• Mechanisms underlying rapid aldosterone effects in the kidney.

      Thomas, Warren; Harvey, Brian J; Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. wthomas@rcsi.ie (2011-03-17)
      The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.
    • Mechanisms underlying rapid aldosterone effects in the kidney.

      Thomas, Warren; Harvey, Brian J; Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont , Hospital, Dublin, Ireland. wthomas@rcsi.ie (2012-02-01)
      The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.
    • Medical confidentiality versus disclosure: Ethical and legal dilemmas.

      Agyapong, V I O; Kirrane, R; Bangaru, R; Department of Psychiatry, Beaumont Hospital, Dublin 9 Ireland. israelhans@hotmail.com (2009-02)
      A case is described of a fifty year old single man who made disclosures about criminal sexual practices during a psychiatric assessment. In common practice with other professional men, a doctor is under a duty not to disclose, without the consent of his patient, information which he has gained in his professional capacity other than in exceptional circumstances. We discuss the ethical and legal considerations surrounding issues of medical confidentiality and the dilemma that sometimes face clinicians, when they feel obliged, in the public interest, to disclose information they have gained in confidence. Breach of confidences can have deleterious consequences; particularly for the doctor-patient relationship, but failure to disclose in some situations could have serious implications for the well-being of the wider society. Doctors should be aware of the basic principles of confidentiality and the ethical and legal framework around which they are built.
    • Medication incidents reported to an online incident reporting system.

      Alrwisan, Adel; Ross, Jennifer; Williams, David; The National Pharmacovigilance Centre, Saudi Food and Drug Authority, Riyadh, Saudi Arabia, aarwisan@sfda.gov.sa. (2011-01-15)
      AIMS: Approximately 20% of deaths from adverse events are related to medication incidents, costing the NHS an additional £500 million annually. Less than 5% of adverse events are reported. This study aims to assess the reporting rate of medication incidents in NHS facilities in the north east of Scotland, and to describe the types and outcomes of reported incidents among different services. Furthermore, we wished to quantify the proportion of reported incidents according to the reporters' profession. METHODS: A retrospective description was made of medication incidents reported to an online reporting system (DATIX) over a 46-month-period (July 2005 to April 2009). Reports originated from acute and community hospitals, mental health, and primary care facilities. RESULTS: Over the study period there were 2,666 incidents reported with a mean monthly reporting rate of 78.2/month (SD±16.9). 6.1% of all incidents resulted in harm, with insulin being the most commonly implicated medication. Nearly three-quarters (74.2%, n=1,978) of total incidents originated from acute hospitals. Administration incidents were implicated in the majority of the reported medication incidents (59%), followed by prescribing (10.8%) and dispensing (9.9%), while the nondescript "other medication incidents" accounted for 20.3% of total incidents. The majority of reports were made by nursing and midwifery staff (80%), with medical and dental professionals reporting the lowest number of incidents (n=56, 2%). CONCLUSIONS: The majority of medication incidents in this study were reported by nursing and midwifery staff, and were due to administration incidents. There is a clear need to elucidate the reasons for the limited contribution of the medical and dental professionals to reporting medication incidents.
    • Mercury enquiries to a national poisons information centre - Poisoning or exposure?

      O'Connor, F; Casey, P B; Tracey, J A; Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. (2010-05)
    • Mesalazine-induced bronchiolitis obliterans organizing pneumonia (BOOP) in a patient with ulcerative colitis and primary sclerosing cholangitis.

      Kevans, D; Greene, J; Galvin, L; Morgan, R; Murray, F E; Department of Gastroenterology, Beaumont Hospital, Dublin, Ireland. (2011-07-14)
    • Metaplastic breast cancer

      Hennessy, B (2011-05)
      Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptornegative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.
    • Meticillin-sensitive Staphylococcus aureus costochondritis in a healthy man.

      Mohammad, Ausaf F; Ambrose, Nicky; Hamnvik, Ole-Petter R; Kearns, Grainne; Department of Rheumatology, Beaumont Hospital, Dublin, Ireland. ausafmohammad@gmail.com (2009-12)
      A 54-year-old previously healthy white man presented to hospital with fever, right parasternal pain and swelling over the right second and third costochondral joints. The symptoms had developed 1 week earlier.
    • MicroRNAs in inflammatory lung disease--master regulators or target practice?

      Oglesby, Irene K; McElvaney, Noel G; Greene, Catherine M; Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. (2010)
      MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.
    • Mini-open retropleural transthoracic approach for the treatment of giant thoracic disc herniation.

      Moran, Catherine; Ali, Zulfiqar; McEvoy, Linda; Bolger, Ciaran; National Centre for Neurosurgery, Research Unit, Beaumont Hospital, Dublin, Ireland. catherinemoran@rcsi.ie (2012-08-01)
      We report on all patients treated for giant thoracic disc herniation in the past 10 years.
    • A minimalist policy for breast cancer surveillance.

      Schapira, D V; Urban, N; Section of Cancer Prevention, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa 33612. (1991-01-16)
    • miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression.

      Oglesby, Irene K; Bray, Isabella M; Chotirmall, Sanjay H; Stallings, Raymond L; O'Neill, Shane J; McElvaney, Noel G; Greene, Catherine M; Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Ireland. (2010-02-15)
      Cystic fibrosis (CF) is one of the most common lethal genetic diseases in which the role of microRNAs has yet to be explored. Predicted to be regulated by miR-126, TOM1 (target of Myb1) has been shown to interact with Toll-interacting protein, forming a complex to regulate endosomal trafficking of ubiquitinated proteins. TOM1 has also been proposed as a negative regulator of IL-1beta and TNF-alpha-induced signaling pathways. MiR-126 is highly expressed in the lung, and we now show for the first time differential expression of miR-126 in CF versus non-CF airway epithelial cells both in vitro and in vivo. MiR-126 downregulation in CF bronchial epithelial cells correlated with a significant upregulation of TOM1 mRNA, both in vitro and in vivo when compared with their non-CF counterparts. Introduction of synthetic pre-miR-126 inhibited luciferase activity in a reporter system containing the full length 3'-untranslated region of TOM1 and resulted in decreased TOM1 protein production in CF bronchial epithelial cells. Following stimulation with LPS or IL-1beta, overexpression of TOM1 was found to downregulate NF-kappaB luciferase activity. Conversely, TOM1 knockdown resulted in a significant increase in NF-kappaB regulated IL-8 secretion. These data show that miR-126 is differentially regulated in CF versus non-CF airway epithelial cells and that TOM1 is a miR-126 target that may have an important role in regulating innate immune responses in the CF lung. To our knowledge, this study is the first to report of a role for TOM1 in the TLR2/4 signaling pathways and the first to describe microRNA involvement in CF.
    • MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation.

      Allott, Emma H; Lysaght, Joanne; Cathcart, Mary Clare; Donohoe, Claire L; Cummins, Robert; McGarrigle, Sarah A; Kay, Elaine; Reynolds, John V; Pidgeon, Graham P; Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. (2011-11-28)
      Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients. © 2011 Wiley Periodicals, Inc.
    • Mo1368 How much is an endoscopist's time worth? Analysis of revenue generated by endoscopic activity

      Anwar, Malik M.; Harewood, Gavin C.; Zeb, Faisal; Hamed, Mohamed A. (2011)
    • Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.

      Pradeep, C-R; Köstler, W J; Lauriola, M; Granit, R Z; Zhang, F; Jacob-Hirsch, J; Rechavi, G; Nair, H B; Hennessy, B T; Gonzalez-Angulo, A M; et al. (2012-02-16)
      A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.
    • The Modified Rivermead Mobility Index: reliability and convergent validity in a mixed neurological population.

      Walsh, Julie M; Barrett, Aileen; Murray, Deirdre; Ryan, Joseph; Moroney, Joan; Shannon, Michelle; Department of Physiotherapy, Royal College of Surgeons in Ireland, and Beaumont Hospital, Dublin, Ireland. walshj7@tcd.ie (2010)
      To assess the inter-rater reliability, internal consistency and convergent validity of the Modified Rivermead Mobility Index (MRMI) in a mixed neurological population.
    • Molecular Targeted Therapy in Ovarian Cancer: What is on the Horizon?

      Kalachand, Roshni; Hennessy, Bryan T; Markman, Maurie; Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland. (2011-05-28)
      Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high-throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles.
    • Molecular targeted therapy in ovarian cancer: what is on the horizon?

      Kalachand, Roshni; Hennessy, Bryan T; Markman, Maurie; Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland., roshnikalachand@physicians.ie (2012-02-01)
      Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high-throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles.
    • Monitoring Clostridium difficile infection in an acute hospital: prevalence or incidence studies?

      Lavan, A H; McCartan, D P; Downes, M M; Hill, A D K; Fitzpatrick, F; Department of Surgery, Beaumont Hospital, Smurfit Building, Dublin 9, Ireland, amandalavan@gmail.com. (2012-02-15)
      BACKGROUND: Surveillance of Clostridium difficile infection (CDI) is an essential component of a CDI preventative programme. AIMS: The aim of this study was to evaluate two methods of CDI surveillance. METHODS: Prevalence of CDI, antibiotic use and associated co-morbidity was assessed weekly on two wards over 6 weeks. In addition, CDI incidence surveillance was performed on all new CDI cases over a 13-week period. Cases were assessed for CDI risk factors, disease severity, response to treatment and outcome at 6 months. RESULTS: Clostridium difficile infection prevalence was 3.5% (range 2.9-6.1%) on the medical ward and 1.1% (range 0-3.5%) on the surgical ward. Patients on the medical ward were older and more likely to be colonised with MRSA; however, recent antibiotic use was more prevalent among surgical patients. Sixty-one new CDI cases were audited. Patients were elderly (mean age 71 years) with significant co-morbidity (median age adjusted Charlson co-morbidity score 5). CDI ribotypes included 027 (29 cases) 078 (5) and 106 (4). Eight patients developed severe CDI, seven due to 027. Antibiotic use was common with 56% receiving three or more antibiotics in the preceding 8 weeks. Twenty-four patients had died at 6 months, five due to CDI. CONCLUSION: Clostridium difficile infection prevalence gives a broad overview of CDI and points to areas that require more detailed surveillance and requires little time. However, patient-based CDI incidence surveillance provides a more useful analysis of CDI risk factors, disease and outcome for planning preventative programmes and focusing antibiotic stewardship efforts.
    • Monitoring medicines use: the role of the clinical pharmacologist.

      Williams, David; Department of Geriatric and Stroke Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. davidwilliams@rcsi.ie (2012-10)
      Appreciation of the potential of newly marketed medicines to produce both benefit and harm has increased the role of the clinical pharmacologist. Pharmacoepidemiology applies epidemiological reasoning, methods and knowledge to the study of the uses and effects of drugs in human populations. Pharmacovigilence identifies and then responds to safety issues about marketed drugs. Whilst adverse drug reaction (ADR) reporting systems can identify potential problems with drugs, determination of causation requires population-based studies of adverse events (including information from large clinical trials), which attempt to link unequivocally the adverse outcome to the drug in question. Pharmacovigilance is closely linked to postmarketing surveillance and is important for determining issues such as the long-term effects of drugs, identification of low-frequency ADRs, the effectiveness of drugs for their licensed indications or in new indications and other factors which may modify the efficacy and effectiveness of the drug in question. The related field of drug utilization developed in parallel with the study of adverse drug reactions, in recognition of the dramatic increase in the marketing of new drugs, the wide variations in the patterns and extent of drug prescribing, the growing concern about ADRs and the increasing costs of drugs. With the ever increasing number of recognized adverse effects of drugs, prescribing errors, patients' expectations concerning drug safety and the need for appropriate new drug appraisal, the clinical pharmacologist will play an important role both in the introduction of new drugs and in improving the safe and effective use of established drugs.