Friday, August 21, 2015

Porcine prion protein amyloid or mad pig disease PSE Porcine Spongiform Encephalopathy ?

Prion

 

Volume 9, Issue 4, 2015

 

Porcine prion protein amyloid

 

DOI:10.1080/19336896.2015.1065373Per Hammarströma & Sofie Nyströma*

 

pages 266-277

 

Received: 1 Jun 2015 Accepted: 17 Jun 2015 Accepted author version posted online: 28 Jul 2015

 

© 2015 The Author(s). Published with license by Taylor & Francis Group, LLC Additional license information

 

 ABSTRACT

 

 Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

 

SNIP...

 

CONCLUDING REMARKS Should the topic of porcine PrP amyloid be more of a worry than of mere academic interest? Well perhaps. Prions are particularly insidious pathogens. A recent outbreak of peripheral neuropathy in human, suggests that exposure to aerosolized porcine brain is deleterious for human health.43,44 Aerosolization is a known vector for prions at least under experimental conditions.45-47 where a mere single exposure was enough for transmission in transgenic mice. HuPrP is seedable with BoPrP seeds and even more so with PoPrP seed (Fig. 1), indicating that humans could be infected by porcine APrP prions while neurotoxicity associated with spongiform encephalopathy if such a disease existed is even less clear. Importantly transgenic mice over-expressing PoPrP are susceptible to BSE and BSE passaged through domestic pigs implicating that efficient downstream neurotoxicity pathways in the mouse, a susceptible host for prion disease neurotoxicity is augmenting the TSE phenotype.25,26 Prions in silent carrier hosts can be infectious to a third species. Data from Collinge and coworkers.21 propose that species considered to be prion free may be carriers of replicating prions. Especially this may be of concern for promiscuous prion strains such as BSE.19,48 It is rather established that prions can exist in both replicating and neurotoxic conformations.49,50 and this can alter the way in which new host organisms can react upon cross-species transmission.51 The na€Ä±ve host can either be totally resistant to prion infection as well as remain non-infectious, become a silent non-symptomatic but infectious carrier of disease or be afflicted by disease with short or long incubation time. The host can harbor and/or propagate the donor strain or convert the strain conformation to adapt it to the na€Ä±ve host species. The latter would facilitate infection and shorten the incubation time in a consecutive event of intra-species transmission. It may be advisable to avoid procedures and exposure without proper biosafety precautions as the knowledge of silence carrier species is poor. One case of iatrogenic CJD in recipient of porcine dura mater graft has been reported in the literature.52 The significance of this finding is still unknown. The low public awareness in this matter is exemplified by the practice of using proteolytic peptide mixtures prepared from porcine brains (Cerebrolysin) as a nootropic drug. While Cerebrolysin may be beneficial for treatment of severe diseases such as vascular dementia,53 a long term follow-up of such a product for recreational use is recommended.

 


 

The case for mad pigs in the US

 

From the Consumer Policy Institute and Consumers Union: March 24, 1997

 

Stephen F. Sundlof, D.V.M., Ph.D

 

Center for Veterinary Medicine Food and Drug Administration 7500 Standish Place, Room 482, HFV 1 RockvLIle, MD 20855

 

Dear Dr. Sundlof:

 

We are writing to you to submit information that has recently come to our attention which suggests that a TSE like disease (transmissible spongiform encephalopathy) might exist in pigs in the U.S. We believe this new informantion calls for intensive research and makes it urgent to ban the use of all mammalian proteins, including swine, in the feed of all food animals, until better answers are found.

 

The evidence for the potential PSE (porcine spongiform encephalopathy ) is as follows. In 1979, an FSQS veternarian, Dr. Masuo Doi, noticed some unusual central nervous system (CNS) symptoms in young (about 6 months old) hogs coming into a slaughter plant In Albany, New York. Since the plant received hogs from a wide variety of sources (New York, Canada, Indiana, Illinois, Ohio, and other Midwestern states) and was not a plant used to dealing with diseased animals, Dr. Doi thought that the problem might be affecting hogs slaughtered nationwide. So, he decided to conduct a detailed study on central nervous system (CNS) symptoms/disease in young hogs coming into that slaughter plant. The study ran for 15 months (January, 1979 to March, 1980) and consisted of extended observations of the behavior of animals with suspected CNS symptoms at the plant, followed by pathological, histopatholpgical, and microbiological work on tissues from various organs of particular animals after slaughter.

 

For his behavioral observational work, Dr. Doi extended the usual two day observation period to three to four days, during which he took careful notes on the animals' behavior and other vital signs. During the 15 month period of the study, some 106 animals exhibiting CNS symptoms were retained during antemortem inspection.

 

A 1980 paper that summarized Dr. Doi's findings on the clinical symptoms and incidence of the 'disease," contained descriptions of these symptoms that sound remarkably similar to the symptoms noted for bovine spongiform encephalopathy (BSE):

 

"Excitable or nervous temperament to external stimuli such as touch to the skin, handling and menacing approach to the animals is a common characteristic sign among swine affected with the disease.... In the advanced stage of the disease, manifestation of neurological signs are evidenced in the form of general ataxia . . . Many animals have been found to be "downers' at first observation; if the hindquarters of these downers are raised they may be able to walk one or two steps and then fall to the ground" (Doi et al., 1980: 2, 4). Indeed, a table of symptoms includes, for the early stage: "excitability and nervousness (squealing, smacking of lips, grinding of teath, chewing, gnawing ant foaming at mouth); stiffness of limbs . . . 'tic'; weakness of hindquarters; focal tremors of skeletal muscles"; and for the advanced stage: depression; ataxia; crossing over of limbs . . . kneeling posture . . . crawling". In addition to his clinical observations, Dr. Doi also made an 8 mm film of thirteen of the affected animals; film of two of the pigs was shown at the MPI National Pathology Meeting in Seattle, Washington on flay 20, 1979.

 

Dr. Doi sent tissue samples from suspect cases to the USDA's Eastern Laboratory in Athens, GA for pathological, histopathogical and microbiological work. Known infectious diseases were ruled out. As Dr. Doi points out, "Histopathological studies of tissue collected from the brain and spinal cord of these animals in the early stage of the disease show congestion, hemorrhage and neuronal degeneration. All animals in the advanced stage of the disease have been confined to have Encephalitis or Meningitis by MPI laboratory" (Doi et al., 1980: 5). Eventually some 60 animals were confirmed by the MPI Laboratory to have encephalitis or meningitis, with no ldentifiable cause. As pointed out in a paper presented at the 1979 MPI National Pathology Meetings,

 

"Since January, a number of hogs in this establishment have been found, in antemortem, to show what appears to be CNS. Sets of tissue samples were sent to the laboratory for examination, various tests were done which include histological study (E H stain), fluorescence antibody technique, virus neutralization and viral and bacteriological isolation. Differential diagnosis was also done to exclude vitamin B deficiency, post vaccination reaction, chlorinated hydrocarbon, arthritis, and transport stress" (Doi et al., 1979). The brains of the 60 animals were examined. The brain of one of these pigs, on histopathological analysis, exhibited signs reminiscent of a TSE. This histopathological work was performed by Dr. Karl Langheinrich, Pathologist-In-Charge at USDA's Eastern Laboratory in Athens, Georgia. According to the USDA FSQS laboratory report, dated early November, 1979, Dr. Langheinrich noted:

 

"Microscopic examination of the barrow tissues revealed a encephalopathy and diffuse gliosis characterized by vacuolated neurons, loss of neurons and gliosis in a confined region (nucleus) of the brain stem (anterior ventral midbrain). Only an empty sometimes divided vacuole was present instead of the normal morphology of a nerve cell. Occasionally a shriveled neuron was seen. According to . . . Pathology of Domestic Animals, . . . 'The degeneration of neurons, the reactivity of the glia .... are the classical hallmarks of viral infection of the central nervous system' .... Scrapie of sheep, and encephalopathy of mink, according to the literature, all produce focal vacuolation of the neurons similar to the kind as described for this pig. I was unable to locate any lead as to the cause of this interesting phenomenon in other species including swine'' (Langheinrich, 1979). Indeed, Dr. Langheinrich's main diagnosis was, " Encephalopathy and diffuse gliosis of undetermined etiology." Portions of the brain were sent for microbiological testing to a neurologist at the University of Georgia, where they came up negative for pseudo-rabies. The brain was unique enough that USDA scientists, such as Dr. Langheinrich and Or. Dot, mentioned it to student and scientific colleagues over the years.

 

In 1979-1980, BSE was completely unknown. However, both the behavior of the pigs, as well as the histopathology on at least one pig, both showed sign consistent with a porcine TSE. This raises particular concern became the affected animal was only 6 months old; in an animal this young, one would rust expect to see any physical signs of TSE in the brain. Histopathology of TSEs can be very variable, so that spongiform appearance (i.e. vacuolated neurons) are not always present. Behavioral changes can be seen in TSE-infected animals before any changes in brain morphology are visible. Dr. Clarence Gibbs, in testimony before a Congressional hearing on the TSE issue on January 29, 1997 made just this point:

 

''In the mid-1960s, we demonstrated with our French and English collaborators that during the early incubation of the TSEs, when the virus titer in the brain was very low, there were already marked functional changes, even though no pathology was yet detectable, even ultrastructurally. A month or hero later, polynucleation of neurons appeared in spider monkeys, incubating kuru, and somewhat later, microvacuolation and membrane changes visible only by electron microscopy. This preceded the pest appearance of astrogliosis and spongiform change. It was only much later that the classical scrapie TSE pathology appeared with virus titers in brain of 10 -5 or higher" (Gibbs, 1997; pg. 4). Given that TSEs can cause behavioral changes in infected animals before any physical changes in the brain can be seen, that the manifestation of TSE in the brain can be quite variable, and that changes in brain morphology are not usually seen in 6 month old animals, we are concerned that the brain of one pig actually showed physical evidence consistent with a TSE.

 

Following the announcement In March, 1996 of ten cases of new variant CJD (Creutzfeldt-Jakob Disease) in the United Kingdom and their possible connection to BSE, Drs. Doi, Langheinrich and others urged reinvestigation of this case.

 

In August, 1996, the USDA sent five slides, one of which was a histopathology slide, to Dr. Janice Miller of USDA's Agricultural Research Servicer . Dr. Miller stained four of the slides for prion protein (she didn't stain the H&E slide). Dr. Miller told Consumers Union that Dr. Patrick McCaskey, USDA/FSIS, in charge of the Research Center at Athens, GA, called her, told her that he had five slides that all showed "problems" and asked her to stain four of them. The H&E slide, which clearly show vacuoles in the neurons (one sign of TSE), wasn't stained because to stain for PrP entails removing the slide cover, baking the slide to destain it and then restaining it for PrP; they didn't want to risk destroying the H&E slide.

 

Dr. Doi had kept frozen samples of the brain and spinal chord of the suspect PSE pig in case the Eastern lab wanted more material for analysis. Unfortunately, these samples were discarded when the packing plant in Albany, NY closed in 1991. It appears that the brain material sent to the Univcrsity of Georgia may have been discarded. [pers com.. Dr. Doi 3/13/97]

 

Dr. Miller found that the PrP stained in the four pig slides was found only on the inside of neurons, while a positive control slide from a scrapie sheep showed massive amounts of extraneuronal staining. In a letter summarizing her results (copy attached), she concludes that the PrP stained in this pig was normal: "In the pig sections you will see a small particulate type of staining that is confined to neurons and as I indicated on the phone, I would interpret as normal PrP. It is in marked contrast to the massive amount of extraneuronal staining seen in the scrapie section" (Miller, 1996).

 

Unfortunately, Dr. Miller's finding toes not conclusively rule out a TSE. We are concerned that while British BSE and serapie create a massive amount of extraneuronal staining, there are TSEs where this isn't the case. Three experiments were done in He U.S. -- in Mission, TX (APHIS work), Pullman, Washington (ARS work), and Ames, Iowa (ARS work) -- to see whether sheep scrapie can possibly infect cows. In all the experiments, cattle were inoculated with tissue from scrapie -infected sheep primarily by intra-cranial injection, but in the case of the Texas and Iowa studies also by oral feeding -- to see if cattle were susceptible to scrapie at all. In all three experiments, the majority of cows injected in the brain with scrapie-infected sheep material (usually brains) also developed a fatal spongiform encephalopathy.

 

However, in all three examples, the symptoms of the spongifonn encephalopathy differed from "mad cow" disease ~ England, as did the appearances of slides from their brains. The brain lesions seen in ail these animals were more variable than those seen in England. When Dr. Miller did similar staining for PrP from these brains (what she called "bovine scrapie") she only found PrP stains on the inside of the neurons, not the massive extraneuronal staining seen in BSE (Miller, pers. comm., March 7, 1997). Thus, Dr. Miller's finding of PrP stains only inside the neurons in the suspect pigs is not particularly reassuring.

 

In November 1996, USDA sent the single histopathology slide to Dr. William Hadlow, one of the foremost spongiform encephalopathy pathologists in the world. (For unknown reasons, Dr. Hadlow was only sent the one slide; he was not told of the existence of the other slides, nor of Dr. Miller's findings, nor was he told or given the behavioral report from Dr. Doi or the morphology work by Dr. Langheinrich, or shown film of the affected pigs [Dr. Hadlow, pers. com., 3/13/97] From this single slide, Dr. Hadlow found some evidence consistent with TSEs but not enough for a conclusive diagnosis. He noted that the slide contained vacuoles inside neurons, one of the signs of a TSE (Dr. Langheinrich had noted this as well).

 

However, since such vacuoles occasionally occur normally in pigs, he thought that was not something special: "About twelve (12) neurons in the parasympathetic nucleus have unilocular optically empty vacuoles in the perikaryon. This is the site where such vacuolated neurons have been seen in the swine (as well as in cats and sheep) as an incidental finding. So I do not think such cells have any significance in this pig" (Hadlow, 1996). However, he did see evidence, Including changes in astrocytes, that suggested a TSE, but without examining other parts of the brain to look for other evidence of TSE, he couldn't be sure:

 

"I am impressed, though, with what seems to be an increase in the number of astrocytes in the section. Some astrocytes are in clusters, some are enlarged and vesicular. Where they are most numerous, a few rod cells (activated microglia) are seen. These findings suggest some perturbation of the nervous tissue. Although such a global response occurs in the transmissible spongifonn encephalopathies, I do no! know its significance in this case without examining other parts of the brain for changes characteristic of these diseases. Thus, from looking; at this one (1) section of brain, I cannot conclude that the pig was affected with a scrapie-like spongiform encephalopathy" (Hadlow, 1996). In sum, Dr. Hadlow~s letter does not rule out the possibility of a TSE. He says that there is suggestive evidence, but that he would need to look at other slides/sections of the brain, to make a conclusive diagnosis.

 

In our view, the implications of this data are extremely serious. Experiments in the United Kingdom have shown that pigs are susceptible to BSE. Pigs inoculated with BSE develop a TSE (Dawson et al., 1990). Feeding experiments are underway in the UK to see if BSE can be orally transmitted to pigs; as of March, 1997, some 6 years after the start of the experiment, none of the pigs fed BSE brain have come down with a TSE. Unfortunately the design of this experiment severely limits what we will learn from it, and will most likely not tell us conclusively if pigs can get BSE from feed. It turns out that the pigs were not fed BSE brain continuously. Rather, the pigs were only fed BSE brain material on three days, over a three week period (i.e.. one day each week). Following these three doses, the pigs were never fed contaminated material again. The total amount of infective material given to the pigs was therefore quite small. Thus, a negative finding would be hard to interpret and would not mean that BSE is not orally active in pigs.

 

We believe that as a top priority USDA should conduct follow-up studies to look for potential CNS/PSE cases in pigs (we plan to communicate about this to USDA separately). In brief, we feel that the following kinds of studies need to be done:

 

i) TSE pathology experts should examine all the slides from the suspect pig (2709). To our knowledge, at least 12 separate slides exist.

 

ii) Determine if any brain material from the suspect pig (2709) still exists at the Unlverslty of Georgia. If so, this material should be retrieved and used for transmission studies. In particular, suckling pigs should be inoculated with the material and then permitted to live unto they die of a disease or old age, at which point their brains should be examined for physical signs of a TSE as well as for immunchistochemical evidence (i.e. staining looking for the abnormal PrP).

 

iii) Increase antemortem inspection for CNS symptoms at hog facilities. Inspectors should be trained to detect the subtle CNS symptoms seen in the Doi et al. study. At a select number of slaughter facilities, animals exhibiting CNS symptoms should be removed and held for observation until they die, at which time their brains should be examined for evidence of a TSE.

 

iv) Research on CNS symptoms among Me 6,000 or so breeding sows which are permitted to live for 3+ years. Sows exhibiting CNS symptoms should be removed and held for observation until they die, at which time then brains should be exernined for evidence of a TSE.

 

While such work is underway, given the above inforrnabon, we believe that as a precutionary measure the FDA must expand the proposed ruminant plus mink-to-ruminnant feed ban to prevent protein from any material, including hogs, being fed to any food animal.

 

Sincerely,

 

Michael Hansen, Ph.D Research Associate

 

Jean Halloran Director

 

References

 

Dawson, M., Wells, G.A.H., Parker, B.N;J. and A.C Scott. 1990. Primary parental transmission of bovine spongiform encephalopathy to the pig. Veternary Record, pg. 338.

 

Doi, M., Matzner, N.D. and C. Rothaug. 1979. Observation of CNS disease in market hogs at Est. 893 Tobin Packing Co., Inc. Albany, New York. United States Department of Agriculture, Food Safety and Quality.Service, Meat and Poultry Inspection Service. 7pp.

 

Doi, M, Langheinrich, K. and F. Rellosa. 1980. Observations of CNS signs in hogs at Est. 893 Tobin Packing C:o., Inc. Presented by Dr. Lngheinrich at the MPI National Pathology Meeting in Seattle, Washington on July 20, 1979.

 

Gibbs, C. 1997. Statement to the Committee on Governnent Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations, U.S. House of Representatives. January 29,1997.

 

Hadlow, WJ. 1996. Letter to Patrick McCaskey, USDA/FSIS/Eastem Lab, dated November 13, 1996.

 

Langheinrich, KA. 1979. USDA/FSQS Laboratory report on specimen 2709. Dated November 8, 1979

 

Miller, J. 1996. Letter to Patrick McCaskey, USDA/ESIS/Eastern Lab, dated September 6, 1996.

 

Dr. Janice Miller, ARS< USDA responds Mon, 31 Mar 1997 Correspondence My involvement in the "pig incident" (I refuse to say "mad pig disease" since no such disease has been recognized):

 

I was asked by Dr. Al Jenny at the National Veterinary Services Laboratory if I had ever done immunohistochemistry on slides that had already been stained by hematoxylin and eosin, the standard stain used for histopathology. I had done it on a few scrapie cases so he asked if I would do the procedure on some pig brain slides that he had received from Dr. Pat McCaskey, an FSIS pathologist in Athens, GA.

 

At the time I didn't know the history of the situation but Dr. Jenny said I should call Dr. McCaskey and discuss it with him before proceeding. Only then did I learn a little about the history of the case. We decided that I wouldn't try to stain all of the slides because I was afraid the procedure required to remove the cover slips might damage the sections and Dr. McCaskey was concerned about preserving the sections for other pathology consultations, if necessary.

 

We agreed that I would stain 4 of the 5 slides, leaving the slide with the best lesions untouched. I was also concerned that I didn't know whether the antiserum we use would stain pig PrP but decided it was worth a try. When I completed the staining procedure the only positive material I observed was a small amount of particulate staining within the cell body of some neurons. We have occasionally observed that kind of staining in brains from control cattle and sheep in our experiments and interpret it to be normal PrP. (A similar finding was reported by Dr. Haritani, who first described the technique for BSE).

 

That observation was reported in our 1994 paper and we stated that consequently we could not interpret intraneuronal staining as indicative of scrapie (although it may be present, the bulk of staining is in neuropil, around vessels and neurons, etc). In that study I think our interpretation was somewhat validated by the very close correlation we had between immunohistochemistry and western blot results. At any rate, I told Dr. McCaskey that my interpretation on the slides was that the only staining present was consistent with normal PrP. The good news was that the antiserum did in fact stain something and that it was in the correct location for normal PrP, indicating that the antiserum would have detected abnormal PrP, had it been present. Subsequently, I called Dr. Richard Rubenstein, who provided the antibody we use, and asked if he knew whether it would react with pig PrP and he said he didn't know. However, he said it reacted with almost all mammalian species, except ferret and mink, that he had tried so he would be surprised if it wasn't reactive with pig PrP.

 

So, having all of this information at hand, people can decide whether the immunohistochemical test means anything or not. The lack of a positive control pig tissue (positive sheep tissue is included in every test) may be viewed by some people as diminishing the value of a negative result, but feel we did the best we could under the circumstances.

 

The above recitation describes my experience with the case in question. I did not photograph the slides and returned all 5 to Dr. McCaskey. It was later that he had Dr. Hadlow look at the case for histopathologic interpretation. I did not examine the slides for that purpose because I do not have experience in scrapie diagnosis and would not consider my observations meaningful.

 

I appreciated the additional information about the original study done by Dr. Doi. Although I've heard bits and pieces of the story from different people, this was the first time I had heard that 60 of the pigs were diagnosed as having encephalitis or meningitis. I think that fact, plus the fact that the pigs were only about 6 months old, should certainly indicate that it's highly unlikey that a spongiform encephalopathy epidemic was causing the CNS signs observed. Whether the 1 pig with the questionable encephalopathy lesions was a TSE could be debated, I suppose. The age would seem to argue against it and the immunohistochemistry result would also (at least that's my opinion).

 

We disagree about the implications of age regarding the liklihood of TSE in a 6-month old pig. Certainly dose has an effect on incubation period in experimental transmissions and probably also in the "natural" acquired transmissions. However, regardless of the manner of transmission, I don't know of any first passage experimental interspecies transmission where the incubation period was as short as 6 months.

 

Early onset in mice were achieved only after adaptation through at least 1 intraspecies transfer. I believe the same is true for development of the hamster models. With regard to acquired transmissions, Linda Detwiler's review on scrapie cites research that indicated infectivity was found in CNS tissues of lambs as early as 4 months of age: however, they were not showing clinical signs. From what I can find in the literature, a clinical case of scrapie under 2 years of age would be exceptional, but with the amount of material published on that disease I wouldn't want to say it hasn't happened.

 

With TME the shortest incubation I've seen reported was 9 months. Elizabeth Williams has indicated that the youngest case of CWD observed in their wildlife facilities was 18 months old. You stated that in England calves were getting BSE by one year. In the experimental BSE transmissions cattle didn't develop clinical signs until the second year of observation and the earlest sign we observed in cattle inoculated with sheep scrapie was 14 months.

 

With respect to swine, the only model we have is the experimental transmission of BSE. The animal first developed signs about 17 months after inoculation. I think that it would be highly unlikely for a 6 month old pig to be showing CLINICAL signs of a TSE (the claim in this particular situation). One can never say never but it seems reasonable to at least examine what is known and make an educated estimate about what is likely.

 

A case-control study of CJD. Dietary risk factors. Am J Epidemiol 122 (3): 443-451 (1985) Davanipour Z, Alter M, Sobel E, Asher DM, Gajdusek DC The mode of natural transmission of Creutzfeldt-Jakob disease remains unknown. In a case-control study conducted in 1981-1983 to evaluate possible dietary and other sources of the disease, 26 cases were ascertained in the mid-Atlantic region of the United States, 23 of which were obtained from accumulated records of the Laboratory of Central Nervous System Studies of the National Institutes of Health. Controls included 18 family members and 22 hospital-matched individuals (total sample size, 66). An increased consumption among patients was found for roast pork, ham, hot dogs (p less than 0.05), roast lamb, pork chops, smoked pork, and scrapple (p less than 0.1). An excess consumption of rare meat (p less than 0.01) and raw oysters/clams (p less than 0.1) was also reported among the patients. Liver consumption, among organ foods, was greater (p less than 0.1) among the cases. If Creutzfeldt-Jakob disease is acquired through ingestion of foods containing the agent, then the food items identified may be among those which need to be evaluated more intensively. Larger case-control studies with more focused dietary questions are warranted.

