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From: TSS ()
Subject: Pathogenesis and transfusion risk of transmissible spongiform encephalopathies
Date: July 31, 2005 at 7:43 pm PST

----- Original Message -----
From: "Terry S. Singeltary Sr."
Sent: Sunday, July 31, 2005 4:48 PM
Subject: Pathogenesis and transfusion risk of transmissible spongiform encephalopathies

##################### Bovine Spongiform Encephalopathy #####################

Pathogenesis and transfusion risk of TSE
Sun Jul 31, 2005 16:38

Pathogenesis and transfusion risk of transmissible spongiform encephalopathies.

Brown P.

NINDS/NIH, Bethesda MD, USA.

The genesis (and pathogenesis) of sporadic and familial forms of human transmissible spongiform encephalopathy (TSE) is unknown, but the disease process may originate spontaneously in the brain as a statistically random event involving misfolding and amyloid formation of the "prion" protein. The pathogenesis of environmentally acquired TSE depends on the route of infection and is likely to involve both neural and haematogenous paths of neuro-invasion. Blood infectivity is well documented in experimental rodent models of TSE and in natural scrapie infections, but has not yet been proved to occur in humans. The knowledge that many plasma pools have included donations from individuals who later died of sporadic Creutzfeldt-Jakob disease (sCJD), together with the failure to identify any affected recipients, implies that the risk is either negligible or absent. In sharp contrast, two out of 26 recipients of labile blood products from individuals who later died from the variant form of CJD (vCJD) have became infected, and the still-living at-risk recipients are under continuing surveillance.

PMID: 16050152 [PubMed - in process]

>>>The pathogenesis of environmentally acquired TSE depends on the route of infection and is likely to involve both neural and haematogenous paths of neuro-invasion.<<<

o.k., so for hypothetical reasons, some percentage of sporadic CJDs do arise spontaneously, by some miracle. i have ask this question before to many scientists that believe this nonsense, i have ask, what percentage of the 85%+ of all cjd ''sporadic'', what percentage do you count of this to be 'spontaenous', 1%, 5%, 50% or 95% ? from what ever percentage that they may suspect might be spontaneous, that what is left, has to have a route and source, and would fall into this category of "The pathogenesis of environmentally acquired TSE depends on the route of infection and is likely to involve both neural and haematogenous paths of neuro-invasion.", WHICH is what myself and others have been saying all along. we dont/didnt know if it might be cwd human tse, scarpie human tse, bse human tse, and or any potential subtypes from each of them would be included in the lump of sporadic CJD victims. with the recent documentation of nvCJD blood transmissions, nvCJD came from BSE in cattle, but yet, we still feed bovine blood back to bovine and other species. personally, from old studies, once more sensitive testing come to pass, i believe infectivity will be found in sporadic CJDs.

something even stranger, usda does not even much believe in the spontaneous BSE in cattle, or don't want to anyway. they are at a crossroads of having to believe it and stanley pushing his cdi test$$$ so for sure, they don't want to have to believe it. so why would it happen for sporadic CJDs???


File Format: PDF/Adobe Acrobat -

Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary

Sr. [] Monday, January 08,200l 3:03 PM freas ...

Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater Greetings, please be advised; with the new findings from Collinge et al; that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc, the commonest sporadic CJD, i only ponder how many of the sporadic CJDs in the USA are tied to this alternate phenotype? these new findings are very serious, and should have a major impact on the way sporadic CJDs are now treated as opposed to the vCJD that was thought to be the only TSE tied to ingesting beef, in the medical/surgical arena. these new findings should have a major impact on the way sporadic CJD is ignored, and should now be moved to the forefront of research as with vCJD/nvCJD. the USA has many TSEs, the USA lacks sufficient testing for TSEs in cattle, and the USA still refuses to rapid TSE test USA cattle in sufficient numbers to find, when the late Dr. Richard Marsh had proven that mink had gone down with a TSE (TME), from being fed on 95%+ downer cattle. the GAO has also warned the industry and the FDA that the ruminant-to-ruminant feed ban has to significantly improved if they expect to keep BSE/TSEs out of USA cattle. Scrapie has increased significantly, and CWD is spreading. all this should warrant CJD/TSEs in humans in the USA to be made reportable on a National bases, immediately... SNIP...FULL TEXT;

Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)

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11. The Chair informed members that the Committee on

Microbiological Safety of Blood Tissues and Organs (MSBTO) had

requested SEAC advice. MSBTO asked whether a scientific

distinction could be drawn between tissue/organ donors that have

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received blood transfusions either a few days or up to a week

before donation (recent blood recipients), or in the more distant

past (historic blood recipients), in terms of the relative load of vCJD

agent that might be present in bone, tissues or organs. A number

of individuals receive blood transfusions shortly before they die and

become tissue/organ donors. Thus, the question related to

whether there is a significant risk of vCJD transmission associated

with such blood transfusions for the recipient of the tissues or

organs. The advice from SEAC would inform possible risk

reduction measures under consideration by the MSBTO. A SEAC

statement would be drafted on the basis of the discussion.

12. Dr Marc Turner (UK Blood Services and Co-Chair of the Bone and

Tissue Subcommittee of the MSBTO) provided the background to

the MSBTO request. Since the identification of two cases of

probable blood transfusion associated transmission of vCJD, the

Blood Services, on the advice of the MSBTO, have deferred blood

donors who themselves have received blood transfusions. This

measure was instituted to reduce the possibility that blood

transfusions could contribute to a self-sustaining vCJD epidemic.

13. Dr Turner explained that the potential risks of vCJD transmission

associated with cell/tissue/organ transplants had also been

considered by a vCJD Subcommittee of the MSBTO. Deferral of

cell/tissue/organ donors that had received a blood transfusion had

been considered. However, in the case of donors of bone marrow,

kidney, liver, heart and lung there are shortages. As the primary

use is for gravely ill individuals, deferral would not be beneficial to

patients. Therefore, for patients urgently in need of potentially lifesaving

operations, deferral of donors of such tissues/organs would

not be instituted.

14. Dr Turner explained that the balance between the potential vCJD

transmission risks and patient benefits for transplants of other

tissues/organs such as bone, tendons, ligaments, corneas, heart

valves and skin was less clear. These tissues were mainly derived

from cadaveric donors and submitted to tissue banks. The majority

of these donors will have received blood transfusions around the

time of death whilst a smaller number will have received historic

blood transfusions. It may be possible to introduce deferral of

historic recipients of transfusions without incurring tissue

shortages. However, deferral of all donors that had received blood

transfusions would incur shortages. MSBTO was seeking advice

from SEAC on whether a scientific distinction could be made

between recent and historic recipients of blood transfusions, in

terms of potential risk of vCJD transmission from transplants. If so,

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could a threshold of transmission risk, in terms of the time following

transfusion for recent and historic transfusion recipients, be


15. Members noted that there were very few data available to answer

these questions. It was suggested that some distinction could be

made between the current risk of transmission via a blood

transfusion, and the historic risk prior to the introduction of

precautionary measures such as leucodepletion and the restriction

on recipients of blood transfusions from donating blood. It was

noted that measures such as leucodepletion reduced, but did not

eliminate infectivity in blood.

16. One member noted that two papers by Beringue et al.1 that

describe early accumulation of PrPres in the spleen of mice

following intraperitoneal inoculation with scrapie complemented the

data presented in SEAC paper 87/3. In the studies, PrPres was

detectable in the spleen within one hour post-inoculation,

increased to a peak at 4 hours, decreased at 6 hours and was

undetectable from 12 or 24 hours before increasing again at

between 5 and 7 days post-inoculation. Although the timing of

PrPres accumulation in these studies differed compared with the

reports presented in SEAC paper 87/3, this was probably due to

strain specific differences in incubation time. It was noted that

most of the inoculum would accumulate, not in the spleen, but in

the liver and lung following injection.

17. Members asked whether the increase in splenic PrPres in the first

few hours post-inoculation reported in the studies by Beringue et

al. (2000) was due to accumulation of the inoculum or replication.

Members were informed that the increase was thought to be due to

accumulation of the inoculum. The inoculum was possibly then

degraded before replication subsequently allowed the agent to be

detected again almost a week later. Another member explained

that although it was not possible at present to definitively

distinguish between agent accumulation and replication, on-going

work at the Institute of Animal Health lent support to this

suggestion. Studies to differentiate between these two processes

were underway. It was likely that the timing of these processes

would differ between different strains of agent.

1 Beringue et al. (2000) Pharmacological manipulation of early PrPres accumulation in the

spleen of scrapie-infected mice. Arch. Virol. Suppl. 39-56.

Beringue et al. (2000) Role of spleen macrophages in the clearance of scrapie agent early in

pathogenesis. J Path. 190, 495-502.

- - 8

18. One member noted that in most of the animal studies under

consideration, brain homogenate had been used as the inoculum.

The infectious agent in such preparations was likely to be in a

more aggregated form than when endogenously produced in

human blood. Accumulation of a more aggregated form of a prion

agent by the liver, lung and spleen would be relatively more


19. In response to a question about the level of infectivity in the blood

of rodent models, members were informed that no studies have

examined the period immediately following inoculation. Infectivity

was difficult to detect in rodent blood.

20. It was noted that the findings from animal models suggest that

there may be windows of increased or decreased risk within the

first week following transfusion. However, members considered

that the data available were too limited, and could not be directly

applied to define windows of lesser or greater transmission risk

from human tissue/organ transplants.

