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12/01/06 By Evelyn Ring Dublin County Coroner, Kieran Geraghty, revealed that the only three Irish vCJD victims lived or had family within five miles of each other and called for a State investigation into his discovery. Mr Moran from Shankill, Co Dublin, said he met with the Tánaiste last September, two months after the death of his son and asked her to provide funding for the victims' families. He said the minister told him that the State was not responsible for the deaths of the vCJD victims because of safeguards that had been put in place in 1990. "I had asked her to put in place some form of funding for the families involved but she just brushed it aside," he said. Mr Moran said his son, like the rest of the family, ate the same meals - meat and vegetables that came from two local supermarkets, and had never spent time in Britain. A spokesperson for Ms Harney said the Irish situation differed fundamentally from that in Britain, where there was a compensation scheme. "There is no firm evidence to date on the source of infection in the Irish cases," he said and added that the situation was under constant review by the relevant public health experts. Consultant neurologist, Dr Michael Hutchinson, said that while it was likely the very first victim to die from vCJD had contracted the disease in Britain, the other two appeared to be indigenous cases. Asked about the cluster of vCJD victims identified by the coroner, Dr Hutchinson said that while it was probably a coincidence that two of the indigenous cases occurred close to each other the matter should still be investigated even if it turned out to be unproductive. Dr Hutchinson said it was most likely that Irish BSE was responsible for two of the vCJD cases. "Any public health concerns should be addressed," he stressed. Dr Hutchinson said the number of vCJD cases had levelled off and it seemed most unlikely that there would be an epidemic. Ireland, however, could expect to see one or two more cases over the next 10 years. He said experts agreed humans developed vCJD as a result of eating the meat of an animal that had Bovine Spongiform Encephalopathy (BSE) and, as yet, there was no evidence of any effective therapy. Q&A Q: What is Variant Creutzfeldt-Jakob disease (vCJD)? A: It is a rare and fatal human disease that causes the brain to waste away. It was first described in March 1996 and linked with eating meat from cattle affected by so-called "mad cow" disease. Q: What is the disease's incubation period? A: Believed to be eight to 10 years. Q: How are people affected by the disease? A: Early psychiatric symptoms most commonly take the form of depression and less often a schizophrenia-like psychosis. Other symptoms include unsteadiness, difficulty walking and involuntary movements. By the time of death, patients are completely immobile and mute. Q: What is the State doing to protect consumers? A: The Food Safety Authority of Ireland say controls in place in Ireland since 1996 are very strict and there are robust controls to ensure maximum consumer protection in relation to BSE. by Donal Bergin Dr Geraghty last week returned a verdict of misadventure at an inquest into the death of Mr Jason Moran from Shankill, Dublin, who died last June from vCJD. Mr Moran’s family and another man with vCJD live within a few miles of each other, as do relations of a woman who is thought to have acquired the disease in the UK. But it would be almost impossible to be find the source of infection for a variety of reasons, National Medical Director of the Irish Blood Transfusion Service Dr William Murphy told IMN. Meanwhile, Dr Murphy said clinical trials were underway in Irish hospitals on a new vCJD prion filter for red cells. He said it hoped to roll out the filter later on this year. Dr Murphy said the initial part of the trial, which started last month, involved around 60 patients, and the second phase would involve a significant expansion of the testing. http://www.irishmedicalnews.ie/articles.asp?Category=news&ArticleID=15292 Greetings, lets look at these questions and answers again with more modern up to date science; Q&A Q: What is Variant Creutzfeldt-Jakob disease (vCJD)? A: It is a rare and fatal human disease that causes the brain to waste away. It was first described in March 1996 and linked with eating meat from cattle affected by so-called "mad cow" disease. ... disease in the United States I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc? Date: Thu, 28 Nov 2002 10:23:43-0000 From: "Asante, Emmanuel A" To: "'flounder@wt.net'" 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 Creutzfeldt-Jakob disease 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 Q: What is the disease's incubation period? A: Believed to be eight to 10 years. ... Creutzfeldt-Jakob Disease Epidemic Jerome N. Huillard dÕAignaux,* Simon N. Cousens, Peter G. Smith Back-calculation analysis of the variant Creutzfeldt-Jakob disease epidemic in the United Kingdom is used to estimate the number of infected individuals and future disease incidence. The model assumes a hazard of infection proportional to the