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Hepatic impairment in coronavirus disease 2019 (COVID-19) may derive from cholangiocyte damage in the beginning, but not from direct infection of hepatocytes. Chronic liver disease patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited overexpression of angiotensin-converting enzyme 2 receptors and overwhelming cytokine storm. Consensus has been reached that we should encourage as many people as possible to be vaccinated in order to achieve herd immunity. SARS-CoV-2 vaccines can prevent or alleviate severe infection and cytokine storm. It is recommended that all adult patients with chronic liver diseases and liver transplant recipients should receive COVID-19 vaccines using the standard dose and schedule. Data is not yet sufficient to compare the efficacy of different types of vaccines used in chronic liver disease patients.

Objective Healthcare agencies recommend limited use of aerosol‐generating procedures to mitigate disease (COVID‐19) transmission. However, total dispersion patterns of aerosols, particularly respirable droplets, via dental ultrasonic units is unclear. The purpose of this study was to characterize and map total spatter, droplet and aerosol dispersion during ultrasonic scaling in simulated and clinical contexts. Methods Ultrasonic scaling was performed on dental simulation units using methylene blue dye‐stained water. All resultant stain profiles were photoanalysed to calculate droplet size and travel distance/direction. Airborne particle concentrations were also documented 0–1.2 m (0–4ft.) and 1.2–2.4 m (4–8ft.) from patients during in vivo ultrasonic scaling with a saliva ejector. Results Stain profiles showed droplets between 25 and 50µm in diameter were most common, with smaller droplets closer to the mouth. In‐vivo particle concentrations were uniformly low. The smallest (10 µm, PM10+) particles were most common, especially within 1.2 m (4ft.) of the patient. Respirable particles (PM2.5) were uncommon. Conclusions Tests showed the highest concentration of small droplets in zones nearest the patient. While uncommon, particles were detected up to 2.4 m (8ft.) away. Furthermore, observed particle sizes were consistent with those that can carry infectious agents. Efforts to mitigate the spread of inhalable aerosols should emphasize proximate regions nearest the procedure, including personal protective equipment and the use of evacuation devices.

Panax notoginseng saponins (PNS), the main bioactive constituents of a traditional Chinese herb Panax notoginseng, were commonly used for ischemic stroke in China. However, the associated cellular and molecular mechanisms of PNS have not been well examined. This study aimed to decipher the underlying molecular target of PNS in the treatment of cerebral ischemia. The oxygen-glucose-deprived (OGD) model of rat brain microvascular endothelial cells (BMECs) was used in this study. The alteration of gene expression in rat BMECs after PNS treatment was measured by microarray and indicated that there were 38 signaling pathways regulated by PNS. Among them, RIG-I receptor and related signaling molecules TNF receptor-associated factor 2 (Traf2) and nuclear factor-kappa B (NF-κB) were significantly suppressed by PNS, which was verified again in OGD-induced BMECs measured by FQ-PCR and western blotting and in middle cerebral artery occlusion (MCAO) rats measured by immunohistochemistry. The levels of TNF-α, IL-8, and the downstream cytokines regulated by RIG-I receptor pathway were also decreased by PNS. Meanwhile, the neurological evaluation, hematoxylin and eosin (HE) staining, and Evans blue staining were conducted to evaluate the effect of PNS in MCAO rats. Results showed PNS significantly improved functional outcome and cerebral vascular leakage. Flow cytometry showed the number of the inflammatory cells infiltrated in brain tissue was decreased in PNS treatment. Our results identified that RIG-I signaling pathway mediated anti-inflammatory properties of PNS in cerebral ischemia, which provided the novel insights of PNS application in clinics.

Dentate nuclei (DN) are vital structures in the anatomical circuits that link the cerebellum to the cerebrum. However, the characteristics of DN functional connectivity (FC) in schizophrenia remain largely unknown. In this study, we investigated the FC of the DN in patients with schizophrenia and examined their possible clinical correlates using resting-state functional magnetic imaging data. We found that the patient group had greater DN FC with the parietal lobe (e.g., postcentral gyrus and superior parietal lobule) and less DN FC with the prefrontal cortex (e.g., superior frontal gyrus), posterior cingulate cortex, and regional cerebellum (e.g., vermis 4-5 and crus I) than did the control group. Furthermore, some abnormal connectivities of the DN with these regions significantly correlated with psychiatric symptoms. These results suggest that the DN circuits are disturbed and may participate in the pathophysiology of schizophrenia.

Background Corticotropin-releasing hormone (CRH) is an important neuromodulator that is widely distributed in the brain and plays a key role in mediating stress responses and autonomic functions. While the distribution pattern of fluorescently labeled CRH-expressing neurons has been studied in different transgenic mouse lines, a full appreciation of the broad diversity of this population and local neural connectivity can only come from integration of single-cell morphological information as a defining feature. However, the morphologies of single CRH neurons and the local circuits formed by these neurons have not been acquired at brain-wide and dendritic-scale levels. Results We screened the EYFP-expressing CRH-IRES-Cre;Ai32 mouse line to reveal the morphologies of individual CRH neurons throughout the whole mouse brain by using a fluorescence micro-optical sectioning tomography (fMOST) system. Diverse dendritic morphologies and projection fibers of CRH neurons were found in various brain regions. Follow-up reconstructions showed that hypothalamic CRH neurons had the smallest somatic volumes and simplest dendritic branches and that CRH neurons in several brain regions shared a common bipolar morphology. Further investigations of local CRH neurons in the medial prefrontal cortex unveiled somatic depth-dependent morphologies of CRH neurons that exhibited three types of mutual connections: basal dendrites (upper layer) with apical dendrites (layer 3); dendritic-somatic connections (in layer 2/3); and dendritic-dendritic connections (in layer 4). Moreover, hypothalamic CRH neurons were classified into two types according to their somatic locations and characteristics of dendritic varicosities. Rostral-projecting CRH neurons in the anterior parvicellular area had fewer and smaller dendritic varicosities, whereas CRH neurons in the periventricular area had more and larger varicosities that were present within dendrites projecting to the third ventricle. Arborization-dependent dendritic spines of CRH neurons were detected, among which the most sophisticated types were found in the amygdala and the simplest types were found in the hypothalamus. Conclusions By using the CRH-IRES-Cre;Ai32 mouse line and fMOST imaging, we obtained region-specific morphological distributions of CRH neurons at the dendrite level in the whole mouse brain. Taken together, our findings provide comprehensive brain-wide morphological information of stress-related CRH neurons and may facilitate further studies of the CRH neuronal system.

Background: The purpose of this study was to investigate whether Gastrodin can activate the Notch 1 signaling pathway in the ischemic brain area to produce neuroprotective effects against cerebral ischemia-reperfusion injury, and to elucidate the role of Notch 1 and NF-κB signaling pathways in the Gastrodin-induced cerebral ischemic tolerance. Material and methods: The focal cerebral ischemia reperfusion model of middle cerebral artery embolism was established. TTC staining was applied to detect cerebral infarction. Tunel/NeuN immunofluorescence double labeling was employed to detect apoptosis. WB was used to detect the expressions of proteins related to the Notch 1 and NF-κB pathways. Results: Gastrodin can reduce neuron apoptosis in hippocampus after MCAO/R injury. After DAPT blocked Notch 1 signaling, the neuroprotective effects of Gastrodin improving neural function score, reducing cerebral infarction volume, and inhibiting neuronal apoptosis, were all reversed. Compared with the MCAO/R group, DAPT blocking Notch 1 signaling can also improve the neurological score of rats after MCAO/R injury, reduce cerebral infarct volume, and reduce neuronal apoptosis. Gastrodin can activate Notch 1 and NF-κB signaling pathways in cerebral ischemic areas and increase the expression of related proteins. After DAPT inhibited the Notch 1 signaling in the ipsilateral brain region, the phosphorylation level was significantly decreased, indicating that the activity of the NF-κB pathway was regulated by the Notch 1 signaling. Conclusion: Gastrodin-mediated protection against cerebral ischemia-reperfusion injury is related to the activation of Notch 1 signaling and the up-regulation of NF-κB signaling pathway activity in neurons of ischemic brain area.

STUDY QUESTION Is there an association between the human testis-specific gene, testis developmental related gene 1 (TDRG1) and human sperm motility? SUMMARY ANSWER TDRG1 is associated with asthenozoospermia and involved in regulating human sperm motility. WHAT IS KNOWN ALREADY Many testis-specific proteins potentially regulate spermatogenesis and sperm motility. We have identified a novel human testis-specific gene, TDRG1, which encodes a 100-amino-acid protein localized in the human sperm tail, yet little is known about its role in human spermatozoa. STUDY DESIGN, SIZE, DURATION Sperm samples were obtained from normozoospermic men and asthenozoospermic men who visited the reproductive medical center at Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China between February 2018 and January 2019. In total, 27 normozoospermic men and 25 asthenozoospermic men were recruited to participate in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS The level of TDRG1 in sperm of normozoospermic and asthenozoospermic men was examined by immunoblotting and immunofluorescence assays. Progressive motility was examined by computer-aided sperm analysis. The correlation between the TDRG1 protein level and progressive motility was analyzed by linear regression. TDRG1 was imported into the sperm of normozoospermic and asthenozoospermic men using a cell-penetrating peptide (CPP)-fused TDRG1 recombinant protein (CPP-TDRG1), and the progressive motility was examined. Also, the altered proteins associated with TDRG1 in asthenozoospermic sperm were detected using label-free quantification method-based quantitative proteomic technology. TDRG1-interacting proteins were identified by co-immunoprecipitation coupled with tandem mass spectrometry analysis. MAIN RESULTS AND THE ROLE OF CHANCE The mean level of TDRG1 was significantly decreased in sperm of asthenozoospermic men compared with normozoospermic men (P LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The sample size was limited and larger cohorts are needed for verifying the positive effect of CPP-TDRG1 on human sperm motility. Furthermore, the caution should be paid that a comprehensive safety examination would be performed to evaluate whether CPP-TDRG1 is a possible treatment approach for asthenozoospermia. WIDER IMPLICATIONS OF THE FINDINGS Our results provide new insights into the mechanisms of sperm motility which may contribute to the diagnosis and treatment for asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S) National Natural Science Foundation of China (81501317 and 81871207 to H.C.; 81771644 to T.L.; 31671204 to X.Z.; 81571432 to Y.T.). The authors have no conflicts of interest to declare.

Background There is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC. Methods We constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG2000. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice. Results Delivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient. Conclusion Our results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.

Most tumors of the digestive system, including esophageal, gastric, liver and colorectal cancer, are malignant tumors that are associated with rates of high morbidity and mortality. The lack of effective methods for early diagnosis is an important cause of poor prognosis for these malignancies. Circular RNAs (circRNAs) belong to a family of endogenous, covalently closed non‑coding RNAs that are characterized as having no 5' cap structures or 3' poly‑A tails. Shortly following discovery, circRNAs were considered to be a product of mis‑splicing and have no significant biological function. However, in recent years, accumulating evidence is demonstrating that they serve key roles in tumorigenesis and have the potential to serve as diagnostic markers. The present article summarizes the biogenesis and function of circRNAs and reviews their role in seven common types of tumor of the digestive system whilst exploring their potential as tumor markers and the significant roles they can serve in the digestive system, in addition to providing a referencing point for future studies of digestive system malignancies.

Background: Although the use of expanded-criteria donors (ECDs) alleviates the problem of organ shortage, it significantly increases the incidence of delayed graft function (DGF). DGF is a common complication after kidney transplantation; however, the effect of DGF on graft loss is uncertain based on the published literature. Hence, the aim of this study was to determine the relationship between DGF and allograft survival. Methods: We conducted a retrospective, multicenter, observation cohort study. A total of 284 deceased donors and 541 recipients between February 2012 and March 2017 were included. We used logistic regression analysis to verify the association between clinical parameters and DGF, and Cox proportional hazards models were applied to quantify the hazard ratios of DGF for kidney graft loss. Results: Among the 284 deceased donors, 65 (22.8%) donors were ECD. Of the 541 recipients, 107 (19.8%) recipients developed DGF, and this rate was higher with ECD kidneys than with standard-criteria donor (SCD) kidneys (29.2% vs. 17.1%; P = 0.003). The 5-year graft survival rate was not significantly different between SCD kidney recipients with and without DGF (95.8% vs. 95.4%; P= 0.580). However, there was a significant difference between ECD kidney recipients with and without DGF (71.4% vs. 97.6%; P = 0.001), and the adjusted hazard ratio (HR) for graft loss for recipients with DGF was 1.885 (95% confidence interval [CI] = 1.305–7.630; P = 0.024). Results showed that induction therapy with anti-thymocyte globulin was protective against DGF (odds ratio= 0.359; 95% CI= 0.197–0.652; P= 0.001) with all donor kidneys and a protective factor for graft survival (HR = 0.308; 95% CI = 0.130–0.728; P = 0.007) with ECD kidneys. Conclusion: DGF is an independent risk factor for graft survival in recipients with ECD kidneys, but not SCD kidneys. Key words: Chronic kidney disease; Delayed graft function; Expanded-criteria donors; Graft survival; Standard-criteria donors

Carbaryl is the representative of carbamate insecticide. As an acetylcholinesterase inhibitor, it poses potential threat to humans and other non-target organisms. Agrobacterium sp. XWY-2, which could grow with carbaryl as the sole carbon source, was isolated and characterized. The carH gene, encoding a carbaryl hydrolase, was cloned from strain XWY-2 and expressed in Escherichia coli BL21 (DE3). CarH was able to hydrolyze carbamate pesticides including carbaryl, carbofuran, isoprocarb, propoxur and fenobucarb efficiently, while it hydrolyzed oxamyl and aldicarb poorly. The optimal pH of CarH was 8.0 and the optimal temperature was 30 ℃. The apparent Km and kcat values of CarH for carbaryl were 38.01 ± 2.81 μM and 0.33 ± 0.01 s−1, respectively. The point mutation experiment demonstrated that His341, His343, His346, His416 and D437 are the key sites for CarH to hydrolyze carbaryl.

Schizophrenia is a complex mental illness with genetic heterogeneity, which is often accompanied by alterations in brain structure and function. The neurobiological mechanism of schizophrenia associated with heredity remains unknown. Recently, the development of trans-scale and multi-omics methods that integrate gene and imaging information sheds new light on the nature of schizophrenia. In this article, we summarized the results of brain structural and functional changes related to the specific single-nucleotide polymorphisms (SNPs) in the past decade, and the SNPs were divided into non-coding regions and coding regions, respectively. It is hoped that the relationship between SNPs and cerebral alterations can be displayed more clearly and intuitively, so as to provide fresh approaches for the discovery of potential biomarkers and the development of clinical accurate individualized treatment decision-making.

Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic-pituitary-adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

Cotinine is a stable toxic contaminant, produced as a by-product of smoking. It is of emerging concern due to its global distribution in aquatic environments. Microorganisms have the potential to degrade cotinine; however, the genetic mechanisms of this process are unknown. Nocardioides sp. strain JQ2195 is a pure-culture strain that has been reported to degrade cotinine at micropollutant concentrations. This strain utilizes cotinine as its sole carbon and nitrogen source. In this study, a 50-kb gene cluster (designated cot), involved in cotinine degradation, was predicted based on genomic and transcriptomic analyses. A novel three-component cotinine hydroxylase gene (designated cotA1A2A3), which initiated cotinine catabolism, was identified and characterized. CotA from Shinella sp. strain HZN7 was heterologously expressed and purified and was shown to convert cotinine into 6-hydroxycotinine. H218O-labeling and electrospray ionization-mass spectrometry (ESI-MS) analysis confirmed that the hydroxyl group incorporated into 6-hydroxycotinine was derived from water. This study provides new molecular insights into the microbial metabolism of heterocyclic chemical pollutants. IMPORTANCE In the human body, cotinine is the major metabolite of nicotine, and 10 to 15% of generated cotinine is excreted in urine. Cotinine is a structural analogue of nicotine and is much more stable than nicotine. Increased tobacco consumption has led to high environmental concentrations of cotinine, which may have detrimental effects on aquatic ecosystems and human health. Nocardioides sp. strain JQ2195 is a unique cotinine-degrading bacterium. However, the underlying genetic and biochemical foundations of cotinine degradation are still unknown. In this study, a 50-kb gene cluster (designated cot) was identified by genomic and transcriptomic analyses as being involved in the degradation of cotinine. A novel three-component cotinine hydroxylase gene (designated cotA1A2A3) catalyzed cotinine to 6-hydroxy-cotinine. This study provides new molecular insights into the microbial degradation and enzymatic transformation of cotinine.

Introduction Standard bi-level non-invasive ventilation with fixed-level pressure support (PS) delivery may not maintain ventilation during the changes in pulmonary mechanics that occur throughout day and night, so average volume-assured pressure support (AVAPS) modes that target a preset volume by adjustment of PS may be effective. Objective Our meta-analysis wants to compare AVAPS and pressure support non-invasive ventilation (PS-NIV) regarding arterial blood gases (ABGs), sleep efficiency and compliance. Method Relevant publications indexed in PubMed, Cochrane Library, Embase, Web of Science, Wanfang Data, China National Knowledge Infrastructure and VIPI were identified. Appropriate articles identified from the reference lists of the above searches were also reviewed. We included randomized controlled trials involved the use of AVAPS and PS-NIV ventilation for chronic respiratory failure. Each included study weighted mean differences, and 95% confidence intervals (CI) were calculated for continuous outcomes. Statistical heterogeneity was assessed using the I2 value ≤ 50% were considered as no statistical heterogeneity and used fixed effects model. Otherwise, a random effects model was used. Results Eight trials were eligible. No significant difference was observed between AVAPS and PS-NIV groups to compare PaCO2 (OR -0.97, CI-2.54-0.61, P = 0.23) and PaO2 (OR -1.81, CI-4.29-0.67, P = 0.15) in ABGs. There was no significant difference between the two groups with sleep efficiency (OR -3.31, CI-7.58-0.95, P = 0.13) and visual analog scale (OR 0.32, CI-6.97-7.61, P = 0.93). Conclusions The evidence shows there is no significant difference in clinical outcomes when comparing AVAPS and PS-NIV used for chronic respiratory failure patients.

Purpose A better understanding of the underlying molecular mechanisms in treatment failure of bevacizumab (BEV) for malignant glioma would contribute to overcome therapeutic resistance. Methods Here, we used a quantitative proteomic method to identify molecular signatures of glioblastoma cell after BEV treatment by two-dimensional liquid chromatography-tandem mass spectrometry analysis and 6-plex iTRAQ quantification. Next, the function of cold-inducible RNA-binding protein (CIRP), one of the most significantly affected proteins by drug treatment, was evaluated in drug resistance of glioma cells by invasion assays and animal xenograft assays. Target molecules bound by CIRP were determined using RNA-binding protein immunoprecipitation and microarray analysis. Then, these mRNAs were identified by quantitative real-time PCR. Results Eighty-seven proteins were identified with significant fold changes. The biological functional analysis indicated that most of the proteins were involved in the process of cellular signal transduction, cell adhesion, and protein transport. The expression of CIRP greatly decreased after BEV treatment, and ectopic expression of CIRP abolished cell migration in BEV-treated glioma cells. In addition, CIRP could bind mRNA of CXCL12 and inhibit BEV-induced increase of CXCL12 in glioma cells. Conclusion These data suggested that CIRP may take part in BEV-induced migration of gliomas by binding of migration-relative RNAs.

Background. Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. Methods. Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of β-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 μmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. Results. Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. Conclusions. Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury.

Herein, direct-laser-writing of TiO2-decorated graphene on indium-tin oxide glass was demonstrated to fabricate a unique photoelectrode with a rapid and stable photoelectrochemical response under visible light; this photoelectrode was then applied in a photoelectrochemical enzymatic biosensor for the sensitive detection of an acetylcholinesterase inhibitor.

Objective To compare the clinical efficacy differences of acupotomy therapy guided by the meridian sinew theory and acupotomy therapy guided by the anatomy theory of western medicine in the treatment of knee osteoarthritis. Methods Sixty-three patients were randomly divided into the acupotomy group of the meridian sinew theory (Group A, n = 32) and the acupotomy group of the anatomy theory (Group B, n = 31). For Group A, with positive reaction points such as the tenderness points of three yang meridians and three yin meridians of the foot, and funicular nodules as the points of needle insertion, the needle-knife, after disinfection and anesthesia, gives priority to longitudinal dissection after insertion, and then carries out subcutaneous sweeping maniplation. For Group B, with 8 points for needle insertion, including the origins and terminations of the medial and lateral collateral ligaments, the origins and terminations of the patellar ligament, the terminations of the quadriceps femoris tendon, and pes anserinus bursa point, the treatment was performed in strict accordance with the four-step procedures of acupotomy (positioning, orientating, pressurizing to separate, and puncturing) after disinfection and anesthesia. The treatment was conducted once a week and three times in total. Statistical analysis was conducted with the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and Visual Analogue Scale (VAS) for overall pain before treatment and at week 2 and 4 during treatment, and the adverse reactions of patients were observed and recorded to evaluate the curative effect. Results During the treatment period, the overall response rates (ORRs, that is markedly effective + effective) were compared between the two groups. The ORR of Group A was 90.63% and that of Group B was 87.09%. There was no statistical significant difference between the two groups (P > 0.05). After treatment, the WOMAC function score of Group A was significantly lower than that before treatment (17.28 ± 10.22 vs 32.75 ± 14.88, P 0.05) between at Week 2 and before treatment, and there was statistically significant difference (3.31 ± 1.56 vs 4.77 ± 1.68, P Conclusion Both acupotomy therapies guided by the meridian sinew theory and by the anatomy theory of Western medicine have good curative effect on knee osteoarthritis, but acupotomy guided by the meridian sinew theory has more superiorities in operability, safety and effectiveness, which is easy to be generalized in grass-roots and community hospitals.

This study was performed to compare the effectiveness of acupotomy based on the meridian-sinew theory with acupotomy based on the anatomical theory in the treatment of knee osteoarthritis (KOA). A total of 124 patients with knee osteoarthritis were randomized into the meridian-sinew (MS) group (63 patients) and anatomy group (61 patients). In the MS group, acupotomy based on the meridian-sinew theory was performed. In the anatomy group, acupotomy based on anatomy was applied. Patients were subgrouped by TCM Constitutions. The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and visual analog scale (VAS) were used to evaluate treatment effectiveness. The results showed that VAS (F = 22.61, p < 0.01 ) and WOMAC (F = 24.84, p < 0.01 ) scores declined with time, and there was no significant difference between the two groups nor subgroups (Yang deficiency subgroup, Yin-Yang harmony subgroup, and the subgroup of the others). A total of 5 patients reported 6 cases of the minor adverse effect, and all patients achieved complete recovery without medical intervention. This study indicates that the effectiveness and safety of acupotomy based on the meridian-sinew theory are equivalent to that of acupotomy based on anatomy in KOA treatment.

