Congressionally Directed Medical Research Programs
National Prion Research Program
Vision: eliminate the occurrence of human transmissible spongiform encephalopathies.
Mission: develop a diagnostic test to detect the presence of prion disease.
The Final Report of the National Prion Research Program
1
Introduction
The Congressionally Directed Medical Research Programs (CDMRP) emerged from heightened public awareness, and increased interest in the community concerning various health issues. These efforts convinced Congress to direct the Department of Defense to manage programs that focus on specific diseases. A unique partnership, forged among the public, Congress, and the military, led to the establishment of CDMRP within the US Army Medical Research and Materiel Command (USAMRMC) in fiscal year 1993 (FY93) to manage these programs. CDMRP has grown to encompass multiple targeted programs and has received $4.36 billion in appropriations through FY07.
During FY02, concerns over potential contamination of the food and blood supply prompted the U.S. Congress (Joint Appropriations Conference Committee Report No. 107-350) to provide the largest single appropriation in history for research on prion disease. The National Prion Research Program (NPRP) was established with $42.5 million from Congress. The FY02 Senate Appropriations Committee Report 107-109, pages 148-149, also stated that the “priority goal… is to rapidly develop a diagnostic test to detect the presence of prion disease.” The Congressional language recognized that there was “currently no test to confirm the presence of the disease” and that this disease “represents a significant threat to the U.S. population.” The direction from Congress was to create a coordinated effort with other Federal agencies in an attempt to develop complementary programs of research and avoid duplicative activities. This influx of funding provided the funds to support established investigators as well as those new to the field to collectively focus on understanding prion disease and developing the components of diagnostic tools. With this increased funding, there was hope of leveraging knowledge to answer the many questions associated with this disease.
This Final Report of the NPRP examines the accomplishments of the NPRP with respect to the guidance set by Congress and in response to the recommendations made by the Institute of Medicine’s Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science. This report discusses the results of the October 2007 NPRP Summit that was convened by CDMRP to address ongoing critical knowledge gaps in the development of ante-mortem diagnostic tools for prion disease and to explore future courses of action for achieving the goal of having a diagnostic test for the detection of prion disease. The Final Report includes conclusions made by the Summit participants regarding the state of the science and recommendations to inform decision makers regarding future policy.
Overview of Prion Diseases
Transmissible spongiform encephalopathies (TSEs) are a group of related diseases including Creutzfeldt-Jacob disease (CJD) and its new variant (vCJD), kuru (all three affect humans), scrapie in sheep and goats, bovine spongiform encephalopathy (BSE; “mad cow disease”), and chronic wasting disease (CWD) in deer and elk. These diseases have long incubation periods of years or decades, cause progressive neurological degeneration, evoke no obvious inflammation or immune response, and are invariably fatal. The current disease theory attributes TSEs to prions, normal cell membrane proteins that can form atypical three-dimensional configurations. Upon infection, the incoming misfolded prion proteins (PrPSc) trigger a cascade converting
The Final Report of the National Prion Research Program 2
normal prion protein (PrPC) or a partially unfolded PrPC intermediate arising from normal conformational fluctuations to a misfolded form, PrPSc. The misfolded prion proteins aggregate in the central nervous system and lead to the symptoms of prion diseases. The initiation of the first prion protein misfolding is unknown, but one model proposes that the conformational change of PrPC to PrPSc is thermodynamically controlled with PrPC conformation favored at equilibrium. PrPSc is favored when it adds onto a seed or fibril-like aggregate of PrPSc proteins. This model predicts that fibril-like prion aggregates can replicate by fragmentation. Thus, transferring misfolded prion proteins to a new host by blood transfusion, tissue transplantation, contact with contaminated surgical instruments, or tissue ingestion can transmit the disease. In sporadic prion diseases, the origin of the prion protein misfolding is unknown. In familial prion diseases, several heritable mutations in the prion protein gene lead to accumulation of misfolded prion protein and subsequent disease manifestations. Scrapie, a prion disease of sheep, has been recognized for centuries, and it was his torically controlled by culling infected animals. When prion disease in cattle (BSE) was identified in the 1980s, it was also controlled by culling infected animals. Prion diseases in humans are relatively rare. Incidence of sporadic CJD (sCJD) in humans is about 1 in 1 million; about 10% of all human TSE cases are familial (i.e. about 1 in 10 million). In 2003, it was estimated that iatrogenic transmission through dura mater or corneal transplants, pituitary hormones, and instruments used in neurosurgery contaminated with prion-infected material had resulted in 250 cases of CJD worldwide. Modification of surgical procedures has eliminated or significantly limited this mode of transmission. Transmission of the human prion disease kuru by ingestion of brain tissue was recognized in the 1950s, and cessation of ritual cannibalism eliminated this mode of transmission. In all of the above examples, transmission is from human to human, or intraspecies transmission.
The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. These circumstances represent a potential threat to blood, blood products, and plasma supplies.
These threats to the food and blood supplies are serious because the incubation time for prion diseases is so long and there is no reliable ante-mortem diagnostic test, i.e., a test that can be performed to detect the disease while the person or animal is alive. Definitive diagnosis can be only made by examining central nervous system tissue at autopsy. Prions do not elicit an obvious immune response, so detection by measuring an immune response in the host has not been possible. Developing a diagnostic test to detect prions in peripheral tissues is dependent on surmounting two major impediments: (1) PrPSc has exactly the same amino acid sequence as PrPC and (2) PrPSc represents only 0.001% of the total prion protein in an affected host.
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Prevention (Workgroup 3)
Dr. Bruno Oesch, Prionics, AG, Switzerland was the moderator for the Prevention Workgroup. Prevention is defined as any activity which reduces the burden of mortality or morbidity from disease. Defining the areas where we can try to prevent the spread of the disease in animals is the best focus. It is important to maintain and improve surveillance in the various species affected by prions: humans, cattle, sheep, deer, elk, and possibly mice and voles. Surveillance is needed on the entry of infectious material into animal feed and subsequently the food chain that may affect humans. Animal feed may consist of many different elements that may contain the
The Final Report of the National Prion Research Program 13
prion protein. Meat and bone meal (MBM) from some animal species is used for animal feed to other species. Also used for animal feed are “specified risk materials” (SRM), which includes the skull, brain, eyes, tonsils, spinal cord and the nerves of animals. SRM is considered high risk for its potential to contain prion proteins. Banning the use of SRM for both human and animal food was critical in halting the epidemic of BSE in the UK and Europe. The success of the ban illustrates the central importance of SRM spread of BSE and underscores the need to monitor and/or prevent the entry of SRM into the food chain.
There is a concern that human infection could occur through prion contaminated blood transfusions, medical instruments, and tissue transplants. The research community needs to develop new methods for inactivation of prion proteins that are compatible with maintaining the viability of biological material for human use. The goal of prevention is to reduce the amount of prion contaminated material to which human may be exposed.
