Saturday, July 22, 2017

Why the U.S. Needs to Continue Prion Disease Surveillance, instead of reducing funding to zero

-----Original Message-----
From: Terry Singeltary
To: desiree_mowry
Cc: Joshua.Jackson
Sent: Fri, Jul 21, 2017 12:32 pm
Subject: Why the U.S. Needs to Continue Prion Disease Surveillance, instead of reducing funding to zero

Greetings Honorable Senator Roy Blunt and Congress Tom Cole et al, 

I’m writing to address my extreme concerns about Creutzfeldt-Jakob Disease (CJD) and the importance of funding Prion Disease surveillance through the CDC. 
 
I am requesting your urgent attention to the need to support Prion Disease Surveillance funding in the FY18 budget of the Centers for Disease Control.  

PLEASE ensure that at least, at the minimum, $6 million is provided in the FY18 appropriations bill for the CDC for Prion Disease activities?

This funding is critical to surveilling and diagnosing CJD cases, and determining whether Mad Cow Disease and Chronic Wasting Disease in deer and elk have been transmitted to humans.  

The Administration has made a very unfortunate proposal to eliminate this funding.  

I urge you to contact the Labor/HHS/Education Appropriations Subcommittee to ensure that they retain in their FY18 spending bill the $6 million in CDC funds allocation for Prion Disease Surveillance.  

This funding was included in FY17 and has been provided for the past 20 years. 
 
Prion diseases including CJD occur when an otherwise normal protein misfolds and replicates rapidly.  It attacks the brain and produces a swift, fatal neurodegeneration.  There are several types of Prion diseases – some triggered by a genetic marker, some that are spontaneous for which the causes are not well understood, and some that are transmissible.
 
I lost my mother to the Heidenhain Variant of Creutzfeldt Jakob Disease December 14, 1997, confirmed. something i would not wish on my worst enemy. sporadic cjd cases have been rising around the globe.
 
Animal forms of Prion disease include Bovine Spongiform Encephalopathy (BSE or Mad Cow Disease) and Chronic Wasting Disease (CWD) in Deer and Elk.   

Mad Cow Disease devastated European cattle herds in the 1990s and infected and killed hundreds of humans (in the form of “variant CJD”). The USA just announced another case of atypical BSE in Alabama L-type BASE, which has now been linked to sporadic CJD, and transmits to cattle.
 
CWD has now spread to 22 states in about 15 years.  Because of its slow incubation period, it is not yet known whether CWD has spread to humans.  ***However, in a recent study where primates genetically similar to humans were fed infected deer meat, they developed fatal prion disease six years later. 

(see study and video of the recent PRION 2017 Conference and updated science zoonosis from prion 2015, 2016, and 2017 conferences reference materials at the bottom...TSS)

Scrapie in sheep and goats have now been linked to humans as sporadic CJD (see recent science below...tss)
 
Of exceptional importance in the fight against Prion Diseases is the $6 million in funding provided to the Centers for Disease Control for “Prion Disease” through the Labor/HHS/Education Appropriations Bill.   This funding supports CDC surveillance and education efforts and – of critical importance – it supports the National Prion Disease Pathology Surveillance Center (NPDPSC, the Center). 
 
Through autopsy, the Center identifies the various strains of Prion Disease and helps monitor whether animal forms of the disease (including “Variant CJD,” transmitted through Mad Cow Disease) are affecting humans, whether the disease is being transmitted through medical procedures (blood transfusions, transplants, or surgical instruments), or whether it was genetic or sporadically occurring.   The Center has developed cutting-edge testing to diagnose Prion Disease through autopsy and spinal fluid diagnostics, as well as genetic testing.
 
For 20 years, the Center has been developing a bio-repository of over 6,000 brains donated post-mortem and over 100,000 other tissue samples in a bio-safety level 2/3 facility.  This repository is critical to ongoing surveillance and would need to be destroyed if funding were stopped. 
 
The Center also serves as a critical resource for families and the medical community.  The Center helps providers to recognize possible cases of Prion Disease and refer families for testing and assistance.  Many families face great difficulty in dealing with providers who lack an understanding of the disease and its progression, or funeral homes that refuse to accept bodies based on misunderstanding of infection risk. 
 
The President’s Budget for FY18 proposed eliminating the CDC’s Prion Disease funding with little explanation other than a claim that it is redundant.  This is patently incorrect.  The USDA involvement is limited to testing some cattle and enforcing cattle processing regulations.  The NIH supports some basic biomedical research in Prion Disease.  Only the CDC and the NPDPSC are undertaking human surveillance, public health, diagnostic testing, bio-banking, and transmissibility studies for Prion Disease.
 
