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Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt–Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood–brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Human prion diseases, including Creutzfeldt‐Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt‐Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc. An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK‐wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study. [ABSTRACT FROM AUTHOR]

This article pays tribute to W.P.T (Philip) James, a highly respected and influential figure in the field of nutrition and obesity. Philip had a successful career, starting with his work at the first obesity clinic in the UK and later becoming the Director of the Rowett Research Institute in Aberdeen. His work had a significant impact on how obesity is perceived and addressed globally, and he played a key role in the development of the Food Standards Agency in the UK. Throughout his career, Philip was supported by his wife Jean, who played an essential role in his work. [Extracted from the article]

Chronic Wasting Disease (CWD) is a prion disease that affects deer, elk, and moose. It has been detected in several countries, but there is no evidence of transmission to humans. However, there is a theoretical concern if human-adapted strains were to appear. The disease can be transmitted through bodily fluids and tissues of infected animals, but there is no treatment or pre-symptomatic test available. Another prion disease called variant Creutzfeldt-Jakob disease (vCJD) is discussed in the document, including its transmission through blood transfusions and plasma-derived products. The document also mentions the genetic factors that influence susceptibility to vCJD and the lack of effective treatments or prevention measures. [Extracted from the article]

This article discusses the role of α-synuclein prion strains in Parkinson's disease (PD) and multiple system atrophy (MSA). It explains the historical background of these disorders and how they were initially thought to be unrelated until the discovery of α-synuclein as the main neuropathological component in both diseases. The article highlights recent advances in cryogenic-electron microscopy that have revealed structural differences in α-synuclein fibrils between PD and MSA patients. It also discusses the ability of α-synuclein prions to spread from cell to cell and the use of animal and cell culture models to study strain biology. The article concludes by emphasizing the importance of incorporating strain biology into the development of biomarkers, diagnostics, and therapeutics for synucleinopathies. [Extracted from the article]

Among the numerous transmissible spongiform encephalopathies (TSEs), bovine spongiform encephalopathy (BSE) is the most well-known TSEs. It is a potential Creutzfeldt–Jakob (CJD) disease mutation that can be transferred through cattle to humans. In several animals, the prion protein gene (PRNP) is recognized to take active part in TSE vulnerability or tolerance. Previous studies have found indels polymorphism in PRNP gene promoter and intron1 region linked to BSE vulnerability. It's linked with 23 bp indels polymorphism in putative promoter and 12 bp indel in intron 1 of the PRNP gene. The aim of this study was to compare the allele, genotype and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak (Bos grunniens) (YK), Zhongdian Yellow cattle (Bos taurus) (YC) and Zhongdian Yakow (Bos primigenius taurus × Bos grunniens) (PK) with worldwide reported healthy or affected BSE cattle, in order to assess their potential resistance to BSE. A comparison of Chinese bovine populations with healthy and BSE-affected German and Swiss cattle from globally was conducted, and result indicating significant difference (p <.001) between healthy and affected cattle. Additionally, as compared to prior studies with Chinese bovine population, the significant results were found. In this study, the allelic frequency D23 finding high deletion in all analyzed Chinese bovine species, and haplotype D12–D23 exhibited a less significant inclination toward susceptibility to BSE. [ABSTRACT FROM AUTHOR]

Simple Summary: Bovine spongiform encephalopathy (BSE), a neurological disorder with a significant effect on cattle health, has been recognized pathologically and medically. It is associated with a 12 bp indel in intron 1 of the PRNP gene and a 23 bp indel polymorphism in the putative promoter. The main focus of this work was to assess the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak, Zhongdian Yellow cattle, and Zhongdian Yakow, as well as to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels using PCR. Two variable sites—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site—were also investigated. Overall, the study results suggest that the PRNP genotype may contribute to the high variation in PRNP expression. Bovine spongiform encephalopathy (BSE) is a fatal disease in cattle caused by misfolded prion proteins and linked to indel polymorphisms in the promoter and intron 1 of the PRNP gene. The aim of this study was to determine the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms and to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels via polymerase chain reaction (PCR) in Zhongdian Yak (Bos-grunniens) (YK), Zhongdian Yellow cattle (Bos-taurus) (YC), and Zhongdian Yakow (Bos-primigenius taurus × Bos-grunniens) (PK). Resultant high allelic frequencies were found in 23− and 12+, while haplotype frequencies were very low in 23+/12 in YK, YC, and PK. PRNP expression was higher in the +−/−− diplotype of the PK and (mean ± SE) was 3.6578 ± 1.85964. Furthermore, two variable sites were investigated—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site. Additionally, reporter gene assays revealed a link between two proposed transcription factors and lower expression levels of the +/+ allele compared with the −/− allele. The expression level of PRNP was shown to be dependent on two indel polymorphisms in the bovine PRNP promoter, which includes binding sites for RP58 and SP1 transcription factors. These findings raised the possibility that the PRNP genotype may contribute to the high variation in PRNP expression. [ABSTRACT FROM AUTHOR]

