Gliomas constitute 36% of all primary brain tumors and 81% of all primary malignant brain tumors. The overall prognosis in patients with gliomas depends mainly on the location and histologic grade of the tumor.<p>The World Health Organization classification of gliomas is the primary basis for guiding therapy and assessing overall prognosis in gliomas. This classification system, based on histological features, often falls short of predicting therapeutic response of individual tumors within the same histological grade. Yet, it still remains the grading method for both research and clinical prospects.<p>Unlike any other organ the brain has multiple protective layers such as the skull that ensure a homeostatic environment. The resulting reduced access to the brain and the absence of plasmatic brain tumor markers bring neuroimaging in a central position in diagnosis and management of brain tumors. Moreover, neuroimaging has evolved from a purely morphologic investigation into a diagnostic tool that allows characterization of particular physical alterations within brain tissue. Understanding the relationship between the physical characteristics of tumor tissue, studied by MR imaging, and biological characteristics of the tumor is therefore important for the appropriate integration of neuroimaging in brain tumor management. The general objective of this work is to define the relationship between physiologybased MR imaging and biological features of glial tumors. Diffusion and perfusionweighted imaging, physiologybased MR techniques provide the data based on physical characteristics of the tissues. Diffusion weighted imaging (DWI) allows the measurement of water molecules diffusivity within the brain tissue by means of apparent diffusion coefficient (ADC) measurements. Perfusion weighted imaging (PWI) is based on changes of MR signal during the passage of contrast material through the intravascular space and allows hemodynamic measurements such as those of cerebral blood volume (CBV)within the brain tissue.<p>Highgrade diffuse gliomas are currently differentiated from low grade diffuse gliomas by increased cellularity with nuclear atypia, mitotic activity, endothelial proliferation and necrosis. Components of the extracellular matrix and angiogenesis constitute some other features of gliomas, which have established links with oncogenic processes that influence the proliferative and infiltrative potentials of these tumors. We have specifically targeted these features in our comparative studies with the working hypothesis that physiologybased MR measurements, obtained in vivo, might provide information that is pertinent in terms of tumor malignancy.<p>We chose to approach the biology of brain tumors in two ways: in vivo, by means of metabolic imaging techniques such as positron emission tomography (PET) and ex vivo, by means of histological and immunohistochemical analyses of tumor specimens.<p>Many studies have investigated the relation between ADC values and cellularity in gliomas. The underlining theory is based on the premise that water diffusivity within the 9 extracellular compartment is inversely related to the content and attenuation of the constituents of the intracellular space. Therefore when cellularity increases, intracellular space volume increases with a relative reduction of the extracellular space, leading to restricted diffusion of water molecules. However other factors may affect the value of ADC in gliomas such as the extracellular matrix which contains various amounts of hydrophilic macromolecules susceptible to change water molecules diffusivity. Hyaluronic acid is one highly hydrophilic component of the extracellular matrix of gliomas and its level of expression changes significantly during the progression to anaplasia in gliomas. Our hypothesis was that hyaluronan may influence ADC values in high and low grade gliomas.<p>We demonstrated a positive correlation between ADC values and the immunohistochemical level of hyaluronan in glial tumors.<p>Previous studies have confirmed the utility of positron emission tomography using C11 Methionine (PETMET) as a prognostic tool in patients with gliomas. Higher MET uptake is associated with greater proliferative potential and a higher level of malignancy in gliomas.<p>The increased aminoacid uptake in gliomas seems to reflect increased transport mediated by aminoacid carriers located in the endothelial cell membrane. Our hypothesis was that CBV measurements, index of tumor vascularity, may be related to tumor aminoacid metabolism.<p>We found a positive correlation between maximum CBV values and maximum MET uptake values in gliomas.<p>A limitation to these preliminary studies was lack of direct correlation between MRbased measurements and histologic and metabolic data. Indeed, glial tumors are known for their remarkable tissue heterogeneity across different grades, within the same grade, and even within a single given tumor. Therefore we used image coregistration and stereotactic biopsies to further assess the relationship between MRbased imaging data and both metabolic and histologic analysis.<p>The second part of our studies was based on measurements at the exact same localization on both MR and PET images where biopsy specimens were performed. We found a local relationship between CBV and MET uptake values. Both measurements correlated with mitotic activity and endothelial proliferation; two features of tumor aggressiveness.<p>In order to quantify tumor cellularity and tumor angiogenesis, we respectively measured cell density and vessel density using immunohistochemical markers to identify vessels. We found a regional relationship between CBV and cell density, as well as vessel density in gliomas whereas no correlation was found regionally between ADC and cell density.