The increase in extracellular dopamine (DA) following cocaine administration plays a major role in cocaine abuse. In vitro, cocaine binds to DA transporters (DAT) and blocks DA uptake. Moreover, cocaine can increase extracellular DA concentration as measured by in vivo neurochemical methods. The present study examined the effects of cocaine and other drugs on DA, NE and 5-HT uptake using an ex vivo assay. Rats were injected i.v. with saline or drug and sacrificed at various time points after injections. Brains were dissected for regional monoamine uptake studies ex vivo. In most brain regions, cocaine given in vivo blocked monoamine uptake as expected. [ H]DA uptake in nucleus accumbens was inhibited with an ED = 22.3 μmol/kg. Cocaine fully inhibited [ H]NE uptake (ED = 4.58 μmol/kg) in the occipital cortex and partially inhibited [ H]5-HT uptake (33% at 30 μmol/kg) in the midbrain. However, under the same conditions [ H]DA uptake in the striatum was not inhibited after injections of cocaine up to 56 μmol/kg. Although the mechanism for this discrepancy is unclear, DA binding and uptake sites may be distinct and/or there may be regional differences in DA transporters.

Skin irritation is a common occupational hazard for employees engaged in the manufacture, transport, and use of industrial chemicals. The most common method used to evaluate dermal irritation and/or corrosion has typically been in vivo tests using rabbits (Draize method). Several in vitro test methods have been developed, with Corrositex being the first to gain approval by a regulatory agency (U.S. Department of Transportation). The purpose of this study was to compare the results of in vitro (Corrositex) assays of dermal irritation/corrosion to in vivo test data for several industrial chemical formulations and to determine the predictability and usefulness of the Corrositex assay for these types of products. Twenty-four (24) formulations were qualified, categorized, and evaluated using the Corrositex method and the results compared to available animal data for each of the formulations. The Corrositex assay accurately predicted a corrosive end point in 8 (57.1%) of the 14 formulations identified as corrosive by the in vivo evaluations. Corrositex accurately predicted a noncorrosive end point for 1 (10%) of 10 formulations determined to be noncorrosive in animal studies. The Corrositex assay overpredicted the packing group for 12 (50%) of the 24 formulations, and underpredicted the packing group for 7 (29.2%) of the 24 formulations. Compared to the in vivo results, Corrositex correctly classified as corrosive or noncorrosive 37.5% of the formulations tested. A concordance of 20.8% for the packing group assignments of the evaluated formulations was calculated. The Corrositex assay did not accurately predict a corrosive end point or packing group assignment for all of the formulations used in this study. Manufacturers should assess the relevance of this method to their products prior to relying on it for compliance with hazardous material and worker safety regulations.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Skeletal fractures due to bone disease impact an estimated 1.5 million Americans per year, creating a large economic burden on our society. Treatment of bone diseases prior to fracture often involves bisphosphonates (current gold-standard in osteoporosis care and prevention). Although bisphosphonates decrease fracture incidence, they often improve bone mass without regard for bone quality. Thus, although bisphosphonates increase the amount of bone present, the inherent bone material strength often decreases, creating a trade-off that increases the risk of atypical fractures after long-term use. This trade-off demonstrates the need for a treatment that targets both bone quality AND quantity. Although bone quality is important, the components of bone that contribute to bone quality are incompletely understood, making it difficult to create new pharmacological agents. With this in mind, my particular area of interest is in understanding how mechanical stimuli protects the formation of bone, leading to improved bone quality. Initially, this area was explored through use of tibial loading in a disease mouse model (osteolathyrism, induced by injection of beta-aminoproprionitrile) as a means of assessing how the body is able to compensate for decreased bone quality. The results of the BAPN and tibial loading studies indicated that injecting mice with BAPN may not be the ideal method to induce osteolathyrism. However, other intriguing results from the BAPN studies then led us into an exploration of how tibial loading itself contributes to bone quality.

Indiana University-Purdue University Indianapolis (IUPUI) / The vascular network highly coordinates with the central nervous system (CNS) on exchanging oxygen, nutrients and information transfer. The resemblance of the two systems at anatomical, cellular, and molecular levels also demonstrates their interdependence. The spinal cord is an integrated part of the CNS. Traumatic spinal cord injury (SCI) causes rapid systemic vascular responses and local neural tissue damage at the initial phase. The early disruption of the spinal vasculature breaks the supply-and-demand balance and facilitates the deterioration of the spinal cord tissue and functional deficits. Therefore, it is important to dissect the mechanism underlying vascular injury-mediated histological and functional consequences in order to develop potential therapeutic strategies. To visualize dynamic vascular changes after an acute SCI, a novel duo-color in vivo imaging technique was successfully developed in adult rats at the cervical level. This technique overcomes previous technical hurdles allowing real-time observation of vascular changes in live animals. Correlated with histological measures, in vivo vascular outcomes revealed a temporospatial relationship with neuronal and axonal loss, myelin disruption, inflammation, and glial responses. For the first time, we defined a “transitional zone” where significant blood vessel dilation and vascular leakage were observed simultaneously with vascular changes occurred at the injury epicenter acutely after SCI. These vascular changes at the transitional zone happened before any other cellular damage after SCI, suggesting a time window to prevent further neuronal damage in this region. Targeting the observed vascular leakage can work as a proof of concept that early vascular dysfunction contributes to the secondary neural tissue damage. Indeed, intravenous delivery of ferulic acid conjugated with glycol chitosan (FA-GC) to the injured sites immediate after SCI resulted in reduced vascular leakage, ventral horn neuronal loss, and partial recovery of forelimb function following a clinically-relevant contusive SCI at the 7th cervical spinal cord level. In conclusion, this work elucidated a novel role and mechanism of early vascular damage in the “transitional zone” prior to the secondary damage of neural tissue in this region and provided a novel treatment strategy for early neuroprotection and functional recovery. / 2021-11-04

京都大学 / 0048 / 新制・課程博士 / 博士(人間・環境学) / 甲第18361号 / 人博第674号 / 新制||人||162(附属図書館) / 25||人博||674(吉田南総合図書館) / 31219 / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)教授 田部 勢津久, 教授 加藤 立久, 教授 杉山 雅人 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18900号 / 医博第4011号 / 新制||医||1009(附属図書館) / 31851 / 京都大学大学院医学研究科医学専攻 / (主査)教授 影山 龍一郎, 教授 野田 亮, 教授 楠見 明弘 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13085号 / 論医博第2126号 / 新制||医||1021(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 渡邊 直樹, 教授 岩田 想, 教授 富樫 かおり / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Iron overload conditions are a prevalent issue in global healthcare that require the accurate monitoring of iron levels to effectively provide treatment. X-ray fluorescence has emerged as a candidate for a point-of-care measurement tool for the detection of trace elements in vivo. This study explores the feasibility of a portable in vivo x-ray fluorescence (IVXRF) instrument using 125I as a point-of-care device in measuring skin iron levels. The system was calibrated using iron-doped water phantoms for various physiologically-applicable iron concentrations. Measurements were conducted on ex vivo rat skin samples (n = 34), which were then compared to a benchmark laboratory-based XRF system. Monte Carlo modelling using MCNP 6.2 was used to simulate the system in different conditions and provide an estimate of the radiation dose of the system on soft tissue. The R2 value for the calibration line of iron concentration in ppm to normalized iron signal was determined to be 0.985 (p < 0.01). For a measurement period of 1800 s real-time, the minimum detectable limit (MDL) of the system is 3.86 ± 0.06 ppm of iron. The R2 value for the linear regression between the IVXRF and benchmark XRF system normalized iron signals was 0.731 (p < 0.01). The R2 value for the linear regression between the IVXRF normalized iron signal and sample injected iron dose was 0.719 (p < 0.01), meaning the system can distinguish between different iron levels in rat skin. From the Monte Carlo simulations, the expected effective dose contribution from the IVXRF system is 101.68 ± 0.03 nSv. The IVXRF system was shown to accurately measure iron concentrations in ex vivo rat skin samples within the iron concentration ranges found within healthy and iron-overloaded patients. Further work shall be conducted to validate the system in in vivo applications. / Thesis / Master of Science (MSc) / Iron overload is a prevalent issue in healthcare, with many individuals experiencing detrimental symptoms, such as organ damage and heart failure. Modern treatment significantly improves quality of life but must be continuously monitored. This thesis covers the development of a non-invasive, cost-effective, and accurate system that can measure skin iron levels in patients to ensure effective monitoring. The results from this thesis suggest that the system can be used for clinical use to measure patient skin iron levels. It can theoretically measure iron in patients with normal and elevated iron levels. Simulation work suggests that the system will lead to negligible risk from radiation exposure. While this thesis and its findings support the feasibility of the system, further work is required before clinical implementation of the device.