IntroductionMad Cow Dis?as?, or Bovin? Spongiform ?nc?phalopathy (BS?), is th? cattl? form of a family of progr?ssiv? brain dis?as?s. Th?s? dis?as?s includ? scrapi? in sh??p, Cr?utzf?ldt-Jakob dis?as? (CJD) in humans, and chronic wasting dis?as? (CWD) in d??r and ?lk. Th?y ar? also known as ?ith?r “prion dis?as?s” b?caus? of th? association of a misfold?d c?llular prion prot?in in pathog?n?sis or “transmissibl? spongiform ?nc?phalopathi?s” (TS?s) b?caus? of th? spong?lik? natur? of th? damag?d brain tissu? . Th? r?c?nt discov?ry of two BS?-inf?ct?d cows, in Canada and in th? Unit?d Stat?s, has dramatically incr?as?d conc?rn in North Am?rica among m?at produc?rs and consum?rs alik? ov?r th? ?xt?nt to which BS? pos?s a thr?at to humans as w?ll as to dom?stic and wild animals. Th? ?urop?an BS? ?pid?mic of th? lat?-1980s s??ms to hav? b??n initiat?d a d?cad? ?arli?r in th? Unit?d Kingdom by chang?s in th? production of m?at and bon? m?al (MBM) from r?nd?r?d liv?stock, which l?d to contamination of MBM with th? BS? inf?ctious ag?nt. Furth?rmor?, th? fact that UK farm?rs f?d this r?nd?r?d MBM to young?r animals and that this MBM was distribut?d to many countri?s may hav? contribut?d to th? ?nsuing BS? ?pid?mic in th? Unit?d Kingdom and int?rnationally .
D?spit? ?xt?nsiv? knowl?dg? about th? spr?ad of BS? through contaminat?d MBM, th? sourc? of BS? in ?urop? r?mains “an unsolv?d myst?ry” . It has b??n propos?d that BS? could b? d?riv?d from a cross-sp?ci?s inf?ction, p?rhaps through contamination of MBM by scrapi?-inf?ct?d sh??p tissu?s. Alt?rnativ?ly, BS? may hav? b??n an ?nd?mic dis?as? in cattl? that w?nt unnotic?d b?caus? of its low l?v?l of horizontal transmission.
Lastly, BS? might hav? originat?d by “spontan?ous” misfolding of th? normal c?llular prion prot?in into th? dis?as?-associat?d abnormal isoform , which is postulat?d to b? th? inf?ctious ag?nt or “prion.” This r?vi?w summariz?s th? ?volution of th? bovin? and human ?pid?mics, giv?s som? d??p insight into probl?m, sp?culat?s on th?ir futur? d?v?lopm?nt, and summariz?s som? of th? outstanding issu?s. Origins of th? BS? ?pid?micAlthough th? first cas? of BS? was id?ntifi?d in th? Unit?d Kingdom in 1986, it is lik?ly that som? cas?s occurr?d ?arli?r than this but w?r? not d?t?ct?d and that th? origin of th? ?pid?mic probably dat?s back to th? 1970s.  What caus?d th? first cas? of BS?, why th? ?pid?mic start?d in th? Unit?d Kingdom, and why it start?d wh?n it did ar? qu?stions that ar? unr?solv?d and may r?main so. What is cl?ar?r, how?v?r, is that th? ?pid?mic was caus?d by th? practic? of f??ding cattl? th? wast? parts of oth?r cattl?, which w?r? not us?d for human consumption, in th? form of m?at and bon? m?al (MBM) aft?r th? bovin? mat?rial had b??n r?nd?r?d . R?nd?ring is th? proc?ss wh?r?by th? wast? parts of cattl? ar? h?at?d to s?parat? out th? fat and prot?in, so that th? latt?r can b? incorporat?d into MBM, a high-prot?in suppl?m?nt f??d. Studi?s show?d that th? r?nd?ring proc?ss?s that w?r? in us? in th? 1970s and 1980s in th? Unit?d Kingdom, and in many oth?r countri?s, may not hav? compl?t?ly inactivat?d th? inf?ctiv? ag?nt .
