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James W. Ironside - One of the best experts on this subject based on the ideXlab platform.
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detection of prions in blood from patients with Variant creutzfeldt jakob Disease
Science Translational Medicine, 2016Co-Authors: James W. Ironside, Fabio Moda, Luis Conchamarambio, Sandra Pritzkow, Fabrizio Tagliavini, Paul E Schulz, Claudio SotoAbstract:Human prion Diseases are infectious and invariably fatal neurodegenerative Diseases. They include sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form, and Variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrPSc) in the blood of patients affected by prion Disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrPSc could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrPSc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology.
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prion infectivity in the spleen of a prnp heterozygous individual with subclinical Variant creutzfeldt jakob Disease
Brain, 2013Co-Authors: Matthew Bishop, James W. Ironside, R G Will, Abigail B Diack, Diane L Ritchie, Jean MansonAbstract:Blood transfusion has been identified as a source of human-to-human transmission of Variant Creutzfeldt–Jakob Disease. Three cases of Variant Creutzfeldt–Jakob Disease have been identified following red cell transfusions from donors who subsequently developed Variant Creutzfeldt–Jakob Disease and an asymptomatic red cell transfusion recipient, who did not die of Variant Creutzfeldt–Jakob Disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of Variant Creutzfeldt–Jakob Disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the Variant Creutzfeldt–Jakob Disease agent. Mice were assessed for clinical and pathological signs of Disease and transmission data were compared with other transmission studies in Variant Creutzfeldt–Jakob Disease, including those on the spleen and brain of the donor to the index case. Transmission of Variant Creutzfeldt–Jakob Disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen homogenates, providing initial evidence of similar transmission properties after propagation in PRNP codon 129 MV and MM individuals. These studies demonstrate that spleen tissue from a PRNP MV genotype individual can propagate the Variant Creutzfeldt–Jakob Disease agent and that the infectious agent can be present in the spleen without CNS involvement.
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validation of diagnostic criteria for Variant creutzfeldt jakob Disease
Annals of Neurology, 2010Co-Authors: C A Heath, J. Mackenzie, M Zeidler, G E Stewart, Sarah Cooper, Katy Murray, Andrea Lowman, Colm Henry, Margaret Macleod, James W. IronsideAbstract:Objective Variant Creutzfeldt–Jakob Disease (vCJD), a novel form of human prion Disease, was recognized in 1996. The Disease affected a younger cohort than sporadic CJD, and the early clinical course was dominated by psychiatric and sensory symptoms. In an attempt to aid diagnosis and establish standardization between surveillance networks, diagnostic criteria were established. These were devised from the features of a small number of cases and modified in 2000 as the clinical phenotype was established. Since then, only minor changes have been introduced; revalidation of the criteria in the current format is overdue. Methods Included in this study are autopsy/cerebral biopsy-proven cases of vCJD referred to the National CJD Surveillance Unit (NCJDSU) between 1995 and 2004 and suspect cases in which an alternative diagnosis was identified following autopsy/cerebral biopsy. Results Over the 10-year period, 106 definite cases of vCJD and 45 pathologically confirmed “noncases” were identified from the archives of the NCJDSU. The median age at onset of the cases was significantly younger than that of the noncases (27 years [range, 12–74 years] vs 43 years [range, 10–64 years]), and the median duration of illness was significantly shorter (14 months [range, 6–39 months] vs 22 months [range, 2–139 months]). The most commonly identified core clinical feature in cases was dementia; persistent painful sensory symptoms were the least frequent. Eighty-eight of 106 (83%) vCJD cases were retrospectively classified as probable in life, 6 cases were classified as possible. Most cases were classified as probable on the basis of core clinical features and brain magnetic resonance imaging. To date, the diagnostic criteria remain 100% specific, with no autopsy/cerebral biopsy-proven noncases classified as probable in life. Interpretation This study confirms that the diagnostic criteria for vCJD are sensitive and specific and provide a useful standard framework for case classification in a surveillance setting. ANN NEUROL 2010
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transmissions of Variant creutzfeldt jakob Disease from brain and lymphoreticular tissue show uniform and conserved bovine spongiform encephalopathy related phenotypic properties on primary and secondary passage in wild type mice
