Transmission Of Bovine Spongiform Encephalopathy Research Articles

The potential size and duration of an epidemic of bovine spongiform encephalopathy in British sheep.

Because there is a theoretical possibility that the British national sheep flock is infected with bovine spongiform encephalopathy (BSE), we examined the extent of a putative epidemic. An age cohort analysis based on numbers of infected cattle, dose responses of cattle and sheep to BSE, levels of exposure to infected feed, and number of BSE-susceptible sheep in the United Kingdom showed that at the putative epidemic peak in 1990, the number of cases of BSE-infected sheep would have ranged from fewer than 10 to about 1500. The model predicts that fewer than 20 clinical cases of BSE in sheep would be expected in 2001 if maternal transmission occurred at a rate of 10%. Although there are large uncertainties in the parameter estimates, all indications are that current prevalence is low; however, a simple model of flock-to-flock BSE transmission shows that horizontal transmission, if it has occurred, could eventually cause a large epidemic.

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

Histological Observations on the Brains of Symptomless 7-Year-old Cattle

The histological changes in the brains of 506 clinically normal 7-year-old cattle, which were part of a cohort study on maternal transmission of bovine spongiform encephalopathy, are described. Vacuolation of the white matter, of unknown aetiology, located particularly in the substantia nigra, was a frequent finding. Vacuolated neurons were commonly observed in the red nucleus (64·3% of the animals) and in the habenular nucleus (50·1%). Spheroids were found in 10·8% of the brains, most frequently in the vestibular nuclei. Cellular inflammatory infiltrates in association with blood vessels occurred in 30% of the animals at various locations in the brain; their aetiology remains uncertain, but they may have reflected subclinical or latent infections. Mineralization of the wall of blood vessels, with proliferation of the intima, was observed frequently in vessels of the internal capsule and was probably associated with ageing. The description of histological findings in the brain of symptomless adult cattle in the present study provides a useful background for diagnostic bovine neuropathology.

Identification of Bovine-Specific DNA in Feedstuffs

Considering the menace of transmission of bovine spongiform encephalopathy, feed components intended for cattle nutrition must be checked for the presence of bovine-derived materials. We have been using a method based on polymerase chain reaction for the identification of bovine-specific mitochondrial DNA sequences for this purpose. The specificity of the primers for polymerase chain reaction has been tested using samples of DNA of other vertebrate species, which may also be present in rendering plant products. The method allows the detection in concentrate mixtures of 0.125% of bovine-derived material. Bovine DNA at concentrations corresponding to less than 0.5% of bovine-derived material was detected in 3 of the 30 samples of concentrate mixtures collected from distributors' stores all over the Czech Republic. All 44 samples of fish meal collected from the same sources were free of bovine-derived material.

Bovine spongiform encephalopathy — Food safety implications

Publisher Summary This chapter discusses bovine spongiform encephalopathy (BSE). BSE is a fatal brain disease of cattle presumed to have originated from the use of rendered scrapie-infected sheep offal as a dietary protein source for cattle. The oral route is the major route of natural transmission of BSE to cattle. Shortly after BSE was identified in cattle, a cluster of human cases of Creutzfeldt-Jakob disease (CJD) with atypical characteristics occurred in the UK. This disease is referred to as variant CJD. Concern that BSE was spreading to man through the food supply engendered a flurry of research to ascertain whether, in fact, they were the same disease, and if so, whether they were spreading to man through the food supply. BSE is an afebrile, neurological disease; it elicits no immune or inflammatory response. Cattle affected by BSE experience a progressive degeneration of the nervous system. The onset of clinical signs is often associated with stress (herd change), calving, or estrus. Clinical signs include heightened sensory perception; changes in temperament, such as nervousness or aggression; abnormal posture, in coordination and difficulty in standing; excessive itching or licking; repetitive movements; decreased milk production; or loss of body weight despite continued appetite.

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.

Scrapie in Britain during the BSE years.

