----- Original Message -----
From: Terry S. Singeltary Sr.
To: [email protected]
Cc: [email protected] ; [email protected] ; Dave Cavenaugh ; [email protected] ; [email protected] ; ??? ;
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: [email protected] ######### 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; [email protected] 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.
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:
[email protected]
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: [email protected] 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
From: Terry S. Singeltary Sr.
To: [email protected]
Cc: [email protected] ; [email protected] ; Dave Cavenaugh ; [email protected] ; [email protected] ; ??? ;
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: [email protected] ######### 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; [email protected] 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.
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:
[email protected]
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: [email protected] 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