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

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

No evidence of subclinical infection in sheep surviving oral challenge with prions

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal zoonotic disease caused by the ingestion of bovine spongiform encephalopathy (BSE)-infected meat products. Although the number of vCJD cases due to dietary exposure has significantly declined, the true burden of subclinical infections remains uncertain. Several large-scale surveys using appendix tissue samples have indicated the presence of abnormal prion protein (PrP Sc; Sc for scrapie) in lymphoid tissue of a small proportion of the UK population. These may represent silent carriers of infection, with the potential to contribute to transmission, persistence and re-emergence of vCJD. Previously, we showed that subclinical infection is a frequent outcome of low-dose prion exposure by blood transfusion in sheep. To determine whether subclinical infection was also found following low-dose exposure by another clinically relevant route for humans, we screened archived tissues from sheep orally challenged with a range of doses of BSE, which did not show clinical or pathological signs of disease after several years of follow-up post-infection. Using a highly sensitive protein misfolding cyclic amplification assay, we were unable to detect PrP Sc in the lymph node/tonsil of 15 sheep, or in a wider range of lymphoid tissues and brain (medulla oblongata) from a subset of 5 sheep. Our findings suggest that the route of infection/exposure may significantly influence the probability of establishing subclinical infection, with the oral route apparently much less efficient than intravenous infection by blood transfusion in sheep. </p

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

Effects of inaccuracies in arterial path length measurement on differences in MRI and tonometry measured pulse wave velocity

Abstract Background Carotid-femoral pulse wave velocity (cf-PWV) and aortic PWV measured using MRI (MRI-PWV) show good correlation, but with a significant and consistent bias across studies. The aim of the current study was to evaluate whether the differences between cf.-PWV and MRI-PWV can be accounted for by inaccuracies of currently used distance measurements. Methods One hundred fourteen study participants were recruited into one of 4 groups: Type 2 diabetes melltus (T2DM) with cardiovascular disease (CVD) (n = 23), T2DM without CVD (n = 41), CVD without T2DM (n = 25) and a control group (n = 25). All participants underwent cf.-PWV, cardiac MRI and whole body MR angiography(WB-MRA). 90 study participants also underwent aortic PWV using MRI. cf.-PWVEXT was performed using a SphygmoCor device (Atcor Medical, West Ryde, Australia). The true intra-arterial pathlength was measured using the WB-MRA and then used to recalculate the cf.-PWVEXT to give a cf.-PWVMRA. Results Distance measurements were significantly lower on WB-MRA than on external tape measure (mean diff = −85.4 ± 54.0 mm,p < 0.001). MRI-PWV was significantly lower than cf.-PWVEXT (MRI-PWV = 8.1 ± 2.9 vs. cf.-PWVEXT = 10.9 ± 2.7 ms−1,p < 0.001). When cf.-PWV was recalculated using the inter-arterial distance from WB-MRA, this difference was significantly reduced but not lost (MRI-PWV = 8.1 ± 2.9 ms−1 vs. cf.-PWVMRA 9.1 ± 2.1 ms−1, mean diff = −0.96 ± 2.52 ms−1,p = 0.001). Recalculation of the PWV increased correlation with age and pulse pressure. Conclusion Differences in cf.-PWV and MRI PWV can be predominantly but not entirely explained by inaccuracies introduced by the use of simple surface measurements to represent the convoluted arterial path between the carotid and femoral arteries

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

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

Look what’s coming over the hill:DAST-10 problem severity among non treatment seeking young people

PurposeThis study aims to provide data on substance use amongst young people in Scotland to inform policy and practice for an age group who generally do not access specialist alcohol and drug services. The main objectives of the study were to assess the problem severity scores of items from a modified version of the DAST-10 brief screening instrument among respondents; examine correlations between a range of variables in relation to DAST-10 problem severity scores; and explore respondent knowledge of how and where to seek help.Design/methodology/approachA fixed quantitative design methodology recruited a non-probability sample of 4,501 respondents from an online survey made available by “We are With you” Scotland.The survey was ethically approved by the School of Education and Social Sciences, University of the West of Scotland. It consisted of 32 questions exploring substances used within the past 12 months, and 12 weeks, and included the DAST-10. We further explored help seeking, and knowledge of support available to respondents.FindingsSubstance use patterns were markedly different from people currently known to specialist alcohol and drug services. Over half of respondents were under 25, and 62% report being employed. The most commonly used substances were cannabis and cocaine. One third of respondents recorded substantial or severe problem severity scores and reside in Scottish Local Authorities with high concentrations of socio-economic inequality.Secure accommodation, stable relationships and being employed are protective factors in relation to reported negative health consequences associated with problem substance use.Just under one third (27%) of respondents report knowing where to seek help for substance use problems; however, they are unwilling to attend existing specialist alcohol and drug services.Research limitations/implicationsA non-probability sample of the Scottish population has a potential for response bias due to how and what way the survey was made available to respondents. It is acknowledged that while useful as a method of generating drug use data, there are limitations in how recently the substance use occurred, and in relation to the types of substances reported (cannabis, cocaine and ecstasy).Practical implicationsThe study provides data to inform wider public health measures in relation to accessing support and addressing societal discrimination associated with the use of substances. The study provides data on service design for young people who do not access specialist alcohol and drug services.Social implicationsThe study informs substance use policy in the Scottish context in relation to a population of young people who use licit and illicit substances. Data contributes to evidence supporting correlations between problematic substance use and socio-economic inequality. Data indicates that existing specialist services require redesign.Originality/valueThe study is the first to be conducted within a Scottish context