京都大学 / 新制・論文博士 / 博士(医学) / 乙第13397号 / 論医博第2221号 / 新制||医||1051(附属図書館) / (主査)教授 伊佐 正, 教授 中本 裕士, 教授 渡邉 大 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21671号 / 医博第4477号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 溝脇 尚志, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

The term “electroluminescence” refers to light emission resulting from the application of an electrical bias. Electron tunneling across a biased, nanoscale junction can serve as the excitation source for photon emission. This effect is also mediated by the plasmonic environment of the junction, where a strong local field can enhance light emission by orders of magnitude. This dissertation presents measurements of electroluminescence from nanoscale gaps and single-molecule junctions. These measurements are made possible by a custom light emission detection system coupled to a scanning tunneling microscope break junction (STM-BJ) instrument. Conductance and light emission data are obtained simultaneously for thousands of junctions. Chapter 1 discusses molecular optoelectronics, a field at the intersection of plasmonic phenomena and molecular electronics, and introduces the STM-BJ technique for measuring molecular junctions. Chapter 2 describes the light emission detection setup that is operated in tandem with the STM-BJ instrument. Chapter 3 presents a study of Au tunnel junctions. This lays the groundwork for the plasmonics at play in these electroluminescent systems, detangling how gap size, electrical bias, and emission wavelength affect plasmonic enhancement. In Chapters 4 and 5, Au-molecule-Au junctions are investigated in some of the first experimental studies of single-molecule electroluminescence at ambient conditions. Chapter 4 uses light emission data from molecular junctions to estimate finite-frequency shot noise and uncover critical information about transmission characteristics. Chapter 5 presents one of the first examples of single-molecule strong light-matter coupling in an electroluminescent system, substantiated by spectroscopy data. This dissertation greatly expands on existing knowledge of plasmonic phenomena, particularly in relation to electroluminescent devices. Furthermore, it lays a strong foundation for single-molecule spectroscopy studies using the STM-BJ technique.

Thesis (MScMed)--Stellenbosch University, 2004. / Copy not signed by author. / ENGLISH ABSTRACT: This study involved 33 patients, 19 men and 14 women. The age range was wide (20-90 years) and median age was 57 years. These patients had a single pulmonary nodule (SPN) defined radiologically as a well defined, round or oval intrapulmonary lung lesion not associated with atelectasis or adenopathy on chest radiography or computed tomography. Patients were investigated with Tc-99m MIBI and TI-201 (25 patients) and with Tc-99m MIBI alone (8 patients). Single photon emission computed tomography images were reconstructed using both iterative reconstruction (Ordered Subsets - Expectation Maximisation: aSEM) and filtered backprojection (FBP), on the Hermes system. Transverse, coronal and sagittal slices were displayed on the screen using a grey scale. The aSEM and FBP images for each study were co-registered semi-automatically using the multimodality programme on the Hermes. The best slice for the lesion was chosen according to the best view used to locate the SPN on chest radiograph. Regions of interest (Ral) were drawn manually outside the outer margin of the detected lesion, first on the aSEM image. This was automatically mirrored on the co-registered FBP image. For most patients, the background was automatically mirrored horizontally on the contralateral side, again, first on the OSEM then automatically on the FBP image. Automatic vertical mirroring or manual horizontal mirroring was used when background was found to be in a visually 'hot' area like the heart or vertebrae. The average counts and standard deviation of the Ral and background were generated automatically. Semi-quantitative image analysis was done by calculating the signal-to-noise ratio (SNR) and tumour-to-background (TIB) ratio using the following formulae: SNR = Mean counts ROI(lesion) - Mean counts background Standard deviation background TIB rati.o = -M---e-a-n-'--c-o--u-n-'t-s- ROI(lesion) Mean counts background Detection was found to be the same for the two reconstruction algorithms, that is, every lesion detected by using OSEM could also be detected by using FBP. However lesion detection did differ between Tl-201 and Tc-99m-MIBI. Sensitivity and specificity were calculated for different thresholds of SNR and TIB ratios. Receiver operating characteristics (ROC) curves were drawn to represent the different sensitivities and specificities at each threshold. Tuberculosis (TB) was not included in this analysis as uptake of Tl-20l was found to be significantly high and comparable to that of malignant nodules. However the effect of OSEM and FBP on the 'positive' TB nodules was assessed separately. By calculating the area under the ROC curves, TI-201 using OSEM was shown to be more accurate at differentiating malignant nodules from benign ones than FBP. Although this difference was not statistically significant (p=0.1 0), there was a clear tendency. The two reconstruction algorithms were found to be almost equally accurate, when using Tc-99m-MIBI, the difference between them being considerably insignificant. In conclusion, it was shown that there is a tendency that OSEM outperforms FBP for studies using Tl-201 but not for Tc-99m-MIBI. / AFRIKAANSE OPSOMMING: Hierdie studie sluit 33 pasiënte in, 19 mans en 14 vroue. Die ouderdomme wissel tussen 20 en 90 jaar met 'n gemiddelde ouderdom van 57 jaar. Elkeen van die pasiënte het 'n enkel longnodule (SPN) op borskas X-straal en/of rekenaar tomografie getoon, wat radiologies gedefinieer word as 'n goed omskrewe, ronde of ovaal intrapulmonale longletsel wat nie met atelektase of adenopatie geassosieer is nie. Pasiënte is met Tc-99m MIDI en TI-201 (25 pasiënte) of slegs met Tc-99m MIBI (8 pasiënte) ondersoek. Enkelfoton emissie rekenaar tomografiese (EFERT) beelde is met beide iteratiewe rekonstruksie (Ordered Subsets - Expectation Maximisation: OSEM) en gefilterde terugprojeksie (FBP) met die Hermes sisteem gerekonstrueer. Transvers, koronale en sagittale snitte is in grysskaal op die sisteem vertoon. Die OSEM en FBP beelde vir elke studie is semi-outomaties gekoregistreer met behulp van die multimodaliteitsprogram op die Hermes. Die optimale snit vir elke letsel is gekies volgens die beste aansig op die borskas X-straalom die SPN te lokaliseer. Gebiede van belang (ROl) is met die hand buite-om die buitenste rand van die letsel getrek op die OSEM beeld en daarna outomaties in die ooreenstemmende area op die gekoregistreerde FPB beeld geplaas. Vir die meeste pasiënte is die agtergrond outomaties as horisontale spieëlbeeld op die kontralaterale kant geplaas, eers op die OSEM en dan outomaties op die FBP beeld. 'n Outomatiese vertikale spieëlbeeld of manuele horisontale verskuiwing van die agtergrondsarea is gedoen indien die agtergrond oorvleuel het met 'n 'warm' area soos die hart of werwels. Die gemiddelde tellings en standaardafwyking van die ROl en agtergrond is outomaties gegenereer. Semi-kwantitatiewe beeldanalise is gedoen deur berekening van die sein-tot-agtergrond verhouding (signal-to-noise ratio - SNR) en tumor-tot-agtergrond (TIB) verhouding met behulp van die volgende formules: SNR = gemiddelde tellings ROI(letsel) - gemiddelde tellings agtergrond Standaard afwyking van agtergrond TIB rati.o = -g=em--id-d-e-l-d-e--te=ll-in-g-s__R:_O-I(-le-t-s'e-l) gemiddelde tellings agtergrond Opsporing is soortgelyk bevind vir die twee rekonstruksie algoritmes, dit wil sê elke letselopgespoor met behulp van OSEM kon ook met FBP opgespoor word. Letselwaameming het egter verskil tussen TI-201 en Tc-99m-MIBI. Sensitiwiteit en spesifisiteit is vir verskillende drempels van SNR en TIB verhoudings bereken. 'Receiver operating characteristics' (ROC) kurwes is getrek om die verskillende sensitiwiteite en spesifisiteite by elke drempel te verteenwoordig. Tuberkulose (TB) is nie in hierdie analise ingesluit nie aangesien opname van Tl-201 beduidend hoog en vergelykbaar met die van maligne nodules was. Die effek van OSEM en FBP op die 'positiewe' TB nodules is egter apart beoordeel. Deur berekening van die area onder die ROC kurwes, is getoon dat OSEM van Tl-201 tomografiese data meer akkuraat as FBP was om maligne van benigne nodules te onderskei. Alhoewel hierdie verskil nie statisties betekenisvol was nie (p=0.10), is daar wel 'n duidelike neiging gevind. Die twee rekonstruksie algoritmes was byna ewe akkuraat wanneer Tc-99m-MIBI gebruik is, met duidelik geen betekenisvolle verskil tussen die algoritmes nie. Gevo lgtrekking In hierdie studie is dit getoon dat daar 'n neiging is dat OSEM beter vaar as FBP vir studies met tallium-201 maar nie vir Tc-99m-MIBI nie.

