Acute kidney injury (AKI) is associated with renal medullary hypoxia. The medullary thick ascending limb (mTAL) in the renal outer medulla is most susceptible to hypoxic injury, due to marginal O2 supply and high O2 consumption. The objectives of this study were to document the earliest effect of hypoxia (8% O2 for 2.5 hrs) on the mTAL function, and to identify strategies to protect the mTAL from hypoxia. The earliest effect of hypoxia is large water diuresis, due to a fall in the medullary osmolality and increase in vasopressinase. Desmopressin acetate (dDAVP), a synthetic vasopressin analogue resistant to vasopressinase that may also increase O2 delivery, prevented water diuresis. A low dose (0.8mg/kg) of furosemide may significantly reduce the mTAL work without a large excretion of essential electrolytes. Large water diuresis may be diagnostically valuable in detecting renal tissue hypoxia, and dDAVP and furosemide may prevent AKI in the clinical setting.

Faculty of Science School of Physiology 9808215t romainh@physiology.wits.ac.za / There is a high prevalence of insulin and leptin resistance and increased cortisol concentrations in sleep apnoea patients, independent of obesity. Chronic intermittent hypoxia is used an experimental animal model to simulate the hypoxia occurring in sleep apnoea patients. The aim of this study was to measure plasma insulin and leptin concentrations and hypothalamic-pituitary-axis activity in rats exposed to either intermittent hypoxia (CIH) or sham hypoxia (SH) for fourteen days. To induce CIH plexiglass cylinders were flushed with 100% nitrogen for nine seconds every 90 seconds, seven hours/day. The rats were weighed each day during the exposure period. Venous blood samples for insulin and leptin were collected on days one, three, five, eight and fifteen. Faecal samples were collected to measure glucocorticoid metabolites. There was no significant difference in the daily change in body weight between the rats exposed to CIH compared to the rats exposed to SH (unpaired t-test). Plasma insulin concentrations were not affected by CIH. In both groups of rats plasma leptin concentrations were significantly higher on day fifteen compared to day five (p=0.03, unpaired t-test). Glucocorticoid metabolites were significantly increased in the intermittent hypoxia group on day two (p=0.003 one-way ANOVA). In conclusion, exposing normal weight rats to CIH for fourteen days resulted in a transient iv increase in HPA axis activity on day two and an elevation in plasma leptin levels, in both groups of rats, at day fifteen.

Intrapulmonary arteriovenous anastomoses (IPAVA) are vascular conduits through which blood flow bypasses the pulmonary circulation, and does not participate in pulmonary gas exchange. Blood flow through IPAVA (QIPAVA) is known to increase with increasing cardiac output, such as exercise, and while breathing normobaric, hypoxic gas at rest or during exercise. Previous studies demonstrate that QIPAVA is decreased at rest and during exercise in hypobaria compared to equivalent normobaric conditions. Studies involving postural changes have shown that QIPAVA may change with body position. In human studies, QIPAVA is measured either by transthoracic saline contrast echocardiography (TTSCE) or by injection of 99mTc-labeled macroaggregates of albumin (99mTc-MAA). It is unknown if discrepancies in measuring QIPAVA in normobaria and hypobaria, and in different body positions, represent real physiological changes or if they are methodological artifacts. In Chapter IV, the effect of hypobaria on QIPAVA was investigated. QIPAVA was reduced during exercise in hypobaria in normoxia and hypoxia compared to normobaric conditions, however gas exchange efficiency was unimpaired. This suggests that pulmonary blood flow may change in hypobaria such that blood flow is directed away from IPAVA. Alternatively, it may suggest that saline contrast is less stable at high altitude and not detected by TTSCE. In Chapter V, the effect of changing body position on QIPAVA as detected by TTSCE was investigated in human subjects at rest. No significant changes were observed in QIPAVA with postural changes. In Chapter VI, a perfusion model was used to investigate behavior of saline contrast microbubbles, MAA, and microspheres (20 µm and 50 µm diameter) encountering a vertical bifurcation. The results indicated that microbubbles and 20 µm microspheres tend to enter the upper branch of the bifurcation, whereas MAA and 50 µm microspheres tend to enter the lower branch. In Chapter VII, the effect of atmospheric pressure on the initial microbubble radius (Ro) of agitated saline contrast microbubbles was investigated. The results of this study demonstrated that the Ro of microbubbles created at sea level pressure was significantly smaller than Ro of microbubbles created at higher altitudes (1,668 m and 5,260 m). / 2019-01-09

The existence of a patent foramen ovale (PFO) has been known about for nearly 2,000 years. The prevalence of a PFO has been shown to be 25-40% in the general population. Despite the fact that blood flowing through a PFO acts as a shunt, there has been little research looking at the effect a PFO has on physiology in otherwise healthy humans. In Chapter IV, the effect of a PFO on core temperature (Tcore) prior to, and during exercise, was investigated. The design of this experiment included appropriate controls for a thermoregulatory study (i.e. measuring at same time of day, appropriate hydration and food intake, etc.). Results from this study indicate that subjects with a PFO (PFO+) have a Tcore that is ~0.4°C higher at rest and during exercise than subjects without a PFO (PFO–). Additionally, this study showed that PFO– subjects do not increase Tcore to the same extent breathing cold air as they do breathing ambient air during a 10-minute exercise bout, whereas there was no difference in Tcore increase between these two conditions for PFO+ subjects. These findings suggest that the difference in Tcore between PFO+ and PFO– subjects is potentially due to differences in respiratory heat loss. The studies for Chapter V examined differences in thermoregulatory and ventilatory responses during hot water (40°C) and cold water (20°C) immersion. This study found that compared to PFO– subjects, PFO+ subjects 1) increase Tcore at the same rate during hot water immersion and 2) do not cool off as quickly during cold water immersion. Additionally, in subjects who reached a ventilatory threshold, PFO+ subjects had blunted ventilatory responses to increased Tcore compared to PFO– subjects. Finally, in Chapter VI it was shown that PFO+ subjects have blunted ventilatory responses during acute exposure to hyperoxic and normoxic hypercapnia. However, there were no differences in ventilatory responses between PFO+ and PFO– subjects during exposure to either isocapnic or poikilocapnic hypoxia. These findings suggest that PFO+ subjects have a blunted central chemoreflex. This dissertation contains previously, unpublished co-authored material.

Wang Chi Chiu. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 294-336). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

In response to low oxygen (hypoxia), cells have evolved sophisticated gene expression programmes for survival and adaption. How the chromatin state coordinates these changes remains largely unknown. Global histone methylation changes occur in response to hypoxia, however, temporal dynamics of histone methylation changes and how they correlate with hypoxia induced gene transcription changes is ill defined. The Jumonji C (Jmjc) histone demethylases are oxygen dependent enzymes and represent a potential link between chromatin structure and oxygen sensing. Many of these enzymes are differentially expressed in hypoxia and some have been found to influence the hypoxic response. Here, the JmjC histone demethylase, KDM2B, is found to be induced at the mRNA level but not at the protein level in response to hypoxia. KDM2B was also found to regulate the transcriptional response hypoxia, in a cell type dependent manner, through control of Hypoxia Inducible Factor (HIF) subunits, HIF 1 and 2α. These findings highlight complex HIF-KDM2B crosstalk involved in the cells response to low oxygen. Additionally, it was found that various histone methylation marks are induced in the early response to hypoxia prior to hypoxia induced gene transcription changes. This demonstrates that chromatin structural marks responds rapidly to changes in oxygen availability. Furthermore the methylation landscape of 2 two active transcription histone methylation marks, H3K4me3 and H3K36me3, were mapped by ChIP sequencing in the acute response to hypoxia. This analyses found specific changes in histone methylation, which correlate with the core gene transcription changes in hypoxia, pointing towards a mechanism by which rapid chromatin changes programs the cell for hypoxic transcription. Finally, KDM5A was identified to, at least in part, regulate early hypoxia H3K4me3 changes and changes in gene expression of a subset of hypoxia responsive genes. Findings described herein provide evidence for the role of chromatin structure dynamics, mediated by chromatin modifying enzymes, in regulating the hypoxic response. Specifically, early histone methylation changes elicited in acute hypoxia may help establish a chromatin landscape for the cell to transcriptionally respond, which is essential for survival and adaptation to hypoxia. Insights into chromatin dynamics in the response to hypoxia and the role played by JmjC histone demethylases in regulating the hypoxic response has the potential for new drug discovery in diseases such as cancer, were hypoxia, epigenetics and JmjC enzymes are often implicated in disease progression.

Adequate levels of dissolved oxygen (DO) are essential to the health of most aquatic organisms. While diel fluctuations in DO concentration are a normal occurrence in aquatic ecosystems, anthropogenically-produced periods of prolonged hypoxia have the potential to cause changes in growth, reproduction and behaviour in animals. My thesis examined reproductive behaviour and physiology of fathead minnows (Pimephales promelas) following exposure to several concentrations of dissolved oxygen. Using a custom-built system that was able to maintain DO concentrations at precise levels, reproductive performance was analyzed under 3.5 mg/l, 4.5 mg/l, 5.5 mg/l and a control of 7.5 mg/l of DO. A second experiment evaluated reproductive performance at 5.0, 5.7, 6.5 and 7.5(control) mg/L.<p> Breeding attempts ceased altogether at 4.5 mg/l and lower. At higher concentrations, the effects of DO on reproductive output were contradictory between experiments. When DO was maintained at 5.5 mg/L in the first experiment, egg production was lower than in the controls. When DO levels of 5.7 mg/L were used in the second experiment, egg production was higher than in the controls. Courtship behaviour decreased significantly compared to the control at DO levels of 4.5 mg/L and lower. No significant differences were observed between treatments in morphometrics, survival, larval deformities, sex steroid levels, vitellogenin levels, hatching success, egg size, fertility, or gonad histology.<p> The results of this study demonstrate that reproductive behaviour may represent a sensitive early marker of reproductive impairment in fathead minnows. Inconsistencies between the two experiments suggest a possible hormetic effect in response to depressed DO in fathead minnows. My results have important implications with respect to Canadian water quality guidelines and applications in the restoration of aquatic systems with lowered DO due to human activities.

Adequate levels of dissolved oxygen (DO) are essential to the health of most aquatic organisms. While diel fluctuations in DO concentration are a normal occurrence in aquatic ecosystems, anthropogenically-produced periods of prolonged hypoxia have the potential to cause changes in growth, reproduction and behaviour in animals. My thesis examined reproductive behaviour and physiology of fathead minnows (Pimephales promelas) following exposure to several concentrations of dissolved oxygen. Using a custom-built system that was able to maintain DO concentrations at precise levels, reproductive performance was analyzed under 3.5 mg/l, 4.5 mg/l, 5.5 mg/l and a control of 7.5 mg/l of DO. A second experiment evaluated reproductive performance at 5.0, 5.7, 6.5 and 7.5(control) mg/L.<p> Breeding attempts ceased altogether at 4.5 mg/l and lower. At higher concentrations, the effects of DO on reproductive output were contradictory between experiments. When DO was maintained at 5.5 mg/L in the first experiment, egg production was lower than in the controls. When DO levels of 5.7 mg/L were used in the second experiment, egg production was higher than in the controls. Courtship behaviour decreased significantly compared to the control at DO levels of 4.5 mg/L and lower. No significant differences were observed between treatments in morphometrics, survival, larval deformities, sex steroid levels, vitellogenin levels, hatching success, egg size, fertility, or gonad histology.<p> The results of this study demonstrate that reproductive behaviour may represent a sensitive early marker of reproductive impairment in fathead minnows. Inconsistencies between the two experiments suggest a possible hormetic effect in response to depressed DO in fathead minnows. My results have important implications with respect to Canadian water quality guidelines and applications in the restoration of aquatic systems with lowered DO due to human activities.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 3 uppsatser.

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