Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts.

AIMS: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE-/- mice with pressure overload. METHODS AND RESULTS: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE-/- background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE-/- mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE-/- mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1ß), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE-/- mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. CONCLUSION: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE-/- mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Hippo pathway activation mediates chemotherapy-induced anti-cancer effect and cardiomyopathy through causing mitochondrial damage and dysfunction.

Rationale: Chemotherapy is a common clinical strategy for cancer treatment. However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition. Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy. Methods and Results: In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis. Hippo pathway inactivation by Mst1-siRNA transfection effectively improved cell survival and mitigated mitochondrial damage and cell apoptosis. Another anti-cancer drug YAP inhibitor verteporfin also induced lower cancer cell viability, apoptosis and mitochondrial injury. Chronic treatment with DOX in vivo (4 mg/kg/week for 6 weeks) caused mitochondrial damage and dysfunction, oxidative stress and cardiac fibrosis, while acute DOX treatment (16 mg/kg single bolus) also induced myocardial oxidative stress and mitochondrial abnormalities. Chronic treatment with verteporfin (2 months) resulted in cardiomyopathy phenotypes comparable to that by chronic DOX regimen. In transgenic mice with cardiac overexpression of kinase-dead mutant Mst1 gene, these adverse cardiac effects of DOX were significantly attenuated relative to wild-type littermates. Conclusions: Anti-cancer action of both DOX and verteporfin is associated with Hippo pathway activation. Such action on cardiac Hippo pathway mediates mitochondrial damage and cardiomyopathy.

Pathogenetic Link of Cardiac Rupture and Left Ventricular Thrombus Following Acute Myocardial Infarction: A Joint Preclinical and Clinical Study.

Background: Cardiac rupture (CR) and left ventricular thrombus (LVT) remain important complications of acute myocardial infarction (MI), and they are currently regarded as independent events. We explored the pathogenetic link between CR and LVT by investigating a murine model of MI with a high frequency of CR and in patients with acute MI. Methods: MI was induced in mice, the onset of CR was monitored, and the hearts of mice with or without fatal CR were histologically examined. Between 2015 and 2022, from patients admitted due to acute MI, the data of patients with CR or LVT were retrospectively collected and compared to uncomplicated patients (control). Results: A total of 75% of mice (n = 65) with MI developed CR 2-4 days after MI. A histological examination of CR hearts revealed the existence of platelet-rich intramural thrombi in the rupture tunnel, which was connected at the endocardial site to platelet-fibrin thrombi within an LVT. In CR or non-CR mouse hearts, LV blood clots often contained a portion of platelet-fibrin thrombi that adhered to the infarct wall. In non-CR hearts, sites of incomplete CR or erosion of the infarct wall were typically coated with platelet thrombi and dense inflammatory cells. Of 8,936 patients with acute MI, CR and LVT occurred in 102 (1.14%) and 130 (1.45%) patients, respectively, with three cases having both complications. CR accounted for 32.8% of in-hospital deaths. The majority of CR (95%) or LVT (63%, early LVT) occurred within 7 days. In comparison to the control or LVT-late groups, patients with CR or early LVT reported increased levels of cellular and biochemical markers for inflammation or cardiac injury. Conclusion: CR and LVT after MI are potentially linked in their pathogenesis. LVT occurring early after MI may be triggered by a thrombo-inflammatory response following wall rupture or endocardial erosion.

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice.

Rationale: Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM). Methods: Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed. Results: In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets. Conclusion: Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.

The capacity for psychotherapy process scale: development and psychometric validation of patient self-reports.

Objective: Studies were conducted to develop and validate the Capacity for Psychotherapy Process Scale (CFPPS), a self-rating measure of capacity for the psychotherapy process from a trans-theoretical perspective. Method: In Study 1, a two-round Delphi methodology consulting 27 and 15 experts, respectively, was used to select items and identify content validity. In Study 2, 279 clients were recruited for exploratory factor analysis (EFA). In Study 3, confirmatory factor analysis and internal consistency analysis were conducted among 390 outpatients; the discriminant validity and predictive validity were studied in 270 outpatients and 82 psychotherapy outpatients, respectively. Results: The Delphi method resulted in 52 items. Through EFA, the CFPPS was reduced to 20 items, focusing on five factors: motivation, belief, self-revelation, persistence, and insight; the internal consistencies were good (0.92 for total scale and 0.82-0.91 for the factors). The CFPPS was not or was only weakly associated with symptoms. The Bonferroni-corrected partial correlation analyses revealed that the CFPPS was positively related to working alliance and session impact. Conclusions: The CFPPS is a preliminary step toward the self-report assessment of the capacity for psychotherapy process from a trans-theoretical perspective and may potentially be used to predict the working alliance and session impact.

AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice.

The opening of endothelial small-conductance calcium-activated potassium channels (KCa2.3) is essential for endothelium-dependent hyperpolarization (EDH), which predominantly occurs in small resistance arteries. Adenosine monophosphate-activated protein kinase (AMPK), an important metabolic regulator, has been implicated in regulating endothelial nitric oxide synthase activity. However, it was unclear whether AMPK regulated endothelial KCa2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of KCa2.3 in human umbilical vein endothelial cells (HUVECs) or mouse second-order mesenteric resistance arteries. In HUVECs, AMPK activation either by activators (AICAR, A769662 and MK-8722) or expression of the constitutively active form of AMPK significantly upregulated KCa2.3 expression. Such effects were abolished by AMPK inhibitor (compound C) or AMPK α1-/α2-siRNA, extracellular-signal-regulated-kinase 5 (ERK5) inhibitor (ERK5-IN-1), and specific siRNA to myocyte-enhancer factor 2 (MEF2) or krüppel-like factor 2/4 (KLF2/4). KCa2.3 expression was significantly reduced in mesenteric resistance arteries in AMPKα2 knockout mice when compared with littermate control mice. Furthermore, in high-fat diet fed mice, 2-week treatment with AICAR restored endothelial KCa2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates KCa2.3 channel expression through the ERK5-MEF2-KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through KCa2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.

Cardiac ß-adrenergic receptor activation mediates distinct and cell type-dependent changes in the expression and distribution of connexin 43.

Activation of the sympatho-ß-adrenergic receptors (ß-ARs) system is a hallmark of heart failure, leading to fibrosis and arrhythmias. Connexin 43 (Cx43) is the most abundant gap junctional protein in the myocardium. Current knowledge is limited regarding Cx43 remodelling in diverse cell types in the diseased myocardium and the underlying mechanism. We studied cell type-dependent changes in Cx43 remodelling due to ß-AR overactivation and molecular mechanisms involved. Mouse models of isoproterenol stimulation or transgenic cardiomyocyte overexpression of ß2 -AR were used, which exhibited cardiac fibrosis and up-regulated total Cx43 abundance. In both models, whereas Cx43 expression in cardiomyocytes was reduced and more laterally distributed, fibroblasts exhibited elevated Cx43 expression and enhanced gap junction communication. Mechanistically, activation of ß2 -AR in fibroblasts in vitro elevated Cx43 expression, which was abolished by the ß2 -antagonist ICI-118551 or protein kinase A inhibitor H-89, but simulated by the adenylyl cyclase activator forskolin. Our in vitro and in vivo data showed that ß-AR activation-induced production of IL-18 sequentially stimulated Cx43 expression in fibroblasts in a paracrine fashion. In summary, our findings demonstrate a pivotal role of ß-AR in mediating distinct and cell type-dependent changes in the expression and distribution of Cx43, leading to pathological gap junction remodelling in the myocardium.

Gal-3 (Galectin-3) and KCa3.1 Mediate Heterogeneous Cell Coupling and Myocardial Fibrogenesis Driven by ßAR (ß-Adrenoceptor) Activation.

