Generation of a new form of human PrPSc in vitro by inter-species transmission from cervids prions
Generation of a new form of human PrPSc in vitro by inter-species transmission from cervids prions
Marcelo A. Barria1, Glenn C. Telling2, Pierluigi Gambetti3, James A. Mastrianni4 and Claudio Soto1,*
1Mitchell Center for Alzheimer’s disease and related Brain disorders, Dept of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA
2Dept of Microbiology, Immunology & Molecular Genetics, and Neurology, Sanders Brown Center on Aging, University of Kentucky Medical Center, Lexington, KY, USA
3Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA
4Dept of Neurology, University of Chicago, Chicago, IL, USA.
Running Title: Conversion of human PrPC by cervid PrPSc
Keywords: Prion / transmissible spongiform encephalopathy / infectivity / misfolded prion protein / prion strains
* To whom correspondence should be addressed. University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030. Tel 713-5007086; Fax 713-5000667; E-mail Claudio.Soto@uth.tmc.edu
Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded prion protein (PrPSc). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the misfolded form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, the newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc. Our results also have profound implications for understanding the mechanisms of prion species barrier and indicate that the transmission barrier is a dynamic process that depend on the strain and moreover the degree of adaptation of the strain. If our findings are corroborated by infectivity assays, they will imply that CWD prions have the potential to infect humans, and that this ability depends on CWD strain adaptation.
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Interestingly, when the Western blot profile of this newly generated form of human PrPSc (termed CWD-huPrPSc) was compared with known strains of human prions, it was clear that CWD-huPrPSc exhibited a different pattern (Fig. 4A). The electrophoretic migration of this protein after PK-digestion is similar to the type 1 strain of sCJD, but its glycosylation profile is clearly different, showing a highly predominant diglycosylated form (Fig. 4A and B). This result suggests that CWD hu-PrPSc corresponds to a new human prion strain. Interestingly, a detailed previous study from Gambetti’s group comparing the biochemical characteristics of PrPSc from cervids and humans showed that CWD PrPSc is similar to sCJDMM1 in terms of electrophoretic mobility (6). However, the misfolded protein associated with CWD is predominantly di-glycosylated, whereas PrPSc from type 1 sCJD is mostly monoglycosylated (6). Based on the fact that transmission of BSE prions to humans resulted in a new form of PrPSc very similar to the one in cattle (6;27), these authors predicted that if humans were infected by CWD it is likely that PrPSc would be of type 1 and with a predominance of the diglycosylated isoform (6). Our results agree with that prediction and suggest that the newly generated CWD-huPrPSc acquires the biochemical properties of the cervid infectious material (Fig. 4A and B). We and others have shown that PMCA replication of PrPSc obtained from experimental rodents, sheep, cervid and human samples faithfully maintains the prion strain characteristics (14;16;26;28-30). To further support the relevance of our results, we performed experiments in which human PrPC was attempted to be converted by either cattle BSE PrPSc or sheep scrapie PrPSc. Whereas the typical vCJD type of PrPSc was generated when human PrPC was converted by BSE PrPSc (Fig. 4C), no human PrPSc was generated under any condition when sheep scrapie PrPSc was used as inoculum (Fig. 4C). These results further validate our PMCA assay.
Discussion CWD is possibly the most worrisome prion zoonosis, because it affects free-ranging animals, making it very difficult to control its spread, and because it is highly efficiently transmitted (1;2). Indeed, in dense free-ranging cervid populations, CWD prevalence can reach as high as 30%, and among captive herds, the prevalence can climb to nearly 100%. The mechanisms and routes of transmission are currently unknown, but likely involve horizontal spread through exposure to prion infected secretions, excretions, or decomposed carcasses (1;2). Moreover, it is likely that CWD prions are progressively accumulating in the environment, since PrPSc binds tightly to soil and can maintain infectivity for a long time (31-33). Currently, it is unknown what proportion of natural CWD cases arises sporadically or comes from horizontal transmission among animals. Based on the available knowledge of the emergence, adaptation and stabilization of prion strains, it is likely that prions appear either spontaneously, through inter-species transmission or by genetic mutations. These “first generation” prions are unstable strains that begin a progressive and gradual process of adaptation that may take several passages and years or decades to complete. In addition natural strain stabilization may take considerable more time than the controlled adaptation done by intracerebral inoculation of brain homogenates in experimental animals. In natural cases, animals usually get infected by peripheral (most likely oral) exposure to small quantities of prions present in peripheral tissues or secretion fluids. Recent data indicates that in some cases the strain characteristics of natural prions in peripheral organs are different than those in the brain even in the same individuals (GCT, unpublished results; MAB and CS, unpublished data). In cervids, there are at least two different strains that can be differentiated by the incubation time and neuropathological characteristics produced when inoculated into transgenic mice expressing deer PrP (34). It is currently unknown the susceptibility of these two strains to human transmission.
Our findings demonstrate that cervid PrPSc, upon strain adaptation by serial passages in vitro or in cervid transgenic mice, is capable of converting human PrPC to produce PrPSc with unique biochemical properties, likely representing a new human prion strain. The newly generated CWD-huPrPSc material has been inoculated into transgenic mice expressing human PrP to study infectivity and disease phenotype and this data will be published elsewhere. We have safely ruled out that human PrPSc generated in these studies is not coming from spontaneous “de novo generation”, since under the conditions used, no spontaneous PK-resistant band was ever detected in brain homogenates of humans or transgenic mice expressing human PrPC, even after more than 20 serial rounds of PMCA (35). Furthermore, none of the many controls included in our experiments in which no PrPSc was added to the reaction, showed any PK-resistant PrP band.
Various studies aimed to analyze the transmission of CWD to transgenic mice expressing human PrP have consistently given negative results (9-11), indicating a strong species barrier. This conclusion is consistent with our many failed experiments to attempt converting human PrPC with natural CWD, even after pushing the PMCA conditions (see figure 1). We found successful conversion only after adaptation of the CWD prion strain by successive passages in vitro or in cervid transgenic mice. We are not aware that in any of the transgenic mice studies the inoculum used was a previously stabilized CWD strain. Although, it has been shown that strain stabilization in vitro by PMCA (17;26) and in vivo using experimental rodents (36) has similarities with the strain adaptation process occurring in natural hosts, we cannot rule out that the type of CWD strain adaptation that is required to produce strains transmissible to humans may take much longer time in cervids or not occur at all. An important experiment will be to study transmissibility to humanized transgenic mice of CWD passed experimentally in deer several times.
Besides the importance of our results for public health in relation to the putative transmissibility of CWD to humans, our data also illustrate a very important and novel scientific concept related to the mechanism of prion transmission across species barriers. Today the view is that species barrier is mostly controlled by the degree of similarity on the sequence of the prion protein between the host and the infectious material (4). In our study we show that the strain and moreover the stabilization of the strain plays a major role in the inter-species transmission. In our system there is no change on the protein sequence, but yet strain adaptation results in a complete change on prion transmissibility with potentially dramatic consequences. Therefore, our findings lead to a new view of the species barrier that should not be seen as a static process, but rather a dynamic biological phenomenon that can change over time when prion strains mature and evolve. It remains to be investigated if other species barriers also change upon progressive strain adaptation of other prion forms (e.g. the sheep/human barrier).
Our results have far-reaching implications for human health, since they indicate that cervid PrPSc can trigger the conversion of human PrPC into PrPSc, suggesting that CWD might be infectious to humans. Interestingly our findings suggest that unstable strains from CWD affected animals might not be a problem for humans, but upon strain stabilization by successive passages in the wild, this disease might become progressively more transmissible to man.
Reference List
snip...
please see full text and many thanks to the Professor Soto and the other Authors of this study AND to The Journal Of Biological Chemistry for the free full text !!!
http://www.jbc.org/content/early/2011/01/04/jbc.M110.198465.long
PLEASE NOTE ;
there are now two documented strains of CWD, and science is showing that indeed CWD could transmit to humans via transmission studies ;
P35
ADAPTATION OF CHRONIC WASTING DISEASE (CWD) INTO HAMSTERS, EVIDENCE OF A WISCONSIN STRAIN OF CWD
Chad Johnson1, Judd Aiken2,3,4 and Debbie McKenzie4,5 1 Department of Comparative Biosciences, University of Wisconsin, Madison WI, USA 53706 2 Department of Agriculture, Food and Nutritional Sciences, 3 Alberta Veterinary Research Institute, 4.Center for Prions and Protein Folding Diseases, 5 Department of Biological Sciences, University of Alberta, Edmonton AB, Canada T6G 2P5
The identification and characterization of prion strains is increasingly important for the diagnosis and biological definition of these infectious pathogens. Although well-established in scrapie and, more recently, in BSE, comparatively little is known about the possibility of prion strains in chronic wasting disease (CWD), a disease affecting free ranging and captive cervids, primarily in North America. We have identified prion protein variants in the white-tailed deer population and demonstrated that Prnp genotype affects the susceptibility/disease progression of white-tailed deer to CWD agent. The existence of cervid prion protein variants raises the likelihood of distinct CWD strains. Small rodent models are a useful means of identifying prion strains. We intracerebrally inoculated hamsters with brain homogenates and phosphotungstate concentrated preparations from CWD positive hunter-harvested (Wisconsin CWD endemic area) and experimentally infected deer of known Prnp genotypes. These transmission studies resulted in clinical presentation in primary passage of concentrated CWD prions. Subclinical infection was established with the other primary passages based on the detection of PrPCWD in the brains of hamsters and the successful disease transmission upon second passage. Second and third passage data, when compared to transmission studies using different CWD inocula (Raymond et al., 2007) indicate that the CWD agent present in the Wisconsin white-tailed deer population is different than the strain(s) present in elk, mule-deer and white-tailed deer from the western United States endemic region.
http://www.istitutoveneto.it/prion_09/Abstracts_09.pdf
PPo3-7:
Prion Transmission from Cervids to Humans is Strain-dependent
Qingzhong Kong, Shenghai Huang,*Fusong Chen, Michael Payne, Pierluigi Gambetti and Liuting Qing Department of Pathology; Case western Reserve University; Cleveland, OH USA *Current address: Nursing Informatics; Memorial Sloan-Kettering Cancer Center; New York, NY USA
Key words: CWD, strain, human transmission
Chronic wasting disease (CWD) is a widespread prion disease in cervids (deer and elk) in North America where significant human exposure to CWD is likely and zoonotic transmission of CWD is a concern. Current evidence indicates a strong barrier for transmission of the classical CWD strain to humans with the PrP-129MM genotype. A few recent reports suggest the presence of two or more CWD strains. What remain unknown is whether individuals with the PrP-129VV/MV genotypes are also resistant to the classical CWD strain and whether humans are resistant to all natural or adapted cervid prion strains. Here we report that a human prion strain that had adopted the cervid prion protein (PrP) sequence through passage in cervidized transgenic mice efficiently infected transgenic mice expressing human PrP, indicating that the species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains. Preliminary results on CWD transmission in transgenic mice expressing human PrP-129V will also be discussed.
Acknowledgement Supported by NINDS NS052319 and NIA AG14359.
PPo2-27:
Generation of a Novel form of Human PrPSc by Inter-species Transmission of Cervid Prions
Marcelo A. Barria,1 Glenn C. Telling,2 Pierluigi Gambetti,3 James A. Mastrianni4 and Claudio Soto1 1Mitchell Center for Alzheimer's disease and related Brain disorders; Dept of Neurology; University of Texas Houston Medical School; Houston, TX USA; 2Dept of Microbiology, Immunology & Molecular Genetics and Neurology; Sanders Brown Center on Aging; University of Kentucky Medical Center; Lexington, KY USA; 3Institute of Pathology; Case western Reserve University; Cleveland, OH USA; 4Dept of Neurology; University of Chicago; Chicago, IL USA
Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded and infectious prion (PrPSc). Chronic wasting disease (CWD) of cervids is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. CWD is highly contagious and its origin, mechanism of transmission and exact prevalence are currently unclear. The risk of transmission of CWD to humans is unknown. Defining that risk is of utmost importance, considering that people have been infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the infectious form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the pathological conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, this newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc, indicating that it corresponds to a novel human prion strain. Our findings suggest that CWD prions have the capability to infect humans, and that this ability depends on CWD strain adaptation, implying that the risk for human health progressively increases with the spread of CWD among cervids.
PPo2-7:
Biochemical and Biophysical Characterization of Different CWD Isolates
Martin L. Daus and Michael Beekes Robert Koch Institute; Berlin, Germany
Key words: CWD, strains, FT-IR, AFM
Chronic wasting disease (CWD) is one of three naturally occurring forms of prion disease. The other two are Creutzfeldt-Jakob disease in humans and scrapie in sheep. CWD is contagious and affects captive as well as free ranging cervids. As long as there is no definite answer of whether CWD can breach the species barrier to humans precautionary measures especially for the protection of consumers need to be considered. In principle, different strains of CWD may be associated with different risks of transmission to humans. Sophisticated strain differentiation as accomplished for other prion diseases has not yet been established for CWD. However, several different findings indicate that there exists more than one strain of CWD agent in cervids. We have analysed a set of CWD isolates from white-tailed deer and could detect at least two biochemically different forms of disease-associated prion protein PrPTSE. Limited proteolysis with different concentrations of proteinase K and/or after exposure of PrPTSE to different pH-values or concentrations of Guanidinium hydrochloride resulted in distinct isolate-specific digestion patterns. Our CWD isolates were also examined in protein misfolding cyclic amplification studies. This showed different conversion activities for those isolates that had displayed significantly different sensitivities to limited proteolysis by PK in the biochemical experiments described above. We further applied Fourier transform infrared spectroscopy in combination with atomic force microscopy. This confirmed structural differences in the PrPTSE of at least two disinct CWD isolates. The data presented here substantiate and expand previous reports on the existence of different CWD strains.
http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099
CJD9/10022
October 1994
Mr R.N. Elmhirst
Chairman
British Deer Farmers Association
Holly Lodge
Spencers Lane
BerksWell
Coventry
CV7 7BZ
Dear Mr Elmhirst,
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.
The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.
The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.
The statistical results reqarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.
I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all. ...end
http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf
UPDATED DATA ON 2ND CWD STRAIN
Wednesday, September 08, 2010
CWD PRION CONGRESS SEPTEMBER 8-11 2010
http://chronic-wasting-disease.blogspot.com/2010/09/cwd-prion-2010.html
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To:
Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam, In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.
That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: [log in to unmask]">[log in to unmask]; [log in to unmask]">[log in to unmask]; [log in to unmask]">[log in to unmask]
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
snip...
full text ;
http://chronic-wasting-disease.blogspot.com/2009/02/exotic-meats-usa-announces-urgent.html
FDA is not recalling this CWD positive elk meat for the well being of the dead elk ;
Wednesday, March 18, 2009
Noah's Ark Holding, LLC, Dawson, MN RECALL Elk products contain meat derived from an elk confirmed to have CWD NV, CA, TX, CO, NY, UT, FL, OK RECALLS AND FIELD CORRECTIONS: FOODS CLASS II
http://chronic-wasting-disease.blogspot.com/2009/03/noahs-ark-holding-llc-dawson-mn-recall.html
see full text ;
http://chronic-wasting-disease.blogspot.com/2009/04/cwd-update-infection-studies-in-two.html
Wednesday, December 29, 2010
CWD Update 99 December 13, 2010
http://chronic-wasting-disease.blogspot.com/2010/12/cwd-update-99-december-13-2010.html
http://chronic-wasting-disease.blogspot.com/
now, just what is in that deer feed? _ANIMAL PROTEIN_
Subject: MAD DEER/ELK DISEASE AND POTENTIAL SOURCES
Date: Sat, 25 May 2002 18:41:46 -0700 From: "Terry S. Singeltary Sr." Reply-To: BSE-LTo: BSE-L
8420-20.5% Antler DeveloperFor Deer and Game in the wildGuaranteed Analysis Ingredients / Products Feeding Directions
snip...
_animal protein_
http://www.surefed.com/deer.htm
BODE'S GAME FEED SUPPLEMENT #400A RATION FOR DEERNET WEIGHT 50 POUNDS22.6 KG.
snip...
_animal protein_
http://www.bodefeed.com/prod7.htm
IngredientsGrain Products, Plant Protein Products, Processed Grain By-Products,Forage Products, Roughage Products 15%, Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Pyosphate, Salt,Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol(source of Vitamin D3), Vitamin E Supplement, Vitamin B12 Supplement,Riboflavin Supplement, Niacin Supplement, Calcium Panothenate, CholineChloride, Folic Acid, Menadione Soduim Bisulfite Complex, PyridoxineHydorchloride, Thiamine Mononitrate, d-Biotin, Manganous Oxide, ZincOxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, DriedSacchoromyces Berevisiae Fermentation Solubles, Cellulose gum,Artificial Flavors added.http://www.bodefeed.com/prod6.htm
===================================
MORE ANIMAL PROTEIN PRODUCTS FOR DEER
Bode's #1 Game PelletsA RATION FOR DEERF3153GUARANTEED ANALYSISCrude Protein (Min) 16%Crude Fat (Min) 2.0%Crude Fiber (Max) 19%Calcium (Ca) (Min) 1.25%Calcium (Ca) (Max) 1.75%Phosphorus (P) (Min) 1.0%Salt (Min) .30%Salt (Max) .70%IngredientsGrain Products, Plant Protein Products, Processed Grain By-Products,Forage Products, Roughage Products, 15% Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Phosphate, Salt,Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol(source of Vitamin D3) Vitamin E Supplement, Vitamin B12 Supplement,Roboflavin Supplement, Niacin Supplement, Calcium Pantothenate, CholineChloride, Folic Acid, Menadione Sodium Bisulfite Complex, PyridoxineHydrochloride, Thiamine Mononitrate, e - Biotin, Manganous Oxide, ZincOxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, DriedSaccharyomyces Cerevisiae Fermentation Solubles, Cellulose gum,Artificial Flavors added.FEEDING DIRECTIONSFeed as Creep Feed with Normal Diet
http://www.bodefeed.com/prod8.htm
INGREDIENTS
Grain Products, Roughage Products (not more than 35%), Processed GrainBy-Products, Plant Protein Products, Forage Products,
__Animal Protein Products__,
L-Lysine, Calcium Carbonate, Salt, Monocalcium/DicalciumPhosphate, Yeast Culture, Magnesium Oxide, Cobalt Carbonate, BasicCopper Chloride, Manganese Sulfate, Manganous Oxide, Sodium Selenite,Zinc Sulfate, Zinc Oxide, Sodium Selenite, Potassium Iodide,Ethylenediamine Dihydriodide, Vitamin E Supplement, Vitamin ASupplement, Vitamin D3 Supplement, Mineral Oil, Mold Inhibitor, CalciumLignin Sulfonate, Vitamin B12 Supplement, Menadione Sodium BisulfiteComplex, Calcium Pantothenate, Riboflavin, Niacin, Biotin, Folic Acid,Pyridoxine Hydrochloride, Mineral Oil, Chromium Tripicolinate
DIRECTIONS FOR USE
Deer Builder Pellets is designed to be fed to deer under rangeconditions or deer that require higher levels of protein. Feed to deerduring gestation, fawning, lactation, antler growth and pre-rut, allphases which require a higher level of nutrition. Provide adequateamounts of good quality roughage and fresh water at all times.
