Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Grupptheraplay : En metod för att stärka barns delaktighet och sociala färdigheter

Detta examensarbete beskriver användningen och betydelsen av grupptheraplay inom kontexterna barnhem och daghem. Syftet med examensarbetet är att öka kunskap om hur man med hjälp av grupptheraplay kan förstärka och utveckla barns sociala färdigheter och delaktighet. Vi har utarbetat två forskningsfrågor som vi utgått från i vårt examensarbete för att uppnå våra syften. Dessa är, 1. Vad är grupptheraplay och 2. Hur kan man tillämpa grupptheraplay i olika kontext med barn under skolålder för att utveckla deras sociala färdigheter? I den teoretiska referensramen i detta examensarbete behandlas utvecklingsteorier, anknytningsteori, teorin om theraplay och teorier om socialt samspel, sociala färdigheter och delaktighet. I den empiriska undersökningen använde vi kvalitativ metod, och vi gjorde sex individuella temaintervjuer med personal från barnhem och daghem, vi utförde tre intervjuer per kontext. Resultatet visar att grupptheraplay fungerar som metod för att stärka barns sociala färdigheter och delaktighet både på barnhem och daghem. Resultaten visar vidare att grupptheraplay hjälper barn med varierande svårigheter inom socialt samspel och sociala färdigheter att utvecklas positivt.This thesis describes the use and meaning of grouptheraplay in the contexts residential care and playschool. The purpose of this thesis is to increase knowledge about how it is possible to strengthen and develop children’s social skills and participation with grouptheraplay. We have been working on two issues, in order to achieve our purpose. These are, 1. What is grouptheraplay? and 2. How can you apply grouptheraplay in different contexts with children under school age in order to develop their social skills? The theoretical part of this thesis handles evolution theories, attachment theory, theraplay theory and theories about participation and social skills. In the empirical study we used qualitative methods. We did six individual thematic interviews with professionals from residential care and playschool; we interviewed three workers from each context. The results show that grouptheraplay is a good method in order to strengthen children’s social skills and participation in residential care and playschool. The results also show that grouptheraplay helps children with different difficulties in social interaction and social skills to develop in a positive direction.Tässä opinnäytetyössä kuvataan ryhmätheraplayn käyttö ja tarkoitusta lastenkodin ja päiväkodin ympäristössä. Työn tarkoituksena on lisätä tietoa siitä miten ryhmätheraplay menetelmän avulla voi vahvistaa ja kehittää lapsen sosiaalisia valmiuksia sekä osallisuutta. Tämän työn keskeiset tutkimuskysymykset ovat, 1. Mitä ryhmätheraplay on ja 2. Miten theraplay menetelmää voi käyttää alle kouluikäisten lasten kanssa erilaisissa ympäristöissä jotta lapsen sosiaaliset valmiudet kehittyisivät? Tämän työn teoreettinen osa käsittelee kehitysteorioita, varhaista vuorovaikutus teoriaa, theraplay menetelmää sekä teorioita jotka käsittelevät sosiaalista vuorovaikutusta, sosiaalista valmiutta ja osallisuutta. Empiirisessä tutkimuksessa käytimme kvalitatiivista menetelmää. Teimme kuusi yksilöllistä teemahaastattelua lastenkodin ja päiväkodin henkilökunnan parissa, teimme kolme haastattelua ympäristöä kohti. Tulokset osoittavat, että ryhmätheraplay toimii menetelmänä joka vahvistaa lapsen sosiaalisia valmiuksia sekä osallisuutta lastenkodissa ja päiväkodissa. Tuloksista ilmenee, että ryhmätheraplay menetelmä auttaa lasta jolla on vaihtelevia hankaluuksia koskien positiivista kehitystä, sosiaalisten vuorovaikutusten ja sosiaalisten valmiuksien kanssa

