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Thesis advisor: Thomas N. Seyfried / GM1 gangliosidosis is a glycosphingolipid lysosomal storage disease caused by a genetic deficiency of acid b-galactosidase (β-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Less information is available on the neurochemical pathology in optic nerve and sciatic nerve of GM1- gangliosidosis. Here we analyzed the lipid content and myelin structure in optic and sciatic nerve in 7 and 10 month old normal β-gal (+/?) and GM1-gangliosidosis β-gal (-/-) mice. Optic nerve weight was lower in the β-gal -/- mice than in unaffected β-gal +/? mice, but no difference was seen between the normal and the β-gal -/- mice for sciatic nerve weight. The concentrations of GM1 and GA1 were significantly higher in optic nerve and sciatic nerve in the β-gal -/- mice than in β-gal +/? mice. The content and composition of myelin-enriched cerebrosides, sulfatides, plasmalogen ethanolamines were significantly lower in optic nerve of β-gal -/- mice than in β-gal +/? mice, however cholesteryl esters were enriched in the β-gal -/- mice. No significant abnormalities in these myelin enriched lipids were detected in sciatic nerve of the β-gal -/- mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal -/- mice were also associated with abnormalities in the X-ray diffraction pattern including myelin content in fresh nerves [M/(M +B)] and periodicity (d). With the exception of a slight reduction in myelin content, no abnormalities in the X-ray diffraction pattern were observed in sciatic nerve of β-gal -/- mice. The results indicate that neurochemical pathology is greater in optic nerve than in sciatic nerve of β-gal -/- mice. / Thesis (MS) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Unlike the peripheral nervous system (PNS), adult neurons in the central nervous system (CNS) have limited regenerative capacity after injury. One interesting phenomenon observed nearly four decades ago was that lesion of a peripheral nerve can significantly enhance the regenerative capacity of the central axons of the corresponding dorsal root ganglion (DRG) neurons, termed a ‘conditioning lesion’, but the underlying mechanism is still not fully understood. Since ATP is released after nerve injury and extracellular ATP has a broad range of biological activities, we postulated that ATP might be the injury signalling molecule that triggers the regenerative machinery in the injured neurons. If that were the case, injection of ATP into a peripheral nerve should be able to mimic the effect of a conditioning lesion. To test this theory, we injected ATP into a peripheral (sciatic) nerve after a dorsal column transection and found that ATP injection did promote the regeneration of injured axons into the lesion cavity. We also found that ATP injection activated transcription factor STAT3 and increased the expression of growth associated protein 43 (GAP43) in the corresponding DRG neurons. ATP injection increased the concentrations of ciliary neurotrophic factor and interleukin-6 in sciatic nerve and DRG. These results indicate that intraneural injection of ATP can mimic conditioning lesion to a certain degree. Most interestingly, we found that a second injection of ATP one week after the first one markedly boosted the effects of the first injection as many more axons grew into or across the lesion compared with double saline injection or ATP plus saline injection. Double ATP injection is also more effective in sustaining the expression of phospho- STAT3 and GAP43. Immunohistochemical analysis showed ATP injection caused little Wallerian degeneration at the injection site. Behavioural tests showed no long-term adverse effects to the injected sciatic nerve. In order to explore the underlying mechanism of ATP induced elevation of the regeneration state of DRG neurons and look for more potent purinoceptor agonists to stimulate axonal regeneration, we first tried to identify the expression of purinoceptor subtypes in sciatic nerves using quantitative PCR and immunohistochemistry. We found that mRNAs for all the four P1 and fourteen P2 purinoceptor subtypes were expressed in the sciatic nerve, DRG or dissociated Schwann cells at various levels. Immunohistochemical analysis showed that purinoceptor subtypes are expressed by different types of cells. Due to the expression of nearly all purinoceptor subtypes in the sciatic nerve, it will be a big challenge to identify the receptor subtype(s) responsible for ATP induced axonal regeneration. We have set up a compartmented co-culture system to test various agonists/antagonists of purinoceptors. Taken together, we have shown that intraneural ATP injection can mimic conditioning lesion in promoting sensory axonal regeneration. Identification of the receptor subtype(s) and other molecules involved in the enhanced regeneration capacity of injured neurons may lead to the development of therapeutic agents to effectively promote the axonal regeneration of both peripheral and central neurons.

The present study has developed poly ε-caprolactone (PCL)/ poly lactic acid (PLA) films with specific internal structure suitable to prepare nerve guide conduit for peripheral nerve repair. The film preparation method has been carried out using an environmental chamber to prepare the solvent cast films with the specific surface structure. Different cellular behaviour of neuronal cell cultures was seen on the pitted films with different pits configurations (size and distribution). The consistent surface morphology provided a reliable surface structure for further in vitro and in vivo studies. The effect of a medical grade sterilisation process using gamma radiation at eight doses (0-45kGy) on PCL/PLA films was explored. It has been shown that material properties, including mechanical strength, were significantly affected, while cellular behaviour and responses (NG108-15) were improved. Grooved films with three groove shapes (Sloped, Square, and V shape) were prepared using patterned silicon substrates, photolithography and wet/dry etching. The groove patterns were successfully transferred and good mechanical strength was observed for grooved PCL/ PLA. Oriented growth of NG108-15 cells was observed on the patterned films with an improved alignment and organisation on SL and V shape grooved films. UV-ozone treatment was used to increase hydrophilicity of PCL/PLA films to improve Schwann cells behaviour. No negative effect was observed on cell growth and proliferation on the treated films however the mechanical properties were reduced. Schwann cells expressed typical long spindle-shape morphology with cell-to-cell interaction in longitudinal direction on the treated grooved films. Consistent to in vitro experiment with NG108-15, Schwann cells alignment was also improved on SL and V shape grooves. A three-week in vivo study was carried out to test grooved and non-grooved conduits in a rat sciatic nerve model. The grooved conduits showed better regeneration, with SL-grooved film showing a significant improvement of nerve regeneration. A separate in vivo study evaluated the effect of wall-thickness on nerve regeneration. However, it was shown that the wall thickness had no positive effect, and the conduit with improved mechanical strength adversely affected the nerve regeneration. In conclusion, a nerve guide conduit was developed with the optimised surface structure to support nerve regeneration. The promising in vitro and in vivo studies together with the suitable biomechanical properties and specific surface structure and morphology indicate that the grooved PCL/PLA conduit is a viable treatment for peripheral nerve repair.

Thesis (M. Med (Rad. Diagn.)) --University of Limpopo, Medunsa Campus, 2011 / Objective: The objective was to determine the incidence of missed pathology on normal non contrast enhanced cranial computed tomography (NECT).Method: Records of cranial computed tomography scans done over a 12 month period at the Dr George Mukhari Hospital were evaluated by three readers. The NECT and contrast enhanced cranial computed tomography (CECT) were read at separate occasions and readers did not have access to a history, each other’s interpretation or to their own interpretation of the NECT when the CECT was evaluated. The data was evaluated and analysed after the 3 readers had seen the cases individually. Interpretation discrepancies were resolved during a meeting between all 3 readers and consensus was reached. Cases with missed pathology on the NECT were evaluated retrospectively at a joint meeting between the 3 readers to determine whether the pathology was visible on the NECT and thus to determine the combined reader error rate. Results: In this study 3.28 % of cases had pathology missed by 3 readers on the NECT. Retrospective viewing reduced this to 1.42% indicating a reader error of 1.85%. This incidence of missed pathology correlates with the most recent studies done. Having a thorough medical history of the patient and selecting those with clinical findings indicating the need for a CECT will reduce the incidence of missed pathology.Conclusion: Patients with a normal NECT and no fever, meningism, confusion, focal/lateralizing signs, a history of tuberculosis or tumours, or risk factors for dural venous sinus thrombosis have a very small chance of missed pathology on NECT. The risk of contrast induced adverse events outweighs the risk of missing pathology on a normal NECT provided there is no clinical indication necessitating a CECT. Omitting unnecessary CECT will in turn reduce the risk of intravenous iodinated contrast and the radiation exposure to the patient. These two factors will ultimately reduce the running cost of the CT department and increase the throughput of patients. Alternatively omitting the NECT will reduce the radiation exposure to the patient.Reporting errors can be reduced by assessing and managing risk factors in each department i.e. viewing conditions and workload.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "December 2002." Typescript. Vita. Includes bibliographical references (leaves 117-119). Also issued on the Internet.

Vagus nerve stimulation (VNS) is an approved therapy for patients suffering from refractory epilepsy. While VNS is currently an open loop system, making the system closed loop can improve the therapeutic efficacy. Electrical recording of peripheral nerve activity using a nerve cuff electrode is a potential long-term solution for implementing a closed-loop controlled VNS system. However, the clinical utility of this approach is significantly limited by various factors, such as poor signal-to-noise ratio (SNR) of the recorded electroneurogram (ENG). In this study, we investigated the effects of (1) modifying the electrode contact dimensions, (2) implementing an external shielding layer on the nerve cuff electrode and (3) exploring shielded bipolar nerve cuff designs on the recorded ENG. Findings from both computer simulations and animal experiments suggest that significant improvements in peripheral nerve recordings can be achieved.

Vagus nerve stimulation (VNS) is an approved therapy for patients suffering from refractory epilepsy. While VNS is currently an open loop system, making the system closed loop can improve the therapeutic efficacy. Electrical recording of peripheral nerve activity using a nerve cuff electrode is a potential long-term solution for implementing a closed-loop controlled VNS system. However, the clinical utility of this approach is significantly limited by various factors, such as poor signal-to-noise ratio (SNR) of the recorded electroneurogram (ENG). In this study, we investigated the effects of (1) modifying the electrode contact dimensions, (2) implementing an external shielding layer on the nerve cuff electrode and (3) exploring shielded bipolar nerve cuff designs on the recorded ENG. Findings from both computer simulations and animal experiments suggest that significant improvements in peripheral nerve recordings can be achieved.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.