Dissertations / Theses on the topic 'Degeneration in art'

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In the present bibliographical research, the theater is analyzed, under a critical perspective, as an imitation of the social representation in the writings of JeanJacques Rousseau, taking as a parameter the criticism elaborated by the philosopher genebrino on the French theater, especially in what concerns The comedy of customs advocated by thinkers such as Voltaire and D'Alembert, as well as his negative response to the question about the contribution of the sciences and the arts to the moral improvement of man, presented in his First Discourse. In this panorama, Rousseau disproves most of the philosophers of his time, showing that art, instead of elevating man to a higher moral level, corrupts it by making it vile and attached to frivolities and luxuries unnecessary to a society Virtuous Indeed, unlike ordinary Enlightenment thought, the Geneva philosopher did not assert that this society and that historical moment in which he was inserted represented the pinnacle of moral progress in the history of human civilization, but rather preached that the man had entered a dangerous Process of moral degeneration, of narcissism, from which the other is taken as a mere projection of itself. In this way, we are dealing with the French theater considerations of some Enlightenment philosophers, as well as the answer given by Rousseau to D'Alembert in the famous missive on the Geneva entry in Diderot's Encyclopaedia. It is concluded that, while recognizing the importance of the sciences and the arts for humanity, Rousseau viewed such dimensions of knowledge as harmful insofar as they served distorted purposes, especially when used as a form of distinction between men. The theater, conceived in this perspective, had the function of being simple distraction for the masses, being mere caricature of the daily life.
Na presente pesquisa de cunho bibliográfico, analisa-se o teatro, sob uma ótica crítica, como imitação da representação social nos escritos de Jean-Jacques Rousseau, tomando como parâmetro a crítica elaborada pelo filósofo genebrino sobre o teatro francês, em especial no que tange a comédia de costumes defendida por pensadores como Voltaire e D‟Alembert, bem como sua resposta negativa à questão acerca da contribuição das ciências e das artes para o aprimoramento moral do homem, apresentada no seu Primeiro Discurso. Neste panorama, Rousseau destoa de grande parte dos filósofos de seu tempo, mostrando que a arte, em vez de elevar o homem a um patamar moral superior, acaba corrompendo-o, tornando-o vil e apegado a frivolidades e luxos desnecessários a uma sociedade virtuosa. Aliás, diferente do pensamento iluminista corrente, o filósofo genebrino não asseverou que aquela sociedade e aquele momento histórico nos quais ele estava inserido representavam o auge do progresso moral da história da civilização humana, mas, antes, preconizou que o homem tinha entrado em um perigoso processo de degeneração moral, de narcisismo, a partir do qual o outro é tomado como mera projeção de si mesmo. Aborda-se, assim, as considerações sobre o teatro francês tecidas por alguns filósofos iluministas, bem como a resposta dada por Rousseau a D‟Alembert na célebre missiva a respeito do verbete Genebra contido na Enciclopédia de Diderot. Conclui-se que, mesmo reconhecendo a importância das ciências e das artes para a humanidade, Rousseau via tais dimensões do conhecimento como danosas na medida em que serviam a propósitos distorcidos, em especial quando utilizadas como forma de distinção entre os homens. O teatro, concebido nesta perspectiva, tinha como função ser simples distração para as massas, sendo mera caricatura da vida cotidiana.

Age-related macular degeneration (AMD) is a principal cause of blindness in the United States and other industrialized nations. An estimated 10 million Americans are afflicted with AMD, which is comparable in scope to the 12 million living with cancer, or the 5 million with Alzheimer’s disease. The prevalence of AMD steadily increases with age, affecting 2% of the population at age 40, and one in four people by age 80. For reasons that are not fully understood, AMD is more common in lightly-pigmented and female populations. Treatment of AMD is largely an unmet need: There are no FDA approved therapies except for a small percentage of individuals with end-stage disease. This dissertation investigates the mechanisms of AMD pathogenesis and offers insight into novel therapeutic strategies for this disease.

[Truncated abstract] Observations are presented from Lake Biwa (Japan) and Lake Kinneret (Israel) showing the ubiquitous and often periodic nature of high-frequency internal waves in large stratified lakes. In both lakes, high-frequency wave events were observed within two distinct categories: (1) Vertical mode one solitary waves with wavelength ˜100-500 m and frequency near 103 Hz and (2) sinusoidal vertical mode one waves with wavelength ˜5-30 m and frequency just below the local maximum buoyancy frequency near 102 Hz. The sinusoidal waves were associated with shear instability and were shown to dissipate their energy sporadically within the lake interior. Conversely, the solitary waves were found to be capable of propagating to the lake perimeter where they may break upon sloping topography, each releasing ˜1% of the total basin-scale internal wave energy to the benthic boundary layer.

