1,843 research outputs found
RIC-HSCT for MF/SS
No full textAdvanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and "down-staging" effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS
Functional magnetic resonance imaging of the mouse brain
No full textFunctional magnetic resonance imaging (fMRI) measuring a blood-oxygen-level dependent (BOLD) signal is the most commonly used neuroimaging tool to understand brain function in humans. As mouse models are one of the most commonly used neuroscience experimental models, and with the advent of transgenic mouse models of neurodegenerative pathologies, there has been an increasing push in recent years to apply fMRI techniques to the mouse brain. This thesis focuses on the development and implementation of mouse brain fMRI techniques, in particular to describe the mouse visual system. Multiple studies in the literature have noted several technical challenges in mouse fMRI. In this work I have developed methods which go some way to reducing the impact of these issues, and I record robust and reliable haemodynamic-driven signal responses to visual stimuli in mouse brain regions specific to visual processing. I then developed increasingly complex visual stimuli, approaching the level of complexity used in electrophysiology studies of the mouse visual system, despite the geometric and magnetic field constraints of using a 9.4T pre-clinical MRI scanner. I have also applied a novel technique for measuring high-temporal resolution BOLD responses in the mouse superior colliculus, and I used this data to improve statistical parametric mapping of mouse brain BOLD responses. I also describe the first application of dynamic causal modelling to mouse fMRI data, characterising effective connectivity in the mouse brain visual system. This thesis makes significant contributions to the reverse translation of fMRI to the mouse brain, closing the gap between invasive electrophysiological measurements in the mouse brain and non-invasive fMRI measurements in the human brain
Development of imaging methods for the lithium-pilocarpine model of epilepsy
No full textAnti-inflammatory therapies are promising candidates for the prevention of brain injury following prolonged seizures (status epilepticus). Biomarkers for therapy monitoring are needed to translate these recent findings to the clinic. The aim of this thesis was to develop imaging methods that can be used to monitor anti-inflammatory therapies and monitor disease progression following prolonged seizures. In order to achieve these goals, the lithium-pilocarpine model was used as a model of status epilepticus and novel MRI imaging methods were employed. Various imaging approaches including: quantitative, structural, molecular and functional imaging were tested for their possible investigative utility as imaging biomarkers for neuroprotective therapies. Alongside this, two different anti-inflammatory therapies were tested for their effectiveness to alter brain injury following status epilepticus. This thesis demonstrates that molecular imaging has potential to monitor neuroprotective therapies. Surprisingly, there was little evidence that the anti-inflammatory therapies tested here had beneficial effects. However, this thesis shows that employing novel imaging approaches and automated analysis methods can enable accurate in vivo assessment of disease altering therapies
Mouse embryo phenotyping using high-resolution 3D imaging
No full textThe immense challenge of annotating the entire mouse genome has stimulated development of cutting-edge imaging technologies in a drive for novel information. These techniques promise to improve our understanding of the genes involved in embryo development, at least one third of which have been shown to be essential. Aligning advanced imaging technologies with biological needs will be fundamental to maximising the number of phenotypes discovered in the coming years. International efforts are underway to meet this challenge through an integrated and sophisticated approach to embryo phenotyping, which will include advanced imaging tools. This thesis investigates advanced imaging methodologies and computational image analysis techniques for mouse embryo phenotyping using magnetic resonance imaging (MRI). Additionally, the novel application of an emerging method called photoacoustic imaging is demonstrated for imaging mouse embryos in utero. First, the lack of tissue staining capabilities that currently limits embryo MR imaging was addressed by investigating the MRI staining properties of two readily available contrast agents and their underlying contrast enhancement mechanisms. A methodological framework was developed for high-throughput screening of embryos using diffusion MRI and implemented to study the splotch mouse model of human neural tube defects. A validation study was carried out to comprehensively assess the accuracy of volumetric measurements generated using a computational image analysis method called segmentation propagation. Finally, an all-optical photoacoustic scanner and novel time-reversal image reconstruction algorithm were developed, enabling photoacoustic imaging of whole embryos in utero. Overall, this thesis presents advanced imaging methodologies and computational image analysis techniques that may form an essential part of the toolkit available for annotating the mouse genome and facilitate identification of novel phenotypes in the coming years
Cardiac Imaging for Regenerative Therapy and Tissue Engineering
No full textCardiovascular disease remains the number 1 cause of death worldwide. Over the past 20 years, therapies for treating cardiac disease have come of age and coronary heart disease in particular has seen a revolution in new treatments such as statins, stents and beta blockers. These therapies have slowed death rates and have shown potential to minimise ischemia induced atrophy following myocardial infarction. Crucially however, they are unable to recover lost heart function due to cardiomyocyte death, resulting in poor prognosis for patients. Myocardial regeneration therapy is a new strategy towards treating cardiac disease that engrafts regenerative cells and biomaterials to the myocardium to stimulate repair of tissue and restore contractile function. Cardiac regeneration therapy has made a rapid translation from preclinical research to clinical trials with the first trial in humans published in 2001. Clinical trials in the years since however have produced underwhelming results and there is a general consensus that further preclinical optimisation with powerful non-invasive imaging data will be key to the future success of regenerative medicine in humans. Magnetic resonance imaging is unparalleled in providing non-invasive multiparametric imaging of both global and regional cardiac structure and function. MRI provides high spatiotemporal resolution and multiple contrast mechanisms revealing information about molecular changes in the myocardium. These imaging abilities make MRI a versatile and powerful tool in the preclinical optimisation of cardiac regeneration therapies. Over the chapters presented in this thesis I have established a set of MR imaging techniques that enable valuable in vivo characterisation of cardiac function and structure in for use in studies of regenerative therapy. It is hoped that the methods developed over the course of this thesis aid in the uptake of imaging applications in studies of regenerative medicine and that the wide range of imaging tools demonstrated help to bring regenerative medicine closer to practical clinical therapy
Imaging mouse models of neurodegeneration using multi-parametric MRI
No full textAlzheimer’s disease (AD) is a devastating condition characterised by significant cognitive impairment and memory loss. Transgenic mouse models are increasingly being used to further our knowledge of the cause and progression of AD, and identify new targets for therapeutic intervention. These mice permit the study of specific pathological hallmarks of the disease, including intracellular deposits of hyperphosphorylated tau protein and extracellular amyloid plaques. In order to characterise these transgenic mice, robust biomarkers are required to evaluate neurodegenerative changes and facilitate preclinical evaluation of emerging therapeutics. In this work, a platform for in vivo structural imaging of the rTg4510 mouse model of tauopathy was developed and optimised. This was combined with a range of other clinically relevant magnetic resonance imaging (MRI) biomarkers including: arterial spin labelling, diffusion tensor imaging and chemical exchange saturation transfer. These techniques were applied in a single time-point study of aged rTg4510 mice, as well as a longitudinal study to serially assess neurodegeneration in the same cohort of animals. Doxycycline was administered to a subset of rTg4510 mice to suppress the tau transgene; this novel intervention strategy permitted the evaluation of the sensitivity of MRI biomarkers to the accumulation and suppression of tau. Follow-up ex vivo scans were acquired in order to assess the sensitivity of in vivo structural MRI to the current preclinical gold standard. High resolution structural MRI, when used in conjunction with advanced computational analysis, yielded high sensitivity to pathological changes occurring in the rTg4510 mouse. Atrophy was reduced in animals treated with doxycycline. All other MRI biomarkers were able to discriminate between doxycycline-treated and untreated rTg4510 mice as well as wildtype controls, and provided insight into complimentary pathological mechanisms occurring within the disease process. In addition, this imaging protocol was applied to the J20 mouse model of familial AD. This mouse exhibits widespread plaque formation, enabling the study of amyloid-specific pathological changes. Atrophy and deficits in cerebral blood flow were observed; however, the changes occurring in this model were markedly less than those observed in the rTg4510 mouse. This study was expanded to investigate the early-onset AD observed in individuals with Down’s syndrome (DS) by breeding the J20 mouse with the Tc1 mouse model of DS, permitting the relationship between genetics and neurodegeneration to be dissected. This thesis demonstrates the application of in vivo multi-parametric MRI to mouse models of neurodegeneration. All techniques were sensitive to pathological changes occurring in the models, and may serve as important biomarkers in clinical studies of AD. In addition, in vivo multi-parametric MRI permits longitudinal studies of the same animal cohort. This experimental design produces more powerful results, whilst contributing to worldwide efforts to reduce animal usage with respect to the 3Rs principles
