Disruption of embryonic blood-CSF barrier in chick embryos reveals the actual importance of this barrier to control E-CSF composition and homeostasis in early brain development

In vertebrates, early brain development takes place at the expanded anterior end of the neural tube. After closure of the anterior neuropore, the brain wall forms a physiologically sealed cavity that encloses embryonic cerebrospinal fluid (E-CSF), a complex and protein-rich fluid that is initially composed of trapped amniotic fluid. E-CSF has several crucial roles in brain anlagen development. Recently, we reported the presence of transient blood-CSF barrier located in the brain stem lateral to the ventral midline, at the mesencephalon and prosencephalon level, in chick and rat embryos by transporting proteins, water, ions and glucose in a selective manner via transcellular routes. To test the actual relevance of the control of E-CSF composition and homeostasis on early brain development by this embryonic blood-CSF barrier, we block the activity of this barrier by treating the embryos with 6-aminonicotinamide gliotoxin (6-AN). We demonstrate that 6-AN treatment in chick embryos blocks protein transport across the embryonic blood-CSF barrier, and that the disruption of the barrier properties is due to the cease transcellular caveolae transport, as detected by CAV-1 expression cease. We also show that the lack of protein transport across the embryonic blood-CSF barrier influences neuroepithelial cell survival, proliferation and neurogenesis, as monitored by neurepithelial progenitor cells survival, proliferation and neurogenesis. The blockage of embryonic blood-CSF transport also disrupts water influx to the E-CSF, as revealed by an abnormal increase in brain anlagen volume. These experiments contribute to delineate the actual extent of this blood-CSF embryonic barrier controlling E-CSF composition and homeostasis and the actual important of this control for early brain development, as well as to elucidate the mechanism by which proteins and water are transported thought transcellular routes across the neuroectoderm, reinforcing the crucial role of E-CSF for brain development.

Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.

The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.

Strategisen muutoksen johtaminen ongelmayrityksessä - case Osuuskauppa Hämeenmaa

Tavoitteet Tutkielman tavoitteena on selvittää ne tekijät, jotka ratkaisivat lähes konkurssissa olleen vähittäiskaupan yrityksen nostamisen todelliseksi menestystarinaksi. Aineisto ja tutkimusmenetelmä Teoreettinen viitekehys tutkielmassa muodostui keskeisten käsitteiden ympärille liittyneiden artikkeleiden sekä kirjallisuuden tarkastelusta tämän tutkielman kannalta. Empiirinen osa sisälsi tutkimuksen toteuttamisen case-yrityksessä, jossa tutkin strategisen muutoksen johtamista teoreettista viitekehystä hyväksikäyttäen. Tutkimusote tutkielmassa oli kvalitatiivinen ja informaation keräämisen metodina oli teemahaastattelu, mikä mahdollisti runsaan ja monipuolisen aineiston keräämisen case-yrityksestä. Tulokset Tutkimus vahvisti aikaisempia käsityksiä arvojen, vision ja strategian merkityksistä muutoksenjohtamisessa. Arvojen osalta tutkimustuloksessa korostuivat johdon oman esimerkin ja voimakkaan tahtotilan merkitykset arvojen sisäistämisessä. Menestyvän vähittäiskaupan yrityksen strategiaprosessi näyttää olevan monia aikaisempia teorioita suoraviivaisempi prosessi. Myös tietojärjestelmien tuen merkitys tuli esille vahvasti.

Logistinen ketju vähittäiskaupan kilpailukykyä lisäävänä tekijänä

Tutkielman tavoitteena on tutkia logistista prosessia vähittäiskaupan kilpailu-kykyä lisäävänä tekijänä. Pääongelmana on selvittää kuinka logistista ketjua johdetaan tehokkaasti vähittäiskaupan asiakasnäkökulma huomioiden. Aihetta on käsitelty määrittämällä logistiikan käsite ja selittämällä logistisen prosessin keskeisiä malleja, logistisen prosessin johtamista, logistiikan kehittymistä, asiakassuhteiden johtamista sekä strategioita varsinkin kilpailun näkökulmasta. Empiirinen osuus on tutkimuksen kannalta keskeinen. Empiirinen tutkimusaineisto on luonteeltaan kvalitatiivinen, jossa henkilökohtaisten haastattelujen avulla kerätty tutkimusaineisto näyttelee merkittävää roolia. Tutkimuksen keskeisimmät tulokset ovat aiemman tutkimuksen ja kirjallisuuden perusteella nelikenttään muotoiltu teoreettinen viitekehys ja tutkimuksen tekijän empiirisen tutkimusaineiston perusteella esiin nostetut logistisen prosessin asiakasodotukset. Keskeisimmät johtopäätökset saaduista tutkimus-tuloksista ovat asiakkaiden halu vaikuttaa ja kehittää toimintaa koko arvoketjussa, tehdyt parannusehdotukset päivittäistavaroiden logistiikkaan ja johtamiseen sekä logistiselle prosessille löytyneet menestystekijät ja päämäärä.

The predictive value of preoperative B-type natriuretic peptide in children undergoing cardiac surgery

Introduction: B-type natriuretic peptide (BNP) is a biomarker of myocardial stress. In children, the value of preoperative BNP on postoperative outcome is unclear. The aim of this study was to determine the predictive value of preoperative NT-proBNP on postoperative outcome in children after congenital heart surgery. Results: Ninety-seven patients were included in the study with a median age of 3.3 years [0.7-5.2]. Preoperative median NT-proBNP was 412 pg/ml [164-1309]. NT-proBNP was above the P95 reference value for age in 56 patients (58%). Preoperative NT-proBNP was significantly higher in patients who had mechanical ventilation duration of more than 2 days (1156 pg/ml [281-1951] vs. 267 pg/ml [136-790], p=0.003) and who stayed more than 6 days in the pediatric intensive care unit (727 pg/ml [203-1951] vs. 256 pg/ml [136-790], p=0.007). However, preoperative NT-proBNP was not significantly higher in patients with an increased inotropic score, a prolonged cardiopulmonary bypass time or an increased surgical risk category. Conclusions: An elevated preoperative NT-proBNP reflects hemodynamic status and cardiac dysfunction, and therefore is a valuable adjunct in predicting a complicated postoperative course. ___________________________________ Introduction: Le peptide natriurétique type B (BNP) est un marqueur reflétant le stress myocardique. Dans la population pédiatrique, la signification des valeurs préopératoire de BNP, en particulier sur l'évolution postopératoire, n'est pas clairement établie. Le but de l'étude est de déterminer la valeur prédictive de la partie NT sérique du BNP (NT-proBNP) sur l'évolution post opératoire d'enfants porteur d'une cardiopathie congénitale et ayant eu une chirurgie cardiaque. Résultats: Nonante-sept enfants ont été inclus dans l'étude, avec un âge médian de 3.3 ans [0.7-5.2]. La valeur médiane du NT-proBNP préopératoire était de 412 pg/ml [164-1309]. Le NT-proBNP préopératoire était supérieur au P95 des valeurs de référence pour l'âge chez 56 patients (58%). Le NT-proBNP préopératoire était significativement plus élevé chez les patients ayant eu plus de deux jours de ventilation mécanique dans la période postopératoire (1156 pg/ml [281-1951] vs. 267 pg/ml [136-790], p=0.003) et ayant été hospitalisés plus de 6 jours dans l'unité de soins intensifs pédiatrique (727 pg/ml [203-1951] vs. 256 pg/ml [136-790], p=0.007). Par contre, le NT-proBNP préopératoire n'était pas significativement plus élevé chez les patients ayant eu un score d'inotrope élevé pendant leur hospitalisation aux soins intensifs, un temps de circulation extracorporelle prolongé ou ayant subi une chirurgie avec un risque chirurgical élevé. Conclusions: Un NT-proBNP sérique élevé en préopératoire reflète l'importance du stress myocardique induit par l'hémodynamique et la dysfonction myocardique, il est un marqueur qui permet d'améliorer l'identification des patients à risque d'avoir une évolution post opératoire compliquée.

Domains of importance to the quality of life of older people from two Swiss regions

BACKGROUND: quality of life (QoL) is a subjective perception whose components may vary in importance between individuals. Little is known about which domains of QoL older people deem most important. OBJECTIVE: this study investigated in community-dwelling older people the relationships between the importance given to domains defining their QoL and socioeconomic, demographic and health status. METHODS: data were compiled from older people enrolled in the Lc65+ cohort study and two additional, population-based, stratified random samples (n = 5,300). Principal components analysis (PCA) was used to determine the underlying domains among 28 items that participants defined as important to their QoL. The components extracted were used as dependent variables in multiple linear regression models to explore their associations with socioeconomic, demographic and health status. RESULTS: PCA identified seven domains that older persons considered important to their QoL. In order of importance (highest to lowest): feeling of safety, health and mobility, autonomy, close entourage, material resources, esteem and recognition, and social and cultural life. A total of six and five domains of importance were significantly associated with education and depressive symptoms, respectively. The importance of material resources was significantly associated with a good financial situation (β = 0.16, P = 0.011), as was close entourage with living with others (β = 0.20, P = 0.007) and as was health and mobility with age (β = -0.16, P = 0.014). CONCLUSION: the importance older people give to domains of their QoL appears strongly related to their actual resources and experienced losses. These findings may help clinicians, researchers and policy makers better adapt strategies to individuals' needs.

MHC/Peptide-Specific Interaction of the Humoral Immune System: A New Category of Antibodies.

Abs bind to unprocessed Ags, whereas cytotoxic CD8(+) T cells recognize peptides derived from endogenously processed Ags presented in the context of class I MHC complexes. We screened, by ELISA, human sera for Abs reacting specifically with the influenza matrix protein (IMP)-derived peptide58-66 displayed by HLA-A*0201 complexes. Among 653 healthy volunteers, blood donors, and women on delivery, high-titered HLA-A*0201/IMP58-66 complex-specific IgG Abs were detected in 11 females with a history of pregnancies and in 1 male, all HLA-A*0201(-). These Abs had the same specificity as HLA-A*0201/IMP58-66-specific cytotoxic T cells and bound neither to HLA-A*0201 nor the peptide alone. No such Abs were detected in HLA-A*0201(+) volunteers. These Abs were not cross-reactive to other self-MHC class I alleles displaying IMP58-66, but bound to MHC class I complexes of an HLA nonidentical offspring. HLA-A*0201/IMP58-66 Abs were also detected in the cord blood of newborns, indicating that HLA-A*0201/IMP58-66 Abs are produced in HLA-A*0201(-) mothers and enter the fetal blood system. That Abs can bind to peptides derived from endogenous Ags presented by MHC complexes opens new perspectives on interactions between the cellular and humoral immune system.

Vähittäiskaupan tavarantoimittaja-arviointi -tapaustutkimus

Organisaatio tarvitsee työkaluja toimittajien suorituskyvyn mittaukseen ja kehittämiseen. Ilman systemaattista mittaamista ja arviointia ostajat eivät tiedä kuinka hyvin toimittajat suoriutuvat velvoitteistaan. Tutkielman tavoit-teena oli analysoida vähittäiskaupan tavarantoimittajien arviointiprosessia keskittyen päivittäistavarakaupan toimialaan ja tavarantoimittajiin sekä luoda toimittajien arviointiin pilottiraportti. Tutkielma on tehty päivittäistavarakaupan kohdeyrityksen toimeksiannosta. Tutkielman teoreettinen aineisto pohjautuu aikaisempaan kirjallisuuteen ja tutkimukseen. Tutkielman empiiriseen osaan aineistoa kerättiin kohdeyrityksen henkilöstön haastatteluilla sekä osallistuvan havainnoinnin avulla. Lisäksi tutkija perehtyi kohdeyrityksessä käytössä olevaan tietovarastointi-sovellukseen. Kirjallisen aineiston avulla rakennettu tutkimuksen teoreettinen osa perustuu aikaisempaan tutkimukseen. Empiirinen osa muodostuu neljästä teemahaastattelusta, jotka suoritettiin kohdeyrityksessä. Haastattelujen tarkoituksena oli rakentaa tutkijalle kuva kohdeyrityksen tavarantoimittaja-arvioinnin nykytilasta. Tutkielmassa havainnollistettiin yksinkertainen raportointimalli yhden tavararyhmän arviointiin ja arviointitiedon analysointiin. Raportointimallilla havainnollistetaan tavarantoimittaja-arviointidatan käyttöä toimittaja-arvioinnissa. Jatkossa on olennaista keskittyä systemaattisen raportoinnin edelleen kehittämiseen ja arviointitiedon hyväksikäyttöön neuvotteluissa toimittajan kanssa. Lisäksi toimittajien luokittelu tavararyhmien sisällä on tärkeää jotta arvioinnissa voidaan keskittyä kaikista tärkeimpiin toimittajiin.

EEG reactivity to pain in comatose patients: Importance of the stimulus type.

INTRODUCTION: Electroencephalogram (EEG) background reactivity is a potentially interesting outcome predictor in comatose patients, especially after cardiac arrest, but recent studies report only fair interrater reliability. Furthermore, there are no definite guidelines for its testing. We therefore investigated the EEG effect of standardized noxious stimuli in comatose patients not reactive to auditory stimuli. METHODS: In this prospective study we applied a protocol using three different painful stimuli (bilateral nipple pinching, pinprick at the nose base, finger-nail compression on each side), grouped in three distinct clusters with an alternated sequence, during EEG recordings in comatose patients. We only analyzed recordings showing any reactivity to pain. Fisher and χ2 tests were used as needed to assess contingency tables. RESULTS: Of 42 studies, 12 did not show any background reactivity, 2 presented SIRPIDs, and 2 had massive artefacts; we thus analyzed 26 EEGs recorded in 17 patients (4 women, 24%). Nipple pinching more frequently induced a change in EEG background activity (p<0.001), with a sensitivity of 97.4% for reactivity. Neither the order of the stimuli in the cluster (p=0.723), nor the cluster order (p=0.901) influenced the results. CONCLUSION: In this pilot study, bilateral, synchronous nipple pinching seems to be the most efficient method to test nociceptive EEG reactivity in comatose patients. This approach may enhance interrater reliability, but deserves confirmation in larger cohorts.

The importance of distinguishing information from evidence/observations when formulating propositions

The value of forensic results crucially depends on the propositions and the information under which they are evaluated. For example, if a full single DNA profile for a contemporary marker system matching the profile of Mr A is assessed, given the propositions that the DNA came from Mr A and given it came from an unknown person, the strength of evidence can be overwhelming (e.g., in the order of a billion). In contrast, if we assess the same result given that the DNA came from Mr A and given it came from his twin brother (i.e., a person with the same DNA profile), the strength of evidence will be 1, and therefore neutral, unhelpful and irrelevant 1 to the case at hand. While this understanding is probably uncontroversial and obvious to most, if not all practitioners dealing with DNA evidence, the practical precept of not specifying an alternative source with the same characteristics as the one considered under the first proposition may be much less clear in other circumstances. During discussions with colleagues and trainees, cases have come to our attention where forensic scientists have difficulty with the formulation of propositions. It is particularly common to observe that results (e.g., observations) are included in the propositions, whereas-as argued throughout this note-they should not be. A typical example could be a case where a shoe-mark with a logo and the general pattern characteristics of a Nike Air Jordan shoe is found at the scene of a crime. A Nike Air Jordan shoe is then seized at Mr A's house and control prints of this shoe compared to the mark. The results (e.g., a trace with this general pattern and acquired characteristics corresponding to the sole of Mr A's shoe) are then evaluated given the propositions 'The mark was left by Mr A's Nike Air Jordan shoe-sole' and 'The mark was left by an unknown Nike Air Jordan shoe'. As a consequence, the footwear examiner will not evaluate part of the observations (i.e., the mark presents the general pattern of a Nike Air Jordan) whereas they can be highly informative. Such examples can be found in all forensic disciplines. In this article, we present a few such examples and discuss aspects that will help forensic scientists with the formulation of propositions. In particular, we emphasise on the usefulness of notation to distinguish results that forensic scientists should evaluate from case information that the Court will evaluate.

One more lie: the Monday effect in Spain’s retail petrol market

Empirical evidence drawn from the economic literature points to a low level of competition in the retail petrol market. Similar evidence can be found for the Spanish market. In fact, both Spain’s antitrust authority -Comisión Nacional de la Competencia- and its energy regulator -Comisión Nacional de la Energía- have recently initiated disciplinary proceedings against the majors on the grounds of suspected price manipulation in the retail petrol market. They are accused of cutting retail prices on Mondays so as to distort the rank position of Spain in European Union statistics in a practice that has received the name of the Monday effect. Here, we analyze this effect by constructing a database that includes daily retail prices for all petrol stations in Spain in the period 2009-2012, and a more detailed database for the city of Barcelona in 2013. Our estimations confirm that: 1- in 2011 and 2012 prices fell on Mondays at retailers branded by majors; 2- prices were unchanged at stations in our two control groups; 3- prices were also seen to fall when a more detailed analysis was conducted, and this price cut was also found in 2013. In short, one more indicator of collusion in this sector and … one more lie.

Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment.

BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.