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The World Health Organisation's (WHO) 'Health for All by the Year 2000' (HFA2000) resolution is intended to promote improvements in the equality of health care provision, the basis of which is universal accessibility to basic health care. The Jordanian Government, in accordance with HFA2000, has attempted to improve accessibility in rural communities by providing an extensive network of basic rural health clinics which are intended to be acceptable and accessible to all communities. Within this context, the research considers two interrelated themes. The first theme considers changes in health and illness practices, and particularly the wide-scale and rapid acceptance of modern medical services at the same time as `traditional' Arabic medicines are becoming relatively unimportant in the north east Badia. This study highlights the connections between health and illness discourses in the past, Bedu social values, and the wider social economic milieu, and how these are reflected in the forms and use of Arabic medicines. The literature widely assumes that culture, `traditional' social structures and attitudes inhibit the acceptance and effective utilisation of modern medical services, and that education, for example, is a key way to address this problem. This research engages with this assumption by evaluating the significance of social values, education and health awareness programmes, knowledge of health issues, together with socio-economic changes in explaining the acceptance of modern medicine and the adoption of preventative medicine and practices, together with changing attitudes to children's health. The second key theme of this research is to examine the extent to which basic government health services have been made accessible to the nomadic, sedentarising and settled rural population of the north east Jordan Badia, and specifically their children, a particularly vulnerable group, and whether this explains patterns of health and illness behaviour. To this end, the importance of geographical, organisational (health service), economic and social factors is evaluated in explaining variations in accessibility mediating the effective utilisation of these services at family level.

Background: Military medicine has historically advanced in war. Advances in concepts, technology, organisation and operational processes have occurred during the contemporary conflicts of the last decade. Aims: To determine whether the advances constitute a ‘Revolution in Military Medical Affairs (RM2A)’; to demonstrate my role within a revolutionary transformation; and to introduce new theory to determine if advances have been appropriately matched to clinical need. Definition: An RM2A is defined here as a radical change in the character or practice of military medicine. Methods: 20 papers are selected (15 first author; 5 second author) that describe the changes in modern combat casualty care. These are clustered into conceptual (doctrine) innovation; changes to organisational structure and operational processes; and advances in technology. These are analysed against Lambeth’s (1997) criteria for a Revolution in Military Affairs (RMA); Cohen’s (2009) three tests for an RMA, but adapted for an RM2A; and Toffler’s (1993) criteria for a ‘true revolution’. The null hypothesis for the novel theory (Homunculus Casualty Theorem) states that the concept, training, equipment and practice changes within the RM2A are not correspondingly or proportionately matched in importance to the immediately life-threatening injuries and physiology of contemporary combat trauma. Results: The creation of new concepts (<C>ABC, DCR) and doctrine (MIMMS, 1st Aid) are demonstrated, incorporating a raft of novel heuristics. Developments in trauma governance are described that have provided both the evidence to drive change and the proof of effect of change. Specific evidence for avoidable in-hospital cardiac arrest is presented, together with an organisational solution for prevention that highlights the NHS barriers to innovation adoption. The results of system transformation are demonstrated as a cohort of 75 unexpected survivors of critical combat injury; traumatic cardiac arrest survival of 24% is unexpectedly high. Conclusions: An RM2A is proven that meets the sentinel criteria. The scope of advances in combat casualty care has appropriately reflected clinical need particularly for the rapid and effective treatment of haemorrhage, although battlefield analgesia has failed to advance. Most importantly, it is asserted that the proven RM2A is responsible for the unexpected positive outcomes following critical combat injury. There is evidence I have played a central role in this transformation of military medicine. Effort to transfer the learning into NHS practice has begun

Following mastectomy for breast cancer a wide variety of surgical techniques are currently available for post mastectomy breast reconstruction where autologous tissue is used to construct a natural looking breast. One of the most common types of reconstructive surgeries use Deep Inferior Epigastric Perforator (DIEP) free flap where skin and adipose tissue along with their blood supplies are transferred from the lower abdomen to the chest. The success of free flap reconstructive surgery depends strongly on the maintenance of adequate perfusion in the flap. Early diagnosis of ischaemia and surgical exploration to restore blood flow can often salvage the flap and may prevent graft failure. Even though many techniques have been used, there is still a need to develop a non-invasive, easy to use, reproducible and inexpensive monitoring device to assess flap perfusion. In an attempt to overcome the limitations of the current flap perfusion monitoring techniques a prototype reflectance three wavelength photoplethysmographic (PPG) sensor was developed. The PPG sensor consisted of two infrared (940 nm), two green (520 nm) and two red (660 nm) LEDs and a photodiode. A PPG processing system was also constructed in order to drive the optical components on the sensor and to detect and pre-process the PPG signals. A Virtual Instrument (VI) was also implemented in LabVIEW in order to display, analyse and archive the PPG signals with the capability of real-time estimation of arterial oxygen saturation (SpO2) values. The system was evaluated in a pilot study on fifteen patients undergoing breast reconstructive surgery using (DIEP) flaps. Good quality red, infrared and green PPG signals were obtained pre-operatively from the donor site (abdomen), intra-operatively (capturing reperfusion of flap following anastomosis) and post-operatively at regular intervals for up to 12 hours post surgery. SpO2 values were also estimated which were found to be in broad agreement with SpO2 values recorded from the commercial pulse oximeter attached to the patients’ finger. The flap PPGs were compared with PPGs and SpO2s acquired from the finger of a small number of patients using a custom made reflectance finger PPG probe, optically and electrically, identical as the flap probe. The finger PPGs were found to be much larger than the flap PPGs which confirms the hypothesis of inadequate perfusion in the flap during and after the operative period. Furthermore the custom made PPG processing system and flap sensor were used successfully on a series of case studies to evaluate the versatility of the system in monitoring PPG signals and estimating blood oxygen saturation in other flaps. These included monitoring two patients undergoing Latissimus Dorsi (pedicle) flap reconstructive surgery and a head and neck free flap surgery where a Vertical Rectus Abdominis Myocutaneous (VRAM) flap was used following total petrosectomy. Also, two patients undergoing reconstructive surgery of the oesophagus using jejunum free flaps were also recruited into the study. For this study a purpose build oesophageal PPG sensor was developed. These case studies demonstrated the ability to use the developed PPG sensors to acquire PPG signals and estimate SpO2s in a variety of flaps. The results have confirmed that the custom made PPG system and sensor has the potential to be used as an alternative technique for monitoring perfusion in various types of flaps at all operative periods.

Work was undertaken in this thesis to assess the use of somatostatin image quantification with SPET and SPET-CT to aid the characterisation of disease within the body. Two radionuclide somatostatin analogues were used for this assessment, the first was NeoSPECT and the second, OctreoScan. The primary aim of work in this thesis was to assess the role of NeoSPECT imaging in the characterisation of disease within the lungs, that is, to differentiate benign from malignant disease. Two forms of image quantification were used in the NeoSPECT assessment, a tumour to background ratio (T:B) and a value of tumour percentage uptake (% uptake). Values of T:B and % uptake were calculated from SPET images acquired 2 hours post injection. T:B results from the benign group (n = 8) demonstrated a median T:B of 2.21, whilst the malignant group (n = 28) demonstrated a median T:B of 2.01. The differences between the groups were tested statistically via a Mann-Whitney test, which showed there to be no statistical difference between the groups (p=0.90, 95.4% CI of (-0.5598, 0.5498)). To undertake the calculation of % uptake a non-patient acquisition (a standard acquisition) was also required, unfortunately not all of the patient cohort used for the T:B assessment had this additional acquisition. As a result of this numbers were low for the % uptake assessment in patients with a benign histology (n = 2), therefore statistical analysis could not be performed. However, review of the range of values for each histology within the malignant group proved useful as no differences were demonstrated between the ranges of values which could help to differentiate between the histologies. Quantification of dual time point imaging was also assessed to determine if there were any variations in values calculated that could also help differentiate the different histologies. For this assessment patients were images at 2 and 4 hours post injection. Results from the Wilcoxon Signed Rank test of the T:B assessment found there to be no statistically significant difference between values of T:B calculated at 2 and 4 hours that was characteristic of tumour type (p=1.0 and p=0.14). The difference in % uptake between 2 and 4 hours was also assessed via a Wilcoxon Signed Rank test, this test also concluded there to be no significant difference value of % uptake between the two acquisitions of the malignant group (p = 0.73). An attempt was also made to quantify ‘other’ uptake within the mediastinum, however, a lack of anatomical information made correlation with histology impossible and as a result no firm conclusions relating image quantification to histology could be drawn from this work. Work from this thesis concluded no quantitative difference between tissue histology could be demonstrated using NeoSPECT, either from single or dual time point imaging. As a result of the NeoSPECT work a number of factors which limited the accuracy and reproducibility of SPET image quantification were identified. Towards the end of the NeoSPECT work hybrid imaging (SPET-CT) became available within the department at Glasgow Royal Infirmary. It was believed that hybrid imaging could resolve some of the limitations and subsequently improve the accuracy of SPET image quantification. However, NeoSPECT was removed from the market for a short period of time and therefore a similar somatostatin analogue, OctreoScan, was used to investigate if the accuracy of somatostatin image quantification could be improved as a result of SPET-CT and its associated reconstruction algorithms including a CT based attenuation correction. Firstly, a qualitative assessment of image quality using the new hybrid reconstructions techniques was undertaken via an observer study. Images were reconstructed with the existing reconstruction techniques, as used for the NeoSPECT work, and with the new hybrid imaging techniques. Four experienced observers blinded to reconstruction technique were asked to score images in terms of their overall image quality. A Friedman test was performed on the scores for each observer, three of the four observers demonstrated a statistically significant difference in their scores between the existing and new hybrid technique (p = 0.00, p = 0.003, p= 0.00), with the new hybrid technique being assigned the highest scores in terms of image quality. Images were also assessed semi-quantitatively via profile analysis which also demonstrated a clear differentiation between the existing and new hybrid techniques with increased image quality being demonstrated in the hybrid data set. The quantitative accuracy of hybrid imaging was also assessed using phantom data. For 111In the difference of the value of absolute activity calculated and that measured varied by 35% but this improved to 21 % when scatter and CT-attenuation based corrections were applied. For 99mTc a much more notable difference between the existing techniques used in chapter 2 and those available from the use of hybrid imaging was demonstrated, the difference in the value of absolute activity calculated and that measured improved from 67% to 0.04%, respectively. Work in this thesis clearly demonstrated an improvement in image quality and accuracy in SPET quantification as a result of hybrid imaging techniques.

Extracellular signal-regulated protein kinase 5 (ERK5) is a member of the mitogen activated protein (MAP) kinase family which is specifically activated by mitogen/extracellular signal regulated kinase kinase-5 (MEK5). Over recent years, abnormal MEK5/ERK5 signalling has been shown to be important in prostate carcinogenesis with increased levels of ERK5 immunoreactivity being associated with Gleason sum score (p<0.0001), bone metastases (p=0.0044) and locally advanced disease at diagnosis (p=0.0023). In addition PC3 cells over-expressing ERK5 displayed enhanced proliferation, migration and invasion. Taken together, these data suggest MEK5/ERK5 pathway to be biological important in prostate cancer and a potential target in invasive prostate cancer. Using siRNA to target ERK5 expression, I found that reduced ERK5 expression significantly inhibited cellular proliferation, motility and invasion in prostate cancer PC3 cells when compared to the controls, (p<0.005). Our group has previously reported upregulated ERK5 expression in primary human prostate cancer specimens. In this study, I was able to validate these results and demonstrate moderate-strong levels of cytoplasmic staining in 63% cases of PIN/PIA. High levels of cytoplasmic (55%) and nucleur (73%) immunoreactivity was also shown in a range of metastatic prostate tumours (n=11). A number of similarities and interactions between ERK5 and ERK1/2 have recently been identified and there is suggestion that ERK5 may in fact regulate some of the cellular functions originally attributed to ERK1/2. Potential ‘cross-talk’ between ERK5 and ERK1/2 signalling was investigated using siRNA for each individual isoform of ERK1/2. ERK1 knockdown resulted in increased ERK5 activation in addition to prolonged ERK2 phosphorylation. Proliferation studies were also performed in PC3 cells, the results of which support published data that ERK1 acts as a negative regulator and ERK2 as a positive regulator of cell proliferation. ERK5 has been shown to regulate the activity of several transcription factors and recent evidence suggests that ERK5 may be heat shock protein (HSP) 90 dependent. To further investigate the ERK5 signalling network and its interacting proteins, I performed mass spectrometry-based quantitative proteomics using SILAC labelled cells. Results from this study support the theory that HSP90 does associate with ERK5 however contrary to published data my results show that it is not involved in ERK5 activation. Our results validate the importance of the MEK5-ERK5 signalling pathway as a potential target for therapy in prostate cancer and highlight a novel functional and biochemical relationship between ERK1 and HSP 90 with ERK5 signalling.

Stroke is a global health concern, with a significant impact on mortality and disability. Motor impairment, including upper limb impairment is particularly common following stroke. Upper limb impairment impacts on an individual’s ability to complete activities of daily living and quality of life. Effective interventions targeted at upper limb recovery are therefore important and further research, within this area, has been identified as necessary. However, challenges researching such complex interventions have been recognised. To attempt to overcome such difficulties the Medical Research Council (MRC) proposed a framework for the development and evaluation of RCTs for complex interventions. In this thesis the MRC framework has been used, focusing on the processes of developing and feasibility/piloting, to provide information for a phase III randomised controlled trial (RCT) of a novel intervention targeted at upper limb recovery following stroke. A systematic review and meta-analysis was undertaken to investigate and clarify any possible association between predictive variables and upper limb recovery. Observational studies of stroke patients investigating at least one predictive variable and its relationship with a defined measure of upper limb recovery at a future time point were included. For this review data analysis combined several approaches. Fifty eight studies were included and 41 predictor variables identified. Initial measures of upper limb function and impairment were found to be the most significant predictors of upper limb recovery; odds ratio (OR) 38.62 (95% confidence interval (CI) 8.40-177.55) and OR 14.84 (95% CI 9.08-24.25) respectively. Neurophysiological factors (motor evoked potentials and somatosensory evoked potentials) were also consistently identified as strongly associated with upper limb recovery; OR 11.76 (95% CI 2.73-69.05) and OR 13.73 (95% CI 2.73-69.05) respectively. Moderate evidence of association was found for global disability and lower limb impairment. Interpretation of results is complicated by methodological factors, particularly relating to the heterogeneous nature of the included studies. In order to identify interventions which show potential for reducing impairment and/or improving upper limb function after stroke, an overview of the available evidence was completed. This systematic review and meta-analysis included Cochrane systematic reviews, other reviews and, where necessary, additional RCTs of interventions to promote upper limb recovery. Thirteen relevant interventions were found, covered by nine Cochrane systematic reviews (bilateral training, constraint-induced movement therapy (CIMT), electromyograhphic (EMG) biofeedback, electrostimulation, hands-on therapy interventions, mental practice, repetitive task training (RTT), electromechanical/robotic devices and virtual reality) and four other reviews (neurophysiological approaches, high-intensity therapy, mirror therapy and splinting). A statistically significant result, in terms of arm recovery, was found in favour of eight of the interventions: CIMT (standardised mean difference (SMD) 0.74 95% CI 0.44-1.03), EMG biofeedback (SMD 0.41 95% CI 0.05-0.77), electrostimulation (SMD 0.40 95% CI 0.02-0.77), mental practice (SMD 1.37 95% CI 0.60-2.15), mirror therapy (SMD 0.41 95%CI 0.05-0.77), RTT (SMD 0.23 95% CI 0.06-0.41), electromechanical/robotic devices (SMD 0.30 95% CI 0.02-0.58) and virtual reality (SMD 0.52 95% CI 0.25-0.78). Two out of the eleven interventions, which investigated hand function outcomes found a positive result (CIMT SMD 0.39 95% CI 0.11-0.68 and repetitive task training SMD 0.27 95% CI 0.06-0.47). Analyses were limited by a relatively small number of RCTs, which were also generally small in size. Heterogeneity of the available data and methodological limitations further impacts on the conclusions. Despite these limitations this overview provided a concise and informative summary of the available evidence. The interventions found to be beneficial, or showing promise tend to include elements of intensive, repetitive, task-specific practice. To build the evidence base for upper limb interventions, two Cochrane systematic reviews were undertaken. These reviews investigated the effects of bilateral training and home therapy programmes on upper limb recovery. Both included RCTs of stroke patients. Eighteen trials were included in the bilateral review, of which 14 were included in the analyses. Most of the included trials were considered to be at high risk of bias and the evidence was further limited by heterogeneity. No statistically significant results were found for any of the primary outcomes. One study found a statistically significant result in favour of another upper limb intervention for performance in extended ADL. No statistically significant differences were found for any of the other secondary outcomes. Four RCTs were included in the home-based therapy programmes review. No statistically significant result was found for any of the outcomes. There is currently insufficient good quality evidence to determine the effects of both the interventions studied. Following the evidence gained from the overview of interventions elements of intensive, repetitive and task-specific practice were to be included in a novel upper limb intervention. Robotic interventions, which incorporate these principles, were also found to have a positive effect on upper limb outcomes. Therefore a pilot, feasibility and acceptability study of a novel device (Armeo®Spring) that included these elements was completed. Medically stable adults with a clinical diagnosis of stroke and arm deficits admitted to an acute stroke unit were recruited. Participants were randomly allocated to experimental intervention (high or low intensity training with the Armeo®Spring arm orthosis) or usual stroke unit care. Primary outcomes were feasibility and acceptability of the experimental device recorded at postintervention. Secondary outcomes were; safety and three efficacy outcomes recorded at post-intervention, and 3 month follow-up. Patient recruitment was challenging; over eight months 393 consecutive stroke admissions were screened and 12 participants recruited. This study demonstrated that per-protocol levels of intensity were not feasible to provide in an acute stroke unit. However, higher levels of intensity could be achieved and this novel intervention was found to be acceptable to patients. This pilot trial also found higher change scores on the three efficacy outcomes within both intervention groups, compared to the control group. Due to small sample size and other possible confounding factors, these findings must be interpreted with caution. Using the MRC complex intervention framework as a guide I completed development and feasibility/piloting work surrounding an upper limb intervention, following stroke. Following the results of this research further development, feasibility/piloting work is suggested for the ArmeoSpring device prior to the undertaking of a phase III RCT. The information gained from this research could be used to inform phase III RCTs of other upper limb interventions.

Joint disease is common in adults and in adolescents. It particularly affects the knee joints. In young people, joint disease has a number of causes including: genetic factors, defects in joint cartilage and sports related injuries. In particular, overtraining and traumatic injuries are common in many sports Participation in sports has expanded during the last two decades in many parts of the world. This has led to an increased number of injuries. Our knowledge of the role of ligaments in the control of movements and how they should be managed after injuries needs to expand as fast as participation rates. The aims of the current study were firstly, to investigate if reflexes can be elicited by electrical stimulation of ligaments. Secondly, to investigate if different muscles are affected differently by these reflexes. The final aim was to investigate if these reflexes can be modulated by posture or muscle activity. A total of 44 volunteers participated in a series of experiments. These experiments were designed to elicit reflexes following electrical stimulation of the collateral knee ligaments during sitting, standing and walking on treadmill. The reflexes were observed in averaged rectified electromyograms from Rectus Femoris, Vastus Medialis, Vastus Lateralis, Lateral and Medial Gastrocnemius and Soleus. Muscle activity was essential if reflexes were to be elicited. No reflexes were elicited in relaxed muscles. During the first series of experiments reflexes in Rectus Femoris, Vastus Lateralis and Vastus Medialis were investigated while the Reflexes were identified as changes in the averaged rectified electromyograms (EMG). The EMG in the immediate post stimulus period was compared with the pre-stimulus control. Inhibitory and excitatory reflexes were elicited following ligament stimulation in all three sets of experiments. The mean latency in quadriceps for early excitation was 57 +/- 6 msec and 67 +/- 10 msec for early inhibitions. The equivalent means were 70 +/- 6 msec and 77 +/- 6 msec for triceps. The shortest latency recorded in quadriceps was 46 msec. Longer latency reflexes were frequently observed. The mean latency in quadriceps for late excitation was 102 +/- 6 msec and 113 +/- 11 msec for late inhibitions. The equivalent means were 110 +/- 6 msec and 119 +/- 11 msec for triceps. There was no significant difference in the latencies of reflexes from MCL and LCL. The latencies in triceps were approximately 10 msec longer (90 msec for quadriceps a 100 msec for triceps) than those in quadriceps and this can be attributed to their longer conduction pathway. The reflexes were also recorded during gait. During walking, the latencies of both excitations and inhibitions were significantly longer than they were during sitting and standing. The mean latency of excitatory reflexes in Vastus Lateralis after LCL stimulation were 71 +/- 5 msec. For inhibitory reflexes the mean latency was 87 +/- 1 msec. The mean latency for excitation reflexes in Lateral Gastrocnemus was 82 +/- 2 msec and for inhibition reflexes was 94 +/- 3 msec. In each set of experiments the shortest latencies were consistent with slow group II or group III afferents excited by relatively strong stimulation. Control experiments using topical cutaneous anaesthesia minimised the possibility of cutaneous contributions to the observed reflexes. It is also possible that the electrical stimulation excited capsular afferents located close to the ligaments. This cannot be settled by the experiment reported in this thesis and the observed reflexes are best described as ligamento-muscular reflexes. These observed effects are consistent with recent results already published by Kim et al in 1995.

The renin-angiotensin system (RAS) regulates blood pressure, and homeostasis through angiotensin II (AngII). Angiotensin converting enzyme 2 (ACE2), a homologue of ACE, metabolizes AngII to Ang1-7. Ang1-7 antagonizes AngII via the receptor MAS. ACE2 also converts AngI to Ang1-9. Very little is known about Ang1-9 although it is thought to be a substrate for Ang1-7 generation via ACE. We investigated Ang1-9 and Ang1-7 function in cardiomyocyte hypertrophy in rat neonatal and primary adult rabbit left ventricular cardiomyocytes. We have shown that Ang1-7 and Ang1-9 blocked AngII-induced hypertrophy. Furthermore, we demonstrated an independent role of Ang1-9 in cardiac hypertrophy and generated evidence that Ang1-9 signals via the angiotensin type 2 receptor. In vivo we delivered Ang1-9 via osmotic minipumps for 4 weeks into stroke-prone spontaneously hypertensive rats. Delivery of Ang1-9 reduced cardiac fibrosis and improved endothelial function compared to control animals. These findings have implications for our understanding of RAS function.

Prostate cancer (PC) is the most common cancer in men. In the UK alone, there are over 30,000 men diagnosed with PC every year. Loss of SPRY2 and activation of receptor tyrosine kinases are common events in PC. However, the molecular basis of their interaction and clinical impact remains to be fully examined. SPRY2 loss may functionally synergise with aberrant cellular signalling to drive PC and to promote treatment resistant disease. Using a combination of in vitro, pre-clinical in vivo models and clinical PC, this thesis shows the impact of SPRY2 loss upon activation of the ErbB signalling system via a positive feedback regulation of the ErbB-PI3K/AKT cascade. Loss of SPRY2 resulted in hyper-activation of PI3K/AKT signalling to drive proliferation and invasion by enhanced internalisation of EGFR/HER2 and their sustained localisation and signalling at the early endosome in a PTEN-dependent manner. This involves activation of p38 MAPK by PI3K to facilitate clathrin-mediated ErbB receptor endocytosis. Furthermore, this thesis suggests a critical role of PI3K/AKT in PC whereby in vitro and in vivo inhibition of PI3K suppresses proliferation and invasion, supporting PI3K/AKT as a target for therapy particularly in patients with PTEN-haploinsufficiency, low SPRY2 and ErbB expressing tumours. In conclusion, SPRY2 is an important tumour suppressor in PC; its loss drives the PI3K/AKT pathway via functional interaction with the ErbB system.