Alterations in compositional and cellular properties of the subchondral bone are linked to cartilage degeneration in hip osteoarthritis.

OBJECTIVE: The subchondral bone is an emerging regulator of osteoarthritis (OA). However, knowledge of how specific subchondral alterations relate to cartilage degeneration remains incomplete. METHOD: Femoral heads were obtained from 44 patients with primary OA during total hip arthroplasty and from 30 non-OA controls during autopsy. A multiscale assessment of the central subchondral bone region comprising histomorphometry, quantitative backscattered electron imaging, nanoindentation, and osteocyte lacunocanalicular network characterization was employed. RESULTS: In hip OA, thickening of the subchondral bone coincided with a higher number of osteoblasts (controls: 3.7 ± 4.5 mm-1, OA: 16.4 ± 10.2 mm-1, age-adjusted mean difference 10.5 mm-1 [95% CI 4.7 to 16.4], p < 0.001) but a similar number of osteoclasts compared to controls (p = 0.150). Furthermore, higher matrix mineralization heterogeneity (CaWidth, controls: 2.8 ± 0.2 wt%, OA: 3.1 ± 0.3 wt%, age-adjusted mean difference 0.2 wt% [95% CI 0.1 to 0.4], p = 0.011) and lower tissue hardness (controls: 0.69 ± 0.06 GPa, OA: 0.67 ± 0.06 GPa, age-adjusted mean difference -0.05 GPa [95% CI -0.09 to -0.01], p = 0.032) were detected. While no evidence of altered osteocytic perilacunar/canalicular remodeling in terms of fewer osteocyte canaliculi was found in OA, specimens with advanced cartilage degeneration showed a higher number of osteocyte canaliculi and larger lacunocanalicular network area compared to those with low-grade cartilage degeneration. Multiple linear regression models indicated that several subchondral bone properties, especially osteoblast and osteocyte parameters, were closely related to cartilage degeneration (R2 adjusted = 0.561, p < 0.001). CONCLUSION: Subchondral bone properties in OA are affected at the compositional, mechanical, and cellular levels. Based on their strong interaction with cartilage degeneration, targeting osteoblasts/osteocytes may be a promising therapeutic OA approach. DATA AND MATERIALS AVAILABILITY: All data are available in the main text or the supplementary materials.

Areal bone mineral density is not associated with femoral stem subsidence in patients younger than 70 years undergoing total hip arthroplasty.

INTRODUCTION: Femoral stem subsidence is a known complication after uncemented total hip arthroplasty (THA). The purpose of this study was to determine the frequency of osteoporosis and to investigate the relationship between areal bone mineral density (aBMD) and subsidence in a cohort of patients younger than 70 years. METHODS: One hundred consecutive patients (age 60 ± 6 years; 52 female, 48 male) undergoing uncemented THA using a collarless press fit femoral stem were retrospectively reviewed. Dual-energy X-ray absorptiometry (DXA) was performed preoperatively at the proximal femur and lumbar spine, and if not feasible at these sites, at the distal radius. DXA results were compared to a cohort of 100 patients ≥ 70 years scheduled for cemented THA. Age, sex, and body mass index (BMI), canal flare index (CFI), and canal fill ratio (CFR) were assessed. Analysis of stem subsidence and migration was performed on standardized, calibrated radiographs obtained postoperatively and at follow-up. RESULTS: The frequency of osteoporosis was considerably lower in the study cohort compared to patients ≥ 70 years (7% vs. 19%, p = 0.02). Illustrated by the high CFR (mean 96 ± 4%) in the mid-stem region, a sufficient press fit was achieved. After a mean follow-up of 7.4 months, the mean stem subsidence was 0.9 ± 0.9 mm. Only two patients had subsidence greater than 3 mm, one of whom was morbidly obese and the other diagnosed with severe osteoporosis. There were no correlations between any of the parameters (CFI, CFR, age, sex, BMI) and femoral stem subsidence. In addition, aBMD T-scores showed no correlations with subsidence. CONCLUSION: aBMD by DXA does not appear to be associated with stem subsidence in patients younger than 70 years and with adequate press fit.

