Assessing false-belief understanding in children with autism using a computer application: a pilot study

We have developed a False-Belief (FB) understanding task for use on a computer tablet, trying to assess FB understanding in a less social way. It is based on classical FB protocols, and additionally includes a manipulation of language in an attempt to explore the facilitating effect of linguistic support during FB processing. Specifically, the FB task was presented in three auditory conditions: narrative, silent, and interference. The task was assumed to shed new light on the FB difficulties often observed in Autism Spectrum Disorder (ASD). Sixty-eight children with ASD (M = 7.5 years) and an age matched comparison group with 98 typically developing (TD) children were assessed with the FB task. The children with ASD did not perform above chance level in any condition, and significant differences in success rates were found between the groups in two conditions (silent and narrative), with TD children performing better. We discuss implications, limitations, and further developments

Expression of Human Endogenous Retrovirus-W Including Syncytin-1 in Cutaneous T-Cell Lymphoma

Peer reviewe

Cultural adaptation and harmonization of four Nordic translations of the revised Premature Infant Pain Profile (PIPP-R)

Publisher's version (útgefin grein)Background: Preterm infants are especially vulnerable to pain. The intensive treatment often necessary for their survival unfortunately includes many painful interventions and procedures. Untreated pain can lead to both shortand long-term negative effects. The challenge of accurately detecting pain has been cited as a major reason for lack of pain management in these non-verbal patients. The Premature Infant Pain Profile (PIPP) is one of the most extensively validated measures for assessing procedural pain in premature infants. A revised version, PIPP-R, was recently published and is reported to be more user-friendly and precise than the original version. The aims of the study were to develop translated versions of the PIPP-R in Finnish, Icelandic, Norwegian, and Swedish languages, and to establish their content validity through a cultural adaptation process using cognitive interviews. Methods: PIPP-R was translated using the recommendations from the International Society for Pharmacoeconomics and Outcomes Research and enhanced with cognitive interviews. The respondent nurse was given a copy of the translated, national version of the measure and used this together with a text describing the infant in the film to assess the pain of an infant in a short film. During the assessment the nurse was asked to verbalize her thought process (thinking aloud) and upon completion the interviewer administered probing questions (verbal probing) from a structured interview guide. The interviews were recorded, transcribed, and analyzed using a structured matrix approach. Results: The systematic approach resulted in translated and culturally adapted versions of PIPP-R in the Finnish, Icelandic, Norwegian and Swedish languages. During the cultural adaptation process several problems were discovered regarding how the respondent understood and utilized the measure. The problems were either measure problems or other problems. Measure problems were solved by a change in the translated versions of the measure, while for other problems different solutions such as education or training were suggested. Conclusions: This study have resulted in translations of the PIPP-R that have content validity, high degree of clinical utility and displayed beginning equivalence with each other and the original version of the measure.Not applicable.Peer Reviewe

Cultural adaptation and harmonization of four Nordic translations of the revised Premature Infant Pain Profile (PIPP-R)

BackgroundPreterm infants are especially vulnerable to pain. The intensive treatment often necessary for their survival unfortunately includes many painful interventions and procedures. Untreated pain can lead to both short- and long-term negative effects. The challenge of accurately detecting pain has been cited as a major reason for lack of pain management in these non-verbal patients. The Premature Infant Pain Profile (PIPP) is one of the most extensively validated measures for assessing procedural pain in premature infants. A revised version, PIPP-R, was recently published and is reported to be more user-friendly and precise than the original version. The aims of the study were to develop translated versions of the PIPP-R in Finnish, Icelandic, Norwegian, and Swedish languages, and to establish their content validity through a cultural adaptation process using cognitive interviews.MethodsPIPP-R was translated using the recommendations from the International Society for Pharmacoeconomics and Outcomes Research and enhanced with cognitive interviews. The respondent nurse was given a copy of the translated, national version of the measure and used this together with a text describing the infant in the film to assess the pain of an infant in a short film. During the assessment the nurse was asked to verbalize her thought process (thinking aloud) and upon completion the interviewer administered probing questions (verbal probing) from a structured interview guide. The interviews were recorded, transcribed, and analyzed using a structured matrix approach.ResultsThe systematic approach resulted in translated and culturally adapted versions of PIPP-R in the Finnish, Icelandic, Norwegian and Swedish languages. During the cultural adaptation process several problems were discovered regarding how the respondent understood and utilized the measure. The problems were either measure problems or other problems. Measure problems were solved by a change in the translated versions of the measure, while for other problems different solutions such as education or training were suggested.ConclusionsThis study have resulted in translations of the PIPP-R that have content validity, high degree of clinical utility and displayed beginning equivalence with each other and the original version of the measure.</p

Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes. Pancreatic islets derived from stem cells are benchmarked against primary cells.Peer reviewe

Phosphodiesterase 3B Is Localized in Caveolae and Smooth ER in Mouse Hepatocytes and Is Important in the Regulation of Glucose and Lipid Metabolism

Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes

Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population

BACKGROUND: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. METHODOLOGY/PRINCIPAL FINDINGS: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. CONCLUSION: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG

Sähköisten myyntitilausten käsittelyprosessin kehittäminen Exide Technologies Oy:lle

Tilaus-toimitusketju on yrityksen prosessi, joka käynnistyy asiakkaan tarjouspyynnöstä, ja päättyy maksetun laskun kirjaamiseen. Tilaus-toimitusketjussa liikkuu tieto, materiaali ja raha, joten tämän prosessin optimoiminen mahdollisimman tehokkaaksi, asiakkaiden toiveiden mukaiseksi ja kohtuuhintaiseksi vaatii monialaista yhteistyötä ja koko prosessin hallintaa. Hyvä asiakaspalvelu on tärkeä osa jokaisen yrityksen toimintaa, ja siihen kuuluu myös mahdollisimman asiakaslähtöinen tilaus -toimitusketju. Asiakkaat arvostavat yleensä nopeaa ja sujuvaa toimitusta. Asiakkaan tilaus käynnistää ketjun, jonka saumattomuus sekä kitkattomuus heijastuvat suoraan asiakkaan kokemaan palveluun. Jotta prosessi olisi sujuva, siitä on tehtävä mahdollisimman yksinkertainen, mikä samalla lisää ketjun joustavuutta. Tilaus-toimitusketjun suunnittelu on hyvin pitkälti yritykselle strateginen päätös, sillä sen kautta yritys päättä miten asiakaskohtaisesti se pystyy asiakkaiden erilaisia toiveita noudattamaan. Hyvä tiedonkulku on tärkeä osa sujuvaa tilaus-toimitusketjua, sillä sen avulla sekä yritys että asiakas pystyvät suunnittelemaan toimintaansa, ja ennakoimaan tulevia tarpeita ja toimituksia. Yritykset ovat viime aikoina siirtyneet yhä enemmän sähköisten tilaustenhallintajärjestelmien käyttöön, ja tämän myötä onkin kehittynyt hyvin laaja kirjo järjestelmiä, joiden tarkoitus on siirtää tietoa tilauksista ja toimituksista nopeasti, virheettömästi ja vaivattomasti. Tämän kaikkien edesauttaa tilaus-toimituskertun sujuvuutta. Tämän työn toimeksiantajayrityksellä on käytössään usean avainasiakkaan tilausportaalit, joiden kautta nämä asiakkaat tekevät tilauksensa. Näiden käyttö on koettu yrityksessä hankaliksi portaalien keskinäisestä erilaisuudesta johtuen. Tämän opinnäytetyöprojektin tarkoitus oli koota yhteen eri portaalien ohjeet, ja muokata ne yhtenäiseen formaattiin, sekä yrityksen tiluksenkäsittelyn näkökulmasta sopivimmiksi. Työn tavoitteena oli parantaa yrityksen asiakas-palvelua helpottuneen tilaustenkäsittelyn myötä, sekä helpottaa myös uusien työntekijöiden perehdyttämistä portaalitilausten käsittelyyn. Työn tuloksena syntynyt ohjeistus koostuu yhteensä kuuden portaalin käyttöohjeesta, ja on laajuudeltaan 21 sivua. Jokainen ohje noudattaa samaa pohjaa, jossa on 9 päälukua: asiakastiedot, salasanakäytännöt, portaalin verkko-osoite, tilauksen saapuminen, toimenpiteet portaalissa, toimenpiteet Phoenixissa, talous/laskutus, yhteystiedot sekä muut huomiot. Paikoin on käytetty kuvia havainnollistamaan portaalien käyttöä. Tämän työn myötä, on valmistunut ohjeiden ensimmäinen versio, joka on tarkoitus ottaa käyttöön yrityksessä kesäkuussa 2017. Tämän jälkeen kerätään palautetta ohjeista ja päivitetään ohjeet saatujen toiveiden mukaan

Aspects of Communication, Language and Literacy in Autism Child Abilities and Parent Perspectives

The main aim of this thesis was to investigate literacy, ‘theory of mind’ (ToM) and narrative ability in children who had screened positive for autism spectrum disorders (ASD) (comprehensively assessed for neuropsychiatric problems), and relate the findings to their structural linguistic capacity, as measured by language tests at the word and sentence levels. Considering the important roles of families in shaping children’s language socialisation, another aim was to explore the parental experiences of having a child go through the neuropsychiatric and language diagnostic process. The thesis includes four substudies. Almost 200 children participated in one or several of the substudies. Children with ASD were recruited after general population screening and non-ASD comparison children were recruited from schools. Eleven parents of the children with ASD were also included. Study I, aimed to investigate early and concurrent predictors of reading ability in children who had screened positive for ASD. Children were grouped into three types of reading profiles at 8 years of age: approximately one third were skilled readers, half had difficulties with both word reading and reading comprehension and one fifth were ‘hyperlexic’ (i.e. strong word decoding but poor comprehension). Children who showed poor reading comprehension also displayed oral language difficulties concurrently and already at age 3 years. In Study II, a computer application, manipulated in three conditions, was used to investigate the influence of verbal support in ToM. Neither verbal support during the ToM conditions nor higher language ability in the children with ASD was obviously linked to a better outcome on the ToM task. As expected, the ASD group performed poorer than age-matched peers without ASD on the ToM task. Study III, aimed to describe oral narrative ability in children with ASD and determine how it is related to structural language ability) and non-verbal cognitive abilities in children with and without ASD. The results for the ASD group were compared with those for both an age-matched and a younger language-matched group of children without ASD. The ASD group used shorter sentences and fewer subordinate clauses in their retold narratives. Further analyses showed that nonverbal sequential reasoning and language ability explained unique variance in their narrative performance. In Study IV, in-depth interviews were conducted with parents of 11 children with ASD included in the thesis. Following a qualitative phenomenological hermeneutic method, the essence that emerged was ‘negotiating knowledge’ and three main themes were: ‘seeking knowledge’, ‘trusting and challenging experts’, and ‘empowered but alone’. To conclude, a clear influence of language was shown for both literacy and narrative ability in children with ASD, implicating a need for a comprehensive assessment of language abilities, in order to better clinically and educationally support children and families. However, the current study also provides evidence that structural language alone cannot explain all aspects of communicative difficulties in ASD. Future studies should continue to focus on structural language ability and other possible predictors of communication development in ASD, and also place more emphasis on the families’ experiences, by involving them in developing future research

Neuron navigator 3 (NAV3) gene aberrations in human cancer : copy number changes and target genes

This thesis is based on the original observation of an allelic deletion of the recently described Neuron navigator 3 (NAV3) gene in patients with primary cutaneous T-cell lymphoma (CTCL) and CTCL-associated lung cancer. Thereafter mutations or copy number changes of NAV3 have been reported in melanoma, glioblastoma (GBM) and adrenal carcinoma. The aim of this study has been to shed light on the function and interactions of the NAV3 protein, as well as characterizing NAV3 copy number changes and their effect on patient survival in several forms of cancer. NAV3 is a novel cancer-associated gene at 12q21. The specific function of NAV3 is not known except that it carries actin-binding domains with ATPase activity, and is therefore likely to have an action on microtubules and cytoskeleton reorganization. The three Navigator genes, NAV1, NAV2 and NAV3 share homology among themselves and among different species. This suggests a central role for the encoded proteins in cell biology. In this study, NAV3 copy number changes have been studied by fluorescence in situ hybridisation (FISH) and array comparative genomic hybridisation (aCGH) in non-melanoma skin cancers, colorectal cancer and neural system tumours, and the relevant NAV3-regulated target genes have been identified. Furthermore, the expression levels of NAV3 and NAV3-regulated signalling molecules have been correlated to disease progression and patient outcome. In Basal cell carcinomas (BCC) and Squamous cell carcinomas (SCC) we found NAV3 copy number loss and corresponding absence of protein in 21% of the BCC and in 25% of the SCC tumours. In the nodular/superficial BCC subgroup, also low-level NAV3 amplification was found. NAV3 aberrations were independent of the known chromosome 6 amplification in BCC. Chromosome 12 polysomy, also independent of chromosome 6 polysomy, was found in 33% and 25% of the invasive type of BCC and in SCC, respectively. In colorectal carcinomas NAV3 deletion and chromosome 12 polysomy were detected in 30% and 70% of MSS carcinomas, and in 12.5% and 50% of MSI carcinomas, but also in 23% and 30% of adenomas, respectively. Low copy number amplification of NAV3 was found in 25% of MSS samples. 119 patient samples representing different central and peripheral nervous system tumours were studied for NAV3 copy number changes. Neuronally differentiated tumours (neuroblastomas and medulloblastomas) entailed more NAV3 aberrations than the glial tumours. In glial tumours, those with grade IV (gliobalstoma (GBM)) had significantly more NAV3 deletions than tumours with grades I, II or III. Log rank analysis also linked NAV3 deletion to a poor prognosis in gliomas. In contrast, glioma patients with NAV3 amplification showed better prognosis than those with normal NAV3 copy numbers. The FISH result was also supported by aCGH analysis, which showed results matching the FISH analysis for tumour samples with NAV3 amplification and deletion. To understand the in vivo functional consequences of NAV3 copy number changes, especially of NAV3 deletion, we silenced NAV3 in normal colon, GBM and primary keratinocyte cells, using a commercially available small inhibitory ribonucleic acid (siRNA) construct. Post transfection RNA samples from several time points were analyzed with Agilent 44K microarray. In GBM and colorectal cell lines we identified, among others, GnRHR and IL-23R as upregulated by NAV3 gene silencing. The upregulation of the selected genes were confirmed by quantitative PCR. In primary keratinocytes, NAV3 silencing led to consistent upregulation of 22 annotated genes, and several Wnt/HH pathway genes were slightly overexpressed too. Taken together the results of this thesis support the previously suggested role of NAV3 as a novel cancer associated gene, and we suggest that NAV3 affects the malignant potential of a given tumour through multiple pathways. This assumption is based on the fact that gene expression analysis of NAV3 silenced cells indicates that NAV3 affects genes with involvement in both inflammation and carcinogenesis.Tämä väitöskirja perustuu alkuperäishavaintoon, jossa hiljattain kuvatun Neuron navigator 3 (NAV3) geenin deletio osoitettiin esiintyvän ihon t-solulymfoomissa sekä näihin liittyvissä keuhkosyövissä. Tämän jälkeen NAV3:n kopiolukumuutoksia on osoitettu myös melanoomissa, glioblastoomissa ja lisämunuaissyövissä. Tämän tutkimuksen tarkoituksena on ollut selventää NAV3 proteiinin funktiota ja vuorovaikutuksia muiden proteiinien kanssa. Lisäksi tutkittiin NAV3 kopiolukumuutoksia sekä niiden vaikutuksia potilasennusteeseen useassa eri syöpätyypissä. -------- NAV3 on uusi syöpään liitetty geeni kromosomissa 12q21. NAV3:n tarkkaa toimintaa ei tiedetä, lukuun ottamatta sitä, että siinä on aktiiniin sitoutuva osa joka toimii ATPaasina. Täten NAV3 luultavimmin vaikuttaa mikrotubuluksiin ja solutukirangan uudelleen järjestelyyn. Kolme Navigator geeniä, NAV1, NAV2 ja NAV3 ovat homologisia sekä keskenään että eri lajien kanssa, mikä antaa viitteitä proteiinien tärkeistä toiminnoista solubiologiassa. Tässä tutkimuksessa NAV3 kopiolukumuutoksia tutkittiin ihosyövissä (ei melanooma), paksusuolen syövissä sekä keskushermoston syövissä kahdella eri menetelmällä: fluorescence in situ hybridisaatio (FISH) ja array comparative genomic hybridisaatio (aCGH). Lisäksi löydettiin useita NAV3:n kohdegeenejä ja selvitettiin NAV3:n ja tämän kohdegeenien ilmentymistasojen vaikutusta tautien etenemiseen. Tyvisolusyövissä (BCC) ja okasolusyövissä (SCC) NAV3 deletio ja siihen liittyvä NAV3 proteiinitason lasku löydettiin 21%:ssa BCC ja 25%:ssa SCC tapauksia. BCCn nodulaarisessa/pinnallisessa alamuodossa löydettiin myös NAV3 amplifikaatioita. Nämä muutokset olivat riippumattomia BCC:n tunnetusta kromosomi 6:n amplifikaatiosta. Kromosomin 12 polysomiaa havaittiin 33 %:ssa invasiivista BCC:tä ja 25 %:ssa SCC:tä. Nämä olivat myös riippumattomia kromosomi 6:n muutoksista. Paskusuolen syövässä NAV3 deletioita havaittiin 30%:ssa ja kromosomi 12 polysomiaa 70%:ssa MSS tapauksia, ja vastaavasti 12.5%:ssa ja 50%:ssa MSI tapauksia, mutta myös 23%:ssa ja 30%:ssa adenoomia. Alhaisen tason NAV3 amplifikaatioita löydettiin 25%:ssa MSS näytteitä. 119 näytettä eri keskushermoston syövistä tutkittiin NAV3 kopiolukumuutosten varalta. Neuronaalisesti erilaistuneista syövistä (neuroblastoomat ja medulloblastoomat) löytyi enemmän NAV3 kopiolukumuutoksia kuin glioomista. Glioomissa gradus IV luokan syövissä (glioblastoomat) löytyi enemmän muutoksia kuin alhaisemman luokituksen syövissä (gradus I-III). Log rank analyysi yhdisti myös NAV3 deletion huonoon ja NAV3 amplifikaation hyvään ennusteeseen glioomissa. Myös aCGH analyysi tuki FISH tuloksia sekä amplifikaatioiden että deletioiden osalta. Ymmärtääksemme NAV3 kopiolukumuutosten (erityisesti deletion) vaikutuksia in vivo, NAV3 geeni vaimennettiin kohdennetun siRNA konstruktin avulla normaalisuolen soluissa, glioblastoomasoluissa sekä primäärisissä keratinosyyteissä. Vaimennuksen jälkeisiä RNA näytteitä useasta aikapisteestä analysoitiin Agilentin 44K mikrosirujen avulla. Glioblastoomasoluissa ja normaali suolen soluissa havaittiin että solumembraanin reseptoreita koodaavien geenien GnRHR ja IL-23R ilmentyminen lisääntyi NAV3 vaimennuksen johdosta. Nämä ilmentymistason nousut varmennettiin myös kvantitatiivisen PCRn avulla. Primäärisissä keratinosyyteissä NAV3 vaimennus johti 22 geenin ilmentymistason nousuun, ja useat Wnt ja HH signalointireittien geenit olivat myös hiukan yli-ilmentyneitä. Tiivistäen tämän väitöskirjan tulokset vahvistavat jo aikaisemmin ehdotettua NAV3:n roolia syöpään liittyvänä geeninä, ja ehdotamme että NAV3 vaikuttaa syöpäsolujen kasvuun usean eri signalointireitin kautta. Tämä olettamus perustuu siihen, että NAV3 näyttää säätelevän useaa geeniä, jotka liittyvät sekä elimistön tulehdusreaktioihin että syövän syntyyn