Diabetes is a rapidly growing disease with 415 million affected adults worldwide. The pancreatic endocrine cells, most importantly the insulin producing β-cells, play an important role in regulating blood glucose homeostasis. Type 1 diabetes (T1D) is characterized by the inability of the pancreas to secrete sufficient amounts of insulin due to autoimmune destruction of insulin producing β-cells. Type 2 diabetes (T2D) on the other hand is characterized by defects in insulin secretion and insulin sensitivity. Alterations in the β-cell mass (BCM) and/or function play a major role in the development and progression of the disease. Understanding BCM dynamics in disease models is therefore a key aspect for better interpretation of research results. In this thesis, we have used optical projection tomography (OPT) as a tool to evaluate a non-invasive imaging modality for β-cell scoring and to study disease dynamics in frequently used animal models for T1D and T2D. The possibility to monitor BCM in vivo would radically improve our competence in studying the pathogenesis of diabetes and in therapeutic interventions. Single photon emission computed tomography (SPECT) is a widely used technique that has become a promising approach to monitor changes in BCM in vivo. A key issue for using this approach is to evaluate the β-cell specificity and read out of the utilized radiotracers. This is most commonly performed by conventional stereological approaches, which rely on the extrapolation of 2D data. We developed a protocol for SPECT-OPT multimodal imaging that enables rapid and accurate cross evaluation of SPECT based assessments of BCM. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of the radiotracer 111In-exendin-3 and insulin positive β-cell volumes respectively between different pancreatic lobes, both visually and quantitatively. We propose SPECT-OPT multimodal imaging as an accurate and better approach for validating the performance of β-cell radiotracers. The leptin deficient ob/ob mouse is a widely used model for studies of metabolic disturbances leading to T2D, including obesity and insulin resistance. By OPT imaging we created the first 3D-spatial and quantitative account of BCM distribution in this model. We observed a previously unreported degree of cystic lesions in hypertrophic islets, that were occupied by red blood cells (RBCs) and/or fibrin mesh. We propose that these lesions are formed by a mechanism involving the extravasation of RBCs/plasma due to increased blood flow and islet vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of these characteristics of β-cell expansion in ob/ob mice presented in this study may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function. The tomographic data, on which this study was based, will be made publically available as a resource to the research community for the planning and interpretation of research involving this model. There are limited studies on early metabolic and functional changes of BCM in the settings of T1D. In order to assess initial metabolic alterations in BCM before the onset of diabetes, we characterized congenic diabetes prone Bio-breeding (BB) DR.lyp/lyp rats, a widely used model for T1D diabetes. We observed lower acute insulin response, reduced islet blood flow and a significant reduction in the BCM of small and medium sized islets at a very early stage (40 days), i.e. before insulitis and development of diabetes. Underlying changes in islet function may be a previously unrecognized factor of importance in the development of T1D.

