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Objective: To investigate the effects of Shenfu Injection (参附注射液, SFI) on endothelial damage in a porcine model of hemorrhagic shock (HS). Methods: After being bled to a mean arterial pressure of 40±3 mm Hg and held for 60 min, 32 pigs were treated with a venous injection of either shed blood (transfusion group), shed blood and saline (saline group), shed blood and SFI (SFI group) or without resuscitation (sham group). Venous blood samples were collected and analyzed at baseline and 0, 1, 2, 4, and 6 h after HS. Tumor necrosis factor-α (TNF-α), serum interleuking (IL)-6, and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM -1), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and Bcl-2, Bax, and caspase-3 proteins were determined by Western blot. Results: The serum level of TNF-α in the SFI group was significantly lower than in the other groups at 0, 1, and 2 h after HS, while the level of IL-6 was lower at 4 and 6 h compared with the saline group (P<0.01 or P<0.05). The concentration of serum IL-10 was significantly higher in the SFI group than in the other groups at 0, 1, 4, and 6 h after HS (P<0.01). Western blot and immunohistochemistry of vascular tissue showed that the expression of caspase-3 was downregulated, and that of Bcl-2 and Bax was upregulated in the SFI group compared to other groups (P<0.05). Conclusion: SFI attenuated endothelial injury in the porcine model of HS by inhibiting cell apoptosis, suppressing the formation of proinflammatory cytokines, and reducing endothelial activation. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa (PA), a Gram-negative bacterium, has a high detection rate in hospital-acquired infections. Recently, the frequent appearance of multidrug-resistant (MDR) PA strain with high morbidity and mortality rates has aggravated the difficulty in treating infectious diseases. Due to its multiple resistance mechanisms, the commonly used antibiotics have gradually become less effective. Qiguiyin decoction (QGYD) is a clinically experienced prescription of Chinese herbal medicine, and its combined application with antibiotics has been confirmed to be effective in the clinical treatment of MDR PA infection, which could be a promising strategy for the treatment of drug-resistant bacterial infections. However, the mechanism of QGYD restoring antibiotics susceptibility to MDR PA remains unclear. In the present study, we investigated the effects of QGYD and levofloxacin (LEV) singly or in combination on MDR PA-induced pneumonia rat models. Further analysis was carried out in the serum differential expression profiles of inflammatory cytokines by cytokine antibody array. Besides, the lung TLR4/MyD88/NF-κB signaling pathway was detected by RT-qPCR. Our results showed that based on the treatment of MDR PA-infected rat model with LEV, the combination of QGYD improved the general state and immune organ index. Furthermore, it moderately increased the expressions of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in the early stage of infection and decreased their release rapidly in the later stage, while regulated the same phase change of anti-inflammatory cytokine IL-10. In addition, the adhesion molecule ICAM-1 was significantly downregulated after QGYD combined with LEV treatment. Moreover, the mRNA expressions of TLR4, MyD88, NF-κB, and ICAM-1 were significantly downregulated. These results indicated that the mechanism of QGYD restoring LEV susceptibility to MDR PA was related to its regulation of inflammatory cytokines and the TLR4/MyD88/NF-κB signaling pathway, which provides theoretical support for the clinical application of QGYD combined with LEV therapy to MDR PA infection. [ABSTRACT FROM AUTHOR]

Gouty arthritis (GA) is a multifactorial disease whose pathogenesis is utterly complex, and the current clinical treatment methods cannot wholly prevent GA development. Western medicine is the primary treatment strategy for gouty arthritis, but it owns an unfavorable prognosis. Therefore, the prevention and treatment of GA are essential. In China, traditional Chinese medicine (TCM) has been adopted for GA prevention and treatment for thousands of years. Gout patients are usually treated with TCM according to their different conditions, and long-term results can be achieved by improving their physical condition. And TCM has been proved to be an effective method to treat gout in modern China. Nevertheless, the pharmacological mechanism of TCM for gout is still unclear, which limits its spread. The theory of prevention and treatment of gout with TCM is more well acknowledged in China than in abroad. In this article, Chinese herbs and ancient formula for gout were summarized first. A total of more than 570 studies published from 2004 to June 2021 in PubMed, Medline, CNKI, VIP, Web of Science databases and Chinese Pharmacopoeia and traditional Chinese books were searched; the current status of TCM in the treatment of GA was summarized from the following aspects: articular chondrocyte apoptosis inhibition, antioxidative stress response, inflammatory cytokine levels regulation, uric acid excretion promotion, immune function regulation, uric acid reduction, and intestinal flora improvement in subjects with gout. The literature review concluded that TCM has a specific curative effect on the prevention and treatment of GA, particularly when combined with modern medical approaches. However, lacking a uniform definition of GA syndrome differentiation and the support of evidence-based medicine in clinical practice have provoked considerable concern in previous studies, which needs to be addressed in future research. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to analyze the efficacy of open reduction and Herbert screw fixation for coronal fractures of the capitellum via the anterior approach in adolescents. Methods: We retrospectively analyzed the clinical and imaging data of 15 adolescents with capitellar fractures who were admitted to our hospital from May 2014 to May 2019. The fracture was reduced through the cubital crease incision via the anterior approach and was internally fixated with Herbert screws. A follow-up was conducted after the operation to examine fracture healing and elbow function. The postoperative functional recovery of patients was evaluated with the Mayo Elbow Performance index (MEPI) and the Broberg-Morrey rating system. Results: Patients underwent surgery 3.7 days after injury on average. Intraoperative fracture reduction was satisfactory. No vascular injury or nerve injury occurred. Bony union occurred in an average of 6 weeks after the operation. All adolescents completed a 12- to 36-month follow-up. At the last follow-up, the Mayo Elbow Performance index was considered excellent in 12 patients and good in three patients. The Broberg-Morrey score was considered excellent in 12 patients, good in two patients, and fair in one patient. Conclusion: Open reduction with Herbert screw fixation via the anterior approach is a feasible surgical method for the treatment of coronal fractures of the capitellum in adolescents. Levels of evidence: Therapeutic, retrospective study-Level IV [ABSTRACT FROM AUTHOR]

Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction. Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. [ABSTRACT FROM AUTHOR]

Background and objective: β-Lactam antibiotics are the recommended first-line treatment for acute bacterial sinusitis. Fluoroquinolones are recommended in patients with hypersensitivity reactions to penicillins, and macrolide antibiotics are no longer recommended. The objectives of this study were to understand whether outpatient antibiotic prescribing practices adhere to treatment guidelines and to describe rates of fluoroquinolone and macrolide antibiotic prescribing for the treatment of sinusitis. Methods: This was a retrospective cross-sectional study using US National Ambulatory Medical Care Survey (NAMCS) data. The prevalence of antibiotic prescribing for sinusitis was estimated, and the antibiotic prescribing pattern was measured. Additionally, significant factors associated with various antibiotic prescribing during the visits related to sinusitis were identified. Results: Among physician visits related to sinusitis from 2013 to 2016 (n = 2739), 66.4% involved antibiotic prescribing. Visits with antibiotic prescribing showed greater proportions of patients aged < 18 years (21.7 vs 11.1%, p < 0.001), patients reporting fever (79.8 vs 50.7%, p < 0.001), and patients seeing family physicians or internal medicine specialists (68.4 vs 44.8%, p < 0.001) than those without antibiotic prescribing. Penicillins, macrolides, cephalosporins, and fluoroquinolones were prescribed in 42.2%, 30.6%, 15.2%, and 9.5% of the visits involving antibiotic prescribing for sinusitis, respectively. The odds of fluoroquinolone/macrolide prescribing were reduced by 73% if patients visited pediatricians and by 59% with otolaryngologists. Conclusions: Macrolides were the most common inappropriate antibiotic class prescribed for sinusitis. This study identifies a need for more focused attention to improve prescribing for sinusitis and adherence to the treatment guidelines. [ABSTRACT FROM AUTHOR]

