DSpace Collection: Surgery (Scholarly Publications)

Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis

2012-06-27T11:28:06Z

Title: Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis Author: O'SULLIVAN, JACINTHA Abstract: Background: To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in patients with inflammatory arthritis. Methods: Fifty patients with inflammatory arthritis underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen patients pre/post-TNFi therapy were also recruited. Normal synovial biopsies were obtained from 10 subjects undergoing interventional arthroscopy. Macroscopic synovitis/vascularity was measured by visual analogue scale. Cell-specific markers CD3 (T cells) and CD68 (macrophages) were quantified by immunohistology. TNFα, IL-6, IFNγ and IL-1β were measured in synovial fluids by MSD multiplex assays. Synovial tissue mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay (RMCA). The direct effect of TNFα on oxidative stress and mitochondrial function was assessed in primary cultures of rheumatoid arthritis synovial fibroblast cells (RASFCs). Mitochondrial mutagenesis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and mitochondrial mass (MM) were quantified using the RMCA and specific cell fluorescent probes. Results: A significant increase in mtDNA mutation frequency was demonstrated in inflamed synovial tissue compared with control (p<0.05), an effect that was independent of age. mtDNA mutations positively correlated with macroscopic synovitis (r=0.52, p<0.016), vascularity (r=0.54, p<0.01) and with synovial fluid cytokine levels of TNFα (r=0.74, p<0.024) and IFNγ (r=0.72, p<0.039). mtDNA mutation frequency post-TNFi therapy was significantly lower in patients with a DAS<3.2 (p<0.05) and associated with clinical and microscopic measures of disease (p<0.05). In vitro TNFα significantly induced mtDNA mutations, ROS, MM and MMP in RASFCs (all p<0.05). Conclusion: High mitochondrial mutations are strongly associated with synovial inflammation showing a direct link between mitochondrial mutations and key proinflammatory pathways. Description: IN_PRESS

Visceral adiposity, insulin resistance and cancer risk

2012-01-25T15:08:42Z

Title: Visceral adiposity, insulin resistance and cancer risk Author: DONOHOE, CLAIRE; REYNOLDS, JOHN Abstract: Background: There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. Methods: Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Results: Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. Conclusions: There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention. Description: PUBLISHED

Internal hernia following total gastrectomy with Roux-en-Y reconstruction.

2012-01-25T14:56:55Z

Title: Internal hernia following total gastrectomy with Roux-en-Y reconstruction. Author: RAVI, NARAYANASAMY; REYNOLDS, JOHN Abstract: Internal herniation is a well-described complication after a gastric bypass, particularly when performed laparoscopically, although it is rarely described following a total gastrectomy. A 55-year-old lady presented with a 24-hour history of vomiting and rigors 10 months after a radical total gastrectomy with Roux-en-Y reconstruction for a gastric adenocarcinoma. Computed tomography (CT) showed a complete small bowel obstruction and a mesenteric swirl sign, indicating a possible internal hernia. The entire small bowel was found at laparotomy to have migrated through the mesenteric defect adjacent to the site of the previous jejunojejunostomy and was dark purple and aperistaltic. The small bowel was reduced through the defect. At a second laparotomy, the small bowel looked healthy and the defect was repaired. Postoperative recovery was unremarkable. Of numerous signs described, the mesenteric swirl sign is considered the best indicator on CT of an internal hernia following Roux-en-Y reconstruction in gastric bypass surgery. A swirl sign on CT in a patient with abdominal pain should always raise the suspicion of an internal hernia. Description: PUBLISHED

Long-term activation of the pro-coagulant response after neoadjuvant chemoradiation and major cancer surgery.

2011-11-21T16:19:57Z

Title: Long-term activation of the pro-coagulant response after neoadjuvant chemoradiation and major cancer surgery. Author: O'DONNELL, JAMES; MAHER, STEPHEN; WHITE, BARRY; PIDGEON, GRAHAM; REYNOLDS, JOHN Abstract: Background: The association between cancer, major surgery and venous thromboembolism (VTE) is well established. Multimodal therapy is increasingly being used as standard treatment for localised gastrointestinal cancer. The aim of this study was to examine the markers of pro-coagulation response and VTE risk in an exemplar multimodal model of pre-operative combination chemotherapy and radiation therapy, followed by complex cancer surgery. Methods: Consecutive patients (n=36) with localised oesophageal cancer were studied at baseline after the first and second cycles of chemoradiation, and on post-operative days 1–28, and at 3, 6 and 9 months. Factors regulating the pro- and anti-coagulant response, as well as pro-inflammatory markers including NFκB activation in peripheral blood mononuclear cells, were examined. All patients received enoxaparin 40 mg s.c. postoperatively up to discharge, and underwent pulmonary CT-pulmonary angiography and venography on day 10 postoperatively. Results: Four (11%) non-fatal thromboembolic events were documented, all after hospital discharge. Neoadjuvant therapy before surgery activated factor VIII (FVIII) and pro-inflammatory NFκB, and increased D-dimers, pro-thrombin fragment 1+2 (F1+2) and the thrombin-anti-thrombin complex (TAT). Surgery significantly (P<0.05) increased pro-thrombin time (PT), activated partial thromboplastin time, fibrinogen, D-dimers, TAT, F1+2 and FVIII up to 6 months. Conclusion: These data highlight the linked pro-coagulant and immunoinflammatory pathways in the multimodal management of oesophageal cancer, and suggest that the duration of current standard thromboprophylaxis regimens warrants further study. Description: PUBLISHED

