The rat spinal cord following traumatic injury: An anatomical and behavioural study examining NADPH-d and fos

The general aim of this current work was to examine spinal cord injury (SCI), and in particular to examine the pathology of injury as it relates to changes in sensory transmission. Due to the limited possibilities for experimentation in humans, a range of animal models of SCI have been developed and are reviewed here. The weight drop SCI model is the most similar to the clinical presentation of SCI in humans and has been widely used in the rat. It was selected for the series of experiments reported in this thesis. Many of the functional deficits produced by SCI result from a cascade of biochemical events set into motion by the injury. Included amongst these is the activation of the enzyme nitric oxide synthase which produces the gaseous neuromodulator, nitric oxide (NO). NO is amongst the most widely distributed and widely utilised molecule in virtually all living organisms, and it is an important signalling molecule in the nervous system. One of the major functions performed by NO appears to relate to sensory transmission, and thus alterations in sensory transmission observed as a result of SCI may involve alterations to NO synthesis. One of the principal aims of this thesis was to examine the effect of SCI on the NO producing cells of the spinal cord and to consider what any changes in NO synthesis may suggest in regards to sensation. NO producing cells were examined using NADPH diaphorase (NADPH-d) histochemistry. As the symptoms of SCI such as motor loss and changes in sensory processing are functional changes, it was also useful to examine changes in neuronal function as a result of SCI. Widespread neuronal function was examined via immunohistochemical detection of the gene product of the immediate early gene, c-fos. It is not known how extensive the biochemical changes resulting from SCI may be, thus another of the aims of the present thesis was to examine the effects of SCI on NO synthesis not only at the level of injury, but also distant to the injury. Findings of the present thesis indicated that traumatic SCI resulted in a decrease in the number of NADPH-d positive cells from the superficial dorsal horn (SDH) of the spinal cord, while the number of these cells are increased in the ventral horn. These changes were restricted to spinal segments adjacent to the injury. Fos expression was also altered by injury and was found to decrease. The most profound changes were found to occur in lamina III, although the other laminae also demonstrated similar changes. Changes in fos expression however were notably more widespread than those for NADPH-d and were not restricted to the level of the injury, occurring at all levels of the spinal cord examined. It was interpreted that alterations in NO synthesis appear to be modulated by the local injury-induced environment while fos expression may be altered by widespread changes to the global level of activity within the central nervous system. Having observed that the number of NADPH-d positive cells of the SDH is reduced following injury, it was of interest to determine whether these cells were in fact killed, or whether they were still present but with reduced NADPH-d activity. Cell counts suggested that the NADPH-d positive cells, which were likely to represent a population of inhibitory interneurons, were not killed following injury, but rather are disrupted such that their normal biochemistry is altered. Since these cells were likely to be inhibitory and were located in laminae involved in sensory transmission, the question arose how disruption of these cells may relate to the neuropathic pain observed to develop following SCI. Thus both NADPH-d and fos expression were again examined, but this time in conjunction with the sensory function of the rats. Sensory thresholds to pain-like behaviour were determined prior to and after injury using Von Frey filaments. Rats that demonstrated a decrease in sensory threshold of at least two Von Frey filament gradations (>70%) were classed as allodynic, while those with a less than a 70% decrease in threshold were classed as non-allodynic. A subpopulation of each of the groups of rats (uninjured, non-allodynic and allodynic) underwent a somatic stimulation paradigm. It was found that stimulation resulted in an increase in the number of NO producing cells but only in the allodynic group of animals. Since this group of animals by definition would perceive this stimulation as noxious, it is likely that the noxious nature of the stimulation resulted in the increased number of NO producing cells observed. This effect occurred only in segments adjacent to the injury. When fos expression was examined in the uninjured animals it was noted that somatic stimulation resulted in a decrease in fos expression, almost exclusively in lamina III. Following injury, there was no change in fos expression in lamina III observed. Instead the only change observed was an increase in fos expression in the deep dorsal horn (DDH, lamina IV and V). This occurred most profoundly in the allodynic group. These results suggested that SCI may lead to misprocessing of sensory signals such that non-noxious somatic stimuli are processed in the DDH rather than lamina III following SCI. It is proposed here that this change in laminae processing may be responsible for the perception of pain towards a non-noxious stimulus, and that the reported injury-induced loss of NO producing inhibitory interneurons in the SDH may be responsible for this alteration in sensory processing following SCI. Sensation is also processed by a number of supraspinal structures and a number of these have been implicated in the development of neuropathic pain states. The effects of SCI on neuronal activity as well as NO synthesis were examined in the periaqueductal grey region of the mid brain (PAG). SCI was shown to result in reduced neuronal activity in the PAG. This reduction in activity did not follow the somatotopy of the lateral column of the PAG (lPAG). It was suggested the reduced activity may not be solely caused by reduced spinal input as a result of SCI. Reduced neuronal activity in the PAG may indicate reduced PAG function, which includes descending modulation of spinal sensory transmission. Injury was not found to alter NADPH-d expression in the PAG. The effect of traumatic lumbar SCI on the parietal (sensorimotor) cortex of the rat was also examined, as loss of inputs following SCI have been shown to result in a profound reorganisation of the cortex. Results indicated that SCI results in a virtual cessation of neuronal activity in areas 1 and 2 of the parietal cortex, likely as a result of lost afferent drive. Theories of cortical plasticity suggest that while the primary inputs via the lumbar spinal cord may be lost following SCI, other less dominants input will remain and become more dominant. It has been proposed previously that cortical reorganisation involves a rapid reorganisation of the entire sensory system. It was interpreted that a similar process may explain the system-wide reduction in neuronal activity observed in the present series of studies