The experimental transmission of bovine spongiform encephalopathy (BSE) to sheep1 raised the possibility that some sheep in the United Kingdom could have been infected during the 1980s after exposure to BSE-contaminated feed. In contrast to new diseases that have appeared in a number of feline species and wild ungulates2, the symptoms of BSE in sheep are very similar to another transmissible spongiform encephalopathy called scrapie, which has been endemic in Britain for over 200 years. Although so far no cases of BSE in sheep have been found, these may have been misdiagnosed as scrapie. Here we present data describing the historical changes in scrapie incidence3, and find no evidence for a peak in scrapie incidence before, during or after the BSE outbreak, making it unlikely that a substantial epidemic of BSE has occurred in the sheep population.

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.

Feed-borne transmission and case clustering of BSE.

An unresolved issue in the epidemiology of bovine spongiform encephalopathy (BSE) in the UK is what precisely determines the degree to which cases of disease in cattle are clustered within herds throughout the course of the epidemic. This paper presents an analysis of feed-borne transmission at the herd level and tests various models of case-clustering mechanisms, associated with heterogeneity in exposure to infectious feed, against observed epidemic pattern. We use an age-structured metapopulation framework in which the recycling of animal tissue between herds via feed producers is explicitly described. We explore two alternative assumptions for the scaling with herd size of the within-herd risk of exposure of an animal to infectious material. We find that whereas exposure heterogeneity caused by variation in feed and offal processing methods and by variation in per-animal feed uptake can explain the pattern of case clustering seen in the BSE epidemic, exposure heterogeneity due to the aggregation of infectivity within feed cannot.

Evaluation of a Fibrin Sealant Free of Bovine-Derived Components in an Experimental Vas Anastomosis Study

Objectives: The risk of transmission of bovine spongiform encephalopathy cannot be excluded from the use of bovine-derived products. The present study was undertaken to evaluate the performance of a new fibrin glue free of bovine-derived components in vas anastomosis and to compare this product to conventional vas anastomosis with fibrin glue. Methods: Bilateral delayed vas anastomosis was performed in 40 Sprague-Dawley rats. All animals underwent a fibrin glue-assisted vas anastomosis with three transmural sutures tied prior to fibrin glue application. The composition and preparation of fibrin glue was similar for all vas anastomoses except the fibrinolysis inhibitor component which was aprotinin (3,000 KUI/ml) in group 1 and tranexamic acid (10 mg/ml) in group 2. The animals (20 rats in both groups) were sacrificed 7 weeks postoperatively and evaluated for gross patency, presence of sperm granuloma and tensile strength measurements at the anastomosis site. Results: No difference was found between the 2 groups for all parameters evaluated whether a bovine-derived or a synthetic fibrinolysis inhibitor component was used. Conclusion: This study showed that tranexamic acid, a fibrinolysis inhibitor, can be substituted for conventional fibrin glue thereby avoiding the risks of bovine products.

Prions and blood products

The transmission of Creutzfeldt-Jakob disease (CJD) by human pituitary-derived growth hormone has led to concerns that blood products might also provide a route for the iatrogenic transmission of CJD. A number of actions have been implemented by regulatory authorities to address such concerns, and numerous studies have been undertaken to determine whether or not there is a risk of CJD being transmitted in this manner. To date, no excess risk has been identified, leading to a growing consensus that there is little or no risk of long established forms of CJD being transmitted to recipients of blood products. This opinion does not extend to new variant CJD (vCJD) which is found predominantly in the UK and is believed to have resulted from the transmission of bovine spongiform encephalopathy (BSE) to humans. Unlike that of CJD, the prevalence of vCJD is not known. In addition, the detection of abnormal prion protein in the tonsils of vCJD-infected individuals has led to speculation that blood infectivity may be greater than in patients with CJD. A number of precautionary measures have been taken to address the possibility that vCJD may be transmissible by blood products; however, further scientific advances are needed to enable this risk to be defined. A suitable screening test is required to identify any infected blood donors, particularly where cellular blood components are being derived from populations believed to be at risk from BSE infection. Recent experimental data suggest that process operations used in the manufacture of plasma products may be capable of removing prion agents to a significant extent. However, further work is required to confirm these observations and to determine whether or not all potential vCJD infectivity would be removed by these means.

The transmission of prions to humans.