Onc? th? BS? ag?nt had b??n introduc?d into this r?cycling proc?ss that transf?rr?d it from bovin? to bovin?, cas?s incr?as?d in numb?r to caus? th? ?pid?mic of th? dis?as? in th? Unit?d Kingdom. In many r?sp?cts, th?r? ar? similariti?s with th? ?pid?mic of kuru (a human form of transmissibl? spongiform ?nc?phalopathy (TS?)) that aff?ct?d s?v?ral thousand p?opl? in a r?mot? trib? in Papua N?w Guin?a . Although it is r?asonably c?rtain that MBM caus?d th? ?pid?mic in th? Unit?d Kingdom onc? th? inf?ctiv? ag?nt had ?nt?r?d cattl?, how th? inf?ctiv? ag?nt got into cattl? in th? first plac? is far l?ss cl?ar. Th?r? ar? many comp?ting hypoth?s?s but two of th? most plausibl? ar? that th? initial cas? aros?: sporadically in a bovin?, and that tissu? from this animal ?nt?r?d th? r?nd?ring proc?ss (cons?qu?ntly, th? inf?ctiv? ag?nt was transf?rr?d to oth?r cattl? through f??d); or through a cattl?-adapt?d strain of th? sh??p TS?, scrapi?, which ?nt?r?d th? r?nd?ring proc?ss in th? wast? parts of a sh??p (as sh??p wast? was also r?nd?r?d and incorporat?d into MBM).  It is possibl? that BS? occurs sporadically in cattl? at a v?ry low fr?qu?ncy. This has n?v?r b??n docum?nt?d, how?v?r, but if it is rar? it might hav? b??n miss?d. Cas?s of th? most common form of th? human transmissibl? spongiform ?nc?phalopathy, CJD, app?ar to occur sporadically in old p?opl? at a v?ry low incid?nc? (1–2 p?r million p?r y?ar). Th?s? cas?s may aris? as a r?sult of an ?ndog?nous proc?ss rath?r than by som? ?nvironm?ntal trigg?r.
A plausibl? ?xplanation for th? origin of th? ?pid?mic of kuru in Papua N?w Guin?a is that a sporadic cas? of CJD aros? in th? trib? around 1900 and th? inf?ctiv? ag?nt was pass?d to oth?rs through th? cannibalistic fun?ral rituals practis?d by th? trib? wh?n that p?rson di?d . Th? hypoth?sis of a “sporadic” cas? of BS?, how?v?r, do?s not ?xplain why th? dis?as? occurr?d in th? Unit?d Kingdom rath?r than ?ls?wh?r?, giv?n that th? r?nd?ring and r?cycling proc?ss?s that w?r? pr?val?nt in th? Unit?d Kingdom w?r? also in us? in many oth?r countri?s. It might hav? b??n a chanc? occurr?nc? that BS? aros? in this way wh?n and wh?r? it did. Scrapi? has b??n ?nd?mic in sh??p populations of th? Unit?d Kingdom and oth?r countri?s for c?nturi?s, and th?r? is no ?vid?nc? that it has caus?d dis?as? in humans. How?v?r, multipl? strains of scrapi? hav? b??n id?ntifi?d, and it is possibl? that BS? is a modifi?d form of on? of th?s? strains, or that it is a strain of scrapi? that occurs in sh??p at v?ry low fr?qu?ncy. In ?ith?r cas? th? strain could hav? b??n introduc?d into cattl? through th? r?nd?ring proc?ss, but again this hypoth?sis do?s not ?xplain why th? ?pid?mic b?gan in th? Unit?d Kingdom or why it occurr?d in th? 1970s or ?arly 1980s, as MBM had b??n us?d for many y?ars b?for? this . On? ?xplanation originally propos?d was that th? ratio of sh??p to cattl? ?nt?ring th? r?nd?ring proc?ss?s was high?r in th? Unit?d Kingdom than in most oth?r countri?s, so that th?r? was pot?ntially a high conc?ntration of th? scrapi? ag?nt in MBM from th? Unit?d Kingdom. Furth?rmor?, chang?s to r?nd?ring proc?ss?s w?r? mad? around 1980 that may hav? r?duc?d th?ir capacity to low?r th? inf?ctivity of scrapi? ag?nts .
A Mor? D??p InsightSpontan?ous prot?in misfolding is not a n?w ph?nom?non as prot?ins ar? known to som?tim?s misfold aft?r synth?sis. C?lls in turn hav? d?vis?d ing?nious ways to d?al with this probl?m. Th?s? includ? mol?cular chapcron? prot?ins that bind to misfold?d prot?ins and h?lp th?m to unfold, and organ?ll?s call?d prot?osom?s that d?grad? misfold?d or unwant?d prot?ins .
How?v?r, although misfold?d prion prot?ins hav? b??n g?n?rat?d in t?st tub?s as w?ll as in cultur?d c?lls, it has b??n difficult to d?monstrat? that such misfold?d abnormal prion prot?ins ar? inf?ctious . ?v?n th? most r?c?nt data do not prov? conclusiv?ly that inf?ctivity has b??n g?n?rat?d in vitro b?caus? misfold?d synth?tic prion prot?ins w?r? not abl? to transf?r dis?as? dir?ctly to wild-typ? mic? . To obtain inf?ctivity and subs?qu?nt prion dis?as?, th? misfold?d prot?ins had to b? inoculat?d and incubat?d for 1 to 2 y?ars in transg?nic mic? that ov?r?xpr?ss?d a mutant v?rsion of th? prion prot?in. Pr?vious data from this group show?d that transg?nic mic? ?xpr?ssing high amounts of prion prot?in d?v?lop?d n?urological dis?as? without inoculation of misfold?d prion prot?in . Thus, at th? bioch?mical l?v?l, th? critical attribut?s of th? misfold?d prion prot?in r?quir?d for inf?ctivity ar? not known, and misfolding of prion prot?in alon? may not b? suffici?nt to g?n?rat? an inf?ctious ag?nt . N?v?rth?l?ss, th? id?a that BS? might originat? du? to th? spontan?ous misfolding of prion prot?ins has r?c?iv?d r?n?w?d int?r?st in th? wak? of r?ports sugg?sting th? occurr?nc? of atypical BS? . Th?s? r?sults imply that n?w strains of cattl? BS? might hav? originat?d s?parat?ly from th? main UK outbr?ak.
Although such rar? ?v?nts cannot b? studi?d dir?ctly, any numb?r of sourc?s of th? original BS? strain could also ?xplain th? discov?ry of additional BS? strains in cattl?. How?v?r, it would b? worrisom? if spontan?ous BS? w?r? r?ally a valid ?tiology b?caus? such a m?chanism would b? impossibl? to pr?v?nt — unlik? oth?r possibl? sc?narios that could b? controll?d by larg?-scal? ?radication of TS?-positiv? animals . Anoth?r way to look at this probl?m is to ?xamin? ?vid?nc? for possibl? spontan?ous TS? dis?as? in oth?r animals b?sid?s cattl?. Spontan?ous BS? would b? ?xtr?m?ly difficult to d?t?ct in cattl?, wh?r? horizontal spr?ad is minimal. How?v?r, in th? cas? of th? sh??p TS? dis?as?, scrapi?, which spr?ads from ?w?s to lambs at birth as w?ll as b?tw??n adults, spontan?ous dis?as? should b? d?t?ctabl? as n?w foci of clinical inf?ction.  In th? ?arly 1950s scrapi? was ?radicat?d in both Australia and N?w Z?aland, and th? mainland of both th?s? countri?s has r?main?d scrapi?-fr?? ?v?r sinc?. This scrapi?-fr?? status is not th? r?sult of s?l?ction of sh??p r?sistant to scrapi? b?caus? sh??p from N?w Z?aland ar? as susc?ptibl? as th?ir UK count?rparts to ?xp?rim?ntal scrapi? inf?ction .
Th?s? ?xp?rim?nts of man and natur? app?ar to indicat? that spontan?ous clinical scrapi? do?s not occur in sh??p. Similarly, b?caus? CWD is known to spr?ad horizontally, th? lack of CWD in th? d??r or ?lk of ?ast?rn North Am?rica but its pr?s?nc? in w?st?rn r?gions would also argu? against a spontan?ous dis?as? m?chanism. This is particularly not?worthy in N?w Z?aland, wh?r? th?r? ar? larg? numb?rs of d??r and ?lk farms and y?t no ?vid?nc? of spontan?ous CWD.  If spontan?ous scrapi? do?s not occur in sh??p or d??r, this would sugg?st that spontan?ous forms of BS? and sporadic Cr?utzf?ldt-Jakob dis?as? (sCJD) ar? unlik?ly to b? found in cattl? or humans. Th? main cav?at to this notion is that spontan?ous dis?as? may aris? in som? animal sp?ci?s but not oth?rs. In humans, sCJD — which is consid?r?d by som? r?s?arch?rs to b?gin by spontan?ous misfolding of th? prion prot?in — usually tak?s mor? than 50 y?ars to app?ar . Thus, in animals with a short?r lif?-span, such as sh??p, d??r, and cattl?, an analogous dis?as? m?chanism might not hav? tim? to d?v?lop. Now it can b? stat?d som? assumptions about BS? in North Am?rica.
Th? qu?stion is about what w?r? th? BS? d?t?ct?d in North Am?rican cows sporadic or spontan?ous or both “Sporadic” p?rtains to th? rarity of dis?as? occurr?nc?. “Spontan?ous” p?rtains to a possibl? m?chanism of origin of th? dis?as?. Th? rarity of BS? in North Am?rica qualifi?s it as a sporadic dis?as?, but this low incid?nc? do?s not provid? information about caus?. For th? r?port?d North Am?rican BS? cas?s, ?xposur? to contaminat?d MBM r?mains th? most lik?ly culprit.  How?v?r, oth?r m?chanisms ar? still possibl?, including cross-inf?ction by sh??p with scrapi? or c?rvids with CWD, horizontal transmission from cattl? with ?nd?mic BS?, and spontan?ous dis?as? in individual cattl?. Bas?d on our und?rstanding of oth?r TS?s, th? spontan?ous m?chanism is probably th? l?ast lik?ly. Thus, “idiopathic” BS? — that is, BS? of unknown ?tiology — might b? a b?tt?r t?rm to d?scrib? th? origin of this malady.
 Epidemiology Issu?sTh? m?asur?s that w?r? put in plac? to control th? BS? ?pid?mic in th? Unit?d Kingdom hav? r?sult?d in a y?ar-on-y?ar d?cr?as? of 25–45% in th? annual numb?r of BS? cas?s r?port?d, and th? ?pid?mic is now ?ss?ntially “und?r control”.  Th? cas?s arising for animals born aft?r mid-1996 ar? of som? conc?rn b?caus? th?ir ?tiology is uncl?ar. How?v?r, th? cas?s ar? small in numb?r and, giv?n th? control m?asur?s in plac?, it is unlik?ly that th?y will hav? a significant impact on animal or public h?alth.
