Megakaryocytes generate platelets by remodeling their cytoplasm first into proplatelets and then into preplatelets, which undergo fission to generate platelets. Although the functions of microtubules and actin during platelet biogenesis have been defined, the role of the spectrin cytoskeleton is unknown. We investigated the function of the spectrin-based membrane skeleton in proplatelet and platelet production in murine megakaryocytes. Electron microscopy revealed that, like circulating platelets, proplatelets have a dense membrane skeleton, the main fibrous component of which is spectrin. Unlike other cells, megakaryocytes and their progeny express both erythroid and nonerythroid spectrins. Assembly of spectrin into tetramers is required for invaginated membrane system maturation and proplatelet extension, because expression of a spectrin tetramer-disrupting construct in megakaryocytes inhibits both processes. Incorporation of this spectrindisrupting fragment into a novel permeabilized proplatelet system rapidly destabilizes proplatelets, causing blebbing and swelling. Spectrin tetramers also stabilize the "barbell shapes" of the penultimate stage in platelet production, because addition of the tetramer-disrupting construct converts these barbell shapes to spheres, demonstrating that membrane skeletal continuity maintains the elongated, pre-fission shape. The results of this study provide evidence for a role for spectrin in different steps of megakaryocyte development through its participation in the formation of invaginated membranes and in the maintenance of proplatelet structure. (Blood. 2011;118(6): 1641-1652) IntroductionBlood platelets, like erythrocytes, must withstand high shear forces during circulation. Retaining their discoid shape is critical to platelets, because their small size and shape cause them to be propelled by blood flow to the endothelial surface, where they are positioned to readily sense and respond to vascular damage. To provide structural support and prevent gross deformations as they circulate, mature platelets contain a robust membrane skeleton that is formed by spectrin molecules, adducin, and actin filament barbed ends. [1][2][3] Two thousand spectrin tetramers, 200-nm-long head-tohead assemblies of ␣␤ heterodimers, compose the bulk of this 2D network. Although less is known about how the spectrin-actin network forms and connects to the plasma membrane in platelets relative to erythrocytes, certain differences between the 2 membrane skeletons have been recognized. First, spectrin strands comprising the platelet membrane skeleton interconnect on the ends of long actin filaments originating from the cytoplasm instead of short actin oligomers. [3][4][5] Therefore, the platelet spectrin lattice and its associated actin filaments assemble into a continuous ultrastructure. Second, tropomodulins do not appear to have a major role in capping actin filament pointed ends, as occurs in erythrocytes. 6,7 Instead, a substantial number of these ends exist free or are capped by Arp2/3 in the res...

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In our study, papillary RCC had a much higher occurrence among black patients compared to non-black patients. This is the first study to document such a great racial disparity among RCC subtypes.

To date, eight cases of Castleman's disease associated with the pancreas have been described in the world literature. We report the first case of unicentric disease situated within the head of the pancreas. In addition, we discuss the diagnostic dilemma Castleman's disease may present to the pancreatic surgeon and review current data on pathogenesis, treatment, and outcome.