Introduction to BSE

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[Note from poster: With all the info flying around about the meat recall, downer cattle, and BSE, I thought it might be helpful for a refresher course on what BSE is. FYI, this came from a meat industry website, but it is informative nonetheless.] Copied from: http://nationalrenderers.org/ AN INTRODUCTION TO BOVINE SPONGIFORM ENCEPAHLOPATHY(BSE) AND THE PRION DISEASES: A QUESTION-ANSWER FORMAT AND REFERENCE Don A. Franco, DVM, MPH, DVPMFormer Vice President, Scientific Services, National Renderers AssociationPresident, Animal Protein Producers

Industry What is BSE? Bovine spongiform encephalopathy (BSE) commonly called "mad cow disease" is a sub-acute neurodegenerative transmissible spongiform encephalopathy first diagnosed and described in Great Britain in November 1986 as an entirely new disease entity in cattle. The disease belongs to a group of other transmissible spongiform encephalopathies (TSEs) in animals and man that are always fatal. What are the other TSEs? In animals: scrapie (sheep and goats); chronic wasting disease (CWD) of deer and elk; transmissible mink encephalopathy (TME) and feline spongiform encephalopathy (FSE) in domestic cats. In humans:

Creutzfeldt-Jakob disease (CJD); kuru (restricted to Papua New Guinea); Gerstmann-Straussler-Scheinker syndrome; fatal familial insomnia (FFI); and variant Creutzfeldt-Jakob disease (first identified in the United Kingdom as a result of transmission of the BSE infectious agent to humans). What is the cause of BSE? The cause of BSE continues to be debated in research and academic circles and remains to be fully validated and accepted universally. The compelling consensus is that the disease is caused by a prion, a rather novel addition to the world of pathogens, and not typical of infectious agents. It (the prion) was first described by Stanley Prusiner of the University of California, San Francisco, who was awarded the Nobel Prize in Medicine in 1997 for his work. What is a prion? A prion or the prion protein (PrP) is a normal cell protein found on nerve cell membranes, therefore, a natural component of nervous tissue. Its finding and original description by Prusiner and associates is the result of extensive research in the transmissible spongiform encephalopathies (TSEs), prototyped by attempts to find the cause of scrapie. Since the infectious agent of scrapie possessed unusual and defying characteristics, especially its resistance to reagents such as formalin and ionizing radiation, thus casting doubt on the long held hypothesis that the disease (scrapie) was caused by a virus, even a non-conventional or "slow" virus. This, then, provided the needed impetus for the ultimate discovery of the prion as the likely causative agent of BSE, and all TSEs, for that matter. What are the properties of the prion? 1. Prions like viruses "multiply" but their properties, structures, and modes of replication appear to be basically different. 2. Unlike viruses, prions contain little or no nuclei acid. 3. Resistance to physical and chemical treatments that inactivate conventional viruses e.g. formalin and ionizing radiation (they retain infectivity for many months in 10% - 12% formalin). 4. No evidence of an immune or inflammatory response. 5. Presence of an amyloid protein, scrapie-associated fibril (SAF). 6. They tolerate a wide range of pH, between 2.5 to

10.5. 7. They are resistant to the action of several enzymes. How does the prion cause disease? Every disease producing infectious organism prior to the advent of prions followed certain basic "rules" in the transmission of disease. They were dependent on nuclei acid for reproduction. The prion, however, can be considered an unconventional infectious agent and does not conform to the traditions of microbiology and disease transmission as exemplified by the bacteria, viruses, and other infectious agents. In essence, we must try to understand the prion concept with an open mind, since it is still being debated in spite of convincing evidence of its role in the transmissible spongiform encephalopathies. The brain makes normal prion protein (PrP), in actuality, continuously, however, the normal prion protein sometimes changes to a disease form and all prion diseases appear to be diseases of protein folding and protein interaction. In essence, the formation of PrP or protease-resistant protein is nothing more than a folding of the normal protein in a different or abnormal pattern, theorizing that the infectious agent of BSE (and all other TSEs) is an abnormal protein. In most of the prion diseases, protease-resistant PrP can be demonstrated either by immunohistochemical identification of PrP amyloid or by immunoblotting of brain homogenates. What are the main characteristics of the transmissible spongiform encephalopathies (TSEs) or prion diseases? 1. Slow, fatal, transmissible diseases of the central nervous

system. 2. Occur in a variety of mammals including humans. 3. They can be experimentally transmitted to rodents. 4. After the initial "infection," the disease can take from months to decades to appear. 5. "Infections" can occur from inoculation or ingestion (the proposed hypothesis suggesting the origin of BSE in the United Kingdom was likely a feed-borne contamination associated with the inclusion of meat and bone meal in cattle rations, possibly carrying the scrapie infectious agent). 6. The TSEs are always fatal and there is currently no sensitive pre-clinical diagnostic test available or effective treatment for any of the diseases. 7. The exact nature of the infectious agent remains unclear and in need of "final" validation beyond the prevailing consensus that it is a prion. 8. It is very possible that a co-factor may be associated with all prion diseases. The most important aspect of scrapie in sheep and BSE in cattle is that they are both prion diseases. In spite of that significant factor, there are many distinct differences. Scrapie, since it was first clinically described in the early 1700s, has been used as the prototype of the transmissible spongiform encephalopathies (TSEs) in research, and in making comparisons with the other evolving encephalopathies. But, there are other distinct differences. In naturally infected sheep with scrapie, the infectious agent is found early in the lymphoreticular system (lymph nodes, spleen, tonsils), nasal mucosa

