Hypoxia and Wnt signaling inversely regulate expression of chondroprotective molecule ANP32A in articular cartilage.

OBJECTIVES: ANP32A is a key protector of cartilage health, via preventing oxidative stress and Wnt hyper-activation. We aimed to unravel how ANP32A is regulated in cartilage. METHODS: A bioinformatics pipeline was applied to identify regulators of ANP32A. Pathways of interest were targeted to study their impact on ANP32A in in vitro cultures of the human chondrocyte C28/I2 cell-line and primary human articular chondrocytes (hACs) from up to five different donors, using Wnt-activator CHIR99021, hypoxia-mimetic IOX2 and a hypoxia chamber. ANP32A was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In vivo, the effect of hypoxia was examined by immunohistochemistry in mice injected intra-articularly with IOX2 after destabilization of the medial meniscus. Effects of Wnt hyper-activation were investigated using Frzb-knockout mice and wild-type mice treated intra-articularly with CHIR99021. Wnt inhibition effects were assessed upon intra-articular injection of XAV939. RESULTS: The hypoxia and Wnt signaling pathways were identified as networks controlling ANP32A expression. In vitro and in vivo experiments demonstrated increases in ANP32A upon hypoxic conditions (1.3-fold in hypoxia in C28/I2 cells with 95% confidence interval (CI) [1.11-1.54] and 1.90-fold in hACs [95% CI: 1.56-2] and 1.67-fold in ANP32A protein levels after DMM surgery with IOX2 injections [95% CI: 1.33-2.08]). Wnt hyper-activation decreased ANP32A in chondrocytes in vitro (1.23-fold decrease [95% CI: 1.02-1.49]) and in mice (1.45-fold decrease after CHIR99021 injection [95% CI: 1.22-1.72] and 1.41-fold decrease in Frzb-knockout mice [95% CI: 1.00-1.96]). Hypoxia and Wnt modulated ataxia-telangiectasia mutated serine/threonine kinase (ATM), an ANP32A target gene, in hACs (1.89-fold increase [95% CI: 1.38-2.60] and 1.41-fold decrease [95% CI: 1.02-1.96]). CONCLUSIONS: Maintaining hypoxia and limiting Wnt activation sustain ANP32A and protect against osteoarthritis.

ANP32A represses Wnt signaling across tissues thereby protecting against osteoarthritis and heart disease.

OBJECTIVES: To investigate how ANP32A, previously linked to the antioxidant response, regulates Wnt signaling as unraveled by transcriptome analysis of Anp32a-deficient mouse articular cartilage, and its implications for osteoarthritis (OA) and diseases beyond the joint. METHODS: Anp32a knockdown chondrogenic ATDC5 cells were cultured in micromasses. Wnt target genes, differentiation markers and matrix deposition were quantified. Wnt target genes were determined in articular cartilage from Anp32a-deficient mice and primary human articular chondrocytes upon ANP32A silencing, using qPCR, luciferase assays and immunohistochemistry. Co-immunoprecipitation, immunofluorescence and chromatin-immunoprecipitation quantitative PCR probed the molecular mechanism via which ANP32A regulates Wnt signaling. Anp32a-deficient mice were subjected to the destabilization of the medial meniscus (DMM) OA model and treated with a Wnt inhibitor and an antioxidant. Severity of OA was assessed by cartilage damage and osteophyte formation. Human Protein Atlas data analysis identified additional organs where ANP32A may regulate Wnt signaling. Wnt target genes were determined in heart and hippocampus from Anp32a-deficient mice, and cardiac hypertrophy and fibrosis quantified. RESULTS: Anp32a loss triggered Wnt signaling hyper-activation in articular cartilage. Mechanistically, ANP32A inhibited target gene expression via histone acetylation masking. Wnt antagonist treatment reduced OA severity in Anp32a-deficient mice by preventing osteophyte formation but not cartilage degradation, contrasting with antioxidant treatment. Dual therapy ameliorated more OA features than individual treatments. Anp32a-deficient mice also showed Wnt hyper-activation in the heart, potentially explaining the cardiac hypertrophy phenotype found. CONCLUSIONS: ANP32A is a novel translationally relevant repressor of Wnt signaling impacting osteoarthritis and cardiac disease.

