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Trabalhos anteriores sobre a síntese de imagens de difusão por ressonância magnética se limitaram a estudos sobre estruturas microscópicas, menores que as dimensões típicas de um voxel (e.g., [BF08] [BF13] [LFS + 10] e [BA94]). Isto decorre em parte devido às metodologias utilizadas, que têm como ponto em comum serem simulações de tipo Monte Carlo, nas quais os elementos mínimos da simulação são as partículas de água. Portanto o custo computacional destas simulações é proporcional ao número de partículas a simular, e isto limita os volumes que podem ser simulados a tamanhos microscópicos. Propomos uma metodologia alternativa, que utiliza a imagem T 2 de uma amostra para sintetizar imagens de difusão por ressonância magnética. Os elementos mínimos desta nova metodologia são os pontos da imagem T 2 , e portanto seu custo computacional é proporcional à resolução da imagem T 2 utilizada, o que permite a síntese a partir de amostras de qualquer tamanho físico. Estas sínteses são realizadas por meio da integração numérica da equação do artigo seminal de Stejskal e Tanner [ST65] que relaciona a atenuação do sinal de ressonância magnética devida à difusão com os parâmetros da sequência de pulsos PGSE. Usamos os parâmetros típicos dessa sequência (b, gamma, tau\', g 0, g, delta e Delta), que podem ser configurados explicitamente em máquinas de ressonância magnética, para calcular valores do coeficiente de difusão aparente D em direções arbitrárias. Desenvolvemos software, disponibilizado [Bor] por licença GPL [Fou07], para realizar estas simulações, e para especificar uma máscara de direções, útil para modelar a difusão de uma amostra. Estas ferramentas permitem o estudo sistemático das variações dos parâmetros na síntese de imagens de difusão por ressonância magnética. Apresentamos um estudo de um fantoma de capilares imersos em água, exemplificando como utilizar as ferramentas para investigar a influência destes parâmetros na difusão da água da amostra. / Previous work on the synthesis of diffusion-weighted magnetic resonance imaging are limited to microscopic structures, smaller than the typical dimensions of a single voxel (e.g., [BF08] [BF13] [LFS + 10] and [BA94]). This is consequence, in part, of the methodologies used, that have in common the adoption of Monte Carlo simulation strategies, in which the minimal elements of simulation are the water particles. Therefore the computational cost of these simulations is proportional to the number of particles to simulate, and this limits the volume to be simulated to microscopic sizes. We propose a novel methodology, that uses the T 2 image from a sample to synthesize diffusion-weighted magnetic resonance images. The mininal elements of this novel methodology are the points of the T 2 image, and therefore its computational cost is proportional to the resolution of the T 2 image to be used, which allows the synthesis from samples of any physical size. These syntheses are made through numerical integration of the equation from the seminal article by Stejskal and Tanner [ST65] that relates the attenuation of the magnetic resonance signal due to diffusion to the parameters of the PGSE pulse sequence. We use the typical parameters of this sequence (b, gamma, tau\', g 0, g, delta and Delta), that can be explicitly configured in magnetic resonance machines, to calculate apparent diffusion coefficients D in arbitrary directions. We developed software, available [Bor] through GPL license [Fou07], to run these simulations, and to specify a mask of directions useful to model diffusion. These tools allow the systematic study of parameter variation in the synthesis of diffusion-weighted magnetic resonance images. We present a case study of a phantom made of capillary tubes immersed in water, to exemplify the use of these tools and how to investigate the influence of parameter variation on diffusion in the sample.

