ATYPICAL CREUTZFELDT JAKOB DISEASE's AND ATYPICAL BSE's - sporadic, spontaneous, or sourced ? Date: July 22, 2007 By Terry S. Singeltary Sr. If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5). http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm Creutzfeldt-Jakob Disease Mortality in Japan, 1979-2004: Analysis of National Death Certificate Data Yuriko Doi1), Tetsuji Yokoyama2), Miyoshi Sakai2) and Yosikazu Nakamura3) 1) Department of Epidemiology, National Institute of Public Health. 2) Department of Technology Assessment and Biostatistics, National Institute of Public Health. 3) Department of Public Health, Jichi Medical University. (Received: September 13, 2006) (Accepted: March 18, 2007) Abstract BACKGROUND: Trend of the mortality rate of Creutzfeldt-Jakob disease (CJD) in Japan is still unclear. This study aimed to estimate annual crude mortality rates due to CJD and examine the CJD mortality trend in Japan during the period of 1979-2004. METHODS: National death certificate data on CJD were used (CJD coded as 046.1 for ICD-9 and A81.0 for ICD-10). Trends in age-standardized mortality rates for CJD were examined by using time series analyses including the joinpoint regression analysis. RESULTS: A total of 1,966 deaths (862 males and 1,104 females) were identified with CJD coded as the underlying-cause-of-death. The annual number of deaths and crude mortality rates peaked in 2004 at 163 (66 for males and 97 for females) deaths and 1.28 (1.06 for males and 1.48 for females) deaths per million population per year, respectively. The age-specific mortality rates rapidly increased with age between 50 and 74 years, especially among females, and sharply declined at 80+ years. Throughout the observed period, there were no significant change points, and the annual percentage changes (95% confidence intervals) were +3.09 (2.18 - 4.02) % for males and +3.90 (2.98-4.83) % and females. The total number of CJD deaths under 50 years of age was 131, and there was found no increase in the annual number of deaths for the past few years in this age group. CONCLUSION: CJD mortality in trend data based on death certificates has significantly increased in Japan during the period of 1979-2004. J Epidemiol 2007; 17: 133-139. Key words: Creutzfeldt-Jakob Syndrome; Regression Analysis; Mortality; Death Certificate; Japan snip... AS demonstrated in this study, we found a significant linear increase in trends for age standardized mortality rates from the disease, with +3-4% of annual percentage change, between 1979 and 2004. In interpreting the results, we should consider some factors that might contribute to a false increase in mortality, such as the change of ICD codes and the enhancement of case findings (e.g., physicians9 recognition of the disease, diagnostic tests, and quality of health care). No revolutionary new diagnostic test for CJD became available throughout the observational period. On the other hand, there were a few critical points of time to consider: in 1991, patients with CJD transmitted by cadaveric dura transplants were identified in Japan9, in 1995, the ICD code for CJD was changed from 9th to 10th version in Japan; and in 1996, a new case of vCJD causally linked to BSE was reported from the United Kingdom.6 Without an abrupt rise of age-standardized mortality rates from CJD after these years for both sexes, however, it is unlikely that these events artificially affected the increase in CJD mortality. Rather, it may be the true fact that in Japan our results reflect to a large extent a genuine increase in CJD. The number of iCJD cases may still increase even after the total ban on the practice of causal grafts.5,8 Regarding sporadic CJD (sCJD), a recent report from the European Unions collective study on CJD suggests that the mortality rates from sCJD increased with time between 1993 and 2002.20 It is quite probable that this temporal increase of sCJD may also exist in Japan. The increase may have been accompanied to some extent by the improvement of physicians diagnostic skills for CJD since 1997 when a manual for clinical practice on CJD was introduced in our country.20,21 click here http://www.jstage.jst.go.jp/article/jea/17/4/133/_pdf doi:10.1016/S0140-6736(02)09384-4 Copyright © 2002 Elsevier Ltd All rights reserved. Fast track — Research Letters Incidence of Creutzfeldt-Jakob disease in Switzerland Markus Glatzel MDa, Colette Rogivue DVMb, Azra Ghani PhDc, Johannes R Streffer MDd, Lorenz Amsler MDb and ProfAdriano Aguzzi MDa, , aInstitute of Neuropathology and National Reference Center for Prion Diseases, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland bFederal Office of Public Health, Division of Epidemiology and Infectious Diseases, Bern, Switzerland cDepartment of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK dDivision of Psychiatry Research, University of Zurich, Zurich, Switzerland Available online 11 July 2002. Summary The incidence of Creutzfeldt-Jakob disease (CJD) in Switzerland increased two-fold in 2001, and figures from the first quarter of 2002 indicate that it continues to rise. Neither age at onset nor duration of disease were different from previous years. Genetic analysis of the 27 reported cases revealed only one disease-associated mutation in the prion gene. None of the recognised risk factors for acquired CJD were reported on the offical notification forms. Glycotype profiling, histopathology, and immunohistochemistry indicate that none of the cases fulfilled the definition of variant CJD, which is thought to be caused by bovine prions. Several scenarios could account for the increase in CJD, including improved reporting, iatrogenic transmission, and transmission of a prion zoonosis. Correspondence to: Prof Adriano Aguzzi click here please notice the dramatic increase in sporadic cjd in France, from 82 in 2005, to 116 in 2006, the highest number of sporadic CJD cases ever documented in a year in France. ...TSS Nombre de cas de maladie de Creutzfeldt-Jakob click here COMPARE SPORADIC CJD TO BASE SLIDES AND SEE FRENCH, ITALIAN, GERMAN, BELGIUM, BASE Atypical Atypical cases of TSE in cases of TSE in cattle and sheep cattle and sheep H. De H. De Bosschere Bosschere CODA/CERVA CODA/CERVA Nat. Ref. Lab. Vet. Nat. Ref. Lab. Vet. TSEs TSEs Belgium Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt-Jakob disease C. Casalone, G. Zanusso, P. Acutis, S. Ferrari, L. Capucci, F. Tagliavini, S. Monaco, and M. Caramelli vol.101: 3065-3070 (2004) http://www.var.fgov.be/pdf/1100_TSEDAY.pdf Creutzfeldt–Jakob disease in Germany: a prospective 12-year surveillance U. Heinemann1, A. Krasnianski1, B. Meissner1, D. Varges1, K. Kallenberg2, W. J. Schulz-Schaeffer3, B. J. Steinhoff4, E. M. Grasbon-Frodl5, H. A. Kretzschmar5 and I. Zerr1 1National TSE Reference Center at Department of Neurology, Georg-August University Göttingen, Germany, 2Department of Neuroradiology, Georg-August University Göttingen, Germany, 3Department of Neuropathology, Georg-August University Göttingen, Germany, 4Epilepsy Center Kork, Diakonie Kork, Germany and 5Department of Neuropathology, Ludwig-Maximilian University Munich, Germany Correspondence to: Inga Zerr, MD, National Reference Center for TSE, Department of Neurology, Georg-August University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany E-mail: IngaZerr@med.uni-goettingen.de Creutzfeldt–Jakob disease (CJD) is a rare and fatal neurodegenerative disorder with a worldwide incidence of 1–1.5 per million. As in other countries, a CJD surveillance unit with a clinical and neuropathological approach was established in Goettingen (Germany) in 1993. Here we report the epidemiological data from a prospective 12-year surveillance. Since 1993, there has been an increasing incidence of CJD, from 0.7 in 1993 to 1.6 in 2005 with a quite stable level since 1998. During this period, the proportion of patients with MV and VV codon 129 genotype rose, possibly because of better identification of atypical subtypes. Six percent of all patients had a PRNP mutation, mainly D178N-129M (FFI), E200K and V210I. Iatrogenic CJD was a rare phenomenon. No patient infected by cadaveric growth hormone extracts was reported. Furthermore, no variant CJD patient has yet been identified in Germany. Differential diagnoses revealed a variety of neurodegenerative diseases, with Alzheimer's disease in the lead. One-third of the non-CJD patients included in this study suffered from a potentially treatable disorder such as metabolic or inflammatory diseases. The incidence and mortality rates in Germany are similar to those in other European countries. In contrast, however, acquired forms, such as iatrogenic and variant CJD are still rare in Germany or have not yet been identified. Key Words: CJD; dementia; epidemiology; diagnosis; CSF; MRI; codon 129 genotype; genetic CJD; reversible/treatable dementia Abbreviations: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt–Jakob disease; FFI, fatal familial insomnia; GSS, Gerstmann–Straeussler–Scheinker syndrome Received August 10, 2006. Revised December 25, 2006. Accepted March 8, 2007. snip... Results Patients Between June 1993 and December 2005, 2094 patients with suspected CJD were referred to the CJD Surveillance Unit Goettingen. Additionally, 76 patients were notified at the time of autopsy (these were included in incidence and mortality calculations) or because a mutation in PRNP was detected without clinical evaluation ( Table 1 ). Of this total of 2170 patients, the diagnosis of sporadic CJD was confirmed neuropathologically in 753 (35%) patients and further 575 (26%) patients were classified as probable sCJD. This reveals an incidence of 0.7 in 1994 to 1.6 in 2005 but an almost stable level since 1998. One hundred and six (5%) patients were classified as possible sCJD with typical clinical symptoms but negative 14-3-3 test and no PSWCs in EEG. Neuropathology failed to detect any hints for prion disease in 102 patients (5%), and in 447 patients (21%) clinical classification as other disease was established. The autopsy rate of all patients was 66% (836/1266), the autopsy rate within the patients classified as other disease 50%. Thus, single cases of unidentified prion disease might be included within the clinically other patients. Additionally, genetic analysis revealed 123 patients with inherited prion disease (6% of all spongiform encephalopathies in this study). A further 10 patients were classified as iatrogenic CJD. Up to now, no patients with vCJD has been confirmed in Germany despite careful surveillance. Classification Six hundred and fifty-eight patients were clinically classified according to the diagnostic criteria and neuropathologically confirmed. The majority of 88% (n = 581) of these patients were finally classified as probable sCJD, and in 47 (7%) patients clinical symptoms allowed the classification as possible sCJD ( Table 2 ). Only in 35 patients (5.3%) sCJD could not be identified by the established clinical criteria and thus were initially classified as other disease. Further analysis of these patients showed five patients classified as other case because of inflammatory findings on routine examination in CSF. Another problem was absence of dementia, isolated dementia or only dementia with cerebellar ataxia at last classification during follow-up, so that these had to be classified as other case (n = 26). The remaining patients were classified as other case (and neuropathology turned out sCJD) because of indications for other diagnoses, such as genetically proven SCA12, paraneoplastic disease (predominant polyneuropathy and massive elevated protein content in CSF), epileptic fits (initially epileptic fits, later reduced vigilance and EEG suggestive of status epilepticus similar to PSWCs) or fluctuations (interpreted as repetitive epileptic events). MRI of these 35 sCJD patients classified as other was available in 26 patients. Thirteen of them (50%) showed the sCJD typical finding of hyperintense basal ganglia. The highest final clinical classification and neuropathological results stratified by age are shown in Table 2 . Autopsy rate was similar