OBJECTIVE To study the effects of Ro 64-6198,a selective nociceptin/orphanin FQ receptor(NOPR)agonist,on heroin self-administration and drug-seeking behavior in rats.METHODS Rats were trained to self-administer heroin intravenously at a dose of 0.05 mg·kg-1 under a fixed ratio 1(FR1)reinforcement schedule.Heroin motivation was assessed using a progressive ratio(PR)schedule.Firstly,a stable heroin self-administered rat model was established before the effects of Ro 64-6198 on heroin rewarding under the FR1 schedule were observed.After three days of self-administration recovery training,the effects of Ro 64-6198 on heroin reward motivation were observed under the PR3-4 schedule.Following extinction,the reinstatement of heroin seeking induced by either conditioned cues or heroin priming was evaluated in rats withdrawn from self-administration.The expressions of cAMP response element-binding protein(CREB)and brain-derived neurotrophic factor(BDNF)in the ventral tegmental area(VTA)were analyzed using Western blotting,while the expression of the NOPR in neurons in the VTA was examined through immunofluorescence staining.RESULTS Pretreatment with 3 mg·kg-1 Ro 64-6198 significantly reduced active responses and heroin infusions during FR1 testing,as well as decreased breakpoints,indicating reduced motivation under the PR schedule.At a dose of 1 mg·kg-1,Ro 64-6198 markedly attenuated the reinstatement of heroin-seeking behavior induced by conditioned cues or heroin priming.Furthermore,the administration of SB-612111,an NOPR antagonist,blocked the inhibitory effects of Ro 64-6198 on cue-induced heroin-seeking,although SB-612111 alone had no effect on heroin-seeking behavior.Ro 64-6198 treatment also suppressed the reduction of both phos-phorylated CREB(p-CREB)and BDNF levels in the VTA and the decreased expression of NOPR and p-CREB in dopaminergic neurons of the VTA.CONCLUSION These results demonstrate that Ro 64-6198 can mitigate heroin-seeking behavior through NOPR activation and CREB/BDNF pathway in the VTA.This study is expected to offer evidence for its potential as a clinical treatment for heroin addiction and relapse.

Objective:To investigate the efficacy of oral folic acid intervention in lung cancer patients with radiation esophagitis (RE) caused by concurrent chemoradiotherapy.Methods:In this randomized, controlled, single-center clinical trial, a total of 82 patients with stage N 2-N 3 lung cancer including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) admitted to the Affiliated Cancer Hospital of Guizhou Medical University from June 2022 to October 2023 were prospectively included. All enrolled patients were randomly divided into the experimental group (folic acid group) and control group according to 1 vs. 1 of simple random method, and patients in both groups were required to receive radiation therapy for lung lesions and mediastinal metastatic lymph nodes [≥2 cycles of chemotherapy were completed during the same period of radiotherapy (≥40 Gy / 20 F) or targeted drugs were given simultaneously]. The severity of RE was evaluated using the modified common terminology criteria for adverse events criteria of the National Cancer Institute in both groups weekly at the onset of radiation esophagitis symptoms and thereafter until 1 week after the end of radiotherapy. Conventional treatment of RE was delivered according to the grading criteria of the Radiation Therapy Oncology Group. Patients in the folic acid group were given with folic acid tablets 30 mg/d orally at the beginning of radiotherapy until the end of radiotherapy, while those in the control group did not receive any drug intervention. The onset time, severity and duration of RE, and changes in the severity of esophageal toxicity after conventional treatment were recorded and analyzed. Serum folate value, serum vitamin B 12 value and homocysteine value were measured before and after radiotherapy. For continuous quantitative variables, independent sample t-test or independent sample rank-sum test was used for comparison among different groups. For categorical data, Chi-square test or Fisher's exact probability method was used for comparison among different groups. Results:During the observation period, no grade 4 or above RE was reported between two groups. The incidence of grade 0, 1, 2 and 3 RE in the folic acid and control groups was 10% (4/40) and 5% (2/41), 70% (28/40) and 42% (17/41), 15% (6/40) and 51% (21/41), 5% (2/40) and 2% (1/41), respectively. The differences were not statistically significant between two groups ( P=0.456). However, the incidence of grade 0-1 RE in the folic acid group was significantly higher than that in the control group ( Z=2.72, P=0.006). The median time of RE in the folic acid group and control group was 12 d (range 7-52 d) and 15 d (range 11-56 d) after the start of radiotherapy, respectively, with no statistically significant difference ( χ2=-0.75, P=0.456). However, median duration of the individual's most severe RE was 12 d (range 4-36 d) and 21 d (range 7-38 d) in the folic acid group and control groups, respectively, and the differences were statistically significant ( χ2=2.10, P=0.039). In the folic acid group, the grades of swallowing with pain and dysphagia were significantly declined after folic acid intervention, especially at 2 weeks after the occurrence of RE ( P=0.001, P=0.002). The remission rate of RE after 1 week in the folic acid group was higher than that in the control group, and the difference was statistically significant ( χ2=7.36, P=0.012). Conclusion:Oral intake of folic acid during concurrent chemoradiotherapy for lung cancer cannot reduce the incidence of RE, but it may reduce its severity, shorten the duration of the most severe RE in individuals, and have a certain protective effect.

Objective:To analyze the changes and significance in clinical cardiac indicators of early cardiac myocardial dysfunction and cardiac substructure dose during conventional radiotherapy for N 2-N 3 non-small cell lung cancer (NSCLC) with mediastinal lymph node metastases. Methods:The data of 34 NSCLC patients with lymph node metastases in regions 4-8 admitted to the Affiliated Cancer Hospital of Guizhou Medical University from June 2022 to August 2023 were observed and analyzed. All patients were treated with volumetric modulated arc therapy with a prescribed dose of 60-70 Gy. Cardiac troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at 6 time points: within 1 week before radiotherapy ( t0); when the cumulative radiotherapy dose reaches 20 Gy ( t20), 40 Gy ( t40), 60 Gy ( t60) during radiotherapy; within 1 week after radiotherapy ( tp); 1 month after radiotherapy( tp1). Left ventricular global longitudinal strain (LVGLS) and left atrial global longitudinal strain (LAGLS) were assessed at 4 time points: t0, t40, tp and tp1, respectively. The changes in cardiac indicators at different time points during radiotherapy and their correlation with substructure doses were analyzed using analysis of variance, linear regression analysis, and Pearson correlation. Results:The correlation between cardiac substructure dose and mean heart dose (MHD) in the study cohort in the descending order was as follows: left ventricle ( B=0.43, P<0.001), right ventricle ( B=0.37, P=0.002), left atrium ( B=0.16, P<0.001), and right atrium ( B=0.15, P=0.001). There were significant differences in the changes of LVGLS and LAGLS across different time points ( F=3.13, P=0.029; F=17.18, P<0.001). At 1 month after radiation, LAGLS was significantly decreased compared to pre-radiation levels ( P=0.009), whereas no significant difference was observed in LVGLS ( P=1.000). No significant differences were observed in the changes of cTnT and NT-proBNP across different time points (all P>0.05). Significant correlations were identified between cTnT and right ventricle mean dose at t40 ( r=0.38, P=0.025), as well as between NT-proBNP and right atrium mean dose at t60 and tp ( r=0.54, P=0.001; r=0.41, P=0.016). Conclusions:At present, there is no significant difference between the sensitive serum markers of myocardial injury and LVGLS in detecting early myocardial injury. LAGLS may hold substantial clinical value. There is uncertainty about radiation injury and repair of various cardiac substructures.

OBJECTIVE: To observe the clinical efficacy of electroacupuncture (EA) at "four points of sacral region" for mild-to-moderate benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). METHODS: A total of 58 patients with BPH/LUTS were randomly divided into a sacral four-point EA group (29 cases, 1 case dropped out) and a conventional EA group (29 cases, 1 case dropped out). EA was applied at bilateral points 0.5 cun lateral to the sacrococcygeal joint and Huiyang (BL35) in the sacral four-point EA group; and was applied at Guanyuan (CV4), Zhongji (CV3), Qugu (CV2) and bilateral Shuidao (ST28), Sanyinjiao (SP6), Zusanli (ST36) in the conventional EA group. Both groups received continuous wave, 2 Hz in frequency, 30 min a time, once every other day, 3 times a week for 4 weeks. Before treatment, after 2 and 4 weeks of treatment, and in follow-up of 1 month after treatment completion, the international prostate symptom score (IPSS), the overactive bladder symptom score (OABSS), the quality of life (QOL) score were observed; before and after treatment, the prostate volume (PV) was measured by abdominal ultrasound; and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: Compared before treatment, the scores of IPSS, OABSS and QOL were decreased after 4 weeks of treatment and in follow-up in both groups (P<0.01, P<0.05). In the sacral four-point EA group, the scores of IPSS and QOL after 4 weeks of treatment and in follow-up were lower than those in the conventional EA group (P<0.05, P<0.01), and the OABSS score in follow-up was lower than that in the conventional EA group (P<0.05). After 4 weeks of treatment and in follow-up, the reductions of IPSS and OABSS scores compared before treatment in the sacral four-point EA group were larger than those in the conventional EA group (P<0.01, P<0.05); After 2, 4 weeks of treatment and in follow-up, the reductions of QOL score compared before treatment in the sacral four-point EA group were larger than those in the conventional EA group (P<0.01). No significant difference in PV was observed after treatment between the two groups (P>0.05). The total effective rate was 75.0% (21/28) in the sacral four-point EA group, which was higher than 39.3% (11/28) in the conventional EA group (P<0.01). CONCLUSION EA at "four points of sacral region" can effectively improve the LUTS, overactive bladder symptom and quality of life in patients with mild-to-moderate BPH, and has good short-term and long-term efficacy, although it can not reduce prostate volume.
Humans ; Male ; Electroacupuncture ; Prostatic Hyperplasia/complications* ; Aged ; Middle Aged ; Lower Urinary Tract Symptoms/physiopathology* ; Acupuncture Points ; Treatment Outcome ; Quality of Life

