Crystal structure of ethyl (6-hydroxy-1-benzofuran-3-yl)acetate sesquihydrate

In the title hydrate, C12H12O4·1.5H2O, one of the water molecules in the asymmetric unit is located on a twofold rotation axis. The molecule of the benzofuran derivative is essentially planar (r.m.s. deviation for the non-H atoms = 0.021à ), with the ester group adopting a fully extended conformation. In the crystal, O-H�O hydrogen bonds between the water molecules and the hydroxy groups generate a centrosymmetric R6 6(12) ring motif. These R6 6(12) rings are fused, forming a one-dimensional motif extending along the c-axis direction

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement. The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment. The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells. This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration

Ge mig självkänsla så ska jag skaffa mig självförtroende : en studie av ryska barnhemsbarns självbild, framtidstro och anknytning

Validerat; 20101217 (root

Att ligga som föräldrarna bäddar : En kvantitativ studie om ungdomars sexuella handlingsutrymme

Sammanfattning Denna studie avser att undersöka ungdomars sexuella handlingsutrymme. Syftet är att studera om det sexuella handlingsutrymmet uppfattas olika när det gäller ungdomar med, respektive utan, en lindrig intellektuell funktionsnedsättning. I analysen har särskild hänsyn tagits till tre bakgrundsfaktorer; ungdomars kön, föräldrars födelseland samt föräldrars religiositet. Definitionen av det sexuella handlingsutrymmet bygger på den unges uppfattning om vårdnadshavarens restriktioner gentemot den unge inom fyra områden; restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap. Studien bygger på en sekundäranalys av kvantitativt datamaterial hämtat från två tidigare studier, Schlytter m.fl. (2009) samt Davidian m.fl. (2012). Det sammanslagna datamaterialet består av 2576 respondenter från årskurs nio i Stockholms stad samt från det nationella programmet på gymnasiesärskolor i Stockholm, Göteborg, Malmö och Uppsala. Frågor som i datamaterialet berör restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap har bearbetats. Analysen av materialet har gjorts utifrån tidigare forskning samt teorin om socialkonstruktivism där respektabilitet, sexuella script samt det romantiska kärlekskomplexet och kärleksideologin varit framträdande begrepp/teorier. Studien visar tre huvudsakliga resultat. För det första att ungdomar med intellektuell funktionsnedsättning uppfattar större begräsningar när det gäller sexuella relationer innan äktenskap än vad ungdomar utan en intellektuell funktionsnedsättning. För det andra att ungdomar utan intellektuell funktionsnedsättning uppfattar större begränsningar i valet av sin framtida äktenskapspartner. Slutligen indikerar resultatet att när hänsyn tas till om ungdomar har föräldrar med hög religiositet, eller två utlandsfödda föräldrar, så är skillnaderna mellan ungdomar med och utan intellektuell funktionsnedsättning små. Abstract The purpose of this study is to investigate adolescents’ understandings of opportunities to enact their sexuality both when a mild intellectual disability is present, and is not. In addressing the aim, three background factors have been taken into consideration; gender, parents country of birth and parents religiosity. In determining adolescents understanding of opportunities to enact their sexuality, the study looked at four outcomes; restrictions on schooling and leisure time, the restriction of heterosexual relations before marriage, restrictions in the choice of future husband or wife and restrictions in sexual relations before marriage. The study is based on quantitative data from two previous studies; Schlytter et.al. (2009) and Davidian et.al. (2012). The database contains 2576 respondents from the ninth grade in Stockholm and from the national programs in secondary special school in Stockholm, Gothenburg, Malmo and Uppsala. Variables that handles restrictions in school and on leisure time, restriction in heterosexual relation before marriage, restrictions in the choice of future husband or wife and restriction in sexual relations before marriage has been processed. The results of the study is analysed based on the theory of social constructivism where respectability, sexual script and romantic love and love ideology has been prominent. The study has three major findings. Firstly, adolescents with a mild intellectual disability experience restrictions in sexual relations before marriage more frequently than adolescents without an intellectual disability. Secondly, adolescents without an intellectual disability experience more limitations concerning the ability too freely choose a future husband or wife by themselves in comparison to adolescents with an intellectual disability. Lastly, the results indicate that the difference between adolescents with or without an intellectual disability and ‘room to act’ in relation to sexuality are small when the adolescents’ parents are born outside of Sweden or are considered by the adolescent to be very religious

Att ligga som föräldrarna bäddar : En kvantitativ studie om ungdomars sexuella handlingsutrymme

Sammanfattning Denna studie avser att undersöka ungdomars sexuella handlingsutrymme. Syftet är att studera om det sexuella handlingsutrymmet uppfattas olika när det gäller ungdomar med, respektive utan, en lindrig intellektuell funktionsnedsättning. I analysen har särskild hänsyn tagits till tre bakgrundsfaktorer; ungdomars kön, föräldrars födelseland samt föräldrars religiositet. Definitionen av det sexuella handlingsutrymmet bygger på den unges uppfattning om vårdnadshavarens restriktioner gentemot den unge inom fyra områden; restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap. Studien bygger på en sekundäranalys av kvantitativt datamaterial hämtat från två tidigare studier, Schlytter m.fl. (2009) samt Davidian m.fl. (2012). Det sammanslagna datamaterialet består av 2576 respondenter från årskurs nio i Stockholms stad samt från det nationella programmet på gymnasiesärskolor i Stockholm, Göteborg, Malmö och Uppsala. Frågor som i datamaterialet berör restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap har bearbetats. Analysen av materialet har gjorts utifrån tidigare forskning samt teorin om socialkonstruktivism där respektabilitet, sexuella script samt det romantiska kärlekskomplexet och kärleksideologin varit framträdande begrepp/teorier. Studien visar tre huvudsakliga resultat. För det första att ungdomar med intellektuell funktionsnedsättning uppfattar större begräsningar när det gäller sexuella relationer innan äktenskap än vad ungdomar utan en intellektuell funktionsnedsättning. För det andra att ungdomar utan intellektuell funktionsnedsättning uppfattar större begränsningar i valet av sin framtida äktenskapspartner. Slutligen indikerar resultatet att när hänsyn tas till om ungdomar har föräldrar med hög religiositet, eller två utlandsfödda föräldrar, så är skillnaderna mellan ungdomar med och utan intellektuell funktionsnedsättning små. Abstract The purpose of this study is to investigate adolescents’ understandings of opportunities to enact their sexuality both when a mild intellectual disability is present, and is not. In addressing the aim, three background factors have been taken into consideration; gender, parents country of birth and parents religiosity. In determining adolescents understanding of opportunities to enact their sexuality, the study looked at four outcomes; restrictions on schooling and leisure time, the restriction of heterosexual relations before marriage, restrictions in the choice of future husband or wife and restrictions in sexual relations before marriage. The study is based on quantitative data from two previous studies; Schlytter et.al. (2009) and Davidian et.al. (2012). The database contains 2576 respondents from the ninth grade in Stockholm and from the national programs in secondary special school in Stockholm, Gothenburg, Malmo and Uppsala. Variables that handles restrictions in school and on leisure time, restriction in heterosexual relation before marriage, restrictions in the choice of future husband or wife and restriction in sexual relations before marriage has been processed. The results of the study is analysed based on the theory of social constructivism where respectability, sexual script and romantic love and love ideology has been prominent. The study has three major findings. Firstly, adolescents with a mild intellectual disability experience restrictions in sexual relations before marriage more frequently than adolescents without an intellectual disability. Secondly, adolescents without an intellectual disability experience more limitations concerning the ability too freely choose a future husband or wife by themselves in comparison to adolescents with an intellectual disability. Lastly, the results indicate that the difference between adolescents with or without an intellectual disability and ‘room to act’ in relation to sexuality are small when the adolescents’ parents are born outside of Sweden or are considered by the adolescent to be very religious

Att ligga som föräldrarna bäddar : En kvantitativ studie om ungdomars sexuella handlingsutrymme

Sammanfattning Denna studie avser att undersöka ungdomars sexuella handlingsutrymme. Syftet är att studera om det sexuella handlingsutrymmet uppfattas olika när det gäller ungdomar med, respektive utan, en lindrig intellektuell funktionsnedsättning. I analysen har särskild hänsyn tagits till tre bakgrundsfaktorer; ungdomars kön, föräldrars födelseland samt föräldrars religiositet. Definitionen av det sexuella handlingsutrymmet bygger på den unges uppfattning om vårdnadshavarens restriktioner gentemot den unge inom fyra områden; restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap. Studien bygger på en sekundäranalys av kvantitativt datamaterial hämtat från två tidigare studier, Schlytter m.fl. (2009) samt Davidian m.fl. (2012). Det sammanslagna datamaterialet består av 2576 respondenter från årskurs nio i Stockholms stad samt från det nationella programmet på gymnasiesärskolor i Stockholm, Göteborg, Malmö och Uppsala. Frågor som i datamaterialet berör restriktioner i skolan och på fritiden, begränsningar i heterosexuella föräktenskapliga relationer, begränsningar i val av framtida äktenskapspartner samt begränsningar i sexuella relationer innan äktenskap har bearbetats. Analysen av materialet har gjorts utifrån tidigare forskning samt teorin om socialkonstruktivism där respektabilitet, sexuella script samt det romantiska kärlekskomplexet och kärleksideologin varit framträdande begrepp/teorier. Studien visar tre huvudsakliga resultat. För det första att ungdomar med intellektuell funktionsnedsättning uppfattar större begräsningar när det gäller sexuella relationer innan äktenskap än vad ungdomar utan en intellektuell funktionsnedsättning. För det andra att ungdomar utan intellektuell funktionsnedsättning uppfattar större begränsningar i valet av sin framtida äktenskapspartner. Slutligen indikerar resultatet att när hänsyn tas till om ungdomar har föräldrar med hög religiositet, eller två utlandsfödda föräldrar, så är skillnaderna mellan ungdomar med och utan intellektuell funktionsnedsättning små. Abstract The purpose of this study is to investigate adolescents’ understandings of opportunities to enact their sexuality both when a mild intellectual disability is present, and is not. In addressing the aim, three background factors have been taken into consideration; gender, parents country of birth and parents religiosity. In determining adolescents understanding of opportunities to enact their sexuality, the study looked at four outcomes; restrictions on schooling and leisure time, the restriction of heterosexual relations before marriage, restrictions in the choice of future husband or wife and restrictions in sexual relations before marriage. The study is based on quantitative data from two previous studies; Schlytter et.al. (2009) and Davidian et.al. (2012). The database contains 2576 respondents from the ninth grade in Stockholm and from the national programs in secondary special school in Stockholm, Gothenburg, Malmo and Uppsala. Variables that handles restrictions in school and on leisure time, restriction in heterosexual relation before marriage, restrictions in the choice of future husband or wife and restriction in sexual relations before marriage has been processed. The results of the study is analysed based on the theory of social constructivism where respectability, sexual script and romantic love and love ideology has been prominent. The study has three major findings. Firstly, adolescents with a mild intellectual disability experience restrictions in sexual relations before marriage more frequently than adolescents without an intellectual disability. Secondly, adolescents without an intellectual disability experience more limitations concerning the ability too freely choose a future husband or wife by themselves in comparison to adolescents with an intellectual disability. Lastly, the results indicate that the difference between adolescents with or without an intellectual disability and ‘room to act’ in relation to sexuality are small when the adolescents’ parents are born outside of Sweden or are considered by the adolescent to be very religious

Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation

T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.Funding Agencies|Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [SB16-0011]</p

Differential effects of estradiol and progesterone on human T cell activation in vitro

Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell-mediated diseases such as multiple sclerosis (MS). Although immune-endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2- and P4-mediated effects on human CD4(+) T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy-relevant E2 concentrations increased activation and the secretion of several immune- and inflammation-related proteins. P4, on the other hand, showed a biphasic pattern, where serum-related concentrations upregulated activation and protein secretion while placenta-relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.Funding Agencies|Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [SB16-0011]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-02776]; Swedish Lions Research Foundation; Swedish Society of Medicine [SLS-879791]; NEURO Sweden [F2018-0052]; Swedish Foundation for MS Research</p