Electric vehicles in action

This thesis analyses the political and practical conditions for introducing electric vehicles in Swedish public authorites and discusses the potential for using electric vehicles in public transport and public fleets. The work has been carried out using an interdisciplinary research approach. Such an approach brings new insights to energy studies; the combination of technical methods and methods from social science allows the technology to be studied in its societal context. Local self-government enables Swedish public authorities to implement local solutions in order to achieve national policy goals. However, the results show that for energy and transport policy a clear allocation of responsibilities between local and regional levels is lacking – and this clarity is also lacking between the different policy areas. The lack of policy integration implies a risk that local policy development can miss the mark when it comes to the overall policy goal. Furthermore, findings show that so-called policy entrepreneurs can succeed in putting electric vehicles on the political agenda, and they can enforce decisions and deploy the vehicles within the public bodies. The usage of plug-in electric vehicles in public fleets has been studied using (among other sources) logbooks, interviews, questionnaires and focus groups. Findings demonstrate a great potential to introduce plug-in electric vehicles through fleets. Although the usage varied slightly during the year, and winter conditions implied a general reduction in use, the results show that the deployment strategy is a central factor for the extent of the vehicle usage. Vehicles that are assigned a certain user or a specific task show a high degree of utilisation. Even though plug-in electric vehicles available through car-pools have a large potential group of users, the options also implies that users can instead choose a conventional vehicle. However, interventions to increase usage have proven to be successful. Policy entrepreneurial actions attract new users and revising organisational regulations, i.e. vehicle or environmental policies, shapes new behaviours. In this study, fleet vehicle users have proven to be relative indifferent to which fuel or technology they use, but acceptance for operation failure is very low. Based on a demonstration project of series hybrid buses in regular service, the possibility of increased electrification of public transport is discussed. The contribution of hybridisation is analysed through assessment of different types of driving conditions. Results show that significant improvements in energy efficiency can be achieved but, because actual and optimal driving conditions differ, there is a risk of overestimating the contribution. Sweden has set very ambitious national targets for its road transport system, i.e. to be fossil-fuel independent by 2030, and electrification is an important measure in reaching this goal. Given the magnitude of the challenge, it is not only the responsible thing to do; findings also show several advantages of introducing electric vehicles in the public sector first. QC 20150916</p

Electric vehicles in action

This thesis analyses the political and practical conditions for introducing electric vehicles in Swedish public authorites and discusses the potential for using electric vehicles in public transport and public fleets. The work has been carried out using an interdisciplinary research approach. Such an approach brings new insights to energy studies; the combination of technical methods and methods from social science allows the technology to be studied in its societal context. Local self-government enables Swedish public authorities to implement local solutions in order to achieve national policy goals. However, the results show that for energy and transport policy a clear allocation of responsibilities between local and regional levels is lacking – and this clarity is also lacking between the different policy areas. The lack of policy integration implies a risk that local policy development can miss the mark when it comes to the overall policy goal. Furthermore, findings show that so-called policy entrepreneurs can succeed in putting electric vehicles on the political agenda, and they can enforce decisions and deploy the vehicles within the public bodies. The usage of plug-in electric vehicles in public fleets has been studied using (among other sources) logbooks, interviews, questionnaires and focus groups. Findings demonstrate a great potential to introduce plug-in electric vehicles through fleets. Although the usage varied slightly during the year, and winter conditions implied a general reduction in use, the results show that the deployment strategy is a central factor for the extent of the vehicle usage. Vehicles that are assigned a certain user or a specific task show a high degree of utilisation. Even though plug-in electric vehicles available through car-pools have a large potential group of users, the options also implies that users can instead choose a conventional vehicle. However, interventions to increase usage have proven to be successful. Policy entrepreneurial actions attract new users and revising organisational regulations, i.e. vehicle or environmental policies, shapes new behaviours. In this study, fleet vehicle users have proven to be relative indifferent to which fuel or technology they use, but acceptance for operation failure is very low. Based on a demonstration project of series hybrid buses in regular service, the possibility of increased electrification of public transport is discussed. The contribution of hybridisation is analysed through assessment of different types of driving conditions. Results show that significant improvements in energy efficiency can be achieved but, because actual and optimal driving conditions differ, there is a risk of overestimating the contribution. Sweden has set very ambitious national targets for its road transport system, i.e. to be fossil-fuel independent by 2030, and electrification is an important measure in reaching this goal. Given the magnitude of the challenge, it is not only the responsible thing to do; findings also show several advantages of introducing electric vehicles in the public sector first. QC 20150916</p

