Peter W. G. Morris

Is globotriaosylceramide a useful biomarker in Fabry disease

Aim: The aim of this study was to determine whether globotriaosylceramide (Gb3) is a useful biomarker in Fabry disease. Methods: The levels of Gb3 were measured in plasma and urine by tandem mass spectrometry in untreated hemizygotes and heterozygotes with Fabry disease and in healthy controls, and the levels were monitored in patients on treatment with enzyme replacement therapy (ERT). Results: Hemizygotes with classic Fabry disease showed elevated levels of Gb3 in both plasma and urine and could readily be distinguished from normal controls. Male patients with the N215S mutation had normal levels in their plasma but 50% had marginally elevated levels in their urine. Thirty‐three percent of proven heterozygotes had elevated Gb3 concentrations in plasma but 97% of those without the N215S mutation (36/37) had an elevated level in urine. The four heterozygotes with the N215S mutation had normal Gb3 levels in urine. The level of Gb3 in plasma initially fell following the start of ERT in all patients who had an elevated level before treatment. However, in a few patients the level subsequently rose. Similar results were found for the levels of Gb3 in urine.

Research into revising the APM Project Management Body of Knowledge

Abstract This paper describes research to review the UK Association for Project Management’s current Project Management Body of Knowledge. The research was commissioned by the APM and six leading companies. The paper describes how and why this work was carried out and sets out the new Body of Knowledge proposed as a basis for certifying competencies and benchmarking best practice and performance.

Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease

SummaryFabry disease is an X-linked disorder of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme α-galactosidase A. This deficiency leads to the progressive accumulation, in lysosomes of visceral tissues and in body fluids of hemizygotes, of the glycosphingolipids globotriaosylceramide (CTH, Gb3 or GL-3) and galabiosylceramide (CDH) and to a lesser extent the blood group AB and B related glycolipids. Elevated levels of the glycosphingolipids are found in the urine of hemizygous males with the classic phenotype, but it is not known whether all symptomatic or asymptomatic heterozygotes have elevated levels. We have therefore measured CTH and CDH quantitatively in a multiplex assay using tandem mass spectrometry in urine from a large cohort (44) of genetically proven or obligate heterozygotes including four with the N215S mutation, from classic hemizygotes (28), from cardiac variant hemizygotes with the N215S mutation (6) and from normal controls. The levels of CTH and CDH were related to both creatinine and sphingomyelin. Urinary CTH was elevated in all 28 classic hemizygotes but only in 4/6 of the cardiac variants. The level was within or just above the normal reference range in the four individuals heterozygous for the N215S mutation but was elevated in 38/40 of the other heterozygotes. Similar results were obtained for CDH, except that only 34/40 heterozygotes had an elevated level. The level of CDH was not elevated in the four heterozygotes and 4/6 of the hemizygotes for the N215S mutation. Combining the levels of CTH and CDH did not improve the discrimination of heterozygotes from controls. The ratio of CDH to CTH was higher in heterozygotes than in hemizygotes. Measurement of urinary CTH gave the best discrimination of heterozygotes from controls.

Managing the institutional context for projects

Project management is widely seen as delivering undertakings on time, on budget, and on scope. This conceptualization fails, however, to address the front end and its management. Addressing the front end moves the discipline to a second, more strategic level. This article proposes a third level of conceptualization: the institutional level, where management is focused on creating the conditions to support and foster projects, both in its parent organization and its external environment. Management here is done for and on the project rather than in or to it. We show that management at this level offers an enlarged research agenda and improvement in performance.

