Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection

Abstract Background Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues. Methods A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention. Results Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level. Conclusion Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention. Trial registration number ISRCTN90852168. Keywords: ADENOMA, BUTYRATE, CYTOKERATINS, DIETARY FIBR

Estimating required information size by quantifying diversity in random-effects model meta-analyses

<p>Abstract</p> <p>Background</p> <p>There is increasing awareness that meta-analyses require a sufficiently large information size to detect or reject an anticipated intervention effect. The required information size in a meta-analysis may be calculated from an anticipated <it>a priori </it>intervention effect or from an intervention effect suggested by trials with low-risk of bias.</p> <p>Methods</p> <p>Information size calculations need to consider the total model variance in a meta-analysis to control type I and type II errors. Here, we derive an adjusting factor for the required information size under any random-effects model meta-analysis.</p> <p>Results</p> <p>We devise a measure of diversity (<it>D</it>²) in a meta-analysis, which is the relative variance reduction when the meta-analysis model is changed from a random-effects into a fixed-effect model. <it>D</it>²is the percentage that the between-trial variability constitutes of the sum of the between-trial variability and a sampling error estimate considering the required information size. <it>D</it>²is different from the intuitively obvious adjusting factor based on the common quantification of heterogeneity, the inconsistency (<it>I</it>²), which may underestimate the required information size. Thus, <it>D</it>²and <it>I</it>²are compared and interpreted using several simulations and clinical examples. In addition we show mathematically that diversity is equal to or greater than inconsistency, that is <it>D</it>²≥ <it>I</it>², for all meta-analyses.</p> <p>Conclusion</p> <p>We conclude that <it>D</it>²seems a better alternative than <it>I</it>²to consider model variation in any random-effects meta-analysis despite the choice of the between trial variance estimator that constitutes the model. Furthermore, <it>D</it>²can readily adjust the required information size in any random-effects model meta-analysis.</p

Sentinel monitoring of activity of out-of-hours services in Norway in 2007: an observational study

<p>Abstract</p> <p>Background</p> <p>In Norway, no valid activity statistics from the primary health care out-of-hours services or the pre-hospital emergency health care system have previously been available.</p> <p>Methods</p> <p>The National Centre for Emergency Primary Health Care has initiated an enterprise called "The Watchtowers" which consists of a representative sample of seven casualty clinics covering 18 Norwegian municipalities. The purpose of the project is to provide routine information over several years, which will enable monitoring, evaluation and comparison of the activities in the out-of-hours services. This paper presents data from 2007, the first full calendar year for the Watchtowers, analyzes some differences in user patterns for the seven casualty clinics involved, and estimates national figures for the use of casualty clinics and out-of-hours services in Norway.</p> <p>Results</p> <p>A total of 85 288 contacts were recorded during 2007 [399 per 1 000 inhabitants] of which 64 846 contacts were considered non-urgent [76.6%]. There were 53 467 consultations by a doctor [250 per 1 000], 8 073 telephone consultations by doctor [38 per 1 000], 2 783 home visits and call-outs by doctor [13 per 1000] and 20 502 contacts managed by nurses on their own [96 per 1000]. The most common mode of contact was by telephone. Women, young children and elderly had the highest rates of contact.</p> <p>Conclusion</p> <p>Norway has a high rate of contacts to the out-of-hours services compared with some other countries with available data. Valid national figures and future research of these services are important both for local services and policy makers.</p

Outside-In Signalling Generated by a Constitutively Activated Integrin αIIbβ3 Impairs Proplatelet Formation in Human Megakaryocytes

BACKGROUND: The interaction of megakaryocytes with matrix proteins of the osteoblastic and vascular niche is essential for megakaryocyte maturation and proplatelet formation. Fibrinogen is present in the vascular niche and the fibrinogen receptor α(IIb)β(3) is abundantly expressed on megakaryocytes, however the role of the interaction between fibrinogen and α(IIb)β(3) in proplatelet formation in humans is not yet fully understood. We have recently reported a novel congenital macrothrombocytopenia associated with a heterozygous mutation of the β(3) subunit of α(IIb)β(3). The origin of thrombocytopenia in this condition remains unclear and this may represent an interesting natural model to get further insight into the role of the megakaryocyte fibrinogen receptor in megakaryopoiesis. METHODOLOGY/PRINCIPAL FINDINGS: Patients' peripheral blood CD45+ cells in culture were differentiated into primary megakaryocytes and their maturation, spreading on different extracellular matrix proteins, and proplatelet formation were analyzed. Megakaryocyte maturation was normal but proplatelet formation was severely impaired, with tips decreased in number and larger in size than those of controls. Moreover, megakaryocyte spreading on fibrinogen was abnormal, with 50% of spread cells showing disordered actin distribution and more evident focal adhesion points than stress fibres. Integrin α(IIb)β(3) expression was reduced but the receptor was constitutively activated and a sustained, and substrate-independent, activation of proteins of the outside-in signalling was observed. In addition, platelet maturation from preplatelets was impaired. CONCLUSIONS/SIGNIFICANCE: Our data show that constitutive activation of α(IIb)β(3)-mediated outside-in signalling in human megakaryocytes negatively influences proplatelet formation, leading to macrothombocytopenia

Evolution of ligand specificity in vertebrate corticosteroid receptors

<p>Abstract</p> <p>Background</p> <p>Corticosteroid receptors include mineralocorticoid (MR) and glucocorticoid (GR) receptors. Teleost fishes have a single MR and duplicate GRs that show variable sensitivities to mineralocorticoids and glucocorticoids. How these receptors compare functionally to tetrapod MR and GR, and the evolutionary significance of maintaining two GRs, remains unclear.</p> <p>Results</p> <p>We used up to seven steroids (including aldosterone, cortisol and 11-deoxycorticosterone [DOC]) to compare the ligand specificity of the ligand binding domains of corticosteroid receptors between a mammal (<it>Mus musculus</it>) and the midshipman fish (<it>Porichthys notatus</it>), a teleost model for steroid regulation of neural and behavioral plasticity. Variation in mineralocorticoid sensitivity was considered in a broader phylogenetic context by examining the aldosterone sensitivity of MR and GRs from the distantly related daffodil cichlid (<it>Neolamprologus pulcher</it>), another teleost model for neurobehavioral plasticity. Both teleost species had a single MR and duplicate GRs. All MRs were sensitive to DOC, consistent with the hypothesis that DOC was the initial ligand of the ancestral MR. Variation in GR steroid-specificity corresponds to nine identified amino acid residue substitutions rather than phylogenetic relationships based on receptor sequences.</p> <p>Conclusion</p> <p>The mineralocorticoid sensitivity of duplicate GRs in teleosts is highly labile in the context of their evolutionary phylogeny, a property that likely led to neo-functionalization and maintenance of two GRs.</p

Natural history of SLC11 genes in vertebrates: tales from the fish world

<p>Abstract</p> <p>Background</p> <p>The <it>SLC11A1/Nramp1 </it>and <it>SLC11A2/Nramp2 </it>genes belong to the <it>SLC11/Nramp </it>family of transmembrane divalent metal transporters, with <it>SLC11A1 </it>being associated with resistance to pathogens and <it>SLC11A2 </it>involved in intestinal iron uptake and transferrin-bound iron transport. Both members of the <it>SLC11 </it>gene family have been clearly identified in tetrapods; however <it>SLC11A1 </it>has never been documented in teleost fish and is believed to have been lost in this lineage during early vertebrate evolution. In the present work we characterized the <it>SLC11 </it>genes in teleosts and evaluated if the roles attributed to mammalian <it>SLC11 </it>genes are assured by other fish specific <it>SLC11 </it>gene members.</p> <p>Results</p> <p>Two different <it>SLC11 </it>genes were isolated in the European sea bass (<it>Dicentrarchus. labrax</it>), and named <it>slc11a2-α </it>and <it>slc11a2-β</it>, since both were found to be evolutionary closer to tetrapods <it>SLC11A2</it>, through phylogenetic analysis and comparative genomics. Induction of <it>slc11a2-α </it>and <it>slc11a2-β </it>in sea bass, upon iron modulation or exposure to <it>Photobacterium damselae </it>spp. <it>piscicida</it>, was evaluated in <it>in vivo </it>or <it>in vitro </it>experimental models. Overall, <it>slc11a2-α </it>was found to respond only to iron deficiency in the intestine, whereas <it>slc11a2-β </it>was found to respond to iron overload and bacterial infection in several tissues and also in the leukocytes.</p> <p>Conclusions</p> <p>Our data suggests that despite the absence of <it>slc11a1</it>, its functions have been undertaken by one of the <it>slc11a2 </it>duplicated paralogs in teleost fish in a case of synfunctionalization, being involved in both iron metabolism and response to bacterial infection. This study provides, to our knowledge, the first example of this type of sub-functionalization in iron metabolism genes, illustrating how conserving the various functions of the SLC11 gene family is of crucial evolutionary importance.</p

The NTI-tss device for the therapy of bruxism, temporomandibular disorders, and headache – Where do we stand? A qualitative systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>The NTI-tss device is an anterior bite stop, which, according to the manufacturer, is indicated for the prevention and treatment of bruxism, temporomandibular disorders (TMDs), tension-type headaches, and migraine. The aim of this systematic review was to appraise the currently available evidence regarding the efficacy and safety of the NTI-tss splint.</p> <p>Methods</p> <p>We performed a systematic search in nine electronic databases and in NTI-tss-associated websites (last update: December 31, 2007). The reference lists of all relevant articles were perused. Five levels of scientific quality were distinguished. Reporting quality of articles about randomized controlled trials (RCTs) was evaluated using the Jadad score. To identify adverse events, we searched in the identified publications and in the MAUDE database.</p> <p>Results</p> <p>Nine of 68 relevant publications reported about the results of five different RCTs. Two RCTs concentrated on electromyographic (EMG) investigations in patients with TMDs and concomitant bruxism (Baad-Hansen et al 2007, Jadad score: 4) or with bruxism alone (Kavaklı 2006, Jadad score: 2); in both studies, compared to an occlusal stabilization splint the NTI-tss device showed significant reduction of EMG activity. Two RCTs focused exclusively on TMD patients; in one trial (Magnusson et al 2004, Jadad score: 3), a stabilization appliance led to greater improvement than an NTI-tss device, while in the other study (Jokstad et al 2005, Jadad score: 5) no difference was found. In one RCT (Shankland 2002, Jadad score: 1), patients with tension-type headache or migraine responded more favorably to the NTI-tss splint than to a bleaching tray. NTI-tss-induced complications related predominantly to single teeth or to the occlusion.</p> <p>Conclusion</p> <p>Evidence from RCTs suggests that the NTI-tss device may be successfully used for the management of bruxism and TMDs. However, to avoid potential unwanted effects, it should be chosen only if certain a patient will be compliant with follow-up appointments. The NTI-tss bite splint may be justified when a reduction of jaw closer muscle activity (e.g., jaw clenching or tooth grinding) is desired, or as an emergency device in patients with acute temporomandibular pain and, possibly, restricted jaw opening.</p

Charting the course for a Blue Economy in Peru: A Research Agenda

Ocean- and coastal-based economic activities are increasingly recognised as key drivers for supporting global economies. This move towards the “blue economy” is becoming globally widespread, with the recognition that if ocean-based activities are to be sustainable, they will need to move beyond solely extractive and exploitative endeavours, aligning more closely with marine conservation and effective marine spatial planning. In this paper we define the “blue economy” as a “platform for strategic, integrated and participatory coastal and ocean development and protection that incorporates a low carbon economy, the ecosystem approach and human well-being through advancing regional industries, services and activities”. In Peru, while the seas contribute greatly to the national economy, the full potential of the blue economy has yet to be realised. This paper presents the findings of an early career scientist workshop in Lima, Peru, in March 2016. The workshop “Advancing Green Growth in Peru” brought together researchers to identify challenges and opportunities for green growth across three Peruvian economic sectors—tourism, transport and the blue economy with this paper exploring in detail the priorities generated from the “blue economy” stream. These priorities include themes such as marine spatial planning, detailed evaluations of existing maritime industries (e.g. guano collection and fisheries), development of an effective MPA network, support for sustainable coastal tourism, and better inclusion of social science disciplines in understanding societal and political support for a Peruvian blue economy. In addition, the paper discusses the research requirements associated with these priorities. While not a comprehensive list, these priorities provide a starting point for future dialogue on a co-ordinated scientific platform supporting the blue growth agenda in Peru, and in other regions working towards a successful “blue economy”

Patient Uncertainty Questionnaire-Rheumatology (PUQ-R): development and validation of a new patient-reported outcome instrument for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in a mixed methods study

Background An in-depth qualitative exploration of uncertainty in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) led to the development of a five-domain conceptual framework of patient uncertainty in these two conditions. The purpose of this study was to develop and evaluate a new patient-reported outcome (PRO) instrument for patient uncertainty in SLE and RA on the basis of this empirically developed conceptual framework. Methods Cognitive debriefing interviews were conducted to pre-test the initial items generated on the basis of the preliminary qualitative exploration of patient uncertainty in SLE and RA. Two separate field tests were conducted in five hospital sites to evaluate the measurement properties of the new instrument; the first to identify and form scales, and the second to assess measurement properties of the final version in an independent sample. Psychometric evaluation was conducted in line with the Rasch Measurement Theory (RMT), examining the extent to which sample to scale targeting was satisfactory, measurement scales were constructed effectively and the sample was measured successfully. Traditional psychometric techniques were also used to provide complementary analyses best understood by clinicians. Results Pre-testing supported the relevance, acceptability and comprehensibility of the initial items. Findings indicated that the Patient Uncertainty Questionnaire for Rheumatology PUQ-R instrument fulfilled the expectations of RMT to a large extent (including person separation index 0.73 – 0.91). The PUQ-R comprises 49 items across five scales; symptoms and flares (14 items), medication (11 items), trust in doctor (8 items), self-management (6 items) and impact (10 items) which further displayed excellent measurement properties as assessed against the traditional psychometric criteria (including Cronbach’s alpha 0.82 – 0.93). Conclusion The PUQ-R has been developed and evaluated specifically for patients with SLE and RA. By quantifying uncertainty, the PUQ-R has the potential to support evidence-based management programmes and research