Approximately, 2/3 of patients with a spinal cord injury (SCI) suffer from chronic pain, leading to a reduction in quality of life. The prevalence of chronic central neuropathic pain (CNP) in the SCI population is 40%. Recent neuroimaging studies provided evidence that CNP is accompanied by modified brain activity at surface and deep cortical levels and that CNP is resistant to different pharmacological and non-pharmacological treatments. Our current knowledge on how CNP affects the brain activity of SCI patients is mainly based on fMRI studies. Although these studies provide precise spatial localisation of brain regions most affected by CNP, they indirectly measure brain activity through measuring blood oxygenation. Therefore they lack information specific to neuronal activity such as dynamic, time and frequency dependant oscillatory activity of cortical structures. Therefore, in Phase 1 of this study, electroencephalogram (EEG) activity of paraplegic patients with CNP (PWP) is compared with the EEG activity of able-bodied (AB) participants and paraplegic patients without CNP (PNP). It was found that CNP leads to frequency dependant EEG signatures both in the relaxed state and during motor tasks that are not restricted to the cortical representation of the body part perceived as being painful. The pharmacological treatment of CNP has a number of side effects and does not provide significant pain relief. The effect of non-pharmacological treatments is inconsistent. Neurofedback (NF) is a non-pharmacological treatment, based on the voluntarily modulation of brain activity to control pain intensity. Using NF training the patient can learn and apply a mental strategy to control pain, without the need for an external device. However, NF requires a large number of training sessions to learn the necessary mental strategy. Therefore, in Phase 2 of this study, the effect on pain intensity of a large number of NF sessions, using different NF training protocols, was assessed. The clinically and statistically significant reduction of pain observed in this study demonstrates that NF training has the potential to manage chronic CNP in paraplegic patients. This study also provides evidence that the reduction of pain achieved using NF training may not be due to a placebo effect. Furthermore, the study demonstrates the immediate global effect of NF training on power and coherence. To date, no neuroimaging studies that have applied NF training with patients with CNP have shown changes in brain activity before the first and after the last training session. Therefore, in phase 3 of this study, the long-term neurological effect of NF training was assessed using EEG. This study provides evidence that NF training does not only induce an effect on spontaneous EEG activity, but also induces changes on evoked EEG activity. In conclusion, this study compared the EEG activity of three groups (AB, PWP, and PNP) and found that CNP (PWP group) leads to frequency dependant dynamic oscillatory signatures. The study also reported that NF training has a potential to reduce pain and this reduction of pain might not be an effect of placebo. Furthermore, it was found that NF training induce long-term changes in the EEG activity recorded in relaxed state and during motor tasks. This long-term change in EEG activity was noticed at the surface and deep cortical structures.

Introduction: Low back pain remains a burden for society, since it can lead to sickness absence and work disability. Physical occupational risk factors can contribute to the development of back pain, yet little is known about any risks in sedentary jobs posed by sitting. The influence of psychosocial factors on back pain and sickness absence amongst sedentary workers is also unclear. The aim of this study was to measure work activities, lumbar movement characteristics, symptoms and psychosocial factors in order to determine associations with low back pain and sickness absence. Methods: Phase 1: involved validation of a fibre-optic goniometer system that attaches to the lumbar spine and hip to continuously measure: (1) activities (sitting, standing, walking); and (2) lumbar movement characteristics (notably sitting postures and kinematics). New questionnaires were also validated to measure aspects of low back discomfort. Phase 2: consisted of a cross-sectional survey of call centre workers (n=600) to collect data on: demographics, clinical and occupational psychosocial factors, and symptoms. An experimental sample (n=140) wore the goniometer system during work. Phase 3: involved a 6-month follow-up survey to collect back pain and sickness absence data (n=367). Logistic regression was used to determine associations (P<0.05) between data. Results: Workers spent 83% of work-time sitting, 26% of which was spent adopting a lordotic lumbar posture. Current back pain (>24hrs: yes/no) was associated with a kyphotic sitting posture (time spent with a lumbar curve ≥180°) (R2 0.05), although future back pain was not. Using multivariable models: limited variety of lumbar movement whilst sitting was associated with future (persistent) LBP, dominating other variables (R2 0.11); yet high levels of reported back discomfort, physical aggravating factors and psychological demand at work were stronger predictors of sickness absence, and dominated other variables (R2 0.24). Interpretation: Workers do not follow the advice from employers to maintain a lumbar lordosis whilst sitting, as recommended by statutory bodies. Furthermore, sitting with a kyphotic posture did not increase the risk of back pain, although a relative lack of lumbar movement did. Thus, ergonomic advice encouraging lumbar movement-in-sitting appears to be justified. Predictors of sickness absence were multi-factorial, and consideration of work-relevant biomedical and psychosocial factors would be more useful than adopting more narrow screening approaches.

Biosensors are often used to detect biochemical species either in the body or from collected samples with high sensitivity and specificity. Those based on piezoelectric sensing methods employ mechanically induced changes to generate an electrical response. Reliable collection and processing of these signals is an important aspect in the design of these systems. To generate the electrical response, specific recognition layers are arranged on piezoelectric substrates in such a way that they interact with target species and so change the properties of the device surface (e.g. the mass or mechanical strain). These changes generate a change in the electrical signal output allowing the device to be used as a biosensor. The characteristics of piezoelectric biosensors are that they are competitively priced, inherently rugged, very sensitive, and intrinsically reliable. In this study, a compound label-free biosensor was developed. This sensor consists of two elements: a Love wave sensor and an electrochemical impedance sensor. The novelty of this device is that it can work in both dry and wet measurement conditions. Whilst the Love wave sensor aspect of the device is sensitive to the mass of adsorbed analytes under both dry and wet conditions with high sensitivity, the sensitivity coefficients in these two conditions may be different due to the different (mechanical) strengths of interaction between the adsorbed analyte and the substrate. The impedance sensor element of the device however is less sensitive to the mechanical strength of the bond between the analyte and the sensing surface and so can be used for in-situ calibration of the number of molecules bound to the sensing surface (with either a strong or weak link): conventional Love wave sensors are not sensitive to material loosely bound to the surface. Thus, a combination of results from these two sensors can provide more information about the analyte and the accuracy of the Love wave sensor measurements in a liquid environment. The device functions with label-free molecules and so special reagents are not needed when carrying out measurements. In addition, the fabrication of the device is not too complicated and it is easy to miniaturise. This may make the system suitable for point-of-care diagnostics and bio-material detection. The substrate used in these sensors is 64°Y–X lithium niobate (LiNbO3) which is a kind of piezoelectric material. On the substrate, there is a pair of interdigital transducers (IDTs) which are composed of 100 Ti/Au split-finger pairs with a periodicity (λ) of 40μm. The acoustic path length, between both IDTs, is 200λ and the aperture between the IDTs is 100λ. On top of the substrate and IDTs, there is a PMMA guiding layer with an optimised thickness ranging from 1000 nm to 1300 nm. In addition, a gold layer with thickness 100 nm is deposited on the guiding layer to act as the electrodes for the electrochemical impedance sensor. The biosensor in this study has been used to measure Protein A, IgG, and GABA molecules. Protein A is often coupled to other molecules such as a fluorescent dye, enzymes, biotin, and colloidal gold or radioactive iodine without affecting the antibody binding site. In addition, the capacity of Protein A to bind antibodies with such high affinity is the driving motivation for its industrial scale use in biologic pharmaceuticals. Therefore, measuring Protein A binding is a useful method with which to verify the function of the biosensor. IgG is the most abundant antibody isotype found in the circulation. By binding many kinds of pathogens including viruses, bacteria, and fungi, IgG protects the body from infection. Also, IgG can bind with Protein A well so the biosensor here could also measure IgG after a Protein A layer is immobilised on the sensing area. GABA is the main inhibitory neurotransmitter in the mammalian central nervous system. It plays an important role in regulating neuronal excitability throughout the nervous system. The conventional method to measure concentrations of GABA under the extracellular conditions is by using liquid chromatography. However, the disadvantages of chromatographic methods are baseline drift and additions of solvent and internal standards. Therefore, it is necessary to develop a simple, rapid and reliable method for direct measurement of GABA, and the sensor here is an