Working mechanism of Hic-5 in human and experimental NAFLD-related liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) is characterized by a wide spectrum of pathological findings, ranging from simple steatosis to steatohepatitis which can progress to cirrhosis and hepatocellular carcinoma. Fibrosis severity is the main determinant of liver-related complications and mortality, therefore its regression is considered an important therapeutic endpoint in clinical trials evaluating pharmacological intervention in NAFLD. Activation of hepatic stellate cells (HSC) by transforming growth factor beta (TGFβ) is a well-established driver of liver fibrogenesis. Recently, a TGFβ-modulated protein, namely hydrogen peroxide-inducible clone 5 (Hic-5) has been proposed as a novel potential therapeutic target for liver fibrosis, since its knockdown attenuated experimental liver fibrosis in mice. However, limited data are available regarding its expression in human HSC, while no study has investigated its role in the setting of NAFLD so far. Based on these premises, the aim of my thesis was first to characterize Hic-5 expression in human HSC according to different hepatic microenvironment (healthy versus fibrotic); secondly to assess whether Hic-5 is expressed in human and experimental NAFLD. To investigate the first aim, primary human HSC were cultured in a new 3-dimensional (3D) culture model based on decellularized human liver extracellular matrix (ECM) scaffolds derived from healthy and cirrhotic livers. Compared to traditional 2D cultures, Hic-5 gene expression was significantly upregulated in HSC cultured in the 3D model. This effect was further enhanced upon TGFβ stimulation in healthy scaffolds. Moreover, higher Hic-5 mRNA levels were detected in HSC cultured in cirrhotic scaffolds compared to healthy scaffolds, suggesting that Hic-5 expression and its modulation by TGFβ are strongly affected by liver- and disease specific ECM features. Based on these preliminary in-vitro results, I decided to further investigate Hic-5 expression in human NAFLD samples obtained from obese patients undergoing bariatric surgery. Immunohistochemical staining showed an increased expression of Hic-5 in fibrotic liver tissue, which overlapped alpha smooth muscle actin (α-SMA) positive areas. In order to better elucidate the role of Hic-5 across NAFLD progression, a nutritional rat model of NAFLD, based on the administration of choline-deficient (CD) diet, was employed and hepatic Hic-5 expression analyzed at different time points. After 3 days of CD diet Hic-5 mRNA levels were not significantly upregulated, suggesting that fatty liver alone without associated liver fibrosis does not affect Hic-5 expression. Accordingly, no difference in α-SMA gene expression was observed compared to control diet. In contrast, administration of CD diet for 7 weeks led to increased mRNA expression of Hic-5 along with αSMA, TGFβ1 and collagen type 1A1. Upregulation of Hic-5 was further confirmed at the protein level by Western blot analysis. Similar findings were obtained when CD diet was given for 11 weeks. Interestingly, the administration of a triiodothyronine(T3)-supplemented diet for 1 week, which has been previously shown to revert rat fatty liver, was able to reduce the expression of Hic-5. The same effect of T3 on Hic-5 was seen on the microenvironment surrounding preneoplastic nodules during NASH-related experimental liver carcinogenesis. Since T3 administration was associated with regression of preneoplastic nodules not expressing Hic-5 or αSMA, we speculate that its antifibrotic effect may contribute to preneoplastic nodules regression. Taken together, these results highlight the role of Hic-5 in HSC activation in vitro and its association with NAFLD progression. Further studies are needed to clarify the molecular mechanisms regulating Hic-5 expression in NAFLD-related fibrosis and the effects of thyroid receptor’s agonists in order to identify potential anti-fibrotic therapie

Can we predict dividend cuts?

