TRPA1 channel mediates organophosphate-induced delayed neuropathy

OBJECTIVE We want to investigate the mechanism of organophosphate-induced delayed neuropathy(OPIDN) and find appropriate therapeutic medicine.OPIDN,often leads to paresthesias,ataxia and paralysis,occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate(OP) insecticides or nerve agents,and may contribute to the Gulf War Syndrome.METHODS FDSS Ca2^(+)-influx assays,single-cell calcium imaging and patch-clamp electrophysiology were the major testing techniques.Transfected HEK293 cells and dorsal root ganglion(DRG) neurons were used to evaluate the effects of compounds.Wild type and trpa1 knockout mice and adult hyline brown hens were used to evaluate the neuropathological damages caused by the OPs.Transmission electron microscopy imaging was used to observe the nerve injuries ultrastructurally.High-throughput screen for TRPA1 inhibitors was accomplished by Ion Works Barracuda(IWB) automated electrophysiology assay.RESULTS TRPA1(Transient receptor potential cation channel,member A1) channel mediates OPIDN.A variety of OPs,exemplified by malathion,activates TRPA1 but not other neuronal TRP channels.Malathion increases the intracellular calcium levels and upregulates the excitability of mouse DRG neurons in vitro.Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors,which resembles the early symptoms of OPIDN.Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene.In the classic hens OPIDN model,malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate(TOCP),which also activates TRPA1 channel.Treatment with HC030031 reduces the damages caused by malathion or TOCP.Duloxetine and Ketotifen,two commercially available drugs exhibiting TRPA1 inhibitory activity,show neuroprotective effects against OPIDN and might be used in emergency situations.CONCLUSION TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.

Salvage irrigation-suction in gracilis muscle repair of complex rectovaginal and rectourethral fistulas

AIM:To evaluate the efficacy of gracilis muscle transposition and postoperative salvage irrigation-suction in the treatment of complex rectovaginal fistulas(RVFs)and rectourethral fistulas(RUFs).METHODS:Between May 2009 and March 2012,11female patients with complex RVFs and 8 male patients with RUFs were prospectively enrolled.Gracilis muscle transposition was undertaken in all patients and postoperative wound irrigation-suction was performed in patients with early leakage.Efficacy was assessed in terms of the success rate and surgical complications.SF-36 quality of life(QOL)scores and Wexner fecal incontinence scores were compared before and after surgery.RESULTS:The fistulas healed in 14 patients after gracilis muscle transposition;the initial healing rate was73.7%.Postoperative leakage occurred and continuous irrigation-suction of wounds was undertaken in 5patients:4 healed and 1 failed,and postoperative fecal diversions were performed for the patient whose treatment failed.At a median follow-up of 17 mo,the overall healing rate was 94.7%.Postoperative complications occurred in 4 cases.Significant improvement was observed in the quality outcomes framework scores(P<0.001)and Wexner fecal incontinence scores(P=0.002)after the successful healing of complex RVFs or RUFs.There was no significant difference in SF-36 QOL scores between the initial healing group and irrigationsuction-assisted healing group.CONCLUSION:Gracilis muscle transposition and postoperative salvage wound irrigation-suction gained a high success rate in the treatment of complex RVFs and RUFs.QOL and fecal incontinence were significantly improved after the successful healing of RVFs and RUFs.

Radial head subluxation in pediatric clinics and emergency departments in China

Purpose:To investigate the characteristics of the onset and treatment of radial head subluxation(RHS)in pediatric clinics and emergency departments.Methods:A retrospective study was performed on 11,404 RHS cases in 9827 children who visited pediatric clinics and emergency departments from January 2015 to December 2018.The patients who with history of trauma and fracture of the affected limb were excluded.The following factors were examined:the mechanisms of RHS,the type of manual reduction,the attending physician's clinical background(emergency surgeon,junior pediatric orthopedic surgeon or senior pediatric orthopedic surgeon),and the epidemiological features(gender,age,climate and location)of the injury.Results:The mean age of the patients was 27.93±17.94 months(range 0.93-214.53 months),with a peak incidence of 10.73-44.53 months.Approximately two-thirds of RHS cases occurred in cold weather from January to March and from September to December.Females accounted for 53.81%(n=6137)of the cases,and left injuries were predominant(56.87%,n=6485)in all cases.Mechanisms of injury were classified as"pull"(90.57%,n=10,339),"fall"(1.56%,n=178),"hit"(0.75%,n=86)and"unknown"(7.02%,n=801).The overall success rate of manual reduction was 99.47%,and the success rate of reduction was higher for senior pediatric orthopedic surgeons than for emergency surgeons and junior pediatric orthopedic surgeons(p<0.05).However,there was still a recurrence rate of 12.16%in the 9827 patients.Conclusion:Younger children are predisposed to RHS,and there is a possibility of recurrence.Trained emergency doctors can handle it well,but it is essential to refer patients to specialists when manual reduction failed.