Variant Creutzfeldt-Jacob Disease Research Articles

Single nucleotide polymorphisms of the prion protein gene (PRNP) in Chinese pig breeds

Prion diseases (transmissible spongiform encephalopathies, TSE), as a group of fatal neurodegenerative diseases, have affected humans and a variety of other mammals. Although no natural TSE have been documented in pigs, appropriate precautions need to be taken to prevent the iatrogenic spread of prion disease through pig-to-human xenotransplantation. Polymorphisms within the open reading frame (ORF) of the single-copy gene of prion protein (PRNP) are associated with susceptibility to scrapie in sheep and variant Creutzfeldt-Jacob disease in humans. We screened polymorphisms in the PRNP gene of 64 China Experimental Minipigs and Beijing Large White pigs. Our findings suggest that the porcine PRNP gene is highly homogenous. The amino acid sequences of the mature prion protein of all samples tested were identical. Four single nucleotide polymorphisms (G11A, G615C, G684A, T726G) in the ORF of the porcine PRNP gene were found, and the G-->C nucleotide substitution resulted in a serine to asparaginate amino acid substitution at codon 4. We conclude that pigs raised under specific pathogen-free conditions, with the exclusion of rendered mammalian material for at least two generations, will have little risk of being infected with a TSE, and even less possibility of transmitting prion disease to humans through xenotransplantation.

Metal microcrystal pollutants; the heat resistant, transmissible nucleating agents that initiate the pathogenesis of TSEs?

This paper exposes the flaws in the conventional consensus on the origins of transmissible spongiform encephalopathies (TSEs) which decrees that the protein-only misfolded 'prion' represents the primary aetiological transmissible agent, and then reviews/presents the emerging data which indicates that environmental exposure to metal microcrystal pollutants (sourced from munitions, etc.) represents the heat resistant, transmissible nucleating agents which seed the metal-prion protein (PrP)-ferritin fibril crystals that cause TSE. Fresh analytical data is presented on the levels of metals in ecosystems which support populations affected by clusters of variant Creutzfeldt-Jacob disease (vCJD), sporadic/familial CJD, and the scrapie types of TSE that have emerged in the UK, Sicily, Sardinia, Calabria and Japan. This data further substantiates the abnormal geochemical template (e.g., elevated strontium (Sr), barium (Ba) and silver (Ag)) which was observed as a common hallmark of the TSE cluster ecosystems across North America, thereby supporting the hypothesis that these microcrystals serve as the piezoelectrion nucleators which seed the growth/multireplication of the aberrant metal-PrP-ferritin fibril features which characterise the neuropathology of the TSE diseased brain. A secondary pathogenic mechanism entails the inactivation of the sulphated proteoglycans which normally regulate the mineralisation process. This can be induced by a rogue metal mediated chelation of free sulphur, or by contamination with organo-sulphur pollutants that substitute at natural sulphur bonds, or via a mutation to the S-proteoglycan cell line; thereby enabling the aberrant overgrowth of rogue fibril crystal formations that possess a piezoelectric capacity which compromises the ability of the contaminated individual to process incoming acoustic/tactile pressure waves in the normal way. The crystals transduce incoming sonic energy into electrical energy, which, in turn, generates magnetic fields on the crystal surfaces that initiate chain reactions of free radical mediated spongiform neurodegeneration. Metal microcrystal nucleating agents provide a group of plausible aetiological candidates that explain the unique properties of the TSE causal agent - such as heat resistance, transmissibility, etc. - which the protein-only prion model fails to fulfill. This paper also discusses the possible nutritional measures that could best be adopted by populations living in high risk TSE ecosystems; as a means of preventing the successful implantation of these rogue microcrystals and their consequent hypermineralisation of the soft tissues within the CNS.

Fashion of the times. The emergence and evolution of new research fields is as much determined by scientific interest as it is by social, political and economic pressures.

Originally coined by social scientists as a term used to describe changes in industrialized countries at the end of the twentieth century, the ‘knowledge society’—in which knowledge and creativity are principal factors for economic and social development—has become the new catchphrase in political, scientific and economic circles. Its popularity might come from its optimism—after all, what is bad about knowledge? However, its widespread use also reflects the growing influence of science on almost every aspect of society, be it health care, reproduction, economics, politics or justice. Yet this is not a one‐way relationship: science, as the most important producer of knowledge, has also come under scrutiny. Society increasingly expects science to tackle problems in all areas, relies on scientists in decision‐making processes and takes a more critical view—not just in the negative sense—of the social relevance of research. “Science and business have been intertwined at least since the nineteenth century,” said Peter Weingart, Director of the Institute for Science and Technology Studies (IWT) at the University of Bielefeld, Germany. “The new aspect of today's debates is that the intensity of this interconnection is increasing and the growth of science plays an important role in this process.” Science is under increasing pressure to leave its ivory tower and have a greater role in society. This raises some important questions. Does the pressure to find a cure for a disease, or to find clear answers to questions about risk, influence the way in which scientists work? What role do commercial interests have in defining new areas of research? What is the fate of new and established research fields once public or commercial interest and funding fade? “When decisions on research topics are based on where you gain the greatest market advantage rather than based on a theoretical framework, this changes the whole …

Epidemiological evidence of higher susceptibility to vCJD in the young.

