Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Non-antigen-specific Immunoadsorption Is a Risk Factor for Severe Postoperative Infections in ABO-Incompatible Kidney Transplant Recipients.

ABO-incompatible (ABOi) living kidney transplantation (KTx) is an established procedure to address the demand for kidney transplants with outcomes comparable to ABO-compatible KTx. Desensitization involves the use of immunoadsorption (IA) to eliminate preformed antibodies against the allograft. This monocentric retrospective study compares single-use antigen-selective Glycosorb® ABO columns to reusable non-antigen-specific Immunosorba® immunoglobulin adsorption columns regarding postoperative infectious complications and outcome. It includes all 138 ABOi KTx performed at Freiburg Transplant Center from 2004-2020. We compare 81 patients desensitized using antigen-specific columns (sIA) to 57 patients who received IA using non-antigen-specific columns (nsIA). We describe distribution of infections, mortality and allograft survival in both groups and use Cox proportional hazards regression to test for the association of IA type with severe infections. Desensitization with nsIA tripled the risk of severe postoperative infections (adjusted HR 3.08, 95% CI: 1.3-8.1) compared to sIA. nsIA was associated with significantly more recurring (21.4% vs. 6.2%) and severe infections (28.6% vs. 8.6%), mostly in the form of urosepsis. A significantly higher proportion of patients with sIA suffered from allograft rejection (29.6% vs. 14.0%). However, allograft survival was comparable. nsIA is associated with a two-fold risk of developing a severe postoperative infection after ABOi KTx.

Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice.

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.

Banded Versus Nonbanded Sleeve Gastrectomy: A Randomized Controlled Trial With 3 Years of Follow-up.

OBJECTIVE: The aim of this study was to compare silicone-banded sleeve gastrectomy (BSG) to nonbanded sleeve gastrectomy (SG) regarding weight loss, obesity-related comorbidities, and complications. SUMMARY BACKGROUND DATA: As a primary bariatric procedure, SG leads to excellent weight loss, yet weight regain is a relevant issue in mid- to long-term follow-up. Retrospective analyses suggest that banding a sleeve using a silicone ring may decrease weight regain and improve weight loss. METHODS: The banded versus nonbanded sleeve gastrectomy single-center, randomized controlled trial was conducted from January 2015 to August 2019. The primary endpoint was defined as excess weight loss 3 years after surgery. Secondary endpoints included the surgery's impact on obesity-related comorbidities, quality of life, and complications. The study was registered under DRKS00007729. RESULTS: Among 94 patients randomized, 97% completed 3-year follow-up. Mean initial body mass index was 50.9 kg/m [95% confidence interval (CI), 49.6-52.2]. Mean adjusted excess weight loss 3 years after SG amounted to 62.3% (95% CI, 56.2-68.5) and 73.9% ( 95% CI, 67.8-80.0) after BSG (difference 11.6%, P = 0.0073). Remission of type 2 diabetes occurred in 66.7% (4/6) after SG and in 91.0% (10/11) following BSG (P = 0.21). Three years after surgery, ring implantation correlated with decreased frequency of symptomatic reflux episodes (P = 0.01) but increased frequency of regurgitation (P = 0.03). The rate of major complications was not different between the study groups (BSG, n = 3; SG, n = 2; P = 0.63). Quality of life was better following BSG (P = 0.001). CONCLUSIONS: BSG provided better weight loss than nonbanded SG 3 years after surgery. Regurgitation was the main clinically relevant negative effect after BSG.

Recurring Anastomotic Leak-A Prospective Clinicopathological Investigation of a Distinct Disease Pattern.

