Wednesday, December 16, 2020

Expanding spectrum of prion diseases Prusiner et al

Expanding spectrum of prion diseases

Jacob I. Ayers; Nick A. Paras; Stanley B. Prusiner 

Emerg Top Life Sci (2020) 4 (2): 155–167.


Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once scrapie was transmitted to rodents, it was discovered that the scrapie pathogen resisted inactivation by procedures that modify nucleic acids. Eventually, this novel pathogen proved to be a protein of 209 amino acids, which is encoded by a chromosomal gene. After the absence of a nucleic acid within the scrapie agent was established, the mechanism of infectivity posed a conundrum and eliminated a hypothetical virus. Subsequently, the infectious scrapie prion protein (PrPSc) enriched for β-sheet was found to be generated from the cellular prion protein (PrPC) that is predominantly α-helical. The post-translational process that features in nascent prion formation involves a templated conformational change in PrPC that results in an infectious copy of PrPSc. Thus, prions are proteins that adopt alternative conformations, which are self-propagating and found in organisms ranging from yeast to humans. Prions have been found in both Alzheimer's (AD) and Parkinson's (PD) diseases. Mutations in APP and α-synuclein genes have been shown to cause familial AD and PD. Recently, AD was found to be a double prion disorder: both Aβ and tau prions feature in this ND. Increasing evidence argues for α-synuclein prions as the cause of PD, multiple system atrophy, and Lewy body dementia.

Keywords:α-synuclein, amyloid beta, neurodegeneration, prion, tau proteins 

Subjects:Aging, Molecular Bases of Health & Disease, Neuroscience



11. Arguments for Alzheimer’s and Parkinson’s diseases caused by prions

Stanley B. Prusiner

Institute of Neurodegenerative Diseases, and Professor of Neurology and Biochemistry, University of California San Francisco

ABSTRACT

Arguments for Alzheimer’s (AD) and Parkinson’s diseases (PD) being caused by prions continue to advance with new evidence. Findings in the brains of deceased AD patients argue that both Aβ and tau prions can be demonstrated by bioassays in cultured cells as well as in transgenic (Tg) mice. Likewise, studies of the brains of deceased MSA patients have been found to contain α-synuclein prions by bioassays in cultured cells and Tg mice. Conversely, the brains of AD patients do not contain α-synuclein prions, and the brains of MSA patients do not contain Aβ or tau prions. Additionally, while the brains of patients who died of either progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) contained tau prions, neither Aβ nor α-synuclein prions were detectable. Merely measuring the levels of Aβ, tau, and α-synuclein appears to give misleading information about the etiology and pathogenesis of neurodegenerative diseases (NDs). From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases. Our findings argue that changes in the conformations of Aβ, tau, and α-synuclein underlie the acquisition of prion infectivity in all of these NDs.


From: "Terry S. Singeltary Sr." <flounder9@verizon.net> 
Date: September 19, 2019 at 2:15:17 PM CDT 
To:
Subject: Arguments for Alzheimer’s and Parkinson’s diseases caused by prions Stanley B. Prusiner

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

Singeltary Comment at very bottom of this Nature publishing;

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.

Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.

where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?

we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.


Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

>>> The only tenable public line will be that "more research is required’’ <<< 

>>> possibility on a transmissible prion remains open<<< 

O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ? 

Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015) 

snip...see full Singeltary Nature comment here; 

Alzheimer's disease

let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease... 

Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy





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

*** Singeltary comment PLoS *** 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ? 

Posted by flounder on 05 Nov 2014 at 21:27 GMT 


IN CONFIDENCE

5 NOVEMBER 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. 

There are also results to be made available shortly 

(1) concerning a farmer with CJD who had BSE animals, 

(2) on the possible transmissibility of Alzheimer’s and 

(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]




re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)


Singeltary Comment at very bottom of this Nature publishing;

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.

Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.

where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?

we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.

That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.

The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? 

who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.

That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.

Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express

if not for the journalist, the layperson would not know about these important findings.

where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?

when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.

to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.

so, who makes that final decision, and how many more decades do we have to wait?

the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?

Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.

FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.

in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.

greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.

my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.

I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...

[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer's and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]

Singeltary Comment at very bottom of this Nature publishing;


THURSDAY, FEBRUARY 7, 2019 

In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology


Subject: CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?

REVIEW

***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***

***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<*** 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***

***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<*** 

***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***

Saturday, February 2, 2019 

CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?


Friday, January 29, 2016

Synucleinopathies: Past, Present and Future, iatrogenic, what if?



FRIDAY, JANUARY 10, 2014

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

Greetings Friends, Neighbors, and Colleagues,

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

Confucius is confused again.

I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.

what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???

it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.

sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.

I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.

I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.

by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?

this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.

the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).


the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.


again, sporadic and familial is a red herring, in my opinion.

also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.

snip...see full text;

Friday, January 10, 2014

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


MONDAY, APRIL 8, 2019 

Studies Further Support Transmissibility of Alzheimer Disease–Associated Proteins


P1-187 AGED CATTLE BRAIN DISPLAYSALZHEIMER’S-LIKE PATHOLOGY THATCAN BE PROPAGATED IN A PRION-LIKE MANNER

Ines Moreno-Gonzalez1, George A. Edwards, III,1, Nazaret Gamez Ruiz1,Priyadarshini Peter1, Rodrigo Morales1, Mercedes Marquez2, Marti Pumarola2,Claudio Soto1,1The University of Texas Health Science Center at Houston, Houston, TX, USA;2Animal Tissue Bank of Catalunya (BT A C), Universidad Autonoma de Barcelona, Barcelona, Spain . Contact e-mail: Ines.M.Gonzalez@uth.tmc.edu

Background: Amyloid beta (Ab) and hyperphosphorylated tau(ptau) are the proteins undergoing misfolding in Alzheimer’s dis-ease (AD). Recent studies have shown that brain homogenates rich in amyloid aggregates are able to seed the misfolding and ag-gregation of amyloidogenic proteins inducing an earlier onset of the disease in mouse models of AD. This seeding behavior is analogous to the disease transmission by propagation of prion protein misfold-ing observed in prion diseases. Prion diseases can be transmitted across species by inoculation of the misfolded prion protein from one specie into an appropriate host. For example, material from cattle affected by bovine spongiform encephalopathy can be propagate in humans inducing variant Creutzfeldt-Jakob disease.

Methods: In this study, we analyzed the presence of AD-related protein aggre-gates in the brain of old cows and investigated whether these aggregates are capable to induce pathology in animal models of AD.

Results: We observed that many of the typical hallmarks detected in human AD brains, including Ab aggregates and tangles, were present in cow brains. When cattle tissue containing Ab aggregates or ptau were intracerebrally inoculated into APP/PS1 or P301Smice, we observed an acceleration of brain misfolded protein deposition and faster cognitive impairment compared to controls. How-ever, when the material was orally inoculated, no effect was observed.

Conclusions: These results may contribute to uncover a previously unsuspected etiology surrounding some cases of spo-radic AD. However, the early and controversial stage of the field of prion-like transmission in non-prion diseases added to the artificial nature of the animal models utilized for these studies, indicate that extrapolation of the results to humans should not be done without further experiments.


P75 Determining transmissibility and proteome changes associated with abnormal bovine prionopathy 

Dudas S (1,2), Seuberlich T (3), Czub S (1,2) 

In prion diseases, it is believed that altered protein conformation encodes for different pathogenic strains. Currently 3 different strains of bovine spongiform encephalopathy (BSE) are confirmed. Diagnostic tests for BSE are able to identify animals infected with all 3 strains, however, several diagnostic laboratories have reported samples with inconclusive results which are challenging to classify. It was suggested that these may be novel strains of BSE; to determine transmissibility, brain material from index cases were inoculated into cattle. 

In the first passage, cattle were intra-cranially challenged with brain homogenate from 2 Swiss animals with abnormal prionopathy. The challenged cattle incubated for 3 years and were euthanized with no clinical signs of neurologic disease. Animals were negative when tested on validated diagnostic tests but several research methods demonstrated changes in the prion conformation in these cattle, including density gradient centrifugation and immunohistochemistry. Currently, samples from the P1 animals are being tested for changes in protein levels using 2-D Fluorescence Difference Gel Electrophoresis (2D DIGE) and mass spectrometry. It is anticipated that, if a prionopathy is present, this approach should identify pathways and targets to decipher the source of altered protein conformation. In addition, a second set of cattle have been challenged with brain material from the first passage. Ideally, these cattle will be given a sufficient incubation period to provide a definitive answer to the question of transmissibility. 

=====prion 2018=== 

Prion Conference 2018

Posted by at No comments:

Wednesday, February 12, 2020

The role of prion‐like mechanisms in neurodegenerative diseases

Invited Review: The role of prion‐like mechanisms in neurodegenerative diseases

Z. Jaunmuktane S. Brandner

First published:23 December 2019 https://doi.org/10.1111/nan.12592

Abstract

The prototype of transmissible neurodegenerative proteinopathies is prion diseases, characterized by aggregation of abnormally folded conformers of the native prion protein. A wealth of mechanisms has been proposed to explain the conformational conversion from physiological protein into misfolded, pathological form, mode of toxicity, propagation from cell‐to‐cell and regional spread. There is increasing evidence that other neurodegenerative diseases, most notably Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α‐synuclein), frontotemporal dementia (TDP43, tau or FUS) and motor neurone disease (TDP43), exhibit at least some of the misfolded prion protein properties. In this review, we will discuss to what extent each of the properties of misfolded prion protein is known to occur for Aβ, tau, α‐synuclein and TDP43, with particular focus on self‐propagation through seeding, conformational strains, selective cellular and regional vulnerability, stability and resistance to inactivation, oligomers, toxicity and summarize the most recent literature on transmissibility of neurodegenerative disorders.

snip...

Transmission between humans

Transmission between humans was first described in prion diseases: kuru was a major epidemic of human prion disease in the people of the Fore linguistic group in the Eastern Highlands of Papua New Guinea. It was transmitted through the practice of engaging in the consumption of dead relatives as a mark of respect and mourning (transumption) 136. Iatrogenic transmission of prion disease was first reported in 1974 in a patient who had received a cadaveric corneal transplant from a donor who, in retrospect, had been identified as having died of CJD 137. Subsequently, the transmission of CJD through cadaver‐derived hormones, most prominently growth hormone (GH), and contaminated dural transplants during neurosurgical (and surgical) procedures have been reported. This resulted in a ban on the use of human cadaver‐sourced hormones in 1985 and cadaver‐derived dural transplants in the 1990s.

For many decades, it was thought that misfolded proteins other than abnormal prion protein do not transmit between humans. This assumption was based on the lack of epidemiological evidence and the absence of any overt clinical neurological manifestations in primate studies 138. Over the last 5 years, this view has fundamentally changed since the publication of several studies providing circumstantial evidence of human transmission of Aβ. In 2015, we observed that patients, who had received pituitary‐derived GH and had died of prion disease, also showed frequent cerebral amyloid angiopathy (CAA) and parenchymal Aβ 41. After this landmark publication, Aβ transmission was also demonstrated in patients who had received contaminated dural grafts 44. Since then, many authors have reproduced these findings in various cohorts of iatrogenic CJD patients 43, 45-47, 139. In retrospect, Aβ pathology in dural graft‐related iatrogenic CJD patients had already been reported before 140, 141, albeit without association with potential transmissibility. Patients who had not contracted CJD, but died from other causes also show Aβ pathology 43. Furthermore, some have developed complications related to amyloid angiopathy, such as intracerebral haemorrhages 48, 49. The pathogenic role of Aβ seeds has been confirmed by the transmission of pituitary‐derived GH, archived in vials for decades, into transgenic mice that developed accelerated amyloid angiopathy 142. A further mode of Aβ transmission was uncovered when we examined unexplained early‐onset CAA in a small series of patients in the 3rd and 4th decades of life. When exploring the clinical history we found that these patients had neurosurgical interventions during childhood with no evidence of cadaveric dural grafting 42, suggesting Aβ transmission through neurosurgery 42 (Figure 4). To date, CAA‐related haemorrhages have been the main complication of iatrogenically transmitted Aβ 42, 48, 49, prompting public health concerns. Cases reported to date have not shown evidence of advanced AD pathology.

image Figure 4 Open in figure viewerPowerPoint

Recent history of published observations on human transmission of amyloid‐β. Initially, the human transmission of amyloid‐β through iatrogenic procedures was reported in the context of transmitted prion disease, with the first landmark study in 2015 documenting widespread parenchymal and vascular amyloid‐β pathology in patients who had received human cadaver derived GH (cd‐GH) treatment several decades earlier. This was followed by a similar observation in patients who had received cadaver derived (cd) dura mater treatment. Later studies described amyloid‐β transmission also independent from prion disease, so far through cadaver derived growth hormone treatment, dura mater grafting and neurosurgical instruments. Two case reports, shown in light green, refer to earlier reports describing amyloid‐β pathology, but not suggesting potential iatrogenic transmissibility. On the far right, the countries of published series are specified.

Human transmission of tau, TDP43 and α‐synuclein pathology has not been proven as yet, but it may just be a matter of time until epidemiological, pathology‐confirmed studies have been conducted. Review of clinical notes from patients, who had died of MSA and PD, showed no evidence of neurosurgical transmission or cadaver‐derived GH treatment 143 and a study of five couples whose spouses had pathologically verified PD, PSP or MSA also did not suggest an increased risk of α‐synucleinopathy development in the other spouse 144. Current absence of evidence, however, is not evidence of the absence of human transmission of misfolded proteins other than prion and Aβ, and further research is necessary before any firm conclusions can be drawn.

A possible explanation of the transmissibility of PrPSc and Aβ, but not tau, α‐synuclein and TDP43, may be related to the differences in cellular localization (extracellular and transmembrane vs. cytoplasmic), rendering prion protein and Aβ more readily available for iatrogenic seed transmission. Another explanation could be related to the incubation periods, which for prion diseases vary from a couple of years to over 40 years 51 and for Aβ, as the current observational studies show (Figure 4), at least 20 years are needed for the pathology to be detectable and manifest clinically. It is plausible that even longer incubation periods, possibly exceeding human lifespan, are required for tau, TDP43 and α‐synuclein pathology development. Further differences could be due to critical mass of initial seeds required, to initiate a self‐amplifying cascade. For example, in vitro studies show that while for tau the minimal propagation unit is as small as tau trimers, larger oligomers comprising up to 100 tau molecules have the greatest seeding efficiently 63. A much higher concentration (at least 10,000 fibrils or oligomers per cell‐like volume) of α‐synuclein, is needed for efficient seeding, with fibrils being more effective at seeding than oligomers 105. In contrast, for tau, using a similar methodological approach (single‐molecular fluorescence resonance energy transfer and kinetic analysis), significantly less oligomers appear to be required for efficient seeding 145. In comparison, in sporadic prion disease in patients with MM genotype at codon 129 of the PRNP gene, the average 50% seeding dose (SD), assessed with RT‐QuIC assay, corresponds to approximately 1010 /g brain, or 1 SD50 unit equivalent to 0.06–0.27 fg of PrPSc 146. As demonstrated in these examples, different methodologies for different neurodegenerative diseases have been applied, with some measuring the oligomer size or number of molecules, and others estimating the concentration or mass.

Of note, research applying kinetic analysis also allow to predict most effective conditions for templated seeding to occur and the suggested relevant factors are: nucleation rate (small number of oligomers or fibrils show most effective seeding at slow nucleation rate) and initial protein concentration and its relationship to critical aggregation concentration (templated seeding is more effective at low concentrations with fewer oligomers needed) 105.

Transmission from animals to humans

Transmission from animals to humans has probably only occurred in the context of BSE. Owing to changes in processing cattle feed, BSE first spread endemically in cattle and was then transmitted, most likely through the food chain, to humans 147. It caused an unusual, early‐onset neurological syndrome, which was later designated as variant CJD (vCJD). Polymorphic variants of the PRNP gene in humans and animals have a strong influence on the transmissibility and development of a clinical phenotype. All but one cases of vCJD occurred in patients with the PRNP codon 129MM genotype. The exception is a patient who presented clinically and radiologically with a sporadic CJD phenotype but showed histologically a prototypical vCJD, and biochemical typing confirmed the BSE/vCJD strain 148. For last several years, no new cases of vCJD have emerged, however, it is debated if the vCJD strain could have adapted into a clinically and histologically classical CJD 149, making it nearly impossible to identify as transmitted form.

Discovery of unusual forms of misfolded protein diseases, such as parkinsonism‐dementia complex of Guam and the recent report of a tauopathy in young East‐African children with nodding syndrome 150, make one consider the possibility of environmental causes, leading to cross‐species transmission of proteins other than prion. As always, such speculations need to be viewed with extreme caution. For tau pathology in particular, its development in patients with long‐standing seizures is well known 151. Thus, tauopathy that has been described in the nodding syndrome, a form of epilepsy with uncontrollable nodding of the head, may well be secondary to the seizures. Recent research, in fact, suggests that epilepsy in patients with nodding syndrome is an immune‐mediated reaction related to parasitic worm onchocerciasis infection 152, further suggesting that tauopathy may, indeed, be secondary.

Conclusion and future perspectives

The concept of a transmissible disease, caused by seeds or template‐directed self‐assembly of proteins has fascinated the scientific community for decades. As highlighted in this review, over the last two decades building on century‐long research in prion diseases, startling revelations, both practical and profound, have been made. The research has furthered the understanding of mechanisms of proteopathic seed development, templated seeding, propagation from cell‐to‐cell and spread from region‐to‐region. While likening misfolded proteins and peptides of common neurodegenerative diseases, such as AD and PD, to prion disease, may have some value in translating the research findings from one field to the other, such comparisons are not always accurate or used attentively. Large gaps remain in understanding the mechanisms of prion and all other neurodegenerative diseases.

The future research focus should be twofold: Firstly, related to public health, to ensure adequate surgical and laboratory instrument decontamination procedures are in place, and prospective epidemiological studies are designed to specifically investigate any potential transmissibility of misfolded proteins and peptides which require long incubation periods to be detectable. There are defined requirements for biosafety procedures to handle cell and animal models, and human tissues in prion disease research and clinical practice. Instead, there are currently no data suggesting that such precautions are warranted for other protein species. Any recommendations to introduce similar requirements for research into other neurodegenerative diseases would add substantial financial and operational barriers and would obstruct advancements in the field. Adherence to good laboratory practice and health and safety guidelines, relevant to human and experimental animal tissue, is currently considered to be appropriate for handling material from neurodegenerative disorders other than prion diseases (see also review: 153). In clinical practice, patients at risk of developing iatrogenic Aβ pathology, notably CAA, should be considered to be followed up with neuroimaging and with appropriate CSF biomarker tests, such as Aβ, tau and other neurodegenerative proteins (e.g. neurofilament light chain). Secondly, further experimental research is needed to unravel the molecular and mechanistic processes leading to initiation of self‐amplification, efficient propagation and spread of proteopathic seeds. The exact role of oligomers in causing neurotoxicity, regional vulnerability, transmissibility and neurodegeneration as discussed in this review needs to be determined. The complexity of genetic and epigenetic alterations, including the role of mosaicism and cell‐ and region‐specific differences in gene and protein expression levels between individuals warrants detailed elucidation. It is likely, that the sum of these research efforts will lead to finding the cure of these devastating diseases.


ALL iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

Singeltary Comment at very bottom of this Nature publishing;

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.

Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.

where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?

we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.

https://www.nature.com/articles/nature15369#article-comments

>>> The only tenable public line will be that "more research is required’’ <<< 

>>> possibility on a transmissible prion remains open<<< 

O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ? 

Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015) 

snip...see full Singeltary Nature comment here; 

Alzheimer's disease

let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease... 

Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy





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

*** Singeltary comment PLoS *** 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ? 

Posted by flounder on 05 Nov 2014 at 21:27 GMT 


IN CONFIDENCE

5 NOVEMBER 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. 

There are also results to be made available shortly 

(1) concerning a farmer with CJD who had BSE animals, 

(2) on the possible transmissibility of Alzheimer’s and 

(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]




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

*** Singeltary comment PLoS *** 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ? 

Posted by flounder on 05 Nov 2014 at 21:27 GMT 


IN CONFIDENCE

5 NOVEMBER 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. 

There are also results to be made available shortly 

(1) concerning a farmer with CJD who had BSE animals, 

(2) on the possible transmissibility of Alzheimer’s and 

(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]




re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)


Singeltary Comment at very bottom of this Nature publishing;

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.

Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.

where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?

we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.

That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.

The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? 

who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.

That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.

Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express

if not for the journalist, the layperson would not know about these important findings.

where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?

when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.

to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.

so, who makes that final decision, and how many more decades do we have to wait?

the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?

Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.

FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.

in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.

greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.

my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.

I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...

[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer's and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]

Singeltary Comment at very bottom of this Nature publishing;


THURSDAY, FEBRUARY 7, 2019 

In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology


Subject: CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?

REVIEW

***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***

***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<*** 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***

***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<*** 

***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***

Saturday, February 2, 2019 

CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?


Wednesday, January 16, 2019 

Multiple system atrophy prions replicate in Tg(SNCAA53T) mice and induce glial pathology throughout the limbic system



TUESDAY, JANUARY 1, 2019 

CHILDHOOD EXPOSURE TO CADAVERIC DURA


SUNDAY, OCTOBER 21, 2018 

***> Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies? 

Singeltary Review


FRIDAY, DECEMBER 14, 2018 

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone December 14, 2018


Tuesday, December 12, 2017 

Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology

http://tauopathies.blogspot.com/2017/12/neuropathology-of-iatrogenic.html

Friday, January 29, 2016

Synucleinopathies: Past, Present and Future, iatrogenic, what if?



FRIDAY, JANUARY 10, 2014

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

Greetings Friends, Neighbors, and Colleagues,

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

Confucius is confused again.

I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.

what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???

it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.

sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.

I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.

I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.

by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?

this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.

the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).


the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.


again, sporadic and familial is a red herring, in my opinion.

also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.

snip...see full text;

Friday, January 10, 2014

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


P132 Aged cattle brain displays Alzheimer’s-like pathology that can be propagated in a prionlike manner

Ines Moreno-Gonzalez (1), George Edwards III (1), Rodrigo Morales (1), Claudia Duran-Aniotz (1), Mercedes Marquez (2), Marti Pumarola (2), Claudio Soto (1) 

snip...

These results may contribute to uncover a previously unsuspected etiology surrounding some cases of sporadic AD. However, the early and controversial stage of the field of prion-like transmission in non-prion diseases added to the artificial nature of the animal models utilized for these studies, indicate that extrapolation of the results to humans should not be done without further experiments. 

P75 Determining transmissibility and proteome changes associated with abnormal bovine prionopathy 

Dudas S (1,2), Seuberlich T (3), Czub S (1,2) 

In prion diseases, it is believed that altered protein conformation encodes for different pathogenic strains. Currently 3 different strains of bovine spongiform encephalopathy (BSE) are confirmed. Diagnostic tests for BSE are able to identify animals infected with all 3 strains, however, several diagnostic laboratories have reported samples with inconclusive results which are challenging to classify. It was suggested that these may be novel strains of BSE; to determine transmissibility, brain material from index cases were inoculated into cattle. 

In the first passage, cattle were intra-cranially challenged with brain homogenate from 2 Swiss animals with abnormal prionopathy. The challenged cattle incubated for 3 years and were euthanized with no clinical signs of neurologic disease. Animals were negative when tested on validated diagnostic tests but several research methods demonstrated changes in the prion conformation in these cattle, including density gradient centrifugation and immunohistochemistry. Currently, samples from the P1 animals are being tested for changes in protein levels using 2-D Fluorescence Difference Gel Electrophoresis (2D DIGE) and mass spectrometry. It is anticipated that, if a prionopathy is present, this approach should identify pathways and targets to decipher the source of altered protein conformation. In addition, a second set of cattle have been challenged with brain material from the first passage. Ideally, these cattle will be given a sufficient incubation period to provide a definitive answer to the question of transmissibility. 

=====prion 2018===





***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts 

S67 PrPsc was not detected using rapid tests for BSE.

***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.

*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***

Posted by Terry S. Singeltary Sr. on 03 Jul 2015 at 16:53 GMT


P.9.21

Molecular characterization of BSE in Canada

Jianmin Yang 1 , Sandor Dudas 2 , Catherine Graham 2 , Markus Czub 3 , Tim McAllister 1 , Stefanie Czub 1 1 Agriculture and Agri-Food Canada Research Centre, Canada; 2 National and OIE BSE Reference Laboratory, Canada; 3 University of Calgary, Canada

Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle. Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres.

Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.

Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal-specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.

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.

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;




On behalf of the Scientific Committee, I am pleased to inform you that your abstract

'Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009'

WAS accepted for inclusion in the INTERNATIONAL SCIENTIFIC EXCHANGE (ISE) section of the 14th International Congress on Infectious Diseases. Accordingly, your abstract will be included in the "Intl. Scientific Exchange abstract CD-rom" of the Congress which will be distributed to all participants.

Abstracts accepted for INTERNATIONAL SCIENTIFIC EXCHANGE are NOT PRESENTED in the oral OR poster sessions.

Your abstract below was accepted for: INTERNATIONAL SCIENTIFIC EXCHANGE

#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Author: T. Singeltary; Bacliff, TX/US

Topic: Emerging Infectious Diseases Preferred type of presentation: International Scientific Exchange

This abstract has been ACCEPTED.

#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Authors: T. Singeltary; Bacliff, TX/US

Title: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Body: Background

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods

12 years independent research of available data

Results

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries.

I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion

page 114 ;

http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf

http://www.isid.org/14th_icid/

http://www.isid.org/publications/ICID_Archive.shtml

http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf

mSphere. 2020 Jan-Feb; 5(1): e00649-19. Published online 2020 Jan 29. doi: 10.1128/mSphere.00649-19 PMCID: PMC6992370 PMID: 31996421 

Correlation between Bioassay and Protein Misfolding Cyclic Amplification for Variant Creutzfeldt-Jakob Disease Decontamination Studies

Maxime Bélondrade,#a Christelle Jas-Duval,#a,b Simon Nicot,#a Lilian Bruyère-Ostells,a Charly Mayran,a Laetitia Herzog,b Fabienne Reine,b Juan Maria Torres,c Chantal Fournier-Wirth,a Vincent Béringue,b Sylvain Lehmann,d and Daisy Bougardcorresponding authora Mark D. Zabel, Editor Mark D. Zabel, Colorado State University; Author information Article notes Copyright and License information Disclaimer Associated Data Supplementary Materials Go to: 

ABSTRACT 

To date, approximately 500 iatrogenic Creutzfeldt-Jakob disease cases have been reported worldwide, most of them resulting from cadaveric dura mater graft and from the administration of prion-contaminated human growth hormone. The unusual resistance of prions to decontamination processes, their large tissue distribution, and the uncertainty about the prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the general population lead to specific recommendations regarding identification of tissue at risk and reprocessing of reusable medical devices, including the use of dedicated treatment for prion inactivation. We previously described an in vitro assay, called Surf-PMCA, which allowed us to classify prion decontamination treatments according to their efficacy on vCJD prions by monitoring residual seeding activity (RSA). Here, we used a transgenic mouse line permissive to vCJD prions to study the correlation between the RSA measured in vitro and the in vivo infectivity. Implantation in mouse brains of prion-contaminated steel wires subjected to different decontamination procedures allows us to demonstrate a good concordance between RSA measured by Surf-PMCA (in vitro) and residual infectivity (in vivo). These experiments emphasize the strength of the Surf-PMCA method as a rapid and sensitive assay for the evaluation of prion decontamination procedures and also confirm the lack of efficacy of several marketed reagents on vCJD prion decontamination.

IMPORTANCE Creutzfeldt-Jakob diseases are neurodegenerative disorders for which transmission linked to medical procedures have been reported in hundreds of patients. As prion diseases, they are characterized by an unusual resistance to conventional decontamination processes. Moreover, their large tissue distribution and the ability of prions to attach to many surfaces raised the risk of transmission in health care facilities. It is therefore of major importance that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated for prion inactivation. We previously described an in vitro assay, which allowed us to classify accurately prion decontamination treatments according to their efficacy on variant Creutzfeldt-Jakob disease. The significance of this study is in demonstrating the concordance between previous in vitro results and infectivity studies in transgenic mice. Furthermore, commercial reagents currently used in hospitals were tested by both protocols, and we observed that most of them were ineffective on human prions.

KEYWORDS: PMCA, bioassay, decontamination, prion, variant Creutzfeldt-Jakob disease

snip...

DISCUSSION We demonstrated in this study that our previous results obtained by monitoring the RSA by Surf-PMCA for the evaluation of decontamination procedures against vCJD prions were concordant with the measure of residual infectivity in tgBov mice.

The choice of the transgenic model for the in vivo assay was driven by literature review. Although vCJD PrPTSE and bovine PrPC differ with regard to their primary sequence, the capacity of vCJD prions to transmit in transgenic mice overexpressing bovine PrP without species barrier has been comprehensively described (39). Due to the absence of this species barrier, it has been reported previously that tgBov line 110 mice were highly susceptible to vCJD prions (38, 40,–42). vCJD represents human infection with bovine spongiform encephalopathy (BSE) from cattle. This phenomenon has been designated “traceback,” and traceback studies have been proven to be a useful tool to identify the origin of prions (39, 43, 44). These results suggest that BSE prions retain their host preference after repeated passages through human PrP (42), as in other species, including sheep, cat, and mouse. It must also be noted that bovine PrP mice succumb quicker with vCJD prions but are intrinsically not more susceptible than tgHu line 650 mice to vCJD prions (45). Although homogenate substrate used for Surf-PMCA originated from tgHu mice (overexpressing 6 times the physiological level of human PrP) (46), survival time bioassays based on this transgenic line are limited by the long incubation period of vCJD (exceeding 500 d.p.inoc when undiluted) (45). tgBov mice (overexpressing 6 times the physiological level of bovine PrP) (47) were previously used and showed a good dynamic range with one animal dying with up to a 10−6 dilution of a vCJD brain homogenate in 500 d.p.inoc (38). Our results are concordant with these data, as 10−2 and 10−3 dilution vCJD-contaminated steel wires implanted in tgHu mice gave an attack rate of 100%; however, the incubation time exceeded 700 d.p.imp—almost the life span of the animals—which precludes their use to monitor a reduction factor. On the other hand, tgBov mice showed a better dynamic range with one animal dying after exposure with a 10−5 dilution vCJD-contaminated steel wires. Surprisingly, whereas attack rates and incubation times obtained with the 10−3 vCJD dilution indicated an expected lower infectivity of steel wire-bound prions than with the diluted prions, very similar results were obtained at the 10−5 dilution limit for the two groups (wires or dilution). One explanation could be that in the case of very low quantity of prions, the process used for wire contamination with IBH (one single wire per well and air drying overnight) may have potentiated vCJD transmission. A second hypothesis would rely on the longer total brain local exposure of mice with wires that remain in the brain for a long time, in contrast to injected brain homogenates that circulate immediately. Despite the relevance of the tgBov model as a vCJD bioassay, the limited dynamic of steel wire endpoint titration (50% attack rate for animals implanted with 10−4 dilution vCJD-contaminated steel wires) and its nonlinear decrease did not allow the calculation of an accurate 50% endpoint titer. Furthermore, although there were initially 10 mice per implantation condition, some animals were lost, which limited statistical significance. However, compared with the 263K hamster model, in which the dilution limit is 10−6 diluted contaminated steel wires (22% transmission rate) (19), the 10−5 dilution limit we obtained with tgBov inoculated with vCJD prions is only 1 log unit less sensitive and allows the comparison of the residual infectivity with the RSA measured by Surf-PMCA. Therefore, when vCJD-contaminated steel wires were treated by either standard or commercial treatments, the tgBov model was sensitive enough for results to be interpreted. Fully effective standard treatments showed no transmission of vCJD in the tgBov mice model. Except for sodium hypochlorite at 2,000 ppm, the other partially effective treatments led to few animals developing TSE. As inferred from the Surf-PMCA results, out of six commercial treatments, four poorly decreased the infectious load adsorbed on steel wires, with treatment A seeming to shorten the survival time compared with the water-only control. Despite PMCA being demonstrated as more sensitive than bioassays by several log units of magnitude for the detection of prions (34, 35, 48, 49), and that, to our knowledge, this is the first time the steel wire assay has been used with vCJD prions, we showed a high concordance between the Surf-PMCA results and the use of steel wires as vCJD carrier in transgenic mice.

We demonstrated using Surf-PMCA and tgBov infectivity studies that some of the commercial chemicals tested were not fully effective for decontaminating vCJD prions on surfaces. However, all these treatments were approved regarding their efficacy on the 263K prion strain. Our results confirm the inaccuracy of 263K prions regarding the validation of decontamination procedures used in health care facilities for the inactivation of vCJD prions. Nevertheless, our results regarding the effectiveness of vCJD prion decontamination by marketed reagents should be mitigated owing to the specific experimental set up whereby wires were air dried after contamination. Although all reagents evaluated in this study were previously validated using similar prion-dried conditions (using 263K prion-contaminated steel wires in hamsters), it is important to note that in health care facilities, it is recommended that MDs are kept continuously moist before prion decontamination. Whether vCJD-bound prions would behave differently if steel wires are kept moist after contamination remains to be established. Our Surf-PMCA method should be able to provide complementary data to help manufacturers of products to evaluate and improve their effectiveness in more real conditions. In addition, although TSE agents have notable extreme resistance to most decontamination processes, iatrogenic transmission of CJD via neurosurgical instruments has been reported in only four cases worldwide, and two cases have occurred because of contaminated stereotactic electroencephalography (EEG) depth electrodes in Switzerland (12). No new cases of iatrogenic transmission of CJD have been reported for several decades, underlining the poor transmission efficiency and the probable effectiveness of risk management procedures currently in place in health care facilities.

Recently, vCJD diagnosis has been possible in plasma samples from clinical and preclinical patients using the PMCA amplification technique (7) and in cerebrospinal fluid samples from clinical vCJD patients, including the first heterozygous methionine/valine patient (29), who might be the first case of a feared second wave of vCJD cases (50, 51). The capacity of PMCA to regenerate infectivity has already been demonstrated on nonhuman prions such as with scrapie prions, for which Moudjou et al. showed that infectivity of a 10−9 dilution of infected brain amplified by one round of PMCA was similar to that of the initial brain (34). Although sometimes debated (52, 53), the infectivity of vCJD PMCA amplicons, as well as the capacities of PMCA amplicons to faithfully maintain the pathological features of the original inoculum, led us to challenge tgBov mice with PMCA amplicons obtained from 10−7 vCJD-contaminated steel wires. By comparing the results with those obtained with a 10−3 vCJD-IBH dilution, we observed an equivalent survival time, demonstrating the ability of PMCA to regenerate at least 4 log units of vCJD infectivity. We also obtained a similar profile on Western blots for the PrPTSE present in the mouse brains. Altogether, these results confirmed that an RSA detected by the Surf-PMCA assay can be linked to residual infectivity in mice.

To extend the use of Surf-PMCA for the evaluation of prion decontamination treatments, it could be of interest to adapt it to other human prions, in particular sporadic CJD prions which represent 85% of TSE cases. Considering the differences of the biochemical properties of PrPTSE among the different sporadic CJD (sCJD) subtypes, such as solubility in detergents, heat stability, or sensitivity to protease digestion (54,–56), the behavior of non-vCJD human prions should be considered with regard to decontamination procedures. Similarly, other protein misfolding diseases such as Alzheimer’s and Parkinson diseases should also be considered on a precautionary basis in the development of decontamination procedures adapted to MDs (57). Adaptation and automation of Surf-PMCA would be of significant interest for a rapid and low-cost evaluation of new decontamination processes regarding misfolding diseases.

snip...see full text;


ALL iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.

cwd tse prion and steel wires

''Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice.''

*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery *** 

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. 


FRIDAY, OCTOBER 04, 2019 

Inactivation of chronic wasting disease prions using sodium hypochlorite

i think some hunters that don't read this carefully are going to think this is a cure all for cwd tse contamination. IT'S NOT!

first off, it would take a strong bleach type sodium hypochlorite, that is NOT your moms bleach she uses in her clothes, and store bought stuff.

Concentrated bleach is an 8.25 percent solution of sodium hypochlorite, up from the “regular bleach” concentration of 5.25 percent.Nov 1, 2013 https://waterandhealth.org/disinfect/high-strength-bleach-2/

second off, the study states plainly;

''We found that a five-minute treatment with a 40% dilution of household bleach was effective at inactivating CWD seeding activity from stainless-steel wires and CWD-infected brain homogenates. However, bleach was not able to inactivate CWD seeding activity from solid tissues in our studies.''

''We initially tested brains from two CWD-infected mice and one uninfected mouse using 40% bleach for 5 minutes. The results from these experiments showed almost no elimination of prion seeding activity (Table 4). We then increased the treatment time to 30 minutes and tested 40% and 100% bleach treatments. Again, the results were disappointing and showed less than a 10-fold decrease in CWD-seeding activity (Table 4). Clearly, bleach is not able to inactivate prions effectively from small brain pieces under the conditions tested here.''

''We found that both the concentration of bleach and the time of treatment are critical for inactivation of CWD prions. A 40% bleach treatment for 5 minutes successfully eliminated detectable prion seeding activity from both CWD-positive brain homogenate and stainless-steel wires bound with CWD. However, even small solid pieces of CWD-infected brain were not successfully decontaminated with the use of bleach.''



i think with all the fear from recent studies, and there are many, of potential, or likelihood of zoonosis, if it has not already happened as scjd, i think this study came out to help out on some of that fear, that maybe something will help, but the study plainly states it's for sure not a cure all for exposure and contamination of the cwd tse prion on surface materials. imo...terry 

However, in a US study conducted in 1996 [34], only 53% of dentists used autoclaves to decontaminate root-canal files. In a survey conducted in France in 2004, only 79% of dentists used an autoclave [35]. The problem of correct use of the autoclaves and regular checking of their efficacy has also been raised by many authors in several countries [34]. A recent survey on dental practice also showed that other elementary precautionary measures against CJD transmission were not widely respected. For example, the vast majority of dentists did not actively seek out patients at-risk for any form of CJD (sporadic, iatrogenic or familial) [36]. Therefore, in the current situation and despite recommended decontamination procedures, the risk of sCJD transmission during dental care might still not be zero. In any case, our findings constitute a strong argument for the strict respect of the official recommendations on decontamination procedures in dentistry, and even suggest that the cost-benefit of single-use endodontic instruments should be re-evaluated.




PLoS One. 2020; 15(1): e0227487.

Published online 2020 Jan 7. doi: 10.1371/journal.pone.0227487

PMCID: PMC6946595

PMID: 31910440

Role of donor genotype in RT-QuIC seeding activity of chronic wasting disease prions using human and bank vole substrates

snip...

Utilizing the same set of samples we also demonstrated that CWD prions sourced from WTD, elk or mule deer can seed human rPrP with high efficiency. To date, we are aware of only one report on the seeding activity of human substrate with CWD prions using RT-QuIC. This report showed that CWD prions from white-tailed deer could be used to seed human substrate (129M) and that the CWD conversion was more efficient than conversion with classical BSE prions [30]. Our study reconfirms that CWD is an efficient seed for human rPrP substrate. The relatively high efficiency of RT-QuIC amplification of CWD prions using human rPrP substrate may seem counter to the status of the broader understanding of CWD not being associated with human disease. This understanding is based on the published body of work on CWD and human transmission from either PMCA based amplification, transgenic mouse studies and non-human primates [31–37]. Collectively this work indicates that the species barrier is strong between humans and cervid CWD, and the efficient converstion of CWD prions using human rPrP by RT-QuIC does not challenge this because RT-QuIC exclusively assess the primary structure compatibility of the substrate with that of the secondary and tertiary structure of the seed. However, RT-QuIC does offer us a means to rapidly assess large numbers of amino acid substitutions between and within species associated with CWD to determine whether. 

snip...


