Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain

Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

Outcomes of laparoscopic bile duct exploration for choledocholithiasis with small common bile duct

BACKGROUND Laparoscopic cholecystectomy(LC)combined with laparoscopic common bile duct(CBD)exploration(LCBDE)is one of the main treatments for choledocholithiasis with CBD diameter of larger than 10 mm.However,for patients with small CBD(CBD diameter≤8 mm),endoscopic sphincterotomy remains the preferred treatment at present,but it also has some drawbacks associated with a series of complications,such as pancreatitis,hemorrhage,cholangitis,and duodenal perforation.To date,few studies have been reported that support the feasibility and safety of LCBDE for choledocholithiasis with small CBD.AIM To investigate the feasibility and safety of LCBDE for choledocholithiasis with small CBD.METHODS A total of 257 patients without acute cholangitis who underwent LC+LCBDE for cholecystolithiasis from January 2013 to December 2018 in one institution were reviewed.The clinical data were retrospectively collected and analyzed.According to whether the diameter of CBD was larger than 8 mm,257 patients were divided into large CBD group(n=146)and small CBD group(n=111).Propensity score matching(1:1)was performed to adjust for clinical differences.The demographics,intraoperative data,short-term outcomes,and long-term follow-up outcomes for the patients were recorded and compared.RESULTS In total,257 patients who underwent successful LC+LCBDE were enrolled in the study,146 had large CBD and 111 had small CBD.The median follow-up period was 39(14-86)mo.For small CBD patients,the median CBD diameter was 0.6 cm(0.2-2.0 cm),the mean operating time was 107.2±28.3 min,and the postoperative bile leak rate,rate of residual CBD stones(CBDS),CBDS recurrence rate,and CBD stenosis rate were 5.41%(6/111),3.60%(4/111),1.80%(2/111),and 0%(0/111),respectively;the mean postoperative hospital stay was 7.4±3.6 d.For large CBD patients,the median common bile duct diameter was 1.0 cm(0.3-3.0 cm),the mean operating time was 115.7±32.0 min,and the postoperative bile leak rate,rate of residual CBDS,CBDS recurrence rate,and CBD stenosis rate were 5.41%(9/146),1.37%(2/146),6.85%(10/146),and 0%(0/146),respectively;the mean postoperative hospital stay was 7.7±2.7 d.After propensity score matching,184 patients remained,and all preoperative covariates except diameter of CBD stones were balanced.Postoperative bile leak occurred in 11 patients overall(5.98%),and no difference was found between the small CBD group(4.35%,4/92)and the large CBD group(7.61%,7/92).The incidence of CBDS recurrence did not differ significantly between the small CBD group(2.17%,2/92)and the large CBD group(6.52%,6/92).CONCLUSION LC+LCBDE is safe and feasible for choledocholithiasis patients with small CBD and did not increase the postoperative bile leak rate compared with choledocholithiasis patients with large CBD.

Methods for simultaneously evaluating reserve and permeability of undersaturated coalbed methane reservoirs using production data during the dewatering stage

In this work,a flowing material balance equation(FMBE) is established for under saturated coalbed methane(CBM) reservoirs,which considers immobile free gas expansion effect at the dewatering stage.Based on the established FMBE,five straight-line methods are proposed to determine the control area,initial water reserve,initial free gas reserve,initial adsorbed gas reserve,original gas in place,as well as permeability at the same time.Subsequently,the proposed FMBE methods for undersaturated CBM reservoirs are validated against a reservoir simulation software with and without considering free gas expansion.Finally,the proposed methods are applied in a field case when considering free gas expansion effect.Validation cases show that the straight-line relationships for the proposed five FMBE methods are excellent,and good agreements are obtained among the actual reserves and permeabilities and those evaluated by the proposed five FMBE methods,indicating the proposed five FMBE methods are effective and rational for CBM reservoirs.Results show that a small amount of free gas will result in a great deviation in reserve evaluation;hence,the immobile free gas expansion effect should be considered when establishing the material balance equation of undersaturated CBM reservoirs at the dewatering stage.