I examine the predictability of dividend cuts based on the time interval between dividend announcement dates using a large dataset of US firms from 1971 to 2014. The longer the time interval between dividend announcements, the larger the probability of a cut in the dividend per share, consistent with the view that firms delay the release of bad news

Pre-adoption market reaction to IFRS 9:a cross-country event-study

We are the first to examine the market reaction to 13 announcement dates related to IFRS 9 for over 5400 European listed firms. We find an overall positive reaction to the introduction of IFRS 9. The regulation is particularly beneficial to shareholders of firms in countries with weaker rule of law and a smaller divergence between local GAAP and IAS 39. Bootstrap simulations rule out the possibility that sampling error or data mining are driving our findings. Our main findings are also robust to confounding events and the extent of the media coverage for each event. These results suggest that investors perceive the new regulation as shareholder-wealth enhancing and support the view that stronger comparability across accounting standards of European firms is beneficial to international investors and outweighs the costs of poorer firm-specific information

Strengthening Institutional Isomorphism in Development NGOs? : Program Mechanisms in an Organizational Intervention

Peer reviewe

POHJOIS-KYMENLAAKSON RINTASYÖPÄHOITAJAN ANTAMA TIETO JA OHJAUS VASTAANOTOILLA : Potilastyytyväisyystutkimus

Tämän tutkimuksen tarkoituksena oli selvittää, miten tyytyväisiä potilaat ovat olleet rintasyöpähoitajan vastaanottokäynteihin Pohjois-Kymen sairaalassa ja kartoittaa mahdollisia kehittämisideoita. Tutkimus toteutettiin kvantitatiivisella eli määrällisellä tutkimusmenetelmällä, jonka aineisto kerättiin kyselylomakkeilla. Kyselylomakkeeseen tuli yhdeksän taustakysymystä, 13 suljettua kysymystä ja yksi avoin kysymys tarkempien tietojen saamiseksi. Taustatiedot tähän tutkimukseen oli haettu alan kirjallisuudesta, elektronisista lähteistä, ja aiheeseen liittyvistä aiemmista tutkimuksista. Täydentävänä tiedonkeruumenetelmänä toteutettiin rintasyöpähoitajan henkilökohtainen asiahaastattelu, jonka avulla saatiin tarkempaa tietoa hänen työnkuvasta. Tutkimuksen kohteena eli perusjoukkona toimi rintasyöpähoitajan vastaanotolla käyvät rintasyöpäpotilaat (N=720). Tässä tutkimuksessa ei ollut resursseja tutkia koko perusjoukkoa rajoitetun aikataulun vuoksi, joten tässä tarkasteltiin vain osaa perusjoukosta. Tutkimuksen otantamenetelmänä toimi harkinnanvarainen otanta eli näyte, sillä tähän tutkimukseen havaintoyksiköt valikoituivat perusjoukosta vain kyselyn ajankohdan perusteella. Tämän tutkimuksen otoskoon tavoite oli perusjoukkoon nähden pieni (n=50), mutta tarpeeksi suuri analyysin tekemiseen tilastollista menetelmää käyttäen. Potilaat vastasivat kyselyyn rintasyöpähoitajan vastaanottokäynnin yhteydessä ja postitse loka-marraskuussa 2016 viikoilla 42– 44. Kyselylomakkeita laitettiin jakoon 50 kappaletta, vastauksia tuli yhteensä 37, joista kaksi oli hylättävä selkeästi puutteellisten tietojen vuoksi. Vastausmäärä (74 % 50:stä) oli hyvä rajattuun aika-tauluun nähden. Lopullinen aineisto (n=35) analysoitiin tilastollisella SPSS-ohjelmalla. Kyselyyn osallistuneet olivat laajalti (46 %) vastanneet kaikkiin lomakkeen väittämiin melko tai täysin samaa mieltä. Kuitenkin suurin osa (54 %) kyselyyn osallistujista vastasi lomakkeessa yhdestä neljään väittämään olleensa melko tai täysin eri mieltä. Kokonaisuudessaan tutkimustulosten mukaan valtaosa (noin 85 %) kyselyyn osallistuneista oli siis tyytyväisiä vastaanottokäynteihin. Tyytymättömyyttä ilmaisi vain pieni osa (noin 15 %) vastaajista. Potilaat kokivat olleensa kaikista tyytyväisimpiä rintasyöpähoitajan antamaan tukeen koskien potilaan omaa päätöksentekoa, saamaansa tietoon liittyen leikkaukseen, vastaanottokäynteihin varattuun aikaan, sekä rintasyöpähoitajan antamaan tietoon jatkohoitoon ja seurantaan liittyvistä asioista. Potilaat olivat tyytymättömimpiä rintasyöpähoitajan antamaan ohjaukseen liittyen mahdollisiin seksuaalisuuden muutoksiin. Luotettavuutta mietittäessä tavoitteeseen päästiin melko hyvin, sillä tutkimusongelmiin saatiin vastaukset. Ainoastaan avoimeen kysymykseen liittyen kehittämisideoihin ei tullut toivottua vastausmäärää. Reliabiliteettia ei ollut tarkoituksenmukaista arvioida, sillä kyselyä ei toistettu eri ajankohtina rajatun aikataulun