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Цыплакова, Е. С., and E. S. Tsyplakova. "Исследование профессионального мышления студентов-психологов : магистерская диссертация." Master's thesis, б. и, 2021. http://hdl.handle.net/10995/100001.
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Объектом исследования является профессиональное мышление студентов-психологов. Предметом исследования являлись предикторы развития диагностического мышления. Магистерская диссертация состоит из введения, трех глав, заключения, списка литературы (61 источник) и приложения, включающего в себя результаты методик (в баллах) и содержание теста. Объем магистерской диссертации 94 страниц, на которых размещены 1 рисунок и 5 таблиц. Во введении раскрывается актуальность проблемы исследования, разработанность проблематики, ставятся цель и задачи исследования, определяются объект и предмет исследования, формулируются гипотезы, указываются методы и эмпирическая база, а также этапы проведения исследования, теоретическая и практическая значимость работы. Первая глава включает в себя обзор иностранной и отечественной литературы по теме исследования профессионального мышления психологов и студентов-психологов. Представлены разделы, раскрывающие структуру феномена, его параметры и механизмы. Выводы по первой главе представляют собой итоги по изучению теоретического материала. Вторая глава посвящена практической деятельности психолога. В ней выделяется психодиагностика, как главная практическая деятельность психолога. Рассматривается структура, механизмы и особенности написания диагностического заключения психологом. Определяются психолингвистические параметры для оценки итоговых заключений студентов. Раскрывать особенности интеллектуальных и личностных характеристик письменной речи психолога. Выводы по главе 2 включают в себя основные результаты. Третья глава посвящена эмпирической части исследования и включает в себя: описание организации и методов проведенного исследования и результатов, полученных по всем использованным методикам (16-факторный личностный опросник Р.Б.Кеттела, опросник «Уровень субъективного контроля» и профориентационный тест на определение склонности и интереса к профессии психолог). Также представлен корреляционный и сравнительный анализ результатов исследования. В заключении в обобщенном виде изложены результаты теоретической и эмпирической частей работы, а также выводы по выдвинутым гипотезам, обоснована практическая значимость исследования и описаны возможные перспективы дальнейшей разработки данной проблематики.The object of the study is the professional thinking of psychology students. The subject of the study was predictors of the development of diagnostic thinking. The master's thesis consists of an introduction, three chapters, a conclusion, a list of references (61 sources) and an appendix that includes the results of the methods (in points) and the content of the test. The volume of the master's thesis is 94 pages, which contain 1 figure and 5 tables. The introduction reveals the relevance of the research problem, the development of the problem, sets the goal and objectives of the research, defines the object and subject of the research, formulates hypotheses, specifies methods and empirical base, as well as the stages of the research, the theoretical and practical significance of the work. The first chapter includes a review of foreign and domestic literature on the topic of research of professional thinking of psychologists and psychology students. The sections that reveal the structure of the phenomenon, its parameters and mechanisms are presented. The conclusions of the first chapter are the results of the study of the theoretical material. The second chapter is devoted to the practical work of a psychologist. It highlights psychodiagnostics as the main practical activity of a psychologist. The structure, mechanisms and features of writing a diagnostic conclusion by a psychologist are considered. Psycholinguistic parameters are determined for evaluating the final conclusions of students. To reveal the features of the intellectual and personal characteristics of the written speech of the psychologist. The conclusions of chapter 2 include the main results. The third chapter is devoted to the empirical part of the study and includes: a description of the organization and methods of the study and the results obtained by all the methods used (the 16-factor personal questionnaire of R. B. Kettel, the questionnaire "The level of subjective control" and the career guidance test to determine the propensity and interest in the profession of psychologist). A correlation and comparative analysis of the results of the study is also presented. In conclusion, the results of the theoretical and empirical parts of the work, as well as conclusions on the hypotheses put forward, are summarized, the practical significance of the study is justified and possible prospects for further development of this problem are described.
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Satterthwaite, Gemma. "Discovery of diagnostic markers for atherosclerosis." Thesis, University of Sheffield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274961.
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Clark, Rachael Louise. "Diagnostic markers of infection, in chronic wounds." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/55725/.
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A complication associated with wound healing is wound infection. The diagnosis of infection in chronic wounds can be a difficult clinical decision. Signs and symptoms used to diagnose infection can often be masked by factors relating to the host, chronic inflammation and the tissue damage, associated with chronic wounds. This Study aimed to determine whether there is a measurable biochemical host response that could serve as potential biomarkers of chronic wound infection, providing an alternative diagnostic tool to aid the Clinician. An in vitro model further investigated the expression of markers from neutrophils, in response to bacterial supernatant from Pseudomonas aeruginosa and Staphylococcus aureus commonly associated with chronic wounds and their infections. Chronic venous leg ulcer and diabetic foot ulcer wound fluids were collected, wound microflora assessed, and a variety of host factors, including serine proteases, matrix metalloproteinase, their inhibitors and cytokines/growth factors, IL-ip, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, 11-12 p40, IL-12p70 and IL-13, angiogenin, IFN-y, TGF-pi, VEGF, TNF-a, TNF-r2, ICAM-1 and IP-10, analysed. No significant differences (p>0.1) in the activities/levels of host factors were observed between non-infected and infected wounds, based on clinical diagnosis. Significant differences (p<0.05) in a variety of these host factors were observed in these ulcer types, upon defining infection by wound microbial bioburden, the number of genera or bacterial species. Of these factors, cytokines were found to distinguish on two of the three defining parameters. Specifically, a number of cytokines were found to be significantly elevated in venous leg ulcer wounds, IL-lp, TNF-a, TNFr2 and ICAM-1, with an additional set of cytokines, IL-2, IL-5, IL-12p40, IL-12p70, IFN-y and TGF-P,, significantly decreased within diabetic foot ulcer wounds. in vitro, neutrophils were treated with Pseudomonas aeruginosa or Staphylococcus aureus 'acellular' supernatants, at mid-log or stationary growth phases, for 4 and 24h. Significant increases (p<0.05) in the levels of proteases and cytokines were observed from neutrophils, treated with both mid-log and stationary phase supernatants, from both species. These increases were both neutrophil donor- and growth phase-dependent. A larger cytokine response was induced from neutrophils stimulated with stationary phase, compared with mid-log phase supernatants. Combined with the increased expression of virulence factors, including bacterial enzymes, this Study suggests that bacterial growth is an important feature of chronic wound infection.
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Andreasen, Niels. "Search for reliable diagnostic markers for Alzheimer's disease /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4039-8/.
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Essack, Magbubah. "Transcription Regulation and Candidate Diagnostic Markers of Esophageal Cancer." Thesis, University of the Western Cape, 2009. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5306_1267148426.
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This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.
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Al-Khalili, Faris. "Coronary heart disease in women : diagnostic and prognostic markers /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4092-4/.
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Dreesman, Alexandra. "Development and evaluation of new diagnostic markers of tuberculosis in children." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/312223.
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Tuberculosis in the number one infectious cause of death worldwide, but remains underappreciated as a cause of mortality in children and difficult to diagnose. Diagnostic difficulties of TB in children are a consequence of the non-specific clinical presentation, the different spectrum of disease in children and the paucibacillary nature of disease making microbiological confirmation challenging in many cases. Moreover, existing immunodiagnostic tests have important limitations, especially with regard to childhood TB: they lack sensitivity to rule out TB, and are unable to offer discrimination between contained infection and active stages of disease. Their limitations are emphasized in the youngest children that are at greatest risk of developing severe disseminated forms of TB. For that reason we developed, at the Laboratory of Vaccinology and Mucosal Immunity (LoVMI), several non-sputum based tests, that offer excellent diagnostic accuracy compared to commercialy available tests, for all forms of TB in children, in an early stage of infection. This research also provided insight in TB pathogenesis. The main results are summarized in a table (chapter General Discussion) and two algoritms (chapter Conclusions and Perspectives).Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished
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Nouzová, Eva. "Eye movements as diagnostic trait markers for adult major depressive disorder." Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230162.
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Diagnosis of Major Depressive Disorder (MDD) is currently symptom-based and no externally validated tests are available for routine use to confirm clinical diagnoses. Eye movement abnormalities in schizophrenia (SCZ) and bipolar disorder (BPAD) have been consistently reported and their potential as a biological trait marker highlighted. Only a limited amount of research has been conducted in MDD. Eye movement performance of MDD patients (n = 99; F:M = 55:44; Mdn age = 48) was investigated using picture free-viewing, smooth pursuit and fixation stability tasks and recorded using a non-invasive EyeLink1000 infra-red eye tracker. Performance was compared with identical measures from SCZ, BPAD, Primary Care depression (DEP) and control participants. Analysis was conducted using analyses of variance and machine learning using Probabilistic Neural Networks (PNN). We discovered a unique MDD specific eye movement phenotype, which differentiated patients with MDD from other diagnostic groups with remarkable accuracy. MDDs generated a markedly poor smooth pursuit performance, characterised by small signal-to-noise ratio, small tracking gain and large positional error. Patients also exhibited a slow average saccade velocity during free-viewing and pursuit, and poor fixation maintenance on a centralised target. A PNN classifier delineated MDD from controls with exceptional statistical sensitivity (100%) and specificity (99%), independent of state or demographics. MDD was delineated from SCZ and BPAD in all models with above 89% sensitivity and 95% specificity. MDD and DEP patients were delineated with remarkable statistical sensitivity (90%) and specificity (98%). This emerging evidence suggests possible subtypes consistent with clinical features. Testretest reliability was high for a majority of performance measures; however some measures were less robust. Brief neuropsychology assessment advocated the role of frontal lobes in oculomotor behaviour. This preliminary evidence argues for a specific MDD oculomotor dysfunction and represents potential for a diagnostically applicable biological trait marker.
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Zheng, Yingye. "Semiparametric methods for longitudinal diagnostic accuracy /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/9580.
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Arko-Mensah, John. "Mycobacterial infection: Immune evasion, host susceptibility and immunological markers of diagnostic importance." Doctoral thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8208.
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IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages in vitro. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.
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Sahli, David. "Early arterial disease of the lower extremities in diabetes diagnostic evaluation and risk markers /." Doctoral thesis, Umeå : Umeå university, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-26711.
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Duong, Veasna. "Dengue in Cambodia : epidemiology, molecular evolution, clinical presentation, laboratory diagnostic and markers of severity." Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20231/document.
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La dengue, maladie transmise par des moustiques, est causée par l'un des 4 sérotypes du virus de la dengue (DENV). Le Cambodge est un pays d'hyperendémicité de la dengue où les 4 sérotypes en co-circulent. Le programme national de lutte contre la dengue a été établi en 2000 et a fourni des données nécessaires dans la compréhension du profil épidémiologique et de l'évolution du DENV. La dynamique d'évolution virale est caractérisée par des événements de disparition et d'émergence de lignées au sein de chaque sérotype en fonction du temps. La dengue se présente sous différentes formes cliniques allant d'une forme asymptomatique aux formes sévères accompagnée d'un syndrome de choc (DSS) et le diagnostic différentiel est souvent compliqué. Dans des contextes cliniques différents et avec des profils biologiques variables, nous avons évalué un test de diagnostic précoce de détection de l'antigène NS1 de la dengue. De plus, nous avons identifié de nombreux profils d'expression biologique spécifiques aux cas de DSS qui pourraient être utilisés comme d'éventuelles cibles pour le développement de nouveaux traitements ou comme des marqueurs de pronosticDengue infection, caused by one of the four serotypes of dengue virus (DENV), is a major cause of morbidity and mortality in the world with an estimated 50-100 million cases annually. In Cambodia, dengue is hyperendemic and all four serotypes are circulating. The active hospital-based surveillance has been established in 2000 and provided important insights in the understanding of the epidemiological profile and of the DENV evolution. The dynamic of evolution of DENV is characterized by complex patterns of lineage turnovers within each serotype, with lineages increasing and decreasing in frequency through time. Dengue manifests in various clinical forms - from asymptomatic to severe form with shock syndrome - and is sometimes difficult to differentiate from other febrile diseases. We have evaluated the performance of a recent diagnostic tool (NS1 antigen detection) - developed to identify dengue at a very early stage on the infection - depending on various clinical and biological patterns. Additionally, genome-wide expression analysis has characterized a large amount of gene signatures specific to dengue shock syndrome which could be used as prognostic markers as well as potential targets for drug design
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Gaigneaux, Anthoula. "Determination of diagnostic and prognostic markers in varied tumoral pathologies by ATR-FTIR spectroscopy." Doctoral thesis, Universite Libre de Bruxelles, 2004. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211150.
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Huggett, M. T. "The use of novel diagnostic cell cycle markers and targeted treatment of pancreaticobiliary cancers." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1433745/.
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Adenocarcinoma of the pancreas is one of the top ten leading causes of cancer deaths. In the UK approximately 8000 people are diagnosed with the disease each year. Surgical resection is the only chance of cure and is only possible in a minority of patients. Even after resection, median survival is only 10–20 months and no more than 5–20% of resected patients survive five years. Earlier diagnostic assays and novel treatments are urgently required to improve outcomes. Chapter 1 summarises clinical aspects of pancreatic cancer and current diagnostic and prognostic tests. Chapter 2 gives an introduction to the cell cycle, initiation of DNA replication, cell cycle checkpoints and how exploitation of these mechanisms can result in selective death of cancer cells. Chapter 3 describes an analysis of four cell cycle proteins - Mcm2, geminin, phosphohistone H3 and Cdc7 - using immunohistochemistry of archived FFPE tissue from patients with pancreatic cancer. Linked clinicopathological variables were used to attempt to predict outcome and to validate Cdc7 as a potential target in the treatment of pancreatic cancer. Chapter 4 describes cell culture techniques that were used to grow pancreatic adenocarcinoma and IMR-90 fibroblast cell lines in the laboratory. Cells were treated with siRNA against CDC7 and a small molecule inhibitor of Cdc7/Cdk9. A variety of techniques including FACS analysis, western blotting, BrdU labelling and apoptosis assays were used to assess the effects of these treatments. Chapter 5 describes the methods and early results obtained from using a novel Mcm5 assay for the determination of malignancy in biliary brushings. Chapter 6 discusses the main conclusions drawn from the work as well as potential future studies.
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Cadd, Verity Anne. "The study of molecular markers for the progression of Barrett's oesophagus to adenocarcinoma to identify markers that can be used as diagnostic tools." Thesis, Cranfield University, 2002. http://dspace.lib.cranfield.ac.uk/handle/1826/3689.
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Barrett's oesophagus is a complication of gastro-oesophageal reflux disease and is the single most important predisposing factor for the development of adenocarcinoma of the oesophagus. New molecular markers are needed for early diagnosis and to monitor disease progression. Telomerase is a ribonuclear protein with reverse transcriptase activity, which uses its own RNA component as a template for the addition of telomeric repeats to the end of chromosomes. Telomerase activity has been studied during the neoplastic progression of Barrett's oesophagus using a TRAP based ELISA technique, which found telomerase to be reactivated early during . disease progression. A non-isotopic method of in situ hybridisation for the detection of the RNA component of telomerase has also been successfully developed. Plasminogen activation is an inducible extracellular proteolytic system involved in the regulation of cellular interactions and invasion. The components of the urokinase-type Plasminogen Activator system have been fully investigated during the progression of Barrett's oesophagus to adenocarcinoma utilising immunohistochemistry and ELISA techniques. Changes in the expression of this invasive phenotype were found to occur late during disease progression in malignant tissues. Two-oesophageal cell-lines have been characterised using molecular biological techniques to detect a range of molecular markers to produce ex vivo models of oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. In order to assess the effects of bile salts and acidity on oesophageal tissues these celllines were then utilised as ex vivo models. Exposure to acidic conditions both alone and with bile salts altered the morphological appearance of the cells and disrupted adhesion molecules in the cellular membrane. Investigations into both telomerase reactivation and the plasminogen activator system have provided new information concerning the nature and timing of molecular changes during the Barrett's metaplasia/dysplasia/adenocarcinoma sequence.
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Ortner, Margarete. "Morpho-functional markers in X-ray computed tomography for respiratory diseases." Paris 5, 2011. http://www.theses.fr/2011PA05S007.
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Ce travail vise à développer un système de diagnostic assisté par ordinateur ciblant les maladies pulmonaires responsables de changements biologiques et morphologiques dans les voies respiratoires. L'intérêt clinique est la compréhension des mécanismes et relations entre la physiologie et le phénotype / génotype du patient. Ce système DAO adopte le concept "image comme marqueur" et explore les données MDCT obtenues en routine clinique. Ainsi, des approches d’investigation basées sur l'image sont abordées pour identifier les marqueurs pathologiques en jeu. L’enjeu majeur est la segmentation volumétrique de la paroi bronchique. La méthode originale développée dans ce travail utilise un modèle de surface active spécifique au patient et évoluant selon une dynamique lagrangienne contrainte par un champ de diffusion. Les autres contributions concernent l’évaluation semi-quantitative de la variation de la forme des bronches et la détection automatique des anomalies. Pour cela, une notion de calibre local a été exploitée. L'épaisseur pariétale ainsi que les simulations d’écoulement quantifient l’effet du remodelage bronchique. Le système est complété par des outils de visualisation intuitive, navigation et interaction. Les solutions développées ont été validées aussi bien sur des données réelles provenant d’études cliniques qui incorporent 150 patients, que sur des données simulées. Ces dernières ont été obtenues en générant des fantômes numériques avec des géométries spécifiques au patient et en simulant l'acquisition TDM. Les résultats montrent une précision de l'ordre de la résolution axiale de l'image et une robustesse vis-à-vis de la variabilité inter-patient et inter-protocoleThe motivation of this work is the development of a computer-aided diagnosis system targeting pulmonary diseases which induce biological and morphological changes to the airway system. The clinical interest lies in understanding the mechanisms and relationships between airway physiology and the clinical phenotype and genotype. Such a CAD system adopts the concept of “Image as Marker” and exploits routinely available MDCT image data. Thus image-based investigation approaches are tackled in order to identify relevant pathological markers. The key issue of our work is the volumetric segmentation of the airway wall. The developed original approach relies on a patient-specific, deformable mesh model evolving according to Lagrangian dynamics, under the constraints of an external diffusion vector field. Other contributions concern semi-quantitative assessment of the airway shape variation and the automatic detection of shape abnormalities exploiting the notion of local maximal airway lumen caliber. The local wall thickness information as well as computational fluid dynamics simulations capture the airway remodeling. Intuitive visualization, navigation and interaction capabilities associated with the extracted quantitative data complete the developed system. All the solutions were quantitatively and qualitatively validated, either on real MDCT images during clinical studies including 150 patients or on simulated data. Latter were achieved by computer phantoms involving patient-specific geometries and CT acquisition simulation. The results reported a precision in the range of the CT image resolution and the robustness towards acquisition and inter-patient variability
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Roupaka, Sofia. "Functional genomics approach to identifying peripheral markers for sheep scrapie." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/33306.
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Scrapie is a transmissible spongiform encephalopathy (TSE) of sheep and goats, for which there is currently no ante-mortem diagnostic test. A rapid, ante-mortem diagnostic test for scrapie would also potentially be important for other TSEs such as bovine spongiform encephalopathy (BSE) and variant Creutzfeldt Jakob's disease (vCJD). The hypothesis of this study was that there is differential gene expression in the blood and peripheral tissues of scrapie infected animals, and that a panel of differentially expressed genes could be identified and used as surrogate markers of infection. An expression screening approach, using real-time PCR and an EST microarray, was used to identify genes that were differentially expressed between SSBP/1 infected and mock-infected control sheep. The animals used in this study were New Zealand Cheviot sheep of three genotypes, the highly susceptible VRQ/VRQ (incubation time 193 ± 12 days), the intermediately susceptible VRQ/ARR (incubation time 325 ± 36 days) and the disease resistant ARR/ARR (no clinical signs of disease), experimentally infected with scrapie strain SSBP/1 and sacrificed at various time points post infection. No differentially expressed candidates were identified in blood. Other microarray experiments in our group had demonstrated evidence of differential expression in spleen fractions enriched for follicular dendritic cells (FDCs). These data were analysed and candidates were selected for quantitative real-time PCR validation, with a view to assessing the expression of validated candidates in blood as a more targeted approach to identifying markers of infection. The gene Early Growth Response 1 (EGR1) emerged as an interesting candidate as its expression was found to be significantly up-regulated in FDC-enriched spleen samples of VRQ/VRQ and ARR/ARR animals over a number of time points post infection. EGR1 expression was steady among all mock-infected controls. There was, however, no evidence of differential expression of EGR1 in blood. This is the first report of differential expression of EGR1 in preclinical spleen samples in sheep. EGR1 is an attractive candidate for a surrogate marker of preclinical infection, as its levels rise very early after infection and remain elevated for a sustained amount of time in the VRQ/VRQ sheep. Elevated expression is also detectable in VRQ/ARR and in ARR/ARR sheep. Further studies with larger sample numbers would be necessary to more accurately estimate the extent of differential expression and to assess its true worth as a diagnostic marker. Expression studies in samples from other TSEs and non-TSE neuropathological disease would also be necessary to establish whether differential expression of EGR1 is specific to TSE disease.
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Kojima, Kyoko. "Mouse modeling of pancreatic ductal adenocarcinoma (PDAC) search for early diagnostic markers and therapeutic targets /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009p/kojima.pdf.
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Honing, Jennifer. "Evaluation and implementation of DNA-based diagnostic methodology to distinguish wheat genotypes." Thesis, Link to the online version, 2007. http://hdl.handle.net/10019/638.
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Nicol, Lisa Margaret. "Diagnostic and prognostic value of current phenotyping methods and novel molecular markers in idiopathic pulmonary fibrosis." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33098.
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Background Idiopathic pulmonary fibrosis (IPF) is a devastating form of chronic lung injury of unknown aetiology characterised by progressive lung scarring. A diagnosis of definite IPF requires High Resolution Computed Tomography (HRCT) appearances indicative of usual interstitial pneumonia (UIP), or in patients with 'possible UIP' CT appearances, histological confirmation of UIP. However the proportion of such patients that undergo SLB varies, perhaps due to a perception of risk of biopsy and additive diagnostic value of biopsy in individual patients. We hypothesised that an underlying UIP pathological pattern may result in increased risk of death and aimed to explore this by comparing the risk of SLB in suspected idiopathic interstitial pneumonia, stratified according to HRCT appearance. Additionally we sought to determine the positive-predictive value of biopsy to diagnose IPF in patients with 'possible UIP HRCT' in our population. In patients with possible UIP who are not biopsied, the clinical value of bronchoalveolar lavage (BAL) is uncertain. We aimed to prospectively study the diagnostic and prognostic value of BAL differential cell count (DCC) in suspected IPF and determine the feasibility of repeat BAL and the relationship between DCC and disease progression in two successive BALs. We hypothesised that BAL DCC between definite and possible IPF was different and that baseline DCC and change in BAL DCC predicted disease progression. Alveolar macrophages (AMs) are an integral part of the lung's reparative mechanism following injury, however in IPF they contribute to pathogenesis by releasing pro-fibrotic mediators promoting fibroblast proliferation and collagen deposition. Expansion of novel subpopulations of pulmonary monocyte-like cells (PMLCs) has been reported in inflammatory lung disease. We hypothesised that a distinct AM polarisation phenotype would be associated with disease progression. We aimed to perform detailed phenotyping of AM and PMLCs in BAL in IPF patients. Several prognostic scoring systems and biomarkers have been described to predict disease progression in IPF but most were derived from clinical trial patients or tertiary referral centres and none have been validated in separate cohorts. We aimed to identify a predictive tool for disease progression utilising physiological, HRCT and serum biomarkers in a unique population of incident treatment naïve IPF patients. Methods Between 01/01/07 and 31/12/13, 611 consecutive incident patients with suspected idiopathic interstitial pneumonia (IIP) presented to the Edinburgh lung fibrosis clinic. Of these patients 222 underwent video-assisted thoracoscopic lung biopsy and histological pattern was determined according to ATS/ERS criteria. Post-operative mortality and complication rates were examined. Fewer than 2% received IPF-directed therapy and less than 1% of the cohort were lost to follow-up. Disease progression was defined as death or ≥10% decline in VC within 12 months of BAL. Cells were obtained by BAL and a panel of monoclonal antibodies; CD14, CD16, CD206, CD71, CD163, CD3, CD4, CD8 and HLA-DR were used to quantify and selectively characterise AMs, resident PMLCs, inducible PMLCs, neutrophils and CD4+/CD8+ T-cells using flow cytometry. Classical, intermediate and non-classical monocyte subsets were also quantified in peripheral blood. Potential biomarkers (n=16) were pre-selected from either previously published studies of IPF biomarkers or our hypothesis-driven profiling. Linear logistic regression was used on each predictor separately to assess its importance in terms of p-value of the associated weight, and the top two variables were used to learn a decision tree. Results Based on the 2011 ATS/ERS criteria, 87 patients were categorised as 'definite UIP', of whom 3 underwent SLB for clinical indications. IPF was confirmed in all 3 patients based on 2013 ATS/ERS/JRS/ALAT diagnostic criteria. 222 patients were diagnosed with 'possible UIP'; 55 underwent SLB, IPF was subsequently diagnosed in 37 patients, 4 were diagnosed with 'probable IPF' and 14 were considered 'not IPF'. In this group, 30 patients were aged 65 years or over and 25/30 (83%) had UIP on biopsy. 306 patients had HRCTs deemed 'inconsistent with UIP', SLB was performed in 168 patients. Post6 operative 30-day mortality was 2.2% overall, and 7.3% in the 'possible UIP' HRCT group. Patients with 'definite IPF' based on HRCT and SLB appearances had significantly better outcomes than patients with 'definite UIP' on HRCT alone (P=0.008, HR 0.44 (95% CI 0.240 to 0.812)). BAL DCC was not different between definite and possible UIP groups, but there were significant differences with the inconsistent with UIP group. In the 12 months following BAL, 33.3% (n=7/21) of patients in the definite UIP group and 29.5% (n=18/61) in the possible UIP group had progressed. There were no significant differences in BAL DCC between progressor and non-progressor groups. Mortality in patients with suspected IPF and a BAL DCC consistent with IPF was no different to those with a DCC inconsistent with IPF (P=0.425, HR 1.590 (95% CI 0.502 to 4.967)). There was no difference in disease progression in either group (P=0.885, HR 1.081 (95% CI 0.376 to 3.106)). There was no statistically significant difference in BAL DCC at 0 and 12 months in either group. There was no significant change in DCC between 0 and 12 month BALs between progressors and non-progressors. Repeat BAL was well tolerated in almost all patients. There was 1 death within 1 month of a first BAL and 1 death within 1 month of a second BAL; both were considered 'probably procedure-related'. AM CD163 and CD71 (transferrin receptor) expression were significantly different between groups (P < 0.0001), with significant increases in the IPF group vs non fibrotic ILD (P < 0.0001) and controls (P < 0.0001 and P < 0.001 respectively). CD71 expression was also significantly increased in the IPF progressor vs non-progressor group (P < 0.0001) and patients with high CD71 expression had significantly poorer survival than the CD71low group (P=0.040, median survival 40.5 and 75.6 months respectively). CD206 (mannose receptor) expression was also significantly higher in the IPF progressor vs non-progressor group (P=0.034). There were no differences in baseline BAL neutrophil, eosinophil or lymphocyte percentages between IPF progressor or non-progressor groups. The percentage of rPMLCs was significantly increased in BAL fluid cells of IPF patients compared to those with non-fibrotic ILD (P < 0.0001) and healthy controls (P < 0.05). Baseline rPMLC percentage was significantly higher in IPF progressors vs IPF non-progressors (P=0.011). Baseline BAL iPMLC:rPMLC ratio was also significantly different between IPF progressor and non-progressor groups (P=0.011). Disease progression was confidently predicted by a combination of clinical and serological variables. In our cohort we identified a predictive tool based on two key parameters, one a measure of lung function and one a single serum biomarker. Both parameters were entered into a decision tree, and when applied to our cohort yielded a sensitivity of 86.4%, specificity of 92.3%, positive predictive value of 90.5% and negative predictive value of 88.9%. We also applied previously reported predictive tools such as the GAP Index, du Bois score and CPI Index to the Edinburgh IPF cohort. Conclusions SLB can be of value in the diagnosis of ILD, however perhaps due to the perceived risks associated with the procedure, only a small percentage of patients undergo SLB despite recommendations that patients have histological confirmation of the diagnosis. Advanced age is a strong predictor for IPF, and in our cohort 83% of patients aged over 65 years with 'possible UIP' HRCT appearances, had UIP on biopsy. BAL and repeat BAL in IPF is feasible and safe (< 1.5% mortality). Of those that underwent repeat BAL, disease progression was not associated with a change in DCC. However, 22% of lavaged patients died or were deemed too frail to undergo a second procedure at 12 months. These data emphasise the importance of BAL in identifying a novel human AM polarisation phenotype in IPF. Our data suggests there is a distinct relationship between AM subtypes, cell-surface expression markers, PMLC subpopulations and disease progression in IPF. This may be utilised to investigate new targets for future therapeutic strategies.Disease progression in IPF can be predicted by a combination of clinical variables and serum biomarker profiling. We have identified a unique prediction model, when applied to our locally referred, incident, treatment naïve cohort can confidently predict disease progression in IPF. IPF is a heterogeneous disease and there is a definite clinical need to identify 'personalised' prognostic biomarkers which may in turn lead to novel targets and the advent of personalised medicines.
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Biesecker, Ronna Lee. "Clinical nutrition expert status as related to selected demographic, diagnostic thinking, knowledge and motivational variables." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/565584.
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Kachroo, Naveen. "Identification of treatment-specific predictive biomarkers in prostate cancer by transcriptional profiling of archival diagnostic biopsies." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707979.
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Ambrosio, Gabriella [Verfasser]. "Ecdysterone Use and Misuse in Sports: Diagnostic Markers in Human Specimen and Determination in Supplements / Gabriella Ambrosio." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1214241166/34.
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Ambrose, Jason H. "Evaluation of a microsphere-based immunoassay (MIA) in measuring diagnostic and prognostic markers of dengue virus infection." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6995.
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Infections with dengue viruses (DENV) constitute both a global problem as well as locally in Florida. DENV comprise four distinct serotypes of single-stranded RNA viruses and belong to the family Flaviviridae. DENV are among the most medically important arboviruses in the world and cases may currently exceed 400 million per annum. Additionally, dengue established its first recorded endemic transmission cycle in the state of Florida in over a half century, first within the Florida Keys during 2009-10 followed by an unrelated outbreak in Martin County in 2013. The clinical profile of DENV infections ranges from a mild febrile illness to severe illness including hemorrhaging and/or shock, occasionally leading to death. Asymptomatic and mild cases also play a role in maintaining transmission cycles. The early diagnosis and management of patients at the clinical level have both proven to be major obstacles in the control of DENV and are important at both the individual and community levels. Individually, the proper management of patients that will progress to severe illness demands that they are identified in order to receive supportive treatment and mitigate associated morbidity and mortality. At the community level, early diagnosis may reduce transmission by limiting the possibility of vector contact with viremic individuals. Early diagnosis is dependent on the detection of viral markers, while a number of host factors may inform prognosis. The microsphere-based immunoassay (MIA) is capable of detecting up to 100 different targets in a single sample and therefore would be useful as a single assay for determining both. This study attempted to develop a diagnostic and prognostic MIA using the DENV NS1 glycoprotein and 5 host markers as targets. For the purposes of DENV NS1 detection in MIA, a set of monoclonal antibodies (mAbs) were subjected to immunoprecipitation and/or Western blot analysis in order to determine immunoreactivity. Two mAbs, 3A5.4 and 3D1.4, were chosen for use in MIA as a capture antibody and a detection antibody, respectively, and the results compared to a commercially available DENV NS1 ELISA. The 5 markers chosen for MIA trials included GM-CSF, IFN-γ, IP-10, IL-10, and MCP-1 and were selected from a panel of 27 markers screened initially in two in vitro models of DENV infection in addition to serum samples. The two cell lines investigated were HPMEC ST1.6R and u937 as both are thought to play important roles in models of DENV pathogenesis. The results of the DENV NS1 detection MIA were initially promising but were ultimately unsuccessful. When measuring host markers in the MIA, results pointed towards certain profiles that may be of future use. IL-10 was found to be elevated in a statistically significant manner in DENV qRT-PCR+ samples (p=0.035) when compared to negative sera. MCP-1 elevation was found to be of borderline significance (p=0.058). Other potential markers based on the results reported here include IP-10, IL-6, IL-8, VEGF, and RANTES. The ultimate goal of measuring host markers is to gain the ability to differentiate patients that will progress to severe illness from those that will recover. In conclusion, despite the failure of the MIA to detect DENV NS1 in human sera, our results in determining host markers and developments leading to successful DENV NS1 detection ELISAs elsewhere lead us to believe that this approach remains promising. Major drawbacks of this study included the lack of samples from patients that experienced severe DENV illness as a comparative group in addition to small sample sizes. Future goals should include determining the reasons for the failure of the MIA in detecting DENV NS1, selecting a panel of appropriate markers to differentiate non-severe from severe cases of DENV prior to progression, and optimizing the inclusion of these markers to an appropriate number.
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Stead, Thomas. "An investigation into the application of design processes to novel self-use molecular diagnostic devices for sexually transmitted infections." Thesis, Brunel University, 2017. http://bura.brunel.ac.uk/handle/2438/15197.
