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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

No description available.

In the peripheral nervous system the myelin sheath is produced by the spiral wrappings of the Schwann cell (SC) membrane around the axon. This provides insulation and increases the velocity of impulse propagation. The structure of myelin is maintained by a group of myelin proteins. Peripheral myelin protein-22 (PMP-22) is a 22 KDa glycoprotein, originally identified following nerve crush injury, that is found within SCs and is identical to the growth arrest specific protein GAS-3. The PMP-22 gene is regulated by two alternative promoters immediately upstream of two alternative non-coding exons. In order to study temporal and spatial expression of the PMP-22 gene and regulation of SC ensheathment and myelination, a transgenic mouse expressing the green fluorescent protein (GFP) driven by the myelin specific PMP-22 promoter was produced. To achieve this the PI promoter isolated from genomic DNA was initially incorporated into a plasmid containing the EGFP gene. In vitro transfection studies demonstrated appropriate expression of EGFP fluorescence. Microinjection of the transgene into pre- implantation fertilised embryos gave rise to three transgenic lines as confirmed by Southern blot and PGR. One founder expressed the transgene in a tissue specific manner. Mosaicism of expression both within an individual and between individuals was noted. In vitro manipulations showed that the expression patterns observed were independent of axonal contact and myelination but could be influenced by the extracellular matrix. These GFP expressing transgenic mice potentially provide a means to determine the dynamics of SC-axon interactions during myelination and the behaviour of transplanted SCs into myelin deficient regions and the SCs response to injury. Preliminary reports of this work are found in abstract form: British Neurosci. Assoc. Abstr., Vol 15, pi04, 1999.

Lower motor neurons of the peripheral nervous system are responsible for innervating skeletal muscle and controlling all voluntary movements of the body. Degeneration of motor neurons underlies conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors that influence the form and function of the peripheral nervous system in vivo will be important for our understanding of the neuromuscular system in health and disease. Here, I have studied the effects of three different genes and their respective protein products on the peripheral nervous system: yellow fluorescent protein (YFP), apolipoprotein E (apoE) and Ercc1 (excision repair cross-complementing group 1). YFP has been used as a reporter protein in many fields of research, including as a powerful tool for visualising neurons in mice. It is used under the assumption that it is biologically inert. However, my findings have revealed that YFP expressed in neurons in mice is not inert: it induces a cell stress response at both the RNA and the protein level and alters the time course of dying-back neuropathy. ApoE is a lipid transport protein with three distinct isoforms in humans (apoE2, apoE3 and apoE4), which are known to differentially affect risk and outcome in a number of central nervous system disorders. However, the effects of different apoE isoforms on the peripheral nervous system have yet to be established. I have shown that apoE4 delays peripheral nerve regeneration and subsequent neuromuscular junction reinnervation compared to apoE3, in the absence of any effects on normal form or function, degeneration or developmental plasticity. Ercc1 protein is involved in several DNA repair systems. Ercc1Δ/- mice have reduced levels of functional Ercc1 protein, which leads to a reduced life span and motor abnormalities, potentially due to a build of up DNA damage. Here I have shown that Ercc1Δ/- mice also have increased abnormalities at the neuromuscular junction (an early pathological target in neurodegeneration) with age. These findings contribute significantly to our understanding of the influence of specific genes on the form and function of the peripheral nervous system in health and disease.

Previous research has demonstrated that the spinal cord is capable of a simple form of instrumental learning. In this instrumental learning paradigm, rats typically receive a complete spinal transection at the second thoracic vertebra, and are tested 24 hours after surgery. Subjects that receive shock to a hind leg quickly learn to maintain the leg in a flexed position, which reduces net shock exposure (Grau et al., 1998). Prior studies have examined the mechanisms that mediate this learning, but little is known about how or where the consequences of learning are stored (memory). The goal of this dissertation proposal is to examine the neural modification(s) that preserve learned behavioral effects over time. It is clear that the central nervous system plays an essential role in instrumental learning. During the acquisition of instrumental learning, the connections between the peripheral nervous system (PNS) and the central nervous system must remain intact (Crown et al., 2002a). Acquisition is also disrupted by intrathecal application of pharmacological agents (lidocaine) that inhibit spinal reflexes (Crown et al., 2002a). The experiments outlined in this dissertation are motivated by an unexpected observation: while application of lidocaine to the spinal cord prior to training blocks acquisition of the instrumental response, inactivating spinal neurons has no effect on the maintenance of the instrumental response. These data suggest that, after the instrumental response is acquired, a peripheral component is capable of maintaining the instrumental response. Aim 1 examined how inhibiting the spinal cord influenced the maintenance of instrumental learning. Intrathecal lidocaine inhibited a spinal withdrawal reflex and instrumental learning, but did not affect the maintenance of the learned response. Expanding on these results, Aim 2 examined how disconnecting the PNS from the spinal cord would influence the maintenance of instrumental learning. If a PNS to spinal cord connection is needed for the maintenance of instrumental learning, then removing that connection by a sciatic transection should disrupt performance of the instrumental response. Together, the results of Aims 1 & 2 confirm that a peripheral alteration contributions to the maintenance of instrumental behavior. In Aim 3, I developed a procedure that would allow for drug delivery directly to the tibialis anterior muscle. If the neuromuscular junction is capable of influencing a spinal reflex, then blocking the neuromuscular junction with an antagonist (curare) should disrupt the acquisition and maintenance of the instrumental response. Based on the results of Aim 3, Aim 4 investigated how other pharmacological manipulations at the neuromuscular junction can influence the acquisition and maintenance of the instrumental response. Using glutamate receptor antagonists (CNQX and MK-801), I showed that glutamatergic signaling plays an essential role.

In the common fruit fly, Drosophila melanogaster, neural cell fate specification is triggered by a group of conserved transcriptional regulators known as proneural factors. Proneural factors induce neural fate in uncommitted neuroectodermal progenitor cells, in a process that culminates in sensory neuron differentiation. While the role of proneural factors in early fate specification has been described, less is known about the transition between neural specification and neural differentiation. The aim of this thesis is to use computational methods to improve the understanding of terminal neural differentiation in the Peripheral Nervous System (PNS) of Drosophila. To provide an insight into how proneural factors coordinate the developmental programme leading to neural differentiation, expression profiling covering the first 3 hours of PNS development in Drosophila embryos had been previously carried out by Cachero et al. [2011]. The study revealed a time-course of gene expression changes from specification to differentiation and suggested a cascade model, whereby proneural factors regulate a group of intermediate transcriptional regulators which are in turn responsible for the activation of specific differentiation target genes. In this thesis, I propose to select potentially important differentiation genes from the transcriptional data in Cachero et al. [2011] using a novel approach centred on protein interaction network-driven prioritisation. This is based on the insight that biological hypotheses supported by diverse data sources can represent stronger candidates for follow-up studies. Specifically, I propose the usage of protein interaction network data because of documented transcriptome-interactome correlations, which suggest that differentially expressed genes encode products that tend to belong to functionally related protein interaction clusters. Experimental protein interaction data is, however, remarkably sparse. To increase the informative power of protein-level analyses, I develop a novel approach to augment publicly available protein interaction datasets using functional conservation between orthologous proteins across different genomes, to predict interologs (interacting orthologs). I implement this interolog retrieval methodology in a collection of open-source software modules called Bio:: Homology::InterologWalk, the first generalised framework using web-services for “on-the- fly” interolog projection. Bio::Homology::InterologWalk works with homology data for any of the hundreds of genomes in Ensembl and Ensembgenomes Metazoa, and with experimental protein interaction data curated by EBI Intact. It generates putative protein interactions and optionally collates meta-data into a prioritisation index that can be used to help select interologs with high experimental support. The methodology proposed represents a significant advance over existing interolog data sources, which are restricted to specific biological domains with fixed underlying data sources often only accessible through basic web-interfaces. Using Bio::Homology::InterologWalk, I build interolog models in Drosophila sensory neurons and, guided by the transcriptome data, find evidence implicating a small set of genes in a conserved sensory neuronal specialisation dynamic, the assembly of the ciliary dendrite in mechanosensory neurons. Using network community-finding algorithms I obtain functionally enriched communities, which I analyse using an array of novel computational techniques. The ensuing datasets lead to the elucidation of a cluster of interacting proteins encoded by the target genes of one of the intermediate transcriptional regulators of neurogenesis and ciliogenesis, fd3F. These targets are validated in vivo and result in improved knowledge of the important target genes activated by the transcriptional cascade, suggesting a scenario for the mechanisms orchestrating the ordered assembly of the cilium during differentiation.

Thesis (M.D.S.)--Dept. of Dental, University of Adelaide, 1985. / Some mounted ill. Includes bibliographical references (leaves 180-190).

nÃo hà / Muitas pesquisas evidenciaram o comprometimento do sistema nervoso perifÃrico na doenÃa inflamatÃria intestinal (DII). AtravÃs do teste de quantificaÃÃo sensitiva (QST) para pesquisa de limiares de sensibilidade a vibraÃÃo ( fibras nervosas grossas) e frio (fibras nervosas finas), (protocolo I) avaliamos 29 pacientes portadores de retocolite ulcerativa (RCU), 30 pacientes portadores de doenÃa de Crohn (DC) e 28 pacientes-controle. Foram aplicados questionÃrios de queixas sensitivas (protocolo II) em 27 pacientes portadores de RCU, 24 pacientes portadores de DC e 25 pacientes-controle. Esses mesmos pacientes realizaram o teste de enrugamento cutÃneo a Ãgua (TEC) (protocolo III), o qual avalia fibras finas do sistema nervoso autÃnomo. O teste de Fisher e teste de hipÃtese qui-quadrado comparando os 3 grupos (RCU, DC e Controle), utilizado na anÃlise do QST revelou maior propensÃo a neuropatia perifÃrica ou alteraÃÃo sensitiva em pacientes RCU e portadores de DII (RCU e DC) quando avaliados respectivamente sensibilidade vibratÃria e tÃrmica ao frio. Resultado de eletroneuromiografia (ENMG) foi anormal em 39,1% dos pacientes RCU e 38,4% pacientes DC. O questionÃrio de queixas sensitivas (protocolo II) revelou prevalÃncia de 51,8 % de queixas sensitivas em pacientes RCU e 50% em pacientes DC. Houve vÃrios tipos de queixas, sendo a mais comum, dormÃncia em mÃos e pÃs. TrÃs pacientes (2 RCU e 1 DC) apresentaram sintomas sugestivos da âsÃndrome das pernas inquietasâ e seis pacientes tinham relatos de tonturas (disfunÃÃo autonÃmica). Dos 14 pacientes RCU e 12 pacientes DC com queixas sensitivas, 57,1% e 25% respectivamente tinham alteraÃÃo em TEC. Dos pacientes RCU e DC que realizaram TEC (protocolo III), 48,1% e 41,7% respectivamente tinham resultado anormal, enquanto a ENMG foi anormal em 30% e 41,2% respectivamente. Podemos enfatizar que o QST e TEC parecem melhores que ENMG para diagnÃstico de alteraÃÃes sensitivas em pacientes com DII, visto que muitas destas alteraÃÃes podem corresponder a neuropatia de fibras finas. / Many studies have demonstrated the involvement of the peripheral nervous system in inflammatory bowel disease (IBD). By quantitative sensation testing (QST) to search for the vibration and cold sensitive thresholds (evaluates thick and small fibres respectively) (protocol I) we assessed 29 patients with ulcerative colitis (UC), 30 patients with Crohnâs disease (CD) and 28 control patients. Questionnaires were applied to sensory complaints (protocol II) in 27 patients with CD, 24 patients with UC and 25 control patients. The same patients underwent stimulated skin wrinkling induced by water (SSW) (protocol III), which evaluates small fibre of the autonomic nervous system. The Fisher test and hypothesis test chi-square comparing the three groups (UC, CD and control) used in analysis of QST revealed more prone to peripheral neuropathy or sensory changes in patients suffering from UC and IBD (UC and CD) when evaluated respectively vibration and cold thermal sensitivity. Results of electromyography (EMG) was abnormal in 39,1% of UC and 38,4% CD patients. The questionnaire of sensory complaints (protocol II) showed prevalence of sensory complaints in 51,8% UC and 50% CD patients. There were several types of complaints, the most common, numbness in hands and feet. Three patients (two UC and one CD) presented with symptoms suggestive of ârestless leg syndromeâ and six patients had reported dizziness (autonomic dysfunction). Of the 14 UC and 12 CD patients with sensory complaints, 57,1% and 25% respectively had change in SSW. Of UC and CD patients who underwent SSW (protoco III), 48,1% and 41,7% had abnormal results, while the EMG was abnormal in 30% and 41,2 % respectively. We emphasize that TEC and QST seem better than EMG for diagnosis of sensory changes in patients with IBD, as many of these changes may correspond to small fibre neuropathy.