attractive choice. When the Love wave sensor works in the liquid media, it can only be used to measure the mass of analytes but does not provide information about the conditions of molecules bound with the sensing surface. In contrast, electrochemical impedance sensing based on the diffusion of redox species to the underlying metal electrode can provide real-time monitoring of the surface coverage of bound macromolecular analytes regardless of the mechanical strength of the analyte-substrate bond: the electrochemical impedance measurement is sensitive to the size and extent of the diffusion pathways around the adsorbed macromolecules used by the redox species probe i.e. it is sensitive to the physical area of the surface covered by the macromolecular analyte and not to the mass of material that is sensed through a mechanical coupling effect (as in a Love wave device). Although electrochemical impedance measurements under the dry state are quite common when studying batteries and their redox/discharge properties, these are quite different sorts of systems to the device in this study. Therefore, integrating these two sensors (Love wave sensor and electrochemical impedance sensor) in a single device is a novel concept and should lead to better analytical performance than when each is used on their own. The new type of biosensor developed here therefore has the potential to measure analytes with greater accuracy, higher sensitivity and a lower limit of detection than found when using either a single Love wave sensor or electrochemical impedance sensor alone.

Phosphate glass fibre polymer composites have the potential to be utilised as degradable orthopaedic implant devices with modifications to the glass fibre composition allowing for materials with tailorable mechanical properties and degradation rates. Accordingly such materials could be advantageous for the development of alternative cranioplasty implant devices. In collaboration with an industrial sponsor, a promising composition of phosphate glass was characterised to assess its potential as a composite reinforcing agent along with the applicability of different composite configurations as possible cranioplasty implants. The CorGlaes® Pure 107 phosphate glass was found to demonstrate suitable dissolution rates for cell culture whilst vibrational spectroscopy and analytical chemistry techniques confirmed its structural features and suitability for fibre manufacturing. The mechanical properties of its bulk and fibre formats were determined to be in line with alternate PG compositions but initial biocompatibility screenings of glass samples using human osteosarcoma cells found this composition to be cytotoxic. This was believed to be due to localised pH changes or from the release of Zn2+ ions towards cytotoxic levels. The absence of a carbonated hydroxyapatite layer formation when immersed in simulated body fluid also indicated that this glass composition possessed no in vitro bioactivity. Composite materials based on CorGlaes® Pure 107 fibres in a polylactic acid (PLA) matrix at a 0.2 fibre volume fraction (Vf) were found to exhibit mechanical properties within the same region as those reported for cranial bones. However rapid dissolution of the reinforcing fibres (due to autocatalysis) led to premature reductions in the composite mechanical properties and resulted in a cytotoxic response during in vitro cell culture. The introduction of a secondary hydroxyapatite filler phase into the CorGlaes® Pure 107 composite to counteract the acidic pH led to changes in the samples mechanical properties and degradation media pH. However this failed to retard the fibre dissolution rate in 0.15Vf composites. At a 0.01Vf, the inclusion of HA produced biocompatible composites compared to the HA free equivalent and was attributed to the reduction of preferential Zn2+ ion release from the glass fibres due to the pH buffering at the fibre-matrix interface. However the low Vf required to achieve biocompatible composites made the CorGlaes® Pure 107 fibres unsuitable as a primary composite reinforcing agent. Consequently phosphate glass fibre composites may be suitable for cranioplasty applications with future hybrid composites allowing for the design of implant materials that are capable of eliciting an immediate in vivo response whilst retaining its long term mechanical properties.