> However, to date, no CWD infections have been reported in people.
key word here is ‘reported’. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can’t, and it’s as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it’s being misdiagnosed as sporadic CJD. …terry
*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***
*** 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).***
Chronic Wasting Disease CWD TSE Prion aka mad deer disease zoonosis
We hypothesize that:
(1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;
(2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;
(3) Reliable essays can be established to detect CWD infection in humans; and
(4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.
ZOONOTIC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE
Prion 2017 Conference
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1 
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen 
This is a progress report of a project which started in 2009. 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves. 
Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice. 
At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation. 
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS 
PRION 2018 CONFERENCE
Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice
Hermann M. Schatzl, Samia Hannaoui, Yo-Ching Cheng, Sabine Gilch (Calgary Prion Research Unit, University of Calgary, Calgary, Canada) Michael Beekes (RKI Berlin), Walter Schulz-Schaeffer (University of Homburg/Saar, Germany), Christiane Stahl-Hennig (German Primate Center) & Stefanie Czub (CFIA Lethbridge).
To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys. Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years.
After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were detected in spinal cord and brain of some euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and pre-clinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles.
Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate.
The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.
Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP.
The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD..
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
READING OVER THE PRION 2018 ABSTRACT BOOK, LOOKS LIKE THEY FOUND THAT from this study ;
P190 Human prion disease mortality rates by occurrence of chronic wasting disease in freeranging cervids, United States
Abrams JY (1), Maddox RA (1), Schonberger LB (1), Person MK (1), Appleby BS (2), Belay ED (1) (1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA..
SEEMS THAT THEY FOUND Highly endemic states had a higher rate of prion disease mortality compared to non-CWD
states.
AND ANOTHER STUDY;
P172 Peripheral Neuropathy in Patients with Prion Disease
Wang H(1), Cohen M(1), Appleby BS(1,2) (1) University Hospitals Cleveland Medical Center, Cleveland, Ohio (2) National Prion Disease Pathology Surveillance Center, Cleveland, Ohio..
IN THIS STUDY, THERE WERE autopsy-proven prion cases from the National Prion Disease Pathology Surveillance Center that were diagnosed between September 2016 to March 2017,
AND
included 104 patients. SEEMS THEY FOUND THAT The most common sCJD subtype was MV1-2 (30%), followed by MM1-2 (20%),
AND
THAT The Majority of cases were male (60%), AND half of them had exposure to wild game.
snip…
see more on Prion 2017 Macaque study from Prion 2017 Conference and other updated science on cwd tse prion zoonosis below…terry
PRION 2019 ABSTRACTS 

1. Interspecies transmission of the chronic wasting disease agent

Justin Greenlee

Virus and Prion Research Unit, National Animal Disease Center, USDA Agriculture Research Service

ABSTRACT

The presentation will summarize the results of various studies conducted at our research center that assess the transmissibility of the chronic wasting disease (CWD) agent to cattle, pigs, raccoons, goats, and sheep. This will include specifics of the relative attack rates, clinical signs, and microscopic lesions with emphasis on how to differentiate cross-species transmission of the CWD agent from the prion diseases that naturally occur in hosts such as cattle or sheep. Briefly, the relative difficulty of transmitting the CWD agent to sheep and goats will be contrasted with the relative ease of transmitting the scrapie agent to white-tailed deer.

53. Evaluation of the inter-species transmission potential of different CWD isolates

Rodrigo Moralesa, Carlos Kramma,b, Paulina Sotoa, Adam Lyona, Sandra Pritzkowa, Claudio Sotoa

aMitchell Center for Alzheimer’s disease and Related Brain Disorders, Dept. of Neurology, McGovern School of Medicine University of Texas Health Science Center at Houston, TX, USA; bFacultad de Medicina, Universidad de los Andes, Santiago, Chile

ABSTRACT

Chronic Wasting Disease (CWD) has reached epidemic proportions in North America and has been identified in South Korea and Northern Europe. CWD-susceptible cervid species are known to share habitats with humans and other animals entering the human food chain. At present, the potential of CWD to infect humans and other animal species is not completely clear. The exploration of this issue acquires further complexity considering the differences in the prion protein sequence due to species-specific variations and polymorphic changes within species. While several species of cervids are naturally affected by CWD, white-tailed deer (WTD) is perhaps the most relevant due to its extensive use in hunting and as a source of food. Evaluation of inter-species prion infections using animals or mouse models is costly and time consuming. We and others have shown that the Protein Misfolding Cyclic Amplification (PMCA) technology reproduces, in an accelerated and inexpensive manner, the inter-species transmission of prions while preserving the strain features of the input PrPSc. In this work, we tested the potential of different WTD-derived CWD isolates to transmit to humans and other animal species relevant for human consumption using PMCA. For these experiments, CWD isolates homozygous for the most common WTD-PrP polymorphic changes (G96S) were used (96SS variant obtained from a pre-symptomatic prion infected WTD). Briefly, 96GG and 96SS CWD prions were adapted in homologous or heterologous substrate by PMCA through several (15) rounds. End products, as well as intermediates across the process, were tested for their inter-species transmission potentials. A similar process was followed to assess seed-templated misfolding of ovine, porcine, and bovine PrPC. Our results show differences on the inter-species transmission potentials of the four adapted materials generated (PrPC/PrPSc polymorphic combinations), being the homologous combinations of seed/substrate the ones with the greater apparent zoonotic potential. Surprisingly, 96SS prions adapted in homologous substrate were the ones showing the easiest potential to template PrPC misfolding from other animal species. In summary, our results show that a plethora of different CWD isolates, each comprising different potentials for inter-species transmission, may exist in the environment. These experiments may help to clarify an uncertain and potentially worrisome public health issue. Additional research in this area may be useful to advise on the design of regulations intended to stop the spread of CWD and predict unwanted zoonotic events.

56. Understanding chronic wasting disease spread potential for at-risk species

Catherine I. Cullingham, Anh Dao, Debbie McKenzie and David W. Coltman

Department of Biological Sciences, University of Alberta, Edmonton AB, Canada

CONTACT Catherine I. Cullingham cathy.cullingham@ualberta.ca

ABSTRACT

Genetic variation can be linked to susceptibility or resistance to a disease, and this information can help to better understand spread-risk in a population. Wildlife disease incidence is increasing, and this is resulting in negative impacts on the economy, biodiversity, and in some instances, human health. If we can find genetic variation that helps to inform which individuals are susceptible, then we can use this information on at-risk populations to better manage negative consequences. Chronic wasting disease, a fatal, transmissible spongiform encephalopathy of cervids (both wild and captive), continues to spread geographically, which has resulted in an increasing host-range. The disease agent (PrPCWD) is a misfolded conformer of native cellular protein (PrPC). In Canada, the disease is endemic in Alberta and Saskatchewan, infecting primarily mule deer and white-tail deer, with a smaller impact on elk and moose populations. As the extent of the endemic area continues to expand, additional species will be exposed to this disease, including bison, bighorn sheep, mountain goat, and pronghorn antelope. To better understand the potential spread-risk among these species, we reviewed the current literature on species that have been orally exposed to CWD to identify susceptible and resistant species. We then compared the amino acid polymorphisms of PrPC among these species to determine whether any sites were linked to susceptibility or resistance to CWD infection. We sequenced the entire PrP coding region in 578 individuals across at-risk populations to evaluate their potential susceptibility. Three amino acid sites (97, 170, and 174; human numbering) were significantly associated with susceptibility, but these were not fully discriminating. All but one species among the resistant group shared the same haplotype, and the same for the susceptible species. For the at-risk species, bison had the resistant haplotype, while bighorn sheep and mountain goats were closely associated with the resistant type. Pronghorn antelope and a newly identified haplotype in moose differed from the susceptible haplotype, but were still closely associated with it. These data suggest pronghorn antelope will be susceptible to CWD while bison are likely to be resistant. Based on this data, recommendations can be made regarding species to be monitored for possible CWD infection.

KEYWORDS: Chronic wasting disease; Prnp; wildlife disease; population genetics; ungulates

Thursday, May 23, 2019 

Prion 2019 Emerging Concepts CWD, BSE, SCRAPIE, CJD, SCIENTIFIC PROGRAM Schedule and Abstracts


see full Prion 2019 Conference Abstracts

THURSDAY, OCTOBER 04, 2018
Cervid to human prion transmission 5R01NS088604-04 Update
snip…full text;
SATURDAY, FEBRUARY 09, 2019
Experts: Yes, chronic wasting disease in deer is a public health issue — for people
SATURDAY, FEBRUARY 23, 2019 

Chronic Wasting Disease CWD TSE Prion and THE FEAST 2003 CDC an updated review of the science 2019


TUESDAY, NOVEMBER 04, 2014 

Six-year follow-up of a point-source exposure to CWD contaminated venison in an Upstate New York community: risk behaviours and health outcomes 2005–2011

Authors, though, acknowledged the study was limited in geography and sample size and so it couldn't draw a conclusion about the risk to humans. They recommended more study. Dr. Ermias Belay was the report's principal author but he said New York and Oneida County officials are following the proper course by not launching a study. "There's really nothing to monitor presently. No one's sick," Belay said, noting the disease's incubation period in deer and elk is measured in years. "


Transmission Studies

Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}....TSS

resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret.

snip.... 


Prion Infectivity in Fat of Deer with Chronic Wasting Disease▿ 

Brent Race#, Kimberly Meade-White#, Richard Race and Bruce Chesebro* + Author Affiliations

In mice, prion infectivity was recently detected in fat. Since ruminant fat is consumed by humans and fed to animals, we determined infectivity titers in fat from two CWD-infected deer. Deer fat devoid of muscle contained low levels of CWD infectivity and might be a risk factor for prion infection of other species. 


Prions in Skeletal Muscles of Deer with Chronic Wasting Disease 

Here bioassays in transgenic mice expressing cervid prion protein revealed the presence of infectious prions in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk to prion exposure. 


*** now, let’s see what the authors said about this casual link, personal communications years ago, and then the latest on the zoonotic potential from CWD to humans from the TOKYO PRION 2016 CONFERENCE.

see where it is stated NO STRONG evidence. so, does this mean there IS casual evidence ???? “Our conclusion stating that we found no strong evidence of CWD transmission to humans”


Subject: CWD aka MAD DEER/ELK TO HUMANS ???

