by Hiu Wong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1991. / Includes bibliographical references. / SUMMARY --- p.1 / INTRODUCTION --- p.4 / LITERATURE REVIEW --- p.8 / Chapter I. --- Nasopharyngeal carcinoma (NPC) --- p.8 / Chapter A. --- Epidemiology of NPC --- p.8 / Chapter B. --- Anatomy of NPC --- p.11 / Chapter C. --- Pathology of NPC --- p.12 / Chapter D. --- Histological classification of NPC --- p.14 / Chapter E. --- Stage classification of NPC --- p.15 / Chapter F. --- Clinical feature of NPC --- p.18 / Chapter G. --- Diagnosis of NPC --- p.19 / Chapter (a) --- Clinical examination / Chapter (b) --- Radiographic examination / Chapter (c) --- Laboratory examination / Chapter (d) --- Biopsy examination / Chapter H. --- Treatment of NPC --- p.21 / Chapter (a) --- Surgery / Chapter (b) --- Chemotherapy / Chapter (c) --- Radiotherapy / Chapter I. --- Prognosis of NPC --- p.23 / Chapter J. --- Etiology of NPC --- p.24 / Chapter (a) --- Dietary factor / Chapter (b) --- Genetic factor / Chapter (c) --- Environmental factor / Chapter (d) --- EBV infection / Chapter (e) --- Others / Chapter II. --- Beta-2 Microglobulin (B2M) --- p.30 / Chapter A. --- Structure and function of B2M --- p.30 / Chapter B. --- Clinical chemistry of B2M --- p.33 / Chapter C. --- B2M and its relationship to immunogenetic system --- p.34 / Chapter D. --- B2M in solid malignancies --- p.35 / Chapter E. --- B2M in hematologic malignancies --- p.36 / Chapter F. --- B2M in non-malignant diseases --- p.38 / Chapter III. --- Epstein - Barr Virus (EBV) --- p.41 / Chapter A. --- Morphology / Chapter B. --- EBV infection --- p.42 / Chapter C. --- EBV and Nasopharyngeal Carcinoma --- p.44 / Chapter D. --- Relationship of EBV to other human disease --- p.46 / Chapter (a) --- The relationship of EBV to IM / Chapter (b) --- The relationship of EBV to BL / Chapter E. --- EBV genome-carrying lymphoid cell lines --- p.50 / Chapter IV. --- TUMOUR ANTIGEN OF SQUEMOUS CELL CARCINOMA --- p.55 / Chapter A. --- The source of TA-4 --- p.55 / Chapter B. --- Characteristics of TA-4 --- p.56 / Chapter C. --- TA-4 in squamous cell carcinoma of uterine cervix --- p.57 / Chapter D. --- TA-4 in other type of squamous cell carcinaoma --- p.58 / MATERIALS AND METHODS / Chapter A. --- Materials --- p.61 / Chapter B. --- Measurement of Beta-2 Microglobulin --- p.63 / Chapter (a) --- Principles / Chapter (b) --- Assay protocol / Chapter (c) --- Reproducibility / Chapter C. --- Detection of EBV antibody titres in human sera --- p.68 / Chapter (a) --- Induction of EA/VCA in Raji/P3HR-1 cell lines / Chapter (b) --- Detection of antibody titres to EA/VCA in human sera / Chapter D. --- Measurement of squamous cell carcinoma associated antigen --- p.75 / RESULTS --- p.79 / Chapter A. --- Diurnal change of serum B2M or TA-4 level --- p.79 / Chapter B. --- The B2M and TA-4 levels in apparently healthy people --- p.81 / Chapter C. --- The usefullness of assay in initial diagnosis and staging --- p.81 / Chapter (a) --- Correlation between serum B2M levels and staging of NPC / Chapter (b) --- Correlation between serum TA-4 levels and staging of NPC / Chapter D. --- Correlation between histological differentiation of NPC and B2M and TA-4 level --- p.91 / Chapter E. --- The usefulness of assay for monitoring the NPC --- p.93 / Chapter (a) --- patients achieved completed remission / Chapter (b) --- patients developed local recurrence / Chapter (c) --- patients developed distant metastases / DISCUSSION --- p.131 / Chapter A. --- Serum B2M in NPC patients --- p.131 / Chapter B. --- Serum TA-4 in NPC ptients --- p.136 / Chapter C. --- EBV antibody titres in NPC patients --- p.137 / Chapter D. --- Conclusion --- p.141 / Chapter E. --- Suggested further study --- p.143 / REFERENCES --- p.146

The aim of this project was to study changes in cardiovascular responses brought about by long term oral treatment of Wistar rats with beta adrenoceptor antagonists. After chronic treatment with propranolol (12 or 60 mg/kg/day for up to 6 weeks) or timolol (1.2, 2.5, 5 or 25 mg/kg/day for up to 17 weeks), the log dose-response curves for mean rises in heart rate and mean arterial pressure on stimulation of the postsynaptic adrenoceptors of the pithed rat by I.V. noradrenaline or isoprenaline were not significantly changed. Chronic propranolol treatment significantly reduced the response of the heart to electrical stimulation of the whole sympathetic outflow but treatment with timolol failed to alter the cardiac chronotropic response. The rises in mean arterial pressure on stimulation of the whole sympathetic outflow were not altered by long term treatment with either propranolol or timolol. The high dose of propranolol significantly reduced the heart rate of conscious rats. However neither the lower dose of propranolol nor any dose of timolol affected heart rate. The systolic pressure of conscious rats was unaltered by treatment with the beta adrenoceptor blockers. The threshold for release of tritiated noradrenaline from the sympathetic nerves on stimulation of the whole spinal outflow was raised by chronic treatment with propranolol or timolol. Timolol significantly increased the concentration of 3H noradrenaline in the blood and decreased the heart content of tritium. Chronic propranolol treatment did not alter the blood or heart levels of 3H noradrenaline. Thus, although the plasma levels of the beta adrenoceptor blocking drugs were probably insufficient to ensure prolonged blockade of postsynaptic receptors, significant changes in presynaptic function were observed. It remains to be seen whether these changes play any significant part in cardiovascular responses to beta adrenoceptor antagonists in clinical practice.

"Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, affecting approximately 20 million people worldwide. AD pathology is primarily characterized by the formation of extracellular amyloid plaques resulting from the aggregation of insoluble amyloid-beta 1-42 (A-beta), and neurofibrillary tangles (NFT’s) resulting from intracellular aggregation of hyperphosphorylated tau protein. The current FDA-approved AD treatments do not stop or reverse neurodegeneration, but only treat the symptoms by increasing acetylcholine neurotransmitter. Our laboratory is attempting to provide an additional therapeutic approach by using neurotrophic factors to block apoptosis or to restore neurons. We previously demonstrated that, in an in vitro model for AD, hEPN-1 neurotrophic factor mimetics can block synthetic A-beta-induced neuronal cell death when added to cultures, presumably by blocking caspase activation. In this thesis, we extended these findings to study the effect of A-beta and hEPN-1 on tau hyperphosphorylation (as measured by immunoblots with phospho-specific antibodies) and nuclear DNA fragmentation (as measured by TUNEL staining), both in vitro and in vivo in AD transgenic mice. We found that A-beta induces the hyperphosphorylation of tau in both mouse N2a and human SHSY neuronal cells, and that hEPN-1 may lower this phosphorylation in N2a cells. Furthermore, we discovered that hEPN-1 can reduce nuclear DNA fragmentation when added both simultaneously to A-beta and 3 and 6 hours post A-beta addition. Finally, in vivo hEPN-1 may lower both tau hyperphosphorylation and caspase-7 related protein (C7RP) in AD transgenic (Tg) mice. The overall results validate our in vitro AD model, show the efficacy of hEPN-1 at blocking A-beta-induced DNA fragmentation even when added post-insult, and show that hEPN-1 may work in an AD mouse model. However, more studies must be conducted to confirm these findings. "

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Metastable b-Ti alloys are titanium alloys with sufficient b stabilizer alloying additions such that it's possible to retain single b phase at room temperature. These alloys are of great advantage compared to a/b alloys since they are easily cold rolled, strip produced and can attain excellent mechanical properties upon age hardening. Beta 21S, a relatively new b titanium alloy in addition to these general advantages is known to possess excellent oxidation and corrosion resistance at elevated temperatures. A homogeneous distribution of fine sized a precipitates in the parent b matrix is known to provide good combination of strength, ductility and fracture toughness. The current work focuses on a study of different mechanisms to engineer homogeneously distributed fine sized a precipitates in the b matrix. The precipitation of metastable phases upon low temperature aging and their influence on a precipitation is studied in detail. The precipitation sequence on direct aging above the w solvus temperature is also assessed. The structural and compositional evolution of precipitate phase is determined using multiple characterization tools. The possibility of occurrence of other non-classical precipitation mechanisms that do not require heterogeneous nucleation sites are also analyzed. Lastly, the influence of interstitial element, oxygen on a precipitation during the oxidation of Beta 21S has been determined. The ingress of oxygen and its influence on microstructure have also been correlated to measured mechanical properties.

There is an urgent need to define the key pathological driving events in human cutaneous squamous cell carcinoma (cSCC) in order to identify novel therapeutic targets. Already the second most common form of human non-melanoma skin cancer, the incidence of cSCC has continued to rise at epidemic proportions over the past two decades. Rarely, cSCC can be highly aggressive, causing significant soft-tissue defects in sun-exposed areas of skin and progressing to metastatic disease, which is usually associated with poor survival. The transforming growth factor-β (TGF-β) signalling pathway is known to play key regulatory roles in skin homeostasis and wound repair. Murine studies indicate that loss of TGF-β signalling is sufficient to drive cSCC, but conclusive evidence for a similar role in human cSCC remains elusive. Combining immunohistochemical and genetic studies of the TGF-β signalling pathway on human cSCC tissue, with a thorough examination of TGF-β responses in human primary cSCC cell lines in-vitro, this thesis aims to investigate the complex role of TGF-β signalling in human cSCC. An extensive tissue micro-array analysis demonstrated the consistent reduction of endogenous TGF-β signalling activity in human primary cSCC. This intriguingly correlated with higher risk thick tumours pathologically, indicating that TGF-β is likely to act primarily as a tumour suppressor in human cSCC and its reduction or loss may impart a significant growth advantage for cSCC tumour cells. This tumour suppressor effect was reflected in-vitro, whereby the majority of primary cSCC cell lines remained sensitive to TGF-β mediated growth arrest. Resistance to TGF-β tumour suppression was also identified, and mechanistically its main protagonist in cSCC cell lines appeared to be mutational loss of TGF-β receptors. Consolidating in-vitro findings, both whole exome sequencing and 454 pyrosequencing of human cSCC tissue revealed frequent functionally damaging mutations of both TGF-β type 1 and type 2 receptors, indicating that mutational loss of the TGF-β pathway may be a key driving event in human cSCC tumourigenesis. Perhaps most interestingly, mutational loss of TGF-β type 2 receptors in cSCC cell lines appeared to result in a novel pro-oncogenic dependence on TGF-β type 1 receptor kinase activity, highlighting not only the important paradoxical role of TGF-β mediated tumour promotion in cSCC, but also the potential for signalling crosstalk between alternative TGF-β superfamily members, namely Activin signalling, to drive tumourigenesis in the absence of active TGF-β signalling. Although further mechanistic studies are required to support this hypothesis, the mutational status of TGF-β type 2 receptors may not only provide a powerful prognostic tool for patients with cSCC, but also represent an important biomarker for the targeted use of TGF-β inhibitors in potentially aggressive disease where pro-tumourigenic responses could be driving disease progression.

