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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
141

Transcriptomic and Functional Analysis of Neuronal Activity and Disease

Krizay, Daniel Kyle January 2022 (has links)
Advances in sequencing technologies have sparked the discovery of new genetic etiologies for neurological and neurodevelopmental disorders. As new disease-causing mutations are unveiled, questions into the specific mechanisms of pathogenicity and potential therapeutic approaches arise. To address these questions, in vivo and in vitro models have been generated and analyzed; but how best to utilize these models, and how well they recapitulate the human brain, is still not fully understood. Within the work discussed in this thesis, we address this problem through the transcriptomic and functional interrogation of these models in the context of neurodevelopment and disease. In Chapter 2 of this thesis, we describe the use of single-cell RNA-sequencing to examine the longitudinal transcriptomic profiles of neuronal network establishment and maturation in ex vivo mouse cortex- and hippocampus-derived cultures. Our data highlights unique developmental transcriptomic profiles for individual genes, disease gene subclasses, and biological processes, and discusses cell population-specific divergent transcriptomic profiles between genes associated with neurological diseases, focusing on epilepsy and autism spectrum disorder. We also compared the data from our ex vivo system to transcriptomic data collected from in vivo neonatal and adult mouse brains and human cortical organoids, highlighting the importance of the generation and consideration of system-specific transcriptomic datasets when looking into a gene, disease, or biological process of interest, and serves as a vital resource for researchers. In Chapter 3, we propose a high-throughput drug discovery paradigm utilizing the application of transcriptome reversal for neurodevelopmental disorder-associated genes that affect the transcriptome. This approach describes the idea that if gene dysregulation is causal for the pathogenicity of a disease, then correcting the transcriptional signature should have a therapeutic effect. We demonstrated that small-molecule induced gene expression changes vary between both cell lines and neural cell populations, and highlight both the importance of selecting the appropriate model of disease and creating cell population-specific signatures for compounds and disease. In Chapter 4, we focus on the utilization of multi-electrode arrays for the electrophysiological characterization of primary cortical networks derived from mouse models of epileptic encephalopathy. This technique allows for the analysis of numerous neuronal and network synchronization metrics for spontaneous longitudinal activity and responses to external stimuli in the form of electrical stimulation and compound addition. In particular, mouse models with mutations in the genes Grin2a, Gnb1, and Scn1a were analyzed. We discovered significant hyperexcitability, bursting, and synchrony phenotypes, and discuss how acute and chronic compound addition can be used to interrogate biological pathways and reverse disease activity signatures.
142

Interferon-gamma and the regulation of neuroinflammation

Millward, Jason Michael, 1976- January 2008 (has links)
No description available.
143

Dementia Care Mapping (DCM): initial validation of DCM 8 in UK field trials.

Brooker, Dawn J.R., Surr, Claire A. January 2006 (has links)
No / Objectives This paper describes DCM 8 and reports on the initial validation study of DCM 8. Methods Between 2001-2003, a series of international expert working groups were established to examine various aspects of DCM with the intention of revising and refining it. During 2004-2005 the revised tool (DCM 8) was piloted in seven service settings in the UK and validated against DCM 7th edition. Results At a group score level, WIB scores and spread of Behavioural Category Codes were very similar, suggesting that group scores are comparable between DCM 7 and 8. Interviews with mappers and focus groups with staff teams suggested that DCM 8 was preferable to DCM 7th edition because of the clarification and simplification of codes; the addition of new codes relevant to person-centred care; and the replacement of Positive Events with a more structured recording of Personal Enhancers. Conclusions DCM 8 appears comparable with DCM 7th edition in terms of data produced and is well received by mappers and dementia care staff.
144

Preservation of self in people with dementia living in residential care: A socio-biographical approach

Surr, Claire A. January 2006 (has links)
No / The maintenance of self in dementia is associated with socio-biographical factors. The theoretical literature suggests that interpersonal relationships, the social context, and the generation of stories are important in maintenance of self. Empirical research on self in dementia supports this but has been predominantly conducted with participants living in the community. Living in residential care brings additional threats to self. This paper presents a study examining the relevance of a socio-biographical theory of self to people with dementia living in residential care. Between 3 and 8 tape-recorded and transcribed unstructured interviews were conducted with 14 people with dementia who were living in 4 residential homes throughout England and Wales, over a 6-24-month period. They were analysed using an interpretive biographical methodology. The results provide evidence to support the relevance of a socio-biographical theory of self to this group. Relationships with family, other residents and care home staff were important for maintenance of self. Social roles related to work, being part of a family, caring for others and being cared for, were particularly significant for self in this group. The creation of a life story, stories of selected life events, and the telling of stories with possible metaphorical interpretations were also important for the maintenance of self. The results also suggest that psychological and embodied factors may be relevant to the self in dementia. The study suggests that staff working in residential homes should consider these elements if they are to provide care that supports maintenance of self for people with dementia. Implications for future research are discussed.
145