The workgroup members suggested that the current surveillance methods need to be maintained and improved. Some group members expressed concern for the level of resources needed being too low to continue current levels of surveillance.
Animal identification is the first step in surveillance. Traceback is a method by which an affected animal can be tracked back to its origin and the potential source of infection. Traceback is done through the National Animal Identification System (NAIS). The USDA representative suggested that traceback was important to reduce the spread of prion disease in livestock. Issues of the business cost for traceback are also a consideration.
Recommendations from Workgroup 3
• Develop policy on CWD surveillance. CWD occurs naturally in the wild among deer, elk, and moose. It poses a threat to hunters and others who consume meat from these animals. Deer meat (venison) is sometimes sent by hunters to commercial processors to be preserved as sausage and jerky (dried meat). If the venison is from a deer with CWD, it could contaminate processing machinery and spread the disease to previously uncontaminated meat products and then to unsuspecting consumers. Another threat is that deer are frequently raised on deer farms for hunting purposes and not monitored for CWD. Deer from farms can be sold and transported across state lines to other commercial farms, posing a significant risk of spreading CWD even further. A federal surveillance and monitoring program for CWD in wild and commercial herds is needed.
• Conduct studies on surgical equipment contamination. The risk of asymptomatic prion contamination occurring in hospitals is not known. The risk of blood and tissue from patients with vCJD contaminating surgical rooms and equipment, as well as methods to inactivate the agent on surgical equipment need to be developed. The data need to be improved and based on today’s hospital environment, e.g., current heat, cleaning, inactivation steps should be reviewed. Prion researchers should initiate laboratory studies to assess the efficiency of hospital cleaning methods using human strains.
The Final Report of the National Prion Research Program 14
• Conduct studies on inactivation. A more systematic approach to studying inactivation of prion material is needed. Autoclaving of whole intact animals is not sufficient. It is unclear what combination of high temperature and pressure is needed to inactivate prions as residual infectivity can still be detectable. Further study needs to be done on the properties of prions as there appear to be a range of different forms, which may have distinct biological characteristics.
• Review the use of MBM and SRM. MBM and SRM are valuable sources of protein in animal feed; they are also potential sources of infection. Surveillance of animals receiving MBM and SRM that are likely to become part of the human supply of food may reduce the risk of transmission.
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Therapeutics and Surveillance (Workgroup 4)
Dr. Phil Minor, National Institute for Biological Standards and Control, Potters Bar, UK was the moderator for the Therapeutics and Surveillance workgroup session.
With the lack of an effective vCJD treatment, surveillance is essential to control transmission. Surveillance studies are a high priority and remain critical to tracking the disease. The workgroup had an active discussion on BSE surveillance. It was suggested that they should treat the US and Canada in the same way by using a high level of surveillance in both countries. BSE is currently classified as a select agent. The U.S. Departments of Health and Human Services (HHS) and Agriculture (USDA) published final rules for the possession, use, and transfer of select agents and toxins (42 C.F.R. Part 73, 7 C.F.R. Part 331, and 9 C.F.R. Part 121) in the Federal Register on March 18, 2005. BSE was listed by the USDA as one of several select agents and toxins that could be used during acts of terrorism. Other examples include avian influenza and foot-and-mouth disease viruses. The issues surrounding select agents were discussed and lead to suggestions for a containment policy.
Tracking of human TSE through autopsies has increased due to support and education of physicians and family members of the deceased. Hopefully, the autopsied tissues will lead to a better understanding of pathological pathways and contribute to the development of diagnostics. Surveillance for prion disease through autopsies is a problem due to difficulty obtaining consent, and not being able to control the risk of infection from autopsied materials. Government agencies could address those issues by increasing support and allocating resources to educate family members, physicians and medical examiners on the need for more autopsies, as well as continuing support for research on decontaminating autopsy laboratories.
Better diagnostics are key to successful treatments in the future. One issue that will need clarification is who should receive prophylactic measures. Should it be assumed any blood donor could be potentially infectious with prion disease? Do all blood product recipients have the same risk of incurring infection? Without better diagnostics to determine the nature and extent of prion disease, it is difficult to focus on prophylactic therapeutics.
In terms of clinical trials, the researchers need to establish a consensus on a standard clinical trial design for general use and there is a need to coordinate the clinical trials. If clinical trial
The Final Report of the National Prion Research Program 15
designs are coordinated in advance among the researchers, results that support surveillance and treatment guidelines will be reached sooner.
In terms of vaccines, the workgroup said vaccines were an important consideration. Studying the immune response during infection is of interest. If the Government had a vaccine or other alternate intervention to stop CWD transmission, this would be of great importance. In relation to CWD and hunters, Government regulators such as State Fish and Wildlife or Game officers need to better promote the requirement to turn in deer heads to determine the real prevalence of the disease. If ante mortem tests were available, State Fish and Wildlife offices could offer them to hunters before they slaughter deer for consumption. However, the repercussions for testing include the socio-economic effects of finding increased prevalence of CWD on the hunting industry.
Recommendations from Workgroup 4
• Reconsider the research safety restrictions related to BSE. The administrative requirements to track every sample, criminal penalties, and inspections associated with the select agent status of BSE make research on it very difficult. The select agent status and Biological Safety Lab (BSL) level required should be based on the type of material being studied and the stage of the experiment, rather than indiscriminately applied to all materials and experiment components. Cattle with BSE should be managed under BSL-2 requirements, not the more restrictive BSL-3 requirements. If management standards are reduced to reflect the nature of the disease, BSE research will be easier and less expensive to perform, while continuing to be safe.
• Improve containment measure standard. Regulators need to revisit containment measures for BSE and scrapie following the most up to date scientific principles. The regulators need to establish a high level committee to devise a standard that is for unique TSE diseases.