Objective: Physical exercise decreases disability and pain associated with chronic articular cartilage degradation. However, understanding of the pathology is lacking. In this study, the levels of 17 biomarkers of inflammation and cartilage degradation were measured in synovial fluid (SF) before and after a 30-minute run in able-bodied and previously-injured individuals. Materials & Methods: Four able-bodied recreational runners (3 men and 1 woman: 24 ± 2 years, 68 ± 7 kg, and 173 ± 9 cm) and 4 recreational runners who had undergone a unilateral anterior cruciate ligament reconstruction (ACLr) (2 men and 2 women: 23 ± 1 years, 71 ± 6 kg, and 175 ± 4 cm) were recruited to participate in this study. Using a saline-assisted method, SF was aspirated before and after both a 30-minute unloading and 30-minute exercise session. Samples were corrected for blood contamination and analyzed for 15 cytokines and 2 matrix metalloproteinases (MMPs). Mixed model analyses were used to determine the main effects of session, case/control status, pre/post aspirations, and the interactions between case/control status and pre/post aspirations. Results: Blood protein contamination was calculated and accounted for in 15 of 32 synovial fluid samples. Granulocyte colony stimulating factor (GCSF) was the only detectable cytokine of the 15 analyzed. No statistical differences were found in GCSF concentrations between pretreatment and posttreatment aspirations (p = 0.45), ACLr and able-bodied control groups (p = 0.60), or unloading and exercise sessions (p = 0.96). MMP-13 was undetectable. No statistical differences were found in MMP-3 between pretreatment and posttreatment aspirations (p = 0.15), ACLr and able-bodied control groups (p = 0.85), or unloading and exercise sessions (p = 0.14).Conclusions: Two (GCSF and MMP-3) of the 17 measured biomarkers were detectable. There were no significant differences in either GCSF or MMP-3 due to a 30-minute run or 30-minute unloading period in either the able-bodied or ACLr participants. Further, there were no significant differences between biomarker concentrations and case-control status. A novel method of controlling for blood contamination in synovial fluid samples was implemented.

Disc degenerative changes are directly or indirectly associated with spinal pain and disability. Literature revealed a high prevalence of disc degeneration in the thoracic region, however thoracic MRI degeneration trends and information on disc biochemical matrix constituents are limited for thoracic discs compared to lumbar and cervical discs. The objective of this thesis was to use MRI to investigate the prevalence of disc degenerative changes affecting the human thoracic spine, and to determine the factors affecting spinal disc biochemical matrix. A 3-point subjective MRI grading scale was used to grade the films. The feasibility of using archived formalin-fixed cadaver material was investigated to analyse collagen and elastin crosslinks. The prevalence of degenerative changes in human thoracic discs and vertebrae (T1 to T12) was determined retrospectively from an audit of 216 MRI cases, using sagittal T1- and T2-weighted MR images. In a subsequent series of ex-vivo studies, human thoracic discs and LF from 26 formalin-fixed and two fresh spines, involving all thoracic levels, were examined macroscopically to determine the degeneration status. Subsequently, disc and ligament tissues were analysed biochemically for collagen (pyridinoline and deoxypyridinoline) and elastin (desmosine and isodesmosine) crosslinks. These crosslinks were extracted from hydrolysed samples by cellulose partition chromatography, and analysed by reverse-phase HPLC. Collagen content was determined using its hydroxyproline content, and proteoglycan content was assayed using a modified DMB assay for chondroitin sulphate. Finally the MRI and macroscopic assessments of thoracic discs, were compared with the biochemical data from two fresh cadaver thoracic spines. The 3-point MRI grading scale had a high inter- (k = 0.57 to 0.78) and intra-rater (k = 0.71 to 0.87) reliability. There were no significant differences in the collagen and elastin content and extent of collagen crosslinks between formalin fixed and unfixed ligament and disc tissues, after 25 weeks of formalin fixation. From the in-vivo MRI series of investigations (n = 216 MRI films), the prevalence of thoracic disc degenerative and vertebral morphological changes revealed significant age, gender and spinal level trends (p < 0.05).Generally, males had a higher propensity for disc degeneration in contrast to females, especially older females, where the trend showed a higher prevalence of osteophytes and vertebral body changes. In particular, the mid and lower thoracic levels have a higher prevalence of degenerative changes, except for osteophytes and anterior vertebral wedging. With increased age, there was a concomitant increase in anterior wedging and bi-concavity and disc degenerative changes except for end-plates. The biochemical investigations on the ex-vivo series of formalin-fixed thoracic discs (n = 303) also revealed significant changes in the disc matrix due to degeneration status, age, gender and spinal regional factors. With increased age, normal disc matrices have significantly lower collagen content and extent of pyridinoline (p < 0.001). In contrast, the degenerated disc matrix revealed significantly higher collagen content and extent of deoxypyridinoline (p < 0.05). These findings suggest that an altered matrix existed in normal ageing discs, which render the disc prone to injury and degeneration over the life span. The higher collagen and deoxypyridinoline in degenerated disc matrices reflects an increase in chondrocyte synthesis, and is also a novel finding, suggesting that they may be used as markers of ageing and degeneration processes. The biochemical investigations on another series of ex-vivo spinal LF tissues (n = 364), revealed that this had a lower collagen and pyridinoline, but significantly higher elastin and deoxypyridinoline compared to spinal discs (p < 0.05). Elastin crosslinks however were difficult to detect in spinal discs, being present in negligible amounts in a few lumbar discs. The elastin crosslinks in the LF were not significantly affected by age, but were significantly higher in calcified, and female ligamentum tissues, and also in the lumbar region (p < 0.05). These MRI prevalence findings enhanced our knowledge of vertebral body and disc degeneration trends in the thoracic region and contributed to the interpretation of MR images for pathology in the human thoracic spine. Information on the associated collagenous and elastic changes in the disc and ligamentum matrices provide original data and insight on the pathogenesis of degeneration in the disc matrix from a biochemical perspective, highlighting gender, age and spinal level influences on the matrix tensile strength and cellular synthetic activities.

