Thesis--University of Helsinki, 1975. / Bibliography, p. 37-43.

München, Techn. Univ., Diss., 2005.

Thesis (Ph.D.)--The University of Texas Southwestern Medical Center at Dallas, 2006. / Embargoed. Vita. Bibliography.

Thesis (M.S.)--Oregon State University, 2007. / Printout. Includes bibliographical references (leaves 54-60). Also available on the World Wide Web.

Thesis (M. S.)--Psychology, Georgia Institute of Technology, 2007. / Schumacher, Eric, Committee Chair ; Corballis, Paul, Committee Member ; Jacko, Julie, Committee Member.

No description available.

The purpose of this study is to examine the association between serum bilirubin and the development of age-related macular degeneration (AMD). The study design includes the utilization of a USA-nationally representative population based cross-sectional study in the National Health and Nutrition Examination Survey: specifically, the NHANES III and continuous NHANES from years 2005-2008. 15,501 survey participants from the NHANES studies chosen for this analysis were interviewed for demographic, behavioral, and medical information, put through a comprehensive medical examination segment, and a laboratory analysis portion. The 15,501 participants were chosen based on their age (40 and above) and the presence of fundus photographs. Fundus photographs were graded using standardized protocol to diagnose early and later AMD, which were combined to form the outcome "AMD" in a binary variable. Serum bilirubin levels were measured using spectrophotometry. Of the 15,501 participants in the study, 1305 (8.9%) were diagnosed with AMD. In a multivariate logistic regression adjusted for age, sex, smoking status, race, and serum C-reactive protein (CRP) levels, bilirubin was significantly associated with AMD (odds ratio, 0.728; confidence interval, 0.547-0.969; P value, 0.0296). The findings of this study indicate that the antioxidative effects of bilirubin may play protective role in the pathology of AMD.

Focal ischemic stroke cause alterations of the brain’s inherent excitation – inhibition balance in neurons around the infarct, and in distant areas connected to the damaged region. These widespread changes contribute to symptomatology and reduce activity in areas that have the capacity to functionally compensate for the effect of the focal lesion. The ability to control excitability in specific brain areas after stroke could restore normal excitability and promote functional recovery. Non-invasive brain stimulation techniques have the potential to produce targeted change in excitability in neural tissue. One such technique, transcranial direct current stimulation (tDCS), modulates cortical excitability in a lasting, polarity-specific manner. The hypotheses of this study were that 1) focal unilateral ischemic damage to the parietal cortex would produce repeatable alterations in the inhibitory network in ipsilateral and contralateral brain areas, and 2) tDCS applied after ischemia would alter the size of the lesion change the inhibitory networks. A unilateral non-invasive photothrombic stroke was produced under isoflurane anesthesia, and cathodal (n=5), anodal (n=5), or sham (n=6) tDCS (5 minutes, 10.0mA) was subsequently administered to the site. Four additional animals were assigned to sham operation groups that did not undergo photothrombosis. Animals recovered for 24 hours, after which their brains were cut, and prepared for single- and double-labeled immunocytochemistry to analyze the functional activity of excitatory neurons and inhibitory interneurons, astrogliosis, and neuronal degeneration. Results demonstrate that unilateral ischemic injury does not produce a hyperexcitability of the contralateral cortex or otherwise alter the activation status of immunohistochemcially-defined inhibitory or disinhibitory neurons, a finding discrepant with the rationale used to treat ischemic injury in humans. Similar findings were identified in the ipsilateral cortex. Results did show that ischemia activated white matter neurons, as well as neurons in layer III ipsilateral to the lesion extending 1-2mm into the intact cortex. Neurons degenerating as observed by Fluoro-Jade B revealed clusters of pyramidal-shaped neurons in layer V which extended quite far from the lesion site. Addition of cathodal, but not anodal tDCS produced an overall decrease in the lesion size, but this decrease was not statistically reliable. Stimulation also did not obviously alter the activation status of inhibitory or disinhibitory neurons. Both types of stimulation prevented the appearance of degenerating cells in layer V, and anodal tDCS reduced the activation of excitatory layer III excitatory neurons. These findings illustrate the utility of using tDCS during the production of a lesion to mitigate the size and impact of lesion and raises questions on the rationale rationale for applying brain stimulation to the contralesional cortex to treat stroke, at least in the acute stage. Finally, the series of studies here illustrate the extent to which the lesion causes widespread and specific neural circuits, and highlights the potential of tDCS use in manipulating the activity of these circuits.

Traumatic brain injury (TBI) is a common event that can lead to profound consequences for the individual involved, and a considerable socio-economic cost. The initial injury event triggers a series of secondary brain injury mechanisms that lead to further mortality and contribute to morbidity. One classical injury pathology is termed traumatic axonal injury (TAI), which in clinical settings produces the picture of diffuse axonal injury. TAI occurs both as a primary insult, and as a consequence of secondary mechanisms. One secondary injury mechanism that worsens TAI may be Wallerian degeneration (WD), a cell-autonomous axonal death pathway. The relationship between traumatic axonal injury and WD is poorly characterised. This thesis explores the basic mechanisms by which a physical axonal trauma can lead to WD, and how modulation of the WD pathway can affect the cellular responses to a traumatic injury. This involves the development and characterisation of in vitro and in vivo models of traumatic axonal injury. These models are then used to explore the response of cellular cultures to injury when treated with pharmacological and genetic modulators of WD. Using a primary neuronal stretch-injury system we demonstrate that rates of neurite degeneration are altered by modulators of the WD pathway but that a purported neuroprotective compound ‘P7C3-A20’ did not protect primary cultures in vivo and did not act via a WD dependent mechanism. An organotypic hippocampal slice stretch injury model was then used to demonstrate genetic rescue of cellular death, and used to assess amyloidogenic responses to injury. Next we established a TBI model using Drosophila Melanogaster, and demonstrated that a loss of function mutation in a key WD gene ‘highwire’ which controls NMNAT levels, was capable of rescuing premature death and a range of behavioral deficits after a high impact trauma. The injury caused dopaminergic neuronal loss and this was rescued by highwire mutation. Furthermore, this dopaminergic neuronal protection extended to a genetic PINK1 model of Parkinsonism. Together these results help establish WD as an important secondary injury mechanism in TBI, and provide evidence that modulation of the WD pathways can improve outcomes in various model systems. This provides a foundation for future translational research into the fields of WD and TBI.

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years. Environmental and genetic risk-factors contribute to the development of AMD. An AMD-risk locus on chromosome 10q26 spans two genes, ARMS2 and HTRA1, and controversy exists as to which variants are responsible for increased risk of disease. Recent work suggests that HTRA1 expression levels are significantly increased in carriers of the risk haplotype associated with AMD. However, relatively little is known about the interactions, substrate specificity and roles in disease played by this secreted serine protease. This thesis aims to elucidate the potential role played by HTRA1 in AMD pathogenesis. A combination of tandem affinity purification (TAP) and yeast two-hybrid techniques was used to identify interacting partners of HTRA1. A number of proteins, with diverse roles in the alternative complement pathway, cell signaling, cell-matrix interactions, inflammation, angiogenesis and fibrosis, were identified. These are attractive candidates for further study as such processes are disturbed in AMD, implicating HTRA1 and its binding partners in disease development. One interacting partner, Complement Factor D (CFD), is a key activator in the alternative complement pathway. CFD, a 24 kDa serine protease, is expressed as an inactive zymogen, from which a signal peptide and activation peptide are cleaved before release of the mature, active protein into the circulation. In vitro studies show that CFD interacts with, and can be a substrate for, HTRA1. The interacting domain between the two proteins is localised to a region of 30 amino acids at the N-terminal end of proCFD. The 5 amino acid pro-peptide of CFD appears to be both necessary and sufficient for proteolysis of CFD by HTRA1. Investigation of the functional relevance of the interaction between HTRA1 and CFD shows that proCFD is cleaved by HTRA1, whilst mature CFD is not subjected to proteolysis. HTRA1-mediated cleavage of CFD forms an active protease, leading to activation of factor B in the alternative complement pathway in in vitro assays. Furthermore, a normal complement response is restored to CFD-depleted serum by addition of proCFD activated by HTRA1. Thus, an HTRA1- mediated increase in alternative complement pathway activity may explain a proportion of the AMD-risk attributed to the chr10q26 locus. Genetic and protein-based approaches were used to study the potential role of CFD in AMD pathogenesis, independent of an interaction with HTRA1. An intronic SNP, rs3826945, was significantly associated with increased risk of AMD in two British case-control cohorts, and in a combined meta-analysis with 4 additional cohorts from North America and Europe (p-value = 0.032, Odds Ratio = 1.112 in 4765 cases and 2693 controls). Assessment of copy number variation and sequencing of CFD did not identify any functional variants which may explain the association with disease. However, plasma levels of CFD were measured by ELISA in 751 AMD cases and 474 controls, and were found to be significantly elevated in AMD cases compared to controls (p-value = 0.00025). This further implicates complement activation in AMD pathogenesis, and makes CFD an attractive candidate for therapeutic intervention. An alteration in the level of activated CFD, possibly mediated via an interaction with HTRA1, either at the systemic or local tissue level, may play a role in disease development and progression.