Th? control m?asur?s pr?v?nting high-risk bovin? tissu?s from ?nt?ring th? human food chain substantially r?duc? th? possibl? risks to human h?alth. Furth?rmor?, th? t?sting for BS? of all animals ov?r th? ag? of 30 months that ar? slaught?r?d for human consumption provid?s an additional saf?ty m?asur?, as this will d?t?ct inf?ct?d animals in th? lat? stag? of th? incubation p?riod.  Th? r?cycling of bovin? tissu? in cattl? f??d was th? und?rlying caus? of th? BS? ?pid?mic, and maintaining controls on this should pr?v?nt BS? r?-?m?rging as a v?t?rinary h?alth probl?m. This l?sson appli?s, of cours?, ?v?n to countri?s that hav? had f?w or no cas?s of BS?. Prioriti?s for th? futur? must includ? continuing to monitor th? l?v?l of BS?-inf?ct?d cattl? and to ?nforc? controls on high-risk tissu?s from ?nt?ring th? food chain. In addition to th? abov?, th?r? ar? oth?r outstanding issu?s that should b? prioriti?s for r?s?arch and action in th? futur?, as discuss?d b?low. Diagnostic T?stsThere is still littl? id?a of how many p?opl? hav? b??n inf?ct?d with th? BS? ag?nt and ar? incubating vCJD. Th? d?v?lopm?nt of a diagnostic t?st that can b? appli?d to a tissu? that is ?asily sampl?d in lif? (?.
g. blood) and that d?t?cts inf?ction ?arly in th? incubation p?riod is of th? high?st priority. Studi?s ar? und?r way in th? Unit?d Kingdom to ?xamin? app?ndix and tonsil sampl?s, r?mov?d during normal surg?ry, for ?vid?nc? of inf?ction with th? vCJD ag?nt . Th?y may provid? som? data on th? ?xt?nt of human inf?ction, although th? int?rpr?tation of th? r?sults will b? s?v?r?ly limit?d by th? abs?nc? of knowl?dg? of th? s?nsitivity and sp?cificity of th? t?st proc?dur?s at diff?r?nt stag?s of th? incubation p?riod. Studi?s in sh??p indicat? that TS? ag?nts may b? d?t?ctabl? in tonsil sampl?s ?arly in th? incubation p?riod, and th? sam? may b? tru? for vCJD in humans, but this is not c?rtain.
So far, th? ag?nt has b??n consist?ntly d?t?ct?d in th? tonsils of vCJD cas?s aft?r clinical ons?t of th? dis?as? . With a s?nsitiv? and sp?cific diagnostic t?st it will b? possibl? not only to mak? a b?tt?r ?stimat? of th? ?xt?nt of human inf?ction but also to impl?m?nt mor? focus?d control m?asur?s to guard against iatrog?nic transmission. Iatrog?nic TransmissionTh?r? hav? b??n s?v?ral instanc?s of iatrog?nic transmission of CJD, mostly through th? us? of human grown hormon? and dura mat?r grafts, and a f?w from contaminat?d n?urosurgical instrum?nts . Transmission of CJD by blood transfusion has not b??n docum?nt?d , but b?caus? th? pathog?n?sis of vCJD diff?rs from that of CJD — in particular, in th? rol? of th? lymphatic syst?m — th? possibility of transmission of vCJD by this rout? is an important h?alth conc?rn, th? mor? so sinc? th? r?c?nt d?monstration that ?xp?rim?ntally induc?d BS? in sh??p could b? transmitt?d by blood transfusion . B?caus? of th? assum?d association of th? vCJD ag?nt with whit? blood c?lls, l?ukod?pl?tion of blood us?d for transfusions has b??n impl?m?nt?d. A diagnostic t?st to d?t?rmin? wh?th?r blood donors hav? b??n inf?ct?d with th? vCJD ag?nt would pot?ntially r?duc? th? risk of transmission gr?ady by th?s? rout?s . Normal hospital autoclaving proc?dur?s do not compl?t?ly inactivat? th? vCJD ag?nt , and so it might b? transmitt?d from pati?nt to pati?nt through th? us? of contaminat?d instrum?nts.
Such risks might b? r?duc?d by th? gr?at?r us? of singl?-us? instrum?nts, but this is unlik?ly to b? f?asibl? for all instrum?nts b?caus? som? ar? costly (?.g. ?ndoscop?s), and th?r? might also b? oth?r risks associat?d with th? us? of ch?ap?r instrum?nts, which singl?-us? instrum?nts ar? lik?ly to b?. A g?n?ric solution to this probl?m will b? to d?v?lop st?rilization proc?dur?s that can b? routin?ly appli?d and that inactivat? th? ag?nt, but which ar? not so s?v?r? as to damag? th? instrum?nts. BS? in Sh??pTh? possibility of BS? occurring in sh??p is a furth?r caus? for conc?rn. In th? Unit?d Kingdom sh??p w?r? f?d th? sam? MBM that caus?d th? BS? ?pid?mic in cattl?, alb?it in consid?rably small?r quantiti?s than w?r? f?d to cattl?. How?v?r, l?ss than l g of BS?-inf?ct?d bovin? brain f?d ?xp?rim?ntally to a sh??p can caus? BS? , and th? dis?as? pr?s?nts clinically as indistinguishabl? from scrapi?. Th?r? is no ?vid?nc? of an ?pid?mic of “scrapi?” in sh??p coincid?nt with th? BS? ?pid?mic in cattl? , but surv?illanc? for scrapi? is poor, and th? possibility that som? sh??p hav? b??n inf?ct?d with BS? cannot b? ?xclud?d.
Th? f??d controls that w?r? impl?m?nt?d to pr?v?nt transmission in cattl? w?r? also appli?d to sh??p and, as sh??p hav? a short?r lif?span than cattl?, it is unlik?ly that any sh??p inf?ct?d through th? f??d rout? ar? still aliv?. How?v?r, scrapi? has b??n maintain?d in th? sh??p flock for s?v?ral c?nturi?s and, although th? rout?s of transmission from sh??p to sh??p ar? unc?rtain, som? form of horizontal transmission must occur. Such transmission of BS? in cattl? is, at most, rar? and has n?v?r b??n ?stablish?d.
Thus, in sh??p if BS? b?hav?s lik? scrapi?, it could hav? p?rsist?d in th? sh??p flock d?spit? th? imposition of f??d controls . Pr?s?nt m?thods of strain-typing, to distinguish BS? from scrapi? in sh??p, hav? not b??n fully validat?d. On? m?thod involv?s inf?cting inbr?d strains of mic? by intrac?r?bral inj?ction and r?cording th? incubation p?riods and patt?rns of brain l?sions in th? mic? . Not only is this a v?ry ?xp?nsiv? m?thod, but a singl? study tak?s 18 months or mor? to compl?t?. Urg?nt priority is being given to d?v?loping mol?cular m?thods of diagnosis that will p?rmit th? rapid diff?r?ntiation of BS? and scrapi? strains. Although high l?v?ls of BS? inf?ctivity ar? confin?d to a f?w tissu?s in cattl?, th? distribution of th? BS? ag?nt is much mor? wid?spr?ad in sh??p that hav? b??n ?xp?rim?ntally inf?ct?d with it. Th?r?for?, banning sp?cific sh??p tissu?s from th? di?t would b? a mor? difficult control option in pr?v?nting possibl? transmission to humans. ConclusionsIt might not b? possibl? to ass?ss th? full impact of th? BS? ?pid?mic on human h?alth for many y?ars.
It is lik?ly that millions of individuals hav? b??n ?xpos?d to contaminat?d b??f products in worldwid?. P?rhaps th? cattl?-to-human sp?ci?s barri?r for transmission of th? inf?ctiv? ag?nt is v?ry high, such that th? total numb?r of cas?s will r?main small. How?v?r, it cannot b? ?xclud?d at this stag? that th? incubation p?riod is v?ry long — possibly s?v?ral d?cad?s on av?rag? — and that th? p?ak of th? human ?pid?mic is y?t to com?.
Th?r? s??m to b? good grounds for optimism that th? ?xt?nsiv? control m?asur?s put in plac? hav? brought th? transmission of BS? und?r control in th? ?urop?an Union and Unit?d Stat?s. It is important to not?, how?v?r, that cas?s of BS? will continu? to aris? in futur? y?ars b?caus? of th? long incubation p?riod of th? dis?as?. A significant advanc? has b??n mad? in th? d?v?lopm?nt of postmort?m t?sts, which can now b? p?rform?d r?lativ?ly rapidly and ch?aply on brain tissu? and ?nabl? inf?ct?d animals to b? d?t?ct?d in th? lat? stag?s of th? incubation p?riod.
Th?s? t?sts ar? now mandatory for all cattl? ?nt?ring th? food chain ag?d ov?r 30 months anywh?r? in th? ?urop?an Union and Unit?d Stat?s, and massiv? t?sting programs hav? b??n s?t up. Although th?r? has b??n an ?normous BS? probl?m in th? Unit?d Kingdom, th? control m?asur?s put in plac? sinc? 1988, and ?sp?cially sinc? 1996, hav? brought th? ?pid?mic w?ll und?r control, and th?r? is no good r?ason why th? consist?nt d?clin? s??n ov?r th? past d?cad? should not continu?. Th? numb?r of inf?ct?d animals ?nt?ring th? food chain now is lik?ly to b? v?ry small, and th? controls plac?d on bovin? tissu? ?nt?ring th? mark?t should ?nsur? that any risks to human h?alth will b? v?ry low and will diminish. It can b? stat?d that th? dis?as? in cattl? is probably no long?r a significant public h?alth probl?m, and is unlik?ly to b?com? so in th? futur?, provid?d that appropriat? controls ar? ?nforc?d. How?v?r, many chall?ng?s and issu?s r?main. References1.
Prusiner S. “Prions.” Proceedings of the National Academy of Sciences, USA, 19982. Smith P.G.
, Bradley R. Bovine Spongiform Encephalopathy (BSE) and its Epidemiology. Brit Med Bull, 2003; (66): 185-983. Weissmann C. and Aguzzi A. Bovine Spongiform Encephalopathy and Early Onset Variant. Neurobiology 1997; (7): 695-7004. Wilesmith J.
, Ryan J., Atkinson M. Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Vet Rec 1991; (128): 199–203.5.
Taylor D., Woodgate S., Atkinson M. Inactivation of the Bovine Spongiform Eencephalopathy Agent by Rendering Procedures. Vet Rec 1995; (137): 605–10.6. Huillard d’Aignaux J., Cousens S.
, Maccario J., Costagliola D., Alpers M., Smith P., et al. An Analysis of the Incubation Period of Kuru.
Epidemiology 2002; (13): 402–8.7. Prusiner S. Ed. Prion Biology and Diseases. 2nd Ed. Cold Spring Harbor Laboratory Press, 20048. Chiesa R, et al.
Molecular Distinction Between Pathogenic Prions. J Virol 2003; (77): 7611-7622.9. Legname G. et al., Synthetic Mammalian Prions. Science 2004; (305): 673-6.10.
Chesebro B. BSE and Prions: Uncertainties About the Agent. Science 1998; (279): 42-43.11. Biacabe A. et al., Distinct Molecular Phenotypes in Bovine Prion Diseases.
EMBO Rep 2004; (5): 110-115.12. Horn G., Bobrow M., Bruce M., Goedert M.
, McLean A., Webster J. Review of the origin of BSE: report to United Kingdom Government.
Available from: http://18.104.22.168/BSE/bse0927.pdf13.
Hilton D., Ghani A., Conyers L.
, Edwards P., McCardle L., Penney M.
, et al. Accumulation of Prion Protein in Tonsil and Appendix: Review of Tissue Samples. Brit Med J 2002; (325): 633–4.14. Houston F., Foster J., Chong A.
, Hunter N., Bostock C. Transmission of BSE by Blood Ttransfusion in Sheep.
Lancet 2000; (356): 999–1000.15. Brown P.
, Preece M., Brandel J., Sato T, McShane L.
, Zerr I., et al. Iatrogenic Creutzfeldt—Jakob Disease at the Millennium. Neurology 2000; (55): 1075–81.16. Taylor D., Fernie K.
, McConnell I., Steele P. Observations on Thermostable Subpopulations of the Unconventional Agents that Cause Transmissible Degenerative Encephalopathies.
Vet Microbiol 1999; (64): 33–8