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 compare the efficacy of oblique lumbar interbody fusion (OLIF) and minimally invasive interbody fusion (MI-TLIF) for degenerative lumbar spondylolisthesis.Methods:Data of 40 patients with I-II degree single level degenerative lumbar spondylolisthesis from January 2018 to December 2018 were retrospectively analyzed. According to the operation procedure, they were divided into two groups: OLIF group and MI-TLIF group, and each group had 20 patients. There were 15 males and 5 females in the OLIF group, aged 50.3±8.8 years; and there were 13 males and 7 females in the MI-TLIF group, aged 51.7±8.7 years. According to the Meyerding's grade system, there were 16 patients of type I in the OLIF group and 15 cases in the MI-TLIF group; and there were 4 patients of type II in the OLIF group and 5 cases in the MI-TLIF group. The operation time, intra-operative hemorrhage, postoperative drainage, recessive blood loss and albumin loss were recorded. The CRP and ESR on the third day after operation, the VAS score and ODI score before and after operation were recorded. The lumbar lordosis (LL), fused segmental lordosis (FSL) and disc height (DH) before and after operation were recorded. The time of getting out of bed and walking and the hospital stay were recorded. Paired t-test was used to analyze the data.Results:Forty patients successfully underwent the operation. The operation time of OLIF group was 96±20 min, with intraoperative blood loss of 61±32 ml and postoperative drainage volume of 18±8 ml. The operation time of MI-TLIF group was 132±26 min, with intraoperative blood loss of 262±102 ml and postoperative drainage volume of 95±42 ml; and there was statistical difference between the two groups ( t=4.901, 8.404, 8.064; P< 0.001). On the third day after operation, the occult blood loss was 139±47 ml in the OLIF group and 486±192 ml in the MI-TLIF group; the albumin loss was 4.2±1.9 g/L in the OLIF group and 10.2±3.9 g/L in the MI-TLIF group; CRP was 34±11 mg/L in the OLIF group and 106±39 mg/L in the MI-TLIF group; ESR was 41±15 mm/1 h in the OLIF group and 71±24 mm/1 h in the MI-TLIF group, and there all were statistical differences between the two groups ( t=7.838, 6.184, 7.983, 4.675; P< 0.001). The VAS scores were 2.2±1.5, 1.8±1.3 and ODI scores were 14%±11%, 59%±17%, respectively. There was no significant difference between the two groups. The LL were 33.41°±9.25°, 32.07°±9.54°, FSL were 11.59°±5.09°, 10.61°±4.56° and DH were 10.35±2.30 mm, 10.85±1.85 mm, respectively. There was no significant difference between the two groups. The follow-up time was 13.5±2.3 months in the OLIF group and 14.1±2.8 months in the MI-TLIF group. Three patients in the MI-TLIF group had radiation pain in the lower extremity on the third day after operation, which relieved after NSAID drugs and mannitol treatment. In the group of OLIF, the skin temperature of the left lower extremity increased in 1 case on the first day after operation, in which sympathetic chain injury was considered, and the patient recovered after 2.5 months; in the group of OLIF, the numbness in the front of the left thigh and the weakness of flexion of the hip was found in 3 cases, in which the edema or injury of the psoas major muscle was considered. Conclusion:Compared with MI-TLIF in the treatment of I, II degree single segment degenerative lumbar spondylolisthesis, OLIF has the advantages of shorter operation time, less intraoperative and postoperative blood loss, lower inflammation index, earlier time to get out of bed and shorter hospital stay. However, the outcomes of the two surgeries were similar.

