<p>In order to improve the diagnosis of coronary artery disease, better methods for detection of myocardial perfusion defects would be useful. One of the methods used for myocardial perfusion evaluation today is magnetic resonance imaging. </p><p>This method could be improved if a contrast agent that induced long-lasting contrast enhancement in the myocardium could be developed. The paramagnetic manganese(II) ion has promising properties for meeting this need, since it enters cardiomyocytes through voltage-gated calcium channels and remains inside the cells for a long time after an intravenous injection. If these properties can be utilized, manganese-enhanced MRI has potential for detecting transient periods of ischemia in a manner similar to the conventional SPECT stress test.</p><p>To investigate the contrast-enhancing properties of the manganese(II) ion, a series of experiments was performed in pigs, using a manganese salt (MnCl₂) and two manganese-based chelates (MnDPDP and MnHPTA) and measuring the longitudinal relaxation rates before and after contrast agent administration. This was done in normal pig myocardium at rest and during dobutamine-induced stress with several different doses of contrast agent, and in a model for coronary artery stenosis using MnCl₂ administered during dobutamine stress to determine whether transient ischemia could be detected with this contrast agent.</p><p>The results of these experiments showed that of the three contrast agents, MnCl₂ induces the greatest increase in ΔR1, followed by MnHPTA. Using MnCl₂ it was possible to produce images on which transient myocardial ischemia was visible, but only during the first 30 minutes after contrast agent injection.</p><p>The stenosis model is still far from the clinical situation and several complications, including the potential toxicity of the manganese(II) ion, remain to be overcome. However, the results from this model are promising for the future development of manganese- enhanced magnetic resonance imaging of transient myocardial ischemia.</p>

In order to improve the diagnosis of coronary artery disease, better methods for detection of myocardial perfusion defects would be useful. One of the methods used for myocardial perfusion evaluation today is magnetic resonance imaging. This method could be improved if a contrast agent that induced long-lasting contrast enhancement in the myocardium could be developed. The paramagnetic manganese(II) ion has promising properties for meeting this need, since it enters cardiomyocytes through voltage-gated calcium channels and remains inside the cells for a long time after an intravenous injection. If these properties can be utilized, manganese-enhanced MRI has potential for detecting transient periods of ischemia in a manner similar to the conventional SPECT stress test. To investigate the contrast-enhancing properties of the manganese(II) ion, a series of experiments was performed in pigs, using a manganese salt (MnCl2) and two manganese-based chelates (MnDPDP and MnHPTA) and measuring the longitudinal relaxation rates before and after contrast agent administration. This was done in normal pig myocardium at rest and during dobutamine-induced stress with several different doses of contrast agent, and in a model for coronary artery stenosis using MnCl2 administered during dobutamine stress to determine whether transient ischemia could be detected with this contrast agent. The results of these experiments showed that of the three contrast agents, MnCl2 induces the greatest increase in ΔR1, followed by MnHPTA. Using MnCl2 it was possible to produce images on which transient myocardial ischemia was visible, but only during the first 30 minutes after contrast agent injection. The stenosis model is still far from the clinical situation and several complications, including the potential toxicity of the manganese(II) ion, remain to be overcome. However, the results from this model are promising for the future development of manganese- enhanced magnetic resonance imaging of transient myocardial ischemia.

<p>Deep vein thrombosis (DVT) and pulmonary embolism (PE) are different aspects of a single condition, venous thrombo-embolic disease (VTE), a major cause of morbidity and mortality in the western world. Rapid diagnosis is critical, as timely medical intervention can have a substantial beneficial effect on the mortality rate.</p><p>Irrespective of its presentation, VTE is a difficult disease to diagnose. Pathologies unrelated to VTE can give rise to a clinical presentation similar to DVT or PE, resulting in a false positive diagnosis. This raises the risk of a patient being treated inappropriately. Therefore, there is a need for an agent that has high specificity and sensitivity for the detection of active blood clots, which are amenable to treatment by anticoagulant and/or thrombolytic therapy. </p><p>This work describes the pre-clinical efficacy studies performed on one such agent, ^99mTc-NC100668. ^99mTc-NC100668 is a substrate for factor XIIIa and as a potential physiological, rather than anatomical, marker of VTE it is hoped it will not give rise to the false negative and positive diagnoses that are inherent in the currently available diagnostic techniques, such as the ventilation perfusion (V/Q) scan, multidetector computer tomography or ultrasound.</p><p>It is reported in this work that ^99mTc-NC100668 uptake and retention in blood clot was rapid and maintained over at least a 4 hour period in a rat model of DVT. Anticoagulant and thrombolytic therapies commonly used to treat thrombosis did not seriously impair the ability of ^99mTc-NC100668 to detect thrombi. No significant tissue retention, which could interfere with the ability to image thrombi <i>in vivo</i>, was observed. Biodistribution and plasma clot uptake studies showed that ^99mTc complex of gly-NC100194, the major metabolite of ^99mTc-NC100668, would be unlikely to affect adversely the clinical utility of the test substance.</p><p>The <i>in vitro</i> uptake of ^99mTc-NC100668 into forming plasma clots indicated that retention into human blood clots would be comparable with the observations made in the rat preclinical models. </p><p>The uptake of ^99mTc-NC100668 <i>in vitro</i> and <i>in vivo</i> was much greater than could be accounted for by physical entrapment into the forming blood clots. The reduced uptake of a biologically inactive analogue of ^99mTc-NC100668 both<i> in vitro</i> and <i>in vivo</i> indicated that the blood clot uptake and retention of ^99mTc-NC100668 was mediated by factor XIIIa.</p><p>In conclusion, ^99mTc-NC100668 might be useful in the detection of thrombo embolism.</p>

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are different aspects of a single condition, venous thrombo-embolic disease (VTE), a major cause of morbidity and mortality in the western world. Rapid diagnosis is critical, as timely medical intervention can have a substantial beneficial effect on the mortality rate. Irrespective of its presentation, VTE is a difficult disease to diagnose. Pathologies unrelated to VTE can give rise to a clinical presentation similar to DVT or PE, resulting in a false positive diagnosis. This raises the risk of a patient being treated inappropriately. Therefore, there is a need for an agent that has high specificity and sensitivity for the detection of active blood clots, which are amenable to treatment by anticoagulant and/or thrombolytic therapy. This work describes the pre-clinical efficacy studies performed on one such agent, 99mTc-NC100668. 99mTc-NC100668 is a substrate for factor XIIIa and as a potential physiological, rather than anatomical, marker of VTE it is hoped it will not give rise to the false negative and positive diagnoses that are inherent in the currently available diagnostic techniques, such as the ventilation perfusion (V/Q) scan, multidetector computer tomography or ultrasound. It is reported in this work that 99mTc-NC100668 uptake and retention in blood clot was rapid and maintained over at least a 4 hour period in a rat model of DVT. Anticoagulant and thrombolytic therapies commonly used to treat thrombosis did not seriously impair the ability of 99mTc-NC100668 to detect thrombi. No significant tissue retention, which could interfere with the ability to image thrombi in vivo, was observed. Biodistribution and plasma clot uptake studies showed that 99mTc complex of gly-NC100194, the major metabolite of 99mTc-NC100668, would be unlikely to affect adversely the clinical utility of the test substance. The in vitro uptake of 99mTc-NC100668 into forming plasma clots indicated that retention into human blood clots would be comparable with the observations made in the rat preclinical models. The uptake of 99mTc-NC100668 in vitro and in vivo was much greater than could be accounted for by physical entrapment into the forming blood clots. The reduced uptake of a biologically inactive analogue of 99mTc-NC100668 both in vitro and in vivo indicated that the blood clot uptake and retention of 99mTc-NC100668 was mediated by factor XIIIa. In conclusion, 99mTc-NC100668 might be useful in the detection of thrombo embolism.

<p>The purpose of this work was to: a) Determine whether the amount of colour in a power Doppler image is dependent on the angle between the examined vessel and the soundbeam and/or on the velocity of the flow within the vessel; b) Investigate if a dependency on flow velocity could be used for the detection of volume flow differences and c) Define clinical applications utilising the improved sensitivity to low flow of PD.</p><p>In the experimental studies (study I and II) a silicon tube in a water bath was insonated, the insonation angle and the volume flow changed and the resulting images stored, transferred to a personal computer and analysed with regard to the amount of colour present in the image.</p><p>In study III and IV the ability of power Doppler to depict low flow was used to produce a map of the perfusion in well perfused organs, lack of colour in all or part of an organ taken as a sign of decreased perfusion. 150 patients with a renal transplant (study III) and 15 patients with abdominal trauma (study IV) were examined; the detected areas of decreased perfusion were correlated to other imaging modalities, laboratory and clinical records in order to determine the underlying pathology.</p><p>In study V the power Doppler sensitivity was used to look for and describe small portosystemic shunts in 141 patients with liver cirrhoses and suspected portal hypertension.</p><p>The colour representation in a power Doppler image was found to be dependent both on the insonation angle and the flow velocity. Computer analysis of the images could detect differences in volume flow down to a change of 10 ml/min.</p><p>Of the 150 renal transplants, areas of decreased perfusion were found in 12, all of which could be given a plausible explanation (2 focal infections, 4 AV fistulae, 1 kinked segmental artery and 5 with problems related to an accessory artery).</p><p>Of the 20 organs (7 livers and 13 spleens) examined in the 15 trauma patients, 5 were found to have areas without colour, corresponding to localised haematomas. Using computed tomography as gold standard, ultrasound showed neither false positive nor false negative findings.</p><p>Of the 141 patients with cirrhosis, 40 had Doppler ultrasound findings of a shunt, consistent with a portal hypertension. 7 of these 40 shunts showed a typical “ball ” or “corkscrew ” pattern.</p><p>Conclusion: The colour in a power Doppler image is dependent not only on reflector concentration (as it should be in theory) but also on the insonation angle and the velocity of the flow. This can be used to detect relative changes in volume flow. Clinical applications of power Doppler include mapping of organ perfusion and the detection of small vessels. These applications are based on the high sensitivity of power Doppler.</p>

