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Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties

Posted Jun 16 2010 11:20am
Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties

Matthew T. Bishopa, Robert G. Willa, and Jean C. Mansonb,1

aNational Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; and bThe Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9PS, United Kingdom

Edited* by Reed B. Wickner, National Institutes of Health, Bethesda, MD, and approved May 19, 2010 (received for review April 15, 2010)

The biological determinants of the phenotypic variation in sporadic Creutzfeldt-Jakob disease (sCJD) are unknown. To categorize sCJD cases, the prion protein (PrP) codon 129 genotype and the biochemical characteristics of the disease-associated form of PrP (PrPSc) can be combined to formsix subgroups (MM1,MM2,MV1,MV2, VV1, and VV2). This classification largely correlates with the known variation in the clinical and pathological features of sCJD, with the MM1 and MV1 cases representing the “classic” phenotype of sCJD. To address how this classification relates to different strains of sCJD we have inoculated each subgroup of sCJD to a panel of mice expressing different forms of the human PRNP gene (129MM, 129VV, and 129MV). We have established that all subtypes are transmissible to at least one genotype of mouse, and both agent and host factors determine transmission efficiency and the form of PrPSc deposited in the brain. Moreover, we have identified four distinct strains of sCJD using our in vivo strain typing panel.

codon 129 genotype mouse model prion disease transmission strains


snip...


Discussion The similarities and differences that have emerged during this study indicate that six subgroups of sCJD, defined here by PrPSc type and PRNP codon 129 genotype, behave as four different strains of agent. Sporadic CJD(MM1) and sCJD(MV1) isolates have identical transmission properties for all three genotypes of mice. The sCJD(MV2) and sCJD(VV2) isolates have very similar transmission properties, and both the sCJD(MM2) and sCJD (VV1) strains behave differently from each other and from the other isolates. To facilitate discussion of this grouping and for future reference we propose to name these major strains “M1CJD,” “V2CJD,” “M2CJD,” and “V1CJD,” respectively. Our studies, based on incubation time, lesion profile, and PrPSc Western blot profile and deposition in the brain using a panel of mice, are based on the “gold standard” strain typing of isolates originally designed using wild-type mice (26). The difference here is that our transgenic mice carrying the human PRNP gene have been substituted for the original wild-type panel, but the inbred nature and gene targeting of these mice ensure that they are suitable for such a panel, because there is only a single PrP amino acid difference between each of the lines. Previous sCJD transmission studies have provided additional evidence for sCJD (MM1) and sCJD(MV1) having similar transmission properties and some evidence for similarities between sCJD(MV2) and sCJD(VV2), but insufficient evidence to make a comparison between sCJD(VV1) and sCJD(MM2) (21, 24, 27). This study is a complete analysis of all major sCJD subgroups in inbred mouse models and is thus capable of a true comparison for distinguishing the codon 129 homozygote and heterozygote response. However, the present study examines only single cases of sCJD, with the assumption that transmission characteristics of a single case will be representative of the particular subgroup. Although typical cases of each subgroup were carefully selected for this study, there is phenotypic variation within sCJD subgroups, and it is therefore essential that the findings in this study are replicated in additional cases. Through a grant from the European Union (NeuroPrion: HUMTRANS) the panel of mice used in this study have been provided to a number of other groups, and transmission studies including a significant number of additional sCJD cases are underway. This is of particular importance for the sCJD(MM2) subgroup because our evidence for a unique strain derives partly from the inefficiency in transmission. Inoculum prepared from this specific patient has been used in parallel wild-type and transgenic studies (28) and shows clear evidence of successful transmission to those mice, confirming that infectivity titer was unlikely to be implicated in our findings.


Evidence in support of these four major strains of sCJD has recently been reported through a very different approach. Using in vitro assays, Uro-Coste et al. (29) examined the protease sensitivity and conformational stability of PrPSc found in 41 patients with sCJD and found groupings identical to those outlined in this study (i.e., MM1 and MV1; MV2 and VV2; MM2; VV1). Because this study was based entirely on in vitro analysis of PrPSc, this suggests that the four strains of agent identified in our study have different conformations of PrPSc. What is perhaps surprising is that only four discrete strains of sCJD have been identified. If the prion protein can exist in many different pathogenic isoforms in a single host, why then do only four different strains of sCJD result in humans? Because the assumption is that each sCJD case arises spontaneously, this would require strong selection factors to be operating for these four strains and against others that may be produced.