BACKGROUND: Intestinal anastomotic insufficiency (AI) is a common problem in visceral surgery associated with overexpression of matrix metalloproteinases (MMPs). In some patients it occurs more than once. The etiology of recurring anastomotic insufficiency (RAI) is not understood yet and should be addressed as an independent disease entity. MATERIALS AND METHODS: Thirty nine consecutive patients with AI were treated at our university center and were included in this prospective study. Clinical data were evaluated by correlative statistical analysis to identify independent risk factors for RAI. Patients were divided in two groups: 18 patients had a single operative revision until restoration (group SAI), and 21 patients had two or more revisions (group RAI). Anastomotic tissue samples as well as untouched bowel wall were collected during reoperations for analysis of MMPs and tissue inhibitor of metalloproteinases (TIMP2). Clinical data were correlated with pathological observations. RESULTS: Significant differences of clinical and molecular pathological data were found between the two groups. Transfusion of red blood cells until the first reoperation and alcohol abuse led to RAI and were the only independent risk factors for RAI in multivariate analysis. Overexpression of MMP-8, -9, and -13 in anastomotic tissue correlated with the administration of red blood cells during initial operation. Reduced expression of TIMP2 was frequent in nearly all patients without differences throughout the subgroups. CONCLUSIONS: RAI seems to have an independent disease pattern. Transfusion of blood products is not only a known risk factor for AI but seems to significantly disturb the anastomotic healing process leading to RAI.

The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model.

OBJECTIVE: To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation. MATERIAL AND METHODS: Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined. RESULTS: Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups. CONCLUSION: Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.

Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study.

PURPOSE: Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. METHODS: Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival. RESULTS: N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51-19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13-12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25-14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12-14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29-3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13-2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13-2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21-5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04-2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. CONCLUSION: Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.

Inducing a humoral immune response to pancreatic cancer antigen.

BACKGROUND: Patients with pancreatic carcinoma have a grim prognosis. Here, we examine the induction of an in vitro antibody response of human B cells to pancreatic carcinoma antigens. MATERIAL AND METHODS: Cells of five cultured pancreatic ductal adenocarcinoma lines were lysed and their plasma membrane fragments isolated in an aqueous two-phase-system. The plasma membrane fragments were then added to cultures of isolated peripheral blood mononuclear cells from healthy volunteers for 14 days to act as a tumor antigen. Also, we added combinations of IL-2, IL-4, IL-21, anti-CD40 mAb and varying protein concentrations of the plasma membrane fragments to these cultures. We then tested characteristics and binding of resulting IgG and IgM against aforementioned tumor plasma membrane fragments and their respective cells using ELISAs. RESULTS: The combination of IL-2, IL-4 and anti-CD40 mAb elicited IgM production showing significant binding (p<0.05) to plasma membrane fragments. PANC-1 antigen and the combination of IL-4, IL-21 and anti-CD40 mAb was able to produce a significant and specific IgG formation against PANC-1 plasma membrane fragments (p<0.05). Tumor antigen, interleukins and anti-CD40 mAb had a significant impact on the binding capacity of these antibodies (p<0.05). IgG binding pancreatic carcinoma cells was observed when the tumor antigen concentration was increased during stimulation (p<0.05). BxPC3 plasma membrane fragments showed inhibitory effects on IgG binding BxPC3 antigens (p<0.05). CONCLUSIONS: A human anti-tumor antibody formation can be induced in vitro using PANC-1 antigens and B cell stimulating agents. This response has the potential to generate antibodies specific to PANC-1 antigens. PRéCIS: The concept presented is novel and a promising approach to eliciting a specific B cell response to tumor antigen. The method may prove useful in understanding and developing anti-tumor immunity.

Validation of undergraduate medical student script concordance test (SCT) scores on the clinical assessment of the acute abdomen.

BACKGROUND: Health professionals often manage medical problems in critical situations under time pressure and on the basis of vague information. In recent years, dual process theory has provided a framework of cognitive processes to assist students in developing clinical reasoning skills critical especially in surgery due to the high workload and the elevated stress levels. However, clinical reasoning skills can be observed only indirectly and the corresponding constructs are difficult to measure in order to assess student performance. The script concordance test has been established in this field. A number of studies suggest that the test delivers a valid assessment of clinical reasoning. However, different scoring methods have been suggested. They reflect different interpretations of the underlying construct. In this work we want to shed light on the theoretical framework of script theory and give an idea of script concordance testing. We constructed a script concordance test in the clinical context of "acute abdomen" and compared previously proposed scores with regard to their validity. METHODS: A test comprising 52 items in 18 clinical scenarios was developed, revised along the guidelines and administered to 56 4(th) and 5(th) year medical students at the end of a blended-learning seminar. We scored the answers using five different scoring methods (distance (2×), aggregate (2×), single best answer) and compared the scoring keys, the resulting final scores and Cronbach's α after normalization of the raw scores. RESULTS: All scores except the single best answers calculation achieved acceptable reliability scores (>= 0.75), as measured by Cronbach's α. Students were clearly distinguishable from the experts, whose results were set to a mean of 80 and SD of 5 by the normalization process. With the two aggregate scoring methods, the students' means values were between 62.5 (AGGPEN) and 63.9 (AGG) equivalent to about three expert SD below the experts' mean value (Cronbach's α : 0.76 (AGGPEN) and 0.75 (AGG)). With the two distance scoring methods the students' mean was between 62.8 (DMODE) and 66.8 (DMEAN) equivalent to about two expert SD below the experts' mean value (Cronbach's α: 0.77 (DMODE) and 0.79 (DMEAN)). In this study the single best answer (SBA) scoring key yielded the worst psychometric results (Cronbach's α: 0.68). CONCLUSION: Assuming the psychometric properties of the script concordance test scores are valid, then clinical reasoning skills can be measured reliably with different scoring keys in the SCT presented here. Psychometrically, the distance methods seem to be superior, wherein inherent statistical properties of the scales might play a significant role. For methodological reasons, the aggregate methods can also be used. Despite the limitations and complexity of the underlying scoring process and the calculation of reliability, we advocate for SCT because it allows a new perspective on the measurement and teaching of cognitive skills.

The chemokine ligand CXCL16 is an indicator of bacterial infection in necrotizing pancreatitis.

OBJECTIVES: Current guidelines tell us that intervention in severe necrotizing pancreatitis ought to be performed as late as possible. However, when pancreatic necrosis becomes infected, the necrotic tissue needs to be removed. Unfortunately, bacterial infection can only be proven by invasive methods. METHODS: Necrotizing pancreatitis with sterile or infected necrosis was induced in mice. Mice serum samples were examined by antibody-based protein array. After identifying candidate proteins that showed strong regulation, the serum concentration of these proteins was examined by sandwich ELISA. Then, human serum samples were collected from patients with mild pancreatitis, severe pancreatitis with and without pancreatic necrosis and patients with microbiologically proven infection of pancreatic necrosis. These serum samples were then analyzed by sandwich ELISA. RESULTS: In mice 6 proteins were strongly up-regulated and were further investigated by ELISAs. Of these proteins, CXCL16 and TRANCE (RANKL) concentrations were analyzed in human serum samples. CXCL16 and TRANCE were increased in patients with pancreatic necrosis and abdominal infection. Receiver operated characteristics showed that CXCL16 was superior in predicting infected pancreatic necrosis when compared to C-reactive protein and TRANCE. CONCLUSIONS: Serum CXCL16 is increased in severe pancreatitis with infected pancreatic necrosis and identifies patients who benefit from surgical necrosectomy.

Organ-specific monocyte activation in necrotizing pancreatitis in mice.

