Substantially High Hidden Blood Loss in Oblique Lateral Interbody Fusion: Retrospective Case Series.

Background and Objectives: Measured blood loss frequently underestimates true blood loss; this discrepancy is called hidden blood loss (HBL). The purpose of the present study was to measure HBL in oblique lateral interbody fusion (OLIF). Materials and Methods: Patients who underwent two-stage OLIF at our institute from September 2017 to September 2021 were retrospectively reviewed. Total blood loss (TBL) and HBL were calculated using the gross formula. The age, sex, body mass index (BMI), operation time, measured blood loss, the number of fused segments, hematocrit (HCT), anticoagulant or platelet medication, blood transfusion, days of hospitalization, pre-/postoperative Japanese Orthopedic Association (JOA) score, and JOA recovery rate were compared. Results: A total of thirteen patients were included in the study. The average age, BMI, number of fused segments, operation time, estimated blood loss, and blood transfusion were 69.5 years, 23.3, 2.5, 250 min, 122 mL, and 230 mL, respectively. Five patients received anticoagulant or platelet therapy. Days of hospitalization, pre-/postoperative JOA score, and JOA recovery rate were 14.9 ± 5.1, 19.9 ± 2.7, and 18.0 ± 43.4%, respectively. The TBL and HBL were 688 and 797 mL, respectively. Stepwise multiple regression analysis revealed that younger age (p = 0.01), female sex (p = 0.01), and number of fused segments (p = 0.02) were significantly associated with higher HBL. Conclusions: The HBL in OLIF was 797 mL, which was more than other previously reported procedures. Therefore, OLIF may not be less invasive in terms of HBL. Blood loss after surgery should be considered, especially when patients are younger, are female, and have a greater number of fused segments.

Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan.

BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

Bilateral L5 pedicle fracture with L5-S1 spondylolisthesis after single-level L4-5 posterior lumbar interbody fusion: illustrative case.

BACKGROUND: Single-level posterior lumbar interbody fusion (PLIF) or transforaminal lumbar interbody fusion (TLIF) is a commonly performed surgical procedure for L4-5 isthmic spondylolisthesis. Postoperative L5 pedicle fracture with rapidly progressive spondylolisthesis at L5-S1 segment after L4-5 PLIF/TLIF is quite rare, and the etiology remains unclear. This report describes this rare complication and proposes a possible etiology focusing on the lumbosacral sagittal imbalance characterized by an anteriorly shifted lumbar loading axis. OBSERVATIONS: The authors report a case complicated by L5 bilateral pedicle fractures and rapidly progressive spondylolisthesis at the L5-S1 segment very early after a single-level PLIF for L4-5 isthmic spondylolisthesis. Meyerding grade III anterolisthesis was observed at L5-S1 segment by 3 months after the initial surgery. Additional surgery was performed, and the fixation was extended to L4-ilium. Fracture healing was observed at 6 months postoperatively. LESSONS: This complication may have been caused by abnormal local shear forces on the posterior neural arch of L5 vertebra and L5-S1 intervertebral disc, which were triggered by the fusion surgery for L4 shear-type spondylolisthesis. L4 sagittal vertical axis is considered a reasonable parameter representing lumbosacral sagittal imbalance with an anteriorly shifted loading axis and may be a candidate for the predictive parameters of this rare complication.

Risk Factors for Cage Migration Following Lateral Lumbar Interbody Fusion Combined With Posterior Instrumentation: A Multicenter Retrospective Study of 983 Cases.

STUDY DESIGN: A multicenter retrospective study. OBJECTIVE: This study aimed to elucidate the incidence and risk factors of lateral cage migration (LCM) after lateral lumbar interbody fusion (LLIF) combined with posterior instrumentation. SUMMARY OF BACKGROUND DATA: LLIF has recently become a widely accepted procedure for the treatment of lumbar degenerative diseases. Although LLIF complications include vascular, nerve, and abdominal organ injuries, few studies have identified specific risk factors for LCM after LLIF. MATERIALS AND METHODS: Between January 2015 and December 2020, 983 patients with lumbar degenerative diseases or osteoporotic vertebral fractures underwent LLIF combined with posterior instrumentation. The fusion sites were located within the lumbosacral lesions. LCM was defined as a change of >3 mm in the movement of the radiopaque marker on radiographs. The patients were classified into LCM and non-LCM groups. Medical records and preoperative radiographs were also reviewed. The 1:5 nearest-neighbor propensity score matching technique was used to compare both groups, and radiologic parameters, including preoperative disk height (DH), preoperative sagittal disk angle, disk geometry, height variance (cage height minus DH), and endplate injury, were analyzed to identify the factors influencing LCM incidence. RESULTS: There were 16 patients (1.6%) with LCM (10 men and 6 women; mean age 70.1 yr). The Cochran-Armitage trend test showed a linear trend toward an increased rating of LCM with an increasing number of fused segments ( P =0.003), and LCM occurred at the terminal cage-inserted disk level in all patients in the LCM group. After propensity-matched analysis, we identified high DH ( P <0.001), large sagittal disk angle ( P =0.009), round-type disk ( P =0.008), and undersized cage selection ( P <0.001) as risk factors for LCM. CONCLUSION: We identified risk factors for LCM after LLIF combined with posterior instrumentation. To avoid this complication, it is important to select the appropriate cage sizes and enhance posterior fixation for at-risk patients.

PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes.

Prostaglandin E2 (PGE2) is one of pro-inflammatory mediators. PGE2 maintains the homeostasis of many organs including articular cartilage, and a previous report showed that continuous inhibition of PGE2 accelerates the progression of osteoarthritis (OA). While PGE2 inhibits matrix metalloprotease (MMP) expression in several types of cells, little is known on direct effects of PGE2 on MMP expression in articular chondrocytes. The objective of this study was to investigate direct effects of PGE2 on IL-1beta-induced MMP-1 and MMP-13 expression and the intracellular signaling in articular chondrocytes. PGE2 showed inhibitory effects on IL-1beta-induced MMP-1 and MMP-13 expression demonstrated by immunoblotting both in OA and normal chondrocytes, which was further confirmed by enzyme-linked immunosorbent assay and immunohistochemistry of explant cultures of articular cartilages. An EP4 agonist, ONO-AE1-329, mimicked the inhibitory effect of PGE2, while an EP4 antagonist, ONO-AE3-208, blocked the effects. PGE2 suppressed the phosphorylation of JNK and ERK MAP kinases, but only knockdown of JNK by specific siRNA mimicked the effect of PGE2. PGE2 further inhibited the phosphorylation of MKK4 without suppression of MKK7 phosphorylation, and of c-JUN to decrease expression levels of MMP-1 and MMP-13. These results demonstrate that PGE2 inhibits IL-1beta-induced MMP-1 and MMP-13 productions via EP4 by suppressing MKK4-JNK MAP kinase-c-JUN pathway.

CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear cells and enhances the production of IL-6.

Although a notable amount of CCL20 is detectable in the synovial fluid of human rheumatoid arthritis (RA), its role in the pathogenesis of RA remains to be determined. IL-1beta vigorously induced the production of CCL20 from FLSs of human RA and the production of CCL20 induced by TNF-alpha was partially attributed to a trace amount of IL-1beta induced by TNF-alpha. Although IL-6 failed to induce CCL20, TNF-alpha-induced IL-6 enhanced the production of CCL20 in an autocrine/paracrine manner. To determine the role of CCL20 and its sole receptor CCR6 in the recruitment of mononuclear cells (MNCs) into the inflamed joint of RA, conditioned medium of IL-1beta-stimulated FLSs was used in migration assays. The conditioned medium significantly recruited CCR6(+) MNCs in a CCL20-dependent manner. The production of CCL20 induced by TNF-alpha and IL-1beta was modified by helper-T-cell-derived cytokines. Interestingly, CCL20 enhanced the production of IL-6 coordinately with the stimulation of IL-17 but not with that of IFN-gamma. These findings imply FLSs stimulated by proinflammatory cytokines recruit CCR6(+) MNCs including IL-17-producing-helper T cells into the inflamed joint, leading to the enhancement of the production of CCL20, which chemokine and IL-17 coordinately induce proinflammatory cytokines.

Risk stratification and clinical course of hepatitis B virus reactivation in rheumatoid arthritis patients with resolved infection: final report of a multicenter prospective observational study at Japanese Red Cross Hospital.

BACKGROUND: The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. METHODS: HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. RESULTS: Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive < 2.1 log copies/mL during the observation period. We designed the following scoring system: HBV reactivation risk score = 1 × (age > 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. CONCLUSIONS: Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.

MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing.

OBJECTIVE: The purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models. METHODS: The expression profiles of chemokines were examined during fracture healing in wild-type (WT) mice using a polymerase chain reaction array and histological staining. The functional effect of monocyte chemotactic protein-1 (MCP-1) on primary mouse bone marrow stromal cells (mBMSCs) was evaluated using an in vitro migration assay. MCP-1-/- and C-C chemokine receptor 2 (CCR2)-/- mice were fractured and evaluated by histological staining and micro-computed tomography (micro-CT). RS102895, an antagonist of CCR2, was continuously administered in WT mice before or after rib fracture and evaluated by histological staining and micro-CT. Bone graft exchange models were created in WT and MCP-1-/- mice and were evaluated by histological staining and micro-CT. RESULTS: MCP-1 and MCP-3 expression in the early phase of fracture healing were up-regulated, and high levels of MCP-1 and MCP-3 protein expression observed in the periosteum and endosteum in the same period. MCP-1, but not MCP-3, increased migration of mBMSCs in a dose-dependent manner. Fracture healing in MCP-1-/- and CCR2-/- mice was delayed compared with WT mice on day 21. Administration of RS102895 in the early, but not in the late phase, caused delayed fracture healing. Transplantation of WT-derived graft into host MCP-1-/- mice significantly increased new bone formation in the bone graft exchange models. Furthermore, marked induction of MCP-1 expression in the periosteum and endosteum was observed around the WT-derived graft in the host MCP-1-/- mouse. Conversely, transplantation of MCP-1-/- mouse-derived grafts into host WT mice markedly decreased new bone formation. CONCLUSIONS: MCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing.

Stromal cell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy.

Stromal cell-derived factor 1 (SDF-1/CXCL12/PBSF) plays important roles in the biological and physiological functions of haematopoietic and mesenchymal stem cells. This chemokine regulates the formation of multiple organ systems during embryogenesis. However, its roles in skeletal development remain unclear. Here we investigated the roles of SDF-1 in chondrocyte differentiation. We demonstrated that SDF-1 protein was expressed at pre-hypertrophic and hypertrophic chondrocytes in the newly formed endochondral callus of rib fracture as well as in the growth plate of normal mouse tibia by immunohistochemical analysis. Using SDF-1(-/-) mouse embryo, we histologically showed that the total length of the whole humeri of SDF-1(-/-) mice was significantly shorter than that of wild-type mice, which was contributed mainly by shorter hypertrophic and calcified zones in SDF-1(-/-) mice. Actin cytoskeleton of hypertrophic chondrocytes in SDF-1(-/-) mouse humeri showed less F-actin and rounder shape than that of wild-type mice. Primary chondrocytes from SDF-1(-/-) mice showed the enhanced formation of philopodia and loss of F-actin. The administration of SDF-1 to primary chondrocytes of wild-type mice and SDF-1(-/-) mice promoted the formation of actin stress fibers. Organ culture of embryonic metatarsals from SDF-1(-/-) mice showed the growth delay, which was recovered by an exogenous administration of SDF-1. mRNA expression of type X collagen in metatarsals and in primary chondrocytes of SDF-1(-/-) mouse embryo was down-regulated while the administration of SDF-1 to metatarsals recovered. These data suggests that SDF-1 regulates the actin organization and stimulates bone growth by mediating chondrocyte hypertrophy.