BackgroundThe strikingly young age of new variant Creutzfeldt-Jacob disease (vCJD) cases remains unexplained. Age dependent susceptibility to infection has been put forward, but differential dietary exposure to contaminated food products in the UK population according to age and sex during the bovine spongiform encephalopathy (BSE) epidemic may provide a simpler explanation.MethodsUsing recently published estimates of dietary exposure in mathematical models of the epidemiology of the new variant Creutzfeldt Jacob disease (vCJD), we examine whether the age characteristics of vCJD cases may be reproduced.ResultsThe susceptibility/exposure risk function has likely peaked in adolescents and was followed by a sharp decrease with age, evocative of the profile of exposure to bovine material consumption according to age. However, assuming that the risk of contamination was proportional to exposure, with no age dependent susceptibility, the model failed to reproduce the observed age characteristics of the vCJD cases: The predicted cumulated proportion of cases over 40 years was 48%, in strong disagreement with the observed 10%. Incorporating age dependent susceptibility led to a cumulated proportion of cases over 40 years old of 12%.ConclusionsThis analysis provides evidence that differential dietary exposure alone fails to explain the pattern of age in vCJD cases. Decreasing age related susceptibility is required to reproduce the characteristics of the age distribution of vCJD cases.

P3-359 Activation of mitogen-activated protein kinases (MAPKS) in hamster brains infected with 263K scrapie agent

Transmission studies in transmissible spongiform encephalopathies (TSEs) have become increasingly important due to the possible transmission of bovine spongiform encephalopathy to humans resulting in new variant Creutzfeldt–Jacob disease. The horizontal transmission of scrapie, a TSE of sheep, is poorly understood. Possible sources of horizontal transmission are the submandibular and parotid salivary glands. TSEs like natural sheep scrapie are characterized by the conversion of a normal protease sensitive prion protein, PrPc, to an abnormal protease resistant prion protein, PrPSc. Since the presence of PrPSc is an indicator of disease, the salivary glands of scrapie-infected sheep were examined for the presence of PrPSc. Although PrPc mRNA was detected in the salivary glands, PrPSc was not found in the salivary glands of scrapie-infected sheep. These data suggest that the salivary glands are unlikely sources of horizontal transmission of natural sheep scrapie.

Management of a CJD case. Part 1. Preoperative organisation of the case.

Recent years have seen the rise of variant Creutzfeldt-Jacob Disease (vCJD), causing great concern amongst the public at large and healthcare professionals, and the implications of the disease are still to be properly determined. In this, the first of two articles, Beverley McNeil outlines the various risk categories of CJD patients, the planning of the case and the handling of associated instrumentation postoperatively. Next month's article will deal with the practicalities surrounding management of the case.

Clinical strategies to avoid blood transfusion

Reducing the exposure to allogenic blood products has important clinical, ethical and cost implications. Serious hazards of transfusion (SHOT) continue to be reported (Figure 1), of which the most important are incompatible reactions due to human error and acute transfusion reactions, followed by transfusion-related graft-versus-host reaction and acute lung injuries. The National Blood Service (NBS) for England and North Wales issues about 2.9 million units of blood annually of which 50% are used perioperatively. The theoretical potential for blood transmission of new variant Creutzfeldt-Jacob disease (nvCJD) has recently placed new demands on the NBS: • in 1998 the NBS introduced leucodepletion of all donor blood • plasma for children born after 1996 is imported • the donor pool may be reduced by 10-50% when the nvCJD blood screening test is introduced, further jeopardizing the national blood supply • the total costs are over £150,000,000.

Molecular-Imaging Probe 2-(1-{6-[(2-Fluoroethyl)(Methyl) Amino]-2-Naphthyl}Ethylidene) Malononitrile Labels Prion PlaquesIn Vitro

The study aimed to evaluate the fluorescent molecular-imaging probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile (FDDNP) for its ability to selectively and reproducibly label prion plaques in fixed, paraffin-embedded cerebellar sections from patients of confirmed Gerstmann-Sträussler-Scheinker disease, sporadic Creutzfeldt-Jacob disease (CJD) with kuru plaques, and variant CJD (vCJD). FDDNP is a highly hydrophobic, viscosity-sensitive, solvent-sensitive, fluorescent substance, whose radiofluorinated analog [18F]FDDNP has recently been successfully used to label senile plaques and neurofibrillary tangles in the living brain of Alzheimer's disease patients with positron emission tomography. Our results show that FDDNP reliably identifies all prion plaques, including small cluster-plaques in vCJD. This finding may open new in vivo diagnostic possibilities for vCJD.

The pathophysiology of variant Creutzfeldt-Jacob disease: the hypotheses behind concerns for blood components and products.

The pathophysiology of variant Creutzfeldt-Jacob disease: the hypotheses behind concerns for blood components and products.

Malnutrition as the cause of variant Creutzfeldt-Jacob disease

The evidence used to support the hypothesis that variant Creutzfeldt-Jacob disease (vCJD) is caused by eating meat from cattle infected with bovine spongiform encephalopathy (BSE) is unconvincing. It is postulated in this paper that the morphological symptoms of both diseases are caused by high concentrations of intracellular calcium (Ca 2+); that in cattle the problem results from the ingestion of grass that contains mycotoxins, and in humans it results from the consumption of a diet abnormally low in protein.

A new dimension to the vCJD epidemic: multiple QTL

In 1996, fears emerged that the human prion disease variant Creutzfeldt-Jacob Disease (vCJD) might correspond to infection with the agent of bovine spongiform encephalopathy (BSE). Research has since confirmed that BSE is likely to have caused vCJD through alimentary contamination. Approximately a million contaminated cattle are thought to have entered the human food chain and, consequently, a major future epidemic of vCJD is predicted.

A new dimension to the vCJD epidemic

In 1996, fears emerged that the human prion disease variant Creutzfeldt-Jacob Disease (vCJD) might correspond to infection with the agent of bovine spongiform encephalopathy (BSE). Research has since confirmed that BSE is indeed likely to have caused vCJD through alimentary contamination. Approximately one million contaminated cattle are thought to have entered the human food chain and, consequently, a major future epidemic of vCJD is predicted.

Does an ultra violet photooxidation of the manganese-loaded/copper-depleted prion protein in the retina initiate the pathogenesis of TSE?

Ecosystems supporting clusters of sporadic transmissible spongiform encephalopathy (TSE) are characterized by common properties of high-manganese/low-copper, zinc, selenium mineral status, and high-altitude/snow-covered/pre-cambrian mountain terrain where above-average intensities of ultra violet/ozone oxidants are prevalent. Cell culture trials have confirmed the hypothesis that manganese (Mn) substitutes at Prion Protein’s (PrP’s) vacated copper (Cu) domain, whereupon PrP loses its Cu-mediated antioxidant function, transforming into a protease-resistant misfolded isoform that aggregates into fibril ‘tombstone’ structures – the key hallmark distinguishing TSE central nervous system (CNS) pathology. The cellular localisation of PrP suggests PrP serves a ‘front line’ contributory role in neutralizing radicals generated by incoming environmental oxidants, whilst an intensive expression of PrP messenger ribonucleic acid (mRNA) in the retina, melanocytes, epidermis, etc., suggests PrP performs a key antioxidant role as a ‘photooxidative shock absorber’; binding of porphyrin IX, Congo red and other photosensitisers to PrPc suggests PrPc serves as an integral associate of the porphyrin/melanin chromophore electron transfer chain; thereby serving as a quencher of singlet O2/superoxide generated by photoenergised chromophores/xeno photosensitisers. It is proposed that sporadic TSE pathogenesis is initiated in the retina of environmentally/genetically predisposed individuals via a two-stage chronic toxic process – Mn substitution at PrP’s Cu domain forming a stable Mn2+-PrP complex, followed by an ultra violet in situ photo-oxidization of the Mn2+ component; whereby the latent ‘Jekyll and Hyde’ capacity of the Mn2+-PrP conjugate is activated into the fully fledged, ‘infectious’ lethal auto-oxidizing, Mn3+-PrP ‘prion’ agent. Thus, PrPc’s Cu-mediated antioxidant function is replaced by a Mn3+-mediated autooxidant dysfunction. Could the UK’s increased loading of a cocktail of environmental oxidants that penetrated the CNS of the UK bovine (ultra violet microwaves/ozone/systemic cu-chelating insecticides) account for a more virulent Mn4+ mediated acceleration of the TSE degenerative process in Mn-contaminated/genetically predisposed individuals, manifesting as the widespread emergence of new-variant bovine spongiform encephalopathy (BSE)/variant Creutzfeldt–Jacob disease (VCJD)/FSE in younger mammals?

The impact of improved safety on maintaining a sufficient blood supply

The impact of improved safety on maintaining a sufficient blood supply is becoming an increasingly real issue facing the National Blood Service in England and North Wales. This paper shows the extent of the impact that safety measures can have on reducing collection levels, without making any value judgement on the safety criteria themselves. It demonstrates that underlying trends in collection are making it increasingly difficult to meet demand. Further potential restrictions, perhaps associated with variant Creutzfeldt-Jacob disease (vCJD), will require a reassessment of the safety–sufficiency trade-off. The analysis strongly suggests that continual enhancement of safety criteria, for both individual donor and patient benefit, will lead to insufficient supply to meet current levels of hospital demand. New approaches are needed to effectively manage blood throughout the supply chain, thereby ensuring sufficient supply.

Gastric acidity protects mice against infection after intragastric administration of the 139A strain of scrapie agent: The potential relevance for variant Creutzfeldt-Jacob disease

Gastric acidity protects mice against infection after intragastric administration of the 139A strain of scrapie agent: The potential relevance for variant Creutzfeldt-Jacob disease

Gastric acidity protects mice against infection after intragastric administration of the 139A strain of scrapie agent: The potential relevance for variant Creutzfeldt-Jacob disease

Gastric acidity protects mice against infection after intragastric administration of the 139A strain of scrapie agent: The potential relevance for variant Creutzfeldt-Jacob disease

Hindsight blinkers Britain's mad cow disease response.

The BSE Inquiry was set up in 1997 following the British government's admission that the so-called mad cow disease, bovine spongiform encepalopathy (BSE), might be transmissible from cows to humans. The remit was to look at events prior to this admission and find out what had happened and what lessons there were for the future. Chaired by a senior judge, Lord Phillips, the Inquiry took two and a half years to complete with 138 days of public evidence from 378 witnesses and cost £27 million. The report provides 167 recommendations and was published this fall.During the crisis there have been 180,000 confirmed cases of BSE in British cattle although up to 1 million may have been infected. While the incidence has fallen dramatically from its peak of around 3,500 per month in 1993, there remains uncertainty about the human consequences. More than 80 British people have died from a disease diagnosed as variant Creutzfeldt–Jacob disease (vCJD) linked to BSE, but the final tally is uncertain and estimates vary enormously. Although BSE has been mostly a British problem until now, cases are appearing in several other countries.

The Plain and the Ugly Prion Infected Neuronal Tissue in an Experimental Animal Model; An Electron Microscopic Study.

Abstract Transmissible encephalopathy of animals (scrapie and bovine spongiform encephalopathy) and of man (Creutzfeldt-Jacob disease, new variant Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinker disease and familial fatal insomnia) have been well characterized as progressive neurodegenerative diseases, often associated with spongiform degeneration, neuronal loss, reactive astrocytic gliosis and variable amyloid plaques, without any sign of an immune response or inflammatory infiltrates. Prion proteins are elements that propagate variability through multiple biologically active conformers of a host encoded sialoglycoprotein (PrPc). The agent responsible for transmissible encephalopathies is composed mainly, if not exclusively, of an isoform of PrP, designated PrPSc. Extensive information of post-mortem material has been described at the light microscopic level, where the emphasis has been on spongiform tissue and amyloid plaques. Our study provides ultrastructural observations of the central nervous system, specifically of degenerating neurons and their associated changes during the course of scrapie infection in a hamster model.

PrP c mRNA, but not PrP Sc is found in the salivary glands of scrapie-infected sheep

Transmission studies in transmissible spongiform encephalopathies (TSEs) have become increasingly important due to the possible transmission of bovine spongiform encephalopathy to humans resulting in new variant Creutzfeldt–Jacob disease. The horizontal transmission of scrapie, a TSE of sheep, is poorly understood. Possible sources of horizontal transmission are the submandibular and parotid salivary glands. TSEs like natural sheep scrapie are characterized by the conversion of a normal protease sensitive prion protein, PrP c, to an abnormal protease resistant prion protein, PrP Sc. Since the presence of PrP Sc is an indicator of disease, the salivary glands of scrapie-infected sheep were examined for the presence of PrP Sc. Although PrP c mRNA was detected in the salivary glands, PrP Sc was not found in the salivary glands of scrapie-infected sheep. These data suggest that the salivary glands are unlikely sources of horizontal transmission of natural sheep scrapie.

The risks of infection transmission by blood transfusion in England.

The review by Soldan and Barbara1 on the risks of infection transmission by blood transfusion is an interesting and comprehensive article. However, there is little reference of prion disease and...