Ribose supplementation alone or with elevated creatine does not preserve high energy nucleotides or cardiac function in the failing mouse heart

Background: Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE). Methods and Results: Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (r2 = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels. Conclusion: Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated

Ribose supplementation alone or with elevated creatine does not preserve high energy nucleotides or cardiac function in the failing mouse heart

Background: Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE). Methods and Results: Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (r2 = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels. Conclusion: Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated

‘My Mother Won the War’: Patriotism and the First World War in Sylvia Townsend Warner’s Scenes of Childhood (1981)

This essay discusses the subversive treatment of the First World War and patriotism in four of Sylvia Townsend Warner’s neglected New Yorker short stories fromthe 1930s, 1940s and 1950s, later collected in Scenes of Childhood and Other Stories (1981)

Changes in creatine transporter function during cardiac maturation in the rat

BACKGROUND: It is well established that the immature myocardium preferentially utilises non-oxidative energy-generating pathways. It exhibits low energy-transfer capacity via the creatine kinase (CK) shuttle, reflected in phosphocreatine (PCr), total creatine and CK levels that are much lower than those of adult myocardium. The mechanisms leading to gradually increasing energy transfer capacity during maturation are poorly understood. Creatine is not synthesised in the heart, but taken up exclusively by the action of the creatine transporter protein (CrT). To determine whether this transporter is ontogenically regulated, the present study serially examined CrT gene expression pattern, together with creatine uptake kinetics and resulting myocardial creatine levels, in rats over the first 80 days of age. RESULTS: Rats were studied during the late prenatal period (-2 days before birth) and 7, 13, 21, 33, 50 and 80 days after birth. Activity of cardiac citrate synthase, creatine kinase and its isoenzymes as well as lactate dehydrogenase (LDH) and its isoenzymes demonstrated the well-described shift from anaerobic towards aerobic metabolism. mRNA levels of CrT in the foetal rat hearts, as determined by real-time PCR, were about 30% of the mRNA levels in the adult rat heart and gradually increased during development. Creatine uptake in isolated perfused rat hearts increased significantly from 3.0 nmol/min/gww at 13 days old to 4.9 nmol/min/gww in 80 day old rats. Accordingly, total creatine content in hearts, measured by HPLC, increased steadily during maturation (30 nmol/mg protein (-2 days) vs 87 nmol/mg protein (80 days)), and correlated closely with CrT gene expression. CONCLUSIONS: The maturation-dependant alterations of CK and LDH isoenzyme activities and of mitochondrial oxidative capacity were paralleled by a progressive increase of CrT expression, creatine uptake kinetics and creatine content in the heart

Evaluating the repeatability and set-up sensitivity of a large field of view distortion phantom and software for magnetic resonance-only radiotherapy

Background and purpose: Magnetic Resonance (MR)-only radiotherapy requires geometrically accurate MR images over the full scanner Field of View (FoV). This study aimed to investigate the repeatability of distortion measurements made using a commercial large FoV phantom and analysis software and the sensitivity of these measurements to small set-up errors. Materials and methods: Geometric distortion was measured using a commercial phantom and software with 2D and 3D acquisition sequences on three different MR scanners. Two sets of repeatability measurements were made: three scans acquired without moving the phantom between scans (single set-up) and five scans acquired with the phantom re-set up in between each scan (repeated set-up). The set-up sensitivity was assessed by scanning the phantom with an intentional 1 mm lateral offset and independently an intentional 1° rotation. Results: The mean standard deviation of distortion for all phantom markers for the repeated set-up scans was for all scanners and sequences. For the lateral offset scan of the markers agreed within two standard deviations of the mean of the repeated set-up scan (median of all scanners and sequences, range 78%–93%). For the 1° rotation scan, 80% of markers agreed within two standard deviations of the mean (range 69%–93%). Conclusions: Geometric distortion measurements using a commercial phantom and associated software appear repeatable, although with some sensitivity to set-up errors. This suggests the phantom and software are appropriate for commissioning a MR-only radiotherapy workflow

Technical assistance, neo-colonialism or mutual trade? The experience of an Anglo/Ukrainian/Russian social work practice learning project

Since the collapse of the Soviet Union there has been a steady stream of Western consultants ready to work in Eastern Europe and Russia and share professional and academic expertise and experience. Social work, unknown as a discrete discipline or profession in the Soviet Union, has been a growth area with funding from a variety of sources to help promote East-West partnerships.Social work theory and practice emphasises critical appraisal of policy and embraces issues of power, discrimination and oppression. Social work educators should therefore be especially alert to the complex ethical questions which these kinds of collaborations raise, and adept at finding practical solutions or workable compromises. This article explores these ethical and political issues with reference to a project to develop social work practice learning in a Russian oblast' (region). The project was an ambitious partnership of British, Ukrainian and Russian educators, involving numerous Russian social work and related agencies, and four Russian universities and colleges in one oblast'. The authors use a series of vignettes to help the reader achieve insights into these East-West transactions. The article concludes with a discussion of different interpretations of these dealings, using three prisms: technical assistance, neo-colonialism and mutual trade

Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes

Background: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. Methods: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. Results: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20%-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. Conclusion: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely as a clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator that delivers appropriate comparisons and drive improvements in care

Smuggling Ships:An Analysis of the Lord Admiral’s Deputation to Bristol Preventing the Sale of Ships to Foreigners, 1624/5

A previously unexamined document within the Society of Merchant Venturers’ (SMV) Book of Trade, dated the 16th of March 1625, constitutes the centrepiece of this study. Using personal transcriptions, this document reveals a seventeenth-century deputation dispatched by George Villiers, the 1st Duke of Buckingham and Lord Admiral, to Bristol's mayor and a prominent city merchant. Buckingham’s directive had a precise aim: preventing the sale of ships over 50 tons in Bristol to ‘any forraigne partes’ without provision of a substantial bond. Drawing from a wealth of sources, including state papers, proclamations, and contemporary accounts, the paper explores why an in-depth primary source analysis renders this initially relatively unassuming document highly fascinating. The analysis proves particularly fascinating in three respects: it refines existing historiography on the clandestine world of smuggling in early modern Bristol by illuminating a form of illicit trade – the smuggling of ships – which has been overlooked in existing accounts; it accentuates the indispensable value of the merchant class and their ships amidst contemporary challenges of piracy and fragile statecraft; and importantly, it unveils an overlooked facet of early national preparations for the Anglo-Spanish war of 1625. In doing so, the paper enriches our understanding of a colourful period of maritime history defined by geopolitical turbulence and economic ambition

Sylvia Townsend Warner and the Question of Feminism

Sylvia Townsend Warner was a self-supporting writer who attacked the subordination of women, celebrated energy and freedom in women, and lived openly in a lesbian marriage. Yet she has not become a feminist heroine: perhaps because her activism was left-wing rather than feminist, perhaps because of her hostility to bossy, entitled women. She loved her father who educated her informally, and her links with his former male pupils at Harrow were important during the 1920s in establishing her as a literary presence. She attacked patriarchal oppression in her fiction, from her first novel, Lolly Willowes, to her last, The Flint Anchor. Of her few essays directly addressing gender politics, the most important is ‘Women as Writers’ (1959), written in unspoken dialogue with Virginia Woolf’s A Room of One’s Own, in which Warner praises women for outwitting the conventions meant to silence them and for the ‘immediacy’ of their writing