Human vCJD Research Articles

Current perspectives on bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease

Bovine spongiform encephalopathy (BSE) clearly originated in the UK, where there have now been more than 180 000 cases. However, through the exportation of cattle and cattle-feed additives from the UK, BSE also became established to a lesser extent in other European countries. There is current concern that BSE might have been distributed more widely as a result of the exportation of cattle or BSE-infected feed or foodstuff not only from the UK but also from other European countries that later became affected. It is now recognized that the transmissible agent that causes BSE also causes a new variant form of Creutzfeldt-Jakob disease (vCJD) in humans, and the evidence for this is presented. This probably resulted from dietary exposure to the bovine agent, and the potential role of mechanically recovered meat is discussed. There is a brief discussion on the controversial issue of the nature of the causal agents of diseases like BSE and vCJD. Whether or not sheep or goats could have become infected with BSE, and whether they represent a human health hazard, is also debated. Finally, the question of the control of BSE, and consequently vCJD, is discussed with regard to the rigorous application of the relevant regulations.

Diagnosis and prevention of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease.

An outbreak of bovine spongiform encephalopathy (BSE) arose in the United Kingdom as a result of prions entering and being recycled through the ruminant food chain. Humans have since developed a variant form of Creutzfeldt-Jakob disease (vCJD), also mostly in the United Kingdom, that occurs in younger individuals and causes prominent psychiatric and/or behavioral manifestations early in disease. Laboratory studies now provide strong evidence that the causative agent of BSE in cattle and vCJD in humans share a common origin. Because of a lack of information regarding the incubation period of vCJD and the number of people who may have been exposed, the future scope of this disease remains unknown. Control of the current and any future outbreaks in cattle requires strict measures to prevent contamination of the animal food chain with prions of any species. Prevention of human exposure mandates the avoidance of neural tissue in all human foods.

HLA-DQ7 antigen and resistance to variant CJD.

Variant Creutzfeldt–Jakob disease (vCJD) in humans is caused by a bovine spongiform encephalopathy (BSE)-like prion strain, and so far about 100 of the many people exposed to BSE prions have developed the condition. Here we show that there is a significantly reduced frequency of the human leukocyte antigen (HLA) class-II type DQ7 in patients with vCJD, but not in those with classical CJD. This apparently protective genetic factor should aid differential diagnosis and may have important implications for understanding host susceptibility to infection by BSE prions, and the distinctive pathogenesis of vCJD, as well as in the identification of targets for prevention and therapy of vCJD.

Florid plaques in ovine PrP transgenic mice infected with an experimental ovine BSE.

The occurrence of the variant Creutzfeldt-Jakob disease (vCJD), related to bovine spongiform encephalopathy (BSE), raises the important question of the sources of human contamination. The possibility that sheep may have been fed with BSE-contaminated foodstuff raises the serious concern that BSE may now be present in sheep without being distinguishable from scrapie. Sensitive models are urgently needed given the dramatic consequences of such a possible contamination on animal and human health. We inoculated transgenic mice expressing the ovine PrP gene with a brain homogenate from sheep experimentally infected with BSE. We found numerous typical florid plaques in their brains. Such florid plaques are a feature of vCJD in humans and experimental BSE infection in macaques. Our observation represents the first description, after a primary infection, of this hallmark in a transgenic mouse model. Moreover, these mice appear to be a promising tool in the search for BSE in sheep.

Developments in microbiological risk assessment for drinking water.

