Parkinson's disease (PD) is a neurodegenerative disorder that is characterised by uncontrollable shaking, muscular rigidity and cognitive impairment, due to low levels of dopamine caused by loss of dopamine containing neurons (DCN). The loss of DCN has been strongly associated with Caspase mediated apoptotic death. At present there are many studies that indicate exercise is beneficial in PD treatment, but there is a lack of research exploring the potential pathways, which exercise can activate and suppress to provide such positive and even negative effects. This study is the first to explore the effect of treadmill exercise on the level of Caspases, along with CAMK-IV protein in different brain regions of MPTP-treated rat model, using WB analysis. The results of this research has demonstrated reduction or completely suppression of some active Caspases, as well as, elevated amount of CAMK-IV in different brain regions of exercised PD animal model. To determine how exercise is reducing and inhibiting activation of Caspases, the first step was to identify how Caspases are stimulated, using ReNcell VM stem cell line that had been differentiated and treated with 6OHDA. The results of the study demonstrated 6OHDA triggered Caspase mediated apoptotic death of dDCN via PERK ER stress and NFκB classical pathway. IF, WB and cell viability analysis, using a wide range of inhibitors, showed that Caspase-2 is activated by the PERK pathway of ER stress and NFB classical pathway in 6OHDA treated dDCN. 6OHDA triggered activation of Caspase- 8 by the classical pathway in NFB mediated death of dDCN. 6OHDA triggered Caspase-4 activation but the exact mechanism involved remains to be identified. Only through understanding the molecular pathways regulating death of DCN in PD, new potential targets for therapy may be identified, which may ultimately reduce further death of DCN and slow PD progression. This proposed study has the potential to seek for more efficient drugs, which can suppress Caspase activation by targeting key targets in the pathways that the Caspases follow. These new specific targeted drugs could be used with treadmill exercise to achieve maximum effect, by slowing down or inhibiting further death of DCN.

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

(3aR)-14a-Acetoxy-3aß,4,14,14aa-tetrahydro-6,7,8-trimethoxybenzo[3,4]furo[3',4':6,7]cycloocta[1,2-f][1,3]benzodioxol-3(1H)-one (steganacin), 56, has been a popular synthetic target due to its perceived cytotoxic activity. Our proposed strategy for the construction of the key 8-membered ring embedded within steganacin was via an oxidative phenolic coupling of an appropriate (3R,4R)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-benzyldihydrofuran-2(3H)-one analogue which were shown to be readily available from commercially available piperonal in six linear steps involving chain extension, reduction, trichloroacetylation and cyclisation via a copper-catalysed Atom Transfer Radical Cyclisation (ATRC) reaction. In this way, copper-catalysed ATRC reaction of (E)-6-(benzo[d][7’,9’]dioxol-1’-yl)allyl-1,1,1-trichloroacetate afforded (R)-4-{(R)-benzo[d][1,3]dioxol-5-ylchloromethyl}-3,3-dichlorodihydrofuran-2(3H)-one in good isolated yield as a mixture of diastereosiomers. Regiospecific functionalisation of these trihalides at the benzylic position (via an SN1, solvolysis, pathway), followed by dehalogenatioin and subsequent enolate alkylation afforded the key butyrolactone intermediates whose oxidative cyclisation was the key bond construct in our approach to steganacin. Contrary to our expectations it was observed that these substrates suffer intramolecular Friedel-Crafts alkylation reactions, favouring a 3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (6 member ring) formation, rather than phenolic oxidative coupling reactions that would favour the steganacin-like (3aR,11aR,Z)-3a,4,11,11a-tetrahydrobenzo[4,5]cycloocta[1,2-c]furan-1(3H)-one (8 member ring) formation, when the oxidant has any Lewis acid capacity. Taking these observations into account we believe that by judicious choice of synthetic route the ATRC chemistry developed during the current research could be applied to a highly convergent (9 step) route to the synthesis of deoxypodophylotoxin.This work also describes, in detail, the efforts of this worker to establish and optimise a robust route that potentially can lead to the formation of steganacin via the alternative route of an initial microwave-assisted Pd-mediated biaryl coupling of either bromopiperonal or an halogenated derivative of the described γ-butyrolactones with an appropriate boronic acid derived from commercially available 3,4,5-trimethoxybenzalcohol to afford the biaryl scaffold present in steganacin. The completion of this synthesis was unfortunately left unaccomplished due to time constraints.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23105号 / 医博第4732号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 上野 英樹, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The mapping of the refractive index of cells has been extensively studied since 1950s. This optical parameter constitutes a key biophysical property strongly correlated to fundamental cell parameters such, e.g., intracellular mass distribution and protein concentration. Experimental studies evidence that the cell refractive index (Refractive Index) provides critical insights to understand diverse cellular structures and interpret pathological states, including diverse stages of diseases. However, measuring the refractive indices of biological specimens satisfying clinical requirements is currently challenging, since there is a lack of spectral signatures of sub-cellular components in the visible range due to their transparent nature. Designing methods capable of extracting visible fingerprints of cellular components remains attracting large research interests. In this work, I have contributed to this project by fabricating and characterizing a black nanostructured membrane that dynamically interacts with cancerous cells and furnishes label-free structural color generation by exploiting the inherent contrast mechanisms of them. Thus, adequately meeting morphology differentiation to assist in biomedical research. I have tested the system with HCT116 colorectal cancer cells. In addition, this special membrane allows refractive index recovery and cell thickness mapping with commonly available bright-field microscopy equipment. Therefore, it is of considerable clinical importance to allow the generation of qualitative information about cell morphology to add in medicine and biophysics research.