Mitoquinone (MitoQ₁₀ mesylate) is a mitochondria-targeted antioxidant for the treatment of neurodegenerative diseases. As the oral bioavailability of mitoquinone is low in rat, it is necessary to better understand the mechanisms of its absorption in rat and in human. The aims of this thesis were 1) to investigate oral absorption mechanisms of mitoquinone in Caco-2 cell monolayers and in a rat intestinal tissue model; 2) to investigate the correlation between chemical structure and permeability of mitoquinone analogues in Caco-2 cell monolayers; and 3) to explore the hypothesis that active transport and/or drug metabolism contribute to the pharmacokinetics of oral mitoquinone in rat. In Caco-2 studies, transport of mitoquinone was polarized with the apparent permeability (P[app]) from basolateral (BL) to apical (AP) (P[appBL to AP]) being >2.5-fold the P[app] from AP to BL (P[appAP to BL]). The P[appBL to AP] value decreased by 26%, 31% and 61% by P-glycoprotein (P-gp) inhibitors verapamil 100 [mu]M, cyclosporine A (CsA) 10 [mu]M and CsA 30 [mu]M, respectively, whereas the P[appAP to BL] increased 71% by CsA 30 [mu]M. Some of the intracellular mitoquinone was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Apical effluxes of mitoquinol sulfate and mitoquinol glucuronide conjugates were significantly decreased by cyclosporine A 30 [mu]M and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 [mu]M, respectively. In the presence of 4% bovine serum albumin on the BL side, the P[appAP to BL] was 4.52 � 0.92 x 10⁶ cm/s. Based on a absorption-disposition model, F[a] value of mitoquinone in human is estimated to be 56%. A bellshaped relationship exists between the Caco-2 permeability of mitoquinone analogues and their lipophilicity. Permeability of mitoquinone analogues initially increases as lipophilicity increase, reaches a maximum, and then decreases due to significant cellular accumulation and active efflux. The physicochemical parameters of mitoquinone and its analogues (such as log P or polar surface area) alone do not predict their permeability across the cell membranes. The bidirectional transport of mitoquinone displays polarity across rat ileal mucosa. The P[app] from s to m (P[app s to m) of mitoquinone decreased and P[app m to s] increased but not significantly by P-gp inhibitor CsA 30 [mu]M. The tissue accumulation of mitoquinone was ~16% of the total amount of mitoquinone added. In addition, several phase I and one phase II metabolites generated by rat ileum tissue were detected. Results from pharmacokinetic studies indicate that mitoquinone was poorly (~24%) but rapidly absorbed and conjugated after oral administration. It was quickly excreted as unchanged drug and as its glucuronides (the major metabolites in rat) into intestine where it was reabsorbed. P-gp inhibition studies in rat indicate that inhibition of P-gp may increase the intestinal absorption of mitoquinone, but cannot change its oral bioavailability due to increased first-pass phase II metabolism and decreased enterohepatic recycling. In conclusion, mitoquinone is poorly absorbed in rat but may be well absorbed in human. The barrier functions of intracellular metabolism and the action of P-gp to oral absorption of mitoquinone in human may be less significant, whereas P-gp play an important role in the absorption and disposition of mitoquinone in rat in vivo. These results, together with those from its analogues, demonstrate that the actual absorption profile of a compound depends on its intrinsic membrane permeability, transporter affinity, metabolizing enzyme affinity and plasma protein binding affinity.

Subsequent to an hypoxic-ischaemic (HI)-insult a multi-faceted complex cascade of events occurs that ultimately results in cellular and neurological impairments within cortical and sub-cortical central nervous system (CNS) regions. In the present studies a modified �Levine� rat-pup model of HI (left carotid artery ligation + 1 hour global hypoxia on post-natal day (PND) 26) was employed to assess the neuroprotective properties of clomethiazole (CMZ; a γ-aminobutyric acid (GABA)A receptor agonist). In this study, histological and electrophysiological paradigms were used to assess the long-term neuroprotective properties of CMZ (414mg/kg/day via mini-pumps). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess other potential CMZ mechanisms. Assessments were carried out 3- and 90-days post-HI, with extensive ipsilateral CNS lesions evident at a gross histological level, at both the early and long-term stages, with CMZ significantly decreasing the lesion size at 3- and 90-days (P<0.01; P<0.05). Evoked field potential analyses were used to assess hippocampal CA1 neuronal activity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function following HI relative to short- and long-term controls (P<0.001, 3- and 14-days; P<0.01, 90-days), with CMZ providing near complete protection (P<0.001 at 3- and 14-days; P<0.01 at 90-days). Both inducible NOS (iNOS) and arginase activities were significantly increased at 3-days (P<0.01), with arginase activity remaining elevated at 90-days post-HI (P<0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P<0.001; P<0.05). These data provide evidence of long-term functional neuroprotection afforded by CMZ in a model of HI-induced neurodegeneration. In addition, under conditions of HI, functional deficits were not restricted to the ipsilateral hemisphere and were due, at least in part, to changes in the activity of NOS and arginase. Underlying mitochondrial dysfunction is eminently present in many neuropathological conditions. The full extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues was assessed following HI. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-days post-HI revealed a significant decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, significant changes in respiratory function were also evident in contralateral regions and cerebellum, 3-days post-HI (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V) and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed ipsilateral mitochondrial impairment following HI. Complexes I, II-III, V and citrate synthase were also impaired, in contralateral regions and cerebellum, 3-days post-HI. CMZ treatment provided significant protection to all mitochondrial aspects of neuronal tissue assessed. This study provides evidence of the full extent of mitochondrial damage following an HI-insult and may contribute, in part, to the impairment seen contralaterally. In addition, protection afforded by CMZ extends to preservation of mitochondrial function and integrity. Cerebral ischaemia-induced angiogenesis has been shown within and around infarcted regions and may contribute to a more favourable neurological outcome. The level of angiogenesis was examined using platelet endothelial cell adhesion molecule-1 (PECAM-1 / CD31). CD31 immunolabelling 7-days post-HI revealed a significant increase in angiogenesis compared with non-intervention controls (P<0.001). Treatment with CMZ decreased the level of angiogenesis compared to HI + saline (P<0.001) back to non-intervention control levels. Conversely, N[omega]-nitro-L-arginine methyl ester (L-NAME) treatment (5mg/kg/day) exacerbated the ischaemic lesion (P<0.001) and resulted in a marked decrease in angiogenesis compared to non-intervention controls (P<0.001). The extent of cerebral infarction in these studies is dependent on the level of NOS activity with CMZ increasing total NOS levels compared to HI + saline, while L-NAME halted the HI-induce increase in total NOS activity (P<0.001). These results show for the first time, that angiogenesis may be used as an assessment of neurodegeneration / neuroprotection in pathologies of cerebral ischaemia and are directly correlated with changes in NOS activity. These studies have therefore shown that following HI, damage also occurs contralateral to the occlusion, and is not restricted to the ipsilateral hemisphere. In addition, the neuroprotective effects of CMZ have been shown to extend out to 90-days post-HI, whereby significant protection to CA1 neuronal activity was seen. These studies also provide in vivo evidence that CMZ may also afford neuroprotection via anti-inflammatory pathways, as evidenced by a decrease in iNOS and arginase activities. Furthermore, these studies have also show evidence that angiogenesis (CD31) can be used as a diagnostic tool to assess neuroprotection / neurodegeneration.

