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From: TSS ()
In Reply to: BSE TESTING CREEKSTONE VS USDA posted by TSS on November 11, 2006 at 3:00 pm:
Case 1:06-cv-00544-JR Document 14-9 Filed 11/03/2006 Page 1 of 47 Creekstone Farms Premium Beef v. USDA Civ. Action No. 06-544 (JR) Plaintiff’s Summary Judgment Reply and Opposition EXHIBIT 8 Case 1:06-cv-00544-JR Document 14-9 Filed 11/03/2006 Page 2 of 47 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA CREEKSTONE FARMS PREMIUM BEEF, LLC, ) ) Plaintiff, ) ) vs. ) Civil Action No. 06-544 (JR) ) UNITED STATES DEPARTMENT OF AGRICULTURE, ) and MIKE JOHANNS, IN HIS CAPACITY AS THE ) SECRETARY OF AGRICULTURE, ) ) Defendants. ) __________________________________________________) DECLARATION OF PAUL W. BROWN, M.D. Paul W. Brown, MD, certifies and states as follows: 1. My entire 43-year career has been devoted to the study of the Spongiform Encephalopathies (TSEs, or ‘prion diseases’) in the National laboratory of Nobel Laureate D. Carleton Gajdusek; and for the last 15 position of Senior Investigator at the National Institute of (NINDS) at the NIH. In this capacity I oversaw and conducted research fatal, neurodegenerative diseases, which include both bovine spongiform commonly referred to as “mad cow” disease, and variant Creutzfeldt-Jakob human TSE infection acquired by the consumption of BSE-contaminated meat 2. Since leaving the NIH two years ago, I have continued to engage in and scientific advisory activities in various aspects of TSE. Ongoing ultra-high pressure methodology to inactivate the agent of BSE; a screening test for TSEs in general, and variant CJD in particular; and a blood infectivity in humans with CJD can be diluted to extinction size of plasma pools used for the extraction of therapeutic proteins have continued to participate in scientific advisory boards, including of LFB (the plasma fractionator in France), co-chairing the scientific pharmaceutical consortium to award research contracts, and advising the global BSE and CJD surveillance, and the Argentine Agriculture also continued to accept invitations to chair and/or lecture at numerous in the Americas and Europe. I am a member of the American College of Physicians, the American Society, the Infectious Diseases Society of America, the American Française de Neurologie, and the American Neurological Association. I infectivity, and inactivation. (A list of scientific papers (published are in press) of which I am an author, primarily regarding TSEs, is 1990, I have been an Associate Editor of the European Journal of 1997, was an Associate editor of the Journal of the Neurological Sciences. 3. Before entering the NIH in the US Public Health Service, I attended (A.B., Magna cum Laude), and the Johns Hopkins School of Medicine (M.D., Honor Society), and undertook Medical Internship and Residency training Hospital in Baltimore, Maryland, and the University of California School Francisco, California. I am a Diplomate of the American Board of (My curriculum vitae is attached to this declaration as Attachment B.) -2 4. At the request of William L. Miller of the William Miller Group, PLLC counsel for Creekstone Farms Premium Beef, LLC), on October 11, 2004, I declaration regarding the current scientific understanding of bovine (BSE) in support of the litigation by Creekstone Farms Premium Beef, LLC voluntarily test for BSE in cattle processed at its plant in Arkansas 11, I have had no relationship with Creekstone Farms. The opinions based solely on my knowledge of BSE and other TSEs that I have gained physician and neuroscientist over the past 45 years. 5. Based on current science, we do not know with certainty how far in displaying clinical signs of BSE a bovine animal could test positive as the rapid test technology developed by Bio-Rad Laboratories, Inc., United States Department of Agriculture to test for BSE. For example, Inspection Agency (CFIA) recently issued a report on a 50-month-old cow that on July 13, 2006 was confirmed as BSE-infected. The CFIA reports This animal was detected and diagnosed with BSE during a pre-clinical disease. The normal disease course to expression of clinical signs in expected to have included an additional three to six months of additional one to two months of clinical expression prior to being symptomatic of BSE and targeted for testing. Had an unrelated disease entry into the surveillance stream, this animal would most likely have clinical signs sometime between 54 and 56 months, not significantly age range of previous cases. -3 Canadian Food Inspection Agency, Report On The Investigation Of The Bovine Spongiform Encephalopathy (BSE) In Canada, available at http://www.inspection.gc.ca/english/anima/heasan/disemala/bseesb/ab2006/7investe.shtml. sample submitted for BSE testing, it would probably have been four to before the cow would have displayed symptoms that might have caused it suspicion of BSE. 6. Experimental studies to determine range of intervals between positive onset of clinical signs have not been done (a critical experiment has in but only infectivity was measured, and tests for the presence of prion done). Wells, G. A. H., S.A. Hawkins, R.B. Green, A.R. Austin, I. Chaplin, M.J. Stack, and M Dawson, 1998, Preliminary observations on the experimental bovine spongiform encephalopathy (BSE): an update, Vet. Wells, G.A.H., J. Spiropoulos, S.A.C. Hawkins, and S. J.Ryder, 2005, experimental bovine spongiform encephalopathy: preclinical infectivity observations on the distribution of lingual tonsil in slaughtered Equally important, field experience in countries that have gone to universal testing above a certain age) has shown that such testing considerably more cases than only testing cattle whose behavior happens of authorities happens to attract the attention of authorities (passive Report on the Monitoring and Testing of Ruminants for the Presence of Spongiform Encephalopathy (TSE) in the EU in 2005, Final Annual Report, Commission, 20 June 2006. (Section 4.2, Chart B2), available at -4 http://ec.europa.eu/food/food/biosafety/bse/annual_reps_en.htm. 7. Assumptions about the likely course of BSE infection in cattle and potential vCJD infection in humans who consume cattle tissues are assumptions or extrapolations from limited data, not tested conclusions. direct evidence of such things as when in life a bovine is most less susceptible, if at all, humans are than cattle; whether shorter the result of exposure to a high dose at a young age or some other susceptibility or the strain of prions); how many humans may ultimately or how effective SRM removal is at reducing the risk of transmission of animal. 8. The question of the interval between when cattle may test positive when those cattle exhibit clinical signs of the disease has in any case recent discovery of atypical cases of BSE that usually occur in older for one reason or another are culled, and are then discovered to test that on visual inspection appear normal are infected, and this fact limited window of 'pre-clinical' positivity in BSE tests, as there are suspicion of infection. The only way that these cattle are identified as testing. The frequency of such infections is not yet known, but so far 1% all the way up to 15% of the total number of test positives. Prion Diseases of NeuroPrion, Network of Excellence, Prion2006, Turin, 2006, Book of Abstracts (hereinafter “Prion2006 Abstracts”), See http://www.neuroprion.com/en/ev_prion2006.html; Brown P, McShane LM, Detwiler L, On the question of sporadic or atypical bovine spongiform -5 Creutzfeldt-Jakob disease, Emerg. Inf. Dis., 2006, 12: 1816-21, in copy of the article is attached to this declaration as Attachment C.) 9. Although these cases of asymptomatic, atypical BSE have been found in cattle, we do not currently know the concentration and distribution of that might have been found in these cattle at an earlier age. Another atypical BSE may be more virulent for humans than typical BSE. This experimental transmission studies in at least 4 different laboratories. onset of disease (shorter incubation periods) following inoculation with typical BSE, and in one study, BSE did not transmit at all. These wild-type mice, bovinized and humanized transgenic mice, and (most primates as recipient animals. Prion2006 Abstracts, See http://www.neuroprion.com/en/ev_prion2006.html. 10. We do not have any direct evidence of how few BSE prions need to be in order for a human to be at risk of vCJD. Just because the disease has enough in a bovine to produce clinical symptoms does not mean that there concentrations of BSE prions in that bovine's tissue to present a risk fact, logic suggests the contrary, because it would imply that all of infected by the consumption of meat products from cattle that were the time of slaughter, which seems highly unlikely.) The available tests believed to have lower limits of detecting concentrations of prions BSE in other cattle, or potentially vCJD in humans. In cattle, the needed to infect a cow by the oral route is only 0.001 gram (Dr. Gerald -6 communication), and this figure has been used for risk analyses in bovine to human 'species barrier' effect has never been documented). 11. Just because cattle are under 30 months of age does not mean that risk of BSE, both because of the facts discussed above about the testing positive for BSE and having sufficiently concentrated prions to humans, and because BSE has been detected in younger cattle in Europe Additionally, the way that the age of cattle to be slaughtered is often not very precise. As a matter of protecting animal and human health from as BSE, detecting even a handful of cases that otherwise would be missed USDA requires testing of agricultural products for numerous diseases extremely rare, such as E. coli. 12. The USDA has performed BSE tests on thousands of cattle younger than 30 months, including thousands that had no clinical signs of BSE. 13. Measures that the United States (and Canada) has put in place to transmission of BSE have substantially reduced the risk in the United eliminated it. Experience has shown that the feed bans are incomplete, limited and because of imperfect implementation. 14. Collecting additional BSE test data from cattle less likely to have of BSE (because they are younger and do not display other risk factors), effective, is not worthless and produces data that could help better distribution in U.S. cattle. (For example, if authorities only tested BSE, the Canadians would not have found BSE in the 50 month old Alberta have outward signs that might have suggested BSE and was born long after -7 cattle feed was believed to have ceased; nor is it likely that either of infected US cows with atypical BSE that tested positive would have been knowledge about atypical BSE, where there are only rarely outward signs animal to be singled out and tested based on suspicion of BSE, makes the asymptomatic cattle even clearer. Voluntary testing does not interfere efforts to test for BSE and to understand the disease. Additionally, in the U.S. are under 30 months of age, many thousands every year are of any other programs under which USDA has prohibited testing for a unlikely that the disease will be found. 15. The USDA recently announced a dramatic (ten-fold) reduction in the cattle it will test for BSE. USDA plans to reduce the current annual only 40,000 (less than 1 % of the cattle that are slaughtered or die Release No. 0255.06, July 20, 2006, available at http://www.usda.gov/wps/portal/!ut/p/_s.7_0_A/7_0_1OB?contentidonly=true&contentid=2006/ government testing does not make any sense for the protection of animal is further indication that voluntary BSE testing is not "worthless." OIE have stated that targeted testing of cattle most likely to have BSE of detecting and monitoring BSE infection in a country's cattle herd, known to have BSE nonetheless have chosen to go far beyond such targeted domestic BSE monitoring programs, especially in view of the growing cattle that have atypical (and asymptomatic) forms of BSE when slaughtered. -8 16. BSE tests do not involve the immune system of the animal that is a sharp distinction between using immunological means to prevent foreign (e.g., active and passive immunization) and the use of an immunologic antibody) to detect infectious prion proteins obtained from the body of of such a test has nothing whatsoever to do with the immune system of dead) animal. USDA thinking on this point is very confused. 