Microelectrode and MicroLED Arrays for Neural Applications

Kumar, Vikrant January 2024 (has links)
Advancements in neural interfacing technologies, such as microelectrode arrays, have significantly contributed to understanding brain function and treating neurological disorders. Decoding the intricacies and functioning of neural circuits is key to further unlocking its potential. Two key approaches, electrical neural recording and optical imaging, have been the basis of stimulating and monitoring neural circuits. Despite the remarkable progress, several key issues such as reliable stimulation of neurons, closed-loop stimulation and monitoring, and undesired background fluorescence during widefield optical imaging remain challenging. After giving a brief background on electrode and microLED arrays, the dissertation delves into the design, microfabrication, and characterization of microelectrode arrays for neural electrical stimulation, recordings, and microLED arrays as a light source for improving optical microscopy. We first discuss a dense conformal electrode array for high spatial resolution stimulation in electrosensory systems. The performance metrics of the integrated system are thoroughly examined through meticulous characterization and optimization processes. Special emphasis is placed on evaluating biocompatibility, electrical properties, and spatial resolution to ensure robust and reliable neural stimulation capability. Next, we discuss a microelectrode device that combines simultaneous electrical recording and 2-photon imaging. We use an Indium Tin Oxide (ITO) material to fabricate a transparent electrode array with a design capable of single neuron recordings. The design, microfabrication, and electrooptical characterization are presented to demonstrate the device’s capability. A system integrating the array with a GRIN lens is also presented to record and image deeper into the brain tissue. Combining both the electrical and optical recordings of neuron ensembles and finding correlations can shed further light on the functioning of neural circuits. To address the problem of unwanted background fluorescence during neural cell imaging, two microLED arrays as light sources are presented. With a microstripe array, we implement optical sectioning structured illumination microscopy (OS-SIM), and with the 2D microLED array, we implemented targeted illumination to reject background fluorescence and improve contrast. We examine the capability of the microLED as a light source with luminance-current-voltage, directivity, and transient measurements. Both implementations highlight the novel non-display application of microLED to address challenges in neural imaging. This research represents a significant contribution to the burgeoning field of neural engineering, offering novel methodologies and technologies that promise to revolutionize our approach to understanding brain functions.
146

A study of the enteric nervous system and interstitial cells of Cajal in a mouse model of Alzheimer's disease.

