Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

【Objective】 To investigate the relationship between cerebrospinal fluid exosome-derived miR-630 and the function of brain microvascular endothelial cells （BMECs）. 【Methods】 The subarachnoid hemorrhage endothelial cell model was established to evaluate the effect of hemorrhagic cerebrospinal fluid （BCSF） on BMECs’ proliferation by MTT assay and cell cycle analysis. qRT-PCR and immunofluorescence staining were used to detect the expressions of endothelial cell tight junction protein （ZO-1） and adhesion molecule （ICAM-1 and VCAM-1）. Changes in NOx concentration were detected by radioimmunoassay. The cerebrospinal fluid exosomes in the experimental group （co-incubated with BCSF） and the control group （normal cerebrospinal fluid） were isolated and identified， and differences in the expressions of cerebrospinal fluid exosomal miR-630 between the two groups were compared. BMECs work changes after the intervention with miR-630 analogue were observed. 【Results】 The proliferation of BMECs was significantly inhibited in the experimental group； the mRNA and protein levels of ICAM-1， VCAM-1 and ZO-1 were significantly decreased， and the function of endothelial cells was significantly inhibited （P<0.05）. After the successful separation and identification of cerebrospinal fluid exosomes， the expression of miR-630 was significantly lower in the experimental group than in the control group （P<0.05）. The function of BMECs was significantly improved with miR-630 mimics. 【Conclusion】 The low expression of miR-630 in cerebrospinal fluid exosomes after subarachnoid hemorrhage is closely related to BMECs injury.

Objective: To explore the therapeutic effect of subcutaneous negative pressure drainage and absorbable suture in preventing postoperative complications of cranioplasty. Methods: The clinical data of 175 cases of skull defect admitted and treated in Department of Neurosurgeryof the Affiliated Hospital of Binzhou Medical University from January 2012 to February 2018 were retrospectively analyzed.According to the different intraoperative treatment methods, 97 cases were treated with thread suture to the galea aponeurotica combined with general drainage(the general drainage group), and 78 cases were treated with absorbable suture to the galea aponeurotica combined with negative pressure drainage(the negative pressure drainage group). The galea aponeurotica were sutured intermittently with both silk thread and absorbable suture, and the drainage tube was placed outside the metal titanium plate under the skin, and removed after 48-72 hours.The postoperative complications of the two groups were compared. Results: The incidence rates of subcutaneous hemorrhage, knotting reaction, infection of incision in the negative pressure drainage group were 1.3%(1/78), 0.0%(0/78), and 0.0%(0/78), respectively, which were significantly lower than those in the average drainage group[11.3%(11/97), 20.6%(20/97), 7.2%(7/97)], the differences were statistically significant(χ²=6.85, 18.16, 4.13, all P<0.05). Conclusion The application of absorbable suture suturing galea aponeurotica and subcutaneous negative pressure drainage in skull repair can significantly reduce and prevent postoperative complications of cranioplasty.

In this study, we used next-generation sequencing methods to screen 300 individuals for BRCA1 and BRCA2. A novel mutation (c.849dupT) in BRCA2 was identified in a female patient and her unaffected brothers. This mutation leads to the truncation of BRCA2 functional domains. Moreover, BRCA2 mRNA expression levels in mutation carriers are significantly reduced compared to noncarriers. Immunofluorescence and western blot assays showed that this mutation resulted in reduced BRCA2 protein expression. Thus, we identified a novel mutation that damaged the function and expression of BRCA2 in a family with breast cancer history. The pedigree analysis suggested that this mutation is strongly associated with familial breast cancer. Genetic counsellors suggest that mutation carriers in this family undergo routine screening for breast cancer, as well as other malignancies, such as prostate and ovarian cancer. The effects of this BRCA2 mutation on drug resistance should be taken into consideration during treatment.
Blotting, Western ; BRCA2 Protein ; Breast Neoplasms* ; Breast* ; Drug Resistance ; Female ; Fluorescent Antibody Technique ; Genes, BRCA2 ; High-Throughput Nucleotide Sequencing ; Humans ; Mass Screening ; Nonsense Mediated mRNA Decay* ; Ovarian Neoplasms ; Pedigree ; Prostate ; RNA, Messenger ; Siblings

Objective To investigate the thawing modes on stability of coagulation control products after frozen,looking for a new theoretical basis for cost control and the quality and safety of laboratory.Methods Using ACL TOP 700 automated co-agulation analyzer and supporting the same batch of reagents and quality control materials conduct of the study:after daily QC,recycled the remaining control materials immediately and dispensed into two EP tubes and frozen at-40℃,respectively thawed by room-temperature and 37℃water bath after 24 hours,and examined together with the date of quality control ma-terial,got 20 pairs of data for analysis the financial impact of two alternate ways on coagulation QC parameters.Results For the room-temperature thawing group,FIB high value increasedby an average 0.23 g/L (t=4.026 9,P<0.05);TT normal value average reduction of 0.46 s (t=-3.813 8,P<0.05),TT high value reduced by an average 0.41s (t=-3.972 8,P<0.05);D-Dimer low-value increased by an average of 14.75 ng/ml FEU (t=2.281 6,P<0.05),while APTT,PT normal and high value,FIB normal value,D-Dimer high value were no significant difference after thawing (P>0.05).For the 37℃water bath group,both normal and high value of APTT,PT,FIB,TT and D-Dimer were no significant difference after tha-wing (P>0.05).Conclusion The commercialization of coagulation control materials can be for the second QC,just follow the principle of rapid after melting and timely detection,other laboratories can be used as a reference.

Objective To investigate the diagnostic value of D-dimer age-adjusted threshold in elderly patients with Pulmonary thromboembolism(PTE).Methods Collected patients older than 50 years of suspected PTE,who visited Yan′an People′s Hospital and the Hospital Affiliated to Yan′an University from June 2015 to September 2016,using the revised Geneva criteria for clinical probability assessment firstly.The low-risk group was excluded from the study;the patients with moderate-to-high risk were performed D-dimer detection and CTPA.All patients determined both by D-dimer age-adjusted thresholds and traditional thresholds,comparing the diagnostic efficacy of the two methods subsequently.Results 163 patients were diagnosed with PTE by CTPA among the 549 subjects,the positive rate was 29.69％.The diagnostic sensitivity of plasma D-dimer was 83.44％,78.53％,the specificity was 17.88％,31.61％ respectively,the missed diagnosis rate was 16.56％,21.47％,respectively.The misdiagnosis rates were 82.12％ and 68.39％,respectively,and the Younden index was 0.013 2 and 0.101 4 respectively.All subjects were divided into four groups according to age:50-60 years,60-70 years,70-80 years,and equal or greater than 80 years age group.Compared with the traditional threshold,the misdiagnosis rates of the four groups of age-adjusted thresholds decreased by 4.00％,15.70％,21.36％ and 17.39％,respectively and the specificity was increased by 1.23,1.65,2.56 and 3.00 times,respectively.Conclusion The diagnostic accuracy of the age-corrected threshold is higher than the traditional threshold;combined with clinical practice,the optimal threshold is determined by the ROC curve,the clinician can serve as a reference.

Objective To evaluate the function of MRE11 in inflammasome activation.Methods Different stimuli,in-cluding Poly(I∶C), Poly(dA∶dT),E.coli gDNA,293T gDNA,CPPD and HSV,were used to identify the effective inflamma-some activator using ELISA.Then, MRE11 siRNA oligos were sythesized and transfected into THP-1 cells while Western blotting was used to analyze the efficacy of MRE 11 knockdown .Finally ELISA and Western blotting were used to analyze the involvement of MRE11 in inflammasome activation induced by Poly (I∶C), Poly(dA∶dT), E.coli gDNA and 293T gDNA. Results The IL-1βsecretion and pro-caspase-1 activation which induced by Poly ( I∶C) , Poly( dA∶dT) , E.coli gDNA and 293T gDNA were reduced with different degrees in MRE 11-knockdown THP-1 cells.Conclusion These results indicate that MRE11 is required for inflammasome activation induced by genetic materials .

Objective Diallyl disulfide ( DADS) has achieved remarkable effects in treatment and research of diverserfied cancers.The article was to explore the effects and the mechanism of DADS on the xenograft growth of human small cell lung cancer ( SCLC) cells in nude mice . Methods A total of 25 nude mice were selected to establish xenograft model of NCI-H446 human SCLC cells.The nude mice bearing with SCLC H446 were divided into 5 groups by random selection:positive control group(DDP 66 mg/kg), negative control group(physiological saline), 20 mg/kg DADS group, 60 mg/kg DADS group and 180 mg/kg DADS group, which is 40.6%, 53.1%and 66.4%, respectively.The growth of xenograft tumor in mice was observed after being treated with differ-ent concentrations of DADS .The morphological changes of the tumors were examined under light microscopy .Phase distribution and apoptosis of xenograft cells were analyzed by flow cytometry ( FCM) . Results The growth of xenograft tumor were inhibited signifi-cantly by DADS, resulting in decreased cell density and cellular atypia .Moreover, xenograft cell cycle was blocked in G 2/M and cell apoptosis rate was enhanced . Conclusion DADS can significantly inhibit the growth of NCI-H446 cells and lead to apoptosis .

Objective To evaluate the feasibility and effect of three-points ablation approach in in treatment of typical atrial flutter guided by CARTO. Methods Twenty-six patients with typical atrial flutter diagnosed by ECG and electrophysiological study (EPS) were enrolled in this study. Activation sequence mapping and linear ablation were performed in 11 patients (conventional group) . Three-points guided linear ablation with CARTO system was performed in another15 patients (three-points group) . Results There was no significant difference in the success rate between the two groups. Both the procedure and fluoroscopic time in three-points group were significantly shorter than that in conventional group [(72.66±29.82) vs (102.52±32.61) min;(4.26±2.76) vs (7.32±3.16) min] . Conclusions The three-points ablations approach is as safe and effective as conventional ablation approach in treatment of typical atrial flutter;however,the former can significantly shorten the procedure time and fluoroscopy time.

BACKGROUNDNeutrophil/lymphocyte ratio (NLR) has been proposed as a novel marker of systemic inflammation and oxidative stress. The objective of this study was to ascertain the relationship between levels of NLR and recurrence of lone atrial fibrillation (AF) after catheter ablation.

METHODSA total of 379 lone AF patients who underwent catheter ablation were enrolled in the study. The NLR before and after catheter ablation was determined. Cox regression analyses were used to estimate the relationship between NLR and the recurrence of lone AF.

RESULTSAfter a mean follow-up of (30.5 ± 5.3) months, 124 (32.7%) patients had AF recurrences. The patients who developed AF recurrence had a higher postablation NLR (post-NLR) than patients with no recurrence (5.74 ± 1.55 vs. 4.66 ± 1.27, P < 0.001). Multivariate Cox regression analysis revealed that post-NLR (hazard ratio (HR) 1.514, 95% confidence interval (CI) 1.364-1.680, P < 0.001), left atrium diameter (HR 1.035, 95% CI 1.001-1.071, P = 0.04) and body mass index (HR 1.028, 95% CI 1.002-1.054, P = 0.03) were independent predictors of AF recurrence. Using a cut-off level of 5.15, post-NLR predicted AF recurrence with a sensitivity of 73% and specificity of 67%.

CONCLUSIONSOur results indicate that an elevated post-NLR is associated with a high rate of lone AF recurrence. A simple measurement of NLR may help us to identify high-risk patients who need pharmacologic intervention to prevent recurrence.

Adult ; Atrial Fibrillation ; surgery ; Catheter Ablation ; Female ; Humans ; Lymphocytes ; immunology ; Male ; Middle Aged ; Neutrophils ; immunology ; Proportional Hazards Models