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Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of H

Posted Sep 09 2010 2:06pm
Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease

Piero Parchi1, Maura Cescatti1, Silvio Notari1, Walter J. Schulz-Schaeffer2, Sabina Capellari1, Armin Giese3, Wen-Quan Zou4, Hans Kretzschmar3, Bernardino Ghetti5 and Paul Brown6 + Author Affiliations 1 Dipartimento di Scienze Neurologiche, Università di Bologna, 40123 Bologna, Italy 2 Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Göttingen, 37075 Göttingen, Germany 3 Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität, D-81377 München, Germany 4 Institute of Pathology, Case Western Reserve University, Cleveland, OH 4410, USA 5 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 6 CEA/DSV/iMETI/SEPIA, 18, Route du Panorama, BP6, 92265 Fontenay-aux-Roses, France Piero Parchi, Department of Neurological Sciences, University of Bologna, Via Foscolo 7, 40123, Bologna, Italy E-mail: piero.parchi@unibo.it

Received March 30, 2010.

Revision received June 11, 2010.

Accepted June 23, 2010.

Summary

Six clinico-pathological phenotypes of sporadic Creutzfeldt–Jakob disease have been characterized which correlate at the molecular level with the type (1 or 2) of the abnormal prion protein, PrPTSE, present in the brain and with the genotype of polymorphic (methionine or valine) codon 129 of the prion protein gene. However, to what extent these phenotypes with their corresponding molecular combinations (i.e. MM1, MM2, VV1 etc.) encipher distinct prion strains upon transmission remains uncertain. We studied the PrPTSE type and the prion protein gene in archival brain tissues from the National Institutes of Health series of transmitted Creutzfeldt–Jakob disease and kuru cases, and characterized the molecular and pathological phenotype in the affected non-human primates, including squirrel, spider, capuchin and African green monkeys. We found that the transmission properties of prions from the common sporadic Creutzfeldt–Jakob disease MM1 phenotype are homogeneous and significantly differ from those of sporadic Creutzfeldt–Jakob disease VV2 or MV2 prions. Animals injected with iatrogenic Creutzfeldt–Jakob disease MM1 and genetic Creutzfeldt–Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt–Jakob disease MM1 prions, whereas kuru most closely resembled the sporadic Creutzfeldt–Jakob disease VV2 or MV2 prion signature and neuropathology. The findings indicate that two distinct prion strains are linked to the three most common Creutzfeldt–Jakob disease clinico-pathological and molecular subtypes and kuru, and suggest that kuru may have originated from cannibalistic transmission of a sporadic Creutzfeldt–Jakob disease of the VV2 or MV2 subtype.

Key words prion diseases neuropathology neurodegenerative disorders phenotype strain typing

Abbreviations CJD Creutzfeldt–Jakob disease NIH National Institutes of Health TSEs transmissible spongiform encephalopathies

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


For Permissions, please email: journals.permissions@oxfordjournals.org



http://brain.oxfordjournals.org/content/early/2010/09/07/brain.awq234




PPo4-1
Creutzfeldt-Jakob Disease in the United States 2003–2007


Robert C. Holman,1 Ermias D. Belay,1 Ryan A. Maddox,1 Arianne M. Folkema,1 Arialdi M. Minino,2 Teresa A. Hammett,1 James J. Sejvar,1 Kenneth D. Kochanek2 and Lawrence B. Schonberger1 1National Center for Emerging and Zoonotic Infectious Diseases; Centers for Disease Control and Prevention (CDC); Atlanta, GA; 2National Center for Health Statistics; CDC; Hyattsville, MD USA


Key words: Creutzfeldt-Jakob disease, United States, epidemiology, mortality


Background. Prion diseases are a family of rare progressive neurodegenerative disorders that affect humans and animals. Creutzfeldt-Jakob disease (CJD), the most common human prion disease, occurs worldwide at approximately 1 case per million persons.


Objectives. To describe the recent occurrence of CJD in the United States.


Results. During 2003 through 2007, an average of 297 deaths with CJD was reported annually in the United States, ranging from 282 in 2004 to 331 in 2007. The average annual age-adjusted incidence for CJD was 0.97 per million persons (95% CI = 0.92–1.0). The average annual incidence for persons <55>55 years of age was 0.2 and 3.8, respectively. The highest rate was among persons 70–79 years of age (5.6). The median age of death was 66 years. Three decedents were reported with variant CJD; evidence indicated that infections were acquired outside of the United States.


Conclusion. The annual CJD incidence rate remained at approximately 1 case per million persons during 2003 through 2007, with the rate much higher in older ages. The monitoring of the occurrence of CJD using the literal text on US death certificates is an important surveillance tool that aids in detecting occurrences of CJD and other novel prion diseases. Methods. Analysis of CJD-related death records for US residents during 2003 through 2007 identified through both multiple cause-of-death data and literal text death certificate searches, along with other surveillance mechanisms.




