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Neurofibromatosis Type 2 (NF2) is a disorder of the nervous system, characterized by the formation of bilateral vestibular schwannoma tumors as well as meningioma and ependymoma tumors. Vestibular schwannomas are Schwann cell tumors that develop from the vestibulocochlear nerve and lead to deafness. NF2 is caused by mutations in the NF2 gene, encoding tumor suppressor protein merlin. NF2 tumors cause many symptoms depending on their location. The only NF2 treatments are surgery and radiosurgery which can impair nerve function, so alternative treatments such as drug-based therapies targeting pathways important for tumor formation, survival, and growth are needed. Targeting complementary pathways can be an effective way to overcome drug resistance. The Phosphoinositide 3 kinase (PI3K) and P21 activated kinases (PAK) pathways help control cellular processes related to tumor formation and are found dysregulated in merlin-deficient cells. Previous screening studies demonstrated synergistic effects of pictilisib (picti), an inhibitor of the PI3K pathway, and PF3758309 (PF), an inhibitor of PAK4 activity, on cell survival in merlin-null cells. To test the efficacy of this drug combination, a combination drug study was run using the NF2 allograft mouse peripheral nerve tumor model. Initial analyses revealed that these treatments and a combination may inhibit tumor growth. The purpose of this study was determining how PI3K and/or PAK inhibition by pictilisib and PF3758309 impact target protein levels in sciatic nerve NF2 allograft tumors. My role was analyzing tumors taken from the NF2 mice for targets proteins relevant to tumor growth and survival by conducting immunohistochemistry and ImageJ quantification. A secondary purpose was identifying possible deleterious side effects of drug treatment on healthy nerves with a qualitative assessment of contralateral sciatic nerves. Assessments support continued x evaluation of each drug for clinical use and show that the combination treatment can reduce cell proliferation and increase cell death.

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本研究的目的是評估長期服用氯胺酮對青少年認知功能和精神健康狀況的影響。 自2009年12月至2011年12月，共300名受試者入組。受試者分為3組：氯胺酮組，氯胺酮及多種藥物組和健康對照組，每組有100名受試者入組。精神狀況評估包括問卷篩查和麵談。所有受試者均完成一套詳細的認知測試。該測試涵蓋一般智慧、語詞記憶、視覺記憶、執行功能、動作速度和語言。 / 氯胺酮組受試者主要濫用氯胺酮，而氯胺酮及多種藥物組受試者除氯胺酮外主要濫用可卡因和冰毒。兩組氯胺酮濫用者最常見的共患精神障礙是抑鬱障礙。在單因素分析中,兩組氯胺酮濫用者在幾乎所有的測試中得分低於健康對照。多因素分析控制混雜因素如年齡、性別、教育程度和Beck 抑鬱量表總分後，兩組氯胺酮濫用組與健康對照組在語詞記憶和視覺記憶仍存在顯著差異。本研究進一步將氯胺酮組及氯胺酮多種藥物組分別分為現用藥者和戒斷者。在氯胺酮組中現用藥者在詞記憶、視覺記憶、動作速度和部分執行功能測試上得分低於戒斷者和健康對照，並且現用者Beck 抑鬱量表總分高於戒斷者和健康對照，而戒斷者和健康對照在認知測試和Beck 抑鬱量表總分沒有顯著差別。但在氯胺酮及多種藥物組，現用藥者和戒斷者均在記憶測試中得分低於及Beck 抑鬱量表總分高於健康對照。另外, 女性氯胺酮濫用組視覺記憶得分低於男性，但女性在語詞記憶得分普遍高於男性。 / 本研究認為氯胺酮或氯胺酮合用多種藥物均能導致記憶和執行功能的損害。這種損害主要與近期濫用氯胺酮有關，並且氯胺酮組現用藥者語詞記憶損害較氯胺酮合用多種藥物現用藥者嚴重。單純氯胺酮導致的記憶和執行功能損害在戒斷1月後明顯好轉但氯胺酮合用多種藥物者戒斷一月後未能見到記憶功能好轉。超過半數的氯胺酮濫用者共患抑鬱障礙。本研究的結果為治療氯胺酮濫用有用資訊，亦有助於戒毒者鞏固其戒斷行為。但氯胺酮所致認知損害的可逆性還需要前瞻性或縱向研究進一步證實，並且這種可逆性損害的機制還不明確。未來的研究還需要進一步明確氯胺酮對人體的損害作用是否具有性別差異性。 / The objective of this study was to evaluate the long-term effect of ketamine use on both the cognition and psychological well-being of youths in Hong Kong. / Three hundred participants were recruited for the study, which lasted from December 2009 to December 2011. Participants were divided into three groups of 100 each: primarily ketamine (Primarily K) users, poly-drug ketamine (Poly K) users and healthy controls (HCs). Psychiatric assessments included screening with self-rating questionnaires and face-to-face interviews. All participants completed a detailed cognitive battery covering general intelligence, verbal memory, visual memory, executive function, motor speed and language. / The participants in the Primarily K group predominantly used ketamine, whereas those in the Poly K group used ketamine in addition to secondary drugs, of which cocaine and methamphetamine were the most frequent. Depressive disorder was the most common psychiatric disorder in both ketamine groups. Univariate analysis also showed the two ketamine groups to score poorly on most of the cognitive tests relative to the HC group. After adjusting for age, sex, education and Beck Depression Inventory (BDI) score, verbal and visual memory remained impaired in both ketamine groups in comparison with the HC group. Ketamine use in the past month was independently related to memory impairment in the Primarily K group. In subgroup analyses of Primarily K users, verbal and visual memory, motor speed, and some of the executive function indexes were significantly impaired in current users but not in ex-users. These findings suggest that the cognitive influence of ketamine is reversible. Moreover, the current ketamine users had a higher BDI score than the ex-users or HCs. However, the ex- and current poly-drug ketamine users exhibited a similar degree of memory impairment compared with the HCs. The female Primarily K users showed more visual memory impairment than their male counterparts, although females generally performed better than males in verbal memory. / In conclusion, the use of ketamine alone and in conjunction with other psychotropic drugs is associated with deficits in memory and executive function. The observed memory impairment was related primarily to recent ketamine use, with current Primarily K users presenting with a more severe memory deficit than current Poly K users. However, the Primarily K group realised improvement in cognitive impairment after abstaining from ketamine, whereas the Poly K group did not. In addition to cognitive functioning difficulties, more than half of the ketamine users suffered from depressive disorder. Moreover, the findings suggest that women may be more sensitive than men to visual memory impairment following chronic ketamine use. The findings of this study will be helpful in treating ketamine abuse, and reinforce the efficacy of abstinence from drugs. Further longitudinal research is needed to determine the reversibility of ketamine’s effects and the mechanism by which that reversibility takes place. Further study is also needed to clarify the drug’s sex-specific effects. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liang, Huajun. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 102-119). / Abstract also in Chinese. / DECLARATION OF ORIGINALITY --- p.I / ACKNOWLEDGEMENTS --- p.II / PUBLICATIONS AND PRESENTATIONS --- p.1 / LIST OF ABBREVIATIONS --- p.XI / LIST OF TABLES AND FIGURES --- p.XIII / ABSTRACT --- p.XV / 摘要 --- p.XVIII / CONTENTS --- p.XX / Chapter CHAPTER 1 --- BACKGROUND --- p.1 / Chapter 1.1 --- Introduction to ketamine and ketamine misuse --- p.1 / Chapter 1.2 --- Effects profile of ketamine in the brain --- p.4 / Chapter 1.2.1 --- Glutamate system dysfunction underlying ketamine actions --- p.4 / Chapter 1.2.2 --- Different effect patterns between acute and repeated administration --- p.7 / Chapter 1.2.3 --- Acute and chronic effects of ketamine on human cognitive functions --- p.9 / Chapter 1.2.4 --- Sex