Influence of health literacy on health-related quality of life after total hip arthroplasty.

INTRODUCTION: Personal knowledge about the own disease, a key component of health literacy (HL), may have a considerable impact on treatment outcomes. The purpose of this study was to investigate whether the patients' knowledge about the surgical procedure, risks, and aftercare, as well as the satisfaction with the preoperative level of information, has an influence on the health-related quality of life (HRQoL) after primary total hip arthroplasty (THA). MATERIALS AND METHODS: A total of 176 patients (68.3 ± 10.3 years, 60.8% female) were evaluated. HRQoL was assessed prior to surgery as well as one and twelve months after THA using the 12-item Short Form Questionnaire. Following standardized surgical informed consent, HL was assessed preoperatively using a self-constructed quiz score, while information satisfaction was measured with a single-item rating scale. Sociodemographic and clinical characteristics, including pain (VAS), functionality (WOMAC), and psychological distress (PHQ-4), were also assessed at baseline. Multiple linear regression analyses were performed to examine whether HL, satisfaction with information, age, social class, WOMAC, VAS, and PHQ-4 predict HRQoL at one and twelve months post-surgery. RESULTS: The average HL quiz score was 23 ± 5.1 out of a possible 33 points. Social class index significantly influenced HL (p < 0.001). A weak correlation between HL and age (r = 0.23, p = 0.01) and no correlation between HL and psychological distress (p = 0.868) were observed. One month after THA, physical HRQoL was significantly predicted by the WOMAC index (p = 0.031) and subjective satisfaction with information (p = 0.022), but not by HL. After twelve months, only the WOMAC was a significant predictor (p < 0.001) of physical HRQoL. CONCLUSION: Although subjective satisfaction with the patient's preoperative level of information had a significant effect on the physical HRQoL at one month after THA, the influence of osteoarthritis severity outweighed this effect after twelve months. HL had no direct influence on HRQoL. These results suggest that patient satisfaction, rather than knowledge, predicts HRQoL.

Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation.

Tissue inhibitor of metalloproteinases-1 (TIMP-1), an important regulator of matrix metalloproteinases (MMPs), has recently been shown to interact with CD74, a receptor for macrophage migration inhibitory factor (MIF). However, the biological effects mediated by TIMP-1 through CD74 remain largely unexplored. Using sequence alignment and in silico protein-protein docking analysis, we demonstrated that TIMP-1 shares residues with both MIF and MIF-2, crucial for CD74 binding, but not for CXCR4. Subcellular colocalization, immunoprecipitation, and internalization experiments supported these findings, demonstrating that TIMP-1 interacts with surface-expressed CD74, resulting in its internalization in a dose-dependent manner, as well as with a soluble CD74 ectodomain fragment (sCD74). This prompted us to study the effects of the TIMP-1-CD74 axis on monocytes and vascular smooth muscle cells (VSCMs) to assess its impact on vascular inflammation. A phospho-kinase array revealed the activation of serine/threonine kinases by TIMP-1 in THP-1 pre-monocytes, in particular AKT. Similarly, TIMP-1 dose-dependently triggered the phosphorylation of AKT and ERK1/2 in primary human monocytes. Importantly, Transwell migration, 3D-based Chemotaxis, and flow adhesion assays demonstrated that TIMP-1 engagement of CD74 strongly promotes the recruitment response of primary human monocytes, while live cell imaging studies revealed a profound activating effect on VSMC proliferation. Finally, re-analysis of scRNA-seq data highlighted the expression patterns of TIMP-1 and CD74 in human atherosclerotic lesions, thus, together with our experimental data, indicating a role for the TIMP-1-CD74 axis in vascular inflammation and atherosclerosis.

Bi-planar calibration method for templating of hip joint arthroplasty: phantom study and proof of concept.

