Efficacy of the fluorescent dyes Fast Blue, Fluoro-Gold, and Diamidino Yellow for retrograde tracing to dorsal root ganglia after subcutaneous injection

The present study was designed to investigate the efficacy of the fluorescent dyes Fast Blue (FB), Fluoro-Gold (FG), and Diamidino Yellow (DY) for retrograde tracing of lumbar dorsal root ganglia after their subcutaneous injection into different hindlimb digits. Injection of equal volumes (0.5 mu l) of 5% FB or 2% FG resulted in similar mean numbers of sensory neurones labelled by each tracer. Injection of equal volumes (0.5 mu l) of FB or FG in a single digit followed 10 days later by a second injection of the same volume of 5% DY into the same digit resulted in similar mean numbers of labelled sensory neurones for each of the three tracers. Furthermore, on average, 75% of all the FB-labelled cells and 74% of all FC-labelled cells also contained DY. Repeating the same experiment with an increased volume of DY (1.5 mu l) resulted in an increase in the mean number of double-labelled profiles to 82 and 84% for FB and FG, respectively. The results show that FB, FG and DY label similar numbers of cutaneous afferents and that a high level of double labelling may be obtained after sequential injections in digits. These properties make them suitable candidates in investigations where a combination of tracers with similar labelling efficacies is needed.

Contrast : a concept in language and its development in Medieval Spanish

The purpose of this PhD thesis is to investigate a semantic relation present in the connection of sentences (more specifically: propositional units). This relation, which we refer to as contrast, includes the traditional categories of adversatives - predominantly represented by the connector but in English and pero in Modern Spanish - and concessives, prototypically verbalised through although / aunque. The aim is to describe, analyse and - as far as possible - to explain the emergence and evolution of different syntactic schemes marking contrast during the first three centuries of Spanish (also referred to as Castilian) as a literary language, i.e., from the 13th to the 15th century. The starting point of this question is a commonplace in syntax, whereby the semantic and syntactic complexity of clause linkage correlates with the degree of textual elaboration. In historical linguistics, i.e., applied to the phylogeny of a language, it is commonly referred to as the parataxis hypothesis A crucial part of the thesis is dedicated by the definition of contrast as a semantic relation. Although the label contrast has been used in this sense, mainly in functional grammar and text linguistics, mainstream grammaticography and linguistics remain attached to the traditional categories adversatives and concessives. In opposition to this traditional view, we present our own model of contrast, based on a pragma-semantic description proposed for the analysis of adversatives by Oswald Ducrot and subsequently adopted by Ekkehard König for the analysis of concessives. We refine and further develop this model in order for it to accommodate all, not just the prototypical instances of contrast in Spanish, arguing that the relationship between adversatives and concessives is a marked opposition, i.e., that the higher degree of semantic and syntactic integration of concessives restricts some possible readings that the adversatives may have, but that this difference is almost systematically neutralised by contextual factors, thus justifying the assumption of contrast as a comprehensive onomasiological category. This theoretical focus is completed by a state-of-the-question overview attempting to account for all relevant forms in which contrast is expressed in Medieval Spanish, with the aid of lexicographic and grammaticographical sources, and an empirical study investigating the expression of corpus in a corpus study on the textual functions of contrast in nine Medieval Spanish texts: Cantar de Mio Cid, Libro de Alexandre, Milagros de Nuestra Sehora, Estoria de Espana, Primera Partida, Lapidario, Libro de buen amor, Conde Lucanor, and Corbacho. This corpus is analysed using quantitative and qualitative tools, and the study is accompanied by a series of methodological remarks on how to investigate a pragma-semantic category in historical linguistics. The corpus study shows that the parataxis hypothesis fails to prove from a statistical viewpoint, although a qualitative analysis shows that the use of subordination does increase over time in some particular contexts.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - A twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.

Persistence of tracer in the application site -a potential confounding factor in nerve regeneration studies

Selective reinnervation of peripheral targets after nerve injury might be assessed by injecting a first tracer in a target before nerve injury to label the original neuronal population, and applying a second tracer after the regeneration period to label the regenerated population. However, altered uptake of tracer, fading, and cell death may interfere with the results. Furthermore, if the first tracer injected remains in the target tissue, available for 're-uptake' by misdirected regenerating axons, which originally innervated another region, then the identification of the original population would be confused. With the aim of studying this problem, the sciatic nerve of adult rats was sectioned and sutured. After 3 days, to allow the distal axon to degenerate avoiding immediate retrograde transport, one of the dyes: Fast Blue (FB), Fluoro-Gold (FG) or Diamidino Yellow (DY), was injected into the tibial branch of the sciatic nerve, or in the skin of one of the denervated digits. Rats survived 2-3 months. The results showed labelled dorsal root ganglion (DRG) cells and motoneurones, indicating that late re-uptake of a first tracer occurs. This phenomenon must be considered when the model of sequential labelling is used for studying the accuracy of peripheral reinnervation.

2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry.

OBJECTIVES: Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. BACKGROUND: We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. METHODS: Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. RESULTS: During the current observation 37,788 doses of Gadolinium based contrast agent were administered to 37,788 patients. The mean dose was 24.7 ml (range 5-80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12%). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05% (linear non-ionic agent gadodiamide) to 0.42% (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05% (risk stratification in suspected CAD) to 0.22% (viability in known CAD). CONCLUSIONS: The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the "off-label" use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events.

Switch to etravirine for HIV-positive patients receiving statin treatment: a prospective study.

BACKGROUND: Lifestyle changes and statins are the cornerstones in management of dyslipidaemia in patients with HIV infection. Replacement of an antiretroviral therapy (ART) component is a proposed therapeutic strategy to reduce cardiovascular risk. In dyslipidaemic patients with HIV infection, we assessed the efficacy of replacing boosted protease inhibitor (bPI) or efavirenz (EFV) by etravirine (ETR) as an alternative to statin therapy. MATERIALS AND METHODS: A prospective, open-label, multicentre, 12-week study of patients with HIV infection on ART including bPI or EFV, and statin treatment. Four weeks after statin interruption, bPI or EFV was switched to ETR (400 mg, 8 weeks) if serum low-density lipoprotein cholesterol (LDL-C) was ≥ 3 mM. The primary endpoint was the proportion of patients on ETR with no indication for statin treatment at study completion. Serum levels of HIV RNA, lipids and biomarkers of cardiovascular disease were also measured. (ClinicalTrials.gov: NCT01543035). RESULTS: The 31 included patients had a HIV-1 RNA < 50 copies/mL (median age, 52 years; median CD4, 709 cell/mL; median LDL-C, 2·89 mM), 68% were on EFV, and 32% were on bPI. At week 4, 27 patients switched to ETR. At study completion, 15 patients (56%) on ETR did not qualify for statin treatment. After the ETR switch, serum levels of the cardiovascular biomarkers sICAM and MCP1/CCL2 decreased by 11·2% and 18·9%, respectively, and those of CCL5/RANTES and tissue inhibitor of metalloproteinase-1 increased by 14·3% and 13·4%, respectively, indicating reduced cardiovascular risk. There were no notable treatment-related adverse events. CONCLUSIONS: Replacing bPI or EFV by ETR is a viable strategy to obviate primary prevention statin treatment.

Sedimentology and Stratigraphy of the Pleistocene sediments in Lake Llauset (Southern Pyrenees, Spain)-a first approach

The high alpine valleys in the Southem Pyrenees are characterised by a many small lakes and ponds. They occur above 2000 m and are said to have been formed by glacial erosion. The sediments in these basins should, therefore, contain s t p tigraphic information since deglaciation, at least. An interesting and may be one of the most important of these basins is Lake Llauset in the Alta Ribagorca. The Llauset basin has recently been developped for hydsopower production. In conection with the construction of the retaining wall at the 'Riegel' the sedimentary filling of the lake basin could be investigated, and the first sedimentological and stratigraphicalresults are presented.

Asiakasarvoa korostavan liikkeenjohdon konsulttiyrityksen kasvumahdollisuudet

Tämän diplomityön tavoitteena on selvittää asiakasarvoa luovat kasvumahdollisuudet eräälle suomalaiselle liikkeenjohdon konsulttiyritykselle. Yrityksen kasvun tulee tapahtua pitkällä aikavälillä kannattavasti ja tukea sen toimintaa sekä liiketoiminnallisia tavoitteita. Työn teoreettiset aihealueet käsittelevät liikkeenjohdon konsultoinnin toimialaa, arvon luomista ja menestymisen edellytyksiä, asiakaspohjaa ja yhteistyömahdollisuuksia sekä kasvun johtamista. Työn empiirisessä osassa näitä aihealueita tutkittiin yrityksestä saatavien havaintojen, asiakaskyselyn sekä osakashaastattelujen avulla. Asiakasarvoa luovien kasvuvaihtoehtojen määrittämisessä käytettiin apuna analyyttistä hierarkiaprosessia. Tutkimuksen keskeisimmät havainnot olivat, että konsultointipalveluiden asiakasarvoa eniten luovat tekijät tärkeysjärjestyksessä ovat lopputuloksen laatu, ihmisten sitouttaminen kehitykseen, toimialaosaaminen, asenne, uudet näkökulmat ja osaaminen sekä hinta. Kohdeyritykselle tutkittiin viittä kasvuvaihtoehtoa ja niiden asiakasarvon tuottamiskykyä. Suositeltavat kasvuvaihtoehdot kohdeyritykselle tärkeysjärjestyksessä ovat asiakaspohjan säilyttäminen, uusien asiakkaiden hankkiminen sekä verkostojen ja allianssien hyödyntäminen.