Susceptibility to classical bovine spongiform encephalopathy (BSE) has been linked to 23 bp indel in promoter and 12 bp indel in the first intron of cattle prion protein gene. This study aimed to investigate 23/12 bp indel polymorphisms in the polymorphisms in cattle prion protein (PRNP) gene to reveal the risk of BSE in Ethiopian cattle. Also, frequency of each polymorphism was compared to the other Bos taurus and Bos indicus breeds. According to results, the insertion variant was detected at a low frequency in all of the study populations at both loci. The 23 bp insertion allele in Fogera breed was relatively lower than Borona and Arsi and the same allele at the same locus in Afar breed was higher than the rest of the breeds (0.16). Due to high linkage disequilibrium (LD) of the deletion allele in Bos taurus, the frequencies of deletion allele at 23 bp (0.84) and 12 bp (0.86) loci in Afar breed were relatively closer than the rest of the breeds. In addition, DD/DD was found as the highly frequent diplotype in all of the breeds. The low frequency of insertion alleles at 23 and 12 bp indel sites demonstrate that Ethiopian cattle have a genetically high risk for BSE. [ABSTRACT FROM AUTHOR]

Efforts to prevent human-to-human transmission of variant Creutzfeldt-Jakob disease (vCJD) by contaminated blood would be aided by the development of a sensitive diagnostic test that could be routinely used to screen blood donations. As blood samples from vCJD patients are extremely rare, here we describe the optimisation of real-time quaking-induced conversion (RT-QuIC) for detection of PrPSc (misfolded prion protein, a marker of prion infection) in blood samples from an established large animal model of vCJD, sheep experimentally infected with bovine spongiform encephalopathy (BSE). Comparative endpoint titration experiments with RT-QuIC, miniaturized bead protein misfolding cyclic amplification (mb-PMCA) and intracerebral inoculation of a transgenic mouse line expressing sheep PrP (tgOvARQ), demonstrated highly sensitive detection of PrPSc by RT-QuIC in a reference sheep brain homogenate. Upon addition of a capture step with iron oxide beads, the RT-QuIC assay was able to detect PrPSc in whole blood samples from BSE-infected sheep up to two years before disease onset. Both RT-QuIC and mb-PMCA also demonstrated sensitive detection of PrPSc in a reference vCJD-infected human brain homogenate, suggesting that either assay may be suitable for application to human blood samples. Our results support the further development and evaluation of RT-QuIC as a diagnostic or screening test for vCJD. [ABSTRACT FROM AUTHOR]

Classical scrapie is a contagious prion disease of sheep and goats. It is endemic in many countries in Europe, North America, and Asia. In Africa, imported scrapie cases have been described in South Africa and Kenia in the past. More recently, several cases have been reported from different regions of Libya, based on clinical signs and histological lesions. Here, we report the results of thorough investigations carried out on a suspect case of scrapie in a 6-year-old Barbarine sheep, born, and bred in Tunisia, showing behavioral changes, weight loss, itching, skin lesions, wool loss, and motor incoordination. Histopathology and immunohistochemistry revealed spongiform change in several brain areas with associated pathological prion protein deposition. Western blotting confirmed the diagnosis and showed a classical scrapie-like molecular pattern of PrPres, different from atypical scrapie and bovine spongiform encephalopathy (BSE) in small ruminants. Sequence analysis of the prion protein gene showed that the animal carried the ARQ/ARQ genotype, one of the most susceptible to classical scrapie. The inoculation of sheep brain homogenate in a susceptible rodent model proved the experimental transmissibility of the disease. These results demonstrate the circulation of classical scrapie in Tunisia and confirm its presence in North Africa, indicating the need to improve epidemiological surveillance and diagnostic capacity for prion diseases in the region. [ABSTRACT FROM AUTHOR]

The article discusses the global shortages of plasma for fractionation (PfF) and the increasing demand for immune globulins (IgG) products, particularly in high-income countries. In the European Union (EU), the volume of PfF collected does not meet the needs of patients for plasma-derived medicinal products (PDMPs). EU countries rely on plasma collected in plasmapheresis centers in the United States, which makes the EU strategically dependent on that country. This dependence on PfF import has negative consequences for global availability, especially in low- and medium-income countries. The article highlights the challenges and complexities in achieving self-sufficiency and strategic independence in PfF supply in the EU, including incomplete legislation, lack of national targets, and the absence of a direct feedback mechanism. The authors suggest strengthening the public sector and developing optimal tendering models for fractionation to increase PfF collection in the EU. [Extracted from the article]

Prion diseases are transmissible, fatal neurologic diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, chronic wasting disease (CWD) in cervids, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Prions are extremely difficult to inactivate and established methods to reduce prion infectivity are often dangerous, caustic, expensive, or impractical. Identifying viable and safe methods for treating prion contaminated materials is important for hospitals, research facilities, biologists, hunters, and meat-processors. For three decades, some prion researchers have used a phenolic product called Environ LpH (eLpH) to inactivate prions. ELpH has been discontinued, but a similar product, Wex-cide 128, containing the similar phenolic chemicals as eLpH is now available. In the current study, we directly compared the anti-prion efficacy of eLpH and Wex-cide 128 against prions from four different species (hamster 263K, cervid CWD, mouse 22L and human CJD). Decontamination was performed on either prion infected brain homogenates or prion contaminated steel wires and mouse bioassay was used to quantify the remaining prion infectivity. Our data show that both eLpH and Wex-cide 128 removed 4.0–5.5 logs of prion infectivity from 22L, CWD and 263K prion homogenates, but only about 1.25–1.50 logs of prion infectivity from human sporadic CJD. Wex-cide 128 is a viable substitute for inactivation of most prions from most species, but the resistance of CJD to phenolic inactivation is a concern and emphasizes the fact that inactivation methods should be confirmed for each target prion strain. [ABSTRACT FROM AUTHOR]

The amyloid properties of RAD51 imply that aberrant protein-based assemblies could potentially affect DNA lesions, thus providing a possible link between protein-based and DNA-based transmission machineries. The authors highlight the biological functions of amyloids formed by proteins containing -barrel domains and discuss probable pathways of amyloid formation by such proteins. The review critically assesses existing diagnostic techniques and explains how the principles and procedures derived from studying transmissible amyloids could be applied to clinical and pre-clinical detection of amyloids involved in other diseases, such as renal amyloids. While some of cases of amyloid-associated diseases are heritable (that is, derived from DNA mutations), the majority of cases are sporadic, and prion-like transmissibility of protein assemblies has been observed at a cellular level and, in some experimental models, even at the organismal level [[14], [16]]. [Extracted from the article]

Bovine spongiform encephalopathy (BSE) is a prion disease that is always fatal in cattle and is considered an important risk factor for human health. Genetic polymorphisms that alter prion proteins may be associated with susceptibility or resistance to infectious spongiform encephalopathy. Therefore, we investigated the distribution of the 23 bp indel variant in the prion protein (PRNP) gene in Jersey cattle in Turkey. A total of 95 unrelated Jersey cattle (79 of reproductive age and 16 of non-reproductive age) from a private farm in Izmir were included in the study. Genomic DNA was obtained from the milk of reproductive-age cattle and the saliva of non-reproductive-age cattle. A 23-bp indel polymorphism in the PRNP gene promoter region was genotyped by polymerase chain reaction (PCR) analysis. The three genotypes of the PRNP 23-bp indel variant were classified as follows: I/I (223 bp), I/D (both 223 and 200 bp fragments), and D/D (200 bp). The frequencies of the I/I, I/D, and D/D genotypes of the PRNP 23-bp indel variant in cattle were 22 (23.16%), 48 (50.53%), and 25 (26.32%). We then examined genotype and allele distribution according to service period. No significant difference was detected in terms of PRNP gene 23 bp-indel variant genotype and allele distribution in the groups created according to the service period (p>0.05). Although the PRNP gene 23 bp-indel variant genotype and allele distribution in jersey-type cattle in Turkey did not differ according to service period, our results may benefit the understanding of the genetic characteristics of the PRNP gene in cattle breeds. [ABSTRACT FROM AUTHOR]

Yoon also added, " I For now i [emphasis added] the ROK and the US are proceeding with discussion regarding the ROK side sharing information, participating together, joint planning, and joint execution [with the US] - regarding concerns on US nuclear assets."[31] The statement suggested that while South Korea accepted US extended deterrence at present, other nuclear options were still on the table for the future. In meetings with their US counterparts, South Korean policymakers have repeatedly raised the same question: can South Korea trust the United States? Strengthening the US-South Korea Alliance The year 2023 marks the 70 SP th sp anniversary of the US-South Korea alliance. [Extracted from the article]

The purpose of this research is to demonstrate the utilization of animal wastes and by‐products in the production of low‐energy and low‐CO2 clinkers and cements in order to preserve natural resources, such as limestone, while reducing CO2 emissions released from the cement manufacturing process and reducing potential health risk to the world population (such as bovine spongiform encephalopathy or other health issues...). Pure calcium sulfoaluminate clinker was produced with calcium hydroxide, aluminum hydroxide, and calcium sulfate hemihydrate; followed by additional clinkers produced from substituting calcium hydroxide with bone ash (from 0 to 100% of the calcium hydroxide replaced). The final clinkers contained various amounts of ye'elimite, calcium aluminate phases, as well as tricalcium phosphate, depending on the firing temperature. Finally, some preliminary results on the hydration process and compressive strength are provided for the production of these binders. [ABSTRACT FROM AUTHOR]

The novel emergence of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom in 1995/96 as a result of the transmission of bovine spongiform encephalopathy (BSE) agents from cattle to humans triggered a previously unprecedented crisis in Europe at the interface of animal health and human public health. This prompted Germany to reconsider, among other things, the practice of reprocessing medical devices with regard to the unconventional BSE/ vCJD pathogens, so-called prions (from “proteinaceous infectious particles”). In 2002, a vCJD task force set up with this objective presented recommendations for minimizing/reducing the risk of vCJD transmission through surgical instruments and other medical devices. According to these recommendations, routine reprocessing should combine at least two procedures that are also (at least partially) suitable for decontamination/inactivation of these pathogens if there is no identifiable risk of contamination with prions. In practice, this includes in particular careful cleaning (decontamination), preferably with alkaline detergents, and subsequent sterilization with moist heat (“steam sterilization”) at 134°C with a holding time of 5 minutes. The validation of the processes is of great importance. From today’s point of view, the central recommendations of the vCJD Task Force for medical device reprocessing have proven to be sustainable with good practicability. The effectiveness of the recommended measures against prions has been confirmed on a broad basis in numerous studies. In line with the paradigmatically high demands that prions place on hygiene in the reprocessing of medical devices, this effectiveness in practice extends simultaneously to conventional pathogens such as bacteria, viruses or fungi. In perspective, this also applies at least in part to potential new challenges, such as those that have been discussed for some time with regard to self-replicating protein particles of Alzheimer’s or Parkinson’s disease and other protein aggregation diseases. [ABSTRACT FROM AUTHOR]

