M.A. / Spinal cord trauma resulting in paraplegia or quadriplegia is one of the most devastating injuries. A frequent complication of spinal cord injury is intractible pain. It compounds a host of personal and social consequences: disruption of personal roles, dysfunctional marital and family relationships, unemployment, financial hardship, depression, anxiety, lowered self-esteem and hopelessness. There is an abundance of research on pain in general, but a dearth of literature on chronic pain in the spinal cord injured population - especially in the South African context. This study examined the psychosocial impact of pain on spinal cord injured patients in a hospital setting. Specifically, it addressed six core research questions, concerned with the physiological components of pain, and the social, affective and rehabilitation consequences of pain for spinal cord injured patients. The effects of etiology and level of lesion, age, gender and culture on the general pain experience were investigated. The purpose of this study was to accurately describe the phenomenon of pain as experienced by spinal cord injured (SCI) patients. The evidence showed that pain was a serious problem for SCI patients. A variety of physical and social modifiers of the pain experience were identified, as were several important temporal features of pain. SCI patients reported high frequencies of social, affective (depression, low selfesteem, suicidal responses and partner relationship problems), and rehabilitation consequences. The etiology of spinal cord injury was found to be related to pain intensity, while the level of the lesion was not associated with pain intensity or frequency. Some effect was found for age, however, gender did not contribute to the variance of any of the dependent variables. The culture of SCI patients plays an important role in both pain perception and the psychosocial and rehabilitation consequences of chronic pain. The results suggest that pain in SCI patients, as in other pain populations, needs to be recognized as a complex, multidimensional phenomena. Successful treatment requires an understanding of the SCI patient's emotional and psychological, as well as his physical requirements. The role of pain assessment is fundamental to any pain management programme.

Spinal cord injury (SCI) is an acute and devastating event that results in significant and permanent life changes for the individuals who are injured, as well as their families and friends. Depression has received more attention from clinicians and researchers than any other psychological issue among persons with SCI. Measurement of depression in this population has a variety of methodological issues, including inconsistent assessments used (self-report versus clinical interviews), varying definitions of depression, inclusion and exclusion of physical symptoms in the assessment process, and use of measures that do not represent DSM-IV criteria for major depressive disorder. The primary goal of this study was to evaluate the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR) and provide descriptive analyses of this measure with persons with SCI. Results showed that somatic symptoms were more frequently endorsed than psychological symptoms in this population. Additionally, scores on the QIDS-SR were significantly associated with a depression diagnosis in the patient's medical chart. However, QIDS-SR scores were not found to be correlated inversely with quality of life scores as predicted. The QIDS-SR was shown to have good internal consistency and convergent validity with patients with SCI. However, it failed to demonstrate construct validity. The QIDS-SR has the potential to be a valid measure with this population and further analysis of the psychometric properties with patients with SCI is warranted.

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Chronic hypersensitive pain states can become established following sustained, repeated or earlier noxious stimuli and are notably difficult to treat, especially in cases where nerve injury contributes to the trauma. A key underlying reason is that a variety of plastic changes occur in the central nervous system (CNS) at spinal and potentially also supraspinal levels to upregulate functional activity in pain processing pathways. A major component of these changes is the enhanced function of excitatory amino acid receptors and related signalling pathways. Here we utilised rodent models of neuropathic and inflammatory pain to investigate whether evidence could be found for lasting hypersensitivity following neonatal (or adult) noxious stimuli, in terms of programming hyper-responsiveness to subsequent noxious stimuli, and whether we could identify underlying biochemical mechanisms. We found that neonatal (postnatal day 8, P8) nerve injury induced either long lasting mechanical allodynia or shorter lasting allodynia that nonetheless was associated with hyper-responsiveness to a subsequent noxious formalin stimulus at P42 despite recovery of normal mechanical thresholds. By developing a new micro-scale method for preparation of postsynaptic densities (PSD) from appropriate spinal cord quadrants we were able to show increased formalin-induced trafficking of GluA1- containing AMPA receptors into the PSD of animals that had received (and apparently recovered from) nerve injury at P8. This was associated with increased activation of ERK MAP kinase (a known mediator of GluA1 translocation) and increased expression of the ERK pathway regulator, Sos-1. Synaptic insertion of GluA1, as well as its interaction with a key partner protein 4.1N, was also seen in adults during a nerve injury-induced hypersensitive pain state. Further experiments were carried out to develop and optimise a new technological platform enabling fluorometric assessment of Ca2+ and membrane potential responses of acutely isolated CNS tissue; 30-100 μm tissue segments, synaptoneurosomes (synaptic entities comprising sealed and apposed pre- and postsynaptic elements) and 150 × 150 μm microslices. After extensive trials, specialised conditions were found that produced viable preparations, which could consistently deliver dynamic functional responses. Responsiveness of these new preparations to metabotropic and ionotropic receptor stimuli as well as nociceptive afferent stimulant agents was characterised in frontal cortex and spinal cord. These studies have provided new opportunities for assessment of plasticity in pain processing (and other) pathways in the CNS at the interface of in vivo and in vitro techniques. They allow for the first time, valuable approaches such as microscale measurement of synaptic insertion of GluA1 AMPA receptor subunits and ex vivo assessment of dynamic receptor-mediated Ca2+ and membrane potential responses.

