A novel, resistance-linked ovine PrP variant and its equivalent mouse variant modulate the in vitro cell-free conversion of rPrP to PrPres

Prion diseases are associated with the conversion of the normal cellular prion protein, PrPc, to the abnormal, disease-associated form, PrPSc. This conversion can be mimicked in vitro by using a cell-free conversion assay. It has recently been shown that this assay can be modified to use bacterial recombinant PrP as substrate and mimic the in vivo transmission characteristics of rodent scrapie. Here, it is demonstrated that the assay replicates the ovine polymorphism barriers of scrapie transmission. In addition, the recently identified ovine PrP variant ARL168Q, which is associated with resistance of sheep to experimental BSE, modulates the cell-free conversion of ovine recombinant PrP to PrPres by three different types of PrPSc, reducing conversion efficiencies to levels similar to those of the ovine resistance-associated ARR variant. Also, the equivalent variant in mice (L164) is resistant to conversion by 87V scrapie. Together, these results suggest a significant role for this position and/or amino acid in conversion

The Potential Role of Superantigens in the Pathogenesis of Bovine Theileriosis

Theileria parva is an intracellular protozoan parasite that produces an acute and often fatal lymphoproliferative disease (East Coast fever) in susceptible cattle. Studies of experimentally infected cattle have demonstrated a massive increase in the cellularity of the lymph node draining the site of inoculation in the early stages of the infection, when the proportion of parasitized cells in the node was very low. The increased cellularity was associated with a marked increase in the number of lymphoblasts within the node. This suggested that an immune response to the parasite does occur in the regional lymph nodes of naive animals, but is ineffective in controlling the infection. The objective of this study was to characterize the primary immune response in the drainage lymph nodes of cattle infected with T. parva and , in particular, to determine whether or not a superantigen was responsible for inducing lymphocyte activation. Flow cytometric analysis of the phenotype of lymph node cells from infected animals revealed that an unusual CD2-CD8+ subset of alpha/beta T cells formed a major component of the responding population. The appearance of this subset coincided with the initial detection of parasites in the node; the numbers peaked 1-2 days later, and then declined rapidly as the proportion of parasitized cells increased. These cells were refractory to stimulation in vitro, and cells with this phenotype did not participate in the in vitro proliferative response of peripheral blood mononuclear cells from naive animals to autologous parasitized cells. Another interesting feature of the lymph node response in T. parva-infected animals was a large influx of macrophages between days 7 and 9 post-infection. The possibility that a superantigen might be triggering the lymph node response of infected animals was investigated by comparing the TCRBV usage of responding cells with the TCRBV repertoire expressed by normal lymph node T cells. Purified populations of activated T cells and CD2-CD8+ T cells expressed a diverse repertoire of TCRBV genes, which suggests that a superantigen is not involved in the response. In this study a total of 29 new TCRBV gene segments were sequenced, permitting the first detailed classification of bovine TCRBV subfamilies, and revealing that diversification of the TCRBV repertoire in cattle has involved gene duplication events distinct from those of humans and mice

The War Books Boom in Britain, 1928–1930

Based on a dataset of unparalleled extent containing nearly 1500 books, this article for the first time offers an analysis of the War Books Boom that combines the qualitative and quantitative. The Boom did not simply rise and fall; an early peak in publication in 1928 was followed by a dip in 1929, as huge successes like R.C. Sherriff’s Journey’s End and Erich Maria Remarque’s Im Westen Nichts Neues (All Quiet on the Western Front) dominated the market and were successful in the subsequent two years in a variety of media. The major peak, far exceeding that of 1928, was in 1930, as both publication and commentary trends spiked. The Boom was understood in commentary as such at the time, and the surrounding discourse saw this moment as a battle for the enduring memory of the conflict between the brutal realism of works such as Remarque’s, his followers and imitators, and a more conservative focus on courage, fortitude and honour. We enrich the existing scholarly understanding of the cultural history of the War Books Boom, drawing on our dataset and the interwar journalism collected in the British Newspaper Archive, and situating these findings among existing scholarship. Taking as starting points Sherriff’s and Remarque’s texts, we identify key publication trends, drawing particular attention to the dominance by publication numbers of non-fiction texts, particularly in life-writing, history and regimental history. We conclude by suggesting further lines along which our method might be used to develop the scholarly understanding of this moment

An Economic Evaluation of Preclinical Testing Strategies Compared to the Compulsory Scrapie Flock Scheme in the Control of Classical Scrapie

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS

Prion diseases are efficiently transmitted by blood transfusion in sheep

The emergence of variant Creutzfeld-Jakob disease, following on from the bovine spongiform encephalopathy (BSE) epidemic, led to concerns about the potential risk of iatrogenic transmission of disease by blood transfusion and the introduction of costly control measures to protect blood supplies. We previously reported preliminary data demonstrating the transmission of BSE and natural scrapie by blood transfusion in sheep. The final results of this experiment, reported here, give unexpectedly high transmission rates by transfusion of 36% for BSE and 43% for scrapie. A proportion of BSE-infected tranfusion recipients (3 of 8) survived for up to 7 years without showing clinical signs of disease. The majority of transmissions resulted from blood collected from donors at more than 50% of the estimated incubation period. The high transmission rates and relatively short and consistent incubation periods in clinically positive recipients suggest that infectivity titers in blood were substantial and/or that blood transfusion is an efficient method of transmission. This experiment has established the value of using sheep as a model for studying transmission of variant Creutzfeld-Jakob disease by blood products in humans. (Blood. 2008; 112: 4739-4745

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study

Background: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pound for the completion of postal questionnaires. Methods: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pound to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pound incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. Results: The response rate following reminders for the historical controls was 78.1% ( 82 of 105) compared with 88.0% ( 389 of 442) for those patients who received the 5 pound payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response ( adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial - the extra cost per additional respondent was almost 50 pound. Conclusion: The direct payment of 5 pound significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study