Studies of the role of nf-κb in controlling osteoclast differentiation and bone loss

Increased osteoclast (OC) bone resorption and/or decreased osteoblast (OB) bone formation contribute to bone loss in osteoporosis and rheumatoid arthritis (RA). Findings of the basic and translational research presented in this thesis demonstrate a number of mechanisms by which cytokine-induced NF-κB activation controls bone resorption and formation: 1) Tumour necrosis factor-α (TNF) expands pool of OC precursors (OCPs) by promoting their proliferation through stimulation of the expression of macrophage colony stimulating factor (M-CSF) receptor, c-Fms, and switching M-CSF-induced resident (M2) to inflammatory (M1) macrophages with enhanced OC forming potential and increased production of inflammatory factors through induction of NF-κB RelB; 2) Similar to RANKL, TNF sequentially activates transcriptional factors NF-κB p50 and p52 followed by c-Fos and then NFATc1 to induce OC differentiation. However, TNF alone induces very limited OC differentiation. In contrast, it pre-activates OCPs to express cFos which cooperates with interleukin-1 (IL-1) produced by these OCPs in an autocrine mechanism by interacting with bone matrix to mediate the OC terminal differentiation and bone resorption from these pre-activated OCPs. 3) TNF-induced OC formation is independent of RANKL but it also induces NF-κB2 p100 to limit OC formation and bone resorption, and thus p100 deletion accelerates joint destruction and systemic bone loss in TNF-induced RA; 4) TNF receptor associated factor-3 (TRAF3) limits OC differentiation by negatively regulating non-canonical NF-κB activation and RANKL induces TRAF3 ubiquitination and lysosomal degradation to promote OC differentiation. Importantly, a lysosomal inhibitor that inhibits TRAF3 degradation prevents ovariectomy-induced bone loss; 5) RelB and Notch NICD bind RUNX2 to inhibit OB differentiation and RelB:p52 dimer association with NICD inhibit OB differentiation by enhancing the binding of RBPjκ to Hes1. These findings suggest that non-canonical NF- κB signaling could be targets to develop new therapies for RA or osteoporosis. For example 1) Agents that degrade TNF-induced RelB could block M1 macrophage differentiation to inhibit inflammation and joint destruction for the therapy of RA; 2)Agents that prevent p100 processing or TRAF3 degradation could inhibit bone resorption and also stimulate bone formation simultaneously for the therapy of osteoporosis.

Organisational and systems factors impacting on patient safety in acute care organisations: lessons from four multi-site research studies

Background Patient safety is concerned with preventable harm in healthcare, a subject that became a focus for study in the UK in the late 1990s. How to improve patient safety, presented both a practical and a research challenge in the early 2000s, leading to the eleven publications presented in this thesis. Research question The overarching research question was: What are the key organisational and systems factors that impact on patient safety, and how can these best be researched? Methods Research was conducted in over 40 acute care organisations in the UK and Europe between 2006 and 2013. The approaches included surveys, interviews, documentary analysis and non-participant observation. Two studies were longitudinal. Results The findings reveal the nature and extent of poor systems reliability and its effect on patient safety; the factors underpinning cases of patient harm; the cultural issues impacting on safety and quality; and the importance of a common language for quality and safety across an organisation. Across the publications, nine key organisational and systems factors emerged as important for patient safety improvement. These include leadership stability; data infrastructure; measurement capability; standardisation of clinical systems; and creating an open and fair collective culture where poor safety is challenged. Conclusions and contribution to knowledge The research presented in the publications has provided a more complete understanding of the organisation and systems factors underpinning safer healthcare. Lessons are drawn to inform methods for future research, including: how to define success in patient safety improvement studies; how to take into account external influences during longitudinal studies; and how to confirm meaning in multi-language research. Finally, recommendations for future research include assessing the support required to maintain a patient safety focus during periods of major change or austerity; the skills needed by healthcare leaders; and the implications of poor data infrastructure.