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Mulsow J.J.W.,Adelaide and Meath Hospital | Feeley T.M.,Adelaide and Meath Hospital | Tierney S.,Adelaide and Meath Hospital | Tierney S.,Royal College of Surgeons in Ireland
American Journal of Surgery | Year: 2012

Little is known of the actual understanding that underlies patient choices with regard to their surgical treatment. This review explores current knowledge of patient understanding and techniques that may be used to improve this understanding. MEDLINE and PubMed were searched using the terms "patient understanding," "patient comprehension," "consent," "video," "multimedia," "patient information leaflet," "internet," "test-feedback," "extended discussion," "shared decision making," and "decision aid." All retrieved peer-reviewed studies were included in the review. Understanding in surgical patients is poor. There is little evidence to support the use of information leaflets, although multimedia appears to be effective in improving patient understanding. The internet is not used effectively as an aid to consent by health care providers. Patients with lower educational levels may gain most from additional interventions. Improving patient understanding does not impact on their satisfaction with the treatment they have received but may reduce periprocedural anxiety. There is a need for greater awareness of patients' information needs, and novel approaches that may enhance decision making through improved understanding are required. © 2012 Elsevier Inc. All rights reserved.


Reeves E.P.,Royal College of Surgeons in Ireland | Williamson M.,Royal College of Surgeons in Ireland | Williamson M.,Adelaide and Meath Hospital | O'Neill S.J.,Royal College of Surgeons in Ireland | And 2 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Inflammation within the cystic fibrosis (CF) lung is mediated by inflammatory chemokines, such as IL-8. IL-8 is protected from proteolytic degradation in the airways by binding to glycosaminoglycans, while remaining active. Evidence that increased hypertonicity of airway secretions induced by hypertonic saline treatment alters levels of IL-8 is lacking. Objectives: To investigate the antiinflammatory effect of hypertonic saline (HTS) treatment within the CF lung by focusing on IL-8. Methods: Degradation of IL-8 in CF lung secretions after treatment with glycosaminoglycan lyases and HTS was analyzed by Western blot analysis and ELISA. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post nebulization of HTS (7% saline). Measurements and Main Results: In vivo CF bronchoalveolar lavage fluid (BALF) IL-8 levels were significantly higher than the control group (P < 0.05). Digesting glycosaminoglycans in CF BALF displaced IL-8 from glycosaminoglycan matrices, rendering the chemokine susceptible to proteolytic cleavage. High sodium concentrations also liberate IL-8 in CF BALF in vitro, and in vivo in CF sputum from patients receiving aerosolized HTS, resulting in degradation of IL-8 and decreased neutrophil chemotactic efficiency. Conclusions: Glycosaminoglycans possess the ability to influence the chemokine profile of the CF lung by binding and stabilizing IL-8, which promotes neutrophil chemotaxis and activation. Nebulized hypertonic saline treatment disrupts the interaction between glycosaminoglycans and IL-8, rendering IL-8 susceptible to proteolytic degradation with subsequent decrease in neutrophil chemotaxis, thereby facilitating resolution of inflammation.


Lanigan F.,Trinity College Dublin | Geraghty J.G.,University College Dublin | Bracken A.P.,Trinity College Dublin | Bracken A.P.,Adelaide and Meath Hospital
Oncogene | Year: 2011

Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. This review focuses on the role of transcriptional regulators in the control of cellular senescence, explores how their function is perturbed in cancer and discusses the potential to harness this knowledge for future cancer therapies. © 2011 Macmillan Publishers Limited All rights reserved.


Wilcz-Villega E.,Adelaide and Meath Hospital | Mcclean S.,Institute of Technology Tallaght | O'Sullivan M.,St James's Hospital
Neurogastroenterology and Motility | Year: 2014

Background: Increased intestinal permeability and altered expression of tight junction (TJ) proteins may be implicated in the pathogenesis of irritable bowel syndrome (IBS). This study aimed to investigate the expression of adherens junction (AJ) protein E-cadherin and TJ proteins zonula occludens (ZO)-1 and claudin (CLD)-1 and associations with IBS symptoms. Methods: Junctional proteins were immunostained in cecal biopsy tissue of Rome II IBS patients (n = 34) comprising both alternating (IBS-A) and diarrhea predominant (IBS-D) subtypes, and controls (n = 12). IBS symptom duration, abdominal pain severity and stool frequency were assessed for IBS patients. Protein expression was determined by immunofluorescence. Key Results: E-cadherin and ZO-1 protein expression was significantly lower (p = 0.03 and p = 0.016, respectively) in the cecal surface epithelium of the IBS group comprising both IBS-A and IBS-D subtypes. CLD-1 expression was not significantly altered compared with controls. On subtype analysis, ZO-1 expression was significantly reduced in both IBS-A and IBS-D compared with controls, whereas E-cadherin was reduced only in IBS-A. Lower E-cadherin expression was associated with longer symptoms duration specifically in IBS-A patients (rs = -0.76, p = 0.004). Reduced E-cadherin associated with abdominal pain severity in the overall IBS group (rs = -0.36, p = 0.041), but this association was unrelated to IBS subtype. Conclusions & Inferences: E-cadherin protein expression in the cecum was significantly lower in IBS-A compared with controls and associated with longstanding symptoms. E-cadherin was further associated with abdominal pain severity in the IBS group overall, but unrelated to IBS subtype. Altered E-cadherin expression may provide novel insights into mechanisms underlying intestinal barrier dysfunction in IBS. In this study, comprising IBS-A and IBS-D subtypes, E-cadherin and ZO-1 protein expression was significantly lower in the cecal surface epithelium compared with controls. Furthermore, reduced E-cadherin expressed in the IBS group was associated with more severe abdominal pain, and in IBS-A with longer duration of symptoms. Altered E-cadherin expression may provide novel insights into mechanisms underlying intestinal barrier dysfunction in IBS. © 2013 John Wiley & Sons Ltd.