21. It was suggested that, on the basis of the evidence available, the

prion agent would have insufficient time to replicate in recipients of

a recent, compared with a historic, blood transfusion. Thus, the

transmission risk following transplantation of a tissue/organ from a

historic transfusion recipient could be higher than from a recent

transfusion recipient.

22. In view of the large proportion of the inoculum sequestered by the

liver, lung and spleen, a member asked whether other

tissues/organs could be relatively free of the inoculum. Members

considered that in the early phase of prion infection following

intravenous administration, the tissue infectivity levels would

correlate with the blood supply to, and blood content of, tissues. In

contrast to times much later in the incubation period, no distinction

could be made between tissues of the lymphoid and central

nervous system and other types of tissue in terms of infectivity

levels. Thus, in the early period following a transfusion with

infected blood, highly vascularised organs such as the liver, lung

and spleen, as well as bone would be more likely to carry

infectivity. Thus, a distinction could be made between tissues that

are highly vascularised and those that are not, in terms of potential

infectivity levels within the first week following blood transfusion.

23. In response to a question about the turnover of tissues in tissue

banks, Dr Turner explained that it was dependent on tissue type.

For example, turnover of heart valves was relatively small but

- - 9

turnover of corneas was larger because they can only be stored for

a short time. Members suggested that data on the turnover or

lifetime of tissues in tissue banks could be used in conjunction with

information on the timing of measures to protect the blood supply

to make some assessment of the relative risks posed by the use of

specific types of tissues/organs.

24. Members asked whether it was possible to screen tissue/organ

donors for markers of infection. Dr Turner explained that in

principal, it would be possible to analyse tonsillar and splenic

samples from cadaveric donors for the presence of PrPSc before

tissues were used. However, the time taken for tests precluded

screening of donors before the use of some tissues with a short ex

vivo lifetime such as organs and corneas. A feasibility study for the

screening of cadaveric donors was under consideration. One

member suggested that retrospective screening of donors would

also help to inform assessment of transmission risks but noted that

ethical considerations would influence such a strategy. Dr Turner

indicated that such strategies were under consideration but the

associated ethical issues raised difficulties.

25. Given tissue infectivity levels in the very early stage of infection are

likely to be associated with blood, members asked whether it was

possible to wash tissues to remove blood and therefore infectivity.

Dr Turner explained that solid organs are perfused, but that even

after perfusion organs are likely to contain significant quantities of

residual blood. Tissues such as tendons and heart valves are

stringently cleaned. The UK Blood Services are currently

investigating processes to remove the blood and bone marrow

from bone. The committee considered that it was important to

investigate processes that would efficiently remove blood and bone

marrow from bone but noted that some processes may damage

the integrity of the bone itself. The committee noted that SEAC

had advised previously to avoid pooling of tissues, such as bone,

which reduces transmission risks by ensuring a one to one

relationship between donor and recipient, preventing possible

multiple transmissions.

- - 9

26. Members questioned the large numbers of cadaveric donors that

are transfused before death, asking whether all such transfusions

were necessary. Dr Turner indicated that a review of the use of

blood was underway, however blood transfusions were normally

conducted to manage underlying medical conditions. In the past,

some donors had been transfused with blood prior to donation to

induce an immunologically suppressive effect, increasing the

- - 10

success of transplantation. More sophisticated methods to

suppress the immune system are now used.

27. Members considered 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. It was 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. A member considered that it

would be important to provide to potential tissue/organ recipients

clear information on the risk of vCJD transmission via the

transplant relative to the risks and benefits of undergoing surgery.

28. Members noted that, until sensitive ante mortem tests, especially

for blood, became available it may not be possible to conduct

definitive experiments that would further inform assessment of the

transplant associated risks of vCJD transmission.

29. In summary, the committee concluded that:

• current transmission risks associated with blood transfusion

are lower compared with historic risks prior to the

introduction of precautionary measures to reduce potential

prion infectivity in blood.

• on the basis of the very limited evidence available it is

unlikely that significant replication of PrP will have occurred

in the first week following a transfusion with infected blood.

• tissue infectivity levels in the first week following transfusion

with infected blood will be related to the blood supply to

tissues. Thus, a distinction may be made between highly

vascularised tissues and other tissues in terms of their

potential infectivity levels within the first week following blood


• if possible, screening of cadaveric donors for the presence of

abnormal PrP prior to transplantation, washing

tissues/organs to remove blood before their use, and

avoiding the pooling of tissues, may reduce transplant

associated transmission risks. Limiting the numbers of

unnecessary blood transfusions would also reduce risk.

• a balance must be struck between the small increased risk

of prion 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. It would be important to explain the

risks and benefits to potential recipients of tissues/organs.


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