Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken

Library of Congress Cataloging-in-Publication Data French, Michael, 1925-Conceptual design for engineers 1 Michael French. --3rd ed. p. cm. Includes bibliographical references and index.

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A method for prediction of the spectrum observed with the laser Doppler flowmeter (LDF) is developed. A detailed analysis of the spectrum observed with steady flows is presented. The effects of diffusive motion of the scattering centers, spatially varying velocities, finite transit time of the centers through the sample volume, and uncertainty in scattering vector are computed. The latter two effects are shown to be identical. A computation of the sample volume size and shape is made using the optical parameters of the system. The calculated linewidths and shapes are in good agreement with data taken on two independent LDF systems. The general formalism is also applicable to measurements made on turbulent fluids and diffusely reflecting solid objects. The special case of a static fluid (zero velocity) is considered in detail and the low angle correction to the conventional expressions used in laser ``beat-frequency'' spectroscopy is developed.

These results suggest that our strategy was successful in reducing macrophage infiltration, but this model of glomerulonephritis is not solely dependent on the presence of CCR2 for progression of disease. After a transient ameliorative effect on proteinuria, CCR2 knockout led to more severe injury in nephritic mice. This raises the intriguing possibility that a CCR2 gene product ameliorates glomerulonephritis in this murine model. Although effects that occur in chemokine knockout mice are not equivalent to those expected with prolonged use of a chemokine antagonist, this study may nevertheless have implications for consideration of long-term use of chemokine antagonists in renal disease.