Faculty Bibliography

PURPOSE: To produce in vivo high-resolution images of the knee and to determine the feasibility of using 7T MR to detect changes in trabecular bone microarchitecture in elite athletes (Olympic fencers) who undergo high impact activity. MATERIALS AND METHODS: The dominant knees of four males from the U.S. Olympic Fencing Team and three matched healthy male controls were scanned in a 7T whole-body scanner using a quadrature knee coil with three-dimensional (3D) fast low angle shot (FLASH): 50 axial images at the distal femur (0.156 mm x 0.156 mm) and 80 axial images at the knee joint (0.195 mm x 0.195 mm). Bone volume fraction (BVF) and marrow volume fraction (MVF) images were computed and fuzzy distance transform (FDT) and digital topological analysis (DTA) were applied to determine: trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp); BVF (BV/TV); trabecular and marrow space surface-to-curve ratio (SC, marker of plate to rod ratio); and trabecular and marrow space erosion index (EI, inverse marker for network connectivity). Quadriceps muscle volume (MV) was calculated as well. We calculated group means and performed two-tailed t-tests to determine statistical significance. RESULTS: Compared to controls, fencers had: decreased Tb.Sp (P = 0.0082 at femur, P = 0.051 at joint); increased Tb.N (P < 0.05 at both femur and joint) and BV/TV (P < 0.001 at both femur and joint); increased trabecular SC and decreased marrow space SC (P < 0.01 at both femur and joint); decreased trabecular EI and increased marrow space EI (P < 0.01 at both femur and joint); and increased MV (P = 0.038). There was no difference in Tb.Th at the distal femur (P = 0.92) or joint (P = 0.71) between groups. CONCLUSION: To our knowledge, this is the first study to perform 7T MRI of the knee in vivo. Elite athletes who undergo high impact activity have increased MV and improved trabecular bone structure compared to controls

Cofilin, in its Ser3 dephosphorylated form, accelerates actin filament turnover in cells. We report here the role of cofilin in platelet actin assembly. Cofilin is primarily phosphorylated in the resting platelet as evidenced by a specific antibody directed against its Ser3 phosphorylated form. After stimulation with thrombin under nonstirring conditions, cofilin is reversibly dephosphorylated and transiently incorporates into the actin cytoskeleton. Its dephosphorylation is maximal 1-2 min after platelet stimulation, shortly after the peak of actin assembly occurs. Cofilin rephosphorylation begins 2 min after activation and exceeds resting levels by 5-10 min. Cofilin is dephosphorylated with identical kinetics but fails to become rephosphorylated when platelets are stimulated under stirring conditions. Cofilin is normally rephosphorylated when platelets are stimulated in the presence of Arg-Gly-Asp-Ser (RGDS) peptide or wortmannin to block alpha(IIb)beta3 cross-linking and signaling or in platelets isolated from a patient with Glanzmann thrombasthenia, which express only 2-3% of normal alpha(IIb)beta3 levels. Furthermore, actin assembly and Arp2/3 complex incorporation in the platelet actin cytoskeleton are decreased when alpha(IIb)beta3 is engaged. Our results suggest that cofilin is essential for actin dynamics mediated by outside-in signals in activated platelets

Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP