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p53 is a tumor suppressor protein with a very low content in the basal condition, but the content rapidly rises during stress conditions including ischemia-reperfusion. An increase in p53 content increases cardiac injury during ischemia-reperfusion. Since mitochondrial damage plays a key role in cardiac injury during ischemia-reperfusion, we asked if genetic ablation of p53 decreases cardiac injury by protecting mitochondria. Isolated, perfused hearts from cardiac specific p53 deletion or wild type underwent 25 min global ischemia at 37 °C and 60 min reperfusion. At the end of reperfusion, hearts were harvested for infarct size measurement. In separate groups, cardiac mitochondria were isolated at 30 min reperfusion. Time control hearts were buffer-perfused without ischemia. Compared to wild type, deletion of p53 improved cardiac functional recovery and decreased infarct size following ischemia-reperfusion. Oxidative phosphorylation was improved in p53 deletion mitochondria following ischemia-reperfusion compared to wild type. The net release of ROS generation from wild type but not in p53 deletion mitochondria was increased following ischemia-reperfusion. Peroxiredoxin 3 (PRDX 3) content was higher in p53 deletion than that in wild type, indicating that p53 deletion increases a key antioxidant. Ischemia-reperfusion led to increased spectrin cleavage (a marker of cytosolic calpain1 activation) in wild type but not in p53 deletion mice. Ischemia-reperfusion increased the truncation of mature AIF (apoptosis inducing factor, an indicator of mitochondrial calpain1 activation) in wild type but not in p53 deletion mice. The loss of cytochrome c from mitochondria was also decreased in p53 deletion following ischemia-reperfusion. Bcl-2 content was decreased in wild type but not in p53 deletion following reperfusion, suggesting that depletion of bcl-2 contributes to permeabilization of the mitochondrial outer membrane. Thus, deletion of p53 decreases cardiac injury by protecting mitochondria through attenuation of oxidative stress and calpain activation during ischemia-reperfusion.

Objectives: Because of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity. Background: The use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity. Methods: After baseline echocardiography, adult male CD1 mice were randomized to either sham or RIPC protocol (3 cycles of 5 min femoral artery occlusion followed by 5 min reperfusion) 1 h before receiving DOX (20 mg/kg, intraperitoneal). The mice were observed primarily for survival over 85 days (86 mice). An additional cohort of 50 mice was randomized to either sham or RIPC 1 h before DOX treatment and was followed for 25 days, at which time cardiac fibrosis, apoptosis, and mitochondrial oxidative phosphorylation were assessed, as well as the expression profiles of apoptosis and autophagy markers. Results: Survival was significantly improved in the RIPC cohort compared with the sham cohort (p = 0.007). DOX-induced cardiac fibrosis and apoptosis were significantly attenuated with RIPC compared with sham (p < 0.05 and p < 0.001, respectively). Although no mitochondrial dysfunction was detected at 25 days, there was a significant increase in autophagy markers with DOX that was attenuated with RIPC. Moreover, DOX caused a 49% decline in cardiac BCL2/BAX expression, which was restored with RIPC (p < 0.05 vs. DOX). DOX also resulted in a 17% reduction in left ventricular mass at 25 days, which was prevented with RIPC (p < 0.01), despite the lack of significant changes in left ventricular ejection fraction. Conclusions: Our preclinical results suggested that RIPC before DOX administration might be a promising approach for attenuating DOX cardiotoxicity.

Activation of calpain 1 (CPN1) and calpain 2 (CPN2) contributes to cardiac injury during ischemia (ISC) and reperfusion (REP). Complex I activity is decreased in heart mitochondria following ISC-REP. CPN1 and CPN2 are ubiquitous calpains that exist in both cytosol (cs)-CPN1 and 2 and mitochondria (mit)-CPN1 and 2. Recent work shows that the complex I subunit (NDUFS7) is a potential substrate of the mit-CPN1. We asked whether ISC-REP led to decreased complex I activity via proteolysis of the NDUFS7 subunit via activation of mit-CPN1 and -2. Activation of cs-CPN1 and -2 decreases mitophagy in hepatocytes following ISC-REP. We asked whether activation of cs-CPN1 and -2 impaired mitophagy in the heart following ISC-REP. Buffer-perfused rat hearts underwent 25 min of global ISC and 30 min of REP. MDL-28170 (MDL; 10 µM) was used to inhibit CPN1 and -2. Cytosol, subsarcolemmal mitochondria (SSM), and interfibrillar mitochondria (IFM) were isolated at the end of heart perfusion. Cardiac ISC-REP led to decreased complex I activity with a decrease in the content of NDUFS7 in both SSM and IFM. ISC-REP also resulted in a decrease in cytosolic beclin-1 content, a key component of the autophagy pathway required to form autophagosomes. MDL treatment protected the contents of cytosolic beclin-1 and mitochondrial NDUFS7 in hearts following ISC-REP. These results support that activation of both cytosolic and mitochondrial calpains impairs mitochondria during cardiac ISC-REP. Mitochondria-localized calpains impair complex I via cleavage of a key subunit. Activation of cytosolic calpains contributes to mitochondrial dysfunction by impairing removal of the impaired mitochondria through depletion of a key component of the mitophagy process.