Duplication of the proteolipid protein (PLP1) gene, which encodes the most abundant protein of central nervous system (CNS) myelin, is the most common cause of Pelizaeus Merzbacher disease (PMD). Various animal models have been generated to study the effect of Plp1 gene overexpression on oligodendrocyte and myelin sheath integrity. The #72 line harbours 3 additional copies of the murine Plp1 gene per haploidic chromosomal set. Homozygous #72 mice appear phenotypically normal until three months of age, after which they develop seizures leading to premature death at around 4 months of age. An earlier study examining the optic nerve showed a progressive demyelination accompanied by marked microglial and astrocytic responses. Using electron microscopy and immunohistochemistry, I demonstrated that initial myelination of the #72 corpus callosum was followed by a progressive demyelination, probably mediated by a distal “dying back” phenomenon of the myelin sheath. No evidence of effective remyelination was observed despite the presence and proliferation of oligodendrocyte progenitor cells (OPCs). A marked increase in density and reactivity of microglia/macrophages and astrocytes, and the occurrence of axonal swellings, accompanied the demyelination. In situ and in vitro evaluation of adult #72 OPCs provided evidence of impaired OPC differentiation. Transplantation of neurospheres (NS) into adult #72 mouse corpus callosum confirmed that axons were capable of undergoing remyelination. Furthermore, NS transplanted into neonatal CNS integrated into the parenchyma and survived up to 120 days, demonstrating the potential of early cell replacement therapy. Taking advantage of the spatially distinct pathologies between the retinal and chiasmal region of the #72 optic nerve, I evaluated the capability of diffusion weighted MRI to identify lesion type. I found significant differences between #72 and wild type optic nerves, as well as between the two distinct pathological regions within the #72 optic nerve. These results confirm the potential of the #72 mouse to serve as a model to study chronic demyelination. The study also demonstrates the utility of the #72 mouse to evaluate cell transplant strategies for the treatment of chronic CNS white matter lesions and PMD. Additionally, DW MRI has potential as a modality capable of diagnosing myelin-related white matter changes, and may be applicable to the clinical setting.

Gastric and oesophageal cancers were responsible for more than one million deaths in 2002. Although global incidence of gastric cancer is decreasing, this malignancy is still the fourth most common cause of cancer worldwide. The incidence of oesophageal adenocarcinoma is rising rapidly, three-fold in the last two decades. The incidence of adenocarcinoma of gastric cardia is stable. In the pathogenesis of both gastric and oesophageal adenocarcinomas, the state of the gastric mucosa and its secretory function plays a central role. Non-cardia adenocarcinoma develops in subjects with H.pylori associated atrophic gastritis and hypochlorhydria. Little is known about the gastric phenotype in patients with adenocarcinoma of the cardia and gastroesophageal junction. Another important but poorly understood risk factor for upper GI adenocarcinoma is male gender. In the first study we aimed to investigate the association between the pattern of H.pylori gastritis and gastric secretory function in 255 H.pylori-infected patients with dyspepsia showing normal endoscopy. Our findings showed that maximal acid output correlates inversely with severity of corpus gastritis, corpus atrophy, and positively related to male gender and serum pepsinogen I. In the second study we compared cancers at the cardia and non-cardia subsites with respect to pre-morbid gastric mucosal atrophy and acid secretion. In a nested case-control study comprising 101,601 men and women enrolled in the Norwegian JANUS cohort, 230 cases of gastric cancer were identified. 