No description available.

Parkinson's disease (PD) is a progressive disorder that affects movement, muscle control and balance. Second only to Alzheimer's disease, PD is one of the most common neurodegenerative disorders in the United States (Lai & Tsui, 2001:135), affecting approximately one million people in the U.S. alone (Parkinson's disease Foundation [PDF], 2009). While the cause of Parkinson's disease remains unknown, there are certain known risk factors associated with the disease. One of the risk factors is increasing age. PD is most frequently associated with older adulthood, affecting one in 100 Americans 60 years and older (PDF). Over the next five decades, the incidence of PD is expected to triple, as the average age of the population increases (Lai & Tsui, 2001:135). Parkinson's disease is a chronic, progressive disorder, with no known cause or promising cure. While substantial information is known about the medical aspect of Parkinson's disease, little is known about the illness experience of living with the disease. The goal of this study was to explore and describe the experiences of people living with Parkinson's disease. The guiding research question was: What are the experiences of people living with Parkinson's disease? A qualitative research approach was followed, with a collective case study research design. The population for this study included people who are in the late stage of Parkinson's disease, thus being diagnosed with Parkinson's disease before 2012 and who are receiving support services from Parkinson's Association of South Africa (PASA). Non-probability purposive sampling was utilized to generate a sample. Ten participants who met the criteria were selected for this study. Semi-structured individual interviews were conducted with participants. Interviews were voice recorded with the permission of the participants and were transcribed. The data gathered were analysed by the researcher and themes and sub-themes were identified. The research findings were presented and critically discussed. Literature control and verbatim quotes were used to support the findings. The conclusions of this study reflected that the experiences of people living with Parkinson's disease are complex. Throughout the study it was found that Parkinson's disease impacts significantly on the physical, psychological and social well-being of people living with this disease in a number of ways. The recommendations offered by this study can be used by professionals working in the field of chronic, geriatric and neurodegenerative illnesses to understand the experiences of people living with Parkinson's disease. / Mini Dissertation (MSW)--University of Pretoria, 2016. / Social Work and Criminology / MSW / Unrestricted

Background: Parkinson's disease (PD) is a debilitating progressive neurological disorder. The main clinical features of PD are: rigidity, bradykinesia, akinesia, and resting tremor. People living with PD often present with impaired gross- and fine upper-limb motor control and ocular tracking. The impaired motor control associated with PD results in difficulty performing basic- and instrumental activities of daily living (BADLs and IADLs). Virtual reality (VR) therapy is an emerging treatment strategy used to address movement impairment in people with neurological diseases, but has not been extensively researched in the rehabilitation of people with PD. This study aimed to determine the effectiveness of VR therapy as a treatment modality for the rehabilitation of upper-limb function during BADLs and IADLs and ocular tracking for people with PD, when compared to conventional physiotherapy. Methods: A single blind randomised control trial was done. Participants were randomly allocated to either the conventional therapy (control) or VR therapy (experimental) groups using the concealed opaque envelope method. Twenty-two participants who gave informed consent were included, if they met the following criteria: Confirmed PD diagnoses; scored above 24/30 for the Mini Mental State Examination; and did not suffer from uncontrolled co-morbid diseases. The control- and experimental groups underwent twelve intervention session of 45 minutes. The control group participated in conventional physiotherapy sessions and the experimental group used the X-box Kinect© VR apparatus during treatment. Participants were assessed at baseline and post-intervention (directly following the 12 session) with the: 9 Hole Peg Test (9HPT), Test d'Evaluation des Membres Superieurs De Personnes Agees (TEMPA) and the King Devick Test. Results: The TEMPA was used to determine unilateral- and bilateral upper-limb function during IADLs and BADLs. Three of the four items of the TEMPA that assessed bilateral upper-limb function indicated statistically significant improvement when the difference between the control and experimental groups were compared post-intervention (Task1 p=0.611; Task 2 p=0.0043; Task 3 p=0.0078; Task 4 p=0.0002). Similarly, three of the four items of the TEMPA that assessed unilateral upper-limb function indicated statistically significant improvement for the experimental group, when compared to the control- group post-intervention (Task 5 p=0.0151; Task 6 p=0.4118; Task 7 p=0.0064; Task 8 p=0.0009). The 9HPT assessed in-hand manipulation and fine upper-limb function. Results from the 9HPT for the left- and right hands of both groups showed clinically significant improvements from baseline to post-intervention, but there was no statistically significant difference between the two groups. The King Devick test was used to assess ocular tracking. The comparison of change between the two groups from baseline to post-intervention on the King Devick did not indicate clinically- or statistically significant change. Discussion and Conclusion: The findings from the bilateral IADL and BADL tasks as measured with the TEMPA are similar to findings in the literature. The results show that VR therapy improve motor control of the upper-limb significantly when both hands work together and when the upper-limbs are moving unilaterally. VR therapy might be more effective than conventional physiotherapy because it allowed for repetitive practice of functional activities, which aided the development of limb control and functional muscle strength. The VR therapy also allowed task-oriented training to occur repetitively. Task-oriented training is known to aid neural plasticity and facilitate functional rehabilitation. The insignificant differences between the groups on the 9HPT is an indication that the task performed for this outcome measure is not specific enough to detect hand function and grip strength. The King Devick test did not indicate change for the control- or experimental groups, which indicates that specific ocular tracking exercises should be included in therapy to address this impairment. / Dissertation (MPhysiotherapy)--University of Pretoria, 2016. / Physiotherapy / MPhysiotherapy / Unrestricted

