From: TSS ()
Subject: ATYPICAL SCRAPIE RESEARCH CONTINGENCY PLANNING
Date: May 3, 2007 at 8:48 am PST
ATYPICAL SCRAPIE RESEARCH CONTINGENCY PLANNING
19 Animal TSEs do not occur in all countries reporting sCJD and the
incidence of sCJD is not lower in countries without animal TSEs. Most
notably sCJD occurs in Australia and New Zealand where there have been
no reported cases of endogenous scrapie in sheep or goats. This fact has
been one argument supporting the view that scrapie is not a risk to human
health. (Will, 1991) Although new cases of TSE resulting from dietary
exposure to an animal TSE would not necessarily be recognised through a
change in sCJD incidence. The occurrence of variant CJD (vCJD) in the
UK is unlikely to have been recognised on this basis alone, since the
annual non-familial CJD incidence (the sum of sCJD and vCJD) did not lie
significantly outside the normal annual variation for sCJD. (Bosque, 2002)
20 However transmission of a French (classical) scrapie sample to C57Bl/6
mice gave similar lesion profiles and Western blotting profiles to those for
the French sCJD and iatrogenic CJD (iCJD) samples used in the same
experiment. (Lasmezas, 2001)
21 Scrapie has also been transmitted to squirrel monkeys (Gibbs, 1980) and
in a reverse experiment CJD was transmitted to two goats which
developed a disease with clinical signs and pathology indistinguishable
from scrapie. (Hadlow, 1980)
Scenario 2(a). Endogenous atypical scrapie cases are found in countries that
have been thought to be free from animal TSEs.
Q2: Would such a finding, in the absence of any other data linking
atypical scrapie to sCJD, affect the Committee’s assessment of the
Scenario 2(b). Extensive surveillance, using tests that are known to detect
atypical scrapie, is undertaken in non-European countries,
such as USA, Australia and New Zealand, and no atypical
scrapie is found.
WRONG, NOR98 NOW DOCUMENTED IN USA
NOR98-LIKE STRAIN OF SCRAPIE FOUND IN WYOMING (1791 lines)
From: Terry S. Singeltary Sr. <[log in to unmask]>
Date: Wed, 11 Apr 2007 15:08:15 -0500
2. Transmission/ species barrier
2.1 Transmission of atypical scrapie
25 When atypical scrapie was first reported it was not clear whether this was
a TSE i.e. transmissible or if it was a neurodegenerative condition with
increased prion protein. Work to assess transmissibility was first
undertaken where there would be little or no species barrier.
26 Limited work has been published to date on the transmissibility of atypical
scrapie. Tg338 mice which overexpress the ovine VRQ prion protein, with
a level in the brain of 8-10 times that in sheep, were inoculated intracerebrally
(i.c.) with brain samples from 2 Norwegian Nor98 cases plus 10
French cases classified as ‘discordant’ in the French surveillance program
(9 sheep (including 3 of the ARR/ARR genotype) and 1 goat). All mice
went down with clinical disease 200-300 days post inoculation (dpi).
Titration of mouse-passaged Nor98 in Tg338 had given an i.c. ID50 of
approximately 1ng brain. Whereas inoculation of Nor98 into inbred mouse
lines (RIII, C57Bl and VM) had failed to transmit after 850 dpi. However,
shortened incubation periods in Tg338 compared to inbred lines had also
been observed with classical scrapie. (Le Dur, 2005) A similarly
overexpressing VRQ transgenic mouse line, Tg301, gave an incubation
period of 73 days for classical scrapie as compared to 423 for RIII mice.
27 The Nor98 and the sheep and goat discordant samples transmitted to
Tg338 all resulted in a unique TSE, different from some 50 classical
scrapie isolates previously transmitted to these mice. The Nor98
proteinase K resistant prion protein (PrPres) Western blot profile was
maintained in the brains of the Tg338 mice and was also detectable in all
the mice inoculated with the French samples. All other analyses, including
lesion profiling, also gave identical results to those from the Nor98
samples. However no abnormal prion protein (PrPsc) was detected in the
cerebellum of the Tg338 mice for any sample in contrast with the high
cerebellar levels found in sheep with atypical scrapie.
28 Defra has funded research projects to investigate the transmissibility of Uk
atypical scrapie isolates to wild type and mice carrying the VRQ and ARQ
alleles of sheep PrP as transgenes (see below). results to date indicate
that UK isolates have a similar transmissibility to Tg338 mice as Nor98 and
Nor98-like isolates from other European countries.
29 Sheep have been challenged i.c. with atypical scrapie in another Defra
funded project. In December 2005 one sheep came down with clinical
disease (at 378 dpi).