over the age groups, ranging between 45 and 88% of the probable and possible sCJD patients, and 39–80% of the patients with other diagnoses. In those classified as probable sCJD, neuropathology confirmed the diagnosis in most patients across all age groups (95–100%). Non-CJD patients within the patients classified as probable (n = 16) suffered mainly from Alzheimer's disease ( Table 2 ). MRI analysis of these patients found none with sCJD typical hyperintense basal ganglia. Clinical classification as possible sCJD shows a broad range of the proportion of confirmed sCJD patients (33–79%). A high number of patients classified as other disease are still alive, which makes a prion disease unlikely in the majority of patients. Clinical and Epidemiological Characteristics in Sporadic CJD Age- and sex-matched incidence showed a peak for both sexes between 70 and 79 years with 5.27 (females) and 5.97 (males), but a marked decrease in the age over 80 years to 1.62 and 1.65, respectively (Fig. 1). Since 1994, there has been an increase in incidence for all age groups. Figure 1. (click image to zoom) sCJD incidence (per year per 1 million inhabitants) stratified by sex in 10-year intervals. Dotted white spots = female; black spots = male; dashed triangles = all. Genetic analysis for polymorphism of codon 129 in all confirmed and probable sCJD patients (available in n = 992) revealed 655 (66%) methionine homozygous (MM), 159 (16%) valine homozygous (VV) and 178 (18%) heterozygous (MV) sCJD patients. Although the numbers of all patients who underwent a genetic analysis per year remained stable, there was a decrease in the proportion of MM in contrast to an increase of MV and VV, but without statistical significance (P = 0.438) (Fig. 2). Median disease duration stratified by genotype was the shortest for MM with 5.3 months (range 1.1–81.4), followed by VV with 7 months (1.6–48.2) and a prolonged disease duration in the MV type with 12 months (range 2–45) (ANOVA P < 0.001). Interestingly, we found a disease duration of more than 24 months mostly in the MV genotype (9.6% of all MV patients), followed by the VV type (7.1% of all VV patients) and the MM type (4.3% of all MM patients) (Fig. 3). MM patients (46%) were predominant within the other cases (39% MV and 15% VV). Additionally, we investigated the influence of codon 129 within the sCJD patients on clinical core data and test sensitivity resulting for the patients with at least one methionine allele in shorter disease duration (P < 0.001) and higher sensitivity of PSWCs (P < 0.001) ( Table 3 ). Figure 2. (click image to zoom) Genotype distribution of all confirmed and probable sCJD patients per year of surveillance. Line with black spots = MM; line with white spots = MV and VV; dotted line = MV; dashed line = VV. Figure 3. (click image to zoom) Kaplan–Meyer survival time of all confirmed sCJD patients stratified by codon 129 genotype. Black line = MM; dashed line = MV; dotted line = VV. In 243 patients, PrPsc type 1 or 2 was available. PrPsc type 1 was associated with shorter disease duration (P < 0.001), higher 14-3-3 sensitivity (P = 0.0013) and higher PSWC frequency (P < 0.001) ( Table 3 ). In combination with the polymorphism at codon 129, the subgroup allocation [according to (Parchi et al., 1999)] is shown in Table 3 . Altogether 56 sCJD patients with age at onset below 50 years were examined (3%), the youngest patient at the age of 19 years. The age group over 80 years at onset consisted of 118 patients (8.8%). Median disease duration in the young patients was longer (16.6 months, range 2.5–81) than in all sCJD (median 6.2 months, P < 0.001). Instead, we found shorter disease duration in the patients over 80 years (3.7 months, range 1.2–18.9, P < 0.001). Results of technical analyses stratified by age at onset revealed a reliably high value for 14-3-3 in over 95% of the age groups over 40 years. In younger patients, 14-3-3 was less frequently positive (76%). In EEG, PSWCs were very rarely found in younger age groups, and there was a continuous increase up to 66% in the age over 80 years. In contrast, MRI showed a decreasing value in the elder patients (Fig. 4). Genotype distribution of codon 129 in the patients below 50 years showed 52% MM, 15% MV and 33% VV with an increase of MM with increasing age and with a relative decrease of the VV subtype (Fig. 5). Figure 4. (click image to zoom) Frequency of sCJD typical diagnostic test results in CSF, EEG and MRI in different age groups. Typical for sCJD is considered when 14-3-3 was positive in CSF, periodic sharp waves complexes are found in EEG and hyperintense basal ganglia in MRI scan (independent of weightening). The differences among the groups are statistically significant for 14-3-3 (ANOVA P = 0.002), EEG (ANOVA P < 0.001) and MRI (ANOVA P = 0.001). Grey = 14-3-3; black = PSWC; light grey = basal ganglia hyperintensities. Figure 5. (click image to zoom) Genotype distribution at different age groups. The differences between the age groups are statistically significant (ANOVA P = 0.04). grey = MM; light grey = MV; black = VV. Inherited Prion Diseases Genetic TSE had a frequency of 6% of all TSE patients in this study. Within the group of patients with available mutation analysis, 7.3% were positive for a PRNP mutation. Genetic analysis for PRNP revealed 32 patients with FFI (26%) (D178N-129M), 12 GSS (10%) and 79 inherited CJD (64%) patients with various mutations. Within the group of inherited CJD we identified 21 patients with E200K and 15 with V210I mutations. Inherited prion disease led to a younger age at onset of 61 years (range 20–83, P < 0.001) and for some mutations to lower sensitivity of clinical tests ( Table 4 ). Several mutations were already reported as case reports (Krasemann et al., 1995; Grasbon-Frodl et al., 2004a, b; Krebs et al., 2005; Roeber et al., 2005). Iatrogenic CJD During the 12 years of surveillance, we identified nine patients with iatrogenic CJD (eight patients due to dura mater grafts and one patient after cornea transplant). The dura patches or the corneal transplant were performed between 1979 and 1987. Incubation time varied from 10 to 24 years (median 18 years) for dura cases and 31 years in the cornea case. Median disease duration is longer than in sCJD with 10 months (range 2.4–19.2) (Lang et al., 1995, 1998, 2001; Kretzschmar et al., 2003). An additional patient died in 2005, suffering from neuropathologically confirmed CJD. Medical history found a cornea transplant 13 years before onset of symptoms, but the donor is not yet identified. Thus, because of the incubation time and medical history, iatrogenic CJD is very likely, but the final confirmation is still pending. Up to now, no human growth hormone-related disease transmission was identified. Differential Diagnosis Differential diagnosis included mainly neurodegenerative diseases [Alzheimer's disease (35%), Lewy-body dementia (9%), multiple system atrophy (MSA 3%)], vascular dementia (16%), malignancies/paraneoplastic diseases (6%) and metabolic dysfunction (8%) ( Table 5 ). Fourteen of these other cases were initially clinically classified as probable sCJD: neuropathologically, these patients suffered from Alzheimer's disease (AD; n = 7), vascular dementia (n = 3), encephalitis (n = 2) and each one from dementia with Lewy bodies (DLB) and DLB associated with Alzheimer's disease. Clinical criteria for possible sCJD were fulfilled in 34 patients, namely 15 patients with Alzheimer's disease and several other diagnoses (inflammatory disease n = 5, mixed dementia n = 4, lymphoma n = 3, metabolic disorder n = 3, vascular dementia n = 2, DLB n = 1, one without clear pathological diagnosis). Alzheimer's disease represents the major group of non-reversible (mainly neurodegenerative) diseases (50%) within all differential diagnoses. A substantial group of 28% (n = 49) suffered from a potentially treatable disorder such as encephalitis, tumour-associated diseases or metabolic disorders. As expected, patients with neurodegenerative disorders had a higher median age at onset than those with potentially treatable disorders ( Table 5 ). snip... Discussion This study analyses a large number of patients with spongiform encephalopathy with different aetiological origin within the population of 83 million inhabitants of Germany since 1993. In keeping with a number of other epidemiological studies in many European countries, we used a prospective approach. We found an increase in incidence (1.1–1.6) and mortality (0.9–1.3) of sCJD during the years 1994–2005 as also described for other countries, but more or less stable levels since 1998. This might be associated with improvement in the diagnostic techniques and better recognition of atypical clinical presentations, which is underlined by a trend towards higher proportion of MV and VV (Brandel et al., 2000; Zerr et al., 2000b; Saiz et al., 2001; Krasnianski et al., 2006b). Furthermore, after the recognition of vCJD and its connection to BSE became widespread, an increased awareness on the part of physicians and relatives might have influence differential diagnostic considerations. In 2001, Switzerland described a rise of incidence from 1.4 in 2000 to 2.5 in 2001 and a stable level of about 2.5 within the last few years (Glatzel et al., 2003). Initial surmises for the presence of a cluster and possible connection to BSE could not be confirmed. Instead, these figures seem to be the effect of better surveillance with a potentially higher percentage of the atypical MV2 subtype. An equivalent sudden rise is not observed in Germany ( Table 1 ). The median age of our sCJD patients (66 years) was comparable to the data from the literature. Incidence and mortality clearly decrease after a peak between 70 and 79 years similar to other studies on sCJD, but in contrast to other neurodegenerative diseases which tend to increase with age (Ott et al., 1998; Ladogana et al., 2005). This finding can be explained by an under-ascertainment of patients in the group of old and very old people. Another potential explanation could be that clinical presentation is less typical in elder people. However, our data found similar diagnostic value of 14-3-3 (>80 years, 94%; 60–69 years, 96%), higher frequency of PSWCs (>80 years, 66%; 60–69 years, 54%), but lower sensitivity of MRI findings (>80 years, 35%; 60–69 years, 57%) in patients over 80 years as compared to the median age groups. The correct clinical classification for sCJD by comparison of clinical classification and autopsy result is similar to middle age groups (Table 2). Hence, there might be other (clinical) factors, which influence the decrease of incidence in the elderly. The patients with 50 years age or younger at symptom onset are rare (3% of all sCJD). While up to now no patient with vCJD in Germany was identified, these patients are of special interest. The clinical syndrome in young sCJD patients in Germany differs not only from vCJD, but also from sCJD patients at the typical age at onset between 60 and 70 years (Boesenberg et al., 2005). Thus, it seems unlikely that a patient with variant CJD was misclassified as sCJD. The detection of the pulvinar sign in the MRI is an important non-invasive tool to distinguish vCJD and sCJD and is reported in 78% of vCJD patients (Will et al., 2000), but also in MV2 sporadic CJD subtype (Krasnianski et al., 2006b). In our subgroup of young sCJD patients, we observed hyperintense basal ganglia in 56%, but no pulvinar sign (Boesenberg et al., 2005). However, because the MRI might be normal in early disease stages, we would like to stress the importance of neuropathological examination of all suspected CJD patients, being extremely important in young patients with dementia. Many reports on patients with clinical syndromes mimicking CJD are found in the literature with a broad range of diagnoses (Haik et al., 2000; Tschampa et al., 2001; Slee et al., 2006; Valadi et al., 2006). Additionally, reports on false positive 14-3-3 and EEG findings exist (Vander et al., 2004; Bersano et al., 2006; Hoffman Snyder et al., 2006). This raises the question of the value of the