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disease that belongs to a group of diseases known as transmissible spongiform encephalopathies (TSEs). It is believed that the infectious agent responsible for prion diseases is abnormally folded prion protein (PrPSc), which derives from a normal cellular protein (PrPC), which is a cell surface glycoprotein predominantly expressed in neurons. There are three different types of BSE, the classical BSE (C-type) strain and two atypical strains (H-type and L-type). BSE is primarily a disease of cattle; however, sheep and goats also can be infected with BSE strains and develop a disease clinically and pathogenically indistinguishable from scrapie. Therefore, TSE cases in cattle and small ruminants require discriminatory testing to determine whether the TSE is BSE or scrapie and to discriminate classical BSE from the atypical H- or L-type strains. Many methods have been developed for the detection of BSE and have been reported in numerous studies. Detection of BSE is mainly based on the identification of characteristic lesions or detection of the PrPSc in the brain, often by use of their partial proteinase K resistance properties. The objective of this paper was to summarize the currently available methods, highlight their diagnostic performance, and emphasize the advantages and drawbacks of the application of individual tests. [ABSTRACT FROM AUTHOR]

Since prion diseases share many molecular features with other neurodegenerative disorders that involve prion-like mechanisms, outcomes from prion research have the potential to cross-fertilize progress in such diseases. Prion diseases are fatal and infectious neurodegenerative disorders and prototypic conformational diseases. Whereas in prion diseases, a bona fide infectious agent (prion) propagates and spreads within and between individuals, prion-like mechanisms are limited to seeded conversion and spread of disease-causing protein aggregates from cell to cell within a host. Real-time quaking-induced conversion (RT-QuIC) is an ultrasensitive in vitro prion amplification method that uses recombinant prion protein (substrate) for real-time detection of prion seeds (template). [Extracted from the article]

Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrPC) into the pathological PrPSc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrPC and PrPSc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrPC-directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining. [ABSTRACT FROM AUTHOR]

Chronic wasting disease (CWD) strains present a novel challenge to defining and mitigating this contagious prion disease of deer, elk, moose, and reindeer. Similar to strains of other prion diseases (bovine spongiform encephalopathy, sheep scrapie), CWD strains can affect biochemical and neuropathological properties of the infectious agent, and importantly interspecies transmission. To date, ten CWD strains have been characterized. The expanding range of CWD in North America and its presence in South Korea as well as Scandinavian countries will potentially result in millions of cervids infected with CWD; thus, novel strains will continue to emerge. In this review, we will summarize the characteristics of known CWD strains and describe the impact of prion protein gene polymorphisms on the generation of strains. We will also discuss the evidence that individual cervids can harbor more than one CWD strain, complicating strain analysis, and affecting selection and adaptation of strains in new hosts. [ABSTRACT FROM AUTHOR]

This article discusses a quality improvement study conducted at Royal Victoria Hospital and Belfast City Hospital in Belfast, Northern Ireland. The study aimed to assess the effectiveness of a short learning module on Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) for endoscopy nurses. Pre- and post-module surveys were used to measure the self-reported improvement in nurse understanding of the diseases. The results showed a significant increase in knowledge confidence among the nurses after completing the module. The study concludes that the education module was effective in informing nurses about CJD and the reasons for implementing policies for at-risk patients. [Extracted from the article]

An interview with Jeffrey Whitsett, neonatologist and pulmonary biologist at the Cincinnati Children's Hospital in Ohio, is presented. Whitsett talks about his decision to go to medical school and to pursue pulmonary biology and neonatology. He discusses continuous positive airway pressure (CPAP), calcium signaling and placentral biology, and his role in the early days of surfactant replacement therapy.

Following the bovine spongiform encephalopathy (BSE) in 2001, processed animal proteins (PAPs) reintroduction is envisaged in non-ruminant feed thanks to their high protein content, easy availability and cost-effective characteristics. PAPs must be submitted to rendering practices, providing sterilization of products, under standardized conditions of temperature and pressure, according to Regulation (EC) No 142/2011. However, the chemical risk associated to these raw materials has been never evaluated. The aim of this study was to develop and validate a reliable liquid chromatography tandem mass spectrometry (LC–MS/MS) method for the determination and quantification of tetracycline residues in PAPs at µg kg−1 level. The LC–MS/MS method performances were evaluated in terms of specificity, linearity (25–500 µg kg−1), limit of quantitation (LOQ) (25 µg kg−1), accuracy and precision (CV% < 25%), uncertainty, recovery (80–120%) and ruggedness. All the evaluated parameters fulfilled the analytical performance criteria, and the validated LC–MS/MS method fits for purpose as confirmatory method on the occurrence of residues (µg kg−1) of tetracyclines in PAPs. PAPs are a powerful product which could be used both as raw materials in feed and in organic fertilizer production in a circular economy context. Therefore, the lack of regulation and control over antibiotic occurrence should be implemented to avoid a misuse and an increment of antibiotic resistance pressure over the environment and to ensure safety of the feed and food chain. [ABSTRACT FROM AUTHOR]

