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From: TSS ()
Subject: COMMITTEE MEMBERS’ BRIEFING FOR PUBLIC Q & A SESSION AT SEAC 94, 21ST SEPTEMBER 2006
Date: October 15, 2006 at 3:06 pm PST

COMMITTEE MEMBERS’ BRIEFING FOR PUBLIC Q & A SESSION

AT SEAC 94, 21ST SEPTEMBER 2006

snip...

Endodontic Dentistry and vCJD

At SEAC 91 (February 2006) the committee reviewed new information

on the potential risks of vCJD transmission via endodontic dentistry

(dental procedures involved in the maintenance of dental pulp and the

treatment of the pulp cavity).

There are no reported definite or suspected cases of vCJD transmission

arising from dental procedures.

SEAC concluded that:

• a preliminary risk assessment produced by DH suggests vCJD

transmission via endodontic dentistry may, under certain

hypothetical but plausible scenarios, be sufficient to sustain a

secondary vCJD epidemic. However, there are uncertainties

around the data and assumptions underpinning the assessment.

Research underway will address some of these uncertainties and

allow the risk assessment to be refined. Once the research is

complete and / or other data become available, the risks should

be reassessed. A watching brief should be maintained.

• it is unclear whether or not vCJD infectivity can be transmitted via

endodontic files and reamers. However, given the plausibility of

such a scenario and the large number of procedures undertaken

annually, it would be prudent to consider restricting these

instruments to single use as a precautionary measure. Since

sufficiently rigorous decontamination of these instruments is

difficult, single use of these instruments would eliminate this risk,

should it exist.

CORRECT AS OF 21ST SEPTEMBER 2006

11

Transmission of prion diseases by blood transfusion

Probable cases of blood transfusion-associated transmission of

vCJD

SEAC was informed of three cases of blood transfusion associated

transmission of vCJD at SEAC 81, 83 and 91 (February 2004, June

2004 and February 2006).

First Case.

The Transfusion Medicine Epidemiology Review (TMER) identified a

case of possible transmission of vCJD by blood transfusion. The

recipient received non-leucodepleted red blood cells in 1996 from a

donor who, at the time of donation, was free of clinical signs of vCJD,

although went on to develop vCJD in 1999. The blood recipient died of

vCJD in 2003.

Second Case

An elderly patient died in 2004 showing no clinical signs of vCJD with

death from an unrelated cause. The patient had received a single unit

of non-leucodepleted red blood cells in 1999 that had been donated by

an individual who was confirmed in 2001 as a definite vCJD case. The

donor’s disease onset was in 2000. There was no evidence of a

spongiform encephalopathy and prion protein accumulation was

detected in the spleen and a cervical lymph node. The case was

methionine/valine at codon 129 of the PrP gene.

Third Case

The case developed symptoms of vCJD approximately 8 years after

receiving a non-leucodepleted blood transfusion from a donor, who had

developed symptoms of vCJD about 20 months later.

In reviewing the three cases the Committee noted:

• in light of these three cases there is a relatively high risk of

transmission of vCJD by blood transfusion.

• it should be a public health priority for all recipients of blood

(leucodepleted or not) from donors incubating vCJD to be subject

to the kind of careful post-mortem examination that had been

possible in this case. This would help to quantify the nature and

magnitude of the risks of transmission of the vCJD agent through

blood donated by preclinical cases of vCJD.

CORRECT AS OF 21ST SEPTEMBER 2006

12

• that active approaches to obtaining tissues for testing and clinical

monitoring of these patients was important both to ensure best

practice clinical care and enhancing understanding of risks.

Early phase of vCJD infection in recipients of blood transfusions

At SEAC 87 (April 2005), the Committee on Microbiological Safety of

Blood, Tissue and Organs asked SEAC whether:

• a scientific distinction could be drawn between historic and recent

blood transfusion recipients in terms of the relative load of the

vCJD agent that may be present in the bone, tissues or organs of

the blood transfusion recipient.

In the context of this question, a recent recipient was defined as having

received a blood transfusion within the week prior to bone, tissue or

organ donation. A historic recipient was defined as having received a

blood transfusion in the more distant past.

SEAC noted that:

• recipients of blood products from vCJD cases had been notified

and deferred from tissue/organ donation. All recipients of

tissues/organs were also deferred from blood transfusion.

• until sensitive ante mortem tests, especially for blood, become

available it may not be possible to conduct definitive experiments

that would further inform assessment of the transplant associated

risks of vCJD transmission.

SEAC concluded that:

• because of a small background risk of vCJD infection in the

population as a whole, tissues/organs from donors that had not

received a blood transfusion carried some risk of vCJD

transmission.

• there is no clinical evidence that vCJD has been transmitted

through tissue/organ transplantation. However, a potential risk of

transmission via this route exists. Relevant data are extremely

limited but suggest that in the early phase of infection, significant

prion replication is unlikely to occur and that, therefore, tissue

levels of abnormal prions following recent transfusions are likely

to be related to the blood supply to each specific tissue.

CORRECT AS OF 21ST SEPTEMBER 2006

13

• a risk of transplant-associated transmission of vCJD exists from

tissue/organ donors that have not received blood transfusions.

The additional risk as a result of a donor having received a recent

blood transfusion is likely to be very small. Post mortem

assessment of donor infection would provide the best method of

risk reduction and enable these risks to be quantified.

• in assessing and communicating the risks a balance must be

struck between the small risk of vCJD transmission by

transplantation and the benefits to patients receiving a transplant,

especially where tissues/organs are scarce and are required for

(potentially) life-saving procedures.

vCJD Infectivity in Blood

At SEAC 90 (November 2005) SEAC reviewed published information in

relation to the key assumptions made in the assessment of exposure to

vCJD infectivity in blood and blood products published in 2003 by Det

Norske Veritas Consulting (DNV).

SEAC considered that all the following key assumptions made in the

DNV assessment appear still to be reasonable:

• Blood from people incubating vCJD is infective.

• Infectivity is constant throughout the incubation period.

• Infectivity of blood from vCJD cases is 10 ID50/ml.

• Intravenous route is 5 times less efficient than the intracranial

route.

• Incubation period for vCJD derived from blood is 15 years.

• All people are assumed to be vulnerable to infection by vCJD,

genetic variations will only affect incubation period.

• Split of infectivity between blood components is: 24% in red cells,

22% in buffy coat (leucocytes and platelets) and 54% in plasma.

• Dose-response function for vCJD infectivity is linear with no

threshold.

CORRECT AS OF 21ST SEPTEMBER 2006

14

SEAC strongly recommended that robust research is undertaken to

examine infectivity levels through the incubation period and the

distribution of infectivity in blood components.

At SEAC 92 (April 2006) the committee reviewed unpublished data

which allowed some of the assumptions of the (DNV) risk assessment

to be reconsidered.

The specific issues considered were: the relative levels of TSE

infectivity in whole blood and in each of the individual blood

components, the change in the level of TSE infectivity in blood over the

course of the incubation period of disease, the relative efficiencies of

the intracranial and intravenous routes of inoculation and the doseresponse

relationship for infection by a TSE. A position statement was

produced as a result of the discussion.

SEAC Concluded that:

• the available data show that blood is infectious during the preclinical

stage of vCJD. Although the precise time in the incubation period of

vCJD at which blood becomes infectious is unclear, data from animal

models suggests it may be infectious from at least, if not before, the

middle of the incubation period.

• the source of infectivity in blood is not understood. Data from rodent

studies suggests that infectivity in whole blood is around 10 ID/mL

and that it mostly resides in the plasma and white blood cell

components with infectivity associated with white blood cells

substantially depleted by extensive washing.

• additional information from other animal models is required to assess

whether the rodent findings may be closely representative of vCJD

infectivity in human blood. It is clear that an infectious dose in blood

can be disseminated but not diluted by distribution to a large number

of recipients.

• pooling of potentially infectious material, or in other ways

disseminating infectious material between a number of recipients,

will not reduce the number of people infected, and is likely to

increase the number of people infected.

snip...

