian animals.
Discussion. This is the first genetic association study on atypical BSE involving a relatively high number of cases from four different countries. The results suggest that polymorphism in the non-coding region of PRNP may play a role in susceptibility of cattle to atypical BSE. The association of the 12-bp deletion allele is in contrast to previously reported findings (Brunelle et al., 2007), mostly involving H-type cases. This may either be the result of the larger number of animals included in our study or reflect differences in the role of genetics in the two distinct BSE phenotypes. One haplotype was found to be less frequent in the BSE group, but this association was not confirmed for the Italian L-type (BASE) cases, suggesting a complex scenario in which probably several factors interact to determinate the disease outcome.
Neurobiology of Disease
A New Mechanism for Transmissible Prion Diseases
Natallia Makarava1, Gabor G. Kovacs2, Regina Savtchenko1, Irina Alexeeva3,
Valeriy G. Ostapchenko1, Herbert Budka2, Robert G. Rohwer3, and Ilia V.
Baskakov1,4 + Author Affiliations
1Center for Biomedical Engineering and Technology, University of Maryland,
Baltimore, Maryland 21201, 2Institute of Neurology, Medical University of
Vienna, A-1097 Vienna, Austria, 3Medical Research Service, Veterans Affairs
Medical Center, University of Maryland, Baltimore, Maryland 21201, and
4Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, Maryland 21201 + Author Notes
V. G. Ostapchenko's present address J. Allyn Taylor Centre for Cell
Biology, Molecular Brain Research Group, Robarts Research Institute, and
Department of Physiology and Pharmacology, University of Western Ontario,
London, Ontario N6A 5KB, Canada.
Author contributions: N.M. and I.V.B. designed research; N.M., G.G.K.,
R.S., I.A., V.G.O., and R.G.R. performed research; N.M., G.G.K., H.B., and
I.V.B. analyzed data; N.M., G.G.K., and I.V.B. wrote the paper.
Abstract
The transmissible agent of prion disease consists of prion protein (PrP) in
β-sheet-rich state (PrPSc) that can replicate its conformation according to a
template-assisted mechanism. This mechanism postulates that the folding pattern
of a newly recruited polypeptide accurately reproduces that of the PrPSc
template. Here, three conformationally distinct amyloid states were prepared in
vitro using Syrian hamster recombinant PrP (rPrP) in the absence of cellular
cofactors. Surprisingly, no signs of prion infection were found in Syrian
hamsters inoculated with rPrP fibrils that resembled PrPSc, whereas an
alternative amyloid state, with a folding pattern different from that of PrPSc,
induced a pathogenic process that led to transmissible prion disease. An
atypical proteinase K-resistant, transmissible PrP form that resembled the
structure of the amyloid seeds was observed during a clinically silent stage
before authentic PrPSc emerged. The dynamics between the two forms suggest that
atypical proteinase K-resistant PrP (PrPres) gave rise to PrPSc. While no PrPSc
was found in preparations of fibrils using protein misfolding cyclic
amplification with beads (PMCAb), rPrP fibrils gave rise to atypical PrPres in
modified PMCAb, suggesting that atypical PrPres was the first product of PrPC
misfolding triggered by fibrils. The current work demonstrates that a new
mechanism responsible for prion diseases different from the PrPSc-templated or
spontaneous conversion of PrPC into PrPSc exists. This study provides compelling
evidence that noninfectious amyloids with a structure different from that of
PrPSc could lead to transmissible prion disease. This work has numerous
implications for understanding the etiology of prion and other neurodegenerative
diseases.
snip...
=======================================
The atypical PrPres described here was very similar to the atypical PrPres
found in patients with sporadic Creutzfeldt-Jakob disease (Zou et al., 2003),
atypical bovine spongiform encephalopathy (H-BSE), which is believed to be
sporadic in origin (Biacabe et al., 2007), or ovine scrapie (Baron et al.,
2008). This current study suggests that atypical PrPres can replicate in animal
brains and that its replication does not require PrPSc assistance; therefore, it
represents one of the transmissible PrP states.
======================================
Received December 20, 2011. Revision received March 20, 2012. Accepted
April 3, 2012.
Thursday, May 24, 2012
A New Mechanism for Transmissible Prion Diseases
From: Terry S. Singeltary Sr.