The experience of illness and employment among young adults with a long-term condition

Employment is currently conceived by the UK government as a panacea for achieving social justice among disadvantaged groups in society. Welfare to work policies are being introduced to increase the employment rates of people with illhealth and/or disability. There is little research on how individuals with chronic illness from childhood fare in the labour market as an adult and the perceptions of these groups towards work and career prospects. A qualitative study was undertaken using grounded theory to explore these issues among adults from three disease categories. In total, 30 respondents were interviewed aged between 20-32 years; 10 with cystic fibrosis, 10 with Type 1 diabetes and 10 with arthritis with gender represented equally across the three groups.Respondents had varying degrees of disease severity. There was, however, a consensus among these young adults in how symptoms were experienced and managed. Respondents viewed themselves as competent individuals and their approach to care reflected this standpoint. Management of illness was largely taken-for-granted and perceived only as intrusive by those with deteriorating health. There was some discrepancy between the apparent advice given by health care professionals and decisions made by individuals about illness which were located in the social fabric of day-to-day activities. No specialist careers guidance had been available to these young adults. Career choice was hindered by lack of educational attainment in some cases and restricted employment opportunities in others. Most respondents were not familiar with welfare to work initiatives. At the point of interview, 20 were in full-time jobs, 2 worked part-time, 3 attended higher educational institutions and 5 were out of work receiving full disabilityrelated benefits. Disclosure of health status in employment emerged as a key issue. Jobs were sought or valued if they were well paid, provided opportunities for advancement and were fulfilling. Half the sample reported having to make some sort of adjustment to manage working lives. The majority of these involved self-care strategies such as buying special adaptations, getting up extra early on work days and making great efforts to accommodate meals into busy schedules. These types of adjustments were seemingly unacknowledged by employers. Few reported direct discrimination in the workplace. Bad employment practice was experienced but this was regarded as poor management behaviour rather than organisational policy. Severity of illness did not appear to be linked to more expressed anxiety about the future. Women in the sample spoke of the tension between lives as desired and lives as experienced in relation to the prospect of having children.These findings are discussed in relation to past and current research about young people, illness and work and contemporary UK polices on employment and health care

A Newly Purchased Letter

The following letter has recently been purchased by Nuneaton Museum and Art Gallery and its pubIication here (as far as we are aware, for the first time) is with the Curator\u27s kind permission. Unfortunately, no year is shown with the date, neither is the correspondent addressed in any other way than by \u27My dear Sir\u27, so it has been impossible to discover to whom it was written. All one can say is that it was penned sometime between 1890 (the date of publication of Oscar Browning\u27s Life of George Eliot) and 1925 when Sir Thomas Clifford Allbutt, the writer of the letter, died - a very long span! T. Clifford Allbutt (1836-1925) met George Eliot in 1868. In 1864 he had been appointed physician to. the Leeds General Infirmary. and George Eliot and Lewes spent two days looking around the new hospital with him. He was the inventor of the clinical thermometer and was once thought to have been the original of Lydgate in Middlemarch, although much more successful than the hapIess character in the novel. 23 Feb St. Radegund\u27s Cambridge My dear Sir, I saw a good deal of George Eliot in the years to which you referred and she would pick up a good deal from me and others about young men in their early medical years. And Lewes being himself a physiologist and often associated with medical men would tell her much and say much before her. Among Lewes\u27 and her friends were Lockhart Clarke, W. F. Parker, (of the shoulder girdle” ) Gardiner (1) of your own town and many others. It was often laughingly said among us that I had sat for Lydgate but this was only banter. She constructed the character as great imaginations can, out of very limited data as Owen constructed the ( see …) etc

