• Laparoscopic Nissen Fundoplication post-oesophageal stenting: an unusual case

      Daruwalla, ZJ; Powles, S; Arumugasamy, M; Patchett, S; Broe, P (Irish Medical Journal, 2012-09)
    • Left versus right deceased donor renal allograft outcome.

      Phelan, Paul J; Shields, William; O'Kelly, Patrick; Pendergrass, Melissa; Holian, John; Walshe, Joseph J; Magee, Colm; Little, Dilly; Hickey, David; Conlon, Peter J; et al. (2009-12)
      It has been suggested that the left kidney is easier to transplant than the right kidney because of the longer length of the left renal vein, facilitating the formation of the venous anastomosis. There are conflicting reports of differing renal allograft outcomes based on the side of donor kidney transplanted (left or right).We sought to determine the effect of side of donor kidney on early and late allograft outcome in our renal transplant population. We performed a retrospective analysis of transplanted left-right deceased donor kidney pairs in Ireland between January 1, 1998 and December 31, 2008. We used a time to death-censored graft failure approach for long-term allograft survival and also examined serum creatinine at different time points post-transplantation. All outcomes were included from day of transplant onwards. A total of 646 transplants were performed from 323 donors. The incidence of delayed graft function was 16.1% in both groups and there was no significant difference in acute rejection episodes or serum creatinine from 1 month to 8 years post-transplantation.There were 47 death-censored allograft failures in the left-sided group compared to 57 in the right-sided group (P = 0.24). These observations show no difference in renal transplant outcome between the recipients of left- and right-sided deceased donor kidneys.
    • Length of stay following elective surgery can we improve efficiency?

      Solon, JG; Coffey, JC; McNamara, DA (Irish Medical Journal, 2013-06)
      Increasing emergency admissions place significant demands on limited hospital resources. We assessed national practices and resources for initiatives to reduce length of stay (LOS) and thereby improve efficiency of resource utilisation. Consultant members of the Irish Association of Coloproctology received a questionnaire seeking information about available initiatives aimed at reducing LOS. 20 out of 32 (62.5%) consultants responded to the questionnaire. Pre-assessment clinics for day surgery were available to 18(90%). Only 13 (65%) had access to pre-assessment clinics for patients requiring longer admissions. 11 (55%) could admit major cases on the day of surgery. Only 9 (45%) surgeons could guarantee immediate re-admission of patients discharged from hospital if needed. There was a divergence of opinion regarding the acceptable average LOS and percentage suitable for day surgery for a variety of common surgical procedures. This study highlights a number of key areas in which certain well-established initiatives could improve efficiency.
    • Life threatening sepsis while on high dose steroids requiring extra-corporeal membrane oxegenation

      Orr, C; McCarthy, C; Gunaratnam, C; Kearns, G (Irish Medical Journal (IMJ), 2013-07)
      We present a case of life-threatening streptococcal sepsis in a young man with a history of Behˆ§etâ s disease within two weeks of commencing high dose corticosteroid therapy for an exacerbation of Behˆ§etâ s disease.
    • Limited-preparation CT colonography in frail elderly patients: a feasibility study.

      Keeling, Aoife N; Slattery, Michael M; Leong, Sum; McCarthy, Eoghan; Susanto, Maja; Lee, Michael J; Morrin, Martina M; Department of Academic Radiology, Beaumont Hospital, Beaumont Rd, Dublin 9, Ireland. aoifekeeling@hotmail.com (2010-05)
      Full colonic preparation can be onerous and may be poorly tolerated in frail elderly patients. The purpose of this study was to prospectively assess the image quality and diagnostic yield of limited-preparation CT colonography (CTC) in elderly patients with suspected colorectal cancer who were deemed medically unfit or unsuitable for colonoscopy.
    • Limiting cardiovascular risk in Irish rheumatoid arthritis patients.

      Ambrose, N L; O'Connell, P; Kearns, G; Rheumatology Department, Beaumont Hospital, Dublin, Ireland. nambrose2001@yahoo.co.uk (2009-03)
      Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease and premature death.
    • Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.

