Researchers estimate one in 2,000 people in the UK carry variant CJD proteins
Monday, October 14, 2013 -
16:55
Around one in 2,000
people in the UK may carry variant CJD proteins, concludes a large scale survey
published on bmj.com today.
The survey provides the
most robust prevalence measure to date - and identifies abnormal prion protein
across a wider age group than found previously and in all genotypes.
An accompanying editorial
says that although the disease remains rare, “infection” may be relatively
common and doctors need to understand the public health measures that are in
place to protect patients.
Variant Creutzfeldt-Jakob
disease (vCJD) is a degenerative brain disease – often called the human form of
bovine spongiform encephalopathy (BSE) or “mad cow disease.” It emerged after
widespread exposure to BSE prions in the late 1980s and early 1990s through
contaminated meat products in the food chain.
Although there have been
only 177 clinical cases of vCJD to date in the UK, previous studies have
estimated that around one in 4,000 people may carry vCJD prions. But uncertainty
remains about how many people will eventually develop the disease.
And it is still not clear
what risk carriers pose of transmitting the disease by blood transfusion or
surgery. Despite this, UK health agencies have already taken steps to secure the
blood supply and reduce any risk of transmission by surgical
instruments.
So a team of UK
researchers decided to conduct a further survey to better understand how many
people in the UK may be carriers and to identify their genetic make-up
(genotype).
They examined over 32,000
anonymous appendix samples from people of all ages who had their appendix
removed between 2000 and 2012 at over 41 hospitals across England.
Of these, 16 samples were
positive for abnormal prion protein, indicating an overall prevalence of 493 per
million population. From this figure, the research team estimate that one in
2,000 people are likely to be carriers.
The presence of prion
protein in those born in 1941-60 did not differ significantly from those born
between 1961 and 1985 and was similar in both sexes.
And when the samples were
grouped into three broad geographical areas (north east and north west; south
east coast, south west, and London, and East and West Midlands), there were no
apparent differences in abnormal prion prevalence.
As well as finding no
particular age group or geographic region affected, no susceptible genotype of
patients was identified.
Genetic testing of the 16
positive samples revealed a higher proportion of valine homozygous (VV) genotype
on the codon 129 of the gene encoding the prion protein (PRNP) compared with the
general UK population. This also differs from the 177 patients with vCJD, all of
whom to date have been methionine homozygous (MM) genotype.
The concern is that
individuals with this VV genotype may be susceptible to developing the condition
over longer incubation periods, or they may not show any clinical signs of
disease, say the authors.
They stress that the
number of patients with clinical vCJD is still well below the number suggested
by the prevalence of abnormal prion protein, even for those who carry the MM
genotype. Nevertheless, they say it is essential to continue research into tests
to detect abnormal prion protein in blood – and to examine tissue from the 1970s
and earlier, before BSE appeared.
In an accompanying
editorial, Roland Salmon, a retired consultant epidemiologist, says that
although we know much about these fascinating, if terrible, diseases, many
important questions remain about their characteristics and what other animal
prion diseases may be transmitted to humans.
He argues that the UK’s
prion research capacity “is well placed to answer such questions” and that
“further disinvestment would be premature.”
Contacts:
Research: Sebastian Brandner, professor of neuropathology, Division of Neuropathology, the National Hospital for Neurology and Neurosurgery, and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
or
Public Health England Press Office, London, UK
Editorial: Roland Salmon,
retired consultant epidemiologist, Cardiff, Wales, UK
Importantly, we have
recently established that a 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.
see ;
Friday, August 16, 2013
*** Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates
http://creutzfeldt-jakob-disease.blogspot.com/2013/08/creutzfeldt-jakob-disease-cjd-biannual.html
*** Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates
http://creutzfeldt-jakob-disease.blogspot.com/2013/08/creutzfeldt-jakob-disease-cjd-biannual.html
Interim data from the unlinked
anonymous survey of the prevalence of abnormal prion protein using archived
appendix tissue show that four samples have tested positive for
disease-associated prion protein (PrPCJD) out of
13,878 suitable specimens examined (288 per million - 95% Confidence Interval
(CI): 79 to 738 per million) (table 1). Using the information collected by the
National CJD Research and Surveillance Unit on the 175 variant Creutzfeldt-Jakob
Disease (vCJD) cases to date, it is possible to conclude that all four
appendices found positive in this survey have not come from known vCJD cases.
Codon 129 analysis of the four positive specimens is underway at the MRC Prion
Unit. Excluding a small survey of tonsils reported in 2004 [1], available data on the prevalence of
PrPCJD in Britain is summarised in table 2 [2-4].
Table 1. Number of
appendix samples tested for disease-associated prion protein (PrPCJD)
in England by birth cohorts, gender and area as at July 2011
(Positive/total, rate per million with 95% confidence intervals)*†
|
Broad geographic area
|
Individuals born between 1941 and 1960
|
Individuals born between 1961 and 1985
|
Total from both birth cohorts
| ||||
|
Female
|
Male
|
Total including unknown gender
|
Female
|
Male
|
Total including unknown gender
| ||
|
North
East and North West
|
0/334
|
1/317
|
1/860
|
0/107
|
0/1176
|
0/3015
|
1/3875
|
|
South
East Coast and South West
|
1/917
|
0/748
|
1/2062
|
0/3026
|
2/2841
|
2/7067
|
3/9129
|
|
West
Midlands
|
0/109
|
0/89
|
0/198
|
0/318
|
0/357
|
0/676
|
0/874
|
|
Total
|
1/1360
|
1/1154
|
2/3120
|
0/4415
|
2/4374
|
2/10758
|
4/13878‡
|
|
Rate
per million (95% confidence intervals)
|
|
641
(78-2314) |
|
186
(23-671) |
288
(79-738) | ||
The ACDP TSE Risk Assessment
Sub-Group has considered the interim data from the current appendix survey and
concluded that the results for the 1961 to 1985 birth cohort 'essentially
reproduce' the results for the earlier survey published in 2004 [5]. Also, two
of the four positives to date in the survey that is underway were in the 1941 to
1960 birth cohort (641 infections per million population - 95% CI 78-2314), so
it is possible prevalence could be higher in the 1941 to 1960 birth cohort
compared to the 1961 to 1985 birth cohort (186 infections per million population
- 95% CI 23-671). The Sub-Group concluded that: 'the precautionary (and maybe
most likely) scenario is that all those with signs of infection in tissue would
have infective blood. So although the contrary assumption could help explain
the small number of blood-borne cases to date, relying on this would be
problematic. Unless there is evidence to the contrary, abnormal prion protein
in tissues can be regarded as a proxy measure for infectivity in blood.' [5].
The current appendix survey is
being conducted by a collaboration of the HPA, the Department of
Neurodegenerative Diseases at the UCL Institute of Neurology and the Animal
Health and Veterinary Laboratories Agency. The survey is collecting and
archiving sufficient (up to 40,000) appendix samples from participating
pathology departments throughout England so that 30,000 suitable specimens from
operations since 2000 can be examined. These anonymous samples are being
unlinked from any patient identifiable information and tested by
immunohistochemistry (IHC) for the presence of PrPCJD. A specimen
unsuitability rate of approximately 18% has been observed in both testing
laboratories which compares favourably against the expected rate of
25%.
The earlier study of appendix
and some tonsil tissue, from operations conducted between 1995 and 1999, found
three positive samples out of 12,674 tested for PrPCJD using the IHC
method [4]. The prevalence estimate calculated from this study was 237 per
million (95% CI: 49-692 per million) - or 380 per million (95% CI=80-1120 per
million) in 20-30 year olds, since all the PrPCJD positive
individuals were in this age group (table 2).
