A comparison of the hypoglycemic effect of insulin with systemic venous and portal venous administration

The hyperglycemic effect of insulin by prolonged intraportal and systemic infusion was measured in unanesthetized dogs with a modified portacaval transposition. There was no significant difference in response with the two routes of administration. The relation of these results to research directed to surgical therapy of diabetes is discussed. © 1963 W. B. Saunders Company

Modelling of tolerance and rebound in normal and diseased rats

The development of rebound and tolerance is an important consideration when optimizing medical therapy, both with respect to drug dosing and adverse effects. By using quantitative approaches to study these processes, potential risks can be minimized. In this thesis nicotinic acid (NiAc)-induced changes in non-esterified fatty acids (NEFA) were used as a tool to investigate key determinants of tolerance and rebound in normal Sprague Dawley and in obese Zucker rats, a disease model of dyslipidaemia. The aim of the studies was to develop and challenge a model that described tolerance and rebound following different durations, rates and routes of NiAc administration. In normal rats, administration of NiAc resulted in a rapid decrease in NEFA plasma concentration, followed by rebound, the extent of which depended on both the level and duration of drug exposure. Rebound oscillations followed long duration of NiAc exposure. During constant drug exposure, increasing NEFA concentrations indicated tolerance development. The pharmacodynamic characteristics of NiAc-induced changes in NEFA differed in normal and diseased rats, with NEFA baseline concentrations being increased, rebound diminished, and tolerance develop¬ment more pronounced in the diseased animals. The non-intuitive pattern of NiAc-induced changes in NEFA was captured by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment inhibited the formation of response and the last stimulated the loss of response. The model was based on mechanistic principles, mimicking the dual actions of insulin in inhibiting the hydrolysis of triglycerides to NEFA and glycerol, and stimulating the re-esterification of NEFA. In both the normal and diseased rats, the model described the pharmacodynamic characteristics adequately. The concentration-response relationship at steady state was shifted upwards and to the right, and was shallower, in diseased rats compared to normal rats. The extent of such shifts demonstrates the impact of disease at equilibrium in the system. These studies have shown that by eliciting different exposure patterns and taking into account both the washout dynamics of the administered drug and the pharmacodynamic characteristics of normal and diseased animals, a mechanistically-based feedback model was able to tease out important information about tolerance and rebound

Glycogen infiltration (so-called hydropic degeneration) of the pancreas in experimental and human diabetes mellitus.

Note: Appendix bound separately in manuscript.In 1901 Weichselbaum and Stangl described unique changes in the islets of Langerhans of 18 pancreases from comatose diabetic human subjects. Having found the affected islet cells uncolored by methods designed to demonstrate hyaline and mucoid forms of degeneration, they (1902) later interpreted the lesion as a manifestation of cytoplasmic vacuolation and liquefaction, and applied the term hydropic degeneration to indicate its presumably aqueous character. Allen (1913) accomplished the first experimental production of a similar lesion in the islets and ductules of the pancreatic remnants of dogs made diabetic by resection of nine-tenths of the pancreas. At about the same time Homans (1914, 1915) demonstrated that in the islets of such experimental material degranulation and vacuolation developed only in the beta cells. Both Allen and Homans failed to find fat, mucin or glycogen in the affected cells; both concluded, as Weichselbaum did, that the vacuoles represented aqueous fluid. Richardson (1939-40), Ham and Haist (1941), Lukens and Dohan (19140, 1942) and Lukens, Dohan, and Wolcott (1943) described the pancreases of dogs and cats treated with anterior pituitary extract; these authors apparently accepted the idea of aqueous vacuolation as the basis of “hydropic degeneration” in their material.[...

Developing a recommender system artifact for patient tailored therapy in the COPE project

Mental health disorders affect people from all over the world of all ages. Depression is of the most common mental health problems and is commonly experienced by women during and after breast cancer treatment. Cognitive Behavioral Therapy (CBT) is a therapy form that has been proven effective in treating symptoms of depression. While CBT has traditionally been given face-to-face with a therapist, Internet-based CBT (iCBT) has shown higher efficiency, without the cost of efficacy. Self-guided iCBT provides an inexpensive alternative of treatment as it does not require a therapist involved, leading to better scaling. It has not shown the same effectiveness and user adherence. This project is part of a larger research project called COPE aiming at providing self-guided iCBT to breast cancer patients in a patient tailored and more efficacious manner. This thesis examines the possibility of integrating the advantages of a therapist guided iCBT into a self-guided iCBT application. An artifact was designed and developed through the method of design science, in an effort to make self-guided iCBT personalized. The artifact is a recommender system that uses content and patient data to recommend the most suited therapy content, as well as a simulation tool for insight and evaluation