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 While withdrawn voluntarily from the U.S. over-the-counter market in 1999 because of rare cardiac arrhythmias when used in high doses, it has been available in generic form in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

  1. Yervand Eduard Karapetyana,1,2,
  2. Gian Franco Sferrazzaa,1,3,
  3. Minghai Zhoua,
  4. Gregory Ottenberga,3,
  5. Timothy Spicerb,
  6. Peter Chaseb,
  7. Mohammad Fallahic,
  8. Peter Hodderb,
  9. Charles Weissmanna,4, and
  10. Corinne Ida Lasmézasa,4
Author Affiliations
  1. Contributed by Charles Weissmann, March 4, 2013 (sent for review January 31, 2012)

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

      Posted by at No comments:

      Tuesday, April 2, 2013

      Human prion diseases: progress in clinical trials

      Human prion diseases: progress in clinical trials




      Inga Zerr, MD




      + Author Affiliations




      National TSE Reference Centre Clinical Dementia Centre Department of Neurology University Medical School Georg-August University Goettingen, Germany




      Correspondence to: Inga Zerr. E-mail: epicjd@med.uni-goettingen.de




      The progress made in understanding disease pathology and phenomenology in prion disorders and recent advances in diagnostic techniques might encourage researchers now to consider therapeutic trials in patients with Creutzfeldt–Jakob disease. Although attempts have been made in the past (Trevitt and Collinge, 2006; Stewart et al., 2008), the drugs tested involved a variety of compounds that belong to antimicrobial, anti-inflammatory or analgesic substance classes and most of the studies are limited to extremely small series or single case reports. Controlled trials are rare but progress in diagnostic techniques, such as imaging, CSF biomarkers and recently developed methods to detect abnormal prion protein in easily accessible body fluids, will hopefully lead to early diagnosis of the disease. Although clinical trials are difficult to perform, they are feasible and clinicians must contemplate several specific problems when evaluating the efficacy of a drug in Creutzfeldt-Jakob disease.




      Sporadic Creutzfeldt–Jakob disease is the most common human prion disease form, but still rare, with an annual incidence range between one and two cases per million per year worldwide (Ladogana et al., 2005). Any potential benefit of a drug must be proven on a large number of patients. Low disease incidence and prevalence are therefore problematic in terms of sample size. The median disease duration reported for all forms of sporadic Creutzfeldt–Jakob disease is ∼6 months (Pocchiari et al., 2004; Heinemann et al., 2007). The disease duration varies, and major determinants of survival such as age at onset, gender and PRNP codon 129 genotype have been identified (Ladogana et al., 2005). Unlike more chronic neurological disorders, prolonging survival from time of diagnosis offers one obvious and tractable outcome for a clinical trial. However, because of rapid disease progression, the clinical diagnosis of Creutzfeldt–Jakob disease is frequently not made until middle and late disease stages.




      There is a wide scope of clinical phenomenology in human prion disease with respect to presenting features, rate of progression and appearance of other clinical manifestation (Parchi et al., 1999; Zerr et al., 2000; Heinemann et al., 2007). Phenotypic variability in the clinical syndrome and neuropathological changes in sporadic Creutzfeldt-Jakob disease were recognized long ago and some attempts have been made to define disease subtypes based on a molecular disease classification (Parchi et al., 1999). But as with many neurological disorders, heterogeneity of the clinical and pathological phenotype may reduce power even if an adequate sample can be recruited for a particular study.




      Taking these considerations into account, clinicians face important decisions when designing a trial to assess efficacy and safety in the context of Creutzfeldt–Jakob disease. Scales have been designed to monitor disease progression in Alzheimer’s disease; and for vascular dementia and frontotemporal dementia (Braaten et al., 2006). Unfortunately, these systems are not suitable for monitoring cognitive decline in patients with Creutzfeldt-Jakob disease because of the different neuropsychological profiles. Also, neurological abnormalities such as ataxia, rigidity or myoclonus need to be monitored in a standard way. Because of the variability in clinical syndromes across molecular Creutzfeldt–Jakob disease subtypes, specific scales, weighted for particular subtypes, would be needed. Anticipating this issue, trial protocols need to include a variety of rating scales designed to probe neurological, cognitive, psychiatric and general functional status.




      The paper by Andrew Thompson and colleagues in the current issue of Brain directly addresses these issues. The goal was to develop a rating scale for the progression of symptoms in prion diseases (the MRC Prion Disease Rating Scale) that could be used as an outcome measure in future clinical trials, as no single scale has been able to capture progression across the full range of functional domains affected in patients with prion diseases. The analysis was performed on data obtained from 437 clinical trial participants over a period of several years. Scale development included semi-quantitative and qualitative carer interviews, item response modelling, inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point MRC Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence. An important point is that the items are weighted according to their relative importance documented by interview with carers. Another advantage is easy application; the scale can be used over the telephone and will allow frequent assessments, which are necessary because of the rapid progression of the disease.




      This is an important and timely study and analysis was carried out in a large cohort. The study addresses a fundamental issue in clinical trials of prion diseases: which scales can be used to monitor the rapid change in several domains including cognitive, motor and global decline? The scales need to be validated in future prospective studies on prion diseases but potentially other rapid progressive neurological conditions too (including Alzheimer’s disease or dementia with Lewy bodies with rapid progression). Clinical research in rare diseases is extremely challenging for logistic, statistical and financial reasons and systematic data collection in a multi-centre/multi-national setting is required to obtain sufficient information in a reasonable time frame. The work presented here is one important step towards achieving the challenging goal to find and then evaluate an effective treatment, or even a cure, for this devastating disorder. © The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain.




      This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.




      References ↵




      Braaten AJ, Parsons TD, McCue R, Sellers A, Burns WJ . Neurocognitive differential diagnosis of dementing disease: Alzheimer's dementia, vascular dementia, frontotemporal dementia, and major depressive disorder. Int J Neurosci 2006;116:1271-93. CrossRefMedline




      Heinemann U, Krasnianski A, Meissner B, Varges D, Bartl M, Stoeck K, et al . Creutzfeldt-Jakob disease in Germany: a prospective 12-year surveillance. Brain 2007;130:1350-9. Abstract/FREE Full Text




      Ladogana A, Puopolo M, Croes EA, Budka H, Jarius C, Collins S, et al . Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 2005;64:1586-91. CrossRef




      Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224-33. CrossRefMedlineWeb of Science




      Pocchiari M, Poupolo M, Croes EA, Budka H, Gelpi E, Collins S, et al . Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 2004;10:2348-59. Search Google Scholar




      Stewart LA, Rydzewska LH, Keogh GF, Knight RS . Systematic review of therapeutic interventions in human prion diseases. Neurology 2008;70:1272-81. CrossRef




      Trevitt CR, Collinge J . A systematic review of prion therapeutics in experimental models. Brain 2006;129:2241-65. Abstract/FREE Full Text




      Zerr I, Schulz-Schaeffer WJ, Giese A, Bodemer M, Schröter A, Henkel K, et al . Current clinical diagnosis in CJD: identification of uncommon variants. Ann Neurol 2000;48:323-9.











      The Medical Research Council Prion Disease Rating Scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies




      Andrew G.B. Thompson1,2, Jessica Lowe1,2, Zoe Fox3, Ana Lukic1,2, Marie-Claire Porter1,2, Liz Ford2, Michele Gorham2, Gosala S. Gopalakrishnan2, Peter Rudge1,2, A. Sarah Walker4, John Collinge1,2 and Simon Mead1,2




      + Author Affiliations




      1 MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, UCLH NHS Trust, Queen Square, London, UK




      2 National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH NHS Trust, Queen Square, London, UK




      3 Joint Research Office Biostatistics Unit, UCL, and Education Unit, UCL Institute of Neurology, London, UK




      4 MRC Clinical Trials Unit, London, UK




      Correspondence to: Professor John Collinge, MD, FRS, FRCP, MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK E-mail: j.collinge@prion.ucl.ac.uk Received October 31, 2012. Revision received December 18, 2012. Accepted January 31, 2013.




      Summary




      Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the UK National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will often struggle to achieve statistical power.




      Key words prion cohort rating scale outcome measure CJD










      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 ; oighotline@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








      Sunday, March 31, 2013


      Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray









      TSS
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      Monday, December 24, 2012

      Immunotherapy in prion disease

      Review Nature Reviews Neurology, advance online publication, Published online 18 December 2012 | doi:10.1038/nrneurol.2012.258


      Subject Categories: Spongiform encephalopathies | Neurodegenerative disease


      Immunotherapy in prion disease


      Yvonne Roettger, Yansheng Du, Michael Bacher, Inga Zerr, Richard Dodel & Jan-Philipp Bach About the authors


      Top of page Abstract Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, describe a group of fatal neurodegenerative disorders affecting both humans and animals. Accumulation of misfolded prion proteins is the pathological hallmark of these disorders; such accumulation occurs in lymphoreticular tissue prior to CNS involvement in scrapie, experimental models and human variant Creutzfeldt–Jakob disease. Lymphoreticular accumulation of misfolded prion protein has not been demonstrated in human sporadic or genetic forms of TSE. Once clinical symptoms develop, all prion disorders have a rapidly progressive and lethal course, and no effective therapy exists. In the past 10 years, antibody-based immunotherapy has been considered for other neurodegenerative disorders associated with protein misfolding and, therefore, might also be an effective approach to prevention or treatment of prion disease. Self-tolerance to endogenous prion protein is, however, a major challenge to the development of effective immunotherapy, as is the risk of adverse effects from active immunization. This Review summarizes the evidence that immunization could slow disease progression or increase lifespan in animal models of prion diseases. The therapeutic potential of these strategies in treating patients with prion diseases is also discussed.


      Top of page Author affiliations Y. Roettger, Y. Du, M. Bacher, I. Zerr, R. Dodel & J. -P. Bach Department of Neurology, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany (Y. Roettger, R. Dodel, J. -P. Bach). Department of Neurology, Indiana University School of Medicine, 975 West Walnut Street IB 457, Indianapolis, IN 46202, USA (Y. Du). Institute of Immunology, University of Marburg, Hans-Meerwein-Strasse, 35043 Marburg, Germany (M. Bacher). National Reference Centre for Transmissible Spongiform Encephalopathies, Department of Neurology, Georg-August-University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany (I. Zerr).


      Correspondence to: R. Dodel dodel@med.uni-marburg.de


      Published online 18 December 2012








      December 13, 2012


      The rise and fall of pentosan polysulfate in prion disease







      TSS




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      Monday, December 17, 2012

      The rise and fall of pentosan polysulfate in prion disease

      December 13, 2012


      The rise and fall of pentosan polysulfate in prion disease


      Next to quinacrine, pentosan polysulfate (PPS) (above) has probably been the second-most examined drug in the treatment of prion disease. PPS never made it to an official clinical trial in the United States, but Japan and the U.K. each ran clinical trials, both of which failed. PPS has since been pretty much abandoned as a potential prion treatment, for more than one reason, but we can learn a lot from the history of research into this compound as an antiprion therapeutic.


      Pentosan polysulfate was tested in mouse models of prion disease as early as 1984, but the real story begins, in a way, with Caughey & Race 1992, who observed that Congo red inhibits PrP accumulation in prion-infected cell culture. Congo red was originally invented as a stain for cellulose but has for decades been used in laboratories as a stain for amyloid plaques, which, after all, earned the name “amyloid” for their misleading resemblance to starch (amylum in Latin), which is composed of the same glucose subunits as cellulose, under staining. Like Alzheimer’s and some other neurodegenerative diseases, scrapie results in the deposition of amyloid plaques in brain tissue. Since Congo red stains (read: binds to) amyloid plaques effectively, Caughey and Race wondered if it might interfere with the formation of amyloid plaques as well. And it did – in fact, it pretty much completely abolished the formation of PrP-res, as shown in Fig 1A:


      But Congo red was not exactly ready for prime time as a therapeutic compound. In fact, according to Wikipedia it’s so toxic that even the textile and paper industries won’t use it anymore (always a bad sign). So Caughey and Race’s discovery touched off a search for less toxic compounds with the same PrP-res-inhibiting property.