Development of MRI Techniques for Experimental Models of Cardiovascular Disease
No full textCardiovascular diseases (CVDs) – including stroke and heart failure – are the leading cause of death worldwide. More people die from CVDs each year than any other cause. Magnetic resonance imaging (MRI) is a powerful technique which is now routinely used for imaging these diseases as it offers high-resolution anatomical detail, exquisite soft-tissue contrast and assessment of function such as tissue water content, oxygenation, metabolism, vascular blood flow and microvascular perfusion. This thesis focuses on the development of MRI techniques for use in pre-clinical animal models of cardiovascular diseases, with a focus on stroke and heart disease. Firstly, in chapter 3, the continued development of an in-house MRI sequence known as extravascular convectography (EVAC) for measuring the flow of interstitial fluid is described. A series of phantom experiments were conducted to assess the sensitivity of the sequence to slow flowing fluid. Next, an in vivo repeatability and reproducibility study was conducted before finally the technique was applied to a rat model of stroke. In chapter 4, a pair of studies was carried out using recently established, advanced cardiac imaging techniques. In the first study, CINE and late gadolinium-enhanced inversion recovery (LGE IR) imaging were used to assess cardiac structure and function in a Prox1-deficient genetic mouse model of dilated cardiomyopathy. In the second part of the chapter, a multi-parametric MRI study – incorporating CINE, LGE IR, arterial spin labeling and T2-mapping – was conducted in a mouse model of reperfused myocardial infarction to assess the extent of area-at-risk and compare with gold-standard histological staining. Finally, in chapter 5, the development of a retrospective high-temporal resolution (HTR) CINE MRI sequence for assessing cardiac diastolic function is described and compared with pulsed wave Doppler ultrasound, which is the currently-accepted standard for measuring diastolic function. The HTR-CINE sequence was established, validated and optimised in phantoms and naïve mouse hearts. Repeatability studies were then carried out to ensure the robustness of the technique before application to a mouse model of myocardial infarction. The overall aim of the research in this thesis is the development of MRI techniques for application to experimental models of cardiovascular disease
Myocardial regeneration: expanding the repertoire of thymosin β4 in the ischemic heart.
No full textEfficient cardiac regeneration postinfarction (MI) requires the replacement of lost cardiomyocytes, formation of new coronary vessels and appropriate modulation of the inflammatory response. However, insight into how to stimulate repair of the human heart is currently limited. Using the embryonic paradigm of regeneration, we demonstrated that the actin-binding peptide thymosin β4 (Tβ4), required for epicardium-derived coronary vasculogenesis, can recapitulate its embryonic role and activate quiescent adult epicardial cells (EPDCs). Once stimulated, EPDCs facilitate neovascularization of the ischemic adult heart and, moreover, contribute bona fide cardiomyocytes. EPDC-derived cardiomyocytes structurally and functionally integrate with resident muscle to regenerate functional myocardium, limiting pathological remodeling, and effecting an improvement in cardiac function. Alongside pro-survival and anti-inflammatory properties, these regenerative roles, via EPDCs, markedly expand the range of therapeutic benefits of Tβ4 to sustain and repair the myocardium after ischemic damage
Preparation of mono-sized epoxy/MF microcapsulesin the appearance of polyvinyl alcohol as co-emulsifier
No full textFor epoxy microcapsules embedded in concrete as mechanic-triggered self-healing adhesive, globular shape with uniform size is the basic requirement to ensure the solid shell broken and the liquid core released at a designed stress. In this paper, monodispersed melamine\u96formaldehyde (MF) resin-walled epoxy E-51 microcapsules were successfully fabricated in an in situ polycondensation process, in which a certain amount of polyvinyl alcohol (PVA) solution was added as coemulsifier to control the microcapsules\u92 shape and size. Detail investigation shows, with the cooperation of PVA, the microcapsule morphologies and size distribution were ease to be adjusted by the parameters such as emulsifying agents, agitation rate, pH value and acidification time
ACT Family Violence Intervention Program review
No full textThis paper reports on a review of the Australian Capital Territory’s Family Violence Intervention Program, which provides an interagency response to family violence matters.
The scope of the review was to analyse the program’s activities and outcomes using 2007–08 data provided by participating agencies, supported by in-depth interviews with key stakeholders including victims whose matters had been finalised in court. After the completion of this report, additional data from 2008–09 and 2009–10 was made available by some Family Violence Intervention Program (FVIP) participating agencies. Although not within the scope of this evaluation, these data pointed to some preliminary improvements in the FVIP
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