1. SUMMARYThis paper considers the development of microbiologicalrisk assessment models for pathogenic agents in drinkingwater with particular reference to Cryptosporidium parvum,rotavirus and bovine spongiform encephalopathy (BSE).The available evidence suggests that there is potential forconsiderable variation in exposures to C. parvum oocyststhrough drinking water, during both outbreak and non-outbreak conditions. This spatial/temporal heterogeneityarises both from variation in oocyst densities in the rawwater and fluctuations in the removal efficiencies of drinkingwater treatment. In terms of risk prediction, modelling thevariation in doses ingested by individual drinking waterconsumers is not important if the dose–response curve islinear and the oocysts act independently during infection.Indeed, the total pathogen loading on the population asrepresented by the arithmetic mean exposure is sufficient forrisk prediction for C. parvum, BSE and other agents of lowinfectivity, providing the infecting particles (i.e. oocysts orBSE prions) are known to act independently. However, formore highly infectious agents, such as rotavirus, ignoring1. Summary, 1912. Introduction, 1922.1 Overview of the risk assessment approach, 1923. Pathogen exposures through drinking water, 1923.1 Pathogen exposures under non-outbreak condi-tions, 1933.1.1 Variation in micro-organism counts withinlarge volume samples, 1933.1.2 Effect of treatment on the spatial distribu-tion of micro-organisms, 1933.1.3 Implication for Cryptosporidium exposures todrinking water consumers under non-out-break conditions, 1953.2 A model for Cryptosporidium oocyst concentrationsin drinking water during an outbreak, 1964. Dose–response curves. Estimating the risk to humansfrom ingesting low pathogen doses, 1974.1 Cryptosporidium parvum, 1974.1.1 Experiments with salmonellas in mice suggestthat pathogens act independently and do notco-operate during infection, 1984.1.2 Acquired protective immunity for Cryptospo-ridium parvum, 1994.1.3 Virulence of different strains of Cryptospori-dium parvum, 1994.2 Human rotavirus, 1994.3 Bovine spongiform encephalopathy, 2004.3.1 The human oral ID

APs, GPs and vCJD

When modelling the growth of any quantity the two simplest models assume either constant growth (where the same amount of new material is added in every time period) or proportionate growth (where the amount of new material in a time period is proportionate to the amount of material already present). For discrete models these growth assumptions lead to, respectively, arithmetic progressions and geometric progressions. The analysis of these sequences is accessible to A level students. It is also a very simple matter to implement such models within a spreadsheet. This allows easy investigation of the models and their sensitivity to parameter values. In this paper we describe an investigation of the applicability of these models to the onset on vCJD in humans. One of the important features of this investigation is that it demonstrates how simple mathematical techniques can sometimes allow a surprisingly robust qualitative conclusion to be drawn using sparse initial data. Given the restricted mathematical techniques required, this makes a powerful introduction to the use of mathematical models, which can be studied during the first week of an undergraduate career.

A Preliminary Report on a Study of BSE in Cattle in Relation to Farm Husbandry: Its Possible Relevance to vCJD and Infertility Problems in Humans

Purpose: To discover any possible links between differing methods of animal husbandry and the occurrence of bovine spongiform encephalopathy (BSE). Design: A retrospective survey conducted by means of a written questionnaire followed up by telephone contact. Materials and Methods: The survey form asked for information on feed and feeding routines, milk yields, breeding problems, bulls used, trace element deficiencies and the use of agrochemicals and pharmaceuticals on the farm. It also asked for information on BSE animals, their dams, siblings and offspring. A database was created to absorb and analyse this information. Fifty-three farms completed survey forms. Of these, thirty-three ran dairy herds and the rest, suckler herds. Results: Husbandry of suckler herds was shown to be generally traditional in nature using far fewer chemicals than the followers of modern agricultural technology. No BSE was recorded in these herds, except in one bought-in animal. Husbandry of dairy herds varied from the highly te...

VCJD - predicting the future?

