Clinical Efficacy of Intra-articular Tranexamic Acid Injection in the Management of Hemophilia with Total Hip Arthroplasty: A 24-month Retrospective Cohort Study.

OBJECTIVE: Total hip arthroplasty (THA) effectively treats end-stage hemophilic hip arthropathy. Given hemophilia's unique characteristics, perioperative bleeding remains a significant risk for patients undergoing THA. Tranexamic acid (TXA), an efficient antifibrinolytic agent, may benefit the outcomes of THA for patients with hemophilia (PWH). This study aims to explore the clinical efficacy of intra-articular injection of TXA in treating perioperative bleeding in PWH and assess its additional clinical benefits. METHODS: The retrospective study comprised data of PWH who received THA from January 2015 to December 2021 in the research center. A total of 59 individuals were included in the study, divided into a TXA group (n = 31) and a non-TXA group (n = 28). We compared various parameters, including total blood loss (TBL), visible blood loss (VBL), occult blood loss (OBL), intraoperative coagulation factor VIII (FVIII) consumption, perioperative total FVIII consumption, hemoglobin (HB), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), length of hospital stay, hospitalization costs, length of surgery, total protein, activated partial thromboplastin time (APTT), D-dimer, rate of joint swelling, hip joint range of motion (ROM), visual analogue scale (VAS), and Harris hip joint function scale (HHS) between the two groups. Follow-up assessments were conducted for up to 24 months. A Student's t test was utilized for the statistical analysis. RESULTS: This study demonstrated that intra-articular TXA effectively reduced TBL (1248.19 ± 439.88 mL, p < 0.001), VBL (490.32 ± 344.34 mL, p = 0.003), and OBL (757.87 ± 381.48 mL, p = 0.004) in PWH who underwent THA. TXA demonstrated effectiveness in reducing VAS scores on POD1, POD7, and POD14 and joint swelling rates on POD1, POD7, POD14, and at discharge (p < 0.05). Additionally, the TXA group achieved higher HHS ratings at all follow-up time points (p < 0.05), showing superior hip joint mobility, lower postoperative inflammation levels, reduced factor VIII consumption during surgery, and less postoperative nutritional loss. No statistically significant differences were observed between the two groups in terms of hospital stay, hospitalization costs, surgery duration, and coagulation indicators. CONCLUSION: Intra-articular injection of TXA reduces perioperative bleeding in PWH undergoing THA while also improving joint mobility, post-operative rehabilitation, and quality of life. This may provide value for the future application of TXA in PWH.

Dnmt3b ablation affects fracture repair process by regulating apoptosis.

PURPOSE: Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism. METHODS: We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3bGli1ER) mice to operated tibia fracture. Fracture callus tissues of Dnmt3bGli1ER mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay. RESULTS: The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3bGli1ER mice much less than control mice. Dnmt3bGli1ER mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3bGli1ER mice as well as the expressions of BCL-2. CONCLUSIONS: Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.

[Advances on pentraxin 3 in osteoporosis and fracture healing].

Pentaxin 3 (PTX3), as a multifunctional glycoprotein, plays an important role in regulating inflammatory response, promoting tissue repair, inducing ectopic calcification and maintaining bone homeostasis. The effect of PTX3 on bone mineral density (BMD) may be affected by many factors. In PTX3 knockout mice and osteoporosis (OP) patients, the deletion of PTX3 will lead to decrease of BMD. In Korean community "Dong-gu study", it was found that plasma PTX3 was negatively correlated with BMD of femoral neck in male elderly patients. In terms of bone related cells, PTX3 plays an important role in maintaining the phenotype and function of osteoblasts (OB) in OP state;for osteoclast (OC), PTX3 in inflammatory state could stimulate nuclear factor κ receptor activator of nuclear factor-κB ligand (RANKL) production and its combination with TNF-stimulated gene 6(TSG-6) could improve activity of osteoclasts and promote bone resorption;for mesenchymal stem cells (MSCs), PTX3 could promote osteogenic differentiation of MSCs through PI3K/Akt signaling pathway. In recent years, the role of PTX3 as a new bone metabolism regulator in OP and fracture healing has been gradually concerned by scholars. In OP patients, PTX3 regulates bone mass mainly by promoting bone regeneration. In the process of fracture healing, PTX3 promotes fracture healing by coordinating bone regeneration and bone resorption to maintain bone homeostasis. In view of the above biological characteristics, PTX3 is expected to become a new target for the diagnosis and treatment of OP and other age-related bone diseases and fracture healing.

