Pleiotropic Effects of Erythropoietin

PhDThe haematopoietic growth factor Erythropoietin (EPO) is essential for the survival of erythroid progenitors to maturation and differentiation. It has been recognised that the EPO signalling pathway is also present in other tissues including the brain and vasculature, and is integral to the physiological response to ischaemia. Exogenous EPO was found to improve the outcome in animal models of stroke. The primary aim of this thesis was to examine whether erythropoietin was protective in a model of acute kidney injury, and to determine the mechanism by which EPO exerted this effect. In vitro experiments using HK-2 cells, a human tubular epithelial cell line, showed that EPO induced dose-dependent changes in cell number, and activated a number of intra-cellular signalling pathways. EPO reduced apoptotic cell death induced by nutrient starvation through the expression of anti-apoptotic proteins. A short-term model of ischaemia reperfusion was used to determine that EPO reduced the development of acute kidney injury, with a reduction in caspase activity and apoptosis. Longer models of ischaemia were then performed to confirm these findings, and showed that a pre-conditioning regime before the onset of the insult was also effective. In order to examine the mechanism of action, EPO was used in a model of cisplatin-induced kidney injury. EPO reduced apoptosis and caspase activation through the maintenance of mitochondrial membrane potential, inhibition of stress kinase signalling, and expression of XIAP and Bcl-XL. EPO also reduced the induction of oxidative stress and PARP-1 activity. EPO was then given to animals exposed to cisplatin and confirmed the finding that pretreatment with EPO significantly reduced cisplatin nephrotoxicity. Finally, EPO was used in a model of myocardial infarction and heart cells in culture to confirm that EPO plays a significant physiological role in cellular protection in multiple tissues

Bench to bedside: A role for erythropoietin in sepsis

Sepsis is the systemic inflammatory response to infection and can result in multiple organ dysfunction syndrome with associated high mortality, morbidity and health costs. Erythropoietin is a well-established treatment for the anaemia of renal failure due to its anti-apoptotic effects on red blood cells and their precursors. The extra-haemopoietic actions of erythropoietin include vasopressor, anti-apoptotic, cytoprotective and immunomodulating actions, all of which could prove beneficial in sepsis. Attenuation of organ dysfunction has been shown in several animal models and its vasopressor effects have been well characterised in laboratory and clinical settings. Clinical trials of erythropoietin in single organ disorders have suggested promising cytoprotective effects, and while no randomised trials have been performed in patients with sepsis, good quality data exist from studies on anaemia in critically ill patients, giving useful information of its pharmacokinetics and potential for harm. An observational cohort study examining the microvascular effects of erythropoietin is underway and the evidence would support further phase II and III clinical trials examining this molecule as an adjunctive treatment in sepsis

Rethinking ‘English as an additional language’: an ethnographic study of young migrants, language and schools.

This thesis is an ethnographic study of adolescent migrants in a South London secondary school. It examines what happens when young people from very different backgrounds encounter the education system in the UK. Very often, they are classified as ‘EAL’ (because they use English as an additional language) and are required to learn the majority language so that they can access the curriculum. I argue that this needs rethinking to take account of the skills, experiences and aspirations of the young people. The thesis is organised into three main parts. The first describes the setting and the broader context, and sets out the methodology that I follow in this study. The second contains the four analytical chapters; the third brings the discussion together, identifying the main findings and discussing the implications for practitioners, schools, policymakers and for the wider debates around migration, language and education. The study develops an innovative theoretical framework that analyses classrooms as spaces of ‘contact’ between young people with very different past experiences. It shows how their migration ‘trajectories’ are a crucial resource as they make sense of the school, and how they draw together resources from other times and places as they do (a process I describe as ‘networking’). The study also shows classrooms to be complex sociolinguistic environments with distinct interactional spaces, allowing the young people great flexibility as they encounter and negotiate the institution and each other. Increasing numbers of young people are moving through the education system in ways that were not foreseen even a few decades ago. Too often, they are defined in terms of linguistic deficiency and their experience of other ways of learning is ignored. This thesis argues for the urgent need to rethink that positioning, and offers an analytical framework to do so

Multiple Interventions for Diabetic Foot Ulcer Treatment Trial (MIDFUT): study protocol for a randomised controlled trial.

