@article{MuellerDeubertSeefriedKrugetal.2017,
  author    = {M{\"u}ller-Deubert, Sigrid and Seefried, Lothar and Krug, Melanie and Jakob, Franz and Ebert, Regina},
  title     = {Epidermal growth factor as a mechanosensitizer in human bone marrow stromal cells},
  series = {Stem Cell Research},
  volume    = {24},
  journal   = {Stem Cell Research},
  doi       = {10.1016/j.scr.2017.08.012},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170247},
  pages     = {69-76},
  year      = {2017},
  abstract  = {Epidermal growth factors (EGFs) e.g. EGF, heparin-binding EGF and transforming growth factor alpha and their receptors e.g. EGFR and ErbB2 control proinflammatory signaling and modulate proliferation in bone marrow stromal cells (BMSC). Interleukin-6 and interleukin-8 are EGF targets and participate in the inflammatory phase of bone regeneration via non-canonical wnt signaling. BMSC differentiation is also influenced by mechanical strain-related activation of ERK1/2 and AP-1, but the role of EGFR signaling in mechanotransduction is unclear. We investigated the effects of EGFR signaling in telomerase-immortalized BMSC, transfected with a luciferase reporter, comprising a mechanoresponsive AP1 element, using ligands, neutralizing antibodies and EGFR inhibitors on mechanotransduction and we found that EGF via EGFR increased the response to mechanical strain. Results were confirmed by qPCR analysis of mechanoresponsive genes. EGF-responsive interleukin-6 and interleukin-8 were synergistically enhanced by EGF stimulation and mechanical strain. We show here in immortalized and primary BMSC that EGFR signaling enhances mechanotransduction, indicating that the EGF system is a mechanosensitizer in BMSC. Alterations in mechanosensitivity and -adaptation are contributors to age-related diseases like osteoporosis and the identification of a suitable mechanosensitizer could be beneficial. The role of the synergism of these signaling cascades in physiology and disease remains to be unraveled.},
  language  = {en}
}
@article{ReichertvonRottkayRothetal.2018,
  author    = {Reichert, Johannes C. and von Rottkay, Eberhard and Roth, Franz and Renz, Tim and Hausmann, Johannes and Kranz, Julius and Rackwitz, Lars and N{\"o}th, Ulrich and Rudert, Maximilian},
  title     = {A prospective randomized comparison of the minimally invasive direct anterior and the transgluteal approach for primary total hip arthroplasty},
  series = {BMC Musculoskeletal Disorders},
  volume    = {19},
  journal   = {BMC Musculoskeletal Disorders},
  number    = {241},
  doi       = {10.1186/s12891-018-2133-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176072},
  year      = {2018},
  abstract  = {Background: The presented prospective randomized controlled single-centre study compares the clinical outcome up to 12 months after total hip arthroplasty using a minimally invasive single-incision direct anterior (DAA) and a direct transgluteal lateral approach. Methods: A total of 123 arthroplasties were evaluated utilizing the Harris Hip Score (HHS), the extra short musculoskeletal functional assessment questionnaire (XSFMA), the Short Form 36 (SF-36) health survey, a Stepwatch™ Activity Monitor (SAM), and a timed 25 m foot walk (T25-FW). Postoperative x-ray images after THA were reviewed to determine inclination and stem positioning. Results: At final follow-up, the XSFMA functional index scores were 10.3 (anterior) and 15.08 (lateral) while the bother index summed up to a score of 15.8 (anterior) and 21.66 (lateral) respectively, thus only differing significantly for the functional index (p = 0.040 and p = 0.056). The SF-36 physical component score (PCS) was 47.49 (anterior) and 42.91 (lateral) while the mental component score (MCS) summed up to 55.0 (anterior) and 56.23 (lateral) with a significant difference evident for the PCS (p = 0.017; p = 0.714). Patients undergoing THA through a DAA undertook a mean of 6402 cycles per day while those who had undergone THA through a transgluteal approach undertook a mean of 5340 cycles per day (p = 0.012). Furthermore, the obtained outcome for the T25-FW with 18.4 s (anterior) and 19.75 s (lateral) and the maximum walking distance (5932 m and 5125 m) differed significantly (p = 0.046 and p = 0.045). The average HHS showed no significant difference equaling 92.4 points in the anterior group and 91.43 in the lateral group (p = 0.477). The radiographic analysis revealed an average cup inclination of 38.6° (anterior) and 40.28° (lateral) without signs of migration. Conclusion: In summary, our outcomes show that after 1 year THA through the direct anterior approach results in a higher patient activity compared to THA utilizing a transgluteal lateral approach while no differences regarding hip function are evident.},
  language  = {en}
}
@article{BoelchRothArnholdtetal.2018,
  author    = {Boelch, Sebastian P. and Roth, Magnus and Arnholdt, Joerg and Rudert, Maximilian and Luedemann, Martin},
  title     = {Synovial fluid aspiration should not be routinely performed during the two-stage exchange of the knee},
