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From: TSS ()
Subject: Research Project: Study of Atypical BSE 2006 ARS Annual Report
Date: January 13, 2007 at 3:16 pm PST

Research Project: Study of Atypical Bse
Location: Virus and Prion Diseases of Livestock

2006 Annual Report

4d.Progress report.
This report serves to document research conducted under a specific cooperative agreement between ARS and the Italian Reference Centre for Animal TSE (CEA) at the Istituto Zooprofilattico Sperimentale, Turin, Italy. Additional details of research can be found in the report for the parent project 3625-32000-073-00D, Transmission, Differentiation, and Pathobiology of Transmissible Spongiform Encephalopathies (TSEs).

The aim of the cooperative research project is (i) to compare the U.S. Bovine Spongiform Encephalopathy (BSE) isolates and the atypical BSE isolates identified in Italy and (ii) to determine whether diagnostic methods routinely used at the USDA are able to identify atypical BSE cases.

Within FY06, formalin fixed and frozen brain materials from animals with typical and atypical Italian (BASE) BSE have been sent by CEA to the USDA-ARS-NADC laboratory in Ames, IA. The serial brain material sections of BSE and BASE (consecutively numbered) will be analyzed in Ames using the USDA immunohistochemistry (IHC) protocol. To evaluate its reproducibility in Italian laboratories and to standardize the method, the USDA IHC protocol is being established at the CEA neuropathology laboratory. As soon as the Ventana NexES IHC Staining System is available to the CEA, the same samples (different cut numbers) will be examined by the CEA using the CEA in-house and the USDA IHC protocol.

In order to evaluate the USDA Western blot method, about 2 gram of typical Italian BSE and about 2 gram of atypical BASE brain tissue have been sent to the USDA-ARS-NADC laboratory. These samples and U.S. typical and atypical BSE samples have been analyzed in parallel using both the USDA and CEA Western blot methods and three different monoclonal antibodies (6H4, P4, SAF 84). These studies were performed during the visit by a CEA collaborator to the USDA-ARS-NADC. The latter studies revealed that both the Italian and USDA extraction and Western blot methods allowed the identification of the typical and atypical BSE samples tested.


http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=408490&showpars=true&fy=2006

ATYPICAL BSE BACKGROUND HISTORY USA

Research Project: Study of Atypical Bse

Location: Virus and Prion Diseases of Livestock

Project Number: 3625-32000-073-07
Project Type: Specific C/A


Start Date: Sep 15, 2004
End Date: Sep 14, 2007


Objective:
The objective of this cooperative research project with Dr. Maria Caramelli from the Italian BSE Reference Laboratory in Turin, Italy, is to conduct comparative studies with the U.S. bovine spongiform encephalopathy (BSE) isolate and the atypical BSE isolates identified in Italy. The studies will cover the following areas: 1. Evaluation of present diagnostics tools used in the U.S. for the detection of atypical BSE cases. 2. Molecular comparison of the U.S. BSE isolate and other typical BSE isolates with atypical BSE cases. 3. Studies on transmissibility and tissue distribution of atypical BSE isolates in cattle and other species.

Approach:
This project will be done as a Specific Cooperative Agreement with the Italian BSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del Piemonte, in Turin, Italy. It is essential for the U.S. BSE surveillance program to analyze the effectiveness of the U.S diagnostic tools for detection of atypical cases of BSE. Molecular comparisons of the U.S. BSE isolate with atypical BSE isolates will provide further characterization of the U.S. BSE isolate. Transmission studies are already underway using brain homogenates from atypical BSE cases into mice, cattle and sheep. It will be critical to see whether the atypical BSE isolates behave similarly to typical BSE isolates in terms of transmissibility and disease pathogenesis. If transmission occurs, tissue distribution comparisons will be made between cattle infected with the atypical BSE isolate and the U.S. BSE isolate. Differences in tissue distribution could require new regulations regarding specific risk material (SRM) removal.

http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=408490

2005 Annual Report


4d.Progress report.
This report serves to document research conducted under a specific cooperative agreement between ARS and the Italian Reference Centre for Animal TSE (CEA) at the Istituto Zooprofilattico Sperimentale, Turin, Italy. Additional details of research can be found in then report for the parent project 3625-32000-073-00D, Transmission, Differentiation, and Pathobiology of Transmissible Spongiform Encephalopathies. The aim of the cooperative research project conducted by the CEA and ARS is to compare the U.S. bovine spongiform encephalopathy (BSE) isolate and the bovine amyloidotic spongiform encephalopathy isolates (BASE) identified in Italy. The first objective was to determine whether diagnostic methods routinely used by USDA are able to identify the Italian BASE cases. For this purpose, CEA received the immunohistochemistry (IHC) protocol developed by APHIS-USDA. The IHC protocol was reproduced and standardized in the CEA laboratory and will be applied to the Italian BSE and BASE cases. Furthermore, fixed brainstem sections and frozen brainstem material from Italian BSE and BASE cases will be sent to ARS for analysis using USDA IHC and Western blot (WB) methods. These studies will enable us to determine whether the present diagnostic tools (IHC and WB) employed at the USDA will be able to detect the Italian BASE cases and also enable us to compare Italian BSE and BASE with the U.S. BSE cases.


http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=408490&showpars=true&fy=2005

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/


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

USA BSE OIG 2006


http://www.usda.gov/oig/webdocs/50601-10-KC.pdf


CDC DR. PAUL BROWN TSE EXPERT COMMENTS 2006


The U.S. Department of Agriculture was quick to assure the public earlier
this week that the third case of mad cow disease did not pose a risk to
them, but what federal officials have not acknowledged is that this latest
case indicates the deadly disease has been circulating in U.S. herds for at
least a decade.

The second case, which was detected last year in a Texas cow and which USDA
officials were reluctant to verify, was approximately 12 years old.

These two cases (the latest was detected in an Alabama cow) present a
picture of the disease having been here for 10 years or so, since it is
thought that cows usually contract the disease from contaminated feed they
consume as calves. The concern is that humans can contract a fatal,
incurable, brain-wasting illness from consuming beef products contaminated
with the mad cow pathogen.

"The fact the Texas cow showed up fairly clearly implied the existence of
other undetected cases," Dr. Paul Brown, former medical director of the
National Institutes of Health's Laboratory for Central Nervous System
Studies and an expert on mad cow-like diseases, told United Press
International. "The question was, 'How many?' and we still can't answer
that."

Brown, who is preparing a scientific paper based on the latest two mad cow
cases to estimate the maximum number of infected cows that occurred in the
United States, said he has "absolutely no confidence in USDA tests before
one year ago" because of the agency's reluctance to retest the Texas cow
that initially tested positive.

USDA officials finally retested the cow and confirmed it was infected seven
months later, but only at the insistence of the agency's inspector general.

"Everything they did on the Texas cow makes everything USDA did before 2005
suspect," Brown said. ...snip...end


http://www.upi.com/


CDC - Bovine Spongiform Encephalopathy and Variant Creutzfeldt ...
Dr. Paul Brown is Senior Research Scientist in the Laboratory of Central
Nervous System ... Address for correspondence: Paul Brown, Building 36, Room
4A-05, ...


http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm

PAUL BROWN M.D.

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

[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

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

Terry S. Singeltary SR.
P.O. Box 42
Bacliff, Texas USA 77518





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