Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases.

Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.

Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin-αv trafficking.

The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET-1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α3 , α4, α5 , α6 and αν ). Experimental findings were validated in human explant oesophageal biopsies, a rat model of gastroesophageal reflux disease (GORD) and in patient tissue microarrays. The bile acid deoxycholic acid (DCA) specifically reduced adhesion of HET-1A cells to vitronectin and reduced cell-surface expression of integrin-αν via effects on endocytic recycling processes. Increased expression of integrin-αv was observed in ulcerated tissue in a rat model of GORD and in oesophagitis and Barrett's intestinal metaplasia patient tissue compared to normal squamous epithelium. Increased expression of integrin-αν was observed in QH BO cells compared to HET-1A cells. QH cells were resistant to DCA-mediated loss of adhesion and reduction in cell-surface expression of integrin-αν . We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin αν expression, providing a novel mechanism for bile acid-mediated erosion of oesophageal squamous epithelium and promotion of BO. Strategies aimed at preventing bile acid-mediated erosion should be considered in the clinical management of patients with GORD.

Free Functional Muscle Transfer Tendon Insertion Secondary Advancement Procedure to Improve Elbow Flexion.

One method of restoring elbow flexion in patients with brachial plexus injuries is through the use of free functional muscle transfer. Most of our patients achieve good outcome, resulting in improved usefulness of the affected limb. However, a minority of our patients have successful reinnervation of the transferred muscle but with a suboptimal strength and range of motion (ROM) of elbow flexion. In this subset of patients, we perform a secondary procedure to improve the moment arm of the muscle on the elbow joint. This involves advancing the transferred muscle distally along the radius. The technique of the advancement procedure is described. We also report on our initial series of 5 patients who underwent this advancement procedure. In one patient, there was improvement in strength alone. In another, there was improvement of the ROM alone. The remaining 3 patients had improvement of both strength and ROM.

Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism.

Bile acids are components of gastro-duodenal refluxate and regarded as causative agents in oesophageal disease but the precise mechanisms are unknown. Here we demonstrate that a specific subset of physiological bile acids affect the protein secretory pathway by inducing ER stress, activating the Unfolded Protein Response (UPR) and causing disassembly of the Golgi apparatus in oesophageal cells. Deoxycholic acid (DCA), Chemodeoxycholic acid (CDCA) and Lithocholic acid (LCA) activated the PERK arm of the UPR, via phosphorylation of eIF2α and up-regulation of ATF3, CHOP and BiP/GRP78. UPR activation by these bile acids is mechanistically linked with Golgi fragmentation, as modulating the UPR using a PERK inhibitor (GSK2606414) or salubrinal attenuated bile acid-induced effects on Golgi structure. Furthermore we demonstrate that DCA, CDCA and LA activate Src kinase and that inhibition of this kinase attenuated both bile acid-induced BiP/GRP78 expression and Golgi fragmentation. This study highlights a novel mechanism whereby environmental factors (bile acids) impact important cellular processes regulating cell homeostasis, including the UPR and Golgi structure, which may contribute to cancer progression in the oesophagus.

A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective.

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective ER stress inhibitor and chemical chaperone. It has therapeutic potential in a wide array of diseases but a specific macromolecular target or molecular mechanism of action remains obscure. This Letter describes an effective new synthetic approach to taurine conjugation of bile acids which we used to prepare 3α-dansyl TUDCA (4) as a probe for TUDCA actions. As a model of ER stress we used the hepatocarcinoma cell line HUH7 and stimulation with either deoxycholic acid (DCA, 200µM) or tunicamycin (5µg/ml) and measured levels of Bip/GRP78, ATF4, CHOP and XBP1s/XBP1u. Compound 4 was more effective than UDCA at inhibiting ER stress markers and had similar effects to TUDCA. In a model of cholestasis using the cytotoxic DCA to induce apoptosis, pretreatment with 4 prevented cell death similarly to TUDCA whereas the unconjugated clinically used UDCA had no effect. 3α-Dansyl TUDCA (4) appears to be a suitable reporter for TUDCA effects on ER stress and related cytoprotective activity.

Multidisciplinary team care for people with rheumatoid arthritis: a systematic review and meta-analysis.

The objective of this study was to systematically review the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of multidisciplinary team (MDT) care for the management of disability, disease activity and quality of life (QoL) in adults with rheumatoid arthritis (RA). Data sources identified published (MEDLINE, PsychINFO, EMBASE, CINAHL, Web of Science, CENTRAL) and unpublished (OpenGrey) literature. Independent data extraction and quality assessment, using the Cochrane risk of bias tool, were conducted by two reviewers. The primary outcome was change in disability at 12 months; secondary outcomes included disability at other time points and disease activity and QoL at 12 months. Where possible, the pooled effect sizes were calculated for inpatient or outpatient MDT interventions. Four hundred and fifteen studies were retrieved. Twelve manuscripts, which reported 10 RCTs, representing 1147 participants were included. Only data from five high- or moderate-quality trials were pooled according to clinical setting. There was no difference in disability between inpatient MDT care and any comparison group [mean difference (95% confidence intervals) 0.04, -0.13 to 0.20] or between outpatient MDT care and comparison groups (0.09, -0.07 to 0.25) at 12 months. There was no difference in disability at 2 years or <12 months or disease activity and QoL at 12 months between MDT care and any comparison group. There is limited evidence evaluating the effect of MDT care on disability, disease activity or QoL in people with RA. There is likely to be no effect of MDT care on disability at 12 months or other time points.

Golgi phosphoprotein 2 (GOLPH2) is a novel bile acid-responsive modulator of oesophageal cell migration and invasion.

BACKGROUND: The aetiology of Barrett's oesophagus (BO) and oesophageal cancer is poorly understood. We previously demonstrated that Golgi structure and function is altered in oesophageal cancer cells. A Golgi-associated protein, GOLPH2, was previously established as a tissue biomarker for BO. Cellular functions for GOLPH2 are currently unknown, therefore in this study we sought to investigate functional roles for this Golgi-associated protein in oesophageal disease. METHODS: Expression, intracellular localisation and secretion of GOLPH2 were identified by immunofluorescence, immunohistochemistry and western blot. GOLPH2 expression constructs and siRNA were used to identify cellular functions for GOLPH2. RESULTS: We demonstrate that the structure of the Golgi is fragmented and the intracellular localisation of GOLPH2 is altered in BO and oesophageal adenocarcinoma tissue. GOLPH2 is secreted by oesophageal cancer cells and GOLPH2 expression, cleavage and secretion facilitate cell migration and invasion. Furthermore, exposure of cells to DCA, a bile acid component of gastric refluxate and known tumour promoter for oesophageal cancer, causes disassembly of the Golgi structure into ministacks, resulting in cleavage and secretion of GOLPH2. CONCLUSIONS: This study demonstrates that GOLPH2 may be a useful tissue biomarker for oesophageal disease. We provide a novel mechanistic insight into the aetiology of oesophageal cancer and reveal novel functions for GOLPH2 in regulating tumour cell migration and invasion, important functions for the metastatic process in oesophageal cancer.

Deoxycholic acid impairs glycosylation and fucosylation processes in esophageal epithelial cells.

