Jonathan Hill

Proteomics identifies thymidine phosphorylase as a key regulator of the angiogenic potential of colony-forming units and endothelial progenitor cell cultures.

Endothelial progenitor cell (EPC) cultures and colony-forming units (CFUs) have been extensively studied for their therapeutic and diagnostic potential. Recent data suggest a role for EPCs in the release of proangiogenic factors. To identify factors secreted by EPCs, conditioned medium from EPC cultures and CFUs was analyzed using a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer combined with offline peptide separation by nanoflow liquid chromatography. Results were verified by RT-PCR and multiplex cytokine assays and complemented by a cellular proteomic analysis of cultured EPCs and CFUs using difference in-gel electrophoresis. This extensive proteomic analysis revealed the presence of the proangiogenic factor thymidine phosphorylase (TP). Functional experiments demonstrated that inhibition of TP by 5-bromo-6-amino-uracil or gene silencing resulted in a significant increase in basal and oxidative stress-induced apoptosis, whereas supplementation with 2-deoxy-d-ribose-1-phosphate (dRP), the enzymatic product of TP, abrogated this effect. Moreover, dRP produced in EPC cultures stimulated endothelial cell migration in a paracrine manner, as demonstrated by gene-silencing experiments in transmigration and wound repair assays. RGD peptides and inhibitory antibodies to integrin &agr;v&bgr;3 attenuated the effect of conditioned medium from EPC cultures on endothelial migration. Finally, the effect of TP on angiogenesis was investigated by implantation of Matrigel plugs in mice. In these in vivo experiments, dRP strongly promoted neovascularization. Our data support the concept that EPCs exert their proangiogenic activity in a paracrine manner and demonstrate a key role of TP activity in their survival and proangiogenic potential.

Beyond the Other? A postcolonial critique of the failed state thesis

This article challenges existing analyses of state failure and their casting of African societies in the role of deviant Other to those of Western Europe and North America. Drawing on insights derived from postcolonial studies, the article argues that the comparative approach to identifying so‐called failed states adopted by this literature contrasts African states to a static, ahistorical definition of the state based on exclusively European values customs, practices, organisation and structures. In this way, failed state analysts constitute the identities of African societies in relation to those of the West, simultaneously attributing negative characteristics to the former and positive to the latter. By calling for a rejection the term failed state the article seeks to challenge the continued positioning of African societies in the role of delinquent, deviant and imperfect Other.

Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina

BACKGROUND Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium. METHODS We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months. RESULTS A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction. CONCLUSIONS In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

Cells as biologics for cardiac repair in ischaemic heart failure

The epidemic of heart failure due to coronary artery disease is a leading cause of morbidity and mortality worldwide. The hallmark of this pathology is maladaptive ventricular remodelling that precipitates contractile dysfunction, and ultimately leads to the overt syndrome of congestive heart failure. The central feature in this malignant cascade is the massive loss of cardiomyocytes, followed by replacement with fibrotic scar; this ultimately leads to organ failure which is further accelerated by haemodynamic overload, inflammatory–oxidative stress, and/or impaired vascularisation. Despite continuous advances in disease management, the available medical, interventional or surgical treatments fall short of addressing the root cause of disease and are typically limited to palliative strategies mitigating disease symptomatology. The rationale for stem cell based regenerative medicine applied to the treatment of heart diseases is based on the realisation that natural self renewing processes innate to the myocardium, while sufficient to sustain normal homeostasis, fall short of salvaging heart muscle following massive injury—as in the setting of myocardial infarction.1 Accordingly, boosting the cardiac reparative capacity through supplementation of stem cell pools has been increasingly considered as a novel therapeutic approach. Indeed, it is now recognised that extracardiac (eg, bone marrow) in addition to intracardiac progenitor cells are mobilised and home to the site of the myocardial injury to participate in the compensatory healing response.1 w1 Furthermore, there is growing evidence that such cells participate in the maturation and induction of collateral vascular growth and neovasculogenesis, and may acquire phenotypic properties of neighbouring cardiac myocytes.1 These findings, propelled by recent progress in developmental biology, offer an unprecedented opportunity to achieve repair of damaged myocardium using stem cells as new therapeutic tools. Here, we focus on the current clinical experience as well needs for successful translation of the emergent field of cell based therapy from proof-of-concept …

Cell-based therapies for cardiac repair : A meeting report on scientific observations and European regulatory viewpoints

In the past decade, novel cell‐based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end‐stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell‐based medicinal products developed for cardiac repair, with a focus on non‐manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non‐clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell‐based therapies for cardiac repair in the context of scientific observations.

Challenging the Failed State Thesis: IMF and World Bank Intervention and the Algerian Civil War

With the onset of civil war in the early 1990s, Algeria appeared to join the growing list of failed African states. The idea of state failure has developed over the past 20 years and is now common currency amongst academics and political leaders alike. The aim of this article is to investigate the analytical usefulness of the academic state failure literature, and its ability to explain the onset and development of socio-political crises in post-colonial African states. The article identifies two important weaknesses in this literature: its dichotomisation of the international and domestic spheres, and the emphasis on domestic factors in its explanation of why such crises occur. Through its analysis of the International Monetary Funds (IMF) and World Banks interventions in Algeria between 1994 and 1999 the article substantiates the criticisms it makes of this literature.

Identity and Instability in Postcolonial Algeria

Abstract This article analyses the nation building efforts of the post-independence regimes of Ahmed Ben Bella, Houari Boumedienne and Chadli Benjedid, and the definition of the nation promoted by them. It is argued that nation building was one of the main strategies adopted by these regimes for consolidating and legitimising their political authority. However, the FIS rejected the balance struck by these regimes between the essentialist themes of Islam and Arabism, and the epochalist theme of socialism. The article therefore highlights how disagreements over national identity influenced the socio-political instability that developed in the country in the late 1980s.

Thoughts of Home: Civil–Military Relations and the Conduct of Nigeria's Peacekeeping Forces

Abstract The aim of this paper is to cast new light on the conduct of Nigerias peacekeeping forces over the past 20 years by examining the Nigerian militarys relationship with its own citizens. Time and again while on operations in Liberia and Sierra Leone, these forces have abused human rights and engaged in criminal activities. That they have continued to do so is evidence of the culture of contempt prevalent in the Nigerian military. The paper argues that this culture is, in part, the result of the militarys treatment of its own civilian population. Its repeated interventions in the political process and actions in the Niger Delta and while performing police duties elsewhere, have given rise to abusive patterns of behaviour which its officers and men have then taken with them when deployed abroad.

The “side‐BASE technique”: Combined side branch anchor balloon and balloon assisted sub‐intimal entry to resolve ambiguous proximal cap chronic total occlusions

Failure to penetrate the proximal cap or cross with equipment remains the most frequent cause of procedural failure in CTO PCI. In the “BASE” technique concerns were raised over the risk of proximal side branch loss. We here describe the evolution of this technique and highlight examples where the sub‐intimal space was accessed proximal to the occlusion by using the side branch. This technique can be of use both in resolving proximal cap ambiguity and also in cases where there is difficulty crossing a resistant proximal cap.

Images in InterventionA Calcific, Undilatable Stenosis: Lithoplasty, a New Tool in the Box?

A 69-year-old man with established coronary artery disease and left ventricular dysfunction (ejection fraction, 40%) with typical Canadian Cardiovascular Society class III angina underwent percutaneous coronary intervention (PCI) for severe diffuse calcific disease in the right coronary artery ([