INTRODUÇÃO: O zumbido é um sintoma muito freqüente e de difícil tratamento. Atualmente, algumas evidências mostraram que o zumbido está associado a alterações funcionais do sistema nervoso central. Nos últimos anos, a modulação da atividade cortical relacionada ao zumbido por meio da estimulação magnética transcraniana repetitiva (EMT) tem sido proposta como um tratamento promissor. Entretanto, nenhum estudo avaliou sua eficácia no controle do zumbido em pacientes sem perda auditiva concomitante, nem seu efeito de longa duração. O objetivo do trabalho foi investigar os efeitos imediatos e a longo prazo da estimulação magnética transcraniana repetitiva de baixa freqüência (1 Hz) em pacientes com zumbido e audiometria normal. MÉTODOS: Utilizando um ensaio clínico aleatorizado, duplo cego e paralelo, foram randomizados 20 pacientes para receber a EMT ativa ou placebo. A estimulação foi aplicada no córtex têmporo-parietal esquerdo por cinco dias consecutivos. A avaliação clínica foi feita por meio do Tinnitus Handicap Inventory e da escala análogo-visual. A avaliação por neuroimagem foi feita por meio do SPECT, o qual foi realizado antes e 14 dias após o período de estimulação. RESULTADOS: Clinicamente, o grupo submetido à estimulação magnética transcraniana ativa apresentou uma melhora significativa do zumbido, mantida por até seis meses, quando comparado ao grupo que recebeu a estimulação placebo. A avaliação por SPECT demonstrou redução do fluxo sanguíneo no lobo temporal esquerdo após o período de estimulação ativa. CONCLUSÃO: Os resultados revelam o potencial terapêutico da estimulação magnética transcraniana como nova ferramenta no tratamento do zumbido, proporcionando redução significativa do incômodo provocado pelo zumbido por até seis meses e reduzindo a atividade neuronal no córtex temporal. / INTRODUCTION: Tinnitus is a frequent disorder which is very difficult to treat. There is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Recently, the targeted modulation of tinnitus-related cortical activity through repetitive transcranial magnetic stimulation (rTMS) has been proposed as a promising new treatment approach. However, its efficacy in patients without hearing loss has never been studied, as well as the long-term duration of its effect. The objective of this study was to investigate both immediate and long-term effect of low frequency (1 Hz) rTMS in patients with tinnitus and normal hearing. METHODS: Using a randomized double-blind and parallel clinical trial, 20 patients were divided to receive either active or placebo transcranial magnetic stimulation over the left temporoparietal cortex for 5 consecutive days. The clinical evaluation was performed by using the Tinnitus Handicap Inventory and the visual analogue scale. The neuroimage evaluation included and ECD-SPECT imaging, which was performed before and 14 days after rTMS. RESULTS: From the clinical point of view, the group submitted to active rTMS presented significant improvement of the tinnitus score, which was sustained up to six months, when compared to the group that received the sham rTMS. SPECT measurements demonstrated a reduction of metabolic activity in the left temporal lobe after active rTMS. CONCLUSION: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus, by demonstrating a significant reduction of tinnitus complaints over a period of at least six months and a significant reduction of neural activity in the temporal cortex.

Bakgrund: Kranskärlssjukdom (CAD) är en hjärtsjukdom som kan diagnostiseras med icke-invasiva metoder, såsom myocardial perfusion imaging med single-photon emission computed tomography (SPECT), och genom invasiva metoder, såsom invasiv koronarangiografi (ICA). ICA är den golden standardmetod för att diagnostisera CAD. Men å andra sidan är ICA mer kostsam än SPECT och kan orsaka många komplikationer. Metoder och resultat: det är en retrospektiv kohortstudie. Studien analyserade 62 patienter som har genomgått både SPECT och ICA under 2018 vid Universitetssjukhuset Örebro (USÖ). Av dessa 62 utförde 56 patienter SPECT först. Analyseringen gjordes för att undersöka hur väl resultatet av ICA-sjukdomsdetektering och lokalisering kunde bestämmas av SPECT. Aktiv CAD definierades som närvaron av en behandling-krävande signifikant stenos vid ICA. SPECT-resultaten visade att 91% av fallen var patologiska och 9% var icke-patologiska. Sensitivitet, specificitet och noggrannhet för SPECT för detektering av aktiv CAD var 89%, 7% respektive 47% vid referens till ICA. Medan positiva prediktiva värden (PV +) och negativa prediktiva värden (PV-) var 48% respektive 40%. SPECT sensitivitet för lokalisering av defekter i referens till ICA var 35% för LAD-defekter, 68% för LCX-defekter och 92% för RCA-defekter. Slutsats: Resultatet skilde sig från den ursprungliga hypotesen. SPECT anses fortfarande vara effektiv för att identifiera patienter med aktiv CAD. Därför kan SPECT användas som initial undersökningsmetod för utvärdering av CAD hos patienter med låg till måttlig risk. SPECT var inte optimalt för att lokalisera defekterna.

