Kakunoshin Yoshida

Cobalt and Chromium Ion Release After Large-Diameter Metal-on-Metal Total Hip Arthroplasty

Seventy-five patients underwent unilateral metal-on-metal total hip arthroplasty using a large-diameter head. Serum levels of cobalt and chromium were determined. Significant increases in both cobalt and chromium were observed at 3 months (cobalt, 1.4 μg/L; chromium, 1.4 μg/L) compared with preoperative values (P < .001). At 1 year, the median cobalt and chromium levels were 2.3 and 2.1 μg/L, respectively, and the levels had increased significantly compared with 3 months (P < .001). There were no significant differences between levels of either metal at 1 or 2 years (cobalt, 2.3 μg/L; chromium, 1.6 μg/L). Pseudotumor occurred in 2 hips. Patients with large-diameter metal-on-metal total hip arthroplasty had higher circulating metal ion levels at 3 months and 1 year, with no additional significant increases at 2 years.

Connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells

Gap junctions (GJs) play an important role in vascular function, stability, and homeostasis in endothelial cells (ECs), and GJs are comprised of members of the connexin (Cx) family. GJs of vascular ECs are assembled from Cx37, Cx40, and Cx43, and we showed that ECs also express Cx32. In this study, we investigated a potential role for Cx32 during vascular inflammation. Expression of Cx32 mRNA and protein by human umbilical venous ECs (HUVECs) decreased following treatment with tumor necrosis factor (TNF)-α, but lipopolysaccharide (LPS) and interleukin (IL)-1β did not affect Cx32 expression. Intracellular transfer of an inhibitory anti-Cx32 monoclonal antibody significantly enhanced TNF-α-induced monocyte chemotactic protein (MCP)-1 and IL-6 expression, but overexpression of Cx32 abrogated TNF-α-induced MCP-1 and IL-6 expression. LPS treatment of Cx32 knock-out mice significantly increased the serum concentrations of TNF-α, interferon-γ, IL-6 and MCP-1, compared to wild-type littermate mice. These data suggest that Cx32 protects ECs from inflammation by regulating cytokine expression and plays an important role in the maintenance of vascular function.

Prevalence of adverse reactions to metal debris following metal-on-metal THA.

The purpose of this study was to determine the prevalence of adverse reactions to metal debris (ARMD) following large-diameter metal-on-metal total hip arthroplasty. The authors examined the potential for using magnetic resonance imaging to screen for pseudotumors in 108 hips 2 years postoperatively. Serum cobalt and chromium concentrations were measured in 80 hips that underwent unilateral total hip arthroplasty. The authors considered pseudotumors and aseptic lymphocyte-dominated vasculitis-associated lesions to be ARMD and compared metal ion levels between hips with ARMD (ARMD group) with hips with no ARMD (non-ARMD group). Magnetic resonance imaging revealed pseudotumors in 9 patients (10 hips, 9%). Five of these 10 hips were symptomatic and underwent revision surgery. Two other patients underwent revision surgery due to symptomatic cup loosening with aseptic lymphocyte-dominated vasculitis-associated lesions. Ten patients (12 hips) had ARMD. Serum cobalt and chromium concentrations were significantly higher in hips with ARMD than hips without ARMD. Other factors, including age, body mass index, sex, clinical score, acetabular cup inclination angle, and femoral head diameter, were not significantly different between the groups. Elevated metal ion levels suggest that ARMD is associated with increased metal wear. Magnetic resonance imaging provides sensitive screening for pseudotumors following metal-on-metal total hip arthroplasty.

The relationships among hemostatic markers, the withdrawal of fondaparinux due to a reduction in hemoglobin and deep vein thrombosis in Japanese patients undergoing major orthopedic surgery.

BACKGROUND The relationships among the hemostatic markers, the development of deep vein thrombosis (DVT) and the withdrawal of fondaparinux due to a reduction in the hemoglobin levels were examined. METHODS Two-hundred twenty-one Japanese patients who underwent major orthopedic surgery and were treated with 1.5mg of fondaparinux instead of 2.5mg of fondaparinux were studied. Forty-seven of 221 patients discontinued fondaparinux treatment (withdrawal group) and 37 patients developed DVT. RESULTS The age, frequency of total knee arthroplasty (TKA), withdrawal of fondaparinux, reduction of hemoglobin and the plasma levels of soluble fibrin (SF), D-dimer and fibrinogen and fibrin degradation product (FDP) on day 1 after the operation were significantly higher in the patients with DVT. Elevated SF, D-dimer or FDP levels were associated with the risk for DVT. The age, frequency of TKA or DVT, anti-Xa activity and the creatinine, FDP and D-dimer levels were significantly higher in the withdrawal group. An anti-Xa level >0.33 mg/l and an elevated D-dimer or FDP level were associated with the risk of withdrawal. CONCLUSION The age and SF levels, TKA and withdrawal of fondaparinux were related to the risk of DVT, and the anti-Xa activity, creatinine level and DVT were related to the risk of withdrawal of fondaparinux due to a reduction in hemoglobin.