There are diverse suggestions as to the origin of sCJD, including proposals that somatic mutations lead to protein misfolding and disease (30) or that sCJD has arisen through infection from an animal source, such as atypical BSE (18, 31). Clearly host PRNP sequence is not the major criteria for separating the four strains, although it does seem to have some influence. If differences in protein misfolding are the basis of the origin of these strains then it remains to be established what influences this characteristic. The quasi-species hypothesis put forward by Collinge et al. (32) suggests that a wide range of mammalian PrPSc conformations are possible but that only a subset are compatible with each individual PrP primary structure. This theory may explain both the influence of the host genotype and the limited range of sCJD strains, but such a hypothesis predicts a wider range of strains emerging from heterozygote individuals, which is not apparent in this study. If the strain of sCJD was directed not by the exact somatic mutation but by the cell type in which it arose, then this may lead to differential misfolding of the protein under control of different misfolding cofactors present in that cell (33), which could explain the limited strains of agent associated with each genotype of PRNP. Alternatively, there may be only a limited number of somatic mutations that give rise to sCJD disease within the lifetime of the individual, and the number of strains may therefore be restricted by those somatic mutations that are capable of causing rapid-onset disease. It may be that in vitro analysis has not revealed the extent of sCJD strains, although some analyses have suggested a greater diversity of strains (16) than predicted by others (17). Further in vivo strain typing will establish the range of sCJD strains.


Our study evaluated the precise effect host PRNP codon 129 genotype has on defining transmission and propagation of sCJD strains in the three genotypes 129MM, 129MV, and 129VV. There were some specific combinations of host and inoculum within the dataset that showed similar characteristics across the experiments, such as the observation that the HuVV genotype line developed clinical TSE features with most inocula. HuVV mice also had the shortest incubation periods by more than 100 d, seen for sCJD(MV2) and sCJD(VV2) inocula. These data predict that for human iatrogenic spread of sCJD as a whole, this genotype may be the most susceptible or may show shorter incubation periods. It is of note that there is an increased prevalence of young (<50 y) VV genotype sCJD cases across European countries (United Kingdom, Germany, Italy, and France) (10). The second common characteristic among the data was that HuMM and HuMV mice had similar levels of clinical disease, and mean incubation periods, for four of the six inocula [excluding sCJD(MM2) and sCJD(VV1)]. This suggests that the methionine allele of PrPC in the heterozygous HuMV mice may have had a dominant effect over the valine allele PrPC with regard to the transmission properties. This study identifies two areas of risk in terms of developing sCJD. The first is that the highest risk of developing CJD after exposure to infection is from strain M1CJD [sCJD(MM1) or sCJD(MV1)] and that the VV genotype confers the highest risk of acquiring infection. The epidemiological findings in sCJD demonstrate that approximately 80% of patients are diagnosed with “classic CJD” types MM1 and MV1, which might intriguingly suggest an infectious rather than genetic origin for the majority of sCJD cases.


PrPSc type has typically been used as a diagnostic indicator of the strain of agent infecting an individual. This study, however, clearly demonstrates that the PrPSc type is a result of the interaction between strain and host. Type 2 PrPSc was seen only in HuVV mice that had short incubation periods, after inoculation with primary or secondary sources of strain V2CJD [sCJD(MV2) and sCJD(VV2)], indicating a specific pathological response from the valine homozygous mouse host and inocula with valine allele type 2 PrPSc. All other mice genotype/inoculum combinations produced type 1 PrPSc.


Second passage of sCJD(MM1), sCJD(MV2), and sCJD(VV2) in the transgenic mice has allowed us to examine the strain– genotype correlation and to assess the potential risk of transmission of these agents within the human population. The sCJD(MM1) strain transmission properties were unaffected by secondary passage; the strain could propagate within non-MM hosts and could transmit from non-MM hosts to all genotypes with the same properties as primary passage. Because of these facts, there may be difficulty in distinguishing sCJD from iatrogenic CJD caused by infection from sCJD(MM1) or the M1CJD strain. However, these data also indicate that passage of the commonest form of sCJD does not cause adaptation to a more highly transmissible form of human TSE. Conversely, the other two sCJD subgroups analyzed by secondary passage seemed to undergo modification of properties dependent on the codon 129 genotype of the source and recipient mouse. The sCJD(MV2) strain transmission properties were unaffected by secondary passage from an HuMM mouse. Inoculation of HuVV mice with sCJD(MV2) from an HuVV mouse produced a reduction in incubation period, suggesting adaptation to a strain with more efficient transmission properties. An overabundance of iCJD cases in VV genotype recipients of contaminated human growth hormone in the United Kingdom supports these data (34), although this is not the case in France (8). A form of adaptation was also observed for HuMMand HuMV mice that received sCJD(MV2) inoculum from an HuMV mouse. Reduction in incubation periods and an increased number of mice positive for vacuolation suggest that a more efficient transmitting strain has been formed. The sCJD(VV2) strain transmission properties showed a similar response as for sCJD(MV2). Transmission properties were unaffected by secondary passage from an HuMV mouse, and inoculation of HuVV mice with sCJD(VV2) from an HuVV mouse produced a reduction in incubation period. Strain adaptation was observed for HuMM and HuMV mice that received inoculum from sCJD(VV2) passaged through an HuMM mouse. Analysis of incubation periods and lesion profile data suggests that the adaptation seen may be producing a host response more similar to that seen for sCJD(MM1) transmission. Therefore if sCJD(MV2) and sCJD(VV2) were to become iatrogenic sources of human infection, the host response may be indistinguishable from sCJD(MM1) and more transmissible with respect to further infection.


The results from this study can be used as a standard against which atypical or novel forms of human TSE can be compared. We have identified four discrete transmission strains, including M1CJD: sCJD(MM1 and MV1); V2CJD: sCJD(MV2 and VV2); V1CJD: sCJD(VV1); and M2CJD: sCJD(MM2). We hypothesize that iatrogenic spread of sCJD will depend on sCJD subgroup source and host codon 129 genotype and could produce more transmissible adapted forms of human TSE, highlighting the continued need for CJD surveillance and iatrogenic transmission risk evaluation. The sporadic CJD transmission strain characterization described in this study will now allow the full range of sCJD strains to be examined and atypical strains of human TSE to be readily identified so that the public health threats from potential new forms of infectious prion disease can be investigated.


snip...see full text ;


http://www.pnas.org/content/early/2010/06/08/1004688107.full.pdf



SOME interesting aspects of this study ;


These data predict that for human iatrogenic spread of sCJD as a whole, this genotype may be the most susceptible or may show shorter incubation periods. It is of note that there is an increased prevalence of young (<50 y) VV genotype sCJD cases across European countries (United Kingdom, Germany, Italy, and France) (10).


The second common characteristic among the data was that HuMM and HuMV mice had similar levels of clinical disease, and mean incubation periods, for four of the six inocula [excluding sCJD(MM2) and sCJD(VV1)]. This suggests that the methionine allele of PrPC in the heterozygous HuMV mice may have had a dominant effect over the valine allele PrPC with regard to the transmission properties. This study identifies two areas of risk in terms of developing sCJD. The first is that the highest risk of developing CJD after exposure to infection is from strain M1CJD [sCJD(MM1) or sCJD(MV1)] and that the VV genotype confers the highest risk of acquiring infection. The epidemiological findings in sCJD demonstrate that approximately 80% of patients are diagnosed with “classic CJD” types MM1 and MV1, which might intriguingly suggest an infectious rather than genetic origin for the majority of sCJD cases.


snip...


Therefore if sCJD(MV2) and sCJD(VV2) were to become iatrogenic sources of human infection, the host response may be indistinguishable from sCJD(MM1) and more transmissible with respect to further infection. END...TSS


Greetings,


IF you consider the many different TSE strains in different species in North America, and then think 'friendly fire' there from. For a few years now there seems to be a rise here in the U.S.A. of sporadic CJD strains of 'unknown phenotype', with ;


5 Includes 28 cases in which the diagnosis is pending, and


17 inconclusive cases; 6 Includes 28 (24 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded


http://www.cjdsurveillance.com/pdf/case-table.pdf



There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.


He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf



ATYPICAL BSE MORE VIRULENT TO HUMANS THAN UK STRAIN 18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7 December 2006 are now available.


snip...


64. A member noted that at the recent Neuroprion meeting, a study was presented showing that in transgenic mice BSE passaged in sheep may be more virulent and infectious to a wider range of species than bovine derived BSE.