http://www.profilenutrition.com/Products/Specialty/deer_builder_pellets.html
===================================================
DEPARTMENT OF HEALTH & HUMAN SERVICESPUBLIC HEALTH SERVICEFOOD AND DRUG ADMINISTRATIONApril 9, 2001 WARNING LETTER01-PHI-12CERTIFIED MAILRETURN RECEIPT REQUESTED
Brian J. Raymond, Owner Sandy Lake Mills 26 Mill Street P.O. Box 117 Sandy Lake, PA 16145
PHILADELPHIA DISTRICT
Tel: 215-597-4390
Dear Mr. Raymond:Food and Drug Administration Investigator Gregory E. Beichner conducted an inspection of your animal feed manufacturing operation, located in Sandy Lake, Pennsylvania, on March 23,2001, and determined that your firm manufactures animal feeds including feeds containing prohibited materials. The inspection found significant deviations from the requirements set forth in Title 21, code of Federal Regulations, part 589.2000 - Animal Proteins Prohibited in Ruminant Feed. The regulation is intended to prevent the establishment and amplification of Bovine Spongiform Encephalopathy (BSE) . Such deviations cause products being manufactured at this facility to be misbranded within the meaning of Section 403(f), of the Federal Food, Drug, and Cosmetic Act (the Act).Our investigation found failure to label your swine feed with the required cautionary statement "Do Not Feed to cattleor other Ruminants" The FDA suggests that the statement be distinguished by different type-size or color or other means of highlighting the statement so that it is easily noticed by a purchaser.
In addition, we note that you are using approximately 140 pounds of cracked corn to flush your mixer used in the manufacture of animal feeds containing prohibited material. This flushed material is fed to wild game including deer, a ruminant animal.Feed material which may potentially contain prohibited material should not be fed to ruminant animals which may become part of the food chain.The above is not intended to be an all-inclusive list of deviations fromthe regulations. As a manufacturer of materials intended for animalfeed use, you are responsible for assuring that your overall operation and the products you manufacture and distribute are in compliance withthe law. We have enclosed a copy of FDA's Small Entity Compliance Guideto assist you with complying with the regulation... blah, blah, blah...
http://www.fda.gov/foi/warning_letters/g1115d.pdf
==================================
snip...end...full text ;
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 1 Terry S. Singeltary Sr. Vol #: 1
http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7 Terry S. Singeltary Sr. Vol #: 1
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7 Terry S. Singeltary Sr. Vol #: 1
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
01N-0423 Substances Prohibited from use in animal food/Feed Ruminant
APE 5 National Renderers Association, Inc. Vol#: 2
APE 6 Animal Protein Producers Industry Vol#: 2
APE 7 Darling International Inc. Vol#: 2
EMC 1 Terry S. Singeltary Sr. Vol#: 3
http://www.fda.gov/ohrms/dockets/dailys/01/Oct01/101501/101501.htm
above urls dead, go here ;
http://madcowfeed.blogspot.com/2008/07/docket-03d-0186-fda-issues-draft.html
Friday, January 7, 2011
MEAT AND BONE MEAL AND MINERAL FEED ADDITIVES MAY INCREASE THE RISK OF ORAL PRION DISEASE TRANSMISSION
Journal of Toxicology and Environmental Health, Part A, 74:161–166, 2011 Copyright © Taylor & Francis Group, LLC ISSN: 1528-7394 print / 1087-2620 online DOI: 10.1080/15287394.2011.529066
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/meat-and-bone-meal-and-mineral-feed.html
Wednesday, January 19, 2011
EFSA BIOHAZ Scientific Opinion on the revision of the quantitative risk assessment (QRA) of the BSE risk posed by processed animal proteins (PAPs)
EFSA Journal 2011;9(1):1947
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/efsa-biohaz-scientific-opinion-on.html
>>> Animals injected with iatrogenic Creutzfeldt-Jakob disease MM1 and genetic Creutzfeldt-Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt-Jakob disease MM1 prions, whereas kuru most closely resembled the sporadic Creutzfeldt-Jakob disease VV2 or MV2 prion signature and neuropathology.... <<<
http://www.jbc.org/cgi/content/abstract/M704597200v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Cross-sequence+transmission+of+sporadic+Creutzfeldt-Jakob+disease+creates+a+new+&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
UPDATED DATA ON 2ND CWD STRAIN
snip... please see full text ;
Tuesday, January 18, 2011
Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/agent-strain-variation-in-human-prion.html
Thursday, December 23, 2010
Molecular Typing of Protease-Resistant Prion Protein in Transmissible Spongiform Encephalopathies of Small Ruminants, France, 2002–2009 Volume 17, Number 1–January 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/molecular-typing-of-protease-resistant.html
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/efsa-and-ecdc-review-scientific.html
Friday, January 21, 2011
Strain-Specific Barriers against Bovine Prions in Hamsters
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/strain-specific-barriers-against-bovine.html
Saturday, December 18, 2010
OIE Global Conference on Wildlife Animal Health and Biodiversity - Preparing for the Future (TSE AND PRIONS) Paris (France), 23-25 February 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/oie-global-conference-on-wildlife.html
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." 49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob ...
............................
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
see full text ;
Tuesday, November 02, 2010
BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992
http://bse-atypical.blogspot.com/2010/11/bse-atypical-lesion-distribution-rbse.html
USA
5 Includes 16 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 21 (19 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
2010
PLEASE NOTE REFERENCE LINES 5. AND 6.
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010) Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 51 33 28 5 0 0
1997 114 68 59 9 0 0
1998 88 52 44 7 1 0
1999 120 72 64 8 0 0
2000 146 103 89 14 0 0
2001 209 119 109 10 0 0
2002 248 149 125 22 2 0
2003 274 176 137 39 0 0
2004 325 186 164 21 0 1(3)
2005 344 194 157 36 1 0
2006 383 197 166 29 0 2(4)
2007 377 214 187 27 0 0
2008 394 231 204 25 0 0
2009 425 259 216 43 0 0
2010 204 124 85 20 0 0
TOTAL 3702(5) 2177(6) 1834 315 4 3
1 Listed based on the year of death or, if not available, on year of referral;
2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia in the other case;
5 Includes 16 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 21 (19 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011
Prions
David W. Colby1,* and Stanley B. Prusiner1,2
http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html
Thursday, December 23, 2010
Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom
http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html
strictly NOT private and confidential $$$
Saturday, January 22, 2011
Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/alzheimers-prion-and-neurological.html
DID EVERYONE FILL OUT THEIR CJD QUESIONNAIRE FROM THE CDC AND OR THE CJD FOUNDATION ???