      Donatello, Simona; Babina, Irina S; Hazelwood, Lee D; Hill, Arnold D K; Nabi, Ivan R; Hopkins, Ann M; Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. (2012-12)
      Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44-driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin-radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-β-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration.
    • Lipoxin A4 stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and cystic fibrosis airway epithelia.

      Verrière, Valia; Higgins, Gerard; Al-Alawi, Mazen; Costello, Richard W; McNally, Paul; Chiron, Raphaël; Harvey, Brian J; Urbach, Valérie; Department of Molecular Medicine, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland. (2012)
      Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl(-) secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA(4) is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA(4) are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA(4) produced a rapid and transient increase in intracellular Ca(2+). We have investigated, the effect of LXA(4) on Cl(-) secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA(4) stimulated a rapid intracellular Ca(2+) increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA(4) stimulated whole-cell Cl(-) currents which were inhibited by NPPB (calcium-activated Cl(-) channel inhibitor), BAPTA-AM (chelator of intracellular Ca(2+)) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA(4) increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA(4) effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl(-) secretion. The LXA(4) stimulation of intracellular Ca(2+), whole-cell Cl(-) currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA(4) in the stimulation of intracellular Ca(2+) signalling leading to Ca(2+)-activated Cl(-) secretion and enhanced ASL height in non-CF and CF bronchial epithelia.
    • LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.

      Bergsson, Gudmundur; Reeves, Emer P; McNally, Paul; Chotirmall, Sanjay H; Greene, Catherine M; Greally, Peter; Murphy, Philip; O'Neill, Shane J; McElvaney, Noel G; Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. bergsson@here.is (2009-07-01)
      There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.
    • Long term outcomes in patients receiving cardiac resynchronization therapy: A 10-year single center Irish registry

      Al Qaseer, M; Collis, R; Jamshaid, M; Collins, A; Sheahan, R (Oxford Journals, 2011-08)
    • Long-term experience of plasmapheresis in antibody-mediated rejection in renal transplantation.

      Brown, C M; Abraham, K A; O'Kelly, P; Conlon, P J; Walshe, J J; Department of Nephrology, Beaumont Hospital, Dublin, Ireland. catherinebrownis@gmail.com (2009-11)
      Antibody-mediated rejection (AMR) continues to pose a serious challenge in renal transplantation with potentially devastating consequences. Treatment options for this condition include plasmapheresis, high-dose intravenous immunoglobulin (IVIG), plasmapheresis with low-dose IVIG, and the use of rituximab (anti-CD20 chimeric antibody). We previously reported on the short-term outcome of plasmapheresis as a rescue therapy for AMR in our centre. We now report on the long-term follow up.
    • Long-term follow-up of non-calcified pulmonary nodules (<10 mm) identified during low-dose CT screening for lung cancer.

      Slattery, Michael M; Foley, Claire; Kenny, Dermot; Costello, Richard W; Logan, P Mark; Lee, Michael J; Department of Radiology, Beaumont Hospital, Beaumont Road, Dublin, Ireland. (2012-09)
      To assess the long-term stability of small (<10 mm) non-calcified pulmonary nodules (NCNs) in high-risk subjects initially screened for lung cancer using low-dose chest computed tomography (LDCCT).
    • Long-term outcome of intensive initial immunosuppression protocol in pediatric deceased donor renal transplantation.

      Olaitan, Oyedolamu K; Zimmermann, Jose A; Shields, William P; Rodriguez-Navas, Guillermo; Awan, Atif; Mohan, Ponnusamy; Little, Dilly M; Hickey, David P; National Kidney and Pancreas Transplantation Centre, Beaumont Hospital, Dublin, Ireland. oyedolamu@yahoo.com (2010-02)
      To report the long-term outcome of deceased donor kidney transplantation in children with emphasis on the use of an intensive initial immunosuppression protocol using R-ATG as antibody induction. Between January 1991 and December 1997, 82 deceased donor kidney transplantations were performed in 75 pediatric recipients. Mean recipient age at transplantation was 12.9 yr and the mean follow-up period was 12.6 yr. All patients received quadruple immunosuppression with steroid, cyclosporine, azathioprine, and antibody induction using R-ATG-Fresenius. Actual one, five, and 10 yr patient survival rates were 99%, 97%, and 94%, respectively; only one patient (1.2%) developed PTLD. Actual one, five, and 10 yr overall graft survival rates were 84%, 71%, and 50%, respectively; there were five cases (6%) of graft thrombosis and the actual immunological graft survival rates were 91%, 78%, and 63% at one, five, and 10 yr, respectively. The use of an intensive initial immunosuppression protocol with R-ATG as antibody induction is safe and effective in pediatric recipients of deceased donor kidneys with excellent immunological graft survival without an increase in PTLD or other neoplasms over a minimum 10-yr follow up.
    • Long-term quality-of-life outcome after mesh sacrocolpopexy for vaginal vault prolapse.

      Thomas, Arun Z; Giri, Subhasis K; Cox, Ann-Marie; Creagh, Tom; Department of Urology and Renal Transplantation, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland. arunthomas75@gmail.com (2009-12)
      To evaluate the long-term outcome of mesh sacrocolpopexy (MSC, which aims to restore normal pelvic floor anatomy to alleviate prolapse related symptoms) and its effect on patient's quality of life, as women with vaginal vault prolapse commonly have various pelvic floor symptoms that can affect urinary, rectal and sexual function.
    • Loss of chromosome 1p/19q in oligodendroglial tumors: refinement of chromosomal critical regions and evaluation of internexin immunostaining as a surrogate marker.

      Buckley, Patrick G; Alcock, Leah; Heffernan, Josephine; Woods, Jack; Brett, Francesca; Stallings, Raymond L; Farrell, Michael A; The Royal College of Surgeons in Ireland, Cancer Genetics, 2nd Floor York House, York Street, Dublin, Dublin 2, Ireland. pbuckley@rcsi.ie (2011-03)
      Loss of chromosome 1p/19q in oligodendrogliomas represents a powerful predictor of good prognosis. Expression of internexin (INA), a neuronal specific intermediate filament protein, has recently been proposed as a surrogate marker for 1p/19q deletion based on the high degree of correlation between both parameters in oligodendrogliomas. The aim of this study was to assess further the diagnostic utility of INA expression in a set of genetically well-characterized oligodendrogliomas. On the basis of a conservative approach for copy number determination, using both comparative genomic hybridization and fluorescent in situ hybridization, INA expression as a surrogate marker for 1p/19q loss had both reduced specificity (80%) and sensitivity (79%) compared with respective values of 86% and 96% reported in the previous report. The histologic interpretation and diagnostic value of INA expression in oligodendrogliomas should therefore be assessed with greater caution when compared with 1p/19q DNA copy number analysis. In addition, DNA copy number aberrations of chromosomes 10, 16, and 17 were detected exclusively in 1p/19q codeleted samples, suggesting that other regions of the genome may contribute to the 1p/19q-deleted tumor phenotype inthese samples.
    • Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer.

      Furlong, Fiona; Fitzpatrick, Patricia; O'Toole, Sharon; Phelan, Sine; McGrogan, Barbara; Maguire, Aoife; O'Grady, Anthony; Gallagher, Michael; Prencipe, Maria; McGoldrick, Aloysius; et al. (2012-04)
      Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC.
    • Low predictive value of positive transplant perfusion fluid cultures for diagnosing postoperative infections in kidney and kidney-pancreas transplantation.

      Cotter, Meaghan P; Smyth, Elizabeth; O'Gorman, Joanne; Browne, Sarah; Hickey, David P; Humphreys, Hilary; Department of Microbiology, Beaumont Hospital, Dublin, Ireland. mcotter@mater.ie (2012-12)
      Infection following transplantation is a cause of morbidity and mortality. Perfusion fluid (PF) used to preserve organs between recovery and transplantation represents a medium suitable for the growth of microbes. We evaluated the relevance of positive growth from PF sampled before the implantation of kidney or kidney-pancreas (KP) allografts.
    • Low total cortisol correlates closely with low free cortisol in traumatic brain injury and predicts mortality and long-term hypopituitarism