Activated protein C stimulates osteoblast proliferation via endothelial protein C receptor.

INTRODUCTION Bone is continually remodeled by the action of osteoblasts, osteocytes, and osteoclasts. Resting osteoblasts are able to proliferate and differentiate into mature osteoblasts when physiologically required, as after tissue injury. Activated protein C (APC) is a serine protease that functions in anticoagulation, anti-inflammation, anti-apoptosis, cell proliferation, and wound repair. In this study, we examined the effect of APC on osteoblast proliferation and differentiation. MATERIALS AND METHODS We examined the presence of protein C in human fracture hematoma by immunohistochemical staining. We then evaluated the effect of APC, diisopropyl fluorophosphate-inactivated APC (DIP-APC) or protein C zymogen on normal human osteoblast (NHOst) proliferation using tetrazolium salt assay in the presence or absence of aprotinin, hirudin, protein C, antibody against protein C, endothelial protein C receptor (EPCR) or protease-activated receptor (PAR)-1. Finally, activation of p44/42 MAP kinase was evaluated by Western blot analysis. RESULTS Both APC and DIP-APC increased osteoblast proliferation in a dose-dependent manner, while protein C did not. The APC-induced increased proliferation of osteoblast was not affected by aprotinin, hirudin, and anti-protein C antibody which inhibits the protease activity of APC. Treatment with protein C or anti-EPCR antibody which inhibits APC binding to EPCR inhibited APC-mediated osteoblast proliferation, while treatment with anti-PAR-1 antibody did not. APC promoted the phosphorylation of p44/42 MAP kinase within osteoblasts; this effect was inhibited by the anti-EPCR antibody. CONCLUSIONS APC stimulates osteoblast proliferation by activating p44/42 MAP kinase through a mechanism that requires EPCR but not PAR-1 or the proteolytic activity of APC. APC generated at fracture sites may contribute to fracture healing by promoting osteoblast proliferation.

Pseudotumor With Dominant B-Lymphocyte Infiltration After Metal-On-Metal Total Hip Arthroplasty With a Modular Cup

We report a case of a patient who underwent metal-on-metal total hip arthroplasty with a modular cup and developed a pseudotumor 5 years postoperatively. Immunohistochemistry showed dominant B-lymphocyte infiltration in the periprosthetic tissue.

Cutting and implanting errors in minimally invasive total knee arthroplasty using a navigation system

PurposeThe purpose of this study was to evaluate the accuracy of bone cutting and implantation in minimally invasive total knee arthroplasty with image-free navigation.MethodsThe alignment of the tibial and femoral bone resection was measured in 40 knees during surgery. The alignment measurement was repeated after cementing the tibial and femoral components. We evaluated the cutting error and the implanting error.ResultsThe mean tibial cutting errors were 0.5 and 0.7° in the frontal and sagittal planes, respectively. The mean femoral cutting errors were 0.5 and 0.9° in the frontal and sagittal planes, respectively. The mean tibial implanting errors were 1.0 and 0.9° in the frontal and sagittal planes, respectively. The mean femoral implanting error was 0.7° in the frontal plane.ConclusionsComputer-assisted navigation was useful in checking the alignment of both bone cut and cementation.

Monitoring for anti-Xa activity for prophylactic administration of Fondaparinux in patients with artificial joint replacement.

The efficacy of measuring anti-Xa activity was evaluated in major orthopedic surgery patients receiving thrombo-prophylaxis with Fondaparinux. Although 98 orthopedic patients including those receiving total hip replacement (THR) and total knee replacement (TKR) were treated with 1.5 mg of Fondaparinux for prophylaxis of deep vein thrombosis (DVT). Sixteen patients developed DVT, but none was associated with a fatal pulmonary embolism. There was a wide range of anti-Xa activity, but there were no patients with less than 0.15 mg/l or more than 0.90 mg/l. Anti-Xa activity gradually increased from days 1 to 8 and showed no significant difference between patients with and without DVT. Anti-Xa activity was correlated with weight, height, body mass index, and antithrombin activity. Postoperative plasma levels of d-dimer and soluble fibrin (SF) were markedly high, and those were significantly reduced at days 1 and 4 of treatment with Fondaparinux. Plasma levels of SF were significantly reduced at days 8 and 15, but d-dimer was not. These findings suggested that there was continued thrombin generation after the injection of Fondaparinux until day 8 and secondary fibrinolysis occurred on day 8. In conclusion, 1.5 mg of Fondaparinux may not be sufficient for the prophylaxis of silent DVT, but it was found to be useful for that of fatal pulmonary embolism. Consequently, monitoring anti-Xa activity may be unnecessary for the administration of Fondaparinux at such doses.

Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability.

INTRODUCTION Protein C inhibitor (PCI), a member of the serine protease inhibitor family, is expressed in various human tissues, including liver and kidneys. In the plasma, PCI physiologically inhibits an anticoagulant serine protease, activated protein C (APC). PCI expressed by cancer cells suppresses tumor invasion by inhibiting urokinase-type plasminogen activator, and inhibits tumor growth and metastasis, which are independent of its protease-inhibitory activity. In the present study, we clarified the effects of host PCI on growth and metastasis of B16 melanoma (B16) cells by comparing between wild-type mice and mice transgenic for human PCI gene (hPCI-TG), which have a tissue distribution of PCI similar to that observed in humans. MATERIALS AND METHODS Growth of intracutaneously-injected B16 cells was evaluated by measuring the tumor volume, and metastatic behavior of intravenously-injected B16 cells by counting the number of metastatic lung nodules. RESULTS Growth of intracutaneously injected B16 cells was significantly faster in wild-type mice than in hPCI-TG mice; however, hPCI-TG mice developed more metastatic nodules of B16 cells in the lungs. Immunohistochemical analysis using anti-mouse fibrinogen antibody revealed more fibrin deposition in the lung in hPCI-TG mice than in wild-type mice. Furthermore, the more invasive behavior observed in hPCI-TG mice was reduced by rabbit anti-human PCI IgG, APC, or soluble TM administration for 3 consecutive days including the day that B16 cells were injected. CONCLUSIONS Our results suggest that like PCI expressed in tumor cells, host PCI also inhibits tumor growth, but host PCI promotes tumor metastasis via its procoagulant properties.

Activated protein C suppresses osteoclast differentiation via endothelial protein C receptor, protease-activated receptor-1, sphingosine 1-phosphate receptor, and apolipoprotein E receptor 2

INTRODUCTION Bone remodeling relies on a delicate balance between formation and resorption of bone tissues, processes in which bone-forming osteoblasts and bone-resorbing osteoclasts play central roles. Recently, we reported that anticoagulant activated protein C (APC) promotes osteoblast proliferation, but the role of the blood coagulation system in bone remodeling remains unclear. In this study, to further elucidate the relationship between bone remodeling and blood coagulation, we investigated the effect of APC on osteoclast differentiation. MATERIALS AND METHODS Normal human osteoclast precursor cells were cultured in their growth medium including soluble RANKL, M-CSF, and FBS, and on days 4 and 7, the culture medium was replaced with the same medium containing various concentrations of APC, protein C (PC), sphingosine 1-phosphate (S1P) receptor agonist, FTY720, or APC+various substances without FBS. On day 8, TRAP-positive multinucleated cells (≥3 nuclei) were counted manually using a light microscope. The effects of APC on NF-κB and NFATc1 activation were evaluated using specific ELISA. RESULTS APC suppressed RANKL-induced osteoclast differentiation, and this APC-induced suppression of osteoclast differentiation was inhibited by zymogen protein C and aprotinin, a serine protease inhibitor. Immunohistochemistry and RT-PCR analyses suggested that endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) were expressed in osteoclast precursor cells and osteoclasts. Both anti-PAR-1 antibody and anti-EPCR antibody (RCR-252), which blocks APC binding to EPCR, inhibited the APC-induced suppression of osteoclast differentiation. FTY720 had no effect on osteoclast differentiation. However, FTY 720 and S1P receptor antagonist, VP 23019, inhibited the APC-induced suppression of osteoclast differentiation. On the other hand, recombinant soluble human ApoER2 and anti-human ApoER2 inhibited the APC-induced suppression of osteoclast differentiation. Further, APC had no effect on NF-κB and NFATc1 activation. CONCLUSIONS APC suppresses human osteoclast differentiation mainly by inhibiting the formation of multinucleated cells via EPCR, PAR-1, S1P receptor, and ApoER2 in a manner that depends on APC protease activity.