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION
http://cjdquestionnaire.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Marcelo A. Barria1, Glenn C. Telling2, Pierluigi Gambetti3, James A. Mastrianni4 and Claudio Soto1,*
1Mitchell Center for Alzheimer’s disease and related Brain disorders, Dept of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA
2Dept of Microbiology, Immunology & Molecular Genetics, and Neurology, Sanders Brown Center on Aging, University of Kentucky Medical Center, Lexington, KY, USA
3Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA
4Dept of Neurology, University of Chicago, Chicago, IL, USA.
Running Title: Conversion of human PrPC by cervid PrPSc
Keywords: Prion / transmissible spongiform encephalopathy / infectivity / misfolded prion protein / prion strains
* To whom correspondence should be addressed. University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030. Tel 713-5007086; Fax 713-5000667; E-mail Claudio.Soto@uth.tmc.edu
Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded prion protein (PrPSc). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the misfolded form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, the newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc. Our results also have profound implications for understanding the mechanisms of prion species barrier and indicate that the transmission barrier is a dynamic process that depend on the strain and moreover the degree of adaptation of the strain. If our findings are corroborated by infectivity assays, they will imply that CWD prions have the potential to infect humans, and that this ability depends on CWD strain adaptation.
snip...
Interestingly, when the Western blot profile of this newly generated form of human PrPSc (termed CWD-huPrPSc) was compared with known strains of human prions, it was clear that CWD-huPrPSc exhibited a different pattern (Fig. 4A). The electrophoretic migration of this protein after PK-digestion is similar to the type 1 strain of sCJD, but its glycosylation profile is clearly different, showing a highly predominant diglycosylated form (Fig. 4A and B). This result suggests that CWD hu-PrPSc corresponds to a new human prion strain. Interestingly, a detailed previous study from Gambetti’s group comparing the biochemical characteristics of PrPSc from cervids and humans showed that CWD PrPSc is similar to sCJDMM1 in terms of electrophoretic mobility (6). However, the misfolded protein associated with CWD is predominantly di-glycosylated, whereas PrPSc from type 1 sCJD is mostly monoglycosylated (6). Based on the fact that transmission of BSE prions to humans resulted in a new form of PrPSc very similar to the one in cattle (6;27), these authors predicted that if humans were infected by CWD it is likely that PrPSc would be of type 1 and with a predominance of the diglycosylated isoform (6). Our results agree with that prediction and suggest that the newly generated CWD-huPrPSc acquires the biochemical properties of the cervid infectious material (Fig. 4A and B). We and others have shown that PMCA replication of PrPSc obtained from experimental rodents, sheep, cervid and human samples faithfully maintains the prion strain characteristics (14;16;26;28-30). To further support the relevance of our results, we performed experiments in which human PrPC was attempted to be converted by either cattle BSE PrPSc or sheep scrapie PrPSc. Whereas the typical vCJD type of PrPSc was generated when human PrPC was converted by BSE PrPSc (Fig. 4C), no human PrPSc was generated under any condition when sheep scrapie PrPSc was used as inoculum (Fig. 4C). These results further validate our PMCA assay.
Discussion CWD is possibly the most worrisome prion zoonosis, because it affects free-ranging animals, making it very difficult to control its spread, and because it is highly efficiently transmitted (1;2). Indeed, in dense free-ranging cervid populations, CWD prevalence can reach as high as 30%, and among captive herds, the prevalence can climb to nearly 100%. The mechanisms and routes of transmission are currently unknown, but likely involve horizontal spread through exposure to prion infected secretions, excretions, or decomposed carcasses (1;2). Moreover, it is likely that CWD prions are progressively accumulating in the environment, since PrPSc binds tightly to soil and can maintain infectivity for a long time (31-33). Currently, it is unknown what proportion of natural CWD cases arises sporadically or comes from horizontal transmission among animals. Based on the available knowledge of the emergence, adaptation and stabilization of prion strains, it is likely that prions appear either spontaneously, through inter-species transmission or by genetic mutations. These “first generation” prions are unstable strains that begin a progressive and gradual process of adaptation that may take several passages and years or decades to complete. In addition natural strain stabilization may take considerable more time than the controlled adaptation done by intracerebral inoculation of brain homogenates in experimental animals. In natural cases, animals usually get infected by peripheral (most likely oral) exposure to small quantities of prions present in peripheral tissues or secretion fluids. Recent data indicates that in some cases the strain characteristics of natural prions in peripheral organs are different than those in the brain even in the same individuals (GCT, unpublished results; MAB and CS, unpublished data). In cervids, there are at least two different strains that can be differentiated by the incubation time and neuropathological characteristics produced when inoculated into transgenic mice expressing deer PrP (34). It is currently unknown the susceptibility of these two strains to human transmission.
Our findings demonstrate that cervid PrPSc, upon strain adaptation by serial passages in vitro or in cervid transgenic mice, is capable of converting human PrPC to produce PrPSc with unique biochemical properties, likely representing a new human prion strain. The newly generated CWD-huPrPSc material has been inoculated into transgenic mice expressing human PrP to study infectivity and disease phenotype and this data will be published elsewhere. We have safely ruled out that human PrPSc generated in these studies is not coming from spontaneous “de novo generation”, since under the conditions used, no spontaneous PK-resistant band was ever detected in brain homogenates of humans or transgenic mice expressing human PrPC, even after more than 20 serial rounds of PMCA (35). Furthermore, none of the many controls included in our experiments in which no PrPSc was added to the reaction, showed any PK-resistant PrP band.
Various studies aimed to analyze the transmission of CWD to transgenic mice expressing human PrP have consistently given negative results (9-11), indicating a strong species barrier. This conclusion is consistent with our many failed experiments to attempt converting human PrPC with natural CWD, even after pushing the PMCA conditions (see figure 1). We found successful conversion only after adaptation of the CWD prion strain by successive passages in vitro or in cervid transgenic mice. We are not aware that in any of the transgenic mice studies the inoculum used was a previously stabilized CWD strain. Although, it has been shown that strain stabilization in vitro by PMCA (17;26) and in vivo using experimental rodents (36) has similarities with the strain adaptation process occurring in natural hosts, we cannot rule out that the type of CWD strain adaptation that is required to produce strains transmissible to humans may take much longer time in cervids or not occur at all. An important experiment will be to study transmissibility to humanized transgenic mice of CWD passed experimentally in deer several times.
Besides the importance of our results for public health in relation to the putative transmissibility of CWD to humans, our data also illustrate a very important and novel scientific concept related to the mechanism of prion transmission across species barriers. Today the view is that species barrier is mostly controlled by the degree of similarity on the sequence of the prion protein between the host and the infectious material (4). In our study we show that the strain and moreover the stabilization of the strain plays a major role in the inter-species transmission. In our system there is no change on the protein sequence, but yet strain adaptation results in a complete change on prion transmissibility with potentially dramatic consequences. Therefore, our findings lead to a new view of the species barrier that should not be seen as a static process, but rather a dynamic biological phenomenon that can change over time when prion strains mature and evolve. It remains to be investigated if other species barriers also change upon progressive strain adaptation of other prion forms (e.g. the sheep/human barrier).
Our results have far-reaching implications for human health, since they indicate that cervid PrPSc can trigger the conversion of human PrPC into PrPSc, suggesting that CWD might be infectious to humans. Interestingly our findings suggest that unstable strains from CWD affected animals might not be a problem for humans, but upon strain stabilization by successive passages in the wild, this disease might become progressively more transmissible to man.
Reference List
snip...
please see full text and many thanks to the Professor Soto and the other Authors of this study AND to The Journal Of Biological Chemistry for the free full text !!!
http://www.jbc.org/content/early/2011/01/04/jbc.M110.198465.long
PLEASE NOTE ;
there are now two documented strains of CWD, and science is showing that indeed CWD could transmit to humans via transmission studies ;
P35
ADAPTATION OF CHRONIC WASTING DISEASE (CWD) INTO HAMSTERS, EVIDENCE OF A WISCONSIN STRAIN OF CWD
Chad Johnson1, Judd Aiken2,3,4 and Debbie McKenzie4,5 1 Department of Comparative Biosciences, University of Wisconsin, Madison WI, USA 53706 2 Department of Agriculture, Food and Nutritional Sciences, 3 Alberta Veterinary Research Institute, 4.Center for Prions and Protein Folding Diseases, 5 Department of Biological Sciences, University of Alberta, Edmonton AB, Canada T6G 2P5
The identification and characterization of prion strains is increasingly important for the diagnosis and biological definition of these infectious pathogens. Although well-established in scrapie and, more recently, in BSE, comparatively little is known about the possibility of prion strains in chronic wasting disease (CWD), a disease affecting free ranging and captive cervids, primarily in North America. We have identified prion protein variants in the white-tailed deer population and demonstrated that Prnp genotype affects the susceptibility/disease progression of white-tailed deer to CWD agent. The existence of cervid prion protein variants raises the likelihood of distinct CWD strains. Small rodent models are a useful means of identifying prion strains. We intracerebrally inoculated hamsters with brain homogenates and phosphotungstate concentrated preparations from CWD positive hunter-harvested (Wisconsin CWD endemic area) and experimentally infected deer of known Prnp genotypes. These transmission studies resulted in clinical presentation in primary passage of concentrated CWD prions. Subclinical infection was established with the other primary passages based on the detection of PrPCWD in the brains of hamsters and the successful disease transmission upon second passage. Second and third passage data, when compared to transmission studies using different CWD inocula (Raymond et al., 2007) indicate that the CWD agent present in the Wisconsin white-tailed deer population is different than the strain(s) present in elk, mule-deer and white-tailed deer from the western United States endemic region.
http://www.istitutoveneto.it/prion_09/Abstracts_09.pdf
PPo3-7:
Prion Transmission from Cervids to Humans is Strain-dependent
Qingzhong Kong, Shenghai Huang,*Fusong Chen, Michael Payne, Pierluigi Gambetti and Liuting Qing Department of Pathology; Case western Reserve University; Cleveland, OH USA *Current address: Nursing Informatics; Memorial Sloan-Kettering Cancer Center; New York, NY USA
Key words: CWD, strain, human transmission
Chronic wasting disease (CWD) is a widespread prion disease in cervids (deer and elk) in North America where significant human exposure to CWD is likely and zoonotic transmission of CWD is a concern. Current evidence indicates a strong barrier for transmission of the classical CWD strain to humans with the PrP-129MM genotype. A few recent reports suggest the presence of two or more CWD strains. What remain unknown is whether individuals with the PrP-129VV/MV genotypes are also resistant to the classical CWD strain and whether humans are resistant to all natural or adapted cervid prion strains. Here we report that a human prion strain that had adopted the cervid prion protein (PrP) sequence through passage in cervidized transgenic mice efficiently infected transgenic mice expressing human PrP, indicating that the species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains. Preliminary results on CWD transmission in transgenic mice expressing human PrP-129V will also be discussed.
Acknowledgement Supported by NINDS NS052319 and NIA AG14359.
PPo2-27:
Generation of a Novel form of Human PrPSc by Inter-species Transmission of Cervid Prions
Marcelo A. Barria,1 Glenn C. Telling,2 Pierluigi Gambetti,3 James A. Mastrianni4 and Claudio Soto1 1Mitchell Center for Alzheimer's disease and related Brain disorders; Dept of Neurology; University of Texas Houston Medical School; Houston, TX USA; 2Dept of Microbiology, Immunology & Molecular Genetics and Neurology; Sanders Brown Center on Aging; University of Kentucky Medical Center; Lexington, KY USA; 3Institute of Pathology; Case western Reserve University; Cleveland, OH USA; 4Dept of Neurology; University of Chicago; Chicago, IL USA
Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded and infectious prion (PrPSc). Chronic wasting disease (CWD) of cervids is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. CWD is highly contagious and its origin, mechanism of transmission and exact prevalence are currently unclear. The risk of transmission of CWD to humans is unknown. Defining that risk is of utmost importance, considering that people have been infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the infectious form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the pathological conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, this newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc, indicating that it corresponds to a novel human prion strain. Our findings suggest that CWD prions have the capability to infect humans, and that this ability depends on CWD strain adaptation, implying that the risk for human health progressively increases with the spread of CWD among cervids.
PPo2-7:
Biochemical and Biophysical Characterization of Different CWD Isolates
Martin L. Daus and Michael Beekes Robert Koch Institute; Berlin, Germany
Key words: CWD, strains, FT-IR, AFM
Chronic wasting disease (CWD) is one of three naturally occurring forms of prion disease. The other two are Creutzfeldt-Jakob disease in humans and scrapie in sheep. CWD is contagious and affects captive as well as free ranging cervids. As long as there is no definite answer of whether CWD can breach the species barrier to humans precautionary measures especially for the protection of consumers need to be considered. In principle, different strains of CWD may be associated with different risks of transmission to humans. Sophisticated strain differentiation as accomplished for other prion diseases has not yet been established for CWD. However, several different findings indicate that there exists more than one strain of CWD agent in cervids. We have analysed a set of CWD isolates from white-tailed deer and could detect at least two biochemically different forms of disease-associated prion protein PrPTSE. Limited proteolysis with different concentrations of proteinase K and/or after exposure of PrPTSE to different pH-values or concentrations of Guanidinium hydrochloride resulted in distinct isolate-specific digestion patterns. Our CWD isolates were also examined in protein misfolding cyclic amplification studies. This showed different conversion activities for those isolates that had displayed significantly different sensitivities to limited proteolysis by PK in the biochemical experiments described above. We further applied Fourier transform infrared spectroscopy in combination with atomic force microscopy. This confirmed structural differences in the PrPTSE of at least two disinct CWD isolates. The data presented here substantiate and expand previous reports on the existence of different CWD strains.
http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099
CJD9/10022
October 1994
Mr R.N. Elmhirst
Chairman
British Deer Farmers Association
Holly Lodge
Spencers Lane
BerksWell
Coventry
CV7 7BZ
Dear Mr Elmhirst,
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.
The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.
The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.
The statistical results reqarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.
I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all. ...end
http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf
UPDATED DATA ON 2ND CWD STRAIN
Wednesday, September 08, 2010
CWD PRION CONGRESS SEPTEMBER 8-11 2010
http://chronic-wasting-disease.blogspot.com/2010/09/cwd-prion-2010.html
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To:
Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam, In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.
That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: [log in to unmask]">[log in to unmask]; [log in to unmask]">[log in to unmask]; [log in to unmask]">[log in to unmask]
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
snip...
full text ;
http://chronic-wasting-disease.blogspot.com/2009/02/exotic-meats-usa-announces-urgent.html
FDA is not recalling this CWD positive elk meat for the well being of the dead elk ;
Wednesday, March 18, 2009
Noah's Ark Holding, LLC, Dawson, MN RECALL Elk products contain meat derived from an elk confirmed to have CWD NV, CA, TX, CO, NY, UT, FL, OK RECALLS AND FIELD CORRECTIONS: FOODS CLASS II
http://chronic-wasting-disease.blogspot.com/2009/03/noahs-ark-holding-llc-dawson-mn-recall.html
see full text ;
http://chronic-wasting-disease.blogspot.com/2009/04/cwd-update-infection-studies-in-two.html
Wednesday, December 29, 2010
CWD Update 99 December 13, 2010
http://chronic-wasting-disease.blogspot.com/2010/12/cwd-update-99-december-13-2010.html
http://chronic-wasting-disease.blogspot.com/
now, just what is in that deer feed? _ANIMAL PROTEIN_
Subject: MAD DEER/ELK DISEASE AND POTENTIAL SOURCES
Date: Sat, 25 May 2002 18:41:46 -0700 From: "Terry S. Singeltary Sr." Reply-To: BSE-LTo: BSE-L
8420-20.5% Antler DeveloperFor Deer and Game in the wildGuaranteed Analysis Ingredients / Products Feeding Directions
snip...
_animal protein_
http://www.surefed.com/deer.htm
BODE'S GAME FEED SUPPLEMENT #400A RATION FOR DEERNET WEIGHT 50 POUNDS22.6 KG.
snip...
_animal protein_
http://www.bodefeed.com/prod7.htm
IngredientsGrain Products, Plant Protein Products, Processed Grain By-Products,Forage Products, Roughage Products 15%, Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Pyosphate, Salt,Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol(source of Vitamin D3), Vitamin E Supplement, Vitamin B12 Supplement,Riboflavin Supplement, Niacin Supplement, Calcium Panothenate, CholineChloride, Folic Acid, Menadione Soduim Bisulfite Complex, PyridoxineHydorchloride, Thiamine Mononitrate, d-Biotin, Manganous Oxide, ZincOxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, DriedSacchoromyces Berevisiae Fermentation Solubles, Cellulose gum,Artificial Flavors added.http://www.bodefeed.com/prod6.htm
===================================
MORE ANIMAL PROTEIN PRODUCTS FOR DEER
Bode's #1 Game PelletsA RATION FOR DEERF3153GUARANTEED ANALYSISCrude Protein (Min) 16%Crude Fat (Min) 2.0%Crude Fiber (Max) 19%Calcium (Ca) (Min) 1.25%Calcium (Ca) (Max) 1.75%Phosphorus (P) (Min) 1.0%Salt (Min) .30%Salt (Max) .70%IngredientsGrain Products, Plant Protein Products, Processed Grain By-Products,Forage Products, Roughage Products, 15% Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Phosphate, Salt,Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol(source of Vitamin D3) Vitamin E Supplement, Vitamin B12 Supplement,Roboflavin Supplement, Niacin Supplement, Calcium Pantothenate, CholineChloride, Folic Acid, Menadione Sodium Bisulfite Complex, PyridoxineHydrochloride, Thiamine Mononitrate, e - Biotin, Manganous Oxide, ZincOxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, DriedSaccharyomyces Cerevisiae Fermentation Solubles, Cellulose gum,Artificial Flavors added.FEEDING DIRECTIONSFeed as Creep Feed with Normal Diet
http://www.bodefeed.com/prod8.htm
INGREDIENTS
Grain Products, Roughage Products (not more than 35%), Processed GrainBy-Products, Plant Protein Products, Forage Products,
__Animal Protein Products__,
L-Lysine, Calcium Carbonate, Salt, Monocalcium/DicalciumPhosphate, Yeast Culture, Magnesium Oxide, Cobalt Carbonate, BasicCopper Chloride, Manganese Sulfate, Manganous Oxide, Sodium Selenite,Zinc Sulfate, Zinc Oxide, Sodium Selenite, Potassium Iodide,Ethylenediamine Dihydriodide, Vitamin E Supplement, Vitamin ASupplement, Vitamin D3 Supplement, Mineral Oil, Mold Inhibitor, CalciumLignin Sulfonate, Vitamin B12 Supplement, Menadione Sodium BisulfiteComplex, Calcium Pantothenate, Riboflavin, Niacin, Biotin, Folic Acid,Pyridoxine Hydrochloride, Mineral Oil, Chromium Tripicolinate
DIRECTIONS FOR USE
Deer Builder Pellets is designed to be fed to deer under rangeconditions or deer that require higher levels of protein. Feed to deerduring gestation, fawning, lactation, antler growth and pre-rut, allphases which require a higher level of nutrition. Provide adequateamounts of good quality roughage and fresh water at all times.
