Tuesday, May 7, 2013

Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?

Article in Press



Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?



Thomas A. Bayer Affiliations Tel.: +49 551 39 22912.



Received 18 October 2012; received in revised form 12 March 2013; accepted 24 March 2013. published online 03 May 2013. Corrected Proof




Abstract




The current review covers proteinopathies an umbrella term for neurodegenerative disorders that are characterized by the accumulation of specific proteins within neurons or in the brain parenchyma. Most prevalent examples for typical proteinopathies are Alzheimer's disease and Parkinson's disease. In healthy brain, these proteins are unstructured as a monomer, serving most likely as the physiological form. In a disease condition, the unstructured proteins experience a conformational change leading to small oligomers that eventually will aggregate into higher order structures. Prion disease is an exception within the family of proteinopathies as the aggregated prion protein is highly infectious and can self-aggregate and propagate. Recent reports might implicate a prion-like spread of misfolded proteins in Alzheimer's and Parkinson's disease; however there are evident differences in comparison to prion diseases. As proteinopathies are caused by the aggregation of disease-typical proteins with an ordered structure, active and passive immunization protocols have been used to expose model systems to therapeutic antibodies that bind to the aggregates thereby inhibiting the prolongation into higher ordered fibrils or dissolving the existing fibrillar structure. While most of the immunization treatments have been only carried out in preclinical model systems overexpressing the disease-relevant aggregating protein, other approaches are already in clinical testing. Taking the core concept of proteinopathies with conformationally altered protein aggregates into account, immunization appears to be a very promising therapeutic option for neurodegenerative disorders.




Keywords: Amyloid, Proteinopathy, Immunization, Clinical trial











Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS



Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer Moore, Zamia Diaz, Kyle S. MacLea, Brian Freibaum, Songqing Li, Amandine Molliex, Anderson P. Kanagaraj, Robert Carter, Kevin B. Boylan, Aleksandra M. Wojtas, Rosa Rademakers, Jack L. Pinkus, Steven A. Greenberg, John Q. Trojanowski, Bryan J. Traynor, Bradley N. Smith, Simon Topp, Athina-Soragia Gkazi, Jack Miller, Christopher E. Shaw, Michael Kottlors et al. Affiliations Contributions Corresponding authors Nature 495,467–473(28 March 2013)doi:10.1038/nature11922Received 05 January 2012 Accepted 17 January 2013 Published online 03 March 2013


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Abstract



Abstract• Author information• Supplementary information Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.



Subject terms: Mechanisms of disease










Advances in Anatomic Pathology: September/October 1995 - Volume 2 - Issue 5 - ppg 314-319


Review Article: PDF Only



Prion Proteinopathies: Fatal Conversion



Goodman, Clay



 
 
 




WELL, it seems the USA mad cow strains in humans classified as type determination pending tdpCJD, VPSPr, sFFI, and sCJD) have steadily increased over the years, and the same old song and dance continues with sporadic CJD cases $$$




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


OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS TRANSMISSIBLE IN BANK VOLES Nonno








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.



SOURCE PRION2012







I believe it was Gambetti et al that coined this term sporadic FFI, from some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it to a true FFI by diagnostic standards to date, so it was then termed a sFFI, confusing matters even worse. ...




A subtype of sporadic prion disease mimicking fatal familial insomnia






THIS seems to raise more questions than answers, confusing the TSEs even worse.


WHAT is sporadic CJD, and how many sub-types and atypical strains, phenotypes etc. will there be, arising from nothing. a spontaneous happening of sorts???


i think not. ...tss







Wednesday, September 21, 2011


PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)







PP1:


Does A “Prion-Like” Mechanism Contribute to the Spreading of Neuropathology in Parkinson’s Disease?