BACKGROUND: Acute necrotizing pancreatitis (NAP) induces a systemic inflammatory response syndrome. We investigated the underlying changes of monocytes using different activation markers. MATERIALS AND METHODS: A retrograde injection of 2 mL/kg bodyweight of sodium taurocholate into the common bile duct of BALB/c mice induced NAP, whereas sham-operated animals (SOP) were treated with saline. After 6, 12, 24, and 48 h, histologic alterations, pancreatic enzymes, and interleukin 6 in serum, albumin, and myeloperoxidase (MPO) in bronchoalveolar lavage fluid were examined. Isolation of mononuclear cells from the blood, spleen, and liver and the subsequent determination of macrophages (F4/80) and their activation marker CD121b and MHCII (1Ad) were performed by fluorescence-activated cell sorting (FACS analyses). RESULTS: After pancreatitis induction, pancreatic enzymes (amylase: SOP 7008 U/L, NAP 37,044 U/L, P < 0.001) and histologic pancreatic damage (SOP 0.80 ± 1.92, NAP 19.6 ± 0.64, P < 0.001) developed instantly. Pulmonary vascular damage and MPO were detected between 6 and 12 h after onset (6 h albumin SOP 132.0 ± 12.0 µg/mL, NAP 267.2 ± 49.6 µg/mL; P < 0.05; MPO SOP 0.23 ± 0.20 ng/mL, NAP 11.29 ± 3.12 ng/mL, P < 0.01). Blood levels of interleukin 6 increased after 12-24 h (12 h SOP 584 ± 300 pg/mL; NAP 2169 ± 942 pg/mL, P < 0.05), whereas monocytes increased fourfold within 48 h (P < 0.05). Furthermore, pancreatitis increased the percentage of activated monocytes in the blood (6 h and/or 48 h: MHCII (1Ad) 2196%/5.65%; CD121b 51,654%/82,146%). Similar observations were made for monocytes from the liver and spleen. CONCLUSIONS: Although inflammatory mediators increased during 24 h after pancreatitis induction, monocyte activation lasted for at least 48 h. The latter is not limited to blood but also detected in isolated liver and spleen monocytes.

Retrospective analyses of trends in pancreatic surgery: indications, operative techniques, and postoperative outcome of 1,120 pancreatic resections.

BACKGROUND: Hospital volume, surgeons' experience, and adequate management of complications are factors that contribute to a better outcome after pancreatic resections. The aim of our study was to analyze trends in indications, surgical techniques, and postoperative outcome in more than 1,100 pancreatic resections. METHODS: One thousand one hundred twenty pancreatic resections were performed since 1994. The vast majority of operations were performed by three surgeons. Perioperative data were documented in a pancreatic database. For the purpose of our analysis, the study period was sub-classified into three periods (A 1994 to 2001/n = 363; B 2001 to 2006/n = 305; C since 2007 to 2012/n = 452). RESULTS: The median patient age increased from 51 (A) to 65 years (C; P < 0.001). Indications for surgery were pancreatic/periampullary cancer (49%), chronic pancreatitis (CP; 33%), and various other lesions (18%). About two thirds of the operations were pylorus-preserving pancreaticoduodenectomies. The frequency of mesenterico-portal vein resections increased from 8% (A) to 20% (C; P < 0.01). The overall mortality was 2.4% and comparable in all three periods (2.8%, 2.0%, 2.4%; P = 0.8). Overall complication rates increased from 42% (A) to 56% (C; P < 0.01). CONCLUSIONS: Mortality remained low despite a more aggressive surgical approach to pancreatic disease. An increased overall morbidity may be explained by more clinically relevant pancreatic fistulas and better documentation.

The degree of local inflammatory response after colonic resection depends on the surgical approach: an observational study in 61 patients.

