Colorectal cancer is the 4th most common cancer in the UK and the second commonest cause of cancer death. Whilst mortality rates from colorectal cancer haven fallen over the last 2 decades, around 40% of those diagnosed with colorectal cancer will die from their disease. Surgery currently remains the only chance of cure. Around 10% of patients present as an emergency with perforation, obstruction or bleeding. Outcomes from these emergency operations are substantially worse than from elective procedures. The presence of a systemic inflammatory response pre-operatively is now widely recognised as a predictor of disease progression and poor outcomes, both long and short term, regardless of tumour stage in those with colorectal cancer. Numerous scoring systems that measure various components of the systemic inflammatory response have been documented, the most commonly used are the modified Glasgow Prognostic Score (mGPS) and the Neutrophil-Lymphocyte Ratio (NLR). The NLR has the advantage of using 2 components of the differential white cell count, which is routinely measured in surgical and oncological practice, whereas CRP is less commonly routinely measured. However, studies utilising the NLR have used a variety of thresholds, making comparison of the results from study to study difficult. Whether one of the components of the NLR is more important than the other remains to be seen and indeed whether there is a more optimal score that utilises the white cell count is not clear. To date no work has examined similar scoring systems in the post-operative period. The present thesis aims to examine the impact of the innate immune response, through such systemic inflammation based scoring systems, on patients undergoing surgery for colorectal cancer. Furthermore, it analyses the nature of the inflammatory response in the post-operative period in order to ascertain whether similar scoring systems may be of clinical utility. Chapter 1 provides an overview of colorectal cancer, its presentation and treatment and its known determinants of outcomes. Furthermore, the immune response to injury and post-operative inflammatory response are discussed. Chapter 2 documents a survey of clinicians who have an interest in systemic inflammation. The survey asks the participants whether they routinely measure systemic inflammation, to what purpose and which scoring system they prefer. Unsurprisingly, the majority of participants use these scoring systems for research purposes only with an even split in terms of which scoring system they prefer to use. Their use in clinical practice remains small but their use in some oncological studies may signify a step towards their incorporation into clinical practice in the future. Chapter 3 presents data from a cohort of patients whom have undergone surgery for colorectal cancer with pre-operative differential white cell counts in order to determine whether any of the white cell count components are important in determining long term outcomes. Only the neutrophil count was independently associated with poor long term survival in patients undergoing surgery for colorectal cancer. These results highlight the importance of both the neutrophil count and the innate immune system in outcomes in patients with colorectal cancer. In chapter 4, a cohort of colorectal cancer patients and a cohort of patients with cancer were utilised in order to determine whether a pre-operative systemic inflammation based score using the neutrophil and platelet count was capable of predicting survival in these patients. This was based on the fact that recent in-vitro work had suggested that a critical checkpoint early in the inflammatory process involved the interaction between neutrophils and activated platelets. The subsequent score – the neutrophil platelet score (NPS)- was shown to be capable of predicting survival, independent of TNM stage, in patients with colorectal cancer and had prognostic value in patients with a variety of other tumours. Chapter 5 describes a systematic review of studies analysing the effect of various surgical procedures on markers of the systemic inflammatory response. Only CRP and IL-6 were found to represent the degree of surgical trauma and invasiveness of the procedure. This work provides a framework for analysing the post-operative SIR and how it is affected by surgery and peri-operative programmes such as ERAS that are reported to improve length of stay and sort term outcomes following surgery for colorectal cancer. It was of interest in the previous chapter that white cell count did not reflect the degree of surgical trauma. Whether individual white cell components act differently and represent the degree of surgical trauma was unclear. Chapter 6 sought to clarify this by analysing, in a cohort of patients undergoing surgery for colorectal cancer, the differential white cell count and whether it reflected the magnitude of injury and short term outcomes. Only the neutrophil count reflected the magnitude of trauma and development of infective complications. However, it remains inferior to other well established markers such as CRP. Whilst the pre-operative systemic inflammatory response is a well-recognised determinant of both long term outcomes and short term outcomes such as infective complications, little work has focussed on the post-operative systemic inflammatory response. In chapter 7, the possibility of the post-operative systemic inflammatory response also being capable of predicting both short and long term outcomes was explored in a cohort of patients whom had undergone surgery for colorectal cancer. A score using the combination of post-operative CRP and albumin was created and called the post-operative Glasgow Prognostic Score (poGPS). In this cohort of patients, this score predicted the development of infective complications and also long term survival. Given that these results would indicate that a reduction in the post-operative systemic inflammatory response would improve outcomes, the clinicopathological factors that may alter this post-operative systemic inflammatory response should be investigated as some of these may be modifiable and may therefore improve outcomes following surgery for colorectal cancer. ERAS programmes have changed perioperative management and are reported to be beneficial in reducing length of hospital stay and post-operative complications. It is purposed that this is due to the reduction on the surgical stress response. However it is unclear which of the components of an ERAS programme are responsible for this reduction in the systemic inflammatory response. Chapter 8 describes a systematic review analysing studies of the various ERAS components and whether there is objective evidence of a reduction in the SIR, evidenced by a reduction in either CRP or IL-6. Only laparoscopic surgery was reported to reduce the SIR in these studies, all the remaining components had either little or no evidence of a reduction in the SIR. Further work is required to ascertain whether any of the other components also reduce the SIR. This will hopefully allow streamlining of the ERAS process in order to improve outcomes. Specific clinicopathological factors that may alter the post-operative systemic inflammatory response are examined in chapter 9. Common clinicopathological factors were examined using the poGPS to ascertain which factors resulted in increased poGPS scores. In those patients undergoing elective surgery, year of operation, ASA grade, pre-operative systemic inflammation, and tumour site were associated with increased poGPS scores. These findings may have important clinical consequences as whilst factors such as ASA grade and BMI are not readily modifiable in the short time frame between diagnosis and surgery, pre-operative inflammation could potentially be targeted with anti-inflammatory medication. / However, more work is required to identify the specific agent and the timing of its delivery. In chapter 10, a cohort of patients undergoing surgery for colorectal cancer in whom there was prescription information available. Patients prescribed aspirin or statin were identified and their post-operative inflammatory response and short term outcomes were compared to those not prescribed aspirin or statins. In 446 patients, neither aspirin nor statin prescription was associated with a reduction in the post-operative systemic inflammatory response. Therefore, it would appear that these medications will not be useful in moderating the systemic inflammatory response following surgery. However, further work is required to identify which medications will be of benefit and should take the format of a randomised controlled trial. Chapter 11 provides a summary of the main findings of this thesis, discussed their implications and provides some discussion surrounding future work in this field.

No description available.

This work was performed between 1979 and 1985 when there was great interest in the role of the recently identified prostacyclin in vascular function and disorders. The discovery of this substance with its powerful vasodilatory and platelet anti-aggregatory powers raised the hypothesis that prostacyclin might be involved in the pathogenesis of portal hypertension, its associated hyperdynamic circulation and typically catastrophic haemorrhage from bleeding oesophageal varices. Partial portal vein ligation in a rat model of portal hypertension was used because of its simplicity and absence of hepato-cellular dysfunction. This model was found to result in short lived hypertension with return to normal pressure by two weeks. Anatomical studies (using venography and corrosion casting) of the changes to the portal venous circulation after partial portal vein ligation, revealed the development of a dominant portosystemic collateral draining into the left renal vein via the left anterior lumbar vein. Ligation of this collateral at the same time as partial portal vein ligation gave a reliable model of permanent portal hypertension. Accurate measurement of prostacyclin proved to be difficult. Initially a bioassay of prostacyclin-like activity was used with success. The rat was found to produce high levels of prostacyclin well within the range of accurate measurement of this assay. Prostacyclin production was shown to increase directly with pressure increase in the portal vein. This direct relationship was confirmed in the acute model where prostacyclin production fell as the portal pressure returned to normal; in the model of chronic portal hypertension, prostacyclin production remained permanently elevated. A radioimmunoassay for 6 ketoPGFIα, the stable breakdown product of prostacyclin, was developed to allow measurement of prostacyclin in human tissue and serum samples (at this time there were no commercially available RIA kits). Initially the Wellcome antiserum was used with accurate measurement in incubated human tissue samples. These studies confirmed greater intrinsic prostacyclin activity in normal mesenteric and portal vein compared to peripheral venous tissues but failed to show any difference in tissue or plasma levels of portal hypertensive compared to normal patients. A second antiserum, the Cardeza antiserum, was then used in the radioimmunoassay. Unlike the Wellcome assay, this antiserum did not require a prostanoid extraction process. Comparison of the two assays in identical samples revealed major differences with large quantities of 6 ketoPGFIα being measured using the Wellcome antiserum with its extraction step compared to virtually none detected using the Cardeza antiserum. The extraction step was resulting in production of cross-reacting prostanoid substances giving falsely high readings. Both radioimmunoassays were abandoned at this stage because of the inaccuracy of the first, and the inability of the second to detect the low levels of 6 ketoPGFIα in human plasma. The human studies were continued using a highly specific and sensitive assay of 6 ketoPGFIα, namely gas chromatography/negative ion chemical ionisation mass spectroscopy (GC/NICIMS). At the time of this work, this methodology was complex, cumbersome, with limited access and the numbers studied were small. Very low levels of 6 ketoPGFIα were found in peripheral blood of normal and portal hypertensive patients who were not bleeding from oesophageal varices, in patients without portal hypertension, portal blood levels of prostacyclin were higher compared to peripheral levels, confirming the finding in the rat and pig that prostacyclin activity is higher in the normal portal circulation compared to peripheral vein. Significantly elevated prostacyclin production was found in both the peripheral and portal blood of portal hypertensive patients who were actively bleeding from oesophageal varices. Portal prostacyclin production was found to be significantly higher in patients with portal hypertension who were actively bleeding compared to normal patients undergoing laparotomy for other conditions. These findings in bleeding patients support the hypothesis that prostacyclin activity is increased in portal hypertension and may play a role in the severity of haemorrhage. In both the animal and human studies a clear effect of surgical intervention on increased prostacyclin production was found. These studies demonstrated for the first time increased prostacyclin production in both developing, and established portal hypertension in both the experimental animal situation and in man. High levels of prostacyclin production were found in the portal circulation of portal hypertensive patients undergoing surgery for uncontrolled variceal bleeding.

