Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform.

INTRODUCTION: An analysis of the activated partial thromboplastin time (APTT) in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE) was carried out. METHODS: The APTT waveform was analyzed in the above patients to monitor edoxaban administration. RESULTS: Of these 99 patients, 12 exhibited deep vein thrombosis, and 25 had massive bleeding. An increased biphasic pattern of the APTT waveform was observed after the administration of edoxaban, but there were no significant differences between the patients with and without complications. The peak times of acceleration, velocity, and 1/2 fibrin formation were significantly prolonged after the administration of edoxaban, especially in patients with massive bleeding, and were moderately correlated with the anti-Xa activity. While the heights of velocity and acceleration peak 2 were lower in patients receiving warfarin treatment than in those receiving edoxaban, the widths of these parameters were significantly longer. The height of 1/2 fibrin formation and the width of acceleration peaks 1 and 2 and the velocity were significantly increased after the administration of edoxaban. CONCLUSION: The peak time of the APTT waveform was significantly prolonged after the administration of edoxaban. The analysis of the APTT waveform may therefore be useful for the prediction of the risk of massive bleeding.

Rebound-associated vertebral fractures after discontinuation of denosumab for the treatment of maxillitis.

We reported a 69-year-old female who discontinued denosumab due to dental treatment and subsequently suffered rebound-associated vertebral fractures 10 months after the last injection. This case raised an alarm regarding the discontinuation of denosumab for dental treatment. Denosumab, a human monoclonal antibody administered by subcutaneous injection, to the best of our knowledge, is the only fully investigated inhibitor of receptor activator of nuclear factor kappa B ligand. Discontinuation of denosumab leads to bone turnover rebound and rapid bone mineral density loss. Several studies have reported rebound-associated vertebral fractures after discontinuation of denosumab. We report on a new case of rebound-associated vertebral fractures after discontinuation of denosumab. A 69-year-old female, who withdrew from denosumab treatment after 3 years due to maxillitis, presented to our hospital with severe low back pain without any history of trauma. Ten months had passed since the last injection. Magnetic resonance imaging showed five acute vertebral fractures, which appeared to be rebound-associated vertebral fractures caused by discontinuation of denosumab due to dental treatment. This case clearly demonstrates the risk of discontinuation of denosumab for dental treatment.

Argatroban more effectively inhibits the thrombin activity in synovial fluid than naturally occurring thrombin inhibitors.

The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.

A retrospective analysis of nonresponse to daily teriparatide treatment.

UNLABELLED: Some patients with osteoporosis do not respond to teriparatide treatment. Prior bisphosphonate use, lower bone turnover marker (BTMs) concentrations, and lower early increases in BTMs were significantly associated with a blunted lumbar spine (LS) bone mineral density (BMD) response to daily treatment with teriparatide, although the impact was limited. INTRODUCTION: Some osteoporosis patients do not respond to teriparatide treatment. To better understand the factors underlying treatment nonresponses, we compared nonresponders' and responders' characteristics. METHODS: We retrospectively analyzed 354 male and female patients with osteoporosis who were administered teriparatide (20 µg/day) for 24 months. The patients were categorized as responders (≥3 % lumber spine (LS) bone mineral density (BMD) increase) or nonresponders (<3 % LS BMD increase), and the groups were compared. RESULTS: The univariate analyses determined that prior bisphosphonate use, a lower baseline procollagen type I N-terminal propeptide (PINP) concentration and a lower urinary N-telopeptide of type I collagen (uNTX) concentration at baseline were significantly associated with teriparatide nonresponses, but these factors were not significant following multivariate analysis. Diminished early increases in the bone turnover markers (BTMs) were also related to nonresponses after teriparatide treatment began. In the nonresponders, the mean (standard deviation (SD)) absolute LS and femoral neck (FN) BMD changes were -0.002 g/cm(2) (0.032) and -0.010 g/cm(2) (0.045), respectively. In the responders, the mean (SD) absolute LS and FN BMD changes were 0.118 g/cm(2) (0.056) and 0.021 g/cm(2) (0.046), respectively. The serum PINP and uNTX levels increased rapidly in both groups, but the responders showed higher early absolute serum PINP and uNTX increases. CONCLUSIONS: The factors associated with nonresponses were prior bisphosphonate use, lower baseline BTM levels, and lower early increases in the BTMs after starting teriparatide treatment, but the impact of these factors on achieving a ≥3 % LS BMD increase at 24 months was limited.

Usefulness of daily teriparatide treatment in elderly patients over 80 years of age.

