No description available.

The main focus of this thesis is chronic musculoskeletal pain (CMSKP) as this equates to the largest proportion of patients with chronic non malignant pain and results in the huge burden on the individual, society and health system. Pain interrupts, demands attention, and is difficult to disengage from and fear, anxiety and catastrophising are seen as major factors moderating the attentional demands of pain. Early work with clinical populations indicates considerable promise for fMRI methods to be used in pain diagnosis and therapy which may improve the categorisation of pain conditions in an objective manner based on a better understanding of central mechanisms. Given that treatment for CMSKP has not advanced for many years and behavioural research has not achieved consistent results, fMRI methods may help to provide further understanding of how pain-related attention, fear and catastrophising affect patients. The aim of the thesis was to explore Blood Oxygen Level Dependent (BOLD) signal changes in response to viewing non-painful pain-relevant stimuli. Three neuroimaging studies were undertaken. Two studies involved a population of CMSKP patients where an emotional counting pain and positive Stroop task was used and the other a modified visual task using pictures of activities of daily living (PHODA). One study recruited a population of chronic low back pain patients (CLBP) using a modified picture task and this also include voxel based morphometry and resting BOLD analyses. The main findings were that patients attended to the pain-related stimuli and BOLD region differences in patients compared to controls showed that anxiety, fear and catastrophising were implicated in the large number of regions traditionally involved in the sensory and emotional processing of pain. BOLD differences were greater with the picture stimuli than with a word stimulus. No differences in brain structure was seen in the CLBP group and resting BOLD results are discussed. Implications, limitations and future research directions are presented.

Cardiovascular disease including myocardial dysfunction and vascular disease is a major cause of morbidity and mortality among patients with type 1 diabetes mellitus. Early detection of myocardial dysfunction and identification of its determinants may be helpful in preventing diabetic heart muscle disease. In this thesis, I studied myocardial and vascular function in 53 subjects – 19 with type 1 diabetes mellitus (aged 21 ± 4 years, HbA1c 8.8 ± 1.6 %) and 34 controls (aged 25 ± 3). I measured myocardial functional reserve using myocardial velocity imaging during dobutamine in 18 patients and 21 controls. The main findings of this thesis were: 1. Longitudinal shortening of the left ventricle was reduced in type 1 diabetes mellitus. (medial mitral annular excursion 1.2±0.2 vs. 1.4±0.2 cm, p =0.01). 2. During dobutamine, long-axis peak systolic velocity was lower in type 1 diabetes by 20% at 10 and 13% at 20 μg/kg/minute (both p =0.05; ANOVA, p=0.003) but systolic velocities at peak dobutamine were similar and thus myocardial functional response was. 3. Longitudinal displacement was reduced in subjects with type 1 diabetes mellitus both at rest and during dobutamine stress. (by 15%, p =0.001). 4. Early diastolic relaxation was lower in type 1 diabetes, measured globally as the mitral E/A ratio (1.5±0.4 cm/s vs. 1.8±0.4 cm/s, p=0.02) or regionally as the early diastolic velocity of the medial mitral annulus (e’ -13.0±2.7 cm/s vs. -14.8±2.0 cm/s, p=0.02). 5. Features of adiposity and adverse lipid profiles, more than glycaemia, are major determinants also for myocardial and vascular dysfunction in young subjects with type 1 diabetes mellitus. In conclusion, there is evidence of myocardial dysfunction in young subjects with type 1 diabetes mellitus, and early changes may be related to metabolic rather than structural changes. Control of other risk factors such as dyslipidaemia, and maintenance of normal body weight, may be important measures in preventing progression of subclinical myocardial dysfunction into overt clinical disease.

Approximately 1400 HIV-positive women are known to become pregnant in the UK each year, the overwhelming majority being from Sub-Saharan Africa. The overall question I pose in this thesis is: how do African women living with HIV in the UK engage with HIV services and interventions during and after pregnancy? The question is addressed through a mixed methods approach. Drawing upon epidemiological data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood, and primary ethnographic data, I examine key outcomes (not receiving antiretroviral therapy during pregnancy, detectable maternal HIV viral load at delivery, vertical transmission, late antenatal booking and maternal loss to follow-up from HIV care after pregnancy), as well as exploring women's experiences. Women from Western Africa and those who had arrived in the UK after conception appeared to be at greater risk of poorer outcomes. Pentecostal beliefs in divine healing, although cited by professionals as a potential barrier to HIV care, did not necessarily prevent women from engaging with HIV services and interventions. Instead, a complex constellation of cultural and structural factors including stigma and lack of UK citizenship rights emerged as a greater challenge to engagement with care. Women described good relationships with their multidisciplinary HIV antenatal teams that fostered confidence in medical systems. On the other hand, some reported negative experiences, particularly with regards to poor maternity care at the time of delivery and difficulties in abstaining from breastfeeding. Overall I found that the majority of African women living with HIV in the UK engage well with HIV services and interventions during and after pregnancy, resulting in low rates of both vertical transmission and loss to follow-up after pregnancy. This highlights women's resilience and determination to engage with HIV care, despite challenges, in order to secure the health of their babies.