incidence of bovine spongiform encephalopathy in the United Kingdom and accounts for precautionary control measures and very wide ranges of incubation periods. The model indicates that current case data are compatible with numbers of infections ranging from a few hundred to several millions. In the latter case, the model suggests that the mean incubation period must be well beyond the human life-span, resulting in disease epidemics of at most several thousand cases. Variant Creutzfeldt-Jakob disease (vCJD) is caused by an agent that is currently indistinguishable from that responsible for bovine spongiform encephalopathy (BSE) in cattle. However, 5 years after the identification of vCJD, great uncertainty remains over how many individuals have been infected with the agent and how many of these individuals will go on to develop clinical disease (1–5). In the absence of a test for infection, one approach to estimating the number of infected individuals is provided by back-calculation, a statistical technique developed in the context of the HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) epidemic (6, 7). This approach makes use of the fact that the number and timing of cases of disease that occur depend on three factors: (i) how many people were infected, (ii) when they were infected, and (iii) how long it takes from infection for disease to become apparent—the incubation period. To use this approach to estimate the number of individuals infected with the vCJD agent, it is necessary to make assumptions about when people were exposed to infection and how long it takes them to develop disease. Previous work has shown that the estimated number of infections/cases produced by this approach is very sensitive to the assumptions made about the incubation period distribution (2, 8, 9). We have developed a family of backcalculation models (10) to explore the prevalence of infection with the vCJD agent and the incidence of clinical vCJD in the UK. The main features of these models are as follows: (i) The hazard of infection was assumed to have been proportional to the incidence of BSE (11). We did not consider onward, human- to-human transmission of the infectious agent. (ii) The incubation period of the disease was assumed to follow an offset generalized F distribution, which has five parameters. We also investigated the lognormal, Weibull, and gamma distributions as special cases of this distribution (12). (iii) We assumed that the incubation period was independent of age at infection (13). (iv) The model was restricted to the 40% (approximately) of the UK population assumed to be methionine homozygous at codon 129 of the prion protein (PrP) gene. (All cases of vCJD identified to date have been of this genotype.) (v) To minimize the impact of reporting delays, we fitted the models to the data on the 82 cases with onsets before 2000 that had been identified by 31 December 2000. The back-calculation model had seven parameters in total [five for the incubation period distribution, one for the hazard of infection, and one for the effect of the specified bovine offals (SBO) ban in 1989]. The model was fitted by the maximum likelihood method, assuming a Poisson likelihood. Because of a very severe parameter identifiability problem, we estimated the incubation period distribution parameters for fixed values of the hazard of infection (corresponding to total numbers of infections ranging from 100 to 12 million) and for fixed effects of the SBO ban ranging from 0 to 90%. Allowing a very flexible incubation period distribution (offset generalized F), we found that the cases observed to date were almost equally compatible with any number of infections up to several millions. However, when a very large number of infections was considered, the model indicated that the average incubation period was likely to be extremely long and, in most instances, well beyond the normal human life-span. As a result, the corresponding epidemic sizes (clinical cases) lay within a much narrower range, from a few hundred to a few thousand cases (Table 1). When making stronger assumptions about London School of Hygiene and Tropical Medicine, Infectious Disease Epidemiology Unit, Keppel Street, London WC1E 7HT, UK. *To whom correspondence should be addressed. E-mail: jerome.huillard@lshtm.ac.uk Table 1. Estimates of numbers of infections, numbers of clinical cases, incubation period parameters, and prediction intervals by assumed incubation period (IP) distribution. Values shown are calculated assuming a SBO ban efÞciency of 80%. snip... the form of the incubation period distribution (i.e., reducing the number of parameters from five), the range for the number of infections with which the observed cases are compatible becomes narrower. For example, using a simple generalized F distribution led to a point estimate of the total number of infections of a few hundred, with an upper 95% confidence limit of about 1000 (and upper 99% confidence limit of 7000). Using an offset lognormal distribution again led to a point estimate of the total number of infections of a few hundred. The predicted course of the vCJD epidemic was