<p>Percutaneous nephrostomy (PCN) is a well-established intervention performed to divert urine from the collecting system in ureteric obstruction or as a prelude to interventional procedures such as stent placement or percutaneous nephrolithotripsy (PCNL). The aim of this thesis is to enhance planning for an optimal insertion of PCN, investigate complications, long-term management, follow-up and outcome in patients with PCN treatment and to increase accuracy in CT-guided punctures.</p><p>To enhance planning for an optimal insertion of PCN prior to PCNL, biomodels from CT data were performed. Eight patients with complex urinary calculi were selected. Multislice CT of the kidney was performed and the CT data were transformed into a biomodel. The biomodels visualised unique structures before surgery, which aided the planning of endourological procedures.</p><p>PCNL is an essential procedure for treating complex urinary calculi. A subcostal approach is preferred to avoid laceration to the lung and pleura. However, a supracostal approach is often preferable, as it gives a better passage to the renal pelvis. The nature and frequency of complications after supra- versus subcostal punctures were studied in 85 patients treated with PCNL. In 63 patients, a subcostal track was established. In 22, a supracostal puncture was chosen. The main difference in preoperative complications was the higher number of patients in the supracostal group complaining of respiratory correlated pain (32%). In the subcostal group, this was (5%). </p><p>401 patients were reviewed retrospectively regarding underlying disease, subsequent management and complications of PCN treatment. The number of major complications was 4%. Minor complications were recorded in 38%, urinary tract infection being the most common. 151/401patients suffered from malignancy. 84/151 of the malignant patients died with the catheter. The median survival time of the patients with malignancies was 255 days and the median catheterisation time was 62 days. </p><p>In order to increase accuracy when performing CT guided punctures, a new puncture guide was evaluated. In 15/17 patients the puncture was successful on the first attempt. The benefits of the puncture guide were the artefact from the needle guide pointing at the target indicating the puncture path and the needle support enhancing an accurate puncture.</p>

<p>The purpose of this thesis was to investigate the utility of the Ultrasmall Superparamagnetic Iron Oxide Particle (USPIO), NC100150 Injection for assessment of macro- and microvascular morphology and function using magnetic resonance imaging. The feasibility of NC100150 Injection was tested for the following applications: Coronary angiography, Thrombus detection, Cardiac function, Myocardial perfusion, Assessment of myocardial blood volume and water exchange and finally assessment of endothelial integrity of the myocardium.</p><p>The test method included computer simulations, in vitro, animal and clinical experiments. The computer simulations included propagation of longitudinal magnetization in non-steady state acquisitions. Animal models used were coronary artery stenosis in pigs, thrombus formation in the jugular vein in pigs, normal pig myocardium and transplanted hearts in rats. A human study of patients with suspected coronary artery disease was also performed.</p><p>The results showed that angiography using an USPIO is less efficient in the coronary arteries than in the peripheral arteries. Direct targeting to thrombus using an USPIO is possible but will be limited by the spatial resolution. An USPIO will enhance gradient echo imaging of cardiac function. T2-weighted myocardial perfusion imaging is feasible as well as assessment of myocardial blood volume and endothelial integrity.</p><p>Due to physiological limitations and technical development the utility of NC100150 Injection for assessment of the macrovascular morphology is limited.However for the assessment of microvascular function, especially perfusion and permeability, NC100150 Injection may contribute to a successful implementation of these methods.</p>

The purpose of this work was to: a) Determine whether the amount of colour in a power Doppler image is dependent on the angle between the examined vessel and the soundbeam and/or on the velocity of the flow within the vessel; b) Investigate if a dependency on flow velocity could be used for the detection of volume flow differences and c) Define clinical applications utilising the improved sensitivity to low flow of PD. In the experimental studies (study I and II) a silicon tube in a water bath was insonated, the insonation angle and the volume flow changed and the resulting images stored, transferred to a personal computer and analysed with regard to the amount of colour present in the image. In study III and IV the ability of power Doppler to depict low flow was used to produce a map of the perfusion in well perfused organs, lack of colour in all or part of an organ taken as a sign of decreased perfusion. 150 patients with a renal transplant (study III) and 15 patients with abdominal trauma (study IV) were examined; the detected areas of decreased perfusion were correlated to other imaging modalities, laboratory and clinical records in order to determine the underlying pathology. In study V the power Doppler sensitivity was used to look for and describe small portosystemic shunts in 141 patients with liver cirrhoses and suspected portal hypertension. The colour representation in a power Doppler image was found to be dependent both on the insonation angle and the flow velocity. Computer analysis of the images could detect differences in volume flow down to a change of 10 ml/min. Of the 150 renal transplants, areas of decreased perfusion were found in 12, all of which could be given a plausible explanation (2 focal infections, 4 AV fistulae, 1 kinked segmental artery and 5 with problems related to an accessory artery). Of the 20 organs (7 livers and 13 spleens) examined in the 15 trauma patients, 5 were found to have areas without colour, corresponding to localised haematomas. Using computed tomography as gold standard, ultrasound showed neither false positive nor false negative findings. Of the 141 patients with cirrhosis, 40 had Doppler ultrasound findings of a shunt, consistent with a portal hypertension. 7 of these 40 shunts showed a typical “ball ” or “corkscrew ” pattern. Conclusion: The colour in a power Doppler image is dependent not only on reflector concentration (as it should be in theory) but also on the insonation angle and the velocity of the flow. This can be used to detect relative changes in volume flow. Clinical applications of power Doppler include mapping of organ perfusion and the detection of small vessels. These applications are based on the high sensitivity of power Doppler.

Percutaneous nephrostomy (PCN) is a well-established intervention performed to divert urine from the collecting system in ureteric obstruction or as a prelude to interventional procedures such as stent placement or percutaneous nephrolithotripsy (PCNL). The aim of this thesis is to enhance planning for an optimal insertion of PCN, investigate complications, long-term management, follow-up and outcome in patients with PCN treatment and to increase accuracy in CT-guided punctures. To enhance planning for an optimal insertion of PCN prior to PCNL, biomodels from CT data were performed. Eight patients with complex urinary calculi were selected. Multislice CT of the kidney was performed and the CT data were transformed into a biomodel. The biomodels visualised unique structures before surgery, which aided the planning of endourological procedures. PCNL is an essential procedure for treating complex urinary calculi. A subcostal approach is preferred to avoid laceration to the lung and pleura. However, a supracostal approach is often preferable, as it gives a better passage to the renal pelvis. The nature and frequency of complications after supra- versus subcostal punctures were studied in 85 patients treated with PCNL. In 63 patients, a subcostal track was established. In 22, a supracostal puncture was chosen. The main difference in preoperative complications was the higher number of patients in the supracostal group complaining of respiratory correlated pain (32%). In the subcostal group, this was (5%). 401 patients were reviewed retrospectively regarding underlying disease, subsequent management and complications of PCN treatment. The number of major complications was 4%. Minor complications were recorded in 38%, urinary tract infection being the most common. 151/401patients suffered from malignancy. 84/151 of the malignant patients died with the catheter. The median survival time of the patients with malignancies was 255 days and the median catheterisation time was 62 days. In order to increase accuracy when performing CT guided punctures, a new puncture guide was evaluated. In 15/17 patients the puncture was successful on the first attempt. The benefits of the puncture guide were the artefact from the needle guide pointing at the target indicating the puncture path and the needle support enhancing an accurate puncture.

The purpose of this thesis was to investigate the utility of the Ultrasmall Superparamagnetic Iron Oxide Particle (USPIO), NC100150 Injection for assessment of macro- and microvascular morphology and function using magnetic resonance imaging. The feasibility of NC100150 Injection was tested for the following applications: Coronary angiography, Thrombus detection, Cardiac function, Myocardial perfusion, Assessment of myocardial blood volume and water exchange and finally assessment of endothelial integrity of the myocardium. The test method included computer simulations, in vitro, animal and clinical experiments. The computer simulations included propagation of longitudinal magnetization in non-steady state acquisitions. Animal models used were coronary artery stenosis in pigs, thrombus formation in the jugular vein in pigs, normal pig myocardium and transplanted hearts in rats. A human study of patients with suspected coronary artery disease was also performed. The results showed that angiography using an USPIO is less efficient in the coronary arteries than in the peripheral arteries. Direct targeting to thrombus using an USPIO is possible but will be limited by the spatial resolution. An USPIO will enhance gradient echo imaging of cardiac function. T2-weighted myocardial perfusion imaging is feasible as well as assessment of myocardial blood volume and endothelial integrity. Due to physiological limitations and technical development the utility of NC100150 Injection for assessment of the macrovascular morphology is limited.However for the assessment of microvascular function, especially perfusion and permeability, NC100150 Injection may contribute to a successful implementation of these methods.