Barthel Index and Age as Predictors of Discharge Destination in Patients with Glioblastoma.

This study aimed to investigate the predictive factors of transfer of glioblastoma multiforme (GBM) patients who underwent rehabilitation in acute care hospitals. We retrospectively identified 85 patients with GBM who underwent rehabilitation at our hospital. Multivariable logistic regression analysis showed that age and Barthel index (BI) at rehabilitation initiation significantly influenced the discharge destination. Cut-off values for these factors were 76 years of age and 30 BI points. These findings could help predict the discharge destination and the choice of rehabilitation strategies of newly diagnosed patients with GBM admitted to an acute care hospital.

Feasibility of methotrexate discontinuation following tocilizumab and methotrexate combination therapy in patients with long-standing and advanced rheumatoid arthritis: a 3-year observational cohort study.

OBJECTIVES: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. METHODS: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. RESULTS: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). CONCLUSIONS: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression.

Lower limb alignment in healthy Japanese adults.

BACKGROUND: Knowledge regarding the normal alignment of the lower limb is important when considering alignment for total knee arthroplasty. However, few studies have explored the lower limb alignment of healthy Japanese subjects. METHODS: Between July and October 2020, we performed whole leg standing radiography of 120 legs of 60 healthy adult Japanese volunteers aged <50 years in the closed-leg stance. The measurement parameters were hip knee ankle angle (positive for varus), percentage of constitutional varus (hip knee ankle angle ≥ 3°), mechanical axis deviation ratio, mechanical lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle (positive for lateral opening), and tibial joint line angle (positive for medial inclination). RESULTS: The mean measured values for all volunteers, men and women, were as follows: hip knee ankle angle (°), 2.3, 2.6, and 2.0; mechanical axis deviation ratio, 35.8, 35.6, and 36.9; mechanical lateral distal femoral angle (°), 86.7, 87.0, and 86.7; medial proximal tibial angle (°), 85.6, 85.0, and 86.2; joint line convergence angle (°), 0.6, 0.3, and 0.8; and tibial joint line angle (°), -1.0, -0.7, -1.4, respectively. The percentage of constitutional varus was 35.8% overall, 35.8% in men and 35.3% in women. Only the medial proximal tibial angle was smaller in men than that in women (p = 0.003). CONCLUSIONS: The mechanical lateral distal femoral and medial proximal tibial angles were smaller, hip knee ankle angle was larger, and percentage of constitutional varus was higher in Japanese subjects than those reported for subjects in other countries. Our findings improve the understanding of Japanese-specific alignments when considering alignment for lower limb surgery, especially, total knee arthroplasty.

Decennial trends in hip fractures over 20 years in Yamagata Prefecture, Japan.

BACKGROUND: Hip fracture is among the most common injuries in elderly people. We aimed to investigate the decennial trends in hip fractures in patients ≥65 years of age. METHODS: A questionnaire was distributed to all hospitals with a Department of Orthopaedic Surgery in Yamagata Prefecture to collect data on hip fractures occurring in 1996, 2006 and 2016. RESULTS: The response rate was 100%. The total numbers of hip fractures in 1996, 2006 and 2016 were 665, 1169 and 1,728, respectively (crude incidence: 258, 373 and 494 per 100,000 person-year, respectively). Injuries frequently occurred in the early morning and daytime morning in 1996. In contrast, they frequently occurred in activity times (e.g., morning and afternoon) in 2006 and 2016. Among the patients, 80-90% were injured by simple falls, and 70-80% were injured indoors. The incidence of trochanteric fractures was approximately 1.8-1.9 times greater than incidence of neck fractures in all years. Especially, trochanteric fractures in females of ≥90 years of age markedly increased. The rate of surgical treatment was the same in 1996 and 2006, but was lower in 2016. In 1996, the percentage of independent walkers at discharge and 1 year later was almost the same. In 2006 and 2016, the rate of independent walkers was low at discharge, but increased 1 year later. The rate of discharge to home decreased gradually. The combined percentage of patients discharged to home and to rehabilitation institutions in 2006 and the percentage of patients who entered the regional referral clinical pathway in 2016 were both approximately 70%, with no marked changes observed. CONCLUSIONS: Hip fractures, especially trochanteric fractures in super-aged females, increased. Discharge to home decreased, and the use of the regional referral clinical pathway was widespread. Ambulation ability was reduced at discharge, but improved after 1 year.

Evaluation of hindfoot and knee alignment by the hip-to-calcaneus view in patients with knee osteoarthritis and healthy individuals.

BACKGROUND: Hip-to-calcaneus (HC) view is a whole-leg standing view that can visualize the hindfoot in detail. The aim of this study was to investigate the reliability and validity of tibiocalcaneal angle in HC view (H-TCA) by comparing it with that in long axial view (L-TCA). We also verified whether periarticular knee alignment parameters, measured conventionally in whole-leg standing radiography, could be measured in HC view. METHOD: Sixty healthy volunteers and 61 patients with medial knee osteoarthritis were included. H-TCA was measured by two examiners in the healthy group, and intra-class correlation coefficients (ICCs) were evaluated. H-TCA and L-TCA were then measured in the healthy and osteoarthritis groups and correlated. Finally, we measured hip-knee-ankle angle, mechanical axis deviation ratio, mechanical lateral distal femoral angle, medial proximal tibial angle, and joint-line convergence angle in HC view and conventional whole-leg standing radiography to evaluate statistical differences and correlations. RESULTS: The intra-observer and inter-observer ICCs were 0.86 and 0.76, respectively. Correlation coefficients (r) between H-TCA and L-TCA were r = 0.87 in healthy group and r = 0.81 in osteoarthritis group, indicating a strong positive correlation in both groups. There was no significant difference in periarticular knee alignment parameters between HC view and conventional whole-leg radiography. CONCLUSIONS: Hindfoot evaluation in HC view showed high intra-observer and inter-observer reliabilities and strong positive correlation with TCA in long axial view. By using HC view before knee surgery, such as total knee arthroplasty, other necessary alignments can be evaluated simultaneously.

Effectiveness of Bone Marrow-Derived Platelet-Rich Fibrin on Rotator Cuff Healing in a Rabbit Degenerative Model.

BACKGROUND: Platelet-rich fibrin (PRF) is a second-generation platelet concentrate. Although peripheral blood-derived PRF (P-PRF) is commonly applied in biological augmentation, there is no report about the therapeutic effect of bone marrow-derived PRF (BM-PRF) for degenerative rotator cuff tears (RCTs). PURPOSE/HYPOTHESIS: To examine the effects of platelet-rich plasma (PRP), P-PRF, and BM-PRF during rotator cuff repair (RCR) in degenerative RCTs in rabbits. We hypothesized that BM-PRF would accelerate the bone-tendon healing after RCR. STUDY DESIGN: Controlled laboratory study. METHODS: Degenerative RCT models were created 2 weeks before beginning the study, and 68 juvenile rabbits were divided into 4 groups: the control, PRP, P-PRF, and BM-PRF groups. RCR without augmentation was done in the control group. PRP was prepared by centrifuging peripheral blood twice using a plastic tube. P-PRF and BM-PRF were prepared by centrifuging peripheral blood and bone marrow, respectively, using a glass tube. Rabbits from PRP, P-PRF, and BM-PRF groups were administered the augmentation in a similar fashion for RCR, between the rotator cuff and the footprint of the humerus. At 4, 8, and 12 weeks, rabbits were euthanized and histologically assessed using hematoxylin and eosin staining, Alcian blue staining, and immunohistochemical staining for type I and III collagen. The sections were also evaluated with immunofluorescence staining of vascular endothelial growth factor (VEGF) at 4 weeks. RESULTS: The continuity was significantly better in the BM-PRF group at 4 weeks (P < .05). Immunofluorescence staining demonstrated that VEGF-positive stained cells were significantly greater in the BM-PRF group than in the control group (P < .01). The modified tendon maturing score was significantly greater in the BM-PRF group than in the control and PRP groups at 12 weeks (P < .05). There was no significant difference in the modified tendon maturing score of the P-PRF group compared with the control group. CONCLUSION: The rabbit model of degenerative RCTs demonstrated that RCR combined with BM-PRF enhanced tendon-bone continuity and increased the VEGF-positive cells at 4 weeks and obtained preferable tendon-bone maturation at 12 weeks. CLINICAL RELEVANCE: RCR augmented with BM-PRF has the potential to improve clinical outcomes for RCTs.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

Assessment of the severity of curly toe.

BACKGROUND: Curly/underlapping toe involves flexion, adduction, and varus deformity of the interphalangeal joints. There are no previous reports showing the relationship between physical examination and X-ray findings among patients with curly toe deformity. METHODS: We investigated the clinical findings of 116 consecutive patients associated with 239 underlapping toes. We compared the age and affected toes between patients whose deformities were pointed out at a pediatric medical examination (group 1) and those referred for medical treatment (group 2). The degree of curly toe deformity was graded by a physical examination and X-ray. RESULTS: The average age at presentation was 2.7 years. The affected toes were significantly different between groups 1 and 2 (p < .001). The morbidity of each toe differed significantly in group 2 (p < .005) but not in group 1. The correlation between the appearance grading and classification by X-ray was very strong using Spearman's rank correlation coefficient. The severity of curly toe was divided into mild in 104 toes, moderate in 105 toes, and severe in 17 toes. The methods of conservative treatment were observation only in 15 cases, manipulations in 30 cases, taping in 67 cases, and a brace in 9 cases. Surgery was performed in 8% of cases. CONCLUSION: Curly toe deformity of the third or fourth toes tend to be referred for medical treatment because of the abnormality. Our grading system using a physical examination and classification by X-ray was useful for assessing the severity of curly toe.

Forefoot Deformities in Patients with Rheumatoid Arthritis: Mid- to Long-Term Result of Joint-Preserving Surgery in Comparison with Resection Arthroplasty.

BACKGROUND: Joint-preserving surgery for the forefoot has been increasingly performed for rheumatoid arthritis (RA). We compared joint-preserving surgeries with resection arthroplasty for RA in the forefoot. METHODS: Forefoot surgeries were performed on 62 toes in 42 patients with RA (men: 2; women: 40) between 2002 and 2018. Three groups were compared: PP-31 toes treated with joint-preserving surgery involving the modified Mann method for the big toe and offset osteotomy for lesser toes, PR-15 toes treated with joint-preserving surgery for the big toe and resection arthroplasty for lesser toes, and RR-16 toes treated with resection arthroplasty for all the toes. RESULTS: The PP group had significantly higher mean scores on a scale for RA in the foot and ankle at the latest follow-up than the RR group (86 vs. 75 points; p < 0.05). Hallux valgus (angle > 20°) of the big toe at the latest follow-up recurred in 10 (32%), 9 (60%), and 16 (100%) patients in the PP, PR, and RR groups, respectively. A revision surgery was performed in one patient each in the PP and PR groups. CONCLUSIONS: Joint-preserving surgery is superior to resection arthroplasty in preventing function loss and the recurrence of hallux valgus.

Differences in subtrochanteric and diaphyseal atypical femoral fractures in a super-aging prefectural area: YamaCAFe Study.

INTRODUCTION: Atypical femoral fractures (AFFs) have been correlated with long-term use of bisphosphonates (BPs), glucocorticoids (GCs), and femoral geometry. We investigated the incidence and characteristics of subtrochanteric (ST) and diaphyseal (DP) AFFs in all institutes in a super-aging prefectural area. MATERIALS AND METHODS: We performed a blinded analysis of radiographic data in 87 patients with 98 AFFs in all institutes in Yamagata prefectural area from 2009 to 2014. Among the 98 AFFs, 57 AFFs comprising 11 ST fractures in 9 patients and 46 DP fractures in 41 patients with adequate medical records and X-rays were surveyed for time to bone healing and geometry. RESULTS: Of the 87 patients, 67 received BPs/denosumab (77%) and 10 received GCs (11%). Surgery was performed in 94 AFFs. Among 4 AFFs with conservative therapy, 3 required additional surgery. In univariate regression analyses for ST group versus DP group, male-to-female ratio was 2/7 versus 1/40, mean age at fracture was 58.2 (37-75) versus 78 (60-89) years, rheumatic diseases affected 55.5% (5/9) versus 4.9% (2/41), femoral lateral bowing angle was 1.7 (0-6) versus 11.8 (0.8-24)°, GC usage was 67% (6/9) versus 4.9% (2/41), and bone healing time was 12.1 (6-20) versus 8.1 (3-38) months (p < 0.05). In multivariate analyses, higher male-to-female ratio, younger age, greater proportion affected by rheumatic diseases, and higher GC usage remained significant (p < 0.05). CONCLUSIONS: The incidence of AFFs in our prefectural area was 1.43 cases/100,000 persons/year. This study suggests that the onset of ST AFFs have greater correlation with the worse bone quality, vice versa, the onset of DP AFFs correlated with the bone geometry. The developmental mechanisms of AFFs may differ significantly between ST and DP fractures.

Effectiveness of Baricitinib in Refractory Seronegative Rheumatoid Arthritis and Uveitis: A Case Report.

Baricitinib is a Janus kinase (JAK) inhibitor used to treat refractory rheumatoid arthritis and blocks the subtypes JAK1 and JAK2. A 35-year-old man with seronegative rheumatoid arthritis complicated by bilateral severe non-granulomatous panuveitis was resistant to steroid treatment, multiple conventional disease-modifying antirheumatic drugs (methotrexate and salazosulfapyridine), and TNF-α inhibitors (adalimumab and infliximab). Therefore, the TNF-α inhibitors were switched to baricitinib to decrease the activity of systemic arthritis. Along with the amelioration of inflammatory activity in seronegative rheumatoid arthritis, the inflammatory activity of uveitis was decreased. Vitreous opacity, serous retinal detachment, and anterior chamber cells showed improvement. Baricitinib was effective not only in refractory systemic arthritis but also in uveitis, which may provide a new treatment option for patients with refractory uveitis.

Comparative study of HO-1 expressing synovial lining cells between RA and OA.

OBJECTIVES: We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex. METHODS: The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by an in situ proximity ligation assay (PLA) with immunofluorescence. HO-1 mRNA was investigated by reverse transcription-polymerase chain reaction. RESULTS: The number of HO-1+ cells from the RA synovium is higher than that from OA synovium. The double positive cells of HO-1 and IgG-Fc/HLA-DR complex were detected by the in situ PLA with immunofluorescence in RA synovium. HO-1 mRNA was detected in both RA and OA synovium. CONCLUSION: A portion of HO-1+ cells with IgG-Fc/HLA-DR complex in lining layer of RA may be concluded as one of antigen presenting cells in RA and may be involved in production of RF.

Disassembly of bilateral bipolar heads within 10 years after hip hemiarthroplasties for avascular necrosis of femoral heads: a case report.

Prosthetic joint surgeries, total hip arthroplasty (THA) or bipolar hemiarthroplasty (BHA) and joint preservation surgeries can be performed for avascular osteonecrosis of femoral head (ONFH) with collapse. Although excellent surgical results have been reported, long-term survivorship and postoperative complications are a great concern. The purpose of this study was to report a case of bilateral disassembly of bipolar heads within 10 years after BHA for ONFH. A 61-year-old man, whose occupation was carpenter, underwent bilateral BHA for ONFH at another hospital when he was 57 years old. He had acute right hip pain during working and visited our institute. Radiographs revealed intra-articular (outer and inner head) disassembly of the right bipolar head, and conversion to THA was performed. Five years later, he had contralateral (left) hip pain. Radiographs revealed disassembly of bipolar head, as had occurred with the right hip, and similar conversion surgery was performed for the left hip. Marked wear and detachment of the polyethylene bearings of the outer head and failure of the locking mechanism between a skirted 22-mm-diameter inner head and polyethylene insert were observed in both hips at each revision surgery. Degeneration of the acetabulum were also observed in both hips. The failure of the self-centering mechanism because of degenerative change of the acetabulum, impingement of the outer head and neck, and high activity seemed to be the causes of disassembly of the bilateral bipolar heads. Therefore, it is important to select the type of prostheses depending on the age, activity and occupation of each patient.

Immunohistochemical Analysis of Inflammatory Rheumatoid Synovial Tissues Using Anti-Human Podoplanin Monoclonal Antibody Panel.

Podoplanin (PDPN) is a transmembrane sialoglycoprotein, which is expressed in several normal tissues and malignant tumors. Although PDPN expression in rheumatoid arthritis (RA) has been reported, the role of PDPN in RA and other arthritic conditions has not been fully elucidated. In this study, we examined PDPN expression in inflammatory synovial tissues using an anti-human PDPN (hPDPN) monoclonal antibody (mAb) panel to select the most useful one for evaluation of synovitis. Synovial tissue samples were obtained from 11 RA patients and 9 osteoarthritis (OA) patients undergoing joint surgery. PDPN-positive cells were immunostained by a panel of PDPN mAbs (NZ-1, LpMab-3, LpMab-7, LpMab-10, LpMab-12, LpMab-13, and LpMab-17), followed by cell grading of inflammation and cell counting of PDPN-positivity by a quantitative analyzer. Immunohistochemistry showed that PDPN was markedly expressed in both macrophage-like type A and fibroblast-like type B lining cells of the hyperplastic synovial lining cell layer, and macrophages and fibroblasts in the stroma of RA. Among anti-PDPN mAbs, LpMab-12 showed the highest score. In inflammatory OA synovium, PDPN expression was also detectable. Although LpMab-12 also showed the highest score in OA, the difference was not statistically significant. The inflammatory synovitis score of RA was significantly higher than that of OA. PDPN was expressed in inflammatory lining cells and sublining stroma of RA and OA synovium. In the seven anti-hPDPN antibodies examined, LpMab-12 was the most stainable antibody for PDPN in RA synovitis. Thus, LpMab-12 for PDPN has a possible and promising specific biomarker for evaluating synovitis in RA and inflammatory OA.

Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements.

The innate immune sensors, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), can recognize not only exogenous pathogen-associated molecular patterns (PAMPs), but also endogenous molecules created upon tissue injury, sterile inflammation, and degeneration. Endogenous ligands are called damage-associated molecular patterns (DAMPs), and include endogenous molecules released from activated and necrotic cells as well as damaged extracellular matrix. TLRs and NLRs can interact with various ligands derived from PAMPs and DAMPs, leading to activation and/or modulation of intracellular signalling pathways. Intensive research on the innate immune sensors, TLRs and NLRs, has brought new insights into the pathogenesis of not only various infectious and rheumatic diseases, but also aseptic foreign body granuloma and septic inflammation of failed total hip replacements (THRs). In this review, recent knowledge is summarized on the innate immune system, including TLRs and NLRs and their danger signals, with special reference to their possible role in the adverse local host response to THRs.

Distribution of Podoplanin in Synovial Tissues in Rheumatoid Arthritis Patients Using Biologic or Conventional Disease-Modifying Anti-Rheumatic Drugs.

OBJECTIVE: Podoplanin (PDPN) mediates tumor cell migration and invasion, which phenomena might also play a role in severe rheumatoid arthritis (RA). Therefore, the precise cellular distribution of PDPN and it's relationships with inflammation was studied in RA treated with biologic disease-modifying anti-rheumatic drugs (DMARD) or conventional DMARDs (cDMARD). METHODS: PDPN+ cells were immunostained by NZ-1 mAb, and scored (3+; >50%/ area, 2+; 20%- 50%, 1+; 5%-20%, 0: <5%) in synovial tissues from RA treated with biologic DMARDs (BIO, n=20) or cDMARD (n=20) for comparison with osteoarthritis (OA, n=5), followed by cell grading of inflammation and cell-typing. RESULTS: Inflammatory synovitis score was 1.4 in both BIO and cDMARD, compared to only 0.2 in OA. PDPN+ cells were found in the lining layer (BIO 1.6, cDMARD 1.3, OA 0.2) and lymphoid aggregates (BIO 0.6, cDMRD 0.7, OA 0.2), and correlated with RA-inflammation in BIO- and cDMARD-groups in both area (r=0.7/0.9, r=0.6/0.7, respectively p<0.05). PDPN was expressed in CD68+ type A macrophage-like and 5B5+ type B fibroblast-like cells in the lining layer, and in IL- 17+ cells in lymphoid aggregates in RA. CONCLUSION: PDPN was markedly increased in the immunologically inflamed RA synovitis, which was surgically treated due to BIO- and cDMARD-resistant RA. PDPN may have potential of a new marker of residual arthritis in local joints for inflammation-associated severe RA.

The Role of Macrophages in the Biological Reaction to Wear Debris from Artificial Joints.

Normal usage of total joint replacements results in the production of wear debris and other byproducts. In particular, polyethylene particles are heavily involved in the stimulation of local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone resorption (osteolysis), and eventually implant loosening. As sentinels of the innate immune system, cells of the monocyte/macrophage lineage initiate the inflammatory cascade that lead to osteolysis. The biological processes involved are complex, based on the unique properties of the monocytes/macrophages, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The interaction with wear debris triggers the release of pro-inflammatory factors such as tumor necrosis factor-α, interleukin-1, and others; pro-osteoclastic factors such as RANKL; and chemokines such as MCP-1 and MIP-1, all of which are crucial to the recruitment, migration, differentiation, and ultimately activation of bone-resorbing osteoclasts. In parallel, other distinct macrophage populations inhibit inflammation and mitigate its consequences on the bone-implant interface. Here, the role of the monocyte/macrophage cell lineage in the initiation and maintenance of the host inflammatory response to wear debris and subsequent periprosthetic osteolysis is presented.

Lipoteichoic acid modulates inflammatory response in macrophages after phagocytosis of titanium particles through Toll-like receptor 2 cascade and inflammasomes.

Toll-like receptor 2 (TLR2) and nucleotide-binding and oligomerization domain-like receptors with a pyrin domain 3 (NLRP3) inflammasomes have been presumed to participate in the pathogenesis of aseptic implant loosening. The aim of this study is to analyze the cellular localization of TLR2 and NLRP3 inflammasomes in the periprosthetic tissue from aseptically loose hip implants as well as the expression of these molecules in macrophages stimulated in vitro with titanium particles (Ti) coated with lipoteichoic acid (LTA). Using immunohistochemistry, immunoreactivity of TLR2 and NLRP3 inflammasomes was found in macrophages within the foreign body granulomatosis. Using RAW264.7 cells, stimulation with Ti increased the messenger RNA (mRNA) levels of TLR2 and TNF-α. Stimulation with LTA-coated Ti enhanced mRNA levels of NLRP3 and IL-1ß, whereas reinforced secretion of IL-1ß was not detected in spite of marked release of TNF-α. Finally, the same cells with silenced Irak2, an adaptor protein in the TLR2 cascade, suppressed this NLRP3 upregulation. This study suggests that TLR2 and NLRP3 inflammasomes are factors involved in cross-talk mediating the foreign body type response to wear particles. In addition, discrepant behavior in the release between TNF-α and IL-1ß release may explain the variable pathomechanisms of aseptic implant loosening without acute inflammatory reactions.

Autoinflammation Around AES Total Ankle Replacement Implants.

BACKGROUND: Failure of total ankle replacement (TAR) can be characterized by early peri-implant osteolysis even in the presence of very modest numbers of wear particles. The hypothesis of the study was that this reaction is in part mediated by autoinflammatory responses mediated via damage-associated molecular patterns (DAMPs, danger signals) and pattern-recognizing danger signal receptors (PRRs). METHODS: Peri-implant tissue and control samples from 10 patients with AES implants were immunostained for hypoxia inducible factor-1α (HIF-1α), activated caspase-3, high-mobility group box 1 (HMGB1), receptor for advanced glycation end product (RAGE), and toll-like receptors TLR2 and TLR4. Results were evaluated on a 0 to 4 scale (from 0% to >50% stained area). RESULTS: Peri-implant tissue around failed TAR implants had a relatively high mean HIF-1α score of 3 on a scale, which however was similar in control samples. HMGB1 (a DAMP) was seen to be mobilized from nuclei to cellular cytoplasm, and the active caspase-3(+) cells were increased. All PRRs were increased in revision samples. CONCLUSIONS: Increased expression of HMGB1 and other danger signals together with increased PRR-dependent responsiveness could contribute to autoinflammatory peri-implantitis, multilocular cyst formation, and osteolysis in failed TAR implants. LEVEL OF EVIDENCE: Level IV, case series.