Objective To observe the efficacy and safety of repetitive transcranial magnetic stimulation(rTMS)on refractory tinnitus and the differences of resting-state functional magnetic resonance imaging(rs-fMRI)imaging between before and after treatment,and to explore the possible central mechanism of rTMS regulation of tinnitus.Methods Thirty-seven patients with refractory tinnitus admitted in Affiliated Hospital of North Sichuan Medical College from September 2022 to February 2023 were selected and were divided into experimental group(n=20)and control group(n=1 7).The experimental group was given true rTMS treatment,and the control group was given sham stimulation with the same parameters.Tinnitus handicap inventory(THI)score,tinnitus loudness visual analogue scale(VAS)score and rs-fMRI scan were performed before and after treatment.Regional homogeneity(ReHo)was calculated after scanning,and the different brain regions were selected as the area of interest(ROI)and the whole brain functional connection(FC)was performed.Results There were no significant differences in age,gender,education level,tinnitus side,course of disease,hearing level,self-rating depression scale,self-rating anxiety scale the experimental group and control group.There were no significant differences in THI and VAS scores between the two groups before treatment;the THI and VAS scores in the experimental group decreased after 2 weeks of rTMS treatment(P＜0.001),while there was no significant difference in the two scores in the control group before and after treatment.Only 3 patients in the experimental group experienced left facial muscle tremor or transient mild scalp pain during treatment,without other serious side effects.The ReHo of the left cerebellar area 9 increased in the experimental group after rTMS(P＜0.005);the ReHo values in the right inferior temporal gyrus,left posterior central gyrus and left anterior central gyrus increased in the control group after intervention(P＜0.005).The FCs between the right inferior temporal gyrus and the left orbital inferior frontal gyrus,the left anterior cingulate gyrus increased in the experimental group(P＜0.005),and FC between the right inferior temporal gyrus and the left superior marginal gyrus decreased(P＜0.005).The FCs between the right cuneus and the left fusiform gyrus,right superior occipital gyrus decreased in the experimental group after rTMS(P＜0.005).The FC between the right cuneus and the left fusiform gyrus increased in the control group after intervention(P＜0.005),while other FCs remained unchanged.Conclusions rTMS has a certain therapeutic effect on refractory tinnitus with higher safety;regulation of auditory brain network and related non-auditory brain network may be one of the central mechanisms of rTMS treating refractory tinnitus.

Objective To evaluate the effect of dexmedetomidine pretreatment on Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway during intestinal ischemia-reperfusion (I/R) in rats.Methods Twenty-four male Spragne-Dawley rats,weighing 180-220 g,were divided into 3 groups (n =8 each) using a random number table method:sham operation group (S group),intestinal I/R group (I group) and dexmedetomidine pretreatment group (DP group).Intestinal I/R model was established by occlusion of the superior mesenteric artery for 1 h followed by 2-h reperfusion in anesthetized rats.Dexmedetomidine 100 μg/kg was intraperitoneally injected at 30 min before ischemia in DP group.Blood samples were collected from hearts at the end of reperfusion for determination of the serum intestinal fatty acid binding protein (I-FABP) level by enzyme-linked immunosorbent assay.The intestinal tissues were obtained at the end of reperfusion for examination of pathologic changes and for determination of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) contents (by enzyme-linked immunosorbent assay) and expression of TLR4,MyD88,phosphorylated NF-κB p65 (p-NF-κB p65) in total protein and NF-κB p65 in nucleoprotein (by Western blot).The degree of intestinal tissue damage was graded using Chiu's scoring system.Results Compared with S group,the Chiu's score and concentrations of IFABP in serum and contents of TNF-α and IL-1β in intestinal tissues were significantly increased,and the expression of TLR4,MyD88 and p-NF-κB p65 in total protein and NF-κB p65 in nucleoprotein was up-regulated in I/R group,and the Chiu's score was significantly increased,the expression of MyD88 and p-NF-κB p65 was up-regulated (P＜0.05),and no significant change was found in serum I-FABP concentration,contents of TNF-α and IL-1β,or expression of TLR4 in total protein and NF-κB p65 in nucleoprotein in DP group (P＞0.05).Compared with I/R group,the Chiu's score,serum I-FABP concentration,and contents of TNF-α and IL-1β were significantly decreased,and the expression of TLR4,MyD88 and p-NF-κB p65 in total protein and NF-κB p65 in nucleoprotein was down-regulated in DP group (P＜0.05).Conclusion The mechanism by which dexmedetomidine pretreatement mitigates intestinal I/R injury may be related to inhibiting activation of TLR4/NF-κB signaling pathway in rats.

Objective To compare the effectiveness of patient-controlled intravenous analgesia with or without background infusion of dezocine plus flurbiprofen axetil injection in patients undergoing laparoscopic colorectal cancer operation. Methods Sixty patients scheduled for laparoscopic colorectal cancer surgery,35 males and 25 females,aged 18-65 years,ASA physical status Ⅰ or Ⅱ,were randomly divided into 2 groups:common-dose background infusion group(Group CB,n = 30),and no background infusion group(Group NB, n = 30). All patients were intravenously administered a PCA pump containing dezocine 0.6 mg/kg,flurbiprofen axetil 3 mg/kg and normal saline in a volume of 120 mL.Patients in Group CB were given background infusion rate of 2 mL/h with PCA bolus dose 2 mL,patients in Group NB were given PCA bolus dose 4 mL only.NRS scores, Ramsay sedation scores,pressing times,consumption of analgesic,supplementary analgesics,incidence of ad-verse reactions,time of first exhaust,time of first leaving bed and patients'satisfaction scores were recorded after surgery. The influence factors of time of first exhaust and time of first leaving bed were also analyzed. Results Compared with group CB,the NRS scores in group NB were higher both at rest and during movement(P<0.05), the Ramsay sedation scores in group NB were lower at 24 and 48 h after surgery(P<0.05),the pressing times in group NB were higher(P < 0.05),the consumption of analgesic in group NB were lower after surgery,and the incidence of using supplementary analgesics was higher(P < 0.05). No statistical difference was found on the in-cidence of adverse reactions between the two groups(P > 0.05). Moreover,the time of first leaving bed in group NB was longer than that in group CB(P<0.05).The satisfaction scores in group NB was lower than that in group CB(P<0.05).The main influence factors of the time of first leaving bed were gender and NRS score during move-ment at 24 h after the operation(P<0.05).The main influence factors of the time of first exhaust were age,BMI and fluid infusion volume(P < 0.05). Conclusion Postoperative patient-controlled intravenous analgesia with background infusion of dezocine and flurbiprofen axetil injection was more efficacious and satisfactory,and more suitable in postoperative pain management.

Objective To observe the effects of the preconditioning of ulinastatin on GES-1 cell injury induced by oxygen and glucose deprivation (OGD). Methods GES-1 cells were cultured in vitro and divided into three groups: normal control group (group N), oxygen and glucose deprivation group (group O), and ulinastatin preconditioning group (group U). The OGD model of GES-1 cells were established by glucose-free medium and three-gas incubator for 6h. Ulinastatin was added to group U 12h before the deprivation of oxygen and glucose. The cell viability and apoptosis were determined by cck-8 and flow cytometry respectively. Western Blot was used to examine the protein expression of Caspase-3 and Cleaved Caspase-3. The TRPV1 mRNA expression was measured by quantitative real-time PCR. Results As compared with group N, the viability of GES-1 was decreased, the apoptotic rate and the expression of Caspase-3 and Cleaved Caspase-3 were increased, and the TRPV1 mRNA expression decreased greatly in group O (P < 0.05). As compared with group O, the aforementioned changes were significantly inhibited in group U. Conclusions Ulinastatin preconditioning could effectively inhibit GES-1 cell injury induced by OGD, which may be related to the inhibition of apoptosis and the upregulation of TRPV1 mRNA expression.

Objective To investigate the therapeutic effect of cell penetrating peptide Tat-LK15 mediating small interfering RNA (siRNA) interference with the expression of neuronal nitric oxide synthase (nNOS) in rat spinal dorsal horn on neuropathic pain. Methods The transfection reagent, Tat-LK15, was used to mediate the transfection of rat spinal dorsal horn (SDH) neuronal cells with carboxyfluorescein (FAM), and then the transfection effect was observed under inverted fluorescence microscope. Fifty healthy male SD rats were randomly divided into 5 groups (n=10): control group, sham operation group (sham group), neuropathic pain group (SNL group), Tat-LK15-nNOS siRNA group (TS group) and Tat-LK15-NC siRNA group (TN group). Neuropathic pain was induced by spinal nerve ligation (SNL), rats in control group did not receive operation and only the spinal nerve was exposed in sham group. Groups SNL, TS and TN were made into the models by SNL and implanted intrathecal catheter, intrathecal administration was performed from the 7th day after model establishment, and 10μl normal saline, 10μl TS complex (including 5μg siRNA) and 10μl TN (including 5μg siRNA) were injected intrathecally each day for 7 days. Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at 1 day before (baseline) and 3, 7, 10 and 14 days after model establishment. Then animals were sacrificed on the 14th day after the operation and the lumbar segment (L4-6) of the spinal cord was removed to detect the expressions of nNOS mRNA and protein using q-PCR and Western blotting analysis. Results Tat-LK15 effectively mediated FAM-siRNA into SDH neuronal cells. Compared with sham group, SNL significantly decreased PWMT and PWTL and increased expressions of nNOS mRNA and protein from the 3rd day (P<0.01), but there was no significant difference between the sham and control group. Tat-LK15-nNOS siRNA complex significantly increased PWMT and PWTL and down-regulated nNOS mRNA and protein expressions in TS group compared with SNL group on the days 10 and 14. There was no significant difference between TN and SNL group. Conclusion Tat-LK15 not only can mediate successful nNOS siRNA transfection and inhibit the expression of nNOS, but also effectively relieve SNL-induced neuropathic pain in rats.

OBJECTIVE:To optimize the processing technology of rehmanniae radix praeparata. METHODS:Using transfer rates of catalpol,rehmaionoside D,acteoside,isoacteoside,polysaccharide as indexes for comprehensive score,heating tempera-ture(pressure),heating time and heating times as investigating factors,L9(34)orthogonal test was used to optimize the processing technology of rehmanniae radix praeparata,and verification test was conducted. RESULTS:The optimal processing technology of rehmanniae radix praeparata was as follow as heating temperature of 125 ℃,pressure of 150 kPa for twice,2 h every time. The comprehensive scores of 3 batches of samples were 0.6985,0.6755,0.7016 in the verification test,respectively,RSDs were less than 5%(n=3). CONCLUSIONS:Optimized processing technology is simple,stable,feasible,and can provide reference for in-dustrial production of rehmanniae radix praeparata.

Objective To observe the effect of parecoxib on intestinal barrier function of septic mice.Methods Sepsis was induced by cecal ligation and puncture (CLP) model.Twenty-one male C57BL/6 mice were randomly divided into three groups (n =7 in each group):group Sham,group CLP,group P (parecoxib 2 mg/kg was administered via gastric tube 2 h after CLP).In vivo intestinal permeability was measured using an in vivo ligated loop model 24 h after surgery.Twenty-one male C57BL/6 mice were randomly divided into three groups as before.The small intestine tissue sample was harvested 24 h after surgery.The intestinal pathological changes were observed under light microscope.The expression of tight junction proteins ZO-1,Occludin,and Claudin-1 in the ileum were measured by Western blot.IL-6 and PGE2 level in the ileum were measured by ELISA.Results Compared with group Sham,the intestinal permeability was significantly increased and there was a significant intestinal pathological injury in group CLP.IL-6 and PGE2 level in the ileum was sig nificantly increased and the expression of tight junction protein ZO-1,Occludin,and Claudin-1 in the ileum were reduced in the group CLP (P＜0.05).Compared with the group CLP,intestinal permeability and pathological injury was significantly reduced in the group P.The levels of IL-6 and PGE2 were significantly decreased (P＜0.05),the expression of ZO-1,Occludin,and Claudin 1 were upregulated in group P (P＜0.05).Conclusion Parecoxib can decrease the levels of proinflammatory factors and up-regulate the expression of tight junction to reverse intestinal barrier dysfunction caused by sepsis in mice.

