Recent evidence suggests that radiation may have a significant effect on tumour vascu lature in addition to damaging tumour cell DNA. It is well established that endothelial cells are among the first cells to respond after administration of ionizing radiation in both normal and tumour tissues. It has also been suggested that microvascular dysfunction may regulate tumour response to radiotherapy at high doses. However, due to limitations in imaging the microcirculation this response is not well characterized. Advances in high-frequency ultrasound and computation methods now make it possible to acquire and analyze 3-D ultrasound data of tumour blood flow in tumour micro-circulation. This thesis outlines the work done to test the hypothesis that single dose 8 Gy radio- therapy produces changes in tumour blood vessels which can be quantified using high- frequency power Doppler ultrasound. In addition, the issue of reproducibility of power Doppler measurements and the relationship between histopathology and power Doppler measurements have been examined.

We demonstrate here that ultrasound-stimulated microbubbles can lead to enhanced cell death within tumors when combined with radiation. The aim of this study was to investigate different ultrasound parameters in conjunction with different concentrations of microbubbles with regards to this effect. Prostate xenograft tumors in Severe Combined Immunodeficient mice were subjected to ultrasound treatment that involved various peak negative pressures (250 kPa, 570 kPa, and 750 kPa), microbubble concentrations (8 µL/kg, 80 µL/kg, and 1000 µL/kg), and different radiation doses (0 Gy, 2 Gy, and 8 Gy). Twenty-four hours after treatment, tumors were excised and assessed for cell death. Histological analyses demonstrated that increases in radiation dose, microbubble concentration, and ultrasound pressure promoted apoptotic cell death and cellular disruption within tumors. Comparable increases in ceramide, a cell death mediator, were identified using immunohistochemistry. We also demonstrate that clinically-utilized microbubble concentrations combined with ultrasound can induce an enhancement in cell death.

Recent evidence suggests that radiation may have a significant effect on tumour vascu lature in addition to damaging tumour cell DNA. It is well established that endothelial cells are among the first cells to respond after administration of ionizing radiation in both normal and tumour tissues. It has also been suggested that microvascular dysfunction may regulate tumour response to radiotherapy at high doses. However, due to limitations in imaging the microcirculation this response is not well characterized. Advances in high-frequency ultrasound and computation methods now make it possible to acquire and analyze 3-D ultrasound data of tumour blood flow in tumour micro-circulation. This thesis outlines the work done to test the hypothesis that single dose 8 Gy radio- therapy produces changes in tumour blood vessels which can be quantified using high- frequency power Doppler ultrasound. In addition, the issue of reproducibility of power Doppler measurements and the relationship between histopathology and power Doppler measurements have been examined.

We demonstrate here that ultrasound-stimulated microbubbles can lead to enhanced cell death within tumors when combined with radiation. The aim of this study was to investigate different ultrasound parameters in conjunction with different concentrations of microbubbles with regards to this effect. Prostate xenograft tumors in Severe Combined Immunodeficient mice were subjected to ultrasound treatment that involved various peak negative pressures (250 kPa, 570 kPa, and 750 kPa), microbubble concentrations (8 µL/kg, 80 µL/kg, and 1000 µL/kg), and different radiation doses (0 Gy, 2 Gy, and 8 Gy). Twenty-four hours after treatment, tumors were excised and assessed for cell death. Histological analyses demonstrated that increases in radiation dose, microbubble concentration, and ultrasound pressure promoted apoptotic cell death and cellular disruption within tumors. Comparable increases in ceramide, a cell death mediator, were identified using immunohistochemistry. We also demonstrate that clinically-utilized microbubble concentrations combined with ultrasound can induce an enhancement in cell death.