vuoksi. Kyselylomakkeet esitestattiin terveydenhoitoalan ammattilaisilla ennen aineiston keruuta, jonka myötä kyselylomakkeeseen saatiin lisää tarkkuutta kehittämisideoiden pohjalta. Lopulta tärkeimpänä tutkimuksen luotettavuutta ja eettisyyttä lisäsi virallisen tutkimusluvan hakeminen Kouvolan kaupungin hyvinvointipalveluiden kautta.The purpose of this research was to find out how satisfied patients were with the breast cancer nurse clinic in Pohjois-Kymi hospital. The research was gathered in a quantitative style and materials were brought together in a questionnaire. The questionnaire had nine background questions, 13 closed questions and one open question to gather more specific information. To ensure the quality of the questionnaire it was handed out to medical professionals in Pohjois-Kymi hospital before being released. The breast cancer patients who visited the breast cancer nurse clinic were at the heart of this research (N=720). Because of a lack of time it was not possible to look into all of the cases, therefore only some of them were studied. Enough people (n=50) were chosen to participate in the research so that the end results could be analysed. The patients answered the questionnaire in October-November 2016, in the weeks of 42-44 by post and while visiting the breast cancer nurse clinic. There were 50 questionnaires handed out, but only 37 of them were received back. Two were disqualified because of a lack of information. The number of replies (74 % of 50) was good considering the amount of time. The final materials (n=35) were analysed with the statistic program SPSS. The background information for this study was gathered from professional literature, electrical sources (internet) and previous studies. The breast cancer nurse was also interviewed about her job to gather more specific information for the research. The 46 % of people that were asked answered that they slightly or completely were satisfied with their appointments. Meanwhile the majority 54 % answered with one to four statements from the questionnaire that they were unsatisfied regarding one or more things about their appointment. In its entirety most of the patients (85 %) were satisfied with their appointments. About unsatisfaction some things about the appointment was indicated only from 15 % of people that were asked. The patients were most satisfied about the support given by the breast cancer nurse in making their own decisions, the information given about operations, the time reserved for each appointment and the information given about follow-up treatment. The patients were most unsatisfied about the guidance given of possible sexual changes. The questionnaire gave accurate results. The open question about development ideas was the only question that did not receive enough comments. It is not practical to estimate the reliability of the results because the questionnaire was not repeated. The questionnaire was tested with health care professionals before being used. This was the questionnaire became more specific. Official permits were sought from Kouvola City Council welfare services to ensure the reliability and ethical accuracy of this research

Measuring disease activity in Crohn's disease

In the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging. © 2012 Springer Science+Business Media, LLC

Valproic acid up-regulates p75NTR and sortilin expression to induce neuronal cell death

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How should we estimate value-relevance models? Insights from European Data

We study the consequences of unobserved heterogeneity when employing different econometric methods in the estimation of two major value-relevance models: the Price Regression Model (PRM) and the Return Regression Model (RRM). Leveraging a large panel data set of European listed companies, we first demonstrate that robust Hausman tests and Breusch-Pagan Lagrange Multiplier tests are of fundamental importance to choose correctly among a fixed-effects model, a random-effects model, or a pooled OLS model. Second, we provide evidence that replacing firm fixed-effects with country and industry fixed-effects can lead to large differences in the magnitude of the key coefficients, with serious consequences for the interpretation of the effect of changes in earnings and book values per share on firm value. Finally, we offer recommendations to applied researchers aiming to improve the robustness of their econometric strategy