Transmissibility of
Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the
molecular underpinnings of prion infectivity
Romolo Nonno, Michele Angelo Di Bari,
Umberto Agrimi & Laura Pirisinu Page 00 | Received 10 Aug 2016, Accepted 19
Sep 2016, Accepted author version posted online: 28 Nov 2016 Download citation
http://dx.doi.org/10.1080/19336896.2016.1239686 Crossmark Select Language▼ Translator
disclaimer Accepted author version
Abstract
Prion diseases, or transmissible
spongiform encephalopathies, have revealed the bewildering phenomenon of
transmissibility in neurodegenerative diseases. Hence, the experimental
transmissibility of prion-like neurodegenerative diseases via template directed
misfolding has become the focus of intense research.
Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited prion disease
associated with mutations in the prion protein gene. However, with the exception
of a few GSS cases with P102L mutation characterized by co-accumulation of
protease-resistant PrP core (PrPres) of ∼21 kDa,
attempts to transmit to rodents GSS associated to atypical misfolded prion
protein with ∼8 kDa PrPres have been unsuccessful. As a
result, these GSS subtypes have often been considered as non-transmissible
proteinopathies rather than true prion diseases. In a recent study we
inoculated bank voles with GSS cases associated with P102L, A117V and F198S
mutations and found that they transmitted efficiently and produced distinct
pathological phenotypes, irrespective of the presence of 21 kDa PrPres in the
inoculum. This study demonstrates that GSS is a genuine prion disease
characterized by both transmissibility and strain variation. We discuss the
implications of these findings for the understanding of the heterogeneous
clinic-pathological phenotypes of GSS and of the molecular underpinnings of
prion infectivity.
Keywords: Gerstmann-Straussler-Scheinker
disease, PrPC, PrPSc, prion infectivity, strain, protein misfolding,
neurodegenerative diseases
Greetings,
IT could also be that this sFFI is just
another case of iCJD (via friendly fire from the surgery for a colloid cyst of
the third ventricle, and two ventricular shunts were placed, one correctly in
the left ventricle, while the second ended in the right thalamus), some 20
years before the onset of symptoms of this so called sFFI case, from some
sub-type of sporadic CJD, now called sporadic FFI ???
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
UPDATE* NOVEMBER 16, 2014
vpspr, sgss, sffi, TSE, an iatrogenic
by-product of gss, ffi, familial type prion disease, what it ???
Friday, January 10, 2014
Greetings again Friends, Neighbors, and
Colleagues,
I would kindly like to follow up on
‘vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ???’ ran across an old paper from 1984, that some might
find interest in, and I will update the link with this old science paper from
1984, a 2010 paper from Japan, and some information on scrapie transmission.
The paper from Japan first, then the 1984 paper, and then the scrapie transmission
studies.
***The occurrence of contact cases raises
the possibility that transmission in families may be effected by an unusually
virulent strain of the agent.
snip...see ;
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic
by-product of gss, ffi, familial type prion disease, what it ???
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF
CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB
DISEASE
R. G. WILL
1984
snip...
***The occurrence of contact cases raises the
possibility that transmission in families may be effected by an unusually
virulent strain of the agent.
From:
Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF
CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
R. G. WILL
1984
snip...
D. Occupation
The possibility of case-to-case
transmission of C.J.D. has led to anxiety among hospital personnel and
laboratory staff regarding the possible risks of transmission by direct contact
with patients suffering from the condition (Mayer, 1979). During the prospective
study reluctance to perform post mortem or carry out electrophysiological
studies was regularly encountered. In the past, epidemiological evidence has
consistently failed to reveal any increased risk related to particular
professions (Bobowick et al., 1973; Matthews, 1975a; Brown et al., 1979b;
Galvez et al., 1980; Kondo and Kuroiwa, 1982) and, with the exception of the
review by Masters et al. (1979a), no increased risk to medical or paramedical
personnel. In the latter study 18 out of 308 cases were described as health
professionals, although as Brown (1980) has pointed out, this may have been due
to case selection. One neurosurgeon has been reported to have died of
pathologically confirmed C.J.D. (Schoene et al., 1981), but although he had
contact with a case of C.J.D. seven years prior to death, no operative
procedure was carried out.
In the retrospective section of this
study no occupational bias was discovered, there was no over-representation of
health care personnel and only one patient, a nurse, was likely to have had
direct contact with patients. In the prospective study, in which details of
occupation throughout life were obtained, there was again no occupational bias.
Possible contact between a dentist dying of confirmed C.J.D. and other patients
is discussed below, but the putative transmission in these cases would have
required direct implantation of the agent during dental procedures.
On the basis of the evidence from this
and previous epidemiological studies, there appears to be no increased risk of
transmission by direct contact with patients. Bodily secretions and excreta do
not contain the agent (Masters et al., 1980) and although viraemia has been
described in experimental transmission in guinea pigs (Manuelidis et al.,
1978b, Gajdusek et al. (1978) suggest that human blood, if ever infective, must
contain a very low titre of the agent. Despite a large number of transmission
experiments no staff at Bethesda have ever contracted the condition (Gajdusek
et al., 1978). Prior to the discovery that C.J.D. was trans- missible no
special precautions were taken during post mortem and indeed the pathology
technician in Dr. Nevin's cases has described eating food off the post mortem
table immediately after necropsy of one of these patients. Despite the lack of
precautions in the past no pathology technicians are known to have developed
C.J.D.
In conclusion, sensible precautions as
advised by both Gajdusek et al. (1977) and the Advisory Group on the Management
of Patients with Spongiform Encephalopathy (1981) are sufficient. Patients do
not require barrier nursing, blood and cerebrospinal fluid specimens should be
treated in the same way as other 'high risk' specimens, and more stringent
precautions should be observed at post mortem. The risk of case-to-case
transmission at neurosurgery is established (as discussed below) and all
instruments should be discarded after use.
E. Past Medical History
An increased incidence of surgical
procedures and neurological and psychiatric illness in C.J.D. has been
described by Masters et ale (1979a). Cases in this series were ascertained from
a variety of sources, including direct referral and a review of the literature
and selection bias cannot be excluded. It is also uncertain whether such an
incidence of past medical or surgical illness differs from the incidence in
this age group in the general population. Other retrospective epidemiological studies
of C.J.D. (Bobowick et al. t 1973; Matthews, 1975a; Brown et al., 1979b; Kondo
and Kuroiwa, 1982) have failed to show an increased incidence of past medical
or surgical illness and combining the results of the Chilean (Galvez et al.,
1980) and Hungarian (Majtenyi, 1978) studies only four patients out of a total
of 67 had a significant past surgical history. In the study in France (Brown et
al., 1979b) 8% of patients had some form of surgical procedure in the five
years prior to developing C.J.D., but the rationale for limiting enquiry to the
preceding five years is unclear in view of the possible incubation period in
C.J.D. of over four decades (Masters et al., 1981a). In the retrospective
survey in this study, which was without temporal limits, 28% of patients had a
past history of some form of major surgery. Without a comparison with the
incidence of major surgery in a matched population the significance of this
figure is uncertain, and it is of note that in 40 patients no past illness was
described.
In the prospective study a more detailed
medical history was obtained and there was no specific factor in the past
medical history common to all patients. As with other proposed risk factors,
only a properly conducted case control study can assess the significance of
putative risk factors discovered in descriptive epidemiological surveys.
The transmission of C.J.D. by corneal
transplantation has been established (Duffy et al., 1974) and it is disturbing
that in one case in this series corneas were removed for transplantation from a
patient dying of C.J.D. and in a further case potentially contaminated corneal
transplants had to be removed when the risks were realised. The recommendation
that corneas must not be taken for transplantation from demented patients, from
patients dying in psychiatric hospitals, nor from patients dying of undiagnosed
neurological disease (Advisory Group on the Management of Patients with
Spongiform Encephalopathy, 1981) should be reinforced.
F. Familial Associations
The overall familial incidence of 6% in
the retrospective section of this study contrasts with the estimated familial
incidence of 15% in a review of the world wide epidemiology of C.J.D. (Masters
et al., 1979a). In individual series higher figures are quoted with, for
example, a familial incidence of 47% in Chile (Galvez et al., 1980) and 35% in
Libyan born Israelis (Neugut et al., 1979). In a comprehensive retrospective
survey of C.J.D. in France (Brown et al., 1979b), however, a 9% familial
incidence was discovered, a figure comparable with this series. The low
familial incidence may reflect either the difficulties of retrospectively
obtaining an accurate family history or an artificially high familial incidence
in relatively selected series due to extensive investigation of individual
families.
The paradox of an apparently dominantly
inherited condition (Masters et al., 1981a) which is yet transmissible is
unresolved. Detailed investigation of individual families suggests that, if
case to case transmission occurs, the incubation period must extend to decades
(Masters et al., 1981a). Although this is compatible with the suspected
incubation period of kuru (Gajdusek, 1979), the tendency for siblings to die at
the same age rather than the same time (Masters et al., 1981a) supports the
presence of a genetic influence. ***The discovery of a discordant identical
twin pair in the present study suggests that even if there is an inherited
susceptibility an environmental factor is necessary for the development of the
condition. It further suggests that genetic integration of the agent is
unlikely, in accordance with experimental evidence in which nuclear fractions
are non-infectious (Millson et al., 1971) and vertical trans- mission has not
been found in the laboratory (Amyx et al., 1981).
In other systematic studies of the
epidemiology of C.J.D. an association with other neurological conditions has
not been described but Masters (1981a) has reported four cases of C.J.D.
occurring within four pedigrees of familial Alzheimer's disease. Adam et ale
(1982) have described a family with a dominantly inherited neurological
disorder sharing features of cerebral amyloidosis, spongiform encephalopathy
and Alzheimer's disease. ***The relationship of C.J.D. to other degenerative
neurological disorders may be a fruitful avenue of further epidemiological
research.
CASE CONTROL STUDY
The objective of the case control study
was to obtain quantitative data on putative risk factors and to identify
potential common exposure to an environmental source of infection. The
difficulties of such a study have been described by Bobowick et al. (1973) and
Kondo and Kuroiwa (1982) in the only previous case control studies of C.J.D. In
a rare condition such as C.J.D. it is difficult to obtain sufficient patient
numbers to achieve statistically valid results. In this study 22 patients were
included in the first 18 months, a number sufficient to exclude any ubiquitous
risk factor but inadequate to distinguish relative risk. The case control study
has, however, continued beyond the time limits of this analysis and to date
over a hundred patients have been included.
The necessity of obtaining information at
second hand introduces a potential source of error in the study of C.J.D. In
this study the level of co-operation and detail of information was clearly
enhanced by interviewing relatives prospectively and for this reason cases
ascertained after death were not included in the prospective study. The
checking of information given by relatives of control cases with the patients
themselves suggested that the quality of information given at second hand was
remarkably accurate.
The selection of controls is critical to
the potential significance of a case control study. In this study age- and
sex-matched controls were obtained from concurrent inpatients. Although in some
cases the discovery of a suitable control proved both difficult and time-consuming,
and in a few cases impossible, it was felt essential to persevere with the
stated protocol in order to avoid the introduction of bias. Both previous case
control studies were carried out retro- spectively and used 'healthy' and
potentially over-matched controls.
Despite the differences between previous
studies and the present case control study, the results were, almost without
exception, both concordant and negative. No difference between patients and
controls was discovered in past surgical or medical history, occupational
history, educational history, eating habits or exposure to animals. Kondo and
Kuroiwa (1982) discovered a correlation between physical injuries and the
development of C.J.D. but could not exclude a methodological bias. No such
correlation was discovered in this study and the subject was not examined in
the study by Bobowick et ale (1973).
In the latter study the consumption of
hog brains by patients was stressed but did not differ from the control group
and in both this study and the study in Japan (Kondo and Kuroiwa, 1982) no
dietary factory was related to increased risk of developing C.J.D.
***The successful oral transmission of
C.J.D. and scrapie to primates (Gibbs et al., 1980) and the close resemblance
between the properties of the transmissible agent in the two conditions (Gibbs
and Gajdusek, 1976) has raised the possibility that the human disease is
contracted from sheep. No direct evidence is available and the concept is based
on inference and interesting but unconvincing anecdotes
(Alter et al., 1971; Lo Russo et al.,
1980; Kamin and Patten, 1984). The patient discovered in this study who had
never been known to eat meat suggests that eating scrapie infected meat cannot
be the only source of C.J.D. in man. C.J.D. occurs in countries in which
natural scrapie has not been observed (Galvez et al., 1980; Kondo and Kuroiwa,
1982) and no relationship was discovered in France (Chatelain et al., 1981)
between the geographic distribution of scrapie and the incidence of C.J.D. A
similar investigation could not be carried out in England and Wales as
notification of scrapie to the Ministry of Agriculture is inconsistent and
sheep farmers often destroy affected animals without seeking veterinary advice
for fear of financial loss.
A detailed residential history was
obtained in cases and controls. Although over-representation of cases was
discovered in certain areas, similar but distinct areas of previous residence
common to an apparent excess of controls was discovered. If C.J.D. does have a
prolonged incubation period extending to decades the detailed study of
residential history may, however, establish potential contact between
individual cases which would be otherwise undetectable. The detailed study of
individual cases in the prospective study has revealed the possibility of
tenuous but extraordinarily coincidental contact between patients.
