Variant CJD: 18 years of research and surveillance
Abigail B Diack, 1, † Mark W Head, 2, † Sandra McCutcheon, 1 Aileen Boyle,
1 Richard Knight, 2 James W Ironside, 2 Jean C Manson, 1, †, * Robert G Will 2,
† Abstract It is now 18 years since the first identification of a case of vCJD
in the UK. Since that time there has been much speculation over how vCJD might
impact on human health. To date there have been 177 cases reports in the UK and
a further 51 cases worldwide in 11 different countries. Since establishing that
BSE and vCJD are of the same strain of agent, we have also shown that there is
broad similarity between UK and non-UK vCJD cases on first passage to mice.
Transgenic mouse studies have indicated that all codon 129 genotypes are
susceptible to vCJD and that genotype may influence whether disease appears in a
clinical or asymptomatic form, supported by the appearance of the first case of
potential asymptomatic vCJD infection in a PRNP 129MV patient. Following
evidence of blood transfusion as a route of transmission, we have ascertained
that all blood components and leucoreduced blood, in a sheep model of vCJD have
the ability to transmit disease. Importantly, we recently established that a
PRNP 129MV patient blood recipient with an asymptomatic infection with limited
PrPSc deposition in the spleen could readily transmit disease into mice,
demonstrating the potential for peripheral infection in the absence of clinical
disease. This, along with the recent appendix survey which identified 16
positive appendices in a study of 32 441 cases, underlines the importance of
continued CJD surveillance and maintaining control measures already in place to
protect human health.
snip...
Emergence of novel strains
Identification of novel strains involves veterinary and medical vigilance,
but it also requires a proper and full characterization of known prion agents.
While the deployment of wild-type mouse panels, transgenic mice, and non-human
primates all rapidly concluded that vCJD was a novel human prion strain related
to BSE (see above), determining how many distinct human prion strains there are
has proved surprisingly difficult, especially for sCJD. Transmission studies in
humanised transgenic mice and non-human primates point to 4 major groups within
sporadic, iatrogenic CJD, Kuru, and some genetic CJD cases, termed M1, V1, M2,
and V2.21,106 Sporadic fatal insomnia and fatal familial insomnia (FFI) together
may represent a sixth strain107 and 2 further transmissible phenotypes can be
derived from GSS disease: one involving a transmissible amyloid phenotype, the
other a fully transmissible spongiform encephalopathy.108,109 The transmission
properties of PrP cerebral amyloid angiopathy and Variable Protease Sensitive
Prionopathy (VPSPr) remain to be reported. The relationship between human
disease phenotypes, agent strain, and prion biochemistry is further complicated
by the now widely recognized phenomenon of distinct PrPres type co-occurrence in
the sCJD, vCJD and VPSPr brain.14,23,110
8
Surveillance for BSE in cattle, sheep, and goats has identified new (or
newly discovered) animal prion diseases including atypical scrapie in sheep and
so called H- and L-type BSE in cattle. These along with chronic wasting disease
(CWD) in deer and elk represent a potential zoonotic risk to human health that
is hard to quantify. While Wilson et al.111 have shown no transmission of CWD,
BASE, H-type BSE, and atypical scrapie to mice expressing wild-type levels of
human PrP, Kong et al.112 demonstrated transmission of BASE to an alternative
line of mice expressing wild-type levels of human PrP. In contrast, Beringue et
al.113 showed transmission of BASE to mice overexpressing human PrP but no
evidence of H-type BSE transmission, furthermore no evidence of CWD transmission
to overexpressing mice has been identified.114,115 This difference in
transmission results may be due to different genetic backgrounds or differences
in PrP expression levels between the different mouse lines. An alternative to
modeling the species barrier is the cell-free conversion assay which points to
CWD as the animal prion disease with the greatest zoonotic potential, after (and
very much less than) BSE.116
6
Surveillance
Continued surveillance for long-term effects of BSE exposure in the UK
human population appears necessary for the foreseeable future in order to
discount possible second wave epidemics that might depend on genetic
susceptibility, subclinical infection, and secondary transmission or disease in
defined at risk patient groups such as hemophiliacs or patient groups in which
full ascertainment is difficult, such as the elderly.