Intramedullary nailing of humeral shaft fractures: failure analysis of a single centre series.

INTRODUCTION: Intramedullary nailing (IMN) is an accepted technique for the treatment of humeral shaft fractures. Previous studies published concerns over whether this technique had higher complication rates such as nonunion and technical failures compared to plate osteosynthesis. We, therefore, conducted a single centre failure analysis to critically evaluate our results regarding IMN of humeral shaft fractures. MATERIALS AND METHODS: Between January 2000 and January 2013, 246 consecutive patients with humeral shaft fractures were enrolled. Inclusion criteria were skeletal maturity and humeral shaft fractures treated with IMN. Exclusion criteria were skeletal immaturity, primary treatment by plate osteosynthesis, primary treatment outside the University Hospitals Leuven, presence of metaphyseal fractures and the presence of pathological fractures. Negative outcome measures such as infection, nonunion and early technical failure were retrospectively assessed. RESULTS: During the study period, 149 patients with 149 fractures met the inclusion criteria. Of these, 14 patients were lost to follow-up, two died from trauma-related causes within the first 30 days after the accident, and eight died from other causes (cardiovascular disease and cancer) leaving 125 patients with 125 fractures for a minimum follow-up period of 12 months. Failure analysis showed that six (4.8 %) patients developed a nonunion. One (0.8 %) patient was diagnosed with a deep infection. In total, five (5 %) patients underwent surgical revision due to early technical failures. CONCLUSIONS: IMN is a valid therapeutic option for humeral shaft fractures. Good surgical technique and soft tissue handling are important for good outcome. Currently, patient demands are receiving greater consideration. In an era where early full range of motion and rapid return to work with minimal scarring is mandatory for most patients, the use of IMN will most likely increase in popularity in the future.

Variation in care and outcome for fragile hip fracture patients: a European multicentre study benchmarking fulfilment of established quality indicators.

PURPOSE: Despite the availability of clinical guidelines for hip fracture patients, adherence to these guidelines is challenging, potentially resulting in suboptimal patient care. The goal of this study was (1) to evaluate and benchmark the adherence to recently established quality indicators (QIs), and (2) to study clinical outcomes, in fragile hip fracture patients from different European countries. METHODS: This observational, cross-sectional multicenter study was performed in 10 hospitals from 9 European countries including data of 298 consecutive patients. RESULTS: A large variation both within and between hospitals were seen regarding adherence to the individual QIs. QIs with the lowest overall adherence rates were the administration of systemic steroids (5.4%) and tranexamic acid (20.1%). Indicators with the highest adherence rates (above 95%) were pre-operative (99.3%) and post-operative haemoglobin level assessment (100%). The overall median time to surgery was 22.6 h (range 15.7-42.5 h). The median LOS was 9.0 days (range 5.0-19.0 days). The most common complications were delirium (23.2%) and postsurgical constipation (25.2%). CONCLUSION: The present study shows large variation in the care for fragile patients with hip fractures indicating room for improvement. Therefore, hospitals should invest in benchmarking and knowledge-sharing. Large quality improvement initiatives with longitudinal follow up of both process and outcome indicators should be initiated.

Corrective limb osteotomy using patient specific 3D-printed guides: A technical note.

We describe the step-by-step process of a corrective osteotomy using 3D printed patient specific guides. Before surgery, bilateral computed tomography (CT) scans are made to plan correction in the affected limb. The digital pre-planning defines the location of the K-wires, drill holes, and the osteotomy site(s). Subsequently, a 3D printed patient specific guide is applied, which indicates the exact position of these drill holes and the osteotomies. This increases the accuracy of the surgery by means of patient specific fit of the guide. During surgery an incision is made and the guide is applied on the bone, which allows the surgeon to perform a very precise osteotomy. Next, the bone is reduced either directly using the plate and marked drill holes, or indirectly using a second reduction guide. In the latter case, the previously drilled K-wires are used to adequately position the reduction guide. Fixation of the bone fragments using plating osteosynthesis finalizes the process. Although this technique has its specific limitations, it might serve as a powerful tool in the treatment of malunion of both articular and nonarticular fractures of the limb.

