High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

In an attempt to explore the relationship between force production during voluntary contractions at different speeds of isokinetic movement and the myofibrillar protein isoform expression in humans, an improved isokinetic dynamometer that corrects for gravitation, controls for acceleration and deceleration, and identifies a maximum voluntary activation was used. Muscle torque recordings were compared at the same muscle length (knee angle) and the torque was calculated as the average torque at each angle over a large knee angle range (75 degrees -25 degrees ) to reduce the influence of small torque oscillation on the calculated torque. Muscle torque at fast (240 degrees s(-1)) versus slow (30 degrees s(-1)) speeds of movement, torque normalized to muscle cross-sectional area (specific tension), and absolute torque at fast speeds of movement were measured in 34 young healthy male and female short-, middle-, and long-distance runners. The relationship between the different measures of muscle function and the expression of myosin heavy chain (MyHC) isoforms using enzyme-histochemical and electrophoretic protein separation techniques were investigated. A significant correlation between the 240 degrees s(-1) vs 30 degrees s(-1) torque ratio and the relative area of the type II fibers and type II MyHC isoforms were observed in both the men (r=0.74; P<0.001) and the women (r=0.81; P<0.05). Thus, the present results confirm a significant relationship between in vivo human muscle function and the MyHC isoform expression in the contracting muscle.

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Distribution of marrow within the skeleton has been determined in man, rabbits, and rats by in vivo labeling of the marrow compartment with radioiron and either assaying each bone separately for radioactivity or obtaining a gamma-ray image of the distribution of the marrow by whole body scanner or positron scintillation camera. In man, extension of marrow into unusual sites was demonstrated after prolonged and severe stimulation, excessive blood loss, or hemolysis for a long period. A rabbit made severely anemic by administration of phenylhydrazine for 7 days showed extension of marrow into the distal portion of the humeri and femora. In rats in which erythropoiesis was stimulated by erythropoietin administration there was no significant increase in total marrow volume and no change in distribution of marrow within the skeleton. The positron scintillation camera provides an excellent method for qualitative evaluation of the marrow distribution. It has sufficient resolving power to give a good picture of the distribution of marrow with Fe52 in a skeleton as small as that of the rat. The distribution apparent from the positron pictures has been confirmed by complete skeletal analysis of individual bones.

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