The incidence of stroke and re-infarction is noticeably high in the first few days following acute myocardial infarction. This finding has raised questions whether the systemic inflammatory reaction secondary to myocardial necrosis is involved. The inflammation might affect the activation of platelets leading to insufficient effect of the antiplatelet treatment given. Furthermore, the importance of platelet reactivity and inflammation in terms of long-term prognosis is not fully understood. The prognostic importance of C-reactive protein (CRP) in relation to clinical variables also needs to be clarified. The present studies are aimed at describing the dynamics of platelet function during the first days of an acute myocardial infarction, in relation to diabetes and inflammation. We also investigated whether increased platelet reactivity or the increased concentration of CRP in blood were related to a worse outcome. Finally, we examined if CRP levels contributed to a predictive model using clinical variables known to affect outcome in patients with AMI.  We used two novel platelet function tests to measure platelet reactivity; the PA-200 (a laser light aggregometer) and the PFA-100 (measures primary haemostasis in whole blood). Platelet aggregation increased during the initial course of an acute myocardial infarction. The increase in platelet aggregation was most pronounced in diabetics and in patients showing higher systemic inflammatory reaction, assessed by measuring the concentration of CRP in blood. The pronounced platelet aggregation occurred despite ongoing antiplatelet and antithrombotic treatment. There was a significant association between the levels of CRP and the degree of platelet reactivity. However, while the CRP levels were associated with a worse outcome (AMI, stroke and death), the results of the platelet function tests were not. The importance of CRP in predicting prognosis depended on which adjustments were made for confounding factors. CRP and prognostic variables in a statistical model predicting death, however, showed that CRP was excluded. Thus CRP did not predict outcome beyond clinical prognostic variables. The results of these studies reinforce the importance of clinical variables such as heart failure, age, atrial fibrillation, smoking status, diabetes and impaired kidney function - all of which were associated with worse prognosis in multivariable analysis.

Non-small cell lung cancer (NSCLC) constitutes a clinically, histologically, and genetically heterogeneous disease entity that represents a major cause of cancer-related death. Early-stage patients, who undergo surgery with curative intent, experience high recurrence rates and the effect of adjuvant treatment is modest. Prognostic biomarkers would be of particular relevance to guide intensified treatment depending on expected outcome and moreover often infer a biological role in tumourigenesis. This thesis presents a translational study approach to establish a well-characterised NSCLC frozen-tissue cohort and to obtain a profile of each specimen with regard to genome-wide copy number alterations, global gene expression levels and somatic mutations in selected cancer-related genes. Furthermore, the generation of a formalin-fixed, paraffin-embedded tissue microarray enabled validation of findings on the protein level using immunohistochemistry. The comprehensive molecular characterisation, combined with data on clinical parameters, enabled the analysis of biomarkers linked to disease outcome. In Paper I, single nucleotide polymorphism arrays were applied to assess copy number alterations in NSCLC and associations with overall survival in adenocarcinoma and squamous cell carcinoma were described. In Paper II, we evaluated expression levels of selected stromal proteins in NSCLC using immunohistochemistry and the adhesion molecule CD99 was identified as an outcome-related biomarker in two independent cohorts. Paper III presents a strategy for prognostic biomarker discovery based on gene expression profiling, meta-analysis, and validation of protein expression on tissue microarrays, and suggests the putative tumour suppressor CADM1 as a candidate biomarker. In Paper IV, we propose a prognostic role for tumour-infiltrating IGKC-expressing plasma cells in the local tumour microenvironment, indicating an involvement of the humoral immune response in anti-tumor activity. In Paper V, we combined next-generation deep sequencing with statistical analysis of the TP53 database to define novel parameters for database curation. In summary, this thesis exemplifies the benefits of a translational study approach, based on a comprehensive tumour characterisation, and describes molecular markers associated with clinical outcome in NSCLC.

Aberrant DNA methylation in gene promoters causes gene silencing and is a common event in prostate cancer development and progression. While commonly identified methylated genes have been analyzed for their potential clinical utility in a variety of cancers, few studies have attempted a genome-wide methylation approach to discover new and possibly improved biomarkers for prostate cancer. In order to identify DNA methylation changes associated with aggressive prostate cancer, we performed a genome-wide analysis of 40 prostate cancers using Agilent human CpG island microarrays. Methylation profiles of candidate genes were validated using quantitative MethyLight technology in an independent series of 219 radical prostatectomies and compared to clinicopathological parameters. The effects of methylation on expression of HOXD3 and HOXD8 and the possible role of HOXD8 in progression of PCa were also investigated. We discovered previously unidentified methylation in the HOXD cluster of genes, namely HOXD3 and HOXD8, as well as TGFβ2 and GENE X as potential prognostic biomarkers. Furthermore, unsupervised clustering of samples by methylation signature indicated ERG oncogene expression as significantly different between clusters. Within the independent cohort, we observed strong correlations between Gleason score (GS) and HOXD3 as well as GENE X, while HOXD3 and HOXD8 methylation were associated with ERG expresson. TGFβ2 was an independent predictor of disease recurrence using Cox multivariate regression analysis. In gene expression studies, both HOXD3 and HOXD8 were elevated in cancers with poor prognosis, while DNA methylation did not correlate with expression levels. Both genes were found to contain alternative transcription start sites, explaining the poor correlation between methylation and expression. Finally, knockdown of HOXD8 expression did not have any effect on viable cells or cell motility in an in vitro model. These results indicate that a panel of novel DNA methylation markers distinguish indolent prostate cancers from aggressive ones, and that expression of HOXD3 and HOXD8 is regulated by mechanisms including, but not dependent on, DNA methylation.

Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.

Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.

The failure of rolling element bearings is one of the foremost causes of breakdown in rotary machinery. So far, a variety of vibration-based techniques have been developed to monitor the condition of bearings; however, the role of vibration behavior is rarely considered in the proposed techniques. This thesis presents an analytical study of a healthy rotor-bearing system to gain an understanding of the different categories of bearing vibration. In this study, a two degree-of-freedom model is employed, where the contacts between the rolling elements and races are considered to be nonlinear springs. The analytical investigations confirm that the nature of the inner ring oscillation depends on the internal clearance. A fault-free bearing with a small backlash exhibits periodic behavior; however, bearings categorized as having normal clearance oscillate chaotically. The results from the numerical simulations agree with those from the experiments confirming bearing’s chaotic response at various rotational speeds. Bearing faults generate periodic impacts which affect the chaotic behavior. This effect manifests itself in the phase plane, Poincare map, and chaotic quantifiers such as the Lyapunov exponent, correlation dimension, and information entropy. These quantifiers serve as useful indices for detecting bearing defects. To compare the sensitivity and robustness of chaotic indices with those of well-accepted fault detection techniques, a comprehensive investigation is conducted. The test results demonstrate that the Correlation Dimension (CD), Normalized Information Entropy (NIE), and a proposed time-frequency index, the Maximum Approximate Coefficient of Wavelet transform (MACW), are the most reliable fault indicators. A neuro-fuzzy diagnosis system is then developed, where the strength of the aforementioned indices are integrated to provide a more robust assessment of a bearing’s health condition. Moreover, a prognosis scheme, based on the Adaptive Neuro Fuzzy Inference System (ANFIS), in combination with a set of logical rules, is proposed for estimating the next state of a bearing’s condition. Experimental results confirm the viability of forecasting health condition under different speeds and loads.