Reconstructing Project Management Reprised: A Knowledge Perspective

In May 2013, Wiley-Blackwell published Reconstructing Project Management (Morris, 2013), a book I had been working on, I suppose, for over 40 years, about the knowledge needed to manage projects and programs effi ciently and effectively. I was invited to summarize the main points in the book in an article for Project Management Journal (PMJ)®, which is what this is. Many academic researchers are primarily interested in projects as examples of temporary organizations, rather than in questions about building a discipline for the delivery of goals. Indeed, they may well be skeptical about our ability to define the kind of normative or prescriptive nature of the knowledge that would be required for such a discipline, or the value of such guidance should it be available. Having spent many years in the ‘real’ world of delivering projects, I believe that there does need to be, and that there is, a discipline for managing projects; and further, that this discipline needs to be enlarged from how many perceive it today. Doing this will not be easy, but the result will be an enormously more useful and relevant body of knowledge. This thesis is explored in the book’s three parts. Part 1 traces how our knowledge of the field developed, and how the subject has come to be constructed in the way we think of it today. Part 2 takes this construct apart— deconstructs it—describing the range of functions and skills that collectively constitute the latest thinking on the discipline. Part 3 then looks at how these elements of project management may need to be recombined— reconstructed—to meet today’s needs and tomorrow’s challenges. We need, I argue, to focus more on enhancing value and influencing context, while making an effective impact and addressing the major issues facing society today. Except for Part 2, which is not reprised here, this paper more or less follows this structure but does so from the perspective of investigating what knowledge we need, as a discipline, to manage projects and programs, efficiently and effectively. Specifically, it investigates: • How our knowledge of managing projects (which, for brevity is often, but not always, taken also to cover programs) was ‘invented.’ (It was not ‘found’); • How robust that knowledge is, in the sense of being reliable and true; and • In what way and to what ends we should be using that knowledge, and why.

Exploring the front-end of project management

This paper is a multi-case study exploratory investigation into the earliest stages of projects and their management. We refer to this throughout the paper as the ‘front-end’. We provide a definition of this phase of the project life cycle and conduct a literature review of the various topics that would suggest themselves to be apposite to the front-end. This includes governance and strategy; requirements and technology; estimating; risk and value; people and learning and development. Following this review of literature, we set out the approach taken in the empirical study. The context for the study was the UK, although many of the organizations investigated had a global presence and some of their projects were multinational in nature. We detail the research methods, the multi-case study route taken and the nature of the in-depth interviews with senior project management representatives from nine extremely credible organizations experienced in managing projects. Our findings are presented so as to identif...

The Strategic Management of Projects

Abstract This paper provides a comprehensive model of the issues that require managing if a project is to successfully initiated and accomplished. The model is illustrated extensively with examples drawn from a wide range of project experiences over the last 40 years. The paper shows the broad range of factors which need to be managed if projects are to be successful; it shows how such a range has so far tended to elude the project management community, which has concentrated rather more on computer systems and organizational techniques than on the strategic factors which are so essential to project success. The paper implicitly makes the point that the Macro-Engineering and Major Project Societies have a central role to play in developing a strategic view of the management of projects as here outlined.

Lessons in managing major projects successfully in a European context

Abstract The Major Projects Association (MPA) has, since 1982, been examining the initiation, assessment, securing and accomplishment of major projects. The development of better guides to the likely success or failure of major projects has been identified in the MPAs work as an area requiring immediate attention. The failure rate of major projects, at least nominally, is dangerously high. Major projects are often embarked upon without sufficient preparation. For this reason, it was considered that a better appreciation of the preconditions of their successes or failures ought to lead to an improved performance record.

The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells.

The Brn-3a POU family transcription factor is able to induce the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53 expression. Thus, in co-transfection experiments, Brn-3a activates the p53 promoter acting via a region from +22 to +67, located between the most proximal (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction of Brn-3a expression using anti-sense constructs reduces endogenous p53 expression in human neuroblastoma or cervical carcinoma cell lines growing in vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53 expression. These results suggest the existence of a negative feedback loop in which elevated Brn-3a expression induces the expression of p53 which, in turn, antagonises the anti-apoptotic activity of Brn-3a.

Cleland and King: project management and the systems approach

Purpose – The purpose of this paper is to review Cleland and Kings Systems Analysis and Project Management, first published in 1968.Design/methodology/approach – The paper takes the form of a review of the book in its historical context and with relevance to its role in establishing project management as a discipline.Findings – The book is a classic but in retrospect it has some short‐comings. These vary from lack of critique of the material to ignoring several of the issues that research shows (and showed at the time) that managers of projects and programs need to address. Had these been covered, the discipline might have been better articulated academically and professionally (which would have been useful given that the PMBOK Guide® was being formulated in the early 1980s).Research limitations/implications – The systems approach that informed the book, and the whole defence‐aerospace program and project world of the second half of the twentieth century, should be critically re‐examined (for example joi...