Re: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory

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From: TSS ()
Subject: Re: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
Date: December 8, 2006 at 11:27 am PST

In Reply to: Re: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory posted by TSS on March 13, 2006 at 2:36 pm:

Volume 12, Number 12–December 2006

PERSPECTIVE

On the Question of Sporadic

or Atypical Bovine SpongiformEncephalopathy and

Creutzfeldt-Jakob Disease

Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§

Strategies to investigate the possible existence of sporadic

bovine spongiform encephalopathy (BSE) require

systematic testing programs to identify cases in countries

considered to have little or no risk for orally acquired disease,

or to detect a stable occurrence of atypical cases in

countries in which orally acquired disease is disappearing.

To achieve 95% statistical confidence that the prevalence

of sporadic BSE is no greater than 1 per million (i.e., the

annual incidence of sporadic Creutzfeldt-Jakob disease

[CJD] in humans) would require negative tests in 3 million

randomly selected older cattle. A link between BSE and

sporadic CJD has been suggested on the basis of laboratory

studies but is unsupported by epidemiologic observation.

Such a link might yet be established by the discovery

of a specific molecular marker or of particular combinations

of trends over time of typical and atypical BSE and various

subtypes of sporadic CJD, as their numbers are influenced

by a continuation of current public health measures that

exclude high-risk bovine tissues from the animal and

human food chains.

SNIP...

Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.

Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).

The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).

To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).

On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.

Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.

For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).

Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.

SNIP...

PLEASE READ FULL TEXT ;

http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm?s_cid=eid06_0965_e

3:00 Afternoon Refreshment Break, Poster and Exhibit Viewing in the Exhibit
Hall

3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve
University

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

http://www.healthtech.com/2007/tse/day1.asp

SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

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

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
collection.

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm

http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf

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:

flounder@wt.net

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 [1] 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?

http://www.neurology.org/cgi/eletters/60/2/176#535

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.

http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama

BRITISH MEDICAL JOURNAL

BMJ

http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2

BMJ

http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk
Materials for Human Food and Requirement for the Disposition of
Non-Ambulatory Disabled Cattle

http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)

http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf

THE SEVEN SCIENTIST REPORT ***

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-EC244-Attach-1.pdf

PAUL BROWN M.D.

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000490-vol40.pdf

9 December 2005
Division of Dockets Management (RFA-305)

SEROLOGICALS CORPORATION
James J. Kramer, Ph.D.
Vice President, Corporate Operations

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000383-01-vol35.pdf

Embassy of Japan
http://www.fda.gov/ohrms/dockets/dockets/02n0273/02N-0273-EC240.htm

Dockets Entered on December 22, 2005
2005D-0330, Guidance for Industry and FDA Review Staff on Collection of
Platelets
by Automated ... EC 203, McDonald's Restaurants Corporation, Vol #:, 34 ...
http://www.fda.gov/ohrms/dockets/dailys/05/Dec05/122205/122205.htm

03-025IF 03-025IF-631 Linda A. Detwiler [PDF]
Page 1. 03-025IF 03-025IF-631 Linda A. Detwiler Page 2. Page 3. Page 4.
Page 5. Page 6. Page 7. Page 8. Page 9. Page 10. Page 11. Page 12.
http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-631.pdf

03-025IF 03-025IF-634 Linda A. Detwiler [PDF]
Page 1. 03-025IF 03-025IF-634 Linda A. Detwiler Page 2.
Page 3. Page 4. Page 5. Page 6. Page 7. Page 8.
http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-634.pdf

Page 1 of 17 9/13/2005 [PDF]
... 2005 6:17 PM To: fsis.regulationscomments@fsis.usda.gov Subject: [Docket
No. 03-025IFA]
FSIS Prohibition of the Use of Specified Risk Materials for Human Food ...
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf

03-025IFA 03-025IFA-6 Jason Frost [PDF]
... Zealand Embassy COMMENTS ON FEDERAL REGISTER 9 CFR Parts 309 et al
[Docket No. 03-
025IF] Prohibition of the Use of Specified Risk Materials for Human Food and
...
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-6.pdf

