BIOIBERICA
SCIENCE BOARD TO THE FDA June 4, 2014 FDA White Oak Campus Bldg 31 Rm 1503
10903 New Hampshire Ave Silver Spring, MD 20993 Barcelona, May 27th 2014
POSITION STATEMENT ON THE REINTRODUCTION OF BOVINE HEPARIN
Commercial heparin drug products were introduced into clinical use more
than 70 years ago. Heparin sodium was first approved by the FDA on February 9th,
1939(1). The first commercial heparin preparations were derived from bovine
tissues (lung or intestinal mucosa). Since most of unfractionated heparin
applications were approved decades ago, there was little or no pharmaceutical
development reported in the applications(2) . In fact, even today unfractionated
heparin is defined as a "natural product that is poorly defined chemically"(2)
or "a substance that is of biological origin and, due to its complexity, a
combination of physico-chemical-biological testing together with testing and
control of the manufacturing process is needed for its characterization and
determination of quality"(3). For this reason, and due to the significant
molecular differences between heparins of different origins that we have
observed in our own studies or that are described in published literature, we
consider that the benefit-risk assessment of the reintroduction of bovine
heparin may be a risky challenge. Since the outbreak of bovine spongiform
encephalopathy (BSE), only heparin derived from pig intestinal mucosa is found
in Europe and USA, because the sourcing of heparin from bovine tissues could
pose a risk to human health after description of the variant of Creutzfeld‐Jacob
encephalopathy (vCJ) as a prion disease transmitted by cows suffering from
BSE.
Though we are sure that the FDA has taken into consideration the scientific
knowledge available on heparin sourced from different species/tissues, we would
like to share our point of view with regards to the reintroduction of bovine
heparin in commercial preparations. In particular, we believe there are two
aspects of utmost importance:
1) the differences in the structural characteristics of heparin from
different origins and
2) the increase of the BSE agent transmission risk via bovine heparin
preparations.
1. Differences in the structural characteristics of heparin from different
origins
Today there are analytical techniques that are able to discern relevant
differences between complex products due to their molecular heterogeneity.
Bioibérica has been studying the Heparin molecule and has found significant
differences between heparins derived from different tissues.
Page 1 of 4
Oficina Comercial: Plaza Francesc Macià, 7, 8º-B. 08029 Barcelona - España.
Tel. (34) 93 490 49 08. Fax (34) 93 490 97 11
Complejo Industrial Bioibérica: Ctra. Nacional II, Km. 680,6. 08389
Palafolls. Barcelona - España. Tel. (34) 93 765 03 90. Fax (34) 93 765 01
02
Our findings are aligned with the data published in the available
literature, which also describes differences between heparins extracted from
different tissues and species. E.g. "Heparins obtained from different tissues
and different species also differ structurally. The most widely used tissue for
the preparation of pharmaceutical grade heparin is porcine intestine. Heparin
prepared from bovine lung differs substantially from porcine intestinal heparin.
Bovine lung heparin has a higher sulfation level and slightly higher molecular
weight than porcine intestinal heparin, increasing its affinity for thrombin
(factor IIa). Porcine intestinal heparin contains an AT binding site primarily
having N-acetyl group in residue A, while bovine lung heparin primarily has an
N-sulfo group residue A, resulting in their slightly different affinities for
AT" (4) .
Particularly important is the fact that these structural differences may
lead to different efficacy or safety profiles: "Pharmaceutical grade heparins
obtained from porcine and bovine intestinal mucosa differ significantly in their
preponderant disaccharide compositions, anticoagulant activities, bleeding
tendencies, doses required to inhibit experimental thrombosis and protamine
neutralization curves. It is possible to obtain a heparin fraction from bovine
mucosa with the typical disaccharide composition, but at a lower yield when
compared with that from porcine source. Even possessing the typical disaccharide
composition this bovine heparin fraction still shows a lower antithrombotic
activity than porcine heparin"(5) . These observations may explain the
increasing reports of bleeding and peri-or post-operative blood dyscrasias
observed in Brazilian patients in 2008, "though it was not possible to correlate
clinical events with specific heparin batches"(6). The heparin preparations from
bovine and porcine origins were interchanged by health professionals in
Brazil.
Also according to the regulatory authorities in Argentina (ANMAT), where
bovine heparin is clinically in use, there were outstanding issues with specific
activities of bovine heparin in the Inspection and Quality Control Program of
2012 (7).
2) Increase of the BSE agent transmission risk via bovine heparin
preparations
The potential for contamination of heparin with the BSE agent has been a
concern of the U.S. Food and Drug Administration (FDA): "FDA is also concerned
about the potential for contamination of heparin with the bovine spongiform
encephalopathy (BSE) agent derived from ruminant materials"(8). Therefore, FDA
Guidance for Industry Heparin for Drug and Medical Device Use: Monitoring Crude
Heparin for Quality recommends testing and confirming the species origin of
crude heparin in each lot of every shipment before use in the manufacture or
preparation of a drug, to ensure the safety of drugs and devices that contain
heparin and to protect public health.
Heparin sourced from bovine species is extracted either from the intestines
or from the lungs. The intestines, from the duodenum to the rectum, of bovine
animals of all ages are currently included in the list of Specified Risk
Material (SRM) in the European Union (Regulation (EC) No 999/2001, as
Page 2 of 4
amended). The distal ileum of the small intestine is also considered as SRM
in U.S.A (§310.22). As far as the lungs are concerned, they are classified in
"Table IB lower-infectivity tissues" (peripheral tissues that have tested
positive for infectivity and/or PrPTSE in at least one form of TSE) according to
WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform
Encephalopathies (2010), though no detectable infectivity or PrPTSE is observed
in cattle.
If materials from bovine species are allowed to be used in the manufacture
of Heparin, all the necessary complementary measures to minimize the risk of
transmission of BSE should be considered. E.g.:
- the source animals and their geographical origin (animals should be
sourced from countries with an active BSE surveillance and never from countries
with undetermined BSE risk status),
- the nature of animal material and procedures in place to avoid
cross-contamination with higher risk materials, and
- the production process validated for the clearance of BSE agents. To sum
up, the reintroduction of bovine heparin in commercial heparin preparations
would need to be thoroughly justified based on overwhelming evidences that the
benefits outweigh the risks, in particular for:
- Differences in the structural characteristics may lead to different
clinical efficacy and safety profile. Clinical and safety data of bovine heparin
should be available according to current non-clinical and clinical guidelines.
If different bovine tissues were used in addition to the current porcine
material, the heterogeneity of the heparin preparations in the market would
increase significantly, and health professionals would need to be warned about
this.
- There should be a scientifically grounded evidence to justify that the
benefits of having commercially available bovine heparin outweigh the increase
of the risk of the BSE agent to be transmitted via bovine heparin. Stringent
measures should be put in place for the sourcing and production of bovine
heparin, which should require dedicated manufacturing facilities to avoid
cross-contamination of the porcine heparin (that could be detected by the
current FDA requirement to test porcine heparin for the absence of ruminant
species contamination by PCR technique).
Sincerely yours, Irene Bartolí Regulatory Affairs BIOIBERICA, S.A.
Page 3 of 4
REFERENCES
(1) Center for Drug Evaluation and Research. Application Number
201370Orig1s000. Summary Review. Ann. T. Farrel, M.D. Acting Division Director.
Heparin sodium, Vials for Injection.
(2) Regulatory Requirements and Recommendations for Heparin Application.
Arthur B. Shaw, Ph.D. Product Quality Reviewer US Food and Drug Administration.
5th Workshop on the Characterization of Heparin Products August 14-15,
2012.
(3) EMA/CHMP/BWP/429241/2013, Guideline on the use of starting materials
and intermediates collected from different sources in the manufacturing of
non-recombinant biological medicinal products (June 2013).
(4) Production and Chemical Processing of Low Molecular Weight Heparins.
Seminars in Thrombosis and Hemostasis, Vol. 25, Suppl. 3, 1999. Robert J.
Linhard, Ph.D and Nur Sibel Gunay, M.S.
(5) Structural and functional differences between bovine and porcine
mucosal heparins. Paulo A. S. Mourão, Laboratório de Tecido Conjuntivo Hospital
Universitário Clementino Fraga Filho Universidade Federal do Rio de Janeiro. 4th
Workshop on the characterization of heparin products 8-9 July, 2010
London.
(6) Heparin: shortage and high selling prices. Should beef mucosa heparin
be reconsidered? Giuseppe Mascellani. 4th Workshop on the characterization of
heparin products 8-9 July, 2010 London.
(7) Regulatory and Dossier Requirements for Heparin in Argentina.
Biochemist M. Verónica López Cepero Division of Identification and
Quantification Department of Biologic Products National Administration of Drugs,
Food and Medical Devices. 5th Workshop on the Characterization of Heparin
Products August 14-15, 2012.
(8) Federal Register Volume 77, Number 29 (Monday, February 13, 2012).
Draft Guidance for Industry on Heparin for Drug and Medical Device Use;
Monitoring Crude Heparin for Quality; Availability.