Background and Objective: Aneurysm rebleeding after rupture can result in a catastrophic outcome with high mortality and morbidity. In this study, we evaluated the correlation of IARS (intracranial aneurysm rupture score) and aneurysm rebleeding. The aim of this study was to explore the clinical utility of IARS for better clinical decision-making.Method: The patients with ruptured intracranial aneurysms between January 2017 and September 2018 were reviewed. Propensity scoring match was performed to construct a cohort. The morphological and hemodynamic parameters were obtained. The difference between stable aneurysms and rebleeding aneurysms was compared. Subsequently, the correlation of IARS and aneurysm rebleeding was studied.Results: The matching process constructed a cohort, including 5 rebleeding aneurysms and 15 stable aneurysms. By comparing the difference between stable aneurysms and rebleeding aneurysms, the statistical significance was found in diameter of neck (p = 0.036), aspect ratio (p = 0.004) and size ratio (p = 0.029), normalized wall shear stress average (p = 0.026), low shear area ratio (p = 0.028), oscillatory shear index (OSI) (p = 0.031), and deviated angle (p = 0.025). The IARS here had a strong correlation with the aneurysm rebleeding, and the interval from the first bleeding to the rebleeding tended to shorten with the increase of IARS (R = 0.715, p = 0.027). IARS had a good predicting value for the aneurysm rebleeding (area under the curve = 0.756, p < 0.001).Conclusion: Based on this preliminary study, intracranial aneurysm rupture score may correlate to the rebleeding in ruptured aneurysms. For ruptured aneurysms with high IARS scores, surgery should be given priority, and medical treatment is not recommended. [ABSTRACT FROM AUTHOR]

Background: A host of systematic reviews and meta-analyses were carried out to estimate the role of corticosteroids in sepsis and septic shock. Discordant opinions were investigated to determine whether patients who experienced sepsis and septic shock could benefit from corticosteroids treatment. Our purpose is to perform a systematic review of overlapping meta-analyses, to explore the role of corticosteroids in the treatment of sepsis and septic shock. Method: Ovid MEDLINE, EMBase, Cochrane Database of Systematic Reviews, and LILACS were searched for eligible studies. Two authors individually extracted the relevant data and evaluated the quality of the meta-analysis using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2) and ROBIS. The Jadad decision algorithm was implemented to identify the meta-analyses that offered the optimal level of evidence. Result: Sixteen meta-analyses met the eligibility criteria. None of the studies that reported mortality illustrated a significant improvement on mortality (14-day and 90-day), but a 28-day mortality on a long course of a low dose corticosteroids was described. Only four studies stated that a long course of low-dose corticosteroids had advantageous effect on 28-day mortality. A meta-analysis by Fang et al. was regarded as the highest level of evidence in the Jadad decision algorithm among the meta-analyses that were investigated in this systematic review. Conclusion: The 28-day mortality was reduced, as well as the mortality in the ICU and hospital and the length of stay in the ICU, using a long course of low-dose corticosteroids. This was demonstrated by a meta-analysis of the current optimal available evidence. Additionally, significant improvements on the adverse events of hyperglycemia and hypernatraemia have been made. [ABSTRACT FROM AUTHOR]

10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) which is a brain-selective prodrug of 17β-estradiol has been reported to improve the cognitive function in Alzheimer's disease (AD) mice model. However, little is known about the potential mechanism for cognitive improvement. In the present study, we used AD mice to investigate the effects and mechanisms of DHED treatment. Female Tg2576 transgenic AD mice were ovariectomized and then treated by implanting Alzet osmotic minipumps containing DHED or vehicle subcutaneously for 8 weeks. Consistent with previous report, DHED treatment ameliorated cognitive function of AD mice with decreasing Aβ levels in the hippocampus. Besides, we also found DHED treatment could reduce oxidative and inflammatory stress and the level of p-tau. The mechanisms underlying the cognitive function improvement may be linked with estrogen receptor (ER)-klf5-NF-κB pathway, demonstrated by decreased expression of klf5 and the secretion of inflammatory cytokines. However, the effects of DHED treatment could be reversed when ERα was inhibited by ICI182780. Taken together, our findings uncovered a new mechanism for DHED to improve the cognitive function of AD mice and may provide a viable therapy to treat AD. [ABSTRACT FROM AUTHOR]

The accurate and instant diagnosis of burn severity is always the key point of optimal wound management and clinical treatment. However, the accuracy of burn depth assessment is low via visual inspection and lacks a quantitative measurement. In this work, a full-field burn depth detection system is proposed using the near-infrared hyperspectral imaging with the ensemble regression. The rotational feature subspace ensemble regression is introduced to establish a complex regression model between the hyperspectral imaging data and the burn depth. By the in vivo measurement of a porcine model, the method can get the average relative error about 7% for the burn depth measurement, which demonstrates that the proposed method can perform an accurate full-field assessment of burn depth and provide more practical references for clinicians. [ABSTRACT FROM AUTHOR]

Given the limited efficacy and potential disadvantages of erythropoiesis-stimulating agents (ESAs) in treating anemia of chronic kidney disease (CKD), the development of better alternative therapies has become a priority. The primary purpose of this study is to investigate the effects of Angelica sinensis polysaccharide (ASP) and its underlying mechanism in the treatment of renal anemia. In the present study, we found that ASP could enhance hypoxic induction of EPO in Hep3B cells, with a mechanism that involved the stabilization of HIF-2α protein. In parallel, ASP rescued the inhibition of EPO, induced by proinflammatory factor TNF-α through blocking GATA2 and NF-κB activation. In a rat model of adenine-induced anemia of CKD, oral administration of ASP corrected anemia and alleviated renal damage and inflammation. By increasing the accumulation of HIF-2α protein and reducing the expression of NF-κB and GATA2 as well as pro-inflammatory cytokines, ASP stimulated both renal and hepatic EPO production, and resulted in an elevation of serum EPO. The restoration of EPO production and EPOR mRNA expression with ASP treatment activated EPOR downstream JAK2/STAT5 and PI3K/Akt signaling, induced their target genes, such as Bcl-xL, Fam132b and Tfrc, and increased Bcl-2/Bax ratio in bone marrow-derived mononuclear cells of CKD rats. Furthermore, we found that ASP suppressed hepatic hepcidin expression, mobilized iron from spleen and liver and increased serum iron. These findings demonstrate that ASP elicits anti-anemic action by restoring EPO production and improving iron availability in the setting of CKD in rats. [ABSTRACT FROM AUTHOR]

Background: Traditional chemotherapy and molecular targeted therapy have shown modest effects on the survival of patients with pancreatic cancer. The current study aimed to investigate the antitumor effects of apatinib, Astragalus polysaccharide (APS), and the combination of both the drugs in pancreatic cancer cells and further explore the molecular mechanisms in vitro. Materials and methods: Expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in human pancreatic cancer cell lines ASPC-1, PANC-1, and SW1990 was detected by Western blotting. Cell proliferation was measured by MTS, and migration and invasion were detected by wound-healing and Transwell assays, respectively. Cell apoptosis rate was determined by flow cytometry and cellular autophagy level affected by apatinib, and APS was analyzed by Western blotting. Results: Human pancreatic cancer cell lines ASPC-1 and PANC-1 expressed VEGFR-2, but VEGFR-2 was not detected in SW1990. Either apatinib or APS inhibited cell proliferation in a dose-dependent manner in ASPC-1 and PANC-1. APS in combination with apatinib showed enhanced inhibitory effects on cell migration and invasion compared with apatinib monotherapy in ASPC-1 and PANC-1. Meanwhile, APS combined with apatinib strongly increased cell apoptosis percentage. Western blotting showed that the combination of APS and apatinib significantly enhanced the downregulation of phosphorylated protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (p-AKT and p-ERK) as well as matrix metalloproteinases-9 (MMP-9) expression. In addition, both apatinib and APS induced cellular autophagy. However, the expression of autophagy-related proteins was not further elevated in the combination group. Conclusion: The study first demonstrated that apatinib showed potentially inhibitory effects in pancreatic cancer cells and that APS enhanced the antitumor effects of apatinib through further downregulating the expression of phosphorylation of AKT and ERK as well as MMP-9. [ABSTRACT FROM AUTHOR]

