Emergence of Classical BSE Strain Properties during Serial Passages of H-BSE in Wild-Type Mice

BACKGROUND: Two distinct forms of atypical spongiform encephalopathies (H-BSE and L-BSE) have recently been identified in cattle. Transmission studies in several wild-type or transgenic mouse models showed that these forms were associated with two distinct major strains of infectious agents, which also differed from the unique strain that had been isolated from cases of classical BSE during the food-borne epizootic disease. METHODOLOGY/PRINCIPAL FINDINGS: H-BSE was monitored during three serial passages in C57BL/6 mice. On second passage, most of the inoculated mice showed molecular features of the abnormal prion protein (PrP(d)) and brain lesions similar to those observed at first passage, but clearly distinct from those of classical BSE in this mouse model. These features were similarly maintained during a third passage. However, on second passage, some of the mice exhibited distinctly different molecular and lesion characteristics, reminiscent of classical BSE in C57Bl/6 mice. These similarities were confirmed on third passage from such mice, for which the same survival time was also observed as with classical BSE adapted to C57Bl/6 mice. Lymphotropism was rarely detected in mice with H-BSE features. In contrast, PrP(d) was detectable, on third passage, in the spleens of most mice exhibiting classical BSE features, the pattern being indistinguishable from that found in C57Bl/6 mice infected with classical BSE. CONCLUSION/SIGNIFICANCE: Our data demonstrate the emergence of a prion strain with features similar to classical BSE during serial passages of H-BSE in wild-type mice. Such findings might help to explain the origin of the classical BSE epizootic disease, which could have originated from a putatively sporadic form of BSE

A C-Terminal Protease-Resistant Prion Fragment Distinguishes Ovine “CH1641-Like” Scrapie from Bovine Classical and L-Type BSE in Ovine Transgenic Mice

The protease-resistant prion protein (PrPres) of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate CH1641 derived from a British natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (BSE). Recent discovery of an atypical form of BSE in cattle, L-type BSE or BASE, suggests that also this form of BSE might have been transmitted to sheep. We studied by Western blot the molecular features of PrPres in four “CH1641-like” natural scrapie isolates after transmission in an ovine transgenic model (TgOvPrP4), to see if “CH1641-like” isolates might be linked to L-type BSE. We found less diglycosylated PrPres than in classical BSE, but similar glycoform proportions and apparent molecular masses of the usual PrPres form (PrPres #1) to L-type BSE. However, the “CH1641-like” isolates differed from both L-type and classical BSE by an abundant, C-terminally cleaved PrPres product (PrPres #2) specifically recognised by a C-terminal antibody (SAF84). Differential immunoprecipitation of PrPres #1 and PrPres #2 resulted in enrichment in PrPres #2, and demonstrated the presence of mono- and diglycosylated PrPres products. PrPres #2 could not be obtained from several experimental scrapie sources (SSBP1, 79A, Chandler, C506M3) in TgOvPrP4 mice, but was identified in the 87V scrapie strain and, in lower and variable proportions, in 5 of 5 natural scrapie isolates with different molecular features to CH1641. PrPres #2 identification provides an additional method for the molecular discrimination of prion strains, and demonstrates differences between “CH1641-like” ovine scrapie and bovine L-type BSE transmitted in an ovine transgenic mouse model

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Possible Case of Maternal Transmission of Feline Spongiform Encephalopathy in a Captive Cheetah

Feline spongiform encephalopathy (FSE) is considered to be related to bovine spongiform encephalopathy (BSE) and has been reported in domestic cats as well as in captive wild cats including cheetahs, first in the United Kingdom (UK) and then in other European countries. In France, several cases were described in cheetahs either imported from UK or born in France. Here we report details of two other FSE cases in captive cheetah including a 2nd case of FSE in a cheetah born in France, most likely due to maternal transmission. Complete prion protein immunohistochemical study on both brains and peripheral organs showed the close likeness between the two cases. In addition, transmission studies to the TgOvPrP4 mouse line were also performed, for comparison with the transmission of cattle BSE. The TgOvPrP4 mouse brains infected with cattle BSE and cheetah FSE revealed similar vacuolar lesion profiles, PrPd brain mapping with occurrence of typical florid plaques. Collectively, these data indicate that they harbor the same strain of agent as the cattle BSE agent. This new observation may have some impact on our knowledge of vertical transmission of BSE agent-linked TSEs such as in housecat FSE, or vCJD

Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype

Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ∼0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ∼6× the normal PrPc level died after a survival periods of 400 days, those with ∼1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein

Reliability, Validity and Responsiveness of the Syncope Functional Status Questionnaire