Closed reduction and plaster immobilization: an alternative solution for patients with developmental dysplasia of the hip who failed Pavlik harness treatment.

BACKGROUND: The current study aims to investigate the clinical efficacy of closed reduction and cast immobilization for patients with developmental dysplasia of the hip (DDH) who failed Pavlik harness treatment. METHODS: Patients with DDH who underwent cast immobilization under general anaesthesia after the failure of the Pavlik harness or Tübingen brace treatment between January 2015 and December 2020 were retrospectively recruited. General information, including Graf classification of initial diagnosis, initial treatment, age of cast immobilization, IHDI classification, AI index, avascular necrosis (AVN), and residual dysplasia, was collected. The incidence of AVN and late acetabular dysplasia (LACD) was also estimated. Moreover, factors related to AVN and LACD were investigated by multiple logistic regression analysis. RESULTS: Thirty-four patients (47 hips) were finally included in the current study. Of these patients, 31 hips (66.0%) were successfully treated with closed reduction and cast immobilization. Open reduction was successfully performed in 16 hips (34.0%). Till the latest follow-up, LACD and AVN were found in 13 (27.7%) and 10 (21.3%) hips, respectively. In the open reduction group, type III and IV of the IHDI classification and type IV of the Ultrasound Graf classification were significantly higher when compared with the closed reduction group. Multiple logistic regression showed that failure of closed reduction was related to the initial types of the Ultrasound Graf and IHDI classifications. CONCLUSIONS: Although the success rate of closed reduction after early harness failure in DDH is only 66%, we still advocate closed reduction as a first-line treatment for children who have failed sling treatment. Even if closed reduction fails, open reduction can still achieve acceptable results.

LIMS2 is Downregulated in Osteosarcoma and Inhibits Cell Growth and Migration.

Methods: GEO, GEPIA, and UALCAN databases were used to assess LIMS2 expression in OS. UALCAN and CCLE databases were applied to assess the methylation levels of LIMS2 in OS tissues and cells, which was verified in OS cells using the methylation specific PCR. The effects of LIMS2 on regulating OS cell growth, migration and invasion were determined by CCK-8, Edu staining, and transwell chambers, respectively. The role of LIMS2 in the activation of MAPK signaling was assessed using western blotting assay in OS cells. Results: LIMS2 expression was declined in OS tissues and cells, while its methylation level was increased. The low expression of LIMS2 was associated with shorter overall survival and disease-free survival. Overexpression of LIMS2 inhibited cell growth, migration, and invasion and decreased the levels of p-ERK/ERK, p-P38/P38, and p-JNK/JNK. Conclusion: LIMS2 expression was decreased in OS, which was associated with hypermethylation level and poor prognosis. LIMS2 overexpression inhibited OS cell growth and migration, which may be caused by the suppression of MAPK signaling.

Hemophilia A developing cerebral infarction after surgical treatment of giant hemophilic pseudotumor: a case report.

BACKGROUND: Cerebral infarction (CI) is an unusual complication in patients with bleeding disorders. To our knowledge, this is the first case of postoperative internal border-zone infarction (I-BZI) from Hemophilia A. CASE PRESENTATION: We present a case of Hemophilia A developing I-BZI, after surgical treatment of giant hemophilic pseudotumor. A 36-year-old man was introduced from other hospital by Hemophilia with giant hemophilic pseudotumor in his left thigh. Patient and his relatives did not have a history of thrombophilia. After excluding the relevant surgical contraindications, we performed the operation of pseudotumor resection. Prior to surgery, blood tests revealed hemoglobin of 137 g/L. FVIII activity was 1.5%. Activated partial thromboplastin time (APTT) was 71.50 s and D-dimer was 3.33 mg/L FEU. Immediately before surgery, the patient received an intravenous infusion of FVIII products (Xyntha®) at a dose of 3500 IU for his body weight of 80 kg. Post-operative day two (POD2), patient developed vomiting, decreased response, and dysarthria. Hemoglobin was 54 g/L with blood pressure of 110/70 mmHg. Magnetic resonance imaging of the brain showed there were multiple acute cerebral infarctions in bilateral lateral ventricles (internal border zone) and multiple ischemic foci in the white matter areas and basal ganglia of the bilateral cerebral hemispheres. This case suggested that acute severe anemia can be one of the causes of I-BZI. CONCLUSIONS: For the treatment of I-BZI caused by acute anemia from Hemophilia A, volume expansion, red blood cell supplement and continuous improvement of coagulation with suitable dose of factor VIII (FVIII) should be considered to improve prognosis.

