Benjamin William Zweifach - US grants

It is our long range objective to apply appropriate methods of statistics required for an in-depth analysis of morphometric measurements of the blood vessel network of the human conjunctiva to achieve the best possible clinical screening test for early detection of diabetes mellitus and to utilize the optimal combination of variables as an index of the progression and severity of the disease. A second important long-term objective is the analysis and interpretation of data obtained in a longitudinal study involving progressive changes in microvascular indices. New methods of variables selection and discriminant algorithms developed at the University of California, San Diego, are already in use and have yielded improvements in percent classified correctly as diabetics or non-diabetics. Techniques are being investigated which would allow inclusion of important non-continuous variables in the discriminant function, such as age, duration of disease, age at onset, insulin dose, fasting blood sugar, to mention just a few. A thorough investigation will be performed on the statistical correlations between conjunctival measurements, such as blood vessel length per unit area, vessel diameter distribution and spacing, with additional indices of vascular involvement; for example, nailfold microvessel measurements and retinal microvessels including data derived from fluorescein angiograms and, where available, histological data.

9512778 Schmid-Schoenbein Skeletal muscle represents the largest organ in the body. Normal contraction of muscle fibers depends on an intact blood flow in this organ, especially in the smallest blood vessels known as the microcirculation. The blood flow in the skeletal muscle microcirculation can be adjusted according to the activity of the muscle fibers. Understanding of blood flow in this organ is an essential element in understanding muscle performance and its failure. The overall objective of the PI's research project is to develop an analysis of blood flow in skeletal muscle from a basic point of view at the cellular and molecular level using rigorous physical language. The PI's previous NSF project has served to obtain basic elements of the analysis, including the actual network microanatomy of the vast number of blood vessels in the microcirculation, the biophysical properties of the blood vessels (arteries, capillaries and veins) and the blood fluid, the display of nerves, lymphatics, and other cells in the muscle. This information was integrated into an analysis of blood flow in resting non-contracting skeletal muscle which is based on basic biomechanical principles and implemented in form of a numerical computation on a digital computer by means of highly efficient algorithms. The predictions of the analysis were compared with all suitable experimental results in the skeletal muscle literature. In addition, the PI has carried out additional experiments on blood flow in skeletal muscle to test the analysis in quantitative details. The analysis provides the first time a comprehensive picture of skeletal muscle blood flow with physical precision. While this approach serves to explain a large number of experimental observations in the past, it has also lead to several discoveries including the following: 1) The basis for the specialized relationship between pressure, which drives the blood in skeletal muscle and blood flow, was identified and its physical origin was identified. 2) The identification of the mechanism that leads to cessation of muscle perfusion during pressure pulsations. 3) The identification of a previously undescribed mechanism for lymph flow in skeletal muscle. Recently, evidence has been obtained for a second valve system in the lymphatics of skeletal muscle, in addition to the well-known intralymphatic valve system. This observation provides the first time a comprehensive understanding of the mechanism by which lymphatics transport fluid and cells. 4) The identification of a new membrane function of the cells lining the blood vessels, i.e. the endothelial cells. 5) Analysis that served as the basis in leading to the discovery of a mechanism by which the small arteries in the microcirculation grow (research by the PI's former student Dr. T.C. Skalak at the University of Virginia, Charlottesville). 6) The discovery of a significant influence that circulating white blood cells have on the perfusion of skeletal muscle, especially when these white blood cells are activated. The PI has also identified a mechanism by which endothelial cells project small cytoplasmic extensions into the lumen of the microvessels in the activated state. These observations are important in regards to muscle fatigue. The proposed research serves as a direct expansion of the current analysis. The future analysis is directed at the following: 1) Expansion of the current analysis to the case of contracting muscle. During contraction, the skeletal muscle fibers compress the blood vessels of the microcirculation and therefore strongly influence the blood flow to the organ. 2) Identification of the biomechanical mechanism by which relatively few circulating white blood cells exert a significant influence on the perfusion of muscle microcirculation. 3) To study the influence of cytoplasm extensions on endothelial cells lining blood vessels on perfusion of the muscle microcirculation. The PI will continue to carry out the experiments on skeletal muscle in rats, so that all prev ious information serves as a basis for the future work without uncertainties regarding species differences. ***