This may only be a reflection of
intensive investigation, but if C.J.D. is transmitted by relatively minor
surgical or dental procedures many years prior to death it is only by the
systematic study of individual cases that potential cross-contamination may be
discovered.
EVIDENCE FOR CASE-TO-CASE TRANSMISSION OF
C.J.D.
The possible iatrogenic transmission of
C.J.D. by neurosurgery, corneal transplantation and stereotactic electrodes has
been suggested in the past (Duffy et al., 1974: Bernouilli et al., 1977;
Masters et al., 1979a). In this series the close temporal relationship of
neurosurgical procedures on two affected patients and three patients,
unaffected at the time but who subsequently developed the disease is described.
This provides strong circumstantial evidence of iatrogenic transmission by
neurosurgery. Although sterilisation procedures have improved since the cases
described, the unusual resistance of the agent and the recent description of
probable neurosurgical transmission in France (Foncin et al., 1980) suggests
that there is a continued risk of accidental transmission. However, brain
biopsy to confirm the diagnosis of C.J.D. is now an unusual event and computed
tomography has obviated the need for ventriculography.
The depth electrodes putatively
responsible for one case of iatrogenic transmission in this series were
inadequately sterilised in formalin and were subsequently used in over 200
patients. The neurosurgical instruments used in the cases of presumed
neurosurgical transmission were sterilised using autoclaving procedures which
were inadequate according to current advice (Gajdusek et al., 1978). However,
despite detailed investigation, no cases other than those described above are
known to have developed C.J.D. Thus, despite the possible implantation of the
agent directly into the central nervous system, a large number of patients
failed to develop the disease. This provides circumstantial evidence of an
inherited susceptibility to the agent and suggests that cases of iatrogenic
transmission may have occurred due to the unfortunate temporal proximity of
susceptible individuals exposed to the agent.
In the close geographic group of three
cases possible nodes of transmission can be suggested, either iatrogenic or
through dental procedures, but these must remain conjectural. It is known,
however, that the similar scrapie agent can be transmitted from the gums of
animals (Adams and Edgar, 1978). Such close spatial clustering of cases is
extremely unusual, being previously reported in England (Matthews, 1975a),
Czechoslovakia (Mayer et al., 1977) and Hungary (Majtenyi, 1978), but not
detected in the study of the epidemiology of C.J.D. in urban Paris (Cathala et
al., 1978) where the incidence was found to be relatively high.
The occurrence of the disease in a
patient who had contact with cases of familial C.J.D., but was not genetically
related, has been described in Chile (Galvez et al., 1980) and in France (Brown
et al., 1979b). In Chile the patient was related by marriage, but with no
consanguinity, and had social contact with subsequently affected family members
for 13 years before developing the disease. The contact case in France also
married into a family in which C.J.D. was prevalent and had close contact with
an affected member. In neither instance did the spouse of the non-familial case
have the disease. The case described in this report was similarly related to
affected family members and social contact had occurred for 20 years prior to
developing C.J.D. If contact transmission had occurred, the minimum
transmission period would be 11 years. Contact between sporadic cases has not
been described and it is remarkable that possible contact transmissions have
all been with familial cases. No method of transmission by casual social
contact has been suggested.
***The occurrence of contact cases raises
the possibility that transmission in families may be effected by an unusually
virulent strain of the agent.
snip...see full text here;
Monday, November 23, 2015
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study
ORIGINAL RESEARCH
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study
Diane L. Ritchie1,*, Susan V. Gibson2,†, Christian R. Abee3, Thomas R. Kreil4, James W. Ironside1 and Paul Brown5
Article first published online: 23 NOV 2015
DOI: 10.1111/trf.13422
© 2015 AABB
Issue
Cover image for Vol. 55 Issue 11
Transfusion
Early View (Online Version of Record published before inclusion in an issue)
Abstract
BACKGROUND
Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease.
STUDY DESIGN AND METHODS
Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion.
RESULTS
No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrPTSE in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Sträussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months.
CONCLUSION
Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period.
2015 PRION CONFERENCE
*** RE-P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. ***
P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
Paul Brown1, Diane Ritchie2, James Ironside2, Christian Abee3, Thomas Kreil4, and Susan Gibson5 1NIH (retired); Bethesda, MD USA; 2University of Edinburgh; Edinburgh, UK; 3University of Texas; Bastrop, TX USA; 4Baxter Bioscience; Vienna, Austria; 5University of South Alabama; Mobile, AL USA
Five vCJD disease transmissions and an estimated 1 in 2000 ‘silent’ infections in UK residents emphasize the continued need for information about disease risk in humans. A large study of blood component infectivity in a non-human primate model has now been completed and analyzed. Among 1 GSS, 4 sCJD, and 3 vCJD cases, only GSS leukocytes transmitted disease within a 5–6 year surveillance period. A transmission study in recipients of multiple whole blood transfusions during the incubation and clinical stages of sCJD and vCJD in ic-infected donor animals was uniformly negative. These results, together with other laboratory studies in rodents and nonhuman primates and epidemiological observations in humans, suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. The issue of decades-long incubation periods in ‘silent’ vCJD carriers remains open.
ran across an old paper from 1984 ;
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent. ***
snip...see full text ;
Alzheimer's, what if ?
SWISS MEDICAL WEEKLY
Alzheimer-type brain pathology may be
transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;
Evidence for human transmission of
amyloid-β pathology and cerebral amyloid angiopathy
07 02:27 AM
Terry S. Singeltary Sr. said:
re-Evidence for human transmission of
amyloid-β pathology and cerebral amyloid angiopathy
2015-12-07 02:27 AM
Terry S. Singeltary Sr. said: re-Evidence
for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015)
doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015
Published online 09 September 2015 Updated online 11 September 2015 Erratum
(October, 2015)
I would kindly like to comment on the
Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist
and Authors of the Nature paper, for bringing this important finding to the
attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics
is getting in the way possibly of more important Transmissible Spongiform
Encephalopathy TSE Prion scientific findings. findings that could have great
implications for human health, and great implications for the medical surgical
arena. but apparently, the government peer review process, of the peer review
science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? it’s
been well documented via the BSE Inquiry. have they not learned a lesson from
the last time?
we have seen this time and time again in
England (and other Country’s) with the BSE mad cow TSE Prion debacle.
That ‘anonymous' Lancet editorial was
disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely
elderly and among them some were on their way to CJD or Alzheimer's. Not a bit
unusual. Then the recipients who got pooled extracts injected from thousands of
cadavers were 100% certain to have been injected with both seeds. No surprise
that they got both diseases going after thirty year incubations.
That the UK has a "system in place
to assist science journalists" to squash embargoed science reports they
find ‘alarming’ is pathetic.