Sent: Friday, May 11, 2012 9:31 PM
To: BSE-L@LISTS.AEGEE.ORG
Subject: [BSE-L] Experimental H-type bovine spongiform encephalopathy
characterized by plaques and glial- and stellate-type prion protein
deposits
Experimental H-type bovine spongiform encephalopathy characterized by
plaques and glial- and stellate-type prion protein deposits
Hiroyuki Okada1*, Yoshifumi Iwamaru1, Morikazu Imamura1, Kentaro Masujin1,
Yuichi Matsuura1, Yoshihisa Shimizu1 , Kazuo Kasai1, Shirou Mohri1, Takashi
Yokoyama1 and Stefanie Czub2
Abstract
Atypical bovine spongiform encephalopathy (BSE) has recently been
identified in Europe, North America, and Japan. It is classified as H-type and
L-type BSE according to the molecular mass of the disease-associated prion
protein (PrPSc). To investigate the topographical distribution and deposition
patterns of immunolabeled PrPSc, Htype BSE isolate was inoculated
intracerebrally into cattle. H-type BSE was successfully transmitted to 3
calves, with incubation periods between 500 and 600 days. Moderate to severe
spongiform changes were detected in the cerebral and cerebellar cortices, basal
ganglia, thalamus, and brainstem. H-type BSE was characterized by the presence
of PrP-immunopositive amyloid plaques in the white matter of the cerebrum, basal
ganglia, and thalamus. Moreover, intraglial-type immunolabeled PrPSc was
prominent throughout the brain. Stellate-type immunolabeled PrPSc was
conspicuous in the gray matter of the cerebral cortex, basal ganglia, and
thalamus, but not in the brainstem. In addition, PrPSc accumulation was detected
in the peripheral nervous tissues, such as trigeminal ganglia, dorsal root
ganglia, optic nerve, retina, and neurohypophysis. Cattle are susceptible to
H-type BSE with a shorter incubation period, showing distinct and
distinguishable phenotypes of PrPSc accumulation.
snip...
The present study demonstrated successful intraspecies transmission of
H-type BSE to cattle and the distribution and immunolabeling patterns of PrPSc
in the brain of the H-type BSE-challenged cattle. TSE agent virulence can be
minimally defined by oral transmission of different TSE agents (C-type, L-type,
and H-type BSE agents) [59]. Oral transmission studies with H-type BSEinfected
cattle have been initiated and are underway to provide information regarding the
extent of similarity in the immunohistochemical and molecular features before
and after transmission.
In addition, the present data will support risk assessments in some
peripheral tissues derived from cattle affected with H-type BSE.
Friday, March 09, 2012
Experimental H-type and L-type bovine spongiform encephalopathy in cattle:
observation of two clinical syndromes and diagnostic challenges
Research article
Thursday, June 23, 2011
Experimental H-type bovine spongiform encephalopathy characterized by
plaques and glial- and stellate-type prion protein deposits
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw
Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1
1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale,
Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research
Institute, Poland; 5Kansas State University (Previously at USDA National Animal
Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the
classical BSE strain (BSE-C) has led to over 200 cases of clinical human
infection (variant CJD). Atypical BSE cases have been discovered in three
continents since 2004; they include the L-type (also named BASE), the H-type,
and the first reported case of naturally occurring BSE with mutated bovine PRNP
(termed BSE-M). The public health risks posed by atypical BSE were largely
undefined.
Objectives: To investigate these atypical BSE types in terms of their
transmissibility and phenotypes in humanized mice. Methods: Transgenic mice
expressing human PrP were inoculated with several classical (C-type) and
atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation
time, characteristics and distribution of PrPSc, symptoms, and histopathology
were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected
with minimal spongiosis and an average incubation time of 20-22 months, whereas
only one of the C-type BSE-inoculated mice developed prion disease after more
than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse
brains was biochemically different from bovine BASE or sCJD. PrPSc was also
detected in the spleen of 22% of BASE-infected humanized mice, but not in those
infected with sCJD. Secondary transmission of BASE in the humanized mice led to
a small reduction in incubation time.*** The atypical BSE-H strain is also
transmissible with distinct phenotypes in the humanized mice, but no BSE-M
transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than
classical BSE, has a lymphotropic phenotype, and displays a modest transmission
barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg
mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
P26 TRANSMISSION OF ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN
HUMANIZED MOUSE MODELS
Liuting Qing1, Fusong Chen1, Michael Payne1, Wenquan Zou1, Cristina
Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi
Gambetti1, Juergen Richt5*, and Qingzhong Kong1 1Department of Pathology, Case
Western Reserve University, Cleveland, OH 44106, USA; 2CEA, Istituto
Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany;
4National Veterinary Research Institute, Poland; 5Kansas State University,
Diagnostic Medicine/Pathobiology Department, Manhattan, KS 66506, USA. *Previous
address: USDA National Animal Disease Center, Ames, IA 50010, USA
Classical BSE is a world-wide prion disease in cattle, and the classical
BSE strain (BSE-C) has led to over 200 cases of clinical human infection
(variant CJD). Two atypical BSE strains, BSE-L (also named BASE) and BSE-H, have
been discovered in three continents since 2004. The first case of naturally
occurring BSE with mutated bovine PrP gene (termed BSE-M) was also found in 2006
in the USA. The transmissibility and phenotypes of these atypical BSE
strains/isolates in humans were unknown. We have inoculated humanized transgenic
mice with classical and atypical BSE strains (BSE-C, BSE-L, BSE-H) and the BSE-M
isolate. We have found that the atypical BSE-L strain is much more virulent than
the classical BSE-C.*** The atypical BSE-H strain is also transmissible in the
humanized transgenic mice with distinct phenotype, but no transmission has been
observed for the BSE-M isolate so far.
III International Symposium on THE NEW PRION BIOLOGY: BASIC SCIENCE,
DIAGNOSIS AND THERAPY 2 - 4 APRIL 2009, VENEZIA (ITALY)
I ask Professor Kong ;
Thursday, December 04, 2008 3:37 PM Subject: RE: re--Chronic Wating Disease
(CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk
Assessment
''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE,
or less virulent than cBSE? just curious.....''
