An investigation of magnetization transfer ratio and T1 hypointense lesion volume in secondary progressive multiple sclerosis.

The data presented in this thesis were collected as part of a trial of neuroprotection with lamotrigine in secondary progressive multiple sclerosis (MS) and comprise clinical assessment and quantitative magnetic resonance imaging (MRI), specifically focussing on T1 hypointense lesion volume (T1LV) and magnetization transfer ratio (MTR). The aim of the study was to evaluate the usefulness of these MRI techniques for monitoring neuropathology in MS by examining the correlation of MRI measures with clinical measures both cross-sectionally and longitudinally and the responsiveness to change of these measures. The potential neuroprotective effect of lamotrigine was assessed by comparing clinical and MRI data in placebo and verum arms of the trial. The introduction briefly summarises: the clinical features of secondary progressive MS; some of the aspects of MS pathology and pathophysiology that may be ameliorated by lamotrigine treatment; some of the techniques for assessing clinical status in MS, including the impact of MS on quality of life (QoL); and the role of quantitative MRI in monitoring putative neurodegeneration in MS. The methods chapter details: the structure and conduct of the trial, including recruitment of subjects, acquisition of clinical and MRI data; and the post-acquisition analysis of the MRI data. The results chapter addresses four issues: the cross-sectional correlation of MRI with clinical measures; the responsiveness to change and longitudinal correlation of MTR measures with clinical measures; the responsiveness to change and longitudinal correlation of T1LV with clinical measures; and the cross-sectional and longitudinal correlation of a large number of MRI and clinical measures with the Multiple Sclerosis Impact Scale (MSIS-29), a measure of the impact of MS on QoL. The conclusions chapter summarises some of the more notable results presented, some of the limitations of the study and proposes some further work that could be done to clarify any areas of uncertainty

'Sinking and swimming in disability coaching': an autoethnographic account of coaching in a new context

In terms of achieving wider health and social outcomes, sport coaching promises much for young people with disabilities. Despite this promise, the experiences and practices of those coaches who enter the disability sport arena are underexplored. This is particularly so for coaches who operate in community participation rather than competitive elite environments. Accordingly, this paper uses an autoethnographic approach to explore the experiences of a basketball coach (Colum), who enters a youth club for disabled participants for the first time. Utilising observational data, reflective field notes, and interviews, five relativist vignettes are collaboratively constructed to represent Colum’s (a pseudonym) experiences across 12 basketball sessions. The vignettes reveal that the disability and community context disrupted Colum’s normative coaching behaviours. An emotional laborious journey is recounted that includes significant lessons, which may impact coaching practitioners, researchers and sport development officers. In addition, the post-sport context (Atkinson, 2010a) is introduced to differentiate the youth club context from Colum’s normative sport context. Furthermore, the concepts of liminality and ludic, which are novel to extant coaching literature, are introduced to explain how and why Colum struggled to find structure within the context of a youth club for disabled participants

Observing CMB polarisation through ice

Ice crystal clouds in the upper troposphere can generate polarisation signals at the uK level. This signal can seriously affect very sensitive ground based searches for E- and B-mode of Cosmic Microwave Background polarisation. In this paper we estimate this effect within the ClOVER experiment observing bands (97, 150 and 220 GHz) for the selected observing site (Llano de Chajnantor, Atacama desert, Chile). The results show that the polarisation signal from the clouds can be of the order of or even bigger than the CMB expected polarisation. Climatological data suggest that this signal is fairly constant over the whole year in Antarctica. On the other hand the stronger seasonal variability in Atacama allows for a 50% of clean observations during the dry season.Comment: 7 Pages, 4 figure

Immunogenicity of a universal HIV-1 vaccine vectored by DNA, MVA and CHADV-63 in a Phase I/IIA clinical trial