CORRECT AS OF 21ST SEPTEMBER 2006

16

Prion reduction filters

At SEAC 91 (February 2006) the UK blood services (UKBS) prion

reduction group asked the committee to comment on the methodologies

used to validate prion reduction filters, this follows the SEAC

recommendation that an independent validation of the filters should be

performed.

The committee concluded that:

• the UKBS should commission an independent validation of such

products.

• filters be evaluated on both leucodepleted and non-leucodepleted

blood, since if they worked well on non-leucodepleted blood it

may be possible to remove the leucodepletion step.

• blood from individuals considered ‘at risk of vCJD’ should be

collected with ethical approval and patient consent.

• it was important to replicate the experiments that the filter

manufacturers performed to test the efficacy and reproducibility of

the filters.

• further experiments to evaluate the filters should include the use

of an additional rodent strain and different forms of inoculum.

These experiments would provide indication of differences in the

efficacy of filters against different strains or TSE agent. It is

critical to include the BSE agent in these studies. Experiments

that tested the removal of endogenous infectivity were important

and that it was crucial to develop a model that was as close as

possible to the human situation.

snip...

CORRECT AS OF 21ST SEPTEMBER 2006

17

Medical Implants Containing Bovine Material

At SEAC 91 (February 2006) the Medicines and Healthcare products

Regulatory Agency (MHRA) asked the committee to consider the

potential BSE risks to humans from medical implants using bovine

material from the USA.

The regulations on medical devices containing animal materials are

based on the principle that TSE risks must be eliminated or reduced as

much as possible and residual risks must be acceptable when weighed

against the benefits to patients. Currently no guidance exists on the

acceptability of TSE risk control measures applied to animal material in

medical devices.

The MHRA requested advice on three 3 issues. (i) can TSE risk

associated with medical implants using USA sourced bovine material be

estimated given that it might vary over time? (ii) is there, or has there

been a significant risk that might warrant action in addition to that

already taken? (iii) can the standards that support the regulations be

altered to facilitate a consistent approach about the acceptability of

products?

The committee concluded that:

• a risk assessment should be conducted on each device because

of the large number of variables that influence associated TSE

risks.

Key factors which should be considered when assessing risks are:

• the animal source. Use of material from closed herds or from

herds that are managed carefully to prevent the introduction of

the BSE agent.

• use of material from young animals would markedly lower risk

compared with older animals.

• the geographical risk of BSE. The geographical BSE risk

status of a country gives an imprecise indication of BSE risk. It

would be better to use an estimated prevalence of BSE in a

country based on data from a robust surveillance system.

• the potential TSE infectivity of the source tissue(s) based on a

careful assessment of the available data on tissue infectivity.

CORRECT AS OF 21ST SEPTEMBER 2006

18

• the site of implantation. Sites with contact with the blood supply

or CNS may increase risk.

• whether TSE testing is undertaken on the source animal(s).

• the number of source animals used for each device.

snip...

CORRECT AS OF 21ST SEPTEMBER 2006

44

Conformation-dependent immunoassay (CDI) for abnormal prions

At SEAC 88 (June 2005), SEAC commented on a recent paper11 which

had reported that the conformation-dependent immunoassay (CDI) for

abnormal prions was more sensitive than other biochemical tests.

The committee:

• commented that, unlike most biochemical tests, it did not rely on

proteinase K (PK) digestion of prions and could detect PK

sensitive forms of abnormal prions.

• expressed caution about the assumption that the test was

capable of measuring the infectious agent, as the form of prion

constituting the infectious agent was still unclear.

11 Safar et al. (2005) Diagnosis of human prion disease. Proc. Natl. Acad. Sci. U S A. 102,

3501-3506.

snip...