Professor Kong reply ;
.....snip
''As to the H-BSE, we do not have sufficient data to say one way or
another, but we have found that H-BSE can infect humans. I hope we could publish
these data once the study is complete. Thanks for your interest.''
Best regards, Qingzhong Kong, PhD Associate Professor Department of
Pathology Case Western Reserve University Cleveland, OH 44106 USA
END...TSS
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
BSE-H is also transmissible in our humanized Tg mice.
The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
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 $$$
ALABAMA MAD COW g-h-BSEalabama
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: maf12@cam.ac.uk Jürgen
A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier
Hall, Manhattan, Kansas 66506-5601, USA
NATURE|Vol 457|26 February 2009
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)
P.9.21
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.
what about that ALABAMA MAD COW, AND MAD COW FEED THERE FROM IN THAT STATE
???
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)
BANNED MAD COW FEED IN COMMERCE IN ALABAMA
Date: September 6, 2006 at 7:58 am PST PRODUCT
a) EVSRC Custom dairy feed, Recall # V-130-6;
b) Performance Chick Starter, Recall # V-131-6;
c) Performance Quail Grower, Recall # V-132-6;
d) Performance Pheasant Finisher, Recall # V-133-6.
CODE None RECALLING FIRM/MANUFACTURER Donaldson & Hasenbein/dba J&R
Feed Service, Inc., Cullman, AL, by telephone on June 23, 2006 and by letter
dated July 19, 2006. Firm initiated recall is complete.
REASON
Dairy and poultry feeds were possibly contaminated with ruminant based
protein.
VOLUME OF PRODUCT IN COMMERCE 477.72 tons
DISTRIBUTION AL
______________________________
PRODUCT Bulk custom dairy pre-mixes,
Recall # V-120-6 CODE None RECALLING FIRM/MANUFACTURER Ware Milling Inc.,
Houston, MS, by telephone on June 23, 2006. Firm initiated recall is complete.
REASON Possible contamination of dairy animal feeds with ruminant derived meat
and bone meal.
VOLUME OF PRODUCT IN COMMERCE 350 tons
DISTRIBUTION AL and MS
______________________________
PRODUCT
a) Tucker Milling, LLC Tm 32% Sinking Fish Grower, #2680-Pellet, 50 lb.
bags, Recall # V-121-6;
b) Tucker Milling, LLC #31120, Game Bird Breeder Pellet, 50 lb. bags,
Recall # V-122-6;
c) Tucker Milling, LLC #31232 Game Bird Grower, 50 lb. bags, Recall #
V-123-6;
d) Tucker Milling, LLC 31227-Crumble, Game Bird Starter, BMD Medicated, 50
lb bags, Recall # V-124-6;
e) Tucker Milling, LLC #31120, Game Bird Breeder, 50 lb bags, Recall #
V-125-6;
f) Tucker Milling, LLC #30230, 30 % Turkey Starter, 50 lb bags, Recall #
V-126-6;
g) Tucker Milling, LLC #30116, TM Broiler Finisher, 50 lb bags, Recall #
V-127-6
CODE All products manufactured from 02/01/2005 until 06/20/2006 RECALLING
FIRM/MANUFACTURER Recalling Firm: Tucker Milling LLC, Guntersville, AL, by
telephone and visit on June 20, 2006, and by letter on June 23, 2006.
Manufacturer: H. J. Baker and Brothers Inc., Stamford, CT. Firm initiated recall
is ongoing.
REASON Poultry and fish feeds which were possibly contaminated with
ruminant based protein were not labeled as "Do not feed to ruminants".
VOLUME OF PRODUCT IN COMMERCE 7,541-50 lb bags
DISTRIBUTION AL, GA, MS, and TN
END OF ENFORCEMENT REPORT FOR AUGUST 9, 2006
###
Subject: MAD COW FEED RECALL AL AND FL VOLUME OF PRODUCT IN COMMERCE 125
TONS Products manufactured from 02/01/2005 until 06/06/2006
Date: August 6, 2006 at 6:16 pm PST PRODUCT
a) CO-OP 32% Sinking Catfish, Recall # V-100-6;
b) Performance Sheep Pell W/Decox/A/N, medicated, net wt. 50 lbs, Recall #
V-101-6;
c) Pro 40% Swine Conc Meal -- 50 lb, Recall # V-102-6;
d) CO-OP 32% Sinking Catfish Food Medicated, Recall # V-103-6;
e) "Big Jim's" BBB Deer Ration, Big Buck Blend, Recall # V-104-6;
f) CO-OP 40% Hog Supplement Medicated Pelleted, Tylosin 100 grams/ton, 50
lb. bag, Recall # V-105-6;
g) Pig Starter Pell II, 18% W/MCDX Medicated 282020, Carbadox -- 0.0055%,
Recall # V-106-6;
h) CO-OP STARTER-GROWER CRUMBLES, Complete Feed for Chickens from Hatch to
20 Weeks, Medicated, Bacitracin Methylene Disalicylate, 25 and 50 Lbs, Recall #
V-107-6;
i) CO-OP LAYING PELLETS, Complete Feed for Laying Chickens, Recall #
108-6;
j) CO-OP LAYING CRUMBLES, Recall # V-109-6;
k) CO-OP QUAIL FLIGHT CONDITIONER MEDICATED, net wt 50 Lbs, Recall #
V-110-6;
l) CO-OP QUAIL STARTER MEDICATED, Net Wt. 50 Lbs, Recall # V-111-6;
m) CO-OP QUAIL GROWER MEDICATED, 50 Lbs, Recall # V-112-6 CODE
Product manufactured from 02/01/2005 until 06/06/2006
RECALLING FIRM/MANUFACTURER Alabama Farmers Cooperative, Inc., Decatur, AL,
by telephone, fax, email and visit on June 9, 2006. FDA initiated recall is
complete.