BACKGROUND: Clinical data indicate that laparoscopic surgery reduces postoperative inflammatory response and benefits patient recovery. Little is known about the mechanisms involved in reduced systemic and local inflammation and the contribution of reduced trauma to the abdominal wall and the parietal peritoneum. METHODS: Included were 61 patients, who underwent elective colorectal resection without intraabdominal complications; 17 received a completely laparoscopic, 13 a laparoscopically- assisted procedure and 31 open surgery. Local inflammatory response was quantified by measurement of intraperitoneal leukocytes and IL-6 levels during the first 4 days after surgery. RESULTS: There was no statistical difference between the groups in systemic inflammatory parameters and intraperitoneal leukocytes. Intraperitoneal interleukin-6 was significantly lower in the laparoscopic group than in the laparoscopically-assisted and open group on postoperative day 1 (26.16 versus 43.25 versus 40.83 ng/ml; p = 0.001). No difference between the groups was recorded on POD 2-4. Intraperitoneal interleukin-6 showed a correlation with duration of hospital stay on POD 1 (0.233, p = 0.036), but not on POD 2-4. Patients who developed a surgical wound infection showed higher levels of intraperitoneal interleukin-6 on postoperative day 2-4 (POD 2: 42.56 versus 30.02 ng/ml, p = 0.03), POD 3: 36.52 versus 23.62 ng/ml, p = 0.06 and POD 4: 34.43 versus 19.99 ng/ml, p = 0.046). Extraabdominal infections had no impact. CONCLUSION: The analysis shows an attenuated intraperitoneal inflammatory response on POD 1 in completely laparoscopically-operated patients, associated with a quicker recovery. This effect cannot be observed in patients, who underwent a laparoscopically-assisted or open procedure. Factors inflicting additional trauma to the abdominal wall and parietal peritoneum promote the intraperitoneal inflammation process.

Dissecting the effect of moxifloxacin in mice with infected necrosis in taurocholate induced necrotizing pancreatitis.

OBJECTIVES: To investigate the limited benefit of antibiotics in ameliorating the outcome of acute necrotizing pancreatitis, we analyzed antibiotic therapy in primarily infected necrotizing pancreatitis in mice with respect to the local pancreatic pathology as well as systemic, pancreatitis induced adverse events. METHODS: Sterile pancreatic necrosis (SN) was induced by retrograde injection of 4% taurocholate in the common bile duct of Balb/c mice. Primarily infected pancreatic necrosis (IN) was induced by co-injecting 10(8) CFU/ml Escherichia coli. 10 mg/kg of moxifloxacin was administered prior to pancreatitis induction (AN). After 24 h, animals were sacrificed to examine serum as well as organs for signs of SIRS. RESULTS: Moxifloxacin significantly reduced bacterial count in pancreatic lysates of animals with infected pancreatic necrosis (IN 4.1·10(7) ± 2.4·10(7) vs. AN 4.9·10(4) ± 2.6·10(4) CFU/g; p < 0.001). However, it did not alter pancreatic histology or pulmonary damage (Histology score: IN 23.8 ± 2.7 vs. AN 22.6 ± 1.7). Moxifloxacin reduced systemic immunoactivation (Serum IL-6: IN 330.5 ± 336.6 vs. 38.7 ± 25.5 pg/ml; p < 0.001), hypoglycemia (serum glucose: IN 105.8 ± 12.7 vs. AN 155.7 ± 39.5 mg/dl; p < 0.001), and serum aspartate aminotransferase (IN 606 ± 89.7 vs. AN 255 ± 52.1; p < 0.05). These parameters were significantly increased in animals with necrotizing pancreatitis. CONCLUSION: In the experimental setting, initial antibiotic therapy with moxifloxacin in acute infected necrotizing pancreatitis in mice does not have a beneficial impact on pancreatic pathology or pulmonary damage. However, other systemic complications induced by infected necrosis in acute pancreatitis are reduced by the administration of moxifloxacin.

Impact of intraoperative temperature and humidity on healing of intestinal anastomoses.

PURPOSE: Clinical data indicate that laparoscopic surgery has a beneficial effect on intestinal wound healing and is associated with a lower incidence of anastomotic leakage. This observation is based on weak evidence, and little is known about the impact of intraoperative parameters during laparoscopic surgery, e.g., temperature and humidity. METHODS: A small-bowel anastomosis was formed in rats inside an incubator, in an environment of stable humidity and temperature. Three groups of ten Wistar rats were operated: a control group (G1) in an open surgical environment and two groups (G2 and G3) in the incubator at a humidity of 60 % and a temperature of 30 and 37 °C (G2 and G3, respectively). After 4 days, bursting pressure and hydroxyproline concentration of the anastomosis were analyzed. The tissue was histologically examined. Serum levels of C-reactive-protein (CRP) were measured. RESULTS: No significant changes were seen in the evaluation of anastomotic stability. Bursting pressure was very similar among the groups. Hydroxyproline concentration in G3 (36.3 µg/g) was lower by trend (p = 0.072) than in G1 (51.7 µg/g) and G2 (46.4 µg/g). The histological evaluation showed similar results regarding necrosis, inflammatory cells, edema, and epithelization for all groups. G3 (2.56) showed a distinctly worse score for submucosal bridging (p = 0.061) than G1 (1.68). A highly significant increase (p = 0.008) in CRP was detected in G3 (598.96 ng/ml) compared to G1 (439.49 ng/ml) and G2 (460 ng/ml). CONCLUSION: A combination of high temperature and humidity during surgery induces an increased systemic inflammatory response and seems to be attenuating the early regeneration process in the anastomotic tissue.

Searching for the molecular benchmark of physiological intestinal anastomotic healing in rats: an experimental study.

PURPOSE: This investigation focuses on the physiological characteristics of gene transcription of intestinal tissue following anastomosis formation. METHODS: In eight rats, end-to-end ileo-ileal anastomoses were performed (n = 2/group). The healthy intestinal tissue resected for this operation was used as a control. On days 0, 2, 4 and 8, 10-mm perianastomotic segments were resected. Control and perianastomotic segments were examined with an Affymetrix microarray chip to assess changes in gene regulation. Microarray findings were validated using real-time PCR for selected genes. In addition to screening global gene expression, we identified genes intensely regulated during healing and also subjected our data sets to an overrepresentation analysis using the Gene Ontology (GO) and Kyoto Encyclopedia for Genes and Genomes (KEGG). RESULTS: Compared to the control group, we observed that the number of differentially regulated genes peaked on day 2 with a total of 2,238 genes, decreasing by day 4 to 1,687 genes and to 1,407 genes by day 8. PCR validation for matrix metalloproteinases-3 and -13 showed not only identical transcription patterns but also analogous regulation intensity. When setting the cutoff of upregulation at 10-fold to identify genes likely to be relevant, the total gene count was significantly lower with 55, 45 and 37 genes on days 2, 4 and 8, respectively. A total of 947 GO subcategories were significantly overrepresented during anastomotic healing. Furthermore, 23 overrepresented KEGG pathways were identified. CONCLUSION: This study is the first of its kind that focuses explicitly on gene transcription during intestinal anastomotic healing under standardized conditions. Our work sets a foundation for further studies toward a more profound understanding of the physiology of anastomotic healing.

Banded Versus Non-banded Sleeve Gastrectomy: 5-Year Results of a 3-Year Randomized Controlled Trial.

PURPOSE: Banded sleeve gastrectomy (BSG) has been shown to enable better weight loss than non-banded sleeve gastrectomy (SG) in retrospective analyses. These findings were supported by two randomized controlled trials (RCT). However, to date, mid-term prospective data is not available. MATERIALS AND METHODS: We invited all 94 patients of an RCT comparing banded to non-banded sleeve gastrectomy at 3 years (DRKS00007729) for a 5-year follow-up visit. Eighty-two patients (BSG n = 42; SG n = 40) came for evaluation. Outcome measures were identical with the RCT to allow longitudinal comparison. Data analysis was descriptive and focused on biometric data, development of comorbidities, mid-term complications, quality of life, and type of body contouring surgery (BCS). RESULTS: The per-protocol analysis revealed a treatment difference of 9% (CI - 1.5 to 19.6) excess weight loss (EWL). Total weight loss (TWL) was 27.4% (CI 23.5-31.3) after SG and 31.6% (CI 27.3-35.5) after BSG. Twenty percent of patients after SG and 11.9% following BSG had been converted to a gastric bypass. Type 2 diabetes went into remission in most patients (SG 66.7% vs. BSG 63.6%). Antihypertensive medication was stopped or reduced in 81.3% after SG and 80% after BSG. Reflux symptoms were similar in both groups (symptoms [Formula: see text] 1/ week: SG 28.2% vs. BSG 26.8%). Frequency of postprandial regurgitation was higher after BSG (SG 23% vs. BSG 59%). Forty percent of patients had undergone BCS at time of follow-up. CONCLUSION: Five-year weight loss after BSG was 9% EWL and 4.2% TWL higher compared to SG. The main added morbidity following BSG was postprandial regurgitation.