Aging impairs mitochondrial function that leads to greater cardiac injury during ischemia and reperfusion. Cardiac endoplasm reticulum (ER) stress increases with age and contributes to mitochondrial dysfunction. Metformin is an anti-diabetic drug that protects cardiac mitochondria during acute ER stress. We hypothesized that metformin treatment would improve preexisting mitochondrial dysfunction in aged hearts by attenuating ER stress, followed by a decrease in cardiac injury during subsequent ischemia and reperfusion. Male young (3 mo.) and aged mice (24 mo.) received metformin (300 mg/kg/day) dissolved in drinking water with sucrose (0.2 g/100 ml) as sweetener for two weeks versus sucrose vehicle alone. Cytosol, subsarcolemmal (SSM), and interfibrillar mitochondria (IFM) were isolated. In separate groups, cardioprotection was evaluated using ex vivo isolated heart perfusion with 25 min. global ischemia and 60 min. reperfusion. Infarct size was measured. The contents of CHOP and cleaved ATF6 were decreased in metformin-treated 24 mo. mice compared to vehicle, supporting a decrease in ER stress. Metformin treatment improved OXPHOS in IFM in 24 mo. using a complex I substrate. Metformin treatment decreased infarct size following ischemia-reperfusion. Thus, metformin feeding decreased cardiac injury in aged mice during ischemia-reperfusion by improving pre-ischemic mitochondrial function via inhibition of ER stress.

Objectives The management of closed diaphyseal humerus fractures in the polytrauma patient varies widely. The aim of this study was to compare outcomes of operative and nonoperative management in this patient population. Design Single-center, retrospective cohort analysis. Setting Urban, Level 1 trauma center. Patients Seventy-one patients with closed diaphyseal humerus fractures, and Injury Severity Score (ISS) of ≥17, treated between 2006 and 2011 were identified. Intervention Patients were treated operatively versus nonoperatively with a functional brace by surgeon preference. Main outcomes Primary outcome was union. Secondary outcomes included time to union, time to release to weightbearing, and complications other than nonunion. Results There was no statistical difference between age, Injury Severity Score, or fracture type between the 2 cohorts. There was a statistically higher incidence of associated orthopaedic injury, and more specifically, lower extremity injury in the group treated with operative intervention. There was no difference in union rates (95% operative, 94% nonoperative), time to union (17 weeks operative, 15 weeks nonoperative), or complication rates between the 2 groups. Time to release to weightbearing was 3 weeks shorter in the operative group (9.3 weeks operative, 12.8 weeks nonoperative). Conclusions Polytrauma patients with closed diaphyseal humerus fractures can be treated successfully with equivalent union rates, time to union, and complication rates when selected for conservative management techniques. The decision to undertake operative management of closed diaphyseal humerus fractures in the polytraumatized patient is multifaceted and should consider patient expectations, demographics, injury profile, and ambulatory status. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Transient, reversible blockade of complex I during early reperfusion after ischemia limits cardiac injury. We studied the cardioprotection of high dose of metformin in cultured cells and mouse hearts via the novel mechanism of acute downregulation of complex I. The effect of high dose of metformin on complex I activity was studied in isolated heart mitochondria and cultured H9c2 cells. Protection with metformin was evaluated in H9c2 cells at reoxygenation and at early reperfusion in isolated perfused mouse hearts and in vivo regional ischemia reperfusion. Acute, high-dose metformin treatment inhibited complex I in ischemia-damaged mitochondria and in H9c2 cells following hypoxia. Accompanying the complex I modulation, high-dose metformin at reoxygenation decreased death in H9c2 cells. Acute treatment with high-dose metformin at the end of ischemia reduced infarct size following ischemia reperfusion in vitro and in vivo, including in the AMP kinase-dead mouse. Metformin treatment during early reperfusion improved mitochondrial calcium retention capacity, indicating decreased permeability transition pore (MPTP) opening. Acute, high-dose metformin therapy decreased cardiac injury through inhibition of complex I accompanied by attenuation of MPTP opening. Moreover, in contrast to chronic metformin treatment, protection by acute, high-dose metformin is independent of AMP-activated protein kinase activation. Thus, a single, high-dose metformin treatment at reperfusion reduces cardiac injury via modulation of complex I.

Background Duchenne muscular dystrophy (DMD) is the most frequently inherited human myopathy and represents the most devastating type of muscular dystrophy. This progressive disease is caused by X-...

Severity of cardiovascular disease increases markedly in elderly patients. In addition, many therapeutic strategies that decrease cardiac injury in adult patients are invalid in elderly patients. Thus, it is a challenge to protect the aged heart in the context of underlying chronic or acute cardiac diseases including ischemia-reperfusion injury. The cause(s) of this age-related increased damage remain unknown. Aging impairs the function of the mitochondrial electron transport chain (ETC), leading to decreased energy production and increased oxidative stress due to generation of reactive oxygen species (ROS). Additionally, ROS-induced oxidative stress can increase cardiac injury during ischemia-reperfusion by potentiating mitochondrial permeability transition pore (MPTP) opening. Aging leads to increased endoplasmic reticulum (ER) stress, which contributes to mitochondrial dysfunction, including reduced function of the ETC. The activation of both cytosolic and mitochondrial calcium-activated proteases termed calpains leads to mitochondrial dysfunction and decreased ETC function. Intriguingly, mitochondrial ROS generation also induces ER stress, highlighting the dynamic interaction between mitochondria and ER. Here, we discuss the role of ER stress in sensitizing and potentiating mitochondrial dysfunction in response to ischemia-reperfusion, and the promising potential therapeutic benefit of inhibition of ER stress and / or calpains to attenuate cardiac injury in elderly patients.

Background ER (endoplasmic reticulum) stress leads to decreased complex I activity in cardiac mitochondria. The aim of the current study is to explore the potential mechanisms by which ER stress leads to the complex I defect. ER stress contributes to intracellular calcium overload and oxidative stress that are two key factors to induce mitochondrial dysfunction. Since oxidative stress is often accompanied by intracellular calcium overload during ER stress in vivo, the role of oxidative stress and calcium overload in mitochondrial dysfunction was studied using in vitro models. ER stress results in intracellular calcium overload that favors activation of calcium-dependent calpains. The contribution of mitochondrial calpain activation in ER stress-mediated complex I damage was studied. Methods Thapsigargin (THAP) was used to induce acute ER stress in H9c2 cells and C57BL/6 mice. Exogenous calcium (25 μM) and H2O2 (100 μM) were used to induce modest calcium overload and oxidative stress in isolated mitochondria. Calpain small subunit 1 (CAPNS1) is essential to maintain calpain 1 and calpain 2 (CPN1/2) activities. Deletion of CAPNS1 eliminates the activities of CPN1/2. Wild type and cardiac-specific CAPNS1 deletion mice were used to explore the role of CPN1/2 activation in calcium-induced mitochondrial damage. Results In isolated mitochondria, exogenous calcium but not H2O2 treatment led to decreased oxidative phosphorylation, supporting that calcium overload contributes a key role in the mitochondrial damage. THAP treatment of H9c2 cells decreased respiration selectively with complex I substrates. THAP treatment activated cytosolic and mitochondrial CPN1/2 in C57BL/6 mice and led to degradation of complex I subunits including NDUFS7. Calcium treatment decreased NDUFS7 content in wild type but not in CAPNS1 knockout mice. Conclusion ER stress-mediated activation of mitochondria-localized CPN1/2 contributes to complex I damage by cleaving component subunits.

Air embolism is a rare, often misdiagnosed, potentially fatal condition. It is most frequently associated with invasive vascular procedures and mechanical ventilation. Air emboli developing from peripheral intravenous lines are uncommon. We present a case of symptomatic venous air embolism likely arising from peripheral intravenous access gained during an interventional pain procedure. This case highlights the need to consider air embolism in the differential diagnoses of patients presenting with neurological symptoms following vascular interventions.

Oesophageal and gastric adenocarcinoma (OGA) treatment remains challenging. Improvements in early diagnosis, staging and management might have contributed to survival prolongation. To examine this hypothesis, we assessed outcomes of resected OGA patients in our institution over 10 years, comparing two time periods, 2001–2005 and 2006–2010. Records from patients who had undergone surgery with radical intent and follow-up for OGA were retrospectively reviewed. Patients followed up at hospitals other than the Royal Marsden Hospital were excluded. Two different cohorts were identified: patients with oesophageal and type I or type II oesophagogastric junction (OGJ) tumours, and patients with gastric and type III OGJ tumours. We identified 360 patients: 147 from 2001–2005 and 213 from 2006–2010. The characteristics were comparable across the two time periods. Between 2001–2005 and 2006–2010, the percentage of R0 resections increased (from 67.1 to 81.1 % for proximal tumours and from 76.3 to 95.9 % for gastric and type III OGJ tumours). The mean number of lymph nodes retrieved increased over time. The 5-year overall survival rate increased significantly from 42.3 to 56.6 % for proximal tumours and from 38.8 to 55.3 % for gastric and type III OGJ tumours. Similarly, the disease-free survival rate significantly increased from 34.6 to 53.5 % for proximal tumours and from 35.9 to 51.1 % for gastric and type III OGJ tumours. This study comprehensively describes the improvement in survival outcomes in a major UK referral centre over a 10-year period, identifying potentially relevant factors such as increased number of R0 resections and higher lymph node yield.

Cardiac ischemia-reperfusion (I/R) damages the electron transport chain (ETC), causing mitochondrial and cardiomyocyte injury. Reversible blockade of the ETC at complex I during ischemia protects the ETC and decreases cardiac injury. In the present study, we used an unbiased proteomic approach to analyze the extent of ETC-driven mitochondrial injury during I/R. Isolated-perfused mouse (C57BL/6) hearts underwent 25-min global ischemia (37°C) and 30-min reperfusion. In treated hearts, amobarbital (2 mM) was given for 1 min before ischemia to rapidly and reversibly block the ETC at complex I. Mitochondria were isolated at the end of reperfusion and subjected to unbiased proteomic analysis using tryptic digestion followed by liquid chromatography-mass spectrometry with isotope tags for relative and absolute quantification. Amobarbital treatment decreased cardiac injury and protected respiration. I/R decreased the content ( P < 0.05) of multiple mitochondrial matrix enzymes involved in intermediary metabolism compared with the time control. The contents of several enzymes in fatty acid oxidation were decreased compared with the time control. Blockade of ETC during ischemia largely prevented the decreases. Thus, after I/R, not only the ETC but also multiple pathways of intermediary metabolism sustain damage initiated by the ETC. If these damaged mitochondria persist in the myocyte, they remain a potent stimulus for ongoing injury and the transition to cardiomyopathy during prolonged reperfusion. Modulation of ETC function during early reperfusion is a key strategy to preserve mitochondrial metabolism and to decrease persistent mitochondria-driven injury during longer periods of reperfusion that predispose to ventricular dysfunction and heart failure.NEW & NOTEWORTHY Ischemia-reperfusion (I/R) damages mitochondria, which could be protected by reversible blockade of the electron transport chain (ETC). Unbiased proteomics with isotope tags for relative and absolute quantification analyzed mitochondrial damage during I/R and found that multiple enzymes in the tricarboxylic acid cycle, fatty acid oxidation, and ETC decreased, which could be prevented by ETC blockade. Strategic ETC modulation can reduce mitochondrial damage and cardiac injury.