Journal of General Virology, 2009Co-Authors: Diane L Ritchie, James W. Ironside, I Mcconnell, Mark Head, Aileen Boyle, Moira E BruceAbstract:Prion strains are defined by their biological properties after transmission to wild-type mice, specifically by their incubation periods and patterns of vacuolar pathology (‘lesion profiles’). Preliminary results from transmissions of Variant Creutzfeldt–Jakob Disease (vCJD) to wild-type mice provided the first compelling evidence for the close similarity of the vCJD agent to the agent causing bovine spongiform encephalopathy (BSE). Complete results from this investigation, including the transmission characteristics of vCJD from brain and peripheral tissues of 10 cases (after primary transmission and subsequent mouse-to-mouse passage), have now been analysed. All 10 vCJD sources resulted in consistent incubation periods and lesion profiles, suggesting that all 10 patients were infected with the same strain of agent. Incubation periods suggested that infectious titres may be subject to regional variation within the brain. Comparison of incubation periods and lesion profiles from transmission of brain and peripheral tissues showed no evidence of tissue-specific modification in the biological properties of the agent. Analysis of the protease-resistant prion protein (PrPres) by Western blotting from primary and subsequent passages in mice showed a glycosylation pattern closely resembling that of vCJD in humans, the so-called BSE ‘glycoform signature’. Minor variations in PrPres fragment size were evident between mouse strains carrying different alleles of the gene encoding PrP both in primary transmissions and on further passages of vCJD brain. Overall, the results closely resembled those of previously reported transmissions of BSE in the same mouse strains, consistent with BSE being the origin of all of these vCJD cases.
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a quantitative study of the pathological changes in the cerebellum in 15 cases of Variant creutzfeldt jakob Disease vcjd
Neuropathology and Applied Neurobiology, 2009Co-Authors: Richard A Armstrong, James W. Ironside, Peter L Lantos, Nigel J CairnsAbstract:Aims: To determine in the cerebellum in Variant Creutzfeldt–Jakob Disease (vCJD): (i) whether the pathology affected all laminae; (ii) the spatial topography of the pathology along the folia; (iii) spatial correlations between the pathological changes; and (iv) whether the pathology was similar to that of the common methionine/methionine Type 1 subtype of sporadic CJD. Methods: Sequential cerebellar sections of 15 cases of vCJD were stained with haematoxylin and eosin, or immunolabelled with monoclonal antibody 12F10 against prion protein (PrP) and studied using spatial pattern analysis. Results: Loss of Purkinje cells was evident compared with control cases. Densities of the vacuolation and the protease-resistant form of prion protein (PrPSc) (diffuse and florid plaques) were greater in the granule cell layer (GL) than the molecular layer (ML). In the ML, vacuoles and PrPSc plaques occurred in clusters regularly distributed along the folia with larger clusters of vacuoles and diffuse plaques in the GL. There was a negative spatial correlation between the vacuoles and the surviving Purkinje cells in the ML. There was a positive spatial correlation between the vacuoles and diffuse PrPSc plaques in the ML and GL. Conclusions: (i) all laminae were affected by the pathology, the GL more severely than the ML; (ii) the pathology was topographically distributed along the folia especially in the Purkinje cell layer and ML; (iii) pathological spread may occur in relation to the loop of anatomical connections involving the cerebellum, thalamus, cerebral cortex and pons; and (iv) there were pathological differences compared with methionine/methionine Type 1 sporadic CJD.
John Collinge - One of the best experts on this subject based on the ideXlab platform.
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detection of prion infection in Variant creutzfeldt jakob Disease a blood based assay
The Lancet, 2011Co-Authors: Julie Ann Edgeworth, Simon Mead, Tracy Campbell, Peter Rudge, Michael Farmer, Anita Sicilia, Paul Tavares, Jon Beck, Jessica Lowe, John CollingeAbstract:Summary Background Variant Creutzfeldt-Jakob Disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. Methods We developed a solid-state binding matrix to capture and concentrate Disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10 −7 to 10 −10 of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10 −6 ). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological Diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. Findings We were able to distinguish a 10 −10 dilution of exogenous vCJD prion-infected brain from a 10 −6 dilution of normal brain (mean chemiluminescent signal, 1·3×10 5 [SD 1·1×10 4 ] for vCJD vs 9·9×10 4 [4·5×10 3 ] for normal brain; p Interpretation These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. Funding UK Medical Research Council.
