Bibliography: leaves 160-171. / xii, 171 leaves, [9] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Evaluates the effect of an anterior surgical approach and antero-lateral inter-body fusion of the cervical spine on spinal cord blood flow and electrical function using a sheep model. / Thesis (M.D.)--University of Adelaide, Dept. of Orthopaedic Surgery & Trauma, 1993?

<p>The gastric mucosa is frequently exposed to endogenously secreted hydrochloric acid of high acidity. Gastric mucosal defense mechanisms are arranged at different levels of the gastric mucosa and must work in unison to maintain its integrity. </p><p>In this thesis, several mechanisms underlying gastric mucosal resistance to strong acid were investigated in anesthetized rats and mice. The main findings were as follows:</p><p>Only when acid secretion occurred did the pH gradient in the mucus gel withstand back-diffusion of luminal acid (100 mM or 155 mM HCl), and keep the juxtamucosal pH (pH_jm) neutral. Thus, when no acid secretion occurred and the luminal pH was 0.8-1, the pH gradient was destroyed. </p><p>Bicarbonate ions, produced concomitant with hydrogen ions in the parietal cells during acid secretion and blood-borne to the surface epithelium, were carried transepithelially through a DIDS-sensitive transport. </p><p>Prostaglandin-dependent bicarbonate secretion seemed to be less important in maintaining a neutral pH_jm. </p><p>Removal of the loosely adherent mucus layer did not influence the maintenance of the pH_jm. Hence, only the firmly adherent mucus gel layer, approximately 80µm thick, seemed to be important for the pH_jm. </p><p>Staining of the mucus gel with a pH-sensitive dye revealed that secreted acid penetrated the mucus gel from the crypt openings toward the gastric lumen only in restricted paths (channels). One crypt opening was attached to one channel, and the channel was irreversibly formed during acid secretion. </p><p>Gastric mucosal blood flow increased on application of strong luminal acid (155 mM HCl). This acid-induced hyperemia involved the inducible but not the neural isoform of nitric oxide synthase. These results suggest a novel role for iNOS in gastric mucosal protection and indicate that iNOS is constitutively expressed in the gastric mucosa. </p><p>It is concluded that a pH gradient in the gastric mucus gel can be maintained during ongoing acid secretion, since the acid penetrates the mucus only in restricted channels and bicarbonate is carried from the blood to the lumen via a DIDS-sensitive transporter.</p>

<p>Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury.</p><p>Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure.</p><p>Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion.</p><p>The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed.</p><p>In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved <i>during</i> CPR, whereas a significant increase was recorded <i>after</i> ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC.</p><p>Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF_2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF_2α, and the prostaglandin 15-K-DH-PGF_2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.</p>

<p>Type 1 diabetes mellitus affects millions of people worldwide. Islet transplantation is a minimal invasive surgical procedure that restores euglycemia and halts the progression of diabetic complications. However, despite transplantation of islets from multiple donors most patients reverse to hyperglycemia within five years. New strategies to improve long-term outcome of islet transplantation are indispensable. This thesis studied differences in the microvasculature between endogenous and transplanted pancreatic islets, and investigated means to improve islet graft revascularization and function. Islet graft microvessels were similar to endogenous islets responsive to adenosine, angiotensin II and nitric oxide (NO). Recipient hyperglycemia induced a higher basal islet graft blood flow, which also was less dependent on NO than in normoglycemic recipients. Transplantation of freshly isolated instead of cultured islets improved graft revascularization, oxygenation and function. Pretreatment of islets with vascular endothelial growth factor decreased their expression of matrix metalloproteinase-9 (MMP-9) and impaired graft revascularization. Moreover, MMP-9 pretreatment <i>per se</i> improved graft revascularization. <i>In vivo</i>, 20-25% of all endogenous rat islets was low oxygenated (pO₂ <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Interestingly, oxygenation was related to metabolism, since well oxygenated islets <i>in vivo</i> had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. In intraportally transplanted islets, the low oxygenated fraction of islets was markedly increased one day post-transplantation, and the oxygenation remained low following revascularization. In summary, these data suggest that a better revascularization of transplanted islets can improve graft function. Furthermore, the oxygenation and metabolism of endogenous islets is tightly regulated. This regulation seems to be disturbed following transplantation, which may contribute to long-term islet graft failure. </p>

Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury. Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure. Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion. The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed. In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved during CPR, whereas a significant increase was recorded after ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC. Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF2α, and the prostaglandin 15-K-DH-PGF2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.

The gastric mucosa is frequently exposed to endogenously secreted hydrochloric acid of high acidity. Gastric mucosal defense mechanisms are arranged at different levels of the gastric mucosa and must work in unison to maintain its integrity. In this thesis, several mechanisms underlying gastric mucosal resistance to strong acid were investigated in anesthetized rats and mice. The main findings were as follows: Only when acid secretion occurred did the pH gradient in the mucus gel withstand back-diffusion of luminal acid (100 mM or 155 mM HCl), and keep the juxtamucosal pH (pHjm) neutral. Thus, when no acid secretion occurred and the luminal pH was 0.8-1, the pH gradient was destroyed. Bicarbonate ions, produced concomitant with hydrogen ions in the parietal cells during acid secretion and blood-borne to the surface epithelium, were carried transepithelially through a DIDS-sensitive transport. Prostaglandin-dependent bicarbonate secretion seemed to be less important in maintaining a neutral pHjm. Removal of the loosely adherent mucus layer did not influence the maintenance of the pHjm. Hence, only the firmly adherent mucus gel layer, approximately 80µm thick, seemed to be important for the pHjm. Staining of the mucus gel with a pH-sensitive dye revealed that secreted acid penetrated the mucus gel from the crypt openings toward the gastric lumen only in restricted paths (channels). One crypt opening was attached to one channel, and the channel was irreversibly formed during acid secretion. Gastric mucosal blood flow increased on application of strong luminal acid (155 mM HCl). This acid-induced hyperemia involved the inducible but not the neural isoform of nitric oxide synthase. These results suggest a novel role for iNOS in gastric mucosal protection and indicate that iNOS is constitutively expressed in the gastric mucosa. It is concluded that a pH gradient in the gastric mucus gel can be maintained during ongoing acid secretion, since the acid penetrates the mucus only in restricted channels and bicarbonate is carried from the blood to the lumen via a DIDS-sensitive transporter.

Type 1 diabetes mellitus affects millions of people worldwide. Islet transplantation is a minimal invasive surgical procedure that restores euglycemia and halts the progression of diabetic complications. However, despite transplantation of islets from multiple donors most patients reverse to hyperglycemia within five years. New strategies to improve long-term outcome of islet transplantation are indispensable. This thesis studied differences in the microvasculature between endogenous and transplanted pancreatic islets, and investigated means to improve islet graft revascularization and function. Islet graft microvessels were similar to endogenous islets responsive to adenosine, angiotensin II and nitric oxide (NO). Recipient hyperglycemia induced a higher basal islet graft blood flow, which also was less dependent on NO than in normoglycemic recipients. Transplantation of freshly isolated instead of cultured islets improved graft revascularization, oxygenation and function. Pretreatment of islets with vascular endothelial growth factor decreased their expression of matrix metalloproteinase-9 (MMP-9) and impaired graft revascularization. Moreover, MMP-9 pretreatment per se improved graft revascularization. In vivo, 20-25% of all endogenous rat islets was low oxygenated (pO2 &lt;10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Interestingly, oxygenation was related to metabolism, since well oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. In intraportally transplanted islets, the low oxygenated fraction of islets was markedly increased one day post-transplantation, and the oxygenation remained low following revascularization. In summary, these data suggest that a better revascularization of transplanted islets can improve graft function. Furthermore, the oxygenation and metabolism of endogenous islets is tightly regulated. This regulation seems to be disturbed following transplantation, which may contribute to long-term islet graft failure.

Chronic muscle pain is a significant medical and social problem and better understanding of the pathophysiological mechanisms involved is an important requirement for further development of diagnostics, treatment and rehabilitation methods. Experimental imaging studies have investigated functional neuroanatomy of different pain components. However, several aspects of brain mechanisms underlying brain processing of muscle pain remain unclear. The general goal of the present thesis was to study functional brain anatomy of systems underlying perception of muscle pain, processing of proprioceptive information and maintenance of fatiguing muscle contractions with an emphasize on their possible interrelations. Four series of experiment were carried out. Using an injection of hypertonic saline (HS) into the m. triceps to induce pain comparable with clinical muscle pain a significant activation of insula and putamen as well as decrease of activity in the temporal and occipital cortex in comparison with control stimulation were revealed. An advanced model of prolonged muscle pain were provided by the infusion of the HS during 20 minutes into m. erector spinae A complex dynamics of brain activity during the habituation to nociceptive stimulation was shown: initial activation of insula changed to decrease of activity in this and several other cortical areas. A conjunction analysis identified activations jointly significant in both experiments (despite localization of HS nociceptive stimulation) in the right insula, occipital and left parietal cortical areas. The study of brain activity in response to different modalities of prorioceptive inputs – passive movements, kinesthetic illusions and muscle vibration showed corresponding different patterns of activation in motor and somatosenory areas and temporal areas. Finally, the study of sustained isometric muscle contractions of various force levels and durations revealed that muscle fatigue is associated with contralateral activation of the motor and somatosensory areas and temporal areas and bilateral activation in the supplementary motor areas and cingular cortex, indicating that increased efforts needed to maintain required force and its eventual breakdown with fatigue might induce activation of additional cortical areas. Analysis of data obtained in all experimental series revealed that insula, secondary somatosensory and auditory areas are activated during both perception of muscle pain and processing of somatosensory afferentation. In conclusion, this thesis has elucidated brain processing of muscle pain showing distributed, bilateral patterns comprised of activated structures predominantly attributed to the medial pain system and deactivated structures. Furthermore, initial and late phases of tonic muscle pain are associated with different brain reactions, namely initial activation of the insula followed by a significant bilateral decrease of activity at the late stage. Area of brain cortex located near lateral sulcus and comprised of secondary somatosensory cortex, posterior part of the insula and adjacent auditory cortex is engaged in the perception of muscle pain and processing of somatosensory afferentation as well as maintenance of fatiguing muscle contractions.

No description available.

<p>Research using mice and rats has gained interest because they are robust test beds for clinical drug development and are used to elucidate disease etiologies. Blood vessel visualization and blood flow measurements are important anatomic and physiologic indicators to drug/disease stimuli or genetic modification. Cardio-pulmonary blood flow is an important indicator of heart and lung performance. Small animal functional imaging provides a way to measure physiologic changes minimally-invasively while the animal is alive, thereby allowing for multiple measurements in the same animal with little physiologic perturbation. Current methods of measuring cardio-pulmonary blood flow suffer from some or all of these limitations-they produce relative measurements, are limited to global or whole animal or organ regions, do not provide vasculature visualization, limited to a few or singular samples per animal, are not able to measure acute changes, or are very invasive or requires animal sacrifice. The focus of this work was the development of a small animal x-ray imaging system capable of minimally invasive real-time, high resolution vascular visualization, and cardio-pulmonary blood flow measurements in the live animal. The x-ray technique used was digital subtraction angiography (DSA). This technique is a particularly appealing approach because it is easy to use, can capture rapid physiological changes on a heart beat-to-beat basis, and provides anatomical and functional vasculature information. This DSA system is special because it was designed and implemented from the ground up to be optimized for small animal imaging and functional measurements. This system can perform: 1) minimally invasive in vivo blood flow measurements, 2) multiple measurements in the same animal in a rapid succession (every 30 seconds-a substantial improvement over singular measurements that require minutes to acquire by the Fick method), 3) very high resolution (up to 46 micron) vascular visualization, 4) quantitative blood flow measurements in absolute metrics (mL/min instead of arbitrary units or velocity) and relative blood volume dynamics from discrete ROIs, and 5) relative mean transit time dynamics on a pixel-by-pixel basis (100 µm x 100 µm). The end results are 1) anatomical vessel time course images showing the contrast agent flowing through the vasculature, 2) blood flow information of the live rat cardio-pulmonary system in absolute units and relative blood volume information at discrete ROIs of enhanced blood vessels, and 3) colormaps of relative transit time dynamics. This small animal optimized imaging system can be a useful tool in future studies to measure drug or disease modulated blood flow dynamics in the small animal.</p> / Dissertation