Objective To evaluate the effects of age factors on sedation induced by dexmedetomidine.Methods One hundred and thirty-nine patients,aged 18-103 yr,with body mass index ≤ 30 kg/m2,scheduled for elective surgeries on lower abdomen or lower extremities,were divided into4 groups according to the age:group Ⅰ (18 yr≤age≤44 yr,n=40);group Ⅱ (45 yr≤age≤59 yr,n=38);group Ⅲ (60 yr≤age≤89 yr,n=39);group Ⅳ (≥90 yr,n=22).A catheter was placed in the subarachnoid space at L3,4 interspace,and ropivacaine 10-20 mg was injected via the catheter.At 20 min after ropivacaine injection,dexmedetomidine 1 μg/kg was infused via a pump over 10 min.The onset time and duration of sedation were recorded,and the occurrence of adverse effects such as hypoxemia,bradycardia and hypotension was observed.Results There was no significant difference in the onset time of sedation and incidence of bradycardia among the 4 groups (P＞0.05).Compared with group Ⅰ,the duration of sedation was significantly prolonged in Ⅱ-Ⅳ groups (P＜0.05).Compared with Ⅱ and Ⅲ groups,the duration of sedation was significantly prolonged in group Ⅳ (P ＜ 0.05).The incidence of hypoxemia and hypotension was significantly higher in group Ⅳ than in Ⅰ-Ⅲ groups (P＜0.05).Conclusion Dexmedetomidine-induced sedation is influenced by age factors,the duration of sedation induced by dexmedetomidine is prolonged,and the occurrence of adverse effects is increased,especially if the patients ≥ 90 yr of age.

Objective To explore the effect of miR-24-2 on the in vitro proliferation of U-2OS cells. Methods U-2OS cells were randomly allocat-ed into 4 groups:miR-24-2 mimic group,miR-24-2 inhibitor group,negative control group,and normal control group. MicroRNAs were transfected into U-2OS cells using Lipofectamine?2000. miR-24-2 expression level and the proliferation of U-2OS cells after transfection were detected by real-time quantitative RT-PCR(RT-qPCR)and MTT proliferation assays,respectively. Results RT-qPCR results showed that miR-24-2 level was sig-nificantly higher in the miR-24-2 mimic group and lower in the miR-24-2 inhibitor group than those in the controls,indicating the successive trans-fection. MTT proliferation assay results proved that the cell viability was significantly lower in the U-2OS cells transfected with miR-24-2 mimic and higher in inhibitor groups compared to the control. Conclusion MiR-24-2 inhibits growth of the U-2OS cells,which could be a potential biomarker in the treatment of osteosarcoma.

Objective To investigate the effects of urotensin Ⅱ/urotensin Ⅱreceptor ( UⅡ/UT) system on the expression of inflammatory signal molecules p 38 mitogen-activated protein kinase ( p38 MAPK) and nuclear factor-κB ( NF-κB ) in lipopolysaccharide ( LPS )-stimulated Kupffer cells ( KCs ) . Methods Rat KCs were isolated and purified by means of in situ perfusion and density gradient centrifuga-tion.The isolated cells were randomly divided into six treatment groups including group 1:UⅡ(-) urantide (-)LPS(-), group 2:UⅡ(+)urantide(-)LPS(-), group 3: UⅡ(-)urantide(+)LPS(-), group 4:UⅡ(-)urantide(-)LPS(+), group 5:UⅡ(+) urantide(-) LPS(+) and group 6:UⅡ(-)urantide(+) LPS(+) .Western blot assay was performed to detect p 38 MAPK/p-p38 MAPK protein and NF-κB p65 sub-unit.The DNA-binding activity of NF-κB was tested by electrophoretic mobility shift assay (EMSA).Re-sults There was no significant difference with the expression of p 38 MAPK protein in KCs among the six groups (P>0.05).The expression of p65 protein and p-p38 MAPK and the DNA-binding activity of NF-κB were significantly enhanced in LPS-stimulated KCs from groups 4, 5 and 6 in comparison with those in group 1 (P<0.01).No significant differences with the levels of p65 protein and phosphor-p38 MAPK and the DNA-binding activity of NF-κB were observed between UⅡ/urantide-treated cells ( group 2 or group 3) and untreated cells (group 1) (all P>0.05), but that were decreased in group 6 than those in group 4 (all P<0.01).Conclusion UⅡ/UT system participated in the activation of p38 MAPK and NF-κB signaling pathways in LPS-stimulated primary Kupffer cells .