Early-life inflammation increases the risk for depression in later life. Here, we demonstrate how early-life inflammation causes adolescent depressive-like symptoms: by altering the long-term neuronal spine engulfment capacity of microglia. For mice exposed to lipopolysaccharide (LPS)-induced inflammation via the Toll-like receptor 4/NF-κB signaling pathway at postnatal day (P) 14, ongoing longitudinal imaging of the living brain revealed that later stress (delivered during adolescence on P45) increases the extent of microglial engulfment around anterior cingulate cortex (ACC) glutamatergic neuronal (ACCGlu) spines. When the ACC microglia of LPS-treated mice were deleted or chemically inhibited, the mice did not exhibit depressive-like behaviors during adolescence. Moreover, we show that the fractalkine receptor CX3CR1 mediates stress-induced engulfment of ACCGlu neuronal spines. Together, our findings establish that early-life inflammation causes dysregulation of microglial engulfment capacity, which encodes long-lasting maladaptation of ACCGlu neurons to stress, thus promoting development of depression-like symptoms during adolescence.

Methomyl {bis[1-methylthioacetaldehyde-O-(N-methylcarbamoyl)oximino]sulfide} is a highly toxic oxime carbamate insecticide. Several methomyl-degrading microorganisms have been reported so far, but the role of specific enzymes and genes in this process is still unexplored. In this study, a protein annotated as a carbamate C-N hydrolase was identified in the methomyl-degrading strain Aminobacter aminovorans MDW-2, and the encoding gene was termed ameH. A comparative analysis between the mass fingerprints of AmeH and deduced proteins of the strain MDW-2 genome revealed AmeH to be a key enzyme of the detoxification step of methomyl degradation. The results also demonstrated that AmeH was a functional homodimer with a subunit molecular mass of approximately 34 kDa and shared the highest identity (27%) with the putative formamidase from Schizosaccharomyces pombe ATCC 24843. AmeH displayed maximal enzymatic activity at 50°C and pH 8.5. K(m) and k(cat) of AmeH for methomyl were 87.5 μM and 345.2 s(−1), respectively, and catalytic efficiency (k(cat)/K(m)) was 3.9 μM(−1) s(−1). Phylogenetic analysis revealed AmeH to be a member of the FmdA_AmdA superfamily. Additionally, five key amino acid residues (162, 164, 191, 193, and 207) of AmeH were identified by amino acid variations. IMPORTANCE Based on the structural characteristic, carbamate insecticides can be classified into oxime carbamates (methomyl, aldicarb, oxamyl, etc.) and N-methyl carbamates (carbaryl, carbofuran, isoprocarb, etc.). So far, research on the degradation of carbamate pesticides has mainly focused on the detoxification step and hydrolysis of their carbamate bond. Several genes, such as cehA, mcbA, cahA, and mcd, and their encoding enzymes have also been reported to be involved in the detoxification step. However, none of these enzymes can hydrolyze methomyl. In this study, a carbamate C-N hydrolase gene, ameH, responsible for the detoxification step of methomyl in strain MDW-2 was cloned and the key amino acid sites of AmeH were investigated. These findings provide insight into the microbial degradation mechanism of methomyl.

Rationale: Rectal atresia caused by necrotizing enterocolitis (NEC) is a serious and rare complication in children. Magnetic compression anastomosis (MCA) has been effectively applied in children with congenital oesophageal atresia and biliary atresia. Herein, we reported a case of successfully application of MCA in an infant with rectal atresia following NEC. Patient concerns: A 30+6 weeks premature birth female fetal infant was transferred to our neonatal intensive care unit due to premature delivery, low birth weight, and neonatal respiratory distress. On postpartum day 11, the infant developed abdominal distension and mucosanguineous feces. This infant was then clinically diagnosed as NEC. She underwent anesthesia and intestinal fistula operation on postpartum day 11 because of NEC. Diagnosis: After 3 months, radiographic examination revealed rectal atresia and stricture. Interventions: This infant was successfully treated with MCA following a cecum-rectal anastomosis and ileocecal valve was reserved. Outcomes: On postoperative day 9, she passed the 2 magnets per rectum. In addition, there were no difficult defecation or fecal incontinence or other short-term complications. After the 7-month follow-up, the patient had an excellent clinical outcome. Lessons: MCA is a feasible and effective method for treating rectal atresia in infants.

Hepatocellular carcinoma (HCC) is a malignant tumor and is associated with necroinflammation driven by various immune cells, such as dendritic cells, macrophages and natural killer cells. Innate immune cells can directly affect HCC or regulate the T-cell responses that mediate HCC. In addition, innate immune cells and T cells are not isolated, which means the interaction between them is important in the HCC microenvironment. Considering the current unsatisfactory efficacy of immunotherapy in patients with HCC, understanding the relationship between innate immune cells and T cells is necessary. In the present review the roles and clinical value of innate immune cells that have been widely reported to be involved in HCC, including dendritic cells, macrophages (including kupffer cells), neutrophils, eosinophils, basophils and innate lymphoid cells and the crosstalk between the innate and adaptive immune responses in the antitumor process have been discussed. The present review will facilitate researchers in understanding the importance of innate immune cells in HCC and lead to innovative immunotherapy approaches for the treatment of HCC.

The residues of bensulfuron-methyl (BSM), a sulfonylurea herbicide, in soil have caused serious damage to the rotation of susceptible crops. Many studies have reported that the removal of BSM in soil was achieved by adding degrading bacteria. However, the mechanisms used by bacteria to degrade BSM in the crop rhizosphere remain unclear. In this study, a BSM-degrading bacterium, Hansschlegelia zhihuaiae S113, was applied to investigate the enhancement of effects mediated by organic acids during the bioremediation of BSM-contaminated maize rhizosphere soil. Organic acids, such as L -malic acid, tartaric acid, and fumaric acid, identified in maize root exudates, significantly stimulated the expression of cheA, which encoded the histidine kinase in strain S113 and contributed to the chemotactic response. This process accelerated the accumulation of strain S113 around the maize roots and promoted the colonization process on maize roots. The growth of strain S113 was significantly increased by L -malic acid but not tartaric acid or fumaric acid. After the S113 suspension was root-irrigated to BSM-contaminated soil, the density of strain S113 colonizing root surfaces and in rhizosphere soil reached 1.1 × 104 cells/g for roots and 4.9 × 104 cells/g in dry soil at 15 d, leading to 80.9% BSM degradation efficiency. The treatment with the addition of a mixture of S113 and L -malic acid completely degraded BSM in rhizosphere soil due to the strong attraction and growth promotion of strain S113 by L -malic acid, with a higher efficiency than that with the extra addition of fumaric acid (89.7%) or tartaric acid (87.0%). This paper revealed the enhancement effects of organic acids identified in root exudates for the in situ bioremediation of BSM-contaminated rhizosphere soil.