173 cases including 144 non-cardia and 44 cardia cancer were enrolled to study. Three controls were matched to each case. Serum pepsinogen I, pepsinogen II, anti-H.pylori IgG antibody and gastrin were measured using serums which had been collected a median of 11.9 years before cancer diagnosis radioimmunoassay method. Non-cardia cancer was positively associated with H.pylori and gastric atrophy. The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H.pylori and atrophy. Cardia cancer was negatively associated with H.pylori, but H.pylori positive cardia cancer showed a positive association with gastric atrophy. The predominant histological subtype of cardia cancer was intestinal and it was not associated with gastric atrophy compared to the diffuse subtype. Cardia cancer in atrophic patients had an intestinal: diffuse ratio similar to non-cardia cancer, whereas cardia cancers in persons without atrophy were predominantly intestinal. These findings indicate two aetiologies of cardia cancer, one associated with H.pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer. In the third study we extended our investigation of the aetiology of cardia cancer by examining the association of both serological evidences of gastric atrophy and gastroesophageal reflux disease (GORD) symptoms with adenocarcinoma of the oesophagus, cardia and non-cardia regions of the stomach. This has been performed for the different histological subtypes of the cancer. We have also included H.pylori status and smoking history which are other well established risk factors for upper GI cancer. This has been undertaken in a population in Northwest Iran with a high incidence of upper gastrointestinal cancer. Serum pepsinogen I/II was used as a marker of atrophic gastritis and categorised to five quintiles. History of GORD symptoms, smoking and H.pylori infection was incorporated in logistic regression analysis. Lauren classification was used to subtype gastric and oesophageal adenocarcinoma. Non-cardia cancer was associated with atrophic gastritis but not with GORD symptoms; 55% of these cancers were intestinal subtype. Oesophageal adenocarcinoma was associated with GORD symptoms, but not with atrophic gastritis; 84% were intestinal subtype. Cardia cancer was positively associated with both severe gastric atrophy and with frequent GORD symptoms though the latter was only apparent in the non-atrophic subgroup and in the intestinal subtype. The association of cardia cancer with atrophy was stronger for the diffuse versus intestinal subtype and this was the converse of the association observed with non-cardia cancer. These findings indicate two distinct aetiologies of cardia cancer, one arising from severe atrophic gastritis and being of intestinal or diffuse subtype similar to non-cardia cancer, and one related to GORD and intestinal in subtype, similar to oesophageal adenocarcinoma. Gastric atrophy, GORD symptoms and histological subtype may distinguish between gastric versus oesophageal origin of cardia cancer. In the fourth study we investigated the relationship between gender and upper gastrointestinal adenocarcinoma. Male gender is a well-established risk factor for oesophageal adenocarcinoma. Male predominance of gastric cancer is related to the histological subtype of the tumour being more marked in the intestinal versus diffuse histological subtype. In addition, global data suggests that the male predominance of upper gastrointestinal cancer is related to the anatomical location, being higher for proximal and lower for distal tumours. However, the proportion of the intestinal histological subtype differs according to anatomical site and it is unclear whether it is the anatomical site or the histological subtype which is associated with the gender phenomenon. We have conducted a population-based study to investigate this. The study was based upon 3270 gastric and oesophageal cancers recorded in West of Scotland Cancer Registry between 1998 and 2002. The Lauren subtype of adenocarcinoma was determined by reviewing 1204 reports and 3241 slides in a sample of 812 cases. Logistic regression models were used to estimate relationship between male predominance and histological subtype, tumour location and age. We found that the crude incidence rate of intestinal subtype was higher in males (23.86/ 100,000 person-years) versus females (9.00/ 100,000 person-years), giving M/F of 2.65. M/F ratio of intestinal subtype cancer was 3.41 at age <50, reached a peak of 7.86 at age 50-59, and then showed a progressive decrease throughout the life. In contrast, the incidence rate of diffuse subtype adenocarcinoma was similar in both sexes (5.58 vs. 5.20 /100,000 person-years) yielding M/F of 1.07. Multivariate analyses including histological subtype, tumour location and age indicated that the male predominance was related to the histological type rather than anatomical location. Intestinal type tumour showed similar male predominance of incidence irrespective of its anatomical location (OR, 95% CI: 2.6, 1.78 – 3.9). Further analysis of the age-specific incidence curves indicated that the male predominance of intestinal subtype was due to a 17.2-year delay of development of this cancer in females.

