• JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

      Donnellan, Fergal; Keating, Niamh; Geoghegan, Paul; Murray, Frank E; Harvey, Brian J P; Keely, Stephen J; Dept. of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Education and Research Ctr., Smurfit Bldg., Beaumont Hospital, Dublin 9, Ireland. (2010-01)
      Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.
    • Juxta-articular myxoma: an unusual benign mesenchymal lesion, readily mistaken for malignancy

      Beggan, C; Davies, K; Kinsella, J; Leader, M (Irish Medical Journal, 2014-07)
      Myxomas are benign tumours of mesenchymal origin. We describe the 1st reported case of paraspinal juxta-articular myxoma. Juxta-articular myxomas show increased cellularity and distinction from cellular myxoma is required. The differential also includes malignant myxofibrosarcoma. For patient prognosis and management it is essential to separate these entities. Complete surgical excision is the mainstay of treatment as local recurrences may occur.
    • Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

      Robinson, G B; Department of Psychology, University of New Brunswick, Fredericton, Canada. (1991-10-18)
      The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.
    • Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.

      Arsov, Todor; Smith, Katherine R; Damiano, John; Franceschetti, Silvana; Canafoglia, Laura; Bromhead, Catherine J; Andermann, Eva; Vears, Danya F; Cossette, Patrick; Rajagopalan, Sulekha; et al. (2011-05-13)
      The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
    • Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

      Krauss, Daniel; Kestin, Larry; Ye, Hong; Brabbins, Donald; Ghilezan, Michel; Gustafson, Gary; Vicini, Frank; Martinez, Alvaro; Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073,, USA. dkrauss@beaumont.edu (2012-02-01)
      PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.
    • Lafora disease: epidemiology, pathophysiology and management.

      Monaghan, Thomas S; Delanty, Norman; Department of Neurology and Neuroscience, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin 9, Ireland. (2010-07-01)
      Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The condition is characterized by epilepsy, myoclonus and dementia. Diagnostic findings on MRI and neurophysiological testing are not definitive and biopsy or genetic studies may be required. Therapy in Lafora disease is currently limited to symptomatic management of the epilepsy, myoclonus and intercurrent complications. With a greater understanding of the pathophysiological processes involved, there is justified hope for future therapies.
    • Language processing abnormalities in adolescents with psychotic-like experiences: An event related potential study.

      Murphy, Jennifer; Blanchard, Mathieu M; Rawdon, Caroline; Kavanagh, Fergal; Kelleher, Ian; Clarke, Mary C; Roche, Richard A P; Cannon, Mary; Department of Psychology, National University of Ireland, Maynooth, Co. Kildare, Ireland; Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland. (2012-05)
      Language impairments are a well established finding in patients with schizophrenia and in individuals at-risk for psychosis. A growing body of research has revealed shared risk factors between individuals with psychotic-like experiences (PLEs) from the general population and patients with schizophrenia. In particular, adolescents with PLEs have been shown to be at an increased risk for later psychosis. However, to date there has been little information published on electrophysiological correlates of language comprehension in this at-risk group. A 64 channel EEG recorded electrical activity while 37 (16 At-Risk; 21 Controls) participants completed the British Picture Vocabulary Scale (BPVS-II) receptive vocabulary task. The P300 component was examined as a function of language comprehension. The at-risk group were impaired behaviourally on receptive language and were characterised by a reduction in P300 amplitude relative to the control group. The results of this study reveal electrophysiological evidence for receptive language deficits in adolescents with PLEs, suggesting that the earliest neurobiological changes underlying psychosis may be apparent in the adolescent period.
    • Laparoscopic adrenalectomy: Single centre experience.

      O'Farrell, N J; Collins, C G; Stafford, A T; Broe, P J; Department of General Surgery, Beaumont Hospital, Beaumont Road, Dublin 9,, Ireland. (2012-02-01)
      BACKGROUND: Laparoscopic adrenalectomy is an attractive alternative to the traditional open approach in the surgical excision of an adrenal gland. It has replaced open adrenalectomy in our institution and we review our experience to date. METHODS: All cases of laparoscopic adrenalectomies in our hospital over eight years (from 2001 to May 2009) were retrospectively reviewed. Patient demographics, diagnosis, length of hospital stay, histology and all operative and post-operative details were evaluated. RESULTS: Fifty-five laparoscopic adrenalectomies (LA) were performed on 51 patients over eight years. The mean age was 48 years (Range 16-86 years) with the male: female ratio 1:2. Twenty-three cases had a right adrenalectomy, 24 had a left adrenalectomy and the remaining four patients had bilateral adrenalectomies. 91% were successfully completed laparoscopically with five converted to an open approach. Adenomas (functional and non functional) were the leading indication for LA, followed by phaeochromocytomas. Other indications for LA included Cushing's disease, adrenal malignancies and rarer pathologies. There was one mortality from necrotising pancreatitis following a left adrenalectomy for severe Cushing's disease, with subsequent death 10 days later. CONCLUSION: Laparoscopic adrenalectomy is effective for the treatment of adrenal tumours, fulfilling the criteria for the ideal minimally invasive procedure. It has replaced the traditional open approach in our centre and is a safe and effective alternative. However, in the case of severe Cushing's disease, laparoscopic adrenalectomy has the potential for significant adverse outcomes and mortality.
    • Laparoscopic hemicolectomy for cutaneous malignant melanoma metastasis to the ileocaecal valve

      Boland, T; Burke, J; Morrin, M; Deasy, J (Irish Medical Journal (IMJ), 2014-02)
      Colonic tumours are most frequently primary and lesions secondary to metastasis are uncommon. Malignant melanoma is an aggressive cancer, with a tendency to metastasize and recur. This report describes the case of a 66-year-old man who underwent wide local excision and adjuvant therapy for malignant melanoma three years prior to presentation with loose stools, abdominal cramps and iron deficiency anaemia. CT colonography showed a 6cm ileocaecal mass, and following a laparoscopic right hemicolectomy, histological examination revealed a metastatic melanoma to the ileocaecal valve. Subsequent positron emission tomography showed no residual metastatic disease. Malignant melanoma metastasis to the colon is a rare clinical entity. Metastectomy via laparoscopic right hemicolectomy is an appropriate and effective treatment.
    • 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)