Atypical Bovine Spongiform Encephalopathies, France, 2001-2007
Volume 14, Number 2–February 2008
Dispatch
Atypical Bovine Spongiform Encephalopathies, France, 2001–2007
Anne-Gaëlle Biacabe,* Eric Morignat,* Johann Vulin,* Didier Calavas,* and Thierry G.M. Baron*
*Agence Française de Sécurité Sanitaire des Aliments, Lyon, France
Suggested citation for this article
Abstract
In France, through exhaustive active surveillance, ≈17.1 million adult cattle were tested for bovine spongiform encephalopathy from July 2001 through July 2007; ≈3.6 million were >8 years of age. Our retrospective Western blot study of all 645 confirmed cases found that 7 were H-type and 6 were L-type.
Most cases of bovine spongiform encephalopathy (BSE) have shown strikingly uniform features. The origin of epidemics, mainly in the United Kingdom but to a lesser extent in other countries, has been foodborne contamination by a single major strain of the transmissible spongiform encephalopathy (TSE) agent (1,2). However, in recent years, 2 distinct forms of the disease have been described; these forms deviate phenotypically from the previously identified classic BSE (C-type) (3,4). Western blot studies of the protease-resistant prion protein (PrPres) showed higher and lower molecular masses of unglycosylated PrPres in these 2 types, subsequently named H-type and L-type compared with C-type BSE (5). In L-type BSE, the most discriminant molecular feature was the lower level of diglycosylated PrPres (4,5). Such cases have now been identified in a number of different countries (6–8).
The origin of H-type and L-type BSE cases is unknown, but they may represent spontaneous or so-called sporadic forms of TSE, reminiscent of most cases of Creutzfeldt-Jakob disease in humans. Transmission studies in wild-type mice (9) or in transgenic mice expressing the bovine PrP gene (5,10–12) have shown that the infectious agents involved in H-type and L-type BSEs differ from the single strain isolated from C-type BSE.
Epidemiologic data are crucial to our understanding of the origin of such cases, but precise prevalence needs to be determined. The prevalence in cattle can now be assessed with accuracy because exhaustive BSE testing of adult cattle was implemented in 2001 in all European member states (January 1 for abattoirs and July 1 for rendering plants). We report the results of a retrospective study to determine the frequency of H-type and L-type BSE identified in France since July 2001.
The Study
A retrospective Western blot study was performed for all confirmed BSE cases diagnosed in France after July 1, 2001, as previously described (13). Briefly, PrPres was extracted using the TeSeE Western blot confirmatory assay (Bio-Rad, Marnes-la-Coquette, France) according to the manufacturer's instructions. For immunoblotting, antibodies RB1, 6H4 (R-Biopharm, St. Didier au Mont d'Or, France), Sha31 from the TeSeE Western blot (Bio-Rad), and SAF84 (kindly provided by J. Grassi, Commissariat Energie Atomique, Saclay, France) were used; these antibodies recognize the bovine PrP sequences 110–113, 156–164, 156–163, and 175–180, respectively. Two Western blot assays were conducted on the brainstem samples and used either an antibody against the PrP core (RB1, 6H4, or Sha31) or a C-terminal antibody (SAF84) (13). The characteristics of H-type and L-type BSE (6,13) that were sought included 1) a higher or lower molecular mass of unglycosylated PrPres with core antibodies in H-type and L-type BSE compared with C-type BSE, 2) a lower proportion of diglycosylated PrPres in L-type BSE, and 3) presence of an additional band at ≈14 kDa with SAF84 in H-type BSE. All cases with features of H-type or L-type BSE were then subjected to further Western blot analyses for detailed quantitative analysis of PrPres molecular features (apparent molecular masses and glycoforms proportions).
Among the 645 BSE cases confirmed between July 1, 2001, and July 1, 2007, 7 H-type and 6 L-type isolates were identified; these had occurred at a frequency of 0–3 H-type and 1 L-type case per year, compared with 6–219 cases of C-type BSE per year (Table). Molecular typing of 48 of these 645 samples was not possible because low levels of PrPres prevented detailed molecular characterization or because sample amount was insufficient. All 13 atypical cases were detected in cattle >8 years of age, from fallen stock (9 cases) or abattoir (4 cases); not 1 atypical case was found among the 98 BSE cases detected by clinical surveillance during this period. These 13 atypical cases were diagnosed by the different rapid BSE tests routinely used in France: 9 by Prionics-Check Western, LIA, or Priostrip (AES, Combourg, France), 3 by ELISA Bio-Rad, and 1 by IDEXX HerdChek (IDEXX Laboratories, Schiphol-Rijk, the Netherlands). During retrospective interviews, the farmer and veterinarian for 6 of these animals reported clinical signs consistent with TSE in 3 fallen stock. This series of 13 cases identified since the beginning of exhaustive active surveillance should be compared with a total of ≈17.1 million adult cattle tested, of which ≈3.6 million were >8 years of age. In addition to these 13 cases, the first case of atypical (H-type) BSE was identified in 2000, during an exhaustive active surveillance program in rendering plants in a limited region of France.