Heart failure is associated with sympatho-ßAR (ß-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and KCa3.1 channels that are upregulated in diverse cells of diseased heart are implicated in mediating myocardial inflammation and fibrosis. It remains unclear whether Gal-3 interacts with KCa3.1 leading to cardiac fibrosis in the setting of ßAR activation. We tested the effect of KCa3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted ß2-TG (ß2AR overexpressed transgenic) mice and determined KCa3.1 expression in ß2-TG×Gal-3-/- mouse hearts. Mechanisms of KCa3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and KCa3.1 was elevated in ß2-TG hearts. Gal-3 gene deletion in ß2-TG mice decreased KCa3.1 expression in inflammatory cells but not in fibroblasts. Treatment of ß2-TG mice with TRAM-34 for 1 or 2 months significantly ameliorated cardiac inflammation and fibrosis and reduced Gal-3 level. In cultured fibroblasts, Gal-3 upregulated KCa3.1 expression and channel currents with enhanced membrane potential and Ca2+ entry through TRPV4 (transient receptor potential V4) and TRPC6 (transient receptor potential C6) channels leading to fibroblast activation. In conclusion, ßAR stimulation promotes Gal-3 production that upregulates KCa3.1 channels in noncardiomyocyte cells and activates KCa3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca2+ entry via TRP channels. Gal-3-KCa3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.

KCa3.1 channel mediates inflammatory signaling of pancreatic ß cells and progression of type 2 diabetes mellitus.

Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate-conductance calcium-activated K+ (KCa3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of KCa3.1 in pancreatic ß cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific KCa3.1 channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of KCa3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of ß-cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic ß cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the KCa3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM-34 or a NF-κB inhibitor pyrrolidinedithiocarbamate. Additionally, expression of KCa3.1 in pancreas islet cells was up-regulated by activation of NF-κB with IL-1ß stimulation. In summary, up-regulated KCa3.1 due to activation of NF-κB pathway leads to pancreatic inflammation via expression and secretion of chemokines and cytokines by pancreatic ß cells, thereby facilitating progression of T2DM.-Pang, Z.-D., Wang, Y., Wang, X.-J., She, G., Ma, X.-Z., Song, Z., Zhao, L.-M., Wang, H.-F., Lai, B.-C., Gou, W., Du, X.-J., Deng, X.-L. KCa3.1 channel mediates inflammatory signaling of pancreatic ß cells and progression of type 2 diabetes mellitus.

Oxidative stress induced by palmitic acid modulates KCa2.3 channels in vascular endothelium.

Elevated plasma free fatty acids level has been implicated in the development of insulin resistance, inflammation, and endothelial dysfunction in diabetic and nondiabetic individuals. However, the underlying mechanisms still remain to be defined. Herein, we investigated the effect of palmitic acid (PA), the most abundant saturated fatty acid in the human body, on small-conductance Ca2+-activated potassium channels (KCa2.3)-mediated relaxation in rodent resistance arteries and the underlying molecular mechanism. The effect of PA on KCa2.3 in endothelium was evaluated using real-time PCR, Western blotting, whole-cell patch voltage-clamp, wire and pressure myograph system, and reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. KCa2.3-mediated vasodilatation responses to acetylcholine and NS309 (agonist of KCa2.3 and KCa3.1) were impaired by incubation of normal mesenteric arteries with 100 µM PA for 24 h. In cultured human umbilical vein endothelial cells (HUVECs), PA decreased KCa2.3 current and expression at mRNA and protein levels. Incubation with the NADPH oxidase (Nox) inhibitor dibenziodolium (DPI) partly inhibited the PA-induced ROS production and restored KCa2.3 expression. Inhibition of either p38-MAPK or NF-κB using specific inhibitors (SB203580, SB202190 or Bay11-7082, pyrrolidinedithiocarbamate) attenuated PA-induced downregulation of KCa2.3 and inhibition of p38-MAPK also attenuated PA-induced phosphorylation of NF-κB p65. Furthermore, DPI reversed the increment of phospho-p38-MAPK by PA. These results demonstrated that PA downregulated KCa2.3 expressions via Nox/ROS/p38-MAPK/NF-κB signaling leading to endothelial vasodilatory dysfunction.

KCa3.1 Channels Promote Cardiac Fibrosis Through Mediating Inflammation and Differentiation of Monocytes Into Myofibroblasts in Angiotensin II -Treated Rats.

Background Cardiac fibrosis is a core pathological process associated with heart failure. The recruitment and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. The KCa3.1 channels are expressed in both ventricular fibroblasts and circulating mononuclear cells in rats and are upregulated by angiotensin II . We hypothesized that KCa3.1 channels mediate the inflammatory microenvironment in the heart, promoting the infiltrated bone marrow-derived circulating mononuclear cells to differentiate into myofibroblasts, leading to myocardial fibrosis. Methods and Results We established a cardiac fibrosis model in rats by infusing angiotensin II to evaluate the impact of the specific KCa3.1 channel blocker TRAM -34 on cardiac fibrosis. At the same time, mouse CD 4+ T cells and rat circulating mononuclear cells were separated to investigate the underlying mechanism of the TRAM -34 anti-cardiac fibrosis effect. TRAM -34 significantly attenuated cardiac fibrosis and the inflammatory reaction and reduced the number of fibroblast precursor cells and myofibroblasts. Inhibition of KCa3.1 channels suppressed angiotensin II -stimulated expression and secretion of interleukin-4 and interleukin-13 in CD 4+ T cells and interleukin-4- or interleukin-13-induced differentiation of monocytes into fibrocytes. Conclusions KCa3.1 channels facilitate myocardial inflammation and the differentiation of bone marrow-derived monocytes into myofibroblasts in cardiac fibrosis caused by angiotensin II infusion.

Effect of Cognitive Behavioral Therapy Versus Interpersonal Psychotherapy in Patients with Major Depressive Disorder: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Practice guidelines have recommended cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) as the treatment of choice for major depression disorder (MDD). However, whether one therapy is better than the other remains inconclusive. The aim of this study was to compare the treatment efficacy of the two treatment approaches for MDD. METHODS: Using the terms "cognitive behavior therapy or cognitive therapy or CBT or CT or cognitive behavioral therapy" and "interpersonal psychotherapy or IPT," we systematically searched PubMed, Psyclnfo and Chinese National Knowledge Infrastructure databases up to February 2017. The language was restricted to be English and Chinese. Therapeutic outcomes, characteristics, and research quality were then extracted and analyzed independently. In accessing the included studies, we followed the criteria suggested by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Data for 946 patients from 10 randomized controlled trials were included in the study. Methodological quality was not optimal in most trials. Meta-analysis showed a mean difference (MD) of -1.31, 95% confidence interval (CI) (-2.49, -0.12) (P < 0.05) in favor of CBT according to the Beck Depression Inventory (BDI), and however, we did not found any statistically significant difference between CBT and IPT on the Hamilton Rating Scale for depression (HRSD) (MD -0.90, 95% CI [-2.18, 0.38]). Subgroup analyses for the studies in which patients were treated only by psychotherapy (MD -1.26, 95% CI [-2.78, 0.35]) and for those which offered more sessions of therapies (MD -0.82, 95% CI [-2.23, 0.59]) showed there was no significant difference between CBT and IPT according to BDI. CONCLUSIONS: Differences in treatment efficacy seem to vary according to different outcome measures. CBT shows an advantage over IPT for MDD according to BDI, and there is no significant difference between the two according to HRSD. These results should be interpreted with caution.

Tyrphostin AG556 increases the activity of large conductance Ca2+ -activated K+ channels by inhibiting epidermal growth factor receptor tyrosine kinase.

The present study was designed to investigate whether large conductance Ca2+ -activated K+ (BK) channels were regulated by epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase. BK current and channel tyrosine phosphorylation level were measured in BK-HEK 293 cells expressing both functional α-subunits and the auxiliary ß1-subunits using electrophysiology, immunoprecipitation and Western blotting approaches, respectively, and the function of rat cerebral basilar arteries was determined with a wire myography system. We found that BK current in BK-HEK 293 cells was increased by the broad spectrum protein tyrosine kinase (PTK) inhibitor genistein and the selective EGFR tyrosine kinase inhibitor AG556, one of the known tyrphostin. The effect of genistein or AG556 was antagonized by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. On the other hand, orthovanadate or EGF decreased BK current, and the effect was counteracted by AG556. The tyrosine phosphorylation level of BK channels (α- and ß1-subunits) was increased by EGF and orthovanadate, while decreased by genistein and AG556, and the reduced tyrosine phosphorylation of BK channels by genistein or AG556 was reversed by orthovanadate. Interestingly, AG556 induced a remarkable enhancement of BK current in rat cerebral artery smooth muscle cells and relaxation of pre-contracted rat cerebral basilar arteries with denuded endothelium, and these effects were antagonized by the BK channel blocker paxilline or orthovanadate. These results demonstrate that tyrosine phosphorylation of BK channels by EGFR kinase decreases the channel activity, and inhibition of EGFR kinase by AG556 enhances the channel activity and dilates rat cerebral basilar arteries.