<p>We concluded that CBV measurements may be used locally as indices of angiogenesis and cellularity in gliomas; whereas local ADC measurements are more variable and may not be used as a marker of cellularity in heterogeneous tumors such as gliomas. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Abstract In the repair of complex congenital heart defects or in surgery of the aortic arch, normal circulation may be temporarily halted to ensure a clean, bloodless operation field. The brain is the organ most vulnerable to ischemic injury during this no-flow period, and the mortality and morbidity of these procedures today consists mostly of neurological complications. Hypothermia decreases the need for oxygen and other metabolites, and cooling the patient with an extracorporeal heart-lung machine can provide enough time to perform the necessary surgical procedures during a circulatory standstill. This procedure is referred to as hypothermic circulatory arrest (HCA). Sometimes the cerebral circulation can be maintained even if the rest of the body undergoes circulatory arrest, and this strategy, involving separate catheterization of brain-destined vessels, is referred to as selective cerebral perfusion (SCP). In this work, four separate brain protection strategies were evaluated. Two studies were performed on a surviving porcine model (I, II) to evaluate neurological recovery as well as cerebral metabolism and histopathology, and two were acute in design (III, IV), employing the modern technology of intravital microscopy to examine cerebral microcirculation. The first study (I) showed that the administration of hypertonic saline dextran (HSD) led to a decrease in intracranial pressure, improved brain metabolism, better neurological recovery and less histopathological injury of the brain tissue in association with HCA. In the second study (II) a novel pharmacological molecule, levosimendan, reduced the intracranial pressure during the operation, but no improvement in terms of cerebral metabolism, neurological recovery or histopathological brain injury was observed after HCA. In the third study (III), real-time intravital microscopy showed that in association with HCA, a leukocyte depleting filter (LDF) attached to the cardiopulmonary bypass circuit reduces the number of activated leukocytes in cerebral microcirculation. In the fourth study (IV), cerebral metabolism and microcirculation were similar during SCP independent of the acid-base management strategy. The results of this work suggest that HSD could be assessed in human trials, that levosimendan needs further studies to optimize its potential, that the LDF functions as designed and that the differences between the α- and the pH-stat acid-base management strategies with SCP did not differ in moderate hypothermia.

Abstract Several in vitro methods using both human and animal tissues have been developed to study hepatic metabolism and placental transfer. The pressure to minimize animal studies has increased during the past few decades due to the public opinion and ethical considerations. However, these methods need further evaluation of their predictive power when applied in vivo. The aim of this work was to produce new information of the metabolism and transplacental passage of several anticonvulsants as well as to evaluate the usefulness of the placental perfusion method and several in vitro methods for analyzing metabolism in the prediction of clinical pharmacokinetics. Carbamazepine (CBZ) metabolism was studied using human and mouse liver microsomes, human hepatocytes, human liver slices and yeast cells expressing recombinant enzymes. All test systems predicted well the major metabolite carbamazepine-10,11-epoxide (CBZ-E). Also, minor metabolites were produced in slightly variable amounts in all systems except cells with recombinant enzymes. All human liver systems demonstrated that CYP3A4 is the principal CBZ metabolising enzyme. However, our results on CBZ-treated mice suggested that the metabolism of CBZ to CBZ-E is mainly mediated by CYP1A1 in C57/BL6 mice. Autoinduction of CBZ metabolism was seen in hepatocytes and in incubations using microsomes from CBZ-treated mice. Human liver and mouse liver microsomes metabolized oxcarbazepine (OCBZ) mainly to its active metabolite, 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ). Also, 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine (10,11-D) and an unknown metabolite were detected. Placental transfer of lamotrigine (LTG) and diazepam (DZP) was considerable in the human placental perfusion system, indicating marked fetal exposure in vivo. The OCBZ, 10-OH-CBZ and 10,11-D analyzed from maternal venous and cord blood also suggested significant fetal exposure. The placental perfusion system predicts well the transplacental passage of LTG and OCBZ and its major metabolite. However, in vivo cord blood concentrations of DZP are higher than maternal concentrations. Placental perfusion studies did not predict this. Still, even with its limitations, the human placental perfusion method provides information that can be used to evaluate the risk factors associated with drug use during pregnancy because understanding of specific transport characteristics is a good basis for rational risk assessment. In conclusion, all of the tested in vitro systems were useful in the prediction of at least some aspects of in vivo pharmacokinetics and metabolism, but validation and refinement are still essential, as is also the need to keep in mind the limitations characteristic of each in vitro method.

