Effect of electroacupuncture on urodynamics and Raf/MEK/ERK signaling pathway in spinal cord tissue of rats with detrusor hyperreflexia after suprasacral spinal cord injury. / ç”µé’ˆå¯¹éª¶ä¸Šè„Šé«“æŸä¼¤åŽé€¼å°¿è‚Œåå°„äº¢è¿›åž‹å¤§é¼ å°¿æµåŠ¨åŠ›å­¦åŠè„Šé«“Raf/MEK/ERK信号通路的影响.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on urodynamics and Raf/MEK/ERK signaling pathway in spine cord tissue of rats after suprasacral spinal cord injury (SSCI), so as to explore its possible mechanism in improving bladder function in rats with detrusor hyperreflexia after SSCI. METHODS: Female SD rats were randomly divided into blank, sham operation, model, EA and EA+PD98059 groups, with 12 rats in each group. Thorax (T) 10 spinal cord transection was performed by surgery. Rats in the EA group were given EA (10 Hz/50 Hz, 20 min) at "Ciliao" (BL32), "Zhongji" (CV3), "Sanyinjiao" (SP6) and "Dazhui" (GV14) once daily for 7 d. Rats of the EA+PD98059 group received intraperitoneal injection of PD98059 (5 mg/kg) 2 h before EA intervention. The urodyna-mics was used to measure the base pressure, leak point pressure, maximum pressure, maximum capacity and comp-liance of bladder, and the morphology of bladder detrusor tissue was observed with HE staining. The TUNEL staining was used to detect the cell apoptosis of the spinal cord tissue. The expression levels of exchange protein directly activated by cAMP 2 (Epac2), Rap, phosphorylated rapidly accelerated fibrosarcoma (p-Raf), phosphorylated mitogen-activated extracellular signal-regulated kinase (p-MEK), phosphorylated extracellular signal regulated kinase 1 and 2 (p-ERK1/2), B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X protein (Bax) were determined by Western blot. RESULTS: Compared with the sham operation group, the base pressure, leak point pressure and maximum pressure of bladder were significantly increased (P<0.01), the maximum bladder capacity and bladder compliance were decreased (P<0.01), the cell apoptosis rate of spinal cord tissue was increased (P<0.01), and the expression levels of Epac2, Rap, p-Raf, p-MEK, p-ERK1/2, and Bcl-2 protein in spinal cord tissue were decreased (P<0.01), while the expression level of Bax protein was increased (P<0.01) in the model group. After the treatment and compared with the model group, the base pressure, leak point pressure and maximum pressure of bladder, the cell apoptosis rate of spinal cord tissue, the expression level of Bax protein were decreased (P<0.05) in the EA group, while the maximum bladder capacity and bladder compliance, the expression levels of Epac2, Rap, p-Raf, p-MEK, p-ERK1/2, and Bcl-2 protein in spinal cord tissue were all increased (P<0.05, P<0.01). In comparison with the EA group, the base pressure, leak point pressure and maximum pressure of bladder, the cell apoptosis rate, the expression level of Bax protein were significantly increased (P<0.05), whereas the maximum bladder capacity, bladder compliance, and the expression levels of p-MEK, p-ERK1/2, and Bcl-2 protein were decreased (P<0.05) in the EA+PD98059 group. Results of HE staining showed disordered transitional epithelial cells and destroyed lamina propria in bladder detrusor tissue, with the infiltration of monocytes in the model group, which was obviously milder in both EA and EA+PD98059 groups, especially in the EA group. CONCLUSIONS: EA can improve the bladder function in detrusor hyperreflexia rats after SSCI, which may be related to its effect in up-regulating Epac2 and Rap, activating the Raf-MEK-ERK pathway, and reducing the cell apoptosis of spinal cord tissue.

Expressions and Prognostic Values of Notch3 and DLL4 in Human Breast Cancer.