In its opinion of 7-8 December 2000 (EC 2000), the SSC ... [PDF]
Page 1. Linda A. Detwiler, DVM 225 Hwy 35 Red Bank, New Jersey 07701 Phone:
732-741-2290
Cell: 732-580-9391 Fax: 732-741-7751 June 22, 2005 FSIS Docket Clerk US ...

http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-589.pdf

----- Original Message -----
From: Terry S. Singeltary Sr.
To: Terry S. Singeltary Sr. ; FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov ; Dave Cavenaugh ; ??? ; Jacqueline Ostfeld ; Jaiok Kim ; hansmi@consumer.org ; Mariko Toya ; Mike Coulthart ; Julie Rawlings
Sent: Thursday, December 07, 2006 9:07 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS 5th FINAL SUBMISSION DECEMBER 12, 2006]

The Lancet 2006; 368:2061-2067

DOI:10.1016/S0140-6736(06)69835-8

Articles

Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report

Stephen J Wroe FRCP a b, Suvankar Pal MRCP a b, Durrenajaf Siddique MRCP a b, Harpreet Hyare FRCR a b, Rebecca Macfarlane MRCS a b, Susan Joiner MSc b, Jacqueline M Linehan BSc b, Sebastian Brandner MRCPath b, Jonathan DF Wadsworth PhD b, Patricia Hewitt FRCPath c and Prof John Collinge FRS a b

Summary
Background
Concerns have been raised that variant Creutzfeldt-Jakob disease (vCJD) might be transmissible by blood transfusion. Two cases of prion infection in a group of known recipients of transfusion from donors who subsequently developed vCJD were identified post-mortem and reported in 2004. Another patient from this at-risk group developed neurological signs and was referred to the National Prion Clinic.

Methods
The patient was admitted for investigation and details of blood transfusion history were obtained from the National Blood Service and Health Protection Agency; after diagnosis of vCJD, the patient was enrolled into the MRC PRION-1 trial. When the patient died, brain and tonsil tissue were obtained at autopsy and assessed for the presence of disease-related PrP by immunoblotting and immunohistochemistry.

Findings
A clinical diagnosis of probable vCJD was made; tonsil biopsy was not done. The patient received experimental therapy with quinacrine, but deteriorated and died after a clinical course typical of vCJD. Autopsy confirmed the diagnosis and showed prion infection of the tonsils.

Interpretation
This case of transfusion-associated vCJD infection, identified ante-mortem, is the third instance from a group of 23 known recipients who survived at least 5 years after receiving a transfusion from donors who subsequently developed vCJD. The risk to the remaining recipients of such tranfusions is probably high, and these patients should be offered specialist follow-up and investigation. Tonsil biopsy will allow early and pre-symptomatic diagnosis in other iatrogenically exposed individuals at high risk, as in those with primary infection with bovine spongiform encephalopathy prions.

Affiliations

a. National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
b. MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
c. National Blood Service, London, UK

Correspondence to: Prof John Collinge

http://www.thelancet.com/journals/lancet/article/PIIS0140673606698358/abstract

TSS

----- Original Message -----
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov ; Dave Cavenaugh ; BLOODCJD@YAHOOGROUPS.COM ; Phyllis.Fong@usda.gov ; ??? ; DebbieOney@aol.com ; Jacqueline Ostfeld ; Bovine Spongiform Encephalopathy ; Jaiok Kim ; hansmi@consumer.org ; Richards, Kate (SEAC) ; Ravirajan, Chelliah (SEAC) ; Keep, Pat (SEAC) ; Perry, Susan (SEAC) ; Mariko Toya ; Mike Coulthart ; cjdvoice@yahoogroups.com ; Julie Rawlings
Sent: Thursday, December 07, 2006 11:10 AM
Subject: TSE advisory committee for the meeting December 15, 2006 [TSS 4TH FINAL SUBMISSION DECEMBER 12, 2006]

TSE advisory committee for the meeting December 15, 2006 [TSS 4TH FINAL SUBMISSION DECEMBER 12, 2006]

Greetings again Dr. Freas et al ;

FDA CERTIFIED MAD COW BLOOD RECALLS ENFORCEMENT REPORT FOR December 6, 2006

PRODUCT
a) Red Blood Cells, Leukocytes Reduced, Recall # B-0283-7;
b) Recovered Plasma, Recall # B-0284-7
CODE
a) and b) Unit: 4037982
RECALLING FIRM/MANUFACTURER
Lifeshare Blood Centers, Beaumont, TX, by fax on November 10, 2005. Firm initiated recall is complete.
REASON
Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX and Switzerland
______________________________

PRODUCT
a) Red Blood Cells, Recall # B-0330-7;
b) Cryoprecipitated AHF, Recall # B-0331-7;
c) Recovered Plasma, Recall # B-0332-7
CODE
a), b), and c) Unit: 5575374
RECALLING FIRM/MANUFACTURER
Recalling Firm: LifeSource, Glenview, IL., by telephone or facsimile on June 14, 2006 and June 16, 2006.
Manufacturer: LifeSource Oak Lawn, Oak Lawn, IL. Firm initiated recall is complete.
REASON
Blood products, collected from a donor who was at increased risk for new variant Creutzfeldt - Jakob disease (nvCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
3 units
DISTRIBUTION
IL and Switzerland

______________________________

PRODUCT
Recovered Plasma, Recall # B-0366-7
CODE
Unit: 6972331
RECALLING FIRM/MANUFACTURER
Florida’s Blood Center, Inc., Orlando, FL, by facsimile on September 3, 2002. Firm initiated recall is complete.
REASON
Blood product, collected from a donor who was at increased risk for new variant Creutzfeldt-Jakob Disease (nvCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE
1 unit
DISTRIBUTION
Austria

______________________________
PRODUCT
a) Red Blood Cells, Leukocytes Reduced, Recall # B-0367-7;
b) Recovered Plasma, Recall # B-0368-7
CODE
a) and b) Unit: 3243882
RECALLING FIRM/MANUFACTURER
Florida’s Blood Center, Inc., Orlando, FL, by telephone on July 22, 2002 or by facsimile on September 4, 2002. Firm initiated recall is complete.
REASON
Blood products, collected from a donor who was at increased risk for new variant Creutzfeldt-Jakob Disease (nvCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
FL and Austria

______________________________

PRODUCT
Recovered Plasma, Recall # B-0403-7
CODE
Unit: 03KP25041
RECALLING FIRM/MANUFACTURER
American National Red Cross, Southern Region, Atlanta, GA, by facsimile dated July 23, 2003. Firm initiated recall is complete.
REASON
Blood product, which was collected from an unsuitable donor based on risk factors for variant Creutzfeldt - Jakob disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE
1 unit
DISTRIBUTION
Switzerland

______________________________

PRODUCT
a) Red Blood Cells, Recall # B-0422-7;
b) Red Blood Cells (Apheresis) Leukocytes Reduced, Recall # B-0423-7;
c) Platelets Pheresis Leukocytes Reduced, Recall # B-0424-7;
d) Fresh Frozen Plasma (Apheresis), Recall # B-0425-7
CODE
a) Unit: 4547142;
b) Unit: 4786424, 4757201, 4650003 and 4658564;
c) Unit: 4947135 (parts 1 and 2);
d) Unit: 4786424, 4757201, 4650003, 4663954, 4652404, 4658564 and 4547142
RECALLING FIRM/MANUFACTURER
Oklahoma Blood Institute, Sylvan N. Goldman Center, Oklahoma City, OK, by facsimile on September 19, 2005. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
14 units
DISTRIBUTION
OK and NY

______________________________
PRODUCT
a) Red Blood Cells, Leukocytes Reduced, Recall # B-0426-7;
b) Recovered Plasma, Recall # B-0427-6
CODE
a) and b) Unit: 4957648
RECALLING FIRM/MANUFACTURER
Oklahoma Blood Institute, Sylvan N. Goldman Center, Oklahoma City, OK, by facsimile on April 26, 2005. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
CA and Switzerland