Sounds like the journalists had it right
in the first place: ‘Alzheimer’s may be a transmissible infection’ in The
Independent to ’You can catch Alzheimer’s’ in The Daily Mirror or ‘Alzheimer’s
bombshell" in The Daily Express.
if not for the journalist, the layperson
would not know about these important findings.
where would we be today with sound
science, from where we were 30 years ago, if not for the cloak of secrecy and
save the industry at all cost mentality?
when you have a peer review system for
science, from which a government constantly circumvents, then you have a
problem with science, and humans die.
to date, as far as documented body bag
count, with all TSE prion named to date, that count is still relatively low
(one was too many in my case, Mom hvCJD), however that changes drastically once
the TSE Prion link is made with Alzheimer’s, the price of poker goes up
drastically.
so, who makes that final decision, and
how many more decades do we have to wait?
the iatrogenic mode of transmission of
TSE prion, the many routes there from, load factor, threshold from said load
factor to sub-clinical disease, to clinical disease, to death, much time is
there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we
make that final decision to do something about it globally? how many documented
body bags does it take? how many more decades do we wait? how many names can we
make up for one disease, TSE prion?
Professor Collinge et al, and others,
have had troubles in the past with the Government meddling in scientific
findings, that might in some way involve industry, never mind human and or
animal health.
FOR any government to continue to
circumvent science for monetary gain, fear factor, or any reason, shame, shame
on you.
in my opinion, it’s one of the reasons we
are at where we are at to date, with regards to the TSE Prion disease science
i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from,
and government, must be removed from the peer review process of sound science,
it’s bad enough having them in the pharmaceutical aspect of healthcare policy
making, in my opinion.
my mother died from confirmed hvCJD, and
her brother (my uncle) Alzheimer’s of some type (no autopsy?). just made a
promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the
past, and a possible future we all hopes never happens again. ...
[9. Whilst this matter is not at the
moment directly concerned with the iatrogenic CJD cases from hgH, there remains
a possibility of litigation here, and this presents an added complication.
There are also results to be made available shortly (1) concerning a farmer
with CJD who had BSE animals, (2) on the possible transmissibility of
Alzheimer’s and (3) a CMO letter on prevention of iatrogenic CJD transmission
in neurosurgery, all of which will serve to increase media interest.]
snip...see full Singeltary Nature comment
here;
see Singeltary comments to Plos ;
Subject: 1992 IN CONFIDENCE TRANSMISSION
OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION
REMAINS OPEN
BSE101/1 0136
IN CONFIDENCE
CMO
From: . Dr J S Metiers DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO
PRIMATES
1. Thank you for showing me Diana
Dunstan's letter. I am glad that MRC have recognised the public sensitivity of
these findings and intend to report them in their proper context. 'This
hopefully will avoid misunderstanding and possible distortion by the media to
portray the results as having more greater significance than the findings so
far justify.
2. Using a highly unusual route of
transmission (intra-cerebral injection) the researchers have demonstrated the
transmission of a pathological process from two cases one of severe Alzheimer's
disease the other of Gerstmann-Straussler disease to marmosets. However they
have not demonstrated the transmission of either clinical condition as the
"animals were behaving normally when killed". As the report emphasises
the unanswered question is whether the disease condition would have revealed
itself if the marmosets had lived longer. They are planning further research to
see if the conditions, as opposed to the partial pathological process, is
transmissible.
what are the implications for public
health?
3. The route 'of transmission is very
specific and in the natural state of things highly unusual. However it could be
argued that the results reveal a potential risk, in that brain tissue from
these two patients has been shown to transmit a pathological process. Should
therefore brain tissue from such cases be regarded as potentially infective?
Pathologists, morticians, neuro surgeons and those assisting at neuro surgical
procedures and others coming into contact with "raw" human brain
tissue could in theory be at risk. However, on a priori grounds given the
highly specific route of transmission in these experiments that risk must be
negligible if the usual precautions for handling brain tissue are observed.
1
92/11.4/1.1
BSE101/1 0137
4. The other dimension to consider is the
public reaction. To some extent the GSS case demonstrates little more than the
transmission of BSE to a pig by intra-cerebral injection. If other prion
diseases can be transmitted in this way it is little surprise that some
pathological findings observed in GSS were also transmissible to a marmoset.
But the transmission of features of Alzheimer's pathology is a different
matter, given the much greater frequency of this disease and raises the
unanswered question whether some cases are the result of a transmissible prion.
The only tenable public line will be that "more research is required’’
before that hypothesis could be evaluated. The possibility on a transmissible
prion remains open. In the meantime MRC needs carefully to consider the range
and sequence of studies needed to follow through from the preliminary
observations in these two cases. Not a particularly comfortable message, but
until we know more about the causation of Alzheimer's disease the total
reassurance is not practical.
J S METTERS Room 509 Richmond House Pager
No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2
>>> The only tenable public line
will be that "more research is required’’ <<<
>>> possibility on a
transmissible prion remains open<<<
O.K., so it’s about 23 years later, so
somebody please tell me, when is "more research is required’’ enough time
for evaluation ?
Self-Propagative Replication of Ab
Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible
Spongiform Encephalopathy prion disease, Iatrogenic,
what if ?
Posted by flounder on 05 Nov 2014 at
21:27 GMT
Sunday, November 22, 2015
*** Effect of heating on the stability of
amyloid A (AA) fibrils and the intra- and cross-species transmission of AA
amyloidosis Abstract
Amyloid A (AA) amyloidosis is a protein
misfolding disease characterized by extracellular deposition of AA fibrils. AA
fibrils are found in several tissues from food animals with AA amyloidosis. For
hygienic purposes, heating is widely used to inactivate microbes in food, but
it is uncertain whether heating is sufficient to inactivate AA fibrils and
prevent intra- or cross-species transmission. We examined the effect of heating
(at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine
AA fibrils using Western blot analysis, transmission electron microscopy (TEM),
and mouse model transmission experiments. TEM revealed that a mixture of AA
fibrils and amorphous aggregates appeared after heating at 100 °C, whereas
autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained
antigen specificity in Western blot analysis when heated at 100 °C or
autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible
pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or
100 °C) was significantly stimulated and resulted in amyloid deposition in
mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly
decreased amyloid deposition. Moreover, amyloid deposition in mice injected
with murine AA fibrils was more severe than that in mice injected with bovine
AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce
amyloid deposition in mice. These results suggest that AA fibrils are
relatively heat stable and that similar to prions, autoclaving at 135 °C is
required to destroy the pathogenicity of AA fibrils. These findings may
contribute to the prevention of AA fibril transmission through food materials
to different animals and especially to humans.
Purchase options Price * Issue Purchase
USD 511.00 Article Purchase USD 54.00
*** Transmission of Creutzfeldt-Jakob
disease to a chimpanzee by electrodes contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx
HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies,
National Institute of Neurological Disorders and Stroke, National Institutes of
Health, Bethesda, MD 20892.
Stereotactic multicontact electrodes used
to probe the cerebral cortex of a middle aged woman with progressive dementia
were previously implicated in the accidental transmission of Creutzfeldt-Jakob
disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed
for all three cases. More than two years after their last use in humans, after
three cleanings and repeated sterilisation in ethanol and formaldehyde vapour,
the electrodes were implanted in the cortex of a chimpanzee. Eighteen months
later the animal became ill with CJD. This finding serves to re-emphasise the
potential danger posed by reuse of instruments contaminated with the agents of
spongiform encephalopathies, even after scrupulous attempts to clean them.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
the
warning shots fired over the bow of the boat that were never heard ;
PITUITARY EXTRACT
This was used to help cows super ovulate.
This tissue was considered to be of greatest risk of containing BSE and
consequently transmitting the disease...
NON-LICENSED HUMAN TISSUE DEVICES WERE
NOT COMMERCIALLY AVAILABLE
snip...
I was quite prepared to believe in
unofficial pituitary hormones, also in the 1970's, whether as described by Dr.
Little, or in other circumstances, for animal use.
snip...
The fact that there were jars of
pituitaries (or extract) around on shelves is attested by the still potent 1943
pituitaries, described in Stockell Hartree et al. (J/RF/17/291) which had come
from the lab. at Mill Hill. Having taken the trouble to collect them, they were
not lightly thrown out...
3. The extraction is from a pool of
pituitary glands collected from abbatoirs and the process used is unlikely to
have any effect on the BSE agent. Hormones extracted from human pituitary
glands have been responsible for a small number of Creutzfeldt Jacob disease in
man.
SEE
LOOPHOLE ;
SEE LOOPHOLE SHOULD BE CLOSED ;
2012 Singeltary on CJD and Alzheimer’s
and iatrogenic threat
Proposal ID: 29403
Alzheimer’s disease and Transmissible Spongiform
Encephalopathy prion disease, Iatrogenic, what if ?
Background
Alzheimer’s disease and Transmissible
Spongiform Encephalopathy disease have both been around a long time, and was
discovered in or around the same time frame, early 1900’s. Both disease, and
it’s variants, in many cases are merely names of the people that first
discovered them. Both diseases are incurable and debilitating brain disease,
that are in the end, 100% fatal, with the incubation/clinical period of the
Alzheimer’s disease being longer than the TSE prion disease. Symptoms are very
similar, and pathology is very similar. I propose that Alzheimer’s is a TSE
disease of low dose, slow, and long incubation disease, and that Alzheimer’s is
Transmissible, and is a threat to the public via the many Iatrogenic routes and
sources. It was said long ago that the only thing that disputes this, is
Alzheimer’s disease transmissibility, or the lack of. today, there is enough
documented science (some confidential), that shows that indeed Alzheimer’s is
transmissible. The risk factor for friendly fire, and or the pass-it-forward
mode i.e. Iatrogenic transmission is a real threat, and one that needs to be
addressed immediately.
Methods
Through years of research, as a layperson, of
peer review journals, transmission studies, and observations of loved ones and
friends that have died from both Alzheimer’s and the TSE prion disease i.e.
Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
The likelihood of many victims of Alzheimer’s
disease from the many different Iatrogenic routes and modes of transmission as
with the TSE prion disease. TSE prion disease survives ashing to 600 degrees
celsius, that’s around 1112 degrees farenheit. you cannot cook the TSE prion
disease out of meat. you can take the ash and mix it with saline and inject
that ash into a mouse, and the mouse will go down with TSE. Prion Infected
Meat-and-Bone Meal Is Still Infectious after Biodiesel Production as well. the
TSE prion agent also survives Simulated Wastewater Treatment Processes. IN
fact, you should also know that the TSE Prion agent will survive in the
environment for years, if not decades. you can bury it and it will not go away.
TSE prion agent is capable of infected your water table i.e. Detection of
protease-resistant cervid prion protein in water from a CWD-endemic area. it’s
not your ordinary pathogen you can just cook it out and be done with. that’s
what’s so worrisome about Iatrogenic mode of transmission, a simple autoclave
will not kill this TSE prion agent.
Conclusions
There should be a Global Congressional Science
round table event (one of scientist and doctors et al only, NO CORPORATE,
POLITICIANS ALLOWED) set up immediately to address these concerns from the many
potential routes and sources of the TSE prion disease, including Alzheimer’s
disease, and a emergency global doctrine put into effect to help combat the
spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and
blood arena’s. All human and animal TSE prion disease, including Alzheimer’s
should be made reportable in every state, and Internationally, WITH NO age
restrictions. Until a proven method of decontamination and autoclaving is
proven, and put forth in use universally, in all hospitals and medical,
surgical arena’s, or the TSE prion agent will continue to spread. IF we wait
until science and corporate politicians wait until politics let science _prove_
this once and for all, and set forth regulations there from, we will all be
exposed to the TSE Prion agents, if that has not happened already. what’s the
use of science progressing human life to the century mark, if your brain does
not work?
combined cannot exceed 350 Words
shortened to proper word count ;
Alzheimer’s disease and Transmissible
Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Background
Alzheimer’s disease and Transmissible
Spongiform Encephalopathy disease have both been around a long time, and was
discovered in or around the same time frame, early 1900’s. Both diseases are
incurable and debilitating brain disease, that are in the end, 100% fatal, with
the incubation/clinical period of the Alzheimer’s disease being longer (most of
the time) than the TSE prion disease. Symptoms are very similar, and pathology
is very similar.
Methods
Through years of research, as a layperson, of
peer review journals, transmission studies, and observations of loved ones and
friends that have died from both Alzheimer’s and the TSE prion disease i.e.
Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I
propose that Alzheimer’s is a TSE disease of low dose, slow, and long
incubation disease, and that Alzheimer’s is Transmissible, and is a threat to
the public via the many Iatrogenic routes and sources. It was said long ago
that the only thing that disputes this, is Alzheimer’s disease
transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s
disease from the many different Iatrogenic routes and modes of transmission as
with the TSE prion disease.
Conclusions
There should be a Global Congressional Science
round table event set up immediately to address these concerns from the many
potential routes and sources of the TSE prion disease, including Alzheimer’s
disease, and a emergency global doctrine put into effect to help combat the
spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and
blood arena’s. All human and animal TSE prion disease, including Alzheimer’s
should be made reportable in every state, and Internationally, WITH NO age restrictions.