The distribution of BSE-infected cattle by birth date (Figure 1) shows that 1 or 2 (H- or L-type cases) were eventually found positive by rapid tests of the brainstem in each annual birth cohort from 1986 through 1997, which compares with up to 221 cattle infected with C-type BSE born during 1990–2001 for which BSE was diagnosed during 2001–2007. All H-type and L-type BSE cases showed similar features (Figure 2) regarding the high apparent molecular masses of unglycosylated PrPres (mean difference of ≈1 kDa using 6H4 antibody) for H-type BSE and lower levels of diglycosylated PrPres (mean difference of 35% using 6H4 antibody) for L-type BSE, compared with C-type BSE. For L-type BSE cases, the differences in apparent molecular masses were more obvious for the diglycosylated band (≈1-kDa difference using 6H4, compared with 0.3 kDa for the unglycosylated band), as previously observed (6). The ≈14-kDa band characteristic of H-type BSE was similarly detected in the 8 isolates with SAF84 antibody but in none of the other cases classified as L-type or C-type BSE.
Conclusions
This study involved exhaustive molecular typing of BSE cases during a given test period and in a country in which BSE testing has been mandatory for all adult slaughtered or fallen cattle. France tests more animals than any other European country; ≈30% of the animals tested in the European Union are tested in France. The estimated frequency of H-type and L-type BSE was 0.41 and 0.35 per million adult cattle tested, respectively (1.9 and 1.7 in cattle >8 years of age). Given the implementation dates of measures to control BSE and the birth dates of these BSE-infected cattle, foodborne exposure to an infectious agent cannot be fully excluded for any of these cattle. However, the distribution of cattle affected by H- and L-type BSE, by year of birth, differs strikingly from that of cattle affected by C-type BSE and is consistent with the hypothesis that H-type and L-type BSE might represent sporadic prion disorders. In comparison with another sporadic prion disease, the annual frequency of sporadic Creutzfeldt-Jakob disease in humans, which is estimated only by analyses of reported clinically suspect cases, is 1–2 cases per million. Similar studies in other countries, instead of those free of C-type BSE, would be useful. An alternative hypothesis to foodborne contamination, such as contamination by a scrapie agent, cannot be fully excluded, as such contamination has been shown to be a risk factor for scrapie in sheep (14).
This study relied on the identification of BSE cases by examination of the brainstem only, as derived from our knowledge of C-type BSE (15). We cannot exclude possible differences in the pathogenesis of atypical BSEs that might result in underestimation of their frequency, e.g., involvement of the brainstem at a later stage than with C-type BSE. This possibility is at least suggested by data available for L-type BSE, which shows a preferential distribution of abnormal PrP in more rostral brain regions (4,12). Studies of the pathogenesis of these novel BSE forms are thus important for understanding of prion disorders of domestic ruminant species.
Acknowledgments
snip...end
http://www.cdc.gov/eid/content/14/2/298.htm
i guess the infamous 'sporadic' and or 'spontaneous' myth for all other strains of mad cow disease, whether
it is the h-base and or l-base, or any sub-type thereof, is an accepted international myth now. only the UK BSE can be transmitted orally to cattle or humans, and all the rest is spontaneous? no recycled feed from atypical TSE can transmit a TSE, and this has been proven?
and they call this science$ i call it BSe. Junk and or political science at its best. ...
once again ;
sporadic CJD is NOT a single strain, phenotype.
sporadic CJD is simply a human TSE, which routes, sources, strains, are unknown.
there are 6 different documented phenotypes of the sporadic CJD, with 'UNKNOWN' sub-types growing.
what would 2nd, 3rd, 4th passage iatrogenic i.e. friendly fire look like from BSE compared to the h-type, compared to l-type ???
spontaneous TSE in the field ??? never has been proven, and highly unlikely that 85%+ of all human TSE i.e. sporadic CJD, just happen without route and source.
Volume 12, Number 12–December 2006
Perspective
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
*Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA
snip...
Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.
Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.
Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.
For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
Archive Number 20071105.3602
Published Date 05-NOV-2007
Subject PRO/AH/EDR> Prion disease update 2007 (07)
PRION DISEASE UPDATE 2007 (07)
snip...
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
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
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
flounder@wt.net
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to
comment on the CDC's attempts to monitor the occurrence of emerging
forms of CJD. Asante, Collinge et al [1] have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest
sporadic CJD. However, CJD and all human TSEs are not reportable
nationally. CJD and all human TSEs must be made reportable in every
state and internationally. I hope that the CDC does not continue to
expect us to still believe that the 85%+ of all CJD cases which are
sporadic are all spontaneous, without route/source. We have many TSEs in
the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by
intracerebral inoculation. With the known incubation periods in other
TSEs, oral transmission studies of CWD may take much longer. Every
victim/family of CJD/TSEs should be asked about route and source of this
agent. To prolong this will only spread the agent and needlessly expose
others. In light of the findings of Asante and Collinge et al, there
should be drastic measures to safeguard the medical and surgical arena
from sporadic CJDs and all human TSEs. I only ponder how many sporadic
CJDs in the USA are type 2 PrPSc?
http://www.neurology.org/cgi/eletters/60/2/176#535
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations.
ISBN 0-387-95508-9 June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
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.
http://www.thepathologicalprotein.com/
doi:10.1016/S1473-3099(03)00715-1Copyright ? 2003 Published by Elsevier Ltd.
Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
"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." ...
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)
http://animalhealthreport2006.blogspot.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/http://www.neurology.org/cgi/eletters/60/2/176#535
please notice Texas 2006 ;
† Confirmed in United Kingdom and reported to Texas Department of State Health Services
through Centers for Disease Control and Prevention.
Only 1 case of variant
CJD has ever been diagnosed in Texas.
The patient was a former resident of the
United Kingdom, where the exposure
was likely to have occurred. Texas has a
population of 23 million, and since the
national rate of sporadic CJD is about 1
per million, it is expected that
approximately 23 cases of CJD would
occur each year in the state. Therefore,
it is believed that CJD is currently underreported
in Texas. ...END...TSS
also see ;
http://www.dshs.state.tx.us/idcu/disease/creutzfeldt-jakob/data/
Creutzfeldt-Jakob Disease in Northeast Texas,
J.A. Rawlings,*1 K.A.
Hendricks1, O.M. Nuno1, D.A. Brown1, D.A. Evans2, Texas Department of
Health, 1Austin and 2Tyler, Texas
Creutzfeldt-Jacob Disease (CJD), a transmissible spongiform encephalopathy, is caused by prions composed of proteinaceous material devoid of nucleic acid. CJD occurs sporadically (generally 1 case/1,000,000 population per year) in older patients (average age of 65) and is characterized by rapidly progressive dementia, accompanied by severe muscle spasms and incoordination. Death usually occurs within 3 to 12 months (average 7 months). CJD activity in Texas, which has a population of nearly 19 million, appeared to be typical. The statewide death rate for 1995 and 1996 was just under 1/1,000,000. In April of 1997, the Texas Department of Health became aware of an increased number of possible CJD cases in a 23-county area of NE Texas with a population of just over one million. After review of medical and pathology records, four patients were identified with definite classic CJD and three were identified with probable CJD. Dates of death for the eight patients were from April, 1996 through mid-July 1997. The patients were from 46 through 65 years of age; four were male and three were female. A case-control study to identify risks for CJD in NE Texas has been initiated.
http://www.jifsan.umd.edu/tse/Rawlings.htm
Division of Neuropathology
Pierluigi Gambetti, M.D.,
Director
-----------------------------------
CASE WESTERN RESERVE UNIVERSITY
March 30, 1998
Dr. Gerald A, Campbell
The University of Texas
Medical Branch at Galveston
Division of Neuropathology
Department of Pathology
Galveston, Texas
Dear Dr Campbell,
We performed Western immunoblot analysis on the frozen tissue from your case #AU97-435 (our #098-28). The Immunoblot reveals the presence of protease-resistant prion protein (PrPres) confirming the diagnosis of prion disease. The immunoblot pattern of PrPres is consistent with the diagnosis of Creutzfeldt-Jakob disease.
Thank you for referring to us this interesting case.
Sincerely,
Piero Parchi, M.D.
Pierluigi Gambetti, M.D.
PP:sbDivision of Neuropathology
Pierluigi Gambetti, M.D.,
Director
Case Western Reserve University
snip...end
-------- Original Message --------
Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD
Date: Thu, 28 Nov 2002 10:23:43-0000
From: "Asante, Emmanuel A" <e.asante@ic.ac.uk>
To: "'mailto:flounder@wt.net"<flounder@wt.net>
Dear Terry,
I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention. Thank you for your interest in the paper. In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask.
Best wishes.
Emmanuel Asante
<>
____________________________________
Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02)New e-mail: e.asante@prion.ucl.ac.uk
(active from now)
____________________________________END...TSS
CJD, PrP Codon 129VV, Novel PrPSc in a Young British Woman
Wed Jan 2, 2008 16:5071.248.140.49
Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman
Simon Mead, PhD, MRCP; Susan Joiner, MSc; Melanie Desbruslais, BSc; JonathanA. Beck, BSc; Michael O’Donoghue, PhD; Peter Lantos, FRCP; Jonathan D. F.Wadsworth, PhD; John Collinge, FRSArch Neurol. 2007;64(12):1780-1784.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease causally related to bovine spongiform encephalopathy that has occurred predominantly in young adults. All clinical cases studied have been methionine homozygotes at codon 129 of the prion protein gene (PRNP) with distinctive neuropathological findings and molecular strain type (PrPSc type4). Modeling studies in transgenic mice suggest that other PRNP genotypes will also be susceptible to infection with bovine spongiform encephalopathy prions but may develop distinctive phenotypes.
Objective
To describe the histopathologic and molecular investigation in ayoung British woman with atypical sporadic CJD and valine homozygosity at PRNP codon 129.
Design Case report, autopsy, and molecular analysis.
Setting Specialist neurology referral center, together with the laboratory services of the MRC [Medical Research Council] Prion Unit.
Subject Single hospitalized patient.
Main Outcome Measures Autopsy findings and molecular investigation results.
Results Autopsy findings were atypical of sporadic CJD, with marked gray and white matter degeneration and widespread prion protein (PrP) deposition. Lymphoreticular tissue was not available for analysis. Molecular analysis of PrPSc (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrPSc type similar to that seen in vCJD (PrPSc type 4). However, this could be distinguished from the typical vCJD pattern by an altered protease cleavage site in the presence of the metal ion chelator EDTA.
Conclusions Further studies will be required to characterize the prion strain seen in this patient and to investigate its etiologic relationship with bovine spongiform encephalopathy. This case illustrates the importance of molecular analysis of prion disease, including the use of EDTA to investigate the metal dependence of protease cleavage patterns of PrPSc.
Author Affiliations: MRC [Medical Research Council] Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, England (Drs Mead, Wadsworth, and Collinge; Mss Joiner and Desbruslais; and Mr Beck); and Institute of Psychiatry, King's College London (Dr Lantos). DrO’Donoghue is now with the Department of Clinical Neurology, Nottingham University Hospitals NHS [National Health Service] Trust, Nottingham, England.
http://archneur.ama-assn.org/cgi/content/short/64/12/1780
North American Equity Research
New York
13 January 2004
BSE (Mad Cow) Update:
Do Reports of sCJD Clusters Matter?