______________________________
PRODUCT
Source Plasma, Recall # B-0428-7
CODE
Unit numbers: CZ002370, CZ002228, CZ002075, CZ001939, CZ001815, CZ001606, CZ001446, CZ001321, CZ001174, CZ001023, CZ000429, 05BOH8576, 05BOHB8345, 05BOHB7973, 05BOHB7506, 05BOHB7237, 05BOHB6811, 05BOHB6587, 05BOHB2953, 05BOHA9332, 05BOHA8899, 05BOHA8411, 05BOHA7656, 05BOHA7425, 05BOHA6814, 05BOHA6254, 05BOHA5564, 05BOHA4492, 05BOHA4107, 05BOHA3933, 05BOHA3374, 05BOHA2517, 05BOHA1831, 05BOHA1470, 05BOHA1244, 05BOHA0819, and 05BOHA0324
RECALLING FIRM/MANUFACTURER
Bio-Blood Components, Inc., Mankato, MN, by facsimile on February 6, 2006. Firm initiated recall is complete.
REASON
Blood products, collected from a donor who was at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
37 units
DISTRIBUTION
CA and Austria

snip...end...TSS

END OF ENFORCEMENT REPORT FOR December 6, 2006

###

http://www.fda.gov/bbs/topics/enforce/2006/ENF00981.html

Prion infections, blood and transfusions

Adriano Aguzzi* and Markus Glatzel

Prion infections lead to invariably fatal diseases of the CNS, including

Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform

encephalopathy (BSE), and scrapie in sheep. There have been hundreds

of instances in which prions have been transmitted iatrogenically among

humans, usually through neurosurgical procedures or administration of

pituitary tissue extracts. Prions have not generally been regarded as bloodborne

infectious agents, and case-control studies have failed to identify

CJD in transfusion recipients. Previous understanding was, however,

questioned by reports of prion infections in three recipients of blood

donated by individuals who subsequently developed variant CJD. On

reflection, hematogenic prion transmission does not come as a surprise, as

involvement of extracerebral compartments such as lymphoid organs and

skeletal muscle is common in most prion infections, and prions have been

recovered from the blood of rodents and sheep. Novel diagnostic strategies,

which might include the use of surrogate markers of prion infection, along

with prion removal strategies, might help to control the risk of iatrogenic

prion spread through blood transfusions. ...

snip...

Last, despite all epidemiological evidence to

the contrary, patients who are methionine/valine

heterozygous at codon 129 of the PRNP gene are

susceptible to infection with vCJD prions, which

raises several important questions. Is the virulence

of BSE prions enhanced when passaged

from human to human, as opposed to the

original bovine to human situation? Passaging

experiments of scrapie infectivity between mice

and hamsters indicate that this scenario is highly

plausible.6 Even more importantly, can vCJD

infection of heterozygous individuals establish

a permanent subclinical carrier state? Although

this situation might constitute a best-case

scenario for the infected individuals, it could be

disastrous from an epidemiological viewpoint,

as it might lead to an unrecognized and possibly

self-sustaining epidemic. ...

snip... full text ;

JUNE 2006 VOL 2 NO 6 AGUZZI AND GLATZEL NATURE CLINICAL PRACTICE NEUROLOGY 329

www.nature.com/clinicalpractice/neuro

Pathogenesis of prion diseases:

current status and future outlook

Adriano Aguzzi and Mathias Heikenwalder

snip...

Abstract | The prion, a conformational variant of a host protein, is the infectious particle

responsible for transmissible spongiform encephalopathy (TSE), a fatal neurodegenerative

disease of humans and animals. The principal target of prion pathology is the brain, yet most

TSEs also display prion replication at extra-cerebral locations, including secondary lymphoid

organs and sites of chronic inflammation. Despite significant progress in our understanding

of this infectious agent, many fundamental questions relating to the nature of the prion,

including the mechanism of replication and the molecular events underlying brain damage,

remain unanswered. Here we focus on the unresolved issues pertaining to prion

pathogenesis, particularly on the role played by the immune system.

snip...

Prion transmission through blood

Prion infectivity can reside in the blood of sheep and

humans. Moreover, prions were reported to be transmitted

by animal blood transfusion prior to the onset of clinical

signs114,124. This potential for inadvertent transmission

of the vCJD agent to humans by blood transfusion was

often regarded as a ‘hypothetical’ risk. However, we now

know that the risk is not hypothetical, and three cases

of transfusion-related transmission of vCJD have been

reported11,125,126, with the likelihood of additional cases in

the future125. Although the number of affected individuals

is small, it represents a high proportion of the maximum

number of possible cases, based on the number of people

that are known to have received prion-contaminated

blood. Consequently, the possible contamination of blood

products with prions will be a significant problem for

transfusion medicine for the foreseeable future. Screening

for contaminated blood products will become important

when the appropriate methodologies are available. In

addition, focusing research on the following questions will

be crucial to tackling this problem effectively: first, which

blood-borne cells have prion infectivity?; second,

which plasma proteins associate with prions127?; third,

are there strain- and species-specific differences between

sheep and humans in terms of the distribution and stability

of blood-borne prions?; fourth, when — following initial

infection — does prion infectivity arise in blood?; and

finally, do generic or specific inflammatory states increase

the likelihood of blood-borne prion infectivity?

snip...

The future of prion science

Considerable knowledge on the biology of prions has

been amassed over the past decade, yet many questions

remain unanswered, including some relating to the

most basic aspects of prion biology. What is the precise

physical nature of the prion? What is the biochemical

basis of prion strains? What factors determine the species

barriers in prion infections? What are the host susceptibility

factors that promote prion infection? And,

finally, what are the molecular mechanisms that will

underpin successful sensitive diagnostics137 and efficacious

therapies? The tools and experimental models

available now should make it possible to answer many

of these questions. The development of new technologies,

and the input of fresh ideas, has opened up new

perspectives on our understanding of the mechanisms

of central and peripheral prion pathogenesis, some of

which could be applicable to other neurodegenerative

diseases.

snip...end...TSS

NATURE REVIEWS | MICROBIOLOGY VOLUME 4 | OCTOBER 2006 | 775

Prion diseases of humans and farm animals:

epidemiology, genetics, and pathogenesis

Adriano Aguzzi

Institute of Neuropathology, Universita¨ tsspital Zu¨ rich, Zu¨ rich, Switzerland

Journal of Neurochemistry, 2006, 97, 1726–1739

The recent discovery of transmission of vCJD via blood in

two individuals has raised concerns that blood-borne prion

transmission, in conjunction with an unknown prevalence of

vCJD-infected carriers, may lead to secondary transmission

of host-adapted prions (Peden et al. 2004). This may result in

a prolongation of the vCJD epidemic or, in the worst-case

scenario, may render vCJD endemic and self-sustained. Here

we review how prions might act as blood-borne infectious

agents, and consider strategies to restrict secondary transmission

of prion diseases.

Diagnosis of CJD

Clinically, patients suffering from CJD typically present

with rapidly progressive cognitive decline, which may be

fulminant and progress to akinetic mutism within weeks.

Cerebellar signs are also very frequent and electroencephalographic

recordings often visualize periodic sharp wave

complexes. The definitive diagnosis of sporadic CJD,

however, must usually await the analysis of central nervous

tissue, bioptically or post mortem. ‘Probable CJD’ cases are

diagnosed mainly on the basis of clinical symptoms when no

histopathological or biochemical confirmation is available.

Such ‘probable CJD’ cases may contaminate mortality

statistics in countries that register CJD cases based on

surrogate markers, including elevation of protein 14.3.3

in the cerebrospinal fluid (Hsich et al. 1996; Zerr et al.

2000).

In the case of vCJD disease, a firm diagnosis can often be

obtained by the biopsy of tonsils, which have been shown to

harbor significant amounts of PrPSc in germinal centers (Hill

et al. 1999). Highly sensitive methods have revealed that at

least one-third of patients with sCJD have deposits of PrPSc

in skeletal muscle and/or spleen (Glatzel et al. 2003a). While

the sensitivity of 30% is insufficient for routine diagnostics,

these data open the possibility of minimally invasive

diagnostics for sCJD, perhaps in combination with more

sensitive methods in the future.

Magnetic resonance imaging has provided evidence of the

frequent presence of hyperintensity in the posterior thalamus

of vCJD patients (Zeidler et al. 2000). This ‘pulvinar sign’

was originally thought to discriminate reliably between sCJD

and vCJD, but cases of sCJD with the same type of

neuroradiological changes have been described (Haik et al.

2003; Rossetti et al. 2004).

Determination of the molecular weight and glycosylation

patterns of PrPSc upon protease digest have established

themselves as proxies for determining strains of human

prions, and for differentiating vCJD from sporadic forms of

the disease (Parchi et al. 1996; Hill et al. 1997). However,

sophisticated analyses with state-of-the art antibodies discriminating

the fragment length of protease-digested PrPSc

have suggested a much more complex reality, and are

questioning the current classification of human prion diseases

(Polymenidou et al. 2005).

snip...

Extraneural PrPSc

Refinements in the technologies for detection of PrPSc have

prompted a renaissance of studies of the distribution of the

disease-associated prion protein in extracerebral organs of

patients. These studies revealed that extraneural PrPSc is

more widespread than previously thought. Zanusso and

colleagues found that PrPSc is readily detectable in the

olfactory mucosa of sCJD victims (Zanusso et al. 2003).

Glatzel and colleagues have found that approximately onethird

of the Swiss sCJD patients display PrPSc in their

skeletal muscle and another third (partially overlapping) had

PrPSc in lymphoid organs (Glatzel et al. 2003a). Further

investigations are underway to determine whether these

findings are universally valid for CJD patients, or are a

specific characteristic of the Swiss CJD collective. If the

latter were true, one might speculate that the abnormal

peripheral pathogenesis of CJD in Swiss patients points to a

specific etiology.

The UK vCJD cases are likely to be primary transmissions

from cattle BSE. However, experimental transmission studies

show that TSE strain characteristics can change upon serial

passages after the original primary transmission (Asante

et al. 2002). Therefore, horizontal vCJD transmission

amongst humans could result in a different phenotype than

vCJD. This scenario calls for innovative studies aimed at

developing and validating classical and emerging, up-to-date

prion strain typing tools.

snip...

MVV and related small-ruminant lentiviruses are endemic

in most, if not all, European small ruminant populations

(Peterhans et al. 2004). The above data suggest that common

viral infections of small ruminants may enhance the spread of

prions. MVV is found within mammary epithelial cells and

macrophages (Carrozza et al. 2003), and has been experimentally

passed to lambs via milk (Preziuso et al. 2004).

Milk is believed to represent a major route of transmission

for the natural spread of MVV. The PrP deposits in CD68+

cells of mammary lymphoid follicles, in concert with the

copious shedding of macrophages into milk of mastitic sheep

(Fig. 2b) (Lerondelle and Ouzrout 1990; Preziuso et al.

2004), raises the question whether coexistence of prion

infection and inflammation in secretory organs may lead to

prion contamination of secretions, and may represent a

cofactor for horizontal prion spread within flocks.

As the kidney is an excretory organ, it was inevitable to

that the question whether nephritis would lead to excretion of

prions into the urine (‘prionuria’) would be raised. This was

indeed found to be the case (Seeger et al. 2005) in mice

suffering from lymphocytic nephritis (Fig. 3). Interestingly,

isolated glomerulonephritis without lymphofollicular

involvement, as in mice deficient for the milk fat globuleepidermal

growth factor-like protein 8, did not lead to

prionuria. These accrued data suggest that prion shedding by

inflamed secretory and excretory organs may represent a

relevant exogenous cofactor that modifies the spread of

prions in populations.

snip...

Concluding remarks

For the past 10 years, prions have been in the public

limelight as the causative agent of ‘mad cow disease’. This

tremendous publicity has influenced political agendas,

attracted large amounts of research funds, and motivated

many researchers to enter the prion field. In the past 2 years,

however, prions have all but disappeared from the public

perception, mainly due to a – possibly premature –

perception that BSE has been defeated. From a scientific

viewpoint, however, the prion problem is enigmatic as ever,

despite all the progress summarized in this review article.

The precise physicochemical nature of the agent is unknown,

the process of prion replication is essentially a black box, the

phenomena underlying the various strains of prions are not

understood, and the function of the normal prion protein is

utterly unclear. Although some of these questions may be

resolved in the near future, others – including the most basic

characteristics of prions – may need to await the development

of novel technologies in imaging and in structural

biology for their resolution. Exciting times lie ahead for

scientists wishing to enter the prion field!

snip...end...TSS

2006 The Author

Journal Compilation 2006 International Society for Neurochemistry, J. Neurochem. (2006) 97, 1726–1739

=====================================================================================

MEDICAL IMPLANTS CONTAINING BOVINE MATERIAL

snip...

USA GBR

15. USA was initially assigned GBR II by the SSC in 20007. A

reassessment by EFSA in 2004 changed the level to GBR III8 (see

Annex 1). This was based upon:

(i) the extent of external challenge since 1980. The USA imported

cattle and MBM from BSE risk countries, including the UK, during

periods of time when a risk of importation of infected animals and

contaminated feed existed (see pages 2-8 of the technical annex at

Annex 1).

(ii) the stability of USA system to mitigate against the external

challenge since 1980. The USA system was considered extremely

unstable such that should BSE infectivity have entered the system

it would have recycled and amplified quickly (see pages 8-14 of the

technical annex at Annex 1).

16. In 2005, BSE was confirmed from a reanalysis of sample collected

as part of routine surveillance from a single native USA animal that

died in 20049 supporting the change in GBR level.

SEAC CONSIDERATION

Implantable medical devices containing bovine material

17. MHRA recently identified a range of implants (heart valves, heart

valve conduits, vascular grafts and pericardial patches) on the UK

market that use bovine tissue (mainly pericardium) sourced from

an open herd in the USA. The devices were certified by a Spanish

Notified Body despite objections being made about the source of

the material by the UK and other Member States. The basis for the

Spanish certification was that no alternative devices would be

available until the manufacturer found another bovine source (i.e.

from a closed herd or from a GBR I country). However, since

these implants were sourced from an open herd in a GBR III

country, MHRA took the view that the TSE-related risk had not

been minimised and the products were removed from the UK

market.

7 http://europa.eu.int/comm/food/fs/sc/ssc/out137_en.pdf

8 http://www.efsa.eu.int/science/tse_assessments/gbr_assessments/573_en.html

9 http://www.aphis.usda.gov/lpa/issues/bse/epi-updates/bse_final_epidemiology_report.pdf

18. The products will not be re-introduced on the UK market until

suitable alternatives are available. However, the devices can be

used in the UK on humanitarian grounds on a named patient basis

where no alternative treatment is available.

19. It is likely that in the past (prior to 1 May 2005 when the additional

certification under the terms of Directive 2003/32/EC was required)

that several thousand devices incorporating material from the

same and similar sources were implanted into patients in the UK.

snip...

Scientific report of the European Food Safety Authority on the

assessment of the Geographical BSE Risk (GBR) of the United

States of America (USA) including

• report

• technical annex

These documents can also be found at:

http://www.efsa.eu.int/science/tse_assessments/gbr_assessments/573_en.html

snip...full text ;

http://www.seac.gov.uk/papers/91-2.pdf

Subject: FDA 50 STATE EMERGENCY BSE CONFERENCE CALL JANUARY 9, 2001

Date: Sun, 7 Jan 2001 09:45:19 -0800
Reply-To: Sustainable Agriculture Network Discussion Group
<[log in to unmask]>
Sender: Sustainable Agriculture Network Discussion Group
<[log in to unmask]>
From: Beth von Gunten <[log in to unmask]>
Subject: [BSE] FDA/IMPORTANT NOTICE: 50 STATE CONFERENCE CALL

IMPORTANT NOTICE: 50 STATE CONFERENCE CALL - BSE

TUESDAY, JANUARY 9, 2001
1:00-2:00 PM EST CALL: 1-888-273-9887

A special "50 STATE CONFERENCE CALL" to discuss BSE (Bovine
Spongiform Encephalopathy) issues for Food and Drug Administration
(FDA) regulated animal feed products in the United States and
imported animal feeds. The conference call will
discuss the FDA proposed response to the current BSE issue and the
assistance needed from state feed and agriculture programs. THIS
ISSUE MAY IMPACT ALL STATES AND ALL ANIMAL FEED AND PRODUCTION
INDUSTRIES.

The 50 State call is scheduled for Tuesday, January 9, 2001 from
1:00-2:00 pm EST. Any state agency responsible for animal feed issues
wishing to participate should call 1-888-273-9887 and ask to be
connected to the "50 State BSE Call". The conference host operator
will explain how to participate, including asking questions during
the call. If possible, please coordinate within your state to utilize
only one phone line per state agency.

We request that you forward this message to your agency management
and feed coordinators or other agencies or departments who may be
responsible for any animal feed issues related to FDA regulated
products.

