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Bax, Trent Malcolm. ""Internet addiction" in contemporary China: individual pathology or pathology of normalcy?" Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45815021.
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Stuart, Persoons Maria Cornelia Johanna. "Cytomegalovirus and vascular pathology." Maastricht : Maastricht : Universiteit Maastricht ; University Library, Maastricht University [Host], 1998. http://arno.unimaas.nl/show.cgi?fid=8496.
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Singh, Mark. "D6 in cutaneous pathology." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4636/.
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Chemokines are central to the migration of leukocytes around the body, during both inflammatory and homeostatic conditions. Chemokines mediate their effects by binding to chemokine receptors found on the migrating cell’s surface. Chemokine binding to the chemokine receptor results in signaling, which allows the cell to migrate towards the epicenter of chemokine production. In addition to ‘classical’ chemokine receptors which are involved in leukocyte migration, a discrete family of chemokine receptors exist which are considered to be ‘atypical’, as binding to their cognate ligands does not result in classical signaling as detected by calcium flux assays. One of these atypical chemokine receptors is the chemokinescavenging receptor D6, which can bind to and internalize at least 14 inflammatory CC chemokines in vitro. In addition, an analysis of D6 function in vivo has shown that D6 is important for the resolution of the inflammatory response. D6 KO mice treated with phorbol ester to the shaved dorsal skin developed an inflammatory skin pathology that resembled the human condition psoriasis in many respects. In contrast, WT mice treated with phorbol ester developed a very mild inflammatory response, which quickly resolved. These data suggested that a loss of D6 expression ‘primed’ the mouse to develop a psoriasisform pathology, requiring only minor irritation/trauma to develop the pathology. Similarly, histologically normal (uninvolved) skin from a psoriatic patient has a propensity to developing inflammatory lesions upon minor trauma, and could also be suggested to be ‘primed’ for lesion development. Collectively, these data led us to the following hypothesis, ‘A loss of D6 expression in uninvolved psoriatic skin is associated with the development of psoriatic lesions’. To test this hypothesis, D6 expression in clinical samples from psoriasis patients was analysed. Full thickness biopsies from psoriasis patients were taken from a histologically normal site (uninvolved psoriatic skin), in addition to an elliptical biopsy covering the skin directly adjacent to the psoriatic lesion (peri-lesional psoriatic skin), in addition to the lesion itself (lesional psoriatic skin). D6 expression was analysed in these biopsies by QPCR and immuno-staining. It was observed that D6 expression was significantly elevated in psoriatic skin compared to healthy control skin. In particular, in uninvolved psoriatic skin D6 was significantly increased compared to healthy control skin, or peri-lesional 3 psoriatic skin or lesional psoriatic skin. The increase in D6 expression in uninvolved psoriatic skin localised to the epidermis and the LVs. A significant increase in PBMC-D6 expression was also noted in psoriatic patients compared to healthy control PBMCs. These data suggest that at sites not directly involved in the pathology, D6 is elevated in an attempt to limit inflammation-induced damage. Further immuno-staining showed the inflammatory CC chemokines CCL2 and CCL5 (both high affinity D6-binding ligands) were detected in uninvolved psoriatic epidermis, but were apparently unable to mediate their function due to the lack of significant leukocyte infiltration into the tissue. These data gave rise to the idea that D6 in uninvolved psoriatic skin was significantly elevated in an attempt to block the release of inflammatory CC chemokines into the dermis, and subsequent migration of inflammatory leukocytes into the tissue, and the onset of lesion formation. Interestingly, D6 expression on the epidermis was strongest towards the lower layers of the epidermis, which suggested a role for epidermal- D6 in ‘barrier function’, preventing the uncontrolled release of inflammatory CC chemokines into the dermis. In addition to inflammatory CC chemokines, a variety of inflammatory cytokines have been previously detected in uninvolved psoriatic skin. Several of these cytokines were shown to increase D6 expression in vitro in this study. Therefore, it is possible the significant increase in D6 expression in uninvolved psoriatic skin is partly mediated by cytokine stimulation. A loss of D6 expression was observed when comparing uninvolved psoriatic skin and perilesional psoriatic skin. These data suggested that a loss of D6 expression occurs directly before the onset of lesion formation. It was also shown in this study that a loss of D6 expression could occur after micro-trauma to uninvolved psoriatic skin, which suggests a possible mechanism of how D6 expression is lost in peri-lesional psoriatic skin. To analyze whether the increase in D6 expression in psoriatic skin was disease specific, or a generic response to cutaneous inflammation, D6 expression in eczema skin was studied. It was found that D6 expression in eczema skin is elevated compared to healthy control skin, but less so compared to psoriatic skin. Collectively these data suggest that increased D6 expression may be a feature of inflammatory skin diseases.
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Dougherty, Janis Ruden Ronald A. "The pathology of addiction /." Online version of thesis, 2009. http://hdl.handle.net/1850/11763.
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Kubarych, Thomas. "Narcissism, personality and personality pathology." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/28380.
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This thesis used the methods of differential, cognitive and theoretical psychology to investigate the relationships between pathology narcissism and maladaptive personality and behaviour in general, and to attempt the beginnings of construct validation of M. Scott Peck's proposed 'evil' subtype of the DSM-IV Narcissistic Personality Disorder in particular. After a review of theoretical and empirical contributions to the psychology of narcissism, two empirical studies were conducted. In the first, joint self-report survey research using 338 subjects investigated the psychometric structure of narcissism, normal and abnormal personality, and constructs theoretically related to narcissism. Item-level exploratory principal components analysis and confirmatory factor analysis resulted in new subscales for the Narcissistic Personality Inventory. Scale-level exploratory principal components analysis of the combined questionnaires found evidence for a five-factor structure of abnormal personality. One of the five factors was related to narcissistic will to power and low agreeableness; another was related to narcissistic self-love and extraversion. Confirmatory factor analysis of a subset of the data found fair fit for the model. The second study investigated the relationships between narcissism, compartmentalisation, splitting, attribution style and response to disconfirming feedback. No evidence was found to support the hypothesis that narcissists have compartmentalised self-concepts. Moderate test-retest and alternative-form reliability data were obtained for the card-sort task used to assess compartmentalisation. No evidence was found that narcissists use splitting to translocate unwanted self-aspects onto others. Narcissistic dominance was associated with claiming personal credit for positive outcomes, while narcissistic vulnerability was associated with self-blame for negative events. Multiple regression with interaction terms indicated that the relationship between narcissism and response to disconfirming feedback is a function of other personality traits such as neuroticism, and may have opposite effects in different personalities and circumstances.
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Wu, Bing. "Pathology of rotator cuff tendonopathy." University of Western Australia. Centre for Orthopaedic Research, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0032.
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Tendonopathy, resulting in the loss of mechanical strength of a tendon, is a serious health problem affecting many people. The common symptom of tendonopathy is pain patients' daily activities, their participation in sport and exercise, and their ability to work are greatly compromised. Tendonopathy is considered to be a degenerative disorder caused by repetitive injury of the tendon. The most common tendon lesions are Achilles tendon rupture, lateral epicondylitis (tennis elbow) and rotator cuff tear. However, in spite of its clinical significance, our knowledge about tendonopathy is still very poor. This research was undertaken to investigate the pathology of tendonopathy. It is proposed that apoptosis, autophagic cell death and myofibroblasts play a role in the progression of tendonopathy in the rotator cuff; the aim of this study was therefore to determine if this was indeed the case. Tendon tissues were collected from 30 patients suffering from rotator cuff tears. A terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL assay) was performed to detect apoptosis. Autophagic cell death of the tenocytes in the ruptured rotator cuff tendon was detected by immunohistochemical staining for ubiquitin. Myofibroblasts were identified immunohistochemically with anti-alpha-smooth muscle actin (anti--SMA) antibody. The distribution of apoptosis, autophagic cell death and myofibroblasts, as well as the total cell density, were assessed respectively and were correlated using a four-category (i.e. graded from 0-3) degeneration of collagen matrix. 6 The results showed that apoptosis, autophagic cell death and myofibroblasts were observed in all of the samples. The highest percentage of autophagic cell death was evidenced in the Grade 2 matrix, while the percentage of apoptosis increased significantly with the increase of matrix degeneration from Grade 0-3; a similar pattern was found for myofibroblasts. The total cell numbers varied among the matrix grades, with the maximum and minimum percentages occurring in Grades 1 and 3, respectively. It can be concluded that apoptosis, autophagic cell death and myofibroblasts might be closely related to the damage of the extracellular matrix (ECM) structure.
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Goszer, Libby. "Adolescent suicidality and attachment pathology." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape15/PQDD_0027/NQ37706.pdf.
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Bruijn, Lambertus Matthias de. "Automatic classification of pathology reports." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1997. http://arno.unimaas.nl/show.cgi?fid=5936.
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Kee, Francis. "Molecular pathology of hepatocellular carcinoma." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/b40203785.
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Roe, Thomas John Kelsey. "TGFβ in protection and pathology." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406711.
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Lee, Martin A. "Imaging pathology in multiple sclerosis." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312191.
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Kee, Francis, and 紀思思. "Molecular pathology of hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40203785.
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Gillespie, Karen R. "Molecular pathology of mammary neoplasia." Thesis, Glasgow Caledonian University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243533.
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Clark, Thomas Justin. "Ambulatory diagnosis of endometrial pathology." Thesis, University of Birmingham, 2003. http://etheses.bham.ac.uk//id/eprint/214/.
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The aim of this thesis was to determine the diagnostic accuracy of outpatient endometrial evaluation using endometrial biopsy (EB), ultrasound scan (USS) and hysteroscopy (OPH) by conducting systematic quantitative reviews of the published literature. The optimum diagnostic strategy in terms of cost-effectiveness (cost per life year gained), was then established for the investigation of women with post-menopausal bleeding (PMB) for endometrial cancer, using the review data in a decision analysis designed to reflect current service provision. Meta-analyses showed that a positive test result following EB or OPH was more useful for predicting endometrial disease than USS, whereas a negative test result following USS was more useful for excluding endometrial disease than EB or OPH. The economic model included 12 diagnostic strategies and indicated that a strategy based on initial diagnosis with USS, using a 5mm double layer endometrial thickness cut-off, was the most cost-effective. Sensitivity analyses showed that initial investigation with EB or USS using a 4mm cut-off were also potentially cost-effective (incremental cost-effectiveness ratios under £30,000 per life year gained) at their most favorable estimates of diagnostic performance, in women under 65 years and at disease prevalence of 10% or more. The choice between initial testing with EB or USS will therefore depend upon patient age and preference, disease prevalence and the availability of high quality USS. In most circumstances women presenting for the first time with PMB should undergo initial evaluation with pelvic ultrasound using a threshold of 4mm or 5mm to define abnormal results.
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Verleyen, Wim. "Machine learning for systems pathology." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4512.
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Systems pathology attempts to introduce more holistic approaches towards pathology and attempts to integrate clinicopathological information with “-omics” technology. This doctorate researches two examples of a systems approach for pathology: (1) a personalized patient output prediction for ovarian cancer and (2) an analytical approach differentiates between individual and collective tumour invasion. During the personalized patient output prediction for ovarian cancer study, clinicopathological measurements and proteomic biomarkers are analysed with a set of newly engineered bioinformatic tools. These tools are based upon feature selection, survival analysis with Cox proportional hazards regression, and a novel Monte Carlo approach. Clinical and pathological data proves to have highly significant information content, as expected; however, molecular data has little information content alone, and is only significant when selected most-informative variables are placed in the context of the patient's clinical and pathological measures. Furthermore, classifiers based on support vector machines (SVMs) that predict one-year PFS and three-year OS with high accuracy, show how the addition of carefully selected molecular measures to clinical and pathological knowledge can enable personalized prognosis predictions. Finally, the high-performance of these classifiers are validated on an additional data set. A second study, an analytical approach differentiates between individual and collective tumour invasion, analyses a set of morphological measures. These morphological measurements are collected with a newly developed process using automated imaging analysis for data collection in combination with a Bayesian network analysis to probabilistically connect morphological variables with tumour invasion modes. Between an individual and collective invasion mode, cell-cell contact is the most discriminating morphological feature. Smaller invading groups were typified by smoother cellular surfaces than those invading collectively in larger groups. Interestingly, elongation was evident in all invading cell groups and was not a specific feature of single cell invasion as a surrogate of epithelialmesenchymal transition. In conclusion, the combination of automated imaging analysis and Bayesian network analysis provides an insight into morphological variables associated with transition of cancer cells between invasion modes. We show that only two morphologically distinct modes of invasion exist. The two studies performed in this thesis illustrate the potential of a systems approach for pathology and illustrate the need of quantitative approaches in order to reveal the system behind pathology.
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Petropoulos, Ioannis. "Corneal nerve pathology in diabetes." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/corneal-nerve-pathology-in-diabetes(9912e560-1032-45cd-8f0a-0477d6605a98).html.