Occupations in Everyday Life for Women from Iran: a Dimension of Participation

Invandrar kvinnor lider av större ohälsa än svenskar och invandrar män. Delaktighet i meningsfulla aktiviteter är viktigt för att utveckla och bibehålla fysisk hälsa, mental hälsa och livstillfredsställelse. Vidare är delaktighet och inflytande i samhället en grundläggande förutsättning för hälsa. Många arbetsterapeuter har pga. okunskap, svårigheter i bemötandet av patienter med annan kulturell bakgrund. Vidare är flera bedömningsinstrument som arbetsterapeuter använder sig av inte anpassade till olika kulturer. Syftet med studien är att undersöka hur kvinnor från Iran är delaktiga i det svenska samhället. Det som mer specifikt undersöktes var vad de iranska kvinnorna fyllde sin vardag med och om de är tillfredställa med det de gör. Författarna använde sig av aktivitetsdagböcker vid insamlingen av data. Vid namngivandet av aktiviteterna inspirerades författarna av ICF:s begreppsapparat. Resultatet visade att majoriteten av kvinnorna var tillfredsställda med sin vardag. De aktiviteter som oftast utfördes av kvinnorna var ”äta och dricka” och ”hemliv”. De aktiviteter som utfördes minst antal gånger under dagen var, ”tillämpa kunskap” och ”motion”. De flesta aktiviteter utförde kvinnorna ensamma eller tillsammans med släkt eller familjemedlem. Aktiviteterna ”rekreation/fritidsaktiviteter utanför hemmet” och ”arbete och sysselsättning” var de aktiviteter som utfördes procentuellt sett oftast tillsammans med vän eller annan person som inte är släkt eller familjemedlem.Immigrant women suffer more from bad health than Swedish people and immigrant men. To develop and maintain physical health, mental health and satisfaction in life, participation in meaningful occupations is important. Further, participation and influence in the society is an essential condition for health. Many occupational therapists have difficulty in treating patients with another cultural backgrounds, due to lack of knowledge. Further, several assessments that occupational therapists use are not adapted to different cultures. The aim of the study was to investigate how women from Iran participate in Swedish society. More specifically, the aim was to investigate what occupations the women fill their everday life with, and whetter they were satisfied with their occupations. An occupational diary was used to collect data. To name the occupations, ICF was used as inspiration. The result showed that most women in general were satisfied with their everday life. The occupations most frequently performed by the women during the day were, “applied knowledge” and “exercise”. The result also implied that the women performed most of the occupations alone or with family. “Recreation outside home” and “work and occupy” were occupations that were done in most cases together with a friend or another person not related to the family

Implementering av SoL 5 kap. 10 § : En kvalitativ studie av anhörigstöd i två kommuner med olika organisationsform

Den 1 juli år 2009 trädde en lagändring i kraft i SoL 5 kap. 10 § som innebär ett förtydligande i att Socialnämnden ska erbjuda stöd eller hjälp för att underlätta för de personer som vårdar en närstående som är långvarigt sjuk eller äldre eller stödjer en person som har funktionshinder. Syftet med denna studie var att undersöka hur implementeringen av SoL kap 5 § 10 ser ut i två kommuner. För att besvara detta använde vi oss utav kvalitativa intervjuer med nyckelpersoner med kunskap inom anhörigstödsarbete. Dessa nyckelpersoner har valts ut i två kommuner med olika organisationsform. De två kommunerna vi valt befinner sig i olika stadier i utvecklingen av implementeringen gällande anhörigstöd. Ur vårt resultat fick vi fram tre olika teman och dessa blev sedan grunden till vår analys och diskussion. Resultatet visar att de två kommunerna organisationsform skiljer sig betydligt åt vilket i sin tur spelar en avgörande roll för hur implementeringen och arbetet med anhöriga ser ut. Resultatet visar även på olika brister som de två kommunerna har, bland annat tid, projekttrötthet och bristande kunskap i vad anhörigstöd faktiskt innebär. Detta resultat analyserade vi med vissa teoretiska utgångspunkter som implementeringsteori och organisationsteori. Resultatet och analysen diskuteras sedan av oss där vi lyfter både de utmaningar och de möjligheter vi kan se i de båda kommunerna