To reduce the transmission risk of bovine spongiform encephalopathy prions (PrPBSE), specified risk materials (SRM) that can harbour PrPBSE are prevented from entering the feed and food chains. As composting is one approach to disposing of SRM, we investigated the inactivation of PrPBSE in lab-scale composters over 28 days and in bin composters over 106–120 days. Lab-scale composting was conducted using 45 kg of feedlot manure with and without chicken feathers. Based on protein misfolding cyclic amplification (PMCA), after 28 days of composting, PrPBSE seeding activity was reduced by 3–4 log10 with feathers and 3 log10 without. Bin composters were constructed using ~ 2200 kg feedlot manure and repeated in 2017 and 2018. PMCA results showed that seeding activity of PrPBSE was reduced by 1–2 log10 in the centre, but only by 1 log10 in the bottom of bin composters. Subsequent assessment by transgenic (Tgbov XV) mouse bioassay confirmed a similar reduction in PrPBSE infectivity. Enrichment for proteolytic microorganisms through the addition of feathers to compost could enhance PrPBSE degradation. In addition to temperature, other factors including varying concentrations of PrPBSE and the nature of proteolytic microbial populations may be responsible for differential degradation of PrPBSE during composting. [ABSTRACT FROM AUTHOR]

This research was organized in order to reveal people's organic plant and animal production, product, information, and consumption habits. In this study, a survey was applied to 399 people. In the study, while 95.0% of the participants knew about organic agriculture, 5.0% reported that they had no information. Do you think the food consumed is safe? The most frequently answered question was sometimes (33.8%), and the rate of those who answered no was 15.3%. They stated that the most important food risk was chemicals (60.4%), GMOs, mad cow disease, and radiation applications, and the least amount (16.0%) was microorganisms. Considering the rate of those who read the labels on the food, 55.1% answered sometimes; 4.5% stated that they have never read. When asked whether organic food is more reliable, 77.9% replied yes. It was determined that 80.2% of the participants consumed organic products. When consumers were asked what their reasons were for not buying organic products, 55.9% said they did not trust that it was organic, 12.8% did not believe that it would bring any additional benefit, and 9.8% said it had a high price. Participants stated that they had heard of the concept of organic feed (84.2%) before, and that the conditions of the shelter affected the quality of animal products (97.5%). It has been observed that the participants are willing to pay more for organic, reliable, and healthy products (78.7%), and they pay attention to being a well-known brand (82.0%) when buying organic animal products. [ABSTRACT FROM AUTHOR]

In 2008, the South Korean government decided to resume importing beef from the United States, which had been stopped since 2003. The government's attempt to reassure citizens with scientific claims met severe resistance, resulting in a whirlwind of political and technoscientific controversies over risks of bovine spongiform encephalopathy (BSE). This article examines memories of protests in 2008 with two objectives; first, to discuss how sub-politics evolves when matters of concern become matters of fact and second, to better understand the aftermath of Korean BSE controversies. Thirty-eight semi-structured interviews with proponents and opponents of the BSE protests were conducted in 2019 and analyzed. Focusing on the complicated discursive struggles over science, society, and their relations, we demonstrated that, along with what people widely accept as the "facts" about US beef, a modern imaginary of science and politics as two separate spheres was reconstructed in Korea. [ABSTRACT FROM AUTHOR]

Establishing a system of Networks of organisations operating in the fields within EFSA's mission is among the tasks of EFSA, according to Regulation (EC) No 178/2002, in order to facilitate a scientific cooperation framework by the coordination of activities, the exchange of information, the development and implementation of joint projects, the exchange of expertise and best practices. The EFSA Scientific Network on bovine spongiform encephalopathies and other transmissible spongiform encephalopathies (BSE‐TSE) was established in 2006 and held its 17th annual meeting on 13‐14 October 2022, as a hybrid meeting. The meeting served as an opportunity to exchange scientific information on BSE‐TSE related issues among EU Member States, countries from the European Free Trade Association, EU candidate countries, EFSA, the European Commission (EC) and ad hoc participants [in the 2022 meeting, represented by the World Organisation for Animal Health (WOAH)]. The topics discussed included: update on the situation and surveillance of CWD in North America and Norway, the molecular characterization of emergent CWD strains in Europe, the impact of feed ban on L‐BSE, the history experimental models using non‐human primates assessing transmissibility, pathogenesis and resistance of prions, a online real‐time pulse survey on the network and TSE in Europe, recent and ongoing activities on TSE of EFSA, WOAH and EC, as well as the preliminary results of the 2021 EU TSE summary report. [ABSTRACT FROM AUTHOR]

The role of the glycosylation status of PrPC in the conversion to its pathological counterpart and on cross-species transmission of prion strains has been widely discussed. Here, we assessed the effect on strain characteristics of bovine spongiform encephalopathy (BSE) isolates with different transmission histories upon propagation on a model expressing a non-glycosylated human PrPC. Bovine, ovine and porcine-passaged BSE, and variant Creutzfeldt-Jakob disease (vCJD) isolates were used as seeds/inocula in both in vitro and in vivo propagation assays using the non-glycosylated human PrPC-expressing mouse model (TgNN6h). After protein misfolding cyclic amplification (PMCA), all isolates maintained the biochemical characteristics of BSE. On bioassay, all PMCA-propagated BSE prions were readily transmitted to TgNN6h mice, in agreement with our previous in vitro results. TgNN6h mice reproduced the characteristic neuropathological and biochemical hallmarks of BSE, suggesting that the absence of glycans did not alter the pathobiological features of BSE prions. Moreover, back-passage of TgNN6h-adapted BSE prions to BoTg110 mice recovered the full BSE phenotype, confirming that the glycosylation of human PrPC is not essential for the preservation of the human transmission barrier for BSE prions or for the maintenance of BSE strain properties. Author summary: Bovine spongiform encephalopathy (BSE), publicly known as "mad cow disease", is a neurodegenerative disorder affecting cattle, caused by unconventional agents called prions. BSE can naturally transmit to human beings, producing the variant form of Creutzfeldt-Jakob disease (vCJD), which caused an unprecedented health and economic crisis in the UE. Prions are composed of PrPSc, a misfolded form of the cellular protein PrPC, which can be variably glycosylated by conjugation with sugar molecules at two positions of its sequence. Several studies reported the role of PrPC-attached sugars on important aspects of prion biology, such as the existence of different prion strains. Here, we demonstrate that it is possible to propagate BSE prions (from different animal and human sources) in a non-glycosylated human PrPC environment without loss of their strain properties. Different BSE isolates were successfully transmitted to a transgenic mouse model expressing non-glycosylated human PrPC, and these animals manifested neuropathological and biochemical signs compatible with BSE. To definitely prove the maintenance of the strain, non-glycosylated BSE prions were transmitted to their original host: transgenic mice expressing cattle PrPC. These animals recovered the full BSE phenotype, confirming that the glycosylation of human PrPC is not relevant for the propagation of this particular prion strain. [ABSTRACT FROM AUTHOR]

Against the background of the scandals regarding the contamination of food with dioxin and nitrophenol, the Bovine spongiform encephalopathy (BSE - "mad cow" disease), the avian and swine flu, the infection of some vegetables with the enterohemorrhagic strain of the bacterium Esterichia coli (EHEC), as well as the fears regarding the use of genetically modified organisms, the request of agricultural products and ecological food increased a lot at the beginning of this millennium. An opportunity for the transition from subsistence agriculture to an agriculture based on economic principles is represented by systems of exploiting poultry on the ground, with free access to outdoor paddocks, as well as ecological growth. In this context, the present paper tries to bring to the fore some opportunities in the organic breeding of some poultry with a special taste, such as capons. The main objectives followed were: some historical landmarks regarding the growth of capons; the review of the practical elements of capon growing and some case studies that show the opportunity of capon growing in Romania for a successful business. The used methods included searching of the various databases with the latest publications in the field and identification of some relevant results. The breeding of capons represents an opportunity for Romanian farmers who want a profitable business, especially since currently, in Romania, the number of such micro-farms is very limited. [ABSTRACT FROM AUTHOR]

The globalisation of food and agricultural trade has brought issues of food safety and biosecurity to the centre of geopolitical research. This paper explores the relationship between food risks and sovereignty practices, a topic that has received relatively scant attention in the scholarship. Going beyond conventional conceptualisations of sovereignty as an external-legal notion that is delimited to the realm of 'high politics' in international relations, this paper points to how it is also expressed and negotiated in quotidian practices of food import and consumption, and how this has contributed to the politicisation of food safety. Focusing on the case of Taiwan, a de facto island state with contested sovereignty status, and comparing the food safety discourses that arose during the outbreaks of Mad Cow Disease and African Swine Fever, we argue that food risks provide opportunities for social and political actors to participate in the everyday construction of sovereignty. While the Taiwanese government's handling of the Mad Cow Disease shows it to be ultimately constrained by the geopolitical reality of fragile sovereignty, the outbreak of African Swine Fever enabled it to legitimise the securitisation of borders and bolster its legitimacy by staging collective defensive actions against perceived external risks. By drawing attention to how sovereignty is produced and performed through practice, this paper further advances recent discussions of sovereignty as a dynamic, social process. [ABSTRACT FROM AUTHOR]

Conformational conversion of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases. However, the conversion mechanism remains to be elucidated. Here, we generated Tg(PrPΔ91-106)-8545/Prnp0/0 mice, which overexpress mouse PrP lacking residues 91-106. We showed that none of the mice became sick after intracerebral inoculation with RML, 22L, and FK-1 prion strains nor accumulated PrPScΔ91-106 in their brains except for a small amount of PrPScΔ91-106 detected in one 22L-inoculated mouse. However, they developed disease around 85 days after inoculation with bovine spongiform encephalopathy (BSE) prions with PrPScΔ91-106 in their brains. These results suggest that residues 91-106 are important for PrPC conversion into PrPSc in infection with RML, 22L, and FK-1 prions but not BSE prions. We then narrowed down the residues 91-106 by transducing various PrP deletional mutants into RML- and 22L-infected cells and identified that PrP mutants lacking residues 97-99 failed to convert into PrPSc in these cells. Our in vitro conversion assay also showed that RML, 22L, and FK-1 prions did not convert PrPΔ97-99 into PrPScΔ97-99, but BSE prions did. We further found that PrP mutants with proline residues at positions 97 to 99 or charged residues at positions 97 and 99 completely or almost completely lost their converting activity into PrPSc in RML-and 22L-infected cells. These results suggest that the structurally flexible and noncharged residues 97-99 could be important for PrPC conversion into PrPSc following infection with RML, 22L, and FK-1 prions but not BSE prions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Most of the 233 worldwide cases of variant Creutzfeldt–Jakob disease (vCJD) have been reported in the United Kingdom and 3 have been associated with transfusion‐transmission. To mitigate the potential vCJD risk to blood safety, Australian Red Cross Lifeblood imposes restrictions on blood donation from people with prior residency in, or extended travel to, the United Kingdom during the risk period 1980–1996. We have modified a previously published methodology to estimate the transfusion‐transmission risk of vCJD associated with fresh component transfusion in Australia if the UK residence deferral was removed. Materials and Methods: The prevalence of current pre‐symptomatic vCJD infection in the United Kingdom by age at infection and genotype was estimated based on risk of exposure to the bovine spongiform encephalopathy agent for the period 1980–1996. These results were used to estimate the age‐specific prevalence of undiagnosed, pre‐symptomatic vCJD in the Australian population in the current year due to prior UK residency or travel. The primary model outputs were the 2020 vCJD risks/unit of vCJD contamination, transfusion‐transmission (infections) and clinical cases. Results: The overall (prior UK residency in and travel to United Kingdom, 1980–1996) mean risk of contamination per unit was 1 in 29,900,000. The risks of resulting vCJD transmission (infection) and clinical case were 1 in 389,000,000 and 1 in 1,450,000,000, respectively. Conclusion: Our modelling suggests that removing the Lifeblood donation deferral for travel to, or UK residence, would result in virtually no increased risk of vCJD transfusion‐transmission and would be a safe and effective strategy for increasing the donor base. [ABSTRACT FROM AUTHOR]