The rising tide of obesity and type 2 diabetes has been recognised to have reached epidemic proportions. There is a significant burden of mortality and morbidity associated with the development of these conditions and current estimates suggest that the burden of disease in the next two decades is likely to place considerable strain upon healthcare systems, particularly in the developing world. The development of insulin resistance is a key contributor to the pathogenesis of type 2 diabetes, however the origin of insulin resistance is complex and it is currently unclear precisely how the inter-related components of this metabolic dysfunction are triggered. Obesity is also implicated in the pathogenesis of insulin resistance and represents a risk factor which is potentially modifiable by lifestyle interventions such as exercise and weight loss. Observational and prospective studies have also shown the benefits of lifestyle intervention in reducing the incidence of diabetes in those judged to be at greater risk. People with a parental history of type 2 diabetes have an increased lifetime risk of diabetes and frequently display metabolic abnormalities which, despite persisting normoglycaemia, are evidence of a ‘pre-diabetic’ state and which may themselves carry increased morbidity and mortality. Observational studies suggest a greater difference in insulin sensitivity between active and sedentary offspring, compared to the difference between active and sedentary individuals with no diabetes family history. This is thought to represent an interaction between positive energy balance, a sedentary lifestyle and a ‘thrifty genotype’. These observations suggest that individuals with a parental history of diabetes are more susceptible to the deleterious health effects of a sedentary lifestyle, but that they may be more responsive to an increase in physical activity. Exercise interventions can be expected to have positive effects upon metabolic health and adiposity however, the individual response to exercise is extremely variable. Other factors such as lifestyle alteration have been implicated in the difference between the observed and predicted response to exercise. Therefore, the aim of this thesis was to examine the physical, metabolic and lifestyle differences between sedentary pre-menopausal women with a parent with type 2 diabetes and matched control subjects with no family history of the condition. In particular, this thesis aimed to explore the effect of an aerobic exercise intervention on metabolic health and body composition, whether the response to exercise is dependent upon a familial history of diabetes and the processes by which exercise might induce any observed changes. In order to explore the impact of a sedentary lifestyle on women with, and without a family history of type 2 diabetes, thirty four pre-menopausal, sedentary women with a parental history of diabetes (Offspring) and thirty six matched women without a familial history of diabetes (Controls) were recruited. Assessments of body composition, insulin sensitivity, adipose tissue-derived hormone concentration, substrate utilisation, endothelial function by carotid-radial pulse wave velocity, cardiorespiratory fitness, diet and habitual physical activity were performed. Twenty eight Offspring subjects and thirty four matched Controls participated in a seven-week aerobic exercise intervention, training at 65-80 % of predicted maximal heart rate with incremental increases in training duration on a weekly basis. The previously described assessments were performed before and 15-24 hours after the intervention and in a subgroup of 19 Controls and 17 Offspring subjects, further assessments of insulin sensitivity, adipose tissue-derived hormone concentration, substrate utilisation and endothelial function were performed after a further three day period without exercise. In order to determine potential mediators of exercise-induced fat loss fifty five women participated in measurements of substrate utilisation, body composition, endothelial function, insulin sensitivity, cardiorespiratory fitness, dietary intake and habitual physical activity prior to, and after the seven week exercise intervention. The findings from these studies confirmed that sedentary women with a family history of type 2 diabetes displayed lower insulin sensitivity than those without a parental history of diabetes. In addition, insulin resistance in this group appears to be related to a greater sensitivity to the influence of adipose tissue, particularly circulating non-esterified fatty acids and adipose tissue-derived inflammatory cytokines. In Offspring alone, baseline insulin sensitivity was associated with plasma adiponectin concentration and negatively associated with circulating non-esterified fatty acid concentration. These associations may represent physiological attempts to compensate for developing insulin resistance. Offspring