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The accurate detection and quantification of human diabetic somatic polyneuropathy (DSPN) are important to define at risk patients, anticipate deterioration, and assess new therapies. Current methods lack sensitivity, require expert assessment and have major shortcomings when employed to define therapeutic efficacy. In recent years, in vivo corneal confocal microscopy (IVCCM) has shown potential as a surrogate endpoint for DSPN.This study aims to investigate fundamental aspects of IVCCM such as repeatability and optimal scanning methodology and establish changes in corneal nerve morphology in relation to the severity of DSPN and regeneration in response to normalisation of hyperglycaemia. Furthermore, it aims to provide a novel fully automated image analysis algorithm for the quantification of corneal nerve morphology and establish the diagnostic ability of CCM.IVCCM shows high repeatability which is enhanced with more experienced observers. Central corneal innervation is comparable to adjacent peripheral innervation in mild diabetic neuropathy but the central cornea may be more sensitive to change. Corneal nerve loss is symmetrical and progressive with increasing neuropathic severity and corneal nerves show significant regenerative capacity following rapid normalisation of glycaemic control after simultaneous pancreas and kidney transplantation. The novel image analysis algorithm strongly correlates with human expert annotation and therefore represents a rapid, objective and repeatable means of assessing corneal nerve morphology. Automated image quantification may replace human manual assessment with high diagnostic validity for DSPN.
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Pryor, Wendy. "Pathology, professionalism, portfolios and progress." Thesis, The University of Sydney, 2010. http://hdl.handle.net/2123/7296.
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Abstract Community-driven standards of professionalism must be addressed, worldwide, at all levels of medical education. The imperative to implement robust strategies to ensure that doctors embrace these standards to justify the autonomy afforded to the medical profession has been a key concern of specialist medical colleges in recent years. Pathologists face unique challenges. Rapid technological change and increasing commercialisation have distanced them further than ever before from patients and other clinicians, resulting in negative stereotypes that impede understanding of professional roles that may have adverse consequences for interdisciplinary communication and patient care. This study explores the socio-cultural and educational factors impacting on the development of professional identity in pathology specialist training in Australia and New Zealand, with the aim of recommending an educational model for the attainment of professionalism. Theories of social identity and education relating to self-regulated and situated learning informed the study and model. Textual data from interviews, surveys and discussions were captured over the course of a professional, college-led intervention that included a new curriculum addressing standards of professionalism in pathology, and an associated portfolio designed as a formative assessment tool. Based on these texts, hermeneutic phenomenological strategies were used to explore the experiences of pathology trainees, their supervisors, educators and clinicians. A pathologist’s professional identity is a self-constructed schema involving value orientations and commitment to goals that reflect beliefs about what it means to be a good pathologist. For many, these values do not correspond to the ideals of professionalism constructed by the community at large. In the face of many social and political pressures, pathologists have developed an identity that conforms to a stereotype in which technical knowledge and skills are strong values that may be detached from the need for competence in the broader, non-technical areas. This identity may be partly founded in career selection, but is perpetuated through interdisciplinary discourse, internalisation, role modelling, work practice and a curriculum and assessment structure that de-emphasises non-technical roles. Trainees are strongly influenced by the values displayed and feedback provided by supervisors who themselves may be subject to the influences of a negative culture. Conflicts between goals and values in technical and non-technical aspects of training can be de-motivating and may constrain the development of a reflective identity that embraces professionalism. Whilst competency-based frameworks such as CanMEDS have been invaluable in drawing attention to the place of non-technical competencies in formal curricula, they do not necessarily take account of the complex and powerful hidden curriculum that lies behind the formal curriculum and exists at the level of role-modelling, stereotyping, work practice and institutional policies. Developing a model of professionalism fit for the purpose of pathology training has involved deconstruction of the CanMEDS model and self-regulated learning processes to carefully examine their parts. The new model reassembles these elements in the situated learning environment and broader cultural and organisational structures applying to pathology. It emphasises alignment of goals, values and processes at all levels of the curriculum, both formal and hidden. The curriculum should integrate and operationalise technical and non-technical competencies with concretely-defined outcomes that are meaningful in the context of pathologists’ roles. Learning portfolios should be simple and flexible, requiring of more than tick-boxes to facilitate reflection. Formative assessment and guided self-assessment from supervisors are critical for the trainee to identify learning needs and to support development of capacity for self-regulation. Onerous formal assessments that devalue professionalism should be reviewed. The College and training institutions must demonstrate commitment to professional values through policy and provision of resources. The approach in this study, which strongly links professional identity development to the attainment of professionalism in medical specialty training, has implications for educators in understanding the many social and educational factors that must be considered in developing curricula for medical professionalism relevant to other disciplines and settings.
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Lam, Alfred. "Molecular Pathology of Oesophageal Tumours." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/365187.
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Oesophageal tumours are very common worldwide. This thesis aims to delineate the clinicopathological features and molecular biology of oesophageal tumours in Hong Kong Chinese. Over a 30-year study period, oesophageal tumours were obtained in the pathology files of the Queen Mary Hospital, Hong Kong. The tumours were prevalent in males and had a modal peak occurrence in the 7th decade. Patients often presented at an advanced stages. At autopsy, the prevalence of incidental oesophageal cancers and early-stage cancers were low. Many histological subtypes of oesophageal cancers were noted and were different from the Western populations. The most common histological subtype was squamous cell carcinoma, often moderately-differentiated. Besides the classical squamous cell carcinomas, variants like mucoepidermoid carcinoma/adenosquamous carcinoma, basaloid squamous carcinoma and sarcomatoid carcinoma were noted. The prognosis of squamous cell carcinoma with a mucin-secreting component (mucoepidermoid carcinoma and adenosquamous carcinoma) was not significantly different from that of patients with pure squamous cell carcinoma or adenocarcinoma. The glandular component of this group of tumours histochemically differentiated in the direction of oesophageal glands. Basaloid squamous cell carcinoma had distinctive clinicopathological features and its long-term prognosis was no worse than squamous cell carcinoma. Glomerulonephritis could be a para-neoplastic manifestation of basaloid squamous carcinoma of oesophagus. Sarcomatoid carcinomas were also found, and rarely double sarcomatoid carcinomas could be noted in the same patient. The other carcinomas noted in the oesophagus were small cell carcinoma and adenocarcinoma. Oesophageal small cell carcinoma was an aggressive tumour. The high proliferative index correlates with aggressive behaviour and high sensitivity to chemotherapy and radiotherapy. Oesophageal adenocarcinoma was uncommon in Hong Kong. On the other hand, intestinal metaplasia, known to be associated with adenocarcinoma, was prevalent at the gastroesophageal junction in Chinese patients undergoing endoscopy. The non-epithelial tumours in the oesophagus comprised melanoma and mesenchymal tumours. Melanoma of the oesophagus was an aggressive tumour. All patients with the tumour had short survival. Mesenchymal tumours consisted of leiomyoma, undifferentiated stromal tumour and autonomic nerve tumour. Intramural metastasis and multiple tumours were frequently observed in oesophageal cancer. This implies that wide excision with wide margins should be considered for local control of the disease. Pre-operative chemotherapy was commonly employed for the treatment of oesophageal cancer. High-grade nuclear pleomorphism in oesophageal carcinomas was correlated to chemo-responsiveness of the tumour. Four cancer cell lines were established from patients with oesophageal squamous cell carcinomas. These newly established cell lines serve as a useful model for studying the molecular pathogenesis, and testing new therapeutic reagents for oesophageal squamous cell carcinoma. Proliferative activity, as defined by the MIB-1 labelling index, was related to tumour differentiation in oesophageal squamous cell carcinoma. The activity was high in poorly-differentiated squamous cell carcinoma, basaloid squamous carcinoma and small cell carcinoma of the oesophagus. MIB-1 labelling index was found to be valuable as an independent prognostic marker in addition to tumour stage and size. Image analysis could assist h~ counting of the proliferative activity. Human papilloma virus was detected in a small proportion of oesophageal squamous cell carcinomas. There was no correlation between the prevalence of HPV and p53 mutation in these tumours. Epstein Barr virus was not detected in squamous cell carcinomas and mesenchymal tumours. The pattern of expression of cytokeratins in oesophageal carcinomas is different from that in normal oesophageal epithelia and varies with differentiation. Cancer-related genes studied in oesophageal cancers were p53, p21, c-erbB-2, PTEN and telomerase activity. p53 mutations were common in oesophageal squamous cell carcinomas and small cell carcinomas. The distribution of p53 mutations in oesophageal cancers suggests that the gene has complex exogenous and endogenous interactions. p53 mutations also appear to play a role in predicting the survival of patients with stage III oesophageal squamous cell carcinomas. The pattern of p21 and p53 expression predicts an aggressive clinical course of oesophageal squamous cell carcinomas. c-erbB-2 (Her-2) oncoprotein was expressed in a portion of oesophageal squamous cell carcinomas and precursor lesions. This suggests that c-erbB-2 activation plays a certain role, mostly probably during the early stages, in carcinogenesis. PTEN/MMAC1 mutations were not detected in oesophageal squamous cell carcinoma. Telomerase activation was common in small cell carcinoma and basaloid squamous cell carcinoma of the oesophagus. The level of telomerase activity had a prognostic role in oesophageal cancer, suggesting a possible therapeutic role of anti-telomerase treatment for this aggressive tumour. Multiple genetic mutations in oesophageal squamous cell carcinomas could be mapped by gene arrays and comparative genomic hybridization. These different newly discovered genetic alterations were analysed both in laboratory and in relationship with the clinical prognosis. Multiple mutations could be detected in dysplasia as well as carcinoma. The techniques identify the roles of some new cancer-related genes like Fra-1, Neogenin, Id-i, CDC2SB and MET in oesophageal squamous cell carcinomas. Chromosomal aberrations were common in oesophageal squamous cell carcinoma. Gain in l2p was found to be indicative of aggressive behaviour and poor prognosis. In summary, identification of the different histological types of oesophageal tumours and their characteristic molecular profiles is essential for both in-depth research and clinical management.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Medicine<br>Full Text
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Karthikeyan, Shanmugam. "Management of rotator cuff pathology." Thesis, University of Warwick, 2016. http://wrap.warwick.ac.uk/89698/.
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The rotator cuff refers to a group of four muscles, which arise from the scapula and insert into the head of humerus forming a cuff around the shoulder joint. They contribute to shoulder movements and provide dynamic stability at the shoulder joint. Pathology of the rotator cuff is the commonest cause for shoulder pain and its severity can vary from subacromial impingement to full thickness tears. NSAIDs and corticosteroids are two of the commonest group of drugs used in treating subacromial impingement syndrome but with conflicting evidence about their relative efficacy and risk of complications. I explored the efficacy of a subacromial NSAID (Tenoxicam) injection in a double blind randomised controlled trial but found it to be less effective compared to a subacromial corticosteroid injection as measured by functional shoulder scores at six weeks. During the trial, I recognised that there were unresolved challenges in using Ultrasonography to diagnose rotator cuff pathology especially in differentiating between partial and full thickness tears. In this thesis, I have presented the normal ultrasound dimensions of the rotator cuff in asymptomatic young adults under the age of forty years, which has not been documented before. The study showed that the measurements are significantly different between men and women but not between dominant and non-dominant arms, suggesting that in every individual the contralateral shoulder can be used as a control, especially where the diagnosis is uncertain. Exploration of factors associated with the pathogenesis of rotator cuff tendinopathy showed that a critical zone of hypoperfusion in the supraspinatus tendon could be a factor but the evidence for it has been contradictory. An observational study presented in this thesis describes the microvascular blood flow in normal and a spectrum of pathological rotator cuffs (subacromial impingement, partial thickness tears and full thickness tears) using Laser Doppler Flowmetry in patients undergoing arthroscopic shoulder surgery. The study showed variations in microvascular blood flow in normal rotator cuffs but no evidence of a “critical zone”. Blood flow was found to be significantly lower in all groups of pathological rotator cuffs.
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Willemse, Feike. "A colored view on quantitative pathology aspects of true color image analysis in routine pathology /." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1996. http://irs.ub.rug.nl/ppn/143919504.
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Harris, Christopher. "Exploring data sharing in pathology through investing the concept of a National Pathology Handbook system /." Leeds : University of Leeds, School of Computer Studies, 2008. http://www.comp.leeds.ac.uk/fyproj/reports/0708/Harris.pdf.
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Brennan, Edwin A. "The Relationship between Combat Experience, Veteran Pathology and the Pathology of Their Intimate Partners| What Factors Predict the Pathology of Veterans and Their Intimate Partners." Thesis, Andrews University, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=13861186.
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<p> Problem Statement: Military members and their family members who are part of the Global War on Terrorism have experienced deployments and war for over sixteen years and with the resulting toll on both the veteran and their intimate partner. As a result, higher levels of pathology, such as PTSD, Anxiety, and Depression have been experienced by this population. While research has studied the effect of combat on military members, very little research has addressed the effects on family members. Further, no research that has been found by this researcher, has addressed the concept of resonating of pathology between the combat veteran and their intimate partner. Resonating of Pathology, or resonating pathology, for the purposes of this study, is the combat veteran and the intimate partner demonstrating the same pathology at similar levels. </p><p> The Veteran’s Healthcare Services have begun to treat couples together and may have also witnessed this phenomenon. Understanding the relationship between combat, veteran pathology, and intimate partner pathology will have implications for practitioners and researchers. Understanding the factors that related to this phenomenon will have implications for both clinicians and researchers. </p><p> Methods: Veterans and their intimate partners from across the United States, (<i>N</i> = 398), were asked to complete a survey through the internet. The couples were asked to complete the survey separately, however, within the same session so that their results could be tied together. The veterans were asked to complete the Combat Exposure Scale (CES), the PTSD Check List for the DSM 5 (PCL–5), the Patient Health Questionnaire 9 (PHQ–9), and the Generalized Anxiety Disorder 7 (GAD–7). The intimate partners were asked to complete the PCL–5, the PHQ–9, and the GAD–7. </p><p> Results: Results suggest that there was a moderate relationship between combat experience and pathology for combat veterans. While other factors were examined to determine what was included to predict pathology within the veteran, combat experience seemed to be the primary factor for predicting PTSD, Anxiety, and Depression in the combat veteran. </p><p> Results also suggested that there was a relationship between the pathology of combat veterans and the pathology their intimate partners, as measured in this research. Not only was there resonating, or resonating of pathology, within the couples, but this tended to occur within categories of pathology such as moderate and severe levels of Anxiety and Depression. While multiple factors such as frequency of communications, number of children, and types of communication were examined, combat experiences tended to be the primary factor for predicting pathology in both the veteran and the intimate partner. </p><p> Conclusion: Combat veterans and their intimate partners appear to be experiencing the phenomenon of resonating, or resonating, of pathology. Couple-analysis demonstrates that this phenomenon is being experienced as a couple and suggests that could have implications for future research and clinical practice. Demographic factors did not seem to influence the pathology for either the veteran or their partner. Combat experience does, however, seem to be a predictor for pathology in not only the veteran but also for the intimate partner as well. </p><p>
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Luther, Jill K. Cook James L. "Comprehensive characterization of canine meniscal pathology." Diss., Columbia, Mo. : University of Missouri-Columbia, 2010. http://hdl.handle.net/10355/.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on July 13, 2010). Thesis advisor: James L. Cook "May 2010" Includes bibliographical references.