Trabalhos anteriores sobre a síntese de imagens de difusão por ressonância magnética se limitaram a estudos sobre estruturas microscópicas, menores que as dimensões típicas de um voxel (e.g., [BF08] [BF13] [LFS + 10] e [BA94]). Isto decorre em parte devido às metodologias utilizadas, que têm como ponto em comum serem simulações de tipo Monte Carlo, nas quais os elementos mínimos da simulação são as partículas de água. Portanto o custo computacional destas simulações é proporcional ao número de partículas a simular, e isto limita os volumes que podem ser simulados a tamanhos microscópicos. Propomos uma metodologia alternativa, que utiliza a imagem T 2 de uma amostra para sintetizar imagens de difusão por ressonância magnética. Os elementos mínimos desta nova metodologia são os pontos da imagem T 2 , e portanto seu custo computacional é proporcional à resolução da imagem T 2 utilizada, o que permite a síntese a partir de amostras de qualquer tamanho físico. Estas sínteses são realizadas por meio da integração numérica da equação do artigo seminal de Stejskal e Tanner [ST65] que relaciona a atenuação do sinal de ressonância magnética devida à difusão com os parâmetros da sequência de pulsos PGSE. Usamos os parâmetros típicos dessa sequência (b, gamma, tau\', g 0, g, delta e Delta), que podem ser configurados explicitamente em máquinas de ressonância magnética, para calcular valores do coeficiente de difusão aparente D em direções arbitrárias. Desenvolvemos software, disponibilizado [Bor] por licença GPL [Fou07], para realizar estas simulações, e para especificar uma máscara de direções, útil para modelar a difusão de uma amostra. Estas ferramentas permitem o estudo sistemático das variações dos parâmetros na síntese de imagens de difusão por ressonância magnética. Apresentamos um estudo de um fantoma de capilares imersos em água, exemplificando como utilizar as ferramentas para investigar a influência destes parâmetros na difusão da água da amostra. / Previous work on the synthesis of diffusion-weighted magnetic resonance imaging are limited to microscopic structures, smaller than the typical dimensions of a single voxel (e.g., [BF08] [BF13] [LFS + 10] and [BA94]). This is consequence, in part, of the methodologies used, that have in common the adoption of Monte Carlo simulation strategies, in which the minimal elements of simulation are the water particles. Therefore the computational cost of these simulations is proportional to the number of particles to simulate, and this limits the volume to be simulated to microscopic sizes. We propose a novel methodology, that uses the T 2 image from a sample to synthesize diffusion-weighted magnetic resonance images. The mininal elements of this novel methodology are the points of the T 2 image, and therefore its computational cost is proportional to the resolution of the T 2 image to be used, which allows the synthesis from samples of any physical size. These syntheses are made through numerical integration of the equation from the seminal article by Stejskal and Tanner [ST65] that relates the attenuation of the magnetic resonance signal due to diffusion to the parameters of the PGSE pulse sequence. We use the typical parameters of this sequence (b, gamma, tau\', g 0, g, delta and Delta), that can be explicitly configured in magnetic resonance machines, to calculate apparent diffusion coefficients D in arbitrary directions. We developed software, available [Bor] through GPL license [Fou07], to run these simulations, and to specify a mask of directions useful to model diffusion. These tools allow the systematic study of parameter variation in the synthesis of diffusion-weighted magnetic resonance images. We present a case study of a phantom made of capillary tubes immersed in water, to exemplify the use of these tools and how to investigate the influence of parameter variation on diffusion in the sample.

Breast cancer is the most common and the second most fatal cancer among women in the U.S. Current knowledge indicates that there is a relationship between high breast density (measured by mammography) and increased breast cancer risk. However, the biology behind this relationship is not well understood. This may be due to the limited information provided by mammography which only yields information on the relative amount of fibroglandular to adipose tissue in the breast. In our studies, breast density is assessed using quantitative MRI, in which MRI-based tissue-dependent parameters are derived voxel-wise by mathematically modeling the acquired MRI signals. Specifically, we use data from a radial gradient- and spin-echo imaging technique, previously developed in our group, to assess fat fraction and T₂ of the water component in relation to breast density. In addition, we use diffusion-weighted imaging to obtain another parameter, apparent diffusion coefficient (ADC) of the water component in the breast. Each parametric map provides a different type of information: fat fraction gives the amount of fat present in the voxel, the T₂ of water spin relaxation is sensitive to the water component in the tissue, and the ADC of water yields other type of information, such as tissue cellularity. The challenge in deriving these parameters from breast MRI data is the presence of abundant fat in the breast, which can cause artifacts in the images and can also affect the parameter estimation. We approached this problem by modifying the imaging sequence (as in the case of diffusion-weighted imaging) and by exploring new signal models that describe the MRI signal accounting for the presence of fat. In this work, we present the improvements made in the imaging sequence and in the parametric mapping algorithms using simulation and phantom experiments. We also present preliminary results in vivo in the context of breast density-related tissue characterization.

The overall aim of the study was to examine relapse among participants in the DWI Prevention Programme and those who get prison sentence after driving when influenced by alcohol and to examine the participants’ attitudes towards drunk – driving, risk behavior and traffic safety. A direct evaluation of the sentence and penal accomplishment is also examined. The sample of the survey study (see article 1) was 44 from the DWI – sample and 44 from the prison – sample that completed a questionnaire answering about their attitudes towards drunk – driving, risk behavior and traffic safety. The results presented in article 2 are based on transcripts of criminal convicts that participated in the DWI Prevention Programme during the period of 1998 – 2002 in the Salten District ( n = 68) and a sample of convicts to an unconditional sentence for drunk - driving in the same time periode (n = 112). The 1st analysis revealed that the DWI – sample had more ideal attitudes towards drunk – driving, risk behavior and traffic safety. There were also significant differences in how they evaluated their sentence and penal accomplishment. The DWI - sample were generally more satisfied with the penal accomplishment, the way they was treated and how the relationships around them were. They were also more satisfied with the contents of the penal accomplishment. Multivariate analysis, Kaplan – Meier and Cox regression was used in the 2nd analysis calculating if there were significant differences between the samples, survival time and to investigate effects of several variables upon the time a specified event takes to happen. In this study the relapse time was shorter for men than for women and the youngest age – groups had a shorter relapse time than the oldest age – groups. The Kaplan – Meier plot revealed that the prison – group have a shorter relapse time compared to the DWI – group. Based on the results of the two articles we can conclude that the DWI Prevention Programme had a very good effect on the participants compared to those who get traditional prison – sentence. The participants in the programme had the most ideal attitudes and the longest survival time after participating. When it comes to survival time among gender and age, women and the older age – groups had the longest survival time.

Background: Angiogenesis is the process by which new blood vessels develop from existing vasculature and is a critical step in all tumours to facilitate growth beyond a few millimetres. As this process is largely inactive in physiological circumstances in adults, it represents an attractive therapeutic target in oncology. Drugs that target the angiogenic process are classified as anti-angiogenic agents. The first anti-angiogenic drug to be approved by the FDA was bevacizumab; a recombinant humanized monoclonal antibody against VEGF. Randomised studies in colorectal cancer (and other solid malignancies) have reported prolonged progression free survival and overall survival for bevacizumab. However, standard radiological criteria, Response Evaluation Criteria In Solid Tumours (RECIST), although widely employed to assess response to therapy in clinical trials, are generally insensitive to the predominantly cytostatic effects of anti-angiogenic and other targeted therapies. Alternative methods of predicting or assessing early response to such agents are needed, particularly given the cost and toxicity implications of such treatments. However, biomarkers to aid selection of patients for anti-angiogenic therapies, including bevacizumab, remain elusive. Purpose: To investigate Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), Diffusion Weighted Imaging (DWI) and circulating angiocytokines, measured using an ELISA multiplex, as prognostic markers in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy. Results: Seventy patients were treated. DCE-MRI and DWI parameters showed good reproducibility with coefficient of variation between 3.7 to 23% for parameters. The median progression free survival, the primary end point of the trial, was 9.3 months. The overall response rate was 44%. The clinical variables which were significant for progression free survival on univariate analysis were: performance status (p=0.005), CEA (p=0.04) and serum LDH (p=0.005). Biomarkers which were significant for progression free survival on univariate analysis were serum VEGF-A (p=0.02), serum HGF (p=0.005), sVEGFR-2 (p=0.02). In each case, low values of the biomarker were associated with improved outcome. Multivariate analysis identified Ktrans (p=0.015), performance status (p=0.008) and serum HGF (p=0.003) as the most significant predictors of progression free survival. A prolonged progression free survival was associated with a good ECOG performance status, high Ktrans and low serum HGF.Conclusions: Whilst these results are encouraging, future work is required to establish whether HGF and Ktrans are prognostic markers for metastatic colorectal cancer and their precise role in the prediction of patients likely to benefit from treatment with bevacizumab.

Driving anxiety that has developed following crashes has been studied relatively frequently, but anxiety per se and its effects on driving has not as yet garnered much attention in the literature. The current study included 1121 participants and found higher levels of general anxiety were related to a wide variety of dangerous driving behaviors. While there were clear and expected sex differences on many dangerous driving variables, there were still more such differences with regard to anxiety levels and independent of sex, higher levels of anxiety were associated with greater levels of dangerous driving. Of particular import, it was found that the high anxiety group had caused significantly more crashes and engaged in more DUI episodes than the low and/or medium anxiety groups. Taken as a whole, the results suggest there is a tremendous need for more research in the area of anxiety and dangerous driving and that interventions for highly anxious drivers may well be warranted.

Introduction: With many thousands of deaths still annually attributable to driving under the influence (DUI), it remains imperative that we continually address the problem of producing and sustaining effective countermeasures, and that we subject these efforts to empirical scrutiny. This article presents relevant findings from state-wide datasets. Results: A formula generating a potentially useful metric for assessing aspects of the DUI prosecutorial chain is presented, focusing on the rate of proactive DUI arrests. While in need of cautious interpretation due to issues of inherent inaccuracies in large databases, small numbers of crashes and/or arrests in multiple jurisdictions, and the lack of replication in other states, the analyses show no relationship between the level of DUI arrest activity and DUI-related crashes. This finding brings into question the efficacy of the many millions of dollars devoted each year to targeted DUI enforcement, as it is currently being implemented. Conclusions: Results are discussed in terms of developing adequate disincentives to DUI so as to raise general deterrence via dramatic increases in proactive DUI enforcement and then engaging in pervasive and persistent social marketing of such efforts to maximize the perception that arrest and punishment for DUI is always imminent, that penalties will be swift, certain, and severe. It is echoed that accurate data need to be collected at all levels of the DUI arrest and prosecution process in every jurisdiction within a state, so as to facilitate the empirical assessment of countermeasure efficacy in reducing alcohol-related crashes. Impact on Industry: Given that this work needs to be replicated, the impact on the traffic safety industry is potentially huge. The present data indicate that law enforcement efforts to further abate DUI-related crashes are apparently ineffective, though likely necessary to maintain reductions achieved in the 80s and early 90s. Thus, to attain additional systematic reductions, a dramatic increase in enforcement will be necessary as will a diversification of abatement efforts, including an increase in aggressive social marketing tactics to positively impact our traffic safety culture by making DUI universally unacceptable (for a discussion of this latter issue and on the use of positive reinforcement to change driver behavior, see Dula & Geller, 2007).

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19172号 / 医博第4014号 / 新制||医||1010(附属図書館) / 32164 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 平岡 眞寛, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diffusion Magnetic Resonance Imaging (DMRI) is a class of Magnetic Resonance Imaging (MRI) techniques with broad medical applications ranging from characterization of tumors and brain damage to potential prediction of stroke. Gradient coil and signal-to- noise ratio (SNR) constraints limit spatial resolution, accuracy, and scan time in DMRI. Achieving high b-values (measures of a scan's sensitivity to diffusion) often require scans with long diffusion gradient pulses, leading to significant magnetic resonance (MR) signal decay before the signal can be sampled. This signal loss reduces the accuracy of diffusion parameter estimation. The ability to sample the MR signal sooner while maintaining the same b-value is restricted by the maximum amplitude and slew rate of gradient coils. A composite system utilizing body and high-powered insert gradient coils can achieve high b-values more quickly, enabling a shorter delay between excitation and signal sampling and improved accuracy of diffusion parameter estimation. Alternately, such a system can achieve higher b-values at an equivalent delay between excitation and signal sampling. This thesis describes the implementation of such a system, experiment design for evaluating the benefits of the system to DMRI, and design of a diffusion phantom. Also included are a characterization of a composite system's improvements to DMRI based on analysis of experimentally-obtained data and simulation results validating those findings. Finally, recommendations for further improvements to diffusion MRI are given.