This programme of work aimed to explore critical power and anaerobic work capacity in upper body exercise, using models commonly applied to lower body exercise. Sixteen untrained male subjects performed upper body exercise on a modified cycle ergometer. They carried out three habituation bouts and two maximal incremental bouts, which were followed by two sets of five constant power bouts in a randomised order. The results from the second set of constant power bouts were used to compare estimates of critical power and anaerobic work capacity from; the linear work vs. time model, the linear time vs. work model, the linear power vs. Iltime model, the hyperbolic power vs. time model, the exponential model and the three parameter non-linear model. The 3-parameter model provided critical power estimates that were very likely to be less than the other models studied, and values of anaerobic work capacity that were very likely to be greater than all of the other models. The exponential model provided estimates of critical power that were almost certainly greater than all of the other models. This would suggest that the selection of model can have marked and systematic effects on the magnitude of the derived parameters. Results from the two sets of constant power bouts were then used to examine their repeatability, and the repeatability of critical power and anaerobic work capacity derived from the linear work vs. time model (when work or time was identified as the dependent variable), the linear power vs. IItime model and the hyperbolic model. The repeatability of the parameters of the exponential model was also determined. There was evidence of heteroscedastic error in the measurement of time to exhaustion in the constant power bouts with a typical error of 18%. A typical error of critical power of between 5 to 6W was evident in the models studied, whilst a 9% typical percentage error was evident for critical power from the exponential model. The typical error in measures of anaerobic work capacity was 17-24%. The relatively poor repeatability of estimates of critical power and anaerobic work capacity may limit their practical application in identifying a particular exercise intensity and in assessing the effect of training and dietary interventions. The effect on parameter estimates of progressively reducing the number of bouts from five to four, three or two bouts was assessed, using combinations of bouts selected to clarify whether any effect was due to the number or the range of bouts. The effect of using as few as two bouts was assessed for the linear work vs. time model and the linear power vs. 11 • time model. The effect on the hyperbolic power vs. time model of progressively reducing the number of bouts to three was also assessed. Combinations of bouts that included higher power output bouts, tended to elevate critical power estimates and reduce estimates of anaerobic work capacity. Selecting a small number of two or three low intensity bouts tended to reduce critical power estimates and elevate anaerobic work capacity in the models studied. There was a tendency towards a reciprocal effect, whereby if critical power was elevated, anaerobic work capacity was reduced and vice versa. Within models, the effect of reducing the range of constant power bouts appeared to be more marked than the effect of reducing the number of bouts. Critical power is thought to identify a threshold of tolerable duration and physiological response in lower body exercise. To determine whether critical power from the hyperbolic model identified a similar threshold of duration and physiological response in upper body exercise, subjects performed two exercise bouts at critical power determined from the hyperbolic model, the mean durations of which were 22.4 ± 10.6 and 23.1 ± 11.3 minutes, with a typical error of 84s. A variety of patterns of physiological response were evident and critical power from the hyperbolic model in upper body exercise did not characterise the intensity associated with the highest steady state values of V02 or blood lactate in all subjects. The results indicate that values of critical power and anaerobic work capacity in upper body exercise are affected by the selection of model and aspects of experimental protocol such as the number and range of bouts, which affects their repeatability. These issues confound the question of whether critical power from the hyperbolic model identifies a threshold of upper body physiological response. Future studies might examine whether one or two single performance tests could provide both valid performance data whilst suggesting changes in aspects of underlying physiology, such as aerobic and anaerobic capacities.

Vibration response analysis has been carried out on human lumbar spines in-vitro and in-vivo. Random vibration in the frequency range between 20 Hz and 2 kHz was applied to the L5 spinous process in the antero-posterior direction while motion response was measured at the other spinous processes of the lumbar spine. Transfer mobility which defines the lumbar spine's motion response to vibratory force was evaluated by using the fast Fourier transform and spectral averaging technique. There was high damping during the in-vitro tests and the lumbar spine was found to behave as a segmented beam hinged at the thoracic and sacral ends. Fundamental mode shape was observed at frequencies lower than 150 Hz and this pattern was also observed with simulated fusion of the facet joints and interbody fusion. Mobility summated for the whole range of frequency could be modelled by an exponential expression. Useful parameters have been identified and they were found to relate to the lumbar spine's vibratory characteristics resulting from structural modifications. Vibration testing performed on normal subjects revealed that a relaxed lumbar spine was highly damped and non-resonant. First flexural vibration mode was observed only under the action of the back extensors. Averaged figures have been established for the coefficients of an exponential expression which fits closely to the summated mobility curve. The mobility and its attenuation coefficients in different frequency bands have been evaluated from twelve normal subjects. Localized attenuation of vibration response and the reduction in mobility were observed on a patient with osteoporotic lumbar spine. Mobility in the low frequencies was reduced while the medium and high band mobility were enhanced in patients with postero-lateral fusion and instrumentation for fixation of the lumbar spine. The attenuation pattern of these patients was consistent, and corresponded to the existence of structural enhancement.

The development of higher wavelength Forster (Fluorescence) Resonance Energy Transfer (FRED substrates has provided a useful enabling tool for the purposes of studying the interactions of drugs, and potential drugs, with biologically active proteins in vitro, overcoming many of the problems such as poor sensitivity and interference associated with traditional fluorescent substrates. In particular these substrates have proven highly useful to the study of peptidases (the proteins responsible for hydrolytic cleavage of the peptide bonds between amino acids during peptide/protein catabolism) where the hydrolysis of fluorophore labelled FRET peptide substrates can be monitored with great sensitivity, as a result of the relatively large changes in fluorescence generated by low levels of substrate turnover. Despite these advantages, to date little investigation has been undertaken into the potential applications for such FRET peptides to the characterisation of physiological interactions. Within this study the potential applications of the higher wavelength FRET pairs fluorescein (fAM) and tetramethylrhodamine (TAMRA) in the characterisation of disintegrin metallopeptidases was investigated with a focus on two areas; .applications within the design of homogenous real-time cellular assays and applications within the characterisation of b!.Qp101ecule binding interactions in vitro. Both areas of study have previously been dem~nstrated to be unsuited to investigation using traditional lower wavelength FRET peptides. For the purposes of evaluating applications to cellular assay design, a FAM-TAMRA substrate for ADAM-17 (TACE) was investigated as a tool to measure TACE surface activity in cultured cell lines. To investigate applications to the study of biomolecule interactions in vitro, a FAM-TAMRA substrate for ADAMTS-4 was. used to characterise exosite binding interactions between ADAMTS-4, its physiological inhibitor, TIMP-3 and its substrate aggrecan. Based on the observations of this study, the use of higher wavelength fluorophores successfully overcomes many of the problems traditionally associated with FRET peptides in these areas, and as such provides a useful tool for use in the characterisation ofphysiological interactions.

The thesis presents some of the work carried out as part of the research and development programme for the provision of practical artificial upper limbs for a group of congenital amputee patients. The account commences by reviewing, in Volume 1, the problems presented by this population of amputees in the context of an ongoing limb fitting servicep and shows hoer the difficulties of prehension arise in this situation. The provision of upper limb prostheses in general is then reviewed with reference to representative literature on the subject, where various inadequacies of existing systems are considered in the context of the imsdiate practical problem of the provision of adequate prehension facilities for bilateral amputees. The experimental and practical work of Volume 2 commences with an appraisal of the requirements for a hand prosthesis in the light of the information derived from Volume Is, and this, together with the results of some simple experiments, leads to a broad specification for a hand mechanism. Various experimental mechanisms are then desoribed, leading to the development of a mechanism suitable for patient trials. The problem of the provision of the cosmetic cover for the meckanism emerges as the major obstacle in the way of further progress, and a new process for cosmetic glove production is devised, This is followed by consideration of the various problems of control associated with the hand prosthesis, some working hardware is developed and guidelines for future work on control are outlined. The thesis concludes with an appraisal of the work following trial fittings on patients, which shows the principles to be successful in Operation and indications for future trends are given

No description available.