The solid-state interaction of palladium (Pd) with single crystal silicon carbide (6H- SiC) before and after annealing has been investigated using Rutherford backscattering spectrometry (RBS) in conjunction with RUMP simulation package, time-of-flight elastic recoil detector analysis (ToF-ERDA), glancing incident X-ray diffraction (GIXRD) and scanning electron microscopy (SEM). A thin layer of Pd (500 A) was deposited onto a clean 6H-SiC substrate at room temper- ature. The prepared difusion couples were then annealed in vacuum at different annealing temperatures for a maximum period of 1 h. The annealing temperature ranged from 2000C to 8000C. The composition of the as-deposited and the annealed samples was measured by using a He+ beam with an energy of 1.6 MeV. The ToF-ERDA measurements were per- formed on the as-deposited sample by using a high energy copper beam (about 30 MeV) for elemental depth distribution. The GIXRD measurements performed on the samples were able to identify the phases that form before and after annealing. The SEM micrograph obtained during this study gave some insight on the surface morphology of the samples before and after annealing. Our results obtained during this study showed that Pd reacts with SiC after annealing at 4000C resulting in the formation of metal-rich silicides and some unreacted Pd. Annealing at higher temperatures (5000C and 6000C) produced metal-rich silicides, which continued to grow until all the Pd has been consumed. Annealing at even higher temperatures (7000C and 8000C), the metal-rich silicides disappear and the silicon rich silicides start appearing. These appear by simply consuming the metal-rich silicides, resulting in the formation of two or more phases. The behaviour of the interaction between Pd with 6H-SiC is different than the Pd-Si system. The reaction temperature of the Pd/SiC are much more higher than those of the Pd/Si system. That is, Pd reacts with Si at temperatures as low as 2500C, while it starts to react with SiC at an annealing temperature of 4000C. In addition to this silicides such as Pd9Si2, Pd4Si form at the initial reaction temperature followed by the formation of the Pd2Si phase at the temperatures above 6000C for the Pd/SiC system. Meanwhile in the Pd/Si system the Pd2Si phase remains stable even after annealing at 8000C. No carbon compounds were observed in the temperature range used in this study and the formation of silicides were found to be accompanied by the formation of free carbon which remained immobile in the system. / Dissertation (MSc)--University of Pretoria, 2012. / Physics / unrestricted

In the study of covert visual attention, two event-related potential (ERP) components have been identified by earlier research. The N2 posterior contralateral (N2pc) component has been suggested to index the enhancement of attention to a specific lateralized target item. The distractor positivity (PD) component has been suggested to index the suppression of distractors appearing in the same search array. Earlier studies have reported different latencies for the PD component depending on the task and experiment. Furthermore, the N2pc and the PD component are not always elicited in the same experiment. Relative target-to-difficult-distractor placement have been shown to affect the mean amplitude of the N2pc. Less is known about how different relative placements affect the PD component. The aim of the present study was to try and elicit both an N2pc and a PD component in the same visual search paradigm. The PD was recorded later time-window which previous studies have suggested to indicate the ending of attention to a previously attended target. Three relative placements were analysed, horizontally opposite, vertically opposite and diagonally opposite. When combining all three relative placements an N2pc component was elicited contralateral to the target. No PD component was found when combining all relative placements. A larger mean amplitude N2pc was measured for the vertically opposite condition. The results are not in line with previous research, that have found the N2pc to be smaller in conditions where both target and distractor are on the same side of the visual field. However, when comparing upper and lower visual field targets the N2pc was found to be larger for lower visual field stimuli, which is in line with previous research. A larger mean amplitude for the PD was found in the diagonally opposite condition. Earlier research has suggested that when difficult distractor and target are located on separate sides of the visual field, this leads to successful inhibition, indexed by the PD component. In contrast to earlier research a larger PD component was not found for upper visual field stimuli. The present study differs from previous studies in the way the target and difficult distractor were placed and analysed. By separating what has previously been called “opposite side” condition into two separate conditions diagonally opposite and horizontally opposite the results from the present study seem to suggest that these two conditions are not synonymous. However, the results should be regarded with caution due to the small sample size. Furthermore, the horizontally opposite side condition also differs from previous studies with regards to relative target and distractor distances, which could have had an effect on the results.