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Background: Family caregivers are essential to the healthcare system. However, they frequently experience negative psychological consequences and clinically significant levels of depression, anxiety and stress. Evidence suggests psychological interventions are effective in promoting the emotional health of dementia caregivers. However, we know little about the mechanisms underpinning therapeutic change. We conducted a systematic realist synthesis to build a theory to explain how interventions work using a context-mechanismoutcome framework. Improving our understanding of mechanisms will enable service providers to tailor appropriate interventions for carers in diverse contexts. Methods: We conducted a systematic review informed by realist methodology. We searched EMBASE, PsychInfo, CINAHL and grey literature using the following terms: dementia, caregiver, psychological intervention and mechanism. We included papers with psychological interventions that had a significant effect on desired outcomes, that outlined the process of change. We will describe an iterative process that has involved stakeholder expertise and feedback, in line with realist quality standards. Results: Searches returned 967 papers. Papers were screened, and 27 empirical papers were included. We identified conceptual models underpinning change, the key ingredients creating therapeutic change and the resources involved. These were synthesised into four context-mechanism-outcome frameworks to guide evidence based, service delivery. Conclusions: The mechanisms of change presented offer service providers a model for tailoring specific interventions to the needs of each caregiver. Realist methodologies can help us better understand research findings and provide us with the best opportunity to influence policy and improve outcomes for people affected by dementia.

BACKGROUND: Improving the quality of life (QOL), of people with dementia living in care homes is a priority. People living in care homes with more severe dementia are often unable to self-report QOL, so proxy ratings are needed. However, we do not know if, or how, paid and family caregiver proxy reports differ in care homes. Aim: To compare paid and family caregiver DEMQOL-Proxy-reports of care home residents with dementia and investigate any differences. METHODS: This study is nested in an epidemiological study of 86 care homes. I compared DEMQOL-Proxy total and global ratings of 1,056 pairs of staff and family carers and explored the associated factors using multilevel modelling. I interviewed 12 staff and 12 relatives about their proxy ratings and analysed their answers thematically. RESULTS: Proxy ratings were weakly correlated (rs = 0.35, p <0.001); paid carers’ median total scores were higher than family carers (104 vs 101; Z = -7.15, p < 0.001). Family carer global ratings were also more negative (X2 = 20.69 (N = 1,016), p < 0.001). Staff and family rated QOL as better when residents had fewer neuropsychiatric symptoms. Staff who were native English speakers rated residents QOL as better. Staff rated residents with severe dementia more highly on QOL. Resident’s QOL was rated more highly in homes with lower staff:resident ratio by staff. Family also rated QOL as higher when the resident spoke English as a first language, had lived for longer in the home and had no recent hospital admission. Resident’s spouses rated residents’ QOL higher than children. Qualitative results suggest differences arise because staff felt good care gave high quality of life but families experience loss and sadness at dementia and care home placement. CONCLUSION: Proxy reports are influenced by the rater and differ systematically between family and paid carers.

One of the most prevalent pollutants in urban cities is diesel exhaust particulate (DEP). Air pollution has been linked with increased risk of recurrent myocardial infarction (MI) and MI related death (Brook, 2008). This may be due, in part, to effects on atherosclerotic plaque stability and blood clotting tendency. Whether exposure to DEP changes the response of the heart to ischaemia, resulting in increased damage after MI is less well documented. The work described in this thesis was designed to investigate the hypothesis that pulmonary instillation of DEP would increase vulnerability of the heart to subsequent myocardial reperfusion injury secondary to activation of a systemic inflammatory response, endothelial dysfunction and triggering of transient receptor potential vanilloid 1 (TRPV1) mediated autonomic reflexes in the lung. Examination of bronchoalveolar lavage (BAL) fluid revealed pulmonary inflammation 6 h after exposure to DEP, characterised by neutrophil infiltration, raised levels of the inflammatory mediator interleukin-6 (IL-6) and an increase in alveolar permeability demonstrated by increased levels of protein in the lavage fluid. Pulmonary inflammation was largely resolved 24 h after exposure. While there was no indication of systemic inflammation at 6 h after DEP instillation, the levels of two inflammatory mediators, IL-6 and tumour necrosis factor alpha (TNFα) were increased in the plasma by 24 h after exposure. DEP had no affect on blood flow responses to the endothelium dependent dilator acetylcholine (ACh) in rat hind-limb vasculature in vivo at 6 or 24 h. In summary, while exposure of rats to DEP can induce both pulmonary and systemic inflammation, it does not modify endothelium-dependent vasodilatation. Ischaemia-reperfusion (I/R) was induced in vivo in anaesthetised rats and ex vivo in buffer perfused hearts from rats that had received DEP in vivo 6 h earlier. In both in vivo and ex vivo I/R models, infarct size (unstained by triphenyltetrazolium choride) was significantly increased in hearts from DEP-instilled rats relative to hearts from saline-instilled or non-instilled rats. Baseline oxidant stress, determined by electron paramagnetic spin resonance (EPR) in heart perfusate, was also significantly higher in perfusate of hearts from DEP-instilled rats. In summary, a single exposure of the lung to DEP leads to priming of the myocardium for I/R injury. As the results cited above illustrated, priming of hearts appeared unlikely to be due to either coronary vascular endothelial dysfunction or systemic inflammation. At 6 h post exposure, DEP was associated with increased blood pressure and myocardial hypersensitivity to ischaemia-induced arrhythmias, both suggestive of sympathetic activation. The beta 1 (β1) selective blocker metoprolol was used to investigate the role of the sympathetic nervous system (SNS) in transmitting the influence of DEP in the lung to the myocardium via β1 adrenoceptor activation. Administration of metoprolol (10 mg/kg, intraperotineal) at the time of DEP instillation into the lung was found to protect the heart from potentiation of ex vivo reperfusion injury. Metoprolol was also effective in reducing oxygen free radical generation from these hearts. The TRPV1 antagonist AMG 9810 was also used to study the role of TRPV1 receptors in mediating the priming influence of pulmonary DEP to the myocardium since activation of sensory receptors have been reported to modify sympathetic output via feedback to the central nervous system (Widdicombe et al., 2001). Coadministration of AMG 9810 (30 mg/kg) in vivo with DEP into the lung was found to prevent enhancement of ex vivo reperfusion injury associated with DEP instillation alone. Collectively these results have demonstrated that a single exposure of the lung to DEP leads to priming of the myocardium for I/R injury. Furthermore, this priming occurs via activation of a pulmonary sensory reflex that is likely to involve secondary activation of systemic β1 adrenoceptors.

The aim of the research described in this thesis was to investigate the structure and function of the bone morphogenetic protein-2 gene in the developing chick limb. A chicken Bmp-2 genomic clone was isolated The intron-exon structure was analysed and a portion of the 5' coding region, that was missing from cDNA clones previously isolated in our laboratory, was sequenced and analysed This 5' sequence and the intron-exon structure were found to be highly conserved with other members of the TGF-β superfamily, and Bmp genes from other species. Preliminary evidence indicates that the Bmp-2 gene has multiple 5' non-coding exons, like Bmp-4 and dpp, but unlike the other TGF-β superfamily genes. In order to analyse the 5' promoter region of the Bmp-2 gene, a novel system was developed for transfecting primary chick mesoderm cells isolated from embryonic limb buds. This transfection system provides as valuable model system in which to analyse the regulation of patterning genes expressed in the limb, since it spears to mimic various aspects of the developing limb, as shown by positional and temporal expression of various marker genes tested in the system. This is particularly useful since there are at present no established chick cell lines. However, we were unable to generate any promoter constructs of the putative promoter region of the Bmp-2 gene, possibly because of a region of instability in the 5' region of the gene. The role of the Bmp-2 gene in development was therefore further investigated by attempting to inhibit Bmp-2 gene function using an antisense RNA strategy. Antisense constructs containing various different regions of the chicken Bmp-2 gene were generated in a retroviral vector, RCAS(BP), which can be targeted to specific areas of the developing chick embryo, by injection or grafting of infected cells. Stage 16-21 embryonic chick limb buds were infected with these antisense Bmp-2 constructs. In preliminary experiments, these retroviral constructs appear to be expressed at relatively high levels in the limb, and to inhibit levels of endogenous Bmp-2 transcripts, as shown by in situ hybridisation. A possible phenotypic effect of this inhibition was shown to be a fusion between the metatarsals of digits III and IV in the wing.

Experiential avoidance (EA) is an unwillingness to remain in contact with private and overt experiences, with higher EA associated with increased psychopathology. This study investigated relationships among EA, age, and the use of emotion words in positive and negative autobiographical narratives, as well as whether EA was associated with depression, anxiety, quality of life, and social support. Participants included younger (n=60) and older adults (n=60), who completed a positive and negative emotion narrative task along with measures of psychopathology. Results indicated that relative to younger adults, older adults spoke for longer time intervals in both narrative conditions. EA did not significantly affect narrative duration in either age cohort. However, despite longer narrative durations, older adults high in EA used fewer negative emotion words in the negative emotion narrative task compared to young adults high in EA. EA was positively associated with anxiety and depression and inversely related to quality of life and social support. Results are explained in the developmental context of the Socioemotional Selectivity Theory (Carstensen, 1991), which posits that young adults are more prone to communicate in situations that involve information attainment, whereas older adults verbal behaviors may be more a function of emotion regulation. Clinical implications are discussed.