No description available.

This thesis aimed to improve the methodology of disease-modification clinical trials in neurodegenerative disorders, with particular reference to Parkinson's disease (PD) and Alzheimer's disease. A systematic review was undertaken to determine what biomarkers for disease progression in PD exist, and whether any have sufficient evidence to be used in clinical trials. Included studies (n=183) were generally of poor quality, being cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, having flawed methodologies and applying simplistic statistical analyses. Insufficient evidence was, therefore, found to recommend the use of any disease progression biomarker in PD clinical trials. A subsequent review in Alzheimer's disease (n=59) demonstrated that these issues were not unique to PD. A 'roadmap' was, therefore, developed to improve future disease progression biomarker studies. The sensitivity to change of a range of PD clinical outcome measures was analysed using data from a follow-up study of an incident cohort of patients with parkinsonism. The MMSE, total UPDRS and PDQ-39 summary index were the most sensitive to change of the continuous outcome measures examined. Amongst binary outcome measures, a new 'dead or dependent' outcome measure was most sensitive to change, and was shown to be a feasible outcome measure for future PD RCTs. Finally, a systematic review was undertaken to examine the validity of differing clinical trial designs used in Alzheimer's disease and PD to demonstrate disease-modification. A variety of design strategies, including wash-in and wash-out analyses, delayed-start designs and long-term follow-up studies, have been used but have methodological limitations. No evidence was found of novel clinical trial designs having been used previously or planned for use in the future. Final recommendations are made that future disease-modification trials should be long-term follow-up studies involving newly diagnosed patients. 'Dead or 'dependent' is highlighted as an efficacious measure to use in such trials.

No description available.

University of Macau / Institute of Chinese Medical Sciences

Traumatic brain injury (TBI) is a devastating problem which stands as a leading cause of death and disability. The elderly is significantly affected by TBI, typically as the result of falls, and recovery is especially limited. This, in part, is associated with decreased tissue-specific stem cell regeneration and replacement of damaged cells in the aged brain. The diminished ability of the aged brain to recover is especially devastating after TBI, likely leading to permanent loss of sensory, motor, and cognitive functions. Studies have shown that the mature mammalian brain contains Neural Stem Cells (NSCs), found in specific regions of the brain, which can generate functional neurons during normal and pathological conditions. Two of those regions, the Dentate Gyrus (DG) of the hippocampus as well as the Subventricular Zone (SVZ) of the lateral ventricles, have proven to be niches for these multipotent NSCs. A key regulator in the maintenance of these NSCs is the Notch signaling pathway, shown to control proliferation, differentiation, and apoptosis of NSCs during development and throughout adulthood. In the current study, we assessed the regulatory mechanisms that drive the regenerative functions of NSCs in a neuropathological state following TBI. Using the Lateral Fluid Percussion Injury model, we analyzed the diffuse effects of the injury response on 3-month old male Sprague-Dawley rats. Immediately following TBI, Notch agonist, antagonist or vehicle was infused into the lateral ventricle for 7 days to assess the role of Notch signaling on neural stem cell proliferation/survival and neurogenesis at 30 days post-TBI. Dividing cells during infusion time were labeled with BrdU via single daily intraperitoneal injections for 7 days. Animals were sacrificed at 30 days post-injury and brain tissues were processed then immunolabeling for BrdU and Doublecortin. We found a higher number of BrdU-positive cells in the FPI+Notch1 agonist group when compared to Sham and FPI+Jagged-1 Fc antagonist groups in the contralateral granular zone. A significant increase in proliferation/survival was also seen in FPI+Notch1 versus Sham/FPI+Jagged-1 Fc and for FPI+Vehicle versus Sham animals in both the ipsilateral and contralateral hilus. DCX immunolabeling did not establish a significant difference in FPI+Notch1 compared to Sham animals, nor across any other groups, which is consistent with what we know of activation of the Notch pathway. Our results demonstrate that Notch1 signaling is directly involved in cellular proliferation/survival of NSCs in the DG following TBI at 30 days post-injury, but further work must be done to understand the fate of these cells. Thus, drug treatment targeting Notch1 signaling could serve as a potential therapeutic target following TBI to preserve NSCs and limit long-term cognitive deficits.

141 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Human Physiology and Pharmacology, 1970

No description available.

A diversity of organisms is endowed with the ability to emit light; this phenomenon is called bioluminescence and occurs mainly in marine organisms. Among echinoderms, some ophiuroid species (Echinodermata, Ophiuroidea) do possess this amazing capability of light production and are used as a study model in our laboratory. The present work investigates nervous control mechanisms of light emission at different levels such as extrinsic and intrinsic controls in three ophiuroid species: Amphiura filiformis, Ophiopsila aranea and Ophiopsila californica. Results were obtained by mean of different techniques such as pharmacology, immunohistochemistry, microspectrofluorometry measurements and patch-clamp. It appears from this study that nervous control of luminescence in ophiuroids presents a high diversity at all levels (e.g. neurotransmitters, second messengers, ion channels). Two new neurotransmitters have been identified as being inductors of light production in A. filiformis (tryptamine/octopamine) and O. californica (tryptamine) but up to now, all potential transmitters tested have failed to trigger luminescence in O. aranea. Some common features have however been highlighted between the studied species as to say the Ca2+ dependence of light emission and the cAMP pathway involvement. Moreover, the hypothesis of an indirect nervous control has been suggested for the three studied species. Therefore, a model can be presented in which neurotransmitters or electrical synapses, depending on the species, could act on the relay cell which would in turn activate the luminous cell (= photocyte) and induce photogenesis.

Thesis (M.S.)--University of Delaware, 2006. / Principal faculty advisor: Michelle A. Provost-Craig, Dept. of Health, Nutrition, and Exercise Sciences. Includes bibliographical references.

Nervous necrosis virus of Epinephelus malabaricus (MGNNV) belongs to the genus of Betanodavirus that causes vacuolating encephalopathy and retinopathy and viral nervous necrosis. A method to purify MGNNV was proposed. The cellular components of SSN-1 reprent few viral receptors for Betanodavirus. Several cellular virus binding proteins (VBPs) were detected by employing the technique of immobilizing virus on nitrocellulose. The least VBPs were found in SSN-1 cell lysate that was treated with proteinase K. The approaches used receptor antagonists to identify the cell receptor. The antagonists are able to block the viral binding and thus potentially directly against the receptor. The results implied that the receptor of serotonin 5-HT1A or £\2 adrenergic may act as the receptor of MGNNV.