|
||||||||||||||||||
 |
From: TSS ()
COMMITTEE MEMBERS’ BRIEFING FOR PUBLIC Q & A SESSION AT SEAC 94, 21ST SEPTEMBER 2006 snip... Endodontic Dentistry and vCJD At SEAC 91 (February 2006) the committee reviewed new information on the potential risks of vCJD transmission via endodontic dentistry (dental procedures involved in the maintenance of dental pulp and the treatment of the pulp cavity). There are no reported definite or suspected cases of vCJD transmission arising from dental procedures. SEAC concluded that: • a preliminary risk assessment produced by DH suggests vCJD transmission via endodontic dentistry may, under certain hypothetical but plausible scenarios, be sufficient to sustain a secondary vCJD epidemic. However, there are uncertainties around the data and assumptions underpinning the assessment. Research underway will address some of these uncertainties and allow the risk assessment to be refined. Once the research is complete and / or other data become available, the risks should be reassessed. A watching brief should be maintained. • it is unclear whether or not vCJD infectivity can be transmitted via endodontic files and reamers. However, given the plausibility of such a scenario and the large number of procedures undertaken annually, it would be prudent to consider restricting these instruments to single use as a precautionary measure. Since sufficiently rigorous decontamination of these instruments is difficult, single use of these instruments would eliminate this risk, should it exist. CORRECT AS OF 21ST SEPTEMBER 2006 11 Transmission of prion diseases by blood transfusion Probable cases of blood transfusion-associated transmission of vCJD SEAC was informed of three cases of blood transfusion associated transmission of vCJD at SEAC 81, 83 and 91 (February 2004, June 2004 and February 2006). First Case. The Transfusion Medicine Epidemiology Review (TMER) identified a case of possible transmission of vCJD by blood transfusion. The recipient received non-leucodepleted red blood cells in 1996 from a donor who, at the time of donation, was free of clinical signs of vCJD, although went on to develop vCJD in 1999. The blood recipient died of vCJD in 2003. Second Case An elderly patient died in 2004 showing no clinical signs of vCJD with death from an unrelated cause. The patient had received a single unit of non-leucodepleted red blood cells in 1999 that had been donated by an individual who was confirmed in 2001 as a definite vCJD case. The donor’s disease onset was in 2000. There was no evidence of a spongiform encephalopathy and prion protein accumulation was detected in the spleen and a cervical lymph node. The case was methionine/valine at codon 129 of the PrP gene. Third Case The case developed symptoms of vCJD approximately 8 years after receiving a non-leucodepleted blood transfusion from a donor, who had developed symptoms of vCJD about 20 months later. In reviewing the three cases the Committee noted: • in light of these three cases there is a relatively high risk of transmission of vCJD by blood transfusion. • it should be a public health priority for all recipients of blood (leucodepleted or not) from donors incubating vCJD to be subject to the kind of careful post-mortem examination that had been possible in this case. This would help to quantify the nature and magnitude of the risks of transmission of the vCJD agent through blood donated by preclinical cases of vCJD. CORRECT AS OF 21ST SEPTEMBER 2006 12 • that active approaches to obtaining tissues for testing and clinical monitoring of these patients was important both to ensure best practice clinical care and enhancing understanding of risks. Early phase of vCJD infection in recipients of blood transfusions At SEAC 87 (April 2005), the Committee on Microbiological Safety of Blood, Tissue and Organs asked SEAC whether: • a scientific distinction could be drawn between historic and recent blood transfusion recipients in terms of the relative load of the vCJD agent that may be present in the bone, tissues or organs of the blood transfusion recipient. In the context of this question, a recent recipient was defined as having received a blood transfusion within the week prior to bone, tissue or organ donation. A historic recipient was defined as having received a blood transfusion in the more distant past. SEAC noted that: • recipients of blood products from vCJD cases had been notified and deferred from tissue/organ donation. All recipients of tissues/organs were also deferred from blood transfusion. • until sensitive ante mortem tests, especially for blood, become available it may not be possible to conduct definitive experiments that would further inform assessment of the transplant associated risks of vCJD transmission. SEAC concluded that: • because of a small background risk of vCJD infection in the population as a whole, tissues/organs from donors that had not received a blood transfusion carried some risk of vCJD transmission. • there is no clinical evidence that vCJD has been transmitted through tissue/organ transplantation. However, a potential risk of transmission via this route exists. Relevant data are extremely limited but suggest that in the early phase of infection, significant prion replication is unlikely to occur and that, therefore, tissue levels of abnormal prions following recent transfusions are likely to be related to the blood supply to each specific tissue. CORRECT AS OF 21ST SEPTEMBER 