Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

Diet and lifestyle behaviours simultaneously act on frailty: it is time to move the threshold of frailty prevention and control forward.

BACKGROUND: To analyse the association among the simultaneous effects of dietary intake, daily life behavioural factors, and frailty outcomes in older Chinese women, we predicted the probability of maintaining physical robustness under a combination of different variables. METHODS: The Fried frailty criterion was used to determine the three groups of "frailty", "pre-frailty", and "robust", and a national epidemiological survey was performed. The three-classification decision tree model was fitted, and the comprehensive performance of the model was evaluated to predict the probability of occurrence of different outcomes. RESULTS: Among the 1,044 participants, 15.9% were frailty and 50.29% were pre-frailty; the overall prevalence first increased and then decreased with age, reaching a peak at 70-74 years of age. Through univariate analysis, filtering, and embedded screening, eight significant variables were identified: staple food, spices, exercise (frequency, intensity, and time), work frequency, self-feeling, and family emotions. In the three-classification decision tree, the values of each evaluation index of Model 3 were relatively average; the accuracy, recall, specificity, precision, and F1 score range were between 75% and 84%, and the AUC was also greater than 0.800, indicating excellent performance and the best interpretability of the results. Model 3 takes exercise time as the root node and contains 6 variables and 10 types, suggesting the impact of the comprehensive effect of these variables on robust and non-robust populations (the predicted probability range is 6.67-93.33%). CONCLUSION: The combined effect of these factors (no exercise or less than 0.5 h of exercise per day, occasional exercise, exercise at low intensity, feeling more tired at work, and eating too many staple foods (> 450 g per day) are more detrimental to maintaining robustness.

[Ligusticum cycloprolactam inhibits IL-1ß-induced apoptosis and inflammation of rat chondrocytes via HMGB1/TLR4/NF-κB signaling pathway].

Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1ß(IL-1ß) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1ß, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1ß-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.

Sublethal effects of emamectin benzoate on development, reproduction, and vitellogenin and vitellogenin receptor gene expression in Thrips hawaiiensis (Thysanoptera: Thripidae).

Thrips hawaiiensis (Morgan) (Thysanoptera: Thripidae) is a sap-sucking pest that seriously damages several crops and reduces their economic value. Exposure to low concentrations of insecticides may have a sublethal effect on surviving insects. In order to provide a reference for the rational application of emamectin benzoate, its sublethal effects on the development and reproduction of T. hawaiiensis were evaluated. Pupal development time was significantly shorter in T. hawaiiensis treated with sublethal concentrations of emamectin benzoate (LC10 and LC20) than in control. Female adult longevity and female total longevity were significantly longer following LC20 treatment than in the control and LC10 treatment groups. Nevertheless, male adult longevity and male total longevity were significantly shorter in the LC10 treatment group than in the control and LC20 treatment groups. The sublethal concentration of emamectin benzoate (LC20) significantly shortened the preadult stages and the mean generation. Meanwhile, it significantly increased the finite rate of increase, intrinsic rate of increase, and net reproductive rate. The fecundity was significantly higher after LC20 treatment than after LC10 and control treatments. Compared with the control group, the LC10 and LC20 groups of T. hawaiiensis adults showed a significantly higher expression of the vitellogenin (Vg) and vitellogenin receptor (VgR) genes, which played a key role in increasing their fecundity. These findings suggest that short-term exposure to sublethal concentrations of emamectin benzoate may lead to a resurgence and secondary outbreak of T. hawaiiensis infestation. The results have practical applications for the management of this important and noxious pest.

eIF3a R803K mutation mediates chemotherapy resistance by inducing cellular senescence in small cell lung cancer.

Drug resistance in small cell lung cancer (SCLC) significantly affects the efficacy of chemotherapy treatment. However, due to the lack of tumor tissue samples, especially serial tumor samples during chemotherapy, the mechanism of chemotherapy resistance has not been fully studied. Circulating tumor DNA, which can be obtained in a noninvasive manner, can complement tumor sampling approaches for research in this field. We identified an SCLC patient with acquired drug resistance from 52 SCLC patients for whom follow-up data were available. By comparing somatic mutations in circulating tumor DNA before and after chemotherapy, for the first time, we found that the somatic mutation eIF3A R803K may be related to acquired chemotherapy resistance. Then, the association between the eIF3A R803K mutation and chemotherapy resistance was confirmed by samples from 254 lung cancer patients receiving chemotherapy. We found that the eIF3a R803K mutation weakened the proliferation ability of tumor cells but increased their resistance to chemotherapy. Further studies revealed that the eIF3A R803K mutation promotes cellular senescence. In addition, fisetin showed a synergistic effect with chemotherapy in eIF3A R803K mutant cells. These results suggest that the eIF3A R803K somatic mutation has the potential to predict chemotherapy resistance in SCLC. Moreover, the eIF3A R803K mutation promotes chemotherapy resistance by inducing senescence. Furthermore, a senolytic drug, fisetin, can reverse chemotherapy resistance mediated by the eIF3A R803K mutation.

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer.

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

A novel model of constrictive pericarditis associated with myocardial fibrosis in rats.

An efficient animal model is fundamental for studies on the underlying mechanisms of constrictive pericarditis (CP). A novel CP rat model was established by pericardial injection composing of lipopolysaccharides (LPS) and talcum powder without thoracotomy. Pathological changes were confirmed by histological staining. E-flow Doppler of mitral valve, tissue Doppler E' in the medial mitral annular (E'sep ) and the lateral mitral annular (E'lat ) were measured to assess ventricular filling function. Circumferential, longitudinal, and radial strains (SC, SL and SR) and the respective strain rates (SrC, SrL and SrR) were analyzed in interventricular septum (IVS) and left ventricular free wall (LVFW). Rat cardiac fibroblasts (CFs) were treated with LPS. The activation of transforming growth factor ß1 (TGF-ß1) was confirmed by Q-PCR and western blot assays. Thickening of pericardium and fibrosis in pericardium and subepicardial myocardium were showed in the model group. Diastolic dysfunction in the CP group was indicated by decreased E'lat and E'lat /E'sep , increased E/E'lat , decreased EFW of SrC and SrL, increased AIVS and decreased E/A of SrC, SrL and SrR. Systolic dysfunction was indicated by decreased SCFW and SLFW in CP rats. The levels of TGF-ß1, p-Smad2/3, α-smooth muscle actin (α-SMA), and collagen-I/III (COL-I/III) were increased in the CP group. The increased TGF-ß1 that induced by LPS activated and phosphorylated Smad2/3 resulting in the secretion of α-SMA and COL-I/III. This model is of vital importance in studying the pathogenesis of CP.

A modified intrafocal pinning technique with three-dimensional planning to facilitate volar plating in dorsally comminuted AO/OTA C2 and C3 distal radius fractures.

BACKGROUNDS: Theaim of this study was to assess the efficacy of a modified intrafocal pinningtechnique with three-dimensional (3D) planning to facilitate volar plating in dorsally comminuted intra-articular distal radius fractures. METHODS: Intotal 35 AO/OTA type C2 and C3 fractures were finally included.The 3D digital model of the fracture was reconstructed based on preoperative computedtomographic (CT) images, with the displacement of the comminuted dorsalfragment and the intra-articular fragment analyzed for preoperative planning. During operation, amodified intrafocal pinning technique was applied percutaneously from thedorsal aspect of the radius to reduce the collapsed intra-articular fragmentfollowing volar plating. Adequate reduction was confirmed in all of patientsconsidering radial height, radial inclination and volar tilt in postoperativeradiographs. RESULTS: No significant fracture re-displacement wasobserved in most of the cases during a mean follow-up period of 17.4 months, exceptfor two patients withthe C3 fracture. All of the patients achieved adequate clinicalROMs at 12 months postoperatively, with a mean DASH score of 12.0. Most of the patients achievedan excellent (n = 21) or good (n = 12) Gartland and Werley wrist score. CONCLUSIONS: Ourmodified intrafocal pinning technique with 3D planning contributes to a satisfactoryclinical and radiological outcome in dorsally comminuted intra-articular distalradius fractures fixed with a volar locking plate. TRIALREGISTRATION: Notapplicable because the design of the study is retrospective.

A unique B cell epitope-based particulate vaccine shows effective suppression of hepatitis B surface antigen in mice.

OBJECTIVE: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. METHODS: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically. RESULTS: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. CONCLUSIONS: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.

What Is the Most Reliable Classification System to Assess Tibial Pilon Fractures?

The aim of this study was to assess inter- and intraobserver agreement of the traditional systems (Ruedi-Allgower, AO [Arbeitsgemeinschaft für Osteosynthesefragen], and Topliss) and the newly proposed Leonetti classification system of pilon fractures. We studied all patients at our center who underwent pilon fracture surgery over a 2-year period: 68 patients (70 legs) were included. Four observers independently classified each pilon fracture according to the Ruedi-Allgower, AO, Topliss, and Leonetti systems by evaluating radiographs and computed tomography images on 2 occasions. The inter- and intraobserver agreements were calculated using the Fleiss kappa test. Interobserver reliability was good for AO types (A, B, and C) and Ruedi-Allgower (κ = 0.71 and 0.61, respectively), whereas the interobserver reliability was moderate for AO groups (A1, A2, A3, B1, B2, B3, C1, C2, and C3), Topliss families, Topliss subfamilies, Leonetti types, and Leonetti subtypes. Intraobserver reproducibility was excellent for the Ruedi-Allgower classification, AO types, and Topliss families and good for AO groups, Topliss subfamilies, and Leonetti types and subtypes. Ruedi-Allgower and AO classification systems are the most reliable among those currently used for pilon fractures, but with lower agreement at the AO group level. The use of Topliss and Leonetti classification systems is not recommended because of less favorable results.

Validation of Single Centre Pre-Mobile Atrial Fibrillation Apps for Continuous Monitoring of Atrial Fibrillation in a Real-World Setting: Pilot Cohort Study.

BACKGROUND: Atrial fibrillation is the most common recurrent arrhythmia in clinical practice, with most clinical events occurring outside the hospital. Low detection and nonadherence to guidelines are the primary obstacles to atrial fibrillation management. Photoplethysmography is a novel technology developed for atrial fibrillation screening. However, there has been limited validation of photoplethysmography-based smart devices for the detection of atrial fibrillation and its underlying clinical factors impacting detection. OBJECTIVE: This study aimed to explore the feasibility of photoplethysmography-based smart devices for the detection of atrial fibrillation in real-world settings. METHODS: Subjects aged ≥18 years (n=361) were recruited from September 14 to October 16, 2018, for screening of atrial fibrillation with active measurement, initiated by the users, using photoplethysmography-based smart wearable devices (ie, a smart band or smart watches). Of these, 200 subjects were also automatically and periodically monitored for 14 days with a smart band. The baseline diagnosis of "suspected" atrial fibrillation was confirmed by electrocardiogram and physical examination. The sensitivity and accuracy of photoplethysmography-based smart devices for monitoring atrial fibrillation were evaluated. RESULTS: A total of 2353 active measurement signals and 23,864 periodic measurement signals were recorded. Eleven subjects were confirmed to have persistent atrial fibrillation, and 20 were confirmed to have paroxysmal atrial fibrillation. Smart devices demonstrated >91% predictive ability for atrial fibrillation. The sensitivity and specificity of devices in detecting atrial fibrillation among active recording of the 361 subjects were 100% and about 99%, respectively. For subjects with persistent atrial fibrillation, 127 (97.0%) active measurements and 2240 (99.2%) periodic measurements were identified as atrial fibrillation by the algorithm. For subjects with paroxysmal atrial fibrillation, 36 (17%) active measurements and 717 (19.8%) periodic measurements were identified as atrial fibrillation by the algorithm. All persistent atrial fibrillation cases could be detected as "atrial fibrillation episodes" by the photoplethysmography algorithm on the first monitoring day, while 14 (70%) patients with paroxysmal atrial fibrillation demonstrated "atrial fibrillation episodes" within the first 6 days. The average time to detect paroxysmal atrial fibrillation was 2 days (interquartile range: 1.25-5.75) by active measurement and 1 day (interquartile range: 1.00-2.00) by periodic measurement (P=.10). The first detection time of atrial fibrillation burden of <50% per 24 hours was 4 days by active measurement and 2 days by periodic measurementThe first detection time of atrial fibrillation burden of >50% per 24 hours was 1 day for both active and periodic measurements (active measurement: P=.02, periodic measurement: P=.03). CONCLUSIONS: Photoplethysmography-based smart devices demonstrated good atrial fibrillation predictive ability in both active and periodic measurements. However, atrial fibrillation type could impact detection, resulting in increased monitoring time. TRIAL REGISTRATION: Chinese Clinical Trial Registry of the International Clinical Trials Registry Platform of the World Health Organization ChiCTR-OOC-17014138; http://www.chictr.org.cn/showprojen.aspx?proj=24191.

