Pharmacology & Therapeutics http://hdl.handle.net/2262/35 2013-05-13T17:39:56Z 2013-05-13T17:39:56Z BENNETT, KATHLEEN http://hdl.handle.net/2262/64044 2012-06-27T13:49:17Z 2011-01-01T00:00:00Z

Title: Antimicrobial management and appropriateness of treatment of urinary tract infection in general practice in Ireland. Author: BENNETT, KATHLEEN Abstract: BACKGROUND: Urinary tract infections (UTIs) are the second most common bacterial infections in general practice and a frequent indication for prescription of antimicrobials. Increasing concern about the association between the use of antimicrobials and acquired antimicrobial resistance has highlighted the need for rational pharmacotherapy of common infections in general practice. METHODS: Management of urinary tract infections in general practice was studied prospectively over 8 weeks. Patients presenting with suspected UTI submitted a urine sample and were enrolled with an opt-out methodology. Data were collected on demographic variables, previous antimicrobial use and urine samples. Appropriateness of different treatment scenarios was assessed by comparing treatment with the laboratory report of the urine sample. RESULTS: A total of 22 practices participated in the study and included 866 patients. Bacteriuria was established for 21% of the patients, pyuria without bacteriuria for 9% and 70% showed no laboratory evidence of UTI. An antimicrobial agent was prescribed to 56% (481) of the patients, of whom 33% had an isolate, 11% with pyuria only and 56% without laboratory evidence of UTI. When taking all patients into account, 14% patients had an isolate identified and were prescribed an antimicrobial to which the isolate was susceptible. The agents most commonly prescribed for UTI were co-amoxyclav (33%), trimethoprim (26%) and fluoroquinolones (17%). Variation between practices in antimicrobial prescribing as well as in their preference for certain antimicrobials, was observed. Treatment as prescribed by the GP was interpreted as appropriate for 55% of the patients. Three different treatment scenarios were simulated, i.e. if all patients who received an antimicrobial were treated with nitrofurantoin, trimethoprim or ciprofloxacin only. Treatment as prescribed by the GP was no more effective than treatment with nitrofurantoin for all patients given an antimicrobial or treatment with ciprofloxacin in all patients. Prescribing cost was lower for nitrofurantoin. Empirical treatment of all patients with trimethoprim only was less effective due to the higher resistance levels. CONCLUSIONS: There appears to be considerable scope to reduce the frequency and increase the quality of antimicrobial prescribing for patients with suspected UTI. Description: PUBLISHED

2011-01-01T00:00:00Z ONDREJCAK, TOMAS ROWAN, MICHAEL JOSEPH HU, NENG WEI http://hdl.handle.net/2262/61632 2012-01-12T14:01:48Z 2012-01-01T00:00:00Z

Title: Glutamate receptors in preclinical research on Alzheimer's disease: update on recent advances Author: ONDREJCAK, TOMAS; ROWAN, MICHAEL JOSEPH; HU, NENG WEI Abstract: The cognitive and related symptoms of Alzheimer's disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer's disease amyloid ß-protein (Aß) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. L-glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble Aß oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. Aß exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Aß-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of Aß have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Aß production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Aß and cellular mechanisms of synaptic failure in early AD. Description: PUBLISHED

2012-01-01T00:00:00Z ROWAN, MICHAEL JOSEPH http://hdl.handle.net/2262/60917 2011-11-24T10:50:59Z 2008-01-01T00:00:00Z

Title: Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Author: ROWAN, MICHAEL JOSEPH Abstract: Alzheimer’s disease (AD) constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of AD have not been achieved. We extracted soluble amyloid β–protein (Aβ) oligomers directly from the cerebral cortex of typical AD subjects. The oligomers potently inhibited long term potentiation (LTP), enhanced long term depression (LTD), and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from AD brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors (mGluR) were required for LTD enhancement and NMDA receptors (NMDAR) for spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the mid-region or C-terminus were less effective. Insoluble amyloid plaque cores from AD cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from AD brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species. Description: PUBLISHED

2008-01-01T00:00:00Z KLYUBIN, IGOR ROWAN, MICHAEL JOSEPH http://hdl.handle.net/2262/60432 2011-11-01T14:25:38Z 2011-01-01T00:00:00Z

Title: Alzheimer's disease brain-derived amyloid-ß-mediated inhibition of LTP In Vivo is prevented by immunotargeting cellular prion protein Author: KLYUBIN, IGOR; ROWAN, MICHAEL JOSEPH Abstract: Synthetic amyloid- protein (A ) oligomers bind with high affinity to cellular prion protein (PrPC), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble A in vitro is controversial. Here we report that intracerebroventricular injection of A -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 immunodepletionofA . Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative A -binding site on PrPC, prevented the inhibition of LTP by AD brain-derived A . In contrast, R1, a Fab directed to the C terminus of PrPC, a regionnotimplicatedinbindingofA ,didnotsignificantly affect theA -mediatedinhibition ofLTP.These data support the pathophysiological significance of SDS-stable A dimer and the role of PrPC in mediating synaptic plasticity disruption by soluble A . Description: PUBLISHED

2011-01-01T00:00:00Z ROWAN, MICHAEL JOSEPH KLYUBIN, IGOR http://hdl.handle.net/2262/56910 2011-06-15T13:53:21Z 2011-01-01T00:00:00Z

Title: Interaction between prion protein and toxic amyloid ß assemblies can be therapeutically targeted at multiple sites. Author: ROWAN, MICHAEL JOSEPH; KLYUBIN, IGOR Abstract: A role for PrP in the toxic effect of oligomeric forms of Aβ, implicated in Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL–PrP interaction. Antibodies directed to the principal PrP/Aβ-binding site and to PrP helix-1, were able to block Aβ binding to PrP suggesting that the toxic Aβ species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM-18, were shown to block the Aβ-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination. Description: PUBLISHED

2011-01-01T00:00:00Z ROWAN, MICHAEL JOSEPH ANWYL, ROGER WANG, QIN-WEN http://hdl.handle.net/2262/40189 2010-06-19T02:01:45Z 2008-01-01T00:00:00Z

Title: Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity Author: ROWAN, MICHAEL JOSEPH; ANWYL, ROGER; WANG, QIN-WEN Abstract: Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-β protein (Aβ). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Aβ from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Aβ42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Aβ-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Aβ42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Aβ-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Aβ. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Aβ-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Aβ42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Aβ42 or the inflammatory cytokines, tumour necrosis factor (TNF-) and interleukin 1β (IL-1β). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Aβ-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Aβ42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses. Description: PUBLISHED

2008-01-01T00:00:00Z ROWAN, MICHAEL JOSEPH ANWYL, ROGER http://hdl.handle.net/2262/40187 2011-03-15T11:02:36Z 2009-01-01T00:00:00Z

Title: Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. Author: ROWAN, MICHAEL JOSEPH; ANWYL, ROGER Abstract: An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments. Description: PUBLISHED

2009-01-01T00:00:00Z ROWAN, MICHAEL JOSEPH KLYUBIN, IGOR ANWYL, ROGER HU, NENG WEI http://hdl.handle.net/2262/40185 2010-06-19T02:01:51Z 2010-01-01T00:00:00Z

Title: GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo Author: ROWAN, MICHAEL JOSEPH; KLYUBIN, IGOR; ANWYL, ROGER; HU, NENG WEI Abstract: Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease. Description: PUBLISHED

2010-01-01T00:00:00Z BENNETT, KATHLEEN http://hdl.handle.net/2262/40166 2010-06-17T02:02:03Z 2007-01-01T00:00:00Z

Title: Comparing primary prevention with secondary prevention to explain decreasing coronary heart disease death rates in Ireland 1985 - 2000 Author: BENNETT, KATHLEEN Abstract: BACKGROUND: To investigate whether primary prevention might be more favourable than secondary prevention (risk factor reduction in patients with coronary heart disease(CHD)). METHODS: The cell-based IMPACT CHD mortality model was used to integrate data for Ireland describing CHD patient numbers, uptake of specific treatments, trends in major cardiovascular risk factors, and the mortality benefits of these specific risk factor changes in CHD patients and in healthy people without recognised CHD. RESULTS: Between 1985 and 2000, approximately 2,530 fewer deaths were attributable to reductions in the three major risk factors in Ireland. Overall smoking prevalence declined by 14% between 1985 and 2000, resulting in about 685 fewer deaths (minimum estimate 330, maximum estimate 1,285) attributable to smoking cessation: about 275 in healthy people and 410 in known CHD patients. Population total cholesterol concentrations fell by 4.6%, resulting in approximately 1,300 (minimum estimate 1,115, maximum estimate 1,660) fewer deaths attributable to dietary changes(1,185 in healthy people and 115 in CHD patients) plus 305 fewer deaths attributable to statin treatment (45 in people without CHD and 260 in CHD patients). Mean population diastolic blood pressure fell by 7.2%, resulting in approximately 170 (minimum estimate 105, maximum estimate 300) fewer deaths attributable to secular falls in blood pressure (140 in healthy people and 30 in CHD patients), plus approximately 70 fewer deaths attributable to antihypertensive treatments in people without CHD. Of all the deaths attributable to risk factor falls, some 1,715 (68%) occurred in people without recognized CHD and 815(32%) in CHD patients. CONCLUSION: Compared with secondary prevention, primary prevention achieved a two-fold larger reduction in CHD deaths. Future national CHD policies should therefore prioritize nationwide interventions to promote healthy diets and reduce smoking. Description: PUBLISHED

2007-01-01T00:00:00Z LAMORDE, MOHAMMED MERRY, CONCEPTA http://hdl.handle.net/2262/39981 2010-06-08T03:49:50Z 2010-01-01T00:00:00Z

Title: Medicinal plants used by traditional medicine practitioners for the treatment of HIV/AIDS and related conditions in Uganda Author: LAMORDE, MOHAMMED; MERRY, CONCEPTA Abstract: Introduction and objectives: In Uganda, there are over 1 million people with HIV/AIDS. When advanced, this disease is characterized by life-threatening opportunistic infections. As the formal health sector struggles to confront this epidemic, new medicines from traditional sources are needed to complement control efforts. This study was conducted to document herbal medicines used in the treatment of HIV/AIDS and related opportunistic infections, and to document the existing knowledge, attitudes and practices related to HIV/AIDS recognition, control and treatment in Sembabule, Kamuli, Kabale and Gulu districts in Uganda. Methods: In this study, 25 traditional medicine practitioners (TMPs) were interviewed using structured questionnaires. Results The TMPs could recognize important signs and symptoms of HIV/AIDS and its associated opportunistic infections. The majority of practitioners treated patients who were already receiving allopathic medicines including antiretroviral drugs (ARVs) prescribed by allopathic practitioners. There were 103 species of medicinal plants identified in this survey. Priority plants identified include Aloe spp., Erythrina abyssinica, Sarcocephalus latifolius, Psorospermum febrifugum, Mangifera indica and Warburgia salutaris. There was low consensus among TMPs on the plants used. Decoctions of multiple plant species were commonly used except in Gulu where monopreparations were common. Plant parts frequently used were leaves (33%) stem bark (23%) and root bark (18%). About 80% of preparations were administered orally in variable doses over varied time periods. The TMP had insufficient knowledge about packaging and preservation techniques. Conclusions: Numerous medicinal plants for treatment of HIV/AIDS patients were identified in the four districts surveyed and the role of these plants in the management of opportunistic infections warrants further investigation as these plants may have a role in Uganda's public health approach to HIV/AIDS control. Description: IN_PRESS

2010-01-01T00:00:00Z