Arthrobacter pascens ZZ21 is a plant-beneficial, fluoranthene-degrading bacterial strain found in the rhizosphere. The production of the phytohormone indole-3-aectic acid (IAA) by ZZ21 is thought to contribute to its ability to promote plant growth and remediate fluoranthene-contaminated soil. Using genome-wide analysis combined with metabolomic and high-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses, we characterized the potential IAA biosynthesis pathways in A. pascens ZZ21. IAA production increased 4.5-fold in the presence of 200 mgL-1 tryptophan in the culture medium. The transcript levels of prr and aldH, genes which were predicted to encode aldehyde dehydrogenases, were significantly upregulated in response to exogenous tryptophan. Additionally, metabolomic analysis identified the intermediates indole-3-acetamide (IAM), indole-3-pyruvic acid (IPyA), and the enzymatic reduction product of the latter, indole-3-lactic acid (ILA), among the metabolites of ZZ21, and subsequently also IAM, ILA, and indole-3-ethanol (TOL), which is the enzymatic reduction product of indole-3-acetaldehyde, by HPLC-MS. These results suggest that the tryptophan-dependent IAM and IPyA pathways function in ZZ21. [ABSTRACT FROM AUTHOR]

Abstract: We retrospectively compared the outcomes of children with severe aplastic anemia (SAA) who received immunosuppressive therapy (IST) or who underwent hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (HID), between 2007 and 2016. A total of 52 children with SAA under the age of 17 years were initially treated with IST (n = 24) or haploidentical HSCT (n = 28) as first‐line treatment. The estimated 10‐year overall survival was 73.4 ± 12.6% and 89.3 ± 5.8% in patients treated with IST or HID‐HSCT (P = .806). The failure‐free survival was significantly inferior in patients receiving IST than in those undergoing transplantation from an HID (52.6 ± 10.5% vs 89.3 ± 5.8, P = .008). In univariate and multivariate analysis, the choice of first‐line immunosuppressive therapy was the only adverse predictor for failure‐free survival. At the last follow‐up, completely normal blood count was observed in 11 of 20 (55.0%) and 24 of 25 (96.0%) live cases in IST and HID‐HSCT cohort (P = .003). These suggest that HSCT from a haploidentical donor could be considered as first‐line treatment in children who lack a matched related donor, especially in experienced transplantation centers. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the anticancer activity of polysaccharide (PGL) from Glehnia littoralis on human lung cancer cell line A549. Based on MTT assay, the results suggested that PGL could significantly reduce A549 cells proliferation in a time- and dose-dependent manner. In addition, PGL displayed an inhibitory activity for the A549 cells migration in Transwell migration assay. The results from both flow cytometry analysis and Hochst 3342 staining of apoptotic cells indicated that PGL could promote apoptosis, and induce cycle arrest of A549 cells. Moreover, immunofluorescence assay elucidated PGL could also down-regulate expression of proliferating cell nuclear antigen (PCNA). Overall, these results showed that PGL exerts a strong anticancer action through inhibiting the A549 cells migration, proliferation and inducing cell apoptosis. It could be a new source of natural anticancer agent against lung cancer with potential value in supplements and medicine. [ABSTRACT FROM AUTHOR]

The treatment of brain arteriovenous malformations supplied by deep perforating arteries (PA) (P-BAVM) remains challenging. The aims of this study were to determine the outcomes after surgical treatment in patients with P-BAVMs and to identify the risk factors associated with postoperative neurological deficits. We retrospectively reviewed the medical charts and imaging records of 228 consecutive patients with BAVMs who underwent microsurgical resection of their BAVMs at Beijing Tiantan Hospital between September 2012 and March 2016. Patients were included if the BAVMs were totally or partially supplied by PA. All patients had undergone preoperative diffusion tensor imaging (DTI), MRI, 3D time-of-flight MRA (3D TOF-MRA) and digital subtraction angiography (DSA) followed by resection. Both functional and angioarchitectural factors were analysed with respect to the postoperative neurological deficits, including motor deficits, visual field deficits and aphasia. Statistical analysis was performed using the statistical package SPSS (version 20.0.0, IBM Corp.). Fifty-nine patients with P-BAVMs were enrolled. Radical obliteration was achieved in all P-BAVMs according to postoperative DSA. Forty-five (76.3%) patients obtained neurological deficits 1 week after surgery. At a mean follow-up of 14.7 ± 9.4 (3-30) months after surgery, 34 patients (57.6%) had long-term neurological deficits. Multivariable logistic regression analyses showed that a shorter lesion-to-eloquent fibre tracts distance (LFD) was an independent risk factor for short- ( P = 0.014) and long-term ( P = 0.013) neurological deficits. The cut-off point of LFD for long-term neurological deficits was 5.20 mm. The predominant supply of the PA ( P = 0.008) was an independent risk factor for long-term neurological deficits. This study identified a high risk of surgical morbidity for P-BAVMs. The predominant supply of the PA and a shorter LFD are crucial risk factors for postoperative neurological deficits in patients with P-BAVMs. [ABSTRACT FROM AUTHOR]

Objective This study aimed to investigate the susceptibility of mice with streptozotocin(STZ)-induced diabetes mellitus (TIDM) to the uptake of pentavalent inorganic arsenic (iAs V ) and the possible molecular mechanism. Methods TIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na 2 HAsO 4 ·12H 2 O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues. Results The concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na 2 HAsO 4 ·12H 2 O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAs V , were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment. Conclusion The increased uptake of iAs V in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression. [ABSTRACT FROM AUTHOR]

Aims Despite more than a century of research, spinal paralysis remains untreatable via biological means. A new understanding of spinal cord physiology and the introduction of membrane fusogens have provided new hope that a biological cure may soon become available. However, proof is needed from adequately powered animal studies. Methods and results Two groups of rats (n=9, study group, n=6 controls) were submitted to complete transection of the dorsal cord at T10. The animals were randomized to receive either saline or polyethylene glycol ( PEG) in situ. After 4 weeks, the treated group had recovered ambulation vs none in the control group ( BBB scores; P=.0145). One control died. All animals were studied with somatosensory-evoked potentials ( SSEP) and diffusion tensor imaging ( DTI). SSEP recovered postoperatively only in PEG-treated rats. At study end, DTI showed disappearance of the transection gap in the treated animals vs an enduring gap in controls (fractional anisotropy/ FA at level: P=.0008). Conclusions We show for the first time in an adequately powered study that the paralysis attendant to a complete transection of the spinal cord can be reversed. This opens the path to a severance-reapposition cure of spinal paralysis, in which the injured segment is excised and the two stumps approximated after vertebrectomy/diskectomies. [ABSTRACT FROM AUTHOR]

Oxabicycloheptene sulfonate (OBHS) is a novel bicyclic core selective estrogen receptor modulator (SERM) with estrogen receptor (ER) antagonistic-activity and anti-inflammatory activity. However, little is known about protective action of OBHS on neurodegenerative disorders. In the present study, OBHS demonstrated a remarkably protective effect against amyloid beta (Aβ) induced cytotoxicity via G-protein-coupled estrogen receptor 1 (GPER1) in rat astroglial cell line (C6). The C6 cell death induced by Aβ was decreased by OBHS (1 μM) treatment for 45 min. This rapid protective action was blocked by GPER1 specific antagonist or siRNA knockdown. Inhibitors of phosphatidylinositol 3-kinase (PI3k)/Akt and extracellular signal-regulated kinase (ERK) activation also exhibited similar effects as GPER1 antagonist in blocking the protective effects of OBHS. Moreover, the expression of anti-apoptotic protein Bcl-2 was also increased by OBHS as a consequence of the activation of GPER1-PI3K/Akt and ERK pathways. Additionally, the phenyl sulfonate moiety of OBHS played a vital role in producing GPER1's agonist property according to the molecular docking analysis. These findings suggest that OBHS provide protection directed at enhancing glial cell survival through the activation of GPER1, which, in turn, offers a novel insight into the molecular mechanisms behind the potential application of OBHS in treating Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

OBJECTIVE We aimed to identify the features of micro RNA (mi RNA) at different fibrotic stages in patients with hepatitis B virus ( HBV)-related liver fibrosis. METHODS Liver tissues were collected from 40 chronic hepatitis B ( CHB) patients at fibrotic stages S0-4. Microarrays of mi RNAs and genomic informatics analysis were performed. RESULTS In total, 105 mi RNAs were differentially expressed in fibrotic tissues ( S1-4 groups) compared with no fibrotic tissues ( S0 group; P < 0.05). Combined with three classifications, 17 differential mi RNAs were found to be closely related to fibrotic stages (over twofold change and P < 0.05). Five mi RNAs had a signature that correlated with serum biochemical parameters and liver inflammatory grades. The receiver operating characteristic ( ROC) curve showed that six mi RNAs performed excellently in the diagnosis of liver fibrosis, with the area under the ROC curve (AUROC) over 0.8; among them hsa-mi R-214-3p had the highest AUROC (0.867). Gene ontology functions of differential mi RNAs mainly involved in the cellular and developmental processes, localization, biological regulation, binding, transcriptional regulator and organelle. We also found that 23 novel signaling pathways were dysregulated in the liver fibrosis. CONCLUSIONS Mi RNA profile signature, including 17 differential mi RNAs and 23 dysregulated signaling pathways, was associated with liver fibrosis. Hepatic inflammatory grades were correlated with the differential mi RNA. Some mi RNAs can be used for the diagnosis of liver fibrosis. [ABSTRACT FROM AUTHOR]

The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca 2 + release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca 2 + levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca 2 + release, ER Ca 2 + levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD. [ABSTRACT FROM AUTHOR]

Purpose: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novelCCM1gene mutation.Materials and methods: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. TheCCM1mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR).Results: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in theCCM1gene in the pedigree. Based on real-time RT-PCR results, we have found that theCCM1mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals.Conclusions: Our finding suggests that the novel nonsense mutation c.1159G>T inCCM1gene is associated with FCCM, and thatCCM1haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases. [ABSTRACT FROM PUBLISHER]

Objective We aimed to describe our single-center experience in treating cerebellar arteriovenous malformations (AVMs) with microsurgical resection. Methods During a 16-year period, 181 patients with cerebellar AVMs were surgically treated at the Department of Neurosurgery in Beijing Tiantan Hospital. Patient functional status was evaluated using modified Rankin Scale (mRS) scores both before treatment and at the last follow-up. The mRS scores at the last follow-up were dichotomized as good outcome (mRS <3) and poor outcome (mRS ≥3). The treatment modalities, post-treatment complications, obliteration rate, and follow-up outcomes were analyzed. Results Of the 181 patients, 172 (95%) patients presented with initial hemorrhage and 62 (34%) patients experienced rehemorrhage before microsurgical treatment. Complete obliteration of the AVMs was achieved in 177 (97.8%) patients. Good functional outcome was achieved in 144 (80%) of the patients. The surgical mortality rate was 4.4% (8/181), and overall mortality rate was 6.6% (12/181). Poor outcome was significantly associated with increasing age ( P = 0.035; odds ratio [OR], 1.030; 95% CI 1.002–1.060), presurgical mRS ≥3 ( P = 0.029; OR, 2.563; 95% CI 1.101–5.968), eloquent AVM location ( P = 0.015; OR, 3.058; 95% CI 1.244–7.516), and presurgical rehemorrhage ( P = 0.008; OR, 3.266; 95% CI 1.358–7.858). Conclusion Good outcome can be achieved by microsurgical resection in most patients with cerebellar AVMs. Increasing age at surgery, poor presurgical functional status, eloquent AVM location, and presurgical rehemorrhage are independent predictors of poor outcomes after AVM resection. We recommend early surgical resection for all surgically accessible cerebellar AVMs to prevent subsequent hemorrhage and resultant poor neurologic outcomes. [ABSTRACT FROM AUTHOR]

Background : Revascularization of the heart after myocardial infarction (MI) using growth factors delivered by hydrogel-based microspheres represents a promising therapeutic approach for cardiac regeneration. Microspheres have tuneable degradation properties and support the prolonged release of soluble factors. Cardiac patches provide mechanical restraint, preventing dilatation associated with ventricular remodelling. Methods: We combined these approaches and produced a compacted calcium-alginate microsphere patch, restrained by a chitosan sheet, to deliver vascular endothelial growth factor (VEGF) to the heart after myocardial injury in rats. Results: Microspheres had an average diameter of 3.2 μm, were nonporous, and characterized by a smooth dimpled surface. Microsphere patches demonstrated prolonged in vitro release characteristics compared to non-compacted microspheres and VEGF supernatants obtained from patches maintained their bioactivity for the 5 day duration of the study in vitro . In vivo , patches were assessed with magnetic resonance imaging following MI, and demonstrated 50% degradation 25.6 days after implantation. Both VEGF (−) and VEGF (+) microsphere patch-treated hearts had better cardiac function than unpatched (chitosan sheet only) controls. However, VEGF (+) microsphere-patched hearts had thicker scars characterized by higher capillary density in the border zone than did those treated with VEGF (−) patches. VEGF was detected in the patches 4 weeks post-implantation. Conclusion: The condensed microsphere patch represents a new therapeutic platform for cytokine delivery and could be used as an adjuvant to current biomaterial and cell-based therapies to promote localized angiogenesis in the infarcted heart. Statement of Significance Following a heart attack, a lack of blood flow to the heart results in loss of heart cells. Growth factors may facilitate growth of blood vessels and heart tissue repair and prevent the onset of heart failure. Determining a way to deliver these growth factors directly to the heart is vital. Here, we combined two biomaterial-based approaches to deliver vascular endothelial growth factor (VEGF) to rat hearts after heart attack: a microsphere for prolonged release of VEGF, and a cardiac patch for mechanical restraint to prevent heart dysfunction. The feasibility of this microsphere patch was demonstrated by surgically implanting it over the infarct region of the heart post-injury. VEGF-patched hearts had better blood vessel growth, tissue repair, and heart function. [ABSTRACT FROM AUTHOR]

Objective Endoscopic biliary radiofrequency ablation (RFA) has been increasingly used to treat unresectable malignant biliary obstruction (MBO). We aimed to perform this systematic review and meta-analysis to evaluate the efficacy and safety for the treatment of malignant biliary obstruction (MBO) and its impact on patient's survival. Methods A comprehensive search of the Cochrane Library, PubMed and EMBASE databases was conducted. A meta-analysis was performed by extracting the data from the included studies with regard to technical effectiveness, overall survival, adverse events and mortality of endoscopic RFA. Results A total of nine studies comprising 263 patients with MBO were included in the analysis. There was a significant increase in the diameter of stricture (3.446 mm, 95% confidence interval [CI] 3.356-3.536 mm) after the endoscopic biliary RFA. The overall survival time was 9.62 months, with pooled 30-day, 90-day and 2-year mortality rates of 2% (95% CI 0.5-5.9%), 21% (95% CI 5-37%), and 48% (95% CI 37-59%), respectively. The pooled rate of adverse events was 17% (95% CI 10-25%), and most complications were mild and managed conservatively. Severe adverse events occurred in three patients (two deaths due to hemobilia and one with partial liver infarction). Conclusions Endoscopic biliary RFA is effective and generally safe in the management of unresectable biliary malignancies, and may improve patients' overall survival. Prospective, randomized controlled studies are required to further support the results. [ABSTRACT FROM AUTHOR]