also displayed an augmented metabolic response to the exercise intervention in comparison to Controls. This study showed a 23% increase in post-intervention insulin sensitivity in Offspring with no significant increase in insulin sensitivity in Controls despite a similar improvement in cardiorespiratory fitness and adherence to the exercise regime. Improved post-intervention insulin sensitivity was accompanied by reduced circulating leptin, increased fat and decreased carbohydrate oxidation in both fasting and post-glucose states. No change in diet was observed but Offspring appeared to increase their level of habitual physical activity. The magnitude of change in insulin sensitivity was associated with a parental history of diabetes, but stronger associations were observed between baseline insulin resistance and an ability to reduce circulating leptin in response to exercise. Wide individual variation in fat mass change was observed in the response to exercise, and as expected the strongest predictor of exercise-mediated fat mass reduction was the net energy cost of the intervention. However, a change in fasting respiratory exchange ratio (RER), suggesting an increase in fat oxidation was also independently associated with reduced fat mass. The combined findings of this thesis suggest that sedentary pre-menopausal daughters of people with type 2 diabetes are more insulin resistant and that this state is, in part, a consequence of heightened sensitivity to fatty acid and inflammatory cytokine release from adipose tissue. However, it would also appear that they represent a high-risk group who are susceptible to the insulin-sensitising effects of exercise and that this may be mediated by a metabolic pathway which involves reductions in circulating leptin concentrations. Finally, the ability to lose fat mass in response to exercise is related to the energy deficit incurred by the activity but also by an individual’s ability to shift fasting substrate utilisation towards fat oxidation. Public health strategies have traditionally focused upon lifestyle interventions which are directed at the population in general. However, awareness of the risks conferred by obesity and familial history of type 2 diabetes and the potential benefits of intervention may suggest that targeting public health resources towards these high-risk groups is a more appropriate and effective strategy.

The selection for specific physical characteristics by dog breeders has resulted in the expression of undesirable phenotypes, either directly or indirectly related to the physical characteristic selected for. One conformation that was considered desirable is extreme brachycephalia, which is associated with secondary physical changes adversely affecting the airways, eyes and central nervous system. Using a large population of pet dogs having diagnostic magnetic resonance imaging (MRI) studies, I demonstrated that the most commonly used historical head phenotype indices (Stockard and Evans indices) can be determined on MR images. I furthermore conformed that olfactory bulb angulation can be used as an alternate for classification of dog into brachycephalic, mesaticephalic and dolichocephalic head shapes, with similar results to the historical indices. The advantages of olfactory bulb angulation are that it only requires a single midline MR image and inclusion of the entire nose is not required. Using the historical indices and olfactory bulb angulation I then examined the effect of increasing brachycephalia on the appearance and dimensions of the nasal and cranial cavity. I established that progressive ventral rotation of the olfactory bulb (increasing brachycephalia) resulted in an alteration in the shape and a reduction in cross-sectional area of the nasopharynx. Similarly, increasing brachycephalia resulted in a reduction in the dorsal area of the ethmoturbinates and a corresponding reduction in the midline area of the olfactory bulb, providing a potential explanation for reduced olfactory acuity in brachycephalic dogs. Finally, I examined the effect of head phenotype on the structures of the middle fossa, the 3rd ventricle, quadrigeminal cistern and interthalamic adhesion. Head phenotype had a lesser effect on these structures, while brain disease (in particular ventriculomegaly) has a substantial effect, the recognition of which I described. These results confirm the potential of olfactory bulb angulation and orientation for objectively determining head phenotype using in vivo MRI, in particular determining the degree of brachycephalia. The study also quantified the effect of brachycephalia on the nasal cavity and rostral and middle cranial fossae dimensions. The objective quantification of head phenotype provides a useful tool for selection of breeding animals to normalise extreme brachycephalia. This might reduce the incidence of the adverse effects associated with extreme brachycephalia.