January 2012 (has links)
蠕動是一種能夠幫助食物通過胃腸道以及促進胃腸道產生能動性的類似波浪的收縮運動。它由一種叫做Cajal (ICC)間質細胞的起搏器細胞產生的慢波所控制。ICCs亦幫助由腸神經系統(ENS)到平滑肌的信息傳導。嚙齒動物和人類實驗表明,老化所導致的ICC細胞數量下降和腸神經退化與排便睏難和便秘有關。通過研究ICC和ENS在正常老化情況下和加速膽碱能神經元喪失的阿爾茲海默症(AD)老鼠模型(Tg2576)中的變化,我們對治療神經退化性疾病也許會有新的認識。本課題的目的在于,研究老化情況下正常老鼠模型及澱粉樣前體蛋白質(APP)過量表達下的AD老鼠模型的胃腸道在形態及功能上的變化。 / 六個月大的Tg2576和同齡野生型對照的全樣載片免疫組化實驗顯示, 十二指腸 (P < 0.05)和迴腸 (P < 0.01)中的腸神經細胞顯著降低,迴腸 (P < 0.001)中的GFAP陽性的腸神經膠質細胞也顯著消失。S100陽性的腸神經膠質細胞在胃竇(胃部中的起搏區域)(P < 0.05), 迴腸 (P < 0.05)和結腸 (P < 0.05)中顯著喪失。這些結果表明,在早期的AD階段,ENS已經出現變質。ICC細胞數量在六個月大的Tg2576和同齡野生型對照的所有腸胃部分並沒有顯著性差異 (P > 0.05)。同時,早期AD階段的基本蠕動節奏也並沒有發生改變。除此之外,結腸和十二指腸的GFAP/S100陽性的腸神經膠質細胞比例並沒有顯著增加,表明在早期AD階段,可能出現了炎症。 / 利用石蠟切片進行β澱粉樣蛋白免疫組化,天狼猩紅溶液化驗和硫代黃素T溶液化驗可以測試不溶的澱粉樣斑塊是否存在。結果指出在六個月大的Tg2576所有腸胃部分都觀察到澱粉樣斑塊聚集而在不同的腸胃部分聚集的程度都有所分別。除了結腸外,六個月大的野生型對照所有腸胃部分都觀察不到澱粉樣斑塊聚集。澱粉樣斑塊形成的增長可能和早期AD階段出現的腸神經細胞和腸神經膠質細胞喪失互相關聯。 / 應用電泳轉移酶標免疫印斑技術,測試六個月大的Tg2576和同齡野生型對照的迴腸和結腸中,膽碱乙酰轉移酶 (ChAT,出自興奮神經元), 神經元型一氧化氮合酶(nNOS,出自抑制神經元), 膠質細胞源性神經營養因子 (GDNF, 出自腸神經膠質細胞)和可溶解的β澱粉樣蛋白寡聚體的表達是否改變。和野生型對照相比,Tg2576的nNOS的表達在迴腸 (P < 0.05) 而不是結腸 (P > 0.05) 中顯著增加。而ChAT,GDNF和各β澱粉樣蛋白寡聚體 (十二聚物,九聚物和六聚物)在六個月大的Tg2576和同齡野生型對照之間並沒有顯著改變 (P > 0.05)。綜上結果表明,在早期AD階段,腸胃道中的抑制信號有所增加,但是β澱粉樣蛋白寡聚體可能不是引致腸胃道中的腸神經細胞和腸神經膠質細胞喪失的原因。 / 在腸胃道的組織學和生化實驗之後,我們利用了微電極陣列 (MEA) 系統來量度出自胃竇和迴腸的慢波信號。量度出來的主導頻率(DF)和功率分佈可以成為測量在老化的ICR老鼠和早期AD階段下腸胃道的功能有沒有變化的參數。在硝苯地平存在下,尼古丁顯著地刺激三個月大 (P < 0.05) 和 六個月大 (P < 0.05) 的ICR老鼠中胃竇和迴腸的慢波活動但未能引起十二個月大 (P > 0.05) 的ICR老鼠中的慢波活動,說明神經退化可能在十二個月的年齡開始。附加了河豚毒素的情況下,尼古丁不能再刺激三個年齡組中胃竇和迴腸的慢波活動 (P > 0.05),由此證明了尼古丁是對腸神經細胞起作用再去激發ICC的活動。六個月大的Tg2576和同齡野生型對照之間的胃竇和迴腸的基准讀數沒有顯著分別 (P > 0.05)。然而,尼古丁顯著地增加野生型對照中胃竇和迴腸的DF和胃電過速範圍 (P < 0.05) 但是不能刺激Tg2576中胃竇和迴腸的電流活動 (P > 0.05),示意在早期AD階段腸胃道中已經出現了腸神經細胞和/或腸神經膠質細胞喪失。 / 綜上所言,研究結果提出AD老鼠模型有形態學,生物化學和功能上的轉變。本課題提供了在研究神經退化疾病上的基礎,也支持ENS是中樞神經系統早期病變前的關口這個假設。 / Peristalsis is the wave-like contraction that moves food along the gastrointestinal (GI) tract and generates GI motility. Peristalsis is modulated by slow waves that originate from pacemaker cells called interstitial cell of Cajal (ICC). ICCs also modulate and transduce inputs from the enteric nervous system (ENS) to the smooth muscle. Recent studies in rodents and humans demonstrated that a decrease in ICC number and enteric neurodegeneration during ageing is associated with difficult bowel movements and constipation. By studying ICC and the ENS during normal aging and in a mouse model (Tg2576) of Alzheimer’s disease (AD) where cholinergic loss may be exaggerated, we may gain new perspectives on the treatment of degenerative diseases. The aim of the present study therefore, was to investigate the morphological and functional changes of the GI tract of mice during ageing and in an AD mouse model over-expressing amyloid precursor protein (APP) using an isolated tissue approach. / Whole mount immunohistochemistry of 6-month-old Tg2576 mice and their age-matched wild type (WT) controls revealed that there were significant losses of enteric neurons in the duodenum (P < 0.05) and ileum (P < 0.001), and of GFAP-positive enteric glial cells in the ileum (P < 0.001). There was also a loss of S100-positive glial cells in the antrum (pacemaker region in the stomach) (P < 0.05), ileum (P < 0.05) and colon (P < 0.05). These results indicated the alteration of the ENS during the early stages of AD. There were no differences in ICC arears of all GI regions between 6-month-old Tg2576 mice and their age-matched WT controls (P > 0.05), and there was no alteration of basal peristaltic rhythm during the early stages of AD. The non-significant increase of GFAP to S100 enteric glial cell ratio in the duodenum and colon might indicate an ongoing inflammatory process in these two GI regions during the early stages of AD. / The presence of insoluble amyloid plaques was studied using Aβ immunohistochemistry, Sirius red assay and Thioflavin-T assay on paraffin wax sections. The aggregation of amyloid plaques was observed in all the GI regions of 6-month-old Tg2576 mice and the levels of amyloid plaque varied in different regions. No amyloid plaques were found in the GI tract of 6-month-old WT animals excepting the colon. The increase in formation of amyloid plaques might be correlated to the losses of enteric neurons and enteric glial cells during the early stages of AD. / Western blot analysis was performed on frozen sections of tissues from the ileum and colon to investigate whether there were changes in choline acetyltransferase (ChAT, from excitatory neurons), neuronal nitric oxide synthase (nNOS, from inhibitory neurons), glial cell line-derived neurotrophic factor (GDNF, from enteric glia) and soluble Aβ oligomers between 6-month-old Tg2576 mice and WT controls. nNOS expression significantly increased in the ileum (P < 0.05) but not in the colon (P > 0.05) of Tg2576 mice compared with WT controls. There were no differences in the expressions of ChAT, GDNF and Aβ oligomers (docecamer, nonamer and hexamer) in the ileum and colon between Tg2576 mice and WT controls (P > 0.05). These results imply that there is an increase in the inhibitory signal in the GI tract during the early stages of AD but soluble Aβ oligomers might not be the cause of neuronal and glial losses in the GI tract. / Following histological and biochemical studies of different GI regions, slow wave signals from the antrum and ileum were measured using a microelectrode array (MEA) system. The dominant frequencies (DFs) and power distributions were measured and these served as parameters for measuring functional changes in the GI tract during ageing in ICR mice and the early stages of AD. In the presence of nifedipine, nicotine significantly stimulated the slow wave activities in the antrum and ileum of 3-month-old (P < 0.05) and 6-month-old (P < 0.05) ICR mice but failed to trigger the slow wave activities in 12-month-old (P > 0.05) ICR mice, suggesting the neurodegeneration might begin with the age between 6 and 12 months. With the addition of tetrodotoxin, nicotine failed to stimulate the slow wave activities in the antrum and ileum of three age groups (P > 0.05) and it showed that nicotine only acted on enteric neurons to trigger the ICC activities. There were no differences in the antral and ileal baseline recordings between 6-month-old Tg2576 mice and their age-matched WT controls (P > 0.05). However, nicotine significantly increased DFs and tachygastria ranges of the antrum and ileum in WT controls (P < 0.05) but failed to increase electrical activitiy of the antrum and ileum in Tg2576 mice (P > 0.05), thus suggesting a loss of neuronal and/or glial cells in the GI tract during the early stages of AD. / In conclusions, these findings suggest the mouse model for AD has morphological, biochemical and functional changes in the GI tract. The present studies provide a foundation for the investigation of degenerative diseases and support the hypothesis that the ENS may be the gateway for the early pathological changes in the central nervous system. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Hui, Chin Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 180-200). / Abstracts also in Chinese. / PUBLICATIONS RELATED TO THE WORK IN THIS THESIS --- p.i / ABSTRACT --- p.ii / 摘要 --- p.iv / ACKNOWLEDGEMENTS --- p.vi / LIST OF ABBREVIATIONS --- p.vii / Chapter CHAPTER 1 --- Introduction --- p.1 / Chapter 1.1 --- General introduction --- p.1 / Chapter 1.2 --- Interstitial cells of Cajal (ICCs) as electrical pacemaker cells in GI tract --- p.1 / Chapter 1.2.1 --- ICC subtypes in GI tract --- p.2 / Chapter 1.3 --- Hypotheses of slow wave generation --- p.4 / Chapter 1.3.1 --- Mechanisms of the NSCC pacemaking hypothesis --- p.5 / Chapter 1.3.2 --- Mechanisms of the alternative hypothesis --- p.6 / Chapter 1.4 --- Involvement of ion channels in slow wave generation of ICC --- p.6 / Chapter 1.4.1 --- Calcium channels --- p.6 / Chapter 1.4.2 --- Sodium channels --- p.7 / Chapter 1.4.3 --- Potassium channels --- p.7 / Chapter 1.4.4 --- Chloride channels --- p.8 / Chapter 1.4.5 --- Non-selective cation channels --- p.8 / Chapter 1.5 --- Distribution of several types of receptors in ICC --- p.11 / Chapter 1.5.1 --- Purinergic receptors --- p.11 / Chapter 1.5.2 --- Muscarinic receptors --- p.11 / Chapter 1.5.3 --- Tachykinin receptors --- p.12 / Chapter 1.5.4 --- Vasoactive intestinal peptide receptors --- p.12 / Chapter 1.5.5 --- Serotonin receptors --- p.13 / Chapter 1.6 --- Introductions and functions of enteric nervous system --- p.15 / Chapter 1.6.1 --- Interaction amongst the central, peripheral and enteric nervous system: brain-gut axis --- p.15 / Chapter 1.6.2 --- Enteric neuronal subtypes in the GI tract --- p.15 / Chapter 1.6.2.1 --- Motor neurons --- p.16 / Chapter 1.6.2.2 --- Interneurons --- p.16 / Chapter 1.6.2.3 --- Intrinsic primary afferent neurons --- p.18 / Chapter 1.6.3 --- Enteric glial cells --- p.18 / Chapter 1.6.3.1 --- Enteric glial subtypes in the GI tract --- p.18 / Chapter 1.6.3.2 --- Communication between enteric neurons and glial cells --- p.19 / Chapter 1.6.3.3 --- Possible functions of enteric glial cells in the GI tract --- p.19 / Chapter 1.6.3.3.1 --- Secretion of neurotrophic factors --- p.20 / Chapter 1.6.3.3.2 --- Secretion of