Table 2. Prevalence
of disease-associated prion protein (PrPCJD) in Britain by birth
cohort and overall: data to July 2011 (Positive/total, rate per million
with 95% confidence intervals*)
|
Birth Cohort
|
Current (2004-July 2011) national
tissue surveys |
Earlier (1995-1999) national tissue
survey [4]
| |||
|
Tonsils
(EIA) [2]
|
Tonsils (IHC) [3]
|
Appendices
|
Appendices
|
Tonsils
| |
|
Pre-1940
|
0/51
|
–
|
–
|
–
|
0/225
|
|
1941-1960
|
0/648
|
–
|
2/3120
641 (78-2314) |
0/573
|
0/266
|
|
1961-1985
|
0/17786
0 (0-207) |
1/9160
109 (3-608) |
2/10758
186 (23-671) |
3/10278
292 (60-853) |
0/694
|
|
1986-1990
|
0/12799
0 (0-288) |
0/135
|
–
|
0/396
|
0/119
|
|
1991-1995
|
0/15147
0 (0-244) |
0/83
|
–
|
–
|
0/106
|
|
1996
and later
|
0/47518
|
0/294
|
–
|
–
|
0/17
|
|
Total
|
0/93949 0 (0-39)
|
1/9672103 (3-576)
|
4/13878 288 (79-738)
|
3/11247 267 (55-779)
|
0/1427 0 (0-2582)
|
In April 2008, the Spongiform Encephalopathy Advisory Committee (SEAC) considered available data from the National Anonymous Tonsil Archive (NATA) [6]. At that time no PrPCJD positive samples had been found in nearly 55,000 samples, analysed by a high throughput enzyme immunoassay technique, including about 11,000 samples from the 1961 to 1985 birth cohort [1]. Statistical analysis of the data from the completed appendix survey and NATA showed that, because of the wide confidence intervals around both prevalence estimates, the data sets were statistically consistent with each other. However, should the lack of PrPCJD positive samples from NATA continue as more samples are collected and analysed, the two data sets will at some stage become discrepant. Subsequently, through applying the immunohistochemistry technique to the tonsils from the 1961 to 1985 birth cohort, one specimen with a single strongly positive follicle was found, leading to the conclusion that there was 'no or one v-CJD positive individual' in this group (table 2) [2].
In the face of continued
uncertainty over possible discrepant results between both prevalence surveys,
together with the urgency to resolve this uncertainty as quickly as possible,
SEAC advised that, provided appendix samples were collected from the appropriate
birth cohort (1941 to 1960 and 1961 to 1985), and these samples were tested
using the same immunohistochemistry technique as used in the previous appendix
tissue study, the data from such a study could be combined with the previous
study [6]. This would allow further refinement of the current estimates for the
prevalence of subclinical infections.
References
1. Frosh A, Smith LC, Jackson CJ, Linehan JM, Brandner S, Wadsworth JDF, et al. Analysis of 2000 consecutive UK tonsillectomy specimens for disease-related prion protein. Lancet 2004; 364: 1260-2.
1. Frosh A, Smith LC, Jackson CJ, Linehan JM, Brandner S, Wadsworth JDF, et al. Analysis of 2000 consecutive UK tonsillectomy specimens for disease-related prion protein. Lancet 2004; 364: 1260-2.
2. Clewley J, Kelly CM,
Andrews N, Vogliqi K, Mallinson G, Kaisar M, et al. Prevalence of disease related prion protein in anonymous
tonsil specimens in Britain: cross sectional opportunistic
survey. BMJ 2009;
338: b1442.
3. de Marco MF, Linehan J,
Gill ON, Clewley JP, Brander S. Large scale immunohistochemical examination for
lymphoreticular prion protein in tonsil specimens collected in
Britain. J Pathol 2010;
222: 380-7.
4. Hilton DA, Ghani AC,
Conyers L, Edwards P, McCardle L, Ritchie D, et al. Prevalence of lymphoreticular prion protein accumulation
in UK tissue samples. J Pathol
2004; 203: 733-9.
5. Advisory Committee on
Dangerous Pathogens TSE Risk Assessment SubGroup. Minutes July 14th 2011:
http://www.dh.gov.uk/ab/ACDP/TSEguidance/DH_125868.
6. Spongiform Encephalopathy
Advisory Committee (SEAC). Position Statement. Prevalence of subclinical variant
Creutzfeldt-Jakob Disease infections. August 2008. SEAC position statement.
Saturday, May 23,
2009
Latest results of HPA study on vCJD-related abnormal prion proteins in extracted tonsils
http://creutzfeldt-jakob-disease.blogspot.com/2009/05/latest-results-of-hpa-study-on-vcjd.html
Latest results of HPA study on vCJD-related abnormal prion proteins in extracted tonsils
http://creutzfeldt-jakob-disease.blogspot.com/2009/05/latest-results-of-hpa-study-on-vcjd.html
From: TSS
Subject: Retrospective study of prion-protein accumulation in tonsil and
appendix tissues
Date: May 12, 2000 at 7:10 am PST
Lancet Research letters Volume 355, Number 9216 13 May 2000
Retrospective study of prion-protein accumulation in tonsil and appendix
tissues
Lancet 2000; 355: 1693 - 1694
James W Ironside, David A Hilton, Azra Ghani, Nicola J Johnston, Lisa
Conyers, Linda M McCardle, Diana Best
To identify individuals who could be at high risk of developing vCJD, a
sensitive immunohistochemical technique was used to detect prion protein in a
retrospective series of over 3000 tonsil and appendix specimens. No positives
were detected but further studies are required to help reduce uncertainties
about possible future numbers of vCJD cases in the UK.
