Osteoinductive potential of recombinant BMP-9 in bone defects of mice treated with antiresorptive agents.

The aim of the present study was to investigate the effects of recombinant human (rh)BMP-9 on bone regenerative potential in a mouse model of antibody-mediated antiresorptive therapy (AMART). A monoclonal anti-murine receptor activator of nuclear factor-kappa B ligand (RANKL) antibody (mAb) was used to create an AMART model in mice. rhBMP-9 combined with collagen membrane was implanted in calvarial defects in mAb-treated mice. After 4 weeks, the bone formative potential in the defects was evaluated by micro-computed tomography and histological approaches. The groups implanted with rhBMP-9-containing collagen membranes demonstrated substantial osteopromotive potential, with significantly greater new bone volume (Sham + BMP-9 group; 0.86 ± 0.29 mm3 and mAb + BMP-9 group; 0.64 ± 0.16 mm3) than control PBS-membranes (Sham + PBS group; 0.44 ± 0.29 mm3 and mAb + PBS group; 0.24 ± 0.12 mm3) in both sham and mAb-treated mice. In line with in vivo study, bone marrow cells isolated from both sham and mAb-treated mice confirmed greater osteogenic potential upon stimulation with rhBMP-9 in vitro. These findings suggest for the first time that local rhBMP-9 administration might be a strategy to accelerate bone regeneration in the context of AMART.

Factor Xa inhibitors for preventing recurrent thrombosis in patients with antiphospholipid syndrome: a longitudinal cohort study.

OBJECTIVE: The objective of this study was to clarify the efficacy and safety of factor Xa inhibitors for antiphospholipid syndrome patients in real world utilization. METHODS: This is a retrospective cohort study comprised of all consecutive patients with antiphospholipid syndrome in our department over a period of 28 years. Patients treated with factor Xa inhibitors were extracted from the cohort. As a control group, patients treated with warfarin were selected from the same cohort with matched age, gender, coexistence of systemic lupus erythematosus, and the presence of antiplatelet therapy, after which we used a propensity score for each of the risk factors as an additional covariate in multivariate Cox proportional hazard regression. The primary endpoint was set as thrombotic and hemorrhagic event-free survival for five years. RESULTS: Among 206 patients with antiphospholipid syndrome, 18 had a history of anti-Xa therapy (five rivaroxaban, 12 edoxaban, one apixaban). Fourteen out of 18 patients on anti-Xa therapy had switched to factor Xa inhibitors from warfarin. Event-free survival was significantly shorter during anti-Xa therapy than that during warfarin therapy (hazard ratio: 12.1, 95% confidence interval: 1.73-248, p = 0.01) ( Figure 1(a) ). Similarly, event-free survival in patients treated with factor Xa inhibitors was significantly shorter compared with controls (hazard ratio: 4.62, 95% confidence interval: 1.54-13.6, p = 0.0075). In the multivariate Cox proportional hazard model, event-free survival in patients with anti-Xa therapy remained significantly shorter (hazard ratio: 11.9, 95% confidence interval: 2.93-56.0, p = 0.0005). CONCLUSIONS: Factor Xa inhibitors may not be recommended for antiphospholipid syndrome.

Administration of Thrombomodulin (CD141) Could Improve Cardiac Allograft Survival in Mice.

Thrombomodulin (TM) is a promising natural anti-coagulant therapeutic protein that is effective in the treatment of disseminated intravascular coagulation. However, the mechanisms by which TM on micro-vessels enable the regulation of intimal hyperplasia remain elusive. We investigated the graft-protective effects of TM in a fully major histocompatibility complex-mismatched murine cardiac allograft transplantation model. CBA recipients transplanted with a C57BL/6 heart received intraperitoneal administration of 0.2, 2.0, and 20.0 µg/day of TM for 8 days. Histological staining was conducted to assess the degree of inflammation and infiltration in the transplanted cardiac grafts. Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST] was 7 days). CBA recipients exposed to the above dosages had significantly prolonged allograft survival (MSTs were 16, 21, and 37.5 days, respectively). Histologic assessments from TM-exposed recipients 2 weeks after grafting showed that the myocardium and vessel structure in their allografts were clearly preserved, and that the infiltration of inflammatory cells around coronary arteries was suppressed. TM can induce the prolongation of fully major histocompatibility complex-mismatched cardiac allograft by exerting graft protective effects within the myocardium and coronary arteries.

Respiratory impedance is correlated with airway narrowing in asthma using three-dimensional computed tomography.

BACKGROUND: Respiratory impedance comprises the resistance and reactance of the respiratory system and can provide detailed information on respiratory function. However, details of the relationship between impedance and morphological airway changes in asthma are unknown. OBJECTIVE: We aimed to evaluate the correlation between imaging-based airway changes and respiratory impedance in patients with asthma. METHODS: Respiratory impedance and spirometric data were evaluated in 72 patients with asthma and 29 reference subjects. We measured the intraluminal area (Ai) and wall thickness (WT) of third- to sixth-generation bronchi using three-dimensional computed tomographic analyses, and values were adjusted by body surface area (BSA, Ai/BSA, and WT/the square root (√) of BSA). RESULTS: Asthma patients had significantly increased respiratory impedance, decreased Ai/BSA, and increased WT/√BSA, as was the case in those without airflow limitation as assessed by spirometry. Ai/BSA was inversely correlated with respiratory resistance at 5 Hz (R5) and 20 Hz (R20). R20 had a stronger correlation with Ai/BSA than did R5. Ai/BSA was positively correlated with forced expiratory volume in 1 second/forced vital capacity ratio, percentage predicted forced expiratory volume in 1 second, and percentage predicted mid-expiratory flow. WT/√BSA had no significant correlation with spirometry or respiratory impedance. CONCLUSIONS & CLINICAL RELEVANCE: Respiratory resistance is associated with airway narrowing.