Effect of Cognitive Behavioral Therapy Versus Interpersonal Psychotherapy in Patients with Major Depressive Disorder: A Meta-analysis of Randomized Controlled Trials / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Practice guidelines have recommended cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) as the treatment of choice for major depression disorder (MDD). However, whether one therapy is better than the other remains inconclusive. The aim of this study was to compare the treatment efficacy of the two treatment approaches for MDD.</p><p><b>METHODS</b>Using the terms "cognitive behavior therapy or cognitive therapy or CBT or CT or cognitive behavioral therapy" and "interpersonal psychotherapy or IPT," we systematically searched PubMed, Psyclnfo and Chinese National Knowledge Infrastructure databases up to February 2017. The language was restricted to be English and Chinese. Therapeutic outcomes, characteristics, and research quality were then extracted and analyzed independently. In accessing the included studies, we followed the criteria suggested by the Cochrane Handbook for Systematic Reviews of Interventions.</p><p><b>RESULTS</b>Data for 946 patients from 10 randomized controlled trials were included in the study. Methodological quality was not optimal in most trials. Meta-analysis showed a mean difference (MD) of -1.31, 95% confidence interval (CI) (-2.49, -0.12) (P < 0.05) in favor of CBT according to the Beck Depression Inventory (BDI), and however, we did not found any statistically significant difference between CBT and IPT on the Hamilton Rating Scale for depression (HRSD) (MD -0.90, 95% CI [-2.18, 0.38]). Subgroup analyses for the studies in which patients were treated only by psychotherapy (MD -1.26, 95% CI [-2.78, 0.35]) and for those which offered more sessions of therapies (MD -0.82, 95% CI [-2.23, 0.59]) showed there was no significant difference between CBT and IPT according to BDI.</p><p><b>CONCLUSIONS</b>Differences in treatment efficacy seem to vary according to different outcome measures. CBT shows an advantage over IPT for MDD according to BDI, and there is no significant difference between the two according to HRSD. These results should be interpreted with caution.</p>

Diagnosis and Management of High-Grade Pancreatic Trauma: Report of 14 Cases.

The aim of this study was to review the diagnosis and operative management of cases of high-grade pancreatic trauma. A retrospective analysis was performed on 14 patients treated for high-grade pancreatic trauma at our institution between December 2008 and November 2013. The patients were treated for injuries resulting from blunt abdominal trauma. The main clinical data of the patients was analyzed, including time to diagnosis, initial serum amylase level, ultrasonography and abdominal computed tomography (CT) findings, pancreatic injury severity as scored according to the American Association for the Surgery of Trauma Organ Injury Scale, injury to other organs, operative treatment method, postoperative complications, and patient outcome. All 14 patients were diagnosed with severe (≥ grade III) pancreatic trauma. Diagnosis was confirmed in all seven hemodynamically stable patients that underwent CT and in 9/13 patients receiving ultrasound examination. All patients underwent surgical operations, including emergency pancreaticoduodenectomy (n = 8), splenectomy with distal pancreatectomy (n = 3), spleen-preserving distal pancreatectomy (n = 1), medial pancreatectomy with Roux-en-Y pancreaticojejunostomy (n = 1), and peripancreatic debridement and drainage (n = 1). Diagnosis was delayed beyond 24 h in two patients, both of whom underwent reoperative peripancreatic debridement and drainage, with one death. The complications included pancreatic fistula (n = 8), peripancreatic abscess (n = 2), hepatic artery hemorrhage (n = 1), gastrointestinal bleeding (n = 1), and intra-abdominal abscess (n = 1). CT is the most reliable method for diagnosing high-grade pancreatic trauma. Aggressive surgical therapy including pancreaticoduodenectomy is acceptable in hemodynamically stable patients.