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The purpose of this research was to investigate the application of design processes to the development of novel self-use molecular diagnostic devices for sexually transmitted infections. The argument proposed in this thesis is that the application of design methods at the earliest research stages into miniaturised, low cost, molecular diagnostic technologies will accelerate and improve the process of translating proof of concept diagnostic technologies into usable devices. Concept development requirements and potential issues and barriers to development were identified through interviews with expert stakeholders. These requirements were further refined through a survey of a multidisciplinary diagnostic medical device research group. An action research method was applied to develop a proof of concept prototype to the preclinical trial stage. Through these research studies, a design process model was formulated for use in a research environment. The application of design methods to the proof of concept prototype described in the thesis have resulted in a preclinical trial prototype that exhibits the necessary features for development into a self-use molecular diagnostic device. Issues and barriers were identified and discussed, design guidelines for further development beyond preclinical trial were defined and a generalised design process model for self-use molecular diagnostic devices for sexually transmitted infections was proposed. This research highlights the need for design methods to be applied at the earliest possible stages of the development of novel molecular diagnostic devices.
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Nagala, Sidhartha. "Correlating thyroid tumour pathology with magnetic resonance biomarkers to improve pre-operative diagnosis." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708232.
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Altadill, Vallespí Tatiana. "Metabolomic study for the identification of diagnostic markers and the characterization of the dissemination process of endometrial cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/462056.
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El càncer d'endometri (CE) és la malaltia ginecològica més habitual dels països desenvolupats i la quarta causa de càncer en dones. Presenta una incidència que es troba en continu creixement en pacients joves. Donada aquesta problemàtica, en les darreres dècades diverses línies de recerca s'han focalitzat en entendre quins són els canvis moleculars i metabòlics associats al CE. El seu diagnòstic recau en l'avaluació d'una biòpsia endometrial, mètode considerat mínimament invasiu. A més a més, el maneig dels pacients es basa en l'avaluació de les característiques clínico-patològiques del tumor; aproximació que no és del tot acurada, ja que alguns casos recauen impredictiblement.
Per tal de solucionar els reptes clínics existents, la meta principal d'aquesta tesi va ser la identificació d'un panell novell de marcadors diagnòstics pel CE així com indagar en les vies metabòliques alterades que es donen de manera paral·lela a l'establiment i el procés de disseminació del CE. Hem aconseguit aquesta meta mitjançant l'ús d'aproximacions basades en la metabolòmica per finalment poder acabar millorant la cura del pacient i reduir la taxa de mortalitat d'aquesta malaltia.
Per aconseguir aquests objectius, hem dividit aquesta tesi en tres capítols, cada un d'ells dirigit a un objectiu específic: 1) Optimitzar els mètodes d'extracció per a l'anàlisi metabolòmic de les vesícules extracel·lulars (VEs) contingudes en biofluids mitjançant l'ús de l'espectrometria de masses associada a cromatografia líquida; 2) Identificació, verificació i validació de marcadors diagnòstics del CE a partir de biofluids humans (plasma, aspirats uterins i VEs aïllats d'ambdós biofluids); 3) Estudi metabolòmic en mostres de teixit de CE per tal de detectar les alteracions moleculars que es donen en la iniciació i en el transcurs de la malaltia.
Com a descobriments importants de la tesi, descrivim aproximacions estandarditzades per a tècniques basades en espectrometria de masses per estudiar els perfils metabolòmics de les VEs que es podran traslladar a altres línies de recerca de cerca de biomarcadors i que podran tenir impacte en clínica translacional així com en la millora del seguiment dels pacients amb CE. També presentem evidències que el cargo enriquit contingut en les VEs ofereixen noves oportunitats per al descobriment de metabòlits poc abundants com a biomarcadors de malalties. Cal destacar que les dades exposades en aquest treball representen un avanç en la comprensió de les alteracions moleculars que es donen en en CE. Els nostres resultats així com els nostres models in vitro posen en evidència el rol oncogènic d' ADAR2 així com el rol que té la via de RNA editing en el CE. Així doncs, aquests estudis suposen un avanç en el camp de recerca del CE demostrant l'ús i la optimització de noves metodologies (metabolòmics en VEs) i guanyant idees cap a les pertorbacions bioquímiques específiques que poden tenir un paper clau en el procés carcinogen del CE.Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries and the fourth most common cancer in women. It shows a continuous increasing incidence among younger patients. Concerning this problematic, many new research lines focused on the better understanding of the molecular and metabolic changes associated to EC have appeared the last decades. Its diagnosis relies on the evaluation of an endometrial biopsy, which is a minimally-invasive method. Moreover, the management of patients is based on the assessment of the clinic-pathological features of the tumor, which is not completely accurate since some cases still recur unpredictably. In order to overcome the existing clinical challenges, the major goal of this thesis work was to identify a novel panel of EC diagnostic markers and to gain insights into altered metabolic pathways that are concomitant with the establishment and dissemination process of EC. We achieved our goal by using metabolomic-based approaches to finally improve patient care and overcome the mortality rate of this malignancy. To reach these objectives, we divided the thesis work into three chapters each one of them addressing a specific objective: 1) Optimization of the extraction methods for the metabolomic analysis of extracellular vesicles (EVs) contained in biofluids using liquid chromatography mass spectrometry (LC-MS) techniques; 2) Identification, verification and validation of EC diagnostic markers from human biofluids (use of plasma, uterine aspirates, and EVs isolated from both biofluids); 3) Metabolomic profiling of EC tissues to elucidate the molecular alterations that take place in the initiation and progression of the disease. As main findings of the dissertation, we describe standardized approaches for MS based metabolomics profiling of extracellular vesicles that can be translated to other biomarker research lines and may have big impact in translational clinics and improving the outcome of EC patients. We also present evidence that the enriched cargo contained in EVs offers new opportunities for the discovery of low abundance metabolites as disease biomarkers. Importantly, we highlight the relevance of the use of proximal biofluids, specifically UA, and EVs in the biomarker research and we opened a new avenue for identification of more specific EC biomarkers. Moreover, the data presented in this dissertation depicts a significant advance in the understanding of the metabolic alterations that take place in EC tumorogenesis. Our results and in vitro models evidenced the oncogenic role of ADAR2 and thus the role of RNA editing pathway in EC. Taken together, these studies help further the field of EC research by demonstrated use and optimization of new methodologies (EVs metabolomics) and gaining insights into specific biochemical perturbations that may have a critical role in endometrial carcinogenesis.
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Söderlin, Maria. "A population-based study on early arthritis in southern Sweden : incidence, preceding infections, diagnostic markers and economic burden /." Linköping : Univ, 2003. http://www.ep.liu.se/diss/med/08/24/index.html.
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Söderlin, Maria. "A population-based study on early arthritis in southern Sweden : Incidence, preceding infections, diagnostic markers and economic burden." Doctoral thesis, Linköpings universitet, Reumatologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5225.
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The total annual incidence of arthritis in this prospective cross-sectional study on adults was 115/100 000. The annual incidence of rheumatoid arthritis (RA) was 24/100 000, 29/100 000 for women, and 18/100 000 for men. For reactive arthritis (ReA) the annual incidence was slightly higher, 28/100 000, and for undifferentiated arthritis 41/100 000. The annual incidence of Lyme disease and sarcoid arthritis was low. The annual incidence of arthritis in this study compares well with findings in earlier reports from both registers and case review studies. Almost 50% of the patients in the series of 71 patients with arthritis of less than 3 months’ duration had a preceding infection. Campylobacter jejuni ReA dominated the enteric ReA group. We found only a few patients with preceding Chl. trachomatis, Chl. pneumoniae, Borrelia burgdorferi or parvovirus B19 infections. The arthritis patients with a preceding infection went into remission more often than the patients without a preceding infection. The disease specificity of anti-CCP antibodies for RA was high, 96%, confirming earlier results. Anti-CCP antibodies differentiated RA from other arthritides. Several patients in the different diagnosis groups had raised serum COMP levels, indicating cartilage involvement very early in the disease, even in mild and self-limiting disease with good prognosis. The economic burden of early joint inflammation was found to be considerable already during the first few months of the arthritis irrespective of diagnosis. Surprisingly, patients with ReA generated almost as high costs as patients with RA during thefirst few months of the disease, even though most of the ReA patients had a relatively mild disease. Sick leave accounted for about 50% of the costs. The distribution of costs in the different patient groups was skewed. The median cost per patient for the group of patients with RA was US$4385, for ReA US$4085, for other types of specified arthritis US$3361, and for undifferentiated arthritis US$1482. This underlines the necessity of quick referral and therapy, not only to decrease the inflammation and prevent functional impairment, but also to decrease the costs of early arthritis.
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Alessandria, Maria <1979>. "Sleep motor activity in parkinsonian syndromes at onset: a prospective study to determine potential diagnostic and prognostic markers." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6657/.
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Aim of this study is to describe the possible diagnostic value of sleep disturbances in the differential diagnosis of neurodegenerative diseases characterized by parkinsonism at onset. 42 consecutive patients with parkinsonian features and disease duration up to 3 years were included in the BO-ProPark study. Each patient was evaluated twice, at baseline (T0) and 16 months later (T1). Patients were diagnosed as Parkinson disease (PD, 27 patients), PD plus (PD with cognitive impairment/dementia or dysautonomia, 4 patients) and parkinsonian syndrome (PS, 11 patients). All patients underwent a full night video-polysomnography scored by a neurologist blinded to the clinical diagnosis. Sleep efficiency and total sleep time were reduced in all patients; wake after sleep onset was higher in patients with atypical parkinsonisms than in PD patients. No significant differences between groups of patients were detected in other sleep parameters. The mean percentage of epochs with enhanced tonic muscle EMG activity during REM sleep was higher in PD plus and PS than in PD. No difference in phasic muscle EMG activity during REM sleep was seen between the two groups. REM behaviour disorder was more frequent in PD plus and PS than in PD patients. Our data suggest that REM sleep motor control is more frequently impaired at disease onset in patients with PS and PD plus compared to PD patients. The presence of RBD or an enhanced tonic muscle EMG activity in a patient with recent onset parkinsonian features should suggest a diagnosis of atypical parkinsonism, rather than PD. More data are needed to establish the diagnostic value of these features in the differential diagnosis of parkinsonisms. The evaluation of sleep disorders may be a useful tool in the differential diagnosis of parkinsonism at onset.
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Liefferinckx, Claire. "Evaluation of disease severity in inflammatory bowel diseases: From predictive diagnostic gene markers to treatment optimization based on pharmacokinetics." Doctoral thesis, Universite Libre de Bruxelles, 2019. https://dipot.ulb.ac.be/dspace/bitstream/2013/286479/3/table.docx.
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Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory immune-mediated diseases of the gastrointestinal tract. Two-thirds of IBD patients will develop severe disease, with complications that will require frequent surgeries and hospital admissions, and will seriously impair their quality of life. The ultimate clinical challenge of precision medicine in IBD is to find predictive markers to anticipate the development of severe disease and to monitor treatment in these patients.In the first part of my PhD thesis, we have carried out several studies monitoring the biologics used in IBD patients with severe disease. We have evaluated the pharmacokinetics of the following biologics used in IBD patients: infliximab, vedolizumab, and ustekinumab. We have focused on measuring trough levels (TLs) (defined as the serum drug level measured just before the next drug administration) early on after initiating biologic treatment to predict patient outcomes, including long- term responses in patients treated with infliximab and vedolizumab. In addition, we are currently conducting a prospective multicentric study that aims to design a pharmacokinetic model of infliximab at induction in IBD patients (EudraCT: CT 2015- 004618-10) (End of study expected by December 2019 but interim analysis available in the present work). Moreover, we have reported on the efficacy of ustekinumab in a large national cohort of highly refractory CD patients and have also examined the benefit of early measurement of ustekinumab TLs in these patients. Finally, we have reported novel findings on the impact of different wash-out periods (defined as the time frame between the discontinuation of one biologic and the initiation of a second biologic on the pharmacokinetics of the second-line biologic). Altogether, over the past 3 years, our data suggest the importance of measuring TLs early on during induction to predict long-term response to biologics during maintenance therapyIn the second part of my PhD thesis, we have analysed the inter-variability of the immune response in healthy subjects. Inflammation is the obvious key driver and underlying mechanism of disease severity in IBD. Therefore, the magnitude of inflammation must help define the phenotype of mild to severe disease. Delineating the inter-variability of the immune response in a healthy cohort constitutes a fundamental step to uncovering the genetic factors underlying this variability. We have performed whole blood cell cultures in a highly selected population of more than 400 healthy subjects stimulated with several Toll-like receptor (TLR) agonists and a T-cell receptor (TCR) antagonist. We found that the magnitude of the immune response (the high- or low-cytokine producer phenotype) was independent of the cytokine measured and the TLR agonists used. Thus, a donor exhibits a specific immune (cytokine) response or “immunotype” across cytokines released and TLR stimulation. Importantly, the high- or low-cytokine producer phenotype was different and did not overlap between the TLR and TCR stimulation conditions. In other words, a donor who is ahigh-cytokine producer following TLR stimulation will not be a high-cytokine producer following TCR stimulation (or the inverse). Therefore, we have defined TLR- or TCR- related Immunotypes (IT) as “a grading classification of the magnitude of the cytokine immune response” with IT1, IT2, and IT3 as low, intermediate, and high immunotypes. This suggests that two independent TLR and TCR ITs (TLR IT1 and TCR IT3) can co-exist in the same subject. We are now currently evaluating the genetic markers underlying these ITs before validating them in large cohort of IBD patients with mild-to-moderate and severe disease.This PhD thesis provides some data suggesting that the assessment of the pharmacokinetics of biologics early on at the initiation of treatment could help predict how the patient will respond in the long run. In parallel, this PhD thesis provides some advances in the understanding of the inter-variability of the immune response, a fundamental step before the identification of potential genetic markers underlying the inter-variability of inflammation and, hence, the severity of disease in IBD.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Rautiola, Davin. "Detection of Homocysteine with Bridged Viologen Chemical Probes." PDXScholar, 2014. https://pdxscholar.library.pdx.edu/open_access_etds/1541.
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Increased blood plasma concentrations of the aminothiol homocysteine (Hcy) are associated with a variety of disease states including those which cause impaired renal function, many forms of cardiovascular disease, and neurodegenerative diseases such as Alzheimer's. Therefore, Hcy has the potential to be a significant diagnostic biomarker. Routine monitoring of Hcy plasma concentration is encumbered by the time and resources required to quantify Hcy using currently accepted instrumental analysis methods. As part of the continuing effort to develop a quick, reliable, inexpensive, and user-friendly test to quantify Hcy at the point of care, we have designed a series of novel colorimetric and fluorescent chemical probes based on bridged viologen structures. The absorbance at 540 nm for the para-bridged bis-nitrile viologen probe (pCN) was found to be proportional to the concentration of Hcy analyte, with LOD = 2.17 μM and LOQ = 6.10 μM where unhealthy Hcy plasma concentrations are > 15 μM. The mechanism of reactivity between pCN and Hcy encompasses a dynamic set of reactions which involve pimerization of radical probe species and thioether adduct formation of pCN with Hcy. Preliminary results with fluorometric analogs of the bridged viologen probes are also presented.
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Luan, Hemi. "Mass spectrometry based metabolomics for biomarkers of Parkinson's disease." HKBU Institutional Repository, 2017. https://repository.hkbu.edu.hk/etd_oa/396.
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Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). However, the relationship between metabolic phenotypes and PD is not fully understood. Mass spectrometry (MS) based metabolomics is a powerful technique, which was frequently used for the sensitive and reproducible detection of hundreds to thousands of metabolites in biofluid samples.. Here we developed and performed MS-based metabolomics studies involving hundreds of human urine samples with data acquired from multiple analytical batches for surveying potential biomarkers of PD. A new software statTarget was developed and introduced. Protocols for liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were developed, including sample preparation, data acquisition, quality controls, quality assurance and data analysis. Urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using LC-MS. Quality control (QC) strategy has been performed in MS-based metabolomics for high reproducibility and accuracy of MS data. GC-MS with methyl chloroformate (MCF) derivatization was used for profiling highly polar metabolites in patients with early-, middle- and advanced-stage PD. Our study revealed the significant correlation between clinical phenotypes and urinary metabolite profiles. Comprehensive metabolomics was successfully developed with the goal of identifying urinary metabolite markers that can be used for evaluating the development of PD. A group of 18 metabolites have shown not only a high discriminating ability for the early-stage PD patients but also accurately distinguished the middle- and advanced- stages patients from control subjects. For the evaluation of PD, 18 metabolites showed good potential as metabolite markers with related metabolic pathway variations observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism.. We have further performed targeted analysis of potential biomarkers by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and GC-MS. The UPLC-MS/MS method was developed and optimized for detecting the concentration variation of metabolites in tryptophan metabolism for alpha-synuclein over-expressed flies (Parkinson's disease model). The altered tryptophan metabolism was proved as one of the common metabolite signatures between PD patients and alpha-synuclein over-expressed fly model of PD, and thus may be used for developing potential markers of the disease and evaluating the efficacy of novel therapeutic agents. An asymmetric labeling strategy and positive chemical ionization gas chromatography-tandem mass spectrometry (PCI-GC-MS-MS) approach was developed for the determination of non-amino organic acids and amino acids, as well as short chain fatty acids. Carboxylic and amino groups could be selectively labelled by propyl and ethyl groups, respectively. The specific neutral losses of C3H8O (60 Da), C3H5O2 (74 Da) and C4H8O2 (88 Da) were useful in the selective identification for qualitative analysis of organic acids and amino acid derivatives. The developed PCI-GC-MS/MS method showed good reproducibility and linear range.. In summary, metabolomics study has its inherent advantage in the characterization of biomarkers for the development of PD and may bring new scientific knowledge as well as impact on the progression of PD and other related neurodegenerative diseases.
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Zeng, Qing-Yin. "Development of molecular techniques for fungal diagnostic research." Doctoral thesis, Umeå : Umeå universitet : Arbetslivsinstitutet, 2005. http://kb.se/resolve?urn=urn:nbn:se:umu:diva-656.
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Wakerley, Eleanor. "The use of squiggling : a play technique as a diagnostic aid in the assessment of secondary school-age children with Asperger syndrome." Thesis, University of Hertfordshire, 2009. http://hdl.handle.net/2299/2930.
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Winnicott’s (1968, 1993) play technique squiggling was piloted as a measure of creative thinking abilities and a potential diagnostic aid in the assessment of Asperger syndrome. The internal consistency and inter-rater reliability of squiggling was found to be acceptable. Mixed results were found between the six subscales in terms of concurrent validity with the Torrance Tests of Creative Thinking (TTCT: Torrance, Bal & Safter, 2008). Squiggling subscales Elaboration and Imagination showed signs of psychometric strength. However, Fluency and Originality require revision. Concurrent validity of the subscales Flexibility and Integration were not established. A matched-participants design enabled testing of hypothesised differences in creative thinking abilities with children with Asperger syndrome using the TTCT (Torrance et al., 2008): Abstractedness, Fluency, Originality, Integration, Elaboration, Resistance to Premature Foreclosure and Flexibility. Children with Asperger syndrome demonstrated a significantly higher level of elaboration and abstract imagination in their drawings relative to a comparison group of typically-developing children matched on age, visual motor integration ability and non-verbal IQ. Findings indicate partial support for the Weak Central Coherence Theory (Shah and Frith, 1983) and Leslie’s (1987) Meta-Representational Deficit hypothesis. Children with Asperger syndrome demonstrated understanding and expression of abstract concepts as graphical representations, thereby supporting their use in clinical assessments and interventions. No support was found for the Executive Dysfunction Theory (Pennington & Ozonoff, 1996) or for the Hyper-Systemising Theory (Baron-Cohen, 2006). Some limitations include the heterogeneity of the clinical group, and the possible confounding effects of verbal intellectual abilities, extrinsic rewards and performance anxiety. Major strengths of the study include a successful matching procedure and the finding of group differences with large effect sizes on particular creative thinking abilities.
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Arrambide, García Georgina. "Study of diagnostic and prognostic clinical, biological, and magnetic resonance imaging markers at the time of a clinically isolated syndrome." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/384610.
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En este trabajo estudiamos marcadores con valor diagnóstico o pronóstico en el momento de presentar un síndrome clínico aislado (CIS, del inglés clinically isolated syndrome). Dado que presentar un CIS representa un riesgo para desarrollar esclerosis múltiple (EM), se considera crucial identificar qué pacientes tendrán un segundo brote y determinar el grado de acumulación de discapacidad a medio y largo plazo. Por ello, aún se considera necesario identificar marcadores que representen los diferentes aspectos de esta enfermedad, especialmente si se demuestra su utilidad en la práctica clínica diaria. Así, nuestro objetivo fue determinar el valor diagnóstico y pronóstico de marcadores clínicos, biológicos y radiológicos en el momento del CIS.
Primero, dado que el espectro de enfermedades de la neuromielitis óptica (NMOSD, del inglés neuromyelitis optica spectrum disorders) es uno de los principales diagnósticos diferenciales de la EM, decidimos evaluar la utilidad de determinar sistemáticamente la presencia de anticuerpos NMO-IgG en el momento del CIS, observando que tal abordaje no es necesario ya que la determinación de este anticuerpo fue negativa en la mayoría de los pacientes. Por tanto, otras características clínicas y radiológicas también deben considerarse durante el diagnóstico diferencial y esta determinación podría realizarse en casos indeterminados. Posteriormente se estableció una colaboración con Aurélie Ruet y Bruno Brochet [Centre Hospitalo-Universitaire (CHU) de Bordeaux, INSERM-CHU centre d’Investigation Clinique, Université de Bordeaux en Francia] para evaluar más a fondo el valor añadido de presentar dos o más factores predictivos de EM, previamente identificados por ellos, en pacientes con CIS que no cumplen los criterios diagnósticos de 2010 para diseminación en espacio, observando que si bien es más bajo, los pacientes con combinaciones de estos factores aún presentan un riesgo de desarrollar EM y deberían ser monitorizados más estrechamente. De igual forma, la utilidad de realizar una RM medular en el momento del CIS se considera un tema controvertido. Por tanto, analizamos su valor diagnóstico y pronóstico añadido, observando que aunque su aportación a los criterios diagnósticos es más bien modesta, la presencia de lesiones medulares representa un riesgo aumentado para evolucionar a una EM y para desarrollar una mayor discapacidad. También establecimos otra colaboración con la compañía israelí Glycominds, Inc., para validar el valor predictivo del gMS-Classifier2, un algoritmo que incorpora anticuerpos anti-glicano IgM en suero, diseñado con el objetivo de identificar pacientes con CIS en riesgo de presentar un segundo brote. El gMS-Classifier2 resultó ser un factor de riesgo independiente para EM, si bien los hallazgos en la RM representan un riesgo más elevado. Finalmente, valoramos varios marcadores biológicos en líquido cefalorraquídeo durante una fase de screening y una de validación que requirió trabajos colaborativos con Jens Kuhle, Ludwig Kappos (Department of Neurology, University Hospital Basel, en Suiza), Luisa María Villar y José Carlos Álvarez-Cermeño [Departamentos de Inmunología y Neurología del Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) en Madrid]. De todos los biomarcadores testados, los niveles basales de NfL resultaron ser factores independientes de riesgo para desarrollar una EM, siendo los hallazgos de RM nuevamente los mayores indicadores de riesgo. Además, los NfL presentaron fuertes correlaciones con los cambios en el volumen cerebral a los cinco años de seguimiento.The present work is concerned with finding diagnostic and prognostic markers at the time of a clinically isolated syndrome (CIS). Given that presenting a CIS indicates the possibility of developing multiple sclerosis (MS), it is considered crucial to identify which patients will present a second attack and to determine the degree of disability accumulation over the medium to long-term. Therefore, the search for markers that capture the different aspects of this disease is still considered necessary, particularly if they demonstrate to be useful in the daily clinical practice. Therefore, we aimed to determine the diagnostic and prognostic value of a number of clinical, biological, and radiological markers available at the time of the CIS. First, considering neuromyelitis optica spectrum disorders (NMOSD) as one of the main differential diagnoses of MS after a first attack, we decided to assess the value of systematically determining NMO-IgG status at the time of a CIS, observing that such approach is not necessary since the antibody determination was negative in most patients. Therefore, other clinical and radiological characteristics should also be taken into account during the differential diagnosis and this test could be considered in indeterminate cases. Next, a collaborative work was established with Drs. Aurélie Ruet and Bruno Brochet [Centre Hospitalo-Universitaire (CHU) de Bordeaux, INSERM-CHU centre d’Investigation Clinique, Université de Bordeaux, France] to further assess the added value of presenting ≥2 predictive factors for MS, previously identified by them, in patients not fulfilling the 2010 criteria for dissemination in space, and observed that although lower, patients with combinations of these predictive factors are still at risk of developing MS and should be monitored closely. Likewise, the usefulness of a baseline spinal cord MRI at the time of a CIS is still somewhat controversial. Therefore, we analysed its added diagnostic and prognostic value, observing that although the diagnostic value is modest, presence of spinal cord lesions do pose an increased and independent risk for both evolution to MS and disability accumulation. One more collaboration was established with the Israeli company Glycominds, Inc., to validate the predictive value of gMS-Classifier2, an algorithm incorporating serum IgM anti-glycan antibodies, designed with the aim of identifying CIS patients at risk of a second demyelinating attack. gMS-Classifier2 turned out to be an independent risk factor for clinically definite MS, although MRI findings still posed a higher risk. Finally, we evaluated a number of biological markers in cerebrospinal fluid during a screening and a validation phase that involved a couple of collaborative works with Jens Kuhle, Ludwig Kappos (Department of Neurology, University Hospital Basel, in Switzerland), Luisa María Villar, and José Carlos Álvarez-Cermeño (Departments of Neurology and Immunology, Multiple Sclerosis Unit, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) in Madrid). Of all biomarkers, only baseline neurofilament light chain levels were independent risk factors for MS with MRI findings again posing the highest risk but, interestingly, they showed very strong correlations with brain volume changes at five years of follow-up.
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Sikes, Tiffany Rochelle. "Validation of Loci Conferring Adult Plant Resistance to Powdery Mildew in Wheat Cultivar Massey and Identification of Diagnostic Molecular Markers." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/64152.
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Powdery mildew, caused by the pathogen Blumeria graminis (DC) Speer (Syn. Erysiphe graminis DC) f. sp. tritici, is a major disease of wheat (Triticum aestivum L.). Race-specific resistance is easily identified in the field due to its qualitative phenotype and it is easy to incorporate because it is inherited as a single gene. Unfortunately, this type of resistance is easily overcome by the pathogen. Traits associated with quantitative trait loci (QTL) such as adult-plant resistance (APR), have become popular with plant breeders because of their durability over a wide geographic range and time. Due to the quantitative nature of these genes, they are difficult to study requiring multiple assessments of disease development under natural conditions in more than one location over a period of several weeks. Numerous QTL for APR to powdery mildew have been mapped in independent studies in different wheat backgrounds. The wheat cultivar Massey has been the subject of several studies due to its APR to powdery mildew that has remained effective for several decades. However, it has been difficult to identity simple sequence repeat (SSR) markers that are tightly linked to the QTL for APR in Massey. Such markers give breeders an advantage by allowing them to quickly identify and select for traits that would be difficult to distinguish in the field among breeding progeny from several backgrounds. Therefore, identification of tightly linked markers associated with APR to powdery mildew is necessary so that these traits can be selected for reliably in progeny.Master of Science
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Hakuna, Lovemore. "Selective Indicators for Optical Determination of Disease Biomarkers." PDXScholar, 2014. http://pdxscholar.library.pdx.edu/open_access_etds/2053.
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The most abundant biological thiols, homocysteine (Hcy), cysteine (Cys) and glutathione (GSH) have been the subject of intense research due to their association with a wide range of diseases. They play a key role in maintaining the redox status of biological systems. Selective detection methods for these thiols are challenging due to their similar structures and properties. Current commercially available detection methods use separations, fragile and expensive enzymatic or immunogenic materials and complex instrumentation. This has led to a global effort towards developing simple and inexpensive optical probes and indicators selective for specific biological thiols.
Highly selective chemical probes and simple methods for detection and potential quantification of Hcy and GSH in their natural biological media have been developed. These indicators and methods are relatively simple and inexpensive for potential application at point of care. The selective detection of Hcy using novel asymmetric viologen chemical probes at room temperature is described as well as the use of commercially available materials under photochemical conditions. These probes respond linearly proportional to increasing Hcy concentrations, potentially enabling the monitoring of Hcy levels in human plasma. Additionally, new methods for the selective determination of GSH in human plasma, as well as its quantification in whole blood deposited on filter paper (dried blood spots), is also presented herein.
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Andries, Anne-Claire. "Diagnostic de la dengue : trois solutions pour améliorer la prise en charge des patients et faciliter les études épidémiologiques." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTS146/document.
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La dengue est une maladie virale des régions tropicales et subtropicales, transmise par les moustiques du genre Aedes. Le virus de la dengue (DENV) appartient à la famille des Flaviviridae, genre Flavivirus. Si la plupart des infections sont asymptomatiques ou se traduisent par un syndrome fébrile sans gravité, le virus peut aussi causer une maladie plus sévère caractérisée par une fuite plasmatique, avec ou sans hémorragie. Sans prise en charge adéquate, les formes les plus sévères peuvent évoluer vers un syndrome de choc, potentiellement mortel. Il n’existe pas de traitement spécifique de la dengue mais une réhydratation adaptée et débutée précocement permet de réduire la survenue de formes sévères de la maladie. Malheureusement, les symptômes initiaux de la dengue avant la survenue des éventuelles complications ne sont pas spécifiques et seul un diagnostic biologique basé sur la détection du génome viral, de l’antigène NS1 ou des anticorps anti-DENV dans le sang des patients permet de confirmer la nature exacte de l’infection. La dengue constitue à l’heure actuelle un problème majeur de santé publique du fait de son expansion mondiale et de l’augmentation annuelle du nombre de cas sévères. Pour assurer la surveillance épidémiologique et le contrôle de la maladie, il est indispensable de développer des outils diagnostiques performants et faciles à mettre en œuvre, à la fois utilisables par les médecins de toutes les structures médicales, des simples centres de soins de santé primaire aux centres de référence, et utilisables lors d’enquêtes épidémiologiques pour l’investigation de nouvelles épidémies. Le travail de cette thèse a porté sur plusieurs aspects de cette problématique. Dans une première partie, un test commercial de diagnostic rapide (TDR) permettant la détection simultanée de la NS1 et des IgG et IgM anti-DENV, a été évalué, en laboratoire spécialisé et sur le terrain, afin de comparer, à partir des mêmes échantillons, les performances du test dans deux situations différentes. La sensibilité s’est révélée plus faible lors de l’utilisation sur le terrain que lors de l’utilisation en laboratoire de référence. La majorité des discordances a été observées pour la détection des IgG et des IgM. L’impact de la mise à disposition du test sur la prise en charge des patients a également été évalué et il s’est avéré qu’au cours de cette étude les pédiatres cambodgiens ont ignorés les résultats du test rapide et ont préféré suivre leur instinct clinique.Un second volet a porté sur la faisabilité d’utiliser les urines et la salive en remplacement du sang veineux pour les tests employés en routine pour le diagnostic de la dengue. Les urines et la salive sont des fluides biologiques plus faciles à prélever que le sang veineux ce qui présente un avantage majeur pour les enquêtes épidémiologiques mais peut également secourir les médecins lorsqu’un prélèvement de sang veineux est difficile à obtenir, par exemple chez les enfants. Bien que les performances des différentes méthodes de diagnostic ne soient pas aussi bonnes avec de l’urine et la salive qu’avec du plasma, les résultats obtenus par PCR en temps réel et avec les ELISAs de détection des anticorps anti-DENV démontrent l’intérêt potentiel de ces deux fluides biologiques pour détecter les infections par le DENV lorsqu’il est difficile d’obtenir du sang veineux. Plusieurs TDR commerciaux développés pour permettre la détection de la NS1 et des anticorps anti-DENV (IgM, IgG et IgA) dans les urines et la salive ont été évalués mais les performances obtenues se sont révélées peu satisfaisantes.Une dernière partie du travail a été consacrée à l’étude de la protéinurie comme marqueur pronostic potentiel de sévérité de la dengue. Ce marqueur biologique ne s’est pas révélé être utile pour diagnostiquer précocement les formes sévères de la maladieDengue is a viral disease transmitted by Aedes species mosquitoes, in tropical and subtropical regions. Dengue virus (DENV) belongs to the family Flaviviridae, genus Flavivirus. Although most DENV infections are asymptomatic or result in a self-limited febrile illness, severe diseases characterized by plasma leakage, with or without hemorrhage, can also occur. Patients with a severe dengue can rapidly progress into a life-threatening shock syndrome if no efficient clinical management is provided. There is no specific treatment available for dengue but an accurate and early fluid therapy substantially reduces the occurrence of severe forms of the disease. Dengue symptoms are typically non-specific until or unless complications develop. Only a biologic diagnosis based on DENV genome, NS1 antigen or anti-DENV antibodies detection enables to confirm dengue cases. Dengue is now a major public health problem due to both its geographical spread and the increase in the number of severe cases. New diagnostic tools are necessary to ensure epidemiological surveillance and control of the disease. These tools need to be effective and easy to use in every medical settings, from the smallest primary health centers to the biggest reference centers, and also usable for epidemiologic studies, e.g. for epidemic investigations. The work presented in this thesis was dedicated to this problematic.In a first part of the work, a rapid diagnostic test (RDT), designed to detect NS1 antigen, anti-DENV IgG and IgM, was evaluated, both in a specialized laboratory and in the field, in order to compare the test performances in two different settings, with the same samples. Interestingly, sensitivity was lower when the test was used in the field compared to the sensitivity of the test when performed in the specialized laboratory. Discordances were mainly observed for IgM and IgG detection. Impact of the use of the RDT on clinical management was also assessed during the field study and it revealed that Cambodian pediatricians ignored the results of the RDT and followed their clinical instinct.A second part of the work was dedicated to the assessment of the usefulness of urine and saliva for dengue diagnostic. Dengue diagnostic normally requires a venous blood sample that can be difficult to obtain in certain conditions such as in children or during epidemiological studies. Urine and saliva are easier to collect as the procedure is non-invasive. We showed that, although the performances of the different diagnostic methods were not as good in saliva and urine as in plasma specimens, the results obtained by qRT-PCR and by anti-DENV antibody ELISA could well justify the use of these two body fluids to detect dengue infection in situations when the collection of blood samples is difficult. Performances of commercial RDTs developed for NS1 and anti-DENV antibodies (IgM, IgG and IgA) detection in urine and saliva specimens were not satisfactory.In the last part of the thesis, the potential use of proteinuria as a prognostic marker of severity was assessed but it didn’t prove to be a useful marker for risk prediction
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Broto, Avilés Marta. "Universal diagnostic platforms based on oligonucleotide codified nanoparticles and DNA microarray devices." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/462828.
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La medicina personalitzada esta prenent rellevància últimament. Aquesta es basa en la monitorització simultània de diferents biomarcadors, els biomarcadors poden ser molècules de diferent naturalesa química. Aquest fet fa palesa la necessitat de desenvolupar aproximacions tecnològiques universals per al diagnòstic capaces de detectar aquests biomarcadors independentment de la seva naturalesa química. En aquests context, la principal finalitat del projecte és el desenvolupament d’una plataforma bioanalítica per al diagnòstic in vitro que sigui multiplexada (per més de un biomarcador) i multimodal (per biomarcadors de diferent naturalesa química). L’aproximació proposada pretén traduir qualsevol interacció biomolecular (biomarcador- bioreceptor) en una senyal amplificada d’ADN que serà finalment detectada en un bioxip d’ADN. Aquesta estratègia s’anomena biobarcode.
Com a prova de concepte de l’aproximació proposada ens hem centrat en la detecció de biomarcadors relacionats amb les malalties cardiovasculars (CVDs) i, també, en fàrmacs relacionats amb el càncer. CVDs són la principal causa de mort al món i inclouen un grup de desordres dels vasos coronaris i sanguinis. La detecció multiplexada i multimodal d’aquests biomarcadors podria ser de gran ajuda en el monitoratge de l’estat del pacient. Per altra banda, la segona causa de mort al món és el càncer, els fàrmacs utilitzats per tractar-lo s’anomenen cytostatics. La proximitat de la dosi tòxica i terapèutica dels fàrmacs cytostatics fa el monitoratge terapèutic dels fàrmacs (TDM) la clau per la optimització del tractament del càncer. Podem assumir que la monitorització del fàrmac juntament amb certs metabòlits milloraria la eficàcia i tolerabilitat, reduint la toxicitat.Personalized therapy has become a crucial issue lately. It should be based on the simultaneous monitoring of different biomarkers which might include molecules of different chemical nature. This fact, calls for developing universal technological diagnostic approaches, able to determine these biomarkers, independently from their chemical nature, while modulating the necessary amplification factor. In this context, the aim of the project is to develop of a universal, multiplexed (for several biomarkers) and multimodal (biomarkers of different chemical nature) in vitro diagnostic bioanalytical platform. The proposed approach (Figure 1) pretends to translate any type of biomolecular interaction (bioreceptor-biomarker) into a PCR-less DNA amplification process that is finally detected on a DNA-microarray biosensor platform. This strategy is called biobarcode assay. As proof-of-concept of the proposed approach, we have focused on the detection of biomarkers related to cardiovascular diseases (CVDs) and, also, drugs related to cancer disease. CVDs are the main cause of death in the world and include a group of disorders of the heart and blood vessels, multimodal and multiplexed detection of CVDs-related biomarkers would help the monitoring of patient status. Otherwise, the second cause of death worldwide is cancer; drugs used to treat cancer are called cytostatics. Closely levels of therapeutic and toxic doses of cytostatics make therapeutic drug monitoring the milestone for the optimization of cancer treatment. It can be assumed that monitoring of drug concentration jointly with main metabolites should improve efficacy and tolerability and reduce toxicity. The main objective of the project will consist on demonstrating that it is possible to analyze targets of different chemical nature, and that the amplification can be modulated by varying the charge of oligonucleotides covalently attached to the nanoparticles.
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Eaton, Michael Campbell. "Assessment of CD44 and K19 as markers for circulating breast cancer cells using immunobead RT-PCR /." Title page, table of contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09MD/09mde14.pdf.
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Colom, Sanmartí Glòria. "A Multiplexed diagnostic approach for cardiovascular disease biomarkers." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396304.
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In the course of this thesis, the optimal epitopes for the subsequent polyclonal rabbit antibody production for cTnI and NT-proBNP have been studied and chosen. cTnI and NT-proBNP are the most relevant cardio-specific biomarkers for the diagnosis of cardiovascular diseases. With these antibodies, a sandwich ELISA for the detection of cTnI has been developed together with a competitive ELISA for the detection of NT-proBNP, both in a microplate format.
It has been observed that cTnI has an extraordinary tendency to non-specifically adsorb itself onto surfaces and other biomolecules. This, with the inability to achieve the required detectability for this biomarker, have been the main problems to face with. Regarding the non-specific adsorption, different additives in the analyte or sample buffer have been evaluated. Thus, 0.15% casein in PBST combined with the use of low adsorption microplates (ImmulonTM 2HB) helps considerably to solve this problem. However, the sensitivity obtained for this assay in aqueous buffer is much lower than that required corresponding to the basal levels of cTnI in the blood.
For the NT-proBNP ELISA development, the required limit of detection was achieved after studying various parameters related to heterology and other physicochemical parameters. Moreover, a good accuracy with NT-proBNP fortified plasma samples was obtained.
It has been possible to develop a multiplexed microarray for the simultaneous detection of 5 biomarkers (cTnI, NT-proBNP, very important in the process of developing cardiovascular diseases, CRP, Cys C and H-FABP). Once the microarray is biofunctionalized using a spatial encoding with the corresponding bioconjugates or capture antibodies, immunoreagents and other biomarkers can be used in a cocktail. Neither cooperativity phenomena (union of immunoreagents that are in solution in sites where there are other biomarkers immobilized) nor cross-reactivity (recognition of different biomarkers from those for which immunoreagents have been developed) have been observed in any case. Only Lp(a) immunoreagents produced such interferences and therefore they were discarded.
It has been highlighted the fact that the biomarkers present in different concentration ranges remains one of the main challenges for the multiplexed diagnosis when simultaneous measurements are desired. In this research, it was impossible to quantify the CRP and Cys C in the same microarray than H-FABP, cTnI and NT-proBNP employing direct samples. Fortunately, the fact of using glass surfaces in which 24 microarrays can be printed, has allowed making these measurements in a simultaneous and parallel way.
With the multiplexed microarray, it has been possible to measure samples from patients with different pathologies. The results show that the efficiency of this microarray is much higher than that of analyzers currently used in clinical laboratories, regarding the ability to measure multiple biomarkers in a large number of samples in a short time and the coherence of the results. Thus, the microarray developed in this PhD thesis has been able to measure all the biomarkers from all patient samples, while analyzers only analyzed some of them,
depending on the pathology, due to the cost (financial and time). The microarray was then able to detect high levels of CRP from patient samples that were not analyzed in clinical laboratory. Additionally, the microarray results are coherent with those obtained with analyzers for those cases in which measures had been made, and the disease had been diagnosed. The results have been satisfactory even in the case of NT-proBNP, which had not reached the detectability baseline even though it was very close. Unfortunately, it was not possible to measure cTnI levels with the microarray as it was expected according to previous studies done with the same immunoreagents. Thus, we can consider this multiplexed microarray as a semi-quantitative method useful for improving the diagnosis of cardiovascular disease for patients who are at different stages of the disease.
Finally, preliminary studies have been realized to implement the multiplexed immunochemical system in a fluorescent optical sensor based on the evanescent wave. This was done with the aim to achieve a POC (point-of-care) device suitable to be used outside hospital premises, adapted to non-specialist users, and facilitate the diagnosis of cardiovascular diseases. Unfortunately, the results obtained point to the need to make greater efforts to increase the detectability of the system, since the LOD values obtained are worse than those achieved with the ELISA or the microarray, far from the basal levels in the case of NT-proBNP.
The main problem in this thesis has been to reach the detection limits required by some biomarkers. Although in the literature and in the market there are assays that have achieved it, this fact mainly lies in the signal acquisition method as well as in the intrinsic sensitivity of the instrument addressed to do so.En el transcurs d'aquesta tesi s'han escollit els epítops òptims per a la conseqüent producció d'anticossos policlonals de conill per a cTnl i NT-proBNP, dos dels biomarcadors més cardio-específics i rellevants pel diagnòstic de malalties cardiovasculars. Amb aquests anticossos s'ha desenvolupat un ELISA sandvitx per a la detecció de cTnl i un ELISA competitiu per a la detecció de NT-proBNP, tots dos en format de microplaca. S'ha observat que la cTnl te una extraordinària tendència a adsorbir-se de forma inespecífica a superfícies i també a altres biomolècules. Pel que fa a l'adsorció inespecífica s'han avaluat diferents additius en el tampó de la mostra o analit veient-se que la caseïna al 0,15% en PBST combinat amb l'ús de microplaques de baixa adsorció (ImmulonTM 2HB) ajuda considerablement a solucionar aquest problema. Tot i això, la sensibilitat obtinguda per aquest assaig en tampó aquós és molt inferior a la requerida corresponent als nivells basals d'aquest analit a la sang. En el desenvolupament de l'ELISA per NT-proBNP, després d'estudiar diferents paràmetres relacionats amb l'heterologia i altres paràmetres físico-químics, s'ha aconseguit assolir el límit de detecció necessari obtenint una bona exactitud amb mostres de plasma fortificades amb l'analit en qüestió. Ha estat possible desenvolupar un microarray multiplexat per a la detecció de 5 biomarcardors (cTnl, NT-proBNP, CRP, Cys C i H-FABP). Un cop biofuncionalitzat el microarray amb els corresponents bioconjugats o anticossos de captura, la resta d'immunoreactius i biomarcadors poden ser utilitzats en forma de còctel sense que en cap cas s'hagin observat fenòmens de cooperativitat ni de reactivitat creuada. Tant sols els immunoreactius de Lp(a) van produir aquestes interferències i per aquest motiu es van descartar. En aquest treball de recerca va ser impossible quantificar la CRP i Cys C en el mateix microarray que la H-FABP, cTnl i NT-proBNP de mostres directes. Afortunadament, el fet d'utilitzar superfícies de vidre en les quals es podien imprimir fins a 24 microarrays ha permès poder fer aquestes mesures de forma simultània i paral•ela. Amb el microarray multiplexat ha estat possible mesurar mostres de pacients amb diferents patologies. Malauradament, no va ser possible mesurar els nivells de cTnl amb aquest microarray, tal com era de preveure d'acord amb els estudis previs fets amb els immunoreactius utilitzats. Així doncs, podem considerar aquest microarray com un mètode semi-quantitatiu multiplexat útil per a la millora del diagnòstic de malalties cardiovasculars. Finalment, s'han realitzat estudis preliminars per implementar el sistema immunoquímic multiplexat en un sensor òptic fluorescent d'ona evanescent amb l'objectiu d'aconseguir un dispositiu POC (point-of-care). Malauradament, els resultats obtingut apunten a que és necessari fer un major esforç per a incrementar la detectabilitat d'aquest sistema, donat que els valors de LOD assolits són pitjors que els aconseguits amb l'ELISA o el microarray i, per casos com l'NT-proBNP, es troben molt allunyats dels valors basals.
