Optimising the medical management of ileoanal pouch related complications and discovering novel therapeutic avenues through metabonomic profiling

Restorative proctocolectomy is considered a quality of life surgical procedure in patients with ulcerative colitis who fail to respond to conventional medical therapies and in some patients with Familial Adenomatous Polyposis. This thesis explores the current management of chronic primary idiopathic pouchitis through a systematic review and meta-analysis. Following this review I have explored the clinical utility of antibiotics and biologics in a cohort of patients with both chronic primary idiopathic pouchitis and pre-pouch ileitis. I have found that the treatment options for chronic pouchitis and pre-pouch ileitis are limited and that long-term treatments such as antibiotics and biologics are ineffective in a significant proportion of patients often leading to a permanent ileostomy. I have also explored the effect of some non-medical therapies including biofeedback and the Renew® anal insert for incontinence and evacuatory problems and have shown that they may be a useful adjunct in the treatment of these pouch related complications. The second focus of the thesis is to try and understand the mechanisms that drive the development of pouchitis. I undertook a systematic review to explore what was already known about the gut microbiota and its role in health and disease of the pouch. I then utilised next generation sequencing technologies to include metataxonomics, nuclear magnetic resonance and mass-spectrometry gas chromatography to link the gut microbiota with the metabolic signatures in serum, urine, faeces and mucosal tissue. I used these techniques to compare patients with pouchitis against healthy controls and patients with Familial Adenomatous Polyposis. These studies have highlighted the importance of the Firmicutes phylum and their role in the production of short chain fatty acids. I have found that a depletion in short chain fatty acids may contribute to the development of pouchitis. Future work may build on methods to increase short chain fatty acid delivery to the pouch through methods such as dietary interventions, distal feeding prior to continuity surgery or direct short chain fatty acid supplementation delivered topically to the pouch.Open Acces

Document Classification Systems in Heterogeneous Computing Environments

Datacenter workloads demand high throughput, low cost and power efficient solutions. In most data centers the operating costs dominates the infrastructure cost. The ever growing amounts of data and the critical need for higher throughput, more energy efficient document classification solutions motivated us to investigate alternatives to the traditional homogeneous CPU based implementations of document classification systems. Several heterogeneous systems were investigated in the past where CPUs were combined with GPUs and FPGAs as system accelerators. The increasing complexity of FPGAs made them an interesting device in the heterogeneous computing environments and on the other hand difficult to program using Hardware Description languages. We explore the trade-offs when using high level synthesis and low level synthesis when programming FPGAs. Using low level synthesis results in less hardware resource usage on FPGAs and also offers the higher throughput compared to using HLS tool. While using HLS tool different heterogeneous computing devices such as multicore CPU and GPU targeted. Through our implementation experience and empirical results for data centric applications, we conclude that we can achieve power efficient results for these set of applications by either using low level synthesis or high level synthesis for programming FPGAs

Effects of HMG‐COA reductase inhibitors (statins) in patients with heart failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106135/1/ejhf80342-6.pd

Analysis of a Splice Array Experiment Elucidates Roles of Chromatin Elongation Factor Spt4–5 in Splicing

Splicing is an important process for regulation of gene expression in eukaryotes, and it has important functional links to other steps of gene expression. Two examples of these linkages include Ceg1, a component of the mRNA capping enzyme, and the chromatin elongation factors Spt4–5, both of which have recently been shown to play a role in the normal splicing of several genes in the yeast Saccharomyces cerevisiae. Using a genomic approach to characterize the roles of Spt4–5 in splicing, we used splicing-sensitive DNA microarrays to identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5 mutants. In the context of a complex, nested, experimental design featuring 22 dye-swap array hybridizations, comprising both biological and technical replicates, we applied five appropriate statistical models for assessing differential expression between wild-type and the mutants. To refine selection of differential expression genes, we then used a robust model-synthesizing approach, Differential Expression via Distance Synthesis, to integrate all five models. The resultant list of differentially expressed genes was then further analyzed with regard to select attributes: we found that highly transcribed genes with long introns were most sensitive to spt mutations. QPCR confirmation of differential expression was established for the limited number of genes evaluated. In this paper, we showcase splicing array technology, as well as powerful, yet general, statistical methodology for assessing differential expression, in the context of a real, complex experimental design. Our results suggest that the Spt4–Spt5 complex may help coordinate splicing with transcription under conditions that present kinetic challenges to spliceosome assembly or function

