Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD.

BACKGROUND: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury. METHODS: IDO-1 expression in mice and human vessels was examined. IDO-1-/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used. RESULTS: Both global IDO-1-/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery. CONCLUSION: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.

Intraoperative amylase level of pancreatic juice as a simple predictor of pancreatic fistula after pancreaticoduodenectomy.

INTRODUCTION: A soft remnant texture of the pancreas is commonly accepted as a risk factor for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD). However, its assessment is subjective. The aim of this study was to evaluate the significance of intraoperative amylase level of the pancreatic juice as a risk factor of POPF after PD. METHOD: This study included 75 patients who underwent PD between November 2014 and April 2020 at Jikei University Hospital. We investigated the relationship between pancreatic texture, intraoperative amylase level of pancreatic juice, results of the pathological evaluations, and the incidence of POPF. RESULTS: Twenty-three patients (31%) developed POPF. The significant predictors of POPF were non-ductal adenocarcinoma (p < 0.01), soft pancreatic remnant (p < 0.01), high intraoperative blood loss (p < 0.01), high intraoperative amylase level of pancreatic juice (p < 0.01), and low pancreatic fibrosis (p < 0.01). Multivariate analysis revealed that the significant independent predictors of POPF were high intraoperative blood loss (p < 0.01) and high intraoperative amylase level of pancreatic juice (p = 0.02). Receiver operating characteristic (ROC) analysis showed that the cut-off value for the intraoperative amylase level of pancreatic juice was 2.17 × 105 IU/L (area under the curve = 0.726, sensitivity = 95.7%, and specificity = 50.0%) CONCLUSIONS: The intraoperative amylase level of pancreatic juice is a reliable objective predictor for POPF after PD.

Does Aspartate Aminotransferase to Alanine Aminotransferase Ratio Predict Acute Kidney Injury After Cardiac Surgery?

BACKGROUND: Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AST/ALT) frequently is used in the diagnosis and prognosis of liver diseases, however it is also used in the diagnosis and prognosis of many other diseases, such as myocardial infarction, acute ischemic stroke, and peripheral artery disease. Acute kidney injury (AKI) is one of the most important complications after cardiac surgery and is one of the main causes of morbidity and mortality. The purpose of the study was to analyze the relationship between AST to ALT and AKI after isolated coronary artery bypass graft surgery (CABG). METHODS: We retrospectively reviewed the prospectively collected data of 253 adult patients, who underwent isolated CABG surgery with normal renal function (baseline serum creatinine value <1.4 mg/dL). Preoperative (T0) and postoperative day 1 and day 3 (T1 and T2) serum AST and ALT levels were analyzed, and AST/ALT was calculated. A preoperative AST/ALT of 1.22 was found to be the best cutoff point for predicting postoperative AKI. Kidney injury was interpreted, according to RIFLE classification. The effect of AST to ALT ratio on AKI after CABG was determined using logistic regression analysis, and the results were expressed as odds ratio (OR) with a 95% confidence interval (CI). A P value < .05 was considered statistically significant. RESULTS: Postoperative AKI occurred in 40 patients (15.8%). On logistic regression analysis, higher AST/ALT both preoperatively and postoperatively were associated with an increased incidence of postoperative AKI (T0: OR, 3.983; 95% CI, 1.940-8.180, P < .001, T1: OR, 2.760; 95% CI, 1.381-5.515, P = .004, T2: OR, 2.515; 95% CI, 1.195-5.294, P = .015). CONCLUSION: Preoperative and postoperative elevated AST to ALT ratio seems to be associated with an increased incidence of AKI after elective isolated CABG surgery.

Pancreatic Inflammation and Proenzyme Activation Are Associated With Clinically Relevant Postoperative Pancreatic Fistulas After Pancreas Resection.

OBJECTIVE: We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs). SUMMARY BACKGROUND DATA: An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis. METHODS: Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice. RESULTS: Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice. CONCLUSIONS: Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.

