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    ABSTRACT: Central to understanding the nature TSE agents (or prions) is how their genetic information is distinguished from the host. Are TSEs truly infectious diseases with host-independent genomes, or are they aberrations of a host component derived from the host genome? Recent experiments tested whether glycosylation of host PrP affects TSE strain characteristics. Wild-type mice were infected with three TSE strains passaged through transgenic mice with PrP devoid of glycans at one or both N-glycosylation sites. Strain-specific characteristics of one TSE strain changed but did not change for two others. Changes resulted from the selection of mutant TSE strains in a novel replicative environment. In general the properties of established TSEs support the genetic independence of TSE agents from the host, and specifically the primary structure of PrP does not directly encode TSE agent properties. However sporadic TSEs, challenge this independency. The prion hypothesis explains emerging TSEs relatively successfully but poorly accounts for the diversity and mutability of established TSE strains, or how many different infectious conformations are sustained thermodynamically. Research on early changes in RNA expression and events at the ribosome may inform the debate on TSE agent properties and their interaction with host cell machinery.
    Prion 06/2013; 7(4).
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    ABSTRACT: Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disorder of cattle, and its transmission to humans through contaminated food is thought to be the cause of the variant form of Creutzfeldt-Jakob disease (vCJD). BSE is believed to have spread from the recycling in cattle of ruminant tissue in meat and bone meal (MBM), however during this time sheep and goats were also exposed to BSE-contaminated MBM. Both sheep and goats are experimentally susceptible to BSE, and while there have been no reported natural BSE cases in sheep, two goat BSE field cases have been documented. While cases of BSE are rare in small ruminants, the existence of scrapie in both sheep and goats is well established. In the UK, during 2006-2007, a serious outbreak of clinical scrapie was detected in a large dairy goat herd. Subsequently, 200 goats were selected for post-mortem examinations, one of which showed biochemical and immunohistochemical features of the disease associated prion protein (PrPTSE) which differed from all other infected goats. In the present study we investigated this unusual case by performing bioassays into a panel of mouse lines. Following characterisation, we found that strain properties such as the ability to transmit to different mouse lines, lesion profile pattern, degree of PrP deposition in the brain and biochemical features of this unusual goat case were neither consistent with goat BSE nor with a goat scrapie herdmate control. However our results suggest this unusual case has BSE-like properties and highlights the need for continued surveillance.
    Journal of General Virology 05/2013;
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    ABSTRACT: The agents responsible for transmissible spongiform encephalopathies (TSEs), or prion diseases, contain as a major component PrP(Sc), an abnormal conformer of the host glycoprotein PrP(C). TSE agents are distinguished by differences in phenotypic properties in the host, which nevertheless can contain PrP(Sc) with the same amino-acid sequence. If PrP alone carries information defining strain properties, these must be encoded by post-translational events. Here we investigated whether the glycosylation status of host PrP affects TSE strain characteristics. We inoculated wild-type mice with three TSE strains passaged through transgenic mice with PrP devoid of glycans at the first, second or both N-glycosylation sites. We compared the infectious properties of the emerging isolates with TSE strains passaged in wild-type mice by in vivo strain typing and by the standard scrapie cell assay in vitro. Strain-specific characteristics of the 79A TSE strain changed when PrP(Sc) was devoid of one or both glycans. Thus infectious properties of a TSE strain can be altered by post-translational changes to PrP which we propose result in the selection of mutant TSE strains.
    The EMBO Journal 02/2013;
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    ABSTRACT: Western blotting has been a key technique for determining the relative expression of proteins within complex biological samples since the first publications in 1979. Recent developments in sensitive fluorescent labels, with truly quantifiable linear ranges and greater limits of detection, have allowed biologists to probe tissue specific pathways and processes with higher resolution than ever before. However, the application of quantitative Western blotting (QWB) to a range of healthy tissues and those from degenerative models has highlighted a problem with significant consequences for quantitative protein analysis: how can researchers conduct comparative expression analyses when many of the commonly used reference proteins (e.g. loading controls) are differentially expressed? Here we demonstrate that common controls, including actin and tubulin, are differentially expressed in tissues from a wide range of animal models of neurodegeneration. We highlight the prevalence of such alterations through examination of published "-omics" data, and demonstrate similar responses in sensitive QWB experiments. For example, QWB analysis of spinal cord from a murine model of Spinal Muscular Atrophy using an Odyssey scanner revealed that beta-actin expression was decreased by 19.3±2% compared to healthy littermate controls. Thus, normalising QWB data to β-actin in these circumstances could result in 'skewing' of all data by ∼20%. We further demonstrate that differential expression of commonly used loading controls was not restricted to the nervous system, but was also detectable across multiple tissues, including bone, fat and internal organs. Moreover, expression of these "control" proteins was not consistent between different portions of the same tissue, highlighting the importance of careful and consistent tissue sampling for QWB experiments. Finally, having illustrated the problem of selecting appropriate single protein loading controls, we demonstrate that normalisation using total protein analysis on samples run in parallel with stains such as Coomassie blue provides a more robust approach.
    PLoS ONE 01/2013; 8(8):e72457.
