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RCSI , is an elite Dublin-based medical institution, situated on St. Stephen's Green. The college is one of the five Recognised Colleges of the National University of Ireland. The college dates back to 1784 and at present incorporates schools of medicine, pharmacy, physiotherapy and nursing, providing both undergraduate and postgraduate levels of medical education.Among medical institutions outside Ireland, the use of the term "Royal College" currently indicates an oversight body for postgraduate medical education. RCSI performs such a function, but it is unique among the four Royal Colleges of Surgeons in that 100 years after its establishment, an undergraduate medical school was founded and this is now Ireland's largest medical school with over 3000 students from 60 countries. The RCSI is a sister institute of the Royal Surgical Colleges of the United Kingdom . Wikipedia.

Dunne E.,Royal College of Surgeons in Ireland
Arteriosclerosis, thrombosis, and vascular biology | Year: 2012

Thrombosis occurs at sites of vascular injury when platelets adhere to subendothelial matrix proteins and to each other. Platelets express many surface receptor proteins, the function of several of these remains poorly characterized. Cadherin 6 is expressed on the platelet surface and contains an arginine-glycine-aspartic acid motif, suggesting that it might have a supportive role in thrombus formation. The aim of this study was to characterize the role of cadherin 6 in platelet function. Platelet aggregation was inhibited by both antibodies and exogenous soluble cadherin 6. Platelet adhesion to immobilized cadherin 6 was inhibited by arginine-glycine-aspartic acid-serine tetrapeptides. Antibodies to α(IIb)β(3) inhibited platelet adhesion to cadherin 6. Because platelet aggregation occurs in fibrinogen and von Willebrand factor double-deficient mice, we investigated whether cadherin 6 is an alternative ligand for the integrin α(IIb)β(3). Platelet aggregation in fibrinogen and von Willebrand factor double-deficient mice was significantly inhibited by an antibody to cadherin 6. In flow-based assays, inhibition of cadherin 6 caused a marked reduction in thrombus formation in both human and mouse blood. This study demonstrates the role of cadherin 6 as a novel ligand for α(IIb)β(3) and highlights its function in thrombus formation.

Wakai A.,Royal College of Surgeons in Ireland
The Cochrane database of systematic reviews | Year: 2013

Current drug therapy for acute heart failure syndromes (AHFS) consists mainly of diuretics supplemented by vasodilators or inotropes. Nitrates have been used as vasodilators in AHFS for many years and have been shown to improve some aspects of AHFS in some small studies. The aim of this review was to determine the clinical efficacy and safety of nitrate vasodilators in AHFS. To quantify the effect of different nitrate preparations (isosorbide dinitrate and nitroglycerin) and the effect of route of administration of nitrates on clinical outcome, and to evaluate the safety and tolerability of nitrates in the management of AHFS. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (1950 to July week 2 2011) and EMBASE (1980 to week 28 2011). We searched the Current Controlled Trials MetaRegister of Clinical Trials (compiled by Current Science) (July 2011). We checked the reference lists of trials and contacted trial authors. We imposed no language restriction. Randomised controlled trials comparing nitrates (isosorbide dinitrate and nitroglycerin) with alternative interventions (frusemide and morphine, frusemide alone, hydralazine, prenalterol, intravenous nesiritide and placebo) in the management of AHFS in adults aged 18 and over. Two authors independently performed data extraction. Two authors performed trial quality assessment. We used mean difference (MD), odds ratio (OR) and 95% confidence intervals (CI) to measure effect sizes. Two authors independently assessed and rated the methodological quality of each trial using the Cochrane Collaboration tool for assessing risk of bias. Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with and without acute coronary syndromes.Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD 0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI 1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after 30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment to the patients (patient satisfaction scores).Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited as three of the studies did not give sufficient detail to allow assessment of potential risk of bias. There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates in AHFS because current evidence is based on few low-quality studies.

Hippocampal sclerosis (HS) is a common pathological finding in patients with temporal lobe epilepsy (TLE) and is associated with altered expression of genes controlling neuronal excitability, glial function, neuroinflammation and cell death. MicroRNAs (miRNAs), a class of small non-coding RNAs, function as post-transcriptional regulators of gene expression and are critical for normal brain development and function. Production of mature miRNAs requires Dicer, an RNAase III, loss of which has been shown to cause neuronal and glial dysfunction, seizures, and neurodegeneration. Here we investigated miRNA biogenesis in hippocampal and neocortical resection specimens from pharmacoresistant TLE patients and autopsy controls. Western blot analysis revealed protein levels of Dicer were significantly lower in certain TLE patients with HS. Dicer levels were also reduced in the hippocampus of mice subject to experimentally-induced epilepsy. To determine if Dicer loss was associated with altered miRNA processing, we profiled levels of 380 mature miRNAs in control and TLE-HS samples. Expression of nearly 200 miRNAs was detected in control human hippocampus. In TLE-HS samples there was a large-scale reduction of miRNA expression, with 51% expressed at lower levels and a further 24% not detectable. Primary transcript (pri-miRNAs) expression levels for several tested miRNAs were not different between control and TLE-HS samples. These findings suggest loss of Dicer and failure of mature miRNA expression may be a feature of the pathophysiology of HS in patients with TLE.

Henshall D.C.,Royal College of Surgeons in Ireland
Frontiers in Molecular Neuroscience | Year: 2013

MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis. © 2013 Henshall.

Smith S.M.,Royal College of Surgeons in Ireland
Cochrane database of systematic reviews (Online) | Year: 2012

Many people with chronic disease have more than one chronic condition, which is referred to as multimorbidity. While this is not a new phenomenon, there is greater recognition of its impact and the importance of improving outcomes for individuals affected. Research in the area to date has focused mainly on descriptive epidemiology and impact assessment. There has been limited exploration of the effectiveness of interventions for multimorbidity. To determine the effectiveness of interventions designed to improve outcomes in patients with multimorbidity in primary care and community settings. Multimorbidity was defined as two or more chronic conditions in the same individual. We searched MEDLINE, EMBASE, CINAHL, CAB Health, AMED, HealthStar, The Cochrane Central Register of Controlled Trials (CENTRAL), the EPOC Register and the Database of Abstracts of Reviews of Effectiveness (DARE), and the EPOC Register in April 2011. We considered randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs), and interrupted time series analyses (ITS) reporting on interventions to improve outcomes for people with multimorbidity in primary care and community settings. The outcomes included any validated measure of physical or mental health, psychosocial status including quality of life outcomes, well-being, and measures of disability or functional status. We also included measures of patient and provider behaviour including measures of medication adherence, utilisation of health services, and acceptability of services and costs. Two review authors independently assessed studies for eligibility, extracted data, and assessed study quality. Meta-analysis of results was not possible so we carried out a narrative synthesis of the results from the included studies. Ten studies examining a range of complex interventions for patients with multimorbidity were identified. All were RCTs and there was low risk of bias. Two of the nine studies focused on specific co-morbidities. The remaining studies focused on multimorbidity, generally in older patients. All studies involved complex interventions with multiple elements. In six of the ten studies, the predominant intervention element was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In the remaining four studies, the interventions were predominantly patient oriented. Overall the results were mixed with a trend towards improved prescribing and medication adherence. The results indicate that it is difficult to improve outcomes in this population but that interventions focusing on particular risk factors or functional difficulties in patients with co-morbid conditions or multimorbidity may be more effective. Cost data were limited with no economic analyses included, though the improvements in prescribing and risk factor management in some studies provided potentially significant cost savings. This review highlights the paucity of research into interventions to improve outcomes for multimorbidity with the focus to date being on co-morbid conditions or multimorbidity in older patients. The limited results suggest that interventions to date have had mixed effects but have shown a tendency to improve prescribing and medication adherence, particularly if interventions can be targeted at risk factors or specific functional difficulties in people with co-morbid conditions or multimorbidity. There is a need for clear definitions of participants, consideration of appropriate outcomes, and further pragmatic studies based in primary care settings.

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