Association of parental obesity with the profile of metabolic-bariatric surgery patients: a cohort study of the German StuDoQ|MBE registry.

OBJECTIVES: To investigate the association of parental obesity (PO) with onset of obesity, pre-surgical disease duration and body mass index (BMI) at the time of surgery in patients undergoing metabolic-bariatric surgery (MBS). DESIGN: This is a cohort study of the German StuDoQ registry for metabolic-bariatric diseases. All surgical cases from initiation of the registry in September 2015 until August 2020 were screened for pertinent information. SETTING: The registry is based on participating German hospitals of various sizes. PARTICIPANTS: A total of 11 891 patients were included in this analysis, 74.2% of which were females and 25.8% males. Roux-en-Y gastric bypass was performed in 5652 (47.5%) cases, sleeve gastrectomy in 4618 (38.8%) cases and one-anastomosis gastric bypass in 1621 (13.6%) cases. RESULTS: One-sided and two-sided PO are independently associated with early-onset obesity (OR 1.61, [95% CI, 1.47 to 1.76], p<0.001 and OR 2.45, [95% CI, 2.22 to 2.71], p<0.001) and prolonged pre-surgical disease duration (regression coefficient 2.39, [95% CI, 1.93 to 2.83], p<0.001 and regression coefficient 4.27, [95% CI, 3.80 to 4.75], p<0.001). Unlike one-sided PO, two-sided PO had a significant association with BMI at the time of surgery (regression coefficient 0.49, [95% CI, 0.14 to 0.85], p=0.006). Age at the onset of obesity and disease duration had a negative association with BMI at the time of surgery (regression coefficient -0.13, [95% CI, -0.14 to -0.11], p<0.001 and regression coefficient -0.05, [95% CI, -0.07 to -0.04], p<0.001). CONCLUSIONS: This study established a clear association between PO status of patients undergoing MBS and their pre-surgical patient profile as well as known risk factors for poor postoperative response.

Effect of Intraoperative Blood Pressure Regulation on Postoperative Hemorrhage After Bariatric Surgery.

INTRODUCTION: With a rising number of bariatric procedures, the absolute number of postoperative complications is increasing, too. Postoperative bleeding, particularly along the staple line, is a recognized challenge. Numerous strategies including reinforcement of the staple line (SLR) have been proposed to improve bleeding rates, but no single technique has shown superiority over the others. In our bariatric center, we have implemented intraoperative blood pressure regulation alone, without SLR, to reduce hemorrhagic complications postoperatively. METHODS: This retrospective observational analysis compares the incidence of postoperative bleeding in two groups of consecutive patients (total n = 438 patients), one with and one without intraoperative blood pressure elevation to 150 mmHg systolic without the additional use of staple line reinforcement. This intervention was integrated into our standard bariatric surgical procedure, no randomization or matching was conducted. Significant postoperative bleeding was defined as drop of hemoglobin of more than 2.5 mg/dl in 48 h and one of the following symptoms: lactate ≥ 2 mmol/L, bloody drainage, quantity of drainage more than 200 ml and/or radiological signs. RESULTS: Defined postoperative bleeding occurred in 33 (7.5%) patients. We observed a decrease in bleeding rates from 10% to 5% (n = 22 vs. n = 11) after introducing intraoperative blood pressure increase (p = 0.034). The rate of revisional surgery for bleeding also decreased from 2.7% to 0.5% (n = 6 vs. n = 1). In multivariate analysis, the intervention with blood pressure elevation showed a significant decrease on bleeding rates (p = 0.038). CONCLUSION: The use of increased intraoperative blood pressure alone, without staple line reinforcement, appears to be an effective and suitable method for reducing post-bariatric hemorrhagic complications.