The use of transcranial Doppler (TCD) ultrasound for the assessment of cerebral blood flow velocity (CBFV) provides an indication of cerebral blood flow assuming the diameter of the insonated vessel remains constant. Studies using TCD have traditionally described cerebrovascular hemodynamics with respect to CBFV and cerebrovascular resistance (CVRi); however, a more complete assessment of the cerebral circulation can be gleaned from the analysis of within beat characteristic of the TCD velocity waveform for the determination of cerebrovascular tone. Therefore, the general purpose of the presented studies was to assess CBFV responses and within beat characteristic for the description of cerebrovascular hemodynamics after long duration spaceflight, with sustained orthostasis, in response to changes in the partial pressure of end tidal carbon dioxide (PETCO2), and with NG stimulation. After long duration spaceflight, cerebrovascular autoregulation was found to be impaired along with a reduction in cerebrovascular CO2 reactivity (Study 1). Additionally, critical closing pressure (CrCP) was found to be increased suggesting potential remodelling of the cerebrovasculature contributing to an increase in cerebrovascular tone (Study 2). With sustained orthostasis, CBFV was found to progressively decrease and to be related to reductions in PETCO2 and increases in CrCP suggesting the contribution of changes in cerebrovascular tone leading to the development of syncope (Study 4). The CBFV reduction with the progression towards syncope was also associated with changes in waveform morphology such that the dicrotic notch point was less than the end diastolic value (Study 3). Mathematical modelling (RCKL) was used to further assess changes in cerebrovascular hemodynamics for physiological interpretation of changes in CBFV waveform morphology and found that the amplitude of the dicrotic notch and the calculation of the augmentation index were both significantly related to vascular compliance before and after stimulation with NG (Study 5). The use of quantitative assessments of common carotid artery (CCA) blood flow as an indicator of cerebral blood flow suggested the dilation of the middle cerebral artery (MCA) with NG (Study 5 and 6) and changes in MCA diameter with acute alterations in PETCO2 (Study 6). CCA and MCA velocity wave morphology were assessed showing that with changes in PETCO2, changes in CBFV velocity wave were not reflected in the CCA trace (Study 7). In addition, further assessment of the CBFV velocity trace and the calculation of CrCP and the augmentation index suggested that with changes in PETCO2 cerebrovascular compliance and cerebrovascular tension, both thought to be components of cerebrovascular tone, change independently (Study 7). Combined, the results of the presented studies suggest that changes in cerebrovascular hemodynamics can be determined from alterations in the CBFV velocity waveform morphology. However, further work is required to determine how these variations relate to specific components of cerebrovascular tone, including alterations in cerebrovascular compliance and vascular tension, and how these variables change with acute and chronic alterations in cerebrovascular hemodynamics.

Ultrasound has become a widely available imaging modality for the investigation of patients with a variety of clinical conditions. Concerns have been raised by clinicians and government alike that a sizeable proportion of this imaging may be unnecessary, inappropriate or of inadequate quality for patient management. This study aims to prospectively evaluate the opinions of treating vascular clinicians as to whether the vascular ultrasound imaging studies that patients bring with them when initially referred are necessary, and technically adequate to permit clinical decision-making for the patient’s management. Vascular clinicians Australia-wide were invited to participate in the study in April 2003. They were asked to recruit their next 50 consecutive new patients, eligible to be enrolled in the study, who presented with ultrasound scans organized by their referring doctor. The clinicians were asked to fill out a two-page proforma detailing the diagnosis, if known, and their opinion regarding the study and report, whether they required further information, and what investigations they would have ordered if seeing the patient for the first time, in a primary setting. 17 vascular clinicians Australia-wide agreed to participate in the study and to recruit their next 50 patients referred to them with vascular ultrasound imaging performed prior to specialist consultation. 473 Proformas were returned for analysis. Of all studies performed, 19 percent were judged unnecessary. Studies that were considered necessary however, were, in some cases, technically inaccurately or inadequately reported in 27 percent of cases, and 67 percent of these studies were then repeated. The NATAVUS Study has demonstrated that a significant percentage of ultrasound imaging performed by referring clinicians to vascular specialists is unnecessary, and that necessary imaging does not, in a large percentage of cases, provide accurate and adequate data to allow for specialist clinical decision-making. The data from this study has the potential to develop guidelines for appropriate use of vascular ultrasound imaging for various vascular conditions. If the results of this study were to be duplicated in a larger study, development and adoption of such guidelines would have the potential to generate significant cost savings to the health system by the elimination of some unnecessary testing. This is of particular relevance with Australia’s ageing population.