The identification of new-variant Creutzfeldt-Jakob disease (nvCJD) in 1996 led to the proposal that this new disease was caused by the transmission of bovine spongiform encephalopathy (BSE) to the human population. The ramifications of such a proposal have been extensive and profound, both politically and on the general public in the UK and other countries. Patients with nvCJD exhibit a consistent set of clinicopathological features, and cases of nvCJD continue to be reported almost exclusively in the UK, the country with by far the highest incidence of BSE. Laboratory studies, including transmission experiments in mice, provide strong support for the hypothesis that nvCJD is caused by BSE.

Cellular prion protein expressed by bovine squamous epithelia of skin and upper gastrointestinal tract

Routes of transmission of bovine spongiform encephalopathy have not yet been determined. We show that bovine squamous epithelia of the skin and upper gastrointestinal tract express Prp(c), suggesting that these epithelia may be a target for prion entry and replication.

A Review of the BSE Epidemic in British Cattle

ABSTRACTBovine 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.

The genetics of prions—a contradiction in terms?

Prion diseases, or transmissible spongiform encephalopathies (TSEs), include bovine spongiform encephalopathy (BSE), 1 and sporadic, familiar, and variant Creutzfeldt-Jakob disease (CJD). So far, 41 deaths in the U K have been attributed to variant CJD 2 which may represent transmission of BSE to human beingsY It may seem paradoxical to discuss genetics in relation to diseases; after all, the prion--here defined as the enigmatic agent that causes transmissible spongiform encephalopathies--is a paradigm of non-genetic pathology. An overwhelming body of evidence agrees that the consists solely of a modified conformer of a normal host protein, termed PrP c. The protein-only hypothesis, originally put forward by Griffith, 6 says that infectivity is identical to PrP s°, an abnormal form of the cellular protein PrP c. Replication occurs by PrP s° recruiting PrP c and converting it into further PrP s°. The newly formed PrP s¢ will join the conversion cycle and lead to a chain reaction of events that results in an ever-faster accumulation of PrP s°. This hypothesis gained widespread recognition and acceptance after Stanley B Prusiner purified the pathological protein (which he termed prpsc) 7 and Charles Weissmann cloned the Prnp gene that encodes PrP sc as well as its normal cellular counterpart, p r p c y Even more momentum was achieved when Weissmann showed that genetic ablation of Prnp protects mice from experimental scrapie on exposure to prions, '° as predicted by the protein-only hypothesis. Today, we know that the principle underlies several biological phenomena, some of which do not necessarily result in brain disease. Most notably, the propagation of certain properties of yeast, which had been unexplained for 20 years, ~ can be conveniently accounted for by a prion hypothesis32 Because yeast prions are not harmful to their infected hosts, and in some cases may even be advantageous, it is attractive to speculate that recruitment of structural traits by protein-protein interactions, besides underlying human diseases, may actually represent a fundamental principle of biology, the prevalence of which may be much greater than thus far recognised. Many variants of the protein-only hypothesis have been formulated, three of which are the most hotly debated (figure 1). Prusiner has been proposing a templatedirected refolding model, which postulates that a physical interaction between PrP c and PrP ~° is a precondition to the structural changes that underlie the pathogenetic conversion of PrP c. Some genetic evidence suggests the existence of a third partner protein, tentatively dubbed protein X, which may act as a molecular chaperon and facilitate misfolding of prpc? 3 Gajdusek and Lansbury and their colleagues ~415 have, instead, speculated that PrP c and PrP s~ exist in a

Risk of transmission of bovine spongiform encephalopathy to humans in the United States: report of the Council on Scientific Affairs. American Medical Association.

