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Li, Sheng Nan. "Investigation on ion channel interactions and neuroprotective activities of novel peptides from medicinal coral." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3952134.
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Hartmann, Bernadette [Verfasser], and Wolfgang [Akademischer Betreuer] Schlegel. "A Novel Approach to Ion Spectroscopy of Therapeutic Ion Beams Using a Pixelated Semiconductor Detector / Bernadette Hartmann ; Betreuer: Wolfgang Schlegel." Heidelberg : Universitätsbibliothek Heidelberg, 2013. http://d-nb.info/1177809451/34.
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Breithaupt, Bernadette [Verfasser], and Wolfgang [Akademischer Betreuer] Schlegel. "A Novel Approach to Ion Spectroscopy of Therapeutic Ion Beams Using a Pixelated Semiconductor Detector / Bernadette Hartmann ; Betreuer: Wolfgang Schlegel." Heidelberg : Universitätsbibliothek Heidelberg, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:16-heidok-156907.
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Rinaldi, Ilaria [Verfasser], and Katia [Akademischer Betreuer] Parodi. "Investigation of novel imaging methods using therapeutic ion beams / Ilaria Rinaldi ; Betreuer: Katia Parodi." Heidelberg : Universitätsbibliothek Heidelberg, 2011. http://d-nb.info/1179230353/34.
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Richards, Duncan B. "Human platelet ion flux and aggregation as pharmacodynamic surrogate markers for therapeutic hypothesis testing in patients with heart failure." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404200.
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Lau, Khim Heng. "Development and application of high-resolution secondary ion mass spectrometry analysis of therapeutic and imaging molecules in cells and tissue sections." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543023.
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Hoppe, Alexander [Verfasser], Aldo R. [Akademischer Betreuer] Boccaccini, and Uwe [Akademischer Betreuer] Gbureck. "Bioactive Glass Derived Scaffolds with Therapeutic Ion Releasing Capability for Bone Tissue Engineering / Alexander Hoppe. Gutachter: Aldo R. Boccaccini ; Uwe Gbureck." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2014. http://d-nb.info/1065004966/34.
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Brecht, Ellliott James. "Neuropeptide Modulation of the Large Conductance Potassium (BK) Channel in the Auditory System: Therapeutic Implications for Age-Related Hearing Loss." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6641.
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The auditory temporal processing deficits associated with age-dependent hearing decline have been increasingly attributed to issues beyond peripheral hearing loss. Age-related hearing loss (ARHL), also known as presbycusis, is linked with changes in the expression of both excitatory and inhibitory neurotransmitters in the central auditory system. There are also age-related changes in the expression and function of the ion channels which mediate action potential firing. The slow, Ca2+ activated, K+ channels of the BK-type are essential in controlling both neurotransmitter release and neural communication via alteration of action potential durations, firing frequency, and neural adaptation. There are many subsets of this type of ion channel located throughout the body, and though it is evident that these channels are involved in cellular activation within the peripheral auditory system, little is known about their contribution to auditory processing in the brain. There is a need for further understanding of the functional involvement and mechanisms of neurotransmitter loss and how this relates to the BK channel and auditory disorders such as presbycusis and tinnitus (the perception of a phantom sound). My research focused on investigating how the downregulation of neurotransmitter production and the reductions in BK channel expression affect ARHL. I also evaluated a custom BK-channel modulating peptide as a path towards a possible therapeutic intervention for age-related hearing loss. This custom peptide is especially useful because it reduces the potential for serious side effects, due to mechanisms which best mimic natural occurring peptide systems.
The initial investigation described in this dissertation measured auditory system changes in aged mice that occurred following a drug-induced increase in the availability of the inhibitory neurotransmitter GABA. This increase in GABA decreased minimum response thresholds in the auditory midbrain of aged mice, bringing them to levels seen in young adult animals. The other changes that occurred following increased GABA availability were increased acoustically driven neuronal firing rates, frequency-dependent decreases in spontaneous rates, and increases in the symmetry of the receptive fields. The return of clear and fine-tuned acoustically-evoked responses in aged mice was a major finding of this experiment.
The second phase of the dissertation built on this demonstration that modulation of the aged auditory system was possible by changing neurotransmitter levels. This second portion of the study focused on how a novel potent neuropeptide (LS3), which increases the probability of the BK channel remaining in the closed conformational state, might invoke alterations in auditory-evoked responses. First, the LS3 neuropeptide was used to modify addictive behavior in the C. Elegans; followed by evaluation of in vitro changes to a human cell line. This study then confirmed that LS3 is a potent BK channel modulator with a greater affinity than those known toxins classified as high-affinity toxins. In vivo testing demonstrated that LS3 could rapidly cross the blood-brain barrier (BBB) following systemic injections, where it altered auditory evoked activity in a manner similar to that of the direct application to the dura over the midbrain. This work demonstrates that the BK channel is highly responsible for the control of auditory-evoked neurological processes, and that a potent BK channel modulator may be useful for the treatment of certain neurological disorders.
The third study was designed to confirm that the BK channel plays an important role in sound-evoked activity generated in the auditory midbrain, by testing the effects of a general BK channel pore blocker, PAX. The results established that the BK channel is vital for sound processing in the midbrain of young adult mice, and is responsible for the maintenance of receptive field properties. I also evaluated the role it plays in temporal processing, which is an underlying mechanism for the processing of neurologically-relevant complex acoustic signals such as speech. Here, blocking of the channel increased (worsened) the threshold for the detection of a silent gap-in-noise and the neural recovery functions that occurred following the stimuli.
The fourth study significantly expanded the in vivo testing of the custom peptide channel blocker, LS3, and added a behavioral measure of changes to auditory perception in addition to the electrophysiology recordings. The auditory-evoked receptive fields from midbrain neurons were modulated in a dose-dependent manner following the application of LS3. The neural recordings took place in the inferior colliculus, where the dorsal region responds to low-frequency sounds and ventral areas to high frequencies. The LS3-induced suppression or enhancement of evoked responses was different for the various tonotopic regions of the auditory midbrain. The improvements shown in receptive fields and improvement in auditory perception indicates a plausible route for direct translational treatment of auditory disorders through small custom peptide therapeutics. These studies provide supportive information about how auditory evoked responses in the midbrain, including the coding of different sound features, are affected by the down-regulation of a key inhibitory neurotransmitter (GABA), and how GABA-dependent neural evoked responses are altered in older mice through the modulation of BK channel activity.
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Ciraldo, Francesca E. [Verfasser], Aldo R. [Akademischer Betreuer] Boccaccini, and Brovarone Chiara [Gutachter] Vitale. "Design, processing and characterization of mesoporous glass coatings with therapeutic ion release capability / Francesca Ciraldo ; Gutachter: Chiara Vitale Brovarone ; Betreuer: Aldo R. Boccaccini." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1225122635/34.
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Ciraldo, Francesca [Verfasser], Aldo R. [Akademischer Betreuer] Boccaccini, and Brovarone Chiara [Gutachter] Vitale. "Design, processing and characterization of mesoporous glass coatings with therapeutic ion release capability / Francesca Ciraldo ; Gutachter: Chiara Vitale Brovarone ; Betreuer: Aldo R. Boccaccini." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1225122635/34.
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Jonsson, Alexander. "Investigation of pore size effects at separation of oligonucleotides using Ion-pair RP HPLC : Examining of how the particle pore size of the stationary phase affects separations of oligonucleotides in therapeutic range." Thesis, Karlstads universitet, Fakulteten för hälsa, natur- och teknikvetenskap (from 2013), 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-73367.
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Oligonucleotides may become a new class of therapies with the potential of curing many today untreatable diseases. Oligonucleotides becomes increasingly more difficult to separate with an increase in length since the relative difference in retention of these very similar compounds becomes increasingly smaller. Therefore, coelution of impurities formed during synthesis may result in insufficient purity, which is necessary for therapeutic treatments. Oligonucleotides are also relatively large biomolecules, possibly consisting of hundreds of nucleotides. As a result, oligonucleotides may have limited diffusion through the stationary phase pores which affects separation performance. Surprisingly few studies have be published in this research area and a wider knowledge in how this affects separation is needed. In this master thesis, separation of deoxythymidine oligonucleotides with 5-30 mers in length were separated with 60, 100, 200 and 300 Å pore size reversed phase C4 columns. It was concluded that pore size resulted in more restricted diffusion if insufficient pore size was used. Poor peak performance was also observed with too large pore sizes which lead to less efficient separations.
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BARRIO, GRACIELA. "Desenvolvimento de tecnologias de preparo de geradores de sup(90)Sr/sup(90)Y na Diretoria de Radiofarmacia do IPEN/CNEN-SP." reponame:Repositório Institucional do IPEN, 2010. http://repositorio.ipen.br:8080/xmlui/handle/123456789/9600.
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Dissertacao (Mestrado)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP
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Félix, Bautista Renato [Verfasser], and Joao [Akademischer Betreuer] Seco. "Monitoring of lateral positions of therapeuthic carbon-ion pencil beams using secondary ion tracking / Renato Félix Bautista ; Betreuer: Joao Seco." Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1236574311/34.
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Siddique, Muhammed Rashid. "Improving leukaemia diagnosis and management with Selected Ion Flow Tube Mass Spectrometry and vibrational spectroscopy techniques." Thesis, Keele University, 2017. http://eprints.keele.ac.uk/3138/.
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Leukaemia is 11th most common cancer worldwide, associated with poor prognosis. The 10 years’ survival for leukaemia is between 44%-47%. One of the main reasons for this is the disease being diagnosed in late stages. Most of leukaemia screening techniques are invasive or give radiation. It is therefore obvious to improve prognosis and refine diagnostic techniques for early detection, and better management of its therapeutic response. Spectroscopic and spectrometric techniques are widely used by a huge group of scientists; as biochemical analysis of the disease, may provide biochemical signatures to be used in diagnostics and management of the disease. In this work, the feasibility of measuring both qualitatively and quantitatively VOCs released by PBMC, leukaemia cells and BM cells in vitro has been shown. There are clear differences in the VOCs profile even among different leukaemia cells lines as well as from leukaemia cells exposed to drugs, PBMCs and bone marrow. These differences in the VOCs release could be exploited towards a clinical application of SIFT-MS in the diagnosis and therapeutic response of the disease. Direct sampling is the most convenient method of sampling, which could avoid loss of the many important VOCs by diffusion and/or absorption. Since it is not very easy to obtain direct breath, appropriate storage of exhaled breath and transportation are very important issues to be considered. My study proved that stability over time might vary for different VOCs, especially those present in smaller concentrations. The addition of Imatinib or Nilotinib to K562 cell clones induces changes in cell biology and cellular structure which translates into changes in the S-FTIR spectra and Raman Spectra of the cells. There are remarkable differences in the biochemical composition of cells incubated at different drug concentrations and at different levels of oxygen. Further studies are needed to confirm these changes in the spectra.
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Munasinghe, Nehan. "Targeting voltage-gated sodium and calcium channels in primary sensory neurons for the development of chronic pain therapeutics." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18928.
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Chronic pain is a debilitating condition that affects both the emotional and physical well-being of an individual. Current therapeutics for chronic pain are relatively ineffective and produce many adverse side effects including tolerance development and addiction. Therefore, the search for novel chronic pain treatments remains a focus of worldwide research. This thesis studied the changes in the function of voltage-gated sodium (NaV) and calcium (CaV) channels in primary sensory neurons located in the dorsal root ganglion (DRG). These neurons are a gateway for sensory processing of nociception. Whole cell patch clamp electrophysiology was conducted on acutely isolated DRG neurons from male Sprague Dawley rats to characterise the activity of a range of compounds. DRG neurons were discriminated based on isolectin-B4 binding (peptidergic neurons do not stain) and cell size (<25 μm= small). The first project aimed to identify the efficacy of two spider toxins, Hs1a and Pn3a that are selective for voltage-gated sodium channel 1.7 (NaV1.7). In humans, the loss function mutation in the SCN9A gene that codes for NaV1.7 cause insensitivity to pain, while the gain of function mutations result in paroxysmal extreme pain disorder, and primary erythromelalgia. NaV1.7, therefore, plays a vital role in pain. In this project, tetrodotoxin (TTX) was utilised as a positive control to inhibit all NaV channel subtypes except NaV1.5 (not expressed in neurons), 1.8, and 1.9. Results revealed that small peptidergic neurons were the most sensitive to TTX, Hs1a, and Pn3a. Since TTX potently blocks NaV1.7 channels, the greater inhibition of sodium current (INa) in small peptidergic neurons corralates with the high level of TTX mediated inhibition. Also, small non-peptidergic DRG neurons had the slowest decay kinetics potentially due to high expression levels of NaV1.8 channels with slower kinetics, which are known to be insensitive to TTX, Hs1a, and Pn3a. In contrast to Hs1a which is equipotent at NaV1.1 and 1.7 channels, Pn3a is at least 40-fold more selective towards NaV1.7 than other NaV channel subtypes. Pn3a inhibited significantly less INa in large peptidergic DRG neurons, which have low levels of NaV1.7 expression compared to small peptidergic neurons. Overall, these results show promise that Pn3a may be able to selectively inhibit NaV1.7 and prevent the generation of action potentials in the DRG neuron to mitigate pain signals from travelling to higher brain regions. μ-Opioid and opioid receptor like receptor 1 (ORL-1) are implicated in pain pathways. However, opioids that mediate their response through μ-opioid receptors are relatively ineffective in chronic pain treatments leading to tolerance development and dependence. Moreover, non-human primates had an analgesic response to intracisternal N/OFQ opening the possibility that ORL-1 receptor-mediated analgesia may be attained in humans despite conflicting outcomes in rodents. Also, both ORL-1 and μ-opioid receptors are located near each other in many neurons throughout the nervous system. Therefore, targeting both μ- and ORL-1 receptors simultaneously has emerged as a novel strategy to treat chronic pain. This synergistic treatment may limit the number of side effects due to reduced activation of a single receptor type. Therefore, a smaller therapeutic dose would be required, and as a result, there would be a decreased probability of tolerance development. In DRG neurons, G-protein coupled receptors linked to ORL-1, and μ-opioid receptors regulate CaV channels. As Ca2+ influx is vital for the regulation of excitability in DRG neurons, a reduction in Ca2+ influx would help decrease the hyperexcitability of sensory neurons and attenuate neurotransmitter release in chronic pain states. Therefore, my second project evaluated the activity of mixed ORL-1 and μ-opioid receptor agonists cebranopadol and [Dmt1]N/OFQ(1-13)-NH2 in DRG neurons of Sprague-Dawley rats that had undergone sciatic nerve ligation to induce chronic pain. Cebranopadol has been tested in multiple models of chronic pain and shown to have analgesic efficacy exceeding opioids with a dose-dependent increase in analgesia, particularly in neuropathic pain models. Previous studies found that [Dmt1]N/OFQ(1-13)-NH2 was similar in potency to N/OFQ in vitro, while in vivo it was approximately 30-fold more potent than N/OFQ and produced longer lasting analgesia. Given the analgesic potential of these compounds, it was of value to evaluate their activity in DRG neurons. Results revealed that both cebranopadol and [Dmt1]N/OFQ(1-13)-NH2 did not show a major difference in the inhibition of Ca2+ current (ICa) between sham surgery and nerve ligated rats. However, reversal of [Dmt1]N/OFQ(1-13)-NH2 mediated inhibition was more substantial when μ- and ORL-1 receptor antagonists were co-applied in comparison to a single antagonist. Thus, it was evident that [Dmt1]N/OFQ(1-13)-NH2 mediated ICa inhibition in DRG neurons was a result of mixed μ- and ORL-1 receptor activity. Results further revealed that the lack of difference between ICa inhibition of sham and nerve-injured rats might be a result of increased ORL-1 receptor-mediated constitutive inhibition of ICa in nerve-injured rats which does not alter based on the time after neuronal isolation. Despite the promising in vitro results of Pn3a, in other studies, it did not show strong analgesia in vivo. Intrathecal Pn3a did not reverse mechanical or thermal allodynia (painful response to a stimulus that is not deemed noxious) in complete Freund's adjuvant treated rats. However, other studies also indicated that NaV1.7 inhibition upregulates endogenous opioids. Therefore, it was of interest to test whether there would be any synergistic effect when an opioid was co-applied with Pn3a in DRG neurons. Results revealed that Pn3a co-applied with μ-opioid receptor agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) produced a greater ICa inhibition than DAMGO alone. However, Pn3a also inhibited ICa independent of opioid receptors. Therefore, the increased ICa inhibition when DAMGO and Pn3a were co-applied must be a result of direct ICa inhibition by Pn3a coupled with G-protein mediated ICa inhibition by DAMGO. Further study in the presence of G-protein inhibitors is required to clarify if Pn3a mediates its ICa inhibition through a G-protein pathway. Overall, these results indicate that the in vivo synergistic analgesia observed in the presence of Pn3a and opioids does not occur within DRG neurons. Nevertheless, the direct inhibition of ICa mediated by Pn3a in DRG neurons may be analgesic as decreased Ca2+ influx could downregulate neurotransmitter release in ascending pain pathways. In general, results of this thesis suggest that future analgesic development needs to focus on combination therapies that show potential to produce more significant pain relief in chronic pain states with fewer side effects and tolerance development.
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McKenney, Ryan Kenneth. "Emerging Therapeutics for Organophosphorus Nerve Agent Poisonings. The Development of a Fluoride Ion Battery System Utilizing Nanoparticles." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1491830263330328.
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Meehan, James. "Inhibition of pH regulation as a therapeutic strategy in breast cancer." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28875.
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The abnormal regulation of H+ ions, leading to a reversed pH gradient in cancer cells when compared to normal cells, is considered to be one of the most distinctive features of cancer. However, this characteristic has yet to be fully exploited as a therapeutic target in cancer. This project assessed whether targeting pH regulating proteins, which permit cancer cells to survive in the hostile hypoxic and acidic tumour microenvironment, could produce an effective therapeutic response in breast cancer. The pH regulating proteins carbonic anhydrase IX (CAIX), Na+/H+ exchanger 1 (NHE1) and vacuolar (H+)-ATPase (V-ATPase) were the focus of this thesis. Initial experiments were conducted in 2D tissue culture before progressing into 3D, using models that more faithfully re-create the in vivo tumour microenvironment. Expression analysis conducted with MCF-7, MDA-MB-231 and HBL-100 human breast cancer cell lines cultured in 2D, and in 3D as multicellular tumour spheroids, showed that protein and mRNA levels of CAIX were very responsive to lower O2 concentrations. Both MDA-MB-231 and HBL-100 cells displayed large increases in CAIX expression levels in hypoxia, with the HBL-100 cell line exhibiting the largest change in CAIX mRNA (42-fold increase) and protein (78-fold increase) levels in 0.5% O2 conditions. Hypoxia inducible factor 1-α (HIF-1α) controls the expression of CAIX, but the induction of CAIX in hypoxic MCF-7 cells was lower in comparison to the other cell lines, despite the presence of similar levels of HIF-1α. The differences in CAIX expression observed between the cell lines was consistent with a varying activity of factor inhibiting HIF-1 (FIH-1), an oxygen sensor that controls signalling through HIF-1α, as siRNA targeting FIH-1 led to increased levels of CAIX in hypoxic MCF-7 cells. While NHE1 protein levels did increase in hypoxic conditions in MCF-7 cells in 3D, overall, the expression levels of both NHE1 and V-ATPase were not as responsive to changes in O2 concentrations when compared to CAIX across differing O2 conditions in each of the cell lines. Inhibitors targeting CAIX, NHE1 and V-ATPase were all shown to reduce cancer cell number in 2D culture conditions. Differing O2 conditions changed the sensitivity of these cell lines to CAIX inhibition. Cells cultured in 20% O2 conditions were responsive to CAIX inhibition, while acute hypoxic cells cultured in 0.5% O2 displayed an increased resistance to drug treatment. Chronically hypoxic cells, which had spent over 10 weeks in 0.5% O2 before treatment, exhibited a re-sensitisation to CAIX inhibition. 3D invasion assays demonstrated that CAIX inhibition significantly reduced the invasion of cells from MDA-MB-231 spheroids into collagen type 1 in both 20% O2 and 0.5% O2 conditions, while drugs targeting either NHE1 or V-ATPase had no such inhibitory effects. Preliminary clonogenic assays, used to assess radiation sensitivity and performed with MDA-MB-231 spheroids, indicated that inhibitors targeting CAIX and NHE1 led to a significant decrease in colony formation when combined with irradiation, compared to either drug treatment or irradiation alone. Further invasion assays, carried out with primary tissue derived from human patients, showed that drugs targeting CAIX retained their inhibitory effects when tested on heterogeneous cancer material of varying tumour subtypes. CAIX inhibition also exhibited anti-cancer effects in vivo on mouse MDA-MB-231 xenografts, significantly reducing the proliferation and growth of tumours within mice. Together, this work demonstrates that inhibitors targeting the pH regulation mechanisms of cancer cells have potential in the treatment of breast cancer, highlighted by their capacity to affect cancer cell number, cancer cell invasion, and their ability to combine with irradiation. Of the 3 pH regulatory molecules studied, CAIX appears to be the target with the most therapeutic potential.
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Abdulkareem, Zana Azeez. "SK potassium and TRPM7 ion channel role in CNS cell survival and breast cancer cell death decisions." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/80343/.
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Cell survival is modulated by a cocktail of ion channels engaging cell life and death decisions through controlling key cellular messages such as apoptosis and proliferation. Unnatural regulation of these processes results in various disorders, for example neurodegenerative diseases, as well as the cancers. Nowadays, these pathologies are affecting millions of people per year in the world. Potassium (K+) ion channels appear to play a potent role in such illnesses since they can control many cellular gates in cell physiology such as ionic homeostasis and signalling cascades. Amongst the K+ channels, small (SK1-3) and intermediate (SK4) conductance Ca2+-activated potassium ion channels have recently been shown to save cells, thereby protecting mitochondrial function which serves as a cell survival platform. In the case of other ion channels, for instance transient receptor potential melastatin 7 (TRPM7), it is also repeatedly stated that such membrane channels shows an impressive and differential role in excitable and non-excitable cell survival. This channel also modulates ionic homeostasis of crucial ions in cellular physiology such as Ca2+. This study reveals that central nervous system (CNS) and breast cancer cells differentially express SK1-4 ion channel subtypes, and their functional presence is pharmacologically confirmed, however, in most cases these results were further clarified through small interference RNA (siRNA) method. Similarly, functional TRPM7 channel expression in CNS cells is also confirmed. In the CNS, SK1-4 channel activation rescues neurons from oxidative stress, whereas, TRPM7 channel inhibition protects CNS cells from this hydrogen peroxide (H2O2) harmful effect, as well as hypoxia and apoptosis, so improving cell survival. Excitingly, SK1-4 channels differentially exist between wild-type and Huntington’s affected mouse striatal cells, where diseased cells lack SK1-3 channels, key players in action potential activity. Interestingly, SK2 or SK3 channel subtypes are also functionally expressed in breast cancer cells with various phenotypes. This study established that these ion channels are powerful agents in a survival role, in fact controlling growth through cross-talk with an apoptotic avenue “intrinsic pathway”. SK2 or SK3 channel activation enhances cell viability, while its inhibition dampens cell growth. It is very noteworthy that SK2 and SK3 channels are not expressed in non-tumorigenic breast cells. In brief, SK1-4 and TRPM7 molecules are clearly implicated in the survival of diverse cell types through an apoptotic route, indicating that these ionic regulators are promising targets in channelopathies related to cellular degeneration and growth.
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Spichler, Anne Stambovsky. "Leptospirose letal aguda em Hamster: caracterização de perfis bioquímicos, histopatológicos e celulares renais, relacionada a ensaios terapêuticos." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-12022008-133227/.
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A leptospirose é uma zoonose de importância mundial, causada por leptospiras patogênicas. Aproximadamente 5 a 10% das infecções humanas cursam com a forma grave. A Doença de Weil é a forma mais comum de doença grave e pode apresentarse com duas formas de evolução, aguda progressiva monofásica ou de curso prolongado. A doença grave se caracteriza por uma combinação de hemorragia, mais comumente pulmonar, icterícia e insuficiência renal, com letalidade de 5 a 15%. O rim é um órgão muito acometido na Leptospirose. Clinicamente o envolvimento renal ocorre de 16 a 40%, com manifestações peculiares como poliúria, hipocalemia, e perda de sódio. A disfunção tubular renal, é característica da leptospirose forma grave, com envolvimento dos transportadores renais de sódio ao longo do néfron, levando às manifestações observadas. A terapêutica antimicrobiana é recomendada na Leptospirose, porém com controvérsias à sua indicação após o quarto dia de doença. Quando da instalação da lesão não haveria benefícios com a utilização de antibióticos. O tratamento pode diminuir a morbidade e letalidade, assim como interferir no envolvimento renal e na expressão dos transportadores renais de sódio. A patogênese pode estar relacionada a efeitos diretos da leptospira ou a resposta inflamatória assim como o estresse oxidativo. A utilização de antioxidantes, pode ser considerada como terapia adjuvante. Nós avaliamos a expressão no túbulo proximal do trocador Na+-H+ (NHE3) e na porção espessa da medula ascendente o cotransportador Na+-K+-2Cl- (NKCC2), no modelo de hamster com as duas formas de evolução de doença grave, mimetizando a doença de humanos realizados em dois experimentos. Os experimentos envolveram animais infectados não tratados e tratados com ampicilina associado ou não ao antioxidante, N-acetilcisteína. A presença de antígenos de Leptospira e a expressão dos transportadores foram avaliadas por imunohistoquímica, e o ácido tiobarbitúrico, marcador de estresse oxidativo, (TBARS) foi quantificado.Hamsters infectados, apresentaram altas quantidades de antígenos nos tecidos-alvo, enquanto que a expressão de ambos os transportadores apresentou-se diminuída. O tratamento com ampicilina esteve associado com mínima detecção ou ausência de antígenos, restabelecimento da expressão dos transportadores nos respectivos locais e redução dos níveis de TBARS. O tratamento precoce e tardio com ampicilina restabeleceu os defeitos tubulares na leptospirose forma grave em ambos experimentos, sem benefícios com a utilização da N-acetilcisteína.Leptospirosis is a zoonosis of worldwide distribution. About 5-10% of all human infections presents with severe forms. Weil\'s syndrome, the most common presentation of severe forms of leptospirosis, may courses either as a single monophasic disease or as a disease with prolonged course, characterized by a combination of hemorrhage, particularly in the lung, renal failure, and jaundice, with fatality rates ranging from 5 to 15%. The kidney is an important target organ in leptospiral infection. Clinically, renal involvement in leptospirosis occurs in 16% to 40% of cases and is unique because of the atypical presentation of polyuria, hypokalemia, and sodium wasting, suggestive of a special form of tubular dysfunction related to the major renal sodium transporters expressed along the nephron. A wide range of antimicrobial therapy for leptospirosis was described and benefits have been disputed for cases with more than four days of clinical disease, because after a threshold of leptospiremia, the delayed use of antibiotics is unlikely to reduce fatality. Antimicrobial therapy is thought to interfere on fatality, renal involvement, and renal sodium transporters expression during severe disease. The pathogenesis may be related to direct effects of leptospiral compounds or inflammatory response due to oxidative stress. Antioxidant could be considered for adjunctive therapy.We evaluated the expression of proximal tubule type 3 Na+/H+ exchanger (NHE3) and thick ascending limb Na+-K+-2Cl- cotransporter (NKCC2) in infected non treated and treated hamsters reproducing the two forms of clinical human presentations of Weil\'s syndrome divided in two experiments. Animals were treated or not with ampicillin and/or N-acetyl-cysteine (NAC). Leptospiral antigen/s and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen/s in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. Early and late ampicillin treatment rescued tubular defects in leptospirosis severe disease in both experiments, and there was no evidence of benefit from antioxidant therapy.
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Vieira, Goncalves Leonam. "Mechanisms of virucidal action of alcohol and metallic ions against nonenveloped viruses." Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/111705/.
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Studying the mechanism of action (MoA) of biocides against pathogenic microorganisms is crucial to understand their efficacy and limitations, and to develop more efficient microbicidal formulations. Combining alcohol and zinc has been reported to enhance microbicidal activity, but the reasons for such activity are unknown. This study focuses on the impact of combining ethanol and zinc salt at pH 10.5 against nonenveloped viruses. The study is focused on three different aspects: i) virucidal activity screening of ethanol:zinc combinations against bacteriophages and human viruses; ii) impact of ethanol:zinc combinations on virus structure, particularly the viral capsid and nucleic acid, using Transmission Electron Microscopy (TEM); Atomic Force Microscopy (AFM) and agarose gel DNA electrophoresis and iii) chemical speciation and stability of ethanol:zinc combinations over time. The combination of ethanol with zinc salt was found to be more effective against viruses than control formulations containing sole active ingredients and/or excipients only. Activity test of 40%(w/v) ethanol with 0.1% (w/v) zinc salt with excipients (RB- 002 formulation) against F116 and adenovirus type 2 (AdV2) at 60 min contact time yielded 0.68 ± 0.02 and 5.26 ± 0.10 log10 reduction, respectively. In comparison, 0.1% (w/v) zinc salt only with excipient (RB-002G formulation) showed no virucidal activity against bacteriophage F116 (0.14 ± 0.02 log10 reduction) and AdV2 (0.80 ± 0.12 log10 reduction) in suspension. Differences between activities against bacteriophage MS2 and poliovirus type 1 were similar as the ones found between F116 and AdV2. Formulation containing 40%(w/v) ethanol with 0.1% (w/v) zinc salt produced a range of structural damage to F116 and attP AdV5 indicating possible capsid alteration. Effect of the combined formulation on viral capsid was confirmed with AFM with a possible decreased in virus capsid stiffness and significant virus capsid height reduction over 10 min contact time. F116 DNA damage was detected upon exposure to 40%(w/v) ethanol with 0.1% (w/v) zinc salt with excipients, but no damage was detected on AdV2 DNA through electrophoresis analysis. The alcohol/zinc formulation system at pH 10.5 was shown to have promising virucidal activity against non-enveloped viruses at room temperature following an alteration of the viral capsid, and possible damage to the viral nucleic acid. This study also showed the limitations of using bacteriophage as surrogate for mammalian viruses.
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Aulock, Sonja von. "Mechanisms of endogenous and therapeutic immune modulation by G-CSF." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965907430.
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Jithesh, P. V. "A systems biology approach to idn etify potential biomarkers and novel therapeutic targets in colorectal cancer." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534721.
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Maurer, Tobias. "CpG-DNA-antigen conjugates a new class of therapeutics? /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974416622.
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Savai, Rajkumar. "Establishment of mouse lung tumor models and development of new therapeutic approaches." Giessen : VVB Laufersweiler, 2006. http://deposit.d-nb.de/cgi-bin/dokserv?idn=980604214.
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Waiczies, Sonia. "Modulation of human antigen-specific T-cell response therapeutic implications for multiple sclerosis /." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969681844.
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Garrett, Ian Ross. "Studies of the effect of metal containing drugs on acute and chronic inflammation /." Title page, table of contents and summary only, 1986. http://web4.library.adelaide.edu.au/theses/09PH/09phg2386.pdf.
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Schräml, Michael. "In vitro protein engineering approaches for the development of biochemical, diagnostic and therapeutic tools." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=979554845.
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Lilie, Hauke. "Design und Assoziation multifunktioneller und therapeutisch wirksamer Proteinkomplexe." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96993629X.
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Dumortier, Jérôme Roland Jean-Pierre Bernadin. "Cytokine gene transfer by adenoviral vectors as a novel therapeutic option for hepatitis B virus infection." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=967343267.
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Linnemann, Elmar. "Galanthamin als Leitstruktur Weiterentwicklung von Therapeutika gegen die Alzheimer'sche Demenz /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965648001.
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Lei, Xia. "Study of Zwitterionic Functionalized Materials for Drug Delivery and Protein Therapeutics." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555511296878391.
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Santillo, Bruna Tereso. "Caracterização fenotípica e funcional de IFN-DCs derivadas de indivíduos infectados pelo HIV-1." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-09122015-130521/.
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A imunoterapia baseada em MoDC constitui uma estratégia para tratamento de indivíduos HIV+. Protocolos para obtenção de MoDC em geral utilizam IL-4 e GM-CSF (IL4-DC). Alguns estudos utilizam as IFN-DC (IFN-α + GM-CSF), que exibem um fenótipo combinado de DC mielóide, DC plasmocitóide (pDC) e célula NK. Esse perfil misto pode aperfeiçoar a imunoterapia para pacientes HIV+. Para tanto, monócitos de pacientes HIV+ foram cultivados com GM-CSF e IL-4 ou IFN-α por 5 dias e estimuladas por 48 horas com pulso de HIV inativado por AT-2 e/ou coquetel de citocinas pró-inflamatórias. Avaliamos a expressão de moléculas de superfície de IFN-DC e ativação de linfócitos T por citometria de fluxo; produção de citocinas IL-12 e IL-10 por ELISA. IFN-DC apresentaram morfologia e fenótipo basais ativados e características de pDC e célula NK, diferente das IL4-DC. As IFN-DC foram capazes de produzir IL-12, estimular a proliferação e produção de IFN-γ de linfócitos TCD4 e CD8, porém similares às IL4-DCs. IFN-DC são capazes de estimular resposta de linfócitos T tanto quanto IL4-DC.Immunotherapy based on MDDCs is a strategy for treating HIV-infected patients. Alternatively to the conventional protocol for DC differentiation based on IL-4 and GM-CSF (IL4-DC) some studies suggest the use of IFN-DC (IFN-α + GM-CSF). These cells exhibit a combined phenotype of myeloid DC, plasmacytoid DC (pDC) and NK. Considering the mixed profile of IFN-DCs alternative protocols can bring novel elements for immunotherapy. Monocytes isolated from HIV-infected patients were cultured in the presence of GM-CSF and IL-4 or IFN-α. On day 5 DCs were pulsed with AT-2-inactivated HIV and stimulated for 48 hours with a cocktail of proinflammatory cytokines. We assessed IFN-DC surface markers expression and T cell activation by flow cytometry; IL-10 and IL-12 production by ELISA. IFN-DC showed activated morphological and phenotypic features during basal state of maturity and exhibited features of pDC and NK different from IL4-DC. The IFN-DC like IL4-DC were able to produce IL-12 and stimulated T cells. So, the IFN-DC were able to stimulate the T cells as well as IL4-DCs.
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Nelvagal, Hemanth Ramesh. "Spinal cord pathology in CLN1 disease : a novel therapeutic target." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/spinal-cord-pathology-in-cln1-disease(8b1dc3ed-dfd9-442d-a427-43ded0d82a6a).html.
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The neuronal ceroid lipofuscinoses (NCLs) are a group of up to 14 inherited progressive neurodegenerative lysosomal storage disorders affecting children and young adults. Together, they are the most common pediatric neurodegenerative storage disorders. Symptoms include loss of vision, epileptic seizures and the loss of cognitive and motor function. A lack of any effective therapies means that all forms are fatal. CLN1 disease or Infantile NCL is one of the most rapidly progressing forms of the disease and is caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase – 1 (PPT1). Ppt1 deficient (Ppt1-/-) mice recapitulate features of the human disease and have proved to be a useful tool in characterizing disease progression and pathology in the brain. However, these pathological changes fail to fully explain the sensorimotor deficits seen in this mouse model as well as in human CLN1 disease. Along with the limited success of various brain directed therapies, this led us to analyze the spinal cord. Our analysis revealed unexpectedly profound and rapidly progressing disease pathology in the spinal cords of these mice, which occurs earlier than similar events in the brain. This included regional atrophy, neuroinflammation, and significant neuron loss at all levels of the cord as well as novel phenotypes indicating a postnatal developmental delay and significant white matter pathology. Automated gait analysis also showed novel early phenotypes in these mice including an increased dependence on the forelimbs for locomotion. Similar spinal cord pathology was also demonstrated in human INCL autopsy samples as well as in mouse models of the other major forms of NCL. Targeting the spinal cords of Ppt1-/-mice with enzyme replacement therapy (ERT) and gene therapy significantly improved disease pathology, motor function and lifespan in these mice, demonstrating the clinical significance of spinal cord pathology in these mice. Furthermore, combining intracranial and intrathecal gene therapy showed a synergistic effect, showing the greatest improvements for any CLN1 disease therapy to date. Taken together, these findings highlight the spinal cord as not only being significantly affected in CLN1 disease, but also as a novel and effective therapeutic target.
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Baskey, Stephen James. "Analysis and Modulation of In Vitro Cell Response to Metal Ions From CoCrMo Alloys Used in Orthopaedic Applications." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32802.
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Despite the high success rates of hip replacements, implant-wear mediated periprosthetic osteolysis remains the most prominent cause of long-term implant failure. Other adverse tissue reactions including hypersensitivity reactions and pseudotumors have also recently been reported as a cause for short-term implant failures. The objectives of this thesis were: 1.) To analyze the effects of Co2+ and Cr3+ released from CoCrMo alloys used in hip implants on macrophage chemokine release; 2.) To determine if Co2+, Cr3+, and the chemokines in cultures of macrophages exposed to Co2+ and Cr3+ can induce migration of T and B lymphocytes; and 3) To analyze the potential modulation of macrophage response to Cr3+ using simvastatin as an anti-inflammatory agent. Results showed that the release of TNF–α and CC chemokines were ion-specific and dose-dependent. Results also suggested that Co2+ and Cr3+ may be capable of directly stimulating the migration of T cells, but not that of B cells, suggesting the potential of these ions to create a micro-environment that would favour a T cell-mediated response in vivo. Results also showed that simvastatin was capable of decreasing chemokine release in macrophages exposed to Cr3+, suggesting its potential to modulate the Cr3+-induced inflammatory response. Together, these studies improve the understanding of the role metal ions play in ion-mediated adverse tissue reactions and potential therapies that may modulate the immune response to metal ions.
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Shattock, Lucy. "Understanding the nature of therapeutic relationships in severe mental illness." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/understanding-the-nature-of-therapeutic-relationships-in-severe-mental-illness(32c4b046-9d04-4a8a-b480-e9b86bb2e3d5).html.
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Paper 1 provides a systematic review of studies investigating therapeutic alliance in the context of psychological interventions for people with psychosis. Twenty-six studies were identified that satisfied the inclusion criteria. The review comments on the nature of alliance across studies, the extent to which alliance predicted outcome, as well as client, therapist and therapy-related factors associated with alliance. Clinical implications are discussed and research recommendations are made. Paper 2 details an investigation into the relationships between attachment, therapeutic alliance and service engagement in a Black sample with psychosis. Twenty eight participants with non-affective psychosis were recruited across a number of outpatient and inpatient services. Participants completed measures of attachment, alliance and service engagement. Staff completed measures of alliance and service engagement. Psychotic symptoms and perceived racial/ethnic discrimination were measured as potential confounders. Results indicated that higher attachment anxiety was associated with poorer client-rated alliance but not staff-rated alliance, except on the goal agreement component. Attachment avoidance was not related to alliance. Attachment was not associated with service engagement. Attachment ratings were also compared to secondary data collected from a large White sample. Clinical implications are discussed and areas for future research are highlighted. Paper 3 provides a critical appraisal of the design, implementation and interpretation of findings for Papers 1 and 2. Strengths and limitations of both papers are discussed, and personal reflections about the research process are included.
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Bell, Rachel Emma. "Investigating BET proteins as a therapeutic target in keloid scarring." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/investigating-bet-proteins-as-a-therapeutic-target-in-keloid-scarring(546987b5-6e89-4713-a30d-af7fed3d2296).html.
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Keloid scars form due to an over-exuberant, fibrotic wound response in the skin of predisposed individuals. There is currently no clear genetic link identified, and limited treatment options available. Epigenetic changes in fibrosis, and specifically in keloids, are beginning to be identified and this offers potential targets for treatment. This project explored the bromodomain and extraterminal (BET) family of proteins: Brd2, Brd3 and Brd4, which function as epigenetic regulators through their binding to acetylated lysine residues, predominantly on histone proteins. We hypothesised that they would be a target of therapeutic value given that their inhibition has shown anti-proliferative and anti-inflammatory properties in other cell types. We identified an overexpression of Brd2 in keloid tissue compared to normal controls, including a possible expression of a differential Brd2 isoform. We then used a small molecule bromodomain inhibitor, I-BET151 (GSK), to investigate the effect of BET protein inhibition in primary dermal fibroblast cultures from normal skin (NDFs) and keloid scars (KDFs). We confirmed previous literature findings, in other disease models, that BET inhibition decreased proliferation, as well as the expression of the inflammatory cytokine interleukin-6 (IL-6). In addition, we identified some more novel effects of BET inhibition, including a decrease in fibroblast contraction in a collagen gel model and decreases in proteolytic activity in fibroblast cultures, as well as a more complex ex vivo tissue model. Interestingly, we also observed profound differences between NDFs and KDFs in their signalling downstream of IL-6 in serum free environments. In particular, a strong induction of pAkt was observed in KDFs after 30 minutes of cytokine stimulation, which was not seen in NDFs, and BET inhibition abrogated this. In conclusion, BET inhibition appears to offer therapeutic value in keloid scars by targeting a number of disease-associated cell behaviours, including aberrant signalling responses, which may influence the fibrotic response. Some of these effects may be of relevance in other disease contexts including cancer, where these inhibitors are currently progressing in clinical trials.
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Jackson, Joshua D. "Investigating therapeutic strategies in a preclinical model for Alzheimer's disease." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/investigating-therapeutic-strategies-in-a-preclinical-model-for-alzheimeras-disease(47574a22-9623-4c3e-9fa2-bd68a82ffc31).html.
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Alzheimer's disease (AD) is a worldwide, incurable disease, and the most common form of dementia. Numbers of cases are rising, and since its discovery the only approved medications have treated only the symptoms, not the pathological cause. With the cost to society rising, the debilitating nature of the disease and the pressure put on the family members and support network of patients, disease modifying therapies are in dire need. Current models have proven an invaluable tool with which to study certain aspects of the disease and the genetics behind it, however the lack of clinically approved medications in the last 20 years suggests new models are needed. Based on the amyloid cascade hypothesis, this thesis initially characterises two models of β-Amyloid oligomer (Aβo) induced cognitive deficits. Both models are created by ICV injection of soluble Aβo into the brain of rat. The models differ only by the molecular weight of the Aβo 1-42, one, referred to as low molecular weight (LMW) Aβo, with stable dimers, trimers and tetramers, the other, referred to as high molecular weight (HMW) Aβo, consisting of assemblies ranging from ~50 to ~150 kDa. It was found that behavioural deficits were similar between the two, with a robust object recognition deficit, but no working memory deficit. Both models also showed a deficit in the synaptic marker PSD-95; however the LMW Aβo caused a deficit in the frontal cortex, whereas the HMW Aβo caused a hippocampal deficit. The role of the cellular prion protein (PrPC) was explored, by blocking its binding to Aβo with the antibody 6D11. Interestingly the two models showed different results. The HMW Aβo deficits were completely blocked by the 6D11 application, however the LMW Aβo deficits were only partially prevented. Finally, Fasudil, a vasodilator approved in parts of Asia, was used to inhibit Rho-kinase, showing a prevention of the cognitive deficits in the HMW Aβo model. The results of this thesis show the ICV administration of Aβo to be a useful model for investigating the effects of Aβo, provides a platform with which to study the differing effects of Aβo with different oligomeric assemblies, and a model to test therapeutic strategies with relevance to AD.
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Al-khalidi, Rasha. "P2RX7 purinoceptor as a therapeutic target in Duchenne muscular dystrophy." Thesis, University of Portsmouth, 2017. https://researchportal.port.ac.uk/portal/en/theses/p2rx7-purinoceptor-as-a-therapeutic-target-in-duchenne-muscular-dystrophy(7560e450-c050-41a0-a3a5-553ed42d6710).html.
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Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in men and currently there is no effective treatment for this debilitating and lethal disorder. Although the absence of dystrophin is identified as the main cause of DMD, multiple secondary changes have been found to result from the dystrophin deficiency both in muscle and in non-muscle tissues. Among these abnormalities, our laboratory and others have demonstrated a dramatic increase in the expression of the P2RX7 receptor in cells and tissues from DMD patients and the mdx mouse model of DMD. The aim of this study was to determine the effects of P2RX7 ablation on biological functions in mdx muscle in situ and to identify suitable diagnostic and prognostic biomarkers for use in studies on the pharmacological inhibition of P2RX7. RNA transcription was profiled in muscle from wild-type and mdx mice, and also from double knock-out mdx/P2rx7-/- mice which lack both functional Dmd and P2rx7 genes, and the effects of P2RX7 antagonists were assessed on pathological markers at the acute disease stage of disease in mdx mice, which resembles the human pathology. RNA sequencing was performed using the Illumina HiSeq 2000 platform to characterise the differential gene expression in tibialis anterior (TA) muscles from four week old wild type, mdx and mdx/P2rx7-/- mice. The biological functions and molecules that are most affected in mdx and corrected in mdx/P2rx7-/- tissues are those of the immune response, including the innate immune response, cytokine regulatory genes and the NF-кB pathway followed by fibrosis, telomerase regulatory genes, atherosclerosis signalling and the LXR/RXR activation pathway. Moreover, activation of the cell cycle, mitochondrial dysfunction, apoptosis and the adherens junction genes were found to be altered in mdx compared to wild type but not normalised in mdx/P2rx7-/- muscles. This analysis also demonstrated that the mdx mutation disrupts the non-sense-mediated RNA decay and splicing mechanisms, which leads to an increase in out-of-frame transcripts that may have unexpected cellular impact. One of these altered transcripts, Bmp7, was significantly down-regulated in the mdx myoblasts, myofibres and in TA muscles and restored to the normal level in mdx/P2rx7-/- muscle. Different analyses were used to map this alteration to the 5'exons of Bmp7 but the identification of this abnormal transcript was not successful. Four P2RX7 antagonists (oxidised ATP, A438079, AFC-5128 and azidothymidine (AZT)) were administered to male mdx mice and their effects on the pathology were analysed using different methods and biomarkers. All of the antagonists inhibited P2RX7 receptor-mediated responses in mdx mice without any detectable side effects. A438079 and AZT were found as the most effective in attenuating the wide range of the pathological features. The reduction in dystrophic features as results of ablation and antagonism the P2RX7 confirms the involvement of this purinoreceptor in the DMD pathology and making it an attractive target for a pharmacological treatment of this lethal disease. Additionally, as AZT is already in clinical use for other diseases, also in children, this drug could be relatively easily re-purposed and trialled for the treatment of DMD.
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Bonaria, Michela Galea. "Constructing bilingualism in the Maltese therapeutic context : a Foucauldian Discourse Analysis." Thesis, University of Roehampton, 2017. https://pure.roehampton.ac.uk/portal/en/studentthesis/constructing-bilingualism-in-the-maltese-therapeutic-context(efa6ca85-38c7-4290-98c6-a95b9f807b21).html.
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To date, there is a dearth of studies addressing therapeutic uses of bilingualism as applied to counselling psychology in postcolonial contexts. This study explored some of the ways in which Maltese therapeutic practitioners1 understood and worked with bilingualism. Nine semi-structured interviews were conducted with accredited therapeutic practitioners. Taking a poststructural epistemological approach, a Foucauldian informed discourse analysis was applied to the data produced. In the analysis, three key discourses were identified: professional, cultural, and deviant that produced bilingualism as a power-laden discursive site of therapeutic ideas and practices. Further examination of how these discourses resourced discursive constructions of Maltese-English bilingualism highlighted how these firstly positioned uses of English and Maltese as serving different therapeutic functions, with participants understanding counselling ideas in English while cultural experiences were best expressed in Maltese. Secondly, some of the postcolonial resonances that privilege English over Maltese were illustrated as still evident in these accounts through the construction of English as sophisticated and Maltese as crude. Finally, code-switching was variously objectified as both facilitative and frustrating in enabling therapeutic communication and maintaining the therapeutic relationship. This analysis therefore contributes to an alternative understanding of bilingualism in Maltese therapeutic practice by highlighting the social, cultural and historical processes that have shaped these discursive constructions. This may inform Maltese practitioners in developing their critical reflexivity regarding the power implications of using Maltese and English, and may also be useful to the wider therapeutic community, including counselling psychologists, working in other bilingual contexts.
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Maitland, Rahat Ashraf. "Mechanisms of insulin resistance in obese pregnant women : potential therapeutic interventions." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/mechanisms-of-insulin-resistance-in-obese-pregnant-women(49f27722-d2ee-46d5-bd3a-4068f17c062b).html.
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Maternal obesity is associated with adverse pregnancy outcomes, especially the development of gestational diabetes mellitus (GDM), with associated risks for mother and infant. Improved understanding of glucose intolerance in obese women and better prediction and prevention of GDM is key to improving the health of mother and her child. This thesis reports two related projects. The first explored mechanisms of insulin resistance and prediction of GDM in obese pregnant women participating in the pilot study for the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a lifestyle intervention RCT. The second investigated the potential of a dietary intervention to improve glycaemic profiles in this high-risk group. Following an 8 week dietary and physical activity intervention, a panel of biomarkers associated with obesity and insulin resistance were measured in 117 women in the pilot trial. At 27+0-28+6 weeks’ no difference was observed between the intervention and control arms but at 34+0-35+6 weeks’, significant reductions in plasma visfatin, cholesterol and LDL cholesterol were observed. Analysis by GDM status, confirmed greater concentrations of fructosamine, AST and insulin and lower plasma leptin and adiponectin in women who developed GDM. An algorithm based on clinical factors alone (age, parity, ethnicity and blood pressure at 15+0-18+6 weeks’ gestation) showed predictive potential which increased significantly with the addition of plasma adiponectin measured at 15+0-18+6 weeks. In obese pregnant women without GDM (n=16,) the effect of a slow-digesting low glycaemic index (SD-LGI) supplement drink was evaluated at 24+0-28+6 weeks’ gestation. Linear regression analysis with mixed modelling (LMM) showed a significant reduction in glycaemia over the 24 hour period following consumption of the test compared to the control supplement and habitual diet. Fasting and nocturnal glucose concentrations were also significantly improved. In summary biomarkers associated with insulin resistance were identified as potential targets for lifestyle interventions aimed at reducing GDM in obese women. A prediction model for GDM identified those at greatest risk and pending validation in the UPBEAT RCT may have the potential for translation into clinical care. Extending the role of interventions further, multiple improvements in parameters of glycaemic control were demonstrated using a SD-LGI nutritional supplement.
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Gibson, Meghan E. "Examining the Role of Magnesium Ions in the Structural Stability of Ribosomal Subunits and An Investigation of a Novel Anticancer Therapeutic: Analyzing the Binding Affinity of a Stapled p53 Peptide Analog for Regulator MDM2." Thesis, Boston College, 2011. http://hdl.handle.net/2345/bc-ir:104431.
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Thesis advisor: Udayan MohantyComputational research can play a crucial component in the discovery of unique biochemical phenomena, from answering fundamental questions about molecular function and structure to the modeling of designed pharmaceuticals to cure many debilitating illnesses. Here computational methods are employed to examine the exquisite role that magnesium ions play in stabilizing ribosomal subunits responsible for protein translation and to analyze the potential of a proposed anticancer drug for a pathway that is impaired in the majority of human cancer cases
Thesis (BS) — Boston College, 2011
Submitted to: Boston College. College of Arts and Sciences
Discipline: College Honors Program
Discipline: Chemistry
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Dreimann, Marc. "Therapeutika des neuropathischen Schmerzes blockieren den TTX-resistenten Natriumkanal des peripheren nozizeptiven Systems." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963032496.
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Hutchinson, Laura. "The role and therapeutic significance of monocarboxylate transporters in prostate cancer." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/the-role-and-therapeutic-significance-of-monocarboxylate-transporters-in-prostate-cancer(280f6221-d12b-4ca9-9322-e0ba1f5511f6).html.
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It has been shown that tumour cells are capable of switching to glycolytic metabolism for the production of ATP even in the presence of oxygen, this is known as aerobic glycolysis or the 'Warburg effect'. The glycolytic phenotype has been associated with tumour aggressiveness and poor outcome in several cancer types. This makes the area of cancer metabolism an attractive area for the potential identification of new therapeutic targets. One key component, required for cells to maintain the glycolytic phenotype, is the presence of monocarboxylate transporters that are capable of exporting lactate. These transporters are vital for the maintenance of the intracellular pH of cells under these conditions. This study was centred around the hypothesis that altering expression of MCTs would impact on the metabolism of tumour cells and, therefore, other key characteristics of cells relating to metastatic capabilities and survival following treatment. For the purpose of this work, prostate cancer cell lines were transfected with lentiviral particles targeting overexpression of MCT1 or MCT4, or knockdown of MCT4. Following transfection, cellular metabolic profiles were assessed under normoxic and hypoxic conditions and the metastatic phenotype of each cell line was investigated. Additionally, the effect of MCT expression on response to chemotherapy and radiation therapy was explored, and a siRNA metabolome screen was performed to identify combinations of targets that may produce synthetic lethality in prostate cancer cell lines. It was shown that changes in the expression of MCT1 or MCT4 did not cause significant changes in the metastatic phenotypes of the prostate cancer cell lines investigated. Some differences were observed in the metabolic pathways used by these prostate cancer cells following alterations in MCT expression. For example, overexpression of MCT1 in DU145 cells resulted in an increase in intracellular lactate. Additionally, MCT4 knockdown in PC3 cells was able to reduce OXPHOS under reduced oxygen. MCT1 overexpression was able to sensitise androgen-independent prostate cancer cells to treatment with chemotherapy and radiation therapy. Furthermore, combinations of siRNA treatments were identified that may be capable of producing synthetic lethality. In summary, findings in this study indicated that targeting MCT1 and MCT4 expression could offer therapeutic benefit in prostate cancer. However, it was also highlighted that the roles of these transporters are specific to cancer type, and even cell line.
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Elvins, Rachel. "Therapeutic alliance and outcome in a treatment trial of depressed adolescents." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/therapeutic-alliance-and-outcome-in-a-treatment-trial-of-depressed-adolescents(478cce6d-4556-46f2-9277-dd40fe096ccd).html.
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Therapeutic alliance is an umbrella term referring to core aspects of the interaction and relationship between patient and practitioner during treatment. It has long been considered an important component of success in psychological and medical treatments. A survey of practitioners in child mental health (Kazdin, 1997) found that 95% thought that the relationship with the patient was the most important predictor of treatment outcome; there is research evidence suggesting the significant impact of alliance quality on outcome in adults and children, for both psychological (Martin et al., 2000, Shirk and Karver, 2003; Shirk, Karver and Brown, 2011) and general medical (Burkitt-Wright et al., 2004) treatments. Alliance, however, has been relatively little researched in childhood and until recently the emphasis (in both research and training) has been much more on the protocol details of treatment methods as opposed to detailed understanding of treatment process and the practitioner-patient relationship. Studies reporting associations between therapeutic alliance and treatment outcome have often been weakened by methodological difficulties in measurement and have failed to settle the direction of causality between symptom change and alliance (Kazdin and Nock, 2003). In treatment trials, alliance is often only measured in the experimental arm; this makes analysis of its effect difficult (Dunn and Bentall, 2007, and Emsley et al., 2010).This study represents an exceptional opportunity to address these limitations. It makes use of data collected during one of the most rigorous recent studies done in child mental health in the UK (Goodyer et al., 2007). This enables detailed study of the therapeutic relationship during treatment and allows testing of the effects of this relationship on the success of treatment. Sessional audiotapes were available within both arms of this trial. Purposeful selection of tapes from both arms of the trial during treatment were transcribed and rated for treatment alliance. Other data already collected in the trial was included in an analysis to address questions of direction of causality of alliance in relation to symptom change during treatment and the way that alliance may explain treatment effect heterogeneity.The results indicate a complex effect of alliance upon outcome. There is a relationship between early alliance score and clinical improvement, but the relationship is not straightforward and the predictive effect of alliance appears to depend on differences in patient groups and therapist effects. Analysis of treatment effect heterogeneity suggests that therapeutic alliance is associated with the individual treatment effect and implies that with poor alliance, more treatment may be detrimental. The complexities of the results are discussed with reference to implications for further research in this area as well as clinical practice.
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Long, Nici Helene. "Therapeutic storytelling in a Pupil Referral Unit : the story of intersubjectivity." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/therapeutic-storytelling-in-a-pupil-referral-unit-the-story-of-intersubjectivity(882def4e-c208-4ff4-a6b8-d0a33a1896cc).html.
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Background: This thesis reflects upon a heuristic study of a Storytelling Programme which took place in a KS3 Pupil Referral Unit. Previous experiences in the field, as a community storyteller, revealed the power of stories to calm and engage young people. In my community work I had seen that storytelling particularly engaged those considered ‘hard to reach.’ This research was designed to explore the storytelling process further with the aim of understanding more about the impact of the process and to understand the key components as identified by the young people themselves. Methodology: A heuristic research methodology was adopted within this study. The Storytelling Programme was delivered to twelve young people at a Pupil Referral Unit in the North West of England. Five of these participants were interviewed along with their teacher, and their reflections were integrated with my own to create a crystallized understanding of the storytelling process, whilst also remaining true to the unique experiences of each participant. Findings: Heuristic analysis of the Storytelling Programme revealed that young participants developed new personal narratives that reflected new ways of being and thinking. Change was demonstrated by the young people expressing a more positive sense of self. A striking finding, echoed by all participants, was the significance of the relationship in facilitating the therapeutic change process. Discussion: Whilst some of the changes could be linked to particular stories, the participants could not articulate whether their increased sense of well-being came from the stories or more generally from the programme or my ‘way of being’ (Rogers, 1980). It appears that stories and the therapeutic relationship intertwine within the storytelling process to create opportunities for therapeutic change. The findings of this study suggest that story is a particularly useful indirect medium to engage ‘hard to reach’ young people who have disorganised attachment styles. Storytelling offers the opportunity to place the intersubjective relationship as central, fostering an implicitly nurturing and co-regulating dyad that can offer reparation as well as the opportunities for catharsis and the development of emotional literacy through the processing of the story material. Conclusion: It appears that storytelling intertwines the interpersonal relationship with the stories to create a process which is both interpersonal and intrapersonal. The storytelling process appears to facilitate dyadic co-regulation, which may be an essential first step in the therapeutic change process. Once in a state of calm the young people could connect to the story stimuli and develop new ways of being and thinking. Whilst stories appear to promote changes at both the relational and semantic level, the findings from this study suggest that the implicit relational changes had primacy in facilitating significant therapeutic change.
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Ryklina, Tatiana. "The role of anomalous phenomena in the therapeutic process : an exploration of counselling psychologists' experience." Thesis, University of Roehampton, 2012. https://pure.roehampton.ac.uk/portal/en/studentthesis/the-role-of-anomalous-phenomena-in-the-therapeutic-process(7a025bd0-3818-4f60-a461-ba88e22e35d5).html.
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The main focus of this research was to explore how counselling psychologists experience what that they cannot understand in the therapeutic process. The study focuses on how counselling psychologists make sense of and manage these experiences, as well as the role such experiences play in therapy. Although the existence of such occurrences are acknowledged in the foundations of many therapeutic approaches (Bion, 1970; Bugental, 1990; Freud 1915; Jung, 1923; Maslow, 1971; Ogden, 1999; Perls, 1973; Rogers, 1961; Stern, 2004) , there seems to be a lack of research in relation to how these phenomena are experienced and what role they play in the therapeutic process. Eight counselling psychologists with ten years of experience in clinical practice were recruited and interviewed using semi-structured interviews. Different aspects of these experiences were explored through applying the qualitative method known as Interpretative Phenomenological Analysis (Smith, 2004). The findings suggest that the way counselling psychologists experience phenomena that cannot be understood strongly relates to anxiety, fear and uncertainty, drawing attention to deep feelings of vulnerability and insecurity. The results demonstrate the ambivalent meanings of such experiences in the therapeutic process, and their significance in the process of therapy. The thesis also comprises the way in which counselling psychologists spoke about these phenomena and how these occurrences were managed by counselling psychologists. Some conclusions were made about what kind of knowledge counselling psychologists relied on while making sense of such phenomena. The recommendations made as a result of the research show validity as they closely relate to the way counselling psychologists explore their own identity as professionals. Also, the research highlighted the essentiality of exploring the role of theoretical knowledge and reflexivity for counselling psychologists. The research also explores unanticipated findings such as the existence of those experiences that need to remain undefinable and the ability of counselling psychologists to let go of the need to make sense of phenomena. The study also addresses the limitations and implications of the research, and suggestions for further research are indicated.
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Becker, Stefanie. "Immuntoxinproduktion in Pflanzen eine innovative Methode zur Herstellung neuartiger Therapeutika gegen das Hodgkin Lymphom /." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=981436803.
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Mccallion, Catriona. "Exploiting graphene as a therapeutics platform in biological systems." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/exploiting-graphene-as-a-therapeutics-platform-in-biological-systems(30409fcf-f482-44ac-bacc-3a9eb5616fe0).html.
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Since its isolation in 2004, the research landscape around graphene and other 2D materials has expanded rapidly and now encompasses fields as diverse as electronic engineering and drug delivery. For biomedical applications, one of the most desirable properties of the graphene family of nanomaterials (GFNs) is their 2D geometry; the high surface area to volume ratio that is characteristic of nanomaterials is taken to its extreme in a material that can be viewed as being entirely surface. This particular property alongside the versatility with which they may be functionalised both makes GFNs well positioned to function as the foundation of highly tailored and multifunctional therapeutics platforms. In this project, two GFN types, namely pristine graphene and graphene oxide, were prepared to form suspensions suitable for application to therapeutics delivery. Firstly, experiments using four essential amino acids with pristine graphitic material were undertaken to assess whether graphene flakes could be suitably exfoliated and suspended using sonication in the presence of aqueous solutions of these biocompatible molecules. A positive correlation was found between the hydrophobicity of the amino acid and the presence of one or more aromatic rings in the amino acid, and the efficacy of exfoliation both in terms of concentration achieved in suspension and flake thinness. However, the system itself was found to be highly complex, both with regards to the sonication used to exfoliate the graphitic flakes, and the interactions between the amino acids and the flakes. These considerations limited the wider applicability of this form of graphene preparation for therapeutics delivery applications. Secondly, work was performed on graphene oxide (GO), a GFN far more studied in the literature, but notoriously heterogeneous. Therefore much of the work completed focused on its characterisation. A combination of established and novel fluorescence-based characterisation methods were used to fully characterise three preparations of GO, before preliminary experiments were undertaken to test their interactions with cell components. The work showed that the inherent fluorescence of GO can be exploited to improve suspension characterisation; raster image correlation spectroscopy (RICS) was used to measure the apparent hydrodynamic radii of the flakes and flow cytometry was used to provide insight into the interactions between GO flakes and serum components. Preliminary cellular experiments confirmed that flow cytometry could be also employed to assess particular graphene characteristics in the context of cell culture, demonstrating the relatively low toxicity of PEGylated GO compared to unfunctionalised GO. Finally, as the therapeutics target for this project was leukaemia, a targeting ligand was designed and synthesised that could bind to CXCR4 - a receptor that is overexpressed on CLL B-cells, as well as many other cancer types. The ligand was synthesised such that it could easily be attached to GO, however its molecular structure is flexible enough that it can be attached to a number of different therapeutics materials. It was confirmed using both competition and functional assays that the molecule was antagonistic, and was able to deliver a conjugated fluorescent molecule specifically to the CXCR4 receptors on primary CLL B-cells. The work presented in this thesis illustrates the complexity that affects the use of GFNs in biomedicine, but also confirms the potential for their future development. The field is still young, and therapeutics delivery is likely to benefit from advances in the preparation of pristine graphene, and from methods to minimise the heterogeneity of GO. These steps will support a route towards clinical application. In addition, as the field of 2D materials expands, other materials with enviable surface area to volume ratios may come to the fore. Furthermore, this thesis has shown the value of exploring novel approaches to the characterisation of GFNs, and has identified approaches that may be exploited to improve applications of GFNs in biomedicine. Additionally, the aim of using GFNs as a platform for a multifunctional therapeutics delivery vehicle was developed with regards to the attractive CXCL12/CXCR4 axis, which is relevant in a large number of disease states including over 20 cancers, by demonstrating a flexible targeting ligand that could be used to exploit the CXCR4 receptor as a drug delivery target.
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Lukei, Eva. "Die Patient-Therapeut-Beziehung in Kurzzeitpsychotherapien eine empirische Untersuchung mit dem Intrex-Fragebogen /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972715584.
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Eid, Basma. "The pharmacology & therapeutic potential of Kv7 channels in the pulmonary circulation." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacology--therapeutic-potential-of-kv7-channels-in-the-pulmonary-circulation(6a9bb4a3-eb2a-4135-91b2-ca598f041f86).html.
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Pulmonary arterial tone is regulated in part by the membrane potential (Em) of pulmonary artery smooth muscle cells (PASMCs). The Kv7 family of K+ channels was recently implicated in regulating Em in rat PASMCs and expression of KCNQ1, KCNQ4 and KCNQ5 mRNA, which encode Kv7 channels, was reported. Kv7 activators were beneficial in two-independent mouse models of pulmonary hypertension (PH), which provides further evidence for their role in regulating pulmonary tone. The goals of this study were to: 1) Elucidate the role of Kv7 channels and Em in the hypertensive pulmonary circulation and 2) Study the effects and mechanism of action of a novel Kv7 modulator, zinc pyrithione (ZnPy) on the pulmonary circulation. PH was induced in male Wistar rats by administering a single 60 µg/kg intraperitoneal injection of monocrotaline (MCT). The effects of Kv7 modulators on hypertensive and control pulmonary arteries (PA) were compared using small-vessel myography. The vasoconstrictor effect of the Kv7 blocker, XE991, was enhanced in MCT PA. The Kv7 activators retigabine and ZnPy showed enhanced efficacy in relaxing MCT PA and suppressed raised intrinsic tone identified in MCT PA relative to control PA. The effects of MCT in responses to Kv7 modulators were pulmonary specific as they were not seen in mesenteric arteries from the same animals. Real-time PCR studies revealed that PA from MCT and control rats showed a similar expression of KCNQ1, KCNQ4 and KCNQ5 mRNA transcripts. I propose that the enhanced effects of Kv7 modulators on PA from MCT rats were due to disease-induced depolarization of PASMCs, which raised intrinsic tone and increased Kv7 channel activation at rest. This is the first evidence that Kv7 channels are functional in this model of PH and may serve as potential drug targets. The effects of ZnPy on PASMCs were studied by patch-clamp electrophysiology. ZnPy consistently hyperpolarized PASMCs and significantly increased the K+ current elicited by a voltage-step from -80 to +40 mV. ZnPy also increased the non-inactivating current recorded at 0 mV in some cells. The effects of ZnPy on Em and K+ currents were inhibited by 10 mM tetraethylammonium (TEA) and 1 µM paxilline but not by 50 nM iberiotoxin. XE991 (10µM) inhibited the ZnPy-induced hyperpolarization without altering its effects on K+ currents, suggesting that the current recorded was not responsible for its effect on Em. When tested on intact vessels, ZnPy consistently produced vasodilation. Its effects were unaffected by TEA, paxilline and iberiotoxin; however, XE991 (100 nM) had an inhibitory effect. The results suggest that ZnPy hyperpolarizes PASMCs by activating a TEA, paxilline and XE991 sensitive, but iberiotoxin insensitive channel, most likely a Kv7 channel. Its ability to dilate PA depended on pharmacologically distinct mechanisms, which are unlikely to involve Kv7 channels.