Hepatobiliary disease can sometimes be difficult to diagnosis due to non-specific clinical signs, and diagnostic imaging is a vital tool in diagnosing these diseases. Multi-slice computed tomographic cholangiography (MSCTC) is a non-invasive way to obtain high quality images of the hepatobiliary system. Our objectives were to determine the best technique for performing MSCTC in normal dogs with regards to contrast agent, dose, and optimal time to imaging. Our test subjects included eight normal adult hounds. Four dogs were administered Cholografin and the other four Biliscopin. Two dose groups were established with four dogs receiving 0.5mL/kg and four receiving 1 mL/kg. Our results demonstrated that MSCTC is feasible in normal dogs and produces high quality images of the hepatobiliary system. The contrast agent Biliscopin at the higher dose subjectively produced the best quality images. The optimal time to image patients following contrast administration varied between contrast agents (15-60 minutes).

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24198号 / 医博第4892号 / 新制||医||1060(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 川口 義弥, 教授 松田 秀一, 教授 小濱 和貴 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This thesis describes an experimental study of the air flow in ventilating ducts in the stators of electric motors and/or generators of conventional design. The objective was to facilitate prediction of local heat transfer coefficients in ventilating ducts. Various flow phenomena were observed and compared with theoretical predictions. While the theory usually used for similar cases was found o be inapplicable, a related theory was found that checked well with experimental results. A stall phenomenon was observed under certain identified conditions. Useful relationships for predicting the flow details were obtained. The relevance of the work is discussed and future work is proposed. / Thesis / Master of Engineering (MEngr)

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A new active-passive approach for the control of noise radiated from a small axial fan was investigated. The approach involved the installation of an axial fan into a short duct with both passive and active noise control functions. First, a systematic methodology for the analytical modeling of finite-length ducts with multiple discontinuities was formulated. The procedure involved the modeling of a duct as a collection of simple duct sections, which were interconnected at multiple junctions. Analytical studies have shown that a short lined duct provides passive noise reduction effects through the mass-loading effect of the duct air volume at low frequencies and the sound absorption by a passive liner at high frequencies. It was also shown that active control can provide further noise attenuations at low-to-mid frequencies, thereby enhancing the overall noise control performance. Two alternate designs of active-passive noise control fan duct were considered. One was a simple non- segmented duct with a 2x2 active control and the other was an internally segmented duct with an 8x8 active control. It was indicated that the latter design possesses a significantly higher global noise control potential than the former with respect to both bandwidth and attenuation level. This was attributed to the reduction of the unwanted pressure contributions from the duct cross modes through the high frequency shifting of the associated cut-on frequencies. The experimental validation of the noise control approach was also carried out. An active-passive noise control fan duct incorporating the segmented duct design with 8x8 active control was constructed in conjunction with a hybrid feedforward-feedback control system. Experimental results have shown significant reductions in the total fan noise power associated with the first four BPF tones by the feedforward control and the broadband fan noise power by the feedback control. The overall active-passive noise control characteristics were observed to be in accordance with the analytical results. / Ph. D.