  series = {BioMed Research International},
  volume    = {2018},
  journal   = {BioMed Research International},
  number    = {6720712},
  doi       = {10.1155/2018/6720712},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176800},
  year      = {2018},
  abstract  = {Purpose. Detection of infection persistence during the two-stage exchange of the knee for periprosthetic joint infection is challenging. Synovial fluid culture (SFC) and synovial white blood cell count (SWBCC) before joint reimplantation are widespread diagnostic means for this indication. The sensitivity and specificity of SFC and of SWBCC for infection persistence before planned reimplantation were evaluated. Methods. 94 two-stage exchanges of the knee with synovial fluid aspiration performed after a drug holiday of at least 14 days and before reimplantation or spacer exchange (planned reimplantation) were retrospectively analyzed. Only cases with at least 3 intraoperative samples at planned reimplantation were included. SFC and SWBCC were compared to pathogen detection (SFC\(_{(culture)}\)/SWBCC\(_{(culture)}\) and to histopathological signs of infection persistence (SFC\(_{(histo)}\)/SWBCC\(_{(histo)}\) from intraoperative samples at planned reimplantation. For SFC, the sensitivity and specificity were calculated. For SWBCC, the optimal cut-off value with its sensitivity and specificity was calculated with the Youden-Index. Results. Sensitivity and specificity of SFC\(_{(culture)}\) were 0.0\% and 98.9\%. Sensitivity and specificity of SFC\(_{(histo)}\) were 3.4\% and 100\%. The optimal cut-off value for SWBCC\(_{(culture)}\) was 4450 cells/μl with a sensitivity of 50.0\% and a specificity of 86.5\%. The optimal cut-off value for SWBCC\(_{(histo)}\) was 3250 cells/μl with a sensitivity of 35.7\% and a specificity of 92.9\%. Conclusion. The detection of infection persistence remains challenging and a consented approach is lacking. The results do not warrant the routine performance of SFC during the two-stage exchange at the knee. SWBCC can be used to confirm infection persistence at high cut-offs, but they only occur in few patients and are therefore inappropriate for the routine use.},
  language  = {en}
}
@article{BoelchGurokGilbertetal.2021,
  author    = {Boelch, Sebastian P. and Gurok, Anna and Gilbert, Fabian and Weißenberger, Manuel and Rudert, Maximilian and Barthel, Thomas and Reppenhagen, Stephan},
  title     = {Why compromise the patella? Five-year follow-up results of medial patellofemoral ligament reconstruction with soft tissue patellar fixation},
  series = {International Orthopaedics},
  volume    = {45},
  journal   = {International Orthopaedics},
  issn      = {0341-2695},
  doi       = {10.1007/s00264-020-04922-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235751},
  pages     = {1493-1500},
  year      = {2021},
  abstract  = {Purpose This study investigates the redislocation rate and functional outcome at a minimum follow-up of five years after medial patellofemoral ligament (MPFL) reconstruction with soft tissue patellar fixation for patella instability. Methods Patients were retrospectively identified and knees were evaluated for trochlea dysplasia according to Dejour, for presence of patella alta and for presence of cartilage lesion at surgery. At a minimum follow-up of five years, information about an incident of redislocation was obtained. Kujala, Lysholm, and Tegner questionnaires as well as range of motion were used to measure functional outcome. Results Eighty-nine knees were included. Follow-up rate for redislocation was 79.8\% and for functional outcome 58.4\%. After a mean follow-up of 5.8 years, the redislocation rate was 5.6\%. There was significant improvement of the Kujala score (68.8 to 88.2, p = 0.000) and of the Lysholm score (71.3 to 88.4, p = 0.000). Range of motion at follow-up was 149.0° (115-165). 77.5\% of the knees had patella alta and 52.9\% trochlear dysplasia types B, C, or D. Patellar cartilage legions were present in 54.2\%. Redislocations occurred in knees with trochlear dysplasia type C in combination with patella alta. Conclusion MPFL reconstruction with soft tissue patellar fixation leads to significant improvement of knee function and low midterm redislocation rate. Patients with high-grade trochlear dysplasia should be considered for additional osseous correction.},
  language  = {en}
}
@article{GenestRakBaetzetal.2021,
  author    = {Genest, Franca and Rak, Dominik and B{\"a}tz, Elisa and Ott, Kerstin and Seefried, Lothar},
  title     = {Sarcopenia and Malnutrition Screening in Female Osteoporosis Patients — A Cross-Sectional Study},
  series = {Journal of Clinical Medicine},
  volume    = {10},
  journal   = {Journal of Clinical Medicine},
  number    = {11},
  issn      = {2077-0383},
  doi       = {10.3390/jcm10112344},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239658},
  year      = {2021},
  abstract  = {Sarcopenia and malnutrition are important determinants of increased fracture risk in osteoporosis. SARC-F and MNA-SF are well-established questionnaires for identifying patients at risk for these conditions. We sought to evaluate the feasibility and potential added benefit of such assessments as well as the actual prevalence of these conditions in osteoporosis patients. We conducted a cross-sectional, single-center study in female osteoporosis patients ≥ 65 years (SaNSiBaR-study). Results of the sarcopenia (SARC-F) and malnutrition (MNA-SF) screening questionnaires were matched with a functional assessment for sarcopenia and data from patients' medical records. Out of 107 patients included in the analysis, a risk for sarcopenia (SARC-F ≥ 4 points) and a risk for malnutrition (MNA-SF ≤ 11 points) was found in 33 (30.8\%) and 38 (35.5\%) patients, respectively. Diagnostic overlap with coincident indicative findings in both questionnaires was observed in 17 patients (16\%). As compared to the respective not-at-risk groups, the mean short physical performance battery (SPPB) score was significantly reduced in both patients at risk for sarcopenia (7.0 vs. 10.9 points, p < 0.001) and patients at risk for malnutrition (8.7 vs. 10.5 points, p = 0.005). Still, confirmed sarcopenia according to EWGSOP2 criteria was present in only 6 (6\%) of all 107 patients, with only 3 of them having an indicative SARC-F score. Bone mineral density was not significantly different in any of the at-risk groups at any site. In summary, applying SARC-F and MNA-SF in osteoporosis patients appears to be a complementary approach to identify individuals with functional deficits.},
  language  = {en}
}
@article{LiedertNemitzHaffnerLuntzeretal.2020,
  author    = {Liedert, Astrid and Nemitz, Claudia and Haffner-Luntzer, Melanie and Schick, Fabian and Jakob, Franz and Ignatius, Anita},
  title     = {Effects of estrogen receptor and Wnt signaling activation on mechanically induced bone formation in a mouse model of postmenopausal bone loss},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {21},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21218301},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285487},
  year      = {2020},
  abstract  = {In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.},
  language  = {en}
}
@article{NedopilDhaliwalHowelletal.2022,
  author    = {Nedopil, Alexander J. and Dhaliwal, Anand and Howell, Stephen M. and Hull, Maury L.},
  title     = {A surgeon that switched to unrestricted kinematic alignment with manual instruments has a short learning curve and comparable resection accuracy and outcomes to those of an experienced surgeon},
  series = {Journal of Personalized Medicine},
  volume    = {12},
  journal   = {Journal of Personalized Medicine},
  number    = {7},
  issn      = {2075-4426},
  doi       = {10.3390/jpm12071152},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281842},
  year      = {2022},
  abstract  = {After starting an orthopedic practice, a surgeon with a fellowship in mechanically aligned (MA) TKA initiated this study to characterize their learning curve after they switched to unrestricted kinematic alignment (KA) TKA using manual instruments. Accordingly, the present study determined for the inexperienced (IE) surgeon the number of cases required to achieve consistent femoral resections and operating times, and whether the femoral resection accuracy, patient-reported outcome measures (PROMs), and component alignment were different from an experienced (E) surgeon. This prospective cohort study analyzed the IE surgeon's first 30 TKAs, all performed with KA, and 30 consecutive KA TKAs performed by an E surgeon. The resection accuracy or deviation was the calipered thickness of the distal and posterior medial and lateral femoral resections minus the planned resection thickness, which was the thickness of the corresponding condyle of the femoral component, minus 2 mm for cartilage wear, and 1 mm for the kerf of the blade. Independent observers recorded the femoral resection thickness, operative times, PROMs, and alignment. For each femoral resection, the deviation between three groups of patients containing ten consecutive KA TKAs, was either insignificant (p = 0.695 to 1.000) or within the 0.5 mm resolution of the caliper, which indicated no learning curve. More than three groups were needed to determine the learning curve for the operative time; however, the IE surgeon's procedure dropped to 77 min for the last 10 patients, which was 20 min longer than the E surgeon. The resection deviations of the IE and E surgeon were comparable, except for the posterolateral femoral resection, which the IE surgeon under-resected by a mean of -0.8 mm (p < 0.0001). At a mean follow-up of 9 and 17 months, the Forgotten Joint Score, Oxford Knee Score, KOOS, and the alignment of the components and limbs were not different between the IE and E surgeon (p ≥ 0.6994). A surgeon that switches to unrestricted KA with manual instruments can determine their learning curve by computing the deviation of the distal and posterior femoral resections from the planned resection. Based on the present study, an IE surgeon could have resection accuracy, post-operative patient outcomes, and component alignment comparable to an E surgeon.},
  language  = {en}
}
@article{HorasvanHerckMaieretal.2020,
  author    = {Horas, Konstantin and van Herck, Ulrike and Maier, Gerrit S. and Maus, Uwe and Harrasser, Norbert and Jakob, Franz and Weissenberger, Manuel and Arnholdt, J{\"o}rg and Holzapfel, Boris M. and Rudert, Maximilian},
  title     = {Does vitamin D deficiency predict tumour malignancy in patients with bone tumours? Data from a multi-center cohort analysis},
  series = {Journal of Bone Oncology},
  volume    = {25},
  journal   = {Journal of Bone Oncology},
  doi       = {10.1016/j.jbo.2020.100329},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230314},
  year      = {2020},
  abstract  = {Vitamin D deficiency is a global health concern that is estimated to afflict over one billion people globally. The major role of vitamin D is that of a regulator of calcium and phosphate metabolism, thus, being essential for proper bone mineralisation. Concomitantly, vitamin D is known to exert numerous extra-skeletal actions. For example, it has become evident that vitamin D has direct anti-proliferative, pro-differentiation and pro-apoptotic actions on cancer cells. Hence, vitamin D deficiency has been associated with increased cancer risk and worse prognosis in several malignancies. We have recently demonstrated that vitamin D deficiency promotes secondary cancer growth in bone. These findings were partly attributable to an increase in bone remodelling but also through direct effects of vitamin D on cancer cells. To date, very little is known about vitamin D status of patients with bone tumours in general. Thus, the objective of this study was to assess vitamin D status of patients with diverse bone tumours. Moreover, the aim was to elucidate whether or not there is an association between pre-diagnostic vitamin D status and tumour malignancy in patients with bone tumours. In a multi-center analysis, 25(OH)D, PTH and calcium levels of 225 patients that presented with various bone tumours between 2017 and 2018 were assessed. Collectively, 76\% of all patients had insufficient vitamin D levels with a total mean 25(OH)D level of 21.43 ng/ml (53.58 nmol/L). In particular, 52\% (117/225) of patients were identified as vitamin D deficient and further 24\% of patients (55/225) were vitamin D insufficient. Notably, patients diagnosed with malignant bone tumours had significantly lower 25(OH)D levels than patients diagnosed with benign bone tumours [19.3 vs. 22.75 ng/ml (48.25 vs. 56.86 nmol/L); p = 0.04). In conclusion, we found a widespread and distressing rate of vitamin D deficiency and insufficiency in patients with bone tumours. However, especially for patients with bone tumours sufficient vitamin D levels seem to be of great importance. Thus, we believe that 25(OH)D status should routinely be monitored in these patients. Collectively, there should be an increased awareness for physicians to assess and if necessary correct vitamin D status of patients with bone tumours in general or of those at great risk of developing bone tumours.},
  language  = {en}
}
@article{OhlebuschBorstFrankenbachetal.2020,
  author    = {Ohlebusch, Barbara and Borst, Angela and Frankenbach, Tina and Klopocki, Eva and Jakob, Franz and Liedtke, Daniel and Graser, Stephanie},
  title     = {Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development},
  series = {Scientific Reports},
  volume    = {10},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-020-70152-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230024},
  year      = {2020},
  abstract  = {Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.},
  language  = {en}
}
@article{ReichelRuecklFenwicketal.2019,
  author    = {Reichel, Thomas and Rueckl, Kilian and Fenwick, Annabel and Vogt, Niklas and Rudert, Maximilian and Plumhoff, Piet},
  title     = {Hibernoma of the upper extremity: complete case of a rare but benign soft tissue tumor},
  series = {Case Reports in Orthopedics},
  volume    = {2019},
  journal   = {Case Reports in Orthopedics},
  doi       = {10.1155/2019/6840693},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201669},
  pages     = {6840693},
  year      = {2019},
  abstract  = {Hibernoma is a rare benign lipomatous tumor showing differentiation of brown fatty tissue. To the author's best knowledge, there is no known case of malignant transformation or metastasis. Due to their slow, noninfiltrating growth hibernomas are often an incidental finding in the third or fourth decade of life. The vast majority are located in the thigh, neck, and periscapular region. A diagnostic workup includes ultrasound and contrast-enhanced MRI. Differential diagnosis is benign lipoma, well-differentiated liposarcoma, and rhabdomyoma. An incisional biopsy followed by marginal resection of the tumor is the standard of care, and recurrence after complete resection is not reported. The current paper presents diagnostic and intraoperative findings of a hibernoma of the upper arm and reviews similar reports in the current literature.},
  language  = {en}
}
@phdthesis{Ege2023,
  author    = {Ege, Carolin},
  title     = {Einfluss der Phosphodiesterase 10A auf cAMP-abh{\"a}ngige Signalwege und deren Effekt auf osteogene Differenzierung und Mechanotransduktion von mesenchymalen Stromazellen},
  doi       = {10.25972/OPUS-32832},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328327},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Humane mesenchymale Stromazellen sind in der Lage in osteogene Zellen zu differenzieren, und f{\"u}r diese osteogene Differenzierung ist mechanische Belastung ein relevanter Kostimulus. Mechanotransduktion hat zur Folge, dass second messenger wie cAMP und cGMP gebildet werden und sich die Ca2+-Konzentration erh{\"o}ht, welche wiederum Transkriptionsfaktoren aktivieren, die die Regulation von Genen osteogener Marker vermitteln. Die second messenger cAMP und cGMP werden abgebaut durch Phosphodiesterasen, jedoch ist die Rolle dieser Phosphodiesterasen w{\"a}hrend der osteogenen Differenzierung oder Mechanotransduktion weiterhin unklar. Das Ziel dieser Arbeit war es, herauszufinden, inwieweit im Besonderen die Phosphodiesterase 10A einen Einfluss nimmt auf die osteogene Differenzierung und die Mechanotransduktion von mesenchymalen Stromazellen und inwiefern sie dabei die cAMP-abh{\"a}ngigen Signalwege moduliert. Langfristig soll hiermit herausgefunden wer-den, welche Bedeutung die PDE10A auf altersinduzierte Krankheiten hat, wobei der Fokus zun{\"a}chst auf der Osteoporose liegen soll. Um dies zu erreichen, wurden experimentelle Versuche zun{\"a}chst mit HEK293- und hMSC-TERT-Zellen als Modell f{\"u}r mesenchymale Stromazellen durchgef{\"u}hrt, dann auch mit den mesenchymalen Stromazellen selbst. Untersucht wurde der Einfluss des PDE10A-Inhibitors Papaverin auf die Zellen und auf deren mechanische Induzierbarkeit, sowieso auf die osteogene Differenzierung der hMSC. Außerdem wurden weitere mechanische Versuche durchgef{\"u}hrt, zur {\"U}berpr{\"u}fung des Effekts der Phosphodiesterase 10A. Es wurde beobachtet, dass die Inhibierung von PDE10A mit Papaverin die osteogene Differenzierung und Mineralisierung vermindert. Außerdem gab es einen ersten Hinweis, dass eine {\"U}berexpression von PDE10A schw{\"a}chenden Einfluss nimmt auf die Expression mechanoresponsiver Gene. Nachfolgend auf diese Arbeit wurde erkannt, dass die Expression von mechanoresponsiven Genen durch die PDE10A-Inhibition unterdr{\"u}ckt wird.},
  subject      = {Mesenchymzelle},
  language  = {de}
}
@article{HeinzMellerLuetkensetal.2023,
  author    = {Heinz, Tizian and Meller, Felix and Luetkens, Karsten Sebastian and Anderson, Philip Mark and Stratos, Ioannis and Horas, Konstantin and Rudert, Maximilian and Reppenhagen, Stephan and Weißenberger, Manuel},
  title     = {The AMADEUS score is not a sufficient predictor for functional outcome after high tibial osteotomy},
  series = {Journal of Experimental Orthopaedics},
  volume    = {10},
  journal   = {Journal of Experimental Orthopaedics},
  doi       = {10.1186/s40634-023-00575-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357765},
  year      = {2023},
  abstract  = {Purpose The Area Measurement And Depth Underlying Structures (AMADEUS) classification system has been proposed as a valuable tool for magnetic resonance (MR)-based grading of preoperatively encountered chondral defects of the knee joint. However, the potential relationship of this novel score with clinical data was yet to determine. It was the primary intention of this study to assess the correlative relationship of the AMADEUS with patient reported outcome scores in patients undergoing medial open-wedge high tibial valgus osteotomy (HTO). Furthermore, the arthroscopic ICRS (International Cartilage Repair Society) grade evaluation was tested for correlation with the AMADEUS classification system. Methods This retrospective, monocentric study found a total of 70 individuals that were indicated for HTO due to degenerative chondral defects of the medial compartment between 2008 and 2019. A preoperative MR image as well as a pre-osteotomy diagnostic arthroscopy for ICRS grade evaluation was mandatory for all patients. The Knee Osteoarthritis Outcome Score (KOOS) including its five subscale scores (KOOS-ADL, KOOS-QOL, KOOS-Sports, KOOS-Pain, KOOS-Symptoms) was obtained preoperatively and at a mean follow-up of 41.2 ± 26.3 months. Preoperative chondral defects were evaluated using the AMADEUS classification system and the final AMADEUS scores were correlated with the pre- and postoperative KOOS subscale sores. Furthermore, arthroscopic ICRS defect severity was correlated with the AMADEUS classification system. Results There was a statistically significant correlation between the AMADEUS BME (bone marrow edema) subscore and the KOOS Symptoms subscore at the preoperative visit (r = 0.25, p = 0.04). No statistically significant monotonic association between the AMADEUS total score and the AMADEUS grade with pre- and postoperative KOOS subscale scores were found. Intraoperatively obtained ICRS grade did reveal a moderate correlative relation with the AMADEUS total score and the AMADEUS grade (r = 0.28, p = 0.02). Conclusions The novel AMADEUS classification system largely lacks correlative capacity with patient reported outcome measures in patients undergoing HTO. The MR tomographic appearance of bone marrow edema is the only parameter predictive of the clinical outcome at the preoperative visit.},
