Thursday, April 4, 2013

Variably protease-sensitive prionopathy in the UK: a retrospective review 1991–2008

Brain (2013) 136 (4): 1102-1115. doi: 10.1093/brain/aws366




Variably protease-sensitive prionopathy in the UK: a retrospective review 1991–2008



Mark W. Head1, Helen M. Yull1, Diane L. Ritchie1, Jan P. Langeveld2, Nicholas A. Fletcher3, Richard S. Knight1 and James W. Ironside1 + Author Affiliations




1 The National Creutzfeldt–Jakob Disease Research and Surveillance Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK 2 Central Veterinary Institute of Wageningen UR, 8200 AB Lelystad, The Netherlands 3 Division of Neurology, The Walton Centre, Lower Lane, Liverpool L97LJ, UK Correspondence to: Dr Mark W. Head, National Creutzfeldt–Jakob Disease Research & Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh EH4 2XU, UK E-mail: m.w.head@ed.ac.uk Received September 24, 2012. Revision received November 14, 2012. Accepted November 26, 2012.




Summary




Variably protease-sensitive prionopathy is a newly described human prion disease of unknown aetiology lying out with the hitherto recognized phenotypic spectrum of Creutzfeldt–Jakob disease. Two cases that conform to the variably protease-sensitive prionopathy phenotype have been identified prospectively in the UK since the first description of the condition in 2008 in the USA. To determine the incidence and phenotype of variably protease-sensitive prionopathy within a single well-defined cohort, we have conducted a retrospective review of patients referred to the National Creutzfeldt–Jakob Disease Research & Surveillance Unit during the period 1991–2008. The approach taken was to screen frozen brain tissue by western blotting for the form of protease-resistant prion protein that characterizes variably protease-sensitive prionopathy, followed by neuropathological and clinical review of candidate cases. Cases diagnosed as sporadic Creutzfeldt–Jakob disease with atypical neuropathology were also reviewed. Four hundred and sixty-five cases were screened biochemically, yielding four candidate cases of variably protease-sensitive prionopathy. One was discounted on pathological and clinical grounds, and one was a known case of variably protease-sensitive prionopathy previously reported, leaving two new cases, which were confirmed biochemically and neuropathologically as variably protease-sensitive prionopathy. A third new case that lacked frozen tissue was recognized retrospectively on neuropathological grounds alone. This means that five cases of variably protease-sensitive prionopathy have been identified (prospectively and retrospectively) during the surveillance period 1991–2011 in the UK. Assuming ascertainment levels equivalent to that of other human prion diseases, these data indicate that variably protease-sensitive prionopathy is a rare phenotype within human prion diseases, which are themselves rare. Biochemical investigation indicates that the abnormal protease-resistant prion protein fragment that characterizes variably protease-sensitive prionopathy is detectable at low levels in some cases of sporadic Creutzfeldt–Jakob disease and conversely, that the form of abnormal prion protein that characterizes sporadic Creutzfeldt–Jakob disease can be found in certain brain regions of cases of variably protease-sensitive prionopathy, indicating molecular overlaps between these two disorders.




Key words



Creutzfeldt–Jakob disease prion disease variably protease-sensitive prionopathy disease phenotype











CJD Figures



last updated 01/04/2013




1. in addition, the NCJDRSU has identified a total of 9 cases of VPSPr.












Prion 7:2, 99–108; March/April 2013; © 2013 Landes Bioscience




mini-Rev iew Mini-REVIEW




A closer look at prion strains



Characterization and important implications



Laura Solforosi,†,* Michela Milani,† Nicasio Mancini, Massimo Clementi and Roberto Burioni


Laboratory of Microbiology and Virology; University Vita-Salute San Raffaele; Milan, Italy


†These authors contributed equally to this work.




Keywords: cellular prion protein (PrPC), scrapie prion protein (PrPSc), transmissible spongiform encephalopathies (TSEs), prion strains, strain mutation, variant Creutzfeldt-Jakob disease, sporadic Creutzfeldt-Jakob disease




Abbreviations: PrPC, cellular prion protein; PrPSc, scrapie prion protein; TSEs, transmissible spongiform encephalopathies; TME, transmissible mink encephalopathy; CJD, Creutzfeldt-Jakob disease; sCJD, sporadic CJD; vCJD, variant CJD; FFI, fatal familial insomnia; BSE, bovine spongiform encephalopathy; CWD, chronic wasting disease; PK, proteinase K; SAF, scrapie-associated fibrils; CNS, central nervous system; WB, western blot; PE, phosphatidylethanolamine; sPMCA, serial protein misfolding cyclic amplification; CPA, cell panel assay




Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrPSc), a pathogenic isoform of the host-encoded cellular prion protein (PrPC). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrPSc conformational and aggregation states.




Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrPSc biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages.




This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves.




Introduction




Transmissible spongiform encephalopathies (TSEs) or prion diseases, such as Creutzfeldt-Jakob disease (CJD) in human, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids and scrapie in sheep, are a group of fatal neurodegenerative disorders. The major neuropathological hallmarks of TSEs are extensive spongiosis, neuronal cell loss in the central nervous system, gliosis,1 and deposition of amyloid plaques.2




*Correspondence to: Laura Solforosi; Email: solforosi.laura@hsr.it Submitted: 08/13/12; Revised: 12/20/12; Accepted: 01/03/13 http://dx.doi.org/10.4161/pri.23490




Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrPSc), a pathogenic isoform of the host-encoded cellular prion protein (PrPC). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrPSc conformational and aggregation states.




Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrPSc biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages.




This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves. ...




snip...




This classification arises from the hypothesis that if the polymorphism 129 can modulate the phenotype of the familial prion diseases (fCJD and FFI, as explained earlier in this review), then probably it can modulate also that of sporadic prion diseases, justifying their heterogeneity. According to this hypothesis, the cases affected by sCJD were divided into six groups according to the genotype of the polymorphism in position 129 and the type of PrPSc. Then, the phenotypes of every group were analyzed to evaluate the homogeneity within every group. The results have permitted a molecular sub-classification of the sCJD.90,91 However, this classification seems not to be sufficient to explain the complexity of the sporadic form of CJD. In fact, in some molecular subtypes, additional variants have been reported, such as MM or VV patients with amyloid plaques, which are absent in the majority of patients with these genotypes.44 Moreover, among patients belonging to the same subgroup, important phenotypic differences can be found, such as, for instance, the extent of neuronal loss or PrPSc deposition differences.92




Even at the biochemical level the complexity is higher: indeed, aside from the migratory differences of the PrPSc of types 1 and 2, there are other properties that could be important during the propagation of the strain, like the presence of other fragments derived from differential cleavage at the C- and N-terminus of the protein, which probably coincide with the presence of other forms of PrPSc with different resistance to PK digestion.44 All these molecular classifications are based upon the principle that in all CNS districts the type of PrPSc is the same, but there are pieces of evidence pointing to the fact that different types of PrPSc can be found in different brain areas.64,93 The first evidence of the presence of more than one form of PrPSc in the brain of a sCJD patient was reported by Puoti in 1999.94 These different types of PrPSc can be found to coexist in the same brain region or they can infect distinct districts. Such co-infection influences the vacuolization and the amyloid aggregates formation.95 Even the ratio between the different glycoforms is determined in a regionspecific manner according to the type of PrPSc (1 or 2) and the genotype of codon 129.




The high degree of phenotypic heterogeneity characterizing sCJD90 can lead to the conclusion that transmission studies will probably identify a broad panel of different prions with a great divergence between strains. However, quite surprisingly, many of the recent studies focusing on the characterization of sCJD subtypes have shown that there is a strong tendency to converge to a limited number of strains. This aspect can find an explanation considering the selection conditions, already described in this review, mediated by the environment in which the prion replicates and by the differences in the amino acid sequence of the PrPC. In particular, studies with bank voles96 and mice97 lead to results that support the idea that there are two principal strains responsible of the sCJD, M1 and V2, and two potential strains, M2 and V1, which need further studies to be confirmed.




