Absence of evidence for a causal link between L-BSE and known forms of sporadic CJD in human PrP transgenic mice
Absence of evidence for a causal link between L-BSE
and known forms of sporadic CJD in human PrP transgenic mice
Emilie Jaumain1, Isabelle Quadrio2,3, Laetitia
Herzog1,Fabienne Reine1, Human Rezaei1, Olivier Andréoletti4, Hubert
Laude1,Armand Perret-Liaudet2,3, Stéphane Haïk5,6 and Vincent Béringue1* +Author
Affiliations
1VIM, INRA, Université Paris-Saclay, 78350,
Jouy-en-Absence of evidence for a causal link between L-BSE and known forms of
sporadic CJD in human PrP transgenic mice, France. 2Neurobiology Laboratory,
Biochemistry and Molecular Biology Department, Hôpitaux de Lyon, Lyon, France.
3University of Lyon 1, CNRS UMR5292, INSERM U1028, BioRan, Lyon, France. 4IHAP,
INRA, Ecole Nationale Vétérinaire de Toulouse, 31000, Toulouse, France. 5INSERM
U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127,
Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France. 6Centre
National de Référence des Agents Transmissibles Non Conventionnels, F-75013
Paris, France.
ABSTRACT
Prions are proteinaceous pathogens responsible for
subacute spongiform encephalopathies in animals and humans. The prions
responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents,
causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of
prions between species is limited by a species barrier, which is thought to
reflect structural incompatibilities between host cellular prion protein (PrPC)
and the infecting pathological PrP assemblies (PrPSc) constituting the prion. A
BSE strain variant, designated L-BSE and responsible for atypical, supposedly
spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic
potential, as evidenced by its capacity to propagate more easily than classical
BSE in transgenic mice expressing human PrPC and in non-human primates. In
humanized mice, L-BSE propagates without any apparent species barrier and shares
similar biochemical PrPSc signatures with the CJD subtype designated
MM2-cortical, thus opening the possibility that certain CJD cases classified as
sporadic may actually originate from L-type BSE cross-transmission. To address
this issue, we compared the biological properties of L-BSE and those of a panel
of CJD subtypes representative of the human prion strain diversity using
standard strain-typing criteria in human PrP transgenic mice. We found no
evidence that L-BSE causes a known form of sporadic CJD.
IMPORTANCE Since the quasi-extinction of classical
BSE, atypical BSE forms are the sole BSE variants circulating in cattle
worldwide. They are observed in rare cases of old cattle, making them difficult
to detect. Extrapolation of our results suggests that L-BSE may propagate in
humans as an unrecognized form of CJD and we urge both the continued utilization
of precautionary measures to eliminate these agents from the human food chain
and active surveillance for CJD phenotypes in the general
population.
FOOTNOTES ↵*Correspondence: Vincent Béringue, vincent.beringue@inra.frsnip...
snip...
Finally, we examined whether L-BSE prions ‘breed
true’ in tg650 mice. tg650-derived L-BSE agents at the first to third passage
were transmitted back into bovine PrP mice (25) via the intracerebral route. As
shown in Table 2, tg650-derived L-BSE prions were as pathogenic as parental
L-BSE prions in these mice. Based on the PrPres glycopattern in the brains of
the diseased mice, the strain type re-isolated was fully consistent with L-BSE
prions (Figure 1G). Together, these data indicate that L-BSE prions were
propagated in human PrP mice without apparent transmission barrier.
Downloaded from http://jvi.asm.org/ on October 4, 2016 by INRA -
France
snip...
Discussion
We further demonstrated in this study that atypical
L-BSE prions propagate with no significant barrier in human PrP transgenic mice
(Met129), as shown by the full disease incidence, the absence of a drastic
reduction in incubation time over 4 passages, the conservation of the L-type
PrPres electrophoretic pattern and the immediate re-isolation of L220 prions in
bovine PrP transgenic mice from the first back-passage onwards. Although
gene-targeted transgenic mice expressing physiological levels of human PrP did
not show any clinical disease on primary challenge with L-BSE prions (33), they
were later found to harbor remnant or low levels of infectivity in their brains
(34), thus suggesting the disease developed at a slow pace. Non-human primates,
which can live longer, were found to succumb to L-BSE more rapidly than C-BSE
(20, 21).
*** Together, these data indicate that L-BSE prions
have a clear zoonotic potential. We found no evidence that L-BSE prions cause a
known form of sporadic CJD. Although tg650-derived L-BSE prions share similar
strain properties with cortical MM2-sCJD prions in terms of PrPres signature,
resistance to guanidinium chloride treatment, lympho-incompetence and
neuroanatomical PrPres deposition, the 2-fold difference in disease progression
over at least four passages and the differential resistance to proteinase K
digestion suggest no etiological link between L-BSE and cortical MM2-sCJD
prions. This absence of an etiological link was further substantiated by the
divergent transmission properties of the two agents in ovine PrP transgenic mice
(17, 24). The extreme rareness of the cortical sCJD MM2 subtype precluded a
comparison with a larger panel of cases to definitively exclude any etiological
link.
Downloaded from http://jvi.asm.org/ on October 4, 2016 by INRA -
France
Our study confirmed the existence of diverse
strains 239 of prions associated with sCJD. We identified 4 distinct groups,
MM1/MV1, MM2-cortical, MV2/VV2 and VV1, as previously inferred from the
transmission or absence of transmission of these subtypes in gene-targeted
transgenic mice expressing human PrP (23, 35). The MV2 and VV2 subtypes,
however, showed dissimilar neuroanatomical distributions of PrPres deposits.
Further studies that include transmission to other human PrP genotypes are
needed to confirm whether MV2 and VV2 prions are truly differentiable with
regard to their biological properties.
The tg650 mouse model allows the gauging of prion
ability to replicate in the lymphoid tissue (6, 16, 36). We showed here that
MV2, VV2 and VV1 sCJD prions replicated in tg650 mouse spleens, albeit at lower
rate than vCJD, as determined by PrPres accumulation levels in this tissue. This
result suggests that the commonly shared view that sCJD prion replication is
primarily confined to the central nervous system (37-39) is subtype dependent.
Refined analysis of spleen tissue from sCJD-affected patients demonstrated the
presence of PrPres in all subtypes (40). The presence of PrPres appeared to
correlate with longer duration of disease, as we found here. Systematic analysis
of clinical sCJD subtypes for the presence of infectivity or seeding activity
(41-43) in central and extraneural tissues (44, 45) is needed to assess the risk
of sCJD iatrogenic spread after surgical procedures in preclinical patients.
Careful extrapolation of our data raises the
possibility that an unrecognized human prion strain type may emerge from the
accidental transfer of L-BSE prions to humans. Together with the risk that L-BSE
prions will propagate with better efficacy in humans than C-BSE prions (19-21,
32), these data highlight the need for continued long-term utilization of
precautionary measures to diagnose (46) and prevent these agents from entering
the human food chain and the maintenance of an active surveillance of prion
strains 263 within the CJD population.
265
Downloaded from http://jvi.asm.org/ on October 4, 2016 by INRA -
France
266 Acknowledgments
snip...
Evidence That Transmissible Mink Encephalopathy
Results from Feeding Infected Cattle
Over the next 8-10 weeks, approximately 40% of all
the adult mink on the farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using
mostly (>95%) downer or dead dairy cattle...
In Confidence - Perceptions of unconventional slow
virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells
3. Prof. A. Robertson gave a brief account of BSE.
The US approach was to accord it a very low profile indeed. Dr. A Thiermann
showed the picture in the ''Independent'' with cattle being incinerated and
thought this was a fanatical incident to be avoided in the US at all costs. .
..
”The occurrence of CWD must be viewed against the
contest of the locations in which it occurred. It was an incidental and
unwelcome complication of the respective wildlife research programmes. Despite
it’s subsequent recognition as a new disease of cervids, therefore justifying
direct investigation, no specific research funding was forthcoming. The USDA
veiwed it as a wildlife problem and consequently not their province!” ...page
26.
*** Spraker suggested an interesting explanation
for the occurrence of CWD. The deer pens at the Foot Hills Campus were built
some 30-40 years ago by a Dr. Bob Davis. At or abut that time, allegedly, some
scrapie work was conducted at this site. When deer were introduced to the pens
they occupied ground that had previously been occupied by sheep.
SPONTANEOUS ATYPICAL BOVINE SPONGIFORM
ENCEPHALOPATHY
***Moreover, sporadic disease has never been
observed in breeding colonies or primate research laboratories, most notably
among hundreds of animals over several decades of study at the National
Institutes of Health25, and in nearly twenty older animals continuously housed
in our own facility.***
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME
Prion Strain to Cynomolgus Macaque
"BSE-L in North America may have existed for
decades"
Tuesday, July 26, 2016
*** Atypical Bovine Spongiform Encephalopathy BSE
TSE Prion UPDATE JULY 2016 ***
Saturday, July 23, 2016
BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION
SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY
2016
Wednesday, September 28, 2016
Norway sides with OIE, decides to expose millions
of consumers to the ATYPICAL BSE SRM TSE Prion aka mad cow type
disease
***Transmission studies to transgenic mice
overexpressing bovine PrP (Tgbov mice) showed that the BASE strain is more
aggressive than the BSE strain [10]. Furthermore, Tg mice overexpressing human
PrP as well as non-human primates are more susceptible to infection with BASE
than with BSE [11]–[14].
Overall these data raise concern about the
potential risk of transmission of BASE to humans and it is urgent to determine
the presence and distribution of infectivity in peripheral tissues of
BASE-affected cattle. To investigate this issue, we inoculated Tgbov mice with
different peripheral tissues from experimentally and naturally BASE-affected
cattle and found that various skeletal muscles contained infectivity and
PrP-immunoreactive deposits within individual fibers.
snip...
The present data offer novel information on the
tropism of the BASE agent and highlight relevant public health issues. While the
transmission barrier for classical BSE is high in most species, BASE prions are
readily transmissible to a variety of mammals including non-human primates
[11]–[13], [35]. Accordingly, the possibility of spreading of BASE prions
through skeletal muscle to other species should be taken into account and
evaluated in risk analysis studies.
Saturday, April 23, 2016
SCRAPIE WS-01: Prion diseases in animals and
zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl
1933-690X online
Taylor & Francis
Prion 2016 Animal Prion Disease Workshop
Abstracts
WS-01: Prion diseases in animals and zoonotic
potential
Juan Maria Torres a, Olivier Andreoletti b, J
uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,
Natalia Fernandez-Borges a. and Alba Marin-Moreno
a
"Centro de Investigacion en Sanidad Animal (
CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes
Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie
MolécuIaires, Jouy-en-Josas. France
Dietary exposure to bovine spongiform
encephalopathy (BSE) contaminated bovine tissues is considered as the origin of
variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the
only recognized zoonotic prion. Despite the variety of Transmissible Spongiform
Encephalopathy (TSE) agents that have been circulating for centuries in farmed
ruminants there is no apparent epidemiological link between exposure to ruminant
products and the occurrence of other form of TSE in human like sporadic
Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the
diversity of circulating TSE agents has never been systematically assessed. The
major issue in experimental assessment of TSEs zoonotic potential lies in the
modeling of the ‘species barrier‘, the biological phenomenon that limits TSE
agents’ propagation from a species to another. In the last decade, mice
genetically engineered to express normal forms of the human prion protein has
proved essential in studying human prions pathogenesis and modeling the capacity
of TSEs to cross the human species barrier.
To assess the zoonotic potential of prions
circulating in farmed ruminants, we study their transmission ability in
transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing
different forms of the human PrPC (129Met or 129Val) are used to determine the
role of the Met129Val dimorphism in susceptibility/resistance to the different
agents.
These transmission experiments confirm the ability
of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129
homozygotes may be susceptible to BSE in sheep or goat to a greater degree than
the BSE agent in cattle and that these agents can convey molecular properties
and neuropathological indistinguishable from vCJD. However homozygous 129V mice
are resistant to all tested BSE derived prions independently of the originating
species suggesting a higher transmission barrier for 129V-PrP
variant.
Transmission data also revealed that several
scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of
cattle BSE. While the efficiency of transmission at primary passage was low,
subsequent passages resulted in a highly virulent prion disease in both Met129
and Val129 mice. Transmission of the different scrapie isolates in these mice
leads to the emergence of prion strain phenotypes that showed similar
characteristics to those displayed by MM1 or VV2 sCJD prion. These results
demonstrate that scrapie prions have a zoonotic potential and raise new
questions about the possible link between animal and human prions.
Tuesday, December 16, 2014
Evidence for zoonotic potential of ovine scrapie
prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1
Caroline Lacroux,1, Jean-Yves Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4,
Séverine Lugan,1, Isabelle Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne
Reine,5, Laetitia Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, &
Olivier Andréoletti1, Affiliations Contributions Corresponding author Journal
name: Nature Communications Volume: 5, Article number: 5821 DOI:
doi:10.1038/ncomms6821 Received 07 August 2014 Accepted 10 November 2014
Published 16 December 2014 Article tools Citation Reprints Rights &
permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is
the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic
potential of scrapie prions remains unknown. Mice genetically engineered to
overexpress the human prion protein (tgHu) have emerged as highly relevant
models for gauging the capacity of prions to transmit to humans. These models
can propagate human prions without any apparent transmission barrier and have
been used used to confirm the zoonotic ability of BSE. Here we show that a panel
of sheep scrapie prions transmit to several tgHu mice models with an efficiency
comparable to that of cattle BSE. The serial transmission of different scrapie
isolates in these mice led to the propagation of prions that are phenotypically
identical to those causing sporadic CJD (sCJD) in humans. These results
demonstrate that scrapie prions have a zoonotic potential and raise new
questions about the possible link between animal and human prions.
snip...
Do our transmission results in tgHu imply that
sheep scrapie is the cause of sCJD cases in humans? This question challenges
well-established dogma that sCJD is a spontaneous disorder unrelated to animal
prion disease. In our opinion, our data on their own do not unequivocally
establish a causative link between natural exposure to sheep scrapie and the
subsequent appearance of sCJD in humans. However, our studies clearly point out
the need to re-consider this possibility. Clarification on this topic will be
aided by informed and modern epidemiological studies to up-date previous
analysis that was performed at the end of the last century3, 4. The value of
such an approach is highlighted by the implementation in the year 2000 of
large-scale active animal TSE surveillance programs around the world that
provided an informed epidemiological-based view of the occurrence and
geographical spread of prion disease in small ruminant populations51. The fact
that both Australia and New-Zealand, two countries that had been considered for
more than 50 years as TSE-free territories, were finally identified positive for
atypical scrapie in their sheep flocks provides an example of how prion dogma
can be reversed52. However, the incubation period for prion disease in humans
after exposure to prions via the peripheral route, such as in iatrogenic CJD
transmission and Kuru, can exceed several decades53, 54. In this context, it
will be a challenge to combine epidemiological data collected contemporarily in
animal populations and humans to investigate the existence of a causative link
between prion disease occurrence in these different hosts. Furthermore, it is
crucial to bear in mind that sporadic sCJD in humans is a rare disease (1–2
individuals per million of the population per year) and that scrapie has been
circulating in small ruminants populations used for food purposes for centuries.
Consequently, it is our opinion that even if a causative link was established
between sheep scrapie exposure and the occurrence of certain sCJD cases, it
would be wrong to consider small ruminant TSE agents as a new major threat for
public health. Despite this, it remains clear that our data provide a new
impetus to establish the true zoonotic potential of sheep scrapie
prions.
Subject terms: Biological sciences• Medical
research At a glance
Research Project: TRANSMISSION, DIFFERENTIATION,
AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Transmission of scrapie prions to primate
after an extended silent incubation period
Authors
item Comoy, Emmanuel - item Mikol, Jacqueline -
item Luccantoni-Freire, Sophie - item Correia, Evelyne - item
Lescoutra-Etchegaray, Nathalie - item Durand, Valérie - item Dehen, Capucine -
item Andreoletti, Olivier - item Casalone, Cristina - item Richt, Juergen item
Greenlee, Justin item Baron, Thierry - item Benestad, Sylvie - item Hills, Bob -
item Brown, Paul - item Deslys, Jean-Philippe -
Submitted to: Scientific Reports Publication Type:
Peer Reviewed Journal Publication Acceptance Date: May 28, 2015 Publication
Date: June 30, 2015 Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S.,
Correia, E., Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O.,
Casalone, C., Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P.,
Deslys, J. 2015. Transmission of scrapie prions to primate after an extended
silent incubation period. Scientific Reports. 5:11573.