The risk of possible transmission of bovine spongiform encephalopathy (BSE) in the United States is a substantial public health concern. To systematically review the current scientific literature and discuss legislation and regulations that have been implemented to prevent the disease. Literature review using the MEDLINE, EMBASE, and Lexis/Nexis databases for 1975 through 1997 on the terms bovine spongiform encephalopathy, prion diseases, prions, and Creutzfeldt-Jakob syndrome. The Internet was used to identify regulatory actions and health surveillance. MEDLINE, EMBASE, and Lexis/Nexis databases were searched from 1975 through 1997 for English-language articles that provided information on assessment of transmission risk. Unique circumstances in the United Kingdom caused the emergence and propagation of BSE in cattle, including widespread use of meat and bonemeal cattle feed derived from scrapie-infected sheep and the adoption of a new type of processing that did not reduce the amount of infectious prions prior to feeding. Many of these circumstances do not exist in the United States. In the United Kingdom, new variant Creutzfeldt-Jakob disease probably resulted from the ingestion of BSE-contaminated processed beef. The United Kingdom and the European Union now have strong regulations in place to stop the spread of BSE. While BSE has not been observed in the United States, the US government has surveillance and response plans in effect. Current risk of transmission of BSE in the United States is minimal because (1) BSE has not been shown to exist in this country; (2) adequate regulations exist to prevent entry of foreign sources of BSE into the United States; (3) adequate regulations exist to prevent undetected cases of BSE from uncontrolled amplification within the US cattle population; and (4) adequate preventive guidelines exist to prevent high-risk bovine materials from contaminating products intended for human consumption.

Experimentally induced bovine spongiform encephalopathy did not transmit via goat embryos.

Goats are susceptible to experimental challenge with bovine spongiform encephalopathy (BSE). This study set out to investigate whether the transmission of BSE could occur in goats following the transfer of embryos from experimentally infected donor females into uninfected recipient females. The results showed no evidence of transmissible spongiform encephalopathy disease in any of the offspring which developed from embryos from infected donors, nor indeed in any of the recipient females used as surrogate dams. In addition, there was no indication of experimental BSE spreading as either a venereal infection to males used in mating or by maternal transmission to offspring born naturally to experimentally infected donors, although numbers were small.

Prion protein and species barriers in the transmissible spongiform encephalopathies

In the transmissible spongiform encephalopathies (TSE), the conversion of the normal protease-sensitive host protein PrP-sen to an abnormal protease-resistant form, PrP-res, is a critical step in disease pathogenesis. Amino acid mismatches between PrP-sen and PrP-res can dramatically affect the amount of PrP-res made and modulate the resistance to cross-species transmission of TSE infectivity. Experiments in transgenic mice, tissue culture cells, and cell-free systems have been used to identify the regions in PrP important in PrP-res formation. These studies have all shown that homology in the middle third of the PrP molecule is critical for the species-specific formation of PrP-res. Polymorphisms within this region correlate with the resistance of hamsters and some goats to scrapie and bovine spongiform encephalopathy (BSE) while homology at critical amino acid residues might facilitate cross-species transmission of BSE to humans. Studies such as these have proven invaluable in understanding the molecular basis of species barriers in the TSE as well as the important secondary structures involved in the formation of PrP-res.

Bovine Spongiform Encephalopathy: Current Status and Possible Impacts

Bovine spongiform encephalopathy is an apparently new disease; first recognized in 1985, its pathological distinction was first reported in 1986. Bovine spongiform encephalopathy is a member of a group of transmissible encephalopathies that includes scrapie in sheep and Creutzfeldt-Jakob Disease in humans. Early indications of its epidemiology suggested that the disease was transmitted via cattle feed containing meat and bone meals from previously infected animals. The tissues most likely to contain infectious agents were considered to be nervous tissues and offal, and their inclusion in ruminant feed was banned in the United Kingdom in 1989; regulations were tightened in 1992. Subsequent diagnosis has indicated that this ban has been effective and that confirmed cases are predicted to decline from a peak in the United Kingdom of 37,490 in 1992, to 7417 actual cases in 1996, and then to virtual extinction in 2001. Subsequent culling of all nonproductive cattle more than 30 mo of age and culling of cohort animals of confirmed cases is likely to reduce the predicted numbers and times significantly. Current interest is in the means of transmission of bovine spongiform encephalopathy within species and possibly to humans. A new variant of Creutzfeldt-Jakob Disease, with 28 cases confirmed, is virtually certain to be bovine spongiform encephalopathy in humans. The outbreak of bovine spongiform encephalopathy has had major impacts on the United Kingdom dairy industry, including the loss of beef from dairy markets, the culling of more than 900,000 dairy bull calves, the removal of all cattle more than 30 mo of age from the human food chain, and now slaughter of cohort animals. Impacts on dairy marketing have yet to be properly assessed.Information and statistics for bovine spongiform encephalopathy can be found on the worldwide web at http://www.maff.gov.uk/maffhome.html.