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Avenant, Carina. "Thinking style preferences in communication pathology." Diss., Pretoria : [s.n.], 2001. http://upetd.up.ac.za/thesis/available/etd-03192007-100706.
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Schieder, Christian, and Anja Lorenz. "Towards a pathology of social media." Universitätsbibliothek Chemnitz, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-82030.
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The full transformational effects of Social Media have yet to be understood. Alongside its heavily discussed benefits, a number of potentially harmful effects have become apparent lately. Phenomena such as still increasing information overload, cyber-bullying, or loss of identity have been described in recent research literature from various domains. By means of a literature review our paper aims at reviewing, cataloguing and classifying these psychological and social disorders that have been reported to be related to Social Media engagement. We distinguish between active participation in and mere exposure to Social Media. Using a psychopathological classification scheme, we structure the identified symptoms and syndromes, providing a common language and taxonomy with which the identified disorders can be described and classified accurately. Thus, we are laying out a foundation necessary for the research into and the understanding of the aetiology and eventually the means for the prevention of the negative effects of Social Media usage within individuals in information societies.
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Faraj, Lana Akram. "Corneal neovascularisation : evaluation, pathology and treatment." Thesis, University of Nottingham, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718466.
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The cornea is the clear window of the eye and its main refractive media. Corneal avascularity is essential to maintain this function, and this is evolutionarily highly conserved. Corneal vascularisation can result from different types of insults, causing reduced vision and posing a threat to the survival of corneal grafts. We prospectively reviewed 165 patients with corneal vascularisation establishing a reproducible classification of corneal vessels. We classified corneal vessels in to young active, old active, mature, partially regressed and regressed vessels. Patterns of vascularisations differed with aetiology as viral keratitis inducing more severe vascularisation most association with lipid deposition in the cornea. Acanthamoeba keratitis however induced less vascularisation despite severe corneal inflammation. Fine needle diathermy was found to be safe and effective method of treating corneal vascularisation and its effectiveness could be improved further by appropriate selection. Subconjunctival injection of Ranibizumab, which is a fragment of a monoclonal antibody (Fab) created form the same mouse antibody as bevacizumab, was effective in regressing corneal vascularisation initially; this was not maintained with a single dose in the presence of active inciting inflammatory process in the cornea. This reinforces the dictum that as long as the stimulus for vascularisation is not addressed measures to reduce vascularisation have only a temporary effect. Fine needle diathermy and anti angiogenic treatments can form components of an overall strategy to mitigate risk of rejection or in dealing with refractory episodes of rejection in the cornea. Isolation of conjunctival vascular endothelial cells proved very challenging. The widely used human umbilical cord endothelial cells also proved great variation in their cell surface marker expression and phenotypic characteristics across different passages. This highlighted the wide variation to be expected and the need for specificity in the targeted population of cells used in designing angiogenesis experiments. With the use of human umbilical cord endothelial cells we demonstrated the in-vitro anti angiogenic effect of the amniotic membrane. The amniotic membrane significantly reduced endothelial cell proliferation, migration and tube formation.
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Song, Jina. "Coagulation factor V : pathology and biochemistry." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/5595.
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ROLE OF GLU96, ASP1O2 AND ASP111 IN FACTOR V
Coagulation factor V activity is unmasked by thrombin-mediated excision
of the central B domain resulting in a noncovalent heterodimer, factor Va. To
understand the role of individual amino acids in maintaining the Ca²⁺-depenadent
subunit interaction, G1u96 (E96A), Asp1O2 (D1O2A) or Asp111 (D111A) were
mutated because of known effects on chelator sensitivity. The primary clotting
activity of each mutant was reduced by “40%. Demonstrating at least two
distinct inhibition mechanisms, only D111A was further inhibited by thrombin
pre-treatment consistent with spontaneous subunit dissociation and severely
inhibited Ca²⁺ binding. The parental factor V construct used here has a truncated
B domain that does not require excision for activity. Therefore inhibition of
D111A by thrombin-cleavage reveals a new B domain function that maintains
factor V in a factor Va-like configuration independent of Ca²⁺ binding. In addition
to Ca²⁺, factor V binds Cu²⁺, but with unknown function. Unexpectedly, D111A
also lost detectable Cu²⁺. Finding that a single amino acid substitution
simultaneously alters Ca²⁺ and Cu²⁺ suggests an interdependent metal ion
binding site. Unlike D111A, the thrombin-mediated factor Va derived from E96A
and D1O2A was stable, had only moderately faster subunit dissociation upon
chelation and had normal metal ion binding. Thus, the current study defines the
highly conserved acidic segment spanning G1u96-Asp112 in factor V as
multifunctional. Of the three amino acids I evaluated, Asp111 is essential and
likely functions through direct and indirect metal ion interactions. G1u96 and
Asp102 individually influence factor V/Va function by more subtle effects at the
metal ion-dependent subunit interface.
FACTOR V-DEFICIENT PATIENT
A factor V-deficient patient due to Y1702C mutation has been studied. The
patient however did not suffer from severe bleeding despite of undetectable
levels of plasma and platelet factor V. A close inspection of the patient’s blood
coagulation cascade showed that the lack of available factor V was compensated
by other factors that influence the intrinsic pathway. This finding suggests that
the commonly observed phenotypic differences shown among factor V-deficient
patients with the same genotypes may be due to existing hypercoagulant factors
that influence the outcome of the disease.
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Horak, E. "Pathology of tumour cell host interactions." Thesis, University of Oxford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379940.
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Boehm, Ernest Andrew. "Vascular smooth muscle energetics and pathology." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308677.
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Benson, Richard. "The pathology of rotator cuff failure." Thesis, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589763.