Abstract The natriuretic peptides are a family of hormones secreted by the heart. They play a fundamental role in salt and water balance and blood pressure regulation. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are the known members of the mammalian natriuretic peptide family. A major stimulus for the secretion of cardiac natriuretic peptides is myocyte stretch. Therefore, the secretion of natriuretic peptides is increased in response to elevated blood volume. Natriuretic peptide production and release is also affected by several other factors, such as endothelin-1 (ET-1), acting in paracrine fashion. The aim of this study was to elucidate factors regulating the novel cardiac peptide hormone, salmon cardiac peptide (sCP), belonging to the family of natriuretic peptides. The role of mechanical load, temperature and ET-1 in sCP secretion and production was studied using in vitro (isolated perfused ventricle preparation) and in vivo methods. Comparisons between the natriuretic peptide systems in fish and mammals were done to clarify functional evolution of this hormone family. Salmon (Salmo salar) was selected as a model, since it has an outstanding adaptability to wide variations in environmental salinity and has developed defence mechanisms against volume or salt load. The results showed that salmon ventricle stores large amounts of the prohormone of sCP, whereas the secreted form is the mature 29-amino acid form. The N-terminal fragment of pro-sCP is co-secreted with sCP in equimolar amounts. sCP is released rapidly in response to appropriate stimulus, whereas induction of its gene expression is slower. Mechanical load is an important regulator of sCP secretion. Temperature also plays a major role in regulating sCP plasma concentration by affecting its elimination from circulation. Additionally, ET-1 is a potent secretagogue of the sCP system and an inotropic agent in salmon heart. Furthermore, the present results reveal remarkable synergism between the cardiac effects of ET-1 and β-adrenergic stimulation. In conclusion, the sCP system in salmon ventricle largely resembles the ANP system in mammalian atrium, while also having specific characteristics, such as a regulated ventricular natriuretic peptide secretion pathway. Therefore, the sCP system offers a unique model for studying mechanisms of natriuretic peptide biology.

INTRODUCTION: Pulmonary embolism (PE) is a major cause of mortality during pregnancy. It is estimated that about 20% of maternal deaths in north america are due to PE. A lung V/Q study in a standard (non-gravid) patient typically consists of a low dosage ventilation study followed by a higher dosage perfusion study. In some centers however, perfusion-only imaging, without accompanying ventilation imaging has been employed. In this method, a several-fold lower dose of radioactivity is used. Perfusion-only imaging has multiple advantages. In addition to reduction of radiation dose to the mother and the fetus, there is decreased cost to the health-care system as well as improved patient convenience and shortened hospital workflow. OBJECTIVES: The present study aimed at assessing the negative predictive value (among other diagnostic accuracy measures) of perfusion-only imaging in a large group of pregnant patients with suspected pulmonary embolism. METHODS: This study was a retrospective cohort study of the entire pregnant patients with suspected PE who underwent V/Q scan at The Ottawa Hospital and their V/Q scans were available in the PACS system. After acquiring REB approval, a comprehensive search in the PACS (Picture Archiving and Communication System) was conducted to find pregnant patients who were assessed for PE in our division since 2004 (the earliest date the V/Q images were available in our system). A statistical consultation was made before the initiation of data collection and at the time of data analysis. All patients who met the inclusion criteria were included. Initially a nuclear medicine resident with 2 years of experience read all the perfusion- only images. The PISAPED criteria were used for image interpretation. Then the results were compared against the reports made by nuclear medicine staffs that were available to us in our electronic system and a final interpretation was made after such comparison. The follow-up clinical notes were used as the gold standard to make a final diagnosis of PE. Finally, diagnostic accuracy measures were calculated. RESULTS: A total of 364 patients were included. Mean maternal age at the time of lung V/Q scan was 30.3 years-old (SD=5.8) ranging from 16 to 51 years-old. From a total of 362 lung perfusion scans, 316/362 (87.3%) scans interpreted as normal, 17/362 (4.7%) scans were interpreted as high probability and 29/362 (8.0%) scans were interpreted as non-diagnostic. Pulmonary embolism was diagnosed in a total of 15 patients directly after performing lung scan. None of the patients with normal perfusion-only scans were diagnosed later with PE, proving a negative predictive value of 100%. The sensitivity and specificity of perfusion-only imaging after including the non-diagnostic studies were 100% (100% to 100%) and 99.1% (88.1% to 94.1%), respectively with a negative predictive value of 100% (100% to 100%) and a positive predictive value of 32.6% (19.1% to 46.2%). Conclusion: The results of the current study show that perfusion-only imaging has a very high negative predictive value for PE in pregnant population and therefore can exclude PE with a very high degree of accuracy.

Coronary artery disease has become a world wide medical problem. There is an overwhelming association between coronary atherosclerosis, angina pectoris, acute myocardial infarction and sudden death. The narrowing of coronary arteries is thought to damage the heart by limiting appropriate changes in coronary blood flow and by causing myocardial ischemia. This thesis attempts to examine the coronary circulation in patients who present with chest pain with and without coronary artery disease. One of the aims of this thesis is to validate the use of a short-lived radionuclide to study changes in regional myocardial perfusion. This technique has been applied in clinical medicine in an attempt to describe the disturbances of regional myocardial perfusion that occur in patients with coronary artery disease. These disturbances of perfusion have been related to the patients' symptoms, the electrocardiogram and the stenosed arteries seen in the arteriogram. Krypton-81m in solution is an inert freely diffusible gas (half-life 13 seconds) which emits a single 190 kev gamma ray. This tracer, a special catheter and a gamma camera have been developed in experiments to measure changes in regional myocardial perfusion. The systematic and rand-Om errors of the method have been defined in experiments. The results show that the mixing and delivered arterial concentration of krypton-81m are stable within a useful physiological range of changes in heart rate, blood pressure and coronary blood flow. Correlations with a reference technique have shown that the method can measure changes in regional myocardial perfusion between O and 3 ml/ml/min. The invasive method, the planar imaging and the need for calibration with washout at high levels of perfusion are investigated and described as limitations that must be considered. Eighty patients presenting with chest pain have been investigated by routine clinical methods, precordial mapping of the electrocardiogram during exercise and coronary arteriography. Changes in regional myocardial perfusion at rest and during atrial pacing has been measured using krypton-81m. The results have shown that stable mixing and delivered arterial concentration of krypton-81m can be achieved in the patients. Fifteen patients with negative exercise tests all demonstrated uniform increases in regional myocardial perfusion with pacing. The remaining 65 patients with positive exercise tests and significant coronary artery disease all showed both regional increases and decreases in myocardial perfusion during atrial pacing. In 16 of the 65 patients the jeopardized segment of ventricular myocardium showed significant increases in perfusion during the first 4 to 7 minutes of pacing. Th e increase stopped and regional perfusion in the affected segment then decreased progressively until the pacing was stopped. In 23 of the 65 patients the affected segment showed no changes in perfusion for 5 to 7 minutes of atrial pacing and then showed progressive decreases in regional myocardial perfusion until the pacing was stopped. Finally, in 26 of the 65 patients the affected segment showed immediate and progressive decreases of regional myocardial perfusion starting with the commencement of atrial pacing. In all the patients with disturbed perfusion ST segment depression in the electrocardiogram appeared after (140 ± 14 sec) the regional decrease of myocardial perfusion in the affected segment. Chest pain always appeared later at 220 ± 19 sec after the appearance of disturbed myocardial perfusion. Regional myocardial perfusion returned to normal in all the patients after the atrial pacing was stopped. There was a spatial relationship between the region of the ventricles affected by disturbed perfusion and the region of the precordium showing abnormal electrocardiographic signs during the exercise test. In conclusion, this clinical study has shown that patients with chest pain who have coronary artery disease suffer decreases of regional myocardial perfusion in affected segments of the ventricles during episodes of angina pectoris induced by atrial pacing. Regional perfusion may increase, remain stable or decrease in the affected segment following the onset of a stress test such as atrial pacing. This probably represents the amount of reserve function and adaptation left in the diseased coronary circulation and may be a useful physiological indicator of the severity of coronary disease and of patients at high risk. ST segment depression and pain have a close temporal relationship to the decreases of regional myocardial perfusion that occur in these patients. These studies suggest that there is a close relationship between myocardial perfusion and metabolism in health and disease. Both myocardial perfusion and metabolism will have to be affected by any rational therapy for angina pectoris and ischemic heart disease.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Goals of this study were to identify and characterize effects of neurokinin A (NKA) in isolated guinea pig hearts. Bradycardia, augmentation of ventricular contractions, and reduction of perfusion pressure were prominent responses to bolus injections of NKA (0.25-25 nmol). NKA was more potent than substance P (SP) in causing bradycardia but did not differ in potency for lowering perfusion pressure. Doses of SP of 25 nmol or less decreased ventricular force, whereas 100 nmol caused a biphasic response. The percent decrease in heart rate produced by 25 nmol NKA was reduced from 58.0 ± 4.8 to 39.6 ± 3.5% in the presence of μM atropine (n = 5). The positive inotropic response to 25 nmol of NKA in spontaneously beating hearts was replaced by a negative inotropic response during pacing (22.5 ± 3.3% increase vs. 11.7 ± 1.7% decrease, n = 5). Reserpine pretreatment did not affect the positive inotropic response to NKA. Specific binding sites for (125)I-labeled NKA were localized to intracardiac ganglia and coronary arteries but not to myocardium. It was concluded that 1) negative chronotropic responses to NKA involve cholinergic and noncholinergic mechanisms, and 2) the positive inotropic response is an indirect action.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21297号 / 医博第4386号 / 新制||医||1030(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 妹尾 浩, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM