THE EFFECT OF A CHALCOGENAPYRYLIUM DYE WITH AND WITHOUT PHOTOLYSIS ON MITOCHONDRIAL FUNCTION IN NORMAL AND TUMOR CELLS

A chalcogenapyrylium dye 8b, which is under investigation for the photodynamic therapy of malignant gliomas (brain tumors), was evaluated for inhibition of mitochondrial function both before and after exposure to laser light of 800 nm. Neoplastic and normal cells forced to use mitochondrial substrates were killed by the light-activation of intracellular 8b as well as exposure to classic mitochondrial inhibitors, rotenone and sodium azide. Correspondingly, cells in glucose-rich media showed little decrease in viability due to the photolysis of intracellular 8b or the presence of mitochondrial toxins. The toxicity of 8b without light activation was found to be the same regardless of the cell's energy source. Measurement of cellular ATP generated during treatment also showed the photolysis of intracellular 8b to be more inhibitory towards mitochondrial function than the unactivated parent compound. We conclude that the chalcogenapyrylium dyes localize to the mitochondrion and that photoactivation results in mitochondrial injury.     

Prediction of a glucose appearance function from foods using deconvolution

The glycaemic response of an insulin-treated diabetic patientgoes through many transitory phases, leading to a steady stateglycaemic profile following a change in either insulin regimenor diet. Most models attempting to model the glucose and insulinrelationship try to model the effect of oral or injected glucoserather than that from the digestion of food. However, it isclear that a better understanding of the glycaemic responsewould arise from consideration of intestinal absorption fromthe gut. It is assumed that this type of absorption can be modelledby a so-called glucose appearance function (systemic appearanceof glucose via glucose absorption from the gut) predicting theglucose load from the food. Much research has been carried outin the areas of hepatic balance, insulin absorption and insulinindependent/dependent utilization. However, little is knownabout intestinal absorption patterns or their correspondingglucose appearance profiles. The strategy under investigation herein is to use deconvolutionor backward engineering. By starting with specific results i.e.blood glucose and insulin therapy, it is possible to work backwardsto predict the glucose forcing functions responsible for theoutcome. Assuming compartmental consistency, this will allowa clearer insight into the true gut absorption process, If successful,the same strategy can be applied to more recent glucose andinsulin models to further our understanding of the food to bloodglucose problem. This paper investigates the Lehmann-Deutsch modified model ofglucose and insulin interaction, created from the model proposedby Berger-Rodbard. The model attempts to simulate the steadystate glycaemic and plasma insulin responses, independent ofthe initial values from which the simulation is started. Glucoseenters the model via both intestinal absorption and hepaticglucose production. We considered a 70kg male insulindependentdiabetic patient with corresponding hepatic and insulin sensitivityparameters of 0.6 and 0.3 respectively. Net hepatic glucosebalance was modelled piecewise by linear and symmetric functions.A first-order Euler method with step size of 15 minutes wasemployed. For the simulation, only Actrapid and NPH injectionswere considered. The injection of insulin and the glucose fluxto the gut were started simultaneously to avoid any delay associatedwith gastric emptying. The systemic appearance of glucose was compared from two viewpoints, not only to assess the strategic principle, but alsoto assess the suitability of the modifications made by Lehmannand Deutsch. The first is a forward prediction using the compartmentalstructure. This analysis involves the rate of gastric emptyingwithout time delay. The second is a backward prediction fromexperimentally observed blood glucose profiles. Investigationsinvolved porridge, white rice and banana containing the samecarbohydrate content (25 g). Results obtained from the firstanalysis were dependent on the rate of gastric emptying, especiallyits ascending and descending branches. Results from the secondanalysis were dependent on the dose and type of insulin administered.Both predicted profiles showed consistency with physiologicalreasoning, although it became apparent that such solutions couldbe unstable. Furthermore, both types of prediction were similarin structure and appearance, especially in simulations for porridgeand banana. This emphasized the consistency and suitabilityof both analyses when investigating the compartmental accuracyand limitations within a model. The new strategic approach was deemed a success within the model,and the modifications made by Lehmann and Deutsch appropriate.We suggest that a gastric emptying curve with a possible gastricdelay is the way forward in regulating the appearance of glucosevia gut absorption. The Lehmann-Deutsch gastric curve is describedby either a trapezoidal or triangular function dependent onthe carbohydrate content of the meal. However, it was clearfrom the results obtained that carbohydrate content is onlyone factor in carbohydrate absorption, and further progressmust inevitably involve other food characteristics and propertiesif we are to improve the glucose flux.     

RISK-BASED MULTIATTRIBUTE DECISION-MAKING IN PROPERTY AND WATERSHED MANAGEMENT

ABSTRACT. Determining best management systems for properties and evaluating their sustainability at the watershed scale are useful and important aspects of integrated watershed management. Multiattribute decision-making (MADM) is very useful for modeling the selection of best management systems for properties in a watershed. This paper reviews four MADM approaches including utility theory, surrogate worth tradeoff, free iterative search and stochastic dominance with respect to a function (SDWF). Emphasis is on determining how the first three methods could be used to determine the best (most preferred) combinations of attributes and associated management systems for a property. An application of the expected utility method with risk neutral preferences is presented in which farmer's preferences for five attributes are used to rank five farming systems for an agricultural watershed in Missouri. A framework is presented for assessing the sustainability of the best management systems for all properties in a watershed and the cost-effectiveness of policies for enhancing sustainable resource management at the watershed scale.