REASON Animal and fish feeds which were possibly contaminated with ruminant
based protein not labeled as "Do not feed to ruminants".
VOLUME OF PRODUCT IN COMMERCE 125 tons
DISTRIBUTION AL and FL
END OF ENFORCEMENT REPORT FOR AUGUST 2, 2006
###
MAD COW FEED RECALL USA EQUALS 10,878.06 TONS NATIONWIDE Sun Jul 16, 2006
09:22 71.248.128.67
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINE -- CLASS II
______________________________
PRODUCT
a) PRO-LAK, bulk weight, Protein Concentrate for Lactating Dairy Animals,
Recall # V-079-6;
b) ProAmino II, FOR PREFRESH AND LACTATING COWS, net weight 50lb (22.6 kg),
Recall # V-080-6;
c) PRO-PAK, MARINE & ANIMAL PROTEIN CONCENTRATE FOR USE IN ANIMAL FEED,
Recall # V-081-6;
d) Feather Meal, Recall # V-082-6 CODE
a) Bulk
b) None
c) Bulk
d) Bulk
RECALLING FIRM/MANUFACTURER H. J. Baker & Bro., Inc., Albertville, AL,
by telephone on June 15, 2006 and by press release on June 16, 2006. Firm
initiated recall is ongoing.
REASON
Possible contamination of animal feeds with ruminent derived meat and bone
meal.
VOLUME OF PRODUCT IN COMMERCE 10,878.06 tons
DISTRIBUTION Nationwide
END OF ENFORCEMENT REPORT FOR July 12, 2006
###
Saturday, July 23, 2011
CATTLE HEADS WITH TONSILS, BEEF TONGUES, SPINAL CORD, SPECIFIED RISK
MATERIALS (SRM's) AND PRIONS, AKA MAD COW DISEASE
Saturday, November 6, 2010
TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the
EU Berne, 2010 TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a
non-profit Swiss Foundation
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN
COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried,
Recall # V-024-2007
CODE
Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER
Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON
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. VOLUME OF PRODUCT IN COMMERCE 42,090 lbs. DISTRIBUTION WI
___________________________________
PRODUCT
Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot-
Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M
CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B
DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal,
JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT
Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral,
BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC
LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall #
V-025-2007
CODE
The firm does not utilize a code - only shipping documentation with
commodity and weights identified.
RECALLING FIRM/MANUFACTURER
Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm
initiated recall is complete.
REASON
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.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
Identification of a second bovine amyloidotic spongiform encephalopathy:
Molecular similarities with sporadic Creutzfeldt–Jakob disease
Cristina Casalone*†, Gianluigi Zanusso†‡, Pierluigi Acutis*, Sergio
Ferrari‡, Lorenzo Capucci§, Fabrizio Tagliavini¶, Salvatore Monaco‡ , and Maria
Caramelli* *Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto
Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, Via Bologna,
148, 10195 Turin, Italy; ‡Department of Neurological and Visual Science, Section
of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134
Verona, Italy; §Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia
Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale
Neurologico ‘‘Carlo Besta,’’ Via Celoria 11, 20133 Milan, Italy
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved December 23, 2003 (received for review September 9, 2003)
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are
mammalian neurodegenerative disorders characterized by a posttranslational
conversion and brain accumulation of an insoluble, protease-resistant isoform
(PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE
agents exist as different phenotypes that can be biochemically differentiated on
the basis of the molecular mass of the protease-resistant PrPSc fragments and
the degree of glycosylation. Epidemiological, molecular, and transmission
studies strongly suggest that the single strain of agent responsible for bovine
spongiform encephalopathy (BSE) has infected humans, causing variant
Creutzfeldt–Jakob disease. The unprecedented biological properties of the BSE
agent, which circumvents the so-called ‘‘species barrier’’ between cattle and
humans and adapts to different mammalian species, has raised considerable
concern for human health. To date, it is unknown whether more than one strain
might be responsible for cattle TSE or whether the BSE agent undergoes
phenotypic variation after natural transmission. Here we provide evidence of a
second cattle TSE. The disorder was pathologically characterized by the presence
of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid
deposition in typical BSE cases, and by a different pattern of regional
distribution and topology of brain PrPSc accumulation. In addition, Western blot
analysis showed a PrPSc type with predominance of the low molecular mass
glycoform and a protease- resistant fragment of lower molecular mass than
BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed
bovine PrPSc was similar to that encountered in a distinct subtype of sporadic
Creutzfeldt–Jakob disease.