Variant Creutzfeldt-Jakob disease (vCJD) is an acquired disorder caused by
the bovine spongiform encephalopathy (BSE) agent in man, and is the only human
prion disease in which the abnormal isoform of the prion protein is consistently
detectable outside the central nervous system. Prion-protein accumulation has
been detected by western blot and immunocytochemistry in several lymphoid
tissues (including the tonsil and appendix) sampled at necropsy1 (JWI,
unpublished), and during life in tonsil biopsy specimens from individuals with
clinically evident vCJD.1 Lymphoid tissue involvement has been shown in scrapie
in sheep and in several experimental scrapie models, usually from an early stage
in the disease incubation period.2 In view of the likely lengthy incubation
period for vCJD in human beings, estimation of future numbers of cases is
difficult, with wide ranges published.3
We investigated the presence of prion protein in surgically resected
appendix and tonsil specimens as an indicator of numbers of individuals in the
UK population who could be at high risk of developing vCJD. Since all cases of
confirmed vCJD to date have been between the ages of 15 and 54 years, we only
examined tissue samples from individuals aged between 10 and 50 years at
operation. Furthermore, only samples taken from 1995 onwards were examined
because these will have had a longer time from possible BSE exposure than
earlier samples, with therefore a greater likelihood of prion protein being
detectable. Examination of the first batches of samples from individuals aged
10-30 years is now complete.
Paraffin-embedded tissue blocks from 4166 appendix and tonsil specimens
were retrieved from archives of pathology departments in the Lothian and
southwest regions of the UK (table). The material was identified by a search of
computerised databases starting in 1998, and working back to 1995. The pathology
case numbers from the materials studied were grouped in batches of at least
1000, and the samples randomised and analysed without knowledge of the original
case number. 4 mm sections were cut from tissue blocks at two levels 100 mm
apart, and pretreated by autoclaving at 121°C for 10 min, followed by immersion
in 96% formic acid for 5 min and digestion with proteinase K (100 mg/mL) for 5
min at room temperature. Prion protein was detected by the well characterised
and widely used mono-clonal antibodies 3F4 (Dako, Ely, UK) and KG9 (IAH TSE
Resource Centre, Compton, UK),1,4 and visualised with the catalysed signal
amplification system (Dako, Ely, UK), which gives superior results, in terms of
sensitivity, to most other immunohistochemical visualisation systems.5
Haematoxylin and eosin-stained sections were assessed to ensure that at least
five lymphoid follicles were present; sections were recorded as positive if
prion-protein staining was detected in follicular dendritic cells or tingible
body macro-phages in lymphoid follicles. Cases with fewer than five lymphoid
follicles were excluded because in a previously reported case,4 and in those
examined at necropsy, prion protein could only be shown in 25% of follicles. The
average number of follicles in those samples included in the study was 20 per
case, giving a 96% chance of a positive sample being declared. Necropsy tonsil
tissues from confirmed cases of vCJD were used as a positive control for each
group of slides stained by immuno-histochemistry for prion protein. Negative
controls were done by omitting the primary antiserum. 30 cases from each batch
of 1000 were exchanged between study centres for quality control and validation
of results. No tonsil or appendix sample was found to be positive for prion
protein (table).
Edinburgh Plymouth Total
Appendix
Total specimens studied 906 3165 4071
Total specimens excluded from analysis 236 760 966
Negative cases 670 2405 3075
Positive cases 0 0 0
Tonsil
Total specimens studied 95 0 95
Total specimens excluded from analysis 0 · · 0
Negative cases 95 · · 95
Positive cases 0 · · 0
Results of prion-protein immunohistochemistry
Prion protein has been previously detected by immunohistochemistry in the
tonsils of all sheep who subsequently went on to develop scrapie by 8 months in
those homozygous for a susceptibility prion-protein polymorphism, and by 15
months in heterozygotes at that locus, but was not detected in those who
remained free of symptoms.2 However, few data are available on vCJD; in one
patient prion protein was detected in an appendix removed in 1995, 8 months
before onset of symptoms,4 and in another case prion protein was not detected in
an appendicectomy specimen removed in 1990, 9 years before onset of symptoms
(unpublished). The mean incubation period for vCJD is unknown, although peak
exposure of the UK population to the BSE agent is likely to have been between
1988 and 1992. By use of a mathematical model to generate epidemic scenarios
that are consistent with age-stratified disease incidence to the end of 1998,3
if we assume that tests are able to detect infection in the last 75% of the vCJD
incubation period (with 100% sensitivity and specificity), then the upper bound
on epidemic size is reduced from several million cases to about 150 000 cases.