Page 4 of 4
snip...see full text ;
Monday, October 31, 2011
Getting the Farm Out of Pharma for Heparin Production
http://transmissiblespongiformencephalopathy.blogspot.com/2011/10/getting-farm-out-of-pharma-for-heparin.html
Wednesday, July 06, 2011
Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation
(see tonnage of mad cow feed in commerce USA...tss)
http://chronic-wasting-disease.blogspot.com/2011/07/swine-are-susceptible-to-chronic.html
In an experimental study of the transmissibility of BSE to the pig, seven of 10 pigs, infected at 1-2 weeks of age by multiple-route parenteral inoculation with a homogenate of bovine brain from natural BSE cases developed lesions typical of spongiform encephalopathy.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=10684682&dopt=Abstract
PLEASE NOTE, these old BSE Inquiry links take a while to open with the wayback machine, so be patient. ...tss
Title: Experimental Intracerebral and Oral Inoculation of Scrapie to Swine: Preliminary Report
In the United States, feeding of ruminant by-products to ruminants is prohibited, but feeding of ruminant materials to swine and poultry still occurs. The potential for swine to have access to scrapie-contaminated feedstuffs exists, but the potential for swine to serve as a host for replication/accumulation of the agent of scrapie is unknown. The purpose of this study was to perform oral and intracerebral inoculation of the U.S. scrapie agent to determine the potential of swine as a host for the scrapie agent and their clinical susceptibility.
snip...
IN CONFIDENCE
EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY
1. CMO should be aware that a pig inoculated experimentally (ic, iv, and ip) with BSE brain suspension has after 15 months developed an illness, now confirmed as a spongiform encephalopathy. This is the first ever description of such a disease in a pig, although it seems there ar no previous attempts at experimental inoculation with animal material. The Southwood group had thought igs would not be susceptible. Most pigs are slaughtered when a few weeks old but there have been no reports of relevant neurological illness in breeding sows or other elderly pigs. ...see full text ;
http://web.archive.org/web/20040302031004/www.bseinquiry.gov.uk/files/yb/1990/08/23001001.pdf
IN CONFIDENCE
So it is plausible pigs could be preclinically affected with BSE but since so few are allowed to reach adulthood this has not been recognised through clinical disease. ...
http://web.archive.org/web/20040904150118/www.bseinquiry.gov.uk/files/yb/1990/08/23002001.pdf
snip...
CONFIDENTIAL
EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY
snip... see full text ;
Thursday, November 10, 2011
National Meat Association v. Harris Docket No., 10-224
DEADSTOCK DOWNER PIGS AND PORCINE SPONGIFORM ENCEPHALOPATHY PSE
Court Likely to Overturn Calif. Law on Livestock
http://transmissiblespongiformencephalopathy.blogspot.com/2011/11/national-meat-association-v-harris.html
Wednesday, July 06, 2011
Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation
(see tonnage of mad cow feed in commerce USA...tss)
http://chronic-wasting-disease.blogspot.com/2011/07/swine-are-susceptible-to-chronic.html
In an experimental study of the transmissibility of BSE to the pig, seven of 10 pigs, infected at 1-2 weeks of age by multiple-route parenteral inoculation with a homogenate of bovine brain from natural BSE cases developed lesions typical of spongiform encephalopathy.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=10684682&dopt=Abstract
PLEASE NOTE, these old BSE Inquiry links take a while to open with the wayback machine, so be patient. ...tss
Title: Experimental Intracerebral and Oral Inoculation of Scrapie to Swine: Preliminary Report
In the United States, feeding of ruminant by-products to ruminants is prohibited, but feeding of ruminant materials to swine and poultry still occurs. The potential for swine to have access to scrapie-contaminated feedstuffs exists, but the potential for swine to serve as a host for replication/accumulation of the agent of scrapie is unknown. The purpose of this study was to perform oral and intracerebral inoculation of the U.S. scrapie agent to determine the potential of swine as a host for the scrapie agent and their clinical susceptibility.
snip...
IN CONFIDENCE
EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY
1. CMO should be aware that a pig inoculated experimentally (ic, iv, and ip) with BSE brain suspension has after 15 months developed an illness, now confirmed as a spongiform encephalopathy. This is the first ever description of such a disease in a pig, although it seems there ar no previous attempts at experimental inoculation with animal material. The Southwood group had thought igs would not be susceptible. Most pigs are slaughtered when a few weeks old but there have been no reports of relevant neurological illness in breeding sows or other elderly pigs. ...see full text ;
http://web.archive.org/web/20040302031004/www.bseinquiry.gov.uk/files/yb/1990/08/23001001.pdf
IN CONFIDENCE
So it is plausible pigs could be preclinically affected with BSE but since so few are allowed to reach adulthood this has not been recognised through clinical disease. ...
http://web.archive.org/web/20040904150118/www.bseinquiry.gov.uk/files/yb/1990/08/23002001.pdf
snip...
CONFIDENTIAL
EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY
snip... see full text ;
Thursday, November 10, 2011
National Meat Association v. Harris Docket No., 10-224
DEADSTOCK DOWNER PIGS AND PORCINE SPONGIFORM ENCEPHALOPATHY PSE
Court Likely to Overturn Calif. Law on Livestock
http://transmissiblespongiformencephalopathy.blogspot.com/2011/11/national-meat-association-v-harris.html
Friday, April 20, 2012
Ultrastructural findings in pigs experimentally infected with bovine spongiform encephalopathy agent
http://madporcinedisease.blogspot.com/2012/04/ultrastructural-findings-in-pigs.html
"The fact that certain medicinal products could be injected directly into the body (most commonly intramuscularly) meant that in theory they would pose a greater risk than beef products in food."
Ultrastructural findings in pigs experimentally infected with bovine spongiform encephalopathy agent
http://madporcinedisease.blogspot.com/2012/04/ultrastructural-findings-in-pigs.html
"The fact that certain medicinal products could be injected directly into the body (most commonly intramuscularly) meant that in theory they would pose a greater risk than beef products in food."
Infectivity of bovine materials used in medicinal products and the
importance of inoculation route
3.221 The risk from infectivity present in medicinal products was
considered by the Southwood Working Party. They noted that ‘the greatest risk .
. . would be from the parenteral injection of material derived from bovine brain
or lymphoid tissue’.538 (As described previously, it was generally accepted that
the oral route was considerably less efficient than the parenteral
route.539)
3.222 In reality, different routes exist within the parenteral category –
intracerebral, intraperitoneal, intramuscular, intravenous, intraspinal and
subcutaneous. Experiments in 1978 looking at several of these routes found the
efficiency between them to vary. Intracerebral and intraspinal were generally
the most efficient, followed by intravenous, intraperitoneal and then
subcutaneous.540 The fact that certain medicinal products could be injected
directly into the body (most commonly intramuscularly) meant that in theory they
would pose a greater risk than beef products in food.
3.223 Various cattle tissues were of relevance to medicinal products,
including insulin, heparin, surgical catgut sutures and serum. The consideration
given to these materials prior to March 1996 is addressed in vol. 7: Medicines
and Cosmetics.
533 SEAC 22/5 534 Wells, G. (1998) Preliminary Observations on the
Pathogenesis of Experimental Bovine Spongiform Encephalopathy (BSE): An Update,
Veterinary Record, 142, 103 535 Wells, G., Hawkins, S., Green, P., Spencer, Y.,
Dexter, I. and Dawson, D. (1999) Limited Detection of Sternal Bone Marrow
Infectivity in the Clinical Phase of Experimental Bovine Spongiform
Encephalopathy (BSE), Veterinary Record, 144, 292–4 536 Scott, M.R., Will, R.,
Ironside, J., Nguyen, H.-O., Tremblay, P., DeArmond, S.J. and Prusiner, S.B.
(1999) Compelling Transgenetic Evidence for Transmission of Bovine Spongiform
Encephalopathy Prions to Humans, Proceedings of the National Academy of Sciences
of the USA, 96, 15137–42 537 Scott, M.R., Safar, J., Telling, G., Nguyen, H.-O.,
Groth, D., Torchia, M., Kochler, R., Tremblay, P., Walther, D., Cohen, F.,
DeArmond, S. and Prusiner, S. (1997) Identification of a Prion Protein Epitope
Modulating Transmission of Bovine Spongiform Encephalopathy Prions to Transgenic
Mice, Proceedings of the National Academy of Sciences of the United States of
America, 94, 14279–84 538 IBD1 tab 2 para. 5.3.3 539 Kimberlin, R. and Walker,
C. (1989) Pathogenesis of Scrapie in Mice after Intragastric Infection, Virus
Research, 12, 213–20; Diringer, H., Beekes, M. and Oberdieck, U. (1994) The
Nature of the Scrapie Agent: The Virus Theory, Annals of The New York Academy of
Science, 724, 246–58; Prusiner, S., Cochran, S. and Alpers, S. (1985)
Transmission of Scrapie in Hamsters, Journal of Infectious Diseases, 152, 971–8
540 Kimberlin, R.H. and Walker, C.A. (1978) Pathogenesis of Mouse Scrapie:
Effect of Route of Inoculation on Infectivity Titres and Dose-Response Curves,
Journal of Comparative Pathology, 88, 39–47
COMMERCIAL IN CONFIDENCE
NOT FOR PUBLICATION
COMMITTEE ON SAFETY OF MEDICINES
WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY
3. Products for injection using bovine tissue
This category includes tissue derived products, other than from brain or
lymphoid tissue and excludes bovine blood.
