Duration of surgical antibiotic prophylaxis and surgical site infection in orthopaedic surgery: A prospective cohort study.

BACKGROUND: The optimal duration for surgical antibiotic prophylaxis (SAP) for preventing surgical site infection (SSI) in orthopaedic surgeries remains poorly supported by high-level evidence. This study aimed to assess the association between SAP duration and the occurrence of SSI within one year postoperatively. METHODS: This prospective cohort study was based on the database from Surgical Site Infection Surveillance and Improvement Project (SISIP) of a tertiary orthopaedic university hospital from October 2014 to December 2020. The main outcome was SSI, defined according to the CDC/NHSN criteria, determined by review of index hospitalization medical records, microbiology laboratory reports, and readmission records for SSI treatment within one-year after discharge. Adjusted Generalized additive models (GAMs) were performed to assess the relationships between SAP duration and SSI, determined the cut-off point of SAP duration, and estimate the relative contribution of each included variable, across the overall cohort and the three subgroups (open fracture, closed fracture, and non-traumatic group). Multivariable logistic regression models were used to estimate the association between prolonging SAP duration based on the cut-off point and SSI. RESULTS: There were 37,046 patients (55.1% male) included, with the overall SSI incidence of 2.35% (871/37,046). In adjusted GAMs, no statistically significant relationships were observed in overall cohort and open or closed group (P>0.05), but a nonlinear relationship was exhibited non-traumatic group (P=0.03); the cut-off point were 2.4 days for overall cohort and 3.6 days (open), 2.6 days (closed), 1.1 days (non-trauma) for three subgroups. In adjusted logistic regression, prolonging SAP duration did not demonstrate a statistically significant protective effect in overall cohort (aOR=0.868; 95% CI, 0.746-1.011) and three groups (open: aOR=0.867; 95% CI, 0.668-1.124; closed: aOR=0.925; 95% CI, 0.754-1.135; non-trauma: aOR=1.184; 95% CI, 0.832-1.683). The relative contribution ranks of SAP duration were 21st overall among 34 factors, 14th for open fractures, 28th for closed fractures, and 3rd for non-traumatic group among 33 factors. CONCLUSION: Prolonged postoperative SAP duration has no protective effect against SSI in orthopaedic surgery. Our findings support current guidelines against the practice of continuing SAP postoperatively.

Elucidation of the relationship between evodiamine-induced liver injury and CYP3A4-mediated metabolic activation by UPLC-MS/MS analysis.

Evodiamine (EVD), which has been reported to cause liver damage, is the main constituent of Evodia rutaecarpa (Juss.) Benth and may be bioactivated into reactive metabolites mediated by cytochrome P450. However, the relationships between bioactivation and EVD-induced hepatotoxicity remain unknown. In this study, comprehensive hepatotoxicity evaluation was explored, which demonstrated that EVD caused hepatotoxicity in both time- and dose-dependent manners in mice. By application of UPLC-Q/TOF-MS/MS, two GSH conjugates (GM1 and GM2) derived from reactive metabolites of EVD were identified, in microsomal incubation systems exposed to EVD with glutathione (GSH) as trapping agents. CYP3A4 was proved to be the main metabolic enzyme. Correspondingly, the N-acetyl-L-cysteine conjugate derived from the degradation of GM2 was detected in the urine of mice after exposure to EVD. For the first time, the iminoquinone intermediate was found in EVD-pretreated rat bile by the high-resolution MS platform. Pretreatment with ketoconazole protected the animals from hepatotoxicity, decreased the protein expression of cleaved caspase-1 and -3, but increased the area under the serum-concentration-time curve of EVD in blood determined by UPLC-QQQ-MS/MS. Depletion of GSH by buthionine sulfoximine exacerbated EVD-induced hepatotoxicity. These results implicated that the CYP3A4-mediated metabolic activation was responsible for the observed hepatotoxicity induced by EVD.

Effect of N-oleoyl dopamine on myofibroblast trans-differentiation of retinal pigment epithelial cells.

Retinal pigment epithelial (RPE) cells contribute to several clinical conditions resulting in retinal fibrotic scars. Myofibroblast trans-differentiation of RPE cells is a critical step in the process of retinal fibrosis. In this study, we investigated the effects of N-oleoyl dopamine (OLDA), a newer endocannabinoid with a structure distinct from classic endocannabinoids, on TGF-ß2-induced myofibroblast trans-differentiation of porcine RPE cells. Using an in vitro collagen matrix contraction assay, OLDA was found to inhibit TGF-ß2 induced contraction of collagen matrices by porcine RPE cells. This effect was concentration-dependent, with significant inhibition of contraction observed at 3 µM and 10 µM. OLDA did not affect the proliferation of porcine RPE cells. Immunocytochemistry showed that at 3 µM, OLDA decreased incorporation of α-SMA in the stress fibers of TGF-ß2-treated RPE cells. In addition, western blot analysis showed that 3 µM OLDA significantly downregulated TGF-ß2-induced α-SMA protein expression. Taken together these results demonstrate that OLDA inhibits TGF-ß induced myofibroblast trans-differentiation of RPE cells. It has been established that classic endocannabinoid such as anandamide, by activating the CB1 cannabinoid receptor, promote fibrosis in multiple organ systems. In contrast, this study demonstrates that OLDA, an endocannabinoid with a chemical structure distinct from classic endocannabinoids, inhibits myofibroblast trans-differentiation, an important step in fibrosis. Unlike classic endocannabinoids, OLDA has weak affinity for the CB1 receptor. Instead, OLDA acts on non-classic cannabinoid receptors such as GPR119, GPR6, and TRPV1. Therefore, our study indicates that the newer endocannabinoid OLDA and its non-classic cannabinoid receptors could potentially be novel therapeutic targets for treating ocular diseases involving retinal fibrosis and fibrotic pathologies in other organ systems.

Opposing roles of ZEB1 in the cytoplasm and nucleus control cytoskeletal assembly and YAP1 activity.

Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma (LUAD), driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migration and Yap1 nuclear transport. Tgfb causes turnover of the scaffold protein Rassf1a, which targets RhoA. Release of this RhoA inhibition in response to Tgfb overcomes Zeb1's block of cytoskeleton assembly and frees it for nuclear transport. A ZEB1 nuclear transport signature highlights EMT progression, identifies dedifferentiated invasive/metastatic human LUADs, and predicts survival. Blocking Zeb1 nuclear transport with a small molecule identified in this study inhibits cytoskeleton assembly, cell migration, Yap1 nuclear transport, EMT, and precancerous-to-malignant transition.

Systematic review and Meta-analysis of 26 randomized controlled clinical trials of Compound Danshen Dripping Pill for non-proliferating diabetic retinopathy.

Objective: Diabetic retinopathy (DR) is the retinal consequence of chronic progressive diabetic microvascular leakage and occlusion. Non-proliferating diabetic retinopathy (NPDR) is the early stage of DR. It eventually occurs to some degree in all patients with diabetes mellitus. In recent years, many clinical trials have shown that Compound Danshen Dripping Pill (CDDP) may be associated with the improvement of NPDR symptoms. The aim of this study was to quantitatively summarize the association between CDDP and the therapeutic effects of NPDR. Methods: It was conducted that a systematic literature search of PubMed, Web of Science, CNKI, VIP and Wanfang Data updated in June 2020 with the following search terms: "diabetic retinopathy" or "retinopathy" or "DR" or "NPDR", in combination with "Compound Danshen Dripping Pill" or "Salvia miltiorrhiza" or "Danshen". Risk ratio (RR) and weighted mean difference (WMD) with their 95% confidence interval (CI) was calculated between treatment and control groups. The sensitivity analyses were undertaken by removing each individual study when high heterogeneity appeared. Subgroup analysis, Meta-regression, and publication bias analysis were also conducted. The strength of evidence was evaluated with the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) method. Results: Twenty-six RCTs involving 2047 subjects were included to conduct a Meta-analysis after screening the studies, extracting the data, and assessing the study quality. The Stata15.0 software was utilized for processing. Meta-analysis indicated that curative effects of treatment group with CDDP was significantly better than control [RR = 0.54, 95% CI (0.40, 0.73); moderate-quality evidence]. In addition, the results showed that CDDP was significantly associated with improving retinal hemorrhages [WMD = -0.62, 95% CI (-0.78, -0.46); low-quality evidence], the vision [WMD = 0.14, and 95% CI (0.09, 0.19), low-quality evidence], fundus fluorescence angiography [RR = 0.37 and 95% CI (0.23, 0.60); low-quality evidence], reduction of retinal microaneurysm [WMD = -3.74 and 95% CI (-4.38, -3.11); moderate-quality evidence], hemangioma volume [WMD = -3.15, 95%CI (-3.45, -2.85); moderate-quality evidence], macular thickness [WMD = -5.52, 95%CI = (-64.27, -48.78); low-quality evidence], mean defect [WMD = -1.65 and 95% CI (-1.95, -1.34); very low-quality evidence], fasting blooding glucose [WMD = -0.95, 95% CI (-1.19, -0.70); low-quality evidence), hemoglobin A1c [WMD = -0.62, 95% CI (-0.93, -0.30); low-quality evidence], high sensitive C reaction protein [WMD = -5.66, 95% CI (-8.01, -3.31); low-quality evidence]. Sensitivity, subgroup, and Meta-regression analyses were also assessed. Conclusion: The study demonstrated that CDDP has beneficial clinical effects for treating NPDR and improve the vision. Moreover, it indicated that oral CDDP in NPDR patients led to significant regulation of serum level of fasting blooding glucose, hemoglobin A1c and high sensitive C reaction protein, which was associated with the pathogenesis of NPDR. However, high-quality and large randomized clinical trials will be needed to prove the consequence in future.

Comparison of open reduction and fixation with hook plate and modified closed reduction and fixation with tightrope loop plate for treatment of rockwood type III acromioclavicular joint dislocation.

OBJECTIVE: To compare the outcomes of open reduction and hook plate fixation (ORHPF) and modified TightRope loop plate fixation (MTRLPF) in the treatment of Rockwood type III acromioclavicular joint dislocation. METHODS: This was a retrospective study. Data on 71 patients with Rockwood type III acromioclavicular joint dislocation who underwent either ORHPF (n = 39) or MTRLPF (n = 32) between January 2016 and October 2019 were extracted and analyzed. Baseline data at injury were compared to evaluate the balance. The disabilities of the arm, shoulder, and hand (DASH) score, Constant-Murley score and visual analog scores (VAS) score at 1 month, 3 months, 6 months and 12 months after operation were compared; further, at 12 months coracoclavicular distance and related complications were evaluated and compared. RESULTS: Both groups did not differ for any baseline data. At 1 and 3 months after operation, MTRLPF group exhibited a significantly better performance than the ORHPF group in VAS (1 month: 2.4 ± 1.8 vs 3.0 ± 1.7; 3 months: 1.2 ± 1.4 vs 1.8 ± 1.6), Constant-Murley (1 month: 75.2 ± 11.2 vs 63.8 ± 13.7; 3 months: 81.4 ± 9.8 vs 75.8 ± 10.6), DASH (1 month: 33.6 ± 6.8 vs 40.6 ± 6.1; 3 months: 21.2 ± 7.4 vs 25.6 ± 6.6). At 6 months, only Constant-Murley remained marginally significant (p = 0.048). At 12 months, no statistical difference was observed for any outcome variable (all P > 0.05 for VAS, Constant-Murley and DASH), coracoclavicular distance (12.7 ± 1.6 mm vs 12.2 ± 1.6 mm; P = 0.374), or overall complication rate (P = 0.763). CONCLUSIONS: For Rockwood type III acromioclavicular joint dislocation, both methods can achieve satisfactory 1-year results, but modified minimally invasive TightRope treatment is more advantageous in early functional recovery at 1 and 3-month follow-ups.

Reparative effects of chronic intermittent hypobaric hypoxia pre­treatment on intervertebral disc degeneration in rats.

Previous studies have indicated that chronic intermittent hypobaric hypoxia (CIHH) preconditioning can inhibit TNF­α and other related inflammatory cytokines and exerts protective effect on intervertebral disc degeneration disease (IDD) in rats; however, the mechanism is still unclear. The present study aimed to explore the repair mechanisms of CIHH on IDD in rats. In the experiment, 48 adult Sprague­Dawley rats were selected and randomly divided into an experimental group (CIHH­IDD), a degenerative group (IDD) and a control group (CON). The CIHH­IDD group of rats (n=16) were treated with CIHH (simulated 3000 m altitude, 5 h per day, 28 days; PO2=108.8 mmHg) before disc degeneration surgery. The IDD group of rats (n=16) underwent tail­vertebral intervertebral disc surgery to establish a model of intervertebral disc degeneration. The CON group of rats (n=16) did not receive any treatments. After surgery, the disc height index was calculated using X­ray analysis of rat tail vertebrae, the degeneration process was observed and repair was evaluated by chemically staining degenerative intervertebral disc tissue slices. The expression levels of basic fibroblast growth factor (bFGF), TGFß1, Collagen I and Collagen II were measured in the intervertebral disc tissue using western blotting; while the expression levels of bFGF, TGFß1 and hypoxia­inducible factor 1­α (HIF­1α) were measured in rat serum using ELISA. The results demonstrated that: i) The degree of intervertebral disc height degeneration in CIHH­IDD rats was significantly lower compared with that in IDD rats (P<0.05); ii) the expression levels of bFGF, TGFß1 and HIF­1α were higher in CIHH­IDD rat serum compared with those in IDD rat serum (P<0.05); iii) optical microscopy revealed that the degree of disc degeneration was relatively mild in CIHH­IDD rats; and iv) the protein expression levels of bFGF, TGFß1 and collagen II were increased in CIHH­IDD rat intervertebral disc tissues compared with those of IDD rats, while the overexpression of collagen I protein was inhibited. Overall, after CIHH pre­treatment, the expression levels of bFGF and TGFß1 were up­regulated, which play notable roles in repairing degenerative intervertebral discs in rats.

Experiment investigation on pulsed gamma-ray fluence rate effect on Yb-doped yttrium aluminum garnet scintillator.

As an ultrafast inorganic scintillator, Yb-doped Y3Al5O12 [yttrium aluminum garnet (YAG)] crystals have potential applications in various fields, such as ultrafast radiation detection, solar neutrino detection, pulsed radiation imaging, and nuclear reaction kinetics diagnosis. In this work, the fluence rate effect of pulsed γ rays on the Yb:YAG scintillation crystal was investigated at the "QiangGuang-I" facility. The experiment results show that the fluence rate linear response upper limit of the Yb:YAG crystal is about 9.1 × 1018 MeV cm-2 s-1. The Yb:YAG crystal changed from colorless to yellow, and the relative light output decreased to 63% of its initial value after the irradiations, which were attributed to the radiation induced damage. It is deduced that oxygen vacancies and divalent Yb cations were generated after the irradiations.

Treatment of posterolateral tibial plateau fractures with a rotational support plate and special pressurizer: technical note and retrospective case series.

BACKGROUND: In tibial plateau fractures, the posterolateral segment of the tibia plateau is frequently affected and challenging to treat. Although there are many surgical approaches and fixation methods for the treatment of these fractures, all of these methods have limitations. We designed a new rotational support plate (RSP) and a special pressurizer that can fix the fracture directly via the anterolateral approach. This method is advantageous because it leads to little trauma, involves a simple operation, and has a reliable fixation effect. This study details the technique of treating these fractures with the RSP and special pressurizer and provides the outcomes. METHODS: From May 2016 to January 2019, the data of 12 patients with posterolateral tibial plateau fractures treated with the RSP and special pressurizer in our hospital were retrospectively analyzed. Postoperative rehabilitation was advised, knee X-rays were taken at follow-ups, and fracture healing, complications, and knee range of motion were assessed. The Hospital for Special Surgery (HSS) knee score and Knee Injury and Osteoarthritis Outcome Score (KOOS) were used to evaluate knee function at the last follow-up. RESULTS: The average follow-up time of all patients was 16.5 months (range, 12-25 months). The average bony union time was 3.2 months (range, 3-4.5 months). At the last follow-up, the average knee range of motion was 138° (range, 107-145°). The average HSS score was 91 (range, 64-98). The average KOOS Symptoms score was 90 (range, 75-96). The average KOOS Pain score was 91 (range, 72-97). The average KOOS ADL score was 91 (range, 74-97). The average KOOS sport/recreation score was 83 (range, 70-90). The average KOOS QOL score was 88 (range, 69-93). Skin necrosis, incision infections, and fixation failure did not occur during the follow-up period. CONCLUSIONS: With our newly designed RSP and special pressurizer, posterolateral tibial plateau fractures can be easily and effectively reduced and fixed through the anterolateral approach, which serves as a novel treatment for posterolateral tibial plateau fractures.

[Measurement and analysis of leg length in adults with unilateral developmental dysplasia of the hip].