There have been seven cases of human sCJD clusters identified in the US in the last 15 years, in which people in a specific location were diagnosed with sCJD, resulting in rates between 2.1 and 8.4 deaths per million people for that specific location compared with the national average of one in 1 million. · There is no proven link between sCJD and BSE, and hence it is considered a different disease from vCJD (which has been linked to BSE). However, the existence of clusters raises the question of “contamination" or “infection”, and also raises the hypothesis that rather than cases of sCJD these might have been cases of vCJD. · Clusters are not spontaneous, they normally have a source. Moreover, some cases of sCJD may have been improperly diagnosed as Alzheimer's.· We continue to believe that as long as no further cases of BSE-positive cows are found in North America and the industry has respected the 1997 ban on animal feed for live cattle, beef consumption in the US will not suffer. · Moreover, due to political pressure we expect key overseas markets (Japan, South Korea, and Mexico) to open up to US beef in the next six months – the recent 20% drop in cattle prices can be attributed mainly to these import bans. · However, two concerns linger and should be kept in mind by investors, 1) Has the 1997 ban on animal feed for live cattle been honored by the beef industry? 2) Can clusters of cases of sporadic CJD (or sCJD) really be a variant of CJD and indeed be linked to BSE? In this note we focus on the issue of sCJD clusters, and the potential impact that the growing debate on clusters could have on beef consumption in the US. United States Foods Pablo E. Zuanic(1-212) mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000366/!x-usc:mailto:622-6744pablo.zuanic@jpmorgan.comChristopher M. Bledsoe(1-212) mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000366/!x-usc:mailto:622-6386christopher.m.bledsoe@jpmorgan.comDaniel Ogbonna(212) 622-6382daniel.c.ogbonna@jpmorgan.com
State of Our Views Regarding BSE in the US
snip...
Existence of Clusters of sCJD May Imply They Are Really Cases of vCJD There have been seven sCJD clusters identified in the US in the last 15 years, in which people in a specific location were diagnosed with sCJD, resulting in rates between 1.2 and 8.4 deaths per million people for that specific location compared with the national average of one in 1 million. The existence of clusters raises the question of “contamination" or “infection”, and also raises the hypothesis that rather than cases of sCJD these might have been cases of vCJD. Clusters are not spontaneous, they normally have a source.
A cluster consists of two statistical improbabilities: 1) multiple cases occurring in a relatively limited geographic area, and 2) multiple cases occurring within the same time period. The most recent cluster was found in Cherry Hill, New Jersey. The others have been found in Lehigh, Pennsylvania (1986-90), Allentown, Pennsylvania (1989-92), Tampa, Florida (1996-97), Oregon (2001-02), and Nassau County, New York (1999-2000). Given that sCJD occurs randomly in one out of one million cases, it is a statistical rarity to find an sCJD cluster – let alone six. The following tables highlight known clusters in the US.
Table 1:
Clustered sCJD Deaths
Local sCJD Deaths
Time Span State Local Area Pop. (MM) Period (mo.) Total Ann'lized
1986-1990 PA Lehigh Valley 0.5 48 18 4.5
1989-1992 PA Allentown 2.5 36 15 5.0
1996-1997 FL Tampa 2.2 18 13 8.7
1996-1999 TX Denton .01 38 4 1.3
1999-2000 NY Nassau County 1.3 12 7 7.0
2001-2002 OR Entire State 3.4 24 14 7.0
2000-2003* NJ Cherry Hill Area 1.7 36 12 4.0
Source: JPMorgan.
The second table, below, shows what portion of the state's total expected sCJD cases (as based on a one per million occurrence) were found in the local cluster, comparing the local cluster's portion of cases with the local area's portion of the state's total population. The greater the factor between the former and the latter suggests a higher statistical improbability that the cluster is spontaneous (sCJD).
Table 2: Clustered sCJD Deaths vs. Expected State Cases
Annual Statewide Local Area (% of Time Span State Local Area sCJD Deaths* exp. state cases state pop.
1986-1990 PA Lehigh Valley 11.9 37.8% 4.5%
1989-1992 PA Allentown 12.0 41.7% 20.8%
1996-1997 FL Tampa 14.1 61.5% 15.7%
1996-1999 TX Denton 20.9 6.1% .02%
1999-2000 NY Nassau County 18.1 38.7% 7.4%
2001-2002 OR Entire State 3.4 205.9% 100.0%
2000-2003* NJ Cherry Hill Area 8.0 50.0% 21.6%
* *State cases are extrapolated based on state population and the 1 per
million national average. Source: JPMorgan.
snip...
Copyright 2003 J.P. Morgan Chase & Co.—All rights reserved.
THIS MATERIAL IS ISSUED AND DISTRIBUTED IN MALAYSIA BY J.P. MORGAN
MALAYSIA SDN. BHD. (18146-X).
########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
https://lists.aegee.org/cgi-bin/wa?A2=ind0401&L=BSE-L&T=0&F=&S=&P=25337
see full text ;
http://cjdtexas.blogspot.com/
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States
http://cjdusa.blogspot.com/
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
SEAC 99th meeting on Friday 14th December 2007
http://seac992007.blogspot.com/
please see full text ;
http://nor-98.blogspot.com/2008/01/atypicalnor98-scrapie-properties-of.html
16 January 2008 - The final minutes of the 98th SEAC meeting have been
published.
PUBLIC QUESTION AND ANSWER SESSION 2
© SEAC 2007
SEAC considered a question about possible links between CJD cases and animal
TSEs in the United States of America (USA).
http://www.seac.gov.uk/summaries/seac99_summary.pdf
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Dispatch
Atypical Bovine Spongiform Encephalopathies, France, 2001–2007
Anne-Gaëlle Biacabe,* Eric Morignat,* Johann Vulin,* Didier Calavas,* and Thierry G.M. Baron*
*Agence Française de Sécurité Sanitaire des Aliments, Lyon, France
Suggested citation for this article
Abstract
In France, through exhaustive active surveillance, ≈17.1 million adult cattle were tested for bovine spongiform encephalopathy from July 2001 through July 2007; ≈3.6 million were >8 years of age. Our retrospective Western blot study of all 645 confirmed cases found that 7 were H-type and 6 were L-type.
Most cases of bovine spongiform encephalopathy (BSE) have shown strikingly uniform features. The origin of epidemics, mainly in the United Kingdom but to a lesser extent in other countries, has been foodborne contamination by a single major strain of the transmissible spongiform encephalopathy (TSE) agent (1,2). However, in recent years, 2 distinct forms of the disease have been described; these forms deviate phenotypically from the previously identified classic BSE (C-type) (3,4). Western blot studies of the protease-resistant prion protein (PrPres) showed higher and lower molecular masses of unglycosylated PrPres in these 2 types, subsequently named H-type and L-type compared with C-type BSE (5). In L-type BSE, the most discriminant molecular feature was the lower level of diglycosylated PrPres (4,5). Such cases have now been identified in a number of different countries (6–8).
The origin of H-type and L-type BSE cases is unknown, but they may represent spontaneous or so-called sporadic forms of TSE, reminiscent of most cases of Creutzfeldt-Jakob disease in humans. Transmission studies in wild-type mice (9) or in transgenic mice expressing the bovine PrP gene (5,10–12) have shown that the infectious agents involved in H-type and L-type BSEs differ from the single strain isolated from C-type BSE.
Epidemiologic data are crucial to our understanding of the origin of such cases, but precise prevalence needs to be determined. The prevalence in cattle can now be assessed with accuracy because exhaustive BSE testing of adult cattle was implemented in 2001 in all European member states (January 1 for abattoirs and July 1 for rendering plants). We report the results of a retrospective study to determine the frequency of H-type and L-type BSE identified in France since July 2001.
The Study
A retrospective Western blot study was performed for all confirmed BSE cases diagnosed in France after July 1, 2001, as previously described (13). Briefly, PrPres was extracted using the TeSeE Western blot confirmatory assay (Bio-Rad, Marnes-la-Coquette, France) according to the manufacturer's instructions. For immunoblotting, antibodies RB1, 6H4 (R-Biopharm, St. Didier au Mont d'Or, France), Sha31 from the TeSeE Western blot (Bio-Rad), and SAF84 (kindly provided by J. Grassi, Commissariat Energie Atomique, Saclay, France) were used; these antibodies recognize the bovine PrP sequences 110–113, 156–164, 156–163, and 175–180, respectively. Two Western blot assays were conducted on the brainstem samples and used either an antibody against the PrP core (RB1, 6H4, or Sha31) or a C-terminal antibody (SAF84) (13). The characteristics of H-type and L-type BSE (6,13) that were sought included 1) a higher or lower molecular mass of unglycosylated PrPres with core antibodies in H-type and L-type BSE compared with C-type BSE, 2) a lower proportion of diglycosylated PrPres in L-type BSE, and 3) presence of an additional band at ≈14 kDa with SAF84 in H-type BSE. All cases with features of H-type or L-type BSE were then subjected to further Western blot analyses for detailed quantitative analysis of PrPres molecular features (apparent molecular masses and glycoforms proportions).
Among the 645 BSE cases confirmed between July 1, 2001, and July 1, 2007, 7 H-type and 6 L-type isolates were identified; these had occurred at a frequency of 0–3 H-type and 1 L-type case per year, compared with 6–219 cases of C-type BSE per year (Table). Molecular typing of 48 of these 645 samples was not possible because low levels of PrPres prevented detailed molecular characterization or because sample amount was insufficient. All 13 atypical cases were detected in cattle >8 years of age, from fallen stock (9 cases) or abattoir (4 cases); not 1 atypical case was found among the 98 BSE cases detected by clinical surveillance during this period. These 13 atypical cases were diagnosed by the different rapid BSE tests routinely used in France: 9 by Prionics-Check Western, LIA, or Priostrip (AES, Combourg, France), 3 by ELISA Bio-Rad, and 1 by IDEXX HerdChek (IDEXX Laboratories, Schiphol-Rijk, the Netherlands). During retrospective interviews, the farmer and veterinarian for 6 of these animals reported clinical signs consistent with TSE in 3 fallen stock. This series of 13 cases identified since the beginning of exhaustive active surveillance should be compared with a total of ≈17.1 million adult cattle tested, of which ≈3.6 million were >8 years of age. In addition to these 13 cases, the first case of atypical (H-type) BSE was identified in 2000, during an exhaustive active surveillance program in rendering plants in a limited region of France.
The distribution of BSE-infected cattle by birth date (Figure 1) shows that 1 or 2 (H- or L-type cases) were eventually found positive by rapid tests of the brainstem in each annual birth cohort from 1986 through 1997, which compares with up to 221 cattle infected with C-type BSE born during 1990–2001 for which BSE was diagnosed during 2001–2007. All H-type and L-type BSE cases showed similar features (Figure 2) regarding the high apparent molecular masses of unglycosylated PrPres (mean difference of ≈1 kDa using 6H4 antibody) for H-type BSE and lower levels of diglycosylated PrPres (mean difference of 35% using 6H4 antibody) for L-type BSE, compared with C-type BSE. For L-type BSE cases, the differences in apparent molecular masses were more obvious for the diglycosylated band (≈1-kDa difference using 6H4, compared with 0.3 kDa for the unglycosylated band), as previously observed (6). The ≈14-kDa band characteristic of H-type BSE was similarly detected in the 8 isolates with SAF84 antibody but in none of the other cases classified as L-type or C-type BSE.
Conclusions
This study involved exhaustive molecular typing of BSE cases during a given test period and in a country in which BSE testing has been mandatory for all adult slaughtered or fallen cattle. France tests more animals than any other European country; ≈30% of the animals tested in the European Union are tested in France. The estimated frequency of H-type and L-type BSE was 0.41 and 0.35 per million adult cattle tested, respectively (1.9 and 1.7 in cattle >8 years of age). Given the implementation dates of measures to control BSE and the birth dates of these BSE-infected cattle, foodborne exposure to an infectious agent cannot be fully excluded for any of these cattle. However, the distribution of cattle affected by H- and L-type BSE, by year of birth, differs strikingly from that of cattle affected by C-type BSE and is consistent with the hypothesis that H-type and L-type BSE might represent sporadic prion disorders. In comparison with another sporadic prion disease, the annual frequency of sporadic Creutzfeldt-Jakob disease in humans, which is estimated only by analyses of reported clinically suspect cases, is 1–2 cases per million. Similar studies in other countries, instead of those free of C-type BSE, would be useful. An alternative hypothesis to foodborne contamination, such as contamination by a scrapie agent, cannot be fully excluded, as such contamination has been shown to be a risk factor for scrapie in sheep (14).
This study relied on the identification of BSE cases by examination of the brainstem only, as derived from our knowledge of C-type BSE (15). We cannot exclude possible differences in the pathogenesis of atypical BSEs that might result in underestimation of their frequency, e.g., involvement of the brainstem at a later stage than with C-type BSE. This possibility is at least suggested by data available for L-type BSE, which shows a preferential distribution of abnormal PrP in more rostral brain regions (4,12). Studies of the pathogenesis of these novel BSE forms are thus important for understanding of prion disorders of domestic ruminant species.
Acknowledgments
snip...end
http://www.cdc.gov/eid/content/14/2/298.htm
i guess the infamous 'sporadic' and or 'spontaneous' myth for all other strains of mad cow disease, whether
it is the h-base and or l-base, or any sub-type thereof, is an accepted international myth now. only the UK BSE can be transmitted orally to cattle or humans, and all the rest is spontaneous? no recycled feed from atypical TSE can transmit a TSE, and this has been proven?
and they call this science$ i call it BSe. Junk and or political science at its best. ...
once again ;
sporadic CJD is NOT a single strain, phenotype.
sporadic CJD is simply a human TSE, which routes, sources, strains, are unknown.
there are 6 different documented phenotypes of the sporadic CJD, with 'UNKNOWN' sub-types growing.
what would 2nd, 3rd, 4th passage iatrogenic i.e. friendly fire look like from BSE compared to the h-type, compared to l-type ???
spontaneous TSE in the field ??? never has been proven, and highly unlikely that 85%+ of all human TSE i.e. sporadic CJD, just happen without route and source.
Volume 12, Number 12–December 2006
Perspective
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
*Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA
snip...
Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.
Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.
Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.
For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
Archive Number 20071105.3602
Published Date 05-NOV-2007
Subject PRO/AH/EDR> Prion disease update 2007 (07)
PRION DISEASE UPDATE 2007 (07)
snip...
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
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
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
flounder@wt.net
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to
comment on the CDC's attempts to monitor the occurrence of emerging
forms of CJD. Asante, Collinge et al [1] have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest
sporadic CJD. However, CJD and all human TSEs are not reportable
nationally. CJD and all human TSEs must be made reportable in every
state and internationally. I hope that the CDC does not continue to
expect us to still believe that the 85%+ of all CJD cases which are
sporadic are all spontaneous, without route/source. We have many TSEs in
the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by
intracerebral inoculation. With the known incubation periods in other
TSEs, oral transmission studies of CWD may take much longer. Every
victim/family of CJD/TSEs should be asked about route and source of this
agent. To prolong this will only spread the agent and needlessly expose
others. In light of the findings of Asante and Collinge et al, there
should be drastic measures to safeguard the medical and surgical arena
from sporadic CJDs and all human TSEs. I only ponder how many sporadic
CJDs in the USA are type 2 PrPSc?
http://www.neurology.org/cgi/eletters/60/2/176#535
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations.
ISBN 0-387-95508-9 June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
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.
http://www.thepathologicalprotein.com/
doi:10.1016/S1473-3099(03)00715-1Copyright ? 2003 Published by Elsevier Ltd.
Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
"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." ...
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)
http://animalhealthreport2006.blogspot.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/http://www.neurology.org/cgi/eletters/60/2/176#535
please notice Texas 2006 ;
† Confirmed in United Kingdom and reported to Texas Department of State Health Services
through Centers for Disease Control and Prevention.
Only 1 case of variant
CJD has ever been diagnosed in Texas.
The patient was a former resident of the
United Kingdom, where the exposure
was likely to have occurred. Texas has a
population of 23 million, and since the
national rate of sporadic CJD is about 1
per million, it is expected that
approximately 23 cases of CJD would
occur each year in the state. Therefore,
it is believed that CJD is currently underreported
in Texas. ...END...TSS
also see ;
http://www.dshs.state.tx.us/idcu/disease/creutzfeldt-jakob/data/
Creutzfeldt-Jakob Disease in Northeast Texas,
J.A. Rawlings,*1 K.A.