Other work presented suggested that BSE and bovine amyloidotic spongiform encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A MUTATION FOUND IN CASES OF SPORADIC CJD.


snip...



http://www.seac.gov.uk/minutes/95.pdf



2008 - 2010


The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.


http://www.cjdfoundation.org/fact.html



CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER


>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<


Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas


Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas. She left 6 Kids and a Husband.The Purpose of this web is to give information in Spanish to the Hispanic community, and to all the community who want's information about this terrible disease.


Physician Discharge Summary, Parkland Hospital, Dallas Texas


Admit Date: 12/29/2009 Discharge Date: 1/20/2010


Attending Provider: Greenberg, Benjamin Morris;


General Neurology Team: General Neurology Team


Linda was a Hispanic female with no past medical history presents with 14 months of incresing/progressive altered mental status, generalized weakness, inability to walk, loss of appetite, inability to speak, tremor and bowel/blader incontinence. She was, in her usual state of health up until February, 2009, when her husbans notes that she began forgetting things like names and short term memories. He also noticed mild/vague personality changes such as increased aggression. In March, she was involved in a hit and run MVA,although she was not injured. The police tracked her down and ticketed her. At that time, her son deployed to Iraq with the Army and her husband assumed her mentation changes were due to stress over these two events. Also in March, she began to have weakness in her legs, making it difficult to walk. Over the next few months, her mentation and personality changes worsened, getting to a point where she could no longer recognized her children. She was eating less and less. She was losing more weight. In the last 2-3 months, she reached the point where she could not walk without an assist, then 1 month ago, she stopped talking, only making grunting/aggressive sounds when anyone came near her. She also became both bowel and bladder incontinent, having to wear diapers. Her '"tremor'" and body jerks worsened and her hands assumed a sort of permanent grip position, leading her family to put tennis balls in her hands to protect her fingers.


The husband says that they have lived in Nebraska for the past 21 years. They had seen a doctor there during the summer time who prescribed her Seroquel and Lexapro, Thinking these were sx of a mood disorder. However, the medications did not help and she continued to deteriorate clinically. Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. The husband says that he does not know any fellow workers with a similar illness. He also says that she did not have any preceeding illness or travel.



http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8



>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<



Monday, March 29, 2010


Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas


http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.html



CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER


http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html



Friday, November 30, 2007


CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION


http://cjdquestionnaire.blogspot.com/



IT would be interested to know more about these cases, especially the genotype. An extensive CJD questionnaire should be required for each victim and their family, asking real questions pertaining to all the pontential routes and sources of the TSE agent.




Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (TRANSCRIPT)



http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/UCM171810.pdf



Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)



http://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html



Manuscript Draft Manuscript Number
Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory

Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary,

Corresponding Author's Institution: na


First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary


Abstract

TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.


http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf


Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009


http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html


Friday, February 05, 2010


New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review


http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html


Saturday, January 2, 2010 Human Prion Diseases in the United States January 1, 2010 ***FINAL***


http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html


my comments to PLosone here ;


http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd



Tuesday, August 11, 2009


Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants


Brian S. Appleby, MD; Kristin K. Appleby, MD; Barbara J. Crain, MD, PhD; Chiadi U. Onyike, MD, MHS; Mitchell T. Wallin, MD, MPH; Peter V. Rabins, MD, MPH



Background: The classic Creutzfeldt-Jakob disease (CJD), Heidenhain, and Oppenheimer-Brownell variants are sporadic CJD (sCJD) phenotypes frequently described in the literature, but many cases present with neuropsychiatric symptoms, suggesting that there may be additional sCJD phenotypes.


Objective: To characterize clinical, diagnostic, and molecular features of 5 sCJD variants. Design: Retrospective analysis. Setting: The Johns Hopkins and Veterans Administration health care systems.


Participants: Eighty-eight patients with definite or probable sCJD.


Main Outcome Measures: Differences in age at onset, illness progression, diagnostic test results, and molecular subtype.


Results: The age at onset differed among sCJD variants (P=.03); the affective variant had the youngest mean age at onset (59.7 years). Survival time (P .001) and the time to clinical presentation (P=.003) differed among groups. Patients with the classic CJD phenotype had the shortest median survival time from symptom onset (66 days) and those who met criteria for the affective sCJD variant had the longest (421 days) and presented to clinicians significantly later (median time from onset to presentation, 92 days; P=.004). Cerebrospinal fluid analyses were positive for 14-3-3 protein in all of the affective variants, regardless of illness duration. Periodic sharp-wave complexes were not detected on any of the electroencephalography tracings in the Oppenheimer-Brownell group; basal ganglia hyperintensity was not detected on brain magnetic resonance imaging in this group either. All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.


Conclusions: The classic CJD phenotype and the Heidenhain, Oppenheimer-Brownell, cognitive, and affective sCJD variants differ by age at disease onset, survival time, and diagnostic test results. Characteristics of these 5 phenotypes are provided to facilitate further clinicopathologic investigation that may lead to more reliable and timely diagnoses of sCJD.


Arch Neurol. 2009;66(2):208-215


snip...


http://archneur.ama-assn.org/


see full text ;


http://creutzfeldt-jakob-disease.blogspot.com/2009/08/characteristics-of-established-and.html


Monday, May 11, 2009


Rare BSE mutation raises concerns over risks to public health


http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html



sporadic CJD and farmers and their wives with BSE herds?

sporadic CJD in a 16 year old?

IF it does not fit, YOU MUST ACQUIT the UKBSEnvCJD only theory !!!



Sunday, August 10, 2008

A New Prionopathy OR more of the same old BSe and sporadic CJD


http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html


Wednesday, March 31, 2010 Atypical BSE in Cattle / position: Post Doctoral Fellow


To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.



http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html



Subject: 14th International Congress on Infectious Diseases H-type and L-type Atypical BSE January 2010

(special pre-congress edition) 18.173 page 189


Experimental Challenge of Cattle with H-type and L-type Atypical BSE


A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H. Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany, 2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch, Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy Secretariat, Ottawa, Canada


Background: After the detection of two novel BSE forms designated H-type and L-type atypical BSE the question of the pathogenesis and the agent distribution of these two types in cattle was fully open. From initial studies of the brain pathology, it was already known that the anatomical distribution of L-type BSE differs from that of the classical type where the obex region in the brainstem always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved.


Methods:We performed intracranial inoculations of cattle (five and six per group) using 10%brainstemhomogenates of the two German H- and L-type atypical BSE isolates. The animals were inoculated under narcosis and then kept in a free-ranging stable under appropriate biosafety conditions.At least one animal per group was killed and sectioned in the preclinical stage and the remaining animals were kept until they developed clinical symptoms. The animals were examined for behavioural changes every four weeks throughout the experiment following a protocol that had been established during earlier BSE pathogenesis studies with classical BSE.


Results and Discussion: All animals of both groups developed clinical symptoms and had to be euthanized within 16 months. The clinical picture differed from that of classical BSE, as the earliest signs of illness were loss of body weight and depression. However, the animals later developed hind limb ataxia and hyperesthesia predominantly and the head. Analysis of brain samples from these animals confirmed the BSE infection and the atypical Western blot profile was maintained in all animals. Samples from these animals are now being examined in order to be able to describe the pathogenesis and agent distribution for these novel BSE types.


Conclusions: A pilot study using a commercially avaialble BSE rapid test ELISA revealed an essential restriction of PrPSc to the central nervous system for both atypical BSE forms. A much more detailed analysis for PrPSc and infectivity is still ongoing.


http://www.isid.org/14th_icid/


http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf


http://www.isid.org/publications/ICID_Archive.shtml



Topic: Emerging Infectious Diseases

Preferred type of presentation: International Scientific Exchange

This abstract has been ACCEPTED.

#0670
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009


Authors: T. Singeltary; Bacliff, TX/US


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


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


Methods 12 years independent research of available data


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


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


Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion


see page 114 ;


http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf


http://www.isid.org/14th_icid/


http://www.isid.org/publications/ICID_Archive.shtml


http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf



Monday, October 19, 2009


Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009


snip...


I ask Professor Kong ;


Thursday, December 04, 2008 3:37 PM
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment



''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious..... ''


Professor Kong reply ;


.....snip


''As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.''


Best regards, Qingzhong Kong, PhD

Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA


END...TSS



I look forward to further transmission studies, and a true ENHANCED BSE/atypical BSE surveillance program put forth testing all cattle for human and animal consumption for 5 years. a surveillance program that uses the most sensitive TSE testing, and has the personnel that knows how to use them, and can be trusted. I look forward to a stringent mad cow feed ban being put forth, and then strictly enforced. we need a forced, not voluntary feed ban, an enhanced feed ban at that, especially excluding blood. we need some sort of animal traceability. no more excuses about privacy. if somebody is putting out a product that is killing folks and or has the potential to kill you, then everybody needs to know who they are, and where that product came from. same with hospitals, i think medical incidents in all states should be recorded, and made public, when it comes to something like a potential accidental transmission exposure event. so if someone is out there looking at a place to go have surgery done, if you have several hospitals having these type 'accidental exposure events', than you can go some place else. it only makes sense. somewhere along the road, the consumer lost control, and just had to take whatever they were given, and then charged these astronomical prices. some where along the line the consumer just lost interest, especially on a long incubating disease such as mad cow disease i.e. Transmissible Spongiform Encephalopathy. like i said before, there is much more to the mad cow story than bovines and eating a hamburger, we must start focusing on all TSE in all species. ...TSS



SEE SOME REFERENCES HERE ;


http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html



Tuesday, June 1, 2010


USA cases of dpCJD rising with 24 cases so far in 2010


http://cjdtexas.blogspot.com/2010/06/usa-cases-of-dpcjd-rising-with-24-cases.html



Monday, April 5, 2010


UPDATE - CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER


http://prionunitusaupdate2008.blogspot.com/2010/04/update-cjd-texas-38-year-old-female.html



Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)

snip...

[Terry S. Singeltary Sr. has added the following comment
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.


The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"



http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101



Saturday, June 12, 2010

PUBLICATION REQUEST AND FOIA REQUEST Project Number: 3625-32000-086-05 Study of Atypical Bse


http://bse-atypical.blogspot.com/2010/06/publication-request-and-foia-request.html



Saturday, June 5, 2010

Research Project: Transmissible Spongiform Encephalopathies: Identification of atypical scrapie in Canadian sheep


http://nor-98.blogspot.com/2010/06/research-project-transmissible.html



Monday, June 14, 2010

A molecular switch controls interspecies prion disease transmission in mice


>>> These observations suggest striking differences in the ß-sheet alignment of PrPSc aggregates between prion-infected 170S and 170N animals and may provide a plausible starting point for clarifying the structural basis of prion species barriers that are highly relevant to public health, including the potential transmissibility of bovine and cervid prions to humans.<<<



http://chronic-wasting-disease.blogspot.com/2010/06/molecular-switch-controls-interspecies.html




JOURNAL OF NEUROLOGY

MARCH 26, 2003

Send Post-Publication Peer Review to journal
Re: RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary
flounder@wt.net

http://www.neurology.org/cgi/eletters/60/2/176#535



Newsdesk The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003 doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI

Tracking spongiform encephalopathies in North America

Xavier Bosch

“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.” 49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of documents on transmissible spongiform encephalopathies (TSE) and realised that if Britons could get variant CJD from bovine spongiform encephalopathy (BSE), Americans might get a similar disorder from chronic wasting disease (CWD)—the relative of mad cow disease seen among deer and elk in the USA. Although his feverish…


http://linkinghub.elsevier.com/retrieve/pii/S1473309903007151



http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(03)00715-1/fulltext



http://www.mdconsult.com/das/article/body/180784492-2/jorg=journal&source=&sp=13979213&sid=0/N/368742/1.html?issn=14733099



Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT


http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT



http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT



2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well


http://www.bmj.com/cgi/eletters/320/7226/8/b#6117



15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.


http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406



THE PATHOLOGICAL PROTEIN

BY Philip Yam

Yam Philip Yam News Editor Scientific American www.sciam.com

Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

CHAPTER 14

Laying Odds

Are prion diseases more prevalent than we thought?

Researchers and government officials badly underestimated the threat that mad cow disease posed when it first appeared in Britain. They didn’t think bovine spongiform encephalopathy was a zoonosis—an animal disease that can sicken people. The 1996 news that BSE could infect humans with a new form of Creutzfeldt-Jakob disease stunned the world. It also got some biomedical researchers wondering whether sporadic CJD may really be a manifestation of a zoonotic sickness. Might it be caused by the ingestion of prions, as variant CJD is?

Revisiting Sporadic CJD

It’s not hard to get Terry Singeltary going. “I have my conspiracy theories,” admitted the 49-year-old Texan.1 Singeltary is probably the nation’s most relentless consumer advocate when it comes to issues in prion diseases. He has helped families learn about the sickness and coordinated efforts with support groups such as CJD Voice and the CJD Foundation. He has also connected with others who are critical of the American way of handling the threat of prion diseases. Such critics include Consumers Union’s Michael Hansen, journalist John Stauber, and Thomas Pringle, who used to run the voluminous www.madcow. org Web site. These three lend their expertise to newspaper and magazine stories about prion diseases, and they usually argue that prions represent more of a threat than people realize, and that the government has responded poorly to the dangers because it is more concerned about protecting the beef industry than people's health.

Singeltary has similar inclinations. ...


http://books.google.com/books?id=ePbrQNFrHtoC&pg=PA223&lpg=PA223&dq=the+pathological+protein+laying+odds+It%E2%80%99s+not+hard+to+get+Terry+Singeltary+going&source=bl&ots=um0PFAZSZD&sig=JWaGR7M7-1WeAr2qAXq8D6J_jak&hl=en&ei=MhtjS8jMJM2ztgeFoa2iBg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CAcQ6AEwAA#v=onepage&q=&f=false



http://www.springerlink.com/content/r2k2622661473336/fulltext.pdf?page=1



http://www.thepathologicalprotein.com/



DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen) USA: Loch in der Mauer Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehördensind lax.Link auf diesen Artikel im Archiv: http://service.spiegel.de/digas/find?DID=18578755

"Löcher wie in einem Schweizer Käse" hat auch Terry Singeltary im Regelwerk der FDA ausgemacht. Der Texaner kam auf einem tragischen Umweg zu dem Thema: Nachdem seine Mutter 1997 binnen weniger Wochen an der Creutzfeldt-Jakob-Krankheit gestorben war, versuchte er, die Ursachen der Infektion aufzuspüren. Er klagte auf die Herausgabe von Regierungsdokumenten und arbeitete sich durch Fachliteratur; heute ist er überzeugt, dass seine Mutter durch die stetige Einnahme von angeblich kräftigenden Mitteln erkrankte, in denen - völlig legal - Anteile aus Rinderprodukten enthalten sind.

Von der Fachwelt wurde Singeltary lange als versponnener Außenseiter belächelt. Doch mittlerweile sorgen sich auch Experten, dass ausgerechnet diese verschreibungsfreien Wundercocktails zur Stärkung von Intelligenz, Immunsystem oder Libido von den Importbeschränkungen ausgenommen sind. Dabei enthalten die Pillen und Ampullen, die in Supermärkten verkauft werden, exotische Mixturen aus Rinderaugen; dazu Extrakte von Hypophyse oder Kälberföten, Prostata, Lymphknoten und gefriergetrocknetem Schweinemagen. In die USA hereingelassen werden auch Blut, Fett, Gelatine und Samen. Diese Stoffe tauchen noch immer in US-Produkten auf, inklusive Medizin und Kosmetika. Selbst in Impfstoffen waren möglicherweise gefährliche Rinderprodukte enthalten. Zwar fordert die FDA schon seit acht Jahren die US-Pharmaindustrie auf, keine Stoffe aus Ländern zu benutzen, in denen die Gefahr einer BSE-Infizierung besteht. Aber erst kürzlich verpflichteten sich fünf Unternehmen, darunter Branchenführer wie GlaxoSmithKline, Aventis und American Home Products, ihre Seren nur noch aus unverdächtigem Material herzustellen.

"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...


http://www.spiegel.de/spiegel/print/d-18578755.html



http://wissen.spiegel.de/wissen/image/show.html?did=18578755&aref=image024/E0108/SCSP200100901440145.pdf&thumb=false



http://service.spiegel.de/digas/servlet/find/DID=18578755



Suspect symptoms

What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?

28 Mar 01

Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284. Subscribe and get 4 free issues. FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.

Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.

Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.

"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris. Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb.

Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health. But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.

Deslys and colleagues were originally studying vCJD, not sCJD. They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three. Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.

As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain. As expected, they all affected the brain in a different way from BSE and vCJD. But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology.

"The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys. "You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie." In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar.

But there are more than 20 strains of scrapie, and six of sCJD. "You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys. Bruce is cautious about the mouse results, but agrees they require further investigation. Other trials of scrapie and sCJD in mice, she says, are in progress.

People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways. Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD.

But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD. "If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."

There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere. Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain. Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.

Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE. And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.


http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html



Sunday, August 09, 2009

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


http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames.html



Tuesday, August 18, 2009


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


http://madcowusda.blogspot.com/2009/08/bse-untold-story-joe-gibbs-and.html




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

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