Thesis (M.Ph.)--Chinese University of Hongkong. / Bibliography: leaves 53-58.

A review of the literature relating to the diseases associated with exposure to asbestos is followed by a description of processes involving materials containing asbestos, and the men employed, in HJ Dockyard, Devonport. The development of preventive measures is explained, and details are given of the precautionary methods which have been introduced as a direct result of the present survey. An account is presented of an extensive survey of the dust concentrations occurring in most of the processes involving asbestos materials in the Dockyard. This survey shows the degree of risk to which men have probably been exposed in the past, and explains how many men, not previously thought to have been at risk, have been exposed to high dust concentrations. A detailed study of the clinical, radiological and physiological changes occurring in the men exposed to asbestos is described, and this is followed by a proportional mortality study of the lung and gastro-intestinal neoplasms occurring in Plymouth males. The report concludes with a general discussion of. the data.

Age-related Macular Degeneration (AMD) is the leading cause of irreversible vision loss among elderly people in developed countries. The non-neovascular or “dry” form of AMD accounts for 85%, whereas the neovascular or “wet” accounts for 15%, of all cases. There are no effective treatments for dry AMD mainly because the molecular mechanisms that lead to the development and progression of AMD are not fully understood. Similarly, while wet AMD is being treated with antibodies against vascular endothelial growth factor (VEGF), the underlying cause that results in the development of wet AMD remains elusive. Cytosolic accumulation of nuclear-DNA (nDNA) fragments has been found to trigger inflammation and mediate the development of multiple diseases. Because inflammation plays a pivotal role in AMD pathogenesis, we thus investigated if accumulation of cytosolic nDNA also contributes to AMD. Our data show that cytosolic nDNA is enriched in macular retinal pigment epithelium (RPE) cells of AMD patients. To study the effect of cytosolic nDNA on RPE cells, we mimicked this pathology by deleting the lysosomal endonuclease Dnase2a, which is responsible for degrading DNA fragments, using CRISPR/Cas9. This resulted in cytosolic accumulation of nDNA in cultured primary human RPE cells as well as in the RPE cell line ARPE-19. Importantly, both RPE cell types with Dnase2a loss became senescent and secreted higher levels of VGEF and pro-inflammatory cytokines compared to control. These effects were mediated by the DNA sensor STING and mTOR pathway. Additionally, similar to other senescent cells, these senescent RPE cells secreted factors that acted in a paracrine manner turning otherwise healthy RPE cells into senescent cells that start secreting VEGF as well as pro-inflammatory cytokines. Finally, we found that mice with Dnase2a deletion develop features of AMD-like retinopathy, including drusen- like deposits, thickened Bruch’s membrane, RPE damage, photoreceptor atrophy, and reduced electroretinogram. The pleiotropic downstream effects of cytosolic accumulation of nDNA in RPE cells, which are consistent with the complex AMD pathology, suggest that this phenomenon contributes to the pathogenesis of AMD and thereby opens new opportunities for therapeutic interventions. / 2020-10-24T00:00:00Z

The aim of this PhD thesis was to explore the way in which recognition memory changes over time. Of particular interest was how forgetting and systems level consolidation processes alter the qualitative nature of recognition judgments and the impact this has on event related potentials (ERPs) recorded during recognition. An emerging body of fMRI and animal work has started to suggest that changes to the neural basis of memory can be observed after intervals in the order of days and weeks. Although much research has examined the ERP correlates of recent recognition, there has been little attempt to compare this to remote recognition. This gap in the literature is investigated in the present PhD thesis over five ERP and two behavioural experiments. The first set of experiments investigated recognition success i.e. the subjective awareness that a stimulus has been encountered before. Previous work has associated familiarity-based recognition with an early midfrontal ERP effect whereas recollection-based recognition has been linked to a later onsetting parietal ERP effect. These effects were compared for recently studied stimuli and stimuli studied 1 week earlier. Results revealed an attenuation of the late parietal effect. This quantitative difference suggests that the neural networks underlying the ERPs for recent and remote recollection remain the same after a 1 week delay but may be less active after a period of forgetting. Behavioural work linked this to a drop in strength and episodic detail for remote recollection. Examining the midfrontal effect over time produced a more complex pattern of results. The effect was not reliable in Experiment 1 for remote familiarity judgments. In follow up experiments, however, midfrontal effects were reliable for week old memories but were not modulated by either delay or memory strength manipulations. These findings do not permit strong conclusions regarding the way familiarity memory and midfrontal ERPs vary over time, other than to say that the midfrontal effect is not a short lived correlate of recognition memory. A second set of experiments investigated how the length of the delay between study and test impacts on retrieval orientation and retrieval effort. Retrieval orientation refers to the way in which participants strategically alter how a memory cue is processed based on current task demands. Results showed ERP differences when remote memories were cued compared to when recent memories were cued. However, these differences were eliminated when recent and remote memory was matched for performance. This finding indicated that effort required at retrieval rather than memory age per se influenced differential cue processing. A follow up experiment supported this claim but found that participants may utilise delay information during recognition in a very general sense. In this experiment, ERPs indicated different cue processing when participants knew the age of the memories they were trying to retrieve compared to when they did not. Taken together, the results suggest that memory age does not influence the ERP correlates of recognition in a direct manner. More important are the indirect changes occurring over time, such as reduced memory strength, reduced episodic detail, slower reaction times and increased effort at retrieval. These variables, and possibly a range of others, should be controlled as far as possible in studies aiming to explore neural changes driven by systems consolidation. Prospective studies, where the learning phase can be controlled makes this aim feasible, as some of the experiments in this thesis have shown. Future work might benefit from focusing more on variations at encoding, rather than large differences in the length of the retention interval, as has been the traditional approach to this issue.

This dissertation involved the design and validation of the Obesity Cognitions Inventory (OCI) which was intended to quantify cognitions associated with obesity. An initial pool of 117 items was refined through expert ratings, a pilot test involving 59 subjects, and a major test and validation using 217 subjects. The resulting 56-item instrument contains scales measuring five types of cognitions: Personal Control, Dietary Restraint, Cost-Benefit Beliefs, Health Knowledge, and Self-Concept. Test-retest reliabilities for these scales range from .69 to .83 and Cronbach alphas range from .57 to .82. Concurrent criterion validity of the OCI was assessed through two methods (a) correlations with percent fat and percent overweight and (b) MANCOVA analyses. These procedures revealed that all scales of the OCI except the Dietary Restraint scale were capable of distinguishing cognitive differences among subjects of varying obesity levels. For males, Personal Control and Self-Concept showed significant differences across obesity levels. For females, Personal Control, Cost-Benefit Beliefs, Health Knowledge, and Self-Concept showed significant differences across obesity levels. For males, subjects of low obesity level were cognitively distinct from those of moderate and high levels of obesity. For females, just the opposite was true, with those of high obesity level differing most from those of moderate and low obesity levels. The only exception to this for females was the Health Knowledge scale where only those of low and moderate obesity levels showed significant cognitive differences. In general, it was concluded that the OCI shows promise as an instrument capable of quantifying the relationship between certain key cognitions and obesity level. The implications this has for cognitive-behavioral treatment of obesity are considered.

Cancer-related fatigue (CRF) is a persistent and debilitating problem for many breast cancer survivors. Although many CRF measurement tools are available, no consensus exists on the most appropriate tool to use for breast cancer survivors. The purpose of this project was to identify the best method of assessing CRF in breast cancer survivors. The practice-focused question inquired about the most appropriate way to assess fatigue in breast cancer survivors. The central concepts of the project were CRF and cancer survivorship. This project was informed by the theory of health as expanding consciousness and Mishel's theory of uncertainty in illness. The sources of evidence included multi-database searches and literature from professional organizations. Results were tracked using preferred reporting items for systematic reviews and metasystems and a literature review matrix. The search identified 14 sources, which were assessed for quality using the grading of recommendations, assessment, development, and evaluation process. The results of this systematic review did not support the use of any particular assessment tool; however, 2 clinical practice guidelines recommended screening using a numerical severity scale followed by detailed assessment of clinically significant fatigue using available assessment tools. Screening can be implemented into the survivorship clinic, allowing nurses to identify potentially clinically significant fatigue so that further workup is done and interventions are implemented. Identifying, assessing, and intervening for clinically significant fatigue can improve the quality of life for breast cancer survivors, contributing to positive social change.