Thermodynamics in the Universe Described by the Emergence of Space and the Energy Balance Relation.

It has previously been shown that it is more common to describe the evolution of the universe based on the emergence of space and the energy balance relation. Here we investigate the thermodynamic properties of the universe described by such a model. We show that the first law of thermodynamics and the generalized second law of thermodynamics (GSLT) are both satisfied and the weak energy condition are also fulfilled for two typical examples. Finally, we examine the physical consistency for the present model. The results show that there exists a good thermodynamic description for such a universe.

Coating the plate with antibiotic cement to treat early infection after fracture fixation with retention of the implants: a technical note.

BACKGROUND: Local antibiotic therapy has gained increasing attraction in the prevention and treatment of fracture infection. However, no reports have used local antibiotic therapy in the management of early infection after fracture fixation with retention of implants. METHODS: The present surgical technique report the use of antibiotic impregnated bone cement in the management of early infection after fracture fixation. Initially, the fractures were fixed with plates. The average time from initial procedure to debridement was15 days (range 9 to 25 days). The infections were treated with irrigation, debridement, and retention of the implant. The lateral surface of the plates was coated with antibiotic cement and the bone defect was filled with antibiotic cement spacer after thorough debridement. RESULTS: Ten patients underwent this technique. The mean follow-up was 2.0 years (range 6 months to 4 years). The bone union rate was 100%, and the average time to bone healing was5.5 months.There was recurrence of infection in one patient before bone healing, but the implants were left in place until bone healed, and the infection was eradicated after implant removal. CONCLUSION: Coating the plate with antibiotic cement is a simple technique which may play a role in the management of early infection after fracture fixation.

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer.

Platinum-based chemotherapy is the standard first-line treatment for most lung cancer patients. However, the toxicity induced by platinum-based chemotherapy greatly impedes its clinical use. Previous studies showed that long non-coding RNAs (lncRNAs) with over 200 nucleotides in length affect drug response and toxicity. In the present study, we investigated the association of well-characterized lung cancer lncRNA polymorphisms with platinum-based chemotherapy toxicity in Chinese patients with lung cancer. A total of 467 lung cancer patients treated with platinum-based chemotherapy for at least two cycles were recruited. We primarily focused on gastrointestinal and hematological toxicities. A total of 14 potentially functional polymorphisms within 8 lncRNAs (HOTTIP, HOTAIT, H19, ANRIL, CCAT2, MALAT1, MEG3, and POLR2E) were genotyped. Unconditional logistical regression analysis was conducted to assess the associations. Gene-gene and gene-environment interactions were identified using the software generalized multifactor dimensionality reduction (GMDR). ANRIL rs1333049 was associated with severe overall toxicity in an additive model (adjusted OR=0.723, 95% CI=0.541-0.965, P=0.028). ANRIL rs1333049 was also associated with severe gastrointestinal toxicity in both the additive (adjusted OR=0.690, 95% CI=0.489-0.974, P=0.035) and dominant (adjusted OR=0.558, 95% CI=0.335-0.931, P=0.025) models. MEG3 rs116907618 was associated with severe gastrointestinal toxicity in an additive model (adjusted OR=1.717, 95% CI=1.007-2.927, P=0.047). GMDR identified the three-factor interaction model of POLR2E rs3787016-HOTTIP rs3807598-chemotherapy regimen as the best predictive model for hematological toxicity. In conclusion, ANRIL and MEG3 genetic polymorphisms are associated with severe platinum toxicity and could be considered as biomarkers for pretreatment evaluation in Chinese patients with lung cancer.

Outcomes of cement beads and cement spacers in the treatment of bone defects associated with post-traumatic osteomyelitis.

BACKGROUND: Cement spacers (Masquelet technique) have traditionally been used for the treatment of segmental bone defects. However, no reports have used cement spacers for the treatment of small/partial segmental bone defects associated with osteomyelitis and compared the outcomes with cement beads. METHODS: We retrospectively analysed 40 patients with post-traumatic osteomyelitis of the tibia who underwent treatment, which was performed in two stages. In the first stage, thorough debridement was performed, and bone defects were filled with either antibiotic-impregnated cement beads (bead group, 18 patients) or spacers (spacer group, 22 patients). In the second stage, the cement beads or spacers were removed (for the spacer group, the induced membrane formed by the spacer was preserved) and the bone defects were filled with cancellous autografts. RESULTS: All patients in the bead group had small/partial segmental bone defects after debridement, while 3 patients in the spacer group had large/segmental bone defects. The mean volume of bone defects of the spacer group (40.4 cm3) was significantly larger than that of the bead group (32.4 cm3). The infection control rate (88.9%,16/18 vs 90.9%, 20/22), bone healing time (8.5 months vs 7.5 months) and complication rates (22.2%, 4/18 vs 27.2%, 6/22) were comparable between bead group and spacer group. CONCLUSION: The results of this study suggest that cement spacers may have an infection control rate comparable to cement beads in the treatment of bone defects associated with post-traumatic osteomyelitis. Furthermore, cement spacers could be used for the reconstruction of small/partial segmental bone defects as well as for large/segmental bone defects, whereas cement beads were not suitable for the reconstruction of large/segmental bone defects.

Comparison of the direct and indirect reduction techniques during the surgical management of posterior malleolar fractures.

BACKGROUND: The optimal method for the reduction and fixation of posterior malleolar fracture (PMF) remains inconclusive. Currently, both of the indirect and direct reduction techniques are widely used. We aimed to compare the reduction quality and clinical outcome of posterior malleolar fracture managed with the direct reduction technique through posterolateral approach or the indirect reduction technique using ligamentotaxis. METHODS: Patients with a PMF involving over 25% of the articular surface were recruited and assigned to the direct reduction (DR) group or the indirect reduction (IR) group. Following reduction and fixation of the fracture, the quality of fracture reduction was evaluated in post-operative CT images. Clinical and radiological follow-ups were performed at 6 weeks, 3 months, 6 months, 12 months, and then at 6 month-intervals postoperatively. Functional outcome (AOFAS score), ankle range of motion, and Visual Analog Scale (VAS) were evaluated at the last follow-up. Statistical differences were compared between the DR and IR groups considering the patient demographics, quality of fracture reduction, AOFAS score, and VAS. RESULTS: Totally 116 patients were included, wherein 64 cases were assigned to the DR group and 52 cases were assigned to the IR group. The quality of fracture reduction was significant higher in the DR group (P = 0.038). In the patients who completed a minimum of 12 months' follow-up, a median AOFAS score of 87 was recorded in the DR group, which was significantly higher than that recorded in the IR group (a median score of 80). The ankle range of motion was slightly better in the DR group, with the mean dorsiflexion restriction recorded to be 5.2° and 6.1° in the DR and IR group respectively (P = 0.331). Similar VAS score was observed in the two groups (P = 0.419). CONCLUSIONS: The direct reduction technique through a posterolateral approach provide better quality of fracture reduction and functional outcome in the management of PMF over 25% of articular surface, as compared with the indirect reduction technique using ligamentotaxis. TRIAL REGISTRATION: NCT02801474 (retrospectively registered, June 2016, ClinicalTrails.gov).

Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen.

OBJECTIVE: This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models. METHODS: Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated. RESULTS: Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcγ receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance. CONCLUSIONS: These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection.

Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress.

BACKGROUND: Aberrant expression of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress. METHODS: Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress. RESULTS: NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking. CONCLUSIONS: These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress.

Antibiotic-impregnated cement spacer as definitive management for osteomyelitis.

BACKGROUND: Osteomyelitis is a challenge for orthopaedic surgeons. There is a lack of scientific evidence to guide treatment. The purpose of this study was to report the clinical outcome of unplanned retention of antibiotic-impregnated cement spacer (ACS) in the management of osteomyelitis. METHODS: Eight patients (7 with tibial infections and 1 with a calcaneal infection) with osteomyelitis received radical debridement and insertion of an ACS into the bone defect as the definitive management. The mean follow-up period was 2 years (6 months to 4 years). All of these patients had a cement spacer in place. RESULTS: No patient exhibited radiographic evidence of excessive bone loss. The patients reported no or occasional mild pain and exhibited complete weight-bearing abilities, with the exception of one patient who required a crutch because of a spinal cord injury. Signs of recurrence of the osteomyelitis were not noted in any of the patients, and no fractures occurred at last follow-up. CONCLUSION: Our study suggests that a proportion of patients with unplanned retention of ACS appear to function well without necessarily requiring further surgical intervention.

Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus.

This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.