differences in addiction --- p.11 / Chapter 1.3 --- Introduction to cognition and intelligence and their assessments --- p.13 / Chapter 1.3.1 --- Memory and memory assessments --- p.13 / Chapter 1.3.2 --- Executive function and assessments of executive function --- p.16 / Chapter 1.3.3 --- Intelligence and intelligence tests --- p.19 / Chapter 1.4 --- Study hypotheses --- p.31 / Chapter CHAPTER 2 --- METHODS --- p.29 / Chapter 2.1 --- Study design --- p.29 / Chapter 2.2 --- Study subjects --- p.31 / Chapter 2.2.1 --- Subject recruitment sites --- p.31 / Chapter 2.2.2 --- Inclusion criteria --- p.32 / Chapter 2.3 --- Data collection --- p.33 / Chapter 2.3.1 --- Demographic information --- p.33 / Chapter 2.3.2 --- Drug use pattern and severity --- p.34 / Chapter 2.3.3 --- Psychiatric comorbidities --- p.34 / Chapter 2.3.4 --- Cognitive function evaluation --- p.40 / Chapter 2.4 --- Statistical methods --- p.44 / Chapter CHAPTER 3 --- RESULTS --- p.45 / Chapter 3.1 --- Demographics and basic information --- p.45 / Chapter 3.2 --- Drug use patterns --- p.47 / Chapter 3.3 --- Comorbid psychiatric problems --- p.51 / Chapter 3.4 --- Cognitive functions --- p.59 / Chapter 3.4.1 --- Cognitive functions among primarily ketamine, poly-drug ketamine and control groups --- p.59 / Chapter 3.4.2 --- Cognitive functions in current and ex-primarily ketamine users --- p.60 / Chapter 3.4.3 --- Cognitive functions in current and ex-poly-drug ketamine users --- p.70 / Chapter 3.4.4 --- Cognitive functions in current primarily ketamine and current poly-drug ketamine users --- p.79 / Chapter 3.4.5 --- Cognitive functions in female and male primarily ketamine users --- p.80 / Chapter CHAPTER 4 --- DISCUSSION --- p.86 / Chapter 4.1 --- Demographics and drug use patterns --- p.86 / Chapter 4.2 --- Effects of ketamine on psychological health --- p.87 / Chapter 4.3 --- Effects of ketamine on cognitive functions --- p.88 / Chapter 4.3.1 --- Effects of primarily ketamine use on memory --- p.90 / Chapter 4.3.2 --- Effects of primarily ketamine use on executive functions --- p.92 / Chapter 4.3.3 --- Effects of poly-drug ketamine use on cognitive functions --- p.96 / Chapter 4.3.4 --- Sex-specific effects of ketamine use on cognitive functions --- p.98 / Chapter CHAPTER 5 --- LIMITATIONS AND CONCLUSIONS --- p.98 / Chapter 5.1 --- Limitations --- p.98 / Chapter 5.2 --- Conclusions --- p.99 / REFERENCES --- p.102

by Andy Cheng Shu Kei. / Year shown on spine: 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves [165-175]). / acknowledgements / abstract / Chapter chapter one --- introduction / Chapter 1.1 --- JUSTIFICATION OF RESEARCH --- p.1 / Chapter 1.2 --- STRUCTURE OF THESIS --- p.4 / Chapter chapter two --- literature review / Chapter 2.1 --- ANATOMY OF DIGITAL NERVE --- p.6 / Chapter 2.2 --- FACTORS AFFECTING RESULTS OF SENSIBILITY RECOVERY --- p.10 / Chapter 2.3 --- NEUROPHYSIOLOGY OF NERVE FIBRE / MECHANORECEPTORS --- p.16 / Chapter 2.4 --- NEUROPHYSIOLOGY OF TACTILE STIMULATION --- p.20 / Chapter 2.5 --- SENSIBILITY TESTING FOR FUNCTIONAL SENSIBILITY --- p.26 / Chapter 2.5.1 --- SEMMES-WEINSTEIN MONOFILAMENT / Chapter 2.5.2 --- CONSTANT TWO-POINT DISCRIMINATION / Chapter 2.5.3 --- MOVING TWO-POINT DISCRIMINATION / Chapter 2.5.4 --- SELF EVALUATION / Chapter chapter three --- retrospective study of the sensibility recovery of peripheral nerve injuries / Chapter 3.1 --- INTRODUCTION --- p.38 / Chapter 3.2 --- OBJECTIVES --- p.38 / Chapter 3.3 --- METHODOLOGY --- p.38 / Chapter 