Faculty Bibliography

Hemangioma is the most common soft-tissue tumor of infancy. Despite the frequency of these vascular tumors, the origin of hemangioma-endothelial cells is unknown. Circulating endothelial progenitor cells (EPCs) have recently been identified as vascular stem cells with the capacity to contribute to postnatal vascular development. We have attempted to determine whether circulating EPCs are increased in hemangioma patients and thereby provide insight into the role of EPCs in hemangioma growth. METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs) were isolated from hemangioma patients undergoing surgical resection (N = 5) and from age-matched controls (N = 5) undergoing strabismus correction surgery. PBMCs were stained with fluorescent-labeled antibodies for AC133, CD34, and VEGFR2/KDR. Fluorescent-labeled isotype antibodies served as negative controls. Histologic sections of surgical specimens were stained with the specific hemangioma markers Glut1, CD32, and merosin, to confirm the diagnosis of common hemangioma of infancy. EPCs harvested from healthy adult volunteers were stained with Glut1, CD32, and merosin, to assess whether cultured EPCs express known hemangioma markers. Hemangioma patients had a 15-fold increase in the number of circulating CD34 AC133 dual-staining cells relative to controls (0.78+/-0.14% vs.0.052+/-0.017%, respectively). Similarly, the number of PBMCs that stained positively for both CD34 and KDR was also increased in hemangioma patients (0.49+/-0.074% vs. 0.19+/-0.041% in controls). Cultured EPCs stained positively for the known hemangioma markers Glut1, CD32, merosin. CONCLUSIONS: This is the first study to suggest a role for EPCs in the pathogenesis of hemangioma. Our results imply that increased levels of circulating EPCs may contribute to the formation of this vascular tumor

Calpains modulate processes that govern the function and metabolism of proteins key to the pathogenesis of Alzheimer's disease, including tau and amyloid precursor protein. Because activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease, we are currently testing the hypotheses that a treatment with calpain inhibitors might restore normal cognition and synaptic transmission in a transgenic model of Alzheimer's disease, the APP (K670N:M671L)/PS1(M146L) mouse. Findings derived from these studies will provide a novel approach to cognitive enhancement in Alzheimer's disease

This article describes software that implements a new tool to administer study questions using the World Wide Web (WWW or Web). The software allows free text answers by the student in addition to the more common check-boxes that indicate selections from a list. The unique feature of this software is that a high level of sophistication can be programmed to generate complex responses to the student. The software is implemented as a Common Gateway Interface (CGI) program that uses a script programmed by the instructor to direct the analysis of the answer the student provides and to construct a response appropriate to that answer. An anonymous log is kept of each student answer so that the performance of the analysis script can be evaluated and the script itself changed or corrected as required. The design criteria for study questions and the value of short responses versus free text in teaching aids such as study questions are discussed

Purpose of review: Osteoarthritis is the most common form of arthritis, affecting a large population of mostly elderly people. No cure for osteoarthritis currently exists. Ultimate treatment is joint replacement. Understanding the mechanisms causing onset and progression is critical. This review describes recent findings that provide new insights into changes of cellular phenotype in osteoarthritis as a possible reason for tissue failure. Recent findings: Recent findings suggest that articular chondrocytes, when stimulated, can undergo hypertrophic and terminal differentiation events similar to those occurring during endochondral bone formation. Interestingly, collagenase-3 (matrix metalloproteinase-13), a main matrix-degrading enzyme in osteoarthritis, is expressed only in terminally differentiated chondrocytes during normal development. Summary: Although terminal differentiation events are required for endochondral bone formation, they lead to cartilage destruction when occurring in articular chondrocytes. Maintaining the articular chondrocyte phenotype and preventing these cells from undergoing hypertrophic and terminal differentiation might provide novel therapeutic targets to prevent onset or progression of osteoarthritis

Active transport of cations is achieved by a large family of ATP-dependent ion pumps, known as P-type ATPases. Various members of this family have been targets of structural and functional investigations for over four decades. Recently, atomic structures have been determined for Ca2+-ATPase by X-ray crystallography, which not only reveal the architecture of these molecules but also offer the opportunity to understand the structural mechanisms by which the energy of ATP is coupled to calcium transport across the membrane. This energy coupling is accomplished by large-scale conformational changes. The transmembrane domain undergoes plastic deformations under the influence of calcium binding at the transport site. Cytoplasmic domains undergo dramatic rigid-body movements that deliver substrates to the catalytic site and that establish new domain interfaces. By comparing various structures and correlating functional data, we can now begin to associate the chemical changes constituting the reaction cycle with structural changes in these domains

MuSK, a muscle-specific receptor tyrosine kinase that is activated by agrin, has a critical role in neuromuscular synapse formation. In cultured myotubes, agrin stimulates the rapid phosphorylation of MuSK, leading to MuSK activation and tyrosine phosphorylation and clustering of acetylcholine receptors. Agrin, however, fails to stimulate tyrosine phosphorylation of MuSK that is force-expressed in myoblasts and fibroblasts, indicating that myotubes contain an additional activity that is required for agrin to stimulate MuSK. Certain glycosyltransferases are expressed selectively at synaptic sites in skeletal muscle, raising the possibility that carbohydrate modifications of MuSK, catalyzed by glycosyltransferases expressed selectively in myotubes, may be essential for agrin to bind and activate MuSK. We identifed two N-linked glycosylation sites in MuSK, and we expressed MuSK mutants lacking one or both N-linked sites into MuSK mutant myotubes to determine whether N-linked carbohydrate modifications of MuSK have a role in MuSK activation. We found that N-linked glycosylation restrains ligand-independent tyrosine phosphorylation of MuSK and downstream signaling but is not necessary for agrin to stimulate MuSK