Separatism in Brittany

The introduction to the thesis attempts to place the separatist movement in Brittany into perspective as one of the various separatist movements with in France, It contains speculation on some possible reasons for the growth of separatist feeling, and defines terms that are frequently used in the thesis. Chapter One gives an account of Breton history, tracing Brittany's evolution as an independent state, its absorption by France, the disappearance of its remaining traces of independence, and the last spasms of action to regain this independence after having become merely part of a centralised state. Chapter Two examines the beginnings and development of a renewed effort to regain some measure of independence, and covers in some detail the period from the early nineteenth century to the end of the Second World War, known in Brittany as that of the first and second emsavs. To clarify a complicated period of development, a lexicon, a list of parties, groupings and devices of the Breton movement, and two flow charts summarising the movement's development from 1914 to I939 are given at the beginning of this chapter. Chapter Three deals with the period from I945 to the present day, known in Brittany as that of the third emsav, and examines in some detail the present state of the Breton movement. Chapter Four examines the work of various Breton writers who have played some part in expressing or shaping the Bretons' awareness of their separate identity, and shows to what extent their writings reflect the historical and political development of Brittany, Chapter Five contains the writer's conclusions and one detailed examination of Breton attitudes to the Breton movement, which helps to put it into its overall Breton perspective. The most important of the appendices to the thesis is the latest available detailed breakdown of the movement

Chronic kidney disease: a large-scale population-based study of the effects of introducing the CKD-EPI formula for eGFR reporting

Objective To evaluate the effects of introducing the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula for estimated glomerular filtration rate (eGFR) reporting in the adult population in routine clinical practice with clinician-directed testing. Design Retrospective study of all creatinine measurements and calculation of eGFRs using Modification of Diet in Renal Disease (MDRD) and CKD-EPI formulae. Setting General population, Oxfordshire, UK. Participants An unselected population of around 660 000. Interventions Reporting of eGFRs using MDRD or CKD-EPI formulae. Primary and secondary outcome measures Evaluation of the effects of the CKD-EPI formula on the prevalence of different stages of chronic kidney disease (CKD). Results The CKD-EPI formula reduced the prevalence of CKD (stages 2-5) by 16.4% in patients tested in primary care. At the important stage 2-stage 3 cut-off, there was a relative reduction of 7.5% in the prevalence of CKD stages 3-5 from 15.7% to 14.5%. The CKD-EPI formula reduced the prevalence of CKD stages 3-5 in those aged <70 but increased it at ages >70. Above 70 years, the prevalence of stages 3-5 was similar with both equations for women (around 41.2%) but rose in men from 33.3% to 35.5%. CKD stages 4-5 rose by 15% due exclusively to increases in the over 70s, which could increase specialist referral rates. The CKD classification of 18.3% of all individuals who had a creatinine measurement was altered by a change from the MDRD to the CKD-EPI formula. In the UK population, the classification of up to 3 million patients could be altered, the prevalence of CKD could be reduced by up to 1.9 million and the prevalence of CKD stages 3-5 could fall by around 200 000. Conclusions Introduction of the CKD-EPI formula for eGFR reporting will reduce the prevalence of CKD in a primary care setting with current testing practice but will raise the prevalence in the over 70s age group. This has implications for clinical practice, healthcare policy and current prevalence-based funding arrangements

DNA methylases for site-selective inhibition of type IIS restriction enzyme activity

DNA methylases of the restriction-modifications (R-M) systems are promising enzymes for the development of novel molecular and synthetic biology tools. Their use in vitro enables the deployment of independent and controlled catalytic reactions. This work aimed to produce recombinant DNA methylases belonging to the R-M systems, capable of in vitro inhibition of the type IIS restriction enzymes BsaI, BpiI, or LguI. Non-switchable methylases are those whose recognition sequences fully overlap the recognition sequences of their associated endonuclease. In switch methylases, the methylase and endonuclease recognition sequences only partially overlap, allowing sequence engineering to alter methylation without altering restriction. In this work, ten methylases from type I and II R-M systems were selected for cloning and expression in E. coli strains tolerant to methylation. Isopropyl β-D-1-thiogalactopyranoside (IPTG) concentrations and post-induction temperatures were tested to optimize the soluble methylases expression, which was achieved with 0.5 mM IPTG at 20 °C. The C-terminal His6-Tag versions showed better expression than the N-terminal tagged versions. DNA methylation was analyzed using purified methylases and custom test plasmids which, after the methylation reactions, were digested using the corresponding associated type IIS endonuclease. The non-switchable methylases M2.Eco31I, M2.BsaI, M2.HpyAII, and M1.MboII along with the switch methylases M.Osp807II and M2.NmeMC58II showed the best activity for site-selective inhibition of type IIS restriction enzyme activity. This work demonstrates that our recombinant methylases were able to block the activity of type IIS endonucleases in vitro, allowing them to be developed as valuable tools in synthetic biology and DNA assembly techniques

NEMA NU 2-2018 performance evaluation of a new generation digital 32-cm axial field-of-view Omni Legend PET-CT

A NEMA performance evaluation was conducted on the new General Electric (GE) digital Omni Legend PET-CT system with 32-cm extended field-of-view. This study marks the introduction of the first-ever commercially available clinical digital bismuth germanate technology. Testing was performed in accordance with the NEMA NU2-2018 standard. A comparison was made with the performance of two other commercial GE scanners with extended fields-of-view. A digital lutetium yttrium orthosilicate system (Discovery MI - 6 ring) and a non-digital bismuth germanate system (Discovery IQ). For the Omni assessment, the tangential, radial, and axial spatial resolutions at 1 cm radial offset were measured as 3.76 mm, 3.73 mm, and 4.25 mm FWHM. The total system sensitivity to a line source at the center was 44.36 cps/kBq. The peak NECR was 501 kcps at 17.8 kBq/mL. The scatter fraction at NECR peak was 35.48%, and the maximum count-rate error at and below NEC peak was 5.5%. Sphere contrast recovery coefficients were from 52% (10 mm) to 93% (37 mm). The system does not use time of flight; thus, no assessment of timing resolution was made. The PET-CT co-registration accuracy was 2.4 mm. The performance of the Omni Legend surpassed that of the Discovery MI on all NEMA tests, except for assessments of background variability (image noise). Time of flight is associated with inherent improvements in signal-to-noise ratio. In lieu of time of flight capabilities, the Omni provides software corrections in the form of a pre-trained neural network (trained on non-ToF to ToF). With such corrections, average performance is competitive when compared to ToF systems. Further validation is required to optimize clinical imaging protocols and hyperparameters associated with such software corrections and to examine the effect of non-linear corrections with varying target size, particularly for real world, clinical scans

Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1.

BACKGROUND AND AIMS: Coronary artery disease (CAD) risk is associated with non-coding genetic variants at the phosphatase and actin regulating protein 1(PHACTR1) gene locus. The PHACTR1 gene encodes an actin-binding protein with phosphatase regulating activity. The mechanism whereby PHACTR1 influences CAD risk is unknown. We hypothesized that PHACTR1 would be expressed in human cell types relevant to CAD and regulated by atherogenic or genetic factors. METHODS AND RESULTS: Using immunohistochemistry, we demonstrate that PHACTR1 protein is expressed strongly in human atherosclerotic plaque macrophages, lipid-laden foam cells, adventitial lymphocytes and endothelial cells. Using a combination of genomic analysis and molecular techniques, we demonstrate that PHACTR1 is expressed as multiple previously uncharacterized transcripts in macrophages, foam cells, lymphocytes and endothelial cells. Immunoblotting confirmed a total absence of PHACTR1 in vascular smooth muscle cells. Real-time quantitative PCR showed that PHACTR1 is regulated by atherogenic and inflammatory stimuli. In aortic endothelial cells, oxLDL and TNF-alpha both upregulated an intermediate length transcript. A short transcript expressed only in immune cells was upregulated in macrophages by oxidized low-density lipoprotein, and oxidized phospholipids but suppressed by lipopolysaccharide or TNF-alpha. In primary human macrophages, we identified a novel expression quantitative trait locus (eQTL) specific for this short transcript, whereby the risk allele at CAD risk SNP rs9349379 is associated with reduced PHACTR1 expression, similar to the effect of an inflammatory stimulus. CONCLUSIONS: Our data demonstrate that PHACTR1 is a key atherosclerosis candidate gene since it is regulated by atherogenic stimuli in macrophages and endothelial cells and we identify an effect of the genetic risk variant on PHACTR1 expression in macrophages that is similar to that of an inflammatory stimulus

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Idiopathic inflammatory myopathies; GenomeMiopatías inflamatorias idiopáticas; GenomaMiopaties inflamatòries idiopàtiques; GenomaObjective The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. Results The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. Conclusion We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.Supported by the Intramural Research Program, National Institute of Environmental Health Sciences, NIH. Dr. Lundberg's work was supported by grants from the Swedish Research Council and Stockholm Regional Council (ALF). Dr. Vencovsky's work was supported by the Czech Ministry of Health–Conceptual Development of Research Organization (award 00023728) (Institute of Rheumatology). Drs. Hanna and Machado's work were supported by the NIHR University College London Hospitals Biomedical Research Centre. Drs. De Bleecker and De Paepe's work were supported by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Dr. Wedderburn's work was supported by Versus Arthritis (awards 21593 and 21552), the Wellcome trust (award 085860), Myositis UK, the Cure JM Foundation, the Remission Charity, and the NIHR Biomedical research Centre at GOSH. Dr. Chinoy's work was supported by the Medical Research Council UK (award MR/N003322/1), Myositis UK, and the NIHR Manchester Biomedical Research Centre Funding Scheme. Dr. Lamb's work was supported by the Medical Research Council UK (award MR/N003322/1) and Myositis UK

Arclight : a pocket ophthalmoscope for the 21st century

PostprintPeer reviewe

Requirement for cystatin C testing in chronic kidney disease:a retrospective population-based study

Creatinine-based estimated glomerular filtration rate (eGFR) determines chronic kidney disease (CKD) stage, but underestimates renal function. The 2014 updated guidance from the National Institute for Health and Care Excellence (NICE) recommends that GPs reduce overdiagnosis of CKD stage 3a (eGFR 45-60 ml/min/1.73 m2) by using the renal biomarker cystatin C.To determine the population requirement for cystatin C testing, compared with current national availability of the assay.Retrospective study of primary care laboratory requests in Oxfordshire, England.The first creatinine results from tests ordered in primary care over a 6-year period (2008-2014) in a population of 600 000 in Oxfordshire were analysed and the number of patients with CKD stage 3a without proteinuria (who, in accordance with NICE guidance, required cystatin C) was determined. A conservative estimate of the national need was provided by scaling the population of Oxfordshire to the national population (CKD prevalence in the county is below the national average). Cystatin C assay availability was determined using national databases of laboratory assay provision.From a population of 600 000, there were 22 240 individuals with stable stage 3a CKD and no proteinuria. As the population of Oxfordshire equates to 1% of the UK population, there is an initial requirement for at least 2 million people to have their CKD status determined with cystatin C testing. Eight laboratories (2.1% of UK laboratories) reported cystatin C assay provision.There is a substantial gap between cystatin C assay requirements in primary care and national assay provision. This is a major barrier to implementing NICE guidance