The kidneys are amazingly versatile organs that perform a wide range of vital bodily functions. This thesis provides an analysis into a range of mathematical models of the tubuloglomerular feedback (TGF) mechanism. The TGF mechanism is an autoregulatory mechanism unique to the kidney that maintains approximately constant blood flow to the organ despite wide fluctuations in pressure. Oscillations in pressure, flow, and sodium chloride concentration have been attributed to the action of the TGF mechanism through a number of experimental studies. These oscillations appear spontaneously or in response to a natural or artificial pressure step or microperfusion. The reason for sustained oscillatory behaviour in nephrons is not immediately clear. Significant research has gone into experimentally determining the signal to the TGF mechanism, but the physiological significance is not mentioned in the literature. Considerable modelling of the oscillations attributed to the TGF mechanism has also been undertaken. However, this modelling uses models that are inherently oscillatory, such as a second-order differential equation or delay differential equations. While these models can be fitted to closely approximate the experimental results they do not address the physiological factors that contribute to sustained oscillations. This thesis aims to determine the contributing factors to the sustained oscillations. By understanding these factors a better hypothesis of the physiological role of the oscillations should be possible. Chapter 3 presents a mathematical model by Holstein-Rathlou and Marsh [28] that uses a partial differential equation (PDE) model for the tubule and a second-order differential equation for the TGF feedback. The remainder of this chapter shows that oscillations occur without an inherently oscillatory second-order differential equation due to the delays in the system. Tubular compliance was also shown to be necessary for sustained oscillations. Sustained oscillations were not exhibited in the TGF model with a noncompliant tubule. Although damped oscillations were exhibited for a wide range of parameter space. Adding compliance to the tubule increased the delay around the loop of Henle. This additional delay elicited sustained oscillations. The computationally expensive PDE model of 3 was simplified to an ordinary differential equation (ODE) model in Chapter 4 by assuming a spatial profile. This model exhibits much of the same qualitative behaviour as the PDE model including sustained oscillations for similar ranges of parameter space. Compliance was also found to be important in the generation of sustained oscillations in agreement with the PDE tubule model. This model is less computationally expensive than the PDE model and allows analysis that was unfeasible with the PDE model. Significant natural and artificial blood pressure fluctuation occur in experimental rat models. Chapter 5 examines the effect of inlet pressure forcing on a nonoscillatory and an oscillatory model. The inherently nonoscillatory noncompliant model becomes oscillatory with a physiologically realistic pressure forcing. The oscillatory compliant model remains oscillatory with the addition of a inlet pressure forcing. Pressure fluctuations were hypothesised to contribute to sustained oscillations and could be validated experimentally. Two extensions to the single nephron TGF models are presented in Chapter 6. A realistic juxtaglomerular delay is added to the single nephron models with both the ODE and PDE tubular models. Physiologically realistic juxtaglomerular delays induce sustained oscillations in the otherwise nonoscillatory noncompliant models. The remainder of this chapter presents a different model for a variable interstitial sodium chloride concentration profile. This model demonstrates experimentally observed function of the countercurrent mechanism by which a concentration gradient is set up and maintained in the interstitium. Two single nephron models with ODE tubular models are coupled in Chapter 7. The coupling is modelled through the effect on the resistance of their neighbouring nephron's afferent arteriole resistance. The coupled nephron model exhibits entrainment as observed experimentally. Inhibiting the oscillation in one nephron reduces the amplitude of the oscillation in its neighbour. This result compares well with experiments where the TGF mechanism in one nephron is blocked by the administration of furosemide.

Detta examensarbete är utfört hos Swisslog under våren 2013. De hade problem med den manuella styrningen av deras pallstaplingskran för höglager, som upplevdes ryckig och svår att kontrollera vid låga hastigheter. Huvudsyftet var att undersöka varför detta fenomen uppstod och hur det kunde lösas med både hård- och mjukvarumässiga metoder. Utöver detta undersöktes hur produktionskostnaden, för delarna av kranen som rör den manuella styrningen, kunde reduceras. Det upplevda fenomenet är känt som biodynamic feedthrough. Det innebär att konstruktionens acceleration matas genom operatörens kropp och skapar en återkoppling till styrdonet, i detta fall en joystick. Operatörens hand ger en oavsiktlig störsignal som gör systemet instabilt som i sin tur skapar en oscillation som ökar i amplitud och är svår eller omöjlig att stoppa. Den föreslagna lösningen är att digitalt lågpassfiltrera styrsignalen från joysticken. Det dämpar de skarpaste spikarna i signalen och förhindrar systemet att ta in de snabba handrörelser som kranens acceleration har skapat. / This bachelor thesis was written at Swisslog, who had a problem with the manual control of their high-bay pallet stacker crane. The ride was perceived rough and hard to control at lower speeds.    The main purpose was to examine the source of the phenomenon and how to solve the problem with both software and hardware. It was also requested to investigate ways to lower production costs of the parts of the crane related to the manual control.   The experienced phenomenon is known as biodynamic feedthrough. It refers to the acceleration of the structure affects the body of the operator causing a feedback loop to the input, in this case a joystick. The hand of the operator causes an involuntary control input and making the system unstable and causing an oscillation increasing in amplitude over time. This may be hard or impossible to stop.   The proposed solution is a low-pass filter applied at the output of the joystick. This attenuates the sharpest spikes from the joystick control signal and prevents the system from receiving the fast hand movements caused by the acceleration of the crane.

There is no abstract available for this thesis. / Department of Physics and Astronomy

Decisions, such as choosing between different rewards, are known to be influenced by a number of variables such as value, uncertainty and delay associated with a rewarding outcome. Various structures in the brain are responsible for handling different aspects of reward related decision making. To understand how such decisions are made, we can attempt to reverse engineer the brain. This involves understanding how brain activity is related to the representation and processing of rewards and also to subsequent behavior in response to rewarding events. One of the central elements of the reward circuitry of the brain is the ventral striatum. It has traditionally been known as the limbic-motor interface and thought to act as a link between various structures in the brain that are responsible for processing reward and reward related behavior. To study the neural processes that underlie processing rewards, I recorded from the ventral striatum of rats as they performed a cue-reward task. The aim of my project was twofold: First, to examine how rats behave in response to changes in value and uncertainty associated with a particular rewarding outcome and second, to investigate how rewards and cues that predict rewards are represented in the neural activity of the ventral striatum. Rats (n=6) were trained on a cue-reward task, where cues indicated the mean or variance of associated outcome distributions. Behavioral responses to the reward predictive cues demonstrated that the rats learned the value and risk associated with subsequent reward outcomes. Ventral striatal gamma oscillations are known to align to rewards in a variety of reward motivated tasks. However, it is not clear if these oscillations are associated with anticipation of obtaining the reward or the reward itself. In previous studies, reward delivery has been correlated with the anticipation of reward. In the current work, a delay is used to distinguish between anticipation of reward and the reward delivery itself. This is achieved by making the rats nose poke for a fixed time interval before the arrival of reward. The analysis presented in this thesis reveals that ventral striatal gamma oscillations occur both during the anticipation and delivery of reward, opening up the possibility of formal tests. They also align to arrival of cues that predict rewarding outcomes. This suggests that gamma oscillations might be essential for modulating behavior in response to cues and rewards both before and after reward delivery. Ventral striatum is ideally situated to modulate behavior in response to rewarding events. Past studies show that ventral striatal neural activity is associated with reward and reward motivated actions. However, as suggested by the research presented in this thesis, it is not clear what specific aspects of the decision making process can be attributed to the ventral striatum once learning in complete. Studying the ventral striatum is important because its malfunctioning is implicated in brain disorders such as drug addiction.

Perinatal asphyxia is a significant contributor to neonatal brain injury. In the clinical environment there is variability in the severity of neural injury in neonates with similar clinical histories. Whilst the duration and intensity of hypoxia is well known to influence the severity of neurological outcome, the global physiological responses to hypoxia may also affect the subsequent variability in neurological outcome. The first step in this project was to identify which physiological response/s during a constant global hypoxic-ischemic insult influence the severity of neurological outcome in the newborn piglet and to assess the relative importance of these responses. Hypoxia/hypercapnia was induced in anaesthetized piglets by reducing the fraction of inspired oxygen to 0.1 (10%) and the ventilation rate from 30-10 breaths per minute for 45 minutes. Neurological outcome was determined by using functional markers including aEEG amplitude and cerebral impedance, and the structural marker microtubule associated protein-2 immunohistochemistry at 6 hours post hypoxia. The results from the initial study indicated that there was significant variability in neurological outcome following a constant hypoxia/hypercapnia insult. Serum cortisol concentrations were highly variable at the end of hypoxia (mean ± SD; 240.7 ± 90.9 nmol/L) and associated with cardiovascular function (time heart rate below baseline; r = 0.69) and neurological outcome (r = 0.70). Cardiovascular function (time heart rate was below baseline) and neurological outcome were strongly associated (r = 0.77). In this study we observed an oscillating pattern in cardiovascular function during hypoxia in some animals. In the regression analysis variability in cortisol concentrations and cardiovascular function explained 68% of the variability in the severity of neurological outcome. Additional physiological factors did not improve the strength of the association with neurological outcome. The variability in the physiological responses, particularly cardiovascular and endocrine responses to hypoxia may be more important determinants of neurological outcome then previously recognised. Results from the initial study opened up several questions about the relationship between cortisol and cardiovascular function during hypoxia and the relationship to the subsequent neurological outcome. Since variability in cortisol concentrations was associated with both cardiovascular function and neurological outcome the second step of this thesis was to investigate what factors contributed to the variability in serum cortisol concentrations during hypoxia. It is important to understand why some individuals produce more cortisol than others, and as a result are protected against brain injury. The aim was to determine if the variability in serum cortisol concentrations was the result of variability in ACTH concentrations during acute global hypoxia. The results from this study showed that early changes in serum cortisol concentration (15 minutes) were not correlated with ACTH (R2 = 0.26, P = 0.1), however, later changes (30 – 45 minutes) were (R2 0.45 - 0.68). This suggests that the primary factor controlling serum cortisol concentrations before hypoxia and during later hypoxia is ACTH concentrations. These data suggest that other factors may control cortisol secretion during early hypoxia; a key mechanism responsible for these changes may be the activity of the sympathetic nervous system and the maturity of the adrenal medullae. Since, higher cortisol concentrations were associated with better cardiovascular function and neurological outcome. As a result of this observation the aim of this study was to determine if cortisol concentrations during hypoxia are the causative factor responsible for improved cardiovascular function and better neurological outcome. The results from this study showed that manipulating serum cortisol concentrations into high (<500nmol/l) and low (>50nmol/l) levels during hypoxia did not affect cardiovascular function (P = 0.68) or neurological outcome (P = 46). Within each group (low, high and control hypoxia group) there was significant variability in cardiovascular function during hypoxia, which was associated with neurological outcome. (r = -0.63, p = 0.01). This study showed that serum cortisol concentrations during hypoxia are not the causative factor impacting on improved cardiovascular function and neurological outcome. It is possible that factors affecting both cardiovascular function and cortisol production such as activity of the sympathetic nervous system, may be a possible mechanism behind the variability in neurological outcome and cardiovascular function. Additionally, this study showed that cortisol concentrations at 3 hours post hypoxia were associated with neurological outcome (r = -0.67, p = 0.01). The animals with poorer outcome may also be those with greater multi-organ damage and thus reduced ability to clear cortisol from the systemic circulation. In light of this finding it may be interesting to assess cortisol concentration in the human neonate at 3 hours post hypoxia and determine the relationship to neurological outcome. In the final study of this thesis the function of the cardiovascular system during hypoxia was investigated in more detail because of its strong association with neurological outcome (results observed in Chapter 2 and 4. Few researchers have reported on oscillations in cardiovascular function, particularly type-3 waves, during hypoxia in the neonate. The aim of this study was to determine the characteristics and occurrence of type-3 waves in the neonatal piglet and their relationship to neurological outcome following acute global hypoxia. The result showed that the development of type-3 waves in cardiovascular function occurred in 56% of animals. An oscillating pattern was significantly associated with better neurological outcome (p = 0.01) and a lower duration of hypotension during hypoxia (p = 0.02), and occurred more frequently in females (p = 0.024). The development of type-3 waves during acute global hypoxia is a key mechanism in promoting natural tolerance; and may be the result of greater activity, maturity or sensitivity of the sympathetic nervous system in females compared to males. This may explain the improved neurological outcome following hypoxia in the female neonate seen in the clinical setting.

Perinatal asphyxia is a significant contributor to neonatal brain injury. In the clinical environment there is variability in the severity of neural injury in neonates with similar clinical histories. Whilst the duration and intensity of hypoxia is well known to influence the severity of neurological outcome, the global physiological responses to hypoxia may also affect the subsequent variability in neurological outcome. The first step in this project was to identify which physiological response/s during a constant global hypoxic-ischemic insult influence the severity of neurological outcome in the newborn piglet and to assess the relative importance of these responses. Hypoxia/hypercapnia was induced in anaesthetized piglets by reducing the fraction of inspired oxygen to 0.1 (10%) and the ventilation rate from 30-10 breaths per minute for 45 minutes. Neurological outcome was determined by using functional markers including aEEG amplitude and cerebral impedance, and the structural marker microtubule associated protein-2 immunohistochemistry at 6 hours post hypoxia. The results from the initial study indicated that there was significant variability in neurological outcome following a constant hypoxia/hypercapnia insult. Serum cortisol concentrations were highly variable at the end of hypoxia (mean ± SD; 240.7 ± 90.9 nmol/L) and associated with cardiovascular function (time heart rate below baseline; r = 0.69) and neurological outcome (r = 0.70). Cardiovascular function (time heart rate was below baseline) and neurological outcome were strongly associated (r = 0.77). In this study we observed an oscillating pattern in cardiovascular function during hypoxia in some animals. In the regression analysis variability in cortisol concentrations and cardiovascular function explained 68% of the variability in the severity of neurological outcome. Additional physiological factors did not improve the strength of the association with neurological outcome. The variability in the physiological responses, particularly cardiovascular and endocrine responses to hypoxia may be more important determinants of neurological outcome then previously recognised. Results from the initial study opened up several questions about the relationship between cortisol and cardiovascular function during hypoxia and the relationship to the subsequent neurological outcome. Since variability in cortisol concentrations was associated with both cardiovascular function and neurological outcome the second step of this thesis was to investigate what factors contributed to the variability in serum cortisol concentrations during hypoxia. It is important to understand why some individuals produce more cortisol than others, and as a result are protected against brain injury. The aim was to determine if the variability in serum cortisol concentrations was the result of variability in ACTH concentrations during acute global hypoxia. The results from this study showed that early changes in serum cortisol concentration (15 minutes) were not correlated with ACTH (R2 = 0.26, P = 0.1), however, later changes (30 – 45 minutes) were (R2 0.45 - 0.68). This suggests that the primary factor controlling serum cortisol concentrations before hypoxia and during later hypoxia is ACTH concentrations. These data suggest that other factors may control cortisol secretion during early hypoxia; a key mechanism responsible for these changes may be the activity of the sympathetic nervous system and the maturity of the adrenal medullae. Since, higher cortisol concentrations were associated with better cardiovascular function and neurological outcome. As a result of this observation the aim of this study was to determine if cortisol concentrations during hypoxia are the causative factor responsible for improved cardiovascular function and better neurological outcome. The results from this study showed that manipulating serum cortisol concentrations into high (<500nmol/l) and low (>50nmol/l) levels during hypoxia did not affect cardiovascular function (P = 0.68) or neurological outcome (P = 46). Within each group (low, high and control hypoxia group) there was significant variability in cardiovascular function during hypoxia, which was associated with neurological outcome. (r = -0.63, p = 0.01). This study showed that serum cortisol concentrations during hypoxia are not the causative factor impacting on improved cardiovascular function and neurological outcome. It is possible that factors affecting both cardiovascular function and cortisol production such as activity of the sympathetic nervous system, may be a possible mechanism behind the variability in neurological outcome and cardiovascular function. Additionally, this study showed that cortisol concentrations at 3 hours post hypoxia were associated with neurological outcome (r = -0.67, p = 0.01). The animals with poorer outcome may also be those with greater multi-organ damage and thus reduced ability to clear cortisol from the systemic circulation. In light of this finding it may be interesting to assess cortisol concentration in the human neonate at 3 hours post hypoxia and determine the relationship to neurological outcome. In the final study of this thesis the function of the cardiovascular system during hypoxia was investigated in more detail because of its strong association with neurological outcome (results observed in Chapter 2 and 4. Few researchers have reported on oscillations in cardiovascular function, particularly type-3 waves, during hypoxia in the neonate. The aim of this study was to determine the characteristics and occurrence of type-3 waves in the neonatal piglet and their relationship to neurological outcome following acute global hypoxia. The result showed that the development of type-3 waves in cardiovascular function occurred in 56% of animals. An oscillating pattern was significantly associated with better neurological outcome (p = 0.01) and a lower duration of hypotension during hypoxia (p = 0.02), and occurred more frequently in females (p = 0.024). The development of type-3 waves during acute global hypoxia is a key mechanism in promoting natural tolerance; and may be the result of greater activity, maturity or sensitivity of the sympathetic nervous system in females compared to males. This may explain the improved neurological outcome following hypoxia in the female neonate seen in the clinical setting.

Thesis (Ph.D.)--Tufts University, 1992. / Submitted to the Dept. of Mechanical Engineering. Adviser: Vincent P. Manno. Includes bibliographical references (leaves 183-193). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph. D.)--University of Sydney, 2002. / Title from title screen (viewed Apr. 28, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Psychological Medicine, Faculty of Medicine. Includes bibliography. Also available in print form.

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: D.E. Winget. Vita. Includes bibliographical references. Also available from UMI.

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 11, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Carmen Chicone Vita. Includes bibliographical references.