Patrik Brundin Neuronal Survival Unit; Wallenberg Neuroscience Center; Dept of Experimental Medical Science; Lund University; Lund, Sweden


Key words: Parkinson’s disease, prion mechanism, alpha-synuclein


Neuropathological aggregates of alpha-synuclein in neuronal cytoplasm and neurites are typical features of Parkinson’s disease (PD). These Lewy neurites and Lewy bodies are prominent in substantia nigra, where dopaminergic neurons degenerate. With advancing disease they are also found in several other widespread brain areas, and it has been suggested that they appear in anterior olfactory structures and the dorsal motor nucleus of the vagal nerve even before the substantia nigra is affected. Recent studies demonstrated that Lewy bodies and neurites appear in grafted embryonic neurons.1-3 They stain for Thioflavin S, are immunoreactive for alpha-synuclein phosphorylated at serine residue 129 and exhibit a fibrillar structure in the electron microscope.4 From 2 to 5% (frequency increases over time) of the grafted dopaminergic neurons display Lewy bodies, starting around one decade after surgery. Despite these changes, some of the PD grafted patients still exhibit signs of functional recovery beyond a decade after surgery. We, and others, are currently exploring possible mechanisms underlying the transfer of alpha-synuclein between cells and their relevance to how neuropathology normally spreads in the PD brain.5,6 We have observed that alpha-synuclein indeed can transfer between cells in culture. The process is clearly time-dependent and once inside the new cell the imported alpha-synuclein can seed aggregation of endogenous alpha-synuclein. Furthermore, we have observed transfer of host-derived alpha-synuclein into embryonic dopamine neurons grafted into the striatum of transgenic mice expressing human alpha-synuclein. We propose that a “prion-like” disease mechanism might contribute to the pathogenesis of PD and other chronic neurodegenerative disorders.6


References


1. Li, et al. Nat Med 2008; 14:501-3. 2. Kordower, et al. Nat Med 2008; 14:504-6. 3. Kordower, et al. Mov Disord 2008; 23:2303-6. 4. Li, et al. Mov Disord 2010; [Epub ahead of print]. 5. Brundin, et al. Nat Rev Neurosci 2008; 9:741-5. 6. Brundin, et al. Nat Rev Mol Cell Biol 2010; 11:301-7. PP: Plenary Lectures Previously published online: www.landesbioscience.com/journals/prion/article/12765


DOI: 10.4161/pri.4.3.12765




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




WP8-4: Prion-like Induction of Alzheimer-type Proteopathy in Transgenic Mice


Lary C. Walker


Yerkes Center; Emory University; Atlanta, GA USA


Key words: abeta, Alzheimer, amyloid, prion, seeding, strains, transgenic, transmission


Alzheimer’s disease and prion disease both involve the accumulation of disease-specific proteins in the brain, suggesting pathogenic commonalities. In Alzheimer’s disease, the aggregation of the protein fragment Aßis a seminal event. Similar to the templated corruption of prion protein, cerebral Aßdeposition can be induced in ß-amyloid precursor protein (APP)-transgenic mice and rats by the intracerebral injection of Aß-rich brain extracts from patients with Alzheimer’s disease or APP-transgenic mice. Our studies indicate that the characteristics of the seeded deposits depend on the source of the seeding extract, the type of host, and the seeded brain region. We are using the amyloid-binding agent Pittsburgh Compound B (PIB) as a marker of a potential AD-specific form of multimeric Aß, and are attempting to induce alternative conformations in the transgenic mouse Aß-seeding model. In addition, we are investigating non-intracerebral routes of administration and the ability of heterologous agents to induce Aßdeposition. Analysis of Aß-seeding in vivo could yield fresh insights into the origins of idiopathic Alzheimer’s disease.


Acknowledgements


Key collaborators on these studies are Mathias Jucker (U. Tübingen), Rebecca Rosen (Emory U.) and Harry LeVine III (U. Kentucky). Supported by NIH RR-00165 and the CART Foundation.




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




PPo9-1: Prion-like Propagation of SOD1 Misfolding in Amyotrophic Lateral Sclerosis