No description available.

Made available in DSpace on 2018-08-02T00:01:57Z (GMT). No. of bitstreams: 1 tese_2859_TeseDoutoradoMaxwellEduardoMonteiro.pdf: 5323783 bytes, checksum: b8588d6e0c9a7068aa2925c5e80e4521 (MD5) Previous issue date: 2010-08-20 / O presente trabalho identifica que dentro da disciplina da Gerência de Redes de Telecomunicações o paradigma do Autogerenciamento apresenta um grande potencial para diminuir o tempo de maturação entre a aquisição de uma tecnologia e a oferta de serviços sobre ela. Entretanto, uma análise da literatura clássica sobre a Gerência de Redes e sobre o estado da arte do Autogerenciamento revela que tanto as técnicas e mecanismos consolidados quanto as mais recentes contribuições não proporcionam a interoperabilidade e o reúso entre as entidades heterogêneas de gerência das Redes de Telecomunicações. Esses gaps impedem avanços na direção de um princípio básico do Autogerenciamento: o estabelecimento de um ecossistema de autogerenciamento. Em resposta a essa lacuna, esta tese propõe uma arquitetura de software cujo objetivo é facilitar a criação de sistemas de Autogerenciamento, conferindo-lhes a oportunidade de estabelecer um ecossistema com as características interoperabilidade e reúso, através da integração semântica apoiada em uma ontologia sobre Redes de Transporte. Ao especificar preliminarmente o Provedor de Serviços Semânticos da Gerência de Redes de Transporte, principal elemento da arquitetura, evidencia-se que um ponto chave para a contribuição pretendida é o uso de ontologias. Sua capacidade de compartilhamento dos conceitos de um domínio, de extensão e de inferência lógica a tornam uma poderosa ferramenta para a constituição do ecossistema de Gerência de Redes. Embora seja delimitado um escopo de desenvolvimento no qual o Provedor de Serviços Semânticos da Gerência de Redes é especializado para as Redes de Transporte, uma maior atenção é dispensada à Ontologia das Redes de Transporte ITU-T G.805. Nessa condição, não é apresentada uma Implementação de Referência para a arquitetura proposta, mas sim uma implementação experimental, através de um protótipo de software. Essa implementação experimental ratifica a viabilidade da proposta e o potencial da mudança de paradigma na criação de sistemas de Autogerenciamento.

No description available.

Refractive laser eye surgery is a specialised field in ophthalmology which aims to correct the refractive disorder of an eye. The most established technique is LASIK, which has shown good results for the treatment of simple myopia. Complex refractive disorders, such as compound myopic astigmatism, have shown less predictable refractive outcomes, and in some cases the severe over- or under-correction can even worsen the preoperative situation and damage the eye. In its first stage, this research aimed to develop a software system able to present and analyse refractive outcomes. Over 2 prototype stages, this research has led to an operational system named IBRA (Internet Based Refractive Analysis), offering web-based data collection and refractive and vector analysis. In a second stage, Nomogram calculation formulas were developed and integrated into IBRA. These formulas were created from linear regression and best-fit analyses of spherical and cylindrical outcome data stored in IBRA. The purpose of the nomogram calculations was to provide surgeons with adjustment factors that could be used to improve the refractive outcome of patients with complex refractive disorders. Two extensive clinical audits and a randomized controlled trial were performed at Moorfields Eye Hospital to evaluate the IBRA nomogram adjustments. This research showed that IBRA was able to achieve a positive health change. In addition, results from the audits and trial contributed to the knowledge of nomogram adjustments and provided a framework in which future investigations on nomogram and treatment modifications could be performed. In addition to the above clinical studies, two evaluations were performed with the use of IBRA and data logging techniques to investigate users‟ behaviour relating to the management of data entry processes and the use of analysis functions. This research revealed the best method for entering refractive data, and was able to identify the most important analysis methods. Finally, the use of IBRA and its user-interface were investigated with a user satisfaction survey. The results from this questionnaire based study showed a high acceptance of the web-based platform of IBRA and indicated points for improvement (Documentation).