By examining the spicific structure of ownership associated with a fideikommiss, this study uses a geographic perspective to explain how Erstavik remain a rural-like area surrounded by urban development. The results based on questionnaire and literature search shows that laws and regulations for fideikommiss does not fully protect property within a fideikommiss from development. However, the consequences of the specific rules for fideikommiss shows to impede urban development within a fideikommiss over time. In addition, the function of the area as a large greenspace with high conservation values largely accessible for visitors, does show to be a likely explanation for the prolongation of Erstavik as a fideikommiss. By analyzing the results in a context of urban greenspace, ecosystem services and land use, previous studies on related topics are presented and compared with for an added scientific perspective. As a method to view Erstaviks fideikommiss from a resource perspective, the local municipality, county administration and landowner gives their view on todays' land use in Erstavik based on each respective agenda. Lastly, the varying meanings of a resource in a context of geography is briefly applied to each respective agenda.

Matric water was measured as the water retained by plant material on a pressure membrane or ultra filter after equilibration under 20 bars nitrogen gas pressure and the removal of free water. At increasing pressures lesser amounts of water are held by matric or colloidal surface forces. Twenty bars pressure, supplied by cylinder nitrogen for 48 hours, was used in this study. Matric water was expressed as a percent of either (a) the dry weight or (b) the original water content. Plant material was oven dried, ground, and then saturated with water prior to the determination. The matric water values of different aged leaves from a number of local species were studied. The highest values of matric water were found in the younger leaves. Both matric water and original moisture content were higher for spring than for fall or midwinter values. The linear relationship between matric water and original moisture content was established for all trees studied. Another linear relation was found between either the matric water or the water content of the tree leaves and the inverse of their age in months. Petioles had a higher matric water value as well as a water content than leaf blades in all the species studied. Roots and old stems had the lowest values of matric water. The matric water values increased during the cold hardening of Cabbage leaves. No appreciable differences in the matric water values for Sunflower leaves grown under different temperatures were found. The crude protein and cell wall materials were isolated and their matric water values studied. Crude proteins had a higher value of matric water than cell wall materials alone. The matric water values of several biocolloidal materials were determined also. Agar had the highest value of matric water, fibrous cellulose the lowest, and the proteins had intermediate values.

This thesis investigates the structure of job-related well-being; the identification of variables that contribute to either psychological well-being or distress; and the causal connections among elements of job-related well-being and intrinsic job satisfaction.Two large samples (n=3,044 and 3,709) from a white-collar public sector organisation were used to test a four monopolar model of affective well-being, and the two bipolar model (enthusiasm-depression and anxiety-contentment) proposed by Warr (1990). Structural equation modelling (LISREL) was used to test both models, and results strongly supported a monopolar structure of affective well-being (enthusiasm, depression, anxiety and relaxation). Following the testing of the models, canonical correlation analyses related the set of the four affective variables and intrinsic job satisfaction to a set of predictors. The predictors were drawn from Wan's (1994) sub-categories of nine features of jobs that purport to enhance psychological well-being at work. Two dimensions were extracted from this analysis. The first dimension was mainly defined by intrinsic job satisfaction (from the dependent variable set) and supervisory support and skill utilisation (from the independent variable set). The second dimension was defined mainly by anxiety (dependent variable set) and job demands (independent variable set). From these results a model was developed based on the additive influences of the independent variables on the outcome variables (i.e., affective well-being and intrinsic job satisfaction) that helped explain psychological well-being and distress at work. Finally, a model was also developed that assumed a causal direction from intrinsic job satisfaction to affective well-being. Using a longitudinal sample (n=220) these causal relations were tested with USREL. Results supported the hypothesis that intrinsic job ++ / satisfaction leads to affective well-being, rather than the alternative model that had the causal connections in the opposite direction. It was also possible to demonstrate with the same data set that one objective organisational variable, namely tenure, affects intrinsic job satisfaction over time, thus arguing against the proposition that intrinsic job satisfaction is dispositional.

Malignant mesothelioma (MM) is an aggressive and highly chemo-resistant tumour of the mesothelium. Asbestos is indicated as the environmental factor most commonly associated with mesothelioma. The chemo-resistance is possibly due to impaired apoptotic mechanisms since it is known most chemotherapeutic drugs act via apoptosis. Murine MM cell lines that have been derived from tumours induced by inoculation of crocidolite asbestos into mice provide a suitable model, since both phenotypic and biological properties are closely similar to the human disease. Four murine MM cell lines were used in this study, namely ABl, AB12, AC29 and AC34. The aim of this study was to determine susceptibility of those MM cell lines to induction of apoptosis and the expression of key molecules in those cells. Many apoptosis-related genes are known, expression of some of these genes in four murine MM cell lines were investigated in this study. Gene expression was determined using conventional reverse transcription PCR (RT-PCR) and quantitated using real-time RT-PCR with SYBR-Green I detection on a Rotor-Gene 2000 (Corbett Research, N.S.W., Australia). Gene expression data was normalised against the most stable housekeeping genes as determined by the geNonn software. Susceptibility of the four murine MM cell lines to apoptosis induction was determined using cisplatin or TNF-a or IFN-y at different concentrations and at different times in the case of cisplatin. Apoptosis was assessed by a DNA laddering assay. Conventional RT-PCR results showed that all four murine MM cell lines expressed DR5, Bax, Bcl-xL, FLIP-L, c-Myc and caspase-3. Fas mRNA was detected in all cell lines except AC29. Neither FasL nor Bcl-2 was expressed in the four murine MM cell lines. / Quantitation of gene expression showed that there were significant differences in Fas, DRS, Bax, Bcl-xL, c-Myc, FLIP-L and caspase-3 mRNA levels across the cell lines (P<0.05). Absence of Fas receptor in AC29 may play a role in the immunogenicity of this cell line. DNA laddering results indicated that cisplatin induced apoptosis in a dose- and time- dependent manner in those MM cell lines. Susceptibility as reflected by the minimum apoptosis-inducing dose varied among the cell lines from 1 pdml (AB12) to 10 & n l (AC34). Susceptibility to TNF-a or IFN-y also varied among the cell lines where AB12 was sensitive while AC29 was resistant to those cytokines. The AC29 and AB1 cell lines were used to examine cisplatin or TNF-a induced genes related to apoptosis, expression of Fas, caspase-3, Bax and Bcl-xL mRNA was determined using real-time RT-PCR after 6 and 24 hours induction with cisplatin or TNF-a. The results demonstrated that caspase-3 and Bax were up-regulated whereas Bcl-xL was down-regulated in AC29 after 6 hours treatment with cisplatin. Although only Bcl-xL was down-regulated in ABl after 6 hours treatment with cisplatin, the down regulation was more pronounced than in AC29. TNF-a induction of gene expression showed that Bcl-xl decreased and Fas was up-regulated significantly in AB1 after 6 hours whereas only Bcl-xL was down-regulated in AC29 after 6 hours and continued to decrease until 24 hours. The differences in gene expression changes were noticed not only between cell lines but also between two inducer agents. There were several significant results of this study. Firstly, gene expression in murine MM was seen to parallel those that have previously been described for the human disease. / Therefore murine MM is likely to be a useful in in vivo model for future studies targeting apoptotic molecules. Secondly, a number of genes were not previously examined in MM were characterized in the murine model. Finally, differences in basal and induced gene expression between cell lines and inducing agents were characterized which should be followed in further studies at the protein level (eg caspase-3 activity).