Objective To develop and validate an early venous thromboembolism(VTE)risk assessment scale for emergency observation patients.Methods ① Based on the characteristics of emergency observation patients,the Delphi expert consultation method and literature review were used to determine scale items and construct a scoring system.②The newly developed VTE scale and its scoring system were analyzed for reliability and validity.③Primary application:collect non acute traumatic observation and rescue patients admitted to Zhejiang Hospital from June 2022 to June 2023 as the research subjects.Patients were divided into survival and non-survival groups based on 28-day outcomes.Differences in VTE scores between the two groups using the new scale,Caprini,and Padua models were compared.The optimal cut-off point was determined using the receiver operator characteristic curve(ROC curve),according to the optimal cut-off value of the new scale score,patients were divided into two groups,and Kaplan-Meier survival curves were used to analyze the 28-day cumulative survival of the two groups of patients.Results ①The preliminary version of the early VTE risk assessment scale for emergency observation patients was developed,comprising 8 items:age,pre examination triage level,underlying diseases,D-dimer levels,activities of daily living(ADL)assessment,coagulation-related indicators,anticoagulants and(or)antiplatelet drugs use,and unhealthy habits.② A total of 121 emergency observation patients were included in the analysis.The test-retest reliability correlation coefficient(R)of the new scale was 0.945(>0.850),split-half reliability was 0.741(>0.700),and Cronbach'sαcoefficient was>0.700.KMO value was 0.715(>0.700),and Bartlett's sphericity test yieldedχ2=167.079,P<0.001,confirming the suitability of the scale for factor analysis.Three factors were identified:basic information,initial assessment,and blood test indicators.Pearson correlation analysis showed the correlation coefficients between the new scale and the Caprini and Padua scores were 0.842 and 0.307,respectively,both P<0.01.③Area under the curve(AUC)of the new scale was 0.566,95%confidence interval(95%CI)was 0.444-0.688,with an optimal diagnostic cut-off value of 13.5 points based on the maximum Youden index.The results of the Kaplan-Meier regression indicated that survival analysis using the 13.5-point cut-off revealed that patients with scores≥13.5 had significantly lower 28-day survival rates than those with scores<13.5(Log-Rank test:χ2=5.609,P=0.018).④The survival group had significantly lower scores than the non-survival group across all scales(new score:10.06±2.84 vs.12.69±3.06,Caprini model:7.22±2.48 vs.9.41±2.64,Padua model:2.91±1.97 vs.4.59±1.07,all P<0.05).Conclusion The early VTE risk assessment scale for emergency observation patients was successfully developed,demonstrating good reliability and validity through statistical analysis.The new scale effectively predicts disease severity and prognosis in emergency observation patients.

Rheumatoid arthritis(RA)is an autoimmune disease characterized by chronic,aggressive joint inflammation,which seriously harms mental and physical health of patients.Efficacy of clinical drugs for RA is limited,so it is a hot issue to seek new therapeutic targets and drugs.Zinc finger protein A20,a cytoplasmic ubiquitin modifier,is closely related to negative regulation of nuclear factor-kappaB(NF-κB),an inflammatory signaling pathway,and has anti-inflammatory and anti-apoptotic effects.A20 is involved in pathogenesis of RA and can improve inflammatory response and bone destruction of RA.Treatment of RA by traditional Chinese medicine has unique advantages of multi-target and multi-pathway,and studies have found that traditional Chinese medicine has a regulatory effect on A20.This paper expounds mechanism of A20 in RA and research progress of traditional Chinese medicine intervention in A20,in order to provide references for treatment and drug development of RA.

OBJECTIVE To study the effects of Ro 64-6198,a selective nociceptin/orphanin FQ receptor(NOPR)agonist,on heroin self-administration and drug-seeking behavior in rats.METHODS Rats were trained to self-administer heroin intravenously at a dose of 0.05 mg·kg-1 under a fixed ratio 1(FR1)reinforcement schedule.Heroin motivation was assessed using a progressive ratio(PR)schedule.Firstly,a stable heroin self-administered rat model was established before the effects of Ro 64-6198 on heroin rewarding under the FR1 schedule were observed.After three days of self-administration recovery training,the effects of Ro 64-6198 on heroin reward motivation were observed under the PR3-4 schedule.Following extinction,the reinstatement of heroin seeking induced by either conditioned cues or heroin priming was evaluated in rats withdrawn from self-administration.The expressions of cAMP response element-binding protein(CREB)and brain-derived neurotrophic factor(BDNF)in the ventral tegmental area(VTA)were analyzed using Western blotting,while the expression of the NOPR in neurons in the VTA was examined through immunofluorescence staining.RESULTS Pretreatment with 3 mg·kg-1 Ro 64-6198 significantly reduced active responses and heroin infusions during FR1 testing,as well as decreased breakpoints,indicating reduced motivation under the PR schedule.At a dose of 1 mg·kg-1,Ro 64-6198 markedly attenuated the reinstatement of heroin-seeking behavior induced by conditioned cues or heroin priming.Furthermore,the administration of SB-612111,an NOPR antagonist,blocked the inhibitory effects of Ro 64-6198 on cue-induced heroin-seeking,although SB-612111 alone had no effect on heroin-seeking behavior.Ro 64-6198 treatment also suppressed the reduction of both phos-phorylated CREB(p-CREB)and BDNF levels in the VTA and the decreased expression of NOPR and p-CREB in dopaminergic neurons of the VTA.CONCLUSION These results demonstrate that Ro 64-6198 can mitigate heroin-seeking behavior through NOPR activation and CREB/BDNF pathway in the VTA.This study is expected to offer evidence for its potential as a clinical treatment for heroin addiction and relapse.

Rheumatoid arthritis(RA)is an autoimmune disease characterized by chronic,aggressive joint inflammation,which seriously harms mental and physical health of patients.Efficacy of clinical drugs for RA is limited,so it is a hot issue to seek new therapeutic targets and drugs.Zinc finger protein A20,a cytoplasmic ubiquitin modifier,is closely related to negative regulation of nuclear factor-kappaB(NF-κB),an inflammatory signaling pathway,and has anti-inflammatory and anti-apoptotic effects.A20 is involved in pathogenesis of RA and can improve inflammatory response and bone destruction of RA.Treatment of RA by traditional Chinese medicine has unique advantages of multi-target and multi-pathway,and studies have found that traditional Chinese medicine has a regulatory effect on A20.This paper expounds mechanism of A20 in RA and research progress of traditional Chinese medicine intervention in A20,in order to provide references for treatment and drug development of RA.

Objective To develop and validate an early venous thromboembolism(VTE)risk assessment scale for emergency observation patients.Methods ① Based on the characteristics of emergency observation patients,the Delphi expert consultation method and literature review were used to determine scale items and construct a scoring system.②The newly developed VTE scale and its scoring system were analyzed for reliability and validity.③Primary application:collect non acute traumatic observation and rescue patients admitted to Zhejiang Hospital from June 2022 to June 2023 as the research subjects.Patients were divided into survival and non-survival groups based on 28-day outcomes.Differences in VTE scores between the two groups using the new scale,Caprini,and Padua models were compared.The optimal cut-off point was determined using the receiver operator characteristic curve(ROC curve),according to the optimal cut-off value of the new scale score,patients were divided into two groups,and Kaplan-Meier survival curves were used to analyze the 28-day cumulative survival of the two groups of patients.Results ①The preliminary version of the early VTE risk assessment scale for emergency observation patients was developed,comprising 8 items:age,pre examination triage level,underlying diseases,D-dimer levels,activities of daily living(ADL)assessment,coagulation-related indicators,anticoagulants and(or)antiplatelet drugs use,and unhealthy habits.② A total of 121 emergency observation patients were included in the analysis.The test-retest reliability correlation coefficient(R)of the new scale was 0.945(>0.850),split-half reliability was 0.741(>0.700),and Cronbach'sαcoefficient was>0.700.KMO value was 0.715(>0.700),and Bartlett's sphericity test yieldedχ2=167.079,P<0.001,confirming the suitability of the scale for factor analysis.Three factors were identified:basic information,initial assessment,and blood test indicators.Pearson correlation analysis showed the correlation coefficients between the new scale and the Caprini and Padua scores were 0.842 and 0.307,respectively,both P<0.01.③Area under the curve(AUC)of the new scale was 0.566,95%confidence interval(95%CI)was 0.444-0.688,with an optimal diagnostic cut-off value of 13.5 points based on the maximum Youden index.The results of the Kaplan-Meier regression indicated that survival analysis using the 13.5-point cut-off revealed that patients with scores≥13.5 had significantly lower 28-day survival rates than those with scores<13.5(Log-Rank test:χ2=5.609,P=0.018).④The survival group had significantly lower scores than the non-survival group across all scales(new score:10.06±2.84 vs.12.69±3.06,Caprini model:7.22±2.48 vs.9.41±2.64,Padua model:2.91±1.97 vs.4.59±1.07,all P<0.05).Conclusion The early VTE risk assessment scale for emergency observation patients was successfully developed,demonstrating good reliability and validity through statistical analysis.The new scale effectively predicts disease severity and prognosis in emergency observation patients.

Objective:To investigate the efficacy of oral folic acid intervention in lung cancer patients with radiation esophagitis (RE) caused by concurrent chemoradiotherapy.Methods:In this randomized, controlled, single-center clinical trial, a total of 82 patients with stage N 2-N 3 lung cancer including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) admitted to the Affiliated Cancer Hospital of Guizhou Medical University from June 2022 to October 2023 were prospectively included. All enrolled patients were randomly divided into the experimental group (folic acid group) and control group according to 1 vs. 1 of simple random method, and patients in both groups were required to receive radiation therapy for lung lesions and mediastinal metastatic lymph nodes [≥2 cycles of chemotherapy were completed during the same period of radiotherapy (≥40 Gy / 20 F) or targeted drugs were given simultaneously]. The severity of RE was evaluated using the modified common terminology criteria for adverse events criteria of the National Cancer Institute in both groups weekly at the onset of radiation esophagitis symptoms and thereafter until 1 week after the end of radiotherapy. Conventional treatment of RE was delivered according to the grading criteria of the Radiation Therapy Oncology Group. Patients in the folic acid group were given with folic acid tablets 30 mg/d orally at the beginning of radiotherapy until the end of radiotherapy, while those in the control group did not receive any drug intervention. The onset time, severity and duration of RE, and changes in the severity of esophageal toxicity after conventional treatment were recorded and analyzed. Serum folate value, serum vitamin B 12 value and homocysteine value were measured before and after radiotherapy. For continuous quantitative variables, independent sample t-test or independent sample rank-sum test was used for comparison among different groups. For categorical data, Chi-square test or Fisher's exact probability method was used for comparison among different groups. Results:During the observation period, no grade 4 or above RE was reported between two groups. The incidence of grade 0, 1, 2 and 3 RE in the folic acid and control groups was 10% (4/40) and 5% (2/41), 70% (28/40) and 42% (17/41), 15% (6/40) and 51% (21/41), 5% (2/40) and 2% (1/41), respectively. The differences were not statistically significant between two groups ( P=0.456). However, the incidence of grade 0-1 RE in the folic acid group was significantly higher than that in the control group ( Z=2.72, P=0.006). The median time of RE in the folic acid group and control group was 12 d (range 7-52 d) and 15 d (range 11-56 d) after the start of radiotherapy, respectively, with no statistically significant difference ( χ2=-0.75, P=0.456). However, median duration of the individual's most severe RE was 12 d (range 4-36 d) and 21 d (range 7-38 d) in the folic acid group and control groups, respectively, and the differences were statistically significant ( χ2=2.10, P=0.039). In the folic acid group, the grades of swallowing with pain and dysphagia were significantly declined after folic acid intervention, especially at 2 weeks after the occurrence of RE ( P=0.001, P=0.002). The remission rate of RE after 1 week in the folic acid group was higher than that in the control group, and the difference was statistically significant ( χ2=7.36, P=0.012). Conclusion:Oral intake of folic acid during concurrent chemoradiotherapy for lung cancer cannot reduce the incidence of RE, but it may reduce its severity, shorten the duration of the most severe RE in individuals, and have a certain protective effect.