INTRODUÇÃO: O zumbido é um sintoma muito freqüente e de difícil tratamento. Atualmente, algumas evidências mostraram que o zumbido está associado a alterações funcionais do sistema nervoso central. Nos últimos anos, a modulação da atividade cortical relacionada ao zumbido por meio da estimulação magnética transcraniana repetitiva (EMT) tem sido proposta como um tratamento promissor. Entretanto, nenhum estudo avaliou sua eficácia no controle do zumbido em pacientes sem perda auditiva concomitante, nem seu efeito de longa duração. O objetivo do trabalho foi investigar os efeitos imediatos e a longo prazo da estimulação magnética transcraniana repetitiva de baixa freqüência (1 Hz) em pacientes com zumbido e audiometria normal. MÉTODOS: Utilizando um ensaio clínico aleatorizado, duplo cego e paralelo, foram randomizados 20 pacientes para receber a EMT ativa ou placebo. A estimulação foi aplicada no córtex têmporo-parietal esquerdo por cinco dias consecutivos. A avaliação clínica foi feita por meio do Tinnitus Handicap Inventory e da escala análogo-visual. A avaliação por neuroimagem foi feita por meio do SPECT, o qual foi realizado antes e 14 dias após o período de estimulação. RESULTADOS: Clinicamente, o grupo submetido à estimulação magnética transcraniana ativa apresentou uma melhora significativa do zumbido, mantida por até seis meses, quando comparado ao grupo que recebeu a estimulação placebo. A avaliação por SPECT demonstrou redução do fluxo sanguíneo no lobo temporal esquerdo após o período de estimulação ativa. CONCLUSÃO: Os resultados revelam o potencial terapêutico da estimulação magnética transcraniana como nova ferramenta no tratamento do zumbido, proporcionando redução significativa do incômodo provocado pelo zumbido por até seis meses e reduzindo a atividade neuronal no córtex temporal. / INTRODUCTION: Tinnitus is a frequent disorder which is very difficult to treat. There is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Recently, the targeted modulation of tinnitus-related cortical activity through repetitive transcranial magnetic stimulation (rTMS) has been proposed as a promising new treatment approach. However, its efficacy in patients without hearing loss has never been studied, as well as the long-term duration of its effect. The objective of this study was to investigate both immediate and long-term effect of low frequency (1 Hz) rTMS in patients with tinnitus and normal hearing. METHODS: Using a randomized double-blind and parallel clinical trial, 20 patients were divided to receive either active or placebo transcranial magnetic stimulation over the left temporoparietal cortex for 5 consecutive days. The clinical evaluation was performed by using the Tinnitus Handicap Inventory and the visual analogue scale. The neuroimage evaluation included and ECD-SPECT imaging, which was performed before and 14 days after rTMS. RESULTS: From the clinical point of view, the group submitted to active rTMS presented significant improvement of the tinnitus score, which was sustained up to six months, when compared to the group that received the sham rTMS. SPECT measurements demonstrated a reduction of metabolic activity in the left temporal lobe after active rTMS. CONCLUSION: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus, by demonstrating a significant reduction of tinnitus complaints over a period of at least six months and a significant reduction of neural activity in the temporal cortex.

In many medical imaging modalities, as photons travel from the emission source to the detector, they are scattered by the biological tissue. Often this scatter is viewed as a phenomenon that degrades image quality, and most research is focused on designing methods for either discarding the scattered photons or correcting for scatter. However, the scattered photons also carry information about the tissue that they pass through, which can perhaps be extracted. In this research, we investigate methods to retrieve information from the scattered photons in two specific medical imaging modalities: diffuse optical tomography (DOT) and single photon emission computed tomography (SPECT). To model the scattering of photons in biological tissue, we investigate using the Neumann-series form of the radiative transport equation (RTE). Since the scattering phenomenon are different in DOT and SPECT, the models are individually designed for each modality. In the DOT study, we use the developed photon-propagation model to investigate signal detectability in tissue. To study this detectability, we demonstrate the application of a surrogate figure of merit, based on Fisher information, which approximates the Bayesian ideal observer performance. In the SPECT study, our aim is to determine if only the SPECT emission data acquired in list-mode (LM) format, including the scattered-photon data, can be used to compute the tissue-attenuation map. We first propose a path-based formalism to process scattered photon data, and follow it with deriving expressions for the Fisher information that help determine the information content of LM data. We then derive a maximum-likelihood expectation-maximization algorithm that can jointly reconstruct the activity and attenuation map using LM SPECT emission data. While the DOT study can provide a boost in transition of DOT to clinical imaging, the SPECT study will provide insights on whether it is worth exposing the patient to extra X-ray radiation dose in order to obtain an attenuation map. Finally, although the RTE can be used to model light propagation in tissues, it is computationally intensive and therefore time consuming. To increase the speed of computation in the DOT study, we develop software to implement the RTE on parallel computing architectures, specifically the NVIDIA graphics processing units (GPUs).