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Background: As one of the most famous natural products, salvianolic acid A (SAA) is undergoing clinical trials for the treatments of angina pectoris and coronary heart disorders. However, the in vivo metabolites of SAA have only been tentatively identified, leading to a barrier for precise therapeutical drug monitoring. Methods: Ultra-high performance liquid chromatography coupled with quadrupole time of flight tandem mass spectrometry (UPLC–Qtof-MS/MS) was firstly employed to acquire high-resolution MS1 and MS2 spectra for all metabolites. Through paying special attention onto the features of ester bond dissociation, metabolism sites were restricted at certain regions. To further determine the metabolism site, such as the monomethylated products (M23, M25, and M26), post collision-induced dissociation energy-resolved mass spectrometry (post-CID ER-MS) was proposed through programming progressive exciting energies to the second collision chamber of hybrid triple quadrupole-linear ion trap mass spectrometry (Qtrap-MS) device. Results: After SAA oral administration, 29 metabolites (M1–M29), including five, thirteen, and sixteen ones in rat plasma, urine, and feces, respectively, were detected in rats. The metabolism route was initially determined by applying well-defined mass fragmentation pathways to those HR-m/z values of precursor and fragment ions. Metabolism site was limited to SAF- or DSS-unit based on the fragmentation patterns of ester functional group. Through matching the dissociation trajectories of concerned 1st-generation fragment ions with expected decomposition product anions using post-CID ER-MS strategy, M23 and M25 were unequivocally assigned as 3'-methyl-SAA and 3''-methyl-SAA, and M26 was identified as 2-methyl-SAA or 3-methyl-SAA. Hydrolysis, methylation, glucuronidation, sulfation, and oxidation were the primary metabolism channels being responsible for the metabolites' generation. Conclusion: Together, the metabolism regions and sites of SAA metabolites were sequentially identified based on the ester bond dissociation features and post-CID ER-MS strategy. Importantly, the present study provided a promising way to elevate the structural identification confidence of natural products and metabolites. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKRS) in patients with multiple intracranial meningiomas (MIMs). The authors performed a retrospective analysis of 42 consecutive patients (7 men and 35 women) with MIMs who underwent GKRS. The median age of the patients at the time of GKRS was 57.5 years (range, 27–77 years). A total of 115 tumors among 42 patients were identified through imaging or postoperative histopathologic examination, of which 90 were treated with GKRS. Follow-up imaging studies were available for 75 tumors in 36 patients (83.3%), with a mean follow-up period of 45.0 months (range, 6.6–90.4 months); 41 patients (97.6%) received clinical follow-up for 16.7 to 106.7 months (average, 57.1 months). Local tumor control was achieved in 68 tumors (90.7%) at the last follow-up. On univariate analysis, surgical resection before GKRS more than once (P = 0.048) and high World Health Organization (WHO) classification (grades II and III) (P = 0.001) were associated with tumor progression. Patients with worsening clinical manifestation showed correlation with peritumor edema (P < 0.001) and had >2 lesions treated by GKRS (P < 0.001) on univariate analysis. GKRS is a safe and effective treatment for MIMs. Variables including surgical resection before GKRS more than once, high grade WHO classification, peritumor edema, and >2 tumors treated by GKRS are predictors of unfavorable outcome after GKRS. [ABSTRACT FROM AUTHOR]

Summary: MicroRNAs are small noncoding RNAs that are central factors between hepatitis C virus (HCV) and host cellular factors for viral replication and liver disease progression, including liver fibrosis, cirrhosis and hepatocellular carcinoma. In the present study, we found that overexpressing miR‐let‐7c markedly reduced HCV replication because it induced haem oxygenase‐1 (HO‐1) expression by targeting HO‐1 transcriptional repressor Bach1, ultimately leading to stimulating an antiviral interferon response and blockade of HCV viral protease activity. In contrast, the antiviral actions of miR‐let‐7c were attenuated by miR‐let‐7c inhibitor treatment, exogenously expressing Bach1 or suppressing HO‐1 activity and expression. A proposed model indicates a key role for miR‐let‐7c targeting Bach1 to transactivate HO‐1–mediated antiviral actions against HCV. miR‐let‐7c may serve as an attractive target for antiviral development. [ABSTRACT FROM AUTHOR]

Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cytotoxic lymphocyte antigen 4 (CTLA4) therapy. Materials and methods: Datasets of gene expression omnibus (GEO), the cancer genome atlas (TCGA), and gene set enrichment analysis (GESA) were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs. CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4, CD3, and granzyme A (GZMA) were validated on 30 cases of Chinese GC. Microsatellite instability (MSI) marker MLH1 and Epstein-Barr virus (EBV) marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization. Results: CTLA4 was upregulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change = 1.586, p <.001) and GSE63089 (fold change = 1.365, p <.001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to expression levels of GZMA (R = 0.701, p <.001) and CD3 (R = 0.750, p <.001). Conclusions: Based on bioinformatics analysis, GSGC should be worth noticed as a potential GC subtypes responsive to anti-CTLA4 treatment. [ABSTRACT FROM AUTHOR]

The staged anaerobic fluidized membrane bioreactor (SAFMBR) is effective to remove organic substances with reduced sludge production by minimizing excess waste sludge. This study investigated the removals of four pharmaceuticals present at trace levels in municipal wastewater by using a SAFMBR. The target pharmaceuticals included ibuprofen, naproxen, carbamazepine, and diclofenac. A pilot-scale SAFMBR with hydraulic retention times (HRTs) from 4.5 to 13.5 hr was established and operated for 450 days with a municipal wastewater spiked with four pharmaceuticals. In the results, the BOD and COD removals were effective and limitedly affected the presence of pharmaceuticals. The BOD removal efficiencies in the anaerobic fluidized membrane bioreactor (AFBR) and anaerobic fluidized membrane bioreactor (AFMBR) were 63.5 ± 28.6% and 81.6 ± 25.1%, respectively. However, the treatment efficiencies of four pharmaceuticals varied. Naproxen that contains electron donating group was treated efficiently (63.8%∼72.1%), whereas the removal efficiencies of ibuprofen (25.0%∼32.4%), carbamazepine (16.6–18.5%), and diclofenac (non-detected) remained low. Ibuprofen was less efficient to compete with other electron acceptors in an anaerobic environment. For pharmaceuticals such as carbamazepine with a high acid dissociation constant (pKa = 13.9) or diclofenac with a high octanol-water partition coefficient (log K OW = 4.51), sorption onto the sludge could be one critical process affecting their concentrations in the water phase. By being positively charged at neutral pH and/or hydrophobic, the pharmaceuticals were initially adsorbed onto sludge, followed by being desorbed when sludge decayed after long operating hours. Nitrogen balance was analyzed to indicate the decay of the bacteria in the AFMBR. Increasing the HRTs only slightly improved the treatment efficiencies (e.g., the naproxen removal was increased from 63.8% to 72.1% when the HRT was increased from 4.5 to 7.5 h). The different processes responsible for the removals of these pharmaceuticals were more critical and their effects were limitedly changed by HRT adjustment, indicating the importance of knowing the properties of a pharmaceutical for selection of a proper treatment approach. Image 1 • Removal of pharmaceuticals in a low-strength wastewater by a SAFMBR was tested. • Naproxen was biologically removed. • Ibuprofen was less efficient as an electron acceptor in biochemical reactions. • Sorption was important for removal of pharmaceuticals with higher p Ka or K OW. • Desorption and re-dissolution of pharmaceuticals occurred when sludge decayed. [ABSTRACT FROM AUTHOR]

Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms responsible for this phenomenon remain elusive, but evidence suggests that ubiquitin-specific peptidases (USPs) may be key regulators in cancer chemo-resistance. The present study aimed to investigate the role of USP9X in gemcitabine resistance using in vitro pancreatic cell lines and a mouse xenograft model. We found that the expression of USP9X in pancreatic cancer cells was positively correlated with gemcitabine resistance, and that inhibition of USP9X by WP1130 sensitized pancreatic cancer cells to gemcitabine. Gemcitabine induced autophagy, and blocking autophagy with chloroquine improved sensitivity to gemcitabine. We also found that WP1130 inhibited gemcitabine-induced autophagy, and blocking autophagy abolished the sensitization effect of WP1130 on gemcitabine in pancreatic cancer cells. Finally, combined gemcitabine and WP1130 treatment enhanced the anti-tumor effect of gemcitabine by suppressing autophagy in vivo. Taken together, these results demonstrate that inhibition of USP9X sensitized pancreatic cancer cells to gemcitabine by inhibiting autophagy, which provides a novel insight into gemcitabine resistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objective To compare the perioperative outcomes and hemodynamic effects at induction of general laryngeal mask airway (LMA) anesthesia with lumbar plexus-sciatic nerve block (LPSB) and general anesthesia with endotracheal intubation (ET) in elderly patients undergoing hip surgery. Methods A total of 63 patients having open reduction internal fixation of an intertrochanteric fracture were randomly assigned to receive LMA anesthesia with LPSB or general anesthesia with ET. Perioperative and postoperative outcomes were compared between the 2 groups. Results Compared with the LMA/block group, there were significant reductions in systolic blood pressure, diastolic blood pressure, and mean arterial pressure at induction in the general endotracheal group (all, P < 0.001). In the general ET group, 84% of the patients experienced at least one episode of significant hypotension, whereas no patient in the LMA/block group had significant hypotension (P < 0.001). There were no changes in cardiac output, cardiac index, stroke volume, and stroke volume index of the LMA/block group, whereas significant changes were noted in the general anesthesia ET group. Significantly fewer complications were noted in the LMA/block group, and LMA block was associated with shorter weaning time, fewer returns to the intensive care unit, and less postoperative pain. Conclusions General LMA anesthesia with LPSB provides better outcomes that general ET anesthesia in elderly patients undergoing hip surgery. [ABSTRACT FROM AUTHOR]

The present study assessed the association between the variants of macrophage scavenger receptor (MSR)1 and chronic obstructive pulmonary disease (COPD), with or without lung cancer in China. COPD and lung cancer were previously regarded as two separate diseases. However, it has since been reported that there are close associations between COPD and lung cancer. Lung cancer may be an outcome of COPD. COPD may also coexist with lung cancer, and patients with COPD with lung cancer tend to have increased mortality. It is important to have a better understanding of the pathogenesis of COPD and the reason why it develops into lung cancer. MSR1 serves a crucial function in phagocytosis, which may be associated with the pathogenesis of COPD and lung cancer in patients with COPD. From 1 July 2015 to 20 February 2016, 100 patients with COPD and lung cancer, 100 patients with COPD without lung cancer and 100 healthy smokers were enrolled at the Shanghai Ruijin Hospital (Shanghai, China) for the genotyping of eight single-nucleotide polymorphisms (SNPs; ex3P36A_C>G, ex3S41Y_C>A, ex4V113A_T>C, ex4P174Y_ G>T, ex6P275A_C>G, ex6R293x_C>T, ex10G369S_G>A and ex11H441R_A>G) via gene sequencing. The genotype frequencies of these SNPs did not significantly differ between patients with COPD with and without lung cancer, and the healthy controls. However, during DNA sequencing, the SNP rs13306550 (IVS4+3A>G) was identified in the splice donor site and was significantly associated with an increased risk of COPD compared with the healthy smokers (P=0.0053). The present study demonstrated that the variant rs13306550 was a risk factor for COPD susceptibility, but that did not influence lung cancer pathogenesis in patients with COPD. However, the mechanisms underlying the influence of rs13306550 on COPD development and progression remain to be elucidated and require further study. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have shown that aquaporin 1 (AQP1) is up-regulated in synovium and cartilage of rheumatoid arthritis (RA) patients and that AQP1 may be involved in joint swelling and synovial inflammation. This study was aimed to investigate the potential therapeutic effect of acetazolamide (AZ, an AQP1 inhibitor) on rat adjuvant-induced arthritis (AIA) and explore its related mechanisms. Materials and methods: Rat AIA was induced by complete Freund’s adjuvant. The effect of AZ on rat AIA was evaluated by secondary hind paw swelling, arthritis index, TNF-α and IL-1β serum levels and histological examination of ankle joint. Proteoglycans expression and mRNA levels of type-II collagen (COII) and aggrecan in cartilage were measured by alcian blue staining and real-time PCR, respectively. The protein levels of AQP1, IκBα, phospho-IκBα (p-IκBα), NF-κB p65 and phospho-NF-κB p65 (p-NF-κB p65) in synovial tissues were detected by western blot. Results: AZ treatment could inhibit secondary hind paw swelling and arthritis index, reduce serum levels of TNF-α and IL-1β, and ameliorate pathological changes of ankle joint in AIA rats. AZ increased proteoglycans production and mRNA levels of COII and aggrecan in cartilage tissues. Moreover, AZ decreased AQP1 protein level and suppressed the activation of NF-κB pathway in synovium, indicated by inhibiting the degradation and phosphorylation of IκBα and reducing p-NF-κB p65 protein level. Conclusions: AZ as an AQP1 inhibitor has a powerful therapeutic effect on rat AIA via inhibiting NF-κB activation, suggesting AQP1 inhibition might be of potential clinical interest in RA treatment. [ABSTRACT FROM AUTHOR]

Malignant proliferation and metastasis in non-small cell lung carcinoma (NSCLC) are great challenges for effective clinical treatment through conventional chemotherapy. The combinational therapy strategy of RNA interfering (RNAi) technology and chemotherapeutic agents have been reported to be promising for effective cancer therapy. In this study, based on multifunctional nanoparticles (NPs), the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA for the effective treatment of orthotopic lung tumor was achieved. The NPs exhibited pH/redox dual sensitivity verified by particle size changes, morphological changes, and in vitro release of drugs. Confocal microscopy analysis confirmed that the NPs exhibited endosomal escape property and on-demand intracellular drug release behavior, which can protect siRNA from degradation and facilitate the chemotherapeutic effect respectively. In vitro tumor cell motility study demonstrated that EZH2 siRNA loaded in NPs can decrease the migration and invasion capabilities of tumor cells by downregulating the expression of EZH2 mRNA and protein. In particular, an antiproliferation study revealed that the co-delivery of siRNA and ETP in the multifunctional NPs can induce a synergistic therapeutic effect on NSCLC. In vivo targeting evaluation showed that cRGDyC-PEG modification on NPs exhibited a low distribution in normal organs and an obvious accumulation in orthotopic lung tumor. Furthermore, targeted NPs co-delivering siRNA and ETP showed superior inhibition on tumor growth and metastasis and produced minimal systemic toxicity. These findings indicated that multifunctional NPs can be utilized as a co-delivery system, and that the combination of EZH2 siRNA and ETP can effectively treat NSCLC. [ABSTRACT FROM AUTHOR]

As a key insulin target tissue for maintaining systemic glucose homeostasis, the liver plays important roles in improving obesity-associated insulin intolerance via selective cannabinoid CB 1 receptor antagonism/inverse agonism. However, it is unclear whether this receptor inverse agonism affects hepatic glucose metabolism. MJ08 is a novel cannabinoid CB 1 receptor antagonist/inverse agonist that has superior inverse agonism over the well-known antagonist/inverse agonist, SR141716 (rimonabant). MJ08 remarkably elevates fasting blood glucose independent of inhibition of insulin release in mice. In the current study, MJ08 was used to investigate the mechanism by which liver cannabinoid CB 1 receptor inverse activation regulates hepatic glucose metabolism. MJ08 stimulated hepatic glucose production (HGP) in a dose-dependent manner and promoted gluconeogenic gene expression in perfused rat liver. SR141716 exhibited similar but weaker effects. The cannabinoid CB 1 receptor agonist (WIN 55,212-2), Gs protein-cyclic AMP (cAMP)-dependent pathway inhibitors (NF449 and H89), β-adrenoceptor antagonist (propranolol), and peripheral sympathetic inhibitor (reserpine) could antagonize MJ08-induced HGP. Furthermore, MJ08 and SR141716 induced monoamine neurotransmitter (noradrenaline) release and increased cAMP content significantly in perfused liver, although only a slight increase was observed in primary cultured hepatocytes. These results indicate that local liver cannabinoid CB 1 receptor inverse agonism via hepatic sympathetic innervation is responsible for the HGP induced by MJ08. Thus, high inverse agonistic activity could increase fasting blood glucose levels and should be avoided in the development of peripheral cannabinoid CB 1 receptor-targeted weight-loss drugs. [ABSTRACT FROM AUTHOR]

Sepsis is characterized by an innate immune response and the following immune dysfunction which can increase the emergence of secondary infections. Ethyl pyruvate (EP) has multiple immunoregulation functions in several serious illnesses, such as burn injury, severe sepsis and acute respiratory syndrome. However, little data was shown the effect of EP administration on immunosuppression post-CLP and the following secondary infection. The cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa (PA) was used as a clinically relevant two-hit model of sepsis. We assessed the survival rate, lung damage and lung bacterial clearance in vehicle or EP treatment group to demonstrate the lung response to Pseudomonas aeruginosa of septic mice. Then cytokines including lung IL-6, IL-1β, IL-10 and plasma HMGB1, apoptosis of splenic immune cells and Foxp3 level on regulatory T cells (Tregs) were studied to demonstrate the mechanisms of EP administration on two-hit mice. We found that the susceptibility of septic mice to Secondary Pseudomonas aeruginosa pneumonia could be down-regulated by ethyl pyruvate treatment and the protective effects of EP may via decreasing lung IL-10 and plasma HMGB1 expression, inhibiting the function of Tregs and relieving the apoptosis of splenic immune cells. The “immune paralysis” post-sepsis still remains a rigorous challenge for curing sepsis, our study may aid in the development of new therapeutic strategies to this problem. [ABSTRACT FROM AUTHOR]

MicroRNA-98 (miR-98) is downregulated in many tumors, and is closely related to tumor progression. In addition, it shows anticarcinogenic functions in various tumor. However, few study show that the biological function and regulatory mechanisms of miR-98 in nasopharyngeal carcinoma (NPC) progression. The identification and its target genes which regulate by dysregulated miRNAs may strengthen our understanding of the molecular mechanisms of NPC. In this study, we observe that miR-98 is not only significantly reduced in NPC tissues, but also decreased markedly in NPC cell lines. Moreover, silencing miR-98 expression studies not only show miR-98 induced cell proliferation, migration and invasion in vitro, but also it promoted xenograft tumor growth in vivo in NPC. Furthermore, western blot assay was used to detected the level of STAT3 protein and we demonstrate that miR-98 regulate cells poliferation, migration and invasion through directly modulating functional target STAT3 by directly binding its 3′-UTR. These findings illustrate miR-98 as a anticarcinogenic functions through targeting STAT3, the miR-98/STAT3 pathway gives new clues for understanding NPC carcinogenesis and provides novel therapeutic targetsfor NPC. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress contribute to emphysema in COPD. Although corticosteroids are the standard of care for COPD, they do not reduce oxidative stress, and a subset of patients is steroid-resistant. Vitamin E isoform γ-tocotrienol possesses both anti-inflammatory and anti-oxidative properties that may protect against emphysema. We aimed to establish the therapeutic potential of γ-tocotrienol in cigarette smoke-induced COPD models in comparison with prednisolone. BALB/c mice were exposed to cigarette smoke for 2 weeks or 2 months. γ-Tocotrienol and prednisolone were given orally. Bronchoalveolar lavage (BAL) fluid and lung tissues were assessed for inflammation, oxidative damage, and regulation of transcription factor activities. Emphysema and lung function were also evaluated. γ-Tocotrienol dose-dependently reduced cigarette smoke-induced BAL fluid neutrophil counts and levels of cytokines, chemokines and oxidative damage biomarkers, and pulmonary pro-inflammatory and pro-oxidant gene expression, but restored lung endogenous antioxidant activities. γ-Tocotrienol acted by inhibiting nuclear translocation of STAT3 and NF-κB, and up-regulating Nrf2 activation in the lungs. In mice exposed to 2-month cigarette smoke, γ-tocotrienol ameliorated bronchial epithelium thickening and destruction of alveolar sacs in lungs, and improved lung functions. In comparison with prednisolone, γ-tocotrienol demonstrated better anti-oxidative efficacy, and protection against emphysema and lung function in COPD. We revealed for the first time the anti-inflammatory and antioxidant efficacies of γ-tocotrienol in cigarette smoke-induced COPD models. In addition, γ-tocotrienol was able to attenuate emphysematous lesions and improve lung function in COPD. γ-Tocotrienol may have therapeutic potential for the treatment of COPD. [ABSTRACT FROM AUTHOR]

Objective: This study aims to introduce a self-designed clavicle reductor and to test the effectivity of a alternative minimally invasive plate osteosynthesis technique (MIPO) for displaced midshaft clavicular fractures (DMCFs) with the application of our self-designed clavicle reductor.Method: From October 2012 to February 2013, 27 male patients who suffered with unilateral displaced midshaft clavicular fracture (DMCFs) were included into our study. Patients were treated by minimally invasive plate osteosynthesis (MIPO) technique with the application of our self-designed clavicle reductor and followed up regularly. Constant-Murley score was employed to test the functional outcomes at one year's follow up.Result: The average follow-up time for the 27 patients was 15.8 months (range, 13-18 months). The average age of all patients was 32.6 (range, 21 to 48). According to OTC system, 12 cases were simple fractures (15-B1), ten cases were wedge fractures (15-B2) and five cases were comminuted fractures (15-B3). With the application of the clavicle reductor, minimally invasive plate osteosynthesis technique can be performed without any barrier in all of the 27 cases. Operative duration was 48.1 minutes (range, 35-65 minutes) and average fluoroscopy time was 12.8 seconds (range, from 7 to 22 seconds). All of the 27 cases healed from four to six months post-operatively. The average Constant-Murley-score of the 27 patients was 92.7 ± 5.88 (range, 80 to 100). No complications were noted.Conclusion: The self-designed clavicle reductor can effectively pave the way for the application of MIPO technique in the treatment of DMCFs. MIPO technique with locking reconstruction plate is a feasible and worthwhile alternative for displaced midshaft clavicular fractures (DMCFs). [ABSTRACT FROM AUTHOR]

Objective and design: Chronic low-grade inflammation occurs in diabetic retinopathy (DR), but the underlying mechanism(s) remains (remain) unclear. NLRP3 inflammasome activation is involved in several other inflammatory diseases. Thus, we investigated the role of the NLRP3 inflammasome signaling pathway in the pathogenesis of DR. Methods: Diabetes was induced in rats by streptozotocin treatment for 8 weeks. They were treated with NLRP3 shRNA or minocycline during the last 4 weeks. High glucose-exposed human retinal microvascular endothelial cells (HRMECs) were co-incubated with antioxidants or subjected to TXNIP or NLRP3 shRNA interference. Results: In high glucose-exposed HRMECs and retinas of diabetic rats, mRNA and protein expression of NLRP3, ASC, and proinflammatory cytokines were induced significantly by hyperglycemia. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were also observed with increased cell apoptosis and retinal vascular permeability, compared with the control group. NLRP3 silencing blocked these effects in the rat model and HRMECs, confirming that inflammasome activation contributed to inflammation in DR. TXNIP expression was increased by reactive oxygen species (ROS) overproduction in animal and cell models, whereas antioxidant addition or TXNIP silencing blocked IL-1β and IL-18 secretion in high glucose-exposed HRMECs, indicating that the ROS-TXNIP pathway mediates NLRP3 inflammasome activation. Minocycline significantly downregulated ROS generation and reduced TXNIP expression, subsequently inhibited NLRP3 activation, and further decreased inflammatory factors, which were associated with a decrease in retinal vascular permeability and cell apoptosis. Conclusions: Together, our data suggest that the TXNIP/NLRP3 pathway is a potential therapeutic target for the treatment of DR, and the use of minocycline specifically for such therapy may be a new avenue of investigation in inflammatory disease. [ABSTRACT FROM AUTHOR]

Background Autophagy maintains cellular homeostasis through engulfing cytoplasmic proteins and organelles, and plays an important role in cancer initiation and progression. Ginsenoside 20(S)-Rg3, an active ingredient of Panax ginseng, exerts anti-cancer functions in various cancers. However, its molecular mechanisms, including its effect on autophagy, are not fully elucidated in tumor models. Methods Ovarian cancer cell line SKOV3 was treated by various concentrations of 20(S)-Rg3. Markers of autophagy were detected by real-time PCR, western blot, immunofluorescence and immunohistochemistry. Cell viability was observed by CCK8 assays and cell migration and invasion were examined with Transwell. Results 20(S)-Rg3 induced autophagy in SKOV3 ovarian cancer cells in a dose-dependent manner as indicated by the upregulation of autophagy-associated molecules including LC3 II, ATG5 and ATG7. The autophagy inhibitor chloroquine antagonized the inhibition of 20(S)-Rg3 on migration and invasion of SKOV3 cells, but slightly enhanced the impairment of 20(S)-Rg3 on cell viability. Immunohistochemistry staining of LC3, ATG5 and ATG7 on subcutaneous xenograft tissue sections from previously established nude mice models showed that 20(S)-Rg3 upregulated LC3, ATG5 and ATG7 as observed in cell models. Conclusion Autophagy induction was one mechanism mediating inhibition of 20(S)-Rg3 on ovarian cancer invasive progression. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigue and muscle weakness. Ginseng is used in the treatment of MG. Ginsenoside Rb1 (G-Rb1), the most abundant ginsenoside in ginseng root, has been proved to be immune regulatory in various diseases. In this study, we investigated the effects and mechanisms of G-Rb1 in treatment for MG in a rat model. Our data showed that G-Rb1 treatment markedly ameliorated the symptoms of experimental autoimmune myasthenia gravis (EAMG) rats, decreased the percentage of Th17 cells in mononuclear cells (MNCs), and increased the number of Treg and Th2 cells in MNCs. We also found that G-Rb1 treatment decreased the serum level of anti-R97–116 peptides IgG1 and IgG2a antibodies. Our findings provide strong evidence that G-Rb1 treatment has immune regulatory effects in EAMG rats, which indicate that G-Rb1 may be employed as a therapeutic medication for MG. [ABSTRACT FROM AUTHOR]