clinical criteria which include clinical signs and symptoms and technical investigations. In our patient group, the value of these criteria seem to be very high, especially for the classification as probable sCJD. The clinical symptoms can be masqueraded by several syndromes, and they might be hard to distinguish without positive 14-3-3, PSWCs or MRI scans. This is underlined by a worse reliability of the classification possible sCJD (in autopsy only 58% confirmed sCJD, 42% other disease). The patients classified as other and later confirmed as sCJD were not recognized because the clinical criteria were not fulfilled (missing dementia, isolated dementia, dementia and ataxia only). The proportion of these patients is relatively low and change of the criteria for less-stringent clinical symptoms might result in decreased specificity. On the other hand, 50% of these patients had typical MRI changes. Thus, MRI can support diagnosis also in atypical patients. Codon 129 polymorphism analyses revealed a genotype distribution as known for sCJD, with an increase of methionine homozygous in favour of MV compared to the normal population. In recent years, the proportion of patients with the MM genotype is slightly decreasing in favour of the MV and the VV type (Fig. 1). This might be due to better diagnosis in patients with atypical subtypes and also explains in part the increase in overall incidence of sCJD since 1993 in Germany. The homozygous patients presented with shorter disease duration than MV patients as reported previously (Deslys et al., 1998; Parchi et al., 1999; Pocchiari et al., 2004). Clinical characteristics in our cohort were influenced by PrPsc type 2 (longer disease duration, less sensitivity of 14-3-3 and EEG) and the presence of at least one valine allele (longer disease duration, less sensitivity of EEG, trend to younger age at onset) ( Table 3 ). These data are in line with studies on sCJD which showed higher sensitivity for 14-3-3 and PSWCs and shorter disease duration for patients with PrPsc type 1 protein (Zerr et al., 2000a; Castellani et al., 2004; Pocchiari et al., 2004; Sanchez-Juan et al., 2006) and lower sensitivity of EEG in presence of a valine allele (Collins et al., 2006). Genetic analysis of the PRNP gene revealed a number of mutations resulting in GSS, FFI or genetic CJD (Windl et al., 1999). The proportion of patients with inherited prion disease in Germany (6%) is comparable to the data given in the literature. The percentage of inherited prion diseases varies among the countries and is higher in Slovakia (69.5%), Italy (17%) and Austria (14%) and lower in Switzerland (1%) and the Netherlands (2%) (Kovacs et al., 2005). The average rate of inherited prion diseases in Europe is 10.2%, and after exclusion of Slovakia (nearly 70% inherited prion diseases), the rate is 9.45%. Thus, the figures from Germany are only slightly lower. The cause of the large variance in proportion of inherited prion diseases between the countries is not clear. One reason of high incidence of inherited prion diseases in other countries might be due to the founder effect (Lee et al., 1999). Because of quite long disease duration, atypical clinical course and low sensitivity of the technical analyses, patients with genetic TSE might be misdiagnosed as another neurodegenerative disorder ( Table 4 ). In Germany, the incidence of iatrogenic transmission has been much lower than for other countries with CJD surveillance. Most iatrogenic cases worldwide (n = 138) are associated with human pituarity growth hormone (n = 105), especially in France and UK (Brown et al., 2000, 2006; Swerdlow et al., 2003). In Germany, there has been no patient with such a transmission reported to date. Of the 10 iatrogenic patients in Germany, eight came from transmission by lyophilized dura mater grafts and two by corneal transplant. As described in the literature, incubation time in the patients in our study varied from 1 to 30 years (Brown et al., 2000; Will, 2003). Analysis of differential diagnosis revealed Alzheimer's disease as the most frequent other diagnosis among our selected patients. This is not surprising, as it represents the most frequent cause of dementia in the elderly (Ruitenberg et al., 2001; McMurtray et al., 2006). Other diagnoses such as inflammatory diseases and metabolic disorders presented with a clinical syndrome similar to that of prion diseases in our study. Surprisingly, a few cases later neuropathologically confirmed as sCJD (supplemental data) were diagnosed clinically as other diseases because of results of the CSF tests which were suggestive of inflammatory illnesses. Thus, in particular, inflammatory diseases of the CNS might represent a problem in differential diagnosis (Poser et al., 1999). Neurodegenerative disorders are especially frequent in patients over 75 years at onset. In contrast, as expected, in younger patients below the age of 50 years at onset, potentially reversible disorders play a major role (Harvey et al., 2003; Sampson et al., 2004). Despite intensive analysis and careful epidemiology, no patient with vCJD has been found in Germany so far. Since the first description in 1996 in the UK, 201 patients have been registered with vCJD worldwide. Although by far most of the cases are still identified in UK, a few patients with vCJD have been reported in several other countries. Thus, further surveillance and evaluation of all suspected CJD patients is necessary to recognize the implications for the healthcare system and allow it to react promptly. click here doi:10.1016/j.vetmic.2006.06.016 Copyright © 2006 Elsevier B.V. All rights reserved. Atypical BSE in Germany—Proof of transmissibility and biochemical characterization A. Buschmanna, A. Gretzschela, A.-G. Biacabeb, K. Schiebelc, C. Coronad, C. Hoffmanna, M. Eidena, T. Baronb, C. Casaloned and Martin H. Groschupa, , aFriedrich-Loeffler-Institut (FLI), Institute for Novel and Emerging Infectious Diseases, Boddenblick 5a, 17493 Greifswald, Insel Riems, Germany bAFSSA-Lyon, Unite ATNC, Lyon, France cInstitut für Biochemie, Universitity Erlangen-Nürnberg, Germany dCEA, Instituto Zooprofilattico di Turino, Turin, Italy Received 11 January 2006; revised 23 May 2006; accepted 2 June 2006. Available online 17 August 2006. Abstract Intensive active surveillance has uncovered two atypical German BSE cases in older cattle which resemble the two different atypical BSE phenotypes that have recently been described in France (designated H-type) and Italy (designated L-type or BASE). The H-type is characterized by a significantly higher molecular size, but a conventional glycopattern of the proteinase K treated abnormal prion protein (PrPSc), while the L-type PrPSc has only a slightly lower molecular size and a distinctly different glycopattern. In this paper we describe the successful transmission of both German atypical BSE cases to transgenic mice overexpressing bovine PrPC. Upon challenge with the L-type, these mice developed BSE after a substantially shorter incubation period than any classical BSE transmission using these mice to date. In contrast, the incubation period was distinctly prolonged when these mice were challenged with the H-type. PrPSc accumulated in the brains of these mice were of the same atypical BSE type that had been used for the transmission. These atypical cases suggest the possible existence of sporadic BSE cases in bovines. It is thus feasible that the BSE epidemic in the UK could have also been initiated by an intraspecies transmission from a sporadic BSE case. Keywords: BSE; Cattle; PrPSc; Biochemical differentiation Corresponding author. Tel.: +49 383517163. Veterinary Microbiology Volume 117, Issues 2-4, 31 October 2006, Pages 103-116 click here Subject: TAFS1 Position Paper on Atypical scrapie and Atypical BSE Date: July 9, 2007 at 1:38 pm PST TAFS1 Position Paper on Atypical scrapie and Atypical BSE TAFS INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a non-profit Swiss Foundation (May 16, 2007) TAFS1 Position Paper on Atypical scrapie and Atypical BSE In recent years there have been a small number of reports in the scientific literature that unusual isolates of BSE have been detected in cattle in various countries around the world. In addition, following the introduction of enhanced surveillance programmes for scrapie in small ruminants in Europe, unusual or unexpected results were also widely reported. In both instances, the shortage of scientific data at the time did not enable scientists to precisely identify what they were dealing with. Because of similarities with the diseases that they were searching for, namely BSE in cattle and scrapie in sheep, the immediate response was to call the isolates “atypical BSE” and “atypical scrapie” for reasons that will be explained below. Some additional local terminology was applied in some countries, but for the moment the term “atypical” is more commonly applied. This paper aims to provide the background to these findings, and explain their signficance. snip... Is it transmissible? ?? Experimentally, it has been shown that it can be transmitted to genetically modified mice(2, and by intracerebral inoculation to sheep (unpublished work in progress). ?? These transmissions do not prove that it will transmit naturally from sheep to sheep, but studies involving oral infection of sheep are under way. ?? Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22). Does it represent a risk to human health? Does it represent a risk to human health? ?? This is currently unknown, but if atypical scrapie is not a new phenomenon, and has simply been discovered recently, then the lack of epidemiological association between TAFS 6 prion diseases in humans and sheep, or consumption of sheep products, suggest that atypical scrapie does not represent a risk to humans. This is not however demonstration of absolute safety. ?? This is currently unknown, but if atypical scrapie is not a new phenomenon, and has simply been discovered recently, then the lack of epidemiological association between TAFS 6 prion diseases in humans and sheep, or consumption of sheep products, suggest that atypical scrapie does not represent a risk to humans. This is not however demonstration of absolute safety. ====================================================== PLEASE NOTE ; EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........ click here 1: J Infect Dis 1980 Aug;142(2):205-8 Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates. Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC. Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation. snip... The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease. ...end (from full text study pdf...TSS) PMID: 6997404 click here EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........ click here 12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY snip... A The Present Position with respect to Scrapie A] The Problem Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries. The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep. It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible. Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias" Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously. snip... 76/10.12/4.6 click here ===================================================== snip... Where has atypical BSE been found? ?? Although the greatest number of cases is in France(12), increasing numbers of cases have now been identified in other countries – Canada (1), Germany (2), Italy (2), Japan (2), Netherlands (4), Poland (7), Sweden (1), Switzerland (1), UK (1), and USA (2). In Sweden and the USA the atypical cases represent the only indigenous cases detected. In other words – typical BSE has not been detected in native cattle in these two countries (34). ?? In France, Poland, Netherlands and Germany both H and L forms of atypical BSE have been reported(25). Is there anything else unusual about the cases? ?? Yes. With the exception of the first Japanese case, others have generally occurred in old cows – 8 to 18 years reported in France, 11 and 15 in Italy. Most BSE cases occur in animals between the age of four and six, although very young and very old animals can be affected too. ?? In one case, still unpublished, a mutation of the PrP gene has been detected, similar to one found in one form of CJD in humans.It has to be stressed that this has not been identified in every case of atypical BSE, although not all have been analysed in this way. snip... Where has atypical BSE been found? ?? Although the greatest number of cases is in France(12), increasing numbers of cases have now been identified in other countries – Canada (1), Germany (2), Italy (2), Japan (2), Netherlands (4), Poland (7), Sweden (1), Switzerland (1), UK (1), and USA (2). In Sweden and the USA the atypical cases represent the only indigenous cases detected. In other words – typical BSE has not been detected in native cattle in these two countries (34). ?? In France, Poland, Netherlands and Germany both H and L forms of atypical BSE have been reported(25). Is there anything else unusual about the cases? ?? Yes. With the exception of the first Japanese case, others have generally occurred in old cows – 8 to 18 years reported in France, 11 and 15 in Italy. Most BSE cases occur in animals between the age of four and six, although very young and very old animals can be affected too. ?? In one case, still unpublished, a mutation of the PrP gene has been detected, similar to one found in one form of CJD in humans.It has to be stressed that this has not been identified in every case of atypical BSE, although not all have been analysed in this way. TAFS 9 Is there more than one strain of atypical BSE? ?? At this stage it is too early to say, but there are early indications that this may be so. Caution is needed because there is a need to be certain that the variations in results are not artifacts, either generated by differences in test methods between countries, or due to degradation of samples before they are tested. This has been shown to generate variations in blotting patterns, but is unlikely to have produced the extensive variations seen in the Italian cases or the H form detected in France and elsewhere. ?? So the key to confirming whether or not H and L isolates actually represent different strains will be further characterization following transmission to laboratory rodents and/or cattle. These are the methods normally used to characterize prion strains comprehensively. ?? This will also help to confirm the extent to which the atypical BSE cases differ from BSE. In the meantime, especially if it proves possible to transmit isolates to other animals, additional biochemical methods can be used to investigate other aspects of prion protein biology of the different isolates. ?? Two publications have already highlighted the difficulties of interpreting data on biological transmissibility. One demonstrates that BSE and “H-type” BSE are different, based upon their behaviour in genetically modified mice, examination of fixed and unfixed brain tissue, and comparison of incubation periods(6). The other, studying “L-type” BSE (Italian BASE), and using different mouse models, acknowledges apparent differences between it and BSE when first inoculated into mice, but claims that further transmission from mouse to mouse by inoculation produces a strain indistinguishable from BSE (by the limited criteria used in the study) (11). ?? These findings suggest that it may prove possible to understand the relationship between BSE and atypical BSE isolates, and between the criteria used to classify them at present, and the actual strain of prion that infects the animal. Is atypical BSE transmissible? ?? Investigations are under way in France, Italy, Germany and Japan. Experimental transmissibility to cattle and primates has now been demonstrated for L-type BSE, and to mice for both H and L types (3, 6, 11). Some of this work remains incomplete and unpublished at the time of writing. ?? This does not prove that atypical BSE transmits from animal to animal naturally. Does it represent a risk to human health? ?? It is too early to tell whether or not it represents a risk to humans. For the moment it is assumed to be a danger, and is treated like BSE. Results of experimental transmission to primates remain unpublished. Some scientists suggest that similarities between the molecular features of H-type BSE and some prion diseases of humans may indicate that they are related. Care must be exercised in interpreting such preliminary data( specifically with regard to suggestions of a cause and effect. ?? Transmissibility to cattle has been confirmed, but remains currently unpublished as the study is incomplete. It may therefore be possible to investigate further, by oral challenge, whether or not the infectious agent is distributed around the body in a different way from BSE, possibly infecting tissues that are not considered-infectious in BSE. This may have implications for risk management and public health. ?? It is however important to remember that so far only small numbers of atypical BSE cases have been detected compared to the many thousands of BSE cases TAFS 10 ?? Depending on how atypical BSE cases arise, they may represent a long term problem when BSE has been eradicated, or they may disappear along with BSE because the controls are equally effective in preventing spread of infection. As transmissibility to cattle has now been partially demonstrated, it can be presumed that atypical BSE may transmit to cattle orally through feed, in which case rendering and feed controls should prevent further transmission by that route. What is the impact of this finding on measures to control BSE, and to protect consumers? ?? At the moment all measures in place to protect cattle and humans from becoming infected with BSE are considered adequate to protect against atypical BSE. Tests used to detect BSE in cattle have detected the atypical cases too, and on brain tissue, which is already defined as SRM in countries where controls are in place. ?? Care will be needed in relaxing such controls, especially if atypical BSE proves to be transmissible directly between cattle, or to humans via tissues that are not currently defined as SRM. ?? Similarly, if atypical BSE is demonstrated to arise spontaneously, rare sporadic cases may be expected to occur in all countries with significant cattle populations. This in itself will challenge expectations of total eradication as a result of controls. Nevertheless, the existence of sporadic cases would indicate potential to give rise to further large epidemics if some protective measures are not maintained indefinitely. These may involve prohibitions on the use of certain proteins in animal feed, more rigorous rendering processes, and possibly continued removal and destruction of certain SRM from human food and animal feed chains. snip... click here Titel Basisproject BSE, scrapie en andere TSEs Abstract [Project objective]: This project takes care of the statutory tasks of TSE diagnosis as well as the enlargement of the basic knowledge on TSEs to keep advices to Government, EU and other expert groups up-to-date. Furtherrmore this project provides basic support to several other (mainly EU) research projects by means of co-finances, samples or animals (mainly sheep and mice). The key objectives of this project are securing the TSE statutory tasks and keeping them up-to-date by surveillance- and research projects, and cooperation in EU projects and TSE expert groups. [Results]: The data obtained will allow us to; Continue, improve and extend the BSE and scrapie surveillance in the Netherlands and act as the national reference lab (NRL) for TSEs. Maintain and expand (if necessary) the basic means like sheep flocks and normal/transgenic mice to be used for pathogenesis research or TSE straintyping. Act as an (inter)national resource for TSE related matters as well as providing presentations at seminars, classes and/or courses. Keeping TSE safety measures and accompanying TSE inactivation methods up-to-date. Gain basic knowledge and networking possibilities by active participation in EU TSE projects. [Progress 2005-2006]: BSE diagnostics (for most up-to-date figures please visit the CIDC website at www.CIDC-Lelystad.nl); o In 2005 and 2006, respectively 7 and 9 clinical suspects have been examined of which one from 2006 was found to be TSE positive. o Active surveillance ( rapid testing ) 2005 and 2006 (till September 1st); ?? Slaughtered animals; resp. 473,436 and 275,000 animal tests performed by private labs under CIDC-Lelystad supervision of which resp. 3 and 1 were confirmed TSE positive. ?? Fallen stock; total 48,856 and 33,371 animals tested by CIDC-Lelystad of which none were found to be positive. ?? Stamping-out animals; 77 and 29 animals tested resp. of which none were found to be TSE positive. Scrapie diagnostics (for most up-to-date figures please visit the CIDC website at www.CIDC-Lelystad.nl); o In 2005 and 2006, respectively 3 and 8 clinical suspects have been examined of which five from 2006 was found to be TSE positive. o Active surveillance ( rapid testing ) 2005 and 2006 (till September 1st); ?? Slaughtered animals; resp. 27,965 and 22,648 animal tests performed by CIDC-Lelystad of which resp. 14 and 5 were confirmed to be TSE positive. ?? Fallen stock; total 11,221 and 7,772 animals tested by CIDC-Lelystad of which resp. 23 and 14 were found to be positive. ?? Stamping-out animals; 2,034 and 576 animals tested respectively. In addition resp. 261 and 248 fallen animals were tested from known positive farms. In total resp. 34 and 34 were found and confirmed to be TSE positive. Scrapie isolate characterisation; o All scrapie isolates from 2002 till August 2006 and several isolates from before 2002 have been tested by the CIDC-developed BSE/Scrapie discriminatory blot test for the presence of the BSE strain. No BSE or BSE-like isolates were found. o In 2005 on two different farms atypical scrapie of the Nor98 type has been diagnosed. In 2006 no atypical scrapie cases have been recorded. Basic means; since several years two independent flocks of sheep are maintained. One flock is kept under scrapie-free conditions while the other is scrapie endemic. Several lines of classical and transgenic mice are maintained for TSE strain typing, sensitive bioassays and/or antibody development. Currently there are two EU projects running and one is starting up this year. The first project aims at the improvement of (pre)clinical diagnosis, the second investigates the routes of pathogenesis of BSE in sheep, while the third will focus on BSE and scrapie in goats. All experimental infections for the first project are still running and no conclusions can be drawn from the preliminary results yet. The second project has determined that the pathogenic route of BSE in sheep is identical to scrapie in sheep. Fortunately, this project also revealed that discrimination between scrapie and BSE in sheep is also possible by a microscopic technique in which accumulated prion proteins are differently stained in specific types of cells by a panel of antibodies. This discriminatory microscopic test, in addition to the certified discriminatory blot test developed by CIDC as well, has been certified by the CRL for use to discriminate BSE from scrapie in sheep as well. [Products]: Articles click here Identification of putative atypical scrapie in sheep in Portugal Leonor Orge,1,2 Alexandre Galo,1 Carla Machado,1 Carla Lima,1 Cristina Ochoa,1 Joa˜o Silva,1 Manuel Ramos1 and J. Pedro Simas2,3 Correspondence J. Pedro Simas jpsimas@igc.gulbenkian.pt 1Laborato´ rio Nacional de Investigac¸a˜o Veterina´ ria, Lisboa, Portugal 2Instituto Gulbenkian de Cieˆ ncia, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal 3Laborato´ rio de Microbiologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Experimental transmission of bovine spongiform encephalopathy to sheep has prompted the implementation of a surveillance plan of scrapie in small ruminants by the European Union in all member states. Since its start over 30 000 animals have been tested, and the first seven cases of sheep with detectable