Hypoxia elicits a carotid body-mediated increase in minute ventilation, called the chemoreflex. Volatile anaesthetics depress this chemoreflex, even at sub-anaesthetic doses. The broad aim of this thesis is to explore how these anaesthetics act on carotid body mechanisms to depress the chemoreflex. The agents studied in this thesis are halothane (a potent depressant of this reflex), isoflurane (a less potent depressant) and sevoflurane (a weak depressant). Intracellular Ca2+ measurements, mitochondrial NADH and potential measurements, and single channel electrophysiology studies were performed on a primary culture of rat carotid body type-1 cells and HEK cells transiently expressing TASK channels. Cells were exposed to hypoxia and/or volatile anaesthetics. The results reveal that on all levels studied, the same order of potency of anaesthetics was observed as seen in human ventilatory studies. Volatile anaesthetics depress the hypoxia evoked Ca2+ entry in the carotid body and increase the activity of K+ background channels both in glomus and HEK cells expressing TASK. Furthermore, on all levels studied, when halothane and isoflurane were applied as a mixture, the effect evoked by the mix was of a lesser magnitude than that of the halothane alone, revealing a novel sub-additive observation, which has not been previously reported in the literature. The anaesthetic action of glomus cells was not exclusive to the TASK channels as application of all three anaesthetics evoked an increase in mitochondrial NADH and caused mitochondrial depolarization in glomus cells. These effects of anaesthetics on mitochondria mimics the effects of hypoxia, the implications of which are discussed in this thesis. Two novel TASK blocking agents A1899 and PK-THPP were able to decrease glomus cell TASK channel activity, even in the presence of a clinically relevant concentration of isoflurane. These agents may be promising as future respiratory stimulants.

No description available.

Background: Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterised by histological evidence of parenchymal extracellular matrix (ECM) accumulation (fibrosis) and allograft vasculopathy. The aim of this study was to compare the effects of rapamycin and cyclosporin therapy, individually as well as in combination, on fibrosis associated gene expression and ECM remodeling in an experimental model of allograft vasculopathy. Methods: Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerised histomorphometry of F344 to Lewis rat aortic allograft sections harvested at serial time points. Expression of fibrosis associated genes was studied by means of semi-quantitative RT-PCR. Results: Rapamycin (0.5mg/kg/day) or cyclosporin (5mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intra-graft gelatinase, collagen III and TIMP 1 mRNA levels. At a lower dose (0.25mg/kg/day) Rapamycin inhibited intimal hyperplasia and medial ECM accumulation however there was a lesser effect on vascular remodeling compared to cyclosporin or rapamycin 0.5mg/kg/day. Combined rapamycin and cyclosporin also inhibited intimal hyperplasia however there was a lesser effect on both vascular remodeling and medial extracellular matrix accumulation. Combined treatment or rapamycin 0.25mg/kg/day monotherapy aortic allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intra-graft MMP 9, TGFp and TIMP 1 mRNA than cyclosporin or rapamycin 0.5mg/kg/day monotherapy. Conclusion: These data suggest that in addition to the tissue response to injury, the alloimmune injury itself may directly contribute to vascular and ECM remodeling. In this experimental model rapamycin inhibited vascular remodeling and ECM accumulation only in the presence of effective immunosuppression.

No description available.

Antipronation foot orthosis are commonly used by health care professionals to treat a variety of lower limb conditions thought to be caused by excessive foot pronation. However, despite their widespread use, laboratory based research indicates that antipronation foot orthosis cause variable joint moment/motion biomechanical responses. If a specific biomechanical response is required to treat a specific clinical condition, it follows that practitioners cannot tailor foot orthosis confidently to alleviate symptoms thought to be associated with excessive pronation. A conceptual framework representing a biomechanical system of foot function was proposed to explain how external forces, foot structure, and neuromuscular factors cause these variable joint moment/motion responses to foot orthosis. Two studies (study 1 & study 2) sought to understand how external forces influenced joint moment/motion responses. Study 1 examined if systematic changes in external forces created by varying APFO geometry correlate to changes in joint moment/motion responses. To answer this research question a pilot study (n = 11) developed suitable increments in anti-pronation orthotic geometry that could systematically alter external forces under the plantar foot. The main study (n = 20) demonstrated that varying orthotic arch geometry and medial heel wedge geometry could systematically alter external forces (measured as peak pressure and centre of pressure) and joint moment/motion responses in foot structures. However, study 1 showed that changes in external forces created by varying APFO geometry are generally not strongly correlated (r < 0.6) to changes in joint moment/motion responses thus indicating that other factors (e.g. structural/neuromuscular) influence biomechanical responses to foot orthoses. On the basis that forces applied to the sole of the foot pass through plantar soft tissues prior to being applied to bones of a joint to affect moments and kinematics, study 2 characterised how soft tissue respond to change in external forces due to change in orthotic geometry. A pilot study (n = 10) developed a reliable method that could be used to quantify soft tissue thickness between the surface of an orthosis and bones overlying the medial arch. The results for the main study (n = 27) found that antipronation orthosis systematically compressed soft tissue structures under the plantar foot. The studies reported in this thesis show that antipronation orthosis can be tailored to systematically alter tissue compression, external forces and joint moment/motion responses. However, systematically altering external forces under the plantar foot with antipronation foot orthosis is not strongly correlated with changes in joint moment/motion responses. This suggests moment/motion responses are strongly influenced by structural features and/or neuromuscular action in combination with external forces. The work presented in this thesis offers a foundation for future studies seeking to understand how foot orthoses alters foot biomechanics.

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This thesis explores what is experienced as difficult, and potentially threshold, concepts in prosthetics. Prosthetics and orthotics education is an under-researched area and this research assists in filling this gap. Consideration is given to the reasons why students have difficulties in learning certain concepts. Attention is also given to why every student does not experience the same concepts as difficult, another under-researched area. Using Interpretative Phenomenological Analysis as both methodology and data analyisis method, with interviews and questionnaires with staff and students for data collection, five difficult concepts were identified in prosthetics. Two concepts are suggested as troublesome but not threshold and three suggested as threshold concepts. Curriculum design is suggested as an additional form of troublesome knowledge affecting students’ engagement with, and their perception of the relevance of a concept to their discipline. Tacit troublesome knowledge is much broader than the episteme of a discipline including mental images, memories, and shortcuts taken by experts. The variation in what is found difficult and by whom is suggested as being due to differences in the prior experience of students. In order to differentiate threshold concepts from other concepts it is suggested that they require both integration and ontological transformation together with procedural concepts and associated contextualised memories, and disciplinary concepts. Several implications for practice are suggested. Curriculum design should be considered, especially for supporting concepts, with learning experiences contextually appropriate for the students’ discipline, an important consideration for multi-disciplinary modules. Due to differences in prior experience, learning activities should be created which both enable students to get to the starting point for the acquisition of, and then further develop their understanding of the threshold concept. Finally further research into threshold concepts should consider a whole programme approach including both staff and students.

No description available.

Anaesthesia is a reversible pharmacological state of the patient where hypnosis, analgesia and muscle relaxation are guaranteed and maintained throughout the surgery. Analgesics block the sensation of pain; hypnotics produce unconsciousness, while muscle relaxants prevent unwanted movement of muscle tone. Controlling the depth of anaesthesia is a very challenging task, as one has to deal with nonlinearity, inter- and intra-patient variability, multivariable characteristics, variable time delays, dynamics dependent on the hypnotic agent, model analysis variability, agent and stability issues. The modelling and automatic control of anaesthesia is believed to (i) benefit the safety of the patient undergoing surgery as side-effects may be reduced by optimizing the drug infusion rates, and (ii) support anaesthetists during critical situations by automating the drug delivery systems. In this work we have developed several advanced explicit/multi-parametric model predictive (mp-MPC) control strategies for the control of depth of anaesthesia. State estimation techniques are developed and used simultaneously with mp-MPC strategies to estimate the state of each individual patient, in an attempt to overcome the challenges of inter- and intra- patient variability, and deal with possible unmeasurable noisy outputs. Strategies to deal with the nonlinearity have been also developed including local linearization, exact linearization as well as a piece-wise linearization of the Hill curve leading to a hybrid formulation of the patient model and thereby the development of multiparametric hybrid model predictive control methodology. To deal with the inter- and intra- patient variability, as well as the noise on the process output, several robust techniques and a multiparametric moving horizon estimation technique have been design and implemented. All the studies described in the thesis are performed on clinical data for a set of 12 patients who underwent general anaesthesia.

Over the past century, abdominal surgery has seen a rapid transition from open procedures to less invasive methods such as laparoscopy and robot-assisted minimally invasive surgery (R-A MIS). These procedures have significantly decreased blood loss, postoperative morbidity and length of hospital stay in comparison with open surgery. R-A MIS has offered refined accuracy and more ergonomic instruments for surgeons, further minimising trauma to the patient. This thesis aims to investigate, design and prototype a novel system for R-A MIS that will provide more natural and intuitive manipulation of soft tissues and, at the same time, increase the surgeon's dexterity. The thesis reviews related work on surgical systems and discusses the requirements for designing surgical instrumentation. From the background research conducted in this thesis, it is clear that training surgeons in MIS procedures is becoming increasingly long and arduous. Furthermore, most available systems adopt a design similar to conventional laparoscopic instruments or focus on different techniques with debatable benefits. The system proposed in this thesis not only aims to reduce the training time for surgeons but also to improve the ergonomics of the procedure. In order to achieve this, a survey was conducted among surgeons, regarding their opinions on surgical training, surgical systems, how satisfied they are with them and how easy they are to use. A concept for MIS robotic instrumentation was then developed and a series of focus group meetings with surgeons were run to discuss it. The proposed system, named microAngelo, is an anthropomorphic master-slave system that comprises a three-digit miniature hand that can be controlled using the master, a three-digit sensory exoskeleton. While multi-fingered robotic hands have been developed for decades, none have been used for surgical operations. As the system has a human centred design, its relation to the human hand is discussed. Prototypes of both the master and the slave have been developed and their design and mechanisms is demonstrated. The accuracy and repeatability of the master as well as the accuracy and force capabilities of the slave are tested and discussed.