Hendricks1, O.M. Nuno1, D.A. Brown1, D.A. Evans2, Texas Department of
Health, 1Austin and 2Tyler, Texas
Creutzfeldt-Jacob Disease (CJD), a transmissible spongiform encephalopathy, is caused by prions composed of proteinaceous material devoid of nucleic acid. CJD occurs sporadically (generally 1 case/1,000,000 population per year) in older patients (average age of 65) and is characterized by rapidly progressive dementia, accompanied by severe muscle spasms and incoordination. Death usually occurs within 3 to 12 months (average 7 months). CJD activity in Texas, which has a population of nearly 19 million, appeared to be typical. The statewide death rate for 1995 and 1996 was just under 1/1,000,000. In April of 1997, the Texas Department of Health became aware of an increased number of possible CJD cases in a 23-county area of NE Texas with a population of just over one million. After review of medical and pathology records, four patients were identified with definite classic CJD and three were identified with probable CJD. Dates of death for the eight patients were from April, 1996 through mid-July 1997. The patients were from 46 through 65 years of age; four were male and three were female. A case-control study to identify risks for CJD in NE Texas has been initiated.
http://www.jifsan.umd.edu/tse/Rawlings.htm
Division of Neuropathology
Pierluigi Gambetti, M.D.,
Director
-----------------------------------
CASE WESTERN RESERVE UNIVERSITY
March 30, 1998
Dr. Gerald A, Campbell
The University of Texas
Medical Branch at Galveston
Division of Neuropathology
Department of Pathology
Galveston, Texas
Dear Dr Campbell,
We performed Western immunoblot analysis on the frozen tissue from your case #AU97-435 (our #098-28). The Immunoblot reveals the presence of protease-resistant prion protein (PrPres) confirming the diagnosis of prion disease. The immunoblot pattern of PrPres is consistent with the diagnosis of Creutzfeldt-Jakob disease.
Thank you for referring to us this interesting case.
Sincerely,
Piero Parchi, M.D.
Pierluigi Gambetti, M.D.
PP:sbDivision of Neuropathology
Pierluigi Gambetti, M.D.,
Director
Case Western Reserve University
snip...end
-------- Original Message --------
Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD
Date: Thu, 28 Nov 2002 10:23:43-0000
From: "Asante, Emmanuel A" <e.asante@ic.ac.uk>
To: "'mailto:flounder@wt.net"<flounder@wt.net>
Dear Terry,
I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention. Thank you for your interest in the paper. In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask.
Best wishes.
Emmanuel Asante
<
____________________________________
Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02)New e-mail: e.asante@prion.ucl.ac.uk
(active from now)
____________________________________END...TSS
CJD, PrP Codon 129VV, Novel PrPSc in a Young British Woman
Wed Jan 2, 2008 16:5071.248.140.49
Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman
Simon Mead, PhD, MRCP; Susan Joiner, MSc; Melanie Desbruslais, BSc; JonathanA. Beck, BSc; Michael O’Donoghue, PhD; Peter Lantos, FRCP; Jonathan D. F.Wadsworth, PhD; John Collinge, FRSArch Neurol. 2007;64(12):1780-1784.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease causally related to bovine spongiform encephalopathy that has occurred predominantly in young adults. All clinical cases studied have been methionine homozygotes at codon 129 of the prion protein gene (PRNP) with distinctive neuropathological findings and molecular strain type (PrPSc type4). Modeling studies in transgenic mice suggest that other PRNP genotypes will also be susceptible to infection with bovine spongiform encephalopathy prions but may develop distinctive phenotypes.
Objective
To describe the histopathologic and molecular investigation in ayoung British woman with atypical sporadic CJD and valine homozygosity at PRNP codon 129.
Design Case report, autopsy, and molecular analysis.
Setting Specialist neurology referral center, together with the laboratory services of the MRC [Medical Research Council] Prion Unit.
Subject Single hospitalized patient.
Main Outcome Measures Autopsy findings and molecular investigation results.
Results Autopsy findings were atypical of sporadic CJD, with marked gray and white matter degeneration and widespread prion protein (PrP) deposition. Lymphoreticular tissue was not available for analysis. Molecular analysis of PrPSc (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrPSc type similar to that seen in vCJD (PrPSc type 4). However, this could be distinguished from the typical vCJD pattern by an altered protease cleavage site in the presence of the metal ion chelator EDTA.
Conclusions Further studies will be required to characterize the prion strain seen in this patient and to investigate its etiologic relationship with bovine spongiform encephalopathy. This case illustrates the importance of molecular analysis of prion disease, including the use of EDTA to investigate the metal dependence of protease cleavage patterns of PrPSc.
Author Affiliations: MRC [Medical Research Council] Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, England (Drs Mead, Wadsworth, and Collinge; Mss Joiner and Desbruslais; and Mr Beck); and Institute of Psychiatry, King's College London (Dr Lantos). DrO’Donoghue is now with the Department of Clinical Neurology, Nottingham University Hospitals NHS [National Health Service] Trust, Nottingham, England.
http://archneur.ama-assn.org/cgi/content/short/64/12/1780
North American Equity Research
New York
13 January 2004
BSE (Mad Cow) Update:
Do Reports of sCJD Clusters Matter?