Neil R. Cashman


University of British Columbia; Vancouver, British Columbia Canada


Key words: protein misfolding, mechanisms of neurodegeneration, transmission


Prion-like propagation of protein misfolding has been implicated in Alzheimer’s, Parkinson’s and Huntington’s diseases, and the tauopathies. Amyotrophic lateral sclerosis (ALS) is a common and incurable adult motor neuron disease, in which mutation of the free-radical defense enzyme superoxide dismutase 1 (SOD1) is responsible for a subtype of familial ALS (fALS). We demonstrate that transfection of fALS SOD1 mutants G127X and G85R, as well as overexpression of non-mutant wild-type (wt) SOD1, can induce misfolding of natively-structured wild-type SOD1 in human mesenchymal and neural cell lines, as determined by molecular surface immunoreactivity with misfolding-specific monoclonal antibodies (mAbs), acquisition of protease sensitivity (suggesting structural loosening), generation of reactive oxygen species (ROS) and formation of non-native intermolecular disulfide bonds. Serial transmission of SOD1 misfolding was established by incubation in conditioned media from mtSOD1- or wtSOD1-transfected HEK cells, and knockdown of endogenous SOD1 expression in HEK cells by siRNA abrogated the transmission of SOD1 misfolding, consistent with endogenously expressed SOD1 being the substrate for conformational conversion. Pre-incubation of SOD1-transfected conditioned media with poly-specific SOD1 antibodies or misfolding-specific mAbs also blocked intercellular transducing activity, and passive administration of misfolding-specific mAbs extends survival in the G37R transgenic mouse model of ALS. We conclude that misfolded SOD1 participates in a template-directed misfolding cascade which provides a plausable molecular mechanism for progression of familial and sporadic ALS. Antibody-mediated neutralization of SOD1 misfolding propagation could prove beneficial in human ALS.




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









Alimentary prion infections: Touch-down in the intestine


Volume 5, Issue 1 January/February/March 2011 Bianca Da Costa Dias, Katarina Jovanovic and Stefan F.T. Weiss View affiliations Hide affiliations Bianca Da Costa DiasSchool of Molecular and Cell Biology; University of the Witwatersrand; Johannesburg, Republic of South Africa Katarina JovanovicSchool of Molecular and Cell Biology; University of the Witwatersrand; Johannesburg, Republic of South Africa Stefan F.T. WeissCorresponding author: stefan.weiss@wits.ac.za School of Molecular and Cell Biology; University of the Witwatersrand; Johannesburg, Republic of South Africa


Neurodegenerative diseases are caused by proteinaceous aggregates, usually consisting of misfolded proteins which are often typified by a high proportion of ß-sheets, which accumulate in the Central Nervous System. These diseases, including Morbus Alzheimer, Parkinson disease and Transmissible Spongiform Encephalopathies (TSEs) also termed prion disorders, afflict a substantial proportion of the human population and as such the etiology and pathogenesis of these diseases has been the focus of mounting research. Although many of these diseases arise from genetic mutations or are sporadic in nature, the possible horizontal transmissibility of neurodegenerative diseases poses a great threat to population health. In this article we discuss recent studies which suggest that the “non-transmissible” status bestowed upon Alzheimer and Parkinson diseases may need to be revised as these diseases have been successfully induced through tissue transplants. Furthermore, we highlight the importance of investigating the “natural” mechanism of prion transmission including peroral and perenteral transmission, proposed routes of gastrointestinal uptake and neuroinvasion of ingested infectious prion proteins. We examine the multitude of factors which may influence oral transmissibility and discuss the zoonotic threats which Chronic Wasting Disease (CWD), Bovine Spongiform Encephalopathy (BSE) and Scrapie may pose resulting in vCJD or related disorders. In addition, we suggest that the 37 kDa/67 kDa laminin receptor on the cell surface of enterocytes, a major cell population in the intestine, may play an important role in the intestinal pathophysiology of alimentary prion infections.








Commentary ß-amyloid oligomers and prion protein: Fatal attraction?


Volume 5, Issue 1 January/February/March 2011 Gianluigi Forloni and Claudia Balducci


Gianluigi Forloni Corresponding author: forloni@marionegri.it


Claudia Balducci Biology of Neurodegenerative Diseases Lab; Department of Neuroscience; “Mario Negri” Institute for Pharmacological Research; Milano, Italy


The relationship between Alzheimer disease (AD) and prion-related encephalopathies (TSE) has been proposed by different points of view. Recently, the scientific attention has been attracted by the results proposing the possibility that PrPc, the protein whose pathologic form is responsible of TSE, can mediated the toxic effect of ß amyloid (Aß) oligomers. The oligomers are considered the culprit of the neurodegenerative process associated to AD, although the pathogenic mechanism activated by these small aggregates remain to be elucidated. In the initial study based on the binding screening PrPc was identified as ligand /receptor of Aß oligomers, while long term potentiation (LTP) analysis in vitro and behavioural studies in vivo, demonstrated that the absence of PrPc abolished the damage induced by Aß oligomers. The high affinity binding Aß oligomers-PrPc has been confirmed, whereas a functional role of this association has been excluded by three different studies. We approached this issue by the direct application of Aß oligomers in the brain followed by the behavioural examination of memory deficits. Our data using PrP knock-out mice suggest that Aß 1-42 oligomers are responsible for cognitive impairment in AD but PrPc is not required for their effect. Similarly, in two other studies the LTP alterations induced by Aß 1-42 oligomers was not influenced by the absence of PrP. Possible explanations of these contradictory results are discussed.











Friday, October 22, 2010


Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis







Friday, September 3, 2010


Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE







Wednesday, January 5, 2011


ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions


David W. Colby1,* and Stanley B. Prusiner1,2











Monday, September 26, 2011


Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS, gCJD, hvCJD, sCJD, TSE, PRION, update 2011








Wednesday, October 27, 2010


A novel variant of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report


snip...


Genetic findings


No mutations were found in the open reading frame after sequencing the prion protein gene (PRNP). A heterozygosis methionine valine (MV) was observed in codon 129.


snip...








Thursday, July 10, 2008


A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008


Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.







Thursday, July 10, 2008


A New Prionopathy update July 10, 2008








***+++***


Thursday, July 10, 2008


A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008 Friday, June 20, 2008








Here we go folks. AS predicted. THIS JUST OUT !




Tuesday, August 03, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein








Monday, August 9, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?


snip...see full text ;










O.K. let's compare some recent cases of this prionpathy in other countries besides Gambetti's first 10 recently, that he claims is a spontaneous event, from a genetic disorder, that is not genetic, but sporadic, that is related to no animal TSE in North America, or the world. ...








Wednesday, October 27, 2010


A novel variant of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report








Sunday, August 09, 2009


CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009








Tuesday, August 18, 2009


BSE-The Untold Story - joe gibbs and singeltary 1999 – 2009








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



The familial mutations, Gajdusek proposed, lowered the barrier to such accidental conversion. "Thus," he wrote in 1996, "with these mutations, this ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's qualification still remained to be refuted: the mutations might simply allow easier entry to a lurking virus. ...page 202 Deadly Feast



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





something to think about for sure.



but i interpret this as (1st not the gold standard, just my opinion;-), as because of certain gene mutations, one or a family, would be more susceptible to the many different strains of TSE, and the many different proven routes and sources, (which will cause different symptoms, different incubation periods from onset of clinical symptoms to death, different parts of the brain infected, etc.). in other words, it's NOT the gene mutation that CAUSES the disease, but the fact that it makes you more SUSCEPTIBLE, to the TSEs from the surrounding environment, and PLUS accumulation, i think this plays a critical role. maybe there is a one dose scenario, but i think there is more of the 'accumulators' that go clinical, than the 'one dose'. and what is the threshold to sub-clinical to clinical ?



anyway, just pondering out loud here.



also, for anyone interested, there are some studies with links to follow here ;








hmmm, 85%+ of all human TSE prion disease i.e. the infamous sporadic CJD i.e. is NOT a single strain, but many strains from unknown route and source, and there has been many of both documented in North America, and no one has ever proven a spontaneous TSE in any natural field case of any species to date. I believe they hypothesized one case in a zoo animal at one point, but could never prove it. please understand too, to date, all iatrogenic CJD is, is sporadic CJD, until route and source is proven.





spontaneous TSE, or just another excuse of a name for the same disease i.e. TSE prion disease ;






Prions: Protein Aggregation and Infectious Diseases


ADRIANO AGUZZI AND ANNA MARIA CALELLA


Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland


snip...


3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. *** So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55-60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.


snip...


Physiol Rev . VOL 89 . OCTOBER 2009 . www.prv.org











*** So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.







*** So far, there is no evidence for spontaneous PrPres formation in any animal or human TSE disease. Moreover, in New Zealand and Australia where scrapie has been eradicated, there is no evidence of spontaneous occurrence of sheep scrapie. In addition, in humans the peak age incidence of sporadic CJD is 55–60 years, and if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age, since more time might allow more opportunity for rare misfolding events.







*** However, a BSE expert said that consumption of infected material is the only known way that cattle get the disease under natural conditons.


“In view of what we know about BSE after almost 20 years experience, contaminated feed has been the source of the epidemic,” said Paul Brown, a scientist retired from the National Institute of Neurological Diseases and Stroke.


BSE is not caused by a microbe. It is caused by the misfolding of the so-called “prion protein” that is a normal constituent of brain and other tissues. If a diseased version of the protein enters the brain somehow, it can slowly cause all the normal versions to become misfolded. It is possible the disease could arise spontaneously, though such an event has never been recorded, Brown said.







*** Conclusion/Significance: Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.












SPONTANEOUS TSE


Perspectives BIOMEDICINE: A Fresh Look at BSE Bruce Chesebro*


Mad cow disease, or bovine spongiform encephalopathy (BSE), is the cattle form of a family of progressive brain diseases. These diseases include scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and chronic wasting disease (CWD) in deer and elk. They are also known as either "prion diseases" because of the association of a misfolded cellular prion protein in pathogenesis or "transmissible spongiform encephalopathies" (TSEs) because of the spongelike nature of the damaged brain tissue (1).


The recent discovery of two BSE-infected cows, one in Canada and one in the United States, has dramatically increased concern in North America among meat producers and consumers alike over the extent to which BSE poses a threat to humans as well as to domestic and wild animals. The European BSE epidemic of the late-1980s seems to have been initiated a decade earlier in the United Kingdom by changes in the production of meat and bone meal (MBM) from rendered livestock, which led to contamination of MBM with the BSE infectious agent. Furthermore, the fact that UK farmers fed this rendered MBM to younger animals and that this MBM was distributed to many countries may have contributed to the ensuing BSE epidemic in the United Kingdom and internationally (2).


Despite extensive knowledge about the spread of BSE through contaminated MBM, the source of BSE in Europe remains an unsolved mystery (2). It has been proposed that BSE could be derived from a cross-species infection, perhaps through contamination of MBM by scrapie-infected sheep tissues (see the figure). Alternatively, BSE may have been an endemic disease in cattle that went unnoticed because of its low level of horizontal transmission. Lastly, BSE might have originated by "spontaneous" misfolding of the normal cellular prion protein into the disease-associated abnormal isoform (3), which is postulated to be the infectious agent or "prion."


Five possible sources of BSE in North American cattle. Sheep, deer, and elk could spread prion diseases (TSEs) to cattle through direct animal contact or contamination of pastures. Endemic BSE has not been proven to exist anywhere in the world, but it is difficult to exclude this possibility because of the inefficient spread of BSE infectivity between individual animals (2). ___BSE caused by spontaneous misfolding of the prion protein has not been proven___. CREDIT: KATHARINE SUTLIFF/SCIENCE


snip...


Nevertheless, the idea that BSE might originate due to the spontaneous misfolding of prion proteins has received renewed interest in the wake of reports suggesting the occurrence of atypical BSE (9-11). These results imply that new strains of cattle BSE might have originated separately from the main UK outbreak. Where and how might such strains have originated? Although such rare events cannot be studied directly, any number of sources of the original BSE strain could also explain the discovery of additional BSE strains in cattle (see the figure). However, it would be worrisome if spontaneous BSE were really a valid etiology because such a mechanism would be impossible to prevent--unlike other possible scenarios that could be controlled by large-scale eradication of TSE-positive animals.


Another way to look at this problem is to examine evidence for possible spontaneous TSE disease in other animals besides cattle. Spontaneous BSE would be extremely difficult to detect in cattle, where horizontal spread is minimal. However, in the case of the sheep TSE disease, scrapie, which spreads from ewes to lambs at birth as well as between adults, spontaneous disease should be detectable as new foci of clinical infection. In the early 1950s scrapie was eradicated in both Australia and New Zealand, and the mainland of both these countries has remained scrapie-free ever since. This scrapie-free status is not the result of selection of sheep resistant to scrapie because sheep from New Zealand are as susceptible as their UK counterparts to experimental scrapie infection (12). These experiments of man and nature appear to indicate that spontaneous clinical scrapie does not occur in sheep. Similarly, because CWD is known to spread horizontally, the lack of CWD in the deer or elk of eastern North America but its presence in western regions would also argue against a spontaneous disease mechanism. This is particularly noteworthy in New Zealand, where there are large numbers of deer and elk farms and yet no evidence of spontaneous CWD. If spontaneous scrapie does not occur in sheep or deer, this would suggest that spontaneous forms of BSE and sporadic Creutzfeldt-Jakob disease (sCJD) are unlikely to be found in cattle or humans. The main caveat to this notion is that spontaneous disease may arise in some animal species but not others. In humans, sCJD--which is considered by some researchers to begin by spontaneous misfolding of the prion protein--usually takes more than 50 years to appear. Thus, in animals with a shorter life-span, such as sheep, deer, and cattle, an analogous disease mechanism might not have time to develop.


What can we conclude so far about BSE in North America? Is the BSE detected in two North American cows sporadic or spontaneous or both? "Sporadic" pertains to the rarity of disease occurrence. "Spontaneous" pertains to a possible mechanism of origin of the disease. These are not equivalent terms. The rarity of BSE in North America qualifies it as a sporadic disease, but this low incidence does not provide information about cause. For the two reported North American BSE cases, exposure to contaminated MBM remains the most likely culprit. However, other mechanisms are still possible, including cross-infection by sheep with scrapie or cervids with CWD, horizontal transmission from cattle with endemic BSE, and spontaneous disease in individual cattle. Based on our understanding of other TSEs, the spontaneous mechanism is probably the least likely. Thus, "idiopathic" BSE--that is, BSE of unknown etiology--might be a better term to describe the origin of this malady. ...


snip...full text ;







DR. DEHAVEN: “All right. I think we've got three different questions in there, and I'll try to touch on each one of them.


“First of all, let me correct just a technical issue, and that is you mentioned 1 in 10,000. And actually our surveillance system currently is designed, the one that we have in place now is designed to detect 1 positive in 1 million cattle, and I gave some numbers between 200,000 and 268,000 that would allow us to detect 1 in 10 million as opposed to 1 in 10,000.


“So we would, if we were able to collect in the ballpark of those numbers of samples then we with increasing numbers of samples have an increasingly statistically valid sample from which to determine, one, whether or not the disease exists and, if so, at what prevalence level.


“So our real emphasis is to test as many of those animals as we can, ensure that we get an appropriate geographical distribution, but not setting a specific number as far as a target. Again, consistent with the recommendation from the International Review Team, their recommendation was to test all of them.


“So that's consistent with where we're going is to test as many as we possibly can.


*** “As far as spontaneous cases, that is a very difficult issue. **___There is no evidence to prove that spontaneous BSE occurs in cattle___; but here again it's an issue of proving a negative. We do know that CJD, the human version of the disease, does occur spontaneously in humans at the rate of about 1 in 1 million. We don't have enough data to definitively say that spontaneous cases of BSE in cattle occur or do not occur.


“Again, it's a very difficult situation to prove a negative.


“So a lot of research is ongoing. Certainly if we do come up with any positive samples in the course of this surveillance we will be looking at that question in evaluating those samples but no scientifically hard evidence to confirm or refute whether or not spontaneous cases of BSE occur.




snip...














Thursday, June 21, 2012


Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism








let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.


This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$


ALABAMA MAD COW g-h-BSEalabama


In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.








her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008).


This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine–human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks.


Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: maf12@cam.ac.uk Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA


NATURE|Vol 457|26 February 2009






Saturday, August 14, 2010


BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY


(see mad cow feed in COMMERCE IN ALABAMA...TSS)






PrPSc complexity in different forms of Creutzfeldt-Jakob disease identified using biochemical approaches


Young Pyo Choi Doctor of Philosophy University of Edinburgh 2010


Abstract Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative diseases affecting humans and animal species. Prion diseases are characterized by the conversion of the host encoded prion protein (PrPC) into a disease-associated isoform (PrPSc), which (according to the prion hypothesis) is thought to be the main component of the infectious agent. PrPSc has been traditionally distinguished from PrPC by its biochemical properties, such as partial resistance to proteolysis and detergent-insolubility. In the absence of a foreign nucleic acid genome associated with prion diseases, efforts to provide a molecular basis for the biological diversity of prions have focused on biochemical characterization of PrPSc. In Creutzfeldt-Jakob disease (CJD) and other forms of human prion disease, the biochemical characterization of PrPSc has been largely restricted to the analysis of PK-resistant fragments of PrPSc (PrPres) by Western blot. However, given recent findings on the complexity of PrPSc identified in laboratory prion strains, PrPres analysis alone may not provide a complete description of PrPSc present in CJD brains. For a more complete characterization of PrPSc in human prion diseases, this study investigated biochemical properties of PrPSc in different forms of CJD by employing approaches that differ in principle from conventional Western blot analysis of PrPres. The novel biochemical approaches used in this study have identified further complexity of PrPSc accumulated in CJD brains, not only between different forms of CJD but also within single cases of individual disease entities. In this study, the two biochemical criteria most frequently used to define PrPSc (3F4 epitope accessibility versus resistance to limited proteolysis) did not always correlate, indicating probable non-uniform distribution of PK-sensitive isoform of PrPSc within the same CJD brains. In variant CJD (vCJD) brains, the thalamic region, which is characterized by distinct neuropathological features, could also be distinguished from frontal cortex and cerebellum by the sedimentation profiles of PrPC and PrPSc on sucrose step gradients. Moreover, the conformational stability of PrPSc was found not to be uniform among human prion diseases and did not correlate with PrPres type or v prion protein genotype. Taken together, the results from this study provide a more complete description of PrPSc species occurring in CJD brains and contribute to a fuller understanding of the agents and the disease processes involved in humans.


snip...


The high susceptibility of PrPC molecules present in non-CJD brains to PK was also observed in a recent study reporting "protease-sensitive prionpathy" cases (Gambetti et al. 2008), in which PrPC molecules became undetectable following treatment even with 1μg/ml PK for 1 hour at 37°C.


SNIP...


In another study describing a novel human prion disease designated "proteasesensitive prionpathy" (or PSPr), the sedimentation profile of PrP from this novel prion disease was different from any of this study's in that quite low levels of PrP were distributed in the intermediate and bottom fractions (Gambetti et al. 2008);


interestingly, the result from GSS with A117V mutation was similar to that of PSPr. In laboratory prion strains such as ME7, 22L in mice or Sc237 in hamsters, PrP dispersed throughout the 10 - 60% gradient after ultracentrifugation (Pan et al. 2004; Pan et al. 2005a; Pan et al. 2005c; Tzaban et al. 2002). The results from these laboratory prion stains were quite similar to those from vCJD Th or FC of MM1 sCJD.


SNIP...


5.3 Implications of this study


The accumulation of PrPSc is the only unambiguous marker of prion infection established to date and PrPSc is the only known component of the infectious prions. PrPSc has been operationally defined by its biochemical properties such as insolubility in non-denaturing detergents and/or resistance to proteolytic degradation (Meyer et al. 1986). The property of PK-resistance has been thoroughly exploited to the extent that the terms of protease-resistant prion protein (PrPres) and diseaseassociated prion protein (PrPSc) are sometimes used interchangeably (Caughey et al. 2009). In the absence of a foreign nucleic acid genome associated with prion diseases, the strain phenomenon in prion diseases has been explained by the conformational difference of PrPSc according to the prion hypothesis (Prusiner 1998). Efforts to provide a molecular basis for the biological diversity of prions have focused on biochemical characterization of PrPSc. In human prion diseases including CJD, much evidence supporting conformation-based strain diversity has been gathered by Western blot analysis of PrPres. Such assays produce information on core fragment size and glycosylation site occupancy of PrPres. Variation in these parameters in combination with PRNP genotype has been invoked as the molecular basis to distinguish different disease phenotypes (Hill et al. 2003; Parchi et al. 1999b; Parchi et al. 1996). Considering recent findings on the complexity of PrPSc largely identified in laboratory prion strains, however, PrPres analysis alone may not provide a complete description of PrPSc present in CJD brains. In that context, this study identifies previously unrecognised heterogeneity in PrPSc in CJD brains through the use of assays that differ in principle from conventional Western blot analysis of PrPres. The novel biochemical approaches employed in this study have identified complexity of PrPSc in CJD brains, not only between different forms of human prion disease but also within individual cases of particular disease entities. Moreover, recent studies have reported that biochemical parameters such as PrPres stability and the size of PrPres aggregates can have significant effects on the biological properties of prions (Colby et al. 2009; Legname et al. 2006; Silveira et al. 2005). Therefore, the results from this study not only provide a more complete description of PrPSc



235



species occurring in CJD but also would contribute to a fuller understanding of the agents that cause the disease in humans. Understanding how the PrPSc complexity newly recognized in this study relates with the disease phenotypes and/or prion strains remains to be determined.





















Wednesday, March 31, 2010


Atypical BSE in Cattle


To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE.


When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.


This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.








Thursday, August 12, 2010


Seven main threats for the future linked to prions


First threat


The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.


***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.


Second threat


snip...













Rural and Regional Affairs and Transport References Committee


The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010


2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49


2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50






14th ICID International Scientific Exchange Brochure -


Final Abstract Number: ISE.114


Session: International Scientific Exchange


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


T. Singeltary


Bacliff, TX, USA


Background:


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


Methods:


12 years independent research of available data


Results:


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


Conclusion:


I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.







Monday, May 23, 2011


Atypical Prion Diseases in Humans and Animals 2011


Top Curr Chem (2011)


DOI: 10.1007/128_2011_161


# Springer-Verlag Berlin Heidelberg 2011


Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar


Abstract


Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.


M.A. Tranulis (*)


Norwegian School of Veterinary Science, Oslo, Norway


e-mail: Michael.Tranulis@nvh.no


S.L. Benestad


Norwegian Veterinary Institute, Oslo, Norway


T. Baron


Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France


H. Kretzschmar


Ludwig-Maximilians University of Munich, Munich, Germany


Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type







snip...SEE MORE HERE ;






Saturday, June 25, 2011


Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque


"BSE-L in North America may have existed for decades"






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


snip...


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






Wednesday, April 24, 2013


Dissociation between Transmissible Spongiform Encephalopathy (TSE) Infectivity and Proteinase K-Resistant PrPSc Levels in Peripheral Tissue from a Murine Transgenic Model of TSE Disease







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







Friday, April 19, 2013


FDA BSE TSE PRION NEWS FEED AND ANNUAL INSPECTION OF FEED MILLS REPORTS HAS CEASED TO EXIST







Monday, March 25, 2013


Minnesota Firm Recalls Bone-In Ribeye That May Contain Specified Risk Materials Recall Release CLASS II RECALL FSIS-RC-024-2013







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







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







Friday, April 19, 2013


Bovine Spongiform Encephalopathy (BSE) Feed Safety Support Program Grants Fiscal Year 2011: October 1, 2010 - September 30, 2011 FDA







Friday, April 19, 2013


APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION







Tuesday, April 30, 2013


Mad cow infected blood 'to kill 1,000’








Wednesday, April 24, 2013


Chimpanzees Released After 30 Years Of Testing, Brace Yourself For Smiles








Tuesday, April 30, 2013


Foodborne Transmission of Bovine Spongiform Encephalopathy to Nonhuman Primates








Friday, November 23, 2012


sporadic Creutzfeldt-Jakob Disease update As at 5th November 2012 UK, USA, AND CANADA








Sunday, December 2, 2012


CANADA 19 cases of mad cow disease SCENARIO 4: ‘WE HAD OUR CHANCE AND WE BLEW IT’








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 $







Sunday, March 31, 2013


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







Monday, April 15, 2013


Dr. Stephen B. Thacker Director Centers for Disease Control and Prevention′s Office of Science, Epidemiology and Laboratory Services (OSELS) dies from Creutzfeldt Jakob Disease CJD







Tuesday, March 19, 2013


Alzheimer's Association 2013 Alzheimer's Disease Facts and Figures


Today, an American develops Alzheimer's disease every 68 seconds. In 2050, an American will develop the disease every 33 seconds.







Wednesday, May 16, 2012


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


Proposal ID: 29403







Wednesday, September 21, 2011


PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)







Sunday, February 10, 2013


Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?







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.







CJD1/9 0185 Ref: 1M51A


IN STRICT CONFIDENCE


Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray


TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES


1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:


i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;


ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and


iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1







BSE101/1 0136


IN CONFIDENCE


5 NOV 1992 CMO From: Dr J S Metters 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 recognized 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 emphasizes 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.


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.


JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2







BSE101/1 0136


IN CONFIDENCE


CMO


From: Dr J S Metters DCMO


4 November 1992


TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES







CJD1/9 0185


Ref: 1M51A


IN STRICT CONFIDENCE


From: Dr. A Wight Date: 5 January 1993


Copies:


Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray


TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES









Thursday, August 4, 2011


Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011 (SEE VIDEO)









TSS

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