Interpretive Summary: The transmissible spongiform
encephalopathies (also called prion diseases) are fatal neurodegenerative
diseases that affect animals and humans. The agent of prion diseases is a
misfolded form of the prion protein that is resistant to breakdown by the host
cells. Since all mammals express prion protein on the surface of various cells
such as neurons, all mammals are, in theory, capable of replicating prion
diseases. One example of a prion disease, bovine spongiform encephalopathy (BSE;
also called mad cow disease), has been shown to infect cattle, sheep, exotic
undulates, cats, non-human primates, and humans when the new host is exposed to
feeds or foods contaminated with the disease agent. The purpose of this study
was to test whether non-human primates (cynomologous macaque) are susceptible to
the agent of sheep scrapie. After an incubation period of approximately 10 years
a macaque developed progressive clinical signs suggestive of neurologic disease.
Upon postmortem examination and microscopic examination of tissues, there was a
widespread distribution of lesions consistent with a transmissible spongiform
encephalopathy. This information will have a scientific impact since it is the
first study that demonstrates the transmission of scrapie to a non-human primate
with a close genetic relationship to humans. This information is especially
useful to regulatory officials and those involved with risk assessment of the
potential transmission of animal prion diseases to humans. Technical Abstract:
Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease
that also causes variant Creutzfeldt-Jakob disease in humans. Over the past
decades, c-BSE's zoonotic potential has been the driving force in establishing
extensive protective measures for animal and human health.
*** In complement to the recent demonstration that
humanized mice are susceptible to scrapie, we report here the first observation
of direct transmission of a natural classical scrapie isolate to a macaque after
a 10-year incubation period. Neuropathologic examination revealed all of the
features of a prion disease: spongiform change, neuronal loss, and accumulation
of PrPres throughout the CNS.
*** This observation strengthens the questioning of
the harmlessness of scrapie to humans, at a time when protective measures for
human and animal health are being dismantled and reduced as c-BSE is considered
controlled and being eradicated.
*** Our results underscore the importance of
precautionary and protective measures and the necessity for long-term
experimental transmission studies to assess the zoonotic potential of other
animal prion strains.
2015
O.05: Transmission of prions to primates after
extended silent incubation periods: Implications for BSE and scrapie risk
assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand,
Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and
Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses,
France
Prion diseases (PD) are the unique
neurodegenerative proteinopathies reputed to be transmissible under field
conditions since decades. The transmission of Bovine Spongiform Encephalopathy
(BSE) to humans evidenced that an animal PD might be zoonotic under appropriate
conditions. Contrarily, in the absence of obvious (epidemiological or
experimental) elements supporting a transmission or genetic predispositions, PD,
like the other proteinopathies, are reputed to occur spontaneously (atpical
animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human
primate models provided the first evidences supporting the transmissibiity of
human prion strains and the zoonotic potential of BSE. Among them, cynomolgus
macaques brought major information for BSE risk assessment for human health
(Chen, 2014), according to their phylogenetic proximity to humans and extended
lifetime. We used this model to assess the zoonotic potential of other animal PD
from bovine, ovine and cervid origins even after very long silent incubation
periods.
*** We recently observed the direct transmission of
a natural classical scrapie isolate to macaque after a 10-year silent incubation
period,
***with features similar to some reported for human
cases of sporadic CJD, albeit requiring fourfold long incubation than BSE.
Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE
and L-type BSE),
***thus questioning the origin of human sporadic
cases. We will present an updated panorama of our different transmission studies
and discuss the implications of such extended incubation periods on risk
assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic
cases***
===============
***our findings suggest that possible transmission
risk of H-type BSE to sheep and human. Bioassay will be required to determine
whether the PMCA products are infectious to these animals.
==============
Tuesday, December 16, 2014
*** Evidence for zoonotic potential of ovine
scrapie prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1
Caroline Lacroux,1, Jean-Yves Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4,
Séverine Lugan,1, Isabelle Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne
Reine,5, Laetitia Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, &
Olivier Andréoletti1, Affiliations Contributions Corresponding author Journal
name: Nature Communications Volume: 5, Article number: 5821 DOI:
doi:10.1038/ncomms6821 Received 07 August 2014 Accepted 10 November 2014
Published 16 December 2014 Article tools Citation Reprints Rights &
permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is
the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic
potential of scrapie prions remains unknown. Mice genetically engineered to
overexpress the human prion protein (tgHu) have emerged as highly relevant
models for gauging the capacity of prions to transmit to humans. These models
can propagate human prions without any apparent transmission barrier and have
been used used to confirm the zoonotic ability of BSE. Here we show that a panel
of sheep scrapie prions transmit to several tgHu mice models with an efficiency
comparable to that of cattle BSE.
***The serial transmission of different scrapie
isolates in these mice led to the propagation of prions that are phenotypically
identical to those causing sporadic CJD (sCJD) in humans.
***These results demonstrate that scrapie prions
have a zoonotic potential and raise new questions about the possible link
between animal and human prions.
Subject terms: Biological sciences• Medical
research At a glance
see more here ;
Monday, May 02, 2016
*** Zoonotic Potential of CWD Prions: An Update
Prion 2016 Tokyo ***
Saturday, April 23, 2016
SCRAPIE WS-01: Prion diseases in animals and
zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl
1933-690X
MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON
CREUTZFELDT JAKOB DISEASE 1978
THE SCRAPIE FILES
CONFIDENTIAL
IN CONFIDENCE
SCJD
Subject: 1978 SCRAPIE IN CONFIDENCE SCJD 1978
SCRAPIE IN CONFIDENCE SCJD
Annex: MEDICAL RESEARCH COUNCIL
IN CONFIDENCE
Circulation Participants MEETING ON THE FEASIBILITY
OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON CREUTZFELDT-JAKOB DISEASE
Minutes of meeting held on Thursday 9 March 1978 at
20 Park Crescent London WIN 4AL Present: Professor J N Walton (Chairman), Dr A M
Adelstein, Professor J R Batchelor, Mr K N Burns (ARC), Professor J A N
Corsellis, Dr T J Crow, Dr R Levy, Professor W B Matthews, Dr J T Stamp,
Professor B E Tomlinson, Professor M P Vessey, Professor P Wildy, Dr A Smithies
(Health Department Observer). Headquarters staff: Dr Katherine levy, Dr Victoria
Harrison, Miss Roberta Withnall. Amlogies for absence: Professor A N Davison, Dr
R H Kimberlin, Dr W A Lishman, Professor C A Mims- 1.