The ventral part of the anteromedial thalamic nucleus (AMv) is in a position to convey information to the cortico-hippocampal-amygdalar circuit involved in the processing of fear memory. Corticotropin-releasing-factor (CRF) neurons are closely associated with the regulation of stress and fear. However, few studies have focused on the role of thalamic CRF neurons in fear memory. In the present study, using a conditioned fear paradigm in CRF transgenic mice, we found that the c-Fos protein in the AMv CRF neurons was significantly increased after cued fear expression. Chemogenetic activation of AMv CRF neurons enhanced cued fear expression, whereas inhibition had the opposite effect on the cued fear response. Moreover, chemogenetic manipulation of AMv CRF neurons did not affect fear acquisition or contextual fear expression. In addition, anterograde tracing of projections revealed that AMv CRF neurons project to wide areas of the cerebral cortex and the limbic system. These results uncover a critical role of AMv CRF neurons in the regulation of conditioned fear memory. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00592-6) contains supplementary material, which is available to authorized users.

Objectives We sought to determine the impact of pretreatment plasma platelet levels, dimerized plasmin fragment (D-dimer) and fibrinogen in recurrent epithelial ovarian cancer (EOC) and the impact of platelet levels on SKOV3 cell lines growth and responsiveness to chemotherapy. Methods Under approval of ethical committee, we identified 104 women with recurrent EOC who underwent treatment between January 2010 and February 2015. Reviewing clinical, laboratory, and pathologic records from this retrospective cohort, we analyzed the correlation between pretreatment plasma D-dimer, fibrinogen, platelet levels and clinicopathological parameters, progression free survival (PFS) and overall survival (OS). Inco-culture experiments human ovarian cancer SKOV3 cell lines were used to test the effect of platelet levels on tumor growth and responsiveness to docetaxel. Results Of the 104 recurrent EOC, thrombocytosis at diagnosis and the decrease of platelet count by less than 25% after primary therapy were associated with worse median progression free survival (P = 0.003;P = 0.021) and median overall survival (P = 0.009;P = 0.009). Mean platelet levels declined at the end of primary therapy(P P = 0.007). In multivariate analysis, elevated platelet levels at primary therapy and the decrease of platelet count less than 25% after primary therapy were unfavorable prognostic factor for PFS(P = 0.022; P = 0.015) and OS(P = 0.013;P = 0.007) in recurrent EOC, but elevated plasma D-dimer and fibrinogen were not. In SKOV-3 ovarian cancer cell lines, suitable concentration platelet co-culture protected against apoptosis (P Conclusions Platelet count during treatment could be used as a biomarker used for monitoring the disease recurrence and predicting treatment response. And platelet with suitable concentration co-culture protected against apoptosis in SKOV3 cell line, which may explain clinical observations.

Background: Coronavirus disease 2019 is an epidemic disease throughout the world. The management of vascular access during the epidemic is currently unknown. Methods: In this multicenter cross-sectional study, we collected vascular access data from hemodialysis patients treated at 44 hospitals in Hubei from 22 January to 10 March 2020. We estimated the management of vascular access during the coronavirus disease 2019 outbreak. Results: Of the 9231 hemodialysis patients included, 5387 patients (58.4%) were men and 2959 patients (32.1%) were older than 65 years. Arteriovenous fistula was the predominant type of vascular access, accounting for 76.5%; 496 patients (5.4%) developed vascular access complications; catheter flow reduction was the most common vascular access complication, and stenosis was the predominant complication among those with arteriovenous access. Overall, 280 vascular access sites were placed in patients newly diagnosed with uremia, of whom 260 (92.8%) underwent catheter insertion; 149 rescue procedures were carried out to treat the vascular access complications, which consisted of 132 catheters, 7 percutaneous transluminal angioplasties, 6 arteriovenous fistula repairs, and 4 arteriovenous fistulas. Occlusion of the arteriovenous access had the highest rescue rate (92.7%), while many other vascular access complications remained untreated; 69 and 142 patients were diagnosed with confirmed and suspected coronavirus disease 2019, respectively. A total of 146 patients died, of whom 29 patients (19.9%) died due to vascular access complications. Conclusion: Catheter flow reduction and stenosis of arteriovenous access were the major vascular access complications. Most of the vascular access sites established were catheters, and many of the vascular access complications remained untreated.

The cehA gene is the earliest reported and most widely found carbaryl hydrolase gene. CehA detoxifies carbaryl and other carbamate pesticides via de-esterification. Currently, there is no systematic research available on substrate preference or the mechanism of CehA action in different hosts. In this study, we found that CehA from different hosts is highly conserved, with more than 99% amino acid sequence similarity, and that transposable elements exist in both the upstream and downstream regions of cehA. By introducing point mutations into the cehA gene of Sphingobium sp. CFD-1, we obtained and heterologously expressed all reported CehA(CehAS) encoding genes. Assays to determine enzymatic properties and substrate profiles of CehAS showed that each CehA has a significant substrate preference for different carbamate insecticides. Specifically, CehA152Phe/Leu determines the catalytic preference for bicyclic carbamate substrates (carbofuran, carbaryl), while CehA494Thr/Ala and 570Thr/Ile determine the preference for monocyclic carbamate substrates (isoprocarb, propoxur) and linear carbamate substrates (oxamyl, aldicarb), respectively. Considering the existence of transposable elements in the flanking regions of cehA, we speculate that the cehA hosts may have acquired the hydrolysis ability, as well as substrate preference for carbamate pesticides, through horizontal gene transfer and genetic copying errors.

Background Bone turnover and metabolic indicators are related to age and gender. Age and gender should be matched in subjects in disease control research of bone turnover and metabolism, but strict matching of gender and age increases the difficulty and cost of the research. Therefore, the aim of this study was to solve it is necessary to strictly match age and gender in clinical research in bone metabolism. Methods A cross-sectional study was conducted from the data were extracted from the HIS of ZhuJiang Hospital. Data relating to seven bone turnover and metabolic indicators from 1036 patients between January 2018 and October 2019 were analyzed. Results P1NP, β-CTx and 25(OH)D were significant different in individuals younger than 20 years of age. ALP was significantly higher in those under 20 years of age and lower at age 20–39 compared with other age groups. The concentrations of Ca and P were different among the groups aged 0–19, 20–39, and 40–59 years of age groups but exhibited no difference above 60 years of age. PTH expression was not dependent on age. P1NP, β-CTx and PTH concentrations were not significantly different between the genders within the same age group. ALP was significantly different between genders within the age range 20–59 years. Ca and 25(OH)D were significantly different between the genders for those older than 60. Serum P was significantly different in the two genders for those aged 40–79. Patients received both alfacalcidol and calcium treatment differently from the others in P1NP, β-CTx, Serum Ca, P and ALP. Conclusion P1NP and β-CTx were highly correlated with age. If these two indictors require analysis in a case control study, the patients and controls should be strictly matched by age under 20 years. The demarcation point for ALP was 40 years of age. Ca and P were strongly recommended strict matching according to age in disease research. The difference in P1NP, β-CTx, 25(OH)D and ALP between genders depends on age differences. Medication history should be considered in bone turnover and metabolic clinical research.

IL-33 is a member of the IL-1 family of cytokines whose role remains controversial in rheumatoid arthritis (RA). The present study was performed to evaluate the correlation of IL-33 with other cytokines and chemokines in serum and the synovia, and to explore the nature of the association. The concentration of IL-33 in samples from 96 patients with RA was analyzed. The response of fibroblast-like synoviocytes (FLSs) to treatment with different concentrations of IL-33 was assessed in vitro. IL-33 was indicated to exhibit an association with multiple cytokines and chemokines in synovial fluid with an inverted-U-shaped trend, including IL-6, IL-1β, IL-8, MIG and IP-10, but not in the serum. Furthermore, in vitro experiments confirmed that IL-33 also exerted a U-type dose-dependent regulatory effect on FLS function. In addition, the data-points do not exactly follow the U-shaped curve fit in most cases, therefore, the applicability of this mathematical model in clinical practice is limited.