 

Sundlof can't comment From: Dr. Stephen Sundlof D.V.M., Ph.D. Director, Center for Veterinary Medicine Food and Drug Administration :

 

At the present time FDA is in the process of developing a final rule which will regulate the feeding of certain animal-derived protein to other animals. In addition to studying the scientific literature pertaining to TSE's, we have received 700 comments relating the proposed rule that was published in the Federal Register on January 3, 1977. The information provided by Dr. Hansen and others will be considered in developing the final rule along with all of the other information and comments that have been officially submitted to FDA. Until the final rule is published, FDA is prohibited from commenting on information that might impact the final rule. Therefore, I am unable to respond to the documents in Dr. Hansen's letter.

 

I do not have access to the photomicrographs of the histopathology slides, and I was unaware of their existance until Dr. Hansen brought the issue to my attention. Furthermore, I do not have addresses or telephone numbers for Drs. Doi. Langheinrich, or Hadlow. Someone from the USDA would have this information but I am not sure who that would be.

 

Webmaster had written: " Do photomicrographs of any of the 12 slides exist? If you have any of them, I would like to scan a few of these and post them at high resolution on the internet so that pathologists world-wide could view and comment on them.

 

Primary parenteral transmission of bovine spongiform encephalopathy to the pig. Veterinary Record 1990 127 13 338 Dawson, M.; Wells, G. A. H.; Parker, B. N. J.; Scott, A. C. Ten, weaned one- to two-week old piglets from a specific pathogen free breeding herd were inoculated under halothane anaesthesia by simultaneous injections intracerebrally (0.5 ml) intravenously (1 to 2 ml) and intraperitoneally (8 to 9 ml) with an inoculum consisting of 10% saline suspension of pooled homogenised brainstem from 4 natural bovine spongiform encephalopathy cases. Control piglets were similarly inoculated with saline. After 69 weeks one challenged pig showed mild aggressive behaviour towards the animal attendants. Intermittent inappetence and depression were also noted. Within one week the behavioural changes included aimless biting activity and there was mild symmetrical ataxia. The ataxia progressed and 5 weeks after onset of signs the gait ataxia was generalised with hypermetria and wide-based stance. At this time the pig was killed. Histopathological examination of the brain revealed spongiosis of grey matter neuropil with greatest intensity in the medial geniculate body, superior colliculus and corpus striatum. There was sparse vacuolation of neuronal perikarya in the dorsal nucleus of the vagina nerve and widespread astrocytic reaction. Characteristic fibrils associated with transmissible spongiform encephalopathies were detected by electron microscopy.

 

One good question is what _pooled_ medical products do they make from pigs. The key issues for spread of this disease are the amplification cycle and distribution pooling. That is, one rotten apple by itself is less of a problem than if it is in a barrel. – webmaster

 


 

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 ;

 


 

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. ...

 


 

snip...

 

CONFIDENTIAL EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

 

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 ;

 


 

we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.

 


 

May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ...

 


 

3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ...

 


 

But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ...

 


 

Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....

 


 

snip...

 

It was not until . . . August 1990, that the result from the pig persuaded both SEAC and us to change our view and to take out of pig rations any residual infectivity that might have arisen from the SBOs.

 


 

4.303 The minutes of the meeting record that: It was very difficult to draw conclusions from one experimental result for what may happen in the field. However it would be prudent to exclude specified bovine offals from the pig diet. Although any relationship between BSE and the finding of a spongiform encephalopathy in cats had yet to be demonstrated, the fact that this had occurred suggested that a cautious view should be taken of those species which might be susceptible. The 'specified offals' of bovines should therefore be excluded from the feed of all species. 17

 


 

7 OF 10 LITTLE PIGGIES WENT ON TO DEVELOP BSE;

 

1: J Comp Pathol. 2000 Feb-Apr; 122(2-3): 131-43. Related Articles, Links Click here to read

 

The neuropathology of experimental bovine spongiform encephalopathy in the pig.

 

Ryder SJ, Hawkins SA, Dawson M, Wells GA. Veterinary Laboratories Agency Weybridge, Woodham Lane, New Haw, Addlestone, Surrey, KT15 3NB, UK.

 

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. The lesions consisted principally of severe neuropil vacuolation affecting most areas of the brain, but mainly the forebrain. In addition, some vacuolar change was identified in the rostral colliculi and hypothalamic areas of normal control pigs. PrP accumulations were detected immunocytochemically in the brains of BSE-infected animals. PrP accumulation was sparse in many areas and its density was not obviously related to the degree of vacuolation. The patterns of PrP immunolabelling in control pigs differed strikingly from those in the infected animals. PMID: 10684682 [PubMed - indexed for MEDLINE]

 


 

Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie.

 

Emerg Infect Dis. 2009 Aug; [Epub ahead of print]

 


 

Wednesday, July 06, 2011

 

Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation snip... In the US, feeding of ruminant by-products to ruminants is prohibited, but feeding of ruminant materials to swine, mink and poultry still occurs. Although unlikely, the potential for swine to have access to TSE-contaminated feedstuffs exists.

 

snip...

 


 

Wednesday, July 06, 2011

 

Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation (see tonnage of mad cow feed in commerce USA...tss)

 


 

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 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... snip... 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.

 

see full text and more transmission studies here ;

 


 

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

 


 

Friday, April 20, 2012

 

Ultrastructural findings in pigs experimentally infected with bovine spongiform encephalopathy agent

 


 

Wednesday, July 29, 2015

 

Porcine Prion Protein Amyloid or mad pig disease PSE

 


 

Monday, August 10, 2015

 

Detection and Quantification of beta-Amyloid, Pyroglutamyl A beta, and Tau in Aged Canines

 


 

Friday, August 7, 2015

 

Transgenic Mouse Bioassay: Evidence That Rabbits Are Susceptible to a Variety of Prion Isolates

 


 

PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS

 

*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***

 

O18

 

Zoonotic Potential of CWD Prions

 

Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1, Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy, 3Encore Health Resources, Houston, Texas, USA

 

***These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.***

 

P.105: RT-QuIC models trans-species prion transmission

 

Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover Prion Research Center; Colorado State University; Fort Collins, CO USA

 

Additionally, human rPrP was competent for conversion by CWD and fCWD.

 

***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.***

 


 

From: Terry S. Singeltary Sr.

 

Sent: Saturday, November 15, 2014 9:29 PM

 

To: Terry S. Singeltary Sr.

 

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

 

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE

 

R. G. WILL

 

1984

 

*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;

 

snip...

 


 

*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***

 


 

*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. These circumstances represent a potential threat to blood, blood products, and plasma supplies.

 


 

O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations

 

Emmanuel Comoy, Jacqueline Mikol, Val erie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France

 

Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods. *** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period, ***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold longe incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), ***is the third potentially zoonotic PD (with BSE and L-type BSE), ***thus questioning the origin of human sporadic cases. We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.

 

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

 

***thus questioning the origin of human sporadic cases...TSS

 

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

 


 

O35

 

J. Mikol1, S. Luccantoni-Freire1, E. Correia1, N. Lescoutra-Etchegaray1, V. Durand1, C. Dehen1, J.P. Deslys1, E. Comoy1

 

1Institute of Emerging Diseases and Innovative Therapies, Service of Prion Diseases, Atomic Energy Commission, 18 Route du Panorama 92265 Fontenayaux- Roses, France

 

E-mail: jacqueline.mikol@wanadoo.fr

 

Uncommon prion disease induced in macaque ten years after scrapie inoculation

 

Introduction: Bovine Spongiform Encephalopathy (BSE) is the single animal prion disease reputed to be zoonotic, inducing variant of Creutzfeldt-Jakob Disease (vCJD) in man, and therefore strongly conditioned the protective measures. Among different sources of animal prion diseases, we show here that after more than ten years of incubation, intracerebral injection of a sheep scrapie isolate can induce a prion disease in cynomolgus macaque, a relevant model of human situation towards several prion strains. Neuropathological studies showed classical and uncommon data.

 

Material and method: The cynomolgus macaque was intracerebrally exposed to a classical scrapie isolate issued from a naturally infected sheep flock. Upon onset of clinical signs, euthanasia was performed for ethical reasons. Classical methods of biochemistry and neuropathology were used.

 

Results: The three elements of the triad were present:

 

spongiosis was predominant in the cortex, the striatum, the cerebellum. Neuronal loss and gliosis were moderate.

 

The notable data were the following

 

(i) the brain was small, the atrophy involved mostly the temporal lobe in which axonal loss was histologically demonstrated

 

(ii) the spongiosis of the Purkinje cells was so intense that most of them were destroyed

 

(iii) there was a neuronal loss and a massive gliosis of the dorsomedialis nucleus of the thalamus

 

(iv) iron deposits were present in the lenticular nucleus. PrPres heavily distributed in the cortex, the basal ganglia and the cerebellum consisted in synaptic deposits and aggregates. Western Blot exhibited a type 1 PrPres in all parts of the brain.

 

Conclusion: We described here the successful transmission of a scrapie prion disease to a non-human primate after an extended incubation period, leading to a fatal, non-relapsing neurological disease with all the features of a prion disease. The cerebral lesional profile we observed was original in comparison to other animal prion diseases (c-BSE, L-type BSE, TME) we previously experimentally transmitted in this model.

 


 

Tuesday, December 16, 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

 


 

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

 


 

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 emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize 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 scrapie problem urgent if the sheep industry is not to suffer grievously.

 

snip...

 

76/10.12/4.6

 


 

Nature. 1972 Mar 10;236(5341):73-4.

 

Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).

 

Gibbs CJ Jr, Gajdusek DC.

 

Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0

 

Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)

 

C. J. GIBBS jun. & D. C. GAJDUSEK

 

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland

 

SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).

 


 


 


 


 

Friday, January 30, 2015

 

*** Scrapie: a particularly persistent pathogen ***

 


 

Thursday, March 26, 2015

 

Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein

 


 

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep

 

J. Virol. doi:10.1128/JVI.01578-10 Copyright (c) 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

 

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep.

 

Chris Plinston, Patricia Hart, Angela Chong, Nora Hunter, James Foster, Pedro Piccardo, Jean C. Manson, and Rona M Barron* Neuropathogenesis Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian, UK; Laboratory of Bacterial and TSE Agents, Food and Drug Administration, Rockville, MD, USA

 

* To whom correspondence should be addressed. Email: rona.barron@roslin.ed.ac.uk .

 

Abstract

 

The risk of transmission of ruminant transmissible spongiform encephalopathy (TSE) to humans was thought to be low due to the lack of association between sheep scrapie and incidence of human TSE. However a single TSE agent strain has been shown to cause both bovine spongiform encephalopathy (BSE) and human vCJD, indicating that some ruminant TSEs may be transmissible to humans. While the transmission of cattle BSE to humans in transgenic mouse models has been inefficient, indicating the presence of a significant transmission barrier between cattle and humans, BSE has been transmitted to a number of other species. Here we aimed to further investigate the human transmission barrier following passage of BSE in a sheep. Following inoculation with cattle BSE, gene targeted transgenic mice expressing human PrP showed no clinical or pathological signs of TSE disease. However following inoculation with an isolate of BSE that had been passaged through a sheep, TSE associated vacuolation and proteinase-K resistant PrP deposition were observed in mice homozygous for the codon 129-methionine PRNP gene. This observation may be due to higher titres of the BSE agent in sheep, or an increased susceptibility of humans to BSE prions following passage through a sheep. ***However these data confirm that, contrary to previous predictions, it is possible that a sheep prion may be transmissible to humans and that BSE from other species may be a public health risk.

 


 


 

BSE: TIME TO TAKE H.B. PARRY SERIOUSLY

 

If the scrapie agent is generated from ovine DNA and thence causes disease in other species, then perhaps, bearing in mind the possible role of scrapie in CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the notifiable disease. ...

 


 

Tuesday, August 4, 2015

 

FDA U.S. Measures to Protect Against BSE

 


 

Thursday, August 20, 2015 Doctor William J. Hadlow RIP

 

William J. Hadlow Dr. Hadlow (Ohio State ’48), 94, Hamilton, Montana, died June 20, 2015.

 


 


 

 

Terry S. Singeltary Sr.

 

 

Monday, August 17, 2015

FDA Says Endoscope Makers Failed to Report Superbug Problems OLYMPUS

Health Aug 17 2015, 2:38 pm ET

 

FDA Says Endoscope Makers Failed to Report Superbug Problems

 

by Associated Press

 

Federal regulators have uncovered new violations by the manufacturer of medical scopes recently linked to outbreaks of deadly "superbug" bacteria at U.S. hospitals.

 

Olympus Corp. failed to alert regulators to a cluster of 16 infections in patients who underwent procedures with the company's scope in 2012, according to a warning letter posted online Monday by the Food and Drug Administration. Olympus did not report the problems to the FDA until 2015, when the company was already under scrutiny for a more recent series of outbreaks.

 

Medical device manufacturers are required to report serious device problems to the FDA within 30 days of learning about them. The infections reported to the company involved a bacterial strain called pseudomonas, which can cause pneumonia, severe sickness and death in hospital patients.

 

Additionally, FDA inspectors found that the company has no standard procedure for promptly reporting serious problems with its devices, a requirement for medical device companies. The FDA inspected four company sites in Japan and the U.S. between March and April this year.

 

A spokesman for the Tokyo manufacturer said in a statement: "We are reviewing the FDA's warning letter so that we can provide the required response in a timely manner."

 

The FDA also posted warning letters Monday to two other scope manufacturers -- Hoya Corporation and Fujifilm Corporation -- citing problems with the testing, design and quality control of their devices. All of the letters are dated Aug. 12.

 

Olympus is the market leader for the devices in the U.S., accounting for about 85 percent of sales, according to the FDA.

 

Medical scopes from Olympus were linked to infections of antibiotic-resistant bacteria at two separate Los Angeles hospitals earlier this year. Hospital staff at Cedars-Sinai and UCLA medical centers said the infections occurred despite following Olympus' instructions for cleaning the devices, known as duodendoscopes.

 

The specialized scopes consist of a flexible fiber-optic tube that is inserted down the throat into the stomach and small intestine to diagnose and treat conditions in the pancreas and bile ducts. The tip of the scope includes moveable instruments designed to remove tumors, gallstones and other blockages.

 

This complex design also makes the instruments difficult to clean. Bodily fluids and other debris can stay in the device's joints and crevices even after cleaning and disinfection.

 

Since 2013, there have been eight outbreaks of antibiotic-resistant bacteria linked to the devices at U.S. hospitals, according to government figures.

 

The FDA previously disclosed that Olympus did not seek federal clearance for the latest version of its duodenoscope, which it began selling in 2010.

 

Despite these problems the FDA has repeatedly said the devices should stay on the market because they fill an important need in a half-million procedures performed each year.

 


 

 

I told Olympus 15 years ago about these risk factors from endoscopy equipment, disinfection, even spoke with the Doctor at Olympus, this was back in 1999. I tried to tell them that they were exposing patients to dangerous pathogens such as the CJD TSE prion, because they could not properly clean them. even presented my concern to a peer review journal GUT, that was going to publish, but then it was pulled by Professor Michael Farthing et al... see ;

 

 some old history on Endoscopy equipment and CJD TSE Prion concerns ;

 

 1999

 

 Subject: CJD * Olympus Endoscope

 

 Date: Sun, 10 Oct 1999 16:41:49 –0500

 

 From: "Terry S. Singeltary Sr."

 

 To: GOLDSS@...

 

 Dear Dr. Goldstine,

 

 Hello Sir, I understand that Olympus has issued a letter to the medical institutions and the CDC, about the dangers of _not_ being able to decontaminate the instruments (endoscope's) via modern autoclaving techniques (boil 3 minutes in 3% SDS or another ionic detergent and autoclave for 1 hour at 134 degrees C). I understand that; "Olympus" has issued a warning, _not_ to attempt to decontaminate the instrument, that they are instructed to destroy them.

 

 (very very wise move);

 

 Please Sir, it is imminent that I receive a copy of this letter, it is very important. This could lead to other company's following through, and lead to awareness of the potential health threats from human T.S.E.'s and the risks through surgery, and not just from endoscopes. It would be most appreciated, if you could send a copy of this document to;

 

 Fax: xxxxx

 

 I look forward, to hearing back from you....

 

 Many Thanks,

 

 Terry S. Singeltary Sr./ Mom DOD 12-14-97 hvCJD

 

 Subject: Re: CJD * Olympus Endoscope

 

 Date: Tue, 12 Oct 1999 15:57:03 –0500

 

 From: "Terry S. Singeltary Sr."

 

 To: GOLDSS@...

 

 References: 1

 

 Dear Mr. Goldstine, Hello again, I hope the CDC has not changed your mind, since our phone call, about sending me the information, in which we spoke of. I am still waiting for the information, re-fax. Someone had told me, you would not send me the information, but I told them you would, due to the importance of it pertaining to public safety, and the fact, you are a Doctor. I hope you don't disappoint me, and the rest of the public, and hide the facts, as the CDC and NIH have for years. Olympus can be part of the Truth, or you can be part of the cover-up. We are going to find out, sooner or later.

 

 I already know, as do many more.

 


 

 Still waiting,

 

Kind Regards,

 

 Terry S. Singeltary Sr.

 

"Terry S. Singeltary Sr." wrote:

 

Dear Dr. Goldstine,

 

 Hello Sir, I understand that Olympus has issued a letter to the medical institutions and the CDC, about the dangers of _not_ being able to decontaminate the instruments (endoscope's) via modern autoclaving techniques (boil 3 minutes in 3% SDS or another ionic detergent and autoclave for 1 hour at 134 degrees C). I understand that; "Olympus" has issued a warning, _not_ to attempt to decontaminate the instrument, that they are instructed to destroy them.

 

 (very very wise move);

 

 Please Sir, it is imminent that I receive a copy of this letter, it is very important. This could lead to other company's following through, and lead to awareness of the potential health threats from human T.S.E.'s and the risks through surgery, and not just from endoscopes. It would be most appreciated, if you could send a copy of this document to;

 

 Fax: xxxxxxx

 

 I look forward, to hearing back from you....

 

 Many Thanks,

 

 Terry S. Singeltary Sr./ Mom DOD 12-14-97 hvCJD

 

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

 

 Something I submitted to GUT previously;

 

 Subject: Re: gutjnl_el;21 Terry S. Singeltary Sr. (3 Jun 2002) "CJDs (all human TSEs) and Endoscopy Equipment"

 

 Date: Thu, 20 Jun 2002 16:19:51 –0700

 

 From: "Terry S. Singeltary Sr."

 

 To: Professor Michael Farthing

 

 CC: lcamp@BMJgroup.com

 

References: 001501c21099$5c8bc620$7c58d182@mfacdean1.cent.gla.ac.uk

 

Greetings again Professor Farthing and BMJ,

 

I was curious why my small rebuttal of the article described below was not listed in this month's journal of GUT? I had thought it was going to be published, but I do not have full text access. Will it be published in the future? Regardless, I thought would pass on a more lengthy rebuttal of mine on this topic, vCJD vs sCJDs and endoscopy equipment. I don't expect it to be published, but thought you might find it interesting, i hope you don't mind and hope to hear back from someone on the questions I posed...

 

Here is my short submission I speak of, lengthy one to follow below that:

 

Date submitted: 3 Jun 2002

 

>> eLetter ID: gutjnl_el;21

 

>> >> Gut eLetter for Bramble and Ironside 50 (6): 888

 

>> >>Name: Terry S. Singeltary Sr.

 

>>Email: flounder@wt.net

 

>>Title/position: disabled {neck injury}

 

>>Place of work: CJD WATCH

 

>>IP address: 216.119.162.85

 

>>Hostname: 216-119-162-85.ipset44.wt.net

 

>>Browser: Mozilla/5.0 (Windows; U; Win98; en-US; rv:0.9.4)

 

>>Gecko/20011019 Netscape6/6.2

 

>> >>Parent ID: 50/6/888

 

>>Citation:

 

>> Creutzfeldt-Jakob disease: implications for gastroenterology

 

>> M G Bramble and J W Ironside

 

>> Gut 2002; 50: 888-890 (Occasional viewpoint)

 


 


 

 >>-----------------------------------------------------------------

 

>>"CJDs (all human TSEs) and Endoscopy Equipment"

 

>>-----------------------------------------------------------------

 

 regarding your article;

 

 Creutzfeldt-Jakob disease: implications for gastroenterology

 

 >>I belong to several support groups for victims and relatives

 

>>of CJDs. Several years ago, I did a survey regarding

 

>>endoscopy equipment and how many victims of CJDs have

 

>>had any type of this procedure done. To my surprise, many

 

>>victims had some kind of endoscopy work done on them.

 

>>As this may not be a smoking gun, I think it should

 

>>warrant a 'red flag' of sorts, especially since data now

 

>>suggests a substantial TSE infectivity in the gut wall

 

>>of species infected with TSEs. If such transmissions

 

>>occur, the ramifications of spreading TSEs from

 

>>endoscopy equipment to the general public would be

 

>>horrible, and could potential amplify the transmission

 

>>of TSEs through other surgical procedures in that

 

>>persons life, due to long incubation and sub-clinical

 

>>infection. Science to date, has well established

 

>>transmission of sporadic CJDs with medical/surgical

 

>>procedures.

 

 Terry S. Singeltary Sr. >>CJD WATCH

 

 Again, many thanks, Kindest regards,

 

 Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518 flounder@wt.net CJD WATCH

 

 [scroll down past article for my comments]

 

 snip...

 

 were not all CJDs, even nvCJD, just sporadic, until proven otherwise?

 

 Terry S. Singeltary Sr., P.O. BOX 42, Bacliff, Texas 77518 USA

 


 

Professor Michael Farthing wrote: Louise Send this to Bramble (author) for a comment before we post. Michael

 

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

 

snip... see full text ;

 

 2003

 

 Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al

 

 Evidence For CJD/TSE Transmission Via Endoscopes

 

 From Terry S. Singletary, Sr flounder@wt.net 1-24-3

 


 

Monday, December 26, 2011

 

Prion Uptake in the Gut: Identification of the First Uptake and Replication Sites

 


 

 Friday, August 10, 2012

 

 Incidents of Potential iatrogenic Creutzfeldt-Jakob disease (CJD) biannual update (July 2012)

 


 

 SNIP...

 

 see more history here ;

 

 OLYMPUS ENDOSCOPY CJD

 


 


 

Tuesday, May 26, 2015

 

Minimise transmission risk of CJD and vCJD in healthcare settings

 

Last updated 15 May 2015

 


 

Saturday, February 21, 2015

 

Design of Endoscopic Retrograde Cholangiopancreatography (ERCP) Duodenoscopes May Impede Effective Cleaning: FDA Safety Communication

 


 

 Thursday, January 22, 2015

 

 *** Transmission properties of atypical Creutzfeldt-Jakob disease: a clue to disease etiology? ***

 


 


 

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

 

Tuesday, August 4, 2015

 

*** FDA U.S. Measures to Protect Against BSE ***

 


 

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

 

*** now, from all the consumption and exposure above, now think iatrogenic cjd tse prion at a hospital near you, what if?

 

Thursday, August 13, 2015

 

Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

 


 

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.

 

Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

 

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.

 


 

SOURCE REFERENCES

 

The infectious agents responsible for transmissible spongiform encephalopathy (TSE) are notoriously resistant to most physical and chemical methods used for inactivating pathogens, including heat. It has long been recognized, for example, that boiling is ineffective and that higher temperatures are most efficient when combined with steam under pressure (i.e., autoclaving). As a means of decontamination, dry heat is used only at the extremely high temperatures achieved during incineration, usually in excess of 600°C. It has been assumed, without proof, that incineration totally inactivates the agents of TSE, whether of human or animal origin.

 


 

Prion Infected Meat-and-Bone Meal Is Still Infectious after Biodiesel Production

 

Histochemical analysis of hamster brains inoculated with the solid residue showed typical spongiform degeneration and vacuolation. Re-inoculation of these brains into a new cohort of hamsters led to onset of clinical scrapie symptoms within 75 days, suggesting that the specific infectivity of the prion protein was not changed during the biodiesel process. The biodiesel reaction cannot be considered a viable prion decontamination method for MBM, although we observed increased survival time of hamsters and reduced infectivity greater than 6 log orders in the solid MBM residue. Furthermore, results from our study compare for the first time prion detection by Western Blot versus an infectivity bioassay for analysis of biodiesel reaction products. We could show that biochemical analysis alone is insufficient for detection of prion infectivity after a biodiesel process.

