Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: Diabetes; imaging; phosphorescence; retina. Includes bibliographical references (p. 69-70).

Zugl.: Köln, Univ., Habil.-Schrift, 2008

Thesis (Ph. D.)--University of Texas at Austin, 2009. / Title from PDF title page (University of Texas Digital Repository, viewed on Sept. 9, 2009). Vita. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Berlin, Freie Univ., Diss., 2004. / Dateiformat: zip, Dateiein im PDF-Format

Made available in DSpace on 2014-08-13T14:50:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-07-19Bitstream added on 2014-08-13T18:01:12Z : No. of bitstreams: 1 000735679_20140819.pdf: 19190 bytes, checksum: aaac2e72d601000e44e2887709dc91eb (MD5) Bitstreams deleted on 2014-08-22T14:57:09Z: 000735679.pdf,Bitstream added on 2014-08-22T15:02:11Z : No. of bitstreams: 1 000735679.pdf: 1127906 bytes, checksum: 39d05c2b84cb87260be1e3e5ece89511 (MD5) / Estudo da variabilidade da frequência cardíaca, no domínio do tempo, realizado em 48 cães de diferentes raças de pequeno a médio porte, com degeneração mixomatosa crônica da valva mitral, estadiados em classes de insuficiência cardíaca congestiva (ICC) proposta pela ISACHC. Os animais apresentaram sinais clínicos de: tosse, cansaço, dispneia no grupo classe 2, em ordem de prevalência. No exame eletrocardiográfico os cães perdem arritmia sinusal respiratória, passando para ritmo sinusal, junto podem apresentar: aumento da onda P em duração e amplitude, complexo QRS em duração e amplitude da onda R quando desenvolvem esta doença valvular e aumentam de classe. Os cães com DMVM em estádios de ICC moderados (classe 2) em comparação com estágios iniciais (classe 1a e classe 1b) da doença apresentaram maiores valores ecocardiográficos: relação AE/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. O presente estudo mostrou que a insuficiência cardíaca em cães com DMVM, tinha diminuído os valores de NN médio (NNm), SDNN, SDNNindex e pNN50%. Inferindo uma diminuição da participação do sistema nervoso parassimpático e um aumento da participação do sistema nervoso simpático. Além disso, foi observado um aumento da FC média e aumento número de complexos QRS (NQRS) que também são indicadores de maior participação do sistema simpático. Determinou-se um predomínio das arritmias ventriculares nos três grupos, com semelhante proporção das arritmias supraventricular no grupo clínico. As arritmias tanto ventriculares como as arritmias supraventriculares foram de caráter isolado nos grupos pré-clínicos e de caráter complexo no grupo clínico. As correlações obtidas no exame Holter foram correlação positiva entre: NNm v/s NQRS na classe 2, classe 1b e classe 1a (r= 0,978, r= 0,932, r= 0,962); NNm v/s pNN50% na classe 2 e classe ... / Study of heart rate variability in the time domain, performed in 48 dogs of different breeds of small to medium sized, with chronic myxomatous degeneration of the mitral valve, aged in heart failure classes (CHF) proposed by ISACHC. The animals showed clinical signs of: cough, fatigue, dyspnea group class 2, in order of prevalence. Electrocardiographic examination in dogs lose respiratory sinus arrhythmia, going to sinus rhythm, with display: increase in p wave duration and amplitude, QRS duration and in R wave amplitude when developing this valvular disease and increase class. Dogs with MMVD in stages of ICC moderate (class 2) compared with early stages (class 1a and class 1b) of the disease had higher echocardiographic values: Relations LA/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. The present study showed that heart failure in dogs with MMVD, had decreased values of NN medium (NNM), SDNN, SDNNindex and pNN50%. Implying a decrease in the participation of the parasympathetic nervous system and an increase in the participation of the sympathetic nervous system. Furthermore, we observed an increase in mean HR and increased QRS complexes (NQRS) which are also indicators of increased participation of the sympathetic system. We determined the prevalence of ventricular arrhythmias in the three groups, with a similar proportion of supraventricular arrhythmias in the clinical group. Both ventricular arrhythmias and supraventricular arrhythmias were isolated character in the pre-clinical and complex character in the clinical group. Especially supraventricular arrhythmias and ventricular arrhythmias may manifest themselves throughout the progression of the disease, initial ventricular arrhythmias, with further increase supraventricular arrhythmias as a consequence of atrial dilation. The correlations obtained in Holter examination were, positive correlation ...

Age-related macular degeneration (AMD) is a prevalent cause of vision loss and irreversible blindness that affects more than 11 million Americans. AMD is a multifactorial disease with a number of genetic, demographic, and environmental risk factors. Currently the etiology of AMD is still unclear and there are no effective cure for this devastating disease, but recent studies have demonstrated that RORA is a candidate gene involved in AMD pathophysiology. RORA is a critical regulator of multiple biological processes and has been implicated in various physiological processes including circadian rhythm, lipid metabolism, photoreceptor development, autism, and inflammation. Our current study will explore in depth the role of RORA in AMD. We will look at the effects of RORA in the retina of mice. Localization studies of retinal tissues obtained from mice with a conditional knockout of RORA in epithelial cells showed little effect of RORA on structural cells of the retina. However, there was a decrease in VEGF and TGF-B proteins in RORA knockout. This is an interesting finding because VEGF and TGF-B has an important function in angiogenesis and neovascularization which are pathophysiological effects of AMD. In addition, we will try to identify gene targets of RORA that have also been linked with AMD. By identifying the targets of RORA and discovering how RORA regulates these targets, we hope to better understand the role of RORA in AMD pathophysiology. ChIP-seq and software analysis of the data was performed to identify all genomic targets of RORA linked with AMD. A number of promising genes were found in both RORA and AMD networks. The next step of this study is to perform quantitative analysis of these genes and how their expression is affected by RORA. Also, we will perform additional conditional RORA knockout models in cone cells and developing retinal cells to further understand the role of RORA in the retina and AMD pathogenesis.

The association between age-related vertebral fractures (VFx) and disc degeneration (DD) is not clear, despite the high prevalence of both conditions. Load is transferred to the vertebra by the adjacent intervertebral discs, and degenerative changes within the disc alter how the net force is distributed over the interface between vertebra and disc, known as the vertebral endplate (EP). The ability of the vertebra to resist fracture depends not only on the magnitude of the net force, but also on the distribution. Multiple lines of evidence suggest that the ability of the vertebra to withstand the distribution of applied force depends on the spatial distribution of bone mineral density (BMD) within the vertebra. First, the strength and stiffness of a region of bone in the vertebra are highly correlated with the BMD of that region. Second, changes in the spatial distribution of regional BMD have been associated with aging and DD. Thirdly, some of these observed changes have been replicated in computer models bone adaption with in the presence of progressive DD, suggesting that bone adaption is occurring in response to the altered force distribution associated with DD, and that maladaptation could elevate the risk of fracture. Notably, the current clinical method of identifying patients at risk of fracture is to use an average measure of BMD for the entire vertebra. The lack of consideration of the spatial distribution of BMD may explain why the clinical method used at present does not adequately identify those at risk of fracture. The possible relationship among spatial distribution of BMD, DD, force distribution across the endplate, and vertebral strength suggests that characterizing the spatial distribution of BMD within a vertebra could add to the understanding of why some vertebra are more likely to fracture. This project sought to determine if an association exists between the spatial distribution of vertebral BMD and disc health in order to provide an improved perspective of the clinical sequelae of DD and to improve the ability of clinicians to identify those who would benefit most from intervention. This study found evidence that the distribution of bone in the vertebral body and EP depend on the health of the adjacent disc. The distribution of pressure in discs favors the anterior most portion of the disc in anteriorly flexed postures and the density in the anterior most portion of the EP appears to respond to this shift, suggesting that bone is adapting to loading patterns associated with certain postures more than others. This study also found association between reduced regional disc height and altered distribution of trabecular density which was positive in the nuclear region and negative in the annular region. In some cases there was a lack of association between disc height and density distribution that may indicate maladaptation and thus increased risk of fracture. This study, being cross-sectional could not identify whether the observed alterations in density and degeneration initiated in the vertebra or the disc. However, this study contributes to the understanding of the relationship between the distribution of vertebral density and the functional properties of the adjacent disc that may ultimately improve the clinician's ability to predict VFx. / 2017-06-21T00:00:00Z