However, an additional concern is associated with idiopathic human prion
disease. Sporadic CJD is not a uniform condition and the phenotype is clearly
influenced by the codon 129 genotype of the patient and the prion protein type
that accumulates in their brain. The etiological basis of the condition might be
presumed to be spontaneously occurring, but this is not known with certainty in
general, or in individual specific cases. Neither are the molecular mechanisms
of spontaneous conversion of the prion protein to its pathogenic form well
understood or easily investigated. Additionally, surveillance identifies
apparently sporadic cases of human prion disease that do not fit well into
currently accepted classification systems. This is exemplified by the recent
identification of a new human prion disease (VPSPr by Gambetti et al.,117) and
its prospective and retrospective identification in other countries
subsequently.16,110 The true prevalence, the relationship to sCJD and the risk
to public health of VPSPr are yet to be determined. 3
Conclusions
Since the identification of vCJD we have made progress in identifying
routes of infection, controlling further infection, producing models of disease,
developing decontamination procedures, and understanding susceptibility to
disease. The vCJD epidemic in the UK now appears to be in decline and it appears
that the control measures in food production and blood supplies have prevented
further vCJD cases arising through dietary/infected blood exposure. Despite
this, there are still ongoing concerns over cases of vCJD arising in countries
where little or no exposure to UK meat products have occurred, the presence of
subclinical vCJD in the UK population with the possibility of further
human-to-human transmission and the identification of new strains of human prion
disease. These scenarios necessitate ongoing studies in understanding
transmission properties, disease diagnosis, and therapeutics. The identification
of novel human prion diseases and the current estimates of subclinical vCJD
infections show the importance of continued CJD surveillance and maintaining
control measures already in place to protect human health.
*** 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.
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
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)
Monday, January 14, 2013
Gambetti et al USA Prion Unit change another highly suspect USA mad cow
victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes
along with this BSe
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
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.
SOURCE PRION2012
I believe it was Gambetti et al that coined this term sporadic FFI, from
some conspicuous sub-type of sporadic CJD possibly?
seems they could not tie it to a true FFI by diagnostic standards to date,
so it was then termed a sFFI, confusing matters even worse. ...
A subtype of sporadic prion disease mimicking fatal familial insomnia
THIS seems to raise more questions than answers, confusing the TSEs even
worse.
WHAT is sporadic CJD, and how many sub-types and atypical strains,
phenotypes etc. will there be, arising from nothing. a spontaneous happening of
sorts???
i think not. ...tss
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein
and heterozygosity methionine/valine at codon 129: Case report
snip...
Genetic findings
No mutations were found in the open reading frame after sequencing the
prion protein gene (PRNP). A heterozygosis methionine valine (MV) was observed
in codon 129.
snip...
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease
update July 10, 2008
Although several subjects had family histories of dementia, no mutations
were found in the PrP gene open reading frame.
Thursday, July 10, 2008
A New Prionopathy update July 10, 2008
***+++***
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease
update July 10, 2008 Friday, June 20, 2008
Here we go folks. AS predicted. THIS JUST OUT !
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein or just more PRIONBALONEY ?
snip...see full text ;
O.K. let's compare some recent cases of this prionpathy in other countries
besides Gambetti's first 10 recently, that he claims is a spontaneous event,
from a genetic disorder, that is not genetic, but sporadic, that is related to
no animal TSE in North America, or the world. ...
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein
and heterozygosity methionine/valine at codon 129: Case report
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
====================================
The familial mutations, Gajdusek proposed, lowered the barrier to such
accidental conversion. "Thus," he wrote in 1996, "with these mutations, this
ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's
qualification still remained to be refuted: the mutations might simply allow
easier entry to a lurking virus. ...page 202 Deadly Feast
===================================
something to think about for sure.
but i interpret this as (1st not the gold standard, just my opinion;-), as
because of certain gene mutations, one or a family, would be more susceptible to
the many different strains of TSE, and the many different proven routes and
sources, (which will cause different symptoms, different incubation periods from
onset of clinical symptoms to death, different parts of the brain infected,
etc.). in other words, it's NOT the gene mutation that CAUSES the disease, but
the fact that it makes you more SUSCEPTIBLE, to the TSEs from the surrounding
environment, and PLUS accumulation, i think this plays a critical role. maybe
there is a one dose scenario, but i think there is more of the 'accumulators'
that go clinical, than the 'one dose'. and what is the threshold to sub-clinical
to clinical ?
anyway, just pondering out loud here.
also, for anyone interested, there are some studies with links to follow
here ;
Thursday, June 21, 2012
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
Friday, May 9, 2014
Distinct Transmissibility Features of TSE Sources Derived from Ruminant
Prion Diseases by the Oral Route in a Transgenic Mouse Model (TgOvPrP4)
Overexpressing the Ovine Prion Protein
*** 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.”
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 BSE infected
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.