and intestine; later in the central nervous system (brain and spinal cord) and placenta. Outside of the dorsal ileum in cattle with BSE, the distribution of infection is in nervous tissue (caudal medulla, spinal cord, dorsal root ganglia, trigeminal ganglia, and the frontal cortex). Scrapie has never been proven to be associated with disease causation in humans while there is compelling epidemiological and research evidence that BSE has a linkage to the variant-Creutzfeldt-Jakob disease (v-CJD) first described in the United Kingdom in 1996. Research evidence also indicates that the infectious agent of scrapie and BSE is not the same. What is the United States Department of Agriculture (USDA) doing about controlling scrapie? The Animal and Plant

Health Inspection Service (APHIS), USDA, is actively pursuing a Scrapie Eradication Uniform Methods and Rules (UMR) as cooperative procedures and standards with Consistent States for controlling and eradicating scrapie. The UM & R provides the minimum program standards and procedures for the Cooperative State-Federal-Industry Scrapie Program. The rule is established to prevent, monitor, control, and eradicate scrapie from domestic sheep and goat flocks, and for maintenance of State status in the Department's scrapie eradication program. This is a positive approach because of the inferences of risk associated with scrapie and the analogy that scrapie may have been a likely contributing factor in the transmission and amplification of BSE in the United Kingdom. What is the origin of BSE? The origin or why the disease

first appeared in the United Kingdom, from a standpoint of genesis, will likely never be known. A very compelling theory, albeit, still a hypothesis, is that the inclusion of meat and bone meal (MBM) from other ruminant processed raw material, with a predominant suggestion that sheep scrapie was a likely factor has been theorized. To date there have been over 180,000 cases in the United Kingdom (U.K.) and about 1400 cases elsewhere in the European Union. This equates to over 99% of all cases being reported in the U.K. The disease's incidence continues to fall rapidly in the U.K. due to stringent controls to combat the disease. In a number of other Member States in the "Union" the disease has shown a sharp increase causing anxiety in the public sector and among government disease control officials. What are the symptoms of

BSE? There is considerable variation in the clinical signs exhibited by cattle. In some instances, the first indication that an animal is affected is observed by the herdsman who notices evidence of changes in behavior exhibited as apprehension and nervousness, especially around doorways. Frenzy is often displayed with changes in sensation and marked sensitivity to touch and noise. Abnormalities of posture and movement, especially low head carriage, hind limb ataxia (failure of muscular coordination), tremors and falling heighten the late neurological signs of the disease. Affected animals have a tendency to lose weight and milk yield is reduced. These signs vary in duration from one to two weeks, but quite often are prolonged up to two months. The

signs are always progressive and end in recumbency (lying down) and death. Does the rendering industry in the United Kingdom have an explanation for the inference or suggested hypothesis that MBM was the factor in transmitting BSE? Several theories have resulted over the years, many associated with point - counter point and lacking in consensus. Some suggestions that have consistently been mentioned as likely contributory are: a marked increase in the total UK sheep population in the late 1970s and early 1980s with a concurrent high incidence of scrapie and the subsequent use of meat and bone meal using infected sheep tissue in the raw material stream for processing; changes from batch cookers to mainly continuous cookers in the rendering process involved lowering of the processing temperatures and a potential for resistance of the infectious

agent (scrapie) to the lowered processing temperature; a discontinuation of the use of solvents for fat extraction caused a decrease in processing time and the inference that together with the lower processing temperature of continuous cooking and a lessening of the time due to the non-use of solvents, the two combined factors were considerate likely causes. The aforementioned changes are obviously coincidental, and devoid of finite proof. There are, however, other husbandry and feeding practices that should be considered contextual to likely cause relevance of BSE in the U.K. There is a tendency due to limited vegetable protein supplements like soybean and corn to include MBM at relatively higher inclusion rates in feed rations in the U.K. and also feeding to calves plenty younger than is customary in the U.S. and most other countries. Also, if the sheep scrapie assumption is indeed valid, the amount of

sheep in the rendering stream would be higher than any other country in the world, except possible Australia and New Zealand and both these countries are considered scrapie-free. REFER TO ATTACHED REFERENCE - THE RENDERING INDUSTRY: A RETROSPECTIVE ANALYSIS OF BSE POLICY. (Feedstuffs, Volume 70, Number 35, August 24, 1998). What is Creutzfeldt-Jakob Disease (CJD)? CJD is the most common of the transmissible spongiform encephalopathies (TSEs) seen in humans and for reasons not fully understood occurs at the rate of one case per million in countries that compile and study health and disease statistics, including the United States. It is considered classical CJD. It is a rapidly progressive fatal disease in which nearly half the affected patients die

