Saturday, March 23, 2013

CJD Incidents Panel to be disbanded

CJD Incidents Panel to be disbanded




The Creutzfeldt-Jakob Disease (CJD) Incidents Panel will be dissolved at the end of March 2013. Subsequently, the following arrangements will apply:




From 1 April 2013, responsibility for investigating, assessing and managing CJD incidents (and where appropriate notifying patients) will be with local trusts, health boards and health protection teams in the same way as most other incidents that place patients at risk; National guidance on CJD incident management will be available to support this and will be published on the legacy Health Protection Agency website [1]. Novel issues that arise with respect to CJD risk management and infection control can be referred to the Advisory Committee on Dangerous Pathogens (ACDP) Transmissible Spongiform Encephalopathy (TSE) Risk Management Sub-Group; Long term public health surveillance of CJD exposures will continue and trusts, health boards and health protection teams are asked to continue reporting the occurrence of incidents to Public Health England, in particular if they involve a patient notification exercise; Infection control guidance from the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy Risk Management Subgroup (ACDP TSE RM SG, formerly the TSE Working Group) to reduce the risk of spread of TSEs in healthcare and community settings can be found at: http://www.dh.gov.uk/health/2012/11/acdp-guidance/. Further/background information:




What is a CJD Incident? – A surgical incident has occurred when a patient with, or at increased risk of, any human prion disease, including all forms of CJD, has had an invasive procedure involving high or medium infectivity tissues for CJD and where TSE instrument precautions were not taken. Patients subsequently exposed to the implicated instruments may need to be informed that they are at increased risk of CJD, depending on the specific circumstances. Questions relating to the interpretation of the guidance should be sent to the HPA/PHE CJD team either via the CJD mailbox cjd@hpa.org.uk (cjd@phe.gov.uk, after 1 April 2013), or to: katy.sinka@hpa.org.uk, emma.hollis@phe.gov.uk.




Note




1. The guidance will be available on the HPA website: Topics › Infectious Diseases › Infections A-Z › Creutzfeldt-Jakob Disease (CJD) › CJD Guidance and Advice.










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









Sunday, February 10, 2013


Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection report/CJD









Thursday, January 17, 2013


TSE guidance, surgical, dental, blood risk factors, Part 4 Infection control of CJD, vCJD and other human prion diseases in healthcare and community settings (updated January 2013)









Monday, December 10, 2012


Report on the monitoring of ruminants for the presence of Transmissible Spongiform Encephalopathies (TSEs) in the EU in 2011 Final version 18 October 2012










Friday, August 24, 2012


Iatrogenic prion diseases in humans: an update










Friday, August 10, 2012


Incidents of Potential iatrogenic Creutzfeldt-Jakob disease (CJD) biannual update (July 2012)











Thursday, July 05, 2012


Incidence of variant Creutzfeldt-Jakob disease diagnoses and deaths in the UK January 1994 – December 2011











Thursday, April 12, 2012


Health professions and risk of sporadic Creutzfeldt–Jakob disease, 1965 to 2010


Eurosurveillance, Volume 17, Issue 15, 12 April 2012


Research articles










Wednesday, August 24, 2011


All Clinically-Relevant Blood Components Transmit Prion Disease following a > Single Blood Transfusion: A Sheep Model of vCJD











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











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 $










*** 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












Monday, October 10, 2011


EFSA Journal 2011 The European Response to BSE: A Success Story












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











Wednesday, May 16, 2012


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


Proposal ID: 29403








 
 
 
 
 

TSS

Links to this post:

Create a Link

<< Home