*** 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. ***
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. ***
see page 176 of 201 pages...tss
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics
of BSE in Canada Singeltary reply ;
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)
UPDATE
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.
please see below from PRION2013 ;
*** This study imply the possibility that the novel BSE prions with high
virulence in cattle will be emerged during intraspecies transmission.
AD.56: The emergence of novel BSE prions by serial passages of H-type BSE
in bovinized mice
Kentaro Masujin, Naoko Tabeta, Ritsuko Miwa, Kohtaro Miyazawa, Hiroyuki
Okada, Shirou Mohri and Takashi Yokoyama National Institute of Animal Health;
Tsukuba, Japan
H-type bovine spongiform encephalopathy (BSE) is an atypical form of BSE,
and has been detected in several European countries, and North America.
Transmission studies of H-type BSE led to the emergence of the classical BSE
(C-BSE) phenotypes during passages in inbred wild type and bovinized
PrP-overexpressing transgenic mice. In this study, we conducted serial passages
of Canadian H-type BSE isolate in bovinized PrP-overexpressing transgenic mice
(TgBoPrP). H-type BSE isolate was transmitted to TgBoPrP with incubation periods
of 320 ± 12.2 d at primary passage. The incubation period of 2nd and 3rd passage
were constant (~= 220 d), no clear differences were observed in their biological
and biochemical properties. However, at the forth passage, 2 different BSE
phenotypes were confirmed; one is shorter survival times (109 ± 4 d) and the
other is longer survival times. TgBoPrP mice with longer incubation period
showed the H-type phenotype of PrPsc profile and pathology. However, those of
shorter incubation period were different phenotypes from previously existed BSE
prions (C-BSE, L-type BSE, and H-type BSE).
*** This study imply the possibility that the novel BSE prions with high
virulence in cattle will be emerged during intraspecies transmission.
www.landesbioscience.com
please see ;
Thursday, August 15, 2013
The emergence of novel BSE prions by serial passages of H-type BSE in
bovinized mice
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.
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)
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
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.
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)
Sunday, December 15, 2013
FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED
VIOLATIONS OFFICIAL ACTION INDICATED OIA UPDATE DECEMBER 2013 UPDATE
P04.27
Experimental BSE Infection of Non-human Primates: Efficacy of the Oral
Route
Holznagel, E1; Yutzy, B1; Deslys, J-P2; Lasmézas, C2; Pocchiari, M3;
Ingrosso, L3; Bierke, P4; Schulz-Schaeffer, W5; Motzkus, D6; Hunsmann, G6;
Löwer, J1 1Paul-Ehrlich-Institut, Germany; 2Commissariat à l´Energie Atomique,
France; 3Instituto Superiore di Sanità, Italy; 4Swedish Institute for Infectious
Disease control, Sweden; 5Georg August University, Germany; 6German Primate
Center, Germany
Background:
In 2001, a study was initiated in primates to assess the risk for humans to
contract BSE through contaminated food. For this purpose, BSE brain was titrated
in cynomolgus monkeys.
Aims:
The primary objective is the determination of the minimal infectious dose
(MID50) for oral exposure to BSE in a simian model, and, by in doing this, to
assess the risk for humans. Secondly, we aimed at examining the course of the
disease to identify possible biomarkers.
Methods:
Groups with six monkeys each were orally dosed with lowering amounts of BSE
brain: 16g, 5g, 0.5g, 0.05g, and 0.005g. In a second titration study, animals
were intracerebrally (i.c.) dosed (50, 5, 0.5, 0.05, and 0.005 mg).
Results:
In an ongoing study, a considerable number of high-dosed macaques already
developed simian vCJD upon oral or intracerebral exposure or are at the onset of
the clinical phase. However, there are differences in the clinical course
between orally and intracerebrally infected animals that may influence the
detection of biomarkers.
Conclusions:
Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route
using less than 5 g BSE brain homogenate. The difference in the incubation
period between 5 g oral and 5 mg i.c. is only 1 year (5 years versus 4 years).
