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NCBA, R-CALF, COOL, USDA (No Politics!)
Is BSE Caused by a VIRUS?
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<blockquote data-quote="flounder" data-source="post: 333463" data-attributes="member: 3519"><p>EUROPEAN COMMISSION</p><p>HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL</p><p>Scientific Steering Committee</p><p>OPINION ON</p><p>ORGANOPHOSPHATE (OP) POISONING AND</p><p>HYPOTHETICAL INVOLVEMENT IN THE ORIGIN OF BSE</p><p>Background</p><p>In its opinion on possible links between BSE and Organophosphates adopted on 25-26 June</p><p>1998 and in its opinion on Hypotheses on the origin and transmission of BSE adopted on 29-</p><p>30 November 2001 the SSC concluded that there is no scientific evidence in support of the</p><p>hypothesis of an OP origin of BSE.</p><p>The issue of organophosphate poisoning has not been dealt with by the SSC so far. The</p><p>concerns expressed in the enquiries cover mainly intoxication by occupational exposure of</p><p>shepherds and farmers to OPs upon use against ecto-parasites, especially in sheep dipping and</p><p>treatment of cattle against Warble Fly infestation. Risks from residues are addressed to a</p><p>lesser extend.</p><p>In early 2003, a large number of additional enquiries on the issue have been addressed to</p><p>European Commission's Health and Consumer Directorate General. Four of these with</p><p>substantial enclosures were by one person. Most of them are addressing both issues: chronic</p><p>organophosphate (OP) poisoning and the origin of BSE.</p><p>Information provided with the enquiries</p><p>In addition to numerous newspaper and magazine articles the enclosures to the enquiries</p><p>provide the Material Safety Data Sheet on diazinon, the OHSA Occupational Safety and</p><p>Health Guideline for Tetraethylpyrophosphate (TEPP), an US agency Hazardous Substances</p><p>Fact Sheet on crufomate, company safety information sheets, some correspondence with UK</p><p>authorities including their activities to improve safe use of these chemicals. The information</p><p>regarding claimed OP chronic poisoning of cases presented does not provide evidence, neither</p><p>for OPs being the cause for diseases nor for their exclusion (i.e., "very low" bloodcholinesterase</p><p>levels, provided without data or comparison with the normal distribution of</p><p>values; successful treatment of a patient for OP clearance without giving any OP data). It</p><p>C:\WINNT\Temporary Internet Files\SSC_Last_OP_Final.doc 2</p><p>seems however, that due to insufficient, non-prudent use of the safety requirements undue</p><p>exposures of shepherds and farmers have occurred.</p><p>There is no additional information on the claimed involvement of OPs in the origin of BSE.</p><p>This applies for both, the hypotheses on the direct effect of OPs as well as on their</p><p>hypothetical role for Cu-deficiency to be involved in the origin of BSE (Cu binding of prion</p><p>protein is known). New publications are mentioned in one enquiry but they have not yet been</p><p>provided. In an Internet search no recent scientifically valid publications were traceable. The</p><p>SSC had been informed that research would be launched on this hypothesis, but no</p><p>information has been provided so far on its status or on results.</p><p>Conclusions</p><p>a) As regards the involvement of organophosphates in the origin of BSE, no new scientific</p><p>information providing evidence or supporting the hypothesis by valid data became</p><p>available after the adoption of the last opinion of the SSC on this issue. Consequently</p><p>there is no reason for modifying the existing opinions.</p><p>b) Regarding the possibility of OP poisoning, the European legislation for registration of</p><p>plant protection products and veterinary medicines – addressed in the enquiries – provide</p><p>the basis for safe use of registered compounds and their formulations. Regarding the</p><p>alleged intoxication cases reported and OP exposure it must be concluded that safety</p><p>measures may not have been strictly followed.</p><p>References</p><p>Brown, D.R., Qin, K., Herms, J.W., Madlung, A., Manson, J., Strome, R., Fraser, P.E., Kruck, T., von</p><p>Bohlen, A., Schulz- Schaeffer, W., Giese, A., Westaway, D. and Kretzschmar, H. (1997) The Cellular</p><p>Prion Protein Binds Copper In Vivo, Nature, 390, 684-7.</p><p>Purdey, M. (2000) Ecosystems Supporting Clusters of Sporadic TSEs Demonstrate Excesses of the Radical-</p><p>Generating Divalent Cation Manganese and Deficiencies of Antioxidant Co-Factors Cu, Se, Fe, Zn Medical</p><p>Hypotheses, 54, 278-306.</p><p>Scientific Steering Committee, 1998. Opinion on possible links between BSE and Organophosphates. Adopted</p><p>on 25-26 June 1998</p><p>Scientific Steering Committee, 2001. Opinion on Hypotheses on the origin and transmission of BSE. Adopted</p><p>on 29-30 November 2001.</p><p></p><p><a href="http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf" target="_blank">http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf</a></p><p> </p><p> </p><p> </p><p>Studies on the Putative Interactions between the Organophosphorus Insecticide Phosmet and Recombinant Mouse PrP and its Implication in the BSE Epidemic</p><p>I. Shaw1, C. Berry2, E. Lane1, P. Fitzmaurice1, D. Clarke3 and A. Holden1</p><p></p><p>(1) Centre for Toxicology, University of Central Lancashire, Preston, UK </p><p>(2) Department of Morbid Anatomy, The Royal London Hospital, London, UK </p><p>(3) CLRC Daresbury Laboratory, Warrington, UK </p><p></p><p></p><p>Abstract It has been suggested that exposure of cattle to the ectoparasiticide Phosmet in the 1980s caused a conformational change in the cellular prion protein (PrPC) to form the BSE prion (PrPSC), which initiated the epidemic of bovine spongiform encephalopathy (BSE). </p><p>Recombinant mouse cellular prion (r[mouse]PrPC) was exposed to the organophosphorus pesticide Phosmet in vitro and the conformation of the prion before and after exposure was monitored using circular dichroism (CD) spectroscopy, utilizing synchrotron radiation at the Council for the Central Laboratory of the Research Councils (CLRC) facilities at Daresbury, UK. Metabolites of Phosmet, generated in situ by rat microsomes, were investigated in the same way, to determine whether they might initiate the conformational change due to their high chemical reactivity.</p><p>Our studies showed that exposure of r[mouse]PrPC to Phosmet or microsomes-generated metabolites of Phosmet did not result in the conformational change in the protein from -helix to -pleated sheet that is characteristic of the PrPC to PrPSC conversion and, therefore, Phosmet is very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein.</p><p>bovine spongiform encephalopathy - circular dichroism spectroscopy - insecticide - organophosphate - Phosmet - prion - protein conformation</p><p></p><p> </p><p></p><p><a href="http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555" target="_blank">http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555</a>)/app/home/contribution.asp?referrer=parent&backto=issue,3,9;journal,31,74;linkingpublicationresults,1:103009,1</p><p></p><p> </p><p></p><p>transmission studies do not lie, amplification and transmission!</p><p></p><p> </p><p>i see NO properties of high levels of Manganese in the diet, combined with low levels of copper, in any of these primate</p><p>transmission studies. </p><p></p><p>1: J Infect Dis 1980 Aug;142(2):205-8</p><p></p><p></p><p>Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to</p><p>nonhuman primates.</p><p></p><p>Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.</p><p></p><p>Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of</p><p>sheep and goats were transmitted to squirrel monkeys (Saimiri</p><p>sciureus) that were exposed to the infectious agents only by their</p><p>nonforced consumption of known infectious tissues. The asymptomatic</p><p>incubation period in the one monkey exposed to the virus of kuru was</p><p>36 months; that in the two monkeys exposed to the virus of</p><p>Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and</p><p>that in the two monkeys exposed to the virus of scrapie was 25 and</p><p>32 months, respectively. Careful physical examination of the buccal</p><p>cavities of all of the monkeys failed to reveal signs or oral</p><p>lesions. One additional monkey similarly exposed to kuru has</p><p>remained asymptomatic during the 39 months that it has been under</p><p>observation.</p><p></p><p>PMID: 6997404</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract</a></p><p> </p><p> </p><p>Oral Transmission And Early Lymphoid Tropism Of Chronic Wasting Disease</p><p>Prpres In Mule Deer Fawns</p><p></p><p>Publication: Journal Of General Virology</p><p>Publication Request Approval Date: June 25, 1999</p><p></p><p>Interpretive Summary: Chronic wasting disease is a transmissible</p><p>spongiform encephalopathy or prion disease of deer and elk. CWD is a</p><p>member of the family of diseases that includes sheep scrapie and bovine</p><p>spongiform encephalopathy (BSE). The natural route of transmission of</p><p>these diseases in ruminant animals is unknown but oral exposure to</p><p>contaminated feeds, bedding, or tissues is presumed to be a major source</p><p>of infection. In this study, mule deer fawns were orally fed an</p><p>infectious homogenate and sacrificed at intervals to examine the</p><p>lymphoid tissue of the alimentary tract for signs of infection. Prion</p><p>protein was detected as early as 42 days and was evident in all fawns</p><p>after 53 days. This paper provides an improved procedure for detecting</p><p>prions in early infection, establishes a protocol for accelerated study</p><p>of transmission routes, and supports the hypothesis that oral exposure</p><p>may reflect the initial pathway of CWD infection in deer.</p><p></p><p>Technical Abstract: Mule deer fawns were inoculated orally with a brain</p><p>homogenate prepared from mule deer with naturally occurring chronic</p><p>wasting disease (CWD), a prion induced transmissible spongiform</p><p>encephalopathy. Fawns were necropsies and examined for PrP-res, a</p><p>protein marker for infection, at 10, 42, 53, 77, 78 and 80 days post</p><p>inoculation using an immunohistochemistry assay modified to enhance</p><p>sensitivity. PrP-res was detected in alimentary-tract- associated</p><p>lymphoid tissues as early as 42 days post inoculation and in all fawns</p><p>after 53 days. These results indicated that CWD PrP-res can be detected</p><p>at least 16 months before clinical signs would be expected to appear and</p><p>may reflect the initial pathway of CWD infection in deer.</p><p></p><p><a href="http://nps.ars.usda.gov/publication...gnum=0000103091" target="_blank">http://nps.ars.usda.gov/publication...gnum=0000103091</a></p><p></p><p>Establishing the transmission of BSE to mink</p><p></p><p>44. Transmissible mink encephalopathy ("TME") is a rare disease of ranch</p><p>reared mink, first recognised in the USA. It had been assumed to be</p><p>scrapie in mink and, like BSE, outbreaks have epidemiological</p><p>features consistent with a foodborne infection, but it has never been</p><p>possible to demonstrate that scrapie infected sheep brain tissue is</p><p>pathogenic to mink by oral exposure. In an incident of TME in</p><p>Stetsonville, Wisconsin, USA in 1985 Dr Richard Marsh observed that</p><p>although the rancher fed 'dead stock', mainly in the form of cattle</p><p>carcasses, sheep tissues had never been fed. Studies in the USA of</p><p>this incident showed not only that cattle inoculated intracerebrally</p><p>with the mink brain developed a fatal spongiform encephalopathy, but</p><p>also that the cattle passaged agent remained pathogenic for</p><p>mink by either intracerebral inoculation or feeding. In the absence of</p><p>reports of a clinical disease homologous to BSE in domestic cattle,</p><p>these findings prompted the suggestion that a rare or occult</p><p>form of such a disease might exist in the USA. Comparison of the</p><p>biological properties of the BSE</p><p>12</p><p>pathogen with those of the Stetsonville isolate was therefore of</p><p>considerable interest in relation to hypotheses concerning possible</p><p>origins of BSE and potential for subclinical infection in cattle.</p><p>45. Proposals to carry out studies with mink in the USA were developed</p><p>in collaboration with, the United States Department of Agriculture</p><p>("USDA") Agricultural Research Service ("ARS") and the</p><p>Department of Veterinary Science, University of Wisconsin, Madison,</p><p>Wisconsin, USA. On 30th October, 1990 I attended a CVL/NPU BSE R&D</p><p>meeting at the NPU in Edinburgh (YB90/10.30/1.1). I reported that brain</p><p>material from BSE affected cows and a control cow (not fed meat and</p><p>bonemeal) had been sent coded to Mr Mark Robinson (USDA) for</p><p>transmission studies in mink. The studies were conducted from February</p><p>1991 under the control and principal funding of USDA-ARS. The results,</p><p>discussed at the tenth CVL/NPU BSE R&D meeting on 27th April, 1993</p><p>(YB93/4.27/1.1) indicated that mink were indeed susceptible to BSE and,</p><p>in contrast to previous attempts to transmit scrapie to the species,</p><p>were susceptible by the oral route of inoculation. The collaboration</p><p>resulted in the publication of a paper: Robinson, M.M. et al (1994)</p><p>Experimental infection of mink with bovine spongiform encephalopathy.</p><p>Journal of General Virology 75, 2151-2155 (J/JVIR /75/2151).</p><p></p><p>snip...</p><p></p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/ws/s065a.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/ws/s065a.pdf</a></p><p></p><p>BSE TO MINK CONFIRMED</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1993/04/27001001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 001001.pdf</a></p><p></p><p></p><p>1: Proc Natl Acad Sci U S A 2001 Mar 27;98(7):4142-7</p><p></p><p>Adaptation of the bovine spongiform encephalopathy agent to primates and</p><p>comparison with Creutzfeldt-- Jakob disease: implications for human health.</p><p></p><p>Lasmezas CI, Fournier JG, Nouvel V, Boe H, Marce D, Lamoury F, Kopp N,</p><p>Hauw JJ, Ironside J, Bruce M, Dormont D, Deslys JP.</p><p></p><p>Commissariat a l'Energie Atomique, Service de Neurovirologie, Direction</p><p>des Sciences du Vivant/Departement de Recherche Medicale, Centre de</p><p>Recherches du Service de Sante des Armees 60-68, Fontenay-aux-Roses,</p><p>France. <a href="mailto:lasmezas@cea.fr">lasmezas@cea.fr</a></p><p></p><p>There is substantial scientific evidence to support the notion that</p><p>bovine spongiform encephalopathy (BSE) has contaminated human beings,</p><p>causing variant Creutzfeldt-Jakob disease (vCJD). This disease has</p><p>raised concerns about the possibility of an iatrogenic secondary</p><p>transmission to humans, because the biological properties of the</p><p>primate-adapted BSE agent are unknown. We show that (i) BSE can be</p><p>transmitted from primate to primate by intravenous route in 25 months,</p><p>and (ii) an iatrogenic transmission of vCJD to humans could be readily</p><p>recognized pathologically, whether it occurs by the central or</p><p>peripheral route. Strain typing in mice demonstrates that the BSE agent</p><p>adapts to macaques in the same way as it does to humans and confirms</p><p>that the BSE agent is responsible for vCJD not only in the United</p><p>Kingdom but also in France. The agent responsible for French iatrogenic</p><p>growth hormone-linked CJD taken as a control is very different from vCJD</p><p>but is similar to that found in one case of sporadic CJD and one sheep</p><p>scrapie isolate. These data will be key in identifying the origin of</p><p>human cases of prion disease, including accidental vCJD transmission,</p><p>and could provide bases for vCJD risk assessment.</p><p></p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...1&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...1&dopt=Abstract</a></p><p> </p><p>this next one frightens me the most, you might want to read</p><p>it twice, and really think about it...TSS</p><p></p><p>1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8</p><p></p><p>Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes</p><p>contaminated during neurosurgery.</p><p></p><p>Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.</p><p></p><p>Laboratory of Central Nervous System Studies, National Institute of</p><p>Neurological Disorders and Stroke, National Institutes of Health,</p><p>Bethesda, MD 20892.</p><p></p><p>Stereotactic multicontact electrodes used to probe the cerebral cortex</p><p>of a middle aged woman with progressive dementia were previously</p><p>implicated in the accidental transmission of Creutzfeldt-Jakob disease</p><p>(CJD) to two younger patients. The diagnoses of CJD have been confirmed</p><p>for all three cases. More than two years after their last use in humans,</p><p>after three cleanings and repeated sterilisation in ethanol and</p><p>formaldehyde vapour, the electrodes were implanted in the cortex of a</p><p>chimpanzee. Eighteen months later the animal became ill with CJD. This</p><p>finding serves to re-emphasise the potential danger posed by reuse of</p><p>instruments contaminated with the agents of spongiform encephalopathies,</p><p>even after scrupulous attempts to clean them.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract</a></p><p></p><p>Proc Natl Acad Sci U S A 1999 Mar 30;96(7):4046-51</p><p></p><p>Natural and experimental oral infection of nonhuman primates by bovine</p><p>spongiform encephalopathy agents.</p><p></p><p>Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P.</p><p></p><p>Ecole Pratique des Hautes Etudes, Laboratoire de Neuromorphologie</p><p>Fonctionnelle, Universite Montpellier II, 34095-Montpellier cedex 5, France.</p><p></p><p>Experimental lemurs either were infected orally with the agent of bovine</p><p>spongiform encephalopathy (BSE) or were maintained as uninfected control</p><p>animals. Immunohistochemical examination for proteinase-resistant</p><p>protein (prion protein or PrP) was performed on tissues from two</p><p>infected but still asymptomatic lemurs, killed 5 months after infection,</p><p>and from three uninfected control lemurs. Control tissues showed no</p><p>staining, whereas PrP was detected in the infected animals in tonsil,</p><p>gastrointestinal tract and associated lymphatic tissues, and spleen. In</p><p>addition, PrP was detected in ventral and dorsal roots of the cervical</p><p>spinal cord, and within the spinal cord PrP could be traced in nerve</p><p>tracts as far as the cerebral cortex. Similar patterns of PrP</p><p>immunoreactivity were seen in two symptomatic and 18 apparently healthy</p><p>lemurs in three different French primate centers, all of which had been</p><p>fed diets supplemented with a beef protein product manufactured by a</p><p>British company that has since ceased to include beef in its veterinary</p><p>nutritional products. This study of BSE-infected lemurs early in their</p><p>incubation period extends previous pathogenesis studies of the</p><p>distribution of infectivity and PrP in natural and experimental scrapie.</p><p>The similarity of neuropathology and PrP immunostaining patterns in</p><p>experimentally infected animals to those observed in both symptomatic</p><p>and asymptomatic animals in primate centers suggests that BSE</p><p>contamination of zoo animals may have been more widespread than is</p><p>generally appreciated.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract</a></p><p></p><p>1: Vet Rec 1993 Apr 17;132(16):403-6</p><p></p><p>Experimental transmission of BSE and scrapie to the common marmoset.</p><p></p><p>Baker HF, Ridley RM, Wells GA.</p><p></p><p>Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex.</p><p></p><p>Two young male common marmosets (Callithrix jacchus) were injected</p><p>intracerebrally and intraperitoneally with a crude brain homogenate</p><p>prepared from a cow with bovine spongiform encephalopathy (BSE). Two</p><p>other marmosets were similarly injected with brain homogenate from a</p><p>sheep with natural scrapie. The two animals injected with scrapie</p><p>material developed neurological signs 38 and 42 months after injection</p><p>and the two animals injected with BSE material developed neurological</p><p>signs after 46 and 47 months. Post mortem examination of the brains</p><p>revealed spongiform encephalopathy especially in the basal nuclei and</p><p>diencephalon of all the animals and, in addition, involvement of the</p><p>cerebral cortex of the marmosets injected with scrapie material. The</p><p>experiment extends the host range of experimental BSE to include a</p><p>primate species.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract</a></p><p></p><p> </p><p>1: J Gen Virol 1991 Mar;72 ( Pt 3):589-94</p><p></p><p>Epidemiological and experimental studies on a new incident of</p><p>transmissible mink encephalopathy.</p><p></p><p>Marsh RF, Bessen RA, Lehmann S, Hartsough GR.</p><p></p><p>Department of Veterinary Science, University of Wisconsin-Madison 53706.</p><p></p><p>Epidemiological investigation of a new incident of transmissible mink</p><p>encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed</p><p>that the mink rancher had never fed sheep products to his mink but did</p><p>feed them large amounts of products from fallen or sick dairy cattle. To</p><p>investigate the possibility that this occurrence of TME may have</p><p>resulted from exposure to infected cattle, two Holstein bull calves were</p><p>injected intracerebrally with mink brain from the Stetsonville ranch.</p><p>Each bull developed a fatal spongiform encephalopathy 18 and 19 months</p><p>after inoculation, respectively, and both bovine brains passaged back</p><p>into mink were highly pathogenic by either intracerebral or oral</p><p>inoculation. These results suggest the presence of a previously</p><p>unrecognized scrapie-like infection in cattle in the United States.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...3&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...3&dopt=Abstract</a></p><p></p><p>1: Ital J Neurol Sci 1983 Apr;4(1):61-4</p><p></p><p>Creutzfeld-Jakob disease in the province of Siena: two cases transmitted</p><p>to monkeys.</p><p></p><p>Fieschi C, Orzi F, Pocchiari M, Nardini M, Rocchi F, Asher D, Gibbs C,</p><p>Gajdusek D.</p><p></p><p>Two cases of histopathologically documented Creutzfeldt-Jakob disease</p><p>were observed in the same area of the province of Siena in 1974-1975.</p><p>The transmission of the disease was obtained through brain homogenates</p><p>and lymphnodes in one of the two cases. This confirms that the agent is</p><p>present in other tissues besides the brain and underlines further the</p><p>analogies between Creutzfeld-Jakob disease and scrapie.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract</a></p><p></p><p></p><p>1: Dev Biol Stand 1993;80:9-13</p><p></p><p>Transmission of human spongiform encephalopathies to experimental</p><p>animals: comparison of the chimpanzee and squirrel monkey.</p><p></p><p>Asher DM, Gibbs CJ Jr, Sulima MP, Bacote A, Amyx H, Gajdusek DC.</p><p></p><p>Laboratory of Central Nervous System Studies, National Institute of</p><p>Neurological Disorders and Stroke, NIH, Bethesda, MD 20992.</p><p></p><p>The agents of kuru and Creutzfeldt-Jakob disease have been consistently</p><p>transmitted from patients with those diseases to chimpanzees and</p><p>squirrel monkeys, as well as to other new-world primates, with average</p><p>incubation periods of two or three years. No other animals have been</p><p>found so consistently susceptible to the agents in human tissues. More</p><p>rapid and convenient assays for the infectious agents would greatly</p><p>facilitate research on the spongiform encephalopathies of humans.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...9&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...9&dopt=Abstract</a></p><p></p><p></p><p>1: J Vet Diagn Invest 2001 Jan;13(1):91-6</p><p></p><p>Preliminary findings on the experimental transmission of chronic wasting</p><p>disease agent of mule deer to cattle.</p><p></p><p>Hamir AN, Cutlip RC, Miller JM, Williams ES, Stack MJ, Miller MW,</p><p>O'Rourke KI, Chaplin MJ.</p><p></p><p>National Animal Disease Center, ARS, USDA, Ames, IA 50010, USA.</p><p></p><p>To determine the transmissibility of chronic wasting disease (CWD) to</p><p>cattle and to provide information about clinical course, lesions, and</p><p>suitability of currently used diagnostic procedures for detection of CWD</p><p>in cattle, 13 calves were inoculated intracerebrally with brain</p><p>suspension from mule deer naturally affected with CWD. Between 24 and 27</p><p>months postinoculation, 3 animals became recumbent and were euthanized.</p><p>Gross necropsies revealed emaciation in 2 animals and a large pulmonary</p><p>abscess in the third. Brains were examined for protease-resistant prion</p><p>protein (PrP(res)) by immunohistochemistry and Western blotting and for</p><p>scrapie-associated fibrils (SAFs) by negative-stain electron microscopy.</p><p>Microscopic lesions in the brain were subtle in 2 animals and absent in</p><p>the third case. However, all 3 animals were positive for PrP(res) by</p><p>immunohistochemistry and Western blot, and SAFs were detected in 2 of</p><p>the animals. An uninoculated control animal euthanized during the same</p><p>period did not have PrP(res) in its brain. These are preliminary</p><p>observations from a currently in-progress experiment. Three years after</p><p>the CWD challenge, the 10 remaining inoculated cattle are alive and</p><p>apparently healthy. These preliminary findings demonstrate that</p><p>diagnostic techniques currently used for bovine spongiform</p><p>encephalopathy (BSE) surveillance would also detect CWD in cattle should</p><p>it occur naturally.</p><p></p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract</a></p><p> </p><p>P.S. the study above confirmed 5 cows and 1 goat transmission of CWD to cattle, </p><p>of the final stages of the study. ...tss</p><p> </p><p>Published online before print March 20, 2001, 10.1073/pnas.041490898</p><p>Neurobiology</p><p>Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt- Jakob disease: Implications for human health</p><p>Corinne Ida Lasmézas*,dagger, Jean-Guy Fournier*, Virginie Nouvel*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas KoppDagger , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce||, Dominique Dormont*, and Jean-Philippe Deslys* </p><p></p><p>snip... </p><p></p><p></p><p>Discussion </p><p></p><p>One aim of this study was to determine the risk of secondary transmission to humans of vCJD, which is caused not by a primarily human strain of TSE agent but by the BSE strain having passed the species barrier to humans. This risk is tightly linked to the capacity of the BSE agent to adapt to primates and harbor enhanced virulence (i.e., induce disease after a short incubation period and provoke disease even if highly diluted) and to its pathogenicity after inoculation by the peripheral route. With respect to the latter, there are huge variations between different TSE agent strains and hosts. For example, the BSE agent is pathogenic to pigs after i.c. inoculation but not after oral administration (23). Thus, we wanted to know to what extent the BSE/vCJD agent is pathogenic to humans by the i.c. and i.v. routes. To achieve this, we used the macaque model. To monitor the evolution of the BSE agent in primates, but also to verify the identity of French vCJD, we conducted parallel transmission to C57BL/6 mice, allowing strain-typing. The experimental scheme is depicted in Fig. 1. </p><p></p><p>Characterization of the BSE Agent in Primates. The identity of the lesion profiles obtained from the brains of the French patient with vCJD, two British patients with vCJD, and nonhuman primates infected with BSE provides experimental demonstration of the fact that the BSE agent strain has been transmitted to humans both in the U.K. and in France. Further, it lends support to the validity of the macaque model as a powerful tool for the study of vCJD. As far as the evolution of the BSE agent in primates is concerned, we observed an interesting phenomenon: at first passage of BSE in macaques and with vCJD, there was a polymorphism of the lesion profile in mice in the hippocampal region, with about half of them harboring much more severe vacuolation than the mice inoculated with cattle BSE. At second passage, the polymorphism tended to disappear, with all mice showing higher vacuolation scores in the hippocampus than cattle BSE mice. This observation suggests the appearance of a variant of the BSE agent at first passage in primates and its clonal selection during second passage in primates. The lesion profiles showed that it was still the BSE agent, but the progressive appearance of a "hippocampal signature" hallmarked the evolution toward a variant by essence more virulent to primates. </p><p></p><p>Characterization of the CJD and Scrapie Strains. Controls were set up by transmitting one French and one U.S. scrapie isolate from ruminants as well as French sCJD and iCJD cases from humans. None of these revealed a lesion profile or transmission characteristics similar or close to those of BSE or vCJD, respectively, thus extending to the present French scrapie isolate the previous observation that the BSE agent was different from all known natural scrapie strains (4, 24).</p><p>The lesion profiles of sCJD and iCJD differed only slightly in severity of the lesions, but not in shape of the profile, revealing the identity of the causative agents. One of us reported the absence of similarity between sCJD (six cases) and U.K. scrapie (eight cases) in transmission characteristics in mice (4). Herein, we made the striking observation that the French natural scrapie strain (but not the U.S. scrapie strain) has the same lesion profile and transmission times in C57BL/6 mice as do the two human TSE strains studied. This strain "affiliation" was confirmed biochemically. There is no epidemiological evidence for a link between sheep scrapie and the occurrence of CJD in humans (25). However, such a link, if it is not a general rule, would be extremely difficult to establish because of the very low incidence of CJD as well as the existence of different isolates in humans and multiple strains in scrapie. Moreover, scrapie is transmissible to nonhuman primates (26). Thus, there is still a possibility that in some instances TSE strains infecting humans do share a common origin with scrapie, as pointed out by our findings. </p><p></p><p>Transmission of vCJD and BSE to Nonhuman Primates. vCJD transmitted readily to the cynomolgus macaque after 2 years of incubation, which was comparable to the transmission obtained from first-passaged macaque BSE and much shorter than the interspecies transmission of BSE. Starting with 100 mg of BSE-macaque brain material, dilutions up to 4 µg still provoked disease. These data suggest that the BSE agent rapidly adapts to primates accompanied by enhanced virulence.</p><p>Examination of macaque brain inoculated with vCJD revealed a similar pathology to that with second-passage BSE. The distribution of vacuolation and gliosis, as well as the pattern of PrP deposition, including the dense, sometimes florid plaques, were similar to the human vCJD and the BSE hallmarks of the first passage (1, 2). These data show that the phenotype of BSE in primates is conserved over two passages. Moreover, they confirm that the BSE agent behaves similarly in humans and macaques, a precious finding that will prove useful in the near future for the design of pathogenesis or therapeutic studies. Because of the number of macaques examined in this study, we can now reliably state that the pathology, in particular the PrP deposition pattern provoked by BSE, is similar in older and very young animals. However, plaque deposition is greater, and mature florid plaques were more numerous, in the young, which may be correlated with a longer duration of the clinical phase observed in this animal (2). This is important with regard to the fact that vCJD has been diagnosed mainly in teenagers and young adults, which raises the concern that older patients may have been misdiagnosed because of an alternative phenotype of the disease. One should bear in mind, however, that cynomolgus macaques are all homozygotes for methionine at codon 129 of the PrP gene. Thus, our observations may not be relevant to humans carrying one or both valine alleles; however, all patients with vCJD reported to date have been M/M at this position (27). </p><p></p><p>Intravenous Transmissions to Nonhuman Primates. Brain pathology was identical in macaques inoculated i.c. and i.v. The i.v. route proved to be very efficient for the transmission of BSE, as shown by the 2-year survival of the animals, which is only 5 months longer than that obtained after inoculating the same amount of agent i.c. As the i.v. injection of the infectious agent implies per se a delayed neuroinvasion compared with a direct inoculation in the brain, this slight lengthening of the incubation period cannot, at this stage, be interpreted as a lower efficiency of infection as regards the i.c. route.</p><p>These data should be taken into account in the risk assessment of iatrogenic vCJD transmission by i.v. administration of biological products of human origin. They also constitute an incentive for a complete i.v. titration.</p><p>Conclusions </p><p></p><p>From BSE and vCJD transmissions in nonhuman primates, a number of conclusions can be drawn that are of major importance for human health: (i) human-adapted BSE appears to be a variant of the BSE agent that is more virulent for humans than cattle BSE and is efficiently transmitted by the peripheral route; (ii) the detection of vCJD in unusually young patients is probably not because of a lack of diagnosis of cases in older patients, thus raising the question of the source of human contamination with BSE early in life; and (iii) iatrogenic transmissions from patients with vCJD would be readily recognized by using the same diagnostic criteria as those applied to vCJD [clinical and pathological criteria (27) comprising neuronal loss and gliosis in the thalamus correlated with high MRI signal (28, 29)], whether such contaminations had occurred by the central or i.v. route. Primary and iatrogenic cases of vCJD could be distinguished on the basis of the patient's clinical history. </p><p></p><p>The risk assessment of biological products of human origin, notably those derived from blood, has been deeply modified by the appearance of vCJD. We confirm that the BSE agent has contaminated humans not only in the U.K. and the Republic of Ireland but also in France, and we show that its pathogenic properties for primates are being enhanced by a primary passage in humans. Considering the flow of potentially contaminated bovine-derived products between 1980 and 1996, it is obvious that further vCJD cases may occur outside the U.K. Thus, and in the light of the present study, it is necessary to sustain worldwide CJD surveillance regardless of national BSE incidence and to take all precautionary measures to avoid iatrogenic transmissions from vCJD. </p><p></p><p>snip...</p><p></p><p><a href="http://www.pnas.org/cgi/content/full/041490898v1" target="_blank">http://www.pnas.org/cgi/content/full/041490898v1</a></p><p></p><p></p><p></p><p>MRC-43-00 [ ] [Text only version of this site] [Print this page]</p><p>Issued: Monday, 28 August 2000 </p><p>NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH FINDINGS RELEVANT TO CJD AND BSE</p><p></p><p>A team of researchers led by Professor John Collinge at the Medical Research Council Prion Unit1 report today in the Proceedings of the National Academy of Sciences, on new evidence for the existence of a ?sub-clinical? form of BSE in mice which was unknown until now.</p><p></p><p>The scientists took a closer look at what is known as the ?species barrier? - the main protective factor which limits the ability of prions2 to jump from one species to infect another. They found the mice had a ?sub-clinical? form of disease where they carried high levels of infectivity but did not develop the clinical disease during their normal lifespan. The idea that individuals can carry a disease and show no clinical symptoms is not new. It is commonly seen in conventional infectious diseases.</p><p></p><p>Researchers tried to infect laboratory mice with hamster prions3 called Sc237 and found that the mice showed no apparent signs of disease. However, on closer inspection they found that the mice had high levels of mouse prions in their brains. This was surprising because it has always been assumed that hamster prions could not cause the disease in mice, even when injected directly into the brain.</p><p></p><p>In addition the researchers showed that this new sub-clinical infection could be easily passed on when injected into healthy mice and hamsters.</p><p></p><p>The height of the species barrier varies widely between different combinations of animals and also varies with the type or strain of prions. While some barriers are quite small (for instance BSE easily infects mice), other combinations of strain and species show a seemingly impenetrable barrier. Traditionally, the particular barrier studied here was assumed to be robust.</p><p></p><p>Professor John Collinge said: "These results have a number of important implications. They suggest that we should re-think how we measure species barriers in the laboratory, and that we should not assume that just because one species appears resistant to a strain of prions they have been exposed to, that they do not silently carry the infection. This research raises the possibility, which has been mentioned before, that apparently healthy cattle could harbour, but never show signs of, BSE.</p><p></p><p>"This is a timely and unexpected result, increasing what we know about prion disease. These new findings have important implications for those researching prion disease, those responsible for preventing infected material getting into the food chain and for those considering how best to safeguard health and reduce the risk that theoretically, prion disease could be contracted through medical and surgical procedures."</p><p></p><p>ISSUED FRIDAY 25 AUGUST UNDER EMBARGO. PLEASE NOTE THAT THE EMBARGO IS SET BY THE JOURNAL.</p><p></p><p>FOR FURTHER INFORMATION CONTACT THE MRC PRESS OFFICE ON 020 7637 6011 (OFFICE HOURS) OR 07818 428297 OR 0385 774357 (OUT-OF-OFFICE-HOURS) OR PROFESSOR JOHN COLLINGE ON 020 7594 3760. PLEASE NOTE THAT OWING TO TRAVEL COMMITMENTS PROFESSOR COLLINGE WILL ONLY BE AVAILABLE UNTIL 16.30 ON FRIDAY 25 AUGUST AND CONTACTABLE AGAIN ON MONDAY 28 AUGUST VIA THE MRC PRESS OFFICE. DR ANDREW HILL (A CO-AUTHOR ON THE PAPER) FROM THE DEPARTMENT OF PATHOLOGY AT THE UNIVERSITY OF MELBOURNE WILL BE AVAILABLE ON 00 61 3 8344 3995 (DURING OFFICE HOURS) OR 00 61 3 9443 0009 (OUT-OF-OFFICE HOURS). PLEASE NOTE THAT AUSTRALIA IS TEN HOURS AHEAD OF UK TIME.</p><p></p><p>NOTES FOR EDITORS</p><p></p><p>Professor Collinge is a consultant neurologist and Director of the newly formed MRC Prion Unit based at The Imperial College School of Medicine at St Mary?s Hospital. He is also a member of the UK Government?s Spongiform Encephalopathy Advisory Committee (SEAC). The MRC prion unit is was set up in 1999, and its work includes molecular genetic studies of human prion disease and transgenic modelling of human prion diseases.</p><p></p><p>Prions are unique infectious agents that cause fatal brain diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and BSE (mad cow disease) in animals. In some circumstances prions from one species of animals can infect another and it is clear that BSE has done this to cause the disease variant CJD in the UK and France. It remains unclear how large an epidemic of variant CJD will occur over the years ahead.</p><p></p><p>The strain of prion used here to infect the mice is the Sc237 strain (also known as 263K) which infects hamsters, and until now was assumed not to infect mice.</p><p></p><p>This research was funded by the Medical Research Council and Wellcome Trust.</p><p></p><p>The Medical Research Council (MRC) is a national organisation funded by the UK tax-payer. Its business is medical research aimed at improving human health; everyone stands to benefit from the outputs. The research it supports and the scientists it trains meet the needs of the health services, the pharmaceutical and other health-related industries and the academic world. MRC has funded work which has led to some of the most significant discoveries and achievements in medicine in the UK. About half of the MRC?s expenditure of £345 million is invested in over 50 of its Institutes and Units, where it employs its own research staff. The remaining half goes in the form of grant support and training awards to individuals and teams in universities and medical schools.</p><p></p><p>The Wellcome Trust is the world's largest medical research charity with a spend of some £600 million in the current financial year 1999/2000. The Wellcome Trust supports more than 5,000 researchers, at 400 locations, in 42 different countries to promote and foster research with the aim of improving human and animal health. As well as funding major initiatives in the public understanding of science, the Wellcome Trust is the country's leading supporter of research into the history of medicine.</p><p></p><p>©2002 Medical Research Council </p><p></p><p><a href="http://www.mrc.ac.uk/index/public_interest/public-press_office/public-press_releases_2000/public-mrc-43-00.htm" target="_blank">http://www.mrc.ac.uk/index/public_inter ... -43-00.htm</a></p><p></p><p></p><p>and for Gods sake, if someone is smearing this cr@p all over there kids</p><p>heads for lice and did not come up with a TSE, i would say this is good case study;</p><p></p><p></p><p>1) None of our animals that contracted BSE were treated with OP's, even</p><p>in utero.</p><p>2) My kids were treated with OP's as infants to control head lice. This</p><p>seems to be endemic as infection waves in UK primary schools (and</p><p>possibly elsewhere).</p><p>3) One might argue if the continued use of british beef in the UK was</p><p>ethical, none the less it happened. We have a duty to learn from it, not</p><p>least a duty to learn on behalf of those people who died so horribly....</p><p> </p><p> </p><p>NOPE, greed and money is the name of the game, they have known for decades;</p><p> </p><p> </p><p> STRICTLY PRIVATE AND CONFIDENTIAL 25, AUGUST 1995 </p><p></p><p>snip... </p><p></p><p>To minimise the risk of farmers' claims for compensation from feed </p><p>compounders. </p><p></p><p>To minimise the potential damage to compound feed markets through adverse publicity. </p><p></p><p>To maximise freedom of action for feed compounders, notably by </p><p>maintaining the availability of meat and bone meal as a raw </p><p>material in animal feeds, and ensuring time is available to make any </p><p>changes which may be required. </p><p></p><p>snip... </p><p></p><p>THE FUTURE </p><p></p><p>4.......... </p><p></p><p>MAFF remains under pressure in Brussels and is not skilled at </p><p>handling potentially explosive issues. </p><p></p><p>5. Tests _may_ show that ruminant feeds have been sold which </p><p>contain illegal traces of ruminant protein. More likely, a few positive </p><p>test results will turn up but proof that a particular feed mill knowingly </p><p>supplied it to a particular farm will be difficult if not impossible. </p><p></p><p>6. The threat remains real and it will be some years before feed </p><p>compounders are free of it. The longer we can avoid any direct </p><p>linkage between feed milling _practices_ and actual BSE cases, </p><p>the more likely it is that serious damage can be avoided. ... </p><p></p><p>SEE full text ; </p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/08/24002001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 002001.pdf</a> </p><p></p><p> </p><p></p><p>BUT, i applaud ranchers that understand the TSE science and not the hype that surrounds it such as 'reader the second' ;</p><p> </p><p> </p><p>>>>Look, Mark Purdey, I applaud you for your perserverance, your bravery in taking on the establishment, and your creativity. It may well be that you were instrumental in bringing the familial and other genetic clusters in Slovenia to the attention of science. </p><p></p><p>I acknowledge that you suffered but your suffering sir is NOTHING compared to the suffering of the families afflicted with CJD and variant CJD and to the extent that your writings are used to ignore public health threats and to avoid taking public health measures that may well protect humans from CJD, then your writings are being ill used. You should acknowledge that and if you do not, I will pay no further attention to you. </p><p></p><p>Your supporters use your writings to (1) deny that CJD is transmissable from person to person, e.g., via contaminated surgical instruments or tissue or blood donations; (2) reject totally the strong hypothesis that variant CJD is due to the BSE epidemic in the UK being "pushed" over the species barrier. They claim that all cases of human CJD are due to metal contamination. It is they who are perverting your theories and therefore subjecting you to ridicule. Unless you deny these things as well and in which case, you should be ignored since in the case of (1) you deny fact and in the case of (2) you reject a hypothesis that must be accepted for the time being and must lead our public health measures given its strength. </p><p></p><p>NO ONE has denied that the ultimate cause of TSEs is unknown. However TSEs ARE transmissable between species, albeit not easily, and they are certainly transmissable among the same species. The suffering of the individual and his/her family who contracts CJD or variant CJD is hideous beyond description. If TSEs are your life work, you had better be taking that into consideration.<<<</p><p> </p><p> </p><p>>>>This is a danger to ranchers and to all humans<<<</p><p> </p><p> </p><p>INDEED there is;</p><p> </p><p> </p><p>CJD FARMERS WIFE 1989</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1989/10/13007001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 007001.pdf</a></p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1989/10/13003001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 003001.pdf</a></p><p></p><p></p><p>20 year old died from sCJD in USA in 1980 and a 16 year</p><p>old in 1981. A 19 year old died from sCJD in</p><p>France in 1985. There is no evidence of an iatrogenic</p><p>cause for those cases....</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/10/04004001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 004001.pdf</a></p><p></p><p>cover-up of 4th farm worker ???</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/10/23006001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 006001.pdf</a></p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/10/20006001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 006001.pdf</a></p><p></p><p>CONFIRMATION OF CJD IN FOURTH FARMER</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/11/03008001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 008001.pdf</a></p><p></p><p>now story changes from;</p><p></p><p>SEAC concluded that, if the fourth case were confirmed, it would be</p><p>worrying, especially as all four farmers with CJD would have had BSE</p><p>cases on their farms.</p><p></p><p>to;</p><p></p><p>This is not unexpected...</p><p></p><p>was another farmer expected?</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/11/13010001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 010001.pdf</a></p><p></p><p>4th farmer, and 1st teenager</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1996/02/27003001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 003001.pdf</a></p><p></p><p>2. snip...</p><p>Over a 5 year period, which is the time period on which the advice</p><p>from Professor Smith and Dr. Gore was based, and assuming a</p><p>population of 120,000 dairy farm workers, and an annual incidence</p><p>of 1 per million cases of CJD in the general population, a</p><p>DAIRY FARM WORKER IS 5 TIMES MORE LIKELY THAN</p><p>an individual in the general population to develop CJD. Using the</p><p>actual current annual incidence of CJD in the UK of 0.7 per</p><p>million, this figure becomes 7.5 TIMES.</p><p></p><p>3. You will recall that the advice provided by Professor Smith in</p><p>1993 and by Dr. Gore this month used the sub-population of dairy</p><p>farm workers who had had a case of BSE on their farms -</p><p>63,000, which is approximately half the number of dairy farm</p><p>workers - as a denominator. If the above sums are repeated using</p><p>this denominator population, taking an annual incidence in the general</p><p>population of 1 per million the observed rate in this sub-population</p><p>is 10 TIMES, and taking an annual incidence of 0.7 per million,</p><p>IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) than</p><p>that in the general population...</p><p></p><p><a href="http://www.bseinquiry.gov.uk/files/yb/1995/01/31004001.pdf" target="_blank">http://www.bseinquiry.gov.uk/files/yb/1 ... 004001.pdf</a></p><p></p><p> </p><p></p><p>1: J Infect Dis 1980 Aug;142(2):205-8 </p><p> </p><p></p><p></p><p>Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.</p><p></p><p>Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.</p><p></p><p>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.</p><p></p><p>PMID: 6997404 </p><p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract</a> </p><p> </p><p> </p><p></p><p>TSS</p></blockquote><p></p>
[QUOTE="flounder, post: 333463, member: 3519"] EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Scientific Steering Committee OPINION ON ORGANOPHOSPHATE (OP) POISONING AND HYPOTHETICAL INVOLVEMENT IN THE ORIGIN OF BSE Background In its opinion on possible links between BSE and Organophosphates adopted on 25-26 June 1998 and in its opinion on Hypotheses on the origin and transmission of BSE adopted on 29- 30 November 2001 the SSC concluded that there is no scientific evidence in support of the hypothesis of an OP origin of BSE. The issue of organophosphate poisoning has not been dealt with by the SSC so far. The concerns expressed in the enquiries cover mainly intoxication by occupational exposure of shepherds and farmers to OPs upon use against ecto-parasites, especially in sheep dipping and treatment of cattle against Warble Fly infestation. Risks from residues are addressed to a lesser extend. In early 2003, a large number of additional enquiries on the issue have been addressed to European Commission’s Health and Consumer Directorate General. Four of these with substantial enclosures were by one person. Most of them are addressing both issues: chronic organophosphate (OP) poisoning and the origin of BSE. Information provided with the enquiries In addition to numerous newspaper and magazine articles the enclosures to the enquiries provide the Material Safety Data Sheet on diazinon, the OHSA Occupational Safety and Health Guideline for Tetraethylpyrophosphate (TEPP), an US agency Hazardous Substances Fact Sheet on crufomate, company safety information sheets, some correspondence with UK authorities including their activities to improve safe use of these chemicals. The information regarding claimed OP chronic poisoning of cases presented does not provide evidence, neither for OPs being the cause for diseases nor for their exclusion (i.e., “very low” bloodcholinesterase levels, provided without data or comparison with the normal distribution of values; successful treatment of a patient for OP clearance without giving any OP data). It C:\WINNT\Temporary Internet Files\SSC_Last_OP_Final.doc 2 seems however, that due to insufficient, non-prudent use of the safety requirements undue exposures of shepherds and farmers have occurred. There is no additional information on the claimed involvement of OPs in the origin of BSE. This applies for both, the hypotheses on the direct effect of OPs as well as on their hypothetical role for Cu-deficiency to be involved in the origin of BSE (Cu binding of prion protein is known). New publications are mentioned in one enquiry but they have not yet been provided. In an Internet search no recent scientifically valid publications were traceable. The SSC had been informed that research would be launched on this hypothesis, but no information has been provided so far on its status or on results. Conclusions a) As regards the involvement of organophosphates in the origin of BSE, no new scientific information providing evidence or supporting the hypothesis by valid data became available after the adoption of the last opinion of the SSC on this issue. Consequently there is no reason for modifying the existing opinions. b) Regarding the possibility of OP poisoning, the European legislation for registration of plant protection products and veterinary medicines – addressed in the enquiries – provide the basis for safe use of registered compounds and their formulations. Regarding the alleged intoxication cases reported and OP exposure it must be concluded that safety measures may not have been strictly followed. References Brown, D.R., Qin, K., Herms, J.W., Madlung, A., Manson, J., Strome, R., Fraser, P.E., Kruck, T., von Bohlen, A., Schulz- Schaeffer, W., Giese, A., Westaway, D. and Kretzschmar, H. (1997) The Cellular Prion Protein Binds Copper In Vivo, Nature, 390, 684-7. Purdey, M. (2000) Ecosystems Supporting Clusters of Sporadic TSEs Demonstrate Excesses of the Radical- Generating Divalent Cation Manganese and Deficiencies of Antioxidant Co-Factors Cu, Se, Fe, Zn Medical Hypotheses, 54, 278-306. Scientific Steering Committee, 1998. Opinion on possible links between BSE and Organophosphates. Adopted on 25-26 June 1998 Scientific Steering Committee, 2001. Opinion on Hypotheses on the origin and transmission of BSE. Adopted on 29-30 November 2001. [url=http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf]http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf[/url] Studies on the Putative Interactions between the Organophosphorus Insecticide Phosmet and Recombinant Mouse PrP and its Implication in the BSE Epidemic I. Shaw1, C. Berry2, E. Lane1, P. Fitzmaurice1, D. Clarke3 and A. Holden1 (1) Centre for Toxicology, University of Central Lancashire, Preston, UK (2) Department of Morbid Anatomy, The Royal London Hospital, London, UK (3) CLRC Daresbury Laboratory, Warrington, UK Abstract It has been suggested that exposure of cattle to the ectoparasiticide Phosmet in the 1980s caused a conformational change in the cellular prion protein (PrPC) to form the BSE prion (PrPSC), which initiated the epidemic of bovine spongiform encephalopathy (BSE). Recombinant mouse cellular prion (r[mouse]PrPC) was exposed to the organophosphorus pesticide Phosmet in vitro and the conformation of the prion before and after exposure was monitored using circular dichroism (CD) spectroscopy, utilizing synchrotron radiation at the Council for the Central Laboratory of the Research Councils (CLRC) facilities at Daresbury, UK. Metabolites of Phosmet, generated in situ by rat microsomes, were investigated in the same way, to determine whether they might initiate the conformational change due to their high chemical reactivity. Our studies showed that exposure of r[mouse]PrPC to Phosmet or microsomes-generated metabolites of Phosmet did not result in the conformational change in the protein from -helix to -pleated sheet that is characteristic of the PrPC to PrPSC conversion and, therefore, Phosmet is very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein. bovine spongiform encephalopathy - circular dichroism spectroscopy - insecticide - organophosphate - Phosmet - prion - protein conformation [url=http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555]http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555[/url])/app/home/contribution.asp?referrer=parent&backto=issue,3,9;journal,31,74;linkingpublicationresults,1:103009,1 transmission studies do not lie, amplification and transmission! i see NO properties of high levels of Manganese in the diet, combined with low levels of copper, in any of these primate transmission studies. 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. PMID: 6997404 [url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract[/url] Oral Transmission And Early Lymphoid Tropism Of Chronic Wasting Disease Prpres In Mule Deer Fawns Publication: Journal Of General Virology Publication Request Approval Date: June 25, 1999 Interpretive Summary: Chronic wasting disease is a transmissible spongiform encephalopathy or prion disease of deer and elk. CWD is a member of the family of diseases that includes sheep scrapie and bovine spongiform encephalopathy (BSE). The natural route of transmission of these diseases in ruminant animals is unknown but oral exposure to contaminated feeds, bedding, or tissues is presumed to be a major source of infection. In this study, mule deer fawns were orally fed an infectious homogenate and sacrificed at intervals to examine the lymphoid tissue of the alimentary tract for signs of infection. Prion protein was detected as early as 42 days and was evident in all fawns after 53 days. This paper provides an improved procedure for detecting prions in early infection, establishes a protocol for accelerated study of transmission routes, and supports the hypothesis that oral exposure may reflect the initial pathway of CWD infection in deer. Technical Abstract: Mule deer fawns were inoculated orally with a brain homogenate prepared from mule deer with naturally occurring chronic wasting disease (CWD), a prion induced transmissible spongiform encephalopathy. Fawns were necropsies and examined for PrP-res, a protein marker for infection, at 10, 42, 53, 77, 78 and 80 days post inoculation using an immunohistochemistry assay modified to enhance sensitivity. PrP-res was detected in alimentary-tract- associated lymphoid tissues as early as 42 days post inoculation and in all fawns after 53 days. These results indicated that CWD PrP-res can be detected at least 16 months before clinical signs would be expected to appear and may reflect the initial pathway of CWD infection in deer. [url=http://nps.ars.usda.gov/publication...gnum=0000103091]http://nps.ars.usda.gov/publication...gnum=0000103091[/url] Establishing the transmission of BSE to mink 44. Transmissible mink encephalopathy ("TME") is a rare disease of ranch reared mink, first recognised in the USA. It had been assumed to be scrapie in mink and, like BSE, outbreaks have epidemiological features consistent with a foodborne infection, but it has never been possible to demonstrate that scrapie infected sheep brain tissue is pathogenic to mink by oral exposure. In an incident of TME in Stetsonville, Wisconsin, USA in 1985 Dr Richard Marsh observed that although the rancher fed 'dead stock', mainly in the form of cattle carcasses, sheep tissues had never been fed. Studies in the USA of this incident showed not only that cattle inoculated intracerebrally with the mink brain developed a fatal spongiform encephalopathy, but also that the cattle passaged agent remained pathogenic for mink by either intracerebral inoculation or feeding. In the absence of reports of a clinical disease homologous to BSE in domestic cattle, these findings prompted the suggestion that a rare or occult form of such a disease might exist in the USA. Comparison of the biological properties of the BSE 12 pathogen with those of the Stetsonville isolate was therefore of considerable interest in relation to hypotheses concerning possible origins of BSE and potential for subclinical infection in cattle. 45. Proposals to carry out studies with mink in the USA were developed in collaboration with, the United States Department of Agriculture ("USDA") Agricultural Research Service ("ARS") and the Department of Veterinary Science, University of Wisconsin, Madison, Wisconsin, USA. On 30th October, 1990 I attended a CVL/NPU BSE R&D meeting at the NPU in Edinburgh (YB90/10.30/1.1). I reported that brain material from BSE affected cows and a control cow (not fed meat and bonemeal) had been sent coded to Mr Mark Robinson (USDA) for transmission studies in mink. The studies were conducted from February 1991 under the control and principal funding of USDA-ARS. The results, discussed at the tenth CVL/NPU BSE R&D meeting on 27th April, 1993 (YB93/4.27/1.1) indicated that mink were indeed susceptible to BSE and, in contrast to previous attempts to transmit scrapie to the species, were susceptible by the oral route of inoculation. The collaboration resulted in the publication of a paper: Robinson, M.M. et al (1994) Experimental infection of mink with bovine spongiform encephalopathy. Journal of General Virology 75, 2151-2155 (J/JVIR /75/2151). snip... [url=http://www.bseinquiry.gov.uk/files/ws/s065a.pdf]http://www.bseinquiry.gov.uk/files/ws/s065a.pdf[/url] BSE TO MINK CONFIRMED [url=http://www.bseinquiry.gov.uk/files/yb/1993/04/27001001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 001001.pdf[/url] 1: Proc Natl Acad Sci U S A 2001 Mar 27;98(7):4142-7 Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt-- Jakob disease: implications for human health. Lasmezas CI, Fournier JG, Nouvel V, Boe H, Marce D, Lamoury F, Kopp N, Hauw JJ, Ironside J, Bruce M, Dormont D, Deslys JP. Commissariat a l'Energie Atomique, Service de Neurovirologie, Direction des Sciences du Vivant/Departement de Recherche Medicale, Centre de Recherches du Service de Sante des Armees 60-68, Fontenay-aux-Roses, France. [email=lasmezas@cea.fr]lasmezas@cea.fr[/email] There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment. [url=http://www.ncbi.nlm.nih.gov/entrez/...1&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...1&dopt=Abstract[/url] this next one frightens me the most, you might want to read it twice, and really think about it...TSS 1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8 Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery. Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them. [url=http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract[/url] Proc Natl Acad Sci U S A 1999 Mar 30;96(7):4046-51 Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P. Ecole Pratique des Hautes Etudes, Laboratoire de Neuromorphologie Fonctionnelle, Universite Montpellier II, 34095-Montpellier cedex 5, France. Experimental lemurs either were infected orally with the agent of bovine spongiform encephalopathy (BSE) or were maintained as uninfected control animals. Immunohistochemical examination for proteinase-resistant protein (prion protein or PrP) was performed on tissues from two infected but still asymptomatic lemurs, killed 5 months after infection, and from three uninfected control lemurs. Control tissues showed no staining, whereas PrP was detected in the infected animals in tonsil, gastrointestinal tract and associated lymphatic tissues, and spleen. In addition, PrP was detected in ventral and dorsal roots of the cervical spinal cord, and within the spinal cord PrP could be traced in nerve tracts as far as the cerebral cortex. Similar patterns of PrP immunoreactivity were seen in two symptomatic and 18 apparently healthy lemurs in three different French primate centers, all of which had been fed diets supplemented with a beef protein product manufactured by a British company that has since ceased to include beef in its veterinary nutritional products. This study of BSE-infected lemurs early in their incubation period extends previous pathogenesis studies of the distribution of infectivity and PrP in natural and experimental scrapie. The similarity of neuropathology and PrP immunostaining patterns in experimentally infected animals to those observed in both symptomatic and asymptomatic animals in primate centers suggests that BSE contamination of zoo animals may have been more widespread than is generally appreciated. [url=http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract[/url] 1: Vet Rec 1993 Apr 17;132(16):403-6 Experimental transmission of BSE and scrapie to the common marmoset. Baker HF, Ridley RM, Wells GA. Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex. Two young male common marmosets (Callithrix jacchus) were injected intracerebrally and intraperitoneally with a crude brain homogenate prepared from a cow with bovine spongiform encephalopathy (BSE). Two other marmosets were similarly injected with brain homogenate from a sheep with natural scrapie. The two animals injected with scrapie material developed neurological signs 38 and 42 months after injection and the two animals injected with BSE material developed neurological signs after 46 and 47 months. Post mortem examination of the brains revealed spongiform encephalopathy especially in the basal nuclei and diencephalon of all the animals and, in addition, involvement of the cerebral cortex of the marmosets injected with scrapie material. The experiment extends the host range of experimental BSE to include a primate species. [url=http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract[/url] 1: J Gen Virol 1991 Mar;72 ( Pt 3):589-94 Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. Marsh RF, Bessen RA, Lehmann S, Hartsough GR. Department of Veterinary Science, University of Wisconsin-Madison 53706. Epidemiological investigation of a new incident of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed that the mink rancher had never fed sheep products to his mink but did feed them large amounts of products from fallen or sick dairy cattle. To investigate the possibility that this occurrence of TME may have resulted from exposure to infected cattle, two Holstein bull calves were injected intracerebrally with mink brain from the Stetsonville ranch. Each bull developed a fatal spongiform encephalopathy 18 and 19 months after inoculation, respectively, and both bovine brains passaged back into mink were highly pathogenic by either intracerebral or oral inoculation. These results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States. [url=http://www.ncbi.nlm.nih.gov/entrez/...3&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...3&dopt=Abstract[/url] 1: Ital J Neurol Sci 1983 Apr;4(1):61-4 Creutzfeld-Jakob disease in the province of Siena: two cases transmitted to monkeys. Fieschi C, Orzi F, Pocchiari M, Nardini M, Rocchi F, Asher D, Gibbs C, Gajdusek D. Two cases of histopathologically documented Creutzfeldt-Jakob disease were observed in the same area of the province of Siena in 1974-1975. The transmission of the disease was obtained through brain homogenates and lymphnodes in one of the two cases. This confirms that the agent is present in other tissues besides the brain and underlines further the analogies between Creutzfeld-Jakob disease and scrapie. [url=http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract[/url] 1: Dev Biol Stand 1993;80:9-13 Transmission of human spongiform encephalopathies to experimental animals: comparison of the chimpanzee and squirrel monkey. Asher DM, Gibbs CJ Jr, Sulima MP, Bacote A, Amyx H, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20992. The agents of kuru and Creutzfeldt-Jakob disease have been consistently transmitted from patients with those diseases to chimpanzees and squirrel monkeys, as well as to other new-world primates, with average incubation periods of two or three years. No other animals have been found so consistently susceptible to the agents in human tissues. More rapid and convenient assays for the infectious agents would greatly facilitate research on the spongiform encephalopathies of humans. [url=http://www.ncbi.nlm.nih.gov/entrez/...9&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...9&dopt=Abstract[/url] 1: J Vet Diagn Invest 2001 Jan;13(1):91-6 Preliminary findings on the experimental transmission of chronic wasting disease agent of mule deer to cattle. Hamir AN, Cutlip RC, Miller JM, Williams ES, Stack MJ, Miller MW, O'Rourke KI, Chaplin MJ. National Animal Disease Center, ARS, USDA, Ames, IA 50010, USA. To determine the transmissibility of chronic wasting disease (CWD) to cattle and to provide information about clinical course, lesions, and suitability of currently used diagnostic procedures for detection of CWD in cattle, 13 calves were inoculated intracerebrally with brain suspension from mule deer naturally affected with CWD. Between 24 and 27 months postinoculation, 3 animals became recumbent and were euthanized. Gross necropsies revealed emaciation in 2 animals and a large pulmonary abscess in the third. Brains were examined for protease-resistant prion protein (PrP(res)) by immunohistochemistry and Western blotting and for scrapie-associated fibrils (SAFs) by negative-stain electron microscopy. Microscopic