Date: September 30, 2002 at 7:06 am PST

From: "Belay, Ermias"

To: Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"

Sent: Monday, September 30, 2002 9:22 AM

Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS

Dear Sir/Madam,

In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.. That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.

Ermias Belay, M.D. Centers for Disease Control and Prevention

-----Original Message-----

From: Sent: Sunday, September 29, 2002 10:15 AM


Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS

Sunday, November 10, 2002 6:26 PM .......snip........end..............TSS

Thursday, April 03, 2008

A prion disease of cervids: Chronic wasting disease 2008 1: Vet Res. 2008 Apr 3;39(4):41 A prion disease of cervids: Chronic wasting disease Sigurdson CJ.

snip...

*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,

snip... full text ; 


> However, to date, no CWD infections have been reported in people. 

sporadic, spontaneous CJD, 85%+ of all human TSE, just not just happen. never in scientific literature has this been proven.

if one looks up the word sporadic or spontaneous at pubmed, you will get a laundry list of disease that are classified in such a way;



key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry 

*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***

*** 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).*** 



FRIDAY, JULY 26, 2019 

Chronic Wasting Disease in Cervids: Implications for Prion Transmission to Humans and Other Animal Species


TUESDAY, JANUARY 21, 2020 

***> 2004 European Commission Chronic wasting disease AND TISSUES THAT MIGHT CARRY A RISK FOR HUMAN FOOD AND ANIMAL FEED CHAINS REPORT UPDATED 2020


***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***

***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<*** 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***

***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<*** 

***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***


***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***


Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.

https://www.nature.com/articles/srep11573 


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, Valerie 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 long 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*** 

=============== 

***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals. 

============== https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf 

***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. 

***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20 

PRION 2016 TOKYO

Saturday, April 23, 2016

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online

Taylor & Francis

Prion 2016 Animal Prion Disease Workshop Abstracts

WS-01: Prion diseases in animals and zoonotic potential

Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20

Title: Transmission of scrapie prions to primate after an extended silent incubation period) 

*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS. 

*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated. 

*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains. http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160

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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.

snip...

76/10.12/4.6


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).



Wednesday, February 16, 2011

IN CONFIDENCE

SCRAPIE TRANSMISSION TO CHIMPANZEES

IN CONFIDENCE


A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes

Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations

*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway

***Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)

Abstract 

Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice.

*** These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.


OR

***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.


OR

*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.


OR here;



*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion poker goes up again $

OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles

Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA

Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.

Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.

Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.

In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.

Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.

The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.


WEDNESDAY, MAY 29, 2019 

Incomplete inactivation of atypical scrapie following recommended autoclave decontamination procedures USDA HERE'S YOUR SIGN!


https://familialcjdtseprion.blogspot.com/2019/02/cwd-gss-tse-prion-spinal-cord-confucius.html

***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***

***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<*** 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***

***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<*** 

***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***


MONDAY, FEBRUARY 25, 2019

***> MAD DOGS AND ENGLISHMEN BSE, SCRAPIE, CWD, CJD, TSE PRION A REVIEW 2019


 [2] UK: SEAC position statement on dentistry

Date: Sat 30 Jun 2007

Source: Position Statement vCJD and Dentistry, Spongiform

Encephalopathy Advisory Committee (SEAC) Update, June 2007 [edited]


Position Statement vCJD and Dentistry

-------------------------------------

Issue

----- 

1. The Department of Health (DH) asked SEAC to advise on the findings of preliminary research aimed at informing estimates of the risk of variant Creutzfeldt-Jakob Disease (vCJD) transmission via dentistry. Background

----------

2. Prions are more resistant than other types of infectious agents to the conventional cleaning and sterilization practices used to decontaminate dental instruments (1). Appreciable quantities of residual material may remain adherent to the surface after normal cleaning and sterilization (2). Therefore, if dental tissues are both infectious and susceptible to infection, the dental instruments are a potential mechanism for the secondary transmission of vCJD. Dentistry could be a particularly significant route of transmission for the population as a whole, due to the large number of routine procedures undertaken and also because dental patients have a normal life expectancy.

This is in contrast with other transmission routes, such as blood transfusion and neurosurgery, where procedures are often carried out in response to some life-threatening condition. Additionally, the ubiquity of dental procedures and the lack of central records on dental procedures means that should such transmission occur, then it would be difficult to detect and control.

3. No cases of vCJD transmission arising from dental procedures have been reported to date (3). Previous DH risk assessments (4,5) have focused on 2 possible mechanisms for the transfer of vCJD infectivity via dental instruments; accidental abrasion of the lingual tonsil and endodontic procedures that involve contact with dental pulp. In considering these assessments, SEAC agreed that the risk of transmission via accidental abrasion of the lingual tonsil appears very low. However, the risk of transmission via endodontic procedures may be higher and give rise to a self sustaining vCJD epidemic under circumstances where (i) dental pulp is infective, (ii) transmission via endodontic instruments is efficient and (iii) a large proportion of vCJD infections remain in a subclinical carrier state (SEAC 91, February 2006). In light of this, SEAC advised that restricting endodontic files and reamers to single use be considered (6). SEAC recommended reassessment of these issues as new data emerge.

New research

------------

4. Preliminary, unpublished results of research from the Health Protection Agency, aimed at addressing some of the uncertainties in the risk assessments, were reviewed by SEAC (SEAC 97, May 2007). The prion agent used in these studies is closely related to the vCJD agent. This research, using a mouse model, shows that following inoculation of mouse-adapted bovine spongiform encephalopathy (BSE) directly into the gut, infectivity subsequently becomes widespread in tissues of the oral cavity, including dental pulp, salivary glands and gingiva, during the preclinical as well as clinical stage of disease.

5. It is not known how closely the level and distribution of infectivity in the oral cavity of infected mice reflects those of humans infected with vCJD, as there are no comparable data from oral tissues, in particular dental pulp and gingiva, from human subclinical or clinical vCJD cases (7). Although no abnormal prion protein was found in a study of human dental tissues, including dental pulp, salivary glands and gingiva from vCJD cases, the relationship between levels of infectivity and abnormal prion protein is unclear (8). Infectivity studies underway using the mouse model and oral tissues that are presently available from human vCJD cases will provide some comparable data. On the basis of what is currently known, there is no reason to suppose that the mouse is not a good model for humans in respect to the distribution of infectivity in oral tissues. Furthermore, the new data are consistent with published results from experiments using a hamster scrapie model (9).

6. A 2nd set of experiments using the same mouse model showed that non-invasive and transient contact between gingival tissue and fine dental files contaminated with mouse-adapted BSE brain homogenate transmits infection very efficiently. It is not known how efficient gingival transmission would be if dental files were contaminated with infectious oral tissues and then subsequently cleaned and sterilized, a situation which would more closely model human dental practice. Further studies using the mouse model that would be more representative of the human situation, comparing oral tissues with a range of doses of infectivity, cleaned and sterilized files and the kind of tissue contact with instruments that occurs during dentistry, should be considered.

7. SEAC considered that the experiments appear well designed and the conclusions justified and reliable, while recognizing that the research is incomplete and confirmatory experiments have yet to be completed. It is recommended that the research be completed, submitted for peer-review and widely disseminated as soon as possible so others can consider the implications. Nevertheless, these preliminary data increase the possibility that some oral tissues of humans infected with vCJD may potentially become infective during the preclinical stage of the disease. In addition, they increase the possibility that infection could potentially be transmitted not only via accidental abrasion of the lingual tonsil or endodontic procedures but a variety of routine dental procedures.

Implications for transmission risks

-----------------------------------

8. The new findings help refine assumptions made about the level of infectivity of dental pulp and the stage of incubation period when it becomes infective in the risk assessment of vCJD transmission from the reuse of endodontic files and reamers (10). For example, if one patient in 10 000 were to be carrying infection (equivalent to about 6000 people across the UK, the best current estimate (11), the data suggest that in the worst case scenario envisaged in the risk assessment, reuse of endodontic files and reamers might lead to up to 150 new infections per annum. It is not known how many of those infected would go on to develop clinical vCJD. In addition, transmission via the reuse of endodontic files and reamers could be sufficiently efficient to cause a self-sustaining vCJD epidemic arising via this route.

9. These results increase the importance of obtaining reliable estimates of vCJD infection prevalence. Data that will soon be available from the National Anonymous Tonsil Archive may help refine this assessment and provide evidence of the existence and extent of subclinical vCJD infection in tonsillectomy patients. Further data, such as from post mortem tissue or blood donations, will be required to assess prevalence in the general UK population (12).

10. Recent guidance issued by DH to dentists to ensure that endodontic files and reamers are treated as single use (13) is welcomed and should, as long as it is effectively and quickly implemented, prevent transmission and a self-sustaining epidemic arising via this route. However, the extent and monitoring of compliance with this guidance in private and National Health Service dental practice is unclear.

11. The new research also suggests that dental procedures involving contact with other oral tissues, including gingiva, may also be capable of transmitting vCJD. In the absence of a detailed risk assessment examining the potential for transmission via all dental procedures, it is not possible to come to firm conclusions about the implications of these findings for transmission of vCJD. However, given the potential for transmission by this route, serious consideration should be given to assessing the options for reducing transmission risks, such as improving decontamination procedures and practice or the implementation of single use instruments.

12. The size of the potential risk from interactions between the dental and other routes of secondary transmission, such as blood transfusion and hospital surgery, to increase the likelihood of a self-sustaining epidemic is unclear.

13. It is likely to be difficult to distinguish clinical vCJD cases arising from dietary exposure to BSE from secondary transmissions via dental procedures, should they arise, as a large proportion of the population is likely both to have consumed contaminated meat and undergone dentistry.

However, an analysis of dental procedures by patient age may provide an indication of the age group in which infections, if they occur, would be most likely to be observed. Should the incidence of clinical vCJD cases in this age group increase significantly, this may provide an indication that secondary transmission via dentistry is occurring. Investigation of the dental work for these cases may provide supporting data. There is no clear evidence, to date, based on surveillance or investigations of clinical vCJD cases, that any vCJD cases have been caused by dental procedures, but this possibility cannot be excluded.

Conclusions

-----------

14. Preliminary research findings suggest that the potential risk of transmission of vCJD via dental procedures may be greater than previously anticipated. Although this research is incomplete, uses an animal model exposed to relatively high doses of infectivity, and there are no data from infectivity studies on human oral tissues, these findings suggest an increased possibility that vCJD may be relatively efficiently transmitted via a range of dental procedures. Ongoing infectivity studies using human oral tissues and the other studies suggested here will enable more precise assessment of the risks of vCJD transmission through dental procedures.

15. Guidance was issued to dentists earlier this year [2007] recommending that endodontic files and reamers be treated as single use, which, provided this policy is adhered to, will remove any risk of a self-sustaining epidemic arising from reuse of these instruments. To minimize risk, it is critical that appropriate management and audit is in place, both for NHS and private dentistry. 16. It is also critical that a detailed and comprehensive assessment of the risks of all dental procedures be conducted as a matter of urgency. While taking into account the continuing scientific uncertainties, this will allow a more thorough consideration of the possible public health implications of vCJD transmission via dentistry and the identification of possible additional precautionary risk reduction measures. The assessment will require continued updating as more evidence becomes available on the transmissibility of vCJD by dental routes, and on the prevalence of infection within the population. A DH proposal to convene an expert group that includes dental professionals to expedite such an assessment is welcomed. Given the potential for transmission via dentistry, consideration should be given to the urgent assessment of new decontamination technologies which, if proven robust and effective, could significantly reduce transmission risks.

References

snip...

Communicated by

Terry S. Singletary, Sr. <flounder@wt.net>

******


***> In summary, our results establish aerosols as a surprisingly efficient modality of prion transmission. This novel pathway of prion transmission is not only conceptually relevant for the field of prion research, but also highlights a hitherto unappreciated risk factor for laboratory personnel and personnel of the meat processing industry. In the light of these findings, it may be appropriate to revise current prion-related biosafety guidelines and health standards in diagnostic and scientific laboratories being potentially confronted with prion infected materials. While we did not investigate whether production of prion aerosols in nature suffices to cause horizontal prion transmission, the finding of prions in biological fluids such as saliva, urine and blood suggests that it may be worth testing this possibility in future studies.



Adriano Aguzzi ''We even showed that a prion AEROSOL will infect 100% of mice within 10 seconds of exposure''

WOW!...tss

P.4.26

Aerosol and intranasal transmission of CWD




J Gen Virol (2010), DOI 10.1099/vir.0.017335-0 © 2010 Society for General Microbiology

Aerosol and Nasal Transmission of Chronic Wasting Disease in Cervidized Mice

Nathaniel D Denkers1, Davis M Seelig1, Glenn C. Telling2 and Edward A Hoover, Jr1,3

1 Colorado State University; 2 University of Kentucky Medical Center

These results demonstrate that CWD can be transmitted by aerosol (as well as nasal) exposure and suggest that exposure via the respiratory system merits consideration for prion disease transmission and biosafety.

Received 30 October 2009; accepted 15 February 2010.





THERE should be a mandatory trace out of these patients, and all patients should know, and if they choose not to, so be it, but the victim, patient, and Doctors of all involved must be made aware, and the hospital, this information should be put in some sort of confidential registry (WHERE INSURANCE COMPANIES CANNOT GAIN ACCESS OF SAID PATIENT/VICTIM), where hospitals and doctors can assess and be made aware of iatrogenic TSE Prion event, so that further iatrogenic transmission can hopefully be avoided. IF not, it's all pointless imo. ...terry

CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF?

''In the 2016 guidance, we recommended that prospective blood donors should be indefinitely deferred if they report having a blood relative with CJD. However, almost all cases reported are sCJD, not a genetic form of CJD. Blood relatives of individuals with sCJD are not at increased risk of developing the disease. The rare genetic forms of CJD (e.g., fCJD, GSS, FFI) share pathophysiological features with sCJD, and the transmission risk by blood components remains theoretical. Consequently, we recommend that establishments may stop asking prospective donors about having blood relatives with CJD.''


FRIDAY, JANUARY 31, 2020 

CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307


Confucius is confused again?

''The rare genetic forms of CJD (e.g., fCJD, GSS, FFI) share pathophysiological features with sCJD, and the transmission risk by blood components remains theoretical. Consequently, we recommend that establishments may stop asking prospective donors about having blood relatives with CJD.''

YET, vpspr, sporadic FFI, sporadic GSS, or the pending cases that can't be identified, are all now listed as sporadic CJD.

WHAT IF, sGSS, sFFI, are of an iatrogenic event from iatrogenic donor being from GSS or FFI?

what if vpspr is another strain of a different sporadic CJD, or familial? see;

7Includes 21 (21 from 2019) cases with type determination pending in which the diagnosis of vCJD has been excluded. 

8The sporadic cases include 3831 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 67 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 35 cases of sporadic Fatal Insomnia (sFI). 

9Total does not include 264 Familial cases diagnosed by blood test only.


under new proposed guidelines ''we recommend that establishments may stop asking prospective donors about having blood relatives with CJD'' (of which i strongly oppose due to the fact sporadic cjd is not a single entity or a spontaneous event, never which have been proven), but under these guidelines, you will miss the vpspr, sgss, and sffi, because they are under sporadic cjd terminology, would you not?

The occurrence of the disease in a patient who had contact with cases of familial C.J.D., but was not genetically related, has been described in Chile (Galvez et al., 1980) and in France (Brown et al., 1979b). In Chile the patient was related by marriage, but with no consanguinity, and had social contact with subsequently affected family members for 13 years before developing the disease. The contact case in France also married into a family in which C.J.D. was prevalent and had close contact with an affected member. In neither instance did the spouse of the non-familial case have the disease. The case described in this report was similarly related to affected family members and social contact had occurred for 20 years prior to developing C.J.D. If contact transmission had occurred, the minimum transmission period would be 11 years. Contact between sporadic cases has not been described and it is remarkable that possible contact transmissions have all been with familial cases. No method of transmission by casual social contact has been suggested.

WHAT IF?

***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.

snip...see full text here;



Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism 

Aušrinė Areškevičiūtė, MSc, Linea Cecilie Melchior, PhD, Helle Broholm, MD, Lars-Henrik Krarup, MD, PhD, Suzanne Granhøj Lindquist, MD, PhD, Peter Johansen, PhD, Neil McKenzie, PhD, Alison Green, PhD, Jørgen Erik Nielsen, MD, PhD, Henning Laursen, Dr.Med, Eva Løbner Lund, MD, PhD Journal of Neuropathology & Experimental Neurology, Volume 77, Issue 8, August 2018, Pages 673–684, https://doi.org/10.1093/jnen/nly043 Published: 07 June 2018

DISCUSSION

This is the first report of presumed sporadic CJD occurring in a person who married into a GSS family. The estimated prevalence of GSS is in the range of 2–5 per 100 million people worldwide, and the annual mortality rate for sCJD in Denmark is 1.46 per 1 million people (31). The population of Denmark consists of 5 740 185 individuals, and there are 2 registered GSS cases that belong to the same family. The Danish GSS family is only the thirty-fourth known GSS family in the world (32). One could assume that the risk for a Danish man with GSS to have a wife or a mother who would develop CJD in her seventies is as high as for any other man. On the basis of the mortality rate for sCJD, and assuming that the incidence of sCJD is the same among married and unmarried people, we could state that 1 man out of 684 932 men has a risk of marrying a woman who would develop CJD. However, in this case, the man a priori had GSS, which means that it would take 1 man out of 684 932 men with GSS for such a pairing to occur. Considering the worldwide rarity of GSS cases, the likelihood for co-occurrence of GSS and sCJD in one family is hence very low and warrants an investigation for the possible transmission of prions routes.


Volume 25, Number 1—January 2019

Research

Variable Protease-Sensitive Prionopathy Transmission to Bank Vol

Romolo Nonno1, Silvio Notari1, Michele Angelo Di Bari, Ignazio Cali, Laura Pirisinu, Claudia d’Agostino, Laura Cracco, Diane Kofskey, Ilaria Vanni, Jody Lavrich, Piero Parchi, Umberto Agrimi, and Pierluigi GambettiComments to Author 

Author affiliations: Istituto Superiore di Sanità, Rome, Italy (R. Nonno, M.A. Di Bari, L. Pirisinu, C. d’Agostino, I. Vanni, U. Agrimi); Case Western Reserve University, Cleveland, Ohio, USA (S. Notari, I. Cali, L. Cracco, D. Kofskey, J. Lavrich, P. Gambetti); University of Bologna, Bologna, Italy (P. Parchi); Istituto delle Scienze Neurologiche di Bologna, Bologna (P. Parchi)

***> However, the VPSPr prion shares the multiplicity of the resPrPD electrophoretic bands with prions from a subset of inherited prion diseases referred to as Gerstmann-Sträussler-Scheinker disease (GSS), prompting the suggestion that VPSPr is the sporadic form of GSS (7,10). Furthermore, the presence of small amounts of sCJD-like 3-band resPrPD has also been signaled in VPSPr (6,11,12).


FRIDAY, JANUARY 10, 2014

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

Greetings Friends, Neighbors, and Colleagues,

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

Confucius is confused again.

I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.
by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.

sporadic CJD, along with new TSE prion disease in humans, of which the young are dying, of which long duration of illness from onset of symptoms to death have been documented, only to have a new name added to the pot of prion disease i.e. sporadic GSS, sporadic FFI, and or VPSPR. I only ponder how a familial type disease could be sporadic with no genetic link to any family member? when the USA is the only documented Country in the world to have documented two different cases of atypical H-type BSE, with one case being called atypical H-G BSE with the G meaning Genetic, with new science now showing that indeed atypical H-type BSE is very possible transmitted to cattle via oral transmission (Prion2014). sporadic CJD and VPSPR have been rising in Canada, USA, and the UK, with the same old excuse, better surveillance. You can only use that excuse for so many years, for so many decades, until one must conclude that CJD TSE prion cases are rising. a 48% incease in CJD in Canada is not just a blip or a reason of better surveillance, it is a mathematical rise in numbers. More and more we are seeing more humans exposed in various circumstance in the Hospital, Medical, Surgical arenas to the TSE Prion disease, and at the same time in North America, more and more humans are becoming exposed to the TSE prion disease via consumption of the TSE prion via deer and elk, cattle, sheep and goats, and for those that are exposed via or consumption, go on to further expose many others via the iatrogenic modes of transmission of the TSE prion disease i.e. friendly fire. I pondered this mode of transmission via the victims of sporadic FFI, sporadic GSS, could this be a iatrogenic event from someone sub-clinical with sFFI or sGSS ? what if?
Thursday, March 8, 2018 

Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein


Furthermore, GSS A117V infected vole brains were able to induce the same disease phenotype in recipient voles within 3–4 months after challenge, proving that a prion agent propagated in the brains of infected animals. These findings imply that brains of GSS patients harbor infectious prions with transmissibility features similar to those found in other human and animal TSEs.