There are few, but worrisome, data available on fingertip radiation exposure of medical personnel during radiosynovectomy (RSV). To reduce radiation exposure, we performed a dedicated application procedure. This report summarizes the acquired skin equivalent dose [Hp(0.07)] of the personnel involved in the preparation and administration of the three RSV !-emitters 90Y, 186Re and 169Er. Over a period of 3 years, 547 joints in 368 patients were treated with 52 421MBq of the aforementioned three radionuclides. The Hp(0.07) was recorded with thermoluminescence dosimeters worn on the dominant index fingertip and was analysed monthly. Eight staff members were exposed to an Hp(0.07) of 492 mSv. The cumulative dose was less than 10 μSv/MBq. The dose per person was 1.1 μSv/MBq in physicians and up to 4.5 μSv/MBq in technicians. The accumulated personal Hp(0.07) during RSV was far below the regulatory limit and published data. / Die Radiosynoviorthese ist ein etabliertes Therapieverfahren zur Behandlung der Synovialitis. Da bei der Radiosynoviorthese die Handhabung von radioaktiven β-Strahlern wie Yttrium, Rhenium und Erbium notwendig ist, sind bestimmte Schutzmaßnahmen einzuhalten. Zum Schutze des Patienten wurden Leitlinien aufgestellt, um die Strahlenbelastung so gering wie möglich zu halten. Die Exposition der bei der Vorbereitung und Applikation beteiligten Ärzte, Radiopharmazeuten sowie beteiligten Krankenschwestern bietet Raum für weitere Verbesserungen. Eine Untersuchung des Bundesamt für Strahlenschutz dokumentiert höchst bedenkliche Zahlen, für die β-Ortsdosimetrie, die die zulässige Jahresdosis um ein Vielfaches überschreiten können. Die Einführung von sogenannten Thermolumineszensdetektoren, getragen als Ringdosimeter an den Grundgelenken der Zeigefinger, sollen realistische Expositionswerte aufzeichnen und somit eine Kontrolle der Dosis ermöglichen. Diese TLD’s sind mit der Markierung „RSO“ gekennzeichnet und werden nur bei der Arbeit mit den radioaktiven Substanzen getragen. Die monatliche Auswertung dokumentiert die Strahlenexposition der beteiligten Personen. In verschiedenen Studien wurden Methoden zur Minimierung der Strahlenexposition getestet. Sie führten zu dem Ergebnis, dass die Abschirmung mit Acrylglas, die Abstandshaltung durch langschenklige Zangen sowie das Tragen von Nitril-Handschuhen am effektivsten zu einer Verringerung der Expositionswerte beitragen. Ziel dieser retrospektiven Auswertung von Daten aus drei Jahren war es, die Effektivität der an der Klinik und Poliklinik für Nuklearmedizin in Würzburg praktizierten Strahlenschutzmaßnahmen zu untersuchen. Über einen Zeitraum von drei Jahren wurden 547 Gelenke in 368 Patienten mit 52.421 MBq, der drei Radionuklide 169Er, 186Re und 90Y behandelt. Die Oberflächenpersonendosis Hp(0,07) wurde mittels Fingerringdosimeter aufgezeichnet. Die acht an der Radiosynoviorthese beteiligten Personen erhielten eine kumulative Hautdosis Hp(0,07) von 498 mSv. Die kumulative Dosis pro Aktivität betrug somit weniger als 10 mSv/Bq. Sie lag pro Arzt bei 1,1 μSv/MBq und pro MTA bei bis zu 4,5 μSv/MBq. Die akkumulierte Hautdosis Hp (0,07) während der Radiosynoviorthese war somit weitaus geringer im Vergleich zu den gesetzlichen Vorgaben und den zur Verfügung stehenden publizierten Daten.

No description available.

Notre projet s'inscrit dans le cadre de la lutte contre la résistance bactérienne et considère une approche radicalement opposée à tout ce qui a été fait jusqu'à présent dans le but de créer de nouveaux antibiotiques. En nous basant sur l'hypothèse qu'il existe d'autres façons pour obtenir un composé réactif que d'inclure le noyau beta-lactame dans une structure bicyclique très tendue (ou de l'activer par des effets électrocapteurs), nous avons imaginé une famille de molécules où l'adaptabilité conformationnelle pourrait être à l'origine de l'activité antibiotique. Il s'agit de beta–lactames bicycliques pontés obtenus au départ de l'acétoxy-azétidin-2-one commerciale, où les positions N1 et C3 sont connectées par des cycles de tailles variables (à partir de n et m = 1), incluant éventuellement des fonctions "activantes" de type carbonyle et/ou une double liaison C=C. La stratégie choisie fait intervenir la métathèse des oléfines (RCM) pour la formation du cycle pontant. Nos dérivés ont fait l'objet d'évaluations théoriques grâce à des modèles d'hydrolyses chimique et enzymatique, et expérimentales grâce à des suivis RMN-1H de l'hydrolyse en milieu basique et à des tests in vitro sur enzymes bactériennes et mammaliennes.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 170-176).