Objectives For patients presenting with adnexal mass, it is important to correctly distinguish whether the mass is benign or malignant for the purpose of precise and timely referral and implication of correct line of management. The objective of this study was to evaluate the performance of Risk of malignancy Indexes (RMI) 1–4, Human Epididymis Protein 4 (HE4) and Risk of Malignancy Algorithm (ROMA) in differentiating the adnexal mass into benign and malignant. Methods A retrospective study using 155 patients diagnosed with adnexal mass between January 2014 to December 2014 in The First Affiliated Hospital of Zhengzhou University was conducted. The patient records were assessed for age, menopausal status, serum CA125 and HE4 levels, ultrasound characteristics of the pelvic mass and the final pathological diagnosis of the mass. RMI1, RMI2, RMI3, RMI4, ROMA were calculated for each patient and the sensitivity, specificity and the Receiver Operating Characteristics (ROC) curves were determined for each test to evaluate their performance. Results Among 155 patients with adnexal masses meeting inclusion criteria, 120 (77.4%) were benign, 8 (5.2%) borderline and 27 (17.4%) were malignant. RMI2 and RMI4 had the highest sensitivity (66.7%) while HE4 had the highest specificity (96.9%).Although ROMA had the highest area under the curve (AUC) of 0.886 it was not found to be statistically superior to the other tests. For epithelial ovarian cancers, ROMA (80%), HE4 (96.9%) and RMI 4 (0.868) had the highest sensitivity, specificity and AUC respectively however, the AUC characteristics were not statistically significant between any groups. Compared to the postmenopausal group (sensitivity 72.2–77.8%) all the tests showed lower sensitivity (42.9%) for the premenopausal group of patients. Conclusions RMI 1–4, ROMA and HE4 were all found to be useful for differentiating benign/borderline adnexal masses from malignant ones for deciding optimal therapy, however no test was found to be significantly better than the other. None were able to differentiate between benign and borderline tumors. All of the tests demonstrated increased sensitivity when borderline tumors were considered low-risk, and when only epithelial ovarian cancers were considered.

This study aimed to investigate whether the routine administration of escitalopram for three months would improve the prognosis of patients with ischemic stroke and decrease the plasma copeptin level. A total of 97 patients with acute cerebral infarction were randomly allocated to receive escitalopram (5-10 mg once per day, orally; n=49) or not to receive escitalopram (control group; n=48) for 12 weeks starting at 2-7 days after the onset of stroke. Both groups received conventional treatments, including physiotherapy and secondary prevention of stroke. The National Institutes of Health Stroke Scale (NIHSS) score was used to evaluate the disability of patients at the initial evaluation and at the monthly follow-up visits for three months. Impairment in the daily activities was assessed using the Barthel Index (BI), while cognitive impairment was assessed using Mini-Mental State Examination (MMSE) score. The psychiatric assessment included the administration of the Present State Examination modified to identify Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) symptoms of depression. The severity of depression was measured using the 17-item Hamilton Rating Scale for Depression (HAMD). During the 3-month follow-up period, 95 patients were included in the analysis (two patients withdrew from the escitalopram group). NIHSS and BI improvement at the 90th day were significantly greater in the escitalopram group (P

Sepsis-associated encephalopathy (SAE) is a common complication that leads to long-term cognitive impairments and increased mortality in sepsis survivors. The mechanisms underlying this complication remain unclear and an effective intervention is lacking. Accumulating evidence suggests the nucleotide-binding domain-like receptor protein3 (NLRP3)/caspase-1 pathway is involved in several neurodegenerative diseases. Thus, we hypothesized that the NLRP3/caspase-1 pathway is involved in NLRP3-mediated pyroptosis, maturation and release of inflammatory cytokines, and cognitive deficits in SAE. We used the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Ac-YVAD-CMK to study the role of the NLRP3/caspase-1 pathway in pyroptosis and cognitive deficits in a mouse model of SAE. Mice were randomly assigned to one of six groups: sham+saline, sham+MCC950, sham+Ac-YVAD-CMK, cecal ligation and puncture (CLP)+saline, CLP+MCC950, and CLP+Ac-YVAD-CMK. Surviving mice underwent behavioral tests or had hippocampal tissues collected for histochemical analysis and biochemical assays. Our results show that CLP-induced hippocampus-dependent memory deficits are accompanied by increased NLRP3 and caspase-1 positive cells, and augmented protein levels of NLRP3, caspase-1, gasdermin-D, and pro-inflammatory cytokines in the hippocampus. In addition, administration of MCC950 or Ac-YVAD-CMK rescues cognitive deficits and ameliorates increased hippocampal NLRP3-mediated neuronal pyroptosis and pro-inflammatory cytokines. Our results suggest that the NLRP3/caspase-1 pathway-induced pyroptosis mediates cognitive deficits in a mouse model of SAE.

Incompletely burned diesel fuel tends to generate soot into the crankcase, resulting in a sharp increase in oil viscosity. Modern diesel engine oils are required to have a good soot dispersion performance, that means the viscosity of the oil will not increase significantly after being mixed with the soot. Carbon black was used as a simulant. The dispersion performance of the oil was evaluated by the viscosity growth rate. Investigate the change in viscosity before and after the oil is added to carbon black. Investigate the effects of different base oils and viscosity index improvers on the viscosity growth rate of the test oils after adding carbon black. Ethylene-propylene copolymer type viscosity index improver (OCP) has the worst soot dispersion performance. Polymethacrylate type viscosity index improver (PMA) has the best soot dispersion performance. Hydrogenated styrene/diene copolymer viscosity index improver (HSD) soot dispersion performance centered. Under the premise of adding the same viscosity index improver, the API Group II and the API Group III base oils disperse better than the API Group I base oils. Systematic study on the effect of viscosity index improvers and base oils on the soot dispersion performance of diesel engine oil, explore the mechanism. Provide strong technical support for the development of modern diesel engine oil.

Circular RNAs (circRNAs) have been identified as crucial regulators of gene expression in human cancer biology. CircZFR is a novel identified circRNA and its effect in bladder cancer remains unclearly. In the present study, we aimed to investigate the role of circZFR in the progression of bladder cancer. First, we demonstrated that the expression of circZFR was higher in bladder cancer tissues and cells compared with adjacent non-tumor tissues and normal bladder epithelial cells. And higher circZFR levels were positively correlated with bladder cancer patients’ pathological T stage, grade, lymphatic metastasis, recurrence, progression-free survival (PFS) and overall survival (OS). Functionally, knockdown of circZFR could significantly prohibit cell growth, migration and invasion, arrest cell cycle as well as promote apoptosis of bladder cancer cells in vitro study. Mechanistically, we observed that circZFR could directly bind to miR-377 as sponge to promote ZEB2 expression in bladder cancer cells. In addition, rescue assays demonstrated that restoration of ZEB2 significantly impaired the suppressive effects of circZFR silencing on bladder cancer cells growth, migration and invasion. Taken together, our results illuminated that circZFR could be a prognostic biomarker in bladder cancer and exerted oncogenic roles through regulating miR-377/ZEB2 axis in bladder cancer, which indicated that circZFR could be a potential therapeutic target for bladder cancer patients treatment.

Perioperative neurocognitive disorders (PND) are characterized by deficits in cognitive functions in the elderly following anesthesia and surgery. Effective clinical interventions for preventing this disease are limited. Growing evidence demonstrates that activation of NOD-like receptor protein3 (NLRP3) inflammasome is involved in neurodegenerative diseases. We therefore hypothesized that activation of NLRP3 inflammasome is linked to neuroinflammation and the subsequent cognitive impairments that occurred in an animal model of PND. In this study, 18-month-old C57BL/6 mice were subjected to an exploratory laparotomy under isoflurane anesthesia to mimic clinical human abdominal surgery. For interventional studies, mice received NLRP3 specific inhibitor MCC950 (10 mg/kg) or the vehicle only intraperitoneally. Behavioral studies were performed at 6 and 7 d after surgery using open field and fear conditioning tests, respectively. Interleukin-1β (IL-1β), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α), ionized calcium-binding adaptor molecule-1 (IBA1) positive cells, glial fibrillary acidic protein (GFAP) positive cells, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1 were measured at 3 days post-surgery. Brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) were measured at 7 days post-surgery. Our data indicates that surgery-induced cognitive impairments were associated with significant increases in IL-1β, IL-18, TNF-α, NLRP3, ASC, cleaved caspase-1, IBA1-positive cells and GFAP-positive cells, and decreases in BDNF and PSD95 expression in the hippocampus. Notably, administration with MCC950 attenuated inflammatory changes and rescued surgery-induced cognitive impairments. Our study suggests that surgery induces neuroinflammation and cognitive deficits that are partly attributed to the activation of NLRP3 inflammasome in the hippocampus of aged mice.

BACKGROUND: To assess the impact of the 21-gene recurrence score (RS) on chemotherapy decision making and survival outcomes for breast cancer patients with >4 positive lymph nodes. METHODS: Patients with non-metastatic estrogen receptor-positive breast cancer with >4 positive lymph nodes diagnosed between 2004 and 2013 were identified using the Surveillance, Epidemiology, and End Results database. The relationships between the 21-gene RS value and survival outcomes, chemotherapy decision-making, and chemotherapy benefit were analyzed. RESULTS: A total of 410 patients were identified, including 191 (46.6%), 164 (40.0%), and 55 (13.4%) in the low-, intermediate-, and high-risk RS groups, respectively. The 21-gene RS assay results were independently related to chemotherapy receipt. A total of 59.0%, 68.0%, and 78.0% of patients received chemotherapy in the low-, intermediate-, and high-risk RS groups, respectively. The 21-gene RS was an independent indicator of breast cancer specific survival (BCSS) and overall survival (OS). Intermediate-risk [BCSS: hazards ratio (HR), 2.832, 95% confidence interval (CI): 1.160–6.910, P=0.022; OS: HR, 3.704, 95% CI: 1.750–7.836, P=0.001] and high-risk RS (BCSS: HR, 6.440, 95% CI: 2.597–15.974, P 4 positive lymph nodes.

SummaryObjective Hypertensive disorders of pregnancy (HDP) have been associated with adverse health outcomes for both mothers and children. Previous studies examining associations of maternal thyroid autoantibodies with HDP indicate conflicting results. The objective of this study was to examine associations of maternal thyroid autoantibodies positivity in the first and the second trimesters with the risk of HDP. Design, Participants and Measurements In the Ma'anshan Birth Cohort study, a population-based prospective study in China, a total of 3474 pregnant women were enrolled between May 2013 and September 2014. Thyroid autoantibodies, including anti-thyroperoxidase autoantibody (TPOAb) and anti-thyroglobulin autoantibody (TgAb), as well as thyroid function tests were measured in both the first and the second trimesters in 2893 pregnant women. Multivariate logistic regression analyses were conducted to calculate the odds ratio (OR) and 95% confidence interval (CI) for the associations between thyroid autoantibodies and HDP. Results Multivariate logistic regression analyses showed that TPOAb positivity in the first trimester was associated with a 1.80 (95% CI=1.17-2.78) increased odds of HDP after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR=1.93, 95% CI=1.17-3.18). In addition, TgAb positivity in the first trimester was associated with a higher risk of HDP (OR=1.78, 95% CI=1.16-2.73) after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR=1.89, 95% CI=1.15-3.11). These associations were also seen among euthyroid women. Women with positive TPOAb in the second trimester seemed to have a higher risk of gestational hypertension (OR=1.87, 95% CI=1.02-3.43) after adjustment for confounders. However, among euthyroid women, TPOAb positivity in the second trimester was not associated with HDP. The TgAb status in the second trimester was not associated with HDP. Conclusions Our results show that TPOAb positivity and TgAb positivity in the first trimester are associated with an increased risk of HDP. These data demonstrate that these associations are even seen among euthyroid women. This article is protected by copyright. All rights reserved.

Background We investigated the effect of lymphadenectomy on the survival outcomes of patients with advanced epithelial ovarian cancer in the Surveillance, Epidemiology, and End Results database according to residual disease status. Methods We evaluated 3048 patients with International Federation of Gynecology and Obstetrics stage-IIIC–IV epithelial ovarian cancer. We assessed the effect of lymphadenectomy stratified by residual disease size on cause-specific survival (CSS). Results A total of 1904 (62.5%) patients received lymphadenectomy, and 1355 (71.2%) patients had nodal metastases. Lymph-node status had no significant association with residual tumor size in the lymphadenectomy group. In multivariate analysis, lymphadenectomy was associated with a significantly better CSS and was an independent prognostic factor for CSS. Patients with >10 lymph nodes removed had better CSS compared with non-lymphadenectomy and 1–10 lymph nodes removed groups. Lymphadenectomy was associated with a significantly better CSS in patients with no gross residual tumor, but not in patients with residual tumor ≤1 cm or >1 cm. Conclusions Lymphadenectomy is significantly associated with a better survival outcome in patients advanced ovarian cancer, but its positive effect diminishes as residual tumor size increases.

Purpose: This study examined the role of marital status on survival outcome of nasopharyngeal carcinoma (NPC) patients using a population-based cancer registry. Methods: Patients with primary NPC diagnosed between 2004 and 2013 were included using the Surveillance, Epidemiology and End Results program. Patient demographic, clinicopathologic features, management, and survival outcomes were compared according to marital status. Cause-specific survival (CSS, NPC-related death) for marital status was analyzed. Results: The data of 3018 patients were included, with 61.4%, 11.1%, 21.8, and 5.6% of patients married, divorced (or separated), single, and widowed, respectively. Widowed patients had the highest proportion of elderly age (p < 0.001), were more likely to be female (p < 0.001), and had more well-to-moderately differentiated (p < 0.001) and node-negative disease (p = 0.038). Widowed patients were also less likely to have received radiotherapy and chemotherapy compared with patients of other marital status (p < 0.001). The 5-year CSS was 76.1%, 70.8%, 73.4%, and 59.8% in the married, divorced, single, and widowed groups, respectively (p = 0.001). Marital status was the independent prognostic factor for CSS. Widowed patients had a significantly increased risk of NPC-related death compared with married (hazard ratio [HR] 2.014, 95% confidence interval [CI] 1.477-2.747, p < 0.001), divorced (HR 1.580, 95% CI 1.087-2.295, p = 0.017), and single (HR 2.000, 95% CI 1.402-2.854, p < 0.001) patients. The divorced (p = 0.067) and single (p = 0.949) groups had similar CSS to the married group. Conclusions: Being widowed was associated with an increased the risk of cancer mortality in NPC compared with being married, divorced, or single.

Background: Venetoclax combined with azacitidine has been demonstrated to have a favorable overall response rate and tolerable safety in acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. Methods: This study retrospectively recruited 64 Adults (≥18 years) with newly diagnosed AML ineligible for intensive chemotherapy who had received at least one cycle of treatment with venetoclax plus azacitidine. The primary endpoint was overall survival (OS). Secondary endpoints were remission rates. Safety was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: The median age of the enrolled patients was 69 years. The median OS for the cohort was 15.5 months, with 21.2 months for complete responders as opposed to 13.3 months for those who did not achieve a complete response. 39 (60.9%) patients achieved composite complete remission (complete remission (CR) + CR with incomplete count recovery (CRi)) and 7/64 (10.9%) achieved morphologic leukemia-free state (MLFS) with a median follow-up time of 14.7 months. The median CR+CRi duration was 10.9 months. It is noteworthy that 43/64 (67.2%) patients achieved the best response after one cycle with a median time of 1.2 months. Normal karyotype (P=0.015) was significantly associated with extended OS in multivariate analysis, while higher white blood cell count (P=0.032), lower platelet count (p=0.018) and antifungal drug combination (P=0.013) were predictors of shortened OS in univariate analysis. Common grade 3/4 Adverse Events (AEs) included infection (68%) and hematological AEs consisting of neutropenia (93%), anemia (90%), leukopenia (86%), thrombocytopenia (77%) and febrile neutropenia (52%). The median neutropenia duration was 16 days. Conclusions: The novel venetoclax-azacitidine combination regimen showed prolonged survival period, promising efficacy, sound and rapid response, and superior tolerance in Chinese patients newly diagnosed AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury. Splenic monocytes from sham and burn mice 24 h following burn injury were treated with consecutive doses of Exendin-4 alone or in combination with an inhibitor of Gαi signaling (pertussis toxin, PTX), or a blocker of protein kinase A (H89). Cell viability was assessed by CCK-8, and the supernatant was collected for cytokine measurement by ELISA. Intracellular cAMP level, phosphorylated PKA activity, and nuclear NF-κB p65 were determined by ELISA, ERK1/2 activation was analyzed by Western blot. The expression of GLP-1R downstream molecules, Gαs, Gαi and G-protein coupled receptor kinase 2 (GRK2) were examined by immunofluorescence staining and Western blot. Exendin-4 could inhibit the viability of monocyte from sham rather than burn mice. Unexpectedly, it could also reduce TNF-α secretion from sham monocyte while increase it from burn monocyte. The increased secretion of TNF-α by Exendin-4 from burn monocyte could be reversed by pretreatment of PTX or H89. Accordingly, Exendin-4 could stimulates cAMP production dose dependently from sham instead of burn monocyte. However, the blunt cAMP production from burn monocyte was further suppressed by pretreatment of PTX or H89 after 6-h incubation. Nevertheless, phosphorylated PKA activity was significantly increased by low dose of Exendin-4 in sham monocyte, by contrast, it was enhanced by high dose of Exendin-4 in burn monocyte after 1-h incubation. Following Exendin-4 treatment for 2 h ex vivo, total nuclear NF-κB and phosphorylated NF-κB activity, as well as cytoplasmic pERK1/2 expressions were reduced in sham monocyte, however, only pERK1/2 was increased by Exendin-4 in burn monocytes. Moreover, reduced expressions of GLP-1R, GRK-2 and Gαs in contrast with increased expression of Gαi were identified in burn monocyte relative to sham monocyte. This study presents an unexpected proinflammatory switch from Gαs to Gαi signaling in burn monocyte, which promotes ERK1/2 and NF-κB activation and the downstream TNF-α secretion. This phenomenon is most probably responsible for proinflammatory response evoked by Gαs agonist Exendin-4 following burn injury.

// Chao Ren 1, 2 , Ya-Lin Tong 3 , Jun-Cong Li 2 , Ning Dong 2 , Ji-Wei Hao 2 , Qing-Hong Zhang 2 and Yong-Ming Yao 1, 2, 4 1 School of Medicine, Nankai University, Tianjin 300071, People’s Republic of China 2 Trauma Research Center, First Hospital Affiliated to The Chinese PLA General Hospital, Beijing 100048, People’s Republic of China 3 Department of Burns and Plastic Surgery, The 181st Hospital of Chinese PLA, Guilin 541002, People’s Republic of China 4 State Key Laboratory of Kidney Disease, The Chinese PLA General Hospital, Beijing 100853, People’s Republic of China Correspondence to: Yong-Ming Yao, email: c_ff@sina.com Keywords: HMGB1, sepsis, lateral ventricles, antagonists, brain injuries Received: July 29, 2016 Accepted: September 04, 2017 Published: October 05, 2017 ABSTRACT Sepsis induced brain injury acts as an acute complication and accounts for deterioration and high mortality rate of septic condition. HMGB1 is a late inflammatory mediator that plays a critical role in brain dysfunction and diseases. However, the role of HMGB1 in sepsis induced brain dysfunction remains intricate. The current study investigated the effect of HMGB1 on brain injury in septic mice model with intracerebroventricular injection of BoxA (a specific antagonist of HMGB1). The expression of HMGB1, morphological changes of brain tissues, apoptosis of brain cells, and alteration of behavior were determined. The expressions of HMGB1 in cortex, hippocampus, and striatum were significantly enhanced in the sepsis group when compared with the sham group. In septic conditions, brain tissues showed significant abnormalities in tissue structure, and increased apoptosis of brain cells which was caspase-3 dependent. Septic mice showed suppression of locomotor activity and impairment of memory and learning. Neutralizing brain HMGB1 significantly improved brain injury and apoptosis of brain cells, and further ameliorated disturbed locomotor activities and damaged memory and learning. However, no significant improvement of survival rate was seen after inhibiting central HMGB1. These results reveal that HMGB1 is a potential target for ameliorating sepsis induced brain injury with early antagonizing.

A novel Gram-stain-positive bacterium, designated djl-8T, was isolated from farmland soil in Nanjing, Jiangsu province, PR China. Cells of strain djl-8T were aerobic, non-motile, non-spore-forming and rod-shaped. The organism grew at 25–37 °C, pH 5.5–8.0 and 0.5–4.0 % NaCl (w/v). The DNA G+C content was 69.3 mol%. The diagnostic diamino acid in the cell-wall peptidoglycan was LL-2, 6-diaminopimelic acid. The major fatty acids (>5 %) were iso-C16 : 0, anteiso-C17 : 0, iso-C15 : 0, 10-Me C17 : 0 and C17 : 1ω8c. The respiratory quinone was MK-8 (H4) and the major polar lipids were phosphatidylglycerol, phosphatidylinositol, diphosphatidylglycerol and unknown phospholipids. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain djl-8T is a member of the genus Nocardioides and shared the highest similarity with Nocardioides ginkgobilobae SYP-A7303T (97.1 %), followed by Nocardioides soli mbc-2T (96.9 %), Nocardioide spyridinolyticus OS4T (96.6 %) and Nocardioides maradonensis RP-B30T (96.6 %). Strain djl-8T exhibited low DNA–DNA relatedness with Nocardioides ginkgobilobae SYP-A7303T (26.9±2.1 %). On the basis of the morphological, physiological, biochemical and chemotaxonomic characteristics presented in this study, strain djl-8T represents a novel species of the genus Nocardioides , for which the name Nocardioides agrisoli sp. nov. is proposed. The type strain is djl-8T (=KCTC 39844T=CCTCC AB 2017058T).

BACKGROUND Mechanical ventilation is an important part of advanced life support in the intensive care unit (ICU). This study aimed to investigate the effects of ABCDE bundle on hemodynamics in patients on mechanical ventilation (MV). MATERIAL AND METHODS This study used a cross-sectional overall controlled approach in which 143 patients on mechanical ventilation were divided into 2 groups. In the pre-ABCDE bundle group (n=70), conventional sedation and analgesia strategy were used. In the post-ABCDE bundle group (n=73), ABCDE bundle was used. Changes in hemodynamics parameters and related prognostic indicators were monitored at various time points before (T0) and at 1 d (T1), 3 d (T3), 5 d (T5), and 7 d (T7) after implementation of the 2 strategies. RESULTS Mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), and oxygenation index (PaO2/FiO2) in the bundle group were improved more significantly than those in the pre-ABCDE bundle group (P