However, if tests are only able to detect infection in the last 50% of the
incubation period, these results do not reduce the previously reported
uncertainty in epidemic size.
Clearly, larger studies are required, some of which are already underway.
Studies with unfixed tissue samples are also planned, allowing western blotting
for prion protein to be undertaken (which might be more sensitive than
immunohistochemistry), with verification of positive samples by transmission
studies. Further data might also become available from animal studies and from
future cases of vCJD in the next few years, which detail how long after exposure
prion protein can be detected in lymphoid tissues with these techniques, and
will aid interpretation of negative findings. We hope that the results of these
studies will allow further reduction in the uncertainty about future numbers of
cases of vCJD.
We would like to thank S Bird (Cambridge) for providing probability values
on the basis of the number of follicles examined. This study was funded by the
UK Department of Health.
1 Hill AF, Butterworth RJ, Joiner S, et al. Investigation of variant
Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy
samples. Lancet 1999; 353: 183-89.
2 Schreuder BEC, van Keulen LJM, Vromans MEW, et al. Tonsillar biopsy and
PrPSc detection in the preclinical diagnosis of scrapie. Vet Rec 1998; 142:
564-68 [PubMed].
3 Ghani AC, Ferguson NM, Donnelly CA, et al. Epidemiological determinants
of the pattern and magnitude of the vCJD epidemic in Great Britain. Proc R Soc
Lond 1998; 265: 2443-52.
4 Hilton DA, Fathers E, Edwards P, et al. Prion immunoreactivity in the
appendix before the clinical onset of new variant Creutzfeldt-Jakob disease.
Lancet 1998; 352: 703-04.
5 Sabattini E, Bisgaard K, Ascani S, et al. The EnVision++ system: a new
immunohistochemical method for diagnostics and research: critical comparison
with the APAAP, ChemMate, CSA, LABC, and SABC techniques. J Clin Pathol 1998;
51: 506-11 [PubMed].
National CJD Surveillance Unit, Western General Hospital, Edinburgh EH4
2XU, UK (James W Ironside FRCPath, L M McCardle FIMLS, D Best); Department of
Histopathology, Derriford Hospital, Plymouth, UK (D A Hilton MRCPath, N J
Johnston, L Conyers); and Welcome Trust for the Epidemiology of Infectious
Disease, University of Oxford, UK (A Ghani PhD)
Correspondence to: Dr James W Ironside
END...TSS
Sunday, August 11, 2013
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
http://creutzfeldt-jakob-disease.blogspot.com/2013/08/creutzfeldt-jakob-disease-cjd-cases.html
Sunday, October 13, 2013
CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/cjd-tse-prion-disease-cases-in-texas-by.html
Sunday, October 13, 2013
Prion Disease Cases in Texas by Year, 2003-2012
http://cjdtexas.blogspot.com/2013/10/prion-disease-cases-in-texas-by-year_13.html
Wednesday, October 09, 2013
WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/why-ukbsenvcjd-only-theory-is-so.html
Tuesday, September 24, 2013
NORDION (US), INC., AND BIOAXONE BIOSCIENCES, INC., Settles $90M Mad Cow
TSE prion Contamination Suit Cethrin(R)
Case 0:12-cv-60739-RNS Document 1 Entered on FLSD Docket 04/26/2012 Page 1
of 15
Monday, September 02, 2013
Atypical BSE: role of the E211K prion polymorphism
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Location: Virus and Prion Research Unit
Sunday, September 1, 2013
Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy
We previously described the biochemical similarities between PrPres derived
from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations
suggest a link between these two uncommon prion phenotypes in a primate model
(it is to note that such a link has not been observed in other models less
relevant from the human situation as hamsters or transgenic mice overexpressing
ovine PrP [28]). We speculate that a group of related animal prion strains
(L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion
diseases in humans with a type 2 PrPres molecular signature (and more
specifically type 2B for vCJD)
snip...
Together with previous experiments performed in ovinized and bovinized
transgenic mice and hamsters [8,9] indicating similarities between TME and
L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME
outbreaks in North America and Europe during the mid-1900s.