Until a proven method of decontamination and autoclaving is proven, and put
forth in use universally, in all hospitals and medical, surgical arena’s, or
the TSE prion agent will continue to spread. IF we wait until science and
corporate politicians wait until politics lets science _prove_ this once and
for all, and set forth regulations there from, we will all be exposed to the
TSE Prion agents, if that has not happened already.
end...tss
Transmissible Spongiform Encephalopathy
prion disease, Iatrogenic, what if ?
Friday, January 29, 2016
Synucleinopathies: Past, Present and
Future, iatrogenic, what if?
Horizontal Transmission of Chronic Wasting
Disease in Reindeer CDC Volume 22, Number 12—December 2016
Sunday, November 13, 2016
Horizontal Transmission of Chronic
Wasting Disease in Reindeer CDC Volume 22, Number 12—December 2016
CHRONIC WASTING DISEASE CWD AND SCRAPIE
TSE PRION ZOONOSIS UPDATE
*** WDA 2016 NEW YORK ***
We found that CWD adapts to a new host
more readily than BSE and that human PrP was unexpectedly prone to misfolding
by CWD prions. In addition, we investigated the role of specific regions of the
bovine, deer and human PrP protein in resistance to conversion by prions from
another species. We have concluded that the human protein has a region that
confers unusual susceptibility to conversion by CWD prions. Student
Presentations Session 2 The species barriers and public health threat of CWD
and BSE prions Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace
Mathiason1, Dr. Edward Hoover1 1Colorado State University Chronic wasting
disease (CWD) is spreading rapidly through cervid populations in the USA.
Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s
because cattle were fed recycled animal protein. These and other prion diseases
are caused by abnormal folding of the normal prion protein (PrP) into a disease
causing form (PrPd), which is pathogenic to nervous system cells and can cause
subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it
has not yet infected humans. On the other hand, BSE was spread only when cattle
consumed infected bovine or ovine tissue, but did infect humans and other
species.
The objective of this research is to
understand the role of PrP structure in cross-species infection by CWD and BSE.
To study the propensity of each species’ PrP to be induced to misfold by the
presence of PrPd from verious species, we have used an in vitro system that
permits detection of PrPd in real-time. We measured the conversion efficiency
of various combinations of PrPd seeds and PrP substrate combinations. We
observed the cross-species behavior of CWD and BSE, in addition to
feline-adapted CWD and BSE.
We found that CWD adapts to a new host
more readily than BSE and that human PrP was unexpectedly prone to misfolding by
CWD prions.
In addition, we investigated the role of
specific regions of the bovine, deer and human PrP protein in resistance to
conversion by prions from another species.
We have concluded that the human protein
has a region that confers unusual susceptibility to conversion by CWD prions.
CWD is unique among prion diseases in its
rapid spread in natural populations. BSE prions are essentially unaltered upon
passage to a new species, while CWD adapts to the new species.
This adaptation has consequences for
surveillance of humans exposed to CWD. Wildlife Disease Risk Communication
Research Contributes to Wildlife Trust Administration Exploring perceptions
about chronic wasting disease risks among wildlife and agriculture
professionals and stakeholders
PRION 2016 TOKYO
Zoonotic Potential of CWD Prions: An
Update
Ignazio Cali1, Liuting Qing1, Jue Yuan1,
Shenghai Huang2, Diane Kofskey1,3, Nicholas Maurer1, Debbie McKenzie4, Jiri
Safar1,3,5, Wenquan Zou1,3,5,6, Pierluigi Gambetti1, Qingzhong Kong1,5,6
1Department of Pathology, 3National Prion Disease Pathology Surveillance
Center, 5Department of Neurology, 6National Center for Regenerative Medicine,
Case Western Reserve University, Cleveland, OH 44106, USA. 4Department of
Biological Sciences and Center for Prions and Protein Folding Diseases,
University of Alberta, Edmonton, Alberta, Canada, 2Encore Health Resources,
1331 Lamar St, Houston, TX 77010
Chronic wasting disease (CWD) is a
widespread and highly transmissible prion disease in free-ranging and captive
cervid species in North America. The zoonotic potential of CWD prions is a
serious public health concern, but the susceptibility of human CNS and
peripheral organs to CWD prions remains largely unresolved. We reported earlier
that peripheral and CNS infections were detected in transgenic mice expressing
human PrP129M or PrP129V. Here we will present an update on this project,
including evidence for strain dependence and influence of cervid PrP
polymorphisms on CWD zoonosis as well as the characteristics of experimental
human CWD prions.
PRION 2016 TOKYO
In Conjunction with Asia Pacific Prion
Symposium 2016 PRION 2016 Tokyo Prion 2016
Cervid to human prion transmission
Kong, Qingzhong Case Western Reserve
University, Cleveland, OH, United States
Abstract
Prion disease is transmissible and
invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting
deer, elk and moose, and it is a widespread and expanding epidemic affecting 22
US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic
prion transmission risks in North America because of huge venison consumption
(>6 million deer/elk hunted and consumed annually in the USA alone),
significant prion infectivity in muscles and other tissues/fluids from
CWD-affected cervids, and usually high levels of individual exposure to CWD
resulting from consumption of the affected animal among often just family and
friends. However, we still do not know whether CWD prions can infect humans in
the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis
has already occurred, and we have no essays to reliably detect CWD infection in
humans. We hypothesize that: (1) The classic CWD prion strain can infect humans
at low levels in the brain and peripheral lymphoid tissues; (2) The
cervid-to-human transmission barrier is dependent on the cervid prion strain
and influenced by the host (human) prion protein (PrP) primary sequence; (3)
Reliable essays can be established to detect CWD infection in humans;and (4)
CWD transmission to humans has already occurred. We will test these hypotheses
in 4 Aims using transgenic (Tg) mouse models and complementary in vitro
approaches. Aim 1 will prove that the classical CWD strain may infect humans in
brain or peripheral lymphoid tissues at low levels by conducting systemic
bioassays in a set of "humanized" Tg mouse lines expressing common
human PrP variants using a number of CWD isolates at varying doses and routes.
Experimental "human CWD" samples will also be generated for Aim 3.
Aim 2 will test the hypothesis that the cervid-to-human prion transmission
barrier is dependent on prion strain and influenced by the host (human) PrP
sequence by examining and comparing the transmission efficiency and phenotypes
of several atypical/unusual CWD isolates/strains as well as a few prion strains
from other species that have adapted to cervid PrP sequence, utilizing the same
panel of humanized Tg mouse lines as in Aim 1. Aim 3 will establish reliable
essays for detection and surveillance of CWD infection in humans by examining
in details the clinical, pathological, biochemical and in vitro seeding
properties of existing and future experimental "human CWD" samples
generated from Aims 1-2 and compare them with those of common sporadic human
Creutzfeldt-Jakob disease (sCJD) prions. Aim 4 will attempt to detect clinical
CWD-affected human cases by examining a significant number of brain samples
from prion-affected human subjects in the USA and Canada who have consumed
venison from CWD-endemic areas utilizing the criteria and essays established in
Aim 3. The findings from this proposal will greatly advance our understandings
on the potential and characteristics of cervid prion transmission in humans,
establish reliable essays for CWD zoonosis and potentially discover the first
case(s) of CWD infection in humans. Public Health Relevance There are
significant and increasing human exposure to cervid prions because chronic
wasting disease (CWD, a widespread and highly infectious prion disease among
deer and elk in North America) continues spreading and consumption of venison
remains popular, but our understanding on cervid-to-human prion transmission is
still very limited, raising public health concerns. This proposal aims to
define the zoonotic risks of cervid prions and set up and apply essays to
detect CWD zoonosis using mouse models and in vitro methods. The findings will
greatly expand our knowledge on the potentials and characteristics of cervid
prion transmission in humans, establish reliable essays for such infections and
may discover the first case(s) of CWD infection in humans.
Funding Agency Agency National Institute
of Health (NIH) Institute National Institute of Neurological Disorders and
Stroke (NINDS) Type Research Project (R01) Project # 1R01NS088604-01A1
Application # 9037884 Study Section Cellular and Molecular Biology of
Neurodegeneration Study Section (CMND) Program Officer Wong, May Project Start
2015-09-30 Project End 2019-07-31 Budget Start 2015-09-30 Budget End 2016-07-31
Support Year 1 Fiscal Year 2015 Total Cost $337,507 Indirect Cost $118,756
Institution Name Case Western Reserve University Department Pathology Type Schools
of Medicine DUNS # 077758407 City Cleveland State OH Country United States Zip
Code 44106
===========================================================
We hypothesize that:
(1) The classic CWD prion strain can
infect humans at low levels in the brain and peripheral lymphoid tissues;
(2) The cervid-to-human transmission
barrier is dependent on the cervid prion strain and influenced by the host
(human) prion protein (PrP) primary sequence;
(3) Reliable essays can be established to
detect CWD infection in humans;and
(4) *** CWD transmission to humans has
already occurred. *** We will test these hypotheses in 4 Aims using transgenic
(Tg) mouse models and complementary in vitro approaches.
============================================================
Key Molecular Mechanisms of TSEs
Zabel, Mark D. Colorado State
University-Fort Collins, Fort Collins, CO, United States
Abstract
Prion diseases, or transmissible
spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases
affecting humans, cervids, bovids, and ovids. The absolute requirement of PrPC
expression to generate prion diseases and the lack of instructional nucleic
acid define prions as unique infectious agents. Prions exhibit species-specific
tropism, inferring that unique prion strains exist that preferentially infct
certain host species and confront transmission barriers to heterologous host
species. However, transmission barriers are not absolute. Scientific consensus
agrees that the sheep TSE scrapie probably breached the transmission barrier to
cattle causing bovine spongiform encephalopathy that subsequently breached the
human transmission barrier and likely caused several hundred deaths by a
new-variant form of the human TSE Creutzfeldt-Jakob disease in the UK and
Europe. The impact to human health, emotion and economies can still be felt in
areas like farming, blood and organ donations and the threat of a latent TSE
epidemic. This precedent raises the real possibility of other TSEs, like chronic
wasting disease of cervids, overcoming similar human transmission barriers. A
groundbreaking discovery made last year revealed that mice infected with
heterologous prion strains facing significant transmission barriers replicated
prions far more readily in spleens than brains6. Furthermore, these splenic
prions exhibited weakened transmission barriers and expanded host ranges
compared to neurogenic prions. These data question conventional wisdom of
avoiding neural tissue to avoid prion xenotransmission, when more promiscuous
prions may lurk in extraneural tissues. Data derived from work previously
funded by NIH demonstrate that Complement receptors CD21/35 bind prions and
high density PrPC and differentially impact prion disease depending on the
prion isolate or strain used. Recent advances in live animal and whole organ
imaging have led us to generate preliminary data to support novel, innovative
approaches to assessing prion capture and transport. We plan to test our
unifying hypothesis for this proposal that CD21/35 control the processes of
peripheral prion capture, transport, strain selection and xenotransmission in
the following specific aims.
2.
Determine whether CD21/35 and C1q differentially bind distinct prion strains
3. Monitor the effects of CD21/35 on
prion trafficking in real time and space
4. Assess the role of CD21/35 in
incunabular prion trafficking
Public Health Relevance
Transmissible spongiform encephalopathies,
or prion diseases, are devastating illnesses that greatly impact public health,
agriculture and wildlife in North America and around the world. The impact to
human health, emotion and economies can still be felt in areas like farming,
blood and organ donations and the threat of a latent TSE epidemic. This
precedent raises the real possibility of other TSEs, like chronic wasting
disease (CWD) of cervids, overcoming similar human transmission barriers. Early
this year Canada reported its first case of BSE in over a decade audits first
case of CWD in farmed elk in three years, underscoring the need for continued
vigilance and research. Identifying mechanisms of transmission and zoonoses
remains an extremely important and intense area of research that will benefit
human and other animal populations.
Funding Agency Agency National Institute
of Health (NIH) Institute National Institute of Allergy and Infectious Diseases
(NIAID) Type High Priority, Short Term Project Award (R56) Project #
1R56AI122273-01A1 Application # 9211114 Study Section Cellular and Molecular
Biology of Neurodegeneration Study Section (CMND) Program Officer Beisel,
Christopher E Project Start 2016-02-16 Project End 2017-01-31 Budget Start
2016-02-16 Budget End 2017-01-31 Support Year 1 Fiscal Year 2016 Total Cost
Indirect Cost Institution Name Colorado State University-Fort Collins
Department Microbiology/Immun/Virology Type Schools of Veterinary Medicine DUNS
# 785979618 City Fort Collins State CO Country United States Zip Code 80523
PMCA Detection of CWD Infection in Cervid
and Non-Cervid Species
Hoover, Edward Arthur Colorado State
University-Fort Collins, Fort Collins, CO, United States Abstract Chronic
wasting disease (CWD) of deer and elk is an emerging highly transmissible prion
disease now recognized in 18 States, 2 Canadian provinces, and Korea.
We have shown that Infected deer harbor
and shed high levels of infectious prions in saliva, blood, urine, and feces,
and in the tissues generating those body fluids and excreta, thereby leading to
facile transmission by direct contact and environmental contamination. We have
also shown that CWD can infect some non-cervid species, thus the potential risk
CWD represents to domestic animal species and to humans remains unknown.
Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are
generated or modified in the proximate peripheral tissue sites, may differ in
subtle ways from those generated in brain, or may be adapted for mucosal
infection remain open questions. The increasing parallels in the pathogenesis
between prion diseases and human neurodegenerative conditions, such as
Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible
protein misfolding disease. The overall goal of this work is to elucidate the
process of CWD prion transmission from mucosal secretory and excretory tissue
sites by addressing these questions:
(a) What are the kinetics and magnitude
of CWD prion shedding post-exposure?