There have been seven cases of human sCJD clusters identified in the US in the last 15 years, in which people in a specific location were diagnosed with sCJD, resulting in rates between 2.1 and 8.4 deaths per million people for that specific location compared with the national average of one in 1 million. · There is no proven link between sCJD and BSE, and hence it is considered a different disease from vCJD (which has been linked to BSE). However, the existence of clusters raises the question of “contamination" or “infection”, and also raises the hypothesis that rather than cases of sCJD these might have been cases of vCJD. · Clusters are not spontaneous, they normally have a source. Moreover, some cases of sCJD may have been improperly diagnosed as Alzheimer's.· We continue to believe that as long as no further cases of BSE-positive cows are found in North America and the industry has respected the 1997 ban on animal feed for live cattle, beef consumption in the US will not suffer. · Moreover, due to political pressure we expect key overseas markets (Japan, South Korea, and Mexico) to open up to US beef in the next six months – the recent 20% drop in cattle prices can be attributed mainly to these import bans. · However, two concerns linger and should be kept in mind by investors, 1) Has the 1997 ban on animal feed for live cattle been honored by the beef industry? 2) Can clusters of cases of sporadic CJD (or sCJD) really be a variant of CJD and indeed be linked to BSE? In this note we focus on the issue of sCJD clusters, and the potential impact that the growing debate on clusters could have on beef consumption in the US. United States Foods Pablo E. Zuanic(1-212) mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000366/!x-usc:mailto:622-6744pablo.zuanic@jpmorgan.comChristopher M. Bledsoe(1-212) mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000366/!x-usc:mailto:622-6386christopher.m.bledsoe@jpmorgan.comDaniel Ogbonna(212) 622-6382daniel.c.ogbonna@jpmorgan.com
State of Our Views Regarding BSE in the US
snip...
Existence of Clusters of sCJD May Imply They Are Really Cases of vCJD There have been seven sCJD clusters identified in the US in the last 15 years, in which people in a specific location were diagnosed with sCJD, resulting in rates between 1.2 and 8.4 deaths per million people for that specific location compared with the national average of one in 1 million. The existence of clusters raises the question of “contamination" or “infection”, and also raises the hypothesis that rather than cases of sCJD these might have been cases of vCJD. Clusters are not spontaneous, they normally have a source.
A cluster consists of two statistical improbabilities: 1) multiple cases occurring in a relatively limited geographic area, and 2) multiple cases occurring within the same time period. The most recent cluster was found in Cherry Hill, New Jersey. The others have been found in Lehigh, Pennsylvania (1986-90), Allentown, Pennsylvania (1989-92), Tampa, Florida (1996-97), Oregon (2001-02), and Nassau County, New York (1999-2000). Given that sCJD occurs randomly in one out of one million cases, it is a statistical rarity to find an sCJD cluster – let alone six. The following tables highlight known clusters in the US.
Table 1:
Clustered sCJD Deaths
Local sCJD Deaths
Time Span State Local Area Pop. (MM) Period (mo.) Total Ann'lized
1986-1990 PA Lehigh Valley 0.5 48 18 4.5
1989-1992 PA Allentown 2.5 36 15 5.0
1996-1997 FL Tampa 2.2 18 13 8.7
1996-1999 TX Denton .01 38 4 1.3
1999-2000 NY Nassau County 1.3 12 7 7.0
2001-2002 OR Entire State 3.4 24 14 7.0
2000-2003* NJ Cherry Hill Area 1.7 36 12 4.0
Source: JPMorgan.
The second table, below, shows what portion of the state's total expected sCJD cases (as based on a one per million occurrence) were found in the local cluster, comparing the local cluster's portion of cases with the local area's portion of the state's total population. The greater the factor between the former and the latter suggests a higher statistical improbability that the cluster is spontaneous (sCJD).
Table 2: Clustered sCJD Deaths vs. Expected State Cases
Annual Statewide Local Area (% of Time Span State Local Area sCJD Deaths* exp. state cases state pop.
1986-1990 PA Lehigh Valley 11.9 37.8% 4.5%
1989-1992 PA Allentown 12.0 41.7% 20.8%
1996-1997 FL Tampa 14.1 61.5% 15.7%
1996-1999 TX Denton 20.9 6.1% .02%
1999-2000 NY Nassau County 18.1 38.7% 7.4%
2001-2002 OR Entire State 3.4 205.9% 100.0%
2000-2003* NJ Cherry Hill Area 8.0 50.0% 21.6%
* *State cases are extrapolated based on state population and the 1 per
million national average. Source: JPMorgan.
snip...
Copyright 2003 J.P. Morgan Chase & Co.—All rights reserved.
THIS MATERIAL IS ISSUED AND DISTRIBUTED IN MALAYSIA BY J.P. MORGAN
MALAYSIA SDN. BHD. (18146-X).
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https://lists.aegee.org/cgi-bin/wa?A2=ind0401&L=BSE-L&T=0&F=&S=&P=25337
see full text ;
http://cjdtexas.blogspot.com/
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States
http://cjdusa.blogspot.com/
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
SEAC 99th meeting on Friday 14th December 2007
http://seac992007.blogspot.com/
please see full text ;
http://nor-98.blogspot.com/2008/01/atypicalnor98-scrapie-properties-of.html
16 January 2008 - The final minutes of the 98th SEAC meeting have been
published.
PUBLIC QUESTION AND ANSWER SESSION 2
© SEAC 2007
SEAC considered a question about possible links between CJD cases and animal
TSEs in the United States of America (USA).
http://www.seac.gov.uk/summaries/seac99_summary.pdf
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
posted by Terry S. Singeltary Sr. at
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