PURPOSE: Calibration of radiographs is a critical step in digital templating for hip arthroplasty. Calibration errors of > 1.5% lead to over- or undersizing of the templated implants and may affect logistics and patient safety. Contemporary calibration methods are known to be imprecise with average errors of 6.5% and wide variance. A novel bi-planar radiograph-based calibration method is proposed, and a phantom study was conducted as proof of concept. METHODS: A spherical external calibration marker (ECM) is placed in front of the pubic symphysis of a pelvic bone model at twelve different positions. For each marker position, standard anteroposterior radiographs and four corresponding lateral radiographs with different degrees of rotation (0°-30°) are taken (overall, 60 radiographs). Calibration factors are calculated for an internal calibration marker (ICM) at the centre of the right hip (reference) and the ECM using a novel algorithm. Rotation and marker positions simulate foreseeable use errors and misplacements and aim to test robustness of the method against these errors. RESULTS: ECM calibration factor was 125.9% (range 124.7-127.2), and the mean ICM calibration factor was 126.6% (range 126.2-127.1) ([Formula: see text]). Four images (8.3%) were beyond the 1% error threshold (all with 30° rotation). The mean difference was 0.79% (SD 0.49). CONCLUSION: The bi-planar method precisely predicts the true calibration factor of the hip joint plane under various conditions. In lateral radiographs, rotation of up to 20° did not adversely affect the precision and all images had calibration errors below the threshold for clinical significance.

Outcome of different reconstruction options using allografts in revision total hip arthroplasty for severe acetabular bone loss: a systematic review and meta-analysis.

INTRODUCTION: Several studies have reported good to excellent outcomes of revision total hip arthroplasty (rTHA) using allografts for treating severe acetabular bone defects. However, precise information on the impact of allograft type and reconstruction method is not available. MATERIAL AND METHODS: Systematic literature search was performed in Medline and Web of Science including patients with acetabular bone loss classified according to the Paprosky classification who underwent rTHA involving the use of allografts. Studies with a minimum follow-up of 2 years published between 1990 and 2021 were included. Kendall correlation was applied to determine the relationship between Paprosky grade and allograft type use. Proportion meta-analyses with 95% confidence interval (CI) were performed to summarize the success of various reconstruction options, including allograft type, fixation method, and reconstruction system. RESULTS: Twenty-seven studies met the inclusion criteria encompassing 1561 cases from 1491 patients with an average age of 64 years (range 22-95). The average follow-up period was 7.9 years (range 2-22). Structural bulk and morselized grafts were used in equal proportions for all Paprosky acetabular defect types. Their use increased significantly with the type of acetabular defect (r = 0.69, p = 0.049). The overall success rate ranged from 61.3 to 98.3% with a random effect pooled estimate of 90% [95% CI 87-93]. Trabecular metal augments (93% [76-98]) and shells (97% [84-99]) provided the highest success rates. However, no significant differences between reconstruction systems, allograft types and fixation methods were observed (p > 0.05 for all comparisons). CONCLUSION: Our findings highlight the use of bulk or morselized allograft for massive bone loss independent of Paprosky classification type and indicate similar good mid- to long-term outcomes of the different acetabular reconstruction options using allografts. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42020223093.

A novel bi-planar calibration method for digital templating in total hip arthroplasty.

In total hip arthroplasty and reconstructive orthopedic surgery, pre-operative digital templating is essential for surgical treatment optimization, risk management, and quality control. Calibration is performed before templating to address magnification effects. Conventional methods including fixed calibration factors, individual marker-based calibration and dual-scale marker methods are not reliable. A novel bi-planar calibration method is described aiming to reduce the error below clinical significance. The bi-planar calibration method requires two conventional orthogonal radiographs and a standard radiopaque marker ball. An algorithm computes the hip plane height parallel to the detector in the antero-posterior radiograph. Foreseeable errors (i.e., patient rotation and misplaced markers or lateral offset) are considered in a correction algorithm. Potential effects of errors are quantified in a standard model. Influence of rotation in lateral radiographs and lateral offset of marker on the calibration factor are quantified. Without correction, patient rotation in the lateral radiograph of 30° results in absolute calibration error of 2.2% with 0 mm offset and 6.5% with 60 mm lateral offset. The error is below the threshold of 1.5% for rotation less than 26° with 0 mm offset and 10° with 60 mm offset. The method is supposed to be reliable in precisely predicting the hip plane and thereby the calibration factor. It may be superior to other methods available. In theory, the method allows correction of clinically relevant rotation of at least 30° and marker displacement without impacting the computed calibration factor.