A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 2: How is healthcare perceived?

Medically unexplained symptoms (MUS) are common among adolescents and an important cause of clinical visits. This study sought to understand the experiences with, and perceptions of, the healthcare of adolescents who have MUS and their parents. Using a qualitative approach, six focus groups and two individual interviews were conducted with a total of ten adolescents and sixteen parents. The participants were recruited in a university hospital in Switzerland. A thematic analysis was conducted in accordance with the Grounded Theory. Six main themes emerged: needing a label for the symptoms, seeking an etiology to explain the symptoms, negotiating the medical system, medication and treatments, interactions with doctors, and the inclusion of parents during consultations. Transcending these themes, however, was the need for good communication between the adolescents, their parents and the clinicians. When explaining the symptoms, clinicians should make sure to discuss the results, investigations and lack of organic origin.

Sertifioidun puuraaka-aineen ja sertifioitujen tuotteiden tietojärjestelmän määrittely

Asiakkaiden kiinnostus tuotteiden raaka-aineiden alkuperää kohden on kasvanut. Puuraaka-aineesta tehtyjen tuotteiden alkuperä voidaan todentaa sertifikaatilla, jos puu on peräisin sertifioidusta metsästä ja sen alkuperäketju tunnetaan. Tieto sertifioidusta tuotteesta kulkeutuu asiakkaalle leimaamalla tuotteita sertifioinnista kertovin merkein tai merkitsemällä esimerkiksi tuotteen asiakirjaan sertifioinnista kertova teksti. Tutkimus tehtiin Stora Enson Imatran tehtaalle, jolla oli tarve uudelle tietojärjestelmälle. Tutkimuksen tarkoituksena oli määritellä sertifioidun puuraaka-aineen käytön ja sertifioituina myytävien tuotteiden seurannan mandollistava tietojärjestelmä. Puun alkuperäketjun hallinnan standardit määiittävät, paljonko sertifioitua puuta kohdennettava tuotteelle, jos tuotteita halutaan myydä sertifioituna. Tietojärjestelmän määrittelyn lisäksi oli tarve selvittää prosessi, kuinka tuotteisiin ja asiakirjoihin saataisiin sertifioinnista kertova leima. Tutkimusta tehdessä selvisi, että tehtaan nykyiset myyntitoiminnot ja tietojärjestelmät asettavat rajoituksia tuotteiden ja asiakirjojen leimaukselle. Prosessia kartoitettiin mm. haastatt elemalla tehtaan ti etojärj estelmi en, myynti- ja varastotoimintojen parissa työskenteleviä ihmisiä. Haastattelujen perusteella koottiin myös tietojärjestelmän asiakasvaatimukset. Vaatimusmäärittelyä tehdessä huomioitiin myös alkuperäketjun hallinnan standardien vaatimukset. Määriteltävän tietojärjestelmän toimintaa pyrittiin havainnollistamaan tehtaan edustajille prototyyppien avulla. Lisäksi tutkimuksessa on pyritty havainnollistamaan järjestelmän toimintaa erilaisin kaavioin ja kuvin. Haasteena työssä oli tulkita standardeja ja kerätä yhteen toisistaan poikkeavia asiakasvaatimuksia.

Cartographie et analyse des données disponibles pour estimer le nombre de préservatifs écoulés sur le marché suisse en une année

