ORCID Profile
0000-0001-5869-2108
Current Organisation
The University of Edinburgh
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Publisher: Elsevier BV
Date: 1997
Publisher: Springer Science and Business Media LLC
Date: 10-06-2011
DOI: 10.1007/S00401-010-0708-8
Abstract: A key event in the pathogenesis of prion diseases is the conversion of the normal cellular isoform of the prion protein into the disease-associated isoform, but the mechanisms operating in this critical event are not yet fully understood. A number of novel approaches have recently been developed to study factors influencing this process. One of these, the protein misfolding cyclical lification (PMCA) technique, has been used to explore defined factors influencing the conversion of cellular prion protein in a cell-free model system. Although initially developed in animal models, this technique has been increasingly applied to human prion diseases. Recent studies have focused on the role of different isoforms of the disease-associated human prion protein and the effects of the naturally occurring polymorphism at codon 129 in the human prion protein gene on the conversion process, improving our understanding of the interaction between host and agent factors that influence the wide range of phenotypes in human prion diseases. This technique also allows a greatly enhanced sensitivity of detection of disease-associated prion protein in human tissues and fluids, which is potentially applicable to disease screening, particularly for variant Creutzfeldt-Jakob disease. The PMCA technique can also be used to model human susceptibility to a range of prions of non-human origin, which is likely to prove of considerable future interest as more novel and potentially pathogenic prion diseases are identified in animal species that form part of the human food chain.
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S0140-6736(98)12075-5
Abstract: Prion diseases are associated with the accumulation of an abnormal isoform of cellular prion protein (PrPSc), which is the principal constituent of prions. Prions replicate in lymphoreticular tissues before neuroinvasion, suggesting that lymphoreticular biopsy s les may allow early diagnosis by detection of PrPSc. Variant Creutzfeldt-Jakob disease (variant CJD) is difficult to distinguish from common psychiatric disorders in its early stages and definitive diagnosis has relied on neuropathology. We studied lymphoreticular tissues from a necropsy series and assessed tonsillar biopsy s les as a diagnostic investigation for human prion disease. Lymphoreticular tissues (68 tonsils, 64 spleens, and 40 lymph nodes) were obtained at necropsy from patients affected by prion disease and from neurological and normal controls. Tonsil biopsy s ling was done on 20 patients with suspected prion disease. Tissues were analysed by western blot to detect and type PrPSc, by PrP immunohistochemistry, or both. All lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD, but not from patients with other prion diseases or controls, were positive for PrPSc. In addition, PrPSc typing revealed a consistent pattern (designated type 4t) different from that seen in variant CJD brain (type 4) or in brain from other CJD subtypes (types 1-3). Tonsil biopsy tissue was positive in all eight patients with an adequate biopsy s le and whose subsequent course has confirmed, or is highly consistent with, a diagnosis of variant CJD and negative in all patients subsequently confirmed to have other diagnoses. We found that if, in the appropriate clinical context, a tonsil biopsy s le was positive for PrPSc, variant CJD could be diagnosed, which obviates the need for a brain biopsy s le to be taken. Our results also show that variant CJD has a different pathogenesis to sporadic CJD.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.BRAINRESBULL.2005.09.010
Abstract: To assess whether heightened oxidative stress plays an early and primary pathogenic role in transmissible spongiform encephalopathies (TSE), we undertook detailed correlative studies using a mouse-adapted model of human disease. The spatio-temporal evolution of the abnormal, protease-resistant isoform of the prion protein (PrP(res)) and neuropathological changes were correlated with the occurrence and type of oxidative stress. Heightened oxidative stress was demonstrated, but restricted to elevated levels of free aldehydic breakdown products of lipid peroxidation, affecting all brain regions to varying extents. The increase in lipid peroxidation was highest over the mid-incubation period, with the onset showing close temporal and general topographical concordance with the first detection of PrP(res) with both pre-empting the typical neuropathological changes of spongiform change, gliosis and neuronal loss. Further, prion propagation over the disease course was assessed using murine bioassay. This revealed that the initial rapid increase in infectivity titres was contemporaneous with the abrupt onset and maximisation of lipid peroxidation. The present results are an important extension to previous studies, showing that heightened oxidative stress in the form of lipid peroxidation is likely to constitute an early primary pathogenic event in TSE, associated temporally with the integral disease processes of prion propagation and PrP(res) formation, and consistent with causal links between these events and subsequent typical neuropathological changes.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Wiley
Date: 12-10-2005
DOI: 10.1111/J.1423-0410.2005.00702.X
Abstract: A substantial body of animal data indicates that transmissible spongiform encephalopathies (TSEs) are transmitted through blood. These data have been augmented in the past year by reports that two recipients of red cells from donors with variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom have acquired this infection. Most of the blood donations collected in countries affected by bovine spongiform encephalopathy (BSE) and vCJD also contribute plasma to fractionation pools. Thus, a number of batches of fractionated products have included plasma from donors who developed vCJD. On the basis of public health strategies influenced, in part, by risk assessments, the UK and the French authorities have instituted measures for recalling products and informing patients of the estimated risks. It is therefore relevant to review the principles used by authorities in generating risk assessments for the transmission of TSEs by blood and blood products. While the general principles are fairly straightforward, the final assessments are very dependent on the magnitude of several key parameters, which are, largely, still unknown. A critical determinant of final product risk is the extent to which the plasma fractionation process will contribute to eliminating the infectious prion agent. Therefore, regulatory and industry measures to characterize fractionation processes for their capacity to eliminate prions are to be strongly encouraged. In the interim, an understanding of the principles used to generate risk assessments should contribute to an enhanced ability to address this threat to patient safety. Authorities should recognize that adequate communication is an integral part of good risk-management practices.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Informa Healthcare
Date: 02-2008
Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is a transmissible neurodegenerative prion disease that continues to present a unique problem for medical diagnostics. Uncertainties remain over the prevalence of vCJD in the UK population and its incubation period in in iduals of different genotypes. Although the infectious agent that causes vCJD is widely distributed in the peripheral tissues of patients and those carrying the disease, it does not provoke any host immune response that would be amenable to detection. The recent realisation that it can be transmitted by blood transfusion, and that in iduals are infectious long before the appearance of symptoms, have increased the need for a blood-screening assay. This paper reviews progress that has been made in the development of potential tests and the protocols that have been devised for their evaluation.
Publisher: Wiley
Date: 02-09-2011
Publisher: Wiley
Date: 02-09-2011
DOI: 10.1111/J.1365-2990.2011.01162.X
Abstract: To determine premortem and post mortem factors affecting quality and yield of RNA isolated from the unique archived brain material in the UK National Creutzfeldt-Jakob Disease Surveillance Unit Brain and Tissue Bank and to compare this to control brain tissue with no neurological disease. In parallel and in replicate, RNA was prepared from the frontal parasagittal or subfrontal cortex of s les dissected from half brains (frozen intact) or from brain s les snap frozen or placed in RNALater. A total of 350 RNA s les from 78 human autopsy cases, 21 variant Creutzfeldt-Jakob disease, 26 other neurological diseases and 31 non-neurological diseases were studied. There was no difference in the quality or yield of RNA isolated from variant Creutzfeldt-Jakob disease, other neurological disease and non-neurological disease brains. RNA preparations from archived frozen half brains or snap frozen autopsy s les were generally of poor quality (RNA integrity number 5). Age at death, gender, post mortem interval and freezer storage time had no effect on RNA quality. Reasonable-quality RNA can be isolated from s les dissected from archived frozen human half brains but repeated s ling results in RNA degradation. Better-quality RNA is obtained from s les placed in RNALater than from snap frozen s les. The quality and yield of RNA are not affected by age at death, gender, post mortem interval of >6 h or freezer storage time.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.EJCA.2006.01.039
Abstract: The SIOP PNET 3 study was designed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy (RT) would improve the outcome for patients with primitive neuroectodermal tumours (PNETs) compared with RT alone. Patients with a histological diagnosis of supratentorial PNET (StPNET) and no radiological evidence of metastatic disease were initially eligible for randomisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site, or RT alone. In respect of the increasing recognition that StPNET were high-risk tumours, randomisation for this group closed in November 1999. This analysis includes both randomised and non-randomised patients with StPNET entered into the study database. Sixty-eight patients aged 2.9-16.6 years (median 6.5 years) were included in the analysis (chemotherapy+RT: 44, RT alone: 24). Fifty-four patients (79%) had a non-pineal and 14 (21%) a pineal site. At a median follow-up of 7.4 years, for all patients overall survival (OS) at 3 and 5 years was 54.4% and 48.3%, respectively. Event-free survival (EFS) at 3 and 5 years was 50.0% and 47.0%, respectively. There was no statistically significant difference in OS or EFS according to treatment received. OS (P=0.05) and EFS (P=0.03) were significantly better for patients with pineal primary sites. EFS for pineal tumours were 92.9% at 3 years and 71.4% at 5 years and for non-pineal primaries 40.7% at 3 years and 40.7% at 5 years. This study confirmed the relatively good survival for non-metastatic pineal PNETs but poor survival of non-pineal StPNETs. There was no evidence that pre-radiation chemotherapy improved outlook. Future treatment programs should be directed at the particular natural history of these tumours, to further define prognostic factors and to explore further biological characteristics.
Publisher: BMJ
Date: 12-1998
Publisher: Elsevier BV
Date: 07-1997
DOI: 10.1016/S0140-6736(05)62356-2
Abstract: The application of autopilot technology is conductive to achieving path planning navigation and liberating labor productivity. In addition, the self-driving vehicles can drive according to the growth state of crops to ensure the accuracy of spraying and pesticide effect. Navigation line detection is the core technology of self-driving technology, which plays a more important role in the development of Chinese intelligent agriculture. The general algorithms for seedling line extraction in the agricultural fields are for large seedling crops. At present, scholars focus more on how to reduce the impact of crop row adhesion on extraction of crop rows. However, for seedling crops, especially double-row sown seedling crops, the navigation lines cannot be extracted very effectively due to the lack of plants or the interference of rut marks caused by wheel pressure on seedlings. To solve these problems, this paper proposed an algorithm that combined edge detection and OTSU to determine the seedling column contours of two narrow rows for cotton crops sown in wide and narrow rows. Furthermore, the least squares were used to fit the navigation line where the gap between two narrow rows of cotton was located, which could be well adapted to missing seedlings and rutted print interference. The algorithm was developed using images of cotton at the seedling stage. Apart from that, the accuracy of route detection was tested under different lighting conditions and in maize and soybean at the seedling stage. According to the research results, the accuracy of the line of sight for seedling cotton was 99.2%, with an average processing time of 6.63 ms per frame the accuracy of the line of sight for seedling corn was 98.1%, with an average processing time of 6.97 ms per frame the accuracy of the line of sight for seedling soybean was 98.4%, with an average processing time of 6.72 ms per frame. In addition, the standard deviation of lateral deviation is 2 cm, and the standard deviation of heading deviation is 0.57 deg. The proposed rows detection algorithm could achieve state-of-the-art performance. Besides, this method could ensure the normal spraying speed by adapting to different shadow interference and the randomness of crop row growth. In terms of the applications, it could be used as a reference for the navigation line fitting of other growing crops in complex environments disturbed by shadow.
Publisher: Elsevier BV
Date: 09-2014
Publisher: American Medical Association (AMA)
Date: 23-04-2014
Abstract: Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events 9.5 vs 9.8 per 100 person-years adjusted hazard ratio, 0.59 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events 1.6 vs 3.3 per 100 person-years adjusted hazard ratio, 0.37 95% CI, 0.19-0.72). Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.
Publisher: Springer Science and Business Media LLC
Date: 10-1996
DOI: 10.1038/383685A0
Abstract: Strains of transmissible spongiform encephalopathies are distinguished by differing physicochemical properties of PrPSc, the disease-related isoform of prion protein, which can be maintained on transmission to transgenic mice. 'New variant' Creutzfeldt-Jakob disease (CJD) has strain characteristics distinct from other types of CJD and which resemble those of BSE transmitted to mice, domestic cat and macaque, consistent with BSE being the source of this new disease. Strain characteristics revealed here suggest that the prion protein may itself encode disease phenotype.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 18-01-2020
DOI: 10.1007/S00401-019-02107-8
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Publisher: Oxford University Press (OUP)
Date: 06-2003
DOI: 10.1093/BRAIN/AWG125
Abstract: According to the protein-only hypothesis of prion propagation, an abnormal isoform (designated PrP(Sc)) of the cellular prion protein (PrP(C)) is the principal or sole component of transmissible prions. However, the existence of multiple prion strains has been difficult to accommodate within this hypothesis. We have previously reported the identification of four types of human PrP(Sc) associated with sporadic and acquired human prion diseases. These PrP(Sc) types are distinguished by differing molecular mass of fragments following limited proteinase K digestion and by differing ratios of di-, mono- and unglycosylated PrP(Sc). That these discrete biochemical features of PrP(Sc) are serially transmissible to human PrP in transgenic mice following experimental transmission suggests that they may be responsible for encoding prion strain ersity. Here we present detailed clinical, pathological and molecular data from a large number of sporadic Creutzfeldt-Jakob disease (CJD) cases. We show that PrP(Sc) types are associated with codon 129 status, duration of illness and neuropathological phenotype. A novel PrP(Sc) type is presented, illustrating further heterogeneity in CJD, and suggesting that further molecular subtypes of CJD may exist at lower frequencies. A molecular classification of sporadic CJD is proposed.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.RADONC.2009.02.017
Abstract: To evaluate the impact of radiotherapy (RT) parameters on outcome in the SIOP/UKCCSG study of pre-RT chemotherapy for Supratentorial Primitive Neuro-ectodermal Tumours. Sixty-two patients aged 2.9-16.6 (median 6.4 years) were eligible. Forty-eight (77%) had non-pineal sites and 14 (23%) had pineal sites. Eleven were randomized to RT alone (6) and five to pre-RT Vincristine, Etoposide, Carboplatin and Cyclophosphamide. Fifty-one were not randomized, 15 receiving RT alone and 36 receiving pre-RT chemotherapy. Craniospinal RT (CSRT) 35 Gy/21 fractions were followed by 20 Gy/12 fractions to primary tumour. Mean CSRT dose was 34.7 Gy and mean total primary dose was 53.4 Gy for those who received radiotherapy. Of 30 relapses, 18 (60%) were local only and 5 (16.7%) were combined local and leptomeningeal. There was no significant impact on Overall Survival (OS) or Event-Free Survival (EFS) of surgery-RT interval for patients treated by pre-RT chemotherapy or RT alone, or duration of RT (completing within 50 days). Planning films were received for 42/54 (77.8%) patients. Fourteen (33%) had one or more targeting deviations (10 cribriform fossa, 11 base of skull). There was a statistically significant increase in the risk of recurrence for patients with cribriform fossa targeting deviations (p=0.033), but not for patients with base of skull targeting deviations (p=0.242). There was no statistically significant difference in OS (p=0.0598) or EFS (p=0.0880) for patients who had one or more targeting deviations compared to those who had none. This study has not demonstrated a statistically significant impact of radiotherapy duration or targeting deviations on OS or EFS, possibly due to small patient numbers. However, multi-institutional SPNET trials should incorporate quality assurance programs including analysis of relapse pattern in relation to primary target volume coverage.
Publisher: Oxford University Press (OUP)
Date: 07-06-2017
DOI: 10.1093/JNEN/NLX041
Publisher: Wiley
Date: 05-03-2009
Publisher: Springer Science and Business Media LLC
Date: 10-12-2015
Publisher: Wiley
Date: 23-01-2009
DOI: 10.1111/J.1537-2995.2008.01954.X
Abstract: Four recent cases of transfusion-related transmission of variant Creutzfeldt-Jakob disease (vCJD) highlight the need to develop a highly sensitive and specific screening test to detect infectivity in the blood of asymptomatic infected in iduals. Protein misfolding cyclic lification (PMCA), a method for the lification of minute amounts of disease-associated abnormal prion protein (PrP(Sc)) to readily detectable levels, could be incorporated into such a test provided that a suitable substrate source for routine use in human PMCA reactions can be found. With the use of seed sources from in iduals with variant and sporadic CJD, the use of human platelets (PLTs) as a PMCA substrate source was evaluated. The effects of seed/substrate prion protein gene (PRNP) codon 129 genotype compatibility on lification efficiency and freeze-thaw on a substrate's ability to support lification and the degree of lification achieved by serial PMCA (sPMCA) were investigated. Seed/substrate PRNP codon 129 compatibility was found to have a major influence on PrP(Sc) lification efficiency. In idual substrates, of the same PRNP codon 129 genotype, could be pooled and stored frozen for use in subsequent PMCA reactions. A consistent 10-fold increase in PrP(Sc) detection sensitivity was achieved after each round of sPMCA, resulting in a 10,000-fold increase in detection sensitivity after four rounds, with no evidence of de novo PrP(Sc) production detected in the unseeded PLT substrate. Providing issues of seed/substrate PRNP codon 129 compatibility are taken into consideration human PLTs are a suitable, readily available, renewable substrate source for use in human PMCA applications.
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 12-2009
Publisher: Wiley
Date: 09-08-2007
DOI: 10.1002/PATH.2204
Abstract: Variant Creutzfeldt-Jakob disease (vCJD) poses a serious risk of secondary transmission and the need to detect infectivity in asymptomatic in iduals is therefore of major importance. Following infection, it is assumed that minute amounts of disease-associated prion protein (PrP(Sc)) replicate by conversion of the host cellular prion protein (PrP(C)). Therefore, methods of rapidly reproducing this conversion process in vitro would be valuable tools in the development of such tests. We show that one such technique, protein misfolding cyclic lification (PMCA), can lify vCJD PrP(Sc) from human brain tissue, and that the degree of lification is dependent upon the substrate PRNP codon 129 polymorphism. Both human platelets and transgenic mouse brain are shown to be suitable alternative substrate sources, and lified PrP(Sc) can be detected using a conformation-dependent immunoassay (CDI), allowing the detection of putative proteinase K sensitive forms of PrP(Sc).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-12-2008
Publisher: SAGE Publications
Date: 25-11-2020
Abstract: Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R 2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87) p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45) p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42) p = 0.0004). Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Anonymized summary data may be requested from the corresponding author.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.EJCA.2009.03.018
Abstract: Relapsed ependymoma in children poses difficult dilemmas in management. Clinico-pathological and treatment data of 108 children with relapsed ependymoma in the United Kingdom (UK) treated between 1985 and 2002 were reviewed to identify prognostic factors affecting survival. The primary site was the most common site of relapse (84%). Overall 25% had metastatic relapse. Surgery at relapse was attempted in only 55%. Radiotherapy was delivered at relapse in 66% infants and 50% of older children were re-irradiated. Overall 5-year survival was 24% and 27% for children less than 3 years of age at initial diagnosis and older children, respectively. Multivariate analysis showed that, for infants, surgery (p=0.01) and radiotherapy (p=0.001) at relapse were independent predictors of survival. For older children regardless of the previous radiotherapy, repeat irradiation was associated with better outcome (p=0.05). Relapse was associated with poor outcome in both age groups. A survival advantage conferred by both radiotherapy and surgery at relapse is independently significant.
Publisher: Public Library of Science (PLoS)
Date: 24-08-2015
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for James Ironside.