Sunday, January 31, 2016

Differential Toxicity of Antibodies to the Prion Protein

Differential Toxicity of Antibodies to the Prion Protein
 
Regina R. Reimann , Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Tiziana Sonati , Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Simone Hornemann, Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Uli S. Herrmann, Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Michael Arand, Affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
 
⨯ Simon Hawke, Affiliation: Vascular Immunology Laboratory, Department of Pathology, University of Sydney, Camperdown, Australia
 
⨯ Adriano Aguzzi * E-mail: adriano.aguzzi@usz.ch
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Differential Toxicity of Antibodies to the Prion Protein Regina R. Reimann, Tiziana Sonati, Simone Hornemann, Uli S. Herrmann, Michael Arand, Simon Hawke, Adriano Aguzzi PLOS x Published: January 28, 2016 DOI: 10.1371/journal.ppat.1005401
 
Abstract Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.
 
Author Summary The human prion disease, Creutzfeldt-Jakob disease (CJD), is a progressive neurodegenerative syndrome. Although far less prevalent, CJD shows many molecular and clinical similarities to Alzheimer's disease, such as the buildup of protein aggregates in the brain and the absence of effective treatments. Many attempts at immunotherapy for Alzheimer’s disease are being reported in specialized journals and in the lay press, and have been linked to strong hopes for a cure. The same therapeutic strategy appears plausible for Creutzfeldt-Jakob disease, and indeed, there are some encouraging preclinical studies. However, there have also been reports that antibodies against the prion protein (PrPC) can also wreak damage on the brain. We have gathered evidence that various antiprion antibodies vary not only in their efficacy but also in their potential to induce serious untoward effects. In a dose-escalation study, we report that all antibodies against a set of epitopes in the globular domain of the prion protein display acute neurotoxicity. These issues need to be carefully assessed before considering any clinical studies involving human subjects.
 
 
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
 
26/01/2016 By Karl Frontzek, et al.:
 
 
Original article | Published 26 January 2016, doi:10.4414/smw.2016.14287
 
Cite this as: Swiss Med Wkly. 2016;146:w14287
 
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
 
 
MY comment as follows ;
 
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
 
07 02:27 AM
 
Terry S. Singeltary Sr. said:
 
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
 
2015-12-07 02:27 AM
 
Terry S. Singeltary Sr. said: 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)
 
 
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.]
 
 
 
 
Terry S. Singeltary Sr. Bacliff, Texas USA 77518
 
snip...see Singeltary comment ;
 
 
Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
 
BSE101/1 0136
 
IN CONFIDENCE
 
CMO
 
From: . Dr J S Metiers DCMO
 
4 November 1992
 
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
 
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. 'This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
 
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed". As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.
 
what are the implications for public health?
 
3. The route 'of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
 
1
 
92/11.4/1.1
 
BSE101/1 0137
 
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required’’ before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
 
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2
 
 
>>> 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 ?
 
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
 
 
 
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, 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,
 
 
Thursday, January 14, 2016
 
Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical Device Safety Fails Patients REPORT
 
how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!
 
how many victims that will never be reported ???
 
 
Sunday, January 17, 2016
 
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
 
 
Saturday, December 12, 2015
 
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
 
 
Tuesday, January 26, 2016
 
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
 
 
Tuesday, January 26, 2016
 
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
 
 
 Terry S. Singeltary Sr. Bacliff, Texas

Saturday, April 6, 2013

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

 

Scientists Identify First Potentially Effective Therapy for Human Prion Disease





By Eric Sauter





Human diseases caused by misfolded proteins known as prions are some of most rare yet terrifying on the planet—incurable with disturbing symptoms that include dementia, personality shifts, hallucinations and coordination problems. The most well-known of these is Creutzfeldt-Jakob disease, which can be described as the naturally occurring human equivalent of mad cow disease.




Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time identified a pair of drugs already approved for human use that show anti-prion activity and, for one of them, great promise in treating these universally fatal disorders.




The study, led by TSRI Professor Corinne Lasmézas and performed in collaboration with TSRI Professor Emeritus Charles Weissmann and Director of Lead Identification Peter Hodder, was published this week online ahead of print by the journal Proceedings of the National Academy of Sciences.




The new study used an innovative high-throughput screening technique to uncover compounds that decrease the amount of the normal form of the prion protein (PrP, which becomes distorted by the disease) at the cell surface. The scientists found two compounds that reduced PrP on cell surfaces by approximately 70 percent in the screening and follow up tests.




The two compounds are already marketed as the drugs tacrolimus and astemizole.




Tacrolimus is an immune suppressant widely used in organ transplantation. Tacrolimus could prove problematic as an anti-prion drug, however, because of issues including possible neurotoxicity.




However, astemizole is an antihistamine that has potential for use as an anti-prion drug. While withdrawn voluntarily from the U.S. over-the-counter market in 1999 because of rare cardiac arrhythmias when used in high doses, it has been available in generic form in more than 30 countries and has a well-established safety profile. Astemizole not only crosses the blood-brain barrier, but works effectively at a relatively low concentration.




Lasmézas noted that astemizole appears to stimulate autophagy, the process by which cells eliminate unwanted components. “Autophagy is involved in several protein misfolding neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases,” she said. “So future studies on the mode of action of astemizole may uncover potentially new therapeutic targets for prion diseases and similar disorders.”




The study noted that eliminating cell surface PrP expression could also be a potentially new approach to treat Alzheimer’s disease, which is characterized by the build-up of amyloid β plaque in the brain. PrP is a cell surface receptor for Aβ peptides and helps mediate a number of critical deleterious processes in animal models of the disease.




The first author of the study, “Unique Drug Screening Approach for Prion Diseases Identifies Tacrolimus and Astemizole as Antiprion Agents,” is Yervand Eduard Karapetyan of The Scripps Research Institute. Other authors include Gian Franco Sferrazza, Minghai Zhou, Gregory Ottenberg, Timothy Spicer, Peter Chase, Mohammad Fallahi, Peter Hodder and Charles Weissmann of The Scripps Research Institute. For more information on the study, see




http://www.pnas.org/content/early/2013/03/29/1303510110.abstract





The research was supported by The Scripps Research Institute, the Alafi Foundation and the National Institutes of Health (Grant MH084512).


 


 
Send comments to: mikaono@scripps.edu






http://www.scripps.edu/newsandviews/e_20130408/lasmezas.html







Sent: Thursday, April 04, 2013 5:04 PM
Subject: Re: [BSE-L] Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

Abstract

Prion diseases such as Creutzfeldt–Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP–FRET-enabled high throughput assay (PrP–FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identifiedastemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the blood–brain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform.

Footnotes

  • 1Y.E.K. and G.F.S. contributed equally to this work.
  • 2Present address: Oncological Dispensary, Histopathology, Stepanakert, Nagorno-Karabakh Republic, 375000 Azerbaijan.
  • 3Present address: OPKO Health Inc., Diagnostic Research, Jupiter, FL 33458.
  • 4To whom correspondence may be addressed. E-mail: lasmezas@scripps.edu or charlesw@scripps.edu.
  • Author contributions: P.H., C.W., and C.I.L. designed research; Y.E.K., G.F.S., M.Z., G.O., T.S., and P.C. performed research; Y.E.K., G.F.S., M.Z., G.O., T.S., P.C., M.F., P.H., C.W., and C.I.L. analyzed data; and C.I.L. wrote the paper.
  • The authors declare no conflict of interest.
  • This article contains supporting information online at
  •  


      http://www.pnas.org/content/early/2013/03/29/1303510110.abstract?sid=ccdac972-b912-4d19-8ba0-48399d33eeee






      Воскресенье, 31 марта 2013, 11:35 -05:00 от "Terry S. Singeltary Sr." :

      Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray
      'Pray por Cristina' video highlights prayer movement for girl with degenerative disease
      Date: 2013-03-31 08:00:00
      March 31, 2013. (ROMEREPORTS.COM) (-VIDEO ONLY-) A social network that allows users to ask and give prayers, MayFeelings.com, published the story of one of its youngest members. Her name is Cristina and is the youngest person in the world that suffers from a degenerative neurological disease called Creutzfeldt-Jakob, a fatal condition that attacks the brain.
      Her parents have tried all they can to try to save her, but no known cure of the disease has been developed. As a result, his father Juan Perican uploaded her story to the social network, which has drawn support from thousands throughout the world.
      Using the hashtag #prayporcristina on Twitter, they ask for prayers. “People call us asking if we need anything, money, if they could help us... but we only want to be with Cristina. We thank them a lot of their support, but we always tell them the same thing: the only thing they can do is pray,” her mother explains in the video.
       
       
       
      sporadic CJD, 11 year old victim, 2 year clinical course to date ???
      Saturday, March 23, 2013
      CJD Incidents Panel to be disbanded
      Thursday, February 21, 2013
      National Prion Disease Pathology Surveillance Center Cases Examined January 16, 2013
      16 YEAR OLD SPORADIC FFI ?
      Monday, January 14, 2013
      Gambetti et al USA Prion Unit change another highly suspect USA mad cow victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes along with this BSe
      Monday, December 31, 2012
      Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State, 2006–2011-2012
      Tuesday, December 25, 2012
      CREUTZFELDT JAKOB TSE PRION DISEASE HUMANS END OF YEAR REVIEW DECEMBER 25, 2012
      Tuesday, June 26, 2012
      Creutzfeldt Jakob Disease Human TSE report update North America, Canada, Mexico, and USDA PRION UNIT as of May 18, 2012
      type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the rise in Canada and the USA
      Wednesday, June 13, 2012
      MEXICO IS UNDER or MIS DIAGNOSING CREUTZFELDT JAKOB DISEASE AND OTHER PRION DISEASE SOME WITH POSSIBLE nvCJD
      *** 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, March 28, 2012
      VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $
      Tuesday, March 5, 2013
      Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)
      FDA believes current regulation protects the public from BSE but reopens comment period due to new studies
      Tuesday, March 05, 2013
      A closer look at prion strains Characterization and important implications Prion
      7:2, 99–108; March/April 2013; © 2013 Landes Bioscience
      Wednesday, March 20, 2013
      GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Product
      From: Terry S. Singeltary Sr.
      Sent: Tuesday, March 19, 2013 2:46 PM
      To: gomezj@gao.gov
      Cc: siggerudk@gao.gov ; youngc1@gao.gov ; wlmailhtml:sentmsg?mailto=mailto%3aoighotline@gao.gov
      Wednesday, February 20, 2013
      World Organization for Animal Health Recommends United States' BSE Risk Status Be Upgraded
      Statement from Agriculture Secretary Tom Vilsack:
      Thursday, February 14, 2013
      The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease
      TSS
      Sunday, March 31, 2013
      Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray



      Yervand Karapetyan
      Post-Graduate student
      Department of Pathology
      Yerevan State Medical University
      Koryun str, 2
      Yerevan 375025
      Republic of Armenia
      tel: 003741 268131
      fax: 003741 527284
      email:yervandkar@yahoo.com