An estimated thirteen million new cancers are diagnosed every year and in many cases patients will be treated with chemotherapeutic agents, either with curative intent or to prolong life and alleviate symptoms. Historically the dose limiting side-effect of these compounds was immune- and myelosupression, however, as our ability to manage these has improved, a secondary dose-limiting side-effect of these compounds has been revealed: neurotoxicity. Several anti-neoplastics, including the vinca alkaloids, cause a distal, bilateral and symmetrical painful peripheral neuropathy primarily affecting the longest neurons of the extremities. The key symptom of this condition is pain, yet current therapies are ineffective in alleviating this; the average patient rates their pain as a seven out of ten in severity and pain results cessation of treatment in up to 40% of patients. One of the main pitfalls in the development of analgesics for this condition is that little is understood about the mechanism by which chemotherapy causes neuropathy. Thus, I have aimed to delineate a novel pathway of the mechanism by which vincristine sulphate (VCR) induces painful peripheral neuropathy. The pathway delineated is based on the observation that there is significant monocyte-macrophage infiltration of the peripheral nerves following VCR administration, in a temporal profile similar to that of the onset of mechanical allodynia (a painful response to normally innocuous stimuli) in the mouse, and that depletion of monocyte/macrophages prior to VCR administration attenuates allodynia. Whilst this depletion is not a viable therapeutic option for patients, it has led us to investigate of the contribution to the development of pain of the CX3CR1 receptor, the level of expression of which is the defining characteristic of monocyte/macrophages. We have established that CX3CR1 plays a critical role in the development of VCR-neuropathy; mice devoid of CX3CR1 exhibit a delay in the onset of allodynia and a reduction in VCR-induced nerve infiltration of CX3CR1+ monocyte/macrophages. We have demonstrated that this infiltration is likely a result of up-regulation of monocyte adhesion molecules on the endothelial cells lining blood vessels. Furthermore, we suggest that at the blood-nerve interface CX3CR1+ monocytes/macrophages are activated by CX3CL1, endogenously expressed on endothelial cells, promoting the production of reactive oxygen species, which subsequently activate the TRPA1 receptor on sensory neurons. This work has led to the conclusion that CX3CR1 antagonists constitute new peripheral targets for the prophylactic treatment of chemotherapy induced painful peripheral neuropathy.

This thesis explores the relationships between the natural environment, urbanisation, and the market economy, in the context of water supply and drainage in eighteenth-century London. It argues that, as a result of the expansion of the built-up area, the institutions that managed London’s water became increasingly vital as the main mediators of the growing distance between the city’s inhabitants and water. In particular, it focuses on the growth of a commercial water supply, and analyses how the allocation of a natural resource became increasingly refracted through the market. As such, the thesis addresses the emergence of a political economy of water and its social and economic ramifications. The thesis takes an interdisciplinary approach, integrating social and environmental history, and it argues that geography should be incorporated in the analysis of the institutions that controlled water. It considers London’s drainage system and its water supply together, as changes in the drainage of surface water played a crucial role in creating the conditions for the privatisation of London’s water supply. The expansion of the supply network, in turn, depended heavily on London’s social geography as well as its topography, as the difference in elevation between a water company’s intake and its customer base proved influential for its failure or success. The increased role of commercial water supply had important consequences as to how eighteenth-century Londoners accessed water. A new analysis of the water companies' level of market penetration adds context to contemporary debates surrounding the way the water market was structured. Finally, an investigation of the provision of free water in emergencies explores the role of private companies in the provision of public goods. The thesis adds to our knowledge about the growing role for institutions in an expanding city. More specifically, it explores how the market mediated relationships between society and nature.

This thesis explored the co-constructed experiences of couples and families in which one person had a diagnosis of dementia. It includes a literature review, a research paper, a critical appraisal and an ethics section. The literature review is a meta-synthesis of 10 qualitative studies which explored the impact living with dementia can have on the couple relationship, or the impact the couple relationship has on dementia. The synthesis resulted in four interrelated themes: (1) togetherness – continuing as ‘we’ are; (2) upsetting and re-defining the balance – a new ‘normal’ is evolving; (3) sensitive attunement – shielding one’s partner from the effects of dementia; and (4) resilience – distancing distress and cherishing the present moment. These themes highlighted couples’ shared efforts to maintain aspects of their relationship in the context of dementia. Findings have important implications for services to support couples’ efforts to enhance their sense of couplehood. The research paper extended these findings to explore shared experiences of family units in which one person has dementia. Semi-structured interviews with seven families were analysed using interpretative phenomenological analysis. This resulted in five themes (1) conflicting identities: person or ‘dementia patient’; (2) loneliness and isolation: finding ways to maintain belonging and connection; (3) family support: protecting and enabling; (4) feeling trapped: shifting power and control; and (5) fear and uncertainty: making sense and reigniting hope. Findings have implications for services to consider the whole family system, encouraging connection and belonging to enhance the natural therapeutic capacity of families. Finally, the critical appraisal includes reflections of a number of ethical, methodological and conceptual issues that became pertinent when conducting this research.

A mutation in the DYT1 gene on chromosome 9q34 is the commonest cause of young-onset primary dystonia. The penetrance of clinical symptoms is low (only 30-40% of gene carriers manifest dystonia), and occurs in an age-dependent fashion. Mutation carriers who pass their mid-twenties without developing symptoms almost invariably stay symptom free for life. DYT1 mutation carriers therefore provide a unique model with which to study brain function in primary dystonia, and factors that may protect against development of clinical symptoms in those who are genetically susceptible. This thesis describes the use of electrophysiological techniques to determine 1) if manifesting DYT1 carriers have similar deficits in motor function to non-genetic primary dystonia, and 2) what are the consequences of the DYT1 mutation for motor system physiology in non-manifesting carriers. We found abnormalities of inhibitory motor circuits at cortical and spinal cord levels in manifesting DYT1 subjects. Surprisingly, we found cortical motor abnormalities of a similar nature and severity in non-manifesting DYT1 carriers, despite their lack of symptoms.

This thesis contains four studies, the first examining methodology issues and four subsequent ones examining somatosensory cortical processing using event-related potentials (ERPs). The methodology section consists of 2 experiments. The first compared the latency variability in stimulus presentation between 3 computers. The second monitored the applied force of the vibration stimuli under experimental conditions to ensure that the chosen method for somatosensory stimulus presentation was consistent and reliable. The next study involved 3 experiments that aimed to characterize the mid to long latency somatosensory event-related potentials to different duration vibratory stimuli using both intracranial and scalp recording. The results revealed differences in the waveform morphology of the responses to and on-off responses, which had not previously been noted in the somatosensory system. The third and fourth studies each consisted of 2 experiments. These examined the discrimination between vibratory stimuli using an odd-ball paradigm to try to obtain a possible 'mismatch' response, similar to that reported in the auditory system. The aim of this study was to clarify some of the discrepancies in the literature surrounding the somatosensory mismatch response and to further characterize this response. The results from intracranial and scalp ERP recordings showed a two-component, negative-positive mismatch response over the anterior parietal region and a negative component over the superior pre-frontal region in response to changes in both frequency and duration. The negative component over the frontal region had never before been described. The last study explored possible interactions between somatosensory and auditory cortical potentials in response to spatially and temporally synchronized auditory and vibratory stimuli. The results showed clear interactions in the cortical responses to combined auditory and somatosensory stimuli in both standard and mismatch conditions.

Heat shock proteins (HSPs) are molecular chaperones with essential roles in cellular function such as modulating the proteolytic machinery and accelerating cell repair. HSP overexpression has been observed in vitro and in vivo under stresses including heat, nutrient deprivation and ischaemia. Experiments in in vivo models of stroke indicate that transgenically overexpressed or virally delivered HSPs can enhance cell survival but cannot always reduce lesion size. This study aims to assess the protective effects of HSPs in a rat model of reversible focal cerebral ischaemia using magnetic resonance imaging (MRI) techniques to measure cerebral blood flow and lesion size. The experiments described used three different herpes simplex virus (HSV) constructs: two potentially therapeutic vectors, HSV-HSP27 and HSV-HSP70, and an HSV-LacZ control vector. Initially, the localization and duration of expression from the viral vector used to deliver the HSP genes into the rat brain was assessed. Subsequently, the effect of pre-ischaemic intra-striatal microinjections of HSV-HSP27 and HSV-HSP70 was evaluated in a middle cerebral artery occlusion (MCAO) model of stroke. Finally, the effect of delivering the same HSPs 30 minutes after ischaemia was assessed. Behavioural tests were carried out in the latter study up to a month after MCAO in order to determine whether HSP treatment induced functional recovery as well as reduction in lesion size. Results suggest that intracerebral microinjections with HSV-HSP27 have a neuroprotective effect pre- and [?] ischaemia. Multislice T2-weighted images show that HSP27 treatment results in a significant reduction in lesion size after MCAO, whereas HSP70 treatment does not affect lesion size compared to controls. Western blots confirm that virally-induced overexpression of both HSP27 and HSP70 is achieved in treated animals. For the first time, non-invasive MRI techniques were used to demonstrate the neuroprotective effect of HSP27 and not HSP70 in a rat model of reversible focal cerebral ischaemia.

The study of antigen-specific intrathecal oligoclonal bands is well established and a number of methods have been used to demonstrate that the relative affinity of the antibody produced in multiple sclerosis is low, and in encephalitis, high. A method colloquially known as Eastern blotting was developed whereby relative affinity of individual clones, rather than total antibody, could be studied and quantified by antigen immunoblotting and investigation of a digitised blot using image-manipulating software. This method was used to show that the pixel density of a band in CSF was significantly greater than the same band in serum in a patient with SSPE, and was thus of intrathecal origin. Eastern blotting was then used on a series of samples from a patient with herpes encephalitis to demonstrate that affinity maturation of the immune response had occurred intrathecally. The method was used qualitatively to investigate a proposal that Acinetobacter sp. infection could be the primary cause of multiple sclerosis: no evidence could be found to support the hypothesis. Another suggested cause of multiple sclerosis, Chlamydophila pneumoniae, was studied using a variety of methods including Western blotting. Again, there was no evidence to support the hypothesis. During the project, an unexpected effect of high-strength thiocyanate was revealed, and limited study of this suggested that thiocyanate had an effect on IgG, possibly related to the age of the sample.

Motor neuron disease (MND) comprises a group of neurological disorders which include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), primary muscular atrophy (PMA), spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (SBMA). These disorders have different etiology and clinical features, but share the striking feature of prevalently affecting motor neurons. A genetic cause has been identified for SBMA, SMA and mutations in a handful of genes currently explain a minority of ALS, PLS and PMA cases. Although many different mechanisms have been postulated to play a role in these diseases, the underlying pathogenetic mechanisms are largely unknown and therapeutic interventions are lacking. The research presented in this thesis focuses on two forms of MND (ALS and SBMA) and on the investigation of the causes and mechanisms underlying these diseases. Firstly, the known genetic causes and clinical features were screened and analysed in cohorts of SBMA and ALS patients. Secondly, the role of FUS, a gene known to cause ALS when mutated, as a potential link between ALS and SBMA, was investigated by using a mouse model of SBMA. Finally, the pathogenic mechanisms underlying ALS were analysed, focusing on two important genes: TARDBP and C9orf72. TARDBP mutations cause of <2% of ALS cases, but TDP43, the protein product of TARDBP, is found in the cytoplasmic inclusions of >98% of ALS patients, highlighting its importance in disease pathogenesis. TDP43 is an RNA binding protein and whether RNA defects are present in patient tissue is yet unclear, due to the poor quality of ALS post-mortem material. High quality biopsy material, from a muscle TDP43-disease, sporadic inclusion body myositis, is here used to analyze if RNA changes are associated with TDP43 mislocalization in patient tissue. The results highlight the complex role of TDP43 in this process. Expansions of a hexanucleotide repeat in a non-coding portion of C9orf72 have recently been identified as the underlying cause of 5-20% of ALS cases. The location of the mutation in a non-coding segment, have suggested a potential role for RNA toxicity. The structure of the expanded RNA sequence is therefore here investigated to gain insight in potential pathogenic mechanisms. In summary, a genetic and clinical characterisation of ALS and SBMA cohorts of patients is performed in order to gain insight in the clinical, genetic and molecular mechanisms of these diseases. Further, molecular biology and structural biology tools are used to progress our understanding of the pathogenetic mechanisms linked to two important players in ALS pathogenesis: TDP43 and C9orf72.

β-catenin is a multifunctional protein with roles in Wnt pathway signal transduction and in cell adhesion. While the normal function of β-catenin is important for CNS development, Wnt pathways have also been intrinsically linked to cancer. Here, the multiple roles of β-catenin in CNS development and in brain tumour pathogenesis were investigated. All experiments used a mouse model where a dominant active form of β-catenin can be induced by Cre mediated recombination of the exon 3 of the CATNNB gene. Three models were established to analyse the effects of dominant active β-catenin: (i) during development with En2Cre, in the midbrain-hindbrain regions, (ii) in mature (L7Cre) Purkinje neurons, and (iii) in adult stem cells using Cre delivery into the SVZ using an established and a specifically developed novel method. En2Cre;β‐cateninlox(ex3) mice express mutant β-catenin in the midbrain-hindbrain junction during early brain development. Although En2 is expressed between E8 and E12.5, the precise timing and duration of stabilized β‐catenin is not known. At later stage, these mice showed decreased motor performance, caused by a significant defect in the vermis region. This phenotype could be rescued by deletion of p53 gene, pointing at a potential role of p53/β-catenin cross-talk. In contrast, constitutive activation of β-catenin in mature cerebellar Purkinje neurons using the L7Cre; β-cateninlox(ex3) model, does not cause cell death or dysfunction of these neurons. To target SVZ stem/progenitor cells, we used an established model with adenovirus-Cre mediated recombination and we developed a highly selective approach through direct, intraventricular injection of Endoxifen into GLAST-Cre(ERT2) mice. Both approaches resulted in similar phenotypes and latencies to tumour development, and required at least one additional tumour suppressor to be inactivated simultaneously to cause brain tumours. The results suggest that β-catenin has diverse effects during different developmental stages. During early development, it causes widespread cell death, whilst no effect is seen in mature cells. In adult SVZ progenitor cells it has no effect unless tumour suppressor genes such as p53 or PTEN are concomitantly inactivated, resulting in formation of brain tumours.

This review considers how young people's Quality of Life (QoL) is affected by the symptoms of Tourette Syndrome (TS). The construct of QoL aims to capture how satisfied a person is with their level of functioning in life, rather than assuming that those with mild symptoms have a higher QoL than those with severe symptoms. This may be particularly relevant in TS, where a strong relationship between symptom severity and well-being has not been established. The research into QoL in TS is limited, but there is a wide body of evidence that suggests TS can impair functioning across many domains. This research reminds us that individuals with TS are coping with more than just tics. Rage attacks, attention and learning difficulties, obsessions and compulsions are also experienced by individuals with TS and can have an equally significant impact on their life.