5. Dr Brian Matthews noted that the available information on the

incidence of CJD in various countries, other than the UK, indicates

that there is no obvious decline in the numbers of cases being

reported. However, in the UK there seems to have been a steady

decline in the number of suspected cases, and therefore of

confirmed cases, for the past several years. He asked 3

questions: (i) What are the causes of the decline in the number of

suspected cases reported in the UK over the past few years? (ii)

What is the effect of this decline in reports of suspected cases on

the certainty of the decline of the number of new cases of vCJD

reported in the UK? (iii) What is the effect of this decline in reports

of suspected cases on the certainty that new cases of iatrogenic

transmission of CJD and/or vCJD could be identified?

6. Professor Ironside commented that the number of suspected cases

of sCJD reported each year had varied since surveillance began,

but numbers had appeared to decline in the past 2 years.

However, this was unlikely to be due to significant numbers of

cases being missed. As a way of checking to see if cases had

been missed, NCJDSU had looked back at diagnosed cases of

atypical dementia but had not identified any cases of CJD. The

recent decrease in numbers of suspected cases reported was

therefore probably due to improvements in clinical diagnostic

criteria and the resultant improved quality of referrals. NCJDSU

had very good links with clinicians and pathologists across the UK.

http://www.seac.gov.uk/pdf/issue_summary.pdf

I find this interesting ;

(i) What are the causes of the decline in the number of

suspected cases reported in the UK over the past few years?

(ii) What is the effect of this decline in reports of suspected cases on

the certainty of the decline of the number of new cases of vCJD

reported in the UK?

SO, the cases of nvCJD in the UK went up for years and years and then started declining as with BSE cases due to the feed ban rules, surveillance, eradication, and other factors, and sporadic CJD cases went up and up too, and then started going down at about the same time. interesting? probably just another coincidence ;-) look at Italy in 2005 98 sporadic CJD cases, Germany 81, and France at 81 cases in 2005 as well, all well known BSE countries, all with increases of sporadic CJD since 1993. ...

http://www.eurocjd.ed.ac.uk/sporadic.htm

-------- Original Message -------- Subject: re-BSE prions propagate as

either variant CJD-like or sporadic CJD Date: Thu, 28 Nov 2002 10:23:43

-0000 From: "Asante, Emmanuel A" To:
"'flounder@wt.net'"

Dear Terry,

I have been asked by Professor Collinge to respond to your request. I am

a Senior Scientist in the MRC Prion Unit and the lead author on the

paper. I have attached a pdf copy of the paper for your attention. Thank

you for your interest in the paper.

In respect of your first question, the simple answer is, yes. As you

will find in the paper, we have managed to associate the alternate

phenotype to type 2 PrPSc, the commonest sporadic CJD.

It is too early to be able to claim any further sub-classification in

respect of Heidenhain variant CJD or Vicky Rimmer's version. It will

take further studies, which are on-going, to establish if there are

sub-types to our initial finding which we are now reporting. The main

point of the paper is that, as well as leading to the expected new

variant CJD phenotype, BSE transmission to the 129-methionine genotype

can lead to an alternate phenotype which is indistinguishable from type

2 PrPSc.

I hope reading the paper will enlighten you more on the subject. If I

can be of any further assistance please to not hesitate to ask. Best wishes.

Emmanuel Asante

<> ____________________________________

Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial

College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG

Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email:

e.asante@ic.ac.uk (until 9/12/02)

New e-mail: e.asante@prion.ucl.ac.uk (active from now)

____________________________________

snip...

full text ;

http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm

BSE prions propagate as either variant CJD-like or

sporadic CJD-like prion strains in transgenic mice

expressing human prion protein

Emmanuel A.Asante, Jacqueline M.Linehan,

Melanie Desbruslais, Susan Joiner,

Ian Gowland, Andrew L.Wood, Julie Welch,

Andrew F.Hill, Sarah E.Lloyd,

Jonathan D.F.Wadsworth and

John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease,

Institute of Neurology, University College, Queen Square,

London WC1N 3BG, UK

1Corresponding author

e-mail: j.collinge@prion.ucl.ac.uk

Variant Creutzfeldt±Jakob disease (vCJD) has been

recognized to date only in individuals homozygous for

methionine at PRNP codon 129. Here we show that

transgenic mice expressing human PrP methionine

129, inoculated with either bovine spongiform

encephalopathy (BSE) or variant CJD prions, may

develop the neuropathological and molecular phenotype

of vCJD, consistent with these diseases being

caused by the same prion strain. Surprisingly, however,

BSE transmission to these transgenic mice, in

addition to producing a vCJD-like phenotype, can also

result in a distinct molecular phenotype that is indistinguishable

from that of sporadic CJD with PrPSc

type 2. These data suggest that more than one BSEderived

prion strain might infect humans; it is therefore

possible that some patients with a phenotype consistent

with sporadic CJD may have a disease arising

from BSE exposure.

Keywords: BSE/Creutzfeldt±Jakob disease/prion/

snip...

Discussion

Prion propagation involves recruitment and conversion of

host PrPC into PrPSc, and the degree of primary structural

similarity between inoculated PrPSc and host PrPC is

thought to be a key component of intermammalian

transmission barriers (Prusiner et al., 1990). It is clear,

however, that prion strain type can also be crucial, as

clearly demonstrated by the very distinctive transmission

Table III. BSE and vCJD transmissions to inbred lines of mice

Inoculum SJL/OlaHsd RIIIS/J FVB/NHsd C57BL/6/OlaHsd

Incubation Clinical Incubation Clinical Incubation Clinical Incubation Clinical

time signs time signs time signs time signs

(days 6 SEM) (days 6 SEM) (days 6 SEM) (days 6 SEM)

BSE (I783) 196 6 13 25/40 241 6 15 20/29 589 6 21 22/31 710 6 15 6/25

vCJD (I336) 139 6 17 6/10 342 6 31 8/8

vCJD (I344) 256 6 46 5/7 402 6 34 7/8

vCJD (I342) 169, 169 2/11 475 6 68 3/10

Transgenic modelling of BSE and vCJD

6363

properties of sporadic CJD 129MM and vCJD 129MM

prions (of identical PrP primary structure) in either 129VV

Tg152 (Hill et al., 1997; Collinge, 1999) or 129MM Tg35

mice. Prion strain type may also affect transmission

barriers via an effect on PrPSc tertiary structure and state of

aggregation (Hill et al., 1997; Collinge, 1999).

These 129MM Tg35 mice, in which human PrPSc types

can be propagated, have been used to study the BSE-tohuman

species barrier. The frequent presence of subclinical

prion disease in vCJD- and BSE-inoculated

129MM Tg35 mice further argues for the need to reassess

current de®nitions of `species' or transmission barriers that

limit prion transmission between different hosts (Hill et al.,

2000). Such barriers have hitherto been quantitated on the

basis of either comparative end-point titrations in the two

respective hosts, or by measuring the fall in incubation

period between primary and subsequent passage as the

prion strain adapts to the new host. Both methods rely on

measurement of time to onset of a clinical syndrome.

Modelling the BSE-to-human barrier in 129MM Tg35

mice would lead to the conclusion, on the basis of induced

clinical disease, that a substantial barrier existed. However,

it is clear that human PrPSc propagation can be

ef®ciently induced by inoculation with BSE or vCJD

prions, suggesting a smaller barrier to infection (but not to

clinical disease) than hitherto thought (Collinge et al.,

1995) in humans of the PRNP 129MM genotype. Humans

infected with BSE prions, but who became asymptomatic

carriers, may nevertheless pose a threat of iatrogenic

transmission via medical and surgical procedures.

Alternatively, it is possible that the lifespan of the

laboratory mouse is insuf®cient to allow expression of

clinical disease in most inoculated mice, whereas a higher

proportion of infected humans might survive the incubation

period to develop clinical signs of disease. Serial

passage studies and titration of prions in these mice are in

progress to study this further.