Amyloid formation is a predominant feature of many human diseases including Alzheimers' disease, Parkinsons' disease, type II diabetes and Creutzfeldt-Jacob disease. The process of amyloidogenesis involves the self-assembly of soluble protein into insoluble fibrous material. Amyloidogenic proteins, which share no common sequence, structure or function, form amyloid fibres which have a common morphology. Neither a detailed structure of mature amyloid or the mechanism by which it forms is fully understood. The work presented in this thesis uses the cystatins as a model system for probing the mechanism of amyloid formation. The formation of amyloid requires a refolding event as the protein involved refolds from its native structure to the cross-p structure common to amyloid. Characterisation of the folding pathway of human cystatin C indicates that it folds via a partially folded kinetic intermediate, in an analogous manner to chicken cystatin. Analysis of the early stages of amyloidogenesis in cystatins indicates domain-swapped dimers are the building block of cystatin amyloid. As is observed with chicken cystatin, the dimerisation of human cystatin C is a bimolecular process. m-value analysis indicates that the structure of the dimerisation transition state is very close to the structure of the unfolded state and is more unfolded than the kinetic intermediate identified in the human cystatin C folding pathway. No terameric species are observed in the amyloidogenesis of human cystatin C, supporting evidence that tetramers are an off-pathway intermediate in the amyloidogenesis of chicken cystatin. Following the formation of dimer, isomerisation of the proline conserved across the cystatins is required prior to the formation of amyloid fibres. A preliminary study of the interaction between human cystatin C and Ap shows that there is no interaction between monomeric hCC and monomeric API-4o. Given that hCC has been shown to inhibit Ap amyloid formation, hCC must interact with one of the oligomeric species of AB that is populated during amyloidogenesis. Further experimentation is required to determine the exact nature of the interaction between hCC and AB.

The aim of this project was to determine the best materials and surface treatments for soft tissue repair and to enhance our understanding of material / cell interactions by comparing the response of human cells growing on a selection of currently approved and novel biomaterials. This study focused on comparing the materials and also investigated the effect of modifying the surfaces using gas plasma and other treatments with the aim of enhancing cell growth. In addition, chitosan was studied to examine the reported bacteriostatic effect and promotion of human cell growth. Chitosan has many properties but this research focused on its reported acceleration of wound healing haemostatic and bacteriostatic properties. To examine the bacteriostatic properties of chitosan, a number of experimental designs were used. The bacteriostatic study led onto a selection of means to incorporate chitosan into/onto some of the biomaterials being tested. A selection of biomaterials were examined for their ability to support tissue growth in native and surface modified forms (plasma treatment/ chitosan treatment). Cells were seeded on the samples and the growth of the cells was measured at weekly intervals. The outcome of this research was that the optimal material for soft tissue repair was found to be polyurethane with an ammonia plasma treatment. This can be made into a mesh prosthesis for hernia repair and can be coated with chitosan to inhibit bacterial colonisation if required.

The review of the literature covers the underpinning neurophysiology of temperature regulation and the causes and consequences of fatigue in the heat and the effect of skin cooling (Chapter 1). To date primarily exercise protocols have been used to investigate the effect of high ambient temperatures on fatigue. If the now well established view that the limiting factor during endurance exercise in the heat is a critically high core body temperature, it is possible that this hyperthermia-induced fatigue could be investigated, in part, by passive heating. The purpose of the first experimental chapter of this thesis (Chapter 2) was to determine whether passive heating to increase core body temperature (Te) would have a detrimental effect on subsequent exercise capacity and perceived exertion (RPE) during exercise in the heat and whether head-cooling during passive heating would attenuate the unpleasant sensations of an elevated T, during subsequent exercise in the heat. The study found exercise time following passive heating was reduced and RPE increased, however, RPE was lower following passive heating with head-cooling. Results suggest increased RPE during exercise in the heat is primarily due to the increase in T; Furthermore, head-cooling attenuates the rise in T, and the effect on RPE is proportional to the rise on Te. The results of Chapter 2 are consistent with the large body of research which states endurance exercise in the heat is limited by high core body temperatures. Further research in this area by Nybo and Nielsen (200 1) suggests that alterations in cerebral brain activity may be associated with hyperthermia-induced fatigue during prolonged exercise in the heat. Very few studies have been conducted on non-sedated human subjects to investigate the role of increasing core body temperature per se on cortical electroencephalography (EEG). An elevated core body temperature increases feelings of heat related fatigue and EEG slowing has been associated with a reduced state of arousal or fatigue in sedated hyperthermic humans, furthermore, cooling the skin has been shown to provide relief from feelings of heat related fatigue, Therefore, Chapter 3 investigated whether passive heating to increase in core body temperature by 1°C in conscious human subjects altered cortical EEG and whether face cooling would reverse any changes in the EEG. This study found that increasing core body temperature by passive heating caused a slowing of the EEG. Furthermore the cortical EEG response to face cooling differed depending on the thermal state of the body. There does not appear to be any published literature describing differences in EEG responses to skin cooling depending on the thermal state of the body. Therefore, Chapter 4 developed the learning's from chapter 3 to further investigate the EEG responses to skin cooling at normal as compared to elevated core body temperatures. This study found that non-noxious hand cooling elicits a different cortical response, depending on the thermal state of the body.A limited number of individuals, primarily endurance athletes and military personal are exposed to situations where core temperature is a limiting factor on physical performance. However, a larger number of individuals work at high environmental temperatures that may influence their cognitive or mental performance. Chapter S of this thesis examined the effects of raising skin and core temperature, separately and in combination on the perceptions of heat related fatigue (alertness, contentment, calmness and thermal comfort), cardiovascular function and on objective measures of cognitive performance (reaction time and accuracy). The results of this study suggest that feelings of heat related fatigue and cardiovascular strain can be attributed to a combination of elevated skin and core body temperature, whereas decrements in cognitive performance can be attributed to an elevated core temperature. The final experimental chapter of this thesis (Chapter 6) investigated whether thermal thresholds, that is, the temperature at which we perceive warmth or coolness, are altered by increasing core and skin temperatures and whether the face differs from other body sites in thermal perception sensitivity. Furthermore, menthol has been reported to alter cutaneous thermal sensation, therefore we also investigated whether the topical application of menthol has an effect on cutaneous thermal thresholds at altered skin and core body temperatures or between body sites. Results of Chapter 6 suggest that the perception of warm sensation and cold sensation required a relative increase or decrease in skin temperature of approximately 3-4°C for perception of warmth or coolness, independent of starting cutaneous temperature. The perception of hot pain corresponded to an absolute value of skin temperature in the region of 46°C. The topical application of menthol raised the threshold for the perception of warm sensation and hot pain and lowered the threshold for the perception of cold sensation.

Of the non-targeted, delayed consequences of exposure to ionising radiation, genomic instability is a particular area of concern, especially with regard to its manifestation in the non-exposed offspring of irradiated parents. However, further analysis of these effects and their implications is mainly limited by our understanding of the underlying mechanisms and the lack of reliable data for humans. As of yet, transgenerational instability has only been consistently demonstrated in animal models using high, acute doses of ionising radiation (> 1 Sv). To investigate the effects of low-dose acute and low dose-rate (chronic) irradiation and whether or not they are capable of destabilizing the genomes of the unexposed offspring, we exposed male BALB/c mice to a range of γ-ray doses (10- 100 cGy) and dose-rates (chronic and acute), and mated them to unexposed BALB/c females 10 weeks post-irradiation. The mutation frequency at the Ms6-hm locus was established in DNA samples extracted from the sperm of directly exposed mice, as well as from the sperm and brains of their F1, using the single-molecule PCR technique. A linear dose-response was observed for direct exposure across the range of acute doses, with a doubling dose of 57 cGy. Furthermore, 100 cGy of acute γ-rays was shown to be more mutagenic than chronic exposure to the same accumulated dose. However, acute exposure to 10-25 cGy failed to manifest genomic instability in the derived offspring. This was also true of low dose-rate exposure to 100 cGy. Only acute paternal exposure to 50 and 100 cGy resulted in transgenerational instability, to a similar extent for both doses. Analogous results were found for both tissues. Taken together, this would imply the presence of a stress-like response where a threshold of acute dose determines the onset of transgenerational instability. Our results also suggest that children whose fathers are subject to most forms of human exposure to ionizing radiation would be safe from the effect.

No description available.