Urinary Neutrophil Gelatinase Associated Lipocalins (NGALs) predict acute kidney injury post liver transplant.

BACKGROUND: Acute Kidney Injury, a common complication of liver transplant, is associated with a significant increase in the risk of morbidity, mortality and graft loss. Current diagnostic criteria leaves a delay in diagnosis allowing further potential irreversible damage. Early biomarkers of renal injury are of clinical importance and Neutrophil Gelatinase Associated Lipocalins (NGALs) and Syndecan-1 were investigated. METHODS: AKI was defined according to the Acute Kidney Injury Network criteria. Urine and blood samples were collected pre-operatively, immediately post-op and 24 h post reperfusion to allow measurement of NGAL and Syndecan-1 levels. RESULTS: 13 of 27 patients developed an AKI. Patients who developed AKI had significantly higher peak transaminases. Urinary NGAL, plasma NGAL and Syndecan-1 levels were significantly elevated in all patients post reperfusion. Urinary NGAL levels immediately post-op were significantly higher in patients who developed an AKI than those that didn't [1319 ng/ml vs 46.56 ng/ml, p ≤ 0.001]. ROC curves were performed and urinary NGAL levels immediately post-op were an excellent biomarker for AKI with an area under the curve of 0.948 (0.847-1.00). CONCLUSIONS: Urinary NGAL levels measured immediately post-op accurately predict the development of AKI and their incorporation into clinical practise could allow early protocols to be developed to treat post transplant AKI.

D-dopachrome tautomerase predicts outcome but not the development of acute kidney injury after orthotopic liver transplantation.

BACKGROUND: Elevated concentrations of D-dopachrome tautomerase (D-DT) were associated with adverse outcome in various clinical settings. However, no study assessed D-DT concentrations in patients requiring orthotopic liver transplantation (OLT). The aim of this observational study was to measure serum D-DT concentrations in patients undergoing OLT and associate D-DT with survival and acute kidney injury (AKI). METHODS: Forty-seven adults with end-stage liver disease undergoing OLT were included. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of D-DT for outcome and AKI after OLT. Survival was analyzed by Kaplan-Meier curves. RESULTS: Serum D-DT concentrations were greater in non-survivors than in survivors prior to OLT (86 [50-117] vs. 53 [31-71] ng/ml, P = 0.008), and on day 1 (357 [238-724] vs. 189 [135-309] ng/ml, P = 0.001) and day 2 (210 [142-471] vs. 159 [120-204] ng/ml, P = 0.004) following OLT. Serum D-DT concentrations predicted lethal outcome when measured preoperatively (AUC = 0.75, P = 0.017) and on postoperative day 1 (AUC = 0.75, P = 0.015). One-year survival of patients with preoperative D-DT concentrations >85 ng/ml was 50%, whereas that of patients with preoperative D-DT concentrations <85 ng/ml was 83% (Chi2 = 5.83, P = 0.016). In contrast, D-DT was not associated with AKI after OLT. CONCLUSION: In patients undergoing OLT, serum D-DT might predict outcome after OLT.

Impact of angiotensin-converting enzyme 2 levels on postoperative pneumonia after esophagectomy.

BACKGROUND: Pulmonary complications after esophagectomy are often fatal. The prediction of postoperative pulmonary complications remains a challenge. Accumulating evidence demonstrates a physiological and pathological role for angiotensin-converting enzyme 2 (ACE2) in the respiratory system. The purpose of this study was to evaluate the predictive value of ACE2 levels for the development of postoperative pneumonia. METHODS: To evaluate the association between serum ACE2 levels and pneumonia after esophagectomy, we retrospectively reviewed the medical records of 80 patients who underwent thoracoscopic esophagectomy for esophageal cancer from 2009 to 2014. RESULTS: Nineteen patients (23.8%) developed pneumonia after esophagectomy. Patients with pneumonia had significantly higher levels of ACE2 from the preoperative day to postoperative day (POD) 3, white blood cell count (POD7), and C-reactive protein (POD3, POD5, and POD7) than patients without pneumonia. Patients with postoperative pneumonia had higher serum ACE2 levels on POD3 than patients without pneumonia. CONCLUSIONS: The elevation of ACE2 levels on POD3 may predict the incidence of pneumonia.

Impact of anatomical position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy for gastric cancer.

BACKGROUND: Laparoscopic surgery for gastric cancer requires traction or compression of the pancreas, with the extent depending on the anatomical position of the pancreas. This study investigated the impact of the position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy (LDG). METHODS: Gastric cancer patients who underwent LDG were assessed retrospectively. The following anatomical parameters were measured retrospectively in preoperative computed tomography sagittal projections: the length of the vertical line between the pancreas and the aorta (P-A length), representing the height of the slope looking down the celiac artery from the top of the pancreas, and the angle between a line drawn from the upper border of the pancreas to the root of the celiac artery and the aorta (UP-CA angle), representing the steepness of the slope. Correlations between each parameter and postoperative complications were analyzed by logistic regression analysis. Pearson's product-moment correlation coefficients were calculated for scatter diagrams for each parameter and drain amylase concentration on postoperative day 1. RESULTS: Analyses were performed in 394 patients. P-A length [odds ratio (OR) 1.905; 95% confidence interval (CI) 1.100-3.300; P = 0.021] was significantly correlated with pancreatic fistula. P-A length (OR 2.771; 95% CI 1.506-5.098; P = 0.001), UP-CA angle (OR 2.323; 95% CI 1.251-4.314; P = 0.008), and low preoperative serum albumin (OR 2.082; 95% CI 1.050-4.128; P = 0.036) were significantly correlated with overall postoperative complications defined as Clavien-Dindo ≥ grade II. P-A length and UP-CA angle showed significant positive correlations with drain amylase concentration on postoperative day 1. CONCLUSION: The position of the pancreas is an independent predictor of pancreatic fistula and/or postoperative complications and correlates with drain amylase concentration after LDG for gastric cancer.

Anti-inflammatory Effects of Enhanced Recovery Programs on Early-Stage Colorectal Cancer Surgery.

BACKGROUND: Postoperative ileus (POI) is observed in 20-30% of patients undergoing colorectal cancer surgery, despite enhanced recovery programs (ERPs). Cyclooxygenase (COX)-2 is identified as a key enzyme in POI, but other arachidonic acid pathway enzymes have received little attention despite their potential as selective targets to prevent POI. The objectives were to compare the expression of arachidonic acid metabolism (AAM) enzymes (1) between patients who underwent colorectal cancer surgery and followed an ERP or not (NERP), (2) and between ERP patients who experimented POI or not and (3) to determine the ability of antagonists of these pathways to modulate contractile activity of colonic muscle. METHODS: This was a translational study. Main outcome measures were gastrointestinal motility recovery data, mRNA expressions of key enzymes involved in AAM (RT-qPCR) and ex vivo motility values of the circular colon muscle. Twenty-eight prospectively included ERP patients were compared to eleven retrospectively included NERP patients that underwent colorectal cancer surgery. RESULTS: ERP reduced colonic mucosal COX-2, microsomal prostaglandin E synthase (mPGES1) and hematopoietic prostaglandin D synthase (HPGDS) mRNA expression. mPGES1 and HPGDS mRNA expression were significantly associated with ERP compliance (respectively, r2 = 0.25, p = 0.002 and r2 = 0.6, p < 0.001). In muscularis propria, HPGDS mRNA expression was correlated with GI motility recovery (p = 0.002). The pharmacological inhibition of mPGES1 increased spontaneous ex vivo contractile activity in circular muscle (p = 0.03). CONCLUSION: The effects of ERP on GI recovery are correlated with the compliance of ERP and could be mediated at least in part by mPGES1, HPGDS and COX-2. Furthermore, mPGES1 shows promise as a therapeutic target to further reduce POI duration among ERP patients.

Surgeon volume and hospital volume in endocrine neck surgery: how many procedures are needed for reaching a safety level and acceptable costs? A systematic narrative review.

The relationship between quality of care and provider's experience is well known in all fields of surgery. Even in thyroidectomies and parathyroidectomies, the emphasis on positive volume-outcome relationships is believed. It led us to an evaluation of volume activity's impact in terms of quality of care. A systematic narrative review was performed. According to the PRISMA criteria, we selected 87 paper and, after the study selection was performed, 22 studies were finally included in this review. All articles included were unanimous in attributing to activity volume of surgeons as well as centers a substantial importance. Some differences in outcomes between these investigated categories have been found: best results of the high volume surgeon is evident expecially in terms of complications, on the contrary best outcomes of a high volume center are mainly economics, such as hospital stay and general costs of the procedures. A cut-off of 35-40 thyroidectomies per year for single surgeon, and 90-100 thyroidectomies for single center appears reasonable for identifying an adequate activity. Concerning parathyroidectomy, we can consider reasonable a cut off at 10-12 operations/year. More studies are needed in a European or more circumscribed perspective.

Sepsis induced by cecal ligation and perforation (CLP) alters nucleotidase activities in platelets of rats.

Sepsis is a potentially lethal condition, and it is associated with platelet alterations. The present study sought to investigate the activity of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'-nucleotidase, and ecto-adenosine deaminase (E-ADA) in the platelets of rats that were induced with sepsis. Male Wistar rats were divided into three groups of ten animals each: a negative control group (normal; NC); a group that underwent surgical procedures (sham); and a group that underwent cecal ligation and perforation (CLP). The induction of sepsis was confirmed by bacteremia, and the causative pathogen identified was Escherichia coli. Hematological parameters showed leukocytosis and thrombocytopenia in animals in the septic group. The results also revealed that there were significant (p < 0.05) increases in adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolyses, and in the deamination of adenosine in the CLP group compared to the sham and control groups. Conversely, ADP hydrolysis was significantly decreased (p < 0.05) in the CLP group compared to the sham and control groups. Purine levels were analyzed by high-performance liquid chromatography (HPLC) in serum samples from control, sham, and CLP groups. Increased concentrations of ATP, adenosine, and inosine were found in the CLP group compared to the sham and control groups. Conversely, the concentrations of ADP and AMP in the CPL group were not significantly altered. We suggest that alterations in hematological parameters, nucleotide hydrolysis in platelets, and nucleotide concentrations in serum samples of rats with induced sepsis may be related to thromboembolic events.

Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass.

BACKGROUND: Diabetic patients are associated with impaired peripheral microvascular function after cardiopulmonary bypass (CPB) and cardiac surgery. We hypothesized that upregulation of the inducible cyclooxygenase 2 (COX-2) contributes to altered microvascular reactivity of peripheral arterioles in diabetic patients undergoing CPB and cardiac surgery. METHODS: Skeletal muscle samples of nondiabetic (ND) patients and patients with diabetes mellitus (DM; n = 8 per group) undergoing cardiac surgery were harvested before and after CPB. The protein expression/localization of COX-2 was assayed by Western blotting and immunohistochemistry. Peripheral arterioles were dissected from the harvested skeletal muscle tissue samples, the isolated arterioles (80-180 µm) were cannulated and pressurized, and changes in diameter were measured with video microscopy. In-vitro relaxation responses of precontracted arterioles were examined in the presence of the endothelium-dependent vasodilator bradykinin (10-10 to 10-6M) and in the presence or absence of the selective COX-2 inhibitor NS398 (10-5M). RESULTS: The post-CPB protein levels of the inducible COX-2 were significantly increased compared with pre-CPB values in both the ND and DM groups (P < 0.05), whereas, this increase was higher in DM than that of ND (P < 0.05). In the DM arterioles, not the ND vessels, bradykinin-induced relaxation response was inhibited in the presence of the specific COX-2 inhibitor NS398 at baseline (P < 0.05). After CPB, bradykinin-induced relaxation response of the ND and DM arterioles was inhibited in the presence of the specific COX-2 inhibitor NS398, but this effect was more pronounced in the diabetic patients (P < 0.05). CONCLUSIONS: Diabetes and CPB are associated with upregulation in COX-2 expression/activation in human peripheral microvasculature. This alteration may lead to altered peripheral microvascular reactivity in diabetic patients undergoing cardiac surgery.