Stroke is the 3rd leading cause of death and the leading cause of major disability worldwide. Currently, there are no neuroprotective drugs approved for the acute treatment of ischaemic stroke. The vast majority of stroke therapeutics failed in clinical trials due to toxic side effects and/or a clinically irrelevant therapeutic window. This thesis is focused on exploiting the delayed neurodegeneration that occurs in the compromised penumbra, as these cells may be capable of being saved by therapeutic intervention in a clinically obtainable window. In order to investigate the ischaemic cascade and be able to draw conclusions that are applicable to humans, the international gold standard animal model for cerebral ischaemia, the filament insertion middle cerebral artery occlusion (MCAO) model, was established at the University of Otago. This model was validated under new laboratory conditions and employed adult male Sprague Dawley rats. After testing multiple occlusion lengths, it was concluded that a 2hr ischaemic period was sufficient to produce a consistent infarct of optimal size. It has been well documented that neuroinflammation contributes to much of the delayed progression of neural injury post-stroke. Therefore, the catechin (-)-epigallocatechin gallate (EGCG), which is an anti-inflammatory, anti-oxidant and free-radical scavenging agent was investigated in the MCAO model of stroke. 50mg/kg i.p. of EGCG or saline was administered immediately post-MCAO and animals were sacrificed at 72hr post-filament insertion. The results confirmed that treatment with EGCG was neuroprotective and non-toxic. However, EGCG also induced an over 50% increase in the risk of haemorrhagic conversions. The anti-platelet effects of EGCG and lack of toxicity suggests that the catechin may prove to be an efficacious prophylactic for stroke. The contrary findings for EGCG treatment led to the re-evaluation of the neuroinflammatory pathway for alternate mechanisms to target therapeutic interventions. The temporal profile of the primary inducible enzymes nitric oxide synthase (NOS), cyclooxygenase (COX) and arginase (and their isoforms) were quantified 0, 3 and 7 days post-stroke. In both hemispheres, total NOS activity exhibited a significant and sustained up-regulation to 7 days post-occlusion. In the ipsilateral hemisphere at least half of the total increase was accounted for by inducible NOS (iNOS) expression. Arginase, which competes with NOS for L-arginine, demonstrated a delayed but significant increase in activity by day 7 in the infarcted hemisphere, thereby correlating well with the downward slope of NOS activity (illustrating the switch in the conversion pathway). COX activity was observably increased in the ipsilateral hemisphere, but the up-regulation did not reach significance by day 7. Alternately, the contralateral hemisphere displayed a significant decrease in activity by day 3. These results give conclusive evidence that the contralateral hemisphere is NOT an appropriate internal control and imply that NOS and COX inhibitors may prove to be efficacious for a much longer therapeutic window than current treatments. However, the delayed induction of COX activity may also indicate that this enzyme has a finite therapeutic window, as it may also stimulate remodelling of surviving neural networks. The prolonged up-regulation of inflammatory mediators implies that there may be an induction of an autoimmune component to the response. Therefore, the thymus (T) lymphocyte activation was quantified up to 14 days post-stroke. Cluster of differentiation (CD) 3⁺ T lymphocytes (equally contributed to by CD4⁺ and CD8⁺ T cells) exhibited a significant and sustained up-regulation in the infarcted region from day 3 up to at least day 14 post-ischaemia. Quantitative analysis of all cells present post-stroke determined that immune cells make up an average of 73% of all cells present in the 'peak' ischaemic areas. The CD4⁺ T helper cell response was delineated by double immunohistochemical labelling. Interferon-γ positively labelled with CD4⁺ T cells at days 3, 7 and 14 post-insult detailing a Th1-driven pro-inflammatory response. This evidence indicates that the autoimmune response is critical post-ischaemia and that it may be highly susceptible to modification by anti-inflammatory therapeutic intervention. The primary downstream effect of the pro-inflammatory/immune cascade is apoptosis. The main organelle responsible for the 'go, no go' response to apoptotic factors is the mitochondria. In order to distinguish whether mitochondrial dysfunction was initiated shortly after ischaemia induction or if it was delayed, like the inflammatory/immune response, to a clinically relevant window, the temporal profile of mitochondrial complex inactivation was studied. It was found that mitochondrial membrane viability was impaired by day 3, followed by a significant decrease in respiratory complex activation and an increase in tissue injury by oxidative stress by 7 days post-ischaemia. These results indicate that targeting the early decrease in membrane viability or mitochondrial permeability transition pore opening combined with anti-apoptotic therapeutics, may attenuate the proceeding mitochondrial impairment in oxidative phosphorylation, reactive oxygen species generation and subsequent cell death cascades. The current investigations into the temporal profile and quantitative contributions of the inflammatory, immune and apoptotic mechanisms post-stroke highlight potential strategies for modulation by acute stroke therapeutics. Furthermore, the general knowledge amassed from these studies dictates the necessity of a new approach to therapeutic intervention. The acknowledgement of so many contributing systems suggests that in addition to a thrombolytic, a combination therapy involving multiple neuroprotectants should be employed to account for the multifaceted nature of the sequelae of ischaemic stroke.

[Truncated abstract] Sporadic inclusion body myositis (sIBM) is a chronic inflammatory disease that is the most common myopathy in individuals above the age of 50 in the Caucasian population. sIBM is characterised by cytotoxic immune infiltration of skeletal muscle, consisting primarily of CD8+ T-cells and macrophages, as well as a degenerative process, with muscle fibre vacuolation and intracellular filamentous inclusions. The pathogenesis of sIBM is likely to involve a complex interaction between genetic and environmental factors. Whilst the physiological and pathological characteristics of sIBM have been clearly identified, the exact origin and genetic basis of the disease remains unknown. A number of studies show that sIBM is associated with alleles of the major histocompatibility complex (MHC) on chromosome 6p21.3 and specifically with two ancestral haplotypes (AH) in Caucasians – the 8.1AH, defined by HLA-B*0801, HLA-DRB1*0301 and the 35.2AH, defined by HLA-B*3501, HLA-DRB1*0101. Mapping studies subsequently showed that sIBM susceptibility likely originates from a 389kb region of the MHC, spanning from centromeric of PBX2 to telomeric of HLA-DRB1. The central hypothesis of this thesis was that susceptibility to sIBM is conferred by a single allele found within a region defined using the 8.1AH, which is also carried by other haplotypes associated with sIBM. Three patient cohorts from Australia, the U.S.A and Japan were studied. ... Of the 32 alleles genotyped, none were found in all susceptibility haplotypes and one was common, but not unique, to the 8.1AH, 7.2AH and 52.1AH. Five SNPs were also found in two of the three haplotypes, although none were specific to the sIBM susceptibility haplotypes. These data suggest that the 8.1AH is likely to carry an sIBM susceptibility allele independent of the 35.2AH, 7.2AH and 52.1AH. Based on the possible mechanism of action in cellular differentiation and its location within the 8.1AH-defined sIBM susceptibility region reported in 2004, NOTCH4 was a strong candidate for conferring sIBM susceptibility. NOTCH4 coding region polymorphisms were thus investigated in a Caucasian patient cohort to assess any possible role in sIBM susceptibility. While the frequency of some alleles were increased in sIBM patients, the strong linkage disequilibrium throughout the MHC prevented confirmation of any alleles as playing a direct role in sIBM. The 8.1AH-derived sIBM susceptibility region was further refined using recombination mapping. This approach used markers characterised against multiple haplotypes to genotype patients carrying part of the 8.1AH to locate a common, overlapping susceptibility region. Recombination mapping of patients revealed a common overlapping region of the 8.1AH, extending from BTNL2 to HLA-DRB3. The results of the study indicate that 8.1AH-derived susceptibility for sIBM is likely to originate from a 172kb region encompassing HLA-DRA, HLA-DRB3 and part of BTNL2. These genes warrant further investigation in future studies.

After dendrite transection, two primary injury current pathways may acount for cell death: (1) the lesion current at the site of injury and (2) the voltage sensitive calcium channels along the dendrite. Lesions were made with a laser microbeam in mouse spinal monolayer cell cultures. Polylysine was tried as a positively charged "molecular bandage" to block the lesion current. The calcium channel blockers, verapamil and nifedipine, were used to reduce the calcium channel current. Control toxicity curves were obtained for all three compounds. The results show that neither verapamil, nifedipine, nor polylysine (MW: 3,300) protect nerve cells after dendrite amputation 100 ptm from the soma. The data also indicate that these compounds do not slow the process of cell death after such physical trauma.

Age-related maculopathy (ARM) is a central retinal disease with unclear pathogenesis. It is the major cause of permanent vision loss in adults over 50 years and is increasing in prevalence and incidence, faster than the aging population would suggest. Early in the disease process (early ARM) there is little or no vision loss and there are only slight retinal changes with abnormal deposits within Bruch's membrane. As the disease progresses (late ARM or age-related macular degeneration, AMD) vision loss may be quite severe due to atrophy (dry AMD) or the development of chorioretinal neovascularisation (CNV, wet AMD). It is hard to predict from conventional eye examinations and clinical vision tests which cases will progress to the severe, dry or wet forms of the disease. Moreover, most of the conventional clinical tests are based upon subjective vision measures. Objective tests which detect ARM earlier would be a useful aid to diagnosis and to monitoring progression. The multifocal electroretinogram (mfERG) is a relatively new clinical tool which enables the recording of electrical potentials from multiple, small areas of the central retina and thus assesses function from specific retinal locations. It is therefore useful in detecting focal retinal diseases such as hereditary or acquired maculopathies or in monitoring retinal laser or surgical treatment effects. There is cone and rod impairment in ARM and histopathological and psychophysical evidence for a preferential vulnerability of rods compared to cones. This research project investigated if an objective tool such as the mfERG could detect early ARM,its progression and the treatment effects of multiple photodynamic therapies (PDT) on retinal function in late ARM, prior to a battery of subjective vision measures. For comparison purposes a subjective assessment of central retinal function was performed using high and low contrast distance visual acuities (VA), near VA, low luminance VA (SKILL cards), contrast sensitivity (Pelli-Robson, P-R), saturated and desaturated Panel D-15 (sat Panel D-15, desat Panel D-15) and central visual fields (Humphrey 10-2, mean sensitivity, MS and mean defects, MD). As an objective assessment of central retinal function the cone- and rod-mediated multifocal electroretinograms were recorded. Subjective and objective tests of retinal function were compared in early ARM and an age-matched control group (chapter 3). Seventeen eyes of seventeen subjects with early ARM and twenty control subjects with normal vision were measured. For the cone-mediated mfERG responses conventional averaging methods were used and results were correlated with subjective