reduced glutathione --- p.20 / Chapter 1.6.3.3.3 --- Secretion of transforming growth factor-beta 1 --- p.21 / Chapter 1.7 --- Interactions amongst ICC, enteric neurons and enteric glial cells --- p.21 / Chapter 1.8 --- Gastrointestinal disorders --- p.22 / Chapter 1.8.1 --- Mechanisms for cell depletion --- p.22 / Chapter 1.8.1.1 --- Autoimmune attack --- p.22 / Chapter 1.8.1.2 --- Hyperglycaemia and diabetes mellitus --- p.24 / Chapter 1.8.1.3 --- Oxidative stress --- p.25 / Chapter 1.8.1.4 --- Ageing --- p.26 / Chapter 1.9 --- Alzheimer’s disease --- p.28 / Chapter 1.9.1 --- Genetics and pathogenesis of Alzheimer’s disease --- p.28 / Chapter 1.9.1.1 --- Aggregation of amyloid beta protein --- p.29 / Chapter 1.9.1.2 --- Genetic factors of AD --- p.29 / Chapter 1.9.1.3 --- Tau hyperphosphorylation and neurofibrillary tangles --- p.31 / Chapter 1.9.2 --- Current treatment for Alzheimer’s disease --- p.33 / Chapter 1.9.2.1 --- Symptomatic treatment --- p.33 / Chapter 1.9.2.2 --- Disease-modifying treatment --- p.34 / Chapter 1.9.2.3 --- Other potential drugs for AD treatment --- p.35 / Chapter 1.9.3 --- Possible animal models for AD investigation --- p.36 / Chapter 1.9.4 --- Possible correlations between Alzheimer’s disease and the enteric nervous system --- p.36 / Chapter 1.10 --- Aim of study --- p.37 / Chapter CHAPTER 2 --- Investigation into the morphologies of enteric nervous system and interstitial cell of Cajal in Tg2576 mice --- p.38 / Chapter 2.1 --- Introduction --- p.38 / Chapter 2.1.1 --- Molecular markers for ICC, ENC, and EGC --- p.38 / Chapter 2.1.2 --- Aims and objectives --- p.39 / Chapter 2.2 --- Materials and methods --- p.41 / Chapter 2.2.1 --- Animals --- p.41 / Chapter 2.2.2 --- Tissue preparation --- p.41 / Chapter 2.2.3 --- Immunohistochemistry --- p.42 / Chapter 2.2.4 --- Image acquisition and analysis --- p.43 / Chapter 2.3 --- Results --- p.44 / Chapter 2.3.1 --- General observations --- p.44 / Chapter 2.3.2 --- Area and pattern of ICCs and the ENS in the stomach --- p.46 / Chapter 2.3.3 --- Area and pattern of ICCs and the ENS in the duodenum --- p.52 / Chapter 2.3.4 --- Area and pattern of ICCs and the ENS in the jejunum --- p.56 / Chapter 2.3.5 --- Area and pattern of ICCs and the ENS in the ileum --- p.60 / Chapter 2.3.6 --- Area and pattern of ICCs and the ENS in the colon --- p.66 / Chapter 2.4 --- Discussion --- p.70 / Chapter 2.4.1 --- Major findings --- p.70 / Chapter 2.4.2 --- Possible alterations of the ENS during AD --- p.70 / Chapter 2.4.3 --- Morphological changes of the ENS in relation to genotype --- p.71 / Chapter 2.4.4 --- Morphological changes of ICCs in relation to genotype --- p.72 / Chapter 2.4.5 --- Morphological changes of the ENS and ICCs in relation to GI regions --- p.72 / Chapter 2.4.6 --- Inflammatory conditions in different GI regions --- p.73 / Chapter 2.5 --- Conclusion --- p.74 / Chapter CHAPTER 3 --- Formation of amyloid plaques in the brain and the GI tract of Tg2576 mice --- p.75 / Chapter 3.1 --- Introduction --- p.75 / Chapter 3.1.1 --- The absence of amyloid plaques in rodents --- p.75 / Chapter 3.1.2 --- Overexpression of human APP in transgenic mice --- p.76 / Chapter 3.1.3 --- Distribution of human APP and Aβ deposition in human and transgenic mice --- p.77 / Chapter 3.1.4 --- Transgene and promoter in Tg2576 mouse --- p.77 / Chapter 3.1.5 --- Methods for Aβ plaque detection --- p.78 / Chapter 3.1.6 --- Aim and objectives --- p.78 / Chapter 3.2 --- Materials and methods --- p.80 / Chapter 3.2.1 --- Animals --- p.80 / Chapter 3.2.2 --- Tissue processing --- p.80 / Chapter 3.2.3 --- Preparation of paraffin wax blocks and slide sections --- p.81 / Chapter 3.2.4 --- Aβ immunohistochemistry --- p.82 / Chapter 3.2.5 --- Sirius red assay --- p.83 / Chapter 3.2.6 --- Thioflavin-T assay --- p.84 / Chapter 3.2.7 --- Image acquisition --- p.84 / Chapter 3.3 --- Results --- p.85 / Chapter 3.3.1 --- Aβ immunohistochemistry --- p.85 / Chapter 3.3.1.1 --- The absence of positive immunoreactivity in the brain --- p.85 / Chapter 3.3.1.2 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.85 / Chapter 3.3.2 --- Sirius red assay --- p.92 / Chapter 3.3.2.1 --- The presence of positive immunoreactivity in the brain of Tg2576 mice --- p.92 / Chapter 3.3.2.2 --- Characteristics of Sirius red staining in the GI tract --- p.92 / Chapter 3.3.2.3 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.92 / Chapter 3.3.3 --- Thioflavin-T assay --- p.98 / Chapter 3.3.3.1 --- The presence of positive immunoreactivity in the brain of Tg2576 mice --- p.98 / Chapter 3.3.3.2 