The Devil and the diableries in the medieval French passion plays

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Gene transfer as a potential treatment for tetrahydrobiopterin deficient states.

Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine (DA), noradrenaline (NA), serotonin and nitric oxide (NO) synthesis in the brain. Inborn errors of BH4 metabolism including GTP cyclohydrolase 1 (GTP-CH) deficiency are debilitating diseases in which BH4, DA, 5-HT and NO metabolism are impaired. Current treatment for these disorders is typically monoamine replacement +/- BH4. Whilst correction of the primary defect is the ideal, BH4 treatment is problematic as it is expensive and inefficacious. One approach to treat BH4 disorders is to use gene therapy as a more permanent, effective alternative. In this thesis the potential of gene therapy in an animal model of partial BH4 deficiency, the hph-1 mouse, was examined. These mice show many neurochemical similarities associated with BH4 deficient states, including impaired BH4 (-69%), DA (-14%), NA (-23%), serotonin turnover (-55%) and NO metabolites in the brain. In cultured astrocytes from hph-1 mice BH4 was significantly lower than wild type (-53%), and produced less BH4 (- 89%) and NO metabolites (-64%) when stimulated with lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma), stimuli that increase GTP-CH and iNOS expression. When hph-1 astrocytes were infected with a recombinant adenovirus encoding human GTP cyclohydrolase (AdGCH), concentration-dependent increases in BH4 levels were observed, with just 1 virus particle per 10 cells resulting in 50-fold increases in BH4. AdGCH can upregulate the impaired NO production observed in hph-1 astrocytes following stimulation with LPS + IFN-y, although only if BH4 was increased prior to stimulation. Examination of the molecular mechanisms behind the impaired NO production in LPS + IFN-y stimulated cells revealed that iNOS dimerisation is attenuated in hph-1 astrocytes when compared wild type (-84%), and could be increased to wild type levels when cells were pre-treated with AdGCH. Analysis of total iNOS protein expression revealed no difference between wild type and hph-1. These results raise the possibility that gene therapy could be used as a corrective solution for tetrahydrobiopterin deficient states

The efect of disinfectant solutions on the durability of the bond between resin based cement and non-precious metal alloy

This study evaluated the effect of disinfectants on the tensile bond strength of Nickel-Chromium alloy bonded with resin cement. 180 pairs of Nickel-Chromium dumbbells were prepared. The dumbbells were divided into 3 groups (n=60), which received one of the following treatments: Sandblasted only (control), sandblasted and Perform®-ID or sandblasted and sodium hypochlorite (SH) before bonding with resin cement. All bonded specimens were stored in distilled water for 24 h and half of the specimens were subsequently thermocycled (500 cycles) before debonding. Tensile bond strength was recorded and each dumbbell was examined for failure mode. Two-way ANOVA analysis indicated that overall there was a statistically significant difference between 24 h and thermocycling test, but no differences between sandblasted only, sandblasted and Perform-ID or sandblasted and SH groups. Post-ANOVA contrasts indicated that only the sandblasted and SH group showed a significant difference between the 24 h and thermocycling test. Disinfectants did not significantly decrease tensile bond strength between Nickel-Chromium dumbbells bonded with resin cement

The efect of disinfectant solutions on the durability of the bond between resin based cement and non-precious metal alloy

This study evaluated the effect of disinfectants on the tensile bond strength of Nickel-Chromium alloy bonded with resin cement. 180 pairs of Nickel-Chromium dumbbells were prepared. The dumbbells were divided into 3 groups (n=60), which received one of the following treatments: Sandblasted only (control), sandblasted and Perform®-ID or sandblasted and sodium hypochlorite (SH) before bonding with resin cement. All bonded specimens were stored in distilled water for 24 h and half of the specimens were subsequently thermocycled (500 cycles) before debonding. Tensile bond strength was recorded and each dumbbell was examined for failure mode. Two-way ANOVA analysis indicated that overall there was a statistically significant difference between 24 h and thermocycling test, but no differences between sandblasted only, sandblasted and Perform-ID or sandblasted and SH groups. Post-ANOVA contrasts indicated that only the sandblasted and SH group showed a significant difference between the 24 h and thermocycling test. Disinfectants did not significantly decrease tensile bond strength between Nickel-Chromium dumbbells bonded with resin cement