17. The USDA allows suppliers of meat and other products to certify that products meet criteria unrelated to food safety (or least, where USDA conclude that there is a food safety benefit). I believe this is true, "natural," "hormone-free, "grass-fed," and other descriptors that USDA legitimate role of the USDA to protect consumers from industry seems unreasonable for USDA to prohibit the private use of its own desire on the part of some consumers to have a higher standard of safety they eat should not be circumvented by this kind of attitude, even if with government assurances of safety based on its own evaluation. I declare under penalty of perjury that the foregoing is true and correct. Executed on October 27, 2006. Paul Brown, M.D. -9 ATTACHMENT A Paul W. Brown, M.D. List of Publications 1991 to Present Paul W. Brown, M.D. LIST OF PUBLICATIONS 1991 TO PRESENT 153. Goldfarb, L.G., Brown, P. and Gajdusek, D.C. Multiple mutations in kuru, Creutzfeldt-Jakob disease, and Gerstmann-Sträussler syndrome. Brain Research, 16: 1 (January), 98-99, 1991. 154. Brown P. and Gajdusek, D.C. New studies on the resistance of scrapie agent to enzymatic digestion, heat and chemical denaturation, and natural weathering. Brain Research, 16: 1 (January), 100-103, 1991. 155. Brown, P. and Gajdusek, D.C. Survival of scrapie virus after 3 years’ interment. Lancet, 337: 8736 (February 2), 269-270, 1991. 156. Goldfarb L.G., Haltia, M., Brown, P., Nieto, A., Kovanan, J., McCombie, W.R., Trapp, S. and Gajdusek, D.C. New mutation in scrapie amyloid precursor gene (codon 178) in Finnish Creutzfeldt-Jakob kindred. Lancet, 337: 8738 (February 16), 425, 1991. 157. Nieto, A., Goldfarb, L.G., Brown, P., McCombie W.R., Trapp, S., Asher, D.M. and Gajdusek, D.C. Codon 178 mutation in ethnically diverse Creutzfeldt-Jakob disease families. Lancet, 337: 8741 (March 9), 622-623, 1991. 158. Fradkin, J.E., Schonberger, L., Mills, J.L., Gunn, W.J., Piper, J.M., Wysowski, D.K., Thomson, R., Durako, S. and Brown, P. Creutzfeldt- Jakob disease in pituitary growth hormone recipients in the United States. Journal of the American Medical Association, 265: 7 (February 20), 880-884, 1991. Also as abstract: Fradkin, J.E., Schonberger, L., Mills, J.L., Gunn, W.J., Piper, J.M., Wysowski, D.K., Thomson, R., Durako, S. and Brown, P. Creutzfeldt- Jakob disease in pituitary growth hormone recipients in the United States. In: “Program and Abstracts, The Endocrine Society 72nd Annual Meeting, Atlanta, GA, June 20-23, 1990, p. 350. 159. Brown, P., Goldfarb, L.G., Brown, W.T., Goldgaber, D., Rubenstein, R., Kascsak, R. J., Piccardo, P., Boellaard, J.W. and Gajdusek, D.C. Clinical and molecular genetic study of a large German kindred with Gerstmann-Sträussler-Scheinker syndrome. Neurology, 41: 3 (March), 375-379, 1991. 160. Brown, P., Goldfarb, L.G. and Gajdusek, D.C. The new biology of spongiform encephalopathy: infectious amyloidoses with a genetic twist. Lancet, 337: 8748 (April 27), 1019-1022, 1991. 161. Pocchiari, M., Peano, S., Conz, A., Eshkol, A., Maillard, F., Brown, P., Gibbs, C.J., Jr., Geng Xi, Y., Tenham-Fisher, E. and Macchi, G. Combination ultrafiltration and 6 M urea treatment of human growth hormone effectively minimizes risk from potential Creutzfeldt-Jakob disease virus contamination. Hormone Research, 35: 3-4 (March-April), 161-166, 1991. 1991 (Con’t.) 162. Brown, P., Goldfarb, L.G., Gibbs, C.J., Jr. and Gajdusek, D.C. The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease. European Journal of Epidemiology, 7:5 (September), 469-476, 1991. 163. Goldfarb, L.G., Brown, P., Mitrová, E., Haltia, M., Cervenáková, L., Goldin, L., Korczyn, A., Chapman, J., Galvez, S., Cartier, L., Rubenstein, R. and Gajdusek, D.C. Familial Creutzfeldt-Jakob disease associated with the PRNP codon 200Lys mutation: an analysis of 45 families. European Journal of Epidemiology, 7:5 (September), 477486, 1991. 164. Mitrová, E., Brown, P., Hroncová, D., Tatara, M. and Zilák, J. Focal accumulation of CJD in Slovakia: retrospective investigation of a new rural familial cluster. European Journal of Epidemiology, 7:5 (September), 487-489, 1991. 165. Haltia, M., Kovanen, J., Goldfarb, L.G., Brown, P. and Gajdusek, D.C. Familial Creutzfeldt-Jakob disease in Finland: epidemiological, clinical, pathological and molecular genetic studies. European Journal of Epidemiology, 1991, 7:5 (September), 494-500, 1991. Also as abstracts: Haltia, M., Kovanen, J., Goldfarb, L.G. and Gajdusek, D.C. Novel mutation in the PRNP amyloid precursor gene co-segregates with Creutzfeldt-Jakob disease in a Finnish family. Abstracts of the 36th Annual Meeting of the Deutsche Gesellschaft für Neuropathologie und Neuroanatomie Düsseldorf, September 16-18, 1991. Clinical Neuropathology, 10: 5 (September/October), 257, 1991 Haltia, M., Kovanen, J., Goldfarb, L.G., Brown, P. and Gajdusek, D.C. A new mutation (at codon 178) in the PRNP amyloid precursor gene Abstracts of the First Hungarian Conference of Neuropathology and the 5th Hungarian-Polish Neuropathological Symposium, Budapest, September 26-28, 1991. Ideggyógyászati Szemle (Neurological Review), 44 (Suppl. 1), 35, 1991. 166. Liberski, P.P., Kwiecinski, H., Barcikowska, M., Mirecka, B., Kulczycki, J., Kida, E., Brown, P. and Gajdusek, D.C. PrP amyloid plaques in Creutzfeldt-Jakob disease of short duration: immunohistochemical studies of 5 cases from Poland. European Journal of Epidemiology, 7:5 (September), 505-510, 1991. 167. Brown, P. The clinical epidemiology of Creutzfeldt-Jakob disease in the context of bovine spongiform encephalopathy. In: “Sub-acute Spongiform Encephalopathies”, R. Bradley, M. Savey and B.A. Marchant, editors. Kluwer Academic Publishers, Dordrecht (The Netherlands), 1991, pp.195-202. 168. Brown, P. and Gajdusek, D.C. The human spongiform encephalopathies: kuru, Creutzfeldt-Jakob disease, and the Gerstmann-Sträussler- Scheinker syndrome. In: “Transmissible Spongiform Encephalopathies: Scrapie, BSE and Related Disorders”, B.W. Chesebro, editor. Current Topics in Microbiology and Imunology, volume 172, Springer Verlag, Berlin, 1991, pp.1-20. 2 1991 (Con’t.) 169. Brown, P. Molecular genetics of spongiform encephalopathy. Neuroscience Facts, 2:19 (October 3), 2, 1991. 170. Brown, P., Goldfarb, L.G., Cathala, F., Vrbovská, A., Sulima, M., Nieto, A., Gibbs, C.J., Jr. and Gajdusek, D.C. The molecular genetics of familial Creutzfeldt-Jakob disease in France. Journal of the Neurological Sciences, 105:2 (October), 240-246, 1991. 171. Scrimgeour, E.M. and Brown, P. BSE and potential risks to slaughtermen. Veterinary Record, 129: 17 (October 26), 390-391, 1991. 172. Liberski, P.P., Brown, P., Shu-Yan, X. and Gajdusek, D.C. The ultrastructural diversity of scrapie-associated fibrils isolated from experimental scrapie and Creutzfeldt-Jakob disease. Journal of Comparative Pathology, 105:4 (November), 377-386, 1991. 173. Trabattoni, G., Lechi, A., Bettoni, L., Macchi, G., Masullo, C., Brown, P. and Pocchiari, M. Creutzfeldt-Jakob disease in Italy (letter to the editor). European Journal of Epidemiology, 7: 6 (November), 713-714, 1991. 174. Goldfarb, L.G., Brown, P., McCombie, W.R., Goldgaber, D., Swergold, G.D., Wills, P.R., Cervenáková, L., Baron, H., Gibbs, C.J., Jr. and Gajdusek, D.C. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proceedings of the National Academy of Sciences (USA), 88:23 (December 1), 1092610930, 175. Laplanche, J.-L., Chatelain, J., Thomas, S., Brown, P. and Cathala, F. Analyse du gene PrP dans une famille d’origine Tunisienne atteinte de maladie de Creutzfeldt-Jakob. Revue Neurologique (Paris), 147: 12 (December), 825-827, 1991. 176. Korczyn, A.D., Chapman, J., Goldfarb, L.G., Brown, P. and Gajdusek, D.C. A mutation in the prion protein gene in Creutzfeldt-Jakob disease in Jewish patients of Libyan, Greek, and Tunisian origin. Annals of the New York Academy of Sciences, 640:(December 3), 171176, 1991. 177. Brown, P., Goldfarb, L.G., McCombie, W.R., Nieto, A., Squillacote, D., Sheremata, W., Little, B.W., Godec, M.S., Gibbs, C.J., Jr. and Gajdusek, D.C. Atypical Creutzfeldt-Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene. Neurology, 42:2 (February), 422-427, 1992. 178. Goldfarb, L.G., Brown, P., Haltia, M., Cathala, F., McCombie, W.R., Kovanen, J., Goldin, L., Nieto, A., Godec, M.S., Asher, D.M.and Gajdusek, D.C. Creutzfeldt-Jakob disease co-segregates with the codon 178Asn PRNP mutation in families of European origin. Annals of Neurology, 31:3 (March), 274-281, 1992. 3 1992 (Con’t.) 179. Brown, P., Goldfarb, L.G., Kovanen, J., Haltia, M., Cathala, F., Sulima, M., Gibbs, C.J., Jr. and Gajdusek, D.C. Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn mutation. Annals of Neurology, 31:3 (March), 282-285, 1992. 180. Brown, P. The phenotypic expression of different mutations in transmissible human spongiform encephalopathy. Revue Neurologique (Paris), 148:5 (May), 317-327, 1992. 181. Chapman, J., Brown, P., Rabey, M.J., Goldfarb, L.G., Inzelberg, R., Gibbs, C.J., Jr., Gajdusek, D.C. and Korczyn, A.D. Transmission of spongiform encephalopathy from a familial Creutzfeldt-Jakob disease patient of Jewish Libyan origin carrying the PRNP codon 200 mutation. Neurology, 42:6 (June), 1249-1250. 1992. Also as abstract: Brown, P., Goldfarb, L.G., Gibbs, C.J., Jr., Gajdusek, D.C., Chapman, J., Rabey, M.J., Inzelberg, R. and Korczyn, A.D. Transmission of spongiform encephalopathy from a Creutzfeldt-Jakob disease (CJD) patient of Jewish Libyan origin carrying the PRNP codon 200 mutation. Abstract no. 781S in: “ American Academy of Neurology 44th Annual Meeting”, San Diego, May 3-9, 1992. Neurology, 42:4 (April), Supplement 3, 370, 1992. 182. Brown, P., Preece, M.A. and Will, R.G. “Friendly fire” in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet, 340:8810 (July 4), 24-27, 1992. 183. Goldfarb, L.G., Brown, P., Vrbovská, A., Baron, H., McCombie, W.R., Cathala, F., Gibbs, C.J., Jr. and Gajdusek, D.C. An insert mutation in the chromosome 20 amyloid precursor gene in a Gerstmann- Sträussler-Scheinker family. Journal of the Neurological Sciences, 111:2 (September), 189-194, 1992. 184. Brown, P., Gálvez, S., Goldfarb, L.G., Nieto, A., Cartier, L., Gibbs, C.J., Jr. and Gajdusek, D.C. Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200 mutation of the PRNP amyloid precursor gene on chromosome 20. Journal of the Neurological Sciences, 112:1,2 (October), 65-67, 1992. 185. Goldfarb, L.G., Petersen, R.B., Tabaton, M., Brown, P, LeBlanc, A.C., Montagna, P., Cortelli, P., Julien, J., Vital, C., Pendelbury, W.W., Haltia, M., Wills, P.R, Hauw, J.J., McKeever, P.E., Monari, L., Schrank, B., Swergold, G.D., Autilio-Gambetti, L., Gajdusek, D.C., Lugaresi, E. and Gambetti, P. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science, 258:5083 (October 30), 806-808, 1992. Also as abstract: Petersen, R.B., Goldfarb, L., Tabaton, M., Brown, P, LeBlanc, A., Montagna, P., Cortelli, P., Monari, L., Autilio-Gambetti, L., Gajdusek, D.C., Lugaresi, E. and Gambetti, P. Fatal familial insomnia and one subtype of familial Creutzfeldt-Jakob disease: effect of a polymorphism on a pathogenic mutation in the prion protein. The FASEB Journal, 7: 4 (February 23), A627, 1993. 4 1992 (Con’t.) 186. Bertoni, J.M., Brown, P., Goldfarb, L.G., Rubenstein, R. and Gajdusek, D.C. Familial Creutzfeldt-Jakob disease (codon 200 mutation) with supranuclear palsy. Journal of the American Medical Association, 268:17 (November 4), 2413-2415, 1992. 187. Goldfarb, L.G., Brown, P. and Gajdusek, D.C. The molecular genetics of human transmissible spongiform encephalopathy. In: “Prion Diseases of Humans and Animals”, S.B. Prusiner, J. Collinge, J. Powell and B. Anderton, editors, Ellis Horwood, Chichester (England), 1992, pp.139-153. 1993 188. Brown, P. The molecular biology and genetics of spongiform encephalopathy. In: “Light and Electron Microscopic Neuropathology of Slow Virus Disorders”, P.P. Liberski, editor. CRC Press, Boca Raton, Florida, 1993, pp.63-100. 189. Liberski, P.P., Guiroy, D.C., Williams, E.S., Yanagihara, R., and Gajdusek, D.C. The amyloid plaque. In: “Light and Electron Microscopic Neuropathology of Slow Virus Disorders”, P.P. Liberski, editor. CRC Press, Boca Raton, Florida, 1993, pp.295-347. 190. Liberski, P.P. and Brown, P. Scrapie-associated fibrils. In: “Light and Electron Microscopic Neuropathology of Slow Virus Disorders”, P.P. Liberski, editor. CRC Press, Boca Raton, Florida, 1993, pp.393414. 191. Brown, P., Kaur, P., Sulima, M.P., Goldfarb, L.G., Gibbs, C.J., Jr. Gajdusek, D.C. Real and imagined clinicopathological limits of “prion dementia”. Lancet, 341:8838 (January 16), 127-129, 1993. 192. Brown, P. “Prion dementia”: Author’s reply to Letters to the Editor concerning Real and imagined clinicopathological limits of “prion dementia”. Lancet, 341:8845 (March 6), 627-628, 1993. 193. Gibbs, C.J., Jr., Asher, D.M., Brown, P.W., Fradkin, J.E. and D.C. Creutzfeldt-Jakob disease infectivity of growth hormone derived from human pituitary glands. New England Journal of Medicine, 328:5 (February 4), 358-359, 1993. 194. Goldfarb, L.G., Brown, P., Haltia, M., Ghiso, J., Frangione, B. and Gajdusek, D.C. Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils. Proceedings of the National Academy of Sciences (USA), 90:10 (May 15), 4451-4454, 1993. 195. Brown, P. EEG findings in Creutzfeldt-Jakob disease (Questions and Answers section). Journal of the American Medical Association, 269: 24 (June 23), 3168, 1993. 5 1993 (Con’t.) 196. Brown, P. Infectious cerebral amyloidosis: clinical spectrum, risks and remedies. In: “Developments in Biological Standardization”, F. Brown, editor. Karger, Basal, 1993, volume 80, pp.91-101. Also as abstract: Brown, P. The clinico-pathologic features of transmissible human spongiform encephalopathy, with a discussion of recognized risk factors and preventive strategies. In: Abstracts of an International Meeting on Transmissible Spongiform Encephalopathies: Impact on Animal and Human Health, Heidelberg, June 23-24, 1992, p.4. 197. Goldfarb, L.G., Brown, P., Little, B.W., Cervenáková, L., Kenney, K., Gibbs, C.J., Jr. and Gajdusek, D.C. A new (two repeat) octapeptide coding insert mutation in Creutzfeldt-Jakob disease. Neurology, 43: 11 (November), 2392-2394, 1993. 198. Barcikowska, M., Liberski, P.P, Boellaard, J.W., Brown, P., Gajdusek, D.C. and Budka, H. Microglia is a component of the prion protein amyloid plaque in the Gerstmann-Sträussler-Scheinker syndrome. Acta Neuropathologica, 85: 6 (May), 623-627, 1993. 199. Chapman, J., Brown, P., Goldfarb, L.G., Arlazoroff, A., Gajdusek, D.C. and Korczyn, A.D. Clinical heterogeneity and unusual presentations of Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation. Journal of Neurology, Neurosurgery and Psychiatry, 56: 10 (October), 1109-1112, 1993. 1994 200. Brown, P. Transmissible human spongiform encephalopathy (infectious cerebral amyloidosis): Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru. Chapter 48 in: “Neuro-degenerative Diseases”, D.B. Calne, editor. W.B. Saunders Co., Philadelphia, 1994, pp.839-876. 201. Brown, P. Infectious cerebral amyloidoses: Creutzfeldt-Jakob disease and the Gerstmann-Sträussler-Scheinker syndrome. Chapter 14 in: “Handbook of Dementing Illnesses”, J C. Morris, editor. Marcel Dekker, Inc., New York, 1994, pp.353-375. Also as abstract: Brown, P. Clinical and laboratory diagnosis of spongiform encephalopathy. XIVth European Congress of Pathology, September 5-10, 1993, Innsbruck, Austria. Pathology Research and Practice, 189: 6-7 (August), 661, 1993. 202. Brown, P., Cervenáková, L., Goldfarb, L.G., Gajdusek, D.C., Haverkamp, A., Haverkamp, C., Horwitz, J., Creacy, S.D., Bever, R.A., Wexler, P., Sujansky, E. and Bjork, R.J. Molecular genetic testing of a fetus at risk of Gerstmann-Sträussler Scheinker syndrome. Lancet, 343: 8890 (January 15), 181-182, 1994. 203. Goldfarb, L.G., Brown, P., Cervenáková, L. and Gajdusek, D.C. Genetic analysis of Creutzfeldt-Jakob disease and related disorders. Philosophical Transactions of the Royal Society of London (Series B), 343: 1306 (March 29), 379-384, 1994. 6 1994 (Con’t.) 204. Brown, P., Goldfarb, L.G., Cervenáková, L., McCombie, W.R., Rubenstein, R., Will, R.G., Pocchiari, M., Martinez-Lage, J.F., Scalici, C., Masullo, C, Graupera, G., Ligan, J. and Gajdusek, D.C. Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine. Neurology, 44: 2 (February), 291-293, 1994. 205. Monari, L., Chen, S.G., Brown, P., Parchi, P., Petersen, R.B., Mikol, J., Gray, F., Cortelli, P., Montagna, P., Ghetti, B., Goldfarb, L.G., Gajdusek, D.C., Lugaresi, E., Gambetti, P. and Autilio-Gambetti, L. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proceedings of the National Academy of Sciences (USA), 91: 7 (March 29), 2839-2842, 1994. 206. Lane, K.L., Brown, P., Howell, D.N., Crain, B.J., Hulette, C.M., Burger, P.C. and DeArmond, S.J. Creutzfeldt-Jakob disease in a pregnant woman with an implanted dura mater graft. Neurosurgery, 34: 4 (April), 737-740, 1994. 207. Alperovitch, A., Brown, P., Weber, T., Pocchiari, M., Hofman, A. R. Incidence of Creutzfeldt-Jakob disease in Europe in 1993. Lancet, 343: 8902 (April 9), 918, 1994. 208. Garruto, R.M. and Brown, P. Tau protein, aluminium, and Alzheimer’s disease (Commentary). Lancet, 343: 8904 (April 23), 989, 1994. 209. Brown, P., Gibbs, C.J., Jr., Rodgers-Johnson, P., Asher, D.M., Sulima, M.P., Bacote, A., Goldfarb, L.G. and Gajdusek, D.C. Human spongiform encephalopathy: the National Institutes of Health Series of 300 cases of experimentally transmitted disease. Annals of Neurology, 35: 5 (May), 513-529, 1994. 210. Brown, P. The “brave new world” of transmissible spongiform encephalopathy (infectious cerebral amyloidosis). Molecular Neurobiology, 8: 2-3 (April-June), 79-87, 1994. 211. Goldfarb, L.G., Brown, P., Cervenáková, L. and Gajdusek, D.C. Molecular genetic studies of Creutzfeldt-Jakob disease. Molecular Neurobiology, 8: 2-3 (April-June), 89-97, 1994. 212. Petersen, R.B., Goldfarb, L.G., Tabaton, M., Brown, P., Monari, L., Cortelli, P., Montagna, P., Autilio-Gambetti, L., Gajdusek, D. C., Lugaresi, E. and Gambetti, P. A novel mechanism of phenotypic heterogeneity demonstrated by the effect of a polymorphism on a pathogenic mutation in the PRNP (prion protein gene). Molecular Neurobiology, 8: 2-3 (April-June), 99-103, 1994. 213. Brown, P., Cervenáková, L., Boellaard, J.W., Stavrou, D., Goldfarb, and Gajdusek, D.C. Identification of a PRNP mutation in Jakob’s original Creutzfeldt-Jakob disease family. Lancet, 344: 8915 (July 9), 130-131, 1994. 7 1994 (Con’t.) 214. Haltia, M., Viitanen, M., Sulkava, R., Ala-Hurula, V., Poyhonen, M., Goldfarb, L., Brown, P., Levy, E., Houlden, H., Crook, R., Goate, A., Clark, R., Korenblat, K., Pandit, S., Keller, H.D., Lilius, L., Liu, L., Axelman, K., Forsell, L., Winblad, B., Lannfelt, L. and Hardy, J. Chromosome 14-encoded Alzheimer’s disease: genetic and clinicopathological description. Annals of Neurology, 36: 3 (September), 362-367, 1994. 215. Brown, P. [Debate] Vertical transmission of prion disease [response to an article entitled “The transmission of prion disease: vertical transfer of prion disease” by R.W. Lacey and S.F. Dealler]. Human Reproduction, 9: 10 (October), 1796-1797, 1994. 216. Martinez-Lage, J.F., Poza, M., Sola, J., Tortosa, J.G., Brown, P., Cervenáková, L., Esteban, J.A. and Mendoza, A. Accidental transmission of Creutzfeldt-Jakob disease by dural cadaveric grafts. Journal of Neurology, Neurosurgery and Psychiatry, 57: 10 (October), 1091-1094, 1994. 217. Cervenáková, L., Brown, P., Goldfarb, L.G., Nagle, J., Pettrone, K., Rubenstein, R., Gibbs, C.J., Jr and Gajdusek, D.C. Infectious amyloid precursor gene sequences in primates used for experimental transmission of human spongiform encephalopathy. Proceedings of the National Academy of Sciences (USA), 91, 25, (December 6), 12159-12162, 1994. 1995 218. Goldfarb, L.G. and Brown, P. The transmissible spongiform encephalopathies. Annual Review of Medicine, 46: 57-65, 1995. 219. Lang, C.J.G., Schüler, P., Engelhardt, A., Spring, A. and Brown, P. Probable Creutzfeldt-Jakob disease after a cadaveric dural graft. European Journal of Epidemiology, 11: 1 (February), 79-81, 1995. 220. Billette de Villemeur, T., Fournier, J-G., Robain, O., Escaig-Haye, Brown, P. Electronmicroscopic detection of prion-protein-positive fibres in brain from iatrogenic Creutzfeldt-Jakob disease. Lancet, 345: 8953 (April 1), 861-862, 1995. 221. Barcikowska, M., Kwiecinski, H., Liberski, P.P., Kowalski, J., Brown, P. and Gajdusek, D.C. Creutzfeldt-Jakob disease with Alzheimer- type Ab-reactive amyloid plaques. Histopathology, 26:5 (May), 445-450, 1995. 222. Reder, A.T., Mednick, A.S., Brown, P., Spire, J.P., Van Cauter, E., Wollmann, R.L., Cervenáková, L., Goldfarb, L.G., Garay, A., Ovsiew, F., Gajdusek, D.C. and Roos, R.P. Clinical and genetic studies of fatal familial insomnia. Neurology, 45: 6 (June), 1068-1075, 1995. Also as abstract: Mednick, A.S., Reder, T., Spire, J.P., Van Cauter, E., Brown, P., Wollmann, R.L., Goldfarb, L.G., Garay, A., Ovsiew, F., Gajdusek, D.C. and Roos, R.P. Fatal familial insomnia (FFI). Proceedings of the 46th Annual Meeting of the American Academy of Neurology, May 1-7, 1994 in Washington, D.C. (Abstract 629P). Neurology, 44: (Suppl 2) 4 (April), A285-286, 1994. 8 1995 (Con’t.) 223. Hainfellner, J.A., Brantner-Inthaler, S., Cervenáková, L., Brown, P., Kitamoto, T., Tateishi, J., Diringer, H., Liberski, P.P., Regele, H., Feucht, M., Mayr, N., Wessely, P., Summer, K., Seitelberger, F. and Budka, H. The original Gerstmann-Stäussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype. Brain Pathology, 5: 3 (July), 201-211, 1995. 224. Budka, H., Aguzzi, A., Brown, P., Brucher, J-M., Bugiani, O., Collinge, J., Diringer, H., Gullotta, F., Haltia, M., Hauw, J-J., Ironside, J.W., Kretzschmar, H.A., Lantos, P.L., Masullo, C., Pocchiari, M., Schlote, W., Tateishi, J. and Will, R.G. Consensus Report: Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathology, 5: 3 (July), 319-322, 1995. 225. Budka, H., Aguzzi, A., Brown, P., Brucher, J-M., Bugiani, O., Gullotta, F., Haltia, M., Hauw, J.-J., Ironside, J.W., Jelinger, K., Kretzschmar, H.A., Lantos, P.L., Masullo, C., Schlote, W., Tateishi, J. and Weller, R.O. Consensus Report: Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathology, 5: 3 (July), 459-466. 226. Tateishi, J., Brown, P., Kitamoto, T., Hoque, Z.M., Roos, R., Wollman, R. and Gajdusek, D.C. First experimental transmission of fatal familial insomnia. Nature, 376: 6539 (August 3), 434-435, 1995. 227. Brown, P., Kenney, K., Little, B., Ironside, J., Will, R., Cervenáková, L., San Martin, R.A., Safar, J., Roos, R., Harris, S., Haltia, M., Gibbs, C.J., Jr. and Gajdusek, D.C. Intracerebral distribution of infectious amyloid protein in spongiform encephalopathy. Also as abstract: Brown, P., Kenney, K., Little, B., Ironside, J., Safar, J., Rohwer, R., Roos, R., Wollmann, R., Gibbs, C.J., Jr and Gajdusek, D.C. Comparison of clinical features, neuropathology, and intracerebral distribution of PrP amyloid protein in the brains of patients with spongiform encephalopathy. Neurobiology of Aging, 15 (Supplement 1), p.S150 (Abstract No. 619), 1994. 228. Beekes, M., Baldauf, E., Cassens, S., Diringer, H., Keyes, P., Scott, A.C., Wells, G.A.H., Brown, P., Gibbs, C.J., Jr. and Gajdusek, D.C. Western blot mapping of disease-specific amyloid in various animal species and humans with transmissible spongiform encephalopathies using a high-yield purification method. Journal of General Virology, 76: 10 (October), 2567-2576, 1995. 229. Brown, P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Current Opinion in Hematology, 2: 6 (November), 472-477, 1995. 230. Brown, P. [Education and Debate] Creutzfeldt-Jakob disease and bovine spongiform encephalopathy: any connection? The jury is still out. British Medical Journal, 311: 7017 (November 25), 1416, 1995. 9 231. Masullo, C., Brown, P.W. and Macchi, G. Creutzfeldt-Jakob disease in an Iranian: the first clinico-pathologically described case. Clinical Neuropathology, 15: 1 (January), 26-29, 1996. 232. Budka, H., Aguzzi, A., Brown, P., Brucher, J.-M., Bugiani, O., Collinge, J., Diringer, H., Gullotta, F., Haltia, M., Hauw, J.-J., Ironside, J.W., Kretzschmar, H.A., Lantos, P.L., Masullo, C., Pocchiari, M., Schlote, W., Tateishi, J. and Will, R.G. Konsensusbericht: gewebsbehandlung bei verdacht auf Creutzfeldt-Jakob- Krankheit und andere spongiforme enzephalopathien (prionen-krankeiten) des menschen. Pathologe, 17: 2 (February), 171-176, 1996. 233. Chapman, J., Arlazoroff, A., Goldfarb, L.G., Cervenáková, L., Neufeld, M.Y., Werber, E., Herbert, M., Brown, P., Gajdusek, D.C. and Korczyn, A.D. Fatal insomnia in a case of familial Creutzfeldt-Jakob disease with the codon 200Lys mutation. Neurology, 46: 3 (March), 758-761, 1996. 234. Liberski, P., Yanagihara, R., Brown, P., Kordek, R., Kloszewska, I., Bratosiewicz., J. and Gajdusek, D.C. Microwave treatment enhances the immunostaining of amyloid deposits in both the transmissible and non-transmissible brain amyloidoses. Neurodegeneration, 5: 1 (March), 95-99, 1996. 235. Brown, P. Bovine spongiform encephalopathy and Creutzfeldt-Jakob the link is unproved but no better explanation is presently forthcoming. British Medical Journal, 312: 7034 (March 30), 790-791, 1996. 236. Salvatore, M., Galvez, S., Brown, P., Macchi, G., Fieschi, C., Cardone, F., Petraroli, R., Colosimo, C., D'Allessandro, M. and Pocchiari, M. Codon 200 mutation in a new Creutzfeldt-Jakob disease family of Chilean origin. Journal of Neurology, Neurosurgery, and Psychiatry, 61: 1 (July), 111-112, 1996. 237. Brown, P. Environmental causes of human spongiform encephalopathy. In: “Methods in Molecular Medicine: Prion diseases", H. Baker and R. Ridley, editors, Humana Press, Totowa, New Jersey, pp.139-154, 1996. 238. Brown, P. Transmissible cerebral amyloidosis. Journal of Neural Transmission, Supplement 47, 219-229, 1996. 239. Scrimgeour, E.M., Brown, P and Monaghan, P. Disposal of rendered specified offal. Veterinary Record, 139: 9 (August 31), 219-220, 1996. 240. Cochran, E.J., Bennett, D.A., Cervenáková, L., Kenney, K., Bernard, Foster, N.L., Benson, D.F., Goldfarb, L.G. and Brown, P. Familial Creutzfeldt-Jakob disease with a five-repeat octapeptide insert mutation. Neurology, 47: 9 (September), 727-733, 1996. 241. Scrimgeour, E.M., Chand, P.R., Kenney, K. and Brown, P. disease in Oman: report of two cases. Journal of the Neurological Sciences, 142: 1-2 (October), 148-150, 1996. 10 1996 (Con’t.) 242. Will, R.G., Zeidler, M., Brown, P., Harrington, M., Lee, K.H. and Kenney, K.L. Cerebrospinal-fluid test for new-variant Creutzfeldt-Jakob disease. Lancet, 348: 9032 (October 5), 955, 1996. 243. Silburn, P., Cervenáková, L., Varghese, P., Tannenberg, A., Brown, Boyle, R. Fatal familial insomnia -a seventh family. Neurology, 47: 5 (November), 1326-1328, 1996. 244. El Hachimi, K.H., Cervenáková, L., Brown, P., Goldfarb, L.G., R., Gajdusek, D.C. and Foncin, J.-F. Mixed features of Alzheimer disease and Creutzfeldt-Jakob disease in a family with a presenilin-1 mutation in chromosome 14. Amyloid, 3: 4 (December), 223-233, 1996. 245. Goldfarb, L.G., Cervenáková, L., Brown, P. and Gajdusek, D.C. Genotype-phenotype correlations in familial spongiform encephalopathies associated with insert mutations. In: "Transmissible Subacute Spongiform Encephalopathies: Prion Diseases". (Proceedings of the IIIrd International Symposium on Transmissible Subacute Spongiform Encephalopathies: Prion Diseases, 18-20 March 1996, Val de Grâce, Paris, France). L. Court and B. Dodet, editors, Elsevier, Amsterdam, 1996 pp.425-431. 246. Cervenáková, L., Brown, P., Piccardo, P., Cummings, J.L., Nagle, J., Vinters, H.V., Kaur, P., Ghetti, B., Gajdusek, D.C. and Goldfarb, L.G. 24-nucleotide deletion in the PRNP gene: analysis of associated phenotypes. In: "Transmissible Subacute Spongiform Encephalopathies: Prion Diseases". (Proceedings of the IIIrd International Symposium on Transmissible Subacute Spongiform Encephalopathies: Prion Diseases, 18-20 March 1996, Val de Grâce, Paris, France). L. Court and B. Dodet, editors, Elsevier, Amsterdam, 1996, pp.433-444. 247. Brown, P. The risk of blood-borne Creutzfeldt-Jakob disease. In: "Transmissible Subacute Spongiform Encephalopathies: Prion Diseases". (Proceedings of the IIIrd International Symposium on Transmissible Subacute Spongiform Encephalopathies: Prion Diseases, 18-20 March 1996, Val de Grâce, Paris, France). L. Court and B. Dodet, editors, Elsevier, Amsterdam, 1996, pp.447-431. Also, with slight modification: Brown, P. The risk of blood-borne Creutzfeldt-Jakob disease. In: Proceedings of the 4th NATO Military and Civil Blood Conference, The Hague, The Netherlands, 5-8 May, 1996. Netherlands Military Medical Review, vol.49 (June-December), pp.37-38. 248. Hainfellner, J.A., Liberski, P.P., Guiroy, D.C., Cervenáková, L., Brown, P., Gajdusek D.C. and Budka, H. Pathology and 547-554, 1997. 249. Epstein, L.G. and Brown, P. Bovine spongiform encephalopathy and a new variant of Creutzfeldt-Jakob disease. Neurology, 48: 3 (March), 569-571, 1997. 11 1997 (Con’t.) 250. Parchi, P. Capellari, S., Chen, S.G., Petersen, R.B., Gambetti, P., Kopp, N., Brown, P., Kitamoto T., Tateishi, J., Giese, A. and Kretzschmar, H. Typing prion isoforms. Nature, 386: 6622 (March 20), 232-234, 1997. 251. Liberski, P.P., Brown, P., Cervenáková, L. and Gajdusek, D.C. Interactions between astrocytes and oligodendroglia in human and experimental Creutzfeldt-Jakob disease and scrapie. Experimental Neurology, 144: 1 (March), 227-234, 1997. 252. El Hachimi, K.H., Chaunu, M.-P., Cervenáková, L., Brown, P. and Foncin, J.-F. Putative neurosurgical transmission of Creutzfeldt- Jakob disease with analysis of donor and recipient agent strains. Comptes Rendus de l’Académie des Sciences (Paris), 320: 4 (April), 319-328, 1997. 253. Cervenáková, L., Rohwer, R., Williams, E.S., Brown, P. and Gajdusek, D.C. High sequence homology of the PrP gene in mule deer and Rocky Mountain elk. Lancet, 350: 9072 (July 19), 219-220, 1997. 254. McLean, C.A., Storey, E., Gardner, R.J.M., Tannenberg, A.E.G, Cervenáková, L. and Brown, P. The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathological phenotypes in an Australian kindred. Neurology, 49: 2 (August), 552-558, 1997. 255. Chen, S.G., Parchi, P., Brown, P., Capellari, S., Zou, W., Cochran, E.J., Vnencak-Jones, C.L., Julien, J., Vital, C., Mikol, J., Lugaresi, E., Autilio-Gambetti, L. and Gambetti, P. Allelic origin of the abnormal prion protein isoform in familial prion diseases. Nature Medicine, 3: 9 (September), 1009-1015, 1997. 256. Heckmann, J.G., Lang, C.J.G., Petruch, F., Druschky, A., Erb, C., Brown, P. and Neundörfer, B. Transmission of Creutzfeldt-Jakob disease via a corneal transplant. Journal of Neurology, Neurosurgery, and Psychiatry, 63: 3 (September), 388-390, 1997. 257. Brown, P. The risk of bovine spongiform encephalopathy ("mad cow disease") to human health. Journal of the American Medical Association, 278: 12 (September 24), 1008-1011, 1997. 258. Liberski, P.P., Brown, P. and Gajdusek, D.C. The evolution of views on the nosological position of transmissible spongiform 1997. 259. Walis, A., Liberski, P.P., Brown, P. and Gajdusek, D.C. Electron microscopic studies of the optic nerve in experimental scrapie and the panencephalopathic type of Creutzfeldt-Jakobd disease. Folia Neuropathologica, 35: 4 (October-December), 255-258, 1997. 260. Martínez-Lage, J.F, Poza, M., Brown, P., Cervenáková, L., Bremón, A.R. and de Pedro, J. Enfermedad de Creutzfeldt-Jakob en Neurocirugía: una revisión de riesgos y medidas de prevención. Neurocirugía, 8: 4 (December), 284-293, 1997. 12 1997 (Con’t.) 261. Brown, P. Spongiform encephalopathies: B-lymphocytes and neuroinvasion. (News and Views). Nature, 390: 6661 (December 18/25), 662-663, 1997. 262. Brown, P., Cervenáková, L., McShane, L., Goldfarb, L.G., Bishop, K., Bastian, F., Kirkpatrick, J., Piccardo, P., Ghetti, B. and Gajdusek, D.C. Creutzfeldt-Jakob disease in a husband and wife. Neurology, 50: 3 (March), 684-688, 1998. 263. Brown, P. Donor pool size and the risk of blood-borne Creutzfeldt- Jakob disease. Transfusion, 38: 3 (March), 312-315, 1998. 264. Zeidler, M. and Brown, P. More patients should be excluded from being tissue donors. British Medical Journal, 316: 7138 (April 11), 1170-1171, 1998. 265. Brown, P. Commentary. BSE: the final resting place. Lancet, 351: 9110 (April 18), 1146-1147, 1998. 266. Fournier, J-G., Escaig-Haye, F., Billette de Villemeur, T., Robain, Lasmézas, C.L., Deslys, J-P., Dormont, D. and Brown, P. Distribution and submicroscopic immunogold localization of cellular prion protein (PrPc) in extracerebral tissues. Cell and Tissue Research, 292: 1 (April), 77-84, 1998. 267. Heldt, N., Boellaard, J.W., Brown, P., Cervenáková, L., Doerr-Schott, J., Thomas, C., Scherer, C. and Rohmer, F. Gerstmann-Sträussler-Scheinker disease with A117V mutation in a second French-Alsatian family. Clinical Neuropathology, 17: 4 (July-August), 229-234, 1998. 268. Parchi, P., Chen, S.G., Brown, P., Zou, W., Capellari, S., Budka, H., Hainfellner, J., Reyes, P.F., Golden, G., Hauw, J.J., Gajdusek, D.C. and Gambetti, P. Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann- Sträussler-Scheinker disease. Proceedings of the National Academy of Sciences (USA), 95: 14 (July 7), 8322-8327, 1998. 269. Brown, P. Commentary. On the origins of BSE. Lancet, 352: 9124 (July 25), 252-253, 1998. 270. Zanusso, G., Liu, D., Ferrari, S., Hegyi, I., Yin, X., Aguzzi, A., Hornemann, S., Liemann, S., Glockshuber, R., Manson, J.C., Brown, P., Petersen, R.B., Gambetti, P. and Sy, M-S. Prion protein expression in different species: analysis with a panel of new mABs. Proceedings of the National Academy of Sciences (USA), 95: 15 (July 21), 88128816, 13 1998 (Con’t.) 271. McLean, C.A., Ironside, J.W., Alpers, M., Cervenáková, L., Anderson, R.McD., Brown, P.W. and Masters, C.L. Comparative neuropathology of kuru with the new variant of Creutzfeldt-Jakob disease: evidence for strain of agent predominating over genotype of host. Brain Pathology, 8: 3 (July), 429-437, 1998. 272. Brown, P., Cervenáková, L. and Powers, J.M. FFI cases from the United States, Australia, and Japan. Brain Pathology, 8: 3 (July), 567-570, 1998. 273. Chapman, J., Cervenáková, L., Petersen, R.B., Estupinan, J., Richardson, S., Vnencak-Jones, C.L., Gambetti, P., Gajdusek, D.C., Korczyn, A.D., Brown, P. and Goldfarb, L.G. APOE in non-Alzheimer amyloidoses: transmissible spongiform encephalopathies. Neurology, 51, 2 (August), 548-553, 1998. 274. Brown P., Rohwer, R.G., Dunstan, B.C., MacAuley, C., Gajdusek, D.C. Drohan, W.N. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion, 38: 9 (September), 810-816, 1998. 275. Brown, P. Author’s Reply to a Letter to the Editor: Origins of BSE. Lancet, 352: 9133 (September 26), 1068-1069, 1998. 276. Brown, P. Transmission of spongiform encephalopathy through biological products. In: “Developments in Biological Standardization”. Brown, F., Griffiths, E., Horaud, F. and Petricciani, J.C., editors. Developments in Biological Standardization, volume 93, Karger, Basel, 1998, pp.73-78. 277. Brown, P., Cervenáková, L., McShane, L., Kleihues, P., Foncin, J.-F., Collins, G., Bastian, F., Goldfarb, L.G. and Gajdusek, D.C. Polymorphic genotype matching in acquired Creutzfeldt-Jakob disease: an analysis of donor/recipient case pairs. In “Prions and Brain Diseases in Animals and Humans”. D.R.O. Morrison, editor. Nato ASI Series A: Life Sciences volume 295, Plenum, New York, 1998, pp.19-24. 278. Piccardo, P., Dlouhy, S.R., Lievens, P.M.J., Young, K., Bird, T.D., Nochlin, D., Dickson, D.W., Vinters, H.V., Zimmerman, T.R., Mackenzie, I.R.A., Kish, S.J., Ang, L-C., De Carli, C., Pocchiari, M., Brown, P., Gibbs, C.J., Jr., Gajdusek, D.C., Bugiani, O., Ironside, J., Tagliavini, F. and Ghetti, B. Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity. Journal of 279. Liberski, P.P., Barcikowska, M., Cervenáková, L., Bratosiewicz, J., Marczewska, M., Brown, P. and Gajdusek, D.C. A case of sporadic Creutzfeldt-Jakob disease with a Gerstmann-Sträussler-Scheinker phenotype but no alterations in the PRNP gene. (Berlin), 96: 4 (October), 425-430, 1998. Acta Neuropathologica 280. Liberski, P.P., Kordek, R., Brown, P. and Gajdusek, D.C. Astrocytes in transmissible spongiform encephalopathies (prion diseases). Chapter 7 in: “Astrocytes in Brain Aging and Neurodegeneration”, Schipper,H.M., editor, R.G. Landes Co., Austin, Texas, 1998, pp.127-163. 14 1998 (Con’t.) 281. Cervenáková, L., Goldfarb, L.G., Garruto, R., Lee, H.-E., Gajdusek, D.C. and Brown, P. Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease. Proceedings of the National Academy of Sciences (USA), 95: 22 (October 27), 1323913241, 1998. 282. El Hachimi, K.H., Chaunu, M.-P., Brown, P. and Foncin, J.-F. Modification of oligodendroglial cells in spongiform encephalopathies. Experimental Neurology, 154: 1 (November), 23-30, 1998. 283. Brown, P. Transmissible spongiform encephalopathy. Chapter 43 in: "Textbook of Clinical Neurology", Goetz, C.G. and Pappert, E.J., editors, W.B. Saunders Co., Philadelphia, 1998, pp.869-875. 284. Brown, P. Iatrogenic Creutzfeldt-Jakob disease. In: “Sterilization of Medical Products”, Morrissey, R.F. and Kowalski, J.B., editors. Proceedings of the VIIth International Kilmer Memorial Conference on the Sterization of Medical Products, Scottsdale, Arizona, March 2-4, 1998. Polyscience Publications, Inc., Champlain NY, 1998, pp.212-218. 285. Brown, P. and Bradley, R. 1755 and all that: a historical primer of transmissible spongiform encephalopathy. British Medical Journal, 317: 7174 (December 19-26), 1688-1692, 1998. 286. Hogan, R.N., Brown, P., Heck, E. and Cavanagh, H.D. Risk of prion disease transmission from ocular donor tissue transplantation. Cornea, 18: 1 (January/February), 2-11, 1999. 287. Bons, N., Mestre-Frances, N., Belli, P., Cathala, F., Gajdusek, D.C. and Brown, P. Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Proceedings of the National Academy of Sciences (USA), 96: 7 (March 30); 4046-4051, 1999. 288. Lee, H.S., Sambuughin, N., Cervenáková, L., Chapman, J., Pocchiari, Litvak, S., Qi, H.Y., Budka, H., del Ser, T., Furukawa, H., Brown, P., Gajdusek, D.C., Long, J.C., Korczyn, A. and Goldfarb, L.G. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. American Journal of Human Genetics, 64: 4 (April), 1063-1070, 1999. 289. Grigoriev, V., Escaig-Haye, F., Streichenberger, N., Kopp, N., Langeveld, J., Brown, P. and Fournier, J-G. Submicroscopic Creutzfeldt-Jakob disease. Neuroscience Letters, 264: 1-3 (April 2), 57-60, 1999. 290. Brown, P., Bradley, R. and Cathala, F. Bref historique des (May 1), 928-933, 1999. 15 1999 (Con’t.) 291. Parchi, P., Giese, A., Capellari, S., Brown, P., Schulz-Schaeffer, W., Windl, O., Zerr, I., Budka, H., Kopp, N., Piccardo, P., Poser, S., Rojiani, A., Streichemberger, N., Julien, J., Vital, C., Ghetti, B., Gambetti, P. and Kretzschmar, H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Annals of Neurology, 46, 2 (August), 224-233, 1999. 292. Brandel, J-P., Cathala, F. and Brown, P. Maladies à prions: encéphalopathies spongiformes subaiguës transmissibles humaines et animales. Chapitre 4 in: Neurogénétique. Affections hérédodégénératives, 1998, pp.35-61. 293. Brown, P. A brief history of scrapie before the prion. In:”The Science and Culture Series”, K. Goebel, editor. International Seminar on Nuclear War and Planetary Emergencies (23rd Session), Erice, Italy, 19-24 August 1998. World Scientific, Singapore, 1999, pp.35-36. 294. Brown, P. Transmissible spongiform encephalopathies. Chapter 59 in: “Neurology in Clinical Practice”, W.G. Bradley, R.B. Daroff, G.M. Fenichel and C.D. Marsden, editors. Butterworth-Heinemann, Newton MA, 1999, volume II, pp.1423-1430. 295. Parchi, P., Brown, P., Capellari, S., Gibbs, C.J., Jr. and Agent strain variation in human prion diseases: insight from transmission to primates. In: “Alzheimer’s Disease and Related Disorders”, K. Iqbal, D.R. Swaab, B. Winblad and H.M. Wisniewski, editors. John Wiley & Sons, London, 1999, pp.561-567. Also as abstract: Parchi, P., Brown, P., Capellari, S., Gibbs, C.J., Jr. and Gambetti, P. Biochemical analysis of strain variation in human prion diseases: insight from transmission to primates. Abstract No.722 in Book of Abstracts, 6th International Conference on Alzheimer’s Disease and Related Disorders, Amsterdam, July 18-23, 1998 296. Brown, P. The risk of blood-borne Creutzfeldt-Jakob disease. In: “Developments in Biologicals”, Brown, F. and Vyas, G., editors. Karger, Basel, 1999, volume 102, pp.53-59. 297. Boellaard, J.W., Brown, P. and Tateishi J. Gerstmann-Sträussler- Scheinker disease -the dilemma of molecular and clinical correlations. Clinical Neuropathology, 18, 6 (November-December), 271-285, 1999. 298. Brown, P., Cervenáková, L., McShane, L.M., Barber, P., Rubenstein, R. and Drohan, W.N. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood products do not transmit Creutzfeldt- Jakob disease. Transfusion, 39: 11/12 (November-December), 1169-1178, 1999. 299. Cervenáková, L., Buetefisch, C., Lee, H-S., Taller, I., Stone, G., Gibbs, C.J., Jr., Brown, P., Hallett, M. and Goldfarb, L.G. Novel PRNP sequence variant associated with familial encephalopathy. American Journal of Medical Genetics (Neuropsychiatric Genetics), 88: 6 (December), 653-656, 1999. 16 1999 (Con’t.) 300. Dickson, D.W. and Brown, P. Multiple prion types in the same brain. Is a molecular diagnosis of CJD possible? Neurology, 53: 9 (December), 1903-1904, 1999. 2000 301. Blanquet-Grossard, F., Sazdovitch, V., Jean, A., Deslys, J-P., Dormont, D., Hauw, J-J., Marion, D., Brown, P. and Cesbron, J.-Y. Prion protein is not detectable in dental pulp from patients with Creutzfeldt-Jakob disease. Journal of Dental Research, 79: 2 (February), 700, 2000. 302. Brown, P., Rau, E.H., Johnson, B.K., Bacote, A.E., Gibbs, C.J., Jr. Gajdusek D.C. New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600°C suggests an inorganic template of replication. Proceedings of the National Academy of Science (USA), 97: 7 (March 28), 3418-3421, 2000. 303. Brown, P. and Lamb, G. Creutzfeldt-Jakob disease and the mortuary profession. The Director, 72: 3 (March), 58-62, 2000. 304. Majtényi, C., Brown, P., Cervenáková, L., Goldfarb, L.G. and A three-sister sibship of Gerstmann-Sträussler-Scheinker disease with a CJD phenotype. Neurology, 54: 6 (June), 2133-2137, 2000. 305. Brown, P. and Cervenáková, L. Authors’ Reply to a Letter to the Editor: Infectivity of buffy coat in variant CJD. Transfusion, 40: 6 (June), 754-755. 306. Fournier, J.C., Kopp, N., Streichenberger, N., Escaig-Haye, F., Langeveld, J. and Brown, P. Electron microscopy of brain amyloid plaques from a patient with new variant Creutzfeldt-Jakob disease. Acta Neuropathologica, 99: 6 (June), 637-642, 2000. 307. Parchi, P., Zou, W., Wang, W., Brown, P., Capellari, S., Ghetti, B., Kopp, N., Schulz-Schaeffer, W.J., Kretzschmar, H.A., Head, M.W., Ironside, J.W., Gambetti, P. and Chen, S.G. Genetic influence on the structural variations of the abnormal prion protein. Proceedings of the National Academy of Science (USA), 97: 18 (August 29), 1016810172, 308. Liberski, P.P., Bratosiewicz, J., Barcikowska, M., Cervenakova, L., Marczewska, M., Brown, P. and Gajdusek, D.C. A case of sporadic Creutzfeldt-Jakob disease with a Gerstmann-Sträussler-Scheinker phenotype but no alterations in the PRNP gene. 100: 2 (August), 233-234, 2000. Acta Neuropathologica 309. Cervenáková, L., Protas, I.I., Hirano, A., Votiakov, V.I., Nedzved, M.K., Kolomiets, N.D., Taller, I., Park, K.-Y., Sambuughin, D., Gajdusek, D.C., Brown, P. and Goldfarb, L.G. Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS). Journal of the Neurological Sciences, 177: 2 (August), 124-130, 2000. 17 2000 (Con’t.) 310. Brown, P. BSE and transmission through blood [Commentary]. 356: 9233 (September 16), 955-956, 2000. Lancet, 311. Brown, P., Preece, M., Brandel, J.-P., Sato, T., McShane, L., Zerr, I., Fletcher, A., Will, R.G., Pocchiari, M., Cashman, N.R., d’Aignaux, J.H., Cervenáková, L., Fradkin, J., Schonberger, L.B. and Collins, S.J. Iatrogenic Creutzfeldt-Jakob disease at the Millennium. Neurology, 55: 8 (October 24), 1075-1081, 2000. 312. Goldfarb, L.G., Bütefisch, C. and Brown, P. Ataxia in the spongiform encephalopathies. In: Handbook of Ataxia Disorders, T. Klockgether, editor. Marcel Dekker, New York, 2000, pp.523-543. 313. Brown, P. Risk of Creutzfeldt-Jakob disease associated with blood or blood products. Proceedings of an INFARMED Workshop held in Evora, Portugal, December 11-12, 1999. In: Jornada Sobre Medicamentos: Hemoderivados e vCJD, J.A. da Silva, editor. INFARMED, Lisboa, 2000, pp.79-84. 314. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies. Report of a WHO Consultation, Geneva, Switzerland, 23-26 March 1999. WHO/CDS/CSR/APH/2000.3 2001 315. Brown, P., Cervenáková, L. and Diringer, H. Blood infectivity and the prospects for a diagnostic screening test in Creutzfeldt-Jakob disease. Journal of Laboratory and Clinical Medicine, 137: 1 (January), 5-13, 2001. [Erratum 137: 4 (April), 230, 2001] 316. Lee, H.-S., Brown, P., Cervenáková, L., Garruto, R.M., Alpers, M.P., Gajdusek, D.C. and Goldfarb, L.G. Increased susceptibility to kuru of PRNP 129 MM genotype carriers. Journal of Infectious Diseases, 183: 1 (January); 192-196, 2001. 317. Brown, P., Will, R.G., Bradley, R., Asher, D.M. and Detwiler, L. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns. Emerging Infectious Diseases, 7: 1(January/February), 6-16, 2001. 318. Brown, P. The pathogenesis of transmissible spongiform encephalopathy: routes to the brain and the possibility of therapeutic barricades. Cellular and Molecular Life Sciences, 58: 1 (February): 259-265, 2001. 319. Brown, P. Authors’ Reply to a Letter to the Editor: Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology, 56: 7 (April 10) 987, 2001. 320. Liberski, P.P., Bratosiewicz, J., Walis, A., Kordek, R., Jeffrey, M. and Brown, P. A special report. I.Prion protein (PrP) – amyloid plaques in the transmissible spongiform encephalopathies, or prion diseases revisited. Folia Neuropathology, 39: 4 (April), 217-235, 2001. 18 2001 (Con’t.) 321. Kennedy, R.H., Hogan, R.N., Brown, P., Holland, E., Johnson, R.T., Stark, W. and Sugar, J. Eye banking and screening for Creutzfeldt- Jakob disease. Archives of Ophthalmology, 119: 5 (May); 721-726, 2001. 322. Brown, P. Afterthoughts about bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. Emerging Infectious Diseases, 7: 3 (June Supplement), 598-600, 2001. 323. Brown, P. tests. 2001. Creutzfeldt-Jakob disease: blood infectivity and screening Seminars in Hematology, 38: 4 (October, Supplement 9), 2-6, 324. Brown, P. Transmissible Spongiform Encephalopathies. Chapter 29 in “Baker’s Clinical Neurology”. R.J. Joynt and R.C. Griggs, editors. CD-ROM, Lippincott Williams & Wilkins, Baltimore, 2001. 325. Panegyres, P.K., Toufexis, K., Kakulas, B.A., Cervenáková, L., Brown, P., Ghetti, B., Piccardo, P. and Dlouhy, S.R. A new PRNP mutation (G131V) associated with Gerstmann-Sträussler-Scheinker disease. Archives of Neurology, 58: 11 (November), 1899-1902, 2001. 326. Brown, P. Transmissible spongiform encephalopathies. In: “Early Onset Dementia”, Hodges, J.R., editor. Oxford University Press, Oxford, 2001, pp.367-384. 327. Brown P. The scientist’s dilemma. In: “Proceedings of Joint WHO/FAO/OIE Technical consultation on BSE: public health, animal health and trade”, Paris, 11-14 June, 2001, pp.74-75. 328. Bons, N., Lehmann, S., Nishida, N., Mestre-Frances, N., Dormont, D., Belli, P., Delacourte, A., Grassi, J. and Brown, P. BSE infection of the small short-lived primate Microcebus murinus. Comptes Rendus de l’Academie de Science (Paris) 325: 12 (December), 1-8, 2001. 329. Cervenáková, L., Brown, P., Hammond, D.J., Lee, C.A. and Saenko, E.L. Factor VIII and transmissible spongiform encephalopathy: the case for safety. Hemophilia, 8: 2 (March) 63-75, 2002. 330. Brown P. What are the current human risks from mad cow disease? MD Consult Infectious Disease, May 9, 2002. http://www.mdconsult.com 331. Liberski, P.P., Bratosiewicz-Wasik, J., Gajdusek, D.C. and Brown, P. Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. I. Alterations of myelinated axons. Acta Neurobiologiae Experimentalis, 63: 3 (June), 121-129, 2002. 332. Liberski, P.P., Bratosiewicz-Wasik, J., Gajdusek, D.C. and Brown, P. Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. II. Astrocytic and macrophage reaction towards axonal destruction. Acta Neurogiologiae Experimentalis, 63: 3 (June), 131-139, 2002. 19 2002 (Con’t.) 333. Liberski, P.P., Gajdusek, D.C. and Brown, P. How do neurons degenerate in prion diseases or transmissible spongiform encephalopathies (TSE’s): neuronal autophagy revisited. Acta Neurogiologiae Experimentalis, 63: 3 (June), 141-147, 2002. 334. Brown, P. Current issues related to the origin and etiology of BSE. Relationship with variant Creutzfeldt-Jakob disease. In: “Report of the PAHO/WHO Consultation on Bovine Spongiform Encephalopathy: Scientific Bases for Policy Decisions in the Americas”, Montevideo, Uruguay, 9-11 April 2001. Veterinary Public Health Program, Pan American Health Organization, Washington, D.C., 2002. 335. Bons, N., Lehmann, S., Mestre-Francès, N., Dormont, D. and Brown, P. Brain and buffy coat transmission of bovine spongiform encephalopathy (BSE) to the primate Microcebus murinus. Transfusion, 42: 5 (May), 513-517, 2002. 336. Brown, P. Drug therapy in human and experimental transmissible spongiform encephalopathy. Neurology, 58: 12 (June 25), 1720-1725, 2002. 337. Brown, P. Transmission of Creutzfeldt-Jakob disease by transfusion. In: “Rossi’s Principles of Transfusion Medicine”, 3rd Edition. T.L. Simon, W.H. Dzik, E.L. Snyder, C.P. Stowell and R.G. Strauss, editors. Lippincott Williams & Wilkins, Philadelphia, 2001, pp.784-788. 338. Dagvadorj, A., Petersen, R.B, Lee, H.S., Cervenakova,L, Budka, H., Boyle, R., Brown, P., Gambetti, P. and Goldfarb, L.G. Spontaneous mutations in the prion protein gene causing transmissible spongiform encephalopathy. Annals of Neurology, 52: 9 (September), 355-359, 2002. 339. Stenland C.J., Lee, D.C., Brown, P., Ironside, J., Petteway, S.R., Jr. and Rubenstein, R. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion, 42: 11 (November), 1497-1500, 2002. 340. Brown, P. Special precautions for autopsies of patients with Creutzfeldt-Jakob disease. Chapter 13 in: “Autopsy Performance and Reporting”, K.A. Collins and G.M. Hutchins, editors, College of Amercian Pathologists, Northfield, Illinois, 2003, pp.105-110. 341. Cervenáková, L., Brown, P., Soukharev, S., Yakovleva, O., Diringer, Saenko, E.L. and Drohan, W.N. Failure of immunocompetitive capillary electrophoresis assay to detect disease-specific prion protein in buffy coat from humans and chimpanzees with Creutzfeldt- Jakob disease. Electrophoresis, 24: 6 (March), 853-859, 2003. 20 2003 (Con’t.) 342. Ricketts, M. and Brown, P. Transmissible spongiform encephalopathy: update and implications for blood safety. Clinics in Laboratory Medicine, 23: 1 (March), 129-137, 2003. 343. Liberski, P.P., Sikorska, B., Bratosiewicz-Wasik, J., Walis, A, Brown, P. and Brown, D. Exuberant cellular reaction of the optic nerves in experimental Creutzfeldt-Jakob disease. Acta Neurobiologiae Experimentalis, 63: 3 (March), 309-318, 2003. 344. Brown, P., Transmissible Spongiform Encephalopathy as a Zoonotic Disease. ILSI Europe Report Series, International Life Sciences Institute, ILSI Press, Brussels, March 2003, 47 pp. 345. Brown, P. Variant CJD transmission through blood: risks to predictors and “predictees”. Transfusion, 43: 4 (April), 425-427, 2003. 346. Brown, P., Meyer, R., Cardone, F. and Pocchiari, M. practical method to prevent human infection. Proceedings of the National Academy of Science (USA), 100: 10 (May 13), 6093-6097, 2003. 347. WHO Guidelines on Transmissible Spongiform Encephalopathies in to Biological and Pharmaceutical Products. Report of a WHO Consultation, Geneva, Switzerland, 3-5 February 2003. http://www.who.int/bloodproducts/tse/en 348. Brown, P. Creutzfeldt-Jakob disease (CJD). In: “Encyclopedia of the M.J. Aminoff and R.B. Daroff, editors, Academic Press, San Diego, 2003, 349. Brown, P. Transmissible Spongiform Encephalopathy. Chapter 43 in: “Textbook of Clinical Neurology”, 2nd Edition, C.G. Goetz, editor, Saunders, Philadelphia, 2003, pp.945-954. 350. Brandel, J.-P., Preece, M., Brown, P., Croes, E., Laplanche J.-L., Will, R. and Alpérovitch, A. Distribution of codon 129 genotypes in human growth hormone-treated CJD patients in France and the United Kingdom. Lancet, 362: 9378 (July 12), 128-130, 2003. 351. Walis, A., Bratosiewicz, J., Sikorska, B., Brown, P., Gajdusek, D.C and Liberski, P.P. Ultrastructural changes in the optic nerves of rodents with experimental Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) or scrapie. Journal of Comparative Pathology, 129: 2-3: (August-October), 213-225, 2003. 352. Cervenakova, L., Yakovleva, O., McKenzie, C., Kolchinsky, S., McShane, L., Drohan, W.N. and Brown, P. Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy. Transfusion, 43: 12 (December), 1687-1694, 2003. 21 353. Brown, P. Fall-out from a possible transfusion-related transmission of vCJD. The Lancet Neurology, 3: 4 (April), 203, 2004. 354. Mills, J.L., Schonberger, L.B., Wysowski, D.K., Brown, P., Durako, S.J., Cox, C., Kong, F. and Fradkin, J.E. Long Term Mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatrics, 2004 144: 4 (April), 430-436, 2004. 355. Sikorska, B., Walis A., Bratosiewicz-Wasik, J., Brown, P. and Liberski, P.P. Fate of myelinated fibres in the optic nerves in experimental Creutzfeldt-Jakoc disease in rodents: an ultrastructural study. Folia Neuropathologica 42: 2 (April-June), 101-105, 2004. 356. Liberski, P.P. and Brown, P. Kuru: a half-opened window onto the landscape of neurodegenerative diseases. Folia Neuropathologica 42: Supplement A (June), 3-14, 2004. 357. Liberski, P.P. and Brown, P. Prion diseases: from transmission experiments to structural biology – still searching for the cause. Folia Neuropathologica, 42: Supplement A (June), 15-32, 2004. 358. Brown, P. Mad cow disease in cattle and human beings. American Scientist, 92: 4 (July-August), 334-341, 2004. 359. Fichet, G., Comoy, E., Duval, C., Antloga, K., Dehen, C., McDonnell, G., Brown, P., Lasmézas, C.I. and Deslys, J-P. Novel methods for disinfection of prion-contaminated medical devices. Lancet, 364: 9433 (August 7), 521-526, 2004. 360. Brown, P. and Cervenáková, L., The modern landscape of iatrogenic Creutzfeldt-Jakob disease and blood screening tests. Current Opinion in Hematology, 11: 5 (September), 351-356, 2004. 361. Brown, P., Rau, E.H., Meyer, R., Lemieux, P., Cardone, F. and Pocchiari, M. ‘Extreme’ inactivation methods for transmissible spongiform encephalopathy agents. In: “Proceedings of the Eighth International Kilmer Conference”, J.B. Kowalski and R.F. Morrissey, editors, Osaka, Japan, October 6-9, 2003. Polyscience Publications Inc., Laval, Canada, 2004, pp.104-111. 362. Brown, P., Rau, E.H., Lemieux, P., Johnson, B.K., Bacote, A. and Gajdusek, D.C. Infectivity studies of both ash and air emissions from simulated incineration of scrapie-contaminated tissues. Environmental Science and Technology, 38: 22 (November 15), 6155-6160, 2004. 363. Yakovleva, O., Janiak, A., McKenzie, C., McShane, L., Brown, P. and Cervenakova, L. Effect of protease treatment on plasma infectivity in variant Creutzfeldt-Jakob disease mice. Transfusion, 44: 12 (December), 1700-1705, 2004. 364. Cervenáková, L. and Brown, P. Advances in test development for transmissible spongiform encephalopahies. Expert Review of Anti-infective Therapy, 2: 6 (December), 873-880, 2004. 22 2005 365. Brown, P. and Abee, C.R. Working with transmissible spongiform encephalopathy agents. Institute for Laboratory Animal Research (ILAR) Journal, 46: 1 (January), 44-52, 2005. 366. Brown, P. and Cervenáková L. A prion lexicon (out of control). Lancet, 365: 9454 (January 8), 122, 2005. 367. Lasmézas, C., Comoy, E., Hawkins, S., Herzog, C., Mouthon, F., Konold, T., Auvré, F., Correia, E., Lecoutra-Etchegaray, N., Salès, N., Wells, G., Brown, P. and Deslys, J.P. Risk of oral infection with bovine spongiform encephalopathy agent in primates. Lancet, 365: 9461 (February 26), 781-783, 2005. 368. Brown, P. Pathogenesis and transfusion risk of transmissible spongiform encephalopathies. In: “Advances in Transfusion Safety”, G. Vyas and A. Williams, editors, Developments in Biologicals, volume 120, Karger, Basel, 2005, pp.27-33. 369. Brown, P. Blood infectivity, processing and screening tests in transmissible spongiform encephalopathies. Vox Sanguinis, 89: 2 (August), 63-70, 2005. 370. Sowemimo-Coker, S., Kascsak, R., Kim, A., Andrade, F., Pesci, S., Kascsak, R., Meeker, C., Carp, R. and Brown, P. Removal of exogenous (spiked) and endogenous prion infectivity from red cells with a new prototype of leukocyte reduction filter. Transfusion, 45: 12 (December), 1839-1844, 2005. 371. Kennedy, R.H., Mills, C.R. and Brown, P. Risk of infectious disease transmission through the use of Allografts. In: “Essentials in Ophthalmology: Oculoplastics and Orbit”, R. Guthoff and J. Katowitz, editors, Springer-Verlag, Berlin, 2005, pp.3-18. 2006 372. Thomzig, A., Cardone, F., Krüger, D., Pocchiari, M., Brown, P. and Beekes, M. Pathological prion protein in muscles of hamsters and mice infected with rodent-adapted BSE or vCJD. Journal of General Virology, 87: 1 (January), 252-254, 2006. 373. Cardone, F., Brown, P., Meyer, R., and Pocchiari, M. Inactivation of transmissible spongiform encephalopathy agents in food products by ultra-high pressure-temperature treatment. Biochimica et Biophysica Acta (Proteins and Proteomics), 1764: 3 (March), 558-562, 2006. 374. Walis, A, Liberski P.P. and Brown, P. Ultrastructural alterations in the optic nerve in transmissible spongiform encephalopathies – a review. Folia Neuropathologica 42: Supplement B (March), 153-160, 2006. 375. Liberski, P.P., Jaskolski, M. and Brown, P. Gerstmann-Sträussler- Scheinker disease. II. An effect of GSS mutation on PRP structure. Folia Neuropathologica 42: Supplement B (March), 153-160, 2006. 23 2006 (Con’t) 376. Liberski, P.P. and Brown, P. Astrocytes in transmissible spongiform encephalopathies (prion diseases). Folia Neuropathologica 42: Supplement B (March), 153-160, 2006. 377. Brown, P. The quest for a pre-clinical blood screening test for TSE. Neuroprion News, No. 5 (April), 2006, p.1. 378. Brown, P. Letter to God. British Medical Journal. 332: 7553 (3 June), 1341. 379. Brown, P. Blood infectivity in the transmissible spongiform encephalopathies. Chapter 4 in: “Creutzfeldt-Jakob Disease: Managing the Risk of Transmission by Blood, Plasma, and Tissues”, Turner M.L., editor. ABBA Press, Bethesda, MD, 2006, pp. 95-118. 380. Minor, P. and Brown P. Diagnostic tests for CJD for ante-mortem screening. Chapter 5 in: “Creutzfeldt-Jakob Disease: Managing the Risk of Transmission by Blood, Plasma, and Tissues”, Turner M.L., editor. ABBA Press, Bethesda, MD, 2006, pp. 119-148. 381. Baribeau, A-M., Bradley, R.B., Brown, P., Goodwin, J., Kihm, U., Lotero, E., O’Conner D., Schuppers, M., and Taylor D. Biodiesel from Specified Risk Material Tallow: an Appraaisal of TSE Risks and Their Reduction. ATF Advanced Technologies & Fuels Canada, Inc., Ottowa, July 2006. 382. Brown, P., Brandel, J.-P., Preece, M. and Sato, T. Iatrogenic Creutzfeldt-Jakob disease: the waning of an era. Neurology, 67:3 (August 8), 389-393. ^^^. Brown, P. Atypical BSE. Neuroprion News, No. 6 (November), 2006, p.1. ^^^. Brown, P., McShane, L. Zanusso G and Detwiler, L. On the question of sporadic or atypical bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Emerging Infectious Diseases, 2006 [IN PRESS] ^^^. Brown, P. and Detwiler, L. Bovine spongiform encephalopathy. In: Food Microbiology: Fundamentals and Froniers”, 3rd edition, Doyle, M.F, ^^^^^^^^^^^^^^^^^^^^^^, editors. ASM Press, Washington D.C., pp.