A systems and cybernetic perspective on complex problem solving

This thesis is concerned with Organisational Problem Solving. The work reflects the complexities of organisational problem situations and the eclectic approach that has been necessary to gain an understanding of the processes involved. The thesis is structured into three main parts. Part I describes the author's understanding of problems and suitable approaches. Chapter 2 identifies the Transcendental Realist (TR) view of science (Harre 1970, Bhaskar 1975) as the best general framework for identifying suitable approaches to complex organisational problems. Chapter 3 discusses the relationship between Checkland's methodology (1972) and TR. The need to generate iconic (explanatory) models of the problem situation is identified and the ability of viable system modelling to supplement the modelling stage of the methodology is explored in Chapter 4. Chapter 5 builds further on the methodology to produce an original iconic model of the methodological process. The model characterises the mechanisms of organisational problem situations as well as desirable procedural steps. The Weltanschauungen (W's) or "world views" of key actors is recognised as central to the mechanisms involved. Part II describes the experience which prompted the theoretical investigation. Chapter 6 describes the first year of the project. The success of this stage is attributed to the predominance of a single W. Chapter 7 describes the changes in the organisation which made the remaining phase of the project difficult. These difficulties are attributed to a failure to recognise the importance of differing W's. Part III revisits the theoretical and organisational issues. Chapter 8 identifies a range of techniques embodying W's which are compatible with .the framework of Part I and which might usefully supplement it. Chapter 9 characterises possible W's in the sponsoring organisation. Throughout the work, an attempt 1s made to reflect the process as well as the product of the author's leaving.

Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers

Aim - The aim of the study was to determine the potential for KV1 potassium channel blockers as inhibitors of human neoinitimal hyperplasia. Methods and results - Blood vessels were obtained from patients or mice and studied in culture. Reverse transcriptasepolymerase chain reaction and immunocytochemistry were used to detect gene expression. Whole-cell patch-clamp, intracellular calcium measurement, cell migration assays, and organ culture were used to assess channel function.  KV1.3 was unique among the  KV1 channels in showing preserved and up-regulated expression when the vascular smooth muscle cells switched to the proliferating phenotype. There was strong expression in neointimal formations. Voltage-dependent potassium current in proliferating cells was sensitive to three different blockers of  KV1.3 channels. Calcium entry was also inhibited. All three blockers reduced vascular smooth muscle cell migration and the effects were non-additive. One of the blockers (margatoxin) was highly potent, suppressing cell migration with an IC of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia. Conclusion - KV1.3 potassium channels are functional in proliferating mouse and human vascular smooth muscle cells and have positive effects on cell migration. Blockers of the channels may be useful as inhibitors of neointimal hyperplasia and other unwanted vascular remodelling events. © 2010 The Author.