3.1 Bovine Pancreas
3.1.1 Insulin
The following companies hold licences for bovine insulin.
Source Country
Denmark
USA
USA
Denmark, Sweden, USA, Italy, Canada, Portugal, Netherlands
In 1988 a sample consignment from UK was used. UK source material is no
longer used.
Comment
There are no bovine insulins manufctured from UK sourced material.
Bovine insulin is not widely prescribed, but has a niche in the market for
diabetics unable to tolerate other products.
3.1.2 Glucagon
bovine pancreas from USA.
as for insulin - Scandinavia, USA, Italy, Canada, Portugal and
Netherlands.
3.1.3
Miscellaneous products containing Bovine Pancreas
3.1.3.1 Zonulysin (Chymotrypsin) - sourced from Canada
3.1.3.2 Streptokinase - culture medium, containing bovine muscle and
pancreas are used in process - all sourced from Germany
3.1.3.3 Fibrinogen + Desoxyribonuclease - bovine pancreas sourced from
Canada and S Africa.
3.2. Vaccines using Bovine Products in process
snip...see full text ;
Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 –0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946
NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND
ANNUAL CONGRESS, 1946
The annual Congress, 1946, was held at the Royal Veterinary College, Royal
College Street, London, N.W.I. from September 22nd to September 27th.
Opening Meeting
[skip to scrapie vaccine issue...tss]
Papers Presented to Congress
The papers presented to this year's Congress had as their general theme the
progressive work of the profession during the war years. Their appeal was
clearly demonstrated by the large and remarkably uniform attendance in the Grand
Hall of the Royal Veterinary College throughout the series; between 200 and 250
members were present and they showed a keen interest in every paper, which was
reflected in the expression of some disappointment that the time available for
discussion did not permit of the participation of more than a small proportion
of would-be contributors.
In this issue we publish (below) the first to be read and discussed, that
by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary Research."
Next week's issue will contain the paper on "Some Recent Advances in Veterinary
Medicine and Surgery in Large-Animal Practice" by Mr. T. Norman Gold, M.R.C.V.S.
In succeeding numbers of the Record will be reproduced, also with reports of
discussions, that by Mr. W. L. Weipers, M.R.C.V.S., D.V.S.M., on the same
subject as relating to small-animal practice, and the papers by Mr. J. N.
Ritchie, B.SC., M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on
"War-time Achievements of the British Home Veterinary Services."
The first scientific paper of Congress was read by Dr. W. S. Gordon,
M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946, when Professor J. Basil
Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal of the Royal Veterinary College,
presided.
Advances in Veterinary Research
by
W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.
Agriculteral Research Council, Field Station, Compton, Berks.
Louping-ill, Tick-borne Fever and Scrapie
In 1930 Pool, Browniee & Wilson recorded that louping-ill was a
transmissible disease. Greig et al, (1931) showed that the infective agent was a
filter-passing virus with neurotropic characters and Browniee & Wilson
(1932) that the essential pathology was that of an encephalomyelitis. Gordon,
Browniee, Wilson & MacLeod (1932) and MacLeod & Gordon (1932) confirmed
and extended this work. It was shown that on louping-ill farms the virus was
present in the blood of many sheep which did not show clinical symptoms
indicating involvement of the central nervous system and that for the
perpetuation and spread of the disease these subclinical cases were probably of
greater importance that the frank clinical cases because, in Nature, the disease
was spread by the tick, lxodes ricinus L. More recently Wilson (1945, 1946) has
described the cultivation of the virus in a chick embryo medium, the pathogenic
properties of this culture virus and the preparation of louping-ill antiserum.
Between 1931 and 1934 I carried out experiments which resulted in the
development of an effective vaccine for the prevention of louping-ill.* This
vaccine has been in general use since 1935 and in his annual report to the
Animal Diseases Research Association this year, Dr. Greig stated that about
227,000 doses of vaccine had been issued from Moredun alone.
Dr. Gordon illustrated this portion of his paper by means of graphs and
diagrams projected by the epidiascope.
This investigation, however, did not begin and end with the study of
louping-ill; it had, by good fortune, a more romantic turn and less fortunately
a final dramatic twist which led almost to catastrope. After it had been
established that a solid immunity to louping-ill could be induced in sheep, a
group of immunized and a group of susceptible animals were placed together on
the tick-infected pasture of a louping-ill farm. Each day all the animals were
gathered and their temperatures were recorded. It was anticipated that febrile
reactions with some fatalities would develop in the controls while the
louping-ill immunes would remain normal. Contrary to expectation, however, every
sheep, both immune and control, developed a febrile reaction. This unexpected
result made necessary further investigation which showed that the febrile
reaction in the louping-ill immunes was due to a hitherto undescribed infective
agent, a Rickettsia-like organism which could be observed in the cytoplasm of
the grannular leucocytes, especially the neutrophil polymorphs (MacLeod (1932),
Gordon, Browniee, Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod
(1936). MacLeod collected ticks over many widely separated parts of Scotland and
all were found to harbour the infective agent of tick-borne fever, and it is
probable that all sheep on tick-infested farms develop this disease, at least on
the first occasion that they become infested with ticks. When the infection is
passed in series through susceptible adult sheep it causes a sever, febrile
reaction, dullness and loss of bodily condition but it rarely, if ever, proves
fatal. It is clear, however, that it aggravates the harmful effects of a
louping-ill infection and it is a serious additional complication to such
infections as pyaemia and the anacrobic infections which beset lambs on the hill
farms of Northern Britain.
Studying the epidemiology of louping-ill on hill farms it became obvious
that the pyaemic condition of lambs described by M'Fadyean (1894) was very
prevalent on tick infested farms Pyaemia is a crippling condition of lambs
associated with tick-bite and is often confused with louping-ill. It is caused
by infection with Staphylococcus aureus and affected animals may show abscess
formation on the skin, in the joints, viscera, meninges and elsewhere in the
body. It was thought that tick-borne fever might have ben a predisposing factor
in this disease and unsuccessful attempts were made by Taylor, Holman &
Gordon (1941) to reproduce the condition by infecting lambs subcutaneously with
the staphylococcus and concurrently producing infections with tickborne fever
and louping-ill in the same lambs. Work on pyaemia was then continued by
McDiarmid (1946a, 1946b, 1946c), who succeeded in reproducing a pyaemic disease
in mice, guinea-pigs and lambs similar to the naturally occurring condition by
intravenous inoculation of Staphylococcus aureus. He also found a bacteraemic
form of the disease in which no gross pyaemic lesions were observed. The
prevention or treatment of this condition presents a formidable problem. It is
unlikely that staphylococcal ???oid will provide an effective immunity and even
if penicillin proved to be a successful treatment, the difficulty of applying it
in adequate and sustained dosage to young lambs on hill farms would be almost
insurmountable.
>From 1931 to 1934 field trials to test the immunizing value and
harmlessness of the loup-ill vaccine were carried out on a gradually increasing
scale. Many thousands of sheep were vaccinated and similar numbers, living under
identical conditions were left as controls. The end result showed that an
average mortability of about 9 percent in the controls was reduced to less than
1 percent in the vaccinated animals. While the efficiency of the vaccine was
obvious after the second year of work, previous bitter experience had shown the
wisdom of withholding a biological product from widespread use until it had been
successfully produced in bulk, as opposed to small-scale experimental production
and until it had been thoroughly tested for immunizing efficiency and freedom
from harmful effects. It was thought that after four years testing this stage
had been reached in 1935, and in the spring of that year the vaccine was issued
for general use. It comprised a 10 percent saline suspension of brain, spinal
cord and spleen tissues taken from sheep five days after infection with
louping-ill virus by intracerebral inoculation. To this suspension 0-35 percent
of formalin was added to inactivate the virus and its safety for use as a
vaccine was checked by intracerbral inoculation of mice and sheep and by the
inoculation of culture medium. Its protective power was proved by vaccination
sheep and later subjecting them, along with controls, to a test dose of living
virus.