UNLABELLED: The percent and absolute lumbar spine and femoral neck bone mineral densities and procollagen type I N-terminal propeptide (PINP) and urinary N-telopeptide level increases noted after teriparatide 20 µg/day treatment for 24 months were similar in the older (age ≥ 80 years) and younger (age < 80 years) subgroups. INTRODUCTION: Many individuals are living into their eighth and ninth decades, but little is known about the efficacy of osteoporosis medication for this population. We retrospectively compared usefulness of daily teriparatide therapy in osteoporosis patients ≥80 and <80 years to detect possible age-related differences. METHODS: We analyzed 628 osteoporosis patients treated with teriparatide 20 µg/day for 24 months. The primary efficacy measures were changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) over 24 months. Changes in serum procollagen type I N-terminal propeptide levels and urinary N-telopeptide (uNTX) excretion were also measured. Patients were divided into age subgroups (older, ≥80 years; younger, <80 years) for BMD and bone turnover marker comparison. RESULTS: In the older subgroup, the percent LS BMD significantly increased by 14.6 ± 10.4 % (mean ± SD) and FN BMD significantly increased by 4.5 ± 10.7 % at 24 months. In the younger subgroup, the percent LS BMD significantly increased by 12.2 ± 8.5 % and FN BMD significantly increased by 2.9 ± 8.3 % at 24 months. In the older subgroup, the mean absolute LS BMD change was 0.111 ± 0.071 g/cm(2) and FN BMD change was 0.019 ± 0.043 g/cm(2). In the younger subgroup, the mean absolute LS BMD change was 0.098 ± 0.065 g/cm(2) and FN BMD change was 0.016 ± 0.045 g/cm(2). The percent and absolute BMD increases in LS and FN and changes in PINP and uNTX were similar between the subgroups. CONCLUSIONS: The usefulness of daily teriparatide treatment is not age dependent.

Usefulness and complications associated with thenar and standard portals during arthroscopic surgery of thumb carpometacarpal joint.

PURPOSE: Advances in small arthroscopy have enabled a minimally invasive surgery for thumb carpometacarpal joints. However, surgery is often difficult using standard CM-radial (CM-R) and CM-ulnar portals (CM-U). Here, we describe the clinical applications and complications associated with using thenar portal (TP) and standard portals. METHODS: Arthroscopic surgeries of thumb carpometacarpal joint were performed in 21 patients including 15 patients with osteoarthritis and six Bennett's fracture-dislocations. Complications and the frequency of use associated with each portal were evaluated. RESULTS: Complications associated with the CM-R portal comprised paresthesia due to damage of the radial nerve branches in two patients. No nerves were damaged but the operation scar became tender at the TP in three patients. The CM-R was used at a lower frequency when the TP was utilized. CONCLUSION: The clinical use of TP may decrease the risk of radial sensory nerve damage through decreasing frequency of use of the CM-R that is located near the nerve. LEVEL OF STUDY: IV.

The value of the high-sensitivity modified Glasgow prognostic score in predicting the survival of patients with a soft-tissue sarcoma.

The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The Hs-mGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of disease-specific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma.

Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis.

OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92.

Analysis of daily teriparatide treatment for osteoporosis in men.

UNLABELLED: The percent and absolute lumbar spine and femoral neck bone mineral densities and absolute procollagen type I N-terminal propeptide (PINP) increases following a 20-µg/day teriparatide treatment for 12 months were similar in men and women regardless of sex differences. INTRODUCTION: Several placebo-controlled studies have measured the effects of daily teriparatide in men and postmenopausal women with osteoporosis but none have directly compared the effects between these groups. We retrospectively compared the effects of daily teriparatide therapy in men and postmenopausal women with osteoporosis and investigated biochemical markers of bone turnover to detect possible sex differences. METHODS: Patients (563; 75 men and 488 women) with osteoporosis were retrospectively investigated. All patients were administered with teriparatide at 20 µg/day for 12 months. The primary efficacy measure was changed in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) after 12 months of treatment. The change in serum levels of procollagen type I N-terminal propeptide (PINP) and urinary N-telopeptide (uNTX) excretion after 4, 8 and 12 months of treatment were also measured. RESULTS: In men, the percent LS BMD significantly increased by 11.3 ± 9.9 % (mean ± standard deviation (SD)) and the FN BMD increased by 0.4 ± 6.4 % without a significant difference at 12 months. In postmenopausal women, the percent LS BMD significantly increased by 9.6 ± 8.1 % and the FN BMD significantly increased by 2.4 ± 7.8 % at 12 months. The percent and absolute BMD increases in LS and FN between men and women were similar. The absolute increases in PINP were similar in both groups at 4, 8 and 12 months. However, the absolute increases in uNTX were significantly lower in men than in women at 8 and 12 months. CONCLUSION: Daily teriparatide treatment was as effective in men as in postmenopausal women regardless of sex differences.

Subcutaneous abscess due to the basidiomycete Phellinus mori in a patient with chronic granulomatous disease.

Chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired phagocyte killing of intracellular pathogens, is characterized by recurrent, life-threatening, bacterial and fungal infections. As a result of improvements in microbiologic culture and identification techniques, a number of unique filamentous fungi have been reported as significant pathogens in patients with CGD. We report a case of subcutaneous basidiomycete Phellinus mori infection in a patient with CGD. To the best of our knowledge, this is the first reported case of human infection by this fungus. The causative fungus was identified on the basis of its morphological characteristics and nucleotide sequence on the internal transcribed spacer region of the ribosomal RNA gene. This is the fifth case report of filamentous basidiomycetes infecting a patient with CGD; all of these cases have been caused by Phellinus species. We highlight the importance of recognizing filamentous basidiomycetes Phellinus species as possible agents of non-Aspergillus fungal infections in patients with CGD.

An algorithm using the early changes in PINP to predict the future BMD response for patients treated with daily teriparatide.

UNLABELLED: About two thirds of patients with a procollagen type I N-terminal propeptide (PINP) increase of >80 µg/l at 1 month after starting teriparatide therapy showed a ≥10 % increase in lumbar spine (LS) bone mineral density (BMD) from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with daily teriparatide. INTRODUCTION: An algorithm using PINP is provided in osteoporotic patients with teriparatide treatment. The correlations between the early changes in PINP and the subsequent BMD changes after daily teriparatide therapy were studied to develop an algorithm to monitor patients. METHODS: We evaluated whether early changes in PINP correlated with the changes in BMD at 12 months and developed an algorithm using the early changes in PINP to predict the upcoming BMD increases. RESULTS: The highest correlation coefficient for the relationship between PINP and LS BMD response was determined for the absolute change in PINP at 1 month and the percent change in LS BMD at 12 months (r = 0.36, p <0.01). Using a receiver operator curve analysis, we determined that an 80 µg/l increase in PINP was the most convenient predictor of a 10% increase in LS BMD from baseline (area under curve = 0.72). Using a cut-off value of 80 µg/l, the positive predictive value for predicting a 10% increase in LS BMD from baseline to 12 months was 65%. CONCLUSION: Greater short-term changes in PINP with teriparatide therapy are associated with greater 12-month increases in LS BMD. About two thirds of patients with a PINP increase of >80 µg/l at 1 month after starting treatment showed a ≥10 % increase in LS BMD from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with teriparatide.

Efficacy of the dynamic radiographs for diagnosing acute osteoporotic vertebral fractures.

UNLABELLED: We investigated the efficacy of dynamic radiographs for diagnosing acute osteoporotic vertebral fractures (OVFs) compared with supine radiographs or sitting radiographs alone. Evaluation of the dynamic radiographs was superior to the other evaluations. Dynamic radiographs provide a convenient and useful method of diagnosing acute OVFs. INTRODUCTION: Identifying acute OVFs on plain radiographs is difficult. We studied a new approach to identify acute OVFs on the basis of fracture mobility. METHODS: We performed a retrospective radiographic analysis of 472 acute OVFs (<3 weeks after onset), which were diagnosed on the basis of magnetic resonance imaging of T5 through L5 (a total of 5,239 vertebrae). Supine lateral radiographs were compared with sitting lateral radiographs to determine the presence or absence of mobility. Vertebrae showing changes in the vertebral body height were diagnosed as acute OVFs. We analyzed the diagnostic accuracy on the basis of comparative supine and sitting lateral radiographs and compared it with that of radiographs obtained in the supine or the sitting position alone. RESULTS: Of the 472 acute OVFs diagnosed, 313 (66 %) exhibited vertebral mobility on supine lateral and sitting lateral radiographs. Correct diagnoses of acute OVFs or no acute OVFs were made in 4,883 vertebrae. There were 159 unreadable OVFs (3 %), and 197 previous OVFs (4 %) were misdiagnosed as acute OVFs. The sensitivity was 66 % and the specificity was 96 %. Evaluation of the mobility of acute OVFs in the supine and the sitting position was superior to evaluation using radiographs in either the supine or the sitting position alone. CONCLUSIONS: Dynamic radiographs provide a convenient way to identify acute OVFs.

Deep-vein thrombosis after resection of musculoskeletal tumours of the lower limb.

The aim of this study was to define the incidence of venous thromboembolism (VTE) and risk factors for the development of deep-vein thrombosis (DVT) after the resection of a musculoskeletal tumour. A total of 94 patients who underwent resection of a musculoskeletal tumour between January 2003 and December 2005 were prospectively studied. There were 42 men and 52 women with a mean age of 54.4 years (18 to 86). All patients wore intermittent pneumatic compression devices and graduated compression stockings. Ultrasound examination of the lower limbs was conducted to screen for DVT between the fifth and ninth post-operative days. DVT was detected in 21 patients (22%). Of these, two were symptomatic (2%). One patient (1%) had a fatal pulmonary embolism. Patients aged ≥ 70 years had an increased risk of DVT (p = 0.004). The overall incidence of DVT (both symptomatic and asymptomatic) after resection of a musculoskeletal tumour with mechanical prophylaxis was high. It seems that both mechanical and anticoagulant prophylaxis is needed to prevent VTE in patients who have undergone the resection of a musculoskeletal tumour.

Outcome of soft-tissue sarcoma patients who were alive and event-free more than five years after initial treatment.

We evaluated the risk of late relapse and further outcome in patients with soft-tissue sarcomas who were alive and event-free more than five years after initial treatment. From our database we identified 1912 patients with these pathologies treated between 1980 and 2006. Of these 1912 patients, 603 were alive and event-free more than five years after initial treatment and we retrospectively reviewed them. The mean age of this group was 48 years (4 to 94) and 340 were men. The mean follow-up was 106 months (60 to 336). Of the original cohort, 582 (97%) were alive at final follow-up. The disease-specific survival was 96.4% (95% confidence interval (CI) 94.4 to 98.3) at ten years and 92.9% (95% CI 89 to 96.8) at 15 years. The rate of late relapse was 6.3% (38 of 603). The ten- and 15-year event-free rates were 93.2% (95% CI 90.8 to 95.7) and 86.1% (95% CI 80.2 to 92.1), respectively. Multivariate analysis showed that tumour size and tumour grade remained independent predictors of events. In spite of further treatment, 19 of the 38 patients died of sarcoma. The three- and five-year survival rates after the late relapse were 56.2% (95% CI 39.5 to 73.3) and 43.2% (95% CI 24.7 to 61.7), respectively, with a median survival time of 46 months. Patients with soft-tissue sarcoma, especially if large, require long-term follow-up, especially as they have moderate potential to have their disease controlled.

The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone.

The aim of this study was to determine whether the level of circulating C-reactive protein (CRP) before treatment predicted overall disease-specific survival and local tumour control in patients with a sarcoma of bone. We retrospectively reviewed 318 patients who presented with a primary sarcoma of bone between 2003 and 2010. Those who presented with metastases and/or local recurrence were excluded. Elevated CRP levels were seen in 84 patients before treatment; these patients had a poorer disease-specific survival (57% at five years) than patients with a normal CRP (79% at five years) (p < 0.0001). They were also less likely to be free of recurrence (71% at five years) than patients with a normal CRP (79% at five years) (p = 0.04). Multivariate analysis showed the pre-operative CRP level to be an independent predictor of survival and local control. Patients with a Ewing's sarcoma or chondrosarcoma who had an elevated CRP before their treatment started had a significantly poorer disease-specific survival than patients with a normal CRP (p = 0.02 and p < 0.0001, respectively). Patients with a conventional osteosarcoma and a raised CRP were at an increased risk of poorer local control. We recommend that CRP levels are measured routinely in patients with a suspected sarcoma of bone as a further prognostic indicator of survival.

Age-adjusted relative suicide risk by marital and employment status over the past 25 years in Japan.

BACKGROUND: There have been no longitudinal studies in Japan examining national-level data for suicide risk by marital and employment status. We examined the age-adjusted relative suicide risk (RR) by marital and employment status from national data acquired for all suicides in Japan occurring in the past 25 years. METHODS: All deaths identified as suicides according to ICD-9 and ICD-10 were extracted from vital statistics data of Japan for the years 1980, 1985, 1990, 1995, 2000 and 2005. Population statistics for Japanese residents aged ≥15 years were obtained from the census. RESULTS: Suicide rates for almost all categories analyzed decreased in both genders between 1985 and 1990 and increased between 1995 and 2000, especially among men. Unemployed and divorced men had a consistently higher RR in each year analyzed. Unemployed and divorced women had a higher risk than those in other categories, especially in 2000 and 2005. In women, particularly in 1980, 1985 and 1990, those who were unemployed and never married had a similar RR to those who were unemployed and divorced. CONCLUSIONS: Unemployed and divorced people were at a high risk of suicide over the past 25 years, particularly in 2000 and 2005. Our findings suggest that the effects of divorce and unemployment on suicide risk are synergistic.