PPo4-7

Creutzfeldt-Jakob Disease Among Blacks in the United States, 1994–2007


Ryan A. Maddox,1 Robert C. Holman,1 Arianne M. Folkema,1 Pierluigi Gambetti,2 Wen-Quan Zou,2 Arialdi M. Minino,3 Lawrence B. Schonberger1 and Ermias D. Belay1 1National Center for Emerging and Zoonotic Infectious Diseases; Centers for Disease Control and Prevention (CDC); Atlanta, GA; 2Department of Pathology; National Prion Disease Pathology Surveillance Center; Case western Reserve University; Cleveland, OH USA; 3National Center for Health Statistics; Centers for Disease Control and Prevention (CDC); Hyattsville, MD USA


Key words: CJD, epidemiology


Introduction. Creutzfeldt-Jakob disease (CJD) incidence is significantly lower in blacks compared to whites in the United States. The reason for this racial discrepancy is unknown. Investigation of CJD cases among black persons could provide insight into the occurrence of human prion diseases.


Results. During 1994–2007, 150 of 3,904 (3.8%) CJD decedents identified in the United States were classified as black; the average annual age-adjusted incidence for this population was 0.41 per million persons. Black males were not at significantly higher risk compared to females (RR 0.97, 95% CI 0.7–1.4), in contrast with the risk of white males compared to females (RR 1.2, 95% CI 1.2–1.3). Although a higher percentage of black CJD decedents were <55 years of age compared to whites (19.3% vs. 12.7%, respectively), the relative risks of black and white CJD decedents being <55 years of age were similar. Clinical information was available for 13 of the 29 (45%) young black CJD cases; the median illness duration of these cases was 6 months (range 1–33 months), and most (76.9%) had neuropathologic confirmation.


Methods. Decedents with CJD were identified from the US national multiple cause-of-death data and other sources. When available, relevant portions of medical records and results from neuropathologic and genetic testing for black decedents <55 years of age were reviewed.

Conclusions. The differences between black and white CJD decedents warrant further investigation. Neuropathologic confirmation and genetic analyses of suspected CJD cases among black persons are especially important because of the rarity of the disease in this population.


SP1-4

Evidence from Molecular Strain Typing


Gianluigi Zanusso Department of Neurological and Visual Sciences; Section of Clinical Neurology; University of Verona; Verona, Italy


Key words: molecular analysis, strain typing, atypical BSE, CJD


In 2001, active surveillance for bovine spongiform encephalopathy (BSE) led to the discovery of atypical BSE phenotypes in aged cattle distinct from classical BSE (C-type). These atypical BSE cases had been classified as low L-type (BASE) or high H-type BSE based on the molecular mass and the degree of glycosylation of of the pathological prion protein (PrPSc). Transmission studies in TgBov mice showed that H-type BSE, C-type BSE and BASE behave as distinct prion strains with different incubation periods, PrPSc molecular patterns and pathological phenotypes. A still unclear issue concerns the potential transmissibility and phenotypes of atypical BSEs in humans. We previously indicated that BASE was similar to a distinct subgroup of sporadic form of Creutzfeldt-Jakob disease (sCJD) MV2, based on molecular similarities and on neuropathological pattern of PrP deposition. To investigate a possible link between BASE and sCJD, Kong et al. and Comoy et al. experimentally inoculated TgHu mice (129MM) and a non-human primate respectively, showing in both models that BASE was more virulent compare to BSE. Further, non-human primate reproduced a clinical phenotype resembling to that of sCJD subtype MM2. Here, we presented a comparative analysis of the biochemical fingerprints of PrPSc between the different sCJD subtypes and animal TSEs and after experimental transmission to animals.



PPo5-26

A Typical Neuropathological sCJD Phenotype with Abundant Cerebral Kuru-type Plaques Sparing the Cerebellar Cortex


Ellen Gelpi,1 Josep Ma Soler Insa,2 Elena Martínez- Saez,3 Jordi Yagüe,4 Carlos Nos,7 Raquel Sanchez-Valle4,5 and Isidro Ferrer6 1Neurological Tissue Bank; University of Barcelona; 2Neurology Department; Hospital St. Joan de Deu, Manresa; 3Vall d’Hebron Research Institute and Pathology Department; 4CJD-Unit; 5Alzheimer disease and other cognitive disorders Unit; Department of Neurology; Hospital Clínic; 6Institut de Neuropatologia; Hospital Universitari de Bellvitge; 7General Subdirectorate of Surveillance and Response to Emergencies in Public Health; Department of Public Health in Catalonia; Barcelona, Spain


We describe an atypical neuropatholgical phenotype of a sporadic Creutzfeldt-Jakob disease (CJD) case. A 64-year-old man presented, 5 months before death, rapidly progressive behavioural disturbances, memory complaints, disorientation, and language alterations. No cerebellar signs were present. MRI showed diffuse atrophy and hyperintensities in parietal, occipital, temporal, and frontal cortices and left caudate nucleus in T2 and FLAIR. No periodic sharp wave complexes were observed in the EEG. A repeated 14-3-3 assay was positive after a first negative result performed 3 weeks before. Neuropathology showed classical CJD changes affecting all cerebral lobes and basal ganglia with small cortical foci of large confluent vacuoles. Cerebellar cortex was relatively well preserved. The most striking feature was the presence of abundant Kuru-type plaques in the cerebral cortex and white matter, and only isolated in cerebellar white matter sparing cerebellar cortex. Immunohistochemistry showed, in addition to unicentric plaques, diffuse synaptic and patchy perivacuolar, as well as plaque-like and periaxonal PrPres deposits. Western blot studies demonstrated PrPres type 2 in frontal cortex and very weak signal in cerebellum. No PRNP mutations were detected, and codon 129 showed methionine homozygosity. This case can not be classified according to the current sCJD classification (Parchi et al. 2009) as it shares histopathological features of both, the mixed MM1/2 and MV2K + 2C subtypes. In contrast, the patient presented clinically as classical MM1 sCJD. This case highlights the complexity of the phenotypic and isotype correlations. It would be of great interest to collect atypical cases to elucidate further mechanisms modulating phenotypic manifestations.



PPo5-29

Neuropathological and Biochemical Characterization of Unusual Cases of Creutzfeldt-Jakob Disease in Young, Prnp 129 mm Subjects


Fabio Moda,1 Giorgio Giaccone,1 Giuseppe Di Fede,1 Alessandro Terruzzi,2 Silvia Suardi1 and Fabrizio Tagliavini1 1Fondazione IRCCS Istituto Neurologico Carlo Besta; Milano, Italy; 2Policlinico S. Marco; Bergamo, Italy


Key words: sporadic Creutzfeldt-Jakob disease, immunohistochemistry, prion disease, prion protein, PRNP, PrP types


Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease of humans with the greatest incidence between 60 and 70 years of age. Different polymorphisms (Methionine/Valine) at codon 129 of PRNP gene and PrPSc type are associated with different disease phenotypes. Approximately 95% of the sporadic 129MM CJD patients have PrPSc type 1 (Parchi classification). Young patients with sCJD are extremely rare, and most of them are 129VV with type 1 PrPSc deposition in the brain. We observed two young patients with CJD (age at death 25 and 34 years) who had not the characteristics of variant CJD neither an history of risk factors for iatrogenic transmission. Both were MM at codon 129, without mutation of the PRNP gene. The clinical course was rather long (26 and 28 months), dominated by behavioral disturbances in the early stage and remarkable for the absence of hallmarks of CJD at CSF analysis, MRI and EEG. These two atypical CJD patients were subjected to biochemical and immunohistochemical analysis. Preliminary results evidenced: (i) presence of type 2A PrPSc with the immunohistochemical counterpart of diffuse, finely granular, synaptic pattern of staining, without any focal perivacuolar PrP deposition; (ii) sparing of basal ganglia and cerebellum; (iii) absence of reactivity with a monoclonal antibody (12B2) specific for type 1 PrPSc. These findings may contribute to clarify the relationship between type of PrPSc, patterns and entity of PrP deposition, distribution and severity of the neuropathological changes and their role in the pathogenesis of prion diseases.



http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099



Tuesday, August 03, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html



Monday, August 9, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?


http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html



Rural and Regional Affairs and Transport References Committee The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010


2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49


2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50


http://www.aph.gov.au/senate/committee/rrat_ctte/mad_cows/report/report.pdf



U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? see video at bottom


http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.html



Sunday, September 6, 2009


MAD COW USA 1997 SECRET VIDEO



http://madcowusda.blogspot.com/2009/09/mad-cow-usa-1997-video.html


Wednesday, June 16, 2010



Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties


http://creutzfeldt-jakob-disease.blogspot.com/2010/06/defining-sporadic-creutzfeldt-jakob.html



ALABAMA MAD COW g-h-BSEalabama



In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.



http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156


http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDF



Saturday, August 14, 2010


BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY


(see mad cow feed in COMMERCE IN ALABAMA...TSS)


http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html


g-h-BSE-alabama E211K mad cows USA how many potential mad cows would that be annually ??


if our ciphering is correct (?), that would be about 35 potential g-h-BSE-alabama E211K mad cows going into the food chain a year.

an incidence of less than 1 in 2000.

let's see, that's 500 such per million.

or 50,000 cows per 100 million (US herd size).

even at less than 1 in a million, with 35 million slaughtered, that's 35 infected cows going into the food chain each year.

hmmm, friendly fire there from ??



Wednesday, July 28, 2010

re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010


http://bse-atypical.blogspot.com/2010/07/re-freedom-of-information-act-project.html




Wednesday, August 11, 2010

Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Vol. 67 No. 8, August 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/heterozygosity-at-polymorphic-codon-219.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 ;

01 Jan 2010 at 18:11 GMT

re-Human Prion Diseases in the United States


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




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


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




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





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




14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

update October 2009

T. Singeltary

Bacliff, TX, USA

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.


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




Wednesday, March 31, 2010

Atypical BSE in Cattle


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




Wednesday, August 18, 2010

Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html




Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)


http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html




Thursday, August 12, 2010

USA Blood products, collected from a donor who was at risk for vCJD, were distributed July-August 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/usa-blood-products-collected-from-donor.html




Thursday, July 08, 2010

GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/07/global-clusters-of-creutzfeldt-jakob.html




Wednesday, September 08, 2010

Emerging Infectious Diseases: CJD, BSE, SCRAPIE, CWD, PRION, TSE Evaluation to Implementation for Transfusion and Transplantation September 2010


http://vcjdtransfusion.blogspot.com/2010/09/emerging-infectious-diseases-cjd-bse.html




NIH may destroy human brain collection

By Steve Mitchell Medical Correspondent

Washington, DC, Mar. 24 (UPI) -- The National Institutes of Health may discard part or all of a rare collection that includes hundreds of human brain samples from patients that suffered from a disorder similar to mad cow disease -- unless another researcher or institution takes them on, United Press International has learned.

Several scientists said the collection, which is held by the NIH's National Institute for Neurological Disorders and Stroke in Bethesda, Md. -- and includes brains and other tissue samples from people afflicted with the brain-wasting illness Creutzfeldt Jakob disease -- is irreplaceable and could even provide insight into treatments for the fatal disorder. Currently, there is no cure for CJD and patients typically die within a year after symptoms begin.

However, NIH officials in control of the collection's fate told UPI the remaining samples are of little scientific value and may be disposed of if researchers outside the agency do not claim it. That position stands in sharp contrast with CJD experts who thought the collection should be preserved.

"It's invaluable," said Dr. Paul Brown, former medical director of the NIH's Laboratory for Central Nervous System Studies, whose expertise is in CJD and mad cow disease (also known as bovine spongiform encephalopathy, or BSE).

The collection is badly in need of organization and no one is certain how many brains or other tissue samples it contains, said Brown, who worked with the collection since its inception in the 1960's until his retirement last year. There could be brains, blood, spinal fluid and various other tissues from 1,000 people or more, he said. Some of the specimens would be of scientific use today, he said.

"This collection has the unique value of stretching back to the beginning of when these diseases were discovered," Brown told UPI, noting that the first samples were obtained in 1963. "It would be as though you had in your hands the possibility of finding out when AIDS started."

Bruce Johnson, a former technician at the CNSS lab who worked extensively with the collection before he retired in 2003, told UPI he was told "in two years they (NIH officials)are going to destroy it, if nobody wants it."

Eugene Major, acting director of the basic neuroscience program at the NIH, said no specific timeframe had been established.

"We have not set a firm deadline date," Major told UPI. "We are working very hard with investigators that we know in order to be able to make sure that whatever we deem is valuable is potentially kept here." Some samples already have been determined not to have any research value and have been "removed and disposed of," he said.

Others samples have been given out to Dr. David Asher at the Food and Drug Administration and Pierluigi Gambetti at the National Prion Disease Pathology Surveillance Center in Cleveland, Ohio.

Major maintained the remaining collection was not particularly valuable for research. "Whatever had been collected here that has not already been distributed to responsible investigators who could use them really has very little remaining value," he said.

Neither Asher nor Gambetti returned phone calls from UPI, but Brown said he thought Asher had received only a dozen or two samples at most and Gambetti had not received much at all.

Neil Cashman, a brain-disease researcher at the University of Toronto's Center for Research in Neurodegenerative Diseases -- who has tried to obtain the collection from the NIH -- said it was priceless.

"It would be like destroying an art museum," Cashman told UPI. "There's all this information and insight that's locked up in these tissues and if it's destroyed it will be lost forever."

The Memorial Institute for Neurodegenerative Diseases Inc., a non-profit organization consisting of more than 40 university and institute researchers from the United States, Canada, United Kingdom and France, also thinks the brain collection is invaluable.

"It is the opinion of the Board of Directors ... of The MIND Inc., that the ... brain bank should not be broken up nor destroyed," said Harry E. Peery, MIND's executive director, in a letter to UPI. "We believe that this collection is of inestimable research value and should be kept intact."

The institute, at the University of Saskatchewan in Saskatoon, applied for possession of the collection in early 2004, but received a letter from the NINDS indicating the fate of the collection had not yet been determined.

"We have heard nothing further since that time" and continue to be interested in acquiring the complete collection, Peery said.

CJD belongs to a group of rare, brain-wasting disorders that are little understood, incurable and fatal. This includes mad cow disease in cows, chronic wasting disease in deer and elk. The most infamous of these illnesses in humans is variant CJD, which people can contract from eating beef products infected with the mad-cow pathogen.

Although vCJD has infected more than 154 people worldwide, only one case has ever been detected in the United States -- in a Florida woman who is thought to have contracted the disease while living in the United Kingdom. However, the NIH brain samples have never been screened for vCJD -- something Johnson thinks is critically important.

"No one has ever looked to see if any American (in the collection) in the past had variant CJD," Johnson said. "You think it would be required that they do that. You think it would be a Congressional mandate that they test these brains: 'Let's see if we've got this disease in our country.'"

Johnson noted at least one brain in the collection he personally had examined -- from a French woman collected in 1971 -- showed evidence of possible vCJD infection, but the sample needed further study to be sure.

Other samples in the collection include the brains of patients who were only 16 years old when they were diagnosed with CJD. This would be unusual for sporadic CJD, because generally it strikes those over age 60. Variant CJD, on the other hand, typically occurs in patients in their 20s or younger.

"I thought it was absolutely vital (to test these brains)," Johnson said. "Maybe there's a dozen cases in there of variant CJD."

Major disagreed. "There's really no reason to do that," he said. "The effort it would take to screen those samples ... would not give us any new insights into variant CJD beyond what it is we already know."

Johnson said he was frustrated with the NIH administration's lack of interest in preserving the collection or testing for vCJD. "They don't understand," he said, "they honest-to-god don't understand what it's all about."

Patient advocates also objected to the possible destruction of the brains.

Terry Singeltary, whose mother died of a type of CJD called Heidenhain variant in 1997, said he is outraged and families of other CJD victims probably will be, too.