  language  = {en}
}
@article{MunawarZhouPrommersbergeretal.2023,
  author    = {Munawar, Umair and Zhou, Xiang and Prommersberger, Sabrina and Nerreter, Silvia and Vogt, Cornelia and Steinhardt, Maximilian J. and Truger, Marietta and Mersi, Julia and Teufel, Eva and Han, Seungbin and Haertle, Larissa and Banholzer, Nicole and Eiring, Patrick and Danhof, Sophia and Navarro-Aguadero, Miguel Angel and Fernandez-Martin, Adrian and Ortiz-Ruiz, Alejandra and Barrio, Santiago and Gallardo, Miguel and Valeri, Antonio and Castellano, Eva and Raab, Peter and Rudert, Maximilian and Haferlach, Claudia and Sauer, Markus and Hudecek, Michael and Martinez-Lopez, J. and Waldschmidt, Johannes and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin},
  title     = {Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma},
  series = {Communications Biology},
  volume    = {6},
  journal   = {Communications Biology},
  doi       = {10.1038/s42003-023-05683-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357609},
  year      = {2023},
  abstract  = {The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.},
  language  = {en}
}
@article{WeissenbergerWagenbrennerNickeletal.2023,
  author    = {Weißenberger, Manuel and Wagenbrenner, Mike and Nickel, Joachim and Ahlbrecht, Rasmus and Blunk, Torsten and Steinert, Andre F. and Gilbert, Fabian},
  title     = {Comparative in vitro treatment of mesenchymal stromal cells with GDF-5 and R57A induces chondrogenic differentiation while limiting chondrogenic hypertrophy},
  series = {Journal of Experimental Orthopaedics},
  volume    = {10},
  journal   = {Journal of Experimental Orthopaedics},
  doi       = {10.1186/s40634-023-00594-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357770},
  year      = {2023},
  abstract  = {Purpose Hypertrophic cartilage is an important characteristic of osteoarthritis and can often be found in patients suffering from osteoarthritis. Although the exact pathomechanism remains poorly understood, hypertrophic de-differentiation of chondrocytes also poses a major challenge in the cell-based repair of hyaline cartilage using mesenchymal stromal cells (MSCs). While different members of the transforming growth factor beta (TGF-β) family have been shown to promote chondrogenesis in MSCs, the transition into a hypertrophic phenotype remains a problem. To further examine this topic we compared the effects of the transcription growth and differentiation factor 5 (GDF-5) and the mutant R57A on in vitro chondrogenesis in MSCs. Methods Bone marrow-derived MSCs (BMSCs) were placed in pellet culture and in-cubated in chondrogenic differentiation medium containing R57A, GDF-5 and TGF-ß1 for 21 days. Chondrogenesis was examined histologically, immunohistochemically, through biochemical assays and by RT-qPCR regarding the expression of chondrogenic marker genes. Results Treatment of BMSCs with R57A led to a dose dependent induction of chondrogenesis in BMSCs. Biochemical assays also showed an elevated glycosaminoglycan (GAG) content and expression of chondrogenic marker genes in corresponding pellets. While treatment with R57A led to superior chondrogenic differentiation compared to treatment with the GDF-5 wild type and similar levels compared to incubation with TGF-ß1, levels of chondrogenic hypertrophy were lower after induction with R57A and the GDF-5 wild type. Conclusions R57A is a stronger inducer of chondrogenesis in BMSCs than the GDF-5 wild type while leading to lower levels of chondrogenic hypertrophy in comparison with TGF-ß1.},
  language  = {en}
}
@article{BaumbachHoertererOppeltetal.2022,
  author    = {Baumbach, Sebastian Felix and H{\"o}rterer, Hubert and Oppelt, Sonja and Szeimies, Ulrike and Polzer, Hans and Walther, Markus},
  title     = {Do pre-operative radiologic assessment predict postoperative outcomes in patients with insertional Achilles tendinopathy?: a retrospective database study},
  series = {Archives of Orthopaedic and Trauma Surgery},
  volume    = {142},
  journal   = {Archives of Orthopaedic and Trauma Surgery},
  number    = {11},
  issn      = {1434-3916},
  doi       = {10.1007/s00402-021-03897-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307963},
  pages     = {3045-3052},
  year      = {2022},
  abstract  = {Introduction Diagnosis and treatment of insertional tendinopathy of the Achilles tendon (IAT) remains a challenge. The aim of this study was to assess the influence of pre-operative radiological pathologies on the patient-reported outcomes following open debridement of all pathologies for IAT. Materials and methods In this IRB-approved retrospective correlation and comparative study, patients with pre-operative imaging were identified from the authors' retrospective IAT database comprising of 118 patients. All were treated by a standardized surgical treatment strategy utilizing a midline, transachillary approach and debridement of all pathologies. A total of fifteen radiologic parameters were measured on radiographs (RX) and MRI. The patient-reported outcomes were assessed using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-G) and the general health questionnaire SF-12 at a minimum follow-up of 12 months. The data are presented as mean ± SD (95\% CI). Results 88 patients (74.6\%) with an average age of 50 ± 12 (47-52) years were included. Radiographs were available in 68 patients and MRI in 53. The mean follow-up was 3.8 ± 1.9 (3.4-4.3) years. The overall VISA-A-G was 81 ± 22 (77-86), the SF-12 PCS 54 ± 7 (52-55), and the SF-12 MCS 52 ± 9 (50-54) points. None of the assessed radiological parameters had a significant influence on the patient-reported outcome following surgical treatment for IAT. Conclusion In this retrospective correlation study, no significant association was found between preoperative radiographic and MRI radiologic parameters for IAT and postoperative patient-reported outcomes (VISA-A-G and SF-12).},
  language  = {en}
}
@article{LuetkensGrunzKunzetal.2023,
  author    = {Luetkens, Karsten Sebastian and Grunz, Jan-Peter and Kunz, Andreas Steven and Huflage, Henner and Weißenberger, Manuel and Hartung, Viktor and Patzer, Theresa Sophie and Gruschwitz, Philipp and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Feldle, Philipp},
  title     = {Ultra-high-resolution photon-counting detector CT arthrography of the ankle: a feasibility study},
  series = {Diagnostics},
  volume    = {13},
  journal   = {Diagnostics},
  number    = {13},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics13132201},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362622},
  year      = {2023},
  abstract  = {This study was designed to investigate the image quality of ultra-high-resolution ankle arthrography employing a photon-counting detector CT. Bilateral arthrograms were acquired in four cadaveric specimens with full-dose (10 mGy) and low-dose (3 mGy) scan protocols. Three convolution kernels with different spatial frequencies were utilized for image reconstruction (ρ\(_{50}\); Br98: 39.0, Br84: 22.6, Br76: 16.5 lp/cm). Seven radiologists subjectively assessed the image quality regarding the depiction of bone, hyaline cartilage, and ligaments. An additional quantitative assessment comprised the measurement of noise and the computation of contrast-to-noise ratios (CNR). While an optimal depiction of bone tissue was achieved with the ultra-sharp Br98 kernel (S ≤ 0.043), the visualization of cartilage improved with lower modulation transfer functions at each dose level (p ≤ 0.014). The interrater reliability ranged from good to excellent for all assessed tissues (intraclass correlation coefficient ≥ 0.805). The noise levels in subcutaneous fat decreased with reduced spatial frequency (p \&lt; 0.001). Notably, the low-dose Br76 matched the CNR of the full-dose Br84 (p 0.999) and superseded Br98 (p \&lt; 0.001) in all tissues. Based on the reported results, a photon-counting detector CT arthrography of the ankle with an ultra-high-resolution collimation offers stellar image quality and tissue assessability, improving the evaluation of miniscule anatomical structures. While bone depiction was superior in combination with an ultra-sharp convolution kernel, soft tissue evaluation benefited from employing a lower spatial frequency.},
  language  = {en}
}
@article{PereiraLipphausErginetal.2021,
  author    = {Pereira, Ana Rita and Lipphaus, Andreas and Ergin, Mert and Salehi, Sahar and Gehweiler, Dominic and Rudert, Maximilian and Hansmann, Jan and Herrmann, Marietta},
  title     = {Modeling of the Human Bone Environment: Mechanical Stimuli Guide Mesenchymal Stem Cell-Extracellular Matrix Interactions},
  series = {Materials},
  volume    = {14},
  journal   = {Materials},
  number    = {16},
  issn      = {1996-1944},
  doi       = {10.3390/ma14164431},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245012},
  year      = {2021},
  abstract  = {In bone tissue engineering, the design of in vitro models able to recreate both the chemical composition, the structural architecture, and the overall mechanical environment of the native tissue is still often neglected. In this study, we apply a bioreactor system where human bone-marrow hMSCs are seeded in human femoral head-derived decellularized bone scaffolds and subjected to dynamic culture, i.e., shear stress induced by continuous cell culture medium perfusion at 1.7 mL/min flow rate and compressive stress by 10\% uniaxial load at 1 Hz for 1 h per day. In silico modeling revealed that continuous medium flow generates a mean shear stress of 8.5 mPa sensed by hMSCs seeded on 3D bone scaffolds. Experimentally, both dynamic conditions improved cell repopulation within the scaffold and boosted ECM production compared with static controls. Early response of hMSCs to mechanical stimuli comprises evident cell shape changes and stronger integrin-mediated adhesion to the matrix. Stress-induced Col6 and SPP1 gene expression suggests an early hMSC commitment towards osteogenic lineage independent of Runx2 signaling. This study provides a foundation for exploring the early effects of external mechanical stimuli on hMSC behavior in a biologically meaningful in vitro environment, opening new opportunities to study bone development, remodeling, and pathologies.},
  language  = {en}
}
@article{SeefriedRakPetryketal.2021,
  author    = {Seefried, L. and Rak, D. and Petryk, A. and Genest, F.},
  title     = {Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa},
  series = {Osteoporosis International},
  volume    = {32},
  journal   = {Osteoporosis International},
  number    = {12},
  doi       = {10.1007/s00198-021-06025-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265310},
  pages     = {2505-2513},
  year      = {2021},
  abstract  = {Summary There is limited understanding of how asfotase alfa affects mineral metabolism and bone turnover in adults with pediatric-onset hypophosphatasia. This study showed that adults with hypophosphatasia treated with asfotase alfa experienced significant changes in biochemical markers of bone and mineral metabolism, possibly reflecting enhanced bone remodeling of previously osteomalacic bone. Introduction Hypophosphatasia (HPP), due to a tissue nonspecific alkaline phosphatase (TNSALP) deficiency, can cause impaired bone mineralization and turnover. Although HPP may be treated with asfotase alfa, an enzyme replacement therapy, limited data are available on how treatment with asfotase alfa affects mineral metabolism and bone turnover in adults with HPP. Methods ALP substrates, bone turnover and mineral metabolism markers, and bone mineral density (BMD) data from EmPATHY, a single-center, observational study of adults (≥ 18 years) with pediatric-onset HPP treated with asfotase alfa (NCT03418389), were collected during routine clinical care and analyzed from baseline through 24 months of treatment. Results Data from 21 patients showed significantly increased ALP activity and reduced urine phosphoethanolamine (PEA)/creatinine (Cr) ratios after baseline through 24 months of asfotase alfa treatment. There were significant transient increases in parathyroid hormone 1-84 (PTH), osteocalcin, and procollagen type 1 N-propeptide (P1NP) levels at 3 and 6 months and in tartrate-resistant acid phosphatase 5b (TRAP5b) levels at 3 months, with a significant decrease in N-terminal telopeptide of type 1 collagen (NTX) levels at 24 months. Lumbar spine BMD T scores continuously increased during treatment. Conclusion Significant changes in bone turnover and mineral metabolism markers after asfotase alfa treatment suggest that treatment-mediated mineralization may enable remodeling and bone turnover on previously unmineralized surfaces. Urine PEA/Cr ratios may be a useful parameter in monitoring treatment during routine care.},
  language  = {en}
}
@article{GenestClaussenRaketal.2021,
  author    = {Genest, F. and Claußen, L. and Rak, D. and Seefried, L.},
  title     = {Bone mineral density and fracture risk in adult patients with hypophosphatasia},
  series = {Osteoporosis International},
  volume    = {32},
  journal   = {Osteoporosis International},
  issn      = {0937-941X},
  doi       = {10.1007/s00198-020-05612-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235793},
  pages     = {377-385},
  year      = {2021},
  abstract  = {Summary In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD. Introduction Hypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce. Methods Retrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history. Results Analysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3\% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20\%) patients (p < 0.001) with 21 of them having biallelic mutations. Conclusion BMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis. Trial registration number German register for clinical studies (DRKS00014022) Date of registration 02/10/2018 - retrospectively registered},
  language  = {en}
}
@article{StratosBehrendtAnselmetal.2022,
  author    = {Stratos, Ioannis and Behrendt, Ann-Kathrin and Anselm, Christian and Gonzalez, Aldebarani and Mittlmeier, Thomas and Vollmar, Brigitte},
  title     = {Inhibition of TNF-α restores muscle force, inhibits inflammation, and reduces apoptosis of traumatized skeletal muscles},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {15},
  issn      = {2073-4409},
  doi       = {10.3390/cells11152397},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286094},
  year      = {2022},
  abstract  = {Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.},
  language  = {en}
}