      That search led ultimately to several hits including cpd-B and curcumin. But the race had been won before it started: a year before Caughey and Race’s discovery, another group had already announced that adminstration of the polyanion compound pentosan polysulfate resulted in a massive extension of survival in scrapie-infected mice [Diringer & Ehler 1991]. In fact, without any fanfare at all, these two had reported a significant effect of pentosan polysulfate as early as 1984, in a study whose primary purpose was to evaluate the efficacy of another polyanion compound: dextran sulfate 500 [Ehler & Diringer 1984]. Predictably, the 1984 study had found that DS500 was only effective against peripheral infection and not intracerebral – “polyanions” by definition are highly charged compounds, which the BBB‘s border control agents hate. But Diringer and Ehler’s 1984 and 1991 studies evaluated PPS’s efficacy only in peripherally infected mice, and only with drug administration either prophylactically or very early in the disease course. Ladogana 1992 had likewise shown efficacy against peripheral infection for DS500, pentosan polysulfate (referred to in that study as SP54) and suramin. In fact, Ladogana even tested DS500 and suramin (but not PPS) against intracerebral infection and found a small but significant effect for DS500.


      So in fact, lots of work on PPS preceded Caughey’s discovery that Congo red inhibits PrP-res formation. But I chose to start the story with that oft-cited paper because it coincided with the beginning of scientific acceptance of the protein-only hypothesis and, with it, a new perspective on what a compound needed to do in order to fight prion infection. The studies by Ladogana, Farquhar, Diringer and Ehler all took place back in the dark ages when people thought scrapie was an “unconventional virus”, so much of the discussion in these papers centers on the supposed “antiviral” properties of DS500 and PPS. By 1993, putting together the newly emerging prion hypothesis (described as “controversial”) with the results from the 1992 Congo red study, Caughey had a better idea of why PPS might have been effective: perhaps it inhibited PrP-res formation just like Congo red. PPS isn’t exceptionally similar to Congo red, but the two do have two sulfate anions in common:


      Congo red


      And sure enough, Caughey was able to show that PPS inhibited PrP-res formation “in vivo” [Caughey & Raymond 1993], by which he actually meant ex vivo: in cell culture, not in a whole organism.


      And curiously, no one provided in vivo validation of this finding for over a decade. Of course, PPS was already known to be effective in vivo – in early or prophylactic administration in peripherally infected mice. What remained was to show that PPS was also effective against intracerebral infection, and that it could abolish the amyloid plaques that characterized scrapie infection in mice and CJD in humans, plaques composed of a protein beginning to gain acceptance as being the pathological agent: PrP.


      Instead, the next decade saw a series of basic science papers on PPS and related molecules such as heparin and heparan sulfate, using these molecules as tools to understand the biological and biochemical properties of PrP [Caughey 1994a, Caughey 1994b, Shyng 1995, Brimacombe 1999]. The most surprising of these was the confirmation that although PPS inhibits PrP-res formation in cell culture, it stimulates PrP-res formation in cell-free conversion [Wong 2001]. One other paper testing PPS in vivo did emerge after several years [Farquhar 1999], but it didn’t cite Caughey’s work and managed to remain wholly agnostic as to the identity of what it called the “bovine spongiform encephalopathy agent”, avoiding calling it either a ”prion” or a “virus”. Farquhar successfully duplicated the earlier in vivo results, showing that a single dose of PPS could dramatically delay disease onset or prevent it altogether, if administered intraperitoneally within several hours of the initial peripheral infection. The results replicated across several different mouse strains, but the issue of PPS’s possible interference with PrP and efficacy against CNS infections was left untouched.


      When evidence on the in vivo efficacy of PPS against CNS prion infections finally did surface after more than a decade, it did so in a spectacular fashion. In 2004, Katsumi Doh-Ura demonstrated that continuous ventricular infusion of PPS of mice could extend survival by as much as 2.4-fold [Doh-Ura 2004]. His primary model was Tg7 mice expressing hamster PrP, infected intracerebrally with 263K hamster prions. Doh-Ura tested not only PPS but also quinacrine (no effect), chloroquine (no effect), E-64d (no effect), and amphotericin B (some effect). The whole experiment was exquisitely designed to test the drugs’ efficacy against CNS infections without bumping up against issues of blood-brain barrier permeability. It must have been an impossibly difficult experiment to pull off: Doh-Ura implanted miniature devices in the backs of the mice, just under the skin, with tubes leading to their left ventricles to continuously drip tiny amounts of PPS for four weeks after implantation until the chemical ran out. And it wasn’t prophylactic, either: the mice were treated beginning at 7, 21, 35 or 42 days post-infection (dpi), meaning the surgery had to be done on already scrapie-infected mice. Perhaps this explains what one prion researcher recently told me: Doh-Ura’s result was the best result there’s ever been for prion therapeutics; it’s just that no one has managed to reproduce it.


      In the published literature, at least, no one has even tried to reproduce it. That’s probably in part because of the technical difficulty involved and in part because Doh-Ura had already left no stone unturned. The incredibly thorough study varied both the dose and the date that drug administration was started, as summarized beautifully in Fig. 2:


      The results are very clear: PPS is most effective at a medium dose of 230 ug/kg/day and when administered as early as possible, though it still has a significant effect when administered late in the disease. At its best, it delayed death from 51 dpi for controls to 123 dpi for mice treated with 460 ug/kg/day starting from 7 dpi.


      Not satisfied to show an effect on just one model, Doh-Ura also varied the mouse model and prion strain in question. His primary experiment used Tg7 mice, which overexpress hamster PrP and no mouse PrP, infected with 263K hamster prions; subsequently he also tested PPS by the same protocol in Tga20 mice (which overexpress mouse PrP) infected with Fukuoka-1 and RML prions. Those experiments showed smaller (regression to the mean, perhaps?) but still quite large, extensions of survival – 117% and 49% respectively when treatment was begun at 14 dpi.


      Doh-Ura also tried subcutaneous administration of PPS with, as would be expected, no effect: PPS could not cross the blood-brain barrier.


      The study didn’t skimp on follow-up experiments to figure out how PPS had worked, either. Doh-Ura did immunohistochemistry on the treated mouse brains and found a remarkable reduction in PrP deposits. In fact, the neurodegeneration that had killed the mice was almost wholly concentrated in the right hemisphere of the brain, while the left hemisphere, where the infusion site was, was spared the worst of it. Doh-Ura also assayed the infectivity of the mouse brains in the same blunt way that it’s still done today – by injecting their brain homogenate into other mice and comparing the survival of those mice to a standard table. Last but not least, Doh-Ura did toxicology experiments on mice, rats, and dogs – again, with intraventricular infusion – to determine the tolerated dose and assess what adverse effects might be anticipated.


      The overall picture was of a drug of fairly low toxicity that reduced infectivity through direct action on the infectious protein itself, largely regardless of prion strain, and could more than double the incubation time of the disease if administered early enough. It was, and probably still is, the strongest result that’s ever been shown for a potential antiprion drug. But there were two catches.


      Two big catches. First, it had to be administered directly into the brain. Second, and more importantly, the study provided no evidence for – indeed, some evidence against – the idea that PPS would work in already-symptomatic animals. As shown in Fig 2B above, Doh-Ura tested PPS at 7, 21, 35, and 42 dpi in mice that showned “definite symptoms” at 49 dpi (though Doh-Ura allowed for the possibility that more subtle earlier symptoms could have gone unnoticed) and died at 51 dpi. The effect of the drug was huge at 7 dpi, small by 35 dpi, and so tiny as to be statistically insignificant by 42 dpi. To help you see this, Doh-Ura has actually drawn line segments connecting through the means of the different groups:


      The the lack of a ‘day 14′ experiment to evenly space the X axis makes the lines a bit misleading (the group means aren’t actually collinear as they appear in this figure), but the trend is pretty obvious. Based on this figure you can have a pretty good guess that mice not treated until they exhibited symptoms at day 49 or day 50 would not experience any increase in survival.


      And Doh-Ura fully recognized this, noting that “our data do not guarantee similar effectiveness in human patients who already have signs and symptoms of the disease”. Acknowledging this, and acknowledging as well the personal and public health risks of installing intraventricular catheters in prion dsiease patients, Doh-Ura still chose to end the paper on an optimistic note. Though the United States was yet to start its own clinical trial of quinacrine, PRION-1, Doh-Ura had read the literature on quinacrine in mice and hamsters and had (correctly) concluded that quinacrine would not prove effective in humans. So he put forth PPS as the next candidate for clinical trials:


      As an immediately applicable remedy, however, continuous intraventricular PPS administration with an infusion device may be a candidate for a clinical trial, with a view to preventing the disease in those people categorized as being at extremely high risk or to improving the prognosis of diseased people with TSEs.


      PPS was already approved in the U.S. (and presumably in Japan too, though I can’t find any confirmation of that online) for interstitial cystitis, a.k.a. painful bladder syndrome, which is basically a diagnosis of exclusion meaning “we can’t identify any other problem to explain your symptoms, so we’ll call it this”. For a review of pentosan polysulfate in painful bladder syndrome, see Teichman 2002. The bladder connection seems at first interesting in light of the known connections between prion disease and bladder problems (see posts on dapsone and ibuprofen), though it’s almost surely a coincidence. In any event, here you have an already approved drug which might be effective against a sudden, deadly disease with no known treatment or cure. Almost immediately, neurologists started trying PPS in their prion disease patients.


      Over the next five years, ambiguous reports of human results trickled in from several places. In the peer-reviewed journals, a handful of case reports arrived, some of which reported considerably extended survival [Todd 2005, Parry 2007, Rainov 2007] and some of which did not [Whittle 2006], though in no case was the patient’s condition seen to actually improve.


      Other reports came from outside the traditional journal setting. A series of short articles in BMJ [Dyer 2003, Gould 2003, Mayor 2003] and a subsequent BBC report documented one family’s battle to get PPS (which is not an approved drug in Britain) approved for their son Jonathan Simms – they eventually prevailed and the young man, though still sick, remained alive with vCJD for 10 years (he passed away in 2011) while being treated with PPS – possibly the same patient from Todd 2005. BBC also reported that MRC had announced the drug “had appeared to help several people live longer than expected.” And in a powerpoint apparently presented at a meeting in Glasgow organized by CJD Alliance, Dr. Ian Bone reported on eight U.K. patients who had, again, lived slightly longer than expected, though with multiple complications related to the ventricular catheters and one possible adverse reaction to the drug itself [Bone 2006].


      That powerpoint is actually a more accessible discussion of the issues involved in the study design than many of the published papers are. Bullets on slides 2 and 23 show a key part of Bone’s thought process: there are too few prion disease patients, and their diseases are too urgent, for there to ever be a large, statistically powered case/control study as is the standard in medicine. Instead, we are stuck with an observational study of a handful of patients – but if we can use a “surrogate marker” to assess disease progression, maybe we can tell if the drug is working in each individual. It is this same thought process that motivates our early biomarkers research goal at Prion Alliance.


      Formal reports on PPS’s efficacy finally came out in 2008-9. Bone reported that the seven patients formally included in the observational study in the U.K. had indeed lived longer than the mean for their respective prion diseases, but clinical symptoms as well as MRI – his “surrogate marker” – both showed continued disease progression after drug treatment began [Bone 2008]. The slightly longer survival might be due to PPS but Bone felt he couldn’t rule out several other possible explanations:


      chance alone and biases such as lead-time bias from attentive carers diagnosing onset early; selection bias from included patients having prolonged survival whilst awaiting PPS or bias from increased use of active interventions for complications in more actively managed PPS patients amongst others


      The report doesn’t take a firm stance for or against continued use of PPS in humans, instead concluding that “More experimental work in animal models is clearly needed” and that “Until then, all patients with prion diseases considering PPS therapy should be informed of existing evidence and, if opting for treatment, managed and monitored in a standardized manner”.


      The following year, Doh-Ura and his colleagues reported on their use of PPS in eleven patients in Japan [Tsuboi 2009] with almost identical results. Again, the patients survived longer than mean for their diseases, but not out of the plausible range, and showed “continued deterioration” after drug treatment commenced.


      Both of these formal reports discuss the possibility that different doses might be more effective, and neither rules out the possibility of further use of PPS. But not much has been published on PPS since then: a Google scholar search for more recent papers on prion pentosan polysulfate since 2011 turned up only one more case report [Terada 2010] and a good review of all the human case reports and observational studies [Appleby 2011].


      In reading all these reports, perhaps the most interesting thing I noticed was in Bone’s Table 1 introducing the seven patients from the U.K. observational study, including their dates of disease onset and treatment and their clinical state [Bone 2008]. The patients had started PPS treatment anywhere from 6 months to 2.5 years after disease onset. At the time that the official observational period commenced (which was for most patients 1-2 years after they had already begun receiving PPS), three were bed-bound and two were chair-bound.


      We don’t know whether the patients were already bed-bound or chair-bound when they started PPS treatment, but given the length of time between disease onset and treatment, it does seem likely that they were very sick by the time they started receiving the drug.


      In the mouse study that touched off all this interest in PPS, Doh-Ura stated that the first noted symptom in the mice was “ambiguous signs of reduced activity” two days prior to death, so on average 49 dpi, while his experiments showed no significant effect of PPS even when started at 42 dpi. Since investigators won’t notice subtle symptoms in a mouse, it is very hard to know what day post infection in a mouse corresponds to the moment, in a human patient, that a diagnosis would be made. But given the disease state of the patients and the length of time between disease onset and initiation of treatment, it seems they were much closer to the equivalent of 49 dpi than they were to 35 dpi (the latest treatment date for which Doh-Ura observed a significant effect), by the time they received treatment.


      Some of the delay in starting treatment for these patients was surely due to the experimental nature of the PPS treatment. But given the swift and unexpected nature of prion diseases, it seems that even under the best of conditions, it is very likely that patients will decline severely before any treatment can be started. Patients will need to exhibit a significant decline before it even triggers a hospital visit, referrals to specialists at tertiary care facilities will have to be made, and diagnosis will not always be quick or easy and tests will not always give immediate confirmation. The only exception to this rule is the handful of genetic prion disease carriers who have chosen to be tested and know their status – but healthy asymptomatic individuals will never go in for intraventricular catheterization.


      Hence the inherent contradiction in pentosan polysulfate: it’s only effective at times when the patient’s condition is not desperate enough to merit such drastic measures.


      Possibly this all could have been recognized at the outset: Doh-Ura’s study was extremely thorough and extremely honest about the fact that PPS required intraventricular infusion and didn’t work late in the disease. But given the complete fatality of prion diseases and the utter lack of any treatments, desperation gave way, and the story of Jonathan Simms as documented by BBC and BMJ shows that even when medical authorities are duly skeptical of a potential treatment, families will actively campaign to be able to use it. After all, they’ve got nothing to lose.













      Wednesday, March 28, 2012


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

      http://prionopathy.blogspot.com/2012/03/variably-protease-sensitve-prionopathy.html


      http://sporadicffi.blogspot.com/





      Friday, November 23, 2012

      sporadic Creutzfeldt-Jakob Disease update As at 5th November 2012 UK, USA, AND CANADA
      http://creutzfeldt-jakob-disease.blogspot.com/2012/11/sporadic-creutzfeldt-jakob-disease.html





      Saturday, December 15, 2012

      Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle -- an update 5 December 2012
      http://bse-atypical.blogspot.com/2012/12/bovine-spongiform-encephalopathy-effect.html






      http://transmissiblespongiformencephalopathy.blogspot.com/





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



      MOM DOD 12/14/97 CONFIRMED hvCJD...

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