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age of onset and death in inherited prion Disease are heritable
American Journal of Medical Genetics, 2009Co-Authors: T Webb, John Collinge, John C Whittaker, Simon MeadAbstract:The common polymorphism at codon 129 of the prion protein gene (PRNP) is known to affect prion Disease susceptibility, incubation period and phenotype. Mouse quantitative trait locus (QTL) studies demonstrate multiple modifiers of incubation time unlinked to Prnp, suggesting the existence of homologous human prion Disease modifiers, but direct evidence of these has been lacking. We investigated the correlation of age at onset and death, expressed as a composite Z score, between parents and offspring in three large UK inherited prion Disease kindreds. Our analysis suggests that overall heritability of the composite phenotype is 0.55 (95% CI 0.35-0.75). This measure may be an underestimate of the total genetic contribution to phenotypic heterogeneity as the analysis does not incorporate the effect of PRNP-linked modifiers. Although the confidence intervals are wide, these data suggest a significant heritable component to phenotypic variability and support attempts to identify human prion Disease modifier genes which would be important in understanding the epidemiology of Variant Creutzfeldt-Jakob Disease (vCJD) in populations with significant exposure to bovine spongiform encephalopathy (BSE) prions.
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Kuru prions and sporadic Creutzfeldt-Jakob Disease prions have equivalent transmission properties in transgenic and wild-type mice
P NATL ACAD SCI USA, 2008Co-Authors: John CollingeAbstract:Kuru provides our principal experience of an epidemic human prion Disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and Variant Creutzfeldt-Jakob Disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from Variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD.
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Prion infectivity in Variant Creutzfeldt-Jakob Disease rectum
GUT, 2007Co-Authors: John CollingeAbstract:Background: Disease-related prion protein (PrPSc) is readily detectable in lymphoreticular tissues in Variant Creutzfeldt-Jakob Disease (vCJD), but not in other forms of human prion Disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic vCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrPSc: prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrPSc concentration typically reflects infectious prion titre.Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrPSc.Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M(+/+) Prnp(o/o))-35 and Tg(HuPrP129M(+/+) Prnp(o/o))-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrPSc that have been observed in vCJD.Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrPSc at a concentration of 10(4.7)-fold lower than that in vCJD brain.Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrPSc as a quantitative marker of prion infectivity in vCJD tissues.
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prion infectivity in Variant creutzfeldt jakob Disease rectum commentary
Gut, 2007Co-Authors: M. W. Head, Emmanuel A Asante, Melanie Desbruslais, Jacqueline M Linehan, Jonathan D F Wadsworth, Susan Joiner, James W. Ironside, Katie Fox, S Brandner, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues in Variant Creutzfeldt-Jakob Disease (vCJD), but not in other forms of human prion Disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD tissues.
Andrew F. Hill - One of the best experts on this subject based on the ideXlab platform.
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human prion protein with valine 129 prevents expression of Variant cjd phenotype
Science, 2004Co-Authors: Jonathan D F Wadsworth, Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Julie Welch, Lisa Stone, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. HillAbstract:Variant Creutzfeldt-Jakob Disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion Disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
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quinacrine does not prolong survival in a murine creutzfeldt jakob Disease model
Annals of Neurology, 2002Co-Authors: Steven J Collins, Andrew F. Hill, Victoria Lewis, Marcus W Brazier, Ashley Fletcher, Colin L MastersAbstract:Paramount among issues relating to the transmissible spongiform encephalopathies (also known as prion Diseases) is the absence of any effective therapy. This need has been heightened by the substantial European and emerging global problem of bovine spongiform encephalopathy and consequent Variant Creutzfeldt-Jakob Disease. Stimulated by the recent reports of a potent antiprion effect in cell culture-based clearance assays, we studied the utility of quinacrine in a well-characterized in vivo model of mouse-adapted transmissible spongiform encephalopathy. Our results failed to show any evidence that quinacrine is effective when using the simple but objective measure of survival prolongation.
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tissue distribution of protease resistant prion protein in Variant creutzfeldt jakob Disease using a highly sensitive immunoblotting assay
The Lancet, 2001Co-Authors: Jonathan D F Wadsworth, Melanie Desbruslais, Susan Joiner, Andrew F. Hill, Tracy Campbell, Philip J Luthert, John CollingeAbstract:Summary Background Variant Creutzfeldt-Jakob Disease (vCJD) has a pathogenesis distinct from other forms of human prion Disease: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues. Quantitation of risk of secondary transmission, and targeting of risk reduction strategies, is limited by lack of knowledge about relative prion titres in these and other peripheral tissues, the unknown prevalence of preclinical vCJD, and a transmission barrier which limits the sensitivity of bioassay. We aimed to improve immunoblotting methods for high sensitivity detection of PrP Sc to investigate the distribution of PrP Sc in a range of vCJD tissues. Methods We obtained tissues at necropsy from four patients with neuropathologically confirmed vCJD and from individuals without neurological Disease. Tissues were analysed by sodium phosphotungstic acid precipitation of PrP Sc and western blotting using high sensitivity enhanced chemiluminescence. Findings We could reliably detect PrP Sc in the equivalent of 50 nL 10% vCJD brain homogenate, with a maximum limit of detection equivalent to 5 nl. PrP Sc could be detected in tissue homogenates when present at concentrations 10 4 –10 5 fold lower than those reported in brain. Tonsil, spleen, and lymph node were uniformly positive for PrP Sc at concentrations in the range of 0·1–15% of those found in brain: the highest concentrations were consistently seen in tonsil. PrP Sc was readily detected in the retina and proximal optic nerve of vCJD eye at levels of 2·5 and 25%, respectively of those found in brain. Other peripheral tissues studied were negative for PrP Sc with the exception of low concentrations in rectum, adrenal gland, and thymus from a single patient with vCJD. vCJD appendix and blood (Buffy coat fraction) were negative for PrP Sc at this level of assay sensitivity. Interpretation We have developed a highly sensitive immunoblot method for detection of PrP Sc in vCJD tissues that can be used to provide an upper limit on PrP Sc concentrations in peripheral tissues, including blood, to inform risk assessment models. Rectal and other gastrointestinal tissues should be further investigated to assess risk of iatrogenic transmission via biopsy instruments. Ophthalmic surgical instruments used in procedures involving optic nerve and the posterior segment of the eye, in particular the retina, might represent a potential risk for iatrogenic transmission of vCJD. Tonsil is the tissue of choice for diagnostic biopsy and for population screening of surgical tissues to assess prevalence of preclinical vCJD infection within the UK and other populations.
Jonathan D F Wadsworth - One of the best experts on this subject based on the ideXlab platform.
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prion infectivity in Variant creutzfeldt jakob Disease rectum commentary
Gut, 2007Co-Authors: M. W. Head, Emmanuel A Asante, Melanie Desbruslais, Jacqueline M Linehan, Jonathan D F Wadsworth, Susan Joiner, James W. Ironside, Katie Fox, S Brandner, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues in Variant Creutzfeldt-Jakob Disease (vCJD), but not in other forms of human prion Disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD tissues.
