BackgroundThe design of environments in which people with dementia live should be understandable, reinforce personal identity and maintain their abilities. The focus on supporting people with dementia to live well has omitted considering the needs or wishes for a supportive physical environment of those who are nearing the end of their lives. Using a combination of focus groups and a Delphi survey, this study explored the views of people with dementia, family carers and professionals on what aspects of the physical environment would be important to support a good quality of life to the very end.MethodsThree focus groups were carried out in three cities along the East Coast of Australia using a discussion guide informed by a literature review. Focus groups comprised recently bereaved family carers of people with dementia (FG1), people with dementia and family carers of people with dementia (FG2) and practitioners caring for people with dementia nearing or at the end of their lives (FG3). Focus group conversations were audio-recorded with participants’ consent. Audio files were transcribed verbatim and analysed thematically to identify environmental features that could contribute to achieving the goal of providing a comfortable life to the end. A list of design features derived from analysis of focus group transcripts was distributed to a range of experts in the dementia field and a consensus sought on their appropriateness. From this, a set of features to inform the design of environments for people with dementia nearing the end of life was defined.ResultsEighteen people took part in three focus groups: two with dementia, eleven current or recently bereaved family carers and five practitioners. There were differences in opinion on what were important environmental considerations. People with dementia and family carers identified comfort through engagement, feeling at home, a calm environment, privacy and dignity and use of technology to remain connected as important. For practitioners, design to facilitate duty of care and institutional influences on their practice were salient themes. Twenty one experts in the dementia field took part in the survey to agree a consensus on the desirable features derived from analysis of focus group transcripts, with fifteen features agreed.ConclusionsThe fifteen features are compatible with the design principles for people with dementia who are mobile, but include a stronger focus on sensory engagement. We suggest that considering these features as part of a continuum of care will support good practice and offer those with dementia the opportunity to live well until the end and give their families a more positive experience in the last days of their lives together.

Introduction The regulation of extracellular proteolytic activity via the plasminogen activation system is complex, involving numerous activators, inhibitors, and receptors. Previous studies on monocytic and colon cell lines suggest that plasmin pretreatment can increase plasminogen binding, allowing the active enzyme to generate binding sites for its precursor. Other studies have shown the importance of pre-formed receptors such as annexin II heterotetramer. However, few studies have used techniques that exclusively characterise cell-surface events and these mechanisms have not been investigated at the breast cancer cell surface.

PAI-1 and PAI-2 (plasminogen-activator inibitor types 1 and 2) are inhibitors of cell surface uPA (urokinase plasminogen activator). However, tumour expression of PAI-1 and PAI-2 correlates with poor compared with good patient prognosis in breast cancer respectively. This biological divergence may be related to additional functional roles of PAI-1. For example, the inhibition of uPA by PAI-1 reveals a cryptic high-affinity site within the PAI-1 moiety for the VLDLr (very-low-density-lipoprotein receptor), which sustains cell signalling events initiated by binding of uPA to its receptor. These interactions and subsequent signalling events promote proliferation of breast cancer cells. Biochemical and structural analyses show that, unlike PAI-1, the PAI-2 moiety of uPA-PAI-2 does not contain a high-affinity-binding site for VLDLr, although uPA-PAI-2 is still efficiently endocytosed via this receptor in breast cancer cells. Furthermore, global protein tyrosine phosphorylation events were not sustained by uPA-PAI-2 and cell proliferation was not affected. We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr.

Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by 213 Bi-labeled plasminogen activator inhibitor type 2 (A-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of A-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human A-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg A-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/ kg/d  5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d  5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of A-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies.