No description available.

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterised by symptoms of hyperactivity, impulsivity and attentional difficulties. Originally thought to be a condition of childhood, ADHD has now been recognised in adults. One of the main theoretical explanations of ADHD is related to deficits in Executive Functioning (EF). The state of current knowledge regarding the relationship between EF and ADHD was reviewed. Findings suggest that adults with ADHD are likely to exhibit deficits in EF mainly related to response inhibition, set-shifting or working memory. Deficits in EF as shown on neuropsychological tests may help to identify people who are at risk of under achieving in various life domains such as education or occupation. Tests of EF which are more ecologically valid may be more sensitive to EF dysfunction than traditional measures. The experience of having adult ADHD and preferences for support were explored using Interpretative Phenomenological Analysis (IPA). Four super- ordinate themes emerged from five interviews: 'Process of adapting to ADHD', 'Social Appraisal', 'Self-regulation' and 'Coping'. Participants described an adjustment process which impacted on their identity and the impact on self-perception was evident. ADHD was not understood well by others and some participants experienced stigma and bullying. A range of coping strategies were identified and clinical implications and limitations of the study were discussed. Finally, a commentary and reflexive analysis of the research process was offered and factors influential to the research were discussed.

Neural stem cell (NSC) transplantation is a promising therapy for the treatment of brain damage. Although the “proof of principle” for NSC transplantation therapy has been demonstrated in a variety of animal models of brain injury (stroke, traumatic brain injury, ageing) and in a clinical setting (Parkinson’s disease), the mechanisms by which grafted stem cells survive, migrate and differentiate in host brain are yet to be elucidated. Initial studies have demonstrated that, after transplantation of the MHP36 neural stem cell line in a focal ischaemia model, the lipid transport protein apolipoprotein E (apoE) is upregulated and co-localised to differentiated cells in parallel with functional recovery. ApoE has been shown to have a critical role in the response to brain injury and repair processes. Furthermore, in humans, three different forms of apoE exist (E2, E3, E4 encoded by the alleles e2, e3, e4) and each of these has a different ability to promote repair, with the E4 form associated with an impaired capacity. This thesis tests the hypothesis that apoE is critical in stem cell integration and investigates whether this effect is APOE genotype dependent, in a mouse model of global cerebral ischaemia. This model was chosen as it produces diffuse selective neuronal damage in the striatum and hippocampus, which also occurs in other conditions such as ageing and Alzheimer’s disease. The studies described in this thesis were designed to test the hypothesis and are outlined as follows: I. Characterisation of neural stem cell grafts in a mouse model of global ischaemia In order to investigate the potential influence of apoE on stem cell grafts, it was first essential to characterise stem cells grafts in mouse brain. Thus, the initial aim of the thesis was to characterise MHP36 grafts in a mouse model of ischaemic neuronal injury. The effect of cyclosporin A (CsA) immunosuppression was also investigated. C57Bl/6J mice underwent an episode of transient global ischaemia induced by bilateral common carotid artery occlusion. Three days following ischaemia, mice received a unilateral striatal graft of fluorescently labelled MHP36 neural stem cells or vehicle; the mice also received CsA or saline. The mice were terminated at either XVII 1 or 4 weeks post-transplantation. This study determined that MHP36 grafts survived and migrated robustly in host ischaemic brain at both 1 week and 4 weeks post-transplantation. Grafted MHP36 cells differentiated into neurons and were able to reduce the extent of ischaemic neuronal damage. An acute host inflammatory response was evoked following MHP36 grafting, but this decreased dramatically by 4 weeks post-transplantation. CsA immunosuppression did not affect MHP36 survival and migration or reduce the host inflammatory response. The successful transplantation and characterisation of MHP36 grafts in mouse brain allowed for future investigation into the genetic factors underlying stem cell graft integration via the use of apoE transgenic mice. II. Influence of apoE on neural stem cell grafts in a mouse model of global ischaemia The aim of this study was to investigate whether endogenous apoE influenced MHP36 survival, migration and differentiation and then to determine potential signalling pathways that may be involved. ApoE deficient mice on a C57Bl/6J background (APOE-KO) and control wildtype C57Bl/6J (WT) mice were subjected to an episode of transient global ischaemia, as in Experiment 1. Two weeks following ischaemia, all mice received unilateral striatal and hippocampal grafts of MHP36 cells. All mice received CsA immunosuppression. Mice were terminated 4 weeks post-transplantation. MHP36 survival and migration was significantly increased in WT as compared to APOE-KO mice. In addition, neuronal differentiation was significantly increased in WT as compared to APOE-KO mice. Increased astrocytic differentiation was observed in the hippocampus, but not striatum of WT as compared to APOE-KO mice. Measurement of the levels of signalling proteins associated with cell survival, extracellular signal-regulated kinase (ERKs) and c-Jun amino-terminal kinase (JNKs) and their phosphorylated forms (pERK and pJNK), indicated selective alterations in JNK with no change in ERK in APOE-KO as compared to WT mice, suggesting that JNK may underlie the apoE effects in stem cell integration. This study demonstrated that apoE strongly influences the survival, migration and differentiation of grafted MHP36 cells and provides initial evidence for the signalling pathways involved. XVIII III. Influence of APOE genotype on neural stem cell grafts in a mouse model of global ischaemia Following the demonstration that endogenous mouse apoE has a critical role in MHP36 graft survival, migration and differentiation, this study sought to investigate whether these effects are influenced by human APOE genotype. Transgenic mice expressing human APOE-e3 or e4, (on an APOE-KO background) and a control group of APOE-KO mice underwent transient global ischaemia and two weeks later MHP36 cells were transplanted unilaterally into the striatum and hippocampus. 1 week after grafting the mice were started on a series of tests for motor balance and coordination using the rotarod, and taken for histology 4 weeks post-transplantation. MHP36 graft survival was significantly improved in APOE-e3 mice compared to APOE-KO and APOE-e4 mice. However, the migration and differentiation of MHP36 cells and motor performance of grafted mice were similar in all three APOE groups, indicating a comparable fate and functional activity within a 4 week survival time. Thus the data indicate that APOE genotype may influence cell survival with minimal effect on stem cell migration and differentiation. The data presented in this thesis demonstrate that endogenous apoE strongly influences MHP36 graft survival, migration and differentiation. Although there was minimal evidence that human APOE genotype influences cell migration and differentiation, stem cell survival was markedly improved in a human APOE-e3 allelic environment, which may affect the effectiveness of stem cells in APOE-e4 individuals.

The healthcare sector is facing a significant challenge: delivering quality clinical care in a costly and intricate environment. There is a general consensus that a solution for many aspects of this problem lies in establishing a framework for effective and efficient clinical decision support. The key to good decision support is offering clinicians just-in-time accessibility to relevant patient specific knowledge. However, at the present time, management of clinical knowledge and patient records is significantly inadequate resulting in sometimes uninformed, erroneous, and costly clinical decisions. One of the contributing factors is that the field of healthcare is characterized by large volumes of highly complex medical knowledge and patient information that must be captured, processed, interpreted, stored, analyzed, and exchanged. Moreover, different clinical information systems are typically not interoperable. This thesis introduces an approach for realizing a clinical decision support framework that manages complex clinical knowledge in a form of evidence-based clinical practice guidelines. The focus of presented work is directed on the interoperability of knowledge, information, and processes in a heterogeneous distributed environment. The main contributions of this thesis include definition of requirements, conceptual architecture, and approach for an interoperable clinical decision support system that is stand-alone, independent, and based on open source standards.

Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs. Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. These results offer mechanistic insights into the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases. / Blodkärlsnybildning, så kallad angiogenes, är viktigt för fysiologiska processer vid embryonal utveckling, vävnadsregenerering och reproduktion. Samma angiogena process kan också under olika sjukdomstillstånd bidra till uppkomst, utveckling och progress av många sjukdomar, såsom cancer, diabeteskomplikationer, ögonsjukdomar, kronisk inflammation samt hjärtkärlsjukdom. Vascular endothelial growth factor (VEGF) är mycket viktig för fysiologisk och patologisk angiogenes. Utöver sin starka angiogena effekt inducerar VEGF även ökad kärlpermeabilitet, som ofta orsakar ödem. VEGF utövar sin effekt på kärlen via två tyrosinkinasreceptorer: VEGFR1 och VEGFR2, där den senare är en funktionell receptor som förmedlar både angiogena signaler och har effekter på vaskulär permeabilitet. För att öka möjlgheterna att studera fysiologiska och patologiska funktioner av VEGF, har vi utvecklat sjukdomsmodeller i zebrafisk - hypoxi-inducerad retinopati och metastasering av cancer. Vi har också givit anti-VEGF och anti-VEGFR-specifika antikroppar till friska möss för att utvärdera VEGFs roll vid stabiliseringen av kärlfunktionen i olika vävnader och organ. Slutligen,utvärderade vi om expressionen av VEGF regleras av dygnsrytmen genom så kallade klock-gener. I papper I utvecklade vi en modell för hypoxiinducerad retinopati hos vuxna zebrafiskar. Vuxna fli1:EGFP zebrafiskar placeras i syrefattigt vatten i 3-10 dagar, varpå retinal nybildning av kärl analyserades. Denna modell ger en unik icke-invasiv möjlighet att studera kinetiskt utveckling av retinopati och den möjliggör bedömning av terapeutiska effekter av oralt givna anti-angiogena läkemedel. I papper II utvecklade vi en zebrafiskmodell för utvärdering av cancermetastasering, som möjliggör studier av detaljerade delprocesser vid hypoxi-inducerad tumörcellsinvasion och metastasering i samband med angiogenes på encellig nivå. I denna modell användes fluorescerande Dil-märkta humana- eller mustumörceller som implanterades vid den perivitellina hålighet hos 48-h-gamla zebrafiskembryon placerade i syrefattigt vatten i 3 dagar. Tumörcellinvasion, metastasering och patologisk angiogenes analyserades med mikroskopi i levande fiskar. Vårt protokoll möjliggör studier av molekylära mekanismer bakom hypoxi-inducerad cancermetastasering. I papper III visas, att systemisk administration av anti-VEGF eller anti-VEGF-receptor (VEGFR)-2 neutraliserande antikroppar in en musmodell orsakar generell kärlregression. Bland alla undersökta vävnader påverkades endokrina körtlar, tarmslemhinna och uterus mest av VEGF eller VEGFR-2 blockad. Långvarig anti-VEGF behandling resulterade i en signifikant minskning av cirkulerande nivåer av det dominerande sköldkörtelhormonet, fritt tyroxin, men inte av trijodtyronin, vilket tyder på att kronisk anti-VEGF behandling försämrar sköldkörtelfunktionerna. Resultaten påvisar risken för biverkningar i friska vävnader av anti-VEGF behandling. I papper IV visar vi att störningar i dygnsrytm genom konstant exponering för ljus och genetisk manipulation av nyckelgener i zebrafisk ledde till nedsatt angiogenes under embryonal utveckling. En bmal1-specifik morfolino hämmade angiogenes i zebrafisk utan att orsaka andra kärl-oberoende fenotyper. Omvänt, en period2 morfolino accelererade angiogeneskärltillväxt, vilket tyder på att Bmal1 och Period2 utövar motsatta effekter påkärlstillväxt. Dessa resultat ger mekanistisk kunskap om den roll som dygnsrytmen har i regleringen av angiogenes, och resultat kan rimligen utvidgas till andra typer av fysiologisk eller patologisk angiogenes. Sammanfattningsvis ger resultaten i denna avhandling ytterligare kunskap om angiogenetiska mekanismer och pekar på möjliga nya terapeutiska mål för behandling av olika angiogenes-beroende sjukdomar.

The National Health Service (NHS) in England is changing, not only in terms of the technical aspects of care (such as that afforded by new technology), but also in the way in which care is delivered to patients. For example, due to the increasing pressures being placed upon health services, hospitals need to develop innovative ways to reduce the length of time patients actually spend in hospital. Whilst this improves capacity planning, bed management and patient flow, it also seeks to ensure improved patient safety by delivering care and ongoing treatment in the most appropriate setting. However, discharging patients from hospital can be challenging and fraught with complexities. Therefore, the efficient and effective management of this process can have a considerable impact on subsequent clinical outcomes and readmission rates. As such, effective discharge planning and practice has become an integral part of health service policy and, in recent years, there has been an increased emphasis placed on the contribution nurses make to this process (Department of Health, 2002; 2005a; 2005b). New recommendations from the Kings Fund (Seale, 2016) suggest that a collaborative relationship between patients, carers, third sector parties and communities is central to the future of the NHS. This is because these perspectives are fundamental; indeed, patients are the reason the NHS exists. Since 2010, this has been the aim of my doctoral research ― to explore a shared leadership approach in determining the principles of care. The purpose of this study is to gain an insight into (and a greater understanding of) patient experiences during the discharge process following percutaneous coronary intervention (PCI) after myocardial infarction (MI) ― commonly known as a heart attack. PCI is a relatively new procedure; since its implementation it has resulted in patients staying in hospital for less than three days. Previous management would regularly result in patients remaining in hospital for longer than seven days. However, reducing the length of stay has potentially impacted how information and communication are both provided and understood by patients on discharge from acute hospital care. Previous research such as Hainsworth (2006), Department of Health (DoH) (2004) and Picker (2010) suggests that whilst there has been a great deal of emphasis placed on policy, there still remains scope for improvement in practice. As qualitative research is a form of social enquiry that focuses on the way people make sense of their experiences and the world in which they live, this research focuses on individuals who have had a heart attack and have then undergone the same treatment. The aim is to understand, describe and interpret their experiences, behaviour and feelings by looking at social processes and interactions. This was based on undertaking three separate focus groups involving patients, clinicians and members of the management team from a local NHS acute hospital in West London. Furthermore, in-depth, semi-structured interviews with eight patients were conducted. The idea behind surveying patients', clinical staff and managers narratives/opinions, was to establish a holistic view of discharge planning and practice. Recommendations for change could then be made dependant on these findings, in order to improve the effectiveness and efficiency of this process, in addition to patients’ experiences. Following the completion of the focus groups and semi-structured interviews, analysis was undertaken to identify whether any common themes emerged across the three different groups. Although the narratives identified varying views, the most significant of the emerging themes was that of communication and the attitude of staff. Indeed, further analysis confirmed that communication was a prevalent issue in all three focus groups. The findings suggest patients have specific individual needs; this would not be surprising given the treatment and care received. Communication was also noted to be a major theme for patients; whilst clearly the majority of patients were relatively happy with the care received, they remained keen to make suggestions for improvement. The attitude of staff also featured strongly; patients were keen to suggest the changes they required and their rationale for these suggestions. The clinicians' themes mirrored the patients' themes, whilst also incorporating resource and innovation. The managers' themes commonly focused on service and proposed new ways of working, which included 'joined-up' working across acute and community services. Furthermore, the clinicians' and managers’ themes recognised that the attitudes of all groups of staff remained a challenge. In conclusion, this study has demonstrated the requirement for and the importance of effective communication throughout the entire discharge process. The aims are as follows: to ensure that post-procedure patients are discharged home or into a community setting safely; that they receive the right care, treatment and information in the most appropriate setting; and that they find and use ways to facilitate their recovery. Furthermore, this study has validated the importance of empowering patients to live with their diagnosed condition/disease by enabling the provision of support post-discharge. To this end, there is a need to ensure that positive values (such as empathy and compassion) remain a core part of the discharge planning process. This can be achieved by recognising each patient as an individual who is trying to make sense of a daunting life-changing experience whilst maintaining their own core belief and value systems. As a result, recommendations for improvements and change within this study have been based upon these findings. Further research needs to be defined to ensure that discharging patients from an acute hospital to their home or community setting remains both safe and effective, whilst also being informative and empowering.

Members of the Mycobacterium abscessus complex (MABSC) are a highly antibiotic-resistant complex of organisms within the genus Mycobacterium, increasingly acknowledged as a significant cause of lung infection in patients with cystic fibrosis (CF) and associated with poor clinical outcomes. Current methods of isolation of MABSC are hindered by the fact that they grow at a slower rate in culture than other microorganisms with many patient samples having to be discarded due to the overgrowth of more rapidly growing species. Decontamination of samples has shown to have an adverse effect upon the viability of MABSC, therefore improvements in the isolation of MABSC are urgently required in order to offer the possibility of a more rapid and accurate diagnosis. A novel medium (RGM) was developed for the isolation of MABSC. Commercially available pre-poured media were compared with RGM and challenged with isolates of rapidly growing mycobacteria and other species. In addition, in a multi-centre study sputum samples collected from patients with CF were inoculated onto RGM medium, BCSA and standard automated liquid culture method and assessed for growth. RGM demonstrated superior sensitivity over currently used methods without any requirement for decontamination and could easily be incorporated into any laboratory alongside routine culture for other CF pathogens. Chromogenic and fluorogenic substrates were investigated for the possibility of differentiating between subspecies within the MABSC complex. However, the results established that these would not provide any additional benefit to RGM. Possible environmental sources were explored in order to establish how patients with CF were acquiring MABSC. Although person-to-person transmission has been suggested, there are very few reports to substantiate this at present and many questions remain unanswered. In this study, MABSC was not isolated from any of the environments screened. Finally, a selection of antimicrobials were investigated against MABSC with the purpose of ascertaining susceptibility and whether any may be used for a more successful treatment outcome. There were no clinically applicable results therefore further work is required in this area. To conclude, RGM is a novel culture medium, which can be embedded alongside routine culture for other CF pathogens without any requirement for decontamination. This means that all respiratory samples submitted from patients with CF can be conveniently cultured for NTM, considerably improving the service offered to clinicians and patients. Furthermore, it is likely that formal AFB culture methods could be replaced by use of such a medium, potentially enabling substantial savings in terms of materials and labour time.

Species relationships of the endemic Elaphoglossum, and the extent and distribution of population genetic diversity were investigated using allozyme analysis in chapter five. As well as supporting the relationships of the taxa in the molecular phylogeny, the allozyme data suggest a hybrid origin of E. dimorphum between E. nervosum and E. bfurcatum. In addition the allozyme data revealed significant genetic differentiation in populations of E. nervosum and E. bfurcatum which should be taken into consideration in any future conservation programme. To conclude, Chapter 5 is a general discussion on the evolution and conservation of island plants, highlighting my research findings from St Helena and comparing it to other studies.

Thesis (Ph.D.)--McMaster University, 2006. / Supervisor: Lee R. Brooks and Geoffrey R. Norman. Includes bibliographical references (leaves 81-90). Mode of access: World Wide Web.

Thesis--M. Phil., University of Hong Kong, 1986.