Individual risk factors for deep infection and compromised fracture healing after intramedullary nailing of tibial shaft fractures: a single centre experience of 480 patients.

INTRODUCTION: Despite modern advances in the treatment of tibial shaft fractures, complications including nonunion, malunion, and infection remain relatively frequent. A better understanding of these injuries and its complications could lead to prevention rather than treatment strategies. A retrospective study was performed to identify risk factors for deep infection and compromised fracture healing after intramedullary nailing (IMN) of tibial shaft fractures. MATERIALS AND METHODS: Between January 2000 and January 2012, 480 consecutive patients with 486 tibial shaft fractures were enrolled in the study. Statistical analysis was performed to determine predictors of deep infection and compromised fracture healing. Compromised fracture healing was subdivided in delayed union and nonunion. The following independent variables were selected for analysis: age, sex, smoking, obesity, diabetes, American Society of Anaesthesiologists (ASA) classification, polytrauma, fracture type, open fractures, Gustilo type, primary external fixation (EF), time to nailing (TTN) and reaming. As primary statistical evaluation we performed a univariate analysis, followed by a multiple logistic regression model. RESULTS: Univariate regression analysis revealed similar risk factors for delayed union and nonunion, including fracture type, open fractures and Gustilo type. Factors affecting the occurrence of deep infection in this model were primary EF, a prolonged TTN, open fractures and Gustilo type. Multiple logistic regression analysis revealed polytrauma as the single risk factor for nonunion. With respect to delayed union, no risk factors could be identified. In the same statistical model, deep infection was correlated with primary EF. CONCLUSIONS: The purpose of this study was to evaluate risk factors of poor outcome after IMN of tibial shaft fractures. The univariate regression analysis showed that the nature of complications after tibial shaft nailing could be multifactorial. This was not confirmed in a multiple logistic regression model, which only revealed polytrauma and primary EF as risk factors for nonunion and deep infection, respectively. Future strategies should focus on prevention in high-risk populations such as polytrauma patients treated with EF.

Worry in normal children.

OBJECTIVE: To investigate worry in a nonclinical sample of children aged 8 to 13 years (N = 193). METHOD: Children were interviewed about the content, characteristics, origins, and severity of their main intense worry. Furthermore, children completed questionnaires to study the relationship between worry, trait anxiety, and depression. RESULTS: Almost 70% of the children reported that they worried every now and then. The content of these worries predominantly pertained to school performance, dying and health, and social contacts. An examination of the characteristics of children's main intense worries revealed that these worries occurred on average 2 to 3 days per week, were accompanied by modest levels of interference and anxiety, elicited relatively high levels of resistance, and were rather difficult to control. A minority of the children were found to exhibit symptoms of worry in the pathological range: the percentages of children who met the DSM-III-R criteria of overanxious disorder and generalized anxiety disorder were 4.7% and 6.2%, respectively. Finally, worry, anxiety, and depression seemed to be strongly related. CONCLUSION: Worry seems to be a common phenomenon in normal children aged between 8 and 13 years.

Symptomatic adenomyomatosis of the gallbladder--report of a case.

Adenomyomatosis of the gallbladder is a benign and degenerative condition of the gallbladder, characterized by proliferation of the mucosa of the gallbladder wall, forming invaginations and diverticula, penetrating a thickened muscular layer: the so-called Rokitansky-Aschoff sinuses (RAS). Most of the patients with adenomyomatosis remain asymptomatic. Hence adenomyomatosis is usually an incidental finding, either on ultrasonography performed for the detection of stones or by histologic examination of surgical gallbladder specimens. Only occasionally does adenomyomatosis not associated with cholelithiasis cause right upper quadrant pain. We report a case of symptomatic adenomyomatosis of the gallbladder. Clinical findings, etiology, diagnosis and therapy are discussed.