Sunday, July 21, 2013
Welsh Government and Food Standards Agency Wales Joint Public Consultation
on the Proposed Transmissible Spongiform Encephalopathies (Wales) Regulations
2013 Singeltary Submission WG18417
Summary results of the second national survey of abnormal prion prevalence in archived appendix specimens August 2012
http://creutzfeldt-jakob-disease.blogspot.com/2012/08/summary-results-of-second-national.html
Tuesday, October 05, 2010
Large-scale immunohistochemical examination for lymphoreticular prion
protein in tonsil specimens collected in Britain
05 Oct 2010 14:46
please see ;
> but the possibility that a small proportion of
human cases so far classified as "sporadic" CJD are of zoonotic origin could not
be excluded.
> 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.
>Recently, however,
so-called atypical forms of prion diseases have been discovered in sheep
(atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble
sporadic or genetic human prion diseases and might be their animal
equivalents.
> This hypothesis
also raises the significant public health question of possible epidemiological
links between these diseases and their counterparts in humans.
>2.66 Dr Fahey also
told the committee that in the last two years a link has been established
between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now
believe that those atypical BSEs overseas are in fact causing sporadic
Creutzfeldt->Jakob disease. They were not sure if it was due to mad sheep
disease or a different form.
>The pathology
features of Nor98 in the cerebellum of the affected sheep showed similarities
with those of sporadic Creutzfeldt-Jakob disease in humans.
>Intriguingly, these
conclusions suggest that some pathological features of Nor98 are reminiscent of
Gerstmann-Sträussler-Scheinker disease.
>These observations
support the view that a truly infectious TSE agent, unrecognized until recently,
infects sheep and goat flocks and may have important implications in terms of
scrapie control and public health.
>These findings raise
some interrogation on the concept of TSE strain and on the origin of the
diversity of the TSE agents and could have consequences on field TSE control
measures.
>In summary, we have transmitted one atypical form
of BSE (BASE) to a cynomolgus macaque monkey that had a shorter incubation
period than monkeys infected with classical BSE, with distinctive clinical,
neuropathological, and >biochemical features; and have shown that the
molecular biological signature resembled that seen in a comparatively uncommon
subtype of sporadic CJD.
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A
Success Story
snip...
EFSA and the European Centre for Disease Prevention
and Control (ECDC) recently delivered a scientific opinion on any possible
epidemiological or molecular association between TSEs in animals and humans
(EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion
confirmed Classical BSE prions as the only TSE agents demonstrated to be
zoonotic so far ***but the possibility that a small proportion of human cases so
far classified as "sporadic" CJD are of zoonotic origin could not be excluded.
Moreover, transmission experiments to non-human primates suggest that some TSE
agents in addition to Classical BSE prions in cattle (namely L-type Atypical
BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic
wasting disease (CWD) agents) might have zoonotic potential.
snip...
Thursday, August 12, 2010 Seven main threats for the
future linked to prions First threat The TSE road map defining the evolution of
European policy for protection against prion diseases is based on a certain
numbers of hypotheses some of which may turn out to be erroneous. In particular,
a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently
identified by systematic testing in aged cattle without clinical signs, may be
the origin of classical BSE and thus potentially constitute a reservoir, which
may be impossible to eradicate if a sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and
some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These
atypical BSE cases constitute an unforeseen first threat that could sharply
modify the European approach to prion diseases.
Second threat
snip...
Monday, May 23,
2011
Atypical Prion Diseases in Humans and Animals 2011
Top Curr Chem (2011)
DOI: 10.1007/128_2011_161
# Springer-Verlag Berlin Heidelberg 2011
Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar
Abstract
Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.
M.A. Tranulis (*)
Norwegian School of Veterinary Science, Oslo, Norway
e-mail: Michael.Tranulis@nvh.no
S.L. Benestad
Norwegian Veterinary Institute, Oslo, Norway
T. Baron
Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France
H. Kretzschmar
Ludwig-Maximilians University of Munich, Munich, Germany
Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type
http://resources.metapress.com/pdf-preview.axd?code=f433r34h34ugg617&size=largest
Atypical Prion Diseases in Humans and Animals 2011
Top Curr Chem (2011)
DOI: 10.1007/128_2011_161
# Springer-Verlag Berlin Heidelberg 2011
Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar
Abstract
Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.
M.A. Tranulis (*)
Norwegian School of Veterinary Science, Oslo, Norway
e-mail: Michael.Tranulis@nvh.no
S.L. Benestad
Norwegian Veterinary Institute, Oslo, Norway
T. Baron
Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France
H. Kretzschmar
Ludwig-Maximilians University of Munich, Munich, Germany
Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type
http://resources.metapress.com/pdf-preview.axd?code=f433r34h34ugg617&size=largest
Rural and Regional
Affairs and Transport References Committee
The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010
2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50
http://www.aph.gov.au/senate/committee/rrat_ctte/mad_cows/report/report.pdf
The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010
2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50
http://www.aph.gov.au/senate/committee/rrat_ctte/mad_cows/report/report.pdf
Atypical BSE (BASE) Transmitted from Asymptomatic
Aging Cattle to a Primate
Emmanuel E. Comoy1*, Cristina Casalone2, Nathalie
Lescoutra-Etchegaray1, Gianluigi Zanusso3, Sophie Freire1, Dominique Marcé1,
Frédéric Auvré1, Marie-Magdeleine Ruchoux1, Sergio Ferrari3, Salvatore Monaco3,
Nicole Salès4, Maria Caramelli2, Philippe Leboulch1,5, Paul Brown1, Corinne I.
Lasmézas4, Jean-Philippe Deslys1
1 Institute of Emerging Diseases and Innovative
Therapies, CEA, Fontenay-aux-Roses, France, 2 Istituto Zooprofilattico
Sperimentale del Piemonte, Turin, Italy, 3 Policlinico G.B. Rossi, Verona,
Italy, 4 Scripps Florida, Jupiter, Florida, United States of America, 5 Genetics
Division, Brigham & Women's Hospital, Harvard Medical School, Boston,
Massachusetts, United States of America
Abstract Top Background
Human variant Creutzfeldt-Jakob Disease (vCJD)
results from foodborne transmission of prions from slaughtered cattle with
classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which
remain mostly asymptomatic in aging cattle, were recently identified at
slaughterhouses throughout Europe and North America, raising a question about
human susceptibility to these new prion strains.
Methodology/Principal Findings
Brain homogenates from cattle with classical BSE and
atypical (BASE) infections were inoculated intracerebrally into cynomolgus
monkeys (Macacca fascicularis), a non-human primate model previously
demonstrated to be susceptible to the original strain of cBSE. The resulting
diseases were compared in terms of clinical signs, histology and biochemistry of
the abnormal prion protein (PrPres). The single monkey infected with BASE had a
shorter survival, and a different clinical evolution, histopathology, and prion
protein (PrPres) pattern than was observed for either classical BSE or
vCJD-inoculated animals. Also, the biochemical signature of PrPres in the
BASE-inoculated animal was found to have a higher proteinase K sensitivity of
the octa-repeat region. We found the same biochemical signature in three of four
human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the
same country as the infected bovine.
Conclusion/Significance
Our results point to a possibly higher degree of
pathogenicity of BASE than classical BSE in primates and also raise a question
about a possible link to one uncommon subset of cases of apparently sporadic
CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of
atypical strains should temper the urge to relax measures currently in place to
protect public health from accidental contamination by BSE-contaminated
products.
Citation: Comoy EE, Casalone C, Lescoutra-Etchegaray
N, Zanusso G, Freire S, et al. (2008) Atypical BSE (BASE) Transmitted from
Asymptomatic Aging Cattle to a Primate. PLoS ONE 3(8): e3017.
doi:10.1371/journal.pone.0003017
Editor: Neil Mabbott, University of Edinburgh, United
Kingdom
Received: April 24, 2008; Accepted: August 1, 2008;
Published: August 20, 2008
Copyright: © 2008 Comoy et al. This is an open-access
article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
Funding: This work has been supported by the Network
of Excellence NeuroPrion.
Competing interests: CEA owns a patent covering the
BSE diagnostic tests commercialized by the company Bio-Rad.
* E-mail: emmanuel.comoy@cea.fr
snip...
In summary, we have transmitted one atypical form of
BSE (BASE) to a cynomolgus macaque monkey that had a shorter incubation period
than monkeys infected with classical BSE, with distinctive clinical,
neuropathological, and biochemical features; and have shown that the molecular
biological signature resembled that seen in a comparatively uncommon subtype of
sporadic CJD. We cannot yet say whether BASE is more pathogenic for primates
(including humans) than cBSE, nor can we predict whether its molecular
biological features represent a clue to one cause of apparently sporadic human
CJD. However, the evidence presented here and by others justifies concern about
a potential human health hazard from undetected atypical forms of BSE, and
despite the waning epizoonosis of classical BSE, it would be premature to
abandon the precautionary measures that have been so successful in reversing the
impact of cBSE. We would instead urge a gradual, staged reduction that takes
into account the evolving knowledge about atypical ruminant diseases, and both a
permanent ban on the use of bovine central nervous system tissue for either
animal or human use, and its destruction so as to eliminate any risk of
environmental contamination.
atypical L-type BASE BSE California
SUMMARY REPORT CALIFORNIA BOVINE SPONGIFORM
ENCEPHALOPATHY CASE INVESTIGATION JULY 2012
Summary Report BSE 2012
Executive Summary
Saturday, August 4, 2012
Final Feed Investigation Summary - California BSE
Case - July 2012
Saturday, August 4, 2012
Update from APHIS Regarding Release of the Final
Report on the BSE Epidemiological Investigation
Sunday, September 25, 2011
Clinical Heidenhain Variant Of Sporadic Creutzfeldt-Jakob Disease (CJD) With Co-occurrence Of Prion Protein Types 1 and 2
http://creutzfeldt-jakob-disease.blogspot.com/2011/09/clinical-heidenhain-variant-of-sporadic.html
Clinical Heidenhain Variant Of Sporadic Creutzfeldt-Jakob Disease (CJD) With Co-occurrence Of Prion Protein Types 1 and 2
http://creutzfeldt-jakob-disease.blogspot.com/2011/09/clinical-heidenhain-variant-of-sporadic.html
g
reetings
cjd world,
I find this very interesting, this coesistence of different TSE prion strains from different TSE sources. this new/old study out reminds me of way back ;
I find this very interesting, this coesistence of different TSE prion strains from different TSE sources. this new/old study out reminds me of way back ;
According to Professor James Ironside of the National CJD Surveillance Unit, Miss Rimmer's case was "unique" and tests showed signs of both vCJD and new variant CJD.
"Our understanding of the case is not complete. It is one of the most unusual and difficult cases I have ever come across," he explained.
"The characteristics of the disease suffered by Miss Rimmer do not fall neatly into any category.
"The investigations that we have performed so far would indicate that this case, unique as it is, has more similarities to sporadic CJD than to new variant."
snip...
Mr Hughes returned a verdict of death by natural causes and concluded that Miss Rimmer died of bronchial pneumonia caused by CJD. ...
http://news.bbc.co.uk/2/hi/uk_news/wales/1300505.stm
SEE ;
Wednesday, October 09, 2013
WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/why-ukbsenvcjd-only-theory-is-so.html
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute,
Norway Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute,
Norway Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (
romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari,
Italy; 3 National Veterinary Institute, Department of Pathology, Oslo,
Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
***Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. *** These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
The epidemiological data are too limited to
conclude whether the Atypical scrapie
agent has a zoonotic potential. Transmission
experiments to human PrP transgenic mice or primates suggest that
some TSE agents other than the Classical BSE
agent in cattle (namely L-type Atypical BSE, Classical BSE in
sheep, TME, CWD agents) might have zoonotic
potential and indicate that that of the L-type Atypical BSE agent
appears similar or even higher than that of
the Classical BSE agent. A single study reported efficient
transmission
of a natural sheep Classical scrapie isolate
to primates.
© European Food Safety Authority,
2011
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76
AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE
Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie A] The Problem Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries. The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep. It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible. Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates.
One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias" Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC. Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC. Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
Wednesday, February 16, 2011
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
http://scrapie-usa.blogspot.com/2011/02/in-confidence-scrapie-transmission-to.html
why do we not want to do TSE transmission studies on chimpanzees $
snip...
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012
NIAA Annual Conference April 11-14, 2011San Antonio, Texas
http://nor-98.blogspot.com/2012/03/atypical-nor-98-scrapie-has-spread-from.html
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.
please see ;
Thursday, August 15, 2013
The emergence of novel BSE prions by serial
passages of H-type BSE in bovinized mice
Sunday, August 09,
2009
***CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames.html
***CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames.html
Wed, 29 Nov 2000 14:14:18
-0500
a private email from the late Dr. Gibbs, a true pioneer in the research of human/animal TSEs and one that never wavered on helping the families and victims of this horrible disease, and one that helped me many times in trying to seek out the truth;
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
==========
CJD VOICE
TSS