Vaccine for issue had to be free from detectable, living virus and capable
of protecting sheep against a test dose of virus applied subcutaneously. The
1935 vaccine conformed to these standards and was issued for inoculation in
March as three separate batches labeled 1, 2, and 3. The tissues of 140 sheep
were employed to make batch 1 of which 22,270 doses were used; 114 to make batch
2 of which 18,000 doses were used and 44 to make batch 3 of which 4,360 doses
were used. All the sheep tissues incorporated in the vaccine were obtained from
yearling sheep. During 1935 and 1936 the vaccine proved highly efficient in the
prevention of loup-ill and no user observed an ill-effect in the inoculated
animals. In September, 1937, two and a half years after vaccinating the sheep,
two owners complained that scrapie, a disease which had not before been observed
in the Blackface breed, was appearing in their stock of Blackface sheep and
further that it was confined to animals vaccinated with louping-ill vaccine in
1935. At that stage it was difficult to conceive that the occurrence could be
associated with the injection of the vaccine but in view of the implications, I
visited most of the farms on which sheep had been vaccinated in 1935. It was at
this point that the investigation reached its dramatic phase; I shall not forget
the profound effect on my emotions when I visited these farms and was warmly
welcomed because of the great benefits resulting from the application of
louping-ill vaccine, wheras the chief purpose of my visit was to determine if
scrapie was appearing in the inoculated sheep. The enquiry made the position
clear. Scrapie was developing in the sheep vaccinated in 1935 and it was only in
a few instances that the owner was associating the occurrence with louping-ill
vaccination. The disease was affecting all breeds and it was confined to the
animals vaccinated with batch 2. This was clearly demonstrated on a number of
farms on which batch 1 had been used to inoculate the hoggs in 1935 and batch 2
to inoculate the ewes. None of the hoggs, which at this time were three-
year-old ewes. At this time it was difficult to forecast whether all of the
18,000 sheep which had received batch 2 vaccine would develop scrapie. It was
fortunate, however, that the majority of the sheep vaccinated with batch 2 were
ewes and therfore all that were four years old and upwards at the time of
vaccination had already been disposed of and there only remained the ewes which
had been two to three years old at the time of vaccination, consequently no
accurate assessment of the incidence of scrapie could be made. On a few farms,
however, where vaccination was confined to hoggs, the incidence ranged from 1
percent, to 35 percent, with an average of about 5 percent. Since batch 2
vaccine had been incriminated as a probable source of scrapie infection, an
attempt was made to trace the origin of the 112 sheep whose tissues had been
included in the vaccine. It was found that they had been supplied by three
owners and that all were of the Blackface or Greyface breed with the exception
of eight which were Cheviot lambs born in 1935 from ewes which had been in
contact with scrapie infection. Some of these contact ewes developed scrapie in
1936-37 and three surviving fellow lambs to the eight included in the batch 2
vaccine of 1935 developed scrapie, one in September, 1936, one in February,
1937, and one in November, 1937. There was, therefore, strong presumptive
evidence that the eight Cheviot lambs included in the vaccine although
apparently healthy were, in fact, in the incubative stage of a scrapie infection
and that in their tissues there was an infective agent which had contaminated
the batch 2 vaccine, rendering it liable to set up scrapie. If that assumption
was correct then the evidence indicated that:-
(1) the infective agent of scrapie was present in the brain, spinal cord
and or spleen of infected sheep: (2) it could withstand a concentration of
formalin of 0-35 percent, which inactivated the virus of louping-ill: (3) it
could be transmitted by subcutaneous inoculation; (4) it had an incubative
period of two years and longer.
Two Frenchmen, Cuille & Chelle (1939) as the result of experiments
commenced in 1932, reported the successful infection of sheep by inoculation of
emulsions of spinal cord or brain material by the intracerebral, epidural,
intraocular and subcutaneous routes The incubation period varied according to
the route employed, being one year intracerebrally, 15 months intraocularly and
20 months subcutaneously. They failed to infect rabbits but succeeded in
infecting goats. Another important part of their work showed that the infective
agent could pass through a chamberland 1.3 filter, thus demonstrating that the
infective agent was a filtrable virus. It was a curious coincidence that while
they were doing their transmission experiments their work was being confirmed by
the unforeseeable infectivity of a formalinized tissue vaccine.
As a result of this experience a large-scale transmission experiment
involving the use of 788 sheep was commenced in 1938 on a farm specially taken
for the purpose by the Animal Diseases Research Association with funds provided
by the Agricultural Research Council. The experiment was designed to determine
the nature of the infective agent and the pathogenesis of the disease. It is
only possible here to give a summary of the result which showed that (1) saline
suspensions of brain and spinal cord tissue of sheep affected with scrapie were
infective to normal sheep when inoculatted intracerebrally or subcutaneously;
(2) the incubation period after intracerebral inoculation was seven months and
upwards and only 60 percent of the inoculated sheep developed scrapie during a
period of four and a half years; (3) the incubation period after subcutaneous
inoculation was 15 months and upwards and only about 30 percent of the
inoculated sheep developed the disease during the four and a half years: (4) the
infective agent was of small size and probably a filtrable virus.
The prolonged incubative period of the disease and the remarkable
resistance of the causal agent to formalin are features of distinct interest. It
still remains to determine if a biological test can be devised to detect
infected animals so that they can be killed for food before they develop
clinical symptoms and to explore the possibilities of producing an immunity to
the disease.
==================================================================
Greetings List Members,
pretty disturbing document. now, what would stop this from happening with
the vaccineCJD in children???
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
2014
Evidence for zoonotic potential of ovine scrapie prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves
Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle
Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia
Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier Andréoletti1,
Affiliations Contributions Corresponding author Journal name: Nature
Communications Volume: 5, Article number: 5821 DOI: doi:10.1038/ncomms6821
Received 07 August 2014 Accepted 10 November 2014 Published 16 December 2014
Article tools Citation Reprints Rights & permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant
Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie
prions remains unknown. Mice genetically engineered to overexpress the human
prion protein (tgHu) have emerged as highly relevant models for gauging the
capacity of prions to transmit to humans. These models can propagate human
prions without any apparent transmission barrier and have been used used to
confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie
prions transmit to several tgHu mice models with an efficiency comparable to
that of cattle BSE. The serial transmission of different scrapie isolates in
these mice led to the propagation of prions that are phenotypically identical to
those causing sporadic CJD (sCJD) in humans. These results demonstrate that
scrapie prions have a zoonotic potential and raise new questions about the
possible link between animal and human prions.
Subject terms: Biological sciences• Medical research At a glance
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01 Most doctors believe that sCJD is caused by a prion protein
deforming by chance into a killer. But Singeltary thinks otherwise. He is one of
a number of campaigners who say that some sCJD, like the variant CJD related to
BSE, is caused by eating meat from infected animals. Their suspicions have
focused on sheep carrying scrapie, a BSE-like disease that is widespread in
flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight
to the campaigners' fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb...
2001
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
Like lambs to the slaughter
31 March 2001
by Debora MacKenzie Magazine issue 2284.
FOUR years ago, Terry Singeltary watched his mother die horribly from a
degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary
was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded
an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number of
campaigners who say that some sCJD, like the variant CJD related to BSE, is
caused by eating meat from infected animals. Their suspicions have focused on
sheep carrying scrapie, a BSE-like disease that is widespread in flocks across
Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight
to the campaigners' fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb.
Scrapie has been around for centuries and until now there has been no
evidence that it poses a risk to human health. But if the French finding means
that scrapie can cause sCJD in people, countries around the world may have
overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD. They
injected the brains of macaque monkeys with brain from BSE cattle, and from
French and British vCJD patients. The brain damage and clinical symptoms in the
monkeys were the same for all three. Mice injected with the original sets of
brain tissue or with infected monkey brain also developed the same
symptoms.
As a control experiment, the team also injected mice with brain tissue from
people and animals with other prion diseases: a French case of sCJD; a French
patient who caught sCJD from human-derived growth hormone; sheep with a French
strain of scrapie; and mice carrying a prion derived from an American scrapie
strain. As expected, they all affected the brain in a different way from BSE and
vCJD. But while the American strain of scrapie caused different damage from
sCJD, the French strain produced exactly the same pathology.
"The main evidence that scrapie does not affect humans has been
epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute
for Animal Health in Edinburgh, who was a member of the same team as Deslys.
"You see about the same incidence of the disease everywhere, whether or not
there are many sheep, and in countries such as New Zealand with no scrapie." In
the only previous comparisons of sCJD and scrapie in mice, Bruce found they were
dissimilar.
But there are more than 20 strains of scrapie, and six of sCJD. "You would
not necessarily see a relationship between the two with epidemiology if only
some strains affect only some people," says Deslys. Bruce is cautious about the
mouse results, but agrees they require further investigation. Other trials of
scrapie and sCJD in mice, she says, are in progress.
People can have three different genetic variations of the human prion
protein, and each type of protein can fold up two different ways. Kretschmar has
found that these six combinations correspond to six clinical types of sCJD: each
type of normal prion produces a particular pathology when it spontaneously
deforms to produce sCJD.
But if these proteins deform because of infection with a disease-causing
prion, the relationship between pathology and prion type should be different, as
it is in vCJD. "If we look at brain samples from sporadic CJD cases and find
some that do not fit the pattern," says Kretschmar, "that could mean they were
caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence
elsewhere. Singeltary and other US activists think that some of these people
died after eating contaminated meat or "nutritional" pills containing dried
animal brain. Governments will have a hard time facing activists like Singeltary
if it turns out that some sCJD isn't as spontaneous as doctors have
insisted.
Deslys's work on macaques also provides further proof that the human
disease vCJD is caused by BSE. And the experiments showed that vCJD is much more
virulent to primates than BSE, even when injected into the bloodstream rather
than the brain. This, says Deslys, means that there is an even bigger risk than
we thought that vCJD can be passed from one patient to another through
contaminated blood transfusions and surgical instruments.
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely
create alarm in some circles even if the result could not be interpreted for
man. I have a view that all these agents could be transmitted provided a large
enough dose by appropriate routes was given and the animals kept long enough.
Until the mechanisms of the species barrier are more clearly understood it might
be best to retain that hypothesis.
snip...
R. BRADLEY
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to
nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep
and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were
exposed to the infectious agents only by their nonforced consumption of known
infectious tissues. The asymptomatic incubation period in the one monkey exposed
to the virus of kuru was 36 months; that in the two monkeys exposed to the virus
of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the
two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively.
Careful physical examination of the buccal cavities of all of the monkeys failed
to reveal signs or oral lesions. One additional monkey similarly exposed to kuru
has remained asymptomatic during the 39 months that it has been under
observation.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie
by natural feeding to squirrel monkeys that we have reported provides further
grounds for concern that scrapie-infected meat may occasionally give rise in
humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Recently the question has again been brought up as to whether scrapie is
transmissible to man. This has followed reports that the disease has been
transmitted to primates. One particularly lurid speculation (Gajdusek 1977)
conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and
transmissible encephalopathy of mink are varieties of a single "virus". The U.S.
Department of Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed for human
or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is
emphasised by the finding that some strains of scrapie produce lesions identical
to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety of laboratory
personnel requires prompt attention. Second, action such as the "scorched meat"
policy of USDA makes the solution of the acrapie problem urgent if the sheep
industry is not to suffer grievously.
snip...
76/10.12/4.6
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
Sunday, May 1, 2011
W.H.O. T.S.E. PRION Blood products and related biologicals May 2011
The pharmaceutical industry
146 Bovine materials were, and are, also used in pharmaceutical, medical
and veterinary medical products (see Annex 1 to Chapter 2 in vol. 7: Medicines
and Cosmetics). The UK pharmaceuticals industry is one of the largest in the
world. In 1997, for example, UK exports were worth over £5 billion and accounted
for around 12 per cent of the world market. There were over 400 pharmaceutical
manufacturers and research organisations in the UK, although the market was
dominated by multinationals such as Glaxo Wellcome, SmithKline Beecham and
Zeneca.9
147 Bovine materials from the slaughterhouse are used directly in
pharmaceuticals. Several injectable medicines are derived directly from bovine
sources. Hormones such as insulin and glucagon may be derived from bovine
pancreases, and protein products such as aprotonin and heparin are derived from
bovine lungs and intestinal mucous respectively. Sutures and some medical
devices such as heart valves and pericardium patches are also derived directly
from bovine materials, in this case the intestines, heart and serous
membranes.
148 Bovine materials are also used indirectly in the manufacture of certain
types of vaccine. Cells which are used to grow these vaccines are nourished in
nutrientrich cultures that contain serum from the blood of foetal or new-born
calves, or bovine serum albumin, which derives from the blood of older cattle.
Bacterial cells are grown in nutrient-rich broths containing peptone derived
from bovine meat, and some allergens are produced in special culture media which
contain digests of calf brain and ox liver. In all these cases the bovine
materials are not a constituent of the final product, but they are used in an
ancillary way in the manufacturing process.
149 Tallow and gelatine are also used in several pharmaceutical and medical
products. Gelatine is widely used as a pill coating and tallow is a constituent
of most creams and ointments. Other uses of bovine products
150 Bovine materials are used in a wide range of processes and products in
many different industries. They are used in toothpaste, chewing gum and pet
food; in fertilisers and cosmetics; and in such varied products as fire
extinguisher foam, buttons, handles, lubricants and racquet strings. Bovine
materials are used in the manufacture of paint. Cattle skins are used for hides,
and other bovine materials are included in cleaning agents used in leather
processing.
9 Britain 1999: The Official Yearbook of the United Kingdom, London, The
Stationery Office, 1998, p. 475
Sunday, December 15, 2013
FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED
VIOLATIONS OFFICIAL ACTION INDICATED OAI UPDATE DECEMBER 2013 UPDATE
Thursday, July 24, 2014
Protocol for further laboratory investigations into the distribution of
infectivity of Atypical BSE SCIENTIFIC REPORT OF EFSA
Discussion: The C, L and H type BSE cases in Canada exhibit molecular
characteristics similar to those described for classical and atypical BSE cases
from Europe and Japan.
*** This supports the theory that the importation of BSE contaminated
feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these
countries. ***
see page 176 of 201 pages...tss
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics
of BSE in Canada Singeltary reply ;
2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried,
Recall # V-024-2007 CODE Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER Pfeiffer, Arno, Inc, Greenbush, WI. by conversation
on February 5, 2007.
Firm initiated recall is ongoing.
REASON Blood meal used to make cattle feed was recalled because it was
cross- contaminated with prohibited bovine meat and bone meal that had been
manufactured on common equipment and labeling did not bear cautionary BSE
statement.
VOLUME OF PRODUCT IN COMMERCE 42,090 lbs. DISTRIBUTION WI
___________________________________
PRODUCT Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL
Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal,
TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY
Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST
POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY
Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC
MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR,
V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML
W/SMARTA, Recall # V-025-2007 CODE The firm does not utilize a code - only
shipping documentation with commodity and weights identified. RECALLING
FIRM/MANUFACTURER Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007.
Firm initiated recall is complete. REASON Products manufactured from bulk
feed containing blood meal that was cross contaminated with prohibited meat and
bone meal and the labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE 9,997,976 lbs. DISTRIBUTION ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
Newberry Feed & Farm, Inc. 2/14/14
Department of Health and Human Services logo Department of Health and Human
Services Public Health Service Food and Drug Administration Atlanta District
Office 60 8th St., NE Atlanta, GA 30309
February 14, 2014
VIA UPS
J. Clint Layne, President/Co-owner Rhett Baker,
Secretary-Treasurer/Co-owner Newberry Feed & Farm Center, Inc. 131 Giff
Street Newberry, SC 29108
WARNING LETTER (14-ATL-04)
Dear Messrs. Layne and Baker,
An inspection of your feed mill located at 2431 Vincent Street, Newberry,
SC 29108 conducted by Investigators from the U.S. Food & Drug Administration
(FDA) and South Carolina Department of Agriculture on September 5-9, 2013
revealed significant violations of Current Good Manufacturing Practice (CGMP)
regulations for Medicated Feeds found in Title 21, Code of Federal Regulations,
Part 225 (21 C.F.R. 225). Such violations cause the medicated feeds manufactured
at your facility to be adulterated within the meaning of Section 501(a)(2)(B) of
the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in
that the methods used in, or the facilities or controls used for the
manufacture, processing, packing, or holding of the medicated feeds do not
conform to or are not operated or administered in conformity with current good
manufacturing practices.
The inspection also revealed significant violations of the requirements set
forth in Title 21, Code of Federal Regulations, Section 589.2000 (21 C.F.R.
589.2000), Animal Proteins Prohibited in Ruminant Feed. This regulation is
intended to prevent the establishment and amplification of Bovine Spongiform
Encephalopathy (BSE). Animal feeds and feed ingredients containing prohibited
mammalian proteins are considered potentially injurious to ruminant and public
health. Because you failed to comply with the requirements set forth in 21
C.F.R. 589.2000, the feed products manufactured and distributed by your facility
are adulterated within the meaning of Section 402(a)(4) of the Act [21 U.S.C.
342(a)(4)] in that they have been prepared, packed, or held under insanitary
conditions whereby they may have become contaminated with filth or rendered
injurious to health. The adulterated feed was subsequently misbranded within the
meaning of Section 403(a)(1) of the Act [21 U.S.C. 343(a)(1)] because it was not
properly labeled with the required BSE cautionary statement.
Medicated Feed CGMP violations observed during the inspection include, but
are not limited to, the following:
1. You failed to ensure that all equipment that comes in contact with the
active drug component, feeds in process or finished medicated feed is subject to
reasonable and effective procedures to prevent unsafe contamination of feeds
with drugs. [21 C.F.R. 225.65(b)]
Your written equipment cleaning procedure that requires flushing with a
minimum of (b)(4) does not appear to be effective to prevent unsafe
contamination of your manufactured feed. During the inspection, our
Investigators observed a build-up of feed residue on surfaces inside the mixer
that was approximately three inches thick in accumulation. This build-up was
observed on the equipment throughout the inspection, including after flushing
had been performed. In addition, the cleaning procedure does not include
cleaning of the hand-add chute or scoops/buckets used to handle ingredients that
are then used to manufacture medicated feed. During the inspection, our
Investigators observed a build-up of feed residues approximately four inches
thick on the inside of the chute used to add the drug ingredients and other
“hand-adds”. Considering the extent of residue accumulation—some of which would
include the drug sources used in your medicated feeds—on surfaces in the mixer
and the hand-add chute, it is likely that chunks of this material break off
periodically, and may sometimes end up in feeds not intended to contain that
drug.
This is a repeat observation from the July 24-26, 2012 inspection. Your
response to the Form FDA 483, Inspectional Observations, issued to you following
the 2012 inspection stated the buckets and scoops would be replaced, and you
would schedule a regular cleaning of the equipment every (b)(4). Based on the
accumulation of residual feed observed on manufacturing equipment during the
inspection and which remained following flushing, you have either failed to
implement the promised corrective action or you have failed to ensure that the
corrective action was lasting and effective in preventing the violation from
recurring.
On October 3, 2013, we received your response to the Form FDA 483 issued to
you following the September 2013 inspection. You state in your response that you
have posted signs, added cleaning of the dump chute to the (b)(4) cleaning
procedure, and increased the physical cleaning of the mixer to (b)(4). You also
state that dedicated scoops will be used for each component or drug and have
ordered disposable liners for the buckets that will be discarded following each
dumping of product. However, you did not provide any documentation to
demonstrate these changes have been made, such as photos of the new sign or
newly cleaned equipment, or copies of the revised cleaning procedure.
2. You failed to investigate and implement corrective action where the
results of assays indicated that the level of drug in medicated feed was not in
accord with label specifications or not within permissible assay limits. An
original or copy of the record of such action must be maintained on the
premises. [21 C.F.R. 225.58(d)]
Your firm failed to adequately investigate and implement corrective action
when you received an assay result on 6/21/13 for a Type C medicated feed
containing Amprolium, showing the drug present at 73% of the concentration
stated on the label. This assay result is outside of the assay limits of 80-120%
established in 21 C.F.R. 558.4. The subsequent review of production and
inventory records conducted by your firm revealed these records were “OK”, and
it was determined the feed sample was taken incorrectly. Your firm’s
“\investigation sheet” dated 6/21/13 states the corrective action as “[t]rying
to make sure the samples are taken correctly.” No technique or procedural
changes were made in response to the described corrective action, however. Thus,
your firm failed to implement any corrective action in response to the out of
specification assay result.
Your firm also received assay results for a Type C medicated broiler feed
containing a Salinomycin concentration of 75% on 7/7/12 and 78% on 8/3/12. These
assay results are outside the specification tolerance of 80-120% of the
concentration stated on the label. [21 C.F.R. 558.4]. Your firm did not initiate
any investigation or corrective action after receiving these results. Failure to
investigate and implement corrective action following an out-of-limits assay is
a repeat observation from the July 24-26, 2012 inspection.
In your response to the Form FDA 483 issued to you following the September
2013 inspection, you state that you have instructed personnel further on
completing the investigation form and have also added sampling instructions to
the procedures manual. However, you did not provide copies of the new/revised
investigation form or the revisions to the procedures manual discussing
sampling.
3. Your daily inventory records fail to record the batches or production
runs (or lots) of medicated feed in which each drug was used. [21 C.F.R.
225.42(b)(6)(iii)] Although your daily inventory records appear to contain all
of the other required information, due to the way the form is designed, there is
only space to record one batch per day per drug and no space to record the name
of the product, lot number, or other identifier for that batch. Your daily
inventory record must reflect every batch or lot of medicated feed manufactured
each day.
4. You failed to document in the daily inventory record actions taken to
reconcile any discrepancies in the daily inventory record. [21 C.F.R.
225.42(b)(6)(v)] For example, the drug inventory conducted on 8/30/13 revealed a
discrepancy with respect to one fifty pound bag of (b)(4)(a Type A medicated
article). It does not appear that your firm took any action to reconcile this
discrepancy.
You state in your response to both #3 and #4 above that you have added an
area to the inventory control sheet to report any drugs that do not reconcile,
and that there is a space to make notes and/or adjustments to inventory to
ensure they reconcile. However, you did not indicate that the inventory control
sheet had been adjusted to provide for the possibility that any single drug may
be used more than once a day, and you did not provide any documentation—such as
a copy of the revised form—to demonstrate that these changes have been made.
5. You have failed to properly identify, store, handle, and control drugs
in your mixing areas to maintain their integrity and identity [21 C.F.R.
225.42(b)(4)]. Our inspection found that your firm was storing bags of Type A
Medicated Articles in a manner and location that allowed them to be covered in
bird droppings.
This finding also relates to your obligations under 21 C.F.R. 225.20(b)(2)
and (3), which requires the facility to be maintained in a reasonably clean and
orderly manner, and for access by birds and other pests to be minimized. During
the September 5-6, 2013 inspection, our Investigators observed birds (greater
than ten) nesting, flying, perched and foraging in the mill. Your response
indicated that you are investigating ways to keep birds out of the mill, but
that you did not yet have a plan at that time. You indicated that you would have
a plan in place by November 1, 2013, but did not provide further information
regarding any plan.
In addition, the following violations of the Animal Proteins Prohibited in
Ruminant Feed regulation [21 C.F.R. 589.2000] were observed during the
inspection:
1. You failed to use clean out procedures or other means adequate to
prevent carryover of protein derived from mammalian tissues to feeds that may be
used for ruminants [21 C.F.R. 589.2000(e)(1)(iii)(B)]. Your feed is therefore
adulterated under Section 402(a)(4) [21 U.S.C. 342(a)(4)] of the Act.
Because your firm uses animal proteins prohibited from use in ruminant
feeds, and also makes feeds for ruminants, you are required to have a cleanout
procedure adequate to prevent carryover into ruminant feeds. As noted above, our
Investigators observed a significant build-up of feed residues inside the feed
mixer and the hand-add chute, which remained following your cleanout procedure.
This equipment is used for processing both proteins derived from mammalian
tissues and feeds for ruminants. Since flushing was ineffective in removing the
accumulated feed from the equipment, your clean out procedure was inadequate to
prevent carryover of protein derived from mammalian tissues to feeds intended
for ruminant animals.
Your response indicates that your corrective actions for this item are the
same as for Item 1 above. However, as noted above, you did not provide any
documentation to demonstrate that the changes you discussed have been made, or
that they were adequate to address this issue.
2. You failed to label all products which contained or may have contained
prohibited materials and that are intended for use in animal feed with the BSE
cautionary statement, "Do not feed to cattle or other ruminants." [21 C.F.R.
589.2000(e)(1)(i).]
As discussed above, your clean out procedure is inadequate to prevent
carryover of protein derived from mammalian tissues to feeds intended for
ruminant animals. Thus, all feeds manufactured using your mixer and hand-add
chute that did not contain the BSE cautionary statement “Do not feed to cattle
or other ruminants,” are misbranded under Section 403(a)(1) [21 U.S.C.
343(a)(1)] of the Act. For example, a batch of Carolina Choice Beef Conditioner
Custom Mix (b)(4), manufactured on September 6, 2013, while there was a
significant build-up of feed residues in the feed mixer, was misbranded as its
label did not contain the required BSE cautionary statement.
The above is not intended to be an all-inclusive list of violations at your
facility. As a medicated and non-medicated feed manufacturer, you are
responsible for assuring that your overall operation and the products you
manufacture and distribute are in compliance with the law. You should take
prompt action to correct these violations, and you should establish procedures
whereby such violations do not recur. Failure to promptly correct these
violations may result in regulatory and/or administrative sanctions. These
sanctions include, but are not limited to, seizure, injunction, and/or notice of
opportunity for a hearing on a proposal to withdraw approval of your Medicated
Feed Mill License under Section 512(m)(4)(B)(ii) of the Act and 21 C.F.R.
515.22(c)(2).
Based on the results of the September 5-9, 2013 inspection, evaluated
together with the evidence before FDA when the Medicated Feed Mill License was
approved, the methods used in, or the facilities and controls used for, the
manufacture, processing, and packing of medicated feeds are inadequate to assure
and preserve the identity, strength, quality, and purity of the new animal drugs
therein. This letter constitutes official notification under the law and
provides you an opportunity to correct the above described violations.
You should notify this office, in writing, within fifteen (15) working days
of the receipt of this letter of the steps you have taken to bring your firm
into compliance with the law. Your response should include an explanation of
each step being taken to correct the violations and prevent their recurrence. In
your response, please include the timeframe in which the corrections will be
completed and provide any documentation that will effectively assist us in
evaluating whether the corrective actions have been made and the adequacy of
such. If you are unable to complete the corrective actions within fifteen (15)
working days, identify the reason for the delay and the time within which you
will complete the corrections. Include copies of any available documentation
demonstrating that corrections have been made.
Your written response should be sent to the U.S. Food and Drug
Administration, Attn: Janice L. King, Compliance Officer, at the address noted
in the letterhead. If you have questions, please contact Mrs. King at
843-746-2990 or write her at the noted address.
Sincerely, /S/ Philip S. Campbell Acting District Director Atlanta District
Office
cc: South Carolina Department of Agriculture, Phillip C. Trefsgar
Tuesday, December 23, 2014
FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED
VIOLATIONS OFFICIAL ACTION INDICATED OAI UPDATE DECEMBER 2014 BSE TSE PRION
Sunday, December 15, 2013
FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED
VIOLATIONS OFFICIAL ACTION INDICATED OIA UPDATE DECEMBER 2013 UPDATE
Friday, April 19, 2013
FDA BSE TSE PRION NEWS FEED AND ANNUAL INSPECTION OF FEED MILLS REPORTS HAS
CEASED TO EXIST
American Association of Zoo Veterinarians Infectious Disease Committee
Manual 2013
BOVINE SPONGIFORM ENCEPHALOPATHY (BSE)
Little is known about atypical BSE. The origin and natural routes of
transmission, if any, have yet to be determined. Almost all cases have been in
older cattle (usually > 8 years of age) that have shown little resemblance to
the clinic-pathological picture seen in classical disease. It has been suggested
that the disease may be sporadic or be caused by a genetic mutation, but no
convincing evidence has been found to support either of these ideas. The correct
answer will probably only come by study of the future annual incidence curves of
both types of disease. Regardless of the origin of atypical BSE, the possibility
of recycling the disease in cattle and other ruminants, as well as the potential
for transmission to humans, mandate a continuation of feed and specified-risk
materials (SRM) bans, together with diagnostic testing programs for some time to
come.
snip...
Naturally occurring cases of BSE in species other than cattle have been
very limited and have been linked to exposure to contaminated feed or infected
carcasses. The majority of cases originated in the UK and like BSE in cattle,
have declined with the implementation of feed controls. None of the exotic
animals were infected in the wild.
Experts who may be consulted: Linda A. Detwiler, DVM Clinical Professor
Department of Pathobiology and Population Medicine
College of Veterinary Medicine Mississippi State University 732-580-9391
Fax: 732-741-7751 ldetwiler@belle-terre.com
Atypical BSE: Transmissibility
BASE (L) transmitted to: cattle (IC) - inc < 20 mos and oral?)
Cynomolgus macaques (IC)
Mouse lemurs (IC and oral)
wild-type mice (IC)
bovinized transgenic mice (IC and IP)
humanized transgenic mice (IC)
H cases transmitted to:
cattle – IC incubations < 20 months
bovinized transgenic mice (IC)
ovinized transgenic mice (IC)
C57BL mice (IC)
One study did not transmit to humanized PrP Met 129 mice
Evaluation of Possibility of Atypical
BSE Transmitting to Humans
Possble interpretation:
L type seems to transmit to nonhuman primates with greater ease than
classical BSE
L type also transmitted to humanized transgenic mice with higher attack
rate and shorter incubation period than classical?
H type did not transmit to Tg Hu transgenic mice
Linda Detwiller, 5/10/2011
I ask Professor Kong ;
Thursday, December 04, 2008 3:37 PM
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform
Encephalopathies (BSE): Public Health Risk Assessment
IS the h-BSE more virulent than typical BSE as well, or the same as cBSE,
or less virulent than cBSE? just curious.....
Professor Kong reply ;
.....snip
As to the H-BSE, we do not have sufficient data to say one way or another,
but we have found that H-BSE can infect humans. I hope we could publish these
data once the study is complete. Thanks for your interest.
Best regards, Qingzhong Kong, PhD Associate Professor Department of
Pathology Case Western Reserve University Cleveland, OH 44106 USA
BSE-H is also transmissible in our humanized Tg mice. The possibility of
more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
P.4.23 Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw
Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1
1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale,
Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research
Institute, Poland; 5Kansas State University (Previously at USDA National Animal
Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the
classical BSE strain (BSE-C) has led to over 200 cases of clinical human
infection (variant CJD). Atypical BSE cases have been discovered in three
continents since 2004; they include the L-type (also named BASE), the H-type,
and the first reported case of naturally occurring BSE with mutated bovine PRNP
(termed BSE-M). The public health risks posed by atypical BSE were argely
undefined.
Objectives: To investigate these atypical BSE types in terms of their
transmissibility and phenotypes in humanized mice.
Methods: Transgenic mice expressing human PrP were inoculated with several
classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the
transmission rate, incubation time, characteristics and distribution of PrPSc,
symptoms, and histopathology were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected
with minimal spongiosis and an average incubation time of 20-22 months, whereas
only one of the C-type BSE-inoculated mice developed prion disease after more
than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse
brains was biochemically different from bovine BASE or sCJD. PrPSc was also
detected in the spleen of 22% of BASE-infected humanized mice, but not in those
infected with sCJD. Secondary transmission of BASE in the humanized mice led to
a small reduction in incubation time. The atypical BSE-H strain is also
transmissible with distinct phenotypes in the humanized mice, but no BSE-M
transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than
classical BSE, has a lymphotropic phenotype, and displays a modest transmission
barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg
mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
14th International Congress on Infectious Diseases H-type and L-type
Atypical BSE January 2010 (special pre-congress edition)
18.173 page 189
Experimental Challenge of Cattle with H-type and L-type Atypical BSE
A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H.
Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany,
2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch,
Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy
Secretariat, Ottawa, Canada
Background: After the detection of two novel BSE forms designated H-type
and L-type atypical BSE the question of the pathogenesis and the agent
distribution of these two types in cattle was fully open. From initial studies
of the brain pathology, it was already known that the anatomical distribution of
L-type BSE differs from that of the classical type where the obex region in the
brainstem always displays the highest PrPSc concentrations. In contrast in
L-type BSE cases, the thalamus and frontal cortex regions showed the highest
levels of the pathological prion protein, while the obex region was only weakly
involved.
Methods:We performed intracranial inoculations of cattle (five and six per
group) using 10%brainstemhomogenates of the two German H- and L-type atypical
BSE isolates. The animals were inoculated under narcosis and then kept in a
free-ranging stable under appropriate biosafety conditions. At least one animal
per group was killed and sectioned in the preclinical stage and the remaining
animals were kept until they developed clinical symptoms. The animals were
examined for behavioural changes every four weeks throughout the experiment
following a protocol that had been established during earlier BSE pathogenesis
studies with classical BSE.
Results and Discussion: All animals of both groups developed clinical
symptoms and had to be euthanized within 16 months. The clinical picture
differed from that of classical BSE, as the earliest signs of illness were loss
of body weight and depression. However, the animals later developed hind limb
ataxia and hyperesthesia predominantly and the head. Analysis of brain samples
from these animals confirmed the BSE infection and the atypical Western blot
profile was maintained in all animals. Samples from these animals are now being
examined in order to be able to describe the pathoge esis and agent distribution
for these novel BSE types.
Conclusions: A pilot study using a commercially avaialble BSE rapid test
ELISA revealed an essential restriction of PrPSc to the central nervous system
for both atypical BSE forms. A much more detailed analysis for PrPSc and
infectivity is still ongoing.
14th ICID International Scientific Exchange Brochure - Final Abstract
Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North
America update October 2009
T. Singeltary Bacliff, TX, USA
Background: An update on atypical BSE and other TSE in North America.
Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE
have all been documented in North America, along with the typical scrapie's, and
atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME.
All these TSE in different species have been rendered and fed to food producing
animals for humans and animals in North America (TSE in cats and dogs ?), and
that the trading of these TSEs via animals and products via the USA and Canada
has been immense over the years, decades.
Methods: 12 years independent research of available data
Results: I propose that the current diagnostic criteria for human TSEs only
enhances and helps the spreading of human TSE from the continued belief of the
UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to
continue to validate this old myth, will only spread this TSE agent through a
multitude of potential routes and sources i.e. consumption, medical i.e.,
surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics
etc.
Conclusion: I would like to submit a review of past CJD surveillance in the
USA, and the urgent need to make all human TSE in the USA a reportable disease,
in every state, of every age group, and to make this mandatory immediately
without further delay. The ramifications of not doing so will only allow this
agent to spread further in the medical, dental, surgical arena's. Restricting
the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD
knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante,
Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis,
Marsh, et al and many more, that the world of TSE Transmissible Spongiform
Encephalopathy is far from an exact science, but there is enough proven science
to date that this myth should be put to rest once and for all, and that we move
forward with a new classification for human and animal TSE that would properly
identify the infected species, the source species, and then the route.
snip... see more breaches in the BSE aka mad cow Triple Firewall, that
never was here ;
Friday, January 23, 2015
*** Replacement of soybean meal in compound feed by European protein
sources and relaxing the mad cow ban $
To date, 27 cases of L-BSE and 24 cases of H-BSE have been reported
worldwide (16), thus meaning that the prevalence of atypical BSE is considerably
lower than that of C-BSE. However, recent studies showed that L-BSE is easily
transmissible to transgenic mice expressing human (17,18) or bovine (19,20)
prion protein, as well as to non-human primates (21), with shorter incubation
periods than for the transmission of C-BSE to these animals.
***The virulent nature of L-BSE has stimulated new concern for human public
health since the transmission of C-BSE to humans resulted in variant
Creutzfeldt-Jakob disease (vCJD) (4-7), a new emergent prion disease.
***Infectivity in skeletal muscle of BASE-infected cattle
***The present data offer novel information on the tropism of the BASE
agent and highlight relevant public health issues. While the transmission
barrier for classical BSE is high in most species, BASE prions are readily
transmissible to a variety of mammals including non-human primates [11–13,35].