Background: Notch signaling played a critical role in promoting breast tumorigenesis and progression. However, the role and prognostic value of Notch3 combined with DLL4 expression in breast carcinoma had not been explored. Methods: The retrospective study enrolled 90 breast cancer tissues and 60 noncancerous tissues from (conceal). The expression and prognostic value of Notch3 and DLL4 in patients with breast carcinoma were investigated using Oncomine and UALCAN database. Notch3 and DLL4 expression levels were detected by quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry. We analyzed the correlation between both proteins expression and clinicopathological parameters and survival data, respectively. Results: The expressions of Notch3 and DLL4 were increased, and Notch3 expression was significantly positively associated with DLL4 in breast carcinoma. The 2 proteins dramatically correlated with advanced stage, high grade and negative Her2 status. The overexpressing of single or both Notch3 and DLL4 resulted in shortened survival of breast cancer patients. And Notch3 overexpression was one of independent risk predictors to poor prognosis. Conclusion: The interaction of Notch3 receptor and DLL4 ligand accelerates oncogenesis, progression, and poor prognosis of breast cancer patients. Notch3 protein may serve as one of biomarker to independently predict prognosis of patients.

Dual Ion-Selective Membrane Deposited Ion-Sensitive Field-Effect Transistor Integrating a Whole Blood Processing Microchamber for In Situ Blood Ion Testing.

Blood ion testing is one of the methods that is commonly used for monitoring the immune status and providing physiological information for disease diagnosis. However, traditional blood ion sensing methods often require well-trained operators to process the whole blood sample and perform the measurements using bulky instruments, making real-time and continuous blood ion sensing at the bedside difficult. To address the above issues, we proposed a dual ion-selective membrane deposited ion-sensitive field-effect transistor (DISM-ISFET) sensor integrating a microchamber to enable on-chip serum extraction and in situ Na+/K+ ion sensing. As a proof of concept, we sequentially dispensed NaCl and KCl solutions at various concentrations on the DISM-ISFET to find out the highest ion sensitivity and selectivity. Next, we also confirm the high red blood cell sedimentation and serum purity using a microchamber. Finally, we evaluated the system performance using nine clinical whole blood samples and compared their Na+/K+ ion-sensing results with a commercial pocket ion meter. To sum up, our results showed that a DISM-ISFET system can successfully extract 200 µL serum from 500 µL whole blood sample and simultaneously achieve Na+/K+ ion sensing. All the sample processes and measurements can be finished within 10 min in a single chip. We envision this compact and easy-to-use system can be potentially used for various medical environments requiring real-time and continuous blood ion monitoring, such as in a hemodialysis room, operation room, and intensive care unit.

Comparison of the disinfection efficacy between ferrate(VI) and chlorine in secondary effluent.

Disinfection is essential for the microbial safety of reclaimed water. Traditional chlorine disinfection leads to secondary problems such as disinfection by-products and chlorine-resistant bacteria. Ferrate (Fe(VI)) is a novel green disinfectant. However, research on the disinfection characteristics of Fe(VI) remains insufficient. This study compared the disinfection efficacy between Fe(VI) and chlorine in secondary effluent, including the inactivation efficiency of coliforms and heterotrophic bacteria and the control effect on typical chlorine-resistant bacteria. The results showed that Fe(VI) was more effective than chlorine in inactivating Escherichia coli and total coliforms at low doses, whereas chlorine was more effective than Fe(VI) in inactivating heterotrophic bacteria. A severe trailing phenomenon was observed in Fe(VI) disinfection. Based on bacterial community structure analysis, Fe(VI) was also found to be capable of controlling the relative abundance of some chlorine-resistant bacteria such as Sphingomonas, Bacillus, Mycobacterium and Legionella except for Pseudomonas. The results of this study could have implications in evaluating Fe(VI) disinfection ability and optimizing Fe(VI) dosing for disinfection.

Analysis of online antenatal education class use via a mobile terminal app during the COVID-19 pandemic.

OBJECTIVE: To understand the use of online antenatal education classes accessed via the Mother and Child Health Handbook app during the COVID-19 pandemic in order to provide a basis and suggestions for optimizing Internet education during pregnancy under public health emergencies. METHODS: We compared and analyzed the use of online antenatal education classes via the Mother and Child Health Handbook app in Hangzhou in 2019 and 2020 (during the COVID-19 pandemic). RESULTS: Between January 1, 2019, and December 31, 2020, a total of 229,794 pregnant women created files and registered for the app, including 124,273 women in 2019 and 105,521 women in 2020. More pregnant women participated in online antenatal education learning (n = 36,379/34.5% vs. 29,226/23.5%, p = 0.000) in 2020 than in 2019. The proportion of pregnant women in the 18-34-year-old group who participated in online learning was higher than that in the advanced age group, and the difference was statistically significant (2019: 24.3% vs. 18.8%, p = 0.000) (2020: 35.7% vs. 27.4%, p = 0.000). More pregnant women accessed online antenatal education during early pregnancy (n = 13,463/37.0% vs. 9088/31.1%, p = 0.000) in 2020 than in 2019. Similar percentages of pregnant women participated in online antenatal education during mid-pregnancy (n = 15,426/52.8% vs. 19,269/53.0%, p = 0.639) in 2019 and 2020. Fewer pregnant women accessed online antenatal education during late pregnancy (n = 10,246/28.2% vs. 9476/32.4%, p = 0.000) in 2020 than in 2019. Fewer pregnant women choose to take 'Puerperal Health' courses in 2020 than in 2019 (early pregnancy: 36.20% vs. 42.79%, p = 0.000; mid-pregnancy: 41.65% vs. 48.19%, p = 0.000; late pregnancy: 55.31% vs. 58.41%, p = 0.000). Fewer pregnant women choose to take 'Psychological Adjustment' courses in 2020 than in 2019 (early pregnancy: 21.59% vs. 29.60%, p = 0.000; mid-pregnancy: 26.20% vs. 40.50%, p = 0.000; late pregnancy: 12.79% vs. 42.53%, p = 0.000). More pregnant women choose to study 'Nutrition and Exercise' in 2020 than in 2019 (early pregnancy: 44.48% vs. 25.95%, p = 0.000; mid-pregnancy: 47.77% vs. 40.75%, p = 0.000; late pregnancy: 55.94% vs. 42.99%, p = 0.000). "Pregnancy Care and Fetal Development" was the most selected course by pregnant women in early pregnancy (2019: 67.50%; 2020: 71.39%) and middle pregnancy (2019: 67.01%; 2020: 82.05%), and the proportion in 2020 was higher than it was in 2019. "Baby care" was the most selected course by pregnant women in late pregnancy, and the proportion in 2020 was higher than it was in 2019 (78.31% vs. 72.85%). CONCLUSION: During the COVID-19 pandemic, online antenatal education was well-used by pregnant women. More women participated in the online antenatal education modules during the COVID-19 pandemic than during 2019.The proportion of choosing different courses for pregnant women before and after the COVID-19 epidemic varied, and the learning course needs of pregnant women in different trimesters were different.

The noteworthy chloride ions in reclaimed water: Harmful effects, concentration levels and control strategies.

Chloride ions (Cl-), which are omnipresent in reclaimed water, can cause various problems in water reuse systems, especially during water transmission and at end use sites. Although reverse osmosis (RO) is considered as an effective technology to reduce chloride, its high investment and complex maintenance requirements hinder its application in many water reclamation plants (WRPs). Recently, several technologies bringing new options to better deal with chloride have gained increased attention. This review provides detailed information on the harmful effects, concentration levels, and sources of chloride in reclaimed water and summarizes and discusses various chloride removal technologies, including non-selective methods (e.g., membrane filtration, adsorption and ion exchange, oxidation, and electrochemical methods) and selective methods (e.g. precipitation and specially designed electrochemical methods). Among these, Friedel's salt precipitation and capacitive deionization showed attractive development potential. This review also proposes a holistic framework for chloride control from aspects of "Fit-for-Purpose" planning, technical system development, and whole process optimization, which could facilitate the planning and operation of long-term sustainable water reuse practices.