Will you please contact [Select: Senate Labor/HHS Chairman Blunt or House Labor/HHS Chairman Cole] to ask them to ensure that $6 million is provided in the FY18 appropriations bill for the CDC for Prion Disease activities?
 
Thank you for your consideration of this request. I will follow up with you soon.

Why the U.S. Needs to Continue Prion Disease Surveillance

• Prion diseases are fatal, rapidly progressive neurodegenerative conditions that have no treatment. The most common prion disease, CJD (Creutzfeldt-Jakob Disease), can occur in humans several ways: sporadically, genetically, or acquired (transmitted through medical or food sources).

• It is not possible to definitively confirm a CJD case or to determine whether it is sporadic, genetic, or acquired without looking at brain tissue, which is typically done through full-brain autopsy. The National Prion Disease Pathology Surveillance Center (NPDPSC) performs autopsy and other testing including spinal fluid and blood.

• In the past, CJD has been transmitted by medical procedures, transplants, human growth hormone (HGH), and pregnancy hormones, food sources, and blood.

• Variant CJD (vCJD) is acquired by consuming meat contaminated by Bovine Spongiform Encephalopathy (BSE, or “mad cow disease.”) Contaminated feed triggered the mad cow outbreak, but BSE can also occur naturally in cattle. Variant CJD is transmissible in humans through blood. CJD has been shown to lie dormant in individuals for up to 50 years.

• The USDA recently reduced the number of cattle is tests for BSE to just 25,000 cattle per year. Thus, human autopsy in cases of suspected CJD is the only truly reliable screen for vCJD in the U.S. This is evident when countries like South Korea monitor US human surveillance to determine whether to allow import of U.S. beef. The UK also imports plasma products from the US because they are confident that U.S. human surveillance at the NPDPSC that would identify vCJD cases.

• Chronic Wasting Disease (CWD) deer and elk presents a disturbing challenge in combatting prion disease. CWD is highly contagious among cervids, spreading from animal to animal through environmental contamination, including soil and plants, and has spread from 2 to 22 states since 2000. • An ongoing study points to the fact that macaques (primates that are genetically close to humans) acquired CWD through oral consumption of infected deer meat. This opens the question of whether humans can acquire CWD from eating deer meat. And if so, how will that disease appear in human brain tissue? The NPDPSC is studying this and collaborating with researchers to learn more.

• All US surveillance of human prion disease is done through the NPDPSC, funded through the CDC.

• NPDPSC is the only center in the U.S. to conduct state of the art testing of spinal fluid and genetic testing for prion diseases like CJD.

• Because they maintain a bank of brain tissue, the NPDPSC is also able to support research and collaborate with research centers. Research is also done through private and NIH funding. NIH-funded research identified an important test to detect prions in spinal fluid, RT-QuIC, which is conducted by the NPDPSC to diagnose CJD.

• Prion Disease research has laid groundwork for discoveries about other diseases including Alzheimer’s , Parkinson’s, and ALS. After the “prion” protein was discovered, these other neurodegenerative diseases were also discovered to be caused by errant proteins. They are now referred to as “prion-like,” and prion disease research has aided discoveries in these other areas as well.

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

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 

 Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO

PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS

PRION 2017 CONFERENCE VIDEO



Chronic Wasting Disease CWD TSE Prion to Humans, who makes that final call, when, or, has it already happened?

TUESDAY, JUNE 13, 2017

PRION 2017 CONFERENCE ABSTRACT First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress


FRIDAY, JUNE 16, 2017

P55 Susceptibility of human prion protein to in vitro conversion by chronic wasting disease prions


TUESDAY, JUNE 13, 2017

PRION 2017 CONFERENCE ABSTRACT Chronic Wasting Disease in European moose is associated with PrPSc features different from North American CWD


TUESDAY, JULY 04, 2017

*** PRION 2017 CONFERENCE ABSTRACTS ON CHRONIC WASTING DISEASE CWD TSE PRION ***


SUNDAY, JULY 16, 2017

*** Temporal patterns of chronic wasting disease prion excretion in three cervid species ***


Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

Location: Virus and Prion Research

Title: Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

Author item Moore, Sarah item Kunkle, Robert item Kondru, Naveen item Manne, Sireesha item Smith, Jodi item Kanthasamy, Anumantha item West Greenlee, M item Greenlee, Justin

Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 3/15/2017 Publication Date: N/A Citation: N/A Interpretive Summary:

Technical Abstract: Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study, neurological signs consistent with prion disease were observed only in one pig: an intracranially challenged pig that was euthanized at 64 months post-challenge. The purpose of this study was to use an antigen-capture immunoassay (EIA) and real-time quaking-induced conversion (QuIC) to determine whether PrPSc is present in lymphoid tissues from pigs challenged with the CWD agent.