The failure of rolling element bearings is one of the foremost causes of breakdown in rotary machinery. So far, a variety of vibration-based techniques have been developed to monitor the condition of bearings; however, the role of vibration behavior is rarely considered in the proposed techniques. This thesis presents an analytical study of a healthy rotor-bearing system to gain an understanding of the different categories of bearing vibration. In this study, a two degree-of-freedom model is employed, where the contacts between the rolling elements and races are considered to be nonlinear springs. The analytical investigations confirm that the nature of the inner ring oscillation depends on the internal clearance. A fault-free bearing with a small backlash exhibits periodic behavior; however, bearings categorized as having normal clearance oscillate chaotically. The results from the numerical simulations agree with those from the experiments confirming bearing’s chaotic response at various rotational speeds. Bearing faults generate periodic impacts which affect the chaotic behavior. This effect manifests itself in the phase plane, Poincare map, and chaotic quantifiers such as the Lyapunov exponent, correlation dimension, and information entropy. These quantifiers serve as useful indices for detecting bearing defects. To compare the sensitivity and robustness of chaotic indices with those of well-accepted fault detection techniques, a comprehensive investigation is conducted. The test results demonstrate that the Correlation Dimension (CD), Normalized Information Entropy (NIE), and a proposed time-frequency index, the Maximum Approximate Coefficient of Wavelet transform (MACW), are the most reliable fault indicators. A neuro-fuzzy diagnosis system is then developed, where the strength of the aforementioned indices are integrated to provide a more robust assessment of a bearing’s health condition. Moreover, a prognosis scheme, based on the Adaptive Neuro Fuzzy Inference System (ANFIS), in combination with a set of logical rules, is proposed for estimating the next state of a bearing’s condition. Experimental results confirm the viability of forecasting health condition under different speeds and loads.

Defects in mismatch repair genes, particularly the hMLH1 and hMSH2 genes, are associated with pathogenesis and prognosis of some cancers. The lack of correlation between replication error phenotype and mutations in hMLH1 in sporadic human cancers suggested that inactivation of the hMLH1 gene may be associated with promoter hypermethylation. This study was to investigate the association of hMLH1 promoter hypermethylation and hMLH1 protein expression in oral cancer. Our results indicated that all 75 cases (100%) were without any methylation of hMLH1 promoter by use of methylation-specific PCR (MSP). Nineteen of 99 cases (19.2%) were partial methylation by HpaII-based PCR. In addition, 24 (26.1%) of 92 cases of OSCC had reduced levels of hMLH1 protein. The concordance analysis showed that the expression level of hMLH1 protein was not correlated with methylation of hMLH1 promoter. Furthermore, the prognosis significance of hMLH1 or hMSH2 proteins on OSCC was also investigated. We analyzed the association of hMLH1 and hMSH2 protein expression with clinicopathological data of 92 cases of OSCC at KSVGH. We found that 24 (26.1%) of 92 cases of OSCC had reduced levels of hMLH1 protein, however only 10 cases (10.9%) had reduced hMSH2 by use of IHC. In addition, the reduced expression of hMLH1 correlated with the tumor differentiation and N classification. However, none of these clinical and pathological characteristics of the OSCC patients were associated with the extent of hMSH2 expression. Finally, previous studies reports that the hMLH1 and Aurora-A are directly involved in the prognosis of several cancers. The expression levels of hMLH1 and Aurora-A protein were investigated in the 138 tumor samples for consecutive patients with pathological confirmed primary buccal carcinoma (BC). Then the association of the protein expression with clinicopathological data and survival were also evaluated. The loss of hMLH1 protein was found in 15 (10.9%) of 138 tumor sections by IHC. In addition, loss of hMLH1 protein expression was not any correlated with clinical features and patients¡¦ prognosis. The up-regulation of Aurora-A protein was found in 118 (85.5%) of 138 tumor sections by IHC. In addition, the up-regulation of Aurora-A protein expression was correlated with the pathological stage and T classification, but Aurora-A protein up-regulation was not correlated with prognosis. In conclusion, promoter methylation of hMLH1 might not play a potent role in the gene expression in oral cancer. Defective expression of hMLH1 but not hMSH2 was associated with the development of OSCC. In addition, the Aurora-A protein expression but not hMLH1 may affect the malignant behavior of BC. However, the hMLH1 and Aurora-A protein expression might be not the prognostic factors for BC patients.

No description available.

This study focuses on medical prognostication in the earliest Indian medical treatise known, the Caraka Saṃhitā. The first chapter gives an overview of the Caraka Saṃhitā, including its main doctrines and philosophy. The second chapter introduces the Indriyasthāna, the section in the Caraka Saṃhitā in which most of the omen literature is collected. The third chapter gives a survey and preliminary analysis of all twelve chapters in the Indriyasthāna. In the final chapter and conclusion, the topic of omen literature in the ancient world in general will be discussed, with a focus on the issue that invariably presents itself in omen literature, “rationality.” / text