http://www.profilenutrition.com/Products/Specialty/deer_builder_pellets.html
===================================================
DEPARTMENT OF HEALTH & HUMAN SERVICESPUBLIC HEALTH SERVICEFOOD AND DRUG ADMINISTRATIONApril 9, 2001 WARNING LETTER01-PHI-12CERTIFIED MAILRETURN RECEIPT REQUESTED
Brian J. Raymond, Owner Sandy Lake Mills 26 Mill Street P.O. Box 117 Sandy Lake, PA 16145
PHILADELPHIA DISTRICT
Tel: 215-597-4390
Dear Mr. Raymond:Food and Drug Administration Investigator Gregory E. Beichner conducted an inspection of your animal feed manufacturing operation, located in Sandy Lake, Pennsylvania, on March 23,2001, and determined that your firm manufactures animal feeds including feeds containing prohibited materials. The inspection found significant deviations from the requirements set forth in Title 21, code of Federal Regulations, part 589.2000 - Animal Proteins Prohibited in Ruminant Feed. The regulation is intended to prevent the establishment and amplification of Bovine Spongiform Encephalopathy (BSE) . Such deviations cause products being manufactured at this facility to be misbranded within the meaning of Section 403(f), of the Federal Food, Drug, and Cosmetic Act (the Act).Our investigation found failure to label your swine feed with the required cautionary statement "Do Not Feed to cattleor other Ruminants" The FDA suggests that the statement be distinguished by different type-size or color or other means of highlighting the statement so that it is easily noticed by a purchaser.
In addition, we note that you are using approximately 140 pounds of cracked corn to flush your mixer used in the manufacture of animal feeds containing prohibited material. This flushed material is fed to wild game including deer, a ruminant animal.Feed material which may potentially contain prohibited material should not be fed to ruminant animals which may become part of the food chain.The above is not intended to be an all-inclusive list of deviations fromthe regulations. As a manufacturer of materials intended for animalfeed use, you are responsible for assuring that your overall operation and the products you manufacture and distribute are in compliance withthe law. We have enclosed a copy of FDA's Small Entity Compliance Guideto assist you with complying with the regulation... blah, blah, blah...
http://www.fda.gov/foi/warning_letters/g1115d.pdf
==================================
snip...end...full text ;
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 1 Terry S. Singeltary Sr. Vol #: 1
http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7 Terry S. Singeltary Sr. Vol #: 1
2003D-0186 Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7 Terry S. Singeltary Sr. Vol #: 1
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
01N-0423 Substances Prohibited from use in animal food/Feed Ruminant
APE 5 National Renderers Association, Inc. Vol#: 2
APE 6 Animal Protein Producers Industry Vol#: 2
APE 7 Darling International Inc. Vol#: 2
EMC 1 Terry S. Singeltary Sr. Vol#: 3
http://www.fda.gov/ohrms/dockets/dailys/01/Oct01/101501/101501.htm
above urls dead, go here ;
http://madcowfeed.blogspot.com/2008/07/docket-03d-0186-fda-issues-draft.html
Friday, January 7, 2011
MEAT AND BONE MEAL AND MINERAL FEED ADDITIVES MAY INCREASE THE RISK OF ORAL PRION DISEASE TRANSMISSION
Journal of Toxicology and Environmental Health, Part A, 74:161–166, 2011 Copyright © Taylor & Francis Group, LLC ISSN: 1528-7394 print / 1087-2620 online DOI: 10.1080/15287394.2011.529066
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/meat-and-bone-meal-and-mineral-feed.html
Wednesday, January 19, 2011
EFSA BIOHAZ Scientific Opinion on the revision of the quantitative risk assessment (QRA) of the BSE risk posed by processed animal proteins (PAPs)
EFSA Journal 2011;9(1):1947
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/efsa-biohaz-scientific-opinion-on.html
>>> Animals injected with iatrogenic Creutzfeldt-Jakob disease MM1 and genetic Creutzfeldt-Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt-Jakob disease MM1 prions, whereas kuru most closely resembled the sporadic Creutzfeldt-Jakob disease VV2 or MV2 prion signature and neuropathology.... <<<
http://www.jbc.org/cgi/content/abstract/M704597200v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Cross-sequence+transmission+of+sporadic+Creutzfeldt-Jakob+disease+creates+a+new+&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
UPDATED DATA ON 2ND CWD STRAIN
snip... please see full text ;
Tuesday, January 18, 2011
Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/agent-strain-variation-in-human-prion.html
Thursday, December 23, 2010
Molecular Typing of Protease-Resistant Prion Protein in Transmissible Spongiform Encephalopathies of Small Ruminants, France, 2002–2009 Volume 17, Number 1–January 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/molecular-typing-of-protease-resistant.html
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/efsa-and-ecdc-review-scientific.html
Friday, January 21, 2011
Strain-Specific Barriers against Bovine Prions in Hamsters
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/strain-specific-barriers-against-bovine.html
Saturday, December 18, 2010
OIE Global Conference on Wildlife Animal Health and Biodiversity - Preparing for the Future (TSE AND PRIONS) Paris (France), 23-25 February 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/oie-global-conference-on-wildlife.html
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." 49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob ...
............................
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
see full text ;
Tuesday, November 02, 2010
BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992
http://bse-atypical.blogspot.com/2010/11/bse-atypical-lesion-distribution-rbse.html
USA
5 Includes 16 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 21 (19 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
2010
PLEASE NOTE REFERENCE LINES 5. AND 6.
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010) Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 51 33 28 5 0 0
1997 114 68 59 9 0 0
1998 88 52 44 7 1 0
1999 120 72 64 8 0 0
2000 146 103 89 14 0 0
2001 209 119 109 10 0 0
2002 248 149 125 22 2 0
2003 274 176 137 39 0 0
2004 325 186 164 21 0 1(3)
2005 344 194 157 36 1 0
2006 383 197 166 29 0 2(4)
2007 377 214 187 27 0 0
2008 394 231 204 25 0 0
2009 425 259 216 43 0 0
2010 204 124 85 20 0 0
TOTAL 3702(5) 2177(6) 1834 315 4 3
1 Listed based on the year of death or, if not available, on year of referral;
2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia in the other case;
5 Includes 16 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 21 (19 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011
Prions
David W. Colby1,* and Stanley B. Prusiner1,2
http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html
Thursday, December 23, 2010
Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom
http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html
strictly NOT private and confidential $$$
Saturday, January 22, 2011
Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/alzheimers-prion-and-neurological.html
DID EVERYONE FILL OUT THEIR CJD QUESIONNAIRE FROM THE CDC AND OR THE CJD FOUNDATION ???
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION
http://cjdquestionnaire.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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