Phenotypic Similarities Between BASE and sCJD. The transmissibility of CJD
brains was initially demonstrated in primates (27), and classification of
atypical cases as CJD was based on this property (28). To date, no systematic
studies of strain typing in sCJD have been provided, and classification of
different subtypes is based on clinical, neuropathological, and molecular
features (the polymorphic PRNP codon 129 and the PrPSc glycotype) (8, 9, 15,
19). The importance of molecular PrPSc characterization in assessing the
identity of TSE strains is underscored by several studies, showing that the
stability of given disease-specific PrPSc types is maintained upon experimental
propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized
mice (8, 29). Similarly, biochemical properties of BSE- and vCJDassociated PrPSc
molecules remain stable after passage to mice expressing bovine PrP (30).
Recently, however, it has been reported that PrP-humanized mice inoculated with
BSE tissues may also propagate a distinctive PrPSc type, with a
‘‘monoglycosylated- dominant’’ pattern and electrophoretic mobility of the
unglycosylated fragment slower than that of vCJD and BSE (31). Strikingly, this
PrPSc type shares its molecular properties with the a PrPSc molecule found in
classical sCJD. This observation is at variance with the PrPSc type found in
M V2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant pattern
but faster electrophoretic mobility of the protease-resistant fragment as
compared with BSE. In addition to molecular properties of PrPSc, BASE and M V2
sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs
as plaque-like and amyloid-kuru plaques. Differences were, however, observed in
the regional distribution of PrPSc. While inM V2 sCJD cases the largest amounts
of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle
BASE these areas were less involved and the highest levels of PrPSc were
recovered from the thalamus and olfactory regions.
In conclusion, decoding the biochemical PrPSc signature of individual human
and animal TSE strains may allow the identification of potential risk factors
for human disorders with unknown etiology, such as sCJD. However, although BASE
and sCJD share several characteristics, caution is dictated in assessing a link
between conditions affecting two different mammalian species, based on
convergent biochemical properties of diseaseassociated PrPSc types. Strains of
TSE agents may be better characterized upon passage to transgenic mice. In the
interim until this is accomplished, our present findings suggest a strict
epidemiological surveillance of cattle TSE and sCJD based on molecular criteria.
Employment Listings position: Post Doctoral Fellow | Atypical BSE in Cattle
Closing date: December 24, 2009
Anticipated start date: January/February 2010
Employer: Canadian and OIE Reference Laboratories for BSE CFIA Lethbridge
Laboratory, Lethbridge/Alberta
The Canadian and OIE reference laboratories for BSE are extensively
involved in prion diseases diagnosis and research. With a recent increase in
research activities and funding, the laboratory is looking to fill two post
doctoral fellow positions. Both positions will be located at the Canadian Food
Inspection Agency (CFIA) Lethbridge Laboratory which offers biosaftey level 3
(BSL3) and BSL2 laboratory space and is well equipped for molecular and
morphologic prion research. The facility also has a BSL3 large animal housing
wing and a state of the art post mortem room certified for prion work.
Successful candidates will have the opportunity to visit other laboratories to
cooperate in various aspects of the projects and to be trained in new techniques
and acquire new skills. With a recent increase in prion disease expertise and
research in Alberta and Canada, these positions will offer significant exposure
to cutting edge prion science via videoconferencing, meetings, workshops and
conferences. These interactions will also provide a valuable opportunity to
present research findings and discuss potential future work opportunities and
collaborations with other Canadian and international research groups.
Atypical BSE in Cattle
BSE has been linked to the human disease variant Creutzfeldt Jakob Disease
(vCJD). The known exposure pathways for humans contracting vCJD are through the
consumption of beef and beef products contaminated by the BSE agent and through
blood transfusions. However, recent scientific evidence suggests that the BSE
agent may play a role in the development of other forms of human prion diseases
as well. These studies suggest that classical type of BSE may cause type 2
sporadic CJD and that H-type atypical BSE is connected with a familial form of
CJD.
To date the OIE/WAHO assumes that the human and animal health standards set
out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE
which include the H-type and L-type atypical forms. This assumption is
scientifically not completely justified and accumulating evidence suggests that
this may in fact not be the case. Molecular characterization and the spatial
distribution pattern of histopathologic lesions and immunohistochemistry (IHC)
signals are used to identify and characterize atypical BSE. Both the L-type and
H-type atypical cases display significant differences in the conformation and
spatial accumulation of the disease associated prion protein (PrPSc) in brains
of afflicted cattle. Transmission studies in bovine transgenic and wild type
mouse models support that the atypical BSE types might be unique strains because
they have different incubation times and lesion profiles when compared to C-type
BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian
hamster the resulting molecular fingerprint had changed, either in the first or
a subsequent passage, from L-type into C-type BSE. 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.
Responsibilities include:
Driving research at the National and OIE BSE reference lab to ensure
project milestones are met successfully. Contributing to the preparation of
project progress reports. Directing technical staff working on the project.
Communicating and discussing results, progress and future direction with project
principle investigator(s). Communicating with collaborative project partners.
Qualifications:
Successful completion of a PhD degree in an area focusing on or related to
prion diseases. Extensive experience with molecular and/or morphologic
techniques used in studying prion diseases and/or other protein misfolding
disorders. Ability to think independently and contribute new ideas. Excellent
written and oral communication skills. Ability to multitask, prioritize, and
meet challenges in a timely manner. Proficiency with Microsoft Office,
especially Word, PowerPoint and Excel.