2006 13 • a risk of transplant-associated transmission of vCJD exists from tissue/organ donors that have not received blood transfusions. The additional risk as a result of a donor having received a recent blood transfusion is likely to be very small. Post mortem assessment of donor infection would provide the best method of risk reduction and enable these risks to be quantified. • in assessing and communicating the risks a balance must be struck between the small risk of vCJD transmission by transplantation and the benefits to patients receiving a transplant, especially where tissues/organs are scarce and are required for (potentially) life-saving procedures. vCJD Infectivity in Blood At SEAC 90 (November 2005) SEAC reviewed published information in relation to the key assumptions made in the assessment of exposure to vCJD infectivity in blood and blood products published in 2003 by Det Norske Veritas Consulting (DNV). SEAC considered that all the following key assumptions made in the DNV assessment appear still to be reasonable: • Blood from people incubating vCJD is infective. • Infectivity is constant throughout the incubation period. • Infectivity of blood from vCJD cases is 10 ID50/ml. • Intravenous route is 5 times less efficient than the intracranial route. • Incubation period for vCJD derived from blood is 15 years. • All people are assumed to be vulnerable to infection by vCJD, genetic variations will only affect incubation period. • Split of infectivity between blood components is: 24% in red cells, 22% in buffy coat (leucocytes and platelets) and 54% in plasma. • Dose-response function for vCJD infectivity is linear with no threshold. CORRECT AS OF 21ST SEPTEMBER 2006 14 SEAC strongly recommended that robust research is undertaken to examine infectivity levels through the incubation period and the distribution of infectivity in blood components. At SEAC 92 (April 2006) the committee reviewed unpublished data which allowed some of the assumptions of the (DNV) risk assessment to be reconsidered. The specific issues considered were: the relative levels of TSE infectivity in whole blood and in each of the individual blood components, the change in the level of TSE infectivity in blood over the course of the incubation period of disease, the relative efficiencies of the intracranial and intravenous routes of inoculation and the doseresponse relationship for infection by a TSE. A position statement was produced as a result of the discussion. SEAC Concluded that: • the available data show that blood is infectious during the preclinical stage of vCJD. Although the precise time in the incubation period of vCJD at which blood becomes infectious is unclear, data from animal models suggests it may be infectious from at least, if not before, the middle of the incubation period. • the source of infectivity in blood is not understood. Data from rodent studies suggests that infectivity in whole blood is around 10 ID/mL and that it mostly resides in the plasma and white blood cell components with infectivity associated with white blood cells substantially depleted by extensive washing. • additional information from other animal models is required to assess whether the rodent findings may be closely representative of vCJD infectivity in human blood. It is clear that an infectious dose in blood can be disseminated but not diluted by distribution to a large number of recipients. • pooling of potentially infectious material, or in other ways disseminating infectious material between a number of recipients, will not reduce the number of people infected, and is likely to increase the number of people infected. snip... CORRECT AS OF 21ST SEPTEMBER 2006 16 Prion reduction filters At SEAC 91 (February 2006) the UK blood services (UKBS) prion reduction group asked the committee to comment on the methodologies used to validate prion reduction filters, this follows the SEAC recommendation that an independent validation of the filters should be performed. The committee concluded that: • the UKBS should commission an independent validation of such products. • filters be evaluated on both leucodepleted and non-leucodepleted blood, since if they worked well on non-leucodepleted blood it may be possible to remove the leucodepletion step. • blood from individuals considered ‘at risk of vCJD’ should be collected with ethical approval and patient consent. • it was important to replicate the experiments that the filter manufacturers performed to test the efficacy and reproducibility of the filters. • further experiments to evaluate the filters should include the use of an additional rodent strain and different forms of inoculum. These experiments would provide indication of differences in the efficacy of filters against different strains or TSE agent. It is critical to include the BSE agent in these studies. Experiments that tested the removal of endogenous infectivity were important and that it was crucial to develop a model that was as close as possible to the human situation. snip... CORRECT AS OF 21ST SEPTEMBER 2006 17 Medical Implants Containing Bovine Material At SEAC 91 (February 2006) the Medicines and Healthcare products Regulatory Agency (MHRA) asked the committee to consider the potential BSE risks to humans from medical implants using bovine material from the USA. The regulations on medical devices containing animal materials are based on the principle that TSE risks must be eliminated or reduced as much as possible and residual risks must be acceptable when weighed against the benefits to patients. Currently no guidance exists on the acceptability of TSE risk control measures applied to animal material in medical devices. The MHRA requested advice on three 3 issues. (i) can TSE risk associated with medical implants using USA sourced bovine material be estimated given that it might vary over time? (ii) is there, or has there been a significant risk that might warrant action in addition to that already taken? (iii) can the standards that support the regulations be altered to facilitate a consistent approach about the acceptability of products? The committee concluded that: • a risk assessment should be conducted on each device because of the large number of variables that influence associated TSE risks. Key factors which should be considered when assessing risks are: • the animal source. Use of material from closed herds or from herds that are managed carefully to prevent the introduction of the BSE agent. • use of material from young animals would markedly lower risk compared with older animals. • the geographical risk of BSE. The geographical BSE risk status of a country gives an imprecise indication of BSE risk. It would be better to use an estimated prevalence of BSE in a country based on data from a robust surveillance system. • the potential TSE infectivity of the source tissue(s) based on a careful assessment of the available data on tissue infectivity. CORRECT AS OF 21ST SEPTEMBER 2006 18 • the site of implantation. Sites with contact with the blood supply or CNS may increase risk. • whether TSE testing is undertaken on the source animal(s). • the number of source animals used for each device. snip... CORRECT AS OF 21ST SEPTEMBER 2006 44 Conformation-dependent immunoassay (CDI) for abnormal prions At SEAC 88 (June 2005), SEAC commented on a recent paper11 which had reported that the conformation-dependent immunoassay (CDI) for abnormal prions was more sensitive than other biochemical tests. The committee: • commented that, unlike most biochemical tests, it did not rely on proteinase K (PK) digestion of prions and could detect PK sensitive forms of abnormal prions. • expressed caution about the assumption that the test was capable of measuring the infectious agent, as the form of prion constituting the infectious agent was still unclear. 11 Safar et al. (2005) Diagnosis of human prion disease. Proc. Natl. Acad. Sci. U S A. 102, 3501-3506. snip... 5. Dr Brian Matthews noted that the available information on the incidence of CJD in various countries, other than the UK, indicates that there is no obvious decline in the numbers of cases being reported. However, in the UK there seems to have been a steady decline in the number of suspected cases, and therefore of confirmed cases, for the past several years. He asked 3 questions: (i) What are the causes of the decline in the number of suspected cases reported in the UK over the past few years? (ii) What is the effect of this decline in reports of suspected cases on the certainty of the decline of the number of new cases of vCJD reported in the UK? (iii) What is the effect of this decline in reports of suspected cases on the certainty that new cases of iatrogenic transmission of CJD and/or vCJD could be identified? 6. Professor Ironside commented that the number of suspected cases of sCJD reported each year had varied since surveillance began, but numbers had appeared to decline in the past 2 years. However, this was unlikely to be due to significant numbers of cases being missed. As a way of checking to see if cases had been missed, NCJDSU had looked back at diagnosed cases of atypical dementia but had not identified any cases of CJD. The recent decrease in numbers of suspected cases reported was therefore probably due to improvements in clinical diagnostic criteria and the resultant improved quality of referrals. NCJDSU had very good links with clinicians and pathologists across the UK. http://www.seac.gov.uk/pdf/issue_summary.pdf I find this interesting ; (i) What are the causes of the decline in the number of suspected cases reported in the UK over the past few years? (ii) What is the effect of this decline in reports of suspected cases on the certainty of the decline of the number of new cases of vCJD reported in the UK? SO, the cases of nvCJD in the UK went up for years and years and then started declining as with BSE cases due to the feed ban rules, surveillance, eradication, and other factors, and sporadic CJD cases went up and up too, and then started going down at about the same time. interesting? probably just another coincidence ;-) look at Italy in 2005 98 sporadic CJD cases, Germany 81, and France at 81 cases in 2005 as well, all well known BSE countries, all with increases of sporadic CJD since 1993. ... http://www.eurocjd.ed.ac.uk/sporadic.htm -------- Original Message -------- Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD Date: Thu, 28 Nov 2002 10:23:43 -0000 From: "Asante, Emmanuel A" To: Dear Terry, I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention. Thank you for your interest in the paper. In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask. Best wishes. Emmanuel Asante <> ____________________________________ Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02) New e-mail: e.asante@prion.ucl.ac.uk (active from now) ____________________________________ snip... full text ; http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein Emmanuel A.Asante, Jacqueline M.Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L.Wood, Julie Welch, Andrew F.Hill, Sarah E.Lloyd, Jonathan D.F.Wadsworth and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.uk Variant Creutzfeldt±Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSEderived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure. Keywords: BSE/Creutzfeldt±Jakob disease/prion/ snip... Discussion Prion propagation involves recruitment and conversion of host PrPC into PrPSc, and the degree of primary structural similarity between inoculated PrPSc and host PrPC is thought to be a key component of intermammalian transmission barriers (Prusiner et al., 1990). It is clear, however, that prion strain type can also be crucial, as clearly demonstrated by the very distinctive transmission Table III. BSE and vCJD transmissions to inbred lines of mice Inoculum SJL/OlaHsd RIIIS/J FVB/NHsd C57BL/6/OlaHsd Incubation Clinical Incubation Clinical Incubation Clinical Incubation Clinical time signs time signs time signs time signs (days 6 SEM) (days 6 SEM) (days 6 SEM) (days 6 SEM) BSE (I783) 196 6 13 25/40 241 6 15 20/29 589 6 21 22/31 710 6 15 6/25 vCJD (I336) 139 6 17 6/10 342 6 31 8/8 vCJD (I344) 256 6 46 5/7 402 6 34 7/8 vCJD (I342) 169, 169 2/11 475 6 68 3/10 Transgenic modelling of BSE and vCJD 6363 properties of sporadic CJD 129MM and vCJD 129MM prions (of identical PrP primary structure) in either 129VV Tg152 (Hill et al., 1997; Collinge, 1999) or 129MM Tg35 mice. Prion strain type may also affect transmission barriers via an effect on PrPSc tertiary structure and state of aggregation (Hill et al., 1997; Collinge, 1999). These 129MM Tg35 mice, in which human PrPSc types can be propagated, have been used to study the BSE-tohuman species barrier. The frequent presence of subclinical prion disease in vCJD- and BSE-inoculated 129MM Tg35 mice further argues for the need to reassess current de®nitions of `species' or transmission barriers that limit prion transmission between different hosts (Hill et al., 2000). Such barriers have hitherto been quantitated on the basis of either comparative end-point titrations in the two respective hosts, or by measuring the fall in incubation period between primary and subsequent passage as the prion strain adapts to the new host. Both methods rely on measurement of time to onset of a clinical syndrome. Modelling the BSE-to-human barrier in 129MM Tg35 mice would lead to the conclusion, on the basis of induced clinical disease, that a substantial barrier existed. However, it is clear that human PrPSc propagation can be ef®ciently induced by inoculation with BSE or vCJD prions, suggesting a smaller barrier to infection (but not to clinical disease) than hitherto thought (Collinge et al., 1995) in humans of the PRNP 129MM genotype. Humans infected with BSE prions, but who became asymptomatic carriers, may nevertheless pose a threat of iatrogenic transmission via medical and surgical procedures. Alternatively, it is possible that the lifespan of the laboratory mouse is insuf®cient to allow expression of clinical disease in most inoculated mice, whereas a higher proportion of infected humans might survive the incubation period to develop clinical signs of disease. Serial passage studies and titration of prions in these mice are in progress to study this further. These studies further strengthen the evidence that vCJD is caused by a BSE-like prion strain. Also, remarkably, the key neuropathological hallmark of vCJD, the presence of abundant ¯orid PrP plaques, can be recapitulated on BSE or vCJD transmission to these mice. However, the most surprising aspect of the studies was the ®nding that an alternate pattern of disease can be induced in 129MM Tg35 mice from primary transmission of BSE, with a molecular phenotype indistinguishable from that of a subtype of sporadic CJD. This ®nding has important potential implications as it raises the possibility that some humans infected with BSE prions may develop a clinical disease indistinguishable from classical CJD associated with type 2 PrPSc. This is, in our experience, the commonest molecular sub-type of sporadic CJD. In this regard, it is of interest that the reported incidence of sporadic CJD has risen in the UK since the 1970s (Cousens et al., 1997). This has been attributed to improved case ascertainment, particularly as much of the rise is reported from elderly patients and similar rises in incidence were noted in other European countries without reported BSE (Will et al., 1998). However, it is now clear that BSE is present in many European countries, albeit at a much lower incidence than was seen in the UK. While improved ascertainment is likely to be a major factor in this rise, that some of these additional cases may be related to BSE exposure cannot be ruled out. It is of interest in this regard that a 2-fold increase in the reported incidence of sporadic CJD in 2001 has recently been reported for Switzerland, a country that had the highest incidence of cattle BSE in continental Europe between 1990 and 2002 (Glatzel et al., 2002). No epidemiological case±control studies with strati®cation of CJD cases by molecular sub-type have yet been reported. It will be important to review the incidence of sporadic CJD associated with PrPSc type 2 and other molecular subtypes in both BSE-affected and unaffected countries in the light of these ®ndings. If human