However, there are rapid progressors among orally dosed monkeys that develop
simian v CJD as fast as intracerebrally inoculated animals.
The work referenced was performed in partial fulfillment of the study “BSE
in primates“ supported by the EU (QLK1-2002-01096).
Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route
using less than 5 g BSE brain homogenate.
look at the table and you'll see that as little as 1 mg (or 0.001 gm)
caused 7% (1 of 14) of the cows to come down with BSE;
Risk of oral infection with bovine spongiform encephalopathy agent in
primates
Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog,
Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie
Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe
Deslys Summary The uncertain extent of human exposure to bovine spongiform
encephalopathy (BSE)--which can lead to variant Creutzfeldt-Jakob disease
(vCJD)--is compounded by incomplete knowledge about the efficiency of oral
infection and the magnitude of any bovine-to-human biological barrier to
transmission. We therefore investigated oral transmission of BSE to non-human
primates. We gave two macaques a 5 g oral dose of brain homogenate from a
BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months
after exposure, whereas the other remained free of disease at 76 months. On the
basis of these findings and data from other studies, we made a preliminary
estimate of the food exposure risk for man, which provides additional assurance
that existing public health measures can prevent transmission of BSE to man.
snip...
BSE bovine brain inoculum
100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg
Primate (oral route)* 1/2 (50%)
Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%)
1/15 (7%)
RIII mice (ic ip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)
PrPres biochemical detection
The comparison is made on the basis of calibration of the bovine inoculum
used in our study with primates against a bovine brain inoculum with a similar
PrPres concentration that was
inoculated into mice and cattle.8 *Data are number of animals
positive/number of animals surviving at the time of clinical onset of disease in
the first positive animal (%). The accuracy of
bioassays is generally judged to be about plus or minus 1 log. ic
ip=intracerebral and intraperitoneal.
Table 1: Comparison of transmission rates in primates and cattle infected
orally with similar BSE brain inocula
Published online January 27, 2005
Calves were challenged by mouth with homogenised brain from confirmed cases
of BSE. Some received 300g (3 doses of 100g), some 100g, 10g or 1g. They were
then left to develop BSE, but were not subjected to the normal stresses that
they might have encountered in a dairy herd. Animals in all four groups
developed BSE. There has been a considerable spread of incubation period in some
of the groups, but it appears as if those in the 1 and 10g challenge groups most
closely fit the picture of incubation periods seen in the epidemic. Experiments
in progress indicate that oral infection can occur in some animals with doses as
low as 0.01g and 0.001g. .........
http://www.defra.gov.uk/animalh/bse/science-research/pathog.html#dose
It is clear that the designing scientists must also have shared Mr
Bradley's surprise at the results because all the dose levels right down to 1
gram triggered infection.
6. It also appears to me that Mr Bradley's answer (that it would take less
than say 100 grams) was probably given with the benefit of hindsight;
particularly if one considers that later in the same answer Mr Bradley expresses
his surprise that it could take as little of 1 gram of brain to cause BSE by the
oral route within the same species. This information did not become available
until the "attack rate" experiment had been completed in 1995/96. This was a
titration experiment designed to ascertain the infective dose. A range of
dosages was used to ensure that the actual result was within both a lower and an
upper limit within the study and the designing scientists would not have
expected all the dose levels to trigger infection. The dose ranges chosen by the
most informed scientists at that time ranged from 1 gram to three times one
hundred grams. It is clear that the designing scientists must have also shared
Mr Bradley's surprise at the results because all the dose levels right down to 1
gram triggered infection.
2012
***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...
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
Saturday, December 15, 2012
Bovine spongiform encephalopathy: the effect of oral exposure dose on
attack rate and incubation period in cattle -- an update 5 December 2012
Friday, May 9, 2014
Distinct Transmissibility Features of TSE Sources Derived from Ruminant
Prion Diseases by the Oral Route in a Transgenic Mouse Model (TgOvPrP4)
Overexpressing the Ovine Prion Protein
Distribution of Peripheral PrPSc in Sheep with Naturally Acquired Scrapie
Research Article
Sunday, May 18, 2014
*** Chronic Wasting Disease CWD TSE PRION DISEASE and the transmission to
other species
Thursday, April 17, 2014
Novant: Three more may have been exposed to disease CJD
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
Subject: Re: Hello Dr. Gibbs...........