These studies further strengthen the evidence that vCJD

is caused by a BSE-like prion strain. Also, remarkably, the

key neuropathological hallmark of vCJD, the presence of

abundant ¯orid PrP plaques, can be recapitulated on BSE

or vCJD transmission to these mice. However, the most

surprising aspect of the studies was the ®nding that an

alternate pattern of disease can be induced in 129MM

Tg35 mice from primary transmission of BSE, with a

molecular phenotype indistinguishable from that of a subtype

of sporadic CJD. This ®nding has important potential

implications as it raises the possibility that some humans

infected with BSE prions may develop a clinical disease

indistinguishable from classical CJD associated with type 2

PrPSc. This is, in our experience, the commonest molecular

sub-type of sporadic CJD. In this regard, it is of interest

that the reported incidence of sporadic CJD has risen in the

UK since the 1970s (Cousens et al., 1997). This has been

attributed to improved case ascertainment, particularly as

much of the rise is reported from elderly patients and

similar rises in incidence were noted in other European

countries without reported BSE (Will et al., 1998).

However, it is now clear that BSE is present in many

European countries, albeit at a much lower incidence than

was seen in the UK. While improved ascertainment is

likely to be a major factor in this rise, that some of these

additional cases may be related to BSE exposure cannot be

ruled out. It is of interest in this regard that a 2-fold

increase in the reported incidence of sporadic CJD in 2001

has recently been reported for Switzerland, a country that

had the highest incidence of cattle BSE in continental

Europe between 1990 and 2002 (Glatzel et al., 2002). No

epidemiological case±control studies with strati®cation of

CJD cases by molecular sub-type have yet been reported.

It will be important to review the incidence of sporadic

CJD associated with PrPSc type 2 and other molecular subtypes

in both BSE-affected and unaffected countries in the

light of these ®ndings. If human BSE prion infection can

result in propagation of type 2 PrPSc, it would be expected

that such cases would be indistinguishable on clinical,

pathological and molecular criteria from classical CJD. It

may also be expected that such prions would behave

biologically like those isolated from humans with sporadic

CJD with type 2 PrPSc. The transmission properties of

prions associated with type 2 PrPSc from BSE-inoculated

129MM Tg35 mice are being investigated by serial

passage.

We consider these data inconsistent with contamination

of some of the 129MM Tg35 mice with sporadic CJD

prions. These transmission studies were performed according

to rigorous biosafety protocols for preparation of

inocula and both the inoculation and care of mice, which

are all uniquely identi®ed by sub-cutaneous transponders.

However, crucially, the same BSE inocula have been used

on 129VV Tg152 and 129MM Tg45 mice, which are

highly sensitive to sporadic CJD but in which such

transmissions producing type 2 PrPSc were not observed.

Furthermore, in an independent experiment, separate

inbred lines of wild-type mice, which are highly resistant

to sporadic CJD prions, also propagated two distinctive

PrPSc types on challenge with either BSE or vCJD. No

evidence of spontaneous prion disease or PrPSc has been

seen in groups of uninoculated or mock-inoculated aged

129MM Tg35 mice.

While distinctive prion isolates have been derived from

BSE passage in mice previously (designated 301C and

301V), these, in contrast to the data presented here, are

propagated in mice expressing different prion proteins

(Bruce et al., 1994). It is unclear whether our ®ndings

indicate the existence of more than one prion strain in

individual cattle with BSE, with selection and preferential

replication of distinct strains by different hosts, or that

`mutation' of a unitary BSE strain occurs in some types of

host. Western blot analysis of single BSE isolates has not

shown evidence of the presence of a proportion of

monoglycosylated dominant PrPSc type in addition to the

diglycosylated dominant pattern (data not shown).

Extensive strain typing of large numbers of individual

BSE-infected cattle either by biological or molecular

methods has not been reported.

Presumably, the different genetic background of the

different inbred mouse lines is crucial in determining

which prion strain propagates on BSE inoculation. The

transgenic mice described here have a mixed genetic

background with contributions from FVB/N, C57BL/6 and

129Sv inbred lines; each mouse will therefore have a

different genetic background. This may explain the

differing response of individual 129MM Tg35 mice, and

the difference between 129MM Tg35 and 129MM Tg45

mice, which are, like all transgenic lines, populations

derived from single founders. Indeed, the consistent

distinctive strain propagation in FVB and C57BL/6 versus

SJL and RIIIS lines may allow mapping of genes relevant

to strain selection and propagation, and these studies are in

progress.

