Faculty Bibliography

Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed exclusively in skeletal muscle, where it is required for formation of the neuromuscular junction. MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. Here, we report the crystal structure of the agrin-responsive first and second immunoglobulin-like domains (Ig1 and Ig2) of the MuSK ectodomain at 2.2 A resolution. The structure reveals that MuSK Ig1 and Ig2 are Ig-like domains of the I-set subfamily, which are configured in a linear, semi-rigid arrangement. In addition to the canonical internal disulfide bridge, Ig1 contains a second, solvent-exposed disulfide bridge, which our biochemical data indicate is critical for proper folding of Ig1 and processing of MuSK. Two Ig1-2 molecules form a non-crystallographic dimer that is mediated by a unique hydrophobic patch on the surface of Ig1. Biochemical analyses of MuSK mutants introduced into MuSK(-/-) myotubes demonstrate that residues in this hydrophobic patch are critical for agrin-induced MuSK activation

This study aimed to determine regional pattern of tissue perfusion in the normal-appearing white matter (NAWM) of patients with primary-progressive (PP), relapsing-remitting (RR) multiple sclerosis (MS) and healthy controls, and to investigate the association between perfusion abnormalities and clinical disability. Using dynamic susceptibility contrast (DSC) perfusion MRI at 3 T, we studied 22 patients with clinically definite MS, 11 with PP-MS and 11 with RR-MS and 11 age- and gender-matched healthy volunteers. The MRI protocol included axial dual-echo, dynamic susceptibility contrast enhanced (DSC) T2*-weighted and post-contrast T1-weighted images. Absolute cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the periventricular, frontal, occipital NAWM and in the splenium of the corpus callosum. Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from <0.0001 to 0.001) and RR-MS (p values from <0.0001 to 0.020). Compared to RR-MS, PP-MS patients showed significantly lower CBF in the periventricular NAWM (p=0.002) and lower CBV in the periventricular and frontal NAWM (p values: 0.0029 and 0.022). EDSS was significantly correlated with the periventricular CBF (r=-0.48, p=0.0016) and with the periventricular and frontal CBV (r=-0.42, p=0.015; r=-0.35, p=0.038, respectively). This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy

OBJECTIVE: The aim of this study was to compare the quality of images obtained with fast 3D T2-weighted turbo spin-echo (TSE) MR cholangiopancreatography (MRCP) sequences and 1-mm isotropic voxels with the quality of conventional 2D MRCP images. SUBJECTS AND METHODS: Thirty consecutively registered patients (14 women, 16 men; average age, 60.2 years; age range, 32-87 years) underwent imaging at 1.5 T with a 6-element body array coil. All imaging was performed with three MRCP techniques: free-breathing 3D T2-weighted TSE (TR/TE, 1,300/680; flip angle, 180 degrees; field of view, 250-300 mm; matrix size, 256 x 256; slice thickness, 1 mm; parallel acquisition technique factor, 2); breath-hold 3D T2-weighted TSE (same parameters as the free-breathing 3D technique); breath-hold coronal and oblique coronal thick-slab 2D TSE without parallel acquisition technique (2,800/1,100; flip angle, 150-180 degrees). Quantitative measures of image signal and contrast were evaluated by analysis of variance and paired Student's t tests. A 5-point scale (1, nondiagnostic, to 5, high diagnostic confidence) was used to compare the 3D and 2D data sets for image quality and definition of biliary and pancreatic ductal anatomic features. Friedman's nonparametric and Wilcoxon's rank sum tests were performed for statistical analysis of the qualitative assessments. RESULTS: Quantitative results showed free-breathing and breath-hold 3D TSE images had significantly higher relative signal intensity and contrast than 2D TSE images (p < 0.0001). The qualitative findings showed that both free-breathing and breath-hold 3D TSE techniques gave better delineation of biliary anatomy (p < 0.0001) than the 2D technique. The overall quality of 3D images was better than that of 2D images, and 3D imaging was better at depicting pancreatic ducts, although the difference did not reach statistical significance. CONCLUSION: Three-dimensional volumetric MRCP images are of superior quality and give better delineation of pancreaticobiliary anatomy than conventional 2D images and have the added advantage of multiplanar and postprocessing capabilities