Filamentous inclusions composed of the microtubule-associated protein tau are found in Alzheimer disease and other tauopathic neurodegenerative diseases, but the mechanisms underlying their formation from full-length protein monomer under physiological conditions are unclear. To address this issue, the fibrillization of recombinant full-length four-repeat human tau was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods and a small-molecule inducer of aggregation, thiazine red. Data were then fit to a simple homogeneous nucleation model with rate constant constraints established from filament dissociation rate, critical concentration, and mass-per-unit length measurements. The model was then tested by comparing the predicted time-dependent evolution of length distributions to experimental data. Results indicated that once assembly-competent conformations were attained, the rate-limiting step in the fibrillization pathway was tau dimer formation. Filament elongation then proceeded by addition of tau monomers to nascent filament ends. Filaments isolated at reaction plateau contained ϳ2 tau protomers/-strand spacing on the basis of mass-per-unit length measurements. The model suggests four key steps in the aggregation pathway that must be surmounted for tau filaments to form in disease.
We present the case of a 15-year-old male with sporadic Burkitt's lymphoma/leukemia. The patient presented with right lower quadrant abdominal pain and masses in the terminal ilium and pelvis, and was subsequently demonstrated to have involvement of the bone marrow. We discuss differential diagnoses and approach to diagnose and stage this disease. A review of the clinical, radiologic, and pathologic features of Burkitt's lymphoma/leukemia are also presented.
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