The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.     

Difference Between Adolescent and Collegiate Baseball Pitchers in the Kinematics and Kinetics of the Lower Limbs and Trunk During Pitching Motion

The purpose of this study was to clarify the differences between adolescent and collegiate baseball pitchers in the kinematic and kinetic profiles of the trunk and lower limbs during the pitching motion. The subjects were thirty-two adolescent baseball pitchers aged 12-15 years (APG) and thirty collegiate baseball pitchers aged 18-22 years (CPG). Three-dimensional motion analysis with a comprehensive lower-extremity model was used to evaluate kinematic and kinetic parameters during baseball pitching. The ground reaction forces (GRFs) of the pivot and stride legs during pitching were determined using two multicomponent force plates. The joint torques of hip, knee, and ankle were calculated by the inverse-dynamics computation of musculoskeletal human models using motion-capture data. To eliminate any effect of variation in body size, kinetic and GRFs data were normalized by dividing them by body mass. The velocity of a pitched ball was significantly higher (p < 0.01) in CPG (35.2 ± 1.9 m·s^-1) than in the APG (30.7 ± 2.7 m·s^-1). Most kinematic parameters for the lower limbs were similar between the CPG and the APG. Maximum Fy (toward the throwing direction) on the pivot leg and Fy and resultant forces on the stride leg at ball release were significantly greater in the CPG than in the APG (p < 0.05). Hip and knee joint torques on the lower limbs were significantly greater in the CPG than in the APG (p < 0.05). The present study indicates that the kinematics of lower limbs during baseball pitching are similar between adolescent and collegiate pitchers, but the momentum of the lower limbs during pitching is lower in adolescent pitchers than in collegiate ones, even when the difference in body mass is considered.

Key points

• Collegiate baseball pitchers can generate the hip and knee joint torques on the pivot leg for accelerating the body forward.
• Collegiate baseball pitchers can generate the hip and knee joint torques to control/stabilize the stride leg in order to increase momentum on the stride leg during the arm acceleration phase.
• The kinematics of the lower limbs during baseball pitching are similar between adolescent and collegiate pitchers, but the momentum of the lower limbs during pitching is lower in adolescent pitchers than in collegiate ones, even when the difference in body mass is considered.
• Adolescent baseball pitchers cannot generate the hip and knee joint torques in the pivot and stride leg for transfer of the energy of trunk and the arm.

Key words: Pitching ball velocity, the open kinetic chain, joint moment, ground-reaction force, motion analysis     

Granulocyte-colony stimulating factor-producing myeloma with clinical manifestations mimicking chronic neutrophilic leukemia

A 68-year-old man was diagnosed as having bronchial asthma in November 1996. He presented with leukocytosis in June 2002. The WBC count was 29,900/microliter with 82% mature neutrophils showing toxic granules. The neutrophil alkaline phosphatase score and serum level of vitamin B12 were elevated. Bone marrow demonstrated myeloid hyperplasia and plasmacytosis. Cytogenetic and molecular analyses were negative for Philadelphia chromosome and BCR/ABL fusion gene. Lambda-type Bence-Jones protein was detected on the serum and urinary immunoelectrophoresis. The coexistence of chronic neutrophilic leukemia and myeloma was suspected based on the clinical features. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Immunohistochemically, atypical plasma cells were positive for anti G-CSF antibody. Finally, we diagnosed this patient as having a G-CSF-producing myeloma. Treatment with melphalan and prednisolone was initiated without beneficial response. He was then admitted to our hospital for ROAD therapy (ranimustine, vincristine, melphalan, and dexamethasone). The neutrophil count decreased in parallel with the serum G-CSF level. These observations indicated that the neutrophilia in this case was probably caused by a reactive response to G-CSF secreted from the myeloma cells.