"A lot of these families went through a lot of heartache and a lot of trouble to get these brain samples to the NIH," Singeltary told UPI. "Now they're just going to discard them because they're not of scientific use? That's just asinine. That stuff is valuable information."

Graham Steel, vice-chair of the Human BSE Foundation in the United Kingdom, told UPI, "The potential loss of such important tissue samples would be a massive blow for TSE (the group of diseases that includes CJD and BSE) research in the United States. This should not be allowed to happen."

Singeltary noted there currently is no cure for these diseases. "If you don't have any answers yet, why would you throw these specimens away?" he asked.

He added that more sensitive tests are just becoming available and could help determine the origin of some of the CJD cases. "We've all been sitting around waiting for more sensitive tests to get validated because we want answers," he said.

"You know, it must be an embarrassment," Johnson said. "Some Senator is going to eventually say 'What is NIH doing about mad cow disease?' And people are going to scratch their heads and say 'not much'." He added, "What's going to happen (is) one of these senators or their wife is going to develop spontaneous CJD one day and ... there's going to be hell raised and they're going to ask, 'Why isn't NIH working on this?'"

--



http://www.washtimes.com/upi-breaking/20050323-053919-8481r.htm



http://www.accessmylibrary.com/coms2/summary_0286-8492054_ITM




http://www.promedmail.org/pls/otn/f?p=2400:1202:9557296506089968094::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,28585





SCIENCE NEWS

Groups seek to save NIH brain collection

Published: April 1, 2005 at 4:48 PM By STEVE MITCHELL, Medical Correspondent

WASHINGTON, April 1 (UPI) -- Scientists, consumer groups and patient-advocates have embarked upon efforts -- including petitioning members of Congress and seeking storage space at a Canadian university -- to prevent the National Institutes of Health from destroying an irreplaceable collection of human brains from patients afflicted with a condition similar to mad cow disease.

As United Press International reported last week, the NIH has begun shopping for a new home for its collection of brains, spinal fluid and other tissues from hundreds of patients around the world who died from Creutzfeldt Jakob disease -- an incurable, fatal, brain-wasting illness. The collection dates back to 1963 and the consensus among scientists in this field is it is invaluable for research and could provide insights that might aid in developing diagnostic tests, treatments or cures for CJD.

NIH officials, however, maintain the remaining samples in the collection -- stored in some 30 freezers by the National Institute for Neurological Disorders and Stroke in Bethesda, Md. -- are of little value and may be disposed of if researchers or institutions do not come forward to claim them.

Families of patients who died of CJD have reacted with outrage, concerned that the effort mounted to collect the brains in the first place has been all for naught. Several have contacted their respective members of Congress and urged them to step in.

"The brains and brain tissue were sent to NIH in good faith for future research and destroying them is an outrage," Terry Singeltary, a patient advocate in Bacliff, Texas, wrote in a letter to Sen. Kay Bailey Hutchinson, R-Texas, and several other members of the state's congressional delegation. Singeltary's mother died of a type of CJD called Heidenhain variant in 1997.

Hutchinson's office did not return a call from UPI.

Eugene Major, who serves as acting director of the NINDS and is responsible for the fate of the brain collection, did not return a call from UPI.

"The patients these brains were taken from suffered greatly before they died of CJD," Heather Larson of Phoenix, whose mother succumbed to CJD last year at the age of 56, wrote in a letter to Arizona Republican Sens. John McCain and Jon Kyl, and Republican Rep. John Shadegg. "Their brains hold answers that can save human lives. Destroying the brains at Bethesda would greatly hinder the research being done to fight this disease and would cost many their lives."

The offices of McCain and Kyl did not return UPI's calls.

"The ravages of this disease, and the toll it takes not only on its victims but on family and loved ones, cannot easily be described to someone who has not witnessed it personally," Patty Cook of Kansas City, Kan., wrote in a letter to Kansas Republican Sens. Sam Brownback and Pat Roberts, and Democratic Rep. Dennis Moore.

"I urge you to do whatever you can to ensure these brains are not destroyed," added Cook, whose mother died of CJD in 1982.

Brownback's office did not return a call from UPI.

CJD belongs to a group of diseases -- called transmissible spongiform encephalopathies or TSEs -- that includes mad cow disease, chronic wasting disease in deer and elk, scrapie in sheep and several types of CJD in humans. There is no cure for CJD and it typically results in death within a year after the onset of symptoms.

Consumer groups also are concerned and are considering taking steps to ensure the brain collection will be preserved.

"This is outrageous," Michael Hansen, a biologist and senior research associate with Consumers Union in Yonkers, N.Y., told UPI. "Those brains are a critical resource for CJD science and they must be at a research facility."

Hansen added that his late friend, Joe Gibbs, the former chief of NINDS's Laboratory of Central Nervous System Studies, told him the brain of famed choreographer George Balanchine, who died of CJD in 1983, resides in the collection.

"How can we claim to be a scientific country if we're going to be throwing away an irreplaceable repository of the first evidence of these diseases?" asked Felicia Nestor, who serves as a consultant to Public Citizen.

There may be hope yet for the collection, however.

Neil Cashman, an expert on TSEs at the University of Toronto's Center for Research in Neurodegenerative Diseases, told UPI he has been attempting to drum up support for acquiring the collection with his colleagues at the University of British Columbia in Vancouver -- where he plans to move this summer.

"I'm trying to organize support for an official letter from UBC to NIH to request the collection," Cashman said.

The letter will probably go out in about a month, he said.

"The goal would be to make it a resource for the world and make the tissues available to scientists who had a reasonable request," he added.

Singeltary said he has heard from at least one other prominent scientist in this field who said they planned to contact the NIH and urge it to reconsider the fate of the collection.

One brain in the collection, that of a French woman who died in 1971, may help provide clues about the origins of variant CJD -- a condition similar to CJD that humans can contract from eating beef products contaminated with the mad-cow pathogen. The first recognized case of vCJD occurred in 1995 in the United Kingdom, but an NIH scientist said he tested the French woman's brain in 2000 and found signs consistent with vCJD -- not CJD.

French researchers currently are re-examining specimens from the case to determine if the woman was indeed infected with vCJD. If she was, it would suggest the disease began infecting people more than 20 years earlier than previously thought.

Cashman said the case underscores the value of the NIH brain collection.

"There is information locked up in these freezers that will be lost forever if this collection is destroyed," he said.

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http://www.upi.com/Science_News/2005/04/01/Groups-seek-to-save-NIH-brain-collection/UPI-72961112392131/




NIH sends mixed signals on CJD brains

By Steve Mitchell Medical Correspondent

Washington, DC, Apr. 7 (UPI) -- A National Institutes of Health official who told United Press International the agency might destroy its collection of brains from human patients afflicted with a condition similar to mad cow disease reportedly has told the head of a patient-advocate group the collection would be preserved.

The official, Eugene Major, acting director of the basic neuroscience program at the NIH, has not responded to e-mail or a phone call from UPI seeking clarification of his remarks, and the official status of the collection remains unknown.

As reported by UPI on March 24, the collection is stored in freezers by the NIH's National Institute for Neurological Disorders and Stroke in Bethesda, Md. It contains brains and other tissue samples from hundreds of people who died from the brain-wasting illness Creutzfeldt Jakob disease, as well as tissues from an untold number of experimental animals.

The consensus of scientists in this field is the collection, which dates back to 1963, is invaluable for research and could even provide insight into treatments for the fatal disorder. Currently, there is no cure for CJD and patients typically die within a year after symptoms begin.

Florence Kranitz, president of the non-profit advocacy group CJD Foundation, told UPI she had "a very long conversation" with Major, in which he told her the remaining tissues in the collection would not be destroyed.

"He reassured me in no uncertain terms," Kranitz said, noting constituents of the foundation and other CJD advocacy groups had been expressing concerns to her the tissues would be destroyed.

Kranitz, who has personal reasons for wanting the collection preserved -- her husband died of CJD in 2000 -- said she plans to meet with Major at the end of April to discuss the issue further.

CJD belongs to a group of diseases collectively known as transmissible spongiform encephalopathies, or TSEs, that includes mad cow disease in cows, chronic wasting disease in deer and elk, and scrapie in sheep. All TSEs are incurable and fatal.

Major previously told UPI some samples already have been destroyed and others have been given to researchers at the Food and Drug Administration and the National Prion Disease Pathology Surveillance Center in Cleveland.

Major said the remaining collection "has very little remaining value" and could be destroyed if another entity does not claim them.

Bruce Johnson, a former NIH scientist who retired at the end of 2003, said he had been told the collection would be destroyed in two years if no one took the samples from the NIH.

In response to hearing that Major had failed to confirm to UPI the brain collection would not be destroyed, Patricia Ewanitz, who lives in Port Jefferson Station, N.Y., and is founder of the advocacy group CJD Voice, said, "The brain tissue might not be indispensable to the National Institutes of Health but it is absolutely necessary to the families who thought enough of science to donate the brains, brain tissue and blood in hopes of someday finding an answer to why their loved one died."

Ewanitz, whose husband died of CJD in 1997, added, "It now seems like such a joke."

Terry Singeltary, whose mother passed away from a type of CJD in 1997, said the NIH should use the samples for scientific research, not just store them in freezers.

Both Singeltary and Ewanitz said they would feel more reassured if Major verified in writing the collection will not be destroyed.

"I would go further and ask Major what he plans to do with them," Singeltary said. "If the samples are just going to sit up there and go bad, then they should give them out to researchers looking for cause and cure."

The revelation the NIH might destroy part or all of the collection sparked an outcry from patient advocates, consumer groups and scientists.

Advocates have been contacting their members of Congress, urging them to investigate and prevent the NIH from destroying the brains. Consumer groups also have gotten involved and scientists have taken steps to obtain the collection or have urged Major not to destroy the samples.

Felicia Nestor, who serves as a consultant to Public Citizen, told UPI she had contacted certain legislators and at least one was considering looking into the situation. Nestor asked the legislator's name be withheld.

Kranitz said Major also told her he plans "to advertise in professional neurological journals and by whatever means necessary to make it known" to researchers in the field the tissues are available.

Major previously said, however, that efforts to inform researchers of the availability of the collection were already underway and included informing NIH grantees. He added he had personally notified researchers at scientific meetings, but no TSE researcher contacted by UPI was aware of this.

"I was never informed," said Laura Manuelidis, an expert on these diseases and section chief of surgery in the neuropathology department at Yale University. She said the first she had heard of the situation was in UPI's March 24 report.

Manuelidis also said she contacted Major, expressing interest in the specimens, but so far has not received a response.

"I sent a letter to (Major) on (March 25) about our interest in these specimens, but he has not replied," she told UPI in an e-mail.

Neil Cashman, a TSE expert at the University of Toronto, who said he was not aware the samples might be destroyed, has lobbied colleagues at the University of British Columbia -- where Cashman is scheduled to move to this summer -- to help draft a letter requesting the collection.

The Memorial Institute for Neurodegenerative Diseases Inc., a non-profit organization consisting of more than 40 university and institute researchers from the United States, Canada, the United Kingdom and France, requested the collection in January, 2004. So far, the institute has not been informed of a decision by the NIH.

Asked if Major had told him whether the collection would be preserved, MIND Executive Director Harry Peery said, "We have heard nothing further from Eugene Major or anyone else at the NIH regarding the brain collection."

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http://www.upi.com/Science_News/2005/04/07/NIH-sends-mixed-signals-on-CJD-brains/UPI-25701112902231/





-------- Original Message --------


Subject: NIH to destroy our loved ones brain tissues, WE NEED YOUR HELP PLEASE Date: Fri, 25 Mar 2005 16:04:57 -0600 From: "Terry S. Singeltary Sr."


To: senator@hutchison.senate.gov


CC: Judith.Zaffirini@senate.state.tx.us, Bob.Deuell@senate.state.tx.us, District98.Truitt@house.state.tx.us, District115.Jackson@house.state.tx.us, Jane.Nelson@senate.state.tx.us, District96.Zedler@house.state.tx.us, Jon.Lindsay@senate.state.tx.us, f-gilstrap@tamu.edu, ka-phillips@tamu.edu


References: <422ca640.3030108@wt.net>


Greetings again Honorable Senator Hutchison and other Honorable Members of Texas Office,


My name is Terry S. Singeltary Sr. I lost my Mother to hvCJD aka mad cow.THE Heidenhain Variant of Creutzfeldt Jakob Disease. (there is more than one strain of mad cow disease and i will reference last)

I am once again writing to you on a matter of extreme importance. I would appreciate your assistance in writing to the National Institutes of Health requesting that the brain tissue collected over the years at NINDS from family members of Creutzfeldt-Jakob Disease victims be preserved and recorded and not discarded.

[See attached articles]

THE WASHINGTON TIMES UNITED PRESS INTERNATIONAL

NIH may destroy human brain collection

By Steve Mitchell Medical CorrespondentWashington, DC, Mar. 24 (UPI) -- ...

SNIP...END...TSS

FINALLY ONE, and only one Senator, did reply to my concerns, and help us with preserving the brain tissue bank at NIH. I had sent a hard copy via US postal to the Honorable Senator John Cornyn (see below), but none of the (above) Senators and other officials ever bothered to reply.

See The Honorable John Cornyn Reply below ;

JOHN CORNYN TEXAS UNITED STATES SENATE WASHINGTON, DC 20510-4305 April 26,2005

Mr. Terry Singeltary

P.O. Box 42

Bacliff, Texas 77518

Dear Mr. Singeltary
In response to your recent request for my assistance, I have contacted the National Institutes ofHealth. I will write you again as soon as I receive a reply. I appreciate having the opportunity to represent you in the United States Senate and to be ofservice in this matter.

Sincerely,

JOHN CORNYN United States Senator JC:djl


===============


JOHN CORNYN TEXAS UNITED STATES SENATE WASHINGTON, DC 20510-4305

May 18,2005

Mr. Terry Singeltary

P.O. Box 42

Bacliff, Texas 77518

Dear Mr. Singeltary
Enclosed is the reply I received from the Department of Health and Human Services in response to my earlier inquiry on your behalf. I hope this will be useful to you. I appreciate having the opportunity to represent you in the United States Senate. Thank you for taking time to contact me. Sincerely,

JOHN CORNYN United States Senate JC:djl Enclosure

DEPARTMENT OF HEALTH & HUMAN SERVICES National Institutes of HealthNational Institute of NeurologicalDisorders and Stroke NINDS Building 31, Room 8A52 31 Center Dr., MSC 2540 Bethesda, Maryland 20892-2540 Phone: 301-496-9746 Fax: 301-496-0296 Email: [log in to unmask]

May 10, 2005

The Honorable John CornynUnited States SenatorOccidental Tower5005 LBJ Freeway, Suite 1150Dallas, Texas 75244-6199

Dear Senator Cornyn
Your letter to the National Institutes of Health (NIH) forwarding correspondence from Mr. Terry S. Singeltary, Sr., has been forwarded to me for reply. Mr. Singeltary is concerned about thepreservation of Creutzfeldt-Jakob disease (CJD) brain samples that have been maintained by theNational Institute of Neurological Disorders and Stroke (NINDS) Intramural Research programfor many years. I am sorry to learn that Mr. Singeltary's mother died of CJD and can certainly understand hisdesire that any tissues that could help investigators unravel the puzzle of this deadly disease arepreserved. I hope he will be pleased to learn that all the brains and other tissues with potential tohelp scientists learn about CJD are, and will continue to be, conserved. (The tissues that arediscarded are those that have either decayed to an extent that renders them no longer appropriatefor research or those for which we do not have sufficient identification.) The purpose of gathering these brains and tissues is to help scientists learn about CJD. To that end, some of the NINDS-held samples are distributed to investigators who can demonstrate thatthey have a compelling research or public health need for such materials. For example, sampleshave been transferred to NIH grantee Dr. Pierluigi Gambetti, who heads the National PrionDiseases Pathology Surveillance Center at Case Western Reserve University in Ohio and workswith the Centers for Disease Control and Prevention to monitor all cases of CJD in the UnitedStates. Dr. Gambetti studies the tissues to learn about the formation, physical and chemicalproperties, and pathogenic mechanisms of prion proteins, which are believed to be involved inthe cause of CJD. Samples have also been transferred to Dr. David Asher, at the U.S. Food andDrug Administration, for use in assessing a potential diagnostic test for CJD.

Page 2 - The Honorable John Cornyn

in closing, we know that donating organs and tissue from loved ones is a very difficult andpersonal choice that must often be made at the most stressful of times. We at the NINDS aregrateful to those stalwart family members who make this choice in the selfless hope that it willhelp others afflicted with CJD. We also know the invaluable contribution such donations maketo the advancement of medical science, and we are dedicated to the preservation of all of thetissue samples that can help in our efforts to overcome CJD.

I hope this information is helpful to you in responding to Mr. Singeltary. Sincerely,

Story C. Landis, Ph.D. Director, National Institute ofNeurological Disorders and Stroke


==================================


NIH says it will preserve CJD brains

By STEVE MITCHELL

WASHINGTON, May 31 (UPI) -- The National Institutes of Health apparently has reversed its position on the fate of an invaluable collection of brains from people afflicted with a condition similar to mad cow disease, saying in a letter to a U.S. senator it will not destroy the collection.

An NIH official had told United Press International previously that the brain collection, which consists of samples from hundreds of people who died from the brain-wasting illness called Creutzfeldt Jakob disease, could be discarded if another entity does not claim them.

That sparked an outcry from patient-advocacy groups, consumer watchdogs and scientists, and the agency now appears to have backed away from that course.

"All the brains and other tissues with potential to help scientists learn about CJD are, and will continue to be, conserved," Story Landis, director of the National Institute of Neurological Disorders and Stroke, which oversees the brain collection, wrote in a May 10 letter to Sen. John Cornyn, R-Texas.

Cornyn had inquired about the status of the collection in April.

Last March, Eugene Major, acting director of the basic neuroscience program at the NIH, told UPI the useful portions of the collection had been doled out to scientists and the remaining samples had "very little remaining value" and could be destroyed.

Landis could not be reached for comment Tuesday. NINDS spokesman Paul Girolami told UPI he had been unable to locate her.

Scientists think the collection, which dates back to 1963, is invaluable for research on CJD and similar diseases and could even provide insight into treatments. There is no cure for CJD and patients typically die within a year after symptoms begin.

"Absolutely, the collection is worth keeping," Bruce Johnson, a former NIH scientist who said he had been told the collection would be destroyed in two years if no one took the samples from the agency, told UPI.

The Memorial Institute for Neurodegenerative Diseases Inc., a non-profit organization consisting of more than 40 researchers from several countries, offered to take the collection off of NIH's hands more than a year ago and so far has not heard anything from the agency, Harry Peery, MIND's executive director, told UPI.

CJD belongs to a group of incurable and fatal diseases collectively known as transmissible spongiform encephalopathies, or TSEs, that includes mad cow disease in cows, chronic wasting disease in deer and elk, and scrapie in sheep.

Variant CJD, or vCJD, is a relatively new TSE, which people can contract from consuming beef products infected with the mad cow pathogen.

Despite Landis' assurance the collection will be preserved, some family members of the patients who donated their brains to the NIH are still skeptical. This is because the wording Landis used in the letter leaves open the possibility that some brain samples are being destroyed.

"The tissues that are discarded are those that have either decayed to an extent that renders them no longer appropriate for research or those for which we do not have sufficient identification," Landis wrote.

"Which ones" are being destroyed? asked Terry Singeltary, who is involved with several CJD patient groups.

"With a system like this, they could destroy whatever and whenever they wanted, for whatever reason they wanted," Singeltary, whose mother died of CJD in 1997, told UPI.

"It's a perfect excuse to discard some suspicious tissue resembling vCJD or some atypical TSE related to animal TSEs in the USA," he added.

Although the collection includes samples from CJD patients as young as 16 that could make them candidates for possible vCJD, the brains have never been screened for evidence of the disease. The only confirmed vCJD case in the United States occurred in a Florida woman who is thought to have contracted the disease in England.

Johnson said he along with renowned CJD expert Paul Brown were in the process of sorting through the samples to match them up with patient identification documents until they both retired. Some of the samples may prove impossible to identify, he said, but he and Brown are the only ones familiar enough with the collection to organize it and neither has been asked back by the agency to aid in the identification process.

Steve Mitchell is UPI's Medical Correspondent. E-mail: [log in to unmask]

Copyright 2005 by United Press International. All Rights Reserved.




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






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