Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development.

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

[Infectious, pathologic humeral fracture in a patient with sickle cell disease-A rare case?] / Infizierte, pathologische Humerusfraktur bei Sichelzellanämie ­ noch ein Einzelfall?

The vaso-occlusive crises of sickle cell disease are accompanied by bone necrosis, which favors endogenous bacterial colonization and thus osteomyelitis. This poses a major challenge for eradication and fracture management.A 22-year-old patient with sickle cell disease sustained a multifragmentary, humeral shaft fracture. During surgical management, pus drained from the fracture site and further diagnostic work-up revealed osteomyelitis with evidence of Klebsiella aerogenes. Septicemia due to Klebsiella aerogenes had been treated 5 months prior to the accident, which occured because of a vaso-occlusive crisis. This is associated with clustered bone necrosis and endogenous germ colonization. Eradication of the germs and fracture care become a challenge. Repeated surgical procedures with segmental transfer can be a successful treatment option.

Conservative versus operative treatment of FFP II fractures in a geriatric cohort: a prospective randomized pilot trial.

A clear recommendation regarding treatment strategy of fragility fractures of the pelvic ring is missing. The most typical fracture pattern is a lateral compression type injury with non-displaced fractures of the anterior pubic rami and a unilateral os sacrum fracture (FFP II). We hypothesized that operative treatment would be superior to conservative treatment. From October 2017 to April 2020, a randomized prospective non-blinded trial with n = 39 patients was carried out. Two arms with 17 operative versus 22 conservative cases were created. Inclusion criteria were a posterior pelvic ring fracture FFP type II, age over 60 years and acute fracture (< 3 weeks). Barthel index, pain level (VAS), quality of life (EQ-5D-3L), and Tinetti-Gait Test were determined on admission, at discharge, and after 3, 6, 12 and 24 months. Median follow-up was 12.9 months. The Barthel index (= 0.325), VAS (p = 0.711), quality of life (p = 0.824), and Tinetti-Gait Test (p = 0.913) showed no significant differences between the two groups after 12 months. Two patients switched from the conservative to the operative arm due to persistent immobilization and pain. The one-year mortality rate showed no significant difference (p = 0.175). Our hypothesis that surgical treatment is superior was refuted. No significant benefit was shown in terms of quality of life, mortality and pain levels. The results suggest a more differentiated treatment approach in the future, with initial conservative treatment preferred. A larger multi-center trial is required to confirm these findings.Trial registration: The study was retrospectively registered with the German Clinical Trials Registry (DRKS00013703) on 10/12/2018.

Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability.

Notch signaling regulates cell fate in multiple tissues including the skeleton. Hajdu-Cheney-Syndrome (HCS), caused by gain-of-function mutations in the Notch2 gene, is a rare inherited disease featuring early-onset osteoporosis and increased risk for fractures and non-union. As the impact of Notch2 overactivation on fracture healing is unknown, we studied bone regeneration in mice harboring a human HCS mutation. HCS mice, displaying high turnover osteopenia in the non-fractured skeleton, exhibited only minor morphologic alterations in the progression of bone regeneration, evidenced by static radiological and histological outcome measurements. Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers. These observations were accompanied by inferior biomechanical stability of healed femora in HCS mice. Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.

Total knee arthroplasty and patelloplasty in a patient with phocomelia caused by thalidomide.

The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors present a case of phocomelia caused by thalidomide with end-stage osteoarthritis and grossly medialized patella. The patient was treated with a cemented constrained non-hinged prosthesis and patelloplasty. Six months later, the patient had complete relief of pain and was able to walk without walking assistance. To our knowledge, total knee replacement in a patient with phocomelia caused by thalidomide has not been described in literature.

The diagnostic accuracy of 332 incisional biopsies in patients with malignant tumors in the musculoskeletal system.

BACKGROUND: It is known that specimen collection followed by histopathological workup is the core of evidence-based medical therapy of musculoskeletal tumors. There exist many controversies about how a biopsy should be performed. While some centers recommend minimal invasive biopsy procedures, mostly the core needle biopsy (CNB), others prefer the incisional biopsy. PURPOSE OF THE STUDY: This study aimed to determine the accuracy of incisional biopsy for malignant tumors in the musculoskeletal system. Moreover, advantages and disadvantages to other biopsy methods are discussed. METHODS: This retrospective, single-center study about 844 incisional biopsies (benign and malignant) analysis the diagnostic accuracy of 332 malignant tumors, concerning the final histopathological result. In addition, surgical complications are analyzed to find the best way to plan and treat patients timely and correct. Secondary endpoints are the patients age, the pure operation time, as well as the type of tumor, and the subsequent therapy. RESULTS: In summary, incisional biopsy corresponded a sensitivity of 100% for malignancy in 844 incisional biopsies and a specificity of 97.6% in 332 malignant tumors, but it features greater operative expense (incision/suture 23.5 min) and the risk of general anesthesia. CONCLUSION: The method of biopsy should be tailored to the individual patient and the experience of the center performing the procedure.

The influence of 3D printing on inter- and intrarater reliability on the classification of tibial plateau fractures.

PURPOSE: Tibial plateau fractures continue to be a challenging task in clinical practice and current outcomes seem to provide the potential for further improvement. Especially presurgical understanding of the orientation of fracture lines and fracture severity is an essential key to sufficient surgical treatment. The object of this study was to evaluate the reliability of modern axial CT-based classification systems for tibial plateau fractures. In addition, the diagnostic-added value of 3D printing on the classification systems was investigated. METHODS: 22 raters were asked to classify 22 tibial plateau fractures (11 AO B- and 11 AO C-fractures) with the AO, the 10-Segment and the Revisited Schatzker classification in a three-step evaluation: first only using CT scans, second with 3D volumetric reconstructions and last with 3D-printed fracture models. Inter- and intraobserver agreement and the subjective certainty were analyzed. Statistics were done using kappa values, percentage match and a univariant one-way analysis of variance. RESULTS: The AO classifications interobserver percentage match and kappa values improved for all raters and recorded an overall value of 0.34, respectively, 43% for the 3D print. The 10-Segment classification interobserver agreement also improved with the 3D-printed models and scored an overall kappa value of 0.18 and a percentage match of 79%. Equally the Revisited Schatzker classification increased its values to 0.31 and 35%. The intraobserver agreement showed a moderate agreement for the AO (0.44) and Revisited Schatzker classification (0.42) whereas the 10-Segment classification showed a fair agreement (0.27). Additionally, the raters changed their classification in 36% of the cases after evaluating the fracture with the 3D-printed models and the subjective certainty regarding the decisions improved as categories of self-reliant diagnostic choices were selected 18% (p < 0.05) more often after using the 3D-printed models. CONCLUSION: Based on the measured outcomes it was concluded that the new classification systems show an overall slight to fair reliability and the use of 3D printing proved to be beneficial for the preoperative diagnostics of tibial plateau fractures. The 10-Segment classification system showed the highest percentage match evaluation of all classification systems demonstrating its high clinical value across all levels of user experience.

Diagnostic and Therapeutic Pathways of Intramuscular Myxoma.

Intramuscular myxomas (IMMs) are benign tumors. Evidence regarding diagnostic and therapeutic pathways is rare, and guidelines do not exist due to their low incidence. The aim of this study was a retrospective analysis at a university cancer center and the interdisciplinary re-evaluation of the individual diagnostic and therapeutic procedures. Overall, 38 patients were included in the study. IMMs occurred mostly in middle-aged women. At the time of first consultation, 57.9% had few symptoms or were asymptomatic. In 92.1% of the cases, the tumor was localized in the extremities. The lower extremity was affected in 73.7%. The average size of IMMs was 5.0 cm. The proximally located tumors in the gluteus, thighs, and upper arms were significantly larger (p = 0.02) than the distally-located tumors in the forearms and lower legs. An MRI was performed in 97.4%. Based on imaging, an IMM was suspected in 5.6% by radiologists and in 54.1% by musculoskeletal surgeons. An incision biopsy was performed in 68.4% and led in 100.0% to the right histopathological diagnosis. In total, 89.5% of IMMs were resected. Postoperative complications requiring revision occurred in 8.8%. Recurrences or degenerations of IMMs were not reported in any of these cases.

Can homogeneous, lipomatous tumors be primarily resected without biopsy? A retrospective analysis of 240 tumors.

BACKGROUND: According to guidelines, every soft tissue tumor (STT) larger than 3 cm should be biopsied before definitive resection. Advances in magnetic resonance imaging (MRI) improve the possibility to give a provisional diagnosis of the tumor's entity. Can lipomas and atypical lipomatous tumors (ALTs) of the extremities therefore be primarily marginally resected based on interpretation of MR images without a previous biopsy?. METHODS: In this retrospective, single-center study, 240 patients with the suspicion of a lipomatous tumor in MRI and surgical treatment in our institution between 2011 and 2020 were included. MR imaging was performed before surgery. All resected specimens underwent histopathological analysis. RESULTS: The collective comprised 142 tumors that were suspected as lipoma or ALT by the radiologist and underwent primary marginal resection (PMR). One case had myxoid liposarcoma that was underestimated on MRI and needed radical follow-up resection. One-hundred forty-one patients were cured after PMR. Ninety-eight patients were biopsied initially and in 93 cases resected afterwards according to the necessary oncological margins. CONCLUSION: In our institution, PMR is performed if a lipoma or ALT is suspected on MR imaging. Our treatment method and the diagnostic algorithm are presented. Primary resection spares patients from one surgical procedure, but a slight risk for underestimation of the tumor remains.

Lipomatous Tumors: A Comparison of MRI-Reported Diagnosis with Histological Diagnosis.

Lipomatous tumors are among the most common soft tissue tumors (STTs). Magnetic resonance imaging (MRI) is a state-of-the-art diagnostic tool used to differentiate and characterize STTs. Radiological misjudgment can lead to incorrect treatment. This was a single-center retrospective study. Two hundred and forty lipomatous tumors were included. MRI diagnoses were categorized as benign, intermediate, or malignant and were compared with histological diagnoses. Tumor volumes were measured by MRI and from surgical specimens. The tumor was correctly categorized 73.3% of the time. A total of 21.7% of tumors were categorized as more malignant in MRI reports than they were by histology, and vice versa for 5.0% of tumors. Volume measured by MRI was not different from actual tumor size in pathology. Atypical lipomatous tumors (ALTs) and liposarcomas (LPSs) were larger when compared with lipomata and occurred in older patients. Based on the MRI-suspected tumor entity, surgical treatment can be planned. Large lipomatous tumors in elderly patients are more likely to be ALTs. However, a safe threshold size or volume for ALTs cannot be determined.

Diagnostic delay in soft tissue tumors: a single-center study of a university cancer center with a focus on health services research.

BACKGROUND: Lumps and soft tissue tumors (STT) are frequent reasons for consulting a physician. Most STT are benign, and lumps are not always associated with a tumor. MRI is the most advanced imaging modality to assist a provisional diagnosis of STT. Only a small fraction of STT is malignant, these soft tissue sarcomas are known for their aggressive growth. The study aims to analyze the influence of the MRI report on the speed of treatment of patients with suspected STT. METHODS: This was a retrospective, longitudinal, single-center study from 2011-2020. We included adult patients who had biopsies or resections of masses suspicious for STT in MRI exams. MRI reports were classified as benign (I), intermediate/unclear (II), or malignant (III). For these cohorts, time was statistically analyzed from MRI scan to first contact with the University cancer center (UCC) and surgery. Furthermore, distance in kilometers from the patients´ home to the UCC was examined and compared to age and suspected malignancy. RESULTS: Three hundred two patients (♀130; ♂172) were included. Histologic analyses revealed 286 tumors. The average age of the patients was 54.7(SD: 16.2) years. Malignant tumors were more often suspected in older patients (p = 0.0098). Patients with a benign diagnosed tumor in MRI contacted the UCC after an average of 31.3 (SD: 47.8) days. In contrast, patients with suspicion of a malignant tumor contacted the UCC significantly earlier, after 14.1 days (SD: 17.1); p = 0.0098. Likewise, the time between first contact and biopsy/resection was 32.8 days (SD: 35.7) for suspiciously benign tumors, and potentially malignant tumors were treated significantly faster 14.8 (SD: 16.0) days; (p = 0.028). Patients traveled on average 47.5 km (range: 0.5-483) to contact a specialized physician at the UCC. Suspected degree of malignancy or patient´s age had no statistical influence on traveled distance. DISCUSSION: The treatment speed depended to a great extent on the suspected malignancy of the STT in the MRI report. The provisional diagnoses from the radiologist highly influenced the time delay between MRI scan and first contact to the UCC and surgical treatment. No discrimination of age or distance to the UCC was observed in this study.

Dislocation of a McMinn-Like Prosthesis with Distinctive Metallosis and Fracture of the Os Ilium.

Osteoarthritis of the hip joint (coxarthrosis) is the most common hip disease in adults. Since the 1960s, total hip arthroplasty (THA) has made great progress and is nowadays one of the most frequently used procedures in orthopedic surgery. Different bearing concepts exist in various implant designs. A metal-on-metal bearing can create metal debris and lead to metallosis. We present a unique case of a 78-year old woman, who received hip resurfacing with a McMinn-like prosthesis 15 years ago. Over the cause of time, metallosis developed and created a bone cyst in the Os ilium, and osteolysis led to a dislocation of the femoral implant. A minor stumble fall led to a fracture of the Os ilium. We present our treatment method with implantation of a cemented THA and refill of the bone cyst with bone from allogene femoral heads. The surgery led to a reconstruction of the physiological center of rotation in the hip. Consequently, to the inpatient stay, the patient took part in a follow-up treatment with intensive physiotherapy. Taken together, the results after total hip arthroplasty are more superior to other hip surface replacements in terms of longevity and patient satisfaction. Especially, metal-on-metal bearing couples carry a great risk of metallosis, which goes a long with pseudotumors, osteolysis, and the elevated metal ions in the blood. Since this case is unique in the literature, no guidelines are noted for surgical treatment. In our opinion, a periprosthetic fracture of this type should be performed in a hospital using extensive endoprosthetic expertise.

Total Hip Arthroplasty in a Patient with Mucopolysaccharidosis Type IVB.

Introduction. Morquio syndrome or mucopolysaccharidosis (MPS) type IV is a rare autosomal recessive lysosomal storage disease, characterized by abnormal metabolism of glycosaminoglycans associated with specific skeletal deformities, also known as dysostosis multiplex. Case Presentation. We present the case of a 23-year-old patient with advanced osteonecrosis of the femoral head (ONFH) on both sides due to Morquio syndrome. A diagnosis of mucopolysaccharidosis type IVB was made after extensive genetic profiling. The patient had the condition for a long time. At 7 years old, the patient was treated with bilateral pelvic Salter's osteotomy. Afterward, the patient was able to walk freely but could never take part in sports. At 22 years old, pain in the hip increased, and magnetic resonance imaging showed a bilateral femur head necrosis. Hence, the patient underwent cementless total hip arthroplasty (THA). Intraoperatively, a periprosthetic fracture occurred. Therefore, revision surgery with internal fixation was performed on the next day. Postoperatively, a weight-bearing restriction of 20 kg on the left leg was imposed for 6 weeks. The patient made a full recovery and was able to move without residual complaints. Annual orthopedic evaluation in patients treated with surgical intervention is recommended. Discussion. Orthopedic challenges for mucopolysaccharidoses and corresponding bone alterations, known as dysostosis multiplex, involving trunk and limbs with typical radiological findings have been well described. The hip is invariably involved, with dysplasia affecting the femoral neck (coxa valga), femoral epiphysis (loss of sphericity, osteonecrosis), and a flared hypoplastic iliac wing. Symptomatic therapy consists, on the one hand, of a surgical procedure and, on the other hand, a variety of supportive measures. However, the management of joint replacement in lysosomal storage diseases has not been well reported. All patients with MPS should be considered at high risk for surgical intervention requiring anesthesia because of airway and cardiac disease manifestations. In the case of a need for THA, we recommend cemented stem fixation because of the overall poor bone quality in patients with Morquio syndrome.

Glucose Metabolism in Osteoblasts in Healthy and Pathophysiological Conditions.

Bone tissue in vertebrates is essential to performing movements, to protecting internal organs and to regulating calcium homeostasis. Moreover, bone has also been suggested to contribute to whole-body physiology as an endocrine organ, affecting male fertility; brain development and cognition; and glucose metabolism. A main determinant of bone quality is the constant remodeling carried out by osteoblasts and osteoclasts, a process consuming vast amounts of energy. In turn, clinical conditions associated with impaired glucose metabolism, including type I and type II diabetes and anorexia nervosa, are associated with impaired bone turnover. As osteoblasts are required for collagen synthesis and matrix mineralization, they represent one of the most important targets for pharmacological augmentation of bone mass. To fulfill their function, osteoblasts primarily utilize glucose through aerobic glycolysis, a process which is regulated by various molecular switches and generates adenosine triphosphate rapidly. In this regard, researchers have been investigating the complex processes of energy utilization in osteoblasts in recent years, not only to improve bone turnover in metabolic disease, but also to identify novel treatment options for primary bone diseases. This review focuses on the metabolism of glucose in osteoblasts in physiological and pathophysiological conditions.

Relevance of Notch Signaling for Bone Metabolism and Regeneration.

Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/ß-catenin, BMP and RANKL/OPG, are outlined.

Third day laboratory follow-up: mandatory for surgical site infections of tibial plateau fractures.

INTRODUCTION: Tibial plateau fractures are common fractures in adults and can be extremely challenging for surgeons. State-of-the-art therapy is open reduction and internal fixation (ORIF), although major complications of ORIF are surgical site infections (SSIs). This is especially critical on the proximal tibia, which is only sparsely covered by soft tissue and has a close relation to the knee joint. We analyzed SSIs after ORIF to correlate established laboratory parameters to the occurrence of SSIs. METHODS: A monocentric case-control study in a Level 1 Trauma Center was conducted. Data were acquired from electronic medical records from 2011 until 2016. White blood cell count (WBC) and C-reactive protein (CRP) were used as laboratory parameters and statistically analyzed. RESULTS: In total, 97 patients were included, with four patients suffering from SSIs. Patients with SSIs had a significantly increased WBC count and CRP levels on the third postoperative day. Infection was diagnosed after rehospitalization, 12 ± 4 weeks after initial surgery. Furthermore, a large bony destruction through trauma coincides with a rise of WBC count with no influence on CRP level. CONCLUSION: We highly recommend a laboratory analysis with WBC count and CRP on the third day after ORIF. Patients with a CRP level above 100 mg/l should be closely watched, even if laboratory parameters few days later are adequate-since a one-time increase above this landmark might be a hint regarding the development of a SSI.

Does eight-plate epiphysiodesis of the proximal tibia in treating angular deformity create intra-articular deformity?

AIMS: Eight-plates are used to correct varus-valgus deformity (VVD) or limb-length discrepancy (LLD) in children and adolescents. It was reported that these implants might create a bony deformity within the knee joint by change of the roof angle (RA) after epiphysiodesis of the proximal tibia following a radiological assessment limited to anteroposterior (AP) radiographs. The aim of this study was to analyze the RA, complemented with lateral knee radiographs, with focus on the tibial slope (TS) and the degree of deformity correction. METHODS: A retrospective, single-centre study was conducted. The treatment group (n = 64 knees in 44 patients) was subclassified according to the implant location in two groups: 1) medial hemiepiphysiodesis; and 2) lateral hemiepiphysiodesis. A third control group consisted of 25 untreated knees. The limb axes and RA were measured on long standing AP leg radiographs. Lateral radiographs of 40 knees were available for TS analysis. The mean age of the patients was 10.6 years (4 to 15) in the treatment group and 8.4 years (4 to 14) in the control group. Implants were removed after a mean 1.2 years (0.5 to 3). RESULTS: No significant differences in RA (p = 0.174) and TS (p = 0.787) were observed. The limb axes were significantly corrected in patients with VVD (p < 0.001). The change in tibial slope (∆TS) did not correlate (r = -0.026; p = 0.885) to the plate's position on the physis when assessed by lateral radiographs. CONCLUSION: We were not able to confirm the reported change in the bony morphology of the proximal tibia on AP radiographs in our patient population. In addition, no significant change in TS was detected on the lateral radiographs. A significant correction of the VVD in the lower limb axes was evident. Position of the implant did not correlate with TS change. Therefore, eight-plate epiphysiodesis is a safe and effective procedure for correcting VVD in children without disturbing the knee joint morphology. Cite this article: Bone Joint J 2020;102-B(10):1412-1418.

Extended approach to the lateral tibial plateau with central meniscal subluxation in fracture repair: feasibility and first clinical and radiographic results.

PURPOSE: Anatomic reduction in tibial plateau fractures remains to be demanding. For further visualisation of and approach to the joint surface an extended lateral approach using a lateral femoral epicondyle osteotomy and subluxation of the lateral meniscus was recently described. First clinical and radiographic mid-term results of this technique are presented in this feasibility study. METHOD: Ten complex tibial plateau fractures treated with extended lateral approach and lateral meniscal subluxation were prospectively analysed. Clinical and radiographic results were objectified according to the Rasmussen scores. RESULTS: After a median follow-up of 8.6 (IQR 4.3) months good to excellent clinical and radiographic results were noted. The clinical Rasmussen Score showed a median of 25 (IQR 2.8) and radiographic a median of 17 (IQR 2.0) points. CONCLUSION: Good to excellent clinical and radiological scores were obtained after using an extended lateral approach with lateral femoral epicondyle osteotomy and central meniscus subluxation. No approach specific complications could be observed.

Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression.

BACKGROUND: Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immune cells is unknown. METHODS: Chimeric mice deficient for Notch3 in hematopoietic cells and/or resident tissue cells were generated, and kidney fibrosis and inflammation after unilateral ureteral obstruction (UUO) were analyzed. Adoptive transfer of labeled bone marrow-derived cells validated the results in a murine Leishmania ear infection model. In vitro adhesion assays, integrin activation, and extracellular matrix production were analyzed. RESULTS: Fibrosis follows UUO, but inflammatory cell infiltration mostly depends upon Notch3 expression in hematopoietic cells, which coincides with an enhanced proinflammatory milieu (e.g., CCL2 and CCL5 upregulation). Notch3 expression on CD45+ leukocytes plays a prominent role in efficient cell transmigration. Functionally, leukocyte adhesion and integrin activation are abrogated in the absence of receptor Notch3. Chimeric animal models also reveal that tubulointerstitial fibrosis develops, even in the absence of prominent leukocyte infiltrates after ureteral obstruction. Deleting Notch3 receptors on resident cells blunts kidney fibrosis, ablates NF-κB signaling, and lessens matrix deposition. CONCLUSIONS: Cell-specific receptor Notch3 signaling independently orchestrates leukocyte infiltration and organ fibrosis. Interference with Notch3 signaling may present a novel therapeutic approach in inflammatory as well as fibrotic diseases.

Osteosynthesis of a Multifragment Femoral Shaft Fracture and Peri-Implant Refracture in an 83-Year-Old Patient with Osteogenesis Imperfecta.

Introduction. Osteogenesis imperfecta (OI) is the term for a heterogenic group of conatal diseases that affect the bone formation. Eight different OI types are known. Patients with types III and IV frequently suffer from fractures without adequate trauma. The literature gives plenty advice for fracture treatment in pediatric OI patients, but there is less for adults, and no recommendations can be found for geriatric OI patients. Case Presentation. We report on an 83-year-old male who suffered from OI type IV. He was able to walk with an individually adapted gait orthosis. In an accident, the patient sustained a distal, multifragment, femoral shaft fracture. The fracture was openly reduced and fixated with a retrograde inserted elastic stable intramedullary nail (ESIN). Three months later, the patient was capable of walking without crutches. Due to another accident, he sustained a peri-implant refracture without failure of the ESIN. We immobilized the leg, and it achieved bony healing without reosteosynthesis. Eleven weeks later, he was again able to mobilize himself with full weight bearing. Discussion. We present a unique case of osteosynthesis in a distal, multifragment, femoral shaft fracture in a geriatric OI patient. No recommendations for the treatment of mature patients with OI can be found in the literature. We present our treatment concept and technique of osteosynthesis with an ESIN. Despite another accident with a peri-implant refracture, sufficient bony healing occurred, which allowed the patient to freely mobilize himself again.