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Heart transplantation has enjoyed a spectacular success over the past 25 years. Prior to 1980 less than 350 operations were carried out with an overall one year survival of less than 60%. In 1995 more than 3,000 transplants were performed with a one year survival of 83%. However, growth and improved survival have both plateaued over the last few years; the former because of the falling donor supply and the latter, in part, because of the use of less suitable donors in an effort to offset the problem of supply. Much attention has been focused on the drama of the surgery and the intricacies of immunological manipulation whilst little effort has been devoted to the area of donor management, despite the fact that primary graft failure is responsible for as many post transplant deaths as either infection or rejection. Optimum preservation of the donor heart has also provided a difficult challenge, such that, despite a considerable scientific effort little advance has been achieved to extend the 4 hour safe storage limit which has remained in place over the past 20 years. In this dissertation the problem has been approached by combining laboratory based preservation models with an objective regime of donor management. A sensitive isolated small animal working heart model was developed and used to characterise cardioplegic induction. Subsequently, the model was used to examine the interaction of oxygen content with the mode of delivery, during preservation. Finally, a number of representative solutions were combined with the most promising oxygen delivery method. These studies served to illustrate the utility of controlled laboratory studies and offer the prospect of more than doubling post storage function. The development of a rigorous donor management regime was also shown to be capable of reducing the variance in haemodynamic parameters by up to 44% whilst safely increasing the donor pool by approximately 30%. It is the contention of this thesis that the only prospect of improving the current impasse with the supply of donor hearts in sufficient quantity and of acceptable quality, is by the combination of appropriate laboratory models with controlled clinical trials.

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Neuroinflammation is a major driver of secondary brain cell death after ischaemic stroke, seizure activity and traumatic brain injury. In a model of excitotoxic neuroinflammation, striatal injection of a toxic dose of AMPA causes cell death in the striatum after 24 hours. Co-injection of AMPA with the pro-inflammatory cytokine interleukin-1β (IL-1β) leads to additional cortical cell death. Injected alone, IL-1β leads to little or no cell death. It is hypothesised that IL-1β may exacerbate cell death by interfering with blood flow coupling. In the first study, two-dimensional optical imaging spectroscopy was used to measure early changes in the haemodynamic response in the anaesthetised rat barrel cortex before and for 6 hours after injection of vehicle, AMPA, IL-1β, or AMPA+IL-1β. After injection of IL-1β, with or without AMPA, the oxygenated blood flow response to mechanical whisker stimulation approximately halved over the course of 6h. In the second study, to determine whether the IL-1β-dependent changes in blood flow response are reflected by altered cellular activity, local field potentials, multi-unit activity and local tissue oxygenation responses to whisker stimulation were recorded simultaneously from the active barrel before and up to 6h after injection. A similar reduction in the size of the oxygenation response was seen again in the IL-1β- and AMPA+IL-1β-treated groups. Importantly, the level of gamma frequency oscillations at stimulus onset decreased within the first hours after injection of AMPA+IL-1β or IL-1β, suggesting a disruption of the fast-spiking interneuron network in the barrel cortex. These findings, along with histological observations of IL-1β-dependent markers of neuroinflammation, suggest that IL-1β may exacerbate AMPA-induced excitotoxicity by potentiating seizure activity and decoupling the neurovascular response in the cortex.

For cardiac surgical patients, the immediate 2-hour recovery period is distinguished by potentially life-threatening haemodynamic instability. To ensure optimum patient outcomes, nurses of varying levels of experience must make rapid and accurate decisions in response to episodes of haemodynamic instability. Decision complexity, nurses’ characteristics, and environmental characteristics, have each been found to influence nurses' decision making in some form. However, the effect of the interplay between these influences on decision outcomes has not been investigated. The aim of the research reported in this thesis was to explore variability in critical care nurses' haemodynamic decision making as a function of interplay between haemodynamic decision complexity, nurses' experience, and specific environmental characteristics by applying a naturalistic decision making design. Thirty-eight nurses were observed recovering patients in the immediate 2-hour period after cardiac surgery. A follow-up semi-structured interview was conducted. A naturalistic decision making approach was used. An organising framework for the goals of therapy related to maintaining haemodynamic stability after cardiac surgery was developed to assist the observation and analysis of practice. The three goals of therapy were the optimisation of cardiovascular performance, the promotion of haemostasia, and the reestablishment of normothermia. The research was conducted in two phases. Phase One explored issues related to observation as method, and identified emergent themes. Phase Two incorporated findings of Phase 1, investigating the variability in nurses' haemodynamic decision making in relation to the three goals of therapy. The findings showed that patients had a high acuity after cardiac surgery and suffered numerous episodes of haemodynamic instability during the immediate 2-hour recovery period. The quality of nurses' decision making in relation to the three goals of therapy was influenced by the experience of the nurse and social interactions with colleagues. Experienced nurses demonstrated decision making that reflected the ability to recognise subtle changes in haemodynamic cues, integrate complex combinations of cues, and respond rapidly to instability. The quality of inexperienced nurses' decision making varied according to the level and form of decision support as well as the complexity of the task. When assistance was provided by nursing colleagues during the reception and recovery of patients, the characteristics of team decision making were observed. Team decision making in this context was categorised as either integrated or non integrated. Team decision making influenced nurses' emotions and actions and decision making practices. Findings revealed nurses' experience affected interactions with other team members and their perceptions of assuming responsibility for complex patients. Interplay between decision complexity, nurses' experience, and the environment in which decisions were made influenced the quality of nurses' decision making and created an environment of team decision making, which, in turn, influenced nurses' emotional responses and practice outcomes. The observed variability in haemodynamic decision making has implications for nurse education, nursing practice, and system processes regarding patient allocation and clinical supervision.

<p>Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients.</p><p>The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations.</p><p>The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment <i>per se</i>, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage.</p><p>The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO₂), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (α-tocopherol) or an aldose reductase inhibitor (AL-1576).</p><p>In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO₂ was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia.</p><p>In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.</p>

Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients. The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations. The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment per se, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage. The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO2), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (α-tocopherol) or an aldose reductase inhibitor (AL-1576). In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO2 was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia. In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.

In neuroscience and biomedical engineering fields, one of the most important issues nowadays is finding a relationship between different brain regions when it is stimulated. Connectivity is an important research area in neuroscience which tries to determine the relationship between different brain region when the brain is stimulated externally or internally. Three main type of connectivity are discussed in this field: Anatomical, Functional and Effective connectivity. Importance of effective connectivity is its ability to detect brain disorders in early stages. Some brain disorders are Schizophrenia, MS and Major Depression disease. Comparing the effective connectivity between a healthy and unhealthy brain will help to diagnose brain disorder. In this master study, two methods named Dynamic Causal Modeling (DCM) and Psychophysiological Interaction (PPI) are used to compare effective connectivity and neuronal activity between different regions of brain when there are three different stimulations. Since the neural activity is latent in fMRI data, there is a need to a model which is able to transfer data from neuronal level to a visible data like Blood-Oxygen level dependent (BOLD) signal. DCM uses a haemodynamic balloon model (HD) to represent this data transfer. The hemodynamic model must be so that the parameters of neural and BOLD signal be the same. It should be noted that what is looked for is not the BOLD signal but the neuronal activity. In this study, as the first step, we did preprocessing of MR images and after ROI`s are created using the program MARSBAR. Ten ROIs, which are thought to have connections between them are selected by considering the stimulations used in the experiments in obtaining the data used in this thesis. The data used contains fMRI images of 11 healthy subjects. Stimulations of experiment are applied to images got from group analysis of 11 healthy subjects. These Stimulations are then used in preparing the design matrix and the parameters related to DCM. These parameters are the values related to connection matrices defining bilinear dynamic model on ROI. Bayesian method is used to select best model between all these models. Another method of PPI is also applied to analyze effective connectivity between 10 ROIs. This method considers two issues of physiological and psychological effects. Like DCM, the preprocessing steps and ROI selection is done for PPI and hemodynamic model is designed for this method. Neural and hemodynamic responses of ROIs are compared using this method.

The diagnostic accuracy attained with the use of transbronchial fine needle aspiration biopsy, aspiration of bronchial secretion, bronchial washing, brush biopsy and forceps biopsy via a flexible fiberoptic bronchoscope was compared in patients with carcinoma of the lung. In endoscopic visible tumours the sensitivity of forceps biopsy was higher than that of the other methods. When forceps biopsy was combined with bronchial washing the overall diagnostic accuracy was significantly higher than that of any of the single methods, while no appreciable increase was obtained by adding additional methods. Selective brush biopsy from every segment bronchus has been established as a method in the search for occult bronchial carcinoma. The extent of respiratory mucosal damage and wound healing after brush biopsy was therefore studied in rabbits. Large differences in the extension and depth of the damage was observed. The basement membrane was often penetrated. Regeneration started during the first day after brush biopsy and a normal ciliated epithelium was restored within three weeks. To determine if the bronchoscope itself damaged the respiratory epithelium, bronchial mucosa was studied in the pig after examination with a flexible fiberoptic bronchoscope. The columnar epithelial cells were torn off in areas where the bronchoscope had rubbed against the airway wall but the basement membrane was not damaged. Since the function of the respiratory epithelium is to remove inhaled particles from the airways, mucociliary clearance was studied in man after fiberoptic bronchoscopy. The study suggests that the tracheobronchial clearance system has a large reserve for mechanical trauma. Mucociliary clearance can however be decreased after fiberoptic bronchoscopy in some patients. An increasing number of patients with impaired cardiopulmonary function are today subjected to examination with flexible fiberoptic broncoscopy. The haemodynamic effects of fiberoptic bronchoscopy performed under topical anaesthesia were therefore studied in patients with restrictive lung disease. The procedure induced marked haemodynamic changes during passage of the larynx and during suctioning. A slight fall in arterial oxygen tension was observed during bronchial suctioning and in the post-bronchoscopic period. Three of ten patients developed ST-T-segment changes during bronchial suctioning. / <p>S. 1-48: sammanfattning, s. 49-126: 5 uppsatser</p> / digitalisering@umu.se

No description available.