Glaucoma is a leading cause of irreversible blindness and visual impairment. In the clinic, glaucomatous damage can be characterized by structural changes in the optic nerve head (ONH) and retinal nerve fibre layer (RNFL) that can be evaluated by various retinal-imaging techniques such as scanning laser polarimetry and optical coherence tomography (OCT). The structural damage can lead to functional damage in the visual field (VF), normally assessed with standard automated perimetry, which assesses the differential light sensitivity in the field of view. The clinical measurements of retinal structure and visual function play an important role in the detection and management of glaucoma, but the data generated is often complex and highly variable, thus making it hard to clinically interpret. The purpose of this thesis was to investigate knowledge mining procedures for extracting clinically useful information from these measurements. Knowledge mining describes iterative divide-and-conquer type analyses of large-scale questions: solutions to individual smaller problems are used to generate better quality knowledge, which in the case of work reported in this thesis can be translated into clinically useful analysis tools. This thesis describes five knowledge mining procedures specifically developed and applied to structural and functional measurements in glaucoma: (1) probabilistic inference to aid image acquisition of OCT images; (2) a robust and efficient segmentation algorithm to extract features of retina tissue layer structures in large-scale 3-dimensional image volumes acquired by OCT; (3) a predictive structure-function relationship model to bridge the retinal structure and visual function measurements in glaucoma; (4) quantification and visualization of structure-function discordance using the model about structure-function relationship; (5) integration of structural and functional measurements to improve the reproducibility of the measurements. In conclusion the knowledge mining approaches improved the acquisition and/or accuracy of the measurements and provide new clinical analysis tools to detect and manage glaucoma.

No description available.

Gene transcription rates are influenced by proteins, known as Transcription Factors (TFs), that interact with DNA. The locations of TFs on the genome directly influence gene expression and the functional characteristics of a cell. TF binding locations can be estimated for entire genomes using high throughput chromatin immunoprecipitation sequencing (ChIP-Seq). While the analysis of ChIP-Seq binding locations is standardized for a single experiment, complications arise when data sets, taken from different labs and experimental conditions, are combined. In this thesis, I present my method for the simultaneous comparison of multiple ChIP-Seq data sets. My method of comparing multiple ChIP-Seq data sets extends the analysis of a single data set through the addition of two stages, a combination stage, and an extraction stage. Typically, one of two approaches are used to combine information from multiple datasets. Either estimated binding sites are extracted from each dataset and then combined (e.g. by various intersections or unions) or the "raw" genomic signals are analyzed by clustering or dimensionality reduction methods. Both approaches have strengths, but also substantial drawbacks. The method presented here relies both on estimating the binding sites and comparing the “raw” genomic signals between data sets. Once the binding locations have been found, the first step in the combination stage is to define an alternate feature space (AFS). The AFS is the union of all binding locations determined for all data sets. The AFS represents a subset of the genome that is likely to have TF binding in any condition where the protein is active. Once the AFS is defined, the read density is determined from the “raw” genomic signal of each of the data sets. The density is determined for all locations in the AFS resulting in a unified density matrix (UDM). The UDM is the final product of the combination stage of the analysis. After the data sets are homogenized into the UDM, the extraction stage is applied to the matrix. The extraction stage consists of applying machine learning techniques and other methods used to analyze the “raw” genomic signal, to help elucidate underlying similarities and differences between the data sets. I applied this method to the binding locations of the TF TAL1 across 22 ChIP-Seq data sets from the hematopoietic and endothelial lineages. Once the UDM had been generated and normalized, using quantile normalization, hierarchical clustering and principle component analysis (PCA) were applied. Clusters, formed by hematopoietic stem cells (HSCs), Erythroid, and T-cell acute lymphoblastic leukemia (T-ALL), were found using hierarchical clustering. The principle components (PCs) of the UDM provided weights for each peak. Using those weights I could separate groups of cellular conditions including T-ALL, Erythroid, HSC, and Endothelial Colony Forming Cells (ECFCs.) The weights also provided a quantitative measure of importance for each peak in the AFS based on how much weight they provided towards the group of interest. Functional analysis techniques, including de novo motif search and Gene Ontology, were applied to the peak partitions defined using the PCs. Motifs that were enriched in the T-ALL TAL1 partition, and not the Erythroid, were annotated and found to be similar to those that had previously been published, including Runx1 motif and a preference for the CC Ebox (CACCTG). In addition to finding the CC Ebox in T-ALL, I also show that it does not form a composite motif with GATA, indicating an alternative mechanism for the binding of TAL1 in T-ALL. This thesis establishes that heterogeneous collections of ChIP-Seq datasets, from multiple labs and experimental conditions, can be meaningfully combined, and provides an algorithmic template for doing so.