Reduced serum cholinesterase activity indicates splenic modulation of the sterile inflammation.

BACKGROUND: Sterile inflammation is an immediate and well-coordinated immune response to surgical injury. The cholinergic system plays a pivotal role in the inflammatory response. Induced inflammation stimulates the vagus nerve, which in turn activates anti-inflammatory nonneuronal processes. Serum cholinesterase (butyrylcholinesterase [BChE]) is an enzyme that hydrolyzes acetylcholine. Measuring the activity of the BChE in blood might indicate the level of the nonneuronal cholinergic activity. The spleen is a major organ of the immune system playing an important role during inflammation. A functional connection of the neuroimmune reflex has thus far been described only in experimental settings. MATERIALS AND METHODS: In 48 patients receiving major pancreatic surgery, BChE activity was measured by applying point-of-care-testing, in addition to standard laboratory tests. RESULTS: The BChE activity decreased in patients receiving surgery. This reduction emerged much earlier than changes in C-reactive protein concentration, an inflammatory biomarker broadly used in the clinical environment. A milder reduction in the BChE activity was observed in patients subjected to surgery with splenectomy than in those with a preserved spleen. CONCLUSIONS: The use of the point-of-care-testing system for quick bedside diagnostics and the rapid effects of inflammation on BChE levels provide a method and a marker to facilitate the early detection of systemic inflammation. Furthermore, this study provides evidence that the experimentally documented neuroimmune interaction is part of the physiological response to surgery-induced sterile inflammation. Splenic function plays an essential role in modulating the cholinergic anti-inflammatory response.

Dynamic changes of paraoxonase 1 activity towards paroxon and phenyl acetate during coronary artery surgery.

BACKGROUND: Serum paraoxonase 1 (PON1), an enzyme associated with high - density lipoproteins (HDL) particles, inhibits the oxidation of serum lipoproteins and cell membranes. PON1 activity is lower in patients with atherosclerosis and in inflammatory diseases. The systemic inflammatory response provoked during cardiopulmonary bypass grafting may contribute to the development of postoperative complications. The aim of the present study was to estimate the dynamic changes in paraoxonase 1 (PON1) activity towards paraoxon and phenyl acetate during and after coronary artery surgery. METHODS: Twenty six patients with coronary heart disease undergoing coronary artery bypass grafting (CABG) were enrolled into the study. Venous blood samples were obtained preoperatively, after aortic clumping, after the end of operation, at 6, 18, 30 and 48 h after operation. Paraoxonase activity was measured spectrophotometrically in 50 mM glycine/NaOH buffer (pH 10.5) containing 1.0 mM paraoxon, and 1.0 mM CaCl2. Arylesterase activity was measured in 20 mM TrisCl buffer (pH 8.0) containing 1 mM phenyl acetate and 1 mM CaCl2. RESULTS: PON1 activity toward paraoxon and phenyl acetate significantly decreased after aorta cross clumping and increased directly after operation. PON1 activity towards paraoxon in preoperative period and PON1 activity towards phenyl acetate in seventh stage of experiment tended to inversely correlate with the occurrence of postoperative complications. CONCLUSION: The paraoxonase 1 plasma activity is markedly reduced during CABG surgery.