The pancreas is a secretory organ composed of exocrine and endocrine compartments. During development, endocrine cells delaminate from the pancreatic epithelium to associate with the local vasculature where they will secrete hormones such as insulin into the blood stream. The exocrine pancreas is composed of ductal cells which form a network of tubes to secrete and transport fluid carrying the digestive enzymes secreted from acini located at the terminal ends of ductal branches. Unlike many branched epithelia, the pancreas does not exhibit a stereotypical branching pattern. The ductal network develops from a mesh of interconnected lumens which are eventually pruned and give rise to a final tree-like structure optimized for the most economical delivery of enzymes and fluid to the digestive tract. In silico modelling suggests that fluid flow plays a role in resolving the final structure of the ductal network during development, indicating that physical forces may play a role in this self-organization Recent work in the adult human pancreas has shown that the cells of the small ducts in the most distal parts of the ductal network do not express the same transcripts as the proximal large ducts. The pancreas derives this structure and function from the differentiation and self-organization of progenitors into terminally differentiated cells which, together with mesenchymal cells and vasculature, contribute to the tissue niche of the organ. Despite the importance of this process in development and disease, little is known about how pancreatic progenitors balance differentiation with morphogenesis. The goal of this project was to uncover niche components that influence the differentiation of pancreas progenitors, and understand how identity and morphogenesis are mediated by niche-driven changes in gene expression. This remains a challenging process to understand due to limited accessibility of the embryonic pancreas. Therefore, human sphere and organoid models represent a valuable tool to address this question and were used together with expression profiling and manipulation of the extracellular environment to understand this relationship during pancreas development. Time-course bulk RNA sequencing of human pancreas progenitor spheres at different days of culture revealed the sequential processes happening as the cells form their niche, and then start proliferating and forming lumen. Notably, at the stage of lumen expansion, we observed an upregulation of genes associated with ductal epithelia, such as CFTR, MUC1, MUC6, and CA2 in tandem with increased expression of genes encoding proteins for ion and fluid secretion. This suggested hydraulics may act to integrate ductal differentiation with luminogenesis, which is consistent with in silico modelling and the secretory function of the pancreatic epithelia. Indeed, driving chloride ion secretion with the CFTR activator forskolin resulted in inflation of the sphere lumen and increased the expression of the ductal genes identified above. Induction of CFTR and MUC1 can also be achieved by inflating the lumen in a CFTR-independent manner using prostaglandin E2. This revealed the changes in gene expression were not due to a small feedback loop under the control of CFTR, and maybe due to morphological changes related to lumen inflation. Importantly, it was revealed that the induction of Cftr expression upon lumen inflation also occurred in pancreas explants isolated from embryonic mice, which suggests the relationship between lumen inflation and ductal identity is conserved between mouse and human. Datamining of single cell RNA sequencing of adult and fetal pancreas samples identified novel marker genes for progenitor, acinar, and large- and small-ducts of the human fetal pancreas. Comparison of these marker genes with gene expression patterns of pancreas progenitor spheres revealed a shift to a small-duct-like identity when the lumen is inflated. This shift seemed to be dependent on inflation of the lumen rather than cAMP signalling, as it is not observed in pancreas progenitors grown in 2D and treated with forskolin. The above experiments suggest a link between lumen inflation and small duct identity but the exact mechanism remains unclear. Lumen inflation is likely driven by an increase in hydrostatic pressure that occurs downstream of changes in osmotic pressure due to ion channel activation. Independent manipulation of osmotic pressure, hydraulic pressure, tissue stretching, and fluid shear stress will be valuable to decipher the mechanisms of ductal gene regulation. Taken together these results support the hypothesis that differential gene expression in ducts of different sizes is regulated by mechanical forces in the pancreas, and 3D sphere culture represents a powerful model to investigate these processes in finer detail.

Thesis (PhD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Diabetes Mellitus (DM) is synonymous with "B-cell failure". Ligation of the pancreatic duct distally to its confluence into the bile duct has been shown to induce endocrine tissue regeneration from a number of probable sources. The cells responsible for regeneration are supposed to possess either dormant pluripotent stem cell ability and/or the plasticity to undergo metaplasia to form new and surplus endocrine tissue able to replace pathologically and/or experimentally compromised pancreas. The sequence of events (cell lineage) during this process of neogenesis, has been the source of controversy for quite some time as various studies suggest that the cell lineage differs from in vivo and in vitro studies, according to experimental model and species of laboratory animal. The object of this study was to utilise an established experimental laboratory animal model to study islet morphological changes, neogenesis and or both in vivo. Further aims of the study were to determine the extent, sequence and magnitude of pancreatic duct ligation (PDL) induced endocrine neogenesis/morphogenesis in a laboratory rat model using occlusive pancreatic duct ligation. PDL's were performed on six groups of 25 normal adult Sprague-Dawley (SD) rats (300g+) according to the method of Hultquist and Jonsson (1965). Experimental animals were sacrificed at 12 hr intervals from day one post-PDL to day 10 and every 24 hrs thereafter to day 14 as described by Wang, Klëppel, Bouwens (1995). Animals received BrdU (a thymidine marker and cell proliferation indicator) 50mglkg intraperitoneally as described by Wang et al. (1995), one hour prior to removal of the pancreas after which it was fixed in Bouin's solution and histologically processed. Seven consecutive 3-6 urn thick serial sections were sequentially stained with H & E, insulin (I), glucagon (G), somatostatin (ST), pancreatic polypeptide (PP), neuropeptide tyrosine (NPY) and peptide tyrosine tyrosine (PYY). Immunolabeling was done according to the method of Guesdon, Temynck , Avrameas (1979). Double immunolabeling for BrdU and each pancreatic peptide was performed on the sections on days 3,5, 7, 9 and 11 as described by Wang et al (1994). Cellular transformation between one and 3Yz days was characterised by simultaneous total deletion and/or transdifferentiation of the acinar compartment and the appearance of immunoreactive cells for I (11.53 ±1.5%), G (1.85 ±0.8%), pp (1.50 ±0.09%), and ST (1.96 ±0.24%). Changes in the endocrine composition in existing islets, occurred along a pathway that saw PP- and ST-cells invading the islet core, islet mantle glucagon deletion and random appearance of all endocrine cell types within the inter-islet interstitium on day 3Yz. Days 4 to 6Yz saw further endocrine expansion while days 7 to 14 were distinguished by islet reconstitution and consolidation. NPY immunoreactivity appeared on day 4Y2 and persisted intermittently throughout while PVV first appeared on day 4 and disappeared after day 7Yz. The results suggest that PDL firstly induced the development of endocrine tissue distributed haphazardly throughout the space previously occupied by acinar parenchyma. Secondly, the appearance of insulin is preceded by the appearance of PP, glucagon and somatostatin by 24-hours. A still to be determined proportion of the ligation induced endocrine formation appeared to be associated with existing islets, resulting in a number of very large islets, some of which might have secretory access through the glomerularlike capillary network known to occupy the islet core. The remainder appeared to form separate "new" islets, which have a dubious access to the blood stream. In conclusion, if it is true that the pancreas can regenerate some of its endocrine tissue then it has potential clinical implication for the stabilising of diabetes mellitus. Ligated exocrine pancreatic tissue, devoid of its acinar component, has been shown to contain notable quantities of insulin positive cells. This presents intriguing possibilities as an alternative for donor tissue, usually obtained from rat foetuses, during foetal rat pancreas transplantation studies. Pancreas tissue harvested from duct ligated rats could replace the foetal tissue currently used in the treatment of experimental diabetes mellitus in laboratory animals in this laboratory. / AFRIKAANSE OPSOMMING: Diabetes Mellitus is sinoniem met B-sel disfunksie. Endokriene regenerasie kan segmenteel bewerkstellig word deur eksperimentele afbinding van die pankreasbuis distaal tot sy samesmelting met die gemene galbuis. 