INTRODUCTION: Diabetes affects more than 425 million people worldwide with a lifetime risk of diabetic foot ulcer (DFU) of up to 25%. Management includes wound debridement, wound dressings, offloading, treatment of infection and ischaemia, optimising glycaemic control; use of advanced adjuvant therapies is limited by high cost and lack of robust evidence. METHODS AND ANALYSIS: A multicentre, seamless phase II/III, open, parallel group, multi-arm multi-stage randomised controlled trial in patients with a hard-to-heal DFU, with blinded outcome assessment. A maximum of 447 participants will be randomised (245 participants in phase II and 202 participants in phase III). The phase II primary objective will determine the efficacy of treatment strategies including hydrosurgical debridement ± decellularised dermal allograft, or the combination with negative pressure wound therapy, as an adjunct to treatment as usual (TAU), compared with TAU alone, with patients randomised in a 1:1:1:2 allocation. The outcome is achieving at least 50% reduction in index ulcer area at 4 weeks post randomisation.The phase III primary objective will determine whether one treatment strategy, continued from phase II, reduces time to healing of the index ulcer compared with TAU alone, with participants randomised in a 1:1 allocation. Secondary objectives will compare healing status of the index ulcer, infection rate, reulceration, quality of life, cost-effectiveness and incidence of adverse events over 52 weeks post randomisation. Phase II and phase III primary endpoint analysis will be conducted using a mixed-effects logistic regression model and Cox proportional hazards regression, respectively. A within-trial economic evaluation will be undertaken; the primary economic analysis will be a cost-utility analysis presenting ICERs for each treatment strategy in rank order of effectiveness, with effects expressed as quality-adjusted life years.The trial has predefined progression criteria for the selection of one treatment strategy into phase III based on efficacy, safety and costs at 4 weeks. ETHICS AND DISSEMINATION: Ethics approval has been granted by the National Research Ethics Service (NRES) Committee Yorkshire and The Humber - Bradford Leeds Research Ethics Committee; approved 26 April 2017; (REC reference: 17/YH/0055). There is planned publication of a monograph in National Institute for Health Research journals and main trial results and associated papers in high-impact peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN64926597; registered on 6 June 2017

Bostonia: The Boston University Alumni Magazine. Volume 16

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs

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Transplant and recipient factors in prediction of kidney transplant outcomes: a UK-wide paired analysis

Background: In kidney transplantation, the relative contribution of various donor, procedure and recipient-related factors on clinical outcomes is unknown. Previous paired studies have largely focused on examining factors predicting early outcomes, where the effect of donor factors is thought to be most important. Here, we sought to examine the relationship between early and long-term outcomes in a UK-wide paired kidney analysis. Methods: UK Transplant Registry data covering 24,090 kidney transplants performed between 2001–2018, where both kidneys from each donor were transplanted, were analysed. Case-control studies were constructed using matched pairs of kidneys from the same donor discordant for outcome, to delineate the impact of transplant and recipient factors on longer-term outcomes. Results: Multivariable conditional logistic regression identified HLA mismatch as an important predictor of prolonged delayed graft function (DGF), in the context of a paired study controlling for the influence of donor factors, even when adjusting for early acute rejection. Prolonged DGF, but not human leucocyte antigen (HLA) mismatch, strongly predicted 12-month graft function, and impaired 12-month graft function was associated with an increased risk of graft failure. Conclusions: This study indicates prolonged DGF is associated with adverse long-term outcomes and suggests that alloimmunity may contribute to prolonged DGF by a mechanism distinct from typical early acute rejection