Different is the case of vCJD. vCJD has been observed in 12 different countries, but in every registered case the same clinical and pathological characteristics have been found.39 In particular, the PrPSc responsible of the vCJD shows a peculiar WB profile, with the unglycosylated form of the protease-resistant PrPSc of 19 kDa (type 2) and a higher representation of the diglycosilated PrPSc (PrPSc 2B) compared with sCJD.39 Nevertheless, using specific antibodies against type 1 PrPSc, a small amount of PrPSc type 1 with a high percentage of diglycosilated form can be detected in association with PrPSc 2B.98 The 2B type is a useful marker for identifying the replication of BSE prions also in other species, including non-human primates.99 In addition, unlike sporadic and genetic CJD, in vCJD the same biological marker (2B type) has been found in all the analyzed brain areas.100 This strong biochemical and pathological homogeneity is in agreement with the hypothesis of the existence of a unique strain. However, unexpectedly, typization experiments of the strains in different transgenic models have given divergent results. In one of these studies, in a context of homotropic transmission, transgenic mice expressing high levels of human PrPC-M129 were inoculated with vCJD isolates coming from France and from the UK.101 All of the French isolates propagated as vCJD, with abundant amyloid plaques and presence of PrPSc 2B.102 Instead, the isolates from the UK led to the propagation of either vCJD or sCJD.103 In particular, the incubation time was shorter and the lesion profile was different compared with the one obtained with the propagation of the classical vCJD strain. Moreover, early replication of the typical agent of the vCJD in lymphoid tissues was detected, indicating that both strains were present in the inoculum.




This new strain with phenotypical features that were similar to sCJD was found to be of type 1 and the transmission in transgenic mice expressing the bovine PrPC failed, unlike the vCJD classical strain (Type 2B).26 The idea that the infection of vCJD contains a minor component of sCJD prions is supported by many pieces of evidence such as the presence of this prion strain at the first passage or the persistence of both types of PrPSc through serial passages in mice.98 In conclusion, although vCJD is one of the most standardized phenotypes among the prion human diseases characterized by a typical form of PrPSc, the transmission studies of vCJD have shown the great potential of divergence of prions, contrary to the results obtained from the studies of sCJD. This data challenge our ability to recognize the pathologies that can derive from the divergence of the BSE strains when they infect humans, both at the pathological and at the biochemical level.




Conclusion




The discovery of prions has led to new interpretations of the pathogenetic mechanism of protein misfolding diseases. Indeed, the common thought was that a protein misfolding disease could only be caused by a mutation in the primary sequence of an endogenous protein, but the discovery of prions changed this view. In fact, it was demonstrated that a seed of misfolded protein can arise from an exogenous infectious protein, which is able to act as a template or as a catalyst for the formation of new aberrant protein.5,6 Importantly, new evidence shows how processes similar to those described for prions could be implicated in the propagation of misfolded proteins of other neurodegenerative pathologies like Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis.104,105




Certainly, one of the most puzzling aspects in the prion field is the existence of different strains of an infectious protein. Nevertheless, such diversity can be accommodated within the protein-only hypothesis, as several robust pieces of experimental evidence indicate that strain-specificity is encoded at the level of the different conformations that the pathogenic protein can adopt. The identification of factors and mechanisms influencing the generation of new prion strains or the selection, from a conformationally heterogeneous PrPSc population, of the most suitable prion conformation in a specific environment, represents an important milestone toward the understanding of the mechanisms of prion strain diversity, which can have fundamental clinical and therapeutic implications. Although considerable advances have been made in the understanding of the phenomenon of prion strains, many pieces of information are still missing, foremost among them the definitive evidence for the structural nature of the differences between prion strains.