 


 

Detection of protease-resistant cervid prion protein in water from a CWD-endemic area

 

The data presented here demonstrate that sPMCA can detect low levels of PrPCWD in the environment, corroborate previous biological and experimental data suggesting long term persistence of prions in the environment2,3 and imply that PrPCWD accumulation over time may contribute to transmission of CWD in areas where it has been endemic for decades. This work demonstrates the utility of sPMCA to evaluate other environmental water sources for PrPCWD, including smaller bodies of water such as vernal pools and wallows, where large numbers of cervids congregate and into which prions from infected animals may be shed and concentrated to infectious levels.

 


 

A Quantitative Assessment of the Amount of Prion Diverted to Category 1 Materials and Wastewater During Processing

 

Keywords:Abattoir;bovine spongiform encephalopathy;QRA;scrapie;TSE

 

In this article the development and parameterization of a quantitative assessment is described that estimates the amount of TSE infectivity that is present in a whole animal carcass (bovine spongiform encephalopathy [BSE] for cattle and classical/atypical scrapie for sheep and lambs) and the amounts that subsequently fall to the floor during processing at facilities that handle specified risk material (SRM). BSE in cattle was found to contain the most oral doses, with a mean of 9864 BO ID50s (310, 38840) in a whole carcass compared to a mean of 1851 OO ID50s (600, 4070) and 614 OO ID50s (155, 1509) for a sheep infected with classical and atypical scrapie, respectively. Lambs contained the least infectivity with a mean of 251 OO ID50s (83, 548) for classical scrapie and 1 OO ID50s (0.2, 2) for atypical scrapie. The highest amounts of infectivity falling to the floor and entering the drains from slaughtering a whole carcass at SRM facilities were found to be from cattle infected with BSE at rendering and large incineration facilities with 7.4 BO ID50s (0.1, 29), intermediate plants and small incinerators with a mean of 4.5 BO ID50s (0.1, 18), and collection centers, 3.6 BO ID50s (0.1, 14). The lowest amounts entering drains are from lambs infected with classical and atypical scrapie at intermediate plants and atypical scrapie at collection centers with a mean of 3 × 10−7 OO ID50s (2 × 10−8, 1 × 10−6) per carcass. The results of this model provide key inputs for the model in the companion paper published here.

 


 

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

 

*** Infectious agent of sheep scrapie may persist in the environment for at least 16 years ***

 

Gudmundur Georgsson1, Sigurdur Sigurdarson2 and Paul Brown3

 


 


 

Friday, January 30, 2015

 

Scrapie: a particularly persistent pathogen

 


 


 


 


 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

 

Terry S. Singeltary, Sr Bacliff, Tex

 

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

 


 

26 March 2003

 

Terry S. Singeltary, retired (medically) CJD WATCH

 

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

 


 

2 January 2000

 

British Medical Journal

 

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

 


 

15 November 1999

 

British Medical Journal

 

vCJD in the USA * BSE in U.S.

 


 

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

 

Singeltary comment Alzheimer’s, transmission, what if ???

 


 

Friday, January 10, 2014

 

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???

 


 


 

Monday, November 3, 2014

 

USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014

 

National Prion Disease Pathology Surveillance Center Cases Examined1 (October 7, 2014)

 

***6 Includes 11 cases in which the diagnosis is pending, and 19 inconclusive cases;

 

***7 Includes 12 (11 from 2014) cases with type determination pending in which the diagnosis of vCJD has been excluded.

 

***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob disease (sCJD),

 

***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr)

 

***and 21 cases of sporadic Fatal Insomnia (sFI).

 


 


 

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

 


 

Thursday, July 24, 2014

 

*** Protocol for further laboratory investigations into the distribution of infectivity of Atypical BSE SCIENTIFIC REPORT OF EFSA New protocol for Atypical BSE investigations

 


 

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 ;

 


 

ruminant feed ban for cervids in the United States ?

 

31 Jan 2015 at 20:14 GMT

 


 

Saturday, January 24, 2015

 

Bovine Spongiform Encephalopathy: Atypical Pros and Cons

 


 

Saturday, January 31, 2015

 

RAPID ADVICE 17-2014 : Evaluation of the risk for public health of casings in countries with a “negligible risk status for BSE” and on the risk of modification of the list of specified risk materials (SRM) with regard to BSE

 


 

Thursday, February 19, 2015

 

Inspections Circumvented for Condemned Cows STATEMENT OF THE HONORABLE PHYLLIS K. FONG INSPECTOR GENERAL

 


 

Tuesday, February 17, 2015

 

Could we spot the next BSE?, asks BVA President

 


 

> Could we spot the next BSE?

 

we have not spotted all the cases the first time around. with Nations like the United States and Canada, organizations like the USDA, OIE, and WTO et al, it was never about ‘spotting’ all the BSE TSE prion cases, it was more about how not to find them. the triple BSE mad cow firewall, was and still is, nothing but ink on paper. ...please see facts ;

 

Saturday, February 14, 2015

 

Canadian Food Inspection Agency Confirms Bovine Spongiform Encephalopathy (BSE) in Alberta

 


 

Tuesday, February 10, 2015

 

Alberta Canada First case of chronic wasting disease found in farm elk since 2002

 


 

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...

 


 

PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS

 

THANK YOU PRION 2015 TAYLOR & FRANCIS, Professor Chernoff, and Professor Aguzzi et al, for making these PRION 2015 Congressional Poster and Oral Abstracts available freely to the public. ...Terry S. Singeltary Sr.

 

O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations

 

Emmanuel Comoy, Jacqueline Mikol, Val erie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France

 

Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods. We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period, with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold longe incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), is the third potentially zoonotic PD (with BSE and L-type BSE), ***thus questioning the origin of human sporadic cases. We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.

 

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

 

*** Scrapie, as recently evoked in humanized mice (Cassard, 2014), is the third potentially zoonotic PD (with BSE and L-type BSE), ***thus questioning the origin of human sporadic cases.

 

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

 


 

PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS

 

*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***

 

O18

 

Zoonotic Potential of CWD Prions

 

Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1, Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy, 3Encore Health Resources, Houston, Texas, USA

 

Chronic wasting disease (CWD) is a widespread and expanding prion disease in free-ranging and captive cervid species in North America. The zoonotic potential of CWD prions is a serious public health concern. Current literature generated with in vitro methods and in vivo animal models (transgenic mice, macaques and squirrel monkeys) reports conflicting results. The susceptibility of human CNS and peripheral organs to CWD prions remains largely unresolved. In our earlier bioassay experiments using several humanized transgenic mouse lines, we detected protease-resistant PrPSc in the spleen of two out of 140 mice that were intracerebrally inoculated with natural CWD isolates, but PrPSc was not detected in the brain of the same mice. Secondary passages with such PrPSc-positive CWD-inoculated humanized mouse spleen tissues led to efficient prion transmission with clear clinical and pathological signs in both humanized and cervidized transgenic mice. Furthermore, a recent bioassay with natural CWD isolates in a new humanized transgenic mouse line led to clinical prion infection in 2 out of 20 mice. These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.

 

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

 

***These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.***

 

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

 

P.105: RT-QuIC models trans-species prion transmission

 

Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover Prion Research Center; Colorado State University; Fort Collins, CO USA

 

The propensity for trans-species prion transmission is related to the structural characteristics of the enciphering and heterologous PrP, but the exact mechanism remains mostly mysterious. Studies of the effects of primary or tertiary prion protein structures on trans-species prion transmission have relied primarily upon animal bioassays, making the influence of prion protein structure vs. host co-factors (e.g. cellular constituents, trafficking, and innate immune interactions) difficult to dissect. As an alternative strategy, we used real-time quakinginduced conversion (RT-QuIC) to investigate trans-species prion conversion.

