Involvement of transverse mesocolon is associated with development of colonic fistula in patients with acute necrotizing pancreatitis.

BACKGROUND: Involvement of transverse mesocolon (TM) during acute necrotizing pancreatitis(ANP) indicates that inflammation has spread from retroperitoneal space to peritoneum. Nevertheless, the impact of TM involvement, as confirmed by contrast-enhanced computed tomography (CECT), on local complications and clinical outcomes was poorly investigated. PURPOSE: This study aimed to explore the association between CECT-diagnosed TM involvement and the development of colonic fistula in a cohort of ANP patients. METHODS: This is a single-center, retrospective cohort study involving ANP patients admitted from January 2020 to December 2020. TM involvement was diagnosed by two experienced radiologists. The study subjects were enrolled consecutively and divided into two groups: TM involvement and non-TM involvement. The primary outcome was colonic fistula during the index admission. Clinical outcomes were compared between the two groups, and the association between the TM involvement and the development of colonic fistula was assessed using multivariable analysis to adjust for baseline unbalances. RESULTS: A total of 180 patients with ANP were enrolled, and 86 (47.8%) patients had TM involvement. The incidence of the colonic fistula is significantly higher in patients with TM involvement (16.3% vs. 5.3%;p = 0.017). Moreover, the length of hospital stay was 24(13,68) days in patients with TM involvement and 15(7,31) days in those not (p = 0.001). Analysis of multivariable logistic regression revealed that TM involvement is an independent risk factor for the development of colonic fistula (odds ratio: 10.253, 95% CI: 2.206-47.650, p = 0.003). CONCLUSION: TM involvement in ANP patients is associated with development of colonic fistula in ANP patients.

Association of demographic and clinical factors with risk of acute pancreatitis: An exposure-wide Mendelian randomization study.

BACKGROUND: The incidence of acute pancreatitis (AP) is increasing over years, which brings enormous economy and health burden. However, the aetiologies of AP and underlying mechanisms are still unclear. Here, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations between all reported possible risk factors and AP using publicly available genome-wide association study summary statistics. METHODS: A series of quality control steps were taken in our analysis to select eligible instrumental single nucleotide polymorphisms which were strongly associated with exposures. To make the conclusions more robust and reliable, we utilized several analytical methods (inverse-variance weighting, MR-PRESSO method, weighted median, MR-Egger regression) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, radial regression and leave-one-out sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on each exposure. A two-step MR method was applied to explore mediators in significant associations. RESULTS: Genetic predisposition to cholelithiasis (effect estimate: 17.30, 95% CI: 12.25-22.36, p = 1.95 E-11), body mass index (0.32, 95% CI: 0.13-0.51, p < 0.001), body fat percentage (0.57, 95% CI: 0.31-0.83, p = 1.31 E-05), trunk fat percentage (0.36, 95% CI: 0.14-0.59, p < 0.005), ever smoked (1.61, 95% CI: 0.45-2.77, p = 0.007), and limbs fat percentage (0.55, 95% CI: 0.41-0.69, p < 0.001) were associated with an increased risk of AP. In addition, whole-body fat-free mass (-0.32, 95% CI: -0.55 to -0.10, p = 0.004) was associated with a decrease risk of AP. CONCLUSION: Genetic predisposition to cholelithiasis, obesity and smoking could be causally associated with an increased risk of AP, and whole body fat-free mass could be associated with a decreased risk of AP.

Early versus delayed intervention in necrotizing acute pancreatitis complicated by persistent organ failure.

BACKGROUND: Current guidelines for the treatment of patients with necrotizing acute pancreatitis (NAP) recommend that invasive intervention for pancreatic necrosis should be deferred to 4 or more weeks from disease onset to allow necrotic collections becoming "walled-off". However, for patients showing signs of clinical deterioration, especially those with persistent organ failure (POF), it is controversial whether this delayed approach should always be adopted. In this study, we aimed to assess the impact of differently timed intervention on clinical outcomes in a group of NAP patients complicated by POF. METHODS: All NAP patients admitted to our hospital from January 2013 to December 2017 were screened for potential inclusion. They were divided into two groups based on the timing of initial intervention (within 4 weeks and beyond 4 weeks). All the data were extracted from a prospectively collected database. RESULTS: Overall, 131 patients were included for analysis. Among them, 100 (76.3%) patients were intervened within 4 weeks and 31 (23.7%) underwent delayed interventions. As for organ failure prior to intervention, the incidences of respiratory failure, renal failure and cardiovascular failure were not significantly different between the two groups (P > 0.05). The mortality was not significantly different between the two groups (35.0% vs. 32.3%, P = 0.83). The incidences of new-onset multiple organ failure (8.0% vs. 6.5%, P = 1.00), gastrointestinal fistula (29.0% vs. 12.9%, P = 0.10) and bleeding (35.0% vs. 35.5%, P = 1.00), and length of ICU (30.0 vs. 22.0 days, P = 0.61) and hospital stay (42.5 vs. 40.0 days, P = 0.96) were comparable between the two groups. CONCLUSION: Intervention within 4 weeks did not worsen the clinical outcomes in NAP patients complicated by POF.

Digenic Inheritance and Gene-Environment Interaction in a Patient With Hypertriglyceridemia and Acute Pancreatitis.

The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy alcohol consumption and an 8-year history of mild HTG. He was hospitalized for alcohol-triggered AP, with a plasma triglyceride (TG) level up to 21.4 mmol/L. A temporary rise in post-heparin LPL concentration (1.5-2.5 times of controls) was noted during the early days of AP whilst LPL activity was consistently low (50∼70% of controls). His TG level rapidly decreased to normal in response to treatment, and remained normal to borderline high during a ∼3-year follow-up period during which he had abstained completely from alcohol. Sequencing of the five primary HTG genes (i.e., LPL, APOC2, APOA5, GPIHBP1 and LMF1) identified two heterozygous variants. One was the common APOA5 c.553G > T (p.Gly185Cys) variant, which has been previously associated with altered TG levels as well as HTG-induced acute pancreatitis (HTG-AP). The other was a rare variant in the LPL gene, c.756T > G (p.Ile252Met), which was predicted to be likely pathogenic and found experimentally to cause a 40% loss of LPL activity without affecting either protein synthesis or secretion. We provide evidence that both a gene-gene interaction (between the common APOA5 variant and the rare LPL variant) and a gene-environment interaction (between alcohol and digenic inheritance) might have contributed to the development of mild HTG and alcohol-triggered AP in the patient, thereby improving our understanding of the complex etiology of HTG and HTG-AP.

Serum magnesium level as a predictor of acute kidney injury in patients with acute pancreatitis.

BACKGROUND: Decreased serum magnesium (Mg2+) is commonly seen in critically ill patients. Hypomagnesemia is significantly more frequent in patients with severe acute pancreatitis. Acute kidney injury (AKI) in patients with acute pancreatitis (AP) is associated with an extremely high mortality. The association underlying serum Mg2+ and AKI in AP has not been elucidated. AIM: To explore the association between serum Mg2+ on admission and AKI in patients with AP. METHODS: A retrospective observational study was conducted in a cohort of patients (n = 233) with AP without any renal injury before admission to our center from August 2015 to February 2019. Demographic characteristics on admission, severity score, laboratory values and in-hospital mortality were compared between patients with and without AKI. RESULTS: A total of 233 patients were included for analysis, including 85 with AKI. Compared to patients without AKI, serum Mg2+ level was significantly lower in patients with AKI at admission [OR = 6.070, 95%CI: 3.374-10.921, P < 0.001]. Multivariate logistic analysis showed that lower serum Mg2+ was an independent risk factor for AKI [OR = 8.47, 95%CI: 3.02-23.72, P < 0.001]. CONCLUSION: Our analysis indicates that serum Mg2+ level at admission is independently associated with the development of AKI in patients with AP and may be a potential prognostic factor.

Machine Learning Models of Acute Kidney Injury Prediction in Acute Pancreatitis Patients.

Background. Acute kidney injury (AKI) has long been recognized as a common and important complication of acute pancreatitis (AP). In the study, machine learning (ML) techniques were used to establish predictive models for AKI in AP patients during hospitalization. This is a retrospective review of prospectively collected data of AP patients admitted within one week after the onset of abdominal pain to our department from January 2014 to January 2019. Eighty patients developed AKI after admission (AKI group) and 254 patients did not (non-AKI group) in the hospital. With the provision of additional information such as demographic characteristics or laboratory data, support vector machine (SVM), random forest (RF), classification and regression tree (CART), and extreme gradient boosting (XGBoost) were used to build models of AKI prediction and compared to the predictive performance of the classic model using logistic regression (LR). XGBoost performed best in predicting AKI with an AUC of 91.93% among the machine learning models. The AUC of logistic regression analysis was 87.28%. Present findings suggest that compared to the classical logistic regression model, machine learning models using features that can be easily obtained at admission had a better performance in predicting AKI in the AP patients.

Gene-environment interaction between APOA5 c.553G>T and pregnancy in hypertriglyceridemia-induced acute pancreatitis.

BACKGROUND: The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex. OBJECTIVE: Herein, we explore a possible gene-environment interaction between APOA5 c.553G>T (p.185Gly>Cys, rs2075291), a common variant associated with altered triglyceride levels, and pregnancy in HTG-AP. METHODS: We enrolled 318 Chinese HTG-AP patients and divided them into 3 distinct groups: Group 1, male patients (n = 183); Group 2, female patients whose disease was unrelated to pregnancy (n = 105); and Group 3, female patients whose disease was related to pregnancy (n = 30). APOA5 rs2075291 genotype status was determined by Sanger sequencing. A total of 362 healthy Han Chinese subjects were used as controls. Data on body mass index, peak triglyceride level, age of disease onset, episode number, and clinical severity of HTG-AP were collected from each patient. Multiple comparisons, between patient groups, between patient groups and controls, or within each patient group, were performed. RESULTS: A robust association of APOA5 rs2075291 with HTG-AP in general, and HTG-AP during pregnancy in particular, was demonstrated. The minor T allele showed a stronger association with Group 3 patients than with either Group 1 or Group 2 patients. This stronger association was due mainly to the much higher frequency of TT genotype in Group 3 patients (20%) than that (<6%) in Group 1 and Group 2 patients. Moreover, the TT genotype was associated with a significantly higher peak triglyceride level in Group 3 patients compared with the GG genotype. CONCLUSION: Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP.

Management of colonic fistulas in patients with infected pancreatic necrosis being treated with a step-up approach.

BACKGROUND: Colonic fistula is a potentially fatal complication in acute necrotizing pancreatitis (ANP), especially in patients with infected pancreatic necrosis (IPN). The aim of this study was to evaluate the feasibility of a step-up approach including percutaneous catheter drainage (PCD) and continuous negative pressure irrigation (CNPI) in a group of patients with colonic fistula. METHODS: A retrospective review of a prospectively collected data was performed. Data were extracted for patients complicated by colonic fistula from January 2010 to January 2017. RESULTS: A total of 1750 patients were admitted with ANP during the study period. Of these patients, 711 (41%) developed IPN and colonic fistula was present in 132 (19%). A step-up approach was adopted for all patients, with 47% avoiding surgery. The mortality in patients requiring surgery (37%) was higher than that in patients managed non-surgically (19%) constituting an overall mortality rate of 29%. In patients managed conservatively, 92% had spontaneous closure of the fistula. CONCLUSION: Colonic fistula is not a rare complication in ANP occurring in 19% of patients with IPN in the current study. A step-up approach was effective and safe in managing colonic fistula and surgery could be obviated in nearly half of the patients.

Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis.

BACKGROUND: Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. OBJECTIVES: The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). METHODS: The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. RESULTS: We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. CONCLUSIONS: Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.

Identification and functional characterization of a novel heterozygous missense variant in the LPL associated with recurrent hypertriglyceridemia-induced acute pancreatitis in pregnancy.

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a life-threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia-induced APIP (HTG-APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. METHODS: The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG-APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. RESULTS: A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. CONCLUSION: This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG-APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG-APIP.

Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking.

BACKGROUND: Hypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG. METHODS: A Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes. RESULTS: The patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene. CONCLUSIONS: This is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG.

Diabetes aggravates acute pancreatitis possibly via activation of NLRP3 inflammasome in db/db mice.

Clinical studies have confirmed that patients with diabetes had an elevated risk of acute pancreatitis (AP) and diabetes was associated with increased severity and mortality in patients with AP. However, these studies failed to prove a cause-and-effect relationship between diabetes and AP. In the present study, we for the first time have evaluated the effects of diabetes on AP by adopting a type 2 diabetes animal model db/db mice and investigated the possible underlying mechanisms. The results showed that in comparison to wide type (WT) mice, db/db mice showed exacerbated pancreatic and pulmonary injuries, elevated serum amylase and lipase levels, increased myeloperoxidase (MPO) expressions in pancreatic and pulmonary tissues as well as increased apoptotic acinar cells after AP induction. Furthermore, we observed that NLRP3 inflammasome in pancreatic tissues was remarkably activated in db/db mice compared with WT mice. In addition, we also found that diabetes could increase the susceptibility of mice to AP. Taken together, our results indicated that diabetes could predispose and aggravate the disease severity of AP potentially via promoting the activation of NLRP3 inflammasome pathway.

Early Prediction of Persistent Organ Failure by Circulating Endothelial Progenitor Cells in Patients With Acute Pancreatitis.

INTRODUCTION: Increased circulating endothelial progenitor cells (cEPC) have been observed in patients with vascular injury associated with sepsis and acute lung injury. However, a role for cEPC in severe acute pancreatitis (SAP) remains unclear. We therefore conducted a prospective study to study whether the quantities of cEPC can predict persistent organ failure (POF) in patients with predicted SAP. METHODS: A total of 42 predicted SAP patients who were admitted within 24 h after symptom onset and 10 healthy control subjects were enrolled in our study. The proportions of cEPC were analyzed based on flow cytometry simultaneously. Vascular endothelial growth factor (VEGF) levels were measured by enzyme-linked immunosorbent assay. RESULTS: The percentage of cEPC was significantly higher in patients with predicted SAP compared with healthy controls. Similarly, the levels of VEGF in peripheral blood were also significantly higher in predicted SAP patients than in the controls. Notably, patients with POF had lower proportion of cEPC compared with patients with transient organ failure (TOF). In contrast, patients with POF had a significantly higher level of VEGF compared with TOF. Of note, the percentages of cEPC were significantly inversely correlated with disease severity scores. More importantly, cEPC showed an excellent discriminative power for predicting POF among predicted SAP patients, whereas plasma VEGF and disease severity scores showed moderate accuracy in predicting future POF. CONCLUSIONS: Peripheral EPC as a novel biomarker is elevated and may aid to predict the development of POF in patients with predicted SAP.

Intercostal artery damage and massive hemothorax after thoracocentesis by central venous catheter: A case report.

Central venous catheters (CVCs) are widely used in various puncture and drainage operations in intensive care units (ICUs) in recent years. Compared to conventional operating devices, CVC was welcomed by clinicians because of the advantages of easy use, less damage to the body and convenient fixation process. We came across a patient with severe acute pancreatitis (SAP) who developed cardiac arrest due to thoracic cavity massive bleeding 24 h after thoracocentesis with CVC. Thoracotomy surgery was carried out immediately, which confirmed an intercostal artery injury. The patient was discharged from hospital without any neurological complications two months later. Here we report this case to remind all the emergency department and ICU physicians to pay more attention to the complication of thoracic cavity bleeding following thoracocentesis conducted by CVC.

Splanchnic vein thrombosis in necrotizing acute pancreatitis: Detection by computed tomographic venography.

AIM: To assess the diagnostic accuracy of computed tomographic venography (CTV) for splanchnic vein thrombosis (SVT) detection in necrotizing acute pancreatitis (AP) patients. METHODS: Forty-three patients with necrotizing AP who underwent both CTV and digital subtraction angiography (DSA) within 3 d were analyzed in this retrospective comparative study. All CTV procedures were performed with a dual-source CT scanner. The presence and location of SVT were determined via blinded imaging data analyses. RESULTS: According to the DSA results, 17 (39.5%) of the total 43 patients had SVT. The sensitivity, specificity, positive and negative predictive values of CTV for SVT detection were 100% (95%CI: 77.1%-100%), 92.3% (95%CI: 73.4%-98.7%), 89.5% (95%CI: 65.5%-98.2%) and 100% (95%CI: 82.8%-100%), respectively. CONCLUSION: CTV is an effective examination for SVT detection in patients with necrotizing AP with high positive and negative predictive values.

Predictors of critical acute pancreatitis: a prospective cohort study.

Critical acute pancreatitis (CAP) has recently emerged as the most ominous severity category of acute pancreatitis (AP). As such there have been no studies specifically designed to evaluate predictors of CAP. In this study, we aimed to evaluate the accuracy of 4 parameters (Acute Physiology and Chronic Health Evaluation [APACHE] II score, C-reactive protein [CRP], D-dimer, and intra-abdominal pressure [IAP]) for predicting CAP early after hospital admission. During the study period, data on patients with AP were prospectively collected and D-dimer, CRP, and IAP levels were measured using standard methods at admission whereas the APACHE II score was calculated within 24 hours of hospital admission. The receiver-operating characteristic (ROC) curve analysis was applied and the likelihood ratios were calculated to evaluate the predictive accuracy. A total of 173 consecutive patients were included in the analysis and 47 (27%) of them developed CAP. The overall hospital mortality was 11% (19 of 173). APACHE II score ≥11 and IAP ≥13 mm Hg showed significantly better overall predictive accuracy than D-dimer and CRP (area under the ROC curve-0.94 and 0.92 vs. 0.815 and 0.667, correspondingly). The positive likelihood ratio of APACHE II score is excellent (9.9) but of IAP is moderate (4.2). The latter can be improved by adding CRP (5.8). In conclusion, of the parameters studied, APACHE II score and IAP are the best available predictors of CAP within 24 hours of hospital admission. Given that APACHE II score is rather cumbersome, the combination of IAP and CRP appears to be the most practical way to predict critical course of AP early after hospital admission.

Efficacy of continuous regional arterial infusion with low-molecular-weight heparin for severe acute pancreatitis in a porcine model.

OBJECTIVE: Administration of heparin or its derivatives has been proved to be beneficial in the treatment of severe acute pancreatitis (SAP). However, drugs administered by conventional intravenous way are difficult to reach the pancreatic tissue and may cause bleeding complications due to coagulation and microcirculatory disturbance following initiation of SAP. In this study, we aimed to assess the effects of low-molecular-weight heparin (LMWH) administered with continuous regional arterial infusion (CRAI) technique in a porcine model of SAP. METHODS: Following baseline measurements, 18 animals were divided into three groups: CRAI group (LMWH infused through placed arterial catheter), venous group (LMWH infused through central venous catheter), and SAP control group. We used retrograde intraductal infusion of sodium taurocholate to induce SAP. Global hemodynamic profiles, urine output, systemic oxygenation, and inflammatory and serum biochemical parameters of the animals were studied. At the end of the experiment, histological examination of pancreas, intestine, and lung was performed. RESULTS: Continuous regional arterial infusion with LMWH remarkably stabilized hemodynamic profiles, improved systemic oxygenation and peripheral perfusion, alleviated histological injury of pancreas (especially for the necrosis scale), and downregulated inflammatory response when compared with the other two groups. Moreover, serum D-dimer level also decreased most significantly in the CRAI group (474 ± 144 vs. 664 ± 155 µg/L in the venous group and 945 ± 351 µg/L in the controls at the end), partly indicating ameliorated coagulation disorders in the study group. No bleeding complication was observed in the CRAI group, whereas two animals in the venous group presented gastrointestinal hemorrhage. CONCLUSIONS: Continuous regional arterial infusion with LMWH exhibits strong therapeutic effects in the course of SAP with great safety. Human studies using this novel therapy are required to assess these potential benefits in the clinical setting.

A double-blind, randomized, controlled study to explore the efficacy of rFVIIa on intraoperative blood loss and mortality in patients with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis is a life-threatening disease. Patients with peripancreatic necrotic infection often require surgical removal of necrotic infected tissue and a wide debridement will cause blood loss and worsen the condition. AIM: To assess whether treatment with NovoSeven, a recombinant activated FVII (rFVIIa), could improve coagulation function and therefore reduce blood loss, blood transfusion and all-cause mortality during necrosectomy in patients with infected necrosis secondary to severe acute pancreatitis. MATERIALS AND METHODS: Severe acute pancreatitis patients admitted to Nanjing Jinling Hospital for necrosectomy were enrolled and randomized to receive either standard treatment or standard treatment plus an intravenous infusion of rFVIIa (40µg per kilogram of body weight per hour) before operation. The prospectively defined primary end points were perioperative coagulation parameters (prothrombin time, activated partial thromboplastin time), blood transfusion unit and blood loss. The secondary end points were operation time, ICU stay and all-cause mortality at 28days after the operation. RESULTS: A total of 64 patients were enrolled (31 in the rFVIIa group and 33 in the control group). Treatment with rFVIIa was associated with a reduction in operation time, red blood cell and fresh froze plasma transfusion, blood loss and prothrombin time compared to the control group (p<0.05 for all). Activated partial thromboplastin time and mortality were similar between the two groups (P>0.05). CONCLUSION: Treatment with rFVIIa significantly improved the extrinsic coagulation function in patients with severe acute pancreatitis and was associated with decreased risk of bleeding. However, rFVIIa did not improve intrinsic coagulation or reduce over-cause mortality. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-TRC-1300389.

Codonopsis pilosula polysaccharide attenuates cecal ligation and puncture sepsis via circuiting regulatory T cells in mice.

BACKGROUND: Codonopsis pilosula polysaccharide (CPPS) isolated from one of the Chinese herbs is known to have a variety of immunomodulatory activities. However, it is not clear whether CPPS can exert an effect on the immune functions of regulatory T cells (Tregs). This study was carried out to investigate the effect of CPPS on the immune function of peripheral blood Tregs in sepsis induced by cecal ligation and puncture (CLP). METHODOLOGY AND PRINCIPAL FINDINGS: BALB/c mice were randomly divided into five groups: sham group, CLP group, CLP with CPPS (40, 100, and 250 mg/kg) treatment group, and they were killed on days 1, 2, 3, and 4 after CLP, respectively, with eight animals at each time point. Magnetic microbeads were used to isolate peripheral blood Tregs and CD4 T cells. Phenotypes of Tregs, such as Toll-like receptor 4 (TLR4) and Foxp3, were analyzed by flow cytometry, and coculture medium cytokines levels were determined with enzyme-linked immunosorbent assay. The levels of TLR4 and the expression of Foxp3 in the Treg from CLP group were markedly increased in comparison to the sham group. Administration of CPPS could significantly decrease the TLR4 level and inhibited the expression of Foxp3 on Tregs in sepsis mice. At the same time, proliferative activity and expression of interleukin 2 and interleukin 2Rα on CD4 T cells were restored. In contrast, anti-TLR4 antibody could block the effect of CPPS on Treg immune function. CONCLUSIONS: Codonopsis pilosula polysaccharide might suppress excessive Tregs, at least in part, via TLR4 signaling on Tregs and trigger a shift of TH2 to TH1 with activation of CD4 T cells in sepsis induced by CLP.