L'Office fédéral de la santé publique (OFSP) a mandaté la Fédération romande des consommateurs (FRC) et l'Institut universitaire de médecine sociale et préventive (IUMSP) pour réaliser une cartographie du marché des préservatifs et analyser les données disponibles pour estimer le nombre de préservatifs écoulés sur le marché suisse en une année. Les données disponibles identifiées sont les suivantes : 1. Données Verein : l'Association pour le label de qualité des préservatifs possède des données sur le nombre de préservatifs testés chaque année pour l'obtention du label OK. Ces données constituent une estimation du nombre de préservatifs ayant suivi la procédure de certification du label OK. Ces dernières années, des entreprises auraient renoncé à leur collaboration avec l'association pour le label de qualité, ce qui réduit la fiabilité de cette méthode pour suivre l'évolution du marché des préservatifs en Suisse. 2. Données douanes : l'Administration fédérale des douanes établit une statistique du commerce extérieur et met à disposition une base de données qui donne accès aux données statistiques d'importation et d'exportation de préservatifs. Etant donné que cette statistique se base sur les données indiquées par les importateurs et les exportateurs, des erreurs de déclaration peuvent être commises. 3. Données IUMSP : entre 1986 et 2011, l'IUMSP a reçu des producteurs/importateurs des données de mises sur le marché de préservatifs. Ces données, fiables car provenant directement des producteurs/importateurs, ne sont malheureusement plus complètes depuis 2012, en raison d'une difficulté croissante à obtenir de telles informations. 4. Données Nielsen et IMS Health : Nielsen et IMS HEalth sont des entreprises privées qui recensent les données de vente des préservatifs en Suisse réalisées dans les commerces de détail, ainsi que dans les drogueries et pharmacies. Ces données constituent des données de vente réelles obtenues grâce à l'enregistrement des mouvements de la marchandise lors du passage en caisse dans les magasins. La couverture des points de vente est élevée (près de 80% pour les données Nielsen) et stable dans le temps.

Classification supervisée multi-étiquette en actes de dialogue: analyse discriminante et transformations de Schoenberg

Abstract This work studies the multi-label classification of turns in simple English Wikipedia talk pages into dialog acts. The treated dataset was created and multi-labeled by (Ferschke et al., 2012). The first part analyses dependences between labels, in order to examine the annotation coherence and to determine a classification method. Then, a multi-label classification is computed, after transforming the problem into binary relevance. Regarding features, whereas (Ferschke et al., 2012) use features such as uni-, bi-, and trigrams, time distance between turns or the indentation level of the turn, other features are considered here: lemmas, part-of-speech tags and the meaning of verbs (according to WordNet). The dataset authors applied approaches such as Naive Bayes or Support Vector Machines. The present paper proposes, as an alternative, to use Schoenberg transformations which, following the example of kernel methods, transform original Euclidean distances into other Euclidean distances, in a space of high dimensionality. Résumé Ce travail étudie la classification supervisée multi-étiquette en actes de dialogue des tours de parole des contributeurs aux pages de discussion de Simple English Wikipedia (Wikipédia en anglais simple). Le jeu de données considéré a été créé et multi-étiqueté par (Ferschke et al., 2012). Une première partie analyse les relations entre les étiquettes pour examiner la cohérence des annotations et pour déterminer une méthode de classification. Ensuite, une classification supervisée multi-étiquette est effectuée, après recodage binaire des étiquettes. Concernant les variables, alors que (Ferschke et al., 2012) utilisent des caractéristiques telles que les uni-, bi- et trigrammes, le temps entre les tours de parole ou l'indentation d'un tour de parole, d'autres descripteurs sont considérés ici : les lemmes, les catégories morphosyntaxiques et le sens des verbes (selon WordNet). Les auteurs du jeu de données ont employé des approches telles que le Naive Bayes ou les Séparateurs à Vastes Marges (SVM) pour la classification. Cet article propose, de façon alternative, d'utiliser et d'étendre l'analyse discriminante linéaire aux transformations de Schoenberg qui, à l'instar des méthodes à noyau, transforment les distances euclidiennes originales en d'autres distances euclidiennes, dans un espace de haute dimensionnalité.

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features.

PURPOSE: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and to study the clinical features of adRP patients. DESIGN: Retrospective clinical and molecular genetic study. METHODS: Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot. RESULTS: We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1-0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families. CONCLUSIONS: The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0%-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases, which could be underdiagnosed.

Imaging the time-integrated cerebral metabolic activity with subcellular resolution through nanometer-scale detection of biosynthetic products deriving from (13)C-glucose.

Glucose is the primary source of energy for the brain but also an important source of building blocks for proteins, lipids, and nucleic acids. Little is known about the use of glucose for biosynthesis in tissues at the cellular level. We demonstrate that local cerebral metabolic activity can be mapped in mouse brain tissue by quantitatively imaging the biosynthetic products deriving from [U-(13)C]glucose metabolism using a combination of in situ electron microscopy and secondary ion mass-spectroscopy (NanoSIMS). Images of the (13)C-label incorporated into cerebral ultrastructure with ca. 100nm resolution allowed us to determine the timescale on which the metabolic products of glucose are incorporated into different cells, their sub-compartments and organelles. These were mapped in astrocytes and neurons in the different layers of the motor cortex. We see evidence for high metabolic activity in neurons via the nucleus (13)C enrichment. We observe that in all the major cell compartments, such as e.g. nucleus and Golgi apparatus, neurons incorporate substantially higher concentrations of (13)C-label than astrocytes.