vision tests. The conventional cone-mediated mfERG failed to distinguish between the early ARM and control subjects whereas subjective vision measures such as HC- and LC-VA, desat Panel D-15, MS, P-R were significantly reduced in the ARM group. However, there were significant correlations between the cone-mediated mfERG and the desat Panel D-15 results in the ARM group. This suggests that the mfERG measures similar retinal processes that detect colour vision deficiency under desaturated conditions. There was no significant correlation between cone-mediated mfERG measures and funduscopic changes. The conclusion from this study was that the subjective vision tests detected early ARM better than the objective cone-mediated mfERG. Thus the aim of detecting early ARM objectively was not met by the cone-mediated mfERG suggesting the need to develop other objective tests such as a rod-mediated mfERG. Whether the preferential rod vulnerability others have reported in early ARM could be detected by the rod-mediated mfERG was determined in the next study (chapter 4). A protocol for recording rod-mediated mfERG responses was developed by determining the optimal testing luminance to reduce the effect of stray light and elicit maximal rod-mediated responses. Sixteen of the seventeen ARM subjects and seventeen control subjects from the previous study were tested. For analysis, a customized computer template fitting method was developed in MATLAB (Mathworks, Natick, MA, USA). This method has been shown to be useful for low signal-to-noise ratio responses that characterize the rod-mediated mfERG. Significantly delayed rod-mediated mfERG responses were found whereas cone-mediated mfERG responses were within the normal range. This suggested that the effect of ARM on the rod system could be detected objectively with the rod-mediated mfERG before changes in the cone-mediated mfERG. Which of the tests best detected progression of vision loss was investigated in chapter 5. Visual function of 26 (13 ARM and 13 control subjects) of the original 37 subjects (17 ARM and 20 control subjects) had cone- and rod-mediated mfERG and the subjective vision measures repeated after one year. The main purpose was to determine which of the tests best detected progression of vision loss. The mfERG results were analysed by using both averaged and local responses and by using the computer template fitting procedure. On average no significant worsening of either objective or subjective function measures was evident after one year. These results reinforce the slow progression of the disease. With a longer follow-up period progression of ARM may translate into measurable changes in the mfERG and the other visual function tests. The effect of multiple photodynamic therapies (PDT) on cone- and rod-mediated function was assessed with the mfERG in the last study (chapter 6). The cumulative treatment effects of PDT in five subjects with late ARM were determined. Having demonstrated that the rod-mediated mfERG was applicable in early ARM, this study also aimed to investigate how useful it was in late ARM where there is substantially greater rod loss. Cone- and rod-mediated mfERGs, visual acuities, contrast sensitivities and central visual fields were investigated a week before treatment began and then one month after each PDT treatment. The subjects received three treatments each over an average period of five and a half months. In some subjects there were significant transient reductions in cone- and rod-mediated amplitudes possibly reflecting alterations in choroidal hypoperfusion dynamics one month after treatment. Further, b-wave component of the mfERG became increasingly misshapen after each PDT treatment suggesting an ischemic insult mainly targeting post-receptoral sites. However, objective and subjective function was stabilized after multiple PDT treatments in most of the subjects. This pilot study of five cases showed that there was no additional damage to cone- and rod-mediated outer retinal function after three PDT treatments. One of the novel findings of this research was that the rod-mediated function measured with the mfERG was impaired in early ARM. This finding supports histopathological and psychophysical evidence of rod vulnerability in early ARM. The results of these studies also suggest that early ARM affects different aspects of visual function which is reflected by different outcomes from objective and subjective vision tests. A model (chapter 7) based upon the results was developed proposing a hypoxic insult with a preferential alteration of post-receptoral sites in early ARM. The cone-mediated mfERG documented the retinal damage and possible treatment effects on outer retinal function of the multiple PDTs which did not further deteriorate. Thus, this technique might assist in the development of optimal treatment modalities for ARM, especially in retreatment regimes. Greater variability was found for the rod-mediated mfERG and its clinical use in PDT treatment regimes still needs to be investigated. In conclusion, this research has provided a better understanding of the disease process and treatment effects in ARM and might contribute to improvements in diagnosis and treatment of ARM.

The purpose of this dissertation was to understand how genetics, socioeconomic status (SES), and lifestyle factors influence the development of age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy in an adult population in Dallas County. Two hundred fifty-three older adults participated in this study as the sample. Crosstabulation and binary logistic regression were utilized to analyze the data. Results indicated a disparity among participants' test scores, visual health status, and perceptions of their visual impairment and highlighted the fact that many seniors are not educated about age-related retinal disorders. Furthermore, variables reaching statistical significance were consistent with the literature included race/ethnicity, age, having a family history of both AMD and diabetes, frequency of eye exams, and level of education. The results not consistent with the literature as affecting visual health included health insurance, access to health care, body weight, and smoking status. Recommendations for future study included applied research focusing on determining risk factors, raising awareness, educating, and providing early detection of these diseases among low to middle income Caucasian, African American, and Hispanic older adults.