Methods: At two months of age, crossbred pigs were challenged by the intracranial route (n=20), oral route (n=19), or were left unchallenged (n=9). At approximately 6 months of age, the time at which commercial pigs reach market weight, half of the pigs in each group were culled (<6 challenge="" groups="" month="" pigs="" remaining="" the="">6 month challenge groups) were allowed to incubate for up to 73 months post challenge (mpc). The retropharyngeal lymph node (RPLN) was screened for the presence of PrPSc by EIA and immunohistochemistry (IHC). The RPLN, palatine tonsil, and mesenteric lymph node (MLN) from 6-7 pigs per challenge group were also tested using EIA and QuIC.

Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%). Conclusions:

This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge.

CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease.

Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.


CONFIDENTIAL

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...


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


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


 snip...see much more here ;

WEDNESDAY, APRIL 05, 2017

Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease


*** THURSDAY, JULY 20, 2017 ***
 
*** USDA OIE Alabama Atypical L-type BASE Bovine Spongiform Encephalopathy BSE animal feeds for ruminants rule, 21 CFR 589.200
 
 
OIE REPORT Bovine spongiform encephalopathy United States of America
 
 
TUESDAY, APRIL 18, 2017 

*** EXTREME USA FDA PART 589 TSE PRION FEED LOOP HOLE STILL EXIST, AND PRICE OF POKER GOES UP ***


TUESDAY, MARCH 28, 2017 

*** Passage of scrapie to deer results in a new phenotype upon return passage to sheep ***


MONDAY, JULY 17, 2017 

National Scrapie Eradication Program May 2017 Monthly Report Fiscal Year 2017


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

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




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. 


 -------- Original Message -------- 

Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD 

Date: Thu, 28 Nov 2002 10:23:43 -0000 From: "Asante, Emmanuel A" e.asante@ic.ac.uk 


Dear Terry, 

I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention. 

Thank you for your interest in the paper. In respect of your first question, the simple answer is, ***yes. 

As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. 

It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. 

It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. 

The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. 

I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask. 

Best wishes. Emmanuel Asante <> 

____________________________________ 

Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02) New e-mail: e.asante@prion.ucl.ac.uk (active from now) 

________

end...TSS

________


***********OCTOBER 2015*************

*** PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS ***

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

P.108: Successful oral challenge of adult cattle with classical BSE

Sandor Dudas1,*, Kristina Santiago-Mateo1, Tammy Pickles1, Catherine Graham2, and Stefanie Czub1 1Canadian Food Inspection Agency; NCAD Lethbridge; Lethbridge, Alberta, Canada; 2Nova Scotia Department of Agriculture; Pathology Laboratory; Truro, Nova Scotia, Canada

Classical Bovine spongiform encephalopathy (C-type BSE) is a feed- and food-borne fatal neurological disease which can be orally transmitted to cattle and humans. Due to the presence of contaminated milk replacer, it is generally assumed that cattle become infected early in life as calves and then succumb to disease as adults. Here we challenged three 14 months old cattle per-orally with 100 grams of C-type BSE brain to investigate age-related susceptibility or resistance. During incubation, the animals were sampled monthly for blood and feces and subjected to standardized testing to identify changes related to neurological disease. At 53 months post exposure, progressive signs of central nervous system disease were observed in these 3 animals, and they were euthanized. Two of the C-BSE animals tested strongly positive using standard BSE rapid tests, 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. 

***Our study demonstrates susceptibility of adult cattle to oral transmission of classical BSE. 

We are further examining explanations for the unusual disease presentation in the third challenged animal.


***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.

P.86: Estimating the risk of transmission of BSE and scrapie to ruminants and humans by protein misfolding cyclic amplification

Morikazu Imamura, Naoko Tabeta, Yoshifumi Iwamaru, and Yuichi Murayama National Institute of Animal Health; Tsukuba, Japan

To assess the risk of the transmission of ruminant prions to ruminants and humans at the molecular level, we investigated the ability of abnormal prion protein (PrPSc) of typical and atypical BSEs (L-type and H-type) and typical scrapie to convert normal prion protein (PrPC) from bovine, ovine, and human to proteinase K-resistant PrPSc-like form (PrPres) using serial protein misfolding cyclic amplifi- cation (PMCA).