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Stanley B. Prusiner
Institute for Neurodegenerative Diseases University of California, San Francisco, CA
Award: DAMD17-03-1-0425
Antemortem Prion Diagnostics
Prions cause bovine spongiform encephalopathy (BSE) of cattle, Creutzfeldt-Jakob disease (CJD) of humans, scrapie of sheep, and chronic wasting disease (CWD) of deer and elk. Four new concepts have emerged from studies of prions. First, prions are infectious proteins that are devoid of nucleic acid. Second, prion diseases may be manifest as infectious, genetic, and sporadic disorders. Third, prion diseases result from the accumulation of PrPSc, the conformation of which differs substantially from that of its precursor PrPC. Fourth, PrPSc can exist in a variety of different conformations, each of which seems to specify a particular disease phenotype. That the mammalian prion contains only PrPSc, thus supporting the hypothesis that prions are infectious proteins, has recently been demonstrated by using recombinant (rec) PrP produced in E. coli (Legname, Nguyen et al. 2005). Late in the course of disease, both humans and animals develop signs and symptoms of CNS dysfunction. At this advanced stage, PrPSc is generally detectable in the CNS when sensitive tests, such as the conformation-dependent immunoassay (CDI), are used (Safar, Geschwind et al. 2005). Towards developing a sensitive and specific presymptomatic diagnostic test for prion disease, we have made advances in understanding the biology of disease progression, elucidating chemical conditions for prion protein (PrP) precipitation, and establishing diagnostic protocols. Using SELDI-TOF MS and a ProteinChip platform in mouse models of prion disease, protein profiles of fractionated brain homogenates were produced from symptomatic CD-1 mice infected with RML prions and compared to controls; 24 protein biomarkers were identified. Additionally, we established a FACS protocol for fractionating human white blood cells (WBCs) from CJD patients. PrPSc in human WBCs will be measured using the CDI. In parallel work aimed to increase the sensitivity of the CDI by precipitation of prions, Keggin-type polyoxometalate (POM) complexes demonstrated superior ability to precipitate selectively disease-causing PrPSc. We propose that prion aggregation may involve multivalent electrostatic interactions between the POM anions and positively charged cleft sites of PrPSc. Using POMs, we are continuing to adapt the CDI to human plasma using samples from healthy controls and patients dying of sporadic CJD. From these studies, we conclude that a protease-sensitive (s) form of PrPSc is present at low concentrations in the plasma of patients with sporadic CJD. Whether or not there is sufficient sPrPSc present in the plasma of CJD patients so that it can be used as a diagnostic marker remains to be established.
References cited
Stanley B. Prusiner1,2,3, Jiri G. Safar1,2, In Su Lee1,5, Laura Moriarty1, Edward Choi1, Giuseppe Legname1,2, Michael D. Geschwind1,2, Stephen J. DeArmond1,2,4, Bruce L. Miller1,2 and Jeffrey R. Long5 1Institute for Neurodegenerative Diseases, Departments of 2Neurology, 3Biochemistry and Biophysics, and 4Pathology, University of California, San Francisco, CA; 5Department of Chemistry, University of California, Berkeley, CA.
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Robert G. Rohwer
VA Maryland Healthcare System, Baltimore, MD
Award: DAMD17-03-1-0756
Development of a Diagnostic for the Detection of PrPres in Blood and Urine
We have developed a sensitive assay based on the ORIGEN electrochemiluminescence technology that is capable of detecting 5 pg/ml prion protein at twice background levels in the presence of plasma. Comparison with other published assay formats indicates that all of the most sensitive assays have similar twice background sensitivities in the presence of plasma. We therefore propose twice background sensitivity as a standard point of comparison between assays. From our infectivity measurements in blood, we deduce that we will need at least 50 fold greater sensitivity to detect endogenous infection-specific prion protein in blood. This can be achieved either by increasing the sensitivity of the assay or concentrating the prion protein before assay.
Our assay development efforts have utilized our laboratory’s quantitative model for blood-borne TSE infectivity in hamsters as well as naturally infected blood from scrapie infected sheep. Infected sheep blood can be obtained in 500 ml quantities equal to those in a human blood donation. This has enabled us to explore several methods of concentrating the prion protein from human scale blood collections prior to assay including precipitants, immuno-affinity, and synthetic ligand-affinity capture methods.
A blood-based diagnostic must also be capable of discriminating infection-specific prion protein from a >10,000 fold excess of native prion protein. We have been exploiting the ORIGEN assay to characterize and optimized protease digestion conditions, differential separation methods, and a novel immunological method.
Urine would be an ideal substrate for TSE diagnosis but initial reports of infection-specific prion protein in urine have proved to be an artifact. However, it is now claimed that urine contains TSE infectivity. We are attempting to verify this claim by applying the same highly sensitive and precise methods that we have developed for assaying TSE infectivity in blood to urine.
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please see full report 90 pages with abstracts here ;
http://cdmrp.army.mil/nprp/NPRP08_Summit_Final_Report_7_2_08.pdf
The National Prion Research Program (NPRP) Congressionally Directed Medical Research Programs
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Prion disease in sheep, known as scrapie, has been recognized for centuries and controlled by removing infected animals from herds (culling). When BSE was identified in cattle in the 1980s, it was also controlled by culling infected animals. Prion diseases in humans are relatively rare. The incidence of CJD in humans is about 1 in 1 million; about 10% of such cases are inherited. However, the potential impact of prion diseases on human health was greatly magnified by the recognition that the transfer of BSE in cows to humans by beef ingestion resulted in vCJD. Changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, but there is concern that CWD of free-ranging deer in the United States might be transferred from deer to humans through venison consumption. Whether BSE and CWD represent a transfer of scrapie in sheep to cows and deer or are newly arisen prion diseases is unknown. The possible transmission of prion disease through other food animals also cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. It is possible that an unknown number of asymptomatic individuals are infected with vCJD from BSE, CWD, or scrapie. This potential threat to blood and plasma supplies is of great concern to both civilian and military health professionals.
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http://cdmrp.army.mil/pubs/pips/nppip.pdf
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES TERRORISM AND OTHER PUBLIC HEALTH EMERGENCIES
http://www.swt.usace.army.mil/library/Terrorism%20and%20Other%20Health%20Emergencies/HHSMedisReferenceGuideFinal.pdf
Headquarters Department of the Army Washington, DC 6 May 2009 Safety Safety Standards for Microbiological and Biomedical Laboratories *Department of the Army Pamphlet 385–69
http://www.army.mil/usapa/epubs/pdf/p385_69.pdf
USAF GUIDELINES FOR INFECTION CONTROL IN DENTISTRY APRIL 2010
http://airforcemedicine.afms.mil/idc/groups/public/documents/afms/ctb_109794.pdf
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas
Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas.She left 6 Kids and a Husband.The Purpose of this web is to give information in Spanish to the Hispanic community, and to all the community who want's information about this terrible disease.-
Physician Discharge Summary, Parkland Hospital, Dallas Texas Admit Date: 12/29/2009
Discharge Date: 1/20/2010
Attending Provider: Greenberg, Benjamin Morris;
General Neurology Team:
General Neurology Team Linda was a Hispanic female with no past medical history presents with 14 months of incresing/progressive altered mental status, generalized weakness, inability to walk, loss of appetite, inability to speak, tremor and bowel/blader incontinence.She was, in her usual state of health up until February, 2009, when her husbans notes that she began forgetting things like names and short term memories. He also noticed mild/vague personality changes such as increased aggression. In March, she was involved in a hit and run MVA,although she was not injured. The police tracked her down and ticketed her. At that time, her son deployed to Iraq with the Army and her husband assumed her mentation changes were due to stress over these two events. Also in March, she began to have weakness in her legs, making it difficult to walk. Over the next few months, her mentation and personality changes worsened, getting to a point where she could no longer recognized her children. She was eating less and less. She was losing more weight. In the last 2-3 months, she reached the point where she could not walk without an assist, then 1 month ago, she stopped talking, only making grunting/aggressive sounds when anyone came near her. She also became both bowel and bladder incontinent, having to wear diapers. Her '"tremor'" and body jerks worsened and her hands assumed a sort of permanent grip position, leading her family to put tennis balls in her hands to protect her fingers. The husband says that they have lived in Nebraska for the past 21 years. They had seen a doctor there during the summer time who prescribed her Seroquel and Lexapro, Thinking these were sx of a mood disorder. However, the medications did not help and she continued to deteriorate clinically. Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. The husband says that he does not know any fellow workers with a similar illness. He also says that she did not have any preceeding illness or travel.
http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
please see full text ; Monday, March 29, 2010 Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas
http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.html
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html
Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)
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[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
14th International Congress on Infectious Diseases H-type and L-type Atypical BSE January 2010 (special pre-congress edition)
18.173 page 189
Experimental Challenge of Cattle with H-type and L-type Atypical BSE
A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H. Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany, 2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch, Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy Secretariat, Ottawa, Canada
Background: After the detection of two novel BSE forms designated H-type and L-type atypical BSE the question of the pathogenesis and the agent distribution of these two types in cattle was fully open. From initial studies of the brain pathology, it was already known that the anatomical distribution of L-type BSE differs from that of the classical type where the obex region in the brainstem always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved.
Methods:We performed intracranial inoculations of cattle (five and six per group) using 10%brainstemhomogenates of the two German H- and L-type atypical BSE isolates. The animals were inoculated under narcosis and then kept in a free-ranging stable under appropriate biosafety conditions.At least one animal per group was killed and sectioned in the preclinical stage and the remaining animals were kept until they developed clinical symptoms. The animals were examined for behavioural changes every four weeks throughout the experiment following a protocol that had been established during earlier BSE pathogenesis studies with classical BSE.
Results and Discussion: All animals of both groups developed clinical symptoms and had to be euthanized within 16 months. The clinical picture differed from that of classical BSE, as the earliest signs of illness were loss of body weight and depression. However, the animals later developed hind limb ataxia and hyperesthesia predominantly and the head. Analysis of brain samples from these animals confirmed the BSE infection and the atypical Western blot profile was maintained in all animals. Samples from these animals are now being examined in order to be able to describe the pathogenesis and agent distribution for these novel BSE types. Conclusions: A pilot study using a commercially avaialble BSE rapid test ELISA revealed an essential restriction of PrPSc to the central nervous system for both atypical BSE forms. A much more detailed analysis for PrPSc and infectivity is still ongoing.
http://www.isid.org/14th_icid/
http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf
http://www.isid.org/publications/ICID_Archive.shtml
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
International Society for Infectious Diseases Web: http://www.isid.org
http://bse-atypical.blogspot.com/2010/01/14th-international-congress-on.html
Sunday, February 14, 2010
[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)
http://bseusa.blogspot.com/2010/02/docket-no-fsis-2006-0011-fsis-harvard.html
http://transmissiblespongiformencephalopathy.blogspot.com/2010/02/transmissible-spongiform-encephalopathy.html
TSE
please read Senate 'Down Under' link at bottom of the following url ;
http://transmissiblespongiformencephalopathy.blogspot.com/
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2
please see full text ;
Monday, April 5, 2010
UPDATE - CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://prionunitusaupdate2008.blogspot.com/2010/04/update-cjd-texas-38-year-old-female.html
Wednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html
Sunday, March 28, 2010
Nor-98 atypical Scrapie, atypical BSE, spontaneous TSE, trade policy, sound science ?
http://nor-98.blogspot.com/2010/03/nor-98-atypical-scrapie-atypical-bse.html
*****URGENT NOTE HERE ABOUT OIE AND THEIR JUNK SCIENCE ABOUT ATYPICAL BSE*****
Wednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html
CJD SURVEILLANCE TEXAS
http://cjdtexas.blogspot.com/2007/12/creutzfeldt-jakob-disease-surveillance.html
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
http://bse-atypical.blogspot.com/2006/08/bse-atypical-texas-and-alabama-update.html
Friday, May 14, 2010
Prion Strain Mutation Determined by Prion Protein Conformational Compatibility and Primary Structure
Published Online May 13, 2010 Science DOI: 10.1126/science.1187107 Science Express Index
http://chronic-wasting-disease.blogspot.com/2010/05/prion-strain-mutation-determined-by.html
Sunday, April 12, 2009
CWD UPDATE Infection Studies in Two Species of Non-Human Primates and one Environmental reservoir infectivity study and evidence of two strains
http://chronic-wasting-disease.blogspot.com/2009/04/cwd-update-infection-studies-in-two.html
Epidemiology of Chronic Wasting Disease: PrPres Detection, Shedding, and Environmental Contamination
1. REPORT DATE 1 August 2009
snip...
EXECUTIVE SUMMARY
Obviously the most important goal is to develop an extremely sensitive assay for the infective prion protein. We have made substantial progress since the start of the grant period but are still short of the goal. In a continuation of the proteomics work initiated last year we identified several candidate proteins that are found in urine of infected deer but not in uninfected controls. For some of these we were able to find antibodies and have confirmed the presence of three of these proteins over time using the samples that have been collected for deer over the infection period. Preliminary results indicate that the levels of the proteins increase during the infection period. We have started optimizing the assays on several of the proteins.
As this is a final report I will not reiterate the details presented in the past five years of the grant. However, I will summarize the results and total the publications etc. We are also in the process of filing a patent disclosure on the biomarker proteins we have identified.
INTRODUCTION
Chronic wasting disease (CWD) of deer (Odocoileus spp.) and elk (Cervus elaphus) is unique among the transmissible spongiform encephalopathies (TSEs) in that it occurs in free-ranging as well as captive wild ruminants and environmental contamination appears to play a significant role in maintenance of the disease. The precise modes of transmission of CWD are not known although we have shown that horizontal transmission and environmental contamination associated with excreta and carcasses may occur (Miller et al., 2004). But maternal transmission does not appear to play a significant role (Miller and Williams, 2003) in maintenance of CWD in cervid populations. Our long-term goal is to better understand the epidemiology of CWD and apply that information to development of strategies for management and control. To that end we are investigating the dynamics and modes of CWD agent shedding from infected mule deer, white-tailed deer, and elk. The approach includes experimentally infecting cervids, serial collections of a variety of biological samples, and assay of these materials by various means to attempt to detect protease resistant prion protein (PrPres). In addition, because of the concern about environmental contamination associated with excreta, we will be collecting and assaying a variety of environmental specimens collected from areas of presumed high, moderate, and low contamination in CWD endemic facilities.