'n Verskeidenheid van selle word vermoedelik by hierdie proses betrek. Dormante stamselle besit die vermoë en/of plastisiteit om 'n aantal vorms van metaplasie te ondergaan om nuwe en/of oortollige endokriene weefsel te vorm wat patologiese en/of eksperimenteel gekompromiseerde weefsel vervang. Die selontwikkelings volgorde wat tydens hierdie proses plaasvind is al vir 'n geruime tyd die middelpunt van 'n meningsverskil. Sommige studies dui daarop dat die in vivo selontwikkelingsvolgorde verskil van in vitro, volgens eksperimentele model en tipe proefdier gebruik. Die doel van die studie was die gebruik van 'n bestaande eksperimentele laboratorium proefdier model om pankreas eiland morfologiese verandering en/ofneogenese of beide in vivo te evalueer. Die oogmerk van die studie was om die omvang en volgorde van veranderings in die endokriene kompartement (neogenese/morfogenese) te bepaal deur gebruik te maak van 'n pankreas buis afbindings (PBA) model wat totale afsnyding van die buis tot gevolg het. PBA's is uitgevoer op ses groepe van 25 volwasse normale Sprague-Dawley (SD) laboratorium rotte (±300g) soos beskryf deur Hultquist en Jonsson (1965). Proefdiere is elke 12 uur geoffer vanaf dag een post-PBA tot dag tien en elke 24 uur daarna tot dag 14 soos beskryf deur Wang, Bouwens, Kloppel (1995) na die toediening van 50 mg/kg 5-Bromo-2-deoksi-uridien intraperitoneaal ('n selprolifererings aanduider) soos beskryf deur Wang et al. (1995). Die pankreas is werwyder, in Bouin se oplossing gefikseer en histologies geprosesseer. Sewe openvolgende seriesnitte (3-6 urn) is alternatiewelik gekleur met H & E, en immunositochemies, soos beskryf deur Guesdon, Terugnek, Avrameas (1979), vir insulien (I), glukagon (G), somatostatien (ST), pankreatiesepolipeptied (PP), neuropeptied tirosien (NPY) en peptied tirosien-tirosien (PYY). BrdU dubbel-immuunkleuring is ingesluit op dae 3,5, 7, 9 en 11 soos beskryf deur Wang et al. (1994). Sellulêre transformasie tussen dae een en 3~ dae is gekenmerk deur gelyktydige en totale uitwissing en/ofmetaplasie van die asinêre kompartement en die verskyning van selle immunorektiefvir I(11.53 ±1.5%), G (1.85 ±0.8%), PP (1.50 ±0.09%), ST (1.96 ±0.24%). Metaplasie was verantwoordelik vir merkbare veranderings in bestaande endokriene weefsel langs In transformasie weg waar eiland insulien kemselle vervang is deur PP- en ST-selle, glukagon buitelaag uitwissing en die toevallige verskyning van alle endokriene seltipes in the inter-eiland interstitium teen dag 3Y2. Dae 4Y2deur 6~ is gekenmerk deur verdere endokrinetoename terwyl dag 7 deur 14 gekenmerk is deur eiland hersamestelling en konsolidering. NPY immunoreaktiwiteit was vanaf dag 4~, met afwisseling, te bespeur terwyl PVV slegs tussen dae 4 en 7 In verskyning gemaak het. . Die resultate suggereer eerstens, PBA induseer die ontwikkeling van oortollige endokriene weefsel op In lukrake wyse versprei deur die ruimte voorheen deur asinêre parenchiem beset. Tweedens, dat die verskyning van insulien deur dié van PP, glukagon en somatostatien met minstens 24-uur voorafgegaan is. Die verhouding, van nuutgevormde endokriene weefsel wat met bestaande eilande assosieer om In aantal baie groot eilande te vorm, moet nog vasgestel word. Sulke strukture mag moontlik afskeidings toegang hê tot die bloedstroom, deur die glomerulusagtige kapillêre netwerk, in die eilandkern teenwoordig terwyl die oorblywende nuutgevormde endokrine weefsel "nuwe" apparte eilande vorm wat wel of gladnie toegang tot die bloedstroom mag hê nie. As gevolgtrekking, indien dit waar is dat volwasse pankreas eilandweefsel wel regenerasie kan ondergaan, dan het dit kliniese implikasie vir die stabilisering van diabetes mellitus. Weefsel verkry uit PBA bevat geen asinêre weefsel nie maar wel merkbare hoeveelhede endokriene weefsel, veral insulin positief. Dit bied dan interessante alternatiewe as skenker weefsel by fetal rot pankreas oorplantings. PBA en/of die oorplanting van pankreasbuis afgebinde weefsel, na in vitro weefsel kultuur, bied moontlikhede vir die behandeling van diabetes mellitus.