BACKGROUND: Patients with transient loss of consciousness (TLOC) have poor health-related quality of life (HR-QoL). OBJECTIVE: To test the reliability, validity, and responsiveness of the disease-specific Syncope Functional Status HR-QoL Questionnaire (SFSQ), which yields two summary scales--impairment score (IS) and fear-worry score (FWS). DESIGN: Cohort-study. PARTICIPANTS: 503 adult patients presenting with TLOC. MEASUREMENTS: HR-QoL was assessed using the SFSQ and the Short Form-36 (SF-36) after presentation and 1 year later. To test reliability, score distributions, internal consistency, and test-retest reliability were assessed. To assess validity, scores on the SFSQ and the SF-36 were compared. Clinical validity was tested using known-group comparison. Responsiveness was assessed by comparing changes in SFSQ scores with changes in health status and clinical condition. RESULTS: Response rate was 82% at baseline and 72% at 1-year follow-up. For all scales the full range of scores was seen. Score distributions were asymmetrical. Internal consistency was high (alpha = 0.88 for IS, 0.92 for FWS). Test-retest reliability was moderate to good for individual items and high for summary scales (inter-class correlation = 0.78 for both IS and FWS). Correlations between SFSQ scores and the SF-36 were modest. The SFSQ did not discriminate between patients differing in age and gender but did discriminate between patients differing in number of episodes and comorbid conditions. Changes in SFSQ scores were related to changes in health status and the presence of recurrences but did not vary by TLOC diagnosis. CONCLUSION: The SFSQ is an adequately reliable, valid, and responsive measure to assess HR-QoL in patients with TLO

Does the cognitive reflection test measure cognitive reflection? A mathematical modeling approach

We used a mathematical modeling approach, based on a sample of 2,019 participants, to better understand what the cognitive reflection test (CRT; Frederick In Journal of Economic Perspectives, 19, 25–42, 2005) measures. This test, which is typically completed in less than 10 min, contains three problems and aims to measure the ability or disposition to resist reporting the response that first comes to mind. However, since the test contains three mathematically based problems, it is possible that the test only measures mathematical abilities, and not cognitive reflection. We found that the models that included an inhibition parameter (i.e., the probability of inhibiting an intuitive response), as well as a mathematical parameter (i.e., the probability of using an adequate mathematical procedure), fitted the data better than a model that only included a mathematical parameter. We also found that the inhibition parameter in males is best explained by both rational thinking ability and the disposition toward actively open-minded thinking, whereas in females this parameter was better explained by rational thinking only. With these findings, this study contributes to the understanding of the processes involved in solving the CRT, and will be particularly useful for researchers who are considering using this test in their research

The influence of traits associated with autism spectrum disorder (ASD) on the detection of fake news.

It has been suggested that neuro-diverse individuals may be particularly good at detecting online deception (Pick 2019). A small-scale exploratory study was conducted to investigate whether individuals with traits associated with Autism Spectrum Disorder (ASD) were more or less accurate in spotting different types of fake news. A non-clinical sample of university students completed an online identification task, where both fake and real articles items were manipulated in terms of their emotive content. When individuals with low and high scores on the Autism-Spectrum Quotient (Baron-Cohen et al. 2001) were compared, there were no significant main effects on detection accuracy. However, there were two significant interactions, indicating an interesting relationship between message emotiveness, ASD and fake news detection. The results contribute to an understanding of how psychological differences, in particular ASD, may affect online judgements and will contribute to a developing body of work relating positive skills of neuro-diverse individuals to the cybersecurity industry

Clinical Manifestations and Case Management of Ebola Haemorrhagic Fever caused by a newly identified virus strain, Bundibugyo, Uganda, 2007-2008

A confirmed Ebola haemorrhagic fever (EHF) outbreak in Bundibugyo, Uganda, November 2007-February 2008, was caused by a putative new species (Bundibugyo ebolavirus). It included 93 putative cases, 56 laboratory-confirmed cases, and 37 deaths (CFR = 25%). Study objectives are to describe clinical manifestations and case management for 26 hospitalised laboratory-confirmed EHF patients. Clinical findings are congruous with previously reported EHF infections. The most frequently experienced symptoms were non-bloody diarrhoea (81%), severe headache (81%), and asthenia (77%). Seven patients reported or were observed with haemorrhagic symptoms, six of whom died. Ebola care remains difficult due to the resource-poor setting of outbreaks and the infection-control procedures required. However, quality data collection is essential to evaluate case definitions and therapeutic interventions, and needs improvement in future epidemics. Organizations usually involved in EHF case management have a particular responsibility in this respect