within 6 months of clinical manifestations of disease. Most patients develop the disease between 55 and 70 years old, showing signs of memory loss, difficulty in walking, visual disturbances and tremors. The disease occurs in three main forms: 1. Sporadic, affecting about 85% of cases with no proven pattern of disease transmission of the affected patients, in reality, the disease just appears. 2. Familial, occurs in about 5-10% of CJD patients and there is normally a family history and evidence of a genetic association. 3. Iatrogenic (induced by treatment) and has been reported mainly among persons who have received growth hormone therapy derived from the pituitary gland, or dura mater and corneal grafts. What does CJD have to do with BSE? CLASSICAL CJD HAS NOTHING TO DO WITH BSE AND THE CONSUMPTION OF MEAT, EVEN IN THE UNITED KINGDOM AND OTHER COUNTRIES THAT HAVE BSE IN THEIR CATTLE HERDS. What then is the association of BSE with CJD? The association of BSE with CJD involves a hypothesis that originated in the United Kingdom and defined by the Spongiform Encephalopathy Advisory Committee (SEAC) based on an interesting and unusual cluster of 10 cases in unusually young patients with CJD that appeared as a distinct clinical entity with unique symptoms and pathology. The age at onset in the initial 10 cases ranged from 16 to 39 years with an atypically prolonged clinical course that varied from 7.5 - 22.5 months with a median of 12 months. Some of the features of this new

syndrome resembled kuru (a TSE that was limited to the Highlands of Papua New Guinea). This finding was indicative that we were dealing with another challenging syndrome within the world of the transmissible encephalopathies. If these cases, however, as postulated, were a result of transmission of BSE to humans, as seems most likely, but still not firmly validated scientifically, it is still unclear why they should be limited to this age group. Equally troubling is why none of these cases had a pattern or history of unusual occupational or dietary exposure to the infectious agent of BSE through consumption of meat that could contain brain, spinal cord or other nervous tissue that predominantly harbor the agent of infection. Regardless of the debate, this unique new disease called Variant Creutzfeldt-Jakob Disease or V-CJD is the

TSE that is currently associated with BSE. The debate as to the linkage and other related factors will continue because of the obvious complexity of the TSEs, but the association appears to be scientifically sound and reasonable. Is the linkage of BSE and v-CJD really convincing, or is it just another of the hypotheses? v-CJD after a careful assessment and evaluation seems to clearly represent the genesis of a new form of prion disease in the United Kingdom. A review of the epidemiology would clearly demonstrate that the statistical probability of such cases occurring randomly or by chance was exceedingly small and ascertainment bias was very unlikely as an explanation. It was becoming increasingly convincing that a new risk factor, BSE, had emerged and seemed specific for the United Kingdom and the possible causation of v-CJD.

Another significant aspect was that the disease has never appeared in any other country hitherto, and only in a country with reported BSE. The same can affirm other episodes of the disease that have occurred in both France and Northern Ireland, both countries also reporting BSE in their cattle herds, and concurrently v-CJD. Research findings have also strongly affirmed the likely linkage of BSE and v-CJD. What about milk and other dairy products from the cattle industry? There is no evidence to date that the infectious agent or prion is transmitted through milk or any dairy products for that matter. The infectious agent in cattle is predominantly limited to the

brain, spinal cord, and in general nervous tissues. In the early stages, the distal ileum is involved. This has been substantiated by the World Health Organization (WHO) that defined risk in a worst case scenario by stating that milk and other dairy products made from milk, even in countries with a high incidence of BSE can be safely consumed. What is the rendering industry doing as part of the BSE control initiative? The rendering industry long before any regulatory controls were instituted in both the United States and Canada took voluntary proactive measures based on the existing information at the time by excluding sheep (1 year or older) from entering the rendering stream. That policy was implemented in 1989 and remains a practice continued today by many rendering companies because of the inference made by British

epidemiologists that rendered sheep raw material included in the production of meat and bone meal was a likely associative link in the transmission of BSE in the U.K. Since that initial voluntary program, the industry has worked closely with other livestock and agricultural coalitions and collaborated in efforts to be part of the "firewall" to prevent any possible amplification of the infectious agent through feed to cattle. The industry also worked cooperatively with the Food and Drug Administration (FDA) in the formulation of the rule that became effective, August 4, 1997 - "Animal Proteins Prohibited From Use in Ruminant Feed," Title 21, Code of Federal Regulations, Part 589.2000." And, additionally, the Animal Protein Producers Industry (APPI), the biosecurity arm of the rendering industry, effective April 1,

2001, has established an inspection audit of all animal protein producers to ascertain compliance with the FDA rule through an independent third party audit performed by a nationally respected firm of auditors, Cook & Thurber of Madison, Wisconsin. Should anyone care to discuss any aspect/concept of this question - answer format on the prion diseases with emphasis on BSE, Don Franco can be contacted by phone at 561-968-1575; by fax at 561-968-3766 or e-mail at Dfranco99 ------- Cary Birdwell HUMANITY IS THE VIRUS!

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