Background The major challenge facing both antibody and T cell-eliciting vaccines against HIV-1 is the extreme variability of the HIV-1 genome: a successful vaccine has to effectively target diverse HIV-1 strains circulating in the population and then must deal with ongoing virus escape in infected individuals. To address these issues, we assembled a vaccine immunogen HIVconsv from the functionally most conserved regions (not epitopes) of the HIV-1 proteome. Methods A gene coding for the HIVconsv immunogen was inserted into plasmid DNA (D), modified vaccinia virus Ankara (MVA; M) and non-replicating adenovirus of a chimpanzee origin ChAdV-63 (C). Currently, combined heterologous prime-boost regimens of these vaccines, namely CM, DDDCM and DDDMC, are being evaluated in a phase I/IIa trial HIV-CORE002 in healthy HIV-1/2-negative volunteers in Oxford. Results Preliminary data indicate that the vaccines are well tolerated and show high immunogenicity. Following the CM regimen, vaccine-induced T cell frequencies reached a median of 5150 (range 1475 to 16495) SFU/106 PMBC ex vivo one week post MVA vaccination. DNA priming increased subsequent T cell responses to ChAdV-63 vaccination (median: C 577 and DDDC 1328 SFU/106 PBMC) and ELISpot responses again peaked 1 week following MVA (median 4500; range 2260-7960 SFU/106 PBMC). Matrix analyses of the participants following CM vaccination showed that T cells responded to a range of peptides across the length of HIVconsv. The CM regimen elicited IFN-γ in both CD4+ and CD8+ T cell subsets and polyfunctional (IFN-γ & TNF-α) responses to HIVconsv peptides. Conclusion Presented data will be very much work in progress. Nevetheless, the HIVconsv vaccines have so far induced T cell responses superior to other HIV-1 vaccine candidates tested to date. ChAdV-63 is the first adenovirus of chimp origin delivering an HIV-1-derived immunogen that has reached the clinic. The work is supported by Medical Research Council UK

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Nitrous oxide-induced myeloneuropathy: a case series.

BACKGROUND: Nitrous oxide (N2O) is the second most common recreational drug used by 16- to 24-year-olds in the UK. Neurological symptoms can occur in some people that use N2O recreationally, but most information comes from small case series. METHODS: We describe 119 patients with N2O-myeloneuropathy seen at NHS teaching hospitals in three of the UK's largest cities: London, Birmingham and Manchester. This work summarises the clinical and investigative findings in the largest case series to date. RESULTS: Paraesthesia was the presenting complaint in 85% of cases, with the lower limbs more commonly affected than the upper limbs. Gait ataxia was common, and bladder and bowel disturbance were frequent additional symptoms. The mid-cervical region of the spinal cord (C3-C5) was most often affected on MRI T2-weighted imaging. The number of N2O canisters consumed per week correlated with methylmalonic acid levels in the blood as a measure of functional B12 deficiency (rho (ρ)=0.44, p=0.04). CONCLUSIONS: Preventable neurological harm from N2O abuse is increasingly seen worldwide. Ease of access to canisters and larger cylinders of N2O has led to an apparent rise in cases of N2O-myeloneuropathy in several areas of the UK. Our results highlight the range of clinical manifestations in a large group of patients to improve awareness of risk, aid early recognition, and promote timely treatment

Culture, entrepreneurship and uneven development: a spatial analysis

Interest in the proposed connection between culture and entrepreneurship has grown significantly in recent years. However, less attention has been given to the nature of the overall impact of this proposed association on development outcomes, particularly at a local level. In response, this paper analyses the relationship between the nature of the culture, entrepreneurship and development experienced across localities, proposing that the link between culture and development is mediated by entrepreneurship. It focuses upon the concept of community culture, as well as embracing a notion of development incorporating both economic and social well-being outcomes. Drawing upon a multivariate spatial analysis of data from localities in Great Britain, the findings indicate that differences in rates of entrepreneurship are strongly influenced by the community culture present in these localities. Furthermore, a bidirectional relationship is found to exist between entrepreneurship and economic and social development outcomes. It is concluded that the embeddedness of local community culture presents a significant challenge for those places seeking to promote entrepreneurially-driven development

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits