Showing papers by "University College Cork published in 2008"

STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation.

Abstract: Objective Older people experience more concurrent illnesses, are prescribed more medications and suffer more adverse drug events than younger people. Many drugs predispose older people to adverse events such as falls and cognitive impairment, thus increasing morbidity and health resource utilization. At the same time, older people are often denied potentially beneficial, clinically indicated medications without a valid reason. We aimed to validate a new screening tool of older persons' prescriptions incorporating criteria for potentially inappropriate drugs called STOPP (Screening Tool of Older Persons' Prescriptions) and criteria for potentially appropriate, indicated drugs called START (Screening Tool to Alert doctors to Right, i.e. appropriate, indicated Treatment). Methods A Delphi consensus technique was used to establish the content validity of STOPP/START. An 18-member expert panel from academic centers in Ireland and the United Kingdom completed two rounds of the Delphi process by mail survey. Inter-rater reliability was assessed by determining the kappa-statistic for measure of agreement on 100 data-sets. Results STOPP is comprised of 65 clinically significant criteria for potentially inappropriate prescribing in older people. Each criterion is accompanied by a concise explanation as to why the prescribing practice is potentially inappropriate. START consists of 22 evidence-based prescribing indicators for commonly encountered diseases in older people. Inter-rater reliability is favorable with a kappa-coefficient of 0.75 for STOPP and 0.68 for START. Conclusion STOPP/START is a valid, reliable and comprehensive screening tool that enables the prescribing physician to appraise an older patient's prescription drugs in the context of his/her concurrent diagnoses.

Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome

Abstract: Bile salt hydrolases (BSHs) catalyze the “gateway” reaction in a wider pathway of bile acid modification by the gut microbiota. Because bile acids function as signaling molecules regulating their own biosynthesis, lipid absorption, cholesterol homeostasis, and local mucosal defenses in the intestine, microbial BSH activity has the potential to greatly influence host physiology. However, the function, distribution, and abundance of BSH enzymes in the gut community are unknown. Here, we show that BSH activity is a conserved microbial adaptation to the human gut environment with a high level of redundancy in this ecosystem. Through metagenomic analyses we identified functional BSH in all major bacterial divisions and archaeal species in the gut and demonstrate that BSH is enriched in the human gut microbiome. Phylogenetic analysis illustrates that selective pressure in the form of conjugated bile acid has driven the evolution of members of the Ntn_CGH-like family of proteins toward BSH activity in gut-associated species. Furthermore, we demonstrate that BSH mediates bile tolerance in vitro and enhances survival in the murine gut in vivo. Overall, we demonstrate the use of function-driven metagenomics to identify functional anchors in complex microbial communities, and dissect the gut microbiome according to activities relevant to survival in the mammalian gastrointestinal tract.

An overlapping essential gene in the Potyviridae.

Abstract: The family Potyviridae includes >30% of known plant virus species, many of which are of great agricultural significance. These viruses have a positive sense RNA genome that is ≈10 kb long and contains a single long ORF. The ORF is translated into a large polyprotein, which is cleaved into ≈10 mature proteins. We report the discovery of a short ORF embedded within the P3 cistron of the polyprotein but translated in the +2 reading-frame. The ORF, termed pipo, is conserved and has a strong bioinformatic coding signature throughout the large and diverse Potyviridae family. Mutations that knock out expression of the PIPO protein in Turnip mosaic potyvirus but leave the polyprotein amino acid sequence unaltered are lethal to the virus. Immunoblotting with antisera raised against two nonoverlapping 14-aa antigens, derived from the PIPO amino acid sequence, reveals the expression of an ≈25-kDa PIPO fusion product in planta. This is consistent with expression of PIPO as a P3-PIPO fusion product via ribosomal frameshifting or transcriptional slippage at a highly conserved G1-2A6-7 motif at the 5′ end of pipo. This discovery suggests that other short overlapping genes may remain hidden even in well studied virus genomes (as well as cellular organisms) and demonstrates the utility of the software package MLOGD as a tool for identifying such genes.

Evolution, Population Structure, and Phylogeography of Genetically Monomorphic Bacterial Pathogens

Abstract: Genetically monomorphic bacteria contain so little sequence diversity that sequencing a few gene fragments yields little or no information. As a result, our understanding of their evolutionary patterns presents greater technical challenges than exist for genetically diverse microbes. These challenges are now being met by analyses at the genomic level for diverse types of genetic variation, the most promising of which are single nucleotide polymorphisms. Many of the most virulent bacterial pathogens are genetically monomorphic, and understanding their evolutionary and phylogeographic patterns will help our understanding of the effects of infectious disease on human history.

Board Structure, Ownership, and Voluntary Disclosure in Ireland

Abstract: Manuscript Type: Empirical Research Question/Issue: This is a cross-sectional study of the relation between corporate governance and voluntary disclosure in Ireland. Research Findings/Results: We report clear evidence that voluntary disclosure increases with the number of nonexecutive directors on the board. Firms that have a nonexecutive chairman make greater voluntary disclosures than other firms. This finding is not robust to the inclusion of other explanatory variables. We find no evidence that ownership structure is related to voluntary disclosure. Theoretical Implications: The results regarding nonexecutive directors are interpreted as independent boards facilitating a reduction in information asymmetry between owners and managers. While this supports the predictions of agency theory, the absence of evidence that ownership structure influences voluntary disclosure does not. It is posited that sociological and organizational factors (e.g., informal networking) that pervade the Irish market mitigate against our disclosure measure capturing all aspects of voluntary disclosure. Furthermore, indirect evidence is provided that there are other costs and benefits to disclosure that vary across firms and may outweigh agency costs in many situations. We conclude that while agency theory has some explanatory power for voluntary disclosure, it cannot explain all the cross-sectional differences in voluntary disclosure by Irish public limited companies. Practical Implications: The results support the attention paid by regulators to the proportion of nonexecutive directors on the board. However, the costs and benefits to disclosure vary across firms. Regardless of agency considerations and regulatory guidelines, firms will ultimately formulate their disclosure policy with reference to overall marginal costs and marginal benefits.

Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments

Abstract: Here we show that blocking the adhesive function of αvβ3 integrin with soluble RGD ligands, such as osteopontin or cilengitide, promoted association of Rab-coupling protein (RCP) with α5β1 integrin and drove RCP-dependent recycling of α5β1 to the plasma membrane and its mobilization to dynamic ruffling protrusions at the cell front. These RCP-driven changes in α5β1 trafficking led to acquisition of rapid/random movement on two-dimensional substrates and to a marked increase in fibronectin-dependent migration of tumor cells into three-dimensional matrices. Recycling of α5β1 integrin did not affect its regulation or ability to form adhesive bonds with substrate fibronectin. Instead, α5β1 controlled the association of EGFR1 with RCP to promote the coordinate recycling of these two receptors. This modified signaling downstream of EGFR1 to increase its autophosphorylation and activation of the proinvasive kinase PKB/Akt. We conclude that RCP provides a scaffold that promotes the physical association and coordinate trafficking of α5β1 and EGFR1 and that this drives migration of tumor cells into three-dimensional matrices.

Empathy and experience in HCI

Abstract: For a decade HCI researchers and practitioners have been developing methods, practices and designs 'for the full range of human experience' On the one hand, a variety of approaches to design, such as aesthetic, affective, and ludic that emphasize particular qualities and contexts of experience and particular approaches to intervening in interactive experience have become focal On the other, a variety of approaches to understanding users and user experience, based on narrative, biography, and role-play have been developed and deployed These developments can be viewed in terms of one of the seminal commitments of HCI, 'to know the user' Empathy has been used as a defining characteristic of designer-user relationships when design is concerned with user experience In this article, we use 'empathy' to help position some emerging design and user-experience methodologies in terms of dynamically shifting relationships between designers, users, and artefacts

Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures

Abstract: Background: Neonatal seizures are often subclinical, making accurate diagnosis difficult. Objective: To describe the clinical manifestations of electrographic seizures recorded on continuous video-EEG, and to compare this description with the recognition of clinical seizures by experienced neonatal staff. Methods: Term infants, at risk of seizures, were monitored by continuous 12-channel video-EEG from Results: Of 51 infants enrolled, nine had electrographic seizures. A further three had clinically suspected seizures, without associated electrographic abnormality. Of the total 526 electrographic seizures, 179 (34%) had clinical manifestations evident on the simultaneous video recording. The clinical seizure activity corresponded to 18.8% of the total electrographic seizure burden. Overdiagnosis also occurred frequently. Of the 177 clinically suspected seizure episodes documented by staff, 48 (27%) had corresponding electrographic evidence of seizure activity Thus, only 9% (48/526) of electrographic seizures were accompanied by clinical manifestations, which were identified and documented by neonatal staff. Conclusion: Only one-third of neonatal EEG seizures displays clinical signs on simultaneous video recordings. Moreover, two-thirds of these clinical manifestations are unrecognised, or misinterpreted by experienced neonatal staff. In the recognition and management of neonatal seizures clinical diagnosis alone is not enough.

Commensal-Induced Regulatory T Cells Mediate Protection against Pathogen-Stimulated NF-κB Activation

Abstract: Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-κB activation associated with infection Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS In vivo NF-κB activation was quantified using biophotonic imaging CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naive animals In vivo imaging revealed profound inhibition of infection and LPS induced NF-κB activity that preceded a reduction in S typhimurium numbers and murine sickness behaviour scores in B infantis–fed mice In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B infantis Adoptive transfer of CD4+CD25+ T cells transferred the NF-κB inhibitory activity Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-κB activation in vivo These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS

Moral Distress Reconsidered

Abstract: Moral distress has received much attention in the international nursing literature in recent years. In this article, we describe the evolution of the concept of moral distress among nursing theorists from its initial delineation by the philosopher Jameton to its subsequent deployment as an umbrella concept describing the impact of moral constraints on health professionals and the patients for whom they care. The article raises worries about the way in which the concept of moral distress has been portrayed in some nursing research and expresses concern about the fact that research, so far, has been largely confined to determining the prevalence of experiences of moral distress among nurses. We conclude by proposing a reconsideration, possible reconstruction and multidisciplinary approach to understanding the experiences of all health professionals who have to make difficult moral judgements and decisions in complex situations.

Genome sequence and rapid evolution of the rice pathogen Xanthomonas oryzae pv. oryzae PXO99A

Abstract: Xanthomonas oryzae pv. oryzae causes bacterial blight of rice (Oryza sativa L.), a major disease that constrains production of this staple crop in many parts of the world. We report here on the complete genome sequence of strain PXO99A and its comparison to two previously sequenced strains, KACC10331 and MAFF311018, which are highly similar to one another. The PXO99A genome is a single circular chromosome of 5,240,075 bp, considerably longer than the genomes of the other strains (4,941,439 bp and 4,940,217 bp, respectively), and it contains 5083 protein-coding genes, including 87 not found in KACC10331 or MAFF311018. PXO99A contains a greater number of virulence-associated transcription activator-like effector genes and has at least ten major chromosomal rearrangements relative to KACC10331 and MAFF311018. PXO99A contains numerous copies of diverse insertion sequence elements, members of which are associated with 7 out of 10 of the major rearrangements. A rapidly-evolving CRISPR (clustered regularly interspersed short palindromic repeats) region contains evidence of dozens of phage infections unique to the PXO99A lineage. PXO99A also contains a unique, near-perfect tandem repeat of 212 kilobases close to the replication terminus. Our results provide striking evidence of genome plasticity and rapid evolution within Xanthomonas oryzae pv. oryzae. The comparisons point to sources of genomic variation and candidates for strain-specific adaptations of this pathogen that help to explain the extraordinary diversity of Xanthomonas oryzae pv. oryzae genotypes and races that have been isolated from around the world.

Prolactin and dopamine: What is the connection? A Review Article

Abstract: Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a 'short-loop feedback mechanism'. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood-brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia.

A fixed-parameter algorithm for the directed feedback vertex set problem

Abstract: The (parameterized) FEEDBACK VERTEX SET problem on directed graphs (i.e., the DFVS problem) is defined as follows: given a directed graph G and a parameter k, either construct a feedback vertex set of at most k vertices in G or report that no such a set exists. It has been a well-known open problem in parameterized computation and complexity whether the DFVS problem is fixed-parameter tractable, that is, whether the problem can be solved in time f(k)nO(1) for some function f. In this article, we develop new algorithmic techniques that result in an algorithm with running time 4kke nO(1) for the DFVS problem. Therefore, we resolve this open problem.

High‐pressure processing – effects on microbial food safety and food quality

Abstract: High-pressure processing (HPP) is a nonthermal process capable of inactivating and eliminating pathogenic and food spoilage microorganisms. This novel technology has enormous potential in the food industry, controlling food spoilage, improving food safety and extending product shelf life while retaining the characteristics of fresh, preservative-free, minimally processed foods. As with other food processing methods, such as thermal processing, HPP has somewhat limited applications as it cannot be universally applied to all food types, such as some dairy and animal products and shelf-stable low-acid foods. Herein, we discuss the effects of high-pressure processing on microbial food safety and, to a lesser degree, food quality.

GLUE-IT and PEDEL-AA: new programmes for analyzing protein diversity in randomized libraries

Abstract: There are many methods for introducing random mutations into nucleic acid sequences. Previously, we described a suite of programmes for estimating the completeness and diversity of randomized DNA libraries generated by a number of these protocols. Our programmes suggested some empirical guidelines for library design; however, no information was provided regarding library diversity at the protein (rather than DNA) level. We have now updated our web server, enabling analysis of translated libraries constructed by site-saturation mutagenesis and error-prone PCR (epPCR). We introduce GLUEIncluding Translation (GLUE-IT), which finds the expected amino acid completeness of libraries in which up to six codons have been independently varied (according to any user-specified randomization scheme). We provide two tools for assisting with experimental design: CodonCalculator, for assessing amino acids corresponding to given randomized codons; and AA-Calculator, for finding degenerate codons that encode user-specified sets of amino acids. We also present PEDEL-AA, which calculates amino acid statistics for libraries generated by epPCR. Input includes the parent sequence, overall mutation rate, library size, indel rates and a nucleotide mutation matrix. Output includes amino acid completeness and diversity statistics, and the number and length distribution of sequences truncated by premature termination codons. The web interfaces are available at http:// guinevere.otago.ac.nz/stats.html.

Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces.

Abstract: Molecular ecological surveys of the human gut microbiota to date have focused on the prokaryotic fraction of the community and have revealed a remarkable degree of bacterial diversity and functionality. However, there is a dearth of information on the eukaryotic composition of the microbiota, and no culture-independent sequence-based surveys of human faeces are available. Culture-independent analyses based on DNA extraction and polymerase chain reaction targeting both the total eukaryotic 18S rRNA genes and fungal internal transcribed regions (ITS), together with culture-dependent analyses of fungi, were performed on a group of healthy volunteers. Temporal analysis was also included wherever possible. Collectively, the data presented in this study indicate that eukaryotic diversity of the human gut is low, largely temporally stable and predominated by different subtypes of Blastocystis. Specific analyses of the fungal populations indicate that a disparity exists between the cultivable fraction, which is dominated by Candida sp, and culture-independent analysis, where sequences identical to members of the genera Gloeotinia/Paecilomyces and Galactomyces were most frequently retrieved from both fungal ITS profiles and subsequent clone libraries. Collectively, these results highlight the presence of unprecedented intestinal eukaryotic inhabitants whose functional roles are as yet unknown in healthy individuals. Furthermore, differences between results obtained from traditionally employed culture-based methods and those obtained from culture-independent techniques highlight similar anomalies to that encountered when first analysing the bacterial diversity of the human faecal microbiota using culture-independent surveys.

M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis

Abstract: M-cells are specialized cells found in the follicle-associated epithelium of intestinal Peyer's patches of gut-associated lymphoid tissue and in isolated lymphoid follicles, appendix and in mucosal-associated lymphoid tissue sites outside the gastrointestinal tract. In the gastrointestinal tract, M-cells play an important role in transport of antigen from the lumen of the small intestine to mucosal lymphoid tissues, where processing and initiation of immune responses occur. Thus, M-cells act as gateways to the mucosal immune system and this function has been exploited by many invading pathogens. Understanding the mechanism by which M-cells sample antigen will inform the design of oral vaccines with improved efficacy in priming mucosal and systemic immune responses. In this review, the origin and morphology of M-cells, and their role in mucosal immunity and pathogenesis of infections are discussed.

Exploring Space and Place With Walking Interviews

Abstract: This article explores the use of walking interviews as a research method. In spite of a wave of interest in methods which take interviewing out of the "safe," stationary environment, there has been limited work critically examining the techniques for undertaking such work. Curiously for a method which takes an explicitly spatial approach, few projects have attempted to rigorously connect what participants say with where they say it. The article reviews three case studies where the authors have used different techniques, including GPS, for locating the interview in space. The article concludes by arguing that researchers considering using walking interviews need to think carefully about what kinds of data they wish to generate when deciding which approach to adopt.

Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival.

Abstract: Purpose: Hypoxia is associated with resistance to radiotherapy and chemotherapy and activates transcription factors that support cell survival and migration. We measured the volume of hypoxic tumor and the maximum level of hypoxia in glioblastoma multiforme before radiotherapy with [ 18 F]fluoromisonidazole positron emission tomography to assess their impact on time to progression (TTP) or survival. Experimental Design: Twenty-two patients were studied before biopsy or between resection and starting radiotherapy. Each had a 20-minute emission scan 2 hours after i.v. injection of 7 mCi of [ 18 F]fluoromisonidazole. Venous blood samples taken during imaging were used to create tissue to blood concentration ( T/B ) ratios. The volume of tumor with T/B values above 1.2 defined the hypoxic volume (HV). Maximum T/B values ( T/B max ) were determined from the pixel with the highest uptake. Results: Kaplan-Meier plots showed shorter TTP and survival in patients whose tumors contained HVs or tumor T/B max ratios greater than the median ( P ≤ 0.001). In univariate analyses, greater HV or tumor T/B max were associated with shorter TTP or survival ( P T/B max ), magnetic resonance imaging (MRI) T1Gd volume, age, and Karnovsky performance score reached significance only for HV (or T/B max ; P Conclusions: The volume and intensity of hypoxia in glioblastoma multiforme before radiotherapy are strongly associated with poorer TTP and survival. This type of imaging could be integrated into new treatment strategies to target hypoxia more aggressively in glioblastoma multiforme and could be applied to assess the treatment outcomes.

Understanding and predicting ecological dynamics: are major surprises inevitable?

Abstract: Ecological surprises, substantial and unanticipated changes in the abundance of one or more species that result from previously unsuspected processes, are a common outcome of both experiments and observations in community and population ecology. Here, we give examples of such surprises along with the results of a survey of well-established field ecologists, most of whom have encountered one or more surprises over the course of their careers. Truly surprising results are common enough to require their consideration in any reasonable effort to characterize nature and manage natural resources. We classify surprises as dynamic-, pattern-, or intervention-based, and we speculate on the common processes that cause ecological systems to so often surprise us. A long-standing and still growing concern in the ecological literature is how best to make predictions of future population and community dynamics. Although most work on this subject involves statistical aspects of data analysis and modeling, the frequency and nature of ecological surprises imply that uncertainty cannot be easily tamed through improved analytical procedures, and that prudent management of both exploited and conserved communities will require precautionary and adaptive management approaches.

Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis.

Abstract: A role for the intestinal microbiota is routinely cited as a potential aetiological factor in colorectal cancer initiation and progression. As the majority of bacteria in the gut are refractory to culture we investigated this ecosystem in subjects with colorectal cancer and with adenomatous polyposis who are at high risk of developing colorectal cancer, using culture-independent methods. Twenty colorectal cancer and 20 polypectomized volunteers were chosen for this analysis. An exploration of the diversity and temporal stability of the dominant bacteria and several bacterial subgroups was undertaken using 16S rRNA gene denaturing gradient gel electrophoresis and ribosomal intergenic spacer analysis (RISA). Metabonomic analysis of the distal gut microbiota's environment was also undertaken. A significantly reduced temporal stability and increased diversity for the microbiota of subjects with colorectal cancer and polyposis was evident. A significantly increased diversity of the Clostridium leptum and C. coccoides subgroups was also noted for both disease groups. A clear division in the metabonome was observed for the colorectal cancer and polypectomized subjects compared with control volunteers. The intestinal microbiota and their metabolites are significantly altered in both colorectal cancer and polypectomized subjects compared with controls.