PrPres deposition in the central nervous system have been identified in Portugal. Notably, the pattern of PrPres distribution in the brainstem was different from that previously described for scrapie and consistent in all seven animals. Moreover, the profile of the electrophoretic mobility of PrPres after proteinase K treatment was equivalent in all cases analysed but distinct from that observed for scrapie. Notably, four animals had genotypes rarely associated with scrapie, including one animal homozygous for A136R154R171. There were no cases found to exhibit vacuolation, a pattern of PrPres distribution or PrPres electrophoretic mobility corresponding to scrapie. These data reveal a putative atypical scrapie strain in Portugal not linked to specific Prnp genotypes. snip... This finding is consistent with the fact that to date no clinical scrapie has been diagnosed in Portugal. Thus, it is not clear if the cases described in this study represent an endemic form of a prion disease in sheep not previously identified and not linked to any specific Prnp genotypes or represent a recently acquired new form of scrapie. In order to gain further insight into the epidemiological and public health relevance of this apparent atypical scrapie, it is extremely important to show if it is transmissible and assess if it constitutes a new scrapie strain like Nor98. The occurrence of such a putative atypical scrapie strain, independently of the Prnp genotype, may be of significance for current EU sheep breeding programmes for selection of non-susceptible haplotypes. Furthermore, given the recent BSE epidemic in Portugal (Donnelly et al., 1999), and thus the geographical risk of transmission of BSE into sheep, a possible link to BSE cannot be excluded. Although, we cannot rule out the possibility of adaptation of BSE in sheep following natural transmission, the fact that the PrPres electrophoretic profile described for this putative atypical scrapie strain is distinct from that observed in BSE experimentally infected sheep, makes this link less probable. click here Subject: Classic Scrapie in Sheep with the ARR/ARR Prion Genotype in Germany and France Date: July 12, 2007 at 9:55 am PST http://www.cdc.gov/eid/content/13/8/pdfs/07-0077.pdf click here Unexpected atypical scrapie case: audit of sample handling and biosecurity S t a t ement from the Chief S c i e n t i f i c A d v i s e r In November 2006 the Veterinary Laboratories Agency (VLA) informed Defra they had detected atypical scrapie in a research flock considered to be free of Transmissible Spongiform Encephalopathies (TSEs). Defra issued an information bulletin1 on the 14th November. The origin of the atypical scrapie case was not clear. I initiated an independent audit of the research facilities concerned with the finding to investigate two aspects: • Sample handling and identification procedures • Biosecurity procedures at the site where the flock is held. The audit was conducted by the UK Accreditation Service (UKAS)2, which has now provided its report. I am confident that the audit has thoroughly investigated the issues concerned, insofar as it was able in the time available, and pleased that the findings will now be considered by the Spongiform Encephalopathy Advisory Committee (SEAC), together with additional evidence, in their scientific assessment of this case and its implications. SIR HOWARD DALTON 9th May 2007 click here Subject: SEAC Food standards agency atypical scrapie contingency plan Date: July 18, 2007 at 12:39 pm PST SEAC Position Statement ---------------------------------------------------------------------------- ---- Food standards agency atypical scrapie contingency plan Issue 1. In June 2006 the Food Standards Agency (FSA) Board considered current precautionary risk management measures for small ruminants. The Board agreed that current precautionary measures were sufficient. However, they wished to develop a contingency plan in case SEAC’s understanding of the risk of atypical scrapie for human health changed. To inform this contingency plan the FSA requested SEAC advice on potential outcomes of research on atypical scrapie, or surveillance results, that may lead to a change in SEAC’s estimate of the risk to human health. Background 2. In February 2006 the SEAC sheep subgroup published a position statement on atypical scrapie1 which concluded that atypical scrapie should be considered a distinct transmissible spongiform encephalopathy (TSE) of small ruminants and not simply a variant of classical scrapie. While there was no evidence that atypical scrapie could infect humans, a theoretical risk could not be excluded. SEAC concluded, however, that there were insufficient data available to adequately assess the potential risks to human health. The subgroup recommended that an adequate assessment of the potential risk to human health of atypical scrapie might come from studies on the prevalence, transmission in animal models, tissue distribution and human health surveillance. 3. SEAC considered the potential significance of the outcomes of these areas of research for the human health risk from atypical scrapie, based on scenarios put forward by the FSA2. Prevalence 4. The SEAC sheep subgroup statement concludes that there could be around 82,000 sheep in the UK infected with atypical scrapie. Future surveillance and epidemiological studies along with the analysis of sheep brain tissue samples dating back to 1964 may confirm the historical presence of the disease, changes in prevalence over time, and whether or not atypical scrapie may occur in countries previously thought to be free from classical and atypical scrapie. SEAC considered that the identification of historical cases, new cases in scrapie-free countries, and changes in prevalence of atypical scrapie would be significant from a public health perspective. If such data indicate that atypical scrapie has been present for many years, and is not increasing in prevalence then, by analogy with classical scrapie the human health risk would be considered low. However, if atypical scrapie were found to be spreading rapidly, this would imply it is a new disease and any human health risk would be more uncertain. It is therefore important to continue to assess the historic prevalence of atypical scrapie, and for archived sheep samples be analysed for the presence of the disease. 5. A human health risk would only be confirmed by concomitant changes in the prevalence of new types of Creutzfeldt-Jakob Disease (CJD). Because of the long incubation periods of prion diseases, such data may not become apparent for many years, although atypical scrapie has been identified in a UK sheep from 1989, implying that humans may have been exposed to atypical scrapie via the dietary route for a number of years. In the absence of data suggesting a link to a new type of CJD SEAC would be unlikely to change its current assessment of the human health risk. Transmission studies 6. Results from transmission studies using non-human primates, particularly via the oral route, would strongly inform the understanding of human health risk. The immune and lymphoreticular systems of non-human primates are closely related to those of humans and the peripheral pathogenesis of TSEs in non-human primates mimics that in humans. However, non-human primates only provide data relating to one genotype, MM, which comprises about 37% of the UK population3. Assessment of the level of risk would require comparison with transmissions of other TSEs in the same models, in particular BSE, some of which are already available. 7. Humanised mice can provide data on all three human prion protein genotypes. It is important to be aware of the possibility that such mice may not show any clinical sign of infection after primary transmission of atypical scrapie, yet a secondary transmission from these animals to others may result in clinical disease due to loss of the interspecies transmission barrier. Although humanised mice are a good model for human disease, it will be critical to compare the behaviour of atypical scrapie with other TSEs, especially classical scrapie and BSE, in several mouse models after secondary transmission in order to obtain the most reliable risk assessments. 8. The barrier to transmission of atypical scrapie between animal and human can be tested in vitro by cell free conversion assays. However, care is needed in interpreting the significance of such experiments as ex vivo data do not always correlate well with in vivo studies. Nevertheless, they could provide data on whether conversion of the normal prion protein in humans to the abnormal form by the atypical scrapie prion is or is not possible. Tissue Distribution 9. Little is known about the tissue distribution of abnormal prion protein (PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie is found to be a health risk to humans, data from studies to assess the tiss

by Terry S. Singeltary Sr. (1 articles, 0 quicklinks, 0 diaries, 8 comments [1 recommended, 0 rejected]) on Tuesday, Jul 24, 2007 at 4:11:17 PM

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greetings editor, i posted a comment to this article ; click here however, only half of it got posted, then i could never get anything else posted, short or long. i agree it's long winded, but needs to be said. with that, here is PART 2 TO MY post. maybe you can post it for me ??? continued part 2 ATYPICAL CREUTZFELDT JAKOB DISEASE's AND ATYPICAL BSE's - sporadic, spontaneous, or sourced ? continued part 2 Tissue Distribution 9. Little is known about the tissue distribution of abnormal prion protein (PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie is found to be a health risk to humans, data from studies to assess the tissue distribution of PrPsc and infectivity are essential to allow an assessment of the risk under specific control measures. Human Health 10. Establishing a definitive link between an animal and a human TSE is extremely difficult. Animal model data will only be indicative, and not definitive, although if carried out appropriately could be strongly indicative of a human health risk. The emergence of a new type of CJD which shows the same transmission characteristics as atypical scrapie in non-human primates and humanised mice would provide a strong indication that transmission had occurred through the consumption of infected material. Thus, ongoing human surveillance is critical. 11. It is difficult to conclude that atypical scrapie is not a human health risk from negative experimental or surveillance results. However, negative results from current and retrospective surveillance and transmission studies, over a significant period of time to allow for possibly long incubation periods, would imply a negligible human health risk. Conclusion 12. It is not possible to assess the human health risk from atypical scrapie, or changes in risk, in the absence of hard scientific data. No single data set is likely to be definitive and it would be essential to consider all the information available, rather than data from single studies in isolation. Studies comparing the properties of atypical scrapie and other TSE agents using the same animal model, especially humanised mice or non-human primates, would be most informative in the short term. Surveillance data to assess any association between forms of CJD and atypical scrapie prevalence would be most persuasive but are unlikely to become available in the short term. SEAC would have to review experimental methods and results, should they emerge, before any conclusion of a change to the risk to human health from atypical scrapie could be made. 1 click here (97 KB) 2 http://www.seac.gov.uk/papers/97-3.pdf (110 KB) 3 Palmer and Collinge (1993) Mutations and polymorphisms in the prion protein gene. Hum. Mutat. 