      Hannon, M J; Crowley, R K; Behan, L A; O'Sullivan, E P; Rogers, B; Rawluk, D; O'Dwyer, R; Agha, A; Thompson, C J (2011-06)
      Published data has demonstrated that low 0900h plasma total cortisol (PTC) in the acute phase following traumatic brain injury (TBI) predicts mortality. However, there is concern regarding the use of PTC to evaluate the pituitary-adrenal axis in acutely unwell patients due to potential discrepancies between PTC and plasma free cortisol (PFC) due to variations in corticosteroid binding globulin (CBG). We hypothesised that low PTC would correlate closely with PFC and would predict mortality and long-term hypopituitarism.100 patients (84 men, median age 33, range 18-75) were recruited on admission with TBI (mean GCS+/-SD = 8.59+/-4.2). Each patient had PTC and CBG measured on days 1, 3, 5, 7, and 10 following TBI. Results were compared with 15 patients admitted to ITU following vascular surgery. A PTC <300nmol/L in a patient in ITU was regarded clinically as inappropriately low. PFC was calculated for 25% of TBI samples and all control samples using Coolen's equation (1). TBI patients reattended for dynamic pituitary testing >6 months after TBI.All controls had PTC >500 nmol/L on day 1, and >300 nmol on days 3–10. By contrast, 78/100 TBI patients had at least one PTC <300 nmol/L.TBI patients in the lowest quartile of final PTC measurement had the highest mortality (p=0.0187). PTC correlated closely with PFC in both TBI patients (r=0.99, p<0.0001) and controls (r=0.99, p<0.0001). 32/79 (40.5%) of TBI survivors attended for dynamic pituitary testing. The median time to dynamic pituitary testing was 14 months (range 6–24 months). 15/32 (46.9%) underwent insulin tolerance testing, 9/32 (28.1%) underwent glucagon testing and 8/32 (25%) underwent short synacthen testing. 6/32 (18.8%) were ACTH deficient, of whom 5/6 (83.3%) previously had low PTC. 6/32 were GH deficient, all of whom previously had low PTC. One patient was gonadotropin deficient; he previously had low PTC. No patients were TSH or prolactin deficient. Overall, 12/32 (37.5%) had one or more pituitary hormone deficits. Lower mean PTC and final PTC were strongly associated with the development of chronic hypopituitarism (p = 0.049 and 0.015 respectively). There were no significant differences between those patients with acute or chronic hypopituitarism and those with no deficits in terms of age, initial GCS or CT appearances.PTC is an accurate surrogate marker of PFC in acutely unwell patients. Low PTC following TBI is predictive of mortality, and long-term hypopituitarism in TBI survivors.
    • Low-dose hydrocortisone (HC) replacement therapy is associated with improved bone remodeling balance in hypopituitary subjects

      Behan, L A; Kelleher, G; Hannon, M J; Brady, J J; Rogers, B; Tormey, W; Smith, D; Thompson, C J; McKenna, M J; Agha, A (2011-06)
      The effect of commonly used glucocorticoid replacement regimens on bone health in hypopituitary subjects is not well known. We aimed to assess the effect of 3 hydrocortisone (HC) replacement dose regimens on bone turnover in this group.10 hypopituitary men with severe ACTH deficiency were randomised in a crossover design to 3 HC dose regimens, Dose A (20mg mane, 10mg tarde), Dose B (10mg twice daily) and Dose C (10mg mane, 5mg tarde). Following 6 weeks of each regimen participants underwent fasting sampling of bone turnover markers.Data from matched controls were used to produce a Z score for subject bone formation and resorption markers and to calculate the bone remodeling balance (formation Z score-resorption Z score) and turnover index ((formation Z + resorption Z)/2). A positive bone remodeling balance with increased turnover is consistent with a favourable bone cycle. Data are expressed as median (range).The Pro Collagen Type 1 Peptide (PINP) bone formation Z-score was significantly increased in Dose C, (1.805 (-0.6-10.24)) compared to Dose A (0.035 (-1.0-8.1)) p<0.05 while there was no difference in the C-terminal crosslinking telopeptide (CTx) resorption Z score. The bone remodeling balance was significantly lower for dose A -0.02 (-1.05-4.12) compared to dose C 1.13 (0.13-6.4) (p<0.05). Although there was a trend to an increased bone turnover index with the lower dose regimen, this was not statistically significant.Low dose HC replacement (10mg mane/5 mg tarde) was associated with increased bone formation and improved bone remodeling balance which is associated with a more favourable bone cycle. This may have a long term beneficial effect on bone health.