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Abstract The thesis has two aims. Firstly, to gain a greater understanding of the intrinsic mechanisms involved in rotator cuff pathology and its progression. Secondly, to investigate how outcome after operative intervention may be influenced by the macroscopic and microscopic appearance of the rotator cuff. It has been hypothesis that rotator cuff disease is part of a continuum from impingement, through partial thickness tear and leading to massive rotator cuff tears. The thesis uses this hypothesis to create a model of the stages of rotator cuff failure using the macroscopic appearance of the rotator cuff. Biopsies were taken from in vivo human rotator cuffs at different stages of the model, and investigated for evidence of a pathological failure cascade. Initially hypoxia and apoptosis were investigated as both had been previously identified as important factors in rotator cuff disease aetiology. Biopsies were analysed using immunhistochemical techniques: TUNEL (a marker for apoptosis) and BNIP-3 (a marker for hypoxia). Both demonstrated increased expression with worsening rotator cuff disease. Therefore, apoptosis appears to increase as the disease progresses and a hypoxic mechanism is implicated. A second study analysed the healing response of the rotator cuff using markers of tendon healing, VEGF( a marker of vascular remodelling) and TSG-6 (a marker of inflammation). They showed evidence of a reduced healing response in large and massive tear groups compared with controls and tendon in earlier disease. In a third clinical study, patients without full thickness tears undergoing subacromial decompression were followed up with Oxford Shoulder Score and the predictive value of the macroscopic and microscopic appearances of the bursa, coracoacromial arch and rotator cuff tendons were assessed. Biopsy samples of bursa and coracoacromial ligament were analysed using basic histological and immunohistochemical techniques. All patients showed statistically significant improvement in OSS but patients with partial tears and hooked acromion did significantly worse. The microscopic appearance did not predict outcome.
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Manson, Stephanie C. "The invisible pathology of multiple sclerosis." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509990.
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Robinson, Kate Louise. "Nutritional pathology during experimental Schistosomiasis mansoni." Thesis, University of Glasgow, 1996. http://theses.gla.ac.uk/4811/.
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Murdoch, Iain. "Presynaptic pathology after acute brain injury." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340811.
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Thornton, Christopher Rowland. "Physiological pathology of clubroot (Plasmodiophora brassicae)." Thesis, University of Sheffield, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272496.
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Ashton, Gabrielle Halusia Shaw. "The molecular pathology of Kindler syndrome." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427700.
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Knolle, Martin Daniel. "Characterisation of proteinases in pulmonary pathology." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608015.
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Friedrich-Nel, Hesta. "Assessment innovation in Radiographic Pathology II." Journal for New Generation Sciences, Vol 3, Issue 2: Central University of Technology, Free State, Bloemfontein, 2005. http://hdl.handle.net/11462/478.
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Published Article<br>Innovation in teaching and learning compel facilitators to explore creative possibilities in teaching and learning. Consequently innovative assessment has replaced traditional assessment methods in the Radiographic Pathology II module. The use of an appropriate variety of assessment methods or approaches is crucial to enhance and support learning and measure performance. Thus assessment has to change from knowledge acquisition and factual recall to assess more embracing and critical learning outcomes such as problem-solving, communication, attitudes, critical thinking, professionalism and ethics. Moreover, assessment has to impact positively on learning, promote deep learning and correspond with the learning outcomes of the module. Addressing these demands in assessment, this paper presents practical examples of assessment innovation during 2004 in the Radiographic Pathology II module.
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Jones, Steve. "Eating pathology : beyond traditional psychotherapeutic approaches." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/18168/.
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First, a systematic literature review assessed the efficacy of third-wave interventions to treat individuals who have been diagnosed with an eating disorder. Twenty-three studies which cover five forms of intervention were considered - Acceptance and Commitment Therapy, Compassion Focussed Therapy, Dialectical Behaviour Therapy, Mindfulness-Based Interventions, and Schema Therapy. At present, this field of research is in its infancy, as is reflected in the quantity and quality of the studies available for this review. Dialectical Behaviour Therapy appears to be the most robust third-wave intervention in this field. A lack of meaningful comparisons means that further research is required to compare third-wave interventions with other evidenced-based psychological interventions. Second, the empirical report developed an eating-pathology-specific measure of interpersonal problems, intended to have greater clinical utility for eating pathology than a generic interpersonal problems measure. A large community sample of participants completed online psychometric measures including a novel eating-specific interpersonal problems questionnaire - the Interpersonal Problems in Eating Disorders scale (IR-ED). Participants also completed a generic measure of interpersonal problems and measures of depression, anxiety, social anxiety and eating pathology. The IR-ED has strong psychometric validity. In comparison to the generic measure of interpersonal problems, the final 15-item version of the IR-ED shows similar associations with depression and anxiety and a superior ability to detect and predict eating pathology. The two components of this thesis expand upon traditional approaches of psychological intervention for people who experience eating pathology by considering the context within which individuals cognitions occur.
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Roomi, Md Waheed. "Molecular pathology of rat hepatic nodules." Thesis, University of Surrey, 1987. http://epubs.surrey.ac.uk/847966/.
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The aim of the present study was to characterize the phenomenon of resistance in putative preneoplastic hepatocyte nodules. These hyperplastic nodules are generated during the development of liver cancer in response to chemical carcinogens, and comprise a population of cells from which hepatocellular carcinoma can develop. As hepatocyte nodules grow in an environment that is otherwise toxic they possess a resistant phenotype. To understand this resistance phenomenon at the biochemical level, several phase I and II drug-metabolizing enzymes in the nodules were examined. Initial experiments were carried out in rats with nodules produced by initiation with diethylnitrosamine, followed by selection with 2-acetylaminofluorene and carbon tetrachloride. These nodules showed a large decrease in phase I enzymes and enzymic activities, such as the cytochromes P-450, cytochrome b[5], total microsomal haem, aminopyrine N-demethylase and ethoxyresorufin 0-deethylase, but glutathione and the phase II enzymes, namely, glutathione S-transferase, UDP-glucuronyl transferase, DT-diaphorase and gamma-glutamyltransferase were significantly increased. The pattern of changes of these drug-metabolizing enzymes of the nodules was similar when the nodules were produced by different initiation-promotion treatments, including diethylnitrosamine plus a choline/methionine-deficient diet, 2-acetamidofluorene plus phenobarbi-tone, or diethylnitrosamine plus orotic acid. In addition, the resistance phenotype was maintained when these nodules were transferred into the spleen of a rat not exposed to chemical carcinogens, and allowed to grow for several months, thus indicating that the newly acquired biochemical pattern in the nodules had become constitutive. Unlike the hepatic nodules generated by previous initiation-pro-motion treatments, nodules generated by the hypolipidemic agent, ciprofibrate, exhibited only a decrease in phase I components of the drug-metabolizing enzymes, with no increase in the phase II components. Similarly, hyperplastic nodules in liver mouse showed a decrease in phase I components, but no increase in phase II components. In addition to cytochrome P-450 and cytochrome b5, the total haem and two other haem containing proteins, namely, catalase and tryptophan 2,3-dioxygenase were also decreased in the nodules. A deficiency in hepatic iron, and a decrease in the activity of delta-ALA-synthetase, the first rate limiting enzyme in haem synthesis, were also apparent. Characterization of the phase II components revealed the presence of a new glutathione-S-transferase polypeptide, which has been shown to be identical to a placental form of the transferase. This polypeptide, although present to a minimal extent, or absent, in normal rat liver, is present in normal male mouse liver. Administration of lead nitrate to rats induces a biochemical pattern in the liver similar to that seen in the hepatocyte nodules, including a decrease of phase I components and an increase in phase II components of the drug-metabolizing enzymes, and the induction of the novel glutathione S-transferase. Further studies with lead nitrate may yield new insights into the mechanisms of production of the biochemical changes induced in the nodules, as this agent generates the same changes within 30 hours. Furthermore, the lead nitrate-induced changes in phase I and phase II enzymes are reversible, while the changes seen in the hyperplastic nodules are not. Thus this study has characterized one pattern of biochemical changes exhibited by the resistant phenotype of hyperplastic hepatic nodules, and a model system has been developed which induces the same changes, more rapidly and in a reversible fashion. One of the important questions yet to be answered however is the biological significance of the resistant phenotype in cancer development. Is the acquisition of resistance only important in expanding the initiated cell population to generate nodules or does it also have a more direct role in the progression of nodules to cancer? This is highly relevant to the clarification of the carcinogenic process in the liver and perhaps in other organs as well.
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Ropelewski, Philip Edward. "Light-Independent Pathology of Rhodopsin Mislocalization." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1586965687533716.
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Edler, Melissa K. "Alzheimer's disease pathology in aged chimpanzees." Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461401487.
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Dinkelacker, Vera. "Network pathology in temporal lobe epilepsy." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066156/document.
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Notre vision de l'épilepsie du lobe temporal avec sclérose hippocampique a beaucoup évolué grâce aux techniques de neuroimagerie multimodale. Initialement perçue comme maladie restreinte à la lésion, à savoir la sclérose hippocampique (SH), elle est aujourd'hui considérée comme un modèle de pathologie en réseau. Cette thèse a pour but d'approfondir les caractéristiques du réseau sous tendant cette épilepsie.Nous avons pour cela recueilli des données de connectivité structurelle, d'EEG et de données cognitives chez une cohorte de 44 patient avec SH unilatérale (22 droite, 22 gauche) et chez 28 sujets contrôle. Nous avons déterminé les régions d'intérêt corticales et le volume hippocampique avec Freesurfer et la connectivité structurelle (locale ou en réseau) avec MRtrix ou FSL.Trois principaux résultats émergent de ces études :1. La connectivité globale montre un pattern de déconnexion très marqué de l'hémisphère gauche en cas de SH gauche. La SH semble donc s'accompagner d'une atteinte de réseau plus importante lorsqu'elle se situe dans l'hémisphère dominant pour le langage.2. La connectivité hippocampo-thalamique est augmentée du côté de la SH. Cette augmentation semble dysfonctionnelle, car corrélée avec une baisse de fonctions cognitives exécutives. 3.L'EEG de ces patients révèle des anomalies interictales ipsi-latérales qui sont corrélées avec une diminution de fonctions cognitives exécutives. Nos données confirment ainsi le concept de l'épilepsie du lobe temporal en tant que pathologie de réseau. L'atteinte structurelle, mais également cognitive s'étend sur des régions à distance de l'hippocampe et affecte notamment les réseaux de langage de l'hémisphère dominant<br>Our vision of temporal lobe epilepsy (TLE) with hippocampal sclerosis has much evolved in recent years. Initially regarded as a disease centered on a single lesion, it is now perceived as a genuine network disease, which we intended to explore with a multimodal approach. We examined structural connectivity, fMRI, EEG and cognitive dysfunction in a cohort of 44 patients with unilateral hippocampal sclerosis (HS, 22 with right, 22 with left HS) and 28 healthy age and gender matched control participants. Cortical regions of interest and hippocampal volumes were determined with Freesurfer, structural connectivity with MRtrix (pairwise disconnections and component effects with Network Based Statistics), or for hippocampal-thalamic connections with FSL. We found a pronounced pattern of disconnections most notably in the left hemisphere of patients with left TLE. Network Based Statistics showed large bi hemispheric clusters lateralized to the diseased side in both left and right temporal lobe epilepsy. We suggest that hippocampal sclerosis is associated with widespread disconnections if situated in the dominant hemisphere. We then determined streamline connections between hippocampus and thalamus and found an increase in connections in relation to the HS. This increase was seemingly dysfunctional as the number of hippocampal-thalamic connections was negatively correlated with performance in executive tasks. EEG analysis revealed predominantly ipsilateral epileptic discharge. The number of sharp waves was highly correlated with a number of executive functions depending on the frontal lobe, hence at distance of the HS. Our data thus confirms the concept of temporal lobe epilepsy as a network disease that finds its expression both in widespread, though lateralized alterations of structural connectivity and in neuropsychological dysfunction way beyond the hippocampus
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Laffe, Stacia A. "Eating pathology in relationship to hopelessness." Online version, 2001. http://www.uwstout.edu/lib/thesis/2001/2001laffes.pdf.
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Cherry, Shirley J. "Radiographic Pathology of the Skeletal System." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/2481.
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LIONETTI, MARIA CHIARA. "LAMINOPATHIES: PATHOLOGY, CELL MECHANICS ANDENVIRONMENTAL INDUCTION." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/620532.
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La lamina nucleare (NL) è un reticolo di proteine fibrillari che riveste la superficie interna della
membrana nucleare. Essa è principalmente composta da filamenti intermedi di tipo V , chiamati
lamìne, e proteine ausiliari ad esse associate (lamin-associated proteins, LAPs). Nei mammiferi le
lamìne sono codificate da tre geni : LMNA, che codifica per la lamìna A e lamìna C (lamìne di tipo
A), LMNB1 e LMNB2 che codificano rispettivamente per la lamìna B1 e B2 (lamìne di tipo B).
Lamìne e LAPs si associano a formare una matrice tridimensionale densa e dinamica che stabilisce
numerose interazioni, sia stabili che transitorie, con diverse classi di molecole biologiche: DNA,
fattori di trascrizione, proteine strutturali. Tutte queste interazioni sono essenziali per fornire
stabilità strutturale e preservare l’integrità nucleare, per collegare fisicamente e funzionalmente la
lamina nucleare al citoscheletro e per organizzare la cromatina. In questo modo, oltre a svolgere un
ruolo strutturale fondamentale, la lamina nucleare risulta ricoprire ruoli chiave anche nei processi di
meccanotrasduzione del segnale e nella regolazione dell’espressione genica ed epigenetica.