calculated under different assumptions about the incubation period distribution (14). No matter which incubation period distribution is used, the point estimates obtained from the model suggest that the epidemic of cases of vCJD is very close to its peak. However, the expected numbers of cases corresponding to the upper limits of infection (14) indicate that the data are also compatible with an epidemic whose peak, many years hence, is determined by mortality among infected individuals from competing causes. Table 1 also presents approximate prediction intervals (15) for annual numbers of cases at different times in the future. These indicate that the annual incidence of vCJD is unlikely ever to be much more than 100 cases (14). None of our models suggest that the number of primary cases of vCJD in methionine homozygotes is likely to be more than a few thousand, even though the number of primary infections could be anything from a few hundred to many thousands or even millions. In interpreting these results, and extrapolating them to other codon 129 genotypes, we must bear in mind our model assumptions. Our key finding that, regardless of the number of infections that have occurred, the number of clinical cases is unlikely to exceed a few thousand (in any one genotype) is sensitive to a number of assumptions. First, we have assumed that in codon 129 methionine homozygotes, the incubation period for vCJD has a unimodal distribution. This is a key assumption that is open to question (16). In mice, there are genetic factors lying outside the coding region of the PrP gene that have an important influence on the incubation period of transmissible spongiform encephalopathies (17–20). It is possible, therefore, that among human codon 129 methionine homozygotes there are other, presently unknown genetic factors that influence the vCJD incubation period. We have used the generalized F distribution, which can take a wide range of unimodal forms. If, across the methionine-homozygous population, the mixture of other genetic factors affecting incubation period results in an overall incubation period distribution that is close to unimodal, we would be confident that, broadly, our findings with respect to the numbers of clinical cases hold. If, however, the overall incubation period distribution is strongly multimodal, there might be many more clinical cases of vCJD than our models predict. If the latter is the case, then the development of reliable back-calculation models will be possible only when the relevant genetic factors have been identified and measured in the population. Strong multimodality is most likely to apply if only a small number of other genetic factors are involved and there was little variation between infected individuals in the infecting dose to which they were exposed. Second, we have assumed that the incubation period distribution does not vary with age at infection. Experimental evidence in mice indicates that, for a fixed dose, incubation period does vary with age at inoculation (21). However, this variation is small, with young mice having incubation periods 7 days longer than older mice, compared with mean incubation periods of several hundred days. If vCJD infections occurred through diet, as we have implicitly assumed, infected individuals may have been exposed to a very wide range of infectious doses whose impact on incubation period is likely to dwarf any small age effects. Third, to extrapolate from codon 129 methionine homozygotes to other genotypes, we need to assume that across codon 129 genotypes the relation between the mean and the variance of the incubation period distribution does not vary greatly. If other genotypes have longer mean incubation periods but with lower variance, then we might observe larger numbers of cases in these genotypes. It is, however, unusual for the variance of a distribution to decrease as the mean increases. If this is not the case, then to extend our results to include all genotypes one could, as a worst-case scenario, multiply our predictions by about 2.5 to obtain a figure for the whole population. A further assumption of the model is that infection was essentially through diet and that the amount of infectivity consumed in food during any given period was proportional to the number of BSE cases occurring up until 1996. In the absence of ongoing human-tohuman transmission of the vCJD agent, our findings are likely to be much less sensitive to this assumption than they are to the assumptions about incubation period. The upper limits of our estimates differ from those presented by Ghani et al. (1). These authors used simulation to identify a range of scenarios compatible with the actual observed incidence. One advantage of this approach is that it allows the incorporation into the model of several parameters that could not be estimated. However, it does not enable any probability statement to be made about the coverage of the range of epidemics that it produces, and running more simulations can only increase the range of scenarios that are plausible. We believe the most likely explanation for the different ranges of cases coming