Stroke is one of the most common causes of disability and death worldwide. The most commonly experienced stroke in the clinical setting is focal ischaemia in which the middle cerebral artery (MCA) is occluded and leads to a complex series of various pathophysiological pathways that ultimately lead to neuronal cell death. Several studies have been conducted on various therapeutic agents in the search for a neuroprotective drug and various animal models have been used to carry out this research. While theanine, a component of green tea and minocycline, a tetracycline antibiotic, have been shown to possess some neuroprotective properties, the mechanisms by which these two agents carry out these effects still remains unclear. The objectives of this study were to investigate the mechanisms by which these drugs carry out these neuroprotective effects and their neuroprotective ability in a MCA occlusion model of focal ischaemia. Ischaemia leads to oxidative stress due to the imbalance of free radicals and the endogenous antioxidant defence system. An antioxidant assay using the stable 2, 2-diphenyl-1-picrylhydrazyl (DPPH●) radical was used to assess the antiradical properties of each drug. It was found that minocycline showed superior antioxidant activity in vitro when compared to theanine. Further studies on the drugs‟ ability to attenuate the Fenton reaction (in which iron catalyses the formation of reactive species) were elucidated using electrochemical analysis, UV/VIS studies, ferrozine and ferritin assays. It was found that minocycline, in contrast to theanine, was able to bind to iron ions and thus potentially prevent the participation of iron in metal catalysed radical reaction. The antioxidant activity of both drugs was further investigated by assessing their effect on cyanide-induced superoxide generation and quinolinic acid (QA)-induced lipid peroxidation (LP). Experimental evidence shows that both drugs had no significant effect on the generation of superoxide in vitro and that there was a significant decrease in LP for minocycline in vitro and theanine in vivo. The metal binding and antioxidant properties were postulated to be a possible mechanism through which these agents reduced lipid peroxidation. A study was conducted to determine the effects of the drugs on the biosynthesis of the neurotoxin, QA and it was found that minocycline increases the levels of holoenzyme activity of tryptophan-2, 3-dioxygenase (TDO) in vitro and that theanine reduces the levels of the same enzyme in vivo after treatment for 10 days. TDO is the enzyme that converts tryptophan to other products that enable enzymatic activity to change it to QA. Minocycline was thought to bring about this effect as it has been shown from preceding experimental studies that it is an effective reducing agent. Theanine on the other hand is hypothesised to bring about a reduction in holoenzyme activity by changing the binding of tryptophan to the enzyme or affecting the radicals that participate in the enzymatic degradation of tryptophan. A focal ischaemic model of stroke was induced by occluding the MCA. Histological examination of the hippocampus post -ischaemia shows a reduction in the size of the infarct after pre-treatment with minocycline only. A further study into the effects of the drugs on the generation of superoxide and on the levels of the endogenous glutathione after a stroke was carried out. Pre-treatment of the animals with either theanine or minocycline showed no significant effects on the generation of the radical species or of the endogenous antioxidant which ruled out these as a mechanism of neuroprotection of both drugs, post-ischaemia.The findings of this study provide novel information on the possible mechanisms by which both theanine and minocycline act to bring about neuroprotection. In particular in this study, pre-treatment with minocycline has shown promise in the focal ischaemic model of stroke.

"Life" may be characterized as a controlled stationary flow equilibrium, maintained by energy consuming chemical reactions. The physiological functioning of these life systems include at least 28 of the elements isolated on the periodic table thus far, most of which are metals. However, as with Paracelsus Principle: "The dose makes the poison", there exists a definite link between metal levels, essential and toxic, and the onset of neurodegenerative diseases. The economic costs of brain dysfunction are enormous, but this pales in comparison to the staggering emotional toll on the victims themselves and their families. In an attempt to improve the understanding of the causes of neurodegeneration, this study focuses on one potential aspect: the possible link between metals and neurotransmitter homeostasis utilising a variety of electronanalytical techniques. Adsorptive cathodic stripping voltammetry was employed to investigate the binding affinities and complex formation of melatonin and its precursor serotonin with calcium, potassium, sodium, lithium and aluminium. The results showed that all the metals studied formed complexes with both pineal indoleamines. However, the stability and affmity of the ligands toward the various metals varied greatly. The study suggests a further role for melatonin, that of metalloregulator and possible metal detoxifier in the brain, the in vivo studies which followed will further substantiate this notion. This research additionally focused on the cholinergic system, in particular acetylcholine complex formation studies with mercury, lead, cadmium, copper and zinc using the adsorptive cathodic stripping voltammetry method. The formation and characterisation of a solid mercury-acetylcholine complex lent further strength to the in situ electrochemical complex formation observed. The results showed the preference of acetylcholine for environmentally toxic heavy metals (such as Cd²⁺) over those divalent cations that occur naturally in the body. The possible metalloregulatory role melatonin played in the three brain regIOns: cerebellum, cortex and corpus striatum of male Wistar rats was studied as an in vivo extension of the earlier in vitro studies. Anodic stripping voltammetry was employed to detect metal levels present. The results showed that daily injections of melatonin was responsible for significantly decreasing copper(I), cadmium(II) and lead(II) levels in various regions of the rat brain of those animals that had undergone a pinealectomy in comparison to the saline injected group having undergone the same treatment. Histological and electrochemical stripping techniques were applied to investigate the implications of high A1³⁺ levels in the brain regions, particularly the hippocampus. Melatonin showed signs of promise in indirect symptom alleviation and by significantly decreasing A1³⁺ levels in rats that had been dosed with melatonin prior to A1³⁺ treatments in comparison with the control groups. Finally a preliminary study outlining a method for the production of a calcium selective microelectrode was undertaken. Further work is still needed to optimise the microelectrode production as well as its possible applications. However, whilst the overall conclusions of this entire multidisciplinary study may indeed only be in effect one piece of a very large puzzle on neurodegenerative diseases, this piece will no doubt serve as a building block for further ideas and work in this field.