Mutazioni a carico dei geni che codificano per le lamìne nucleari sono associate ad un'ampia ed
etogenea classe di patologie note come laminopatie. Tra queste, una delle più controverse ed
interessanti è la Hutchison-Gillford Progeria Syndrome (HGPS), una malattia genetica rara dovuta a
una mutazione puntiforme nel gene LMNA. Tale mutazione risulta nella produzione di una versione
tronca della lamìna A, mancante di 50 amminoacidi, conosciuta come Progerina. HGPS è
principalmente caratterizzata da alterazioni morfologiche del nucleo e invecchiamento precoce. I
soggetti affetti da Progeria, infatti, fin dai primi anni di vita sviluppano condizioni patologiche
tipiche dell’età senile quali cataratta, diabete e l'osteoporosi pur preservando le normali funzioni
congnitive. Questi pazienti muoiono tipicamente per complicanze cardiovascolari intorno ai 14 anni di
età, in media.
Considerando la sindrome di Hutchinson-Guilford come un esempio estremo di ciò che alterazioni
della lamina nucleare comportano, durante il mio dottorato di ricerca ho investigato diversi aspetti
riguardanti la biologia della lamina nucleare con particolare interesse all'impatto che perturbazioni
strutturali della lamina nucleare possono avere sulle normali funzioni cellulari, la meccanica
cellulare, la regolazione dell'espressione genica e l’ interconnessione esistente tra integrità della
lamina nucleare, processo di invecchiamento e stress ossidativo.
Per ottenere una visione d’insieme del contributo della lamina nucleare sia in condizioni fisiologiche
che patologiche, sono state adottate strategie di ricerca basate su approcci interdisciplinari e
integrativi in grado di tenere conto degli aspetti strutturali, meccanici e molecolari.
Per fa questo, in prima instanza sono state effetuate delle analisi bionformatiche: tutti i dati di
trascrittomica relativi a pazienti HGPS, presenti in database pubblici e in letteratura, sono stati
raccolti e analizzati rispetto a dati equivalenti ottenuti da controlli sani.
Tale analisi ha permesso di delineare profilo di espressione genica tipico di pazienti HGPS e di
individuare i pathways deregolati in presenza della patologia.
È stato inoltre studiato l’impatto che alterazioni della lamina nucleare hanno sulle connessioni
fisiche e funzionali che questa stabilisce sia con elementi nucleari ed extra-nucleari, in un modello
cellulare in cui è possibile indurre sperimentalmente, in modo controllato, l’espressione della forma
mutata di Lamìn A responsabile dell’ HGPS. Tale modello cellulare ricapitola fedelmente il peculiare
fenotipo cellulare dei pazienti risultando essere una valida alternativa all’utilizzo di linee primarie
derivanti dai pazienti.
Infine, l'interdipendenza tra stress ossidativo, invecchiamento e lamìne nucleari è stata investigata in
un nuovo modello cellulare di stress ossidativo sviluppato nel nostro laboratorio, efficiente nel
ricapitolare il processo di invecchiamento, in vitro.<br>ABSTRACT
The nuclear lamina (NL) is a fibrillary protein network lining the inner surface of the nuclear
envelope. It is mainly composed by type V intermediate filaments called lamins and lamin-associated
proteins. Three lamin genes are present in Mammals: LMNA, which encodes lamin A and lamin C (Atype
lamins), as well as, LMNB1 and LMNB2 that encode lamin B1 and B2 (B-type lamins)
respectively. Lamins and LAPs associate to form a dense and dynamic three-dimensional matrix that
establishes a huge number of stable and transient interactions with different classes of molecules:
DNA, transcription factors, nuclear pore complexes and structural proteins of the cytoskeleton. All of
these interactions are essential to provide nuclear structural stability and integrity, to physically and
functionally link nuclear lamina to the cytoskeleton and to organizes chromatin. Thus NL, in
addition to play a fundamental structural role, it is also a key player in cellular mechanotransduction
processes and gene expression and epigenetic regulation.
Mutations in genes encoding for lamins are associated with a wide a range of diseases, named
laminopathies. Among these, the most interesting one is Hutchison-Gilford Progeria Syndrome
(HGPS), a rare fatal genetic disorder due to do a point mutation in LMNA. This mutation results in
the production of a truncated version of lamina A, lacking 50 amino acids, known as Progerin. HGPS
is mainly characterized by morphological changes in the nucleus and premature aging. HGPS patients
indeed, from their first years of life, develop pathological conditions typical of the elderly such as
cataracts, diabetes and osteoporosis while preserving the normal cognitive functions. These patients
typically die from cardiovascular complications around 14 years of age, on average.
Considering Hutchinson-Guilford Progeria Syndrome as an extreme example of what nuclear lamina
aberration entails, during my PhD I investigated many aspects of nuclear lamina biology with
particular regard to the impact of nuclear lamina structural perturbations on cell functions,
mechanics, gene expression regulation and the interconnection existing between nuclear lamina
integrity, ageing process and oxidative stress.
Indeed, to gain a comprehensive picture of nuclear lamina biology in health and disease, it has been
adopted interdisciplinary and integrative research strategies able to take into account structural,
mechanical and molecular aspects.
Bioinformatics study has been performed: public available transcriptomic data of HGPS patients
have been analysed with respect of those of healthy matched controls. This analysis allowed to
delineate the typical global gene expression profile of HGPS patients and to identify all the
deregulated pathways in the presence of the pathology.
Moreover, impacts of lamina alterations on its physical and functional connections with extra-nuclear
and nuclear elements have been studied in an inducible expression cellular model of the mutated form
of Lamin A responsible for HGPS. This cellular model faithfully recapitulates the peculiar cellular
phenotype of the HGPS patients resulting to be a valid alternative to primary cell lines deriving from
the patients.Finally, the interdependence between oxidative stress, ageing and lamins has been investigated in a
novel oxidative stress cellular model developed in our laboratory, that is also efficient in
recapitulating typical ageing profile.
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Glatzel, Markus. "Epidemiology and molecular pathology of prion diseases /." Zürich, 2003. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253382.
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Thorpe, Callum. "Immunity and pathology to Chlamydia pneumoniae infection." Thesis, Imperial College London, 2006. http://hdl.handle.net/10044/1/11264.
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Saglani, Sejal. "The pathology of infant and preschool wheeze." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430129.
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Bridges, Leslie Roy. "Comparative pathology of Alzheimer's disease and CJD." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446438.
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Branca, Caterina, Darren M. Shaw, Ramona Belfiore, Vijay Gokhale, Arthur Y. Shaw, Christopher Foley, Breland Smith, et al. "Dyrk1 inhibition improves Alzheimer's disease-like pathology." WILEY, 2017. http://hdl.handle.net/10150/626504.
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There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-beta (Ab) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Ab levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.