Synthetic polymer material modified by d-peptide and its targeted application in the treatment of non-small cell lung cancer.

Liposomes functionalized with targeted material offer a breakthrough compared with passive drug delivery. Here, we designed a polymer material, VAP-PEG3350-DSPE (VAP-PEG-DSPE), modified with a d-peptide VAP ligand that combines tumor-homing VAP with GRP78 receptor, a cancer marker on the membranes of many cancer cells. This paper establishes a docetaxel-loaded lipid nanodisk modified with multifunctional material to evaluate its anti-NSCLC efficacy in vivo. Additionally, the present study verified that VAP-conjugated nanodisks adapt to the developed tumor vasculature of the lung cancer microenvironment, making it a promising nanocarrier for NSCLC-targeting therapy. Moreover, in vitro and in vivo experiments demonstrated the targeting ability of VAP-DISK/DTX to tumor cells. Lung slices of mice also demonstrated the safety of VAP-DISK/DTX. The encapsulation efficiency of docetaxel-disks (VAP-DISK/DTX) was as high as 92.46±4.48%. Encapsulating anti-cancer drugs in lipid nanoparticles is thus an effective mechanism to change the pharmacokinetic and pharmacodynamic characteristics of drugs.

Effect of different maintenance doses of caffeine citrate on ventilator weaning in very preterm infants with respiratory distress syndrome: a prospective randomized controlled trial. / ä¸åŒç»´æŒå‰‚é‡æž¸æ©¼é ¸å’–å•¡å› å¯¹æžæ—©äº§å„¿å‘¼å¸çª˜è¿«ç»¼åˆå¾æ’¤æœºå½±å“ï¼šå‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To study the effect of different maintenance doses of caffeine citrate on the success rate of ventilator weaning in very preterm infants (gestational age of ≤32 weeks) with respiratory distress syndrome (RDS). METHODS: A total of 162 preterm infants with RDS who were admitted to the hospital from January 2016 to December 2018 were enrolled in this prospective trial. These infants had a gestational age of ≤32 weeks and required invasive mechanical ventilation. They were randomly divided into a high-dose caffeine group and a low-dose caffeine group, with 81 infants in each group. Within 6 hours after birth, both groups were given caffeine at a dose of 20 mg/kg. After 24 hours, the high- and low-dose caffeine groups were given caffeine at a maintenance dose of 10 mg/kg and 5 mg/kg, respectively. The two groups were compared in terms of re-intubation rate within 48 hours after ventilator weaning, durations of ventilation and oxygen therapy, enteral feeding, weight gain, and the incidence rates of complications and adverse reactions during hospitalization. RESULTS: The high-dose caffeine group had a significantly lower re-intubation rate within 48 hours after ventilator weaning than the low-dose caffeine group (P<0.05), with frequent apnea as the main reason for failed ventilator weaning in both groups. The high-dose caffeine group had significantly shorter durations of mechanical ventilation and oxygen therapy than the low-dose caffeine group (P<0.05). There were no significant differences between the two groups in the time to total enteral feeding, average daily weight gain, body weight at discharge, and the incidence rates of complications (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intracranial hemorrhage) and adverse reactions (tachycardia, hypertension, and feeding intolerance) (P>0.05). CONCLUSIONS: A high maintenance dose of caffeine can safely and effectively reduce the incidence rate of apnea after ventilator weaning and the failure rate of ventilator weaning in RDS preterm infants with a gestational age of ≤32 weeks, and therefore, it holds promise for clinical application.

Association Between Androgenic Alopecia and Coronary Artery Disease: A Cross-Sectional Study of Han Chinese Male Population.