In this essay, two voices are heared, from two women: a certain artist Xena, who talks about her life and its dramas, interwoven with her own experiences from her diaries; and the voice of Maria, who analyzes Xena's life story and her art, diffracted through the prim of the history of 21stC art.  Art the outset, "President of Crimea. Constitution", announces its author as Xena-Maria; but it is not yet clear whether the author is one person or two, nor who they are. Is it Maria who writes here, or Xena, or both? Or are they one and the same person? But at the end of the story, which is told rather in a form of certain legends and fairy tales, Maria and Xena turn into one whole, and meaningfully put an ellipsis after the words "to be continued". This reception was specially intended by the artist Maria Kulikovska, author of this essay, in order to protect both herself and the reader from possible persecutions by migration services and goverment officials of various countries, especially Russia. Also, for her it is an opportunity to step aside and analyze her own life and art form a third person, about which, perhaps, a fictional character from her childhood talks - a sensible step for Maria Kulikovska. The step that her creative language conceptually continues is to replicate casts of her own body and establish them in different spaces and contexts. So she fairly confuses the viewer as to where is the truth, and where is fiction; where is herself, and where is her clone - only now, here, she has applied the same trick in her text. This essay tells a very personal story of the life of a human body, a migrant woman in forced relocation, displacements, alienation and persecutions for her views on life and the conduct of society, and for her moral values expressed throught architecture, sculpture, drawings, performances, actions and public statements. Through the prism of geopolitical upheavals, it tells the artist's own story: How her analysis of own body position and boundaries helped her overcome stigma regarding the body of a woman from Eastern Europe, and how art can save and redeem in an unending inner drama.

碩士
中國醫藥大學
醫學研究所碩士班
95
Objective. Age-related macular degeneration (AMD) is a degenerative macular disorder and leading cause of blindness in the elderly. This study investigated possible association of angiogenic growth factor, inflammatory genes and recently AMD-susceptibility gene polymorphisms with the pathogenesis of AMD. We examined genetic polymorphisms in nine candidate genes to evaluate their relevance as risk or protective factors for AMD. Method. Ninety-five patients with AMD and 90 healthy unrelated controls in Taiwan were recruited. We genotyped the following polymorphisms: VEGF (-2578；-634；+936), TNF-α (-1031；-863；-857；-308；-238；+489), IL-6 (-572), IL-8 (-251), IL-1β(-511), TGF-β1(-509), IL-10 (-1082；-819；-592) and HTRA1 rs11200638, LOC387715 genes by PCR-RFLP method. Real-time PCR was used to determine VEGF-1498 polymorphism. Results. The distribution of VEGF and TNF-α gene polymorphisms were significantly different from the patients with AMD and control subjects. High frequency of the VEGF 936 T allele was observed in the AMD group compared with control subjects (22.3 % vs 14.0%, OR=1.761, 95% CI=1.02~3.04, p=0.038). Furthermore, haplotype analysis revealed that there was high frequency of the CTCC/CTGC genotype in the control subjects compared with AMD group (33.3% vs 20%, OR=2.0, 95% CI=1.027~3.897, p=0.040). The absence of the TNF-α-1031 CC genotype among AMD group was significantly different from control subjects (6.7% vs 0%, p=0.026). However, haplotype analysis revealed that there was high frequency of the TACGG haplotype in the control subjects compared with AMD group (6.7% vs 1.1%, OR=6.714, 95% CI=1.481~30.435, p=0.011). The absence of the TCCGG/TACGG genotype among AMD group was significantly different from control subjects (0.0% vs 8.9%, p=0.003). Combining the data on the VEGF polymorphisms with the TNF-α polymorphisms, there was high frequency of the VEGF CTCC/CTGC and TNF-α TCCGG/TACGG carriers in the control subjects compared with AMD group (5.6% vs 0.0%, p=0.026). In addition, we also verified the distribution of HTRA1 and LOC387715 gene polymorphisms were significantly different between the patients with AMD and control subjects. The high frequency of the HTRA1 AA and LOC387715 TT genotype were observed in the AMD group compared with control subjects. ( 55.9% vs 25.0%, p=6.65×10-6 and 61.2% vs 32.1%, p=3.57×10-4, respectively). All other genes polymorphisms weren’t significantly different between the patients with AMD and control subjects. Conclusion. The VEGF 936 CC SNP and CTCC/CTGC genotype may be a protective factor of AMD. Similar, TNF-α promoter TACGG haplotype and TCCGG/TACGG genotype also had protective effect. Combining the VEGF and TNF-α polymorphisms, we also found TNF-α TCCGG/TACGG and VEGF CTCC/CTGC had protective effect. Thus, we speculate that the interaction and regulation between the VEGF and TNF-α genes may be one of the important factors for the development of AMD. In addition, we also verified that HTRA1 AA and LOC387715 TT genotypes are risk factors for AMD.