Histologic image-based ensemble model to identify myenteric plexitis and predict endoscopic postoperative recurrence in Crohn's disease: a multicentre, retrospective study.

BACKGROUND AND AIM: Myenteric plexitis is correlated with postoperative recurrence of Crohn's disease when relying on traditional statistical methods. However, comprehensive assessment of the myenteric plexus remains challenging. This study aimed to develop and validate a deep learning system to predict postoperative recurrence through automatic screening and identification of features of the muscular layer and myenteric plexus. METHODS: In this study, we retrospectively reviewed 205 patients who underwent bowel resection surgery from 2 hospitals. Patients were divided into a training cohort (n=108), an internal validation cohort (n=47) and an external validation cohort (n=50). A total of 190960 patches from 278 whole-slide images of surgical specimens were analysed using ResNet50, and 6144 features were extracted after transfer learning. We used five robust algorithms to construct classification models. The performances of the models were evaluated by the area under the receiver operating characteristic curve in three cohorts. RESULTS: The stacking model achieved satisfactory accuracy in predicting postoperative recurrence of CD in the training cohort (AUC: 0.980; 95% CI 0.960-0.999), internal validation cohort (AUC: 0.908; 95% CI 0.823-0.992), and external validation cohort (AUC: 0.868; 95% CI 0.761-0.975). The accuracy for identifying the severity of myenteric plexitis was 0.833, 0.745, and 0.694 in the training cohort, internal validation cohort and external validation cohort, respectively. CONCLUSIONS: Our work initially established an interpretable stacking model based on muscular layer and myenteric plexus features extracted from histologic images to identify the severity of myenteric plexitis and predict postoperative recurrence of CD.

Altered fecal microbiome and metabolome profiles in rat models of short bowel syndrome.

Introduction: Short bowel syndrome (SBS) is featured by impaired nutrients and fluids absorption due to massive small intestine resection. Gut dysbiosis has been implicated in SBS, this study aimed to characterize the metagenomic and metabolomic profiles of SBS and identify potential therapeutic targets. Methods: Fecal samples from SBS and Sham rats (n = 8 per group) were collected for high-throughput metagenomic sequencing. Fecal metabolomics was measured by untargeted liquid chromatography-mass spectrometry. Results: We found that the species-level α-diversity significantly decreased in SBS rats, accompanied by altered microbiome compositions. The beneficial anaerobes from Firmicutes and Bacteroidetes were depleted while microorganisms from Lactobacillus, Escherichia, Enterococcus, and Streptococcus were enriched in faces from SBS rats. LEfSe analysis identified 17 microbial species and 38 KEGG modules that were remarkably distinct between SBS and Sham rats. In total, 1,577 metabolites with known chemical identity were detected from all samples, among them, 276 metabolites were down-regulated and 224 metabolites were up-regulated in SBS group. The typical signatures of SBS fecal metabolome comprised reduced short-chain fatty acids and products of amino acid metabolism (indole derivatives and p-cresol), as well as altered bile acid spectrum. We revealed 215 robust associations between representative differentially abundant microbial species and metabolites, the species with the same changing trend tended to have a similar correlation with some certain metabolites. Conclusion: The fecal microbiome and metabolome significantly altered in SBS. Our findings may lay the foundation for developing new strategies to facilitate intestinal adaptation in SBS patients.

Investigation of trends in gut microbiome associated with colorectal cancer using machine learning.

Background: The rapid growth of publications on the gut microbiome and colorectal cancer (CRC) makes it feasible for text mining and bibliometric analysis. Methods: Publications were retrieved from the Web of Science. Bioinformatics analysis was performed, and a machine learning-based Latent Dirichlet Allocation (LDA) model was used to identify the subfield research topics. Results: A total of 5,696 publications related to the gut microbiome and CRC were retrieved from the Web of Science Core Collection from 2000 to 2022. China and the USA were the most productive countries. The top 25 references, institutions, and authors with the strongest citation bursts were identified. Abstracts from all 5,696 publications were extracted for a text mining analysis that identified the top 50 topics in this field with increasing interest. The colitis animal model, expression of cytokines, microbiome sequencing and 16s, microbiome composition and dysbiosis, and cell growth inhibition were increasingly noticed during the last two years. The 50 most intensively investigated topics were identified and further categorized into four clusters, including "microbiome sequencing and tumor," "microbiome compositions, interactions, and treatment," "microbiome molecular features and mechanisms," and "microbiome and metabolism." Conclusion: This bibliometric analysis explores the historical research tendencies in the gut microbiome and CRC and identifies specific topics of increasing interest. The developmental trajectory, along with the noticeable research topics characterized by this analysis, will contribute to the future direction of research in CRC and its clinical translation.

Earlier anti-TNF therapy reduces the risk of malnutrition associated with alterations in body composition in patients with Crohn's disease.

Background: Anti-TNF therapy has been found to exert an influence on long-term nutritional status and even reverse malnutrition in patients with Crohn's disease. Aims: to observe the effect of anti-TNF therapy on nutritional status in patients with Crohn's disease, investigate the correlation between the timing of anti-TNF therapy and the human body composition and examine independent body composition factors for predicting malnutrition in these patients. Methods: This was a retrospective study of 115 patients with Crohn's disease. Body composition parameters were assessed by bioelectrical impedance analysis. The nutritional status of the patients was determined by NRS2002 and MNA. Results: The BMI, BFMI, FFMI, BCMI, SMI, BMC, intracellular water, protein and BMR were significantly lower in patients without any biologic agents (p < 0.05). Negative correlations were found between BMC, intracellular water, extracellular water, protein and BMR and the interval between the first symptom and first dose by Spearman's correlation analysis (r < 0, p < 0.05). Low BMI (OR 0.602, 95% CI 0.434-0.836, p = 0.002), low FFMI (OR 0.678, 95% CI 0.507-0.906, p = 0.009), and low BCMI (OR 0.564, 95% CI 0.367-0.868, p = 0.009) were independent risk factors for malnutrition in Crohn's disease patients. Anti-TNF therapy tended to reduce the malnutrition probability as assessed by Cox regression analysis (OR: 0.217, 95% CI 0.057-0.821, p = 0.024). Conclusion: Body composition analysis is predictive of malnutrition in patients with Crohn's disease. Early application of anti-TNF therapy significantly affected skeletal muscle mass, fat mass and bone mineral content, supporting their long-term nutritional status and reducing their probability of malnutrition.

Pathological Nodal Staging Score for Gastric Signet Ring Cell Carcinoma: A Clinical Tool of Adequate Nodal Staging.

Background: Gastric signet ring cell carcinoma (GSRCC) is a subset of gastric cancer with distinct histological and inconsistent prognosis outcome. Currently, the association between the adequate regional lymph node and proper nodal staging in GSRCC is rarely noticed. Materials and methods: Clinical data of GSRCC were retrieved from the Surveillance, Epidemiology, and End Results database. Beta-binomial distribution model was employed for the estimation of the probability of missing nodal disease, followed by the development of a nodal staging score (NSS). Results: A total of 561 GSRCC patients were included in this study, with 193 in lymph node-negative and 368 in lymph node-positive diagnoses. As the number of examined lymph nodes increased, the probability of missing nodal disease decreased rapidly, with T stage-specific curves. The probability of missing nodal disease in T4 was lower than that in T1. NSS calculation indicated that T1 stage patients commonly had NSS > 0.8. However, with the NSS of T2−T4 to reach 0.8, the number of examined lymph node was required to be larger than 12 in T2, 17 in T3 and 27 in T4. NSS ≥ 0.75 (quantile 75%) subgroup in T2−T4 subgroups tended to have better outcome; however, without significant prognostic value. Conclusions: NSS is served as a reliable and feasible tool in adequate nodal staging of GSRCC with statistical basis and provides further evidence for clinical decision making.

Evaluation of open reduction of distal humerus fractures in children after implementation of an enhanced recovery after surgery program.

OBJECTIVE: This study assessed whether an enhanced recovery after surgery (ERAS) protocol could be beneficial for children with distal humerus fractures. METHODS: Children with distal humerus fractures (n = 85) were randomly assigned to the ERAS and control groups and subjected to different perioperative managements. This was followed by the evaluation of their intraoperative characteristics (operation time and bleeding), postoperative characteristics (food intake conditions, pain scores, and discharge time), and postoperative functions. RESULTS: The operation time, intraoperative bleeding, and postoperative hematological indices did not differ significantly between the two groups. Preoperative thirst and hunger were considerably less and the initial food intake duration following surgery was markedly shorter in the ERAS group than in the control group, whereas no difference between the groups was observed in the incidences of postoperative nausea and vomiting. A markedly reduced highest postoperative pain score and reduced mean pain score and demand for additional analgesic interventions were observed in the ERAS group compared with those in the control group, although the differences were not statistically significant. No noticeable between-group differences were observed in the incidences of postoperative incision problems, aspirational pneumonia, and gastroesophageal reflux. The total length of hospital stay was not significantly different between the two groups. However, the length of postoperative hospital stay was remarkably shorter and the elbow joint function at 2 months after surgery was significantly improved in the ERAS group compared with those in the control group. CONCLUSION: The ERAS protocol can ameliorate preoperative discomfort and postoperative pain, shorten the postoperative hospital stay, and accelerate postoperative functional recovery without increasing the risks of postoperative nausea, vomiting, and poor incision healing and is, therefore, worthy of clinical application.

Preoperative Anti-TNF Therapy is Associated with a Shorter Length of Resected Bowel in Patients Undergoing Ileocolic Resection for Crohn's Disease.

BACKGROUND: Massive or repeated intestinal resections for Crohn's disease (CD) could lead to disabling consequences. The present study aimed to assess the effect of preoperative anti-TNF therapy on the length of resected bowel and identify risk factors for postoperative morbidity following ileocolic resection for CD. METHODS: Patients undergoing elective ileocolic resection for CD were included prospectively. Medical variables including demographics, Montréal classification, preoperative treatment, surgical details and 30-day postoperative morbidity were collected. Potential impact of preoperative anti-TNF treatment on length of ileocolic specimen and risk factors for postoperative morbidity were investigated. RESULTS: One hundred and eight-four patients were included in this study, and 66 (35.9%) of them received anti-TNF agents within 8 weeks prior to surgery. Primary anastomosis was performed in 145 patients (78.8%). The mean length of resected intestine was 10 cm shorter in subjects receiving preoperative anti-TNF treatment than those without preoperative anti-TNF therapy (P < 0.001). The rates of postoperative overall, infectious and intra-abdominal septic morbidity were 29.9%, 19.0% and 7.6%, respectively. In multivariate analysis, anti-TNF therapy < 8 weeks before surgery was independently associated with a shorter length of resected bowel but didn't increase overall and septic complications, while systemic steroids use within 8 weeks prior to surgery independently increased overall complications and intra-abdominal sepsis. CONCLUSIONS: Preoperative anti-TNF therapy was associated with a shorter length of resected bowel but not the overall and septic postoperative complications in ileocolic resection for CD. Weaning off systemic steroids before surgery may improve postoperative outcomes in patients with CD.

Review article: insights into the bile acid-gut microbiota axis in intestinal failure-associated liver disease-redefining the treatment approach.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) increases mortality of patients with intestinal failure (IF), but lacks effective prevention or treatment approaches. Bile acids, gut microbiota and the host have close and complex interactions, which play a central role in modulating host immune and metabolic homeostasis. Increasing evidence suggests that derangement of the bile acid-gut microbiota (BA-GM) axis contributes to the development of IFALD. AIMS: To review the BA-GM axis in the pathogenesis and clinical applications of IFALD, and to explore future directions for effective disease management. METHODS: We conducted a literature search on bile acid and gut microbiota in IF and liver diseases. RESULTS: The BA-GM axis demonstrates a unique IF signature manifesting as an increase in primary-to-secondary bile acids ratio, disturbed enterohepatic circulation, blunted bile acid signalling pathways, gut microbial dysbiosis, and altered microbial metabolic outputs. Bile acids and gut microbiota shape the compositional and functional alterations of each other in IF; collaboratively, they promote immune dysfunction and metabolic aberration in the liver. Diagnostic markers and treatments targeting the BA-GM axis showed promising potential in the management of IFALD. CONCLUSIONS: Bile acids and gut microbiota play a central role in the development of IFALD and make attractive biomarkers as well as therapeutic targets. A multitarget, individualised therapy aiming at different parts of the BA-GM axis may provide optimal clinical benefits and requires future investigation.

MiR-125-5p/IL-6R axis regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway.

This study explored the effects of miR-125-5p and interleukin-6 receptor (IL-6 R) on ulcerative colitis (UC) cell models and mouse models. The sera derived from UC patients and healthy subjects were collected for expression analysis. UC in vitro models and in vivo model were constructed and used. Expressions of miR-125-5p, IL-6 R, AK1/STAT3 and NF-κB pathways, and inflammatory factors, histopathology and apoptosis were determined by conducting a series of molecular experiments. The relationship between miR-125-5p and IL-6 R was analyzed by TargetScan7.2 and verified by dual-luciferase assay. The disease activity index (DAI) score, weight change, and colon length of the mice were recorded and analyzed. Decreased expression of miR-125-5p in the sera of UC patients was related to the increased expression of its target gene IL-6 R. In vitro, up-regulation of miR-125-5p decreased IL-6 R expression, contents of inflammatory factors in THP-1 cells and cell apoptosis of NCM460, and inhibited the activation of JAK1/STAT3 and NF-κB pathway. However, down-regulation of miR-125-5p produced the opposite effects to its up-regulation. IL-6 R overexpression partially reversed the effects of miR-125-5p up-regulation on UC cell models. In vivo, miR-125-5p overexpression significantly improved the severity of colitis, including DAI score, colon length, tissue damage, apoptosis, and inflammatory response, in the mice in the UC group. In addition, miR-125-5p up-regulation significantly reduced the expression of IL-6 R in the UC mice, and reduced the expression levels of JAK1, STAT3 and p65 phosphorylation. MiR-125-5p targeting IL-6 R regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway.

Sphingosine kinase 1 regulates HMGB1 translocation by directly interacting with calcium/calmodulin protein kinase II-δ in sepsis-associated liver injury.

Previously, we confirmed that sphingosine kinase 1 (SphK1) inhibition improves sepsis-associated liver injury. High-mobility group box 1 (HMGB1) translocation participates in the development of acute liver failure. However, little information is available on the association between SphK1 and HMGB1 translocation during sepsis-associated liver injury. In the present study, we aimed to explore the effect of SphK1 inhibition on HMGB1 translocation and the underlying mechanism during sepsis-associated liver injury. Primary Kupffer cells and hepatocytes were isolated from SD rats. The rat model of sepsis-associated liver damage was induced by intraperitoneal injection with lipopolysaccharide (LPS). We confirmed that Kupffer cells were the cells primarily secreting HMGB1 in the liver after LPS stimulation. LPS-mediated HMGB1 expression, intracellular translocation, and acetylation were dramatically decreased by SphK1 inhibition. Nuclear histone deacetyltransferase 4 (HDAC4) translocation and E1A-associated protein p300 (p300) expression regulating the acetylation of HMGB1 were also suppressed by SphK1 inhibition. HDAC4 intracellular translocation has been reported to be controlled by the phosphorylation of HDAC4. The phosphorylation of HDAC4 is modulated by CaMKII-δ. However, these changes were completely blocked by SphK1 inhibition. Additionally, by performing coimmunoprecipitation and pull-down assays, we revealed that SphK1 can directly interact with CaMKII-δ. The colocalization of SphK1 and CaMKII-δ was verified in human liver tissues with sepsis-associated liver injury. In conclusion, SphK1 inhibition diminishes HMGB1 intracellular translocation in sepsis-associated liver injury. The mechanism is associated with the direct interaction of SphK1 and CaMKII-δ.

Normothermic extracorporeal membrane oxygenation support: Improving the function of intestinal grafts obtained from cardiac death donors.

Extracorporeal membrane oxygenation (ECMO) could ameliorate the energy status and viability of bowel grafts from cardiac death donors. However, the function of these grafts after transplantation is not clear. The purpose of the study was to evaluate the early function of intestinal grafts after transplantation from expected cardiac death donors supported with normothermic extracorporeal support using a porcine allogeneic orthotopic segmental small bowel transplantation model. Eighteen domestic crossbred donor pigs were assigned to living donation (LD), donation after cardiac death (DCD), and ECMO groups. In the LD group, small bowels were harvested and preserved immediately in cold storage. In the other two groups, the donor pigs received conventional rapid recovery treatment or 1-hour normothermic extracorporeal support after 10-minutes expected cardiac arrest. Subsequently, the small bowels were removed and preserved in cold storage. After 5-6 hours of preservation, small bowel grafts were transplanted into the recipient pigs that underwent enterectomy. The pathology and electron microscopy results, cell apoptosis rate, tight junction protein expression level in the intestinal mucosa, and plasma endotoxin level were evaluated after transplantation. All grafts functioned on the basis of the maltose absorption test results at day 7 after transplantation. There were no significant differences in the morphological changes in the intestinal mucosa among the three groups at day 7 after transplantation. The cell apoptosis rate and plasma endotoxin level in the ECMO group did not differ significantly than those in the LD group, but were evidently lower than those in the DCD group (P < .001). The intestinal absorptive function improved significantly in the ECMO group in contrast with that in the DCD group (P < .001). Short-term ECMO intervention can alleviate ischemia-reperfusion injuries in intestinal grafts and improve intestinal absorptive function in the early stage after transplantation. Reducing caspase-3 protein expression and cell apoptosis in the intestinal mucosa may be one of the protective mechanisms of ECMO intervention.

MicroRNA-150 functions as a tumor suppressor and sensitizes osteosarcoma to doxorubicin-induced apoptosis by targeting RUNX2.

Osteosarcoma (OS) is the most common form of bone malignancy in children and adolescents. MicroRNAs (miRNAs) have been associated with the development and progression of OS. In the present study, reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8, luciferase and Transwell assays were performed to investigate the biological function of microRNA-150 (miR-150) in OS. The results revealed that miR-150 was significantly downregulated in OS cell lines (HOS, SAOS2, MG-63 and U2OS) in comparison with the normal osteoblast cells (hFOB1.19). Overexpression of miR-150 significantly inhibited cell proliferation in OS cells. miR-150 could sensitize OS cells to chemotherapy treatment of doxorubicin. Runt-related transcription factor 2 (RUNX2) was identified as a target gene of miR-150. RUNX2 knockdown exhibited similar inhibitory effects on both OS cell proliferation and chemotherapy sensitivity. Restoration of RUNX2 reversed the biological function of miR-150. Finally, miR-150 overexpression and RUNX2 knockdown enhanced caspase-3 cleavage. Taken together, the present study established a novel molecular mechanism, in that miR-150 plays tumor suppressor and chemoprotective roles by targeting RUNX2 in OS, indicating that miR-150 may be a potential therapeutic target for OS therapy in the future.

Perioperative Surgical Home Model Improves Outcomes in Crohn's Disease Patients Undergoing Disease-Related Surgery.

BACKGROUND: To evaluate Perioperative Surgical Home (PSH) practice model implementation in Crohn's disease (CD) patients undergoing disease-related surgery. METHODS: A retrospective analysis of CD patients requiring disease-related surgery in the Shanghai Ninth People's Hospital was undertaken. Subjects were divided into a non-PSH group consisting of 49 patients (June 2016 to November 2017) and a PSH group consisting of 72 patients (December 2017 until May 2019). Conventional treatment was used for the non-PSH group, while in the PSH group, a standardized pre- and postoperative management routine was employed. The postoperative lengths of stay and incidences of postoperative complications were analyzed. RESULTS: There were no significant differences in demographics, reasons for surgery, preoperative BMIs, and preoperative hemoglobin between the two groups (P > 0.05). The overall incidence of complications in the PSH group was dramatically lower than that in the non-PSH group (26.4% vs. 44.9%, P = 0.035). In the PSH group, postoperative length of stay was significantly shorter than that in the non-PSH group (11.5 ± 5.7 vs. 9.0 ± 6.8, P < 0.001). CONCLUSIONS: The PSH conditioning routine in CD patients undergoing disease-related surgeries suggests a trend of fewer postoperative complications and shorter lengths of hospital stay. The PSH model may have clinical advantages when applied to CD patients.

Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction.

Background: Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell apoptosis, translocating from mitochondria to the cytosol after an apoptotic insult. Our previous study indicated pre-treatment with UCF-101, a specific inhibitor of Omi/HtrA2, could significantly reduce neuronal apoptosis and attenuate sepsis-induced cognitive dysfunction. Various hypotheses involving blood-brain-barrier (BBB) disruption have been proposed to account for sepsis-associated encephalopathy (SAE). Here, we attempted to explore whether interference of Omi/HtrA2 by RNA interference or UCF-101 pre-treatment can improve sepsis-induced disruption of BBB using human cerebral microvascular endothelial cell line (hCMEC/D3) in vitro and if so, to explore mechanisms involved Omi/HtrA2 protease mediates BBB disruption in SAE. Methods: hCMEC/D3 cell monolayers were intervened by different concentrations of LPS (0-50 µg/mL) over experimental period. Pharmacological or gene interventions (by silencing RNA of Omi/HtrA2) were used to study molecular mechanisms involved in sepsis-associated Omi/HtrA2 translocation, cell apoptosis and BBB dysfunction. BBB function was assessed by trans-endothelial electrical resistance (TEER) and permeability to labeled dextrans (FITC-4kDa). Tight junction (TJ) integrity was assessed by immunofluorescence, western blotting and transmission electron microscopic (TEM) analyses. Apoptosis was determined using flow cytometry and TUNEL assay. Mitochondrial membrane potential (MMP) and oxidative stress were also investigated. Results: LPS affects hCMEC/D3 TJ permeability in a concentration- and time-dependent manner. LPS intervention resulted in a significant disruption of BBB, as manifested by decreased TEER (by ~26%) and a parallel increased paracellular permeability to FITC- (4kDa) dextrans through hCMEC/D3 monolayers. The inhibition of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA reduced LPS-induced brain endothelial cell apoptosis, and resulted in significant improvement on LPS-induced BBB disruption as well as decreased occludin, claudin-5 and ZO-1 expressions. Omi/HtrA2 manipulated endothelial cell apoptosis by shifting into cytosol and inducing X-linked inhibitor of apoptosis protein (XIAP) degradation. UCF-101 administration or Omi/HtrA2 shRNA intervention did attenuate the degradation of XIAP, Poly ADP-ribose polymerase (PARP) cleavage, and caspase-3 cleavage. However, only UCF-101 partly prevented the mobilization of Omi/HtrA2 from the mitochondria to the cytosol after LPS intervention. That abrogation of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA resulted in a significant improvement on LPS-induced decrease of MMP. Oxidative stress was significantly increased in the LPS treated group compared to the control or NC-shRNA group. However, abrogation of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA did not significantly improve oxidative injury. Conclusions: Our study indicated an important role of Omi/HtrA2 in manipulating LPS-induced cell apoptosis and BBB integrity by translocating from mitochondria into cytosol in brain endothelial cells. Omi/HtrA2 induced mitochondrial pathway apoptosis, which involves inhibition of an important antiapoptotic protein XIAP and influence on MMP. Therapeutic methods that inhibit Omi/HtrA2 function may provide a novel therapeutic measure to septic encephalopathy.

Vitamin D Improves Intestinal Barrier Function in Cirrhosis Rats by Upregulating Heme Oxygenase-1 Expression.

Intestinal barrier dysfunction always accompanies cirrhosis in patients with advanced liver disease and is an important contributor facilitating bacterial translocation (BT), which has been involved in the pathogenesis of cirrhosis and its complications. Several studies have demonstrated the protective effect of Vitamin D on intestinal barrier function. However, severe cholestasis leads to vitamin D depletion. This study was designed to test whether vitamin D therapy improves intestinal dysfunction in cirrhosis. Rats were subcutaneously injected with 50% sterile CCl4 (a mixture of pure CCl4 and olive oil, 0.3 mL/100 g) twice a week for 6 weeks. Next, 1,25(OH)2D3 (0.5 µg/100 g) and the vehicle were administered simultaneously with CCl4 to compare the extent of intestinal histologic damage, tight junction protein expression, intestinal barrier function, BT, intestinal proliferation, apoptosis, and enterocyte turnover. Intestinal heme oxygenase-1 (HO-1) expression and oxidative stress were also assessed. We found that vitamin D could maintain intestinal epithelial proliferation and turnover, inhibit intestinal epithelial apoptosis, alleviate structural damage, and prevent BT and intestinal barrier dysfunction. These were achieved partly through restoration of HO-1 and inhibition of oxidative stress. Taken together, our results suggest that vitamin D ameliorated intestinal epithelial turnover and improved the integrity and function of intestinal barrier in CCl4-induced liver cirrhotic rats. HO-1 signaling activation was involved in these above beneficial effects.

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy.

BACKGROUND/AIMS: the pathogenesis of sepsis-associated encephalopathy (SAE) is multifactorial, involving neurotransmitter alterations, inflammatory cytokines, oxidative damage, mitochondrial dysfunction, apoptosis, and other factors. Mitochondria are major producers of reactive oxygen species, resulting in cellular injury. Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell death; it is translocated from mitochondria to the cytosol after an apoptotic insult. We previously found that UCF-101, a specific inhibitor of Omi/HtrA2, has neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats. In this study, the mechanisms and molecular pathways underlying these effects were investigated. METHODS: Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy and were administered vehicle or UCF-101 (10 µmol/kg). The hippocampus was isolated for subsequent analysis. Omi/HtrA2 expression in the mitochondria or cytosol was evaluated by immunofluorescence or western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was utilized to evaluate levels of apoptosis, and western blotting was used to evaluate apoptosis-related proteins, such as cleaved caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). Tight junction expression was assessed by immunofluorescence and western blotting. Mitochondrial function, inflammatory cytokines, and oxidative stress were also assayed. In addition, a wet/dry method was used to evaluate brain edema and Evans blue extravasation was used to evaluate blood-brain barrier (BBB) integrity. RESULTS: After CLP treatment, the hippocampus exhibited a mild increase in Omi/HtrA2 expression; cytosolic Omi/HtrA2 expression increased significantly, whereas mitochondrial Omi/HtrA2 expression was reduced, indicating that CLP-induced oxidative stress resulted in the translocation of Omi/HtrA2 from mitochondria to the cytosol. Hippocampal cleaved caspase-3, caspase-9, and PARP levels were significantly higher in animals treated with CLP than in sham-operated animals, while XIAP expression was lower. Treatment with UCF-101 prevented the mobilization of Omi/HtrA2 from mitochondria to the cytosol, attenuated XIAP degradation, and decreased cleaved caspase-3, caspase-9, and PARP expression as well as apoptosis. UCF-101 also reversed the decreased mitochondrial complex I, II, and III respiration and the reduced ATP caused by CLP. In addition, UCF-101 treatment resulted in a significant improvement in BBB integrity, as demonstrated by increased occludin, claudin-5, and zonula occludens 1 levels and reduced Evans blue extravasation. No significant effects of UCF-101 on brain edema were found. Inflammatory cytokines and oxidative stress were significantly higher in the CLP-treated group than in the sham-operated group. However, the inhibition of Omi/HtrA2 by UCF-101 significantly alleviated these responses. CONCLUSION: Our data indicated that Omi/ HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy. Inhibition of Omi/HtrA2 by UCF-101 leads to neuroprotection by inhibiting the cytosolic translocation of Omi/HtrA2 and antagonizing the caspase-dependent apoptosis pathway. Therapeutic interventions that inhibit Omi/HtrA2 translocation or protease activity may provide a novel method to treat SAE.

Surgery for chronic radiation enteritis: outcome and risk factors.

BACKGROUND: Surgery is required in approximately one-third of patients with chronic radiation enteritis (CRE). The aim of this study was to explore the short- and long-term outcomes after surgery for CRE and risk factors of postoperative morbidity. METHODS: Clinical features and surgical outcomes of patients undergoing surgery for CRE were retrospectively reviewed. Risk factors of postoperative morbidity were analyzed using univariate and multivariate analysis. Survival and reoperation rates for CRE were evaluated. RESULTS: Among the 404 patients included, 351 patients (86.88%) received resectional surgery, whereas the remaining patients received conservative procedures. No differences were detected between patients with resection and those without resection with regard to major morbidity (P = 0.486) and surgical complications (P = 0.715). Laparoscopy resulted in a shorter postoperative hospital stay (P = 0.035). After multivariate analysis, history of hypertension (odds ratio [OR] = 2.490; P = 0.046), previous acute radiation enteritis (OR = 1.832; P = 0.033), intraoperative blood loss of more than 200 mL (OR = 2.235; P = 0.006), and thrombocytopenia (OR = 2.544; P = 0.016) were determined as independent predictors of postoperative major morbidity. During follow-up, 22 patients required reoperation for CRE recurrence, and the reoperation rate was significantly lower in patients receiving resectional surgery (P = 0.005). CONCLUSIONS: Resection is feasible for CRE with acceptable postoperative morbidity and lower reoperation rate. Correction of preoperative thrombocytopenia, minimizing intraoperative blood loss, and close monitoring of hypertensive patients and those with history of acute radiation enteritis are critical to reduce postoperative complications.

Associations between body composition and nutritional assessments and biochemical markers in patients with chronic radiation enteritis: a case-control study.

BACKGROUND: Chronic radiation enteritis (CRE) is defined as loss of absorptive capacity after irradiation due to chronic inflammation and damage of intestinal mucosa, which may lead to varying degrees of malnutrition. The aim of this study was to evaluate the potential correlation between the nutritional status and systemic inflammation in patients with CRE. METHODS: Medical records of 92 patients with CRE and 184 age- and sex-matched controls in a single center from January 2010 to October 2015 were retrospectively reviewed. All enrolled subjects underwent nutritional status analysis, including three different nutritional indices: Nutritional Risk Screening-2002 (NRS-2002), Patient-generated Subjective Global Assessment (PG-SGA) and Controlling Nutritional Status (CONUT), bioelectrical impedance spectroscopy (BIS), and biochemical markers, within 24 h of admission. RESULTS: The results showed that NRS-2002, PG-SGA and CONUT were all positively correlated with neutrophil/lymphocyte ratio (NLR) (r = 0.304, 0.384 and 0.425, all p < 0.001) and C-reactive protein (CRP) (r = 0.357, 0.479 and 0.230, all p < 0.001), while negatively correlated with albumin (r = -0.612, -0.727 and -0.792, all p < 0.001) and total cholesterol (TC) (r = -0.485, -0.545 and -0.473, all p < 0.001) in patients with CRE, respectively. Body cell mass (BCM) has been deemed a key body composition parameter. It was positively correlated with albumin (r = 0.489, p < 0.001) and TC (r = 0.237, p < 0.001), while negatively correlated with NLR (r = -0.140, p = 0.02) and CRP (r = -0.215, p < 0.001). A multivariate linear regression analysis showed that values of intracellular water (ß coefficient = 0.760, p < 0.001), extracellular water (ß coefficient = 0.006, p = 0.011), protein (ß coefficient = 0.235, p < 0.001) and CRP (ß coefficient = 0.001, p = 0.009) were independent determinants of BCM. CONCLUSION: This study revealed that BIS combined with nutritional assessments and biochemical markers were appropriate methods to assess the nutritional and inflammatory status in patients with CRE. Furthermore, the nutritional status was verified to be significantly correlated with systemic inflammation.

[Feasibility of laparoscopic surgery for chronic adhesive small bowel obstruction].

OBJECTIVE: To determine the feasibility and possible superiority of laparoscopic surgery for chronic adhesive small bowel obstruction(CASBO). METHODS: Clinical data of 36 CASBO patients who underwent laparoscopic surgery in Jinling Hospital from March 2011 to August 2014 were retrospectively reviewed. In addition, 36 cases, matched by age, gender, previous abdominal surgery history, body mass index(BMI) and abdominal adhesion grade, who underwent open surgery from April 2007 to February 2011 were used as controls. General information, operative findings and short-term outcomes were compared between two groups. RESULTS: There were no statistically significant differences in baseline data between the two groups (all P>0.05). Among 36 cases in laparoscopic surgery group, 17 underwent complete laparoscopic surgery, 10 underwent laparoscopic assisted surgery and 9 were converted to open surgery, respectively. The conversion rate was 25%(9/36). Reason of laparoscopic assisted surgery in 3 cases was uncertainty of small bowel injury, in 5 cases was further dissection of intra-loop adhesion and in 2 cases was intestinal resection. Reasons for conversion were small bowel injury in 3 cases and severe adbesion at the abdominal wall in 6 cases. There were no differences between two groups in terms of adhesion score, intra-operative blood loss, operation time, need for small bowel resection, total hospital charge and intra- or post-operational complications. As compared to open surgery, laparoscopic surgery significantly shortened the incision length [median 2 (0 to 10) cm vs. 12(7 to 16) cm, P=0.000], and hospital stay [median 5 (2 to 28) days vs. 7 (4 to 26) days, P=0.001], and improved postoperative recovery of bowel movement [median 2(1 to 20) days vs. 3 (2 to 10) days, P=0.001]. CONCLUSION: Laparoscopic surgery can improve postoperative recovery of CASBO with similar morbidity as open surgery.

Intestinal Conditioning After Cardiac Arrest: The Use of Normothermic Extracorporeal Membrane Oxygenation in the Non-Heart-Beating Animal Model.

The effect of normothermic extracorporeal membrane oxygenation (NECMO) on small bowel preservation in a clinically relevant large animal model of expected donation after cardiac death (eDCD) was evaluated. Thirty domestic crossbred donor pigs were divided into five groups. The first group served as the live donation (LD) group, the second group served as the donation after cardiac death (DCD) group, and the remaining were further assigned into three subgroups: E1 group (1 h NECMO support), E3 group (3 h NECMO support), and E5 group (5 h NECMO support). Pathology, electron microscopy, energy metabolism, cell apoptosis, and tight junction (TJ) protein expression level of intestinal mucosa and the level of plasma d-lactic acid were evaluated in normal, cardiac death and at the end of extracorporeal support, respectively. The mean arterial pressure and PaO2 were maintained over 60 and 267 mm Hg during NECMO support, respectively. One hour of extracorporeal support could improve the energy status in intestines of the DCD group. Although the histologic damage and apoptosis of the E1 group had no significant difference with those of the LD and DCD groups (P > 0.05), the levels of intestinal mucosa TJ protein decreased (P < 0.05), and plasma d-lactic acid increased progressively (P < 0.05). With the extension of extracorporeal support, the degree of intestinal mucosa damage and intestinal permeability gradually increased, as well as the content of adenosine triphosphate in intestinal mucosa. The normothermic extracorporeal support for 1 h in DCD is beneficial for improving the energy status and viability of the bowel. However, the integrity of intestinal mucosa was destroyed gradually as extracorporeal support time went by. And the activation of intestinal epithelial apoptosis and hyperoxia might be the factors that lead to intestinal mucosa injury.