Background: Burn-induced hypertrophic scars are disfiguring and can be associated with severe and intractable pruritus. No effective treatment modalities are currently available for symptomatic control of pruritus for most patients. We assessed the effect of the Antipruritic Hydrogel (CQ-01) in the symptomatic treatment of severe and intractable pruritus associated with burn-induced hypertrophic scars in a prospective, multicenter, controlled trial.Methods: A pilot study was conducted in healthy adult volunteers to identify the most appropriate hydrogel formulation. A selected preparation called Chongqing No. 1 (CQ-01; a guar gum-based hydrogel impregnated with peppermint oil, menthol, and methyl salicylate by a nanoemulsion), showed an excellent symptomatic relief in an exploratory study in 2 patients with intractable pruritus. A statistically powered, prospective, multicenter, controlled study was then conducted in 74 patients to evaluate the efficacy and safety of a 24-h application of CQ-01 compared to a gel control and a negative control on three separate areas in each patient. Symptom assessment was based on our visual analog JW scale (ranging from 0 to 100) at baseline and various time points up to 7 days after application. Follow-up studies were conducted to determine the reproducibility of CQ-01 in repeated applications.Results: Of the 74 enrolled subjects, the only observed adverse event was skin irritation reported in 6 patients (8%) and resolved shortly after gel removal. Compared to the baseline, the gauze negative control had a mean JW score reduction of 7; while the gel control and CQ-01 had a drop of 18 (p<0.001) and 36 (p<0.001), respectively. The CQ-01 clinical effect was significant for up to 3 days and waned slowly from 3 to 7 days. There was no statistical correlation between the treatment response and any of the demographic, patient or burn-related factors. Further studies showed a trend that repeated applications might be more effective, suggesting the absence of tachyphylaxis.Conclusions: This prospective, multicenter, controlled study showed that this novel hydrogel CQ-01 is safe and provides significant symptomatic relief for severe and intractable pruritus associated with hypertrophic scars, an unmet medical need for these patients. This effect is independent of the etiology of the burn trauma, extent of the scarring, and duration of the scar formation. [ABSTRACT FROM AUTHOR]

Purpose: We generated a folate-conjugated porphyrin nanoparticle (porphysome) suitable for multimodal non-invasive active macrophage tracking post-myocardial infarction (MI).Procedures: Macrophage uptake of folate-conjugated porphysomes was selective. Folate-porphysome cardiac macrophage tracking was detected in vivo using radioligand and fluorescent imaging. To track post-MI macrophage mobilization, cardiac fluorescence signal in folate-porphysome-injected mice was measured for 9 day post-MI. Active macrophage phenotype was assessed using immunohistochemistry.Results: Heart active macrophage presence peaked on day 1, returned to baseline by day 3, and peaked again on day 7 post-MI. Macrophages were distributed throughout the left ventricle at day 1, but aggregated within scar tissue at day 7. Macrophage phenotype was pro-inflammatory (TNFα(+)) at day 1, whereas scar-resident macrophages expressed anti-inflammatory markers (IL-10, TGFβ) at day 7. However, day 7 macrophages outside the scar expressed neither pro- nor anti-inflammatory markers.Conclusions: We established that folate-porphysomes are suitable for non-invasive imaging of macrophages and used it to investigate active macrophage behavior in the infarcted heart. [ABSTRACT FROM AUTHOR]

Background: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer.Methods: Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed.Results: Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors.Conclusions: These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

ContextMurraya paniculata(L.) Jack (Rutaceae), Qianlixiang in Chinese, is distributed in China. As an important traditional Chinese medicine (TCM), it demonstrates many bioactivities, such as febrifuge, astringent, anti-dysenteric, and tonic. Objective: The objective of this study is to evaluate the anti-inflammatory effect of three flavonoids isolated fromM. paniculatain lipopolysaccharide (LPS)-activated murine macrophage cell line and ethanol-induced gastric damage on gastric epithelial cell (GES-1). Materials and methodsThree identified flavonoids were isolated from stems and leaves ofM. paniculatausing ultra performance liquid chromatography (UPLC). Cell viability was measured with MTT, mouse peritoneal macrophages and GES-1 cells were incubated with 0, 0.01, 0.1, 1, 10, and 100 μM P1, P3 and P8 for 24, 48, and 72 h. The inhibitory effect of pretreatment with various concentrations of 5,7,3′,4′,5′-pentamethoxyflavone (P1), 5,7,3′,4′-tetramethoxyflavone (P3), or 5-desmethylnobiletin 5-hydroxy-6,7,8,3′,4′-pentameth-oxyflavone (P8) ranging from 0.03 to 30 μM on nitric oxide (NO) secretion was quantified by the Griess assay for 24 and 48 h, while interleukin-6 (IL-6) was measured by ELISA for 24 and 48 h. ResultsThe effects ofP1,P3, andP8on mouse peritoneal macrophages and GES-1 cells were not attributable to cytotoxic effects at the doses of 0–10 μM. The IC50value of P1 is 53.40 μM, P3 is 120.98 μM, and P8 is 10.73 μM. The concentration of the three flavonoids had the best effects of anti-inflammation upon NO inhibition at the dose of 3 μM.P3had the highest inhibition on IL-6 production. The GES-1 cells pretreated with three flavonoids showed a significant increase in the level of NO (P1: 7.94 ± 0.0635 μM,P3: 8.81 ± 0.0159 μM, andP8: 8.51 ± 0.0522 μM) at 24 h and a more significant increase at 48 h (P1: 9.34 ± 0.0975 μM,P3: 11.9 ± 0.0672 μM, andP8: 9.34 ± 0.0454 μM). Discussion and conclusionThe current results suggested that the anti-inflammatory activity of three flavonoids was mainly manifested in the reduction of production of NO and IL-6 production. Analysis of the structure–activity relationship indicated that the double bond at C2–C3and the position of the B ring at C2/C3seemed to be indispensable for the anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Objective To explore outcomes after microsurgery of brain arteriovenous malformations (AVMs) that failed to be obliterated by Gamma Knife radiosurgery (GKRS). Methods From January 2000 to January 2014, 42 consecutive patients underwent surgical resection of persistent AVMs after GKRS. These 42 patients with AVMs who underwent radiosurgery (radiosurgery group) were individually matched with 42 patients with AVMs who did not undergo radiosurgery (no radiosurgery group) based on patient and AVM characteristics. The modified Rankin Scale was used to assess neurologic status of patients. The effects of GKRS on AVM resection and surgical outcomes were analyzed. Results After GKRS, the mean AVM volume was significantly reduced by 76.8% ( P < 0.01), the size was reduced by 41% ( P < 0.01), and the Spetzler-Martin grade was reduced in 61.9% of the patients ( P < 0.01). During the time interval from radiosurgery to surgical resection, subsequent hemorrhages led to significant neurologic deterioration ( P = 0.046). Compared with the control group, the frequency of preoperative embolization, operative time, and blood loss were significantly lower in the radiosurgery group (all P < 0.05). The no radiosurgery group had a significantly higher rate of worsening in mRS scores at 6 months after surgery (40.5% vs. 16.7%, P = 0.029). Good neurologic status (mRS score <3) was achieved in 81% of the radiosurgery group and 83% of the no radiosurgery group at the final follow-up evaluation. Conclusions GKRS performed several years before microsurgical resection can facilitate resectability of AVMs and decrease the rate of postoperative neurologic deterioration. For patients with persistent AVMs several years after GKRS, microsurgical resection is recommended to achieve good clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective To identify whether age, sex, and lesion location are associated with initial presentation in patients with brain arteriovenous malformations (AVMs). Methods Collected data of 3299 consecutive patients with AVM treated at Beijing Tiantan Hosptial from January 1980 to January 2015 were analyzed. The variables assessed were age at diagnosis, sex, AVM location, and mode of initial presentation. Results Initial presentation was AVM hemorrhage in 57.9%, seizure in 20.9%, chronic headache in 14.9%, focal neurologic deficit in 5.2%, and incidental in 1.2%. Younger age and female sex were associated with initial hemorrhage (all P < 0.05). Hemorrhage was more likely to occur in patients with AVMs in the basal ganglia, the corpus callosum, the ventricles, the cerebellum, and the brainstem (all P < 0.05). Male sex was associated with initial seizure ( P < 0.05). Initial seizure was more likely to occur in patients with AVMs in the frontal, temporal, parietal, frontotemporal, and frontoparietal lobe (all P < 0.05). Compared with frontal AVMs, temporal AVMs were more likely to present with hemorrhage ( P < 0.05) and less likely to present with seizure ( P < 0.05). AVMs involving the occipital lobe were more likely to present with chronic headaches ( P < 0.05). Conclusions Initial AVM presentation varied with patient age, sex, and AVM locations. Younger age, female sex, and deep and infratentorial locations may be associated with initial hemorrhage. Male sex and frontal, temporal, and parietal AVM locations may be predictors of initial seizure. Chronic headache was more likely to occur in patients with AVMs involving the occipital lobe. [ABSTRACT FROM AUTHOR]

It has been suggested that continuous exposure of peritoneal mesothelial cells (PMCs) to high glucose-containing peritoneal dialysis (PD) solutions may result in peritoneal inflammatory injury and impairment of local peritoneal host defence. Here, we investigated the effect of glucose-based PD solutions on mitochondrial reactive oxygen species (ROS) and nod-like receptor 3 (NLRP3) inflammasome activation in human PMCs (HPMCs). Exposure of HPMCs to high glucose-based PD solutions resulted in ROS production, which can trigger NLRP3 activation, leading to IL-1β secretion. Additionally, resveratrol (RSV) treatment induced mitophagy/autophagy via adenosine monophosphate-activated protein kinase (AMPK) activation. Increased mitochondrial ROS concentrations and IL-1β upregulation were confirmed following inhibition (siRNA against Beclin1 and ATG5 or autophagy inhibitor 3MA), but not induction (RSV), of mitophagy/autophagy. Furthermore, we observed that ATG5 and Beclin1 downregulation sensitised cells to IL-1β release induced by MSU or nigericin, which is an NLRP3 inflammasome activator. RSV treatment attenuated this effect. Taken together, this study may provide a potential therapeutic strategy for peritoneal inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS. [ABSTRACT FROM AUTHOR]

Objective We reviewed our prospective study of patients with occipital arteriovenous malformations (AVMs) to assess whether the display of optic radiation diffusion tensor imaging (DTI) during neuronavigation-guided surgery can reduce the severity of postoperative visual field deficits (VFDs) and to evaluate the factors associated with visual field preservation. Methods Forty-six consecutive patients with occipital AVMs were randomized in our study. DTI of the optic radiation was displayed during neuronavigation surgery in 24 patients. The other 22 patients were treated surgically without neuronavigation. Modified Rankin Scale (mRS) scores and visual fields were evaluated preoperatively, immediately after surgery, and at the last follow-up. Results The patients' baseline characteristics and AVM features were statistically similar between the 2 surgical groups. The postoperative obliteration rate was 100%. The postoperative mRS scores did not differ between the 2 groups ( P > 0.05). Preexisting VFDs were more common ( P = 0.00004) in patients who bled than in those with unruptured AVMs. The application of DTI-incorporated neuronavigation reduced the frequency and severity of postoperative VFDs ( P = 0.013 and 0.001, respectively). Visual fields were more likely to be preserved in patients with an AVM >5 mm from the optic radiation ( P = 0.025). Conclusions A history of hemorrhage is an independent risk factor for VFDs associated with occipital AVMs. Although not showing superiority in postoperative mRS, functional MRI navigation-guided surgery may help to radically resect occipital AVMs and preserve patient visual fields. A 5-mm distance from the optic radiation may be a suitable safety margin for visual field preservation. [ABSTRACT FROM AUTHOR]

Background and Aim: Endoscopic management of benign biliary stricture (BBS) remains challenging. There is no reported method for the amelioration of biliary fibroplasia endoscopically. We report our initial experience of radiofrequency ablation (RFA) for the management of BBS. Methods: Nine patients with BBS (postoperation stricture four, liver transplant three, and chronic inflammation two), seven of whom had previously unsuccessful endoscopic or percutaneous interventions, were enrolled. Intraductal bipolar RFA was delivered at power of 10 W for 90 s per stricture segment, followed by balloon dilatation with/without stent placement. Results: All patients had immediate stricture improvements after RFA. No severe adverse event occurred except for one patient with mild post-endoscopic retrograde cholangiopancreatography pancreatitis. During median (SD) follow-up duration of 12.6 (3.9) months, BBS resolution without the need for further stenting was achieved in four patients whereas two patients had stent(s) in situ waiting scheduled removal. However, one patient had stricture relapse after initial resolution, one underwent surgery, and another patient died of other cause. Conclusions: Endobiliary RFA appears to be safe and effective for the treatment of BBS, especially for refractory cases. Further studies are warranted. [ABSTRACT FROM AUTHOR]

Background Aquagenic acrokeratoderma (AA) is a rare condition with female predilection that occurs after brief water exposure and disappears minutes to an hour after drying. The pathogenesis remains unclear. Methods Four Chinese patients with AA were reported and analyzed. Results There were 2 males and 2 females (age range: 14-33 years) who presented with a 2-week to more than 10-year history of small white papules coalescing into edematous plaques on the hands; lesions appeared within 5-10 minutes of water exposure, began to regress in 3–20 minutes and disappeared within 5 minutes to one hour after drying. Warm water provoked the lesions more rapidly than cold water. Lesions of a female patient could be triggered by detergent. In another female patient, lesions also involved the feet and were associated with palmoplantar erythema and hyperhidrosis. Biopsy from the lesion of one patient after water exposure revealed hyperkeratosis, mild hypergranulosis, and dilatated eccrine ducts. Biopsy from the lesion of another patient after drying showed normal epidermis and dermis. Two patients were treated with topical formalin 3% in alcohol, and two with 3% potassium aluminium sulfate solution with partial relief without any adverse effects. Conclusion AA may occur in both males and females and may involve the feet. Warm water triggers the lesions more rapidly than cold. Topical formalin 3% in alcohol and 3% potassium aluminium sulfate solution may be optional therapy. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic analysis of family data on blood pressure (BP) is often compromised by the effects of antihypertensive medications. A review of numerous clinical trials that investigated the effects of BP-lowering medications is summarized here. Methods: Published clinical trials, including 137 clinical trials with monodrug therapies and 28 clinical trials of combination drug therapies with a total of 11,739 participants, were reviewed from PubMed. Six major classes/groups of antihypertensive medications were categorized by ethnicity, including angiotensin-converting enzyme (ACE) inhibitors, α1-blockers, cardioselective β-blockers (β1-blockers), calcium channel blockers, thiazide and thiazide-like diuretics, and loop diuretics. Results: Using sitting or supine BP, for ethnic groups combined, monodrug therapy with ACE inhibitors showed a weighted average effect of lowering the systolic and diastolic BP by 12.5/9.5 mm Hg; α1-blockers by 15.5/11.7 mm Hg; β1-blockers by 14.8/12.2 mm Hg; calcium channel blockers by 15.3/10.5 mm Hg; thiazide diuretics by 15.3/9.8 mm Hg; and loop diuretics by 15.8/8.2 mm Hg. However, ACE inhibitors, α1-blockers, and β1-blockers were less effective in African Americans than in non-African Americans, whereas calcium channel blockers, thiazide diuretics, and loop diuretics were more effective in African Americans than in non-African Americans. For two-drug combination therapy with ethnic groups combined, the BP-lowering effect of the second medication, when compared to its effect as monodrug therapy, was 84% and 65% for systolic and diastolic BP, respectively. Conclusions: The BP-lowering effects reported here may be used to impute the pretreatment BP levels, which can improve the information content and hence the power of epidemiologic analysis in studies where use of antihypertensive medications is a confounding factor in the BP measurements. [Copyright &y& Elsevier]

Background: Silver and photothermal therapy (PTT) have been widely used for eradicating the drug-resistant bacteria. However, the risks of excess of silver for humans and the low efficiency of PTT still limit their in vivo therapeutic application. Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. Results: In this study, a chemo-photothermal therapeutic platform based on polydopamine (PDA)-coated gold nanorods (GNRs) was developed. The PDA coating acquired high Ag+ ions loading efficiency and Cy5-SE fluorescent agent labeled glycol chitosan (GCS) conjugation (Ag+-GCS-PDA@GNRs). This platform became positively charged in the low pH environment of the abscess, allowing their accumulation in local infection site as revealed by thermal/florescence imaging. The loaded Ag+ ions was released in a pH-sensitive manner, resulting in selective Ag+ ions delivery to the abscess environment (pH ~ 6.3). More importantly, the ultralow dose of Ag+ ions could effectively damage the bacterial membrane, causing the permeability increase and the heat resistance reduction of the cell membrane, leading to the large improvement on bactericidal efficiency of PTT. On the other hand, the hyperthermia could trigger more Ag+ ions release, resulting in further improvement on bactericidal efficiency of chemotherapy. Combinational chemo-hyperthermia therapy of Ag+-GCS-PDA@GNRs could thoroughly ablate abscess and accelerate wound healing via a synergistic antibacterial effect. Conclusions: Our studies demonstrate that Ag+-GCS-PDA@GNRs is a robust and practical platform for use in chemo-thermal focal infection therapy with outstanding synergistic bacteria ablating. [ABSTRACT FROM AUTHOR]

Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter A1 (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypo-phosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Sp1), protein kinase C ζ (PKCζ) and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Sp1, PKCζ and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKCζ/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27. [ABSTRACT FROM AUTHOR]

Objective The treatment of brain arteriovenous malformations (BAVMs) supplied by the anterior choroidal artery (AChA), or aBAVMs, remains challenging. The aim of this study was to determine the surgical outcomes and risk factors for worsened muscle strength (MS) after surgery in patients with aBAVMs. Methods We retrospectively reviewed 266 consecutive patients with BAVMs who underwent microsurgical resection of their BAVMs between September 2012 and June 2016. Patients were included if the BAVMs were entirely or partially supplied by the AChA. All patients had undergone preoperative diffusion tensor imaging, magnetic resonance imaging, 3-dimensional time-of-flight magnetic resonance angiography, and digital subtraction angiography followed by resection. Both functional and angioarchitectural factors were analyzed with respect to the change in MS. Results We identified 29 patients with aBAVMs who underwent surgical resection of the nidus. Radical resection was achieved in all patients. Thirteen (44.8%) patients suffered from postoperative short-term and 11 (37.9%) suffered from long-term MS deterioration. A shorter lesion-to-corticospinal tract distance (LCD) ( P = 0.004) was significantly associated with postoperative short-term worsened MS. Shorter LCD ( P = 0.018) and nidus supplied by cisternal segment of AChA ( P = 0.026) were independent risk factors for the long-term MS worsening. The amplitudes and potential changes of intraoperative motor-evoked potential monitoring were consistent with the surgical outcomes. Conclusions Surgical treatment of aBAVMs can cause a high incidence of MS deficits. Niduses supplied by cisternal segment of AChA and shorter LCD were crucial risk factors for postoperative MS worsening. Motor-evoked potential monitoring was an effective intraoperative technique to predict postoperative MS deficits. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have emerged as promising candidates for multiple biomedical applications. Major types of EVs include exosomes, microvesicles, and apoptotic bodies (ABs). ABs are conferred most properties from parent cells in the final stages of apoptosis. A wide variety of sources and stable morphological features are endowed to ABs by the rigorous apoptotic program. ABs accommodate more functional biomolecules by relying on the larger volume and maintaining their naturalness in circulation. The predominant body surface ratio of ABs facilitates their recognition by recipient cells and is advantageous for interactions with microenvironments. ABs can modulate and alleviate symptoms of numerous diseases for their origins, circulation, and high biocompatibility. In addition, ABs have been emerging in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. Here, we aim to present a thorough discussion on current knowledge about ABs. Of particular interest, we will summarize the application of AB-based strategies for diagnosis and disease therapy. Perspectives for the development of ABs in biomedical applications are highlighted. [Display omitted] • Apoptotic bodies (ABs), released during apoptosis, are a unique subset of extracellular vesicles (EVs). • Advanced techniques provide excellent opportunities for studying ABs for biomedical applications. • ABs-mediated transportation of biomolecules is important in physiological processes and disease development. • ABs are playing an emerging role in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. [ABSTRACT FROM AUTHOR]

Objective Temporo-occipital junction arteriovenous malformations (TOJ-AVMs) do not often involve eloquent brain cortex, but rather exist beside functional fiber tracts. The objective of this study was to determine the outcomes after surgical treatment in patients with TOJ-AVMs and to identify risk factors associated with postoperative neurologic deficits. Methods We retrospectively studied 41 patients with TOJ-AVMs. All patients underwent preoperative diffusion tensor imaging. Every potentially involved function (visual field and language) was studied as an independent function object (FO). The function-related optic radiation or arcuate fasciculus was tracked. Lesion-to-eloquent fiber distances (LFDs) were analyzed in regard to postoperative neurologic deficits. The areas under the receiver operating characteristic curves were compared. Results There were 58 FOs analyzed. Of these, 26 (44.8%) FOs led to short-term neurologic deficits, and 21 (36.2%) FOs resulted in long-term neurologic deficits. LFD was a significant predictor of short-term ( P = 0.002) and long-term ( P = 0.007) neurologic deficits. The Spetzler-Martin (S-M) score was associated with short-term neurologic deficits ( P = 0.045), but it was not associated with long-term neurologic deficits. The area under the receiver operating characteristic curve of LFD was higher than that of the S-M score in predicting short-term neurologic deficits (0.89 vs. 0.72, P = 0.04) and long-term neurologic deficits (0.90 vs. 0.62, P = 0.002). The cutoff point for LFD in predicting long-term neurologic deficits was 3.10 mm. Conclusions Patients with TOJ-AVMs have a high risk of surgical morbidity, although they often have relatively low S-M scores; LFD is a crucial risk factor associated with postoperative neurologic deficits in patients with TOJ-AVMs. [ABSTRACT FROM AUTHOR]

Background Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with increased intracranial pressure, and these patients are unstable with a high risk of rebleeding. Computed tomography angiography (CTA) has been proposed as an examination tool for the rapid detection of ruptured aneurysms. We aimed to determine the safety and efficacy of CTA alone for surgical treatment of poor-grade aSAH compared with digital subtraction angiography (DSA). Methods We conducted a multicenter retrospective analysis of 144 patients with poor-grade aSAH who underwent surgical treatment for 2 different cohorts. Patients were grouped into CTA alone and DSA groups. Baseline characteristics, postoperative complications, and clinical outcomes at discharge and at last follow-up were compared between the 2 groups. Multivariate logistic regression models were used to assess the association between CTA alone and clinical outcomes after we adjusted for potential confounders. Results Of the 116 patients included, 42 (36.2%) patents received CTA alone and 74 patients (63.7%), including 12 patients with CTA and DSA and 62 patients with DSA alone, received DSA before surgical treatment. Patients with larger ruptured aneurysms ( P = 0.006), aneurysm sizes of larger than 5 mm ( P = 0.025), presence of single aneurysms ( P = 0.018), and presence of intraventricular hemorrhage ( P = 0.019) more often received CTA alone. All ruptured aneurysms were clipped successfully during surgery. There were no statistically significant differences in postoperative complications and clinical outcomes between the 2 groups. Conclusions Although CTA alone can be safely and effectively used in most patients requiring surgical treatment, additional DSA may be considered in patients with smaller ruptured aneurysms or in those with multiple aneurysms. [ABSTRACT FROM AUTHOR]

The rapid development and clinical trials of biodegradable nanoparticles (NPs) are heavily hindered by many factors, including poor drug loading, low drug concentration at disease sites, lack of active targeting function, etc . Herein, we developed a new smart and hype-responsive polyprodrug platform with five key elements ( i.e . chemically incorporated drug molecules in backbone, stimuli-responsive bond, hyper-fast chain-breakage ability, hydrophilic segment and targeting ligand). Using 10-hydroxycamptothecin (HCPT) as model drug, we designed and prepared an exemplified redox-responsive amphiphilic polyprodrug via polycondensation and “click” chemistry. This polymer is composed of a hydrophobic HCPT-based polyprodrug, a hydrophilic poly(ethylene oxide) (PEG) chain and a tumor-targeting RGD tail. Employing nanoprecipitation technique, small-sized NPs (<70 nm) can be obtained. The in vitro and in vivo results prove that this newly developed nanoplatform has the following unique characteristics: 1) high and constant drug loading (>36 wt.%), 2) excellent tumor-targeting performance, 3) hyper-fast redox-responsive drug release (around 70% accumulative release within 2 h), 4) long blood circulation and 5) significant inhibition of tumor growth without side effects. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop an efficient and no pollutants deproteinization method for polysaccharide (AGP) from Arca granosa based on the palygorskite adsorption treatment (PAT). Firstly, the optimal adsorption conditions were obtained by the response surface methodology (RSM) as follows: adsorption for 136 min at 60 °C with the dosage of 0.27 g. Under the optimal conditions, the deproteinization ratio (Dr%), recovery ratio (Rr%) and selectivity coefficient (K C) were 87.35 ± 0.44%, 92.89 ± 0.41% and 12.28 ± 0.64, respectively. Then, the adsorption kinetics and isotherms experiments indicated that the adsorption process was endothermic and spontaneous, and were fitted well by the pseudo-second-order equation and the Freundlich equation, respectively. In addition, compared with the classical Sevag method, the PAT method was proven to be reliable. More importantly, the palygorskite was reusable and the deproteinization process produced no pollutants. These results demonstrated that the PAT method present a highly efficient and environmental friendly technique for the large-scale deproteinization of polysaccharides. An efficient and no pollutants deproteinization method based on the palygorskite adsorption treatment (PAT) was developed successfully. The adsorption conditions, adsorption behaviors, and the reusability were investigated, respectively. In addition, the reliable of the PAT method was studied by compared with the Sevag method. Image 1 • Palygorskite adsorption deproteinization is proven effective and reliable. • Adsorption conditions of palygorskite adsorption treatment (PAT) are optimized. • The fundamental adsorption behaviors of the PAT method are investigated. • The PAT method is no pollutants and suitable for large-scale deproteinization. [ABSTRACT FROM AUTHOR]

Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9 mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68 + macrophage and CD11b + Gr1 + neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine. [ABSTRACT FROM AUTHOR]

NLRC5, as the largest member of nucleotide-binding domain and leucine-rich repeat (NLR) family, was involved in various physiological processes, such as inflammation, fibrosis, innate immunity and diabetic nephropathy. However, the role of NLRC5 in acute kidney injury remains unclear. The aim of this study was to investigate the role of NLRC5 in human renal proximal tubular epithelial cells (HK-2) exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that the expression of NLRC5 was significantly up-regulated in HK-2 cells exposed to H/R. Knockdown of NLRC5 significantly improved the viability of HK-2 cells exposed to H/R. In addition, knockdown of NLRC5 efficiently inhibited H/R-induced oxidative stress and apoptosis in HK-2 cells. Mechanistically, knockdown of NLRC5 markedly enhanced the activation of PIK3/Akt signaling pathway in H/R-stimulated HK-2 cells. In summary, our findings indicate that knockdown of NLRC5 attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background Seizure is the second-most common presentation in patients with arteriovenous malformations (AVMs) and superimposes a significant burden on pediatric patients. Postoperative seizure risk in unruptured AVMs is underreported in the pediatric AVM literature. We aimed to characterize and identify predictive factors for postoperative seizures in this study. Methods We performed a retrospective review of all surgically treated pediatric patients with unruptured AVM at our institution from 2001 to 2014. Patients younger than 18 years of age were included. Baseline variables was compared against our outcome of interest, which was defined as patients with or without follow-up seizures. Multivariable Cox regression was performed to identify potential predictive factors. Results The average age of all patients was 13.1 years, and 68.2% were male. Nine patients were asymptomatic (13.6%), and seizure presentation occurred in 57.6% ( n = 38). During an average follow-up of 4.2 years, 12 (18.2%) patients experienced postoperative seizures, with 5 (17.9%) of 28 patients with seizures being de novo. In patients with seizure presentation, 81.6% were completely seizure-free throughout follow-up. In multivariable analysis, larger AVM size (hazard ratio [HR] 1.63, P = 0.023) and temporal location (HR 8.35, P = 0.007) were found to increase the risk of follow-up seizures. On the contrary, seizure presentation (HR 1.91, P = 0.369) and postoperative infection (HR 2.37, P = 0.265) were not associated. Conclusions Surgery may eliminate most seizures with low risk of inducing de novo seizures in pediatric patients with unruptured AVM. Predictive factors for postoperative seizures included large AVM size and temporal location. For selected unruptured AVMs with small size and nontemporal location, consideration of surgery as primary treatment for persistent seizures is a reasonable option. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the efficacy of the topical administration of mupirocin and other practices in central venous catheter (CVC) care to prevent central line-associated bloodstream infections (CLABSI) in patients with major burns.Methods: Patients with major burns admitted to a burn ICU were divided into four groups and disinfected at the CVC exit site with single povidone iodine (PVP-I) or PVP-I plus topical mupirocin ointment three times a day or once a day, respectively. The bacterial colonization of the skin at the CVC exit site and CVC tips and the incidence of CLABSI were recorded, and the risk factors were analyzed.Results: Administering mupirocin (RR=0.316, p=0.001), increasing the frequency of insertion-site care (RR=0.604, p=0.008), and avoiding cannulation at the burn site (RR=0.148, p<0.001) reduced skin colonization at the CVC insertion site. Topical administration of mupirocin significantly reduces both the bacterial colonization rate at CVC tips (RR=0.316, p=0.001) and the incidence of CLABSI (5.3 vs. 29.1 per 1000 catheter days, p<0.001).Conclusions: Mupirocin is effective in the prophylaxis of CLABSI. Other CVC care practices were also found to affect the level of bacterial colonization, but their efficacy in preventing CLABSI needs to be evaluated further. [ABSTRACT FROM AUTHOR]