Induction of macrophage inflammatory cytokines by Ox-LDL is ABCA1 dependent

Objective The current study aimed to evaluate whether the induction of macrophage inflammatory cytokines by Ox-LDL is related to the expression of ABCA 1 pathway. Methods After THP 1/PMA macrophages were transfected with ABCA1 antisense oligonucleotides （100nmol/L） followed by treatment with Ox-LDL （30mg/L）, the expressions of ABCA1, ICAM-1 and MCP-1 mRNA and protein were determined by real-time fluorescent quantitative RT-PCR, Western blot or ELISA. Results Ox-LDL induced expressions of ABCA1, ICAM-1, and MCP-1 at both mRNA and protein levels from THPI/PMA macrophages. Transfection with ABCAI antisense oligonucleotides reduced ABCA1 mRNA levels after 3 and 6 hours and protein levels after 12 and 24 hours. The expression of ICAM-1 and MCP-1 induced by Ox-LDL was also decreased after inhibition of ABCA 1 protein expression by ABCA 1 antisense oligonucleotide decreased. Conclusion The induction of macrophage inflammatory cytokines by Ox-LDL is partially dependent on expression ofABCA1. Our studies disclose new functions of ABCA1 in macrophages Objective The current study aimed to evaluate whether the induction of macrophage inflammatory eytokines by Ox-LDL is related to the expression of ABCA 1 pathway. Methods After THP 1/PMA macrophages were transfected with ABCA1 antisense oligonucleotides （100nmol/L） followed by treatment with Ox-LDL （30mg/L）, the expressions of ABCA1, ICAM-1 and MCP-1 mRNA and protein were determined by real-time fluorescent quantitative RT-PCR, Western blot or ELISA. Results Ox-LDL induced expressions of ABCA1, ICAM-1, and MCP-1 at both mRNA and protein levels from THPI/PMA macrophages. Transfection with ABCAI antisense oligonucleotides reduced ABCA1 mRNA levels after 3 and 6 hours and protein levels after 12 and 24 hours. The expression of ICAM-1 and MCP-1 induced by Ox-LDL was also decreased after inhibition of ABCA 1 protein expression by ABCA 1 antisense oligonucleotide decreased. Conclusion The induction of macrophage inflammatory cytokines by Ox-LDL is partially dependent on expression ofABCA1. Our studies disclose new functions of ABCA1 in macrophages

阀芯形状对套筒式调节阀内空化流动的影响研究（英文）

目的:套筒式调节阀内空化的发生不仅会增加整个管路系统的能量损耗,而且会造成阀体及管路的失效破坏。本文旨在探讨四种不同形状的阀芯对套筒式调节阀内不同阀芯位移工况下的空化流动及空化强度的影响,为套筒式调节阀的优化设计及空化控制提出建议。创新点:1.根据四种不同形状的阀芯,研究套筒式调节阀内阀芯形状对流动及空化特性的影响;2.建立数值模型,对套筒式调节阀在不同阀芯形状和不同阀芯位移条件下进行流动及空化分析。方法:1.建立带有不同形状阀芯的套筒式调节阀数值计算模型,并比较分析阀芯形状对阀内速度、压力及空化情况的影响(图4,8和11);2.建立不同阀芯位移条件下的阀门数值模型,比较分析阀芯位移对阀内速度、压力及空化情况的影响(图6和10);3.建立不同形状阀芯及不同阀芯位移下的阀门模型,分析阀芯形状和位移对阀内流动及空化特性的综合影响(图7和13)。结论:1.在四种不同形状阀芯的条件下,高速流动区域和空化发生区主要位于套筒与阀芯之间的间隙;2.在直筒形和椭球形阀芯条件下的阀内空化强度明显强于平底形和圆台形阀芯条件下的空化强度,因此平底形和圆台形阀芯在空化控制方面具有更好的效果;3.在四种不同形状阀芯的条件下,随着阀芯位移的增加,阀内由空化产生的蒸汽总体积先增加后减少。