 

To assess trans-species conversion in the RT-QuIC system, we compared chronic wasting disease (CWD) and bovine spongiform encephalopathy (BSE) prions, as well as feline CWD (fCWD) and feline spongiform encephalopathy (FSE). Each prion was seeded into each host recombinant PrP (full-length rPrP of white-tailed deer, bovine or feline). We demonstrated that fCWD is a more efficient seed for feline rPrP than for white-tailed deer rPrP, which suggests adaptation to the new host.

 

Conversely, FSE maintained sufficient BSE characteristics to more efficiently convert bovine rPrP than feline rPrP. Additionally, human rPrP was competent for conversion by CWD and fCWD. ***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.

 

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

 

***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.***

 

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

 


 

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...

 


 

Thursday, January 15, 2015

 

41-year-old Navy Commander with sporadic Creutzfeldt–Jakob disease CJD TSE Prion: Case Report

 


 

Saturday, January 17, 2015

 

*** Becky Lockhart 46, Utah’s first female House speaker, dies diagnosed with the extremely rare Creutzfeldt-Jakob disease

 


 

FDA SCIENCE BOARD TO THE FOOD AND DRUG ADMINISTRATION BOVINE HEPARIN Wednesday, June 4, 2014

 

SCIENCE BOARD TO THE FOOD AND DRUG ADMINISTRATION

 

Wednesday, June 4, 2014

 

FDA White Oak Campus

 

Building 31, Room 1503

 

10903 New Hampshire Avenue

 

Silver Spring, Maryland 20993

 

The meeting was convened at 8:32 a.m., Russ ALTMAN,

 

snip...

 

So it has been shown -- so how would you -- there is a risk, though. There is a theoretical risk of any herd or whatever having contamination. So how can you mitigate even that very small risk? It has been shown that the existing manufacturing processes could remove or inactive BSE agents if present. This is because they're an extremely robust extraction under very harsh conditions.SCIENCE BOARD TO THE FOOD AND DRUG ADMINISTRATION

 

The FDA has guidelines regarding TSEs that can be applied to heparin, and these generally were developed by CBER and include control of animal sources, which obviously is critical, selection of the type of tissue used, incorporation of risk-reduction steps into the production process. And, of course, this is typical for any animal source material or even human source material that we use in other people, and so that's what we'd like to talk about today.

 

UNIDENTIFIED SPEAKER: Janet, what's a TSE?

 

DR. WOODCOCK: Pardon me?

 

UNIDENTIFIED SPEAKER: What is a TSE?

 

snip...see ;

 

Sunday, February 08, 2015

 

FDA SCIENCE BOARD TO THE FOOD AND DRUG ADMINISTRATION BOVINE HEPARIN BSE CJD TSE PRION Wednesday, June 4, 2014

 


 

From: Terry S. Singeltary Sr.

 

Sent: Saturday, November 15, 2014 9:29 PM

 

To: Terry S. Singeltary Sr.

 

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

 

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE

 

R. G. WILL

 

1984

 

*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;

 

snip...

 


 

Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle

 

Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

 

snip...

 

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...

 


 

In Confidence - Perceptions of unconventional slow virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells

 

3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. ...

 


 

human cwd will NOT look like nvCJD. in fact, see ;

 

*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***

 


 

Thursday, July 30, 2015

 

*** Professor Lacey believes sporadic CJD itself originates from a cattle infection number of cattle farmers falling victim to Creutzfeld-Jakob Disease is much too high to be mere chance

 


 

 

TEXAS CWD TSE PRION IN CERVID DEER

 

 

where is the official announcement of this 4th case (or more cases), by the TAHC and or the TPWD?

 

why is the media having to do the TAHC and or the TPWD job, and reporting this critical information to the public domain?

 

of course, it took 7+ months and an act of Congress to finally confirm and announce to the public that last mad cow in Texas as well. political science as usual in Texas.

 

TAHC TPWD CATERING PROTECTING THE INDUSTRY AT ALL COST, INCLUDING HUMAN AND ANIMAL HEALTH, TO HELL WITH THE PUBLIC. out of sight, out of mind...not!

 

a review since the TEXAS 84th Legislature commencing this January, deer breeders are expected to advocate for bills that will seek to further deregulate their industry...

 

Sunday, December 14, 2014

 

TEXAS 84th Legislature commencing this January, deer breeders are expected to advocate for bills that will seek to further deregulate their industry

 


 

Tuesday, December 16, 2014

 

Texas 84th Legislature 2015 H.R. No. 2597 Kuempel Deer Breeding Industry TAHC TPWD CWD TSE PRION

 


 

Wednesday, July 01, 2015

 

TEXAS Chronic Wasting Disease Detected in Medina County Captive Deer

 


 

Thursday, July 09, 2015

 

TEXAS Chronic Wasting Disease (CWD) Herd Plan for Trace-Forward Exposed Herd with Testing of Exposed Animals

 


 

Tuesday, July 14, 2015

 

Texas Parks and Wildlife Commission Special Meeting Thursday on Chronic Wasting Disease CWD

 


 

Tuesday, July 21, 2015

 

*** Texas CWD Medina County Herd Investigation Update July 16, 2015 ***

 


 

Thursday, August 06, 2015

 

WE HAVE LOST TEXAS TO CWD TASK FORCE CATERING TO INDUSTRY

 


 

Friday, August 07, 2015

 

Texas CWD Captive, and then there were 4 ?

 


 

*** Danger of Canned Hunting Indiana Wildlife ***

 


 

I spoke with MASTER Obi-Wan Kenobi about all this. see Obi’s reply ;

 

GRASSHOPPER TO MASTER Obi-Wan Kenobi CWD TEXAS CAPTIVE

 

‘’I see no evidence whatsoever here for a genetic link. The numbers are statistically insignificant and co-housing in contaminated facilities would strongly predispose to this outcome.’’

 

‘’if the father did have a bad amino acid variant allele, it would be diluted to heterozygozity with a normal gene in the half the four descendants since the father never would have survived to breeding age with two bad copies. sort of like met/val at position 129 in humans with greatly lengthened incubation times if prnp is propagating at all. Mutations such as repeat expansion leading to positive dominant infection have not been documented in cervids.’’

 

On 09 08 15, at 9:09 AM, Terry S. Singeltary Sr. wrote: ‘’

 

cwd Texas and then there were 4?

 

genetic link ?

 

He said 42 deer have been killed and tested since July 28, and three additional positives were the result.

 

***He added that all four deer confirmed to have the disease were males from the same father, which leads him to believe the problem is genetic.

 

snip...

 


 

HAVE YOU BEEN THUNDERSTRUCK ?

 


 

on my mothers grave, when I wrote up the ‘have you been thunderstruck’ about super ovulation, and what if? I had no clue about all this. hell, I had it in draft for a month. then a week or so later, bam.

 

it’s been like this all along Obi-Wan Kenobi.

 

every shooting pen owner in Texas are praying this familial cwd is the going thing now.

 

no link to sperm.

 

no link to super ovulation.

 

they sell those sperm straws like the meth heads and crack heads sell meth and crack.

 

genetic link with four deer in the same herd, same father ?

 

familial ?

 

sperm ?

 

super ovulation ?

 

what say ye master ?

 

grasshopper

 

Friday, August 07, 2015

 

Texas CWD Captive, and then there were 4 ?

 


 

PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS

 

*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***

 

O18

 

Zoonotic Potential of CWD Prions

 

Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1, Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy, 3Encore Health Resources, Houston, Texas, USA

 

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***These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.***

 

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P.105: RT-QuIC models trans-species prion transmission

 

Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover Prion Research Center; Colorado State University; Fort Collins, CO USA

 

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***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.***

 

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From: Terry S. Singeltary Sr.

 

Sent: Saturday, November 15, 2014 9:29 PM

 

To: Terry S. Singeltary Sr.

 

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

 

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE

 

R. G. WILL

 

1984

 

*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;

 

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*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***

 


 

*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. These circumstances represent a potential threat to blood, blood products, and plasma supplies.

 


 

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

 

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Tuesday, May 26, 2015

 

*** Minimise transmission risk of CJD and vCJD in healthcare settings ***

 

Last updated 15 May 2015

 


 

 

NOW THINK EXPOSURE THERE FROM ALL THE ABOVE, AT A HOSPITAL NEAR YOU, what if ???
 

 

Terry S. Singeltary Sr.