2, 168-173. Page updated: 16 July, 2007 http://www.seac.gov.uk/statements/fsa-scrapieplan.htm Published online before print October 20, 2005 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102 Medical Sciences A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes ( sheep prion | transgenic mice ) Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *, Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ||, Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude * *Virologie Immunologie Moléculaires and ||Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005) Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health. snip... In conclusion, decoding the biochemical PrPSc signature of individual human and animal TSE strains may allow the identification of potential risk factors for human disorders with unknown etiology, such as sCJD. However, although BASE and sCJD share several characteristics, caution is dictated in assessing a link between conditions affecting two different mammalian species, based on convergent biochemical properties of disease associated PrPSc types. Strains of TSE agents may be better characterized upon passage to transgenic mice. In the interim until this is accomplished, our present findings suggest a strict epidemiological surveillance of cattle TSE and sCJD based on molecular criteria. ... ----------------- Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R., T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B. contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data; and H.L. wrote the paper. 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 http://www.pnas.org/cgi/content/abstract/0502296102v1 Medical Sciences Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt-Jakob disease Cristina Casalone *, Gianluigi Zanusso , Pierluigi Acutis *, Sergio Ferrari , Lorenzo Capucci , Fabrizio Tagliavini ¶, Salvatore Monaco ||, and Maria Caramelli * *Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna, 148, 10195 Turin, Italy; Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134 Verona, Italy; Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale Neurologico "Carlo Besta," Via Celoria 11, 20133 Milan, Italy Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003 (received for review September 9, 2003) Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called "species barrier" between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease. C.C. and G.Z. contributed equally to this work. ||To whom correspondence should be addressed. E-mail: salvatore.monaco@mail.univr.it. www.pnas.org/cgi/doi/10.1073/pnas.0305777101 http://www.pnas.org/cgi/content/abstract/0305777101v1 ProMED-mail ****** [2] Germany: Characterization of atypical BSE Date: Sun 20 Aug 2006 From: Terry Singeltary Source: Vet Microbiol., 14 Aug 2006 (E-pub ahead of print) [edited] Germany: Characterization of an atypical form of bovine spongiform encephalopathy (BSE) ----------------------------------------------- The following recently published paper is reproduced here because of its relevance to theories of the origin of new variant CJD, the human form of BSE. Title of paper: Atypical BSE in Germany - Proof of transmissibility and biochemical characterization. By Buschmann A, Gretzschel A, Biacabe AG, Schiebel K, Corona C, Hoffmann C, Eiden M, Baron T, Casalone C, Groschup MH. At the Friedrich-Loeffler-Institut (FLI), Institute for Novel and Emerging Infectious Diseases, Boddenblick 5a, 17493 Greifswald, Insel Riems, Germany. ABSTRACT. Intensive active surveillance has uncovered 2 atypical German BSE (bovine spongiform encephalopathy) cases in older cattle which resemble the 2 different atypical BSE phenotypes that have recently been described in France (designated H-type) and Italy (designated L-type or BASE). The H-type is characterized by a significantly higher molecular size, but a conventional glycopattern of the proteinase K treated abnormal prion protein (PrP(Sc)), whereas the L-type PrP(Sc) has only a slightly lower molecular size and a distinctly different glycopattern. In this paper, we describe the successful transmission of both German atypical BSE cases to transgenic mice over-expressing bovine PrP(C). Upon challenge with the L-type, these mice developed BSE after a substantially shorter incubation period than any classical BSE transmission using these mice to date. In contrast, the incubation period was distinctly prolonged when these mice were challenged with the H-type. PrP(Sc) accumulating in the brains of these mice were of the same atypical BSE type that had been used for the transmission. These atypical cases suggest the possible existence of sporadic BSE cases in bovines. It is thus feasible that the BSE epidemic in the UK could have also been initiated by an intraspecies transmission from a sporadic BSE case. -- Terry S. Singeltary Sr. [Terry Singeltary Sr. has added the comment that these atypical cases suggest the possible existence of sporadic BSE cases in bovines. It is thus feasible that the BSE epidemic in the UK could have also been initiated by an intraspecies transmission from a sporadic BSE case. - Mod.CP] ****** [3] China (Hong Kong SAR): Suspected vCJD case Date: Thu 31 Aug 2006 From: ProMED-mail Source: Xinhua News Agency online, Wed 30 Aug 2006 [trans. from Chinese by Mod.RY, edited] China (Hong Kong SAR): Suspected 2nd Case of CJD (new var.) now discounted ----------------------------------------------- The Department of Health of the Hong Kong [SAR] government and Bureau of the Hong Kong Hospital Administration issued a joint statement on Wed 30 Aug 2006 reporting that a suspected case of variant Creutzfeldt-Jakob disease (vCJD) was being assessed in Hong Kong. So far, laboratory test results have proved negative, and it remains uncertain whether the suspected case is truly a case of vCJD. The patient is a 23-year old male born in Britain who returned to Hong Kong at the beginning of April this year [2006]. He became ill and was unconscious on 6 Apr 2006, when he was admitted to the Overseas Chinese Hospital in Guangzhou, and was subsequently transferred to the Prince of Wales Hospital in the Hong Kong SAR for treatment. The patient's condition is critical at the present time due to necrotic changes in some of his organs. Though the patient shows clinical symptoms similar to those observed in vCJD, electroencephalograms (EEC) and magnetic resonance imaging (MRI) do not correspond with those observed in vCJD. Tonsil tissue samples were sent by the hospital to Britain for further examination, but proved negative. Therefore, so far, there is no definite indication that the patient is suffering from vCJD. The Bureau of HK Hospital Administration has stated that vCJD is a rare degenerative disease of brain and is not contagious. Nevertheless, the hospital's disease control and prevention authority will follow a set of strict procedures for disinfection of medical instruments that have been used for examination and treatment of the patient to avoid transmission to other patients. Hong Kong's 1st case of confirmed vCJD was discovered in 2001. The patient was a 34-year-old woman who had lived in Britain for an extended period of time and eventually succumbed to the disease in 2002. [Byline: Tang Yun and Kuang Peng] -- ProMED-mail [There appears to be no positive reason to diagnose the patient's illness as vCJD. The report, however, is a reminder that there has been a previous vCJD case in Hong Kong, a fact that has been overlooked in most accounts of vCJD in the literature. - Mod.CP] snip... http://www.promedmail.org CJD (NEW VAR.) UPDATE 2006 (10) ******************************* A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases snip... [These data are accessible via . - Mod.CP] -- ProMED-mail ****** [2] Correction Date: Tue 5 Sep 2006 From: "Terry S Singeltary Sr" Characterization of atypical BSE in Germany: correction ------------------------------------------------------- [In the Moderator's comment accompanying the abstract of the paper entitled "Atypical BSE in Germany-Proof of transmissibility and biochemical characterization'" by A Buschmannaet et al, (see part [2] of CJD (new var.) update 2006 (09) 20060904.2519) it was wrongly implied that Terry S Singeltary Sr endorsed the conclusions of the paper, whereas his comments were intended merely to highlight the conclusions of the paper. Namely that the atypical cases suggested the possible existence of sporadic BSE cases in bovines and perhaps the BSE epidemic in the UK could have also been initiated by an intraspecies transmission from a sporadic BSE case. I apologize for inadvertently misrepresenting Terry's views. - Mod.CP] Terry S Singeltary Sr has written the following. "In fact I disagree with the spontaneous/sporadic BSE/TSE theory, IF this is what the authors of this paper meant by 'sporadic BSE' to mean. For one thing, it has never been proven. IF atypical BSE i.e. BASE is so similar to some sporadic CJDs, then how did they all of a sudden become spontaneous? Could it not be so simple as an atypical BSE i.e. BASE was transmitted the same way most of all of the other BSE cattle were i.e. feed of just an atypical source, thus causing atypical strain? Why would these animals not develop an atypical BSE i.e. BASE from the same oral route? WHAT about an atypical strain mutating to become infectious via a lateral or horizontal mode in the bovine, as with CWD and scrapie? Also, please explain to me how a distinct synthetic prion, of a strain that is supposedly unlike any other we have ever seen, how can this explain 6 different documented phenotypes of sporadic CJD to date? It's like trying to explain away all the 6 phenotypes of sporadic CJD with the spontaneous theory, it's just not scientific. OR, if you render an atypical TSE of what ever phenotype, in what ever species, of the atypical strain and feed it to another whatever species, nothing happens x 1 x 2 x 3 x 4 etc passage? This all has been proven? Please show me these transmission studies? What Prusiner and Soto produced in vitro did not look like any natural field TSE, and as far as this in vitro TSE being infectious, well this was questionable too. If this was the case, then why does CWD not spontaneously happen in geographical areas where it has never been documented, OR with scrapie, as in scrapie free New Zealand? If TSE were to arise spontaneously, I don't see how the scientific arena can dictate which animal TSE can arise spontaneously, and which ones cannot, without any scientific evidence to support this to date, and by even suggesting this in this study, was not scientific. The words sporadic and spontaneous are very confusing in the world literature of human and animal TSE and, in my opinion, should not be used as terminology of any TSE." -- Terry S Singeltary Sr snip... http://www.promedmail.org/ ATYPICAL SCRAPIE AND BSE HAVE NOW BEEN DOCUMENTED IN USA (imported atypical scrapie from Belgium FOIA mouse bio-assays result request still denied) Research Project: Study of Atypical Bse Location: Virus and Prion Diseases of Livestock Project Number: 3625-32000-073-07 Project Type: Specific C/A Start Date: Sep 15, 2004 End Date: Sep 14, 2007 Objective: The objective of this cooperative research project with Dr. Maria Caramelli from the Italian BSE Reference Laboratory in Turin, Italy, is to conduct comparative studies with the U.S. bovine spongiform encephalopathy (BSE) isolate and the atypical BSE isolates identified in Italy. The studies will cover the following areas: 1. Evaluation of present diagnostics tools used in the U.S. for the detection of atypical BSE cases. 2. Molecular comparison of the U.S. BSE isolate and other typical BSE isolates with atypical BSE cases. 3. Studies on transmissibility and tissue distribution of atypical BSE isolates in cattle and other species. Approach: This project will be done as a Specific Cooperative Agreement with the Italian BSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del Piemonte, in Turin, Italy. It is essential for the U.S. BSE surveillance program to analyze the effectiveness of the U.S diagnostic tools for detection of atypical cases of BSE. Molecular comparisons of the U.S. BSE isolate with atypical BSE isolates will provide further characterization of the U.S. BSE isolate. Transmission studies are already underway using brain homogenates from atypical BSE cases into mice, cattle and sheep. It will be critical to see whether the atypical BSE isolates behave similarly to typical BSE isolates in terms of transmissibility and disease pathogenesis. If transmission occurs, tissue distribution comparisons will be made between cattle infected with the atypical BSE isolate and the U.S. BSE isolate. Differences in tissue distribution could require new regulations regarding specific risk material (SRM) removal. click here click here SCRAPIE UPDATE USA AS OF MARCH 2007 NOR98 INCLUDED click here NOR98-LIKE STRAIN OF SCRAPIE FOUND IN WYOMING (1791 lines) From: Terry S. Singeltary Sr. <[log in to unmask]> Date: Wed, 11 Apr 2007 15:08:15 -0500 click here Date: Tue, 10 Jul 2007 15:56:51 -0500 Re: FOIA REQUEST FOR ATYPICAL TSE INFORMATION ON VERMONT SHEEP (1034 lines) From: Terry S. Singeltary Sr. Date: Wed, 11 Jul 2007 16:36:17 -0500 click here Date: Wed, 11 Jul 2007 16:36:17 -0500 click here SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM 1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype of 'UNKNOWN' strain growing. ... click here Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. click here BRITISH MEDICAL JOURNAL BMJ http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406 BMJ http://www.bmj.com/cgi/eletters/320/7226/8/b#6117 JOURNAL OF NEUROLOGY MARCH 26, 2003 RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States Email Terry S. Singeltary: flounder@wt.net 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? http://www.neurology.org/cgi/eletters/60/2/176#535 doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk Tracking spongiform encephalopathies in North America Xavier Bosch Available online 29 July 2003. Volume 3, Issue 8, August 2003, Page 463 “My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.” http://www.thelancet.com/ Wilbur Clarke (reference the Mission, Texas scrapie transmission transmission to cattle study) is now the State Veterinarian for Montana based at Helena. I was given confidential access to sections from the Clarke scrapie-cattle transmission experiment. Details of the experimental design were as supplied previously by Dr. Wrathall (copy of relevant information appended). Only 3 animals (2 inoculated with 2nd pass Suffolk scrapie and 1 inoculated with Angora goat passaged scrapie) showed clinical signs. Clinical signs were characterised by weakness, ''a stilted hindlimb gait'', disorientation, ataxia and, terminally, lateral recumbency. The two cattle from which I examined material were inocluated at 8 months of age and developed signs 36 months pi (goat scrapie inoculum) and 49 months pi (one of the Suffolk scrapie inoculated) respectively. This latter animal was killed at 58 months of age and so the clinical duration was only 1 month. The neuropathology was somewhat different from BSE or the Stetsonville TME in cattle. Vacuolar changes were minimal, to the extent that detection REQUIRED CAREFUL SEARCHING. Conversely astrocyte hypertrophy was a widespread and prominent feature. The material requires DETAILED NEUROPATHOLOGICAL ASSESSMENT BUT WHETHER OR NOT THIS WILL BE DONE REMAINS A QUESTION. Transmission Studies Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}...TSS resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret. snip... Appendix 3 VISIT TO USA - DR A E WRATHALL - INFO OH BSE AND SCRAPIE 1. Dr Clark lately of the Scrapie Research Unit, Mission Texas has successfully transmitted ovine and caprine scrapie to cattle. The experimental results have not been published but there are plans to do this. This work was initiated in 1978. A summary of it is:- Expt A 6 Her x Jer calves born in 1978 were inoculated as follows with a 2nd Suffolk scrapie passage:- i/c 1ml; i/m, 5ml; s/c 5ml; oral 30ml. 1/6 went down after 48 months with a scrapie/BSE-like disease. Expt B 6 Her or Jer or HxJ calves were inoculated with angora Goat virus 2/6 went down similarly after 36 months. Expt C Mice inoculated from brains of calves/cattle in expts A • B were resistant, only 1/20 going down with scrapie and this was the reason given for not publishing. Diagnosis in A, B, C was by histopath. No reports on SAT were given. 2. Dr Warren Foote indicated success so far in eliminating scrapie in offspring from experimentally- (and naturally) infected sheep by ET. He had found difficulty in obtaining embryos from naturally infected sheep (cf SPA). 3. Prof. A Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr A Thiermann showed the picture in the "Independent" with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. BSE was not reported in USA. 4. Scrapie incidents (ie affected flocks) have shown a dramatic increase since 1978. In 1953 when the National Control Scheme was started there were 10-14 incidents, in 1978 - 1 and in 1988 so far 60. 5. Scrapie agent was reported to have been isolated from a solitary fetus. 6. A western blotting diagnostic technique (? on PrP) shows some promise. 7. Results of a questionnaire sent to 33 states on the subject of the national sheep scrapie programme survey indicated 17/33 wished to drop it 6/33 wished to develop it 9/13/2005 33 Page 15 of 17 8/33 had few sheep and were neutral Information obtained from Dr Wrathall's notes of a meeting of the U.S. Animal Health Association at Little Rock, Arkansas Nov. 1988. end...TSS >> Differences in tissue distribution could require new regulations >> regarding specific risk material (SRM) removal. snip...end full text 33 PAGES ; http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf click here It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE. http://www.bseinquiry.gov.uk/ 1: J Infect Dis. 1994 Apr;169(4):814-20. Intracerebral transmission of scrapie to cattle. Cutlip RC, Miller JM, Race RE, Jenny AL, Katz JB, Lehmkuhl HD, DeBey BM, Robinson MM. USDA, Agriculture Research Service, National Animal Disease Center, Ames, IA 50010. To determine if sheep scrapie agent(s) in the United States would induce a disease in cattle resembling bovine spongiform encephalopathy, 18 newborn calves were inoculated intracerebrally with a pooled suspension of brain from 9 sheep with scrapie. Half of the calves were euthanatized 1 year after inoculation. All calves kept longer than 1 year became severely lethargic and demonstrated clinical signs of motor neuron dysfunction that were manifest as progressive stiffness, posterior paresis, general weakness, and permanent recumbency. The incubation period was 14-18 months, and the clinical course was 1-5 months. The brain from each calf was examined for lesions and for protease-resistant prion protein. Lesions were subtle, but a disease-specific isoform of the prion protein was present in the brain of all calves. Neither signs nor lesions were characteristic of those for bovine spongiform encephalopathy. MeSH Terms: Animals Brain/microbiology* Brain/pathology Cattle Cattle Diseases/etiology* Cattle Diseases/pathology Encephalopathy, Bovine Spongiform/etiology* Encephalopathy, Bovine Spongiform/pathology Immunoblotting/veterinary Immunohistochemistry Male Motor Neurons/physiology Prions/analysis Scrapie/pathology Scrapie/transmission* Sheep Sleep Stages Time Factors Substances: Prions http://www.ncbi.nlm.nih.gov/ 9/13/2005 Page 16 of 17 Intracerebral transmission of scrapie to cattle FULL TEXT PDF; SNIP... Discussion WE conclude that American sources of sheep scrapie are transmissible to cattle by direct intracerebral inoculation but the disease induced is NOT identical to BSE as seen in the United Kingdom. While there were similarities in clinical signs between this experimental disease and BSE, there was no evidence of aggressiveness, hyperexcitability, hyperesthesia (tactile or auditory), or hyperemetria of limbs as has been reported for BSE (9). Neither were there extensive neurologic lesions, which are primary for BSE, such as severe vacuolation of neurons and neuropil or neuronal necrosis and gliosis. Although some vacuolation of neuropil, chromotolysis in neurons, and gliosis were seen in the brains of some affected calves, these were industinguishable from those of controls. Vacuolated neurons in the red nucleus of both challenged and normal calves were considered normal for the bovines as previously described (50). PrP-res was found in ALL CHALLENGED CALVES REGARDLESS OF CLINCIAL SIGNS, and the amount of PrP-res positively related to the length of the incubation. ... snip... WE also conclude from these studies that scrapie in cattle MIGHT NOT BE RECOGNIZED BY ROUTINE HISTOPATHOLOGICAL EXAMINATION OF THE BRAIN AND SUGGEST THAT DETECTION OF PrP-res by immunohistochemistry or immunoblotting is necessary to make a definitive diagnosis. THUS, undiagnosed scrapie infection could contribute to the ''DOWNER-COW'' syndrome and could be responsible for some outbreaks of transmissible mink encephalopathy proposed by Burger and Hartsough ( and Marsh and harsough (52). ... snip... Multiple sources of sheep affected with scrapie and two breeds of cattle from several sources were used inthe current study in an effort to avoid a single strain of either agent or host. Preliminary results from mouse inoculations indicate multiple strains of the agent were present in the pooled inoculum (unpublished data). ... Transmission of the sheep scrapie to cattle was attempted in 1979 by using intracerebral, intramuscular, subcutaneous, and oral routes of inoculation of 5, 8- to 11-month old cattlw with a homologous mixture of brain from 1 affected sheep (61, 62). ONE of the 5 cattle develped neurologic signs 48 months after inoculation. Signs were disorientation, incoordination, a stiff-legged stilted gait, progressive difficulty in rising, and finally in terminal recumbency. The clinical course was 2.5 months. TWO of the 5 cattle similarly inoculated with brain tissue from a goat with scrapie exhibited similar signs 27 and 36 months after incoluation. Clinical courses were 43 an 44 days. Brain lesions of mild gliosis and vacuolation and mouse inoculation data were insufficient to confirm a diagnosis of scrapie. This work remained controversial until recent examination of the brains detected PrP-res in all 3 cattle with neurologic disease but in none of the unaffected cattle (62). Results of these studies are similar to ours and underscore the necessity of methods other than histopathology to diagnose scrapie infection in cattle. We believe that immunologic techniques for detecting PrP-res currently provide the most sensitive and reliable way to make a definitive diagnosis... http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf Visit to USA ... info on BSE and Scrapie click here snip...full text ; click here What Do We Feed to Food-Production Animals? A Review of Animal Feed Ingredients and Their Potential Impacts on Human Health Amy R. Sapkota,1,2 Lisa Y. Lefferts,1,3 Shawn McKenzie,1 and Polly Walker1 1Johns Hopkins Center for a Livable Future, Bloomberg School of Public Health, Baltimore, Maryland, USA; 2Maryland Institute for Applied Environmental Health, College of Health and Human Performance, University of Maryland, College Park, Maryland, USA; 3Lisa Y. Lefferts Consulting, Nellysford, Virginia, USA snip... Table 1. Animal feed ingredients that are legally used in U.S. animal feeds Animal Rendered animal protein from Meat meal, meat meal tankage, meat and bone meal, poultry meal, animal the slaughter of food by-product meal, dried animal blood, blood meal, feather meal, egg-shell production animals and other meal, hydrolyzed whole poultry, hydrolyzed hair, bone marrow, and animal animals digest from dead, dying, diseased, or disabled animals including deer and elk Animal waste Dried ruminant waste, dried swine waste, dried poultry litter, and undried processed animal waste products snip... Conclusions Food-animal production in the United States has changed markedly in the past century, and these changes have paralleled major changes in animal feed formulations. While this industrialized system of food-animal production may result in increased production efficiencies, some of the changes in animal feeding practices may result in unintended adverse health consequences for consumers of animal-based food products. Currently, the use of animal feed ingredients, including rendered animal products, animal waste, antibiotics, metals, and fats, could result in higher levels of bacteria, antibioticresistant bacteria, prions, arsenic, and dioxinlike compounds in animals and resulting animal-based food products intended for human consumption. Subsequent human health effects among consumers could include increases in bacterial infections (antibioticresistant and nonresistant) and increases in the risk of developing chronic (often fatal) diseases such as vCJD. Nevertheless, in spite of the wide range of potential human health impacts that could result from animal feeding practices, there are little data collected at the federal or state level concerning the amounts of specific ingredients that are intentionally included in U.S. animal feed. In addition, almost no biological or chemical testing is conducted on complete U.S. animal feeds; insufficient testing is performed on retail meat products; and human health effects data are not appropriately linked to this information. These surveillance inadequacies make it difficult to conduct rigorous epidemiologic studies and risk assessments that could identify the extent to which specific human health risks are ultimately associated with animal feeding practices. For example, as noted above, there are insufficient data to determine whether other human foodborne bacterial illnesses besides those caused by S. enterica serotype Agona are associated with animal feeding practices. Likewise, there are insufficient data to determine the percentage of antibiotic-resistant human bacterial infections that are attributed to the nontherapeutic use of antibiotics in animal feed. Moreover, little research has been conducted to determine whether the use of organoarsenicals in animal feed, which can lead to elevated levels of arsenic in meat products (Lasky et al. 2004), contributes to increases in cancer risk. In order to address these research gaps, the following principal actions are necessary within the United States: a) implementation of a nationwide reporting system of the specific amounts and types of feed ingredients of concern to public health that are incorporated into animal feed, including antibiotics, arsenicals, rendered animal products, fats, and animal waste; b) funding and development of robust surveillance systems that monitor biological, chemical, and other etiologic agents throughout the animal-based food-production chain “from farm to fork” to human health outcomes; and c) increased communication and collaboration among feed professionals, food-animal producers, and veterinary and public health officials. REFERENCES...snip...end Sapkota et al. 668 VOLUME 115 | NUMBER 5 | May 2007 • Environmental Health Perspectives click here If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5). http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm Greetings again from Bacliff, Texas, FROM the findings of Mission Texas, where one strain of USA sheep scrapie transmitted to cattle, which did not show pathological findings of that of BSE, but very different from BSE, thus, the findings of atypical BSE in the USA bovine should be of no big surprise. especially since everything but the kitchen sink have been rendered and fed back to animals for human and animal consumption, including different strains of TSE infected sheep, goat, deer, elk, and cattle, all of which have been infected with TSE for years in the USA, even a few TME mink could be thrown in the recipe for a long and enduring TSE epidemic via a multitude of already proven routes and sources of this agent i.e. Transmissible Spongiform Encephalopthies (TSE). WE can sit on our laurels and explain it all away as a sporadic and or spontaneous happening without any proof, or we can do what should have been done long ago, do away with the UKBSEnvCJD ONLY MYTH! Terry S. Singeltary Sr. sporadic CJD, the big lie Sent: Monday May 28, 2007 Subject: THE BIG LIE SPORADIC CJD AND MAD COW DISEASEs i.e. TSE Terry S. Singeltary Sr. POLICY IN CONFIDENCE; CONFIDENTIAL; CJD IN FARMER WITH BSE COW ie OCCUPATIONAL EXPOSURE Subject: POLICY IN CONFIDENCE: CJD IN FARMER WITH BSE COW POLICY IN CONFIDENCE: CJD IN FARMER WITH BSE COW LIKELY TO ATRACT MEDIA ATTENTION click here click here click here CONFIRMED CJD IN FARMER WITH BSE COW line to take, sporadic CJD click here click here click here click here click here SECOND CASE CJD IN DAIRY FARMER click here CJD IN AN INDIVIDUAL OCCUPATIONALLY EXPOSED TO BSE ii. on page 2 the sentence ''He had drunk pooled milk from the herd which included that from the affected animal'' will mislead the uninformed. It needs to be made clear that milk from a cow which is suspected to be affected with BSE cannot be drunk or added to the bulk milk produced by the rest of the herd. iii. in the final paragraph I suggest that the phrase ''and a causal link with BSE is at most conjectural'' BE DELETED: the first paragraph of the sentence would then stand as a clear statement that the CJD case was likely to have been a CHANCE PHENOMENON. click here ''DH is aware of a second case of CJD in a dairy farmer who has had BSE in his herd. We cannot comment on the details of the case, but we know of nothing to suggest this is anthing other than a sporadic case of CJD. ......... click here IF PRESSED: The numbers concerned are very small, and it is not possible to draw any conclusions from such small numbers. This issue is being considered by the Government's expert advisers.... click here THE FARMER IS THOUGHT TO HAVE HAD AT LEAST TWO CASES OF BSE IN HIS HERD, which were diagnosed in 1992. The farmer is reported to have asssisted in calving and to have drunk milk from his herd. This does not suggest that this is anything other than a sporadic case of CJD. ... click here CONFIDENTIAL CONFIRMED CASE OF CJD IN DAIRY FARMER click here 3. Neither Dr Will nor the CJD surveillance unit intend to disclose the existence of this case or make any comment at present unless it attracts media attention. snip... HUMAN CASE DETAILS CONFIDENTIAL snip... 6. CJD IN FARMERS The second annual report on CJD surveillance in the UK, which is about to be published, gives occupational history details of 29 definite and probable CJD cases recorded in people who had a history of employment at any time in particular occupational groups of potential significance for the occurrence of the disease. The 29 cases were amongst 95 diagnosed over a 3 year period: the other 66 cases did not fall into such occupational groups. These relevant details are:- MEDICAL/PARAMEDICAL/DENTISTRY 7 ANIMAL LABORATORY 1 PHARMACEUTICAL LABORATORY 0 RESEARCH LABORATORY 0 FARMERS/VETERINARY SURGEONS 7 BUTCHERS/ABATTOIR WORKERS/OCCUPATION INVOLVING DIRECT CONTACT WITH ANIMAL OR CARCASES 5 OCCUPATION INVOLVING ANIMAL PRODUCTS 9 snip... full text ; click here Rocky Mountain oysters, mountain oysters, prairie oysters, Montana tendergroin or swinging sirloin POLICY IN CONFIDENCE 1. The article in the Daily Mail of 12 August again raises the question of a CAUSATIVE LINK BETWEEN BSE AND CJD. This follows the death of a second farmer from CJD... snip... I am, however, concerned about how DH and MAFF would respont to public concern generated if there are further CJD cases among farmers. snip... 4. Unwelcome, though it maybe to the Tyrrell Committee, I think they must be asked at their next meeting to give further thought to what they might advise the Department and MAFF if ANOTHER FARMER (or TWO) DEVELOPS CJD. OR, if a butcher or abattoir worker develops the disease. 5. Although the Committee were given plenty of advance warning about the second farmer, they may NOT BE SO FORTUNATE NEXT TIME ROUND. Some Contingency planning on the Committee's response to a further case of CJD in a farmer seems essential. At the same time the Committee should consider if there is SPECIAL RISK TO FARMERS, FOR EXAMPLE THEIR HISTORICAL HABIT OF CHEWING CATTLE NUTS, that might be implicated. .....(oh my GOD...tss) click here Ministers will note from this that experts are of the view, that there is unlikely to be a direct link between the cases of BSE, and the occurance of CJD in the farmer. (NOTE CJD increasing over 3 years. ...TSS) click here 'AGE AT ONSET' is therefore likely to be a reflection of particulary aetiological factors, about which, for sporadic CJD at least, much is yet unknown. IT has therefore been suggested that examination of the f/d i/p of other groups with TSE's, and comparison with that of CJD subsets might help to elucidate aetiological mechanisms for sporadic CJD in particular; i.e. ALMOST A REVERSAL OF THE ORIGINAL UNDERTAKING. click here OCCUPATIONAL EXPOSURE TO BSE AND CJD 2. The Tyrrell Committee met on 7 October and the significance of the two cases of CJD reported in dairy farmers who had BSE-affected animals on their farms was discussed at some length, AS WERE THE IMPLICATIONS OF A THIRD (OR FORTH) similar case. 3. The Committee were unable to identify any possible risk factors over and above those that they had already considered, both in general and with particular of TASTING THE FEED does continue but there was no consensus about the value of advising farmers to discontinue this practice. Feed currently in use does not pose a risk because of the ruminant-ruminant feed ban. click here MRC STRAIN CHARACTERISATION OF THE CREUTZFELDT-JAKOB DISEASE AGENT BY TRANSMISSION TO MICE In view of the CONCERN that exposue to BSE OR SCRAPIE MAY POSE A RISK TO HUMANS, it is proposed investigate the relationship between sporadic creutzfeldt-jakob disease..... click here 3. While Committee may have no leads to pursue on why farmers might be at increased risk, I hope they understand the urgency with which they will need to respond if or when a THIRD FARMER DEVELOPS CJD. click here INCREASE IN SPORADIC CJD click here occupational click here see full text ; click here HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007. With all the science to date refuting it, to continue to validate this myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, surgical, blood, medical, cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route. This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from subclinical to clinical disease, and of that, I even believe that physical and or blunt trauma may play a role of onset of clinical symptoms in some cases, but key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain. BUT, to continue with this myth that the U.K. strain of BSE one strain in cows, and the nv/v CJD, one strain in humans, and that all the rest of human TSE is one single strain i.e. sporadic CJD (when to date there are 6 different phenotypes of sCJD), and that no other animal TSE transmits to humans, to continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human. WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. My name is Terry S. Singeltary Sr. and I am no scientist, no doctor and have no PhDs, but have been independently researching human and animal TSEs since the death of my Mother to the Heidenhain Variant of Creutzfeldt Jakob Disease on December 14, 1997 'confirmed'. ...END Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518

by Terry S. Singeltary Sr. (1 articles, 0 quicklinks, 0 diaries, 8 comments [1 recommended, 0 rejected]) on Tuesday, Jul 24, 2007 at 5:17:49 PM

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Is It A Cluster Yet? Public Health Officials Have Few Answers About CJD Cases SNIP... "If it's from beef, am I next?" she asks pointing out that she and Patrick ate the same meals for 22 years. Martha Rosenberg is staff cartoonist for the Evanston Roundtable. click here COMMENT TO : Is It A Cluster Yet? Public Health Officials Have Few Answers About CJD Cases ATYPICAL CREUTZFELDT JAKOB DISEASE's AND ATYPICAL BSE's - sporadic, spontaneous, or sourced ? Date: July 22, 2007 By Terry S. Singeltary Sr. PART 1 click here PART 2 click here TSS

by Terry S. Singeltary Sr. (1 articles, 0 quicklinks, 0 diaries, 8 comments [1 recommended, 0 rejected]) on Tuesday, Jul 24, 2007 at 5:30:25 PM

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