Accordingly, the possibility of spreading of BASE prions through skeletal muscle
to other species should be taken into account and evaluated in risk analysis
studies.
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw
Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1
1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale,
Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research
Institute, Poland; 5Kansas State University (Previously at USDA National Animal
Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the
classical BSE strain (BSE-C) has led to over 200 cases of clinical human
infection (variant CJD). Atypical BSE cases have been discovered in three
continents since 2004; they include the L-type (also named BASE), the H-type,
and the first reported case of naturally occurring BSE with mutated bovine PRNP
(termed BSE-M). The public health risks posed by atypical BSE were largely
undefined.
Objectives: To investigate these atypical BSE types in terms of their
transmissibility and phenotypes in humanized mice. Methods: Transgenic mice
expressing human PrP were inoculated with several classical (C-type) and
atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation
time, characteristics and distribution of PrPSc, symptoms, and histopathology
were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected
with minimal spongiosis and an average incubation time of 20-22 months, whereas
only one of the C-type BSE-inoculated mice developed prion disease after more
than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse
brains was biochemically different from bovine BASE or sCJD. PrPSc was also
detected in the spleen of 22% of BASE-infected humanized mice, but not in those
infected with sCJD. Secondary transmission of BASE in the humanized mice led to
a small reduction in incubation time. The atypical BSE-H strain is also
transmissible with distinct phenotypes in the humanized mice, but no BSE-M
transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than
classical BSE, has a lymphotropic phenotype, and displays a modest transmission
barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg
mice. The possibility of more than two atypical BSE strains will be
discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
SUMMARY REPORT CALIFORNIA ATYPICAL L-TYPE BOVINE SPONGIFORM ENCEPHALOPATHY
CASE INVESTIGATION JULY 2012 CALIFORNIA
Summary Report BSE 2012
Executive Summary
Saturday, August 4, 2012
Final Feed Investigation Summary - California atypical L-type BSE Case -
July 2012
Saturday, August 4, 2012
Update from APHIS Regarding Release of the Final Report on the BSE
Epidemiological Investigation
Wednesday, December 31, 2014
NASDA BSE, CWD, SCRAPIE, TSE, PRION, Policy Statements updated with
amendments passed during the NASDA Annual Meeting Updated September 18, 2014
Sunday, January 11, 2015
Docket No. APHIS-2014-0107 Bovine Spongiform Encephalopathy; Importation of
Animals and Animal Products Singeltary Submission
2001
Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001
Date: Tue, 9 Jan 2001 16:49:00 -0800
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
[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.
snip...full text ;
Thursday, January 15, 2015
41-year-old Navy Commander with sporadic Creutzfeldt–Jakob disease CJD TSE
Prion: Case Report
Subject: *** Becky Lockhart 46, Utah’s first female House speaker, dies
diagnosed with the extremely rare Creutzfeldt-Jakob disease aka mad cow type
disease
what is CJD ? just ask USDA inc., and the OIE, they are still feeding the
public and the media industry fed junk science that is 30 years old.
why doesn’t some of you try reading the facts, instead of rubber stamping
everything the USDA inc says.
sporadic CJD has now been linked to BSE aka mad cow disease, Scrapie, and
there is much concern now for CWD and risk factor for humans.
My sincere condolences to the family and friends of the House Speaker Becky
Lockhart. I am deeply saddened hear this.
with that said, with great respect, I must ask each and every one of you
Politicians that are so deeply saddened to hear of this needless death of the
Honorable House Speaker Becky Lockhart, really, cry me a friggen river. I am
seriously going to ask you all this...I have been diplomatic for about 17 years
and it has got no where. people are still dying. so, are you all stupid or
what??? how many more need to die ??? how much is global trade of beef and other
meat products that are not tested for the TSE prion disease, how much and how
many bodies is this market worth?
Saturday, January 17, 2015
*** Becky Lockhart 46, Utah’s first female House speaker, dies diagnosed
with the extremely rare Creutzfeldt-Jakob disease
who’s kidding whom $$$ i.e. USDA INC AND THE OIE
2014
***Moreover, L-BSE has been transmitted more easily to transgenic mice
overexpressing a human PrP [13,14] or to primates [15,16] than C-BSE.
***It has been suggested that some sporadic CJD subtypes in humans may
result from an exposure to the L-BSE agent.
*** Lending support to this hypothesis, pathological and biochemical
similarities have been observed between L-BSE and an sCJD subtype (MV genotype
at codon 129 of PRNP) [17], and between L-BSE infected non-human primate and
another sCJD subtype (MM genotype) [15].
snip...
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far
*** but the possibility that a small proportion of human cases so far
classified as "sporadic" CJD are of zoonotic origin could not be excluded.
*** Moreover, transmission experiments to non-human primates suggest that
some TSE agents in addition to Classical BSE prions in cattle (namely L-type
Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME)
and chronic wasting disease (CWD) agents) might have zoonotic potential.
snip...
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
*** Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
*** These atypical BSE cases constitute an unforeseen first threat that
could sharply modify the European approach to prion diseases.
Second threat
snip...
*** HUMAN MAD COW DISEASE nvCJD TEXAS CASE NOT LINKED TO EUROPEAN TRAVEL
CDC ***
Sunday, November 23, 2014
*** Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas
in June 2014 confirmed as USA case NOT European ***
the patient had resided in Kuwait, Russia and Lebanon. The completed
investigation did not support the patient's having had extended travel to
European countries, including the United Kingdom, or travel to Saudi Arabia. The
specific overseas country where this patient’s infection occurred is less clear
largely because the investigation did not definitely link him to a country where
other known vCJD cases likely had been infected.
Sunday, December 14, 2014
*** ALERT new variant Creutzfeldt Jakob Disease nvCJD or vCJD, sporadic CJD
strains, TSE prion aka Mad Cow Disease United States of America Update December
14, 2014 Report ***
http://transmissiblespongiformencephalopathy.blogspot.com/2014/12/alert-new-variant-creutzfeldt-jakob.html
J Neurol Neurosurg Psychiatry 2002;72:792-793 doi:10.1136/jnnp.72.6.792 Short report
Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth
hormone
E A Croes1, G Roks1,*, G H Jansen3, P C G Nijssen2, C M van Duijn1
+ Author Affiliations 1Genetic Epidemiology Unit, Department of
Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO
Box 1738, 3000 DR Rotterdam, Netherlands 2Department of Neurology, St Elisabeth
Hospital, PO Box 90151, 5000 LC Tilburg, Netherlands 3Department of Pathology,
University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht,
Netherlands
Correspondence to: Professor C M van Duijn, Genetic Epidemiology Unit,
Department of Epidemiology and Biostatistics, Erasmus University Medical Centre
Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; vanduijn@epib.fgg.eur.nl
Received 27 December 2001 Accepted 12 March 2002 Revised 1 March 2002
Abstract
A 47 year old man is described who developed pathology proven
Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human
derived growth hormone (hGH) as part of a diagnostic procedure. The patient
presented with a cerebellar syndrome, which is compatible with iatrogenic CJD.
This is the longest incubation period described so far for iatrogenic CJD.
Furthermore, this is the first report of CJD after diagnostic use of hGH. Since
the patient was one of the first in the world to receive hGH, other cases of
iatrogenic CJD can be expected in the coming years.
snip...
An incubation period as long as 38 years had never been reported for
iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation period in 55
patients with hGH related CJD in a cohort of 1361 French hGH recipients. The
median incubation period was between 9 and 10 years. Under the most pessimistic
model, the upper limit of the 95% confidence interval varied between 17 and 20
years. Although the infecting dose cannot be quantified, it can be speculated
that the long incubation period in our patient is partly explained by the
administration of a limited amount of hGH. This hypothesis is supported by
experimental models, in which higher infecting doses usually produce shorter
incubation periods.6 Since our patient was one of the first in the world to
receive hGH, this case indicates that still more patients with iatrogenic CJD
can be expected in the coming years. Another implication of our study is that
CJD can develop even after a low dose of hGH. This case once more testifies that
worldwide close monitoring of any form of iatrogenic CJD is mandatory.
http://jnnp.bmj.com/content/72/6/792.long
Saturday, December 13, 2014
*** Terry S. Singeltary Sr. Publications TSE prion disease Peer Review
***
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14,
2001 JAMA
snip...
http://transmissiblespongiformencephalopathy.blogspot.com/2014/12/terry-s-singeltary-sr-publications-tse.html
J Neurol Neurosurg Psychiatry 2002;72:792-793 doi:10.1136/jnnp.72.6.792 Short report
Saturday, December 13, 2014
Thursday, January 22, 2015
Transmission properties of atypical Creutzfeldt-Jakob disease: a clue to
disease etiology?
Tuesday, December 30, 2014
TSEAC USA Reason For Recalls Blood products, collected from a donors
considered to be at increased risk for Creutzfeldt-Jakob Disease (CJD), were
distributed END OF YEAR REPORT 2014
TSS
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