(b) Are excreted prions biochemically
distinct, or not, from those in the CNS?
(c) Are peripheral epithelial or CNS
tissues, or both, the source of excreted prions? and
(d) Are excreted prions adapted for
horizontal transmission via natural/trans-mucosal routes?
The specific aims of this proposal are:
(1) To determine the onset and
consistency of CWD prion shedding in deer and cervidized mice;
(2); To compare the biochemical and
biophysical properties of excretory vs. CNS prions;
(3) To determine the capacity of peripheral
tissues to support replication of CWD prions;
(4) To determine the protease- sensitive
infectious fraction of excreted vs. CNS prions; and
(5) To compare the mucosal infectivity of
excretory vs. CNS prions.
Understanding the mechanisms that enable
efficient prion dissemination and shedding will help elucidate how horizontally
transmissible prions evolve and succeed, and is the basis of this proposal.
Understanding how infectious misfolded proteins (prions) are generated,
trafficked, shed, and transmitted will aid in preventing, treating, and
managing the risks associated with these agents and the diseases they cause.
Public Health Relevance
Chronic wasting disease (CWD) of deer and
elk is an emergent highly transmissible prion disease now recognized throughout
the USA as well as in Canada and Korea. We have shown that infected deer harbor
and shed high levels of infectious prions in saliva, blood, urine, and feces
thereby leading to transmission by direct contact and environmental
contamination. In that our studies have also shown that CWD can infect some
non-cervid species, the potential risk CWD may represents to domestic animal
species and humans remains unknown. The increasing parallels in the development
of major human neurodegenerative conditions, such as Alzheimer's and
Parkinson's diseases, and prion diseases add relevance to CWD as a model of a
transmissible protein misfolding disease. Understanding how infectious
misfolded proteins (prions) are generated and transmitted will aid in
interrupting, treating, and managing the risks associated with these agents and
the diseases they cause.
Funding Agency Agency National Institute
of Health (NIH) Institute National Institute of Neurological Disorders and
Stroke (NINDS) Type Research Project (R01) Project # 4R01NS061902-07
Application # 9010980 Study Section Cellular and Molecular Biology of
Neurodegeneration Study Section (CMND) Program Officer Wong, May Project Start
2009-09-30 Project End 2018-02-28 Budget Start 2016-03-01 Budget End 2017-02-28
Support Year 7 Fiscal Year 2016 Total Cost $409,868 Indirect Cost $134,234
Institution Name Colorado State University-Fort Collins Department
Microbiology/Immun/Virology Type Schools of Veterinary Medicine DUNS #
785979618 City Fort Collins State CO Country United States Zip Code 80523
LOOKING FOR CWD IN HUMANS AS nvCJD or as
an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ *** 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).***
Monday, May 02, 2016
*** Zoonotic Potential of CWD Prions: An
Update Prion 2016 Tokyo ***
Saturday, April 23, 2016
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 online
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 ef?ciency comparable to that of cattle BSE.
While the ef?ciency 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.
why do we not want to do TSE transmission
studies on chimpanzees $
5. A positive result from a chimpanzee
challenged severly would likely create alarm in some circles even if the result
could not be interpreted for man. I have a view that all these agents could be
transmitted provided a large enough dose by appropriate routes was given and
the animals kept long enough. Until the mechanisms of the species barrier are
more clearly understood it might be best to retain that hypothesis. snip... R.
BRADLEY
*** 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.
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.
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896
printl 1933-690X online
Monday, May 09, 2016
A comparison of classical and H-type
bovine spongiform encephalopathy associated with E211K prion protein polymorphism
in wild type and EK211 cattle following intracranial inoculation
Monday, August 22, 2016
*** CREUTZFELDT JAKOB DISEASE USA 2015
SPORADIC CJD TOTAL FIGURES REACHES HIGHEST ANNUAL COUNT TO DATE AT 239
CONFIRMED CASES ***
Transmission of scrapie prions to primate
after an extended silent incubation period
***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.***
Thursday, August 18, 2016
*** PROCEEDINGS ONE HUNDRED AND
Nineteenth ANNUAL MEETING of the USAHA BSE, CWD, SCRAPIE, PORCINE TSE PRION
October 22 28, 2015 ***
Tuesday, August 9, 2016
*** Concurrence with OIE Risk
Designations for Bovine Spongiform Encephalopathy [Docket No. APHIS-2015-0055]
Saturday, July 23, 2016
*** BOVINE SPONGIFORM ENCEPHALOPATHY BSE
TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE
JULY 2016
Tuesday, July 26, 2016
*** Atypical Bovine Spongiform
Encephalopathy BSE TSE Prion UPDATE JULY 2016
Saturday, July 16, 2016
*** Importation of Sheep, Goats, and
Certain Other Ruminants [Docket No. APHIS-2009-0095]RIN 0579-AD10
WITH great disgust and concern, I report
to you that the OIE, USDA, APHIS, are working to further legalize the trading
of Transmissible Spongiform Encephalopathy TSE Pion disease around the globe.
THIS is absolutely insane. it’s USDA INC.
Thursday, October 22, 2015
*** Former Ag Secretary Ann Veneman talks
women in agriculture and we talk mad cow disease USDA and what really happened
those mad cows in Texas ***
Monday, June 20, 2016
*** Specified Risk Materials SRMs BSE TSE
Prion Program ***
Thursday, April 14, 2016
Arizona 22 year old diagnosed with
Creutzfeldt Jakob Disease CJD
Thursday, January 15, 2015
41-year-old Navy Commander with sporadic
Creutzfeldt–Jakob disease CJD TSE Prion: Case Report
Saturday, January 17, 2015
*** Becky Lockhart 46, Utah’s first
female House speaker, dies diagnosed with the extremely rare Creutzfeldt-Jakob
disease
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION
REPORT DECEMBER 14, 2015
Sunday, August 21, 2016
Kay Ellen Roedl Schwister Deceased August
7, 2016 at the age of 53 with Creutzfeldt-Jakob disease CJD TSE Prion
spontaneous sporadic, zoonosis, or iatrogenic?
Monday, August 22, 2016
*** CREUTZFELDT JAKOB DISEASE USA 2015
SPORADIC CJD TOTAL FIGURES REACHES HIGHEST ANNUAL COUNT TO DATE AT 239
CONFIRMED CASES ***
Tuesday, November 22, 2016
AGFC finds 28 new cases of CWD in north
Arkansas
Friday, November 11, 2016
Canada Transmissible Spongiform
Encephalopathy TSE Prion Report Update
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