The agenda will be as follows:

1. Center For Veterinary Medicine (FDA) - Discussion of the problem
related to BSE events in Europe and the impact on US feed ingredients
for animals and feed operations. Discussion of the proposed
actions/inspections/compliance of licensed and unlicensed feed mills,
commercial feed manufacturers, animal feed imports, renderer's,
protein blenders, on-farm mixers, and ruminant feeders.

2. Office of Regional Operations (FDA) - Discussion of
contracting/working with states to inspect the universe of feed
mills/industry for "Animal Proteins Prohibited from Use in Animal
Feed". Discussion of working with FDA field offices.

3. Questions and answers.

Richard H. Barnes, Director
Division of Federal-State Relations (HFC-150)
5600 Fishers Lane Room 1207
Rockville, Md. 20857
ph: (301) 827-6906 FAX: (301) 443-2143
Email: [log in to unmask] http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0101&L=sanet-mg&P=13410
Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001 Date: Tue, 9 Jan 2001 16:49:00 -0800 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de ######### Bovine Spongiform Encephalopathy ######### Greetings List Members, I was lucky enough to sit in on this BSE conference call today and even managed to ask a question. that is when the trouble started. I submitted a version of my notes to Sandra Blakeslee of the New York Times, whom seemed very upset, and rightly so. "They tell me it is a closed meeting and they will release whatever information they deem fit. Rather infuriating." and i would have been doing just fine, until i asked my question. i was surprised my time to ask a question so quick. (understand, these are taken from my notes for now. the spelling of names and such could be off.) [host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch. [TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds? [no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.] [host Richard] could you repeat the question? [TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds? [not sure whom ask this] what group are you with? [TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide. [not sure who is speaking] could you please disconnect Mr. Singeltary [TSS] you are not going to answer my question? [not sure whom speaking] NO from this point, i was still connected, got to listen and tape the whole conference. at one point someone came on, a woman, and ask again; [unknown woman] what group are you with? [TSS] CJD Watch and my Mom died from hvCJD we are trying to tract down CJD and other human TSE's world wide. i was invited to sit in on this from someone inside the USDA/APHIS and that is why i am here. do you intend on banning me from this conference now? at this point the conference was turned back up, and i got to finish listening. They never answered or even addressed my one question, or even addressed the issue. BUT, i will try and give you a run-down for now, of the conference. IF i were another Country, I would take heed to my notes, BUT PLEASE do not depend on them. ask for transcript from; RBARNS@ORA.FDA.GOV 301-827-6906 he would be glad to give you one ;-) snip...full text ; http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/96n0417/96N-0417-EC-2.htm http://www.fda.gov/OHRMS/DOCKETS/AC/01/slides/3681s2_09.pdf
Volume 12, Number 12–December 2006

PERSPECTIVE

On the Question of Sporadic

or Atypical Bovine SpongiformEncephalopathy and

Creutzfeldt-Jakob Disease

Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§

Strategies to investigate the possible existence of sporadic

bovine spongiform encephalopathy (BSE) require

systematic testing programs to identify cases in countries

considered to have little or no risk for orally acquired disease,

or to detect a stable occurrence of atypical cases in

countries in which orally acquired disease is disappearing.

To achieve 95% statistical confidence that the prevalence

of sporadic BSE is no greater than 1 per million (i.e., the

annual incidence of sporadic Creutzfeldt-Jakob disease

[CJD] in humans) would require negative tests in 3 million

randomly selected older cattle. A link between BSE and

sporadic CJD has been suggested on the basis of laboratory

studies but is unsupported by epidemiologic observation.

Such a link might yet be established by the discovery

of a specific molecular marker or of particular combinations

of trends over time of typical and atypical BSE and various

subtypes of sporadic CJD, as their numbers are influenced

by a continuation of current public health measures that

exclude high-risk bovine tissues from the animal and

human food chains.

SNIP...

Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.

SNIP...

PLEASE READ FULL TEXT ;

http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm?s_cid=eid06_0965_e

3:00 Afternoon Refreshment Break, Poster and Exhibit Viewing in the Exhibit
Hall

3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve
University

6:30 Close of Day One

http://www.healthtech.com/2007/tse/day1.asp

SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

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

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
collection.

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm

http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf

JOURNAL OF NEUROLOGY

MARCH 26, 2003