THURSDAY, DECEMBER 12, 2019 

Heidenhain Variant Creutzfeldt Jakob Disease hvCJD, sporadic spontaneous CJD and the TSE Prion December 14, 2019


SUNDAY, DECEMBER 29, 2019 

Variant CJD 18 years of research and surveillance


WEDNESDAY, DECEMBER 04, 2019 

Three Cases of Creutzfeldt-Jakob Disease with Visual Disturbances as Initial Manifestation


Friday, September 27, 2019

Prion disease and recommended procedures for flexible endoscope reprocessing – a review of policies worldwide and proposal for a simplified approach Singeltary, GUT journal and Bramble et al 

snip...


i tried to tell GUT journal, and Bramble et al this way back, decades ago...terry

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

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


Professor Michael Farthing wrote:

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

-----Original Message----- 

From: Terry S. Singeltary Sr. [mailto:flounder@wt.net] ;

Sent: 03 June 2002 17:14 


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

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Date submitted: 3 Jun 2002 eLetter ID: gutjnl_el;21

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

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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) 



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"CJDs (all human TSEs) and Endoscopy Equipment" 

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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

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

snip...see full text;

Friday, September 27, 2019

Prion disease and recommended procedures for flexible endoscope reprocessing – a review of policies worldwide and proposal for a simplified approach Singeltary, GUT journal and Bramble et al 


THURSDAY, SEPTEMBER 26, 2019 

Veterinary Biologics Guideline 3.32E: Guideline for minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics


SATURDAY, SEPTEMBER 21, 2019

National Variability in Prion Disease–Related Safety Policies for Neurologic Procedures


Wednesday, September 11, 2019 

Is the re-use of sterilized implant abutments safe enough? (Implant abutment safety) iatrogenic TSE Prion


FRIDAY, SEPTEMBER 06, 2019 

Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines



MONDAY, AUGUST 26, 2019

Creutzfeldt Jakob Disease CJD, TSE, Prion, Surveillance Update August 2019


SUNDAY, MARCH 10, 2019 

National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated Feb 1, 2019 Variably protease-sensitive prionopathy VPSPr


SUNDAY, DECEMBER 29, 2019 

Variant CJD 18 years of research and surveillance


***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***

***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<*** 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***

***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<*** 

***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***


RESEARCH ARTICLE

Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads

Simone HornemannID1 *, Petra Schwarz1 , Elisabeth J. Rushing1 , Michael D. Connolly3 , Ronald N. Zuckermann3 , Alice Y. Yam2¤ , Adriano AguzziID1 * 1 Institute of Neuropathology, University of Zurich, Zurich, Switzerland, 2 Novartis Vaccines and Diagnostics Inc., Emeryville, California, United States of America, 3 Biological Nanostructures Facility, The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America ¤ Current address: Sutro Biopharma, San Francisco, California, United States of America * Adriano.Aguzzi@usz.ch (AA); Simone.Hornemann@usz.ch (SH)

Abstract

Prions cause transmissible infectious diseases in humans and animals and have been found to be transmissible by blood transfusion even in the presymptomatic stage. However, the concentration of prions in body fluids such as blood and urine is extremely low; therefore, direct diagnostic tests on such specimens often yield false-negative results. Quantitative preanalytical prion enrichment may significantly improve the sensitivity of prion assays by concentrating trace amounts of prions from large volumes of body fluids. Here, we show that beads conjugated to positively charged peptoids not only captured PrP aggregates from plasma of prion-infected hamsters, but also adsorbed prion infectivity in both the symptomatic and preclinical stages of the disease. Bead absorbed prion infectivity efficiently transmitted disease to transgenic indicator mice. We found that the readout of the peptoidbased misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions. The reliable and sensitive detection of prions in plasma will enable a wide variety of applications in basic prion research and diagnostics.


TUESDAY, FEBRUARY 11, 2020 

England Creutzfeldt-Jakob disease (CJD) biannual update (February 2020) Health Protection Report Volume 14 Number 3 11 February 2020


MONDAY, FEBRUARY 10, 2020 

Correlation between Bioassay and Protein Misfolding Cyclic Amplification for Variant Creutzfeldt-Jakob Disease Decontamination Studies


ALL iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.
Tables of Cases Examined

National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated December 9, 2019

Year Total Referrals² Prion Disease Sporadic Familial Iatrogenic vCJD

1999 & earlier 380 230 200 27 3 0

2000 145 102 90 12 0 0

2001 209 118 110 8 0 0

2002 241 144 124 18 2 0

2003 259 160 137 21 2 0

2004 316 181 164 16 0 1³

2005 327 178 156 21 1 0

2006 365 179 159 17 1 2⁴

2007 374 210 191 19 0 0

2008 384 221 205 16 0 0

2009 398 232 210 21 1 0

2010 401 246 218 28 0 0

2011 392 238 214 24 0 0

2012 413 244 221 23 0 0

2013 416 258 223 34 1 0

2014 355 208 185 21 1 1⁵

2015 402 264 244 20 0 0

2016 396 277 248 29 0 0

2017 375 266 247 19 0 0

2018 309 223 204 18 1 0

2019 351 220 183 16 0 0

TOTAL 72086 4399⁷ 3933⁸ 428⁹ 13 4

1Listed based on the year of death or, if not available, on year of referral; 

2Cases with suspected prion disease for which brain tissue was submitted; 

3Disease acquired in the United Kingdom; 

4Disease acquired in the United Kingdom in one case and in Saudi Arabia in the other; 

5Disease possibly acquired in a Middle Eastern or Eastern European country; 

6Includes 20 cases in which the diagnosis is pending, and 19 inconclusive cases; 

7Includes 21 (21 from 2019) cases with type determination pending in which the diagnosis of vCJD has been excluded. 

8The sporadic cases include 3831 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 67 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 35 cases of sporadic Fatal Insomnia (sFI). 

9Total does not include 264 Familial cases diagnosed by blood test only.



''In the 2016 guidance, we recommended that prospective blood donors should be indefinitely deferred if they report having a blood relative with CJD. However, almost all cases reported are sCJD, not a genetic form of CJD. Blood relatives of individuals with sCJD are not at increased risk of developing the disease. The rare genetic forms of CJD (e.g., fCJD, GSS, FFI) share pathophysiological features with sCJD, and the transmission risk by blood components remains theoretical. Consequently, we recommend that establishments may stop asking prospective donors about having blood relatives with CJD.''

Greetings FDA et al, 

I would again kindly like to comment on Docket Number: FDA-2012-D-0307, Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry.

I still believe, that it is extremely dangerous to continue to base the safety of blood from the TSE Prion, by only believing the nvcjd only theory. 

TSE Prion disease have expanded to other species i.e. the camel, and we now know that cwd and scrapie will transmit to pigs by oral routes. 

Chronic Wasting Disease CWD TSE Prion in cervid has exploded across the USA, Canada, Mexico has now clue, Norway, Sweden, Finland, S. Korea, and we know that cwd is detected in the blood of cervid. CWD TSE Prion is highly infectious, and the risk factors from blood there from are very real.

we also know that all iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.

with the blood of cervid and cwd tse prion being detected there from, the science showing that cwd zoonotic potential is now real, the many different strains of cwd to date, with no real factor of how many different strains there are, with science now showing that indeed BSE, Scrapie, and CWD, both typical and atypical strains, showing scientific links to sporadic cjd, and that cwd in humans would would NOT look like nvcjd, but science shows that it would look like sporadic cjd, therefore, iatrogenic cjd from human cwd exposure is very real threat, i find these weakening of rules for blood risk factors from all the different strains of sporadic cjd very worrisome, especially now that officials are classifying vpspr, sgss, sffi, as sporadic cjd cases. we have no clue whether or not these are from iatrogenic events or not. this will be a foolish move if we put once again, corporate interest over human and animal health, but does not surprise me. 

THIS will be very dangerous, and a foolish move for people who need blood, and for the medical and surgical theaters, and humans there from, and simply are not based on sound science imo, but are based on corporate greed. 

WE KNOW now that the real statistics on human TSE Prion IS NOT one in a million, but data now shows that sporadic CJD, 85%+ of all human TSE Prion, the read statistics now show that those figures are one in 5,000. and sporadic cjd is NOT a single strain, but many, many, different strains, and the routes and sources are simply unknown. 

NO WHERE IN SCIENCE LITERATURE HAS THE SPONTANEOUS CJD EVER BEEN PROVEN, without route and source, a happenstance of bad luck, this is simply wishful thinking$ 

TO weaken, instead of enhance and strengthen the risk of sporadic CJD tse prion from blood products by this Docket Number FDA-2012-D-0307 Recommendations, will only enhance the risk of TSE Prion to hemophiliacs, the medical and surgical arenas around the globe

yes, human tse prion are now 1 in 5,000. let that sink in. 

MONDAY, JANUARY 20, 2020
sporadic CJD one in a million, FAKE NEWS PEOPLE!
this myth has been incorrect for decades, and had been stated as such by a few, but again, the media is too lazy to do it's job and print the facts.

Human TSE Prion of which 85%+ there from i.e. sporadic CJD strains, are now documented to be one in 5,000!
https://creutzfeldt-jakob-disease.blogspot.com/2020/01/sporadic-cjd-one-in-million-fake-news.html

FRIDAY, JANUARY 31, 2020

CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307


THURSDAY, JANUARY 30, 2020 

Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission


ALL iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.

Terry S. Singeltary Sr.

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