How to apply:
Please send your application and/or inquiry to: Dr. Stefanie Czub, DVM,
Ph.D. Head, National and OIE BSE Reference Laboratory Canadian Food Inspection
Agency Lethbridge Laboratory P.O. Box 640, Township Road 9-1 Lethbridge, AB, T1J
3Z4 Canada
phone: +1-403-382-5500 +1-403-382-5500 ext. 5549 email:
stefanie.czub@inspection.gc.ca
Contact Info:
Last Updated: 12/10/2009 1:35:18 PM
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
snip...
2012 CALIFORNIA ATYPICAL L-TYPE BASE BSE MAD COW, SPONTANEOUS AND FEED $$$
Saturday, May 26, 2012
Are USDA assurances on mad cow case 'gross oversimplification'?
SNIP...
What irks many scientists is the USDA’s April 25 statement that the rare
disease is “not generally associated with an animal consuming infected feed.”
The USDA’s conclusion is a “gross oversimplification,” said Dr. Paul Brown,
one of the world’s experts on this type of disease who retired recently from the
National Institutes of Health. "(The agency) has no foundation on which to base
that statement.”
“We can’t say it’s not feed related,” agreed Dr. Linda Detwiler, an
official with the USDA during the Clinton Administration now at Mississippi
State.
In the May 1 email to me, USDA’s Cole backed off a bit. “No one knows the
origins of atypical cases of BSE,” she said
The argument about feed is critical because if feed is the cause, not a
spontaneous mutation, the California cow could be part of a larger outbreak.
SNIP...
MAD COW USDA ATYPICAL L-TYPE BASE BSE, the rest of the story...
***Oral Transmission of L-type Bovine Spongiform Encephalopathy in Primate
Model
***Infectivity in skeletal muscle of BASE-infected cattle
***feedstuffs- It also suggests a similar cause or source for atypical BSE
in these countries.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
full text ;
atypical L-type BASE BSE
Tuesday, May 1, 2012
BSE MAD COW LETTERS TO USDA (Tom Vilsack, Secretary of Agriculture) and FDA
(Magaret Hamburg, Commissioner of FDA) May 1, 2012
Wednesday, May 2, 2012
ARS FLIP FLOPS ON SRM REMOVAL FOR ATYPICAL L-TYPE BASE BSE RISK HUMAN AND
ANIMAL HEALTH
Friday, May 4, 2012
May 2, 2012: Update from APHIS Regarding a Detection of Bovine Spongiform
Encephalopathy (BSE) in the United States
Sunday, March 11, 2012
APHIS Proposes New Bovine Spongiform Encephalopathy Import Regulations in
Line with International Animal Health Standards Proposal Aims to Ensure Health
of the U.S. Beef Herd, Assist in Negotiations
Wednesday, April 4, 2012
Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine
Products APHIS-2008-0010-0008 RIN:0579-AC68
Sunday, May 6, 2012
Bovine Spongiform Encephalopathy Mad Cow Disease, BSE May 2, 2012 IOWA
State University OIE
Friday, May 11, 2012
Experimental H-type bovine spongiform encephalopathy characterized by
plaques and glial- and stellate-type prion protein deposits
Re: [BSE-L] Experimental H-type bovine spongiform encephalopathy
characterized by plaques and glial- and stellate-type prion protein deposits
“Unfortunately, a detailed and all-encompassing analysis of neuropathology
and topographical distribution of immunolabeled PrPSc in H-type BSE-affected
cattle could not be performed, since only the obex region is routinely sampled
for BSE surveillance testing and the remaining brain as well as the carcasses
are not available in most countries [3,10,12,13,24-27]. Recently, clinical signs
and biochemical properties of experimental German H-type BSE cases have been
reported [20]. The primary objective of this study was to investigate the
transmissibility of H-type BSE, using a field isolate detected in the active
surveillance program in Canada [12]. The secondary objective was to extend the
knowledge of the topographical distribution and deposition patterns of
immunolabeled PrPSc in H-type BSE.”
PLEASE SEE ;
Tuesday, November 02, 2010
BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only)
diagnostic criteria CVL 1992
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 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. ...
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM
THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS
"All of the 15 cattle tested showed that the brains had abnormally
accumulated PrP"
2009
''THE LINE TO TAKE'' ON IBNC $$$ 1995 $$$
1995
page 9 of 14 ;
30. The Committee noted that the results were unusual. the questioned
whether there could be coincidental BSE infection or contamination with scrapie.
Dr. Tyrell noted that the feeling of the committee was that this did not
represent a new agent but it was important to be prepared to say something
publicly about these findings. A suggested line to take was that these were
scientifically unpublishable results but in line with the policy of openness
they would be made publicly available and further work done to test their
validity. Since the BSE precautions were applied to IBNC cases, human health was
protected. Further investigations should be carried out on isolations from
brains of IBNC cases with removal of the brain and subsequent handling under
strict conditions to avoid the risk of any contamination.