First experiences of ethanol hybrid buses operating in public transport

Abstract: With the ambitions to further increase its share of more sustainable vehicles, Stockholm Public Transport Authority (SL) carried out a project to evaluate the performance of ethanol hybrid buses together with bus manufacturer Scania and bus operator Nobina. Ethanol hybrid buses were operating in regular suburban public transport traffic in Stockholm between May 2009 and June 2010. The purpose of this paper is to evaluate the potential of the ethanol hybrid buses in general and their energy efficiency in particular. The evaluation is based on experimental data, mainly from standardised duty cycle tests, but also general experiences during the trail, for example error reports. The buses have a series hybrid powertrain with super capacitors as energy storage. At favourable conditions the fuel reduction is approximately 20 %. The potential additional fuel savings of the start/stop software has been tested and adds at least another 10 % fuel reduction. Not all of the hybrid system&apos;s components are yet robust enough, thus they need further development to fully commercial. Hybrid city buses have great potential but are currently not technically mature and proven, nor have the overall costs over the lifetime of the vehicle reached a commercial level as yet

Undersökning av svenska läkares acceptansbeteende gentemot nya teknologiker

The introduction of new, innovative technologies within cancer diagnosis is needed, however, the barriers to entering the healthcare market are high, with various regulations and stakeholders to consider. The purpose of this thesis is to research doctors’ attitudes toward the current and emerging methods within cancer diagnosis, with the ultimate objective of providing insights into how companies can affect doctors’ technology acceptance behavior. Understanding of the end-user can facilitate the early involvement of doctors in a company's development process, which can contribute to a successful introduction of a new technology to the healthcare market. This thesis adopts a qualitative single case study approach, where the empirical data was collected through semi-structured interviews. The interviews were conducted with doctors specialized in General Medicine and Obstetrics and Gynecology. The findings reveal that doctors are cautiously positive towards new technologies, but require them to deliver greater benefits compared to their costs, have high performance, and have good usability. In addition, they demand them to be supported by research studies that substantiate their efficacy. Furthermore, a company must build trust by means such as establishing credibility and demonstrating a clear clinical purpose. The thesis also concludes that doctors’ attitudes are influenced by their belief systems and social factors, including the opinions of colleagues or hospital leaders. Finally, the findings suggest that companies should conduct research studies, create resource-sharing collaborations, involve doctors early in the development process, and establish effective communication strategies to influence doctors’ technology acceptance behaviors.Det finns ett uttalat behov av att introducera innovativa teknologier inom cancerdiagnostik till marknaden, men hälso- och sjukvårdsmarknaden har höga inträdesbarriärer men många regulationer och aktörer att ta hänsyn till. Syftet med denna studie är att fördjupa förståelsen av läkares inställning till existerande och nya teknologier inom cancerdiagnostik. Det yttersta målet är att bidra med insikter rörande hur företag kanpåverka läkares acceptans av nya teknologier. Genom förbättrad förståelse och tidig involvering av slutanvändaren, i detta fall läkarna, kan en introduktion av nya teknologier simplifieras. Denna studie innefattar en kvalitativ, enkel fallstudie, där datainsamlingen skett genom semistrukturerade intervjuer. Dessa intervjuer hölls med läkare med specialisering inom allmänmedicin samt obstetrik och gynekologi. Resultatet visar att läkarna har en försiktigt positiv attityd till nya teknologier, men har höga krav på prestation, användbarhet och nytta-kostnad förhållandet. De kräver även att teknologin stöds av noga utförda forskningsstudier som kan påvisa dess effektivitet och nytta. Studien visar även att företag måste bygga förtroende hos läkarna, genom att exempelvis visa på ett tydligt kliniskt syfte. Vidare visar resultatet att läkarnas attityder influeras av deras trossystem samt sociala faktorer, däribland kollegors och sjukhusledares åsikter och rekommendationer. Slutligen uppmanas företag att genomföra forskningsstudier, etablera samarbeten mellan berörda grupper, involvera läkare tidigt i utvecklingsprocessen, och etablera effektiva kommunikationsstrategier för att påverka läkares acceptans av ny teknologi