The Sanatorium in the Treatment of Phthisis.1

n/

Self-report mental imagery and social desirable responding

The relationship between scores on self-report imagery questionnaires and sub-types of socially desirable responding was investigated across five papers. Paulhus (2002) has proposed a distinction between two forms of social desirable responding: the egoistic bias which is the tendency to claim positive social and intellectual qualities, and the moralistic bias which is the claiming of positive moral qualities. The research made use of the Balanced Inventory of Desirable Responding (BIDR; Paulhus, 2002) which has separate scales to measure both biases. The papers found the following: 1) ‘greater’ imagery ability was always associated with higher social desirable responding; 2) correlations with self-report imagery scales and egoism were always higher than those with moralism; 3) the magnitude of correlations between imagery scales and egoism was generally in the r= .20 to .35 range and so sometimes exceeded a r=.25 criterion for acceptability set by McKelvie (1994); 4) significant correlations between imagery properties and egoism were seen for scales measuring vividness of visual imagery and for some other visual properties of images such as ease of image generation; 5) the size of imagery scale–egoism correlations were themselves correlated positively with the extent to which participants rated imagery properties as measuring imagery ability and the extent to which the imagery property was desired; 6) the imagery scale–egoism correlations were of a similar size for imaging real world items and spatial ability test type items; and 7) the imagery scale–egoism correlations were largely independent of correlations with trait anxiety. The findings suggest that the self-report imagery questionnaire–egoistic bias correlations mostly reflect distortion of scores, and that the size of the relationship is stronger than previously thought. However, the size of this relationship does not appear to reach to the extent where it impacts notably on imagery questionnaire performance

Adult college learners of British Sign Language : educational provision and learner self-report variables associated with exam success

This study investigated educational provision and learner self-report factors associated with exam success for adult learners of British Sign Language (BSL) studying either Level 1 or Level 2 courses. These levels are equivalent to the first and second year of a United Kingdom General Certificate of Secondary Education (GCSE) qualification. Two hundred and thirty five students from three further education colleges answered a self-report questionnaire covering a range of variables. Analysis of the data suggests that: 1) success rates differed markedly for Level 1 and 2; 2) enhancements of educational provision, such as the use of extra conversational classes, appeared to play a role in increasing exam success rates; 3) individual factors associated with exam success varied between course level and between types of provision; 4) variables related to exam success at Level 2 were more numerous and more specifically related to the learning of sign language than those seen at Level 1; 5) Effect sizes seen for enhancements of educational provision were larger in size than for individual characteristics. These results offer insights into the factors that affect the success rates of people learning sign language

Subtle Cardiovascular Dysfunction in the Unilateral 6-Hydroxydopamine-Lesioned Rat

The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV), diurnal rhythms of heart rate (HR), core body temperature (cBT) and locomotor activity (LA). Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function (“disengage” test), and prominent apomorphine rotation (all P < .05 versus controls). Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n = 8) versus controls (n = 6; P < .05). Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls). LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction

Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

Balancing health care education and patient care in the UK workplace: a realist synthesis

Introduction: Patient care activity has recently increased without a proportionate rise in workforce numbers, impacting negatively on healthcare workplace learning. Healthcare professionals are prepared in part by spending time in clinical practice, and for medical staff this constitutes a contribution to service. While stakeholders have identified the balance between healthcare professional education and patient care as a key priority for medical education research, there have been very few reviews to date on this important topic.Methods: We conducted a realist synthesis of the UK literature from 1998 to answer two research questions: (1) What are the key workplace interventions designed to help achieve a balance between healthcare professional education and patient care delivery? (2) In what ways do interventions enable or inhibit this balance within thehealthcare workplace, for whom and in what contexts? We followed Pawson's five stages of realist review: clarifying scope, searching for evidence, assessment of quality, data extraction, and data synthesis.Results: The most common interventions identified to balance healthcare professional education and patient care delivery were ward round teaching, protected learning time and continuous professional development. The most common positive outcomes were simultaneous improvements in learning and patient care or improved learning or improved patient care. The most common contexts in which interventions were effective were primary care, postgraduate trainee, nurse, and allied health professional contexts. By far the most common mechanisms through which interventions worked were organisational funding, workload management and support.Discussion: Our novel findings extend existing literature in this emerging area of healthcare education research. We provide recommendations for the development of educational policy and practice at the individual, interpersonal and organisational levels and call for more research using realist approaches to evaluate the increasing range of complex interventions to help balance healthcare professional education and patient care delivery