The primary objective of antenatal assessment and monitoring is to ensure wellbeing of the fetus and the mother. There are different methods of assessment during pregnancy and in labour. Doppler ultrasound is one of the tests widely used in clinical practice in the evaluation of pregnancies that are at a greater risk of developing maternal or fetal complications due to uteroplacental insufficiency. Doppler ultrasound enables evaluation of sequential changes in circulatory haemodynamics in the fetus by evaluation of the fetus for signs of brain sparing and severity of redistribution of circulation. Recognition of abnormal Doppler flow patterns helps the clinician to optimise the appropriate timing of delivery. Identification of the ‘high risk’ fetus, before any changes of fetal compromise become evident, still remains one of the major dilemmas in contemporary clinical practice. This thesis seeks to explore the role of Doppler monitoring fetal intrauterine central shunts as a method of identifying the ‘high-risk’ fetus before any other established parameters, such as, fetal biometry, fetal weight or flow waveforms in umbilical artery become abnormal. This thesis also evaluates the role of serial Doppler monitoring of fetal central shunts in those fetuses where IUGR has been established. This is based on the premise that the intrauterine shunts are present in fetal circulation to work closely with the placenta to ensure appropriate nutrition and oxygenation of the fetus, bypassing the lungs. Four prospective longitudinal studies were designed to evaluate the role of fetal intrauterine shunts in adaptive response mechanisms in cardiovascular stress. Two models were taken into consideration: an ‘acute cardiovascular stress’ model and a ‘chronic cardiovascular stress’ model. To study the ‘response to acute cardiovascular stress’ in high-risk fetuses, a cohort of mothers undergoing fetal intrauterine transfusion for fetal anaemia were selected. These fetuses were scanned immediately before and after transfusion, and Doppler flows through all the intrauterine shunts were documented and compared with fetoplacental and cerebral circulation. To study the ‘response to chronic cardiovascular stress’, a prospective longitudinal observational study was designed and the sequence of changes in Doppler ultrasound of the fetal central shunts studied and compared with the Doppler flow waveforms of normal pregnancies with a group of pregnancies complicated by uteroplacental insufficiency. Normograms were designed for all the Doppler parameters and flows from adverse pregnancy outcomes were compared to the normogram. The pregnancy outcomes in the longitudinal study were correlated with placental pathology. Our study showed that although changes were demonstrated in the flow patterns within central shunts, these changes were not statistically significant in the ‘acute cardiovascular stress model’, suggesting that there may be other haemodynamic alterations in acute cardiovascular stress. However, in the ‘chronic cardiovascular stress model’, the results suggest that the intrauterine cardiac shunts may play an important role in redistribution of fetal flows in early stages of growth restriction, suggesting that Doppler ultrasound monitoring of foramen ovale can be potentially used as a screening tool to identify high-risk fetuses as early as 16 weeks. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1349883 / Thesis (Ph.D.) - University of Adelaide, School of Paediatrics and Reproductive Health, 2009

Doctor of Philosophy (Medicine) / This work investigates a number of issues. Firstly it examines ultrasonic fetal biometry, the parameters and techniques for accurate measuring and reviews the procedure adopted for graph formation and application of regression analysis for a mathematical model to describe the relationship between fetal size and weeks of gestation. Next it establishes new Australian fetal measurement charts for the crown rump length, head circumference and abdominal circumference, based on an Australian population, to replace the charts currently in use that are over 20 years old and relate to middle class white American and British women. The new graphs, along with previous work completed by the author in 1999 on the BPD, OFD femur and humerus length, were subsequently accepted by the Australasian Society for Ultrasound in Medicine (ASUM) in 2001 as the new Australian standard for ultrasonic fetal measurements. The accuracy of first trimester ultrasound dating is also investigated, displaying the variations seen in the crown-rump length due to fetal flexion and the implications of inaccurate measuring. The third study examines inter- and intra-sonographer ultrasonic fetal measurement reproducibility in the final 6 weeks of pregnancy. The study highlights the importance of sonographer competence, standardised measuring protocols, image planes and reference charts, particularly for patients undergoing ultrasound examinations for fetal growth assessment at different practices. The fourth study looks at the incidence of fetal macrosomia and birth complications in Chinese women and Caucasian women in two time periods, 1992 and 1999/2000. The results showed a rise in macrosomic babies born to Chinese immigrants from 4% of total Chinese births in 1992 to 9.8% in 1999/2000. There was also a rise in the rate of macrosomia among Caucasian women with respective rates of 11 and 14% for the same periods. The incidence of post partum haemorrhage increased significantly over this time in both Chinese immigrant and Caucasian women. Interventions declined in all Caucasian birth-weight ranges whilst interventions for Chinese births remained stable except between 3500grams and 4000grams, where interventions rose from 35.7% to 60.5%. Fetal macrosomia is a complication of pregnancy that is increasing in incidence. One of the causes of fetal overgrowth is uncontrolled gestational diabetes mellitus and so if women thus diagnosed are closely monitored, the risks of a macrosomic baby and associated birth complications may be reduced. The final study examines the effect of gestational diabetes mellitus (GDM) on fetal growth. GDM is a complication of mid to late pregnancy caused by glucose intolerance. In the Australian population up to 8% of all pregnancies can be affected. In the Australian Chinese community the GDM rate is as high as 15% compared with 4% in Caucasian women. The risks to the fetus as a result of GDM include increased perinatal mortality, large for gestational dates, macrosomia and prematurity. The aim of this study was to determine whether the fetuses of women diagnosed with GDM were significantly larger for dates for any of the commonly ultrasonically measured fetal parameters, than in the general pregnant population. The results show that if the glycaemic levels are properly controlled, fetal size should not be compromised. The abdominal circumference measurement appears to be the important marker for fetal macrosomia, particularly in the Chinese population. The study also assessed fetal weight gain from 36 weeks gestation to term in Caucasian women with GDM and Chinese pregnancies both with and without GDM. No statistically significant difference was seen in daily weight gain between the groups investigated.

Regensburg, Univ., Diss., 2008

Thesis (M.S.M.E.)--University of Delaware, 2008. / Principal faculty advisors: Thomas S. Buchanan and Kurt T. Manal, Dept. of Mechanical Engineering. Includes bibliographical references.