31. Mr. Bradley informed the Committee that the CVO had informed the CMO
about the IBNC results and the transmission from retina and he, like the
Committee was satisfied that the controls already in place or proposed were
adequate. ... snip... see full text
http://web.archive.org/web/20030327015011/http://www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf
Wednesday, July 28, 2010
Atypical prion proteins and IBNC in cattle DEFRA project code SE1796 FOIA
Final report
Tuesday, November 02, 2010
BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only)
diagnostic criteria CVL 1992
2012
Friday, May 25, 2012
R-CALF USDA’s New BSE Rule Eliminates Important Protections Needed to
Prevent BSE Spread
Thursday, June 14, 2012
R-CALF USA Calls USDA Dishonest and Corrupt; Submits Fourth Request for
Extension
R-CALF United Stockgrowers of America
Monday, June 18, 2012
R-CALF Submits Incomplete Comments Under Protest in Bizarre Rulemaking
“Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products”
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
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.
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
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.
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.
Thursday, January 26, 2012
Facilitated Cross-Species Transmission of Prions in Extraneural Tissue
Science 27 January 2012: Vol. 335 no. 6067 pp. 472-475 DOI:
10.1126/science.1215659
Saturday, February 11, 2012
Prion cross-species transmission efficacy is tissue dependent
Thursday, January 26, 2012
The Risk of Prion Zoonoses
Science 27 January 2012: Vol. 335 no. 6067 pp. 411-413 DOI:
10.1126/science.1218167
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
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).
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).
Wednesday, February 16, 2011
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
why do we not want to do TSE transmission studies on chimpanzees $
snip...
5. A positive result from a chimpanzee challenged severly would likely
create alarm in some circles even if the result could not be interpreted for
man. I have a view that all these agents could be transmitted provided a large
enough dose by appropriate routes was given and the animals kept long enough.
Until the mechanisms of the species barrier are more clearly understood it might
be best to retain that hypothesis.
snip...
R. BRADLEY
Friday, February 11, 2011
Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues
Monday, April 25, 2011
Experimental Oral Transmission of Atypical Scrapie to Sheep
Volume 17, Number 5-May 2011
Sunday, April 18, 2010
SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in
animals and humans Webnachricht 19 Januar 2011
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive
Prionopathy and Gerstmann-Sträussler-Scheinker Disease
RESEARCH
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May
2011
Experimental Oral Transmission of Atypical Scrapie to Sheep
Marion M. Simmons, S. Jo Moore,1 Timm Konold, Lisa Thurston, Linda A.
Terry, Leigh Thorne, Richard Lockey, Chris Vickery, Stephen A.C. Hawkins,
Melanie J. Chaplin, and John Spiropoulos
To investigate the possibility of oral transmission of atypical scrapie in
sheep and determine the distribution of infectivity in the animals’ peripheral
tissues, we challenged neonatal lambs orally with atypical scrapie; they were
then killed at 12 or 24 months. Screening test results were negative for
disease-specifi c prion protein in all but 2 recipients; they had positive
results for examination of brain, but negative for peripheral tissues.
Infectivity of brain, distal ileum, and spleen from all animals was assessed in
mouse bioassays; positive results were obtained from tissues that had negative
results on screening. These fi ndings demonstrate that atypical scrapie can be
transmitted orally and indicate that it has the potential for natural
transmission and iatrogenic spread through animal feed. Detection of infectivity
in tissues negative by current surveillance methods indicates that diagnostic
sensitivity is suboptimal for atypical scrapie, and potentially infectious
material may be able to pass into the human food chain.
SNIP...
Although we do not have epidemiologic evidence that supports the effi cient
spread of disease in the fi eld, these data imply that disease is potentially
transmissible under fi eld situations and that spread through animal feed may be
possible if the current feed restrictions were to be relaxed. Additionally,
almost no data are available on the potential for atypical scrapie to transmit
to other food animal species, certainly by the oral route. However, work with
transgenic mice has demonstrated the potential susceptibility of pigs, with the
disturbing fi nding that the biochemical properties of the resulting PrPSc have
changed on transmission (40). The implications of this observation for
subsequent transmission and host target range are currently unknown.
How reassuring is this absence of detectable PrPSc from a public health
perspective? The bioassays performed in this study are not titrations, so the
infectious load of the positive gut tissues cannot be quantifi ed, although
infectivity has been shown unequivocally. No experimental data are currently
available on the zoonotic potential of atypical scrapie, either through
experimental challenge of humanized mice or any meaningful epidemiologic
correlation with human forms of TSE. However, the detection of infectivity in
the distal ileum of animals as young as 12 months, in which all the tissues
tested were negative for PrPSc by the currently available screening and confi
rmatory diagnostic tests, indicates that the diagnostic sensitivity of current
surveillance methods is suboptimal for detecting atypical scrapie and that
potentially infectious material may be able to pass into the human food chain
undetected.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May
2011
OIE Scrapie Chapter Revision • Current draft recognizes Nor98-like scrapie
as a separate disease from classical scrapie • USDA provided comments on the
draft to OIE
Atypical scrapie/Nor 98 October 2009
Last year, after examining member country submissions and investigating
rigorous scientific research, the World Organisation for Animal Health (OIE)
decided that Nor 98 should not be listed in its Terrestrial Animal Health Code.
The Code sets out trade recommendations or restrictions for listed diseases or
conditions, and the OIE determined there was no need for such recommendations
around Nor 98.
Sutton reported that USDA has urged the World Organization for Animal
Health (OIE) to categorize Nor98-like scrapie as a separate disease from
classical scrapie. Currently, the OIE has proposed a draft revision of their
scrapie chapter that would exclude Nor98-like scrapie from the chapter. USDA
will be submitting it's comments on this proposal soon.
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.
• 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
BSE: TIME TO TAKE H.B. PARRY SERIOUSLY
If the scrapie agent is generated from ovine DNA and thence causes disease
in other species, then perhaps, bearing in mind the possible role of scrapie in
CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the
notifiable disease. ...
Thursday, March 29, 2012
atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012
NIAA Annual Conference April 11-14, 2011San Antonio, Texas
Monday, June 11, 2012
another atypical Nor-98 Scrapie case documented in Canada for 2012
too bad Canada’s policy on BSE aka mad cow type disease, and the reporting
there from of completed cases, have ceased to exist on the CFIA site for the
public to follow.
you have to request a copy. CFIA ceased giving those copies out to me. ...
•Request a copy of a completed BSE investigation report for a case after
January 2009
Sunday, May 27, 2012
CANADA PLANS TO IMPRISON ANYONE SPEAKING ABOUT MAD COW or ANY OTHER DISEASE
OUTBREAK, CENSORSHIP IS A TERRIBLE THING
Wednesday, June 13, 2012
MEXICO IS UNDER or MIS DIAGNOSING CREUTZFELDT JAKOB DISEASE AND OTHER PRION
DISEASE SOME WITH POSSIBLE nvCJD
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE
RISE IN NORTH AMERICA
Sunday, February 12, 2012
National Prion Disease Pathology Surveillance Center Cases Examined1
(August 19, 2011) including Texas
Terry S. Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health
Crisis
full text with source references ;
price of prion poker goes up again $$$
Monday, June 11, 2012
Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance
for Industry: Revised Preventive Measures to Reduce the Possible Risk of
Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease
by Blood and Blood Products”
Subject: Bovine Spongiform Encephalopathy; Importation of Bovines and
Bovine Products APHIS-2008-0010-0008 RIN:0579-AC68
Comment from Terry Singeltary Document ID: APHIS-2008-0010-0008 Document
Type: Public Submission This is comment on Proposed Rule: Bovine Spongiform
Encephalopathy; Importation of Bovines and Bovine Products Docket ID:
APHIS-2008-0010 RIN:0579-AC68
Topics: No Topics associated with this document View Document: More
Document Subtype: Public Comment Status: Posted Received Date: March 22
2012, at 12:00 AM Eastern Daylight Time Date Posted: March 22 2012, at 12:00 AM
Eastern Daylight Time Comment Start Date: March 16 2012, at 12:00 AM Eastern
Daylight Time Comment Due Date: May 15 2012, at 11:59 PM Eastern Daylight Time
Tracking Number: 80fdd617 First Name: Terry Middle Name: S. Last Name:
Singeltary City: Bacliff Country: United States State or Province: TX
Organization Name: CJD TSE PRION Submitter's Representative: CONSUMERS
Comment: comment submission Document ID APHIS-2008-0010-0001 Greetings
USDA, OIE et al, what a difference it makes with science, from one day to the
next. i.e. that mad cow gold card the USA once held. up until that fateful day
in December of 2003, the science of BSE was NO IMPORTS TO USA FROM BSE COUNTRY.
what a difference a day makes$ now that the shoe is on the other foot, the USDA
via the OIE, wants to change science again, just for trade $ I implore the OIE
decision and policy makers, for the sake of the world, to refuse any status quo
of the USA BSE risk assessment. if at al, the USA BSE GBR should be raise to BSE
GBR IV, for the following reasons. North America is awash with many different
TSE Prion strains, in many different species, and they are mutating and
spreading. IF the OIE, and whatever policy makers, do anything but raise the
risk factor for BSE in North America, they I would regard that to be highly
suspicious. IN fact, it would be criminal in my opinion, because the OIE knows
this, and to knowingly expose the rest of the world to this dangerous pathogen,
would be ‘knowingly’ and ‘willfully’, just for the almighty dollar, once again.
I warned the OIE about all this, including the risk factors for CWD, and the
fact that the zoonosis potential was great, way back in 2002. THE OIE in
collaboration with the USDA, made the legal trading of the atypical Nor-98
Scrapie a legal global commodity. yes, thanks to the OIE and the USDA et al,
it’s now legal to trade the atypical Nor-98 Scrapie strain all around the globe.
IF you let them, they will do the same thing with atypical BSE and CWD (both
strains to date). This with science showing that indeed these TSE prion strains
are transmissible. I strenuously urge the OIE et al to refuse any weakening to
the USA trade protocols for the BSE TSE prion disease (all strains), and urge
them to reclassify the USA with BSE GBR IV risk factor. SEE REFERENCE SOURCES IN
ATTACHMENTS
SEE Terry S. Singeltary Sr. Attachment WORD FILE ;
Wednesday, April 4, 2012
Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine
Products APHIS-2008-0010-0008 RIN:0579-AC68
layperson
TSS
posted by Terry S. Singeltary Sr. at
10:31 AM
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