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human prion protein with valine 129 prevents expression of Variant cjd phenotype
Science, 2004Co-Authors: Jonathan D F Wadsworth, Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Julie Welch, Lisa Stone, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. HillAbstract:Variant Creutzfeldt-Jakob Disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion Disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
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tissue distribution of protease resistant prion protein in Variant creutzfeldt jakob Disease using a highly sensitive immunoblotting assay
The Lancet, 2001Co-Authors: Jonathan D F Wadsworth, Melanie Desbruslais, Susan Joiner, Andrew F. Hill, Tracy Campbell, Philip J Luthert, John CollingeAbstract:Summary Background Variant Creutzfeldt-Jakob Disease (vCJD) has a pathogenesis distinct from other forms of human prion Disease: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues. Quantitation of risk of secondary transmission, and targeting of risk reduction strategies, is limited by lack of knowledge about relative prion titres in these and other peripheral tissues, the unknown prevalence of preclinical vCJD, and a transmission barrier which limits the sensitivity of bioassay. We aimed to improve immunoblotting methods for high sensitivity detection of PrP Sc to investigate the distribution of PrP Sc in a range of vCJD tissues. Methods We obtained tissues at necropsy from four patients with neuropathologically confirmed vCJD and from individuals without neurological Disease. Tissues were analysed by sodium phosphotungstic acid precipitation of PrP Sc and western blotting using high sensitivity enhanced chemiluminescence. Findings We could reliably detect PrP Sc in the equivalent of 50 nL 10% vCJD brain homogenate, with a maximum limit of detection equivalent to 5 nl. PrP Sc could be detected in tissue homogenates when present at concentrations 10 4 –10 5 fold lower than those reported in brain. Tonsil, spleen, and lymph node were uniformly positive for PrP Sc at concentrations in the range of 0·1–15% of those found in brain: the highest concentrations were consistently seen in tonsil. PrP Sc was readily detected in the retina and proximal optic nerve of vCJD eye at levels of 2·5 and 25%, respectively of those found in brain. Other peripheral tissues studied were negative for PrP Sc with the exception of low concentrations in rectum, adrenal gland, and thymus from a single patient with vCJD. vCJD appendix and blood (Buffy coat fraction) were negative for PrP Sc at this level of assay sensitivity. Interpretation We have developed a highly sensitive immunoblot method for detection of PrP Sc in vCJD tissues that can be used to provide an upper limit on PrP Sc concentrations in peripheral tissues, including blood, to inform risk assessment models. Rectal and other gastrointestinal tissues should be further investigated to assess risk of iatrogenic transmission via biopsy instruments. Ophthalmic surgical instruments used in procedures involving optic nerve and the posterior segment of the eye, in particular the retina, might represent a potential risk for iatrogenic transmission of vCJD. Tonsil is the tissue of choice for diagnostic biopsy and for population screening of surgical tissues to assess prevalence of preclinical vCJD infection within the UK and other populations.
Susan Joiner - One of the best experts on this subject based on the ideXlab platform.
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Variant creutzfeldt jakob Disease in a patient with heterozygosity at prnp codon 129
The New England Journal of Medicine, 2017Co-Authors: T H Mok, Simon Mead, Susan Joiner, Zane Jaunmuktane, Tracy Campbell, Catherine Morgan, Benjamin R Wakerley, Farhad Golestani, Peter Rudge, Rolf H JagerAbstract:In this case study, Variant Creutzfeldt–Jakob Disease (CJD) is shown to occur in a young man with heterozygosity, rather than homozygosity, at codon 129 of the prion protein gene (PRNP).
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prion infectivity in Variant creutzfeldt jakob Disease rectum commentary
Gut, 2007Co-Authors: M. W. Head, Emmanuel A Asante, Melanie Desbruslais, Jacqueline M Linehan, Jonathan D F Wadsworth, Susan Joiner, James W. Ironside, Katie Fox, S Brandner, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues in Variant Creutzfeldt-Jakob Disease (vCJD), but not in other forms of human prion Disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD tissues.
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human prion protein with valine 129 prevents expression of Variant cjd phenotype
Science, 2004Co-Authors: Jonathan D F Wadsworth, Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Julie Welch, Lisa Stone, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. HillAbstract:Variant Creutzfeldt-Jakob Disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion Disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
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bse prions propagate as either Variant cjd like or sporadic cjd like prion strains in transgenic mice expressing human prion protein
The EMBO Journal, 2002Co-Authors: Emmanuel A Asante, Melanie Desbruslais, Ian Gowland, Andrew L Wood, Julie Welch, Jacqueline M Linehan, Sarah E Lloyd, Susan Joiner, Andrew F. Hill, Jonathan D F WadsworthAbstract:Variant Creutzfeldt–Jakob Disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or Variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these Diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a Disease arising from BSE exposure.