Length Polymorphisms in Heme Oxygenase-1 and AKI after Cardiac Surgery.

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme, which may be involved in the pathogenesis of AKI. Length polymorphisms in the number of GT dinucleotide repeats in the HO-1 gene (HMOX1) promoter inversely associate with HMOX1 mRNA expression. We analyzed the association between allelic frequencies of GT repeats in the HMOX1 gene promoter and postoperative AKI in 2377 white patients who underwent cardiac surgery with cardiopulmonary bypass. We categorized patients as having the short allele (S; <27 GT repeats) or long allele (L; ≥27 GT repeats), and defined AKI as an increase in serum creatinine ≥0.3 mg/dl within 48 hours or ≥50% within 5 days, or the need for RRT. Compared with patients with the SS genotype, patients with the LL genotype had 1.58-fold (95% confidence interval, 1.06 to 2.34; P=0.02) higher odds of AKI. After adjusting for baseline and operative characteristics, the odds ratio for AKI per L allele was 1.26 (95% confidence interval, 1.05 to 1.50; P=0.01). In conclusion, longer GT repeats in the HMOX1 gene promoter associate with increased risk of AKI after cardiac surgery, consistent with heme toxicity as a pathogenic feature of cardiac surgery-associated AKI, and with HO-1 as a potential therapeutic target.

[Analysis of the Relationship between the Change of Drain Amylase Value and Postoperative Pancreatic Fistula after Pancreaticoduodenectomy].

To diagnose postoperative pancreatic fistula(POPF)after pancreaticoduodenectomy(PD)during early post operative days, we evaluatedwhether a change in drain amylase value(DAV), WBC value, or CRP value predicted clinically significant POPF. One hundred thirty patients underwent substomach preserving PD(SSPPD)from 2005 to 2016 in our institution andwe examinedDAV, WBC, andCRP values at POD 1, 3, and 5. Seventy-five patients(57.7%)were equivalent to ISGPF grade A at POD 3.We analyzedthese 75 cases by following 5 factors(DAV at POD 3>1,500 U/L, DAV at POD 5>1,000 U/L,WBC value at POD 5≤9,000/mL, DAV of POD 5 decreased to 1/3 from DAV of POD 3, CRP value not improved≥50%from POD 3 to 5) andwere concernedwith the crisis of the grade B/C POPF at final diagnosis after POD 5. In conclusion, DAV of POD 5 decreased to 1/3 from DAV of POD 3, andthe CRP value having not improved(≥50%from POD 3 to 5)were significant risk factors for POPF grade B andC by Cox proportional hazard models.

Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury.

Neuroinflammation plays an important role in the pathophysiology of surgical brain injury (SBI). Phosphoinositide 3-kinase gamma (PI3Kγ), predominately expressed in immune and endothelial cells, activates multiple inflammatory responses. In the present study, we investigated the role of PI3Kγ and PI3Kγ-activated phosphodiesterase 3B (PDE3B) in neuroinflammation in a rat model of SBI. One hundred and fifty-two male Sprague Dawley rats (weight 280-350 g) were subjected to a partial right frontal lobe corticotomy model of SBI. A PI3Kγ pharmacological inhibitor (AS252424 or AS605240) was administered intraperitoneally. PI3Kγ siRNA, human recombinant active-PI3Kγ protein, or human recombinant active-PDE3B protein were administered intracerebroventricularly. Post-SBI assessments included neurobehavioral tests, brain water content, Western blot, and immunohistochemistry. Endogenous PI3Kγ levels were increased within peri-resection brain tissues after SBI, accompanied by increased brain water content and neurological functional deficits. There was a trend toward increased endogenous PDE3B phosphorylation after SBI. The selective PI3Kγ inhibitors AS252424 and AS605240 reduced brain water content surrounding corticotomy and improved neurological function after SBI. SBI increased and PI3Kγ inhibitor decreased levels of myeloperoxidase, cluster of differentiation 3, mast cell degranulation, E-selectin, and IL-1 in peri-resection brain tissues. Direct administration of human recombinant active-PI3Kγ protein and active-PDE3B protein countered the protective effect of AS252424. PI3Kγ siRNA reduced PI3Kγ levels, decreased brain water content within peri-resection brain tissues, and improved neurological function after SBI. Collectively, our findings suggest that PI3Kγ contributed to neuroinflammation after SBI. The use of selective PI3Kγ inhibitors may be a novel approach to ameliorating SBI via their anti-inflammation effects. Significance statement: Life-saving or elective neurosurgeries often involve unavoidable damages to neighboring, nondiseased brain tissues. Such surgical brain injury (SBI) is attributable exclusively to the neurosurgical procedure itself and may cause postoperative complications that exacerbate neurological function. Although the importance of this medical problem is fully acknowledged, intraoperative administration of adjunctive treatment such as steroids and mannitol to patients undergoing neurosurgery appear not to be efficient remedies for SBI. To date, the issue of perioperative neuroprotection specifically against SBI has not been well studied. Using a clinically relevant rat model of SBI, we are exploring a new neuroprotective strategy targeting phosphoinositide 3-kinase gamma (PI3Kγ). PI3Kγ activates multiple inflammatory responses. By attenuating neuroinflammation, selective PI3Kγ inhibition would limit postoperative complications and benefit neurological outcomes.

Meta-analysis of drain amylase content on postoperative day 1 as a predictor of pancreatic fistula following pancreatic resection.

BACKGROUND: Drain amylase content in the days immediately after major pancreatic resection has been investigated previously as a predictor of postoperative pancreatic fistula (POPF). Its accuracy, however, has not been determined conclusively. The purpose of this study was to evaluate the accuracy of drain amylase content on the first day after major pancreatic resection in predicting the occurrence of POPF. METHODS: A literature search of the MEDLINE, Embase and Scopus(®) databases to 13 May 2015 was performed to identify studies evaluating the accuracy of drain amylase values on day 1 after surgery in predicting the occurrence of POPF. The area under the hierarchical summary receiver operating characteristic (ROC) curve (AUChSROC ) was calculated as an index of accuracy, and pooled estimates of accuracy indices (sensitivity and specificity) were calculated at different cut-off levels. Subgroup and meta-regression analyses were performed to test the robustness of the results. RESULTS: Thirteen studies involving 4416 patients were included. The AUChSROC was 0·89 (95 per cent c.i. 0·86 to 0·92) for clinically significant POPF and 0·88 (0·85 to 0·90) for POPF of any grade. Pooled estimates of sensitivity and specificity were calculated for the different cut-offs: 90-100 units/l (0·96 and 0·54 respectively), 350 units/l (0·91 and 0·84) and 5000 units/l (0·59 and 0·91). Accuracy was independent of the type of operation, type of anastomosis performed and octreotide administration. CONCLUSION: Evaluation of drain amylase content on the first day after surgery is highly accurate in predicting POPF following major pancreatic resection. It may allow early drain removal and institution of an enhanced recovery pathway.

NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice.

Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1ß (IL-1ß), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1ß, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice.

Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance.

Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by D-[6,6-²H2]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (∼34%, P<0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (V(ADP)) for pyruvate (∼61%, P<0.05, and ∼40%, P<0.001, respectively), whereas V(ADP) for glutamate and palmitoyl-L-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P<0.05) and IFM (2.5-fold, P<0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (∼32%, P<0.01) and positively correlated to the decline in peripheral insulin sensitivity (r=0.748, P<0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H2O2 and O2·â» emission was measured spectrofluorometrically, and H2O2 was increased in SSM, IFM, and liver mitochondria (∼2.3-, ∼2.5-, and ∼2.3-fold, respectively, all P<0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.