COX-Derived prostanoid pathways in gastrointestinal cancer development and progression: Novel targets for prevention and intervention

2011-11-15T15:14:01Z

Title: COX-Derived prostanoid pathways in gastrointestinal cancer development and progression: Novel targets for prevention and intervention Author: REYNOLDS, JOHN; O'SULLIVAN, JACINTHA; CATHCART, MARY CLARE; PIDGEON, GRAHAM; O'BYRNE, KEN Abstract: Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers was significantly reduced by daily aspirin intake. A number of randomised controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signalling have been investigated in cancer development/progression. PGE2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA2 in G.I. caners has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD2 and its metabolite 15 d-PGJ2, PGF1α and PGI2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. Description: PUBLISHED

Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue

2011-10-05T15:08:50Z

Title: Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue Author: LYSAGHT, JOANNE; DONOHOE, CLAIRE; PIDGEON, GRAHAM; REYNOLDS, JOHN; CASEY, RORY; RAVI, NARAYANASAMY; ALLOTT, EMMA; HOWARD, JULIA MARY Abstract: Obesity has been associated with increased incidence and mortality of oesophageal and colorectal adenocarcinoma. Excess central adiposity may drive this association through an altered inflammatory milieu. Utilizing a unique adipose tissue bioresource we aimed to determine the pro-tumour properties of visceral adipose tissue. Comparing subcutaneous and visceral adipose tissue depots, we observed significantly higher levels of VEGF and IL-6, along with significantly higher proportions of CD8+ T cells and NKT cells in visceral adipose tissue. Significantly higher levels of VEGF were observed in the conditioned media from visceral adipose tissue of centrally obese compared to non-obese patients. We also report a significant increase in oesophageal and colorectal tumour cell proliferation following culture with conditioned media from visceral adipose tissue of centrally obese patients. Neutralizing VEGF in the conditioned media significantly decreased tumour cell proliferation. This novel report highlights a potential mechanism whereby visceral adipose tissue from centrally obese cancer patients may drive tumour progression. Description: PUBLISHED

Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxiainduced mitochondrial mutagenesis in inflammatory arthritis

2011-09-26T15:40:30Z

Title: Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxiainduced mitochondrial mutagenesis in inflammatory arthritis Author: O'SULLIVAN, JACINTHA Abstract: INTRODUCTION: To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. METHODS: Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay. RESULTS: 4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO2 levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found. CONCLUSIONS: High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment. Description: PUBLISHED

Cancer Cachexia:Mechanisms and Clinical Implications

2011-08-29T09:36:03Z

Title: Cancer Cachexia:Mechanisms and Clinical Implications Author: REYNOLDS, JOHN; DONOHOE, CLAIRE Abstract: Cachexia is amultifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be fully elucidated. Cachexia is compounded by anorexia and the relationship between these two entities has not been clarified fully. Inconsistencies in the definition of cachexia have limited the epidemiological characterisation of the condition and there has been slow progress in identifying therapeutic agents and trialling themin the clinical setting. Understanding the complex interplay of tumour and host factors will uncover new therapeutic targets. Description: PUBLISHED

Day care general anaesthesia for a child with bardet-biedl syndrome.

2011-06-14T13:23:22Z

Title: Day care general anaesthesia for a child with bardet-biedl syndrome. Author: CROWE, SUZANNE Abstract: Bardet-Biedl syndrome is a very rare autosomal-recessive disorder with pan-systemic effects. The perioperative period may be hazardous for patients with this disorder. We describe the presenting features and management of a child who was scheduled for elective ambulatory general anesthesia and discuss the relevant points for the busy anesthesiologist. Description: PUBLISHED

Impact of a new electronic handover system in surgery

2012-02-15T03:07:48Z

Title: Impact of a new electronic handover system in surgery Author: RYAN, SIOBHAN; CONLON, KEVIN CHRISTOPHER; TIERNEY, SEAN; RIDGWAY, PAUL Abstract: Changing patterns of workflow in the hospital setting have highlighted the need for improvements in effective and safe handover of patient details. Financial constraints mean that hospitals are under increasing pressure to maximise efficiency and reduce length of stay of patients in hospitals and to reduce overtime bills for junior doctors. The European Working Time Directive (EWTD) for junior doctors also requires hospitals to comply with the 48 hour working week. This means the introduction of a shift-based work practice for junior doctors and subsequently an increased number of handovers between surgical on-call teams. Description: PUBLISHED