Purpose. To determine the prevalence, causes, and associations of visual impairment (VI) among participants aged 60 years or older in a rural community in China. Methods. A community-based survey was undertaken in a rural town located in Eastern China and 4579 people aged 60 years or older participated in the study. Presenting visual acuity was assessed using a Snellen chart with tumbling-E optotypes and anterior segment was examined using a slit-lamp. VI was defined as presenting VA <6/18 and it included moderate VI (<6/18 to 6/60) and blindness (<6/60). Results. The prevalence of VI was 5.4% (95% confidence interval [CI] 4.7–6.0). In multivariate analysis, the presence of VI was positively associated with increasing age (odds ratio [OR] = 1.12, 95% CI 1.10–1.16, per year increase), female gender (OR = 2.33, 95% CI 1.53–3.55), the presence of hypertension (OR = 1.31, 95% CI 1.001–1.85), living alone (OR = 1.52, 95% CI 1.08–2.62), and increased sleeping hours (OR = 1.10, 95% CI 1.001–1.22). Drinking 3 or more glasses of green tea per day was inversely associated with VI (OR = 0.79, 95% CI 0.63–0.98). Conclusion. VI was less prevalent in this community compared with previous report in other areas in China. [ABSTRACT FROM AUTHOR]

Human glycoprotein 130 (gp130) is a signal-transducing receptor for interleukin 6 (IL-6), whose signaling plays a critical role in chronic inflammation and cancer. The soluble form of gp130 specifically inhibits IL-6 trans-signaling. However, achieving high-level expression of a large glycoprotein such as gp130 is difficult. Here, we designed and constructed one Fc-gp130-pcDNA mammalian expression vector, with the mouse IgG2a Fc fragment added to the N-terminus of human gp130, which greatly increased the secretion of recombinant gp130 protein from Expi293F suspension cells. Recombinant fusion Fc-gp130 was easily and efficiently purified from the supernatant of transfected cells by one-step affinity chromatography. Moreover, Fc-gp130 could automatically form dimers by the disulfide bond. Fc-gp130 was confirmed as a more efficient IL-6 trans-signaling blocker by its higher biological activity against signal transducer and activator of transcription 3 (STAT3). This purified active Fc-gp130 could be used to develop valuable therapeutic agents against inflammatory diseases and cancers. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to assess the outcomes of displaced femoral shaft fractures (DFSFs) treated by antegrade nailing with the assistance of a newly invented intramedullary (IM) reduction device.Methods: From December 2012 to August 2013, 43 adult patients with unilateral DFSFs, including 31 males and 12 females, were enrolled into this study. During the operation, the device was used to adjust the direction of guide wire to insert it into the medullary cavity of distal femur and used as a "joystick" to align the femoral shaft fractures before the insertion of IM nail. The operative time and fluoroscopy time were recorded. Follow-up was conducted to assess the fracture union and functional recovery of the affected limbs.Results: The IM reduction device was used intra-operatively to advance the guide wire into the distal femoral medullary cavity successfully in all 43 cases, with a single attempt in 37 cases and two or three attempts in six cases. The average operative time and fluoroscopy time were 58.3 minutes (40-85 minutes) and 9.2 seconds (4.1-21.8 seconds), respectively. All fractures healed well on an average of 5.4 months post-operatively. No limb-length discrepancy or observable malalignment was noted at the follow ups.Conclusions: The IM reduction device can facilitate the insertion of a guide wire into the distal femoral medullary cavity in a closed and controllable manner, be used as a "joystick" to align the femoral shaft fracture, and subsequently facilitate IM nail insertion in the proper position. [ABSTRACT FROM AUTHOR]

Background: Urothelial cancer associated 1 (UCA1) is a long noncoding RNA (lncRNA) which has gained more attention in recent years due to its aberrant expression in embryogenesis and a broad range of cancer tissues and cells. Importantly, multiple studies have shown that UCA1 plays oncogenic roles in tumor growth and metastasis, and it may act as a potential biomarker and therapeutic target for human cancers. However, the molecular mechanism of UCA1 in cancer initiation, progression and metastasis remains incompletely understood. Thus, gaining a better understanding of the functional mechanism of UCA1 in cancer onset and progression is of the utmost significance for evaluating the potential application of UCA1. Results and discussion: In this review, we discuss UCA1 expression profiling, isoform, expression regulation, biological role and mechanism for UCA1 tumor-promoting effect. We further discuss the potential clinical application of UCA1 as a promising diagnostic biomarker or therapeutic target for human cancers. Conclusion: UCA1 functions as an oncogenic lncRNA in several malignancies, and it might become a potential biomarker or therapeutic target for human cancers. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a serious complication of sepsis, which has a high mortality rate. Growth arrest-specific protein 6 (Gas6), the protein product of the growth arrest specific gene 6, has been shown to have an anti-apoptotic effect as well as pro-survival capability. Here, we investigated the effects of Gas6 on sepsis-associated AKI in mice subjected to cecal ligation and puncture (CLP). We found that the administration of rmGas6 significantly reduced serum urea nitrogen and creatinine and improved the survival of septic mice. Furthermore, the renal pathological damage induced by CLP was attenuated by rmGas6 treatment. Finally, rmGas6 reduced the renal tissue apoptotic index and the expression of Bax, while it upregulated the expression of Bcl-2. The data suggest that rmGas6 might be used as a potential therapeutic agent for sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

Raspberry is well known as rich source of antioxidants, such as polyphenols and flavonoids. However, after consumption, the antioxidants are subjected to digestive conditions within the gastrointestinal tract that may result in structural and functional alterations. Our previous study indicated that acrylamide (AA)-induced cytotoxicity was associated with oxidative stress. However, the protective effect of wild raspberry extract produced before and after in vitro gastrointestinal digestion against AA-induced oxidative damage is unclear. In the present study, we found that wild raspberry extract produced after digestion (RD) had a pronounced protective effect against AA-induced cytotoxicity compared with that produced before digestion (RE). Further investigation indicated that RD significantly inhibited AA-induced intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse and glutathione (GSH) depletion. Moreover, LC–MS analysis revealed that wild raspberry underwent gastrointestinal digestion significantly increased the contents of esculin, kaempferol hexoside and pelargonidin hexoside. [ABSTRACT FROM AUTHOR]

Rosiglitazone, which is mainly used in the treatment of diabetes mellitus, is also involved in the regulation of inflammation. The peroxisome proliferator-activated receptor (PPAR)-γ receptor subtype appears to play a pivotal role in the regulation of inflammation. However, the exact mechanism for the protective effects of rosiglitazone against inflammation such as liver injury remains unclear. The aim of this study was to investigate the effects of rosiglitazone on inflammation in the liver of rats treated with D-GaIN/LPS. Male Sprague-Dawley rats were injected with D-GaIN/LPS with or without pre-administration of rosiglitazone (3, 10, or 30 mg/kg, intraperitoneal injection). Our data showed that rosiglitazone significantly inhibited D-GaIN/LPS-induced hepatotoxicity in a dose-dependent manner, as indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Western blot analysis showed that rosiglitazone significantly decreased protein expression levels of COX-2 and production of pro-inflammatory markers, including TNF-α and IL-6, in D-GaIN/LPS-treated rat liver. The results indicated that the inhibition of D-GaIN/LPS-induced inflammation by rosiglitazone can be attributed, at least partially, to its capacity to regulate the the immunoregulatory transcription factor nuclear factor kappa B (NF-κB) signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Submucosal tunneling endoscopic resection (STER) can be adequately adopted as an effective treatment for submucosal tumors (SMTs) originating from the muscularis propria (MP) layer at the esophagus and cardia. However, it has been seldom used for gastric SMTs. Our purpose was to evaluate the clinical impact of STER for gastric SMTs arising from the MP layer.Methods: Thirty-two patients with gastric SMTs from the MP layer were retrospectively included. The main outcome measurements were complete resection rate, adverse events, local recurrence, and distant metastases during follow-up.Results: Of the 32 lesions, 12 were located in the gastric corpus close to the cardia, 3 in the gastric fundus close to the cardia, 6 in the lesser curvature of the gastric corpus, and 11 in the greater curvature of the gastric antrum. STER was successfully performed in all patients with en bloc resection of tumors. The mean tumor size was 2.3 cm (range 1.0-5.0 cm). The complete resection rate was 100%. The operation time ranged from 25 to 125 min (mean 51.8 min). All complications related to STER were successfully managed with conservative treatments. Local recurrence or distant metastasis did not occur during a follow-up period of 6-32 months.Conclusion: STER is a safe and effective therapeutic strategy for eligible gastric SMTs originating from the MP layer. Submucosal tunneling in the stomach may be more challenging than that in the esophagus, but does not increase procedure-related adverse events or prevent successful STER for eligible gastric SMTs. [ABSTRACT FROM AUTHOR]

Objective: Preeclampsia (PE) is a serious condition affecting pregnant women and placing both the mother and fetus at risk. While little is known about the pathogenesis of PE, there is evidence for involvement from the maternal innate immune system, specifically, signaling arising from monocytes. The present study was to explore the role of Toll-like receptor (TLR) 4 on peripheral blood monocyte in the pathogenesis of PE.Methods: This study included 22 patients with established preeclampsia and 23 healthy pregnant women (HP). All participants gave informed written consent for 4 mL of fresh venous blood to be collected into a tube containing heparin. The expression of TLR4 on monocytes was evaluated by flow cytometry (FCM). Monocytes were stimulated with LPS for 18 h and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-α) in supernatants was analyzed with Luminex platform (Luminex Corporation, Austin, TX). The expression of TLR4 and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-α) was compared between women with PE and healthy pregnant women.Results: Compared with controls, the percentage of TLR4+ monocytes was significantly higher in PE patients. Collected monocytes stimulated with lipopolysaccharide (LPS) to induce inflammation had increased cytokine production, and monocytes from PE patients produced more IL-6 and TNF-α, and less IL-10 than cells from healthy participants. PE patients also showed a positive correlation between the percentage of TLR4+ monocytes and serum levels of IL-6 and TNFα.Conclusions:These results suggest that TLR4 signaling may play a role in the pathogenesis of preeclampsia. [ABSTRACT FROM PUBLISHER]

Background Although neuraminidase inhibitors (NI) are the mainstay of treatment for influenza infection, prescribing practice for these agents is not well described. Additionally, benefit is contested. Objectives We examined provider prescriptions of NI during the 2009 pandemic and post-pandemic periods. We also evaluated the effectiveness of NI in reducing severity of influenza infection. Study design Data on NI prescription and severity of influenza infection were compiled in healthy pediatric and adult beneficiaries enrolled in a prospective study of influenza like illness conducted at five military medical centers over five years. Subjects underwent nasal swabs to determine viral etiology of their infection. Demographic, medication and severity data were collected. Subjects with positive influenza were included. Results Two hundred sixty three subjects were influenza positive [38% [H1N1] pdm09, 38.4% H3N2, and 20.5% B); 23.9% were treated with NI. NI were initiated within 48 h in 63% of treated subjects. Although NI use increased over the five years of the study, early use declined. Most measures for severity of illness were not significantly reduced with NI; adults treated within 48 h had only a modest reduction in duration and severity of some of their symptoms. Conclusions NI use in our population is increasing, but early use is not. NI use resulted in no reduction in complications of illness. Resolution of symptoms and reduction in severity of some symptoms were slightly better in adults who were treated early. These modest benefits do not support routine treatment with NI in otherwise healthy individuals with influenza. [ABSTRACT FROM AUTHOR]

Recent case series have shown that enteroscopy is safe and effective to remove entrapped small bowel foreign bodies. However, the optimal timing for the foreign body retrieval in terms of duration of entrapment and when to consider surgical intervention are unknown. In this case series, we report that antegrade and retrograde enteroscopy can be used safely to retrieve foreign bodies entrapped in the small bowel for longer than 70 days. In total, 20 patients (mean age, 48 years; 11 females) with entrapped foreign bodies in the small intestine underwent antegrade, retrograde, or combined double balloon enteroscopy for retrieval of objects. Symptoms prompted removal of entrapped, nonsharp objects in all patients and included abdominal pain, nausea, and vomiting. The mean time of entrapment was 83 days (range, 4-272 days). There were 15 cases of retained video capsule endoscopy (VCE) with a mean entrapment time of 106 days (range, 7-272 days). Two VCEs could not be removed safely with enteroscopy. Other retained small bowel objects included in this study were nails and fish hooks. Their average entrapment time was 13 days (range, 4-43 days). Of the 30 enteroscopies, there was only 1 case (3%) with a complication (perforation). According to this case series, experienced endoscopists can safely and effectively retrieve foreign bodies in the small bowel, particularly VCE, that are retained for extended periods of time. [ABSTRACT FROM AUTHOR]

BACKGROUND Axillary bromhidrosis is a distressing problem, which has a strong negative effect on one's social life. OBJECTIVE To evaluate the effects and complications of the surgical modality for the treatment of axillary bromhidrosis. METHODS One hundred fifteen patients with axillary bromhidrosis were treated. Two incisions were made transversely along the marked lines on the axillary crease. Subdermal undermining of the marked area with a depth of 0.3 to 0.5 cm and transverse detachment were performed, allowing the exposure of the skin flaps. Skin flaps were carefully separated from the skin. The apocrine glands, follicles, and fats were dissected, and the axillary superficial fascia was maintained. RESULTS All patients achieved good results in terms of malodor elimination during the follow-up period. All patients reported reduction in axillary sweating. Postoperative complications were minor, including small hematoma (3 cases), delayed wound healing (5 cases), pressure blister (5 cases), and slightly wound scar (2 cases). No infection, skin necrosis, malodor, or recurrence was observed. One hundred eleven patients (96.5%) were very satisfied and 4 (3.5%) patients satisfied with the procedure, with none regretful. CONCLUSION The procedure has the advantage of a high success rate in radical elimination of the malodor with minor complications. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancers encompass gallbladder carcinoma, and intrahepatic, perihilar and distal cholangiocarcinoma. Upregulated serum CYFRA 21-1 has been reported in intrahepatic cholangiocarcinoma. Aims: The present study aimed to explore the clinical significance of serum CYFRA 21-1 in all biliary tract cancer subtypes. Methods: Serum CYFRA 21-1, carbohydrate antigen 19-9 and carcinoembryonic antigen were quantitated preoperatively, postoperatively and during follow-up in 134 malignant and 52 benign patients. Receiver operator characteristic curves of biomarkers were analyzed. Level of CYFRA 21-1 was correlated with patients' clinicopathological features and follow-up data. Results: CYFRA 21-1 was significantly upregulated in biliary malignancies, and expressional difference existed between these subtypes. Based on the maximal Youden's index, cutoff values were selected (ng/mL): 2.61 for biliary tract cancers (sensitivity 74.6 % and specificity 84.6 %); 3.27 for intrahepatic cholangiocarcinoma (75.6 and 96.2 %) and gallbladder carcinoma (93.7 and 96.2 %); 2.27 for perihilar cholangiocarcinoma (71.0 and 71.2 %); and 2.61 for distal cholangiocarcinoma (63.3 and 84.6 %). CYFRA 21-1 showed better diagnostic performance than other biomarkers in gallbladder carcinoma and intrahepatic cholangiocarcinoma; its performance was not inferior to that of the combination of these three biomarkers and declined after curative resection and re-elevated when tumor recurred, which was correlated with tumor aggressiveness and TNM stage; it was an independent predictor for 1-year recurrence-free survival and overall survival on multivariate analysis. Conclusion: Serum CYFRA 21-1 represents a reliable biomarker for gallbladder carcinoma and intrahepatic cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

We previously showed the impairment of insulin-regulated gene expression in the primary hepatocytes from Zucker fatty (ZF) rats, and its association with alterations of hepatic glucose and lipid metabolism. However, the molecular mechanism is unknown. A preliminary experiment shows that the expression level of protein kinase C ζ (PKCζ), a member of atypical PKC family, is higher in the liver and hepatocytes of ZF rats than that of Zucker lean (ZL) rats. Herein, we intend to investigate the roles of atypical protein kinase C in the regulation of hepatic gene expression. The insulin-regulated hepatic gene expression was evaluated in ZL primary hepatocytes treated with atypical PKC recombinant adenoviruses. Recombinant adenovirus-mediated overexpression of PKCζ, or the other atypical PKC member PKCι/λ, alters the basal and impairs the insulin-regulated expressions of glucokinase, sterol regulatory element-binding protein 1c, the cytosolic form of phosphoenolpyruvate carboxykinase, the catalytic subunit of glucose 6-phosphatase, and insulin like growth factor-binding protein 1 in ZL primary hepatocytes. PKCζ or PKCι/λ overexpression also reduces the protein level of insulin receptor substrate 1, and the insulin-induced phosphorylation of AKT at Ser473 and Thr308. Additionally, PKCι/λ overexpression impairs the insulin-induced Prckz expression, indicating the crosstalk between PKCζ and PKCι/λ. We conclude that the PKCζ expression is elevated in hepatocytes of insulin resistant ZF rats. Overexpressions of aPKCs in primary hepatocytes impair insulin signal transduction, and in turn, the down-stream insulin-regulated gene expression. These data suggest that elevation of aPKC expression may contribute to the hepatic insulin resistance at gene expression level. [ABSTRACT FROM AUTHOR]

B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of bipolar disorder, and may be involved in the therapeutic action of anti-manic drugs. The aim of this study was to investigate serum levels of Bcl-2 in bipolar patients in a manic phase, and evaluate the Bcl-2 changes after treatment. We consecutively enrolled 23 bipolar inpatients in a manic phase and 40 healthy subjects; 20 bipolar patients were followed up with treatment. Serum Bcl-2 levels were measured with assay kits. All 20 patients were evaluated by examining the correlation between Bcl-2 levels and Young Mania Rating Scale (YMRS) scores, using Spearman׳s correlation coefficients. The serum Bcl-2 levels in bipolar patients in a manic phase were higher than in healthy subjects, but without a significant difference. The YMRS scores were significantly negatively associated with serum Bcl-2 levels ( p =0.042). Bcl-2 levels of the 20 bipolar patients were measured at the end of treatment. Using the Wilcoxon Signed Rank test, we found no significant difference in the Bcl-2 levels of bipolar patients after treatment. Our results suggest that Bcl-2 levels might be an indicator of severity of manic symptoms in bipolar patients in a manic phase. [ABSTRACT FROM AUTHOR]

Background: The 595 nm tunable pulsed dye laser has been used in China for more than 10 years. However, no studies about its effect and side-effect in treatment of superficial hemangioma have been documented. Objective: This study was designed to retrospectively summarize its usage in Chinese patients. Methods: Infant patients with superficial hemangioma, who had received 595 nm tunable pulsed dye laser treatment in our laser center in the last 10 years, were recruited. Detailed demographics, results of assessment about their degree of clearance and clinical examination for treatment complications were entered into SASS10.0 version database, and statistical analyses were conducted. Results: Six hundred and fifty-seven cases with superficial hemangioma were recruited. The overall effectiveness rate was 91.17%. Female patients respond better than male, the difference was statistically significant ( p < 0.001). Lesions at different part of the body respond differently to the treatment with lesions on extremities show the best result. The response rate does not increase with time of treatments. The most common side-effects were pigment changes and skin atrophy, which usually resolve spontaneously and disappear completely in a few months. Conclusions: Our experience confirmed the satisfactory clinical efficacy and safety of the 595 nm tunable pulse dye laser in the treatment of childhood superficial hemangioma. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common disease associated with tissue inflammation, physical disability and imbalanced homeostasis in cartilage. For advanced treatments, biological approaches are currently focused on tissue regeneration and anti-inflammation. This study was undertaken to evaluate the therapeutic efficacies of hyaluronic acid (HA) and platelet-rich plasma (PRP) (HA+PRP) on OA. Articular chondrocytes were obtained from five OA patients. The optimal HA and PRP concentrations were evaluated by MTT assay. The expressions of chondrogenic and inflammatory genes were analyzed by RT-PCR. Signaling pathway was examined by immunoblotting and the expressions of OA pathology-related chemokines and cytokines was demonstrated by real-time PCR-based SuperArray. The therapeutic efficacies of HA+PRP were then demonstrated in 3D arthritic neo-cartilage and ACLT-OA model. Here we showed that HA+PRP could greatly retrieve pro-inflammatory cytokines-reduced articular chondrocytes proliferation and chondrogenic phenotypes, the mechanism of which involve the sequential activation of specific receptors CD44 and TGF-βRII, downstream mediators Smad2/3 and Erk1/2, and the chondrogenic transcription factor SOX9. The real-time PCR-based SuperArray results also indicated that OA pathology-related chemokines and cytokines could be efficiently suppressed by HA+PRP. Moreover, the cartilaginous ECM could be retrieved from inflammation-induced degradation by HA+PRP in both 2D monolayer and 3D neo-cartilage model. Finally, the intra-articular injection of HA+PRP could strongly rescue the meniscus tear and cartilage breakdown and then decrease OA-related immune cells. The combination of HA+PRP can synergistically promote cartilage regeneration and inhibit OA inflammation. This study might offer an advanced and alternative OA treatment based on detailed regenerative mechanisms. [ABSTRACT FROM AUTHOR]

Four oxoisoaporphine-lipoic acid hybrids were designed, synthesized, and investigated in this study. To develop the hybrids, the oxoisoaporphine fragment was used for its inhibition of cholinesterases and β-amyloid (Aβ) aggregation, while the unit of lipoic acid was used for its radical-capturing and neuroprotective effects. The hybrids exhibited moderate inhibitory effects on the activity of acetylcholinesterase (AChE), with IC 50 values in the micromolar range and low toxicity in SH-SY5Y cells. Moreover, the learning and memory abilities, climbing capability, and average life expectancy of the Aβ42 transgenic Drosophila were all significantly improved by the hybrids. They also enhanced the intracephalic antioxidant activity, the metabolism, and the activity cholinesterase in the flies. More strikingly, Aβ42 aggregation in the hybrids-treated Drosophila was attenuated with effective neuroprotection. Our results indicate the potential of using these oxoisoaporphine-lipoic acid hybrids in AD treatments. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility of and indication for laparoscopic methods for neonates with congenital duodenal obstruction. Patients and Methods: From September 2009 to October 2012, 40 newborns with duodenal obstruction underwent exploratory laparoscopy. With a lower-pressure pneumoperitoneum of 6-8 mm Hg and a suspending suture for the right liver elevator, the procedure was performed using four trocars 3-5 mm in diameter. Under laparoscopic vision, the causes of duodenal obstruction were diagnosed, and then the operation methods were determined by the type of obstruction. Results: Of the 40 cases, 4 were duodenal atresia (type II), 8 were duodenal stenosis, 8 were annular pancreas, and 20 were congenital intestinal malrotation. For the cases with duodenal diaphragmatic stenosis a partial excision of the diaphragm was performed after longitudinal incision of the anterior part of the duodenum followed laparoscopically by a transverse suture. For the cases with duodenal atresia (type II) and annular pancreas, a duodenal diamond anastomosis was successfully carried out through a laparoscopic approach. Ladd's operational method was performed in the cases with congenital intestinal malrotation. Feedings were started on postoperative Day 3-7, without abdominal distention and vomiting, and discharge from the the hospital was on postoperative Day 9-14. Conclusions: Congenital duodenal obstruction is a common malformation in neonates. The laparoscopic procedure is an important method of diagnosing, and correct operational methods are the key to improve the therapeutic effect in the treatment of congenital duodenal obstruction. The laparoscope has the value of a small incision, microinvasion, and better recovery in diagnosis and treatment for congenital duodenal obstruction. The laparoscopic methods can be performed in neonates safely and are appropriate for a full-term newborn with tolerance to CO2 pneumoperitoneum. [ABSTRACT FROM AUTHOR]

Background: A circular muscle myotomy preserving the longitudinal outer esophageal muscular layer is often recommended during peroral endoscopic myotomy (POEM) for achalasia. However, because the longitudinal muscle fibers of the esophagus are extremely thin and fragile, and completeness of myotomy is the basis for the excellent results of conventional surgical myotomy, this modification needs to be further debated. Here, we retrospectively analyzed our prospectively maintained POEM database to compare the outcomes of endoscopic full-thickness and circular muscle myotomy. Study Design: According to the myotomy depth, 103 patients with full-thickness myotomy were assigned to group A, while 131 patients with circular muscle myotomy were assigned to group B. Symptom relief, procedure-related parameters and adverse events, manometry outcomes, and reflux complications were compared between groups. Results: The mean operation times were significantly shorter in group A compared with group B (p = 0.02). There was no increase in any procedure-related adverse event after full-thickness myotomy (all p < 0.05). During follow-up, treatment success (Eckardt score ≤ 3) persisted for 96.0% (95 of 99) of patients in group A and for 95.0% (115 of 121) of patients in group B (p = 0.75). There were no statistically significant differences in pre- and post-treatment D-value of symptom scores and lower esophageal sphincter pressures between groups (both p > 0.05). The overall clinical reflux complication rates were also similar (21.2% vs 16.5%, p = 0.38). Conclusions: Short-term symptom relief and manometry outcomes of each method were comparable. Full-thickness myotomy significantly reduced the procedure time but did not increase the procedure-related adverse events or clinical reflux complications. [Copyright &y& Elsevier]

Objective: Manual acupuncture has commonly been used in China, either alone or in combination with conventional medicine, to treat diabetic peripheral neuropathy (DPN). The objective of this study was to perform a systematic review to evaluate the potential benefits and harms of manual acupuncture for DPN to justify its clinical use. Methods: We searched for published and unpublished randomized controlled trials of manual acupuncture for DPN till 31 March 2013. Revman 5.2 software was used for data analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval (CI). Results: A total of 25 trials involving 1649 participants were included. The methodological quality of included trials was generally poor. Meta-analysis showed that manual acupuncture had better effect on global symptom improvement compared with mecobalamin (RR 1.31, 95%CI 1.21 to 1.42), vitamin B1 and B12 (RR 1.55, 95%CI 1.33 to 1.80), and no treatment (RR 1.56, 95%CI 1.31 to 1.85), and that the combination of manual acupuncture and mecobalamin had better effect compared with mecobalamin alone on global symptom improvement (RR 1.56, 95%CI 1.28 to 1.90). Adverse events were not reported in any trials. The asymmetric funnel plot suggested publication bias. Conclusions: Despite the number of trials of manual acupuncture for DPN and their uniformly positive results, no clinically relevant conclusions can be drawn from this review due to the trials’ high risks of bias and the possibility of publication bias. Clearly defined and internationally acknowledged outcome measures are required for future study. There remains an urgent need for training Chinese researchers in conducting unbiased trials as well as prospectively registering all initiated Chinese trials to avoid publication bias. [ABSTRACT FROM AUTHOR]

Interleukin-17A (IL-17A) produced by Th17 cells, contributes to the pathogenesis of various autoimmune diseases by stimulating the release of cytokines and chemokines and its regulation. Anti-IL-17A antibody which blocks the function of IL-17A has been proved to be an effective treatment of autoimmune disease. The aim of our study was to generate a potential humanized anti-IL-17A therapeutic monoclonal antibody (mAb) through a comprehensive panel of in vitro and in vivo biological activity studies, as well as physicochemical characterization. HZD37-5, a humanized monoclonal antibody specifically recognizing N78 loci of IL-17A, binds to human and rhesus monkeys, blocks IL-17 induced signal transduction and the release of IL-6, IL-8, CXCL-1 and G-GSF. In an in vivo efficacy mouse model, HZD37-5 significantly inhibited human IL-17A induced-keratinocyte chemoattractant (KC) secretion in a dose-dependent manner. The pharmacokinetics (PK) study result of HZD37-5 in rhesus monkeys indicated that HZD37-5 had favorable PK characteristics with limited distribution (78.0–78.8 ml/kg), slow elimination (5.00–6.45 ml/day/kg), long half-life (9.1–10.7 days) and high bioavailability (103%) following a single IV or SC dose at 1.5 mg/kg. These findings provided a comprehensive preclinical characterization of HZD37-5 and supported that it may be developed as a potential therapeutic for the treatment of autoimmune diseases, including psoriasis, psoriatic arthritis, axial spondyloarthritis, etc. • Immunization and selection of candidate antibodies in New Zealand white rabbit. • Humanization of 37# rabbit antibody. • Affinity and neutralization activities of humanized antibodies HZD37-1 and HZD37-5. • HZD37-5 inhibited keratinocyte chemoattractant (KC) release induced by human IL-17A in mice. • Epitope mapping for HZD37-5 and pharmacokinetics (PK) of HZD37-5 in rhesus monkeys. [ABSTRACT FROM AUTHOR]

Background: Although the platinum regimen is adopted widely nowadays in spite of the excessive side effects, there is still no international standard for palliative chemotherapy of advanced gastric cancer. This meta-analysis assessed the efficacy and tolerability of platinum versus non–platinum chemotherapy as first-line palliative treatment in patients with inoperable, advanced gastric cancer. Methods: Randomized phase II and III clinical trials on first-line palliative chemotherapy in inoperable, advanced gastric cancer were identified by electronic searches of PubMed, Embase, and the Cochrane Controlled Trial Register, and hand searches of relevant abstract books and reference lists. Response rates, overall survival, and toxicity were analyzed. Depending on whether new-generation agents (S-1, taxanes and irinotecan) were utilized, the non–platinum regimens were divided into two subgroup. Results: Compared to non-platinum regimens containing new-generation agents, the use of platinum-based regimens was associated with better response (risk ratio (RR) = 1.94, 95%CI[1.48, 2.55], p<0.001), an increase of overall survival (hazard ratio (HR) = 0.85, 95%CI[0.78, 0.92], p<0.001), a higher risk of hematological and non-hematological toxicity. No statistically significant increase in response (RR = 1.03, 95%CI [0.85, 1.24], p = 0.76) or overall survival (HR = 1.07, 95%CI [0.88, 1.30], p = 0.49) was found when platinum therapies were compared to new-generation agent based combination regimens. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nausea and vomiting, and neurotoxicity, but not for diarrhea and toxic death rate. Conclusion: New-generation agent based combination regimens achieved similar response rate and overall survival as platinum-based therapy that had generally higher side effects. S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable, advanced gastric cancer as first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Unlike the mammalian fetus, whose growth is supported by the sustained provision of maternal nutrients, poultry embryos undergo development in a relatively closed space, and the yolk sac serves as the sole nutrient supply for embryonic development throughout the whole incubation period. To increase our understanding of the muscle developmental patterns in the final stage of incubation and early days posthatching, we used late-term duck embryos and newly hatched ducklings as animal models. Pectoralis muscle samples were collected at 22 days (22E) of incubation, 25 days (25E) of incubation, hatching and day 7 posthatching. The pectoralis muscle mass, muscle fibre bundles and myofibre cross-sectional area showed a marked reduction from 22E to hatching, but they increased dramatically by day 7 posthatching. The mRNA expression of Atrogin-1, a key mediator of the ubiquitin system responsible for protein degradation, increased dramatically with the age of late-term duck embryos, but it decreased by day 7 and reached a very low level. The extent of mRNA expression of FoxO1, one of the transcription factors of the Atrogin-1 gene, exhibited a transient increase at 25E and then decreased from hatching to day 7. The phosphorylated p70 ribosomal protein S6 kinase 1 (S6K1)/S6K1 ratio exhibited a dramatic reduction from 22E to hatching ( P < 0.05) and then increased by day 7. The results of the present study indicated that there was a developmental transition of pectoralis muscle from atrophy in late-term duck embryos to hypertrophy in neonates. [ABSTRACT FROM AUTHOR]

Objective: Kienböck's disease is difficult to treat and optimal treatments for stages II to III continue to elude investigators. We hypothesized that impacting the ischemic cancellous trabeculae and increasing the strength and rigidity of the lunate with balloon kyphoplasty can prevent lunate collapse, relieve the symptoms, and increase wrist range of motion. The purpose of this study was to demonstrate the feasibility of percutaneous balloon kyphoplasty for treatment of stage II to III Kienböck's disease. Methods: The study group comprised five patients (two in stage II, three in stage III). All were treated with balloon kyphoplasty. Pain, strength, and wrist flexion/extension range of motion were evaluated preoperatively and postoperatively. The Mayo Wrist Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score were used to evaluate outcomes. Patient satisfaction was also assessed. Comparisons between preoperative and postoperative data were made with SPSS software. Results: Clinical data were collected at a mean of 26.6 months (range 24-28 months) postoperatively. Pain was significantly reduced from 6.8 ± 0.8 in the visual analog scale preoperatively to 0.6 ± 0.9 at the 24-month follow-up. Strength and range of motion were improved postoperatively in all patients. The mean DASH score was 11.3 (range 6.7-18.3), and the mean Mayo Wrist Score was 78 (range 75-80). All five patients returned to their previous occupations. Conclusions: Balloon kyphoplasty can prevent lunate collapse, reduce pain, and improve wrist function of patients with stage II to III Kienböck's disease. Further studies regarding the feasibility of this new approach are warranted. [ABSTRACT FROM AUTHOR]

This study aims to introduce a self-navigated plate, which is characterized by the presence of a groove at each end of the plate, in treating tibial fractures. The plate is inserted subperiosteally across the fracture line when the fracture is effectively reduced. A second plate of the same is then placed over the subcutaneous one and serves as a guide for percutaneous insertion of screws through the holes of subperiosteal plate into the bones to secure the fracture. Seven patients with tibial shaft fractures were treated by minimally invasive plate osteosynthesis (MIPO) using this plate. The average operative time was 47 min, and the average fluoroscopy time was 19 s. All fractures healed from 3 to 6 months postoperatively, and excellent functional recovery was observed in all patients. In conclusion, the economical-friendly self-navigated plate is a good and effective alternative fixation method in treating tibia fractures by MIPO. [ABSTRACT FROM AUTHOR]

