Saturday, March 23, 2013
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
http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/all-clinically-relevant-blood.html
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
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