3.4 --- RESULTS --- p.42 / Chapter 3.5 --- DISCUSSION AND IMPLICATION --- p.43 / Chapter chapter four --- longitudinal study of the sensibility recovery of digital nerve injuries / Chapter 4.1 --- INTRODUCTION --- p.45 / Chapter 4.2 --- OBJECTIVES --- p.45 / Chapter 4.3 --- METHODOLOGY --- p.46 / Chapter 4.4 --- RESULTS --- p.50 / Chapter 4.5 --- DISCUSSION AND IMPLICATION --- p.57 / Chapter chapter five --- "functional sensibility - normative values and correlation with age, sex,occupation and skin hardness in local chinese population" / Chapter 5.1 --- INTRODUCTION --- p.59 / Chapter 5.2 --- OBJECTIVES --- p.60 / Chapter 5.3 --- METHODOLOGY --- p.60 / Chapter 5.4 --- RESULTS --- p.64 / Chapter 5.5 --- DISCUSSION AND IMPLICATION --- p.84 / Chapter chapter six --- prospective randomised study of early tactile stimulation in digital nerve injuries / Chapter 6.1 --- INTRODUCTION --- p.87 / Chapter 6.2 --- OBJECTIVES --- p.88 / Chapter 6.3 --- METHODOLOGY --- p.89 / Chapter 6.4 --- RESULTS --- p.95 / Chapter 6.5 --- DISCUSSION AND IMPLICATION --- p.115 / Chapter chapter seven --- conclusions and recommendations / Chapter 7.1 --- CONCLUSIONS --- p.121 / Chapter 7.2 --- RECOMMENDATIONS --- p.125 / appendices / Chapter I --- INSTRUCTION MANUAL FOR ASSESSING FUNCTIONAL SENSIBILITY --- p.126 / Chapter II --- CLASSIFICATION OF LEVEL OF FINGER DEXTERITY IN WORK --- p.129 / Chapter III --- RANDOM TABLE IN MAIN STUDY --- p.132 / Chapter IV --- SCHEMATIC DIAGRAM OF INTERNAL STRUCTURE OF TACTILE STIMULATOR --- p.133 / Chapter V --- CONSENT FORM --- p.134 / Chapter VI --- ASSESSMENT FORM IN RETROSPECTIVE STUDY --- p.135 / Chapter VII --- ASSESSMENT FORM IN LONGITUDINAL AND MAIN STUDY(LEFT HAND) --- p.137 / Chapter VIII --- ASSESSMENT FORM IN LONGITUDINAL AND MAIN STUDY(RIGHT HAND) --- p.138 / Chapter IX --- ASSESSMENT FORM IN CORRELATIONAL STUDY --- p.139 / Chapter X --- INTER-RATER VARIATION IN ASSESSING SENSIBILITY RECOVERY IN LONGITUDINAL STUDY --- p.140 / Chapter XI --- NORMATIVE VALUES OF FUNCTIONAL SENSIBILITY AND SKIN HARDNESS --- p.142 / Chapter XII --- INTER-RATER VARIATION IN ASSESSING SENSIBILITY RECOVERY IN MAIN STUDY --- p.162 / references

published_or_final_version / Anatomy / Master / Master of Philosophy

The pattern of regenerating optic axons following various surgical manipulations in the goldfish brain has been studied using ('3)H proline radioauthography. The results demonstrate that in most cases severed optic axons regenerate preferentially into degenerating axonal pathways. It is therefore suggested that the degenerating axonal debris and the concomitant glial proliferation in a degenerating pathway, in some way, influences the entry of regenerating optic axons into the path. However, in view of the exceptional cases in which regenerating optic fibers either failed to grow into a degenerating pathway, or grew into pathways which apparently did not degenerate, it is further suggested that the influence of the degenerating pathways on the regenerating optic axons is neither 'compelling' nor 'restrictive'. Similarly, although the results also demonstrate that denervated optic terminal zones may influence the choice of pathways by regenerating axons and that the proximity of a pathway to the regenerating optic axons may do so as well, such influences are also neither 'compelling' nor 'restrictive'. Taken together, the data presented here indicate that the guidance of regenerating optic axons is probably influenced by a combination of these factors.