Assessing the causal relationship of birth weight and childhood obesity on osteoarthritis: a Mendelian randomization study.

Obesity is associated with osteoarthritis (OA), but few studies have used fetal origin to explore the association. Our study aims to disentangle the causality between birth weight, childhood obesity, and adult OA using Mendelian randomization (MR). We identified single nucleotide polymorphisms (SNPs) related to birth weight (n = 298,142) and childhood obesity (n = 24,160) from two genome-wide association studies contributed by the Early Growth Genetics Consortium. Summary statistics of OA and its phenotypes (knee, hip, spine, hand, thumb, and finger OA) from the Genetics of Osteoarthritis Consortium (n = 826,690) were used to estimate the effects of SNPs on OA. Multivariable MR (MVMR) was conducted to investigate the independent effects of exposures. It turned out that genetically predicted standard deviation increase in birth weight was not associated with OA. In contrast, there was a marginally positive effect of childhood obesity on total [odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.00, 1.15 using IVW], knee (OR = 1.13, 95% CI = 1.05, 1.22 using weighted median), hip (OR = 1.13, 95% CI = 1.04, 1.24 using IVW), and spine OA (OR = 1.12, 95% CI = 1.03, 1.22 using IVW), but not hand, thumb, or finger OA. MVMR indicated a potential adulthood body mass index-dependent causal pathway between childhood obesity and OA. In conclusion, no association of birth weight with OA was suggested. Childhood obesity, however, showed a causality with OA in weight-bearing joints, which seems to be a general association of obesity with OA.

Radiation-induced tumor immune microenvironments and potential targets for combination therapy.

As one of the four major means of cancer treatment including surgery, radiotherapy (RT), chemotherapy, immunotherapy, RT can be applied to various cancers as both a radical cancer treatment and an adjuvant treatment before or after surgery. Although RT is an important modality for cancer treatment, the consequential changes caused by RT in the tumor microenvironment (TME) have not yet been fully elucidated. RT-induced damage to cancer cells leads to different outcomes, such as survival, senescence, or death. During RT, alterations in signaling pathways result in changes in the local immune microenvironment. However, some immune cells are immunosuppressive or transform into immunosuppressive phenotypes under specific conditions, leading to the development of radioresistance. Patients who are radioresistant respond poorly to RT and may experience cancer progression. Given that the emergence of radioresistance is inevitable, new radiosensitization treatments are urgently needed. In this review, we discuss the changes in irradiated cancer cells and immune cells in the TME under different RT regimens and describe existing and potential molecules that could be targeted to improve the therapeutic effects of RT. Overall, this review highlights the possibilities of synergistic therapy by building on existing research.

Finite element analysis of sacral-alar-iliac screw fixation for sacroiliac joint dislocation.

The percutaneous sacroiliac (SI) screw is a common fixation option for posterior ring disruption in pelvic fractures. However, SI screw placement is difficult and can injure adjacent neurovascular structures. The sacral-alar-iliac screw (SAI) is a safe, reliable free-hand sacral pelvic fixation technique. To investigate the biomechanical stability of SAI for SI joint dislocation, finite element analysis was performed in unstable Tile-Type B and C pelvic ring injuries. The displacement in S1 (fixation of a unilateral S1 segment with one SI screw), TS1 (fixation of the S1 segment with a transsacra 1 screw), TS2 (fixation of the S2 segment with a transsacra 2 screw), S1AI, and S2AI exceeded the normal SI joint mobility. Sufficient stability after SI joint dislocation was obtained with (TS1 + TS2), (TS2 + S1), (S1AI + S2AI + rod), (S1AI + S2AI), and (S1 + S2AI + S1 pedicle) fixation. The TS1 + TS2 group had the smallest displacement and lowest peak screw stress, followed by (S1 + S2AI + S1 pedicle) placement. Our findings suggest that SAI screws are a valuable option for SI joint dislocation.

Preoperative excessive lateral anterior tibial subluxation is related to posterior tibial tunnel insertion with worse sagittal alignment after anterior cruciate ligament reconstructions.

Objective: To investigate whether preoperative lateral anterior tibial subluxation (LATS) measured from magnetic resonance imaging (MRI) can influence tibial insertion and postoperative sagittal alignment after anterior cruciate ligament reconstructions (ACLRs). Methods: 84 patients who underwent single-bundle ACLRs were retrospectively investigated. Among them, 39 patients (LATS of <6 mm) 23 patients (LATS of ≥6 mm and <10 mm) and 22 patients (excessive LATS of ≥10 mm) were defined as group 1, 2 and 3, respectively. LATS, the position of graft insertion into tibia as ratio of anterior-posterior width (AP ratio) and the sagittal graft angle (SGA) were postoperatively assessed from MRI at 2-year follow-up. Following linear regression analyses were employed. Results: The group 3 exhibited the largest preoperative LATS and remained the most postoperative LATS. Moreover, the group 3 possessed the most posteriorly located tunnel insertion with the largest AP ratio and the most vertical graft orientation. Of all included patients, a moderate correlation was demonstrated between pre- and postoperative LATS (r = 0.635). A low correlation was observed between preoperative LATS and AP ratio (r = 0.300) and a moderate correlation was displayed between AP ratio and SGA (r = 0.656). Conclusion: For ACL injuries with excessive LATS (≥10 mm), most posteriorly located tibial insertion was found out, and worse sagittal alignment containing high residual LATS was associated with more vertical graft orientation following ACLRs.

E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2.

Aberrant activation of inflammation signaling triggered by tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and interleukin-17 (IL-17) is associated with immunopathology. Here, we identify neural precursor cells expressed developmentally down-regulated gene 4-like (NEDD4L), a HECT type E3 ligase, as a common negative regulator of signaling induced by TNF-α, IL-1, and IL-17. NEDD4L modulates the degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) via constitutively and directly binding to MEKK2 and promotes its poly-ubiquitination. In interleukin-17 receptor (IL-17R) signaling, Nedd4l knockdown or deficiency enhances IL-17-induced p38 and NF-κB activation and the production of proinflammatory cytokines and chemokines in a MEKK2-dependent manner. We further show that IL-17-induced MEKK2 Ser520 phosphorylation is required not only for downstream p38 and NF-κB activation but also for NEDD4L-mediated MEKK2 degradation and the subsequent shutdown of IL-17R signaling. Importantly, Nedd4l-deficient mice show increased susceptibility to IL-17-induced inflammation and aggravated symptoms of experimental autoimmune encephalomyelitis (EAE) in IL-17R signaling-dependent manner. These data suggest that NEDD4L acts as an inhibitor of IL-17R signaling, which ameliorates the pathogenesis of IL-17-mediated autoimmune diseases.

Treatment of Fracture of the Calcaneus via Bone Axial X-Ray Image-Based Minimally Invasive Approach.

To discuss the values of two bone axial X-ray image-based minimally invasive approach surgeries in the diagnosis and treatment of fracture of the calcaneus, 80 patients diagnosed with fracture of the calcaneus by bone axial X-ray examination were selected and divided equally into the minimally invasive longitudinal approach (MILA) group (40 cases) and the sinus tarsal approach (STA) group (40 cases). Besides, the duration of operation, the incidence of complications, the time-to-start weight training, and the American Orthopaedic Foot and Ankle Society (AOFAS) foot function scoring system between the patients in the two groups were compared. The results showed that the duration of operation and incidence of complications among the patients in the MILA group (42.87 ± 5.12 minutes, 20%) were both superior to those among the patients in the STA group (60.43 ± 7.31 minutes, 32.5%). The time-to-start weight training in the MILA group was 5.2 weeks, which was obviously shorter than that in the STA group (5.7 weeks). The difference in AOFAS scores between the two groups was not significant. The walking pavement score in the MILA group (4.2 ± 0.37 points) was slightly higher than that in the STA group (3.3 ± 0.45 points), and the differences demonstrated statistical meaning (P < 0.05). To sum up, the bone axial X-ray image is an essential examination method of diagnosing fracture of the calcaneus. The two minimally invasive methods both showed good clinical therapeutic effects. The operation of MILA was relatively shorter with fewer complications and is worthy of being promoted as an effective treatment method of fracture of the calcaneus.

Anterior Tibial Subluxation of Lateral Compartment Is Associated With High-Grade Rotatory Instability for Acute But Not Chronic Anterior Cruciate Ligament Injuries: An Magnetic Resonance Imaging Case-Control Study.

PURPOSE: To investigate whether anterior tibial subluxation obtained from magnetic resonance imaging (MRI) could be a predictor of high-grade rotatory instability for anterior cruciate ligament (ACL) injuries, including acute and chronic cases. METHODS: From September 2016 to August 2018, we retrospectively investigated 163 patients with ACL injuries who subsequently underwent primary ACL reconstruction. Among them, 30 patients with high-grade rotatory instability (grade II/III pivot shift) were included in the high-grade group, and their age and sex were matched 1:2 to low-grade cases (3 months) phases. RESULTS: The high-grade group had a larger anterior tibial subluxation of lateral compartment (8.1 mm vs 5.9 mm; P =.004) than the low-grade group, whereas no significant difference was found in anterior tibial subluxation of medial compartment (P > .05). Moreover, high-grade anterior tibial subluxation of lateral compartment (≥6 mm) was found to be an independent predictor (odds ratio, 12.992; P = .011) associated with concomitant meniscal tears after ACL injuries. Anterior tibial subluxation of lateral compartment demonstrated statistical significance between the two groups when comparing subgroups within 3 months but not beyond 3 months. CONCLUSION: In ACL-injured patients, high-grade anterior tibial subluxation of lateral compartment (≥6 mm) could be a unique predictor of high-grade knee rotatory instability for acute but not chronic injuries. Prolonged time from injury to surgery and lateral meniscus tears were risk factors for high-grade rotatory laxity in chronic patients. LEVEL OF EVIDENCE: Level III, retrospective prognostic trial.

2-methylbenzoyl berbamine, a multi-targeted inhibitor, suppresses the growth of human osteosarcoma through disabling NF-κB, ERK and AKT signaling networks.

Osteosarcoma is the most common malignant bone tumor in children and young adults, and it has a survival rate of only 60% with current cytotoxic chemotherapy combined with aggressive surgery. The aim of this study was to evaluate the therapeutic efficacy of the berbamine derivative 2-methylbenzoyl berbamine (BBD24) for osteosarcoma in vitro and in vivo. We used human osteosarcoma cell lines, primary osteosarcoma cells and mouse models to evaluate the inhibitory effects of BBD24 on osteosarcoma and to determine the molecular mechanism. Our results showed that BBD24 inhibited the growth of the human osteosarcoma cell lines HOS and MG63 in a time- and dose-dependent manner. BBD24 also exhibited significant inhibitory effects on primary osteosarcoma cells. In contrast, BBD24 did not affect normal blood cells under the same conditions. Treatment with BBD24 induced apoptosis, necrosis and autophagy in osteosarcoma cells. Western blot analysis revealed that BBD24 activated the caspase-dependent pathway and downregulated the NF-kB, AKT, and ERK pathways. Finally, BBD24 treatment induced a significant inhibitory effect on the growth of osteosarcoma in nude mice. Our findings indicate that BBD24 is a multitarget inhibitor and may represent a new type of anticancer agent for osteosarcoma treatment.

Fractionated Radiation Therapy for Large and Giant Cavernous Sinus Hemangioma: A Retrospective Study.

Purpose: Surgical resection has been traditionally used as a treatment for cavernous sinus hemangioma (CSH). However, this is usually difficult due to tumor vascularity and results in complications especially in large and giant CSH (volume >20 cm3). Previous studies have reported that radiotherapy (RT) provides an alternative treatment modality for hemangiomas. However, the optimized dose and fractions which control CSH and also protect the cognitive function remain unclear. This study reports our experience in the management of symptomatic large and giant CSH. Methods: Fifty-four patients with symptomatic large (20 cm3 40 cm3, >4 cm in diameter) CSH were enrolled in a retrospective study between January 2007 and December 2018. The prescription dose to the target margin was 50 Gy in 25 fractions. Results: The mean pre-RT tumor volume was 60.9 cm3 which ranged from 20.2 to 230.5 cm3. The clinical data obtained was analyzed retrospectively following a mean follow-up period of 35.0 months which ranged from 1 to 140 months. All patients experienced tumor shrinkage within 3 months after radiotherapy. There was an average mean tumor reduction of 79.7% (range, 48.4-98.5%) with no patients experiencing tumor progression and recurrence. All the 54 patients experienced symptomatic improvement within 1 month to 12 months after radiotherapy. Within the entire follow up period, no patients experienced any form of permanent complications or symptomatic radiation toxicity. Neurocognitive impairment studies were conducted before and after radiotherapy on 28 patients while the studies were conducted after the last follow up in 40 patients. The cognitive function of all the participants had normal MoCA-scores of 28.25 pre-radiotherapy. The post-treatment MoCA-scores were also clinically stable (28.04, p = 0.78), and the average MoCA-score did not show any decline until the last follow-up (27.61, p = 0.13). Conclusion: The optimal dose and fractions of radiotherapy treatment for symptomatic large and giant cavernous sinus hemangioma remain unclear. This study, therefore, used a marginal dose of 50 Gy in 25 fractions in radiotherapy and this was proven to be effective and relatively safe in the treatment of symptomatic large and giant CSHs.

Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: A new mechanism of intervertebral disc degeneration.

Low back pain (LBP) is one of the most common complains in orthopedic outpatient department and intervertebral disc degeneration (IDD) is one of the most important reasons of LBP. The mechanisms of IDD contain a complex biochemical cascade which includes inflammation, vascular ingrowth, and results in degradation of matrix. In our study, we used both in vitro and in vivo models to investigate the relation between tissue inhibitor of metalloproteinase-3 (TIMP3) expression and IDD. Loss of TIMP3 expression was found in degenerative intervertebral disc (IVD), this change of expression was closely related with the dephosphorylation of smad2/3. Overexpression of TIMP3 significantly inhibited the release of TNF-α and matrix degradation induced by Lipopolysaccharide. Vascular ingrowth was also suppressed by TIMP3 in the in vitro and in vivo models. Further, animal experiments confirmed that the degeneration of IVD was reduced after overexpression of TIMP3 in nucleus pulposus. Taken together, our results indicated TIMP-3 might play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target in the future.

Ginkgolide B exerts anti-inflammatory and chondroprotective activity in LPS-induced chondrocytes.

BACKGROUND: Osteoarthritis (OA) is one of degenerative and chronic diseases of articular joints. Articular cartilage is an avascular tissue, and its primary cellular component is chondrocytes. The main characteristic of OA is non-classic inflammation and cartilage degeneration. Ginkgolide B (GB) is a component of Ginkgo biloba which has diverse bioactivities. OBJECTIVES: The present study uses an in vitro experimental model to detect the underlying anti-inflammatory and chondroprotective effects of GB and provides a new way for future clinical therapy of OA. MATERIAL AND METHODS: Rat chondrocytes were isolated, cultured and treated with 1 µg/mL lipopolysaccharide (LPS) and/or different concentrations of GB. Cell Counting Kit-8 (CCK-8) was used to test the cell viability of chondrocytes, and chondrocytes apoptosis was detected using a cell apoptosis kit. Collagen-II and aggrecan expression were detected by immunohistochemistry. Relative expression of genes was detected by real-time PCR and western blot. RESULTS: Ginkolide B did not inhibit chondrocyte proliferation, and ginkgolide B inhibited LPS induced matrixdegradation in chondrocytes. Ginkgolide B also reversed LPS-induced collagen-II and aggrecan decreased in chondrocytes via upregulated synthesis-related gene expression and downregulated matrix-degrading enzyme gene expression. Furthermore, we found that ginkgolide B significantly inhibited LPS-induced MAPK pathway activation. CONCLUSIONS: The results of our study suggest that ginkgolide B exerted anti-inflammatory and chondroprotective effects in LPS-induced chondrocytes, and might be an underlying therapy for OA afterwards.

Enhanced regeneration of large cortical bone defects with electrospun nanofibrous membranes and low-intensity pulsed ultrasound.

Poly-L-lactic acid (PLLA) nanofibrous membranes are widely utilized for tissue regeneration. Low intensity pulsed ultrasound (LIPUS) has been considered as a feasible modality for bone union. The aim of the present study was to investigate the potential synergistic effect of LIPUS and PLLA electrospun nanofibrous membranes on large cortical bone defects in rabbits in vivo. The bilateral rabbit tibia defect model was constructed using 18 adult NZ rabbits and the defect sites were treated with the nanofibrous membranes combined with LIPUS or nanofibrous membranes alone. A total of 3 to 6 weeks after surgery, bone defect healing was evaluated radiologically and histologically. Radiographs demonstrated that nascent bone formation in the central part of the defect regions was only observed in the nanofibrous membrane plus LIPUS group, whereas the bone defects were not fully healed in the group treated with nanofibrous membrane alone. Histology analysis of the LIPUS-treated group indicated that bone formation was thicker and more mature in the center of the defect site of the nanofibrous membrane plus LIPUS group. However, no differences were detected in the spatial and temporal pattern of the newly formed bone. Furthermore, the bone scores in the nanofibrous membrane plus LIPUS group were significantly greater than the scores exhibited in the nanofibrous membrane group at 3 and 6 weeks after surgery, respectively (P<0.01). In conclusion, the PLLA electrospun nanofibrous membrane combined with LIPUS indicated the capacity to improve the formation of nascent bone in rabbits with tibia defects. Further studies are required to fully elucidate the cell ingrowth depths inside nanofibrous membranes with scanning electron microscopy and the molecular effects of LIPUS on integrin and fibronectin.

Computed tomography angiography and magnetic resonance imaging performance of acute segmental single compartment syndrome following an Achilles tendon repair: A case report and literature review.

Acute compartment syndrome of the lower extremity is a serious postinjury complication that requires emergency treatment. Early diagnosis is of paramount importance for a good outcome. Four muscle compartments in the calf (anterior, lateral, deep posterior, and superficial posterior) may be individually or collectively affected. Acute segmental single-compartment syndrome is an extremely rare condition characterized by high pressure in a single compartment space with threatening of the segmental tissue viability. In this case report, we describe a young man with Achilles tendon rupture who complained of postoperative pain in the anterior tibial region. Emergent computed tomography angiography and magnetic resonance imaging revealed local muscle edema. Segmental anterior compartment syndrome was diagnosed and fasciotomy was performed.

Unilateral versus bilateral pedicle screw fixation in short-segment lumbar spinal fusion: a meta-analysis of randomised controlled trials.

OBJECTIVE: We performed this meta-analysis of randomised controlled trials to compare the efficacy and safety of unilateral with bilateral fixation in short-segment lumbar spinal fusion. METHODS: Predefined terms were used to search electronic databases to identify relevant research. Randomised controlled trials (RCTs) published in English and Chinese during 1990-2015 investigating efficacy and safety of unilateral and bilateral fixation in short-segment lumbar spinal fusion were included. Data of fusion rate, complications, visual analogue scale (VAS), Oswestry Disability Index (ODI), estimated blood loss (EBL) and length of hospital stay were extracted and analysed. Two reviewers independently searched information sources, selected eligible research, analysed data and evaluated risk of bias. RESULTS: Eleven RCTs comprising 756 participants were analysed. There was no significant difference in fusion rate, device-related complication, ODI, VAS and length of hospital stay between bilateral and unilateral groups. The unilateral group had the obvious advantage of reduced blood loss [mean difference (MD) -143.57, 95 % confidence interval (Cl) -206.61 to -80.54, P < 0.0001) and operation time (MD -52.72, 95 % Cl -73.58 to -31.87, P < 0.00001). CONCLUSION: Unilateral pedicle screw fixation is equally as effective as bilateral pedicle screw fixation in short-segment lumbar spinal fusion and may reduce operation time and blood loss.

Gambogic acid inhibits invasion of osteosarcoma via upregulation of TIMP-1.

Gambogic acid (GA), the natural product, has been demonstrated to be a promising chemotherapeutic drug for osteosarcoma (OS) due to its ability to induce apoptosis and cell cycle arrest. To date, no studies have examined the role of GA in metastatic bone disease. Matrix metalloproteinases (MMPs) play critical roles in invasion and metastasis, and the tissue inhibitors of metalloproteinase (TIMP) family regulates the activity of multifunctional metalloproteinases. In this study, we investigated the gene expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in OS cell lines treated by the GA. The expression of MMP-9 and TIMP-1 were studied by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. In vitro invasion of OS cell lines (Saos-2, MG-63) were investigated by the Matrigel invasion assay. Mean MMP-9 protein and mRNA expression was significantly suppressed; in addition, mean TIMP-1 protein mRNA expression were upregulated by increasing GA concentrations. GA reduced the invasiveness of OS cell lines dose-dependently. Furthermore, specific inhibition of TIMP-1 secretion with siRNA against TIMP-1 significantly reduced the effect of GA on OS cell lines. Overall, our findings suggest that GA reduces the invasive potential of OS cells via attenuation of MMP-9 and upregulation of TIMP-1. Moreover, TIMP-1 played an important role in the reduction of invasive potential of the OS cells which were treated by GA.

Pure alumina bearings with cementless stems versus sandwich bearings with cemented stems in total hip arthroplasty.

BACKGROUND: Ceramic bearing surfaces have been introduced to prevent osteolysis after total hip arthroplasty (THA), but little is known about the difference in clinical and radiological results between pure alumina and sandwich alumina bearings. The purpose of this study was to analyze the results obtained with third-generation alumina-on-alumina THA with two different designs both in liner and femoral stem fixation after a minimum follow-up of 4.2 years. METHODS: The results of 195 primary alumina-on-alumina THAs in 167 patients were evaluated. The procedures were performed between January 1998 and October 2006. Three patients died and 11 patients were lost to follow-up, leaving a total of 153 patients (181 hips) available for study. In the 88 group A patients, 107 hips were implanted using pure alumina bearings with cementless femoral stems. These patients were followed for (6.84 ± 1.49) years. In the 65 group B patients, 74 hips were implanted using sandwich alumina ceramic bearings with cemented femoral stems. These patients had a follow-up period of (7.73 ± 1.60) years. Patients in both groups were evaluated clinically and radiographically. RESULTS: One ceramic liner fracture occurred in group A and five took place in group B (P < 0.05), four of them revised for liner fracture. In each group, one acetabular shell migration happened without liner breakage and two hips developed deep infections, and all these six hips received revisions. Nine femoral components loosened in group B, with seven undergoing revisions. Kaplan-Meier survivorship at 5 years for revision of any component for any reason in group A was 96.26% compared to 90.54% in group B (P < 0.05). Better function was determined in group A (average Harris hip scores: 92.13 ± 2.85) than in group B (average Harris hip scores: 86.03 ± 4.21) and the difference was significant (P < 0.05). Squeaking was not recorded in either group. CONCLUSIONS: The sandwich design of the acetabular bearings can not reduce the migration rate in ceramic bearings but increase the liner fracture rate compared to pure ceramic liners. The high loosening rate in fluted and taped designed cemented stems with sandwich liners warrant caution to their use.