Salamanders have a remarkable ability to regenerate complex body parts including the limb, tail, and central nervous system. Although salamander regeneration has been studied for several hundred years, molecular-level studies have been limited to a relatively few important transcription factors and signaling molecules that are highly conserved among animals. Physiological genomic approaches were used here to investigate spinal cord and limb regeneration. Chapter 2 reports that hundreds of gene expression changes were identified during spinal cord regeneration, showing that a diverse injury response is activated in concert with extracellular matrix remodeling mechanisms during the early acute phase of natural spinal cord regeneration. Chapter 3 presents results that identify the salamander ortholog of mammalian Nogo-A, a gene known to inhibit mammalian nerve axon regeneration. Nogo-A gene expression was characterized during salamander development and adulthood in order to address the roles of Nogo-A in the nervous system. Chapters 4 and 5 use physiological genomic approaches to examine limb regeneration and why this process is dependent upon an intact nerve supply. Results presented in Chapter 4 showed that many processes regulated during early limb regeneration do not depend upon nerve-derived factors, but striking differences arise between innervated and denervated limbs by 14 days after amputation. Chapter 5 identified genes associated with peripheral nerve axon regeneration and identified gene candidates that may be secreted by nerves to support limb regeneration. Lastly, chapter 6 characterizes the expression of a developmentally important family of genes, matrix metalloproteinases, during tail regeneration. These results suggest that matrix metalloproteinases play multiple roles throughout the regeneration process. Primarily, this dissertation presents data from the first genomic studies of salamander regeneration. The results suggest genes such as matrix metalloproteinases, and molecular pathways such as the Wnt and FGF signaling pathways that can be exploited to enhance regenerative ability in humans.

Purpose: The purpose of this study was to assess whether the factors historically presented in the literature to differentiate vocal cord dysfunction (VCD) from breathing difficulties of other etiologies accurately predict and identify patients who have VCD. The researchers were also interested in whether patients with VCD have a higher risk of misdiagnosis than patients with breathing difficulties of other etiologies. Finally, the present study investigated whether patients with VCD were more likely to have their symptoms attributed to psychological factors than patients with breathing difficulties of other etiologies. Method: A survey comprised of 23 questions regarding the participants’ previous and current diagnoses, triggers that precede breathing difficulty, and whether or not the participants have ever been misdiagnosed was posted to internet support groups, websites, blogs, and forums. The final participant pool included 20 participants with VCD and 25 participants with asthma. Results: None of the factors investigated accurately differentiated participants with asthma from participants with VCD one hundred percent of the time. However, participants with VCD were more likely to report throat tightness during an attack, association of an attack with symptoms of acid reflux, and rapid resolution of symptoms without treatment. Conversely, participants with asthma were more likely to report expiratory stridor and chest tightness, full resolution of symptoms with use of asthma medications, nocturnal symptoms or symptoms just after waking, and symptoms that seemed to be triggered by environmental agents or allergens. Preliminary findings from the present study suggest that patients with VCD are both more likely to receive a misdiagnosis and have their symptoms attributed to psychological factors than participants with asthma. Conclusion: A diagnosis of VCD must be made very carefully, ideally with instrumental evaluation of the vocal mechanism during an acute “attack” of breathing difficulty. The factors identified in the literature to differentially diagnose patients with asthma from patients with VCD do not accurately differentiate these populations. These findings suggest that continued education about the nature of VCD and differential diagnosis should be paramount to medical professionals. / text

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