OBJECTIVE: To measure and analyze the radiographic characteristics of the leg length discrepancy in adult patients with unilateral developmental dysplasia of the hip (DDH). METHODS: The clinical data of 112 patients with unilateral DDH who met the selection criteria between January 2016 and June 2018 were retrospectively analyzed. There were 16 males and 96 females with an age of 20-76 years (mean, 42.9 years). According to the Crowe classification, there were 25 hips of type Ⅰ, 26 hips of type Ⅱ, 15 hips of type Ⅲ, and 46 hips of type Ⅳ (26 hips of type ⅣA without secondary acetabular formation, and 20 hips of type ⅣB with secondary acetabular formation). Full-length X-ray films of the lower limbs in the standing position were used to measure the following parameters: greater trochanter leg length (GTLL), greater trochanter femoral length (GTFL), lesser trochanter leg length (LTLL), lesser trochanter femoral length (LTFL), tibial length (TL), and intertrochanteric distance (ITD). The above parameters on the healthy and affected sides were compared and the difference of each parameter between the healthy and affected sides was calculated. Taking the difference of 5 mm between the healthy side and the affected side as the threshold value, the number of cases with the healthy side was greater than 5 mm and the affected side was greater than 5 mm were counted respectively. The difference of the imaging parameters between the healthy side and the affected side were compared between different Crowe types and between type ⅣA and type ⅣB. RESULTS: There was no significant difference in GTLL and LTFL between healthy and affected sides ( P>0.05); LTLL and TL of affected side were longer than healthy side, GTFL and ITD were shorter than healthy side, and the differences were significant ( P<0.05). The constituent ratio of long cases on the affected side of TL and LTLL was greater than the constituent ratio of long cases on the healthy side, while the constituent ratio of long cases on the healthy side of GTFL and ITD was greater than the constituent ratio of long cases on the affected side; there was no obvious difference in the constituent ratio of long cases on the healthy side or the affected side of GTLL and LTFL. The comparison between different Crowe types showed that only the difference in TL between type Ⅰ and type Ⅳ was significant ( P<0.05), the difference of each imaging parameter among the other types showing no significant difference ( P>0.05). Compared with type ⅣB, the differences of GTLL, TL, and ITD of type ⅣA were bigger, and the differences were significant ( P<0.05); the differences of other parameters between type ⅣA and type ⅣB were not significant ( P>0.05). CONCLUSION: In adult unilateral DDH patients, the leg length on the healthy side and the affected side is different, and the difference mainly comes from the TL and ITD, which should be paid attention to in preoperative planning.

Preoperative deep venous thrombosis (DVT) after femoral neck fracture in the elderly, the incidence, timing, location and related risk factors.

OBJECTIVE: To investigate the epidemiologic characteristics of deep venous thrombosis (DVT) in elderly patients with femoral neck fracture. METHODS: Retrospective analysis was performed on elderly patients with femoral neck fractures admitted to two institutions from January 2016 to October 2019. Duplex ultrasonography (DUS) was used to detect DVT. Patients' hospitalization medical records were retrieved to collect the data, which were related to demographics, comorbidities, injury and laboratory results on admission. Patients with preoperative DVT were defined as the case group and those without DVT as control group, and compared using the univariate analyses. Multivariate logistic regression analysis was used to identify the independent factors associated with DVT. RESULTS: Totally, 980 patients met the predefined criteria and were included. Sixty-seven patients were diagnosed to have preoperative DVT, with incidence of 6.8% for overall, 1.7% for proximal and 5.1% for distal DVT. The mean time from injury to diagnosis of DVT was 6.0 ± 4.7 days (median, 5.0). Most (76.1%) patients with DVT had thrombi solely in the injured extremity, in contrast with 14.9% (10/67) in the uninjured and 9.0% (6/67) in both injured and uninjured extremity. Multivariate analysis showed chronic renal insufficiency (OR, 3.37; 95%CI, 1.57 to 7.28), current smoking status (OR, 2.42; 95%CI, 1.23 to 5.63), time from injury to DUS (OR, 1.26; 95%CI, 1.07 to 1.61) and PLT > 220*109/L (OR, 1.94; 95%CI, 1.31 to 3.77) were independent factors for DVT. CONCLUSION: Preoperative DVT is not very prevalent following elderly femoral neck fractures, but with a certain proportion in the uninjured extremity, necessitating the more attention. These identified risk factors aid in patient counseling, individualized risk assessment and risk stratification, and should be kept in mind.

The occurrence rate and clinical application of Osteo-line on the femur neck.

BACKGROUND: This study was done to observe the incidence of Osteo-line on the femur neck and to explore the clinical application of Osteo-line in osteotomy. METHODS: Eighty-nine adult femur specimens were selected to observe the incidence of Osteo-line on the femur neck. From August 2015 to January 2019, a total of 278 patients who completed unilateral hip arthroplasty at the Third Hospital of Hebei Medical University were retrospectively included. Patients who accepted osteotomy via Osteo-line on the femur neck were defined as the experimental group (n = 139), and patients who accepted osteotomy via traditional method (The femoral distance 1.5 cm above the trochanter was retained for osteotomy by visual inspection.) were defined as the control group (n = 139). According to the postoperative pelvic X-ray, Photoshop was used to evaluate the leg length discrepancy (LLD) by the CFR-T-LT method. RESULTS: Among the 89 specimens, the incidence of anterior Osteo-line was 75.28%, and the incidence of posterior Osteo-line was 100%. According to the clinical application results, the incidence of anterior Osteo-line on the femur neck was 80%, and the incidence of posterior Osteo-line was 100%. The Osteo-line was clearer than those on the femoral specimens. Twenty-six cases had LLD greater than 1 cm (9.29%), including 2 cases in the experimental group and 24 cases in the control group. The average postoperative LLD in the experimental group (0.19 ± 0.38 mm) was significantly shorter than in the control group (0.54 ± 0.51 mm)(P = 0.005). CONCLUSION: The incidence of Osteo-line on the femur neck was high, and patients who accepted osteotomy via Osteo-line on the femur neck can achieve shorter postoperative LLD than the control group.

Patient and Perioperative Factors Influencing the Functional Outcomes and Mortality in Elderly Hip Fractures.

This study aimed to evaluate the functional outcomes and mortality following hip fracture surgery in elderly patients, and to identify the associated risk factors. Between January 2016 and December 2017, 480 consecutive patients were finally included for data analyses. The Harris score and Barthel index were used to evaluate the hip function and ability to perform activities of daily living (ADL). Univariate and multivariate logistics regression analyses were performed to determine the independent risk factors for mortality, poor hip function or poor ability to perform ADL. The mortality rate was 15.6% (75/480). In the survivors, poor outcome developed in 133 (32.8%) patients and poor ADL was in 72 (17.8%) patients. The independent factors that influenced mortality were advanced age (p = 0.033), male gender (0.031), living in rural area (p < 0.001), self-reported diabetes (p = 0.005), tumor (p = 0.024), preoperative delay >7 days (p = 0.020), postoperative drainage use (p = 0.034), WBC > 10 × 109/L (p = 0.005), reduced RBC (p = 0.011), PLT < 100 × 109/L (p < 0.001), ALB < 35 g/L (p < 0.001) and CK > 200 U/L (p = 0.003). The independent factors that influenced the hip function were male gender (p = 0.009), WBC > 10 × 109/L (p < 0.001), lower HBG (p = 0.005), and ALB < 35 g/L (p < 0.001). The independent factors that influenced the ability to perform ADL were diagnosis of trochanteric fracture (p = 0.048), preoperative delay > 7 days (p = 0.027), postoperative drainage use (p = 0.010), elevated WBC (p = 0.020), lower HGB (p < 0.001), PLT < 100 × 109/L (p = 0.002), and ALB < 35 g/L (p < 0.001). Although most of risk factors were not modifiable, they aid in patient individual risk evaluation, risk stratification, and counseling patients or relatives.

Upregulation of Sirt1 by tyrosol suppresses apoptosis and inflammation and modulates extracellular matrix remodeling in interleukin-1ß-stimulated human nucleus pulposus cells through activation of PI3K/Akt pathway.

Intervertebral disc degeneration (IDD) is the major pathogenesis of lower back pain. Tyrosol is a polyphenolic compound that exhibits anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Herein, we explored the effects and mechanisms of tyrosol on IDD progression in interleukin (IL)-1ß-stimulated human nucleus pulposus cells (HNPCs). Cell viability and apoptosis were detected by CCK-8 and flow cytometry analysis, respectively. The production of tumor necrosis factor-α (TNF-α), IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2) was examined to evaluate inflammation. The mRNA expression of matrix metalloproteinases (MMPs) (MMP-3/9/13), collagen type II, SRY-related high mobility group box 9 (SOX-9), and aggrecan was measured by qRT-PCR. Protein levels of silent information regulator 2 homolog 1 (Sirt1), phosphorylated protein kinase B (p-Akt), Akt, collagen type II, SOX-9, and aggrecan were determined by western blot. Results showed that tyrosol attenuated IL-1ß-induced viability reduction, apoptosis, and caspase-3/7 activity in HNPCs. The increase in the production of TNF-α, IL-6, NO, and PGE2 in IL-1ß-treated HNPCs was abolished by tyrosol treatment. Tyrosol treatment reversed IL-1ß-induced upregulation of MMP-3, MMP-9, and MMP-13, and downregulation of collagen II, SOX-9, and aggrecan in HNPCs. Additionally, tyrosol treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in IL-1ß-stimulated HNPCs. Sirt1 was upregulated by tyrosol, and Sirt1 silencing inhibited Akt phosphorylation in HNPCs. Sirt1 knockdown attenuated the effects of tyrosol on IL-1ß-induced apoptosis, inflammation, and ECM remodeling in HNPCs. In summary, upregulation of Sirt1 by tyrosol suppressed apoptosis and inflammation and regulated ECM remodeling in IL-1ß-stimulated HNPCs through activation of PI3K/Akt pathway.

Epidemiological Study of Tibial Plateau Fractures Combined with Intercondylar Eminence Fractures.

OBJECTIVE: To investigate the epidemiological characteristics of tibial plateau fractures combined with intercondylar eminence fractures and identify the risk factors. METHODS: This retrospective study enrolled patients with tibial plateau fractures who were treated in the third hospital of Hebei Medical University from January 2015 to December 2018; 1020 patients (693 [68%] men and 327 [32%] women) meeting the inclusion and exclusion criteria had a mean age of 45.2 ± 13.8 years. In total, 506 (50%) cases were left injuries, 495 (48%) were right injuries, and 19 (2%) were bilateral injuries. Among them, 458 (44.9%) with a mean age of 47.0 ± 13.9 years had intercondylar eminence fractures, including 324 men and 134 women. A total of 562 (55.1%) patients were identified without intercondylar eminence fractures, including 369 (65.7%) men and 193 (34.3%) women with an average age of 43.8 ± 13.6 years. The distribution characteristics of tibial plateau fractures with intercondylar eminence involved were identified. The potential associations among fractures and various other factors, such as age, gender, occupation, and mechanism of injury, were explored. RESULTS: The highest proportion age group of tibial plateau fractures included the ages 35-54 years, with more men than women for both age groups. For males, the highest proportion age group was 35-44 years, and for females, it was 55-64 years (χ 2 = 71.336, P < 0.01). According to Schatzker classification, type IV tibial plateau fractures had the highest risk of intercondylar eminence being involved (70.6%) without significance with type V (69.5%) and VI (68.2%) but with greater significance with types I (11.9%), II (39.2%), and III (9.4%, χ 2 = 280.187, P < 0.01). Multiple analysis showed that simple fractures, including types I, II, and III (OR 0.108, 95% CI: 0.080-0.145), were less likely to involve intercondylar eminence fractures than complex fractures, including types IV, V, and VI. Patients aged >74 years were more likely to have intercondylar eminence fractures compared with other age groups. Retired patients (OR 4.332, 95% CI: 1.147-16.362) were more likely to have fractured intercondylar eminence. CONCLUSION: The current study revealed the characteristics of tibial plateau fractures, especially those involving intercondylar eminence fractures, as well as their proportion, distribution, and risk factors, which can be used as reference data for clinical assessment and surgical protocol selection.

Clerodane Diterpenoids Isolated from the Leaves of Casearia graveolens.

A phytochemical survey aiming to acquire pharmacologically active substances has resulted in the isolation of nine new clerodane diterpenoids, named graveospenes A-I (1-9), from the leaves of Casearia graveolens. Spectroscopic methods were employed to establish the structures with their absolute configurations being confirmed by ECD data analysis. A biological evaluation was performed, and compound 1 was found to be cytotoxic to both human lung cancer cells (A549) and human hepatocellular carcinoma cells (HepG2). A mechanism-of-action study on 1 revealed this compound to induce apoptosis of A549 cells and impede them at the G0/G1 stage.

Discovery of endogenous inverse agonists for G protein-coupled receptor 6.

The orphan G protein-coupled receptor 6 (GPR6) is highly expressed in the striatum and has been linked to multiple striatal pathologies. The identification of endogenous ligands and their mechanisms of action at GPR6 will help to elucidate the physiological and pathological roles of the receptor. In the current study, we tested the concentration-dependent effects of a variety of endocannabinoid-like N-acylamides on GPR6 signaling. Here, we demonstrate for the first time that N-arachidonoyl dopamine, N-docosahexaenoyl dopamine, N-oleoyl dopamine and N-palmitoyl dopamine exert inverse agonism at GPR6. This effect was concentration-dependent, with potencies in the micromolar range, and functionally selective for ß-arrestin2 recruitment. Structure-activity relationship studies demonstrate that both the N-acyl side chain and the dopamine head group are important for these ligands to act on GPR6. Our discovery of these N-acyl dopamines as endogenous inverse agonists for GPR6 moves us one step further in understanding the roles GPR6 play in neurodegenerative and neuropsychiatric disorders related to striatal dysfunction.

A Novel Method of the Treatment for Posterolateral Tibial Plateau Fractures.

Reduction and fixation of posterolateral tibial plateau fracture via a posterolateral approach is challenging, and the posterolateral approach itself may injure the posterolateral ligament complex of the knee and can result in knee instability. We developed a new curved support plate (CSP) that can pass, via traditional anterolateral approach, through the superior tibiofibular interval and effectively support the posterolateral fragments. The purpose of our study was to determine the biomechanical reliability of the new plate and report the preliminary efficacy of the CSP for posterolateral tibial plateau fracture. In the biomechanical experiment, 40 synthetic tibias were used to create posterolateral shearing tibial fracture models, which were randomly assigned to groups A to D. Vertical displacement of the posterolateral fragments was measured under axial loads of 500 to 1,500 N. The new plate and 3.5-mm lateral locking plate exhibited similar control over fragment displacement. From June 2016 to August 2017, eight patients with posterolateral tibial plateau fracture underwent treatment with the CSP. Hospital for Special Surgery (HSS) knee score, knee flexion and extension ranges of motion, and complications were recorded to evaluate treatment effects. Eight patients (five men and three women, mean age 44 years [range, 23-66 years]) were enrolled in the study. Mean follow-up time was 13 months (range, 7-19 months). All patients achieved radiographic bone union by 3.3 months (range, 3-4 months) postoperatively. There were no complications of neurovascular injury, deep vein thrombosis, infection, and implant loosening throughout the follow-up period. At final follow-up, mean HSS score was 92.6 (88-96), with a mean knee flexion of 131.25 degrees (120-135 degrees) and a mean knee extension of 1 degree (0-5 degrees). Fixation of posterolateral tibial plateau fracture was easily and successfully achieved using our newly designed CSP, which may provide a new choice for posterolateral tibial plateau fractures.

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol.

The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using ß-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.

Combination of Ginsenoside H dripping pills and cyclophosphamide improve paraneoplastic syndrome and inhibit postoperative recurrence via the reversion of Th1/Th2 shift.

Non-small-cell lung cancer (NSCLC) is recognized as the most common malignant disease worldwide and combination treatment is recommended as its first line therapy. As a Ph2 clinical product, Ginsenoside H dripping pills (GH) is proposed as an adjuvant of chemotherapy. In the present study, we utilized a postoperative model to evaluate the efficacy of GH on the functions of anti-recurrence and improvement of life quality when combined with chemotherapeutic drug cyclophosphamide (CTX). Specifically, the anti-recurrence effect was evaluated by tumor inhibiting rate and the improvement of life quality was evaluated by the remission of splenomegaly and emaciation. The underlying mechanisms were explored via quantitative real time-PCR, Elisa and IHC staining. Results showed that GH had a synergy when combined with CTX against tumor recurrence, significantly improved the life quality of postoperative patients via remitting splenomegaly and emaciation. H&E staining showed that GH could increase the number of splenic T cells, which were inhibited after CTX administration. Furthermore, the reversion of Th1/Th2 shift, which had been verified by different methods, may account for one of the mechanisms of the synergy. All these results indicated Ginsenoside H dripping pills as a promising adjuvant for postoperative chemotherapy of NSCLC.