Trans-fracture approach for ORIF of coronal shear fractures of the distal humerus.

INTRODUCTION: Open reduction and internal fixation (ORIF) of comminuted coronal shear fractures of the distal humerus is challenging. When a concomitant lateral condyle fracture is present, it may be used for a trans-fracture approach to facilitate exposure and fracture reduction. This study aimed to investigate the frequency of lateral condyle fractures in coronal shear fractures of the distal humerus and analyze fracture reduction, fracture union and clinical results following ORIF through a trans-fracture approach. MATERIALS AND METHODS: All adult patients who underwent treatment for an acute distal humerus fracture during a three-year period in our level-one trauma center were identified. All fractures were classified according to the Orthopaedic Trauma Association (OTA/AO) fracture classification system and all B3 fractures were classified according to the Dubberley classification. B3 fractures with a concomitant radial condyle fracture were identified. The clinical and radiological results, (Mayo Elbow Performance Score = MEPS, Visual Analogue Scale = VAS, range of motion), complications and revision surgeries were analyzed. RESULTS: 53 patients (mean age 52 ± 19 years) were identified. 13 fractures (24.5%) were B3 fractures. Four of them (30.8%) had a concomitant radial condyle fracture. All of these patients underwent ORIF with headless cannulated compression screws and a (postero-)lateral locking plate through a trans-fracture approach. At a minimum follow-up of 24 months, the MEPS was 88 ± 12 points, the VAS was 2 ± 1 and the range of motion was 118° ± 12°. All fractures showed anatomic reduction. One patient developed partial avascular necrosis and underwent arthrolysis at 6 months. One patient underwent partial hardware removal and lateral collateral ligament bracing at 6 months. CONCLUSIONS: Lateral condyle fractures are present in about one third of coronal shear fractures of the distal humerus. This injury can be used for a trans-fracture approach to facilitate exposure and to reliably achieve anatomic fracture reduction.

Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques.

AIMS: Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory properties. However, the mechanisms underlying hMSC function in these processes are unclear. Recently, we described that miRNA let-7f controls hMSC invasion guided by inflammatory cytokines and chemokines. Here, we investigated the role of let-7f in hMSC tropism to human atheromas and the effects of the plaque microenvironment on cell fate and release of soluble factors. METHODS AND RESULTS: Incubation of hMSCs with LL-37, an antimicrobial peptide abundantly found in plaques, increased biosynthesis of let-7f and N-formyl peptide receptor 2 (FPR2), enabling chemotactic invasion of the cells towards LL-37, as determined by qRT-PCR, flow cytometry, and cell invasion assay analysis. In an Apoe-/- mouse model of atherosclerosis, circulating hMSCs preferentially adhered to athero-prone endothelium. This property was facilitated by elevated levels of let-7f in the hMSCs, as assayed by ex vivo artery perfusion and two-photon laser scanning microscopy. Exposure of hMSCs to homogenized human atheromatous plaque material considerably induced the production of various cytokines, chemokines, matrix metalloproteinases, and tissue inhibitors of metalloproteinases, as studied by PCR array and western blot analysis. Moreover, exposure to human plaque extracts elicited differentiation of hMSCs into cells of the myogenic lineage, suggesting a potentially plaque-stabilizing effect. CONCLUSIONS: Our findings indicate that let-7f promotes hMSC tropism towards atheromas through the LL-37/FPR2 axis and demonstrate that hMSCs upon contact with human plaque environment develop a potentially athero-protective signature impacting the pathophysiology of atherosclerosis.