lesions in the brain were subtle in 2 animals and absent in the third case. However, all 3 animals were positive for PrP(res) by immunohistochemistry and Western blot, and SAFs were detected in 2 of the animals. An uninoculated control animal euthanized during the same period did not have PrP(res) in its brain. These are preliminary observations from a currently in-progress experiment. Three years after the CWD challenge, the 10 remaining inoculated cattle are alive and apparently healthy. These preliminary findings demonstrate that diagnostic techniques currently used for bovine spongiform encephalopathy (BSE) surveillance would also detect CWD in cattle should it occur naturally. [url=http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract[/url] P.S. the study above confirmed 5 cows and 1 goat transmission of CWD to cattle, of the final stages of the study. ...tss Published online before print March 20, 2001, 10.1073/pnas.041490898 Neurobiology Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt- Jakob disease: Implications for human health Corinne Ida Lasmézas*,dagger, Jean-Guy Fournier*, Virginie Nouvel*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas KoppDagger , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce||, Dominique Dormont*, and Jean-Philippe Deslys* snip... Discussion One aim of this study was to determine the risk of secondary transmission to humans of vCJD, which is caused not by a primarily human strain of TSE agent but by the BSE strain having passed the species barrier to humans. This risk is tightly linked to the capacity of the BSE agent to adapt to primates and harbor enhanced virulence (i.e., induce disease after a short incubation period and provoke disease even if highly diluted) and to its pathogenicity after inoculation by the peripheral route. With respect to the latter, there are huge variations between different TSE agent strains and hosts. For example, the BSE agent is pathogenic to pigs after i.c. inoculation but not after oral administration (23). Thus, we wanted to know to what extent the BSE/vCJD agent is pathogenic to humans by the i.c. and i.v. routes. To achieve this, we used the macaque model. To monitor the evolution of the BSE agent in primates, but also to verify the identity of French vCJD, we conducted parallel transmission to C57BL/6 mice, allowing strain-typing. The experimental scheme is depicted in Fig. 1. Characterization of the BSE Agent in Primates. The identity of the lesion profiles obtained from the brains of the French patient with vCJD, two British patients with vCJD, and nonhuman primates infected with BSE provides experimental demonstration of the fact that the BSE agent strain has been transmitted to humans both in the U.K. and in France. Further, it lends support to the validity of the macaque model as a powerful tool for the study of vCJD. As far as the evolution of the BSE agent in primates is concerned, we observed an interesting phenomenon: at first passage of BSE in macaques and with vCJD, there was a polymorphism of the lesion profile in mice in the hippocampal region, with about half of them harboring much more severe vacuolation than the mice inoculated with cattle BSE. At second passage, the polymorphism tended to disappear, with all mice showing higher vacuolation scores in the hippocampus than cattle BSE mice. This observation suggests the appearance of a variant of the BSE agent at first passage in primates and its clonal selection during second passage in primates. The lesion profiles showed that it was still the BSE agent, but the progressive appearance of a "hippocampal signature" hallmarked the evolution toward a variant by essence more virulent to primates. Characterization of the CJD and Scrapie Strains. Controls were set up by transmitting one French and one U.S. scrapie isolate from ruminants as well as French sCJD and iCJD cases from humans. None of these revealed a lesion profile or transmission characteristics similar or close to those of BSE or vCJD, respectively, thus extending to the present French scrapie isolate the previous observation that the BSE agent was different from all known natural scrapie strains (4, 24). The lesion profiles of sCJD and iCJD differed only slightly in severity of the lesions, but not in shape of the profile, revealing the identity of the causative agents. One of us reported the absence of similarity between sCJD (six cases) and U.K. scrapie (eight cases) in transmission characteristics in mice (4). Herein, we made the striking observation that the French natural scrapie strain (but not the U.S. scrapie strain) has the same lesion profile and transmission times in C57BL/6 mice as do the two human TSE strains studied. This strain "affiliation" was confirmed biochemically. There is no epidemiological evidence for a link between sheep scrapie and the occurrence of CJD in humans (25). However, such a link, if it is not a general rule, would be extremely difficult to establish because of the very low incidence of CJD as well as the existence of different isolates in humans and multiple strains in scrapie. Moreover, scrapie is transmissible to nonhuman primates (26). Thus, there is still a possibility that in some instances TSE strains infecting humans do share a common origin with scrapie, as pointed out by our findings. Transmission of vCJD and BSE to Nonhuman Primates. vCJD transmitted readily to the cynomolgus macaque after 2 years of incubation, which was comparable to the transmission obtained from first-passaged macaque BSE and much shorter than the interspecies transmission of BSE. Starting with 100 mg of BSE-macaque brain material, dilutions up to 4 µg still provoked disease. These data suggest that the BSE agent rapidly adapts to primates accompanied by enhanced virulence. Examination of macaque brain inoculated with vCJD revealed a similar pathology to that with second-passage BSE. The distribution of vacuolation and gliosis, as well as the pattern of PrP deposition, including the dense, sometimes florid plaques, were similar to the human vCJD and the BSE hallmarks of the first passage (1, 2). These data show that the phenotype of BSE in primates is conserved over two passages. Moreover, they confirm that the BSE agent behaves similarly in humans and macaques, a precious finding that will prove useful in the near future for the design of pathogenesis or therapeutic studies. Because of the number of macaques examined in this study, we can now reliably state that the pathology, in particular the PrP deposition pattern provoked by BSE, is similar in older and very young animals. However, plaque deposition is greater, and mature florid plaques were more numerous, in the young, which may be correlated with a longer duration of the clinical phase observed in this animal (2). This is important with regard to the fact that vCJD has been diagnosed mainly in teenagers and young adults, which raises the concern that older patients may have been misdiagnosed because of an alternative phenotype of the disease. One should bear in mind, however, that cynomolgus macaques are all homozygotes for methionine at codon 129 of the PrP gene. Thus, our observations may not be relevant to humans carrying one or both valine alleles; however, all patients with vCJD reported to date have been M/M at this position (27). Intravenous Transmissions to Nonhuman Primates. Brain pathology was identical in macaques inoculated i.c. and i.v. The i.v. route proved to be very efficient for the transmission of BSE, as shown by the 2-year survival of the animals, which is only 5 months longer than that obtained after inoculating the same amount of agent i.c. As the i.v. injection of the infectious agent implies per se a delayed neuroinvasion compared with a direct inoculation in the brain, this slight lengthening of the incubation period cannot, at this stage, be interpreted as a lower efficiency of infection as regards the i.c. route. These data should be taken into account in the risk assessment of iatrogenic vCJD transmission by i.v. administration of biological products of human origin. They also constitute an incentive for a complete i.v. titration. Conclusions From BSE and vCJD transmissions in nonhuman primates, a number of conclusions can be drawn that are of major importance for human health: (i) human-adapted BSE appears to be a variant of the BSE agent that is more virulent for humans than cattle BSE and is efficiently transmitted by the peripheral route; (ii) the detection of vCJD in unusually young patients is probably not because of a lack of diagnosis of cases in older patients, thus raising the question of the source of human contamination with BSE early in life; and (iii) iatrogenic transmissions from patients with vCJD would be readily recognized by using the same diagnostic criteria as those applied to vCJD [clinical and pathological criteria (27) comprising neuronal loss and gliosis in the thalamus correlated with high MRI signal (28, 29)], whether such contaminations had occurred by the central or i.v. route. Primary and iatrogenic cases of vCJD could be distinguished on the basis of the patient's clinical history. The risk assessment of biological products of human origin, notably those derived from blood, has been deeply modified by the appearance of vCJD. We confirm that the BSE agent has contaminated humans not only in the U.K. and the Republic of Ireland but also in France, and we show that its pathogenic properties for primates are being enhanced by a primary passage in humans. Considering the flow of potentially contaminated bovine-derived products between 1980 and 1996, it is obvious that further vCJD cases may occur outside the U.K. Thus, and in the light of the present study, it is necessary to sustain worldwide CJD surveillance regardless of national BSE incidence and to take all precautionary measures to avoid iatrogenic transmissions from vCJD. snip... [url=http://www.pnas.org/cgi/content/full/041490898v1]http://www.pnas.org/cgi/content/full/041490898v1[/url] MRC-43-00 [ ] [Text only version of this site] [Print this page] Issued: Monday, 28 August 2000 NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH FINDINGS RELEVANT TO CJD AND BSE A team of researchers led by Professor John Collinge at the Medical Research Council Prion Unit1 report today in the Proceedings of the National Academy of Sciences, on new evidence for the existence of a ?sub-clinical? form of BSE in mice which was unknown until now. The scientists took a closer look at what is known as the ?species barrier? - the main protective factor which limits the ability of prions2 to jump from one species to infect another. They found the mice had a ?sub-clinical? form of disease where they carried high levels of infectivity but did not develop the clinical disease during their normal lifespan. The idea that individuals can carry a disease and show no clinical symptoms is not new. It is commonly seen in conventional infectious diseases. Researchers tried to infect laboratory mice with hamster prions3 called Sc237 and found that the mice showed no apparent signs of disease. However, on closer inspection they found that the mice had high levels of mouse prions in their brains. This was surprising because it has always been assumed that hamster prions could not cause the disease in mice, even when injected directly into the brain. In addition the researchers showed that this new sub-clinical infection could be easily passed on when injected into healthy mice and hamsters. The height of the species barrier varies widely between different combinations of animals and also varies with the type or strain of prions. While some barriers are quite small (for instance BSE easily infects mice), other combinations of strain and species show a seemingly impenetrable barrier. Traditionally, the particular barrier studied here was assumed to be robust. Professor John Collinge said: "These results have a number of important implications. They suggest that we should re-think how we measure species barriers in the laboratory, and that we should not assume that just because one species appears resistant to a strain of prions they have been exposed to, that they do not silently carry the infection. This research raises the possibility, which has been mentioned before, that apparently healthy cattle could harbour, but never show signs of, BSE. "This is a timely and unexpected result, increasing what we know about prion disease. These new findings have important implications for those researching prion disease, those responsible for preventing infected material getting into the food chain and for those considering how best to safeguard health and reduce the risk that theoretically, prion disease could be contracted through medical and surgical procedures." ISSUED FRIDAY 25 AUGUST UNDER EMBARGO. PLEASE NOTE THAT THE EMBARGO IS SET BY THE JOURNAL. FOR FURTHER INFORMATION CONTACT THE MRC PRESS OFFICE ON 020 7637 6011 (OFFICE HOURS) OR 07818 428297 OR 0385 774357 (OUT-OF-OFFICE-HOURS) OR PROFESSOR JOHN COLLINGE ON 020 7594 3760. PLEASE NOTE THAT OWING TO TRAVEL COMMITMENTS PROFESSOR COLLINGE WILL ONLY BE AVAILABLE UNTIL 16.30 ON FRIDAY 25 AUGUST AND CONTACTABLE AGAIN ON MONDAY 28 AUGUST VIA THE MRC PRESS OFFICE. DR ANDREW HILL (A CO-AUTHOR ON THE PAPER) FROM THE DEPARTMENT OF PATHOLOGY AT THE UNIVERSITY OF MELBOURNE WILL BE AVAILABLE ON 00 61 3 8344 3995 (DURING OFFICE HOURS) OR 00 61 3 9443 0009 (OUT-OF-OFFICE HOURS). PLEASE NOTE THAT AUSTRALIA IS TEN HOURS AHEAD OF UK TIME. NOTES FOR EDITORS Professor Collinge is a consultant neurologist and Director of the newly formed MRC Prion Unit based at The Imperial College School of Medicine at St Mary?s Hospital. He is also a member of the UK Government?s Spongiform Encephalopathy Advisory Committee (SEAC). The MRC prion unit is was set up in 1999, and its work includes molecular genetic studies of human prion disease and transgenic modelling of human prion diseases. Prions are unique infectious agents that cause fatal brain diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and BSE (mad cow disease) in animals. In some circumstances prions from one species of animals can infect another and it is clear that BSE has done this to cause the disease variant CJD in the UK and France. It remains unclear how large an epidemic of variant CJD will occur over the years ahead. The strain of prion used here to infect the mice is the Sc237 strain (also known as 263K) which infects hamsters, and until now was assumed not to infect mice. This research was funded by the Medical Research Council and Wellcome Trust. The Medical Research Council (MRC) is a national organisation funded by the UK tax-payer. Its business is medical research aimed at improving human health; everyone stands to benefit from the outputs. The research it supports and the scientists it trains meet the needs of the health services, the pharmaceutical and other health-related industries and the academic world. MRC has funded work which has led to some of the most significant discoveries and achievements in medicine in the UK. About half of the MRC?s expenditure of £345 million is invested in over 50 of its Institutes and Units, where it employs its own research staff. The remaining half goes in the form of grant support and training awards to individuals and teams in universities and medical schools. The Wellcome Trust is the world's largest medical research charity with a spend of some £600 million in the current financial year 1999/2000. The Wellcome Trust supports more than 5,000 researchers, at 400 locations, in 42 different countries to promote and foster research with the aim of improving human and animal health. As well as funding major initiatives in the public understanding of science, the Wellcome Trust is the country's leading supporter of research into the history of medicine. ©2002 Medical Research Council [url=http://www.mrc.ac.uk/index/public_interest/public-press_office/public-press_releases_2000/public-mrc-43-00.htm]http://www.mrc.ac.uk/index/public_inter ... -43-00.htm[/url] and for Gods sake, if someone is smearing this cr@p all over there kids heads for lice and did not come up with a TSE, i would say this is good case study; 1) None of our animals that contracted BSE were treated with OP's, even in utero. 2) My kids were treated with OP's as infants to control head lice. This seems to be endemic as infection waves in UK primary schools (and possibly elsewhere). 3) One might argue if the continued use of british beef in the UK was ethical, none the less it happened. We have a duty to learn from it, not least a duty to learn on behalf of those people who died so horribly.... NOPE, greed and money is the name of the game, they have known for decades; STRICTLY PRIVATE AND CONFIDENTIAL 25, AUGUST 1995 snip... To minimise the risk of farmers' claims for compensation from feed compounders. To minimise the potential damage to compound feed markets through adverse publicity. To maximise freedom of action for feed compounders, notably by maintaining the availability of meat and bone meal as a raw material in animal feeds, and ensuring time is available to make any changes which may be required. snip... THE FUTURE 4.......... MAFF remains under pressure in Brussels and is not skilled at handling potentially explosive issues. 5. Tests _may_ show that ruminant feeds have been sold which contain illegal traces of ruminant protein. More likely, a few positive test results will turn up but proof that a particular feed mill knowingly supplied it to a particular farm will be difficult if not impossible. 6. The threat remains real and it will be some years before feed compounders are free of it. The longer we can avoid any direct linkage between feed milling _practices_ and actual BSE cases, the more likely it is that serious damage can be avoided. ... SEE full text ; [url=http://www.bseinquiry.gov.uk/files/yb/1995/08/24002001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 002001.pdf[/url] BUT, i applaud ranchers that understand the TSE science and not the hype that surrounds it such as 'reader the second' ; >>>Look, Mark Purdey, I applaud you for your perserverance, your bravery in taking on the establishment, and your creativity. It may well be that you were instrumental in bringing the familial and other genetic clusters in Slovenia to the attention of science. I acknowledge that you suffered but your suffering sir is NOTHING compared to the suffering of the families afflicted with CJD and variant CJD and to the extent that your writings are used to ignore public health threats and to avoid taking public health measures that may well protect humans from CJD, then your writings are being ill used. You should acknowledge that and if you do not, I will pay no further attention to you. Your supporters use your writings to (1) deny that CJD is transmissable from person to person, e.g., via contaminated surgical instruments or tissue or blood donations; (2) reject totally the strong hypothesis that variant CJD is due to the BSE epidemic in the UK being "pushed" over the species barrier. They claim that all cases of human CJD are due to metal contamination. It is they who are perverting your theories and therefore subjecting you to ridicule. Unless you deny these things as well and in which case, you should be ignored since in the case of (1) you deny fact and in the case of (2) you reject a hypothesis that must be accepted for the time being and must lead our public health measures given its strength. NO ONE has denied that the ultimate cause of TSEs is unknown. However TSEs ARE transmissable between species, albeit not easily, and they are certainly transmissable among the same species. The suffering of the individual and his/her family who contracts CJD or variant CJD is hideous beyond description. If TSEs are your life work, you had better be taking that into consideration.<<< >>>This is a danger to ranchers and to all humans<<< INDEED there is; CJD FARMERS WIFE 1989 [url=http://www.bseinquiry.gov.uk/files/yb/1989/10/13007001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 007001.pdf[/url] [url=http://www.bseinquiry.gov.uk/files/yb/1989/10/13003001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 003001.pdf[/url] 20 year old died from sCJD in USA in 1980 and a 16 year old in 1981. A 19 year old died from sCJD in France in 1985. There is no evidence of an iatrogenic cause for those cases.... [url=http://www.bseinquiry.gov.uk/files/yb/1995/10/04004001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 004001.pdf[/url] cover-up of 4th farm worker ??? [url=http://www.bseinquiry.gov.uk/files/yb/1995/10/23006001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 006001.pdf[/url] [url=http://www.bseinquiry.gov.uk/files/yb/1995/10/20006001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 006001.pdf[/url] CONFIRMATION OF CJD IN FOURTH FARMER [url=http://www.bseinquiry.gov.uk/files/yb/1995/11/03008001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 008001.pdf[/url] now story changes from; SEAC concluded that, if the fourth case were confirmed, it would be worrying, especially as all four farmers with CJD would have had BSE cases on their farms. to; This is not unexpected... was another farmer expected? [url=http://www.bseinquiry.gov.uk/files/yb/1995/11/13010001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 010001.pdf[/url] 4th farmer, and 1st teenager [url=http://www.bseinquiry.gov.uk/files/yb/1996/02/27003001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 003001.pdf[/url] 2. snip... Over a 5 year period, which is the time period on which the advice from Professor Smith and Dr. Gore was based, and assuming a population of 120,000 dairy farm workers, and an annual incidence of 1 per million cases of CJD in the general population, a DAIRY FARM WORKER IS 5 TIMES MORE LIKELY THAN an individual in the general population to develop CJD. Using the actual current annual incidence of CJD in the UK of 0.7 per million, this figure becomes 7.5 TIMES. 3. You will recall that the advice provided by Professor Smith in 1993 and by Dr. Gore this month used the sub-population of dairy farm workers who had had a case of BSE on their farms - 63,000, which is approximately half the number of dairy farm workers - as a denominator. If the above sums are repeated using this denominator population, taking an annual incidence in the general population of 1 per million the observed rate in this sub-population is 10 TIMES, and taking an annual incidence of 0.7 per million, IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) than that in the general population... [url=http://www.bseinquiry.gov.uk/files/yb/1995/01/31004001.pdf]http://www.bseinquiry.gov.uk/files/yb/1 ... 004001.pdf[/url] 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. PMID: 6997404 [url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract]http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract[/url] TSS [/QUOTE]
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