Faculty Bibliography

Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.

Fracture susceptibility depends jointly on bone mineral content (BMC), gross bone anatomy, and bone microarchitecture and quality. Overall, it has been estimated that 50-70% of bone strength is determined genetically. Because of the difficulty of performing studies of the genetics of bone strength in humans, we have used the HcB/Dem series of recombinant congenic (RC) mice to investigate this phenotype. We performed a comprehensive phenotypic analysis of the HcB/Dem strains including morphological analysis of long bones, measurement of ash percentage, and biomechanical testing. Body mass, ash percentage, and moment of inertia each correlated moderately but imperfectly with biomechanical performance. Several chromosome regions, on chromosomes 1, 2, 8, 10, 11, and 12, show sufficient evidence of linkage to warrant closer examination in further crosses. These studies support the view that mineral content, diaphyseal diameter, and additional nonmineral material properties contributing to overall bone strength are controlled by distinct sets of genes. Moreover, the mapping data are consistent with the existence of pleiotropic loci for bone strength-related phenotypes. These findings show the importance of factors other than mineral content in determining skeletal performance and that these factors can be dissected genetically.

Hospitals of all sizes should provide an orientation for their newly hired critical care nurses-but when the hospital is a rural community facility, resources for such programs may be in especially short supply. In this article, we describe how our hospital overcame staffing and funding shortages to create a successful, collaborative orientation program for its critical care nurses.

Expression of pulmonary eotaxin protein and mRNA was determined in six subjects with atopic asthma and five nonatopic normal subjects. Levels of eotaxin expression and eosinophil mobilization were compared before and after segmental allergen challenge in subjects with atopic asthma. In the absence of allergen challenge, we found significantly higher levels of eotaxin in the bronchoalveolar lavage (BAL) fluid of subjects with asthma than in that of normal subjects (25 +/- 3 versus 15 +/- 2 pg/ml, p < 0.05). BAL eotaxin levels increased after segmental allergen challenge in all six subjects with atopic asthma tested, with a mean increase from 22 +/- 4 to 53 +/- 10 pg/ml (p = 0.013). Segmental allergen challenge was associated with a significant increase in the percentage of BAL macrophages and eosinophils that were immunopositive for eotaxin. Eotaxin mRNA was detectable by northern analysis in BAL cells exclusively from allergen-challenged segments. Allergen- induced increases in eotaxin levels were strongly associated with increases in BAL eosinophil recovery (r(2) = 0.88, p = 0.0036). Segmental allergen challenge also increased eotaxin expression in airway epithelial and endothelial cells obtained by endobronchial biopsy. These findings demonstrate, for the first time, that the airways of subjects with allergic asthma respond to allergen by increasing eotaxin expression. The tissue loci of eotaxin expression, the levels of eotaxin recovered in BAL fluid, and the association of eotaxin levels with eosinophil mobilization suggest either that eotaxin plays a mechanistic role in allergen-induced airway eosinophilia or that it serves as a biomarker for the causal mechanisms

Many of the most common foot problems develop from ill-fitting or poorly designed shoes, inappropriate exercise, carrying around too much weight, and poor circulation. Lamms and Couzens describe two of the most common foot afflictions, along with recommendations to remedy them

Gleevec works by hitting a specific molecular target in the cell. In particular, it inhibits three different proteins involved in the cell's internal signalling system. Many cancer cells divide incessantly because these systems have been thrown into hyperdrive by some genetic accident. Gleevec cuts off this signaling by slipping into a pocket on the surface of the signaling protein. This pocket is meant to be occupied by another protein known as ATP

Last week at a meeting of the American Society of Clinical Oncology in San Francisco, scientists reported that Gleevec had also worked in about 60 percent of nearly 200 cases with [Todd Hendrickson]'s type of cancer, known as GIST for gastrointestinal stromal tumor. But it is too early to know how long the remissions will last and how long patients will need to take Gleevec. Gleevec, for example, inhibits three different proteins involved in the cell's internal signaling system. Many cancer cells divide incessantly because their internal signaling systems have been thrown into hyperdrive by some genetic accident. Gleevec cuts off this signaling by slipping into a pocket on the surface of the signaling protein. This pocket is meant to be occupied by another protein known as ATP. With the pocket jammed, the protein can no longer function. Cancer cells are daunting to treat because they often have a number of genetic mutations. They quickly develop resistance to the drugs that are thrown at them, suggesting that no one drug will ever be much use by itself. The unexpected success of Gleevec has raised oncologists' hopes that other drugs like Gleevec, alone or in combination, may bring down many different types of tumors. If the drugs do not cure the cancer, they may allow people to live with it as a chronic disease