Wilcz-Villega E.M.,Adelaide and Meath Hospital | McClean S.,Institute of Technology Tallaght | O'Sullivan M.A.,Adelaide and Meath Hospital | O'Sullivan M.A.,St James's Hospital
American Journal of Gastroenterology | Year: 2013

OBJECTIVES:The objective of this study was to investigate how mast cell tryptase may influence intestinal permeability and tight junction (TJ) proteins in vitro and explore translation to irritable bowel syndrome (IBS).METHODS:We investigate. The effect of: (1) tryptase on Caco-2 monolayers, (2) mast cell degranulation in a Caco-2/human mast cell-1 (HMC-1) co-culture model, (3) mast cell degranulation±tryptase inhibition with nafamostat mesilate (NM). Epithelial integrity was assessed by transepithelial resistance (TER), permeability to fluorescein isothiocyanate (FITC)-dextran and transmission electron microscopy (TEM). The expression of junctional proteins zonula occludens-1 (ZO-1), junctional adhesion molecule-A (JAM-A), claudin-1 (CLD-1), CLD-2, CLD-3, occludin and E-cadherin was determined by western blot analysis and immunofluorescence confocal microscopy. Based o. The in vitro results, we further assessed JAM-A expression in biopsy tissue (cecum) from 34 IBS patients, 12 controls, and 8 inflammatory controls using immunofluorescence confocal microscopy and explored associations between JAM-A and IBS symptoms.RESULTS: ptase disrupted epithelial integrity in Caco-2 monolayers as shown by a significant decrease in TER, an increase in permeability to FITC-dextran, and a decrease i. The expression of junctional proteins JAM-A, CLD-1, and ZO-1 within 24 h. Correspondingly, i. The Caco-2/HMC-1 co-culture model we showed a significant decrease in TER, an increase in permeability to FITC-dextran, an. The presence of open TJs (TEM) in response to mast cell degranulation within 24 h. In this co-culture model, mast cell degranulation significantly decreased JAM-A and CLD-1 protein expression at 24 h. Tryptase inhibition (NM) significantly reduce. The effect of mast cell degranulation o. The junctional protein JAM-A, TER, and FITC-dextran flux. In IBS, epithelial JAM-A protein expression was significantly reduced in IBS tissue compared with controls. Lower JAM-A expression was associated with more severe abdominal pain (r s =-0.69, P=0.018) and longer duration of symptoms (r s =-0.7, P=0.012) in IBS-alternating subtype.CONCLUSIONS:uced JAM-A expression in vitro appears to contribute t. The underlying mechanisms of altered epithelial integrity in response to tryptase released from degranulating mast cells. In IBS, JAM-A expression was significantly reduced i. The cecal epithelium and associated with abdominal pain severity. JAM-A may provide new insights int. The underlying mechanisms in IBS.


Burke A.C.,Adelaide and Meath Hospital | Giles F.J.,National University of Ireland
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: Ara-C (cytarabine arabinoside) is a deoxycytidine analog that has an established role in the treatment of hematologic malignancies, especially acute myeloid leukemia. Resistance to ara-C occurs and impacts negatively on survival. To combat this, an elaidic acid ester of ara-C, called elacytarabine, has been developed. This novel agent is highly efficacious in cells with demonstrable resistance to the parent agent, including in solid tumor xenografts. Areas covered: The mechanisms that account for the increased clinical activity of elacytarabine are discussed, including its ability to bypass the specialized transmembrane nucleoside transport system on which ara-C depends, its prolonged retention within the cell and its alternative effect on the cell cycle. The development and synthesis and pharmacokinetics are outlined, with emphasis on lipid vector technology. Ten clinical trials involving elacytarabine, either as monotherapy or part of a combination regimen, have been carried out in both solid tumor and hematologic malignancies. The efficacy and side effect profile results are summarized. Expert opinion: Clinical trials in patients with hematological malignancies are reporting very encouraging efficacy results with an acceptable side effect profile. Elacytarabine has the potential to play an important role in the treatment of multiple malignancies in the future and results from an ongoing Phase III clinical trial are eagerly awaited. © 2011 Informa UK, Ltd.


McCabe J.,Adelaide and Meath Hospital | Ayuk J.,Queen Elizabeth Hospital | Sherlock M.,Adelaide and Meath Hospital | Sherlock M.,Trinity College Dublin
Neuroendocrinology | Year: 2016

Acromegaly is a rare condition characterized by excessive secretion of growth hormone (GH), which is almost always due to a pituitary adenoma. Acromegaly is associated with significant morbidity such as hypertension, type 2 diabetes, cardiomyopathy, obstructive sleep apnoea, malignancy and musculoskeletal abnormalities. Acromegaly has also been associated with increased mortality in several retrospective studies. This review will focus on the epidemiological data relating to mortality rates in acromegaly, the relationship between acromegaly and malignancy, the role of GH and insulin-like growth factor-I in assessing the risk of future mortality, and the impact of radiotherapy and hypopituitarism on mortality. © 2015 S. Karger AG, Basel. All rights reserved.


Matthew Widdowson W.,Adelaide and Meath Hospital | Gibney J.,Adelaide and Meath Hospital
Clinical Endocrinology | Year: 2010

Context/objectives GH replacement increases muscle mass and reduces body fat in growth hormone deficiency (GHD) adults. A recent meta-analysis has demonstrated that this improvement in body composition is associated with improved exercise performance. The current meta-analysis was carried out to determine whether high-quality evidence exists to support a beneficial effect of GH replacement on strength. Design/methods An extensive Medline search/literature review identified eight studies with utilizable, robust data, involving 231 patients in nine cohorts. Previously unpublished data were sought from authors and obtained in two cases. All studies included were randomized, double-blind, placebo-controlled, of parallel or cross-over design and of an average 6·7 months duration. Information was retrieved in uniform format, with data pertaining to patient numbers, study-design, GH-dose, mean age, IGF-I levels and muscle strength measurements (isometric or isokinetic quadriceps strength) recorded. Data were analysed using a fixed-effects model, utilizing continuous data measured on different scales. A summary effect measure (d s) was derived for individual strength variables, whereas an overall summary effect was derived from the sum of all studies incorporating different variables; 95% CIs were calculated from the weighted variances of individual study effects. Results Analysis revealed no significant improvement, neither when all studies were combined (ds = +0·01 ± 0·26) nor when measured individually (isometric quadriceps strength, ds = +0·02 ± 0·32 and isokinetic quadriceps strength, ds = 0·00 ± 0·45). Conclusions Evidence from short-term controlled studies fails to support a benefit on muscle strength of GH replacement in GHD patients, which is likely to occur over a longer time-course, as seen in open-label studies. © 2010 Blackwell Publishing Ltd.


Manecksha R.P.,Adelaide and Meath Hospital | Cullen I.M.,Adelaide and Meath Hospital | Ahmad S.,Adelaide and Meath Hospital | McNeill G.,Adelaide and Meath Hospital | And 4 more authors.
European Urology | Year: 2012

Background: Botulinum toxin A is effective for treatment of idiopathic detrusor overactivity (IDO). The trigone is generally spared because of the theoretical risk of vesicoureteric reflux (VUR), although studies assessing injection sites are lacking. Objective: Evaluate efficacy and safety of trigone-including versus trigone-sparing intradetrusor injections of abobotulinumtoxinA in patients with IDO. Design, setting, and participants: Twenty-two patients from one centre were randomised to trigone-including or trigone-sparing injections. Intervention: Injection of 500 U abobotulinumtoxinA diluted to 20 ml into 20 trigone-including or trigone-sparing sites. Measurements: The primary outcome measure was total overactive bladder symptom score (OABSS) at 6 wk. The OABSS questionnaire was completed at 0, 6, 12, and 26 wk. Baseline and postinjection urodynamic studies and micturating cystourethrograms were performed. Baseline values and subsequent time points were compared by t test. A mixed-effect model was used for repeated measures in time. Results and limitations: For symptom scores at baseline compared with scores at 6 wk postinjection, the mean total OABSS improved from 22.4 to 8.7 (p < 0.001) in the trigone-including group compared with 22.7 to 13.4 (p < 0.03) in the trigone-sparing group. The difference in mean change from baseline was 4.4 points in favour of the trigone-including group (p = 0.03). The total OABSS at 12 and 26 wk and the urgency subscale scores at 6, 12, and 26 wk showed significant improvement in favour of the trigone-including group. Mean postvoid residual volumes and clean intermittent self-catheterisation rates between the two groups were similar. No patients developed VUR. Performing injections under general anaesthetic was a limitation, as tolerability under local anaesthetic was not assessed. A further limitation is the lack of a trigone-only arm. Conclusions: Trigone-including injections are superior to trigone-sparing injections for the treatment of refractory IDO and did not cause VUR in this study. © 2011 European Association of Urology.


Kelleher F.C.,Adelaide and Meath Hospital | McDermott R.,Adelaide and Meath Hospital
European Journal of Cancer | Year: 2010

The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin's lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered.1 In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system.2-5 Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic.6 Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities. © 2010 Elsevier Ltd. All rights reserved.

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