Understanding the physiology of gastro-oesophageal junction (GOJ) is important as failure of its function is associated with reflux disease, hiatus hernia and cancer. It has been suggested that the increased intra-abdominal pressure produced by central obesity may increase acid reflux during transient lower oesophageal sphincter relaxations (TLOSRs) and also predispose to short segment reflux. In recent years, we have seen impressive developments in high resolution technologies allowing measurement of luminal pressure, pH and impedance. One obvious deficiency is our lack of technique to monitor the movement and location of the GOJ over a prolonged period of time. Both in-vitro and in-vivo studies indicated that it was possible to monitor the position of the GOJ by means of clipping a magnet to the squamo-columnar junction and which was detected by a novel linear probe consisting of a series of Hall Effect sensors. The accuracy for detection of position of the GOJ with this new technique was superior to 10 mm and was as good as fluoroscopy in the detection of position with a correlation co-efficient of 0.96. Without the risk of radiation associated with fluoroscopy, the new probe could be applied over a much longer period than had been previously possible. Three factors were identified from in-vitro studies which could limit accuracy of the Hall Effect-based probe. These factors were firstly, poor magnet orientation and distance, secondly, the effect of temperature, and thirdly the presence of other ferromagnetic materials. Newer probe having 3-dimensional capabilities is in development. The temperature effect could be reduced by calibrating the probe within a water bath heated to body temperature prior to insertion. Using alongside a 2.7 mm manometer, the ferromagnetic effect could be reduced. While oesophageal shortening during TLOSRs is due to longitudinal muscle contraction but relatively little is known about the behaviour of the GOJ during its restitution. The return movement of the GOJ is particularly important as failure of this process will produce a persisting hiatus hernia. Detailed examination on migration of the GOJ during TLOSRs and swallows had been performed in 12 healthy subjects. Proximal displacement of the GOJ was present transiently during TLOSRs and swallows but the displacement of up to 9 cm (median 4.3 cm) during TLOSRs represented very severe herniation of the GOJ. In addition, there was a rapid initial return of the GOJ following TLOSRs when the CD was relaxed and its correlation with amplitude suggested it is due to elastic recoil of the POL. This marked stretching of the POL during TLOSRs may contribute to its weakening and development of established hiatus hernia. Epidemiological evidence suggests an association between obesity, reflux disease and hiatus hernia but mechanisms are unclear. Study was performed to assess the structure and function of the GOJ in asymptomatic subjects with and without obesity and the effects of elevating intra-abdominal pressure with waist belt. Sixteen subjects were recruited to achieve two groups defined by normal (eight) or increased (eight) waist circumference, matched for age and gender. Our studies demonstrated that increased WC and waist belt caused marked changes in the functioning of the GOJ and LOS leading to increased gastric acid penetration within the high pressure zone. This appears to occur by retrograde flow within the closed sphincter and by increased short segment reflux during TLOSRs and subsequent impaired clearance. This increased intra-sphincteric acid exposure is occurring in asymptomatic volunteers and may explain the high incidence of inflammation and columnar metaplasia observed at the GOJ in asymptomatic subjects. Our observations may also be relevant to the aetiology of adenocarcinoma of the cardia which shares epidemiological risk factors of the oesophageal adenocarcinoma but has a much weaker association with reflux symptoms. To conclude, a new technique has been developed allowing accurate and prolonged detection of position and movement of the GOJ without any radiation risk. Using alongside high resolution manometry and pHmetry, the new technique allows detailed examination of the structure and function of the GOJ providing important insights on the pathophysiology of reflux disease in normal subjects with and without central obesity and waist belt.

Despite many studies of language use in motivational interviewing, the vast majority have based this upon the quantitative coding of practitioner and client linguistic behaviours in order to relate these to client change outcomes. The current study aimed to investigate how clients and practitioners co-constructed the process of change using discourse analysis. Ten MI sessions for alcohol use were analysed in terms of how alcohol was verbally constructed, the functions and effects of rhetorical strategies employed and subject positions. Power and subjectivity were considered alongside these strands of analysis. The findings suggest that clients and therapists constructed alcohol as either a destroyer or facilitator, drawing upon discourses of differing degrees of power, which impacted upon the availability of client positions of agency and expertise in relation to alcohol. There was also a diversity of function within categories of client and practitioner speech. These findings have implications for clinical practice, in terms of moving beyond the recognition of ‘types of client talk’ and responding with an ‘MI consistent’ verbal behaviour, and moving towards reinvigorating the spirit of MI in relation to clinical outcome.