BSE prion infection can result in propagation of type 2 PrPSc, it would be expected that such cases would be indistinguishable on clinical, pathological and molecular criteria from classical CJD. It may also be expected that such prions would behave biologically like those isolated from humans with sporadic CJD with type 2 PrPSc. The transmission properties of prions associated with type 2 PrPSc from BSE-inoculated 129MM Tg35 mice are being investigated by serial passage. We consider these data inconsistent with contamination of some of the 129MM Tg35 mice with sporadic CJD prions. These transmission studies were performed according to rigorous biosafety protocols for preparation of inocula and both the inoculation and care of mice, which are all uniquely identi®ed by sub-cutaneous transponders. However, crucially, the same BSE inocula have been used on 129VV Tg152 and 129MM Tg45 mice, which are highly sensitive to sporadic CJD but in which such transmissions producing type 2 PrPSc were not observed. Furthermore, in an independent experiment, separate inbred lines of wild-type mice, which are highly resistant to sporadic CJD prions, also propagated two distinctive PrPSc types on challenge with either BSE or vCJD. No evidence of spontaneous prion disease or PrPSc has been seen in groups of uninoculated or mock-inoculated aged 129MM Tg35 mice. While distinctive prion isolates have been derived from BSE passage in mice previously (designated 301C and 301V), these, in contrast to the data presented here, are propagated in mice expressing different prion proteins (Bruce et al., 1994). It is unclear whether our ®ndings indicate the existence of more than one prion strain in individual cattle with BSE, with selection and preferential replication of distinct strains by different hosts, or that `mutation' of a unitary BSE strain occurs in some types of host. Western blot analysis of single BSE isolates has not shown evidence of the presence of a proportion of monoglycosylated dominant PrPSc type in addition to the diglycosylated dominant pattern (data not shown). Extensive strain typing of large numbers of individual BSE-infected cattle either by biological or molecular methods has not been reported. Presumably, the different genetic background of the different inbred mouse lines is crucial in determining which prion strain propagates on BSE inoculation. The transgenic mice described here have a mixed genetic background with contributions from FVB/N, C57BL/6 and 129Sv inbred lines; each mouse will therefore have a different genetic background. This may explain the differing response of individual 129MM Tg35 mice, and the difference between 129MM Tg35 and 129MM Tg45 mice, which are, like all transgenic lines, populations derived from single founders. Indeed, the consistent distinctive strain propagation in FVB and C57BL/6 versus SJL and RIIIS lines may allow mapping of genes relevant to strain selection and propagation, and these studies are in progress. That different prion strains can be consistently isolated in different inbred mouse lines challenged with BSE prions argues that other species exposed to BSE may develop prion diseases that are not recognizable as being caused by the BSE strain by either biological or molecular strain typing methods. As with 129MM Tg35 mice, the prions replicating in such transmissions may be indistinguishable from naturally occurring prion strains. It remains of considerable concern whether BSE has transmitted to, and is being maintained in, European sheep ¯ocks. Given the diversity of sheep breeds affected by scrapie, it has to be considered that some sheep might have become infected with BSE, but propagated a distinctive strain type indistinguishable from those of natural sheep scrapie. ...snip...end THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger ] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible http://www.pnas.org/cgi/content/full/041490898v1 Characterization of two distinct prion strains http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471 p.s. please note the 47 PENDING CASES to Sept. 2005 p.s. please note the 2005 Prion D. total 120(8) p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN??? p.s. please note 2004 prion disease (6) 6=7 TYPE snip... http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf As of August 31, 2005, there were 115 scrapie infected snip... full text ; http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html Published online before print October 20, 2005 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102 A newly identified type of scrapie agent can naturally ( sheep prion | transgenic mice ) Annick Le Dur *, Vincent Béringue *, Olivier Scrapie in small ruminants belongs to transmissible A.L.D. and V.B. contributed equally to this work. To whom correspondence should be addressed. Hubert Laude, E-mail: laude@jouy.inra.fr www.pnas.org/cgi/doi/10.1073/pnas.0502296102 12/10/76 snip... A The Present Position with respect to Scrapie Scrapie is a natural disease of sheep and goats. It is a slow The field problem has been reviewed by a MAFF working group It is clear that scrapie in sheep is important commercially and Recently the question has again been brought up as to whether Whether true or not. the hypothesis that these agents might be snip... 76/10.12/4.6 http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf ALL human TSEs must be made reportable Nationally and Internationally... TSS
|