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










*** 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 $








*** 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.






*** atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012


NIAA Annual Conference April 11-14, 2011


San Antonio, Texas










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












NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS


"All of the 15 cattle tested showed that the brains had abnormally accumulated PrP"


2009








''THE LINE TO TAKE'' ON IBNC $$$ 1995 $$$


1995


page 9 of 14 ;


30. The Committee noted that the results were unusual. the questioned whether there could be coincidental BSE infection or contamination with scrapie. Dr. Tyrell noted that the feeling of the committee was that this did not represent a new agent but it was important to be prepared to say something publicly about these findings. A suggested line to take was that these were scientifically unpublishable results but in line with the policy of openness they would be made publicly available and further work done to test their validity. Since the BSE precautions were applied to IBNC cases, human health was protected. Further investigations should be carried out on isolations from brains of IBNC cases with removal of the brain and subsequent handling under strict conditions to avoid the risk of any contamination.


31. Mr. Bradley informed the Committee that the CVO had informed the CMO about the IBNC results and the transmission from retina and he, like the Committee was satisfied that the controls already in place or proposed were adequate. ...


snip... see full text















Wednesday, July 28, 2010


Atypical prion proteins and IBNC in cattle DEFRA project code SE1796 FOIA Final report








IN CONFIDENCE


BSE ATYPICAL LESION DISTRIBUTION








Tuesday, November 02, 2010


IN CONFIDENCE


The information contained herein should not be disseminated further except on the basis of "NEED TO KNOW".


BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992










HARVARD BSE RISK ASSESSMENT AND REASSESSMENT OF SUPPRESSED HARVARD RISK ASSESSMENT THAT WAS SO FLAWED $$$















Thursday, February 14, 2013


The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease











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










Sunday, March 31, 2013


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








USDA TRIPLE BSE MAD COW FIREWALL, SRM, FEED, AND SURVEILLANCE




2012


***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...








Síndrome de Alpers uma variante da Doença de Creutzfeldt-Jakob?


Alpers’ disease a variant of Creutzfeldt-Jakob Disease?


Henrique Pott Jr.1, Maria Cristina Furian Ferreira2, Amilcar Castro de Mattos3




ABSTRACT


The dementia, is usually associated with other neurological abnormalities, and a definitive diagnosis of most syndromes depends on neuropathological examination. Creutzfeldt-Jakob disease in children presents neuropathological examination similar to Alpers’ disease, which have given attention to the differential diagnosis between these syndromes. The aim of this study was to report a case of progressive degenerative spongiform encephalopathy in infancy with study of autopsy. Keywords. Dementia, Differential Diagnosis, Creutzfeldt-Jakob Syndrome, Alpers Syndrome. Citation. Pott Jr. H, Ferreira MCF, Mattos AC. Alpers’ disease a variant of Creutzfeldt-Jakob Disease?





snip...





Case Description




Female patient, 5 years, with frame clinical and progressive encephalopathy in our hospital since 6 months of age. As showed inrespiratory sufficiency, was kept breathing assist from since that date. Clinical data of early admission exclude the possibility of secondary ischemic to trauma during dleivery. The worsening progressive neurological reflexes, including deep, led to succesive clinical and laboratory investigations pouco enlightening.




snip, see full text ;











Friday, December 07, 2012


ATYPICAL BSE BRAZIL 2010 FINALLY CONFIRMED OIE 2012









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, 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 ;









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)








P.9.21


Molecular characterization of BSE in Canada


Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada


Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.


Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.


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


Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.


*** It also suggests a similar cause or source for atypical BSE in these countries.











what about that ALABAMA MAD COW, AND MAD COW FEED THERE FROM IN THAT STATE ???






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)


BANNED MAD COW FEED IN COMMERCE IN ALABAMA


Date: September 6, 2006 at 7:58 am PST PRODUCT


a) EVSRC Custom dairy feed, Recall # V-130-6;


b) Performance Chick Starter, Recall # V-131-6;


c) Performance Quail Grower, Recall # V-132-6;


d) Performance Pheasant Finisher, Recall # V-133-6.


CODE None RECALLING FIRM/MANUFACTURER Donaldson & Hasenbein/dba J&R Feed Service, Inc., Cullman, AL, by telephone on June 23, 2006 and by letter dated July 19, 2006. Firm initiated recall is complete.


REASON


Dairy and poultry feeds were possibly contaminated with ruminant based protein.


VOLUME OF PRODUCT IN COMMERCE 477.72 tons


DISTRIBUTION AL


______________________________









PRODUCT Bulk custom dairy pre-mixes,


Recall # V-120-6 CODE None RECALLING FIRM/MANUFACTURER Ware Milling Inc., Houston, MS, by telephone on June 23, 2006. Firm initiated recall is complete. REASON Possible contamination of dairy animal feeds with ruminant derived meat and bone meal.


VOLUME OF PRODUCT IN COMMERCE 350 tons


DISTRIBUTION AL and MS


______________________________


PRODUCT


a) Tucker Milling, LLC Tm 32% Sinking Fish Grower, #2680-Pellet, 50 lb. bags, Recall # V-121-6;


b) Tucker Milling, LLC #31120, Game Bird Breeder Pellet, 50 lb. bags, Recall # V-122-6;


c) Tucker Milling, LLC #31232 Game Bird Grower, 50 lb. bags, Recall # V-123-6;


d) Tucker Milling, LLC 31227-Crumble, Game Bird Starter, BMD Medicated, 50 lb bags, Recall # V-124-6;


e) Tucker Milling, LLC #31120, Game Bird Breeder, 50 lb bags, Recall # V-125-6;


f) Tucker Milling, LLC #30230, 30 % Turkey Starter, 50 lb bags, Recall # V-126-6;


g) Tucker Milling, LLC #30116, TM Broiler Finisher, 50 lb bags, Recall # V-127-6


CODE All products manufactured from 02/01/2005 until 06/20/2006 RECALLING FIRM/MANUFACTURER Recalling Firm: Tucker Milling LLC, Guntersville, AL, by telephone and visit on June 20, 2006, and by letter on June 23, 2006. Manufacturer: H. J. Baker and Brothers Inc., Stamford, CT. Firm initiated recall is ongoing.


REASON Poultry and fish feeds which were possibly contaminated with ruminant based protein were not labeled as "Do not feed to ruminants".


VOLUME OF PRODUCT IN COMMERCE 7,541-50 lb bags


DISTRIBUTION AL, GA, MS, and TN


END OF ENFORCEMENT REPORT FOR AUGUST 9, 2006


###








Subject: MAD COW FEED RECALL AL AND FL VOLUME OF PRODUCT IN COMMERCE 125 TONS Products manufactured from 02/01/2005 until 06/06/2006


Date: August 6, 2006 at 6:16 pm PST PRODUCT


a) CO-OP 32% Sinking Catfish, Recall # V-100-6;


b) Performance Sheep Pell W/Decox/A/N, medicated, net wt. 50 lbs, Recall # V-101-6;


c) Pro 40% Swine Conc Meal -- 50 lb, Recall # V-102-6;


d) CO-OP 32% Sinking Catfish Food Medicated, Recall # V-103-6;


e) "Big Jim's" BBB Deer Ration, Big Buck Blend, Recall # V-104-6;


f) CO-OP 40% Hog Supplement Medicated Pelleted, Tylosin 100 grams/ton, 50 lb. bag, Recall # V-105-6;


g) Pig Starter Pell II, 18% W/MCDX Medicated 282020, Carbadox -- 0.0055%, Recall # V-106-6;


h) CO-OP STARTER-GROWER CRUMBLES, Complete Feed for Chickens from Hatch to 20 Weeks, Medicated, Bacitracin Methylene Disalicylate, 25 and 50 Lbs, Recall # V-107-6;


i) CO-OP LAYING PELLETS, Complete Feed for Laying Chickens, Recall # 108-6;