Endoplasmic reticulum (ER) stress, a disturbance of the ER function, contributes to cardiac injury. ER and mitochondria are closely connected organelles within cells. ER stress contributes to mitochondrial dysfunction, which is a key factor to increase cardiac injury. Metformin, a traditional anti-diabetic drug, decreases cardiac injury during ischemia-reperfusion. Metformin also inhibits ER stress in cultured cells. We hypothesized that metformin can attenuate the ER stress-induced mitochondrial dysfunction and subsequent cardiac injury. Thapsigargin (THAP, 3 mg/kg) was used to induce ER stress in C57BL/6 mice. Cell injury and mitochondrial function were evaluated in the mouse heart 48 hours after 1-time THAP treatment. Metformin was dissolved in drinking water (0.5 g/250 ml) and fed to mice for 7 days before THAP injection. Metformin feeding continued after THAP treatment. THAP treatment increased apoptosis in mouse myocardium compared to control. THAP also led to decreased oxidative phosphorylation in heart mitochondria-oxidizing complex I substrates. THAP decreased the calcium retention capacity, indicating that ER stress sensitizes mitochondria to mitochondrial permeability transition pore opening. The cytosolic C/EBP homologous protein (CHOP) content was markedly increased in THAP-treated hearts compared to control, particularly in the nucleus. Metformin prevented the THAP-induced mitochondrial dysfunction and reduced CHOP content in cytosol and nucleus. Thus, metformin reduces cardiac injury during ER stress through the protection of cardiac mitochondria and attenuation of CHOP expression.

INTRODUCTION Non-occlusive small bowel necrosis (NOSBN) has been associated with early postoperative enteral feeding. The purpose of this study was to determine the incidence of this complication in an elective upper gastrointestinal (GI) surgical patient population and the influence of both patient selection and type of feeding jejunostomy (FJ) inserted, based on the experience of two surgical units in affiliated hospitals. PATIENTS AND METHODS The records were reviewed of 524 consecutive patients who underwent elective upper GI operations with insertion of a FJ for benign or malignant disease between 1997 and 2006. One unit routinely inserted needle catheter jejunostomies (NCJ), whilst the other selectively inserted tube jejunostomies (TJ). RESULTS Six cases of NOSBN were identified over 120 months in 524 patients (1.15%), with no difference in incidence between routine NCJ (n = 5; 1.16%) and selective TJ (n = 1; 1.06%). Median rate of feeding at time of diagnosis was 105 ml/h (range, 75–125 ml/h), and diagnosis was made at a median of 6 days (range, 4–18 days) postoperatively. All patients developed abdominal distension, hypotension and tachycardia in the 24 h before re-exploratory laparotomy. Five patients died and one patient survived. CONCLUSIONS The understanding of the pathophysiology of NOSBN is still rudimentary; nevertheless, its 1% incidence in the present study does call into question its routine postoperative use especially in those at high risk with an open abdomen, planned repeat laparotomies or marked bowel oedema. Patients should be fully resuscitated before initiating any enteral feeding, and feeding should be interrupted if there is any evidence of feed intolerance.

Preoperative cisplatin/fluorouracil is used for the treatment of localised oesophageal carcinoma. This phase II study aimed to assess the efficacy and safety of administering preoperative epirubicin/cisplatin/capecitabine (ECX). Patients with stage II or III oesophageal/gastro-oesophageal junctional adenocarcinoma from one institution received 4 cycles of ECX (epirubicin 50 mg m(-2) day 1, cisplatin 60 mg m(-2) day 1, capecitabine 625 mg m(-2) b.i.d. daily) followed by surgery. The primary end point was the pathological complete response (pCR) rate based on a Simon two-stage design. Secondary end points included overall and progression-free survival (OS/PFS). Thirty-four patients were recruited: median age 60 years (range 41-81), 91% male, 97% PS 0/1, 80% T3, 68% N1. Thirty-one patients completed four ECX cycles. Grade 3/4 toxicitiesor=5% included neutropenia (62%), hand-foot syndrome (15%) and nausea/vomiting (9%). Thirteen out of 28 (46%) evaluable patients responded to chemotherapy by EUS (or=30% reduction in maximal tumour thickness). Twenty-six out of 34 (76%) patients underwent resection (R0=73%, R1=27%). Post-operatively, two patients died within 60 days of surgery. The pCR rate was 5.9% (95% CI 0-14%) in the intent-to-treat population. According to the statistical design, this prompted early study termination. However, with a median follow-up of 34 months the median OS and 1- and 2-year survival rates were 17 months, 67 and 39% respectively. Median PFS was 13 months. Of the 14 relapsed patients, 10 presented with distant metastases. Preoperative ECX is feasible and well tolerated. Although associated with a low pCR rate, survival with ECX was comparable with published studies suggesting that pCR may not correlate with satisfactory outcome from preoperative chemotherapy for localised oesophageal adenocarcinoma.

