Background: Critical care is the term used to encompass ‘intensive care units’, ‘intensive treatment units’ and ‘high dependency units’. These units provide expert care for critically ill patients who require constant, close monitoring and specialist nursing to keep them alive. Previous research has shown that admission to critical care can be a frightening, upsetting and traumatic experience. Haematological cancer patients who receive a haematopoietic stem cell transplant (HSCT) frequently require admission to critical care as a result of this potentially curative but extremely aggressive treatment. No previous research has explored the unique experience of HSCT patients admitted to critical care. Aim: To gain an in-depth understanding of the experience of cancer patients’ admission to critical care. Methods: Five HSCT patients who had been admitted to critical care completed semi-structured interviews. Transcripts were analysed using Interpretative Phenomenological Analysis. Results: Six superordinate themes were identified: gaps in recollection, unreal experiences, being in the right place, unexpected and unprepared, role of family and life after critical care. It was clear that despite the patients recalling potentially distressing experiences from their stay in critical care, they had no regrets about having the transplant and viewed their admission as being worth it. Themes are discussed in relation to relevant literature. Conclusions: This study offered a unique insight into the experience of being admitted to critical care following stem cell transplant. Implications for the treatment and care of cancer patients admitted to critical care are discussed.

Background: The prevalence of mental ill-health and problem behaviour within the intellectually disabled population is reported to range from 30 to 50%. However, the longer term outcomes of mental ill-health and problem behaviour, such as persistence, new onset, remission and resilience, are unknown. Accordingly, the factors predictive of such outcomes are also unknown. Aims: To determine the long term outcomes of mental ill-health and problem behaviour, and the factors predictive of and associated with such outcomes, over a 10 year time-period in a cohort of adults with mild to profound intellectual disabilities. Method: A population-based cohort of adults with intellectual disabilities (n=100) was investigated at three time points over a 10 year period. Data were collected using a range of measures. Descriptive statistics were derived and regression analyses performed to determine factors predictive of outcomes. Results: The rate of psychopathology was found to have increased in the cohort over the 10 year period. Factors predictive of this increase were experiencing an angry interaction and trusting to share a secret with only one person, or anyone. The majority of the cohort experienced episodic mental ill-health, with relapse being predicted by being female and experiencing life events. New onset of mental ill-health was predicted by experiencing life events, and resilience was predicted by not experiencing life events and having urinary continence. Problem behaviours were persistent in 50%, with 50% remitting. New onset of problem behaviours was predicted by not experiencing life events, and resilience was predicted by having mild intellectual disabilities, not experiencing an angry interaction and having more than one close friend. Small but significant negative correlations were found between psychopathology and participation in social, leisure, and peer activities. Findings should be interpreted with caution due to the small sample size. Conclusions: The present study is the only existing longitudinal investigation following an adult cohort with mild to profound intellectual disabilities, at several time points over a 10 year period. Therefore, future research is needed to confirm findings. Given the increase in psychopathology, more effective monitoring, treatment and intervention is needed.

Human cytomegalovirus (HCMV) infection in newborns and immunocompromised individuals with immature or deficient immune systems can cause life-threatening diseases. The clinical and subsequent economical burden of HCMV infection led the US Institute of Medicine designating a vaccine for HCMV as the highest level of priority. Complex virus-host interactions have developed over millions of years of co-evolution, making the understanding of the pathogenesis of HCMV disease particularly challenging. Consequently, a crucial factor in aiding the development of effective vaccinations and therapies to significantly reduce morbidity and mortality associated with HCMV infection is elucidating what immune mechanisms contribute to/impede protection against infection. For example, is the induction of immunomodulatory agents such as cytokines beneficial or harmful to the host during infection? Given the known immunosuppressive properties of one such cytokine, interleukin-10 (IL-10), in conjunction with the evolutionary acquisition by HCMV of its own IL-10 homologue, I hypothesised that mammalian- and viral-IL-10 suppress protective immunity during acute CMV infection. Utilising a mouse model of CMV infection, I revealed a surprising antiviral role for IL-10 during acute infection in vivo, which was achieved via limitation of activation-induced death of NK cells. The IL-10-related cytokine interleukin-22 (IL-22) provides critical protection against certain infectious agents and I therefore hypothesised that IL-22 provides protective immunity during acute CMV infection. Utilising the murine infection model once more, I discovered a tissue-specific antiviral role for IL-22 during acute infection in vivo and made the surprising finding that neutrophils play a protective role during infection. I also demonstrated that neutrophils can directly inhibit viral replication in vitro. Thus, novel insights into cytokine biology in the context of viral infections in vivo revealed by these studies highlighted important considerations for future research into herpesvirus infections, and has major implications for the treatment of this important infectious disease.

Nucleotide excision repair (NER) is critical for maintaining genome integrity. How chromatin dynamics are regulated to facilitate this process in chromatin is still under exploration. Htz1 (H2A.Z), a highly conserved histone H2A variant, is incorporated into the nucleosomes around the promoters of many genes in S. cerevisiae. Htz1 is involved in the maintenance of genome stability, DNA transcription activation, DNA replication and DNA repair. In this study, I employed Saccharomyces cerevisiae, as a model organism. In this thesis, I examined the role of histone Htz1 in the response to UV light at specific regions using a high resolution approach and throughout the entire yeast genome using chromatin-immunoprecipitation coupled to microarrays. htz1Δ and its deposition related mutants are more sensitive to UV and CPD removal was impaired in total DNA from both htz1Δ and swr1Δ strains. Acetylation of Htz1 at K3, 8, 10, 14 does not contribute to UV sensitivity or CPD removal from total DNA. CPD removal experiments at the MFA2 promoter and the HMRa1 coding region have showed that Htz1 has a role in NER and it likely only affects repair at local nucleosomes containing Htz1. My ChIP experiments at MFA2 and HMRa1 indicate that Htz1 enhances the binding of the HAT Gcn5 to Htz1 containing chromatin and this promotes histone H3 hyperacetylation in Htz1 nucleosomes in the MFA2 promoter after UV irradiation. As a result of this optimal level of histone H3 acetylation occur and the binding of Rad14 to damaged DNA is also enhanced at this region. My genome-wide study shows that UV does not influence the localization of Htz1 as it still resides at the pre-UV sites. Htz1 and H3 K9K14 acetylation is found to be associated with each other genome-wide. This is believed to be via the interaction between Htz1 and Gcn5. These results show that there is a positive role of Htz1 in promoting efficient GG-NER.

The complement system has crucial functions in host defence. Novel data revealed a role for complement components in the pathology of osteoarthritis (OA). CD59a is a regulator of the terminal complement pathway in mice; the purpose of the study was to determine if CD59a-/- mice have an osteoarthritic bone phenotype. Osteoblast (OB) mineralisation, colony forming unit (CFU) and OCG assays were performed in vitro from bone marrow preparations of 8-20 week old mice. Decreased CFU differentiating towards osteoblasts and adipocytes (n=1 only), as well as an increased OCG, was revealed in male CD59a deficient (-/-) over wildtype (WT) mice. OCG in females were comparable. A human CD59 knockdown system utilising short hairpin (sh) ribonucleic acid (RNA) delivered by adenoviruses was established but did not differentiate into osteoclasts (OC). In vivo the bone phenotype of CD59a-/- mice was established for femora and vertebra L6 via X-ray, microcomputed tomography and histology. In male mice femoral length was increased in CD59a-/- versus WT mice at 8-10, 20 and 50 weeks. Cortical bone volume was increased whilst bone mineral density (BMD) was reduced in CD59a-/- versus WT mice at 8-10 and 20 weeks. Trabecular bone analysis of the distal femur (and spine) showed increased trabecular bone ratio, number, thickness, connectivity and total BMD in CD59a-/- over WT at 8-10 (and 20) weeks of age. In female mice there was no difference in femoral length and trabecular bone, but cortical BMD was raised at 50 weeks (CD59a-/- versus WT). Finally, histology revealed enhanced mineral apposition rate and OC surface as well as reduced osteoid surface in male CD59a-/- over WT mice at 8-10 weeks of age. Increased bone growth and turnover related to CD59a gene deletion were gender specific. These studies highlight CD59a as a potential target for OA treatment.

Given the global rise of diabetes, the low uptake of GP services and prescribed medicine among UK Chinese is worrying. Little is known about their management of symptoms, compliance with treatment and implementation of lifestyle changes inherent in living with diabetes. Even less is known about whether they use Chinese folk medicine as part of their treatment regime. This qualitative study reduces this information gap based on data collected through focus group discussions and individual interviews. Eight focus group discussions were held in Leeds, Bristol, Birmingham and London with 37 foreign-born UK Chinese participants, including patients, friends and family members. On completion of the eight focus groups, 22 semi-structured individual interviews were conducted with both foreign and British-born Chinese with diabetes. Findings from the focus groups include (i) a reluctance to accept diabetes as a chronic illness, (ii) persistence in the use of folk remedies and (iii) an absence of use of professional Chinese medicine for diabetes, with the exception of one participant. Findings from the individual interviews on ideas about diabetes were similar to those from the focus groups, with further developments in the images of diabetes. With regards to self-management regimes, different coping styles indicated high levels of anxiety and uncertainty surrounding the nature of diabetes. Use of medicine, Chinese or otherwise, was found to be linked to levels of trust and integration with the host community. Themes consistent in both phases of the study include firstly, the description of diabetes as an illness with ‘no tail’ (mouhmei/meiwei 没尾) – the tail representing an end of an illness. Secondly, the cultural practice of food abstinence (gaihhauh/jikou 戒口) was perceived to be an effective method of control and prevention of the deterioration of diabetes. Finally, the relentless search for a cure expressed as ‘cutting the tail’ (tueihmei/duanwei 段尾) was evident in all the interviews. This study highlights the difficulties experienced by ethnic groups whose folk models of illness differ from those of biomedicine. It also addresses two important issues in the management of chronic illness: coping with uncertainty and the importance of trust. These results can help inform the future planning and delivery of healthcare services for ethnic minority groups.

Activation of complement and its terminal pathway leads to the formation and insertion of the membrane attack complex (MAC) in the membranes of target cells. Complement is activated in tumours as is clear from the presence of complement activation products in cancer tissues. Over-expression of membrane bound complement regulators on tumour cells together with endogenous recovery mechanisms restricts complement activity and results in escape from lytic killing; nevertheless, sublytic MAC deposition is not without consequence. Sublytic MAC assembly on nucleated cells causes cell activation, secretion of extracellular matrix and pro-inflammatory cytokines and may cause protection from apoptosis. Signalling of these events is unclear. The global effects of sublytic MAC were addressed in the murine colon carcinoma cell line (CT26) through the use of microarray technology. Cells were exposed to sublytic complement attack using pooled normal human serum (pNHS) and compared to MAC-inhibited controls generated using pNHS containing the C5 inhibitor OmCI. Total RNA was extracted at 0, 1 and 12 hours post-exposure and subjected to microarray analysis using the Illumina platform. Top statistically significant changes were then identified and a list of genes upregulated at both time points was uploaded to MetaCore and a gene network generated. From this a number of co-regulated genes which converged on the EGFR were highlighted. These were cxcl1, amphiregulin and matrix metalloproteinases (Mmp) 3 and 13. Both the top statistically significant and network derived genes were validated using qPCR. Changes in protein levels were then tested using western blot analyses for Mmp3 and Areg. Inhibition of the MEK/ERK, and to a lesser extent PI3K/Akt, signalling suppressed the gene upregulation that occurred in response to MAC but inhibition of p38 and JNK had no effect, implicating a MEK/ERK- PI3K co-activation. MAC deposition and not C5a/C5aR axis signalling was shown to be responsible for the mmp3 gene upregulation response. Identification of MAC-mediated events and the signalling pathways involved may provide insight into the mechanisms by which complement activation influences tumour growth. In particular the data suggest that sublytic MAC deposition might promote a gene expression response which pushes the cells to a more aggressive phenotype by the upregulation of proliferative, survival, invasion and migratory signals. This in turn will inform strategies that seek to harness complement or complement regulation in tumour immunotherapy.

The Natural Killer (NK) cell activating receptor DNAM-1 (CD226) is stimulated through recognition of CD112 (nectin-2) and CD155 (nectin-like molecule 5; PVR) on target cells. HCMV UL141 elicits protection from NK-cells by down-regulating CD155 from the cell surface and sequestering it in the ER (Tomasec, 2005). Here, HCMV UL141 was shown to be involved in the down-regulation of CD112. Interestingly, UL141 appeared necessary but not sufficient to modulate CD112 expression. This thesis therefore focused on a hypothesis whereby UL141 was acting with one or more additional HCMV genes to target CD112 for degradation. This project was the first to utilise an entire recombinant adenovirus (RAd) library expressing individual HCMV ORFs (RAd-HCMV-ORF library) to screen for function. The RAd-HCMV-ORF library clearly provided an extremely powerful tool for the screening of HCMV gene function as results were highly repeatable and robust. The co-infection of RAd-UL141 and RAd-US2 resulted in a single, clear, positive hit in the final screening process. This hit was further verified by immunoblot where CD112 appeared to be down-regulated in cells infected with both RAd-UL141 and RAd-US2, compared to controls. While a Hela-US2 cell line which stably expressed US2 also down-regulated CD112 when infected with RAd-UL141. A RCMVΔUS1-11 virus was constructed, which failed to down-regulate CD112 from the cell surface of RCMVΔSU1-11 infected cells. The addition of proteasome inhibitors was able to partially restore CD112 expression in HCMV infected cells (Prod'homme et al., 2010). It therefore appeared that US2 and UL141 act to degrade CD112 via the proteasome during HCMV infection. CD112 downregulation may have the potential to prevent DNAM-1:CD112 interaction between HCMV infected targets and effector cells of the immune system, providing another facet to HCMV’s ability to avoid the human immune response.

No description available.

This study views J. R. R. Tolkien's Lord of the Rings trilogy against its Anglo-Saxon background, specifically in light of Tolkien's 1936 Beowulf essay, and contends that the author consciously attempted to recreate the mood of the heroic poem. Chapter I compares Tolkien's use of historical perspective in Lord of the Rings with that of the Beowulf poet. His recognition of the poet's artistic use of history is stated in the "Beowulf" essay. Chapter II makes comparisons between Good and Evil as they are revealed in Beowulf and in the trilogy. Once again, much of the evidence for this comparison is found in Tolkien's Beowulf criticism. Chapter III examines the comitatus relationship fundamental to the heroic poem and to Lord of the Rings. It is the major element in Tolkien's portrayal of Good. Chapter IV concludes the study by asserting that the trilogy must be viewed as an heroic elegy, in exactly the same way that Tolkien viewed Beowulf. Thus, the theme of the trilogy, like Beowulf, is the mutability of man.