Primary Sjögren's Syndrome: health experiences and predictors of health quality among patients in the United States

<p>Abstract</p> <p>Objective</p> <p>To assess the health related quality of life of patients with primary Sjögren's Syndrome (PSS) in a large US sample.</p> <p>Methods</p> <p>Questionnaires were mailed to 547 patients with a confirmed diagnosis of PSS (PhysR-PSS) and all active members of the Sjögren's Syndrome Foundation USA (SSF-PSS), half of whom identified a friend without PSS to also complete the survey.</p> <p>Results</p> <p>277 PhysR-PSS patients were compared to 606 controls. The mean age was 62 years in the PhysR-PSS group and 61 years in the control group. 90% in both groups were women. Time from first symptom to diagnosis of PSS was a mean of 7 years. Sicca related morbidity, fatigue severity, depression and pain (assessed by validated questionnaires, PROFAD-SSI, FACIT-F, CES-D, BPI) were significantly greater, and all eight SF-36 domains were significantly diminished, in patients compared to controls. Somatic fatigue was the dominant predictor of physical function and of general health. Depression was the dominant predictor of emotional well being. Health care utilization was higher in patients than controls, including out of pocket dental expenses (mean: PhysR-PSS = $1473.3, controls =$503.6), dental visits (mean: PhysR-PSS = 4.0, controls = 2.3), current treatments (mean: PhysR-PSS = 6.6, controls = 2.5), and hospitalizations (53% PhysR-PSS, vs. 40% controls).</p> <p>Conclusion</p> <p>Diminished health quality and excess health costs are prevalent among PSS patients. Health experiences and functional impact of PSS is similar among US and European patients. Delayed diagnosis, sicca related morbidity, fatigue, pain and depression are substantial suggesting unmet health needs and the importance of earlier recognition of PSS.</p

A high throughput molecular force assay for protein-DNA interactions.

An accurate and genome-wide characterization of protein–DNA interactions such as transcription factor binding is of utmost importance for modern biology. Powerful screening methods emerged. But the vast majority of these techniques depend on special labels or markers against the ligand of interest and moreover most of them are not suitable for detecting low-affinity binders. In this article a molecular force assay is described based on measuring comparative unbinding forces of biomolecules for the detection of protein–DNA interactions. The measurement of binding or unbinding forces has several unique advantages in biological applications since the interaction between certain molecules and not the mere presence of one of them is detected. No label or marker against the protein is needed and only specifically bound ligands are detected. In addition the force-based assay permits the detection of ligands over a broad range of affinities in a crowded and opaque ambient environment. We demonstrate that the molecular force assay allows highly sensitive and fast detection of protein–DNA interactions. As a proof of principle, binding of the protein EcoRI to its DNA recognition sequence is measured and the corresponding dissociation constant in the sub-nanomolar range is determined. Furthermore, we introduce a new, simplified setup employing FRET pairs on the molecular level and standard epi-fluorescence for readout. Due to these advancements we can now demonstrate that a feature size of a few microns is sufficient for the measurement process. This will open a new paradigm in high-throughput screening with all the advantages of force-based ligand detection. Graphical abstract: A high throughput molecular force assay for protein–DNA interaction

Tree scattering amplitudes of the spin-4/3 fractional superstring I: the untwisted sectors

Scattering amplitudes of the spin-4/3 fractional superstring are shown to satisfy spurious state decoupling and cyclic symmetry (duality) at tree-level in the string perturbation expansion. This fractional superstring is characterized by the spin-4/3 fractional superconformal algebra---a parafermionic algebra studied by Zamolodchikov and Fateev involving chiral spin-4/3 currents on the world-sheet in addition to the stress-energy tensor. Examples of tree scattering amplitudes are calculated in an explicit c=5 representation of this fractional superconformal algebra realized in terms of free bosons on the string world-sheet. The target space of this model is three-dimensional flat Minkowski space-time with a level-2 Kac-Moody so(2,1) internal symmetry, and has bosons and fermions in its spectrum. Its closed string version contains a graviton in its spectrum. Tree-level unitarity (i.e., the no-ghost theorem for space-time bosonic physical states) can be shown for this model. Since the critical central charge of the spin-4/3 fractional superstring theory is 10, this c=5 representation cannot be consistent at the string loop level. The existence of a critical fractional superstring containing a four-dimensional space-time remains an open question.Comment: 42 pages, 4 figures, latex, IASSNS-HEP-93/57, CLNS-92/117