Abstract: Myocardial TGF-β expression is upregulated in experimental models of myocardial infarction and cardiac hypertrophy, and in patients with dilated or hypertrophic cardiomyopathy. Through its effects on cardiomyocytes, mesenchymal and immune cells, TGF-β plays an important role in the pathogenesis of cardiac remodeling and fibrosis. TGF-β overexpression in the mouse heart is associated with fibrosis and hypertrophy. Endogenous TGF-β plays an important role in the pathogenesis of cardiac fibrotic and hypertrophic remodeling, and modulates matrix metabolism in the pressure-overloaded heart. In the infarcted heart, TGF-β deactivates inflammatory macrophages, while promoting myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways. Thus, TGF-β may serve as the “master switchThis article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure”. for the transition of the infarct from the inflammatory phase to formation of the scar. Because of its crucial role in cardiac remodeling, the TGF-β system may be a promising therapeutic target for patients with heart failure. However, efforts to translate these concepts into therapeutic strategies, in order to prevent cardiac hypertrophy and fibrosis, are hampered by the complex, pleiotropic and diverse effects of TGF-β signaling, by concerns regarding deleterious actions of TGF-β inhibition and by the possibility of limited benefit in patients receiving optimal treatment with ACE inhibitors and β-adrenergic blockers. Dissection of the pathways responsible for specific TGF-β-mediated actions and understanding of cell-specific actions of TGF-β are needed to design optimal therapeutic strategies. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure”. [Copyright &y& Elsevier]

Purpose: To compare the efficacy and safety of manual limbal markings and wavefront-guided treatment with iris-registration software in laser in situ keratomileusis (LASIK) for myopic astigmatism. Setting: National Taiwan University Hospital, Taipei, Taiwan. Methods: Eyes with myopic astigmatism had LASIK with a Technolas 217z laser. Eyes in the limbal-marking group had conventional LASIK (PlanoScan or Zyoptix tissue-saving algorithm) with manual cyclotorsional-error adjustments according to 2 limbal marks. Eyes in the iris-registration group had wavefront-guided ablation (Zyoptix) in which cyclotorsional errors were automatically detected and adjusted. Refraction, corneal topography, and visual acuity data were compared between groups. Vector analysis was by the Alpins method. Results: The mean preoperative spherical equivalent (SE) was −6.64 diopters (D) ± 1.99 (SD) in the limbal-marking group and −6.72 ± 1.86 D in the iris-registration group (P = .92). At 6 months, the mean SE was −0.42 ± 0.63 D and −0.47 ± 0.62 D, respectively (P = .08). There was no statistically significant difference between groups in the astigmatism correction, success, or flattening index values using 6-month postoperative refractive data. The angle of error was within ±10 degrees in 73% of eyes in the limbal-marking group and 75% of eyes in the iris-registration group. Conclusion: Manual limbal markings and iris-registration software were equally effective and safe in LASIK for myopic astigmatism, showing that checking cyclotorsion by manual limbal markings is a safe alternative when automated systems are not available. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. [Copyright &y& Elsevier]

Abstract: One major polysaccharide fractions, glucose, were isolated from the polysaccharides extract of Astragalus (AP), a valuable traditional Chinese medicine, using thin-layer chromatography (TLC) and Sephadex G-100 chromatography. HPLC and IR methods were used for a qualitative and quantitative determination of from polysaccharides of Astragalus. The HPLC method was validated for linearity, precision and accuracy. The results indicated that polysaccharides of Astragalus is an α-(1→4)-d-glucan with α-(1→6)-linked branches attached to the O-6 of branch points. Bioactivity tests showed that polysaccharides of Astragalus is active for spleen lymphocytes proliferation. The polysaccharides also presented anti-inflammatory activities. These data together suggest that polysaccharides of Astragalus presents significant immune modulating activity, thus supporting the popular use of the polysaccharides in the treatment of gastric cancer diseases. [Copyright &y& Elsevier]

Abstract: Thoracic sonography has been advocated as being complementary to small-bore catheter drainage in pleural effusions. However, it is not known whether the initial sonographic appearances of empyemas or complicated parapneumonic effusions (CPPEs) can predict the outcomes of small-bore catheter drainage for these pleural insults. This retrospective study investigated the outcomes of patients who had been diagnosed with empyema and CPPE and had received ultrasound-guided small-bore catheter (size from 12F to 16F) drainage in a tertiary university hospital from September 2005 to August 2007. Patients were excluded when empyemas or CPPEs were traumatic, they were less than 18 years old or their charts were incomplete. We evaluated 141 small-bore catheters in 70 patients with empyemas and 71 patients with CPPEs over a two-year period. The mean age was 58±15 y and the male gender was more frequent (112 men, 79%). The overall successful rate of small-bore catheter drainage in empyemas or CPPEs was 63% (89/141). The sonographic appearances of these empyemas or CPPEs exhibited a complex septated pattern in 57% (81/141) of patients and a complex nonseptated pattern in 43% (60/141) of patients. The success rate in a complex nonseptated sonographic pattern was significantly higher than in a complex septated sonographic pattern (48/60, 80% vs. 41/81, 51%, respectively; p =0.001). Moreover, patients with complex septated sonographic patterns also had higher intensive care unit admission rates compared with nonseptated sonographic patterns (22/81, 27%, vs. 8/60, 13%, respectively; p =0.0047), as well as infection-related mortality rates (17/81, 21% vs. 4/60, 7%, respectively; p =0.018). The appearance of sonographic septation is a useful sign to help predict the outcome of small-bore catheter drainage in cases of empyemas or CPPEs. Patients with a complex septated sonographic pattern have a poorer prognosis for a successful outcome, higher ICU admission rate and a higher mortality rate. [Copyright &y& Elsevier]

Abstract: This study was conducted to explore the modulation of GTPs on cognitive performances in psychological stress rats. Wistar rats were randomly assigned to five groups as follows: control group, stress group, and three stress groups with low, medium and high-doses of GTPs modulation respectively. The changes of cognitive performances were examined by open-field test, water maze and step-through test. Results demonstrated that serum levels of cortisol were all increased obviously in four stress groups. The cognitive performances of stress group were changed evidently. And these changes were improved in stress medium and high-doses of GTPs modulation groups. In addition, plasma levels of IL-6 and IL-2 were increased in four stress groups, serum norepinephrine and dopamine were decreased dramatically in stress group and stress low-dose GTPs modulation group. The serum norepinephrine and dopamine levels in stress medium and high-doses of GTPs modulation groups were increased in contrast to that of stress group. Furthermore, the changes of anti-oxidative capacity in brain tissue were also measured. Except superoxide dismutase, the changes of malondialdehyde, reactive oxidative species and total anti-oxidative capacity of stress group were significantly different from that of control group. These changes in stress medium and high-doses of GTPs modulation groups were improved. Our results suggested that psychological stress impaired body''s cognitive performances, and moderate GTPs modulation could improve these abnormal changes. To our knowledge, this is the first report showing the improving effects of GTPs on cognitive dysfunctions induced by psychological stress. [Copyright &y& Elsevier]

Abstract: Arsenic compounds have been used as anti-cancer agents in traditional Chinese medicine. Ionizing radiation (IR) is one of the most effective tools in the clinical treatment of cancer. The induction of apoptotic cell death is a significant mechanism of tumor cells under the influence of radio-/chemotherapy, and resistance to these treatments has been linked to some cancer cell lines with a low propensity for apoptosis. A combination of different anti-tumoral treatment modalities is advantageous in limiting non-specific toxicity often observed by an exceedingly high dose of single regimen. The present study aimed at investigating the enhanced effects and mechanisms in cell cycle distribution and apoptosis of U937 cells, a human pre-monocytic leukemia cell line lacking functional p53 protein, after combination treatment with irradiation and As2O3. Our results indicated that combined treatment led to activation of cdc-2, which is related to the expression of cyclin B. In addition, combined treatment increased apoptotic cell death in U937 cells, which is correlated with the induction of mitotic arrest, the increase in intracellular reactive oxygen species (ROS) generation, the decrease in B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell leukemia/lymphoma XL (Bcl-XL) levels, the loss of mitochondria membrane potential, and the activation of caspase-3. We found that combining radiation and As2O3 may be an effective strategy against p53-deficient leukemia cells. [Copyright &y& Elsevier]