From unstable internal fixation to biological osteosynthesis. A historical overview of operative fracture treatment.

The first techniques of operative fracture treatment were developed in the 19th century. In fact, these methods only consisted of an open reduction of the fracture followed by a usually very unstable fixation. This method gave rise to the combination of the disadvantages of the conservative and the operative fracture treatment: the fracture had to be opened with a real risk for (sometimes lethal) infection, the bone healing was disturbed, there was muscular atrophy and joint stiffness. The successes were very rare and catastrophes were often seen. Küntscher's endomedullary rods can be considered as the first useful implants in the treatment of diaphyseal fractures. Reaming of the medullary canal and the development of interlocking nails have enlarged the indications for intramedullary nailing. The classic Dynamic Compression Plates from the seventies were the key to a very rigid fixation, leading to primary bone healing. Nevertheless, the use of strong plates and reamed nails disturbed the vascularisation of the bone fragments, leading to a high infection rate (particularly in open fractures) and delayed union (particularly after plate and screw fixation). These insights lead to the development of the "biological osteosynthesis" : a terminology introduced to indicate a new type of osteosynthesis leading to a sufficiently stable fixation of the bone fragments allowing early mobilisation, but without major disturbance of the vascularisation. The unreamed nail can also be considered as a biological osteosynthesis and in a lot of cases it is the implant of choice for tibial and femoral shaft fractures, especially in polytrauma patients. Finally, some new devices contributing to the principles of biological osteosynthesis like locking plates and the LIS-System are gaining popularity.

The importance of magnetic resonance imaging in the diagnosis and treatment of diffuse lymphangioma.

In this study, we will investigate the importance of MRI in the diagnosis and treatment of diffuse lymphangioma. Twenty-nine patients with lymphangiomas were treated at the U.Z. Leuven between March 1988 and September 1997. They all underwent a total surgical excision of the lesion. A global recurrence rate of 34.45% corresponds with a recurrence rate of 30.76% found in literature. In our study, a remarkable difference in recurrence rates is noticed between cystic hygroma (5/19 patients or 26.39%) and the more diffuse types of lymphangioma (5/10 patients or 50%). On three patients, preoperative MRI was performed. All these illustrate the important role of MRI in the diagnosis of lymphangioma, namely the characteristic appearance of the lesions on T1- and T2-weighted images and the better visualization of the lymphangioma extent. In line with the high recurrence rates of diffuse lymphangiomas and the advantages of MRI of these lesions, the role of MRI in the treatment of diffuse lymphangiomas is discussed.

Cement augmentation of hip implants in osteoporotic bone: how much cement is needed and where should it go?

Several studies proved the beneficial effect of cement augmentation of proximal femoral nail antirotation (PFNA) blades on implant purchase in osteoporotic bone. We investigated the effect of different localizations and amounts of bone cement. Polyurethane foam specimens were instrumented with a PFNA blade and subsequently augmented with PMMA bone cement. Eight study groups were formed based on localization and amount of cement volume related to the blade. All specimens underwent cyclic loading with physiological orientation of the force vector until construct failure. Foam groups were compared between each other and to a cadaveric control group. The experiments revealed a significant dependency of implant purchase on localization and amount of cement. Biomechanically favorable cement positions were found at the implant tip and at the cranial side. However, none of the tested augmentation patterns performed significantly inferior to the cadaveric benchmark. These findings will allow surgeons to further reduce the amount of injected PMMA, decreasing the risk of cement leakage or cartilage damage.

Selecting an appropriate and reimbursed anti-osteoporotic treatment option: a practical tool in the Belgian setting.

Osteoporosis is a highly prevalent and often undertreated disease in the elderly. Osteoporosis-related fractures are associated with significant morbidity and mortality. Anti-osteoporotic drugs are only reimbursed by the Belgian government if strict conditions are fulfilled. The aim of this paper was to create a practical tool to guide the physician and other health care professionals to make an appropriate choice. Two flowcharts, based on Belgian reimbursement criteria and literature review were developed. Both tools provide an overview of the reimbursed pharmacological agents in the management of osteoporosis in male and female subjects.

Biomechanical evaluation of bone-cement augmented Proximal Femoral Nail Antirotation blades in a polyurethane foam model with low density.

BACKGROUND: Helically shaped cephalic implants have proven their benefit to provide an improved stabilization of unstable hip fractures. However, cut out ratios up to 3.6% still occur. This in vitro study evaluated the biomechanical performance of a novel cement augmentation technique of the Proximal Femoral Nail Antirotation in surrogate femora. METHODS: Four study groups were formed out of 24 polyurethane foam specimens with low density. Proximal Femoral Nail Antirotation blades were implanted, either non-augmented, or augmented using 3ml of injectable Polymethylmethacrylate bone-cement. The influence of implant mal-positioning was investigated by placing the blade either centered in the femoral head or off-centric in an anteroposterior direction. All specimens underwent cyclic loading under physiological conditions. Starting at 1000 N, the load was monotonically increased by 0.1N/cycle until construct failure. Movement of the head was identified by means of optical motion tracking. Non-parametric test statistics were carried out on the cycles to failure, to compare between study groups. FINDINGS: Compared to control samples; augmented samples showed a significantly increased number of cycles to failure (P=0.012). In the groups with centric position of the Proximal Femoral Nail Antirotation blade, cement augmentation led to an increase in loading cycles of 225%. In the groups with off-centric positioning of the blade, this difference was even more accentuated (933%). INTERPRETATION: Cement augmentation of the Proximal Femoral Nail Antirotation blade with small amounts of bone-cement for treatment of osteoporotic hip fractures clearly enhances fixation stability and carries high potential for clinical application.

Endoscopic thoracic sympathectomy for posttraumatic complex regional pain syndrome.

INTRODUCTION: Posttraumatic complex regional pain syndrome (CRPS) has a strongly negative impact on rehabilitation and activities of daily living. Treatment is most often unrewarding. AIM: To analyze the efficacy of endoscopic thoracic sympathectomy (ETS) in reducing pain and disability associated with CRPS prospectively. PATIENT AND METHODS: Over a 5-year period, 12 patients (7 females and 5 males; median age 46.5 [range 34-60 years]) with posttraumatic CRPS underwent unilateral ETS. The median duration of CRPS symptoms before ETS was 3.8 months (range 1.2-19.9). The sympathetic chain was resected from the 2nd to the 5th rib, and the nerve of Kuntz was severed. Median postoperative 16 months (range 12-40). Pain was assessed, at rest (passive) and during movement (active), using a visual analogue scale (VAS) from 0 to 10. RESULTS: One patient (8%) suffered a hydrothorax and 3 patients (25%) complained of contralateral compensatory hyperhydrosis. At 1 month (n = 12), 2 months (n = 7), 6 months (n = 12), and 1 year (n = 12) after ETS, there was a significant decrease in passive and active VAS (P < 0.05). Ten out of the 12 patients (83%) needed fewer analgesics after surgery, and eight (67%) did not need analgesics at all. The median sleep duration improved significantly from a preoperative value of 2 h (range 1-7) to a postoperative value of 6.25 h (range 3.5-8) (P < 0.001). Overall, patient satisfaction was 83%. CONCLUSION: ETS is effective at decreasing pain and improving quality of life, and should therefore be considered in the treatment of CRPS.

Trans-iliac-sacral-iliac-bar procedure to treat insufficiency fractures of the sacrum.