Objective To investigate the effects of target-controlled infusion (TCI)of dexme-detomidine on the median effective concentration of effect-site (Ce50 )of propofol at loss of conscious-ness (LOC)in patients.Methods Sixty-four patients,28 males and 36 females,aged 20-60 years, ASA physical status Ⅰ or Ⅱ,scheduled for elective surgery,were randomly allocated to receive dexmedetomidine of 0 ng/ml (group P),dexmedetomidine of 0.4 ng/ml (group D1),dexmedetomi-dine of 0.6 ng/ml (group D2)and dexmedetomidine of 0.8 ng/ml (group D3)for 1 5 min before TCI of propofol,n =1 6 in each group.The propofol infusion was started to provide an effect-site concen-tration of 1.0 μg/ml,and increased by 0.2 μg/ml when propofol effect-site concentration and target concentration were equilibrium until LOC.Results The Ce50 (95%CI )at loss of consciousness in groups P,D1,D2 and D3 were 2.30 (2.24-2.36)μg/ml,1.92 (1.87-1.96 )μg/ml,1.60 (1.55-1.65)μg/ml and 1.41 (1.35-1.45 )μg/ml,respectively.There was a negative correlation between the effect-site concentration of propofol-induced LOC and target concentration of dexmedetomidine (r=-0.84,P <0.01).Compared with groups P,D1 and D2,the incidence of bradycardia was higher in group D3 (P <0.05).Conclusion The Ce50 of propofol-induced LOC gradually decreases with in-creasing target concentration of dexmedetomidine.Combining propofol with dexmedetomidine of 0.4 or 0.6 ng/ml that can reduce the Ce50 of propofol-induced LOC,which is suitable for induction of an-esthesia with a lower incidence of bradycardia.

Objective To evaluate the sedative interaction between dexmedetomidine and propofol.Methods Sixty-four American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients,aged 20-60 yr,with body mass index of 19.0-25.0 kg/m2,scheduled for elective surgery under general anesthesia,were allocated into 4 groups (n =16 each) using a random number table:different target concentrations of dexmedetomidine groups (D1-4 groups).Dexmedetomidine was administered by target-controlled infusion (TCI) with the Markku model.The target plasma concentrations of dexmedetomidine were 0,0.4,0.6 and 0.8 ng/ml in D1-4 groups,respectively.At 15 min of dexmedetomidine TCI,propofol was given by TCI with Schnider model,and the initial target effect-site concentration was set at 1.0 μg/ml.After the target effect-site and plasma concentrations were balanced,the target effect-site concentration of propofol was gradually increased in increments of 0.2 μg/ml until loss of consciousness (Observer's Assessment of Alertness/Sedation Scale score was 1).The model of pharmacodynamic interaction was used to analyze the sedative interaction between the two drugs.Results There was no statistically significant difference in residual sums of squares fitted by using the model of pharmacodynamic interaction between the target effect-site concentration of propofol and target plasma concentration of dexmedetomidine at loss of consciousness (P＞0.05).The linear dimensionless parameter of pharmacodynamic interaction was 0.The median effective effect-site concentration of propofol was 2.38 μg/ml at loss of consciousness,and the median effective plasma concentration of dexmedetomidine was 2.03 ng/ml at loss of consciousness.Conclusion Dexmedetomidine and propofol interact additively in terms of sedation.

Objective To investigate the role of TRPV1 in exacerbation of gastric mucosal injury in a rat water immersion restraint stress (WIRS) model by acute postoperative pain. Methods Thirty Wistar rats were randomly divided into normal controlled group (N group, n=10), WIRS model group (WIRS group, n=10) and surgery after WIRS group (WS group, n = 10). The general extent of gastric mucosal injury was observed and assessed for gastric mucosal ulcer index (UI), intragastric pH and serum SOD/MDA ratio were measured and the expression of TRPV1 mRNA in gastric mocusal was accessed by Real-time Quantitative PCR. Immunohistochemistry was performed to detect the mean density of TRPV1. Results Compared with NC group, WIRS group showed obvious gastric mocusal injure with higher UI , lower values of intragastric pH serum SOD/MDA ratio and TRPV1 (P<0.05). The treatment with surgery after onset of WIRS significantly aggravated the gastric mucusal erosion and hemorrhage, with UI increased (P < 0.05), the value of intragastric pH, serum SOD/MDA ratio and TRPV1 further reduced (P < 0.05). Meanwhile, TRPV1 was inversely correlated with UI, and positively associated with intragastric pH and serum SOD/MDA ratio. Conclusion TRPV1 expression in gastric mocusal of AMGL model is inhibited by acute postoperative pain. TRPV1 may involve in the exacerbation of gastric mucosal injury in WIRS model by acute postoperative pain.