Dual-scale single marker calibration for digital templating of total hip arthroplasty in standing radiographs: a prospective clinical study.

PURPOSE: Accuracy of calibration of radiographs significantly influences the quality of digital templating for total hip arthroplasty (THA). The standard of care is calibration with external calibration markers (ECM). This method is associated with significant errors. Dual-scale single marker (DSSM) calibration methods may improve accuracy. The present prospective observational study is the first to analyze the application of a DSSM method in standing pelvis radiographs. METHODS: 100 patients with unilateral THA underwent antero-posterior pelvis radiographs with ECM and DSSM. The hip components were used as reference calibration factor (internal calibration factor; ICM). Absolute differences of calibration factors for ECM and DSSM from ICM were calculated. Absolute relative deviations (ARD) were calculated. Subgroup analysis for sex and WHO BMI category was performed. Furthermore, patients reported subjective comfort for each marker using a 10-point scale and choosing the preferred marker. RESULTS: Maximum magnification factor differences from the ICM were 23.3% and 9.5% and mean absolute differences were 12.5% and 2.1% for the ECM and DSSM, respectively. ARD from ICM was significantly lower for DSSM compared to ECM (p < 0.001). Absolute differences increased with BMI category using ECM; calibration by DSSM was consistent in all subgroups. Patients preferred DSSM over ECM (n = 53) or were indifferent (n = 20). Comfort was rated significantly higher for DSSM versus ECM (p < 0.001). CONCLUSION: DSSM method showed superior results in comparison to the ECM method for calibration of digital radiographs. DSSM could be used to improve digital templating in standing radiographs.

Lateral Ulnar Collateral Ligament Reconstruction for Posterolateral Rotatory Instability After Failed Common Extensor Origin Release: Outcomes at Minimum 2-Year Follow-up.

BACKGROUND: In patients with chronic lateral epicondylitis who have failed nonoperative treatment, open or percutaneous release of the common extensor origin (CEO) without subsequent reconstruction tends to result in good clinical outcomes. However, surgery can lead to iatrogenic injuries of the lateral collateral ligamentous complex, causing posterolateral rotatory instability (PLRI). PURPOSE: To determine the clinical outcomes of lateral ulnar collateral ligament (LUCL) reconstruction using a triceps tendon graft after failed open CEO surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 103, patients underwent revision surgery at a single institution because of PLRI after failed open release of the CEO (Hohmann procedure) between January 2007 and October 2016. The primary surgery had been performed at other institutions in all cases. Of these patients, 72 were available for follow-up (49 by clinical examination, 23 by telephone interview). Standardized clinical examination; Mayo Elbow Performance Score (MEPS); 11-item version of the Disabilities of the Arm, Shoulder and Hand Score (QuickDASH); subjective elbow value (SEV); and patient satisfaction were assessed at least 2 years after LUCL reconstruction. RESULTS: The mean age of patients in the study was 46.9 years (range, 21-74 years), and the mean follow-up was 2.8 years after revision surgery. The mean MEPS was 78.9, and the mean QuickDASH score reached 20.4. The mean SEV was 78.6%, and 75% of the patients rated the surgery as good to excellent. Complications were detected in 14% of the patients, and 9 needed revision surgery, primarily owing to graft failure with recurrent instability (n = 5). CONCLUSION: LUCL reconstruction in patients with PLRI after release of the CEO can restore elbow stability and achieve high patient satisfaction. However, outcome scores and revision rates in this cohort were inferior to published outcomes of primary LUCL reconstruction for treatment of noniatrogenic or traumatic PLRI.

Investigation of distal femur microarchitecture and factors influencing its deterioration: An ex vivo high-resolution peripheral quantitative computed tomography study.

