The Development of a Tory Ideology and Identity 1760-1832

This thesis examines the ideas which underpinned early nineteenth century Toryism and their development in the late eighteenth century. It argues that a distinct, coherent, refined Tory identity emerged from the Tory splits between 1827 and 1830. This was preceded by a process of renegotiation and consolidation in Tory ideology and identity from 1760 onwards. The period between the accession of George III, in 1760, and the passage of the First Reform Act, in 1832, witnessed consistent and sustained crises regarding the constitution established in Church and state. The outbreak of revolutions in America and France reinvigorated debates regarding the nature and location of political sovereignty as well as the relationship between the crown and parliament. Lengthy wars against each nation were followed by severe economic depressions, the apparent proliferation of domestic political radicalism, and intermittent, but determined, demands for parliamentary reform. In addition, there were persistent attempts to alter the religious basis of the constitution to accommodate both Protestant pluralism and, from 1801, predominantly Catholic Ireland. This thesis contends that the debates surrounding these issues contributed to the rehabilitation and renegotiation of late-seventeenth-century and early-eighteenth-century Tory ideas. It also contends that, in moments of crisis and reaction, old Toryism converged with the conservative elements of an increasingly fractured Whig tradition in defence of the constitutional status quo. This convergence, apparent in the opening decades of George III’s reign, was consolidated in the context of the French Revolution. Consequently, after 1812, a broad, but loose, ideological consensus emerged, labelled as Tory, underpinned by anti-populism, commitment to the preservation of Christian orthodoxy, and the establishment of the Church of England. However, below this broad ideological umbrella, differences persisted which created tensions, contributing to the divisions between 1827 and 1830, and, through them, the refinement of Tory identity

Fatigue after stroke: its frequency, natural history and associations with mood, physical activity and physical fitness

Background: Fatigue is common and distressing after stroke. Many stroke survivors say it is their worst or one of their worst symptoms. The frequency of clinically significant fatigue, whether fatigue is likely to be more or less problematic over time, and its aetiology are unknown. There are currently no known treatments. One hypothesis is that fatigue after stroke is triggered by physical deconditioning which sets up a self-perpetuating cycle of fatigue, avoidance of physical activity, further deconditioning and more fatigue. Another theory is that low mood may contribute to fatigue. Aims: This thesis therefore aims to investigate the frequency and natural history of fatigue after stroke and to explore its associations with mood, physical activity and/or fitness. Method: These aims were addressed by carrying out: 1) a systematic review of all longitudinal observational studies which have assessed fatigue on at least two separate time points and reported its frequency, 2) a systematic review of all observational studies which have measured both fatigue poststroke and one or more measures of physical activity and/or fitness at the same time point and 3) a longitudinal cohort study which assessed clinically significant fatigue, mood and physical activity and fitness at one, six and 12 months after stroke. Results: Frequency of fatigue ranged from 30% to 92% at first time point and frequency of fatigue decreased over time in seven of the ten studies identified in the systematic review of longitudinal studies. The second systematic review found that only two of the eight studies identified found a significant direct relationship between fatigue and physical activity and/or fitness poststroke. In the longtidudinal cohort study, clinically significant fatigue was identified in 32.6% of 132 participants at one month and was still present in a fifth of 91 participants at 12 months, two-thirds of participants who had clinically significant fatigue at one month did not have it by six months and that most (60.4%) individuals either reported fatigue at all three time points or that they did not have fatigue at any time point. There were significant associations between daily step count and fatigue at each time point (p=<0.0001, 0.011, 0.006). Physical activity (p=0.002, 0.006) and anxiety (p=<0.0001, 0.001) at one month were independent significant predictors of fatigue severity at six and 12 months after stroke. Age, gender, fatigue before stroke, step count and anxiety at one month accounted for 22% and 27% of the variance in fatigue severity at six and 12 months respectively. No significant associations were found between fatigue and measures of physical fitness. Discussion and conclusion: The findings suggest that although fatigue is common and persistent after stroke, it is more likely to become less problematic over time. They also suggest that the de-conditioning hypothesis of the aetiology of fatigue may be too simplistic and that other factors are involved in the development and perpetuation of fatigue after stroke. Implications are that patients should be assessed for fatigue early after stroke and that the development of an intervention which increases activity and/or reduces anxiety may be beneficial

Expression stability of commonly used reference genes in canine articular connective tissues

<p>Abstract</p> <p>Background</p> <p>The quantification of gene expression in tissue samples requires the use of reference genes to normalise transcript numbers between different samples. Reference gene stability may vary between different tissues, and between the same tissue in different disease states. We evaluated the stability of 9 reference genes commonly used in human gene expression studies. Real-time reverse transcription PCR and a mathematical algorithm were used to establish which reference genes were most stably expressed in normal and diseased canine articular tissues and two canine cell lines stimulated with lipolysaccaride (LPS).</p> <p>Results</p> <p>The optimal reference genes for comparing gene expression data between normal and diseased infrapatella fat pad were <it>RPL13A </it>and <it>YWHAZ </it>(M = 0.56). The ideal reference genes for comparing normal and osteoarthritic (OA) cartilage were <it>RPL13A </it>and <it>SDHA </it>(M = 0.57). The best reference genes for comparing normal and ruptured canine cranial cruciate ligament were <it>B2M </it>and <it>TBP </it>(M = 0.59). The best reference genes for normalising gene expression data from normal and LPS stimulated cell lines were <it>SDHA </it>and <it>YWHAZ </it>(K6) or <it>SDHA </it>and <it>HMBS </it>(DH82), which had expression stability (M) values of 0.05 (K6) and 0.07 (DH82) respectively. The number of reference genes required to reduce pairwise variation (V) to <0.20 was 4 for cell lines, 5 for cartilage, 7 for cranial cruciate ligament and 8 for fat tissue. Reference gene stability was not related to the level of gene expression.</p> <p>Conclusion</p> <p>The reference genes demonstrating the most stable expression within each different canine articular tissue were identified, but no single reference gene was identified as having stable expression in all different tissue types. This study underlines the necessity to select reference genes on the basis of tissue and disease specific expression profile evaluation and highlights the requirement for the identification of new reference genes with greater expression stability for use in canine articular tissue gene expression studies.</p

Mixed metal nanoparticle assembly and the effect on surface enhanced raman scattering

Here we report the assembly of mixed metal nanoparticles using an oligonucleotide-templated approach. Substitution of one of the gold nanoparticle probes with an analagous silver probe to produce a hetero-metal duplex permitted surface enhanced Raman scattering of the dye label, exploiting the improved surface enhancement properties of silver nanoparticles whilst maintaining the surface chemistry benefits of gold nanoaprticle

Comparison of Raman and near-infrared chemical mapping for the analysis of pharmaceutical tablets

Raman and near-infrared (NIR) chemical mapping are widely used methods in the pharmaceutical industry to understand the distribution of components within a drug product. Recent advancements in instrumentation have enabled the rapid acquisition of high-resolution images. The comparison of these techniques for the analysis of pharmaceutical tablets has not recently been explored and thus the relative performance of each technique is not currently well defined. Here, the differences in the chemical images obtained by each method are assessed and compared with scanning electron microscopy with energy dispersive X-ray microanalysis (SEM-EDX), as an alternative surface imaging technique to understand the ability of each technique to acquire a chemical image representative of the sample surface. It was found that the Raman data showed the best agreement with the spatial distribution of components observed in the SEM-EDX images. Quantitative and qualitative comparison of the Raman and NIR images revealed a very different spatial distribution of components with regards to domain size and shape. The Raman image exhibited sharper and better discriminated domains of each component, whereas the NIR image was heavily dominated by large pixelated domains. This study demonstrated the superiority of using Raman chemical mapping compared with NIR chemical mapping to produce a chemical image representative of the sample surface using routinely available instrumentation to obtain a better approximation of domain size and shape. This is fundamental for understanding knowledge gaps in current manufacturing processes; particularly relating the relationship between components in the formulation, processing condition, and final characteristics. By providing a means to more accurately visualize the components within a tablet matrix, these areas can all be further understood

Expression stability of commonly used reference genes in canine articular connective tissues

Background: The quantification of gene expression in tissue samples requires the use of reference genes to normalise transcript numbers between different samples. Reference gene stability may vary between different tissues, and between the same tissue in different disease states. We evaluated the stability of 9 reference genes commonly used in human gene expression studies. Realtime reverse transcription PCR and a mathematical algorithm were used to establish which reference genes were most stably expressed in normal and diseased canine articular tissues and two canine cell lines stimulated with lipolysaccaride (LPS). Results: The optimal reference genes for comparing gene expression data between normal and diseased infrapatella fat pad were RPL13A and YWHAZ (M = 0.56). The ideal reference genes for comparing normal and osteoarthritic (OA) cartilage were RPL13A and SDHA (M = 0.57). The best reference genes for comparing normal and ruptured canine cranial cruciate ligament were B2M and TBP (M = 0.59). The best reference genes for normalising gene expression data from normal and LPS stimulated cell lines were SDHA and YWHAZ (K6) or SDHA and HMBS (DH82), which had expression stability (M) values of 0.05 (K6) and 0.07 (DH82) respectively. The number of reference genes required to reduce pairwise variation (V) to <0.20 was 4 for cell lines, 5 for cartilage, 7 for cranial cruciate ligament and 8 for fat tissue. Reference gene stability was not related to the level of gene expression. Conclusion: The reference genes demonstrating the most stable expression within each different canine articular tissue were identified, but no single reference gene was identified as having stable expression in all different tissue types. This study underlines the necessity to select reference genes on the basis of tissue and disease specific expression profile evaluation and highlights the requirement for the identification of new reference genes with greater expression stability for use in canine articular tissue gene expression studies

Renal peroxiredoxin 6 interacts with anion exchanger 1 and plays a novel role in pH homeostasis.

Peroxiredoxin 6 (PRDX6) is one of the six members of the PRDX family, which have peroxidase and antioxidant activity. PRDX6 is unique, containing only one conserved cysteine residue (C47) rather than the two found in other PRDXs. A yeast two-hybrid screen found PRDX6 to be a potential binding partner of the C-terminal tail of anion exchanger 1 (AE1), a Cl(-)/HCO(3)(-) exchanger basolaterally expressed in renal α-intercalated cells. PRDX6 immunostaining in human kidney was both cytoplasmic and peripheral and colocalized with AE1. Analysis of native protein showed that it was largely monomeric, whereas expressed tagged protein was more dimeric. Two methionine oxidation sites were identified. In vitro and ex vivo pull-downs and immunoprecipitation assays confirmed interaction with AE1, but mutation of the conserved cysteine resulted in loss of interaction. Prdx6 knockout mice had a baseline acidosis with a major respiratory component and greater AE1 expression than wild-type animals. After an oral acid challenge, PRDX6 expression increased in wild-type mice, with preservation of AE1. However, AE1 expression was significantly decreased in knockout animals. Kidneys from acidified mice showed widespread proximal tubular vacuolation in wild-type but not knockout animals. Knockdown of PRDX6 by siRNA in mammalian cells reduced both total and cell membrane AE1 levels. Thus, PRDX6-AE1 interaction contributes to the maintenance of AE1 during cellular stress such as during metabolic acidosis.Human kidney sections were prepared by Suzy Haward, Addenbrooke's Human Research Tissue Bank, which is supported by the Cambridge Biomedical Research Centre. We thank Dr. Aron Fisher (Institute for Environmental Science, University of Pennsylvania) for the kind gift of Prdx6−/− mice and reagents, Carsten Wagner (Zurich) for antisera, Jane Clarke (University of Cambridge) for modified pRSET-A vector, and Kamburapola Jayawardena for mass spectrometry (CIMR). This work was funded by the Wellcome Trust (award 088489/Z/09/Z to FEKF and Strategic award 100140/Z/12/Z to the Cambridge Institute for Medical Research), and the Jack Kent Cooke Foundation (scholarship to SLS).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ki.2015.27

Responsible use of antibiotics on sheep farms: application at farm level

There is currently global concern over rising levels of antibiotic resistance among commensal and pathogenic bacteria in human and animal populations. Unless urgent action is taken by the medical and veterinary professions, it is thought that we will enter a postantibiotic era in which bacterial diseases that were readily treatable with antibiotics will kill once again. Consequently, antibiotic use in both the human and animal health industries has come under intense scrutiny. Long-held ideas and accepted behavioural norms have rightly been challenged. Progress in the agricultural industries has developed apace with the establishment of the Responsible Use of Medicines in Agriculture Alliance Targets Task Force in December 2016 and Defra’s call for the implementation of sector-specific targets on the use of antibiotics. This article describes how veterinary surgeons and sheep farmers can work together to plan, prevent and protect against three specific disease management issues – infectious lameness, enzootic abortion of ewes and neonatal bacterial infections – by replacing, refining and reducing the use of antibiotics on farm, based on guidelines drawn up by the Sheep Veterinary Society