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    ABSTRACT: Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) (or prion disease) that is readily transmissible to sheep by experimental infection and has the shortest incubation period in animals with the ARQ/ARQ PRNP genotype (at codons 136, 154, and 171). Because it is possible that sheep in the United Kingdom could have been infected with BSE by being fed contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection; however, this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (∼24 h, 2 to 3 weeks, 3 months, and 6 months) and adult sheep. The incidence of clinical BSE disease after inoculation was high in unweaned lambs (∼24 h and 2 to 3 weeks old) but much lower in older weaned animals The incubation period was also found to be influenced by the genotype at codon 141 of the PRNP gene, as lambs that were LF heterozygotes had a longer mean incubation period than those that were homozygotes of either type. The results suggest that sheep in the United Kingdom would have been at high risk of BSE infection only if neonatal animals had inadvertently ingested contaminated supplementary foodstuffs.
    Journal of Virology 08/2012; 86(21):11856-62.
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    ABSTRACT: Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrP(C)) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C) protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter.
    PLoS ONE 01/2012; 7(12):e50623.
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    ABSTRACT: The transmission of bovine spongiform encephalopathy (BSE) to humans as variant Creutzfeldt-Jakob Disease (vCJD) raised concerns about potential secondary transmissions due to the resistance of the agents causing transmissible spongiform encephalopathies (TSEs), sometimes known as prions, to commonly used methods of sterilization, notably steam sterilization (or autoclaving). It has been suggested that surgical instruments and other medical devices might retain sufficient infected tissue debris after cleaning and steam sterilization to infect patients on whom they are subsequently used. To determine whether concerns about the lack of efficacy of steam sterilization of vCJD were justified. The reduction in infectivity of brain macerates of vCJD brain after steam sterilization using the standard temperatures and time recommended for autoclaving in UK hospitals (134-137°C for 3 min) was measured. Reductions in titre of 10(2.3) to >10(3.6) ID(50) were found. In three of four samples, infectivity was recovered after steam sterilization. As noted previously, TSE strains derived from BSE sources appear to be more resistant to steam sterilization and other forms of heat inactivation than other TSE sources.
    The Journal of hospital infection 11/2011; 80(1):46-51.
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    ABSTRACT: Aortic coarctation (AC) is a significant cause of secondary hypertension and is diagnosed in childhood in the vast majority of patients. Mild or moderate coarctation may exist undetected into adult life, when it usually presents due to its sequelae. The authors present the case of a 20-year-old woman, previously extensively investigated for severe hypertension, who was admitted following sever, sudden-onset headache. CT scanning of the head showed the presence of subarachnoid blood (SAH), with subsequent CT angiography revealing two intracerebral aneurysms as the source. On attempting to catheterise the femoral artery her pulses were noted to be weak and during passage of the catheter she was found to have significant AC. The aneurysms were duly treated with detachable coils and the clinical course with regard to the SAH was unremarkably safe for high-pressure headache.
    Case Reports 01/2010; 2010.
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    ABSTRACT: Early confirmation of aneurysmal cause for SAH can expedite patient management and thus minimise rebleed risk. CT Angiography is the first-line method for diagnosing the cause of SAH in most UK regions. We wanted to assess the use of CTA in this context in the East of Scotland and determine how imaging delays contribute to overall delay from ictus to aneurysm treatment. A prospective audit of aneurysmal SAH admissions over a three month period to the Neurosciences Unit in Edinburgh was performed. The time from diagnosis of SAH to aneurysm imaging with CTA and/or DSA and time from aneurysm confirmation to definitive treatment was ascertained. Twenty nine patients with aneurysmal SAH were admitted during the audit. Four patients had CTA expeditiously after SAH was diagnosed; the remaining 25 patients had a substantially greater wait for aneurysm imaging, involving transfer to a neuroscience centre. Average excess delay was 17 hours for CTA (72 hours for DSA). CTA widely available and accurate method of determining the cause of SAH. Performing immediate CTA after SAH is confirmed could reduce delays to aneurysm treatment by up to 64%. By thus reducing rebleeds post SAH, immediate CTA could reduce poor outcomes in the East of Scotland.
    Scottish medical journal 11/2009; 54(4):20-3.
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    ABSTRACT: Endovascular coiling of intracranial aneurysms carries a risk of complications. Early detection and management of complications can improve clinical outcomes. AngioCT is a new imaging technology enabling CT-like images to be generated on a flat-panel digital subtraction angiography system, which can provide immediate "on angio table" identification and thorough assessment of such complications. We prospectively audited its utility during aneurysm coiling in patients following subarachnoid haemorrhage (SAH). A prospective series of 44 patients with SAH undergoing endovascular coiling with AngioCT was audited for image quality and the influence of the AngioCT on patient management. In a parallel experimental study, radiation doses were measured and image quality parameters on standard phantoms were established. In all patients, AngioCT provided adequate diagnostic information. In 40.9% of patients, AngioCT was a substantial or major factor in determining the management immediately after coiling. Using a 10-s high-dose acquisition technique, acceptable image quality could be obtained rapidly with a radiation dose just over half that for a conventional CT scan of the head (35 mGy versus approximately 60 mGy). No patient in this series required conventional CT to clarify the AngioCT appearance. AngioCT has many applications in the neurointerventional setting. In particular during coiling, AngioCT provides a rapid way to clarify concerns or identify complications and in some cases was the major factor influencing further patient management immediately after coiling. AngioCT images were judged of adequate quality to be clinically useful in all patients in this series.
    Neuroradiology 05/2008; 50(4):321-30.
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