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.98 / Chapter 3.4 --- Discussion --- p.104 / Chapter 3.4.1 --- The presence of a small amount of amyloid plaques in the brain of young Tg2576 mice --- p.104 / Chapter 3.4.2 --- The presence of amyloid plaques in the GI tract --- p.104 / Chapter 3.4.3 --- Plaque formation in relation to genotype --- p.105 / Chapter 3.4.4 --- Possible effects of amyloid plaques in the brain and GI tract --- p.106 / Chapter 3.5 --- Conclusion --- p.108 / Chapter CHAPTER 4 --- Expression of Aβ oligomers, ChAT, nNOS and GDNF in the GI tract of Tg2576 mice --- p.109 / Chapter 4.1 --- Introduction --- p.109 / Chapter 4.1.1 --- Common and peripheral types of ChAT --- p.109 / Chapter 4.1.2 --- Three subtypes of NOS --- p.111 / Chapter 4.1.3 --- Functions of glial cell line-derived neurotrophic factor in the ENS --- p.112 / Chapter 4.1.4 --- Neurotoxicity of soluble Aβ peptides --- p.113 / Chapter 4.1.5 --- Aims and objectives --- p.113 / Chapter 4.2 --- Materials and methods --- p.115 / Chapter 4.2.1 --- Animals --- p.115 / Chapter 4.2.2 --- Preparation of materials --- p.115 / Chapter 4.2.3 --- Sample preparation --- p.117 / Chapter 4.2.4 --- Separating and stacking gels preparation --- p.118 / Chapter 4.2.5 --- Western blot --- p.119 / Chapter 4.2.6 --- Image acquisition and analysis --- p.120 / Chapter 4.3 --- Results --- p.122 / Chapter 4.3.1 --- Increase in nNOS expression in the ileum of Tg2576 mice --- p.122 / Chapter 4.3.2 --- No changes in the expressions of Aβ oligomers, ChAT, nNOS and GDNF in the colon of Tg2576 mice --- p.122 / Chapter 4.4 --- Discussion --- p.127 / Chapter 4.4.1 --- The absence of “cholinergic hypothesis of AD in the GI tract of Tg2576 mice --- p.127 / Chapter 4.4.2 --- Increased expression of nNOS in the ileum of Tg2576 mice --- p.128 / Chapter 4.4.3 --- Neuronal and glial losses may be related to the reduced GDNF expression --- p.129 / Chapter 4.4.4 --- No relationship between the Aβ oligomers and neuronal damages in the GI tract --- p.129 / Chapter 4.5 --- Conclusion --- p.129 / Chapter CHAPTER 5 --- Microelectrode array (MEA) study on slow wave activity in the GI tract --- p.131 / Chapter 5.1 --- Introduction --- p.131 / Chapter 5.1.1 --- Components in peristalsis-controlling unit --- p.131 / Chapter 5.1.2 --- Techniques in evaluating slow wave activity --- p.131 / Chapter 5.1.2.1 --- Patch clamp --- p.132 / Chapter 5.1.2.2 --- Calcium imaging --- p.132 / Chapter 5.1.3 --- Application of microelectrode array in evaluating slow wave activity --- p.134 / Chapter 5.1.4 --- Aims and objectives --- p.136 / Chapter 5.2 --- Methods and materials --- p.137 / Chapter 5.2.1 --- Animals --- p.137 / Chapter 5.2.2 --- Tissue preparation --- p.137 / Chapter 5.2.3 --- Electrical recordings --- p.138 / Chapter 5.2.4 --- Analysis and Statistics --- p.139 / Chapter 5.3 --- Results --- p.142 / Chapter 5.3.1 --- Experiments on ICR mice --- p.142 / Chapter 5.3.1.1 --- Nicotine stimulates the slow wave activity in the antrum in the presence of NIF but not in the presence of NIF and 500 nM TTX --- p.142 / Chapter 5.3.1.2 --- Nicotine stimulates the slow wave activity in the ileum in the presence of NIF but only partially stimulates activity in the presence of NIF and 500 nM TTX --- p.152 / Chapter 5.3.1.3 --- The use of 1 μM TTX completely blocked the nicotine stimulation in the ileum --- p.160 / Chapter 5.3.1.4 --- The dominant frequency of baseline increased in the ileum of 12-month-old ICR but not in the antrum in the presence of NIF --- p.162 / Chapter 5.3.2 --- Experiments on Tg2576 mice and their wild type controls --- p.164 / Chapter 5.3.2.1 --- No differences in both antral and ileal baseline DFs between 6- month-old non-transgenic and Tg2576 mice --- p.164 / Chapter 5.3.2.2 --- Nicotine stimulates slow wave activity in the antrum of 6-month-old wild type controls but not of Tg2576 mice --- p.164 / Chapter 5.3.2.3 --- Nicotine stimulates slow wave activity in the ileum of 6-month-old wild type controls but not of Tg2576 mice --- p.167 / Chapter 5.4 --- Discussion --- p.171 / Chapter 5.4.1 --- Pharmacological effects of nicotine in the GI tract --- p.171 / Chapter 5.4.2 --- Excitatory effects of nicotine in the slow wave activities of the stomach and ileum --- p.172 / Chapter 5.4.3 --- Changes of ICC functions and neuronal activities during ageing --- p.174 / Chapter 5.4.4 --- Enteric neurodegeneration leads to alteration in the ENS function in Tg2576 mice --- p.175 / Chapter 5.4.5 --- Conclusion --- p.176 / Chapter CHAPTER 6 --- Concluding discussion --- p.177 / REFERENCES --- p.180
147

Post-TBI Hippocampal Neurogenesis in Different TBI Models

Patel, Kaushal S 01 January 2016 (has links)
Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years after injury. In this study we investigate the chronic consequences of TBI on adult neurogenesis and the possible involvement of chronic-inflammation in regulating adult neurogenesis. We used two popular TBI animal models, Control Cortical Impact (CCI) and Lateral Fluid Percussion Injury (LFPI) models, to examine focal and diffuse injury responses respectively. Adult rats received CCI, LFPI, or sham injury and were sacrificed at either 15 days or 3 months after injury to examine either subacute or chronic TBI-induced responses respectively. We found no change in levels of proliferation activity at both time points in both TBI models compared to sham animals. Using Doublecortin immunolabeling we found an enhanced generation of new neurons at 15 days after injury and by 3 months this activity was significantly reduced in both TBI models compared to sham animals. We also found persistent inflammation in the injured brains at both time points. Morphological assessment showed that LFPI model of TBI causes shrinkage of the ipsilateral hippocampus. Our results show that moderate TBI induced hippocampal neurogenesis in both models at the early time post-injury. However, at chronic stage, reduced hippocampal neurogenesis is observed in both models and this is accompanied by chronic inflammation. These results suggest that persistent inflammatory responses maybe detrimental to normal neurogenic activity, leading to cognitive impairment and neurodegeneration in long-term TBI survivors.
148

A MECHANISTIC STUDY OF AN iPSC MODEL FOR LEIGH’S DISEASE CAUSED BY MtDNA MUTATAION (8993 T>G)

Galdun, John P 01 January 2016 (has links)
Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts reprogrammed to induced pluripotent stem cells maintain the same level of mutation burden seen in the original patient cell line. Mutation burden was maintained through several passages and spontaneous differentiation. This cell based model could be useful for future pathogenesis studies, or therapeutic drug screenings in a patient and tissue specific manner.
149

Neuropatia auditiva/dessincronia auditiva: um estudo em alunos de três escolas especiais para deficientes auditivos da cidade de São Paulo / Auditory neuropathy/auditory dys-synchrony: a study with the hearing impaired students of three special schools in the city of São Paulo

Sanfins, Milaine Dominici 15 January 2004 (has links)
Introdução: A Neuropatia auditiva/Dessincronia auditiva (NA) é um transtorno que foi identificado há apenas 20 anos, os pacientes que possuíam este transtorno eram diagnosticados como deficientes auditivos como conseqüência da falha no diagnóstico. Com o surgimento do registro das Emissões Otoacústicas e sua presença no repertório de testes de avaliação auditiva, foi possível ao clínico fazer o diagnóstico de NA. Assim sendo, é possível que alguns indivíduos que foram diagnosticados como portadores de uma perda auditiva neurossensorial, tivessem, na verdade, NA. Objetivos: O objetivo deste estudo foi caracterizar o tipo e grau da deficiência auditiva em uma população de deficientes auditivos da cidade de São Paulo; verificar a época da suspeita pelos pais da deficiência auditiva bem como do diagnóstico audiológico nestes indivíduos; identificar os participantes cujas avaliações comportamentais são incompatíveis com as avaliações eletrofisiológicas, visando identificar casos de Neuropatia Auditiva e realizar estudo qualitativo de casos dos participantes com incompatibilidade de respostas nas avaliações comportamentais e eletrofisiológicas. Método: Foram avaliados 89 deficientes auditivos de três escolas especiais da cidade de São Paulo e 11 do setor de Audiologia Educacional da Faculdade de Medicina da Universidade de São Paulo através de alguns testes audiológicos: imitanciometria, audiometria tonal limiar (ATL), emissões otoacústicas (EOA) e potencial evocado auditivo do tronco-encefálico (PEATE). Resultados: Dos 100 participantes deste estudo, 99% apresentaram uma deficiência auditiva do tipo neurossensorial e em 50% o grau predominante da deficiência auditiva foi profundo, um deles não conseguiu realizar a ATL. A média de idade da suspeita dos pais foi de 15,52 meses e o diagnóstico clínico foi de 25,07 meses, em todos os grupos a suspeita dos pais foi anterior ao diagnóstico. Apenas um participante apresentou avaliações comportamentais incompatíveis com as eletrofisiólogicas, todavia, no decorrer da pesquisa o quadro foi modificado, sendo que a flutuação da audição foi o fator mais marcante observado. Conclusões: Os resultados sugerem que a NA é um transtorno raro mesmo na população dos deficientes auditivos e alertam para a necessidade de acompanhar longitudinalmente os casos de suspeita do transtorno / Introduction: Auditory Neuropathy/Auditory Dys-synchrony (AN) is a disorder identified only 20 years ago. Due to diagnosis failure, patients with this disorder were diagnosed as hearing impaired. AN diagnosis was made possible upon the appearance of OAE\'s recordings and its presence in hearing evaluation battery. Therefore, it is possible that some individuals who have been diagnosed as suffering from sensorioneural hearing loss had indeed AN. Purpose: The purpose of this study was to characterize the type and degree of auditory impairment in a population of the hearing impaired in the city of São Paulo; to verify when parents had the suspicious of the hearing impairment and when was the audiological diagnosis done in these individuals; to identify the subjects whose behavioral evaluations are not compatible with the electrophysiological evaluations in order to identify Auditory Neuropathy events and carry out a qualitative study of the cases of subjects with incompatibility of responses in the behavioral and electrophysiological evaluations. Method: 89 hearing impaired individuals from three school for the deaf in the city of São Paulo, and 11 from the Educational Audiology Division of the Medicine School of the University of São Paulo were evaluated in some audiological tests: imitanciometry, audiometer evaluation (AE), otoacoustic emissions (OAE) and Auditory Brainstem Response (ABR). Results: Out of the 100 subjects in this study, 99% presented a sensorioneural hearing loss, and in 50% the predominant degree of auditory loss was profound, one of the subjects was not able to perform AE. The average age of parents suspicion was 15.52 months and the clinical diagnosis was 25.07 months, in all the groups the parents suspicion was prior to the formal diagnosis. Only one subject presented behavioral evaluations incompatible with the electrophysiological, however, in the course of the research the chart was changed, whereas the hearing fluctuation was the most remarkable factor observed. Conclusions: The results suggest that AN is a rare disorder even in the hearing impaired community and alert the need of long term follow up in the cases of suspected disorder
150

Kuru in contexts

Wilson, Christine, University of Western Sydney, College of Arts, Education and Social Sciences, School of Humanities January 2001 (has links)
It has been a widely accepted belief in scientific and public discourse at the end of the twentieth century that cannibalism was the principal means of transmission of the disease call 'Kuru'.The study argues that other explanations might have been excluded from consideration, in particular, iatrogenic transmission.Circumstantial evidence in support of this proposition is examined.The work begins with an examination of the relationship between a number of diseases including, X disease, poliomyelitis, louping ill, scrapie and kuru through the first half of the twentieth century. Major themes of the work revolve around the boundary between research on animal and human disease, the complexities of research in this area, and the different messages that exist simultaneously in three domains: scientific research and publications, government and institutional archives, and the public domain. The thesis argues that the circumstantial evidence presented needs to be considered seriously and that further research in the area is required before we can come to a reliable understanding of the factors involved in the transmission of kuru / Doctor of Philosophy (PhD)

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