Severe erosive arthropathy requiring surgical treatments in systemic lupus erythematosus.

We report a case of 43-year-old woman with an overlap syndrome of systemic lupus erythematosus (SLE) and dermatomyositis who developed erosive arthritis with extracapsular cysts involving multiple joints. An extensive synovectomy for the left wrist joint and a total joint replacement for the right hip joint were required to achieve complete symptom relief. She was not diagnosed with rheumatoid arthritis (RA). This was a rare case of SLE manifesting non-RA erosive arthritis that required surgical interventions.

Biological activation of bone-related biomaterials by recombinant adeno-associated virus vector.

Gene therapy is a promising clinical tool that is no longer limited as a method to supplement genetic deficits, but rather is considered reliable for delivering proteins to specific tissues or cells. Recombinant adeno-associated virus (rAAV) vector is one of the most potent gene transfer vehicles. Many biomaterials have been used in reconstructive surgery, but their biological inactivity has limited their use. To overcome shortcomings of available bone-related biomaterials, we investigated the combination of rAAV with biomaterials. Taking advantage of the method of lyophilizing rAAV onto biomaterials, we showed that an rAAV coating successfully induced beta-galactosidase protein expression by rat fibroblasts on hydroxyapatite, beta-tricalcium phosphate, and titanium alloy in vitro. beta-Galactosidase expression was detected for 8 weeks after implantation of rAAV-coated hydroxyapatite into rat back muscles in vivo. A coating of bone morphogenetic protein-2-expressing rAAV induced significant de novo bone formation on hydroxyapatite in rat back muscles. Our study demonstrates that the combination of lyophilized rAAV and biomaterials presents a promising strategy for bone regenerative medicine.

Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model.

OBJECTIVE: Stromal cell-derived factor 1 (SDF-1; CXCL12/pre-B cell growth-stimulating factor) is a dominant chemokine in bone marrow and is known to be involved in inflammatory diseases, including rheumatoid arthritis. However, its role in bone repair remains unknown. The purpose of this study was to investigate the role of SDF-1 and its receptor, CXCR4, in bone healing. METHODS: The expression of SDF-1 during the repair of a murine structural femoral bone graft was examined by real-time polymerase chain reaction and immunohistochemical analysis. The bone graft model was treated with anti-SDF-1 neutralizing antibody or TF14016, an antagonist for CXCR4, and evaluated by histomorphometry. The functional effect of SDF-1 on primary mesenchymal stem cells was determined by in vitro and in vivo migration assays. New bone formation in an exchanging-graft model was compared with that in the autograft models, using mice partially lacking SDF-1 (SDF-1(+/-)) or CXCR4 (CXCR4(+/-)). RESULTS: The expression of SDF1 messenger RNA was increased during the healing of live bone grafts but was not increased in dead grafts. High expression of SDF-1 protein was observed in the periosteum of the live graft. New bone formation was inhibited by the administration of anti-SDF-1 antibody or TF14016. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. Bone formation was decreased in SDF-1(+/-) and CXCR4(+/-) mice and was restored by the graft bones from CXCR4(+/-) mice transplanted into the SDF-1(+/-) femur, but not vice versa. CONCLUSION: SDF-1 is induced in the periosteum of injured bone and promotes endochondral bone repair by recruiting mesenchymal stem cells to the site of injury.

A novel femoral intramedullary plug with sliding mechanism.

A novel femoral intramedullary plug with a sliding mechanism has been developed and evaluated clinically. The new plug consists of a pair of specially designed components, each shaped like an obliquely cut cylinder. Postoperative plain radiographs of 30 arthroplasties using the plug were examined for cement leakage, plug migration, and radiolucent line formation between the cement and the femoral cortex. Plugging was complete in 22 cases. Leakage of the cement was seen in 4 cases, and migration of the plug was seen in the other 4 cases. Our study showed the efficacy of the plug in occluding the femoral canal completely in 14 of 22 cases. The plug appears to be promising for clinical applications, because it has good biocompatibility and can occlude the femoral canal tightly.