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / Oxaliplatina (OXL) à um composto de platina de terceira geraÃÃo com potente atividade citotÃxica contra vÃrios tipos de cÃncer, possuindo um efeito colateral de difÃcil tratamento, uma severa neuropatia perifÃrica. Estudos sugerem que o oxalato, metabÃlito da OXL, està envolvido no desenvolvimento dessa neuropatia sensitiva perifÃrica (NSP); de modo que foi publicada a sÃntese de um anÃlogo (LLC-1402) da OXL, livre de oxalato, tendo propriedades antitumorais (LIU et al., 2013). O objetivo do trabalho à estudar o papel do oxalato na neuropatia induzida por OXL em camundongos, comparando a OXL com LLC-1402. A NSP foi induzida por 2 injeÃÃes (iv.) por semana de OXL (2 mg/kg), em camundongos machos Swiss, durante 4  semanas, totalizando 9 injeÃÃes. LLC-1402 (7, 14 e 28 mg/kg) foi administrado (iv.) seguindo o mesmo esquema. Foram realizados testes nociceptivos (Von Frey eletrÃnico e TIC), semanalmente. Depois, foi escolhida a dose de 14 mg/kg do LLC-1402 para fazer um outro experimento, no qual foi acrescentada a injeÃÃo ip. de oxalato (1,7 mg/kg). No 28 dia, foi feita coleta de sangue para contagem total de leucÃcitos e dosagens bioquÃmicas. Nos 28 e 56 dias, foi feita a coleta de medula espinhal e GRD para imunofluorescÃncia para ATF-3, c-FOS, iNOS e NeuN. Os resultados mostraram que a OXL e o LLC-1402 foram capazes de diminuir o limiar de retirada da pata e o tempo de retirada da cauda significativamente (p<0,05), comparado ao grupo controle. A injeÃÃo de LLC-1402 junto com oxalato e somente oxalato tambÃm foi capaz de reduzir o limiar de retirada da pata e o tempo de retirada da cauda. Os grupos tratados com OXL, LLC-1402 e oxalato mostraram uma reduÃÃo significativa da contagem total de leucÃcitos. Para as dosagens bioquÃmicas (TGO, TGP, ureia, creatinina), nÃo houve diferenÃa estatÃstica entre os grupos. Houve um aumento da imunoexpressÃo de c-Fos no GRD nos grupos tratados com OXL, LLC-1402 e LLC-1402 junto com oxalato nos 28 e 56 dias, e somente oxalato no 28 dia. Foi observado esse aumento no corno dorsal da medula espinhal no 28 dia em todos os grupos tratados. Foi observado um aumento da imunoexpressÃo de ATF-3, no GRD e corno dorsal da medula espinhal, em todos os grupos tratados, nos 28 e 56 dias. NÃo houve diferenÃa significativa entre os grupos no GRD nem medula espinhal na imunoexpressÃo de iNOS no 56 dia; jÃ, no 28 dia, houve um aumento da imunoexpressÃo de iNOS no GRD. Os resultados mostraram que o oxalato pode estar envolvido parcialmente na NSP induzida por OXL. / Oxaliplatin (OXL) is a third generation platinum compound with potent cytotoxic activity against several types of cancers, having a side effect is difficult to treat, a severe peripheral neuropathy. Studies suggest that oxalate, OXL metabolite, is involved in the development of peripheral sensory neuropathy (PSN); so that was published the synthesis of an OXL analogue (LLC-1402), oxalate free, which has antitumor properties (LIU et al., 2013). The objective of this research is to study the role of oxalate in OXL induced neuropathy in mice, comparing OXL with LLC-1402. The PSN was induced by two injections (iv.) OXL (2 mg/ kg) per week, in male Swiss mice, for 4  weeks, totaling 9 injections. LLC-1402 (7, 14 and 28 mg / kg) was administered (iv.) following the same scheme. Nociceptive tests were performed (electronic von Frey and tail immersion test) weekly. After, it was chosen dose of 14 mg / kg of the LLC-1402 to perform another experiment, in which was added oxalate injection (1.7 mg/kg). In the 28th day, it was made blood collection for total leukocyte count and biochemical measurement. In the 28th and 56th days, spinal cord and DRG were removed for immunofluorescence for ATF-3, c-FOS, iNOS and NeuN. The results showed that both OXL and LLC-1402 were able to decrease the paw withdrawal threshold and tail withdrawal time significantly (p<0.05) compared to the control group. The injection of LLC-1402 together with oxalate and only oxalate was also able to reduce the paw withdrawal threshold and the tail withdrawal time. Moreover, all groups treated with OXL, LLC-1402 and oxalate showed a significant reduction in the total leukocyte count. The biochemical measurement (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, urea, creatinine) showed no statistical difference between the groups. The results also showed increased c-Fos immunoexpression in GRD in groups treated with OXL, LLC-1402 and LLC-1402 together with oxalate in the 28 and 56 days, and only oxalate the 28th day. This increase was observed in the dorsal horn of the spinal cord at 28th day in all the treated groups. It was not observed this increase in the dorsal horn of the spinal cord in the 56th day. It was observed an increase in immunoexpression of ATF3 in DRG and spinal cord of dorsal horn in all treated groups in the 28th and 56th days. iNOS immunofluorescence showed no significant difference between groups in the DRG nor spinal cord, already in the 28th day, there was an increase in immunoexpression of iNOS in GRD. Thus, the results showed that the oxalate may be partially involved in PSN induced OXL.