Introduction and background The Chairman opened the
meeting by explaining that its purpose was to advise the Neurosciences Board on
the value and feasibility of carrying out epidemiological studies on
Creutzfeldt—Jakob (C—J) disease; suggestions for work on other aspects of the
disease were not, however, precluded.
***The meeting had been called following the
Agricultural Research Council's (ARC) report of their Advisory Committee on
Scrapie, a document which should be regarded as confidential. One of the main
issues which merited discussion was whether those whose occupation suggested
they might be in contact with scrapie had a higher risk of developing C—J
disease. While fully appreciating that the problem of infectivity was one of
great concern the present meeting was not constituted to discuss this problem
per se. The recently set up ARC Advisory Group on Scrapie would be taking up
this question; it was also of concern to the Health Departments who wished to be
kept informed of developments. Mr Burns reported that the ARC had already had
preliminary discussions on the safety aspects which would be necessary in the
event of C—J work being carried out in their Institute at Compton. Dr Levy
agreed to act as liaison officer between the two Councils and the Health
Departments.
The meeting considered the mortality data provided
by OPCS (CJD 78/2) and that provided by Professor Matthews (paper tabled). The
interpretation of these data was complicated by possibilities of both under and
over reporting. Under-reporting was likely in that G—J disease might:
(a) be undiagnosed, particularly in large mental
hospitals; and
(b) not appear on death certificates either
because the actual cause of death was eg. bronchial pneumonia, or because
reference to dementia (in any form) was excluded to spare the feelings of the
family. Over-reporting might occur because, although the rapidly progressive
form of the disease was readily diagnosed in life, the less dramatic forms were
more difficult. to recognise clinically and could be diagnosed in error (see
below). It was notes: that the OPCS data showed an apparently higher incidence
of the disease in social class I: a possible explanation was that this group was
investigated more carefully. An added difficulty, common to all occupational
data obtained from death certificates alone, was that it was based solely on
information provided by the person registering the death. Professor Vessey drew
attention to the temporal differences between the OPCS data and those provided
by Professor Matthews.
S 803/10 78/3.9/1.1
The meeting then considered the implication of:
a) incompleteness; and
b) inaccuracy of the data. Incompleteness would
matter if it was associated with the factor under study, eg. if only those cases
occurring in certain occupational groups were missing: if accurate incidence,
prevalence or mortality rates were required; and in examining space/time
clustering (see below). Inaccuracy would matter less since the dilution of the
mortality data with diseases other than C—J would merely tend to weaken any
association present.
3. Accuracy of clinical diagnosis: neuropathology
The neuropathologists present explained that it was
now generally considered that there were 3 categories of the disease:
(i) a rapidly progressive form of subacute
spongiform encephalopathy (the Nevin—Jones Syndrome) usually leading to death
within 6—9 months; this is the only form which has been transmitted to animals;
(ii) a variant in which the cerebellum appears to
bear the brunt of the pathology and
(iii) "classical" C—J disease which follows a more
protracted course. Diagnosis is based on the typical EEG picture - which in the
slower forms of the disease may not arise until late in the course of the
illness — and on the characteristic spongiform features seen on
neuropathological examination. The less rapidly progressive forms could be
confused with other forms of dementia or arteriosclerotic disease, Alzheimer's
disease with myoclonus, myoclonic epilepsy, corticostrionigral degeneration,
Pick's disease or motor neurone disease.
While there could be doubt about a diagnosis made
on a biopsy specimen it would be very rare for a neuropathologist to make a
mistake at autopsy. However, in less specialised hands there was a very
significant chance that cases could be missed.
Dr Stamp pointed out that in scrapie no spongiform
encephalopathy was detected and that in many cases confirmed by transmission
experiments no neuropathological abnormality could be found.
4. Specialist care of C—J patients
The question of whether C—J patients Were in the
main looked after by neurologists or by psychiatrists was discussed. The View of
the meeting was that most patients were seen by neurologists, but that there
might be an unknown, even considerable number of cases (presumably of the more
chronic form) in major mental hospitals.
5. Frequency of biopsies and post
mortems
Until a few years ago a biopsy was carried out in
the majority of suspected case. referred to major centres: the situation had now
changed and biopsies were performed less often, partly because diagnosis could
be based on the clinical and EEG picture .
Dr Adelstein pointed out that 50% of C-J deaths
recorded in the OPCS figures had come to post mortem, during the six year period
up to 1976. The figures may be dropping for both biopsies and post mortems not
only because they are thought unnecessary in view of the improvement in other
methods of diagnosis but also because of both the shortage of neuropathologists
and their awareness of the possible infectivity of the agent.*
*‘There is no evidence to suggest that there is
only one agent; there may well be several. But for the purposes of this record
the term 'agent‘ is used throughout
-2-
78/3.9/1.2
6. Gajdusek's evidence
The Chairman invited Professor Wildy to speak to
his paper (CJD 78/3) on the hazards of the C—J agent and other possible agents
to hospital staff and pathologists. Professor Wildy emphasised that in general
Gajdusek's evidence should be treated with great caution since his hypothesis
was based on the presumed analogy with the scrapie agent (or agents). Hard data
were not available about the C—J agent itself. It was resistant to many physical
and chemical treatments: there was a need to establish a reliable means of
sterilisation, as Gajdusek's published data on autoclaving was open to
criticism. It is likely that, as with scrapie, some C—J strains would prove to
be much more resistant than others.
7. Risk of infection
The two reports of iatrogenic man—to—man
transmission of C—J disease have involved corneal grafting and neurosurgery
respectively. While the implications for sterilisation of instruments etc. had
been widely discussed in the literature the additional point was made that
corneae for grafts were often obtained from old peoples' homes: caution should
therefore be exercised in using tissue from this source.
Overall there was no indication either from OPCS
data or from anecdotal evidence that pathologists, mortuary attendants or
research workers had ever developed C—J disease. On available evidence it was,
however, clear that contact between C—J infected material and lacerated skin
must be avoided. Nor was there evidence that anyone working with scrapie
diseased animals (veterinary surgeons, slaughter house workers, butchers,
shepherds and shepherdesses or research workers) have developed the disease. It
was nonetheless worth undertaking retrospective epidemiological studies if only
to provide reassurance that there was no excess mortality from C—J disease in
these and other professional groups — including neurosurgeons, neurologists,
undertakers and embalmers. It should however be borne in mind that some of the
latter categories may be under—represented, occupation euphemisms having been
used on the death certificates.
8. Prevalence and mode of infectivity of C—J agent
While the prevalence and mode of infectivity of the
C—J agent are unknown it would be difficult to account for the world wide
distribution of the disease unless the agent were common. If prevalence were low
it would be difficult to postulate how the agent would replicate. This suggested
that one might be dealing with a transferred ubiquitous and relatively banal
agent — the analogy being measles and SSPE. It was agreed that while this was
pure speculation, the possibility could not be ruled out. Dr Crow pointed out
that the age incidence of C—J disease would not suggest that it was due to an
infective agent. In this connection Dr Stamp reported that both lateral and
vertical transmission occur in scrapie: genetic factors determine the incubation
period and so—called "resistant" sheep may die before there was time for them to
show clinical signs of the disease. It was not known how scrapie was
transmitted, though it can exist outside its host for an indefinite period.
However the usefulness of the scrapie analogy is uncertain. Dr Stamp emphasised
that in scrapie the innoculated and natural disease are two very different
conditions.
-3-
78/3.9/1.3
9. Clusters, familial incidence and conjugal C—J
disease
Geographical and temporal clustering have been
reported; these however had been small and difficult to evaluate statistically.
In Professor Tomlinson's experience all cases of C—J were referrals from the
better known neurological or psychiatric centres, implying that clustering could
be an artefact. Professor Vessey offered with colleagues to examine the data
provided by OPCS and Professor Matthews to see if these revealed any evidence of
clustering. Different incubation periods could be built in and contact between
cases could be looked for - the complex statistics had been worked out for
Hodgkin's disease. The technique involved was nevertheless a crude one. Familial
cases had been reported but the numbers involved were too low to be significant.
Occurrence of the disease in cousins (2 in the UK, and 2 in the USA) and two
cases of conjugal C—J disease were briefly mentioned.
10. Genetic screening, including HLA status
Professor Batchelor confirmed that the HLA status
of C—J patients had not been investigated. Dr Stamp reported that there was no
association with mouse histocompatibility antigens in scrapie; this had not been
investigated in sheep. Professor Batchelor said that typing would not be
difficult: 30—60 patients would be required depending on the rarity of the
antigen. General genetic screening might also be worthwhile; he suggested that
the Galton laboratories might be approached with a view to studying various
isoenzymes in such cases. Samples of serum should be stored for future study of
antibody profiles.
11 . General conclusions
(i) The meeting could only confirm that the
epidemiology of C—J disease is poorly understood.
(ii) The existing mortality data were likely to be
inaccurate; so far as they went no occupational association with the disease
could be demonstrated. The prevalence and mode of infectivity of the agent were
unknown and clusters reported had been small and difficult to evaluate
statistically.
(iii) Gajdusek‘s evidence was open to criticism:
however, while his assertions are unsupported by hard data, his claims might
nonetheless have substance.
(iv) While the-analogy with scrapie was interesting
and the scrapie and C—J agents displayed similarities in behaviour and
character, there was no proof that the scrapie agent was in any way associated
with C-J disease.
12. Possible action
The following suggestions were made about action
which might be taken:
(1) OPCS might be asked to provide data on the
occupations listed for all deaths due to dementia and the other diseases with
which C—J might be confused recorded within, say, the last 3 years.
(ii) OPCS might be asked to collect prospectively
notifications of all deaths from C—J disease, the dementias and other diseases
with which it might be confused.
(iii) The data provided by OPCS might be correlated
with that obtained by Professor Matthews (confirming diagnoses from case notes
etc. in at least a sample of these cases) to see how many of the same C—J
patients were involved. These data should be analysed for evidence of
clustering.
-4- 78/3.9/1.4
(iv) Data provided by the Doll/Hill study of
34,000 doctors on the medical register in 1953 might (with the authors'
agreement) be utilised to see if any excess death rates from C—J-disease, the
dementias or other diseases with which it may be confused, could be identified
among certain specialist groups.
(v) HLA status of C—J patients should be
determined.
(vi) General genetic screening might be undertaken
of patients with C—J disease.
(vii) Samples of serum from C—J patients should be
stored for future study of antibody profiles.
(viii) Although technically outside their remit the
meeting recommended that good work should be encouraged on the isolation,
characterisation, distribution in the body, routes of infection and methods of
destruction of the C—J agent.
The Chairman closed the meeting by thanking the
participants for attending and for their help in reaching these
conclusions.
78/3.9/1.5
BE SURE TO SEE THIS NEXT ONE WITH
FIGURES...TSS
STUDIES ON CREUTZFELDT-JAKOB DISEASE
i enclose a
list of ICD categories showing the numbers of deaths attributed to each (as
underlying cause) in England and Hales in 1975. ICD NO...Number of Certificates
examined xxxxx...18...15 mentioned C-J xxxxx...122...1 mentioned C-J with
dimentia, 24 mentioned Alzheimer’s disease, 1 mentioned Pick’s disease.
xxxxx...22...4 mentioned Myoclonic epilepsy xxxxx...384...none mentioned
Corticostrionigral degeneration xxxxx...2...none mentioned Corticostrionigral
degeneration
snip...
1979 SILENCE ON CJD AND SCRAPIE 1980 SILENCE ON CJD
AND SCRAPIE *** 1981 NOVEMBER
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
why do we not want to do TSE transmission studies
on chimpanzees $ IN CONFIDENCE TRANSMISSION TO CHIMPANZEES snip... 5. A positive
result from a chimpanzee challenged severely 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
full text ;
RB3.20 IN CONFIDENCE TRANSMISSION TO
CHIMPANZEE
1. Kuru and CJD have been successfully transmitted
to chimpanzees but scrapie and TME have not.
2. We cannot say that scrapie will not transmit to
chimpanzees. There are several scrapie strains and I am not aware that all have
been tried (that would have to be from mouse passaged material). Nor has a wide
enough range of field isolates subsequently strain typed in mice been inoculated
by the appropriate routes (i/c, i/p and i v);
3. I believe the proposed experiment to determine
transmissibility, if conducted, would only show the susceptibility or resistance
of the chimpanzee to infection/disease by the routes used and the result could
not be interpreted for the predictability of the susceptibility for man.
Proposals for prolonged oral exposure of chimpanzees to milk from cattle were
suggested a long while ago and rejected.
4. In view of Dr Gibbs‘ probable use of Chimpazees
Mr Wells‘ comments (enclosed) are pertinent. I have yet to receive a direct
communication from Dr Schellekers but before any collaboration or provision of
material we should identify the Gibbs' proposals and objectives.
5. A positive result from a chimpanzee challenged
severely 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.
*** A negative result would take a lifetime to
determine but that would be a shorter period than might be available for human
exposure and it would still not answer the question regarding mans'
susceptibility.
*** In the meantime no doubt the negativity would
be used defensively.
*** It would however be counterproductive if the
experiment finally became positive- We may learn more about public reactions
following next Monday‘s meeting. CVO (+ Mr. Wells’ comments) Dr. T W A Little
Dr. B J Shreeve R Bradley September 1990 90/9.23/1/1
Tuesday, May 31, 2016
Priority Interim Position Paper PROTECTING THE FOOD
CHAIN FROM PRIONS Perspectives
TUESDAY, AUGUST 9, 2016
Concurrence with OIE Risk Designations for Bovine
Spongiform Encephalopathy [Docket No. APHIS-2015-0055]
BILLING CODE: 3410-34-P DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service
Monday, June 20, 2016
Specified Risk Materials SRMs BSE TSE Prion
Program
Tuesday, April 19, 2016
Docket No. FDA-2013-N-0764 for Animal Feed
Regulatory Program Standards Singeltary Comment Submission
Wednesday, April 25, 2012
4th MAD COW DISEASE U.S.A. CALIFORNIA ATYPICAL
L-TYPE BSE 2012
Saturday, August 4, 2012
Final Feed Investigation Summary - California BSE
Case - July 2012
SUMMARY REPORT CALIFORNIA BOVINE SPONGIFORM
ENCEPHALOPATHY CASE INVESTIGATION JULY 2012
Summary Report BSE 2012
Executive Summary
Saturday, August 4, 2012
Update from APHIS Regarding Release of the Final
Report on the BSE Epidemiological Investigation
Qualitative Analysis of BSE Risk Factors in the
United States February 13, 2000 at 3:37 pm PST (BSE red book)
Tuesday, June 07, 2016
Comparison of two US sheep scrapie isolates
supports identification as separate strains
Research Project: TRANSMISSION, DIFFERENTIATION,
AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Thursday, June 09, 2016
Scrapie Field Trial Experiments Mission, Texas, The
Moore Air Force Base Scrapie TSE Prion Experiment 1964
How Did CWD Get Way Down In Medina County,
Texas?
2016 PRION CONFERENCE TOKYO
*** NIH awards $11 million to UTHealth researchers
to study deadly CWD prion diseases Claudio Soto, Ph.D. *** Public Release:
29-Jun-2016
I urge everyone to watch this video closely...terry
*** you can see video here and interview with Jeff's Mom, and scientist telling
you to test everything and potential risk factors for humans ***
Sunday, July 24, 2016
Chronic Wasting Disease Prions in Elk Antler Velvet
and Marketing of this Product in Nutritional Supplements for Humans? Research
Project: TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES: THE ROLE OF GENETICS, STRAIN
VARIATION, AND ENVIRONMENTAL CONTAMINATION IN DISEASE CONTROL
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT
DECEMBER 14, 2015
Thursday, April 14, 2016
Arizona 22 year old diagnosed with Creutzfeldt
Jakob Disease CJD
Tuesday, July 12, 2016
Chronic Wasting Disease CWD, Scrapie, Bovine
Spongiform Encephalopathy BSE, TSE, Prion Zoonosis Science History see history
of NIH may destroy human brain collection
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of
gss, ffi, familial type prion disease, what it ???
Monday, November 3, 2014
*** The prion protein protease sensitivity,
stability and seeding activity in variably protease sensitive prionopathy brain
tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob
disease
*** The discovery of previously unrecognized prion
diseases in both humans and animals (i.e., Nor98 in small ruminants)
demonstrates that the range of prion diseases might be wider than expected and
raises crucial questions about the epidemiology and strain properties of these
new forms. We are investigating this latter issue by molecular and biological
comparison of VPSPr, GSS and Nor98.
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS
TRANSMISSIBLE ...price of prion poker goes up again $
OR-10: Variably protease-sensitive prionopathy is
transmissible in bank voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1
Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1
Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto
Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche,
Università di Bologna; Bologna, Italy; 3Case Western Reserve University;
Cleveland, OH USA
Background. Variably protease-sensitive prionopathy
(VPSPr) is a recently described “sporadic”neurodegenerative disease involving
prion protein aggregation, which has clinical similarities with non-Alzheimer
dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have
been reported in Europe and USA, of which 19 cases were homozygous for valine at
codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive
feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with
proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like
electrophoretic pattern similar to that described in GSS cases. The clinical and
pathological features of VPSPr raised the question of the correct classification
of VPSPr among prion diseases or other forms of neurodegenerative disorders.
Here we report preliminary data on the transmissibility and pathological
features of VPSPr cases in bank voles.
Materials and Methods. Seven VPSPr cases were
inoculated in two genetic lines of bank voles, carrying either methionine or
isoleucine at codon 109 of the prion protein (named BvM109 and BvI109,
respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3
were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain
pathological assessment and western blot for PK-resistant PrPSc (PrPres) with
mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM)
gave positive transmission in BvM109. Overall, 3 voles were positive with
survival time between 290 and 588 d post inoculation (d.p.i.). All positive
voles accumulated PrPres in the form of the typical PrP27–30, which was
indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1
cases.
In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed
positive transmission until now. Overall, 5 voles were positive with survival
time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all
BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low
molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and
12B2, while being negative with SAF32 and SAF84, suggesting that they are
cleaved at both the C-terminus and the N-terminus. Second passages are in
progress from these first successful transmissions.
Conclusions. Preliminary results from transmission
studies in bank voles strongly support the notion that VPSPr is a transmissible
prion disease. Interestingly, VPSPr undergoes divergent evolution in the two
genetic lines of voles, with sCJD-like features in BvM109 and GSS-like
properties in BvI109.
The discovery of previously unrecognized prion
diseases in both humans and animals (i.e., Nor98 in small ruminants)
demonstrates that the range of prion diseases might be wider than expected and
raises crucial questions about the epidemiology and strain properties of these
new forms. We are investigating this latter issue by molecular and biological
comparison of VPSPr, GSS and Nor98.
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new
sporadic disease of the prion protein or just more Prionbaloney ?
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS
TRANSMISSIBLE ...price of prion poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE
PRIONOPATHY IS TRANSMISSIBLE IN BANK VOLES Nonno
Monday, February 24, 2014
Sporadic Fatal Insomnia in an
Adolescent
To the best of our knowledge, this is the first
case of CJD combined with Lewy body disease and argirophilic grain disease.
Furthermore, we believe this case is an extremely rare combination of
MM2-cortical-type and MM2-thalamic-type sporadic CJD (sCJD), which explains the
broad spectrum of MM2-type sCJD findings and symptoms. Moreover, histological
features of possible Alzheimer's disease were also reported.
Wednesday, September 03, 2014
Coexistence of mixed phenotype Creutzfeldt-Jakob
disease, Lewy body disease and argyrophilic grain disease plus histological
features of possible Alzheimer's disease: A multi-protein disorder in an autopsy
case
Sunday, August 09, 2009
CJD...Straight talk with...James
Ironside...and...Terry Singeltary... 2009
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary
1999 – 2009
RE: re-Human Prion Diseases in the United States
Singeltary PLoS part 2 flounder replied to flounder on 02 Jan 2010 at 21:26 GMT
No competing interests declared.
see full text ;
Diagnosis and Reporting of Creutzfeldt-Jakob
Disease Singeltary, Sr et al.
JAMA.2001; 285: 733-734. Vol. 285 No. 6, February
14, 2001 JAMA Diagnosis and Reporting of Creutzfeldt-Jakob Disease To the
Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the
annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable
since 1985. These estimates, however, are based only on reported cases, and do
not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis
alone would drastically change these figures. An unknown number of persons with
a diagnosis of Alzheimer disease in fact may have CJD, although only a small
number of these patients receive the postmortem examination necessary to make
this diagnosis. Furthermore, only a few states have made CJD reportable. Human
and animal transmissible spongiform encephalopathies should be reportable
nationwide and internationally. Terry S. Singeltary, Sr Bacliff, Tex 1. Gibbons
RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United
States: 1979-1998. JAMA. 2000;284:2322-2323.
26 March 2003 Terry S. Singeltary, retired
(medically) CJD WATCH I lost my mother to hvCJD (Heidenhain Variant CJD). I
would like to comment on the CDC's attempts to monitor the occurrence of
emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate phenotype
that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD.
However, CJD and all human TSEs are not reportable nationally. CJD and all human
TSEs must be made reportable in every state and internationally. I hope that the
CDC does not continue to expect us to still believe that the 85%+ of all CJD
cases which are sporadic are all spontaneous, without route/source. We have many
TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral
inoculation. With the known incubation periods in other TSEs, oral transmission
studies of CWD may take much longer. Every victim/family of CJD/TSEs should be
asked about route and source of this agent. To prolong this will only spread the
agent and needlessly expose others. In light of the findings of Asante and
Collinge et al, there should be drastic measures to safeguard the medical and
surgical arena from sporadic CJDs and all human TSEs. I only ponder how many
sporadic CJDs in the USA are type 2 PrPSc?
Sent: Monday, January 08,2001 3:03 PM
FDA CJD BSE TSE Prion Scientific Advisors and
Consultants Staff January 2001 Meeting Singeltary Submission 2001 FDA CJD TSE
Prion Singeltary Submission
2 January 2000 British Medical Journal U.S.
Scientist should be concerned with a CJD epidemic in the U.S., as
well
15 November 1999 British Medical Journal vCJD in
the USA * BSE in U.S.
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
1:54 PM
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