INTRODUCTION For neoplasms that arise in the third and fourth parts of the duodenum (D3, D4), a duodenectomy that preserves the pancreas can provide adequate tumour clearance while avoiding the additional dissection and risk of the common alternative, pancreatoduodenectomy. PATIENTS AND METHODS Pancreas-sparing distal duodenectomy (PSDD) was performed in 14 patients with infrapapillary duodenal neoplasms between 1991–2002, and the clinical outcome is reviewed. The operation entails careful separation of the lower pancreatic head from D3, complete mobilisation of the ligament of Treitz and end-to-end duodenojejunal anastomosis 1–3 cm below the major duodenal papilla. RESULTS There were 9 men and 5 women of median age 56 years, who presented with iron-deficiency anaemia (n = 8), gastric outlet obstruction (n = 4), anaemia and gastric outlet obstruction (n = 1), epigastric pain or mass (1 each). There were 11 malignant neoplasms (adenocarcinoma 5, stromal tumour 4, recurrent seminoma 1, plasmacytoma 1), 2 benign neoplasms (villous adenoma, lipoma) and 1 patient with steroid-induced ulceration. In addition to D3 and D4, resection included the distal part of D2 in 5 patients, while 4 required concomitant partial colectomy. Median operation time was 240 min and median blood loss 1197 ml, being greater for malignant than benign lesions (1500 ml versus 700 ml). There was one death from gangrenous cholecystitis, one early re-operation for anastomotic bleeding and one late re-operation for delayed gastric emptying secondary to anastomotic stricture, but no pancreatic complications. At a median follow-up of 47 months, three patients had died of recurrent disease while the other 10 were alive and well with no upper gastrointestinal symptoms. CONCLUSIONS Provided there is a minimum 1-cm clearance at the papilla, PSDD is a useful alternative to formal pancreatoduodenectomy in patients with unusual neoplasms arising from the third and fourth parts of the duodenum. Although a major undertaking in its own right, it avoids the extra time of a pancreatic resection and the extra risk of a pancreatic anastomosis.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes a crucial role in protection against ischemia (ISC)-reperfusion (REP) injury by driving expression of anti-apoptotic and anti-oxidant genes. STAT3 is also present in the mitochondria, where it modulates the activity of the electron transport chain (ETC) and the permeability transition pore. Transgenic mice that overexpress a mitochondrial-targeted, transcriptionally inactive STAT3 in cardiomyocytes (MLS-STAT3E mice) exhibit a persistent, partial blockade of electron transfer through complex I that uniquely did not lead to tissue dysfunction at baseline, yet increased mitochondrial ischemic tolerance. The direct contribution of non-transcriptional, mitochondria-localized STAT3 to protection during ISC-REP remains to be established. We hypothesized that the enhanced mitochondrial tolerance to ischemia present in MLS-STAT3E mice would decrease cardiac injury during ISC-REP. In the isolated buffer-perfused heart model, MLS-STAT3E hearts exhibit a decreased infarct size compared to non-transgenic littermate hearts. Contractile recovery, expressed as a percent of LV developed pressure before ISC, is improved in MLS-STAT3E mice. Mitochondria isolated at the end of 60 min. of REP from MLS-STAT3E hearts show attenuated ROS release. The partial and persistent blockade of complex I present in MLS-STAT3E mice decreases cardiac injury during REP, in part via a persistent decrease in ROS production and attenuation of mitochondrial permeability transition pore opening at the onset of REP. In vivo, MLS-STAT3E hearts exhibit substantially higher postoperative survival rate and a substantial decrease in myocardial infarct size. STAT3 mediates cardioprotection not only via canonical action as a transcription factor, but also as a modulator of ETC activity directly in the mitochondria.

The BioEnterics intragastric balloon (BIB) is used in the treatment of morbid obesity, as a method for short-term weight loss, especially before definitive surgery. Previous studies have demonstrated that patients who have a BIB inserted can achieve 48% reduction of their excess weight, although this is not maintained in the long term [1–5]. The BIB is recommended to stay in place for 6 months and either removed or replaced after that period, because the risk of spontaneous rupture owing to material degradation increases. Although most patients tolerate intragastric balloons well, BIBs can sometimes cause complications. These are usually mild, although rarely they can be severe. Mild complications include abdominal and back pain or discomfort, nausea, and vomiting. These tend to last only for a short period after balloon insertion and are usually selflimiting. More severe complications include dislocation of the balloon causing intestinal obstruction and upper gastrointestinal bleeding and perforation, especially during balloon insertion or removal. We present the case of a patient with gastric perforation 2 months after the insertion of a BIB and describe the operative management and reviewing the literature. We also present a video clip from the operative findings and surgical repair.

We reviewed data on 63 patients with mantle cell lymphoma (MCL) with leukaemia (n = 16) and chronic lymphocytic leukaemia (CLL, n = 47), splenectomized over a 10-year period. Primary indications for surgery were cytopenia(s) or autoimmune phenomena and progressive or refractory disease with splenomegaly. The spleens removed were on average larger in MCL (median 2.6 kg) than in CLL (1.0 kg). Splenectomy improved the blood counts in 62% of patients with MCL and 47% with stage C CLL, both with cytopenias. The MCL patients showed a decrease in the leucocytosis (medians 60.3-29.1 x 10(9)/l before and after splenectomy), whereas there was an increase in the leucocytosis in CLL (medians 24.2-44 x 10(9)/l). With a median follow up post splenectomy of 10 months (range: < 1-128), 18 patients (four MCL and 14 CLL) have not required further therapy for up to 66 months. We conclude that splenectomy is a useful treatment in MCL and advanced CLL for the correction of cytopenias, reducing the leucocyte count and allowing prolonged periods of clinical remission without therapy. Differences seen between MCL and CLL in spleen size, and in response of the leucocytosis suggest a central role for the spleen in the evolution of MCL with leukaemia.

Different gastrojejunal anastomotic (GJA) techniques have been described in laparoscopic Roux-en-Y gastric bypass (LRYGB). There is conflicting data on whether one technique is superior to the other. We aimed to compare hand-sewn (HSA), circular-stapled (CSA) and linear-stapled (LSA) anastomotic techniques in terms of stricture rates and their impact on subsequent weight loss. A prospectively collected database was used to identify patients undergoing LRYGB surgery between March 2005 and May 2012. Anastomotic technique (HSA, CSA, LSA) was performed according to individual surgeon preference. The database recorded patient demographics, relevant comorbidities and the type of GJA performed. Serial weight measurements and percentage excess weight loss (%EWL) were available at defined follow-up intervals. Included in the data were 426 patients, divided between HSA (n = 174, 40.8 %), CSA (n = 110, 25.8 %) and LSA (n = 142, 33.3 %). There was no significant difference in the stricture rates (HSA n = 17, 9.72 %; CSA n = 9, 8.18 %; LSA n = 8, 5.63 %; p = 0.4006). Weight loss was similar between the three techniques (HSA, CSA and LSA) at 3 months (40.6 % ± 16.2 % vs 35.92 % ± 21.42 % vs 48.21 % ± 14.79 %; p = 0.0821), 6 months (61.48 % ± 23.94 % vs 58.16 % ± 27.31 % vs 60.18 % ± 22.26 %; p = 0.2296), 12 months (72.94 % ± 19.93 % vs 69.72 ± 21.42 % vs 66.05 % ± 17.75 %; p = 0.0617) and 24 months (73.29 % ± 22.31 % vs 68.75 % ± 24.71 % vs 69.40 % ± 23.10 %; p = 0.7242), respectively. The stricture group lost significantly greater weight (%EWL) within the first 3 months compared to the non-stricture group (45.39 % ± 16.82 % vs 39.22 % ± 21.93 %; p = 0.0340); however, this difference had resolved at 6 months (61.29 % ± 18.50 % vs 59.79 % ± 23.03 %; p = 0.8802) and 12 months (71.59 % ± 18.67 % vs 68.69 % ± 22.19 %; p = 0.5970). There was no significant difference in the rate of strictures between the three techniques, although the linear technique appears to have the lowest requirement for post-operative dilatation. The re-intervention rate will, in part, be dictated by the threshold for endoscopy, which will vary between units. Weight loss was similar between the three anastomotic techniques. Surgeons should use techniques that they are most familiar with, as stricture and weight loss rates are not significantly different.

Abdominal and pelvic adhesions are a major cause of morbidity. Appendicitis and appendicectomy are the commonest cause of intra-abdominal adhesion formation. Peritoneal injury, from a variety of causes, leads to peritoneal inflammation and with it the production of plasminogen activator inhibitors. These inhibitors result in the loss of normal mesothelial fibrinolytic activity, and if prolonged, this allows the organisation of fibrinous adhesions into permanent fibrous adhesions. Adhesions may be prevented by minimising injury and there is increasing evidence that laparoscopic surgery is an important method of adhesion prevention. A wide variety of products have been used experimentally to prevent adhesion formation but clinical interest at present is focused on the use of bioresorbable membranes which allow localised adhesion prevention. These products have been proven effective by randomised clinical trials and their use as a routine method of preventing intra-abdominal adhesion formation is likely to increase.

Life expectancy of HIV-infected patients has improved in the recent decade with the use of antiretroviral therapy. Hence, more HIV-infected patients with chronic co-morbidities are being followed by different specialities. Diabetes and obesity are two of the co-morbidities. We looked at the outcome of bariatric surgery for 3 HIV-infected patients. We concluded that bariatric surgery is safe and can reduce pill burden. However, a multi-disciplinary team approach is needed to ensure that the right patients are selected and on-going support available to achieve the best outcome.

Background Faced with upward pressure on costs from ageing populations and new technologies, those responsible for funding health care are seeking innovative ways of providing that care at lower cost. A common strategy is to shift care from the inpatient to the outpatient setting. This, taken with pressure for greater accountability and improved training, is creating great challenges for those responsible for organizing outpatient care. This paper seeks to review these challenges and the various responses to them. Methods A critical review of literature on the changing role of outpatient care, with an emphasis on the current situation in the United Kingdom. Results Many diverse responses have been developed to address the changing nature of outpatient care. These have certain features, including the recognition that clinicians have the ability to initiate, rather than simply react to change, and an appreciation of the value of clear and definable objectives for outpatient care. They range from discrete interventions addressing a single concern to wholesale restructuring of the system of care, such as one-stop clinics. Conclusion There is now considerable evidence on what can and should be done to improve the existing system of outpatient care.

Substance P (SP) and calcitonin gene-related peptide (CGRP) are well established mediators of inflammation. Therefore, inhibition of the biosynthesis of these neuropeptides is an attractive potential strategy for pharmacological intervention against a number of inflammatory diseases. The final step in the biosynthesis of SP and CGRP is the conversion of their glycine-extended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4-phenyl-3-butenoic acid (PBA) is a PAM inhibitor, and we have also shown that in vivo inhibition of serum PAM by PBA correlates with this compound's ability to inhibit carrageenan-induced edema in the rat. Here we demonstrate the ability of PBA to inhibit all three phases of adjuvant-induced polyarthritis (AIP) in rats; this represents the first time that an amidation inhibitor has been shown to be active in a model of chronic inflammation. We recently introduced 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid (AOPHA) as one of a new series of mechanism-based amidation inhibitors. We now report for the first time that AOPHA and its methyl ester (AOPHA-Me) are active inhibitors of serum PAM in vivo, and we show that AOPHA-Me correspondingly inhibits carrageenan-induced edema in rats in a dose-dependent manner. Neither PBA nor AOPHA-Me exhibits significant cyclooxygenase (COX) inhibition in vitro; thus, the anti-inflammatory activities of PBA and AOPHA-Me are apparently not a consequence of COX inhibition. We discuss possible pharmacological mechanisms that may account for the activities of these new anti-inflammatory compounds.

OBJECTIVE. The aim of this pilot study was to assess the feasibility of external surfacecoil MRI as a new method of imaging the esophagus and esophageal cancer.CONCLUSION. The results for the 10 patients investigated indicate that by using a high-resolution axial T2-weighted sequence (small field of view, thin section images), MRI provides detailed imaging of the anatomic layers of the esophageal wall and tumor. Three independent radiologists found good correlation in the morphologic appearance and extent of tumor between MRI and matched histology sections. This study illustrates the potential of the technique as an alternative form of local staging for esophageal cancer.

This paper describes the spectrum of imaging features of oesophageal adenocarcinoma seen using high-resolution T2-weighted (T2W) magnetic resonance imaging (MRI). Thirty-nine patients with biopsy-proven oesophageal adenocarcinoma were scanned using an external surface coil. A sagittal T2W sequence was used to localise the tumour and to plan axial images perpendicular to the tumour. Fast spin-echo (FSE) T2W axial sequence parameters were: TR/TE, 3,300–5,000 ms/120–80 ms; field of view (FOV) 225 mm, matrix 176×512(reconstructed) mm to 256×224 mm, giving an in-plane resolution of between 1.28×0.44 mm and 0.88×1.00 mm, with 3-mm slice thickness. Thirty-three patients underwent resection and the MR images were compared with the histological whole-mount sections. There were four T1, 12 T2, and 17 T3 tumours. The T2W high-resolution MRI sequences produced detailed images of the oesophageal wall and surrounding structures. Analysis of the imaging appearances for different tumour T stages enabled the development of imaging criteria for local staging of oesophageal cancer using high-resolution MRI. Our study illustrates the spectrum of appearances of oesophageal cancer on T2W high-resolution MRI, and using the criteria established in this study, demonstrates the potential of this technique as an alternative non-invasive method for local staging for oesophageal cancer.

Objectives To assess the impact of highly active antiretroviral therapy (HAART) on rates of change of antiretroviral treatment among patients co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in the Australian HIV Observational Database (AHOD). Methods Analysis was based on 805 of the 2218 patients recruited to the AHOD by March 2003, who had commenced HAART after 1 January 1997, who had recorded test results for HBV surface antigen and anti-HCV antibody, and who had follow-up of more than 3 months. The effect of hepatitis co-infection on the rate of antiretroviral treatment change after commencing HAART was assessed using a random-effect Poisson regression model. Results Among those included in the analyses, the prevalences of HBV and HCV were 4.8% and 12.8%, respectively. The overall rate of combination antiretroviral treatment change was 0.74 combinations per year. Factors independently associated with an increased rate of change of combination antiretroviral treatment were: prior AIDS-defining illness; prior exposure to double combination antiretroviral therapy; and antiretroviral treatment class. Co-infection with HBV and/or HCV was not found to be significantly associated with the rate of combination antiretroviral treatment change. Conclusions While both HBV and HCV co-infections are relatively common in the AHOD, they do not appear to be serious impediments to the treatment of HIV-infected patients.

153 Background: Oesophagogastric adenocarcinoma (OGA) has a poor prognosis, even for patients (pts) with operable disease. We conducted a retrospective study to assess relapse characteristics to see if these could influence follow-up strategies. Methods: We performed a retrospective review of all pts with OGA who had surgery with radical intent at the Royal Marsden between January 2001 – December 2010. Details of first relapse, including date, site, symptoms, method of relapse detection, tumour markers and treatment were recorded. Association of survival outcomes with relapse characteristics was determined by Cox regression univariate analysis. Results: 360 pts with OGA had surgery and 72.8% received neoadjuvant or peri-operative chemotherapy. After a median follow-up of 61.7 months, the median disease-free survival (DFS) was 35.6 months (95% CI 27.0 – 65.4) and median overall survival (OS) was 59.6 months (95% CI 40.7 – 81.2). 147 pts (40.8%) had disease recurrence. 51.0%, 78.9% and 91.8% of relapses occurred within 1, 2 and 3 years respectively. 78.9% of pts had distant relapse only, 7.5% had anastomotic recurrence and 13.6% had both. R1/2 resection was associated with a shorter time to distant relapse (p

169 Background: OGA is a lethal cancer globally. Overall survival (OS) has improved in the last decade, potentially due to stage migration and changes in management of early stage cancer. To examine this hypothesis we assessed outcomes of resected OGA patients (pts) at RM over 10 years (y), comparing 2 time periods, 2001-2005 (A) and 2006-2010 (B). Methods: Electronic records of all pts who had undergone surgery with radical intent for OGA between 01/2001 and 12/2010 were reviewed. Pt age, sex, ECOG PS, pre-operative staging investigations (CT, EUS, PET-CT), perioperative therapy, pathological stage, dates of death, last follow up and treatment for recurrent disease were recorded. Disease-free (DFS), OS and survival beyond relapse (SBR) were estimated using the Kaplan Meier method; co-variates were compared using the log rank test and Hazard ratios calculated using cox regression within the 2 time periods. Results: 367 pts were identified; 151 (A) and 216 (B). Median age was 67y (A) and 66y (B). Gender distribution, PS, site of primary and pre-intervention lymph node status were comparable. PET-CT use increased from 9% (A) to 37% (B), p75% pts in both groups were treated with chemotherapy; use of perioperative therapy increased over time (19% of treated pts in A vs 52% in B). Conversely use of pre-operative therapy alone decreased over time (75% of treated pts A vs. 45% in B). Rates of R0 resection increased from 75% (A) to 89 % (B) (p=0.001). Median number of resected lymph nodes was 20 (A) and 31 (B). ≥T3 tumours (46% vs 33%) and ≥N1 lymph nodes (53% vs 48%) were more common in A. After a median follow-up of 95 (A) and 59 (B) months, relapse occurred in 47% (A) and 38% (B). 5y DFS for A and B was 34% vs. 51% [HR 0.59, (0.45-0.78), p

The move to primary care led purchasing in the NHS1 is focusing attention on the role of outpatient review, especially for postoperative patients. General practitioners have questioned whether such routine reviews could be reduced, describing them as of limited clinical value and a waste of patients' time.2 Some surgeons agree, noting that most patients' postoperative problems are identified by general practitioners before their appointment.3 The limited evidence available suggests that there are indeed opportunities for change. A randomised controlled trial comparing postoperative follow up in outpatient clinics and general practice found no difference in readmission rates or mortality, and patients were equally satisfied with either method.4 The general practice option was, however, cheaper for both the patient and the …

A 28-year-old female presented with a 4 year history of intermittent right upper quadrant pain. Clinical examination and ultrasound suggested a diagnosis of cholelithiasis and the patient was eventually booked for a laparoscopic cholecystectomy. Intraoperatively the patient was found to have gallbladder agenesis and small bowel malrotation with the duodenojejunal flexure to right of midline. The gallbladder fossa was filled with fibrous tissue. Both gallbladder agenesis and midgut malrotation are rare congenital abnormalities. Gallbladder agenesis has a similar presentation to more common gallbladder pathologies, such as cholecystitis. This case illustrates the limitations of and our over reliance on radiological imaging. Moreover, it highlights the need to have a high index suspicion of gallbladder agenesis when ultrasound is inconclusive. Further investigations and imaging with modalities such as MRI should be used to reduce the risks associated with unnecessary surgical intervention.

Background There is no standard systemic therapy for metastatic esophageal cancer progressing after 1st/2nd line chemotherapy (Thallinger et al, 2011, JCO, 4709-14). High EGFR expression is associated with poor prognosis in esophageal cancer. A phase II trial of the EGFR kinase inhibitor gefitinib showed good tolerance with 11% partial responses and a trend towards improved survival (Ferry et al. Clin Cancer Res 2007, 13: 5869-75). Four other phase II trials showed objective responses with gefitinib or erlotinib. Cancer Research UK funded this pivotal phase III trial with free study drug provided by Astra Zeneca UK. Methods Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status (PS) 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: overall survival (OS) - an increase from 10-18% in 1yr OS is detectable with 450 patients, power 82.5%, significance level 5%, analysed with Kaplan-Meier and log-rank test. Secondary outcomes include safety, PFS, HRQL (EORTC QLQ-C30 and QLQ-OG25) and predictive biomarkers. Results Recruitment of 450 patients from 51 UK centres occurred Mar 2009-Nov 2011. Baseline characteristics were well-balanced - median age 64 years; 83% male; 76% adenocarcinoma; 78% esophageal; PS0 25%, PS1 54%, PS2 21%. Median PFS was P 35 days, G 49 days (HR = 0.795, 95%CI 0.66, 0.96, p = 0.017). Median OS was P 3.60 months, G 3.73 months (HR = 0.90, 95%CI 0.74, 1.09, p = 0.285). No significant safety concerns emerged. PS is a highly significant prognostic factor for both PFS (median PFS: PS0 1.8, PS1 1.4, PS2 1.0 months) and OS (median OS: PS0 6.0, PS1 3.9, PS2 2.0 months). Disease control rate at 8 weeks in patients with measurable disease was P 16.0%, G 25.5% (p = 0.014). HRQL was assessed for the pre-specified outcomes of QoL, dysphagia, eating and odynophagia, the latter of which was improved for gefitinib (p = 0.004). Conclusion COG is the first large randomised trial in the 2nd/3rd line setting in esophageal cancer. Although the primary OS endpoint was not acheived, there was significant PFS improvement and palliation. Durable responses were seen, and the translational study (Trans-COG) is investigating the correlation of benefit with biomarkers. Disclosure D.R. Ferry: Consultant role for Astra Zeneca Honoraria from Astra Zeneca Research funding from Astra Zeneca M. Harrison: Wife has shares in Astra Zeneca. Otherwise no conflicts of interest A. Chatterjee: Received and honoraria for a presentation on gefitinib. otherwise no conflicts of interest A. Garcia-Alonso: A consultant/advisory role for Roche. otherwise no conflicts of interest J. Jankowski: Consultant to AstraZeneca. No other conflicts of interest R.D. Petty: Consultant for Roche and Astra Zeneca (compensated) Honoraria from Roche and Pfizer Research funding from Roche All other authors have declared no conflicts of interest.

Last night I had a dream. My wife and I, tiring of the constant struggle to maintain standards in our professional and home lives, and recognising that the battlefront most obviously under pressure was the housework, made the radical decision to employ a cleaner. “Let’s commission a new service,” we trilled, brimming with enthusiasm after a recent practice based commissioning meeting. Lively debate about the sort of service we required and a thorough options appraisal followed; and at last, one bright Monday morning, our new cleaner stood on our doorstep, mop in hand, prim, confident, and keen. Life was great as she competently and professionally fulfilled the duties we asked of her, and our house was gradually restored to its PC state (that’s pre-children, not politically correct, which of course it has always been). “Hang on,” we said to ourselves, “we know that things are …

Inflammatory myofibroblastic tumour (IMT) is a benign, nonmetastasizing proliferation of myofibroblasts with a potential for local infiltration, recurrence and persistent local growth. We report a case of a 51 year-old female, who had excision of a gallbladder tumour. Histopathology showed it to be IMT of the gallbladder. The approach to these tumours should be primarily surgical resection to obtain a definitive diagnosis and relieve symptoms. IMT has a potential for local infiltration, recurrence and persistent local growth.

Type 1 neurofibromatosis (NF-1) is an autosomal dominant disorder with variable penetrance; approximately 50% of cases present as new mutations We report a case of a 56 year-old man with Von Recklinghausen's disease, carcinoma of the ampulla of Vater and incidental benign gastrointestinal stromal tumours of the jejunum. Coexistence between ampullary carcinoid, ectopic pancreatic tissue in the jejunum and neurofibroma of the jejunum in NF-1 has been previously described however; the association of synchronous carcinoma of the ampulla of Vater and gastrointestinal stromal tumour of the jejunum in NF-1 has not been previously reported.