That different prion strains can be consistently isolated

in different inbred mouse lines challenged with BSE

prions argues that other species exposed to BSE may

develop prion diseases that are not recognizable as being

caused by the BSE strain by either biological or molecular

strain typing methods. As with 129MM Tg35 mice, the

prions replicating in such transmissions may be indistinguishable

from naturally occurring prion strains. It

remains of considerable concern whether BSE has transmitted

to, and is being maintained in, European sheep

¯ocks. Given the diversity of sheep breeds affected by

scrapie, it has to be considered that some sheep might have

become infected with BSE, but propagated a distinctive

strain type indistinguishable from those of natural sheep

scrapie. ...snip...end


AND the new findings of BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic Creutzfeldt-Jakob disease


http://www.pnas.org/cgi/content/abstract/0305777101v1


Adaptation of the bovine spongiform encephalopathy agent to primates
and comparison with Creutzfeldt- Jakob disease: Implications for
human health

THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*,
Virginie Nouvel*,

Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger

] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique

Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible
for French iatrogenic growth hormone-linked CJD taken as a control is
very different from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate;

http://www.pnas.org/cgi/content/full/041490898v1

Characterization of two distinct prion strains
derived from bovine spongiform encephalopathy
transmissions to inbred mice

http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471


SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is
with a human TSE surveillance system that is terrible
flawed. in 1997 cases of the _reported_ cases of cjd
were at 54, to 163 _reported_ cases in 2004. see stats
here;

p.s. please note the 47 PENDING CASES to Sept. 2005

p.s. please note the 2005 Prion D. total 120(8)
8=includes 51 type pending, 1 TYPE UNKNOWN ???

p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN???

p.s. please note 2004 prion disease (6) 6=7 TYPE
UNKNOWN???


http://www.cjdsurveillance.com/resources-casereport.html


CWD TO HUMANS = sCJD ???


AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.

snip...

http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf


ATYPICAL TSEs in USA CATTLE AND SHEEP ?


http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf


Infected and Source Flocks

As of August 31, 2005, there were 115 scrapie infected
and source flocks (figure 3). There were 3 new infected
and source flocks reported in August (Figure 4) with a
total of 148 flocks reported for FY 2005 (Figure 5).
The total infected and source flocks that have been
released in FY 2005 are 102 (Figure 6), with 5 flocks
released in August. The ratio of infected and source
flocks released to newly infected and source flocks for
FY 2005 = 0.69 :
1. In addition, as of August 31, 2005, 574 scrapie
cases have been confirmed and reported by the National
Veterinary Services Laboratories (NVSL), of which 122
were RSSS cases (Figure 7). This includes 55 newly
confirmed cases in August 2005 (Figure 8). Fifteen
cases of scrapie in goats have been reported since 1990
(Figure 9). The last goat case was reported in May 2005.

snip...

full text ;

http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html

Published online before print October 20, 2005

Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102
Medical Sciences

A newly identified type of scrapie agent can naturally
infect sheep with resistant PrP genotypes

( sheep prion | transgenic mice )

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 *
*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, and approved September
12, 2005 (received for review March 21, 2005)

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.


--------------------------------------------------------------------------------


Author contributions: H.L. designed research; A.L.D.,
V.B., O.A., F.R., T.L.L., J.-L.V., and H.L. performed
research; T.B., B.B., P.S., and S.L.B. contributed new
reagents/analytic tools; V.B., O.A., and H.L. analyzed
data; and H.L. wrote the paper.

A.L.D. and V.B. contributed equally to this work.

To whom correspondence should be addressed.

Hubert Laude, E-mail: laude@jouy.inra.fr

www.pnas.org/cgi/doi/10.1073/pnas.0502296102


http://www.pnas.org/cgi/content/abstract/0502296102v1

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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf


ALL animals for human/animal consumption must be tested for TSE.

ALL human TSEs must be made reportable Nationally and Internationally...

TSS




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