While fractures of the distal femur are often considered as fragility fractures, detailed knowledge of the bone microarchitecture at this skeletal site is largely unavailable. Initial evaluation of a patient cohort with distal femur fractures showed a markedly increased occurrence in elderly women. The purpose of this study was to determine the extent to which demographic characteristics of distal femur fractures are reflected by general age- and sex-specific variations in local microarchitectural parameters. Fifty cadaveric femora were collected from 25 subjects (12 females, 13 males, age 25-97 years). A volume of interest within 3 cm proximal to the condyles was analyzed using high-resolution peripheral quantitative computed tomography (HR-pQCT), which revealed impaired trabecular and cortical bone microarchitecture in women compared to men as well as in osteoporotic compared to normal or osteopenic subjects, as classified by dual-energy X-ray absorptiometry (DXA) T-score. Linear regression analyzes showed negative associations between age and HR-pQCT parameters in women (e.g., cortical thickness -14 µm/year, 95% CI: -21 to -7 µm/year), but not in men (e.g., cortical thickness 1 µm/year, 95% CI: -12 to 14 µm/year). HR-pQCT parameters showed strong positive associations with areal bone mineral density (aBMD) determined by DXA at the hip in both sexes. Taken together, our findings suggest that female sex, advanced age, and low aBMD represent major risk factors for impaired microarchitecture at the distal femur. Both the diagnostic value of DXA for predicting distal femur fractures and the efficacy of bone-specific agents on fracture risk reduction should be investigated in the future.

Prevalence of osteoporosis and osteopenia in elderly patients scheduled for total knee arthroplasty.

INTRODUCTION: Osteoporosis is a common comorbidity in elderly patients with osteoarthritis (OA) and may increase perioperative complications in orthopedic surgery (e.g., component migration, periprosthetic fractures). As there is no investigation of bone mineral density (BMD) in elderly patients prior to total knee arthroplasty (TKA) in Europe, we investigated this issue with a particular focus on a potential treatment gap. MATERIALS AND METHODS: We assessed the BMD by dual-energy X-ray absorptiometry (DXA) in 109 consecutive elderly patients (age ≥ 70 years) scheduled for TKA. In addition to a detailed assessment of osteoporosis and osteopenia, the influence of clinical risk factors and radiological OA severity on BMD was evaluated using group comparisons and linear regression models. In addition, we analyzed differences in BMD between patients scheduled for TKA vs. total hip arthroplasty (THA). RESULTS: Of the included 109 patients, 19 patients (17.4%) were diagnosed with osteoporosis and 50 (45.9%) with osteopenia. In the osteoporotic patients, a clinically relevant underdiagnosis concomitant with a serious treatment gap was observed in 95.0% of the patients. Body mass index, OA grade, and glucocorticoid use were identified as independent factors associated with BMD. No differences in BMD were found between the patients scheduled for TKA vs. THA. CONCLUSIONS: Considering the high prevalence of osteoporosis and osteopenia in elderly patients, DXA screening should be recommended for patients ≥ 70 years indicated for TKA.

Costal Cartilage Calcification: Prevalence, Amount, and Structural Pattern in the General Population and Its Association with Age: A Cadaveric Study.

Importance: Costal cartilage calcification (CCC) of the cartilage graft, commonly used in reconstruction of nasal/auricular deformities, can cause poor surgical outcome, but structural and quantitative analyses are lacking. Objective: To compare the prevalence, amount, and structural pattern of CCC from individuals by gender and age, as measured by digital contact radiography. Design, Setting, and Participants: This is a cross-sectional cadaveric study (n = 92) of the seventh rib cartilage. CCC prevalence/amount/structural pattern (central [c]/peripheral [p]/diffuse [d]) was analyzed within three age groups: I (<40 years), II (40-70 years), and III (>70 years). Main Outcomes and Measures: Qualitative and quantitative CCC analyses were set in relation to gender/structural pattern/age. Results: CCC prevalence was gender independent (96.7%) and occurred in c/p/d: 12.4%/22.4%/65.2%. Structural CCC pattern differed between age groups (I: 80%; c/p/d: 26.7%/46.6%/6.7%; II: 100%; c/p/d: 18.0%/30.8%/51.2%; III: 100%; p/d: 2.6%/97.4%). The mean CCC amount (9.1%) was gender independent and showed a significant correlation with age (p = 0.001). The mean amount showed a significant difference between the structural pattern [d/p: 3.3 times higher (p = 0.006), d/c: 7.7 times higher (p < 0.001)] and age groups (I/II/III: 6.4/8.5%/10.9%), whereby the amount was higher in groups II (factor: 7.4; p < 0.001) and III (factor: 16.5; p < 0.001) compared with group I. Conclusions: These data show an age-/gender-independent high CCC prevalence in the general population (96.7%). CCC already occurred in young donors (<40 years) with a not negligible amount (6.4%). CCC increased with age and structural analysis showed a gender-/age-specific pattern, whereby males were prone to peripheral/females to central CCC. Diffuse CCC was observed as an age-independent sign for high CCC levels.

Expression of Surface-associated 82 kDa proMMP-9 in Lymphatic Leukemia Blast Cells Differentially Correlates With Prognosis.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) degrade extracellular matrix and process regulatory proteins. Recently, a membrane-bound 82kDa variant of proMMP-9 identified on myeloid blasts was shown to be associated with prognosis. PATIENTS AND METHODS: To investigate the role of 82kDa proMMP-9 with acute lymphoblastic leukemia (ALL) and chronic lymphoid leukemia (CLL), we performed flow-cytometry analysis of expression on ALL blasts (n=18) and CLL lymphocytes (n=21) from blood and correlated data with clinical parameters. RESULTS: In ALL, mature B-linear blasts expressed higher levels of 82kDa proMMP-9 compared to T-linear blasts. Elevated levels of 82kDa proMMP-9 were found in elderly patients and at patients with relapse. No correlation was observed on blood cells and extramedullary disease. In CLL, the 82kDa proMMP-9 expression did not correlate with any of the clinical parameters. CONCLUSION: Our findings suggest that higher levels of 82kDa proMMP-9 expression on blast cells may correlate with a more unfavorable ALL-subtype. Further studies are required to clarify the prognostic role of the 82kDa pro-MMP-9 expression.

Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release.

Bone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

Implications of component size and calibration error on digital templating for total hip arthroplasty. A visual matrix from a simple mathematical model.

OBJECTIVE: Preoperative digital templating is a standard procedure in total hip arthroplasty. Deviations between template size and final implant size may result from inaccurate calibration, templating as well as intraoperative decisions. So far, the explicit effect of calibration errors on templating has not been addressed adequately. MATERIALS AND METHODS: A mathematical simulation of calibration errors up to ± 24% was applied to the templating of acetabular cups (38 to 72 mm diameter). The effect of calibration errors on template component size as deviation from optimal size was calculated. RESULTS: The relationship between calibration error and component size deviation is inverse and linear. Calibration errors have a more pronounced effect on larger component sizes. Calibration errors of 2-6% result in templating errors of up to two component sizes. Common errors of up to 12% may result in templating errors of 3-4 sizes for common implant sizes. A tabular matrix visualizes the effect. CONCLUSION: Calibration errors play a significant role in component size selection during digital templating. Orthopedic surgeons should be aware of this effect and try to identify and address this source of error.

Restoration of the hip geometry after two-stage exchange with intermediate resection arthroplasty for periprosthetic joint infection.

Two-stage exchange with intermediate resection arthroplasty (RA) is a well-established surgical procedure in the treatment of chronic periprosthetic joint infection (PJI), whereby a higher failure rate of final hip geometry restoration due to tissue contraction is controversially discussed. The aim was to evaluate radiographic changes of hip geometry parameters during PJI treatment and to determine the impact of the intermediate RA on the final joint restoration after reimplantation of a total hip arthroplasty (reTHA). Radiographic parameters (leg length (LL), femoral offset (FO), horizontal/vertical acetabular center of rotation distance (h/vCORD)) of 47 patients (mean age: 64.1 years) were measured on standard radiographs of the pelvis and compared between four different stages during PJI treatment (pre-replacement status (preTHA), primary total hip arthroplasty (pTHA), RA and reTHA). The RA duration (mean: 10.9 months) and the number of reoperations during this period (mean: n = 2.0) as well as their impact on hip geometry restoration were evaluated. Between preTHA and pTHA/reTHA an equivalent restoration was measured regarding the FO (p < 0.001/p < 0.001) and hCORD (p = 0.016/p < 0.001), but not regarding the LL and vCORD. In contrast, analysis revealed no influence of RA and an equivalent reconstruction of LL (p = 0.003), FO (p < 0.001), v/hCORD (p = 0.039/p = 0.035) at reTHA compared to pTHA. Furthermore, RA duration (p = 0.053) and the number of reoperations after RA (p = 0.134) had no impact on radiographic hip geometry restoration. The two-stage exchange with intermediate RA does not alter the preexisting hip joint parameters, whereby a good restoration of the final hip geometry, independent of the duration or the number of reoperations, can be achieved.

[Cost analysis of inpatient versus outpatient intravenous antibiotic treatment for periprosthetic joint infections : A simulation]. / Kostenanalyse stationärer und ambulanter intravenöser Antibiotikatherapie periprothetischer Gelenkinfektionen : Eine Simulation.

BACKGROUND: Parenteral antibiotic administration in the treatment of periprosthetic joint infections (PJI) often requires inpatient settings. This is associated with significant costs to the healthcare system. OBJECTIVE: The costs of inpatient parenteral antibiotic treatment (IPAT) and simulated costs of outpatient parenteral antibiotic treatment (OPAT) were compared in patients with PJI. Evaluations were carried out from the perspectives of cost bearers (insurances) and healthcare providers (hospitals). MATERIAL AND METHODS: The analysis and simulations were performed for all cases with the ICD-10 diagnosis T84 in the treatment year 2015. RESULTS: The simulated reduction of 159 bed-days in the 12 patients included in the study resulted in a reduction of the total costs of>18,000 € from the perspective of the health insurance. From the perspective of the hospitals the pure proceeds were improved by >22,000 €. The total costs of OPAT were >57,000 € for the health insurance. For hospitals the difference of policlinic proceeds and costs of OPAT showed a loss of >1500 €. CONCLUSION: For hospitals the OPAT is overall financially advantageous. Further advantages due to opportunity costs seem to be interesting. For cost bearers OPAT is associated with an additional financial expenditure, particularly due to costs of outpatient medication. The private sector should be considered due to the assumed additional burden as well as the assumed patient comfort.

Bi-cruciate retaining total knee arthroplasty: a systematic literature review of clinical outcomes.

Total knee arthroplasty (TKA) has been shown to have good long-term outcomes and survivorship. Nonetheless, dissatisfied patients are frequently reported in the literature. Bi-cruciate retaining total knee prostheses (BCR TKA) were designed to address the demand for more kinematically functional implants that better reconstruct natural knee kinematics. In BCR TKA, the anterior cruciate ligament (ACL) is preserved. Improved patient-reported outcomes and satisfaction levels are expected. This review aimed to summarize indications for and clinical outcomes of BCR TKA. A systematic literature review on BCR TKA was performed. 24 articles were included for data analysis. Indications covered osteoarthritis, inflammatory arthritis and others. The degree of deformity was often but not always limited to minor axial deformity and contractures: maximum acceptable varus/valgus deformity reached 10°-30° and flexion contractures of 15°-65°. ACL intactness was macroscopically examined intraoperatively in nine studies and clinically tested in ten studies (e.g., Lachmann Test, drawer-test). Objective and patient-reported outcome scores were reported for follow-up periods of up to 22 years. Survival rates varied significantly. For first generation implants, 22-year survival reached 82% while a second generation design was associated with 13.5% revision rate at 18 months. Reasons for varying outcomes were not clear and may be attributed to the implant itself, surgical techniques and patient specific variables including changed expectations and functional demand. The literature has not shown clear indications and guidelines for the use of BCR implants. The promising results of first generation BCR TKA designs may be optimized through improved implant designs in the future. Further studies are advocated to provide the necessary evidence of second generation BCR TKA designs.