The recent emergence of variant Creutzfeldt-Jakob disease (vCJD) in the UK, and demonstration that vCJD is caused by the same prion strain that causes bovine spongiform encephalopathy, have led to concerns about the possibility of a human epidemic. Although only 79 cases of vCJD have occurred to date, it is likely that hundreds of thousands of infected cattle entered the human food chain in the late 1980s and early 1990s, and the average incubation period of vCJD is unknown. Mathematical models have not yet been able to give useful predictions of future numbers of cases, and in the absence of a blood test for vCJD, current attempts to reduce uncertainties about future numbers of cases are based on the accumulation of PrPSc in lymphoreticular tissues. Extensive lymphoreticular PrPSc accumulation has been seen in all cases of symptomatic vCJD so far examined, and in one case 8 months prior to the onset of symptoms. Animal models of prion disease suggest that lymphoreticular involvement occurs early in the incubation period and reliably predicts future neurological disease. Based on these data, large scale anonymous studies looking for PrP accumulation in surgically removed tonsillectomy and appendicectomy specimens are underway. Examination of the first 3000 specimens has not revealed any positive samples, but at the moment the significance of negative findings is uncertain. It is anticipated that by the time these studies are complete more data will be available on how early PrP can be demonstrated in lymphoreticular tissue in vCJD, which together with the results from examination of further samples, will allow some comment as to the likelihood of a large human vCJD epidemic.

BSE and transmission through blood

Whether the outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the UK will ultimately affect hundreds, or tens of thousands of people, cannot yet be predicted. 1 Ghani AC Ferguson NM Donnelly CA Anderson RM Predicted vCJD mortality in Great Britain. Nature. 2000; 406: 583-584 Crossref PubMed Scopus (179) Google Scholar If large numbers of apparently healthy people are now silently incubating infections with bovine spongiform encephalopathy (BSE), the implications for public health include the possiblity that blood from such individuals may be infectious. Established facts about infectivity in the blood of human beings and animals with transmissible spongiform encephalopathies (TSEs) are as follows: 2 Brown P Can Creutzfeldt-Jakob disease be transmitted by transfusion?. Curr Opin Hematol. 1995; 2: 472-477 Crossref PubMed Scopus (94) Google Scholar , 3 Brown P Cervenakova L McShane LM Barber P Rubenstein R Drohan WN Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion. 1999; 39: 1169-1178 Crossref PubMed Scopus (267) Google Scholar , 4 Rohwer RG. Titer, distribution, and transmissibility of blood-borne TSE infectivity. Presented at Cambridge Healthtech Institute 6th Annual Meeting “Blood Product Safety: TSE, Perception versus Reality”, MacLean, VA, USA, Feb 13–15, 2000. Google Scholar •Blood, especially the buffy-coat component, from animals experimentally infected with scrapie or CJD and from either a clinical or preclinical incubation phase, is consistently infectious when bioassayed by intracerebral or intraperitoneal inoculation into the same species; •In naturally infected animals (sheep and goats with scrapie, mink with transmissible mink encephalopathy, and cows with BSE), all attempts to transmit disease through the inoculation of blood have failed; •Blood from four of 37 human beings with clinically evident sporadic CJD has been reported to transmit the disease after intracerebral inoculation into guineapigs, mice, or hamsters. But each success has been questioned on technical grounds and has not been reproducible; and •Epidemiological data have not revealed a single case of CJD that could be attributed to the administration of blood or blood products among patients with CJD, or among patients with haemophilia and other congenital clotting or immune deficiencies who receive repeated doses of plasma concentrates. Transmission of BSE by blood transfusion in sheepWe have shown that it is possible to transmit bovine spongiform encephalopathy (BSE) to a sheep by transfusion with whole blood taken from another sheep during the symptom.free phase of an experimental BSE infection. BSE and variant Creutzfeldt-Jakob disease (vCJD) in human beings are caused by the same infectious agent, and the sheep-BSE experimental model has a similar pathogenesis to that of human vCJD. Although UK blood transfusions are leucodepleted—a possible protective measure against any risk from blood transmission—this report suggests that blood donated by symptom—free vCJD-infected human beings may represent a risk of spread of vCJD infection among the human population of the UK. Full-Text PDF

Transmission of BSE by blood transfusion in sheep

We have shown that it is possible to transmit bovine spongiform encephalopathy (BSE) to a sheep by transfusion with whole blood taken from another sheep during the symptom-free phase of an experimental BSE infection. BSE and variant Creutzfeldt-Jakob disease (vCJD) In human beings are caused by the same infectious agent, and the sheep-BSE experimental model has a similar pathogenesis to that of human vCJD. Although UK blood transfusions are leucodepleted--a possible protective measure against any risk from blood transmission--this report suggests that blood donated by symptom-free vCJD-infected human beings may represent a risk of spread of vCJD infection among the human population of the UK.

The Welfare Problems Associated with Using Transgenic Mice to Bioassay for Bovine Spongiform Encephalopathy

Prion diseases are fatal neurodegenerative disorders, epitomized by the the recent bovine spongiform encephalopathy (BSE) epidemic in cattle and the emergence of a novel variant of Creutzfeldt-Jacob disease (vCJD) in humans. In prion disease, the agent of infection is believed to be composed of proteinaceous particles, termed prions, which are converted from a normal isoform into a pathogenic isoform during pathogenesis. A bioassay to detect pathogenic prions of BSE in bovine products consumed by humans was unattainable until the development of transgenic mice, due to the significantly lower susceptibility of wild-type mice to BSE. Transgenic mice have now been generated which express the bovine prion protein and are susceptible to BSE. Following an intracerebral injection with brain homogenate of BSE-infected cattle, transgenic mice develop numerous clinical signs of prion disease, including truncal ataxia (inability to coordinate the torso's muscular activity), increased tone of the tail, generalized tremor, and lack of a forelimb extensor response. In this study, the ethical score system devised by Porter (1992) was applied to the BSE bioassay as a tool for identifying welfare issues affecting animals used in the bioassay. We acknowledge that there are limitations to the use of the information arising from the application of the Porter scoring scheme for assessing the justification to proceed with any animal experiment; notwithstanding these problems, however, our application of the Porter model to the BSE bioassay enabled us to identify potential targets for refinement: pain involved, duration of distress and the duration of the experiment. This was despite lenient scoring for the duration of distress and pain experienced by the mice, and optimal scoring for the quality of animal care. The targets identified for refinement are discussed in relation to the method of inoculation, the duration of the bioassay, and the duration of the clinical phase, with the objective of exploring ways of reducing the severity of the bioassay.

A Review of the BSE Epidemic in British Cattle

ABSTRACT Bovine spongiform encephalopathy (BSE) was first diagnosed in British cattle in 1986. The infectious agents of transmissible spongiform encephalopathy (TSE) diseases are believed to be infectious proteins or prions. They can remain infectious despite exposures to disinfectants, autoclaving, radiation, and ultraviolet light. TSEs affect animals as well as humans and are characterized by progressively severe psychomotor dysfunction and long incubation periods. As of August 27, 1999, 175,404 cases of BSE have been confirmed in Great Britain with 1,787 additional confirmed cases in Northern Ireland (as of August 31, 1999). Mathematical and statistical analyses of the BSE epidemic data suggest that the incidence of BSE in Great Britain and Northern Ireland will continue its rapid decline. Evidence relating to maternal and horizontal transmission of BSE is discussed. Public concern remains focused on the probable link between BSE infection in cattle and a new variant of Creutzfeldt‐Jakob Disease (vCJD) in humans, another TSE. Given the long and variable incubation periods associated with TSEs, and a possible genetic component, the eventual magnitude of this human epidemic remains uncertain.

Predicting the size of the epidemic of the new variant of Creutzfeldt‐Jakob disease

In response to a paper published in a previous issue of British Food Journal, it criticises the methodology of the previous research. Examines the earlier findings on the projected epidemic size of the new variant of Creutzfeldt‐Jakob Disease (vCJD) in humans. Argues that the earlier research is flawed and there exists no data which can provide adequate predictions for the extent of the vCJD epidemic.