• Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

      Barry, Andrew E; Klyubin, Igor; Mc Donald, Jessica M; Mably, Alexandra J; Farrell, Michael A; Scott, Michael; Walsh, Dominic M; Rowan, Michael J; Department of Pharmacology and Therapeutics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland, Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland, and Dublin Brain Bank, Pathology Department, Beaumont Hospital, Dublin 9, Ireland. (2011-05-18)
      Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.
    • An application of principal component analysis to the clavicle and clavicle fixation devices.

      Daruwalla, Zubin J; Courtis, Patrick; Fitzpatrick, Clare; Fitzpatrick, David; Mullett, Hannan (2010-03-26)
      Abstract Background Principal component analysis (PCA) enables the building of statistical shape models of bones and joints. This has been used in conjunction with computer assisted surgery in the past. However, PCA of the clavicle has not been performed. Using PCA, we present a novel method that examines the major modes of size and three-dimensional shape variation in male and female clavicles and suggests a method of grouping the clavicle into size and shape categories. Materials and methods Twenty-one high-resolution computerized tomography scans of the clavicle were reconstructed and analyzed using a specifically developed statistical software package. After performing statistical shape analysis, PCA was applied to study the factors that account for anatomical variation. Results The first principal component representing size accounted for 70.5 percent of anatomical variation. The addition of a further three principal components accounted for almost 87 percent. Using statistical shape analysis, clavicles in males have a greater lateral depth and are longer, wider and thicker than in females. However, the sternal angle in females is larger than in males. PCA confirmed these differences between genders but also noted that men exhibit greater variance and classified clavicles into five morphological groups. Discussion And Conclusions This unique approach is the first that standardizes a clavicular orientation. It provides information that is useful to both, the biomedical engineer and clinician. Other applications include implant design with regard to modifying current or designing future clavicle fixation devices. Our findings support the need for further development of clavicle fixation devices and the questioning of whether gender-specific devices are necessary.
    • Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

      Gray, Sarah E; Kay, Elaine W; Leader, Mary; Mabruk, Mohamed; Pathology Department, Royal College of Surgeons in Ireland and Beaumont Hospital,, Dublin, Ireland. (2012-02-01)
      BACKGROUND: The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC). AIM: To determine the role played by APC gene in the genesis of cutaneous SCC. MATERIALS AND METHODS: Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in twenty-two histologically confirmed cutaneous squamous cell carcinomas (SCC) using microsatellite markers, proximal to the APC gene. Immunohistochemical analysis of APC protein expression was also examined in the cutaneous SCC. RESULTS: AI/LOH was detected in 60% of the SCC samples using D5S346 marker (proximal to the APC gene). Ninty-five percent of the SCC samples showed positive reduced APC expression, however the localization of the APC protein was abnormal. CONCLUSION: The abnormal expression of APC suggests that APC gene may play a role in cutaneous SCC development.
    • Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

      Gray, Sarah E; Kay, Elaine W; Leader, Mary; Mabruk, Mohamed; Pathology Department, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin, Ireland. (2011-05)
      The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC).
    • Analysis of Margin Index as a Method for Predicting Residual Disease After Breast-Conserving Surgery in a European Cancer Center.

      Bolger, Jarlath C; Solon, Jacqueline G; Power, Colm; Hill, Arnold D K; Department of Surgery, Beaumont Hospital, Dublin 9, Ireland, jarlathbolger@yahoo.co.uk. (2011-06-03)
      INTRODUCTION: Breast-conserving surgery (BCS), followed by appropriate adjuvant therapies is established as a standard treatment option for women with early-stage invasive breast cancers. A number of factors have been shown to correlate with local and regional disease recurrence. Although margin status is a strong predictor of disease recurrence, consensus is yet to be established on the optimum margin necessary. Margenthaler et al. recently proposed the use of a "margin index," combining tumor size and margin status as a predictor of residual disease after BCS. We applied this new predictive tool to a population of patients with primary breast cancer who presented to a symptomatic breast unit to determine its suitability in predicting those who require reexcision surgery. METHODS: Retrospective analysis of our breast cancer database from January 1, 2000 to June 30, 2010 was performed, including all patients who underwent BCS. Of 531 patients who underwent BCS, 27.1% (144/531) required further reexcision procedures, and 55 were eligible for inclusion in the study. Margin index was calculated as: margin index = closest margin (mm)/tumor size (mm) × 100, with index >5 considered optimum. RESULTS: Of the 55 patients included, 31% (17/55) had residual disease. Fisher's exact test showed margin index not to be a significant predictor of residual disease on reexcision specimen (P = 0.57). Of note, a significantly higher proportion of our patients presented with T2/3 tumors (60% vs. 38%). CONCLUSIONS: Although an apparently elegant tool for predicting residual disease after BCS, we have shown that it is not applicable to a symptomatic breast unit in Ireland.
    • Analysis of margin index as a method for predicting residual disease after breast-conserving surgery in a European cancer center.

      Bolger, Jarlath C; Solon, Jacqueline G; Power, Colm; Hill, Arnold D K; Department of Surgery, Beaumont Hospital, Dublin 9, Ireland,, jarlathbolger@yahoo.co.uk. (2012-02-01)
      INTRODUCTION: Breast-conserving surgery (BCS), followed by appropriate adjuvant therapies is established as a standard treatment option for women with early-stage invasive breast cancers. A number of factors have been shown to correlate with local and regional disease recurrence. Although margin status is a strong predictor of disease recurrence, consensus is yet to be established on the optimum margin necessary. Margenthaler et al. recently proposed the use of a "margin index," combining tumor size and margin status as a predictor of residual disease after BCS. We applied this new predictive tool to a population of patients with primary breast cancer who presented to a symptomatic breast unit to determine its suitability in predicting those who require reexcision surgery. METHODS: Retrospective analysis of our breast cancer database from January 1, 2000 to June 30, 2010 was performed, including all patients who underwent BCS. Of 531 patients who underwent BCS, 27.1% (144/531) required further reexcision procedures, and 55 were eligible for inclusion in the study. Margin index was calculated as: margin index = closest margin (mm)/tumor size (mm) x 100, with index >5 considered optimum. RESULTS: Of the 55 patients included, 31% (17/55) had residual disease. Fisher's exact test showed margin index not to be a significant predictor of residual disease on reexcision specimen (P = 0.57). Of note, a significantly higher proportion of our patients presented with T2/3 tumors (60% vs. 38%). CONCLUSIONS: Although an apparently elegant tool for predicting residual disease after BCS, we have shown that it is not applicable to a symptomatic breast unit in Ireland.
    • Analysis of trends and seasonal variation in primary cutaneous melanoma: an Irish study.

      Downes, M R; Fan, Y; Murphy, G; Gulmann, C; Department of Histopathology, Beaumont Road, Dublin, Ireland Department of Mathematical Sciences, University College Dublin, Belfield, Dublin 4, Ireland Department of Dermatology, Beaumont Hospital, Beaumont Road, Dublin, Ireland. (2010-11-10)
      A seasonal variation in the presentation of cutaneous melanoma has been documented in several studies. We performed a retrospective review of primary cutaneous melanomas (n = 263) from our institution to examine whether the seasonal patterns of presentation noted in the literature would be similar in Ireland, a climate with low ambient sunshine. A summer : winter ratio was determined for age, gender, subtype, location and Breslow thickness. We found an increase in total numbers of melanomas, particularly in men. The summer : winter ratio was 2.39 for all patients (95% CI 1.60-3.57, P < 0.001), with seasonal variations noted for location, thickness and subtype (excluding lentigo). Melanomas presenting over the summer tended towards a greater Breslow thickness than did those presenting in winter. This subclassification of primary cutaneous melanoma with summer : winter ratios based on patient and tumour characteristics gave remarkably similar results to previously published reports, notwithstanding the low levels of annual ambient sunshine in Ireland.
    • Analysis of waiting times on Irish renal transplant list.

      Phelan, P J; O'Kelly, P; O'Neill, D; Little, D; Hickey, D; Keogan, M; Walshe, J; Magee, C; Conlon, P J; Department of Nephrology, Beaumont Hospital, Dublin, Ireland. paulphel@gmail.com (2011-04-06)
      A number of recipient variables have been identified which influence waiting list times for a renal allograft. The aim of this study was to evaluate these factors in the Irish population.
    • Analyzing proteasomal subunit expression reveals Rpt4 as a prognostic marker in stage II colorectal cancer.

      Centre for Systems Medicine and Department of Physiology and Medical Physics,, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Surgery,, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland. (2012-02-01)
      Colorectal cancer is a leading cause of cancer-related deaths worldwide. Early diagnosis and treatment of colorectal cancer is the key to improving survival rates and as such a need exists to identify patients who may benefit from adjuvant chemotherapy. The dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in oncogenesis and cancer cell survival, and proteasome inhibitors are in clinical use for a number of malignancies including multiple myeloma. In our study, we examined the protein expression of several key components of the UPS in colorectal cancer using immunohistochemistry to determine expression levels of ubiquitinylated proteins and the proteasomal subunits, 20S core and Rpt4 in a cohort of 228 patients with colon cancer. Multivariate Cox analysis revealed that neither the intensity of either ubiquitinylated proteins or the 20S core was predictive in either Stage II or III colon cancer for disease free survival or overall survival. In contrast, in Stage II patients increased Rpt4 staining was significantly associated with disease free survival (Cox proportional hazard ratio 0.605; p = 0.0217). Our data suggest that Rpt4 is an independent prognostic variable for Stage II colorectal cancer and may aid in the decision of which patients undergo adjuvant chemotherapy.
    • Anaplastic thyroid cancer, tumorigenesis and therapy.

      O'Neill, J P; Power, D; Condron, C; Bouchier-Hayes, D; Walsh, M; The Department of Otolaryngology, The Royal College of Surgeons in Ireland, Beaumont Hospital, The Education and Research Building, Beaumont, Dublin 9, Ireland. joneill@rcsi.ie (2010-03)
      Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.
    • Anatomic variation of the clavicle: A novel three-dimensional study.

      Daruwalla, Zubin J; Courtis, Patrick; Fitzpatrick, Clare; Fitzpatrick, David; Mullett, Hannan; Department of Orthopaedic Surgery, Beaumont Hospital, Dublin, Ireland. zubinjimmydaruwalla@rcsi.ie (2010-03)
      An understanding of the complex anatomy of the clavicle is helpful in the treatment of clavicular fractures. Using three-dimensional (3D) statistical shape analysis, the author presents a novel method to assess geometric morphology of the clavicle. Fifteen fresh frozen shoulder specimens were scanned using high-resolution computerized tomography (CT) but four were excluded from the study. A further 16 high-resolution CT scans of the clavicle were obtained by searching the hospital database. All 27 scans were reconstructed and subsequently imported into and analyzed using a specifically developed statistical software package. Using statistical shape analysis, geometric parameters were then measured. Both gender as well as side specific geometric morphology were observed. Clavicles in men were longer, wider, and thicker than in women. Right clavicles had a greater medial depth than left clavicles, especially in women. Clavicles in men had a greater lateral depth than in women. The sternal angle in women was larger than in men. Using 3D statistical shape analysis and applying it to the clavicle standardizes the study of its anatomy, rules out any variability, and calculates morphological parameters that are accurate, precise, and reproducible. This unique approach provides information that is useful not only to the clinician but also in the modification of current or design of future clavicle fixation devices. More importantly, from an anatomy standpoint, implementation of this novel approach in anatomical studies would eliminate intra- and interobserver variation and allow all studies to be standardized and thus more comparable.
    • Anterior Hypopituitarism is Rare and Autoimmune Disease is Common in Adults with Idiopathic Central Diabetes Insipidus.

      Academic Department of Endocrinology, Beaumont Hospital / RCSI Medical School,, Dublin 9, Ireland And Endocrine Unit, Royal Victoria Infirmary, Newcastle, Hospitals NHS Trust and University of Newcastle, Newcastle-Upon-Tyne, NE1 4LP,, United Kingdom. (2012-02-01)
      Objective: Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, though many of these are thought to have an autoimmune basis. Published data has suggested that anterior hypopituitarism is common in childhood onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. Design and Patients: We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone MRI scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. Results: One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. 33% had at least one autoimmune disease in addition to central diabetes insipidus. Conclusions: Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not therefore be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.
    • Anti-apoptotic effects of Z alpha1-antitrypsin in human bronchial epithelial cells.

      Greene, C M; Miller, S D W; Carroll, T P; Oglesby, I K; Ahmed, F; O'Mahony, M; Taggart, C C; McElvaney, N G; O'Neill, S J; Dept of Medicine Respiratory Research Division, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. cmgreene@rcsi.ie (2010-05)
      alpha(1)-antitrypsin (alpha(1)-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of alpha(1)-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z alpha(1)-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved. Control, M variant alpha(1)-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-kappaB activation and induced expression of a selection of pro- and anti-apoptotic genes. Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-kappaB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-kappaB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies. The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.
    • Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis.

      Barry, Helen; Hardiman, Orla; Healy, Daniel G; Keogan, Mary; Moroney, Joan; Molnar, Peter P; Cotter, David R; Murphy, Kieran C; Department of Psychiatry, Royal College of Surgeons in Ireland, RCSI Education, and Research Centre, Beaumont Hospital, Dublin 9, Ireland. (2012-02-01)
      We present four cases of confirmed anti-NMDA receptor encephalitis; three presented initially with serious psychiatric symptoms and the other developed significant psychiatric symptoms during the initial phase of illness. Brain biopsy findings of one patient are also described. Psychiatrists should consider anti-NMDA receptor encephalitis in patients presenting with psychosis and additional features of dyskinesias, seizures and catatonia, particularly where there is no previous history of psychiatric disorder.
    • Anti-proline-glycine-proline or antielastin autoantibodies are not evident in chronic inflammatory lung disease.

      Greene, Catherine M; Low, Teck Boon; O'Neill, Shane J; McElvaney, Noel G; Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. cmgreene@rcsi.ie (2010-01-01)
      In patients with chronic inflammatory lung disease, pulmonary proteases can generate neoantigens from elastin and collagen with the potential to fuel autoreactive immune responses. Antielastin peptide antibodies have been implicated in the pathogenesis of tobacco-smoke-induced emphysema. Collagen-derived peptides may also play a role.
    • Anti-VEGF strategies - from antibodies to tyrosine kinase inhibitors: background and clinical development in human cancer.

      Korpanty, Grzegorz; Smyth, Elizabeth; Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland. greg.korpanty@gmail.com. (2012)
      Tumour angiogenesis (formation of new blood vessels supporting tumour growth and metastasis) is a result of complex interactions between the tumour and the surrounding microenvironment. Targeting tumours with anti-angiogenic therapy remains an exciting area of preclinical and clinical studies. Although many significant advances have been achieved and the clinical use of anti-angiogenic drugs is now well recognized in many solid malignancies, these therapies fall short of their anticipated clinical benefits and leave many unanswered questions like exact mechanism of action, patients' selection and monitoring response to anti-angiogenic drugs. Tumour angiogenesis is controlled by complex signaling cascades and ongoing research into molecular mechanisms of tumour angiogenesis not only helps to understand its basic mechanisms but hopefully will identify new therapeutic targets. In 2012, both monoclonal antibodies and small molecule tyrosine kinase inhibitors remain the two major clinically useful therapeutic options that interfere with tumour angiogenesis in many solid malignancies.
    • Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q.

      Kelly, Kevin; Murphy, Philip; Department of Haematology, Beaumont Hospital, Dublin, Ireland. kevrkelly77@hotmail.com (2008-12)
      Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.
    • Appendiceal intussusception and endometriosis mimicking colorectal cancer.

      Hanly, A M; Ryan, E M; McNamara, D A; Department of Colorectal Surgery, Beaumont Hospital, Dublin. amhanly@indigo.ie (2011-02)
    • Appendiceal intussusception and endometriosis mimicking colorectal cancer.

      Hanly, A M; Ryan, E M; McNamara, D A; Department of Colorectal Surgery, Beaumont Hospital, Dublin. amhanly@indigo.ie (2012-02-01)