BACKGROUND: Osteoporosis is an increasing problem attributed to the greater longevity of the population and the incidence of fractures related to osteoporosis. The presence of osteoporotic bone, comorbidities, and functional status of the patient require adequate solutions to improve the clinical outcome of sacral insufficiency fractures. Conservative treatment by means of prolonged bed rest and analgesics are associated with increased risks and complications. A sacroplasty significantly improves the functional outcome. We describe the trans-iliac-sacral-iliac-bar (TISIB) procedure and our clinical experience to treat insufficiency fractures of the sacrum. MATERIALS AND METHODS: The records of 19 consecutive patients with a mean age of 71.7 years (range: 57-82 years) who had been managed with a TISIB procedure from 2005 till 2007 were reviewed retrospectively. There were 15 females and 4 males. Predisposing factors for sacral insufficiency fractures were osteoporosis (n = 12, 63%), radiotherapy (n = 6, 32%), and rheumatoid arthritis (n =1). Diagnosis with a mean delay of 3.7 months was mainly made by CT. All patients were preoperatively and at follow-up assessed by means of the visual analogue score (VAS), analgesic consumption, and the ability to perform activities of daily living (ADLs) using a 5-point pain scale: 1, without pain; 2, mild pain; 3, moderate pain; 4, severe pain and, 5 unable to perform ADLs because of pain. RESULTS: The average duration of postoperative follow-up was 9 months (range: 3-24.5 months). No neurological complications occurred during the surgery. A postoperative radiographic study showed a well-positioned bar in every case. The mean VAS improved 44.7 mm (preoperative: 67.8; at follow-up: 23.2). Fifteen patients (79%) consumed narcotic analgesics before surgery, and only one (5%) at follow-up; two patients (10%) consumed NSAIDS before surgery and three (15%) after. Two patients (10%) consumed minor analgesics before, and 11 (58%) after the procedure. Finally, four patients (21%) were not taking any analgesics at follow-up. Before surgery, 9 patients (47%) were able to perform ADLs with a pain score of 4; 6 (32%) with a score of 3, and 4 (21%) a score of 2. At follow-up 1 (5%) did have a score of 4; 1 (5%) a score of 3, 8 (42%) a score of 2 and 9 (47%) a pain score of 1. CONCLUSION: A TISIB PROCEDURE RELIES ON THE PRINCIPLES OF FRACTURE TREATMENT: fracture stabilisation and compression. The incapacitating problem of an insufficiency fracture of the sacrum can be elegantly solved by means of this minimally invasive procedure. A near-immediate improvement is noticed when looking at the VAS score, analgesics consumption, and the ability to perform ADLs.

Total hip replacement for acetabular fractures. Results in 121 patients operated between 1983 and 2003.

UNLABELLED: Total hip replacement has an important role in the treatment of acetabular fractures. Immediate total hip arthroplasty is only indicated for some rare cases but late reconstruction is performed more frequently and may follow failed non-operative or operative treatment of the original acetabular fracture. INTRODUCTION: The purpose of this study is to determine the results of the use of total hip replacement for the treatment of acetabular fractures and to compare the results of the early and late reconstruction group. MATERIALS AND METHODS: 121 acetabular fractures treated with total hip arthroplasty between 1983 and 2003 at the University Hospitals Gasthuisberg in Leuven, Belgium were retrospectively studied. The patients were divided into two groups. In the "early reconstruction group" total hip arthroplasty was performed as primary treatment of the acetabular fracture. In the "late reconstruction group": total hip arthroplasty was performed following failed operative or non-operative treatment of the acetabular fracture. The indications for total hip arthroplasty and the surgical technique in both the early and late reconstruction group were compared. Secondly, complications were reviewed in both groups and a functional scoring system was applied for each patient. RESULTS: Primarily there was a significant difference in the age of the patient population of each group with a predominance for older patients in the early reconstruction group. Secondly, less revisions were performed in the early reconstruction group: 8% compared to 22% in the late reconstruction group. DISCUSSION: The results obtained in our patient groups were compared to the results found in literature by a Medline search. In general, our results were comparable to the results found in literature but a remarkable difference was found between different authors. CONCLUSION: Total hip replacement for acetabular fractures is rarely indicated in the acute phase. After failed treatment of an acetabular fracture, total hip replacement has to be considered as a salvage procedure. In both cases, one may not forget total hip arthroplasty is a severe intervention associated with a high number of complications.