Six rounds of serial PMCA was performed using 10% brain homogenates from transgenic mice expressing bovine, ovine or human PrPC in combination with PrPSc seed from typical and atypical BSE- or typical scrapie-infected brain homogenates from native host species. In the conventional PMCA, the conversion of PrPC to PrPres was observed only when the species of PrPC source and PrPSc seed matched. However, in the PMCA with supplements (digitonin, synthetic polyA and heparin), both bovine and ovine PrPC were converted by PrPSc from all tested prion strains. On the other hand, human PrPC was converted by PrPSc from typical and H-type BSE in this PMCA condition.

Although these results were not compatible with the previous reports describing the lack of transmissibility of H-type BSE to ovine and human transgenic mice, 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.


P.170: Potential detection of oral transmission of H type atypical BSE in cattle using in vitro conversion

***P.170: Potential detection of oral transmission of H type atypical BSE in cattle using in vitro conversion

Sandor Dudas, John G Gray, Renee Clark, and Stefanie Czub Canadian Food Inspection Agency; Lethbridge, AB Canada

Keywords: Atypical BSE, oral transmission, RT-QuIC

The detection of bovine spongiform encephalopathy (BSE) has had a significant negative impact on the cattle industry worldwide. In response, governments took actions to prevent transmission and additional threats to animal health and food safety. While these measures seem to be effective for controlling classical BSE, the more recently discovered atypical BSE has presented a new challenge. To generate data for risk assessment and control measures, we have challenged cattle orally with atypical BSE to determine transmissibility and mis-folded prion (PrPSc) tissue distribution. Upon presentation of clinical symptoms, animals were euthanized and tested for characteristic histopathological changes as well as PrPSc deposition.

The H-type challenged animal displayed vacuolation exclusively in rostral brain areas but the L-type challenged animal showed no evidence thereof. To our surprise, neither of the animals euthanized, which were displaying clinical signs indicative of BSE, showed conclusive mis-folded prion accumulation in the brain or gut using standard molecular or immunohistochemical assays. To confirm presence or absence of prion infectivity, we employed an optimized real-time quaking induced conversion (RT-QuIC) assay developed at the Rocky Mountain Laboratory, Hamilton, USA.

Detection of PrPSc was unsuccessful for brain samples tests from the orally inoculated L type animal using the RT-QuIC. It is possible that these negative results were related to the tissue sampling locations or that type specific optimization is needed to detect PrPSc in this animal. We were however able to consistently detect the presence of mis-folded prions in the brain of the H-type inoculated animal. Considering the negative and inconclusive results with other PrPSc detection methods, positive results using the optimized RT-QuIC suggests the method is extremely sensitive for H-type BSE detection. This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.




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. ***

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.

see page 176 of 201 pages...tss


*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply;


***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 flounder on 03 Jul 2015 at 16:53 GMT 


2014 

***Moreover, L-BSE has been transmitted more easily to transgenic mice overexpressing a human PrP [13,14] or to primates [15,16] than C-BSE. 

***It has been suggested that some sporadic CJD subtypes in humans may result from an exposure to the L-BSE agent. 

*** Lending support to this hypothesis, pathological and biochemical similarities have been observed between L-BSE and an sCJD subtype (MV genotype at codon 129 of PRNP) [17], and between L-BSE infected non-human primate and another sCJD subtype (MM genotype) [15]. 

snip... 


Saturday, April 23, 2016

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

Juan Maria Torres a, Olivier Andreoletti b, Juan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,

Natalia Fernandez-Borges a. and Alba Marin-Moreno a

"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie Mol├ęcuIaires, Jouy-en-Josas. France

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.

To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.

These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.

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. 


SPONTANEOUS ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY

***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.***


why do we not want to do TSE transmission studies on chimpanzees $

5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.

snip...

R. BRADLEY


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. 


TUESDAY, JULY 18, 2017 

MINK FARMING USA TRANSMISSIBLE MINK ENCEPHALOPATHY TSE PRION DISEASE SURVEILLANCE AND TESTING


National Prion Center could lose all funding just as concern about CWD jumping to humans rises

SATURDAY, JULY 15, 2017 

National Prion Center could lose all funding just as concern about CWD jumping to humans rises


ALZHEIMER'S DISEASE, TSE PRION, iatrogenic, WHAT IF?

>>> 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-╬▓ 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;
 
 
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
 
 
Sunday, November 22, 2015
 
*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract
 
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.
 
Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00
 
 

Ann N Y Acad Sci. 1982;396:131-43. 

Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease). 

Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC. 

Abstract 

Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

 
*** 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.
 
 
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
 
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
 
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
 
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
 
Terry S. Singeltary, Sr Bacliff, Tex
 
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
 

Needless Conflict



with extreme urgency and sincerity, 

Terry S. Singeltary Sr.

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