The article focuses on scrapie that is one of secrecy, mystery and progress and with the first known scrapie report dated nearly 300 years ago, many theories on origin, transmission, and relatedness to other neurodegenerative diseases have been proposed and consequently disproved. Topics include considered the scrapie learning curve has since been steep, but great leaps have brought us closer to identifying its etiology.

The red meat industry has some social and economic functions. Policies for the aforesaid sector are important in terms of their impact on the relevant product group, national economies, and the healthy and balanced diet of people in the context of the accessibility of product prices. At this point, it is important to examine the supply and demand, prices and import decisions of red meat with a holistic approach. Red meat industry is affected by changes in processes of import decisions, meat prices, meat production amount etc. The aim of this study is to examine the red meat sector in Turkey in the period of 2003-2019. In the study, red meat supply-demand, price formation and import are examined graphically based on red meat production, consumption, price and import indicators. In this context, it can be said that to regulate meat import in a way that does not make sector dependent on imports, to take measures to maintain the quality standard, to take steps to revive the red meat sector in Turkey, to increase the measures required to prevent the diseases such as mad cow that the sector in question is facing, and also, manufacturers' access to training on the subject are important factors for the sector. [ABSTRACT FROM AUTHOR]

The hydrogenation reaction provided compound B 3 b (5 -H, major) and its isomer B 3' b (5 -H, minor) and the ratio (confirmed by SP 1 sp H NMR) was poor (84:16, Table 1, entry 1). The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate (3:1)) to give compound B 4 b and its 3 -OH isomer B 4' b ( B 4 b : B 4' b = 19:1). Compound B 2 b was prepared by a Wittig reaction in 98% yield and its double bond showed a single I trans i stereoisomer, based on SP 1 sp H NMR and SP 13 sp C NMR data. Cholesterol is metabolized to primary bile acids (BAs), such as cholic acid and chenodeoxycholic acid, by cytochrome P450 in the liver. [Extracted from the article]

• Mitochondria are paramount to central nervous system health and maintenance. • Mitochondrial capacity is compromised in prion diseases. • Mitochondria dysfunction exacerbates the progression and severity of prion diseases. • Mitochondria-targeted antioxidants in prion models have shown promising results. • Mitochondrial transplant may help to develop promising therapeutic options. Prion diseases encompass a group of incurable neurodegenerative disorders that occur due to the misfolding and aggregation of infectious proteins. The most well-known prion diseases are Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (also known as mad cow disease), and kuru. It is estimated that around 1–2 persons per million worldwide are affected annually by prion disorders. Infectious prion proteins propagate in the brain, clustering in the cells and rapidly inducing tissue degeneration and death. Prion disease alters cell metabolism and energy production damaging mitochondrial function and dynamics leading to a fast accumulation of damage. Dysfunction of mitochondria could be considered as an early precursor and central element in the pathogenesis of prion diseases such as in sporadic CJD. Preserving mitochondria function may help to resist the rapid spread and damage of prion proteins and even clearance. In the war against prions and other degenerative diseases, studying how to preserve the function of mitochondria by using antioxidants and even replacing them with artificial mitochondrial transfer/transplant (AMT/T) may bring a new hope and lead to an increase in patients' survival. In this perspective review, we provide key insights about the relationship between the progression of prion disease and mitochondria, in which understanding how protecting mitochondria function and viability by using antioxidants or AMT/T may help to develop novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Prion diseases are transmissible spongiform encephalopathies caused by deleterious prion protein (PrPSc) derived from normal prion protein (PrPC), which is encoded by the prion protein gene (PRNP). We performed an in‐depth examination to detect PrPSc by using enzyme immunoassay (EIA), real‐time quaking‐induced conversion reactions (RT‐QuIC) and protein misfolding cyclic amplification (PMCA) in nine brain tissues derived from three Holstein cattle carrying the E211K somatic mutation of the bovine PRNP gene. The EIA, RT‐QuIC and PMCA analyses were not able to detect the PrPSc band in any tested samples. To the best of our knowledge, this report is the first to describe an in‐depth examination of PrPSc in cattle carrying the E211K somatic mutation of the bovine PRNP gene. [ABSTRACT FROM AUTHOR]

Since 2004, a novel bovine spongiform encephalopathy (BSE), distinct from the conventional 'classical BSE' (C‐BSE), has been reported as an atypical BSE. Atypical BSE is detected mostly in aged cattle, and it is suggested that atypical BSE may occur spontaneously. Relaxation of the relevant countermeasures such as feed ban, which prevents the use of bovine meat‐and‐bone meal as feed, has been discussed in recent years owing to the decrease in C‐BSE cases. If atypical BSE occurs spontaneously without exposure to an agent called abnormal prion protein (PrPSc), complete removal of these measures will be difficult. In this study, we verified the possibility that L‐BSE, which is a subtype of atypical BSE, occurs spontaneously. We first hypothesized that L‐BSE occurs only through the process of infection via oral exposure. If the hypothesis was true, the infection of L‐BSE would be mostly limited to calves under 1 year of age due to their high susceptibility, and the feed ban would effectively reduce the number of infected calves by birth cohort. Thus, we created a mathematical model to estimate the number of infected calves by birth cohort and compared the effectiveness of the feed ban on C‐BSE and L‐BSE. The number of tested animals and detected cases in nine European countries were used for this analysis. Our results showed that the estimated number of infected calves in the birth cohort indicated that feed ban was less effective on L‐BSE. This result supports the alternative hypothesis that at least a part of the L‐BSE can occur without infection via oral exposure. Our results suggest that the complete abolition of countermeasures, such as feed ban, should be discussed carefully. As for the occurrence mechanism, although there remains uncertainty to reach conclusions, it is reasonable to assume that L‐BSE can occur spontaneously at present. [ABSTRACT FROM AUTHOR]

The article focuses on the essential role of supplementary feeding stations (SFS) in Bulgaria, highlighting their history, regulatory compliance, and impact on vulture conservation, with recent efforts to establish a network of local feeding sites (LFS) for enhanced conservation measures.

Infectious prion diseases have very long incubation periods, and the role that subclinical infections play in transmission, persistence and re-emergence of these diseases is unclear. In this study, we used a well-established model of vCJD (sheep experimentally infected with bovine spongiform encephalopathy, BSE) to determine the prevalence of subclinical infection following exposure by blood transfusion from infected donors. Many recipient sheep survived for years post-transfusion with no clinical signs and no disease-associated PrP (PrPSc) found in post mortem tissue samples by conventional tests. Using a sensitive protein misfolding cyclic amplification assay (PMCA), we found that the majority of these sheep had detectable PrPSc in lymph node samples, at levels approximately 105–106 times lower than in equivalent samples from clinically positive sheep. Further testing revealed the presence of PrPSc in other tissues, including brain, but not in blood samples. The results demonstrate that subclinical infection is a frequent outcome of low dose prion infection by a clinically relevant route for humans (blood transfusion). The long term persistence of low levels of infection has important implications for prion disease control and the risks of re-emergent infections in both humans and animals. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies (TSE), caused by abnormal prion protein (PrPSc), affect many species. The most classical scrapie isolates harbor mixtures of strains in different proportions. While the characterization of isolates has evolved from using wild-type mice to transgenic mice, no standardization is established yet. Here, we investigated the incubation period, lesion profile and PrPSc profile induced by well-defined sheep scrapie isolates, bovine spongiform encephalopathy (BSE) and ovine BSE after intracerebral inoculation into two lines of ovine PrP (both ARQ/ARQ) overexpressing transgenic mice (Tgshp IX and Tgshp XI). All isolates were transmitted to both mouse models with an attack rate of almost 100%, but genotype-dependent differences became obvious between the ARQ and VRQ isolates. Surprisingly, BSE induced a much longer incubation period in Tgshp XI compared to Tgshp IX. In contrast to the histopathological lesion profiles, the immunohistochemical PrPSc profiles revealed discriminating patterns in certain brain regions in both models with clear differentiation of both BSE isolates from scrapie. These data provide the basis for the use of Tgshp IX and XI mice in the characterization of TSE isolates. Furthermore, the results enable a deeper appreciation of TSE strain diversity using ovine PrP overexpressing transgenic mice as a biological prion strain typing approach. [ABSTRACT FROM AUTHOR]

Early in this century, the crisis connected to the spread of bovine spongiform encephalopathy caused a great concern related to the use of animal by-products (ABPs). According to the Commission Regulation (EU) No 1069/2009, these materials are classified in three categories according to their related risk. In 2011 Commission Regulation (EU) No 142/2011 established that meat and bone meal (MBM) and fat deriving from ABPs not intended for human consumption (category 1 and 2) are required to be permanently marked with glyceroltriheptanoate (GTH), at a minimum concentration of 250 mg kg–1 of fat, while category 3 processed animal proteins (PAPs) must not contain this compound. PAPs are bio resources, which could be used in a renewable and regenerative way in a circular economy model for a conscious usage of raw materials. The aim of this study was to provide information on GTH occurrence in MBM and, if any, in PAPs. Samples were collected from 2017 to 2021 and analysed by GC-MS. Detected non-compliant samples were exclusively of MBM category 1 and 2, probably due to the addition of an inadequate amount of GTH during the manufacturing processes. These results highlighted the importance of National Monitoring Programs as a useful tool to minimise safety related risk due to the misuse of GTH. Thus, investigating the critical points in feed supply-chain and sharing the information on its occurrence may help to improve animal and human wellness and safety. [ABSTRACT FROM AUTHOR]

Background: Human prion diseases, including Creutzfeldt-Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence.Methods: We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80-120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls.Findings: We treated six patients (two men; four women) with CJD for 7-260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22-70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66-182 nM).Interpretation: Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure.Funding: The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC. [ABSTRACT FROM AUTHOR]