Enriching Discourse on Public Domains

Studying microvascular responses to iontophoresis of vasoconstricting drugs contributes to a better understanding of the regulatory mechanisms of cutaneous vessels, but measuring these responses with laser-Doppler flowmetry at basal blood flow conditions is technically challenging. This study aimed to investigate whether the measurement of cutaneous vasoconstrictor responses to noradrenaline (NA) and phenylephrine (PE), delivered by iontophoresis, is facilitated by predilatation of the microvascular bed using local heating. We used different drug delivery rates (100 s x 0.12 mA, 200 s x 0.06 mA, 300 s x 0.04 mA) to investigate whether predilatation affects the local drug dynamics by an increased removal of drugs from the skin. In a predilatated vascular bed, iontophoresis of NA and PE resulted in a significant decrease in perfusion from the thermal plateau (p andlt; 0.001). The decrease was 25-33%, depending on drug delivery rate. In unheated skin, a significant vasoconstriction was observed (p andlt; 0.001), with 17% and 14% decrease from baseline for NA and PE, respectively. These results indicate that predilatating the cutaneous vascular bed by local heating facilitates measurement of vasoconstriction with laser-Doppler flowmetry and does not seem to significantly affect the result by an increased removal of drugs from the skin.Original Publication: Joakim Henricson, Yashma Baiat and Folke Sjöberg, Local Heating as a Predilatation Method for Measurement of Vasoconstrictor Responses with Laser-Doppler Flowmetry, 2011, MICROCIRCULATION, (18), 3, 214-220. http://dx.doi.org/10.1111/j.1549-8719.2010.00079.x Copyright: Wiley http://eu.wiley.com/WileyCDA/Brand/id-35.html</p

Är att en citatmarkör?

Artikel i konferensrapport.I artikeln presenteras en studie av hur konnektiven att används i citatkontext i svenska ungdomssamtal. Materialet utgörs av svenska samtal inspelade i Helsingfors, på finskdominerade orter i Finland (s.k. svenska språköar) och i Göteborg. En genomgående frågeställning är den regionala variationen, där skillnaden ter sig klarast mellan de finlandssvenska och de göteborgssvenska samtalen. I de göteborgssvenska samtalen verkar att ha bevarat sin funktion som subjunktion och förekommer i första hand framför indirekta citat, medan att i de finlandssvenska samtalen i högsta grad även förknippas med direkta citat

The Role of Suppressor of Fused in Development and Tumorigenesis in the Mouse

Embryonic development is a process that involves a number of evolutionarily wellconserved signaling cascades, including the hedgehog pathway. Mutations in components of this pathway have been identified in certain developmental disorders, and in many different kinds of cancers. In fact, the most common cancer in the Western World, basal cell carcinoma (BCC) of the skin, is due to mutations that cause aberrantly activated hedgehog signaling. This thesis focuses on a protein known as Suppressor of fused (Sufu), which is an essential tumor suppressor within the hedgehog pathway. In PAPER I, we made the surprising observation that Sufu actually plays a fundamental role in the mammalian hedgehog signaling pathway, in contrast to its role in fruit flies and even zebrafish. In these organisms, Sufu plays an insignificant part in normal hedgehog signaling, since its absence only results in minor phenotypic changes. However, in the mouse, we showed that loss of Sufu leads to embryonic death in midgestation with the embryos exhibiting severe cephalic defects and an open neural tube. We also demonstrated that the Sufu loss-of-function phenotype was due to ligandindependent activation of the hedgehog signaling pathway. In humans, Gorlin syndrome is a rare developmental disorder that in the majority of cases is due to inactivating mutations in the gene that encodes the hedgehog receptor, PTCH1. This leads to overactivated hedgehog signaling, since PTCH1 is no longer able to inhibit the signal transducer, Smoothened (SMO). Gorlin syndrome involves an array of different developmental defects, but it also leads to increased tumor susceptibility, especially in the form of multiple BCCs. In PAPER I we discovered that mice, heterozygous for the Sufu gene, develop features of Gorlin syndrome, including a skin phenotype with BCC-like attributes, in addition to developmental aberrations in the form of jaw keratocysts. In addition, we showed that the extent of epidermal skin changes correlated with increased hedgehog pathway activation. The BCC-like lesions in Sufu+/- mice are reminiscent of basaloid follicular hamartomas (BFH), which are more benign lesions than BCCs. In PAPER II, the aim was to investigate whether the Sufu+/- skin lesions would develop into full-blown BCCs if Trp53 was knocked out simultaneously. Trp53 is a well-known tumor suppressor gene that can enhance hedgehog-driven tumors, and is often mutated in sporadic BCCs, sometimes in combination with PTCH1 mutations. We showed that Sufu+/- mice on a Trp53 null background develop medulloblastomas and rhabdomyosarcomas, which is consistent with previous reports. Surprisingly, however, the Sufu+/- skin phenotype was not altered in the absence of Trp53, and showed no changes in latency, multiplicity, cellular phenotype or proliferative capacity during the lifespan of the mice. This finding suggests a differential, tissue-specific sensitivity to Sufu and Trp53 gene loss, possibly linked to developmental phase and proliferative potential in specific tissues. In PAPER III, we studied developmental and differentiation processes in the absence of Sufu, using embryonic stem cells (ESCs) derived from Sufu-/- preimplantation embryos. Sufu-/- ESCs were found to express typical pluripotency markers, but the activity of the hedgehog pathway was increased only modestly compared to wild-type ESCs, as indicated by Gli1 target gene expression. The Sufu-/- ESCs formed embryoid bodies in vitro, which, in later stages, were smaller than their wild-type counterparts, suggesting a deficiency in proliferation. To test the differentiation capacity of the Sufu-/- ESCs in vivo, the cells were injected subcutaneously into nude mice to form teratomas. Teratomas from Sufu-/- ESCs developed at efficiencies and latencies equivalent to teratomas from wild-type ESCs, yet in stark contrast to wild-type, Sufu-/- teratomas were dominated by neuroectodermal tissues and were deficient in the mesodermal derivatives, cartilage and bone. These findings call attention to the central role played by Sufu in the hedgehog signaling pathway, and propose a function for Sufu in ectodermal-mesodermal cell fate decision. In a PRELIMINARY STUDY, we have generated conditional Sufu mutant mice with the aim of deleting Sufu in specific tissues at specific time-points. These studies are ongoing, and experiments to create mice with complete loss of Sufu in the K5 (basal cell) compartment of the skin have been initiated. In summary, the studies in this thesis highlight an essential role for Sufu in the hedgehog signaling pathway during development and tumorigenesis in mammals

The translation of an incubator: the case of the Lighthouse in Bubulo, Uganda

This article reviews a social entrepreneurial initiative to set up a solar-powered incubator in Bubulo, Uganda, initiated by a group of Sweden-based entrepreneurship students. Using an Actor-Network Theory-informed approach, it addresses the question of how the original aims of the initiative shifted as it moved from Sweden to Uganda, securing new allies and resources. In the tracing of this movement from northern Europe to central Africa, concepts from Actor-Network Theory, such as ‘translation’ and ‘drift’, are drawn upon. Thus, the text deals with spatial aspects of social entrepreneurial projects, heeding the call from Steyaert and Dey, who list ‘spatializing’ as one of ‘nine verbs that can keep the social entrepreneurship research agenda “dangerous”’. The text thus engages in the debate on the merits of business incubation in low-income countries–a topic currently high on the international development policy agenda. The study, it is argued, prompts scholars and policy-makers to shift perspectives when evaluating what this type of initiatives achieve. Rather than ‘creating’ entrepreneurship, projects like the Lighthouse are better seen as efforts to ‘mobilize’ existing activities. Moreover, the article also raises the issue of whether the classic incubator-as-we-know-it is a suitable model for the generation of economic activity in low-income countries

Genetic modifiers of ambulation in the cooperative international Neuromuscular Research Group Duchenne natural history study

OBJECTIVE: We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort. METHODS: We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression) and for population stratification (multidimensional scaling of genome-wide markers). RESULTS: Hispanic and South Asian participants (n=18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p=0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year-earlier median LoA (p=0.048). This difference was greater (1.9 years, p=0.038) in GC-treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p=0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p =0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC. INTERPRETATION: SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMDFil: Bello, Luca. Children's National Medical Center; Estados Unidos. Università di Padova; ItaliaFil: Kesari, Akanchha. Children's National Medical Center; Estados UnidosFil: Gordish Dressman, Heather. Children's National Medical Center; Estados UnidosFil: Cnaan, Avital. Children's National Medical Center; Estados Unidos. The George Washington University; Estados UnidosFil: Morgenroth, Lauren P.. Children's National Medical Center; Estados UnidosFil: Punetha, Jaya. Children's National Medical Center; Estados Unidos. The George Washington University; Estados UnidosFil: Duong, Tina. Children's National Medical Center; Estados UnidosFil: Henricson, Erik K.. University of California at Davis; Estados UnidosFil: Pegoraro, Elena. Università di Padova; ItaliaFil: McDonald, Craig M.. University of California at Davis; Estados UnidosFil: Hoffman, Eric P.. Children's National Medical Center; Estados Unidos. The George Washington University; Estados UnidosFil: Dubrovsky, Alberto. Cooperative International Neuromuscular Research Group Investigators; ArgentinaFil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Cooperative International Neuromuscular Research Group Investigators; Argentina. Fundación Favaloro; ArgentinaFil: Cooperative International Neuromuscular Research Group Investigators. No especifica

The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study.

IntroductionDuchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints.MethodsEvaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry.ResultsBaseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of &lt;350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD &lt;325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation.ConclusionFindings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials

COMPETENCY SUPPLY WITHIN A MUNICIPAL ADMINISTRATION - A Talent Management Perspective in Public Elderly Care

Purpose: There is a lack of knowledge concerning how the public sector engages with the phenomenon of Talent Management, and how the public context pressure this work. Thus, the aim of this thesis relates to these notions and explores these subjects through the following research questions: Viewed from a broad and critical lens: how does the theoretical concept of talent management compare to a competency supply strategy in a public elderly care administration in Sweden? Viewed from an institutional perspective: What internal and external factors pressure the creation and implementation of a public elderly care administration’s competency supply strategy, and what does this imply for public sector TM implementation? Theory: The first theory used was Talent Management as a theoretical lens. Institutional theory was used to analyse internal and external pressures. Method: A qualitative case study within a public elderly care industry in Sweden, consisting of eight semi-structured interviews from individuals working directly and indirectly with the creation and implementation of a competency supply strategy. Result: Results indicated that the systematic and strategic work with attraction, recruitment, development and training, and retention related to the theoretical concept of Talent Management. An inclusive approach to Talent Management was also found. Results further highlighted the importance of including the institutional perspective from several angles, both internally and externally