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Janes, Holly. "Adjusting for covariate effects in biomarker studies using the subject-specfic threshold ROC curve /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/9536.
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Poon, Chung Yan. "Nanoparticles assisted disease biomarkers sensing by microscopic and spectrometric methods." HKBU Institutional Repository, 2016. https://repository.hkbu.edu.hk/etd_oa/300.
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Nanoparticles has drawn attention in the past few decades for their large surface area-to-volume ratio, unique optical property, fast mass transportation and etc. They are widely applied in biomedical field as they are excellent signal transducers. Among all detection approaches, fluorescence detection, especially fluorescence resonance energy transfer (FRET), is one of the most popular approaches for their great convenience. In the first detection scheme, a well-designed nanoprobe was utilized for direct trypsin quantification. Herein, a graphene quantum dot (GQD) applied as a donor while a coumarin derivative, CMR2, acted as an acceptor. Moreover, bovine serum albumin (BSA), as a protein model, was not only considered as a linker for the donor-acceptor pair, but also a fluorescence enhancer of the quantum dots and CMR2. In the presence of trypsin, BSA was digested, thus, the FRET system was destroyed. Consequently, the emission peak of the donor was regenerated while the emission of the acceptor was reduced. The trypsin was quantified by a ratiometric measurement for two emission peaks. The detection limit of trypsin was 0.7 g/mL, which is 0.008-fold of the average trypsin level in acute pancreatitis patient's urine. Moreover, the approach was proved to be highly selective, suggesting a high potential for fast and low cost clinical screening. On the other hand, the optical property of nanoparticle has captured a great attention as its light scattering is highly sensitive to local dielectric environment. Two light scattering based detection approaches were demonstrated, including simple counting method and plasmonic scattering enhancement method. For simple counting method, antibody modified nanoparticle was applied to target antigen, providing a sensitive but direct approach for cancer biomarkers quantification. As a proof of concept, prostate-specific antigen (PSA) was chosen as an example. Antibody-conjugated silver nanoparticles (AgNP-Ab) were served as the probe to capture PSA, forming AgNP-Ab-PSA complexes. Since the number of complexes was corresponding to the amount of PSA, the antigen was quantified by counting the number of silver nanoparticle under dark field microscopy (DFM) coupled with charge-coupled device (CCD) camera. The detection limit of 9 pM of this assay was well below the PSA threshold of prostate cancer patient, suggested the feasibility of our assay in diagnosis application. Besides counting of nanoparticle, the scattering intensity of nanoparticle is also informative. In the third assay, immobilized capture antibody-conjugated gold nanoparticles (AuNP-Abcapture) were firstly utilized in capturing the target analyte, followed by the introduction of strong scattering detection antibody-conjugated silver nanoparticles (AgNP-Abdetection). In the presence of the corresponding antigen, the two metallic probes sandwiched the antigen and stayed at close proximity, resulting a strong plasmonic coupling effect of those nanoparticles. Consequently, the scattering intensity of gold nanoprobe was greatly enhanced. The antigen was quantified by measuring the intensity change before and after the immunoreaction. To demonstrate the high flexibility of this assay, several antigens including carcinoembryonic antigen (CEA), PSA and alpha fetoprotein (AFP) were quantified with this method, giving detection limit at 1.7 pM, 3.3 pM and 5.9 pM respectively, which were much lower than their cut-off levels of corresponding diseases. Detections of CEA, PSA and AFP in real sample were demonstrated, suggesting a high potential in clinical application.
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Barve, Aabha. "Development of an Optical Method for the Detection of Homocysteine as a Disease Biomarker Using Fluorescein-Aldehydes." PDXScholar, 2015. https://pdxscholar.library.pdx.edu/open_access_etds/2221.
Full textAbstract:
Homocysteine is a natural occurring aminothiol. It is an intermediate product in the metabolism of methionine. Methionine is an essential amino acid required for protein synthesis. Metabolic irregularities disrupt homocysteine levels in plasma. Elevated homocysteine levels are directly linked to folate and cobalamin (vitamin B12) deficiencies, and are an independent risk factor for cardiovascular diseases. High homocysteine levels have also been associated with Alzheimer's, osteoporosis, renal failure, cancer, birth defects and pregnancy complications. The association of elevated homocysteine levels with cardiovascular disease and other diseases has generated great interest in the detection of homocysteine.
An optical method for the detection of homocysteine has been developed using fluorescein mono- and dialdehydes. Selectivity for homocysteine was achieved based on the characteristic differences between 5- and 6-membered ring heterocyclic amines formed upon the reaction with fluorescein mono- and dialdehydes. 6-membered ring homocysteine-derived thiazinane-4-carboxylic acids were found to be more basic than 5-membered cysteine-derived thiazolidine-4-carboxylic acids. Fluorescence enhancement in response to homocysteine was thus attained by tuning pH and excitation wavelengths. Furthermore, the design and synthesis of a more sensitive fluorophore, fluorescein tri aldehyde has been accomplished based on the aforementioned findings to enable the detection of homocysteine at physiological levels. Calculations of Mulliken charges revealed that the formation of thiazinanes results in modulation of the electron density on the fluorophore leading to higher fluorescence.
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Roller, Benjamin Thomas. "A nanoencapsulated visible dye for intraoperative delineation of brain tumor margins." Thesis, Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42805.
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Brain and central nervous cancer presents a significant clinical burden, accounting for 2.4% of all cancer deaths. High grade glioma is particularly deadly, with 5 year survival times of 35% or less. Traditional treatment includes tumor resection followed by radiation therapy or chemotherapy. Aggressive resection is essential in order to prolong patient life. In fact, several studies have shown that life expectancy increases with increased extent of resection. Extent of resection is burdened by the fact that surgeons must be careful not to remove functional brain tissue.
Resection is incomplete more often than not due to lack of visual cues for the surgeon. He must rely on tactile sensation to distinguish tumor from healthy tissue. Methods such as intraoperative MRI and CT exist, but these require expensive equipment and special training that is not available in all surgical environments. Some laboratories have proposed small molecule dyes to solve this problem, but these are insufficient when used in an invasive tumor model. It was the goal of this research to provide an objective cue in the form of a nanoencapsulated visible dye without the need for additional equipment of changes to the surgery process itself other than injection of the dye.
We hypothesized that the nanocarrier would allow staining of the tumor through passive targeting by taking advantage of the enhanced permeability and retention effect. Once the nanocarriers have reached the desired target, they would not diffuse out into healthy tissue due to their large size compared to small molecule dyes, which readily diffuse out and stain healthy tissue.
To test this hypothesis, we prepared and characterized a liposomal nanocarrier encapsulating Evans blue dye. The nanocarrier was tested for safety in vitro and in vivo, then used to delineate tumor margins in an invasive rat glioma model in vivo. Microscopic analysis was then conducted to ensure only tumor tissue was stained by the nanocarrier. This thesis presents a successful method of tumor border delineation to provide surgeons with positive visual cues without the need for changes in surgical environment or techniques.
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Schönhals, Elske Maria [Verfasser], and Christiane [Akademischer Betreuer] Gebhardt. "Identifying novel diagnostic SNP markers for potato (Solanum tuberosum L.) tuber starch and yield by association mapping / Elske Maria Schönhals. Gutachter: Christiane Gebhardt." Köln : Universitäts- und Stadtbibliothek Köln, 2014. http://d-nb.info/1054420394/34.
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Garzorz-Stark, Natalie [Verfasser], Kilian G. [Akademischer Betreuer] Eyerich, Carsten [Gutachter] Schmidt-Weber, and Johannes [Gutachter] Ring. "Novel diagnostic tools and markers for inflammatory skin diseases / Natalie Verena Garzorz-Stark. Betreuer: Kilian G. Eyerich. Gutachter: Carsten Schmidt-Weber ; Johannes Ring." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1101695153/34.
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Garzorz-Stark, Natalie [Verfasser], Kilian G. Akademischer Betreuer] Eyerich, Carsten [Gutachter] Schmidt-Weber, and Johannes [Gutachter] [Ring. "Novel diagnostic tools and markers for inflammatory skin diseases / Natalie Verena Garzorz-Stark. Betreuer: Kilian G. Eyerich. Gutachter: Carsten Schmidt-Weber ; Johannes Ring." München : Universitätsbibliothek der TU München, 2016. http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20160512-1293741-1-6.
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Brennecke, Johannes. "Molecular diagnostics of the bacterial response to antibiotic therapy." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28843.
Full textAbstract:
Bacterial bloodstream infections (BSIs) are a major healthcare problem causing high mortality and economic cost. BSIs require an immediate initiation of antibiotic therapy as any delay is associated with a mortality increase. With the emergence of antimicrobial resistance, the choice of the appropriate antibiotic becomes increasingly difficult, thus creating an urgent need for new diagnostics, ideally to be done at the point of care. The current gold standard is blood culture with subsequent susceptibility testing although several molecular methods have recently entered the market. However, in many instances there is a discrepancy between the in-vitro data provided by the test and the outcome of antimicrobial therapy in-vivo because current diagnostics fail to take into account the impact of the environment in the patient such as the immune system, pharmacokinetics and pharmacodynamics or bacterial fitness. In this thesis, it was hypothesised that the measurement of the bacterial gene expression after the beginning of antibiotic therapy might be a more accurate indicator of the therapy outcome because it reflects the bacterial response under in-vivo conditions. In the first part of the thesis the expression of a set of pre-defined mRNA markers was investigated under various conditions. Experiments conducted with clinical E. coli isolates incubated in human whole blood revealed an excellent correlation between the gene expression, the treatment outcome, the antibiotic susceptibility and the genetic background for three different classes of antimicrobial drugs. The second part of the thesis describes the extraction of bacterial RNA from human whole blood specimen. The effect of different agents for the lysis of human blood cells and the impact of co-purified human RNA were analysed and a method for high yield extraction of undegraded bacterial RNA was established. The third part of the thesis investigates two methods for the sensitive measurement of the bacterial gene expression. This is relevant because the bacterial loads in BSI patients are extremely low. For genes with high gene expression levels both methods yielded reliable results but were unable to quantify the expression of the previously investigated mRNA markers due to their low copy numbers. Other approaches, especially those based on single cell measurements, might be able to overcome the problem in the future and should be explored in greater detail. Overall, the foundations for a future diagnostic test based on the measurement of the bacterial gene expression have been laid in this work. Future work should address the mRNA quantification and further evaluate the connection between gene expression and therapy outcome, e.g. in animal models. A future diagnostic test should also fulfil point-of-care requirements. This will include integrated sample preparation and quantification as well as a time-to-result in the range of a few minutes.