out of our work and that of Ghani et al. is that the coverage probabilities of those intervals are different. Our models suggest that the number of primary cases of vCJD in methionine homozygotes is unlikely to exceed a few thousand, but that considerably greater uncertainty surrounds the number of primary vCJD infections that have occurred. Whether a few hundred or many more people have been infected has important consequences for public health and, in particular, for the risk of secondary transmission (22). If secondary transmission does occur, the mean incubation period in secondary cases may be much shorter than in primary cases (23). In the absence of a reliable test for asymptomatic infection, considerable uncertainty about the number of infected individuals may remain for a number of years. References and Notes snip... www.sciencemag.org/ Estimation of Epidemic Size and Incubation Time Based on Age Characteristics of vCJD in the United Kingdom Alain-Jacques Valleron,1 Pierre-Yves Boelle,1 Robert Will,2 Jean-Yves Cesbron3 The size of the variant Creutzfeldt-Jakob Disease (vCJD) epidemic in the United Kingdom is a major public health concern and a subject of speculation. The cases are young (mean age 5 28). Assuming that the risk of developing the disease in susceptible exposed subjects decreases exponentially with age after age 15, that all infections occurred between 1980 and 1989, and that the distribution of the incubation period is lognormal, we estimate that the mean duration of the incubation period is 16.7 years [95% conÞdence interval (CI): 12.4 to 23.2] and that the total number of cases will be 205 (upper limit of the 95% CI: 403). snip... The distribution of the vCJD incubation period that best fits the data within the framework of our model has a mean of 16.7 years, with a standard deviation of 2.6 years. The 95% upper percentile of this distribution is 21.4 years. The 95% confidence interval (CI) of the estimates of the mean and standard deviation is relatively narrow: The 95% CI for the estimate of the mean incubation period is 12.4 to 23.2 years, and the 95% CI of the standard deviation is 0.9 to 8 years (10). The decrease in susceptibility to infection in exposed subjects older than 15 years, as estimated from the parameter a, was found to be very sharp: 16% per year of age (CI: 12 to 23%). This means that, under the best fitting hypothesis, an individual aged 20 years in 1981 had 55% less risk of becoming infected than a child aged 15 years (99.9% for an individual aged 70). The model predictions fit the past cumulated incidences, as shown in Fig. 2. Similarly, there is a good fit to the observed age distribution (10), as the model predicts that 22 out of the first 97 diagnosed cases should be less than 20 years of age (19 in the surveillance data set) and 82 should be less than 40 years of age (87 in the surveillance data set). Details of the variation in the risk function (14) with age and time up to 2012 are shown in Fig. 3: The model predicts that the peak of the epidemic will be in 2000/2001 and that the annual number of cases should gradually decrease after this date. The total number of expected vCJD cases is, according to our model, low at 205 cases (upper limit of the 95% CI: 403). One prediction from the model is that in the next few years, the age distribution will become bimodal and that the proportion of older patients will increase. The model presented here addresses human infections occurring between 1980 and 1989, as we assume that the likelihood of new human infection with BSE after the bovine SRM ban in 1989 should have been considerably reduced. The strength of the method used in this report is that it is focused on the most striking epidemiological characteristic of vCJD, namely, the age distribution of the cases. In contrast to other models, which are based primarily on scenarios related to dietary exposures to BSE in the United Kingdom, our method does not make any assumptions about this parameter that cannot currently be estimated. To express the necessary dependence between age and force of infection, we made one of the most parsimonious choices possible, i.e., a function beginning with a plateau during childhood, followed by an exponential decrease. The sensitivity analysis in which all possible alternatives to the 15-year age limit were tested ruled out an even simpler model with only one exponential function (age limit 5 0) and found as the optimal value an age limit of 16. We have no clear physiological explanation for this age limit: Although a relation with puberty may be hypothesized, experimental evidence should be sought to support such a possibility. The results presented here are based on a lognormal distribution of the incubation period, which is commonly used in the epidemiology of infectious diseases. However, we repeated the estimation process assuming that the incubation period was Gamma distributed and found almost identical values for the incubation parameters, the future epidemic size of the epidemic, and the occurrence of a bimodal age distribution in the future (10). The incubation time we find for vCJD is longer