BODY
Aim 1: Develop analytical tools to detect PrPCWD in excreta, blood, and environmental samples.
Biomarker Discovery for Chronic Wasting Disease
Initial Identification of Biomarkers
We have accomplished an extensive analysis of urine from CWD-positive animals. The analysis has identified 11 potential biomarkers, as represented in Table 1. Urine is an ideal source for biomarkers (Aguzzi A, 2004) and we feel strongly that markers found in the urine will also be present in the serum and other tissues of infected animals and our preliminary results are confirming this. The potential protein markers were identified based on their similarity to known proteins from other mammals, since the deer genome sequence has not been characterized. As such, it is imperative that we accurately identify these proteins. We present them here as CWD-1 thru 11 because we are not completely sure of the proteins identity (except where noted) even though we are seeing antibody crossreactivity as will be demonstrated in the following pages. Additionally, several of the proteins have a number of isoforms and we are unsure of which isoform we have identified that we are now seeing in blood and urine samples. Research contained within this proposal will appropriately identify the proteins.
Table 1: The identified potential biomarkers of Chronic Wasting Disease.
Biomarker Possible Physiological Role Summary
CWD-1 Required for a specialized brain endocytosis responsible for generating the synaptic vesicles that store and then release neurotransmitters. Also implicated in Alzheimer’s and early loss of cognitive ability.
CWD-2 Reported roles in cell function, clotting, memory and necrosis. Implicated in Alzheimer’s and its role in cleaving CWD-1 (see above) and is hypothesized to be partly responsible for early loss of cognitive ability.
CWD-3 Molecular chaperone in the eukaryotic cytosol assisting in protein folding.
CWD-4 A protein truncated in some forms of schizophrenia.
CWD-5 Found in Alexander’s disease, a progressive neurological disorder, associated with the destruction of white matter.
CWD-6 Indicator of multi-drug resistance in lung cancer.
CWD-7 A protein scaffold that is involved throughout the cell cycle.
CWD-8 A serine threonine protein kinase involved in mitosis.
CWD-9 Transmembrane protein that plays a critical role in cell adhesion.
CWD-10 Light chain IgG (Serban A, 2004)
CWD-11 An unknown protein that is visibly increased throughout the progression of the disease. Plans for its identification are underway.
Preliminary screening of samples with biomarker antibodies Initially to determine which of the proteins have merit as biomarkers for CWD, we purchased commercially available antibodies against the human or mouse forms of the protein, when available. This predisposes the interpretations to be overly cautious. However, the fact that those proteins for which we were able to obtain antibodies are showing up-regulation, or higher expression, in response to the diseased state strongly suggests we are on the right track. We have not tested some of the biomarkers as commercially available antibodies do not exist for them and we
currently do not have funding to generate those antibodies. So we have 6 markers (CWD 1,2,3,4, 10 and 11) that we have positive preliminary data on and that merit further validation. Given that we developed these protein biomarkers from urine, our initial screens of available proteins focused on urine from both positive and negative animals. Figure 2 shows the potential that these biomarkers hold. Using an off-the-shelf antibody to another species we obtained positive results. Further, we obtained results that show a tendency of the proteins to be increasingly abundant as the disease progresses. Urine is an ideal source of biomarker material in humans, but may prove less than ideal when trying to test for CWD. However, urine has been identified as an acceptable medium for the development of diagnostic tools (Aguzzi A, 2004).
Densitometry on the western blot of CWD-1 tested in urine shows a significant trend for the biomarker to be quantifiably higher as the disease progresses (Figure 3A). Figure 3B illustrates that there are still potential biomarkers to be discovered. Although it is beyond the scope of this grant to identify this potential marker, their existence helps to define the potential that protein biomarkers have in diagnosing CWD. All western blot results shown were performed on 10X concentrated urine. Recent analysis indicates that we can indeed detect the markers in unconcentrated urine (Figure 4). Further, the biomarkers can be observed and demonstrate a quantifiable difference throughout the disease state.
Testing in feces was undertaken as another means by which to indicate disease. Some preliminary successes were accomplished (data not shown). However, fecal samples have proved very difficult to analyze. Given that CWD is the only one of the TSE diseases that lends itself to being monitored through feces, we have not chosen to continue this line of research. Serum and urine are far more useful when applied to human TSE’s and the TSE’s that are known to affect humans, which CWD does not.
Further diversification of the medium of detection to serum broadens the capability of the biomarkers. We have met with limited success in this endeavor largely due to the non specific nature of the antibodies. One clear success on this front is CWD-4 (which according to literature should be represented by a 100kDa and 75kDa band), which is visible at appropriate molecular weights (Figure 5) in the infected animal and clearly less prevalent in the non-infected animals.
We are basing our premise that these will be good biomarkers for the disease on the fact that even with the imperfect antibodies and conditions, we are seeing the protein(s) in the infected animals at well above background levels as the disease progresses in the urine, serum and feces. Perhaps most importantly, we see signal above background very early in the infection.
Preliminary Results Summary
Results obtained thus far are very promising but underscore the need to develop species specific antibodies. The different and complex mediums in which we are testing require specific antibodies if these biomarkers are ever to be used to develop a quick, ante mortem test.
The different TSE diseases lend themselves to detection via biomarkers in different mediums. It is not very efficient to collect urine from wild animals within wild populations such is the case in CWD. As well, blood and serum work well for BSE in the feedlot or slaughter house but urine would seem to be the easiest medium of detection in CJD or vCJD. In both of these mediums we have had success in detecting the markers. The limiting factor is non-specificity to the species. Having multiple biomarkers would allow a testing format that would not rely on a single marker, thus reducing the possibility of getting false positive or negative results. A multiple marker format would also alleviate the argument raised against the use of ESM as an indicator of TSE disease, which is that different individuals have varying levels of transcript (Glock B, 2003) As with all biomarkers there is the potential that the markers may be abundant in other states than the disease of interest. However, a multiple marker format would alleviate that concern. In our proposed system only having one marker indicate positive would not be a positive result. It would require more than one of the markers to indicate the presence of the disease with certainty. Further, our proposed method of utilizing the known light chain IgG (CWD-10) as a fail-safe control alleviates that concern that one marker is insufficient to diagnose the diseased state. With specific antibodies we can determine not only which of the biomarkers are amenable to detection but if they are preferentially detected in one medium and not another.
Given that our laboratory has an extensive library of CWD infected tissues in addition to the facilities and equipment required, we are proposing to develop the biomarkers further using CWD as our TSE of choice. We do expect to be able to test the relevance of our biomarkers in other TSE diseases, but that is beyond the scope of this grant. It is our goal to establish which of the biomarkers, when specific antibodies are used for detection, are useful for confirming the disease. As well, we will establish which biomarkers are useful when applied to urine or serum. With that information we can then develop a test format that will quickly and accurately diagnose the presence of CWD.
KEY RESEARCH ACCOMPLISHMENTS
Determined that high sensitivity detection of the prion protein cannot be accomplished with out sacrificing both false negative and positive results. Confirmed difficulties reported by others with all of the amplification methods, particularly the false positives, which obviate their standard use for detection. Identified several proteins that can serve as biomarkers for detection of CWD in live animals from both urine and serum. Aim 2. Evaluate multiple biological samples collected from experimentally infected mule deer, white-tailed deer, and elk throughout the CWD incubation period.
KEY RESEARCH ACCOMPLISHMENTS
• CWD infections established, confirmed, and monitored to terminus in mule deer and white-tailed deer and elk. • Serial samples of excreta collected from throughout the disease course from both mule deer and white-tailed deer and elk are available for analysis of prion shedding patterns. • Genetic influences on disease course in infected white-tailed deer and elk demonstrated, affording opportunities to evaluate the influence of genotype on agent shedding. • Archived materials shared with other laboratories to advance overall progress on developing sensitive assays for prion detection in blood and excreta, investigating potential routes of prion shedding in deer and elk, and exploring patterns of prion shedding during the disease course. Aim 3. The goal of this Aim is to determine if PrPres can be detected in samples collected from facilities contaminated with the CWD agent.
KEY RESEARCH ACCOMPLISHMENTS
• CWD infections established and confirmed in mule deer and white-tailed deer. • PrPCWD demonstrated in tonsil and rectal mucosa biopsies from infected mule deer and white-tailed deer.
• Clinical CWD demonstrated in experimentally infected mule deer and white-tailed deer. • Archived materials shared with other laboratories to advance overall progress on developing sensitive assays for prion detection in blood.
PUBLICATIONS ARISING FROM GRANT WORK
(2007) Chang, B., X. Cheng, S. Yin, T. Pan, H. Zhang, P. Wong, S.-C. Kang, F. Xiao, H. Yan, C. Li, L. L. Wolfe, M. W. Miller, T. Wisniewski, M. I. Greene, and M.-S. Sy.. Test for detection of disease-associated prion aggregate in the blood of infected but asymptomatic animals. Clinical and Vaccine Immunology 14:36-43.
(2007) Wolfe, L. L., T. R. Spraker, L. González, M. P. Dagleish, T. M. Sirochman, J. C. Brown, M. Jeffrey, & M. W. Miller. PrPCWD in rectal lymphoid tissue of deer (Odocoileus spp.). Journal of General Virology 88: 2078-2082.
(2008) Benjamin D. Brooks, Amy E. Albertson, Justin A. Jones, Jonathan O. Speare, Randolph V. Lewis, Efficient screening of high-signal and low-background antibody pairs in the bio-bar code assay using prion protein as the target, Analytical Biochemistry 382: 60-62.
(2009) Brooks, Benjamin and Lewis, Randolph V. Identification of Problems Developing an Ultrasensitive Immunoassay for the Ante Mortem Detection of the Infectious Isoform of the CWD-Associated Prion Protein, Journal of Immunoassay and Immunochemistry, 30: 135– 139.
OTHER COLLABORATIONS ARISING FROM GRANT WORK
Surplus samples collected in the course of investigations supported by this grant have been shared with at least three other collaborating institutions (Rocky Mountain Laboratories, NIHNIAID; Case Western Reserve University; Institute for Neurodegenerative Diseases, University of California, San Francisco) in the hopes of advancing scientific understanding of CWD in particular and prion diseases in general. Other similar collaborative endeavors will be supported as feasible using materials arising from our work.
http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA511155&Location=U2&doc=GetTRDoc.pdf
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease
2008 1: Vet Res. 2008 Apr 3;39(4):41
A prion disease of cervids: Chronic wasting disease
Sigurdson CJ.
snip...
*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,
snip...
full text ;
http://chronic-wasting-disease.blogspot.com/2008/04/prion-disease-of-cervids-chronic.html
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To:
Cc: "Race, Richard (NIH)" ; ; "Belay,
Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was
attached to your email), we did not say CWD in humans will present like
variant CJD.
That assumption would be wrong. I encourage you to read the whole
article and call me if you have questions or need more clarification
(phone: 404-639-3091). Also, we do not claim that "no-one has ever been
infected with prion disease from eating venison." Our conclusion stating
that we found no strong evidence of CWD transmission to humans in the
article you quoted or in any other forum is limited to the patients we
investigated.
Ermias Belay, M.D.
Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: rr26k@nih.gov; rrace@niaid.nih.gov; ebb8@CDC.GOV
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG
HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
SEE also ;
A. Aguzzi - Chronic Wasting Disease (CWD) also needs to be addressed. Most
serious because of rapid horizontal spread and higher prevalence than BSE in
UK, up to 15% in some populations. Also may be a risk to humans - evidence
that it is not dangerous to humans is thin.
http://www.tseandfoodsafety.org/activities/bse_conference_basel_april_02/2summar
SNIP...END...TSS
Chronic Wasting Disease and Potential Transmission to Humans
Ermias D. Belay,* Ryan A. Maddox,* Elizabeth S. Williams,? Michael W. Miller,? Pierluigi Gambetti,§ and Lawrence B. Schonberger*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; ?University of Wyoming, Laramie, Wyoming, USA; ?Colorado Division of Wildlife, Fort Collins, Colorado, USA; and §Case Western Reserve University, Cleveland, Ohio, USA
Suggested citation for this article: Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. Chronic wasting disease and potential transmission to humans. Emerg Infect Dis [serial on the Internet]. 2004 Jun [date cited]. Available from:
http://www.cdc.gov/ncidod/EID/vol10no6/03-1082.htm
----------------------------------------------------------
Chronic wasting disease (CWD) of deer and elk is endemic in a tri-corner area of Colorado, Wyoming, and Nebraska, and new foci of CWD have been detected in other parts of the United States. Although detection in some areas may be related to increased surveillance, introduction of CWD due to translocation or natural migration of animals may account for some new foci of infection. Increasing spread of CWD has raised concerns about the potential for increasing human exposure to the CWD agent. The foodborne transmission of bovine spongiform encephalopathy to humans indicates that the species barrier may not completely protect humans from animal prion diseases. Conversion of human prion protein by CWD-associated prions has been demonstrated in an in vitro cell-free experiment, but limited investigations have not identified strong evidence for CWD transmission to humans. More epidemiologic and laboratory studies are needed to monitor the possibility of such transmissions.
snip...full text ;
http://www.cdc.gov/ncidod/EID/vol10no6/03-1082.htm
Volume 12, Number 10-October 2006
Research
Human Prion Disease and Relative Risk Associated with Chronic Wasting Disease
Samantha MaWhinney,* W. John Pape,? Jeri E. Forster,* C. Alan Anderson,?§ Patrick Bosque,?¶ and Michael W. Miller#
*University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA; ?Colorado Department of Public Health and Environment, Denver, Colorado, USA; ?University of Colorado School of Medicine, Denver, Colorado, USA; §Denver Veteran's Affairs Medical Center, Denver, Colorado, USA; ¶Denver Health Medical Center, Denver, Colorado, USA; and #Colorado Division of Wildlife, Fort Collins, Colorado, USA
Suggested citation for this article
The transmission of the prion disease bovine spongiform encephalopathy (BSE) to humans raises concern about chronic wasting disease (CWD), a prion disease of deer and elk. In 7 Colorado counties with high CWD prevalence, 75% of state hunting licenses are issued locally, which suggests that residents consume most regionally harvested game. We used Colorado death certificate data from 1979 through 2001 to evaluate rates of death from the human prion disease Creutzfeldt-Jakob disease (CJD). The relative risk (RR) of CJD for CWD-endemic county residents was not significantly increased (RR 0.81, 95% confidence interval [CI] 0.40-1.63), and the rate of CJD did not increase over time (5-year RR 0.92, 95% CI 0.73-1.16). In Colorado, human prion disease resulting from CWD exposure is rare or nonexistent. However, given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated.
snip... full text ;
http://0-www.cdc.gov.mill1.sjlibrary.org/ncidod/EID/vol12no10/06-0019.htm
full text ;
http://chronic-wasting-disease.blogspot.com/2006_12_01_archive.html
CHRONIC WASTING DISEASE BLOG
http://chronic-wasting-disease.blogspot.com/
Subject: BSE: TIME TO TAKE H.B. PARRY SERIOUSLY
If the scrapie agent is generated from ovine DNA and thence causes disedase in other species, then perhaps, bearing in mind the possible role of scrpaie in CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the notifiable disease. ...
http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1988/06/08004001.pdf
http://scrapie-usa.blogspot.com/2007/12/scrapie-hb-parry-seriously-yb886841.html
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
EMBO reports 4, 5, 530–533 (2003) doi:10.1038/sj.embor.embor827 AOP Published online: 11 April 2003
Widespread PrPSc accumulation in muscles of hamsters orally infected with scrapie
Achim Thomzig, Christine Kratzel, Gudrun Lenz, Dominique Krüger & Michael Beekes
Robert Koch-Institut, P26, Nordufer 20, D-13353 Berlin, Germany
To whom correspondence should be addressed Michael Beekes Tel: +49 30 4547 2396; Fax: +49 30 4547 2609; BeekesM@rki.de
Received 13 February 2003; Accepted 13 March 2003; Published online 11 April 2003.
Abstract
Scrapie, bovine spongiform encephalopathy and chronic wasting disease are orally communicable, transmissible spongiform encephalopathies (TSEs). As zoonotic transmissions of TSE agents may pose a risk to human health, the identification of reservoirs for infectivity in animal tissues and their exclusion from human consumption has become a matter of great importance for consumer protection. In this study, a variety of muscles from hamsters that were orally challenged with scrapie was screened for the presence of a molecular marker for TSE infection, PrPSc (the pathological isoform of the prion protein PrP). Sensitive western blotting revealed consistent PrPSc accumulation in skeletal muscles from forelimb and hindlimb, head, back and shoulder, and in tongue. Previously, our animal model has provided substantial baseline information about the peripheral routing of infection in naturally occurring and orally acquired ruminant TSEs. Therefore, the findings described here highlight further the necessity to investigate thoroughly whether muscles of TSE-infected sheep, cattle, elk and deer contain infectious agents.
EMBO reports 4, 5, 530–533 (2003) doi:10.1038/sj.embor.embor827 AOP Published online: 11 April 2003
http://www.nature.com/embor/journal/v4/n5/full/embor827.html
snip...
Greetings,
Unusual event if you consider the officials hypothisis that Nor-98 atypical scrapie is a spontaneous event. seems there was a great deal of spontaneous mutations for the this time period ;-)...TSS
Atypical Nor-98 states in this report for January 2010 include ; Maine, Pennsylvania, Ohio, and Oregon
kind regards, terry
Monday, December 14, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
hmmm, this is getting interesting now...
Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,
see also ;
All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.
http://cjdusa.blogspot.com/2009/09/co-existence-of-scrapie-prion-protein.html
see full text ;
Monday, December 14, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
http://nor-98.blogspot.com/2009/12/similarities-between-forms-of-sheep.html
Sent: Friday, April 16, 2010 11:38 AM Subject: PRO-MED ATYPICAL SCRAPIE
Background ----------- "Retrospective studies have identified cases predating the initial identification of this form of scrapie, and epidemiological studies have indicated that it does not conform to the behaviour of an infectious disease, giving rise to the hypothesis that it represents spontaneous disease. However, atypical scrapie isolates have been shown to be infectious experimentally, through intracerebral inoculation in transgenic mice and sheep. [Many of the neurological diseases can be transmitted by intracerebral inoculation, which causes this moderator to approach intracerebral studies as a tool for study, but not necessarily as a direct indication of transmissibility of natural diseases. - Mod.TG]
"The 1st successful challenge of a sheep with 'field' atypical scrapie from an homologous donor sheep was reported in 2007.
"Results -------- "This study demonstrates that atypical scrapie has distinct clinical, pathological, and biochemical characteristics which are maintained on transmission and sub-passage, and which are distinct from other strains of transmissible spongiform encephalopathies in the same host genotype.
"Conclusions ------------ Atypical scrapie is consistently transmissible within AHQ homozygous sheep, and the disease phenotype is preserved on sub-passage."
Lastly, this moderator wishes to thank Terry Singletary for some of his behind the scenes work of providing citations and references for this posting. - Mod.TG]
The HealthMap/ProMED-mail interactive map of Australia is available at
http://www.promedmail.org/pls/otn/f?p=2400:1001:962575216785367::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,81729
please see full text ;
Sunday, April 18, 2010
SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010
http://scrapie-usa.blogspot.com/2010/04/scrapie-and-atypical-scrapie.html
NOW WHAT ABOUT THE INFAMOUS AUGUST 4, 1997 PARTIAL AND VOLUNTARY MAD COW FEED BAN ???
nothing but ink on paper $$$
Monday, April 5, 2010
Update on Feed Enforcement Activities to Limit the Spread of BSE April 5, 2010
http://madcowfeed.blogspot.com/2010/04/update-on-feed-enforcement-activities.html
Terry S. Singeltary Sr. (Submitted question): Monday, March 1, 2010
ANIMAL PROTEIN I.E. MAD COW FEED IN COMMERCE A REVIEW 2010
http://madcowfeed.blogspot.com/2010/03/animal-protien-ie-mad-cow-feed-in.html
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
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PRODUCT Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007 CODE Cattle feed delivered between 01/12/2007 and 01/26/2007 RECALLING FIRM/MANUFACTURER Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007. Firm initiated recall is ongoing. REASON Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE 42,090 lbs.