2.2 Transgenic mice expressing the human prion protein (PrP) gene
30 Having established the transmissibility of atypical scrapie to ovine PrP
transgenic mice the important question for human risk is the relative
transmissibility to mice expressing the human PrP gene. transgenic mouse
models carrying various alleles of human PRNP have been developed and
their response to challenges with BSE, vCJD, sCJD CWD and scrapie
have been described.
31 Tg35 and Tg45 mice expressing the human 129 M PrP gene were
challenged with BSE and vCJD prions which transmitted disease resulting
in neuropathology and Western blotting profiles of the source diseases.
However Tg152 mice expressing the human 129 V PrP gene showed
decreased transmission, as might be expected from the known human
results, but gave a Western blotting pattern for PrPres and a weak, diffuse
disease-associated prion protein (PrPd) distribution in the brain that
differed from that for BSE, vCJD or Tg35/45 mice. (Wadsworth, 2004)
Further different results were found, with four distinct phenotypes, when
heterozygous 129 MV mice were bred from Tg45 and Tg152 and
inoculated with vCJD and BSE, providing information for comparison with
human CJD. (Asante, 2006)
32 The potential susceptibility of humans to CWD has also been investigated
in transgenic mice. Mice expressing the human 129 M prion protein at 1-
or 2-fold that in wild-type mice, or the elk 132 M prion protein (at 2-fold)
were inoculated with brain tissue from elk CWD or human sCJD cases.
CWD transmitted to all but one of the elk transgenic mice by 178 dpi,
whereas the human transgenic mice survived at least 756 or 657 (two
different mouse lines) with no detectable PrPd. Control inoculations of
sCJD produced disease after an average of 263 or 226 days in the mice
expressing the human protein. (Kong, 2005) Similar results of positive
transmission were obtained when a more extensive range of CWD cases
from elk, mule deer and white-tailed deer were inoculated into transgenic
mice overexpressing the prion protein gene of each cervid species and of
no transmission of these CWD cases to transgenic mice overexpressing
the human, ovine or bovine prion proteins. (Tamguney, 2006)
33 Mice which overexpress the prion protein transgene be more susceptible
to the inoculated disease as they produce abnormally high levels of the
transgenic normal cellular prion protein (PrPc). As an alternative mice have
been developed where the mouse PrP gene has been directly replaced by
the human (or other) gene, such that protein expression is regulated in the
normal way, and they are therefore more likely to respond to any natural
changes that may occur as the result of infection.
34 Such mice with the human 129 MM, VV and MV genotypes have been
produced. Transmission of vCJD and BSE to these mice by i.c. inoculation
was analysed in comparison to the identical mice expressing the bovine
gene. The human gene targeted mice were susceptible to vCJD
(measured by clinical disease or detectable PrPd) with 11/17 of the MM,
11/16 MV and 1/16 VV showing positive transmission. Inoculation of BSE
gave no positive transmission results for groups of 18, 23 and 22 human
transgenic MM, MV and VV mice respectively, whereas all 22 bovine
transgenics were susceptible. (Bishop, 2006) These results are interpreted
as suggesting a significant species barrier for humans to BSE and a much
lower barrier for secondary transmission of vCJD between humans, with all
genotypes being susceptible to varying degrees. A lengthy pre-clinical
phase for vCJD is also predicted. Detailed analysis of these mice has also
provided information on the possible neuropathological and biochemical
characteristics that might result from human to human transmission of
2.3 Non-human primates
36 In the US a large number of samples from human TSE cases from 1963-
1993 have been inoculated into a range of non-human primate species
and the resulting disease studied. (Brown, 1994)
37 A limited number of experiments have been carried out to inoculate nonhuman
primates with animal TSEs. Two adult squirrel monkeys inoculated
i.c. with brain from a mule deer with clinical CWD came down with clinical
disease and were euthanized at 31 and 34 months post inoculation.
Histology showed typical spongiform change and PrPres could be detected
by Western blotting. (Marsh, 2005) Historically squirrel monkeys have
been inoculated with a number of other TSEs which have produced
disease with relatively short incubation periods – transmissible mink
encephalopathy (TME), scrapie, sCJD and kuru.
38 A series of experiments have been carried out in which cynamolgus
macaques were inoculated i.c. and intratonsilar with BSE, sCJD, iCJD
(growth hormone) and vCJD and oral BSE in which the resulting diseases
closely mimicked these diseases in humans. Detailed studies of the
resulting tissue distribution (Herzog, 2005) and a comparison of the
neuropathology and PrPres profile with that found in humans show that
BSE is the agent responsible for UK vCJD and French vCJD and that
these differ from the iCJD and sCJD cases tested. (Lasmezas, 2001)
Results of studies of two macaques, which are all of the 129 MM
genotype, fed 5g of BSE infected bovine brain were used to estimate the
human oral ID50 as being in the range 150 – 1,500g. One of the two
macaques having developed disease at 60 months, but with the other
showing no clinical signs at 76 months, including a negative tonsil biopsy
at 72 months. These results were compared with those for cattle and RIII
mice to provide the estimate. (Lasmezas, 2005)
39 A range of TSEs – 2 pooled sCJD cases, 3 pooled vCJD cases and
leukocytes from chimpanzee-passaged Gerstmann-Straussler-Scheinker
disease (GSS) were inoculated i.c. into squirrel monkeys at two dilutions
and the resulting clinical signs, neuropathology and biochemistry were
analysed. (Williams, 2007) In particular a systematic behavioural study
was undertaken, in which the behaviours were noted to differ from those
reported for cynamolgus macaques by Lasmezas et al.
40 At the time of writing it is not known if experiments to inoculate atypical
scrapie into non-human primates are underway.
55 Whilst the incidence of sCJD shows natural statistical variation from one
year to another recent increases have been noted in a number of
countries, but are usually attributed to improved diagnosis in the absence
of any other epidemiological evidence. However in 2001 and the first
quarter of 2002 significant increases were reported for Switzerland raising
the incidence to 2.7 and 3.9 per million, respectively. Cases were fully
investigated but no explanation for this increase was found, which was
considered unlikely to be due to chance fluctuation or ascertainment bias.
(Glatzel, 2002) sCJD incidence remained at a level averaging 2.42 cases
per million from 2001-2004, but decreased to previous levels in 2005.
56 A number of sub-types of sCJD have been recognised based on PrP 129
genotype and the clinical, pathological and biochemical features of the
disease which may relate to distinct human prion strains. Classification can
be complicated in some cases by the presence of more than one PrPsc
sub-type in the brain.(Parchi, 1999b; Hill, 2003; Schoch, 2006: Wadsworth,
57 In addition new cases of sCJD have occurred that appear to lie outside the
normal disease spectrum, including a sporadic disease resembling FFI.
(Yamamoto, 2003; Zanusso, 2007; Mastrianni, 1999; Parchi, 1999a and
reviewed in Wadsworth, 2007)
58 In the absence of any definitive data on the aetiology of sCJD it is normally
assumed to arise from an age-related somatic cell mutation in the PRNP
gene, a spontaneous conversion of PrPc into PrPsc or an imbalance in the
normal in vivo regulation of the synthesis and degradation of normal PrP
protein and/or the abnormal form. (Reviewed in Belay, 1999; Johnson,
59 However a number of polymorphisms have now been associated with
increased or decreased susceptibility to sCJD. The best known is the
encoding of methionine or valine at codon 129, but polymorphisms have
also been found upstream of PRNP Exon 1 (Mead, 2001) and in a large
German case control study in the 5’ UTR of the PRNP gene several
polymorphisms have been identified which act independently of codon
129. (Vollmert, 2006) Alternatively another polymorphism in the regulatory
region of PRNP has been associated with susceptibility in codon 129 MV
heterozygotes. (Bratosiewicz-Wasik, 2007)
60 Case control studies for surgery or treatment with blood/products have not
shown any definite links. (Brown, 1987; Van Duijn, 1998) Some links with
surgery were shown in a study by Ward et al (2002) when using telephone
recruited controls rather than hospital controls, but results showed a
negative risk from surgery, such as neurological, tonsillar or
appendectomies for which an association might be anticipated, and a
positive risk with gynaecological or gastrointestinal surgery. This supports
the possibility that some cases classified as sCJD may have an iatrogenic
61 In view of the unknown human health implications of atypical scrapie and
the possible altered clinical phenotype of vCJD in individuals of non-MM
genotype, the UK Chief Medical Officers recently sent a letter to
neurologists to remind them to remain vigilant and refer unusual
neurological cases through the established national arrangements for
referral and reporting of suspect cases of human prion disease.
62 It is obviously extremely difficult to establish a definitive link between an
animal and a human TSE. “But a rare disease may be caused by rare
exposure to its causative agent, especially if the rate of infection is
inefficient”. (Brown, 1987)
WHAT DID DID 16 YEAR OLD VICKEY RIMMER HAVE ??? SPORADIC CJD
WHAT DID ALL THOSE FARMERS AND THERE WIVES HAVE ??? SPORADIC CJD
POLICY IN CONFIDENCE: CJD IN FARMER WITH BSE COW
LIKELY TO ATRACT MEDIA ATTENTION
CONFIRMED CJD IN FARMER WITH BSE COW
line to take, sporadic CJD
SECOND CASE CJD IN DAIRY FARMER
CJD IN AN INDIVIDUAL OCCUPATIONALLY EXPOSED TO BSE
ii. on page 2 the sentence ''He had drunk pooled milk from the herd which included that from the affected animal'' will mislead the uninformed. It needs to be made clear that milk from a cow which is suspected to be affected with BSE cannot be drunk or added to the bulk milk produced by the rest of the herd.
iii. in the final paragraph I suggest that the phrase ''and a causal link with BSE is at most conjectural'' BE DELETED: the first paragraph of the sentence would then stand as a clear statement that the CJD case was likely to have been a CHANCE PHENOMENON.
''DH is aware of a second case of CJD in a dairy farmer who has had BSE in his herd. We cannot comment on the details of the case, but we know of nothing to suggest this is anthing other than a sporadic case of CJD. .........
The numbers concerned are very small, and it is not possible to draw any conclusions from such small numbers. This issue is being considered by the Government's expert advisers....
THE FARMER IS THOUGHT TO HAVE HAD AT LEAST TWO CASES OF BSE IN HIS HERD, which were diagnosed in 1992. The farmer is reported to have asssisted in calving and to have drunk milk from his herd. This does not suggest that this is anything other than a sporadic case of CJD. ...
CONFIRMED CASE OF CJD IN DAIRY FARMER
3. Neither Dr Will nor the CJD surveillance unit intend to disclose the existence of this case or make any comment at present unless it attracts media attention.
HUMAN CASE DETAILS CONFIDENTIAL
6. CJD IN FARMERS
The second annual report on CJD surveillance in the UK, which is about to be published, gives occupational history details of 29 definite and probable CJD cases recorded in people who had a history of employment at any time in particular occupational groups of potential significance for the occurrence of the disease. The 29 cases were amongst 95 diagnosed over a 3 year period: the other 66 cases did not fall into such occupational groups.
These relevant details are:-
ANIMAL LABORATORY 1
PHARMACEUTICAL LABORATORY 0
RESEARCH LABORATORY 0
FARMERS/VETERINARY SURGEONS 7
INVOLVING DIRECT CONTACT WITH ANIMAL
OR CARCASES 5
OCCUPATION INVOLVING ANIMAL PRODUCTS 9
snip... full text ;
POLICY IN CONFIDENCE
1. The article in the Daily Mail of 12 August again raises the question of a CAUSATIVE LINK BETWEEN BSE AND CJD. This follows the death of a second farmer from CJD...
I am, however, concerned about how DH and MAFF would respont to public concern generated if there are further CJD cases among farmers.
4. Unwelcome, though it maybe to the Tyrrell Committee, I think they must be asked at their next meeting to give further thought to what they might advise the Department and MAFF if ANOTHER FARMER (or TWO) DEVELOPS CJD. OR, if a butcher or abattoir worker develops the disease.
5. Although the Committee were given plenty of advance warning about the second farmer, they may NOT BE SO FORTUNATE NEXT TIME ROUND. Some Contingency planning on the Committee's response to a further case of CJD in a farmer seems essential. At the same time the Committee should consider if there is SPECIAL RISK TO FARMERS, FOR EXAMPLE THEIR HISTORICAL HABIT OF CHEWING CATTLE NUTS, that might be implicated. .....(oh my GOD...tss)
Ministers will note from this that experts are of the view, that there is unlikely to be a direct link between the cases of BSE, and the occurance of CJD in the farmer.
(NOTE CJD increasing over 3 years. ...TSS)
'AGE AT ONSET' is therefore likely to be a reflection of particulary aetiological factors, about which, for sporadic CJD at least, much is yet unknown. IT has therefore been suggested that examination of the f/d i/p of other groups with TSE's, and comparison with that of CJD subsets might help to elucidate aetiological mechanisms for sporadic CJD in particular; i.e. ALMOST A REVERSAL OF THE ORIGINAL UNDERTAKING.
OCCUPATIONAL EXPOSURE TO BSE AND CJD
2. The Tyrrell Committee met on 7 October and the significance of the two cases of CJD reported in dairy farmers who had BSE-affected animals on their farms was discussed at some length, AS WERE THE IMPLICATIONS OF A THIRD (OR FORTH) similar case.
3. The Committee were unable to identify any possible risk factors over and above those that they had already considered, both in general and with particular of TASTING THE FEED does continue but there was no consensus about the value of advising farmers to discontinue this practice. Feed currently in use does not pose a risk because of the ruminant-ruminant feed ban.
