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Modulation of tumour oxygenation may be used to increase or decrease tumour hypoxia in order to improve the effect of radiotherapy or bioreductive drugs, respectively. Magnetic resonance imaging (MRI) and near infrared spectroscopy (NIRS) are techniques sensitive to blood deoxyhemoglobin concentration (Hb) that can be used to investigate tumour hypoxia indirectly via blood oxygenation levels. In this study we have used NIRS to determine absolute Hb and changes in deoxyhemoglobin and oxyhemoglobin (HbO) in subcutaneous rodent tumours for challenges that alter blood flow and oxygenation, with the aim to better interpret our MRI data. Both carbogen [95% O + 5% CO] and 100% O breathing produced a similar and significant reduction in Hb and increase in HbO, but a negligible change in HbT (= Hb + HbO). In contrast, N breathing to terminal anoxia and intravenous hydralazine produced a negligible increase in Hb, but large reductions in HbO and HbT. HbT is proportional to blood volume, so our data suggests large blood volume decreases occur with challenges likely to cause reduced arterial blood pressure. Hence MRI techniques that measure the R* relaxation rate, which varies linearly with total Hb, will underestimate the effects of hypotensive agents at increasing tumour hypoxia.

The reliable and reproducible creation of an animal model of focal cerebral ischemia is not easily accomplished. Using a transortibal approach, we showed that occlusion of the posterior cerebral artery (PCA), middle cerebral artery (MCA), and the contralateral anterior cerebral artery (ACA) created a large cortical and subcortical stroke in the non-human primate (NHP). Subsequently, we created the same stroke endovascularly in the NHP. Using the endovascular stroke model in the NHP, we measured brain temperature with thermocouples and cerebral blood flow (CBF) by stable xenon CT in one NHP, and CMRO and CBF by positron emission tomography (PET) in another NHP.

Two female non-human primates () weighing 7.0 and 8.0 kg, respectively, were studied under fentanyl-diazepam anesthesia with continuous monitoring of arterial blood pressure, rectal temperature, and end-tidal CO with intermittent blood gas measurements. Using an endovascular approach, the PCA (P2), MCA (Ml), and the ICA at the bifurcation and contralateral ACA produced a large hemispheric stroke. In the right ischemic hemisphere, temperatures increased by 2°C–3°C. PET measurement of CBF and CMRO showed that CMRO increased in the region of the ischemic stroke. We found that both hyperthermia and hypermetabolism occur in acute stroke.

Cerebral hemoglobin concentration (cHbc), a major determinant of oxygen transport capacity in the brain, shows a considerable variability due to physiological and methodological factors. In order to determine the (relative) contribution of these factors, the cHbc variability within the first 6 hours of life was studied in 28 very preterm infants using near infrared spectrophotometry (NIRS). Mean cHbc values were 46.4 ± 14.1 µmol/1 (2.75 ± 0.84 ml/100 g). Is the variability in cHbc related to the methodology of cHbc measurements or to physiological variables? A statistical model of stepwise regression (backward selection) with 13 independent variables and with cHbc as a dependent variable showed that, from the total variability of ± 14.1 µmol/1, only 3.7 µmol/1 (26%) were of methodological origin, while the major portion, 9.3 µmol/1 (66%) were related to four physiological variables: birth weight, gestational age, blood glucose and transcutaneous carbon dioxide tension. The remaining 1.1 µmol/1 (7.8%) were unexplained.

We conclude that NIRS, which allows continuous monitoring of cerebral oxygenation and metabolism even in the first hours of postnatal life, is a valid technique to measure cHbc in very preterm infants. The major portion of the large variability of early cHbc registrations can be attributed to physiological factors.

The benefits of a mouse model are efficiency and availability of transgenics/knockouts. Quantitation of cerebral blood in small animals is difficult because the cannulation procedure may introduce errors. The [C]-iodoantipyrine autoradiography (IAP) method requires both the tissue concentration and the time course of arterial concentration of the [C] radioactive tracer. A single point-analysis technique was evaluated for measuring blood flow in mice (30 g ± 0.3 g; n=11) by using computational models of sensitivity analysis, which quantitates relationships between the predictions of a model and its parameters. Using [C]-IAP in conjunction with mathematical algorithms and assumed arterial concentration-versus-time profiles, cortical blood flow was deduced from single-point measurements of the arterial tracer concentration. The data showed the arterial concentration profile that produced the most realistic blood flows (1.6 ± 0.4; mean ± SD, ml/g/min) was a profile with a ramp time of 30 sec followed by a constant value over the remaining time period of 30 sec. Sensitivity analysis showed that the total experimental time period was a more important parameter than the lag period and the ramp period. Thus, it appears that the accuracy of the assumption of linearly increasing arterial concentration depends on the experimental time period and the final arterial [C]-iodoantipyrine concentration.

The effect of temperature upon the oxygen partial pressure profiles (and hence upon flux) of oxygen through respiring tissues of differing architecture is examined. We have considered the two situations of respiring sheets of tissue and of respiring spheres.

Sheets of respiring tissue can model to some extent the behaviour of skin (which abandons its own temperature stasis in response to its obligations in the control of overall body temperature).

The oxygen profiles of spheres of respiring tissues subject to temperature shifts is investigated since it is a model for solid tumour oxygen kinetics where a spherical tumour, inadequately supplied with a capillary network, is being treated by one or another form of hyperthermia during cancer therapy.

It is known that oxygen tension in tissue (pO) will change in response to an alteration of physiological parameters including: pCO in arterial blood, blood flow, capillary density, oxygen carrying capacity, and p50 of hemoglobin. We have used modeling to compute the change of pO in response to changes of each physiological parameter and related these changes to experimental data.

The oxygen distribution in a Krogh cylinder was computed assuming a linear decrease of hemoglobin saturation from the arterial to the venous end of the capillary. Parameters of the model were used to compute the baseline cerebral pO expressed as the mean value of the pO over the whole cylinder. These parameters were adjusted to derive pO values close to those measured at the relevant experimental conditions. Then each desired parameter was varied to calculate the change in pO related to this parameter.

Effects of different factors on cerebral pO were modeled and compared with experimental values obtained with various experimental interventions including: changing CBF, modifying p50 with the allosteric modifier RSR13, modification of capillary density, and hemoglobin content. An acceptable agreement of the computed and the experimental changes of the cerebral pO was obtained for these experimental conditions.

EPR oximetry is a technique that can make repeated non-invasive measurements of the pO in tissues. To extend the application of EPR oximetry to humans, India ink is the probe of choice because appropriate India inks have EPR signals whose line widths are sensitive to changes in oxygen concentrations, and, most importantly, India ink already has been used extensively in humans as a marker in the skin, lymphatics, various organs during surgery, tumors, and for decoration as tattoos.

We have developed an India ink that has good sensitivity to oxygen, high stability in tissues, good signal intensity, and minimal toxicity. In this article we describe the various properties of this India ink, results obtained from our animal experiments, and our first preliminary clinical results, which are part of the first systematic clinical use of EPR oximetry. The clinical results indicate that it is possible to do repeated measurements over several months and probably years after the injection of the ink, indicating that long-term follow-up studies are feasible. We are very encouraged with these results and are confident that EPR oximetry using India ink will be a non-invasive, fast, and reliable technique for pO measurements in clinical studies.

The cylindrical steady-state model developed by Krogh with Erlang has served as the basis of understanding oxygen supply in living tissue for over eighty years. Due to its simplicity and agreement with some observations, it has been extensively used and successfully extended to new fields, especially for situations such as drug diffusion, water transport, and ice formation in tissues. However, the applicability of the model to make even a qualitative prediction of the oxygen level of specific volumes of the tissue is still controversial. We recently have developed an approximate analytical solution of a steady-state diffusion equation for a Krogh cylinder, including oxygen concentration in the capillary. This model was used to explain our previous experimental data on myocardial pO in isolated perfused rat hearts measured by EPR oximetry. An acceptable agreement with the experimental data was obtained by assuming that a known limitation of the existing EPR methods—a tendency to over-weight low pO values—had resulted in an under-estimate of the pO. These results are consistent with recent results of others, which stress the importance of taking into account the details of what is measured by various methods.

Identification of increased stroke risk in a population of symptomatic patients with occlusive vascular disease (OVD) is presently accomplished by measurement of oxygen extraction fraction (OEF) or cerebrovascular reserve (CVR). However, many regions identified by compromised CVR are not identified by OEF. Our aim was to determine whether the response of OEF to acetazolamide, namely, oxygen extraction fraction response (OEFR) would identify those hemispheres in hemodynamic compromise with normal OEF. Nine patients symptomatic with transient ischemic attacks and strokes, and with occlusive vascular disease were studied. Anatomical MRI scans and T-weighted images were used to identify and grade subcortical white matter infarcts. PET cerebral blood flow (CBF) and OEF were measured after acetazolamide. The relationship between CVR and oxygen extraction fraction response (OEFR) showed that positive OEFR occurred after acetazolamide despite normal baseline OEF values. The two hemispheres with positive OEFR were also associated with severe (> 3 cm) subcortical white matter infarcts. We found that the OEFR was highly correlated with CVR and identified hemispheres that were hemodynamically compromised despite normal baseline OEF.

Almost a century ago, Einstein and Sutherland independently derived equations that describe the relationship between diffusion of solutes and the molecular parameters of those solutes. In that time it has been recognized that, although the equations adequately describe the diffusion of large and medium-sized molecules, there is deviation from this relationship for small molecules. Many authors have attempted to redefine the equations for diffusion, with varying degrees of success, but generally have not attempted to consider the fundamental events that may be occurring at the molecular level during the diffusion of small molecules. In this presentation, we attempt to provide such an explanation, particularly with respect to the diffusion of oxygen through water. We consider the possibility of a random rotational model that complements the (slower) translational process of traditional diffusion and thereby provides accelerated diffusion of small molecules. It is hoped that our description of this model may provide a basis for the development of mathematical modelling of the process.