N-Butanol Extract of Modified You-Gui-Yin Attenuates Osteoclastogenesis and Ameliorates Osteoporosis by Inhibiting RANKL-Mediated NF-κB Signaling.

Postmenopausal Osteoporosis (PMOP) is the most prevalent primary osteoporosis, attributable to an imbalance in osteoblast and osteoclast activity. Modified You-Gui-Yin (MYGY), a traditional Chinese herbal formula, is able to effectively treat PMOP, while the critical components and pharmacological mechanisms of MYGY are still unclear. In this study, we aimed to investigate the therapeutic effects and underlying mechanisms of N-butanol extract of MYGY (MYGY-Nb) in ovariectomized (OVX)-induced osteoporosis mice. Histological staining and micro-computed tomography (µCT) analysis showed that MYGY-Nb was more effective in the suppression of OVX-induced bone loss than MYGY original formula. Subsequently, liquid chromatography and mass spectrometry analysis identified 16 critical compounds of MYGY-Nb and some of them are reported to affect osteoclast functions. Furthermore, in vivo and in vitro experiments demonstrated that MYGY-Nb significantly attenuated osteoclastogenesis by down-regulating RANKL-mediated NF-κB signaling. In conclusion, our study indicated that MYGY-Nb suppresses NF-κB signaling and osteoclast formation to mitigate bone loss in PMOP, implying that MYGY-Nb and its compounds are potential candidates for development of anti-PMOP drugs.

Network pharmacology-based pharmacological mechanism prediction on Eucommia ulmoides against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Eucommia ulmoides (EU) is a kidney-tonifying Chinese medicine that has been applied to treat RA for decides. The present study aims to explore pharmacological mechanisms of EU against RA using network pharmacology approach. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of EU, and their relative targets were fished from UniProt database. RA-related targets were screened from GeneCards database and DisGeNET database. The overlapping genes between EU and RA were identified by Venn diagram, and further analyzed for protein-protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Fifty active ingredients were identified in EU, and corresponded to 207 targets. Meanwhile, 499 targets were closely associated with RA development. A total of 50 overlapping genes between EU and RA were identified, which were regarded as therapeutically relevant. GO enrichment analysis indicated that EU exerted antiRA effects depending on regulating multiple biological processes including inflammatory response, oxidative stress, cell apoptosis and matrix catabolism. Several key pathways such as TNF pathway, IL-17 pathway, T cell receptor pathway, NOD-like receptor pathway and Toll-like receptor pathway, were involved in the above biological processes. Network pharmacology revealed that EU exerts therapeutic effects on RA through multi-ingredients, multi-targets and multi-pathways, which provides basis for its clinical application and promising directions for subsequent research.

The association between dietary inflammation index and the risk of rheumatoid arthritis in Americans.

BACKGROUND: The correlation between dietary inflammation index (DII) and rheumatoid arthritis (RA) has been found, but the effect of confounding factors is not considered. This study aims to further explore the association between DII and RA risk by taking the Americans as the research object. METHODS: The data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES) database included 1819 self-reported RA individuals and 8602 non-RA individuals. The analytical methods include logistic regression, additive model, smooth curve fitting, and the recursive algorithm. RESULTS: There was a positive correlation between DII and RA in Americans (ß = 1.068, 95% CI = 1.026 to 1.111, P = 0.001). This result was still presented in the subgroup analysis, including age less than 50 years, female, other Hispanics, BMI ≥ 25, and federal poverty rate > 185%, and it was more pronounced in smokers. The results show that the superposition of DII and other risk factors would increase the risk of RA (ß > 1.068). In addition, individuals with RA are inadequate in intake of anti-inflammatory foods, in line with the Mediterranean diet. CONCLUSIONS: The inflammatory potential of the diet is positively correlated with the risk of RA, and has a superimposed effect with other risk factors, increasing the probability of the risk of disease. These results emphasize that reducing the intake of pro-inflammatory foods may be an effective measure to prevent the onset of rheumatoid arthritis. However, eating anti-inflammatory foods exclusively is not the best option. Intaking some pro-inflammatory foods like protein, energy, and total saturated acids may be necessary to maintain the physiological function of the human body. Key Points • Dietary inflammation index (DII) is positively correlated with RA risk. • When DII and other risk factors appear at the same time, the effects of the two will be superimposed on each other, increasing the risk of RA. • When the DII is the same, Hispanic has a higher incidence of RA. • Among the pro-inflammatory foods, the intake of protein, energy, and saturated fatty acids is still required by RA patients.

Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein.

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.

CD38 Drives Progress of Osteoarthritis by Affecting Cartilage Homeostasis.

OBJECTIVE: To observe expression of CD38, a key modulator of nicotinamide dinucleotide (NAD+) metabolism in mice with knee osteoarthritis, and protective effect of CD38 inhibition during the osteoarthritis (OA) development. METHOD: The destabilization of the medial meniscus (DMM) model was performed in mice to mimic the process of OA. Immunofluorescence of CD38 was performed to evaluate its response during the OA process. Limb bud-derived mesenchymal cells were isolated for micromass culture. 100 nM or 1 µM CD38 inhibitor (78c) treatment for 14 days and CD38 sgRNA infection were then used to explore the effects of chondrogenic differentiation via Alcian blue staining. The expressions of chondrogenic markers were detected using RT-PCR and Western blot. To explore the protective effect of CD38 inhibitor on cartilage degradation during OA in vivo, a CD38 inhibitor was injected into the knee joint after DMM operations. Micro-CT analysis and Safranin O-fast green staining were used to evaluate subchondral bone micro-architecture changes and cartilage degeneration. RESULTS: Compared to the control group, the CD38 expression in superficial cartilage was obviously increased in DMM group (P < 0.05). During the normal chondrogenic differentiation, the extracellular matrix formed and expression of Sox9, Col2, aggrecan increased apparently while CD38 expression decreased, which could be reversed with ablation of CD38 in limb bud-derived mesenchymal cells. Consistent with findings in vitro, CD38 blockage via CD38 inhibitor injection protected against osteosclerosis in medial subchondral bone and cartilage degeneration in DMM-induced experimental mice. Compared to the Sham group, DMM mice showed significantly increased values of BV and BV/TV in subchondral bone (P < 0.05) and Mankin score, which could be rescued by 78c treatment (P < 0.05). Also the CD38 inhibitor contributed to homeostasis of anabolism and catabolism by upregulating Sox9, Col2, aggrecan and downregulating Runx2, Col10 and Mmp13. CONCLUSION: This study primarily implicates CD38 as an important regulator of chondrogenic differentiation. Inhibition of CD38 demonstrated protection against cartilage degeneration, which suggests that CD38 could be a potential therapeutic target for OA.

Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass.

Obesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.

Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation.

No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.

Fractions of Shen-Sui-Tong-Zhi Formula Enhance Osteogenesis Via Activation of ß-Catenin Signaling in Growth Plate Chondrocytes.

Background: Shen-sui-tong-zhi formula (SSTZF) has been used to treat osteoporosis for decades and shows excellent clinical efficacy. This article aims to explore the optimal anti-osteoporotic ingredient and its precise mechanisms in mice models. Methods: In this study, we first screened the optimal anti-osteoporosis fraction of SSTZF extract in vivo, and then further explored the mechanism of its effects both in vivo and in vitro. Ten-week-old female C57BL/6J mice were administrated with each fraction of SSTZF. At 10 weeks after ovariectomy (OVX), femurs were collected for tissue analyses, including histology, micro-CT, biomechanical tests, and immunohistochemistry for ALP, FABP4, and ß-catenin. Additionally, we also evaluated the mRNA expression level of ALP and FABP4 and the protein expression level of ß-catenin after being treated with SSTZF extract in C3H10T1/2 cells. Moreover, we investigated the anti-osteoporosis effect of SSTZF extract on mice with ß-catenin conditional knockout in growth plate chondrocytes (ß-catenin Gli1ER mice) through µCT, histology, and immunohistochemistry analyzes. Results: At 10 weeks after treatment, osteoporosis-like phenotype were significantly ameliorated in SSTZF n-butanol extract (SSTZF-NB) group mice, as indicated by increased trabecular bone area and ALP content, and decreased lipid droplet area and FABP4 content. No such improvements were observed after being treated with other extracts, demonstrating that SSTZF-NB is the optimal anti-osteoporosis fraction. Additionally, the elevated ß-catenin was revealed in both OVX mice and C3H10T1/2 cells with SSTZF-NB administered. Furthermore, a significant osteoporosis-like phenotype was observed in ß-catenin Gli1ER mice as expected. However, SSTZF-NB failed to rescue the deterioration in ß-catenin Gli1ER mice, no significant re-upregulated ALP and downregulated FABP4 were observed after being treated with SSTZF-NB, demonstrating that SSTZF-NB prevents bone loss mainly via ß-catenin signaling. Conclusion: SSTZF-NB enhances osteogenesis mainly via activation of ß-catenin signaling in growth plate chondrocytes. SSTZF-NB is the optimal anti-osteoporosis fraction of SSTZF and it can be considered a salutary alternative therapeutic option for osteoporosis.

Fluid Homeostasis May Predict the Prognosis of Non-infectious Fever After Total Knee Arthroplasty Within 7-Day: A Retrospective Cohort Study.

Background: In the perioperative management of Total Knee Arthroplasty (TKA), postoperative fever has always been a concern. Current research focuses on infectious fever, and there is no relevant research on the occurrence of non-infectious fever (NIF) and its risk factors. Hence, the aim of this study was to clarify the risk factors for NIF after TKA, and construct an easy-to-use nomogram. Methods: A retrospective cohort study was conducted. Consecutive patients undergoing primary unilateral TKA were divided into the non-infectious fever group and the control group. Clinicopathological characters were collected from electronic medical records. Univariate Logistic regression was used to analyze the related independent risk factors. The optimal threshold for each selected factor and combined index was determined when the Youden index achieved the highest value. And the predictive nomogram was developed by these independent factors. Results: Ultimately, 146 patients were included in this study. Of them, 57 (39.04%) patients experienced NIF. Results of the univariable logistic regression analysis indicated that intraoperative blood loss (OR, 1.002; 95% CI, 1.000-1.0004), postoperative drainage fluid volume (OR, 1.003; 95% CI, 1.001-1.006) and frequency of blood transfusion (n = 1; OR, 0.227; 95% CI, 0.068-0.757) were independent risk factors of NIF occurrence. The predictive nomogram that incorporated the above independent risk factors was developed, and it yielded an areas under the curves (AUC) of 0.731 (95% CI: 0.651-0.801; P < 0.0001) with 54.39% sensitivity and 82.02% specificity. Conclusions: Non-infectious fever after TKA prolongs the time of antibiotic use and hospital stay. Our results demonstrated that the nomogram may facilitate to predict the individualized risk of NIF occurrence within 7-day by intraoperative blood loss, postoperative drainage fluid volume and frequency of blood transfusion.

The in Situ NHC-Palladium Catalyzed Selective Activation of B(3)-H or B(6)-H Bonds of o-Carboranes for Hydroboration of Alkynes: An Efficient Approach to Alkenyl-o-carboranes.

An in situ Pd-NHC catalyzed selective B(3,6)-H activation for hydroboration of internal alkynes has been accomplished under mild conditions. This work offers a facile approach for the synthesis of alkenyl-o-carboranes and has important reference for selective functionalization of B(3,6)-H bonds.

Palladium Catalyzed Selective B(3)-H Activation/Oxidative Dehydrogenative Coupling for the Synthesis of Bis(o-carborane)s.

A palladium catalyzed selective B(3)-H activation/oxidative dehydrogenative coupling for the synthesis of bis(o-carborane)s connected with B(3)-B(3') and B(3)-B(6') bonds has been developed for the first time. A plausible mechanism involving stepwise activation of B(3)-H and B(3'/6')-H bonds by PdII and PdIV was proposed. This work is the first example and the most efficient protocol for synthesis of bis(o-carborane)s connected with B(3)-B(3') and B(3)-B(6') bonds, which has important reference for design, synthesis, and application of bis(o-carborane)s in related fields.

Amygdalin Promotes Fracture Healing through TGF-ß/Smad Signaling in Mesenchymal Stem Cells.

Chondrogenesis and subsequent osteogenesis of mesenchymal stem cells (MSCs) and angiogenesis at injured sites are crucial for bone fracture healing. Amygdalin, a cyanogenic glycoside compound derived from bitter apricot kernel, has been reported to inhibit IL-1ß-induced chondrocyte degeneration and to stimulate blood circulation, suggesting a promising role of amygdalin in fracture healing. In this study, tibial fractures in C57BL/6 mice were treated with amygdalin. Fracture calluses were then harvested and subjected to radiographic, histological, and biomechanical testing, as well as angiography and gene expression analyses to evaluate fracture healing. The results showed that amygdalin treatment promoted bone fracture healing. Further experiments using MSC-specific transforming growth factor- (TGF-) ß receptor 2 conditional knockout (KO) mice (Tgfbr2Gli1-Cre ) and C3H10 T1/2 murine mesenchymal progenitor cells showed that this effect was mediated through TGF-ß/Smad signaling. We conclude that amygdalin could be used as an alternative treatment for bone fractures.

Radix Rehmanniae Praeparata promotes bone fracture healing through activation of TGF-ß signaling in mesenchymal progenitors.

BACKGROUND: Radix Rehmanniae Praeparata (RR), the steamed roots of Rehmannia glutinosa, is a traditional Chinese medicine with the function of kidney-nourishing, and it has been safety used for centuries to treat bone-related disorders. The aim of this study is to investigate the positive effect and underlying mechanism of RR enhancing bone fracture healing in mouse model. METHODS: Ten-week-old C57BL/6J mice were subjected to a unilateral open transverse tibial fracture and provided a daily treatment of RR. Bone samples were harvested for tissue analyses including x-ray, µCT, histology, histomorphometry, biomechanical testing, immunohistochemical (IHC) and quantitative gene expression analysis. To determine the role of TGF-ß in accelerating fracture healing effect of RR, aforementioned experiments were performed on Gli1-CreER; Tgfbr2 flox/flox (Tgfbr2Gli1ER) conditional knockout mice. RESULTS: RR promoted bone fracture healing and strengthened bone intensity in wild-type and Cre- mice with the activation of TGF-ß/Smad2 signaling, on the contrary, RR failed to accelerating fracture healing in Tgfbr2Gli1ER mice. CONCLUSION: RR promotes bone fracture healing by intensify the contribution of Gli1+ cells on bone and cartilage formation mainly in TGF-ß-dependent manner. RR is an alternative option for clinical treatment of fracture.

Biomechanical, histologic, and molecular characteristics of graft-tunnel healing in a murine modified ACL reconstruction model.

PURPOSE: The purpose of our study was to introduce and validate a metal-free, reproducible and reliable mouse model of anterior cruciate ligament (ACL) reconstruction (ACLR) surgery as an effective tool for a better understanding of molecular mechanisms of graft-tunnel healing after ACLR. METHODS: A total of 150 C57BL/6 mice were randomly allocated into five Groups: Group 1 (mice with intact ACL), Group 2-4 (mice underwent modified ACLR surgery and sacrificed 1-, 2-, and 4-weeks after surgery), and Group 5 (mice underwent unmodified ACLR surgery and sacrificed 4 weeks after surgery). Micro-computed tomography (CT), biomechanical histological as well as immunohistochemical (IHC) analyses were performed to characterize the modified ACLR. RESULTS: Micro-CT analysis demonstrated there is a non-significant increase in BV/TV and BMD of the bone tunnel during the tendon-to-bone healing following ACLR. Biomechanical tests showed that the mean load-to-failure forces of Group 3 and 4 are equal to 31.7% and 46.0% of that in Group 1, while the stiffness was 33.1% and 57.2% of that of Group 1, respectively. And no obvious difference in biomechanical parameters was found between Group 4 and 5. Histological analysis demonstrated that formation of fibrovascular tissue in the tibial tunnel and aperture in Groups 4 and 5 and direct junction appeared between tendon graft and tunnel both in Groups 4 and 5. IHC results showed that there are gradually enhanced expression of Patched1, Smoothened and Gli2 concomitant with decreased Gli3 protein in the tendon-bone interface during the tendon-bone healing process. CONCLUSION: We introduced a metal-free, reproducible and reliable mouse model of ACLR compared to the unmodified ACLR procedure, and characterized the expression pattern of key molecules in Ihh signaling during the graft healing process. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: In the present study we introduced and validated, for the first time, a metal-free, reproducible and reliable ACLR mouse model, which could be used to investigate the detailed molecular mechanisms of graft-tunnel healing after ACLR. We also explored new strategies to promote the healing of tendon-to-bone integration.