STRAIN CHARACTERISATION OF THE CREUTZFELDT-JAKOB DISEASE AGENT BY TRANSMISSION TO MICE
In view of the CONCERN that exposue to BSE OR SCRAPIE MAY POSE A RISK TO HUMANS, it is proposed investigate the relationship between sporadic creutzfeldt-jakob disease.....
3. While Committee may have no leads to pursue on why farmers might be at increased risk, I hope they understand the urgency with which they will need to respond if or when a THIRD FARMER DEVELOPS CJD.
CJD FARMERS WIFE 1989
cover-up of 4th farm worker ???
CONFIRMATION OF CJD IN FOURTH FARMER
now story changes from;
SEAC concluded that, if the fourth case were confirmed, it would be
worrying, especially as all four farmers with CJD would have had BSE
cases on their farms.
This is not unexpected...
was another farmer expected?
4th farmer, and 1st teenager
Over a 5 year period, which is the time period on which the advice
from Professor Smith and Dr. Gore was based, and assuming a
population of 120,000 dairy farm workers, and an annual incidence
of 1 per million cases of CJD in the general population, a
DAIRY FARM WORKER IS 5 TIMES MORE LIKELY THAN
an individual in the general population to develop CJD. Using the
actual current annual incidence of CJD in the UK of 0.7 per
million, this figure becomes 7.5 TIMES.
3. You will recall that the advice provided by Professor Smith in
1993 and by Dr. Gore this month used the sub-population of dairy
farm workers who had had a case of BSE on their farms -
63,000, which is approximately half the number of dairy farm
workers - as a denominator. If the above sums are repeated using
this denominator population, taking an annual incidence in the general
population of 1 per million the observed rate in this sub-population
is 10 TIMES, and taking an annual incidence of 0.7 per million,
IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) than
that in the general population...
CJD YOUNG PEOPLE
in the USA, a 16 year old in 1978;
ALSO IN USA;
(20 year old died from sCJD in USA in 1980 and a 16 year
old in 1981. see second url below)
in France, a 19 year old in 1982;
in Canada, a 14 year old of UK origin in 1988;
in Poland, cases in people aged 19, 23, and 27 were identified in
a retrospective study (published 1991), having been originally
misdiagnosed with a viral encephalitis;
Creutzfeldt's first patient in 1923 was aged 23.
20 year old died from sCJD in USA in 1980 and a 16 year
old in 1981. A 19 year old died from sCJD in
France in 1985. There is no evidence of an iatrogenic
cause for those cases....
USA MAD COW STRAIN MORE VIRULENT TO HUMANS THAN UK STRAIN
18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7
December 2006 are now available.
64. A member noted that at the recent Neuroprion meeting, a study was
presented showing that in transgenic mice BSE passaged in sheep may be more
virulent and infectious to a wider range of species than bovine derived BSE.
Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the
prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A
MUTATION FOUND IN CASES OF SPORADIC CJD.
3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse
Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve
Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain
discovered recently in Italy, and similar or different atypical BSE cases
were also reported in other countries. The infectivity and phenotypes of
these atypical BSE strains in humans are unknown. In collaboration with
Pierluigi Gambetti, as well as Maria Caramelli and her co-workers, we have
inoculated transgenic mice expressing human prion protein with brain
homogenates from BASE or BSE infected cattle. Our data shows that about half
of the BASE-inoculated mice became infected with an average incubation time
of about 19 months; in contrast, none of the BSE-inoculated mice appear to
be infected after more than 2 years.
***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than
classical BSE in humans.***
6:30 Close of Day One
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...
There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance
He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
BRITISH MEDICAL JOURNAL
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to
comment on the CDC's attempts to monitor the occurrence of emerging
forms of CJD. Asante, Collinge et al  have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest
sporadic CJD. However, CJD and all human TSEs are not reportable
nationally. CJD and all human TSEs must be made reportable in every
state and internationally. I hope that the CDC does not continue to
expect us to still believe that the 85%+ of all CJD cases which are
sporadic are all spontaneous, without route/source. We have many TSEs in
the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by
intracerebral inoculation. With the known incubation periods in other
TSEs, oral transmission studies of CWD may take much longer. Every
victim/family of CJD/TSEs should be asked about route and source of this
agent. To prolong this will only spread the agent and needlessly expose
others. In light of the findings of Asante and Collinge et al, there
should be drastic measures to safeguard the medical and surgical arena
from sporadic CJDs and all human TSEs. I only ponder how many sporadic
CJDs in the USA are type 2 PrPSc?
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518