PURPOSE: This research aimed to investigate the correlation between androgenic alopecia (AGA) and coronary artery disease (CAD) and analyze its value in predicting the severity of coronary atherosclerosis in the Han Chinese male population. PATIENTS AND METHODS: A total of 402 Han Chinese male patients aged 28-75 years were enrolled and performed coronary angiography (CAG) after admission. According to the BASP classification, the participants were divided into mild, moderate and severe AGA. CAD was determined via CAG and defined as stenosis of ≥50% in at least one major coronary artery, and the Gensini score was calculated to evaluate the severity of coronary atherosclerosis. RESULTS: In this study, CAD status (P = 0.002), dyslipidemia status (P = 0.002), age (P = 0.003) and coronary atherosclerosis severity (P < 0.001) were different in patients with different levels of AGA. Multivariate logistic regression analysis revealed that severe AGA was independently correlated to CAD risk (OR, 2.111; 95% CI 1.152 to 3.870, P = 0.016), while the relative CAD risk of early-onset AGA was 2.292 (OR, 2.292; 95% CI 1.132 to 4.640, P = 0.021). AGA status (OR, 2.247; 95% CI 1.396 to 3.617, P = 0.001), severe AGA (OR, 2.360; 95% CI 1.506 to 3.699, P < 0.001) and early-onset AGA (OR, 3.474; 95% CI 2.069 to 5.832, P < 0.001) were all independently associated with the severity of coronary atherosclerosis. The area under the receiver operating characteristic (ROC) curve plotted using severe AGA was 0.601, which is predictive of severe coronary atherosclerosis. Moreover, the presence of severe AGA increases the risk of developing CAD associated with obesity (SI = 1.663, SIM = 1.222, AP = 0.289), diabetes (SI = 2.239, SIM = 1.149, AP = 0.503) and dyslipidemia (SI = 1.062, SIM = 0.646, AP = 0.045). CONCLUSION: This study suggested that AGA is independently associated with CAD in a Han Chinese male population. AGA may be a simple and feasible method for screening CAD and indicative of the severity of coronary atherosclerosis.

An insight to sequential ozone­chlorine process for synergistic disinfection on reclaimed water: Experimental and modelling studies.

Water reclamation plants (WRPs) are facing the challenges of ensuring microbial safety and require efficient disinfection systems. Sequential ozone­chlorine disinfection is supposed to be a favorable alternative for reclaimed water disinfection. This study compared the inactivation efficiency of E.coli by single ozone, single chlorine, and sequential ozone­chlorine disinfection approaches. Notably, a single ozone or chlorine process could only achieve a log removal rate of up to 5 log, whereas the sequential ozone­chlorine disinfection could completely inactivate microorganisms (7.3 log). For sequential ozone­chlorine disinfection, the efficiency of chlorination was improved by 2.4%-18.5%. The synergistic effect mainly attributed to the elimination of chlorine consuming substances by ozone. Through the chlorine decay model (CRS) fitting and calculating the integral CT value, the enhancement ability of ozone to chlorine disinfection was quantified. By introducing an enhancement coefficient (ß), a succinct and accurate model was established to estimate the inactivation rate of sequential ozone­chlorine disinfection (mean absolute percentage error: 0.035). The results and methodology of this study are informative to optimize the disinfection units of WRPs.

Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

[Value of anti-neutrophil cytoplasmic antibody in assessing the severity of bronchiolitis obliterans in children].

OBJECTIVE: To study the value of anti-neutrophil cytoplasmic antibody (ANCA) in assessing the severity of bronchiolitis obliterans (BO) in children. METHODS: A prospective analysis was performed on 59 children who were diagnosed with BO from June 2009 to October 2014. ELISA was used to measure the concentrations of myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA in serum. According to the results of ELISA, the children were divided into three groups: double-negative ANCA (n=22), single-positive ANCA (n=17), and double-positive ANCA (n=20). The three groups were compared in terms of the scores of BO risk factors, clinical symptoms, chest high-resolution computed tomography (HRCT), and lung pathology on admission, as well as the changes in the expression level of ANCA and the scores of clinical symptoms and chest HRCT over time. RESULTS: Compared with the double-negative ANCA group, the double-positive ANCA group had a significantly higher score of BO risk factors (P<0.05), and the single-positive ANCA group and the double-positive ANCA group had significantly higher scores of clinical symptoms, chest HRCT, and lung pathology (P<0.05). The children were followed up for 6 months after discharge, and there were significant reductions in MPO-ANCA and PR3-ANCA titers from admission and discharge to the end of follow-up (P<0.05), as well as a significant reduction in the score of clinical symptoms from admission to the end of follow-up (P<0.05), while there was no significant change in the score of chest HRCT from admission to the end of follow-up (P>0.05). The single-positive ANCA and double-positive ANCA groups still had a significantly higher score of clinical symptoms than the double-negative ANCA group (P<0.05). CONCLUSIONS: The expression level of ANCA is correlated with the severity of BO in children and thus has certain clinical significance in disease evaluation.

Microbial transformation of progesterone and dydrogesterone by bacteria from swine wastewater: Degradation kinetics and products identification.

Natural and synthetic progestogens in livestock environments have become a concern due to the frequent presence and potential adverse effects on aquatic organisms. Here we investigated the biotransformation of progestogens by wastewater-borne bacteria in the field and laboratory under oxic and anoxic conditions. The results showed that all progestogens dissipated faster under oxic conditions than under anoxic conditions, and natural progesterone transformed faster than synthetic progestogens. Meanwhile, dozens of bacterial strains capable of degrading progestogens were successfully isolated from the swine wastewater, and Bacillus sp. P19 and Bacillus sp. DGT2 were found the best for progesterone and dydrogesterone transformation, respectively. In the degradation experiments using a single bacterial strain, progesterone and dydrogesterone dissipated under oxic conditions with half-lives of 11.6 h and 18.2 h, respectively. The transformation pathways were proposed based on the identified transformation products. The findings from this study showed that progestogens can be biotransformed, but not fully mineralized in the environment.

Synthesis and antidepressant-like activity of novel alkoxy-piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.

miR-373 promotes neuroblastoma cell proliferation, migration, and invasion by targeting SRCIN1.

INTRODUCTION: Previous studies have shown that miR-373 functions as either a tumor suppressor or an oncogene depending on which type of cancer it's operating in. However, the functional role of miR-373 in neuroblastoma (NB) remains largely unclear. METHODS: Expression of miR-373 and SRC kinase signaling inhibitor 1 (SRCIN1) in 20 metastatic and 20 primary NB tissues was detected by quantitative real-time PCR (qRT-PCR) and Western blotting. MTT assay, flow cytometry analysis and transwell migration and invasion assays were performed to evaluate the influence of miR-373 inhibition on the growth, migration and invasion of NB cells, respectively. In vivo experiment was applied to determine the effect of miR-373 inhibition on tumor growth. Dual-luciferase reporter assay was used to confirm the interaction between miR-373 and SRCIN1. RESULTS: We observed a significant increase in the expression of miR-373 in metastatic NB samples compared with primary NB samples, and this was inversely correlated with SRCIN1 expression. Functional studies revealed that depletion of miR-373 inhibited in vitro NB cell growth, migration and invasion, and also suppressed tumor growth in an in vivo mouse model. Moreover, we identified that SRCIN1 was a direct and functional target gene of miR-373. Silencing of SRCIN1 partially rescued the antimiR-373-mediated inhibition of cell growth, migration and invasion. CONCLUSION: The data from our study verified a potential oncogenic role of miR-373 in NB cells that occurs through direct targeting SRCIN1. The newly identified miR-373/SRCIN1 axis represents a new potential candidate for therapeutic intervention of malignant NB.

Acid-Sensing Ion Channel 1a Modulates NMDA Receptor Function Through Targeting NR1/NR2A/NR2B Triheteromeric Receptors.

