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Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

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Coagulation-related genes (CRGs) have been demonstrated to be essential for the development of certain tumors; however, little is known about CRGs in lung squamous cell carcinoma (LUSC). In this study, we adopted CRGs to construct a coagulation-related gene prognostic signature (CRGPS) using machine learning algorithms. Using a set of 92 machine learning integrated algorithms, the CRGPS was determined to be the optimal prognostic signature (median C-index = 0.600) for predicting the prognosis of an LUSC patient. The CRGPS was not only superior to traditional clinical parameters (e.g., T stage, age, and gender) and its commutative genes but also outperformed 19 preexisting prognostic signatures for LUSC on predictive accuracy. The CRGPS score was positively correlated with poor prognoses in patients with LUSC (hazard ratio > 1, p < 0.05), indicating its suitability as a prognostic marker for this disease. The CRGPS was observed to be inversely correlated with the degree of infiltration of natural killer cells. For some tumors, patients with lower CRGPS scores are more likely to experience enhanced immunotherapy effects (area under the curve = 0.70), which implies that the CRGPS can potentially predict immunotherapy efficacy. A high CRGPS score is predictive of an LUSC patient being sensitive to several drugs. Collectively, these findings indicate that the CRGPS may be a reliable indicator of the prognoses of patients with LUSC and may be useful for the clinical management of such patients.

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OBJECTIVE: This study sought to explore the clinical value of matrix metalloproteinases 12 (MMP12) in multiple cancers, including lung adenocarcinoma (LUAD). METHODS: Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of MMP12. The expression of MMP12 between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of MMP12 expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly. RESULTS: MMP12 mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) (P < .05). MMP12 expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high MMP12 expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, P < .05). The elevated MMP12 expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, P < .05). Some pan-cancer findings regarding MMP12 are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels (P < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease (P < .05). CONCLUSIONS: MMP12 is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.

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BACKGROUND: The clinical value of pyroptosis-related genes (PRGs) in lung adenocarcinoma (LUAD) remains obscure. OBJECTIVE: The study attempts to explore PRGs in LUAD, which will enable an understanding of LUAD from the perspective of PRGs. METHODS: Lung adenocarcinoma patients were diagnosed using pathology, and their clinical information was collected from several public databases. A PRGs prognostic signature (PPS) for LUAD patients was established based on a multivariate Cox regression analysis. The differential expression of PRGs was identified using standardized mean differences in 6,958 samples. The area under the curve (AUC) was used to evaluate the predictive effects of the PPS to determine the survival rate of LUAD patients. Decision curve analysis was utilized to assess the clinical significance of the PPS in LUAD. RESULTS: The PPS consists of five PRGs, namely CASP3, CASP9, GSDMB, NLRP1, and TNF. The prognostic effect of the PPS is evident in all the predicted one-, three-, and five-year survival rates (AUCs ≥ 0.58). The PPS represents an independent risk factor for the prognosis of LUAD patients (hazard ratio > 1; 95% confidence interval excluding 1). The PPS risk score can predict the prognosis of LUAD patients more accurately than PRGs of the PPS and multiple clinical parameters, such as age, tumor stage, and clinical stage. The decision curve analysis revealed that the nomogram based on the PPS and clinical parameters might result in better clinical decisions. CONCLUSION: The PPS makes it feasible to distinguish LUAD from non-LUAD. Thus, the underlying significance of the PPS in distinguishing LUAD from non-LUAD is promising.

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OBJECTIVE@#To explore influence of external factors of wind, cold and dampness on clinical symptoms in knee osteoarthritis (KOA) patients with different constitutions of traditional Chinese medicine.@*METHODS@#A cross-sectional stratified study was performed to select 108 patients with GradeⅡKOA in Kellgren & Lawrence (K-L) classification, including 22 males and 86 females, aged from 47 to 75 years old with an average of (60.7±6.0) years old;body mass index(BMI) ranged from 17.87 to 31.22 kg·m-2 with an average of (23.80±2.86) kg·m-2. According to Classification and Judgment of TCM Physique (ZYYXH/T157-2009), the types of TCM physique were determined and divided into 4 layers according to the deficiency and actual physique. Among them, there were 24 patients without biased physique, 12 males and 12 females, aged from 51 to 73 years old with an average of(62.8±6.0) years old, BMI ranged from 17.87 to 31.14 kg·m-2 with an average of (24.32±3.25) kg·m-2;there were 46 patients with virtual bias constitution, including 7 males and 39 females, aged from 47 to 70 years old with an average of (60.0±5.8) years old, BMI ranged from 19.38 to 31.22 kg·m-2 with an average of(23.42±2.97) kg·m-2;There were 26 patients with solid bias constitution, including 2 males and 24 females, aged from 48 to 75 years old with an average of (60.4±5.8) years old, BMI ranged from 21.16 to 30.76 kg·m-2 with an average of (24.15±2.33) kg·m-2;there were 9 patients with special constitution, 1 male and 8 female, aged from 53 to 75 years old with an average of (59.8±7.5) years old, BMI ranged from 19.26 to 26.67 kg·m-2 with an average of (23.79±2.49) kg·m-2. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to evaluate severity of clinical symptoms. The wind-cold-dampness external factor score was calculated through the questionnaire of wind-cold-dampness syndrome scale to evaluate degree of influence of wind-cold-dampness external factor. Pearson correlation analysis and partial correlation analysis were used to calculate the correlation coefficient between severity of external factors affecting wind, cold and dampness and severity of clinical symptoms in patients with different TCM constitution stratification.@*RESULTS@#There was no statistical significance between total score of wind-cold-dampness and WOMAC score in patients with no biased constitution and special condition. Total wind-cold-dampness score of patients with virtual biased constitution was positively correlated with WOMAC stiffness score (r=0.327, P=0.032), and total wind-cold-dampness score of patients with solid biased constitution was positively correlated with WOMAC pain score (r=0.561, P=0.005) and WOMAC overall score (r=0.446, P=0.033). After further adjusting for the interaction of external factors of wind-cold-dampness, there was no statistical significance between wind-cold-dampness scores and WOMAC scores in patients with solid biased constitution. The score of dampness and pathogenic factors was positively correlated with WOMAC stiffness score (r=0.414, P=0.007).@*CONCLUSION@#The external factors of wind-cold dampness have different effects on the clinical symptoms of KOA patients with different TCM constitutions. Compared with other constitutions, the rigid symptoms of patients with asthenic biased constitutions are more susceptible to dampness pathogenic factors.

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BACKGROUND: The role of pyroptosis-related genes (PRGs) in esophageal adenocarcinoma (EAC) remains unknown. METHODS: In this study, the first PRGs prognostic signature (PPS) of EAC was constructed based on the results of multivariate stepwise Cox regression analysis. Based on 1,047 samples of EAC and normal esophagus (NE), differentially expressed PRGs were selected for the establishment of the PPS. The discrimination effect of this PPS was detected by receiver operating characteristic curves, and the prognosis value of this PPS was determined through Cox regression analysis and Kaplan-Meier curves. Net benefits of the EAC patients from the nomogram (constructed based on the PPS and some clinical parameters) were assessed via decision curve analysis. The potential molecular mechanism of the PPS in EAC was explored via gene set enrichment analysis. The ability of PPS to distinguish EAC and NE was evaluated based on the results of summary receiver operating characteristic curves. RESULTS: The significant prognostic value of PPS can be observed at all of the training cohort, test cohort, and validation cohort, such as its independent risk role in the prognosis of the EAC patients (hazard ratio > 0; 95% CI not including 0). The positive net benefits of the nomogram for the EAC patients can be detected via decision curve analysis, and the potential molecular mechanism of the PPS in EAC is likely related to cell pyroptosis. Last, some of the PRGs (particularly CASP5) included in this PPS specifically support its feasibility for identifying EAC (area under the curves > 0.7). CONCLUSIONS: The construction of this PPS in EAC enhances the present understanding of the relationship between PRGs and EAC, thus representing a novel approach to the clinical identification and management of EAC based on PRGs.

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Dearomatization of indole is a useful strategy to access indolimines: a motif widely exists in biologically active molecules and natural products. Herein, an efficient method for the dearomatization of 2,3-disubstituted indoles to generate diverse indolimines with tetrasubstituted allenes is described. This work accomplishes dearomatization of 2,3-disubstituted indoles through 1,8-addition of (aza)-para-quinone methides, which are generated in situ from propargylic alcohols. A series of synthetically useful indolimines containing quaternary carbon centers and tetrasubstituted allenes can be accessed in good yields (up to 99%). Additionally, the separability of product isomers, diversified product transformations, and easy scale-up of the reaction demonstrate the potential application of this method.

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Cyclin-dependent kinase 1 (CDK1) plays a significant role in certain malignancies. However, it remains unclear whether CDK1 plays a role in esophageal squamous cell carcinoma (ESCC). The aim of this study was to analyze the expression and clinical value of CDK1 in ESCC. CDK1 protein in 151 ESCC tissues and 138 normal esophageal tissues was detected by immunohistochemistry. RNA-seq of eight pairs of ESCC and adjacent esophageal specimens was performed to evaluate the levels of CDK1 mRNA. Microarray and external RNA-seq data from 664 cases of ESCC and 1733 cases of control tissues were used to verify the difference in CDK1 expression between the two groups. A comprehensive analysis of all data was performed to evaluate the difference in CDK1 between ESCC tissues and control tissues. Further, functional enrichment analyses were performed based on differentially expressed genes (DEGs) of ESCC and co-expressed genes (CEGs) of CDK1. In addition, a lncRNA-miRNA-CDK1 network was constructed. The expression of CDK1 protein was obviously increased in ESCC tissues (3.540 ± 2.923 vs. 1.040 ± 1.632, P < 0.001). RNA-seq indicated that the mRNA level of CDK1 was also highly expressed in ESCC tissues (5.261 ± 0.703 vs. 2.229 ± 1.161, P < 0.0001). Comprehensive analysis revealed consistent up-regulation of CDK1 (SMD = 1.41; 95% CI 1.00-1.83). Further, functional enrichment analyses revealed that the functions of these genes were mainly concentrated in the cell cycle. A triple regulatory network of PVT1-hsa-miR-145-5p/hsa-miR-30c-5p-CDK1 was constructed using in silico analysis. In summary, overexpression of CDK1 is closely related to ESCC tumorigenesis.

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A novel Brønsted acid catalyzed 1,8-addition mediated (3 + 4)-annulation of in situ generated propargylic p-quinone methides with 2-indolylmethanols is described. This method provides a convenient and mild approach to structurally interesting and synthetically important polysubstituted indole-fused oxepines in high yields. Moreover, 2-indolylmethanols as four-atom synthons in the (3 + 4)-annulations under Brønsted acid conditions have been explored for the first time.

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Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Brønsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.

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Herein, we report an efficient Brønsted acid-catalyzed formal (3+3)-annulation of (aza)-para-quinone methides generated in situ from propargylic alcohols with naphthol derivatives, which involves a 1,8-conjugate addition/6-endo annulation process. This protocol provides an effective method for preparing important functionalized pyranocoumarins under mild conditions.

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Lung squamous cell carcinoma (LUSC) is the main pathological type of pulmonary malignant tumors; at present, less than 10% of patients with advanced metastatic LUSC live for more than 5 years. We previously reported that low expression of miRNA-126-3p is associated with the occurrence and progression of lung adenocarcinoma (LUAD). Here, we examined expression of miRNA-126-3p in 23 samples from patients with LUSCs and 23 normal control specimens by quantitative real-time PCR (RT-qPCR). Associations between miRNA-126-3p expression and clinical features were studied from materials derived from Gene Expression Omnibus (GEO) chips and The Cancer Genome Atlas (TCGA) database. Twelve online platforms were used to identify candidate target genes of miRNA-126-3p. Further analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein-protein interaction (PPI) network were performed on the target genes. GEO microarray analysis, TCGA data mining, RT-qPCR, and integration analysis consistently reported low expression of miRNA-126-3p in LUSC. A total of 42 genes were identified as potential target genes of miRNA-126-3p from online platforms, GEO microarrays, and the TCGA database. GO and KEGG analyses demonstrated that the target genes are involved in several biological processes that promote the progression of LUSC. SOX2, E2F2, and E2F3 were selected as hub genes from the PPI network for further analysis. In summary, our results suggest that the low expression of miRNA-126-3p may play a role in promoting the development of LUSC and miRNA-126-3p may be a biomarker for LUSC early diagnosis and prognosis.

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RATIONALE: Hiccups are a common clinical symptom, and persistent hiccups and intractable hiccups severely impair the individual's quality of life. To date, there has been no effective treatment specifically for hiccups. Herein, we report 2 cases with intractable or persistent hiccups that were successfully treated with extracranial acupuncture. PATIENT CONCERNS: The first case is a 46-year-old woman who presented with a 7-year history of intractable hiccups that had worsened over the past 3 years. She also complained of chest tightness, dyspnea, palpitations, dreaminess, dysphoria, intolerance of cold, and hypohidrosis. The second case is a 75-year-old man who presented with a 7-day history of persistent hiccups and hematemesis for 3 hours. The patient's persistent hiccups were treated using traditional Chinese acupuncture, but the patient reported no remarkable benefit. DIAGNOSES: They were diagnosed as intractable or persistent hiccups. INTERVENTIONS: They were treated with extracranial acupuncture. OUTCOMES: The hiccups completely disappeared. During the follow-up period, the hiccups did not reappear. LESSONS: According to neural balance theory, an episode of the hiccups is caused by an imbalance of the nervous system. Extracranial acupuncture in the area adjacent to the external occipital protuberance affects the intracranial nervous system, which can effectively control the hiccups. Our study provides a new approach to the treatment of hiccups.

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An efficient and straightforward Lewis-acid-mediated stereoselective (4 + 3)-cyclization of indole-substituted alkylidene malonates and donor-acceptor cyclopropanes has been developed involving the Friedel-Crafts/Michael addition cyclization cascade. This reaction provides a mild and effective method for the construction of synthetically and structurally interesting functionalized cycloheptannelated indoles.

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Objective:To investigate the effects of micropulse laser photocoagulation under threshold on serum malondialdehyde(MDA) and chemokine levels in patients with proliferative diabetic retinopathy(PDR).Methods:From October 2014 to February 2016, 102 patients with PDR who were treated in Lishui People's Hospital were selected and divided into two groups by random number table method, with 51 cases in each group.The patients in the control group were treated with traditional grating laser, and the patients in the observation group were treated with micropulse laser photocoagulation under threshold.The levels of MDA and chemokine were compared before and after treatment, and the changes of vision and clinical efficacy were observed.Results:The total effective rate of the observation group was 90.20%(46/51), which was higher than that of the control group [76.47%(39/51)](χ 2=19.585, P<0.01). Before treatment, there were no statistically significant differences in serum MDA, chemokine and visual acuity between the two groups(all P>0.05). After treatment, the serum MDA and chemokines in the observation group were (8.57±2.48)μmol/L and (1.58±0.51)ng/L, respectively, which were lower than those in the control group [(10.92±3.16)μmol/L and (2.83±0.92)ng/L]( t=4.178, 8.486, all P<0.05), which in both two groups after treatment were lower than those before treatment(all P<0.05). The visual acuity of the observation group was (0.66±0.19), which was higher than that of the control group(0.43±0.13)( t=7.135, P<0.05). Conclusion:Micropulse laser photocoagulation under threshold can effectively alleviate oxidative stress and reduce serum MDA and chemokine levels in patients with PDR.

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Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancers worldwide. Transcription factor PTTG1 was seen highly expressed in a variety of tumors and was related to the degree of tumor differentiation, invasion, and metastasis. However, the clinical significance of PTTG1 had yet to be verified, and the mechanism of abnormal PTTG1 expression in ESCC was not clear. In this study, the comprehensive analysis and evaluation of PTTG1 expression in ESCC were completed by synthesizing in-house immunohistochemistry (IHC), clinical sample tissue RNA-seq (in-house RNA-seq), public high-throughput data, and literature data. We also explored the possible signaling pathways and target genes of PTTG1 in ESCC by combining the target genes of PTTG1 (displayed by ChIP-seq), differentially expressed genes (DEGs) of ESCC, and PTTG1-related genes, revealing the potential molecular mechanism of PTTG1 in ESCC. In the present study, PTTG1 protein and mRNA expression levels in ESCC tissues were all significantly higher than in non-cancerous tissues. The pool standard mean difference (SMD) of the overall PTTG1 expression was 1.17 (95% CI: 0.72-1.62, P < 0.01), and the area under curve (AUC) of the summary receiver operating characteristic (SROC) was 0.86 (95% CI: 0.83-0.89). By combining the target genes displayed by ChIP-seq of PTTG1, DEGs of ESCC, and PTTG1-related genes, it was observed that PTTG1 may interact with these genes through chemokines and cytokine signaling pathways. By constructing a protein-protein interaction (PPI) network and combining ChIP-seq data, we obtained four PTTG1 potential target genes, SPTAN1, SLC25A17, IKBKB, and ERH. The gene expression of PTTG1 had a strong positive correlation with SLC25A17 and ERH, which suggested that PTTG1 might positively regulate the expression of these two genes. In summary, the high expression of PTTG1 may play an important role in the formation of ESCC. These roles may be completed by PTTG1 regulating the downstream target genes SLC25A17 and ERH.

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The aim of this study was to assess the effect of preoperative sleep quality on acute postoperative pain in breast cancer patients.The Pittsburgh Sleep Quality Index questionnaire (PSQI) was used to assess the overall sleep status of women scheduled for unilateral modified radical mastectomy in the past month. Based on the responses, patients were allocated to good sleep group or poor sleep group. Postoperatively, acute pain was assessed using the numerical rating score in the first 24 hours; in addition, the requirement of analgesics and the incidence of postoperative complications were recorded.A total of 108 breast surgery patients were enrolled. Based on the PSQI results, 55 (51%) patients were allocated to poor sleep group and 53 (49%) to good sleep group. Pain scores were similar in the 2 groups at the end of surgery (P = .589); however, poor sleep group reported higher postoperative pain scores than the good sleep group at 2 (P = .002), 6 (P < .001), 12 (P < .001), and 24 (P = .002) hours after surgery. The incidence of severe pain in the poor sleep group was higher than that in the good sleep group (27% vs 8%, P = .018), and the ratio of participants who required rescued analgesics was greater in the poor sleep group (52% vs 22%, P = .002). In addition, patients with poor sleep quality had more postoperative complications and longer hospital stay.In this study, breast cancer patients with poor preoperative sleep quality reported more severe postoperative pain, required more analgesics, experienced more complications, and had longer hospital stay.

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OBJECTIVE@#To study role of TLR4/NF-κB pathway for early change of synovial membrane in knee osteoarthritis rats.@*METHODS@#Eighteen male SD rats weighted (200±20) g were randomly divided into 2 groups, namely control and model group, and 9 in each group. Knee OA model group was established by using modified Hulth method in model group. Control group was not treated. Synovial tissue and serum was extracted at 4 and 21 d after operation. Expression of CD14, TLR4, IL-1β, TNF-α, ADAMTS-4, MMP-13 were detected by real-time PCR respectively. NF-κB p65 protein was detected by Western-blot; serum concentrations of haluronic acid (HA), N-propeptide of type III procollagen(PIIINP) was detected by Elisa.@*RESULTS@#Expression of CD14, ADAMTS-4, and NF-κB p65 in model group were higher than that of control group at 4 and 21 days after operation, while expression of TLR4, IL-1β, TNF-α and MMP-13 were higher than that of control group at 21 days after operation(<0.01). Concentration of PIIINP and HA in model group were higher than that of control group at 4 days after operation, while there was no significant difference at 21 days after operation.@*CONCLUSIONS@#NF-κB pathway could mediate occurrence of KOA by early activating and triggeringg synovial increasingly secreting inflammatory secretion CD14, TLR4, IL-1β, TNF-α, ADAMTS-4, MMP-13, PIIINP and HA.

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BACKGROUND AND STUDY AIMS: The approach to small bowel preparation before capsule endoscopy (CE) is still suboptimal. PATIENTS AND METHODS: One hundred eighty patients were randomly allocated to 3 groups. Patients in Group A took 250 mL 20% mannitol and 1 L 0.9% saline orally at 05:00 hours on the day of the procedure. In Group B the same preparation was taken at 20:00 on the day before, and at 05:00 on the day of CE; in addition, 20 mL oral simethicone was taken 30 minutes before CE. Group C was treated identically to Group B, except that the patients fasted for 3 days and took 3 g senna orally 3 times daily before CE. The length of bowel containing green luminal contents was assessed by ImageJ software and bowel cleanliness was evaluated by computed assessment of the cleansing score. RESULTS: Cleansing of the whole small bowel and the distal small bowel were significantly different between the 3 groups (χ = 22.470, P = .000; χ = 17.029, P = .000, respectively). There were also significant differences between the 3 groups in the length of small bowel and specifically the length of the distal small bowel containing green luminal contents (χ = 12.390, P = .000, χ = 15.141, P = .000, respectively), but not with regard to the proximal small bowel (χ = 0.678, P = .509). CONCLUSIONS: Three days fasting and oral senna, combined with 20% mannitol and simethicone, before CE, can reduce the effects of bile on the small bowel and improve small bowel cleansing, especially in the distal small intestine.

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BACKGROUND: Chemotherapy has been associated with hyperalgesia. This prospective study was designed to investigate the effect of intraperitoneal chemotherapy with lobaplatin on post-operative pain intensity and sufentanil requirements after laparoscopic transabdominal resection of rectal cancer. METHODS: Eighty subjects (40 subjects treated with intraperitoneal chemotherapy and 40 subjects without chemotherapy treatment) scheduled for laparoscopic transabdominal resection of rectal cancer were included in this study. All subjects received standardized anesthetic and patient-controlled analgesia using sufentanil for 72 h post-surgery, as the only analgesics. Pain intensity scores, cumulative sufentanil requirements and side effects were recorded until 72 h post-surgery. RESULTS: Following intraperitoneal chemotherapy, patients had a significantly higher total post-operative sufentanil requirement (193 µg vs. 142 µg; P = 0.008), significantly higher verbal rating scale post-surgery pain intensity scores at rest and with coughing (P < 0.05), and a significantly worse functional activity score (P < 0.05) over 72 h, compared with those without intraperitoneal chemotherapy. There were no post-operative differences in the incidence of side-effects (post-operative nausea [P = 0.189], vomiting [P = 0.311], pruritus [P = 0.263], respiratory depression [P = 1.000], and dizziness [P = 0.712]) between the two groups. CONCLUSION: Intraperitoneal chemotherapy is associated with significantly increased post-operative sufentanil requirements and pain intensity, suggesting chemotherapy-associated hyperalgesia.