While technological advances in computing and telecommunications are revolutionising the way many organisations work, healthcare systems in The Gambia are very much lagging behind. No proper patient records or filing systems are in place. Delivery of effective healthcare depends on availability of routinely collected, good quality health data to provide useful information that is accessible when and where it is needed. Presently, in The Gambia, there is considerable scope for improvement in relation to such data. Electronic patient record system is long overdue. This research, focuses on the development of a Health Information System (HIS) capable of providing doctors, nurses and other healthcare professionals with quick and easy access to the appropriate information needed to care for their patients. A systems analysis has been undertaken to identify the full need for patient health data, the range of users and the extent of present paper-based provision. From this analysis, a requirements specification has been produced for a proposed health information and administration system (HIAS) to become operational and also successful in terms of efficiency and effectiveness. The requirements specification has taken the form of a series of precise statements of needs, buttressed with a corresponding justification in each case. By assessing what information and communication technology (lCT) is required and feasible, affordable and available in The Gambia, based on the extensive fieldwork involving interviews, observational study and questionnaires, a design specification (the logical and physical framework for the proposed ,IUAS) has also been produced as a precursor to the development of the proposed HIAS prototype. The approach,used will aid any implementor to progress from the proposed system to a fully functional one in an efficient and timely manner. Constraints in the programme of research were such that it was not possible to continue on with a prototype implementation based on this design. Hence it is now for The Gambia government to study and implement the proposed system. Several recommendations have been made in the areas of policies to be implemented, resources needed and training and motivation. In conclusion, the study has demonstrated the value or role of health informatics in the provision of health care in a developing country. It has contributed in the understanding of the complexities of the problems in The Gambia and developing countries, building this understanding in terms of requirements analysis and design specification and in methodological issues.

Significant advances have been achieved in the fields of medical informatics and artificial intelligence in medicine in the past three decades and, having demonstrated an ability to support clinical decisions, knowledge-based systems are becoming increasingly ubiquitous in various clinical settings. Nonetheless, few systems have so far been successful in entering routine use. On the one hand, primarily due to methodological difficulties and with very few exceptions, developers have failed to show that pertinent systems are effective in improving patient care. On the other hand, support systems have not been sufficiently well integrated into the routine information processing activity of the clinical users. As a consequence, their clinical utility is disputed and constructive assessmenist further hindered. This thesis describes the development of an intelligent clinical information management support system designed to overcome these obstacles through the adoption of an integrated approach, geared toward the solution of the problems encountered in the acquisition, organisation, review and interpretation of the clinical decision supporting information utilised in the process of monitoring intensive care unit patients with acid-base balance disorders. The system was developed to support this activity incrementally, using the methods of object-oriented analysis, design and implementation, with the active participation of a clinical advisor who assessed the functional and ergonomic compatibility of the system with the supported activity and the integration of a previously validated prototype knowledge-based data interpretation system, which could not evaluated in the clinical setting for the reasons described above.

The objective of this research programme is the development of a comprehensive mathematical model of the patient - artificial kidney machine system consisting of several interconnected subsystems of the human organism. The model is based on current general physiological knowledge, but can be tailored to simulate individual patients by adjusting model parameters. Model parameters for individual patients may be obtained by using a parameter identification technique and available past data of the patient. The model is designed to be used in an interactive mode by the renal clinician. Using the model as a predictive instrument, the clinician would be aided in the selection of optimal therapeutic procedures for individual patients. The model can also be used to represent the renal - body fluid system of a normal, healthy human. As such, it may be used as a vehicle with which to test hypotheses concerning the functioning of the complex and poorly understood control mechanisms of this system. Validation of the model was performed using pattern recognition feature comparison and classical least squares techniques.

No description available.

It is well acknowledged that molecular oxygen (O2) constricts vascular tissue under physiological conditions. In hypoxia, the decrease in partial pressure of O2 (pO2) within the tissue may be due to either a reduction in O2 supply or an increased O2 demand. The pulmonary circulation responds to a decrease in O2 by inducing vasoconstriction, whereas the systemic circulation induces vasorelaxation. Systemic vasorelaxation in hypoxia occurs by one of two presumed mechanisms, direct, in which smooth muscle cells can no longer sustain adequate contraction, or indirect, in which vasodilatory molecules are produced. Since the early 1990’s, several laboratories worldwide hypothesised that the vasodilatory molecules released under hypoxic conditions originated from the red blood cell (RBC). Several mechanisms have been proposed to date, including nitrite (NO2-) reduction by haemoglobin (Hb) to nitric oxide (NO), S-nitrosation of Hb to S-nitrosohaemoglobin (HbSNO) and adenosine triphosphate (ATP) binding to P2Y receptors on the vascular endothelium. Although there has been extensive research within this field, a clear mechanism by which vasorelaxation occurs is yet to be fully elucidated. Therefore, the aims of this thesis were to determine the vasodilatory specie(s) released from RBCs and the mechanism by which vasorelaxation occurs. Myography experiments were conducted using dissected rabbit thoracic aortae. Rings were equilibrated at various O2 concentrations, directly influencing tissue pO2. Bolus administration of oxygenated RBCs, isolated Hb or Krebs-Henseleit (KH) buffer to pre-constricted hypoxic rings induced a transient relaxation which was immediately followed by a post-constriction of equivalent magnitude. Interestingly, oxygenated KH buffer alone could induce relaxation of aortic rings in a similar manner to RBCs and Hb, demonstrating that O2 itself relaxes hypoxic vascular tissue. In addition, the extent of vasorelaxation was inversely related to the tissue pO2. Oxygenated KH buffer alone induced vasorelaxation in hypoxic pre-constricted rings pre-incubated with NOS inhibitor, L-NMMA, indicating an endothelium-independent mechanism. Subsequent experiments investigated the role of soluble guanylate cyclase (sGC) in the context of these findings. A number of studies have shown that sGC does not bind O2. However, the results present herein demonstrate that O2 can stimulate an enhanced activity of soluble guanylate cyclase (sGC), increasing the production of cyclic guanosine monophosphate (cGMP). Importantly, this could occur in the absence of NO but was found to be dependent upon the presence of haem. In order to compare O2-induced vasorelaxation in a vessel with an alternative function, the left anterior descending (LAD) artery was dissected from porcine hearts. Hypoxic pre-constricted LAD rings relaxed 20% more to a bolus of oxygenated RBCs or KH buffer compared to rabbit aortic rings and this was not due to an increased expression of sGC within the smooth muscle. Further experiments aimed to show whether vessel size had an effect upon the magnitude of O2-induced vasorelaxation in hypoxia. O2 induced a greater vasorelaxation in rings of smaller inner diameter. In conclusion, the results within this thesis show a direct relaxant effect of O2 that is mediated via the sGC-cGMP pathway and suggest a role for O2 in response of vascular smooth muscle in acute hypoxia.

Molluscum contagiosum virus (MCV) is a significant human pathogen causing benign tumours in the human skin. Molluscum contagiosum (MC) infection is most common in children, young adults and immunodeficient individuals. MCV replicates well in the human skin in vivo, but conditions that support MCV replication in vitro are unknown. The lack of in vitro cell culture system has significantly limited progress in MCV research. The aims of this study were, (i) To develop a reporter assay for the sensitive detection and quantitation of MCV infections in vitro, (ii) To express suitable MCV virion surface antigens to develop a sensitive MCV ELISA assay, and (iii) To raise and characterize monoclonal antibodies (mAbs) against these antigens for the detection of MCV in infected human skin. All goals were achieved. A reporter assay based on simultaneous transfection of luciferase/EGFP reporter plasmids and infection with live MCV worked well and was used to test the infectivity of MCV in several human and animal cells. A novel C-terminal MC084 ELISA was established and used to determine MCV seroprevalence in two European populations. mAbs against MC084 and MC133 were raised and partially characterized. Interesting findings were that MCV not only infects human keratinocytes, but also a wide range of animal and human cells in vitro, which, however, do not support replication. Our MCV ELISA gives seroprevalences in UK and German general populations comparable with previous Australian and Japanese studies (<40 years of age). Surprisingly, in older age groups (vaccinated against smallpox), a significantly higher MCV seroprevalence was observed. This was not due to crossreactivity with VACV. We propose this increase may be due to childhood MCV antibodies being boosted by subsequent vaccination or vice versa. Finally, the mAbs raised are unique reagents and will be used in future work to test a hypothesis that MCV replicates in human epidermal stem cells.