The over-activation of N-methyl-D-aspartate receptors (NMDARs) is the main cause of neuronal death in brain ischemia. Both the NMDAR and the Acid-sensing ion channel 1a (ASIC1a) are present in the postsynaptic membrane of the central nervous system (CNS) and participate in physiological and pathological processes. However, the specific role played by ASIC1a in these processes remains elusive. We hypothesize that NMDARs are the primary mediators of normal synaptic transmission and excitatory neuronal death, while ASIC1a plays a modulatory role in facilitating NMDAR function. Using various experimental approaches including patch-clamp recordings on hippocampal slices and CHO cells, primary cultures of hippocampal neurons, calcium imaging, Western blot, cDNA transfection studies, and transient middle cerebral artery occlusion (tMCAO) mouse models, we demonstrate that stimulation of ASIC1a facilitates NMDAR function and inhibition of ASIC1a suppresses NMDAR over-activation. One of our key findings is that activation of ASIC1a selectively facilitates the NR1/NR2A/NR2B triheteromeric subtype of NMDAR currents. In accordance, inhibition of ASIC1a profoundly reduced the NMDAR-mediated EPSCs in older mouse brains, which are known to express much higher levels of triheteromeric NMDARs than younger brains. Furthermore, brain infarct sizes were reduced by a greater degree in older mice compared to younger ones when ASIC1a activity was suppressed. These data suggest that ASIC1a activity selectively enhances the function of triheteromeric NMDARs and exacerbates ischemic neuronal death especially in older animal brains. We propose ASIC1a as a novel therapeutic target for preventing and reducing the detrimental effect of brain ischemia in humans.

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory.

The Medial Habenular (MHb) and the Lateral Habenular nuclei are 2 main parts of the habenular complex (Hb). Recent studies showed that MHb plays an important role in memory, and in the expression of ErbB4. However, the expression of MHb ErbB4 receptor and its role in fear memory is not well understood. In this study, western blotting and quantitative real-time polymerase chain reaction were used to assess the protein and mRNA levels of ErbB4 in the process of contextual fear conditioning. A pharmacological approach was used to block and stimulate the ErbB4 receptor. Contextual fear conditioning tests induced a significant increase on the expression of ErbB4 at various times in the Hb and the MHb. Moreover, the blockade and stimulation of MHb ErbB4 receptors did not affect the fear formation but impaired and improved the contextual-dependent fear expression. Furthermore, in vitro electrophysiological recordings showed that the blockade of the MHb ErbB4 receptor reduced the presynaptic gamma-amino butyric acid release. ErbB4 is a susceptible gene for schizophrenia and the above findings may provide new insights into the mechanisms of fear-related responses.

Preliminary investigation on the abnormal mechanism of CD4+FOXP3+CD25high regulatory T cells in pediatric B-cell acute lymphoblastic leukemia.

