David Adams - US grants

Work will be done investigating geometric-analytic properties of domains as they relate to solutions of partial differential equations. The work concentrates on the boundaries of domains for it is at the boundary where the nature of solutions tends to be obscure. Among the concepts which have evolved in the measurement of boundary regularity, one of the most important is that of capacity, or more precisely, the capacity of a set. Although there are a number of types of capacity one may define, the source of theory almost surely rests with electrostatics and measurement of how well a conductor can support a charge. This in itself is a question about solutions of a partial differential equations. Several questions in the theory of capacities will be addressed in this work. The first is concerned with nature of weighted capacities arising in the study of degenerate elliptic equations. One wishes to chacterize the boundary regular points or the removable singularities for solutions. The capacities (set functions) are built out of the differential operator. Certain fundamental questions as yet are incompletely answered. They include how weighted capacity depends on the weight at least as far as null sets are concerned. One would also want to be able to classify regular points into equivalence classes according to types of degeneracy. On a larger scale, results on equivalence of capacities and concepts of regularity for nonlinear equations are only just appearing. This research will have application to the theory of partial differential equations and potential theory.

Post-cardiotomy cardiogenic shock is a significant clinical problem that will effect approximately 1% of all patients undergoing cardiac surgery this year. Experience with mechanical ventricular assistance in these patients at the Brigham and Women's Hospital as well as nationally has been very disappointing, and only approximately 25% of such patients supported with conventional technology will survive to discharge. We are very interested in pursuing the possibility of using genetically modified porcine xenografts to provide temporary cardiac support. Thus far, we have performed transplant surgeries on 11 baboons. Some animals received the heterotopic heart transplant and the others the kidney transplant from the transgenic pig donors to the baboons. The experiments are in progress and the data being generated from those experiments is under continuous evaluation. The initial phase of experiments will address the immunologic questions of graft rejection upon transplantation. These studies will utilize heterotopic transplants attached to an artery and vein in the neck of recipients treated with cyclosporine and leflunomide. Control animals will receive hearts from non-transgenic swine. In a separate experiment we plan to perform a small number of isolated heterotopic kidney grafts obtained from the same transgenic swine cardiac donor as a pilot for possible future research. Early results suggest that modified cardiac xenografts which

DESCRIPTION (provided by applicant): Although alcoholic liver disease (ALD) is a major public health problem how alcohol stimulates inflammatory damage in the liver is poorly understood. Alcoholic hepatitis (AH), characterized by chronic inflammation and parenchymal infiltration by T cells and neutrophils via the sinusoids, is a critical determinant of disease progression. Circulating lymphocytes must recognize and bind to endothelial cells before they can enter tissue and there is evidence that specific combinations of chemokines and adhesion molecules regulate binding to sinusoidal endothelium including the novel adhesion molecule VAP-1 and CXCRS-binding chemokines, all of which show increased he expression in AH. VAP-1 is a monoamine oxidase and its enzymic activity appears to be critical for its adhesive function. We have developed an in vitro model in which human sinusoidal endothelial cells are grown under conditions of blood flow that mirror those in vivo allowing us to study lymphocyte interactions with endothelium at physiological flow rates. In addition we have adapted this assay for co-cultures of endothelial cells and hepatocytes or Kupffer cells allowing us to study the contribution of cell types on lymphocyte recruitment in response to alcohol. Specific aims are: 1) to determine if lymphocytes from patients with AH show increased adhesion to sinusoidal endothelium and if so to demonstrate the molecules involved, 2) to define the role of specific molecules including VAP-1 and CXCR3 in this process, 3) to use flow-based co-cultures to determine if alcohol and acetaldehyde activate sinusoidal endothelium and lymphocyte transmigration directly or via paracrine effects mediated by Kupffer cells or hepatocytes, 4) to define the role of NFkB signaling in ethanol mediated endothelial activation. These studies are unique because they investigate the adhesion of human cells under flow. They offer us the opportunity to determine the molecules involved in liver-infiltration in alcoholic hepatitis and how alcohol and its metabolites activate these processes. Understanding the molecular basis of lymphocyte adhesion to sinusoidal endothelium in ALD will elucidate the pathogenesis of liver damage and may suggest new therapeutic targets to prevent tissue-damage in response to alcohol.