Date: Wed, 29 Nov 2000 14:14:18 –0500
From: "Clarence J. Gibbs, Jr., Ph.D."
To: "Terry S. Singeltary Sr." References:
<3a254430 .9fb97284="" wt.net="">
Hi Terry:
326 E Stret N.E., Washington, D. C. 20002.
Better shrimp and oysters than cards!!!!
Have a happy holiday and thanks for all the information you bring to the
screen.
Joe Gibbs ==========
Tuesday, August 18, 2009
* BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009
CJD QUESTIONNAIRE USA
CJD and Baby foods (the great debate 1999)
Subject: Re: Girl, 13, shows CJD symptoms.
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
Date: Wed, 24 Nov 1999 11:35:44 -0600 Content-Type: text/plain
Parts/Attachments: text/plain (67 lines)
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
Sunday, May 18, 2008
BSE Inquiry DRAFT FACTUAL ACCOUNTS DFAs
Monday, May 19, 2008
*** SPORADIC CJD IN FARMERS, FARMERS WIVES, FROM FARMS WITH BSE HERD AND
ABATTOIRS ***
Saturday, April 19, 2014
*** Exploring the zoonotic potential of animal prion diseases: In vivo and
in vitro approaches ***
*** These results would seem to suggest that CWD does indeed have zoonotic
potential, at least as judged by the compatibility of CWD prions and their human
PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests
that if zoonotic CWD occurred, it would most likely effect those of the PRNP
codon 129-MM genotype and that the PrPres type would be similar to that found in
the most common subtype of sCJD (MM1).
Friday, April 25, 2014
Accuracy of administrative diagnostic data for pathologically confirmed
cases of Creutzfeldt-Jakob disease in Massachusetts, 2000-2008
Article in Press
CANADA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic
CJD’s). ...tss
PLEASE NOTE, type determination pending Creutzfeldt Jakob Disease (tdpCJD)
in Canada is also on a steady increase.
please see ;
> 3. Final classification of 50 cases from 2009, 2010, 2011 and 2012 is
pending.
CJD Deaths Reported by CJDSS1, 1994-20122
CJD Deaths Reported by CJDSS1, 1994-20122
As of May 31, 2012
SEE DECEMBER 2012 CANADA
USA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic
CJD’s). ...tss
National Prion Disease Pathology Surveillance Center
Cases Examined1
(May 18, 2012)
5 Includes 14 cases in which the diagnosis is pending, and 18 inconclusive
cases;
6 Includes 17 (16 from 2012) cases with type determination pending in which
the diagnosis of vCJD has been excluded. The Sporadic cases include 16 cases of
sporadic Fatal Insomnia (sFI) and 42 cases of Variably Protease-Sensitive
Prionopathy (VPSPr) and 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
Rev 5/18/2012
> 6 Includes
> 17 (16 from 2012) cases with type determination pending in which the
diagnosis of vCJD has been excluded.
> The Sporadic cases include 16 cases of sporadic Fatal Insomnia (sFI)
and 42 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 2118 cases
of sporadic Creutzfeldt-Jakob disease (sCJD).
WELL, it seems the USA mad cow strains in humans classified as type
determination pending tdpCJD, VPSPr, sFFI, and sCJD) have steadily increased
over the years, and the same old song and dance continues with sporadic CJD
cases $$$
Creutzfeldt-Jakob Disease CJD cases rising North America updated report
August 2013
*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada
seeing an extreme increase of 48% between 2008 and 2010 ***
Sunday, October 13, 2013
*** CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
Tuesday, April 01, 2014
Questions linger in U.S. CJD cases 2005, and still do in 2014
Sunday, March 09, 2014
A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of
Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease
FDA TSEAC CIRCUS AND TRAVELING ROAD SHOW FOR THE TSE PRION DISEASES
Sunday, April 06, 2014
SPORADIC CJD and the potential for zoonotic transmission there from, either
directly or indirectly via friendly fire iatrogenic mode, evidence to date
Wednesday, December 11, 2013
*** Detection of Infectivity in Blood of Persons with Variant and Sporadic
Creutzfeldt-Jakob Disease ***
Sunday, April 06, 2014
SPORADIC CJD and the potential for zoonotic transmission there from, either
directly or indirectly via friendly fire iatrogenic mode, evidence to date
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ???
layperson
Terry S. Singeltary Sr.