j) CO-OP LAYING CRUMBLES, Recall # V-109-6;


k) CO-OP QUAIL FLIGHT CONDITIONER MEDICATED, net wt 50 Lbs, Recall # V-110-6;


l) CO-OP QUAIL STARTER MEDICATED, Net Wt. 50 Lbs, Recall # V-111-6;


m) CO-OP QUAIL GROWER MEDICATED, 50 Lbs, Recall # V-112-6 CODE


Product manufactured from 02/01/2005 until 06/06/2006


RECALLING FIRM/MANUFACTURER Alabama Farmers Cooperative, Inc., Decatur, AL, by telephone, fax, email and visit on June 9, 2006. FDA initiated recall is complete.


REASON Animal and fish feeds which were possibly contaminated with ruminant based protein not labeled as "Do not feed to ruminants".


VOLUME OF PRODUCT IN COMMERCE 125 tons


DISTRIBUTION AL and FL


END OF ENFORCEMENT REPORT FOR AUGUST 2, 2006


###








MAD COW FEED RECALL USA EQUALS 10,878.06 TONS NATIONWIDE Sun Jul 16, 2006 09:22 71.248.128.67


RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINE -- CLASS II


______________________________


PRODUCT


a) PRO-LAK, bulk weight, Protein Concentrate for Lactating Dairy Animals, Recall # V-079-6;


b) ProAmino II, FOR PREFRESH AND LACTATING COWS, net weight 50lb (22.6 kg), Recall # V-080-6;


c) PRO-PAK, MARINE & ANIMAL PROTEIN CONCENTRATE FOR USE IN ANIMAL FEED, Recall # V-081-6;


d) Feather Meal, Recall # V-082-6 CODE


a) Bulk


b) None


c) Bulk


d) Bulk


RECALLING FIRM/MANUFACTURER H. J. Baker & Bro., Inc., Albertville, AL, by telephone on June 15, 2006 and by press release on June 16, 2006. Firm initiated recall is ongoing.


REASON


Possible contamination of animal feeds with ruminent derived meat and bone meal.


VOLUME OF PRODUCT IN COMMERCE 10,878.06 tons


DISTRIBUTION Nationwide


END OF ENFORCEMENT REPORT FOR July 12, 2006


###








2007






10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN COMMERCE USA 2007


Date: March 21, 2007 at 2:27 pm PST


RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II


PRODUCT


Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007


CODE


Cattle feed delivered between 01/12/2007 and 01/26/2007


RECALLING FIRM/MANUFACTURER


Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.


Firm initiated recall is ongoing.


REASON


Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.


VOLUME OF PRODUCT IN COMMERCE


42,090 lbs.


DISTRIBUTION


WI


___________________________________


PRODUCT


Custom dairy premix products:


MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007


CODE


The firm does not utilize a code - only shipping documentation with commodity and weights identified.


RECALLING FIRM/MANUFACTURER


Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete.


REASON


Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.


VOLUME OF PRODUCT IN COMMERCE


9,997,976 lbs.


DISTRIBUTION


ID and NV


END OF ENFORCEMENT REPORT FOR MARCH 21, 2007








Saturday, August 4, 2012


Final Feed Investigation Summary - California BSE Case - July 2012













What irks many scientists is the USDA’s April 25 statement that the rare disease is “not generally associated with an animal consuming infected feed.”



The USDA’s conclusion is a “gross oversimplification,” said Dr. Paul Brown, one of the world’s experts on this type of disease who retired recently from the National Institutes of Health.



"(The agency) has no foundation on which to base that statement.”



“We can’t say it’s not feed related,” agreed Dr. Linda Detwiler, an official with the USDA during the Clinton Administration now at Mississippi State.



In the May 1 email to me, USDA’s Cole backed off a bit. “No one knows the origins of atypical cases of BSE,” she said








Saturday, May 26, 2012


Are USDA assurances on mad cow case 'gross oversimplification'?












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









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










TSS

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