The current study aimed to investigate the changes and regulatory mechanism of cluster of differentiation (CD)4+CD25high forkhead box protein 3 (Foxp3+) regulatory T cells (Tregs) in childhood B-cell acute lymphocytic leukemia (B-ALL). A total of 18 children with B-ALL and 15 age-matched healthy children were included. Reverse-transcription quantitative polymerase chain reaction was used to evaluate the mRNA levels of Foxp3, cytotoxic T-lymphocyte associated protein 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3), interleukin (IL)-2 receptor (R)ß/γ, IL-6Rα/ß, mothers against decapentaplegic homolog (Smad)3/4 and runt-related transcription factor (RUNX)1/3 in CD4-positive cells. The concentration of cytokines in plasma were measured using a cytometric bead array. Additionally, the proportion of CD4+CD25highFoxp3+ Tregs and levels of associated proteins was analyzed using flow cytometry. The results demonstrated that the proportion of CD4+CD25highFoxp3+ and expression of Foxp3 in children with B-ALL was significantly higher compared with healthy controls (P<0.05) and that transcription levels of CTLA4, GITR and LAG3 were also significantly elevated (P<0.05). Compared with healthy controls, the expression of IL-2Rα/ß and its downstream molecule phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in CD4-positive cells significantly increased (P<0.05); however, no significant difference of IL-2Rγ levels was identified between the two groups. Correlation analysis demonstrated a significant positive correlation between the expression of phosphorylated (p) signal transducer and activator of transcription factor (STAT)5 and CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.17; P<0.05). The plasma concentration of TGF-ß, the expression of its receptor TGF-ßRI/II and downstream molecules Smad3/4 were significantly upregulated in children with B-ALL (P<0.05), whereas the expression of RUNX1/3 was lower compared with healthy controls (P<0.05). Furthermore, the expression of Smad3 and RUNX1 was positively correlated with CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.87 and 0.60, respectively; P<0.05). Additionally, the expression of pSTAT3 in CD4-positive cells decreased significantly in pediatric patients with B-ALL when compared with healthy controls; however, plasma concentrations of IL-6 was significantly higher (P<0.05). Furthermore, a negative correlation was identified between pSTAT3 and CD4+CD25highFoxp3+ Tregs in pediatric patients with B-ALL (r=-0.39; P<0.05). However, no significant differences in IL-6Rα/ß expression were identified between the two groups. The results demonstrated that the excessive activation of IL-2/pSTAT5 and TGF-ß/Smad signaling, and insufficiency of pSTAT3 may be correlated with increased CD4+CD25highFoxp3+ Tregs in pediatric B-ALL.

Effects of placental cord drainage in the third stage of labour: A meta-analysis.

Observational studies have demonstrated that placental cord drainage can shorten the length of the third stage of labour and reduce blood loss during vaginal deliveries. The aim of our work was to evaluate the existing evidence for the effectiveness of placental cord drainage in the third stage of labour. PubMed, Embase, the Cochrane Library, Web of Science, Google Scholar and 50 journals were searched up to the 4th of June, 2017. Randomized controlled trials comparing placental cord drainage with no cord drainage in the third stage of labour during vaginal delivery were included. Nine studies with 2653 participants were included. Compared with clamping the umbilical cord, umbilical cord drainage during the third stage of labour shortened the third-stage duration by 2.28 minutes (95% confidence interval (CI), -3.22 to -1.33), but did not reduce the amount of blood loss (-31.99 mL, -86.08 to 22.09). For women with normal vaginal deliveries, the incidence of postpartum haemorrhage was reduced by 3%. Placental cord drainage is a simple and non-invasive procedure that should be considered after delayed cord clamping. Further studies about the physiological processes and effects of placental cord drainage in additional circumstances are needed.

Misoprostol for medical treatment of missed abortion: a systematic review and network meta-analysis.

The efficacy and safety of misoprostol alone for missed abortion varied with different regimens. To evaluate existing evidence for the medical management of missed abortion using misoprostol, we undertook a comprehensive review and meta-analysis. The electronic literature search was conducted using PubMed, the Cochrane Library, Embase, EBSCOhost Online Research Databases, Springer Link, ScienceDirect, Web of Science, Ovid Medline and Google Scholar. 18 studies of 1802 participants were included in our analysis. Compared with vaginal misoprostol of 800 ug or sublingual misoprostol of 600 ug, lower-dose regimens (200 ug or 400 ug) by any route of administration tend to be significantly less effective in producing abortion within about 24 hours. In terms of efficacy, the most effective treatment was sublingual misoprostol of 600 ug and the least effective was oral misoprostol of 400 ug. In terms of tolerability, vaginal misoprostol of 400 ug was reported with fewer side effects and sublingual misoprostol of 600 ug was reported with more side effects. Misoprostol is a non-invasive, effective medical method for completion of abortion in missed abortion. Sublingual misoprostol of 600 ug or vaginal misoprostol of 800 ug may be a good choice for the first dose. The ideal dose and medication interval of misoprostol however needs to be further researched.