DISTRIBUTION WI
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Terry S. Singeltary Sr. (Submitted question):
PRODUCT Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007 CODE The firm does not utilize a code - only shipping documentation with commodity and weights identified. RECALLING FIRM/MANUFACTURER Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete. REASON Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not b Terry S. Singeltary Sr. (Submitted question): Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
http://www.fda.gov/bbs/topics/enforce/2007/ENF00996.html
NEW URL
http://www.fda.gov/Safety/Recalls/EnforcementReports/2007/ucm120446.htm
Terry S. Singeltary Sr. (Submitted question): Monday, March 8, 2010
UPDATE 429,128 lbs. feed for ruminant animals may have been contaminated with prohibited material Recall # V-258-2009
http://madcowfeed.blogspot.com/2010/03/update-429128-lbs-feed-for-ruminant.html
see canine spongiform encephalopathysee full text, and be sure to read the BSE Inquiry documents toward the bottom ;
http://caninespongiformencephalopathy.blogspot.com/2010/03/canine-spongiform-encephalopathy-aka.html
http://caninespongiformencephalopathy.blogspot.com/
Thursday, March 19, 2009
MILLIONS AND MILLIONS OF POUNDS OF MAD COW FEED IN COMMERCE USA WITH ONGOING 12 YEARS OF DENIAL
http://madcowfeed.blogspot.com/2009/03/millions-and-millions-of-pounds-of-mad.html
Friday, April 23, 2010
Upcoming BSE Webinar on Thursday, April 22, 2010 a review
http://bseusa.blogspot.com/2010/04/upcoming-bse-webinar-on-thursday-april.html
CJD USA RISING, with UNKNOWN PHENOTYPE ;
5 Includes 41 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 46 cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
my comments to PLosone here ;
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd
Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html
WHY does the O.I.E. recognize the U.S.A. and all of North America as a BSE controled risk, even though the G.A.O. and the O.I.G repeatedly reported of the failures and flaws of not only the BSE surveillance program in the USA, also the ruminant feed ban of August 4, 1997, where it still fails today in 2010 ?
Wednesday, April 28, 2010
BSE, Scrapie, CWD, REPORT OF THE MEETING OF THE OIE TERRESTRIAL ANIMAL HEALTH STANDARDS COMMISSION Paris, 8-12 February 2010
REPORT OF THE MEETING OF THE OIE TERRESTRIAL ANIMAL
http://usdameatexport.blogspot.com/2010/04/bse-scrapie-cwd-report-of-meeting-of.html
Tuesday, May 11, 2010
Current risk of iatrogenic Creutzfeld-Jakob disease in the UK: efficacy of available cleaning chemistries and reusability of neurosurgical instruments
http://creutzfeldt-jakob-disease.blogspot.com/2010/05/current-risk-of-iatrogenic.html
Thursday, May 06, 2010
Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus
Published online before print May 5, 2010 (Neurology 2010, doi:10.1212/WNL.0b013e3181e39703)
Received November 10, 2009 Accepted March 9, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/05/sporadic-creutzfeldt-jakob-disease.html
WHO WILL WATCH THE CHILDREN FOR CJD OVER THE NEXT 5 + DECADES ???
For 4+ years, dead stock downer cows, the most high risk cattle for mad cow type disease, and other deadly pathogens, were fed to our kids, via the NSLP and the USDA all across our Nation.
Do you actually believe that the USDA et al jumped in on the law suit against Westland/Hallmark, at the time the largest beef recall in USA history, just because a few animals were abused on a video, or to cover their ass, for letting our children, from school district to school district, from state to state, be fed dead stock downer cows.
>>> In the papers, the government alleges the meatpacking plant slaughtered and processed downer cows for nearly four years - from January 2004 to September 2007 - at the average rate of one every six weeks... <<<
http://downercattle.blogspot.com/2009/09/suit-meatpacker-used-downer-cows-for-4.html
Do you actually believe all these schools recalled this meat because of a few cattle being abused, see list ;
FNS All Regions Affected School Food Authorities By State United States Department of Agriculture Food and Nutrition Service National School Lunch Program March 24, 2008 School Food Authorities Affected by Hallmark/Westland Meat Packing Co. Beef Recall February 2006 - February 2008
http://www.fns.usda.gov/fns/safety/Hallmark-Westland_byState.pdf
IF url does not work above, go to this link to find out if any of your children and their school were part of this recall ;
go to this site ;
http://www.fns.usda.gov/fns/
left hand corner search ;
Hallmark/Westland Meat Packing Co. Beef Recall your should get this ;
http://65.216.150.153/texis/search?pr=FNS
1 through 1 of 1 matching documents, best matches first. sort by date 1: Hallmark - Westland SFA Reporting by State - 3-24-2008.xls Lunch Program March 24, 2008 School Food Authorities Affected by Hallmark/Westland Meat Packing Co. Beef Recall February 2006 - February 2008 The U.S. Department of Agriculture ...
http://www.fns.usda.gov/...ety/Hallmark-Westland_byState.pdf
PLEASE SEE ALSO ; Members of The HSUS are also concerned about the meat products provided to their children through the National School Lunch Program. More than 31 million school children receive lunches through the program each school day. To assist states in providing healthful, low-cost or free meals, USDA provides states with various commodities including ground beef. As evidenced by the HallmarkNVestland investigation and recall, the potential for downed animals to make their way into the National School Lunch Program is neither speculative nor hypothetical.
http://biotech.law.lsu.edu/cases/FDA/hsus-v-schafer-usda-complaint.pdf
some history on dead stock downers in the USA ;
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...
http://web.archive.org/web/20030516051623/http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
TME
http://transmissible-mink-encephalopathy.blogspot.com/2009/07/transmissible-mink-encephalopathy.html
http://transmissible-mink-encephalopathy.blogspot.com/2007/12/phenotypic-similarity-of-transmissible.html
http://transmissible-mink-encephalopathy.blogspot.com/
Monday, April 12, 2010
Senator Kay Bailey Hutchison says NO to safer food and S. 510 FDA Food Safety Modernization Act of 2009
http://fdafailedus.blogspot.com/2010/04/senator-kay-bailey-hutchison-says-no-to.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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