fMRI evidence for a cortical hierarchy of pitch pattern processing

Pitch patterns, such as melodies, consist of two levels of structure: a global level, comprising the pattern of ups and downs, or contour; and a local level, comprising the precise intervals that make up this contour. An influential neuropsychological model suggests that these two levels of processing are hierarchically linked, with processing of the global structure occurring within the right hemisphere in advance of local processing within the left. However, the predictions of this model and its anatomical basis have not been tested in neurologically normal individuals. The present study used fMRI and required participants to listen to consecutive pitch sequences while performing a same/different one-back task. Sequences, when different, either preserved (local) or violated (global) the contour of the sequence preceding them. When the activations for the local and global conditions were contrasted directly, additional activation was seen for local processing in right planum temporale and posterior superior temporal sulcus (pSTS). The presence of additional activation for local over global processing supports the hierarchical view that the global structure of a pitch sequence acts as a “framework” on which the local detail is subsequently hung. However, the lateralisation of activation seen in the present study, with global processing occurring in left pSTS and local processing occurring bilaterally, differed from that predicted by the neuroanatomical model. A re-examination of the individual lesion data on which the neuroanatomical model is based revealed that the lesion data equally well support the laterality scheme suggested by our data. While the present study supports the hierarchical view of local and global processing, there is an evident need for further research, both in patients and neurologically normal individuals, before an understanding of the functional lateralisation of local and global processing can be considered established

Within the Walls Project: Comparing Heritage Values as Action within Council & Community Asset Transfer Practices, York, UK 2014-2016

This study compares the heritage values of different community groups and one local authority in York as part of the Within the Walls Project (a Collaborative Doctoral Award with the City of York Council). Focusing on the UK Localism Act (2011) and redistribution of power to community groups, this study investigates values as action towards enhancing or protecting heritage in places, through which new values and collaborative relationships emerge. The study focuses on the priorities of the City of York Council and the process of Community Asset Transfers, which although is not a mechanism of the Localism Act, is demonstrated to support localism policies nonetheless. The three main contributions of this research include; demonstration through innovative visualisations that it is possible to plot the movement and creation of values within different heritage practices; evidence that physical place impacts upon collaborative relationships in heritage projects (essentially, that the existence of physical infrastructure can foster cooperative activities); and lastly, deep ethnographic insight and pragmatic recommendations were offered into the CAT process, an under-researched area of the heritage sector.

Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.

There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.This work was funded by the Medical Research Council (G0901303) of the UK. We also wish to thank the Cambridge Eye Trust for their support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/cddis.2016.11

Associations between patient factors and successful colon capsule endoscopy – a prospective cohort study

Funding statement This study was funded by an NHS Highland Research Development and Innovation grant. Acknowledgements We would like to thank all patients and staff involved in the ScotCap evaluation. We would also like to thank The Data Lab for their contribution to the project.Peer reviewedPostprin

fMRI Evidence for a Cortical Hierarchy of Pitch Pattern Processing

Pitch patterns, such as melodies, consist of two levels of structure: a global level, comprising the pattern of ups and downs, or contour; and a local level, comprising the precise intervals that make up this contour. An influential neuropsychological model suggests that these two levels of processing are hierarchically linked, with processing of the global structure occurring within the right hemisphere in advance of local processing within the left. However, the predictions of this model and its anatomical basis have not been tested in neurologically normal individuals. The present study used fMRI and required participants to listen to consecutive pitch sequences while performing a same/different one-back task. Sequences, when different, either preserved (local) or violated (global) the contour of the sequence preceding them. When the activations for the local and global conditions were contrasted directly, additional activation was seen for local processing in right planum temporale and posterior superior temporal sulcus (pSTS). The presence of additional activation for local over global processing supports the hierarchical view that the global structure of a pitch sequence acts as a “framework” on which the local detail is subsequently hung. However, the lateralisation of activation seen in the present study, with global processing occurring in left pSTS and local processing occurring bilaterally, differed from that predicted by the neuroanatomical model. A re-examination of the individual lesion data on which the neuroanatomical model is based revealed that the lesion data equally well support the laterality scheme suggested by our data. While the present study supports the hierarchical view of local and global processing, there is an evident need for further research, both in patients and neurologically normal individuals, before an understanding of the functional lateralisation of local and global processing can be considered established