It is generally accepted that esophageal adenocarcinoma arises from a Barrett's metaplastic lesion. Altered glycoprotein expression has been demonstrated in tissue from patients with Barrett's esophagus and esophageal cancer but the mechanisms regarding such changes are unknown. The bile acid deoxycholic acid (DCA) alters many cell signaling pathways and is implicated in esophageal cancer progression. We have demonstrated that DCA disrupts Golgi structure and affects protein secretion and glycosylation processes in cell lines derived from normal squamous epithelium (HET-1A) and Barrett's metaplastic epithelium (QH). Cell surface expression of glycans was identified using carbohydrate-specific probes (wheat germ agglutinate, conconavalin A, peanut agglutinin, lithocholic acid and Ulex europaeus agglutinin) that monitored N-glycosylation, O-glycosylation and core fucosylation in resting and DCA-treated cells. DCA altered intracellular localization and reduced cell surface expression of N-acetyl-D-glucosamine, α-methyl-mannopyranoside (Man/Glc) and fucose in both cell lines. Furthermore, DCA reduced the expression of epithelial growth factor receptor and E-cadherin in a manner analogous to treatment of cells with the N-glycan biosynthesis inhibitor tunicamycin. This is the first study to identify an altered Golgi structure and glycomic profile in response to DCA in esophageal epithelial cells, a process which could potentially contribute to metaplasia, dysplasia and cancer of the esophagus.

Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators.

Ursodeoxycholic acid (UDCA) is used for the treatment of hepatic inflammatory diseases. Recent studies have shown that UDCA's biological effects are partly glucocorticoid receptor (GR) mediated. UDCA derivatives were synthesized and screened for ability to induce GR translocation in a high content analysis assay using the esophageal cancer SKGT-4 cell line. UDCA derivatives induced GR translocation in a time dependent manner with equal efficacy to that of dexamethasone (Dex) and with greatly increased potency relative to UDCA. The cyclopropylamide 1a suppressed TNF-α induced NF-κB activity and it induced GRE transactivation. 1a was unable to displace Dex from the GR ligand binding domain (LBD) in a competition experiment but was capable of coactivator recruitment in a time-resolved fluorescence energy transfer assay (TR-FRET). This represents a novel mechanism of action for a GR modulator. These derivatives could result in a new class of GR modulators.

The Irish Nursing Minimum Data Set for mental health--a valid and reliable tool for the collection of standardised nursing data.

AIMS AND OBJECTIVES: To test the validity and reliability of the newly developed Irish Nursing Minimum Data Set for mental health (I-NMDS (MH)) to ensure its clinical usability. BACKGROUND: Internationally, difficulties exist in defining the contribution mental health nursing makes to patient care. Structured information systems, like the Nursing Minimum Data Set, have been developed internationally to gather standardised information to increase the visibility of nursing in the health care system. DESIGN: This study employed a quantitative, longitudinal research design. METHOD: A convenience sample of mental health nurses (n = 184) collected data on the nursing care of patients (n = 367) from care settings attached to 11 hospitals across Ireland. Exploratory factor analysis (EFA), ridit analysis and Cronbach's alpha coefficient were used to establish the construct and discriminative validity and scale score reliability of the I-NMDS (MH). RESULTS: Goodness of Fit scores indicated that the I-NMDS (MH) possesses good construct validity. Alpha coefficients for each factor were above the recommended 0.7 level. Ridit analysis inferred that the I-NMDS (MH) discriminated between elements of nursing care across acute inpatient and community based care settings. CONCLUSIONS: The I-NMDS (MH) possesses a sound theoretical base, has scale score reliability and possesses good discriminative validity. The valid and reliable I-NMDS (MH) is the first NMDS to be developed specifically for mental health. RELEVANCE TO CLINICAL PRACTICE: Data collected using the I-NMDS (MH) will increase the visibility of the contribution mental health nurses make to healthcare delivery. In addition, it will support evidence based practice in mental health to improve further the effectiveness of nursing care in the future.

Bile acids modulate the Golgi membrane fission process via a protein kinase Ceta and protein kinase D-dependent pathway in colonic epithelial cells.

Deoxycholic acid (DCA) is a secondary bile acid that modulates signalling pathways in epithelial cells. DCA has been implicated in pathogenesis of colon carcinoma, particularly by activation of the protein kinase C (PKC) pathway. Ursodeoxycholic acid (UDCA), a tertiary bile acid, has been observed to have chemopreventive effects. The aim of this study was to investigate the effect of DCA and UDCA on the subcellular localization and activity of PKCeta and its downstream effects on Golgi structure in a colon cancer cell model. PKCeta expression was localized to the Golgi in HCT116 colon cancer cells. DCA induced fragmentation of the Golgi in these cells following activation of PKCeta and its downstream effector protein kinase D (PKD). Pretreatment of cells with UDCA or a glucocorticoid, dexamethasone, inhibited DCA-induced PKCeta/PKD activation and Golgi fragmentation. Knockdown of glucocorticoid receptor (GR) expression using small interfering RNA or inhibition using the GR antagonist mifepristone attenuated the inhibitory effect of UDCA on Golgi fragmentation. Elevated serum and faecal levels of DCA have been previously reported in patients with ulcerative colitis (UC) and colon cancer. Analysis of Golgi architecture in vivo using tissue microarrays revealed Golgi fragmentation in UC and colorectal cancer tissue. We have demonstrated that DCA can disrupt the structure of the Golgi, an organelle critical for normal cell function. Inhibition of this DCA-induced Golgi fragmentation by UDCA was mediated via the GR. This represents a potential mechanism of observed chemopreventive effects of UDCA in benign and malignant disease of the colon.

Support networks of older people living in the community.

Aim. The aim of the study was to identify the social support networks of older people living in the community in Ireland using Wenger's (1994) network typology. Background. The population of older people in the community is increasing. With increasing age and changes in family circumstances a substantial proportion of older people will require social, psychological and instrumental support. However a lack of adequate social support networks for vulnerable older people can result in poor health, loneliness and isolation. Method. A national, cross-sectional telephone survey of 683 people aged between 65 and 99 years was undertaken using the Practitioner Assessment of Network Type as the basis for identifying social support networks. Results. The results demonstrated that the majority of older people were living in stable and supportive social networks and reported high levels of contact with family, friends and neighbours. However, a significant minority of older people were living in vulnerable networks. Older people in these networks are susceptible to loneliness, isolation and poor emotional and physical health. Conclusion. Through the identification of people in vulnerable networks, nurses working both in the hospital and community setting can ensure that formal support is aimed at providing care to older people who do not have access to informal care networks. Furthermore, the predictive utility of the Practitioner Assessment Network Type (PANT) can enable nurses to identify people at risk of poor social support.

Ambiguities and conflicting results: the limitations of the kappa statistic in establishing the interrater reliability of the Irish nursing minimum data set for mental health: a discussion paper.

BACKGROUND: In a study to establish the interrater reliability of the Irish Nursing Minimum Data Set (I-NMDS) for mental health difficulties relating to the choice of reliability test statistic were encountered. OBJECTIVES: The objective of this paper is to highlight the difficulties associated with testing interrater reliability for an ordinal scale using a relatively homogenous sample and the recommended kw statistic. METHOD: One pair of mental health nurses completed the I-NMDS for mental health for a total of 30 clients attending a mental health day centre over a two-week period. Data was analysed using the kw and percentage agreement statistics. RESULTS: A total of 34 of the 38 I-NMDS for mental health variables with lower than acceptable levels of kw reliability scores achieved acceptable levels of reliability according to their percentage agreement scores. CONCLUSION: The study findings implied that, due to the homogeneity of the sample, low variability within the data resulted in the 'base rate problem' associated with the use of kw statistic. Conclusions point to the interpretation of kw in tandem with percentage agreement scores. Suggestions that kw scores were low due to chance agreement and that one should strive to use a study sample with known variability are queried.

Collaboration: leveraging resources and expertise.

Successful collaboration is an art form but can be developed through several smart practices. The authors discuss the meaning of collaboration, stakeholder perceptions of collaborative partnerships, and the experience of Summer Scholars, a nonprofit community organization that successfully uses collaboration to accomplish its mission. Further, they offer strategies for successful collaborative efforts.

Developing a data dictionary for the irish nursing minimum dataset.

One of the challenges in health care in Ireland is the relatively slow acceptance of standardised clinical information systems. Yet the national Irish health reform programme indicates that an Electronic Health Care Record (EHCR) will be implemented on a phased basis. [3-5]. While nursing has a key role in ensuring the quality and comparability of health information, the so- called 'invisibility' of some nursing activities makes this a challenging aim to achieve [3-5]. Any integrated health care system requires the adoption of uniform standards for electronic data exchange [1-2]. One of the pre-requisites for uniform standards is the composition of a data dictionary. Inadequate definition of data elements in a particular dataset hinders the development of an integrated data depository or electronic health care record (EHCR). This paper outlines how work on the data dictionary for the Irish Nursing Minimum Dataset (INMDS) has addressed this issue. Data set elements were devised on the basis of a large scale empirical research programme. ISO 18104, the reference terminology for nursing [6], was used to cross-map the data set elements with semantic domains, categories and links and data set items were dissected.

Towards a nursing minimum data set for Ireland: making Irish nursing visible.

AIM: The aim of this study was to identify patient problems, nursing interventions and nursing outcomes to be included in a nursing minimum data set for Ireland. BACKGROUND: In 2002, a research programme funded by the Irish Health Research Board, was established to develop and test a nursing minimum data set to capture the nursing contribution to patient care in Ireland. A nursing minimum data set is comprised of the smallest number of information items required to capture the range of patient problems, nursing interventions and nursing outcomes recorded by nurses on a regular basis. Nursing minimum data sets have been developed in several countries for a range of applications such as workforce planning, financing nursing care, examining patient profiles and forecasting trends in nursing diagnoses. METHOD: Eleven focus groups were conducted with 59 registered general nurses to explore their conceptualizations of patient problems, nursing interventions and nursing outcomes. In addition, data relating to nurses' recordings of patient problems, nursing interventions and nursing outcomes were collected from a sample of 45 sets nursing records. The research took place between January 2003 and April 2004. FINDINGS: A range of patient problems, nursing interventions and outcomes were identified that were similar to those found in existing nursing minimum data sets. However, several new items and categories of items were also identified, justifying the empirical approach taken to generate the initial list of items. Data from nursing records supported several points raised in focus groups and also highlighted some inconsistencies between nurses' perceptions and recordings of what they do. CONCLUSION: Our research identified several new types of indirect interventions and managing/organizing activities in addition to items found in existing nursing minimum data sets. The importance of these aspects of the nursing contribution to patient care will be tested further in the development of the Irish nursing minimum data set.

Social regulation, medicalisation and the nurse's role: insights from an analysis of nursing documentation.

BACKGROUND: Medicine is recognised as a dominant source of governmentality and social regulation, and although nursing has been implicated in the same process, analytical work in this area has been sparse. OBJECTIVES: The article aims to present an analysis of nursing records in order to understand the structural and social processes that mediate the texts. METHODS: 45 sets of nursing records drawn from four clinical sites in Ireland were subjected to a discourse analysis. RESULTS: This article focuses on two main themes that were derived from data: (i) the manner in which nurses controlled, regulated and invigilated patients' activities of daily living and (ii) the way in which activities of daily living were mediated by a biomedical worldview in the clinical settings. Through the organising framework of Activities of Daily Living (ADLs), normative social practices relating to hygiene, eating and drinking, sleeping and so forth were surveyed and monitored within clinical settings. We construct qualitative categories around a range of ways that nurses assessed and judged patients' capacities at ADLs. Furthermore, it is argued that the framework of ADLs epitomises the medicalisation of normative social practices, whereupon the most mundane of normal functions become redefined as an actual or potential clinical pathology, legitimating nursing interventions. According to the nursing documentation, biochemical interventions in the form of various medications were the most dominant means through which nurses attempted to restore or improve the functional capacity of an ADL. CONCLUSION: We conclude by proposing that nurses' invigilation of patients' ADLs is not necessarily a repressive feature of nursing practice, but rather has the potential to be used to advocate on patients' behalf in certain circumstances.

Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF).

Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.