^^^-^^^. [IN PRESS] ^^^. Sikorska, B., Liberski, P. and Brown, P. Neuronal autophagy and aggresomes constitute a significant part of neurodegenerations in experimental scrapie. [IN PRESS] 2007 ^^^. Georgsson, G., Sigurdarson, S. and Brown, P. The infectious agent of sheep scrapie may survive in the environment for at least sixteen years. Journal of General Virology, [IN PRESS] 24 2007 (Con’t) ^^^. Williams, L., Brown, P., Ironside, J., Gibson, S., Will, Rl, Ritchie, D., Kreil, T.R.and Abee, C. Clinical, neuropathological, and immunohistochemical features of sporadic and variant forms of Creutzfeldt-Jakob disease in the squirrel monkey (Saimiri sciureus}. Journal of General Virology, 2007. [IN PRESS] ^^^. Larramendy-Gozalol, C., Berret, A, Daudigeos E, Mathieu, E., Antonangeli, L., Riffet, C., Petit, E., Papy-Garcia, D., Barritault, D., Brown, P. and Deslys, J.-P. Characterization of CR36, a new heparan mimetic, and Pentosan Polysulfate in the treatment of prion diseases. [SUBMITTED] Journal of General Virology, 2007 ^^^. Brown, P. Transmissible spongiform encephalopathy. Chapter 43 in: “Textbook of Clinical Neurology”, 3rd edition, Goetz, C., editor. W.B. Saunders, Philadelphia, 2007, pp. ^^^-^^^. [IN PRESS] ^^^. Martinez-Lage, J.F., Brown, P. and Martin, P.M. Enfermedades por priones adquiridas: enfermedad de Creutzfeld-Jakob yatrógena. Chapter 11 in: “^^^^^^^^^^^^^^^^^^^^^^ [IN PRESS] ^^^. Liberski, P.P., Brown, D.R., Caughey, B. and Brown, P. Neuronal cell death caused by a misfolded protein in transmissible spongiform encephalopathies (prion diseases). ^^^-^^^, 2006 [IN PRESS]. Autophagy 2: 3 (Oct/Nov/Dec), ^^^. Pan, T., Sethi, J., Nelsen, C., Cervenakova, L., Lohman, K., Wegrzyn, R., Rucolph, A., Brown, P. and Orser, C.S. Evidence for PRPTSE in blood by the misfolded protein diagnostic Assay. Transfusion, [IN PREPARATION] 25 ATTACHMENT B Paul W. Brown, M.D. Curriculum Vitae CURRICULUM VITAE Present address Birthdate/Place Education and experience Society affiliations Paul W. Brown, M.D. 7815 Exeter Road Bethesda, Maryland 20814 Telephone (301) 652-5940 Fax (301) 652-4312 e-mail paulwbrown@comcast.net 12 March 1936, Hackensack, New Jersey, USA A.B. (Magna cum Laude), Harvard College, 1957 M.D., The Johns Hopkins School of Medicine, 1961 Internship and 1st year medical residency: Osler Medical Service, The Johns Hopkins Hospital, 1961-1963 Research Associate, NINDS, NIH, 1963-1965. Staff Associate, National Institute of Child Health and Human Development, (NICHHD), NIH, 1965-70 2nd year medical residency, University of California San Francisco Medical Center, 1965-66 3rd year medical residency, Osler Medical Service, The Johns Hopkins Hospital, 1966-67 Chargé de Recherche, L'Institut National de la Santé et de la Recherche Médicale (INSERM), and Medical Consultant, American Embassy, Paris, 1971-72 Staff Associate, NINDS, NIH, 1971-89 Visiting Scientist, INSERM, Laboratoire de Neurovirologie, Clinique des Maladies du Système Nerveux, Hôpital de la Salpêtrière, Paris, 1977-78 Medical Director, US Public Health Service, 1979-1999 Senior Investigator, NINDS, 1990-2004 American College of Physicians American Epidemiological Society Infectious Diseases Society of America American Society for Virology Société Française de Neurologie American Neurological Association Languages English and French Publications Over 380 papers during a span of 40 years, mainly dealing with transmissible spongiform encephalopathy (TSE), and especially the topics of epidemiology, infectivity, and inactivation Editorial European Journal of Epidemiology, Associate editor, Honors and -Henry Strong Denison Scholar, The Johns Hopkins School recognitions School of Medicine, 1961 -Alpha Omega Alpha (AOA), Johns Hopkins Chapter, 1961 -Diplomate, American Board of Internal Medicine, 1968 -Prix Léopold Trasbot, Académie Vétérinaire de France, 1980 -Fellow, National Multiple Sclerosis Society, 1971-72 -Fellow, Committee to Combat Huntington’s Chorea, 1973 -Chairman, DHHS Interagency Epidemiology Subcommittee on Human Growth Hormone and Creutzfeldt-Jakob disease, 1985 to present -Lawson Wilkins Pediatric Endocrine Society Lecture, Los Angeles, California, 1987 -Thomas Campione Lecture, Northwestern University School of Medicine, 1987 -USPHS Commendation Medal, 1990 -Arnold Barnett Lecture, Wichita Society of Neuroscience, 1991 -Member, WHO Expert Advisory Panel on Neurosciences, 1991-1993 -Consultant to PAHO (Pan American Health Organization) for the evaluation of bovine spongiform encephalopathy in Latin America, 1992 -USPHS Outstanding Service Medal, 1992 -Consultant to EEC Biomed 1/2 Project: Surveillance of Creutzfeldt-Jakob disease in the European Community, 1992 to present -Andrew Mark Lippard Memorial Lecture, College of Physicans and Surgeons of Columbia University, 1995 -Chairman, WHO consultation on TSE and Medical Products (1997) -Transmissible Spongiform Encephalopathies Advisory Committee, Center for Biologics Evaluation and Research, FDA: Chairman 1997-2001; Ad hoc member 2001-present -Chairman, Neurodegererative Diseases Working Group, World Federation of Scientists, 1998-2000 2 Honors and -Chairman, WHO consultation on TSE and Infection Control recognitions Guidelines (1999) (continued) -Distinguished Scientist Seminar Lecturer, University of South Alabama School of Medicine, 2000 -Marie C. and Joseph C. Wilson Memorial Lecture, University of Rochester Medical Center, 2000 -Bill Stone Distinguished Speaker, 2001 South Texas Blood & Tissue Center -Convocation Lecture and Seminar, Berea College, 2001 -Fredrich Deinhardt Lectureship, 18th Annual Clinical Virology Symposium, Clearwater Beach, Florida, 2002 -Board of Governors and Board of Scientific Directors, The Memorial Institute for Neurodegenerative Diseases of Saskatchewan, Canada, 2003 -Eagleson Lecture, American Biological Safety Association Conference, 2004 -Plenary Lecture, European Network of Excellence Neuroprion Conference, Paris, 2004 -Co-Chairman, Dominique Dormont Memorial Conference, Paris, 2005 -Co-President, Fondation Alliance de Biotechnologie, Paris, 2006 onwards 3 ATTACHMENT C Brown, P, McShane, LM, Zanusso, G, Detwiler, L, On the question of bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease PERSPECTIVE On the Question of Sporadic or Atypical Bovine SpongiformEncephalopathy and Creutzfeldt-Jakob Disease Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§ Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk for orally acquired disease, or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence of sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. Bovine spongiform encephalopathy (BSE) was first recognized in 1986 in the United Kingdom and quickly reached epidemic proportions, affecting >30,000 cattle per year by 1992. Because of continuing exportation of both live cattle and meat and bone meal rendered from the carcasses of slaughtered cattle, the disease spread throughout most of Europe and a few non-European countries.By 2006, 20 years after its first appearance in the United Kingdom, the disease had been reported in an additional 24 countries (1). *Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA Beginning toward the end of the 1980s in the United Kingdom, and in the 1990s in other countries, numerous regulations were enacted to minimize the entry of contaminated tissues into both the animal and human food chains and to eliminate the international spread of disease. These measures have been extraordinarily successful, to the extent that no new countries have been added to the list during the past year and the number of new cases has dramatically diminished in most countries in which BSE has appeared (the situation in some countries with insufficient surveillance remains unclear). Although the origin of the epidemic is thought to have been caused by a species-crossing contamination by sheep scrapie during the course of rendering and recycling carcass meat and bone meal as cattle feed, an alternative hypothesis suggested an origin in a similarly recycled case of spontaneously occurring disease in cattle. The pros and cons of these competing ideas have been argued elsewhere (2,3), and neither will ever be convincingly proved or disproved. Thus, the phenomenon of spontaneous disease remained in limbo until the recent discovery of “atypical” strains of BSE reopened the question. In this article we consider the importance of atypical BSE within the overall concept of sporadic (spontaneous) disease and whether such cases, if they exist, could account for at least some cases of apparently sporadic Creutzfeldt-Jakob (CJD) in humans. Sporadic BSE Obviously, the ideal country in which to examine the question of sporadic BSE would have a large national herd that was guaranteed never to have been exposed to environmental sources of infection. Such an ideal will never be realized. Until recently, the United States appeared to have at least approached the ideal by having a large national Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, herd, an adequate testing program, and an apparently small risk for contamination by imported cattle or cattle feed. That position was made vulnerable in late 2003 by the discovery of a case of BSE imported from Canada and was eliminated altogether by the subsequent discovery of 2 indigenously infected animals in widely separate regions of the country. Although the 2 indigenous cases might represent sporadic disease, the continuing identification of cases in western Canada, coupled with a history of substantial numbers of cattle imported from Canada into the United States (both indigenous US animals had the same molecular “signature” as the most recent Canadian case), makes it difficult to ignore the possibility of undetected instances of feed contamination from imported and recycled infectious carcasses. At present, the 2 best countries in which to undertake testing programs would be Argentina and Australia; both have large national herds (˜50 million and 30 million animals, respectively), and both are considered to be free of orally acquired BSE infections, on the basis of importation history, nutritional practices, and adequacy of surveillance (4). Even in these countries, however, the discovery of a case of BSE could not be guaranteed to be spontaneous because of the widespread global distribution of potentially infected cattle and cattle feed and the vagaries of international trade: imperfect record keeping, lack of compliance, and just plain deception. By way of illustration, an incident occurred many years ago that involved a particularly bulky shipment labeled as a pesticide. The large quantity seemed unusual to the customs inspector, who opened it and discovered that the shipment contained meat and bone meal destined to be spread on fields to inhibit grazing by deer, a serious agricultural pest. Thus, a study of sporadic BSE would only be truly convincing if no cases were identified. Moreover, the criteria for answering the question of sporadic BSE are different than for orally acquired BSE. Most importantly, we do not know at what age sporadic cases of BSE might occur, but they are unlikely to be in the 3- to 5-year-old age group in which orally acquired BSE is most prevalent. If the age distribution of sporadic disease in cattle were to mimic that of sporadic CJD in humans, it would not peak until 14–20 years of age (the last third of the ˜20-year natural life span of a cow). Substantial numbers of such older cattle do not exist, and thus it may never be possible to state with assurance that spontaneous BSE does not occur. Even if we accept this practical constraint, we can still take advantage of the fact that in many countries a proportion of the total slaughter population consists of breeding stock and dairy cows that are culled at >7 years of age, and animals that go directly to rendering plants or die “on farm” further increase this number. Argentina, for exam Bovine Spongiform Encephalopathy and CJD ple, with a national herd of ˜50 million cattle, in 2005 recorded nearly 1.4 million deaths from slaughter and natural causes in animals >7 years (L. Mascitelli, pers. comm.). Approximately 10% of cases of sporadic CJD occur in patients 25–50 years of age; this age in humans corresponds to the middle third of a cow’s normal life span, or 7–13 years of age (Figure 1). If the age distribution of sporadic BSE followed the same pattern, negative test results in a total of ˜3 million animals randomly selected from this group would allow us to be 95% confident that sporadic BSE is not present at a prevalence >1 per million, and ˜4.5 million negative animals would raise the level of confidence to 99%. Larger numbers of BSE-negative animals would be required to achieve these levels of confidence for a maximum prevalence <1 per 10 million cattle (Table 1, Figure 2). Even the least rigorous negative result—a prevalence not greater than that of sporadic CJD in humans, or 1 per million—would require several years to achieve, and it is perhaps unrealistic to suppose that the motivation to prolong the testing program will endure much beyond the global disappearance of orally acquired BSE and variant CJD. Nevertheless, to the degree that testing older as well as younger adult animals approached these numbers, both statistical and consumer confidence would increase, and at the very least provide reassurance that the occurrence of sporadic disease must be exceedingly rare, with little likelihood of posing a risk to either human or animal nutrition. Atypical BSE Because of its contemporary nature, the study of atypical BSE is very much a work in progress, with comparatively little published data and many unknowns. The first 2 cases to be identified were a serendipitous discovery made in the course of an unrelated experimental study that required a detailed neuropathologic and immunochemical Figure 2. Maximum prevalence according to number of negative cattle at 95% (solid line) and 99% (dashed line) confidence levels. See Table 1 for exact numbers and statistical method. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, PERSPECTIVE examination of the entire brain (5). The absence of clinical signs in these older animals, the unusual distribution of PrPTSE, together with amyloid plaques, and a Western blot pattern that differed from the stereotypic pattern seen in typical BSE left little doubt about the probability that a new “atypical strain” had been identified (bovine amyloidotic spongiform encephalopathy[BASE]). Although no further cases were found in nearly 200 cattle examined in Italy, the initiation of Western blot studies of animals in other countries with screening test programs began to yield additional atypical patterns (Table 2, Figure 3) (6–14; P. Lind, pers. comm.). Two major patterns have been described, named L (resembling the original Italian case pattern with a lower molecular weight than typical BSE) and H (for a distinct pattern first seen in France with a higher molecular weight than typical BSE). It is not yet clear whether other mixed patterns result from technical procedures in different laboratories or whether a more complicated scheme of classification will evolve as more atypical patterns are discovered. In addition, Western blots of PrPTSE are a fragile basis on which to define a BSE phenotype. Little or no information is available about either the clinical status or neuropathologic features of these animals. We know that cases have occurred in different breeds and PrP genotypes, and we also know that very few of the animals have had the typical clinical picture of BSE (behavioral disturbances, sensory signs, ataxia, and tremors), but a cloud of ambiguity surrounds the clinical picture even in those animals for which an extensive post-hoc investigation was undertaken. The fact that few detailed neuropathologic results are available is explained by the need to preserve at least a full half brain for examination, which is presently not done in any of the various countries that have screening test programs. In the future, the brain as well as the carcass must be retained in cold storage until the test results are known. The frequency of atypical cases is another unknown. Published (7,12) and unpublished (11,13) observations indicate that in some countries it might be as high as 5%–10% of the total number of older animals diagnosed by rapid screening tests (e.g., 2/27 in Germany, and 1/9 in Canada), which would seem to be a surprisingly high proportion of spontaneously occurring cases. However, data are not yet sufficient to estimate the overall prevalence of atypical BSE, i.e., cases per million tested animals of all ages. In this context, a word is in order about the US testing program. After the discovery of the first (imported) cow in 2003, the magnitude of testing was much increased, reaching a level of >400,000 tests in 2005 (Figure 4). Neither of the 2 more recently indigenously infected older animals, with ambiguous or no clinical features, would have been detected without such testing, and neither would have been identified as atypical without confirmatory Western blots. Despite these facts, surveillance has now been decimated to 40,000 annual tests (USDA news release no. 0255.06, July 20, 2006) and invites the accusation that the United Figure 1. Distribution of ages at onset of illness in 500 cases of neuropathologically verified or experimentally transmitted sporadic Creutzfeldt-Jakob disease. Approximately 10% of cases occur in patients during the middle third (25–49 years) of a human lifespan, which corresponds to age in cattle of ~7–13 years. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, Bovine Spongiform Encephalopathy and CJD States will never know the true status of its involvement with BSE. In short, a great deal of further work will need to be done before the phenotypic features and prevalence of atypical BSE are understood. More than a single strain may have been present from the beginning of the epidemic, but this possibility has been overlooked by virtue of the absence of widespread Western blot confirmatory testing of positive screening test results. These new phenotypes may be found, at least in part, to result from infections at an older age by a typical BSE agent, rather than neonatal infections with new “strains” of BSE. Neither alternative has yet been investigated. Sporadic CJD The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals. Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incuba tion periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12). The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a Figure 3. Representation of Western blots of PrPTSE patterns of typical bovine spongiform encephalopathy (BSE) and the 2 major types of atypical BSE. M.W., molecular weight in kilodaltons; L type, atypical “light” pattern; H type, atypical “heavy” pattern. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, PERSPECTIVE Figure 4. Numbers of tested cattle in the United States, 2000–2007. Number tested in 2006 as of October; number tested in 2007 proposed by the US Department of Agriculture. glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12). To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17). On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD' that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters. Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative. For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5). Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable Figure 5. Diagram of 2 possible informative trends in the incidence of bovine spongiform encephalopathy (BSE) and Creutzfeld-Jakob disease (CJD). The left panel shows the likely trends of typical BSE and variant CJD (vCJD). The right upper panel shows 1 possible pair of trends of atypical BSE and sporadic CJD (sCJD) that might occur in conjunction with the typical BSE/vCJD trends, and would be consistent with the interpretation that atypical BSE is not sporadic and not related to sCJD. The right lower panel shows a second possible associated pair of trends consistent with the interpretation that atypical BSE is sporadic and might also be related to the type 2 M/V subset of apparently sCJD. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared. Acknowledgments We thank Victoria E. Bridges and Chris Kopral for providing data about annual cattle slaughter numbers from the Food Safety and Inspection Service of the US Department of Agriculture (USDA) and for estimates of cattle dying on farms from data supplied by the National Animal Health Monitoring System, Animal and Plant Inspection Services, Veterinary Service, USDA. This study was funded in part by grant # 4AN/F10 “Studio dei meccanismi patogenetici delle malattie neurodegenerative per la diagnosi e lo sviluppo di approcci terapeutici” from the Istituto Superiore di Sanità, Rome, Italy Dr Brown has recently retired after a 41-year career in the Laboratory of CNS Studies at the National Institutes of Health, where he focused on studying transmissible spongiform encephalopathies. References 1. World Organization for Animal Health. Bovine spongiform encephalopathy. Geographical distribution of countries that reported BSE confirmed cases since 1989 [cited 2006 Oct 24]. Available from http://www.oie.int/eng/info/en_esb.htm 2. Brown P, Bradley R, Detwiler L, Dormont D, Hunter N, Wells GAH, et al. Transmissible spongiform encephalopathy as a zoonotic disease. International Life Sciences Institute (ILSI) Europe Report Series. Brussels: ILSI Press; 2003. 3. Horn GM, Bobrow ME, Bruce M, Goedert M, McLean A, Webster J. Review of the origin of BSE 2001, London: Stationery Office; 2001. 4. World Organization for Animal Health. Bovine spongiform encephalopathy. Recognition of the bovine spongiform encephalopathy status of member countries [cited 2006 Oct 24]. Available from http://www.oie.int/eng/info/en_statesb.htm Bovine Spongiform Encephalopathy and CJD 5. Casalone C, Zanusso G, Acutis P, Ferrari S, Capucci L, Tagliavini F, et al. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt- Jakob disease. Proc Natl Acad Sci U S A. 2004;101:3065–70. 6. Danish Institute for Food and Veterinary Research [cited 2006 Oct. 24]. Available from http://www.dfvf.dk/Default.asp?ID=8147&M= News&PID=89507&NewsID=792 7. Polak M, Rozek W, Rola J, Zmudzinski JF. Prion protein glycoforms from BSE cases in Poland. Bulletin of the Veterinary Institute of Pulawy. 2004;48:201–5. 8. De Bosschere H, Roels S, Vanopdenbosch E. Atypical case of bovine spongiform encephalopathy in an East-Flemish cow in Belgium. Int J Appl Res Vet Med. 2004;2:52–4. Available from http://www.jarvm. com/articles/Vol2Iss1/DEBOSSCHERE.htm 9. Yamakawa Y, Hagiwara K, Nohtomi K, Nakamurua Y, Nishijima M, Higuchi Y, et al. Atypical proteinase K-resistant prion protein (PrPrres) observed in an apparently healthy 23-month-old Holstein steer. Jpn J Infect Dis. 2003;56:221–2. 10. Biacabe AG, Laplanche JL, Ryder S, Baron T. Distinct molecular in bovine prion diseases. EMBO Rep. 2004;5:110–4. 11. Canadian Food Inspection Agency. Report on the investigation of the sixth case of bovine spongiformencephalopathy (BSE) in Canada [cited 2006 Oct]. Available from http://www.inspection.gc.ca/english/ anima/heasan/disemala/bseesb/mb2006/6investe.shtml 12. Buschmann A, Gretzshel A, Biacabe AG, Schiebel K, Corona C, Hoffmann C, et al. Atypical BSE in Germany—proof of transmissibility and biochemical characterization. Vet Microbiol. 2006; 117:103–16. 13. Book of abstracts. Prion 2006, International Conference on Prion Diseases of NeuroPrion, Network of Excellence, Turin, Italy, 2006 Oct 3–6 [cited 2006 Oct 24]. Available from http://www. neuroprion.com/en/ev_prion2006.html 14. Seuberlich T, Botteron C, Wenker C, Café-Marçal V, Oevermann A, Haase B, et al. Spongiform encephalopathy in a miniature zebu. Emerg Infect Dis. 2006;12:xxx–xxx. [THIS ISSUE] 15. Wadsworth JDF, Asante EA, Desbruslais M, Linehan JM, Joiner S, Gowland I, et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science. 2004;306:1793–6. 16. Wientjens DP, Davanipour Z, Hofman A, Kondo K, Matthews WB, Will RG, et al. Risk factors for Creutzfeldt-Jakob disease: a reanalysis of case control studies. Neurology. 1996;46:1267–91. 17. Van Duijn CM, Delasnerie-Lauprêtre N, Masullo C, Zerr I, de Silva R, Wientjens DPWM, et al. Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993–1995. Lancet. 1998;351:1081–5. Address for correspondence: Paul Brown, 7815 Exeter Rd, Bethesda, MD 20814, USA; email: paulwbrown@comcast.net Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12,
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