than in human growth hormone–related CJD, which is between 9 and 10 years (15) in the sensitive homozygous genotypes. It is shorter than the one estimated in Kuru (16), which may exceed three decades, although, a priori, one would have expected a longer value because in Kuru, there is no species barrier and the disease was transmitted orally as in vCJD. The PRNP 129 genotype has a crucial importance in determining the risk of developing CJD. Yet to date, all tested vCJD patients have been homozygous for methionine at codon 129, as are about 40% of the total UK population. If there are two subpopulations of vCJD patients, one with “short” incubation times and methionine homozygosity, the other with “long” incubation times and valine homozygosity or heterozygosity, our method would not identify the second distribution parameters, because cases of vCJD with genotypes other than methionine homozygosity have not yet been identified. Our age-risk model allows an estimate of the future size of the epidemic. If we independently introduce our estimates of the incubation period in the Ghani or Cousens models, we find similar “low” predictions: 80 to 630 cases with the Ghani model and 801 with the Cousens model (17). In conclusion, our prediction of the epidemic of vCJD lies in the “optimistic” end of the ranges of previously published figures, and this low value is in favor of a large species barrier between cattle and humans. References and Notes snip... www.sciencemag.org/ SEAC Statement -------------------------------------------------------------------------------- Summary of SEAC’s discussion on the second presumed case of blood transfusion-associated infection with vCJD 13. SEAC noted that the patient was heterozygous at codon 129 of the PRNP gene and that this was the first time infection with the vCJD agent had been reported in an individual not methionine homozygous. This indicated that genotypes other than the methionine homozygous were susceptible to infection with the vCJD agent. Uncertainties remain as to the relative susceptibility of heterozygotes to food borne (or other) infection or the possible outcomes of infection. The committee agreed that the similarities between the western blot band analysis and PrPres glycoprofile seen in this case and in cases of vCJD who were methionine homozygous was reassuring with respect to the ability to make the diagnosis of vCJD in those of genotypes other than methionine homozygous. http://www.seac.gov.uk/statements/state070804.htm http://www.seac.gov.uk/pdf/cjd.pdf Q: How are people affected by the disease? A: Early psychiatric symptoms most commonly take the form of depression and less often a schizophrenia-like psychosis. Other symptoms include unsteadiness, difficulty walking and involuntary movements. By the time of death, patients are completely immobile and mute. ... This study characterizes the type and timing of psychiatric manifestations snip... CONCLUSIONS Historically, psychiatric manifestations have been described as a relatively Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,† Fred G. van Zijderveld,† Moira E. Bruce,‡ James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease Control (CIDC)-Lelystad, † Lelystad, The Netherlands; Institute for Animal Health, Neuropathogenesis Unit, ‡ Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform encephalopathy). Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151–157; DOI: 10.2353/ajpath.2006.050766) snip... Discussion In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component of PrPSc from the vCJD brain. Western blot analysis of PrP in a sample of cerebral cortex from a of vCJD during digestion with proteinase K is shown. Time points assayed are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). Duplicate blots were probed with 3F4, which detects both type 1 and type 2 PrPSc, and with 12B2, which detects type 1. The insert shows a shorter exposure of the same time course study from a separate experiment also probed with 3F4. Both blots included samples of cerebral cortex from a case of sporadic CJD MM1 (Type 1) and molecular weight markers (Markers) indicate weights in kd. Figure 7. A minority type 1-like PrPSc is found in vCJD tonsil, vCJD to mice and in BSE. Western blot analysis of PrPSc in a concentrated sample of tonsil from a case of vCJD (Tonsil), in a concentrated brain of a wild-type mouse (C57BL) infected with vCJD and in a sample of cattle BSE brain (BSE) is shown. Tissue extracts were digested with proteinase K. Duplicate blots were probed with either 3F4 or 6H4, both of which detect type 1 and type 2 PrPSc, and with 12B2, which detects type 1. The blots included samples of cerebral cortex from a case of sporadic CJD MM1 (Type 1) and molecular weight markers (Markers) indicate weights in kd. Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological significance remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a situation reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this report on vCJD, where type 1 is present in all samples investigated but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative balance between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the “glycoform signature” of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is likely to continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative limitations and that any mechanistic explanation of prion replication and the molecular basis of agent strain variation must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally predominates. Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in addition to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE infection or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note that this minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship between the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments snip... Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157 AJP January 2006, Vol. 168, No. 1 ...TSS http://neurology.thelancet.com Published online October 31, 2005 Creutzfeldt-Jakob disease Magdalini Polymenidou, Katharina Stoeck, Markus Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi Summary Background The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc. Findings We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern. Interpretation The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? Q: What is the State doing to protect consumers? A: The Food Safety Authority of Ireland say controls in place in Ireland since 1996 are very strict and there are robust controls to ensure maximum consumer protection in relation to BSE. Editorial team (eurosurveillance.weekly@hpa.org.uk), Eurosurveillance Editorial Office Another case of probable variant Creutzfeldt-Jakob disease (vCJD) has been identified in Ireland [1]. Three cases of vCJD have now been reported in Ireland, although the first, in 1999, was thought not to be indigenous as the patient had lived in England for several years during the high risk period [2]. If the recent probable case is indigenous, this will be Ireland’s second. vCJD appears to be transmissible by blood transfusion, as demonstrated by a case in the United Kingdom in 2003 [4]. The patient had donated blood and two patients were treated with different components of this donation. One recipient patient subsequently died shortly afterwards of an unrelated underlying condition. The recipient of the other blood component has been informed [5]. People who spent even just one year in the United Kingdom between 1980 and 1996 have been excluded from giving blood in Ireland since November 2004 (people who spent 5 years in the UK during this time have been barred since 2001, people who spent 3 years since May 2004). All people who ever received a blood transfusion since 1980 were also excluded from donating in May 2004. http://www.eurosurveillance.org/ew/2005/050707.asp Age Profile County Breakdown Herd Type The total number of cases in 2005 was 69. This compares with 126 cases for 2004 which represents a year-on-year reduction of 44% in the number of confirmed cases. The equivalent number of cases was 186 in 2003 and 333 cases for the equivalent period in 2002. This week's case was identified under the active surveillance programme. Under the active surveillance programme, testing of a proportion of fallen stock and cattle destined for human consumption was initiated in July 2000. This was extended in January 2001 to test all cattle over 30 months destined for human consumption and all casualty animals. Since July 2001 all fallen cattle are also tested. Over 2.75 million tests have been carried out up to the end of 2004 under the active surveillance programme (over 662,000 in 2001; over 688,000 in 2002; over 700,000 in 2003 and over 701,000 tests were carried out during 2004). Over 676,000 tests were carried out between January and November 2005. The underlying trend remains positive and the increasing age profile of animals confirmed with the disease indicates that the enhanced controls introduced in 1996 and early 1997 are proving effective. The effectiveness of Ireland's BSE controls was recognised by the EU's Scientific Steering Committee which indicated, in a report on Ireland's BSE risk published in May 2000, that controls in this country were stable from 1996 onwards, very stable from 1997 onwards, and optimally stable since 1st January, 1998. The range of controls in place to protect consumers and to eradicate the disease continues to be rigorously enforced. In particular it should be noted that specified risk material is removed fromall cattle slaughtered. Department of Agriculture and Food 1: Details of BSE confirmations for week-ending 16th December 2005 RESULTS OF BSE TESTING FOR THE YEAR 2004 *One rapid test positive could not be confirmed. Considering other criteria, a suspicion of BSE remains and the herd has been depopulated on a precautionary basis. **This figure differs from the number of confirmed cases because the confirmed cases total includes cases which were rapid test positive in December 2004, but were confirmed in January 2005. RESULTS FOR THE YEAR 2005 T0-DATE Definition of categories http://www.agriculture.gov.ie/index.jsp?file=areasofi/bse/bse_confirmations.xml
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